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A TEXT-BOOK 



OF 



PHARMACOLOGY 



THERAPEUTICS 



OR THE 



ACTION OF DRUGS IN HEALTH AND DISEASE 



BY 

ARTHUR R. CUSHNY, M.A., M.D., LL.D ., F.R.S. 

PROFESSOR OF PHARMACOLOGY IN THE UNIVERSITY OF LONDON; EXAMINER IN THE 

UNIVERSITIES OF LONDON, MANCHESTER, OXFORD, CAMBRIDGE, GLASGOW AND 

LEEDS; FORMERLT PROFESSOR OF MATERIA MEDICA AND THERAPEUTICS 

IN THE UNIVERSITY OF MICHIGAN 



SIXTH EDITION, THOROUGHLY REVISED 



ILLUSTRATED WITH 70 ENGRAVINGS 




LEA & FEBIGER 

PHILADELPHIA AND NEW YORK 
1915 

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Entered according to the Act of Congress in the year 1915, by 

LEA <& FEBIGER, 
in the Office of the Librarian of Congress. All rights reserved. 



Authority to use for comment the Pharmacopoeia of the United States of America 
(Eighth Decennial Revision), in this volume, has been granted by the Board of 
Trustees of the United States Pharmacopoeial Convention; which Board of Trustees 
is in no way responsible for the accuracy of any translations of the Official Weights 
and Measures, or for any statement as to strength of Official Preparations. 



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OSWALD SCHMIEDEBERG 
dem Meister, vom Schuler gewidmet 



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PREFACE TO THE SIXTH EDITION. 



In this edition the space devoted to many of the less important 
and less reliable drugs has been further curtailed and others have 
been omitted altogether from consideration. This appears to be 
in accordance with the general trend of medical progress, and thera- 
peutics would probably not have suffered from an even more drastic 
selection. But a text-book must not only describe the virtues of the 
established remedies, but must also point out the worthlessness of 
many preparations which still enjoy an unmerited popular reputation. 
I would appeal to teachers and especially to the members of examining 
boards to restrict further the drugs which the student has to study. 
For as long as he has to learn the supposed virtues of a host of obscure 
substances, he will tend to use them in practice, even if only tentatively. 
This in turn necessitates their inclusion in the pharmacopoeias, which 
again gives them some standing and perpetuates them as subjects of 
teaching and examination. If examiners would break this vicious 
circle, they would greatly lighten the burden of the student, and would 
render the subject of pharmacology more attractive to him. There 
is no question that the insistence on numberless preparations of drugs 
of questionable value has discouraged interest in therapeutics. 

On these grounds I have omitted many preparations which are 
still to be found in the pharmacopoeias, but which appear to me to be 
superfluous. Some chapters have been much curtailed, others recast and 
expanded, all have been carefully revised. Among those which have 
been much altered are the chapters on the general anesthetics, opium, 
digitalis, ergot, and adrenaline. Several new chapters have been added, 
among them those on the new organic arsenical compounds, on atophan 
and on the pituitary extract. Extensive changes have been made 
in the classification, which is now based on the organs on which 
the drugs exercise their most characteristic action rather than on a 
consideration of the whole of their effects. This new arrangement 



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vi PREFACE 

bears a closer relation to the therapeutic uses than that adopted in 
former editions. A large number of drugs chiefly used for their local 
action as antiseptics and disinfectants has been collected into one group 
and discussed together. I hope that these changes, which I have found 
useful in my own classes, may prove acceptable to others. 

A. It. C. 
London, 1915. 



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CONTENTS 



Introduction 17 

General Theories of Pharmacological Action 19 

Stimulation, Depression, Irritation 21 

Distribution and Concentration 22 

Elective Affinity of Drugs. Protoplasm Poisons * . 23 

Remote, Local, and General Action 24 

Salt-action 25 

Conditions Modifying the Effects of Drugs 27 

Methods of Administration 32 

The Chemical Characters of Drugs 36 

The Pharmacopoeias and Pharmacopoeial Preparations 39 

PART I. 

SUBSTANCES WHICH ARE CHARACTERIZED CHIEFLY BY THEIR 

LOCAL ACTION 43 

I. Demulcents 43 

II. Emollients 46 

III. Sugars and Flavoring Substances 49 

IV. Simple Bitters 51 

Pepper Group 53 

V. Digestive Ferments 54 

1. Pepsin 55 

2. Pancreatic Ferments 55 

3. Vegetable F'erments 56 

4. Diastase 57 

VI. Volatile Oil Series 57 

1. Volatile Oils Used as Flavoring Agents and Carminatives . 61 

2. Camphor 05 

3. Ether and Chloroform (Local Action) 69 

4. Malodorous Volatile Oils 71 

VII. Skin Irritants and Counter-irritation 72 

1. The Turpentine Oil Group 80 

2. Mustard 82 

3. Cantharidin Series 83 

VIII. Purgatives 87 

1. Mild Aperients, the Castor Oil Group 90 

2. The Anthracene Purgatives 93 

3. The Jalap and Colocynth Group 96 

IX. Saline Cathartics 101 

X. Vegetable Astringents — Tannic Acid Series 109 

XI. Bile 114 



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viu CONTENTS 

XII. Anthelmintics 115 

1. Male Fern (Aspidium, Filix-mas) 116 

2. Cusso 118 

3. Pelletierine 119 

4. Thymol 120 

5. Santonin 121 

XIII. Antiseptics and Disinfectants 124 

I. Surgical Antiseptics and Disinfectants 131 

1. Carbolic Acid 131 

2. Cresols 137 

3. Other Aromatic Surgical Disinfectants 138 

4. Mercuric Perchloride 139 

5. Other Metallic Disinfectants 139 

6. Oxidizing Disinfectants 140 

Peroxide of Hydrogen 140 

Other Oxidizing Disinfectants 142 

7. Boracic Acid and Borax 143 

8. Potassium Chlorate 145 

9. Iodine 149 

10. Iodoform 149 

II. Antiseptics Used Chiefly in Skin Diseases 152 

1. Pyrogallol , 152 

2. Chrysarobin 153 

3. Naphthol 154 

4. Resorcin 155 

5. Tar 155 

III. Intestinal Disinfectants 157 

Salol 157 

Other Intestinal Disinfectants 158 

IV. Genito-urinary Antiseptics 158 

1. Volatile Oils 158 

2. Hexamethylentetramine, Urotropine 160 

3. Minor Genito-urinary Antiseptics 161 

V. Antiseptics in Pulmonary Disease 162 

Creosote 162 

VI. Disinfectants for Rooms, Furniture, Etc 163 

1. Formaldehyde 163 

2. Sulphur Dioxide 165 

3. Chlorine and Bromine 166 

4. Other Disinfectants 168 

PART II. 

SUBSTANCES CHARACTERIZED CHIEFLY BY THEIR ACTION 

AFTER ABSORPTION 169 

I. Narcotics of the Methane Series 169 

Alcohol-chloroform Group 169 

1. Alcohol 172 

2. General Anaesthetics — Ether and Chloroform 195 

3. Nitrous Oxide 224 

4. Soporifics — Chloral Group 228 

II. Opium Series 236 

Minor Drugs of the Opium Series .... 257 



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CONTENTS ix 

III. Cannabis Indica 258 

IV. Bromides 260 

V. Strychnine — Nux Vomica 266 

VI. Picrotoxin 277 

VII. Caffeine 280 

Coffee and Tea 289 

Minor Diuretics 291 

VIII. Saline Diuretics 292 

Peripheral Nervous Action 295 

IX. Curara Group 298 

Coniine 302 

Gelsemium 303 

Sparteine 303 

. X. Nicotine Group 304 

Tobacco 312 

XI. The Atropine Series 314 

Alkaloids 330 

Agaricin 335 

XII. Pilocarpine and Muscarine 336 

XIII. Physostigmine 345 

XIV. Cocaine 350 

Substitutes for Cocaine 361 

Yohimbine 363 

XV. Adrenaline 364 

XVI. Ergot 373 

XVII. Pituitary Extract . . . ' 381 

Other Organic Extracts (Organotherapy) 384 

XVIII. Hydrastine and Hydrastinine 385 

XIX. The Nitrites 387 

XX. The Digitalis Series 395 

XXI. Aconitine 425 

XXII. Veratrine 430 

XXIII. Apomorphine 434 

XXIV. Emetine (Ipecacuanha) 437 

XXV. Colchicine 440 

XXVI. Phenylquinoline Carbonic Acid (Atophan) 443 

XXVII. Saponin, Sapotoxin and Solanine 445 

XXVIII. PrussicAcid 449 

XXIX. Aspidosperma, or Quebracho 454 

XXX. Quinine 455 

XXXI. The Antipyretics (Acetanilide and Antipyrine Series) .... 470 

XXXII. Salicylates 485 

XXXIII. Toxins and Antitoxins 494 

Antidiphtheritic Serum 496 

Antitetanus Serum 497 

Antimeningitis Serum 497 

Antivenin 498 

XXXIV. Benzoic Acid .499 

XXXV. Some Minor Poisons 502 

1. Nitrobenzol Compounds 502 

2. Toluylendiamine 503 

3. Benzol .503 

4. Phloridzin 504 



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X CONTENTS 

XXXVI. Sodium Chloride and Water 505 

XXXVII. Potassium Salts 513 

Lithium, Caesium, Rubidium 515 

XXXVIII. Ammonium 515 

XXXIX. Iodides 518 

XL. Iodine 525 

XLI. Thyroid Gland 527 

XLII. Sulphites 535 

XL1II. Hydrates and Carbonates of the Alkalies 536 

Piperazine and Quinic Acid 545 

XLIV. Acetates and Citrates 545 

XLV. Ammonia and Carbonate of Ammonia 546 

XLVI. Acids 549 

XLVII. Calcium 556 

XLVIII. Oxalates and Fluorides ,565 

XLIX. Barium, Strontium, and Magnesium 566 

L. Sulphides 568 

LI. Charcoal 570 

LII. Carbonic Acid 571 

LIII. Oxygen 574 

LIV. Phosphorus 576 

LV. Arsenic 587 

LVI. Organic Arsenic Combinations 602 

1. Cacodylatcs • 604 

2. Atoxyl 604 

3. Salvarsan 605 



PART III. 

THE HEAVY METALS 611 

Heavy Metals 611 

I. Antimony 618 

II. Mercury ' 622 

III. Iron 640 

IV. Lead 650 

V. Copper 658 

VI. Zinc 662 

VII. Silver 664 

VIII. Bismuth 669 

IX. Aluminium and Alum 672 

X. Minor Metals 674 



PART IV. 

I. Cod-liver Oil 681 

Hypophosphites and Glycerophosphates . 684 

II. Menstrua and Mechanical Remedies . -. 684 

r 

CLASSIFICATION OF DRUGS ACCORDING TO THEIR THERAPEUTIC 

USES 687 

Index 693 

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A TEIT-BOOK OF PHARMACOLOGY. 



INTRODUCTION. 

Pharmacology is the study of the changes induced in living organ- 
isms by the administration in a state of minute division of such un- 
organized substances as do not act merely as foods. Many of the best 
known of these substances are used to counteract the effects of disease, 
or to reinforce the tissues in their struggle to maintain their functions, 
when these are rendered abnormal. These substances are known as 
drugs, and the art of applying drugs in disease is Therapeutics. Other 
substances are of little or no value in disease, but are of importance 
because they act as poisons, that is, cause dangerous or fatal symptoms 
in man or animals, when they are ingested in quantity. The practical 
study of the effects of these poisons in man — the diagnosis and the 
treatment of poisoning, and the methods of detecting the poison — is 
termed Toxicology. But the explanation of the symptoms induced 
by chemical substances belongs to the field of pharmacology, which 
includes not only the effects of drugs and poisons, but those of any 
substance which induces changes in the living organism, whether those 
changes are of benefit to it, injurious, or indifferent. 1 

The substances must, of course, conform to the requirements of the defini- 
tion. Thus, a needle introduced into the tissues induces effects which are 
outside the field of pharmacological investigation, because it is not in a state 
of minute division. But the iron of the needle may be reduced to a fine 
powder and induce changes in the body which are then the legitimate subject 
of research. Similarly the drug must be introduced from without, for many 
active agents are formed within the body, but their study belongs rather to 
the departments of physiology and pathology; and the effects of organized 
bodies introduced from without are now studied under bacteriology. Phar- 
macology is really a department of biology, very closely related to the other 
sciences included by that term. Thus, as physiology is the study of the life 
of the normal organism, pharmacology is the study of the organism rendered 
abnormal by drugs, while in pathology the phenomena of life under disease 
are examined. All three subjects may be pursued without reference to the 
practical needs of medicine, and all three are closely interconnected and 
mutually dependent, for, in many instances, the normal condition of an organ 
can be recognized only by considering the results of its destruction by disease 

i it is quite impossible to distinguish between drugs and poisons. Almost all remedies 
given in excess cause dangerous or fatal symptoms, while many poisons are valuable 
remedies in small doses. Some bodies may in fact be remedies, foods, or poisons accord- 
ing to the quantity ingested and the method of application. 

2 r- (17) i 

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18 INTRODUCTION - 

(pathology), or of its paralysis or stimulation by chemical agents (pharma- 
cology). Similarly, many of the features of disease are now recognized to be 
due to the presence of unorganized poisons formed in and by the tissues, and 
it accordingly becomes difficult to define accurately the limits of pathology 
and pharmacology. 

The great interest of pharmacology does not lie in its purely bio- 
logical aspects, however, but in its relation to the treatment of disease. 
As long as we are ignorant of how a remedy acts in any disease, the 
treatment is purely empirical; when the mode of action is understood, 
much greater accuracy can be attained in the treatment. The object 
of pharmacology is to explain the mysteries of therapeutics, whether 
the subject is studied at the bedside or in the laboratory. The exact 
way in which a drug changes the diseased condition can often be followed 
only imperfectly in man, and recourse must be had to experiments on 
healthy or diseased animals to elucidate the principles on which it 
should be employed. In addition, the experimental investigation of 
new chemical bodies has very frequently demonstrated properties 
which are of therapeutic value; almost all the new drugs introduced 
in the last half-century have found their way to the wards through the 
experimental laboratories. 

Pharmacology is one of the most recent developments of medical and 
biological science. It is true that from the earliest times attempts 
have been made to explain the effects of drugs on the then prevailing 
theories of pathology, but the objective study of the action of drugs on 
the organism has been a development of the nineteenth century, or it 
might almost be said, of the second half of it. The study of drugs was 
termed Materia Medica up to this time, and comprised an examination 
of their botanical and chemical properties along with some account of 
the diseases in which they had proved of value. This descriptive 
rather than experimental study has been continued under the name of 
Pharmacognosy, but is now pursued by pharmacists chiefly. Undoubt- 
edly the student of medicine ought to know those characters of drugs 
which are of importance in modifying their action and application, 
but it is undesirable that his valuable time should be occupied in the 
detailed description of crude substances, which he may probably never 
have an opportunity of seeing in his future practice. 

Another subject which now occupies a much less prominent position 
in medical study than formerly, is Pharmacy, or the art of preparing 
drugs for therapeutic use. Some general knowledge of the methods 
used is no doubt indispensible to the educated physician, but the 
details may be left to the pharmacist. Pharmacy will probably 
occupy a still more subordinate position in medical education as the 
tendency to include only one or two drugs in a prescription becomes 
more widespread. As long as a dozen or more components went to 
make one mixture, it was of importance to know their solubility and 
their interactions, but with the decay of the complex prescription 
the study of pharmacy by medical students has certainly become less 
imperative. 

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GENERAL THEORIES OF PHARMACOLOGICAL ACTION 19 



GENERAL THEORIES OF PHARMACOLOGICAL ACTION. 

A number of drugs affect* the organism only through their obvious 
physical properties, as when an inert oily body is applied to an 
abraded surface and promotes its healing by protecting it from irrita- 
tion and from the evaporation of fluid, or when common salt absorbed 
into the blood changes its osmotic tension, and thus alters the distri- 
bution of fluids in the tissues. On the other hand, many effects are 
due to simple chemical reactions; for instance, bicarbonate of potas- 
sium may be used to neutralize the hydrochloric acid of the gastric 
juice, just as it combines with acid in a test-tube, and many of the 
effects of oxalates arise from their forming insoluble salts with the 
calcium of the tissues. In the great majority of drug effects, however, 
no such simple relations as these obtain and the mode of action remains 
unknown. One view which has been widely held, postulates that where 
a drug affects a cell it enters into a definite chemical combination with 
the constituent protoplasm, similar to the ordinary compounds of the 
chemical laboratory. This theory has not been supported by evidence, 
and, while it has not been disproved, there are many difficulties in its 
acceptance; one of these is that the same action may be induced by a 
series of drugs which have no chemical reactions in common and which 
therefore cannot be supposed to enter into the same chemical combina- 
tion with the cell protoplasm. In recent years there has been a tendency 
to attribute the action of drugs rather to their physical properties, and 
there can be no question that these play a large part in determining 
the effects; for example, unless a drug is soluble in the fluids of the body 
it cannot be absorbed and circulate in the blood, and, similarly, unless 
it is soluble in the cell contents it may have difficulty in entering the 
cells. Many drug effects have been ascribed to this selective absorption 
alone, a drug acting on all cells into which it can enter, by changing the 
relations of the cell constituents in which it is dissolved; but objections 
have been raised to this view which cannot be neglected. (See Meyer- 
Overton theory of narcosis.) Similarly, attention has been drawn to 
the possibility that some effects may arise from the drugs altering the 
surface tension of a cell in relation to the surrounding fluids. It has 
been shown that in some cases in which true chemical combinations 
were believed to be formed between cell constituents and drugs, the 
connection is really of the loose natureknown as "adsorption compounds/' 
which are best illustrated in the combination of dyes with fibres 
(see Heavy Metals); the formation of these adsorption compounds is 
associated with a change of electrical charge and some authorities 
are disposed to attribute some other pharmacological actions to a similar 
change in electrical state. Finally, it is believed that in most instances 
drugs act on a cell only when they have penetrated into its interior, 
but the virtues of certain remedies have been shown to be due to their 
failure to penetrate the cells, which leads to an alteration in the relation 
of the fluids in which they are dissolved and those in the interior of the 



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20 INTRODUCTION 

cells with which they are in contact (see Salt-action). And Straub has 
brought forward some evidence that certain very powerful drugs act 
by altering the cell surface without penetrating into the interior, while 
others effect changes only as they penetrate the surface, and lose their 
efficiency as they accumulate in the interior. Changes in the intra- 
cellular membranes have been suggested by others as an explanation 
of most drug effects; it is held that a drug may reduce the permeability 
of the cellular membranes by altering their electric charges and thus 
retard the free passage of ions which is necessary for full activity; 
other poisons may accelerate their movement, and thus increase the 
activity. 

These views have all been supported by a certain amount of evidence, 
and there is every reason to believe that these physical properties are 
important factors in the action of some drugs. But it is equally obvious 
that no one of them will explain the whole of pharmacological action, 
and there is reasonable doubt whether the whole of the physical char- 
acters taken together will suffice for this. From the present confusion 
the only legitimate conclusion seems to be that the activity of drugs 
depends on a large variety of factors and that pharmacological action 
cannot be brought under any one law, either chemical or physical. 

This view stands in conflict with a theory which has been widely 
held, and which postulates that the pharmacological action depends 
directly on the chemical structure of a drug and may in fact be deduced 
in large part from a consideration of its structural formula. Plausible 
arguments in favor of this view have been drawn from the resemblances 
in action presented by certain chemical groups; for example, a large 
number of soporifics belong to the group of the simpler methane com- 
pounds, and the heavy metals offer certain resemblances in their effects 
in the body just as they react similarly to some chemical tests. But 
it is equally probable that these resemblances depend on some physical 
property which is common to each group, and which has a more imme- 
diate bearing on their action than the actual structure. Of course the 
physical characters, themselves, ultimately depend on the chemical 
composition, and the reaction in the organism, therefore, ultimately 
arises from the chemical composition, but as it is at present impossible 
to derive the physical properties from a consideration of the chemical 
formula, it appears futile to attempt to derive the action in the organ- 
ism from it. And whenever an attempt is made to follow the relationship 
between chemical composition and pharmacological action in detail, the 
analogy breaks down, because factors which it is impossible to deduce 
from the chemical structure or formulae, intrude themselves; for example, 
the series of lower alcohols of the methyl series show a regular progressive 
increase in toxicity so that some of the higher members might be 
expected to form very powerful poisons, but as a matter of experience 
these prove to be harmless because they become insoluble in the fluids 
of the body. 



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STIMULATION, DEPRESSION, IRRITATION 21 

STIMULATION, DEPRESSION, IRRITATION. 

When a cell is affected by a poison, the extent of its activity is 
changed but not the kind. The reflex movements ma}' be augmented 
under strychnine or may be lessened under chloral, but they remain 
reflex and cannot under any circumstances partake of the nature of 
voluntary movements. In other words, the effects of drugs are quan- 
titative, not qualitative, the activity of living matter may be changed, 
but the form which the activity assumes is unchangeable. 

Drugs which increase* the activity of any organ or function are said 
to stimulate it, while those which lessen the activity are said to depress 
it. Another condition induced by drugs is irritation, for although this 
term is often applied loosely as a synonym for stimulation, the two 
conditions are not identical. Stimulation is properly used to indicate 
an increase in the specialized function of a cell, producing, for instance, 
in the spinal cord an increase in the reflex excitability. Irritation, 
on the other hand, is used rather in reference to the changes in the 
conditions common to all forms of living matter, that is, it indicates a 
change in the nutrition and growth of the cell, rather than in the 
specialized functions. Irritation may thus be induced in all kinds 
of tissues and is the commonest change caused by drugs in the less 
differentiated forms, such as the connective tissues and ordinary 
epithelia; while stimulation is met with in the more highly specialized 
cells, such as those of the heart, nervous system, or secretory glands. 
In many instances the irritant action of drugs may be explained by 
their known reactions with the proteins of the cell; for example, sub- 
stances which dissolve proteins, or precipitate them, or withdraw fluid 
from them, all tend to cause irritation when they are applied to living 
tissues. In other cases irritation appears to be induced through some 
action the nature of which is quite unknown. 

When stimulation is prolonged or excessive, the protoplasm gener- 
ally becomes depressed and finally loses its activity entirely (paral- 
ysis). Some authorities have asserted that depression is invariably 
preceded by stimulation, and that stimulation sufficiently prolonged 
invariably leads to depression and paralysis. Both statements are too 
absolute, although they are true in the great majority of cases. For 
example, the action of atropine on the terminations of the cardiac 
inhibitory nerves is purely depressant. Even the most minute quan- 
tities of this alkaloid never increase the activity of these terminations, 
for if a quantity too small to weaken them is ingested,^ it has appar- 
ently no effects whatever, and as the dose is increased, the first effect 
is depression. 

Depression, whether induced directly, or following on stimulation, 
has been shown in several instances to resemble the fatigue induced 
by the prolonged exercise of the normal organ, and it is probably true 
that depression and fatigue are, in all instances, identical in appear- 
ance, although not necessarily identical in cause. For example, the 
phenomena of fatigue of the terminations of the motor nerves in 



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22 INTRODUCTION 

muscle resemble exactly those induced by curara, but in the former 
the cause may be that the conducting substance of the nerve ends has 
been used up by the repeated passage of impulses, white in the latter 
the conducting substance is so changed that it becomes incapable of 
transmitting stimuli to the muscles. The final result is, of course, 
the same; there being no available conducting substance, impulses 
fail to reach the muscle. But the fatigued terminations rapidly 
recover, as conducting substance is reformed, while the curarized 
recover only when the poison is eliminated. 

In most cases an excessive dose of a stimulating poison leads to 
depression and paralysis. The cell becomes functionally dead, but if 
the failure of its function does not involve the death of the organism, 
it may recover and reassume its ordinary function as if no stage of 
inactivity had intervened. Excessive irritation, on the other hand, 
leads to actual death and disintegration, from which there is no 
recovery. For example, the cells of the spinal cord are first stimu- 
lated and later paralyzed by a large dose of strychnine, but this is not 
fatal to cold-blooded animals, and after a few days the spinal cord 
regains its normal function, as the poison is eliminated. On the other 
hand, the injection of an irritant into the subcutaneous tissues causes 
dilatation of the vessels, effusion of fluid, and increased growth and 
rapid division of the cells. If only a small quantity be injected, this 
condition is recovered from, although it generally leaves evidence of 
its presence in the form of an increase in the fibrous tissue. But if 
the irritation be intense, the cells undergo degeneration and die, and 
an abscess is formed. The cells thus destroyed can never recover as 
the paralyzed ones do. They are either absorbed, or removed by the 
opening of the abscess, and their room is filled by the overgrowth of 
the neighboring tissues. 

DISTRIBUTION AND CONCENTRATION. 

The distribution of a drug in the different tissues and organs of the 
body must influence its action; and it might be expected that those 
organs which contain it in largest proportions would show greater 
changes than others in which it is present in smaller amounts. But this 
is not found to be true in many instances; for example, the liver often 
contains larger quantities of alkaloids than any other tissue, yet no 
symptoms may arise from this organ. The relative concentration in 
which a drug is present in the different tissues thus does not determine 
the extent to which these are involved in the action. But if an organ 
reacts to a drug, the degree of its reaction depends on the concentration 
in which the drug is presented to it and the problem in therapeutics 
is very generally to bring up the concentration in one organ to the 
efficient threshold without involving other organs; for example, in 
chloroform anaesthesia the object is to cause sufficient concentration 
in the brain without involving the heart and respiration. 

The concentration of a drug in a cell depends in the first instance on 



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ELECTIVE AFFINITY OF DRUGS 23 

the concentration in which it is present in the surrounding fluids, for 
the passage into the cell appears to be a simple diffusion which follows 
the law of mass action. And in many cases there seems to be no greater 
concentration than is in accord with diffusion, the drug being present 
in the cell in the same concentration as in the fluid; for example, 
carbolic acid is not actively taken up by bacteria. In other instances 
the drug is deposited in the cell in some form of combination, chemical 
or physical, and the diffusion continues until the cell may contain the 
whole of the drug and the surrounding fluid is free from it; an instance 
of this is presented by the accumulation of mercury in bacteria. As 
the drug is accumulated in the cell it may finally reach a strength that 
provokes reaction, but in some instances the drug accumulates in large 
amount without interfering with the functions of the cell. 

The concentration of a drug in the tissues depends primarily on the 
dose given, but this is modified by the rate of absorption and the rate 
at which the body frees itself from the drug by excreting it, or changing 
it into harmless forms. Small divided doses of a remedy may thus 
never cause the same symptoms as the administration of the same 
amount undivided. The most striking instance of this is offered in 
anaesthesia, for during an operation of an hour's duration much larger 
amounts of chloroform or ether are taken into the tissues than would 
be fatal if inhaled more rapidly; the fatal concentration is not reached 
because while absorption is going on throughout the stage of anaesthesia, 
excretion is proceeding equally rapidly. 

ELECTIVE AFFINITY OF DRUGS. PROTOPLASM POISONS. 

Most drugs have an elective affinity for certain definite tissues. 
Thus, some attack the heart only, others the central nervous system 
and others the terminations of the motor nerves in muscle. Among 
the cardiac poisons again, some act on the ventricle, others on the 
auricle, and among the poisons of the central nervous system, some act 
primarily on the cortex, others on the medulla oblongata and others 
on the spinal cord. This elective affinity is not merely a question of 
degree, as is sometimes stated, for a drug which has a powerful action 
on the brain may have no effect on the heart except when administered 
in such quantities as alter the physical characters of the blood. A 
drug may even alter different structures in diametrically opposite 
directions. Thus, atropine depresses certain nerve terminations, but 
stimulates the brain; and curara, which paralyzes the peripheral ter- 
minations of the motor nerves, stimulates the spinal cord. In some 
instances the immunity of a cell to the action of a drug may perhaps 
be explained by the latter failing to penetrate into its interior, but 
this is not true in all cases. 

The fields of activity of different drugs vary greatly in extent. One 
may comprise only the terminations of the secretory fibres in the sweat 
glands (agaricin), while another, which affects these in the same way, 
may involve many other terminations in its action (atropine). Most 



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24 INTRODUCTION 

poisons, however, while acting on a certain narrow area in small doses, 
extend the limits of their activity when larger quantities are ingested. 
Thus, a poison which acts in small doses on the medulla oblongata 
only, may, when exhibited in larger quantities, involve the spinal cord 
and the brain, and in still greater concentration may affect the heart 
and other organs. No poison is known that acts equally on all organs 
and tissues, but those which have a wide field of operation are often 
known as protoplasm poisons. These paralyze any form of living 
matter when they are brought in contact with it in sufficient quantity, 
but if they are injected into the blood and thus distributed equally 
throughout the body, they invariably select some special organ as the 
chief seat of their activity. This is exactly parallel to the behavior 
of chemical agents in the laboratory. For example, acetate of lead 
added to a solution of a chloride, or of a sulphate, precipitates it, but 
added to a mixture of the two, throws down more of the sulphate 
than of the chloride. Nitrate of silver, on the other hand, precipitates 
the chloride only. Acetate of lead may be compared to the proto- 
plasm poisons, nitrate of silver to those with a less extensive field of 
action. As protoplasm poisons affect a large number of different 
forms of living matter, it follows that they alter the nutrition rather 
than specialized functions. Many of them cause irritation; others are 
used to destroy or retard the growth of microbes and are known as 
disinfectants or antiseptics. 

REMOTE, LOCAL, AND GENERAL ACTION. 

Drugs change directly only those organs and tissues with which they 
come into immediate contact. But the alteration of one part of the 
organism very often entails that of another to which the drug may not 
have access, or for which it has no special affinity, because impulses 
are transmitted through the nerves, or changes are induced in the cir- 
culation and nutrition. Thus irritation of the skin may alter the rate 
of the pulse by impressions being transmitted by the cutaneous nerves 
and reflected along the inhibitory nerves of the heart. Similarly a 
poison that weakens the heart may induce disorder of the respiration, 
from the circulation being deficient in the medulla oblongata; and 
depression of the brain may lessen the oxidation in the muscles, 
because it leads to lessened movements. These secondary changes, 
which are not due to the direct action of the drugs on the organs con- 
cerned, are known as remote or indirect effects. 

The local action of a drug is that induced at the point of application 
before it enters the circulation, the general or systemic action is that 
due to its elective affinity for certain organs to which it is carried by 
the blood. The local effects are very often entirely different in nature 
from the general action, for a drug may act as an irritant at the point 
of application and as a depressant to the brain when it is carried to it 
in the blood. Local effects may be induced wherever the drug can be 
applied — in the skin, the alimentary tract, the respiratory passages, 



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SALT- ACT ION 25 

and the other mucous membranes. They also occur in the subcu- 
taneous tissues when the poison is injected hypodermically, and in any 
of the deeper organs and tissues which can be reached by the needle of 
the syringe. Local remedies may cause irritation, or may protect the 
surface from irritation, may depress the sensory end-organs and cause 
local anaesthesia, or lessen secretion, or alter the functions at the point 
of application in many other ways. They may also have remote 
effects, as has been mentioned. Many drugs have only a local action, 
because they are not absorbed, are absorbed in inactive forms, or are 
excreted or deposited as rapidly as they pass into the circulation, so 
that enough is not present in the blood at any one time to induce 
general effects. On the other hand, many powerful poisons have little 
or no effect at the point of application, but possess an elective affinity 
only for some organ to which they are carried by the circulation. 



SALT-ACTION. 1 

Salt-action is the term applied to a series of reactions which occur 
from the physical effects of solutions, and which are analogous to 
changes in dead tissues and are explained in the same way. Salt-action 
is elicited by any substance which can circulate in the body in sufficient 
concentration; it is oftenest seen under the salts of the alkalies, but 
is equally elicited by sugar, urea, and other harmlesss organic substances; 
on the other hand the more powerful poisons never reach the concentra- 
tion in the tissues which is necessary to elicit salt-action. 

Salt-action depends on the relative ease with which a salt and the 
water in which it is dissolved diffuse into the cells with which they 
come in contact. When a solution of salt is brought in contact with 
one containing sugar, the salt molecules and ions rapidly diffuse into 
the sugar solution and the sugar molecules into the salt solution until 
the whole becomes homogeneous, each part containing the same amount 
of sugar and salt. In the same way if a living cell be brought into a 
solution of sugar, there is often a diffusion in both directions, the sugar 
passing into the cell and the salts of the cell passing into the solution 
until the fluid within and without the cell becomes identical in com- 
position. If much sugar diffuses into the cell this may disturb the 
equilibrium, and changes in the activity of the cell may follow, or if 
the salts and other diffusible bodies in the cell escape in large quantities 
into the fluid, this may again change the life processes in the cell. Marked 
reactions may thus arise from changes in the constituents of the liquids 
surrounding a cell even though these constituents are comparatively 
inactive themselves; and the reduction in the amount of a constituent 
of the plasma may prove as harmful as its presence in excess, by causing 
the escape of essential constituents of the cell. 

1 A more detailed account of the salt-action in different organs will be given in the 
Chapter on Sodium Chloride and Water, to which the reader is referred. Here only the 
general principles are dealt with. 



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26 INTRODUCTION 

Pure water diffuses readily into all cells and causes disturbance 
in their functions from reducing the concentration of their soluble con- 
stituents. And some solids also appear to diffuse with little difficulty 
into many cells. But it is found that most dissolved substances meet 
with some resistance in entering cells, and that different tissues also 
vary in this relation, one set of cells taking up many salts with readiness, 
while another set permits the passage of few of these and rejects others. 
When a salt can penetrate a cell readily, the water in which it is dis- 
solved also finds no resistance to its entry, and the contents of the cell 
are thus diluted as much as if they had been exposed to pure water. 
On the other hand, if a salt cannot penetrate into a cell, it holds back 
a certain proportion of the water in which it is dissolved, and osmotic 
currents are set up between the soluble bodies and water in the interior 
of the cell and the solution outside it. If the latter is the stronger in 
osmotic pressure (hypertonic solution), the water of the cell diffuses 
into the external solution; if the osmotic pressure of the cell contents 
is the higher, the movement of the water is toward the interior and the 
solution is said to be hypotonic; if the osmotic pressure in the cell 
contents is equal to that of the solution (isotonic solution) there is no 
movement of the water and the volume of the cell remains unchanged. 
The behavior of a cell and the surrounding fluid is thus of the same 
character as that observed between the fluids on the two sides of a 
membrane in the physical laboratory; but no dead membrane is 
known which differs so much in its behavior to various salts as the 
living cell, and the behavior of fluids and salts is further complicated 
by the fact that the permeability of the different cells varies greatly. 

As an example of salt-action the reactions of the red-blood cells may 
be given: water penetrates into these readily, and when the cells are 
placed in distilled water it passes into them until they swell up and 
burst; ammonium chloride penetrates readily also, and in solutions of 
this salt the red cells behave almost as if they were placed in distilled 
water; sodium chloride hardly penetrates these cells, and when they 
are placed in a solution of sodium chloride of the same osmotic pressure 
as that in the interior of the cell (isotonic), there is no movement of 
water into the interior since the water of the solution is held back by 
the sodium chloride; if a solution of lower osmotic pressure (hypotonic) 
is employed, a certain amount of water is taken up from it by the cell, 
the weaker sodium chloride being unable to compete with the attraction 
of the stronger solution in the interior of the cell. On the other hand 
if a solution of higher osmotic pressure (hypertonic) be used, it with- 
draws fluid from the cell, which shrinks, because the salts in the interior 
are unable to retain the water against the stronger concentration 
outside. The behavior of the epithelium of the intestine toward these 
salts offers a contrast to that of the red-blood cells, for the chlorides 
of sodium and of ammonium are both readily absorbed by the intestine; 
on the other hand the sulphate of sodium fails to penetrate the red cells 
and enters the intestinal epithelium with great difficulty. 

Soluble salts exist in the body mainly as ions, and each ion exerts 



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CONDITIONS MODIFYING THE EFFECTS OF DRUGS 27 

the same osmotic pressure as an undissociated molecule. And each 
ion possesses an independent pharmacological action. For example, 
when cyanide of potassium is given, the action may arise from either the 
potassium or the cyanide ion, and when potassium hydrate is applied, 
the effects may arise from either the K-ion or from the HO-ion. In 
many instances one ion is so powerful that the other may be neglected ; 
thus when potassium cyanide is given, the cyanide acts in such minute 
quantities compared with the comparatively inert K-ion that the latter 
is never present in sufficient quantity to elicit symptoms. On the other 
hand when the ions are more equal in power each has to be taken into 
account in analyzing the action; thus when magnesium sulphate is 
administered, the Mg-ion and the S0 4 -ion each bear a part in the effects. 
Many drugs are not dissociated in the tissues and act only as mole- 
cules and not as ions; thus C 2 H 6 HO does not dissociate the HO-ion 
as KHO does, and none of the characteristic effects of this ion are 
elicited by the former. This has often given rise to confusion, especially 
in connection with organic bromine compounds. The bromide ion has a 
valuable action which follows when the dissociable bromides are given, 
but no such effects follow from such bodies as CHBr 3 because these do 
not dissociate the Br-ion. Compounds which dissociate poisonous 
ions are thus to be differentiated from others in which the same con- 
stituents are present in undissociable combinations. Another example 
of this is offered by the toxicity of potassium cyanide, which liberates 
the CN-ion, and the inactivity of potassium ferrocyanide, which contains 
CN but does not dissociate the CN-ion but the more complex, harmless 
ferrocyanide ion. 

CONDITIONS MODIFYING THE EFFECTS OF DRUGS. 

The effects of drugs on the living organism are subject to some 
modifications in certain individuals and under some conditions, which 
it is of importance that the physician should recognize, as the dose 
has to be altered when they are present. One of these is the Sue and 
Weight. If the same amount of a poison be distributed through the 
tissues of a large individual as of a small one, the concentration is lower 
in the organs of the former and less effect is therefore observed. This 
has been ascertained chiefly in animal experiment, in which the effects 
of drugs can be estimated much more exactly than in man, but it 
undoubtedly holds good for human beings also. Very large indi- 
viduals, then, require a somewhat larger dose than ordinary persons, 
while in treating individuals of small stature, the dose has to be 
reduced. 

The Age of the patient has also to be taken into account in prescrib- 
ing. Children ought to receive much smaller doses than adults. The 
more powerful action of drugs in children is due in part to their 
smaller size, in part to the more active growth of certain tissues and 
to the less complete development of others, such as the central nervous 
system. The dose for a child is generally calculated according to 



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28 INTRODUCTION 

Young's formula, in which a fraction obtained by dividing the age by 
the age + 12, is taken as the proportion of the adult dose required. 

Thus, for a child of four years, the dose would be (4 + i2 = ) \ °f the 

adult dose, for one of one year ( x - + 12 =) T ^ of the adult dose. 

Neither Young's formula nor any of the others which have been 
devised in its stead is to be regarded as more than a very general 
approximation, to which there are many exceptions. For example, 
the narcotics, particularly opium and its preparations, must be given 
during the first year of life in much smaller quantities than are indicated 
by Young's rule, while alcohol may be administered in comparatively 
large doses. 

The usual dose advised has to be modified for children then, and 
may be taken as that suitable from 20-60 years. After this age is 
passed, it is again reduced somewhat, so that from 70-80 about £ of 
the adult dose is advised, and after 85 it may be reduced to J. There 
are exceptions to this rule also, large doses of the purgatives, for 
example, being often necessary in old people. 

Sex. — Women generally require somewhat smaller doses than men, 
because of their smaller size, and, it is often stated, because their tissues 
react more strongly to some drugs, though this has not yet been satis- 
factorily established. 

Temporary conditions also influence the activity of drugs. Thus, 
after a meal, a poison is absorbed more slowly from the stomach than 
when it is taken fasting, and any local irritant action is also less 
marked, because the drug is diluted by the contents of the stomach. 
Irritation of the stomach and intestine may also modify the effects of 
drugs; thus in some forms of dyspepsia the absorption is slower than 
usual and little effect may be induced by the ordinary dose, w r hile irri- 
tant drugs naturally cause more disturbance of the digestion in these 
cases. Vomiting and diarrhoea, of course, tend to lessen the action of 
drugs by removing them rapidly from the alimentary canal. 

During pregnancy, purgatives have to be used with great care, 
because they induce congestion of the pelvis, and may lead to abortion. 
Drugs acting on the uterus, or inducing a marked fall of blood pres- 
sure, are to be avoided because the former may cause the evacuation of 
the uterine contents, while the latter may lead to asphyxia of the foetus. 
Many drugs pass from the mother to the child, and this is to be borne 
in mind, as quantities which are insufficient to poison the former may 
have more serious effects on the latter. During lactation, it is impor- 
tant to remember that active bodies may be excreted in the milk, and 
may either act on the child or render the milk distasteful to it. In 
menstruation, purgatives are to be avoided, as they tend to increase 
the flow, and all very active drugs are to be used with care or aban- 
doned temporarily. 

The Time of Administration has also some influence on the effects of 
drugs. The body is generally more resistant in the morning than in 
the evening, especially in the case of narcotic drugs; thus a dose of a 



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CONDITIONS MODIFYING THE EFFECTS OF DRUGS 29 

soporific which may have little or no effect in the early hours, induces 
sound sleep when given in the evening, because the brain is already 
fatigued and depressed. 

Idiosyncrasy is used to denote an unusual effect for which no expla- 
nation can be found. Some persons react more readily than usual to 
the ordinary dose, while in other instances, a much larger quantity can 
be taken without any effect. Others, again, show symptoms which 
are entirely different from, and which may, in fact, be diametrically 
opposed to those ordinarily observed. These idiosyncrasies are nat- 
urally more frequently seen and are better known, when they arise 
from widely used drugs. Thus the modern antipyretics have so often 
induced abnormal symptoms that these are well known, but it is not 
improbable that if other drugs had been used, or rather abused, to the 
same extent, they would be found to induce unusual reactions in an 
equally large number of individuals. An idiosyncrasy, as has been 
said, cannot be explained in the present state of knowledge, but some 
conditions which have been termed idiosyncrasies are probably due to 
abnormally rapid, or to retarded absorption or excretion. Idiosyn- 
crasies are not confined to human beings, for not infrequently one 
animal reacts quite differently from others of the same species. 

As has been mentioned, one form of idiosyncrasy consists in the 
failure of the individual to react to the ordinary dose of a drug. This 
is known as Tolerance, and this particular form of idiosyncrasy may 
be termed congenital tolerance. Certain species of animals tolerate 
quantities of drugs which would be fatal to others of the same size. 
In fact, so frequently is this the case that it is impossible to determine 
the fatal dose of any drug on an animal from experiments performed 
upon others of a different species, even though it be nearly related. 
One of the most remarkable examples of this form of tolerance. is met 
with in the hedgehog, which resists large doses of many very active 
poisons. Another well-known example is the tolerance of the rabbit 
of large quantities of atropine. 

A form of tolerance which is a matter of everyday observation is that 
induced by the prolonged use of a drug, which has been called acquired 
tolerance, or mithridatism, from the belief that Mithridates protected 
himself in this way from the danger of poisoning. The most familiar 
example of this form of tolerance is that acquired for tobacco (nico- 
tine); the first cigar often induces violent poisoning, but if a habit 
be formed, considerable amounts of nicotine may be absorbed without 
apparent harm, because the tissues become accustomed to the presence 
of small quantities of nicotine, and thus fail to react to it. Nicotine, 
in fact, becomes a normal constituent of the tissues. This tolerance 
is entirely different from the immunity induced by toxins (see Toxins), 
and it is desirable that the two terms should be kept distinct. 

Very often while tolerance for a poison is established in certain tissues, 
others suffer from the prolonged use of excessive quantities; for example, 
although the seasoned smoker does not suffer from the nausea and 
vomiting which followed his first essay, other organs may in course of 

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30 INTRODUCTION 

time become involved, such as the heart or the eye. It is to be noted 
that tolerance is soon lost if the drug be discontinued for some time. 
This is of great importance in cases of opium-eating, for a person who 
has taken opium for a long time acquires a tolerance for the drug, so 
that sometimes enormous quantities are required in order to induce the 
ordinary effects; but if the habit be discontinued for some time, the 
tolerance is lost, and a dose which would formerly have had little effect 
may now induce dangerous poisoning. The prolonged use of one drug 
may establish tolerance for others of the same class. Thus chronic 
drunkards are not influenced by large quantities of alcohol, and are 
also more resistant to the action of chloroform than ordinary persons, 
this being due to the fact that chloroform and alcohol act 6n the same 
nerve cells in the same direction, and probably induce the same changes 
in the protoplasm. 

In some instances when tolerance is established for a drug, it is 
found that the tissues destroy more of it than previously (morphine and 
alcohol), or excrete it more rapidly, as is said to occur under atropine 
in some animals, or absorb it less readily (arsenic). The drug thus 
never reaches the same concentration in the tissues and the absence 
of action is thus partly explained. In addition to this, however,, the 
organs normally affected become less susceptible to the drug;, for 
though in morphine tolerance much more is destroyed than in normal 
persons, enough remains in the blood to cause deep narcosis in ordinary 
persons, yet no symptoms are induced in the patient. • 

The Cumulative Effect of drugs is another phenomenon caused by 
their continued ingestion. Small doses of certain drugs taken repeat- 
edly for some time eventually cause symptoms which are much mpre 
marked than those that follow the first dose. In many instances 
this seems due to the accumulation of considerable quantities in the 
tissues. The absorption may be more rapid than the excretion, and 
each new dose thus adds to the total quantity in the blood and organs 
more than is lost in the same time by excretion. The classical example 
of cumulative action is that of digitalis, but it is much more frequently 
induced by such drugs as mercury, arsenic, or the iodides, for the 
so-called chronic poisoning induced by these is really an example 
of cumulative action. Another form of cumulation is said by Straub 
to occur in chronic lead poisoning; here the symptoms appear to arise 
not from the poison collecting in the tissues until it reaches an efficient 
concentration, but from the cumulative effect of continually repeated 
injuries from the presence of lead, though these injuries are individually 
too slight to be noted. Cumulative action may occur along with 
tolerance, as has been stated. Thus the tolerance of certain tissues for 
nicotine does not protect others from the effects of the abuse of tobacco. 

Synergists. — The presence of another drug having the same effects 
in the body often increases the action of a remedy to an unexpected 
extent. This is the ground for the prescription of several remedies 
acting in the same way. 1 For example, several purgatives prescribed 

1 The less important ones are sometimes termed adjuvants. 

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CONDITIONS MODIFYING THE EFFECTS OF DRUGS 31 

together often act more efficiently than any one given in quantity 
equal to all of them. It is quite impossible to explain this except 
by assuming that, although all are alike in their chief features, they 
differ in the details of their reactions, so that parts of the alimentary 
canal which might escape one are affected by another, and the mixture 
thus acts more universally than any one of the components. Other 
examples of synergism are offered by the narcotics, for it has been 
shown that a mixture of morphine and chloral, for example, is more 
efficient than either administered alone in larger dose. Another recent 
example is offered by the use of mercury and arsenical compounds in 
syphilis, which reacts better than when either of these is used alone. 

On the other hand, a drug may fail to elicit any symptoms if an 
antagonistic substance be present in the body. Thus in cases where 
a powerful nervous depressant, such as chloroform, has been inhaled, 
strychnine may have little or no effect on the spinal cord in doses 
which would normally increase the reflexes to a marked extent. In 
the same way, if the terminations of the inhibitory fibres of the heart 
are paralyzed by atropine, a poison which normally slows the heart 
by stimulating these terminations will have no such effect except in 
very much larger doses. 

Hunt has recently discovered a series of relations between drugs, 
which do not seem to fall into either of these categories. Thus the 
administration of alcohol renders animals more susceptible to the 
action of acetonitrile, and thyroid feeding has the same result in rats, 
while it increases the resistance to acetonitrile in mice. 

Similar modifications of the effects of drugs may be induced by 
poisons formed by pathological changes in the tissues, or by an unusual 
state of irritation or of depression of the tissues themselves. For 
example, in hot weather and in tropical climates, purgatives are found 
much more efficient than in colder climates, either because there is 
some poison which acts along with the purgative, or because the 
mucous membrane is more irritable than usual. That some such 
factor is present in these conditions is shown by the frequent occur- 
rence of diarrhoea without the use of drugs. Similarly when an antago- 
nistic poison is formed in the tissues in the course of a disease, a drug 
may have little or no effect. 

Pathological conditions very often modify the effects of drugs to a 
very considerable extent, and in a way which cannot be explained at 
present. For example, the antipyretics reduce the temperature in 
fever, but have no effect on it in health; the bromides lessen the con- 
vulsions in epilepsy, but have much less effect in depressing the brain 
in normal persons. The question may therefore be raised whether 
the examinatin of the effects of drugs in normal animals is of much 
value in indicating their therapeutic action. But in reply it may be 
said that in a large number of instances drugs are given, not in order 
to act upon the diseased tissues, but upon healthy ones. The object 
of the therapeutist is very generally not to restore the diseased tissue 
but to relieve it from work, and to allow it rest so as to promote its 



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32 INTRODUCTION 

restoration by nature. For instance, in diseases of the cardiac valves, 
drugs are given, not with the object of restoring their integrity, but to 
act upon the healthy heart muscle, and to obviate the disturbance of 
the circulation which is caused by the destruction of the valves. In 
inflammation of the kidneys, the physician seldom attempts to reduce 
the inflammation by the action of drugs on the cells involved, but 
confines his attention to removing by other channels the products of 
tissue waste, which would normally be excreted by the kidney. So 
that in most instances drugs are given to act on normal tissues, or on 
tissues which are so little affected by disease that they react to remedies 
in the same way as the normal. In other cases the action of drugs 
on diseased tissues or on the causes of disease may be investigated by 
inducing the disease in animals, as has been done very largely in recent 
years in various infectious diseases. 1 



METHODS OF ADMINISTRATION. 

The effect of a remedy is often determined very largely by the 
method in which it is administered. As regards the local action, this 
is sufficiently obvious, for an irritant applied to the skin could scarcely 
be expected to cause the same symptoms as if it were applied to the 
stomach and intestine. But the same holds true for the general action 
in most instances, because some tissues and organs absorb much more 
rapidly than others, and a larger quantity of the drug therefore passes 
through them into the blood in a given time. Thus, if a poison which 
is absorbed slowly, be rapidly excreted, so little of it may exist in the 
blood and tissues at any given time that no effects are induced, while 
if it be rapidly absorbed by some other method of administration, the 
same dose can exert some action before it is excreted. 

Drugs are applied for their Local Action to the skin, to the mucous 
membranes of the alimentary, respiratory, and genito-urinary tracts, 
and to the conjunctiva and cornea. Not infrequently they are injected 
by means of the hypodermic needle into the subcutaneous tissues for 
their local effects, and the attempt is continually being renewed to 
treat even the deeper tissues and organs locally by the injection of 
remedies into them. The objects of local medication are very diverse, 
and can be treated of only in connection with the individual drugs. 
The methods of application are also so numerous that only a few of the 
chief can be mentioned. Drugs intended for application to the skin 
are often formed into salves or ointments (unguenta) by mixing them 
with oily or fatty substances, which adhere to the skin and do not 
jdry up, and which in addition to serving as a means of applying an 
active substance, protect the surface from the air and from irritation. 
Other preparations for application to the skin, such as the plasters 
(emplastra), resemble the ointments in their general characters, but 

1 This method of investigation and its results are sometimes known as chemotherapy, 
but they do not differ in essentials from those of pharmacology. 



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METHODS OF ADMINISTRATION 33 

also give mechanical support and bind surfaces together from their 
being spread on paper or cloth, which thus serves as a flexible splint. 
The collodions and cerates resemble the plasters, the oleates the oint- 
ments. In addition to these special preparations, drugs may be applied 
to the skin in solutions, or as powders, or solid masses may be used to 
cauterize it. 

The methods of applying drugs to the alimentary tract and to the 
lungs for their local action are for the most part similar to those used 
for drugs which are intended to be absorbed. The mouth and throat 
may be washed out with solutions, which are gargled (gargarismata), 
or may be treated with powders, or lozenges (trochisci), which are 
slowly dissolved and thus permit of a more prolonged and constant 
action in the mouth than is possible if the drug be swallowed imme- 
diately. The nose may be washed out with solutions of active drugs, 
or powders may be drawn into the nostrils as snuffs; the latter often 
cause sneezing, and are sometimes known as sternutatories, or errhines. 
The larynx may be treated locally by the application of powders or 
of very small quantities of fluids by means of the laryngoscopic mirror 
and probe. Solutions are generally used for application to the con- 
junctiva, but a more permanent effect can often be obtained from 
ointments, lamellae, or powders which are less liable to be washed away 
by the tears. The urethra, vagina and uterus are treated by the 
injection of solutions, or by ointments and powders. Bougies, which 
are occasionally advised, are formed by incorporating an active drug 
in some substance which is solid At ordinary temperatures, but melts 
when introduced into the organ and allows the drug to come into 
contact with the surface. The rectum may similarly be treated by the 
injection of drugs in solution or suspension (enemata), or by the use 
of suppositories. Drugs are not infrequently applied hy the rectum 
in order to elicit their action after absorption, but much oftener for 
their local action on the bowel. Enemata may be either large (a pint 
or more) or small (2-5 c.c, §-1 fl. dr.). The large enemata are used 
either to wash out the intestines, and may then contain an antiseptic 
or astringent, or to induce peristalsis and evacuation of the bowel, 
when they are made up of water with or without soap or other slightly 
irritant substances. The small enemata are used chiefly to induce 
evacuation, and contain more irritant substances, such as glycerin 
alone or along with some more active body. The suppositories are 
formed of cacao-butter, which is solid at room temperatures, but melts 
at the temperature of the rectum. 

Drugs whose G.eneral Action is to be elicited after their absorption 
are given by the mouth, except when some special character in them 
or in the disease renders some other method preferable. They may be 
given by the mouth in solution in water, alcohol, oils, or other more 
or less indifferent bodies. The disagreeable taste of many remedies, 
however, often precludes this method, and these may be ordered in the 
form of pills, or in capsules, which are formed of gelatin or similar 
substances and are dissolved in the stomach and intestines. Very 
3 

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34 INTRODUCTION 

often the disagreeable taste may be concealed by the addition of sugar, 
or of some strongly tasting but agreeable body, such as a volatile oil. 
Insoluble drugs may be given as powders, as they have little or no 
taste. Powders are also used as a means of administering soluble 
drugs, if they have not a disagreeable taste and have no marked local 
action, but very deliquescent drugs should not be given in this form. 
Insoluble drugs are sometimes ordered in suspension in mucilaginous 
fluids; and oils which are distasteful to many people, may be given 
mixed with water and gums (emulsions). 

The rate of absorption from the alimentary canal varies greatly 
with different drugs and also with the form in which they are adminis- 
tered. The first point will be treated of in connection with the indi- 
vidual drugs. As regards the second, it may be stated that drugs are 
more rapidly absorbed when they are swallowed in solution, and that 
when much inert and insoluble matter is associated with them, their 
absorption is much retarded. Thus, common salt passes more rapidly 
into the blood when it is dissolved before being taken than when it is 
swallowed dry, and morphine is absorbed much more quickly when it 
is administered pure than when, as in opium, it is mixed with a mass 
of gums and other bodies. This fact is taken advantage of in practice 
by giving drugs in solution when rapid absorption is desirable, and by 
giving less pure forms when the local action on the stomach and bowel 
is to be elicited. The more concentrated the solution, the greater is 
the irritant action on the stomach, and thus where irritation of the 
stomach is desired, either the solid drug or a strong solution is given; 
but as a general rule the local action on the stomach is to be avoided, 
and drugs are therefore ordered in as dilute solution as is possible 
without increasing the bulk to too great an extent. It is to be noted 
that drugs which are insoluble in the test-tube may be .rendered soluble 
by the action of the gastric and intestinal juices, while many which 
are given in solution, are precipitated by the proteins in the stomach. 

The great mass of drugs absorbed from the stomach and intestine 
is carried to the liver before reaching the general circulation, and this 
is of great importance in determining their effects in the body, as 
some of them are retained in that organ, and are either entirely 
destroyed or escape so slowly that they have no perceptible effect. 

Another important method of administering drugs for their general 
action and also for their local effects is by inhalation into the lungs. 
Only volatile drugs can be used thus for their general action. They 
are absorbed very rapidly owing to the extensive surface to which they 
are applied, and also because volatile substances penetrate the tissues 
more readily than others. The best examples of inhalation are offered 
by the general anesthetics, chloroform and ether. Most substances 
absorbed by the lungs are also excreted by them, and this leads to an 
important practical point in regard to the anaesthetics. For the passage 
of gases or vapors through the lining epithelium of the alveoli depends 
in most instances upon their partial pressure, that is, upon their con- 
centration in the air and blood respectively. Accordingly, when the air 



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METHODS OF ADMINISTRATION 35 

contains more chloroform vapor than the blood, the anaesthetic passes 
into the blood, but as soon as the condition is reversed, and the blood 
contains more chloroform than the air of the alveoli, it commences to 
pass backward. The more concentrated the vapor inhaled, the more 
chloroform is contained in the cubic centimeter of blood, and the 
greater is the action on the nervous centres and the heart. 

Less volatile substances are sometimes inhaled into the lungs for 
their local action, and even non-volatile bodies suspended in a spray 
of vapor may be thrown into the respiratory passages, but it may be 
questioned whether these last really reach the alveoli except in traces. 

Drugs are also applied to the skin in order to elicit their general 
action. Volatile bodies are certainly absorbed by it, although much 
more slowly than by the lungs or by the stomach and intestine. Solu- 
tions in water of non-volatile drugs are not absorbed from the skin, 
but solutions of certain remedies in alcohol, oils, fats, ether, and some 
other substances which are capable of dissolving or mixing with the 
fatty covering of the skin, are absorbed fairly rapidly if they are 
rubbed in thoroughly. This method of application (inunction) has 
been used chiefly for the absorption of mercury, as the local action on 
the stomach and bowel is thus avoided. (See Mercury.) Alkaloids 
do not appear to be absorbed by the skin even when dissolved in oils 
or alcohol. 

The hypodermic method is of comparatively recent origin, but is 
being more widely used every year. In it drugs are injected through 
a fine hollow needle into the subcutaneous, or, in the case of more 
irritant substances, into the muscular tissue, where they meet with 
fewer sensory nerves. Absorption occurs more rapidly than when 
drugs are given by the mouth, the local action on the alimentary 
canal is avoided, and the physician is more certain that the whole 
of the remedy is effective, provided it. is soluble and is not pre- 
cipitated at the point of injection. At the same time, the method 
has certain drawbacks, the chief of which are the pain of the injection 
and the danger of injecting a powerful remedy into one of the sub- 
cutaneous veins. Hypodermic injection should be made only by 
the physician or trained attendant, for incalculable injury has been 
done by entrusting patients with the syringe, particularly for the 
injection of morphine and cocaine. The needle and syringe ought to 
be disinfected, and the substance injected should be aseptic, and this 
renders the method inconvenient. As a general rule, solutions in 
water or in dilute alcohol are used for injection, but the insoluble 
salts of mercury have also been injected, suspended in oil (see Mercury). 
Irritant drugs are to be avoided as far as possible, as they £ause great 
pain, swelling and sometimes suppuration, even when the injection 
has been carried out aseptically. Hypodermic injection is used very 
largely to elicit the general action of a remedy, but also for the local 
effects, as when cocaine is injected in order to produce local anaesthesia. 
Solutions of inert bodies have also some anaesthetic action, probably 
owing to their mechanical action on the sensory nerve fibres. As 



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36 INTRODUCTION 

the absorption from the subcutaneous tissues is so much more rapid 
than that from the stomach and intestine, when the drug is in perfect 
solution, the dose has to be reduced. As a general rule, about one-half 
of the ordinary amount is sufficient. 

Deeper injections are sometimes made for their local action on the 
organs. Thus, antiseptics have been injected into lung cavities, caustics 
into tumors, local anaesthetics into the spinal canal, and direct applica- 
tions have been made to the nerves in sciatica and other similar 
disorders. 

Intravenous injection is the most certain method of bringing drugs 
into the circulation and tissues, and is at the same time the most 
rapid. It is, therefore, very largely used in experiments on animals, 
and in recent years has been widely practised in man in such diseases 
as syphilis and malaria, in which it is desirable to induce a definite 
concentration of a remedy in the blood rapidly. Cardiac and circulatory 
stimulants, such as strophanthin and adrenaline, have also been admin- 
istered in this way. The dose must be very much smaller than that 
employed by the mouth, but it is impossible as yet to state exactly 
what fraction will induce the same effects. 

Drugs are occasionally applied by the rectum for their general 
action, as has been mentioned. The local effects on the stomach are 
avoided by this method, and morphine and opium are, therefore, not 
infrequently administered thus. The rate of absorption from the 
rectum as compared with that from the stomach and bowel is still a 
disputed point, and some physicians recommend that the dose be 
reduced to three-fourths, while others recommend one and one-half 
times that given by the mouth. 

Drugs are not administered by the other mucous membranes for 
their general effects, but it must not be forgotten that symptoms may 
arise from their application to them for their local action. Similarly, 
drugs applied as dressings to wounds or abrasions have very often 
given rise to severe or fatal poisoning from being absorbed into the 
blood and tissues. 

THE CHEMICAL CHARACTERS OF DRUGS. 

Many substances which induce changes in the living organism are 
comparatively simple chemical compounds. In the inorganic materia 
medica are found many salts, bases and acids, and a few uncombined 
elements, such as mercury and phosphorus, while organic chemistry 
offers hydrocarbons, alcohols, ethers, phenols, ketones, aldehydes, acids, 
and many other compounds which require no special mention. But 
some groups of substances which occur widely in plants require some 
discussion before the individual members are taken up severally. 

The first group of these is formed by the Alkaloids, which are sub- 
stituted ammonias, and have a more or less strongly alkaline reaction, 
so that they are often known as the vegetable bases. They contain 
carbon, hydrogen, nitrogen, and, as a general rule, oxygen, although 



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THE CHEMICAL CHARACTERS OF DRUGS 37 

some of them, such as coniine, are devoid of it. Like ammonia, they 
combine with acids readily without eliminating hydrogen, and the 
salts thus formed resemble those of ammonia in many respects, among 
others in being thrown out of combination by the fixed alkalies. Many 
vegetable alkaloids are derived from pyridine, quinoline and isoquino- 
line by the addition of hydrogen, and generally by the substitution 
of one or more of the hydrogen atoms by side chains of greater or less 
complexity. 

CH 

HC^ ^CH HC/ Y ^CH HC^ y \ CH 





HC V /CH HC V X /CH 

\/C 
N CH N CH CH 

Pyridine. Quinoline. Isoquinoline. 

But others appear to be derivatives of the pyrrol and oxazine groups, 
while in others the nitrogen is attached to radicles belonging to the 
methane or open-chain series; some artificial alkaloids are derivatives 
of aniline. 

CH CO 



HC. iCH / 

YLC / X .C— NHt HC^ N CH 



I 



HC V / CH HC \ / CH HC \ >CH 



NH CH N 

Pyrrol. Aniline. Oxazine. 

Finally the purine bodies (see Caffeine group) may be included 
although they are only feebly basic. 

Some of the vegetable alkaloids have been formed synthetically in 
the laboratory, and the constitution of some of the others is perfectly 
well known, but many of them have not yet been isolated, and there 
are probably others whose existence is not even suspected. These 
vegetable alkaloids occur in almost all parts of plants, although they 
are found in greatest abundance in the seeds and roots. The same 
alkaloid is often found in most of the plants of a gefriis, or it may 
occur in one or two species of a genus and in other plants which are 
in no way related. Very often several alkaloids are found in a plant, 
and these may differ entirely in their action on animals, although not 
infrequently all the alkaloids of a plant resemble each other in their 
effects. The alkaloids are found most abundantly in dicotyledonous 
plants, but some are obtained from the monocotyledons. Muscarine, 
ergotoxine and other bases are found in the fungi, and quite recently 
alkaloids have been isolated from the suprarenal capsule of animals 
and from the skin of the salamander. 

The alkaloids are very often only slightly soluble in water, but 
form salts which are generally more soluble. Many of the bases are 



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38 INTRODUCTION 

dissolved by ether, chloroform and amyl alcohol, while the salts are 
insoluble in these. Both bases and salts are generally fairly soluble 
in alcohol. The alkaloids are precipitated from solution by a large 
number of reagents, of which the most important are the chlorides of 
platinum and of gold, tannic acid, phosphotungstic and phospho- 
molybdic acid, the double iodides of potassium and mercury, and of 
potassium and cadmium, and iodine held in solution in water by 
potassic iodide. The hydrates and carbonates of the alkalies and the 
alkaline earths precipitate the alkaloids from solutions of the salts in 
water, a point of some importance in prescribing these bodies. 

In cases of poisoning when the alkaloid has been taken by the mouth, 
it may be precipitated in the stomach by dilute alkalies or better by 
tannin solutions. The poison should then be removed by inducing 
vomiting or by washing out the stomach with the stomach tube. 

Another important class of vegetable poisons is formed by the 
Glucosides (glycosides), or saccharides, which are esters (compound 
ethers) composed of sugars and hydroxyl substances, and which liberate 
sugar when they are heated with acids, or sometimes with alkalies, 
or when certain unorganized ferments act on them. The sugar formed 
in this way is often glucose, but not invariably so; the other decom- 
position products have been identified only in a few instances. Many 
of the glucosides contain only carbon, hydrogen and oxygen, a few have 
nitrogen in addition, and one or two sulphur. In some instances the 
remainder, after the sugar is split off, is an alkaloid, e. g., solanidine. 
Glucosides differ greatly in their solubility in water and alcohol; com- 
paratively few of them are soluble in ether. Some of the glucosides 
are powerful poisons, others have little or no action. 

Resins, an ill-defined group, are found in many plants, and are char- 
acterized by their smooth, shining fracture, and by their insolubility 
in water and solubility in ether, chloroform, volatile oils, benzol and, 
in many cases, in alcohol. They seem to be formed in plants by the 
oxidation of volatile oils, and are often acid or anhydride in character, 
while others are apparently alcohols or esters. The resins are almost 
invariably composed of several different substances mixed together. 
Many of the resins are local irritants, and some are poisonous in com- 
paratively small quantity from the powerful action they exert on the 
intestine. 

Oleoresins are solutions of resins in ethereal oils, which lend them 
a characteristic odor and taste. 

The term "Balsam" is often used as synonymous with oleoresin, but 
most writers restrict it to those oleoresins which contain benzoic and 
cinnamic acid along with other constituents. (See Benzoic Acid.) 

Gum-resins are mixtures of resins and gums, generally containing 
some volatile oils. They are insoluble in water, but the resin is sus- 
pended in it by the gum. On the other hand, the resin is dissolved 
by alcohol, while the gum remains insoluble. 

Gums are amorphous, transparent substances, composed of carbo- 
hydrates of the formula C 6 Hi O 5 and are thus nearly related to cellulose 



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PHARMACOPEIAS AND PH ARM ACOP(EI AL PREPARATIONS 39 

and starch. Some of them are soluble in water, while others merely 
swell to a jelly in it; they are insoluble in alcohol. They generally 
occur in plants in combination with calcium, magnesium or potassium; 
they have no poisonous action, but form a protective covering for 
irritated surfaces, and are largely used to suspend in water substances 
which are insoluble in it, such as resins and oils. 

Volatile oils occur in plants in large numbers. (See page 57.) 
Fats, oils, sugars, acids, starch, proteins, coloring matter, ferments 
and other bodies which occur in plants, and are contained in many of 
the preparations used in therapeutics, are not generally possessed of 
any action of importance. 

THE PHARMACOPCHAS AND PHARMACOPCEIAL PREPARATIONS. 

Almost all governments have found it necessary to regulate the 
preparation of drugs used in therapeutics, and for this purpose issue 
at intervals codes of instructions defining the characters of the drugs 
and giving the exact formulae according to which they are to be pre- 
pared for use. In the United States, where the government has not 
undertaken this as yet, a code has been prepared by a voluntary asso- 
ciation of physicians and pharmacists. These codes are known as 
Pharmacopoeias, and some differences exist between those of different 
states, although the most important drugs are found in all of them. 
All the drugs used in therapeutics are not found in the pharmacopoeias, 
for these are issued only at intervals of several years, and in the mean- 
time valuable remedies may be introduced. The official definition of 
therapeutic substances is of advantage to both physician and pharma- 
cist, as it assures the former that the drug he prescribes will have a 
uniform quality, wherever in the country it is dispensed, while the 
pharmacist is saved from the continual preparation of remedies in 
different forms, by their being prescribed in one recognized strength. 

The pharmacopoeias contain a large number of pure substances such 
as salts, acids, bases, alkaloids, and these require no further description. 
On the other hand, many of the drugs are given in an impure form, 
either because the active principle is unknown, or because its isolation 
is attended with difficulty and expense. Thus many of the vegetable 
remedies are presented in the pharmacopoeias as solutions or solids 
which contain not only the active principle but gums, sugars, coloring 
matter, and many other impurities. These are provided in different 
forms to allow of variation in their administration. In addition, the 
pharmacopoeias contain a number of official prescriptions, that is, 
mixtures of active substances in such proportions as are ordinarily pre- 
scribed. These are generally designated by the addition of "compound" 
(compositus) to the name of the chief ingredient. Most pharmaco- 
poeias continue to use Latin in the titles of the drugs, and this is not 
due to mere pedantry or conservatism, as is often stated. For the 
popular name of a drug is often used for several different substances, 
while the Latin name in a prescription indicates that drug which is 



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40 INTRODUCTION 

known by the term in the pharmacopoeia. In the same way it is found 
necessary to maintain Latin terms in botany and zoology in order to 
define accurately the species. 

Many crude or unprepared drugs are found in the pharmacopoeias, 
such as leaves, roots, flowers, or even whole plants. These are used 
chiefly for the preparation of other more readily applicable remedies, 
but are sometimes prescribed as powders or in pills. 

The following preparations 1 are official : 

a. Aqueous Preparations. 

Aqua, medicated waters, generally contain only traces of some volatile 
substance, such as an ethereal oil or chloroform, in solution in water, and 
these are used in prescriptions as more agreeable to the taste and smell than 
pure water but have no further effect. In the U. S. P. the solutions of 
ammonia, and hydrogen peroxide are also included under aquae, but these 
are used only to elicit the specific effects of these drugs and are powerful poisons. 
In the B. P. these strong solutions are included in the liquores. 

Liquores (U. S. P.) are solutions in water of soluble substances. Many of 
these are one per cent, in strength. 

Liquores (B. P.) are solutions in the widest sense, in water, alcohol, or other 
fluids. 

Decocla, or decoctions, are impure solutions of vegetable principles, which 
are obtained by boiling parts of plants in water. 

Infusa, or infusions, are solutions obtained by soaking parts of plants in 
water, which may be hot or cold, but is not kept boiling. Infusions and de- 
coctions are weak preparations and decompose rapidly so that they are used 
only when recently prepared. 

Mishirce, or mixtures, are generally preparations in which substances in- 
soluble in water are suspended in it by means of gums or similar viscid sub- 
stances. But some of them contain only soluble bodies. 

Emulsa (U. S. P.), emulsions, are formed by suspending oils in water by 
means of gums or other viscid bodies, 'the B. P. contains no official emul- 
sions, the corresponding preparations being known as misturce. 

Mucilagines, mucilages, are solutions in water of gums, starch, and similar 
bodies. 

Syrupij syrups, are strong solutions of sugar in water, which may be used 
alone, or may be impregnated with more active bodies. Similar preparations 
formed with honey instead of syrup (sometimes known as mellita) are official, 
as Mel Rosas (U. S. P.), Mel Boracis (B. P.). 

Lotiones (B. P.), lotions, or washes. This term is used to designate two 
preparations of mercury, the black and yellow wash. 

b. Alcoholic Preparations. 

Spiritus, spirits, are solutions of volatile bodies in alcohol, and often owe 
their chief action to the solvent and not to the drug contained in it. 

Elixiria (U. S. P.), elixirs, differ from spirits chiefly in containing sugars, 
which are added in order to improve their taste. 

Tincturce, tinctures, are solutions in alcohol of medicinal substances, which 
are generally formed by soaking parts of plants in it. They contain both 
volatile and non-volatile ingredients, but the latter are generally the more 
important. 

1 The student is advised to omit the following list for the present, and to refer to it 
only as he takes up the preparations of the individual drugs. Most of these preparations 
are found in both pharmacopoeias. Those which occur only in the British are indicated 
by B. P., while those which are confined to the United States are marked U. S. P. 



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PHARMACOPEIAS AND PHARMACOPCEIAL PREPARATIONS 41 

Fluidextracta (U. S. P.), Extracta Liquida (B. P.), fluid extracts, are pre- 
pared from plants by forming solutions in water or more frequently in alcohol, 
and evaporating them until the solutions contain as many cubic centimeters 
as the original crude drugs weighed in grammes; that is, the volume of the 
fluid extract corresponds to the weight of the crude drug. When the active 
principle is assayed, however, the liquid extract is diluted to contain a definite 
amount of it, and without reference to the quantity of the crude drug used. 

The tinctures and fluid extracts are the most commonly used liquid prepa- 
rations, and most of the important drugs are prepared in one or both of 
these forms. 

c. Other Fluid Preparations, 

Glycerita (U. S. P.) or Glycerina (B. P.) are solutions of medicinal substances 
in glycerin. 

Collodia, collodions, are solutions of medicinal substances in collodion. 

Aceta, or medicated vinegars, are solutions of medicinal substances in vine- 
gar or acetic acid. 

Linimenta, liniments, embrocations, are preparations in which active rem- 
edies are dissolved or suspended in dilute alcohol, oils, or water. They generally 
contain an oil or soap and are intended to be applied to the skin. 

d. Solid and Semi-Solid Preparations. 

Extracta, extracts, are formed from solutions such as tinctures, decoctions, 
or infusions by evaporation, which is continued until there remains a solid 
mass. The extracts thus contain all the substances which are taken up by 
the solvent, except those which are driven off or decomposed at the tempera- 
ture at which evaporation is carried on. 

Piluke, pills, are globular masses of small size, such as admits of their being 
easily swallowed. They are formed from extracts, or from powders, by the 
addition of some substance to give them the necessary cohesion and consistency. 
Pills generally weigh 0.1-0.3 G. (2-5 grs.). The U. S. P. determines the com- 
position and size of the official pills, so that the doses can be modified only 
by ordering several pills to be taken, at one time. The B. P. leaves the pills 
unformed, so that they may be prescribed of any size. The Pilulae of the B. P. 
really correspond not to the Pilulae, but to the Massae of the XL S. P. 

Masses (U. S. P., masses, are preparations made up of the proper consist- 
ency for pills. They are invariably prescribed in the form of pills. 

Confectiones, confections or electuaries, are soft, solid preparations consist- 
ing of sugar or honey impregnated with some more active body. 

Suppositoria, or suppositories, are intended for insertion into the rectum, 
urethra, or vagina, and are, except in one or two cases, formed by mixing the 
active ingredient with cacao-butter. Suppositories for the rectum are conical 
in shape and weigh about a gramme (15 grs.). Those for the urethra {bougies) 
are of the same weight, but are pencil-shaped, while the vaginal suppositories 
are globular, and weigh about 3 grammes (45 grs.). 

Pulveres, powders, are simply dry substances in a state of fine division. 
Most of the official powders are mixtures of several active bodies. 

Triturationes (U. S. P.), triturations, are formed from powders by diluting 
them with nine parts of sugar of milk. 

TabetUe, tablets (B. P.) are formed of chocolate in which an active drug is 
incorporated, and weigh 5 grs. or less. 

Trochisci, troches, or lozenges, are solid masses, generally of a flattened shape, 
and consist of powders or other bodies, incorporated in sugar and gum. 

Lamella? (B. P.), or discs, are small discs formed of gelatin with some gly- 
cerin, each weighing 3 V-*V g*« They are impregnated with an active drug, 
and are applied to the conjunctiva in order to elicit the local effects. 

Unguenta, ointments, salves, are soft, oily substances which are applied 
to the skin by rubbing. (See page 46.) 



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42 INTRODUCTION 

Cerata (U. S. P.), cerates, resemble ointments, but are rendered harder by 
the addition of wax. (See page 46.) 

Emplastra, plasters, are adhesive bodies of a still harder consistency than 
cerates, and soften only when heated. 

CharUs, papers, are preparations of active substances which are spread in 
a thin layer upon paper. 

Unofficial Preparations. 

Cachets, are thin discs of dough of the shape of a soup-plate and varying 
from J in. to 1J in. in diameter. When two of them are placed together with 
their concave sides toward each other, they form a receptacle in which powders 
are dispensed. The edges stick together when they are moistened. A some- 
what similar method of dispensing is in gelatin capsules, which may be hard 
or soft, and which are made in different sizes. The hard capsule is used for 
solids, the soft for liquids. Sometimes the latter contain as much as 15 c.c. 
(J fl. oz.), but these are difficult to swallow. 

Tablettce, tablet triturates, or compressed tablets, are formed from fine powders 
which are moistened and rendered coherent by some liquid and then compressed 
in moulds. They are generally about 5 grs. in weight, and disintegrate in the 
stomach more rapidly than other preparations. 

Cataplasmata, or poultices, are not official preparations now, but are in 
common use. They are generally made of linseed meal, oatmeal, or bread 
crumb, which is formed into a paste with hot water, enclosed in thin cotton 
or linen and applied to the skin. Mustard and other remedies may be added 
to the poultice in order to induce special effects, and in some cases a poultice 
consists merely of drugs enclosed in a cloth sack, as in charcoal or spice poultices. 

Enemata, clysmata, or clysters, are liquid substances injected into the rec- 
tum for their local or general effects. (See page 33.) 



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PART I. 

SUBSTANCES WHICH ARE CHARACTERIZED 
CHIEFLY BY THEIR LOCAL ACTION. 

This class contains a very considerable part of the drugs included 
in the pharmacopoeias, although it bears a smaller proportion than 
formerly to the other classes. There is still, however, in it a large 
number of drugs which have practically identical effects, and there is 
no question that it might be considerably curtailed without loss to 
therapeutic practice. Many of its members are irritants, and these 
have been subdivided for convenience into groups according to the 
organs on which they exert their chief action and the purposes for 
which they are used in therapeutics, as gastric, intestinal, cutaneous 
irritants. Others act as protectives, covering injured surfaces (demul- 
cents, emollients), and still others precipitate the proteids on the 
surfaces to which they are applied (astringents). Others seem to act 
chiefly by affecting the taste and the digestion. Finally the drugs used 
to destroy intestinal parasites, and those that are employed to act 
on bacteria are discussed. 

I. DEMULCENTS. 

A large number of colloid substances — chiefly gums, dextrins, sugars 
and starches — owe their use in medicine, not to any changes they 
vproduce in the cells with which they come in contact, but to the fact 
fthat they are cohesive and serve to protect surfaces mechanically. 
When they are applied to a sensitive surface, they .retard the movement 
of fluid or air against it and thus preserve it from the effects of these 
agents. This may be illustrated by familiar examples in which the 
taste of food is altered by their presence, although they have often no 
taste or odor in themselves. Sugar dissolved in mucilage tastes less 
sweet than in water, and acids are also less appreciated, as may be 
observed in many fruits. For example, the raspberry contains more 
acid and less sugar than the currant, but in the former the acid taste is 
concealed by the presence of large quantities of colloids, so that the 
raspberry is regarded as a sweet fruit, the currant as an acid one. Even 
cold is felt less when a colloid substance is present in the fluid swallowed; 
thus, ice-cream or iced milk does not feel so cold on the tongue and 
throat as frozen water, because the colloid protein substances form 
a protecting layer, over the surface, and prevent the cold mass from 
reaching the sensory terminations so freely as it otherwise would. A 

n (43) T 



44 SUBSTANCES ACTING LOCALLY 

number of experiments carried out by Tappeiner 1 show that other 
organs may be protected in the same way by colloid solutions. Strong 
salt solution applied to a motor nerve first stimulates and then slowly 
paralyzes it, but Tappeiner found that both of these effects are much 
less marked if the solution be made up with mucilage instead of with 
water, because the salt does not reach the nerve so readily. In the 
same way, intense pain is caused in a wound by strong salt solution, 
but is much less severe if the solution contain colloid material. 

When demulcents reach the stomach, they act as protectives in some 
measure so that the reflexes from the epithelium are less active; and 
irritants cause less inflammation if they are suspended in demulcents 
than if they are dissolved in water; at the same time the presence 
of colloid unabsorbable bodies may increase the efficiency of purgatives 
by preventing their absorption in the upper part of the bowel. The 
digestion of proteins outside the body is retarded by the presence 
of the demulcents, and probably this is also true of the process in the 
stomach. Colloid bodies also retard the absorption of fluids from the 
stomach and bowel, and this leads to a feeling of distention, which 
is much less marked if the same amount of fluid be swallowed without 
colloid; for instance, water is absorbed more rapidly than milk or beer. 

The colloids are absorbed slowly, and probably only in a condition 
of semi-decomposition. After absorption, they are oxidized in the 
tissues and therefore act as foods to some extent, although their slow 
absorption prevents their being of much value. They have, of course, 
no effect as demulcents after absorption, but the large quantity of fluid 
with which they are generally taken may be of benefit in some con- 
ditions* 

Demulcents are used to cover inflamed surfaces; in tonsillitis, for 
example, they may be applied as gargles, or better by sucking lozenges 
containing them. They are not often applied externally for this pur- 
pose, as they are liable to serve as media for the growth of micro- 
organisms. In gastric and intestinal catarrh their use is objectionable 
for the same reason, their slow absorption leading to decomposition 
with the formation of irritants, which may do more harm than is 
counterbalanced by their protective action. Instead of demulcents, 
some of the oils, such as olive oil (p. 48), have been recommended as 
protectives in disease of the stomach and intestine. 

In acute irritant poisoning the demulcents are often of great value, 
as they protect the stomach wall from the effects of the poison. The 
best remedy in these cases, because the most readily obtainable, is 
milk or white of eggs. 

Their effects in retarding the absorption of other remedies may be 
taken advantage of. Thus opium and extract of mix vomica are pre- 
scribed when the local action on the bowel and stomach is desired, while 
the pure alkaloids, morphine and strychnine are administered for their 
effects after absorption. 

1 Tappeiner, Archives internat. d. Pharmacodyn., vol. x., p. 67, 

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DEMULCENTS 45 

Demulcents are often given instead of pure water in cases where it 
is desired to administer large quantities of fluid, as they have more 
"body" and are more agreeable to the taste. Thus, barley water or 
some other demulcent may be advised in order to assuage the thirst of 
fever, or to dilute the urine when it is too concentrated or too acid. 

Demulcents are often used as the basis of enemata which are 
intended to be absorbed, because solutions containing colloids are less 
irritant and therefore less liable to set up peristalsis than pure water. 
For this purpose starch solution is generally used. 

Some of the gums, notably acacia and tragacanth, are seldom 
advised as demulcents, but are often prescribed in order to hold in 
suspension in water such insoluble bodies as resins and oils, or to give 
cohesion to pills and lozenges. 

Preparations. 

Acacia (U. S. P.), Acacia Gummi (B. P.) (gum arabic), a gummy exuda- 
tion obtained from Acacia Senegal, consists of the potassium, magnesium and 
calcium salts of a weakly acid substance, arabin, or arabinic acid (CeHioO*). 
It is soluble in equal parts of water, and is used as a demulcent, but more 
largely as a vehicle for other drugs. 

Mucilago Acacle (U. S. P., B. P.). Dose, 16 c.c. (4 fl. drs.). 

Syrupus Acacice (U. S. P.). 

Tragacantha (U. S. P., B. P.), a gummy exudation from various species 
of Astragalus, contains salts of arabin and tragacanthin. Tragacanthin differs 
from arabin in not dissolving, but merely swelling up into a jelly in water. 
Tragacanth is used chiefly to suspend heavy powders in water. 

Mucilago Tragacanthce (U. S. P., B. P.). Dose, 16 c.c. (4 fl. drs.). 

Glycerinum Tragacanthce (B. P.), a solution of tragacanth in glycerin and 
water. 

Puhris Tragacanthce Compositus (B. P.), contains tragacanth, gum acacia, 
starch and sugar. Dose, 10-60 grs. 

Amjrfom (U. S. P., B. P.), or starch, may be formed into a jelly by boiling 
in water, and may then be used for the same purpose as the demulcents. 

Glyceritum Amyli (U. S. P.), Glycerinum Amyli (B. P.), is a jelly formed by 
heating starch with water and glycerin. 

Amygdala Dulcis (U. S. P., B. P.), or sweet almonds, the seed of Prunus 
amygdala dulcis, contains a fixed oil and emulsin, a ferment, but, unlike the 
bitter almond, no amygdalin. When triturated with water it forms an emul- 
sion, or mixture, which is bland and demulcent. 

Emulsum Amygdala (U. S. P.). Dose, 120 c.c. (4 fl. oz.). 

Pulvis Amygdalae Compositus (B. P.), contains sugar and acacia with almond. 

Syrupus Amygdake (U. S. P.) is formed from a mixture of sweet and bitter 
almonds, and therefore contains a small proportion of prussic acid. Dose 4 c.c. 
(1 fl. dr.). 

Glycyrrhisa (U. S. P.), Glycyrrhizae Radix (B. P.), or liquorice-root, the 
root of Glycyrrhiza glabra (var. glandulif era) , is used as a demulcent, and 
more largely to flavor medicines. It has a pleasant, sweet taste, owing to the 
presence of Glycyrrhizin, an acid glucoside. 

Extractum Glycyrrhizce (U. S. P., B. P.). Dose, 1 G. (15 grs.). 

Extractum Glycyrrhizce Purum (U. S. P.). Dose, 1 G. (15 grs.). 

Fluidextractum Glycyrrhizce (U. S. P.), Extractum Glycyrrhizce Liquidum 
(B. P.). Dose, 2 c.c. (30 mins.). 

Pulvis Glycyrrhiz.e Compositus (U. S. P., B. P.), contains senna. Dose, 
4 G. (60 grs.). 



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46 SUBSTANCES ACTING LOCALLY 

Mistura Glycyrrhiz^e Composita (U. S. P.), "Brown Mixture," con- 
tains opium, antimony and spirits of nitrous ether. Dose, 8 c.c. (2 fl. dra.). 

The extract is largely used in the form of lozenges for its demulcent action, 
and is very frequently used to make up pills. It is slightly laxative, and may 
be used as a pleasant aperient for children; the compound powder is more 
reliable for this purpose owing to its containing senna, one of the vegetable 
purgatives. The brown mixture is used in cough and in catarrh of the air 
passages. 

Numbers of other substances are used as demulcents in domestic medicine, 
and are found in different pharmacopoeias. Examples of these are sassafras 
pith (Sassafras Medulla), slippery elm ( Ulmus), marshmallow root (AUhaa), 
linseed (Linum), barley (Hordeum), salep, verbascum and quince seeds. Iceland 
moss is a lichen (Cetraria islandica), and contains starch bodies together with 
acids, which can be removed by soaking in dilute alkaline solutions for some 
time. Irish moss or Carragheen (Chondrus), a seaweed gathered on the coasts 
of Ireland and Massachusetts, contains a carbohydrate, carrageenin. The 
decoction forms a jelly when cold, and was formerly supposed to form a 
valuable food in illness, but it is of little value for this purpose, for only about 
iv-ik of the jelly is solid matter, the rest water. Couch-grass, the rhizome of 
Agropyrum repens (Triticum) is used in the form of a decoction as a beverage 
in fever, and to dilute the urine. It has a certain popular reputation as a 
diuretic in suppression of the urine, calculus, etc., but this is entirely unmerited, 
for it increases the urine simply by the water given with it. 



H. EMOLLIENTS. 

Emollients are bland, oily substances which are applied to the skin 
to protect it from irritation, and to render it softer and more elastic; 
they thus bear the same relation to the skin as the demulcents to the 
mucous membranes. Their effect in rendering the skin softer and 
more pliable may be due in part to their penetration into the surface 
layers, but may also be explained by the slight congestion induced by 
the rubbing and massage used in their application. 

The older emollients were chiefly animal and vegetable fats and 
oils, but several newer drugs of this class are derived from petroleum. 
The effects of these drugs when applied to the skin are purely local. 
No doubt some small percentage is absorbed into the tissues, but this 
has no known effect in man, and although the fats and oils are valuable 
foods when taken internally, this plays no part in their effects when 
applied to the skin. 

The emollient preparations promote the absorption by the skin of 
drugs dissolved in them, because they mix readily with the thin layer 
of oily sebaceous matter which covers it. The active substances dis- 
solved in them therefore come into intimate contact with the absorbing 
cells lining the ducts of the glands, while watery solutions are separated 
from the living cells by a layer of sebum. If this layer be dissolved 
off by alcohol, watery solutions are also absorbed rapidly, and alcoholic 
solutions are absorbed as quickly as oily solutions, because the alcohol 
is miscible with the sebum. The absorption by the skin varies con- 
siderably according to the emollient used, and it is found that some drugs 
are taken up more easily from one ointment, others from another; the 
difference doubtless arises from the relative solubility in the emollient 



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EMOLLIENTS 47 

and in the absorbing cells, but is still to be investigated. Aqueous 
solutions come into more intimate contact with the cells of the mucous 
membranes and with the subcutaneous tissues, and are therefore more 
readily absorbed by these than oily solutions. To ensure rapid absorp- 
tion, a drug should be dissolved in some emollient if it is to be absorbed 
by the skin, in water when it is to be administered internally or hypo- 
dermically. Solutions in oil of such antiseptics as carbolic acid are 
much less powerful than those in water, because carbolic acid being 
more soluble in oil fails to diffuse into the watery protoplasm of the 
microbe, for which it has less affinity. But antiseptics which are 
more soluble in water than in oils are said to be equally active in 
both solvents. 

The emollients are applied as protectives in abrasions, cuts, bruises, 
chapped hands, burns; they are less often used alone in extensive skin 
diseases, but are usually prescribed in these as the basis of ointments 
in which other remedies are incorporated. There is no question that 
the protection afforded to the part and the exclusion of the air by 
the oily emollient plays an important part in the action of these reme- 
dies, and it seems probable that in many cases equally good results 
would follow the application of the emollient without any active 
ingredient. 

The emollient ointments are also applied to wounds and mucous 
membranes as protectives and also as vehicles for other remedies. 
Here they have a more lasting effect than watery applications, which 
are more readily absorbed. Emollients are seldom applied to the 
mouth because of their unpleasant oily taste, but the eye, nose, 
urethra, vagina and rectum are often treated with them. 

Preparations. 

Adeps (U. S. P., B. P.), lard; the prepared internal fat of the abdomen 
of the pig, purified by washing in water, melting and straining. 

Adeps Benzoinatus (U. S. P.), Adeps Benzoatus (B. P.), benzoinated lard, 
is prepared from lard by the addition of benzoin, which is slightly antiseptic 
and preserves it from becoming rancid. 

Unguentum (U. S. P.), ointment, is a mixture of lard and yellow wax, and 
is the basis of many other ointments. 

Unguentum Diachylon (U. S. P.) is formed from lead plaster and olive oil, 
perfumed with oil of lavender. The lead is inert, the action being identical 
with that of ordinary ointment. 

Lard contains the ordinary constituents of animal fats, stearin, palm i tin, 
and olein and is seldom used alone, but forms the basis of numerous ointments. 

Adeps Lan» Hydrosus (U. S. P., B. P.), hydrous wool-fat, lanolin, the puri- 
fied fat of sheep-wool, mixed with not more than 30 per cent, of water. 

Adeps Lanx (U. S. P., B. P.), wool-fat without water. 

Unguentum Lanm Compositum (B. P.), containing lard, wool-fat and paraffins. 

Lanolin has been used extensively in medicine only in the last few years. 
It consists of cholesterin esters with some impurities, does not become rancid, 
and differs from the older fats also in being miscible in twice its weight of water 
without losing its ointment consistency. Lanolin is very often used as an 
emollient application, as well as to form a basis for more active drugs. The 
unhydrated wool fat is too sticky to be satisfactory. The hydrated form 



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48 SUBSTANCES ACTING LOCALLY 

is generally too hard to be used as an ointment and is therefore diluted with soft 
paraffin (3 parts) or olive oil (equal parts). 

Petrolates or Paraffins. When the more volatile constituents of petroleum 
are distilled off, there remains a number of higher hydrocarbons, chiefly of 
the marsh gas series, which are used in medicine as emollients. The lower 
of these hydrocarbons are fluid at ordinary temperatures and are known as 

Petrolatum Liquidum (U. S. P.), Paraffinum Liquidum (B. P.), a colorless, 
oily transparent liquid without odor or taste. When these are removed there 
remains 

Petrolatum (U. S. P.) and Petrolatum album (U. S. P.), Paraffinum 
molle (B. P.), soft petrolate, vaselin, which has the consisteney of an oint- 
ment, is yellow or white in color, and is liquefied a few degrees above the tem- 
perature of the blood. When the distillation is carried further, the residue 
is solid at ordinary temperatures, and is known as 

Paraffinum (U. S. P.), Paraffinum Durum (B. P.), or hard paraffin, which 
melts at a somewhat higher temperature than vaselin. 

Soft petrolate is more extensively used than the others as an emollient and 
as a basis for ointments, and has the advantage over the older lard that it 
does not become rancid; as a general rule it is too soft but may be made of the 
proper consistency by the addition of lanolin or of starch or zinc oxide (equal 
parts); or the Unguentum Paraffini (B. P.), containing hard and soft paraffin 
and beeswax, may be employed. Liquid petrolate has been used to dissolve 
irritant substances for subcutaneous injection, as less pain is caused than when 
water is used. 

Several Oils are also used as emollients. 

Oleum Olivw (U. S. P., B. P.), olive oil, a fixed oil obtained from the ripe fruit 
of the olive, Olea europsea. 

Oleum Amygdalce Expressum (U. S. P.), Oleum Amygdala (B. P.), a fixed 
oil expressed from bitter or sweet almonds. It is to be distinguished from the 
volatile oil obtained from the bitter almonds. The fixed oil contains no prussic 
acid. 

Unguentum Aqu.e Rosje (U. S. P., B. P.), cold cream, is formed of white 
wax, oil of almonds, and some borax, scented with rose water. 

Oleum Gossypii Seminis (U. S. P.), Cotton-seed oil. 

These all resemble each other in their composition, and may be used as 
emollients. Olive oil is generally preferred to the others, but is much more 
expensive, and it is probable that much of the so-called olive oil is really puri- 
fied cotton-seed oil. Olive oil has been advised as a cholagogue, but has been 
shown by more exact methods of research to have no effect whatever on the 
secretion of the bile. It sometimes gives relief in biliary colic and dysentery 
and in some gastric disorders accompanied by pyloric spasm, probably from 
its acting as a protective to the mucous membrane of the stomach and duo- 
denum and lessening the acid gastric secretion. A wineglassful is given two or 
three times a day before meals; in these large doses it possesses a high food value. 

Cera Flava (U. S. P., B. P.), yellow wax. Cera Alba, white wax. 

Cetaceum (U. S. P., B. P.), spermaceti, obtained from the cachelot (Phys- 
eter macrocephalus), one of the whales. 

Sevum Praeparatum (U. S. P., B. P.), mutton suet, is obtained from the 
abdominal fat of the sheep and is of much harder consistency than lard. 

These preparations are not used alone, but are often added to the emollients 
and ointments in order to give them a firmer consistency, which is especially 
desirable in hot climates and in summer. 

Ceratum (U. S. P.), a mixture of 3 parts of wax with 7 of lard. 

Glycerinum (U. S. P., B. P.), glycerin, a liquid obtained by the decom- 
position of animal or vegetable fats or fixed oils, and containing not less than 
95 per cent, of absolute glycerin, C 3 H6(OH)s; clear, colorless, of a syrupy 
consistence, oily to the touch, with a sweet taste and no odor, soluble in water 
and alcohol. 



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SUGARS AND FLAVORING SUBSTANCES 49 

Glycerin is used as a solvent for a number of other drugs, the preparations 
being known as glycerites (U. S. P.), glycerines (B. P.). 

Glycerin is somewhat irritant to the unbroken skin, when it is applied in 
the pure form, and even diluted glycerin causes pain and smarting when it is 
apphed to unprotected surfaces such as cuts or burns, but the pain soon dis- 
appears, and glycerin then acts as a protective. The irritation is due to the 
glycerin abstracting the fluids of the tissues owing to its avidity for water. 
Glycerin and its preparations are used very extensively as applications to slight 
wounds, in irritation of the skin and lips from exposure to cold, and in similar 
conditions. They are often apphed to hard, dry crusts on the skin in order 
to soften them and permit of their removal. 

Along with the emollients, or oily protectives, may be mentioned 
another class of mechanical agents, the Dusting Powders. Any dry, 
insoluble, fine powder applied to irritated surfaces of the skin, or 
slight abrasions, will protect these from the air, and from contact with 
the clothes and other sources of pressure. These powders, at the 
same time, soak up any secretions, and render the injured spot less 
liable to bacterial infection, as they form a more or less impermeable 
crust. Powders used for this purpose should not be absorbed, or, if 
absorbable, should not induce any toxic effects. Those most commonly 
employed are the phosphate and carbonate of lime, talc (Talcum, 
Talcum Purificatum, U. S. P.) (magnesium silicate), Fullers' earth and 
kaolin (aluminum silicates), starch, and Lycopodium (U. S. P.), which 
consists of the spores of Lycopodium clavatum (club moss). 

A large number of powders are used as surgical dressings, most of 
them being credited with more or less antiseptic power. In many 
instances, however, their antiseptic action is so slight that it would 
appear that most of their virtues are due to their mechanical pro- 
perties, and not to their bactericidal action. 



m. SUGARS AND FLAVORING SUBSTANCES. 

Sugars are used in medicine chiefly to disguise preparations of 
unpleasant taste, and in the small quantities usually employed have 
little further effect. In large quantities sugars, like other diffusible 
bodies, act as irritants to the stomach and bowel, and comparatively 
small quantities of some sugar substances possess an aperient action; 
this seems to be due to their colloid form, as pure sugar has no such 
effect, and it is possible that they merely delay the absorption of fluid, 
and thus cause softer evacuations than would otherwise occur. 

Preparations. 

Saccharum (U. S. P.), Saccharum Purificatum (B. P.), sugar. 

Strupus (U. S. P., B. P.), a concentrated solution of sugar. Syrup is the 
basis of a large number of medicated syrups of the pharmacopoeias. Sugar 
and syrup are used exclusively to sweeten mixtures and to aid in the suspen- 
sion of insoluble bodies. In place of ordinary syrup many of the flavored 
preparations may be used, such as the syrups of citric acid, acacia, almonds, 
or of the volatile oil group. 
4 

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50 SUBSTANCES ACTING LOCALLY 

Saccharum Lactis (U. S. P., B. P.), sugar of milk, lactose, is not so sweet 
as ordinary sugar, and is much less liable to deliquesce, so that it is used largely 
to give bulk to powders. It has been said to have diuretic properties when 
given with large quantities of water, and to cause purgation when given in 
a more concentrated solution. Asses' milk contains more lactose than cows' 
milk, and has been recommended for its slight aperient action in chronic con- 
stipation. 

Maltum (U. S. P.), malt, barley grain partially germinated and then dried. 

Mel, honey, and Mel Depuratum (U. S. P., B. P.), or clarified honey, are 
used to give taste to mixtures, and have a very slight aperient action, so that 
they may be advised as articles of diet in habitual constipation. Some medi- 
cated honeys are used, of which Mel Roses is included in the U. S. P., Mel Bor- 
acts in the B. P. 

Syrupus Glucosi (B. P.), a mixture of liquid glucose and syrup. 

A number of saccharine preparations with a slight aperient effect are in- 
gredients of the preparations of the more powerful purgatives. Thus manna 
{Manna U. S. P.) obtained from the flowering ash, is contained in the Infusum 
Sennse Co. U. S. P., and purging Cassia {Cassia Pulpa, B. P.), tamarinds {Tarn- 
arindus, B. P.), figs and prunes form constituents of the confection of Senna 
and other preparations. They are not prescribed alone, but the fruits may be 
advised as articles of diet where a mild laxative is required. The tamarind 
pulp may owe its aperient action in part to the presence of tartrates, citrates, 
malates, and other cathartic salts. (See Saline Cathartics.) 

Frequently other flavors are preferred to sugar, which is especially 
disliked in fever cases, as sweet fluids do not quench the thirst so 
effectually as acids and bitters. Many of the preparations of the 
volatile oils and some of the demulcents are used almost exclusively 
as flavoring agents, and in some both sugar and volatile oil are com- 
bined, as in the syrups. 

Instead of sugar some artificial compounds have been introduced of 
late years. Glusidum (B.P.), Benzosulphinidum (U.S.P.), or Saccharin, 

C 6 H 4 ^gQ^NH, and its sodium salt, C 6 H 4 (^gQ ^)NNa, or soluble 

saccharin are the best known of these. Saccharin is a light, white, 
crystalline powder, soluble in 400 parts of water and in 25 parts of 
alcohol. It is about 500 times as sweet as sugar, and gives a distinct 
flavor to 70,000 times its weight of water. It does not taste exactly 
like sugar, however, there being a distinct flavor besides that of sweet- 
ness, and patients generally object to it after a short time. It has 
been used as a substitute for sugar in diabetes, a disease in which 
sugar is to be avoided as far as possible. Some writers state that in 
the presence of saccharin the digestive ferments act more slowly than 
usual, but the retardation is only trifling and does not preclude the 
use of saccharin in the small quantities necessary to sweeten the food. 
Even very large doses of saccharin may be injected intravenously in 
animals without other effect than some depression and stupor. 

Some pharmacopoeial preparations are designed to give color to solutions, 
but are seldom or never prescribed, although they are sometimes added by 
the pharmacist. 

Among these are cochineal (Coccus, U. S. P., B. P., Tinctura Cocci, B. P.) 
and saffron. 



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SIMPLE BITTERS 51 



I?. SIMPLE BITTERS. 

This group includes a number of substances which have little in 
common except their bitter taste and their comparative inactivity in 
the body. Several alkaloids may be placed in it, Berberine, Biurine, 
Menispermine and Canadine, for, although these are poisonous in very 
large quantities, they are harmless in those in which they are con- 
tained in the preparations used in therapeutics. In addition to these 
there may be placed in it numerous neutral bodies, possessing an 
intensely bitter taste, but with little or no further action, such as the 
Quassiins, Columbin and a few weak acids and glucosides. 

Pharmacological Action. — These substances, or rather the preparations 
containing them, are largely used in therapeutics in order to increase 
the appetite, and their administration is often followed by a distinct 
improvement in the digestion and an increase in weight. 

Alimentary Tract. — These effects are explained by the action of bitter 
substances in increasing the secretion of gastric juice, which has been 
shown to occur in man and animals by a number of experiments. 
This is not, however, through the bitters acting on the gastric mucous 
membrane directly, for when they are applied through a gastric 
fistula, they have no specific action on the secretion. Pawlow has 
shown that the chief factor that determines the activity of the gastric 
secretion is the odor and taste of food; thus in dogs with oesophageal 
fistulae, in which the food swallowed does not pass into the stomach 
but escapes through a wound in the oesophagus, the taste and odor 
of food cause a profuse secretion of gastric juice (psychical secretion). 
Bitters given shortly before augment this reflex, and the same effect 
is seen when the mouth is merely rinsed with bitter solution. The 
action of the bitters is therefore to increase the psychical secretion of 
gastric juice, possibly because of the contrast offered by the bitter and 
the pleasant tastes. The inference may be drawn that the therapeutic 
effects are best elicited when the bitters are given shortly before a 
meal, and this accords with universal experience. And the use of 
the bitters is attended with benefit only in cases in which the gastric 
juice is deficient. The increase of the gastric juice is followed as 
usual by a more active secretion by the pancreas. In addition, it is 
to be remembered that the improvement is largely subjective, and that 
the bitters are capable of producing a considerable impression upon 
patients, so that the effects may be due in part to suggestion and not 
to any real action of the drug. 

In comparison with their effects on secretion, the other changes induced 
in the alimentary tract by the bitters are insignificant. They have little or 
no effect on the activity of the ferments in themselves, but the tannin and 
colloids of the usual preparations may retard their action. And they do not 
affect the growth of bacteria or yeasts. Absorption from the alimentary tract 
and the movements of the stomach and bowel are not altered by their presence. 
The salivary secretion is generally augmented by bitter tastes, and some increase 
in the leucocytes and red cells of the blood is said to occur after their use. 



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52 SUBSTANCES ACTING LOCALLY 

In very large quantities some of the bitters produce effects that are obviously 
due to their absorption, but these play no part in their therapeutic effects and 
have seldom or never been elicited in man. 

Preparations. 

Gentiana (U. S. P.), Gentian® Radix (B. P.), gentian, the root of Genti- 
ana lutea, contains a glucoside, gentiopicrin, and a trace of tannic acid. 1 G. 
(15 grs.). 

Extractum Gentians (U. S. P., B. P.). 0.25 G. (4 grs.). B. P., 2-8 grs. 

Fluidextractum Gentiana (U. S. P.). 1.0 c.c. (15 mins.). 

Tinctura Gentians Composita (U. S. P., B. P.), containing gentian, bitter 
orange peel, and cardamom, 4 c.c. (1 fl. dr.) (J-l fl. dr. B. P.). 

Infusum Gentiance Compositum (B. P.), containing gentian, bitter orange 
peel, and fresh lemon peel, J-l fl. oz. 

Quassia (U. S. P.), Quassia Lignum (B. P.), the wood of Picraena excelsa, 
contains several neutral bitter substances, resembling each other closely chem- 
ically and known as quassiins. 

Extractum Quassle (U. S. P.), 0.065 G. (1 gr.). 

Tinctura Quassle (U. S. P., B. P.), 2 c.c. (30 mins.) (B. P., J-l fl. dr.) 

Infusum Quassle (B. P.), J-l fl. oz. 

Calumba (U. S. P.), Calumb® Radix (B. P.), columbo, the root of Jateor- 
rhiza palmata, or Columba, contains columbin, a neutral body, columbic acid, 
and three alkaloids, columbamine, jateorrhizine, and palmitine closely resemb- 
line berberine. 

Tinctura CALUMBiB (U. S. P., B. P.), 4 c.c. (1 fl. dr.). (i-1 fl. dr. B. P.). 

Infusum Calumbce (B. P.), i-1 fl. oz. 

Chirata (B. P.), Chiretta, the plant Swertia chirata, contains a glucoside, 
chiratin, and ophelic acid. 

Tinctura Chiratas (B. P.), i-1 fl. dr. 

Infusum Chiratce (B. P.), J-l fl. oz. 

Many other remedies have been used in medicine, which owe their reputa- 
tions to their bitterness only. As a general rule they have been introduced as 
possessing specific properties in some such disease as gastric cancer, but have 
failed to maintain their promise and gradually are recognized to be in no way 
superior to gentian and other established bitters. Their use as bitters often forms 
a prelude to their complete abandonment. Among these unnecessary bitter 
drugs may be mentioned Taraxacum, the root of the dandelion; Berberis, the 
rhizome and roots of the barberry, containing the alkaloid berberine; Pareira, 
the root of Chondrodendron tomentosum, containing two alkaloids, bebeerine and 
chondrodine; Serpentaria, snakeroot, the rhizome and roots of two species of 
Aristolochia, containing an unknown bitter principle and an alkaloid, aristolo- 
chine, and Humulus, hops with its preparation Lupulin, a glandular powder 
which contains a bitter neutral principle, an acid and resins. These still receive 
recognition in the pharmacopoeias, if not in practical therapeutics. Others, 
which have reached a further stage on the path to oblivion, but which are 
still heard of occasionally are Cusparia (Angostura bark), Nectandrce Cortex 
(Bebeeru bark), Condurango (Marsdenia Condurango) and Coto. 

Instead of the simple bitters, cinchona and nux vomica preparations 
are often used in small quantities. Many of the preparations which 
will be enumerated under the volatile oil series owe much of their 
effect to the bitter which accompanies the volatile oil, and in numerous 
other pharmaeopoeial preparations bitters are present, although their 
effect is hidden by the action of the drug in other directions. 

Therapeutic Uses. — The bitters are used chiefly to increase the appe- 
tite and the digestion. In convalescents, in persons of sedentary 



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SIMPLE BITTERS 53 

habits, and occasionally in chronic dyspeptic conditions they are of 
value, while in cases of more acute gastric irritability and in hyper- 
acidity they may do harm rather than good. Gentian, Quassia, 
Calumba and Chirata are the only simple bitters that are largely 
used, and the first is much the most important. They are generally 
prescribed as tinctures, fluid extracts or other fluid preparations. 
The last three may be prescribed with iron preparations, as they contain 
little or no tannic acid and thus cause no precipitate. Pills are some- 
times prescribed with extract of gentian or quassia, but it seems open 
to question whether these ingredients have really any effect when 
given in this form, as the bitter taste, on which their action depends, 
is largely concealed. Compound tincture of gentian is sometimes used 
to give flavor rather than for any effect on the digestion. 

Quassia infusion (10 per cent.) is injected as an enema in the round 
worms of children. 

Several of the drugs mentioned, such as taraxacum and gentian, have been 
supposed to have a specific action on the liver, but there are no sufficient 
grounds for this belief. The supposed virtues of pareira as a diuretic and 
of berberine, buxine, and other alkaloids as substitutes for quinine in ma- 
laria have also proved to have no foundation, and the popular reputation of 
hops as a narcotic probably arises from its association with alcohol in beer. 
Cotoin and Goto bark are said to have some special effect in lessening diar- 
rhoea, in addition to their action as bitters. 

Bibliography. 

Gottlieb. Arch. f. exp. Path., xxxiii, p. 261. 

Rieder. Ibid., lxiii, p. 303. 

Scanzoni. Ztschr. f. Biol., xxxiii, p. 462. 

Jodlbauer. Arch, internat. d. Pharmacodyn., x, p. 201. 

Pawiow u. Schumowa-Simanowskaja. Arch. f. (Anat. u.) Phys., 1895, p. 53. 

Brnz. Virchow's Archiv, xlvi, p. 129. 

Juhna. Arb. des pharmak. Ins tit. Dorpat, iv. p. 81. (Condurango.) 

PohL Arch. f. exp. Path. u. Pharm., xxix, p. 282 (Aristolochine.) 

Parkas. Pfluger's Archiv, xcii, p. 61. (Lupulinic acid.) 

K. v. Bunge. Arb. des pharmak. Institut. Dorpat, xi, xii, p. 135. (Berberine.) 

Mosse u. TauU. Ztschr. f. klin. Med., xliii, p. 257. 

Ramm. Historische Studien a. d. pharmak. Instit. Dorpat, ii, p. 1. 

Borissow. Arch. f. exp. Path. u. Pharm., Ii, p. 363. 

Karb, Deut. Arch. f. klin. Med., lxxvi, p. 30. (Goto.) 

Reichmann. Ztschr. f. klin. Med., xiv, p. 177. 

Robert International Congress, Berlin, 1890, iv, p. 58. (Cetrarin.) 

Biberfeld. Ztschr. f. exp. Path. u. Pharm., vii, p. 569. (Calumba.) 



Pepper Group. 

The pepper group comprises a few drugs which are used for their 
effect on digestion but which have a much more pungent taste than 
the bitters, and cause marked irritation when they are applied in large 
doses. They thus stand midway between the simple bitters and 
the carminative volatile oils, and are sometimes known as aromatic 
stomachics. 



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54 SUBSTANCES ACTING LOCALLY 

Black Pepper contains a weakly basic substance, Piperine (which is broken 
up by caustic alkalies into Piperidine and Piperinic acid), in addition to a 
volatile oil and a bitter pungent resin. Piperine is insoluble in water, and has 
therefore no taste when absolutely pure, but is hot and pungent to the taste 
when it is taken in solution. 

Pyrethrum, or pellitory, contains similar constituents but is scarcely used 
except as an ingredient of insect powders. 

Capsicum, or Cayenne pepper, contains Capsaicin, a neutral body with a hot 
pungent taste. 

Many other plants contain irritant principles which have been employed as 
stomachics. Thus the use of mustard as a condiment depends on its forming 
irritant sulphur compounds, but mustard is used in medicine only as a skin 
irritant and will be discussed under that heading. 

The horseradish (Armoracia, B. P.) and the formerly official scurvy-grass 
(Cochlearia officinalis) resemble mustard, and owe their activity to their 
containing similar or identical sulphur compounds. 

Pepper and capsicum are largely used as condiments, and are compara- 
tively seldom prescribed in therapeutics. Both are used in domestic medi- 
cine as. skin irritants, and capsicum is prescribed where a strong stomachic 
irritant is required. The tincture has been employed in chronic alcoholism 
in order to provide a substitute for the local irritant effects of spirits in the 
stomach. 

Preparations. 

Piper (U. S. P.), black pepper, the unripe fruit of Piper Nigrum. 

Oleoresina Piperis (U. S. P.), 0.03 G. (J gr.). 

Pyrethrum (U. S. P.), pellitory, the root of Anacyclus Pyrethrum. 

Capsicum, Cayenne pepper, chillies, the fruit of Capsicum fastigiatum 
(U. S. P.); Capsici Fructus, the dried fruit of Capsicum minimum (B. P.). 

Tinctura Capsici (U. S. P., B. P.), 0.5 c.c. (8 mins.), (5-15 mins., B. P.). 

Oleoresina Capsici (U. S. P.), 0.03 G. (J gr.). 

Fluidextractum Capsici (U. S. P.), 0.05 c.c. (1 min.). 

Armoraciffi Radix (B. P.), horseradish root, the fresh root of Cochlearia 
Armoracia. 

Piper Methisticum, or Kava Kava, is used in the South Sea Islands to pre- 
pare an intoxicating liquor, which according to Kesteven, differs from the 
alcoholic preparations in producing marked muscular weakness without affect- 
ing the mental powers. Other observers state, however, that it causes confusion 
and sleep very much as alcohol does. Its local action resembles that of pepper, 
and like it, it has been advised in gonorrhoea. Its virtues seem to reside in two 
resinous bodies. 

Bibliography. 

Buchheim. Arch. f. exp. Path. u. Pharm., v, p. 465. 

Jungst. Ibid., xxiv, p. 315. 

Hogyes, Ibid., ix, p. 117. 

Kesteven. Practitioner, xxviii, p. 199. 

Lewin. Berlin, klin. Woch., 1886, p. 7. 

Cerna. Therapeut. Gazette, 1891, p. 7. 



V. DIGESTIVE FERMENTS. 

A number of digestive ferments have been introduced into thera- 
peutics for the treatment of gastric and intestinal disorders. The 
earlier members of the series were proteolytic ferments, intended to 
reinforce the pepsin of the stomach, but of recent years the amylolytic 
ferments have also been strongly advocated. 



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DIGESTIVE FEkMENTS 55 

1. Pepsin. 

The pharmacopoeial preparations of pepsin are generally obtained 
from the pig's stomach. It digests only in acid solution, the best 
results being obtained in a solution of 0.2 per cent, of hydrochloric 
acid. In alkaline solution it is inert, and in fact is rapidly decomposed, 
so that when pepsin and alkaline carbonates or bicarbonates are 
prescribed together, the effects are due to the alkalies only. 

Pepsin is used in therapeutics on the theory that the stomach does 
not secrete enough of the ferment in certain conditions. But it may 
be questioned whether this is true in even a small proportion of the 
cases treated with pepsin, for the gastric juice is almost always capable 
of digesting proteins if it is acid in reaction. In a number of forms of 
dyspepsia the acid secretion is insufficient, but the ferment is almost 
always present in quantity, for it digests proteins outside the body 
as soon as it is acidulated. Pepsin is indicated then only in the rare 
cases in which the contents of the stomach acidulated with hydro- 
chloric acid fail to digest proteins. It is very often administered in 
other forms of dyspepsia, and certainly does no harm, but there is no 
question that it is entirely unnecessary in the great majority of the cases 
in which it is prescribed. 

Preparations. 

Pepsinum (U. S. P., B. P.), a proteolytic ferment obtained from the gland- 
ular layer of fresh stomachs from healthy pigs, and capable of digesting not 
less than 3,000 times its own weight of freshly coagulated egg albumin. 1 It 
is a fine, white, amorphous powder or thin scales, free from offensive odor 
and having a mildly acid or saline taste, usually followed by a suggestion of 
bitterness. 0.25 G. (4 grs.), (B. P. 5-10 grs.), in powder, or in solution in 
0.2 per cent, hydrochloric acid. 

Pepsin is generally given during or after meals. As has been stated, it is very 
rarely indicated, as the gastric juice almost always contains sufficient ferment. 

Glycerinum Pepxini (B. P.) contains hydrochloric acid. A fluid drachm 
represents 5 grs. of pepsin. 1-2 fl. drs. 

Many other preparations of pepsin are used in popular medicine, to a less 
extent by the profession. Pepsm wines, for example, are often taken as tonics 
and digestives, but have only the effects of alcoholic beverages. 

2. Pancreatic Ferments. 

The pancreatic ferments have also been introduced into thera- 
peutics, generally in the form of an extract of the gland, pancreatin. 
These ferments differ from pepsin in acting only in alkaline or neutral 
solution, and besides digesting proteins, form sugar from starch and 
saponify and emulsify fats. The pancreatic ferments are rendered 
inert by a comparatively short exposure to the acid gastric juice. 

The value of pancreatin is even more problematical than that of 
pepsin, for though it would no doubt be valuable where the digestive 
ferments, particularly those of the pancreas, were deficient, this has 

i The B. P. preparation may be obtained from the pig, sheep or calf and is required 
to digest 2500 time* its weight of hard-boiled white of egg. 

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56 SUBSTANCES ACTING LOCALLY 

not been shown to occur. On the other hand, the pancreatic ferments 
are certainly destroyed in passing through the stomach. It has been 
suggested, however, that they may act in the stomach, if they are 
given before or with the food, as the acid gastric juice is only secreted 
slowly, and some time must elapse before the pancreatin is rendered 
inert. Attempts have been made to preserve the pancreatin from the 
deleterious effects of the gastric juice by administering it in capsules 
which are dissolved only in the intestine. It is certainly possible that 
the pancreatin may be useful in certain cases, where the ferments of 
the pancreas are absent and the acid of the stomach so deficient as 
not to be destructive, but there is no reason to suppose that this series 
of accidents occurs at all frequently, and it is impossible to diagnose 
inefficiency of the pancreatic secretion. Pancreatin is now used chiefly 
to digest the food before it is taken, about 5 grains sufficing for a pint 
of milk. It has been applied to cancerous tumors in the hope of 
destroying the malignant tissue, but has not proved of value. 

Preparations. 

Pancreatinum (U. S. P.), a mixture of the enzymes naturally existing in 
the pancreas of warm-blooded animals, usually obtained from the fresh pan- 
creas of the pig. It forms a yellowish, yellowish-white, or grayish, amorphous 
powder, having a faint, not disagreeable odor and a meat-like taste, and is 
slowly soluble in water. 0.5 G. (8 grs.), in powder or in capsules. Keratin 
capsules have been proposed in order to protect the pancreatin from the gastric 
juice. 

Liquor Pancreatis (B. P.), a liquid preparation containing the digestive 
principles of the fresh pancreas of the pig. Two cubic centimeters of the 
solution ought to digest 80 c.c. of milk. 

In connection with the digestive ferments may be mentioned ingluvin, an 
extract of the fowl's gizzard, which was a few years ago highly recommended 
as a remedy in the sickness of pregnancy, but has proved entirely valueless. 

3. Vegetable Ferments. 

Besides these animal digestive ferments, a number of vegetable proteolytic 
enzymes are known, and have enjoyed a more or less short-lived popularity. 
Probably many more plant juices are able to digest proteins than are at present 
generally recognized; thus many of the bacteria liquefy gelatin and albumin, 
and the insectivorous plants, such as Drosera (sundew) and Dionea, secrete 
a digestive fluid. Figs, pine-apple (bromelin) , the scarlet pimpernal (Anagellis 
arvensis), and many others of the higher plants have been shown to possess 
these ferments, but the best known of these is the Carica papaya, or pawpaw, 
which contains a digestive ferment known as papain, papayotin, or papoid. 
The ferment acts in neutral, slightly acid, or alkaline solution at the temperature 
of the body and in the cold. It has been used instead of pancreatin and pepsin 
in disorders of the digestion, and also as an anthelmintic. Diphtheritic mem- 
branes have been .treated by the frequent application of papain solution; the 
underlying disease was not favorably influenced, however, and the treatment 
has been abandoned. Papain solution has also been injected by the hypo- 
dermic needle into tumors and abscesses, with the intention of digesting the 
new growth, or accelerating the progress of the abscess toward the surface, but 
the results obtained do not encourage its further use. Peptones are unques- 
tionably formed in the tumors when papain is injected. 

Several milk-curdling ferments have been found in plants, but none of them 
have been used in therapeutics. 



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VOLATILE OIL SERIES 57 



4. Diastase. 



Several amylolytic or sugar-forming ferments have been used more 
or less in therapeutics, the first of these being the diastase or enzyme 
of malty which is known under the names of malt extract, maltzyme, 
maltine, etc. When grain is allowed to germinate, its starch is formed 
into a soluble form (sugar) by means of a ferment known as diastase, 
and it was supposed that this diastase might aid the digestion of starchy 
foods in the body. When malt extract is formed at a low temperature, 
it unquestionably contains diastase and is capable of digesting starch, 
but many of the extracts on the market are quite inert, the ferment 
having been destroyed by heat. Those extracts are therefore devoid 
of digestive power, but form a pleasant, easily digested food. They 
often contain alcohol, and are then indistinguishable from beer or stout. 
More recently, some other sugar-forming ferments have been brought 
forward, notably Taka-diastase obtained from Eurotium oryzae, a 
mould of the aspergillus family; it has been recommended in cases in 
which there is supposed to be a deficient digestion of starch. It ceases 
to act in the gastric juice as soon as the acidity exceeds 0.1 per cent.,, 
but may be able to digest a certain amount of starch in the mouth and 
stomach before it is destroyed. The question at once arises, however, 
whether the ordinary digestive juices are ever unable to digest the 
starch of the food. And although a new term, " amylaceous dyspepsia," 
has been introduced to indicate this class of cases, if they should be 
found to exist, it must be admitted that no satisfactory evidence of their 
existence has been brought forward as yet. It is stated that more starch 
is found to be digested in the stomach after the administration of diastase, 
but this seems to be beside the point, for it merely indicates that less 
starch reaches the intestine for the pancreatic juice to act upon. Until 
it is shown that in some cases the digestion of starch by the intestinal 
ferments is insufficiently performed, the diastase preparations would 
seem to be superfluous. 

VI. VOLATILE OIL SERIES. 

The group of volatile, ethereal, or essential oils contains a large 
number of preparations in the pharmacopoeias of all countries. These 
oils are obtained from plants by distillation, or more rarely by pressure, 
and must be distinguished by the student from the fatty or fixed oils, 
which are non-volatile. The volatile or ethereal oils are found chiefly 
in the fruits and flowering parts of plants, and are very widely diffused 
through the vegetable kingdom, though some orders, such as the 
Labiate, Umbelliferse, Aurantiaceee, Cruciferae, and Coniferse, are pre- 
eminent in their production. They are all strongly odorous, and are 
therefore used in perfumery, and to conceal nauseous odors and tastes 
in medicine. 

Their composition is extremely variable. The commonest constituents are 
Terpenes, and some oils contain these only, while in a few oils no terpene has 



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58 SUBSTANCES ACTING LOCALLY 

been found (Attar of Roses). Terpenes are hydrocarbons of the aromatic 
series, and possess the general formula (C*H 8 )n. The great majority of them, 
or the terpenes proper (Ci Hi 6 ), are combinations of a dihydrobenzol with 
propyl and methyl (C 6 H4(H2)CaH 7 CHa). Some twelve terpenes of this for- 
mula are known, varying in their chemical structure and in their stereometrical 
form. Another group of these hydrocarbons is formed by the Sesquiterpenes 
(Ci*H 2 4), while a few Diterpenes (C*oH M ) are known. Some volatile oils consist 
of these hydrocarbons only, but most of them contain in addition some oxidized 
aromatic substances, such as phenols, ketones, aldehydes, acids, and their 
compounds; as instances of these may be cited camphor, thujon (from oil of 
absinthe), sabinol (oil of savine), safrol, thymol, eucalyptol, myristicin and 
vanillin. Many of these oxidized products crystallize out when the volatile 
oil is cooled sufficiently, and especially on long standing, and the resulting solid 
is known as a Stearoptene, while the fluid remaining is sometimes called Ekeop~ 
tene. The oils containing oxygen are not so volatile as the pure hydrocarbons, 
but the odor is often due chiefly to the oxidized substances. A very few oils 
contain nitrogenous bodies, generally in the form of cyanides, while, on the other 
hand, the majority of the volatile oils of the Cruciferse contain sulphur bodies, 
which lend them a pungent disagreeable odor, quite different from that of the 
other oils. 

The volatile oils are generally clear, colorless fluids, although some 
of them are green or blue in color. After long keeping they often 
acquire a yellowish color and an acid reaction, from the formation of 
resins. They are generally light, sparkling fluids, but the oils of copaiba 
and cubebs are more viscid. They are insoluble in water except in very 
small amount, which, however, is enough to lend their characteristic 
odor to the solution; in strong alcohol, ether, benzol, chloroform, and 
fixed oils, they are freely soluble. 

Many of the plants from which the volatile oils are obtained possess 
other active constituents, such as bitters, and as many of the prepara- 
tions used in therapeutics are formed, not from the distilled oils, but 
from the crude parts of plants, it must be noted that the oil is not the 
only active principle in them. 

Action Externally. — The volatile oils all possess antiseptic properties, 
which are doubtless due in part to their volatility and their solubility 
in lipoids enabling them to penetrate readily into protoplasm. Many 
of them appear to be more germicidal than carbolic acid in favorable 
circumstances, but they are generally too insoluble in water to be 
employed easily in surgery. 

Applied to the skin, they cause redness, itching and warmth, owing 
to a local dilatation of the vessels, which may be due to the penetration 
of the oil to the cutaneous arterioles or veins, or to a local reflex from 
the irritated terminations of the sensory nerves. When painted on the 
mucous membranes, such as those of the eye or nose, or on wounds, the 
volatile oils cause similar irritation, which is betrayed by redness and 
congestion, pain and smarting. 

Action on the Alimentary Canal. — Strong solutions of the oils have 
generally a hot, burning taste, and if kept in the mouth, cause redness 
and irritation of the mucous membranes, although some of them induce 
a sense of coolness at first. At the same time the organs of smell are 



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VOLATILE OIL SERIES 59 

affected by these oils, which are almost all possessed of characteristic 
odors. The irritation of the mouth leads to a reflex secretion of saliva, 
which is often very profuse. The antiseptic action of the oils is exercised 
in the mouth as elsewhere, and may have a beneficial effect in some 
conditions. 

On passing into the stomach, the oils cause the same sensation of 
warmth in that organ, and this is accompanied by a sense of well- 
being and comfort, the appetite is often increased, and any feeling of 
distention after meals is relieved. This is often attended by the eruc- 
tation of quantities of gas. Substances which produce these effects in 
the stomach are known as carminatives, and many explanations of 
their action have been offered. The antiseptic action may occasionally 
play a part in the carminative action, and possibly the secretion may be 
encouraged by the slight irritation and by the agreeable odor and taste; 
the activity of the ferments is rather retarded than augmented. The 
movements of the stomach are distinctly lessened by even small quan- 
tities of the volatile oils, and the muscle relaxes. This may relieve the 
feeling of distention and allow the escape of the contents by arresting 
spasmodic contractions of the sphincters; the action appears to be a 
direct one on the muscle of the walls. 

In the intestine the volatile oils in small quantities also lessen the 
contraction of the muscle walls and this often relieves flatulence and 
distention and lessens the spasms which cause colic. Small quantities 
are often incorporated in the preparations of the more powerful pur- 
gatives to lessen the pain and griping which these are liable to induce. 

Excretion. — Many of the terpenes are oxidized to phenols in the 
body and are then excreted in the urine, for the most part in combina- 
tion with glycuronic or sulphuric acid. Traces pass out in the expired 
air and impart an odor to the breath. The urine also contains some in 
a free form and may thus smell of the original oil or of some of its 
derivatives. Some of the constituents of the oils are oxidized to acids 
and excreted in the urine as salts. 

In the course of excretion, some of the oils cause irritation of the 
lungs and kidneys, so that some of them are employed to increase the 
bronchial secretion, while others have a distinct diuretic action. This 
irritant action is of course not confined to the tissue, but extends to 
microbial guests, so that some of the volatile oils are given internally 
almost exclusively for their antiseptic action in the urine. 

Poisoning. — The various oils differ a good deal in their activity 
while resembling each other closely in the general characters of their 
effects. All of them may produce marked irritation of the stomach 
and bowel when given in large quantities, but the oils of tansy, sage, 
and English pennyroyal are distinguished especially by the violent 
inflammation they cause, and by the frequency with which fatal poison- 
ing occurs from their use. The symptoms are those of acute gastric, 
intestinal, and often renal irritation — vomiting, purging, acute pain 
in the abdomen, blood in the stools and in the vomited matter, collapse, 
weakness of the pulse and respiration, anuria, or albumin and blood 



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60 SUBSTANCES ACTING LOCALLY 

in the urine, and convulsive attacks ending in coma and death. Great 
hyperemia of the abdominal organs, often blood in the peritoneal 
cavity, and sometimes acute inflammation of the kidney are the chief 
post-mortem appearances. The hyperemia and congestion of the 
organs of the abdomen may cause abortion in pregnancy, or increase 
the menses, and in the majority of cases of poisoning, these oils have 
been taken with the object of inducing abortion. In many instances, 
however, the drug has proved fatal without this end being achieved. 

General Action. — The small quantities of volatile oils administered in ordi- 
nary medicinal use pass through the tissues without modifying them percept- 
ibly, their only effects arising in the organs by which they are absorbed and 
excreted. In large quantities, however, some of them (the oils of wormwood, 
nutmeg, sage, savine among others) produce symptoms from a direct action on 
the central nervous system, which is first stimulated and then depressed. 

The relative importance of these two stages differs in different oils, some, 
e. g. y turpentine oil, causing only a transient excitement, followed by marked 
weakness and depression, while others, such as the oil of absinth, cause very 
marked excitement and convulsions. The activity of the oils as nervous poisons 
also varies greatly, some producing only insignificant effects on the central 
nervous system compared with those from their local action, while in others, 
such as the oil of absinth or wormwood, the symptoms from the nervous system 
predominate in cases of poisoning. As a general rule the higher divisions of the 
central axis are affected more than the lower, and epileptiform or clonic convul- 
tions may be induced (camphor), or tremors similar to those described under 
carbolic acid and presumably of similar origin (safrol and nutmeg oil). In many 
cases a combination of excitement and ataxia is observed, the animal moving 
about restlessly, but being unable to balance itself. In the later stages of 
poisoning the spontaneous movements cease, while the excitation of the lower 
centres still persists, and wild convulsive movements accompany the final arrest 
of the respiration. The respiratory centre is finally depressed, but this depres- 
sion is often preceded by stimulation, the breathing increasing both in rapidity 
and in volume. The vasomotor centre undergoes similar changes, the blood- 
pressure falling from some oils immediately, from others only after a preliminary 
increase. 

The heart does not seem to be affected by most of the volatile oils, except 
indirectly from the collapse and shock. The frog's heart perfused with Ringer's 
solution containing a volatile oil is often accelerated, but soon becomes slow and 
weak. 

Involuntary muscle suspended in Ringer's solution containing even small 
amounts of volatile oil ceases its rhythmical movements and relaxes, apparently 
from a direct action of those bodies on the muscle fibre. The same action is 
seen in the uterus suspended in this way, so that it seems unlikely that these 
oils cause any contraction of this organ directly such as would explain their use 
as abortifacients. 

Some of the constituents of the oils (pulegon, myristicin, safrol) cause fatty 
degeneration of various organs, especially of the liver and kidney, while others 
of very similar constitution have no such effect. 

Most of the oils are poisonous to the protozoa in fairly dilute solutions; as 
a general rule the movements of these organisms are accelerated by very small 
quantities of the oils. The protozoa are much more susceptible to the oils than 
the bacteria, some of which continue to live in 5 per cent, solutions. 

Although these general effects of the volatile oils have no therapeutic im- 
portance, the frequent occurrence of epilepsy and insanity in habitual absinth 
drinkers and occasional poisoning from others of the series have given them 
some practical interest. 



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VOLATILE OIL SERIES 61 

1. Volatile OOs Used as Flavoring Agents and Carminatives. 

As regards their use as flavoring agents but little need be said, one 
preparation is used by one physician, another by another, and the 
selection is largely a matter of custom and taste. The orange prepa- 
rations are probably more generally appreciated by patients than any 
others. Carminatives are used only when no marked irritation of the 
stomach or intestine is present, in cases where the gastric juice seems 
unable to cope with the food ingested, especially in persons of seden- 
tary habits. In cases of colic, flatulence and abdominal distention 
they are often of use, provided that these are not due to peritonitis 
and other inflammatory diseases. Several of them have been employed 
as surgical antiseptics, but they are more widely used as parasiticides 
for scabies, pediculi, etc. Some of the oils, such as oil of cloves, are 
used in dentistry to relieve pain, and also for their antiseptic action; 
the relief of pain is due to their paralyzing the exposed nerve ends after 
a preliminary irritation. Eucalyptus has been advised in septic con- 
ditions and in malaria but is of no value in these conditions; its chief 
constituent, eucalyptol (Ci Hi 8 O), is equally devoid of any special 
virtues to distinguish it from the other volatile oils. Volatile oil prepa- 
rations are sometimes given internally in the hope that in their excretion 
through the lungs they will exercise an antiseptic action in pulmonary 
disease, but the traces excreted in this way are quite incapable of any 
noticeable effect on microbial growth, and the tubercle bacillus, against 
which these measures are most frequently directed, appears to be 
peculiarly resistant to the action of this group of remedies. They are 
frequently inhaled with a similar object. Some of them have been used 
as anthelmintics to destroy tapeworm in the intestine, and thymol 
has recently proved very effective in destroying the intestinal parasites 
in uncinariasis (see Thymol). Externally some of them are used as 
mild skin-irritants, generally in the form of spirits. Arnica has a 
great popular reputation as a stimulating local remedy in bruises and 
sprains, although it has no specific action and is in no way preferable 
to the other members of the series. 

The volatile oils are largely used as flavors in cookery and sweet- 
making, and are important constituents of many of the popular liqueurs, 
and therefore have a certain dietetic importance. 

Preparations. 

Crude Drags. — Many of the pharmacopoeial preparations are whole plants, 
seeds, leaves, or flowers, and are never prescribed, although some of them 
are used in popular medicine in the form of infusions Or "teas." The virtues 
of these old-fashioned remedies lie perhaps more in the large draughts of warm 
water than in the traces of volatile oil which they contain, but the presence 
of the latter prevents, to some extent, the nausea produced by warm water 
alone. These infusions are used to induce perspiration in fevers or chills, 
as diuretics, or to relieve colic and griping, and generally contain about a 
tablespoonful of the herb to one or two cupfuls of water. Those most fre- 
quently used for this purpose are peppermint and spearmint leaves and tops 



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62 SUBSTANCES ACTING LOCALLY 

(Mentha Piperita and Mentha Viridis, U. S. P.); Coriander seeds (Corian- 
drum, U. S. P., Coriandri Fructus, B. P.); Chamomile flowers (Anthemis, 
U. S. P., and Matricaria, U. S. P.); Anise (Anisum, U. S. P., the fruit of Pim- 
pinella anisum) ; Elderflower and Horehound (Marrubium, U. S. P., leaves 
and tops). In different countries, however, the constituents of the herbalist 
receipes vary according to the local flora. The U. S. Pharmacopoeia recog- 
nizes a number of other crude drugs of this group, but as these are seldom 
or never prescribed, they need only be enumerated here: Rosa Gallica (red 
rose petals), Eucalyptus, Limonis Cortex (lemon peel), Aurantii Dulcis Cor- 
tex, Aurantii Amari Cortex (sweet and bitter orange peel), CaryophyUus (cloves), 
Pimenta (allspice), Cinnamomum (cinnamon), Sassafras (sassafras bark), 
Famiculum (fennel), Vanilla (vanilla), Cardamomum (cardamom), Carum 
(caraway), Myristica (nutmeg), Salvia (sage), Arnica, and Zingiber (ginger). 
The British Pharmacopoeia is less lavishly supplied with these little used crude 
drugs. It contains Coriandri Fructus (coriander seeds), Aurantii Cortex 
Recens and Siccatus (fresh and dried orange peel), Cinnamomi Cortex (cin- 
namon bark), Cardaniomi Semina (cardamom seeds), and Zingiber (ginger). 

Bitter Almonds (Amygdala Amara, U. S. P., B. P.) may be mentioned here, 
as, although they contain no volatile oil in themselves, one is formed from them 
when they are bruised in water. They contain a glucoside, amygdalin, and 
a ferment, emulsin, which, in the presence of water, decomposes the amygdalin 
into dextrose, prussic acid, and benzaldehyde. 

Amygdalin. Dextrose. Prussic acid. Benzaldehyde. 

CwHnNOu + 3H*0 - 2(C*H«Oi) + HCN + CvHeO + H2O 

The prussic acid and benzaldehyde, which are probably in combination and 
not merely mixed together, are known as the oil of bitter almonds, which is 
much more poisonous than the other volatile oils, owing to its containing 
prussic acid. Emulsin is also contained in the sweet almond, but no amyg- 
dalin, so that no prussic acid is formed when it is pounded in water. The 
fixed oil of almonds is formed from bitter and sweet almonds, but contains 
no prussic acid. Laurel leaves, and the bark of the Virginian prune, or cherry 
(Prunus Virginiana, U. S. P., Pruni Virginiana Cortex, B. P.), also contain 
amygdalin, or some nearly related substance, and emulsin, and form benzalde- 
hyde and prussic acid when rubbed up with water. The Virginian cherry 
bark has, however, a more bitter taste than the others, from the presence of a 
resin or some other unknown body. 

The Volatile Oils themselves are also represented in unnecessarily large 
numbers in the pharmacopoeias. 

U. S. P. — Oleum Mentha Piperita (oil of peppermint), 01. Mentha? Viridis 
(spearmint), 01. Gaultheria (wintergreen), 01. Lavandula Florum (lavender), 
01. Eucalypti (eucalyptus), 01. Limonis (lemon peel), 01. Aurantii Corticis 
(orange peel), Oleoresina Zingiberis (ginger), 01. Amygdala Amarm (bitter 
almonds), 01. CaryophyUi (cloves), 01. Pimenta (allspice), 01. Cari (caraway), 
01. Cinnamomi (cinnamon), 01. Coriandri (coriander), 01. Cajuputi (cajuput), 
01. Sassafras (sassafras), 01. Anisi (anise), 01. Famiculi (fennel), 01. Rosmarini 
(rosemary), 01. Hedeoma (pennyroyal), 01. Juniperi (juniper), 01. Rosce (oil, 
attar or otto of roses), 01. Betula (birch), 01. Thymi (thyme), 01. Myristicm 
(nutmeg). Dose 0.2 c.c. (3 mins.). 

B. P. — Oleum Anethi (oil of dill), 01. Anisi (anise), 01. Cajuputi (cajuput), 
01. Carui (caraway), 01. CaryophyUi (cloves), 01. Cinnamomi (cinnamon), 
01. Coriandri (coriander), 01. Eucalypti (eucalyptus), 01. Lavandula (lavender), 
01. Limonis (lemon), 01. Mentha Piperitce (peppermint), 01. Myristicm (nut- 
meg), 01. Rosmarini (rosemary). Dose $-3 mins. 

The majority of these oils resemble each other very closely in their effects 
and require no special comment. Oil of roses is so expensive that it is never 
used in medicine, especially as it has no special advantages over the others. 



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VOLATILE OIL SERIES 63 

The oils of rosemary, juniper, and savine are more irritant than the others, 
and are seldom used. The oils of wintergreen and of birch consist mainly 
of methyl-salicylate, and may be used instead of the other salicylates. Nut- 
meg and mace oils are more poisonous than the others, not from their local 
irritant action so much as from their effects after absorption. Oil of bitter 
almonds contains a very variable amount of prussic acid and therefore cannot 
be substituted for the other volatile oils, but its preparations are so dilute as 
to be devoid of all danger. 

The volatile oils themselves are comparatively little used. A single drop 
may be added to powders, pills or solutions to give a pleasant odor, and their 
presence in tooth powders renders these more or less strongly antiseptic. Oc- 
casionally they are given in cases of colic or in chill by pouring a few drops on 
a piece of sugar which is sucked. 

Spiritus are formed from many of the volatile oils by dissolving 
them in alcohol, sometimes with the addition of water and sometimes 
with some of the crude drugs, so that the preparation is really a mixture 
of tincture and spirit. The spirits or essences of the volatile oils are 
used very largely as flavoring agents in mixtures for internal use, 
and are often added to external applications to lend them odor. They 
may also be prescribed where alcohol is indicated but is distasteful to 
the patient; the spirits of the volatile oils contain nearly double the 
amount of alcohol in brandy, and have to be diluted accordingly. 
Any of them may be used as carminatives, but the spirits of pepper- 
mint, cinnamon, anise and lavender are more frequently used for 
this purpose than the others. Spirit of juniper is often given as a 
diuretic, either alone or along with other drugs. Spirit of rosemary 
is generally used externally. Many of the common perfumes are 
spirits of different volatile oils; thus eau de Cologne contains the oils 
of bergamot, lemon, rosemary, lavender and orange-flower, along with 
acetic ether and alcohol. 

The dose of the spiritus as carminatives is 2-4 c.c. (30-60 mins.) 
They are often prescribed along with other stomachics, such as mix 
vomica, cinchona, or the bitters. 

U. S. P. — Spiritus Amygdalm Amara, Spir. Anisi, Spir. Aurantii Com. 
positus (containing the oils of orange peel, lemon, coriander, and anise), Spir- 
Cinnamomi, Spir. Gaultherice, Spir. Juniperi, Spir. Juniperi Compositus (con- 
taining oils of juniper, caraway, and fennel; 8 c.c. (2 fl. drs.). Spir. Lavan- 
dula, Spiri Mentha Piperita, Spir. Mentha Viridis. 

Elixir Aromaticum and Elixir Adjuvans are preparations of the Spir. Aurantii 
Compositus, which are used exclusively as flavors. 

B. P. — Spiritus Anisi, Sp. Cajuputi, Sp. Cinnamomi, Sp. Juniperi, Sp. 
Lavandula, Sp. Mentha Piperita, Sp. Myristica, Sp. Rosmarini. 

Aquae. — The volatile oils are very insoluble in water, but when they 
are shaken in it, enough remains in the water to give it the odor and 
taste of the oil. In the process of obtaining the oils from the crude 
drugs by distillation, some oil is held by the water, and a number of 
these waters (aquae) are contained in the pharmacopoeias. They are 
used as substitutes for distilled water in making up prescriptions, the 
small quantity of volatile oil serving merely to give a pleasant odor 
and taste. 



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64 SUBSTANCES ACTING LOCALLY 

U. S. P. — Aqua Anisi, Aq. Aurantii Flor. and Aq. Aurantii Florum Fortior 
(the latter containing twice as much volatile oil as the former), Aq. Cinna- 
momi, Aq. Fanvcvli, Aq. Menth. Piperita, Aq. Menth. Viridis, Aq. Rosa, 
Aq. Rosa Fortior (the latter twice as strong as the other. 

B. P. — Aqua Anethi, Aq. Anisi, Aq. Aurantii Floris, Aq. Cinnamomi, Aq. 
Mentha Piperita, Aq. Rosa. 

Some of the preparations containing volatile oils are derived not 
from the oil itself, but from the crude drug, and therefore contain 
non-volatile substances which are generally absent from the prepara- 
tions already mentioned. As a general rule these non- volatile bodies 
are inactive, but in some cases, bitters or resins are contained in the 
preparations, and may influence their action. Thus a bitter glucoside, 
hesperidin, is found in the orange peel, and is present in the prepa- 
rations formed directly from it, while it is absent from those formed 
from the volatile oil. Ginger contains a resin of hot, burning taste, 
which increases the carminative action of the oil. Cinnamon contains 
some tannic acid, which passes over in the tincture, while a fixed oil 
is contained in cardamom. 

Among the preparations formed from the crude drugs are the 
Syrups, which are used exclusively as flavoring agents. 

U. S. P. — Syrupus Aurantii Florum, Syr. Amygdala, Syr. Aurantii, Syr. 
Rosa, Syr. Zingiberis, Syr. Pruni Virginiana. Dose, 4-16 c.c. (1-4 fl. drs.). 

B. P. — Syrupus Aromaticus (containing tincture of orange and cinnamon 
water), Syr. Aurantii, Syr. Aurantii Floris, Syr. Limonis, Syr. Piuni Virgini- 
ana, Syr. Zingiberis. Dose, 2-4 c.c. (£-1 fl. dr.). 

The Tinctures are used for the same purposes as the spirits of the 
pure oils, and in the same dose, 1-4 c.c. (15-60 mins.). 

U. S. P. — Tinct. Aurantii Amari, Tinct. Aurantii Dulcis, Tinct. Limonis 
Corticis, Tinct. Cardamomi Composita (containing cardamom, cinnamon, car- 
away), Tinct. Cinnamomi, Tinct. Lavandula Composita (oils of lavender, 
rosemary, cinnamon, cloves, nutmeg), Tinct. Vanilla, Tinct. Zingiberis. ' 

B. P. — Tinct. Aurantii, Tinct. Cardamomi Composita (containing carda- 
mom, caraway, cinnamon), Tinct. Cinnamomi, Tinct. Lavandula Composita 
(lavender, rosemary, cinnamon, nutmeg), Tinct. Limonis, Tinct. Pruni Vir- 
giniana, Tinct. Zingiberis. 

Fluid Extracts of the volatile oil series. 

U. S. P. — Fluidextractum Aurantii Amari, 1 c.c. (15 mins.). 

Fluidextractum Pruni Virginiana, 2 c.c. (30 mins.). 
- Fluidextractum Zingiberis, 1 c.c. (15 mins.). 

Fluidextractum Aromaticum, 1 c.c. (15 mins.), from aromatic powder. 

Other Preparation^ 

Pubis Aromaticus *(U. S. P.) contains cinnamon, cardamom, ginger, and 
nutmeg in powder, and is a useful carminative in doses of 1 G. (15 grs.). 

Puhis Cinnamomi Compositus (B. P.) contains cinnamon, cardamom and 
ginger, and is used as a carminative in doses of 10-60 grs. 

Pure Principles used as flavors:' 

Safrolum (U. S. P.), safrol (CeHyCsHVOOCHz), a pure principle found 
in sassafras and other volatile oils, possesses an odor like sassafras. It is a 
colorless or faintly yellow liquid, soluble in alcohol and ether. Dose, 0.3 c.c. 
(5 mins.). 



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VOLATILE OIL SERIES 65 

Vanillinum (U. S. P.), vanillin (C«H,OHOCH,COH), occurs in vanilla 
and is also made synthetically. It forms white needle crystals, slightly soluble 
in water, easily soluble in alcohol and ether, and possesses the odor and taste 
of vanilla. Dose, 0.03 G. (£ gr.). # 

Benzaldehydum (U. S. P.), benzaldehyde (C«H»COH), occurs in the oil of 
bitter almonds, and is also made artificially. It is a colorless fluid with the 
odor and taste of bitter almond oil, very slightly soluble in water, but freely 
miscible with alcohol. Dose, 0.03 c.c. (i min.). 

Eugenol (U. S. P.), a phenol (OH,OHOCH,C,H.) obtained from oil of 
cloves and other oils, and forming a colorless liquid with an odor like cloves, 
and a hot, burning taste. Dose, 0.2 c.c. (3 mins.). 

These principles are used exclusively to give flavor and color. 

BlBUOGKAPHY. 

BuchoiUz. Arch. f. exp. Path. u. Pharm., iv, p. 1. (Antiseptic action.) 

Bokorny. Arch. f. d. ges. Physiol., lxxiii, p. 555. 

Bitu, Arch. f. exp. Path. u. Pharm., v, p. 109; viii, p. 50. 

Pohl. Ibid, xxv, p. 51. 

Brandl, Scamoni, Farnsteiner. Ztschr. f. Biol., xxix, p. 277; xxxiii, pp. 462, 475. 
(Action on absorption from stomach and bowel; compare papers by Pawlaw and his 
pupils. Arch, des Scienc. biolog., ii and iii.) 

Heffter. Arch. f. exp. Path. u. Pharm., xxv, p. 342. (Safrol, etc.) 

Winiernitz. Ibid., xlv. p. 163. 

Fromm v. Hildebrandt. Ztschr. f. physiol. Chem., xxxiii, p. 579; xxxvi, p. 441. 

Lindenujnn. Arch. f. exp. Path. u. Pharm., xlii, p. 356; Ztschr. f. Biol., xxxix, p. 1. 

Culhbert HaH Eucalyptus Oils. Thesis, Sydney. 1904. 

Mattel, Arch, internat. de Pharmacodyn., 14, p. 331. 

Lapin. Inaug. Diss., Dorpat, 1893. (01. Menth. pip.) 

Schwafy. Arch. f. exp. Path., lxx, p. 71. 

Macht. Jour, of Pharm., iv, p. 547. 

Cushny. Proc Roy. Soc. Med. Therap., Section I, p. 39. (Nutmeg.) 

Dale. Ibid., II, p. 69. (Nutmeg.) 

2. Camphor. 

Some erf the volatile oils deposit crystalline substances or stearop- 
tenes after standing for some time, especially when they are exposed 
to cold. As a general rule these bodies are present in only small amount, 
and have not been investigated apart from the volatile oils, of which 
they form constituents; but a few of them have attracted attention 
in therapeutics, not only on account of their local effects, which resemble 
those elicited by the volatile oils in general, but also because of their 
action in the tissues after absorption. The chief of these is Camphor, 
which has been used in Chinese medicine for many centuries, and which 
has also played a considerable role in Western therapeutics. It is 
derived from the Cinnamomum camphora of China and Japan, and 
possesses the formula doHieO, differing from the terpenes in possessing 
a ketone ( = CO) link. 

Another body closely resembling ordinary camphor is Borneol or Borneo- 
camphor (CioHigO), which is derived from the Dryobalanops aromatica, and 
which apparently differs from ordinary camphor in containing the group 
( = CHOH) instead of ( = CO). Ngai-camphor, which is obtained from Blumea 
balsamifera, is very closely related to borneol. Another stearoptene which 
has been used in medicine apart from the volatile oils, is Menthol (C )0 HtoO), 
which is obtained from the oil of peppermint, and apparently contains a 



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66 SUBSTANCES ACTING LOCALLY 

CHOH group like boraeol, but is more completely hydrated. Borneol has 
been prepared synthetically from camphor, and menthol from menthane, 
which occurs in oil of peppermint. Thujon, an isomer of camphor occurring 
in the oil of wormwood or absinthe and in many other plants, has not been 
used in medicine, but is of great importance as the cause of epilepsy in chronic 
absinthe drinkers. 

Symptoms. — Camphor acts as an irritant to the skin and mucous 
membranes like the volatile oils, and has a hot, bitter taste, and induces 
in small quantities a feeling of warmth and comfort in the stomach, 
while after large doses nausea and vomiting may be caused by gastric 
irritation. It is rapidly absorbed and in large doses induces headache, 
a feeling of warmth, confusion, and excitement in man, with slowing 
of the pulse and flushing of the skin. This excitement may be shown in 
hilarity and delirium with hallucinations, in restlessness, or in sudden 
violent movements, which pass into epileptiform convulsions. These 
alternate with pauses of quiet and unconsciousness, which become longer 
until the patient sinks into complete stupor. In some cases of poisoning 
no excitement is observed, the patient falling into a condition of drowsi- 
ness, unconsciousness and stupor immediately. In the lower mammals, 
camphor induces very similar symptoms, wild excitement and epilepti- 
form convulsions, followed by depression, stupor, collapse, and death 
from failure of the respiration. Not infrequently, however, the respira- 
tion ceases during a convulsion and fails to return when it passes off. 

In the frog no excitement is observed except from the local irri- 
tation; the animal falls into a condition of depression, in which no 
spontaneous movements are made, although the reflexes seem to be 
little affected at first. Later, the reflexes disappear and the animal lies 
completely paralyzed. 

Action: Central Nervous System. — In the frog camphor depresses the 
brain and later the spinal cord, so that the action is a descending 
paralysis similar to that seen under chloroform and other anaesthetics; 
thujon often induces violent spasms, which appear to arise from stimula- 
tion of the spinal cord and medulla oblongata. 

The convulsions in mammals are certainly not due to any action 
on the spinal cord, but to stimulation of the higher areas of the 
nervous axis. The cerebral cortex is involved in the action, for the 
convulsions are less marked on its removal; but in the lower mammals 
the chief action seems to be exerted on the nervous centres situated 
between the cerebral peduncles and the medulla oblongata. It is not 
improbable that in man the cerebral action may be more marked than 
that on the lower areas, for on descending lower in the scale it is found 
that the cerebral action becomes less evident; thus in birds the removal 
of the cerebrum seems to have no effect on the convulsions. The loss 
of consciousness and the stupor observed in man and the higher animals 
point to a final paralysis of the cerebral cortex. Later the spinal cord 
and the medulla are paralyzed and respiration ceases; some observers 
state that the reflexes of the spinal cord are first augmented by large 
doses of camphor but others describe depression as the first result. 



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VOLATILE OIL SERIES 67 

The Terminations of the Motor Nerves are paralyzed in the frog by 
large doses of camphor, but not in mammals. The Muscles are weak- 
ened and paralyzed when they are directly exposed to its solutions or 
vapor. 

The Heart is sometimes slowed by camphor and its allies in man 
and animals, but is generally little affected in either strength or rate. 
It has been stated that the heart has less tendency to pass into fibrilla- 
tion under camphor, but this is not confirmed. Similarly, camphor 
has been credited with dilating the coronary vessels and thus promoting 
the nutrition of the heart, but according to Meyer this occurs only 
under poisonous quantities and is therefore devoid of therapeutic 
interest. In the frog camphor appears to have some stimulant action 
on the heart muscle when directly applied to it, but in mammals its 
effects on the heart in therapeutically possible amounts are trifling or 
entirely negative. 

In mammals, camphor reduces the blood-pressure, though there is 
sometimes a transient rise at first. The fall in pressure appears to be 
due to dilatation of the peripheral vessels; the pulmonary vessels 
share in this dilator action. It is not quite clear whether this action 
is exercised directly on the vessel walls or centrally, but the former is 
the more probable view. When sufficient camphor is given to cause 
convulsions, great variations in the blood-pressure occur, a very marked 
rise being observed during the convulsive attacks, while in the interval 
it falls to below the normal height; these variations appear to arise 
from a direct action on the vasomotor centre, which partakes in the 
general stimulation. The peripheral vessels have been found to be 
dilated by camphor solutions perfused through them, and this action 
may explain the slight fall in pressure often seen after absorption of 
the drug. This slight dilation of the vessels is the only change in the 
circulation observed after camphor, unless when quantities sufficient 
to cause convulsions are injected. 

The Respiration is somewhat slower and deeper than normal, but 
this alteration is generally insignificant. During the convulsions it 
is arrested, while in the intervals it may be accelerated from the 
muscular exertion during the spasms. 

The normal Temperature is not affected by camphor, but in fever 
it acts as an antipyretic, like many other aromatic bodies. 

Camphor is partially oxidized in the tissues, forming camphorol 
(CioHieOj), which is Excreted in the urine in combination with glycu- 
ronic acid, as a- and /9-camphoglycuronic acid, and also in part in 
combination with a nitrogenous body, which is probably uramidogly- 
curonic acid. Camphorol acts like camphor, but its glycuronic acid 
combinations are inactive, so that the effects of camphor pass off 
quickly in such animals as the dog, in which these combinations are 
rapidly formed. 

Camphor is possessed of some antiseptic action, although it is much 
weaker than some of the bodies of the carbolic acid group, and also 
than many of the volatile oils. Leucocytes cease their movements 



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68 SUBSTANCES ACTING LOCALLY 

at once when exposed to camphor solutions or vapor, and Darwin 
found that it acts as a stimulus to the tentacles of Drosera, an insectiv- 
orous plant, and apparently renders them more sensitive to mechanical 
irritation. 

Camphor produces redness and a feeling of warmth when rubbed 
into the Skin. Sometimes, however, a distinct sensation of cold may 
be experienced, providing the rubbing is not too energetic. Menthol 
generally induces this feeling of cold, accompanied by more or less 
prickling, and afterward by heat and burning. The cold is not due 
to cooling of the skin, for the vessels of the part are dilated, and the 
thermometer indicates a higher skin temperature there than in other 
parts of the body. It has been ascribed to menthol being more irritant 
to the terminations of certain nerves which convey the sensation of 
cold than to those of the heat nerves and pain nerves, but this is denied 
by Rollett who states that menthol acts only on the terminations of 
the nerves of common sensation or pain. A feeling of numbness and 
partial ansesthesia follows its application after some time, and a 10 per 
cent, solution has been found to produce anaesthesia of the cornea, 
which, however, is preceded by pain and smarting. 

The action of borneol, menthol, bromated camphor, and camphorol is 
almost identical with that of camphor itself. Borneol is less irritant locally, 
and the convulsions are less severe than after camphor, so that animals seldom 
die during the convulsive stage, and may remain in a state of stupor and col- 
lapse for one or two days before the respiration finally ceases. After menthol, 
the convulsions are even less developed than after borneol. Both of these are 
excreted in combination with glycuronic acid. Bromated camphor seems to 
resemble borneol more closely than camphor or menthol, while amido-cam- 
phor produces symptoms similar to those of camphor, but is much less powerful. 
Natural camphor is dextrorotary; the laevorotary isomer has been formed 
recently, and is found to resemble the natural form except in being rather more 
toxic. 

Preparations. 

Camphora (U. S. P., B. P.) (GoHi 6 0), Laurel camphor, a stearoptene ob- 
tained from Cinnamomum Camphora, forms white translucent, crystalline 
masses, which are almost insoluble in water but dissolve readily in alcohol, 
ether, chloroform, fixed and volatile oils. 0.125 G. (2 grs.), in emulsion or 
pill (B. P., 2-5 grs.). 

Aqua Camphorce (U. S. P., B. P.). 

Spiritus Camphors (U. S. P., B. P.), 1 c.c. (15 mins.). B. P., 5-20 mins. 

Linimentum Camphors, camphorated oil (U. S. P., B. P.). 

Linimentum Camphora Ammoniatum (B. P.), compound camphor liniment. 

Tinctura Camphors Composita (B. P.), paregoric, contains 1 part of 
morphine in 2000, i. e. f each fluid drachm is equivalent to J grain of opium. 
i-1 fl. dr. 

Camphor is also an ingredient in the camphorated tincture of opium, or 
paregoric (U. S. P.) and in soap liniment and chloroform liniment. 

Menthol (U. S. P., B. P.) (Ci H 20 O), a stearoptene obtained from the oil of 
peppermint, consists of colorless crystals slightly soluble in water, freely soluble 
in alcohol or ether. 

Therapeutic Uses. — Camphor is used externally in the form of the 
liniment or spirit as a mild rubefacient in bruises and sprains, and 



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VOLATILE OIL SERIES 6ft 

also to destroy parasites. Internally the spirit is prescribed as a 
carminative and as an intestinal disinfectant. It is frequently given 
to prevent "chill," and may relieve the congestion of internal organs 
through dilating the skin vessels. 

There is no reason to believe that camphor in even the largest thera- 
peutic doses has any effect after absorption except a slight dilatation 
of the skin vessels, and it is possible that this also may arise from its 
gastric effects. Its former uses in hysteria, epilepsy and other nervous 
disorders, as an aphrodisiac and as an anaphrodisiac were all equally 
irrational; if any improvement occurred, it was due to hypnotic 
suggestion and not to the action of the drug. 

It has been used in unconsciousness and collapse arising from different 
causes, and in the depression and weakness of acute fevers. In many 
of these cases, a marked improvement in the pulse is said to have been 
observed; this, like the similar improvement seen after alcohol, may 
perhaps be explained by its action as a local stomachic irritant produc- 
ing changes in the circulation reflexly. Solutions of camphor have 
been injected subcutaneously in these cases, but they cause pain and 
swelling at the point of injection. 

Camphor is often prescribed in expectorant mixtures, especially 
in combination with opium, as in paregoric. 

Menthol is used almost exclusively for its effects on the sensory 
nerve terminations, and is applied by rubbing the crystals or sticks 
on the skin in case of headache and neuralgia. 

Borneol and monobromated camphor are entirely superfluous. The latter 
was at one time used as a sedative in nervous excitement, but does not seem 
to have been at all beneficial and has fallen into disuse. 

Bibliography. 

Rovighi. Zts. f. phys. Chem., xvi, p. 20. 

Schmiedeberg u. Meyer. Ibid., iii, p. 422. 

Stockman. Journ. of Physiol., ix, p. 66. 

Lewin. Arch. f. exp. Path. u. Pharm., xxvii, p. 226. 

Gottlieb. Ibid., xxx, p. 31. Ztachr. f. exp. Path. u. Ther., ii, p. 385. 

Meyer. Arch. f. exp. Path. u. Pharm., xxix, p. 438. 

Wiedemann. Ibid., vi, p. 216. 

Goldseheider. Arch. f. Anat. u. Phys., 1886, p. 555. 

RoUett. FflOger's Archiv, lxxiv, p. 418. 

Seligmann, Boehme. Arch. f. exp. Path. u. Pharm., Iii, pp. 333, 346. 

Winterberg. Pflttger's Archiv, xciv, p. 455; Ztschr. f. exp. Path. u. Ther., iii, p. 182. 

Magnan. Compt. rend, de TAcad., lxviii, p. 825. (Absinth.) 

Hildebrandt. Arch. f. exp. Path. u. Pharm., xlviii, p. 451. (Thujon.) 

Liebmann. Ibid., lxviii, p. 59. 

3. Ether and Chloroform (Local Action). 

In addition to their use as anaesthetics, chloroform and ether are 
sometimes prescribed for the same purposes as the volatile oils. 
Chloroform has a hot, sweetish taste, while ether is bitter and suffo- 
cating in the mouth; a sensation of heat and often of pain in the 
stomach follows when they are swallowed, and chloroform may cause 



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70 SUBSTANCES ACTING LOCALLY 

gastric irritation and catarrh when given undiluted. When ether has 
been exposed to air and sunlight and to a varying temperature, it may 
contain acetaldehyde and peroxide bodies, which render it more irritant 
to the mucous membranes. The whole effect is similar to that produced 
by the volatile oils, but absorption probably takes place more rapidly. 
On the skin, ether evaporates too rapidly to cause much irritation, 
but chloroform is occasionally used as a rubefacient in the form of a 
liniment. 

Preparations. 

The pure substances may be administered by the mouth, but more frequently 
other preparations are prescribed. 

Chloroform, 0.3 c.c. (5 mins.). 

JSther, 1 c.c. (15 mins.). 

Spiritus jEtheris (U. S. P., B. P.), 4 c.c. (1 fl. dr.). B. P. 20-40 mins. 

Spiritus jEtheris Compositus (U. S. P.), (Hoffmann's Anodyne) contains 
a number of esters of ethyl and other substances known as "ethereal oil," 
together with ether and alcohol, 4 c.c. (1 fl. dr.). 

Spiritus Chloroformi (U. S. P., B. P.), 2 c.c. (30 mins.) (5-20 m. for re- 
peated doses, B. P.). 

Aqua Chloroformi (U. S. P., B. P.). 

Linimentum Chloroformi (U. S. P., B. P.). 

Therapeutic Uses. — These preparations are used for the same pur- 
poses as the corresponding preparations of the volatile oils. Thus the 
spirits may be prescribed as carminatives or in colic, while the liniment 
is used as a counter-irritant. Chloroform water is an antiseptic of 
considerable power, but is too volatile for surgical use. 

Spirits of ether and ether itself are often given internally or sub- 
cutaneously in cases of shock or sudden collapse in the same way as 
brandy or whiskey, though Elfstrand states that ether injected hypo- 
dermically has no effect on the heart or blood-pressure; spirits of 
ether contains a much larger percentage of alcohol than ordinary 
whiskey. Both ether and chloroform, but more especially the latter, 
have been used internally for tapeworm with success. There is always 
some danger, however, that, besides destroying the parasite, they may 
cause irritation and lasting injury to the intestinal wall. 

Hoffmann's anodyne is a favorite carminative, and is often added to 
other drugs to lend them an agreeable odor and taste. It is also used 
in dilution as a stimulant in the same indefinite way as wine and spirits, 
and its large percentage of alcohol, together with the bouquet given 
it by the various esters present, entitle it to be ranked among the 
alcoholic preparations. 

Both spirits of ether are used occasionally in expectorant mixtures 
and are believed to increase the bronchial secretion. 

Ether evaporates very rapidly and leaves a sensation of cold, and 
when thrown on the skin in a fine spray it produces sufficient cold 
to numb sensation in the part and allow of minor surgical operations 
(see uses of cocaine). Instead of ether still more volatile substances, 
such as ethyl chloride (boiling point 12.5° C), methyl chloride (boiling 



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VOLATILE OIL SERIES 71 

point —23° C.) and liquefied carbon dioxide have been introduced. 
These are supplied in pressure cylinders, and are allowed to escape 
against the skin. 

The local anaesthesia produced bears no relation to their action when 
inhaled, but is due simply to the cold produced by their evaporation. 
The vessels of the part contract, and the absence of blood and hardness 
of the tissues facilitate some operations, but the subsequent reaction 
is liable to produce considerable soakage of blood from the wound. 
The cold elicited ought not to be great enough to actually freeze the 
tissues, otherwise the healing may be slow. The intense cold is often 
quite as painful as the operation itself would be without any anaesthetic. 

4. Malodorous Volatile Oils. 

Some of the volatile oils differ from the others in possessing an odor 
which is disagreeable and nauseating to most people, although not to 
all. The best known of these are the Oils of Asafcetida and Valerian. 
The former occurs along with resins and gums exuding from some 
species of Ferula, and contains several organic sulphur compounds, to 
which it owes its odor. Oil of Valerian, from Valeriana officinalis, is 
almost without odor when freshly distilled, but when kept for some 
time and exposed to the air, it assumes a somewhat unpleasant pene- 
trating odor. It contains two terpenes, borneo-camphor, and numerous 
esters of formic, acetic and valerianic acid. While both of these oils 
are generally regarded as possessing very unpleasant odors, asafcetida 
is used in India as a condiment, and valerian was formerly used in 
England as a perfume. Another drug of the same kind formerly in 
use is Sumbul, the root of Ferula Sumbul. 

Asafcetida and valerian are used in hysterial affections, and the 
benefits accruing from their administration have generally been 
attributed to the mental impression produced by their unpleasant 
odor and taste, and not to any action they produce after absorption. 1 

The ordinary valerianic salts have no further effects than other 
salts of the acetic acid series, so that it is quite irrational to use such 
bodies as valerianate of quinine for their action in hysteria. 

Asafcetida is also used like the other volatile oils as a carminative 
and as an expectorant, and the emulsion is given by the mouth or in 
an enema to relieve abdominal distention. 

Preparations. 

Asafcetida (U. S. P.), a mixture of volatile oil, gum, and resin from Ferula 
foetida. 0.25 G. (4 gre.) 
Emulsum Asafcetidw, 16 c.c. (4 fl. drs.). 
PUuUb Asafcetida, 2 pills. 
Tinctura Asafcetidce, 1 c.c. (15 mins.). 

» Kionka (Arch, internat. de Pharmacodyn., xiii, p. 215) ascribes the effect of valerian 
to a definite action on the psychical functions and the circulation exercised by some 
valerianic esters of the oil, and has recommended some artificial esters (Valyl) as a 
substitute for the valerian preparations; but his statement requires further confirmation. 



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72 SUBSTANCES ACTING LOCALLY 

Asafetida (B. P.), a gum-resin obtained from the root of Ferula foetida and 
probably other species. 5-15 grs. 

Tinctura Asafetida, J-l fl. dr. 

Pihda Aloes ei Asafetida, 4-8 grs. 

Spiritus Ammonias Fetidus, 20-40 mins. for repeated administration; for a 
single administration 60-90 mins. 

Valeriana (U. S. P.), Valerian* Rhiioma (B. P.), valerian, the rhizome and 
roots of Valeriana officinalis. 

Fluidextractum Valeriana (U. S. P.), 2 c.c. (30 mins.). 

Tinctura Valeriana (U. S. P.), 4 c.c. (1 fl. dr.). 

Tinctura Valeriana Ammoniata (U. S. P., B. P.), 2 c.c. (30 mins.). B. P., 
J-l fl. dr. 

VH. SKIN IRRITANTS AND COUNTER-IRRITATION. 

The practice of applying irritants to the skin in internal diseases 
is one of great antiquity. The theories on which this therapeutic 
method is based have changed with the advance of medical knowledge, 
until, no explanation satisfactory to modern scepticism being forth- 
coming, the use of these remedies has fallen into a certain disrepute 
in the last few years. The old theory of revulsion or derivation was at 
first based on the belief that disease was a malignant entity or humor, 
which might be drawn from the deeper organs to the surface by means 
of irritation of the skin. Later, it was supposed that the congestion of 
the diseased organs might be relieved by the withdrawal of fluid to 
the skin, and this belief has been held in more or less modified forms in 
quite modern times. In addition, it was recognized very early that 
irritation of the skin relieved pain in many instances. The -means by 
which the skin irritation was attained were extremely numerous and 
varied; large numbers of drugs have been used, and in addition mechan- 
ical devices of all kinds were employed, such as burning, electrical 
currents, or the introduction of setons. In many of these the idea of 
irritation was combined with that of leaving a way of escape for humors. 
This latter is only of historical interest, but the practice of relieving 
internal organs by external irritation or countewrrtiation persists still, 
and perhaps merits more attention than it receives at the hands of 
many physicians. 

The effects of an irritant applied to the skin are local and remote. 
The first symptoms of irritation are congestion and redness of the 
part, and many drugs which produce only this degree of irritation in 
ordinary circumstances, are known as Rubefacients. Stronger irritants 
cause blistering, and are called Vesicants, while some drugs which 
cause irritation and small discrete suppurations, receive the name of 
Pustulants. 

Local Symptoms. — The application- of an irritant to the skin causes 
a feeling of warmth, and often of itching, which may later become 
intensified into actual pain. The skin becomes red, congested, warm, 
and at first is more sensitive to touch and painful stimuli, though 
the sensitiveness is afterward lessened. This condition persists for 
a longer or shorter time according to the nature of the irritant, and 



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SKIN IRRITANTS AND COUNTER-IRRITATION 73 

then passes off slowly. Very often desquamation follows, if the rube- 
facient has acted for some length of time. Stronger irritation is followed 
at first by the same results, but soon small globules of fluid appear 
below the epidermis, and these coalesce so as to form a large accumula- 
tion of fluid, which raises the epidermis completely off the true skin, 
forming a blister. If the irritant be removed, the fluid of the blister 
undergoes a slow absorption, so that in the course of a few days the 
epidermis forms an empty sack, which, however, is not obliterated by 
the adhesion of the walls. If the blister be opened, the sensitive dermis 
is exposed, and the secretion of fluid continues for some time, until a new 
epidermis has been formed. 

The distinct and separate points of inflammation caused by the 
pustulants are due to their affecting the orifices of the skin glands 
and not intervening tissue. This has been ascribed in some instances 
to the drug being rendered irritant at these points by the presence 
of acids formed by the decomposition of the sebum and perspiration; 
a simpler explanation is that the pustulants cannot pass through the 
horny epidermis, but act as irritants wherever they come in contact 
with living tissue, that is, at the orifices of the glands. They cause the 
same sensation of warmth and prickling of the skin as the other irritants, 
but even in the earlier stages of their action small, dark-red, raised 
points are observed, exactly as in some of the exanthemata, and these 
afterward form small abscesses. If the application be persisted in, 
these discrete abscesses may burst through the intervening tissues and 
become confluent, and large abscesses have thus been formed in the 
skin. When the irritant is removed before the formation of pus, the 
inflammation of the ducts slowly subsides and the epidermis peels off 
as after the milder irritants. Pustulants are seldom employed at the 
present time; croton oil applied vigorously may induce pustulation, 
and tartar emetic was formerly largely used for this purpose. 

The local effects of the rubefacients and vesicants are identical 
with those of acute inflammation. The pain and discomfort are due 
to the action on the nerve terminations, while the redness and swelling 
betray the local dilatation of the vessels. This latter appears to be 
due to a reflex from the sensory terminations to the vasodilator nerve 
ends on the vessels; the central nervous system is not involved in this 
reflex, for it occurs after division of the nerves of the part, but not 
after the peripheral fibres have degenerated; it is thus of the nature of 
an axon reflex (Bruce). The dilatation of the vessels and the slowing 
of the blood current in them lead to the transudation of fluid and 
leucocytes into the tissues, especially at the points where the irritation 
is greatest, and the accumulation eventually pushes off the horny 
epidermal layer from the living layers and forms a blister. The fluid 
in the blister has been shown to contain some of the irritant, which 
diffuses into it through the epidermis. The oedema and swelling is not 
confined to the skin, but extends into the subcutaneous tissue and the 
more superficial layers of muscle. 



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74 



SUBSTANCES ACTING LOCALLY 



If the irritation be continued long enough, suppuration may com- 
mence in the blister and lead to deep erosion of the tissues. 

Remote Action. — Ix>cal irritation cannot exist without causing 
certain general changes which affect the whole organism, and which 
arise from the reflex stimulation of various centres in the medulla 
oblongata. Attempts to base the explanation of counter-irritation 
on these general effects have all failed, however, and many of them 
are elicited only by widespread irritation or by more intense localized 
irritation than is induced by ordinary therapeutic methods. 



Fia. l 







Diagram to illustrate the effects of visceral disease on sensation (after Mackensie) 
S, diseased viscus, with afferent nerve fibre N and efferent fibre N' issuing from the 
same area of the spinal cord. The impulses from the diseased area induce a condition of 
heightened sensibility in the shaded area. E, a motor nerve fibre to muscle, which 
carries more impulses than usual from the area in the cord and thus leads to a tonic 
contraction of the muscle. A, the afferent nerve from the muscle and A' from the skin 
entering the cord in the sensitive area and thus giving rise to the sense of pain and tender- 
ness, which is referred to the peripheral distribution in the skin and muscle. 



The centres involved are those regulating the heart, the tone of the vessels, 
and the respiration. Moderate irritation of the skin causes an acceleration of 
the heart-rhythm, while more powerful irritation slows the heart through the 
inhibitory centre. The blood-pressure measured in the arteries is considerably 
increased by ordinary irritation of the skin, but if it be very severe or wide- 
spread, the slowness of the pulse may cause a fall of tension. This increase in 
the blood-pressure is due to the reflex stimulation of the vasomotor centre, 
which causes a constriction of the arterioles of the abdominal organs chiefly, 
while the vessels of the limbs and probably those of the skin are not contracted. 
The result is that more blood is supplied to the muscles and skin and less to 
the internal organs than normally. 

The effects of skin irritation on the respiration are less uniform. In the 
rabbit the breathing is sometimes accelerated, sometimes slowed by mild 
stimulation, while stronger stimuli seem to slow it always. The effect of the 



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SKIN IRRITANTS AND COUNTER-IRRITATION 75 

application of skin irritants on the respiration in man has not been observed 
accurately, but that sudden stimulation of the skin causes gasping and irregular- 
ity of the respiration, may be observed whenever cold water comes in .contact 
with the more sensitive parts of the body. 

Some change in the temperature of the body has been observed when the skin 
is irritated, but in man this is said to amount to less than . 1° C. as a general rule. 
The internal heat tends to fall, while that of the skin rises, from the change in the 
distribution of the blood which has been described above. 

The metabolism has been found to be altered by the application of irritants 
to the skin, and, although in the experiments on which this statement is based, 
the surface exposed to the irritant was larger than that affected in therapeutics, 
it seems probable that some change is produced by the ordinary agents also. 
Zuntz and Rohrig found that bathing animals in strong salt solution increased 
the oxygen absorbed and the carbonic acid excreted much more than bathing 
in ordinary water, and Paalzow obtained the same result from the application of 
mustard plaster. The nitrogen of the urine is also said to be increased. This 
increase in the oxidation of the tissues is of the same nature as that produced 
by cold, and is due to an augmentation of the muscular activity, which, however, 
is too slight to cause any perceptible movement. 

Irritation of the skin induces leucocytosis in the same way as irritation 
of the alimentary canal. This is especially evident after the application of 
a vesicant such as cantharides plaster, while rubefaction seems to have less 
effect. 

Lastly, in considering the effects of skin irritation on the general vitality, it 
may be mentioned that a sudden application may awake the consciousness, as 
is seen in the effects of dashing cold water on the chest, or of striking the hands 
in narcotic poisoning. Another example is seen in the improved mental con- 
dition so often observed in fever patients treated with cold baths. This im- 
provement is due to the local action on the skin, and not, as is often said, to 
the fall in temperature, for the latter is often insignificant. 

All of these effects are produced by irritation at any point of the 
surface, and are quite insufficient to explain the practical use of counter- 
irritants to affect a particular organ. For example, in gastric disorders 
a counter-irritant is often applied just over the ensiform cartilage, 
while in facial neuralgia a blister behind the ear often gives relief. 
If the beneficial results were due to the general alteration of the circula- 
tion, respiration, or temperature, there would be no reason to vary 
the point of application, for the effect would not vary. 

It has been shown by several observers (Zuelzer, Lazarus-Barlow) 
that when an irritant is applied to the skin, the muscles beneath are 
congested and rich in lymph, and Erlanger states that solutions are 
absorbed more quickly from the pleural cavity when mustard is applied 
to the skin of the chest and attributes this to an acceleration of the 
lymph stream. But these observations apply only when the organs 
to be affected are not only contiguous, but also continuous with those 
directly affected, and offer no explanation of the effects of irritation of 
the skin upon the stomach or lungs. 

Much light has been thrown on the subject by the observations of 
Mackenzie and Head, who found that visceral disease is often accom- 
panied by tenderness of the skin and underlying muscles, and that 
the pain arising in these cases is referred to this area of skin and not 
to the organ involved. Thus in painful diseases of the stomach, 



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76 SUBSTANCES ACTING LOCALLY 

tenderness is often found in the skin and muscles of the epigastrium, 
while in oesophageal stricture, pain may be referred to a point near 
the angle of the scapula and to another in the neighborhood of the 
apex beat. Similarly in heart disease, pain is often felt in the left 
chest-wall and shoulder extending down the left arm. These points 
are, of course, only connected with the diseased organ by means of 
nerve-fibres, and it thus appears that impulses from such an organ 
arouse a condition of heightened sensibility in the region of the cord 
on which they impinge; this affects all the synapses in the neighbor- 
hood (Fig. 1), so that impulses from very different structures may 
be altered by the affection of one. The sensation of pain aroused by 
this exaggerated sensibility is of course referred to the periphery, not 
to the focus in the cord, and this gives the impression of tenderness 
in the skin and muscles. It therefore seems probable enough that an 
affection of these superficial areas may affect the corresponding inter- 
nal organ more than the rest of the body, and this is exactly what is 
required to explain the benefits derived from the use of counter- 
irritants. It is especially noticeable that several of the points affected 
by internal disease are precisely those points at which experience has 
shown irritation to be most beneficial (Fig. 2). Thus the application 
of a blister over the epigastrium has long been recognized as a means 
of relieving gastric disorders. Similarly the old treatment of iritis by 
means of a blister on the temple may be justified by the fact that 
Head found areas of tenderness on the temple accompanying this 
disease. 

The exact nature of the effects of counter-irritation on the internal 
organs has not been ascertained, but it would seem most probable that 
an alteration in the calibre of the vessels is induced. These alterations 
may be accompanied by changes in the activity of the organs; for 
example, there seems good reason to believe that in many cases irritants 
applied to the abdomen produce evacuation of the bowels. The most 
obvious effect of counter-irritation very often is the relief of pain, and 
this seems explicable in the light of the observations of Mackenzie 
and Head. For if the pain in visceral disease is due to the disorder 
of the synapses in the spinal cord at the level at which the fibres from 
the viscus and from the superficial tissues meet, it is possible that 
new impulses reaching this area from the skin may alter its condition 
or may occupy a common path to the brain to the exclusion of impulses 
arising from the seat of disease. 

Besides these physiological effects of counter-irritation, it must not 
be forgotten that a great impression is produced on the patients, and 
that some of the benefit may be due to hypnotic suggestion. 

Therapeutic Uses. — Local irritants are applied occasionally to pro- 
duce an alteration in the nutrition and blood supply of the skin itself 
and of the subcutaneous tissues. Thus in some chronic inflammatory 
conditions, with effusions into, or indurations of the subcutaneous 
tissues, the improvement of the circulation produced by slight irritation 



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SKIN IRRITANTS AND COUNTER-IRRITATION 



77 



may be of benefit. An example of this is the treatment of ulcers of 
old standing with irritants. Another case in which a slight inflam- 
matory attack causes very obvious improvement, is in corneal opacity, 
which may be removed entirely in some cases by the acute inflam- 
matory reaction produced by such irritants as abrin. Probably a 
similar effect is produced on subcutaneous effusions, as in bruises. 
Some interesting experiments on this subject have recently been per- 
formed by Wechsberg, who induced suppuration in both hind legs of 



Fig. 2 




The right side is divided into segments which correspond to some of the skin areas 
in which Head found tenderness in internal diseases. 1. Area of tenderness in disease 
of the lungs. 2. In diseases of the stomach. 3. In ovarian disease. 4. In disease of the 
Fallopian tubes and other appendages. On the left side are represented the points of 
application of counter-irritants in disease of the lungs (A), of the stomach (B), of the. 
ovary (C)» and tn ^ uterine appendages (D). 

rabbits by the injection of irritants and then treated the one leg by the 
application of various irritants to the skin, while the other was left 
untreated as a control. He invariably found the abscess of the leg 
subjected to treatment less extensive and showing a greater tendency 
to heal than the other, and accounts for this by the oedema induced by 
the skin irritant diluting the original irritant and promoting its 



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78 SUBSTANCES ACTING LOCALLY 

absorption. The increased blood supply leads to a larger supply of 
leucocytes and protective substances around the inflammation than 
would otherwise be present. He found that the absorption of pigments 
from the rabbit's ear was much accelerated by the application of 
irritants to the skin over the part, and cites this as evidence that toxins 
are removed more rapidly under similar treatment. For these purposes 
only the milder irritants are required; in fact, vesication may do more 
harm than good. Mild irritation alters the sensitiveness of the sen- 
sory organs of the skin, and heat is often applied to alleviate pain and 
discomfort in the skin itself. In other instances pain is increased by 
heat, and, in fact, it is sometimes applied in the treatment of local 
anaesthesia, with the object of rendering the surface more sensitive. 
In many forms of skin disease, mild irritants are found to be of 
benefit; this is sometimes attributed to their antiseptic action, but the 
slight irritation is undoubtedly of some importance. 

Counter-irritants are used in a large number of diseases, often 
without any definite idea of what precise effects they will elicit, but 
merely because they have been found to give relief in similar conditions. 
As a general rule they are placed over the affected organ, and this 
corresponds fairly in most cases of disease of the trunk with Head's 
area of skin tenderness. In the head, however, the segmental arrange- 
ment has been rendered very irregular by the compression in develop- 
ment, and counter-irritants are often found to be most effective when 
placed at some distance from the seat of pain, e. g., behind the ear 
in some forms of facial neuralgia. They are used in acute inflammation 
of the lungs and pleura, in gastric disorders accompanied by much 
pain, in colic and in neuralgia and neuritis. Their action is very uncer- 
tain, but their application is often followed by great relief, more espe- 
cially of pain. They are also used occasionally in shock or collapse, 
not for their effect on any individual organ, but to elicit the reflex 
alterations in the circulation which have already been described. A 
blister is often recommended in internal haemorrhage, and may very 
possibly lessen the bleeding by altering the distribution of the blood 
in the organs, although it is difficult to estimate how far the improve- 
ment is due to the remedy and how far it is spontaneous. In order 
to produce any marked effect on internal organs, the more powerful 
irritants must be used, such as mustard or cantharides. It is not 
necessary, however, to produce actual vesication in the great majority 
of cases. Formerly blisters were opened and fresh irritants applied 
on the raw surface in order to prolong the effects, but this treatment 
was extremely painful, besides being liable to set up suppuration and 
ulceration, and it is very questionable whether any equivalent benefit 
followed. 

Counter-irritation must be applied only with the greatest caution in 
weak, badly nourished, or very old persons, as it may cause sloughing. 
In diabetes, the tendency to gangrene contra-indicates blistering, and 
in very young children only mild irritants are used. 



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SKIN IRRITANTS AND COUNTER-IRRITATION 79 



Bibliography. 

Naumann. Vierteljahrsch. f. prakt. Heilkunde, lxxvii, p. 1 and xciii, p. 133. 

Zalzer. Deutsche Klinik., 1865, p. 127. 

Rdhrig and Zuntz. Pfluger's Archiv, iv, p. 57. 

Paalzow. Ibid., iv, p. 492. 

Maniegazza. Schmidt's Jahrb., cxzxiii, p. 153. 

Jacobson. Virchow's Archiv, lxvii, p. 166. 

Head. Brain, xvi, p. 1; xvii. p. 339. 

Mackenzie. Symptoms and their interpretation, 1909, p. 80. 

WinterniU. Arch. f. exp. Path. u. Pharm., xxxv, p. 77; xxxvi, p. 212. 

Wes&Uy. Centralbl. f. Chirur., xxx, No. 36. 

Buchner, Fucks, Meade. Arch. f. Hygiene, xl, p. 347. 

Wechsberg. Ztschr. f. klin. Med., xxxvii, p. 360. 

Erlanger. Zeitschr. f. exp. Path. u. Ther., ix, p. 22. 

An enormous number of drugs produce irritation of the skin, and it 
would be idle to attempt to enumerate them here. In many instances, 
however, the irritant action is insignificant in comparison with the 
other effects produced, and these will, therefore, be discussed else- 
where; among these are found some of the alkaloids, the acids and 
alkalies, and many other inorganic preparations. Irritation of the 
skin may also be produced by heat and cold, and in fact burning in 
various forms was formerly used as a means of counter-irritation. 
Heat is still employed to cause irritation of the skin and subcutaneous 
tissues, and to promote their circulation. Thus, poultices, and hot 
water compresses are beneficial in many local inflammations, though 
the same effects may generally be obtained by the use of the milder 
irritants. A variety of apparatus has been devised for the application 
of air heated to 250° F., or even higher to rheumatic joints, but it 
may be questioned whether the results are more favorable than those 
obtained by poultices and other methods. Another method by which 
hyperemia of a whole limb may be attained has been introduced 
by Bier, who advises the application above the seat of disease of an 
elastic bandage which is tight enough to retard slightly the venous 
flow, but leaves the circulation of the limb otherwise intact; satis- 
factory results have been recorded from this treatment in many con- 
ditions, and these are generally ascribed to the accumulation of leuco- 
cytes and alexines in the tissues. Somewhat similar results may be 
obtained in the trunk by dry cupping, in which the blood is drawn to 
the diseased superficial tissue by applying a glass tightly to the skin 
and exhausting the air in its interior. Another method by which 
chronic inflammatory conditions have been treated with the view of 
inducing an acute reaction is the application of solid carbonic dioxide; 
this has been employed chiefly in open wounds and in disease of mucous 
membranes. 

Apart from those drugs in which the irritation of the skin is merely 
an incident in a wider general action, there are a number of prepara- 
tions which are used almost exclusively for this puropse. They may 
be divided into three classes: the volatile irritants, such as turpentine 



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80 SUBSTANCES ACTING LOCALLY 

oil; the mustard series, some of which are also volatile; and those 
which are either non-volatile or only boil at high temperatures, such 
as cantharidin. 

1. The Turpentine Oil Group. 

Under the volatile irritants may be included a large number of the 
ethereal oils and many members of the methane and of the aromatic 
series; but among the ethereal oils those which possess a low boiling 
point, that is, those which contain a large proportion of terpene, with 
comparatively little oxygen, are found to possess a more penetrating 
action than the others. At the same time, the taste and odor of these 
oils is often less pleasant than that of the others, so that they are less 
used as flavors and carminatives. The oils derived from the Conif- 
ere have, for this reason, been more largely used than the others for 
their effect on the skin, although several ^other volatile preparations 
are recognized by the pharmacopoeia for this purpose. The action of 
these oils is similar in other respects to that of the general group 
(see p. 57), so that it need not be discussed here. 

Preparations. 

Terebinthina, turpentine (U. S. P.), a concrete oieoresin obtained from 
Pinus paiustris and other species of Pinus. 

Oleum Terebinthina (U. S. P.), oil of turpentine, a volatile oil distilled 
from turpentine. 

Oleum Terebinthina Rectificatum (U. S. P., B. P.), is formed from 
ordinary oil of turpentine by redistillation and consists of a mixture of ter- 
penes (CioHu). Dose, 1 c.c. (15 mins.); as an anthelmintic, 8-15 c.c. (2-4 
fl. drs.). 

Emulsum Olei Terebinthince (U. S. P.), 4 c.c. (1 fl. dr.). 

Linimentum Terebinthinw (U. S. P., B. P.). 

Linimentum Terebinikinm Aceticum (B. P.), is formed by mixing turpen- 
tine, glacial acetic acid, and camphor liniment. 

Terebenum (U. S. P., B. P.), a liquid formed from oil of turpentine by the 
action of sulphuric acid. It consists of a number of terpenes, one of which 
is the pure substance known as terebene. Its odor is more pleasant than that 
of turpentine oil, which it closely resembles otherwise. Dose 0.5 c.c. (8 mins.). 

Terpini Hydras (U. S. P.), terpin hydrate, is a crystalline substance (CioHh 
(OH) 2 + H 2 0) derived from oil of turpentine by the action of nitric acid in 
the presence of alcohol and water. It possesses almost no odor, is insoluble in 
water, and melts at about 116° C. Dose 0.125 G. (2 grs.). 

Oleum Juniperi (U. S. P., B. P.), oil of Juniper, is derived from the juni- 
per berries and consists mainly of terpenes. Dose, 0.2 c.c. (3 mins.). 

Spiritus Juniperi (U. S. P., B. P.), 2 c.c. (30 mins.); B. P. 5-20 mins. 

Spiritus Juniperi Compositus (U. S. P.), 8 c.c. (2 fl. drs.). 

In addition to these preparations the following may be mentioned here as 
possessing similar action and uses. 

Linimentum Chloroformi (U. S. P., B. P.). 

Linimentum Camphors (U. S. P., B. P.). 

Linimentum Camphorce Ammoniatum (B. P.). 

Linimentum Saponis (U. S. P., B. P.), very slightly irritant. 

Arnica and its preparations enjoy a popular reputation as skin applications 
but do not appear to have any action which entitles them to consideration. 



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SKIN IRRITANTS AND COUNTER-IRRITATION 81 

Therapeutic Uses. — Turpentine oil is used externally as a rubefacient, 
and differs from mustard and cantharidin in its greater penetrating 
power. It is not so irritant, however; it blisters only after long applica- 
tion, and the vesication produced is very painful and heals slowly, 
from the vapor penetrating into the deeper tissues. It is, therefore, 
employed to produce rubef action only, and ought to be removed 
when this is attained. For this purpose any of the liniments of the 
group may be employed, or a more intense action may be got from the 
"turpentine stupe," which is made by dipping flannel in hot water, 
wringing it dry, and then dropping warm turpentine oil on it. 1 Tur- 
pentine preparations are used especially in rheumatic affections of the 
joints or muscles, and in sciatica. The oleoresin may be formed into 
ointment, or plaster, and used as a feeble stimulant in skin diseases. 
Turpentine oil is a fairly strong antiseptic, and is less irritant than 
many of the more powerful ones. It is often inhaled in lung diseases 
such as tuberculosis or gangrene, and has the effect of lessening the 
odor in the latter; the oil may be simply allowed to evaporate, but is 
much more efficient when sprayed into the air. Many of the resorts 
for phthisical patients are stated to be rendered especially suitable 
for this disease by the neighborhood of coniferous forests, which are 
supposed to dissipate the oils into the atmosphere; but this is probably 
only an insignificant factor in the treatment. Turpentine oil is occasion- 
ally added to baths in order to cause a slight general irritation of the 
skin, which may be of benefit in some skin diseases and also in general 
debility under certain conditions; and pine-needle baths have some 
reputation in Germany for the same reason, the water being supposed 
to extract the oil. 

Internally, turpentine oil is occasionally employed as a vermifuge, 
but is inferior to other preparations used for this purpose. A few 
drops are often added to purgative enemata to increase their efficiency. 
It has been given by the mouth in order to lessen flatulence and to 
disinfect the intestine in various diseases, among others, typhoid 
fever, although its value here is disputed. Preparations of turpentine 
oil and juniper are reliable and fairly powerful diuretics, but must 
not be prescribed in irritation of the kidney. The turpentine prepara- 
tions have a certain reputation as expectorants, and terebene has been 
especially advised for this purpose; they are also given internally 
as pulmonary disinfectants and in neuralgia and internal hemorrhage, 
and are probably entirely valueless for these purposes. Old oil of 
turpentine was formerly advocated in phosphorus poisoning, but this 
treatment has proved to be erroneous. 

Along with these may be mentioned a series of resins which have some 
slight irritating effect on the skin, and have been used in the treatment of 
skin diseases. 

1 Alcohol has recently been applied in a similar way in phlegmon and other forms 
of inflammation. Gauze is soaked in alcohol (60-96 per cent.), wrung out, wound round 
the affected part and covered with cotton and oil-cloth. 
6 

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82 SUBSTANCES ACTING LOCALLY 

Resina (U. S. P., B. P.), Tesin, colophony, is the residue left after distilling 
off the volatile oil from turpentine. 

Ceratum Resince (U. S. P.). 

Ceratum Resince Composition (U. S. P.). 

Emplastrum Resince (B. P.), adhesive plaster. 

Unguentum Resina (B. P.). 

Guaiacum (U. S. P.), Guaiaci Resina (B. P.), the resin obtained from Guaia- 
cum officinale, contains several resinous acids, some volatile oils and gums. 
It is colored deep blue by oxidizing agents. 

Tinctura Guaiaci (U. S. P.), 4 c.c. (1 fl. dr.). 

Tinctura Guaiaci Ammoniata (U. S. P., B. P.), 2 c.c. (30 mins.). B. P. 
$-1 fl. dr. 

Myrrha (U. S. P., B. P.), a gumresin obtained from Commiphora Myrrha 
(U. S. P.), from Balsamodendron Myrrha (B. P.), containing a small Quantity 
of volatile oil 

Tinctura Myrrhm (U. S. P.), 1 c.c. (15 mins.); B. P., 30-60 mins. 

Many other resins have been used in therapeutics, but have been aban- 
doned, a fate by which these survivors seem to be threatened. They are oc- 
casionally used externally as mild irritant applications in skin affections. Gal- 
banum, Ammoniacum, Guaiacum, and Myrrh, have been used internally for 
many different purposes, as expectorants, diaphoretics, diuretics, aperients, 
and have enjoyed a reputation in the treatment of amenorrhcea. They may be 
used to suspend insoluble bodies, as the gum contained causes them to form 
emulsions when water is added. 

2. Mustard. 

Mustard occurs in two forms in the pharmacopoeias, Black Mustard, 
Sinapis nigra, and White Mustard, Sinapis alba. Black Mustard 
contains a glucoside, Potassium Myronate or Sinigrin, and a ferment, 
Myrosin, which decomposes it in the presence of water into dextrose, 
potassium bisulphate and allyl-isosulphocyanate or volatile oil of 
mustard. 

Sinigrin. Volatile oil. 

CioHisKN&Oio - CSNCH* + CeHwOi + KHSO« 

Volatile oil of mustard is formed in various other Crucifera when they are 
mixed with water. Thus horseradish root (Armoracia, B. P.) contains it, while 
the allied species Cochlearia officinalis apparently contains the corresponding 
isobutyl compound. 

White mustard contains another glucoside, Sinalhin, which is also 
decomposed by the Myrosin in the presence of water. The products 
are entirely different, however, dextrose, sulphate of sinapine (an 
alkaloid), and an oil of mustard containing an aromatic nucleus being 
formed. 

Sinalbin. Oil of mustard. Sinapine sulphate. 

CioHuNa&Ow - C«H*(OH)CH*NCS + CwH»NO»H,S04 + C.Hi,0. 

The oil of white mustard differs from that of the black in being 
less irritant, and in being destroyed by heat. 

Action. — Either of these oils is intensely irritant when applied to 
the skin, and if left long enough produces blistering, which is more 
painful than that caused by cantharides, and is said to heal less 



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SKIN IRRITANTS AND COUNTER-IRRITATION 83 

readily. This is probably due to the oils penetrating more deeply 
into the tissues, and thus setting up more extensive inflammation. 
Mustard is accordingly used only to induce rubefaction, and ought to 
be removed before actual vesication occurs. When the crude drug is 
moistened and applied to the skin, the oil is formed only slowly, so 
that the longer it remains applied, the more intense is the action. 
The glucosides in themselves have little or no action, and the products 
of their decomposition are harmless, with the exception of the oils. 

Preparations. 

Sinapis Alba (U.S. P.), the dried ripe seeds of Brassica alba. 

Sinapis Nigra (U. S. P.), the dried ripe seeds of Brassica nigra. 

Charta Sinapis (U. S. P.), black mustard powder rendered adhesive by 
India-rubber, applied to sheets of paper and dried. 

Oleum Sinapis Volatile (U. S. P., B. P.)., derived from black mustard. 

Linimentum Sinapis (B. P.), formed from volatile oil of mustard, camphor, 
and castor oil. 

Uses. — Mustard is largely used as a condiment and to promote 
appetite, but is never prescribed for this purpose. In large quantities 
it causes violent irritation of the stomach and bowel, with vomiting, 
purging, acute pain and tenderness in the abdomen, and collapse. 
Mustard and warm water is a convenient emetic in emergencies, as in 
cases of poisoning. 

The plaster or leaf (charta) is the form in which it is generally used 
in therapeutics. It contains the glucoside, which is slowly decom- 
posed by the ferment when the plaster is dipped in warm water for a 
few minutes before application. Another popular application is the 
mustard poultice, in which powdered mustard is sprinkled on an ordi- 
nary poultice. Mustard is also added to baths occasionally when 
slight irritation and consequent congestion is desired over a large 
surface. For this purpose 2-4 teaspoonfuls of the dry powder are 
added for each gallon of water. In preparations of mustard it is 
important to avoid a temperature of over 60° C. (140° F.), as the 
ferment is destroyed above this. The plaster is left on the skin only 
for 15 to 30 minutes, when it is used as a rubefacient. 

3. Cantharidin Series. 

Another series of local irritants comprises non-volatile substances, 
of which cantharidin (C10H12O4) is the best known. It is an anhydride 
and when acted on by bases forms cantharidates, which resemble it 
in action. It is found in Spanish fly (Cantharis vesicatoria, or Lytta 
vesicatoria) and in several allied species of Coleoptera (beetles). 

Action. — Appli**! to the skin, cantharidin produces redness, smart- 
ing and pain, followed very soon by small vesicles, which later coalesce 
into one large blister. This is much less painful than the vesication 
produced by mustard, because less of the irritant penetrates into the 
deeper tissues than in the case of the volatile mustard oil. If the 



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84 SUBSTANCES ACTING LOCALLY 

blister be broken, however, and the unprotected dermis be allowed to 
come in contact with the irritant, violent inflammation with much 
pain, suppuration and even sloughing may follow. 

When large quantities of cantharidin are given internally, the same 
irritant action takes place along the alimentary tract. If taken in 
solution, blisters arise in the mouth and throat, and the pain and 
swelling in the oesophagus may be so acute as to prevent swallowing. 
The irritation of the stomach produces vomiting, followed by purging 
with excruciating pain in the abdomen, and all the symptoms of shock 
and collapse. 

Cantharidin is absorbed from the alimentary canal, and also to a 
less extent from the skin, but has no important action on the internal 
organs, with the exception of those by which it is eliminated. Vomiting 
occurs on subcutaneous injection from some of the poison being excreted 
into the alimentary tract. Comparatively small quantities irritate 
the bladder, and cause a constant desire to micturate, with pain in 
doing so. In somewhat larger amount it sets up an acute nephritis 
with albuminuria, pain in the kidney region, and sometimes blood in 
the urine. The inflammation of the bladder and urethra produces 
intense pain and often priapism; in women abortion is said to occur 
occasionally, and in both sexes the irritation may lead to increased 
sexual desire. 

The irritation of the kidneys by small doses increases their secretion, 
and cantharides was therefore considered a diuretic formerly. The 
tendency to produce nephritis renders it a dangerous internal remedy, 
however, and its diuretic power is quite insignificant in comparison 
with that of caffeine. 

Animals vary very considerably in the degree in which they react to can- 
tharidin, the most noted example being the hedgehog, which is capable of 
surviving a dose of the poison sufficient to poison an adult man. Fowls and 
rabbits also possess a high degree of congenital tolerance for this poison, although 
none of these is absolutely insusceptible to it. 

Preparations. 

U. S. P. — Cantharis, Spanish Fly, the dried beetle, Cantharis vesicatoria. 
Ceratum Cantharidis (U. S. P.). 
CoUodium Cantharidatum (U. S. P.). 
Tinctura Cantharidis (U. S. P.), 0.3 c.c. (5 mins.) 

B. P. — Cantharidlnum, C10H12O4, obtained from various species of Cantharis 
or of Mylabris. 
Emplastrum Cantharidini, containing 0.2 per cent. 
Emplastrum Calefaciens, warming plaster, 0.02 per cent. 
Unguentum Cantharidini, 0.033 per cent. 
Liquor Epispasticux, blistering liquid, 0.04 per cent. 
Tinctura Cantharidini, 0.01 per cent. 2-5 mins. 

Therapeutic Uses. — This drug is at present used almost exclusively 
as a skin irritant, and more particularly as a vesicant. In the United 
States the cerate is generally used for this purpose, and is applied to 



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SKIN IRRITANTS AND COUNTER-IRRITATION 85 

the skin by means of adhesive plaster; the corresponding preparation 
of the B. P. is the cantharidin plaster. It is to be noted that in order 
to produce actual blistering, the plaster has to remain in contact with 
the skin some 8-10 hours, but an equal effect may be achieved by 
replacing the plaster by a hot poultice after 4-6 hours, when the skin 
irritation has reached the stage of redness. Cantharides is also used 
to cause rubefaction and commencing vesication (flying blister); this 
may be done by the use of these preparations, or by means of the 
warming plaster, B. P. Blistering collodion or blistering liquid, is used 
rarely in unmanageable cases in which there is a risk of the plaster 
being removed by the patient. The ointment is said to induce blister- 
ing sooner than the plaster. 

Cantharidin is liable to be absorbed from the skin, and its application 
is therefore avoided where there is any tendency to renal inflammation. 

Cantharides has been used not infrequently as an aphrodisiac, and 
several cases of poisoning have occurred from its administration for 
this purpose. In cattle it is largely employed to this end in some 
countries, and in man it has undoubtedly similar effects in some cases 
through the irritation of the bladder and urethra, but its use for this 
purpose is always liable to produce nephritis. As an emmenagogue, 
cantharides has a certain popular reputation, which, however, has been 
shown to be unmerited, any influence which it may possess on the 
menstrual flow being quite insignificant, and probably due only to the 
irritation of the bladder and urethra. 

Cantharides has been advised internally in some forms of renal and vesical 
disease, but it is an exceedingly dangerous remedy in these conditions. It 
is sometimes a constituent of hair washes, its irritant action on the skin being 
credited with causing a more rapid growth of the hair. 

In cases of Poisoning with cantharides, the stomach ought to be 
emptied as rapidly as possible by the stomach tube, provided the 
oesophagus allows of its passage. Demulcents and albuminous sub- 
stances are of use in slowing the absorption, but all oily or fatty bodies 
must be avoided, as they tend to dissolve the cantharidin and thus 
promote its absorption. Opium may be given for the pain, and if 
collapse sets in, the ordinary measures must be taken to combat it. 
EUinger states that the action on the kidney in rabbits is more severe 
when the urine is acid than when it is alkaline, and this suggests the 
treatment of the renal symptoms with alkalies. 

Poison Ivy and Poison OaJc.— The commonest form of poisoning in 
the United States is the skin eruption produced by the leaves of poison 
ivy and poison oak (Rhus toxicodendron and venenata), which Pfaff 
showed to be due to the presence of a neutral body, Toxicodendrol; 
this has recently been stated to be of glucosidal nature. The effects 
of poison ivy can arise only from touching the plant, the poisonous 
principle not being volatile. Very minute quantities of toxicodendrol 
are sufficient to produce skin eruptions, however, xinnr m £- causing 



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86 SUBSTANCES ACTING LOCALLY 

distinct symptoms in susceptible persons. The popular belief that 
skin affections can be induced by approaching the plant, without 
actually touching it, is probably accounted for by the facts that the 
eruption may be very late in making its appearance, and that poison 
ivy is very frequently mistaken for harmless climbing plants. The 
statement that the poison ivy does not affect some individuals is also 
probably erroneous, though persons of delicate skin are undoubtedly 
more susceptible. Immunity is not acquired for the poison by repeated 
attacks of dermatitis. 

In the dermatitis from poison ivy, Pfaff recommends the skin to 
be washed and scrubbed with soap and water, or with alcohol, or a 
solution of lead acetate in alcohol. Ointments and oily liniments are 
to be avoided, as they dissolve the toxicodendrol and tend to spread it 
over the skin and thus produce further inflammation. For the same 
reason, the alcohol used to wash the part must be removed entirely, as 
the poisonous principle is soluble in it, while insoluble in water. Potas- 
sium permanganate solution is said to be an efficacious application. 

Eruptions similar to that from poison ivy arise from contact with 
a number of other plants of which the best known is the Primula 06- 
conica; this plant secrets some unknown substance which is intensely 
irritant to the skin of many people, and has frequently given rise to 
severe inflammation in gardeners and others. Cash found an alkaloid 
obtained from East India Satinwood (Chloroxylon) equally irritant 
when applied to the skin; the dermatitis from these bodies often appears 
only 2-3 weeks after contact with them, and even after apparently 
complete recovery the skin remains especially sensitive to a reapplication 
of the poison. 

A number of the Ranunculaceae are irritant to the skin like cantharides, but 
the active constituent has not been definitely determined. Mezereum, which 
was formerly official, is similarly irritant, apparently from the presence of an 
irritant oil (Springenfeldt) . Cardol, found in the fruits of Anacardium occi- 
dentale and in Semecarpus anacardium, is a very powerful irritant, and has 
been used to a limited extent as a vesicant. Cardol is probably a mixture of a 
number of substances, but it is unknown to which of these it owes its activity. 
Euphorbin is said by Buchheim to be the irritant principle in the Euphorbia resin 
(Euphorbia resiniera, etc.), and to resemble cantharidin in its anhydride form, 
but the salts and the euphorbic acid which is formed from them by acids are 
inactive. A very poisonous member of the Euphorbiaceae is the Manicheel tree, 
growing in the West Indies, and it apparently belongs to this series. 

Capsicum (p. 54) contains one or more non-volatile irritant substances and 
is used occasionally as a skin irritant. Pepper is also used as a rubefacient in 
domestic medicine. 

Chaulmoogra Oil, obtained from Taraktogenos Kurzii, is apparently similar 
in character to the members of this group, although it is less irritant. It is 
used externally as an application to bruises, and both externally and inter- 
nally in leprosy, although it is probably of little avail in this disease. Croton 
oil has also been used as a skin irritant, but will be treated of in connection 
with the purgatives (page 96). 

Many other plants possess irritant, poisonous properties, which would ap- 
parently entitle them to a place in this series, but so little is known of their 
active principles and of their effects, that they may be omitted for the present. 



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PURGATIVES 87 

Bibliography. 

Aufrechi. Centralbl. f. med. Wissensch., 1882, pp. 545, 849. 

EUinger. Arch. f. exp. Path. u. Pharm., lviii, p. 424. Mftnchen. med. Woch., 1905. 

Liebreich. Therap. Monateheft, 1891, p. 169; 1892, p. 294; 1895, p. 167. 

Buchheim. Arch. d. Heilkunde, xiii, p. 1. 

Roal u. Gilg. Ber. Deutsch. Pharm. Gesell., xxii, p. 296. (Poison Ivy.) 

Lewin. Deutsch. med. Woch., 1901, p. 184. 

Pfaff. Journ. of Exp. Med., ii, p. 181. (Toxicodendrol.) 

Warren. Pharm. Journ. and Trans., 1909, pp. 531, 562. 

Acree and Syme. Journ. Biol. Chem., ii, p. 547. 

Springenfeldt. Inaug. Diss., Dorpat., 1890. (Mesereum.) 

Cash. Brit. Med. Journ., October 7, 1911. (Chloroxylon.) 

Noel et Lambert. Arch, de Pharmacodyn., iv, p. 169. (Pulsatilla and anemonin.) 



Vm. PURGATIVES. 

Purgatives are drugs which are employed in medicine to evacuate 
the bowel of its contents. Many drugs produce evacuation in the 
course of their action, but have other effects of importance and are not 
included in this class. Thus the members of the preceding class of 
skin irritants induce diarrhoea, but this is accompanied by irritation of 
the mouth, throat and stomach, and in many other forms of poisoning, 
diarrhoea is a prominent feature, but is accompanied by vomiting or 
some other symptom. The ideal purgative is devoid of any effects 
whatsoever, save in the intestine; it passes through the stomach with- 
out materially deranging its function, and is not absorbed, or at any 
rate is absorbed so slowly that it has time to unfold its action through- 
out the intestine. The vegetable purgatives act through their irritant 
properties, which in some instances are elicited only by the action of 
the secretion of the intestines and of the neighboring glands. Thus 
some of the purgatives pass through the stomach in the form of bland, 
non-irritant compounds (castor oil), which are broken up by the digestive 
processes in the intestine, while others perhaps owe their activity in 
the intestine to their solution or supension in the juices. 

Many classifications of the purgatives have been based on their 
effects, and some of the terms are still retained, such as aperient, 
eccoprotic, laxatwe, purgative, cholagogue, hydragogue, cathartic, or 
drastic. But the effect of the purgatives is determined largely by 
the dose and by the condition of the intestine, so that a small dose may 
act as an aperient, laxative or eccoprotic, while a larger quantity of 
the same drug, or even the same dose in a more susceptible individual, 
may act as a drastic or hydragogue cathartic. They are therefore 
classified in three groups: (1) the mild aperients, castor oil group; (2) 
the purgatives of the anthracene series; (3) the jalap and colocynth 

group. 

Symptoms. — In moderate doses the purgatives simply hasten the 
normal movements of the intestines, and the stool is of the ordinary 
appearance and consistency (laxative, aperient, or eccoprotic action). 
In larger quantities they cause a more profuse evacuation than normally, 
and the stools, which are repeated at short intervals, are of a looser, 



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88 SUBSTANCES ACTING LOCALLY 

more fluid consistency. Their action is accompanied by considerable 
pain and colic, and the hurried movements of the intestine are shown 
by the characteristic gurgling sounds. Large quantities of the more 
powerful purgatives may cause all the symptoms of acute enteritis, 
the stools at first contain the ordinary faecal substances accompanied 
by more fluid than usual, but later consist largely of blood-stained 
mucous fluid with little or no resemblance to ordinary faeces. This 
violent purgation, which is not induced in therapeutics, is accom- 
panied by pain and tenderness in the abdomen, and may induce shock, 
collapse, and eventually death. 

Action. — The origin of the fluid of the stools after purgatives has 
been much debated. According to many authors, they accelerate the 
passage of the intestinal contents so much that there is no time for 
the absorption of the fluid, and the faeces escape in the fluid condition 
in which they normally exist in the small intestine. Other investigators 
hold that purgatives cause fluid to pass into the intestine, either by 
increasing the normal secretions, or by causing an inflammatory 
exudate from the vessels. These contradictory views are probably 
due to the methods adopted, and the quantity of the drug used. In 
small quantities, such as are used in the vast majority of cases in thera- 
peutics, the irritation produced by the purgatives is apparently only 
enough to accelerate peristalsis somewhat, and the fluid of the stools 
is drawn partly from the food and partly from the ordinary secretions 
of the digestive organs. In these cases the intestine is not actually 
inflamed, although some congestion may occur in it, as in all organs in 
a state of abnormal activity. On the other hand, when large quantities 
are ingested a true inflammation of the intestine occurs, manifested 
by increased movement, congestion, exudation of fluid into the lumen 
of the bowel, and pain. In these cases the intestine presents the 
usual signs of inflammation; it is red and congested, and contains a 
muco-purulent fluid and often blood. The matter, therefore, resolves 
itself into a question of dose; if it be small, the fluid is not an exudate, 
if it be large the fluid is partly an inflammatory product. The stools 
following the administration of purgatives differ from the normal 
faeces in containing a larger proportion of water and also of soluble 
substances. In fact, they resemble rather the contents of the small 
intestine than the normal excreta, and contain bodies which would 
normally have been absorbed and utilized, but which have been hurried 
through the bowel too rapidly to permit of their being taken up by the 
epithelium. 

The colic produced by purgatives is not due to the inflammation of 
the intestinal wall, but is explained by the more vigorous contractions 
of the walls of the bowel and the difficulty in forcing on hard faecal 
masses in the large intestine. The tenderness produced by large 
quantities of the purgatives, on the other hand, would seem to indicate 
inflammation. 

In the accelerated peristalsis ordinarily induced by the purgatives, 
the central nervous system is not involved ; the irritation of the mucous 



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PURGATIVES 89 

membrane renders it more sensitive to the stimuli which it ordinarily 
receives from the contents, and the nervous impulses resulting from 
these are transmitted to the intestinal nervous plexus and give rise to 
the reflex inhibition and contraction of the muscular coats by which 
the peristaltic movement is carried out. 

The different purgatives seem to act on different parts of the bowel 
(Magnus). Thus senna, and in all probability the other anthracene 
purgatives, appear to have no effect on the movements of the stomach 
and small intestine, but act only in the large intestine; the contents 
reach the colon at the normal rate, but as soon as they have left the 
small bowel, rapid movement begins and they are evacuated almost 
immediately. Castor oil on the other hand accelerates the peristalsis 
of the small intestine, through which the food passes very rapidly, while 
the large gut is much less irritated. Colocynth quickens the movement 
of both small and large intestine and considerable quantities of fluid 
are effused into the lumen. All three arrest the antiperistaltic move- 
ments in the large intestine. 

Some of the purgatives cause evacuation of the bowel when they are 
injected subcutaneously or intravenously (senna, aloes, cascara, colo- 
cynth, podophyllum), and croton oil has long been rubbed on the skin 
in order to relieve constipation, and is found to cause intestinal inflam- 
mation and purging when injected intravenously. It has accordingly 
been suggested that these have a specific action on the bowel quite 
apart from their irritant effects; but it is probable that their intestinal 
effects are here due to their excretion into the bowel, which has been 
shown to occur in several instances. Other irritants applied subcutane- 
ously or intravenously often produce similar effects on the alimentary 
canal. 

The interval which elapses between the administration of a purga- 
tive and its effects varies with the dose, and also with the individual 
drug. In ordinary therapeutic doses, evacuation of the bowels occurs 
in most cases in 5-10 hours, but if large quantities of the more powerful 
purges, such as jalap or croton oil, be given, the effects may be elicited 
in two hours. Aloes and podophyllum differ from the others in the 
length of the interval, catharsis rarely or never occurring earlier than 
10-12 hours after their administration, and often only after 20-24 
hours. 

The movement of the intestine induced by purgatives is accom- 
panied by an increase in the leucocytes of the blood similar to that 
observed in other forms of intestinal activity, e. g. r during digestion. 

The effects of the purgatives vary greatly in different animals. 
Thus, the rabbit is very refractory to most of the series, and often is 
killed by intestinal irritation without any evacuation being produced. 
The frog is unaffected by quantities which would produce poisoning 
in man, while the dog and cat respond much more readily. 

It was formerly supposed that purgatives increased the secretion of 
bile, and certain of them, which were believed to have a special activity 
in this direction, were known as Cholagogues. It has been shown of 



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90 SUBSTANCES ACTING LOCALLY 

recent years that none of them possesses any action on the secretion of 
bile, although they may increase its excretion by hurrying it through 
the intestine and preventing its reabsorption. On the other hand, 
the presence of bile in the intestine is a condition necessary to the 
activity of many of the purgatives. Thus Buchheim and Stadelmann 
found that in the absence of bile podophyllum, jalap, scammony, 
rhubarb, and gamboge are either quite inactive or very much less 
powerful than usual. This is probably due to some solvent action of 
the bile, for Stadelmann found that when soaps were given with some 
of these drugs their activity returned, and in other cases a comparatively 
slight modification of their chemical form was sufficient to restore their 
activity, even in the absence of either bile or soap. Analogous results 
have been observed from other causes than the absence of bile; thus 
some of the pure principles of the purgatives are much less active than 
the crude drugs because the impurities of the latter alter their solubility. 
This alteration of the solubility may act in two ways: if the principle 
is rendered too soluble, it may be absorbed in the stomach and upper 
part of the bowel, and therefore fail to produce purgation; on the - 
other hand, it may be rendered so insoluble that it fails to come into 
intimate contact with the bowel wall, and therefore does not irritate 
it. The effects of such colloid substances as the bile and gums is to 
delay the absorption of soluble substances in the upper part of the 
bowel and at the same time to keep the insoluble resins in suspension. 
Few of the purgatives have any appreciable action after absorption, 
but general effects may be produced indirectly from their intestinal 
action. It is probable that reflexes are elicited by irritation of the 
bowel analogous to those discussed under skin irritants, but in addition, 
the congestion of the bowel produced by its activity must alter con- 
siderably the distribution of the blood in the body. The belief in 
the efficacy of a purge in congestion of the brain may thus be based 
on a true "revulsive" action; for the dilatation of the intestinal vessels 
must necessarily lower the blood-pressure and thereby lessen the blood 
supply to the brain. The congestion of the intestine is accompanied 
by a similar condition in the other pelvic organs, and the purgatives 
therefore often cause congestion of the uterus, with excessive men- 
strual flow, or in the case of pregnant women, abortion. Lastly, a 
certain amount of fluid is withdrawn which would otherwise be 
excreted by the urine, which is found to be proportionately diminished 
in amount. 

1. Mild Aperients, the Castor Oil Group. 

Castor Oil (Oleum Ricini) resembles olive oil in most respects, but 
on saponification forms ricinoleic acid instead of oleic acid. This 
acid (C17H32 (OH)COOH) differs from the fatty acids obtained from 
ordinary oils in being unsaturated and in containing a hydroxyl group. 
Castor oil is itself a bland, non-irritating fluid, but on passing into 
the intestine is saponified by the pancreatic juice, and the ricinoleates 
thus formed are irritant and cause purgation. When the oil is saponified 



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PURGATIVES 91 

and the free acid given by the mouth, the effects are quite different 
from those of the oil, for the taste is acrid and unpleasant, and dis- 
comfort, nausea and vomiting may follow its ingestion from its irritant 
action on the stomach. The oil, on the other hand, has a bland, if 
unpleasant, taste, and produces no effects on the stomach. Several 
other esters of ricinoleic acid have been shown by Meyer to resemble 
the glycerin ester (castor oil) in their purgative effects. 

Castor oil is absorbed from the intestine and disappears in the tissues 
in the same way as an ordinary oil. It may be given in very large 
quantities without producing any symptoms, save those of a mild laxa- 
tive. It is occasionally used as an emollient to the skin, and has been 
employed as a solvent for application to the eye. The harmless nature 
of castor oil is shown by its use in China as an article of diet. 

In the beans from which castor oil is derived, a toxalbumin is found, which 
was at one time supposed to be the active principle of the oil. (See Ricin.) 
It has been shown, however, that the .oil is entirely free from this poison, and 
that its action is due solely to the ricinoleate. 

Preparations. 

Oleum Ricini, a fixed oil expressed from the seed, or bean of Ricinus com- 
munis. Dose, U. S. P., 16 c.c. (4 fl. drs.) ; B. P., 1-8 fl. drs. 

Mistura Olei Ricini (B. P.), made up with cinnamon and orange flower 
water by means of mucilage, 1-2 fl. oz. 

Castor oil is difficult to take owing to its unpleasant taste. It may be given 
alone, in an emulsion flavored with sugar and some volatile oil, in wine, spirits, 
or glycerin, or in flexible capsules. 

• C (CeH40H) 2f 

Phenolphthalein, c#H4< >0 a synthetic substance, has been 

CO 

used of late years as a mild aperient. It is very insoluble in water 
and is not irritant when applied to the ordinary mucous membranes. 
In the bowel it is dissolved by the bile and alkali and develops a mild 
irritant action and thus accelerates the peristalsis in the same way 
as castor oil. Most of the phenolphthalein administered by the mouth 
is not absorbed but appears in the stools. A small amount undergoes 
absorption and is excreted in the urine; if the urine is alkaline it is 
colored a brilliant pink. Phenolphthalein is practically not poisonous 
when ingested intravenously in animals. It causes a mild laxative effect 
when injected subcutaneously, and this arises from its being excreted 
into the bile and thus carried to the gut. In the large intestine it is 
reabsorbed into the blood and again carried to the liver and returned 
to the gut. It therefore acts for several days as a mild aperient, but 
as it is gradually eliminated in the urine and stools, the action passes 
off. Tetrachlorphenolphthalein acts in the same way as phenolph- 
thalein but is excreted only by the bile when injected subcutaneously 
and thus acts for a longer time. 

Phbnolphthaleintjm (B. P.), a crystalline powder, white or grayish-white, 
soluble in 600 parts of water or in 10 parts alcohol. The solution turns red 
when alkali is added. Dose, 0. 1-0.3 G. (2-5 grs.) in powder, pills, or capsules. 
It has been injected hypodermically in solution in olive oil. 

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92 SUBSTANCES ACTING LOCALLY 

Sulphur is in itself an inert body, but while much the greater por- 
tion escapes in the stools unchanged when it is swallowed, some of it 
forms sulphides in the mucous membrane of the intestine, and these 
cause irritation, increased peristalsis and a soft, formed stool; in large 
quantities it has caused, in some instances, more severe symptoms 
with bloody evacuations. The sulphides form some hydrogen sul- 
phide, which gives rise to eructation. Some 10-20 per cent, of the 
sulphur taken by the mouth is absorbed as sulphide, which is excreted 
to a small extent by the lungs, giving the characteristic disagreeable 
odor to the breath, and to a much larger extent by the urine as sulphates 
and in organic combination. In one experiment, Presch found the 
urea of the urine considerably increased (10 per cent.) under sulphur, 
and Umbach found it increased by pure calcium sulphide; whether, 
as this would suggest, the sulphides augment the nitrogenous waste 
as a general rule, can only be determined by further experiment. It 
has been advised in a number of constitutional diseases and in chlorosis 
and joint diseases. 

Applied to the skin in ointment, sulphur appears to be formed in 
part to sulphide, particularly if some alkali be added; the sulphide 
is destructive to animal parasites and sulphur ointment has therefore 
been used in the treatment of scabies, but has been supplanted largely 
by balsam of Peru. 

Preparations. 

Sulphur Sublimatum (U. S. P., B. P.), Flowers of Sulphur, sublimed sulphur, 
and Sulphur Lotum (U. S. P.), washed Flowers of Sulphur, form fine yellow 
powders insoluble in water and very slightly soluble in alcohol. 

Sulphur Prcecipitatum (U. S. P., B. P.), Milk of Sulphur, is prepared from sul- 
phide of calcium by precipitation and forms a fine, almost white powder with- 
out odor or taste, insoluble in water, and only very slightly soluble in alcohol. 

Dose of all three preparations, U. S. P., 4 G. (60 grs.); B. P., 20-60 grs. 

Unguentum Sulphuris (U. S. P., B. P.), formed from sublimed sulphur, 
which is also contained in the Compound Liquorice Powder. 

Trochiscus Sulphuris (B. P.) contains 5 grs. of sulphur. 

Confertio Sulphuris (B. P.), 60-120 grs. 

Crude sublimed sulphur often contains arsenic, but the B. P. preparation is 
practically free from it. The milk of sulphur is in a finer state of division than 
the flowers, and is said to be a somewhat more active aperient. 

Glycerin. — When glycerin is injected into the rectum, it withdraws 
fluid from the mucous membrane and thus causes irritation, persistalsis,, 
and evacuation of the bowels; the stool is of almost ordinary con- 
sistency, and no pain or colic is felt subsequently, nor does the remedy 
cause more than one evacuation. Glycerin may be injected into the 
rectum for this purpose (dose 2-5 c.c, ^-1 teaspoonful), but a more 
convenient form is the glycerin suppositories, Suppositoria Glycerini, 
w r hich are made up with stearic acid and sodium carbonate, U. S. P., 
with gelatin, B. P. These suppositories are found not to keep well, 
as the glycerin tends to attract moisture and then escapes; to avoid 
this they are often encased in paraffin, which is broken off immediately 



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PURGATIVES 93 

before they are inserted. Glycerin suppositories are used in constipation 
instead of the ordinary aperients. I^arge doses of glycerin taken intern- 
ally sometimes cause purgation, but it is not a reliable remedy when 
administered in this way. 

Glycerin in large quantities is poisonous, whether it is taken by the mouth 
or injected hypodermically or intravenously. It is true that no case of glycerin 
poisoning in man is known, but large doses are fatal to animals in the course 
of a few hours. The chief symptoms are restlessness, agitation, acceleration of 
the heart and respiration, general weakness, tremor and convulsions, which 
finally end in somnolence, coma, and death from failure of the respiration. 
Glomerulonephritis has also been observed in animals. Glycerin is absorbed 
rapidly from the intestine, and undergoes combustion in the tissues, only a very 
small fraction of it reappearing in the urine. 



2. The Anthracene Purgatives. 

A number of purgatives, Rhubarb, Senna, Aloes, Cascara and Fran- 
ffula, owe their activity to the presence of irritant anthracene (CuHio) 
compounds, only a few of which have been isolated. The chemical 
examination of these drugs is a matter of great difficulty, as they 
each contain several active principles which are very nearly related 
to each other, and some of which are undoubtedly the products of the 
decomposition of more complex bodies. 

All those which have been completely isolated hitherto have proved to be 
derivatives of anthraquinone, 

CH CH CH CH CO CH 

/\ c /\ c /\ /\ c /\ c /\ 

HC/ \/ \/ VCH HC/ \/ \/ \CH 

hc\ A /\ /ch hc\ A A Jen 

\/ C \/ C \/ \/ C \/ C \/ 

CH CH CH CH CO CH 

Anthracene. Anthraquinone. 

and some of the oxyanthraquinones seem to be widely distributed. Thus all 
the members of the group contain Emodin or trioxymethylanthraquinone, 
(Ci4H4(CH 3 )(OH) 8 Oj), and several of them contain Chrysophanic acid or dioxy- 
methj'lanthraquinone, (CuH*(CH»)(OH) 2 Oj). In addition, a number of other 
anthracene bodies occur in these purgatives, some of them combined with 
sugars to form glucosides, but little is known regarding them and hardly any 
of them are definitely established as pure substances. Among the names applied 
to these bodies are cathartin or cathartic acid, frangulin, aloin > but it is to be 
noted that the bodies designated by these names vary in character and are 
alternately asserted to be pure principles and composite mixtures by different 
investigators. 

None of the pure principles are as satisfactory in their action as the 
crude drugs, perhaps because they are less soluble in the intestine. For 
example, aloin is less certain in its effects than aloes, and it seems to 
be indisputable that the crystalline aloin itself is inactive in the bowel, 
but is there changed under certain conditions to an amorphous corn- 



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94 SUBSTANCES ACTING LOCALLY 

pound which has irritant effects. The presence of bile in the intestine 
is not necessary to elicit the action of this group, except perhaps in the 
case of rhubarb. 

The absorption of these bodies has not been satisfactorily deter- 
mined in most cases. The urine is rendered yellow after rhubarb and 
senna, owing to the absorption and excretion of chrysophanic acid, 
but it is questionable whether the more active principles pass into the 
urine in appreciable amounts. When aloin is injected subcutaneously 
or intravenously, it is excreted for the main part into the bowel, and 
there produces irritation and catharsis. The yellow pigment of the 
urine after rhubarb and senna becomes a purple red on the addition of 
alkalies; the milk and skin also are said to assume a yellowish tinge 
from the presence of chrysophanic acid. 

In the rabbit aloin seldom causes purgation, and is excreted by the 
kidney in considerable quantity, especially when injected hypoder- 
mically. In passing through this organ it causes marked irritation 
and epithelial necrosis, which often proves fatal in a few days. No 
irritation of the kidney occurs in man, the dog, or the cat after aloin. 
Injected intravenously in animals, aloin induces powerful contrac- 
tions of the uterus, apparently from direct action on the organ. The 
same effect probably occurs when it is absorbed from the alimentary 
tract, and its use is not advisable during pregnancy or menstruation. 

Rhubarb contains a considerable amount of tannic acid, which acts 
as an astringent and therefore tends to cause constipation after the 
evacuation of the bowels. It is not well tolerated in some cases, its 
administration being followed by nausea, headache and giddiness, 
more rarely by skin eruptions of different kinds. Senna preparations 
are generally found to have a greater tendency to produce griping 
than the other members of this series. 

Preparations. 

U. S. P. — Rheum, rhubarb, the rhizome of Rheum officinale. 1 G. (15 grs.). 
Extractum Rhei, 0.25 G. (4 grs.). 
Fluidextractum Rhei, 1 c.c. (15 mins.). 

Pilule Rhei Composite (aloes, myrrh, and oil of peppermint), 2 pills. 
Pulvis Rhei Compositus (Gregory's Powder) contains magnesia and ginger. 
Dose, 2 G. (30 grs.). 

Tinctura Rhei y 4 c.c. (1 fl. dr.). 

Tinctura Rhei Aromatica (contains several volatile oils), 2 c.c. (30 mins.). 

g£££ to ABO-AT.CU. ( D °-> 8 - (^ **>• 

B. P. — Rhei Rhizoma, rhubarb, the rhizome of Rheum palmatum; 3-10 grs. 
for repeated administration; for a single administration, 15-30 grs. 

Pilula Rhei Composita (contains rhubarb, aloes, myrrh, and oil of pepper- 
mint), 4-8 grs. 

Pulvis Rhei Compositus (Gregory's Powder) contains rhubarb, light 
magnesia and ginger, 10-60 grs. 

Tinctura Rhei Composita, formed from rhubarb, cardamom and cori- 
ander, J-l fl. dr. for repeated administration; 2-4 fl. drs. for a single admin- 
istration. 

Syrupus Rhei, \-2 fl. drs. 



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PURGATIVES 95 

U- S. P. — Senna, the leaflets of Cassia acutifolia (Alexandria Senna), and 
of Cassia angustifolia (India Senna). 

Fluidextractum Sennm, 2 c.c. (30 mins.). 

Infusxjm Senn^: Compositum (Black Draught) contains senna, manna, 
magnesium sulphate and fennel, 120 c.c. (4 fl. oz.). 

Syrupus Senn^, 4 c.c. (1 fl. dr.). 

Senna is also contained in the compound syrup of sarsaparilla and in the 
compound liquorice powder. 

Senna is often administered as a simple infusion, senna tea, a teaspoonful 
of the leaves being used in a cupful of water. 

B. P. — Senna, the dried leaflets of Cassia acutifolia (Alexandrian senna), and 
of Cassia angustifolia (Tinnevelly senna). 

Syrupus SennjE, £-2 fl. drs. 

Infusxjm Senn^b, £-1 fl. oz.; as a draught, 2 fl. oz. 

MiSTURA SennjE Composita (Black Ih-aught), formed from magnesium sul- 
phate, liquorice, compound tincture of cardamom, aromatic spirit of ammonia, 
and infusion of senna, £-2 fl. oz. 

Confectio SennjE, formed of senna, coriander, figs, tamarinds, cassia, 
prunes, liquorice, and sugar, 60-120 grs. 

U. S. P. — Aloe, the inspissated juice of the leaves of several species of aloe. 

Aloe Purificata, aloes from which insoluble impurities have been removed, 
0.25 G. (4 grs.). 

Aloinum, a neutral principle obtained from aloes, 0.065 G. (1 gr.). 

Extractum Aloes, 0.12 G. (2 grs.). 

PiLUL-fi Aloes, 2 pills. 

Pilulje Aloes et Ferri, 2 pills. 

Tinctuba Aloes, 2 c.c. (30 mins.). 

Aloes is also contained in compound rhubarb pill, compound extract of 
colocynth, and compound tincture of benzoin. 

B. P. — Aloe, the dried juice of Aloe chinensis and other species, 2-5 grs. 

Aloinum, £-2 grs. 

Extractum Aloes, 1-4 grs. 

Pilula Aloes, 4-8 grs. 

Piltjla Aloes et Ferri, 4-8 grs. 

Pilula Aloes et Asafetid.*;, 4-8 grs. 

Decoctum Aloes Compositum (aloes, myrrh, potassium carbonate, liquorice, 
compound tincture of cardamom), £-2 fl. oz. 

Aloes is also contained in the compound extract of colocynth, compound 
colocynth pill, pill of colocynth and hyoscyamus, compound tincture of benzoin 
and compound rhubarb pill. 

U. S. P. — Frangula, Buckthorn, the bark of Rhamnus frangula. 

Fluidextractum FranguUe, 1 c.c. (15 mins.). 

U. S. P. — Rhamnus Purshiana, Cascara sagrada, the bark of Rhamnus 
Purshiana. 

Extractum Rhamni Purshiance, 0.25 G. (4 grs.). 

Fludextractum Rhamni Purshiance Aromaticum, 1 c.c. (15 mins.). 

Fluidextractum Rhamni Purshiance, 1 c.c. (15 mins.). 

B. P. — Cascara Sagrada, the dried bark of Rhamnus Purshianus. 

Extractum Cascam Sagradae Siccum, 2-8 grs. 

Extractum CascarjE Sagrad.*j Liquidum, \-\ fl. dr. 

Syrupus Cascarce Aromaticus, J-2 fl. drs. 

Two artificial compounds of oxyanthraquinone have recently been intro- 
duced under the name of purgatin and exodin. They are quite insoluble in 
water and tasteless but are decomposed in the intestine and act there like the 
other purgatives. Purgatin colors the urine red and has some tendency to irri- 
tate the kidneys. Dose, 0.5-1.0 G. (8-15 grs.), in friable tablets or suspended 
in water. These bodies have no advantages over the natural purgatives and 
the possibility of their inducing nephritis renders their use inadvisable. 



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96 SUBSTANCES ACTISG LOCALLY 

s 

Of these numerous preparations, the most extensively prescribed are 
the pills. The fluid preparations have an unpleasant, bitter taste, and 
are therefore less used, unless when disguised by the addition of sugar 
or volatile oils. The syrups of rhubarb and senna are often admin- 
istered to children, and the confection of senna and the compound 
liquorice powder are also pleasant, easily taken preparations. The 
compound infusion or mixture of senna and the compound rhubarb 
powder are old and tried preparations, in which the virtues of the 
vegetable purgative are combined with those of a saline cathartic and 
antacid respectively; they are both possessed of a harsh, unpleasant 
taste. Frangula is comparatively rarely used, but the fluid extract of 
cascara sagrada, which is practically identical with it, is a very popular 
remedy in habitual constipation. 

3. The Jalap and Colocynfh Group. 

The third group of the vegetable purgatives comprises a number of 
resinous glucosides and acids, whose more intimate chemical structure 
is unknown, though a number of them appear to be nearly related 
chemically, so that it is possible that they all contain a common radicle 
like the members of the anthracene group. 

Jalap resin contains two anhydride glucosides, Convolwdin and Jalapin, 
the latter only in very small quantity. Scammony consists very largely of 
Jalapin. Elaterium contains elalerin, a very powerful purgative of which little 
is known. Podophyllum contains two isomeric principles, Podophyllotoxin and 
Picropodophyllin. Gamboge owes its activity to Cambogic acid, which, how- 
ever, is insoluble, and seldom acts unless it is accompanied by the inactive 
bodies of the crude drug. Colocynthin is a glucoside occurring in the colocynth 
fruit, and forms Colocynthein and sugar when treated with acids; colocynthein 
is said to be even more irritant than colocynthin. Euonymus owes its activity 
to a resinous glucoside, Euonymin. Croton oil contains a resinous anhydride 1 
dissolved in an inactive oil. The seeds from which the oil is obtained contain a 
poisonous protein, but this is not contained in the oil. Many other plants con- 
tain similar resinous purgative substances, and some of these are used as remedies 
to some extent, but so little is known of their properties and they are so seldom 
employed that they may be omitted here. 

Action. — These substances are in general much more powerful than 
any of the other purgatives, and are therefore classed together as the 
drastic purgatives or hydragogue cathartics. In small quantities they 
cause evacuation more rapidly than the anthracene purgatives, and 
in somewhat larger doses produce profuse watery stools with much 
pain and often tenesmus. In cases of poisoning, the bowel undergoes 
acute inflammation, and blood is passed in the stools, which often 
contain shreds of epithelium from the walls. The irritant action is not 

1 The action of croton oil is often stated to be due to crotonoleic acid derived from the 
oil in the same way as ricinoleic acid is obtained by the saponification of castor oil. This 
is incorrect, however, the croton resin which is the active principle of croton oil having no 
relation to the oil in which it is dissolved. Several other plants contain similar principles, 
e. g., Jatropha curcas, which bears the Barbadoes nuts, or purging nuts, and Garcia 
nutans and several species of Omphalea (Cash). 



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PURGATIVES 97 

confined to the bowel apparently, for their administration is some- 
times followed by uneasiness in the stomach, and occasionally by nausea 
and vomiting. On, the other h$nd, moderate quantities are said not to 
induce colic so frequently as some of the anthracene purges. 

Several of these resinous purges are irritant to the skin and especially to 
the mucous membranes of the eye ; nose, and throat. Thus jalap, podophyl- 
lum and colocynthin all cause pain and irritation when they are applied to 
the nostrils in fine powder, and croton oil and podophyllum have been used as 
skin irritants. 

The presence of bile in the intestine increases the purgative action of almost 
all these bodies, and in fact, seems essential for the action of most of them. 

Podophyllotoxin and colocynthin cause purgation when injected subcu- 
taneously; this is probably owing to their excretion into the bowel, as the 
former has been detected in the faces after this method of administration. Podo- 
phyllotoxin causes glomerular nephritis and haemorrhages into various organs 
when administered hypodermically or intravenously in large quantities, and 
when added to blood in a test-tube, it causes the formation of methaemoglobin 
in the corpuscles. It has been said to have a depressant action on the central 
nervous system, but this is probably a result of the shock and haemorrhage 
produced by its intestinal action. Colocynthin is said to cause renal inflam- 
mation when applied subcutaneously or taken internally, and even when the 
powder is inhaled dining its manufacture. Jalapin and convolvulin given by 
the mouth cannot be found in the faeces or urine, and are therefore supposed to 
undergo partial or complete oxidation in the body. Convolvulin is found in 
the urine, however, when it is injected intravenously, and no purgation follows 
this method of administration; so that it is probable that convolvulin is decom- 
posed in the bowel when it is administered internally. Euonymin has the same 
effect on the heart as digitalis, and will be mentioned along with it, although 
it has a mild purgative action and is used chiefly as an aperient. 

Preparations. 

Colocynthis (U. S. P.), Colocynthidis Pulpa (B. P.), colocynth, the fruit of 
Citrullus Colocynthis deprived of its rind. 

Extradum Colocynthidis (U. S. P.), 0.03 G. (i gr.). 

Extractum Colocynthidis Compositum (U. S. P., B. P.) (containing colo- 
cynth, aloes, scammony and cardamom), 0.5 G. (7£ grs.) (B. P., 2-8 grs.). 

PiLULuB Cathartics Composite (U. S. P.) (compound extract of colocynth, 
jalap, gamboge, and calomel), 2 pills. 

Pilule Cathartics Vegetabiles (U. S. P.) (contain compound extract 
of colocynth, jalap, leptandra, podophyllum, hyoscyamus and oil of pepper- 
mint), 2 pills. 

Pilula- Colocynthidis Composita (B. P.) (colocynth, aloes, scammony 
resin, potassium sulphate and oil of cloves), 4-8 grs. 

Pilula Colocynthidis et Hyoscyami (B. P.) (compound pill of colocynth 
and extract of hyoscyamus), 4-8 grs. 

Oleum Tiglii (U. S. P.), Oleum Crotonis (B. P.), a fixed oil expressed from 
the seed of Croton Tiglium. 0.05 c.c. (1 min.). 

Podophyllum (U. S. P.), PodophylM Rhizoma (B. P.), the rhizome and roots 
of Podophyllum peltatum. 

Fluidextractum PodophyUi (U. S. P.), 0.5 c.c. (8 mins.). 

Resina Podophylu (U. S. P., B. P.), 5-15 mgs. GVJ gr.); B. P., J-l gr. 

Tinctura Podophylu (B. P.), 5-15 mins. 

Podophyllin varies considerably in composition, and ought to be avoided. 

Jal&pa (U. S. P., B. P.), the tuberous root of Exogonium Purga (U. S. P.), 
of Ipomcea Purga (B. P.). 0.3-1 G. (5-15 grs.). 

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98 SUBSTANCES ACTING LOCALLY 

Resina Jalaps (U. S. P., B. P.), 0. 125 G. (2 grs.); 2-5 grs., B. P. 

Pulvis Jalaps Compositus (U. S. P., B. P.) contains jalap and bitartrate 
of potassium. 2 G. (30 grs.); 10-60 grs., B. P. 

Scammonias Radix (B. P.), Scammony r^ot, the dried root of Convolvulus 
Scammonia. 

Scammonium (U. S. P.) Scammonice Resina (B. P.), 0.2 G. (3 grs.); 4r-8 grs., 
B. P. 

Scammony is also contained in the compound colocynth preparations. 

Euonymus (U. S. P.), Euonymi Cortex (B. P.), Wahoo, the dried root-bark 
of Euonymus atropurpureus. 

Extractum Euonymi (U. S. P.), 0. 125 G. (2 grs.)- (B. P.), 1-2 grs. 

Efoterinum (U. S. P.), CjoHmO*, a neutral principle obtained from elaterium, 
a substance deposited by the juice of the fruit of Ecballium Elaterium 
(squirting cucumber). 5 mgs. (iV gr.). 

Trituratio Elaterini (U. &. P.) (one part elaterin in 9 parts sugar of milk), 
0.03G.(igr.). 

Cambogia (U. S. P. ), Gamboge, a gum resin obtained from Garcinia Han- 
burii. Dose, 0.125 G. (2 grs.). 

The resinous purgatives are generally administered in pill form; 
very frequently two or more are combined in one pill, or they may be 
prescribed along with extract of belladonna or hyoscyamus, or with a 
drop of some carminative oil or resin, to prevent the pain and griping 
which often accompanies their action. Croton oil is often given in a 
pill made up with breadcrumb, or a single drop may be given on a 
lump of sugar or in solution in castor oil. The importance of these 
purgatives is much less than it was formerly, and several of them are 
very seldom used; the most important are colocynth, podophyllum, 
croton oil, and jafap. In large doses they act rapidly, with the excep- 
tion of podophyllum, which induces purgation very slowly (10-20 
hours). 

Therapeutic Uses of the Purgatives. — The purgatives are employed 
to cause evacuation of the bowel when for any reason its peristalsis is 
slow. In the choice of a purgative, the advantages of the vegetable 
purgatives must be weighed against those of the saline cathartics and 
of the mercurial preparations. In ordinary constipation of short 
standing, in which the peristalsis may merely seem somewhat more 
sluggish than usual, the milder laxatives are prescribed — castor oil, 
sulphur, senna, rhubarb, aloes, frangula, or cascara sagrada. The 
first two cause least disturbance of the bowel, but are disagreeable to 
take, and are less commonly prescribed for adults than rhubarb or 
cascara, or small doses of colocynth or podophyllum. In children or 
in debility in adults, senna and castor oil are frequently used; sulphur 
is often given along with magnesia in constipation in children, and in 
haemorrhoids in which it is often beneficial, not owing to any specific 
action on the haemorrhoids but because it renders the stools softer 
and less liable to cause irritation mechanically. 

In chronic constipation which cannot be controlled by hygienic 
measures, or by the use of a special dietary such as fruits, or coarse 
meal, and where the intestine has apparently taken on a sluggish 
habit, rhubarb, cascara, aloes, phenolphthalein, or colocynth may be 



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PURGATIVES 99 

ordered, but the saline cathartics often prove more satisfactory. 
Rhubarb tends to cause some constipation after its laxative effects, 
but is often used in these cases, as it possesses some bitter stomachic 
action, which compensates for its astringent after-effects. This bitter 
action is often given to the other purgatives by the addition of gentian, 
nux vomica, or cinchona. In obstinate constipation, in which the 
bowel contains hard faecal masses, the milder purgatives often provoke 
griping without relieving the condition, and in these cases larger doses 
of colocynth, jalap, podophyllum, or croton oil are used, along with 
some of the extracts of the atropine group or with a carminative oil. 
They may be prescribed along with some of the saline cathartics, as 
in the compound infusion of senna or the compound powder of jalap. 

Croton oil is used especially where the drug is required to be of 
small bulk and the administration is attended with special difficulty; 
thus in unconsciousness or mania, one or two drops may be given on 
sugar. In lead colic, croton oil is said to act more rapidly and efficiently 
than the others. 

In some forms of diarrhoea constant irritation seems to be kept up 
by the presence of irritants in the bowel, and the indications are the 
removal of these by a purge rather than the administration of astrin- 
gents. Castor oil, senna and rhubarb are especially adapted for this 
purpose; the first two because they increase the irritation of the bowel 
less than the others, the latter because of its subsequent astringent 
action. 

A purgative is often administered as a preliminary in the treatment 
of malaria, syphilis and other conditions, and seems to have beneficial 
effects, although these are difficult to explain. In the beginning of 
acute fevers also, a purge is often useful, perhaps through the conges- 
tion of the bowel withdrawing the blood from the rest of the body, or 
through the removal of poisonous substances formed by the decom- 
position of the intestinal contents. In congestion of the brain and in 
high blood-pressure a purgative is often administered with good 
effects, which may also be attributed to the accumulation of blood in 
the mesenteric circulation, to the actually lessened bulk of the blood, 
and perhaps to some action analogous to counter-irritation of the skin. 
For these purposes a sharp purge is generally used, such as croton oil 
or some other of the jalap and colocynth series. 

The more powerful purgatives, especially elaterin, were formerly 
largely used to remove fluid from the body in cases of dropsy or 
oedema, and they were generally prescribed along with the saline 
cathartics for this purpose. Other means, such as diuretics, are gen- 
erally preferred now from a fear that the violent purging may weaken 
the patient, but good results are often obtained by means of this 
treatment, especially as a preliminary to the use of digitalis. 

The specific action of aloes on the uterus, perhaps aided by the 
congestion of the pelvic organs from its purgative effects, has led to 
its use in amenorrhoea; it is generally administered along with iron, 
which improves the condition of the blood. 



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100 SUBSTANCES ACTING LOCALLY 

The purges act as intestinal disinfectants by removing the micro- 
organisms mechanically, though the vegetable purges are less used 
for this purpose than calomel. A purgative is administered to remove 
poisons in the intestine when they have pased beyond the stomach 
or when they are excreted into the bowel. 

Purgatives are contra-indicated in conditions of acute intestinal 
irritation, and during menstruation and pregnancy, owing to the con- 
gestion of the pelvic organs, which may lead to an excessive flow in the 
one case and to abortion in the other; aloes is especially dangerous 
in these conditions. In collapse, asthenia and anaemia, powerful pur- 
gatives are contra-indicated, owing to the irritation they produce. In 
hemorrhoids, aloes is often said to do harm by increasing the conges- 
tion of the rectum, and powerful purges are injurious from the straining 
they cause, but if constipation is present, a mild purgative is beneficial. 
In all those conditions, if a purgative is required, either castor oil, 
senna, or rhubarb ought to be chosen. 

Repeated attempts have been made to produce evacuation of the bowels 
by substances injected subcutaneously, but the ordinary purgatives are not 
suitable as they cause intense pain at the seat of injection. Physostigmine 
has been employed frequently, and more recently tetrachlorphenolphthalein 
has been used by Abel and Rowntree in solution in oil. 

Another method by which the purgatives may be administered is in enema. 
The addition of purgatives, such as castor oil, and of bile to the ordinary 
enemata has been practised for many years, and small quantities of other 
purgatives have occasionally been employed in oil or glycerin. 

Bibliography of the Purgatives. 
Purgative action in general. 

Brunton. Practitioner, xii, p. 342. 

Stadelmann. Berliner klin. Woch. f 1896, p. 181. Archiv. f. exp. Path. u. Pharm., 
xxxvii, p. 352. 

Wood. Amer. Journ. of Med. Sciences, lx, p. 75. 

Hitler. Ztschr. f. klin. Med., iv, p. 481. 

Kohlstock. Charite-annalen, xvii, p. 283. 

Magnus. Ergebnisse der Physiologic, ii, (2), p. 661. (Literature.) 

Tappeiner. Arch, internat. de Pharmacodyn., x, p. 80. 

Dixon. Brit. Med. Journ., Oct. 18. 1902. 

Castor oil group. 

Meyer. Arch. f. exp. Path. u. Pharm., xxviii, p. 145: xxxviii, p. 336. 

Magnus. Arch. f. d. ges. Phys., cxxii, p 261. 

Abel and Rowntree. Journ. of Pharmacology, i, p. 231 (phenolphthalein) . 

Presch. Virchow's Archiv, cxix, p. 148 (sulphur). 

Umbach. Arch. f. exp. Path. u. Pharm., xxi, p. 166 (sulphur). 

Heffler. Ibid., Ii, p. 175 (sulphur). 

Taegen. Ibid., lxix, p. 263 (sulphur). 

Anthracene purgatives. 

Aloin. Meyer. Arch. f. exp. Path. u. Pharm., xxviii, p. 186. 
Kohn. Bed. klin. Woch., 1882, p. 68. 
Murset. Arch. f. exp. Path. u. Pharm., xix, p. 310. 
Esselmont. Ibid., xliii, p. 274. 



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SALINE CATHARTICS 101 

Tsckireh. Bericht. d. deutsch. pharmaceut. Gesellsch., 1898, p. 174. 
Senna. Stockman. Arch. f. exp. Path. u. Phann., xix, p. 117. 
Magnus. Arch. f. d. ges. Phys., cxxii. p. 251. 
Vielh. Munch, med. Woch., 1901, No. 35. 
Frangula. Baeumker. Inaug. Diss., Gottingen, 1880. 
WeyL Pflfiger's Archiv, xliii, p. 367. 

Jalap and Colocynth Series. 

Podophyllum. Podwyssotzki. Arch. f. exp. Path. u. Phann. xiii, p. 29. 

Neuberger. Ibid., xxviii, p. 32. 

Disquc. Inaug. Diss., Rostock, 1913. 

Jalap. J. Midler. Inaug. Diss., Dorpat, 1885. 

Scher. Inaug. Diss., Dorpat, 1895; Virchow-Hirsch Jahresber., 1895, p. 380. 

Coloctnth. Padtberg. Arch. f. d. g. Physiol., cxxxiv, p. 627. 

Elaterium. Kdhler. Virchow's Archiv, xlix, p. 408. 



DC. SALINE CATHARTICS. 

Dilute solutions of such salts as the chlorides, iodides, and bromides 
of the alkalies are absorbed rapidly from the alimentary canal, but 
some of the other salts of these metals apparently permeate the epithe- 
lium with greater difficulty, and their solutions therefore remain unab- 
sorbed for a longer time in the intestine. The contents of the intestine 
and the stools thus contain more fluid than usual and these salts are 
known as the saline cathartics. The chief salts of sodium and potassium 
which have this intestinal action are the sulphates, phosphates, tartrates 
and citrates; less known ones are the malates and ferrocyanides. 

In these effects the acid constituent, or anion, is obviously the chief 
factor, for the same base, or cation, is present in readily absorbed salts 
such as the chlorides. And no pronounced differences between the 
action of chlorides and sulphates are observed, unless the salt can be 
given in large quantities, as is possible in the case of the salts of the 
alkalies. The effects of the sulphate and hydrochlorate of morphine, 
for example, may be taken as identical, because the anion is present 
in so small amount as to be practically inert. 

The anion of a salt may also fail to be taken up readily by the bowel; 
for example, magnesium chloride is absorbed slowly although other 
chlorides permeate rapidly, and magnesium salts thus act as purgatives 
in the same way as sulphates. When both ions are slowly absorbed, 
as in the case of magnesium sulphate, the cathartic action is naturally 
more powerful than when only one has this character. 

The chief saline cathartics used in therapeutics are the sulphate of 
sodium (Glauber's salt), the sulphate of magnesium (Epsom salt), 
the double tartrate of sodium and potassium (Rochelle salt) and the 
phosphate of sodium. In addition the oxide and carbonate of magnesium 
have some purgative action from being formed into soluble salts in the 
stomach and intestine. But besides these, many other salts are slowly 
absorbed and might therefore be used for this purpose. Thus the 
sulphates, citrates, or tartrates, of any of the alkalies or of the non- 
poisonous alkaloids might be used for this purpose, provided they are 
soluble, and any of the magnesium salts might be used in the same way. 



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102 SUBSTANCES ACTING LOCALLY 

Symptoms. — The external application of solutions of the saline 
cathartics has the same effect as that of any other indifferent salts, 
such as sodium chloride. 

Most of the cathartics have a harsh, bitter, unpleasant taste, and 
when taken in concentrated solution, may induce some nausea, partly 
from the taste, and partly from the " salt-action' ' on the stomach, 
which they possess like other soluble bodies. Dilute solutions, however, 
provoke no such symptoms, but after one or two hours induce a profuse 
watery evacuation of the bowels. This is sometimes preceded by some 
pain and griping, but these are not nearly so frequent or so severe as 
after the vegetable purgatives. Not infrequently the urine is increased 
in amount afterward, or it may be found to have an unusually high 
percentage of salts. If a moderate quantity of a dilute solution be given, 
only one evacuation follows, but large doses of concentrated solutions 
induce repeated stools, which at first contain some fsecal matter, but 
later consist mainly of bile-stained mucous fluid. 

Action: Intestine. — The saline cathartics differ from the vegetable 
purgatives in not inducing irritation of the intestine, unless when they 
are given in very large quantities. The characteristic effect is not 
irritation, but retarded absorption. The slow absorption of the salt 
entails the slow absorption of the fluid in which it is dissolved, for the 
salt holds on to the water and only permits of its being taken up by 
the bowel if an equivalent amount of salt is also absorbed. If a solution 
of sodium chloride isotonic with the blood serum be administered by 
the mouth to a dog with a csecal fistula, little or none of it reaches the 
wound, as it is all absorbed in the stomach and small intestine. If, 
on the other hand, an equal amount of an isotonic solution of sodium 
sulphate be administered in the same way, most of the solution 
escapes by the fistula, only some 10-20 per cent, having been absorbed 
by the stomach and small intestine. In a normal dog or in the human 
subject, a much larger amount of fluid therefore reaches the large intes- 
tine if sodium sulphate be dissolved in it than if sodium chloride be 
used instead. The contents of the large intestine are consequently 
more fluid than usual, and are passed down more easily toward the 
rectum. At the same time the weight and distention of the bowel 
induces increased peristalsis and the whole is evacuated. This increased 
peristalsis is due, however, not to any irritant action such as has been 
found to be induced by rhubarb or croton oil, but to the large amount 
of fluid contents. 

This accelerated passage along the bowel has been observed in man 
by means of the Rontgen rays, and appears to resemble that previously 
described in animals. When the distended small intestine empties 
its contents into the colon, the large bowel adopts a more rapid but 
otherwise normal movement and this leads to the evacuation of the 
rectum; the first stool may thus be of almost normal consistency, 
but this is generally followed by a profuse watery movement which 
may contain the greater part of the salt administered. 

If a weaker solution of sodium sulphate is administered, the only 



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SALINE CATHARTICS 103 

difference is that more of the fluid is absorbed and less reaches the 
large intestine; but however weak the solution, more of it reaches 
the large intestine than if a correspondingly weak solution of common 
salt had been given. 

If a hypertonic solution be administered, the effect is somewhat 
different. The salt is still unabsorbed, but it draws fluid from the 
blood into the bowel from its having higher osmotic pressure than the 
blood. A similar draining of the body fluids occurs when concen- 
trated solutions of common salt reach the bowel, but the cathartic 
salts are much more powerful, because they do not pass out of the 
bowel into the blood so easily. Instead of an exchange of salt and 
fluid being carried on by the blood and intestinal contents, the blood 
gives up its fluid without any sufficient compensation in salt. Even- 
tually the intestinal fluid becomes isotonic, and then. some absorption 
of both salt and fluid occurs; in fact, some salt has been absorbed all 
along, as the epithelium is not absolutely impermeable to the cathartics. 
But much less of the sulphate is absorbed than of the chloride given 
in equal concentration, and as a general rule a strong solution causes 
such an accumulation of fluid that the bowel becomes distended and 
evacuates its contents. If, however, from any cause this fails to occur, 
a gradual absorption follows and the whole salt and fluid in the bowel 
is absorbed. These salts may fail to purge, for example, when the 
blood and tissues contain very little fluid, as in animals which have 
been deprived of water for several days previously. In this case the 
osmotic pressure in the bowel is unable to draw fluid from the con- 
centrated blood, which on the other hand has a higher attraction 
for the fluid in the bowel than usual. But where large quantities of 
fluid are present in the tissues, as in oedema and dropsy, the saline 
cathartics drain them through the blood into the bowel, and very 
profuse evacuation occurs, with the disappearance of the exudate. 

The saline cathartics fail to penetrate the intestinal epithelium, 
just as sodium chloride fails to penetrate the blood corpuscles (p. 26), 
through some peculiar physical character, which prevents them following 
the ordinary process of diffusion and which is at present unknown. 
In this relation it has been found by Hofmeister and Pauli that the 
purgative salts have a greater tendency to precipitate proteins and 
have less tendency to permeate into unorganized colloids than most of 
the non-purgative salts. In numerous other instances the sulphates, 
tartrates, and other cathartic anions have proved slower in permeating 
into living cells than the chlorides and bromides, and their effects on 
the blood cells, muscle, nerve, and some other tissues show marked 
deviations from those of the halogen salts. Another curious relation 
between the purgative anions is that their calcium salts are all very 
much less soluble than those of the salts which penetrate the epithelium, 
and it seems probable that they precipitate the calcium in the bowel 
wall. Most of the cathartic anions are bivalent or trivalent, but this 
is not true for all of them, for the higher members of the acetate series 
are absorbed with the greatest difficulty by the intestine. 



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104 SUBSTANCES ACTING LOCALLY 

The saline cathartics induce certain changes in the Blood indirectly 
through their action on the intestine. They prevent the absorption 
of the fluid of the food, or, if in sufficient concentration, actually draw 
fluid from the blood and tissues into the bowel, and under both con- 
ditions the blood becomes more concentrated than usual; in the first 
case because it is not reinforced by the usual amount of fluid from 
the food, in the second because it actually loses fluid into the intestine. 
This concentration of the blood leads to a sensation of thirst, and to 
a lessened excretion of fluid by the kidneys and other glands. 

A certain amount of salt and of fluid is absorbed from the intestine, 
unless purgation follows very rapidly, and this salt acts in the blood 
and tissues in the same way as the salts which do not act as cathartics. 
When very dilute solutions of these salts are given, therefore, the 
blood becomes less concentrated and diuresis follows, but this does 
not occur so soon as after a similar solution of common salt, because 
the absorption is somewhat slower. Stronger cathartic solutions 
at first cause a concentration of the blood and lessened urine, but 
afterward the excess of salt in the blood may cause diuresis. The 
greater the purgative action, the less the diuretic, because more fluid 
and more of the cathartics are thrown out in the stools. If no purga- 
tion follows for any reason, as when the blood has been concentrated 
by long abstinence from water, the whole of the salt eventually passes 
into the blood and is excreted by the kidney, and may cause very con- 
siderable diuresis and a still further concentration of the blood. The 
sulphates are absorbed by the epithelium of the renal tubules with 
much greater difficulty than chloride, and thus offer osmotic resistance 
to the absorption of the fluid in the tubules; sulphates absorbed into 
the blood therefore induce a more profuse diuresis than an equal amount 
of chloride, but less of the former reaches the blood generally, so that 
the chlorides are better practical diuretics. 

From the above it can be at once inferred that a saline cathartic 
injected intravenously causes no purgation, for instead of preventing 
the passage of fluid from the bowel into the blood, it rather encourages 
its absorption by increasing the osmotic pressure of the blood. And 
similarly the hypodermic injection of these salts is not followed by 
purging. A certain amount of discussion has been carried on in the 
last few years on this point, but the result has been to confirm this 
view and to indicate that experiments which seemed to oppose it were 
erroneously performed. 

The statement is sometimes made that the saline cathartics act as 
cholagogues, i. e., increase the secretion of bile, but this has not been 
confirmed by more careful observations. 

The Temperature is often somewhat reduced by the action of the 
saline cathartics, but seldom more than one-half degree. 

The habitual use of saline cathartics is often efficient in Reducing 
the Weight in obesity, and many of the natural mineral waters have 
a considerable reputation in the treatment of such cases. This appears 
to be due in part to less proteins and fats being absorbed from the 



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SALINE CATHARTICS 105 

intestine, in part to the fluids of the body being decreased. There 
seems no reason to suppose that any marked change in the nitrogenous 
metabolism is induced by the cathartics, for the nitrogen in the urine 
is often practically unaltered in amount. 

When purgation follows the administration of a saline cathartic, 
the most of the salt escapes in the feces, never having been absorbed 
at all. When the salt fails to purge, however, and is absorbed, it 
undergoes the usual exchanges in the tissues and is excreted by the 
urine. There is no reason to suppose that any of it appears again in 
the stomach or intestine. 

The Sulphates seem to pass through the tissues without injuring them, 
and but little effect is observed from injecting considerable quantities into 
the blood. When the sulphate ion is combined with a poisonous base, such as 
potassium or magnesium, the injection is of course followed by characteristic 
symptoms; but the anion seems to be comparatively harmless, and when the 
potassium or magnesium salt is taken by the mouth it also is quite devoid of 
general action. 

The Phosphates are also very inactive after absorption. When they are 
injected subcutaneously or intravenously the metaphosphates and pyrophos- 
phates are poisonous, but this appears to be due to their alkalinity (Starken- 
stein). Phosphates absorbed in man and in the carnivora are excreted by the 
kidney and increase the acidity of the urine; in the herbivora they are excreted 
exclusively by the bowel wall. 

The Tartrates are slowly oxidized in the tissues to carbonates but a con- 
siderable quantity is excreted in the urine unchanged. Injected into the blood 
directly, the tartrates seem to act as heart poisons, and in the rabbit nephritis 
is induced by their hypodermic application, but no such effects are observed 
in man from their administration by the mouth even in enormous quantities. 

The oxide and carbonate of magnesium differ from the other saline 
cathartics in being very insoluble and in possessing an alkaline reaction. 
Part of that ingested is formed into magnesium chloride in the stomach, 
however, and the carbonic acid present in the intestine may dissolve 
part by forming the bicarbonate. Their alkalinity serves to remedy 
any excessive acidity of the stomach or intestine, while at the same 
time they are mildly cathartic. The prolonged use of large quantities 
of magnesia has in some cases led to the formation of large concretions 
in the bowel, resulting in obstruction. 



Preparations. 

Sodii Sulphas (U. S. P., B. P.), Glauber's salt (Na*S0 4 , 10H 2 O), soluble in 
about 3 parts of cold water, 16 G. (240 grs.) ; B. P., 30-240 grs. 

Magnesii Sulphas (U. S. P., B. P.). Epsom salts (MgS0 4 , 7H 2 0), soluble in 
1 J parts of cold water, 16 G. (240 grs.); B. P., 30-240 grs. 

These are crystalline salts with a harsh, bitter taste. 

Sodii Phosphas (U. S. P., B. P.) (Na 2 HP0 4 + 12H 2 0), a crystalline salt 
with a cool, saline taste, soluble in about 6 parts of cold water, 2 G. (30 grs.); 
B. P., 30-120 grs. (repeated), 150-240 grs. (single). 

Liquor Sodii Phosphatis Compositus (U. S. P.) contains sodium nitrate and 
citric acid. Dose, 8 c.c. (2 fl. drs.). 



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106 SUBSTANCES ACTING LOCALLY 

Potassii Bitartras (U. S. P.), Potassi Tartras Addas (B. P.), cream of tartar 
(KHC4H4OO, a crystalline powder with a pleasant acidulous taste, soluble in 
200 parts of water, 2 G. (30 grs.); B. P., 15-60 grs. % 

Potassii et Sodii Tartras (U. S. P., B. P.), Rochelle salt (KNaC^O. 
+ 411*0), crystals or powder with a cool saline taste, soluble in 1.2 parts of 
cold water, 8 G. (120 grs.); B. P., 120-240 grs. 

Magnesia (B. P.), Magnesii Oxidum (U. S. P.), magnesia (MgO). 2 G. 
(30 grs.); B. P., 5-60 grs. 

Magnesii Carbonas (U. S. P., B. P.) (MgCO,) 4 Mg(OH), + 5H,0). 3 G. 
(45 grs.); B. P., 5-60 grs. 

These form white amorphous powders with an earthy, not saline, taste. 
They are insoluble in water, but the carbonate is dissolved by excess of carbonic 
acid. 

Effervescing Preparations. 

Pulvis Effervescenb Compositus (U. S. P.), Pulvis Sod^e Tartaratjb 
Effervescens (B. P.), Seidlitz powder. 

This. powder is made up in two papers, of which the blue one contains a 
mixture of 3 parts of Rochelle salts and one part of sodium bicarbonate, in all 
10.4 G. (160 grs.), while the white paper contains 2.25 G. (2.5 G. B. P.) of 
tartaric acid. When the powders are dissolved separately in water and the 
solutions mixed, the tartaric acid acting on the bicarbonate releases carbonic 
acid with effervescence. 

Liquor Magnesii Citratis (U. S. P.) is a solution of magnesium citrate with 
excess of citric acid to which potassium bicarbonate is added. The whole is 
bottled tightly and effervesces when the cork is removed. 360 c.c. (12 fl. oz.). 

Magnesii Sulphas Effervescens (B. P., U. S. P.), a mixture of Epsom salts, 
sodium bicarbonate, tartaric, and citric acids, which effervesces when mixed 
with water. 16 G. (240 grs.); B. P., 60-180 grs. for repeated administration; 
for a single administration J-l oz. 

Sodii Sulphas Effervescens (B. P.), a similar mixture containing the sulphate 
of soda instead of that of magnesia. 60-120 grs. for repeated administration; 
for a single administration i~i oz. 

Sodii Phosphas Effervescens (B. P., U. S. P.), similar to the above, but con- 
taining the phosphate in place of the sulphate. 8 G. (120 grs.); B. P., 60-120 
grs. for repeated administration and J-J oz. for a single administration. 

Many other effervescent mixtures are used instead of the official ones — among 
them the tartrates and citrates of the alkalies, the acetate of magnesium, etc. 

The sulphates of sodium and of magnesium, the tartrates of sodium and 
potassium and the phosphate of sodium are given in solution, the last often in 
milk. Unless under special conditions the salts ought not to be in greater 
concentration than 5-10 per cent. Magnesia and magnesium carbonate are 
administered in powder, sweetened if necessary. The effervescent preparations 
are always to be taken in solution in about a tumbler of water; in some instances 
in which this was not understood, severe distention of the stomach with alarm- 
ing symptoms have arisen from the carbonic acid being freed in the stomach. 
The effervescent preparations ought to be kept dry, and the solution of mag- 
nesium citrate has to be kept tightly corked. 

Very often the natural mineral waters are used instead of the pharmaco- 
pceial preparations, the best known purgatives among these being the Hunyadi- 
Janos water and Carlsbad water, which contain the sulphates of sodium and 
magnesium. "Carlsbad salts" are obtained by the evaporation of the waters, 
but are very often artificial imitations. Many other springs have the same 
effects, and a widespread belief exists that the natural waters are "more effi- 
cient" or "less depressant" or have some mystical virtues that are not shared 
in by the artificial salts, but this belief does not seem to have any real basis, 
and is probably a survival of the old religious belief in the healing properties 
of springs. 



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SALINE CATHARTICS 107 

In the natural waters the purgative salts are always accompanied by other 
less active ones, such as the chlorides of sodium, calcium, etc. 

Agar-Agar may be mentioned here as, although it has no chemical relation to 
the saline cathartics, its action presents certain analogies and it has been used 
for similar purposes. It is obtained from various East Indian sea-weeds, and 
consists mainly of gelose, a carbohydrate which is indigestible and unabsorbable 
and retains water in the alimentary canal in the same way as the saline cathar- 
tics. It thus increases the bulk of the contents of the bowels and causes their 
evacuation. It is used in constipation in quantities of 5-15 G. (75-225 grs.), 
either suspended in water or food. It is almost tasteless. 

Other inert and unabsorbable fluids may be used to increase the intestinal 
contents and thus promote peristalsis; thus the liquid petrolate or paraffin 
(p. 48) has been advised in constipation. 

Therapeutic Uses. — The saline cathartics are very largely used to 
relieve constipation. Habitual constipation seems to be caused by 
insufficient peristalsis, and the slow passage of the contents through 
the intestines allows of a more complete absorption than usual, this in 
turn rendering the faeces hard and dry and difficult to move onward. 
The saline cathartics increase the fluidity of the intestinal contents, 
and thus facilitate their expulsion, and this is probably the only effect 
they have when taken in small quantities, and especially in dilute 
solution as in the natural mineral waters. In larger quantities, how- 
ever, more water is retained in the bowel, and the weight and disten- 
tion cause peristalsis, while in sufficient quantity they draw fluid 
from the blood and cause profuse watery discharges. When a very 
complete evacuation is desired, the saline cathartics may be given 
along with some of the vegetable purgatives. Such mixtures are the 
official Black Draught (see Senna) and the compound powder of Jalap. 
The saline cathartics act much more rapidly than the vegetable pur- 
gatives, and a common method of combining their effects is to give 
the latter in the evening and the saline the following morning; in the 
same way a mercurial purge, such as calomel, given in the evening, 
may be followed by a Seidlitz powder in the morning. 

The chronic constipation due to sedentary habits is much benefited 
by the saline cathartics, more especially by dilute solutions taken 
before breakfast. The sulphates and tartrates are harsh and unpleasant 
to the taste, and the natural waters are often preferred, or one of 
the effervescent preparations may be used in those cases. 

The sulphates and tartrates are more frequently used where a single 
large dose has to be prescribed in order to empty the bowel, but here 
also the Seidlitz powder may be advised instead, as being more agreeable 
to the taste. These cathartics were at one time used in fever, partly 
from a theory that they reduced the temperature; they are certainly 
less liable to cause pain and griping than the vegetable purgatives, 
and thus tend to disturb the patient less. 

The sodium phosphate is often prescribed for children, either as a 
powder to be given in jelly, or in solution in milk or other food, which 
completely hides its taste. 

The saline cathartics are used to lessen intestinal putrefaction, and 



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108 SUBSTANCES ACTING LOCALLY 

are sometimes very efficient, though they do not act through any anti- 
septic power, but simply by removing the putrefying mass. The 
phosphate of sodium has been especially recommended in some forms of 
diarrhoea in children. 

The saline cathartics are administered to remove accumulations of 
fluid in the body arising from cardiac or renal insufficiency, or from 
an old effusion. For this purpose the sulphate of magnesium is used 
in a large dose, dissolved in about its own weight of water; if purgation 
does not follow in 1-3 hours, an enema may be necessary, or the saline 
may be given along with a vegetable purgative. This form of treat- 
ment was very popular at one time, but is liable to weaken and depress 
the patient, and is specially contra-indicated, therefore, in asthenic 
conditions. Other methods of removing accumulations of fluid are by 
the use of diuretics (see caffeine), diaphoretics (see pilocarpine), or 
cardiac remedies (digitalis). 

As diuretics the saline cathartics are inferior to other salts, such 
as the acetates or nitrates. Large quantities of dilute solutions of the 
purgative salts are of value in the treatment of some forms of obesity, 
the mineral waters being generally prescribed for this purpose, or the 
patient being sent to drink them at their source. 

Magnesia and magnesium carbonate are less liable to purge than 
the soluble salts, and are specially indicated in hyperacidity of the 
stomach or in acid putrefaction in the bowel. They cause less irritation 
than the carbonates of the alkalies because of their insolubility, and 
at the same time have the advantage of acting as mild purgatives, 
while the lime preparations which are insoluble, tend to induce con- 
stipation. The magnesia preparations may be used also in diarrhoea 
as antacids, as they have no irritant action on the bowel. A com- 
bination of antacid, carminative, saline and vegetable aperient is found 
in Gregory's powder, which contains magnesia, rhubarb, and ginger 
(p. 94). Freshly prepared magnesia is recommended in arsenic poison- 
ing to form an insoluble precipitate in the stomach, and in poisoning 
with acids it is also of value when it can be obtained readily. In both 
cases it is to be given in large quantities. 

The phosphate of sodium has been given in various bone diseases, as in osteo- 
malacia and rickets, this treatment being founded on the belief that the soften- 
ing of the bones is due to the lack of phosphates in the food, but there is no 
reason to suppose that this idea is correct, and the treatment is not attended 
with success. It has also been recommended in the uric acid diathesis. The 
phosphates have been supposed to be of benefit in nervous diseases, on the 
theory that these were due to the insufficiency of phosphorus in the brain, and 
glycerophosphates have been introduced for the same reason, but there is 
never any deficiency in the supply of phosphates in the food, and in practice 
no benefit is seen from the use of these salts. 

Bibliography. 

Hay. Saline cathartics, Journ. of Anat. and Phys., xvi and xvii; also in monograph, 
Edinburgh, 1884. 

London. Zts. f. klin. Med., xiii, p. 48. 

Dapper. Ibid., xxx, p. 371. Arch. f. Verdauungskrank, iii, p. 1. 



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VEGETABLE ASTRINGENTS 109 

Heidenhain. Pflttger's Archiv, lvi, p. 579. 

Kdvesi. Centralbl. f. Physiol., 1897, p. 553. 

Hamburger. Arch. f. Anat. u. Phys., 1896, p. 428. 

Hdber. Pfliiger's Archiv, lxx, p. 624. 

Wallace and Cushny. Am. Journ. of Physiol., i, p. 41 1. PflQger's Archiv, Ixxvii, p. 202. 

Gamgee, Priestley, and Larmuth. Journ. of Anat. and Phys., xi, p. 255. (Phosphates.) 

Bergmann. Arch. f. exp. Path. u. Pharm., xlvii, p. 77. 

Swiatecki. Ztschr. f. phys. Chem., xv, p. 49. 

Padtberg. Arch. f. d. ges. Physiol., cxxix, p. 476. 

Heer. Arch, internat. de Pharmacodyn., xxi, p. 321. „ 

X. VEGETABLE ASTRINGENTS— TANNIC ACID SERIES. 

A large number of vegetable substances owe their action to their 
containing tannin substances, while in many other preparations the 
effect of more important constituents is modified by the presence of 
these widely distributed bodies. Tannic acid proper (C14H10O9) is 
a very feebly acid substance derived from the oak gall, and seems to 
consist of an anhydride combination of gallic acid, C 7 H 6 6 , into which 
it is very easily decomposed. Gallic acid is formed from a large number 
of other bodies which closely resemble tannic acid in their general 
features, but are by no means identical with it. Their constitution 
is altogether unknown, but they possess a number of reactions in 
common and are generally classed together as the tannic acid substances. 
Some of them contain a sugar, and tannin or tannic acid is therefore 
sometimes said to be a glucoside. These bodies precipitate albumins, 
gelatin, alkaloids and some glucosides, and the salts of the heavy 
metals; the salts of iron form a bluish-black or greenish-black precipi- 
tate. 

Action. — The pharmacological effects of these bodies are due to 
their precipitating albumins and other proteins, and this reaction 
may therefore be described before their action in the body. If tannic 
acid solution be added to a neutral solution of albumin or gelatin, 
a white precipitate falls, which is entirely insoluble in water, but is 
soluble in excess of albumin or gelatin, in acetic or lactic acid, and in 
alkaline solutions. 1 Solutions of pepsin and of peptones are also pre- 
cipitated by tannic acid unless in the presence of an acid. If protein 
tannate be exposed to the action of the gastric juice, it undergoes 
digestion and is dissolved in the same way as an ordinary coagulated 
protein such as fibrin. During the process the tannic acid is set free 
from its combination apparently, and can precipitate undigested 
proteins, although it has no effect on the peptones in the acid medium. 
When a soluble tannate Js formed by the addition of soda or potash to 
a tannic acid solution, the presence of proteins produces no precipitate, 
the affinities of the acid being satisfied by the alkali, and for the same 
reason the tannic acid precipitate is dissolved in the presence of alkalies. 

Tannic acid applied to animal tissue, as in the tanning of leather, 
causes a precipitation of the proteins, and the tissue becomes harder 

1 Some discrepancies in the accounts of different authors in regard to these reactions 
are perhaps due to variations in the amount of the neutral salts in their preparations. 



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110 SUBSTANCES ACTING LOCALLY 

and tougher and tends to shrink together; at the same time it has less 
tendency to undergo putrefactive changes and does not lose its flexi- 
bility, as it would in drying. 

Tannic acid solutions have a harsh, bitter, "astringent" taste, and 
produce in the mouth a feeling of constriction, dryness and roughness, 
along with a sense of stiffness in the movements of the tongue, and some 
loss of taste. These effects are due to the coagulation of the superficial 
layers of protein both within and without the epithelium, which substi- 
tutes for the ordinary smooth surface a firmer, less even one over which 
the tongue can no longer move easily. The feeling of constriction may, 
perhaps, be caused by an actual shrinking of the superficial layers of 
the epithelium, or may be due merely to the impaired movements and 
sensation. 

The astringent feeling is continued in the throat as the solution is 
swallowed, and occasionally some discomfort or even nausea and vomit- 
ing are provoked by it, but as a general rule, no such effects are 
observed. The stools are rendered harder and firmer by the admin- 
istration of tannic acid, and constipation is often produced by it. In 
excess, tannic acid sometimes causes irritation of the intestine and 
diarrhoea, but beyond these symptoms of local irritation of the stomach 
and bowel, no effects arise from even enormous quantities of the drug. 

In the stomach, tannic acid combines with any protein substance 
with which it may come in contact and precipitates it, but as digestion 
progresses, this combination is broken up, as the peptones do not com- 
bine with tannic acid in acid solution, and the astringent action is 
therefore exercised on the walls of the stomach and intestine. Ordinary 
quantities cause the same superficial coagulation as in the mouth, 
but if large doses be given when the stomach and intestine are not 
protected by foodstuffs, a more complete coagulation of the mucous 
membrane takes place and the consequent irritation results in vomit- 
ing, and sometimes in diarrhoea. The increase in the consistency of 
the stools is probably due to the layer of coagulated protein acting as 
a protective to the bowel, lessening its irritability and thus retarding 
its movements so that there is longer time for the absorption of the 
fluid part of its contents, although this proceeds more slowly under 
tannic acid than normally (Gebhardt). The secretion of mucus by 
the intestinal epithelium is lessened (Frey), and this may also retard 
the passage of the contents. Hesse states that the constipating action 
is exercised chiefly in the large bowel when tannalbin is given, but this 
may not hold for the ordinary forms of tannin. Yeasts and microbes 
are precipitated by tannin, and this may tend to lessen the fermenta- 
tion in the bowel in some cases, although some preparations of tannic 
acid which have been examined in regard to this point have been found 
to have little or no effect on intestinal putrefaction. 

The local application of tannic acid causes a diminution of the 
secretions of glands, as has been demonstrated by Schtitz. This is 
due to its effects upon the protoplasm of the secreting cells, which 
probably undergo the initial stages of coagulation. 



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VEGETABLE ASTRINGENTS 111 

It is often stated that tannic acid constricts the vessels of any part 
to which it is applied, but this is not supported by accurate observations. 
In acting as a protective to mucous surfaces, it may reduce congestion, 
but there is no reason to suppose that it acts more directly on the vessel 
walls, or, in fact, that it ever reaches them in an active form. In the 
same way it may indirectly lessen the inflammatory exudation from 
the vessels and the leucocytosis. 

When tannic acid comes in contact with blood in a test-tube it pre- 
cipitates the proteins, and when it is injected intravenously, the pre- 
cipitate formed leads to the formation of emboli. 

The fate of tannic acid in the body has given rise to some discussion. 
When it is taken internally, a small proportion is sometimes eliminated 
by the bowel unchanged, but very often none is to be found in the stools; 
traces are apparently absorbed and excreted in the urine in both man 
and animals, although some investigators have failed to detect these. 
When sodium tannate is administered internally, a distinctly larger 
amount of it is absorbed and reappears in the urine. But much the 
greater part of the tannic acid is decomposed in the intestine into gallic 
acid, some of which often passes out in the stools, some in the urine. 
Only about 1 per cent, of the tannic acid swallowed reappears in the 
excretions, either as tannic or gallic acid; the rest apparently undergoes 
complete oxidation in the tissues, for no further trace of it can be found. 
After tannic acid is administered, some tannic or gallic salt is present 
in the blood, for iron salts give a darker color to it, but it is impossible 
to state whether this is tannin or a gallate, although in all probability 
it is the latter. According to Harnack, the gallic acid in the urine 
sometimes forms pyrogallol on standing, but this poisonous substance 
is not formed from tannic acid in the intestine or tissues. 

Tannic acid then does not exist in the tissues as such, but only in 
the form of traces of the gallate or tannate of sodium, which are so 
small as to be devoid of astringent properties. The effects of tannic 
acid are therefore limited to the point of application, and there is no 
evidence of any weight that it exercises any action after absorption. 
The alkaline tannates are generally believed to be entirely devoid of 
astringent effects, but the tannic acid is freed to some extent by such 
feeble acids as carbonic acid, so that the astringent action is present 
in the intestine. 

Tannic acid is often said to lessen the albuminuria in certain forms of Bright's 
disease, but the only exact determinations which have been made in man 
showed that no such effect was present, and in Ribberts' experiments the 
animals were moribund when the improvement occurred, and no safe deduc- 
tions can be made therefore. The urine is sometimes said to be diminished 
by tannic acid, but this statement is based on error. Last of all, tannic acid 
is said to lessen internal hemorrhage by contracting the vessels, but tannate 
of sodium, the only form in which it can exist in the blood is entirely devoid of 
action. 

Gallic acid given by the mouth is absorbed and is excreted by the kidneys 
to some extent. Much of it disappears in the tissues, however, apparently by 
oxidation. Gallic acid has no astringent properties and is quite useless in 
therapeutics. 

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112 SUBSTANCES ACTING LOCALLY 

The numerous preparations of the pharmacopoeias which owe their activity 
to their containing tannic acid, differ from the pure drug in that the acid is 
only slowly dissolved out from the colloid mass, and therefore acts less on the 
stomach and affects a greater length of intestine. 

Preparations. 

Acidum Tannicum (U. S. P., B. P.), tannic acid, gallotannic acid or digallic 
acid (HCuH»0»), an organic acid obtained from nut-gall. 0.5 G. (7 J grs.); 
B. P., 5-10 grs. 

Glyceritum Acidi Tannici (U. S. P.), Glycerinum Acidi Tannici (B. P.). 

Unguentum Acidi Tannici (U. S. P.), 20 per cent. 

Trochisci Acidi Tannici (U. S. P.), 0.06 G. (1 gr.); (B. P.), £ gr. in each. 

Suppositoria Acidi Tannici (B. P.), 0.2 G. (3 grs.) in each. 

Gambir (U. S. P.), an extract prepared from the wood of Ourouparia Gambir, 
1 G. (15 grs.). 

Tinctura Gambir Composita (U. S. P.), (flavored with cinnamon), 4 c.c. 
(1 fl. dr.). 

Gambir has been substituted for the Catechu of former editions of the U. S. P. 

Catechu (B. P.), an extract of the leaves and young shoots of Uncaria 
Gambier, 5-15 grs. 

Tinctura Catechu, J-l fl. dr. 

Trochiscus Catechu, each containing 0.06 G. (1 gr.) of catechu. 

Pulvis Catechu Compositus contains catechu, kino, krameria, cinnamon, and 
nutmeg, 10-60 grs. 

Krameria (tL S. P.), Krameriae Radix (B. P.), Rhatany, the root of Krameria 
triandra, Krameria ixina and Krameria argentea. 

Extractum Kramerle (B. P.), 0.3-1 G. (5-15 grs.). 

Fluidextractum Kramerice (U. S. P.), 1 c.c. (15 mins.). 

Tinctura Kramerice (U. S. P., B. P.), 4 c.c. (1 fl. dr.); B. P., £-1 fl. dr. 

Trochiscus Kramerice (B. P.), each containing 1 gr. 

Kino (U. S. P., B. P.), the inspissated juice of Pterocarpus Marsupium, 0.5 
G. (74 grs.); B. P., 5-20 grs. 

Tinctura Kino (U. S. P., B. P.), 4 c.c. (1 fl. dr.); B. P., J-l fl. dr. 

Pulvis Kino Compositus (B. P.), contains 5 per cent, of opium, 5-20 grs. 

Other astringent drugs of this series, which offer no advantages over those 
already given are Witchhazel (Hamamelidis Folia and Cortex), the leaves 
and bark of Hamamelis Virginiana; Logwood ( Hcematoxylon) , the wood of 
Haematoxylon campechianum; Eucalyptus gum (Kino Eucalypti), obtained 
from several species of Eucalyptus; Nut-gall (GaUa) an excrescence on one of 
the oaks caused by the punctures and ova of an insect, Cynips Gallae tinctoria. 
These are still contained in the pharmacopoeias, but promise to follow a large 
number of similar bodies which have been discarded. 

Several new preparations of tannic acid have been introduced into thera- 
peutics of late years, chiefly for use as intestinal astringents. Tannic acid itself 
is liable to produce irritation of the stomach, and to be decomposed or ab- 
sorbed to a large extent before it reaches the large intestine, and although 
the cruder preparations are less liable to these changes, even they are by no 
means devoid of disagreeable features. Meyer, therefore, introduced tannigen, 
or diacetyl tannin, which is insoluble in water but appears to be dissolved in 
the intestine and there to act like tannic acid. Tannoform and tannopin are 
similar compounds. Tannalbin is a combination of tannic acid and albumen, 
dried at such a temperature as to prevent the action of the gastric juice upon it, 
but capable of l>eiiig broken up by the more powerful pancreatic fluid. It is 
entirely insoluble and is not astringent until digested in the bowel, so that it 
has no irritant action on the stomach and is tasteless. Tannocol is a combina- 
tion of tannic acid and gelatin, resembling tannalbin in most respects. The 
dose of these artificial compounds is 0.5-2 G. (10-30 grs.) in powder. 



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VEGETABLE ASTRINGENTS 113 

Several combinations of gallic acid have been introduced of late years as 
astringents, but they are merely inert protective powders. 

Therapeutic Uses. — The preparations of tannic acid ought to be used 
for their local effects exclusively. They are applied externally in 
cases of excessive secretion, as in local sweating or weeping ulcers, and 
occasionally to harden the skin. For this purpose tannic acid may be 
used in solution in water, or in the form of the glycerite or ointment, 
or some other fluid preparation may be preferred. A similar use is 
made of the metallic astringents, lead, zinc, and alum salts. Tannic 
acid is used as a mouth wash in cases of swollen gums, or relaxed 
throat, and may here be prescribed in a flavored solution or in the 
form of lozenges, of which the pharmacopoeia offers a choice. In 
certain forms of diarrhoea the astringent action of tannic acid is of 
considerable value, and occasionally when such drugs as cod-liver 
oil cause diarrhoea, tannic acid prevents this action without hindering 
their general effects. The pure drug is seldom used in these cases, 
as it is liable to derange the stomach and to form compounds with the 
albumins before it reaches the bowel, and catechu, krameria or kino 
is accordingly prescribed, either in the form of pills or in fluid prepara- 
tions ; a useful preparation is the compound kino powder, which com- 
bines the astringent action of tannin with the specific action of opium 
on the intestine (compare the similar preparations of lead and opium). 
Tannic acid stops hemorrhage by precipitating the proteins, when it 
comes into immediate contact with the bleeding point, but it is not 
of so much value for this purpose as some of the metallic astringents. 
When the bleeding point can be reached directly the pure acid is used, 
but for hemorrhage of the intestine or stomach one of the extracts is 
preferred. Large enemata containing tannic acid have been advised in 
cholera, dysentery, and similar conditions. 

In cases of poisoning with metals and alkaloids, tannic acid is often 
used to cause their precipitation in the stomach, but the tannate 
formed must be removed at once, as it is gradually dissolved in the 
digestive fluids. The administration of tannic acid is therefore only 
a temporary expedient to allow of active measures being taken to 
empty the stomach. 

Some individuals are peculiarly susceptible to the action of tannic 
acid, which induces local irritation and inflammation wherever it is 
applied in these cases. 

Bibliography. 

Hennig. Arch. f. physiol. Heilkunde, xii, p. 599. 

Lcwin. Virchow's Archiv, lxxxi, p. 74. Deutsch. med. Woch., 1904, p. 803. 
Stockman, Brit. Med. Journ., 1886, ii, p.- 1077. Arch. f. exp. Path. u. Pharm., xl, p. 147. 
Mdrner. Ztschr. f. phys. Chem., xvi, p. 255. 
Heinz, Virchow's Archiv, cxvi, p. 220. 
Schaix. Arch. f. exp. Path. u. Pharm., xxvii, p. 202. 
Meyer. Deutsch. med. Woch., 1894, p. 626. 
Gotlleib. Ibid., 1896, p. 163. 
Rost. Arch. f. exp. Path. u. Pharm., xxxviii. p. 346. 

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114 SUBSTANCES ACTING LOCALLY 

Harnack. Zeitschr. f. phyaiolog. Chemie, xxiv, p. 115. 
Flatow. Deutsch. med. Woch., Therap. Beilaaj., 1899, p. 37. 
Straub. Arch. f. exp. Path. u. Pharm., xlii, p. 1. 
Oebhardi. Deutsch. Arch. f. khn. Med., Ixvi, p. 585. 
Frey. Arch. f. d. ges. Phys., cxxiii, p. 491. 
Hesse. Ibid., cli. p. 363. 

XI. BILE. 

The bile is very seldom used in therapeutics at the present day, 
although it was formerly credited with great healing virtues. It has 
a bitter taste, and may have some effect like the vegetable bitters, but 
has no advantage over these, and is not likely to be used to promote 
the appetite now, although it was formerly used a a stomachic. The 
bile is found to precipitate the peptones in test-tube experiments, but 
does not appear to retard digestion in the stomach materially, judging 
from experiments carried out in a case of gastric fistula. In the in- 
testine it is generally believed to act as an antiseptic, chiefly because 
the stools have a strong putrefactive odor in cases of retention of bile. 
Limbourg has also shown that the addition of bile to protein solutions 
delays their decomposition, while there is some evidence that it pro- 
motes pancreatic digestion. It has some purgative action, as is shown 
by the obstinate constipation which often occurs when it is prevented 
from reaching the intestine; according to Stadelmann, the bile acids 
irritate the mucous membrance of the large bowel and thus induce 
purgation. Some of the drastic purgatives fail to act in the absence of 
bile, apparently because they are not dissolved by the other secretions 
(p. 90). Bile increases the activity of the fat-splitting ferment of the 
pancreas and thus augments the absorption of fats, but it is doubtful 
whether bile given by the mouth has this action. Most of the bile 
given by the mouth is absorbed in the intestine and carried to the 
liver, which excretes it again, while a small quantity of the bile acids 
escapes in the urine. In the liver it increases the secretion of both the 
fluid and the solids of the bile; in fact, the bile is the only reliable 
cholagogue known. The constituent which acts on the secretory liver 
cells seems to be the bile acids, and their increase is greater than can 
be accounted for merely by the excretion of that administered, so that 
it would seem that they exercise some specific stimulant action on the 
secretory cells. The bile pigment is also augumented when bile acids 
are absorbed, owing to the destruction of the red cells of the blood, as 
the liberated haemoglobin is carried to the liver and there formed into 
bile pigment. 

Bile given by the mouth does not cause any symptoms except those from 
the intestine and liver. WheD it is injected into the blood, however, it depresses 
the central nervous system and the heart muscle from its direct action on these 
organs, and dissolves the red cells of the blood in the same way as the saponins, 
which it resembles in reducing the surface tension. Muscles and nerves sus- 
pended in a solution of bile salts rapidly lose their irritability, and some uni- 
cellular organisms are killed and dissolved by them. The poisonous constituent 
of the bile seems to be the salts of the bile acids, but several authors have stated 
that the pigment is also active. 



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ANTHELMINTICS 115 

Fraser discovered that the bile acts to some extent as an antidote to the 
snake venoms through its containing cholesterin, which retards the absorption of 
the venom; it is much more efficient when it is mixed. with the poison before its 
application, than when it is injected after the bite. Others have found that the 
bile of animals dying of an infectious disease (rinderpest) possesses some cura- 
tive properties in other animals suffering from the same malady, this being 
explained by the excretion of the antitoxin in the bile. 

Bile has been used as a purgative, and it has been particularly recom- 
mended in the form of an enema. It does not seem to be reliable, 
however, and presents no advantages over soaps and similar sub- 
stances. 

As a cholagogue it is without rival, but no condition is known in 
which an increase of the bile secretion is indicated, for though it has 
been proposed to expel gall-stones by raising the pressure in the gall- 
ducts by cholagogues, it is found that when the pressure is only slightly 
increased, the secretion is arrested. It is inconceivable that the small 
rise in pressure could force out an impacted gall-stone. 

Bile might be used to aid the absorption of fats, particularly when 
it is deficient in the bowel; in a case of biliary fistula Joslin found that 
much less fat and nitrogenous food escaped in the stools when the 
patient was treated with bile pills, than when no treatment was adopted. 

Preparations. 

Fd Bovia (U. S. P.), ox gall, the fresh bile of the ox. 

Fel Bovis Pwrificatum (U. S. P.), Fd Bovinum Purificatum (B. P.), is formed 
from the fresh bile by the addition of alcohol, filtration and evaporation to 
pillular consistency. 

Bile is always prescribed in the form of pills made from the purified prep- 
aration. 0.5G. (7i grs.) ; B. P., 5-15 grs. 

Bibliography. 

Stadehnann. Arch. f. ezp. Path. u. Pharm., xxxvii, p. 352. Ztschr. f. Biolog., xxxiv, p. 1. 

Rywosch. Arb. a. d. pharm. Instit. su Dorpat, ii, p. 102; vii, p. 157. 

LimbouTQ. Ztschr. f. phys. Chem., xiii, p. 196. 

Pfaff and Balch. Journ. of Ezp. Med., ii, p. 49. 

Frater. Brit. Med. Journ., 1897, ii, pp. 125 and 595; 1898, ii, p. 627. 

Joslin. Journ. of Ezp. Med., v, p. 513. 

Cohnheim. Biochem. Centralbl., i, p. 171. 



XH. ANTHELMINTICS. 

Anthelmintics are drugs which are used to kill or remove intestinal 
worms. They are often divided into vermicides and vermifuges, 
according as they kill or merely cause the expulsion of the worm, 
but this is determined largely by the quantity which comes in contact 
with the parasite and the rapidity with which the bowel is evacuated. 

In order to possess any value as an anthelmintic, a drug must, of 
course, act more strongly on the parasite than on the host, and this 
more intense effect may be attained either by a specific action on the 
parasite, or by the drug failing to be absorbed from the alimentary 



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116 SUBSTANCES ACTING LOCALLY 

canal. As a matter of fact, the anthelmintics have not been shown 
to possess any such specific action, but seem to injure most forms of 
living matter; this has been demonstrated more particularly for muscle 
tissue. Their use is thus rendered possible only by their slow absorp- 
tion which permits of their acting on the parasite in greater concen- 
tration than on any of the tisues of the host. 

Before the administration of an anthelmintic, the bowel ought to be 
emptied of its contents as far as possible by a light, easily digested 
diet and a laxative, and a brisk purge ought to follow some hours 
later, in order to remove the dead or stupefied worm. The anthel- 
mintic is often prescribed along with a purge. 

A number of drugs belonging to other groups are used occasionally 
as anthelmintics. Thus several of the volatile oils — tansy, turpentine- 
have some reputation; and chloroform is also administered occasionally 
by the mouth for its action on the parasites, but, like the volatile oils, 
is apt to produce gastric and intestinal irritation. The less easily 
absorbed antiseptics, such as naphthol, have been used with good 
results. Large enemata of salt solutions, or of infusion of quassia, 
are thrown into the rectum when the worms infest the large intestines. 
Many other drugs enjoy some popular reputation as "worm-cures," 
but have proved inferior to the recognized remedies. 

Male fern, cusso and pomegranate are those most largely used for 
tapeworm; thymol has been used with great success in hookworm 
(uncinariasis) while santonin is the chief anthelmintic in infection with 
round worm. 

1. Male Fern (Aspidium, Filiz-mas). 

A number of ferns contain bodies which present considerable resem- 
blance to each other from a chemical as well as from a pharmacological 
point of view, and which may therefore be classed together, at any 
rate until further information is available regarding them. The best 
known of these is the male fern (Aspidium, Filix-mas). 

The active constituent of this remedy was supposed to be Filicic Acid by 
Poulsson, but Boehm has found other neutral and acid bodies present, Aspid- 
inin, Flavaspidic Acid, Albaspidin, and Aspidinol — and Kraft has added 
Filmaron and Flavaspidinin. These bodies are all derivatives of phloroglucin 
and butyric acid, and it is still uncertain whether the effects of male fern are 
to be attributed to any one of them or whether all of them may not share in 
the action. Jacquet holds that the chief therapeutic factor is the filmaron, but 
that the others also have some effect. 1 

Action. — The extract or olepresin of male fern, which is the only 
one of these plants used in regular medicine, as a general rule passes 
through the bowel without causing any symptoms whatever. The 
quantity of active substance dissolved, while sufficient to destroy the 

1 Nearly related bodies have been found in Aspidium athamanticum (Uncomocomo) , 
which contains two forms of Pannic Acid, and in Aspidium spinulosum, while smaller 
quantities of acids occur in a large number of ferns. Several of these ferns enjoy a repu- 
tation as anthelmintics for tapeworm, and their virtues are generally considered due to 
these bodies. 



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ANTHELMINTICS 117 

parasite, is too small to produce any effects on the host, and escapes 
with the other contents of the bowel, or if absorbed does not cause 
any symptoms. In rare cases, however, where large quantities are 
administered, or where some unknown conditions favor the absorption 
and retention of an unusually large amount of the active constituents, 
grave and even fatal symptoms may supervene. These consist in 
vomiting and purging, with acute pain in the abdomen, muscular 
weakness, confusion and somnolence, with occasional twitching of the 
muscles, or slight convulsive movements, collapse, coma, and death. 
The stomach and intestine are found congested and swollen, and some- 
times covered with small ecchymoses. In some cases icterus has been 
observed to follow the administration of male fern, probably from the 
duodenal catarrh, but possibly from destruction of the red blood cells 
the number of which has been found to be diminished in some instances 
(Georgiewsky). In other cases permanent or temporary blindness has 
resulted from neuritis and subsequent atrophy of the optic nerve. 

In the rabbit, filicic acid produces very similar symptoms. The congestion 
of the stomach and intestine is evidently due to the local irritation produced 
by the poison, while the other symptoms point to changes induced in the cen- 
tral nervous system. The spinal cord is stimulated, for the reflex excitability 
is increased, but the higher parts of the central nervous system seem. to be 
depressed, and the paralysis of the respiratory centre is the cause of death, 
although the heart is also weakened by filicic acid. Inflammation of the kidney 
is said by some authors to occur, and in some cases Poulsson found evidence 
of glycuronic acid in the urine. 

In the frog, a mixture of depression and stimulation of the central nervous 
system is produced by filicic acid, along with distinct diminution in the strength 
of the skeletal muscles and the heart. 

Aspidin (from Aspidium spinulosum) causes dyspnoea .and paralysis of the 
spontaneous and respiratory movements in frogs* fibrillary twitching of the 
muscles sets in after some time and is succeeded oy convulsive movements or 
tonic spasms, which indicate an increased activity of the reflexes of the spinal 
cord. The heart is depressed and eventually paralyzed, and the peripheral 
muscles are also weakened. The muscular tissue of the invertebrates is more 
powerfully affected by the constituents of male fern, and Straub attributes its 
action on the tapeworm to its paralyzing muscle. Mammals do not seem to 
be affected by aspidin injected hypodermically or administered by the mouth, 
but when it is introduced directly into the bloodvessels, it proves fatal by 
paralyzing the respiratory centre. Aspidinin induces very similar symptoms 
in the frog, while the other constituents are less active. 

The blindness which has been observed in some cases of male fern poison- 
ing has also been produced in dogs; it occurs chiefly in young, weakly, and 
anaemic individuals. 

Pannic acid differs from filicic chiefly in its acting more strongly on muscle 
and less on the central nervous system of the frog. 

Preparations. 

Aspidium (U. S. P.), Filix-mas (B. P.), Male fern, the rhizome of Dryopteris 
Filix-mas and of Dryopteris marginalis. 

Oleoresina Aspidii (U. S. P.), 2 G. (30 grs.). 

Extractum Fiucis Liquidum (B. P.) contains 20 per cent, of active princi- 
ples, 45-90 mins. 

These are practically identical in composition; the first is an acetone, the 
second an ether extract. 

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118 SUBSTANCES ACTING LOCALLY 

Therapeutic Uses. — Male fern is used exclusively in the treatment of 
tapeworm and of Anchylostomum duodenale. Previous to its admin- 
istration the bowel ought to be emptied, as far as possible, by a mod- 
erately light diet for one or two days and, where necessary, by a 
purgative. The oleoresin, or liquid extract, is then to be administered 
in the form of pills or enclosed in a capsule or suspended in mucilage, 
and another purgative is required some 6-12 hours later. In case 
the parasite fails to be dislodged, several days ought to be allowed to 
elapse before a second dose is given. Poulsson recommends that oily 
substances be avoided during the "cure," as they dissolve the active 
bodies, and thus promote their absorption. Other authorities dispute 
this view and some consider that oils in dissolving the active principles 
render them more poisonous to the parasites, but it is certainly sug- 
gestive that in many cases of poisoning with male fern castor oil had 
been given along with it or soon after. Marked anaemia, general debility 
and chronic alcoholism seem to predispose to male-fern poisoning, and 
the drug is accordingly to be used with care in these conditions. 



Bibliography. 

Poulsson, Arch. f. exp. Path. u. Pharm., xxix, p. 1; xxxv, p. 97; xli, p. 246. 

Robert. Therap. Monatsheft, 1893, p. 136. 

Birch-Hirschfeld. Graefe's Arch. f. Ophthalmologic, l. f p. 225. 

Jacquel. Therap. Monataheft, August, 1904. 

Georgiow8ky. Ziegler's Beitrage, xxiv, p. 1. 

Boehm. Arch. f. exp. Path. u. Pharm., xxxv, p. 1; xxxviii, p. 35. 

Straub. Ibid., xlviii, p. 1. 

Walko. Deutsch. Arch. f. klin. Med., lxiii, p. 348. 

2. Cusso. 

Cusso, or Kousso, contains a neutral body, Kosotoxin, which is 
soluble in alcohol and in alkaline fluids, but is insoluble in water; it is 
a compound of phloroglucin and butyric acid like the constituents 
of male fern, which it resembles somewhat in its pharmacological 
action. 

Cusso has a bitter, somewhat astrigent taste, and sometimes causes 
nausea and vomiting and some looseness of the bowels. In rare cases 
prostration and collapse, with irregularity of the pulse, are said to 
have occurred from its use. 

In the frog, kosotoxin paralyzes the nerve ends like curara, and has a 
specific action on the striped muscular tissue, which it weakens and eventually 
paralyzes. The heart muscle undergoes similar changes. In mammals the 
muscular action is well developed, but is accompanied by some stimulation of 
the medullary centres, indicated by rapid, dyspnoeic breathing, salivation and 
vomiting. The stools are often fluid, and the urine is increased in amount. 
When it is injected directly into the circulation, some convulsive movements 
are often observed, and the heart is weakened and paralyzed. Kosotoxin 
seems to be a general protoplasm poison, as is indicated by its action on muscle, 
and by its retarding the growth of yeast. 



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ANTHELMINTICS 119 

Preparations. 

Cusso (U. S. P., B. P.), (Kousso or Brayera), the pistillate flowers of Hagenia 
Abyssinica (Brayera anthelmintica). 

Cusso is generally given by suspending 15 G. (J oz.) of the powdered flowers 
in water. Kosotoxin has not yet been prescribed for therapeutic purposes. 
The usual preliminary treatment ought to be instituted, but no purge is required 
after Cusso as a general rule. It is used exclusively as an anthelmintic in cases 
of tapeworm. 

Bibliography. 

Leichtenrino- Arch. d. Pharm., ccxxxii, p. 50. 
Handmann. Arch. f. exp. Path. u. Pharm., xxxvi, p. 138. 

3. Pelletierine. 

The bark of the pomegranate contains a very large amount of tannic 
acid (20-25 per cent.), along with several alkaloids, of which Pelle- 
tierine, or Punicine, and Isopunicine alone are active in ordinary doses. 
All the pomegranate alkaloids are closely related chemically to each 
other and to tropine (see atropine). None of them can be classed 
among the more active poisons as far as man and the higher animals are 
concerned. 

In man, large doses cause heaviness, confusion, giddiness, and very 
marked weakness of the limbs. The consciousness is but little affected 
but the sight is often dim and uncertain, and in' one case complete 
blindness persisted for several days. Occasionally nausea and dis- 
comfort in the abdomen are complained of, and more rarely vomiting, 
tremors, and cramps of the leg muscles are produced; the gastric 
symptoms are perhaps due to the large quantity of tannic acid in the 
drug rather than to the alkaloids. 

In the frog and in most mammals, pelletierine causes a distinct increase in 
reflex irritability of the spinal cord and medulla oblongata, along with some 
depression of the higher divisions of the central nervous system. Very large 
doses weaken or paralyze the conductivity of the nerve plates in the frog, 
like curara. The heart muscle is also acted on and its pulsations are slowed in 
the frog, although they may be temporarily augmented in force. 

Pelletierine and isopunicine have a specific action on tapeworms, 
for Schroeder found that a solution of one part in 10,000 was sufficient 
to kill them in ten minutes, while a stronger solution had practically 
no effect upon other intestinal worms. 

Preparations. 

Granatum (U. S. P.), Pomegranate, the bark of the stem and root of Punica 
Granatum 2 G (30 grs.) 

Fluidexiraelum Granati (U. S. P.), 2 c.c. (30 mins.). 

PelleiierincB Tannas (U. S. P., B. P.), a mixture in varying proportions of 
the tannates of four alkaloids (punicine, isopunicine, methylpunicine and 

rudopunicine), obtained from pomegranate bark. Dose, 0.25 G. (4 grs.); 
P. 2-8 grs. 



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120 SUBSTANCES ACTING LOCALLY 

Therapeutic Uses. — Granatum is used exclusively as an anthelmintic, 
and the crude bark has now been displaced almost entirely by the 
tannate. The preliminary treatment is the same as that given under 
aspidium, and a purge ought to be given 1-2 hours after the vermicide. 

Bibliography. 

Dujardin-BeaumeU. Bull, de Therap., xcviii, p. 433. 

Berenger-Feraud, Ibid., xcvii, pp. 8. 337, 391. 

r. Schroeder. Arch. f. exp. Path. u. Pharm., xviii, p. 381, and xix, p. 290. 

Heme. PflQger's Archiv, xcii, p. 464. 



is a reddish-brown powder which consists of the minute glands and 
hairs obtained from the surface of the fruits of Mallotus Philippensis. It 
contains two or more substances which have been termed Kamalin, RoUlerin t 
or Mattotoxin, and which are probably neutral bodies like kosotoxin, but it is 
not known which of these is the active constituent. Kamala is used in cases 
of tapeworm in doses of 2-8 G. (30 gre.-J oz.) suspended in water. It acts 
as an intestinal irritant, causing purging and, more rarely, nausea and vomit- 
ing. No purge is necessary, therefore, after the powder. An alcoholic tinc- 
ture of kamala has been found quite as efficient as the powder. 

Areca Nut, the seeds of the palm Areca Catechu, is used in veterinary medi- 
cine as a remedy in tapeworm. It contains a fluid alkaloid arecoline (C 8 HwN0j), 
which resembles pilocarpine in action. In addition, it contains several inactive 
alkaloids and tannic acid. 

4. Thymol. 

Thymol (Ci H u O) is a crystalline substance obtained from the 
volatile oil of Thyme and other plants, and chemically is a homologue 
of phenol. It is very insoluble in water and when taken in solid form 
appears to be absorbed from the alimentary tract with difficulty. 

In man, thymol has caused depression, nausea, vomiting, headache 
and confusion with roaring sounds in the ears and alarming weakness 
of the heart resulting in giddiness and collapse. Its irritant action on 
the mucous membrane may cause burning sensations in the stomach 
and vomiting. 

In poisoning in animals it induces a condition of weakness and 
apathy which passes into collapse and death, generally without any 
convulsions. Fatty degeneration of the liver, congestion or even 
consolidation of the lungs, and irritation of the intestine are found 
postmortem. It is much less irritant than carbolic acid, and is said to 
be a more powerful germicide. Thymol is excreted in the urine in 
combination with sulphuric and glycuronic acid; it is said to have 
caused renal irritation in some cases as shown by the appearance 
of albumin and even of blood in the urine. 

Thymol (U. S. P., B. P.) (CeHaCHrCHaOH) occurs in common thyme and 
other plants, and forms large colorless crystals which have the odor of thyme 
and are very insoluble in water. The pharmacopoeias give the dose as 0.125 G. 
(2 grs.) , but in hook-worm disease it is given up to 2 G. (30 grs.) 

Thymol was used at one time in y 1 ^ per cent, solution as an antiseptic 
lotion and also as a mouth wash or gargle. It has also been given 



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ANTHELMINTICS 121 

as an internal antiseptic in acute rheumatism, typhoid fever and tuber- 
culosis, but without success. At present it is used widely as an anthel- 
mintic in hook-worm disease (ankylostomiasis or uncinariasis); it is 
given in capsules or emulsions in doses of 30 grains repeated in two 
hours and followed in six or eight hours by a brisk saline purge. The 
bowel should be emptied as far as possible by light diet and an aperient 
before the treatment is begun. 

Bibliography. 

Husemann. Arch. f. exp. Path. u. Pharm., iv, p. 280. 

Blum. Zts. f. physiol. Chem., xv , p. 514. Deutsche med. Woch., 1891, p. 186. 

Lewin. Virchow's Arcbiv, lxv, p. 164. 

Baelz. Arch, der Heilkunde, xviii, p. 60. 

SchulU. Journ. Amer. Med. Asao., 1911, ii, p. 1102. 

5. Santonin. 

Santonin (C15H18O3) is an anhydride of santonic acid, a derivative 
of naphthalene. It occurs in Artemisia pauciflora along with a nearly 
related body (artemisin) and a volatile oil (cineol). Santonin is very 
insoluble in water, but is dissolved by alkalies, with which it forms 
santonates. 

Action. — Owing to its insolubility in water, santonin has only a 
slightly bitter taste in the mouth. It is partially dissolved in the 
stomach and passes into the bowel where it effects the removal of some 
forms of intestinal worms. Under special conditions part of the santonin 
may be absorbed in the bowel, however, and general poisoning results 
without the parasites being affected. A certain amount of absorption 
occurs in every case, as is shown by the disorders of color vision and 
by the yellow coloration of the urine. At first objects appear of a bluish 
color to the patient, but this aberration is of comparatively short dura- 
tion and may in fact pass unnoticed. It is followed by a much longer 
period of "yellow sight" or xanthopsia, during which objects that are 
brightly illuminated seem to have a yellow tinge, blue seems green, 
and violet is indistinct, although in dimmer lights the violet may still 
predominate. In severe poisoning the appreciation of the darker colors 
becomes very imperfect, and violet and even blue may fail to be dis- 
tinguished from black. In general the violet end of the spectrum is 
shortened, while the yellow impresses the retina more vividly than 
normally. In some cases the senses of taste and smell, and more rarely 
the hearing are also deranged. These symptoms all pass off in the 
course of a few hours, a second stage of "violet sight" occasionally 
intervening before complete recovery. 

The symptoms produced by the absorption of large quantities of 
santonin are so uniform in man and the other mammals that it is suffi- 
cient to enumerate those observed in experiments on the dog. The 
first distinct effects are generally twitching of the muscles of the head, 
frequently beginning on one side. These are followed by rolling of 
the eyes; grinding of the teeth, flexion and extension of the neck and 



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122 SUBSTANCES ACTING LOCALLY 

rotation of the head from side to side, later by regular epileptiform con- 
vulsions in which the animal is first thrown into opisthotonos and then 
into clonic spasms of the limbs and trunk. These are interrupted by 
intervals of repose during which a curious momentary contraction of all 
the muscles of the body is often noticed. During the convulsive seizures 
the respiration is irregular and insufficient, and in fatal cases it fails 
to return after the convulsion passes off, and the animal dies of as- 
phyxia. In man, some confusion, nausea and vomiting occasionally 
occur after quantities which are too small to produce convulsions, and 
in several cases aphasia has been observed. In frogs, convulsions are 
produced by santonin as in mammals, but they are preceded by a 
prolonged stage of depression, which is entirely absent in the higher 
animals. 

These symptoms manifestly point to changes in the central nervous 
system. The xanthopsia is generally referred to a specific action on 
the retina, though some hold that the central apparatus of vision in 
the brain is the seat of the action. The condition has been ascribed 
to a preliminary stimulation and subsequent depression of the sense 
organs for the perception of the violet and eventually of the blue rays 
of the spectrum, or more precisely to some obstruction to the regener- 
ation of the substance in the retina which normally appreciates violet 
rays (Filehne). The clonic nature of the convulsions at once points 
to an affection of the brain rather than of the cord, and the epileptiform 
convulsions are generally regarded as arising from stimulation of the 
cortex in the higher animals and man, though the basal cerebral ganglia 
may also be involved; the sudden contractions observed in the intervals 
of repose are ascribed to stimulation of the gray matter in the region 
of the pons. Although these parts of the central nervous system are 
the most susceptible to the action of santonin, large quantities also 
affect the cord after division of the medulla oblongata and produce 
tonic convulsions resembling those seen in strychnine poisoning. 

The medullary centres seem to be comparatively little affected by 
santonin, the respiration being interfered with during the spasms, but 
returning to its ordinary rate and strength during the intervals. The 
circulation is altered only by the asphyxia, and the heart continues to 
beat long after the respiration has ceased. 

Santonin undergoes some oxidation in the tissues and is excreted in 
the faeces and urine in several forms, two of which have been examined 
by Jaffe and found to be oxysantonins. The urine and sometimes 
the faeces have a deep yellow color, which changes to red or purple 
when alkalies are added. A similar reaction is obtained from the urine 
after the administration of chrysophanic acid, as in rhubarb or senna. 

Santonin is universally used as a remedy for the round worm, Ascaris 
lumbricoides, and most clinicians believe that it has a specific poisonous 
action on these animals, and that its undoubted effects are due to its 
killing them. In experiments on the entozoa outside the body, however, 
von Schroeder found that santonin solutions were by no means fatal 
to them, and he explains their therapeutic effects by supposing that 



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ANTHELMINTICS 123 

santonin renders the intestine so unpleasant an abode for the parasites 
that they migrate from it voluntarily into the large bowel, and are 
carried out by the purgative. The worms are often found in active 
movement when passed after santonin, although this movement ceases 
very soon afterward from the exposure to cold. 

The santonates act in precisely the same way as santonin, but are less suit- 
able as anthelmintics, owing to their greater solubility and rapid absorption. 

Preparations. 

Santoninum (U. S. P., B. P.), CuHi 8 8 , a neutral principle derived from 
Artemisia pauciflora, is colorless when freshly prepared, but assumes a yellow 
color when exposed to the light. This does not seem to impair its activity 
materially, but it is preferable to avoid it by keeping santonin in amber-colored 
vials. Dose, 0.065 G. (1 gr.); B. P., 1-3 grs. 

Trochiscus Santonini (B. P.), each containing 1 gr.; (U. S. P.), \ gr. 

Therapeutic Uses. — Santonin is used almost exclusively to remove 
Ascaris lumbricoides from the intestine. It is much less effective 
against tapeworm or other intestinal parasites. It may be prescribed 
as a powder, or lozenge, or in solution in oil. 

The bowel ought to be emptied by suitable diet and a laxative before 
the santonin is administered, and a sharp purge ought to be given two 
to four hours afterward in order to bring away the entozoa. 

Santonin has been advised in some retinal diseases, but the results 
have generally been unsatisfactory. 

Bibliography. 

Binz. Arch. f. exp. Path. u. Pharm., vi, p. 300. 

Lewin. Berl. klin. Woch., 1883, p. 170. 

Luchsinoer, Pfluger's Archiv, xxxiv, p. 293. 

Jaffe. Ztschr. f. klin. Med., xvii. Suppl., p. 7. Ztschr. f. phys. Chem., xxii, p. 538. 

Kramer. Ztschr. f. Heilkunde, xiv, p. 303. 

Turtschaninow. Arch. f. exp. Path. u. Pharm., xxxiv, p. 208. 

r. Schroeder. Ibid., xix, p. 290. 

NageL Ztschr. f. Psychol, u. Phys. d. Sinnesorgane, xxvii. p. 267. 

Harnack. Zts. f. klin. Med., xxv, p. 16; Arch. f. exp. Path. u. Pharm., xlvi, pp. 272, 447. 

Rose. Virchow's Archiv, xvi, p. 233; xviii, p. 15; xix, p. 522; xx, p. 245; xxviii, p. 30. 

Ha/ner. Arch. f. Ophthalmol, xiii, p. 309. 

Filehne. Pflttger's Archiv, lxxx, p. 96. 

Spigelia. 

Another remedy used in cases of round worm is pink root, Spigelia mari- 
tima, the active principle of which is unknown, although an alkaloid, spige- 
line, is said to occur in it. Occasional cases of poisoning have been observed, 
especially in children, the symptoms consisting in flushing and dryness of the 
skin, often with some oedematous swelling of the face, delirium and sopor 
followed by dimness of sight or temporary blindness. In frogs spigelia ap- 
pears to depress the brain and spinal cord, and the heart beats more slowly 
and weakly, while in rabbits the most prominent symptoms arise from the 
breathing, which becomes slow and labored and finally ceases in a convulsive 
attack. In the dog and cat its injection is followed by vomiting, great weak- 



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124 SUBSTANCES ACTING LOCALLY 

ness and incoordination of the movements, restlessness, rapid dyspnceic res- 
piration and finally by stupor, coma and death from failure of the respiratory 
centre. 

Spigelia (U. S. P.), the rhizome and roote of Spigelia marilandica. 

Fluidcxtractum Spigeliw (U. S. P.), 4 c.c. (1 fl. dr.). 

The fluidextract is used to remove round worms, which it seems to effect 
in very much the same way as santonin. It ought to be preceded and followed 
by a purge. 



Xm. ANTISEPTICS AND DISINFECTANTS. 

Various balsams, tars and other aromatic bodies have long enjoyed 
a certain reputation in the treatment of wounds, but the whole course 
of surgery was changed about 1870 when Lister introduced the system- 
atic application of antiseptics to wounded tissues. The general principle 
underlying this treatment was that infection arises from the invasion 
of the tissues by microorganisms and that it can be combated either 
by preventing them from reaching a wound or by retarding their growth 
on the injured surface by means of antiseptic drugs. The first of these 
which he introduced was carbolic acid, and this held its position unchal- 
lenged for several years, when it was discovered that many other 
substances were equally destructive to the microorganisms and were 
less poisonous to the invaded tissues. Of late years the tendency has 
been rather to prevent the infection of the tissues by careful manipula- 
tion (asepsis), but when this is impossible the use of antiseptics and 
disinfectants is still necessary, and even the newer aseptic surgery 
depends in part on the use of disinfectants to cleanse the skin and 
instruments. 

A disinfectant in the strict use of the term is a substance used to 
destroy microbes, while an antiseptic, while not actually killing the 
germs, prevents their growth as long as it remains in contact with 
them. A disinfectant is accordingly only intended to act for a short 
time, for if the infected matter be once rendered sterile it can only 
become dangerous by being again contaminated. For example, a 
room requires only to be disinfected after a case of infectious disease. 
A wound, on the other hand, even though completely disinfected may 
become contaminated again very easily and an antiseptic may be 
required to prevent the further growth of microbes. Many sub- 
stances are disinfectant in large quantities and antiseptic in more 
dilute solutions, but others are too weak to disinfect thoroughly though 
they retard the growth of pathogenic organisms, and still others may 
be employed to disinfect but are unsuitable for use as antiseptics, 
either because they are too poisonous to be applied for a sufficient 
time, or because they lose their activity on contact with living matter 
(e. g., oxidising disinfectants). 

A very large number of substances possess disinfectant properties, 
that is, are capable of destroying microbes when they can be applied 
in sufficient quantity. They have no specific action on the microbes, 
however, but act as general protoplasm poisons destroying living tissue 



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ANTISEPTICS AND DISINFECTANTS 125 

of all kinds wherever they come in contact with it. On the other hand, 
drugs such as strychnine, which act on specialized parts of the vertebrate 
organism and have less effect on the less differentiated tissues, are 
equally harmless to the undifferentiated protoplasm of the microbes. It 
is of importance to note that the ordinary antiseptics do not act more 
strongly on microbes than on the tissues in which they are embedded. 
The destruction of the septic organisms in a wounded surface entails 
the destruction of the surrounding cells also. Thus disinfection can 
only be carried out in a part in which the superficial cells are not of 
vital importance and may be restored by new growth. It is therefore 
impossible to disinfect the tissues of the body as a whole, because a 
drug circulating in the blood in sufficient quantity to destroy the bacteria 
in the body would be equally detrimental to the organs in which they 
are embedded. Unless a drug has a specific affinity for the parasite, 1 
much greater than that for the tissues of the host, it can only be used 
where the parasite can be overwhelmed by a massive dose, and this at 
the expense of the neighboring tissues. In spite of much endeavor, 
no chemical substance is yet known which possesses this specific pre- 
dilection for the invading microbes of most diseases. Certain apparent 
exceptions to this rule will be discussed later. 

The antiseptics and disinfectants act upon most forms of living 
matter, and in many instances their effects are obviously due to their 
possessing powers of oxidizing or of coagulating proteins. In other 
instances their destructive action is not so open to explanation. And 
the amount of destruction induced varies with the degree to which the 
poison penetrates the tissues to which it is applied. For example, 
mercuric chloride diffuses deeply into tissues to which it is applied 
and causes wide destruction, while the oxidizing disinfectants lose their 
efficacy on meeting proteins and thus affect only the most superficial 
cells. If microbes were confined to the surface, the latter would be suffi- 
cient for their destruction, but in order to disinfect a wound it is neces- 
sary to penetrate more deeply and thus efficient disinfection implies a 
certain amount of destruction of the tissues in which the microbes are 
harbored- This local destruction of cells and nervous structures induces 
pain and irritation and all efficient disinfectants are irritants. Their 
action as irritants arises from the same qualities as their disinfectant 
power, namely, from their general toxicity to living matter, and it is 
impossible to dissociate the one from the other and to produce non- 
irritant effective disinfectants. 

When a surface has been poisoned by means of disinfectants, it 
heals less quickly, and this has led to the more sparing use of antiseptics 
and to the development of the aseptic method, in which organisms are 
excluded instead of being admitted and then destroyed. 

In addition to their local effect, many of the antiseptic and disinfectant 
drugs have a further poisonous action when they are absorbed and 

1 A drug -which has a specific affinity for a parasite as compared to the organs of the 
host is said to be parasitotropic, while the affinity for the organs in general is called its 
organotropic tendency. 



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126 SUBSTANCES ACTING LOCALLY 

circulate in the blood, and this had led to a further limitation of their 
use. This general action does not necessarily arise from the qualities 
which render them antiseptic, and may be avoided by care in the choice 
of the drug and in its use. 

The action of different drugs upon the microorganisms varies in 
nature in the same way as the action on other living cells. Some ap- 
parently penetrate into the interior in virtue of their solubility in lipoids, 
and this penetration is facilitated by anything which decreases their 
solubility in the surrounding medium. Others accumulate on the surface 
of the organisms by adsorption, so that the microbe is surrounded by a 
dense layer of disinfectant. Yet others appear to enter into true chemical 
combination with the constituents of the parasites. Some of the anti- 
septics (e . g., carbolic acid) enter the cell by simple diffusion and do not 
accumulate in its interior in greater concentration than in the solution 
surrounding it. Others (e. g. t corrosive sublimate) tend to accumulate 
in the cell and on its surface by adsorption, and thus are withdrawn 
from the solution if a sufficient number of microbes are present. 

The efficiency of any disinfectant naturally depends on the con- 
centration in which it comes in contact with the microbes and the time 
during which it remains in contact with them. Thus a solution of mer- 
curic chloride of the strength of 1 in 3000 is much more efficient than 
one of 1 in 10,000, and after exposure to a solution for five minutes far 
fewer microbes escape than after exposure for two minutes. Another 
factor is the temperature at which the microbes are exposed to the 
disinfectant, for it is found that when the latter is kept at about 30° C. 
far fewer bacteria escape than when ordinary room temperature prevails. 
Different species of microbes vary in their resistance, and different 
cultures of the same microbe and even different individuals of the same 
culture exhibit marked variations in susceptibility. The effect also 
often varies inversely with the number of microbes present, because 
each of these withdraws a certain amount of the disinfectant and thus 
reduces the general concentration of the solution. And other proteins 
have the same influence as the microbes themselves, for they offer the 
disinfectants the same surface for adsorption or combine with some of 
them in the same way as the proteins of the microbes. Thus a con- 
centration which is sufficient to sterilize water infected with bacteria, 
may have little or no effect if applied to a suppurating wound, because 
the greater part of the disinfectant is taken up or otherwise rendered 
inactive by the proteins of the secretion, leaving only a low concentration 
to act on the microorganisms. Thus Bechhold has shown that many 
substances which are powerful disinfectants in ordinary fluids, lose 
their activity in protein solutions, owing to their forming combina- 
tions with the proteins, so that though they are not dangerous to the 
host, they are comparatively innocuous to the microbes in the tissues; 
in fact they act on proteins and not specifically on microbes; when 
the proteins are present in small amount, as in an emulsion of bacteria 
in water, these disinfectants are active enough, but when the bacteria 
are distributed among the proteins in an infected wound, the amount of 



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ANTISEPTICS AND DISINFECTANTS 127 

the disinfectant that falls to the share of the bacterial proteins is too 
small to be effective. For example, a disinfectant which prevented 
the growth of diphtheria germs in broth when added in the proportion 
of one in half a million, had no action on the germs in the tissues when it 
was present in the proportion of one in five thousand, because it com- 
bined with the tissue proteins in preference to those of the bacilli. 

This again indicates the limitation of disinfectant therapeutics, 
which cannot be overcome as long as the drugs have no elective affinity 
for the invading organisms but act equally strongly on the tissues of the 
higher animals. 

If a poison is to penetrate into the interior of an organism in quan- 
tity, it must be as soluble in the protoplasm as in the fluid in which 
it is applied, for it is obvious that it will not leave a medium in which 
it is readily soluble for one in which it is dissolved with difficulty. 
Accordingly, it is found that fats and oils in which the members of 
the aromatic series are very soluble are not suitable as media for their 
application, for the poisons remain in the oily menstruum and fail to 
penetrate the microbes in which they are less soluble. On the other 
hand, the addition of inorganic salts to an aqueous solution of carbolic 
acid often increases its antiseptic power, because the poison becomes 
less soluble in the water and shows a greater tendency to escape from 
it into the interior of the microbes. 

There is reason to believe that solutions containing several disinfec- 
tants are more strongly antiseptic than those containing an equal 
percentage of the individual pure bodies; for example, a mixture of 
carbolic acid and mercuric perchloride, is more efficient than a much 
stronger solution of either alone. This appears to be due to a change in 
the solubility of the disinfectant, at any rate in some cases. 

Disinfectants and antiseptics are used for a large variety of purposes 
and it may be well to consider the principles which underlie their uses 
before discussing the special features of each drug. 

1. In Surgery, Lister advised that not only infected wounds should be 
treated with disinfectants but that infection of any wound should be 
guarded against by the application of antiseptics which would retard 
the growth of microbes. It is now recognized, however, that a clean 
wound requires no antiseptics and heals more quickly if they are avoided. 
And disinfection in surgery is now applied only to tissues already the 
seat of infection, and to objects which may come in contact with a clean 
wound. Among the latter, those which offer the greatest difficulty 
are the skin of the patient and of the operator, and a large number of 
drugs have been employed to disinfect these and render them harmless. 
Among the disinfectants more commonly used to disinfect the skin or 
to destroy the organisms in a wound already infected, are the carbolic 
acid group, mercuric chloride, the oxidizing disinfectant group, and 
iodine, of which the last has recently been the most popular. The 
disinfectant must be applied in solution or suspension in water, and 
should induce as little irritation as is compatible with its fulfilling its 
purpose. This is of special importance in dealing with the delicate, 



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128 SUBSTANCES ACTING LOCALLY 

sensitive mucous membranes such as the eye, which cannot be subjected 
to such treatment as would be necessary in other parts of the body. 
A danger which is smaller now than formerly is from the absorption 
of the disinfectant giving rise to general poisoning. This arose as a 
general rule not from the drug applied during the operation, but from 
its too lavish use in the subsequent dressings. But cases of poisoning 
are still met from the use of powerful disinfectants to wash out large 
abscesses, the uterus, of other organs. 

Instruments, ligatures, etc., are generally disinfected by heat, but 
are often kept in dilute solutions of carbolic acid or other disinfectant 
until required. 

The relative disinfecting power of the drugs used in surgery has been 
investigated repeatedly but no satisfactory ratio can be given as yet, 
because it is impossible to imitate the conditions in a septic wound 
closely enough in experimental determinations. And estimations of the 
relative power in destroying organisms in water or in gelatin cultures 
depend upon a variety of conditions, such as the number of organisms 
and the completeness with which the disinfectant is removed before 
test growths are made. It is generally held that among the disinfectants 
used in surgery mercuric perchloride is superior to the carbolic acid 
group, and that both of these penetrate more efficiently than the oxidiz- 
ing disinfectants. 

2. In the Treatment of Skin Diseases, a number of disinfectants have 
been employed, and where the area of infection is small it may be 
permissible to use the more powerful ones if necessary. But in wide- 
spread disease the dangers of local irritation and of absorption preclude 
all except the least noxious, and it remains a question how far these 
act in retarding the growth of an infecting organism, and how far their 
effects may be due to their causing slight irritation and improved 
nutrition. Some dermatologists hold the view that these mild skin 
remedies owe much of their value to their reducing properties. Among 
these remedies are chrysarobin, pyrogallol, naphthol, and the tar 
series. 

3. To Disinfect the Intestine. — Septic processes may occur either in 
the contents of the intestine or in its walls, the former affecting the 
general organism only by the production of poisonous or irritant sub- 
stances which may be absorbed, while in the latter the tissues of the wall 
themselves become the seat of active disease. It is possible that an 
admixture of a disinfectant with the contents of the bowel may retard 
their putrefaction, and this method of treatment has been largely em- 
ployed. When the evidence of its efficacy is examined, the results prove 
to be disappointing; the amount of double sulphates or of indol in the 
urine is said to be diminished, and the number of microbes in the fjeces 
to be reduced under the use of these intestinal antiseptics, but this 
is no longer regarded as unequivocal evidence that the disintegration 
of the food by microbes is retarded; and in addition these changes 
in the urine and the faeces have not been confirmed by many observers. 
There is some rather unconvincing clinical evidence of improvement 



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ANTISEPTICS AND DISINFECTANTS 129 

under this treatment, but it is now recognised to be more in accord with 
general aseptic procedure to remove the putrefying contents by means 
of a purgative, than to attempt to render them sterile in the bowel 
by means of disinfectants. 

When the bowel wall itself is the seat of infection the use of antiseptics 
and disinfectants is still less supported by the results. And it seems very 
unlikely that a drug powerful enough to destroy the microbes har- 
bored in the mucous membrane will leave the latter uninjured. In 
typhoid fever, in which this treatment has been carefully followed, 
the number of typhoid bacilli in the stools has not diminished to any 
noticeable extent, and the use of these drugs does not relieve the 
symptoms or shorten the duration of the disease. 

Any drug used for the disinfection of the intestine must not be 
irritant, nor very poisonous. It must not be too soluble, since other- 
wise it may be absorbed from the upper part of the bowel, and on the 
other hand it must be soluble to some extent, or it cannot mix very 
intimately with the contents of the intestine. Carbolic acid is scarcely 
fitted for this purpose, for it irritates the stomach and is also rapidly 
absorbed. Some of the cresols have been recommended of late years, 
and the naphthalin preparations have also enjoyed some reputation. 
Salol and its congeners have the advantage of being almost completely 
insoluble and harmless in the stomach and of being dissolved and 
rendered active by the intestinal juices. The purgatives are the most 
efficacious treatment and, among these, the mercurials are largely used. 

4. To Destroy Pathogenic Germs in the Tissues After Absorption. — It is 
now recognized to be hopeless to attempt to find a single body which 
will destroy all forms of bacteria in the tissues, while leaving the host 
uninjured, but there is still reason to believe that in the future specific 
antiseptics may be found for at least some of the constitutional diseases. 
Such a specific action is seen in the effects of quinine on the organism 
of malaria, of salicylates in rheumatic fever, of mercury, arsenic and 
antimony in various protozoal infections, and of emetine in amoebic 
dysentery, 1 all of these apparently acting more strongly on the cause of 
the disease than on the tissues of the patient. While it may be hoped 
that the antiseptic treatment of internal maladies has not reached its 
final limit, it is futile to attempt to disinfect the tissues generally with 
ordinary agents, which are much too poisonous. 

5. In the Treatment of Septic Genito-urinary Diseases. — The treatment 
of general infections in the tissues with non-specific disinfectants is 
hopeless for the reasons given above. On the other hand, good results 
are obtained in infection of the genito-urinary tract through which 
many of the antiseptics are eliminated from the body. In the course 
of their elimination they are concentrated; thus a quantity of dis- 
infectant which is inactive when distributed through the protein-rich 

i It is to be remarked that in malaria, syphilis, dysentery , and trypanosomiasis, in 
which specifics have been obtained, the disease is due to invasion by protosoa, while most 
of the infections of which the cause is known, arise from bacteria, and these appear to 
be much less susceptible to the action of chemical agents. 

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130 SUBSTANCES ACTING LOCALLY 

tissues of the body, may very well be efficacious when it is dissolved in 
the comparatively small quantity of the urine, and especially since 
here it finds no protein to combine with except that of the tract through 
which it passes. On the other hand, in their passage through the body 
the antiseptics are generally formed into combinations which are less 
irritant and also less poisonous to the microorganisms. There is, how- 
ever, no question that the continual washing of the genito-urinary 
tract with the antiseptics in the course of their excretion reduces the 
number of the organisms in the urine and relieves septic conditions. 
The drugs used for this purpose must not be too irritant to the mucous 
membranes of the alimentary tract, and must be easily absorbed and 
not dangerously poisonous. Many of the aromatic series, such as 
salicylates, have been employed, and some of the volatile oils. An 
important advance has recently been made in urotropin, which is 
harmless and inactive itself but frees formaldehyde in acid urine. In 
addition to this method of treatment, antiseptics and disinfectants may 
be applied by injection into the urethra and bladder by the ordinary 
surgical procedure. 

6. In the Treatment of Pulmonary Infections. — Traces of some of the 
more volatile antiseptics are eliminated in the breath, and this has 
suggested their internal use to destroy microbes in the lungs, especially 
the tubercle bacillus. It may be stated, however, that careful observers 
are united in the belief that this form of medication is entirely useless. 
The case of the lungs differs entirely from that of the kidney, for in the 
former there is no concentration of the disinfectant in the organ, but 
it is excreted in even greater dilution than that in which it circulates 
in the general tissues. In addition it is impossible for an antiseptic to 
reach the lungs in sufficient concentration to incommode the resistant 
microbes without destroying the delicate pulmonary epithelium, 
unless the drug has a specific affinity for the parasites, which none of 
the general antiseptics has proved to possess. Antiseptic remedies 
have also been inhaled in vapor or spray, and have been injected into 
the trachea or even into the lung directly, but as far as the tubercle 
bacillus is concerned, they have had no result in the hands of more 
careful observers. In cases of gangrene of the lung, foetid bronchitis, 
etc., the inhalations relieve the patient to some extent and certainly 
lessen the offensive odor. 

7. In Infections of Other Secretions and Organs, the use of antiseptics 
has not proved successful. In the bile, thymol and urotropin have 
been found after administration by the mouth, and the latter has 
been shown to occur in the cerebrospinal fluid and in many other 
excretions, but it is to be noted that urotropin is in itself inactive and 
is disinfectant only through its liberation of formaldehyde, which has 
not been shown to take place except in the urine. 

8. To Disinfect Rooms, Furniture, Clothing, Excrementa, the strongest 
and cheapest drugs which are available are employed. It is quite 
futile to attempt to carry out such disinfection unless with concen- 
trations which would be immediately fatal to all higher organisms, 



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ANTISEPTICS AND DISINFECTANTS 131 

For rooms and furniture, formaldehyde or sulphur dioxide are best 
adapted as they are volatile and penetrate fairly, but the latter bleaches 
all dyed material. Clothes are best disinfected by heat, or formaldehyde 
solution may be employed. Excrement may be disinfected by chlorine 
or lime; crude carbolic acid and tar are less certain, and the oxidizing 
disinfectants are expensive when used in quantity. 

Bibliography. 

Gerhardt. Ergebniase der Physiol., iii, p. 153. 

Mieczkowski. Mit. a. d. Grengebiet, ix, p. 405. 

Koch. Mittheilung aus dem Kaiserlich. Gesundheitaamt., i, p. 234. 

Jalan de la Croix. Arch. f. exp Path. u. Pharm., xiii, p. 175. 

Sternberg. Bull, of National Board of Health, 1881. 

Krdnig u. Paul. Ztochr. f. Hygiene, xxv, p. 1. 

Spiro u. Bruns. Arch. f. exp. Path. u. Pharm., xli, p. 353. 

Bechhold u. Ehrlich. Ztschr. f. physiol. Chem., xlvii, p. 173; lii, p. 177. 

Chick and Martin. Journ. of Hygiene, viii, pp. 92, 655, 698. 

Verhoeff and Ellis. Journ. Amer. Med. Asso., 1907, i, p. 2175. 

Cooper. Biochem. Journ., vii, p. 175. 

Kuster. Arch. f. Hygiene, 1, p. 364; Zeitschr. f. Hyg., lxxiii, p. 205. 

Reichel. Biochem. Zeitschr., xxii, pp. 129, 175, 201. 

Paul* Birstein u. Reuse. Biochem. Zeitschr., xxv, p. 367; xxix, pp. 202, 249. 

Harris. Therap. Research Com. Amer. Med. Asso., 1912, p. 151. 

Many antiseptics and disinfectants are used for a variety of purposes 
and might be classed under several of these headings. The following 
arrangement is therefore an arbitrary one, and merely points to the 
use for which the drug has been considered most adapted. 

I. Surgical Antiseptics and Disinfectants. 
1. Carbolic Aero. 

Carbolic acid, or phenol, the first of the modern antiseptics to be 
introduced, acts like the rest of the simpler benzol compounds as a 
General Protoplasm Poison, although in the vertebrates it affects the 
central nervous system more powerfully than the other tissues. 

Its poisonous effects are well seen when it is applied to unicellular 
organisms, such as the protozoa. Even dilute solutions cause immediate 
arrest of all movements; the organism assumes a spherical shape 
and loses its transparency, and, unless the solution be very attenuated, 
dies in the course of a few minutes. Plant cells are acted on the same 
way, and the individual cells of more highly organized animals, such 
as the ciliated epithelium of the air passages and the spermatozoa, are 
killed at once when brought in contact with carbolic acid. There is 
some evidence, however, that very dilute solutions of carbolic acid, 
as of other antiseptics, tend to increase the activity of protoplasm, for 
while solutions of phenol, such as are used as surgical antiseptics, are 
immediately fatal to the yeast plant, very dilute solutions increase its 
activity. The effect of carbolic acid on protoplasm has, however, been 
studied chiefly in the bacteria. Its antiseptic power, while always 
considerable, is found to vary greatly with the species of microbe. 



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132 SUBSTANCES ACTING LOCALLY 

Thus, while it is fairly poisonous to the ordinary pyogenic organisms, 
it has to be present in very concentrated form to destroy the more 
resistant spores of anthrax, and like other antiseptics, is much less 
poisonous to the microbes than to the protozoa and other simple forms 
of life. The development and reproduction of many microorganisms 
has been found to be much delayed, or altogether prevented, as long 
as they remained in a solution of one part of carbolic acid in 400-600 
parts of water, but in order to kill them very much more concentrated 
solutions (5 per cent.) were required, and Koch found that the spores 
of the anthrax bacilli were destroyed by 5 per cent, carbolic solution 
only after they had remained in it for two days. 

It seems to vary considerably in its action on the unorganized fer- 
ments; thus it is said not to retard appreciably the fermentations 
produced by emulsin, diastase and myrosin, even when present in 
the solution up to 5 per cent., while pepsin, ptyalin and the rennet 
ferment are weakened by somewhat smaller quantities. 

Carbolic acid precipitates Proteins in solution and also in the cells. 
It does not seem to enter into any firm combination with them, for 
it can be washed out of the precipitate with comparative ease. It 
results from this that carbolic acid penetrates more thoroughly than 
the metallic antiseptics, which are rendered insoluble by the albumin 
they meet, and whose action therefore tends to remain confined to the 
surface. 

This coagulation of the proteins occurs whenever carbolic acid is 
brought in contact with the tissues. On the Skin a white, opaque scar 
is formed by concentrated phenol, which becomes red and shining 
afterward and then falls off in a few days, leaving a light brown 
stain which may remain for several weeks. Even a 5 per cent, solution 
applied to the fingers produces tingling and warmth, which is often 
followed by opacity and shrinking of the epidermis and a sense of 
numbness. This numbness may amount to almost complete anaethesia 
if more concentrated solutions are applied, no pain being felt even 
when the skin is cut through. When applied for some time and pre- 
vented from evaporating, carbolic acid may cause extensive dry gangrene 
of the part, from its penetrating through the surface layer and reaching 
the deeper tissues. Applied to a Wound in 5 per cent, solution, phenol 
induces pain and irritation followed by local anaesthesia, and a white 
pellicle of coagulated proteins is formed. It causes irritation and necrosis 
of the Mucous Membranes, and if applied in sufficient quantity may 
lead to sloughing and acute inflammation. This local effect may prove 
fatal from shock and collapse when large quantities of the undiluted 
acid are swallowed, the effects resembling exactly those produced 
by other corrosive substances. Carbolic acid is rapidly absorbed from 
the stomach and bowel, but after some time the absorption is much 
slowed owing to local changes in the vessels of the intestine. 

General Action. — In man delirium and excitement have been observed 
in some cases, but convulsions are comparatively rarely seen. When 
large quantities are taken, immediate unconsciousness may result 



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ANTISEPTICS AND DISINFECTANTS 133 

and death follow within a few minutes. How far this is due to the local 
corrosion, and how far the direct action on the central nervous system is 
involved, cannot be determined. In more gradual poisoning, depres- 
sion and weakness, headache, nausea and vomiting are followed by 
giddiness, noises in the ears, pallor and collapse, with irregular pulse 
and respiration, and cold perspiration; fainting and unconsciousness 
then lead to failure of the breathing and death. Fatal poisoning may 
arise from swallowing a concentrated or a dilute solution, or from 
absorption from wounds and abscesses. It has also occurred in man 
from absorption through the unbroken skin. 

The autopsy sometimes gives no special indications of the cause of 
death, save the local corrosion of the alimentary canal. Inflammation 
and necrosis of the intestine is said to have been observed in some 
cases in which the poison was absorbed from skin wounds, and fatty 
degeneration is sometimes induced in the liver and the renal epithelium, 
but is not constant. 

In the frog carbolic acid first causes depression and loss of the spon- 
taneous movements, and later fibrillary twitching in the muscles, 
augmented reflex excitability and finally tonic convulsions. These 
may last for some time and then complete paralysis of the central 
nervous system supervenes, while the heart and the peripheral nerves 
and muscles remain active. A dilute solution of carbolic acid applied 
directly to the exposed spinal cord paralyzes the sensory elements 
immediately, while leaving unaffected the motor fibres and the cells 
of the anterior horn (Baglioni). 

In mammals very similar symptoms are produced, save that there 
is often no noticeable preliminary stage of depression. Some weakness 
and lethargy may be present, however, and is followed by marked 
muscular tremor, which resembles the shivering produced by cold. At 
intervals this is interrupted by sudden twitches in different muscles, 
and later by clonic convulsions. The respiration and the pulse are at 
first accelerated, but afterward are slow, irregular, and weak. The 
movements become feeble and appear at longer intervals, the respiration 
is shallow and irregular, and the animal passes into a condition of 
collapse, in which, however, the sensibility to pain is often preserved. 
Eventually death occurs from asphyxia. After very large doses the 
collapse may be immediate, no convulsions being observed, the heart 
and respiration often ceasing simultaneously. In most cases salivation 
is a marked symptom, and the temperature often falls far below the 
normal. 

Central Nervous System. — The convulsions in the frog arise from 
increased irritability of the spinal cord, especially of the anterior horn 
cells, for they are not arrested by section of the medulla oblongata. 
In mammals the sudden contractions of isolated muscles appear due 
to a similar action on the spinal cord, but the clonic convulsions and 
the persistent tremors are probably of cerebral origin, and Berkholz 
found the cerebral cortex abnormally irritable after carbolic acid. 
The rarity of convulsions in man has not been satisfactorily explained. 

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134 SUBSTANCES ACTING LOCALLY 

In some cases the course of the intoxication is too short, the large 
amount of poison swallowed inducing immediate collapse, while in 
others their absence may be due to the debility of the patient from 
disease; but in a considerable number of cases of poisoning in which 
neither of these conditions was present, no convulsions were observed. 
The primary stimulation of the central nervous system in animals is 
followed by depression and paralysis if large doses are administered. 

The acceleration of the Respiration and of the Heart seen in mammals 
has been supposed to be an indirect result of the increased muscular 
movement and convulsions, but this seems to be incorrect, for the heart 
is found to be accelerated before the convulsive movements and tremor 
appear, and the frog's heart is accelerated in cases where no movements 
whatever occur. It would seem probable that the acceleration of the 
heart is due to direct action on the muscle or on the regulating nerves. 
The subsequent slowing is undoubtedly due to muscular action. 

The acceleration of the respiration precedes the increased move- 
ment also, and would therefore seem to be due to action on the medul- 
lary centre, which is first stimulated and later paralyzed. The vaso- 
motor centre is said by Gies to be depressed at once by the injection 
of carbolic acid into the blood, but it may be questioned whether it 
too is not first excited when the poison is absorbed more slowly. It 
is undoubtedly depressed in the later stages of poisoning, and this, 
together with the weakness and slowness of the heart, causes a fall in 
the blood-pressure and collapse. 

The peripheral Nerves and Muscles do not seem to be affected in 
general poisoning in mammals, although in the frog their irritability 
and the capacity for work of the muscle may be somewhat reduced. 

On the direct application of solutions of carbolic acid to the nerves 
or muscles, these are killed at once, like other forms of living matter; 
even dilute solutions paralyze the nerve fibrils and terminals and thus 
induce local anaesthesia. 

The increased Secretion of saliva, perspiration and tears which is 
seen in poisoning in mammals is probably of central origin, and may 
possibly be associated with the nausea and vomiting. 

The fall in Temperature in carbolic acid poisoning seems, for the 
main part, to be due to the collapse, although it is impossible to state 
how far this may be aided by some alteration of the regulating function, 
such as is seen in the closely related group of the antipyretics. 

Carbolic acid added to the defibrinated Blood leads to the slow for- 
mation of methsemoglobin, but this does not occur in the living animal. 
Occasionally some destruction of the red-blood cells is caused in 
animals through the injection of carbolic acid directly into the blood- 
vessels, and in one case of poisoning in man haemoglobin was detected 
in the urine, indicating that some of the red cells of the blood had 
been destroyed. 

Excretion. — Some of the carbolic acid absorbed is oxidized to hydro- 
quinone and pyrocatechin, and these and also the unaltered carbolic 
acid are excreted in the urine in combination with sulphuric and 



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ANTISEPTICS AND DISINFECTANTS 135 

glycuronic acid. The hydroquinone and pyrocatechin tend to become 
further oxidized to colored substances and the urine therefore assumes 
a dark, dusky-green color which may change to brown or even black. 
This change may occur in the body, and the urine is very often passed 
of a greenish-brown color, but further oxidation takes place on exposure 
to the air, resulting in deeper coloration which commences at the surface 
of the fluid and gradually extends downward. The depth of the shade 
depends not on the amount of phenol sulphate in the urine, but on that 
of the dioxybenzols, and a darker urine is often observed, therefore, 
when the absorption has occurred from an open wound (in which the 
conditions are especially favorable to oxidation) than from much larger 
quantities absorbed from the alimentary canal. 

The presence of glycuronates in the urine may lead to its reducing 
Fehling's solution, and thus give rise to the suspicion of glycosuria. 
On the other hand, the passage of these bodies through the kidney 
often causes some irritation and albuminuria. The double sulphates 
of the urine are, of course, much increased, and the inorganic sulphates 
are correspondingly diminished. 

The Chlarphenols, in which chlorine is substituted for one or more of the 
hydrogen atoms of carbolic acid, are much more poisonous to microorganisms 
than the original substance, while their toxicity in mammals is not increased 
in the same ratio. A similar intensifying effect is seen in the chlorine sub- 
stitution products of the narcotic series, e. g., chloroform. The most poisonous 
of the monochlorphenols is parachlorphenol. Bromol or tribromphenol has 
been used to a limited extent in therapeutics as a disinfectant and caustic. 

Preparations. 

Acidum Carbolicum (B. P.), Phenol (U. S. P.), carbolic acid or phenol 
(CtHftOH) forms colorless, deliquescent crystals when recently prepared, but 
often assumes a reddish tinge from oxidation. It has a characteristic odor 
and is intensely corrosive. It is soluble in about 20 parts of water, but be- 
comes liquid when 10 parts of water are added to 90 of the crystals, forming 
the Acidum Carbolicum Liquej 'actum (B. P.), Phenol Liquef actum (U. S. P.). 
This must be carefully distinguished from the ordinary solution of carbolic 
acid, which contains only 2 to 5 per cent, of phenol, while the liquefied carbolic 
acid contains about 90 per cent. 

Glycerilum Phenolis (U. S. P.), Glycerinum Acidi Carbolici (B. P.), 20 per 
cent, of carbolic acid in glycerin. 0.3 c.c. (5 mins.). 

Unguentum Phenolis (U. S. P.), Unguentum Acidi Carbolici (B. P.), 3 per 

cent. 

Carbolic acid is generally used in 2-5 per cent, solution. A crude, impure 
form may be employed to disinfect stools, latrines, etc. The ointment is com- 
paratively seldom prescribed, as it is found more irritant than many other 
equally powerful antiseptics. The glycerite may be used as a very weak caustic. 
Solutions of carbolic acid in oil have little or no antiseptic action, because they 
fail to penetrate into the microbes. 

Therapeutic Uses. — Carbolic acid is used as an antiseptic in surgical 
operations in 2-5 per cent, solution in water. It now plays a much 
less important r61e in surgery than it did in the first days of antisepsis; 
in fact in many clinics it is now employed only to preserve the instru- 

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•136 SUBSTANCES ACTING LOCALLY 

ments from infection. Its irritant action and the danger of absorption 
have also rendered it unpopular as a dressing or lotion after operations 
or injuries, where there is any large absorbent surface, or where irrita- 
tion is liable to be injurious, as in most forms of skin disease. 

It is still used as a disinfectant in septic wounds, though greater 
reliance is. now placed on corrosive sublimate. Strong carbolic acid 
has been applied to disinfect wounds, its poisonous effects being avoided 
by immediately washing it off with alcohol. 

Harrington has recently drawn attention to the danger of applying 
dilute solutions in bandages to injured fingers and hands; he found 
records of over a hundred cases in which this had led to gangrene, 
necessitating amputation. 

Carbolic acid had a limited use as a caustic in the form of the 
liquefied preparation, and was less painful than most other caustics. 
It has also been employed in itching skin diseases, but is inferior to 
the cocaine series. Internally, it was at one time advocated as an 
intestinal disinfectant and as a remedy in constitutional diseases, but 
this has long been abandoned. 

Poisoning. — In carbolic acid poisoning, when it has been taken by 
the mouth, the first treatment is the removal of the poison by the 
stomach tube and the thorough lavage of the stomach with water to 
which 10 per cent, of alcohol may be added; the alcohol dissolves the 
poison more readily than water and thus facilitates its removal, but 
has no other antidotal action, and should be removed from the stomach 
as completely as possible; when absorption has occurred from the skin 
or from a wound the dressing should be removed at once. The com- 
bination of phenol with sulphuric acid in the tissues forms a compara- 
tively harmless body, and Baumann and Preusse therefore suggested 
the administration of sodium sulphate in large quantities. It is found, 
however, that this is of little or no use, because the phenol does not 
combine sulphates as such in the body, but with organic sulphur com- 
pounds which are only in process of being oxidized to sulphuric acid. 
When coma and collapse set in, the patient is to be sustained by the 
application of warmth externally, and by the administration of such 
central nervous stimulants as caffeine or strychnine; artificial respiration 
may eventually be used, although there is little prospect of resuscitation 
if the intoxication has advanced so far. The corrosion induced by car- 
bolic acid locally may be treated by washing the part with alcohol, 
which dissolves the acid readily. 

Bibliography. 

Husemann. Arch. f. exp. Path. u. Pharm., iv, p. 280. 

Baumann and his pupils. Pfluger's Archiv, xiii, p. 285. Zts. f. phys. Chem., i, p. 244, 
ii, pp. 273, 350; iii, pp. 156, 177. Arch. f. Anat. u. Phys., 1879, p. 245. 
Bill. Amer. Jour, of Med. Sci., Ixiv, p. 17. 

Salkowsky, Hoppe-Seyler, Plugge. Pfluger's Archiv, v, pp. 335, 470, 538. 
Prudden. Amer. Jour, of Med. Sci., lxxxi, p. 82. 
Tauber. Arch. f. exp. Path. u. Pharm., xxxvi, p. 197. 
Schmtedeberg. Ibid., xiv, p. 288. 
Turtschaninow. Ibid., xxxiv, p. 208. 



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ANTISEPTICS AND DISINFECTANTS 137 

SoUmann, Brown, Clarke, Journ. Amer. Med. Ass., March 17, 1906; March 23, 1907. 
Journ. of Pharmacology, i, p. 409. 

Baglioni. Arch. f. (Anat. u.) Phys., 1900, Supplem., p. 193. Ztschr. f. allg. Physiol., 
iii, p. 313. 

Minervini. Arch. f. klin. Chirurg., lx, p. 687. 

Harrington. Amer. Jour, of Med. Sci., cxx, p. 1. 

Schultzen, Graebe, Nattnyn. Arch. f. Anat. u. Phys. 1867, pp. 166, 349. 

Nencki. Ibid., 1870, p. 399. Zts. f. physiol. Chem., iv, p. 32fo. Arch. f. exp. Path, 
u. Pharm., i, p. 420; xxx, p. 300. 

2. Cresols 

Of late years the cresols or cresylic acids (CeH4.CH3.OH) have been 
substituted for carbolic acid to a considerable extent in surgery. 
There are three isomeric cresols which all resemble carbolic acid closely 
in. action, and which present only minor points of difference from 
each other. Metacresol is said to be less poisonous and less irritant 
than carbolic acid, while it is credited with a niore powerful antiseptic 
action; orthocresol, on the other hand, is said to be more dangerous 
than carbolic acid, and paracresol to be the most poisonous of all. 
But the differences in toxicity between the cresols are too small to be of 
practical importance, and their germicidal action is approximately equal 
when they are used in suspension with soaps, as is usually the case. 

Many cases of suicidal poisoning with cresol preparations have 
occurred and have presented symptoms similar to those of carbolic 
acid poisoning — collapse and exhaustion followed by coma and death; 
in some cases marked alterations have been found in the liver along with 
nephritis and haemolysis. Much of the cresol absorbed undergoes 
complete oxidation in the tissues, but about one-third of that ingested 
is excreted in the urine in combination with sulphuric and glycuronic 
acids. 

The cresols are constituents of tars and other crude disinfectants. 
In pure form they are only slightly soluble in water, and it has been found 
necessary to form them into emulsions or suspensions for surgical use. 
A large number of these cresol preparations are available and differ 
chiefly in the way in which they are suspended in water (creolin, solveol, 
solvtol, lysol) . These preparations are not devoid of poisonous properties 
as is often stated; on the contrary they are little if at all less dangerous 
than carbolic acid. Their germicidal action has been overrated by some 
authorities and has been denied by others. On the whole they appear 
to be more powerfully antiseptic than carbolic acid when they are used 
in emulsion form; their insolubility in water facilitates their passage 
into the bacteria in which they are more soluble; and the emulsion 
form has a further advantage as the fluid coming in contact with the 
bacteria must always be saturated with the antiseptic. Cresol has been 
given as an intestinal disinfectant, but has not proved more useful 
than the other drugs used with this object. 

The chlorcresols are said to be more strongly germicidal than the cresols 
themselves, while their toxicity is not increased in the same degree or may 
even be reduced; a suspension of chlorcresols has been introduced as an anti- 
septic, but has not yet been widely used. 

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138 SUBSTANCES ACTING LOCALLY 



Preparations. 

Cresol (U. S. P., B. P.), a mixture of the three cresols, forms a colorless or 
straw-colored fluid with a phenol odor. Soluble in 60 parts of water. Dose, 
0.05 c.c. (1 min.).; B. P. 1-3 mins. 

Liquor Cresolis Compositus (U. S. P.), Liquor Cresol Saponalus (B. P.), Cresol 
50 per cent, suspended in water by means of soap, is used diluted to about 5 
per cent, as a surgical disinfectant. 

Bibliography. 

Seybold. Ztschr. f. Hygiene, xxix, p. 377. 
ToUens. Arch. f. exp. Path. u. Pharm., lii, p. 220. 
Kochmann. Arch, internat. de Pharmacodyn., xiv, p. 401. 
Blumenthal. Biochem. Ztschr., i, p. 134; vii, p. 39. 
Wandel. Arch. f. exp. Path. u. Pharm., lvi, p. 161. 
Schneider. Arch. f. Hygiene, lxvii, p. 1. 
Hale. Hygienic Laboratory, Bulletin No. 88, 1913. 
Siegfried u. Zimmerman. ' Biochem. Ztschr., xlvi, p. 210. 

3. Other Aromatic Surgical Disinfectants. 

Many other members of the benzine or aromatic series have enjoyed 
a more or less transient reputation as surgical disinfectants and anti- 
septics. Thus Thymol (C6H3CH3C3H7OH), obtained from oil of thyme, 
was used to a limited extent as an antiseptic lotion in ^ per cent, 
solution and also as a mouth wash and gargle, but in this strength it 
is only feebly active and it is too insoluble in water to form a really 
effective germicide. It is used as an anthelmintic chiefly (p. 120). 

Salicylic add (C 6 H 4 OHCOOH) and sodium salicylate (C«H 4 OHCOONa) 
were at one time used as antiseptic washes in surgery, and indeed prom- 
ised to supplant carbolic acid for this purpose as they are less irritant 
and less poisonous. The acid is destructive to the pyogenic micro- 
organisms suspended in water but has much less effect than carbolic 
acid when proteins are present, and its use has been abandoned in 
practice by most surgeons. The salicylates are used almost exclusively 
for their specific action in acute rheumatism. 

The mdphocarbolates (or paraphenolsvlphonates) of sodium and zinc are less 
poisonous than carbolic acid, as the sulphon group lessens the toxicity in the 
same way as the carboxyl one, but they are at the same time very much weaker 
in germicidal power. They have been used as external antiseptics, and the sul- 
phocarbolate of sodium has been administered to arrest fermentation in the 
stomach with little success. Aseptol or sozolic acid is a 33 per cent, solution of 
ortho-phenol-sulphonic acid in water, but very often contains some of the para- 
acid. Of the three phenol-sulphonic acids, the ortho- is the most strongly 
antiseptic and the para- the least useful. 

Sodii Phenolsulphonas (U. S. P.), or sodium para-phenol-sulphonate (CgH<- 
OHS0 2 ONa,2H 2 0), forms colorless, transparent prisms, without odor, and 
with a saline taste. Soluble in 5 parts of water. 0.25 G. (4 grs.). 

The oxynaphtoic acids (Ci H 6 OH COOH) possess antiseptic properties, 
which are said to be somewhat greater than those of carbolic and salicylic 
acids, but they are less soluble in water, while the sodium salt is less antiseptic. 
The acids are irritant and produce diarrhoea and symptoms similar to those of 
salicylic acid. They seem to be at least as poisonous as carbolic ackL and have 
been used as external antiseptics only to a very limited extent. J 

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ANTISEPTICS AND DISINFECTANTS 139 

Turpentine oil and many of the other volatile oils enjoy a reputation as 
antiseptics and disinfectants, and have been applied to disinfect the skin before 
operations and for similar purposes. 

Chloroform may also be mentioned as a disinfectant in use in the laboratory 
though it has never been adopted in surgical operations. 

Alcohol is a disinfectant when used in 50-70 per cent, dilution, and has 
been used to clean and disinfect the skin and hands before operation. 

4. Mercuric Perchlorede. 

Soon after the treatment of wounds with carbolic acid was estab- 
lished, its rival, corrosive sublimate, was introduced as a more powerful 
disinfectant. There is no question that the claim was justified and that 
corrosive sublimate in ordinary surgical practice has greater germicidal 
and antiseptic powers than carbolic acid. At the same time bacteria 
must be exposed for a longer time to its action before they are de- 
stroyed, and it has a more injurious effect on the tissues with which 
it comes in contact and is more poisonous when it is absorbed. A 
certain amount of mercury remains attached to the proteins of the 
microbes and restrains their reproduction even when it does not act- 
ually kill them; owing to this fact corrosive sublimate has been credited 
with greater disinfectant power than it merits, for it is found that on 
the complete removal of the mercury many of the inactive organisms 
recover; in practice its action is therefore partly disinfectant and partly 
antiseptic. The symptoms of mercuric poisoning and the general action 
will be discussed under the chapter on mercury (see Index). 

Mercuric chloride solution (1 in 2000-4000) is used extensively in sur- 
gery to disinfect the hands, skin and wounds, but is very irritant to the 
unbroken skin even and must not be applied to more delicate tissues. 
It corrodes steel and this precludes its use to preserve instruments 
before use. It is sometimes employed in the form of a soap and to 
impregnate bandages, cottonwool, gauze, catgut, etc., but it renders all 
of these irritant and corrosive so that they should not be applied 
directly to wounded surfaces. It differs from the carbolic acid group in 
preserving its disinfectant powers in oils and fatty vehicles, in which it 
is only slightly soluble and which it therefore leaves readily for the 
fluids of the microbes. It also differs from carbolic acid in the fact 
that the presence of sodium chloride reduces its disinfectant action 
because it lessens the amount of the free Hg ion. The disinfectant 
action of corrosive sublimate is much diminished by the presence of 
protein and it has less penetrating power than carbolic acid. It pre- 
cipitates the protein like other metallic salts and has a further specific 
toxic action on living tissue. Various other mercurial salts have been 
suggested as disinfectants, for example the cyanide and periodide; but 
these have no advantages over the perchloride. 

5. Other Metallic Disinfectants. 

The salts of several other metals have been used as disinfectants 
and antis%>tics. Silver nitrate is the most important of these and 

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140 SUBSTANCES ACTING LOCALLY 

plays a large r61e in the treatment of infections of the mucous 
membranes, especially that of the eye. This disinfectant action is 
accompanied by intense irritation, but silver nitrate has very slight 
powers of penetration because it is rendered insoluble and there- 
fore inactive by the chlorides of the tissues. Silver nitrate is used 
in solutions of 1 to 2 per cent, as a disinfectant in infectious oph- 
thalmia, or in more dilute form (1 in 200-400) for more frequent 
application. It has also been used as an injection in gonorrhoeal infec- 
tion of the urethra in the strength of 1 in 500-2000 and in various 
other conditions. General poisoning is unknown from this use of silver, 
but its intensely caustic action and the limited extent to which it pene- 
trates have prevented its wider employment. This irritant action of 
the nitrate has led to the introduction of various other salts and prepara- 
tions (see Silver), which are less dissociated in solution and thus are 
less corrosive. But these lose their disinfectant power in the same ratio 
as they become less irritant, for the tissue destruction arises from the 
same factor as the disinfectant action, the free silver ion. The effects 
of silver after absorption will be discussed later (see Index). 

6. Oxidizing Disinfectants. 
Peroxide of Hydrogen. 

Hydrogen peroxide or dioxide (H2O2) tends to break down into 
water and oxygen very rapidly in the presence of many substances, 
which in themselves may be either oxidizing or reducing. Among the 
bodies which induce this decomposition are the peroxidase ferments, 
which are found in all forms of living matter, and the peroxide of 
hydrogen is therefore decomposed when brought in contact with the 
tissues; the oxygen thus liberated tends to oxidize its surroundings 
and its chief effects are therefore due to its oxidizing properties. It 
is generally met with in -dilute solution in water, and in this form 
alone is used in medicine. Brought in contact with the skin, peroxide 
of hydrogen solution is decomposed, and numerous bubbles of oxygen 
are formed, 1 but this decomposition proceeds much more rapidly when 
it is applied to denuded surfaces or to mucous membranes. The 
oxygen is formed in such quantity that some irritation may follow, 
and thus dogs often vomit when it is administered in quantity by the 
mouth. When it is injected subcutaneously, a large amount of oxygen 
is formed in the subcutaneous tissues, but some of the peroxide 
escapes decomposition and is absorbed into the blood. Here the 
decomposition proceeds more violently, the red-blood cells having a 
strong catalytic action, and the oxygen set free may cause emboli and 
lead to sudden death. The formation of emboli is seen most frequently 
in the rabbit, but was in all probability the cause of death in one case 
of fatal poisoning in man, in which a solution of hydrogen peroxide 

1 A concentrated solution is said to corrode the skin, leaving a white eschar. 

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ANTISEPTICS AND DISINFECTANTS 141 

had been used to wash out the pleural cavity. 1 Emboli are not formed 
in the dog on hypodermic injection, nor in either dogs or rabbits poisoned 
by the stomach — in the latter case probably because the liquid is more 
slowly absorbed and is almost entirely decomposed in the mucous 
membrane. Even in the blood and tissues the whole of the peroxide 
is not decomposed, for several observers have found traces of it excreted 
in the urine. 

The catalysis of hydrogen peroxide occurs in the lower forms of 
life as well as in the higher. Thus germinating seeds, yeasts, infusoria 
and the microbes all free oxygen from the solution, and in fact, a 
rough estimate of the number of microbes in water may be formed 
from the amount of oxygen given off by it on the addition of the per- 
oxide (Gottstein). This decomposition is fatal to most of these lower 
forms, from the nascent oxygen, and peroxide of hydrogen is therefore 
a powerful disinfectant in water, a 3 per cent, solution proving as strongly 
bactericidal as a 1 per mille solution of corrosive sublimate; but when 
the microbes are contained in a medium with much organic substance, 
as in wounds, the bactericidal action is very much reduced. This appears 
to be due to the too rapid decomposition of the peroxide, which escapes 
as bubbles of oxygen, comparatively little oxidation taking place. 
This may be exemplified by its action on the blood; when normal 
blood in a test-tube is treated with peroxide, it froths up and the oxygen 
escapes, leaving the blood unaltered. If, however, some hydrocyanic 
acid has been added to the blood sometime previously so as to weaken 
the ferment, there is little or no effervescence and the hemoglobin is 
changed to methaemoglobin by the peroxide remaining and freeing its 
oxygen more slowly. The peroxide therefore oxidizes most powerfully 
when it is slowly decomposed, while the rapid action of the ferments 
tends to dissipate the oxygen in the molecular form which has com- 
paratively slight oxidizing and disinfectant powers. 

In recent years, attention has been drawn to other bodies analogous to 
hydrogen peroxide, some of which possess powerful microbicidal properties. 
The peroxide is represented by the structural formula H — — O — H and one of 
the hydrogens may be replaced by benzoyl or acetyl, forming C 6 H 6 CO — O — OH 
(benzo-peracid) or CHsCO — OOH (aceto-peracid). These bodies give off oxygen 
more slowly than hydrogen peroxide and surpass it in germicidal power; in 
fact they are as powerful disinfectants as corrosive sublimate in favorable 
conditions. Unfortunately these peracids are too unstable for practical use; 
and the organic peroxides, such asdiacetyl peroxide (CH s CO— O— 0— COCH 3 ), 
which form the peracids in water have not proved so useful clinically as the 
laboratory results seemed to promise. 

Preparations. 

Aqua Hydrogenii Dioxidi (U. S. P.), Liquor Hydrogenii Peroxidi (B. P.), 
solution of hydrogen dioxide or peroxide, contains about 3 per cent, by weight 
of the pure dioxide. Each volume of this solution is capable of setting free 

i j n several other instances hemiplegia has been observed, apparently from embolism 
of the cerebral arteries. 



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142 SUBSTANCES ACTING LOCALLY 

10 volumes of oxygen when completely decomposed. Some acid is added to 
the peroxide solution in order to retard its decomposition, but it gradually 
changes when kept, so that only freshly prepared solutions are of full strength. 
The solution is colorless and odorless, but has an acid taste from the added 
acid, and the oxygen freed in the mouth gives a curious sensation and forms a 
froth. 

Therapeutic Uses. — Hydrogen dioxide is used locally as a disinfectant 
solution in suppuration, diphtheria, and urethral infection. In pus 
cavities the oxygen is freed with great rapidity, and the pus-corpuscles 
are said to be disintegrated. The catalysis is due in part to these 
corpuscles, in part to the microbes, and the extent of the suppuration 
may be estimated from the amount of effervescence. Peroxide solutions 
differ from most other disinfectants in the short duration of the action, 
which passes off as soon as all the oxygen is liberated. In addition to 
its microbicidal action proper, this agent loosens and destroys masses 
of infected material by the mechanical effect of the liberation of the 
gas, and the wound or cavity is thus cleaned by it more perfectly than 
by washing with ordinary disinfectant solutions. Most surgeons believe 
that this mechanical action is of more importance than the direct 
germicidal effect. The solution has been recommended for use in oph- 
thalmic practice, and for this purpose may be diluted one half. 

Peroxide has been used to destroy the bacteria of drinking water and 
10-15 c.c. of the pharmacopoeial solution is found to reduce the bacteria 
in a liter of water more than 100 times; about twice as much is required 
to have the same effect in milk. 

Bibliography. 

GuUmann. Virchow's Archiv, lxxiii, p. 23; lxxv, p. 255 

Schwerin. Ibid., lxxiii, p. 37. 

Altehoefer. Centralbl. f. Bacterid., viii, 1890, p. 129. 

Gottstein. Virchow's Archiv, cxxxiii, p. 295. 

SpiUer. PflOger's Archiv, lxvii, p. 615. 

Honsell. Beitrage z. klin. Chir., xxvii, p. 127. 

uoew. U. S. Depart, of Agriculture Rep., No. 68. 

Xovy and Freer, Journ. of Exp. Med., vi. (Peracids.) 

Other Oxidizing Disinfectants. 

Some older disinfectants also owe their powers to liberated oxygen, 
and among these that most largely employed is the Permanganate of 
Potassium. 

When a solution of this salt comes in contact with organic matter, 
such as albumin, the permanganate at once parts with some of its 
oxygen, which attaches itself to the albumin. Permanganate is thus 
poisonous to protoplasm, not through the presence of the whole mole- 
cule, but in consequence of the oxidation of the proteins. As soon as 
the permanganate is reduced, it of course loses this action, so that the 
oxidizing effect is limited to the skin and the surface of the mucous 
membranes. Concentrated solutions irritate, and even corrode the 
skin, and induce gastro-enteritis when swallowed. Permanganate 



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ANTISEPTICS AND DISINFECTANTS 143 

solutions are disinfectants of considerable power, owing to their oxi- 
dizing and thus destroying bacteria. They fail to penetrate deeply in 
an active form, and this renders them of less value than many other 
disinfectants, except in very superficial infection. 

Potassii Permanganas (U. S. P., B. P.) (KMn0 4 ) forms slender crystals of 
a dark purple color and a sweetish, afterward disagreeable and astringent 
taste, soluble in sixteen parts of water, reduced by alcohol and other organic 
bodies. 0.065 G. (1 gr.); B. P., 1-3 grs. 

The permanganate has been used internally in amenorrhoea and 
chlorosis. 

Externally it is used for its disinfectant and deodorant action, as 
an application to gangrenous ulcers, cancerous sores, diphtheria, and 
gonorrhoea. In dilute solution it may be used as a gargle and mouth 
wash (£ per cent.), to disinfect the hands (1 per cent.), which it stains 
brown, and for other similar purposes. 

It has recently been recommended in poisoning with phosphorus, 
prussic acid, morphine and other alkaloids, on the theory that these 
poisons are oxidized by it in the stomach, and thus rendered harmless. 
For this purpose it is given in one-third per cent, solution. But per- 
manganate also oxidizes the gastric mucous membrane, and it has not 
been shown that it attacks morphine in preference to the proteins; 
the treatment is certainly less reliable than the use of the stomach tube; 
permanganate has of course no action on morphine after absorption. 
In snakebite, permanganate has been used to wash the wound and also 
to inject around it; it has no effect upon the poison already absorbed. 

Condy's Fluid is a strong solution of impure permanganate, which 
is of use to disinfect and deodorize urinals and faeces, but must be 
poured on them, and cannot be employed to disinfect rooms. 

Some of the caustics owe part of their action to the oxygen liberated 
when they come in contact with organic matter. Thus Chromic Acid 
destroys tissue in part through its acidity but this is reinforced by its 
oxidizing powers. 

Other oxidizing bodies have been used as antiseptics and disinfectants. 
Thus Calcium Peroxide or Gorit has been recommended as a gastric 
and intestinal disinfectant for children in doses of 0.2-0.6 G. in milk. 
Zinc peroxide and magnesium peroxide have also been suggested, the 
former for external, the latter for internal use. 

Similarly the Persidphates of potassium and sodium (Na^Oa), 
persodine, possess strong oxidizing properties from their liberating 
oxygen in contact with organic matter. They are only feebly poisonous 
but have not been extensively used as yet. 

7. Boracic Aero and Borax. 

Boracic or boric acid (B(OH) 3 ) is a very weak acid, and it is doubtful 
whether the hydrogen ions or acidity play any part in its action, or 
whether the whole is not to be referred to the rest of the molecule. 
The ordinary sodium compound, borax, Na^Ov, is stated by some 



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144 SUBSTANCES ACTING LOCALLY 

authors to be equally active, but is alkaline in reaction, so that the 
exact relative importance of the two ions of boric acid cannot be deter- 
mined. 

Action. — Boracic acid and borax are only feebly toxic, but large 
quantities taken by the mouth cause gastric and intestinal irritation, 
as is evidenced by vomiting and purging, and even smaller amounts 
are said to act as mild aperients in some cases. Not infrequently 
repeated small doses of boric acid have induced albuminuria, especially 
in persons predisposed to it. Moderate doses are without effect on the 
metabolism, but larger quantities (5-10 G. per day in dogs) increase 
the nitrogen excretion in .the urine. A dose of 30-60 grs. of boric acid 
is found to increase the bulk of the faeces in man by retarding the 
absorption of the proteins and fats. 1 Both borax and boracic acid are 
rapidly absorbed by the bowel, and do not affect the intestinal putre- 
faction. 

Boracic acid has been widely used as an antiseptic dressing, and a 
number of cases of serious poisoning have been recorded from its ab- 
sorption. The symptoms arose in part from the alimentary canal, 
uneasiness in the abdomen, vomiting, diarrhoea, dryness of the throat 
and difficulty in swallowing; sleeplessness, great muscular weakness 
and depression, dimness of sight and headache were also complained 
of, and in severe cases collapse and death followed. The prolonged 
use of boracic acid, internally or externally, has repeatedly led to 
falling of the hair, eczema, and psoriasis. Papular eruptions and local 
cedemas and swelling of the skin appear, and a gray line on the gums, 
similar to that seen in lead poisoning, is stated to occur along with 
irritation of the mouth. 

Boracic acid and borax are excreted in the urine, in which they 
appear within a few minutes after ingestion; over half the quantity 
taken is excreted within twelve hours, but afterward the elimination 
proceeds more slowly, so that traces may be found in the urine for 
five days or more; the urine becomes alkaline after sufficient amounts 
of borax, as after any other alkaline preparation. Boracic acid and 
its sodium salt have some antiseptic power, for in 2$ per cent, solution 
almost all forms of bacilli stop growing; but they are not destroyed, 
even the delicate anthrax bacilli being found capable of further growth 
after exposure to a 4 per cent, solution for twenty-four hours. Boracic 
acid is therefore valueless as a disinfectant, but has been used as an 
antiseptic dressing; it has the advantage over many other antiseptics 
of inducing very little irritation and of being only slightly poisonous, 
but experience has shown that it cannot be used with impunity in very 
large quantities. 

Acidum Boricum (U. S. P., B. P.), Boric or Boracic Acid (H»BO»), color- 
less crystals, with a faintly bitter taste, soluble to about 4 per cent, in water, 
more so in alcohol and glycerin. 0. 5 G. (7 \ grs.) ; B. P., 5-15 grs. 

1 The body weight often falls under borax treatment, and this has been attributed to 
augmented fat destruction by Rost and Rubner, who state that a corresponding increase 
in the carbonic acid elimination accompanies it. 



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ANTISEPTICS AND DISINFECTANTS 145 

Glycerilum Boroglycerini (U. S. P.), Glycerinum Acidi Borici (B. P.). Boro- 
glycerin is a compound formed by heating boric acid in glycerin, and the 
official glyceritum or glycerinum contains this dissolved in glycerin, about 30 
parts of boric acid being used to form 100 parts. 

Liquor Antisepticus (U. S. P.), containing 2 per cent, of boric acid, along 
with benzoic acid, thymol, eucalyptol, and oils of peppermint, wintergreen, and 
thyme. 

Unguentum Acidi Borici (B. P., U. S. P.), 10 per cent. 

Sodii Boras (U. S. P.), Borax Purificatus (B. P.), Borax (Na,B 4 O 7 +10H,O) 
forms colorless crystals with a sweetish alkaline taste. It is soluble in water (25 
parts) to which it gives an alkaline reaction. 0.5 G. (7J gra.); B. P., 5-15 grs. 

Glycerinum Boracis (B. P.) (1 in 6). 

Boracic acid has been used as a surgical antiseptic in solution 
(4 per cent.), ointment, or lint, and the solution of the acid or of 
borax is also used as a wash in aphthae and other forms of irritation of 
the mouth. Boracic acid solution has been given internally in dilute 
watery solution as a genito-urinary disinfectant, has also been injected 
into the bladder, and is frequently used in ophthalmic surgery, as 
being less irritant to the eye than the more powerful antiseptics. In 
internal medicine the acid and the salt have been used in epilepsy, 
and also in the hope of dissolving uric acid calculi, but have not been 
shown to be efficient for either purpose. Boracic acid and borax are 
sometimes added to milk or other food as preservatives, and it has 
been much discussed whether the habitual use of such preserved food 
is likely to prove deleterious to the health. The general result of the 
investigations is that, while no preservative should be added to food 
unless it is absolutely unavoidable, boric acid is less liable to derange 
the health than most other preservatives. Foods preserved with 
boracic acid should not be used by delicate individuals or by children, 
however, and the quantity of the acid used must be strictly limited. 

Bibliography. 

Neumann. Arch. f. exp. Path. u. Pharm., xiv, p. 149. 

Forster. Arch. f. Hygiene, ii, p. 75. 

Rost u, Sonntag. Arb. a. d. Kaifl. Oesundheitaamte, xix, p. 110. 

Heffter. Ibid., xix, p. 97. 

Chittenden and Gies. Am. Journ. of Phys., i, p. 1. 

WOd. Lancet, 1899, i, p. 23. 

Tunnicliffe and Rosenheim. Journ. of Hygiene, i, p. 168. 

Vaughan and Veenboer. Amer. Medicine, March 15, 1902. 

8. Potassium Chlorate. 

The chlorate of potassium, introduced into therapeutics on the erro- 
neous theory that it would supply oxygen to the tissues, has been used 
very extensively for its effects in certain diseases of the mouth. It 
was supposed to be entirely devoid of poisonous properties, but was 
shown by Jacobi to give rise to very grave and even fatal symptoms 
in some instances. But the conditions which determine their appear- 
ance are not universally present, for very often large quantities have 
been taken with impunity. 

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146 SUBSTANCES ACTING LOCALLY 

Symptoms. — The chlorates have a cool, saline taste, which persists 
for a long time owing to their being excreted in part in the saliva. 
Concentrated solutions may cause nausea and vomiting from their 
local salt-action in the stomach, and their absorption is often followed 
by considerable diuresis from a similar action in the kidney. In the 
great majority of cases no further effects are observed. 

In some individuals, however, symptoms arise from a single large 
dose, or from smaller quantities taken repeatedly. In Acute Chlorate 
Poisoning, the first symptom is often prolonged and violent vomiting, 
with pain in the stomach region; diarrhoea and a dark cyanotic color of 
the skin and mucous membranes follow, the respiration is at first 
dyspnoeic and then weak, the pulse quick and feeble, sometimes irregular. 
The patient complains of headache, giddiness and muscular weakness, 
is restless, and eventually bcomes comatose before death. 

In Subacute Poisoning, vomiting and diarrhoea are also observed, 
and the vomited matter often contains large quantities of bile, less 
often blood. There may be complete anuria for some time, or the 
urine is scanty and at first dark colored, then deep reddish-brown; 
it contains haemoglobin, methsemoglobin, and haematin in solution. 
On standing, it deposits casts of brown amorphous particles, which 
arise from the destruction of the red cells of the blood, and chlorates 
are contained in it in considerable quantity. The methaemoglobin 
may disappear from the urine after one or two days, but the casts 
remain longer. The skin is often icteric in color, and in some cases 
erythematous eruptions have been observed. Headache, muscular 
weakness and abdominal pain are complained of, and uremic symp- 
toms may arise — delirium and convulsions, or confusion and coma. 
Death has followed from these last as late as a week after the first 
symptoms of poisoning were observed, but in several cases complete 
recovery has followed even the gravest symptoms. 

Action. — These symptoms arise from the action of chlorates on the 
red cells of the blood and especially on the haemoglobin. When chlorate 
solution is added to blood in a test-tube it slowly forms methaemoglobin 
and hcematin, and the blood assumes a chocolate brown color. Later, 
the red cells tend to become laked and the methsemoglobin is freed in 
the serum. This action on the blood is generally ascribed to the oxidizing 
properties of the chlorates, for other oxidizing agents have the same 
effects; some oxidizing agents induce marked haemolysis with little 
methaemoglobin, while in others the latter feature is the predominating 
one. There is, however, some difficulty in explaining the chlorate action 
by oxidation, for these salts are very stable and have practically no 
oxidizing action at body temperature. 

When this transformation of the haemoglobin takes place in the 
vessels, asphyxia results from the inability of the blood to carry 
available oxygen, and this is unquestionably the chief cause of the 
symptoms and of the fatal issue in the most acute form of intoxication. 
When a considerable amount of haemoglobin is transformed, but suffi- 
cient remains to continue the respiration of the tissues, the subacute 



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ANTISEPTICS AND DISINFECTANTS 147 

form of poisoning results from the haemolysis; the haemoglobin and frag- 
ments of the corpuscles obstruct the renal tubules with masses which 
may appear as casts in the urine, or may cause complete suppression ; 
the fatalities in subacute chlorate poisoning appear to be the result of 
these renal changes. Some of the products of the haemoglobin are 
deposited in the liver and spleen and often cause enlargement of these 
organs; the bile pigment is increased in amount and the bile passes 
through the duct with difficulty and this leads to the absorption of bile 
and jaundice. 

The haemoglobin of most animals seems equally easily transformed 
to methaemoglobin by chlorates when it is dissolved in water, but the 
blood-corpuscles of the rabbit and guinea-pig resist their action much 
more than do those of the dog and of man. Apparently the corpuscles 
of the rabbit are less permeable by chlorate than those of the carnivora 
and man and the true chlorate symptoms are rarely elicited in rabbits, 
while dogs and cats show the same effects as man. 

Chlorate has little or no direct effect on the central nervous system 
or the circulation, though these are secondarily affected by the asphyxia 
and renal changes. 

Very little chlorate is reduced in the blood and tissues, for 90-96 per 
cent, of the amount administered has been recovered from the urine. 
Small quantities appear also in the saliva and in other secretions, 
such as the perspiration, milk, tears, and nasal mucus, and some has 
been found to pass from the mother to the foetus in utero. 

Chlorates hardly retard the growth of bacteria in cultures more than 
other indifferent salts, and no adequate explanation has been offered 

for their use in infections of the mouth and throat. 

» 

The Bromates and Iodates have been much more seldom the subject of 
investigation than the chlorates, and are not used in therapeutics. The iodates 
are more poisonous than the bromates and these again than the chlorates; the 
iodates destroy the red cells more rapidly but form less methsemoglobin than 
the chlorates in test-tube experiments. Iodates induce fatty degeneration of 
the liver and congestion and extravasation in the alimentary tract. Some 
iodide is formed from them in the body. 

The action of the Perchlorates has been examined by Kerry and Rost. In 
the frog the perchlorate of sodium (NaClCM induces fibrillary twitching and 
clonic contractions of the muscles; the contraction of the muscle is prolonged 
in the same way as by yeratrine, and rigor eventually follows as in caffeine 
poisoning. The reflex excitability is increased and the heart is slow and irregu- 
lar. The effects of the perchlorate on mammals differ considerably in different 
species; in the rat, mouse, and guinea-pig the reflex excitability is enormously 
increased and tetanic convulsions may arise from this action; in the cat a 
certain stiffness, muscular paresis and tremor can be made out after the injec- 
tion of large quantities of perchlorate, but these animals as well as the rabbit 
and dog are not killed by even very large quantities. 

Potassii Chloras (U. S. P., B. P.), (KCIO3), 0.25 G. (4 grs.) ; B. P., &-15 grs. 

Trochisci Potassii Chloratis (U. S. P.) contain 0.15 G. (0.2 G., B. P.) 
chlorate of potassium in each lozenge. 

The chlorates are colorless prismatic crystals with a saline taste, and are 
given in solution or in lozenges when used internally. The dry salts form 



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148 SUBSTANCES ACTING LOCALLY 

explosive mixtures with organic or other reducing substances, and such mix- 
tures are therefore to be kept cool, and ought not to be ground together, as 
heat and pressure are liable to cause explosions. 

Therapeutic Uses. — The chlorate of potassium is used chiefly as a 
mouth wash and gargle in irritable conditions of the mouth and throat, 
such as aphthae, and in the tenderness and ulceration of the gums and 
mouth induced by the prolonged use of mercury. It may also be given 
as a prophylactic to lessen stomatitis when mercury is being prescribed. 
In catarrh of the throat it is often used with apparently good effects. 
It is rarely employed in diphtheria now. 

It is used in 2-4 per cent, solution, or the official lozenge may be 
prescribed. In children a somewhat stronger solution with syrup or 
honey may be used to brush out the mouth, but care should be taken 
that none is swallowed. The local action of the chlorates has not been 
explained, and it may be due to the salt-action in part, though not 
wholly. It has been suggested that they are oxidizing disinfectants, 
but there is no reason to suppose that they are changed here any 
more than in the tissues in general. It is not impossible that equally 
satisfactory results might be obtained by the use of the chlorides or 
nitrates. Chlorate of potassium has been given internally in cases of 
diphtheria and in some diseases of the mouth, but it does not seem to 
have any therapeutic value unless when applied locally. Some benefit 
may arise from its contact with the mouth and throat in the process 
of swallowing and from its excretion in the saliva. In addition the 
internal administration of the chlorate is liable to induce dangerous 
poisoning. 

Poisoning. — The fatal dose of chlorate varies extremely, as little as 
1 G. (15 grs.) having proved fatal in a child, while 40-50 G. (10-12 
drs.) have been swallowed by adults without marked symptoms. 
Chlorate poisoning is now very rare; it is said to be more liable to 
occur in nephritis than in normal persons. As a general rule symp- 
toms appear only two to three hours after the drug has been taken, 
and the treatment is purely symptomatic — central nervous stimulants, 
ice for vomiting etc.; alkalies may be given to lessen the formation 
of methsemoglobin and diuretics and large amounts of fluid to flush 
out the kidneys. 

Bibliography. 

Marchand. Virchow's Archiv, lxxvii, p. 455. Arch. f. exp. Path u. Pharm., xxii, p. 
201; xxiii, pp. 273 and 347. 

Merino. Das chlorsaure Kali, 1885, Berlin. 

Stokvis. Arch. f. exp. Path. u. Pharm., xxi, p. 169. 

Cahn. Ibid., xxiv, p. 180. 

Lewin u. Posner. Centralbl. f. d. med. Wissensch., 1887, p. 354. 

Diltrich. Arch. f. exp. Path. u. Pharm., xxix, p. 247. 

Binz. Ibid., x, p. 153; xxxiv, p. 185. 

Falck. Pfluger's Archiv, xlv, p. 304. 

Dreser. Arch. f. exp. Path. u. Pharm., xxxiv, p. 204. (lodatea, Bromatea.) 

Kerry u. Rost. Ibid., xxxix, p. 144. (Perchlorates.) 

Mathews. Amer. Journ. of Physiol., xi, p. 237. 

Cushny. Arch. f. exp. Path., Schmiede berg's Festschr., p. 126. 



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ANTISEPTICS AND DISINFECTANTS 149 



9. Iodine. 

Iodine has recently been used largely to disinfect the skin before 
operation, as it is found to penetrate readily into the pores and has a 
very powerful germicidal action. Its irritant effects preclude its more 
general use. It is generally employed in the strength of 2^-5 per cent, 
in 10 per cent, potassium iodide solution or in alcohol, and is painted 
on the site of operation a few minutes before the incision is made. 

10. Iodoform. 

A number of iodine compounds have been introduced into thera- 
peutics as applications to wounded surfaces. The most widely known 
of these is Iodoform (CHI 3 ), which corresponds in its chemical structure 
to chloroform, and has been used very extensively in surgery; it formerly 
gave rise to poisoning repeatedly. 

Symptoms. — The symptoms of iodoform intoxication in man gen- 
erally set in with anxiety, general depression and discomfort. The 
patient becomes sleepless and restless, complains of giddiness and 
headache and often of the taste and odor of iodoform in the mouth 
and nose. The pulse is generally greatly accelerated, and a rise of 
temperature is said to have occurred in some cases in which no septic 
poisoning could be found to account for it. The depression deepens 
into true melancholia accompanied by hallucinations, the patient often 
suffering from the illusion of persecution, which may induce him to 
attempt suicide. As a general rule this melancholia is followed by 
attacks of violent delirium and mania, lasting for hours or days, and 
in fatal cases, by collapse and death. In other cases the condition has 
passed into permanent insanity and dementia. A rarer result of the 
absorption of iodoform is deep sleep passing into stupor and collapse 
without any symptoms of cerebral excitement. 

In milder cases of poisoning the patient suffers only from the 
unpleasant taste and odor, from headache and not infrequently from 
nausea and vomiting. 

In the dog and cat iodoform generally causes deep sleep and stupor, 
with lessened excitability of the spinal cord and of the motor areas of 
the brain; but after large doses excitement and convulsions of clonic 
and tonic types have been observed. In the frog it paralyzes the central 
nervous system and the heart without eliciting any symptoms of excite- 
ment. No narcosis is observed in the rabbit even after fatal doses. 
After prolonged administration albuminuria is often observed in animals, 
and the iodine of the thyroid has been found to be increased by iodo- 
form, as by other bodies which free iodine in the tissues. 

After fatal iodoform poisoning in man and animals, the liver, kidney, 
heart and muscles are generally found to have undergone fatty degenera- 
tion. In addition, irritation of the gastric and intestinal mucous mem- 
brane has been observed, arid the epithelial cells are often degenerated. 



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150 SUBSTANCES ACTING LOCALLY 

Ecchymoses occur beneath the endocardium, in the kidney and else- 
where, and congestion of the meninges is described. 

Absorption and Excretion. — Iodoform is readily decomposed in the 
presence of alkaline fluids and in protein solutions, and some decom- 
position undoubtedly takes place in wounds; the iodine liberated com- 
bines with the alkalies of the fluids to form iodides, for these have 
been shown to be present, and iodalbuminates are presumably formed 
in the same way as by free iodine. Some of the iodoform is perhaps 
absorbed unchanged. After iodoform absorption, iodine has been 
shown to be present in the saliva, perspiration and bronchial secretion, 
as after the ingestion of iodine or iodides; but it is chiefly excreted in 
the urine in the form of iodides and partly in organic combination. 
The tissues apparently retain it very tenaciously, for iodides have been 
found in the urine for more than a month after the administration of 
iodoform. 

In considering the symptoms of iodoform intoxication, it must be 
recognized, therefore, that a very complex condition is present. Some 
iodoform may circulate in the blood unchanged and give rise to the 
cerebral symptoms. Other symptoms are due to the presence of 
iodine and iodides in the blood and tissues. Lastly, the acceleration 
of the heart and some other symptoms are due to abnormal activity 
of the thyroid secretory cells. It is possible that the cerebral symp- 
toms may arise from the thyroid gland through the action of iodoform 
on it, but this has not been demonstrated. 

Iodoform has no marked Local Action on the skin or mucous mem- 
branes. Some persons have a special idiosyncrasy for it which betrays 
itself in an eruption developed in the skin near where iodoform 
has been applied; Bloch states that a skin graft from these persons 
implanted in a normal individual continues to show this reaction, but 
believes that the idiosyncrasy is not limited to iodoform but extends to 
many other methyl compounds. It seems to have some anaesthetic 
action, when applied in large quantity to wounded surfaces. Iodoform 
was at first applied to wounds in the belief that its Antiseptic properties 
were equal to or even exceeded those of carbolic acid. But cultures of 
bacteria are not prevented from developing by the addition of iodoform. 
It has therefore been suggested that while iodoform in itself possesses 
no antiseptic virtues, the iodine formed from it in the wound may 
retard the growth of septic germs; but microbes drawn from wounds 
under iodoform treatment are not retarded or weakened in their 
development. Some of the advocates of the iodoform treatment, 
therefore suppose that it diminishes the secretion of the wounded sur- 
face and thus affords a less suitable medium for the growth of the 
germs; in this relation it may be mentioned that Binz found the 
emigration of the leucocytes from the bloodvessels hindered by the local 
application of iodoform. Finally iodoform may retard the growth of 
microbes to some extent by forming a crust over the wounded surface, 
and mechanically preventing them from penetrating to it. 

The intensely disagreeable odor of iodoform and its toxicity have 

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Antiseptics and disinfectants 151 

led to the introduction of numerous substitutes. None of these seem 
to be very poisonous, and in most of them the iodine of the molecule 
is not liberated in the wound or tissues. It is of course impossible to 
stare how far they are capable of replacing iodoform, as long as their 
exact action in wounds is unknown. 

The first of these substitutes, was iodol or tetraiodpyrrol (CJ4NH), which 
has no odor or taste, is insoluble in water, but is absorbed from mucous sur- 
faces and from wounds. It is decomposed in the tissues ? and leads to the ex- 
cretion of iodides in the urine, and in very large doses gives rise to symptoms 
in animals resembling those produced by iodoform. Others are aristol or 
dithymol-diiodide (C«HiCHsCaH 7 OI)2, and the potassium, sodium, mercury, 
and zinc salts of soziodolic acid (C«HiIiHOSOiOH). Iodine compounds of 
phenol-phthalein are known by the trade names of nosophen, antinosine, and 
eudoxine. Triiodocresol is known as losophan, while europhen is a more complete 
combination of cresol and iodine; loretin and vioform are derivatives of quino- 
line containing iodine. (See also under Bismuth and Alum.) These later "sub- 
stitutes" for iodoform differ entirely from it and from iodol in the fact that iodine 
is not liberated by the tissues; what value they possess is probably due to their 
acting as absorbent powders, and precipitated chalk would presumably be as 
efficient. 

Iodoformum (U. S. P., B. P.), iodoform (CHI 8 ), forms small, lemon-colored 
crystals, possessing a very penetrating, persistent, and disagreeable odor and 
taste, practically insoluble in water, soluble in alcohol, ether, fixed oils, glycerin, 
etc. 0.25 G. (4 grs.); B. P., J-3 grs. in pills or capsules. 

Unguentum Iodoformi (U. S. P., B. P.), contains 10 per cent, iodoform. 

Thymolis Iodidum (U. S. P.), Aristol (C«H,CH,C^ 7 OI) 3 , a yellowish- 
brown powder; tasteless, odorless, insoluble in water. 

lodolum (U. S. P.), CJ4NH, a light grayish-brown crystalline powder, taste- 
less, odorless, insoluble in water. Dose, 0.25 G. (4 grs.). 

The Sozoiodalate of potassium is slightly soluble in water, the sodium and 
zinc salts more soluble. Mercury forms an insoluble salt which may be dis- 
solved by the addition of sodium chloride. 

Therapeutic Uses. — Iodoform has been used to a very limited extent 
internally in the treatment of syphilis, and as an intestinal disinfectant. 
It is chiefly employed in surgical treatment as an application to wounds, 
skin diseases and burns. In granulating surfaces with a profuse secretion, 
and in slowly healing abscess cavities, it seems to be especially valuable. 
It may be applied as a dusting powder, as an ointment, or in gauze 
or bandages saturated with it. It has been shown that it has very weak 
antiseptic properties, and many surgeons take the precaution of dis- 
infecting the powder before applying it, and use it for its effect on the 
tissues of the wound and not for its effects on the germs. Applied in 
ordinary quantity to small surfaces it seems to be a perfectly safe 
remedy, cases of poisoning occurring only when large cavities are plugged 
with it, or when it is applied to very large absorbent surfaces. 

Iodoform has been credited with some specific action in tubercular 
disease, but has proved almost inert toward the bacillus. The favor- 
able results in the local treatment of tubercular abscesses, laryngeal 
ulcers and similar conditions may with greater probability be attributed 
to its action on the granulation tissue. In syphilitic ulcers and chancres, 
iodoform has been used very largely and with good effects. 



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152 SUBSTANCES ACTING LOCALLY 

Iodol may be used as a substitute for iodoform, and is applied in 
the same way. The sozoiodolates are used as powders or ointments, 
or in the case of the sodium, zinc and mercury salts, in solution. 
The last is poisonous, and is comparable to corrosive sublimate in 
its effects. 

Bibliography. 

Bin*. Arch. f. exp. Path. u. Pharm., viii, p. 309; xiii, p. 113. Virchow's Archiv, lxxxix, 
p. 389. 

Behring. Deutsch. med. Woch., 1882, p. 278. 

Zeiler. Arch. f. klin. Chirurg., xxviii, p. 590. Zte. f. physiol. Chemie, viii, p. 70. 

Mulzer. Ztechr. f. exp. Path. u. Ther., i, p. 446. 

Falkson. Arch. f. klin. Chirurg., xxviii, p. 112. 

Neisser. Virchow's Archiv, ex., p. 381. 

Block. Zeitschr. f. exp. Path. u. Ther., ix, p. 609. 

Marcus. Berl. klin. Woch., 1886, p. 342. (Iodol.) 

Sattler. Fortschr. d. Med., 1887, p. 362. (Iodol.) 

Lomry. Arch. f. klin. Chirurg., liii, p. 787. 

Meyer. Ibid., lv, p. 676. 



n. Antiseptics Used Chiefly in Skin Diseases. 

1. Pyrogallol. 

Pyrogallol, C«H 8 (OH) 8 the only trioxybenzol that has been largely 
used, produces nervous symptoms resembling those of carbolic acid, when 
given in very large doses to animals. In the cases of poisoning which 
have been observed in man, the symptoms arose almost exclusively 
from changes in the blood corpuscles. The red-blood cells become 
shrunken and angular and lose most of their haemoglobin, which escapes 
into the plasma and is changed into methaemoglobin; the blood there- 
fore assumes a chocolate-brown color, which may be detected in the 
living animal by the discoloration of the skin and mucous membranes. 
If the intoxication is not too acute, icterus follows, and haemoglobin 
and methaemoglobin are excreted in the urine. In the blood, fragments 
of red cells and " shadows," or red cells deprived of their coloring matter, 
are seen in large numbers, and the spectrum of methaemoglobin can be 
obtained easily. The kidneys are also affected, and the resulting neph- 
ritis is indicated by the presence in the urine of albumin, epithelium 
and casts, along with the products of the decomposition of the blood. 
The nephritis may lead to uremic convulsions, which are sometimes 
accompanied by the nervous tremors characteristic of this series, and 
also by dyspnoea and cyanosis from the lack of haemoglobin in the blood. 
The formation of methaemoglobin is due to the reducing properties of 
the drug. Pwgallol is excreted in part in combination with sulphuric 
acid in the urine, in part as unknown oxidized products, which give, 
the urine a dark brown or black color, even when no blood pigments 
are contained in it. 

The skin is dyed brown when pyrogallol is applied to it, from the 
products of oxidation formed. 



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ANTISEPTICS AND DISINFECTANTS 153 

PyrogaUol (U. S. P.), pyrogallic acid (C«Ha(OH) 8 , light, colorless crystals 
or laminae when freshly prepared, which rapidly assume a darker color on 
exposure to light and air. It is very soluble in water and reduces the salts 
of the heavy metals even in the cold. It is used only externally. 

PyrogaUol is used in the treatment of several forms of skin disease, 
especially in psoriasis, in which it is applied in ointment (5-20 per 
cent.). It is dangerous to apply it to very large surfaces, however, 
and many authorities therefore advise the use of chrysarobin in its 
stead. PyrogaUol ought never to be used internally. Its curative 
action in skin diseases may be due to its slight irritant and antiseptic 
properties, but is referred by some to its reducing action. 

Bibliography. 

Wedl. Wiener Sitxungsber, lxiv, p. 405. 

Neisser. Zts. f. klin. Med., i, p. 88. 

Weyl u. Anrep. Arch. f. Anat. u. Phys., 1880, p. 234. 

2. Chrysarobin. 

Chrysarobin is a mixture in varying proportions of several bodies 
which are closely related to the active principles of the anthracene 
purgatives. It is found in an impure form (Goa powder) in cavitiep in 
the Andira araroba, a tree growing in India and Brazil. Chrysarobin 
applied to the skin in a concentrated form, or in susceptible persons, 
causes itching, redness and swelling, less frequently papular or pustular 
eruptions; the skin and clothing are stained a reddish-brown color 
where it is applied. When swallowed, chrysarobin acts as a gastro- 
intestinal irritant, causing vomiting and purging; some of it is absorbed, 
and in its excretion by the kidneys it causes in the rabbit nephritis 
with albumin and even blood in the urine. In man, slight albuminuria 
has been observed in some instances after its application to the skin; 
in animals the epithelium of the renal tubules has been found to be 
necrosed, the glomeruli being less frequently affected. It was antici- 
pated that it would undergo oxidation to chrysophanic acid in the 
body, and this is true for a part of that absorbed, but most of it passes 
through the tissues unchanged. 

Ckrysarobinum (U. S. P., B. P.), a substance obtained from Goa powder, 
which is found in the trunk of Andira araroba. It consists for the most part 
of chrysarobin, but contains some chrysophanic acid. 

Unguentum Chrysarobini (B. P.), 4 per cent. (U. S. P.), 6 per cent. 

Chrysarobin is used in skin diseases, especially in psoriasis, in which 
it is applied in ointment. Its effects, like those of pyrogallol, have 
been ascribed to its reducing action. Chrysophanic acid might be 
used also for this purpose were its isolation not attended with such 
expense. Some confusion has arisen from chrysarobin having been at 
first supposed to be chrysophanic acid. 



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154 SUBSTANCES ACTING LOCALLY 



3. Naphthol. 

The naphthols, C10H7OH, resemble carbolic acid in their antiseptic 
action but are much less soluble and less corrosive. Alpha-naphthol 
has been found to be more strongly antiseptic than the beta compound, 
and may be more poisonous, as is generally stated, but no satisfactory 
investigation has appeared regarding this point. Beta-naphthol is 
several times as strongly germicidal as carbolic acid, and is the form 
used in therapeutics. 

Large doses of the Naphthols induce symptoms similar to those of 
carbolic acid poisoning, except that in the dog no convulsions have 
been observed, and in the other mammals they seem less pronounced. 
They are irritating to the mucous membranes when they come in con- 
tact with them in solution or in vapor; thus they cause sneezing and 
coughing when applied to the respiratory passages, and in the course 
of excretion induce pain in the bladder and urethra with strangury 
and swelling of the mucous membrane. Injected subcutaneously or 
absorbed from the alimentary canal in animals, they induce acute 
nephritis with the appearance of albumin and haemoglobin in the 
urine, and some nephritis has been caused in man from their external 
application. They seem to have less effect on the circulation and 
respiration than the other aromatic antiseptics, but resemble them in 
tending to destroy the red cells of the blood. 

Occasionally naphthol has given rise to imperfect sight and partial 
retinal degeneration in man, and changes in the eye have been observed 
repeatedly in experiments on animals in which naphthol was absorbed. 
The retina is seen to be dotted over with bright points or to contain 
large yellow plaques. Atrophy of the optic nerve may follow or sub- 
retinal effusion, and cataract has been developed in some experiments, 
from an inflammatory infiltration beginning in the ciliary body and 
iris and extending into the lens and finally into the posterior surface 
of the cornea. While the ocular effects in man have never reached this 
intensity, Hoeve has observed some defects of vision induced by the 
use of naphthol internally or externally, and cautions against its pro- 
longed use. 

The naphthols are excreted in the urine in combination with glycuronic 
and sulphuric acids, and these combinations and their oxidized products 
give the urine a reddish-brown color which may become deeper on 
exposure to the air. 

Naphthalan, CioH 8 , the hydrocarbon from which naphthol is derived, is less 
soluble and does not give rise to acute symptoms in animals, but after pro- 
longed treatment with it animals suffer from diarrhoea and nephritis, with 
albumin and casts in the urine. The same changes in the retina are induced 
by naphthalin as by the naphthols. The antiseptic value of naphthalin is small, 
but it is oxidized to naphthols in the tissues and these acquire a toxic action. 
It is excreted in the urine as naphthol and further oxidation products, in com- 
bination with glycuronic and sulphuric acid. 



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ANTISEPTICS AND DISINFECTANTS 155 

Bbtanaphthol (U. S. P.), Naphthol (B. P.), Beta-naphtol (C10H7OH), 
white or yellowish-white, insoluble crystals or powder, with a faint phenol 
odor and a hot taste. 0.25 G. (4 grs.) B. P., 3-10 grs. 

Therapeutic Uses. — Beta-naphthol was at first introduced as an external 
application in various forms of skin disease, in which it is used in ointment 
(5-10 per cent.). Naphthalin was also employed in the same way, but 
has not proved so popular. Beta-naphthol has also been given internally 
as an intestinal disinfectant, but has not been efficacious. It has been 
employed as an anthelmintic to a limited extent, and apparently with 
some success, though it has not proved so reliable as some of the older 
drugs used for this purpose. Naphthol is more largely used than naph- 
thalin in internal medication, and may be prescribed as a powder or in 
capsules. Naphthalin and naphthol ought to be avoided in irritation of 
the kidneys, bladder or urethra. 

Bibliography. 

WUlem. Therap. Monataheft, 1888, p. 20. 
Baatz. Centralbl. f. inn. Med., 1894, p. 867. 
Lesnik. Arch. f. exp. Path. u. Pharm., xziv, p. 168. 
Magnus. Therap. Monata., 1887, p. 387. 
Klingmann. Virchow's Arch., cxliz, p. 12. 
v. d. Hoeve. Arch. f. Ophthalmol., liii, p. 74. 
Edlefsen. Arch. f. exp. Path., liii, p. 429. 

4. Resorcin. 

The three dioxybenzols — resorcin, pyrocatechin and hydroquinone — resem- 
ble carbolic acid in their effects, but produce a more intense stimulation 
of the central nervous system, for convulsions have been observed in man 
after their use. This is especially true for the last two, resorcin being much 
less toxic than these. Resorcin seems to be equally or more strongly anti- 
septic than phenol, and is somewhat less poisonous, while the others are 
more dangerous; it is less irritant and caustic than carbolic acid. All three 
dioxybenzols are excreted in the urine in combination with sulphuric and 
glycuronic acids. They are in part subjected to further oxidation, leading to 
coloration of the urine similar to that seen in carbolic acid poisoning. 

Resorcinol (U. S. P.) Resorcinum (B. P.), resorcin, metadioxybenzol (C 6 H 4 - 
(OHj)), colorless, very soluble crystals, with a faint aromatic odor. 0.125 G. 
(2 grs.); B. P. 1-5 grs. 

Resorcin has been applied in ointment (5-10 per cent.) in skin diseases, and 
has been injected in cystitis and gonorrhoea in solution (1-3 per cent.), but in 
both cases is liable to produce irritation and pain. As an internal remedy it 
was formerly used as an antipyretic and as an intestinal disinfectant but has 
fallen into complete disuse. 

Bibliography. 

Andeer. Centralbl. f. d. med. Wis., 1881-1889. 
Martin. Therap. Gaz., 1887, p. 289. 
Surbeck. Deutsch. Arch. f. klin. Med., xxxii, p. 515. 
Danilewsky. Arch. f. exp. Path. u. Pharm., xxxv, p. 105. 

5. Tar. 

Long before carbolic acid and its congeners were known, tars and other 
crude preparations enjoyed a reputation in the treatment of wounds, 



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156 SUBSTANCES ACTING LOCALLY 

and some of these have been retained in medicine and are widely used. 
Among these the tar obtained by the dry distillation of different woods 
is included; its constituents vary with the source, but the creosols 
(Ce^CHa.OH.OCHa), guaiacols (C 6 H 4 OH .OCH 3 ), and other less poison- 
ous aromatic compounds are present in larger quantity than the phenols 
and dioxybenzols, and wood-tar is therefore less poisonous than carbolic 
acid, and its simpler homologues. At the same time these higher com- 
binations seem to have the same antiseptic powers as the simpler 
benzol derivatives, so that several of the crude preparations possess 
considerable value in surgery and medicine. 

Preparations. 

Pix Liquida (U. S. P., B. P.), tar, is obtained from the wood of Pinus palus- 
tris and other species of Pinus by destructive distillation, and contains a very 
large number of aromatic bodies mixed with others of less importance. 

Oleum Picis Liquida (U. S. P.), oil of tar, is a volatile fluid distilled from 
tar, and consists almost entirely of guaiacols and their compounds. 0.2 c.c. 
(3mins.). 

Syrupus Picis Ldquidce (U. S. P.), syrup of tar, 4 c.c. (lfl. dr.). 

Unguentum Picis Liquidce (U. S. P., B. P.). 

Tar has also been used with considerable success as an antiseptic in 
skin diseases, in which it may be applied either alone or as an ointment. 
It is only slightly irritating to the skin, and some absorption occurs, 
as is often seen by the dark color of the urine. Internally it has been 
used occasionally as an anthelmintic and intestinal disinfectant, much 
more frequently as an " expectorant* ' in cough mixtures. Whether 
it has any effects on the lungs in these cases may be questioned. It is 
generally given as the syrup. 

Tar is a valuable disinfectant, which is very generally available 
and is much cheaper than the purer bodies of the aromatic series. It 
may be used for the disinfection of excrementa, latrines, etc., where 
the cost of even crude carbolic acid would be prohibitive. 

Bibliography. 

Nencki u. Sieber. Arch. f. exp. Path. u. Pharm., xxxiii, p. 1. 
Strdm. Arch. d. Pharmacie, ccxxxvii, p. 525. 

Ichthyol is derived from the tar of a bituminous shale which is found in the 
Tyrol, and which contains the remains of many fossil fishes. It has a high 
percentage of sulphur, and possesses some antiseptic action, although it is 
believed to be less powerful than carbolic acid. Applied to the skin, ichthyol 
causes slight irritation, which is apparently of benefit in some cutaneous diseases, 
and it has therefore been used extensively for this action. A certain amount 
of absorption occurs when it is rubbed into the skin, for the sulphur of the urine 
has been found to be augmented. Taken internally in large quantities, it acts 
as a gastric and intestinal irritant and produces diarrhoea, but it is only very 
feebly poisonous. 

Ichthyol has been strongly recommended in the treatment of a number of 
skin diseases, including erysipelas. It is generally used as an ointment con- 
taining equal parts of ichthyol and of vaseline, but may be used in 10 per cent. 



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ANTISEPTICS AND DISINFECTANTS 157 

or even weaker dilution. Ichthyol has been enthusiastically praised as a remedy 
in the most diverse conditions, and it seems probable that its sphere of utility 
will be very much more restricted in the future, if it does not disappear from 
therapeutics entirely. 

Many other drugs applied to the skin may exercise some germicidal 
action along with their other properties, but are discussed elsewhere. 
(See zinc, lead, sulphur ointments.) 

m. Intestinal Disinfectants. 

Salol. 

Salol , or phenyl-salicylate (C«H 4 OH COO C«H 5 ) , may be taken as a type 
of the drugs used to disinfect the intestine, or at any rate to retard the 
growth of bacteria in the contents and the wall of the bowel. It is a 
very insoluble, crystalline body, which has little or no local action 
in the mouth or stomach, but is decomposed in, the intestine by the 
fat-splitting ferment of the pancreatic juice. Some decomposition also 
appears to occur in the stomach, at any rate under certain conditions. 
The products of its decomposition, salicylic and carbolic acids, are 
absorbed and produce their usual effects. Salol is used chiefly as ,a 
substitute for salicylic acid, but the formation of phenol from it in the 
body must not be overlooked, for in several cases of dangerous poisoning 
which have been observed under it, the symptoms were those character- 
istic of carbolic acid, and the urine became dark in color from the 
phenol oxidation products. In moderate quantities, salol produces 
the disturbances of hearing observed under salicylic acid, without any 
symptoms of carbolic poisoning. 

Other salicylic acid compounds, similar to salol, are betol or naphthalol 
(the beta-naphthol salicylate), cresalol (cresol salicylate), thymosalol 
(from thymol), guaiacolscdol. They are less poisonous than salol, but 
have not been largely used. 

Salol (B. P.), Phenylis Salicylas (U. S. P.), phenyl salicylate (CeHr- 
OHCOOC»H0, a white crystalline powder, odorless or faintly aromatic, almost 
tasteless, almost insoluble in water, decomposed by the pancreatic juice into 
salicylic acid and phenol. 0.5 G. (7£ grs.); B. P., 5-20 grs., in powder or 
capsule. 

Salol has been used to lessen putrefaction in the bowel, and even 
to act upon the bacilli of typhoid fever and of tubercle infecting the 
intestinal wall. Kumagawa, however, states that the putrefaction 
in the bowel as measured by the indican in the urine is unchanged by 
its administration, and he found enormous numbers of bacteria in the 
faeces afterward. It certainly seems of little value in typhoid fever 
or in tuberculosis of the intestine. Intestinal calculi have been formed 
in a few instances from prolonged treatment with salol, which failed 
to be decomposed in the intestine and formed masses of considerable 
size. 



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158 ' SUBSTANCES ACTING LOCALLY 

Salol has been used to diagnose stenosis of the pylorus, as it was supposed 
that in these cases the reaction of salicylic acid in the urine would be delayed 
when salol was given. But some salol is absorbed from the stomach, and the 
interval before salicylic acid appears in the urine varies widely in normal per- 
sons, so that the test is of little value. 

Salol has some value as a genito-urinary disinfectant, partly owing to the 
salicylic acid component and partly to the phenol developed. 

It is used as a substitute for salicylic acid in rheumatic fever, and has the 
advantage of being tasteless and of producing no irritation in the stomach. 
On the other hand, the considerable amount of carbolic acid freed by its decom- 
position has given rise to poisoning in some cases. Externally it is of little 
or no value as an antiseptic, as it is only active when decomposed by the microbes 
which it is designed to destroy. 

Bibliography. 

Nencki. Arch. f. exp. Path. u. Pharm., xx, p. 367. 
Lesnik. Ibid., xxiv, p. 167. 

Other Intestinal Disinfectants. 

Most of the drugs possessing disinfectant properties have been used 
at one time or another in the hope of reducing the intestinal putrefaction, 
but have generally been abandoned after a shorter or longer vogue. 
Among these may be mentioned carbolic acid, corrosive sublimate, 
resorcin, naphthol and thymol. As has been stated (p. 128), there is 
little prospect of destroying bacteria imbedded in the wall of the intestine 
without serious injury to the mucous membrane. On the other hand 
putrefaction of the contents of the bowel is better treated by their 
evacuation than by attempts to retard the process in the body. 

IV. Genito-urinary Antiseptics. 

1. Volatile Oils. 

A group of volatile oils is used chiefly for genito-urinary disinfection. 
The best known of these are the Oils of Copaiba, Cubebs and Sandalwood, 
which resemble each other closely in character. Oil of cubebs and 
oil of copaiba contain a large proportion of sesquiterpene (C15H24), 
and the oil of sandalwoood has two oxidized substances (santalol and 
santalal), which can be reduced to a sesquiterpene identical with that 
of copaiba. In copaiba the volatile oil is associated with one or more 
resinous acids, and in cubebs there is in addition to resinous acids a 
bitter substance, Cubebin, which is not absorbed from the stomach and 
bowel, however, and is entirely inactive. Cubebs and copaiba have 
long been used as genito-urinary disinfectants, while sandalwood oil 
is a more recent addition to the group, which is less disagreeable to 
take and has less tendency to disturb the disgestion. These oils have 
the irritant effects on the skin, stomach and intestine common to the 
class of volatile oils (p. 57), are absorbed readily and are excreted 
partly by the lungs, but chiefly by the kidneys in combination with 



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ANTISEPTICS AND DISINFECTANTS 159 

glycuronic acid; some oil is unchanged, some is partially oxidized in 
the tissues. 

The products of the oils excreted in the urine appear to have some 
antiseptic action, for the urine of persons treated with them putrefies 
more slowly than ordinary urine and the growth of many of the more 
common germs is retarded by it; thus Jordan found that the urine was 
powerfully germicidal to a staphylococcus after sandalwood oil had 
been taken, and this action persisted even when the urine was rendered 
alkaline; on the other hand the colon bacillus grew luxuriantly; others 
have found the gonococcus grow readily in media made up with such 
urine. Winternitz therefore attributes the undoubted efficacy of these 
oils in gonorrhoea to their lessening the inflammatory exudate rather 
than to their antiseptic action, without denying that the latter may 
also be of some importance. 

In large quantities, these oils cause irritation in the bladder and 
urethra, which leads to a constant desire to micturate, and to much 
pain and difficulty in doing so; sometimes the pain is so great as 
to lead to complete retention. When the urethra or bladder is in 
a state of inflammation, these symptoms are produced by even small 
doses, so that these oils are generally avoided in the acute stages of 
inflammation, and only given later when the disease has passed into 
the subacute or chronic stage. They are used in some inflammatory 
affections of the bladder, but much more extensively in gonorrhoea. 

Copaiba and cubebs both contain resinous acids in addition to the 
volatile oil, and these possess considerable diuretic powers, and are 
also credited, along with the oils, with some action on the bronchial 
mucous membrane, so that they often form constituents of "expec- 
torant" mixtures, prescribed to lessen the secretion of the bronchi. 
These resins are excreted in the urine, and are precipitated by the 
addition of acids; this precipitate has sometimes been mistaken for 
albumin, but can easily be distinguished from it by the addition of 
alcohol, which redissolves the resin but not the protein. The urine is 
often found to reduce Fehling's solution from the glycuronic acid 
combined with the oil. The oil of sandalwood is excreted more rapidly 
than the others. Copaiba and cubebs are less irritant to the stomach 
than many of the other volatile oils, but after their prolonged adminis- 
tration (especially in the case of copaiba) symptoms of gastric dis- 
turbance sometimes appear in loss of appetite and uneasiness in the 
stomach. Sandalwood oil is said to be less irritant than the others. 
Occasionally skin eruptions occur after the use of these oils; they are 
generally of the nature of urticaria, sometimes of erythema nodosum, 
and only very rarely is eczema seen. The cause of these skin eruptions 
is unknown, but they may be due to the gastric disturbance. 

Preparations. 

Copaiba (U. S. P., B. P.), Balsam of Copaiba, Copaiva, the oleoresin of 
Copaiba Langsdorffii and of other species of Copaifera. Dose, 1 c.c. (15 mins.) ; 
B. P., i-1 A- dr. 



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160 SUBSTANCES ACTING LOCALLY 

Oleum Copaiba (U. S. P., B. P.), the oil freed from the resin by distilla- 
tion, 0.5 c.c. (8 min8.); B. P., 5-20 mins. 

Cubeba (U. S. P.), Cubeba Fructus (B. P.), Cubebs, the unripe fruit of 
Piper Cubeba. 1 G. (15 grs.). 

Oleum Cubeba (U. S. P., B. P.), 0.5 c.c. (8 mins.); B. P., 5-20 mins. 

Oleoresina Cubeba (U. S. P.), 0.5 G. (7 J grs.). 

Trochisci Cvbebce (U. S. P.). 

Oleum Santali (U. S. P., B. P.), Sandalwood oil, distilled from the wood 
of Santalum album. Dose, 0.5 c.c. (8 mins.) ; B. P., 5-30 mins. 

Santabl and santalal and some of their compounds have been introduced as 
gonosan and sarUyl (santalol salicylate), etc. 

Therapeutic Uses. — As has been mentioned, these drugs find their 
most extensive application in the subacute stages of cystitis and gonor- 
rhoea. They are also used in bronchial disease with an excessive flow 
of mucopurulent secretion; less often copaiba is prescribed along 
with other diuretics to promote the secretion of urine. The cubeb 
lozenges are sucked in hoarseness and relaxed sore throat, and often 
give relief owing to the pungent peppery action. 

In gonorrhoea the therapeutic agent is undoubtedly the volatile oil, 
the resin having little or no antiseptic action. The oils and the oleo- 
resins are often administered in capsules, as they have an unpleasant 
odor and taste, especially those of copaiba. They may also be given 
as emulsions, and cubebs is sometimes prescribed as a powder suspended 
in mucilage. 

Several other oils have been used as substitutes for Copaiba and Cubebs. 
Among these may be mentioned Gurjun Balsam, which is obtained from Dip- 
terocarpus alatus, and contains a sesquiterpene and a resin. It has been used 
in gonorrhoea and as a local application in leprosy. Various peppers have 
been employed as substitutes for cubebs in gonorrhoea, among them Matico, 
but they have not proved so useful as the three typical oils. 

Bibliography. 

BernaUik. Vierteljahrschrift f. prakt. Heilkunde, Ixxxi, p. 9, and c, p. 239. 

Quincke. Arch. f. exp. Path. u. Pharm., xvii, p. 273. 

Heffter. Ibid., xxxv, p. 369. 

Winternitz. Ibid., xlv, p. 163. 

Karo. Ibid., xlvi, p. 242. 

Hildcbrandt. Ztschr. f. physiol. Chem. f xxxvi, p. 442. 

Sachs. Wiener, klin. Woch., xv, p. 442. 

Jordan. Brit. Med. Journ., 1913, ii, p. 648. 

See also the bibliography of the volatile oils in general. 

2. Hexamethylentetramine, Urotropine. 

Urotropine, or hexamethylentetramine ( (CH 2 )«N4), has no important 
action itself, but is of interest from its liberating formaldehyde in 
the course of its excretion in the urine; formaldehyde is a powerful dis- 
infectant, and the small quantities liberated from urotropine are sufficient 
to prevent putrefaction of the urine for many hours. It seems superior 
to any other urinary antiseptic, microbes in the urine decreasing in 



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ANTISEPTICS AND DISINFECTANTS 161 

number or sometimes disappearing altogether within a few hours of 
its administration. Formaldehyde is formed from urotropin only in 
acid urine, and if the urine is alkaline urotropine has no disinfectant 
action in the urinary passages; when, however, in those cases the 
reaction of the urine is rendered acid by the administration of acid 
phosphates, formaldehyde is formed from urotropine and satisfactory 
results follow, Urotropine is readily soluble and permeates freely into 
most organs and secretions of the body; thus it has been found in the 
bile, pancreatic juice and cerebrospinal fluid, and this has suggested its 
use in infections of these fluids. But there is no evidence that formal- 
dehyde is liberated from it anywhere except in acid urine, and there is 
equally little ground for believing that urotropine is of benefit in infections 
of the gall-bladder, pancreas, or central nervous system. No symptoms 
arise from ordinary doses of urotropine, but large quantities have 
occasionally given rise to pain and discomfort in the bladder, and more 
rarely to hcematuria; the irritant here is not the urotropine itself but 
the formaldehyde liberated by it. Formaldehyde forms some soluble 
combinations with uric acid, and this suggested the use of urotropine 
in gravel, calculus, gout, and similar conditions, but the results have 
been disappointing. 

Hexamethylenamina (U. S. P.), Hexamina (B. P.), Urotropine 
( (CHO6N4), is a white crystalline powder, very soluble in water and 
giving off formaldehyde in acid solution. Dose, 0.25 G. (4 grs.), 5-15 
grs., B. P.; to be taken in a glass of water. 

Urotropine is used in cystitis and urethritis and to destroy typhoid 
bacilli in cases in which they are eliminated by the kidney. It may 
also be given as a prophylactic before a catheter is passed. In order 
to secure that the urine shall be acid, urotropine is often given along 
with acid sodium phosphate. 

Numerous compounds of urotropine have been introduced of late years by 
rival manufacturers, but none of these has proved superior to the original drug, 
and none of them form formaldehyde in alkaline urine. 

Bibliography. 

Nicolaier. Zta. f. klin. Med., xxxviii, p. 350; Deutsch. Arch. f. klin. Med., Ixxxi, p. 
181; lxxxviii, p. 168. 

SoUmann. Journ. Amer. Med. Assoc, September 5, 1908. 
Richardson. Journ. of Exp. Med., iv, p. 19. 
Jordan, Walker. Brit. Med. Journ., 1913, ii, pp. 648, 654. 
Hamlik and Collin*. Arch. Inter. Medicine, 1913, p. 578. 

3. Minor Genito-urinary Antiseptics. 

The salicylates have some effect in retarding the growth of micro- 
organisms in the genito-urinary tract and sodium salicylate and salol 
(p. 157) have been used for this purpose. Benzoic acid and ammonium 
benzoate are also used to disinfect the urine, and, as in the case of sali- 
cylate, act well when it is acid, but lose their effect largely when it is 
11 

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162 SUBSTANCES ACTING LOCALLY 

alkaline. Arbutin, a glucoside contained in the uva ursi, is also credited 
with some antiseptic properties, but is less used now than formerly. 
Boric acid and borax are both good genito-urinary antiseptics and 
differ from the other more active drugs of this class in retaining their 
disinfectant action when the urine is alkaline. Finally the urine is a 
much less favorable medium for bacterial growth when it is acid, and 
anything which promotes the acidity (acid phosphate or benzoic acid), 
has thus some antiseptic value. 

7. Antiseptics in Pulmonary Disease. 

Creosote. 

Creosote may be regarded as a wood-tar from which the more poison- 
ous phenols and the less volatile bodies have been eliminated, leaving 
guaiacols and creosols as the chief constituents. Its action is similar 
to that of carbolic acid, except that it has less tendency to induce 
nervous symptoms, and is less irritant and poisonous. On the other 
hand, it seems at least as strongly antiseptic as carbolic acid, and, 
according to some investigators, far excels it as a germicide. Its 
chief constituents, the Creosols (CcHsCHaOH.OCHa) and Guaiacols 
(Cel^OH.OCHs), resemble carbolic acid and the other aromatic phenols 
in their action. They are excreted in the urine for the most part in com- 
bination with sulphuric and glycuronic acids. 

Guaiacol is readily absorbed from the skin when rubbed into it 
and considerable amounts can be regained from the urine afterwards. 
When large quantities are thus taken up from the skin, they often 
cause a rapid fall of fever temperature with exhaustion and all the 
symptoms of mild collapse, followed by shivering and rigor and a 
return of the high temperature. This condition of poisoning is exactly 
similar to that seen under other benzene derivatives of simple con- 
stitution. 

Guaiacol carbonafe ( (CtHtO^COs) is almost insoluble and tasteless, 
and liberates guaiacol in the intestine. 

Preparations. 

Creosotum (U. S. P., B. P.) is obtained from wood-tar, preferably from 
beech tar, and is an almost colorless, oily liquid with a smoky odor and hot, 
burning, acrid taste. It is slightly soluble in water, and mixes readily with 
alcohol. It tends to darken in color when exposed to the light. 0.2 c.c. (3 
mins.); 1-5 mins. B P 

Aqua Creosoti (U. S. P.), a very dilute solution of creosote in water, less 
than 1 per cent. 8 c.c. (2 fl. drs.). 

Unguentum Creosoti (B. P.), 10 per cent. 

Creosote may be administered in pills, capsules, in solution in alcohol or 
cod-liver oil, or as a mixture. The wine of creosote, which has been a popular 
remedy, contains it dissolved in wine along with some brandy and tincture of 
gentian. It ought not be allowed to reach the mucous membranes in a con- 
centrated form, as it is liable to irritate them. 



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ANTISEPTICS AND DISINFECTANTS 163 

Guaiacol (U. S. P., B. P.) (CeH4.OH.OCH,), colorless crystals, or fluid with an 
agreeable aromatic odor, soluble in 80 parts of water and in alcohol. Dose, 
0.5 c.c. (8 mins.) in solution in alcohol or cod-liver oil, or in pills. 

Guaiacolis Carbanas (U. S. P., B. P.) ( (C 7 H 7 0)iCOs), an almost tasteless 
powder, is given in cachets in doses of 1 G. (15 grs.). 

Therapeutic Uses. — Creosote is comparatively seldom used except 
in the treatment of pulmonary phthisis and gangrene, and chronic 
bronchial inflammation. It is generally given by the mouth in these 
cases, but has also been injected hypodermically or into the rectum; 
the vapor is recommended as an inhalation, and some practitioners 
have injected creosote solution into the trachea, in order to ensure its 
reaching the lungs. None of these methods are believed to give such 
good results as the ordinary administration by the mouth. Guaiacol 
and guaiacol carbonate have recently been substituted for the creosote 
and are more pleasant forms. The carbonate has also been employed 
as an intestinal disinfectant. 

The results of creosote medication are still disputed. Many clinicians 
state that a general improvement follows it in phthisical patients, 
that the appetite is improved, the cough and expectoration lessened, 
and that the patient feels stronger and better. On the other hand, 
others are extremely sceptical as to any benefits arising from creosote, 
and regard it as merely one of the countless remedies which have been 
recommended in this condition, and which, after a shorter or longer 
period of popularity, have passed into oblivion. 

It is generally supposed by the advocates of the creosote treatment 
that the remedy destroys the tubercle bacillus in the lungs through its 
antiseptic properties. On the other hand, animals infected with 
tubercle and treated with creosote die as soon as controls which are 
untreated, and the sputum of phthisical patients treated with creosote 
is as virulent as that of others not so treated. Besides, the adminis- 
tration of creosote by other ways than by the mouth is said to be very 
much less efficacious. Another explanation of the creosote action is 
that it acts as an intestinal antiseptic and prevents the secondary 
infection of the bowel; but it has been objected to this that the other 
intestinal antiseptics are of little value in tuberculosis. It seems 
useless to speculate on the method of action until it has been definitely 
determined that creosote is of value in phthisis, and this can be done 
only by careful statistical inquiry. The medical profession seems to 
have much less faith in the efficacy of the creosote treatment than it 
had a few years ago, when it was not generally recognized that pul- 
monary tuberculosis is curable by hygienic measures in a considerable 
proportion of instances. 

VI. Disinfectants for Booms, Furniture, Etc. 

1. Formaldehyde. 

Formaldehyde (HCOII), the aldehyde derived by oxidation from 
methyl alcohol, is a very powerful germicide, while it is not very danger- 
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164 SUBSTANCES ACTING LOCALLY 

ous to the higher animals. The aldehyde is a colorless gas and has been 
used either in solution in water (formaline) or as a vapor. As a germicide 
it is estimated to be equally efficient with corrosive sublimate, and its 
volatility enables it to penetrate much more rapidly so that it may be 
used for purposes for which the latter is unsuitable. 

Action. — The vapor is very irritant* when inhaled, causing stinging 
and prickling in the nose and throat, salivation and tears, and bronchial 
irritation and catarrh. In the few cases of poisoning in man recorded 
the symptoms were those of gastric irritation and consequent collapse. 
When swallowed by animals the watery solution produces nausea and 
vomiting, which are followed by narcosis, coma, and in the rabbit by 
convulsions and opisthotonos. The respiration in the dog is very greatly 
accelerated some time before death, while in the rabbit this is not so 
marked or is entirely absent. The blood-pressure is increased at first, 
and the heart is slow from direct action on the cardiac muscle. For- 
maldehyde is rapidly absorbed from the alimentary tract and also by 
the lungs but quickly disappears from the blood owing to its oxidation 
and excretion; some formic acid is said to be formed from it, and for- 
maldehyde has been detected in the urine, the gastro-intestinal secretions, 
and the expired air. 

The powerful action of formaldehyde on microbes and on mucous 
membranes is believed by Loew to be due to its combining with the 
amino groups in the proteins, and as a matter of fact, a number of 
changes have been described in the reaction of proteins exposed to 
this gas. For example, egg albumen and serum to which formal- 
dehyde solution has been added are not precipitated by heat and are 
less easily digested by ferments, while casein is not coagulated by the 
rennet ferment. Some of the ferments (pepsin and diastase) are not 
affected by small amounts of formaldehyde, while trypsin and papain 
lose their activity wholly or in part. * 

Preparations. 

Liquor Formaldehydi (U. S. P., B P.), formalin, a solution of formalde- 
hyde in water containing not less than 37 per cent, of the gas, which may be 
obtained from it by distillation. 

Paraform, a solid polymer of formaldehyde, which is decomposed by heat 
and liberates the formaldehyde in gaseous form. 

Some formaldehyde may be formed by the incomplete combusion of methyl 
alcohol, and several lamps have been devised with this object in view, but have 
not proved satisfactory. 

Uses. — Formaldehyde is too irritant to admit of its use as an anti- 
septic in medicine and surgery, but it has been largely employed to 
disinfect instruments, furniture, clothes and rooms, which cannot be 
sterilized by heat. Diluted liquor (4 per cent.) may be used for 
some of these purposes, or the vapor may be disengaged by distillation 
from the liquor or by heating paraform. Large rooms filled with for- 
maldehyde vapor and left for some hours are found to be almost com- 
pletely sterilized, so that cultures of the pathogenic microbes exposed 



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ANTISEPTICS AND DISINFECTANTS 165 

in them cease to grow even when removed from the atmosphere. Novy 
makes the room to be disinfected as nearly air-tight as possible and 
distils the formaldehyde into it through the key-hole of the door. 
He states that the gas disengaged from 150 c.c. (5 oz.) of 40 per cent, 
liquor is sufficient for each 1000 cubic feet of space, if the room be 
closed for ten hours. The odor of formaldehyde may then be removed 
by sprinkling ammonia solution with which it forms a solid combination. 
The disinfectant action of formaldehyde is increased by moderate 
warmth, and a longer time must be allowed for it to act if the temperature 
of the room is below 50° F. Formaldehyde not only destroys the 
microbes, but also alters the toxins formed by them so that they are no 
longer poisonous, even in very large quantities. 

Formaldehyde has frequently been added to food, especially to 
milk, as a preservative. Tunnicliffe and Rosenheim found that added 
to milk in the proportion of one to five thousand, formaldehyde did 
not seem to be deleterious to healthy children, but in the case of a 
weakly child the protein waste was increased, and it is certainly not 
to be regarded as a harmless method of preserving food. 

Formaldehyde is not alone in its germicidal action, although it is much 
more powerful than the other less volatile and less active aldehydes, such as 
acetaldehyde. 

Bibliography. 

Loew. Ein natGrliches System der Giftwirkungen, Munchen, 1893, p. 58. 

Koch, Amer. Journ. of Physiol., vi, p. 327. 

Fischer. Journ. of Exp. Med., vi, p. 487. 

Dieudonne. Arbeit, a. d. Gesundheitsamt., xi, p. 534. 

Anderson. Bulletin No. 39 of the Hygienic Laboratory, Washington, D. C. 

Pohl. Arch. f. exp. Path. u. Pharm., xxxi, p. 295. 

Ermengem et Sugg* Arch, de Pharmacodyn., i, p. 141. 

Aronson. Zts. f. Hygiene, 1897, xxv, p. 168. 

StrVver. Ibid., p. 357. 

McOuigan. Journ. Amer. Med. Asso., 1914, i, p. 984. 

Benedicenti. Arch. f. [Anat. u.J Phys., 1897, pp. 210 and 219. 

Novy and Waite. Medical News, lxxii, p. 641 (1898). 

Bliss and Novy. Journ. of Exp. Med., iv, p. 47. 

Tunnicliffe and Rosenheim. Journ. of Hygiene, i, p. 321. 

2. Sulphur Dioxide. 

Sulphurous acid is a powerful reducing agent, as it becomes oxidized 
to sulphuric acid, and this renders it poisonous to protoplasm in general, 
quite apart from its acidity. Sulphurous acid anhydride is accordingly 
used to a considerable extent to disinfect rooms and furniture after 
infectious diseases; for this purpose sulphur is burned in the room, 
which ought to be rendered as air-tight as possible, and the fumes are 
allowed to act for several hours before the room is ventilated. The 
value of this method of disinfection has been called in question, but 
there is no doubt that sulphurous acid gas is fairly germicidal when it 
is applied along with moisture. It is not capable of such a wide applica- 
tion as formaldehyde, because sulphurous acid bleaches many coloring 



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166 SUBSTANCES ACTING LOCALLY 

matters, and the procedure is open to the objection that it may lend a 
sense of security which is quite unwarranted, and may lead to the 
neglect of other measures. The disinfection to be of any value must 
be thoroughly carried out, and can only be applied to inanimate objects, 
as the fumes are fatal to the higher animals, even when much less con- 
centrated than are necessary to destroy bacteria. In order to be of 
service, at least one volume of S0 2 ought to be present in each hundred 
volumes of air, and even this concentration is insufficient to destroy 
the spores of bacteria. Novy 1 recommends 3-6 pounds of sulphur to be 
burned for each 1000 cubic feet of space; the walls and floor should 
be sprayed with water, and the room must be kept perfectly closed for 
at least twenty hours. 

The chief symptoms of poisoning with sulphurous acid are those of 
irritation of the mucous membranes, and if the solution be swallowed 
these may not differ from those of other irritants. 

In poisoning from the inhalation of the anhydride, on the other 
hand, the symptoms arise chiefly from the respiratory tract. Even 
in five parts in 10,000 it acts as an irritant, causing sneezing, coughing 
and lachrymation, and in somewhat greater concentration it becomes 
entirely irrespirable; still smaller quantities in the air cause bronchial 
irritation and catarrh, when inhaled for some time. Sulphurous acid 
is neutralized and oxidized for the most part to sulphates in the tissues, 
or probably partly in the course of absorption. 

3. Chlorine and Bromine. 

Chlorine and bromine resemble each other closely in the effects 
which they induce in all forms of living matter. These may be explained 
in part by their replacing hydrogen in its combinations in the proteins 
and forming hydrochloric or hydrobromic acid with the hydrogen set 
free, in part by their combining with the hydrogen of water and thus 
liberating nascent oxygen, which then acts on the tissues. These 
processes are believed to account for the fact that chlorine is a much 
more powerful disinfectant in moist air than in dry. In the higher 
organisms all of these reactions probably occur together. 

.Action. — Chlorine and bromine are general protoplasm poisons; 
thus 3 parts of chlorine in 1000 parts of moist air are sufficient to 
destroy the spores of most bacteria in the course of three hours, and 
the infusoria and the higher plants have been shown to be equally 
susceptible to the influence of the gas. Even smaller quantities of 
bromine are disinfectant. 

In the higher animals and in man chlorine and bromine act as 
irritants, causing irritation and redness, and even blistering of the skin 
when applied to it in solution, and eliciting when swallowed intense 
inflammation and corrosion of the mouth, throat, and stomach, with 
collapse and all the ordinary effects of gastric irritation. Air con- 

1 Novy and Waite. Medical News, lxxii, p. 641. 

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ANTISEPTICS AND DISINFECTANTS 167 

taining even a very small proportion of chlorine irritates the eyes, 
nose, larynx and the deeper respiratory passages; bronchitis, pulmonary 
congestion and haemorrhages, coughing and pain in the thorax are 
induced by quantities that cause little or no irritation of the mouth 
and nose. Lehmann found that one volume of chlorine or bromine 
vapor in one million parts of air causes some irritation, but no serious 
results, but that ten volumes in the same amount of air inhaled for 
some time, cause haemorrhage and inflammation of the lungs, severe 
bronchitis, and other similar effects. After fatal poisoning from the 
inhalation of bromine, he observed marked irritation of the gastric 
mucous membrane, while this symptom was absent after chlorine. 
Another point in which bromine differs from chlorine is in its powerful 
action on the hair, which is rendered soft and gelatinous, and eventually 
removed entirely by exposure for some time to the vapor. 

These symptoms of chlorine and bromine poisoning are caused by their 
local action only; they are changed to hydrochloric and hydrobromic acids, 
and these again to chlorides and bromides in the course of absorption. Atten- 
tion has been drawn to a number of cases in which symptoms arose in work- 
men in chemical factories where chlorine is liberated by electrolysis, or more 
rarely in others where hydrochloric acid is formed in large quantities. The 
most marked symptom is an affection of the sebaceous glands, from which the 
condition receives its name of chlorine acne, but this often induces headache, 
sleeplessness, loss of appetite, and anaemia. No satisfactory explanation of 
the symptoms has been given, nor is it known whether the chlorine or some 
unknown body is the cause (Lehmann, Jacquet). 

Preparations. 

Liquor Chlori Compositus (U. S. P.), chlorine water, contains about 4 parts 
of the gas in 1000 parts of water. It is a clear, greenish liquid with the suffo- 
cating odor of chlorine and is liable to form hydrochloric acid, especially when 
exposed to the air and sunlight. It ought therefore to be freshly prepared when 
the full strength is required. 

Calx Chlorinata (U. S. P., B. P.), chlorinated lime, bleaching powder, some- 
times erroneously called chloride of lime, is a mixture of calcium hypochlorite 
(Ca(C10)2), calcium chloride (CaCU), lime and water. The hypochlorite is 
very unstable and gives off chlorine in air, and especially in the presence of 
an acid. Chlorinated lime forms a white or grayish-white powder, with the odor 
of chlorine. It is only partially soluble in water and must contain not less than 
30 per cent, of available chlorine. 

Liquor Sodce Chlorinate (U. S. P., B. P.), solution of chlorinated soda, Labar- 
raque's solution or Javelle's solution, is formed from chlorinated lime and 
contains hypochlorite of sodium (NaCIO) and chloride of sodium. Like the cor- 
responding lime salts, it has the odor of chlorine and bleaches vegetable colors. 
It must contain at least 2.4 per cent, by weight of available chlorine. 

The chlorine preparations are chiefly used to disinfect feces, urinals 
and to a less extent rooms and houses; for this purpose chlorinated 
lime is the most suitable, especially when acid is added to it in excess. 
The room ought to be hermetically sealed, and the fumes are of no 
value as disinfectants unless they are present in such quantity as to 
render the air quite irrespirable. They have the disadvantage that they 



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168 SUBSTANCES ACTING LOCALLY 

bleach most of the colors used in dyeing, and fail to penetrate in sufficient 
quantity into the clothing, which they also corrode to some extent. 
Chlorinated lime exposed in the sick-room merely serves as a deodorant, 
and has no disinfectant value, but has the disadvantage of giving a 
false feeling of security like other similar measures. Chlorine seems 
inferior to sulphurous acid anhydride, and still more so to formaldehyde 
as a disinfectant, not from its being weaker in action, but because it 
is more difficult to apply in sufficient quantity. Chlorinated lime can, 
however, be applied in urinals and closets, where both these disinfectants 
are unavailable. Here it acts again as a deodorant, while its disinfectant 
value is smaller. 

Chlorine water and the solution of chlorinated soda are still occasion- 
ally used as disinfectant, deodorant solutions in the treatment of foul 
sores, and, more rarely, to disinfect the hands before operation; both 
preparations are very irritant, however. Chlorine water much diluted 
has been used as a gargle, as a vaginal injection and for other similar 
purposes. 

Bibliography. 

Binz. Arch. f. ezp. Path. u. Pharm., xxxiv, p. 194. 

Lehmann. Arch. f. Hygiene, vii, p. 231; xxxiv, p. 308; xlvi, p. 322. 

Fischer u. Proskauer. Mittheil. a. d. Gesundheitsamt, ii, p. 228. 

Cash. Reports of Brit. Local Gov. Board, 1886. 

Jacquet. Semaine medicale, December 31, 1902. 

4. Other Disinfectants. 

Many other substances may be employed as disinfectants of urinals, 
latrines, faeces, etc., the chief determining consideration being the 
cost of the material in most cases. Thus tar, or crude carbolic acid 
may be used to disinfect fecal matter, and unslaked lime is applied to 
bodies in epidemics in the hope of preventing the liberation of infectious 
organisms. The most certain disinfectant, where it is available, is moist 
heat, which is generally used to disinfect clothes and bedding which 
have been in contact with infected persons. 



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PART II. 

SUBSTANCES CHARACTERIZED CHIEFLY BY 
THEIR ACTION AFTER ABSORPTION. 



I. NARCOTICS OF THE METHANE SERIES. 
ALCOHOL-CHLOROFORM GROUP. 

A large number of the simpler methane compounds of the open-chain 
series caus e depression of the central nervous system, more especially 
of the c erebrum, and some of them are perhaps the most extensively 
used of all drugs, for among them are the universally used surgical 
anaesthetics, the soporifics, and alcohol. The general action of all of 
these is similar in character and consists of a first stage of jmperfect— 
c apaciousnes s and confused ideas, followed by one of wil^l e xcitement , 
and eventually by co mplete unconsciousn ess, which may terminate in 
death. The second stage is much more marked after some of the 
series than after others, and is often entirely absent. It has given 
rise to the theory that these drugs stimulate the nerve cella -before 
paralyzing them, but an alternative explanation is that the functions 
of control and inhibition argS coocnc dr^tPd" the' centres of motion are 
thus left free and act more strongly than normally. This question 
has been most discussed in regard to alcohol, and will receive greater 
attention under that heading. 

The action on the central nervous system is elicited by comparatively 
small quantities of these drugs, but other forms of living matter are also 
affected by them in somewhat greater concentration, and their action 
may in short be considered as coextensive with life , though in man and 
the higher animals the symptoms from the brain predominate. 

The different members of the group vary greatly in their chemical 
affinities and in their tendency to enter into chemical combinations, and 
no relation can be found between their narcotic action and the presence ' 
of any one radical. This suggests that their effects depend on the prop - 

ertifia-fi Lthe Ig ftlflTiP 1 * a *\ fjjg]^2l!j an( * not on a c hemical combination 
being formed^ith any constituent" 6F"the tissues. A very interesting 
view has recently been suggested by Meyer and Overton, who attribute 
the common action of these narcotics to a common physical character. 
They point out that practically all of them are more soluble in oils and 
lipoids than in water and that when one of these drugs in watery solution 
meets an oil or lipoid it passes from the water to the oil and remains 
dissolved in it. The same process occurs when these drugs are carried 
in the blood; they tend to leave the watery plasma and to accumulate 

(169) 



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170 SUBSTANCES ACTING AFTER ABSORPTION 

in the lipoids of the body, and as the nprvp ^fc pro rinWt in ]jpftjd g i 
the narcotics accumulate in the brain. This is a purely physical process 
and the amount of the drug taken up from the blood is determined 
by its relative solubility in the lipoids and in the blood (coefficient of 
partition between oils and water). According to Meyer's view, the 
presence o f the drugs in the lipoids renders these more fluid and thus 
changes their relations to the~otlier^ aa]2^ehts of the cell s; this derang e- 
ment of their normal conditioa impairs theTuoction nf fhpgp pp |]g a ricT 
lessensthelFactivity, that is, ca uses narcosis. This very attractive 
thetfrylias Tieeii supported by a number of experiments and serves to 
explain a large number of observations; the accordance of the coefficient 
of partition and the narcotic power is seen to be very close, especially 
when members of a homologous series are compared; for example, 
the narcotic action of the simple alcohols rises from methyl and ethyl 
alcohol through propyl and butyl alcohol to amyl alcohol, which is 
the most powerful of the series, and the tendency of the alcohols to 
pass from wate r into oil rises simil arly. On the other hand when the 
hydroxyPgrOTips of the alcohols are increased, as in the series ethyl 
alcohol, glycol and glycerine, the partition ropffipjpn t hntmppr) g\] anA 

Txrnit>T folia, nnrl trip nfijgot jc p.vt\nr\ f jfplinps 

The experiments of Meyer, Overton and their followers suffice 
to show that these physical properties are factors in the narcotic 
action. But these are not the only determining influences. For when 
the relative narcotic action of less nearly related bodies are compared, 
the dependence on the partition coefficient is less exact; for example, 
the relative coefficients of partition of alcohol, chloral and acetone are 
approximately 1 :2 :6, but their narcotic action is 1 : 16 : 1. There is 
evidently some lujknowq^factor which plays an important r61e in 
determining the action, {resides th e solubility coe fficient. It seems 
likely that the distribution in the tissues, and the cftncentration of th e 
narcoti cs in the cent ra l nervo us system is largely determined by ffie 
relatjygt-SQl ubility in""wa ler and lipoids, but-that after the narcotics 
have penetrated into tETbraifr cell the effects depend on some further 
quality which is still unknown. 1 

Various suggestions have been made of late years as to the nature of narcosis. 
The old view that it was due to changes in the blood supply and to anaemia of 
the brain has long been abandoned, since it was shown that the brain of a frog 
in which the blood was replaced by saline solution, could still be anaesthetized. 
There is no question that the action of the narcotics is a direct one on the 
nervous structures, and that the changes in the brain circulation, which are 
similar to those in normal sleep, are the result and not the cause of the narcotic 
action. 

Verworn believes that narcosis arises from the arrest of the oxidations in the 
cells, and in many instances a lessened oxidation has been shown to be present 

1 A suggestion has been made that these narcotics may act by changing the surface 
tension of the cell contents and thus disorganizing the life processes. It seems clear that 
this will not serve to explain every case, however, and in fact is less satisfactory than the 
Meyer-Overton view. It appears unlikely that any one physical property determines 
the action of these bodies, though the sum-total of the physical properties may suffice 
to do so. 



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NARCOTICS OF THE METHANE SERIES 171 

during narcosis. But on the other hand narcosis may be induced in cells which 
live in the absence of oxygen (intestinal parasites), and cases are known in which 
narcosis is not accompanied by lessened oxidation. The decrease in oxidation 
which is seen in narcosis may thus be the result and not the cause of the essen- 
tial action. 

Lillie holds that the essential feature of narcosis is the diminished permea- 
bility of the cell membranes by ions, which can no longer penetrate as is necessary 
for activity. This diminished permeability may be the result of changes in the 
lipoids such as are demanded in the Meyer-Overton theory. 

Certain features of the chemical constitution of the members of this group 
have already been mentioned. Thus it is found that, as a general rule, the higher 
members of a series are more strongly depressant than the lower, provided they 
are sufficiently soluble in water to be taken up by the blood, and a correspond- 
ing increase in the partition coefficient is presented. The increase in hydroxyl 
groups which augments the solubility in water has the opposite effect, lowering 
the narcotic action; but if the hydroxyl is substituted by chlorine the narcotic 
action returns; for example, propionic alcohol (C1H7OH) is narcotic but gly- 
cerin (C»Hi(OH)j) is indifferent, while trichlorhydrin (C«H 6 Cls) is less soluble 
in water and again acts as a narcotic. 

The presence of the carboxyl group (COOH) generally prevents any nar- 
cotic action, probably because the acids formed circulate as salts and these can- 
not penetrate the cells in sufficient concentration. Butyric acid is said to have 
some narcotic effect, but this may arise from the presence of esters. When hy- 
drogen a oms of these acids are replaced by chlorine or bromine, they acquire 
a much stronger action; thus acetic acid is practically devoid of narcotic action, 
while some of the chloracetic and bromacetic acids are narcotic. But their effects 
on the other organs of the body preclude their use in therapeutics. 

This augmented action through the substitution of halogens for hydrogen is 
seen in many other instances; for example, methane (CH 4 ) is practically not 
depressant, but if one, two, or three of the hydrogen atoms in the molecule 
be substituted by chlorine, forming CHsCl,CHsOs, and CHC1*, the narcotic 
power increases with each CI added. 

This increased activity of the halogen compounds is not due to any action 
of chlorine or bromine on the nerve cells, for these elements are not freed from 
their compounds, which act as unchanged molecules; for example, chlorine is 
not liberated from chloroform in the tissues, but the whole molecule CHCli 
acts as an anaesthetic, while methane has no such action. 

The chlorine and bromine derivatives of methane are not only more power- 
ful drugs, but also more powerful poisons than the ordinary compounds; much 
less chloroform is required to anaesthetize than methane, but much less is 
required to kill. In addition, these compounds, especially those contain- 
ing chlorine, seem to have a more powerful action on the heart and circulation 
and on the metabolism than the others. In other words, the chlorine bodies 
have a less specific action on the nerve cells and thus involve a larger number of 
tissues in their effects. (See Chloroform.) 

Many methane compounds are not narcotic because they contain more active 
radicles. Thus ethane (CJIe) is a member of the narcotic series, but ethyl 
nitrite (CjHjO — NO) cannot be classed with it, because the — — NO group 
has a very powerful and entirely different effect; very small quantities of 
ethyl nitrite are required to produce the nitrite effect, so that the depressant 
action is pushed into the background. Members of the methane series often 
lose their depressant action when combined with nitrogen so as to form sub- 
stituted ammonia. Thus trimethylamine (N(CH s )a) has no depressant action, 
although each of the methyl radicles alone would possess it. Again, the sub- 
stitution of a member of the aromatic series for one of the fatty substances 
sometimes changes the action from that characteristic of the alcohol-chloro- 
form group to that of the benzol series. For example, ether (C 2 H 6 — O — 
CjHO is one of the most valuable anaesthetics, but if one ethyl radicle be sub- 



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172 SUBSTANCES ACTING AFTER ABSORPTION 

stituted by phenyl (C«H» — O — CtH»), it loses this property entirely. Others, 
however, retain their depressant action, as, for example, acetophenone (C$H»— 
CO — CH,). 

While the members of this group resemble each other closely in 
their effects on the central nervous system, they are used for very 
different purposes in therapeutics and may therefore be discussed in 
three subgroups: 1 , alcohol; 2, general anaesthetics, and 3, soporifics 
i)r hypnntiH, It must be recognized, However, that there is no hard 
and fast line dividing these subgroups; for the anaesthetics, chloroform 
and ether, may be used in small quantities to produce rest and sleep, and 
would then, strictly speaking, be soporifics; while, on the other hand, 
chloral and sulphonal, which are generally used as hypnotics, give rise 
to complete anaesthesia when administered in large quantities. 



Bibliography. 

Meyer. Arch. f. exp. Path. u. Pharm., xlii, p. 100; xlvi, p. 338. 

Overton. Studien liber die Narcoae, Jena, 1901. 

Gottlieb. Ergebnisse der Physiol., i, 2, p. 666. 

Mayer. Arch. f. exp. Path. u. Pharm., xxi, p. 97, 119. 

Pohl. Ibid., xxiv, p. 142. 

Marshall and Heath. Journ. of Physiol., xxii, p. 38. 

Kionka. Arch, internat. de Pharmacodyn., vii, p. 475. 

LUlie. Amer. Journ. of Physiol, 1912, xxix, p. 372. 

Fnhner. Ztschr. f. Biol., 1912, Ivii, p. 465. 

Winterstein. Biochem. Zeitschr., li, p. 143. 

Loewe. Ibid., Ivii, p. 161. 

1. Alcohol. 

Ethyl alcohol (CH 3 CH 2 OH) has been known in an impure form 
since the earliest times, ^and as far back as the history of medicine 
extends, has been used as a drug. Its medicinal reputation has under- 
gone many fluctuations, by many held to be a panacea, by others it has 
been considered of importance only as a poison. 

Alcoholic liquors are generally prepared by the fermentation of 
sugars, which either exist preformed in the fruits, or are derived from 
starch by a preliminary ferment action. The simple liquors (wines 
and beers) generally contain only a low percentage of alcohol (2-20 
per cent.), and the stronger preparations (spirits) are prepared from 
them by distillation, which raises the percentage to 30-60 per cent, 
and at the same time removes the non-volatile constituents. Spirits 
and liquors are not, however, simple mixtures of alcohol and water but 
contain many other volatile substances, the character of which is little 
known, and which are called cenanthic ethers. Some of them have 
been shown to be higher members of the alcoholic series, while others 
would seem to be of entirely different constitution. 

Action. — The value of alcohol in medicine depends upon three chief 
points: 1, its irritant local action; 2, its action on the central nervous 
system, and 3, its value as a food. 



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ALCOHOL 173 

The irritant action is not so marked as that of many other substances, 
but is of much greater importance, owing to the habitual use of this 
drug. It is probably due to the partial precipitation of the proteins 
of the cells, and is shown by the results of its application to the skin, 
to wounds, and to the mucous membranes. Applied to the skin in 
sufficient concentration (e. g., 60-90 per cent.), it produces redness, 
itching and a feeling of heat like other volatile and irritant substances, 
such as the volatile oils. Alcohol is, however, much less irritant and 
at the same time more volatile than these, so that unless its evaporation 
is prevented, it may produce a sensation of cold and have little or no 
irritant action; this is especially the case when dilute alcohol is used, 
no very distinct appearances of irritation of the skin being produced by 
solutions under 40-50 per cent. In ulcers and other unprotected 
surfaces, the irritant action is much greater and its application is 
attended by pain and smarting; the precipitation of the proteins lends 
alcohol an astringent action in certain concentrations, but if it pene- 
trate deeper it may destroy the cells and it then becomes a corrosive 
until it is diluted by the fluids. 

Its effects on mucous membranes are similar to those on wounds. 
In the mouth strong alcohol produces a burning, unpleasant sensation 
which passes to the throat and stomach when it is swallowed, and if 
the concentrated vapor be inhaled, it causes irritation and reflex 
closure of the glottis. The effects of alcohol on the digestive functions 
are so important that they will receive further attention (p. 179). 

The action of alcohol on the Nervous Centres differs a good deal in 
individuals. In small quantities it generally produces a feeling of 
well-being and good-fellowship, along with increased confidence in the 
powers, mental and physical, of the subject of the experiment. Larger 
quantities are followed by a certain amount of excitement, marked by 
laughter, loquacity, and gesticulation. The face becomes flushed and 
hot, the eyes brighter and livelier, the pulse is accelerated. Even at 
this stage self-control is partially lost and the will power is weakened. 
The speech may be brilliant, but it often betrays the speaker; the 
movements are more lively, but they are often undignified. The loss 
of self-control is often indicated further by furious outbursts of anger 
and unreasonableness, or by the indulgence in maudlin sentimentality 
and sensual fancies. The sense of responsibility and the power of 
discrimination between the trivial and the important are lost, and 
the individual has no regard for the feelings of others, or the ordinary 
conventions of life. If the bout be further continued, the movements 
become uncertain, the speech becomes difficult and stammering, the 
walk becomes a stagger, and a torpid slumber follows. Often nausea 
and vomiting set in, although these are entirely absent in some cases. 
On awakening from slumber, very great depression is generally suffered 
from, together with nausea and vomiting, and want of appetite, which 
may last for several days and is associated with all the symptoms of 
acute gastric catarrh. 

Very large quantities of alcohol lead to a deep, torpid sleep, which 



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174 SUBSTANCES ACTING AFTER ABSORPTION 

eventually passes into total unconsciousness, resembling the condition 
in chloroform anaesthesia; the respiration becomes stertorous and slow, 
and the face, which has hitherto been flushed, becomes pale or cyanotic. 
This condition may last for several hours and end in death from failure 
of the respiration, but in other cases the anaesthesia becomes less deep 
and after a very prolonged sleep the patient recovers. When the stage 
of anaesthesia is reached, it lasts very much longer than that produced 
by chloroform and ether. It is said that persons rarely or never recover 
if unconsciousness lasts longer than 10-12 hours after the drinking bout. 

The effects of alcohol vary greatly, however, in different individuals 
and in the same individual at different times. One person is rendered 
sentimental, another bellicose, while in a third there may be no appear- 
ance of excitement, the first distinct symptom being profound slumber. 
When drinking is indulged in in company, the excitement stage is a very 
common phenomenon, but if alcohol is taken without the exhilarating 
accompaniments of bright lights and exciting companionship, it is much 
less frequently seen, and the question has therefore arisen how far the 
environment produces the excitement in alcoholic intoxication. 

It may be stated at once that there exist two distinct views as to the 
action of alcohol on the central nervous system: the one stoutly upheld 
by Binz and his pupils, that alcohol first stimulates and then depresses 
the nerve cells; the other championed by Schmiedeberg, Bunge and 
their followers, that it depresses the central nervous system from the 
beginning. The symptoms of excitement require no explanation on 
the first theory, which is rather to be looked on as the natural expression 
of the facts observed. On the other hand, Schmiedeberg explains 
them as not due to true stimulation of the motor areas, but as the 
result of these areas being freed from control by the weakening of the 
highest functions of the brain — the will and self-restraint. Even the 
smallest quantities of alcohol tend to lessen the activity of the brain, 
the drug appearing to act most strongly, and therefore in the smallest 
quantities, on the most recently acquired faculties, to annihilate those 
qualities that have been built up through education and experience, 
the power of self-control and the sense of responsibility. 

The question is a most difficult one to decide, for on the one hand it 
has been shown that the simplest movement is the result of a combi- 
nation of motor and inhibitory impulses from the brain, while on the 
other hand the measurement of the relative strength of these impulses 
is one of the most difficult problems of biology. The advocates of the 
stimulant action point to the confidence in their own powers exhibited 
by intoxicated persons, to the brilliancy of the after-dinner speech, and 
*o the excitement stage as evidences of the increased activity of the 
brain. But their opponents question whether the confidence is accom- 
panied by any really increased physical strength, and point out that 
the brilliancy of speech may be due to the environment and to the 
speaker having lost his habitual shyness and nervousness, and that the 
excitement is generally absent when the associations are different, or 
degenerates into a form which more distinctly resembles depression. 



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ALCOHOL 175 

More definite evidence for or against the stimulant action of alcohol 
has therefore been sought by comparing the amount of work which 
can be done with and without it; and an apparent confirmation of 
Bunge's view has been found in the results of the use of alcohol by 
troops on the march, for repeated experience has shown that those 
regiments which were not supplied with alcohol marched farther and 
were in better condition at the end of the day than others to which it 
had been given. The experiments of Durig in climbing lead to the 
same result, the total work done being smaller under alcohol and the 
expenditure of energy greater. Forms of work requiring larger drafts 
upon the intelligence than the marching of soldiers are also performed 
less correctly with alcohol than without it; thus typesetters can do 
more work and make fewer errors when they abstain from its use. 

The capacity for work depends not so much upon the actual strength 
of the muscles as upon the condition of the brain, and these experi- 
ments are therefore generally quoted as evidence of the depressant 
action of alcohol. Their results are not incompatible with the view 
that alcohol primarily stimulates the nerve cells, however, for Binz 
and his followers allow that the stimulation is transient and is followed 
by depression, and if a sufficient time elapse after the alcohol is taken, 
the stage of depression is elicited and the total work may thus be reduced. 

Attempts have been made to measure the work done under alcohol, 
b} T recording with the ergograph the work of which a muscle is capable 
before it is completely fatigued. The best investigations are those of 
Rivers, who took the precaution of disguising the alcohol with flavors 
so that the subject of the experiment was unaware when alcohol was 
given. His results igdicate that small quantities of alcohol (5-20 c.c, 
corresponding to about a tablespoonful and a wineglassful of spirits) 
have very little effect on muscular work measured in this way. When 
larger amounts of alcohol were taken, Rivers found that an exceptional 
amount of work could be performed before fatigue appeared, but he 
considers this due to the fact that the alcohol could no longer be con- 
cealed and the subject was now influenced by suggestion. 

In measurements of intellectual work, the factor of suggestion is of still 
greater moment and the observations of Kraepelin lose much of their 
importance from the fact that the subjects knew when alcohol had been 
given them. He concluded that the receptive and intellectual powers were 
weakened by very small quantities of alcohol, while the motor functions 
seemed to be facilitated by small, and retarded by large quantities. 
For example, a person under even a small dose of alcohol makes more 
errors than usual in adding a row of figures and in reading a series 
of unconnected syllables, and apparently recognizes letters and words 
somewhat more slowly. It is interesting to find that the subject of 
the experiment is quite unaware of the inferiority of his work and is 
often persuaded that it is unusually good. It must be added that 
this depressant effect is not equally elicited in different individuals, 
and even 100 c.c. of alcohol (corresponding to about half a pint of 
spirits) fails to induce it in some persons. Kraepelin's latest investi- 



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176 SUBSTANCES ACTING AFTER ABSORPTION 

gations tend to show that this effect of alcohol lasts much longer than 
is generally recognized, the mental equilibrium being reinstated only / 
12-24 hours after even very moderate indulgence in alcohol. He 
leans to the view that alcohol weakens and paralyzes some parts of 
the brain, while primarily stimulating others, but brings forward no 
new evidence that this stimulation is not fictitious and really due to 
the removal of the barriers of self-restraint by the paralysis of higher 
areas. Most other psychological experiments give similar results, and no 
unequivocal evidence of the initial stimulant action on the brain has 
yet been adduced, for each new feature may be interpreted as really due 
to the depression of controlling or inhibitory functions. Of course, 
there is no absolutely convincing proof that no stimulation of the motor 
areas occurs, and no physiological proof of the existence even of control- 
ling areas can be adduced, much less of their paralysis by alcohol. On 
the other hand, the effects of alcohol on cerebral activity are very 
different from those of caffeine, which definitely increases both mus- 
cular and mental efficiency, and thus is the typical brain stimulant. 
Exaggerated importance has been attached to this question from the 
idea that it is more justifiable to employ a "stimulant" than a "de- 
pressant," but in therapeutics this is not a valid argument for or 
against the use of alcohol. 

In the lower parts of the central nervous system the evidences of 
primary depression are less open to question. For example, the cgfib, 
dinatiw ^f the movements s uffers at an early stage in alcohol drink- 
ing, long before the generally reco gni zed forms of lack of coordination, 
such as indistinct speech and staggering, appear. In the spinal cord 
alcohol causes a depression of the reflex irritabil ity, which passes into 
complete paralysis some time before the respiration ceases. 

Alcohol has been found to cause a prolonged secretion of the cerebro- 
spinal fluid and to raise the pressure in the subarachnoid space, and 
it has been suggested that this may account in part for its after effects 
which have generally been attributed to gastric disturbance. 

Acute alcoholic intoxication leads to very distinct alterations in the histo- 
logical appearance of the cells of the central nervous system, which have been 
described by Dehio, Stewart, &nd others. The chief change noted by them 
consists in replacement of the chromatin network by fine granules, which in 
turn seem to become dissolved in the general cytoplasm. Staining reagente, 
therefore, give rise to a diffused coloration of the cell rather than to localized 
masses of color, such as are seen in the normal cell. 

The^aedulla oblongata is the last part of the central nervous system 
to be acted oil "by alcohol, or at any rate to undergo complete paralysis. 
The Respiratory and Circulatory Centres preserve their functions long 
after the occurrence of complete unconsciousness and the disappearance 
of the ordinary reflexes. The same question has been raised in regard 
to the respiratory centre, as has been already discussed in the con- 
sideration of the brain, and the same two opposing views have been 
upheld. These are of greater importance as regards the respirator}' 



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ALCOHOL 177 

centre, because the advocates of the stimulation theory advise the use 
of alcohol in conditions of the respiration in which it is directly contra- 
indicated if the other view be the correct one. The question here is 
apparently much more simple, because the activity of the respiratory 
centre can be estimated directly by measuring the number of the 
respirations and the amount of air inhaled during each; but a large 
number of such experiments have been performed with very varying 
results. If thp number of the respirations be counted in a person in 
the excitement stage of alcoholic intoxication, it is often found to be 
much greater than normally, but this may be due to the muscular 
movements and need not indicate any direct action of the drug on the 
medullary centre. And, of course, this excitement stage is not elicited 
in therapeutics, and the value of alcohol as a respiratory stimulant 
must therefore be estimated in cases in which no such excitement is 
caused. A number of such estimations have been made in man and 
animals, and on the whole the evidence shows that in man even when 
no excitement is produced and in some instances even when sleep 
follows, the amount of air inhaled is larger than before the drug was 
administered (Jaksch, Zuntz and Berdez, Geppert, Weissenfeld, Wen- 
delstadt) ; the increase is generally more evident when alcohol is taken 
during fatigue and exhaustion than in ordinary conditions. This 
may not indicate a direct stimulation of the respiratory centre, how- 
ever, for the increase is often not greater than that following an ordinary 
meal, and may therefore be attributed to the respiratory centre being 
indirectly affected by the activity of the stomach and intestine. The 
actual excitability of the respiratory centre may be measured by its 
response to the inhalation of carbon dioxide, and Loewy's observations 
by this method do not lend support to the view that the excitability 
is augmented. There is therefore no sufficient evidence that the respira- 
tory centre is directly stimulated in man, and the increase in the amount 
of air inhaled may be due to the peripheral action of alcohol. 

In the dog, no acceleration of the respiration occurs after alcohol, while 
in the rabbit, on the other hand, the respiration is much accelerated, and the 
amount of air inhaled shows a corresponding increase. It is still a matter of 
dispute, however, whether this arises from direct action on the centre or from 
the irritation of Jbhe stomach, the dilatation of the vessels, and other peripheral 
effects (Jacquet, Wilmanns, Singer). 

In short, there is no unequivocal evidence that the increase in the respi- 
ration under alcohol in health is due to direct stimulation of the respiratory 
centre, while on the other hand, no depression of the activity of this centre 
occurs except at a late stage of alcohol poisoning. Alcohol is often said to slow 
the respiration in fever patients and to stimulate it in cases of shock. In the 
first case the improvement (when present at all) is probably due to the alcohol 
lessening the excitement through its narcotic action, while its value in shock is 
disputed by most careful observers. 

From a practical point of view the question is of little importance, 
for the changes in the respiration induced by alcohol are too small and 
too inconstant to play any part in the treatment of respiratory disorders. 
12 

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178 



SUBSTANCES ACTING AFTER ABSORPTION 



Circulation. — The pulse is accelera ted during the excitement of 
alcoholic intoxication, but this is due to the ^pi^awl nmgcujaE *ff™* 
nnH not ta jiny H \reot nr*|jnn n the heart, for Jacquet has shown that the 
pulse rate is unaltered by alcohol in normal cases, provided that no 
excitement be produced by the environment. In animals also, the 
pulse rate is very little altered by alcohol, except in very large quantities, 
when it is slowed. The blood-pressure is said to be slightly increased 



Fig. 3 




Tracing of the movements of the ventricle (lower) and auricle (upper) of the dog when 
a large dose (20 c.c. or } oz.) of 50 per cent, alcohol is suddenly thrown into a vein. The 
levers move upward during systole, downward during diastole. A, normal. B, in- 
jection. The systole of the auricle is very much weakened, the diastole is less affected. 
The ventricular systole is comparatively little changed, although it also is a litUe weaker. 
The effect passes off very rapidly, so that at the end of the tracing both chambers have 
almost recovered. A very similar effect is seen under chloroform. (Fig. 10.) (The 
tracing is to be followed from right to left.) 



in man in some cases after moderate quantities of alcohol (15-30 c.c), 
but in at least an equal number of observations it was found to be 
slightly reduced, and in many no definite change could be made out. 
In animals the blood-pressure has been found to be slightly increased 
by some observers, to be reduced by others. Brooks, who has succeeded 
in registering the blood-pressure painlessly in unansesthetized animals, 
found that alcohol given by the mouth increased the arterial tension 
for about five minutes and then reduced it. When it was injected intra- 



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ALCOHOL 179 

venously or by a gastric fistula, the tension was reduced. Alcohol is 
believed by some to augment the strength of the heart, but the change 
is small in extent and inconstant in its appearance. Largerquantities 
aff ect the heart int he y^p* w*y as **hpr and chloroform, wpalfAning 
th e auricular and later the y' anfr i™ | l nr systole flPf* indxidng dilatation 
a nd slowing of both chambers (F ig. 3). The action of alcohol on 
the heart is much less than that of chloroform, however, about 200 
times as much being required to arrest the frog's heart; and Loeb 
found that the mammalian heart continues to beat when perfused with 
two per cent, alcohol. 

The flushing of the skin which occurs in alcoholic intoxication indi- 
cates dil ution of tj|ft sign xfiSSfik ) and this is sometimes accompanied 
by a very Hifft* con striction of the vessels of t he i nterna l organs. 
These seem to arise from central vasomotor action, but whelEer it is 
due to direct stimulation of the centres or arises from a reflex from 
the periphery, is not yet determined. V ery larg e, quantities of jftl g fthfll 
ca use a ma rked, fall in. the arterial tension, through weakening the 
vaso-constrictor centres and the heart muscle, b ut the quantities of 
alcohol r equired to cause any. great fall in bloocitpresaOTe are Tar m 

F XCesS of thosfi used in f^rftpgiitW 

On the whole, the action on the circulation of small quantities of 
alcohol (£-1 oz.) may be favorable in some conditions, but is so slight 
and inconstant that it is impossible to regard it as a basis on which 
serious therapeutics can be founded. The slowing of the heart which 
often follows the administration of alcohol in fever, would seem due 
rather to its di mijiishing the cerebral excitement than to its dire ct 
action on the heart. 

Alcohol has little effect on Muscle or on peripheral Nerves when it is car- 
ried to them by the blood, but Lee states that frog's muscle is strengthened 
by small quantities and weakened by larger amounts. This has been inter- 
preted as indicating that small quantities of alcohol are utilized by the muscle 
as a source of energy, while this effect disappears under larger quantities which 
unfold the toxic action of the drug. And Durig's experiments show that in man 
alcohol may be utilized for work in the same way as the ordinary sources of 
energy, such as sugar. When the frog's nerve is exposed to alcoholic vapor its 
irritability is first increased and later diminished if the quantity applied be 
large enough. Th q sensory fibres are said to be depressed bef ore th e motor. 

The effect of alcohol on the Digestion has been the subject of many 
investigations, both from the clinical and the experimental point of 
view. There exists a widespread belief in both lay and medical circles 
that small quantities of alcohol taken before a meal increase the ap pe- 
tite, while after food they a ccelerat e a the dj gestion. it is obvious that 
alcohol may affect digestion either by altering tfie activity of the fer- 
ments in the digestive canal, or by altering the secretion, movement, 
or absorption of the stomach and intestine. The digestive power of 
the ferments outside the body has been found to be unaltered or slightly 
increased when pure alcohol is present in very small quantity. But 
when more than traces of alcohol are present, the gastric and pancreatic 



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180 SUBSTANCES ACTING AFTER ABSORPTION 

juices are retarded, and even small quantities of the ordinary wines 
and beers have this detrimental effect. It does not seem likely that 
the initial very slight augmentation of the ferment action plays any 
important role in the effects of alcohol on the stomach. 

The presence of alcohol in the mouth causes (according to Chitten- 
den, Mendel and Jackson) a very appreciable increase in the secretion 
of the saliva, presumably by reflex action, and a similar increase in the 
gastric juice may probably follow from its local irritant action on the 
stomach. But, apart from this, it appears to exert a specific action on 
the secretion after its absorption into the circulation. For when it is 
injected into the rectum, a profuse secretion from the gastric mucous 
membrane follows, and when part of the stomach is isolated from the 
rest of the organ, so that alcohol given by the mouth fails to enter it, 
this part still shares in the secretion; the pepsin secretion is not always 
correspondingly augmented. It has been further demonstrated that 
the absorption of fluids from the stomach and bowel is much acceler- 
ated by the addition of alcohol, and the movements of the stomach are 
said to be augmented by moderate quantities. 

Digestion in the stomach may thus be fc influenced in two opposite 
directions when alcohol is administered in the usual form of wine, 
spirits, or beer. Th e action on the fer ments is deleterious, while th e 
changes in the ctnmQnh WQ H +ko nrggSBSS ^^" on and moveme nt 
TuifHjir nrrrlrratiftd fth">nrpt lf>n i ATE h^"^™' 01 ; n mary ™°^ These 
t'woopposing factors may neutralize each other, as in the dog, in which 
the rate of digestion is scarcely altered, the retarding effects of alcohol 
on the proteolysis being compensated for by the more abundant secre- 
tion of the juice, which continues after the alcohol is absorbed, and 
therefore after its deleterious effects on the fermentation have disap- 
peared. (Chittenden, Mendel and Jackson.) In man the result 
varies, the one factor predominating in some cases, the other in others. 
Thus, while Kretschy and Buchner found that the digestion of proteins 
in the human stomach was distinctly retarded by alcohol and beer, 
Eichenberg, Wolffhardt and others state that small quantities of alcohol 
or wine accelerate the digestion, and Gluzinsky came to the conclusion 
that as long as alcohol remains in the stomach the digestion is retarded, 
but that after its absorption the digestion progresses more rapidly 
than if no alcohol had been given. Zuntz and Magnus-Levy have 
shown that the addition of beer to the dietary does not affect the ab- 
sorption and utilization of the food by the tissues. It is not unlikely 
that the taste has some influencejm thejssujt, that in those who enjoy 
the taste of alcohol, It induces a more rapid secretion and an improved 
digestion, while in those to whom it is disagreeable, the secretion is 
less altered. 

The divergence of opinion exists only in regard to the effects of 
small quantities, for all are agreed as to the deleterioi] ^ affirm <J any 
but moderate doses of alcohol on the digestion. After large quantities 
(50 c.c.) the irritation of the stomach wall leads to a profuse secretion 
of mucus, and to nausea and vomiting. There is every reason to sup- 



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ALCOHOL 181 

pose that this ig Hup tn t he loflal ^ itntinn , flmri nnt tn thr nrtinn nf th r 
abs orbed alcohol on the nervous centre s. A large dose of concentrated 
alcohol sometimes leaves evidehce of its irritant action in redness and 
injection of the mucous membrane, an3, it is said, in ecchymoses, 
but in most cases of fatal poisoning no such appearances are to be 
observed after death. 

Is Alcohol a Food? — It has been shown that only 5 per cent, or less of 
the ingested alcohol is excreted, while the rest of that absorbed from 
the stomach and bowel, amounting to over 9 5 per cent., undergoe s 
combustion in the tissues. This oxidation apparently progresses 
slowly, appreciable amounts being found in the blood twenty-four 
hours after its ingestion; this accords with Kraepelin's statement that 
its effect on the brain can be detected for 12-24 hours. In undergoing 
combustion alcohol gives up energy to the body, and therefore is technic- 
ally a food, but this does not imply that it is an advisable food in all 
. conditions. Experiments in which the carbonic acid excretion was 
measured under alcohol show that no more energy is required for its 
absorption than for that of other foods, and that alcohol taken in addition 
to the ordinary food is either itself transformed into tissue, or under- 
goes oxidation instead of some substance which in turn is used to build 
up the body. Recent investigations seem to indicate that alcohol is 
more readily utilized by the tissues than the carbohydrates, even when 
these are present in the food in large amounts; so that the administra- 
tion of alcohol leads to an economy in these. This diminished oxidation 
of carbohydrates in the tissues in turn leads to the deposit of fat, which 
has been shown to occur in animals treated with alcohol and is a common 
observation in man (Togel, Brezina and Dtirig). Alnnhr^ therefore. 

acts aS a Subst itUJf fp* nniJvdiyHMitPQ in tViP fnnn* 

It has long T>een recognized that when insufficient fat and carbohy- 
drate is supplied to the body, the proteins are drawn upon to make 
good the deficiency and the nitrogen eliminated rises accordingly. 
On the other hand, when the fats and carbohydrates of the food are 
increased, the organism economizes its protein and the nitrogen tends 
to fall. This is the most accurate method of testing the food value of 
non-nitrogenous substances, and alcohol has been the subject of a 
number of such investigations, which have finally decided this much 
disputed question (Neumann, Atwater and Benedict, and Rosemann 
and his pupils). The results may be best illustrated by an account of 
Neumann's first experiment. 

This Tasted 35 days, divided into six periods. The proteins of the 
food and the carbohydrates remained constant throughout, while alcohol 
was substituted for part of the fat for some time (see Fig. 4). During 
the first five days the nitrogen excreted was practically equal to that 
of the food (nitrogenous equilibrium), while during the next four 
days one half of the fat of the food was omitted and the immediate 
result was an increase in the nitrogen excreted, indicating that the 
proteins of the body w r ere being drawn upon to make good the deficit 
in the fat of the food. The next ten days a quantity of alcohol chem- 



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182 



SUBSTANCES ACTING AFTER ABSORPTION 



ically equivalent to the fat deficit was taken and the nitrogen elimina- 
tion slowly fell to the normal (equilibrium). In the first five days of 
this period, however, the nitrogen remained high, showing that alcohol 
did not at first replace the fats completely. In the fourth period of 
six days, the same amount of fat was given as at first, while the alcohol 
was continued, and the nitrogen fell much below the amount ingested; 
i. e. f the alcohol again led to a saving of the proteins. Next, both 
alcohol and fat were omitted for four days and the proteid tissues were 
again drawn upon. Finally the original diet was resumed and the 
nitrogenous equilibrium was at once restored. From this experiment 
Neumann drew the conclusion that alcohol can replace a chemically 
equivalent amount of fat in the dietary, for otherwise the nitrogen 
would not have returned to the normal toward the end of the third 
period; and alcohol given along with a sufficient dietary leads to a 



Fig. 4 



CUVB 

PERIODS 

fATOF 
FOOO 

ALCOHOL 

mrnooEH 


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The effect of alcohol on nitrogen elimination. The wave-line represents the nitrogen 
excreted. It rises rapidly in the second period when the fat of the food was reduced to 
one half, but soon falls in the third period where alcohol was substituted. 100 g. of alco- 
hol is chemically equivalent to 78 g. of fat. (After Neumann.) 



further economy of the proteins just as additional fat would do; other- 
wise the nitrogen would not have fallen below the point of equilibrium 
in the fourth period. 

The final result of all these investigations is that alcohol can take 
the place of some of the fat in the food, and leads to the same economy 
of protein as the ordinary non-nitrogenous constituents of the dietary. 
The first three or four days during which alcohol is substituted for fat 
it has little or no tendency to economize the proteins, but this is true 
of other forms of food also, any sudden change in the non-nitrogenous 
food leading to a temporary increase in the nitrogen excreted, which 
persists until the tissues have become accustomed to the new dietary. 

Metabolism. — It was formerly supposed that alcohol economized the 
body tissues in some ill-defined way, by means of a direct action on 
the protoplasm of the cells; as it was expressed, alcohol lessened the 



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ALCOHOL 183 

Combustion of the tissues. But moderate quantities of alcohol appear 
to have no action on the ggpewU nafitflbolism evpept tW whiVh it. g%reg 
w ijh other nitrogen free foods . When very large quantities of alcohoT 
are taken, and depression and sleep follow, the co mbustion of the body 
is reduced, not through any action on the protoplasm gdigfillly, but 
tnrougtf the muscular movements being lessened. In the same way, 
during the excitement stage, the carbonic acid exhaled is dnnht]e<^ 
miieh jnereRsed. because more energy and more of the body tissues are 
used up in the violent movements. But Mendel and Hilditch state 
that the uric acid of the urine is considerably increased by moderate 
quantities in man, and this increase is shared in by both the endogenous 
uric acid and that of the food. Thin nprrifir nrtiflP nn the nnV arid 
ex cretion lys not \ \f** n <*Tj\\*\^fA The purin bases are increased to a 
smaller extent, while the creatinin excretion remains unchanged. 

Influence on Infection. — Persons addicted to the use of alcohol are 
known to show less re sistance in acute disease and in operations accom- 
panie d by shock t %p nTnre tempera te individuals, and in very intem- 
cases the prognosis must be guarded in an attack which would 
ordinarily be accompanied with little danger. This has been confirmed 
by a number of experiments on animals which were subjected to large 
doses of alcohol and then inoculated with pathogenic germs (Laitinen). 
The results have invariably shown a greater susceptibility to infection 
and a greater mortality than in control animals which had received 
no alcohol. A similar effect was observed when toxins were injected 
instead of bacteria, and great difficulty was encountered in rendering 
animals immune to the diphtheria toxin if they had previously been 
treated with alcohol. Various explanations of this reduced resistance 
have been given, Rubin ascribing it to paucity or inactivity of the 
leucocytes, while Abbot and Bergey found a reduction in the hemolytic 
complement, which suggests that the susceptibility to infection may be 
due to the failure to form the specific complement to the bacterial toxin. 
It is often stated that alcohol given in the treatment of infectious diseases 
must have a similar deleterious effect on the resistance of the tissues, 
but this has not been shown to be the case. 

These clinical and experimental results have raised the question 
whether the ordinary dietetic use of alcohol in even small quantities 
(15-30 c.c.) may not lead to impairment of the resistance to infectious 
disease, and much interest attaches to Laitinen's later work, in which 
animals were treated with quantities of alcohol corresponding to those 
habitually used by temperate persons. The general result appears 
to be that the prolonged use of small quantities in animals (0.1 c.c. 
per kilo.) may affect their susceptibility to disease, but the average 
mortality is not greater than that of the controls to which no alcohol 
has been given. 

A much more distinct effect from small doses of alcohol, such as 
correspond to temperate use in man, has been observed by Hunt, who 
finds that animals thus treated become more susceptible to the action 
of methyl cyanide. This poison acts in the tissues through being 



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184 SUBSTANCES ACTING AFTER ABSORPTION 

oxidized to hydrocyanic acid, and Hunt believes that the effect of the 
prolonged treatment with alcohol is to facilitate this oxidation, and 
that the reaction is evidence of an alteration of the metabolism of the 
body in this direction. The great importance of this observation lies 
in the fact that the modification of the metabolism which it demon- 
strates, arises from the prolonged use of quantities of alcohol which 
are too small to give rise to definite symptoms of intoxication. Appar- 
ently the alteration is associated with the development of tolerance for 
alcohol. 

The Temperature of the body falfr snnr ^what afte r the administration 
of alcohol, but this is not due to ahy diminution m the oxidation and in 
the heat formed, but to the g^fp+gr output nf heat from the dilation 
of-tbe-skio^vessels. The fall in temperature is comparatively slight, 
seldom being more than J-l° C, but it would seem that exposure to 
cold causes a greater fall in the temperature after alcohol than in normal 
conditions; this is perhaps due to the temperature-regulating mechanism 
being rendered less sensitive by alcohol. 

The fall in temperature produced by alcohol is generally accom- 
panied by a feeling of heat, and a thermometer applied to the skin 
may actually show a rise of several degrees, because more warm blood 
flows through the dilated vessels. If much excitement and movement 
follow the ingestion of alcohol, no fall in the temperature may result, 
the increased heat formed during the movement compensating for the 
increased output, and in some cases a rise of temperature occurs from 
the same cause. Very large quantities of alcohol may lead to a fall 
in temperature of 3-5° C, owing to the lessened movements during 
unconsciousness. 

Absorption and Excretion. — Alcohol is absorbed rapidly ? about ffi _ 
per cent, of that ingested being taken up in the stomach and 80 per 
cent, in the small intestine. It is found in largest proportions in the*" 
bloo d and the centra l nervous system ; Grehant found as much as tT 
pats per thousand in the blood of animals, but more than this was 
inevitably fatal; in a case of deep alcoholic coma in man the blood 
contained 2.25 parts per thousand (Sweisheimer). Traces remain in 
the blood for about twenty-four hours, but over 95 per cent, of that 
ingested is oxidized in that time. The alcohol which escapes com- 
bustion in the tissues is excreted by the kidneys unchan ged, 1 and 
by the Ju ngs. 2 The excretion~of alcohol by the lungs is increased by 
muscular exertion and the consequent hyperpnoea, and that by the 
kidneys may similarly be increased by large amounts of fluid; and more 
is excreted when the alcohol is taken on an empty stomach than when 
it is taken with food; but even in these conditions over 90 per cent, 
undergoes complete combustion in the tissues. Traces are sometimes 

1 Some of the alcohol in the urine is combined with glycuronic acid in the rabbit, 
but not in man. 

* Traces of alcohol are exhaled by the breath, but ethyl alcohol fails to escape in 
this way in measurable quantities. The odor of the breath after spirit drinking arises 
from the higher alcohols and other by-products present in these and not from the ethyl 
alcohol. 



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ALCOHOL 



185 



found in the s weat and milk , but there is no foundation for the legend 
that children may be intoxicated, or acquire a taste for strong drink 
from the.alcohol absorbed in the milk of a drunken mother or wet-nurse. 
The amount and quality of the milk are unaffected by the administration 
of alcohol (Rosemann). Brauer states that alcohol is eliminated in 
some quantity in the bile and is then reabsorbed in the intestine; this 
is more marked in the case of amyl alcohol than in that of ethyl alcohol, 
and the alcohol in the bile is accompanied by albumin, epithelial cells, 
and casts of the finer bile ducts. 

Repeated doses of alcohol produce XfiteiftQfifi*- which, although not so 
great as that acquired for morphine and nicotine, involves the pre- 
scription of double or triple doses in persons addicted to drinking. 
This tolerance has been shown by Pringsheim to arise in part from 
the tissues acquiring an inciefliBfr Lgapacity to oxidize alcohol: and as 
oxidation begins almost as soon as absorption, a large quantity of 



Fig. 5 



0.6 
0.5 
0.4 
0.3 
0.2 
0.1 



The percentage of alcohol in the blood after giving 5 c.c. per kg. to rabbits. The per- 
centage is indicated on the perpendicular line, the hours after administration along the 
horizontal. The broken line represents the changes in percentage in a normal animal, 
the unbroken that in an animal which had acquired tolerance through prolonged treat- 
ment with alcohol previously. (Pringsheim.) t 































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2 1 


3 14 



alcohol taken by an habitual drinker may not le ad to the accumulatio n 
in the blood of a sufficient quantity to induce symptoms of intrnriwtrrm' 
(Fig. 5). But in addition to this factor, the brain reacts less than 
normally, for Sweisheimer finds that a given concentration of alcohol 
in the blood induces greater intoxication in an abstinent than in a 
tolerant person. In tolerance the amount of alcohol excreted in the 
breath and urine may sink to less than 1 per cent., all the rest under- 
going combustion in the tissues. The close relationship between the 
narcotics of the fatty series is indicated by the fact that much more 
rhlnrnfomi Qr ether than usual is r equired to anaesthetize persons in 
whom a tolerance for alcohol has been VsTaEnsEecT" 
Although alcohol seems to increase the Urine to some extent, it can- 
hgRflid to be a powerf ul diuretic in it g * lf , Qr> ^ the diuresis may be 
exptSined in large part by the quantities of fluid taken with the alcohol 
and by the accelerated absorption from the alimentary tract. Some of 



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186 SUBSTANCES ACTING AFTER ABSORPTION 

the spirituous liquors, such as gin, produce a profuse secretion of the 
urine, but this is due to their other constituents, and not to the alcohol. 

Alcohol is generally credited with . Aphrodisiac powers, that is, with 
increasing sexual desire, although no less an autKorit^TEan Shakespeare 
states that it prevents the consummation of sexual intercourse. The 
unquestionable tendency toward sexual excess observed in intoxication 
is due, not to any effects on the generative organs, but to the loss of 
self-control, from the cerebral action of the poison. 

Alcohol possesses only ja weak yAntteepticja ction, for while the 
growth of some bacteria is delayed somewhatin a 1 : 1000 solution, 
many grow abundantly in 4 per cent, alcohol, and some in even 
stronger solutions. Its disinfectant action has been the subject of a 
number of researches recently and has been found to vary with the 
conditions. Dry bacteria may be exposed to absolute alcohol for 
twenty-four hours without losing their vitality, while 60-70 per cent, 
alcohol is fatal to them, and also to moist organisms. The explanation 
of this curious observation seems to be that alcohol fails to penetrate 
microbes unless in the presence of water. In less than 40 per cent, 
the action is very slow, so that the limits of alcohol as a disinfectant 
may be placed at 50-70 per cent.; in this strength it is equivalent 
to about 3 per cent, carbolic acid, provided that it does not cause 
large precipitates of protein. Many bodies which are antiseptic when 
dissolved in water have comparatively little effect when dissolved 
in alcohol. 

Other simple life forms are more susceptible to the action of alcohol 
than the bacteria, though it does not act on these in such dilution as 
on the mammalian nerve cell. Even the plants can be subjected to its 
influence, showing that in sufficient quantity it is a general protoplasm 
poison. In most cases a stage of increased activity precedes that of 
depression and this has been used as an argument in favor of the primary 
stimulant action of alcohol in the brain. 

Methyl alcohol, or wood alcohol, has assumed great importance lately from 
a large number of cases of poisoning having occurred from its being substi- 
tuted for ethyl alcohol as an intoxicant, or in some patent remedies. In animal 
experiments it is found that given in single doses it is slightly less poisonous 
than ethyl alcohol, the action coming on somewhat more slowly, but lasting 
a longer time; the symptoms of gastric irritation are generally more marked 
than those induced by ethyl alcohol, and very often some convulsive move- 
ments are observed (Hunt). When the administration is repeated, methyl 
alcohol is found much more poisonous than ethyl, and this may probably 
be ascribed to the more prolonged action of the former. Thus it has been 
shown that when equal amounts of methyl and ethyl alcohol are administered 
to animals, over a third of the methyl alcohol can be found in the tissues after 
forty-eight hours, while of the ethyl alcohol only about one-tenth remains after 
fifteen hours. About 40 per cent, of the methyl alcohol is oxidized in forty-eight 
hours, while 25 per cent, escapes in the breath and urine. Pohl has pointed out 
that while ethyl alcohol undergoes complete combustion in the tissues, methyl 
alcohol is oxidized to formic acid and possibly to formic aldehyde, both of which 
are much more poisonous than the original alcohol. It seems a fair inference 
that the prolonged action and the consequent greater toxicity of the lower 
alcohol may be due to these products. 



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ALCOHOL 187 

In man the symptoms of wood alcohol poisoning differ from those of ordi- 
nary spirits in the m arked muscular weakness and defective cardia c action, 
which are followed by nausea, vomiting, WUHla, <5V delirium 01 a mucTTmdre 
intense and persistent character than those seen in intoxication with ethyl 
alcohol. In a considerable number of cases death has followed from a single 
dose smaller than would have been fatal had ethyl alcohol been swallowed, 
and in some f»nn^ Wnl nui Ff r manent blindness has followed or accompanied 
recovery. This condition is more often the result of repeated ingestion of the 
alcohol, however, and is due to optic neuritis and subsequent complete optic 
atrophy. The large number of cases of blindness or fatal intoxication collected 
by BuUer and Wood demonstrate clearly the danger incurred in the use of 
this poison internally or even externally, or by inhalation of its vapor. Optic 
atrophy has been induced in animals repeatedly by the administration of wood 
alcohol while it is hardly liable to occur from ethyl alcohol. 

The other alcohols are mainly of interest as impurities of the preparations 
of ethyl alcohol. They all resemble it in their general effects, but differ from 
it in toxicity; propyl alcohol is more powerful than ethyl, butyl than propyl, 
and amyl than any of them. Amyl alcohol, or fusel oil, is present in small 
quantity in most forms of spirits. It resembles ethylic alcohol in general, but 
is more irritant locally, and is believed by some authorities to have more deleter- 
ious effects in chronic poisoning than pure ethylic alcohol. This is not based 
on any very satisfactory evidence, however, and all the characteristic symp- 
toms of chronic alcoholism have been produced in animals by pure ethyl alcohol. 
Furfurol is also present in many forms of spirits, but in such small quantities that 
it does not play any r61e in the symptoms induced by them. 

Preparations. 

Alcohol (U. S. P.) contains 92 per cent, of alcohol (C,H*HO) by weight. 

Alcohol Absolutum (U. S. P., B. P.), absolute alcohol, contains not more 
than 1 per cent., by weight, of water. 

Alcohol Dilvium (U. S. P.) contains about 41 per cent., by weight, of alcohol. 

Spiritus Rectificatus (B. P.), rectified spirit, contains 90 parts of pure alcohol, 
by volume, and 10 parts of water (85.65 per cent., by weight, of alcohol). 
There are four official dilutions in the B. P., containing 70, 60, 45, and 20 per 
cent, of alcohol by volume respectively. 

Spiritus Frumenti (U. S. P.), whiskey, contains 44r-50 per cent, of alcohol 
by weight, and is obtained by distillation of an extract of fermented grain. 

Spiritus Vini Gallici (U. S. P.), brandy, contains 39-47 per cent, of alcohol 
by weight, and is obtained by the distillation of fermented grape juice. 

Non-pharmacopceial spirits, which are used occasionally in medicine, are 
gin and rum. 

These Spirits all contain, roughly speaking, about 30-40 per cent, of alcohol 
along with other volatile substances, some of which are alcohols of the same 
series as ordinary alcohol (butylic, amylic, etc.), while others are of entirely 
unknown constitution — the cenanthic ethers. Brandy and whiskey act very 
much in the same way as pure alcohol. When freshly distilled they are more 
irritant and less pleasantly flavored than when kept for some years but do 
not seem more deleterious. Numerous other preparations containing large 
quantities of alcohol, such as the spirits of the volatile oils, might also be in- 
cluded in this group, but they are not used, as a general rule, for the same 
purposes as the alcoholic preparations proper, and their effects are in part 
due to the volatile oils contained. Some of them have, however, been em- 
ployed as intoxicants instead of brandy or whiskey, and Eau de Cologne and 
other essences have gained a certain notoriety as a means of secret drinking 
among women. The liqueurs are too numerous to mention, and their com- 
position is extremely diverse. Many of them contain considerable quanti- 
ties of sugar, and the combination of alcohol and sugar would seem peculiarly 



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188 SUBSTANCES ACTING AFTER ABSORPTION 

deleterious to the gastric mucous membrane. Others, such as cherry water 
(Kirschwasser), contain hydrocyanic acid, and the others various bodies of the 
volatile oil series. None of them seem to have any properties which would 
recommend their use in therapeutics. 

The Wines and Beers are much weaker preparations of alcohol, the lighter 
wines (hock and claret) containing about £-8 per cent, ethyl alcohol, while in 
sherry and port it may amount to 15-20 per cent. In addition, the wines 
contain the same volatile constituents as brandy, although in smaller amounts. 
The red wines contain a form of tannic acid derived from the skin of the grapes, 
and both red and white often contain considerable quantities of acids, chiefly 
tartaric acid. The amount of sugar varies with the different wines, and in fact 
in wine from the same locality but of different seasons. These constituents may 
lend to the wines a local deleterious action on the stomach, more especially 
when they are taken habitually. Champagne and the other sparkling wines 
contain large quantities of carbonic acid, which acts as a stimulant to the 
gastric mucous membrane. Champagne is considered one of the most 
"stimulant" of alcoholic preparations, although it contains a very low per- 
centage of alcohol compared with spirits, a fact which is of some significance 
in the explanation of the "stimulant" effects of alcohol. 

The beers are not pharmacopceial, and are less frequently advised than the 
other preparations. They generally contain a comparatively small percentage 
of alcohol (4-10 per cent.), along with a large amount of solids. These solids 
consist mainly of dextrin, sugar, and other starch products, which retard the 
absorption of the fluid, but are of considerable value as foods. The hops added 
in the preparation have probably no action save as bitter stomachics. The 
alcohol of beer is comparatively slowly absorbed owing to the colloid constituents, 
and this allows time for fermentation changes in the sugars and dextrins, which 
may perhaps account for the discomfort produced by malt liquors in persons 
of feeble digestion. When beers and porter do not derange the digestion, they 
are the most nutritive of all the alcoholic preparations, owing to the large amount 
of carbohydrates they contain. 

Therapeutic Uses. — Alcohol is used externally in very dilute solution 
as a cooling application to the skin, and in threatening bedsores, in 
which it is often applied as brandy, whiskey, or dilute alcohol in order 
to harden the epidermis. It has been employed as an antiseptic and 
mild irritant to broken surfaces, and if applied to the skin in concen- 
trated form, and especially if kept from evaporation, acts as a rubefa- 
cient and irritant. Its use to wash the skin and hands before operations 
arises from its power of cleansing the skin and removing the oils and 
fats rather than from its exercising any disinfectant action. In the 
form of diluted claret it is not infrequently used as an astringent gargle. 

The indications for the interned use of alcohol are ill defined, and 
cases which one physician would treat with alcohol often seem to pro- 
gress as favorably without it in the hands of another. It has been 
prescribed very largely in the past as a "stimulant" under the impression 
that it increases the activity of the circulation, respiration, and other 
functions of the body. The basis for this belief has been discussed 
already, and the results may be stated shortly: alcohol may promote 
the vital functions to a slight extent, but this action is very transient 
and inconstant in its occurrence and is quite insufficient basis for any 
therapeutic application. The action which lends alcohol its value in 
therapeutics is not its stimulant but its narcotic action, which allays 
the anxiety and distress of the patient, promotes rest and sleep, and thus 



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ALCOHOL 189 

aids toward healing, or at the worst renders illness more tolerable. 
Small quantities of other narcotics might be substituted for alcohol, 
but none of them perhaps excel it in producing that spirit of hopeful- 
ness and restful confidence which contributes so much to recovery. 

One series of symptoms which is often treated with wines is of gastric 
origin, and is manifested in want of appetite and enfeeblement of 
the digestion; in some of these cases the alcoholic preparations seem to 
be beneficial, while in others they appear to be positively harmful. 
This may be explained by the effect of alcohol on secretion and absorp- 
tion, only those cases in which secretion is deficient being benefited, 
but the tastes of the patient are a more important factor; if he enjoys 
the taste and odor of wine, its administration may promote his appetite, 
while, on the other hand, if he has a distaste for wine, it will prove 
harmful. There is no question that the functions of the stomach are 
increased by pleasing, and retarded by unpleasant tastes and odors. 
In these cases "dry" wines are to be preferred, as the sugar of the 
sweet wines may irritate the stomach; champagne may be used, and 
the wine ought to be given immediately before or during a meal. 

Cases of hemorrhage, shock and other forms of severe and sudden 
depression of the heart and central nervous system are very frequently 
treated by the administration of strong alcoholic preparations, such as 
brandy and whiskey, this treatment being based upon the belief that 
alcohol is a cardiac and respiratory stimulant. It is extremely difficult 
to estimate the value of a remedy in these conditions, and it is possible 
that it may be of benefit in some cases by lessening the anxiety and pain 
of the patient if he is conscious. But the beneficial effects of alcohol in 
these cases has been much questioned in recent years, and the belief 
that it is of little value is certainly more widely held at present that at 
any previous time; in experimental shock in animals, Crile found that 
alcohol generally increased the danger when given in average doses, 
and that smaller doses had no beneficial effects, but it is quite possible 
that in man different results may be obtained, from alcohol acting as a 
narcotic and removing nervous symptoms which would not arise in 
the lower animals. In unconsciousness it is probably of no value. 

In sudden chill with a tendency to fever, alcohol is often of great 
benefit, especially when taken in the form of brandy or whiskey 
diluted with hot water. Its efficacy here would seem due to the relief of 
the congestion of the internal organs by the return of the blood to the skin. 

In many cases of acute inflammatory disease, the prescription of 
alcohol seems to be attended with benefit, while in others it seems 
rather to increase the severity of the symptoms. No special indications 
can be given for alcohol in these cases, and the physician must be 
guided by its effects. It may tend to allay the irritability of the nervous 
centres, and thus reduce the delirium and slow the heart and respiration 
by lessening the muscular movement; Cabot and Dening and his 
pupils state that the administration of alcohol to patients is not followed 
by any significant rise of blood-pressure, but by a slight fall in most 
cases. Moreover, the tissue waste is much increased in fever, and at 



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190 SUBSTANCES ACTING AFTER ABSORPTION. 

the same time the food absorption is less than normally, so that many 
of the symptoms may be due to starvation of the tissues. The food- 
value of alcohol is unchanged by the presence of fever (Ott) ; it demands 
less energy from the digestive organs than fats and starchy foods, and 
has a higher value as a producer of energy than sugar. It cannot 
supply the place of the nitrogenous foods, but given along with 
them, may lead to a greater economy of the tissues. Strong wines 
or diluted spirits are generally employed here and ought to be given 
in small quantities frequently. 

Alcohol was formerly advocated especially in septic conditions, and 
here it may be of value on the same grounds as in acute fevers, 
although it does not seem to have any specific action in septic dis- 
ease, as was once believed. A protest has recently been raised against 
the use of alcohol in these cases, on the ground that animals subjected 
to alcohol succumb more readily to infection than controls which 
have received no treatment, and this has been shown to be true even 
when the dose of alcohol was proportionate to that often advised in 
the treatment of these cases in man (Laitinen). This is undoubtedly 
an objection of great weight, but it must not be forgotten that though 
alcohol may be deleterious in this way, this may be more than compen- 
sated for by its value as a food and by its narcotic effects allaying 
the nervous irritability and promoting sleep; this narcotic action may 
very well be conceived to be of benefit to man, while actually prejudicial 
to animals. 

In some chronic forms of nervous disease alcohol may also be of 
value, although its administration must always be guarded, owing to 
the tendency to the formation of the alcohol habit. Thus, in some 
forms of melancholia and of neuralgia it gives relief, and some authorities 
recommend its use in small quantities in cases of distress of mind from 
any cause, such as grief, business anxiety or depression; undoubtedly 
alcohol improves these conditions by its narcotic action on the brain, 
but the danger of the alcohol habit is so great that many physicians 
refuse to take the responsibility of prescribing the drug in these cases. 

In certain forms of brain defect, notably in epilepsy, alcohol often 
acts with unusual power and sometimes appears to cause a prolonged 
nervous disturbance which is very deleterious in these subjects. 

In chronic conditions of cachexia and loss of flesh in general, and 
during convalescence, alcoholic preparations are often advised simply 
as foods, and in these cases the ales, beers and porters are generally to 
be preferred to the others, provided always that the stomach is not 
irritated by them, as they contain other foodstuffs of value in addition 
to the alcohol. 

In poisonous snake bite, alcohol is generally administered in enor- 
mous quantities, either as whiskey or brandy, but it is really of no 
value in these cases. 

Alcohol is of value as a mild hypnotic, a comparatively small quantity 
taken before retiring being often sufficient to secure quiet and refreshing 
sleep. Beer, or spirits and water, is generally used for this purpose. 



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ALCOHOL 191 

Brandy has a certain reputation in the treatment of the milder 
forms of diarrhoea, while the other spirits have no effect in this condition. 
The way in which it acts here is unknown. 

In the prescription of alcohol, the ordinary spirits, brandy or 
whiskey, are very much more frequently advised than the pure 
preparations, as tie latter are more apt to pall upon the taste of the 
patient. Both of these spirits ought to be diluted with at least an 
equal quantity of water. The wines are more used in chronic condi- 
tions, although diluted spirits may be advised here also. Beers are 
employed only in debility unaccompanied by gastric symptoms. 

Alcohol can be given to children in relatively larger quantities than 
to adults, and again in old age no such reduction in the dose is required 
as in the case of many other drugs. Where -a tolerance for alcohol 
has been established, the dose has often to be more than doubled in 
order to have any effect, and in acute febrile conditions very large 
quantities of alcohol are often given without intoxication, though it 
seems questionable whether an equally beneficial result could not be 
attained with much smaller doses. In gastric irritation, most prepa- 
rations of alcohol are contra^indicated, but champagne is often of 
benefit in checking vomiting, especially that of pregnancy and of sea- 
sickness, this effect being due to the carbonic acid, not to the alcohol. 
In nephritis and other inflammatory conditions of the genito-urinary 
tract, alcohol is generally avoided on account of its supposed effects on 
the epithelium. 

In regard to the Habitual Use of Alcohol by healthy persons, all authori- 
ties agree that it is a luxury, that it is entirely unnecessary for the 
growth and maintenance of the body, and that it neither promotes 
greater healthfulness nor in any way retards the onset of disease. It is 
true that it-is utilized by the body as a food, but its value as such is 
limited because only small quantities can be taken without disturbance 
of the nervous system. At the same time it is difficult to prove that 
the moderate use of alcohol is injurious, for when taken after work 
it seems to cause no impairment of the capacity for work next day and 
often seems to remove the sense of fatigue. And in many it undoubt- 
edly promotes happiness and allays the worries and anxieties of life. 
Attempts have been made to show that even the moderate use of 
alcohol lessens the resistance to the onset of disease, but these have 
not been successful. There are, however, two considerations which may 
be brought against the use of alcohol even in the most strictly limited 
quantities. The first of these is drawn from the statistics of life insurance, 
in which it is found that the prospects of longevity are considerably 
better for total abstainers than for even moderate users of alcohol. 
The second is that in a small percentage of persons the moderate use 
of alcohol leads to chronic alcoholism. 

The habitual indulgence in alcohol to excess is more easily intelligible 
than some other chronic intoxications, for, unlike nicotine, alcohol 
is taken not only for its local effects on the organs of taste and on the 
mucous membranes of the mouth and stomach, but also for its action 



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192 SUBSTANCES ACTING AFTER ABSORPTION 

on the brain in numbing the consciousness of unhappiness, and this 
weakening of the higher sensibilities by drink is generally the object 
sought by the drunkard. He finds that under alcohol his habitual 
depression disappears, and he loses the sense of degradation and remorse 
which possesses him when sober. The depression returns in exaggerated 
form after the effects of the drug have passed off, but it can be removed 
again by the same means, and in this way the habit is formed, each 
successive dose being rendered necessary by the depression produced 
by its predecessor. This descent into chronic drunkenness fe facilitated 
by the lessening of the self-control, owing to the action of alcohol on the 
brain. The victim may form the best of resolutions, but his impaired 
will power and self-control are unable to carry them out. 

The symptoms of Chronic Alcoholism are unfortunately common, but 
may be treated better in detail in connection with various forms of 
disease, with which they are associated more closely than with the 
effects produced by the medicinal use of the drug. The earliest symp- 
toms are generally observed in the stomach, throat and larynx, and 
consist of a chronic catarrh, which is often accompanied by skin affec- 
tions, such as injection of the cutaneous vessels (especially of those of 
the face), acne, or pustular eruptions. Fatty degeneration occurs in the 
liver especially, and is said to be accompanied by a marked decrease in 
the lecithin and other lipoids of the cells. Cirrhosis of the liver is not 
now believed to be the direct result of alcoholism. Fatty degeneration 
is also found in the arterial walls throughout the body, and favors the 
development of atheroma and arteriosclerosis, which may lead to 
small aneurysmal dilatations, ecchymoses, or apoplexy. The heart 
undergoes more or less fatty change, which is accompanied by dilatation 
and weakness. In the central nervous system, the nutrition is imperfect 
owing to the vascular changes, but in addition to this, alcohol has a 
special action on the neurons, which is betrayed by the disappearance 
of the chromatin granules, and eventually by shrinkage of the whole 
cell. These alterations in the central nervous system lead to impairment 
of memory, self-control and the other higher mental processes. Tremor, 
convulsive attacks, hallucinations and mania are eventually followed 
by idiocy and paralysis in the worst forms of the disease. The periph- 
eral nerves seem to be acted on directly as well as through the changes 
in the centres, for neuritis has been frequently observed, ending in 
local paralysis. A form of amblyopia commencing by atrophy of the 
retinal ganglion cells and later extending to the fibres of the optic 
nerve has recently received some attention; it is much more readily 
elicited by methyl than by ethyl alcohol. A characteristic result of 
chronic alcoholism is delirium tremens, an acute attack of insanity, 
which is liable to occur after any shock, such as haemorrhage or acute 
disease, but which is said to be also produced by the sudden withdrawal 
of alcohol, and sometimes occurs without any apparent immediate 
cause. It is characterized by tremor, perspiration, sleeplessness, fear, 
excitement, and hallucinations of the various senses, which differ from 
many other hallucinations of insanity in consisting of the multiple 



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ALCOHOL 193 

appearance of the same object. These objects are often animals, such 
as snakes, rats, dogs, but the hallucinations are not confined to those 
of sight, for whispering voices are complained of not infrequently. 

The more severe forms of chronic alcoholism are confined almost 
entirely to the drinkers of undiluted spirits. Beers and wines seldom 
cause any distinct lesions in the brain in themselves, unless spirits are 
also indulged in. The abuse of the weaker preparations of alcohol is 
always liable to lead to that of the stronger, however, as tolerance is 
established and the former lose their effect. The combination of spirits 
and malt liquors is said to be more liable to produce delirium tremens 
than the abuse of either alone. 

The disastrous effects of the abuse of alcohol are seen in the statistics 
of the hospitals, prisons, and asylums in nearly all countries, but more 
especially in those in which the population is addicted to spirits. A 
large percentage of crimes are admittedly done under the influence of 
alcohol or as a direct result of alcoholic excess, which is also responsible 
for a large part of the poverty and misery of the lowest classes of the 
population. A considerable proportion of the admissions to lunatic 
asylums is also often ascribed to alcoholism, although Mott has pointed 
out that this factor is not infrequently exaggerated. And it must be 
taken into account that only the more extreme cases come under the 
categories of criminals or lunatics, and the enormous number of cases 
of disease directly caused or aggravated by the lesions due to alcohol 
escapes recognition. At the same time, it is beginning to be appreciated 
that chronic alcoholism itself is probably due to a mental defect, so that 
in a certain number of these cases of insanity and crime, the over- 
indulgence in alcohol must probably be considered a symptom and 
not a cause. On the other hand, alcoholic excess aggravates tie mental 
defect in these cases both by its direct action and through the social 
and economic disabilities which arise from it; and this aggravation 
of a congenital weakness can be avoided only by abstention from 
alcoholic beverages. Attempts have been made of late years to demon- 
strate that the effects of alcohol are hereditary, that the children of 
alcoholists supply a larger proportion of cases of insanity and crime 
than those of the rest of the population. It would seem more probable, 
however, that the alcoholic excesses of the parent have no direct effect 
on the offspring, except in their nutrition at birth, but that the mental 
defect which leads to alcoholic excess in the one generation is inherited 
and leads to crime or insanity in the next. The deleterious effect 
of the alcoholic habit in the parent on the nutrition of the offspring 
is a well-established fact. It has been shown experimentally by 
Hodge, who states that only a small percentage of the puppies born 
of parents treated with alcohol survive, and further that they are 
peculiarly liable to infectious disease, such as distemper. 

The treatment of acute alcoholic intoxication is to evacuate the stomach 

by means of the soft elastic tube. The patient ought to be put in bed 

and kept warm, as there is a tendency to a marked fall in the body 

temperature. In case of great congestion of the brain, cold may be 

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194 SUBSTANCES ACTING AFTER ABSORPTION 

applied in the form of ice-bags to the head, and some authorities recom- 
mend bleeding. In cases of extremely deep unconsciousness, nervous 
stimulants, such as caffeine or strychnine, may be had recourse to, and, 
as a last resort, artificial respiration. 

Chronic alcoholism is to be treated by the withdrawal of the poison, 
and this is best done gradually, as the immediate stoppage may lead to 
delirium tremens. It is often necessary to incarcerate the patient in 
some retreat. A large number of drugs have been advocated in these 
cases, some of them, such as opium, acting as substitutes for alcohol, 
others (capsicum) replacing the local action on the stomach. The use 
of opium and other narcotics may, however, lead to a craving for these 
which is quite as serious as the original condition. Another method 
of treatment, which appears to be successful in some cases, is the addi- 
tion of nauseating drugs such as ipecacuanha or apomorphine to the 
alcohol which is supplied to the patient. The association of nausea 
with liquor eventually becomes so strong that alcohol in any form 
becomes distasteful. The organic lesions must be treated individually. 

The treatment of delirium tremens generally consists in the use of 
chloral or opium to lessen the excitement. It is often necessary, or at 
any rate advisable, in these cases to allow small quantities of alcohol, 
as the sudden withdrawal may aggravate the condition. 

Bibliography. 

An admirable critical survey is given by Abel, Atwater, Chittenden, and Welch, in 
Physiological Aspects of the Liquor Problem, Boston and New York, 1903. 

O. Rosenfeld. Der Einfluss des Alkohols auf den Organismus. Wiesbaden, 1901 
(very complete bibliography). 

Binz, Jaksch. Verhandl. des VII, Congress f. innere Medicin, 1888, pp. 70, 86. 

Bunge. Die Alkoholfrage, Leipsig, 1887. 

Jacquet. Die Stellungsnahme des Antes sur Abstinenzfrage, Basel, 1896. 

PofU. Arch. f. exp. Path. u. Pharm., xxxi, p. 281. Schmiedeberg's Festschrift, p. 427. 

Chittenden and Mendel. Amer. Jour, of the Med. Sciences, 1896, p. 35. 

Kraepelin. Ueber die Beeinflussung einfacher psychischer Vorgange durch einigc 
Arsnernittel, Jena, 1892. And in Kraepelin's Psychologische Arbeiten, i-iv, passim. 

River 8. The influence of alcohol and other drugs on fatigue, London, 1908. 

Ndcke. Deutsch. Arch. f. klin. Med., xxv, p. 416. (Delirium tremens.) 

Boer. Arch. f. [Anat. u.] Phys., 1898, p. 283. 

Spiro. Munch, med. Woch., 1901, p. 1871. 

Chittenden, Mendel, and Jackson. Amer. Journ. of Physiol., i, p. 164. 

Brauer. Ztschr. f. physio 1. Chem., xl, p. 182. 

Pring8heim. Biochem. Ztschr., xii, p. 143. 

Reid Hunt. Hygienic Laboratory Report, fao. 33, Washington, 1907. 

Durig. Arch. f. d. ges. Phys., cxiii, pp. 213. 341. 

Schumberg. Arch. f. [Anat. u.l Phys., 1899, Suppl., p. 289. 

Scheffer. Arch. f. exp. Path. u. Pharm., xliv, p. 24. 

Hellsten. Skand. Arch. f. Phys., xvi, p. 139; xix, p. 201. 

Dixon. Journ. of Phys., xxv, p. 346. 

Loeb. Arch. f. exp. Path. u. Pharm., lii, p. 459. 

Kochmann. Arch, internat. de pharmacodyn., xii, p. 329. 

Bachem. Ibid., xiv, p. 437. 

Schnyder. Pfluger's Archiv, xciii, p. 451. 

Ro8emann. Pfluger's Archiv, lxxvii, p. 405; lxxxvi, p. 307. 

Neumann. Arch. f. Hyg., xxxvi, p. 1; xii, p. 85. 

Atwater and Benedict. U. S. Dept. of Agriculture Exper. Station Bulletin No. 69. 

Oti. Arch. f. exp. Path. u. Pharm., xlvii, p. 267. 

Grehant. Journ. de l'Anatomie, xxxvi, p. 143. 



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ETHER AND CHLOROFORM 195 

Abbott. Journ. of Exp. Med., i, p. 477; Univ. of Pennsylvania Med. Bull., Sept., 1902- 

Laitinen. Ztschr. f. Hygiene, xxxiv, p. 206; lviii, p. 139. 

BircK-Hirschfeld. Arch. f. Ophthalmologic, lii, p. 358; liv, p. 68. 

Paton and Eason. Jour, of Physiol., xxvi, p. 166. 

Harrington. Boston Med. and Surg. Journal, 1903. (Germicidal action.) 

BuUer and Wood. Journ. of Amer. Med. Assoc, 1904, ii. 

Brooks. Journ. Amer. Med. Assoc, 1910, ii, p. 372. 

Mendel. and HUdilch. Amer. Journ. Physiol., xxvii, p. 1. 

Sweisheimer. Deutsch. Arch. f. klin. Med., cix, p. 271. 

VdUz. Arch. f. d. ges. Phys., cxxxviii, p. 85; cxlii, p. 210; cxlv, p. 210. 

T&gel, BreHna, and Dung. Biochem. Ztschr., 1, p. 296. 

Dennig, Hindelang, and OrUnbaum. Deutsch. Arch. f. klin. Med., xcvi, p. 153. 

MoU. Brit. Med. Journ., 1911, i, p. 1381. 

2. General Anaesthetics— Ether and Chloroform. 

The term general anaesthetics is employed to indicate substances 
used to produce unconsciousness sufficiently complete to allow of sur- 
gical operations being performed. In the history of medicine there 
are repeatedly abscure allusions to substances used for this purpose, but 
it was not until the end of the first half of the nineteenth century that 
the era of surgical anaesthesia really opened. In 1798 Davy advised 
the use of nitrous oxide as an anaesthetic, but no practical use was 
made of his suggestion, and Wells may be said to have rediscovered 
this property of the gas in 1844, though his efforts to introduce it into 
general use met with no greater success than Davy's. Long used 
ether in 1842-1843 in surgical operations, but did not give any pub- 
licity to his discovery, and the honor of demonstrating publicly the 
practical use of ether in surgery must be awarded to Jackson and 
Morton in 1846. In 1847 Simpson introduced chloroform to the 
medical profession as a substitute for ether, over which he supposed 
it to possess several advantages. Its pharmacological action had been 
examined some months earlier by Flourens, but Simpson appears 
to have made his investigations quite independently. Chloroform 
soon ousted ether in popular favor in Europe, and although in America 
a considerable number of surgeons continued to use it, ether had prac- 
tically fallen into complete disuse throughout Europe, save in Lyons, 
until a few years ago. The continually increasing number of accidents 
in chloroform anaesthesia has, however, caused a reaction to set in in 
favor of ether, and it seems probable that it will once more be reinstated 
as the rival, and perhaps as the superior, of chloroform throughout the 
world. Even in 1880, however, Kappeler could write that in Germany 
chloroform was used exclusively. 

Many attempts have been made to introduce other substances of 
the methane series as substitutes for the two generally recognized 
anaesthetics, but as yet no other has attained popular favor. Soon 
after the introduction of ether and chloroform, nitrous oxide gained a 
permanent footing as an anaesthetic for short operations. 

These anaesthetics are invariably given by inhalation and not by the 
stomach, as it is found that the exact depth of the narcosis can be 
much more easily controlled by the former method. Both the absorp- 



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196 SUBSTANCES ACTING AFTER ABSORPTION 

tion and excretion of these drugs occur almost entirely by the lungs, 
according to the ordinary physical laws of the absorption of gases by 
fluids. The more concentrated the vapor of chloroform in the lungs, 
the greater is the quantity absorbed into the blood and the deeper the 
narcosis. By regulating the proportion of the vapors in the air in- 
haled, therefore, an ansesthesia of any desired depth may be induced. 
The degree of narcosis and of danger is not indicated by the actual 
amount of the anaesthetic which has been used, but by the concentra- 
tion of the vapors which have been inhaled; one patient may in the 
course of a long operation, inhale and again exhale many ounces of 
chloroform without danger, while another may be thrown into a position 
of extreme peril by the inhalation of a few drops of chloroform in con- 
centrated vapor. 

Symptoms. — The action of chloroform and ether may be divided 
into three stages: (1) that of imperfect consciousness; (2) that of 
excitement; (3) that of anaesthesia. 

The first effect of their application is a feeling of asp^vxi^ ( which is 
e specially marked in the case of ether, and of warmth of the fac$ p,nd 
hrnH irntl irvrntii n-^Y ot the whole body. Th e senses become less a cute, 
the patient seeming to see only through a veil of mist, and the voices 
of those in the immediate neighborhood appearing to come from a 
distance. Ringing, hissing and roaring in the ears and a fefiliag_£f_ 
s t j ffnftsft and of inability to move the limbs herald the approach of 
unconsciousness. With the exception of the first feeling of suffocation, 
the sensations are generally pleasant. D uring this stage the face is 
generally flush ed, the pupils enlarged, the pjilftg is ymp JEESE acSIefat^T" 
flB^th? r^pifflTirr n may be rendered irregular by the sen^ of suffocation , 
or irjfiy hp; glight ly q vufke n ^ H Even at this early stage sensation is 
blunted. 

The second stage of * Y ™|p™gnti_va ries extremely in different indi- 
viduals. In some cases, especiallyirT children, it is entirely absent, 
and in others its presence may be indicated merely by tremor, by the 
stretching of the limbs, or by irregularities in the respiration, but in 
the majority of cases of ansesthesia it is much more marked. It often 
begins by movements of the arms, designed either to push away the 
inhalation mask or to enable the patient to rise; soon his other muscles 
are involved in the movement; he struggles, shouts, sings, groans, 
or bursts into laughter. The movements are not generally uncoor- 
dinated, but are evidently the result ofji ome dr^pm-lik e condition of 
the consciousness, and these dreams are often connected with the 
operation or with the surroundings of the patient before the inhalation 
began. They are, of course, determined largely by his natural mode 
of thought — one person prays aloud and sings hymns; another abuses 
the surgeon, the hospital and all his recent surroundings, while yet 
another is overcome with the fear of impending death and laments 
his unfortunate position. In this stage the pulse is f^ftrpMy Tok- 
ened, the skinjs flushed &nd often ^cyanotic*, the respiration is extre mely 
"Irregular from the struggling, and the pupil continues somesEEZ 



ETHER AND CHLOROFORM 197 

dil ated. If the anaesthetic be pushed, however, the movements soon 
become less powerful, the muscles relax and the stage of anaesthesia 
sets in. 

In the third stage the face assumes a ea1m r death-like appearance 
from ifa* relaxation of t^ Q HMwoles, + h " pupils contract someachat fl "d 
dn nn{ rear* t^ lffi+ The reflex es 'tiwp^j nw * " f * h " ]<agf fn 6° 
H ; "fft^ ^ rlrvnir* of tW Av^liHn ^m inching the. H\m *fi The pulse 
is'^generally somewhat slow and weak; the face is pale in chloroform 
anaesthesia, but may be suffused and cyanotic after ether. The respira- 
tion is slow and shallow, but regular. This stage of anaesthesia may 
be kept up for hours without much change by the repeated inhalation 
of small quantities, although the pulse tends to become weaker and 
the respiration shallower unless the greatest care be exercised, and 
the body temperature invariably sinks. When the admini stration 
^£eas§s, the p atient passes again through the excitement stage, which. 

however iff nf)f generally as vi^ent, although it may be more pr o- 

longed, and then often sinks into sleep, which lasts several hours. 
Not infrequently, however, instead of sleep, nausea, giddiness and 
vomiting continue for some time after the recovery of consciousness. 

In surgical anaesthesia, the third stage is often interrupted by short 
intervals of semi-consciousness and slight excitement if the adminis- 
tration of the drug be interrupted occasionally. 

The use of these drugs is so widespread, and the indications of 
danger in anaesthesia are so important that a more detailed account 
of the alterations observed during their use in the human subject may 
be inserted here. 

The pulse is often somewhat accelerated before anaesthesia, owing to 
the anxiety and nervousness of the patient, and in the first, and still 
more the second stage, a further acceleration may occur from the same 
cause, although in other instances marked slowing of the pulse may 
set in here from reflex, stimulation. When the stage of anaesthesia is 
reached, the pulse becomes slower and weaker than normally, and this 
change increases with the depth of the anaesthesia produced. It 
remains perfectly regular, however, in ordinary cases, and, in fact, 
unless the anaesthesia has reached an extremely dangerous stage. In 
very prolonged, deep anaesthesia the weakness of the pulse may give 
rise to anxiety, especially if the temperature of the body is very low. 

The respiration is generally fairly regular until the second stage, 
save that the breath may be held for some time owing to the choking 
sensation, and a deep gasp may follow; coughing is occasionally met 
with, especially in the first stage of ether anaesthesia. In the second 
stage, the respiration is extremely irregular when the excitement is 
violent. The respiratory muscles are involved in the general convul- 
sive movements, so that no air whatever can enter the lungs for several 
moments, and then several deep gasps may follow and load the blood 
with concentrated vapor. During the third stage the respiration 
becomes regular but shallower and slower than before the anaesthetic 
was applied, and if the operation be prolonged, the weakness of the 



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198 SUBSTANCES ACTING AFTER ABSORPTION 

respiration may give rise to alarm. Large quantities of saliva and 
mucus may hinder the respiration and require removal, and a common 
occurrence is the production of snoring from the falling back of the 
tongue, and this may also require attention. 

The behavior of the pupU is of some importance in anaesthesia. 
During the first and second stages it is generally somewhat dilated, 
but as soon as. complete unconsciousness is attained, it becomes rather 
narrower than it is normally. As the patient recovers, the slight 
dilatation recurs, and if the respiration and circulation be danger- 
ously weak, this dilatation also occurs in most cases. Dilatation of 
the pupil in the stage of anaesthesia, therefore, indicates danger, unless 
it is accompanied by symptoms of returning consciousness, such as 
reflex movements and vomiting. 

TW faypersfifirrflftn of saliva and of bronchial mucu s is much more 
marked in ether than in chloroform anaesthesia. Fojiniing occurs so 
frequently during anaesthesia that it may be looked upon rather as one 
of the attendant phenomena than as an accident. It may set in prac- 
tically at any time, but is more often seen in the late than the early 
stages, and more frequetly when the anaesthetic is applied soon after 
a meal than when the stomach is empty. 

Action. — The action of ether and chloroform on the Central Nervous 
System is evidently similar to that of alcohol, although the phenomena 
habitually elicited in the use of the former are very rarely produced 
by the latter. In all three intoxications, however, there may be ob- 
served the stages of lessened consciousness, of excitement, and of total 
unconsciousness. Alcohol was formerly administered in very large 
quantities to allow of surgical procedure, and ether has not infrequently 
been used as an habitual intoxicant. 

These anaesthetics produce the same progressive paralysis of the 
central nervous system as alcohol, commencing with the highest cerebral 
functions, those of self-control, and passing downward through the 
lower intracranial divisions. The spinal cord is affected before the 
medullary centres, which are the last part of the central nervous system 
to become paralyzed. The question arises here, as under alcohol, 
whether a stage of stimulation does not precede the depression of the 
motor functions, and it is certainly difficult to believe that the wild 
excitement often seen in the second stage is due to the suppression 
of the self-control only. It may be remarked that the depression of 
the motor areas has been shown experimentally in the case of chloroform 
and ether, a much stronger electric stimulus being necessary to produce 
movement of a limb after these drugs than before them; their excita- 
bility by the electric current has not been tested, however, during the 
excitement stage. 

The anaesthesia is not produced equally rapidly throughout the 
body, the back and the extremities first becoming insensible, then 
the genital organs and rectum and, last of all, the parts supplied 
by the trigeminus. The reflexes of the spinal cord are depressed 
by small quantities of ether or chloroform and are finally paralyzed 



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ETHER AND CHLOROFORM 



199 



Fia. 6 



completely. The character of the reflex is changed, for Sherrington 
finds that stimulation of an afferent nerve which normally causes a 
reflex contraction, may under chloroform be followed by inhibition. 
A similar reversal has been described in 
the medulla oblongata by Bayliss. 

Both of the anaesthetics affect the sen- 
sory functions before the motor, as is 
shown by movements occurring long after 
all sensation has disappeared. And Bern- 
stein found in some cases that if chloroform 
was excluded from an area of the spinal 
cord by destruction of part of the pia 
mater, reflexes could be elicited in other 
parts of the cord by the irritation of sen- 
sory nerves whose cells lay in the protected 
area, while irritation of nerves, the cells of 
which were exposed to the chloroform, had 
no effect (Fig. 6). In the protected area 
there were, of course, both motor and 
sensory cells, and an impulse reaching the 
protected sensory cell was transmitted to 
the neighboring and also to more distant 
motor cells. An impulse reaching the 
exposed sensory cell, on the other hand, 
was not transmitted to the motor cells, 
although these were shown by the first 
part of the experiment to be capable of 
stimulation. This experiment is best 
interpreted by supposing that the anaes- 
thetics act first on the first synapse in the 
cord that is met by an afferent impulse. 
Later, however, the motor cells or their 
synapses are also paralyzed, as is shown 
by stimulation of the cord having no effect, 
even when the respiration is still active. 

Electrical stimulation of the cerebral 
motor areas produces movement for some 
time after sensation has been lost, but as 
the anaesthesia becomes deeper, their irri- 
tability disappears. Finally the medullary 
centres are also paralyzed by the anaes- 
thetic. There is some evidence that they 
are first stimulated directly by chloroform 
and ether (page 200). The medullary 
centres are liable to be affected by reflex 
stimulation up to the moment at which 
they cease to send out impulses, for the 
respiratory centre responds to stimulation 




Diagram of the spinal cord: 
A-B part of the cord exposed to 
the action of chloroform; B-C 
part unaffected. A sensory im- 
pression traveling by the pos- 
terior root fibre D does not elicit 
a reflex movement, but one reach- 
ing the cord through the unaf- 
fected root E causes reflex 
impulses, which may be sent 
out by the motor cells F, F in 
the unaffected area, or by F' % F' 
in the poisoned area. The cells 
of the anterior horns F, F' and 
the dendrites surrounding them 
are, therefore, intact after the 
reflex arc is interrupted at some 
other point. 



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200 



SUBSTANCES ACTING AFTER ABSORPTION 



of the superior laryngeal nerve as long as the respiration continues. 
It is possible that the motor cells are not directly paralyzed by the 
drug, but can only send out impulses received from the sensory cells, 
and that the paralysis of these is the cause of the asphyxia. 

Shortly stated, the direct action of chloroform and ether on the central 
nervous system is a descending depression and paralysis which affects 
the medullary centres last of all, and which involves the synapses on the 
sensory and receptive tracts sooner than the motor neurons. 



Fio. 7 



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Tracings of the respiration (upper) and blood-pressure (lower) of a rabbit at the begin- 
ning of ether inhalation, which is indicated by the arrow. The respiration immediately 
br 30* -? very shallow, and then after a pause becomes slow and deep (reflex inhibition). 
The oiood-pressure rises and the pulse is slowed by reflexes acting on the vasomotor and 
vagus centres. The normal condition is restored at once when the ether is removed 
from the nose at A. 

The action of chloroform and ether on the Respiratory Centre is 
partly direct and partly indirect. In the first stage, the respiratory 
movements may be slowed or stopped temporarily by a reflex action 
set up by the irritation of the terminations of the trigeminus in the 
nose and throat and of the pneumogastric in the larynx and bronchi, 
but this interruption is only of short duration and may be induced by 
any irritant applied to the respiratory passages (Fig. 7). During the 
second stage the respiration is often rendered irregular by the convulsive 
struggling, which produces alternately periods of asphyxia and deep 
gasping movements. There is further some evidence that the respiratory 
centre is rendered more irritable by low concentrations of the anaesthetics, 



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ETHER AND CHLOROFORM 201 

more especially by ether. During the third stage, the respiration is 
regular and no reflex disturbance occurs, because the sensibility is so 
dulled that the continued irritation of the nerve ends causes no reflex 
response. In this stage the breathing is slow and shallow, mainly because 
the ordinary movements of the body are suppressed and thus less 
carbonic acid is carried to the centre, that is, the normal stimulus of 
the respiratory centre is diminished; partly, because the centre is 
reduced in excitability by the direct action of the anaesthetic. If the 
drug be pushed, the weakness and slowness of the movements increase, 
until the respiration ceases entirely from paralysis of the centre; in 
addition to its direct action on the centre, chloroform affects the 
respiration in deep anaesthesia by inducing anaemia of the medulla 
through its effects on the circulation. 

The effects of the anaesthetics on the Circulation are extremely com- 
plicated, because the heart, the medullary centres and the peripheral 
vessels are all involved in the action, and in addition the changes in 
the respiration and the stage of excitement add to the difficulty of the 
subject. The changes observed in the pulse in man have already been 
described (p. 197). The blood-pressure in man has been found to be 
reduced by chloroform even in the earlier stages, and in deep anaesthesia 
the fall may be very marked. Under ether the pressure rises slightly 
in the first and second stages, partly from the reflexes arising from the 
local irritation, partly from the muscular movements, and partly 
perhaps from stimulation of the vasomotor centre. During complete 
anaesthesia it falls again to slightly above the normal or a few milli- 
meters below it, but never reaches a point indicating grave circulatory 
disturbance (Blauel, Cook and Briggs). 

In animals, the first change in the blood-pressure is often a slowing 
or even standstill of the heart from the irritation of the air passages 
stimulating the inhibitory centre reflexly. The blood-pressure may 
thus fall abruptly, but in other instances the inhibition of the heart 
may be compensated by vasoconstriction from reflex stimulation of the 
vasomotor centre, so that the blood-pressure may rise while the h t'is 
slowed (Fig. 7). Later, the blood-pressure falls slightly in chloroform 
anaesthesia, but strong vapor causes a marked and dangerous fall. 
The heart survives after the respiration fails in most experiments but 
the blood-pressure is very distinctly lower at this time (Fig. 8). Under 
ether the blood-pressure often is slightly lower, but it remains much 
higher than under chloroform when the respiration fails (Fig. 9). The 
cause of the fall in blood-pressure under chloroform has been much 
disputed, but is now generally ascribed to the action on the heart. 
Ether being less poisonous to the heart has a correspondingly slight 
action on the blood-pressure. 

Heart. — The frog's heart under chloroform or ether beats more 
slowly and more weakly, and at the same time undergoes a certain 
amount of dilatation, all owing to the paralyzing effects of these drugs 
on the cardiac muscle. 

The effects on the mammalian heart under chloroform are very 



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202 



SUBSTANCES ACTING AFTER ABSORPTION 



similar. The slowing is not so marked, however, as the weakness and 
the dilatation, so that the rhythm of the pulse does not indicate the 



Fig. 8 




The respiration (lower tracing) and blood-pressure (upper tracing) in chloroform anaes- 
thesia in a cat. At C strong vapor was inhaled and a rapid fall in the blood-pressure 
began. The respiration ceased, the heart continuing to beat for some time. (Contrast 
Fig. 9.) 

extent to which the heart is affected. The auricles are weakened by 
smaller quantities than the ventricles, which relax more completely 

Fig. 9 




Respiration (lower tracing) and blood-pressure (upper tracing) of a cat under ether. 
At E strong vapor was inhaled and soon afterward the respiration ceased, while the 
blood-pressure remained high for some time afterward. (Contrast blood-pressure in 
Fig. 8.) 

in diastole, however (Fig. 10). The diminution in the strength of the 
auricles progresses rapidly, while the ventricular dilatation soon reaches 



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ETHtiR AND CHLOROFORM 203 

a maximum and is accompanied by lessened force of contraction. The 
auricular weakness soon becomes so great that practically no blood is 
expelled by its systole, and the slowing of the heart, which has not been 
very marked up to this point, becomes distinct. The ventricular con- 
tractions next become extremely weak and occasionally fail entirely, 
and soon afterward the heart comes to a standstill in diastole. In 
its w r eakened state, the heart can be inhibited more easily than usual, 
and vagus stimulation may arrest it finally, the contractions not 
returning after the stimulation ceases (Embley). 

When ether is inhaled in high concentrations the changes in the 
heart resemble those under chloroform, but it is difficult to elicit the 
extreme weakness and the standstill unless asphyxia is present also. 

Fig. 10 




Myocardiographic record of the movements of the right auricle (upper tracing) and 
right ventricle (lower tracing) of the dog during the inhalation of concentrated chloro- 
form vapor. During systole the lever attached to the auricle moves from £>' to S', that 
attached to the ventricle from D to S. In diastole they return to D' and D respectively. 
At A, concentrated chloroform was inhaled. The excursion of the levers toward systole 
rapidly diminished, while that of the ventricle towards D was somewhat augmented. 
After a short time the auricle ceased in diastole, while the ventricle continued to beat, 
though much weakened. At B, the chloroform was shut off and the heart began to recover 
very soon afterward. 

The relative toxicity of chloroform and ether in the heart has been 
examined by perfusing their solutions in Ringer's solution through the 
coronary vessels; 0.001 per cent, of chloroform had a distinctly delete- 
rious action and 0.015 was sufficient to arrest it, while 0.4 per cent, of 
ether was required to stop the heart perfused in the same way. This 
indicates that chloroform is 25-30 times as poisonous to the mammalian 
heart as ether; the same proportion has been found in cold-blooded 
animals. 

Vessels. — It has been shown experimentally (Gaskell and Shore) 
that the vasomotor centre is first stimulated by chloroform, but this 
has very little influence on the calibre of the bloodvessels or on the 
arterial pressure, owing* to the direct action on the vessel walls and heart. 
In the later stages the vasoconstrictor centre undergoes some obscure 
change, so that sensory impulses which normally excite it and cause 



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204 SUBSTANCES ACTING AFTER ABSORPTION 

constriction of the vessels, now inhibit it and cause dilatation of the 
vessels (Bayliss). The vasodilator centre continues to respond in its 
normal way to sensory impulses. Ether seems to have little or no 
direct action on the vaso-constrictor centre, but the dilatation of the 
skin vessels indicates that it excites the vasodilator function. 

The direct action on the vessel walls seems to be of greater impor- 
tance than that on the innervating centres. When chloroform circu- 
lates in the vessels in the concentrations used in anaesthesia it tends 
to relax them from a depressing effect on the muscle fibres; all the 
vessels are not equally affected, however, those of the splanchnic area 
dilating more readily than those of the limbs, which may even be con- 
stricted. Chloroform in higher concentration may tend to constrict 
also the mesenteric vessels, but this does not occur in the intact animal, 
in which such concentrations would prove immediately fatal to the heart. 

In practice, the low blood-pressure under chloroform is mainly due 
to the action on the heart; in less degree to the dilatation of the vessels 
in the abdomen. 

Ether dilates the peripheral vessels like chloroform when it is perfused 
through them, and if it is inhaled in abundance of air this dilatation 
occurs in the living animal and may cause a fall in blood-pressure. This 
is often absent however, because the direct vascular action is opposed 
by the vasomotor centre which is excited by an insufficient air supply; 
for in ether anesthesia there is very often present a partial asphyxia 
induced by the close approximation of the inhaler to the mouth and 
nose. 

Syncope in Anaesthesia. — In a certain number of experiments the 
reaction of the circulation to chloroform is very different from the gradual 
depression described above. In these, the heart suddenly becomes 
irregular or ceases to beat abruptly, the blood-pressure falls to zero, 
and after a few gasping respirations all movements cease (Fig. 11). 
This sudden heart failure often occurs in the early stages of anaesthesia, 
or when the inhalation is irregular or has been suspended. Embley 
has explained it by inhibitory stimulation from which the weakened 
heart cannot recover. But Levy attributes it to the onset of ventricular 
fibrillation and has brought a large amount of evidence for his view. 
This fibrillation is often the culmination of a series of irregularities, 
such as extrasystoles and tachycardia, but may not be preceded by these 
in all cases. It indicates a condition of abnormal irritability of the 
heart under chloroform, and other experiments have given some evidence 
for a phase of increased excitability preceding the depression ordinarily 
observed. This form of cardiac failure is very often final, but in a small 
proportion of cases the heart resumes its normal contractions and the 
animal recovers. Fibrillation is especially liable to occur from sensory 
nerve stimulation during light anaesthesia, and it is possible that here 
the excitatory effect on the heart is reinforced by reflexes through the 
accelerator apparatus or by an increased secretion of the suprarenal 
glands. It is not proved that the inhibitory nerves are involved in this 
form of heart failure, though there is some evidence in favor of this view. 



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ETHER AND CHLOROFORM 



205 



Ether does not seem to have any such action on the heart, and fibrilla- 
tion of the ventricle has not been observed under it. In fact, sudden 
circulatory failure under ether is a very rare occurrence, compared 
with chloroform. Henderson suggests that these rare fatalities under 
ether may be the result of a great reduction of the carbonic acid of the 
blood (acapnia), from excessive breathing during the excitement stage or 
during imperfect anaesthesia. Acapnia is 
known to act deleteriously on the heart, but FlQ - n 

further work is required before this view of 
the fatalities under ether can be regarded as 
established. 



The Muscles and Nerves are not affected by 
chloroform or ether when inhaled, but when a 
frog's muscle is exposed to an atmosphere of either 
of them, it is weakened, loses its irritability and 
eventually passes into rigor mortis; the limb mus- 
cles in mammals are weakened when strong solutions 
(0.1-0.2 per cent.) are perfused through them, but 
are unaffected by concentrations which arrest the 
heart in a few minutes. Waller has shown that 
when a frog's nerve is exposed to chloroform or 
ether vapor in weak dilution, its irritability is at 
first increased; strong vapor, on the other hand, 
abolishes the excitability temporarily in the case 
of ether,, generally permanently in that of chloro- 
form, which is much the more powerful nerve 
poison of the two. The sensory fibres are said to 
be paralyzed sooner than the motor when chloro- 
form or ether is applied to a mixed nerve (Pereles 
and Sachs), and some motor fibres of a trunk may 
remain unaffected, while others are paralyzed. The 
local paralyzing effects of ether have been elicited 
repeatedly in the human subject by its subcu- 
taneous injection, and have occasionally been fol- 
lowed by neuritis and permanent weakness. 




Tracing of the blood-press- 
ure (lower) and of the respi- 
ration (upper) of a cat under 
chloroform; failure of the 
heart (ventricular fibrilla- 
tion) immediately after vio- 
lent struggling. The blood- 
pressure falls rapidly, while 
deep, gasping respiration con- 
tinues for a short time and 
then ceases. (Levy.) 



Chloroform and ether dissolve the Red 
Corpuscles and free the haemoglobin when 
they are shaken with defibrinated blood out- 
side the body, and chloroform is said to 
retard the reduction of oxyhemoglobin by forming a loose combination 
with it; Da Costa holds that ether tends to destroy the red cells during 
anaesthesia, and advises caution in its administration in cases in which 
a diminution in their numbers may be of serious import. In the blood, 
chloroform is carried by the red cells for the most part, less than 10 per 
cent., being free in the plasma. It appears to form a loose combina- 
tion or solution in the cholesterin and lecithin of the corpuscles. Ether 
is said to be more equally distributed between the corpuscles and plasma. 

The amount of chloroform in the blood during the stage of anaesthesia 
is about 25-35 mgs. in 100 c.c. When the respiration fails the blood 
is found to contain 40-70 mg. per 100 c.c. (Buckmaster and Gardner). 



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206 SUBSTANCES ACTING AFTER ABSORPTION 

During the induction of anaesthesia the arterial blood contains more 
than the venous, part of the chloroform being taken up by the tissues 
as it passes through the capillaries. On the other hand, as the anaesthesia 
passes off, the venous blood contains more than the arterial, the anaes- 
thetic taken up from the tissues in the capillaries being eliminated 
in the lungs. Nicloux states that in light anaesthesia from ether the 
blood contains about 100-110 mgs. per 100 c.c, in deep anaesthesia 
130-140 mgs., while 160-170 mgs. per 100 c.c. proves fatal from failure 
of the respiration. The margin of safety in anaesthesia is thus narrower 
than is generally recognized, for the concentration in the blood necessary 
for anaesthesia is about half that which is fatal. 

The effects of chloroform and ether on the Pupil present some varia- 
tion in different animals, and, indeed, are not very constant in man. 
No entirely satisfactory explanation of their mechanism has been 
offered as yet. The dilatation of the pupils in the first and second 
stages is merely the accompaniment of the general excitement and 
anxiety, and is not specific. The contraction in the stage of uncon- 
sciousness is similar to that seen in natural sleep, and is evidently of 
central origin. The dilatation occurring during wakening or vomiting 
is evidently caused by the same process as that of the preliminary 
stages. Just before death the pupil dilates, and this may perhaps be 
attributed to the effects of asphyxia on the muscle of the iris, and is 
so. frequently observed in death from other causes that it cannot be 
regarded as a direct result of the chloroform. 

The local effects of the anaesthetics on the Alimentary Canal and 
Respiratory Passages are confined to irritation with resultant reflexes. 
Thus the profuse secretion of saliva and of mucus is due to the irri- 
tation causing increased activity of the glands reflexly, and can be 
arrested by atropine. It has been stated that the bronchial rhonchi 
are due entirely to aspirated saliva, but this is incorrect, as they occur 
in animals to which the anaesthetic has been given through a tracheal 
cannula. The irritation is much greater when concentrated ether 
fumes are inhaled than in ordinary chloroform anaesthesia. 

The vomiting which is so often a feature of anaesthesia may arise 
in part from the irritating action on the stomach of the chloroform 
or ether swallowed in the mucus, but is probably partly of central origin, 
for vomiting also occurs when ether is injected intravenously in man 
and also under nitrous oxide anaesthesia in some cases; here the local 
irritation can only play a small part, and the medullary centre is prob- 
ably involved directly. The ordinary movements of the stomach 
and intestine do not seem to be influenced by anaesthesia, unless when 
it is accompanied by asphyxia, when the peristalsis may be increased. 

.The Kidney appears to be affected in a certain proportion of cases 
of anaesthesia in man, as is shown by the appearance of albumin in the 
urine. Chloroform induces typical fatty degeneration occasionally, 
while albuminuria has been observed in a certain proportion of cases 
after ether. The proportion of cases in which this organ is affected 
seems to vary extraordinarily, some authorities finding albuminuria 



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ETHER AND CHLOROFORM 207 

in 30 per cent, of the cases where chloroform was used; while others 
could detect it in less than 8 per cent. Kemp ascribes the renal effects 
of ether to vasoconstriction, but this is not an immediate action of 
ether, but arises from partial asphyxia from the inhaler being applied 
too closely; when asphyxiation is avoided, albuminuria is hardly met 
with under ether, and most surgeons consider chloroform far more 
deleterious to the kidney. The secretion of urine is generally diminished 
during anaesthesia with chloroform or ether, from the reduced blood- 
pressure and imperfect aeration of the blood. After recovery from ether 
anaesthesia some diuresis may occur, or the urine may remain scanty 
for some hours. 

The Uterine Contractions during parturition seem little influenced 
by moderate anaesthesia, but are somewhat slowed in the deeper stages. 
Chloroform and ether pass into the foetal blood, and some experi- 
ments are recorded in which the foetus was killed by the inhalation, 
while the mother recovered. This may be caused either by the direct 
action of the drug on the young animal, or by the low maternal blood- 
pressure leading to its asphyxia. It does not seem dangerous to 
induce a moderate degree of anaesthesia during labor in human beings, 
although here, too, the effects on the child are shown by an increase 
in the nitrogen excretion in the urine for some days; some authorities 
attribute many of the diseases of the first days of life to the use of 
chloroform during labor, but the evidence is not convincing. 

The Temperature falls during anaesthesia of even ^hort duration. 
Thus Kappeler found it reduced 0.2-1.1° C. when chloroform was 
inhaled 15-40 minutes, and a fall of 3-5° C. has been observed during 
very long anaesthesia. This action is due partly to the greater output 
of heat through the dilated skin vessels, but mainly to lessened heat 
production from the diminished muscular movement. It is not neces- 
sary to assume, therefore, as some writers do, that the anaesthetics lessen 
the heat production by their direct effects on the tissues in general. 

Of late years a good deal of interest has been manifested in the 
effects of the anaesthetics on the Metabolism of the tissues, and it is now 
generally recognized that chloroform, in addition to its action on the 
central nervous system, produces marked changes in the nutritive 
processes of protoplasm. The simpler organisms, which are devoid 
of nervous structure, are killed in comparatively dilute solutions, and 
chloroform water, therefore, prevents or retards putrefaction and the 
fermentation of yeasts. It seems to hinder the action of some fer- 
ments, such as pepsin and rennet ferment, when added in compara- 
tively large quantities, but increases their activity in greater dilution. 
Plants cease to assimilate carbonic acid, but are not killed by chloro- 
form except in very large quantities. In the higher animals and in man, 
the processes of life and nutrition of the different organs also undergo 
alteration, quite apart from the effects on the nervous system. Thus fatty 
infiltration of various organs is produced by chloroform administered 
repeatedly and even by a single inhalation in some cases. The organs 
implicated in this change are the liver, heart and kidneys more espe- 



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208 SUBSTANCES ACTING AFTER ABSORPTION 

cially, but degeneration of ordinary muscle has also been observed occa- 
sionally. If this process attains a certain degree of development, it may 
lead to failure of the heart, but otherwise the tissues recover in the 
course of a few days. Traces of fatty infiltration have been observed 
after prolonged ether narcosis also, but they are so slight that no sig- 
nificance attaches to them from a practical point of view (Selbach). 
Given in small quantities for several months, chloroform leads to atrophic 
cirrhosis of the liver, and, to a less extent, of the kidneys, spleen and 
lungs, this cirrhotic change forming a sequel to preliminary fatty changes 
of the parenchymatous cells. In young adults chloroform has occasion- 
ally given rise to a form of liver affection which closely resembles 
acute yellow atrophy. In these cases after recovery from the anaes- 
thetic, the patient becomes restless and uneasy and in a few hours 
delirium and coma may appear. Jaundice, cutaneous haemorrhages 
(from a diminished amount of fibrinogen in the blood), tenderness over 
the liver suggest an affection of this organ, and in fatal cases it is 
found to present the same appearance as in acute yellow atrophy, the 
cells in the centre of the lobules having undergone necrosis; chemical 
examination proves that an acute autolytic destruction of the organ 
has occurred (Wells). In animals this necrosis is less liable to occur 
if the diet previously has been rich in carbohydrates, while fats seem 
to predispose to it. 

The effects of chloroform on the nutrition of the tissues are shown 
in the urine secreted during and after anaesthesia, though they are 
more marked when the drug is swallowed, from its being more slowly 
absorbed and thus acting for a longer time. The nitrogen eliminated 
is considerably increased, and the unoxidized sulphur shows a similar 
augmentation, and these would seem to indicate an increased protein 
destruction and a disturbance of the oxidation in the tissues; another 
observation pointing in the same direction is the appearance of creatin 
in the urine and the reduced excretion of creatinin. 

The carbohydrate metabolism is also impaired, for acetone and sugar 
are often present in the urine after chloroform, and it has long been 
known that diabetes is liable to be aggravated by this anaesthetic 
and may prove fatal. The sugar of the blood is increased and the 
glycogen of the liver diminished or absent, from a specific action on the 
liver cells (Paton). 

Bile pigment is said to occur in the urine in a considerable number 
of cases of anaesthesia with chloroform, especially one or two days 
after the administration. The chlorides and the acidity of the urine are 
augmented and this has sometimes been regarded as evidence that 
chloroform is decomposed in the tissues, but the chlorides are also 
increased by ether though not in the same degree. 

These effects of chloroform on the metabolism resemble very closely 
those of phosphorus poisoning, and have, like them, been ascribed to 
autolysis and the formation of acid in excess in the tissues. They 
seem to occur only after those substances of the fatty series in which 
chlorine is substituted, ether having little or no effect in producing 



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ETHER AND CHLOROFORM 209 

fatty degeneration or in changing the proportion of the sulphur com- 
pounds in the urine. An excess of sugar is found in the blood after 
ether anaesthesia in dogs and leads to glycosuria; this is due to changes 
in the liver, but probably arises from partial asphyxia during the inha- 
lation and not from any direct action of the ether on the metabolism 
(Hawk). 

Immunity. — Anaesthesia with' chloroform or ether reduces the resist- 
ance of the tissues and renders animals more susceptible to the invasion 
of bacteria and to the action of toxins. 

Distribution in the Body. — When chloroform or ether vapor is inhaled, 
it passes rapidly into the blood by diffusion and is distributed through- 
out the body, mainly by the blood cells in the case of chloroform, while 
the plasma carries a considerable amount of ether. The anaesthetic 
immediately begins to leave the blood for the tissues and appears to be 
taken up especially by the central nervous system, in which it is found 
in larger quantities than in the muscles, liver, or blood. This unequal 
distribution probably arises from the greater amount of lipoid substances 
in the central nervous system, which dissolve the chloroform and ether 
and retain them. This flow from the pulmonary alveoli to the blood 
and thence to the tissues lasts until the vapor tension is the same in 
each, and the amount in the brain is thus determined by that in the 
blood, which again depends on that in the alveoli. If the inhalation 
ceases, the tension in the lungs falls and a backward flow follows from 
the blood into the air and from the brain into the blood. 

The Excretion of both ether and chloroform takes place mainly by 
the lungs. Most of the anaesthetic is eliminated very rapidly, tut 
traces of chloroform are said to be found in the breath for twenty-four 
hours after the inhalation and even longer in cases in which there is a 
tenacious mucous secretion from the bronchi. As far as is known this is 
the only way in which ether is excreted, but small quantities of chloro- 
form escape by other channels, for it has been found in the urine, and 
is said to occur in the perspiration and the milk. 1 

Differences Between Chloroform and Ether. — Ether and chloroform 
resemble each other closely in their general effects, but differ in power 
and in other points of importance. Their relative strength as anaes- 
thetics is shown by a comparison of the vapor concentration of each 
in a hundred volumes of air required to induce anaesthesia. 

Chloroform. Ether. 

. 5-0 .7 1 . 5-2 . 5 I nsufficient to cause anaesthesia. 

1 . 3-3 . 5 Causes anaesthesia on prolonged inhalation. 

2.0 6.0 Arrests respiration after some time. 

The amount of anaesthetic in 100 c.c of the blood shows the same 
proportion. 

Chloroform. Ether. 

25-35 mgs. 100-140 mgs. Anaesthesia. 

40-70 mgs. 160-170 mgs. Respiratory arrest. 

1 The statement that some carbon monoxide is formed in the tissues from the oxi- 
dation of chloroform is erroneous. 
14 



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210 SUBSTANCES ACTING AFTER ABSORPTION 

The depressant effect of chloroform on the brain is thus 3-3§ times 
as great as that of ether, and its power to arrest respiration is about 
three times as great. The depressant action on the heart of chloroform is 
about 25-30 times that of ether, and the extremely dangerous cardiac 
syncope which is seen under chloroform is very rare under ether. Ether 
has to be given in more concentrated form to produce anaesthesia, and, 
therefore, produces more irritation of the air passages, as shown by the 
greater secretion of saliva and mucus, by coughing, and by the sensa- 
tion of asphyxia. Anaesthesia is produced with greater difficulty, more 
slowly and often less perfectly than with chloroform, and the stage of 
excitement is generally more violent and prolonged. But the pulse is 
not nearly so much affected as by chloroform; it may be somewhat 
slower than usual, but is full and strong. The concentration of chloro- 
form which is necessary to produce anaesthesia is very close to the con- 
centration which causes serious impairment of the heart's action, while, 
on the other hand, 3$ per cent, ether vapor is sufficient to maintain 
narcosis, but a very much stronger concentration is required to cause a 
dangerous condition of the heart. In the same way, the difference in 
the concentration required to produce anaesthesia and that which will 
stop the respiration is smaller in chloroform than in ether, and the 
anaesthetist has thus more leeway when he uses the latter. The changes 
in the metabolism following the use of chloroform are not produced 
to the same extent, if at all, by ether. 

Regarding the Choice of an Anaesthetic, it must be said that each has 
its advantages, but that ether is less liable to cause dangerous symp- 
toms than chloroform, and ought, therefore, to be used wherever special 
circumstances do not indicate the latter. Chloroform is always pre- 
ferred by the patient, for it causes less irritation and less feeling of 
suffocation, and it is often preferred by the surgeon because it induces 
anaesthesia sooner and less of it is required. In cases where excite- 
ment is to be avoided as much as possible, or in which very deep 
anaesthesia with complete muscular relaxation is required, and in irri- 
table conditions of the air passages, chloroform ought to be used rather 
than ether. In drunkards, ether sometimes fails to induce deep anaes- 
thesia, and in very hot climates anaesthesia with ether may be difficult 
and unpleasant to induce owing to its rapid evaporation, so that in 
these cases chloroform may be necessary. Lastly, where artificial lights 
are necessary (except the electric incandescent), or where the actual 
cautery is to be used, ether b dangerous on account of its inflammability, 
and chloroform is indicated. On the other hand, chloroform is specially 
contra-indicated in cases of fatty change of the heart and in renal disease. 
The disadvantages of both anaesthetics may often be avoided by inducing 
unconsciousness by chloroform and prolonging it by small quantities 
of ether. The effects of the prolonged use of chloroform are avoided 
in this way, and at the same time the excitement is less marked, and less 
irritation of the air passages is elicited than if the anaesthesia had been 
induced by concentrated ether vapor. 



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ETHER AND CHLOROFORM 211 

The Dangers of Anesthesia are caused only in part by the direct 
action of the ether or chloroform, for fatal accidents have occurred 
from objects such as false teeth or tobacco plugs falling into the air 
passages and causing asphyxia, while vomited matter has been drawn 
into the larynx in some cases. Very often the relaxation of its muscles 
permits the tongue to fall back into the throat, rendering the breathing 
labored and stertorous; this is at once relieved when the tongue is 
drawn forward. The accumulation of saliva and mucus or blood in the 
throat may lead to similar symptoms. In these accidents the chloroform 
or ether is only indirectly the cause, but in a large and ever-increasing 
number of cases, the fatal effects must be ascribed to the direct action 
of the anaesthetics. The proportion of accidents during anaesthesia is 
very difficult to estimate, and great discrepancies occur in the statistics 
of different surgeons. Thus, in one of the London hospitals, one death 
occurred from chloroform in 1236 cases of anaesthesia; Juillard gives 
one in 3258, McGuire one in 15,000, as the proportion of fatalities, 
while Lawrie gives a series of over 40,000 cases without a single death. 
A fair average would seem to be one death in 3000 chloroform inhala- 
tions. The statistics of ether fatalities also vary from one death in 
3000 to one in 16,000 cases, but probably one in 10,000-12,000 cases 
would represent the average mortality. 1 

The Cause of Death in anaesthesia has been a subject of discussion 
for over fifty years, and it is only now being recognized that there are 
at least two different forms of fatality which may occur. The first 
of these may be termed Cardiac Syncope, and occurs chiefly in chloro- 
form anaesthesia, to which it contributes the greater part of the fatali- 
ties. In these cases it is generally stated that the pulse suddenly 
disappears, the patient's face assumes a death-like pallor, the reflexes 
fail and the pupils dilate. The breathing suddenly becomes deep and 
labored (this often being the first symptom observed) and ceases after 
a short time. This accident is generally stated to occur in the early 
stages of anaesthesia, often before the operation has begun, but it is also 
met with after vomiting and other interruptions to a smooth course of 
anaesthesia. No explanation of the fatality was given until Embley's 
and Levy's researches on animals showed that a similar sudden heart 
failure may be observed experimentally. Embley regards these accidents 
as the result of excessive and abnormal inhibitory activity, and it is not 
impossible that the inhibitory apparatus may be involved in some of 
them. But Levy's explanation (p. 204) that the ventricle passes into 
fibrillation is more satisfactory and more in accordance with the clinical 
observations. The conditions which favor the onset of this condition 
are still obscure. Imperfect anaesthesia is obviously one of them, 
but this may conduce to the fibrillation either through permitting 
reflexes to act on the heart, or by throwing that organ into the state of 
irritability in which fibrillation is liable to occur. Fibrillation has not 

1 Gurlt's careful statistics of 330,000 cases of anaesthesia gave a mortality of 1 in 2000 
for chloroform and 1 in 5000 for ether, but these both seem unusually high. 



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212 SUBSTANCES ACTING AFTER ABSORPTION 

been shown to occur under ether, and sudden cardiac syncope is a 
very rare occurrence under it and has not been investigated except by 
Henderson, whose views have been given already (p. 205). 

A second form of accident in anaesthesia may be termed that from 
Overdosage and is less likely to be fatal. In this form the respiration 
becomes shallower and finally ceases while the pulse can still be felt, 
or the heart beat can still be felt or heard. The interval between 
the failure of the breathing and that of the pulse varies in different 
accounts and in some both are said to have disappeared simultaneously. 
But in these cases the gasping respiration is not seen, which is character- 
istic of the cardiac syncope. This accident occurs more especially when 
the anaesthetic has been pushed, or after prolonged inhalation. It 
may occur under chloroform or ether, and the majority of fatalities 
under the latter appear to be of this character, while the great bulk 
of chloroform deaths are due to cardiac syncope. This death from 
overdosage is easily elicited in animals (Figs. 8 and 9), and has been 
the subject of a large amount of experimental investigation, which has 
been directed chiefly to the question whether the respiration or the 
heart is the first to fail. This appears to depend on the concentration 
of the anaesthetic. If dilute chloroform or ether be inhaled, the respira- 
tion always ceases several minutes before the heart, which continues to 
beat fairly strongly at first but rapidly becomes weaker. If more 
concentrated vapor be used, the respiration again ceases before the 
heart, which is, however, much weakened and comes to a standstill 
after a short interval; and as the concentration is increased, the weak- 
ness of the heart, at the moment fyhen the respiration fails, also 
increases, and the interval between the arrest of the respiration and 
that of the heart-beat becomes shorter. Finally, when air saturated 
with vapor is inhaled, the interval between the two is so short as to be 
inappreciable (Fig. 12). When concentrated vapor of either chloro- 
form or ether is inhaled, the pulse may be so weak as to be no longer 
perceptible before the respiration ceases, and the anaesthetist, therefore, 
believes that heart failure has been the cause of death, but if the move- 
ments of the heart be registered directly, it is found beating as long 
as the respiratory movements are carried on. The importance of the 
condition of the heart is further shown by the results of attempts to 
resuscitate the animal after the respiration has ceased; for if artificial 
respiration be commenced at once, the animal can invariably be restored 
to life, provided the heart has not been weakened too much; but if 
concentrated vapors have been inhaled, the heart is unable to carry 
on the circulation, and the animal cannot be resuscitated. 

Hill has recently pointed out that the failure of the respiration may 
be caused in part by the anaemia of the central nervous. system from 
the fall in blood-pressure. The weakness of the heart induced by 
chloroform is therefore fraught with double danger, for not only is the 
circulation imperilled by it but the respiration is indirectly weakened. 

From a practical point of view, it is of comparatively little impor- 
tance whether there are a few fluttering beats of the heart after the 



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ETHER AND CHLOROFORM 213 

last inspiration or not. The all-important question is whether the 
heart has been so injured as to be unable to carry on the circulation, 
and this is decided by the concentration of the vapor that has been 
inhaled. Even when dilute vapor of chloroform is inhaled, the heart 
is considerably injured when the respiration ceases, while under ether, 
unless very concentrated fumes be inhaled, the weakness of the heart 
is very much less. 

The autopsy in cases of death by chloroform or ether shows no 
specific lesions. The blood is often dark colored from the asphyxia, 
and the heart is found dilated. Irritation of the respiratory passages 
may be present in ether poisoning, and the odor of the anaesthetic may 
be recognized in the different organs. Microscopic examination may 
show some alterations in the cells of the respiratory centre and cardiac 
ganglia, fragmentation of the heart muscle, and some degeneration of 
the liver, kidneys, spleen and heart after chloroform (Poroschin). 

Fig. 12 




D 



E 



Diagram representing the state of the heart at the failure of respiration from an anaes- 
thetic (chloroform or ether). A represents the respiratory movements, which cease very 
early in the tracing, £, the pulsations of the heart at this point if the anaesthetic vapor 
has been much diluted with air, C if it is of medium strength, D if very concentrated, and 
E if saturated. The heart pulsations are recorded by the mercury manometer. 

Of late years a good deal of interest has been excited by the dis- 
covery that the perils of anaesthesia are not over when consciousness 
returns, but that, fatal consequences may follow several days later. 
These late fatalities are due to fatty changes of the heart, liver and 
kidneys or to diabetic coma in the case of chloroform, to bronchitis, 
pulmonary oedema and pneumonia after ether. No reliable data are 
as yet available as to the frequency of these sequelae, as it is very 
difficult to distinguish between the results of the anaesthetic and the 
ordinary forms of disease. Even the proportion of cases in which 
albuminuria occurs after chloroform seems to vary remarkably in 
different hospitals, for it is given as low as 5 per cent, by some authors 
and as high as 30 per cent, by others; this may perhaps be explained 
by differences in the duration of the anaesthesia. The irritant effects 



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214 SUBSTANCES ACTING AFTER ABSORPTION 

of ether and the liability to pulmonary affections afterward have been 
so evident that some surgeons have returned to the use of chloroform, 
believing that the late effects in ether claimed as high a proportion of 
victims as the more immediate effects of chloroform. This irritant 
action of ether may be avoided to some extent by allowing the vapor 
to be inhaled in a more dilute form than is often used in inducing 
anaesthesia. And there is reason to believe that the pulmonary effects 
are often intensified by the air inhaled being chilled by the evaporation 
of the ether, and that they may be lessened if this is avoided by suitable 
inhalers. 

Apparatus and Principles. — The principles on which the safe pro- 
duction of anaesthesia is based, then, are comparatively simple, but 
their interpretation into practice has given rise to various methods. 
A large number of inhalers have been introduced with the object of 
permitting of only a certain degree of concentration of the vapors. 
But the great majority of these are entirely erroneous in principle; 
the -concentration of the vapor being determined by the character 
of the respiration of the patient, and the number of accidents has not 
been appreciably reduced by their use. In one of these the amount 
of oxygen available for respiration was found to be reduced to 5 per 
cent., while the carbonic acid had risen to 7.8 per cent, after two min- 
utes' respiration. This mixture of gases is insufficient to support the 
combustion of a candle, and is very near that which is immediately 
fatal to animal life. In another the concentration of the vapor was 
found to vary between 1.2 and 16.4 volumes per cent. Several appa- 
ratus have recently been constructed on correct principles, which 
allow of an exact gradation in the strength of the vapor inhaled, but 
they are exceedingly cumbrous, and while they might be used in hos- 
pitals, are certainly not available for ordinary practice. 

The advantage of this principle of measuring the concentration of the 
vapors is further only relative,, for it has been shown that vapors so dilute 
as to be absolutely safe do not induce anaesthesia within a reasonable 
time. Thus 1 per cent, chloroform seems to be practically safe, but 
no surgeon will wait |-f hr. for the anaesthetist. To induce anaesthesia, 
therefore, vapors have to be used which would in time be fatal, and 
only after the reflexes disappear is it possible to reduce the concentration 
to the point of absolute safety. The responsibility of the anaesthetist 
is, therefore, lessened, but by no means entirely removed by these 
methods. In the vast majority of cases, however, much simpler 
apparatus is used, and the ordinary mask or towel on which the anaes- 
thetic is poured is not responsible for a larger proportion of accidents 
than the more complicated forms of apparatus. When no inhaler is 
used, the anaesthetist attempts to regulate the concentration of the 
vapor according to the symptoms, and this can be done with complete 
success by watching the respiration closely. If the breathing be shallow, 
much less concentrated vapor is inhaled into the alveoli than if it be 
deep and gasping, for in ordinary respiration the air in the smaller 
bronchioles and alveoli is not exchanged directly with every respiration, 



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ETHER AND CHLOROFORM 2l5 

but only by a process of diffusion from the larger air passages. The 
deeper the respiration, however, the further does the vapor penetrate 
and the lower the concentration needed to change the quantity in the 
blood. An experienced anaesthetist, by watching the respiration, raising 
the mask during deep breathing and replacing it when it becomes 
steady, can regulate with sufficient nicety the concentration of the 
anaesthetic in the alveoli and thereby the quantity in the blood. When 
anaesthesia has been attained, he of course reduces the concentration 
until the return of the reflexes indicates awakening consciousness, and 
even then applies much smaller quantities than were necessary at first. 

This method of inducing anaesthesia requires the anaesthetist to watch 
only the respiration and the reflexes, and is that advised by Simpson 
and his followers (see Hyderabad Commission Report). A further 
safeguard has been sought for in the condition of the pulse, and this 
would seem the natural consequence of what has been stated above as to 
the importance of the condition of the heart. The pulse, however, is 
not very reliable as a guide in anaesthesia, for in the second stage, in 
which a certain number of fatalities occur, it is quickened by the excite- 
ment and may be irregular, and only gives indications of danger when 
it is too late to take measures to prevent it. In the third stage it may 
become gradually weaker, and thus indicate approaching danger, but 
if the respiration be watched the warning is given earlier. A large 
number of anaesthetists advise, however, the pulse and respiration both 
be watched, and this would seem to be the safest method, provided 
always that the anaesthetist does not depend on the pulse too much for 
indications of danger, and does not allow it to distract his attention 
from the more important indications given by the respiration. 

Preliminary Examination. — Before anaesthesia, a careful examination 
should be made of the condition of the patient, and if there is great 
anxiety and excitement, a hypodermic injection of morphine may be 
given beforehand, or chloral may be prescribed, but these are rarely 
necessary. Valvular disease of the heart does not contra-indicate an 
anaesthetic unless there are marked symptoms of inefficiency, such as 
dropsy or oedema. In fatty disease of the heart, on the other hand, 
chloroform is to be avoided, and if it seems extensive, ether is also 
dangerous from the strain put on the circulation during the excite- 
ment. Chloroform is liable to induce fatty degeneration of the heart, 
and for this reason it would not seem advisable to use it in successive 
operations on the same patient. Atheromatous arteries are dangerous 
from the tendency to apoplexy during the second stage also, and if 
anaesthesia is absolutely necessary, an opiate ought to be given pre- 
viously. Anaesthesia is said to be dangerous in cases of brain tumor, 
and this may possibly arise from the fragility of the vessels. In cases 
of bronchitis and catarrh of the air passages, chloroform is to be pre- 
ferred to ether as it is less irritating, while in Bright's disease chloro- 
form is generally more injurious than ether from the resultant albu- 
minuria and tendency to fatty degeneration, although ether is also 
believed by many to disturb the renal functions. Advanced diabetes 



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216 SUBSTANCES ACTING AFTER ABSORPTION 

contra-indicates anaesthesia, the sugar increasing in the urine after- 
wards and coma and death sometimes supervening in the course of a 
few days. Da Costa recommends that where there are symptoms of 
anaemia, an examination of the blood should be made before anaes- 
thesia, and states that where the haemoglobin is found to be deficient, 
great care is necessary and that where it is lower than 50 per cent, of 
the normal, an anaesthetic is contra-indicated. 

Practical Anaesthesia. — The patient should have a light, easily di- 
gested meal 2-4 hours before, so that the stomach may be empty and 
vomiting avoided as far as possible. The bowels should also be regu- 
lated the day before for the same reason. He should then be laid on 
a table of suitable height with a low pillow, and should remove false 
teeth and any other foreign object from the mouth. The clothing 
about the neck, chest and abdomen is to be loosened or removed to 
allow of perfectly free respiration, but warm blankets or warm bottles 
should be applied as far as possible to prevent the fall of temperature 
if the operation is likely to be a long one. The eyes are closed in order 
to protect the conjunctiva from the irritating vapor. The anaesthetic 
is then applied on a towel or on a mask, which ought to be freely per- 
meable by the air, and ought not to fit closely to the face. Masks were 
formerly employed to administer ether (closed method) in which the 
respiration was seriously impeded, so that the patient was partially 
asphyxiated besides receiving a highly concentrated ether vapor. It 
must be remembered that the air passes through cloth with much 
greater difficulty when it is wet by the saliva and mucus, and that a 
mask which is freely permeable at the commencement of an operation, 
may lead to asphyxia after it has been soaked during the first and 
second stages. The patient is instructed to breathe as regularly as 
possible, or to count from one upwards, and some of the anaesthetic is 
dropped on the mask. If the breath be held, the mask should be 
raised a little from the face, as the next inspiration will be a very deep 
one. During the excitement stage the respiration is irregular, and 
great care must be taken to avoid the inhalation of too concentrated 
vapor. As soon as the conjunctival reflex disappears, the mask ifc 
raised, and is replaced only when it reappears or when the patient 
evinces signs of pain. The object of the anaesthetist should be to main- 
tain an even anaesthesia and to avoid sudden changes; this is best 
attained by raising and lowering the mask slightly, or by varying the 
number of drops of anaesthetic falling on it; the inhalation should not 
be completely interrupted except in danger. Throughout the anaesthesia 
care must be taken to prevent any interference with the respiration 
by the operator leaning on the thorax or abdomen. Very often ster- 
torous respiration sets in from the tongue falling back into the throat, 
and this has to be remedied by pressing forward the angle of the jaw, 
or if this is not sufficient, by pulling out the tongue with a blunt-pointed 
forceps. Vomiting is a very common occurrence in anaesthesia, and when 
it sets in, the head is turned to one side and the vomited matter removed 
with a sponge. 



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ETHER AND CHLOROFORM 217 

A more serious accident is the failure of the respiration. A reflex 
arrest often occurs in the first stage, but is not of importance in itself, 
but only from the deep gasping inspiration which follows it. If the 
anaesthetic be given too long in concentrated form, however, the respi- 
ration fails from direct action on the centre, and this demands imme- 
diate attention. The head ought to be lowered at once, and the lower 
limbs elevated, in order to drive the blood to the head as far as pos- 
sible and thus remedy the anaemia of the brain from the weakness of 
the heart that accompanies the cessation of the respiration. The 
epiglottis must be raised by pressing forward the angles of the jaw 
(Hare), or by dragging forward the base of the tongue with hook or 
finger. Artificial respiration in one or other form ought to be commenced 
at once, and carried on as long as is necessary; a large number of methods 
of performing artificial respiration have been proposed, but they can 
only be taught in a practical class and need not be entered upon here. 1 
If the pulse is weak, intermittent pressure over the heart may aid it in 
carrying on the circulation, and in some cases the abdominal cavity 
has been rapidly opened and the heart compressed between one hand 
below the diaphragm and the other on the chest wall. This heroic 
measure has in some cases restored the heart beat and the respiration. 
Various drugs have been recommended in these cases, but it is exceed- 
ingly questionable whether they are really of service; alcohol, ammonia 
and ether have been injected subcutaneously, and may conceivably 
cause such local irritation as to reinstate the respiration reflexly, although 
this is improbable. Strychnine, caffeine and atropine have been 
injected as respiratory stimulants, and digitalis to strengthen the heart 
contraction; as a matter of fact, however, if the circulation is strong 
enough to cause the absorption of these drugs and carry them to the 
respiratory centre and the heart, the patient will recover with the 
artificial respiration alone, while on the other hand, they are of no 
value unless absorbed. Nitrite of amyl is useless, as it can only affect 
the heart by reducing the blood-pressure, which is already dangerously 
low. In animal experiments, the best results are obtained by the 
intravenous or intracardiac injection of adrenaline in saline solution. 

Cardiac syncope and fibrillation is the most dangerous accident of 
anaesthesia, and probably is irremediable when fully developed. The 
treatment consists in inversion, artificial respiration, and massage of the 
heart. Embley recommends the injection of atropine, on the view that 
the condition is due to inhibition, and it might be thrown into the 
heart directly by means of a long hypodermic needle. The experiments 
of Levy show that adrenaline favors ventricular fibrillation under chloro- 
form, and this powerful stimulant is therefore inadmissible in syncope. 

In the course of very long operations it is recommended to allow 
the patient to almost recover consciousness at intervals, but this is 
deprecated by Henderson and Levy as favoring the onset of syncope. 
It must be remembered that in prolonged anaesthesia comparatively 

1 For a comparison of the efficacy of different forms see Sch&fer, Medico-Chirurgical 
Transactions, vol. lxxxvi, supplement, 1904. 



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218 SUBSTANCES ACTING AFTER ABSORPTION 

small quantities are required to maintain unconsciousness when it is 
once completely reached, and at the same time that, owing to the fall 
of temperature and the prolonged action of the drug, the quantity 
necessary to produce cessation of the respiration and the heart is much 
smaller than during shorter operations. . In order to induce anaes- 
thesia within a reasonable time, comparatively strong vapor may be 
used, but as soon as unconsciousness is reached, the vapor ought to be 
diluted as far as is compatible with the continuation of the narcosis. 1 

On the completion of the operation, the patient seldom requires 
further attention from the anaesthetist; after prolonged anaesthesia 
heat may be applied by warm bottles, etc., as the temperature often 
continues to fall for some time after the administration of the drug 
has ceased. If vomiting persists after the recovery of consciousness, 
ice may be sucked, or bismuth may be prescribed. The inhalation 
of vinegar has been recommended and relief is sometimes given by 
lavage of the stomach. 

The patient should always be placed in the recumbent position 
when possible, as otherwise the weakened heart tends to drive the 
blood in the direction of least resistance, that is, downward, and in 
the depressed condition of the vasomotor centre, this is not counter- 
acted by the contraction of the arterioles of the abdomen, and anaemia 
of the brain and fainting are liable to result. The operation ought 
not to be commenced until anaesthesia is complete; otherwise reflex 
inhibition of the heart or syncope may result and lead to fatal results. 

Various drugs have been advised as preliminaries to anaesthesia, 
generally with the object of preventing the reflex arrest of the respira- 
tion and heart. Thus atropine has been proposed to paralyze the 
vagus, and to arrest the mucous secretion and vomiting, and spraying 
of the nose with cocaine has recently been advised to paralyze the 
sensory terminations and so prevent the irritation which sets up the 
reflexes. It has been proposed to dilute ether or chloroform vapor 
with oxygen instead of air, but this has no advantages. In order to 
avoid the unpleasant suffocating effects of ether and to permit of less 
concentrated vapor being used, the injection of 0.01 G. (£ gr.) of mor- 
phine along with 0.5 mg. (y^ gr.) of hyoscine has been advocated as a 
preliminary to ether anaesthesia, and this has become a routine pro- 
cedure in some clinics from which satisfactory results are recorded. In 
others, some less unpleasant anaesthetic, such as nitrous oxide or ethyl 
chloride, is used to induce anaesthesia, which is afterward maintained 
by ether. 

Intravenous Infusion Anaesthesia. — The intravenous injection of ether 
has been advocated recently (Burkhardt), with the object of avoiding 
the local irritant effects of ether vapor in the lungs, and has proved 

1 In anaesthesia with measured percentages of chloroform, Alcock found it best to 
commence with vapor of 1 per cent., rising to 2 per cent, after two minutes and to 2J-3 
per cent, in five minutes; this strength was continued until anaesthesia was attained, after 
which the concentration was reduced to 2 per cent, and further to 1 per cent, in the course 
of twenty minutes. 



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ETHER AND CHLOROFORM 219 

useful, especially in operations on the mouth and throat, in which the 
anaesthetist is liable to be hampered by the surgeon. A solution of 
5-8 per cent, of ether in sterilized Ringer's solution is slowly infused 
through a cannula introduced into a vein, and as anaesthesia is induced 
the rate of flow is lessened until the point is reached which is just suffi- 
cient to maintain unconsciousness. An injection of atropine is often 
given previously to lessen the mucous secretion of the bronchi, and 
morphine and hyoscine are also injected previously by some anaes- 
thetists. The method has advantages in some conditions but is liable 
to cause hemoglobinuria and is not adapted for ordinary surgical work, 
in which the inhalation method is simpler and involves less apparatus. 
Vomiting and marked mucous secretion occur from intravenous anaes- 
thesia, the latter perhaps from the ether excretion through the lungs, 
which proceeds rapidly. Soporifics, such as hedonal, have been sub- 
stituted for ether for infusion, but induce a very prolonged anaesthesia, 
which in some cases has proved fatal. 

Various Mixtures of the Anesthetics have been advised at different times. 
Of these the ACE mixture (alcohol 1, ether 2, and chloroform 3 parts by vol- 
ume) is the best known. Its use has, however, been attended with numerous 
fatalities, as was only to be expected from a consideration of the volatility of 
the different ingredients. Ether, being the most volatile, is first inhaled, and 
then chloroform, and last of all the alcohol. The safe concentration of ether 
is, however, much greater than that of chloroform, and a vapor which may 
be perfectly safe as long as it consists of ether for the most part, may become 
exceedingly dangerous when it consists of chloroform. This method, therefore, 
increases the responsibility of the anaesthetist by leaving him in complete 
ignorance as to the composition of the anaesthetic at any given time. The same 
criticism applies to a mixture of anaesthetics advocated by Schleich and con- 
taining ether, chloroform and petrol, which enjoyed a brief popularity some 
years ago. 

The action of such mixtures is a simple sum of the actions of the constituents; 
the presence of chloroform does not intensify the anaesthetic action of ether, 
except in so far as the chloroform itself anaesthetizes. In other words there is 
no synergism between chloroform and ether such as has been shown to exist 
between morphine and hyoscine for example. 

Ethyl Chloride (CJEIsCl) has been advocated of recent years as an anaesthetic 
for minor operations and examinations, and possesses the advantages of acting 
very quickly and of leaving no after effects except occasionally some nausea, 
the patient generally feeling perfectly well in a few minutes. It is kept in 
sealed tubes and inhaled through a mask as it is extremely volatile, boiling 
at about 12° C. Anaesthesia is obtained in about two to five minutes, but 
complete muscular relaxation is often absent. Recovery follows a few min- 
utes after the removal of the mask. It is not unpleasant to inhale and gen- 
erally induces no excitement or other unfavorable symptoms. The pulse 
is generally slowed, while the respiration is deep. Embley states that in ani- 
mals the effects are similar to those of chloroform, but that it is less poisonous 
to the heart, about nineteen times as concentrated vapor being necessary to 
weaken it. The concentration of ethyl chloride vapor necessary to induce car- 
diac inhibition is four times that of chloroform, and this inhibition is not fatal 
as the heart muscle is less affected. The vapor may be inhaled in 5-7 per 
cent, concentration without inducing inhibition in the dog. Nicloux found 
about 20 mgs. of ethyl chloride per 100 c.c. in the blood in light anaesthesia, 
from 30 to 150 mgs. in deep anaesthesia and 40-180 at death. A number of 
fatalities have occurred under its use, about one in three thousand of those 



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220 SUBSTANCES ACTING AFTER ABSORPTION 

anaesthetized. Some major operations have been performed under ethyl chloride, 
but it is found difficult to maintain a uniform anaesthesia, owing to the rapidity 
with which consciousness returns. It is often employed to introduce anaesthesia, 
which is then maintained with ether. Ethyl chloride should not be administered 
in larger quantities than 4-5 c.c. 

Various other members of the fatty series have been introduced as general 
anaesthetics at different times, but few of them have proved to have any advan- 
tage over chloroform and ether, and fatalities have occurred after all of those 
that have received a wide trial. Pental, trimethylethylene ((CH^i C = CHCH!) 
was introduced for short operations but a number of accidents occurring 
under it have curtailed its use. It produces anaesthesia before the reflexes 
disappear or the muscles relax, and not infrequently the jaws are tightly closed 
after consciousness is lost. In some cases tremor and convulsive attacks have 
occurred during its administration, but it seems to have very little action 
on the heart or circulation. Ethyl Bromide (CiH^Br) has also been used for 
short operations instead of chloroform, and produces anaesthesia with great 
rapidity. Consciousness returns quickly after the removal of the mask, but 
the inhalation is not so pleasant as that of ethyl chloride and patients com- 
plain of greater depression and discomfort afterward. Hennicke found that 
10 vol. per cent, of ethyl bromide were necessary to anaesthetize animals within 
five minutes, and that if this concentration were maintained, death occurred in 
fifteen minutes, so that it is by no means to be considered a perfectly safe 
anaesthetic; several deaths have occurred from its use in dentistry. Both 
pental and ethyl bromide are administered on a mask in the same way as ether. 
Ethyl bromide must be distinguished from ethylene bromide (CiHjBri) which 
is a much more dangerous anaesthetic. Ethyl bromide is very liable to decom- 
position when kept long, and is often furnished in an impure form; it ought 
to be perfectly colorless, as a yellowish color indicates decomposition, often 
with the presence of free bromine. 

The other members of this series possess no practical importance. It may 
be mentioned that tetrachloride of carbon (CCU) differs from the others in 
causing convulsions, while perchlorethane (CiCl«) is a crystalline solid and 
possesses too high a boiling point to be available for inhalation. 

Therapeutic Uses. — Anaesthesia is generally induced for the purpose 
of surgical operations and examinations, and in labor. Until recent 
years, when it was necessary to perform an operation or manipulation 
involving much pain, the surgeon had to consider only which of the 
two general anaesthetics was the better adapted to the case. But the 
improvements introduced in the methods of inducing local anaesthesia 
and the reintroduction of nitrous oxide and ethyl chloride as surgical 
anaesthetics have now enlarged his field of choice, and the further 
question has to be met whether unconsciousness is desirable, or whether 
the necessities of the case may not be met by paralyzing sensation at 
the seat of operation only. The advantages claimed for local anaes- 
thesia will be discussed under cocaine, but the general conditions in 
which chloroform and ether are to be preferred may be stated shortly 
(see also nitrous oxide). General anaesthesia is absolutely essential 
where complete relaxation of the muscles is desired, and where the 
movements of the patient may imperil the success of the operation. 
Operations on the abdominal organs and around joints and such others 
as involve wide and deep incisions will almost certainly continue to be 
performed under chloroform or ether, although a few such operations 
have been performed under cocaine. In many less serious operations 



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ETHER AND CHLOROFORM 221 

it is necessary also to have recourse to the older methods, which allow 
greater freedom to the surgeon, who is under no apprehension that 
he may reach a sensitive area and has thus one less source of anxiety 
than if the anaesthesia were localized. Another argument for the use 
of general anaesthetics is the effect which the anxiety and the sights 
and sounds of the operating room may have on a nervous patient even 
when no actual pain is felt. And a considerable amount of practice 
is required before complete local anaesthesia can be induced over an 
extensive field of operation, while the surgeon has often to interrupt 
his manipulations in order to admit of a fresh area being rendered 
analgesic. But there is no question that many operations in which 
ether or chloroform have hitherto been employed, will in the future be 
performed more often under local anaesthesia or nitrous oxide. In 
this class may be included most minor operations in which only very 
short or partial anaesthesia is necessary and in which no complications 
are to be anticipated. Nitrous oxide and ethyl chloride are scarcely 
to be regarded as rivals to ether and chloroform in any but minor 
operations. But in these they have the great advantage that the 
patient can be dismissed within a few minutes after the operation is 
completed, while if ether, or chloroform is employed complete recovery 
is only reached after several hours; when the latter are used in minor 
operations, the discomfort resulting from the anaesthetic may be alto- 
gether out of proportion to the actual surgical manipulation. 

During labor only the lighter degrees of anaesthesia are necessary, 
the object being to dull the pain without lessening to any marked 
extent the reflex irritability of the spinal cord, and accidents are 
extremely rare in this use of anaesthetics, although the common state- 
ment that they are unknown is incorrect. Some cases have been 
recorded in which it is believed that chloroform was fatal to the child 
and not to the mother, but it is, of course, impossible to state with 
certainty that the anaesthetic was the cause of death. If too deep 
anaesthesia is produced, however, it is quite conceivable that the labor 
may be prolonged, or the blood-pressure so reduced as to lead to an 
imperfect exchange of gases in the placenta and thus to the death of 
the infant; or, as another explanation it might be suggested that the 
irritability of the respiratory centre of the child may be so reduced 
that it fails to react when the placental circulation is interrupted. 

Anaesthetics are also employed in cases of extreme irritability of 
the central nervous system, as in strychnine poisoning, tetanus or other 
convulsive affections. In order to reduce these, it is unnecessary to 
produce deep anaesthesia, a few whiffs of chloroform being generally suf- 
ficient to produce quiet, often without affecting the consciousness to any 
marked extent. In cases of very acute pain, chloroform or ether may be 
used, but as a general rule morphine or opium is preferable, as the action 
lasts much longer and the administration is much more convenient. 

The local action of chloroform and ether on the stomach and skin 
is entirely independent of their action as anaesthetics, and has been 
discussed separately (see page 69). 



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222 SUBSTANCES ACTING AFTER ABSORPTION 

Preparations. 

U. S. P. — Chloroformum, a liquid containing 99-99.4 per cent, by weight 
of absolute chloroform (CHCU) and 0.6-1 per cent, of alcohol. 

jEther, ether, a liquid composed of about 96 per cent, by weight of absolute 
ether or ethyl oxide ((C*Hi)iO) and about 4 per cent, of alcohol containing a 
little water. 

JSthylis Chloridum, ethyl chloride (CiHiCl), an extremely volatile liquid 
boiling at 12.5-13° C. (about 55° F.). 

B. P. — Chloroformum, contains 98 per cent, of chloroform (CHCU), and 2 
per cent, of absolute alcohol. Its specific gravity is 1.483-1.487. 

J2ther Purificatus, ether, contains about 95 per cent, of absolute ether 
((CfcHOiO) along with some alcohol and water and has a specific gravity of 0.720. 

Ethyl Chloridum, CiH*C1, a very volatile liquid of specific gravity 0.92-0.96, 
and containing not less than 99.5 per cent, of ethyl chloride. 

Chloroform is ordinarily formed by the action of chlorine on alcohol, the 
chlorine being added in the form of chlorinated lime. The crude drug is 
purified by repeated washing with water and sulphuric acid, and dried over 
calcium chloride. The fatalities following its use have frequently been ascribed 
to impurities, and a certain demand has arisen for a purer article than that 
required by the pharmacopoeias. Another method of preparation has therefore 
been introduced, the decomposition of chloral by soda (Chloroformum e Chloral 
pr&paratum). Other pure forms are prepared from ordinary chloroform by 
crystallizing it by cold (Pictet), or by forming a compound with salicylid and 
decomposing it again by slight heat, Chloroform (Anschutz) or Chloroform 
(Salicylid). 

The impurities of chloroform are due partly to imperfect manufacture and 
partly to decomposition. Along with the chloroform there distils over a 
small quantity of heavy, oily fluid, which may be isolated by Pictet's method, 
but whose composition is entirely unknown. DuBois-Reymond found that 
this fluid acted more strongly on the heart than pure chloroform, but it is 
very questionable whether the minute quantities inhaled in ordinary anaes- 
thesia produce effects of any importance, and, on the other hand, it is quite 
certain that the use of absolutely pure chloroform does not prevent accidents. 
Chloroform undergoes decomposition when exposed to light and air, hydro- 
chloric acid and chlorine being set free in small quantity. These can affect 
the course of anaesthesia only through their local irritant action, but if present 
in sufficient quantity may cause the respiration to be more irregular than 
usual in the earlier stages; the chloroform used for anaesthetic purposes ought, 
therefore, to be kept in a dark place or in colored bottles. Another decom- 
position occurs when chloroform is evaporated in the neighborhood of a large 
flame, such as that from gas or lamps, and hydrochloric acid and carbonylchloride 
(CClaO) are formed, the latter being a gas with exceedingly irritant properties. 

Chloroform is a heavy volatile fluid, of characteristic pleasant odor and hot, 
sweetish taste. Its specific gravity is 1.476 (U. S. P.) and 1.483-1.487 (B. P.), 
and it boils at 60-61° C. A number of tests are given for impurities, but those 
of importance can generally be detected by the odor, especially if some chloro- 
form is allowed to evaporate in a watch-glass, when the last drop ought to 
have no irritant effect when inhaled. Chlorine and hydrochloric acid may be 
tested for by shaking the chloroform with distilled water, and testing the latter 
with potassium iodide and starch and with silver nitrate. The water ought 
to give no acid reaction to litmus. If left in contact with concentrated sulphuric 
acid, chloroform should not become darker within one hour, as this indicates 
the presence of some foreign unstable body. The other impurities require 
complicated chemical processes for their detection. 

Ether is prepared by the action of sulphuric acid on alcohol, and is sub- 
sequently purified by washing with water and alkalies. It seldom contains 
impurities of importance. ^Ethcr purificatus (B. P.) or iEther (U. S. P.) is a 
very volatile fluid, of a suffocating, irritant odor and bitter taste. Its specific- 



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ETHER AND CHLOROFORM 223 

gravity is 0.716-0.717 (U. S. P.) ? and 0.720 (B. P.), and its boiling point 
is 35° C. It evaporates very rapidly in the air and should leave no foreign 
odor and no residue. When ether has been exposed to air and sunlight and to a 
varying temperature, it may contain acetaldehyde and peroxide bodies, which 
render it more irritant to the mucous membranes. It should not color litmus 
paper, nor be colored within an hour when shaken with potassium hydrate 
solution. Ether vapor is exceedingly inflammable when mixed with air, and 
it should therefore be kept in a cool place, away from gas flames or lamps. 

Ethyl Chloride is obtained by the action of hydrochloric acid on alcohol, and 
is a gas at normal temperatures, but is supplied condensed into a colorless fluid 
with a pleasant odor. It is very volatile, inflammable and mobile, and is liable 
to contain traces of the same impurities as have been mentioned under chloro- 
form. It should be kept in a cool place, away from lights or fire. 

Bibliography of the ANiESTHETics. 

The literature up to 1880 is given in Kappeler's "Anaesthetics," Stuttgart, 1880. 

Dastre. Les Ansesthesiques, Paris, 1890. 

Report of the Hyderabad Chloroform Commission, Bombay, 1891, and Lancet, 1890. 
The criticisms on the report are dealt with in the Lancet, 1890-91, and in the British 
Medical Journal, 1890-91. 

MacWiUiam. Proc. Roy. Soc, liii, p. 464; Journ. of Physiol., xxv, p. 236. 

Cook and Briggs. Johns Hopkins Hospital Report, xi, p. 451. 

Blauel. Beitr&ge s. klin. Chir., xxxi, p. 271. 

Embley. Brit. Med. Journ., April, 1902. Journ. of Phys., xxxii, p. 147. 

Bayliss. Proc. Roy. Soc, B., lxxx, p. 365. 

Buck-master and Gardner. Proc. Roy. Soc, B, lxxviii, lxxix, lxxxiv, p. 347. 

Sherrington and Sowton, Waller, Horsley, and others. Brit. Med. Journ., July 12, 
1902; July 18, 1903; July 23, 1904; Sept. 24, 1904; July 9, 1910. 

Loeb. Arch. f. exp. Path. u. Pharm., li, p. 82. 

Schafer and Scharlieb. Trans. Roy. Soc. Edinb., xli (ii), p. 311. 

Pohl. Arch. f. exp. Path. u. Pharm., xxviii, p. 239. 

Ungar. Vierteljahr. f. ger. Med., xlvii, p. 98. 

Kast u. M ester. Zts. f. klin. Med., xviii, p. 469; Zts. f. phys. Chem., xi, p. 277; xii, 
p. 267. 

Ambrosius. Virchow's Archiv, ex xxviii, Suppl., p. 193. 

Lippmann. Mittheil. a. d. Grensgebiet der Med. u. Chir., iv, p. 21. 

Selbach. Arch. f. exp. Path. u. Pharm., xxxiv, p. 1. 

Spenzer. Arch. f. exp. Path. u. Pharm., xxxiii, p. 407. 

Rosen/eld. Ibid., xxxvii, p. 52. 

Dreser. Beitr&ge zur klin. Chirurg., x, p. 412, and xii, p. 353. Arch, f . exp. Path. u. 
Pharm., xxxvii, p. 375. Bull. Johns Hopkins Hosp., vi, p. 7, 1895. 

Wells. Journ. Biol. Chem., v, p. 129. 

Howland and Richards. Journ. Exp. Med., xi, p. 344. 

Kemp. New York Med. Journ., 1899, ii, p. 732. 

Thompson, Buxton, Levy. Brit. Med. Journ., 1900, ii, p. 883. 

Da Costa. American Medicine, May 18, 1901. Annals of Surgery, Sept., 1901. 

SneL Berlin, klin. Woch., 1903, p. 212. 

Braun. Arch. f. klin. Chirurg., Ixiv, p. 201. 

Honigmann. 'Arch. f. klin. Chirurg., lviii, p. 730. 

Kionka. Ibid., 1, p. 339. 

Pick. Arch. f. exp. Path. u. Pharm., xlii, p. 412. 

Elfsbrand. Ibid., xiiii, p. 435. 

Sackur. Virchow's Arch., exxxiii, p. 30. (Pental.) 

Henderson. Amer. Journ. of Physiol., xxviii, p. 275. 

Leuwen. Arch. f. d. ges. Phys., cliv, p. 307. 

Levy. Heart, 1913, iv, p. 319. 

Burkhardt. Arch. f. exp. Path., lxi, p. 213. 

Madelung. Ibid., lxii, p. 409. 

Zoep/el. Arch. f. exp. Path. u. Pharm., xlix, p. 89. (Ethyl chloride.) 

Cole. Brit. Med. Journ., June 20, 1903. (Ethyl bromide.) 

McCardie. Lancet, April 4, 1903. (Ethyl chloride.) 

Embley. Proc Roy. Soc, lxxviii, B., p. 391. (Ethyl chloride.) 

Montgomery and Bland. Journ. of Amer. Med. Assoc, April 2, 1904. (Ethyl chloride.) 



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224 SUBSTANCES ACTING AFTER ABSORPTION 



3. Nitrous Oxide. 

The oldest of the anaesthetics, nitrous oxide, N 2 0, does not belong 
to the methane series, but may be discussed at this point. 

Symptoms. — When a mixture of nitrous oxide and air is inhaled 
for a few seconds, a condition resembling alcoholic intoxication is 
produced, with much hilarity and laughter, so that the oxide is known 
popularly as "laughing gas." Even at this point a certain amount 
of anaesthesia is obtained, and it was the observation that persons fall- 
ing during this stage did not complain of pain that first suggested to 
Wells the anaesthetic properties of the gas. Davy had noted these 
forty years previously, but his suggestion that nitrous oxide might be 
used in surgical operations passed unnoticed. 

The inhalation of a mixture of nitrous oxide, 4 parts, and oxygen, 
1 part, causes after a few seconds a rushing, drumming, hammering 
in the ears, indistinct sight, and a feeling of warmth and comfort. 
The movements become exaggerated and uncertain, the gait is stag- 
gering, and the body sways from side to side. The patient seems 
brighter and more lively, and often bursts into laughter. Somewhat 
later a feeling of drowsiness may come on, but this is not constant; 
the sensibility to pain is much less acute than normally, but no com- 
plete anaesthesia is produced by this mixture of gases; the sense of 
touch is comparatively little altered, and total unconsciousness never 
results. The pupil is generally slightly dilated, the face flushed, and 
the pulse somewhat accelerated. 

When pure nitrous oxide is inhaled without the admixture of oxygen 
the patient passes almost instantaneously through the symptoms 
already described, but then loses consciousness completely; the face is 
cyanotic, the respiration becomes stertorous and dyspnoeic and ceases 
after a weak convulsion, while the heart continues to beat for some 
time afterwards. If the mask through which the patient has been 
inhaling the gas is removed when the cyanosis becomes marked, very 
complete anaesthesia lasts for 30-60 seconds, and the patient then 
recovers within a few minutes and suffers from no after-effects what- 
ever. No prolonged anaesthesia can be produced, however, as the 
respiration becomes endangered if the mask be kept on longer than the 
beginning of the cyanotic stage. 

Action. — Nitrous oxide supports combustion outside the body, for 
if a glowing splinter of wood be held in it, it bursts into flame exactly 
as if it were immersed in oxygen. In the tissues of the body, however, 
nitrous oxide behaves in the same way as any other indifferent gas, such 
as hydrogen or nitrogen; that is, the tissues exposed to it suffer from 
asphyxia owing to the oxygen of the air being excluded. Thus, plants 
do not grow in an atmosphere of nitrous oxide and seeds do not germinate. 
Animals die after inhaling nitrous oxide in almost the same time as after 
hydrogen or nitrogen, and at death the spectrum of the blood shows 
no oxyhaemoglobin to be present, the tissues having used up all the 
available oxygen. Nitrous oxide, therefore, does not suppor t com - 



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NITROUS OXIDE 225 

hiistipn in the ftnjmal hortv. the nitrogen is no.t split off from the 
oxygen at body temperature as it is when the oxide is exposed to high 
temperatures outside the body. 

But nitrous oxide has a spe cial effect on thfl <^entrfl.l nervous sy stein. 
although in the rest of the tissues it aotaaly. fry excluding the oxygen; 

it rUnrggggg *hf, frrain fry virtue nf jfq mnWiilar forjp just ias phlnrnfnrm 

or ether does. This has been shown in a variety of ways; thus, if it 
were a perfectly indifferent body no more effect would be produced by 
it when mixed with one-fourth of its volume of oxygen than by air, 
which consists of 1 part of oxygen and 4 parts of an indifferent gas, 
nitrogen. But 80 per cent, nitrous oxide has definite effects on the 
behavior of animals, as has been mentioned, and even 73 per cent, 
produces some slowing of the respiration. The narcotic action, was 
demonstrated very clearly by Paul Bert in a series of experiments on 
man and animals. He noted that only imperfect anaesthesia was pro- 
duced by 80 per cent, nitrous oxide, while the pure gas produced asphyxia. 
The problem was to introduce as much gas into the blood as would 
pass in under pure nitrous oxide, and at the same time to supply sufficient 
oxygen to prevent asphyxia. The absorption of nitrous oxide depends 
upon its partial pressure in the lungs, as it is simply dissolved in the 
blood without forming any real combination with it, and the quantity 
absorbed by the blood may be augmented by increasing the barometric 
pressure. Bert, therefore, administered a mixture of 80 parts nitrous 
oxide and 20 parts oxygen to animals in a glass case in which the pressure 
was raised one-fourth above the ordinary atmospheric pressure. The 
absorption of the nitrous oxide was the same as if the animal had 
breathed the pure gas at the ordinary air pressure, and at the same time 
as much oxygen was absorbed as in ordinary air. The result was a 
complete anaesthesia without asphyxia, which could be maintained for 
three days without injury to the animal (Martin). Kemp has recently 
shown that mixtures of oxygen and nitrous oxide can be inhale frr 
some ti me and p r ftd llpp anmthHg^whi^h passes off at once when 
nitr offeiTi n fl lih i titutrri fnr nitrour oYJf ff He lias further investigated 
the blood gases during nitrous oxide anaesthesia, and finds that the 
oxygen contained in the blood at the deepest stage of anaesthesia is 
quite sufficient to maintain life and consciousness were no nitrous oxide 
present. Again Goltstein found that frogs were narcotized in five and 
one-half minutes in* an atmosphere of nitrous oxide, in one and one- 
quarter hours in hydrogen, and showed that the nareosis and death in 
mammals from nitrous oxide differed in several details from that under 
indifferent gases. There can, therefore, be no doubt that nitrous oxide 
has distinct effects on the central nervous system, although it is indiffer- 
ent to the other tissues. The anaesthesia is due to a specific action on the 
nervous tissues althougjil his may be_ rei nforced by the n^phyy?Pi p™^r»t 
And Bert's and Martin's experiments would indicate that death occurs, 
not from the direct action of the nitrous oxide on the respiratory centre, 
but from the lack of oxygen, although the depression of the centre is 

undoubtedly a contributing factor. ** . — 

15 

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226 SUBSTANCES ACTING AFTER ABSORPTION 

The same question arises regarding the action on the nerve cells as 
has been met with in the members of the methane series, and here 
again the prelimi nary excitemen t may indicate not stimulation of the 
brain areas, but lessened activity of the functions of control and restraint. 

The respiratory centre is depressed when the gas is inhaled in com- 
paratively dilute form, for Zuntz and Goltstein found the breathing 
slower and deeper after 73 per cent. The respiration ceases some- 
what earlier under nitrous oxide than under indifferent gases, which 
would indicate that the cessation of the breathing is due at any rate 
in part to the specific depressant action. In asphyxia from nitrous 
oxide there is l ess convulsive movemen t than under hydrogen, owing 
to the general depression of the nerve cells. 

The circulation_i§_ little, affected by. the nitrous _pxide directly, the 
rise in the blood-pressure and slowness of the pulse being due to the 
asphyxial condition of the blood; the pulse is not so slow as in ordinary 
asphyxia or in asphyxia from nitrogen or hydrogen, because the inhibi- 
tory centre is less capable of activity. Th e heart is not affec ted directly, 
but only by the lack of oxygen. 

The blood dissolves, jnore nitrfmn -exide -than.. water r apparently 
because it is taken up by the lipoids of the corpuscles in the same way 
as chloroform. Nicloux found about 40 mgs. in 100 c.c. blood at the 
beginning of anaesthesia, 50 mgs. in complete anaesthesia, and 60 mgs. 
when" the respiration ceased. 

Nitrous oxide is a gas at ordinary temperature and pressure, and is 
invariably administered by inhalation from a cylinder into which it 
has been forced under high pressure. The mask generally covers both 
nose and mouth, and the inhalation is carried on until distinct cyanosis 
appears, when the anaesthesia is sufficient to allow of short operations, 
such as those of dentistry. It is much the safest of the anaesthetics, 
for millions of persons have been subjected to its influence, and only 
a few cases of death are reported from its use, and several of these do 
not seem to have been due to the direct action of the gas. 

Ethyl chloride (see p. 219) has been introduced as a substitute for 
nitrous oxide, and has supplanted it to a certain extent, as it is more 
easily administered and the apparatus necessary is less cumbrous. 
On the other hand, nitrous oxide is responsible for much fewer accidents. 
Unfortunately, the anaesthesia cannot be kept up except for a very short 
time, which is quite insufficient to allow of ordinary operative pro- 
cedures. A number of attempts have been made to prolong the anaes- 
thesia, of which Bert's was much the most successful. The operator, 
patient and attendants were enclosed in an air-tight chamber, the 
air pressure was raised by means of force pumps, and Bert's mixture of 
oxygen and nitrous oxide was inhaled by the patient. A whole series 
of major operations were performed in this way, the anaesthesia being 
complete as long as was desired, and the patient recovering a: few minutes 
after the mask was removed. But the method was expensive and the 
apparatus cumbrous, and Bert later proposed to induce anaesthesia by 
the pure gas and to maintain it by administering alternately pure nitrous 



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NITROUS OXIDE 227 

oxide and nitrous oxide diluted with oxygen. A practical method of 
carrying out this form of anaesthesia has been devised by Hewitt, whose 
apparatus consists essentially of two reservoirs, the one containing 
oxygen, the other nitrous oxide, and of a mixing chamber with a stop- 
code by which the proportion of oxygen is regulated. The inhalation 
is commenced with pure nitrous oxide or with a mixture containing 
only 2 per cent, of oxygen. When anaesthesia is attained the percentage 
of oxygen is increased to 5-8 per cent, by turning the stopcock, and the 
symptoms determine the further changes, returning consciousness 
necessitating a diminution in the oxygen, stertor and cyanosis an 
increase. This form of anaesthesia is admirably adapted for minor 
operations and has been maintained in some cases for as long as an hour. 
The circulation and respiration are less seriously altered than by any 
other method that induces general anaesthesia, and the return of con- 
sciousness is almost immediate. The great drawback to its use is the 
cumbrous apparatus required and the large amount of gas used, amount- 
ing to about 100 gallons for anaesthesia of half an hour. Complete mus- 
cular relaxation is seldom attained and this precludes its use in many 
operations, in which, however, it may be employed at first and then be 
replaced by chloroform or ether, whose preliminary disagreeable effects 
are thus avoided. In some operations 80 per cent, nitrous oxide has been 
used after partial anaesthesia had been attained by the hypodermic 
injection of morphine and hyoscine, and the results have been favorable. 
Klikowitsch proposed the use of 80 per cent, nitrous oxide, not for 
complete anaesthesia, but to relieve pain and spasm in cases of asthma, 
in labor and similar conditions. The patient could inhale it if neces- 
sary without the presence of a medical attendant, and it had the 
advantage over the other depressants that it need only be inhaled 
when an attack of pain was approaching and that it left no depression 
afterward. But 80 per cent, is apt to induce symptoms closely resemb- 
ling those of alcoholic intoxication. 

The high blood-pressure induced by nitrous oxide asphyxia is some- 
times^sald to be dangerous in elderly persons from their liability to 
apoplexy, and of the few fatalities under the gas several would seem 
due rather to this than to the drug directly, but the danger is often 
overstated, and, in fact, it is a question whether the shock caused by 
the operation without gas would not be more dangerous than the effects 
of the gas itself. No such symptoms arise when the nitrous oxide is 
diluted with oxygen as in Hewitt's method. 

Occasionally som e^glycosuria occ urs after the inhalation, not owing 
to the gas itself, but to the accompanying asphyxia. It is merely 
temporary and has no practical importance. 

The treatment of accidents in anaesthesia under nitrous oxide con- 
sists in artificial respiration alone. 

Bibliography. 



Paul Bert. Comptes rendus, lxxxvii, p. 728, and xevi, p. 1271. 
Hermann. Arch. f. Anat. und Phys., 1864, p. 521. 
Jolyet el Blanche. Arch, de Phys., 1873, p. 364. 



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228 SUBSTANCES ACTING AFTER ABSORPTION 

GolUtein. Pfluger's Arch., xvii, p. 331. 

Klikovritich. Virchow's Arch., xoiv, p. 148. (Literature.) 

Martin. Comptes rendus, cvi, p. 290. 

Van Arsdale. Am. Journ. Med. Sciences, cii, p. 131. 

Wood. Dental Cosmos, 1893. 

Kemp. Brit. Med. Journ., 1897, ii, p. 1480. 

Hewitt. Anaesthetics and their administration, London, 1900. 

4. Soporifics. — Chloral Group. 

Some twenty years after the introduction of the anaesthetics, a new 
interest was given to the methane series by the examination of chloral 
hydrate (CC1 3 CH(0H) 2 ) by Liebreich. Henceforth the attention of 
investigators was diverted from the quest of anaesthetics to that of 
hypnotics, with the result that a "number of valuable drugs have been 
added to therapeutics. These soporifics, or narcotics, have the same 
general action as the anaesthetics, but are used only to produce the first 
effects of imperfect consciousness or sleep. The anaesthetics might be 
used for this purpose were it not for the comparatively short time 
during which their action persists. Narcotics are required to produce 
a slight but lasting effect, and for this purpose the gradual absorption 
from the stomach is better adapted than the rapid absorption and 
equally rapid elimination by the lungs. The narcotics are, therefore, 
less volatile than the anaesthetics, and ought to be soluble in water and 
not irritant in the stomach, so as to permit of rapid absorption. The 
most widely used members of this group are chloral, paraldehyde, svl~ 
phonal and veronal, but many others have received attention. They 
all resemble each other in their general soporific action, and that of 
chloral may be taken as typical of all; in their other characters some 
differences are presented and these will be taken up for each individual 
drug. 

Symptoms. — Chloral in 15-30 gr. doses produces drowsiness and 
weariness, which soon pass into a condition resembling natural sleep 
very closely, from which the patient can be awakened by ordinary 
means, such as touching, loud sounds, or pain. The respiration and 
pulse are somewhat slower than in waking moments, but scarcely more 
so than in natural sleep, and the somewhat narrowed pupil and unal- 
tered excitability of the reflexes are also common to both conditions. As 
a general rule, the sleep passes off in five to eight hours and leaves no 
unpleasant results, but sometimes headache, giddiness, and confusion 
are complained of. Occasionally no real sleep is produced by chloral, 
a condition exactly resembling alcoholic intoxication following its 
administration and continuing for some time. 

When larger quantities (75 grs.) are taken, the sleep is much deeper, 
the patient cannot be aroused to complete consciousness, the reflexes 
are distinctly lessened and the sensation of pain is less acute, although 
no complete anaesthesia is present. The respirations are fewer and the 
pulse may be slow and somewhat weak. The sleep lasts very much longer 
(ten to fifteen hours), and nausea, vomiting, headache and confusion often 
remain after consciousness is regained. In still larger quantities chloral 



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SOPORIFICS— CHLORAL GROUP U% 

produces a condition resembling Exactly the third stage of anaesthesia. 
The reflexes are entirely absent and no movement is elicited by painful 
operations, the muscles are completely relaxed, the respiration and 
pulse are both slow and weak, and eventually asphyxia occurs from 
paralysis of the respiratory centre. The heart continues to beat for a 
short time after the breathing ceases. 

The first stage is the only one elicited in therapeutics. The use of 
chloral as an anaesthetic in man would be quite unjustifiable, because 
it is impossible to adjust the dose accurately enough to allow of com- 
plete anaesthesia without danger of respiratory failure. 

Action. — The Central Nervous System is depressed and eventually 
completely paralyzed by chloral and its allies. Unlike the anaesthetics 
and alcohol, however, chloral rarely causes excitement, but this may 
be due to the facts that the surroundings of the patient are less likely 
to cause excitement and that the drug itself causes less local irritation. 
The results of psychological experiments on the effects of small doses 
of the narcotics seem to indicate that they all depress the sensory or 
receptive functions of the brain, while its motor activity is much 
reduced by chloral and sulphonal, *but may appear to be actually 
increased by paraldehyde; this apparent stimulation is analogous to 
that under alcohol and may be explained by lessened control. The 
deep induced by the dulling of the perceptions may be interrupted by 
more intense stimuli from without. In particular, acute pain may 
prevent sleep after chloral, which seems to have no specific effects on 
pain sensation such as is possessed by morphine. In larger quantities, 
however, even .very great disturbance of the environment produces no 
interruption of the sleep, and the reflex response to irritation is very 
much lowered. The motor areas of the brain cortex are rendered less 
irritable by chloral, and eventually fail to react to the strongest electrical 
stimulation. The reflexes of the spinal cord are depressed and finally 
paralyzed before the failure of the respiration; this depressant action on 
the spinal reflexes is much more marked than that seen under merpkine. 
The last part of the central nervous system to be attacked is the medulla 
oblongata, for although the respiration is somewhat slower and shallower 
after small quantities, it is scarcely more affected than in ordinary 
sleep, and Loewy found that both the excitability of the centre and the 
volume of the inspired air were very similar in the two conditions. 
As the dose is increased, however, the respiration becomes very slow 
and weak, and finally ceases from paralysis of the centre. 

The heart is somewhat slower after chloral in moderate doses, but 
scarcely more so than in natural sleep. There is often some flushing 
of the face and head from some obscure central action, but the blood- 
pressure is little affected in the therapeutic use of the drug. In poisoning, 
the blood-pressure is reduced by weakness of the vasomotor centre and 
of the heart, the latter manifesting itself also in slowing of the pulse. 
This action on the circulation from poisonous doses is more evident 
under chloral than under the other hypnotics which do not contain 
chlorine. The same difference is met with in ether and chloroform, 



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230 SUBSTANCES ACTING AFTER ABSORPTION 

of which the latter affects the circulation more strongly. And the 
action on the heart in chloral poisoning resembles that of chloroform, 
the auricles being affected sooner than the ventricles and the strength 
of contraction falling more than the rate. 

Locally, chloral has an irritant action when applied in concentrated 
solution and this leads occasionally to nausea and vomiting when it is 
prescribed with insufficient fluid. This irritant action induces red- 
ness and even vesication when chloral is applied to the skin; it is said 
to corrode when applied to unprotected surfaces, and certainly possesses 
antiseptic properties like chloroform. It is rapidly absorbed when 
given by the mouth and is carried to the central nervous system where 
it is taken up by the cells until they contain more than the blood cor- 
puscles or the cells of other organs, such as the liver. Liebreich intro- 
duced chloral as a hypnotic in the belief that it was decomposed in 
the blood and chloroform liberated, but this has been shown to be 
erroneous, no chloroform being found in the blood or expired air after 
chloral. Chloral has no action on muscle or nerve in the living animal, 
but when it is applied to the exposed nerve it first irritates and later 
paralyzes it, and injected directly into the artery of a muscle it causes 
immediate rigor. The temperature falls after the administration of 
chloral from the lessened muscular movement, and perhaps from the 
increased output of heat through the dilated skin vessels. 

The effects of chloral on the tissue-change have been found to corre- 
spond very closely to those of chloroform. Thus fatty degeneration 
of various organs has been produced by the prolonged administration 
of chloral and its compounds, and the increase in the nitrogen, phos- 
phates and sulphur, especially of the unoxidized sulphur, in the urine 
points to augmented destruction of the proteins of the body, together 
with imperfect oxidation. The acidity of the urine is much increased 
by the presence of urochloralic acid. Chloral was formerly supposed to 
lead to glycosuria, but this has been shown to be erroneous, the reducing 
substance in the urine being urochloralic acid, and not sugar. In 
addition to this effect on the tissues generally, less oxygen is absorbed 
and less carbonic acid excreted owing to the diminished muscular 
movement. 

Chloral is reduced in the tissues to trichlorethyl alcohol (CC1 8 CH 2 - 
OH), which combines with glycuronic acid to form urochloralic acid, 
and is excreted in this form in the urine. Some escapes by the kidneys 
unchanged, however, and some is thrown into the stomach, and this 
may account for the nausea and discomfort felt after awaking in some 
cases. 

The other hypnotics of this series, with the exception of chloralose, 
correspond exactly with chloral as far as their action on the central 
nervous system is concerned. The chief difference in their effects 
is seen in the circulation and metabolism, which are comparatively 
little affected by those which do not possess substituted chlorine 
atoms. 



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SOPORIFICS— CHLORAL GROUP 231 

Paraldehyde (CeHuOs), a polymer of ethylaldehyde, resembles alcohol 
in its effects though it is a much more powerful narcotic and rarely induces 
any symptoms of excitement. It does not affect the heart directly 
even in large doses and has no such effects on the protein metabolism 
as have been observed under the prolonged administration of chloral; 
the pulse is slightly slower and the carbonic acid exhaled is less than 
normally, but these changes are due to the muscular movements being 
lessened, and are hardly greater in extent than occur in natural sleep. 
Very large quantities have been taken without fatal results, and in 
fact without any more serious consequences than prolonged uncon- 
sciousness. Paraldehyde, however, has a most unpleasant odor and a 
hot, burning taste, which renders its administration somewhat difficult. 
In addition it is excreted in part by theiungs, though mainly in the urine, 
and the odor remains in the breath for some time after the patient 
aw akens 

Sulphonal ((CHcbCCSQAHs),) and its allies, Trional ((C 2 H B CH,C- 
(S0 2 C 2 Hb)2) and Tetronal ((Ct^)iC(SQCiHs)2)j have no immediate 
action on the circulation even in large doses, though it is stated that 
their prolonged use is deleterious to the heart, and they appear to be 
more uncertain in their narcotic action in cases of heart disease than in 
other conditions. They are practically tasteless powders, and are 
therefore easily taken, but their insolubility in water readers their 
absorption slow and uncertain, and sleep is therefore late in following 
their administration, while, on the other hand, depression, drowsiness 
and lack of energy are often complained of the day after. There is 
some evidence that they exercise a deleterious effect on the liver, for the 
relation of urea to the total nitrogen of the urine is changed and the 
metabolism of the purine bodies is also affected. 

The use of the sulphonal group, especially when prolonged, has led 
in many cases to a series of symptoms, the most characteristic of which 
is the appearance in the urine of a reddish-brown pigment, haemato- 
porphyrin, an iron-free product of the decomposition of haemoglobin. 
This occurs most frequently in anaemic women, and is accompanied by 
constipation, pain in the stomach region and vomiting, weakness and 
ataxia, confusion and partial paralysis, and eventually by suppression 
of the urine or by collapse and death. These symptoms may appear 
several days after a single dose, sometimes after an interval of one or 
two weeks. The excretion of haematoporphyrin in the urine appears 
due to some obscure change in the liyer; it occurs in traces in the rabbit's 
urine normally and in larger quantities after the animal has been treated 
with sulphonal (Neubauer). In other animals the prolonged adminis- 
tration of sulphonal often causes albumin and casts in the urine, while 
haemorrhages in the kidneys have been produced in them by the adminis- 
tration of only a few doses. The amount of haematoporphyrin in the 
urine is sometimes very large; in one case Tyson and Croftan found 
that the quantity passed in one day indicated the destruction of one- 
seventeenth of the total haemoglobin of the body. Very large doses 
are said to produce convulsive movements in animals, while ordinary 



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232 SUBSTANCES ACTING AFTER ABSORPTION 

ones cause sleep and subsequent drowsiness. Sulphonal is decomposd 
in the body and is excreted largely as ethylsulphonic acid in the urine, 
in which traces of the unchanged substance have also been found. The 
decomposition is a slow process, however, for Kast found sulphonal in 
the blood many hours after its administration. The ethylsulphonic 
acid seems to have no action whatever in itself, so that the narcosis is 
due to the unchanged molecule of sulphonal. 

Veronal, diethylbarbituric acid ((C2H 5 )2C(CONH)jCO), and its sodium 
salt, medinal (NaCgHiiOsN 2 ), seem to be devoid of action except on the 
central nervous system, and thus approach the ideal more closely than 
any of the others. In ordinary doses (5-10 grs.) they induce natural 
sleep without subsequent depression, and larger quantities deepen and 
lengthen the unconsciousness without other organs than the central 
nervous system being involved, though the patient may complain of 
lethargy and drowsiness subsequently. Fatal poisoning has occurred 
from very large quantities (e. g. f 150 grs.), the sleep passing into coma, 
ending in respiratory failure. From 50-90 per cent, has been recovered 
unchanged from the urine, the rest apparently undergoing oxidation in 
the tissues. They act as hypnotics in smaller quantities than any of 
the others of this series. In some animals veronal causes increased 
reflexes and even general convulsions, but this effect has not been seen 
in man. 

Butylchloral, or Crotonchloral (CsH 4 Cl s CH(OH) 2 ), was said by Liebreich 
to possess a specific analgesic action on the nerves of the face and head, 
but this has been shown to be incorrect and, as its effects are identical 
with those of chloral in almost all respects, crotonchloral seems entirely 
superfluous. 

Chloralamide, or chloralformamide (CCUCHOH-NHCHO), was introduced 
as tending to depress the heart less than chloral, but this has not been demon- 
strated. It is said to be less irritant than chloral in the stomach, but to be 
somewhat slower and less certain in its effects. Chloral is formed by its de- 
composition in the body, and is excreted as urochloralic acid, and fatty degener- 
ation has been observed after its prolonged administration. 

Chloralose (CgHnCUOe), a sugar compound of chloral, acts much more like 
morphine than like chloral, depressing the psychical functions, while increasing 
the reflexes until convulsions resembling those of strychnine may be produced. 
The heart is comparatively little affected, and the respiration remains strong 
unless very large doses are given. In man it induces sleep, which is sometimes 
attended by distinctly exaggerated reflexes, however, especially when large 
doses are given. 

Amylene Hydrate, or dimethylethylcarbinol ((CH,) a COHCH a CH,), is closely 
allied to paraldehyde in its effects but is twice or thrice as powerful, 
while it is only one-half as strong as chloral. It is said to depress the heart 
more than paraldehyde, but less than chloral, and to produce excitement and 
convulsions in the carnivora, but not in the herbivora. Even in man, it causes 
excitement more frequently than most other soporifics, and Harnack and 
Meyer state that it first stimulates and then depresses the respiratory centre 
as well as other parts of the central nervous system, and that it induces a very 
marked fall in the temperature. It has little or no effect on the general meta- 
bolism, and is excreted in the urine in combination with glycuronic acid in the 
rabbit, but is exhaled by the lungs for the most part by the dog and possibly 
by man. It is less certain in its action than chloral but has not received so wide 



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SOPORIFICS—CHLORAL GROUP 233 

a trial as it would seem to merit. A combination of chloral and amylene hydrate 
has been introduced under the name of Donniol, but offers no advantages over 
chloral. 

Urethane, or ethyl carbamic ester (CONHjCXVHt), is too weak and inconstant 
in its action in man to be satisfactory. In many cases it is an almost perfect 
hypnotic, easily taken in solution, producing light sleep with no after-effects, 
but in others it seems to have little or no hypnotic effect. It is oxidized in the 
body to urea. Hedonal, the amyl carbamic ester (CONHjOCjHn), appears to 
have a greater hypnotic effect than urethane, but also fails to induce sleep 
in a considerable proportion of cases. It is followed by no after-effects and is 
oxidized in the body in the same way as urethane. 

Bromoform, (CHBr 8 ) has anaesthetic properties like chloroform, but is not 
volatile enough for inhalation. Of late years it has been used internally in 
whooping-cough, and in this relation it is important to remember that it gives 
rise to fatty degeneration when taken continuously. A number of cases of 
alarming poisoning in children have been recorded from its use. It has also 
been used occasionally in insomnia. 

Bromal (CBr a COH) differs in several respects from chloral in its action. 
In animals its injection "is followed by restlessness and excitement, and then 
by stupor, which is often accompanied by dyspnoea, and ends in failure of 
the respiration, or in convulsions. The pupil is much contracted, and profuse 
salivation is observed. It acts on the heart like chloral but is much more poison- 
ous, and is scarcely used in therapeutics. 

Chloretone, trichlorpseudobutylalcohol (CCUCCCHa^OH), resembles chloral 
in most respects, but is less liable to irritate the stomach. Very large doses 
have been swallowed without producing any untoward symptoms, but the 
hypnotic effect is obtained by the use of smaller doses than are necessary in 
the case of chloral. Like chloral, chloretone has some virtues as an antiseptic, 
and in addition it paralyzes the terminations of the sensory nerves when it is 
applied locally and has proved of value as a local anaesthetic. 

Isopral, the trichlorisopropylalcohol (CCUCHCHjOH), resembles chloretone 
closely. 

Many other similar bodies have been introduced as hypnotics, but have 
not proved to possess any advantages over those already enumerated. Among 
these are hypnone (C«H 6 COCH,), neuronal ((C 2 H 6 ) 2 BrCCONH,), bromural, 
and brometone. 

Tolerance is soon acquired for each of these drugs, and when it is 
developed for one, large doses of any of the others are required in 
order to produce sleep. Tolerance for alcohol also involves the use of 
larger quantities of the hypnotics, and in fact often leads to the com- 
plete failure of any except the most powerful. 

Not infrequently the hypnotics lead to skin eruptions, especially 
when used for some time. These assume various forms, the most 
common being of the erythema order, but among others urticaria, pur- 
pura, papular eruptions and blisters occur. 

Habit. — Prolonged abuse of chloral leads to a condition somewhat 
resembling that seen in chronic alcoholism or morphinism, and marked 
by general depression and cachexia, with impairment of the mental 
powers, digestive disturbance and exanthemata. The sudden with- 
drawal of the drug in these cases has sometimes led to symptoms 
resembling those of delirium tremens. Cases of sulphonal and veronal 
habit have also been reported with symptoms resembling those of the 
chloral habit. 



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234 SUBSTANCES ACTING AFTER ABSORPTION 

Preparations. 

Chloralum Hydratum (U. S. P.), Chloral Hydras (B. P.) (CCUCH(OH) a 
or (CCUCOH+H2O), a crystalline solid, of a characteristic pungent odor, and 
hot, acrid taste, readily soluble in water, alcohol, ether and oils, is almost 
invariably prescribed in dilute solution in svrup. Its deliquescent properties 
preclude its use in most of the solid preparations, and its irritant effects contra- 
indicate hypodermic injection. Dose, 1 G. (15 grs.) ; B. P., 5-20 grs., which 
may be repeated if necessary, in one or two hours. 

Syrupus Chloral (B. P.) (20 per cent.), £-2 fl. drs. 

Paraldehydum (U. S. P., B. P.) (CeHnOi) a colorless fluid of •strong, char- 
acteristic odor and burning taste. It may be prescribed in brandy and water, 
or in water up to 10 per cent., or in capsules. 2 c.c. (30 mins.) ; B. P., J-2 fl. 
drs. 

Barbitonum (B. P.), Veronal (CjH*)jC(CONH)jCO, colorless crystals with 
a faint bitter taste, soluble in 145 parts of water; prescribed in powders or 
tablets, to be dissolved in warm water or milk. Dose, 0.3-0.5 G. (5-8 grs.). 

Sulphonal (B. P.), Sulphonmethanum (U. S. P.) ((CH,),C(SO,C,H 6 )2), 
a crystalline powder, without taste or odor. It may be prescribed in powder 
form to be taken one to two hours before retiring, but is soluble in hot water 
or milk, and when given in solution acts more rapidly and leaves less confusion 
afterward. It is prescribed in doses of 1 G. (15 grs.); B. P. 10-30 grs. 

Svlphonethvlmethanum (U. S. P.) . Meihy Sulphonal (B. P.), TrionaL (CH,C 2 H»- 
C'(SOiCsHft)i) resembles sulphonal, but is more soluble and has a bitter taste. 
1 G. (15 grs.); B. P., 10-20 grs. 

Mthylis Carbamas (U. S. P.), urethane (CO'OCjH 6 'NHi), colorless crystals, 
odorless, with a cool, saline taste, very soluble in water, alcohol, and ether. 
Dose, 1-5 G. (15-75 grs.). U. S. P., 1 G. (15 grs.). 

Bramoformum (U. S. P.) (CHBri), a heavy, transparent, colorless liquid with 
an ethereal odor and a taste like that of chloroform, very little soluble in 
water, but readily soluble in alcohol. Dose, 0.2 c.c. (3 mins.). 

Chiwdfarmamidum (U. S. P.), Chloral Formamidum (B. P.), or chloralamide 
(CCljCHOHNH'COH), a white crystalline powder with a faintly bitter taste; 
prescribed in powder or in solution in water or spirit. Dose, 1 G. (15 grs.).; 
B. P., 15-45 grs. 

Unofficial. 

Tetronal resembles sulphonal closely, and may be prescribed in the same 
dose and form. 

Medinal or sodium veronal, a white crystalline powder soluble in 5 parts 
of water with a bitter alkaline taste. Dose 0.3-0.6 G. (5-10 grs.) in water. 

Amyleni Hydras ( (CHj)iCOHCHiCHi), a colorless liquid of pungent taste, 
and of an odor somewhat resembling camphor. It may be prescribed in capsules, 
or up to 10 per cent, in water. Dose, 3-5 c.c. (40-80 mins.). 

Hedonal, a crystalline powder with a taste resembling that of menthol, very 
slightly soluble in water. Dose, 2 G. (30 grs.) in powder or tablets. 

Chloretone (CdjC(CH 2 )aOH), colorless crystals with a strong camphora- 
ceous odor, slightly soluble in water, very soluble in alcohol; it may be pre- 
scribed in tablets. Dose, 0.3-1 G. (5-;15 grs.). 

Proponal differs from veronal only in having propyl substituted for ethyl, 
and is used in the same dose. 

Isopral (C^HjCljCHOH), white crystals with a camphoraceous odor and 
aromatic biting taste, soluble in 30 parts of water; prescribed in doses of 0.5- 
0.75 G. (5-8 grs.). 

Therapeutic Uses. — In ordinary practice chloral and veronal are the 
best of the group. Sulphonal and its allies should be avoided on account 
of their capricious poisonous action. Paraldehyde is disagreeable, 



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SOPORIFICS— CHLORAL GROUP 235 

but has been advised as a substitute for chloral in cases where there is 
a tendency to form the habit, as here its disagreeable properties are 
of advantage. Other drugs which are used to cause sleep are opium and 
morphine, cannabis indica, alcohol, bromides, and hyoscine. 

The hypnotics are chiefly used to produce rest and sleep in cases 
of insomnia, and in almost every form of nervous excitement. Until 
the discovery of the therapeutic value of chloral, opium was used 
in most of these cases, and when sleeplessness is due to pain it is still 
preferable to the more modern remedies, which have comparatively 
slight influence on acute pain, except in very large doses. But in 
delirium, mania and convulsions of various kinds, their action on the 
nerve centres is preferable to that of opium, especially where these 
convulsions are of spinal origin or of a reflex nature; thus, in strych- 
nine poisoning and in tetanus, chloral is of great value, although in 
the former it may have to be reinforced by chloroform during the 
convulsions. In delirium from fever or from uremic intoxication and 
similar causes, comparatively small doses often produce most satis- 
factory results, and in various spasmodic 'affections, such as cough, 
asthma and choreic movements, it is exceedingly useful. Chloral has 
also been advised to lessen the pains of labor. 

Most of the soporifics have been used more or less extensively as 
hypnotics in simple insomnia and in insanity, but when the disturb- 
ance assumes a more violent character there is a disposition to return 
to the use of chloral, as at once the speediest and surest remedy of the 
whole group. When there is any reason to suspect fatty degeneration 
of the heart, however, some hypnotic which does not contain chlorine 
ought to be substituted for it, and paraldehyde, hedonal and veronal 
have been introduced in succession to supply the need. In other forms 
of heart disease, chloral may be used without danger and is often of 
great value as a hypnotic; the dread of its affecting the heart delete- 
riously in ordinary doses is quite unfounded. Chloral is often prescribed 
along with opium, and, when thus combined, smaller quantities of each 
drug are required than would be necessary if either were prescribed 
alone, and the sleep following is very deep and restful. It is also used 
very often to reinforce the action of the bromides. 

Chloral has been used externally as a counter-irritant and anti- 
septic, but is more expensive than many other equally efficacious 
remedies. Chloretone solution is an efficient local anaesthetic on 
wounded surfaces, and has been recommended in cases of gastric irri- 
tation and vomiting, which it relieves by paralyzing the terminations 
of the sensory nerves in the mucous membrane of the stomach. 

In cases of acute Poisoning with chloral, the treatment consists in the 
immediate evacuation of the stomach by the stomach tube. Emetics 
are of less value owing to the depression of the medullary centres. 
The patient ought to be kept warm, and caffeine or strychnine may be 
given as a respiratory stimulant, while the complete failure of the 
breathing has to be met by artificial respiration. In acute poisoning 
with the other members of the series the same general treatment is to 



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236 SUBSTANCES ACTING AFTER ABSORPTION 

be applied. When a patient has formed the habit of taking one of these 
drugs, it is generally necessary to send him to a retreat. It seems 
advisable to withdraw the drug gradually. 

Bibliography. 
Chloral. 

IAebreich. Das Chloral, ein neues Hypnoticum, Berlin, 1868. 

Lewisson. Arch. f. Anat. u. Phys., 1870, p. 346. 

Harnack u. Witkowski. Arch. f. exp. Path. u. Pharm., xi, p. 1. 

v. Merino. Arch. f. exp. Path., iii, p. 185. Zts. f. phys. Chem., vi, p. 480. 

Taniguli. Virchow's Arch., cxx, p. 121. 

Remerlz. Inaug. Diss., Halle, 1893. Fortschr. der Med., 1893, p. 265. 

Harnack u. Kleine. Ztsch. f. Biol., xxxvii, p. 417. 

Rohde. Arch. f. exp. Path., lxix, p. 213. 

Sulphonal. 

Kast. Berl. klin. Woch., 1888, p. 309. Arch. f. exp. Path., xxxi, p. 69. 
Kast u. Weiss. Berl. klin. Woch., 1896, p. 621. 
Vanderlinden u. Debuck. Arch, de Pharmacodyn., i, p. 431. 
Neubauer. Arch. f. exp. Path. u. Pharm., xliii, p. 456. 
Tyson and Croftan. Philad. Med. Journ., 1902, p. 882. 

Veronal. 

Fischer and v. Merino. Therap. d. Gegenwart, xlv, p. 97. 

Bachem. Arch. f. exp. Path., Ixiii, p. 228. 

Ordber. Biochem. Ztschr., xxxi, p. 1. 

Jacobj and Roemer. Arch. f. exp. Path., lxvi, pp. 241-312. 

Amylene Hydrate, and other Soporifics. 

v. Merino. Therap. Monatsh., 1887, p. 249. 

Friedl&nder. Ibid., 1893, p. 370. 

Harnack u. Meyer. Ztschr. f. klin. Med., xxiv, p. 374. 

CerveUo. Arch. f. exp. Path., xvi, p. 265. (Paraldehyde.) 

Lahousse. Arch, de Pharmacodyn., i. p. 209. (Butylchloral.) 

Henriol u. Richet. Arch, de Pharmacodyn., iii, p. 191. (Chloralose.) 

SchmiedeberQ. Arch. f. exp. Path. u. Pharm., xx, p. 203. (Urethane.) 

Bradbury. Croonian Lectures, Brit. Med. Jour., 1899. 

Houghton and Aldrich. Journ. Am. Med. Assn., Sept. 23, 1899. (Chloretone.) 

Sollmnnn and Hatcher. Journ. Amer. Med. Assn., Aug. 8, 1908. 



H. OPIUM SERIES. 

Opium has been used in medicine since a very remote period, and 
although many substitutes have been proposed for it of late years, it 
still occupies a position of its own in therapeutics. It is the dried 
juice of the Papaver somniferum, a poppy which is grown chiefly in 
India, China, Egypt, Persia and Asia Minor, but has been cultivated 
in colder climates and is said to produce a more powerful opium there. 
Opium owes its activity to a large number of alkaloids, of which Mor- 
phine, Codeine, Papaverine, Narcotine, and Thebaine are the most im- 
portant. 1 The total alkaloids in opium vary from about 5-25 per cent., 

1 Others are Pseudomorphine, Codamine, Laudanine, Laudanosine, Meconidine, 
Lanthopine, Cryptopine, Protopine, Papaveramine, Rhceadine, Oxynarcotine, Narceine, 
Hydrocotarnine, Gnoscopine (or racemic Narcotine), and Tritopine; many of those occur 
only in traces. 



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OPIUM 237 

and different specimens may contain very different quantities of each 
alkaloid; for instance, morphine may vary from 2.7-22.8 per cent. The 
average percentage of morphine is 10, of narcotine 6, papaverine 1, 
codeine 0.5, thebaine 0.3 and narceine 0.2; the others occur in too 
small quantity to have any influence on the action of the crude drug. 
The alkaloids are found in opium in combination with meconic, lactic, 
and sulphuric acids. The empirical formulae of most of the alkaloids 
have been determined, those of the most important being morphine 
(C17H19NO3), codeine (CigH^iNOs), narcotine (C22H28NO7), papaverine 
(C20H21NO4), thebaine (C19H21NO3). Morphine, codeine and thebaine 
are derivatives of phenanthrene (ChHh) ; the morphine molecule con- 
tains two hydroxyls, one of which is substituted by methoxyl in codeine, 
and in thebaine both are thus substituted and some other changes occur 
in the constitution. Narcotine, papaverine and some of the other 
alkaloids are isoquinoline derivatives. 

The action of opium is mainly due to the large amount of morphine 
contained in it, though the other alkaloids may reinforce its effects. 
Morphine acts chiefly on the central nervous system, but it also affects 
some peripheral organs, such as the intestine. Its action varies con- 
siderably in different animals, and it is therefore necessary to con- 
sider its effects at some length upon the different classes. 

Symptoms. — In Man small quantities of morphine (£ gr.) lessen the 
voluntary movements and produce a drowsiness which soon passes into 
sleep, unless the patient is continually aroused by his surroundings. 
As long as he is kept awake, his actions and movements show nothing 
abnormal, but it is impossible to keep his attention directed to any 
object for long, and as sooh as he is left to himself for a few moments 
he sinks into sleep. After small quantities there is no difficulty in 
arousing him; in fact, the sleep seems lighter than usual and may 
resemble rather a state of abstraction or "brown study." In this con- 
dition the imagination is not depressed to the same extent as the reason, 
and it is often stated, therefore, that opium at first stimulates the 
intellectual powers. This is incorrect, however — the self-control 
and judgment are lessened, and although the stream of thought may 
seem more rapid and the images more vivid than usual, the logical 
sequence and the ideas of time and space are lost, and the condition 
may rather be compared to dreaming than to a real increase of the 
intellectual powers. This stage of abstraction is not by any means 
generally observed and soon passes into sleep, but the unchecked 
imagination may still persist in the form of dreams. Even in this 
early stage pain is felt less acutely, the respiration is slow, and the 
pupil contracted. 

In larger quantities (J- \ gr.), morphine produces deep, dreamless 
sleep, from which the patient is still easily aroused, but which returns 
at once when he is left undisturbed. When once aroused, he can be 
kept awake or can be aroused again after a short interval much more 
easily, some time elapsing apparently before the same degree of depres- 
sion is reached again. As the dose is increased, the sleep deepens 



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238 SUBSTANCES ACTING AFTER ABSORPTION 

into torpor, from which he can be awakened only with difficulty, and 
eventually all efforts to arouse his attention are fruitless and he sinks 
into coma, which may be reached very soon after a large dose. During 
this deeper sleep and coma the respiration is very slow, the pulse is 
regular, full, and of moderate speed. The pupils are contracted to a 
small point and the mouth and throat are dry. The face is purple 
and congested, and the skin feels warm, although the temperature may 
be low. The breathing generally becomes slower and weaker, and 
occasionally periodic (Cheyne-Stokes). The cyanosis increases, the 
pulse becomes smaller and often quicker, the pupils remain contracted, 
but dilate widely just before the final arrest of the respiration. The 
heart continues to beat feebly for a short time afterward. 

After small doses of morphine the patient generally awakes refreshed, 
and, save for occasional dryness of the throat and slight nausea, 
apparently quite normal. Not infrequently, however, headache is 
complained of, and sometimes nausea and vomiting, accompanied by 
marked depression. In rare cases delirium, and even convulsions, 
have been observed soon after its injection, but these symptoms of 
excitement are so rare in the human subject as to be classed as idio- 
syncrasies. Some skin affections, such as itching, and redness, are 
occasionally seen while the action is passing off. 

The lower Mammals are much less susceptible to morphine than man, 
and the action differs in the different species and, to a less extent, 
among the individuals of the same species. While in man depression 
of the central nervous system is the dominating feature, the lower 
animals often exhibit symptoms of excitation of some nervous 
areas. In the dog, the first symptom is not infrequently vomiting and 
defaecation, and then the animal passes into a light sleep, from which 
he can be easily aroused by touching or by noise, but which rapidly 
becomes deeper, so that greater force has to be used to waken him. 
When once awakened, he seems to sleep less heavily for a short time, 
and a much slighter stimulus is enough to arouse him if it is applied 
soon afterwards. When awakened he may perform apparently volun- 
tary movements for a short time, although more clumsily than in his 
normal state, but no complete consciousness is present, the animal is 
stupid and drowsy and soon sinks back into deep slumber again. 
The sensation of pain seems to be much lessened but not entirely 
abolished, and reflex movements are difficult to elicit. • After larger 
quantities an exaggerated sensibility to external stimulation seems 
present, for the animal starts convulsively at loud sounds and on 
pinching, but when left undisturbed lies in profound sleep. The 
respiration is at first quick atid dyspnoeic, the dog panting as if after 
a long run, but later it becomes slow and labored; the pupil is nar- 
rowed; the circulation seems less affected, although a congestion of 
the skin and mouth is often observed. The reflex irritability may be 
distinctly increased by large quantities, and before the respiration 
finally ceases, convulsions generally occur, but these are asphyxial in 
origin and are not due to the direct action of the alkaloid. 



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OPIUM 239 

In the rabbit and other rodents the symptoms are similar to those seen 
in the dog, but the depression is even more marked. An increase in 
the reflex irritability to external stimulation is also evident here, while 
the respiration is slowed from the beginning. In the cat and the other 
felidse, morphine induces wild excitement which may last for several 
hours, the animal rushing round its cage and appearing unable to rest 
for a moment. This excitation is accompanied by a certain degree of 
depression of the intelligence, however, for no attempt to escape is 
made and obstacles are not avoided so carefully as by the normal animal. 
After large doses violent clonic and tonic convulsions may arise and 
prove fatal from exhaustion. Small quantities of morphine produce 
drowsiness in the horse, ass or goat, larger quantities restlessness and 
excitement which may pass into convulsions and death. 

In Birds morphine causes vomiting, drowsiness, sleep and stupor, 
with slow and imperfect respiration, very much as in mammals; in 
common with all the lower animals they are much less susceptible to 
its influence than man, but the tolerance does not seem greater than 
that of rabbits and dogs when the drug is administered hypodermically. 
It seems to be absorbed with difficulty from the crop. 

The Frog is remarkably tolerant of morphine, no change whatsoever 
following the injection of quantities which would cause distinct symp- 
toms in man. The first effects elicited are a diminution of the spon- 
taneous movements, which become clumsy and ill-coordinated, and 
finally cease. This condition may last for several hours, when a series 
of symptoms of an entirely different nature appear. The reflex response 
to irritation is distinctly depressed during the first stage, but in this 
second phase it begins to return, and eventually a condition of exag- 
gerated reflex irritability sets in reseiiibling that seen in strychnine 
poisoning, except that the frog seems more easily exhausted. The same 
tetanic contractions of the muscles are observed, however, with opis- 
thotonos and cessation of the respiration, interrupted by periods of 
quiescence and exhaustion. The animal often dies in these convulsions, 
but it may survive to pass again through a stage of depression before 
regaining its normal condition. 

Action. — The action of morphine on the Central Nervous System 
in man is almost purely depressant, but it differs from the alcohol- 
chloroform group in its selective action on the respiration and on pain 
sensation, which are both much reduced by doses which have little 
effect on the general consciousness. The pain of disease is deadened 
or even entirely removed, while the intelligence is almost as acute as 
usual, and the patient is able to answer questions and converse freely, 
and may seem unusually sensitive to impressions caused by loud noises 
or sudden flashes of light. But while a constant pain is alleviated, 
a sudden shock causes almost as much pain as without morphine, and 
when the patient is once aroused, the sensitiveness to pain apparently 
persists for some time. Morphine thus seems to lessen the power of 
attention, and under it the individual remains almost unconscious of 
any constant stimulus, but he can be aroused by a sudden intense 



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240 SUBSTANCES ACTING AFTER ABSORPTION 

stimulus and only relapses to his former lethargy after some time. 
This specific action on pain indicates that morphine depresses with 
special power the paths by which pain stimuli reach the consciousness; 
it has been suggested that it may interrupt these paths at their synapses 
in the region of the basal cerebral ganglia (Head). 

The motor areas of the cerebral cortex are not affected by small doses 
of morphine, but larger quantities lower and eventually abolish the 
excitability by electric shocks. Exner found that the interval between 
a signal and the movement in response is not altered, but others state 
that the reaction to a slight touch is retarded. The acuteness of sen- 
sation, as indicated by the smallest distance between two points on 
the skin which the patient can recognize as distinct, is reduced by mor- 
phine owing to the central depression; it has no direct action on the 
sensory organs themselves. 

While the effects of morphine on the central nervous system in man 
are chiefly depressant, and this is especially marked in pain sensation 
and respiration, some other areas seem to be exceptionally resistant 
to its action. Thus the circulatory centres in the medulla are little 
affected directly by quantities which depress the respiration to a 
dangerous extent. And there is, according to one view, an actual 
stimulation of the nerve centre which causes contraction of the pupil. 

In animals, the central nervous symptoms of morphine poisoning 
present an extraordinary mixture of stimulation and depression and the 
relative prominence of these varies widely, in different species. The 
stimulation effect on the brain is best manifested in the wild excitement 
of the cat and its allies under morphine, while the narcotic action 
predominates in the rabbit and to a less extent in the dog; even in the 
cat some depression of the intelligence is to be made out. In the cat 
and rabbit the respiration is depressed as in man, but in the dog there is 
a stage of marked acceleration present at first. In the dog the vomit- 
ing centre is excited and the cardiac inhibitory centre of the medulla 
is also stimulated. It is impossible at present to suggest any general 
theory of the action of morphine on the nerve cells which covers these 
differences in the behavior of different animals and also in the reaction 
of different nerve centres in the same animal. 

The effect of morphine on the Spinal Cord has been studied almost 
exclusively in the frog. The reflex irritability in these animals is 
first diminished to a slight extent, and then increased to the same 
degree as by strychnine. In all animals the cord is less depressed than 
in the corresponding stage of chloral poisoning, for if two animals are 
poisoned, the one with morphine, the other with chloral, until no 
voluntary movements occur, the reflexes of the one poisoned with 
morphine are always found more active than those of the other. 

To sum up the action of morphine on the central nervous system, it 
produces great depression which is especially marked in the sensation 
of pain and in the respiration; the cerebral motor functions are less 
affected than the power of perception, the will, and the attention. 
In man the failure of the respiration closes the course of the intoxication, 



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OPIUM 



241 



but in the cold-blooded animals a further development of excessive 
reflex irritability follows which may pass into tonic convulsions. Even 
in the higher animals and man some indication of this action on the 
cord may occur, and in the feline group this stimulation involves not 
only the cord, but also the motor areas of the brain. 

Respiration. — In man and in most other animals the respiration is 
slowed by morphine from the beginning 1 (Fig. 13), and as the dose is 
increased, the slowing becomes progressively greater. After small 
quantities the breathing may be rather shallower, especially if sleep 
follows; but as the rate slows the depth increases, though not suffi- 
ciently to compensate for the slowing, and the total air breathed may 
fall to one-half the normal or less. The characteristic effect of morphine 
is thus a diminution in the rhythm of the centre, which remains sus- 
ceptible to reflex stimulation, but is unable to accelerate the discharge 
of impulses to the same extent as normally. The inhalation of carbon 
dioxide in unpoisoned animals quickens and deepens the respiration, but 
under morphine, while it deepens it as much as before, it is unable to 

Fiq. 13 



l ; 






Respiration of the cat. At M , injection of morphine intravenously. The respiration 
is immediately slowed and the movement is increased in depth. 

quicken it in the same measure. If morphine causes rest and sleep, less 
carbon dioxide is formed in the tissues and though less is excreted owing 
to the slowness of the breathing, there may be no accumulation in the 
blood and the depth of the respiration remains unchanged or may be 
shallower. But if the slowing is more marked, the gas accumulates in 
the blood and acting on the respiratory centre deepens the breathing, as 
it cannot accelerate it except to a limited extent. 

In the later stages of morphine poisoning, the breathing often becomes 
irregular, and this irregularity may have a periodic character, a series 
of deep respirations being followed by several progressively weaker 
ones and then by complete inactivity for several seconds. The breathing 
then recommences with a very slight movement, followed by a series 
increasing regularly in strength and then again descreasing (Fig. 14). 
This form of respiration (Cheyne-Stokes) appears to arise in part from 
the depression of the respiratory centre, in part from the asphyxia 



1 In the dog there is often a preliminary stage of rapid, panting respiration, which 
may be secondary to the emetic action in this animal. 
16 



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242 SUBSTANCES ACTING AFTER ABSORPTION 

of the heart, which results from the inefficient respiration and which 
leads to periodic variations in the blood-pressure and in the blood- 
supply to the brain (Barbour). When the respiratory centre is once 
aroused by the accumulation of carbon dioxide and by the anaemia, it 
remains less narcotized for some time and thus a series of respirations 
follow which reduce the carbon dioxide of the blood and also relieve 
the asphyxia of the heart. The blood-supply to the brain increases, 
and thus the stimuli to the respiratory centre furnished by the carbon 
dioxide and the anaemia are both removed and the centre again becomes 
dormant (Fig. 14) until asphyxia of the heart and the carbon dioxide 
again arouse it to a new phase of activity. 

Fig. 14 




Tracings of the respiration (upper) and blood-pressure (lower) during Cheyne-Stokes 
respiration in a cat under a large dose of morphine. (Barbour.) 

Towards the end the respiration becomes gradually slower and 
weaker, and often loses its periodic character. Even after conscious- 
ness fails to be aroused by the most powerful shocks, some influence 
may be exerted on the respiratory centre. Thus the sudden applica- 
tion of cold water may cause several deep respirations, although it 
fails to dispel the stupor, but the respiration finally fails to react to 
these applications and soon afterwards ceases. 

Jackson has recently noticed that morphine and many of the other 
alkaloids of opium constrict the bronchi in animals; this appears to 
arise from a direct action on the bronchial muscle. It is not known 
that any such effect occurs in man in morphine poisoning. 

Morphine has little direct action on the Circulation in man; the 
heart is often slightly accelerated at first, perhaps from the slight 
nausea. In the dog the heart is slowi and irregular from powerful 
stimulation of the vagus centre. 



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OPIUM 243 

The blood-pressure remains high and the peripheral arteries in 
general show no change of calibre, with the exception of those of the 
skin, especially of the head and neck, which are dilated, rendering the 
face flushed and hot; as asphyxia comes on the flush becomes more 
dusky and cyanotic, but the vessels remain dilated, so that the face is 
of a bloated, purple color. The dilatation of these vessels, which is 
due to some obscure central action, has little influence on the general 
pressure, but causes a sense of warmth in the skin, which is occasionally 
followed by itching and discomfort. It may account in part for the 
increased perspiration often observed, although this is doubtless con- 
tributed to by other factors. As asphyxia advances, the pulse may 
become slow, while the blood-pressure varies, either rising from the 
asphyxial activity of the vasomotor centre or falling from the slowness 
of the heart. These effects are entirely absent if the blood be suffi- 
ciently aerated by artificial respiration, and are, therefore, to be 
regarded as indirect results of the action on the respiratory centre. 

The selective action of morphine is thus well illustrated in its effects 
on the medulla oblongata in man, for the respiratory centre is para- 
lyzed before the centres for cardiac inhibition and vaso-constriction are 
affected to any marked extent. 

The peripheral Muscles and Nerves are also unaffected by morphine 
in any except overwhelming doses. Even when directly applied to 
the nerve it has but little effect on the irritability (Waller). It is often 
stated that the sensory terminations are paralyzed by morphine, and 
solutions are therefore injected into the seat of pain, or liniments are 
rubbed into the skin over it, but as a matter of fact, morphine seems 
entirely devoid of any such local action. The sensibility of the skin 
is lowered by an injection, it is true, but no more so at the point of 
application than in other parts of the body, so that the action appears 
to be central. 

In morphine poisoning in man, the Pupil is contracted to pin-hole 
dimensions until just before the final asphyxia, when it dilates widely. 
In some animals, such as the dog and rabbit, the same effects are seen, 
while in birds the pupil remains unaffected, and in animals in which 
morphine causes movement and excitement, it is dilated widely. The 
contraction arises from direct or indirect stimulation of the oculomotor 
centre, and not from any local changes in the eye, for when applied 
directly to the conjunctiva morphine has no effect; atropine applied to 
the conjunctiva at once removes the myosis produced by morphine. 
The terminal dilatation seen in man is not due to any direct action 
of the poison, but is a result of the general asphyxia. 

As a general rule the Secretory Glands seem to be rendered less active 
than usual by morphine. When it produces nausea it may increase 
the saliva and the mucus, but these are the usual accompaniments of 
this condition and cannot be considered due to any special action of 
the poison. The sweat glands are exceptions to the general rule, how- 
ever, for slight perspiration is generally observed from the therapeutic 
action, and profuse perspiration is seen before death in some cases in 



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244 SUBSTANCES ACTING AFTER ABSORPTION 

man from the effects of the asphyxia. The urine does not generally 
show any distinct alteration after morphine in man, but there is not 
infrequently retention in the bladder because the sphincter reflex is 
absent. 

The Alimentary Canal manifests some distinct changes under mor- 
phine, which have not yet been completely explained. In the human 
subject its injection is occasionally followed by some nausea, which is 
much more frequently present, however, during recovery from the 
drug. In the dog nausea and vomiting are almost invariable sequelae 
of its application in any form, and from the rapidity with which 
they follow its subcutaneous injection would seem to be due to 
its acting on the medullary centre. Small quantities of opium or 
morphine lessen the sensation of hunger in the human subject, but this 
is probably to be attributed to central action rather than to any effects 
on the stomach. Riegel states that in man and the dog the gastric 
secretion is generally retarded at first but is subsequently increased 
to a considerably extent. This occurs whether the drug be admin- 
istered by the mouth or hypodermically and is therefore due to some 
change induced by it after absorption. The pancreatic secretion is 
lessened by morphine from direct action on the gland. The rate of 
absorption in the stomach and bowel appears to be unchanged by 
morphine. 

The effects on the intestine vary with the species of animal. In man 
morphine slows the peristalsis and induces constipation, and in most 
animals small quantities have this effect; opium and morphine are very 
extensively used in therapeutics to quiet the movements of the bowel. 
Magnus found that the constipating action could be elicited after all the 
nerves to the stomach and bowel were divided, so that it is quite inde- 
pendent of the action on the central nervous system. He states that 
the passage of food through the stomach is much delayed in the cat 
through a persistent contraction of the sphincter antri pylorici which 
keeps the contents in the cardiac end, and later of the pyloric sphincter 
which delays their passage into the duodenum. Their passage through 
the bowel is also slower than usual, and this retardation of the intestinal 
peristalsis is especially marked when it has been previously accelerated 
by irritant purgatives such as colocynth. This slow passage of the 
contents along the canal permits of more complete absorption of the 
fluids and thus leads to the stools being fewer and of firmer consistence. 
In addition there is less secretion from the intestinal mucous membrane 
under morphine. In man, the effects of morphine in the movements 
of the alimentary canal resemble those in animals in general characters. 
But the delay in the stomach is less marked, while that in the intestine 
is greater. The contents pass through the small gut more slowly than 
normally and make a prolonged stay in the caecum and lower part 
of the ascending colon, and this delay in the large bowel is the chief 
factor in the constipation. The action in slowing the gastric movements 
is most marked in the young and may be almost unnoticeable in adults 
(Zehbe). In both cases the action is a peripheral one in the wall of the 



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OPIUM 245 

stomach and bowel. Very large doses cause violent peristalsis and 
repeated evacuation of the bowel in the dog and cat, but this effect 
does not occur in man even in morphine poisoning; it has not been 
satisfactorily explained. 

Morphine frequently causes a slight fall in the Temperature, which 
may be explained by the less active movements and the dilatation of 
the cutaneous vessels; sometimes a slight preliminary rise in the tem- 
perature has been seen in man^ It is found that animals under mor- 
phine react less to an increase in the surrounding temperature than 
unpoisoned ones; L e., a normal animal exposed to a high temperature 
takes measures to prevent its internal temperature from rising above 
the normal, while, under morphine, these measures are less effective, 
and the temperature rises more rapidly and to a greater height; this 
indicates that the temperature centre in the brain is rendered less 
sensitive. 

Metabolism. — The excretion of carbonic acid is lessened during the 
depression stage, while in those animals in which excitement is pro- 
duced, it may be considerably augmented from the increased muscular 
movement. The imperfect respiration leads to an increase in the 
lactic acid of the blood and urine and to the disappearance of glycogen 
from the liver. Sugar may appear in the urine from the same cause. 

Excretion. — Morphine is excreted mainly by the digestive tract, in 
the saliva, stomach and bowel, and is therefore found in large quan- 
tities in the faeces even after hypodermic injection. Traces of it 
occur also in the urine after large doses. It appears in the stomach 
very soon after injection; a weak reaction occurring after two and one- 
half minutes according to Alt, but after about an hour no further 
excretion into the stomach has been shown to occur, although its nar- 
cotic action persists much longer. A certain amount of the morphine 
undergoes partial oxidation in the tissues, and some oxidation products 
have been said to occur in the urine. 

Tolerance. — The continued use of morphine or opium leads to a con- 
dition of tolerance, in which enormous doses of the drug are necessary 
to elicit any effect. Faust has succeeded in producing a similar state 
in dogs, and finds that much more morphine is oxidized in the tissues 
in this condition than in untreated animals; for when a normal dog 
received an injection of morphine, over 60 per cent, of the amount 
injected could be recovered from the stools, while when a much larger 
quantity was injected into a tolerant animal, none whatever was found 
in the excreta. The absence of symptoms from large doses in mor- 
phinists is not due wholly to the poison being oxidized before it can 
reach the brain, however, for Cloetta was able to isolate large quantities 
from the tissues of animals in which tolerance had been established. 
And while tolerance is easily acquired by some centres, others fail to 
develop it; thus dogs which have become so tolerant that even large 
quantities fail to induce narcosis, continue to react to even small quanti- 
ties by slowing of the pulse; the cerebral nerve cells have become 
tolerant, but those of the vagus centre have failed to do so (Egmond). 



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246 SUBSTANCES ACTING AFTER ABSORPTION 

Some nerve cells thus become habituated to the presence of morphine 
in the blood and cease to react to it as strongly as in normal individuals, 
while others remain susceptible; in addition, the tissues acquire a 
greater power of oxidizing morphine. The attempt to find "anti- 
morphine serum" has proved fruitless. 

Codeine given in moderate quantities resembles morphine in its 
action in man but is much weaker. Thus one grain of codeine induces 
sleep and relieves pain in about the same degree as one-fourth grain of 
morphine; the sleep is said to be not so deep and restful as that which 
follows the administration of morphine, and the patient is liable to be 
awakened by slight noises, and is restless and often unrefreshed when 
he awakens. Somewhat larger quantities, instead of inducing deeper 
sleep, increase the restlessness and cause a considerable exaggeration 
in the reflex excitability. The respiration is slowed in the same way 
as by morphine but here again morphine is at least four times as power- 
ful; large doses of codeine do not slow the respiration further. The 
pupil is slightly contracted during the codeine sleep, but dilates when the 
excitement stage follows. Codeine thus depresses the central nervous 
system in man, though there are indications of stimulation also when 
large quantities are used. In animals these symptoms of excitation 
are more obvious, however, especially in the spinal cord, in which the 
reflexes are rendered more acute and may finally give rise to spasms. 
In the cat morphine induces cerebral excitement, but under codeine 
this is often seen in the dog also and even to a slight extent in man. 

Codeine acts less on the stomach and bowel than morphine, but when 
given in doses adequate to cause narcosis, it also causes constipation. 
It is excreted by the urine unchanged and none has been shown to 
undergo destruction in the tissues, as occurs in the case of morphine. 
No tolerance is acquired for codeine even after long use, and patients 
may in fact appear more susceptible to the drug, a dose which at first 
gave relief now causing nausea and vomiting. It is possible that this 
may indicate a tolerance of some parts of the central nervous system, 
which is not shared by the vomiting centre. 

Codeine is methylmorphine, and a number of similar compounds have been 
formed artificially, such as ethylmorphine and amylmorphine. Two of these, 
ethylmorphine (Dionine) and benzylmorphine (Peronine) have been introduced 
into therapeutics, but appear to possess no advantages over codeine. 

Oxydimorphine (CuHuNsOe) has been found in opium by some investi- 
gators, and has a very weak narcotic action resembling that of morphine. 

Heroine, diacetylmorphine, is an artificial alkaloid formed from morphine 
by substituting acetyl for its two hydroxyls, and has attracted some attention 
recently through its being advocated as a respiratory sedative in cough. It 
appears to resemble morphine in its general effects, but acts more strongly on 
the respiration, and is therefore more poisonous. The action on the respiration 
is the same in kind as that of morphine but is stronger, and the advantages 
claimed for heroine by its advocates have not been jconfirmed by impartial 
investigation. It appears to have rathfiMHtffe depressant effects on the cerebrum 
than codeine. In animals large doses cause excitement and convulsions, and in 
man these have also been observed in cases of poisoning; the exhaustion from 
these convulsions, is the cause of death in animals. Heroine is excreted mainly 



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OPIUM 24? 

in the urine unchanged, but some is found in the stools. When it is given for 
some time, the tissues learn to destroy it and it no longer appears in the excre- 
tions. A certain tolerance is observed, for the narcotic action becomes less 
marked and may entirely disappear, but the exciting action of large doses 
remains unaffected (Langer). Cases of heroine habit have been described 
repeatedly. On the whole the evidence of experimental and clinical observers 
seems to indicate that heroine deserves a place between morphine and codeine. 

Papaverine stands midway between codeine and morphine in its action on 
the central nervous system, but is a comparatively weak poison. Even in 
large quantities it has not the soporific action of morphine, nor does it produce 
the same degree of excitement as codeine. Comparatively small quantities 
are followed by sleep, but this does not become deeper as the dose is increased.- 
On the contrary, the reflex excitability is augmented, and after very large 
quantities some tetanic spasm may be elicited, but this seems to be of spinal 
origin entirely, while that produced by codeine points rather to an affection of 
the lower part of the brain. Papaverine has more tendency to slow the heart 
rhythm than either morphine or codeine; it apparently acts directly on the 
heart muscle and not through the regulating centres. The blood-pressure is 
little affected by ordinary quantities, however. Papaverine is said to have a 
greater action in lessening peristalsis than the other alkaloids. 

Narcotine resembles codeine rather than morphine, but has even less depres- 
sant action, especially in mammals. In the frog a short stage of depression 
is elicited, but this soon gives place to strychnine-like exaggeration of the 
reflex excitability. In mammals there may be but little appearance of depression, 
the injection being followed by a condition of excitement immediately — rest- 
lessness and tremors with increased reflexes, which eventually lead to con- 
vulsions, during which the animal generally succumbs exactly as in strychnine 
poisoning. The pulse is considerably slower after narcotine injection, from a 
direct action of the drug on the heart. The sympathetic ganglia are first stimu- 
lated and then paralyzed. Narcotine is a very much less poisonous body than 
either morphine or codeine, and very large quantities have been administered 
repeatedly with little or no narcotic effect. It is a compound of hydrocotarnine, 
another opium alkaloid, with opianic acid. Hydrocotarnine apparently acts 
very much in the same way as narcotine, but produces even less depression. 

Narceine has little or no action of any kind. It is exceedingly insoluble 
in water, and its salts are broken up in aqueous solution, so that it is probably 
absorbed very slowly and imperfectly. 

Thebaine seems to have practically no depressant action. It sometimes 
produces some heaviness and confusion in man, but this is accompanied by 
symptoms exactly resembling those described under strychnine, and it may 
therefore be considered as belonging to the latter series rather than to that 
of morphine; it is very much less active than strychnine, however. Thebaine 
seems to differ from morphine also in its effects on the bowel, for Vamossy 
finds that it increases peristalsis instead of allaying the irritability. Laudanine 
seems to resemble thebaine very closely in its effects. 

The other alkaloids occur in very minute quantities in opium and possess 
no great iilterest from the therapeutic point of view. Very little has been 
done to elucidate their pharmacological action, but those which have been 
examined seem to produce effects resembling those of the better known mem- 
bers of the group. In frogs, small doses of Cryptopine and Protopine produce 
a narcotic condition similar to that following the injection of morphine, but 
the reflex irritability does not show the same exaggeration afterward; larger 
quantities cause complete paralysis of the whole central nervous system and 
.partial paralysis of the terminations of the motor nerves, which gives rise to 
irregular contractions and relaxations of the muscles when the nerves are 
stimulated (Hale). In mammals, no depression occurs, but restlessness and 
eventually convulsions, which do not seem to be of spinal origin but rather 
suggest a stimulation of the cerebrum and midbrain. The heart is slow and 



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248 SUBSTANCES ACTING AFTER ABSORPTION 

weak, and some depression of the vaso-motor centres is caused by large quantities 
of the poisons. The respiration does not seem to be depressed, but rather to be 
accelerated, save by the largest doses. They paralyze the terminations of the 
sensory nerves on local application in the same way as cocaine. The action of 
these two alkaloids on the heart would seem to be further developments of 
the heart action noted after narcotine and papaverine. 

In man morphine is much the most dangerous of the opium alkaloids, 
because death is produced in the narcotic stage through asphyxia. 
In most animals, however, thebaine, codeine and laudanine are more 
toxic, because the failure of the respiration does not occur in the stage 
of depression, but during the convulsions. 

Opium itself contains, besides the alkaloids already discussed, various 
acids with which they are in combination, meconic, lactic, and sul- 
phuric acid, but none of these possess any action of importance. 
Along with these are found gums, sugars, albumins, wax and the other 
common constituents of plant juices, but these merely tend to delay 
the absorption of the active constituents, and cannot be said to play 
any part in the effects of opium. Of the alkaloids, morphine is present 
in greatest abundance, and is also the most powerful in its effects 
on man. According to most observers the action of opium on the brain 
is practically identical with that of morphine, when due allowance 
is made for the slower absorption of the crude drug from the bowel; 
if any difference exists, it is so small as to be inappreciable in ordinary 
cases. But an old view that opium is a better narcotic than morphine 
has recently been resuscitated, and a preparation of all the alkaloids of 
opium without the other constituents has been introduced under the 
name of Pantopon (omnopon). This has not been shown to have more 
narcotic action than the morphine that it contains, and its composition 
varies considerably. According to Straub, the alleged superiority of 
opium over morphine as a narcotic is due to its containing narcotine, 
which in itself has comparatively little depressant power, but which 
intensifies that of morphine to a marked extent when they are adminis- 
tered together. He has therefore introduced morphine-narcotine meco- 
nate under the name of Narcophine as superior to morphine in narcotic 
power while less depressant to the respiration. The superiority 
of these preparations as narcotics over morphine has not yet been 
established, and their relative power in relieving pain is also unknown. 
As regards their action on the alimentary tract, opium and. pantopon 
are practically identical, morphine is less constipating than pantopon, 
and narcophine is the least active of all. The greater sedative effect 
of opium and pantopon on the intestine may probably be due to the 
presence of papaverine (Zehbe) and codeine (Hesse). 



U. S. P. Preparations. 

Opium, the dried milky exudation obtained by incising the unripe capsules 
of Papaver somniferum, yields when moist not less than 9 per cent, of crystal- 
lized morphine. Dose, 0.1 G. (1| grs.). 



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OPIUM 249 

Opii Pulvis, dried and powdered opium, yielding 12 per cent, of crystal- 
lized morphine. Dose, 0.065 G. (1 gr.) . l 

Extractum Opii, the dried aqueous extract, contains 20 per cent, of mor- 
phine. Dose, 0.03 G. (4 gr.). 

Tinctura Opii (Laudanum) contains 10 per cent, of opium, or from 1.2 to 
1.25 per cent, of morphine. Dose, 0.5 c.c. (8 mins.). 2 

Pulvis Ipecacuanha et Opii (Dover's Powder), 10 per cent, each of opium 
and ipecacuanha powders. Dose, 0.5 G. (7£ grs.). 

Piltdce Opii, each containing 0.065 (1 gr.) of powdered opium or 0.008 (J gr.) 
of morphine. Dose, 1 pill. 

Tinctura Opii Camphorata (Paregoric) contains four parts of opium per 
thousand, along with benzoic acid, camphor, oil of anise and glycerin. Dose, 
8 c.c. (2 fl. drs.). 3 

Morphina (CnHuNOs+HjO), colorless crystals without odor but with a 
bitter taste, practically insoluble in water and only slightly soluble in alcohol. 
Dose, 0.010 G. (i gr.). 

Morphine Hydrochloridum. 

Morphine Sulphas. 

The hydrochloride and sulphate are soluble in about 15-17 parts of water, 
less so in alcohol. They form white, silky crystals with a bitter taste. Dose, 
0.015 G. (i gr.). 

Codeina (CiglfciNOs+HiO), white or nearly transparent crystals with a 
faintly bitter taste, soluble in 80 parts of water and in 1.6 parts of alcohol. 
Dose, 0.03 G. (igr.). 

CoDEiNiB Phosphas, white needle-shaped crystals with a bitter taste, soluble 
in about 2 parts of water. Dose, 0.03 G. (£ gr.). 

Heroine, or diacetylmorphine hydrochloride (unofficial), a white crystalline 
powder soluble in 3 parte of water. Dose, 3-10 mgs. (sV-J gr.). 

B. P. Preparations. 

Opium, the juice obtained by incision from the unripe capsules of Papaver 
8omniferum, inspissated by spontaneous evaporation. When dried it contains 
9J-10J per cent, of anhydrous morphine. Dose, J-2 grs. 

Extractum Opii Siccum contains 20 per cent, of morphine. Dose, J-l gr. 

Tinctura Opii, Laudanum, contains 1 per cent, of morphine, or about 1 gr. 
of opium in 10 mins. Dose, 5-15 mins. for repeated administration; for a 
single administration 20-30 mins. 

Tinctura CamphorjB Composita, Paregoric 4 or Paregoric Elixir, contains 
camphor, benzoic acid, oil of anise and } gr. of opium in each fl. dr. (?V per 
cent, of morphine. Dose, £-1 fl. dr. 

Pulvis Ipecacuanha Compositus, Dover's Powder, contains 10 per cent, 
each of opium and ipecacuanha in powder. Dose, 5-15 gr. 

Pulvis Kino Compositus contains 5 per cent, of opium along with kino 
and cinnamon. Dose, 5-20 grs. 

Pulvis Cretjs Aromaticus cum Opio contains 2\ per cent, of opium along 
with aromatic chalk powder. Dose, 10-60 grs. 

1 Practically identical forms are Opium deodoratum and Opium granulatum, each con- 
taining 12 per cent, of morphine. Dose, 0.065 G. (1 gr.). 

1 Another 10 per cent, tincture is Tinctura Opii Deodoratu Dose, 0.5 c.c. (8 mins.). 

•An unimportant preparation is Mistura Glycyrrhizce Composita (Brown Mixture), 
formed from liquorice, syrup, acacia, wine of antimony, spirits of nitrous ether and 
camphorated tincture of opium, and containing only about 1 part of opium in 2000. 
Dose, 8 c.p. (2 fl. drs.). 

4 Scotch Paregoric or Tinctura Opii Ammoniata contains ammonia, benzoic acid, oil 
of anise and nearly 5 grs. of opium in the fluid oz. (0.1 per cent, morphine). Dose, 
J-l fl. dr. 



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250 SUBSTANCES ACTING AFTER ABSORPTION 

Pilula Plumbi cum Opio contains 12 per cent, of opium along with lead 
acetate. Dose, 2-4 grs. 
Pilula Saponis Composita, contains 20 per cent, of opium. Dose, 2-4 grs. 
Suppositoria Plumbi Composita, each contains 3 grs. of lead acetate and 

I gr. of opium. 1 

MoRPHiNiB Hydrochloridum (Ci7Hi»NOa,HCl,3H 2 0), acicular prisms soluble 
in 24 parts of cold water, one part of boiling water, or 50 of alcohol. Dose, 
Hgr- 

Morphines Tartras* ((CnH^NOa^CiHeCMHiO), a white powder soluble in 

II parts of cold water, insoluble in alcohol. Dose, ^-£ gr. 
Liquor Morphine Hydrochloride 1 per cent., 10-60 mins. 

Injectio MoRPHiNiE Hypodermica contains 2\ per cent, of the tartrate. 
Dose by subcutaneous injection, 5-10 mins. 

Suppositoria Morphine,* each contains } gr. of morphine hydrochloride. 

Codeinjs Phosphas ((Ci7Hi 8 (CH.)NO,,HsP04)*3H 2 0), white crystals with a 
slightly bitter taste, soluble in 4 parts of water, much less soluble in alcohol. 
Dose, J-l gr. 

Syrupus Codeinje Phosphatis, one fluid drachm contains } gr. of codeine 
phosphate. Dose, £-2 fl. drs. 

Diamorphince Hydrochloridum, Heroine or diacetylmorphine hydrochloride, a 
white, crystalline powder having a bitter taste and soluble in 3 parts of water. 
Dose, jH gr. 

Therapeutic Uses. — Opium is one of the most important and most 
extensively used drugs in the pharmacopoeias at the present day as 
in the past. Of late years the crude drug has been largely replaced 
by morphine, but the action is the same, and although morphine is 
preferable in most cases, opium is still specially indicated for certain 
purposes. In almost any disease, conditions which are favorably 
influenced by morphine may present themselves, and these conditions 
alone can be discussed here. 

Pain. — As has been repeatedly mentioned, opium or morphine has 
a special analgesic action which is not shared by its modern rivals 
of the methane series, and which justifies the celebrated dictum of 
Sydenham that without opium few would be callous enough to practise 
therapeutics. The general statement may suffice that severe pain 
indicates opium. Even where the disease itself is one which would 
in ordinary circumstances contra-indicate it, it must always be taken 
into consideration whether the relief of the pain and its attendant 
restlessness may not counterbalance the disadvantages of the narcotic. 
At the same time the danger of inducing the craving for morphine 
cannot be forgotten, for the use of morphine to subdue pain is perhaps 

1 Other preparations of opium are Pulvis Opii Compositus, containing 10 per cent, of 
opium along with pepper, ginger, caraway, and tragacanth (dose, 6-15 grs.), and Pilula 
Ipecacuanha cum ScUla formed from Dover's powder and squills and containing 5 per 
cent, of opium. Dose, 4-8 grs. 

* The acetate, Morphines Acetas, resembles the tartrate except in being less soluble 
and more readily decomposed. 

8 Other preparations containing morphine are the two lozenges, Trochiscus Morphines 
and Trochiscus Morphirue et Ipecacuanhas, each of which contains ■$ I J gr. of morphine, 
while the latter contains in addition ^ gr. of ipecacuanha. Morphine is too powerful 
a drug to be dispensed in lozenges. The Tinctura Chloroformi et Morphines Composita 
(chlorodyne) contains one per cent, of morphine, chloroform, prussic acid, capsicum, 
cannabis indioa, oil of peppermint, and glycerin, and is superfluous. Dose, 5-15 mins. 



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OPIUM 251 

the most fruitful cause of the habit. It is often found that compara- 
tively small quantities of opium are sufficient to remove or at any rate 
to dull pain, but after repeated doses the quantity has to be increased 
owing to tolerance being attained. Codeine may be used instead of 
morphine to allay pain, but has to be given in at least four times as 
large doses, and is ineffective in severe pain. Some forms of pain are 
relieved by the members of the antipyrine series, but these are less 
certain and more limited in their action than morphine. On the other 
hand the antipyretics often relieve pain without inducing sleep, and in 
this possess a great advantage over opium in the treatment of headache, 
neuralgia, and similar conditions. 

Sleeplessness. — Opium was formerly the only drug used to induce 
sleep, but since the discovery of chloral and its congeners, it is used 
less frequently. These fail entirely to replace it, however, where the 
sleeplessness is due to pain, while, on the other hand, they are more 
efficacious in some conditions of excitement. Not infrequently opium 
and chloral are prescribed together for this purpose, and the combi- 
nation acts more efficiently than either of the drugs alone. Each is, 
of course, prescribed in considerably smaller amount than if adminis^. 
tered separately. Opium is less efficient than chloral when there is 
apparently an increased activity of the motor functions of the brain, 
as in wild delirium and mania, and sometimes seems to increase the 
excitement even, but this general statement is subject to numerous 
exceptions, and morphine is still largely used in many such disorders. 
In the true convulsive diseases, such as tetanus, epilepsy and chorea, 
chloral is preferable. In certain forms of motor excitation, especially 
in insanity, hyoscine is indicated as a sedative, and in cases of sleep- 
lessness from anxiety and worry potassium bromide is generally pre- 
ferred to any of the more powerful sedatives. The beneficial effect of 
morphine in many acute febrile conditions is undeniable, and, as in the 
case of alcohol, is due to its lessening the pain and discomfort of the 
patient and inducing rest. A good deal of difference of opinion exists 
as to the advisability of administering opium or morphine in these 
conditions, and there is no question that the routine treatment of fever 
by narcotics is to be deprecated; but on the other hand, restlessness 
and discomfort may in themselves aggravate the disease, and morphine 
is distinctly indicated under these circumstances. 

The preparations chiefly used to relieve pain and promote sleep are 
the extract, laudanum, opium pill, or compound soap pill, and the 
morphine salts and their solutions, including the hypodermic injec- 
tion. 

In Respiratory Disorders opium and morphine are largely used for 
their effects on the centre. Where it is desirable to lessen its irrita- 
bility, as, for example, in excessive cough and dyspnoea, opium may 
be indicated. On the other hand, when there is a profuse expectora- 
tion, the irritability of the centre cannot be lowered without danger, 
and opium is contra-indicated. Opium gives relief in cases of asthma, 
but there is always danger of inducing the habit. 



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252 SUBSTANCES ACTING AFTER ABSORPTION 

Opium is often combined with expectorants in the treatment of 
cough, and a number of suitable preparations are provided in the 
pharmacopoeias, such as paregoric, Dover's powder and other prepara- 
tions containing ipecacuanha, and codeine phosphate. The object 
of combining expectorants with opium is to allay excessive coughing; 
the opium reduces the excitability of the centre, while the expectorant 
causes a secretion of mucus in the respiratory passages and thus pro- 
tects the irritated mucous membrane. The combination is indicated 
only in dry cough with little expectoration, and when there is abundant 
sputum to be removed by coughing the treatment may be harmful. 
Codeine is often preferred to morphine in these cases, because it reduces 
the excitability of the respiratory centre with less marked cerebral 
depression. Heroine and dionine were introduced as superior to codeine 
in this respect, but impartial investigators of these drugs have generally 
failed to obtain better results from them than from codeine and mor- 
phine. 

In Peritonitis and Intestinal Disorders opium is indicated doubly; 
first, for its general action in allaying pain and restlessness; and 
secondly, for its special action in lessening the movement of the intes- 
tine. Opium is preferable to morphine for these purposes because it 
lies longer in the bowel, and therefore evolves a stronger action there 
than on the rest of the economy, and also because the minor alkaloids 
have some constipating effect. In colic, especially lead colic, it often 
relieves the pain without increasing the constipation and seems to allay 
the spasm of the bowel without stopping entirely its peristalsis. In 
diarrhoea opium may be given to check the excessive peristalsis, though 
in the severer forms of dysentery it generally fails to have this effect, 
and in septic purging is rather to be avoided. In perforation and 
hemorrhage from the bowel, opium is the most efficient of all remedies, 
as it allows adhesions or clots to be formed by checking movements of 
the intestine, which would provoke further leakage. 

The B. P. offers a number of preparations specially designed for 
use in intestinal disorders and especially in diarrhoea, such as the com- 
pound kino powder, the compound chalk powder, the lead and opium 
pill, and the compound lead suppository and morphine suppository. 
Instead of these the tincture, extract, or other simple preparation may 
be used. 

In Haemorrhage, where the bleeding point cannot be reached, opium 
or morphine is most valuable. This is not from any direct effect on 
the vessels or blood, but because it allays the restlessness which follows 
the loss of large quantities of blood and thus allows the blood to clot 
in the ruptured vessel. The same preparations are suitable here as 
for pain. 

In Vomiting morphine is sometimes used in small quantities, but it 
seems doubtful whether with any benefit. 

Morphine is not infrequently given as a preliminary to general 
Anaesthesia in nervous patients (£ gr.), and in recent years operations 
have often been performed under morphine and hyoscine (scopola- 



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OPIUM 253 

mine) alone. For this purpose $ gr. (10 mgs.) of morphine and about 
2-J-fr gr. (0.3 mg.) of hyoscine are injected an hour and a half before 
the operation, and again half an hour before it. The anaesthesia 
induced is often sufficient, and, if necessary, a few drops of ether or 
chloroform may be inhaled to complete it. 

Opium has been used instead of quinine in Malaria, and though it 
cannot be said to replace the latter, has a distinct effect in some cases 
apparently. Of course, symptoms may arise in malaria as in other 
diseases in which opium is specially indicated, but apart from this, 
cases of malaria of old standing seem to be benefited by opium with 
or without quinine. 

Opium or morphine has sometimes been used in Diabetes with good 
effects; for though the glycosuria seldom disappears under its use, 
it is lessened in some cases (Kaufmann). Codeine has been advised 
instead of morphine in this disorder, as it is less likely to cause con- 
stipation and gastric disturbance. 

Lastly, opium is used as a Diaphoretic, and for this purpose it is 
generally combined with ipecacuanha and prescribed as Dover's powder. 
Although in itself it has little or no diaphoretic action, opium may 
augment the effects of ipecacuanha through dilating the skin vessels. 
Opium and its alkaloids have no effect applied to the skin, and the 
plasters, ointments and other similar preparations are obsolete. 

Codeine is much less often used than morphine in therapeutics. It 
is of comparatively little value in allaying pain or excitement, but 
has been found of benefit in the sleeplessness of melancholia. It is 
used not infrequently as a sedative in cough, and, as has been stated, 
in diabetes. There is little or no tendency to form the codeine habit, 
and it has been suggested as a substitute for morphine in morphino- 
mania, but has not proved efficient in this condition. 

Opium- and morphine are contra-indicated in children at the breast, 
in whom even minute quantities (e. g., one drop of laudanum) may 
produce the most alarming symptoms of poisoning. After one year 
this special susceptibility seems to pass off and the dose of morphine 
has not to be reduced more than that of other drugs (Dobeli). In 
great weakness, especially in cases where the respiration is barely 
sufficient to aerate the blood, or where profuse expectoration is present, 
morphine has to be administered with the greatest care. In cerebral 
congestion and meningitis the opiates are generally contra-indicated. 
It must be remembered also that both opium and morphine are liable 
to disturb the digestion and to cause nausea and want of appetite, 
and that these may prevent their use in cases in which they would 
otherwise be suitable. In some persons opium invariably causes nausea 
and vomiting, either soon after its administration or while its effects 
are passing off. For this idiosyncrasy morphine may be substituted 
for opium, although this is often equally nauseating, or chloral and 
bromides may be prescribed with opium to prevent the unpleasant 
after-effects. In all chronic painful diseases opium or morphine has to 
be given guardedly, on account of the risk of the formation of the 



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254 SUBSTANCES ACTING AFTER ABSORPTION 

opium habit; the patient ought to be kept in ignorance of the drug 
used as far as possible, and it should be alternated with others. Of 
course, in cases of incurable, hopeless disease, where life can only last 
a comparatively short time and is attended by severe suffering, this 
objection does not hold, and it may be necessary to administer morphine 
without stint and in ever-increasing quantity. 

Morphine and opium are often said to be contra-indicated in Bright's 
disease of the kidney. This seems to be due to the belief that mor- 
phine is excreted in the urine, which has now been shown to be erro- 
neous. There seems no reason to believe that morphine is harmful 
in these conditions, and in some forms of uraemia it has even been of 
considerable benefit. 

Acute Poisoning with morphine or opium is one of the commonest 
forms of intoxication, with the exception of the alcoholic. It is often 
difficult to diagnose from other forms of unconsciousness, but the 
extreme contraction of the pupils gives a clue, as a general rule, 
and if opium has been used, the breath often has the characteristic 
odor. 

The treatment of acute morphine or opium poisoning should consist 
in removing the poison from the body and in guarding against failure 
of the respiration; 

The first object is best attained by washing out the stomach with 
the stomach tube, as emetics generally fail when morphine has been 
absorbed owing to the depression of the centre. Even when morphine 
has been injected hypodermically, gastric lavage may have some value 
as some of the poison is excreted into the stomach. Water should be 
used to wash out the stomach; dilute potassium permanganate solution 
has been advised, but tends to oxidize the gastric mucous membrane 
rather than the morphine. A sharp purge may be given to remove the 
morphine excreted into the bowel and also to promote excretion by 
irritating the mucous membrane. 

In morphine poisoning the danger is failure of the respiratory centre. 
This may be combated by the use of respiratory stimulants of which the 
best is caffeine (often given in the form of hot coffee). Strychnine has 
also an antagonistic action to morphine and may be injected. And 
atropine has been used to increase the excitability and appears to be of 
value in small quantities; but not more than -^ grain should be used 
as larger amounts tend to weaken the respiration. Caffeine is safer 
and is at least as efficacious in arousing the depressed centre. 

Besides increasing the excitability of the centre by these drugs, the 
normal stimulus may be augmented. Thus respiration may be aroused 
reflexly from the skin by dashing cold water on it, or by irritating it 
with the electric current, or by flicking it with wet cloths. But the chief 
normal stimulus of the respiratory centre is the carbonic acid of the 
blood, and an attempt should be made to increase this and thus to pro- 
mote the aeration. This may be attained by keeping the patient in 
motion as far as is possible, in order that the muscles may supply C0 2 , 
but as this may have to be done for several hours, it entails great fatigue 



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OPIUM 255 

both for patient and attendant. A more rational method of enriching 
the blood with C0 2 would be to allow the patient to breathe air con- 
taining 7-10 per cent, of the gas, which might be kept in readiness in 
the hospitals where opium poisoning is often encountered. 

Finally, if the respiration fails in spite of these measures, artificial 
respiration must be employed and continued as long as the heart beats. 
Cases of recovery from enormous doses of morphine are recorded in 
which artificial respiration was maintained for many hours. 

Chronic Opium or Morphine Poisoning is a not infrequent condition, 
and, unfortunately, seems to be increasing rapidly. Among Eastern 
nations, especially in China and India, opium is smoked, and some of 
the morphine is carried over in the smoke and absorbed from the 
respiratory tract. This habit is rare in European peoples, among 
whom the drug is taken by the mouth, generally in the form or lauda- 
num or of pills, or is injected hypodermically as morphine hydro- 
chloride or sulphate. Of the three methods the first seems to be the 
least harmful, for in some parts of China the majority of the adult 
population seems to indulge in it without the serious results which are 
met with in the Western opium-eaters and morphinomaniacs. This 
result may be due in part to race, or to the fact that the opium-smoker 
never attains to the immense doses taken daily in the cases of the habit 
met with in Europe and America. In the beginning the quantity 
used is small, but as tolerance is attained, ever larger quantities are 
required to produce any effect, until, as De Quincy states in his 
"Confessions of an Opium-eater," 320 grains of opium may be 
required to stay the craving. The effects are generally described as 
stimulant, but it seems possible that they consist rather in depression 
of the sensibility, by which the unfortunate patient becomes uncon- 
scious of the miseries of his condition, and may accordingly be able to 
perform his duties and maintain appearances better than when de- 
prived of the poison. The symptoms of the opium habit are exceed- 
ingly indefinite, and the diagnosis is often almost impossible. The 
statements of the patient ought not to be taken into consideration, 
because these unfortunates seem to have lost all idea of honor and 
truthfulness. As a general rule they are nervous, weak in character 
and wanting in energy, and utterly unfit for work unless when sup- 
plied with the drug. The pupils are often contracted, the heart some- 
times irregular, and tremors and unsteadiness in walking may be 
apparent. The appetite is bad and a considerable loss in weight occurs, 
and the movements of the bowels are irregular, constipation alternating 
with diarrhoea. Eventually melancholia and dementia may follow 
the prolonged use of opium, and especially of morphine. Some continue 
the habit for many years, however, and it would seem with comparative 
immunity. If morphine is injected habitually, evidence may be ob- 
tained from the small needle marks on the front of the body, which often 
give rise to multiple abscesses of small size from carelessness in the 
disinfection of the syringe. When other evidence fails, it may be neces- 
sary to give a moderate dose disguised in some unusual way and to 



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256 SUBSTANCES ACTING AFTER ABSORPTION 

observe if it induces sleep; in habitual users the ordinary dose will have 
little or no effect. 

The treatment of chronic morphine poisoning is not very promising. 
The will and self-control would seem completely paralyzed in many 
cases, and although the patient wishes to be freed from his enemy, he 
seems utterly unable to withstand the craving. The only means of 
treatment which promises success in most cases is the strict r%ime of 
an asylum or retreat, where the patient is kept under constant super- 
vision. The immediate removal of the drug often produces such 
intense misery and depression as to seem actually dangerous; but the 
withdrawal ought not to be too gradual, and ought to be complete 
after two or three weeks at the most. The patient has to be watched 
carefully for long after he has apparently recovered, as relapses are 
exceedingly common. 

The morphine habit has often been combated by the substitution of 
other drugs, such as cocaine, but the result generally has been that a 
new and even more dangerous habit has been substituted for, or often 
merely grafted on, the original. Numerous drugs have been proposed 
for the cure of morphinomania, but none of them seems to have the 
slightest effect. 

Bibliography. 

The literature of opium is so immense that only a few of the more important phar- 
macological papers can be mentioned here. 

CI. Bernard. Lecons sur les Ansesthesiques et sur l'asphyxie. Paris, 1875. 

08cheidlen. Untersuchungen aus dem phys. Lab. su Wurzburg, ii, p. 1. 

Filehne. Arch. f. exp. Path., x, p. 442; xi, p. 45. Pfluger's Arch., ixii, p. 201. 

Loewy. Pfluger's Archiv, xlvii, p. 601. 

v. Schroeder. Arch. f. exp. Path. u. Pharm., xvii, p. 96. 

Witkowski. Arch. f. exp. Path. u. Pharm., vii, p. 247. 

Pohl. Arch. f. exp. Path. u. Pharm., xxxiv, p. 87. 

AU. Berl. klin. Woch., 1889, p. 560. 

Stockman and Dott. Proc. Roy. Soc. Edinburgh, 1890. British Medical Journal. 
1890, ii, p. 189, and 1891, i, p. 157. 

Engel. Arch. f. exp. Path. u. Pharm., xxvii, p. 419. (Protopine.) 

Rheiner. Therap. Monatsch., 1889, p. 393. (Codeine.) 

Dreser. Ibid., 1898, p. 509. 

Stur8berg. Arch, de Pharmacodyn., iv, p. 325. 

Winternitz. Pfluger's Arch., lxxx, p. 344. 

Riegel. Ztschr. f. klin. Med., xl, p. 347. 

Holsti. Ibid., xlix, p. 1. 

Ba8hford. Arch, internat. de* Pharmacodyn., viii, p. 311. 

Faust. Arch. f. exp. Path. u. Pharm., xliv, p. 217. 

Cloetta. Ibid, 1, p. 453. 

Bouma. Ibid., 1, p. 353. (Codeine.) 

Rtibsamen. Ibid., lix, p. 227. 

Gottlieb and Ecckhout. Ibid., Schmiedeberg-Festschr., p. 235. 

Magnus. Ergebnisse d. Physiol., i, 2, p. 437 (Respiration); ii, 2, p. 657 (Intestinal 
Action). Pfluger's Arch., cxv, p. 316; cxxii, p. 251; cxxxix, p. 318 (Padtberg). 

Hale. Amer. Journ. of Phys., xxiii, pp. 389, 408. 

Kaufmann. Ztschr. f. klin. Med., xlviii, p. 260. 

v. Egmond. Arch. f. exp. Path. u. Pharm., lxv, p. 197. 

Dbbeli. Monatshcfte f . Kinderheilkunde, ix, No. 8. 

Straub. Biochem. Ztschr., xli, p. 419; xlii, p. 316. 

Cushny. Journ. of Pharmacol, and Exp. Ther., iv, p. 363. 



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OPIUM 257 

Longer. Biochem. Ztschr., zlv, p. 221. 

Zehbe. Therap. Monatsh., 1913, p. 406. 

Hesse u. Neukirch. Arch. f. d. ges. Physiol., cli, p. 309. 

Jackson. Journ. of Pharmacol, and Exp. Ther., vi, p. 57. 

Minor Drags of the Opium Series. 

In some other members of the poppy family (Papaveracese), alkaloids are 
found which bear a close resemblance to those of opium. These are Cheli- 
donine, a-, /?- and y-Homochelidonine, Chelerythrine and Sanguinarine; Proto- 
pine is also found in a number of other papaveraceae. These alkaloids are 
met with in very small quantities in various plants, of which Sanguinaria 
Canadensis (Bloodroot) and Chelidonium majus (Celandine) are the best 
known. 

Chelidonine and a-homochelidonine resemble morphine in their effects on 
the central nervous system, but have even less stimulant effect. In the frog no 
secondary increase in the reflex irritability is produced, but in some mammals 
a slight stimulation of the spinal cord may be caused. They have the same 
effect as protopine and cryptopine on the nerve-ends and heart, and like them 
produce insensibility of the skin and cornea when applied locally, through 
paralyzing the terminations of the sensory nerves. The heart is slowed, partly 
owing to stimulation of the inhibitory centre in the medulla, and partly through 
direct action on the cardiac muscle. 

Sanguinarine has very little depressant action, but causes tetanus and wild 
excitement, so that as far as its action on the central nervous system is con- 
cerned, it deserves a place between codeine and thebaine of the morphine 
series. It possesses the same peripheral action as protopine, however, and 
the heart is slowed through direct affection of the muscle. Sanguinarine para- 
lyzes the peripheral sensory endings when applied locally, but this paralysis 
is preceded by a stage of irritation. It causes violent peristalsis of the bowel, 
and increases the secretion of saliva. 

P-homochelidonine resembles protopine and cryptopine closely in its effects, 
causing the same stimulation of the lower parts of the brain with very slight 
effects on the intellectual powers, slowing the heart through its muscular action 
and paralyzing the sensory terminations. 

Chelerythrine paralyzes the central nervous system without any preliminary 
increase in the reflex irritability, possesses the peripheral action of protopine 
and cryptopine, and first irritates, and then paralyzes the sensory terminations. 

None of these alkaloids have been used in therapeutics, and there would 
seem to be no indication for them that is not as well met by opium or morphine. 
None of the plants containing them have been used to any great extent, although 
Sanguinaria Canadensis was formerly occasionally prescribed as a nauseating 
expectorant and emetic. 

Anhalonium. — A number of alkaloids, some resembling morphine, others 
like strychnine in their effects on animals, have been isolated from dif- 
ferent members of the Anhalonium genus (Fam. Cactacese). In Mexico, and 
along the southern boundary of the United States, where those plants are 
indigenous, some of them are used as narcotics in the religious rites of the 
Indians and are known as Pellote, Peyotl, or Muscale or Mezcal Buttons. 
The symptoms arise for the most part from the cerebrum and differ from those 
of opium and cannabis indica in the frequency with which color visions are 
induced, -these consisting in constantly shifting flashes of brilliant tints. Mezcal 
eating does not induce merriment like cannabis nor sleep like morphine, but 
depression of some functions is indicated by the imperfect coordination of the 
movements, the retarded perception, and the errors in the estimation of time. 
The exaltation seems to be caused for the most part by one of the alkaloids, 
mezcaline. Very large doses have induced unpleasant symptoms through 
depression of the respiration. Anhalonium and pellotine, one of its alkaloids, 
have been used as narcotics in a few cases of insomnia. 

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258 SUBSTANCES ACTING AFTER ABSORPTION 



Bibliography. 

H. Meyer. Arch. f. exp. Path. u. Pharm., xxix, p. 397. 

Schmidt. Arch, der Pharmacie, ccxxxix, p. 393. 

Lewin. Arch. f. exp. Path. u. Pharm., xxiv, p. 401 ; xxxiv, p. 374. 

Heffter. Ibid., xxxiv, p. 65; xl, p. 385. 

Mogilewa. Ibid., xlix, p. 137. 

Prentiss and Morgan. Med. Record, August 22, 1896. 

Dixon. Journ. of Physiol., xxv, p. 69. 



m. CANNABIS INDICA. 

The hemp plant possesses no pharmacological interest when grown 
in temperate regions, but when cultivated in warm climates as in 
India, Egypt or the southern United States, it develops products 
which induce marked derangement of the central nervous system. 
The Indian plant was formerly supposed to be a distinct species, but 
differs so little from the European form that botanists now consider 
them merely varieties. The old name of Cannabis Indica has, how- 
ever, been retained in medicine. Its introduction into Western medi- 
cine dates only from the beginning of last century, but it has been 
used as an intoxicant in Asiatic countries and in Africa since unknown 
time, and under the names of Hashish, Bhang, Ganja, Charas or 
Churrus, is habitually indulged in by some one or two hundred mil- 
lions of mankind. Some of the preparations are smoked either alone 
or mixed with tobacco; others form an intoxicating drink, while in 
others it is mixed with sugar or honey and taken as a confection. 

The active principle of Indian hemp has been found by Wood, Spivey and 
Easterfield to be a red oil or resin boiling at a high temperature, which they 
term Cannabinol; this was found by Marshall to induce the typical effects of 
cannabis indica in man and animals. Frankel states that cannabinol is a phe- 
nolaldehyde of the formula OH.C2oH M COH. 

Symptoms. — The effects of cannabis indica are chiefly due to the 
changes in the central nervous system, in which it induces a mixture 
of depression and stimulation similar to that seen occasionally under 
morphine. Its action is much less constant, however, and seems to 
depend very largely on the disposition and intellectual activity of the 
individual. The preparations used also vary considerably in strength, 
and the activity of even the crude drug seems to depend very largely 
on the climate and season in which it is grown, so that great discrep- 
ancies occur in the accounts of its effects. Soon after its administra- 
tion, the patient passes into a dreamy, semi-conscious state, in which the 
judgment seems to be lost, while the imagination is untrammeled by 
its usual restraints. The dreams assume the vividness of visions, are 
of boundless extravagance, and, of course, vary with the character and 
pursuits of the individual. In the eastern races they seem generally 
to partake of an amorous nature. The true believer sees the gardens 
of paradise and finds himself surrounded by troops of houris of un- 



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CANNABIS INDICA 259 

speakable beauty, while the less imaginative European finds himself 
unaccountably happy and feels constrained to active movement, often 
©f a purposeless and even absurd character. Ideas flash through the 
mind without apparent continuity, and all measurement of time and 
space is lost. True halluncinations may appear, but are often absent, 
the chief features of the action being merriment, comfort, well-being, 
and self-satisfaction. Often less pleasant thoughts obtrude themselves, 
however, such as the fear of impending death or of some imminent, 
indefinite danger. During this period the consciousness is not entirely 
lost, for the patient often feels that his dreams are unreal, his satis- 
faction unfounded and his movements ridiculous, but he cannot restrain 
them; he can give a coherent account of his condition when aroused 
and answers questions intelligently. The sensation of pain is lessened 
or entirely, absent, and the sense of touch is less acute than normally. 
Later the dreams alternate with periods of complete unconsciousness, 
from which the patient can be aroused easily, and the symptoms 
eventually pass into tranquil sleep, from which he awakens refreshed, 
and, as a rule, without any feeling of depression or nausea. In the 
majority of cases the preliminary stage of exaltation is very short or 
entirely absent in Europeans, the first effects of the drug often being 
heaviness, drowsiness, noises in the ears and numbness of the extrem- 
ities, which pass into deep sleep. According to Dixon, the drug is 
much more exhilarating when inhaled than when swallowed, and this 
may account for some of the variations in its action. In some cases, 
acute mania and convulsive attacks have been developed, and among 
the natives of India catalepsy occasionally occurs. 

In animals the effects of cannabis indica seem to resemble those in 
man and present the same marked variations; a stage of exaltation 
with increased movement is sometimes present and is followed by 
depression, lassitude, and sleep. The reflex excitability is first increased 
and then diminished in frogs. Vomiting is often induced in dogs and 
cats, but cannabis indica differs from opium in producing no disturb- 
ance of the digestion and no constipation. The heart is generally 
accelerated in man when the drug is inhaled; the intravenous injection 
in animals slows the pulse partly through inhibitory stimulation and 
partly through direct action on the heart muscle. This action on the 
heart is stated by Dixon to be the cause of death after poisonous 
quantities, for he found the respiration persist for some seconds after 
standstill of the heart. The pupil is generally somewhat dilated. 
Polyuria is stated to occur in dogs, in which cannabinol appears to be 
excreted by the kidneys in combination with glycuronic acid (Frankel). 

Death from acute poisoning is extremely rare, and recovery has 
occurred after enormous doses. The continued abuse of hashish in the 
East sometimes leads to mania and dementia, but does not cause the 
same disturbance of nutrition as opium, and the habitual use of small 
quantities, which is almost universal in some Eastern peoples, does not 
seem detrimental to them, although among Europeans it might possibly 
be as fatal as that of morphine. Some tolerance is rapidly acquired. 



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260 SUBSTANCES ACTING AFTER ABSORPTION 



Preparations. 

Cannabis Indica (U. S. P., B. P.), Indian hemp, the flowering tops of the 
female plant of Cannabis sativa (hemp), grown in the East Indies. 

Extractum Cannabis Indices (U. S. P., B. P.), 0.01 G. (J gr.); B. P., J-l gr. 

Tinctura Cannabis Indict (U. S. P., B. P.), 0.6 c.c. (10 mins.); B. P., 
5-15 mins. 

The preparations vary extremely in strength and many are entirely inert, 
especially when they have been kept some time. Physiologically tested prep- 
arations are provided by many firms. 

Therapeutic Uses. — Cannabis indica is used as a hypnotic in cases of 
sleeplessness from nervous exhaustion and, less often, from pain. It 
is not nearly so reliable as opium, and in fact produces sleep in only 
about 50 per cent, of the cases, according to some authors. On the 
other hand, it does not disturb the digestion and produces no subse- 
quent nausea and depression, and may therefore be employed in some 
cases in which opium is contra-indicated. It' is of use in some cases of 
migraine, and has been prescribed as a substitute for opium in mental 
diseases. 

Bibliography. 

Marshall. Lancet, 1897, i, p. 235. American Medical Journal, 1893, ii, p. 8S2. 

Dixon. Brit. Med. Jour., 1899, ii, p. 136. 

Frankel. Arch. f. exp. Path. u. Pharm., xlix, p. 266. 



IV. BROMIDES. 

It was formerly widely believed that the bromides had no further 
action than the chlorides, and that any effects observed from potas- 
sium bromide were due to the potassium ion, the bromide ion being 
indifferent. There is now no question, however, that the bromides 
have distinctive effects, for all bromides induce changes in the central 
nervous system, which are not elicited by the chlorides. The bromide 
of potassium is the salt most generally used. 

Symptoms. — The local action on the alimentary tract is the same as 
that of sodium chloride and other salts; the bromides have a bitter 
salt taste and induce salivation and thirst, and in large quantities 
irritation of the stomach, nausea, and vomiting. Ocasionally diarrhoea 
has been observed from concentrated solutions reaching the intestine. 

General Symptoms. — Apart from these results of local irritation, the 
first symptom is often a dull, heavy headache, with a feeling of lassi- 
tude, fatigue, disinclination for exertion, mental or physical, and often 
muscular weakness. Thought is slow and confused, the memory is 
indistinct, ideas are put into words with difficulty and the speech is 
accordingly slow and hesitating. External objects and movements 
are perceived, but arouse no interest in the patient, and very often 
this state of apathy passes into drowsiness and sleep. The bromides, 
however, have not the sleep-compelling power of morphine or chloral, 
and the sleep is never very deep and is not refreshing, the patient 



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BROMIDES 261 

sometimes feeling dull and unfit for exertion after it, and some 
mental confusion often persisting for several hours after waking. 
The reflexes are much depressed by large doses of bromide, so that 
touching the back of the throat does not induce nausea, although the 
sensation of touch may persist. The mucous membranes of the 
genito-urinary tract are also less sensitive, or rather their irritation 
is less liable to set up reflex movements. After very large doses of 
the bromides the conjunctiva may sometimes be touched without 
causing winking, and lessened sensation in the skin has been noted 
in some cases. The pulse and respiration are slower than usual after 
large doses, but scarcely more so than in sleep. An increase in the 
urine is often observed. 

Acute fatal poisoning with bromides has seldom or never occurred 
in man, but after enormous doses prolonged sleep or stupor has been 
seen, and confusion and apathy lasting for several days. 

When bromide is given repeatedly in large doses, a series of symp- 
toms is often induced to which the name of Bromism has been applied. 
It occurs much more rapidly in some persons than in others, and may 
suddenly appear after the patient has been taking the drug for months 
without any untoward results. The commonest symptoms of bromism 
are skin eruptions of various kinds, very often commencing as acne 
of the face. In severe cases the pustules of acne may coalesce and 
form small abscesses, which are followed by ulcers. In other cases 
the skin affection partakes rather of the nature of a localized blush or 
erythema and sometimes copper-colored blotches have been observed. 
Some disturbance of the digestion and loss of appetite is often met 
with from the local action of large quantities of the salt on the 
stomach. Affections of the respiratory passages are not produced so 
often by the bromides as by the iodides, but have been met with, and 
consist in an increased secretion of mucus by the bronchial and nasal 
epithelium. The mental symptoms are merely exaggerations of those 
observed after one large dose. The memory is especially defective, 
sometimes sudden lapses occurring, sometimes a general inability to 
remember the most recent events being met with. The patient is 
indifferent to his surroundings, speaks slowly and stammers, mispro- 
nounces ordinary words or misses several words out of a sentence. 
The gait is uncertain and tremor often accompanies any movement, 
the expression of the face is stupid and apathetic, and the eyes are 
heavy and lack lustre. 

These symptoms generally disappear on the withdrawal of the drug, 
but in his reduced condition the patient is of course liable to fall a 
victim to infectious disease, and in a number of cases of chronic bromide 
poisoning the immediate cause of death has been an attack of bronchitis 
or pneumonia. 

Action. — The effects of the bromides on animals can be examined only 
by the use of sodium bromide, as when the potassium salt is used, the 
action is complicated by the presence of potassium effects, which 
are often sufficient to obscure the slight depression of the brain which 



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262 SUBSTANCES ACTING AFTER ABSORPTION 

is the really characteristic effect of the bromide ion. In the frog, for 
example, potassium chloride is capable of inducing depression of the 
central nervous system, and the slightly greater depression induced 
by the bromide may well be overlooked; it appears, however, that 
bromides have very little true depressant action on the frog. The 
typical bromide action may be induced with greater clearness in mammals 
by the use of sodium bromide in repeated doses, and in dogs symptoms 
of depression and imperfect coordination have been observed, and some- 
times stupor and death from failure of the respiration; the symptoms 
of central nervous depression can be elicited by a single large dose in 
the guinea-pig — lethargy, incoordination of movements, deep sleep 
passing into coma and often ending in death. The most characteristic 
action, however, is obtained from the administration of the drug to 
patients, as the affection of the central nervous system is so slight 
after all but extreme doses, that in order to produce distinct symptoms 
in the less sensitive animals, quantities must be used which entail the 
additional complications induced by salt-action. 

The irritation of the throat and stomach, the nausea, vomiting and 
rarer diarrhoea must be attributed for the most part to the action of 
the salt in withdrawing fluid from the mucous membranes, and may 
be avoided by the use of dilute solutions and by their administration 
when the stomach is full. 

The depression and other mental symptoms are due to a direct 
action on the Central Nervous System. Albertoni found that the irri- 
tability of the motor areas of the dog's brain was very distinctly 
reduced by the administration of bromides, and in particular that a 
stimulus which normally would have spread over a wide area and 
given rise to an epileptiform convulsion, caused only localized con- 
tractions after bromides, while convulsive poisons entirely failed to 
act. Loewald found some psychical processes, such as those involved 
in the addition of numbers, uninfluenced by bromides, while a series 
of figures could be learned by rote only with great difficulty; he there- 
fore considers that the action is limited to certain definite functions. 
The reflexes are also reduced very considerably by bromides, and 
according to many observers the passage of impulses from the sensory 
to the motor cells of the cord is interrupted, while the connection 
between the cerebral centres and the motor cells of the cord is main- 
tained intact. In man the most striking instance is the absence of 
reflex nausea when the back of the throat is touched. While reflex 
movements cannot be elicited, the sensation often remains unimpaired, 
but after large doses a more or less complete anaesthesia is said to be 
produced. This anaesthesia extends to the skin when very large quan- 
tities are administered, and the cutaneous sensation is said to be blunted 
when comparatively small doses are taken; the action is purely central, 
the peripheral sense organs remaining unaffected. 

The respiration is slower under bromides, owing to the lessened 
movement, but is scarcely more reduced than in normal sleep. The 
sexual instincts are depressed or entirely suspended, either from the 
action on the brain or from the lessened reflex activity. 

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BROMIDES 263 

The bromide ion is almost as indifferent to most of the tissues as the 
chloride; for example, muscle and nerve live almost as long in solutions 
of sodium bromide as in those of the chloride of equivalent concentration. 
The heart may be perfused with saline containing bromide instead of 
chloride for many hours and is only slightly affected. When bromides 
are given by the mouth, the heart is not affected; potassium bromide 
injected intravenously in animals is poisonous to the heart as are the 
other potassium salts, but potassium bromide taken by the mouth 
has no effect on the heart. The vessels of the pia mater have been 
observed to be contracted under the bromides, but not more than in 
normal sleep, and this anaemia of the brain is the result, not the cause 
of the depression. The temperature is often reduced in animals under 
bromides from the lessened movement and consequent lessened produc- 
tion of heat. 

The skin eruptions arise in the great majority of cases from the 
glands, and in fact generally remain confined to them. Bromide has 
been found in the acne pustules, but the old view that the acne is due 
to bromine being freed in the glands is undoubtedly incorrect. 

Distribution and Excretion. — The bromides are rapidly absorbed by 
the mucous membranes, and some bromide reaction can be obtained 
from the urine a few minutes after they have reached the stomach. 
Their distribution in the body resembles exactly that of the chloride; 
thus they are found in largest amounts in the blood plasma and have 
little tendency to accumulate in the organs. They occur in all the 
secretions and fluids of the body; they may be found in the form of 
hydrobromic acid in the stomach, and traces are found in the sweat 
and milk and in the hair where chloride occurs naturally. The brain 
and spinal cord do not contain larger quantities than the other organs 
and never approach the amount contained in the blood plasma; the 
skin appears to contain a larger amount than most other organs. 

The whole behavior of the bromides in the body indicates that most of 
the tissues are unable to differentiate them from the normal chloride ions, 
and react to a dose of bromide in the same way as to one of common 
salt. Thus the administration of bromide is followed by the excretion 
of an equivalent amount of salt, but the kidney does not discriminate 
between the two forms circulating in the blood but eliminates a mixture 
of chloride and bromide exactly in the same proportion as these occur 
in the blood. If it were possible to follow the course of the individual 
ions in the body after a dose of common salt, it would probably be 
found that although an equivalent amount of salt is soon eliminated 
in the urine, the actual chloride ions taken would only be represented 
in this excretion to a limited extent, the rest being furnished by that 
previously present in the blood and tissues; the rest of the new chloride 
would gradually be eliminated in diminishing proportions. This is 
what occurs in the nearly related bromides; at first the amount excreted 
bears a high proportion to that of the chloride, but this falls off rapidly 
and some bromide appears in the urine for long afterward. Thus, 
after a single dose of 30 grs. the urine was found to contain bromide 



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264 SUBSTANCES ACTING AFTER ABSORPTION 

for two months, only about 10 per cent, being eliminated in the first 
24 hours. When the treatment is continued, the bromide therefore 
tends to accumulate in the body, but the proportion excreted rises 
with the increase of the salt in the blood, until an equilibrium is reached, 
exactly as much bromide appearing in the urine as is absorbed from the 
stomach. The excretion then continues long after the treatment is 
discontinued. 

When the body is thus saturated with bromide, the blood plasma and 
all the fluids may contain as much bromide as chloride; for example, 
the gastric juice may contain even more hydrobrominic acid than 
hydrochloric acid. The bromides are not simply added to the normal 
salts of the blood, but supplant the chlorides, which are excreted in 
quantity, so that the normal salt concentration of the blood is main- 
tained, though the chloride is much diminished. During bromide 
treatment, therefore, and especially in bromism, not only is there an 
excess of bromide in the body, but also a deficiency of chlorides, and 
it has been much discussed whether the symptoms of bromism and the 
sedative effects of bromide arise from the action of the bromide directly, 
or are the results of the deficiency of chloride. In favor of the latter 
view, it is urged that the bromide action is elicited more readily when 
the chloride of the food is lessened, and that the addition of chloride 
to the dietary often relieves the symptoms of bromism and on the other 
hand restores the epileptic seizures which have disappeared under, 
bromide treatment. And Loeb finds that certain fish are depressed in 
bromide solution but remain normal if chloride is added. But all 
of these observations may be explained by the acknowledged fact that 
the administration of chloride promotes the excretion of bromide and 
thus lessens the concentration of bromide in the fluids of the body. 
And on the other hand it is found that animals may be narcotized with 
bromide quite rapidly, long before it is possible that a serious fall in 
the chlorides of the blood has occurred. So that the bromides appear 
to possess a definite action on the nerve cells, quite apart from the 
deficiency in chlorides. In practice, however, the bromide action is 
accompanied by chloride poverty and on the other hand any excess 
of chloride reduces the concentration of bromide and thus interferes 
with the treatment. The same is true of other measures which tend 
to withdraw bromide, such as the use of diuretics. 

The bromides of sodium, potassium and ammonium have identical 
effects in man when given by the mouth. In animals when they are 
injected intravenously, the potassium and ammonium bromides may 
present in addition the action of the potassium and ammonium ions. 

Preparations. 

Potassii Bromidum (U. S. P., B. P.) (KBr), 1 G. (15 grs.) ; B. P., 5-30 grs. 
Sodii Bromidum (U. S. P., B. P.) (NaBr), 1 G. (15 grs.); B. P., 5-30 grs. 
Ammonii Bromidum (U. S. P., B. P.) (NH 4 Br), 1 G. (15 grs.); B. P., 5-30 grs. 
The bromides are all colorless crystalline bodies without odor but with a 
saline, bitter taste, and are very soluble in water. They are almost always 



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BROMIDES 265 

prescribed in solution, which may be flavored with some aromatic syrup; they 
are not given hypodermically owing to the large dose necessary. 

A number of other bromide combinations are used in therapeutics, such as 
the hydrobromide of quinine, but here the bromide ion is present in very small 
quantity compared with the alkaloid, and in the doses used in therapeutics 
has no appreciable effect. In monobromated camphor the bromine is present 
in a different form and no bromide ion is liberated, and the bromine in this 
compound seems to have little or no effect. Sabromine, the dibrombehenate of 
calcium ( (CwHuOjBrjJjCa), has been introduced as a substitute for the alkali 
salts, but differs from them in being stored in the fatty tissues and in only slowly 
freeing the bromide ion. It has not been proved to be of value. Bromipin 
and Bromeigon and other bromine compounds have not proved equal to the 
bromides in practice. Strontium bromide and hydrobromic acid are quite 
superfluous. 

Therapeutic Uses. — The bromides are used chiefly in the treatment 
of epilepsy, in which they cannot be replaced by any other drug, and 
the prognosis of which has been entirely changed since their introduc- 
tion. In a few cases the bromide treatment is said to cure epilepsy — 
the attacks do not return after the treatment is stopped — but this is 
exceedingly rare; in others the bromides have no effect, but in the 
great majority of cases (90-95 per cent.) the number of attacks is 
much smaller, or the patient may be entirely free from them as long 
as the treatment is persevered with, although they return as soon as it 
is given up. Very often no improvement is observed during the first 
few days, until the tissues have become saturated with bromide, but 
in other cases the spasms disappear immediately. The bromide of 
potassium is more commonly used than the others, and the general 
impression is that it is more efficient and more certain in its effects, 
but some physicians prefer the bromide of ammonium or of sodium, 
and others still prefer a mixture of two bromides. In severe cases it 
is sometimes found that the bromide action is strengthened by the 
addition of cannabis indica, opium or chloral, although the last two 
are to be used with caution. In the treatment of epilepsy it is well 
to begin with small doses and to increase them up to 10 G. per day, 
or until the desired effect is attained, or some complication, such as 
widespread skin affections, precludes their further use. When little 
chloride is taken in the food, the excretion of bromine is much retarded, 
and, on the other hand, the addition of chloride to the dietary accel- 
erates the bromide excretion. The restriction of the salt in the food 
of epileptics under bromide treatment has. therefore been suggested 
with the object of saturating the tissues with smaller doses of bromide 
than would otherwise be necessary. In practice, however, it is difficult 
to reduce materially the chlorides of the food, and equally satisfactory 
results may be obtained, with less hardship to the patient, by slightly 
increasing the dose of bromide. The use of bromide has to be continued 
for many months or years in epilepsy and the aim should be to reduce 
the dose to the lowest efficient one and to maintain this without variation. 
It may also be useful to keep the chloride of the food fairly constant 
and to avoid any treatment which may disturb the concentration of 
bromide in the blood, such as diuresis or violent purgation. 



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266 SUBSTANCES ACTING AFTER ABSORPTION 

The acne is very often a troublesome accompaniment of the bromide 
action, and in fact may prevent the use of this valuable drug in other- 
wise suitable cases. It may often be prevented by scrupulous cleanli- 
ness of the skin, and frequently yields to treatment with small doses 
of arsenic. 

The bromides are not so effective in other affections of the central 
nervous system, although some success has attended their use in chorea, 
in the convulsions of children, and in some form of hysteria. They 
have also been used in tetanus and in strychnine poisoning, but are 
inferior to other remedies, such as chloral. Neuralgia is sometimes 
improved by bromide treatment, especially when it arises from worry, 
anxiety, or overwork. 

As soporifics, bromides often fail entirely, or induce such depression 
and confusion subsequently as to preclude their use. This prolonged 
action doubtless arises from the slow excretion of the bromide, the great 
proportion of that taken remaining in the tissues for more than 24 hours. 
In sleeplessness from anxiety they are often valuable, however, and 
it is found that the dose of chloral may be considerably lessened if it is 
prescribed along with bromides. In sleeplessness from pain bromide is 
of little or no value. The bromides are little suited for use in a single 
dose unless it be a large one. On the other hand their very prolonged 
action is very valuable in cases of exaltation and nervousness in which 
it is desired to allay the excitability without causing actual sleep, and in 
which an immedite effect is not so necessary as a prolonged slight action. 

Bromides have been used with good results in sea-sickness, in the 
sickness of pregnancy, and, it is said, in whooping cough. 

Bibliography. 

Krpsz. Arch. f. exp. Path. u. Pharm., vi, p. 1. 
Albertoni. Ibid., xv, p. 248. 

Loewald, Ach. Kraepelin's Psycholog. Arb., i, p. 489; iii, p. 203. 
Wier8ma. Ztsch. f. Psych, u. Phys. d. Sinnesorganc, xxviii, p. 179. 
Heffter. Ergebnisse der Physiologie, ii, 1, p. 102. 

v. Wyaa. Arch. f. exp. Path. u. Pharm., lv, p. 266; lix, p. 189. Deutch. med. Woch., 
1913, p. 345. 

Amory. Bromide of Potassium and Bromide of Ammonium, Boston, 1872. 

Hale and FUhman. Amer. Jour, of Physiol., xxii, p. 32. 

EUinger and Kotake. Arch. f. exp. Path., lxv, p. 87. 

Januschke and Inaba. Zcitschr. f. d. ges. exp. Med., i, p. 129. 

Bdnniger. Zeitschr. f. exp. Path., u. Ther. t vii, p. 556. 

Bernoulli. Arch. f. exp. Path. u. Pharm., lxxiii, p. 353. 

V. STRYCHNINE— NUX VOMICA. 

Strychnine is the chief alkaloid occurring in several species of 
Strychnos, of which the best known are Strychnos nux vomica and 
Strychnos Ignatia. It is found chiefly in the seeds, and is generally 
accompanied by the nearly related alkaloid Brucine. 

A large number of alkaloids have been found to resemble strychnine in 
their action, such as the Thebaine found in opium, and the Gelseniine of Gelse- 
mium semperviren8, while it is difficult to decide whether several others ought 
to be classed with morphine or with strychnine. 



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STRYCHNINE— NUX VOMICA 267 

Strychnine seems to be a quinoline derivative, although its exact constitution 
is unknown. Its formula is C21H22N1O2, while that of brucine is C23H26N2O4. 
They are both derivatives of a substance of the formula C16H17N2O2, brucine 
differing from strychnine in having two methoxyl groups. It seems not 
unlikely that they are both nearly related to curarine, the alkaloid of curara, 
which is derived from some other species of the genus Strychnos. 

The alkaloids of the strychnine group have a powerful stimulant 
action on the central nervous system, especially on the spinal cord, 
throughout the vertebrate kingdom. 

Symptoms. — In ordinary therapeutic doses strychnine, like other 
bitter substances (page 51), improves the appetite and often leads to 
a distinct amelioration of the subjective symptoms, the patient feeling 
stronger and more hopeful. The special senses are rendered more 
acute by small quantities of strychnine, for differences can be recog- 
nized between shades of color which seem identical to the normal 
vision; the field of vision is widened, and in certain conditions of 
amblyopia light is rendered much more distinct. In the same way 
the hearing seems to be more acute, and the sense of touch is much 
more delicate. Some cases have been noted in which disagreeable 
odors were rendered pleasant by strychnine, but this would seem to 
be a rare idiosyncrasy. In larger doses strychnine increases the reflex 
movements, and the sense of touch is rendered distinctly more acute. 

Fig. 15 




A rabbit during a Strychnine convulsion. 

In cases of poisoning with strychnine, these effects are present but 
are not generally observed by the patient, whose first complaint is of a 
feeling of stiffness in the muscles of the neck and face. This is soon 
followed by an increased reflex reaction, so that a slight touch causes a 
violent movement, and even a sound or a current of air is sufficient to 
cause a sudden start. The increased reflex irritability is generally 
accompanied by some restlessness, and animals sometimes seem to make 
attempts to escape from bright light. Some tremor or involuntary 
twitches may be observed in the limbs, and then a sudden convulsion 
occurs in which all the muscles of the body are involved, but in which 
the stronger extensor muscles generally prevail. In animals the head 
is drawn back, the hind limbs extended, and the trunk forms an arch 
with its concavity backward (opisthotonos) (Fig. 15). In man the 



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268 SUBSTANCES ACTING AFTER ABSORPTION 

same convulsions are seen and are accompanied by strong contraction 
of the face muscles, producing a hideous grin which has been called 
the r'isus sardonicus. The respiratory muscles are involved in the 
general paroxysm and the blood rapidly becomes deoxygenated, as is 
shown by the blue, cyanotic color of the lips and face in man. The 
muscles feel hard and firm at the commencement of the convulsion, 
but very soon a tremor may be made out, which becomes more distinct, 
and after a few intermittent contractions the animal sinks back in 
a condition of prostration (Fig. 16). The respiration generally returns, 
and becomes fairly regular for a short time. Immediately after a 
convulsion the reflex irritability may be low, but it soon regains its 
former exaggerated condition and a second convulsion occurs, exactly 
resembling the first. Mammals, as a general rule, succumb after two 
or three convulsions, the respiration failing to return after the spasm. 

Fio. 16 




A rabbit when the strychnine spasm is passing off. The head is supported to prevent 

it falling on the table. 

In some cases, however, the convulsions become shorter and the intervals 
of quiescence longer, the respiration becomes weak, the reflex irritability 
gradually lessens and the animal dies from asphyxia. In frogs, where the 
breathing can be dispensed with for long periods, the alternation of 
convulsions and periods of quiescence may continue for hours or days, 
but these are of the same general character as those described in mam- 
mals. After very large quantities no convulsions may occur, the animal 
dying almost immediately of asphyxia from paralysis of the central 
nervous system. 

Action. — The whole character of the intoxication points to an affec- 
tion of the Central Nervous System, and it has been found that the 
symptoms are unaltered when the drug is prevented from reaching the 
peripheral nerves and muscles. The chief symptoms arise from the 
spinal cord, for the convulsions are at least as well marked in frogs 
and mammals in which the brain has been destroyed or severed below 
the medulla oblongata. The intellect in man remains unclouded until 
the end, except for the asphyxia produced by the stoppage of the 
respiration; the patient is perfectly conscious of his condition, and 
suffers excruciating pain from the violent contractions of the muscles. 

The special senses are rendered more acute by small doses of strych- 
nine, and this is apparently due to its effects on the central nervous 



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STRYCHNINE— NUX VOMICA 269 

system in the case of touch, taste and smell, but there is reason to 
believe that the increase in the field of vision and the increased sensi- 
tiveness to slight differences in light are to be attributed to its acting 
on the cells of the retina and not to cerebral changes. For when 
strychnine salts are injected in the temple or applied to the conjunc- 
tiva, the sight of the corresponding eye is improved while the other 
remains unaffected (Filehne); if the strychnine acted centrally it 
could do so only by being carried to the brain by the blood, but this 
would affect each hemisphere equally. The affection of one eye only 
is explained by the strychnine diffusing through the lymph spaces, 
and this is said to have occurred in the case of various dyes which 
were applied in the same way and were then found in the retina. 

Ergographic experiments have shown that small doses of strychnine 
augment the capacity for muscular work to a considerable degree, 
and delay the onset of fatigue; this excitation phase is followed by 
one in which the capacity is lowered. Electrical stimulation of the 
motor areas of the brain is more effective under strychnine than in 
umpoisoned animals, but this does not necessarily indicate that the cells 
of these areas are acted on directly, for the same apparent increased 
irritability of the cortical areas is seen when the poison acts on the 
cord only, and it may therefore be the result of the spinal action. 

The convulsions are, as has been stated, of spinal origin. 1 It has 
been shown in addition that they are reflex, that provided no stimulus 
reaches the cord from without, no convulsion occurs. As has been 
already remarked, the convulsions are preceded by a stage of increased 
reflex, and in fact the first convulsion is often seen to follow a stimulus, 
such as a blow or a loud noise. Afterwards they may seem to occur 
without any such impulse, but this is merely because a very slight or 
even imperceptible stimulus is enough to induce them. For example, 
a slight contraction of a muscle may induce a convulsion, as is seen 
very frequently in the frog, where a very slight stimulus, in itself 
apparently too weak to cause a convulsion, is followed by an ordinary 
reflex contraction, and this leads to a spasm. The absence of con- 
vulsions when external stimuli are cut off may, however, be demon- 
strated conclusively in various ways. Thus Poulsson found that a frog 
dipped in cocaine solution undergoes no convulsions after strychnine, 
the cocaine used being sufficient to paralyze the sensory terminations, 
but not to have any direct effect on the cord. Claude Bernard showed 
this even more conclusively by dividing all the posterior roots of the 
spinal nerves in the frog and then injecting strychnine, when no con- 
vulsions occurred except when the ends of the cut roots were stimulated. 
The convulsions therefore follow only on the passage of an impulse from 
without to the spinal cord, and are merely a further development of the 
preceding stage of exaggerated reflex irritability. 

The characteristic feature of strychnine poisoning is thus the changed 

1 In this term is included not only the spinal cord proper, but also those parts of the 
brain which correspond to the cord in performing simple reflex movements. 



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270 



SUBSTANCES ACTING AFTER ABSORPTION 



Fio. 17 



response to external stimuli. In the unpoisoned animal the reflex 
movement following a stimulus is always of the same kind; for example, 
if the leg of a decapitated frog be dipped in acid it makes certain move- 
ments to withdraw the limb, and no 
matter how often the irritation be re- 
peated, the same movements are produced, 
though it is true that if stronger acid be 
used the movement is more violent and 
a greater number of muscles are involved. 
In this movement certain muscles con- 
tract while their antagonists are inhibited; 
for example, in drawing the toe away from 
an irritant the anterior muscles of the leg 
contract, while the gastrocnemius is re- 
laxed. The same irritation which pro- 
duced in the unpoisoned animal a simple 
withdrawal of the limb, causes after 
strychnine stronger and more extensive 
contractions, and the movement is not 
confined to the two hind legs but spreads 
over the whole body. All the muscles 
contract together, there being no inhibi- 
tion of antagonists, and the resultant 
movement has thus quite a different char- 
acter; the gastrocnemius being stronger 
than the anterior leg muscles, the foot is 
extended and thrust against the irritant 
instead of being withdrawn from it. This 
change in the character of the reflex 
movement has been the subject of careful 
investigation by Sherrington, who finds 
that in mammals a stimulus which nor- 
mally causes inhibition of a muscle, causes 
contraction under strychnine. This re- 
versal occurs whether the stimulus is 
derived from the periphery and the con- 
sequent movement is a reflex one, or from 
the brain. In both cases the reversal of 
the character of the movement arises from 
changes in the spinal cord, the impulse 
from the brain or periphery bearing its 
normal character, but changing its nature 
in passing through the cord. It is some- 
times stated that the inhibitory impulse 
is actually changed to a motor one, but 
this is not necessarily the case; for it 
seems probable that every impulse reach- 
ing the cord is in part inhibitory, in part 




Diagram of the spinal cord of 
the frog. A-B, the part of the cord 
exposed to strychnine. B-C, the 
unaffected sone. An impulse 
reaching the cord through the sen- 
sory fibre E passes to the motor 
cells FF and induces an ordinary 
reflex movement, showing that the 
cells FF are not altered by strych- 
nine. On the other hand, an im- 
pulse reaching the cord through 
the sensory fibre D causes tetanic 
convulsions not only in the muscles 
supplied by the motor cells F' F\ 
which are under the influence of 
the poison, but also in those sup- 
plied by FF, which have been 
shown to be free from the strych- 
nine action. 



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STRYCHNINE— NUX VOMICA 271 

motor, but in the unpoisoned animal the inhibitory factor prevails while 
in strychnine poisoning the motor predominates. The strychnine may 
thus merely increase the motor element in the impulse without actually 
reversing the inhibitory one. 

When an external stimulus is sufficient to cause a convulsive move- 
ment in a poisoned animal, the contraction is always maximal; a 
stronger stimulus produces no greater effect. 

There are strong grounds for the belief that the cells of the anterior 
horn are not necessarily involved in the strychnine action (Fig. 17). 
For when strychnine is applied in solution to the cord of the frog at 
the level of the cells connected with the nerves to the fore limbs, irri- 
tation of the hind foot produces an ordinary response in the hind limbs, 
while the anterior part of the body remains motionless; that is, strych- 
nine has not penetrated to the cells connected with the hind limbs. 
Irritation of the fore limbs, on the other hand, produces tetanus not 
only of these, but also of the hind limbs, although the motor cells of 
the hind limbs have been shown to be outside the poisoned area. 
Tetanus can, therefore, be produced in parts whose motor cells are 
unpoisoned. The increased strength of the contraction is due, not to 
augmented energy in the anterior horn cell, but to the impulses which 
these receive being much stronger. This experiment suggests further 
that the synapse round the motor cell is not the point chiefly affected 
by strychnine. And the posterior root ganglion is not the seat of 
action, for convulsions may be elicited by stimulation of the posterior 
roots above this point. The action may thus be localized in some 
point between the entrance of the afferent fibre and the synapse round 
the motor cell. The depressants of the alcohol-chloroform group 
appear to act at the same point as strychnine (p. 199). x 

An impulse travelling up a nerve in an unpoisoned frog reaches the 
cord and may there pass through a number of paths and in each is 
subjected to various influences, so that it arouses different motor cells 
to different degrees of activity, or actually inhibits the activity of some 
of them; in this way a coordinated movement follows. Under strych- 
nine these influences, which may be figured as varying resistances in 
the different paths, disappear, and the impulse passes untrammeled 
along all available paths and reaches the motor cells in much greater 
force than normally and thus arouses a more powerful reaction from 
them and a correspondingly strong muscular contraction. But the 
resistance in the different paths is essential to coordinate the move- 
ment and the increased muscular contraction is thus no longer coor- 
dinated, all the muscles contracting together and the character of the 
•movement being determined by their relative strength. The action 
of strychnine may thus be explained by supposing that it removes 

1 Several investigators (Ryan, McGuigan, Barenne) have thrown some doubt recently 
upon this view of strychnine action, and claim that their experiments on mammals indi- 
cate that the motor cells are also involved in the strychnine action and that convulsions 
arise only when the drug reaches the anterior horn cells. The subject requires further 
investigation, • 



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272 SUBSTANCES ACTING AFTER ABSORPTION 

resistances to the passages of impulses through some of the synapses of 
the spinal cord and thus extends the area on which an impulse acts, 
and also liberates it from the normal coordinating influences. 

It must be remarked that while the resistance is much reduced, it 
is not entirely removed, and the ordinary path is still somewhat more 
easily traversed than the others, for very weak irritation often causes 
an ordinary reflex response in the frog, while a slightly stronger stimulus 
throws it into opisthotonos. Baglioni has shown that a single stimulus 
is not sufficient to cause complete tetanus, but that the movement 
induced by the first shock leads to secondary stimuli arising from the 
joints and tendons which are moved; the arrival of these secondary 
stimuli in the cord maintains it in activity, and the muscles conse- 
quently remain contracted until the cord is fatigued and refuses to 
react to the persistent stimuli from the periphery. The muscles then 
relax and an interval of quiescence follows until the cord has recovered 
its irritability. 

Besides the spinal cord, all other regions in which simple reflexes can 
be produced, are affected by strychnine. Thus the medullary centres 
are thrown into the same condition, and their responses to stimuli are 
equally exaggerated; but they are in constant receipt of impulses, and 
strychnine, by increasing the efficiency of these, augments the tone of 
the medulla oblongata, when it is given in small quantities. 

Artificial respiration has been shown to delay the onset of convul- 
sions in animals, but it is still an open question whether this is due to 
the better aeration of the blood (Osterwald) or to the effects of the 
mechanical movements (Gies and Meltzer). 

The stimulation of the spinal cord by strychnine is followed by 
depression and paralysis. Even during the first stage the stimulation 
is mixed with depression, for though a more violent response is induced 
by a sensory stimulus, this cannot be repeated so often as in the normal 
frog, as the cord becomes fatigued more readily. The sensory part of the 
spinal cord seems to be paralyzed somewhat earlier than the motor 
cells, but these also lose their irritability after a time and no further 
movement can be elicited either by reflex or by direct stimulation of the 
cord. 

Strychnine seems to have no direct action on the voluntary Muscles; 
it is stated that minute quantities increase their tone, that is, render 
them more tense, so that they are prepared for immediate contraction, 
but this is due to action on the cord and not on the muscle fibres. 

The Terminations of the Motor Nerves are paralyzed by large doses 
of strychnine in the same way as by curara. This effect is scarcely 
seen in mammals, as central paralysis always precedes it and destroys 
life, but in some species of frogs the nerve ends are paralyzed before 
the central nervous system. This paralysis is not due to the exhaustion 
of the nerve ends through the tetanus, but is a direct action on the 
terminations, although the exhaustion may contribute to the result. 

The Respiration is quickened by small quantities of strychnine, espe- 
cially when the centre is depressed by the previous administration of 



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STRYCHNINE— NUX VOMICA 



273 



a narcotic. During the convulsions the breathing is arrested by the 
violent contractions of the diaphragm and the other respiratory muscles, 
but during the intermissions it continues fairly regular. After one or 
two spasms it often fails to be reinstated, and the animal dies of asphyxia; 
in other experiments it undergoes a gradual diminution in rate and 
strength, and eventually ceases from gradual paralysis of the centre. 
A reversal of the respiratory reflexes is sometimes seen after large 
doses in animals and is analogous to that described in the inhibitory 
reflexes of the spinal cord. 

Fig. 18 



*M**rfHtf»*" 




•wp^^ 




I 1 1 11 I 1 



I I I I 1 II I 1 1 I 1 



Tracings of the blood-pressure (upper) and intestinal volume (lower) from a curarized 
cat, showing the effect of the intravenous injection of a dose of strychnine sufficient to 
cause spasms in an uncurarized animal. The blood-pressure rises, while the mesenteric 
vessels are contracted from spasm of the vasomotor centre (Bayliss). 



The Heart, is- not directly affected by strychnine in mammals, though 
it is sometimes slightly slowed by stimulation of the inhibitory centre. 
During and after a convulsion it may be accelerated as in violent 
exertion from any cause. Very large quantities slow and weaken the 
frog's heart. 

The Vasomotor Centres are stimulated by small quantities, so that 
the splanchnic vessels are constricted, while the cutaneous and perhaps 
18 



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274 SUBSTANCES ACTING AFTER ABSORPTION 

the muscular vessels tend to dilate from stimulation of the vasodilator 
centre. The blood is thus deflected to some extent from the internal 
organs to the skin and limbs. Larger quantities tend to disorganize 
the vasomotor centre in a way analogous to that described in the spinal 
cord, for Bayliss finds that inhibitory reflexes involving the vasomotor 
centre are changed to motor ones; thus stimulation of the depressor 
nerve after strychnine causes a rise in blood-pressure. 

During the convulsions the blood-pressure is raised to an extreme 
height, partly owing to the activity of the vasomotor centre and 
perhaps partly from the blood being pressed out of the abdominal 
organs and the muscles by the violent contractions. Immediately 
after a convulsion the blood-pressure falls, probably from the exhaus- 
tion of the centre. The blood-pressure remains elevated much longer 
in curarized than in uncurarized animals, which would seem to indicate 
that the fall in pressure is partly due to the substances produced by 
muscular activity. 

In the Alimentary Tract, strychnine has the same action as any 
other bitter substance, and it produces a flow of saliva and increased 
appetite if taken before meals. (See Stomachic Bitters, page 51). It 
seems to be absorbed from the intestine mainly. After absorption it 
is said to increase the movements of the bowel from some action on 
the muscle or on the ganglionic plexus in the bowel wall. 

Metabolism. — Strychnine produces an enormous activity of the mus- 
cles, and, therefore, increases very greatly the consumption of oxygen 
and the output of carbonic acid. This is accompanied by an increased 
formation of heat, which would lead to a rise in the temperature of the 
body were it not counteracted by an equal or even greater increase 
in its dissipation through the skin. As a result the temperature is 
generally lowered in rabbits, while it sometimes rises slightly in dogs 
and cats. The skin temperature, on the other hand, rises considerably 
because more blood flows through it than usual. 

Glycosuria occurs in frogs and in young mammals, and the glycogen 
of the liver and muscles disappears in most animals under strychnine; 
the increased muscular movement and the disturbance of the respiration 
are probably the explanation of both of these phenomena. 

Strychnine is eliminated in the urine chiefly. Its excretion begins 
three hours after its injection, but is exceedingly slow, and the reaction 
is often given by the urine for three to eight days afterward. Traces 
of the alkaloid also appear in the stomach after its hypodermic injec- 
tion, and it is not improbable that some of it undergoes oxidation in 
the tissues. Only a very slight degree of tolerance is developed for 
strychnine, even after very prolonged administration. 

The action of strychnine is almost identical throughout the vertebrate 
kingdom. Man is more susceptible than other mammals, and young animals 
are more refractory than adults, perhaps owing to the less developed condition 
of the central nervous system. The domestic fowl tolerates comparatively 
larger quantities without symptoms. The characteristic convulsant action is 
not elicited in most invertebrates, in which it generally induces paralysis only. 



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STRYCHNINE— NUX VOMICA 275 

Brucine, the second alkaloid of nux vomica, resembles strychnine closely 
in action but is much weaker, from 30 to 40 times as large a dose being required 
to produce the same effect. It differs from strychnine also in possessing a much 
more powerful action on the nerve terminations in voluntary muscle, especially 
in some species of frog. It is credited with weak local anaesthetic properties. 

Preparations. 

Nnx Vomica (U. S. P., B. P.), the seeds of Strychnos nux vomica, contains 
not less than 1.25 per cent, of strychnine along with brucine (0.7-1.5 per cent.) 
and tannin, which gives a dark green coloration with iron salts. Dose 0.065 G. 
(1 gr.); B. P., 1-4 grs. The preparations are assayed to a definite strength of 
strychnine. 

Extractum Nucis Vomicae (U. S. P., B. P.), 5 per cent., 0.015 G. (J gr.); 
B. P. J-l gr. 

Tinctura Nucis VomicjE (U. S. P., 0.1 per cent.), (B. P., 0.125 per cent.), 
0.6 c.c. (10 mins.); B. P., 5-15 mins). 

Strychnine Nitras (U. S. P.), 0.001 G. (A gr.). 

Strychnine Hydrochloride (B. P.), A-tV gr. 

Liquor Strychnine Hydrochloridi (B. P.) (1 per cent.), 2-8 mins. 

Injectio Strychninw Hypodermica (B. P.) (0.75 per cent, of the hydrochloride), 
5-10 mins. hypodermically. 

The extract is generally prescribed in pill form, while strychnine nitrate 
or hydrochloride may be given in solution, pill or tablet; where rapid action 
is desired, it is injected subcutaneously. A number of unnecessary preparations 
containing strychnine and iron and quinine are contained in the pharmacopoeias, 
which also mention a fluid-extract (U. S. P., 1 per cent.), and a liquid extract 
(B. P., 1.5 per cent.). 

Therapeutic Uses. — Strychnine is used largely for its local action on 
the digestive organs as a stomachic bitter, and is generally prescribed 
in the form of the tincture or the extract for this purpose, as in this 
way it is less rapidly absorbed than when given as an alkaloidal salt. 
It may be combined with the cinchona preparation or with one of the 
simple bitters. 

Small quantities of strychnine are of benefit in many ill-defined 
conditions of weakness, cachexia, and "want of tone" generally. The 
results are probably partly due to its stomachic effects in increasing 
appetite and digestion, but the action on the central nervous system 
cannot be overlooked. The slight increase in the irritability of the 
cord probably leads to an improvement in almost all of the nutritive 
functions through increasing the contraction of the vessels and pro- 
ducing greater activity of the muscles. In this way strychnine per- 
haps deserves the name of "tonic" more than most of the drugs to 
which it is applied. 

As a stimulant to the central nervous system strychnine has found 
wide application in almost every form of paralysis, and as long as dis- 
tinct anatomical lesions of the central nervous axis are absent, it may 
be of benefit; for instance, it is often valuable in lead poisoning; but 
where the continuity of the axis is broken by haemorrhage or by the 
destruction of the nerve cells, little improvement is to be anticipated 
from its use, though it may serve to delay or prevent the atrophy of 
peripheral nerves and muscles in some of these cases. When the 



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276 SUBSTANCES ACTING AFTER ABSORPTION 

paralysis is due to an inflammatory process, strychnine is to be used 
with the greatest care, or is perhaps better avoided entirely as long 
as the irritation is present, as it seems to increase and prolong the 
inflammation when used early in these cases. The other central nervous 
stimulants, such as caffeine or atropine, have not been employed in these 
forms of paralysis. 

Strychnine is used as a respiratory stimulant in some forms of pul- 
monary disease in which it is desirable to increase the respiration or 
to provoke coughing. It has been advised in failure of the respiration 
during anaesthesia, and is certainly more likely to be beneficial than 
the great majority of drugs suggested for this purpose. Too large 
doses must not be injected in these cases, however, as strychnine 
paralyzes the respiratory centre itself when given in excess. In other 
forms of poisoning in which the respiratory centre seems in danger, 
and in shock, strychnine may also be of service, especially when it is 
injected hypodermically. Other respiratory stimulants which may be 
substituted for strychnine for these purposes are caffeine and atropine. 

In amaurosis or amblyopia unassociated with atrophy of the optic 
nerve, and even in commencing atrophy, strychnine has frequently 
improved the vision. In many cases it fails to produce any benefit, 
and the exact conditions in which improvement can be looked for are 
unknown. 

Strychnine has been used in heart disease, but all exact observations 
agree that it has no beneficial action (Parkinson and Rowlands). In 
weakness of the circulation from inefficiency of the vasomotor centre 
it may act, though Crile denies it any value in the treatment of the 
low blood-pressure of shock, and Cabot could not find any change in the 
blood-pressure after its use in a number of conditions in which it is 
ordinarily advised. Cook and Briggs found the blood-pressure increased 
in certain cases of vasomotor paresis, however, when ^V~rV 8*- °f 
strychnine was injected hypodermically. In rare cases this weakness 
of the medullary centre simulates heart disease, and this may account 
for the belief in the virtues of strychnine as a cardiac tonic. 

Strychnine is said to be of value in chronic alcoholism in lessening 
the depression which forms one of the chief difficulties in the treatment. 

Poisoning. — In cases of strychnine poisoning, the first treatment 
consists in the evacuation of the stomach by means of emetics, or, 
better, by the stomach tube; it may be necessary to give chloroform, as 
the attempt to pass the tube is often followed by violent convulsions. 
Preparations of tannic acid, such as strong tea, may be given in order 
to form the insoluble tannate, which, however, must be removed as 
quickly as possible, as it is broken up by the acid gastric juice and 
the strychnine is rapidly absorbed. To combat the convulsions, depres- 
sants to the central nervous system should be given, and, although 
chloral is usually advised, chloroform or ether is often preferable. 
It is unnecessary to produce deep anaesthesia, a few whiffs of chloro- 
form being often sufficient to allay the convulsions. The advantage 
of the anaesthetics over chloral is that they can be removed if any 



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PICROTOXIN 277 

symptoms of strychnine paralysis appear. Opium has been suggested, 
but is not nearly so efficacious in strychnine poisoning as members 
of the methane series. If the paralysis comes on, artificial respiration 
may be attempted, although the poison is excreted too slowly from the 
organism to permit of much hope of recovery. 

Bibliography. 

Poulsson. Arch. f. ezp. Path. u. Pharm., xxvi, p. 22. 

Igersheimer. Ibid., liv, p. 73. 

Harnack. Arch. f. exp. Path. u. Pharm., xlix, p. 157. 

Delexenne. Arch, de Physiol. (5), vi, p. 890. 

Houghton and Muirhead. Medical News, 1895, i, p. 612. 

Ryan, McOuigan, and Becht. Journ. of Pharm. and Exp. Ther., ii, p. 319; v, p. 469. 

Barenne. Folia neurobiologica, iv, p. 467; v f p. 42; vi, p. 277. 

Tiedemann. Ztschr. f . allg. Phys., xi, p. 183. 

Mays. Journal of Phys., viii, p. 391. 

Filehne and his pupils. Pfluger's Archiv, lxxxiii, pp. 369, 397, 403. 

Singer. Arch. f. Ophthalmologic 1, p. 665. 

08terwald. Arch. f. exp. Path., xliv, p. 451. 

Verworn and Baglioni. Arch. f. [Anat. u.J Phys., 1900, p. 385, Supplement, pp. 152, 
193. Ztschr. f. allg. Physiol., ii, p. 556, iv, p. 113. 
"* MelUer, Salant, and Oies. Journ. of Exp. Med., vi, p. 107; Amer. Journ. of Phys., ix. 

Sherrington. Proc. Royal Society, lxxvi, B, p. 287; Journ. of Phys., xliii, p. 232. 

Baylies. Ibid., lxxx, p. 353. 

Hale. Journ. of Pharmacology, i, p. 39. 

Parkinson and Rowlands. Quart. Jour, of Med., vii, p. 42. 

In addition, strychnine was studied by Magendie, CI. Bernard, and Orfila. 



VI. PICROTOXIN. 

Picrotoxin is the best known nfember of a group of convulsive poisons, 
which resemble each other very closely in action, but of whose chemistry 
little is known beyond the fact that they are devoid of nitrogen. It is 
obtained from the Anamirta paniculata (Anamirta cocculus, Menis- 
permum cocculus), and is a neutral indifferent body. Picrotoxin 
(CsoHmOu) may be broken up into picrotoxinin (C^HieOe), which 
resembles it in its effects on animals, and picrotin (CieHwO?), which 
is inactive. 

Other poisons resembling picrotoxin are Cicutoxin, derived from the Cicuta 
virosa, or water hemlock, and probably from other species of Cicuta, (Enan- 
thotoxin, the active principle of (Enanthe crocata, water dropwort, or dead 
tongue, and Coriamyrtin, which occurs in several species of Coriaria, of which 
the best known is the Coriaria myrtifolia or currier's sumach. Tutin, the 
active principle of the toot or tutu poison of New Zealand, is obtained from other 
species of coriaria; some of these bodies are glucocides. Camphor and some 
other volatile oil derivatives, notably the Thujon of absinthe also resemble 
picrotoxin in their effects, and the same is true of two alkaloids Samandarine 
and Samandaridine isolated by Faust from the skin of the newt. Lastly, a 
number of the members of the digitalis series may be decomposed into bodies 
which, devoid of the characteristic cardiac action of digitalis, produce the 
same symptoms as picrotoxin. Among these may be mentioned Toxiresin, 
obtained from digitoxin, Digitaliresin from digitalin, and Oleandresin from 
oleandrin. 



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278 SUBSTANCES ACTING AFTER ABSORPTION 

Symptoms. — The symptoms, which are often somewhat late in 
appearing, are very similar in all classes of vertebrates. In man vomit - 
ing is not infrequently observed after members of this series, or the 
first symptoms may be salivation, acc eleration of the resp iration, and 
some slowness of the- pulse and palpit a tion ef the hpart A condition 
of g +r p" r anS^inconscioiianess follow s and then a series of powerful 
convulsions, which, commencing in tonic spasms, soon change to clonic 
movements of the limbs and jaws. The respiration is interrupted 
during these spasms, but is reinstated during the intervals of quiet 
and collapse which follow them. The convulsions return after a short 
pause, and this alteration of spasm and quiet may continue for some 
time, although the respiration often fails to return after one of the 
spasms, and fatal asphyxia results. 

Similar effects are observed in the lower mammals. After a pre- 
liminary stage in which twitching of the muscles and vomiting often 
occur, and in which the respiration is accelerated, while the pulse is 
slow, a violent emprosthotonic convulsion sets in, but soon changes 
to clonic movements; these may last for some time, but eventually 
become weaker and give place to a condition of quiet and depression. 
An increase in the reflex excitability is noticeable during this interval, 
the animal is easily startled and occasional twitching of the muscles 
may be observed. Very soon a second convulsion sets in, and this 
may be fatal from asphyxia, but the symptoms often continue for an 
hour or more, violent spasms alternating with periods of depression 
and collapse. In the frog clonic convulsions are also the chief feature 
of the intoxication. Very often the animal becomes distended with air 
during the convulsions, and gives a curious cry in releasing it. The 
heart is alway s slowed and may cease to beat altogether for a 
time. 

Action. — The clonic convulsions of picrotoxin poisoning are altogether 
different from those of strychnine and other similar bodies, which 
induce prolonged tonic convulsions, and it was early surmised that the 
members of this series act on a different part of the Central Nervous 
System. In the fish convulsions arise from picrotoxin after all the 
nervous system has been removed except the spinal cord. In the frog 
they persist after ^ihe-cerebrum has been destroyed, and even when all 
of the brain abov^JJiejiifidull^oblongata has* been removed, although 
they are weakened by the destruction of the uplic lubes, un lliu ullier 
hand, they disappear, or at any rate lose their typical character when 
the mH" 11 ?! oblong ata is remov ed. In mammals, the convulsions are 
less typical when tne cerebral hemispheres are removed and disappear 
when the pons is destroyed. The seat of action thus seems to move 
upward as the higher parts of the central nervous system become more 
developed, the chief effects arising from the spinal cord and medulla 
and optic lobes in the frog and from the cerebrum and mid-brain in 
mammals. It is possible that in man the cerebrum is even more involved 
in the action than in the lower mammals. In Toot poisoning in man, 
it is often observed that a confused mental condition is present 



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PlCROTOXltf 279 

and that the memory is impaired after the attack and even for some 
days later. 

The stimulation of the medulla is seen in the acceleration of the 
respiration, in the slow pulse, which is due to inhibitory action, in a very 
marked rise of the blood-pressure, and in the vomiting and salivation. 
In many animals the reflexes are found to be increased when the 
medulla is severed from the cord, and this indicates that the spinal 
cord is also more excitable than normally. Grunwald suggests that 
the .centres controlling the cranial and sacral antonomic nerves are 
especially susceptible to the action of these poisons. 

The Heart is rendered slow bv picrotoxin : this is due principally to 
stimulation of the inhibitory centre in the medulla, since on division 
of the vagi the heart returns to almost its normal rate. Some direct 
depression of the heart is observed after large doses in the frog. Picro- 
toxin causes a very marked rise in the arterial tension from stimulation 
of the vaso-constrictor centres in the medulla and upper part of the 
cord. 

The Respiration is accelerated before any convulsions set in, and 
in the intervals between the spasms it is also very rapid, owing to 
the action on the centre. Late in the intoxication the breathing 
may become slo w and labored, probably from approaching central 
paralysis. 

The Vomiting often observed in man and the dog under picrotoxin 
is probably of central origin and not due to gastric irritation. 

The peripheral Nerves and Muscles do not seem to be affected by 
these poisons. 

The fate of picrotoxin in the body and the way in which it is 
ex creted are unknow n. T.ilrg nth,f> r mnvnkivp pnfao yis. it tend s to 
lo wer the temperat ure when it is given in quantities insufficient to 
cause convulsions. 

The convulsions of picrotoxin and its allies disappear when chloro- 
fr^-jri ^r ^hlo^] jg administered. On the other hand, the respiration, 
weakened by narcotic poisons such as chloral, is accelerated by picro- 
toxin, the blood-pressure rises, and the sleep is less prolonged. Animals 
are not awakened at once from narcosis by picrotoxin, but coriamyrtin 
has this effect. 

Picrotoxin is not antidotal in morphine poisoning in animals, but 
may possibly be so in man. 

Therapeutic Uses. — Picrotoxin has been used as an ointment to 
destroy pediculi, and in some forms of skin disease, but is too poisonous 
to be recommended for this purpose. It has been proposed to give it 
by subcutaneous injection in cases of collapse and in narcotic poisoning, 
but it has not been employed for this purpose in therapeutics as yet. 
It has some reputation in the profuse night-sweats of phthisis, which 
it diminishes in a certain proportion of cases, probably by increasing 
the respiration and thus preventing the stimulation of the nervous 
mechanism of perspiration through the partial asphyxia. Dose, ftV~7<r 
gr. in pill or tablet. 

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280 SUBSTANCES ACTING AFTER ABSORPTION 

Bibliography. 

Luchsinoer. Pfluger's Arch., zvi, p. 530. 

Marshall. Trans. Royal Soo. Edinburgh, xlvii (ii), p. 287 (Toot plant); Journ. of 
Pharm. and Exp. Ther., iv, p. 135 (coriamyrtin). 

Kdppen. Arch. f. exp. Path. u. Pharm., xxix, p. 327. 

Gottlieb. Ibid., xxx, p. 21. 

Harnack. Ztach. f. klin. Med., xxv, p. 16. 

Pohl. Arch. f. exp. Path., xxxiv, p. 259. (Cicutoxin and (Enantho toxin.) 

Perrier. Ibid., iv, p. 191. (Toxire&in, digitaliresin, etc.) 

Faust, Ibid., xli, p. 299; xliii, p. 84. (Samandarin.) 

FitcheU and Malcolm. Quart. Journ. Exp. Phys, ii, p. 335. 

GrUnwald. Arch. f. exp. Path. u. Pharm., lx, p. 249. 

VII. CAFFEINE. 

In a number of plants used in different parts of the world to form 
beverages and condiments, there are found the xanthine compounds, 
Caffeine, Theobromine and Theophylline (Theocine), which have been 
employed in therapeutics of late years, and have, therefore, acquired 
a double importance as drugs and as articles of diet. The wide- 
spread use of preparations of these by uncivilized peoples is a curious 
and unexplained fact, especially as they possess neither peculiar taste 
nor odor to guide in the selection of the plants in which they exist. 
Besides, caffeine and its, allies in moderate quantities induce no marked 
symptoms, such as follow the use of alcohol, opium or hashish and 
explain their use among widely separated peoples. On the contrary, 
the only effects to be observed are a brightening of the intellectual 
faculties and an increased capacity for mental and physical work. 
Coffee, the use of which is derived from the Arabians, is the berry of 
Coffea Arabica and contains caffeine; tea, the leaves of Thea Chinensis, 
contains caffeine along with theophylline. Cacao, cocoa, or chocolate 
is depved from the seeds of Theobroma cacao, a tree indigenous in 
Brazil and Central America and contains theobromine. In central 
Africa, the Cola or Kola nut (Sterculia acuminata) is used by the 
natives, and contains caffeine with small quantities of theobromine. 
In Brazil, Guarana paste is formed from the seeds of Paullinia sor- 
bilis, and contains caffeine and theobromine, while in the Argentine 
Republic, Yerba Mate or Paraguay tea (Ilex Paraguayensis) is. used to 
form a beverage which contains a small quantity of caffeine. Another 
species of Ilex is met with in Virginia and Carolina under the name of 
Apalache tea or Youpon, and also contains caffeine. 

These three principles, caffeine, theobromine and theophylline, are 
purine derivatives closely related to the xanthine bodies found in the 
urine and tissues of the animals; theobromine and theophyllin are 
dimethylxanthine and caffeine is trimethylxanthine. 

Xanthine Theobromine 

NH— C— N v CHaN— C— N v 

I II >CH | || >CH 
CO C— NET CO C— NCHa' 

II II 

HN— CO NH— CO Theophylline Caffeine 

CHaN— C— N N CHiN— C— N x 

I II >h | !| yen 

CO C-NH 7 CO C— NCHa' 

CH 3 N— co CHsN— ce^C^ 



CAFFEINE 281 

Action. — These all resemble each other in most points of their phar- 
macological action, although caffeine acts on the central nervous system 
as well as on the kidneys, muscle and heart, while theobromine has 
comparatively little effect except on the last three. 

Central Nervous System. — In man, caffeine stimulates the central 
nervous system, in particular that part associated with the psychical 
functions. The ideas become clearer, thought flows more easily and 
rapidly, and fatigue and drowsiness disappear. Not infrequently, how- 
ever, connected thought is rendered more difficult, for impressions 
follow each other so rapidly that the attention is distracted, and it 
requires more and more effort to limit it to a single object. If the 
quantity ingested is small, however, the results are of distinct benefit 
in intellectual work. The capacity for physical exertion is also aug- 
mented, as has been demonstrated repeatedly by soldiers on the march, 
and more recently by more exact experiments with the ergograph. The 
stimulation of the higher nervous centres is often manifested in the 
insomnia and restlessness which in many people follow indulgence in 
coffee or tea late at night. Kraepelin has investigated the effects of 
caffeine from the psychological point of view, and finds that both tea 
and coffee facilitate the reception of sensory impressions and also the 
association of ideas, especially in fatigue, while the transformation of 
intellectual conceptions into actual movements is retarded. This he 
regards as due to stimulation of the highest or controlling functions 
of the brain, caffeine acting on the same parts as are first affected by 
alcohol and the methane derivatives, but altering them in the opposite 
direction. The effect of caffeine on the acuteness of the senses has 
been demonstrated by the greater accuracy of touch under its influence. 

Large quantities of caffeine often cause headache and some confusion, 
and in rare cases of special susceptibility a mild form of delirium may 
be elicited, or noises in the ears and flashes of light may indicate derange- 
ment of the special senses. The pulse is quickened, and occasionally 
palpitation and uneasiness in the region of the heart are complained of. 
Convulsive movements of the muscles of the hand, and tremor in 
different parts of the body have also been recorded in some cases. 
These effects are induced only with difficulty in habitual drinkers of 
tea or coffee, so that the continued administration of small quantities 
of caffeine evidently gives rise to tolerance. 

In the lower mammals the injection of large quantities of caffeine is 
followed by symptoms closely resembling those induced by strychnine. 
The reflex irritability is remarkably increased, the lightest touch being 
followed by powerful contraction of almost all the muscles of the body. 
After a time these contractions occur without any apparent stimulus, 
and culminate in tonic convulsions which last for several seconds. 
During these, the respiration ceases because the respiratory muscles are 
involved in the spasm, and accasionally it fails to be reinstated when 
the convulsions pass off. In other instances the spasms become weaker 
and occur at longer intervals; the respiration diminishes in frequency 
and depth and eventually ceases. 



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282 SUBSTANCES ACTING AFTER ABSORPTION 

The symptoms induced by caffeine in the lower mammals are due 
for the most part to its acting on the spinal cord in the same way as 
strychnine, though small doses may act on the brain, for they often 
elicit restlessness and timidity without any marked change in the reflex 
excitability. The centres in the medulla oblongata are also involved 
in the effects, as is indicated by acceleration of the breathing and occa- 
sionally by some slowness of the pulse from action on the pneumogastric 
centre. 

Frogs show no nervous symptoms that cannot be ascribed to action 
on the spinal cord, and in some species these are elicited with con- 
siderable difficulty owing to the muscular action described below\ 

On comparing the effects of caffeine and strychnine on the central 
nervous system, it will be found that while there is a general similarity 
in their action, the latter causes more marked stimulation of the lower 
divisions and has less action on the cerebrum in mammals and man. 
They both produce a general increase in the activity of nerve cells, 
but caffeine acts more on the psychical, strychnine more on the reflex 
functions. 

Fig. 19 





A muscular fibre of the frog (highly magnified). A, normal; B, after the application 
of caffeine solution. The coarse strise in B are the folds of the sarcolemma. 

Theophylline resembles caffeine in its action on the central nervous 
system, w r hile theobromine induces few or no symptoms of stimulation. 
The monomethyl-xanthines and xanthine itself stimulate the central 
nervous system in the frog (Schmiedeberg). 

The Muscular action of caffeine is best seen in the Rana temporaria 
(grass frog), although it is also induced in other species of frogs, and 
some rigidity may be elicited in mammals by very large doses. When 
a few drops of caffeine are injected into the leg of a frog there follows 
a peculiar stiffness and hardness in the muscles around the point of 
injection, which slowly spreads to other parts of the body and induces 
the appearance of rigor mortis. The same effect is observed when 
teased muscle fibres are subjected to a caffeine solution under a high- 
pow r er microscope. The fibres contract, become white and opaque, and 
look stiff and inflexible; the transverse strife disappear, w T hile the longi- 
tudinal become more easily visible (Fig. 19). This appearance is 



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CAFFEINE 283 

due to the death and rigor mortis of the fibres, in which the myogen is 
formed into myogen-fibrin apparently; the same change occurs when 
caffeine is added to myogen in the test-tube. 

In small quantities caffeine increases the irritability of muscle as 
well as its absolute strength and extensibility; that is, the muscle con- 
tracts on a weaker stimulus and against a greater load than it does 
normally. The amount of work done before fatigue sets in is also 
increased, unless when large quantities are applied, when the capacity 
for work is lessened; and with the first appearance of rigor it ceases 
to react to stimuli altogether. Sobieranski has recently shown that in 
ordinary doses caffeine increases the work done by the human muscles 
when they are stimulated by electric shocks. The universally recog- 
nized effect of tea and coffee in increasing the capacity for physical 
work and in relieving fatigue has generally been regarded as due to 
changes in the nerve cells, but the peripheral action on the muscle may 
also play a part in it. While the action of theobromine on the central 
nervous system is much less marked than that of caffeine, muscle enters 
into rigor after the former more readily, and xanthine exceeds even 
theobromine in its power to produce this change. 

Circulation. — In man, ordinary doses of caffeine often induce some 
slowing of the pulse, which apparently arises from a mild stimulation 
of the inhibitory centre in the medulla; but not infrequently no altera- 
tion in the pulse rate is observable. The blood-pressure does not appear 
to be materially altered by caffeine, a slight rise of 5-10 mm. occurring 
in individuals, but not very frequently. Sometimes palpitation is 
complained of in excessive tea and coffee drinkers, and this may perhaps 
indicate stronger action of the inhibitory centres, but may equally w T ell 
be attributed to gastric disturbance. The effects of therapeutic doses 
of caffeine on the circulation in man are quite insignificant. 

When caffeine is injected in large quantities intravenously in animals, 
the heart is accelerated considerably without any significant change 
in the extent of systole and diastole. The acceleration is not dependent 
on changes in the regulating nerves of the heart, but arises from a direct 
stimulating action on the cardiac muscle, and especially on that part 
from which the rhythm originates. Vagus stimulation has less effect 
than usual, but this is due to increased irritability of the heart and not 
to partial paralysis of the nerve ends. A similar acceleration is induced 
by caffeine after division of both accelerator and vagus nerves and after 
the paralysis of the inhibitory terminations by atropine. Still larger 
quantities of caffeine injected intravenously in mammals cause weakness 
and irregularity of the heart. The quantities used in therapeutics in 
man seem insufficient to induce either the acceleration or the subsequent 
irregularity observed in animals. The acceleration of the heart is not 
always accompanied by an increase in the amount expelled per minute 
(Bock), for the contractions may follow each other so quickly that there 
is not sufficient interval for the inflow of blood. 

The blood-pressure under these large intravenous injections in animals 
often rises to some extent, but not infrequently shows little alteration, 



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284 SUBSTANCES ACTING AFTER ABSORPTION 

and the increase in the blood-pressure is rarely significant. Caffeine 
tends to stimulate the vasomotor centre in the medulla, and this would 
raise the blood-pressure, were it not for a simultaneous widening of the 
vessels through a direct action on the walls; this neutralizes in large 
part the central action on the circulation, so that the blood-pressure 
shows only slight changes (Sollmann and Pilcher). When very large 
quantities weaken the heart, the blood-pressure falls to a considerable 
extent, but if convulsions supervene it may again rise. 

The direct dilator effect of caffeine has sometimes been observed 
in the coronary vessels of the heart, and has led to the use of caffeine 
in conditions in which narrowing of these vessels is diagnosed. There 
is no reason to suppose that the quantities used in therapeutics have 
any effect whatever on the vessels. Theobromine and xanthine have 
an action on the heart and vessels similar to that of caffeine. 

Fig. 20 




Respiration of a rabbit which had been slowed by morphine. At C, caffeine was in- 
jected intravenously and the respiration was at once greatly accelerated and moved 
toward the inspiratory position. 

In the frog's heart, caffeine in small quantities accelerates and 
strengthens the beat for a short time, while larger amounts slow the 
beat and lessen the relaxation of the heart, which finally passes into 
rigor resembling that seen in the skeletal muscles. 

The Respiration is quickened by caffeine, owing to a stimulant action 
on the medullary centre. This is seen in the improvement of the 
respiration in cases of dangerous poisoning with alcohol, opium and 
other drugs which prove fatal by depressing the centre, but is much less 
marked in normal animals. The quicker respiration is often more 
shallow than before the administration of caffeine, but the total air 
breathed is increased and the blood is better aerated ; the lessened con- 
tent of carbon dioxide in the blood causes the breathing to be shallower 
through lessening the stimulus to the respiratory centre. The action 
of caffeine on the centre is thus diametrically opposed to that of mor- 
phine. 



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CAFFEINE 



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Fig. 21 



The Temperature has been found to be raised by caffeine through its 
action on the nervous centres and perhaps on the muscles. The increase 
is, however, comparatively insignificant 
(0.5-1° C.) and is seen only in cases in 
which an almost poisonous dose has been 
used. 

The Alimentary Tract is not affected by 
caffeine, but after theobromine discomfort 
and loss of appetite are sometimes com- 
plained of, probably owing to changes in 
the gastric mucous membrane. These 
are much more marked after even small 
doses of theophylline, and small haemor- 
rhages and erosions have been found in the 
stomach, both in man and animals ( Allard) . 

Kidney. — The most important property 
of caffeine from a therapeutic point of 
view is its power of increasing the secre- 
tion of urine. It is an everyday experience 
that strong coffee or tea increases the 
urine to a much greater extent than the 
same amount of water, and this has been 
shown to be due to the caffeine contained 
in these beverages. Caffeine injected 
intravenously in the rabbit has a similar 
diuretic effect, though there is often a 
short preliminary period in which the 
secretion is actually diminished; this is 
especially marked when the injection is 
made rapidly, and may arise from cir- 
culatory changes or perhaps from the 
action of an overwhelming dose in the 
kidney itself. The caffeine diuresis is 
accompanied by an increase in the volume 
of the kidney which may be registered by 
the oncometer, and which indicates that 
the renal vessels undergo dilatation under 
the drug. Some observers have attempted 
to explain the increase in the urine as due 
to the dilatation of the vessels, but the 
general view is that this dilatation is 
merely the accompaniment of the aug- 
mented activity of the kidney and not 
its cause. 

Among those who recognize the direct 
action on the kidney as the cause of 

the increased secretion, a further divergence of opinion is met with, 
one party holding that caffeine lessens the reabsorption in the cells 




Caffeine diuresis in a rabbit. The 
amount of urine passed in ten 
minutes is represented by the 
height of the rectangles. The first 
of these, A-B, represent the normal 
secretion. At B a small dose, and 
at C a large dose of caffeine was 
injected intravenously, and the 
secretion is accordingly increased. 
The shaded part of the rectangles 
represents the amount of solids in 
the urine. It will be noted that 
these are increased but not in the 
same ratio as the fluid. The dotted 
line represents the average height 
of the blood-pressure during each 
period of ten minutes. 



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2S() SUBSTANCES ACTING AFTER ABSORPTION 

of the tubules and thus permits the glomerular secretion to reach 
the ureters in larger quantity than normally, while the other maintains 
that caffeine increases the activity of the cells of the tubules and thus 
adds to the glomerular secretion more than usual. The question can 
only be solved when the physiology of the kidney is determined more 
satisfactorily; the experiments of Cullis seem to argue in favor of the 
latter view, for in the frog the caffeine diuresis continues after the 
blood supply to the glomerulus is cut off so that only the secretion of 
the tubules can reach the ureters. Barcroft states that caffeine increases 
the metabolism of the kidney when it causes diuresis, and subsequently 
depresses it; in this second stage such diuretics as act on the glomerulus 
only continue to be effective, while those that presumably affect the 
tubules fail to increase the urine. He therefore concludes that caffeine 
first stimulates the secretion of the renal tubules and in large doses 
paralyzes it. On the other hand, other observers state that in uranium 
poisoning in which the renal tubules are primarily affected, caffeine 
continues to act as a diuretic as long as urine is secreted, which suggests 
that the tubules are not the seat of action of caffeine. 

Caffeine does not injure the kidney even when it is given in large 
doses and for prolonged periods; it thus differs from most other diuretics 
and may be administered in renal disorders without risk of increasing 
the lesions. 

In the caffeine diuresis the fluid part of the urine is increased chiefly, 
but the solids also undergo an augmentation, though not to the same 
extent. Among the solids the chief increase is seen in the sodium 
chloride, the nitrogenous constituents undergoing less alteration, 
although they also rise in amount. The dilution of the urine reduces 
the concentration of acid, and in addition the alkali of the blood escapes 
through the kidney in larger quantity, so that the urine in caffeine 
diuresis is more nearly neutral and is less irritant to the urinary passages 
than normally. 1 

The excretion of large quantities of fluid in the urine is, of course, 
accompanied by a diminution of the fluids of the blood, but the latter 
soon recuperates itself from the tissues. If there is any accumulation 
of liquid, such as oedema, it is drained into the blood to replace the 
fluid thrown out by the kidney, and caffeine may accordingly be used 
to remove oedema or dropsy in this way. If no such accumulation, 
exists, the blood draws on the fluids of the intestine and stomach, and 
their withdrawal leads to the sensation of thirst. As a diuretic, caffeine 
is distinctly inferior to theobromine; in the first place, because the 
diuresis is less certain and is often accompanied by nervous symptoms — 
sleeplessness and restlessness; and secondly, because the increase in the 
secretion is smaller and lasts for a shorter time. Theophylline is said 
to act on the kidney even more powerfully than theobromine. 

1 A small amount of sugar is often found in the urine of rabbits after caffeine, and 
this has been stated to arise from an excess of sugar in the blood; this hyperglycemia 
appears to proceed from excessive action of the suprarenal glands from the excitement 
in rabbits, and has no clinical significance (Stenstrom). 



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CAFFEINE 287 

Excretion. — Caffeine is excreted in the urine to a very small extent 
as such. I)uring its passage through the body it loses its methyl 
groups and first becomes dimethyl- and then monomethylxanthine. 
Eventually xanthine is formed and this probably breaks up into urea. 
In the urine are found small quantities of the unchanged drug, accom- 
panied by larger quantities of dimethylxanthine and monomenthylxan- 
thine. After theobromine and theophylline some of the unchanged 
drug is found in the urine along with monomethylxanthine. The 
uric acid of the urine is not increased by any of these drugs. 

The exact order in which the methyl groups are. lost in the tissues appears 
to differ in different animals; in the dog all three isomeric dimethylxanthines 
are formed from caffeine and after large doses appear in the urine, although 
theophylline predominates, while in the rabbit and in man paraxanthine is 
formed in larger amounts. The monomethylxanthines are also excreted in 
different proportions in different animals, heteroxanthine prevailing in man 
and the rabbit. 

Tolerance. — A certain degree of tolerance is acquired from the pro- 
longed use of coffee, tea, or chocolate, as is shown by the absence of 
diuresis. Apparently the caffeine and its allies undergo more rapid 
destruction, but this does not explain the tolerance completely, for 
even after prolonged administration large quantities of these bodies 
may be obtained from the tissues, which must have ceased to react to 
them, as well as learning to destroy them more rapidly than normally. 

Theobromine resembles caffeine in its effects except that it has little 
or no action on the central nervous system. It is esteemed a more 
powerful diuretic and generally has no other effects in man. When 
large doses are taken for some time, it tends to act on the stomach, 
causing loss of appetite and nausea. 

Theophylline or Theocine is the most powerful diuretic of the group, 
but in a number of cases has a deleterious action on the stomach and 
in several instances epileptiform convulsions have followed its use. 

Preparations. 

Caffeina (U. S. P., B. P.), long, white, silky crystals, without odor, but 
posessing a bitter taste, but little soluble in cold water, more so in alcohol, 
still more so in boiling water. 0.065 G. (1 gr.) ; B. P., 1-5 grs. Caffeine is best 
prescribed either in powder or in tablets. It may also be given in water with 
salicylate of sodium, which aids its solution. The two following preparations 
are unsatisfactory: 

Caffeina Citraia (U. S. P.), Caffeinw Citras (B. P.), a white powder consisting 
of a weak chemical combination of citric acid and caffeine. It is decomposed 
by mixture with more than 3 parts of water. 0.125 G. (2 grs.); B. P., 2-10 grs. 

Caffeina Citraia Effervescens (U. S. P.), Caffeina Citras Effervescens (B. P.), 
a mixture of citrated caffeine with sodium bicarbonate, tartaric and citric acids. 
On throwing the powder in water it effervesces, owing to the acids acting on 
the bicarbonate and liberating carbonic acid. This preparation contains only 
2 per cent, of caffeine. Dose, 4 G. (60 grs.) ; B. P., 60-120 grs. 

Theobromina (unofficial) is a crystalline powder even less soluble than 
caffeine, and is absorbed with difficulty when given alone. It is generally 



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288 SUBSTANCES ACTING AFTER ABSORPTION 

prescribed in doses of 0.5 G. (8 gra.) three times a day, but larger quantities 
may be given. Solutions of salicylate of sodium dissolve it much more readily 
than pure water. 

Theobromine et Sodu Salicylas (B. P.), Diuretine is a double salt of 
8odium-theobromine with the salicylate of sodium and is soluble in one part 
of water; it contains 40 per cent of theobromine and 35 per cent, of salicylic 
acid. The dose is 10-20 grs. (0.6-1 . 2 G.) either in powder form or in solution. 

Agurine differs from diuretine only in containing sodium acetate instead of 
salicylate. 

Theocine, an artificial theophylline, is a white crystalline powder, slightly 
soluble in water. Dose, 0.2-0.3 G. (3-5 grs.) in powder or tablets. 

It is preferable in therapeutics to use the pure principles rather than such 
impure forms as Guarana (U. S. P.), or Kola nut. 

Therapeutic Uses. — The action of caffeine on the central nervous 
system has led to. its employment in a number of different conditions. 
Thus, in nervous exhaustion it may be used to stimulate the brain, and 
in collapse its action on the respiratory centres has been found of 
value. In narcotic poisoning with failing respiration, caffeine may be 
used to stimulate the centre in place of strychnine or atropine; in 
opium poisoning more particularly, strong coffee has long been used, 
but caffeine might be substituted with advantage. Its stimulant 
action on the brain, and more especially on the respiration, renders 
it an antidote in dangerous cases of alcoholic poisoning also. Some 
forms of migraine and headache are relieved by caffeine, but in others 
it seems rather to intensify the pain; this effect probably arises from 
the action on the brain and may be compared to the relief of fatigue; 
headache is often treated by a mixture of caffeine and one of the anti- 
pyretic series, such as phenacetine. 

Caffeine has been used in diseases of the' heart on the supposition 
that it increases the power of the heart like digitalis, for which it is 
often said to be a substitute. But it has not any action on the heart 
in such quantities as can be used in therapeutics, and its use for this 
purpose is not founded on any accurate clinical observations. Its 
reputation as a cardiac stimulant may probably arise from its efficacy 
in removing dropsy in heart disease, but this is the result of its renal 
action and the heart is not affected directly. 

In their action on the kidney the members of the caffeine series 
stand preeminent, no other drug producing such a copious flow of urine 
as either caffeine or theobromine. As has been explained already, the 
latter is to be preferred to caffeine as a diuretic, and may be used in 
all cases in which there is a pathological accumulation of fluid in the 
body, whether of cardiac, hepatic, or renal origin. The results are 
most brilliant, however, in cases of cardiac dropsy, and here it may 
be prescribed along with one of the digitalis series. It must be em- 
phasized, however, that in these cases it cannot supplant digitalis, but 
merely aids in the removal of the fluid. In cases of hepatic dropsy, 
caffeine and theobromine have also proved of service, although here 
the treatment can only be considered palliative. In renal dropsy 
theobromine has been used with somewhat variable results; it does 



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CAFFEINE 



289 



not seem to increase the albumin in the urine, but not infrequently 
little or no diuresis follows its administration. This is only to be expected 
where the renal cells are in such a condition as to be incapable of stimula- 
tion. * Where the disease is less developed, the members of this series 
produce the usual increase in the secretion. The question of the use 
of these diuretics in renal disease is still undecided and requires further 
accurate observation. In experimental nephritis in animals they often 
act efficiently in washing out the detritus of the tubules, but it is 
unknown whether they have any permanent beneficial effect. 



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Action of theobromine in cardiac dropsy. A case of cardiac dropsy treated with diure- 
tine (theobromine-sodium salicylate) during the period marked with the black line below. 
Dose, 10 grs. three times a day. The urine per day in ounces is marked in the unbroken 
line. The body weight fell continuously, (dotted line) as the dropsy disappeared, and 
when the normal weight of almost 80 pounds was reached, the diuresis became less marked, 
as there was no longer so much fluid to draw upon. 

Inflammatory effusions do not seem to be lessened to any marked 
extent by either caffeine or theobromine. 

Other efficient diuretics are the saline diuretics (p. 292), and the 
mercurial salts. Digitalis and its allies also promote diuresis, but 
mainly indirectly by improving the circulation. 



Coffee and Tea. 

Coffee is not used in medicine, but in view of its immense dietetic 
importance it may be mentioned here in what respects it differs from 
the pure caffeine. The coffee bean contains about 0.6-0.7 per cent, 
caffeine, and a cup of coffee is equivalent to 1^-3 grs. of caffeine along 
with some volatile substances, such as furfuralcohol, produced by 
the roasting; these have been called Coffeon and resemble in their 
action the volatile oils. 
19 

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290 SUBSTANCES ACTING AFTER ABSORPTION 

Tea contains a larger percentage of caffeine (about 1J— 2 per cent.), 
but as less tea is used than coffee, each cup may be considered to con- 
tain 1^—3 grs. In green tea there is a considerable quantity of a volatile 
oil which also passes into the infusion, and the flavor of black tea also 
arises from volatile substances ( Theon). Both black and green tea con- 
tain about 7 per cent, of tannic acid, but this is only extracted slowly. 
The bitter taste in tea that has been prepared too long is due to the 
tannic acid passing into solution. 

The wakefulness and the relief from fatigue which are produced 
by tea and coffee are undoubtedly due to the caffeine contained in 
them, and are to be ascribed to the central action chiefly, although 
its action on the muscles may also be of some value here. On the 
other hand, the feeling of well-being and comfort produced by coffee 
after a full meal is similar to the carminative effects of the volatile 
oils and appears to be due to the local action in the stomach of the 
volatile constituents of coffee. Apart from this local action, these 
volatile bodies seem to have no effect whatever on the economy. It 
is stated that caffeine accelerates slightly the action of the digestive 
ferments outside the body, but that coffee and tea retard it. And when 
coffee and tea are introduced directly into the stomach of animals, 
the former is found to cause a transient rise in the secretory activity, 
while the latter arrests secretion at once; but it is possible that the 
psychical effect of the taste in man may alter this effect. Coffee is said 
to increase the peristaltic movements of the intestine, while caffeine 
has no effect on them. There is a widespread belief that excessive 
tea-drinking disturbes gastric digestion and this has generally been 
attributed to the tannic acid contained in it. It is not unlikely that the 
caffeine and theophylline may also play a part in this gastric action 
by causing irritation of the mucous meipbrane. 

It was formerly stated that coffee lessened the tissue change and 
that it ought therefore to be included among foods, but it has been • 
shown conclusively that far from lessening the metabolism of the body, 
coffee and tea increase it, the amount of urea and carbonic acid excreted 
being considerably augmented by their use. This is only to be expected 
from the increased activity of the nervous centres, which leads to 
increased movement and increased consumption. 

Chocolate contains theobromine (0.5-1 per cent.), instead of caf- 
feine, and besides this a large amount of fat (cacao-butter, 15-50 per 
cent.), starch and albumins. The theobromine does not possess the 
stimulant action of caffeine on the nervous system, and chocolate may 
therefore be taken where coffee or tea produces wakefulness. The 
starch and fat are assimilated by the tissues so that chocolate is a true 
food. But Neumann finds that cocoa retards the absorption of the 
proteins and fats of the food, especially those forms of cocoa in which 
the fat has been partially removed. On the other hand, cocoa with a 
large percentage of oil delays the gastric secretion and may give rise 
to a feeling of heaviness and discomfort in the stomach. Its con- 
tinued use may cause dyspepsia, partly from this cause and partly 



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CAFFEINE 291 

from theobromine acting on the gastric mucous membrane. There is 
no question that the food value of cocoa and chocolate is often over- 
estimated. It allays hunger, but this is only in part from its being 
a food, the local detrimental effect on the gastric mucous membrane 
tending to lessen appetite. 

Bibliography. 

Schmiedeberg. Arch. f. exp. Path., ii, p. 62. Ber. deutsch. Chem. Geaellsch., xxxiv, 
p. 2550. 

Archangehky. Arch, internat. de Pharmacodyn., vii, p. 405. 

Bock. Arch. f. exp. Path., xliii, p. 317. 

Filehne. Arch. f. Anat. und Phys., 1886, p. 72. 

v. Schrdder. Arch. f. exp. Path., xxii, p. 39; xxiv, p. 85. 

Atbanese. Ibid., xxxv, p. 449; xliii, p. 305. 

Bondzynski u. Gottlieb. Arch f. exp. Path., xxxvi, p. 45; xxxvii, p. 385. 

Heerlein. Pflttger's Arch., lii, p. 165. 

Sobieraneki and Modrakowski. Pflttger's Arch., xcviii, pp. 135, 217. 

Kraepelin. Ueber die Beeinflussung einfacher psychischer Vorgange durch einige 
Arzneimittel (Jena, 1892) and Psycholog. Arbeiten, i, p. 378; iii, p. 203. 

Rivers and Webber. Journ. of Phys., xxxvi, p. 33. 

CuHie. Journ. of Phys., xxxiv, p. 250. 

Erdmann. Arch. f. exp. Path. u. Pharm., xlviii, p. 233. 

Gourewit8ch. Arch. f. exp. Path., lvii, p. 214. 

Pawinsky. Ztschr. f. klin. Med., xxiii, p. 440; xxiv, p. 315. 

Neumann. Arch. f. Hygiene, lviii, p. 1. 

v. Furth. Arch. f. exp. Path. u. Pharm., xxxvii, p. 389. 

KrUger. Bericht. d. deutsch. chem. Gesell., 1899, pp. 2818, 2677, 3336. Arch. f. 
exp. Path. u. Pharm., xlv, p. 259. Ztschr. f. phys. Chem., xxi, p. 169; xxxvi, p. 1. 

Ach. Arch. f. exp. Path. u. Pharm., xliv, p. 319. 

Cu8hny and Van Naien. Arch, internat. de Pharmacodynamic, ix, p. 169. 

Anten. Ibid., vii, p. 455. 

AUard. Deutsch. Arch. f. klin. Med., lxxx. (Theocine.) 

Impens. Arch, internat. de Pharmacodyn., x, p. 463. (Methylxan thine.) 

Stcnstr&m. Biochem. Ztschr., xlix. p. 225. (Glycaemia.) 

Barcrofl and Stranb. Journ. of Phys., xli, p. 145. 

SoUman and Pitcher. Journ. of Pharm. and Exp. Ther., iii, pp. 19, 267, 609. 

Boycott and Ryffel. Journ. of Pathology, xvii, p. 458. 

Hedinger. Deutsch. Arch. f. klin. Med., c, p. 305. 

Minor Diuretics. 

A large number of vegetable drugs have enjoyed a reputation in the 
past as diuretics but are passing into disuse. Many of them owe their 
position merely to the large quantities of water in which they are taken ; 
and some of them, such as barley, only lend body and taste to water. 
Others have a slight diuretic action in themselves but are superfluous 
since the introduction of caffeine and its allies. 

Uva Ursi, the leaves of the bearberry, Arctostaphylos Uva Ursi, and of allied 
plants, contains two glucosides, Arbuiin and Methylarbutin, along with large 
quantities of tannin and some inactive bodies. These glucosides are decom- 
posed by the action of acids or of emulsin into glucose and hydroquinone or 
methylhydroquinone, and this change seems to occur in the body, for some 
hydroquinone appears in the urine though most of the arbutin is excreted 
unchanged; it is not unlikely that the decomposition occurs from bacterial 
action in the intestine. 



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292 SUBSTANCES ACTING AFTER ABSORPTION 

Uva ursi is found to have some diuretic action, which is obviously due to 
its acting on the renal epithelium, and the urine is found to undergo putre- 
faction much more slowly than usual. Both the diuretic and the antiseptic 
action appear to be due to the undecomposed arbutin, though the hydroqui- 
none may reinforce the glucoside in retarding putrefaction. 

The urine is often dark in color after uva ursi or arbutin, and this tint deep- 
ens when it is allowed to stand, from the hydroquinone undergoing further 
oxidation; a similar change occurs in carbolic acid poisoning. When decompo- 
sition of the urine occurs m the bladder, as in cystitis, the urine may have this 
dark color when passed. 

Large quantities of uva ursi cause nausea, vomiting, and diarrhoea, but 
Lewin states that this disturbance of the alimentary canal may be avoided 
by administering the glucosides instead of the cruder preparations. 

Buchu, the leaves of several species of Barosma, contains a volatile oil, which 
is excreted by the kidneys and increases the urine slightly; it also has a feeble 
antiseptic action in the urine. 

Scoparius, the tops of the common broom plant (Cytisus scoparius), con- 
tains a resinous substance, scoparin, which seems to act on the kidney as a mild 
diuretic and accounts for the reputation which broom-tops have long enjoyed. 
The alkaloid sparteine, which also occurs in scoparius, has no action on the 
kidney. 

Many other resinous bodies are used in popular medicine to increase the urine, 
but have little or no effect. Among these may be mentioned Zea, or cornsilk, 
and Chimaphila or pipsissewa. Cubebs, Copaiba, and Cantharides have some 
action as diuretics but are more useful for their other effects. 



Preparations. 

Uva Ursi (U. S. P.), Uva Ursi Folia (B. P.), the leaves of Arctostaphylos 
Uva-ursi (bearberry). 

Fluidextractum Uvoe Ursi (U. S. P.), 2 c.c. (30 mins.). 

Infusum Uvce Ursi (B. P.), §-1 fl. oz. 

Arbutin has been advised in doses of 1-4 G., in sweetened solution. 

Buchu (U. S. P.), Buchu Folia (B. P.), the leaves of Barosma betulina. 

Fluidextractum Buchu (U. S. P.), 2 c.c. (30 mins.). 

Infusum Buchu (B. P.), 1-2 fl. oz. 

Scoparius (U. S. P.), Scoparii Cacumina (B. P.), the tops of Cytisus scoparius 
or broom, is used in the form of an infusion (B. P. 1-2 fl. oz.), or a decoction 
(1 oz. to the pint of water), \ pint in twenty-four hours. 

Therapeutic Uses. — These drugs are all used as mild diuretics and disinfectants 
of the urinary tract, and are generally prescribed along with more powerful 
remedies. They give relief in catarrh and inflammation of the bladder by dilut- 
ing the urine and thus rendering it less acid and less irritant to the inflamed 
mucous membranes. 

Vm. SALINE DIURETICS. 

The amount of urine is increased by all solids which are eliminated 
by the kidney, as well as by an excess of fluid in the blood. For the 
kidney is unable to excrete solids except in solution, and every molecule 
which is passed through it carries with it a certain amount of water to 
augment the secretion. Only substances which can circulate in the body- 
in considerable quantities can be used to increase the urine in this way, 
and in practice the chief diuretics of this class are comprised in the 
indifferent salts and similar harmless bodies. In order to act as diuretics 



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SALINE DIURETICS 293 

these must be readily absorbed from the alimentary tract and this 
excludes a large class of salts which increase the urine greatly when they 
are injected intravenously, but which are absorbed with difficulty and 
are therefore used mainly for their effects on the intestine (see Saline 
Cathartics, p. 101). 

Among the saline diuretics are the chlorides of sodium, potassium 
and ammonium, though these are seldom prescribed for this purpose; 
their diuretic action is seen, however, in the treatment at spas and 
watering-places. The cerebral action of the bromides precludes their 
use as diuretics, though an increased secretion of urine accompanies 
their use in therapeutics. The iodide of potassium is often added to 
other diuretics to reinforce their action, but is liable to' induce other 
symptoms when given in large quantities. The typical saline diuretics 
are, however, the nitrates of the alkalies and the urea group. 

The Nitrates have a cool, saline taste, and ordinary doses taken in 
water have no effect except an augmented flow of urine. Very large 
quantities taken in concentrated solution may cause gastro-intestinal 
irritation, giving rise to pain in the stomach region, nausea, vomiting 
and sometimes diarrhoea, and blood may be present in the vomited 
matter and in the stools. The urine is often abundant, but may be 
scanty or entirely suppressed. These symptoms may be followed by 
great muscular weakness, apathy, collapse, and eventually coma and 
death. At the autopsy the stomach and intestines are found red and 
congested, and very often contain blood extravasations. The kidney 
is said to have presented the symptoms of acute nephritis and haemor- 
rhages in some cases of poisoning. 

When dilute solutions of the nitrates are used, much less irritation 
is induced, and, in fact, large quantities may be taken thus without 
causing any symptoms whatever except diuresis. 

Action. — The effects of nitrates are for the most part those of an 
indifferent and diffusible salt, but it is possible that this may be rein- 
forced by some further irritant action, for smaller quantities of the 
nitrates than of the chlorides are sufficient to induce irritation, and 
solutions of the nitrates isotonic with the blood cause irritation and 
congestion in the intestine and are slowly absorbed. This irritant 
effect of the nitrates has been explained by Binz and Barth as the 
result of the reduction of the nitrates to nitrites in the alimentary 
canal and tissues, but no symptoms of nitrite action seem to have been 
observed in cases of poisoning with nitrates. Haldane has recently 
shown that nitrite is formed from the nitrate used in the preservation 
of meat By salting, and that some nitrous-oxide haemoglobin is formed 
and gives a bright red color to the meat. The presence of this pigment 
may perhaps explain the red color of the intestine in some cases of 
poisoning in which extravasations of blood are not marked. 

The nitrates have long been used as diuretics, more especially the 
nitrate of potassium. The diuresis is generally attributed to the salt- 
action, but there may be in addition a true stimulation of the kidney 
similar to that observed under the action of many other drugs which 



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294 SUBSTANCES ACTING AFTER ABSORPTION 

are irritant to the bowel. The nitrate of potassium is generally con- 
sidered a better diuretic than the sodium salt. 

The Fate of the Nitrates in the Body is still obscure owing to difficulties 
in their quantitative estimation. Some of that ingested undergoes 
reduction in the alimentary tract and tissues, for the nitrite reactions 
are given by some organs and by the urine. And it seems likely that 
a portion may undergo still further reduction to ammonia or some of 
its compounds. Most of it appears in the urine as nitrate when large 
doses are given, but some investigators state that after moderate 
quantities in man (1-3 G.) they could observe no nitrate in the urine, 
the whole having undergone some change in the passage through the 
body. Some of the nitrate seems to be excreted in the saliva and 
perspiration, possibly unchanged, although it is rapidly reduced to 
nitrite in these secretions, and may in fact be changed to this form 
in the secretory cells. 

Urea in the course of its excretion through the kidney carries with it 
a considerable amount of water, and when injected intravenously is a 
powerful diuretic. It is rapidly absorbed from the intestine and is 
practically devoid of action in the tissues even in large doses. 

Ammonium Acetate and Citrate are indifferent salts but undergo 
oxidation in the tissues and finally form urea which acts as a diuretic 
in passing through the kidney. They were formerly supposed to in- 
crease the secretion of sweat but this action is insignificant. 

Preparations. 

Potassii Nitras (U. S. P., B. P.), Nitre, Saltpetre (KNO,), 0.5 G. (7J grs.); 
B. P., 5-20 grs; colorless crystals with a cool, saline taste, very soluble in water, 
prescribed in dilute solution. 

Urea (CO(NH 2 )*), colorless crystals with a cool saline taste, soluble in equal 
parts of water. Dose 1-4 G. (15-60 grs.), in solution. 

Therapeutic Uses. — The saline diuretics are seldom used except as 
ingredients of diuretic mixtures; e. g. 9 along with digitalis, or to render 
the urine more dilute and thus to reduce its acidity in irritation of the 
genito-urinary tract. They were formerly employed largely in fevers 
and in various disorders of the metabolism, such as rheumatism or 
gout, but in none of these have they proved useful. The nitrates are 
to be given with care when there is any irritation of the stomach and 
intestine. Authorities differ as to whether these diuretics may be 
prescribed in irritation of the kidney, but in every case they ought 
to be well diluted. 

Paper impregnated with saltpetre is used in asthma by burning 
it in the sick room, when the pyridine and nitrites relieve the spasms 
by relaxing the bronchial muscles. Saltpetre may be used in cigars 
or cigarettes for the same purpose, and the tobacco may contain also 
the leaves of belladonna or some of its allies, as these have a special 
action on the bronchial muscle. 



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PERIPHERAL NERVOUS ACTION 295 



Bibliography. 

Binz et Gerlinger. Arch, internat. de Pharmacodyn., ix, p. 441. 

LittUjohn. Edinburgh Med. Journ., 1885, p. 97. 

Roehmann. Zte. f. Physiol. Chem., v t p. 233. 

Weyl. Virchow's Arch., xcvi, p. 462; ci, p. 175; cv, p. 187. 

Richet. Comptes rend. d. 1. Soc. de Biol., 1886, xxxviii, p. 486. 

Heffter. Ergebnisse der Physiologie, ii, 1, p. 112. 

Haldane. Journ. of Hygiene, i, p. 115. 

Ro8t. Arch. f. [Anat. u.] Physiol., 1901. p. 534. 



PERIPHERAL NERVOUS ACTION. 

A considerable number of alkaloids act by interrupting the passage 
of impulses from the central nervous system to the peripheral muscles 
and organs in the same way as if the nerves were divided by opera- 
tion, while others have the opposite effect of generating impulses in the 
periphery which arouse these peripheral organs with results which are 
identical with those following stimulation of the nerves supplying these 
organs. The point of action of these alkaloids has been definitely 
shown in all cases n ot to be the nerve fibres themselves but the app a- 
ratus in which thf y fprminnfr No poHon is If nmrn thnt circulating in 
the blood, affects the nerve fibres direr^l v; all effects which at first sight 
appear to suggest this have been proved to arise from action at the 
origin of the neuron in the central nervous system or at its termina- 
tion in the periphery. Among these terminations, the^pfiriphecal ^>np° 
of the afferent nerve s (Fig. 23, Ac) seem peculiarly resistant to the 
action of drugs, for with the exception of aconitine and its allies, no 
drug is known to affect these when it reaches theml)y way of the cir- 
culation; on the other hand many drugs exercise a powerful action on 
them when applied to th em directly , that is, in quantities which if 
carried in the blood would prove fatal from action elsewhere. 

The efferent nerves are divided into two great classes which differ 
in many respects (Fig. 23). The first consists of those which, emerging 
from the central nervous system run direct to the v oluntary pr m g relps 
and terminate in expansions on the muscle fibres (Fig. 23, 277). Certain 
drugs, of which ^yjaia ia thft type, interrupt the connection between 
these nerves and the muscles, so that stimulation of the nerve no longer 
causes contraction of the muscle, although direct stimulation of the 
muscle has its usual effect. Other alkaloids (e. g., nicotine, physostig- 
mine), which apparently act on the same^point as_ cur ara b ut in the 
o pposite direc tion, cause fibrillary twitching of the muscle fibres; but 
after c urara, nicotine ^apd physostigmine are i neffective unless in very 
large quantities and, on the other hand, the effects of a small amount 
of curara may be removed by those drugs. 

The second group of efferent nerve fibres are known as the autonomic 
syst em and end in a "^yforK ground gnnglkn cells From these ganglion 
cells, fibres proceed which again terminate in a network over a number 
of organs and muscles, which are not generally under the control of 



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296 



SUBSTANCES ACTING AFTER ABSORPTION 



the will and are known as the vegetative organs. An impulse travelling 
from the central nervous system to such an organ as the heart thus 
passes through two sets of terminations, thftfif in the ganglia and those 
o n the muscle or glaa dLcell- There are thus two points at which drugs* 
mSy interrupt the passage of impulses or at which they may originate 
new impulses. The network around ganglion cells is not known to be 
affected by any alkaloid, but the ganglion cell which is enclos ed is the 
seat of action of a number of poisons, of which the type js_jiicQiine. 
Stimulation of the ganglion cells, such as occurs under small quantities 

Fio. 23 




Diagram of the peripheral nervous system and its connections with the central axis. 
/, an autonomic nerve originating from the cranial division (C), and terminating in a 
ganglion N, from which a fibre runs to involuntary muscle; II, an autonomic sympathetic 
nerve rising in the dorso-lumbar cord (D-L) and passing to a ganglion from which a fibre 
runs to unstriated muscle; II I, a nerve from the cervical cord running to striated muscle; 
IV, a. sensory nerve from the skin to the cervical cord; V, an inhibitory, and VI, a motor 
sympathetic fibre running to ganglion cells from which fibres reach involuntary muscle. 
N, ganglia where nicotine acts; At, myoneural junctions of cranial autonomic nerve, 
where atropine acts; C indicates the point where curara acts; Ac, sensory ends (aconi- 
tine) ; Ad, sympathetic myoneural junctions (adrenaline) ; E, motor sympathetic endings 
(ergotoxine and adrenaline). 

of nicotine, has the same result as electrical stimulation of the nerve 
fibres central to the ganglion (preganglionic) or between the ganglion 
and the peripheral organs (postganglionic); the same effect follows 
nicotine after the preganglionic fibres are divided, but no action is seen 
if the postganglionic fibres are divided or if their connections with 
the organs are paralyzed by other drugs. Paralysis of the ganglion 
cells, such as is caused by large doses of nicotine, has the effect of cutting 
off the impulses from the central nervous system and electric stimulation 
of -the preganglionic fibres is ineffective, while stimulation of the post- 



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PERIPHERAL NERVOUS ACTION 297 

ganglionic fibres has its usual effect, and drugs acting on the termina- 
tions of these fibres are unchanged in action. 1 

All the autonomic ganglia react in the same way to nicotine, but 
it is otherwise with the connections of the postganglionic neurons with 
the organs, which are the only other points at which drugs can act on 
the path from the central nervous system to the periphery. Here 
it is found that certain alkaloids react with some terminations and 
not with others, and in some cases this has been correlated with their 
anatomical origin, in others with their physiological function. The 
autonomic system is divided into two great grou ps, the sympathetic, 
which originates in the thoracic and lumbar aplnai cord, and the cranio- 
sacral which rises from the cranial and sacral segments; the connections 
of the postganglionic fibres of these in the organs show marked diver- 
gences in their reaction to drugs. Thug^ adrenaline has the same eff ect 
as sti mulating the w h ole of the s ympathetic* nerve* (fiffrfT 1 " f ^~ g ™ nf 
nervegT Ta^ ^ nn p ^'fflt. nn * k ? ecaajasaeca] fivstem: and it has been 
shown to exercise its action on the connections between the postgang - 
li onic fibres and the muscl e. Firpptvyinp ^imilfirly flrif*** 1 *^ fl y m - 
pathetic system, but only those of its fibres which transmit i^otor 
i mpulse s, the inhibitory fibres remaining unaffected; and, again, the 
action is on the same neuromuscular connections of thejostgaflglipnjc 
fibres . Stimulation by drugs of these neuromuscular connections has the 
same effect as stimulation of the nerve fibres; paralysis cuts off the 
impulses from the central nervous system, and also from the ganglia 
and postganglionic fibres. The cranial au tonomic fihr^ af e selected 
by a tropine and muscarine , tho ugh their action is not limited to thes e; 
many of the effects of atropine can be shown to be due t o its inter- 
™T* ; "g t Ko flfir r " niiq/>1 » p Q +h "f rhp! ramud ftiff ftnomic svs trm, w^ft* 
sim^ arly musca rine Ttimu lirtnn-t hfe same point s. On the other hand, 
some ot their effects appear to arise from action at similar points on 
gymjp+Win postganglionic fibres. Not infrequently the motor inner- 
vation of an organ is derived from the craniosacral division, while the 
inhibitory originates in the sympathetic or, vice versa, the cranial may 
be inhibitory and the sympathetic augmentor; in these instances the 
exact action of a drug may be difficult to determine owing to the fact 
that stimulation of the augmentor has the same effect as paralysis of 
the inhibitory terminations. 

It was formerly taught that these drugs act on the terminations of the 
nerves which are recognizable histologically. But it has been shown 
in many instances that the action may be elicited in an organ whose 
nerves have been divided and have degenerated, and in which no nerve 
terminations survive. It is obvious, therefore, that the drugs do not 

1 Anatomically the network round the ganglion cell corresponds to the nerve ends 
in voluntary muscle and the enclosed ganglion cell to the muscle fibre. It is, therefore, 
interesting to find that a number of drugs which act on the myoneural junction in muscle 
also affect the ganglion cells; examples are curara and its allies and nicotine. On the 
other hand some alkaloids which act on the myoneural junctions in voluntary muscle 
affect the myoneural junction of the postganglionic fibres (physostigminc). 



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298 SUBSTANCES ACTING AFTER ABSORPTION 

prndi^p t^^ ir effects by. action j)n^he^nat omical nerve, end, im^on 
something lying between it and the organ. This hypothetical point 
has been termed the myoneural junction and is supposed by Langley 
to contain specific receptors which combine with the poisons. The 
essential characteristic of the myoneural junction lies in the fact that 
i t^ does no tjdegenerate with the nerve and therefore is presumably of 
muscular origin^ while on the other ha ndit is not amjjcacitik fox it ™«y 
bej aaralyz ed (e. g., by curara) without the contractility of the muscle 
Being altered. It is convenient to continue the use of the w T ords nerve 
ends or terminations in describing the action of these alkaloids, but 
these must be understood to connote not the anatomical structures 
but something intervening between them and the contractile substance. 

DC CURARA GROUP. 

Curara, woorara, urari or woorali, is an arrow poison used by the 
natives of South America, who prepare it by extracting the bark of 
plants of the genus Strychnos, such as S. toxifera. 

Different preparations of curara were found by Boehm to contain different 
alkaloids. That formerly obtainable owed its activity to Curarine, but the 
curara now exported contains Tubocurarine, which resembles curarine in its 
action, and C 'urine , a weaker poison, which has an entirely different effect. 
Another preparation examined by him contained three alkaloids, Protocurine, 
Protocuridine and Protocurarine, the last of which is the most powerful of 
all the curara alkaloids. Most of the experiments on which the statements 
regarding curara action are based, were performed with the crude drug, but 
the alkaloids seem to have a very similar effect, with the exception of curine. 

Action. — The chief effect of curara is the a rrest of aJJ Yrl" ni>nr |Y 
movements thronjrh an interruption of the connections .beb££ftB-4he 
P Ar ichfirftl n » r Vfift andjhe striated mu§cie fibres- In the mammal the 
muscles give way one after the other until the animal lies helpless on 
the ground. It can still move its limbs, but cannot recover its ordi- 
nary position, and soon the limbs become totally paralyzed and the 
respiratory mnvemP nfg al™»g p^rc^t, although they too are stow, w«ak 
anijerjty. Eventually thejces pirati on ceases also, and asphyxia fol- 
lows but is not betrayed by the us ual con vulsions owjpp tn the m^t™» 
impulses being unable to reach the muscles. Th e heart soon fails 
fro m the as phyxia and not through the direct action, ofihe-poisori. 

In the frog similar symptoms are seen, but here the arrest of the 
respiration is not necessarily fatal, as the skin carries on the exchange 
of gases, and recovery not infrequently occurs after two or even five 
days of complete paralysis. The cause of the curara paralysis was 
demonstrated by the classical researches of Claude Bernard and Kolli- 
ker. If the sciatic nerve of the frog be stimulated during the par- 
alysis no movement follows, but if the artery of one leg be ligatured 
before the application of the poison this limb remains unparalyzed 
and reacts to reflex irritation, while the rest of the body is perfectly 



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CURARA GROUP 299 

motionless. These facts can only be interpreted in one way; the 
paralysis is ppriphpra ] and nnf. ggg itral, and may, therefore, be due to 
action either o n +h«» muackj the narye tmaks, ™ 4he intermediate 
Ttrnrhirrr That it is not due to the muscle is shown by the fact that 
direct stimulation causes the same movement as usual. On the other 
hand, in the experiment in which the artery is ligatured, stimulation 
of the nerves above the ligature, that is, where the poison has access 
to the nerve fibres, causes contraction, so that the nerve trunks do not 
seem affected. This may be shown in another way; if a nerve-muscle 
preparation be made and the nerve be laid in a solution of curara, con- 
traction of the muscle still occurs on stimulation of the nerve, but if 
the muscle be laid in the curara solution stimulation of the nerve has 
no effect, while direct stimulation still causes contraction. Curara 
therefore acts on the connection between the nerve and muscle within 
the muscle itself and paralyzes it without previous stimulation. 

Action on Nerve-ends.— Since the investigations of. Bernard and 
Kolliker, the action of curara has been known to be peripheral, and 
it has been tacitly accepted that it could be localized in the anatomical 
structure known as the motor end-plates. Of late years facts have 
been accumulating which seemed difficult to reconcile with this view, 
and Langley has recently shaken its foundations by showing that curara 
continues to act after the muscle plate has lost its function. For the 
action of nicotine on the muscles is opposed by curara, not only in 
normal muscles, but also in those in which the nerves and nerve-endings 
have degenerated through section. The action of curara here must be 
exerted, not on the end-plate, but on some undegenerated substance, 
which has been termed the myoneural junction and which normally 
serves to transfer the nerve impulse from the nerve-plate to the actual 
contractile substance of the muscle. 

Here, perhaps, better than elsewhere it can be shown that the condition 
of "paralysis" produced by poisons is analogous to that termed by physiol- 
ogists "fatigue." It is known that on stimulating a nerve rapidly by electric 
shocks, or otherwise, the muscle at first contracts with every stimulation, but 
eventually ceases to respond, owing to "fatigue" of the nerve ends, that is, 
to their inability to transmit impulses from the nerve to the muscle. If now 
the response to nerve stimulation of a muscle to which a minute quantity of 
curarine has been applied, be compared with that of a normal one, it is found 
that the poisoned one ceases to respond much sooner than the other — i. e., 
its nerve ends become fatigued much sooner. The more curara is applied, 
the sooner does it fatigue, until at last no response at all can be elicited from 
it. The " paralysis" of the nerve terminations by curara then is of the same 
nature as physiological "fatigue," and other conditions of "paralysis" are 
also analogous to those produced by over-stimulation, though the exact condition 
of the paralyzed organ may not be the same as the fatigued one. Thus there 
is some reason to suppose that in the curarized terminations the substance 
which is normally consumed in transmission is present, but in a form which 
cannot be utilized, while in fatigue it has all been exhausted by the impulses 
which have already passed through. 

Curara acts first on the nerves of the toes, ear and eye, later those 
supplying the limbs, head and neck, and, last of all, those supplying 



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300 SUBSTANCES ACTING AFTER ABSORPTION 

thfijayscles of respiration. At first slight movements can be per- 
formedTTSecaiise Single impulses can pass* through the nerve ends, 
but sustained contractions such as are necessary to preserve the equi- 
librium, cannot be maintained, and the animal therefore falls. The 
intermittent impulses to the respiratory muscles still allow time in the 
interval for the recovery of the terminations, but as the intoxication 
proceeds the number of impulses which can pass through becomes 
fewer and fewer, and the movement therefore assumes more and more 
the character of a jerk and eventually ceases. 

Small. dosfiSL do not ft %p* th<> jnnprva+i^n n f mg^Qpfid »>"°»i^ and 
the strict demarcation of its action is seen very distinctly in organs 
which consist partly of striated and partly of unstriated fibres. Thus 
in the oesophagus, the striated muscle fibres no longer contract on 
stimulation of the vagus after curara, while the unstriated continue to 
respond as usual. In the iris of the mammals, vhich consists of un- 
striated muscle, curara has no effect, while the striated muscle of the 
bird's iris ceases to respond to stimulation of the motor oculi, but 
contracts on direct stimulation. The terminations of the nerves in the 
heart are not affected, but the nerves of the lymph hearts of the frog 
are paralyzed. The nerve ends in striated muscle in invertebrates 
appear to be immune to curara (Straub). The nerve fibres seem un- 
affected by curara, for stimulation causes the usual electrical changes 
in them. 

The Sfyn»p*iiiAtift flaagli ft are paralyzed hv la^ e doses, and stimulation 
of the preganglionic nerve fibre has no effect. For example stimulation 
of the vagus does not slow the heart, and stimulation of the chorda 
tympani does not cause secretion because the impulses fail to pass 
the ganglia on their course. The terminations of the postganglionic 
fibres are not affected apparently, for stimulation has its usual 
effect. 

The peripheral terminations of the afferent or sensory nerves seem 
unaffected, for if the artery of one leg be ligatured before the application 
of curara, reflex movements may be obtained in it from stimulation of 
any part of the body, while if the sensory terminations were paralyzed, 
reflexes could be elicited only by the irritation of parts to which the 
poison had not penetrated, i. e., from the ligatured leg. 

Thfixeii tral n ervous ^stemja^aidJiiifi^mulatedby largequantities 
oLcuraraT^TRe heart is .not directly. affected y but large quantities may 
paralyze the vagus ganglia and release the heart from inhibition. At 
the same time the blood-pressure may fall from paralysis of the ganglia 
on the-vasoconstrictor nerves. The movements of the intestine, spleen 
and other organs are sometimesaccelerated through a similar paralysis 
of the ganglia on inhibitory nerves. 

Metabolism. — The cessation of the ordinary movements after curara 
and under artificial respiration has generally been accompanied by a 
marked decrease in the oxygen absorption and the carbonic-acid excre- 
tion,~¥ut"Trankund'GebhaTd^ state that this is not the -ease ^when the 
temperature is maintained by the application of heat. Sugar and 



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CURARA GROUP 301 

lactic acid are often found in the urine after curara, but this is due to 
partial asphyxia and not to the direct action of the poison; the glyco- 
gen of the liver and muscles disappears from the same cause. 

Curaxa is excreted by the kidneys apparently unchanged. It has 
long been known that this arrow poison may be swallowed with impu- 
nity, provided there is no wounded surface in the mouth or throat, and 
that it is therefore perfectly safe to suck the poison from a wound. 
This has been explained in various ways, some holding that the 
absorption from the stomach is so slow that the kidneys are able to 
excrete the poison as fast as it reaches the blood and that this prevents 
its accumulating in sufficient quantity to affect the tissues. Others 
suppose that the liver retains and destroys it, and a third view is that 
it is rendered innocuous in passing through the stomach walls. 

The characteristic action of curara on the myoneural junction in 
striated muscle is antagonized to some extent by pbysostigmine , 

nirvvh'np, ftpd snm* nthpr alkaloids. 

Curine, the second alkaloid found by Boehm in some specimens of curara, 
is a much less poisonous body than curarine. It possesses some action on 
the heart, the. same appearances following its injection in the frog as after 
digitalin and veratrine, while in mammals the rhythm is slow even after 
paralysis of the inhibitory mechanism. 

Curara i$ an extract of varying constitution and strength and the active con- 
stituents are freely soluble in acidulated water, Attempts have been made to 
use curara in various forms of convulsive spasms, but without adequate results. 

Paralysis of the terminations of the motor nerves in striated muscle — the 
so-called " Curara-Action" — is elicited by a large number of poisons, but in 
few of them is it the first effect of their application. Many drugs induce it 
only when injected in large quantities and at the end of a series of phenomena 
produced by their action on other parts of the body; it is observed much more 
frequently in frogs than in mammals, and is often of little importance com- 
pared to the other symptoms. Among the bodies which resemble curara more 
closely in their action, the peripheral paralysis playing the chief rdle in their 
effects, are the ammonium compounds formed from the natural alkaloids by 
the substitution of an alkyl, e. g., methylstrychnine, amylquinine, etc. 1 Some 
of the ammonium salts and many of the alkyl combinations of ammonium, 
phosphorus, arsenic and of several metals, also cause it. 



Bibliography. 

C. Bernard. Comptee rendus, xxxi, p. 533; xliii, p. 825. 

KQUiker. Virchow's Archiv, x, p. 3. 

Overend and TiUie. Arch. f. exp. Path. u. Pharm., xxvi, p. 1; xxvii, p. 1. 

Boehm. Ibid., xxxv, p. 16; lviii, p. 265; lxiii, p. 177. 

Santes8on. Ibid., xxxv, p. 23. Skand. Arch. f. Physiol., x and xi. 

FiXhner. Arch. f. exp. Path. u. Pharm., lviii, p. 1. 

Langley. Journ. of Physiol., xxxvi, p. 347; xxxvii, pp. 165, 285. 

Edmunds and Roth. Amer. Journ. Physiol., xxiii, p. 28. 

Straub. Pfluger's Arch., lxxix, p. 379. 

Meyer. Ergebnisse der Physiol., i (2), p. 200. 

Frank and Oebbard. Ztschr. f. Biol., xliii, p. 117. 

1 Boehm has recently stated that tubocurarine, which is the active constituent of 
much of the modern curara, is really one of those methyl bases (methylcurine) . 



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302 SUBSTANCES ACTING AFTER ABSORPTION 



Coniine. 

Coniine is one of the simpler derivatives of Piper idine, which is obtained 
from Pyridine by reduction. A series of alkaloids may be formed from piperi- 
dine by substituting methyl, ethyl, propyl or other alkyls for hydrogen, and 
one of these, propyl-piperidine, is the natural alkaloid coniine and was the 
first alkaloid to be formed synthetically. 

Pyridine. Piperidine. Coniine. 

CH CH» CH» 

HC/\CH H»C/\CH» HtC/\CH» 



HC\/CH H,C\/CH* HtC\/CH— C.Ht 

N NH NH 

Coniine is found in Hemlock (Conium maculatum), along with two nearly 
allied alkaloids, Methylconiine and Conhydrine. The action of these and of 
the other simple piperidine compounds resembles that of coniine, but is much 
weaker. 

Symptoms. — The general symptoms induced in man by poisonous doses of 
coniine are weakness, languor and drowsiness which does not pass into actual 
sleep. The movements are weak and unsteady, the gait is staggering, and 
nausea and vomiting generally set in, along with profuse salivation. In most 
cases the intelligence remains clear to the end, as is related of the death of 
Socrates from hemlock poisoning, but in some instances imperfect vision and 
hearing have been noted. The pupils are somewhat dilated. Tremors and 
fibrillary contractions of the muscles are often seen in animals, and some 
observers state that actual convulsions occur. The breathing becomes weaker 
and slower and death occurs from its arrest. 

Action. — Coniine does not possess any action of importance on the central 
nervous system. It is possible that in fatal poisoning the respiratory centre 
may be depressed, but most observers believe that the terminal asphyxia is due 
to paralysis of the nerve terminations in the respiratory muscles. And the twitch- 
ing and tremor which are sometimes seen, appear to arise from a partial paralysis 
of the peripheral nerves similar to that seen under curara. It also resembles 
curara in paralyzing the sympathetic ganglia, but this paralysis seems to be 
preceded by a short stage of stimulation; the ganglia are affected by quantities 
of coniine which are insufficient to cause paralysis of the nerves to voluntary 
muscle, but its action on these ganglia is not so powerful as that of nicotine, 
and the details of this action may therefore be left for discussion under the 
latter drug. 

The heart is affected through the stimulation and subsequent paralysis of 
the ganglia on the inhibitory fibres, which leads first to slowing and later to 
some acceleration of the pulse. The blood-pressure is increased for a short time 
from stimulation of the ganglia on the course of the vasoconstrictor nerves. 
The respiration is sometimes accelerated slightly at first but soon becomes 
slow and labored, and then irregular, and finally ceases while the heart is still 
strong. The red blood cells of the frog show numerous vacuoles in coniine 
poisoning and these persist long after recovery (Gurber). 

Coniine is rapidly excreted in the urine, so that its action passes off very soon 
even when quite large doses are taken. The treatment of coniine poisoning 
therefore consists in evacuation of the stomach and artificial respiration. 

Piperidine acts in the same way as coniine, but more weakly, while methyl- 
and ethyl-piperidine stand between them in toxicity. 

Pyridine resembles piperidine in most features but does not paralyze the 
ganglia nor increase the blood-pressure. It is excreted in the urine as methyl- 
pyridine, a combination between it and the alkyl occurring in the tissues. A 
similar synthesis occurs between methyl and tellurium (see Tellurium). 



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CURARA GROUP 303 

Quinoline and isoquinoline cause in mammals a condition of collapse similar 
to that seen under the antipyretics and the benzol compounds. 

Hemlock or Conium, long widely used in therapeutics, has failed to maintain 
its position on more accurate investigation and has passed into disuse. 

Bibliography. 

Prevost. Arch, de Physiol. (2), vii, p. 40. 

Boehm. Arch. f. exp. Path. u. Pharm., xv, p. 432. 

Hayashi and Muto. Ibid., xlviii, p. 356. 

QUrber. Arch. f. Anat. und Phys., 1890, p. 401. 

Cushny. Journ. of Exp. Med., i, p. 202. 

Moore and Row. Journ. of Phys. f xxii, p. 273. 

Stockman. Journ. of Phys., xv, p. 245. 

Cohn. Zts. f. phys. Chem., xviii, p. 112; xx, p. 210. 

Gelsemium. 

Gelsemium sempervirens (Yellow Jasmine or Carolina Jasmine) contains 
several alkaloids, of which Gelsemine 1 is inactive in mammals, while a mixture 
of two or more alkaloids, which is known as Gelseminine, is a poison of the 
coniine type and is the real active principle of the drug as far as mammals are 
concerned. 

Action. — The symptoms of gelsemium poisoning resemble those of coniine 
so closely that the reader may be referred to the description given under the 
latter. There is here again a question whether the final asphyxia is due to 
paralysis of the respiratory centre or of the nerve terminations, but most in- 
vestigators lean to the view that the action is central and arises from a gradual 
depression of the medullary centre. 

The pupil is very widely dilated by gelseminine when a solution is applied 
locally to the eye, much less so in general poisoning, in which the respiration 
generally fails before the pupil is fully dilated. The power of accommodation 
is also entirely lost when gelseminine or gelsemium tincture is applied to the 
eye. This mydriatic effect has not been explained, but the most plausible 
suggestion would seem to be that gelseminine paralyzes the terminations of the 
oculomotor nerve in the eye in the same way as atropine. Gelseminine differs 
from atropine in its behavior to other nerves, however, for it paralyzes the 
inhibitory cardiac fibres and the chorda tympani through acting on the gan- 
glionic structures on their course and not on the extreme terminations. Its 
action on the ganglia, as far as it is known, resembles that of coniine, but it 
does not cause any increase in the arterial tension, such as is observed under 
this poison. 

The tincture of gelsemium (U. S. P., B. P.), has been employed in doses of 
5-15 mins. in facial neuralgia, and a mixture of the alkaloids has been applied 
locally to dilate the pupil, but has never attained any wide use. 

Bibliography. 

Ringer and Murrell. Lancet, 1876, i, p. 82. 

Putzeys and Romiee. Memoire sur Taction physiologiquo de la Gelsemine, Bruxelles, 
1878. 

Cushny. Arch. f. exp. Path. u. Pharm-, xxxi, p. 49. 

Sparteine. 

Another alkaloid which resembles coniine closely in its action is Sparteine, 
which is found in the common broom plant (Spartium or Cytisus scopanus), 
and in various species of lupines. It is a pyridine derivative possessing the 
formula Ci b E 26 N 2 , and is a fluid, but forms crystalline salts. 

i Gelsemine is frequently known as gelseminine, a use of the term which leads to 
some confusion, and which is not based on the history of the drug. 

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304 SUBSTANCES ACTING AFTER ABSORPTION 

Action. — The general effects of sparteine are Almost identical with those of 
coniine, but it seems very probable that the central nervous system is little 
affected by it, the whole of the phenomena pointing to a paralysis of the motor 
nerve terminations and of the sympathetic ganglia. Sparteine has more effect 
than coniine on the heart, which it depresses, so that the rhythm is slow and the 
contractions weak. When injected into a vein, sparteine induces less increase 
in the arterial tension than coniine, probably because the contraction of the 
vessels is counterbalanced by the weakness of the heart. No increase in the 
arterial tension is observed from the administration of sparteine internally 
and even the slight rise of pressure induced by intravenous injection is of only 
short duration. 

Sparteine is very much less poisonous than either coniine or gelseniinine; 
it proves fatal to animals by paralyzing the terminations of the phrenic nerves 
in the diaphragm. 

The stow puke and slight rise of pressure observed in experiments in animals 
when sparteine is injected intravenously have led some writers to ascribe to 
it an action similar to that of digitalis, and at one time sparteine was used to 
some extent as a substitute for the latter; both experimental and clinical 
observations, however, go to show that these claims are quite unfounded, and 
sparteine is comparatively little used at the present time, and possesses no 
properties which are likely to reinstate it in favor. 

Sparteine sulphate (U. S. P.), has been advised in heart disease in doses 
varying from T \ gr. up to 12 grs., but is of no value. Its reputation appears 
to have arisen from the use of broom tops as a diuretic, but this action 
is not due to the sparteine, but to scoparin (p. 292). 

Bibliography. 

Fick. Arch. f. exp. Path. u. Pharm., i, p. 397. 
Masius. Bull, de TAcad. Roy. de Med. de Belgique, 1887. 
Cuahny and Matthews. Arch. f. exp. Path. u. Pharm., xxxv, p. 129. 
Muio and Uhizaka. Ibid., 1, p. 1. 

X. NICOTINE GROUP. 

Nicotine, the well-known alkaloid of tobacco (Nicotiana tabacum), 
is a vol atile fluid, possessing a strong alkaline reaction , and forming 
"sal ts with acids, most of which_aje_ amorphous. It is a combination 
of pyridine with a hydrated pyrrol ring as shown by the structural 
formula — 

CH HtC CHj 



HCi 
HCI 



{ \o-ch( Ic 

I r*.vt >/ _._ 



iCHi 
-H N— CH, 



N 

Nicotine is the only constituent of tobacco which possesses any 
toxicological interest, although several other alkaloids are present in 
comparatively small amounts. It is accompanied by a volatile oil in 
dried tobacco, but this is only developed during the processes of prepa- 
ration and seems to have no action apart from that of the other volatile 
oils. The odor and flavor, and probably the "strength," of tobacco 
depend in part upon the quantity and quality of this oil, in part 
on some products of the decomposition of nicotine. Absolutely pure 

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NICOTINE GROUP 305 

nicotine has comparatively little odor, but it decomposes when kept, 
becomes dark colored, and acquires the characteristic odor of tobacco. 

Nicotine is also found in the pituri plant (Duboisia Hopwoodii), 
the leaves of which are used by the Australian natives in the same way 
as tobacco by the civilized races. 

Lobeline (C18H23NO2), an alkaloid obtained from Lobelia inflata or 
Indian Tobacco, and Cytwine, (C11H14N2O), the alkaloid of laburnum 
(Cytisus laburnum), gorse and other plants, resemble nicotine very 
closely in action, and another body of the same type of action is the 
artificial quaternary ammonium base, Methylhordenine. 

These alkaloids act chiefly on the ce ntral nervous system, t he sym- 
pathetic ganglia, and the pymif? 1 ™ 1 junctions in yftly ntarv mfusxje. 

Sji uipUJlWT— Poisonous doses administered to man or other mammals 
cause a hot , burnin g^ sensation in the mouth, whi c h sp reads down the 
rasoph ftgus to the stomach, anri is foUg wed hy salivation; "nausea"; vomit- 
ing^jind Hometimes purging, THp j^rpafhing is quirk, dfiep.anc} lahwfdj 
and js n ffon a rrn^panifyl ^3 f moist +«*** - Th e pul s e is- generally slow 
and sometimes weak at first, and then becomes very rapid, but after 
very large doses may be first accelerated nT ?d then slow and feeble. Some 
"IfUtftl confusion, great muscular weakness, giddiness and restlessness 
are followed by loss 6F coordinating power and partial or. complete 
unconsciousness. Clonic compulsions set in later, accompanied by 
fibrillary twitching of various muscles, and eventually a tetanic spasm 
closes the scene by imii ilinji Ihn n spiration In other instances the 
convuls ions are fo ll owed by collapse with complete relaxation of the 
muscles^ihe reflexes^ disappear/jQifi" respiration becomes "Slow and 
weak and finally ceases, the heart continuing to beat for some time 
afterward. Very large doses of nicotine may prove fatal within a few 
se cond s; the symptoms are those of sudden paralysis j>f_the„ central 
nervous system, including the respiratory centre, and no convulsions 
are developed. 

In the frog the same excitement and violent convulsions are seen 
as in mammals, but the respiration soon ceases, and there follows a 
" cataleptic" stage in which the animal assumes a characteristic attitude. 
The fore legs are crossed in front of the sternum and are rigid, the 
thighs are at right angles to the axis of the body and the legs are flexed 
on them but are not rigid. When a leg is drawn down it at once returns 
to its original position, and the frog still attempts to escape when it 
is aroused. Fibrillary contractions are observed in many of the muscles. 
Somewhat later, the reflexes disappear, the muscles become flaccid, 
and eventually complete paralysis occurs from a peripheral, curara-like 
action. 

Nicotine has but little toxic action on the lowest invertebrates, but 
as the nervous system begins to be differentiated it causes paralysis, 
and still higher in the scale the paralytic action is preceded by a stage 
of stimulation. 

Circulation. — The action on the circulation is extremely complex, 
as a number of factors are involved. After moderate quantities the 
20 

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SUBSTANCES ACTING AFTER ABSORPTION 



he art is slo w and may stand still in diastole for a few seconds, but 
then recovers gradually and regains its former rhythm or becomes 
somewhat quicker. The slow pulse is due to stimulation of th^gangli^ 
on ffie v agus nery e (Fig. 24, N), exactly the same effects being pro- 



Fio. 24 ^ 




Diagram of the regulating nerves of the heart. P, inhibitory cranial autonomic 
fibres (vagus), terminating around ganglion cells in the auricle (A). The axis cylinders 
issuing from these cells terminate on the muscular fibres of the auricle and ventricle ( TO • 
R, accelerator sympathetic fibres terminating around ganglion cells in the stellate gang- 
lion G. The axis fibres of these ganglion cells run through the Annulus Vieussenii and 
terminate on the muscular fibres of the auricle and ventricle. N, N' points at which 
nicotine, coniine, curarine, etc., act — the ganglion cells surrounded by the terminations 
of the nerves. M , points at which muscarine and atropine act — the terminations of the 
fibres which arise from the intra-cardiac ganglia on the cranial autonomic path. E, points 
at which adrenaline acts — the myoneural junction on the sympathetic path. 

duced as by stimulation of the vagus fibres in the neck. It is not 
affected by section of the cervical pneumogastric, as the path from the 
ganglia to the cardiac muscle fibres is still intact, but on the other 
hand, it is prevented by atropine, which paralyzes the terminations 
of the postganglionic fibres, and therefore blocks the passages of im- 



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NICOTINE GROUP 307 

pulses from the ganglia to the muscle. It is also prevented by a number 
of drugs, such as curara and coniine, which paralyze the ganglia. 

This 'itimiilntivn of the ganglia, ia ,qL short duration, sqqji passing 
in to paralysis, so that on stimulating the vagus after nicotine there is 
no slowing of the heart but often some acceleration, due to the fact 
that the accelerating fibres running along with the inhibitory in the 
vagus nerve have no ganglionic apparatus in the heart, and are therefore 
unaffected by nicotine. Although inhibitory impulses can no longer 
reach the heart from above, stimulation of the venous sinus in the 
frog still causes arrest of the heart, since the stimulating current here 
reaches the inhibitory nerves beyond the paralyzed ganglia (Fig. 24, X), 
and these preserve their usual irritability. In the same way muscarine, 
which acts upon the postganglionic inhibitory terminations in the heart 
muscle (Fig. 24, M), can slow the rhythm even after the ganglia have 
been paralyzed by nicotine. 

In addition to its action on the peripheral inhibitory ganglia, nico- 
tine seems to stimulate the v agus centre in jh e medulla, as the slowing 
is greater when the vagi arelntact than wHen they are divided. But 
apart from this action on the inhibitory apparatus, nicotine also stimu- 
lates, and in large quantities paralyzes, the ganglia on the accelerator 
fibres, so that when the inhibitory mechanism has been put out of 
action by atropine, moderate quantities of nicotine inc rease the rate, 
while larger a mounts paralyze the. arrelsrator ganglia (N', Fig. 24) and 
thus telnfto'slow the heart. A further action is said to be exercised on 
the hfinrj^rmigfl^jtsplfj whi^h is first fltinrmlaif > 4-fmd then depressed 
(WertKeimer). 

On the injection of nicotine into a vein or subcutaneously, an im- 
mense augmentation of the arterial tension occurs; this may be due in 
part to stimulation of the vaso-constrictor centre in the medulla, but 
is to be ascribed chiefly to stimulation of the ganglia on the course 
of the vasoconstrictor nerves. 

The constriction of the vessels can be observed in many parts of the body 
— mesentery, foot, rabbit's ear, etc. In these parts the pallor produced by 
the narrowing of the vessels is followed by redhess and congestion owing to 
the paralysis of the ganglia, and at the same time the pressure falls to a level 
somewhat below the normal. In some parts of the body no constriction of 
the vessels occurs; for example, the dog's lip and mouth are congested first 
and then become pale. This flushing seems partly due to the stimulation of the 
ganglionic apparatus on the vase-dilator fibres for the lips and mouth, and 
partly to the constriction of the vessels in the splanchnic area diverting the 
blood current to those parts which are less abundantly supplied with con- 
strictor fibres, for it occurs after removal of the superior cervical ganglion con- 
taining the vasodilator fibres. 

After a few minutes the blood-pressure falls to the normal level or 
lower, but a second injection again produces a similar rise in the arterial 
tension, unless the first was large enough to weaken the ganglia. 

In the rabbit nicotine tends to induce lesions of the aorta with sub- 
sequent calcareous degeneration, which resembles the atheromatous 



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308 SUBSTANCES ACTING AFTER ABSORPTION 

patches seen in man. This is due to the veryhigh blood-pressure, and 
similar effects are seen from~acfrenaiine~and from other measures which 
increase the blood-pressure, such as pressure on the abdominal aorta. 

Respiration. — The respiration is at *j rg t ^p^ «" d shallow with some 
deficiency in the expiratory movements, but after a time, while main- 
taining the acceleration, it becomes deeper. It is liable to be inter- 
rupted at this stage by the convulsions, but if these do not prove fatal, 
it gradually becomes slower while remaining deep. Later, pauses in 
the position of expiration appear, and the movements become weaker 
until they disappear, the animal dving of asphyxia. The respiratory 
centre is first^atimulated jm3 then de pressecTahd paralyzed and its 
failure is the cause of death/the heart contmuinj^toT)eat for some time 
afterward although slowly and weakly. 

The bronchial muscle relaxes after a transient constriction when 
nicotine or lobellne is ingested, these changes being brought about by 
stimulation of the ganglia on the course of the vagus fibres which cause 
contraction of the bronchial muscle, and later of those on the sym- 
pathetic fibres which inhibit the contraction. 

Most of the Secretions are increased tftmpncQriJx.i)y nmtin^ The 
glands investigated have generally been the salivary, where it is found 
that the secretion is increased by the injection of small quantities, but 
is after ward depr essed, while large doses diminish it at once. The seat 
of -actton is agauT the ganglionic apparatus on the secretory nerves. 
If the chorda tympani be stimulated in the normal animal a large 
secretion of saliva at once follows, but if a sufficient quantity of nicotine 
be injected, no such effect follows its stimulation. If, however, the 
nerve fibres be stimulated between the ganglion cells and the gland 
(at X in Fig. 25), the secretion again follows as before. On the other 
hand, nicotine increases the secretion whether the chorda be intact 
or not, but ceases to act if the connection between the ganglion cells 
and the gland be interrupted. Nicotine thus first stimulates and then 
paralyzes the ganglia on the course of the chorda tympani and of the 
sympathetic fibres supplying the gland. Pilocarpine and muscarine 
cause profuse salivation after nicotine because they stimulate the 
postganglionic terminations in the gland cells, and it is therefore im- 
material whether the connection with the central nervous system be 
interrupted or not. On the other hand, the reflex secretion* of saliva 
normally produced by irritation of the mouth or by chewing is prevented 
by nicotine. Atropine stops the secretion produced by nicotine by 
paralyzing the postganglionic terminations. 

The other secretory glands are affected in the same way by nicotine, 
their secretions being first increased by the stimulation of the ganglia 
on the course of their secretory nerves, and then being lessened by their 
paralysis. Thus the secretion of sweat and bronchial mucus is found 
to be markedly increased. The urine and bile have not been shown 
to be affected by nicotine, as their secretion does not seem to be so 
dependent upon nervous influences. The activity of the suprarenal 
glands is increased by nicotine, probably by its action on the ganglia 



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NICOTINE GROUP 



309 



on the course of the innervating fibres; this results in an augmented 
secretion of adrenaline into the bloodvessels, which in turn affects a 
number of organs, such as the iris and uterus, and introduces a new 
complication in the action of nicotine. 



Fiq. 25 




Diagram of the innervation of the submaxillary gland. P f cranial autonomic fibres 
(chorda tympani), terminating around a ganglion cell in the hilus of the submaxillary 
gland. The axis from this ganglion cell runs to the secretory epithelium. R, sympathetic 
fibres, terminating around a ganglion cell in the superior cervical ganglion Q. The axis 
from this cell runs to the secretory epithelium. In the diagram the nerves are represented 
as running to separate acini. N, N' f ganglion cells surrounded by the terminations of 
the nerves — the points at which nicotine acts. M, the terminations of the secretory fibres 
connected with the chorda tympani — the points at which atropine, muscarine, and pilo- 
carpine act. E, the terminations of the secretory fibres connected with the sympathetic 
— the point at which adrenaline acts. 



Nicotine produces ext reme Nyisea, an d Vnmifiny when taken even 
in comparatively small quantities, a fact which is generally recognized 
by tyros in smoking. This may be in part central in origin, but is 
mainly due to the powerful contractions of the stomach walls. This 
contraction extends throughout the intestlnar tract, so "that repeated 
Evac uation of thn B owel wmr^ Somewhat larger quantities may lead 



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310 SUBSTANCES ACTING AFTER ABSORPTION 

to a tetanic contraction of the whole intestine with almost complete 
obliteration of the Jumen. This exagge ration of thfi prrintnjtir con- 
traction is probably due to stimulation of the motor ganglia in the 
intestinal wall, and 4 subsequent paralysis of these structures leads to 
a failure of local stimuli to induce peristalsis. A further effect of nicotine 
in the bowel is due to its stimulating the ganglia on the fibres of the 
splanchnic which inhibit the rhythmical pendulum movements. These 
are arrested by the pijection of nicotine, but return in exaggerated 
form as the ganglionic stimulation passes into paralysis. The mesenteric 
vessels are narrowed at first from stimulation of the ganglia on the 
course of the vaso-constrictor nerves, but congestion follows the depres- 
sion of these ganglia and the blood-pressure falls. 

Similar changes are produced by ni^iim* in thp hl a dHer, \ sh\rh is 
tfypeqEn jmto tetanic con traction. The urine is therefore expelled very 
soon after the injection of nicotine and this probably gave rise to the 
erroneous view that the renal secretion was increased. T^ uter us is 
strongly contracted in pregnant animals, but is inhibited in the non- 
pregnant cat, in which the inhibitory nerves are more powerful than 
the contractor ones. 

The action of nicotine on the Pupil varies in different animals, for 
while in the cat and dog its application either intravenously or locally 
produces marked but transitory dilation, in the rabbit partial con- 
striction sets in immediately. In cases of acute poisoning in man 
cont raction is generally seen at fi rst an d is followed bv dilat ation. In 
birds nicotine causes very marked contraction of the pupil, appar- 
ently owing to direct action on the muscle of the iris. The size of 
the pupil is regulated by two sets of nerves, the motor oculi and the 
sympathetic, and the ciliary fibres of both of these are interrupted by 
ganglia in their passage from the brain to the iris, those of the motor 
oculi by the ciliary ganglion, those of the sympathetic by the superior 
cervical ganglion (see Fig. 26, p. 320); the varying effects of nicotine 
may be due to its stimulating the one ganglion more strongly in one 
species of animals, the other in another. It is found, however, that 
atropine does not remove the effects of nicotine on the rabbit's eye, 
which would seem to indicate an action on the muscular fibres of the 
iris. Several other effects on the orbital muscles are seen; thus in 
cats and dogs the nictitating membrane is withdrawn, the eye opens 
and is directed forward, while in the rabbit these symptoms are pre- 
ceded by a stage in which the nictitating membrane is spread over the 
cornea and the eye is tightly closed; these all arise from stimulation and 
subsequent paralysis of the superior cervical ganglion. 

Ni ^ntine 1 then, firs * ^tjnii^tpg a n dJl\terj)araly zes all the Autonomic 
Ganglia , whether applied locally to them or injected into the circulation. 
In these ganglia, the characteristic formation is the basket-like arrange- 
ment of the terminations of the entering nerve, which surround a large 
nerve cell from which an axis cylinder runs to the muscle or secretory 
cell. A nerve impulse from the central nervous system passes from the 
basket to the cell and thence to the periphery. Langley has shown that 



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NICOTINE GROUP 311 

nicotine acts on the cell of the perip h eral neuron , and not on the net- 
work around it, for the same effect is obtained from the application 
of the poison after the network has degenerated. 

In the frog nicotine produces fibrillary twitching and slow, pro- 
longed contraction of the Muscles, which are not prevented by previous 
division of the nerves leading to them, but disappear on the injection 
of curara; on the other hand, the paralysis induced by curara may be 
partially removed by small quantities of nicotine. This indicates that 
the fibrillary contractions arise neither from action on the central ner- 
vous system nor on the contractile substance of the muscle itself. And 
Langley has recently shown that the fibrillary twitching and slower 
contractions occur in muscles in which the nerve ends have degen- 
erated from division of the nerves, so that nicotine acts on some recep- 
tive substance peripheral to the anatomical nerve ends and intervening 
between these and the contractile substance of muscle. A similar 
effect is seen in reptiles and birds; in mammals the twitching of the 
muscles is prevented by section of the nerves, and is, therefore, due to 
central action, but large quantities of nicotine cause paralysis exactly 
like curara. 

tu~ con^uJaioaa seaa ' %n W k eeld n™ A ^nrm-H™*^ animals evi- 
dence the influence of nicotine on the Central Nervou s System. The 
spinltf COfd is thrown into a condition of exaggerated irritability, and 
the reflexes are correspondingly increased, but the convulsions do not 
seem to be due so much to the spinal cord as to the medulla oblongata 
and hind brain, for they are not to njc hut elnnie in nharao ter. and are 
much weaker after division of the cord immediately below the medulla 
than in the intact animal. The medullary stimulation also betrays 
itself in the r apid and dffp i^pi™^™^ and is perhaps in part respon- 
sible for the inhibitory slowing of the heart and the rise in the blood- 
pressure. The higher centres in the brain seem to participate but 
little in the stimulant action of nicotine, which is short-lived, and 
soon gives way to marked depression of the whole central nervous 
system, manifested in the slow respiration, the low blood-pressure, the 
disappearance of the reflex movements and the final unconsciousness. 

The Excretion of nicotine is probably carried on mainly by the kid- 
neys, for it is found in thfr i i rinft vrry irmn nftm* it rntrrn the blood. 
It has also \ }een (fcteete<| \r\ | f he saliva and perspiration. It has been 

shown repeatedly that nicotine and some other alkaloids are weakened 
in toxic effect or rendered entirely inactive by being mixed with an 
e xtrac k-pj-4he liver or of the suprarenal capsules; but no satisfactory 
explanation is forthcoming, though there is every reason to suppose 
that much of the nicotine absorbed from the stomach and intestine is 
thus modified in its passage through the liver. 

When small quantities of nicotine are ingested repeatedly, the body 
soon gains a certain Tolerancy . and no symptoms whatever are pro- 
duced by doses which in ordinary cases would produce grave poison- 
ing. A familiar example of this tolerance is seen in the practice of 
smoking. The first use of tobacco in the great majority of indi- 



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312 SUBSTANCES ACTING AFTER ABSORPTION 

viduals is followed by vomiting and depression, which may even amount 
to collapse, but after a few experiences no symptoms follow smoking, 
owing to the cells of the body becoisiBiL tolerant of th ej^oisonand learn- 
ing to destroy^k-niore rapidly (DixoiTand Lee). Insome individuals 
no such tolerance is developed, and in every case the tolerance is 
much more limited and more difficult to acquire than that for morphine. 
In animal experiments it is often found that while one application of 
nicotine produces considerable ganglionic stimulation, the second has 
much less effect. This is probably due, not to the establishment of 
tolerance, but to the first dose having produced primary stimulation 
and then depression of the ganglia, this depression, while not amounting 
to complete paralysis, being sufficient to counteract to some exent the 
stimulant action of the second injection. True tolerance is attained 
very imperfectly by animals from the use of repeated small doses, but 
when larger amounts are used some tolerance is soon acquired (Edmunds) . 
Animals which have acquired tolerance for nicotine also resist the action 
of lobeline. 

Therapeutic Uses. — Lobelia was formerly used as an emetic, but is unreliable, 
and is liable to give rise to the most alarming symptoms of poisoning. It is 
occasionally used in the form of the tincture (Dose, U. S. P., 1 c.c, B. P., 
5-15 mins.), to relax the spasm of the bronchial muscle in asthma, and may 
also aid in this condition by rendering the mucous secretion more fluid through 
its nauseating action. But its effects must be carefully watched, as the prepara- 
tions seem to vary in strength, and alarming symptoms and even fatal results 
have sometimes followed its use. In any case it is inferior to atropine and its 
allies in this condition. Nicotine and the other members of the group are 
not used in therapeutics. 

Tobacco. 

Tobacco had been in use among the aboriginal tribes of America 
before they became known to civilization. It was introduced into 
Europe soon after the discovery of America, and its use as an article 
of luxury, beginning in England, soon spread to the continent, and in 
spite of papal bulls and numerous efforts on the part of the secular 
authorities, has continued to enthral a considerable portion of the 
human race. The most widespread use of tobacco — smoking — is also 
the most ancient one, having been that of the aboriginal Indians. 
Snuff-taking, introduced by Francis II. of France, remained fashion- 
able for a long time, but is now almost obsolete. Tobacco-chewing 
is a more modern development, but shows no signs of abatement. 
Curiously enough, the leaves of the pituri plant, which contain nicotine, 
are formed into a mass and chewed by the natives of Australia. In 
smoking, snuffing or chewing, nicotine is absorbed; tobacco smoke 
always contains nicotine, though the amount varies with different 
kinds of tobacco and also with the way in which it is smoked; but a 
large proportion of that contained in tobacco passes over in the smoke 
along with pyridine and some of its derivatives. In snuff the nicotine 
is generally small in amount, while in chewing tobacco there is generally 
a varying amount of foreign matter, such as molasses. 



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NICOTINE GROUP 313 

The enjoyment derived from the use of tobacco has never been 
adequately explained, and it is not even proved that nicotine is essential 
to the pleasurable results; consideration of the pharmacological effects 
of nicotine gives no clue, for these are of the opposite nature. It has 
been suggested that smoking gives repose and thereby improves intel- 
lectual work, but this is denied by many habitual smokers. It has 
also been stated, and denied, that the mental energy is reduced by the 
use of tobacco, and an attempt has been made to demonstrate this by 
measuring the amount of work done with and without tobacco; but 
investigators are not agreed on the results, which probably depend 
largely upon the individual. One fact is certain, that the tobacco 
habit cannot be compared with the use of such drugs as morphine, 
cocaine, or alcohol, for it is not taken with the purpose of producing 
stimulation or depression of the central nervous system, and it seemsl 
doubtful whether the nicotine ordinarily absorbed really has any action/ 
whatsoever. Perhaps the local effects on the mouth, nose and throat 
play a larger part in the effects of tobacco than is generally recognized. 
A certain amount of rhythmic movement demanding no exertion seems 
in itself to have a soothing, pleasure-giving effect, for it is otherwise 
impossible to explain the satisfaction enjoyed by many in chewing 
tasteless objects, such as gum or straws. A curious fact which tends 
to show that tobacco smoking is not carried on for the sake of the 
nicotine absorbed, is that the pleasure derived from a pipe or cigar is 
abolished for many persons if the smoke it not seen, as when it is smoked 
in the dark; and very few blind men enjoy smoking. 

Most people may indulge in the moderate use of tobacco for many 
years with perfect impunity, but its excessive use is followed in many 
individuals by a number of symptoms, some of them trivial, others 
indicating grave changes in important organs. 

One of the commonest effects of overindulgence in tobacco is a 
Mii.™^ inflowflyflo+ipp n f fh n thront n n d npppr parts of the respirat ory 
passages*. leadiug-toJioarseness and excessive secretion of the mucous 
glandsu-Jfhis is explained by the constant application to the throat 
of an irritant nllfflilinp T ro p™*i and is probably not due to the specific 
action of nicotine. A similar irritated condition of the tongue is 
frequently met with, more especially when the hot vapor is constantly 
directed on one part, as in pipe smoking, and it is sometimes stated 
that the constant irritation thus produced renders the tongue and lip 
more liable to cancerous disease. Dy spepsia , want of appetite, and 
consequent loss of flesh may also be explained by the local frritation 
produced by^fchd-nicotine swallowed in the saliva. A common result 
of the abuse of tobacco is palpitation jmd irregularity of the heart, 
which has been attributed to changes in the inhibitory mechanism. 
Another important symptom is dimness pf_yision, especially for colors, 
and imperfect accommodation, which may go on to complete blindness 
in one or both eyes. In early cases the retina often appears pale, and 
if the condition persists, atrophy of the optic nerve may result, prob- 
ably following on degenerative changes in the ganglion cells of the 



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314 SUBSTANCES ACTING AFTER ABSORPTION 

macular region of the retina. This tobacco amblyopia is held by some 
to occur only when the tobacco habit is accompanied by alcoholic excess. 
Smoking causes a slight rise of blood-pressure in some individuals, 
and this has aroused apprehensions that it may tend to favor arterio- 
sclerosis, but the change is so slight that these fears are quite ground- 
less. Nervous symptoms, such as tremor, exaggeration of the reflexes, 
headache and giddiness, are sometimes developed in workmen in 
tobacco factories, but they do not seem to be induced by smoking or 
chewing tobacco, though depression, muscular weakness and giddiness 
are sometimes complained of. In the great majority of cases of chronic 
tobacco poisoning, the symptoms disappear on abandoning the habit, 
or even on restricting the daily consumption. A series of subjective 
and even objective symptoms are said to be induced in neurotic subjects 
by the sudden withdrawal of tobacco. 

Esser has recently stated that chronic nicotine poisoning in animals 
induces marked disturbance of the heart, and that degeneration of the 
vagus fibres is recognizable histologically; changes have also been 
found in the nerve cells of the spinal cord and sympathetic ganglia 
similar to those described under chronic alcoholic poisoning. 



Bibliography. 

Langley and Dickinson (Journ. of Phys., xi, p. 265) give all the more important experi- 
mental literature up to 1890. 

Langley, Langley and Sherrington, Langley ana* Anderson. Journ. of Phys., xii, xiii, 
xv, and xxvii, p. 224; xxxvi, p. 347; xxxvii, pp. 165, 285. 

Wertheimer et Colas. Archiv. de Physiol. (5), iii, 189 1, P- 341. 

Bayliss and Starling. Journ. of Phys., xxiv, p. 99. 

Hatcher. Amer. Journ. of Phys., xi. p. 17. 

Dixon and Brodie. Journ. of Phys., xxix, p. 168. 

Esser. Arch. f. exp. Path. u. Pharm., xlix, p. 190. 

Greenwood. Journ. of Phys., xi, p. 573. (Action on Invertebrates.) 

Moore and Row. Journ. of Phys., xxii, p. 273. 

Winterberg. Arch. f. exp. Path. u. Pharm., xliii, p. 400. 

Habermann. Ztschr. f. physiol. Chem., xxxiii, p. 55. 

Edmunds. Journ. of Pharmacology, i, p. 27. 

Dixon and Lee. Quart. Journ. Exp. Physiol., v, p. 373. 

Birch-Hirschfeld. Arch. f. Ophthalmologic, liii, p. 79. 

C. W. Edmonds. Amer. Journ. of Phys., xi, p. 79. (Lobeline.) 

Dale and Laidlaw. Journ. of Pharm. and Exp. Therap., iii,' p. 205. * (Cytisine.) 



XI. THE ATROPINE SERIES. 

The atropine series contains a number of very closely allied alkaloids 
of which the chief are A tropin e, Hyoscymnine and Hyoscine or Scopo- 
lamine. They are found in several plants of the Solanaceae order, and 
in most cases several of them occur together. 

Atropine may be broken up by the action of alkalies into an alkaloid, 
Tropine, and Tropic Acid. The former is a pyridine compound very 
closely allied to Ecgonine (see Cocaine) as may be seen by its structural 
formula, while the latter is an aromatic acid. 



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THE ATROPINE SERIES 315 

Atropine. 



Tropin© radicle. Tropic acid radicle. 

CH2--CH CHa 

I I 

N (CHa)CHO— CO— CH— C«H* 

I I I 

CH«— CH — CHi CH2OH 



Atropine is racemic hyoscyamine, that is, it consists of equal parts of 
laevohyoscyamine and dextrohyoscyamine, but, as the latter is only 
feebly active in the body, the action of atropine is practically that 
of its lsevohyoscyamine half. Laevohyoscyamine is formed in the 
plants, and is readily changed to atropine in the plant cells and also 
in the process of extraction, so that the relative proportion of the 
isomers in the plants and in the preparations varies. 

Hyoscine, or Scopolamine, was formerly supposed to be another 
isomer of atropine, but has lately been shown to differ slightly in its 
formula, which is C17H21NO4. It is very closely allied to atropine, 
and is decomposed into tropic acid and Scopoline (Oscine), which is 
nearly related to tropine. 

A number of other alkaloids have been described in different plants, generally 
associated with one or more of those already mentioned. But on examination 
these have generally proved to be mixtures of atropifte, hyoscyamine and 
hyoscine. Thus the Duboisine of Duboisia myoporoides, the Mandragorine 
of Mandr agora (Mandrake) and the Daturine of Datura stramonium have 
all failed to maintain their position as new bases and have proved to be mixures 
of the established alkaloids in varying proportions. Atropamine, Belladonnine 
or Apoatropine is found along with atropine in some plants (belladonna), and 
may be formed artificially from atropine by the removal of a molecule of water; 
it is a compound of tropine and atropic acid. Pseudo-hyoscy amine is said to 
differ from atropine and hyoscyamine in some of its chemical relations, but 
has not been the subject of much work as yet. Atroscine is isomeric with scopo- 
lamine, and the same relation exists between them as between atropine and 
hyoscyamine. 

After atropine had been found to be a compound of tropine and 
tropic acid, a number of other acids were attached to tropine in the 
same way as tropic acid. These artificial alkaloids are known as Tro- 
peineSy and in action resemble atropine in some points while differing 
from it in others. The only artificial tropeine which has as yet been 
used in medicine is the compound of tropine and oxytoluic acid known 
as Homatropine. Scopoleines have been formed by substituting other 
acids for the tropic acid of scopolamine, but none of them have proved 
of value in therapeutics as yet. 

It must be understood that the combination of tropine and its allies 
with tropic acid does not partake in any way of the nature of the 
combination of an ordinary alkaloid, such as morphine, with an acid. 
The bond is the much closer one seen in the compound ethers, and the 
resulting substance is alkaline and combines with acids to form salts 
exactly as other alkaloids do. 



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316 SUBSTANCES ACTING AFTER ABSORPTION 

The chief plants containing these alkaloids are Atropa Belladonna 
(Deadly nightshade), Hyoscyamus niger (Henbane), and Datura Stra- 
monium (Thornapple). 

Of less importance are Duboisia myoporoides, Scopola atropoides, and Man- 
dragora autumnalis, or Atropa mandragora (Mandrake); another species of 
Duboisia contains nicotine. 

A number of other Solanacese — e. g., tobacco and potato leaves, are said 
to contain small quantities of the atropine alkaloids but the quantity present 
here is too small to be of any importance. 

These alkaloids all resemble each other closely in the effects pro- 
duced by them in animals. Some differences in the symptoms exist, 
however, and the action of atropine alone will first be described and 
later the points in which that of hyoscyamine and of hyoscine differ 
from it. 

Atropine acts as a sti mulant to the central nervous s ystem and also 
affects a nu mber of peripheral organs; in some of these the ch&nges 
are due to the interruption of nerve paths, while in others these remain 
intact under atropine. 
| Symptoms. — In man j^ gr. (0.6 mg.), causes some dryness of the 
; mouth and throat, and thirst; the skin also feels dry, and the heart may 
be accelerated after a short period of slowing. Doses of ^ gr. (2.5 mgs.) 
are followed by marked dryness of the skin and throat, thirst, difficulty 
in swallowing and hoarseness in speaking. There is often nausea, and 
in some cases vomiting, headache, and giddiness; the pupils are wider 
\ than normal and the sight may be indistinct, especially for near objects. 
j The respiration may be quicker and the pulse often beats at one hundred 
' per minute or more. A symptom that is often present, though by no 
, means invariably so, is redness of the skin, more especially of the head 
j and neck; the conjunctiva may also be congested. After larger doses 
the same symptoms are observed, but are soon followed by others of 
graver import. The patient can no longer swallow, although suffer- 
ing from intense thirst, the heart is generally extremely rapid, speech 
is difficult and hoarse, and the pupils are dilated until the iris almost 
disappears. Restlessness and garrulity point to an increase in the 
irritability of the brain; the patient at first talks in a perfectly normal 
way but soon becomes confused, begins a sentence and does not finish 
it, often bursts into laughter or sobs, and in short becomes delirious 
and eventually maniacal. Often marked tremor of different muscles 
may be observed, and eventually convulsions set in and may be the 
cause of death through the failure of the respiration. As a general 
rule, however, the stage of excitement passes into one of depression, 
the patient sinks into a sleep, which deepens into stupor and coma, 
the respiration and heart become slow, weak and irregular, and death 
eventually occurs from asphyxia. 

In the frog the injection of small quantities of atropine is followed 
by a period of depression and paralysis of the peripheral nerve termina- 
tions resembling that seen under curara; after a few days there super- 



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ATROPINE 317 

venes a stage of increased reflex excitability and tonic convulsions 
indistinguishable from those seen under strychnine. This stage slowly 
passes off and the animal again becomes normal. 

Action. — These symptoms in man and other mammals, indicate 
stimulation of the Central Nervous System followed by depression. 
Those observed in man sometimes resemble those seen in the excite- 
ment stage of alcohol poisoning, and it has been suggested that in 
both the cause is rather a lessening of the control normally exercised 
by the higher powers over the lower motor areas than a true stimula- 
tion of the latter. But this is shown to be incorrect by the fact that 
in atropine poisoning the motor area is more easily stimulated by the 
electric current than normally. The stimulant action of atropine 
is also seen in the increased reflex response to irritation of the skin, 
as well as in the augmented activity of the centres in the medulla. 
The nervous symptoms under atropine, therefore, arise from true 
stimulation of the central nervous system, but they are wholly different 
from those produced by strychnine, because the latter acts more espe- 
cially on the lower parts of the nervous axis, while atropine acts more 
strongly on the higher divisions. The most marked symptoms of 
strychnine poisoning arise from the spinal cord and medulla oblongata, 
and consist in increased reflex movements and convulsions, while 
those caused by atropine are rather to be referred to the brain, and 
consist in increased coordinated movements, such as talking and 
delirium, the exaggerated reflex being of minor importance. 

Atropine differs from caffeine, on the other hand, in its effect on the 
brain, for under the latter the psychical functions are those affected 
first of all. It would seem probable, then, that each of these three 
stimulates the whole of the central nervous system more or less, but 
that while strychnine acts more strongly on the lower divisions, the 
spinal cord and medulla, and caffeine on the highest functions, the 
psychical, atropine occupies a midway position, and exercises its chief 
action on the motor divisions of the brain. These are rendered so 
excitable that the controlling areas can no longer keep them in check, 
and an increase in movement occurs somewhat resembling that seen 
when the controlling areas are depressed by alcohol. The stimulant 
action spreads downward when large quantities have been absorbed, 
and involves the medulla oblongata and spinal cord, so that symptoms 
resembling those seen in strychnine poisoning may make their appear- 
ance. After the stimulation has lasted some time, depression sets in 
and may go on to complete paralysis of the central nervous system, 
which is fatal to mammals through cessation of the respiration. Even 
during the stimulation stage some symptoms of depression are to be made 
out, exactly as has been described under strychnine. 

The peripheral action of atropine involves a number of secretory 
glands, organs containing unstriped muscular tissue, and the heart. 

Most of the Secretions are decreased by the application of atropine 
— salivary, gastric, pancreatic, mucus, and sweat. This is due, not 
to any action upon the secretory cells, but to the failure of nervous 



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318 SUBSTANCES ACTING AFTER ABSORPTION 

impulses. It has been investigated most carefully in the salivary 
glands, but enough work has been done on the others to show that the 
process is the same in all. The secretion of saliva in the normal animal 
seems to occur only when impulses reach the gland cells by one of two 
paths — through the chorda tympani, or through the cervical sympathetic 
fibres. If the chorda typani be divided and put on electrodes and a 
cannula be passed into Wharton's duct, a rapid flow occurs through it 
on stimulation of the nerve, which ceases or is very much diminished 
on stopping the stimulation. If how atropine be injected, stimulation 
causes no increase in the secretion, and atropine, therefore, seems to 
paralyze some part of the peripheral secretory apparatus. The chorda 
tympani passes through ganglion cells on its way to the gland cells, 
and the impulses might be hindered in their passages through these, as 
actually occurs under the action of some drugs. (See Nicotine.) But 
this is not the explanation of the inefficiency of chorda stimulation, as 
is shown by the fact that if the electrodes be pushed into the hilus of the . 
gland so as to stimulate the nerve fibres beyond the ganglia no secretion 
follows. Another explanation would be that the gland cells themselves 
are paralyzed by atropine, but this is shown not to be the case, for 
on stimulating the sympathetic, which supplies the same cells as the 
chorda tympani, the usual secretion follows. The site of action of atro- 
pine, therefore, seems to lie between the ganglion cells on the course 
of the chorda tympani and the secretory cells, that is, the point of 
attack is the terminations of the nerve fibres in the gland cells. -The 
action is limited to certain definite terminations, for it has been noted 
already that the sympathetic secretory fibres are not paralyzed, and it 
was discovered by Heidenhain that the vasodilator fibres of the chorda 
tympani are not paralyzed by atropine. Stimulation of the nerve 
after atropine therefore induces no secretion, but the gland becomes 
red and swollen, and the blood escapes from the veins in larger quantity 
and in spurts in the same way as in the unpoisoned animal under chorda 
stimulation. Atropine, then, seems to select the terminations of the 
secretory fibres of the chorda tympani for paralysis and to leave all 
others unaffected. The secretion of saliva seems to occur generally 
only on the arrival of impulses by way of the chorda tympani, so that 
on the paralysis of its terminations the secretion ceases entirely. 

In the same way the other glands of the mouth, throaty nose and respira- 
tory passages cease secreting after atropine, and the effect is the char- 
acteristic dryness of the mouth, the hoarseness of the voice, and the 
thirst and difficulty in swallowing complained of after its administration. 

The secretion of the gastric juice has recently been shown to be 
diminished or entirely arrested by atropine, which paralyzes the 
terminations of the secretory fibres of the pneumogastric nerve in the 
stomach. The hydrochloric acid of the secretion is more reduced 
than either the pepsin or the fluid as a whole. The secretion of pan- 
creatic juice is reduced after atropine, and stimulation of the pneumo- 
gastric has no effect on it, while in the normal animal it accelerates 
the flow. The secretion induced by the specific pancreatic hormone, 



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ATROPINE 319 

secretin, continues, showing that atropine does not act on the cells 
of the pancreas, but only isolates them from the pneumogastric nerve. 
But as the formation of secretin depends on the passage of hydrochloric 
acid into the duodenum, and this is lessened by the action on the gastric 
glands, the pancreatic secretion is further reduced in this indirect way. 
The secretion of tears is diminished by atropine, presumably from 
the interruption of the nervous connections of the lachrymal glands. 
The bile is also said to be somewhat lessened by atropine. The pro- 
duction of sugar from the glycogen of the liver has been recently shown 
to be controlled by branches of the cceliac plexus, but these have no 
effect after atropine, so that the terminations of the nerves in the liver 
cells seem to be paralyzed also. 

The same paralysis is produced in the terminations of the nerves in 
the sweat glands. Stimulation of the sciatic nerve as a general rule 
causes perspiration in the foot of the cat and dog, but after atropine 
this effect is absent, because the impulses cannot reach the cells through 
the paralyzed terminations, and the skin therefore becomes dry and 
hot. The local application of atropine to the skin has no effect on the 
sweat secretion, as it does not penetrate to the glands. The secretion 
of milk is not materially changed by atropine, whether the alkaloid 
is carried to it by the blood or is applied locally; and such drugs as 
increase the milk secretion (pituitary extract) are not antagonized by 
atropine. This is in accord with the physiological observation that 
the mammary gland continues to secrete after all its nerves have been 
cut and allowed to degenerate; in other words the mammary secretion 
is largely independent of the central nervous system. 

The kidney is not controlled so directly by nerve influences as most 
of the glands, and atropine causes little or no change in the amount 
of urine except what is probably the indirect result of the arrest of the 
other secretions. The secretion of lymph is not altered by atropine, 
so that it is probably not controlled by nerves in the same way as the 
true secretions. 

All Organs Containing Unstriped Muscle (apart from the arterial wall) 
seem to be altered by atropine. Thus the movements of the pupil 
and oesophagus (except in animals in which these consist of striped 
muscle), stomach, intestine, bladder, uterus, spleen and thoracic duct 
are affected by atropine. 

The dilatation of the pupil occurs on internal administration as well as 
on the application of minute quantities locally, and is due to paralysis 
of the myoneural junctions in the circular muscle of the iris. This is 
shown by the fact that stimulation of the motor oculi nerve or of the 
postganglionic fibres from the ciliary ganglion is without effect. This 
limits the paralysis to the periphery, and that the muscle is not acted 
on is shown by its reacting to electrical stimulation. The local nature 
of the action may be further shown by carefully applying a minute 
quantity of the drug to one side of the cornea, when dilatation of one 
half or less of the pupil occurs, the rest remaining contracted. The 
motor oculi (Fig. 26) constantly transmits impulses through the 



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320 



SUBSTANCES ACTING AFTER ABSORPTION 



ciliary nerves to the sphincter muscle of the iris and keeps the pupil 
moderately contracted, and when these impulses can no longer reach 
the iris owing to the interruption of the path, the sphincter relaxes 
and the pupil dilates. The contractile substance does not seem to 
be affected by the ordinary application of atropine, but if strong solu- 



Fio. 26 




Diagram of the innervation of the iris. P, a fibre of the motor oculi passing from 
the brain to the ciliary ganglion '(AO, in which it terminates around a nerve cell, which 
sends an axis cylinder to terminate, M, in the circular fibres of the iris. R, a sympathetic 
nerve fibre issuing from the lower cervical cord, running through the stellate and inferior 
cervical ganglia and terminating around a ganglion cell in the superior cervical ganglion, 
G. The axis cylinder from this nerve cell runs to the iris (passing the ciliary ganglion) 
and terminates, C, on the radiating fibres. M is the point acted on by atropine and 
muscarine. N,N', the ganglion cells, is the seat of action of nicotine. C, the terminations 
in the dilator fibres, that of cocaine and adrenaline. 

tions be continuously applied, it may be paralyzed by it as by many 
other drugs. Atropine antagonizes the action of pilocarpine in the 
pupil after degeneration of the motor oculi, and the receptor for these 
alkaloids therefore does not undergo degeneration and must be situated 
in the muscle between the nerve ends and the contractile substance. 



The constrictor muscle is constantly opposed by dilator fibres, and when 
the former is thrown out of activity by the paralysis of the terminations of 
the motor oculi, the radiating fibres cause an active dilatation. If, however, 
the radiating muscular fibres be separated from their innervating centre by 
section of the cervical sympathetic nerve in the neck, they also cease to con- 
tract and there is no active dilatation, so that atropine causes less widening 
of the pupU than it would if impulses continued to reach the radiating muscle. 



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ATROPINE 



321 



After the application of atropine to the eye, the iris often relaxes with suffi- 
cient force to tear weak adhesions to the lens, and if the iris be attached at 
two points to the lens, atropine causes a bow-shaped dilatation between them, 
the concavity being directed inward. The dilatation is therefore an active 
movement, accomplished by the contraction of the radiating muscular fibres, 
but these are not put in motion by the action of atropine on the radiating 
muscles of the iris, or their nerves, but by the normal impulses descending 
from the central nervous system, which after atropine are not counterbalanced 
by impulses reaching the circular fibres. 



The dilatation of the pupil effected by atropine is not quite maxi- 
mal, for stimulation of the cervical sympathetic trunk generally 
increases it, though but slightly. It differs considerably in different 
animals, being more complete in man, the dog and the cat than in 
the rabbit, entirely absent in birds and reptiles, and elicited with diffi- 
culty in the frog. In birds and reptiles the iris consists of striped 
muscle fibres, and accordingly atropine has no action on the nerve 
terminations. 



Fig. 27 



Fig. 28 



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Charts of the changes in the accommodation (pp) and in the pupil (drf) under atropine. 
The impairment of the accommodation and the widening of the pupil are indicated by 
downward movements of the lines, while the return to the normal is shown by an upward 
movement. In Fig. 27 the time from the application of atropine is given in minutes to 
show the beginning of the action; in Fig. 28 the time is in hours to show the gradual 
recovery. (After Lewin and Guillery.) 



When complete dilatation is attained, the pupil ceases to contract 
in bright light, as the impulses descending from the central nervous 
system are prevented from reaching the muscle, although the rest of 
the reflex arc is intact. The retina is unprotected from bright light and 
this often gives rise to pain and discomfort in the eyes and headache. 

Besides the dilatation of the pupil, a further result of the applica- 
tion of atropine to the eye is the paralysis of the accommodation. Near 
objects are no longer seen clearly, while distant ones are as distinct 
as formerly or may be even more distinct in some eyes. The action 
is here again on the myoneural junction, in this case in the ciliary 
muscle. On local application the relaxation of the lens occurs later, 

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322 



SUBSTANCES ACTING AFTER ABSORPTION 



and disappears earlier than the dilatation of the pupil, and larger 
quantities are required to produce it. 

The intraocular pressure appears to be unchanged by atropine in the 
normal eye, but when there is a tendency to hypernormal pressure, 
atropine often augments it considerably whether it is applied locally 
or is carried to the eye by the circulation. This is apparently the 
indirect result of the dilation of the pupil, by which the lymph outflow 
is obstructed; in the normal eye this is not sufficient to raise the pressure, 
but in eyes in which the outflow is already deficient the additional 
hindrance may suffice to increase the tension and precipitate an attack 
of glaucoma. 

The bronchial muscle normally contracts when the pneumogastric 
nerve is stimulated, but makes no response after atropine, which par- 
alyzes the myoneural terminations; the sympathetic fibres which inhibit 
the bronchial muscle and dilate the bronchi are unaffected by atropine. 

Fig. 29 * 




Movements of the intestine. At P, pilocarpine causes a violent tetanic contraction, 
which is maintained until at A atropine is applied, when the spasm is immediately 
relieved. The normal pendulum movements continue afterward. (Magnus.) 



The terminations of the nerves in the unstriped muscle of the 
cesophcujus are affected in the same way as in the bronchial muscle. 
A curious contrast has been noted by Luchsinger in the behavior of 
the oesophagus in rabbits and cats, in the former of which the muscle 
is striated, while in the latter the upper part is striated, the lower 
is unstriated. Atropine, he found, paralyzes the vagus in those parts 
which are unstriped, while leaving unaffected those in which the fibres 
are striped. Exactly the opposite occurs after curara, which paralyzes 
the nerve supply of the striped muscle, while leaving the unstriped 
active. 

It is possible that the difficulty in swallowing, which is so well 
marked in cases of poisoning by atropine, may be due in part to the 



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ATROPINE 323 

paralysis of the motor nerve, but it is generally attributed to the 
absence of the mucous secretion and consequent dryness of the passages. 

Atropine has generally a sedative effect on the movements of the 
stomach and intestine, though vomiting is not infrequently observed 
in cases of poisoning, and less often free evacuation of the contents 
of the bowel. After very small quantities the normal peristalsis is 
not affected, and the movement induced by ordinary doses of the purga- 
tives is not arrested, but the griping pains resulting from large doses 
or from the more violent purgatives are absent or less marked if atro- 
pine is given along with them. Similarly, the violent peristaltic and 
tetanic contractions seen after such poisons as pilocarpine and mus- 
carine are prevented by the preliminary injection of atropine. 

These results suggested that atropine paralyzes the terminations of 
some of the extrinsic nerves of the stomach and bowel in the same 
way as it paralyzes the oculomotor terminations in the iris. But this 
proves to be incorrect, for the vagus and splanchnic nerves continue to 
exert their ordinary influence after atropine. In fact, these small 
doses of atropine appear to arrest only certain abnormal violent 
forms of contraction, and as they do this without interfering with the 
normal peristalsis and without interrupting the path of nervous im- 
pulses from the brain to the bowel, it must be accepted that these 
abnormal forms arise from some mechanism which is distinct from 
that presiding over the ordinary peristalsis, and which does not lie on 
the path of the nerve impulses. 

This action on abnormal contractions is the only one induced by 
therapeutic doses of atropine, but in animal experiments large quantities 
tend to increase the peristalsis from some action exerted on the plexus 
of Auerbach (Magnus). It is possible that this increased peristalsis 
may account for the vomiting and purging sometimes seen in cases of 
poisoning. Finally, very large quantities paralyze the muscle fibres, 
but this probably does not occur in the intact animal. 

Atropine exercises the same sedative effect on the movements of 
other organs as on those of the bowel. Thus, the spleen, uterus and 
bladder react like the stomach and bowel, several poisons failing to 
induce contractions after atropine, while stimulation of the nerves 
continues to be effective. It has been observed frequently in cases of 
poisoning that the urine is ejected soon after the ingestion of the poison, 
and subsequently there is a desire to micturate without the ability 
to do so. The rhythmical contractions of the ureters are said to be 
accelerated by small doses, but to be slowed and arrested by larger 
amounts. 

Atropine paralyzes the Inhibitory Terminations of the Vagus in the 
Heart, and stimulation of this nerve therefore causes no changes in 
the pulse after its administration. Nicotine in large doses also removes 
the inhibitory power of the vagus, but acts on a different part of the 
nerve, namely, on the ganglia. That atropine does not act here but 
on the terminations has been shown by a number of observations. 
Thus, in the normal frog's heart, and even after paralysis of the 



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324 SUBSTANCES ACTING AFTER ABSORPTION 

ganglia on the course of the vagus, electrical stimulation of the venous 
sinus causes slowing and standstill of the heart, because the stimulus 
reaches the postganglionic nerve fibres (Fig. 24, p. 306); but after 
atropine, no slowing follows stimulation of the sinus. Again, several 
drugs stimulate the ends of the vagus in the heart and act on parts 
in which no ganglia exist, but these drugs have no effect whatever 
after atropine. Small quantities of atropine have no further action 
on the heart than the paralysis of the inhibitory nerve ends. The 
terminations of the accelerator nerve are unaffected, exactly as the 
terminations of the sympathetic in the salivary glands, and the 
heart muscle is neither stimulated nor depressed. The heart is there- 
fore placed in the same position as if the vagus were divided in the 
neck, and, accordingly, it is accelerated in some animals, while in others 
the rhythm is unchanged. In the dog there is marked quickening 
of the heart after atropine, because normally impulses are constantly 

Fia. 30 ( 

■iuiuu*. ^umm 




Tracings of the ventricle (lower) and auricle (upper) of the dog's heart. During 
systole the levers moved upward; during diastole, downward. At A, the heart was 
normal; at B, the inhibitory fibres were stimulated electrically, and this was continued 
throughout the tracing. The ventricular rhythm became slow and irregular, while the 
auricle stood still in diastole. At C, atropine sulphate was injected into a vein, and at 
D the effects of the inhibition began to pass off, although the stimulation was continued. 

transmitted from the inhibitory centre in the medulla, and these pre- 
vent the heart from beating as rapidly as it would if freed from the 
nervous control. In the cat the tone of the vagus is less, and the 
changes produced by atropine are correspondingly smaller, w r hile in 
the rabbit and frog there is generally no inhibitory retardation of the 
heart, and atropine therefore produces little change. In man the 
effects vary considerably with the age of the patient. The inhibitory 
fibres seem almost inactive at birth, but their tone increases with age 
up to 25-35 years, and from this time lessens again and is very slight 
in old age. Atropine does not quicken the heart in the newborn child, 
but up to about 30 the acceleration increases with the age, and from 
this point onwards it lessens again until the heart is accelerated by 
only 4-5 beats per minute in patients between 80-90 years. Along 
with the acceleration of the pulse the other effects of vagus section 
are also produced — increase in the extent of systole, decrease in the 
diastole and augmentation of the output of the heart per minute. 



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ATROPINE 325 

Stimulation of the vagus causes no retardation of the pulse after atropine, 
but, on the contrary, is not infrequently followed by acceleration from the 
presence of accelerator fibres which are not affected by atropine. 

Large quantities of atropine, besides paralyzing the vagus, weaken and 
depress the heart muscle, and the contractions consequently become slower and 
weaker and the output of the heart is less than normal. Even therapeutic doses 
injected hypodermically in man slow the pulse for a short time, apparently 
from direct action on the heart muscle; the first effect is thus a fall in the 
pulse rate followed by marked acceleration. 

The peripheral action of therapeutic doses of atropine is due to its 
paralyzing receptors in a number of organs. Some of these are nor- 
mally put in action by nerve impulses, which they transmit to the 
contractile or secretory cells, and their paralysis by atropine leads to 
the failure of part of the nervous control of the organ (many glands, 
pupil, bronchial muscle, oesophagus, and heart). In other organs the 
receptors do not lie in the path of nerve impulses and their paralysis 
by atropine therefore does not affect the nervous control of these 
organs (muscle of stomach, intestine, spleen, uterus, and bladder). 
The effects of atropine on these organs is in fact only detected by the 
cessation of unusual movements induced by certain poisons and by 
some pathological conditions (see also muscarine and pilocarpine, 
p. 338). The organs thus affected receive their innervation from 
the autonomic system, some of them from the craniosacral division, 
some others from the sympathetic; atropine cannot be said to affect 
either of these divisions exclusively, but its action on the myoneural 
junctions of the craniosacral division is more prominent than that on 
the sympathetic. 

The voluntary Muscles are not directly affected by atropine. An 
action similar to that of curara is seen in the frog under large doses, 
and evidence of a similar action in mammals is offered by the fact 
that the twitching induced by physostigmine through its action on 
the myoneural junctions is antagonized by atropine; but no true curara 
action is induced by atropine in mammals. 

The terminations of the Sensory Nerves are depressed by its local 
application. Thus, when atropine is applied to an irritated surface of 
the skin or to a mucous membrane, numbness is produced and the sen- 
sation of pain is lessened; no such effect occurs when atropine ointment 
is rubbed on the unbroken skin and the local anaesthetic effect is not 
elicited by its internal administration. 

Circulation. — The changes in the circulation under atropine arise 
for the most part from the changes in the heart. The blood-pressure 
often falls for a few minutes at first from the direct action on the heart 
muscle and then rises above the normal from the acceleration when this 
is marked. But the rise in pressure from the acceleration is not great 
unless there is unusual activity of the inhibitory mechanism previously. 
There is no evidence that the vasoconstrictor centre in the medulla 
is excited by atropine, and although concentrated solutions of atropine 
perfused through the vessels cause them to dilate from action on their 



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326 SUBSTANCES ACTING AFTER ABSORPTION 

walls, this does not occur in the living animal. Very large amounts 
of atropine depress the heart and consequently the blood-pressure falls; 
the respiration fails in cases of poisoning before the heart is seriously 
injured. In poisoning there is often flushing of the skin of the head 
and neck and a rash resembling that of scarlet fever, and these have 
been regarded as due to dilatation of the arterioles from stimulation of 
the vasodilator centre; the flush is said to disappear on section of the 
cervical sympathetic cord, which would suggest its central origin. The 
rash .usually disappears after a few hours, but is sometimes followed 
in a day or two by desquamation. 

The action of atropine on the Respiration has been the subject of 
much discussion in recent years. It is sometimes slower at first but 
then becomes quicker, and the amount of air inspired per minute is 
considerably increased from stimulation of the respiratory centre. 
After large doses this quickened breathing is frequently interrupted 
by convulsive movements, and such an interruption often proves to 
be final. It if returns, the movements become shallower and slower 
in the stage of depression of the nervous centres, and the failure of the 
respiration is the cause of death in fatal cases of poisoning. 

Atropine often induces a marked rise in Temperature, the cause of 
which cannot be said to be definitely known. According to Ott the 
dissipation of heat is increased, but the heat formation undergoes a 
still greater augmentation. This seems to be independent of the cir- 
culatory changes and also of the convulsions, and is attributed by him 
to direct action on the heat centres of the brain. 

Distribution and Excretion. — Atropine is rapidly absorbed and may 
be found in most organs. It is excreted in the urine in man and most 
animals, partly as unchanged atropine, partly broken up into tropine; 
from a third to a half of that ingested reappears in the urine, and traces 
have been found in the milk and also in the foetal blood. The rest of 
the atropine undergoes oxidation in the body, but it is not determined 
where this destruction occurs except in the case of the rabbit where 
it seems to be rapidly decomposed by ferment action in the blood; the 
blood of man, the dog and many other animals does not seem to possess 
this property. 

Tolerance. — Most animals withstand much larger quantities of 
atropine than man, and an especial degree of tolerance is met with 
in the herbivora; rabbits, for example, may be fed for weeks on bella- 
donna leaves without showing any symptoms; this is undoubtedly 
the result of the active decomposition of the alkaloid which occurs in 
their serum. It has also been observed that the action of atropine on 
the heart and other organs passes off more quickly in rabbits than in 
other animals and this again arises from the atropine being destroyed 
so rapidly. A certain degree of tolerance may also be acquired by other 
animals through the continued administration of atropine, which ceases 
to elicit the symptoms from the central nervous system in the doses 
previously sufficient and later seems to have a weaker and shorter action 
on the peripheral organs. 



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ATROPINE 327 

Hyoscyamine is rarely obtainable in pure form, as it is almost always 
mixed with atropine, into which it changes when kept in solution and 
perhaps even when dry. It paralyzes the same peripheral mechanisms 
as atropine, but acts almost exactly twice as strongly on them. Its 
action on the central nervous system in mammals resembles that of 
atropine and the fatal dose is the same, but in the frog it has less ten- 
dency to cause convulsions. No narcotic influence is exercised on 
either frogs or mammals; the belief that it induces sleep is founded 
on observations in which hyoscine was mixed with the hyoscyamine 
employed. 

The action of atropine, as has been stated, is compounded of that of natural, 
or kevorotary, hyoscyamine with that of its dextrorotary isomer. The latter 
does not exist free in nature and possesses little or no action on the nerve 
terminations, while it stimulates the spinal cord of the frog more than either 
atropine or hyoscyamine. The peripheral action of atropine is thus due to 
its containing hyoscyamine, and as a grain of atropine contains only half a 
grain of hyoscyamine the former naturally exercises only half the effect of a 
grain of hyoscyamine. On the other hand, the half grain of dextrorotary 
hyoscyamine in a grain of atropine is almost inert on the nerve terminations, 
but exercises the same effect on the central nervous system as its laevorotary 
complement. Atropine thus acts on the central nervous system in mammals 
in the same strength as hyoscyamine, but only half as strongly in the periphery. 

Scopolamine, or Hyoscine, resembles atropine closely in its peripheral 
action, except that it passes off more quickly. The inhibitory termina- 
tions in the heart are paralyzed; but the therapeutic dose in man 
is too small to elicit this effect, and the pulse is therefore unaltered in 
rate or may be slower, owing to the hypnotic action. Applied to the 
conjunctiva it produces mydriasis and loss of accommodation more 
quickly than atropine, but for a much shorter time; pure hyoscine acts 
about twice as strongly on the nerve terminations as atropine, or about 
equally strongly with hyoscyamine. The effects on the central nervous 
system present the greatest divergences from those described under atro- 
pine, for the characteristic stimulation is absent in the great majority 
of cases. As a general rule, scopolamine produces a marked sensation 
of fatigue and drowsiness, the patient moves about less and speaks less, 
and a condition in no way dissimilar to the natural sleep follows. In 
many cases, however, a short stage of excitement with giddiness, un- 
certain movements and difficult and indistinct speech precedes sleep, 
and occasionally symptoms exactly resembling those produced by 
atropine follow the administration of hyoscine, especially if large doses 
are employed. Sleep generally lasts from 5-8 hours, and the patient 
may then remain quiet for several hours longer. As a general rule, 
after small doses no confusion is complained of on awakening, but 
dryness of the throat and thirst are often present. Larger doses do not 
cause deeper sleep but give rise to delirium and excitement resembling 
those following atropine. 

In one or two cases collapse has been observed after scopolamine. 
The respiratory centre does not seem to be stimulated as by atropine, 
the respiration generally becoming slower from the beginning. 



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328 SUBSTANCES ACTING AFTER ABSORPTION 

In the lower mammals scopolamine reduces the excitability of the 
motor areas as tested by electric shocks, while the reflex excitability 
in the frog is not increased as by atropine. Hyoscine appears to be 
excreted or destroyed in the tissues much more rapidly than atropine, 
for its effects last a shorter time. 

The action of hyoscine, then, seems to correspond with that of atro- 
pine, save that the central nervous system is here depressed, while the 
action on the peripheral nerve ends is stronger. It depresses the brain 
in very small quantities, £ mg. (jfa gr.) being generally sufficient to 
cause sleep. It does not seem to be so dangerous as the others of the 
series, for a dose of 5 mgs. (y 1 ^ gr.) has been recovered from in man, 
and over half a gramme (7£ grs.) administered to a small cat did not 
kill the animal. A certain degree of tolerance is produced after repeated 
use, so that the dose has to be increased after a week or two. 

Hyoscine is much less reliable as a hypnotic than morphine or the 
members of the chloral group. It is most effective when sleep is pre- 
vented by motor excitement, and the sleep seems to arise from the 
relief of this condition and not from depression of the consciousness. 

Hyoscine is laevorotary to polarized light; the racemic form, which is often 
present in commercial hyoscine, acts only one-half as strongly on the per- 
ipheral organs, because in it the kevorotary alkaloid is mixed with the dextro- 
rotary isomer, which is almost inactive. The cerebral action is equal, however, 
in the two forms. 

The other natural alkaloids have been less carefully examined than 
the three foregoing and possess no therapeutical interest. 

Among the artificial tropeines only one has received much attention 
at the hands of either experimental or practical therapeutists. This 
is Homatropine, a compound of tropine and mandelic acid, which re- 
sembles atropine in its action, but is much less poisonous. When 
applied to the eye, it dilates the pupil almost as rapidly as atropine, 
but less completely, and the action passes off much sooner. It has less 
tendency to increase the intraocular tension than atropine owing to its 
shorter action. 

Methylatropine or Eumydrine, an artificial compound of atropine, 
seems to take a place intermediate between atropine and homatropine, 
being weaker than the former but more active than the latter. It has 
been used to some extent in opthalmology. 

The other tropeines vary in their action on the lower animals, many of them 
failing to act on the peripheral organs, while others have the peripheral action 
of atropine but in a weaker degree; the compounds of tropine with the acids 
of the methane series possess much less of the peripheral atropine action than 
the others. It was formerly believed that even the compounds with the 
aromatic acids were devoid of this action unless the acid possessed a hydroxyl 
group, but this general statement has been shown to be erroneous by Gottlieb's 
work. A considerable variation also exists in the effects of the tropeines on the 
central nervous system, some causing excitement like atropine, while others 
act as depressants and therefore resemble hyoscine. 



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ATROPINE 329 

Tropine itself is a weakly toxic, basic substance, which in large quantities 
stimulates the frog's heart, but does not paralyze the vagus nor the oculomotor 
terminations on local application. After the injection of large quantities, 
dilatation of the pupil has been observed, it is true, but this does not seem to be 
of the same origin as that produced by atropine. 

Some artificial scopoleines have been found devoid of action on the nerve ends 
in the pupil and heart and on the salivary secretion. They possess a certain 
stimulant effect on the heart muscle like some of the artificial tropeines, and all 
produce more or less depression of the central nervous system and narcosis. 

The action of the Crude Drags is very similar to that of the active 
principles already discussed. The peripheral action of all of thehi is 
therefore almost identical in kind, though varying in degree. In con- 
sidering their effects on the central nervous system it must be remem- 
bered that those containing much atropine are more stimulant, those 
with hyoscine more sedative. But as the relative amount of the different 
alkaloids changes with various conditions such as the age of the plant 
and the methods of preparation, it is obvious that accurate results can 
be obtained only by the use of the pure principles. Even when a 
preparation is accurately standardized in the content of alkaloids, 
as in the U. S. P. and B. P., its power may vary very widely according 
to the proportion of lcevorotary alkaloid (hyoscyamine) to racemic 
(atropine). 

Preparations. 

U. S. P. — Belladonna Folia, the leaves of Atropa Belladonna, containing 
0.35 per cent, of mydriatic alkaloids. Dose, 0.065 G. (1 gr.). 

Extractum Belladonna Fouorum (1.4 per cent.), 0.01 G. (i gr.). 

Tinctura Belladonna Fouorum (0.035 per cent.), 0.5 c.c. (8 mins.). 

Emplastrum Belladonna (0.4 per cent, of alkaloids). 

Belladonna Radix, the root of Atropa Belladonna, containing 0.5 per cent, 
of alkaloids. Dose, 0.045 G. (f gr.). 

Linimentum Belladonna (nearly 0.5 per cent.), containing camphor. 

Hyoscyamus, the leaves of Hyoscyamus niger, henbane (0.08 per cent, of 
alkaloids). Dose, 0.25 G. (4 grs.). 

Extractum Hyoscyami (0.3 per cent, of alkaloids), 0.065 G. (1 gr.). 

Tinctura Hyoscyami (0.007 per cent, of alkaloids), 1 c.c. (15 mins.). 

Stramonium, the dried leaves of Datura Stramonium (0.35 per cent, of 
alkaloids). Dose, 0.065 G. (1 gr.). 

Extractum Stramonii (1.4 per cent, or alkaloids), 0.01 G. (i gr.). 

Tinctura Stramonii (0.03 per cent, of alkaloids), 0.5 c.c. (8 mins.). 

Scopola, the dried rhizome of Scopola carniolica (0.5 per cent, of alkaloids) . 
Dose, 0.045 G. (J gr.). 

B. P. — Belladonna Folia, the fresh leaves and branches of Atropa Belladonna, 
containing 0.3 per cent, of alkaloids. 

Belladonna Radix, the root of Atropa Belladonna. 

Extractum Belladonnas Siccum (1 per cent, of alkaloids), J-l gr. 

Tinctura Belladonna (0.035 per cent, alkaloids), 5-15 mins. 

Linimentum Belladonna (0.375 per cent.), with camphor. 

Emplastrum Belladonna (0.25 per cent.). 

Hyoscyami Folia, the fresh leaves, flowers and branches of Hyoscyamus 
niger, henbane. 

Extractum Hyoscyami (0.3 per cent, alkaloids), 2-8 grs. 

Tinctura Hyoscyami, £-1 fl. dr. 

Stramonii Folia, the dried leaves of Datura Stramonium. 

Tinctura Stramonii, 5-15 mins. 



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330 SUBSTANCES ACTING AFTER ABSORPTION 

Alkaloids. 

Atropine Sulphas (U. S. P., B. P.), a white crystalline powder, with a 
very bitter taste, soluble in water and alcohol. Dose, 0.0004 G. ( T | T gr.); 
B. P., sJo-iiff gr- 

Oleatum Atropince (U. S. P.), 2 per cent. 

Liquor Atropines Sulphatis (B. P.), 1 per cent., J-l min. 

Lamellce Atropince (B. P.), gelatin discs, each containing j^W gr. of atropine 
sulphate. 

Hyoscyamine is not procurable in even approximately pure form and might 
well t>e dispensed with, as it offers no advantages over atropine. The sulphate 
and hydrobromide have been used in the same dose as atropine. 

HrosciNiB Hydrobr9Midum (U. S. P., B. P.), (Ci 7 H,iN04HBr,3H,0), the 
hydrobromide of hyoscine or scopolamine. It is obtained from hyoscyamus, 
scopola and other Solanace®, and forms colorless, transparent crystals with an 
acrid, bitter taste, and is very soluble in water, less so in alcohol. 0.5 mg. 
(iJ» gr.); B. P., 2 io-iJo gr. 

Scopolamines Hydrobromidum (U. S. P.) is identical with Hyoscine hydro- 
bromide. 

HomatropinjB Hydrobromidum (U. S. P., B. P.), (Ci«HnNO»HBr), the 
hydrobromide of an alkaloid prepared from tropine by condensation with 
mandelic (oxytoluic) acid, a white crystalline powder soluble in 6 parts of 
cold water. 

Lamellce Homatropince (B. P.), gelatin discs, each weighing ^ gr. and 
containing r J ff gr. of homatropine hydrobromide. 

Methylatropince Nitras or Eumydrin (unofficial) an alkaloid prepared from 
atropine, forms a white crystalline salt readily soluble in water. Dose 1-3 mg. 

Therapeutic Uses. — The numerous changes produced by atropine and 
its congeners on the organism would indicate for them a very wide 
sphere of usefulness were it possible to elicit their action on one organ 
without affecting others, and this difficulty may perhaps be overcome 
in the future, when the different individuals of the series have been 
more carefully compared, and new tropeines and other modifications of 
the tropine radicle are available in therapeutics. 

The peripheral action of the whole series, as far as it is at present 
known, is so uniform that any member might be used to elicit it, but 
the only one that has come into general use for its peripheral effects 
is atropine. The purposes for which atropine is employed may be 
divided into groups as follows: 

To Arrest or Lessen Secretions. — In rare cases of excessive salivation 
atropine has proved of service, but it is much more frequently used to 
lessen the perspiration, especially in the later stages of phthisis. For 
this purpose comparatively small quantities, such as J mg. (^^ gr.) 
given by the mouth or hypodermically, are generally sufficient, or the 
extract or tincture of belladonna may be used instead; eumydrin has 
also been employed for this purpose in somewhat larger doses than 
atropine. In local sweating, atropine is often applied locally in the form 
of an ointment, liniment, or plaster, although Tappeiner has found that 
it has no effect when thus employed. It is also used to arrest the secre- 
tion of the milk, a belladonna plaster being strapped over the gland. It 
seems probable that this acts merely as a mechanical support and that 



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ATROPINE 331 

the same result would follow the application of simple adhesive plaster 
without atropine. 

To Paralyze the Cardiac Inhibitory Terminations. — For this purpose 
a slightly larger quantity is required than is necessary to stop the 
secretions, and the administration of sufficient atropine to paralyze 
the vagus (1 mg.) therefore involves unpleasant dryness of the throat 
and difficulty in swallowing. In cases where slowing of the heart 
tends to be dangerous in itself, more especially in poisoning with 
muscarine, pilocarpine and their allies, atropine is indicated. It may 
also be used for diagnostic purposes, to find if bradycardia is due to 
disease of the heart muscle or to inhibition. It may be repeated here 
that the resultant quickening is much less in old than in middle-aged 
people, and it is said that in many cases of old aortic lesion the adminis- 
tration of atropine is followed by little or no acceleration. Some forms 
of intermission of the pulse are due to unusual activity of the inhibitory 
apparatus, and these may be remedied by atropine; but this inter- 
mission possesses little importance, and seems to require no therapeutic 
treatment. Atropine may be used to diagnose it from the more sig- 
nificant forms present in organic disease of the heart. The use of atropine 
to paralyze the vagus terminations before the administration of an 
anaesthetic has been discussed already. (See p. 218.) 

To Paralyze the Terminations of the Motor Nerves in the Iris and Ciliary 
Muscles. — It is used for this purpose largely in ophthalmology as a 
means of diagnosis and of treatment, and the precise conditions in 
which it is indicated may be treated better in text-books on this sub- 
ject than here. For these objects, solutions of the alkaloidal salts are 
generally applied to the conjunctiva, when enough of the alkaloid 
passes into the eye by a process of imbibition to produce marked local 
effects without affecting more distant organs. In order to dilate the 
pupil, extremely dilute solutions are used; a few drops of a solution 
of one in 1,000, or even of one in 10,000 are quite sufficient. Much 
stronger solutions are required to paralyze the accommodation, and as 
a general rule 1 per cent, is used. These strong solutions produce 
complete paralysis in 1-1£ hours, and the accommodation does not 
recover completely until after 5-7 days, while the pupil may not 
regain its normal size for 10-14 days. The application of even 
weaker atropine solution renders the sight imperfect for an incon- 
veniently long period, and hyoscine and homatropine are therefore 
much used in its stead. The symptoms produced by a 1 per cent, 
solution of homatropine pass off, or at any rate become very much less 
marked in the course of 36 hours. These are consequently preferable 
for diagnostic purposes, while atropine is rather to be used where it 
is desirable to produce a paralysis of longer duration, as in various 
inflammatory conditions of the iris or cornea. Atropine is also pref- 
erable where complete paralysis of the accommodation is necessary, as 
homatropine often fails to effect this. Atropine and its congeners 
are contraindicated where there is any suspicion of glaucoma, as, 
owing to their action on the intraocular pressure, they may either 
aggravate the disease already present or precipitate an acute attack. 



332 SUBSTANCES ACTING AFTER ABSORPTION 

When dilatation of the pupil is necessary and there is reason to ap- 
prehend the results on the intraocular pressure, homatropine should be 
employed, as its effects can be readily controlled by eserine. Numer- 
ous cases of poisoning have arisen from the extensive use of atropine 
in diseased conditions of the eye. It is often asserted that it passes 
down with the tears through the lachrymal duct and is absorbed from 
the nose, throat and stomach, but as a matter of fact it may be absorbed 
from the conjunctiva itself. The symptoms are generally only the 
milder ones of atropine poisoning — dryness of the throat and slight 
excitement — but dangerous and even fatal poisoning has also arisen 
from its local application. In many cases this is due to the appli- 
cation of unnecessarily strong solutions to the eye, but, on the other 
hand, some patients seem abnormally sensitive to the action of 
atropine, and hyoscine, or better homatropine, ought to be preferred. 
In rare cases a curious inflammatory condition of the conjunctiva is set 
up by atropine, and this is often supposed to be due to the use of 
irritant preparations, but sometimes seems to follow the application 
of the absolutely pure alkaloid, and is apparently an idiosyncrasy; it 
may, perhaps, be explained by the arrest of the ordinary secretions of 
the lachrymal gland and conjunctiva in these cases. Sometimes discs 
of gelatin impregnated with atropine or homatropine sulphate (B. P.) 
are applied to the conjunctiva instead of solutions of the -salts. Eumy- 
drine may be substituted for homatropine in ophthalmology, but offers 
no advantages. 

To Relax Spasm of the Intestines. — In various forms of colic atropine 
is of very great service in lessening pain and allowing the passage of 
the intestinal contents; for instance, it is preferable to morphine in 
lead colic, as it does not cause constipation. Hernia and volvulus are 
sometimes reduced by atropine injected hypodermically (3 mg. or -^ 
gr.). It is often prescribed along with purgatives in order to lessen 
the griping which they produce, and has been used as a laxative in 
some forms of constipation with considerable success. For action on 
the bowel it is generally prescribed in pill form as one of the extracts 
of belladonna or hyoscyamus. The object of prescribing an impure 
preparation instead of the alkaloid is to allow of a strong local action 
along the intestinal wall along with a slow and imperfect absorption, 
as the pure alkaloidal salts are liable to be absorbed in the duodenum. 

To Relax Spasms of the Involuntary Muscles of Other Organs. — In the 
spasmodic contraction of the ureters and bile ducts due to calculi, 
atropine is occasionally prescribed either in the form of a pill or in 
solution for internal i}se, or by hypodermic application. In some 
forms^of asthma due to contraction of the bronchial muscles, atropine 
has been applied locally *by means of a spray or given internally, and 
stramonium leaves are often found of benefit when made up into 
cigarettes and inhaled when the attack comes on; 1 the smoke has been 

1 Another ingredient of these asthma cigarettes is often nitrate of potassium, which 
is reduced to nitrite in the course of combustion and passing into the lungs in this 
form dilates the bronchi by action on the bronchial muscle. 



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ATROPINE 333 

shown to contain small quantities of the alkaloids. Some cases of 
asthma are said to have been permanently cured by treatment with 
atropine internally. An ointment of atropine has also been applied 
to the cervix uteri with the hope of relaxing spasm during labor, but 
the results are somewhat questionable. Perhaps this action in relax- 
ing spasmodic contractions may also explain the beneficial effects 
obtained in cases of incontinence of urine in children, in which bella- 
donna has long been the most reliable remedy. 

To Lessen Pain. — Belladonna liniment, plaster and ointment have 
long enjoyed a considerable reputation as local anodynes, and atropine 
has not infrequently been injected into painful areas. This anodyne 
action is very weak compared with that of cocaine, however, and the 
preparations of atropine have been less used of late years. In some 
forms of gastralgia atropine has also been suggested. 

The Effects on the Central Nervous System of the members of this 
group are very different, and the purposes for which they are used are 
diametrically opposed. Atropine is used as a stimulant in various 
conditions of depression of the brain and medulla oblongata. Thus, 
in collapse its hypodermic injection may be of use to stimulate the 
respiration and at the same time to free the heart from excessive in- 
hibition. In dangerous poisoning from narcotic and hypnotic drugs, 
more especially in opium poisoning, atropine has been largely used. A 
long and weary dispute as to the value of atropine in those cases has 
been carried on, for the history of which the reader is referred to the 
recent paper by Bashford. The results indicate that atropine is useful 
in morphine poisoning through stimulating the respiratory centre, which 
is the danger point. But it must be employed in small qunatities 
(1.5 mg. or ■£$ gr.), as large doses, such as have frequently been advised, 
tend to depress the central nervous system and thus to aid rather than 
to antagonize the action of morphine on the respiration. It may be 
questioned whether in any case atropine may not be replaced by caffeine 
with advantage. The former stimulates the medullary centres, but 
subsequently paralyzes them, while caffeine, even in comparatively 
large quantities, does not seem to have a depressant action in man. 

Atropine at one time had some reputation in the treatment of epi- 
lepsy. It has been shown both clinically and experimentally that this 
reputation was undeserved, the number of attacks and their violence 
being rather increased than diminished by its exhibition; the belief 
in its powers arose from the use of impure preparations containing 
hyoscine. 

In some spasmodic diseases, such as whooping-cough, belladonna 
preparations have long enjoyed a wide reputation; this may possibly 
be explained either by the hyoscine reducing the excitability of the 
respiratory centre, or by atropine relaxing bronchial spasm. 

Hyoscine, or scopolamine, has been used as a narcotic to depress the 
central nervous system; it is of great efficacy in insanity, producing 
sound and refreshing sleep, but is of less value in controlling the 
excitement during the day, and may in fact increase it. Hyoscine is 



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334 SUBSTANCES ACTING AFTER ABSORPTION 

also used with benefit in various forms of tremor of central origin, 
and is said to lessen sexual excitement. Its hypnotic action does not 
seem to be of the same nature as that of opium, for in sleeplessness 
produced by pain it is of comparatively little value, and it has no 
power to relieve pain itself. It differs from chloral in not inducing 
deep sleep, for patients under the influence of hyoscine can always be 
aroused and are much less confused than after chloral. The special 
indications for hyoscine seem to be sleeplessness due to abnormal 
activity of the motor areas and some forms of tremor. 

Comparatively recently morphine and hyoscine have been injected 
as a preliminary to surgical operations, but as a general rule the 
narcosis induced is insufficient. As a preliminary to the use of ether 
the procedure seems to be of value, as much less of the anaesthetic is 
required; 10 mgs. (J gr.) of morphine and 0.3 mg. (^-^ gr.) of hyo- 
scine are injected 1£ hours before the operation. 

Poisoning. — In cases of poisoning with belladonna and its allies the 
trea