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PHARMACOLOGY, THERAPEUTICS 

AND 

MATERIA" MEDICA 



*■ 



A TEXT-BOOK 



OF 



PHARMACOLOGY, THERAPEUTICS 



AND 



MATERIA MEDICA 



BY 

T. LAUDEE ptUNTON, M.D., D.Sc, F.E.S. 

FELLOW OF THE ROYAL COLLEGE OF PHYSICIANS; ASSISTANT - PHYSICIAN AND LECTDREB- 

ON MATERIA MEDICA AT ST BARTHOLOMEW'S HOSPITAL; EXAMINER IN MATERIA 

MEDICA IN THE UNIVERSITIES OF OXFORD AND OF LONDON ; LATE EXAMINER 

IN THE UNIVERSITY OF EDINBURGH, IN THE VICTORIA UNIVERSITY, 

AND IN THE ROYAL COLLEGE OF PHYSICIANS, LONDON 



ADAPTED TO THE 

Wmittlt states; $&armaw>;poeta 

FRANCIS H. WILLIAMS, M.D.Boston, Mass. 
THIRD EDITION 

CONTAINING THE 

ADDITIONS (1891) TO THE BBITISH PHABMACOPCEIA 

Hon&on 
MACMILLAN AND CO. 

AND NEW YORK 

1893 
« 

The right of translation is reserved 



First edition printed 1885 ; second, March' 1887 ; Addenda inserted July 1887 
Additions (1891) to the British Pharmacopoeia. Reprinted November 1891,1893. 



TO 

fflje 'gKemorB of 
SIR EOBEET CHRISTISON, Baet. &c. 

HIS HONOURED TEACHEB 

AND TO 

CARL LUDWIG 

HIS BELOVED MASTER 

THIS BOOK IS GBATEFULLY DEDICATED 

BY 

THE AUTHOE 



PBEFACE 

TO 

THE THIED EDITION. 



The rapid exhaustion of the second edition of this work has pre- 
vented me from making as many improvements in the present 
edition as I could have desired. At the same time I have tried,, 
as far as the short time at my disposal would allow, to amend 
the imperfections of former editions, as well as to bring the work 
up to date and render it more useful by the introduction of new 
matter. 

The treatment of one of the most important portions of Phar- 
macology, viz. the Connection between Chemical Constitution 
and Physiological Action, is still very meagre, because I. find that 
the size of this work would be too much increased were I to treat 
the subject fully, and I am therefore preparing a small text-book 
upon it. 

The struggle for existence between microbes and the living 
organism, which in the first edition was only illustrated by a 
single diagram of a bacillus and amoeba, is now fully illustrated 
by woodcuts copied from Metschnikoff's paper. The views of 
Hughlings Jackson on the nervous system have been illustrated 
by a diagram which, when covered with successive layers of thin 
and semi-transparent paper, exhibits the effect of anaesthetics 
and narcotics in successively abolishing various faculties. The 
recent work of Kiihne and Politzer on the mode of action of 
curare has been noticed, and the pathology of tremor discussed. 
The section on the action of drugs upon the eye has been care- 
fully revised. The section on antipyretics has been rendered 
somewhat fuller, and some diagrams illustrating the pathology, 
of fever and the mode of action of antipyretics have been intro* 
duced,* but it is very difficult in the present state of our know- 
ledge to deal satisfactorily with this subject. Paragraphs on.thei 



viii PEEFACE TO THE 

treatment of cough and on the pathology and treatment of 
asthma have been introduced. The researches of Adami on 
diuretics have been noticed, but they have not necessitated any 
essential change in the text, as the communication between the 
portal vein of the kidney and the renal artery had been already 
allowed for in describing Nussbaum's researches in the first 
edition. The views expressed in the first edition regarding the 
mode of action of caffeine have been confirmed and extended by 
the observations of Schroeder and Munk. The researches of 
Jendrassik on the diuretic action of calomel and the explanation 
advanced by Locke have been noticed. 

The arrangement of the Vegetable Materia Medica has been 
almost entirely remodelled on Hooker's plan, and a short intro- 
duction has been added to it, in which I have tried to show the 
use of botanical arrangement, as well as to- protest against the 
abuse of it in the examination of students in Materia Medica. 

By the use of small type for matters which are of practically 
little interest to general students, and yet are occasionally wanted 
for reference, a certain amount of space has been gained, at the 
same time that the general student is enabled at a glance to 
distinguish the parts which are of little or no interest to him. 
Notwithstanding my efforts to condense it, the present edition 
contains about 120 pages more than the second, but by using 
thinner paper the bulk of the volume has been little, if at all, 
increased. 

The General Index has been carefully revised. The Index of 
Diseases and Eemedies ha3 been revised to a certain extent, but 
it still remains a mere skeleton of what it ought to be. It is 
little more than a list of drugs which have been recommended 
by somebody or other at some time or other in the treatment of 
certain diseases. In a few instances the conditions supposed to 
indicate the use of one drug in preference to another have been 
given, but I have not yet been able to sift the statements which 
have been made regarding the different drugs. The only use of 
the Index at present is simply to remind the practitioner who is 
treating a disease of the names of drugs which have been proposed 
as remedies for it. Thus, under the head of Hydrophobia I have 
mentioned a number of remedies which have been used or pro- 
posed, because those who may have to treat a case of this disease 
may wish to try some remedy, although my own experience leads 
me to think that almost all well-marked cases will have a fatal 
isBue whatever the drugs employed may be. 



THIED EDITION. ix 

The idea of a Therapeutic Index was taken from that in 
Ringer's ' Therapeutics,' and I wished to make one still more full 
and complete by comparing his index with those of Bartholow and 
H. C. Wood, with Waring's ' Therapeutics,' and with the wonder- 
ful ' Medical Digest ' of Dr. Neale. After I had begun to do this, 
I found that a similar idea had occurred to Dr. S. 0. L. Potter, 
who had already published an index of ' Comparative Thera- 
peutics,' in which he gave a list of remedies taken from the works 
of Aitken, Bartholow, Niemeyer, Phillips, Piffard, Binger, Stille, 
Tanner, Trousseau, H. C. Wood, Waring, and some others. 
After finding that Dr. Potter had already compared together 
more works than I expected to do, I used his list, along with 
Naphey's ' Medical Therapeutics ' and Neale's ' Medical Digest,' 
in preparing my Index. I was unable, however, even with the 
aid of these works, to make the Index anything more than a 
mere list of names, excepting in a few instances. So imperfect 
was it, indeed, that up to the last moment I intended to cancel 
it, and would have done so had not a case occurred in my own 
practice which showed me that even a mere list of drugs may 
sometimes be desirable. I was not unmindful of the old adage 
that ' Fools and children should not see half-done things,' but I 
felt confident that the majority of my readers would not belong 
to either of these classes, and so I allowed the Index to remain. 
My intention to cancel it, however, led me to omit an acknow- 
ledgment of my indebtedness to Dr. Potter, and I have pleasure 
in acknowledging it now. 

My use of Dr. Potter's book has led me to include in the 
Therapeutic Index one remedy which the homoeopaths claim as 
theirs. His book contains a list of remedies taken from homoeo- 
pathic works as well as from those I have already named. The 
two classes of remedies are kept apart in different columns ; but 
I find that, in one instance at least, the amanuensis whom I 
employed to copy out a number of the drugs from Dr. Potter's 
book has made a mistake in the, column, and has taken ' Apis ' as 
a remedy for tonsillitis from the Homoeopathic column. To the 
best of my knowledge this is the only remedy I have taken from 
a homoeopathic source. If any other remedies claimed as 
-' homoeopathic ' have been introduced, they have, I think, been 
copied from the works of one or other of the authors already 
mentioned, and in Dr. Phillips's work there are some remedies 
mentioned without references. But as I intended up to the last 
moment to cancel the whole list, my revision of it was hasty and 



x PBEFACE TO THE 

imperfect; and as I omitted to expurgate 'Apis,' I may also 
possibly have overlooked other remedies. If any such omission 
has occurred I am sincerely sorry, and I can assure the homoeo- 
paths that it is perfectly unintentional. 

Perhaps it may be well to take this opportunity of saying a 
few words in regard to homoeopathic remedies and homoeopathy 
generally. 

The mere fact that a drug in small doses will cure a disease 
exhibiting symptoms similar to those produced by a large dose 
of the drug does not constitute it a homoeopathic medicine, for 
this rule was known to Hippocrates, and the rule similia simi- 
libus curantur was recognised by him as true in some instances. 
But Hippocrates was not a homoeopath, and he recognised the 
fact that, while this rule was sometimes true, it was not invari- 
ably so. 

It seems to me that, in founding the system of homoeopathy, 
Hahnemann has proceeded with his facts as he did with his medi- 
cines — diluting his active drugs with inert matter, and diluting 
his facts with much nonsense. 

In what I am about to say, I may be to some extent open to 
correction, for I cannot claim to know his doctrines so thoroughly 
as those who believe in and follow him. So far, however, as I 
know his doctrines, it seems to me that they consist in raising 
the rule similia similibus curantur to the rank of a regular law ; 
in claiming a curative power for infinitesimal doses, and in be- 
lieving that the diminution in the dose of the drug was made up 
for by the potency conferred upon it through prolonged tritura- 
tion. It is no doubt true that in some instances the power of a 
drug may be increased by trituration, inasmuch as fine subdivi- 
sion either makes it more easily absorbed or alters its chemical 
composition, as in the case of mercurial compounds, where the 
prolonged exposure to the air and friction involved in the tri- 
turation may greatly increase the power of the drug by oxidising 
it, and changing it from a mercurous to a mercuric salt. But 
in both cases the increased activity conferred upon the drug is 
strictly limited, although it may be great in the case of the salts 
of mercury. To suppose it to be exerted ad infinitum is sheer 
nonsense, and the absurdity of infinitesimal doses has been so 
often demonstrated that it is useless to say more about it. 

I think one is justified in describing Hahnemann's experiment 
with cinchona bark as the foundation-stone of his doctrine of 
homoeopathy; for Dr. NankivelL in his Presidential Address to 



THIED EDITION. xi 

the British Homoeopathic Congress at Norwich, says, with regard 
to the action of quinine in ague, that ' it was this very instance 
of successful empirical treatment, of specific medicinaj action, 
that led Hahnemann first to investigate the actions of drugs on 
the healthy human frame, and thus to lay "the foundation of the 
most complete and lucid system of scientific therapeutics that 
the world has yet seen.' But I have shown in the body of this 
work (p. 52) that, although Hahnemann's observations were in 
all probability perfectly correct, the conclusions he drew from 
them were utterly erroneous. 

But there is another side to the question which I think it is 
only fair to consider also. While Hahnemann's theory was 
certainly bad, there can, I think, be little doubt that he, like 
Paracelsus and Priessnitz, has done good service to medical 
practice. Paracelsus gathered information from shepherds, wise 
women, and quacks of all sorts, and thereby obtained a know- 
ledge of popular remedies, not generally employed by the profes- 
sion, but which were nevertheless useful. 

Priessnitz did not invent the use of cold water as a remedy, 
for it was known nearly eighteen hundred years before his time. 
Musa ' saved the life of Augustus by the cold bath, but, not 
knowing exactly how and when to employ it, he killed the nephew 
of the Emperor by it, and such failures brought the treatment 
by water into discredit. Priessnitz revived it, and now in the 
use of cold sponging, wet packs, baths and douches we have a 
powerful means of treating fever and curing disease. 

Hahnemann also did good, and the system which he founded 
has done great service by teaching us the curative power of 
unaided Nature, the use of diet and regimen in treating disease, 
and the more than inutility, the actual hurtfulness, of powerful 
drugs in many instances. The physician is bound to do the 
very utmost he can for his patient, and his very anxiety has 
frequently led him to do harm. He has been afraid to leave the 
cure of disease to Nature, and by the administration of powerful 
drugs has frequently injured instead of benefited his patient. 
The use of infinitesimal doses which could not affect the body 
of the patient one way or the other, but kept the mind of both 
patient and physician easy, and allowed the vis medicatrix natures 
free scope, has helped us to. a more perfect knowledge of the 
natural course of disease. The use of infinitesimal doses has also 
led to much care being bestowed by those who use them upon 
diet and regimen. When a physician administered a large dose 



xii PEEFACB TO THE 

of tartar emetic or of salts and senna, he knew that his remedies 
would produce vomiting or purgation respectively with consider- 
able certainty, whatever the diet or regimen of the patient might 
be ; but the case was quite different with infinitesimal doses. If 
a patient was being treated with carbo vegetabilis in the thirtieth 
dilution, the utmost care was necessary in regard to his diet, for 
if he happened to eat a single piece of burned toast at breakfast, 
he would consume at the one meal as much vegetable charcoal 
as would, when properly diluted, have served him for medicine 
during the remainder of his natural life. 

Moreover, the homoeopathic practice of giving only one drug 
has tended greatly to dimmish the practice of polypharmacy, and 
the tinctures, powders, and globules they employ show us a good 
example in regard to the administration of remedies in ah agree- 
able form. But, although this mode of practice may be employed 
by homoeopaths, it is not homoeopathic. We are not homoeopaths 
because we use a single drug at a time and give half an ounce of 
infusion of digitalis to a patient suffering from heart-disease 
without thinking it necessary to mix it with broom, squill, or 
spirit of nitrous ether. Nor are we homoeopaths because we use 
l-50th of a grain of digitalin instead of the infusion of digitalis. 
Nor are we homoeopaths even if we get a manufacturing chemist 
.to make up the digitalin into a globule with a quarter of a grain 
of sugar of milk instead of with five grains of extract of Kquorice. 
Nor do we become homoeopaths merely because we may employ 
a small dose instead of a large one, and begin with ten drops of 
the infusion of digitalis instead of half an ounce. 

It is not the use of a single drug at a time, of a small dose, 
of a globule, nor even, as we have already seen, of a drug which 
may produce symptoms similar to those of the disease, that con- 
stitutes homoeopathy. The essence of homoeopathy, as es- 
tablished by Hahnemann, lies in the infinitesimal dose and the 
universal application of the rule similia similibus curaniur. But 
the infinitesimal doses are so absurd that I believe they have 
been discarded by many homoeopaths. To such men all that 
remains of homoeopathy is the universality of the rule similia 
similibus curantur, and the only difference between them and 
rational practitioners lies in the fact that the latter regard the 
rule as only of partial application. At first sight this difference 
may seem to be only slight, but it is not so in reality ; for white 
the rational practitioner, refusing to be bound by any ' pathy,' 
whether it be allopathy, antipathy, or homoeopathy, seeks to 



THIED EDITION. xiii 

trace each symptom back to the pathological change which caused 
it, and, by a knowledge of the action of drugs on each tissue and 
organ of the body, to counteract these pathological changes, the 
homoeopath professes to be in possession of a rule which will 
enable him to select the proper remedy in each case by a consi- 
deration of the symptoms, without reference to the pathological 
condition. He may thus dispense with anatomy, physiology, 
pathology, and pharmacology. All that is necessary is a list of 
morbid symptoms on the one hand, and a list of the symptoms 
produced in healthy men by various drugs on the other. 

It is the falsity of the claim which homoeopathy makes to 
be in possession, if not of the universal panacea, at least of the 
only true rule of practice, that makes homoeopathy a system of 
quackery ; yet this arrogant claim constitutes the essence of the 
system, and the man who, leaving Hahnemann and going back 
to Hippocrates, regards the rule similia similibus curantur as 
only of partial and not of universal application, has no longer 
any right to call himself a homoeopath. 

Yet we hear some leading homoeopaths say, 'We do not 
claim any exclusiveness for our method,' ' and then complain 'that 
they are excommunicated by the medical profession. If they 
have renounced the errors of Hahnemann's system, they ought 
not to retain its name, but frankly acknowledge their error and 
return to rational medicine, of which Hippocrates is regarded 
as the father. As a medical man is bound to do his utmost for 
the good of his patient, it is obvious that, although he may 
employ baths or packs as a mode of treatment, he cannot, 
without becoming untrue to his profession, throw aside all other 
means of treatment and become a hydropath ; nor can he consult 
on equal terms with those who, either through ignorance or 
wilful blindness, deny the use of other means of cure and limit 
themselves to the application of water. What is true of hydro- 
pathy is true of homoeopathy. I dislike controversy extremely, 
and should not have taken up so much of the preface with con- 
troversial matter had I not been forced to defend myself by the 
attacks which certain homoeopaths have made upon' me. 

I may now turn to the pleasanter task of acknowledging my 
indebtedness to many friends who have helped me in the pre- 
paration of this edition. In addition to some of those who 
helped me with former editions, I have to thank Dr. Hughlings 

1 Preface by Eichard Hughes to The Medical Treatment of our Time. London : 
Unwin Brothers, Ludgate Hill. 



xiv PEEFACE TO THE THIED EDITION. 

Jackson for assistance in the construction of the diagram 
which illustrates his views of the nervous system ; Mr. W. H. 
Jessop and Mr. Tweedy for much aid and many suggestions in 
revising the section on diseases of the eye ; and I am especially 
grateful to my friend, Dr. Thin, who has greatly added to the 
value of the book by writing an account of the uses of various 
remedies in skin diseases. I am indebted to Mr. Whitehead, Dr. 
Halliburton, and especially to Dr. Sidney Martin, for their assist- 
ance in passing this edition through the press. To Dr. Martin 
I am also indebted for many valuable suggestions, and for such 
an amount of help that, but for him, the preparation of this 
edition would certainly have been delayed for many months. 

T. LAUDEE BEUNTON. 
March, 1887. 



PBEFACE 



TO 



THE FIEST EDITION. 



Some apology is required for the long delay in the appearance 
of this work, for a number of years have now elapsed since it was 
advertised as being in the press. More than fifteen years ago, I 
had a work on Materia Medica completely written out and ready 
for the printer. Some time afterwards, all the arrangements 
had been made for its publication, and in the course of a few 
weeks it was to have been issued from the press. Just as I was 
about to send it to the printer, however, I asked for a little 
delay in order that I might make some improvements and remove 
some redundancies, for the work as it then stood was considerably 
larger than the present one. 

As I went through it, I found so many unsatisfactory state- 
ments and uncertainties regarding the mode of action of drugs, 
which I thought I could decide by a few experiments, that I 
wished for a little time in order that those doubtful points might 
be settled ; but as I went on the labour grew, other engage- 
ments became pressing, and longer and longer delay was required. 
From greater experience as a teacher and examiner also, I came 
to the conclusion that the plan of the work might be altered 
with advantage ; and so finally the whole manuscript was thrown 
aside, and the book entirely re-written. 

In the original work I discussed the physiological and thera- 
peutical actions of each drug separately, in the same way as in 
the third part of the present work, though on a much more 
extended scale. I found, however, that this plan necessitated a 
good deal of repetition regarding the experimental methods by 
which the action of the drugs had been ascertained. 

Moreover, the physician does not want to know only what the 
actions of any one drug are ; he rather requires a knowledge of 



xvi PREFACE TO THE 

classes of drugs, and of the manner in which the actions of the 
individual members of a class differ from each other. He requires, 
in fact, a knowledge of the ways in which the various functions 
of the body can be influenced by drugs both in health and 
disease, in order that he may restore health to his patients. 

It has appeared to me, therefore, better to devote a complete 
section of the work to a discussion of the methods by which 
the action of drugs is determined; io the manner in which 
each function of the body can be modified by drugs ; and to the 
general rationale of the use of drugs in disease, i.e. to devote a 
section to general pharmacology and general therapeutics. 

Considerable experience both in teaching and examining 
has shown me that students sometimes find a difficulty in 
applying physiology to pharmacology and therapeutics, and I 
find that many others are, like myself, apt to forget those parts 
of physiology which they are not constantly studying. I have 
therefore thought it well, for the sake both of students and 
practitioners, to give a short account of the normal functions of 
the different parts of the body, before proceeding to discuss the 
alterations which are produced in them by drugs, or which they 
undergo in disease. In the case of the heart and the kidneys 
also, where the action of drugs is complicated and difficult, I have 
found it necessary to enter a little more fully into the physiology 
of these organs than is done in the ordinary text-books." 

I have found that a similar difficulty occurs with pathology 
as with physiology, and I have therefore occasionally discussed 
pathological questions when I have thought that by doing so I 
could render the action of drugs in disease more intelligible, and 
thus aid the student of rational therapeutics. 

In the second part of the work on general pharmacy, I have 
classed together the various pharmaceutical preparations, and 
given lists of them for reference. It is by no means my intention 
that these should be learned by heart by any student, and indeed 
I think it is well to take this opportunity of protesting against 
the injustice of the demands which are sometimes made upon the 
memories of students. 

It is probable that the majority of the best and most successful 
practitioners would be very much puzzled if they were required to 
state the exact quantity of every ingredient in each pill or each 
ointment that they prescribe, or the exact quantity of the crude 
drug from which the infusions or tinctures which they use have 
been made. They know the action .of the pill or ointment, they 



FIEST EDITION. xvii 

know the action of the infusion or tincture, and they do not trouble 
themselves about details which are only useful to the chemist who 
is making up the preparation. 

It is very greatly to be regretted, for it is a stumbling-block in 
the way of true progress, that students who have afterwards to 
become medical practitioners and not pharmaceutical chemists, 
should be asked at examinations the quantities of crude drugs 
from which particular preparations are made — quantities which 
even the manufacturing chemist himself would never dream of 
carrying in his memory, but would obtain by reference to his books 
whenever he required them. As the late Professor Sharpey used 
very truly to say, ' You may as well require of a medical student 
a knowledge of the whole art of cutlery before you set him to 
dissect.' Medical science is now advancing in every direction, and 
unless we cut off some of the less useful kinds of information, 
which medical students were formerly obliged to acquire, it 
becomes impossible for them to learn all that is truly valuable. In 
Materia Medica we now oblige them to learn the physiological 
action of drugs, a subject regarding which, until quite recently, 
little or nothing* was known, and to oblige them to learn all this, in 
addition to what they were formerly expected to know, is to treat 
them as Pharaoh treated the Israelites, and compel them to make 
the same number of bricks, while giving them no straw. 

I am so much impressed with the necessity of lessening the 
amount of unnecessary work sometimes required as a preparation 
for examinations, that at first I omitted from this book all 
reference to the composition of pharmaceutical preparations. But 
as it is intended not only as a text-book for students, but also for 
the use of practitioners, I afterwards considered that it might be 
convenient to have the composition of some pharmaceutical 
preparations, at least, for the purpose of reference. I have omitted 
the composition of such preparations as are like to be got ready- 
made from a chemist, but have inserted the composition of 
infusions which often need to be prepared when required. I have 
also given the composition of various compound pills, but only 
for the purpose of reference. 

In consequence of this change in the plan of the work while it 
was passing through the press, the preparations of rhubarb have 
been omitted from their proper place at page 924, and are to be 
found at page 1005. 

In the preparation of this work I have to acknowledge my 



xviii PREFACE TO THE FIRST' EDITION. 

obligations to the admirable works of Bartholow, Binz, Buchheim, 
Dujardin-Beaumetz, Edes, Husemann, Nothnagel and Bossbach, 
Binger, Schmiedeberg, and H. C. Wood. Messrs. Chapman, 
Soutter, Spencer, Spry, 1 Steinthal, Stubbs, Walsh, 1 Wells, and 
Wright for the excellent notes they took of my lectures; to 
Dr. D'Arcy Power for the verification of references ; to Dr. 
Mitchell Bruce, Mr. T. W. Shore, and Mr. H. W. Gardner for 
much kind assistance in the preparation of the work, and to 
Prof. Matthew Hay, of Aberdeen, whose criticisms and suggestions 
have been invaluable. To Dr. Francis H. Williams, of Boston, 
Mass., I am indebted for the adaptation of this work to the 
United States Pharmacopoeia, which by tending to familiarise 
medical men on each side of the Atlantic with the preparations 
employed in both countries may, I trust, tend to facilitate the 
introduction of an International Pharmacopoeia. 

T. LAUDEE BBUNTON. 

March, 1885. 

1 These names were inadvertently omitted in the preface to the first edition, 
but were mentioned in the preface to the second. 



Articles and Preparations included in the British Pharma- 
copoeia of 1885, which were not in that of 1867 nor 
in the ' Additions ' of 1874. 



Acidum Borieum. 

Acidum Carbolicum Liquefactum. 

Acidum Chromicum. 

Acidum Hydrobromicum Dilutum. 

Acidum Lacticum. 

Acidum Lacticum Dilutum. 

Acidum Meconicum. 

Acidum Oleicum. 

Acidum Phosphoricum Concentratum. 

Acidum Salicylicum. 

Alcohol Ethylicum. 

Aloin. 

Anisi Fructus. 

Anisi Stellati Fructus. 

Apomorphinse Hydrochloras. 

Aqua Anisi. 

Argeuti et Potassii Nitras. 

Arseuii Iodidum. 

Bismuthi Citras. 

Bismuthi et Ammonii Citras. 

Butyl-Chloral Hydras. 

Caffeina. 

Caffeince Citras. 

Calamina Preparata. 

Calcii Sulphas. 

Calx Sulphurata. 

Chrysarobinum. 

Cimiciiugaa Bhizoma. 

Cinchonidina Sulphas. 

Cinchoninffi Sulphas. 

Coca. 

Cocaine Hydrochloras. 

Codeina. 

Collodium Vesicans. 

Cupri Nitras. 

Elaterinum. 

Ergotinum. 

Extractum Belladonna? Alcoholicum. 

Extractum Cascarse Sagradse. 



Extractum Cascare Sagradas Liquidum. 

Extractum Cimicifugse Liquidum. 

Extractum Cocse Liquidum. 

Extractum Gelsemii Alcoholicum. 

Extractum Jaborandi. 

Extractum Bhamni Frangule. 

Extractum Bhamni Frangulffi Liquidum. 

Extractum Taraxaci Liquidum. 

Gelsemium. 

Glycerinum Aluminis. 

Glycerinum Plumbi SubaCetatis. 

Glycerinum Tragacanthas. 

Inf usum Jaborandi. 

Injectio Apomorphinse Hypodermica. 

Injectio Ergotini Hypodermica. 

Iodoformum. 

Jaborandi. 

Lamella; Atropine. 

Lamella? Cocaine. 

Lamellse Physostigmine. 

Liquor Acidi Chromici. 

Liquor Ammonii Acetatis Fortior. 

Liquor Ammonii Citratis Fortior. 

Liquor Arsenii et Hydrargyri Iodidi. 

Liquor Calcii Chloridi. 

Liquor Ferri Acetatis. 

Liquor Ferri Acetatis Fortior. 

Liquor Ferri Dialysatus. 

Liquor Morphine Bimeconatis. 

Liquor Sodii Ethylatis. 

Lupulinum. 

Menthol. 

Morphine Sulphas. 

Oleatum Hydrargyria 

Oleatum Zinoi. 

Oleo-Besina Cubebe. 

Oleum Eucalypti. 

Oleum Pini SyWestris. 

Oleum Santali. 



XX 



AETICLES ADDED AND OMITTED. 



Paraffinum Durum. 

Paraffinum Molle. 

Physostigmina. 

Pilocarpine Hydrochloras. 

Potassii Cyanidum. 

Quininas Hydrochloras. 

Ehamni Frangulas Cortex. 

Ehamni Purshiani Cortex. 

Salicinum. 

Sodii Bromidum. 

Sodii Iodidum. 

Sodii Salicylas. 

Sodii Sulphis. 

Sodii Sulphocarbolas. 

Sodium. 

Spiritus ^Etheris Compositus. 

Spiritus Cinnamomi. 

Staphisagrias Semina. 

Suppositoria Iodoform!. 

Tabellaj Nitroglycerin!. 



Thymol. 

Tinctura Chloroformi et Morphinsa. 

Tinctura Cimicifugse. 

Tinctura Gelsemii. 

Tinctura Jaborandi. 

Tinctura Podophylli. 

Trochisci Acidi Benzoici. 

Trochisci Santonini. 

Unguentum Acidi Borici. 

TJnguentum Acidi Carbolici. 

Unguentum Acidi Salicylici. 

Unguentum Calamines. 

Unguentum Chrysarobini. 

Unguentum Eucalypti. 

UnguentumHydrargyriNitratisDilutum. 

Unguentum Iodoformi. 

Unguentum Staphisagrise. 

Unguentum Zinci Oleati. 

Vapor Olei Pini Sylvestris. 

Zinci Sulphocarbolas. 



Articles and Preparations included in the British Pharma- 
copeia or 1867 or in the ' Additions ' of 1874, but 
omitted in the British Pharmacopoeia of 1885. 



Areca. 

Cadmii Iodidum. 

Castoreum. 

Decoctum Ulmi. 

Digitalmum. 

Dulcamara. 

Enema Tabaci. 

Ferri Iodidum. 

Ferri Oxidum Magneticum. 

Ferri Peroxidum Humidum. 

Hydrargyri Iodidum Viride. 



Infusum Dulcamaras. 
Liquor Atropia. 
Mistura Gentianse. 
Pilula Quinias. 
Ehamni Succus. 
Sodas Acetas. 
Stramonii Folia. 
Syrupus Bhamni. 
Tinctura Castorei. 
Ulmi Cortex. 
Unguentum Cadmii Iodidi. 



Articles and Preparations the Names of which have 
been altered. 



Former Names, 1867 or 1874. 
Aconitia 

Albumen Ovi . . 
Ammonias Benzoas . 
Ammoniae Carbonas 
AmmonisB Nitras . 
Ammoniae Phosphas 
Arnicas Badix 



Present Names, 1885. 
Aconitina. 
Ovi Albumen. 
Ammonii Benzoas. 
Ammonii Carbonas. 
Ammonii Nitras. 
Ammonii Phosphas. 
Arnicas Bhizoma. 



ALTERATIONS OF NAME. 



xxi 



Former Names, 1867 or 1874. 
Assafostida . 
Atropia 

Atropias Sulphas . 
Berberies Sulphas 
Calcis Carbonas Prsecipitata 
Calcis Hydras 
Calcis Hypophospliis . 
Calcis Phosphas . 
Calx Chlorata 
Canellas Alba? Cortex . 
Caidp.momura 
Cataplasma Sodas Chloratas 
Catechu Pallidum 
Cinchonas Flavas Cortex 
Cinchonas Pallidas Cortex 
Decoctum Cinchonas Flavas 
Ecbalii Fructus . 
Emplastrum Cerati Saponis 
Enema Assafoetidas 
Enema Magnesia? Sulphatis . 
Extractum Cinchonas Flavas 
Ferri et Ammonia Citras 
Ferri et Quinias Citras . 
Hydrargyri Sulphas 
Infusum Cinchonas Flavas 
Liquor Ammonias Acetatis 
Liquor Ammonias Citratis 
Liquor Atropias Sulphatis 
Liquor Bismuthi et Ammonias Citratis 
Liquor Calcis Chlorates 
Liquor Magnesias Carbonatis 
Liquor Magnesias Citratis 
Liquor Morphias Acetatis 
Liquor Morphias Hydrochloratis 
Liquor Potasses Pcrmanganatis 
Liquor Sodas Arseniatis 
Liquor Sodas Chloratas . 
Liquor Strychnias 
Lithias Carbonas . 
Lithias Citras 



Liquidum 



Magnesias Carbonas 
Magnesias Carbonas Levis 
Magnesias Sulphas 
Morphias Acetas . 
Morphias Hydrochloras 
Physostigmatis Faba . 
Pilula Aloes et Assafoetidas 
Pilula Assafcetidas Composita 
Podophylli Badix 
Potasses Acetas 
Potassas Bicarbonas 
Potassee Bichromas 



Present Names, 1883. 
Asafostida. 
Atropina. 
Atropines Sulphas. 
Beberinas Sulphas 
Calcii Carbonas Precipitata. 
Calcii Hydras. 
Calcii Hydrophosphis, 
Calcii Phosphas. 
Calx Cblorinata. 
Canellas Cortex. 
Cardamomi Semina. 
Cataplasma Sodas Chlorinates. 
Catechu. 

Cinchonas Cortex. 
Cinchonas Cortex. 
Decoctum Cinchonas [Bubras], 
Ecballii Fructus. 
Emplastrum Saponis Fuscum. 
Enema Asafostidas. 
Enema Magnesii Sulphatis. 
Extractum Cinchonas [Bubras] Liquidum. 
Ferri et Ammonii Citras. 
Ferri et Quinines Citras. 
Hydrargyri Persulphas. 
Infusum Cinchonas [Bubras] Acidum. 
Liquor Ammonii Acetatis. 
Liquor Ammonii Citratis. 
Liquor Atropines Sulphatis. 
Liquor Bismuthi et Ammonii Citratis. 
Liquor Calcis Chlorinates. 
Liquor Magnesii Carbonatis. 
Liquor Magnesii Citratis. 
Liquor Morphinas Acetatis. 
Liquor Morphines Hydrochloratis. 
Liquor Potassii Permanganatis. 
Liquor Sodii Arseniatis. 
Liquor Sodas Chlorinate. 
Liquor Strychninas Hydrochloratis. 
Lithii Carbonas. 
Lithii Citras. 
Magnesia Ponderosa. 
Magnesii Carbonas Ponderosa. 
Magnesii Carbonas Levis. 
Magnesii Sulphas. 
Morphinas Acetas. 
Morphinas Hydrochloras. 
Phosostigmatis Semen. 
Pilula Aloes et Asafcetidte. 
Pilula Asafoetidas Composita. 
Podophylli Bhizoma. 
Potassii Acetas. 
Potassii Bicarbonas. 
Potassii Bichromas. 



xxii ALTERATIONS AND SUBSTITUTIONS. 

Former Names, 1867 or 1874. Present Names, 1885. 

Potasss Carbonas .... Potassii Carbonas. 

Potassse Chloras Potassii Chloras. 

Potassae Citras Potassii Citras. 

Potassse Nitras ..... Potassii Nitras. 

Potasss Permanganas .... Potassii Permanganas. 

Potassse Prussias Flava . . . Potassii Ferrocyanidum. 

Potassse Sulphas Potassii Sulphas. 

Potassse Tartras Potassii Tartras. 

Potassse Tartras Acida .... Potassii Tartras Acida. 

Quinife Sulphas Quininse Sulphas. 

Serpentarise Radix .... Serpentarise Ehizoma. 

Sodre Arsenias Sodii Arsenias. 

Sodffi Bicarbonas Sodii Bicarbonas, 

Sodas Carbonas ... . . - Sodii Carbonas. 

Sodas Carbonas Exsiccata . . . Sodii Carbonas Exsiccata. 

Sodse Citro-tartras Efiervescens . . Sodii Citro-tartras Effervescens. 

Sodas Hypophosphis .... Sodii Hypophosphis. 

Sodse Nitras Sodii Nitras. 

Sodas Phosphas Sodii Phosphas. 

Sodas Sulphas Sodii Sulphas. 

Sodas Valerianas Sodii Valerianae. 

Strychnia Strychnina., 

Suppositoria Morphia; .... S.uppositoria Morphinse. 

Suppositoria Morphise cum Sapone . Suppositoria Morphinse cum Sapone. 

Tinctura Assafoetidas .... Tinctura Asafoetidas. 

Tinctura Quinise Tinetirra Quininse. 

Tinctura Quinise Ammoniata . . Tinctura Quininas Ammoniata. 

Trochisci Morphiaa .... Trochisci Morphinae. 

Trochisci Morphias et Ipecacuanha . Trochisci Morphinse et Ipecacuanb.se. 

Trochisci Potassse Chloratis . . . Trochisci Potassii Chloratis. 

Trochisci Sodse Bicarbonatia . . Trochisci Sodii Biearbonatis. 

Unguentum Aconitiae .... Ungue,ntum Aconitinas. 

Unguentum Atropise .... Unguentum Atropines. 

Unguentum Veratrise .... Unguentum Veratrinse. 

Valerianse Radix Valeriana} Rhizoma. 

Vapor Conise Vapor Coninse. 

Veratria Veratrina. 

Veratri Viridis Radix .... Veratri Viridis Rhizoma. 

Vinum Quinise ..... Vinum Quininse., 



Substitutions. • 



Antimonium Nigrum Purificatum for Antimonfum Nigrum. 
Cinchonas Rubral Cortex ) f Cinchonas' Flavas Cortex. 



(in preparations) [ " t 

Pulvis Elaterini Compositus „ 

Tinctura Cinchonas [Rubra] „ 
Unguentum Glycerini Plumbi ) f 

Subacetatis J " \ 



Cinehonse Pallidas Cortex. 
Pulvis Elaterii Compositus. 
Tinctura Cinehonse Flavse. 
Unguentum Plumbi Subacetatis Com- 
positum. 



ALTERATIONS. 



xxiu 



Pkepabations the Composition op which has been altered. 



(Minor alterations are not included.) 



Acidum Sulphurosum. 

Alumen. 

Antimqnium Sulphuratum. 

Extractum Cinchona Liquidum. 

Infusum Cinchonas Acidum. 

Injectio Morphine Hypodermica. 

Liquor Epispasticus. 

Liquor Iodi. 

Oleum Phosphoratum. 

Pilula Phosphori. 

Pulvis Glyoyrrhizse Compositus. 



Tinctura Quininse. 

Unguentum Hydrargyri Ammoniati. 

The fatty basis of the four suppositories 

of B.P. 1867 is now oil of theobroma 

only. 
In some of the ointments paraffins have 

been substituted for lard. 
Scammony Besin has been substituted 

for Scammony in most preparations 

of Scammony. 



The strengths of the following preparations have been altered from 1 in 109 

to 1 m 100. 



Liquor Arsenicalis. 
Liquor Arsenici Hydrochloricus. 
Liquor Atropine Sulphatis. 
Liquor Morphine Acetatis. 



Liquor. Morphine Hydrochloratis. 
Liquor Potassii Permanganatis. 
Liquor Sodii Arseniatis. 
Liquor Strychnine Hydrochloratis. 



CONTENTS. 



PAGE 

INTRODUCTION 3 



SECTION I. 
GENEKAL PHAEMACOLOGY AND THEEAPEUTICS. 

CHAPTER I. 

General Relations between the Okganish and Substances Affecting: it, 

pp. 9-32. 

List of Elements . , 9 

Nature of Elements 11 

Classification of Elements . . . . . ... . • .15 

Mendelejeff's Classification of the Elements 19 

Organic Radicals 20 

Chemical Reactions and Physiological Reactions 24 

Relation between Isomorphism and Physiological Action .... 26 

„ „ Spectroscopic Characters and Physiological Action . . . 27 

„ „ Atomic Weight and Physiological Action . ... 28 

Connection between Chemical Constitution and Physiological Action . . 30 

CHAPTER H. 

Circumstances which Affect the Action of Dbuos on the Obganism, 
pp. 33-56. 

Local and Remote Action . . . 33 

Interaction of Various Functions 33 

Direct and Indirect Action ' . - . 34 

Selective Action of Drugs . . 34 

Primary and Secondary Action - . • 35 

Relation of Effect to Quantity of the Drag 36 

Homoeopathy .... ........ 36 

Dose ...-.■ .37 

Size .. •'.*.. •»«••■« .37 

Mode of Administration "', 38 

Absorption of Drugs . . . > . . . . . . .39 

Duration of Action • . .-•<>. . 41 



xxyi CONTENTS. 

PAGE 

Cumulative Action 41 

Effect of Different Preparations 42 

„ Fasting 43 

„ Conditions of the Stomach 43 

Habit 43 

„ Temperature '44 

„ Climate 48 

Time of Day 48 

„ Season 48 

„ Disease 49 

Use of Experiments . • 49 

Comparative Pharmacology 50 

Idiosyncrasy 51 

Experiments upon Healthy Men 51 

Fallacies of Experiment upon Man 52 

Experiments in Disease 52 

Objections to Experiment 53 

Erroneous Deductions from Experiments 55 



CHAPTEE HI. 

Action op Dhugs on Protoplasm, Blood, and Low Organisms, pp. 57-108. 

Action of Drugs on Albumin 57 

„ „ Protoplasmic Movements 59 

Method of Experimentation . ■ . • . . . ^ . - . - . . . 59 

Amoeba . . . . . . . . • . - . - . . . • . . . . 60 

Leucocytes .■.>.-, . • . . • 61 

Effect -of Drugs on leucocytes . ■ 61 

Movements of Leucocytes in the Blood-vessels 62 

,i Bed Blood Corpuscles 63 

Action' of Drugs on Infusoria 63 

Relations of Motion and Oxidation 65 

Oxidation of Protoplasm 67 

Oxygen-carrying Power of Protoplasm • 68 

Ozonising Power of Protoplasm 69 

Aotion of Drugs on Oxidation 69 

Seduction by Protoplasm 70 

Action of Drugs on Blood 70 

Catalysis— Fermentation— Inorganic Ferments 73 

Ferments, Organic and Organised . . ' * ' 74 

Action of Drugs on Enzymes . . . 76 

^yjnogens 80 

Organised Ferments .._..,.,., 80 

leasts . . .... ^ ., ... , 81 

Moulds . .,.,.,.,;>..,.. 82 

Bacteria ..,.,.,., 82 

Struggle for. Existence, between the Organism and Microbes • , . .. . 85 

Action of Drugs on the Movenjents.of Bacteria ■ ..,.,.,.,.,. 88 

■ „ „ , Reproduction of Bacteria .,.,.,.,. . .89 

it » , . »t . , ii Mode of Experimenting on . . 89 

„ , i, , Particular Species, of Bacilli ,.,.,. . .92 

l',n . >• . , ii . , .« Mode of, Experimenting on . 92 



CONTENTS. xxvii 

PAGE 

Action of Drugs on Development and Growth of Bacilli 95 

Influence on Antiseptics of the Solvent 96 

„ „ „ Admixture 96 

„ „ „ Temperature . . • . . . . 96 

. Alterations in Bacteria by Heat and Soil 96 

Possible Identity of different Forms, of Bacteria 97 

Action of Bacteria and. their Products on the Animal Body .... 98 

Alkaloids formed by Putrefaction — Ptomaines 99 

,, „ „ Leucomaines 101 

Effect of Drugs on the Action of Bacteria in the Animal Body . . . . 102 

Antiseptics — Antizymotics— Disinfectants — Deodorizers .... 103 

Uses of Antiseptics 104 

Disinfectants 106 

, Deodorizers 106 

Antiperiodics 107 



CHAPTER IV. 

Action of Drugs on Invertebbata, pp. 109-116. 

Action of Drugs on Medusae 109 

„. . „ Mollusca 114 

„• ■ „ Ascidians 114 

, Annnlosa 114 



. CHAPTEB V. 
Action of Drugs on Muscle, pp. 117-143. 

Action of Drugs on Voluntary Muscle 117 

Irritability of Muscle . .' 119 

Contraction of Muscle . . ; 119 

Latent Period of Muscle . 120 

Summation of Stimuli 122 

Contraction of Muscle 122 

Fatigue ..... f 123 

Contracture 124 

Tetanus : 12S 

'Muscular Poisons .' .' .' . .' .' .' .' ." ' . . . 126 

Massage 131 

Propagation of the Contraction Wave in Muscle ; 131 

Rhythmical Contraction of Muscle . . . 131 

Pathology of Tremor . . . . 133 

Treatment of, Tremcr ., .. .. .. .. . 13ft 

Connection between. Chemical Constitution and Physiologjpal Action on, 

Muscle .".*,.' . * . . .13.4 

Action of Drugs, on Muscle is Relative and not Absolute . . . . . 136 

„ „ on Involuntary Muscular Fibre . 137 

Effect of Stimuli .138 

Relation of Contractile Tissue to the Nerves ....... 139 

Propagation of Contraction Waves . . 139 

Artificial Bhvthm, ....... . 140 

Hypothetical Considerations regarding the Action of Drugs on Muscle . . 141 



xxviii CONTENTS. 

CHAPTER VI. 
Action op Drugs on Nerves, pp. 144-158* 

FAGS 

General Action of Drugs on the Nervous System 144 

Action of Drugs on Motor Nerves 146 

Methods of Experiment .... 147 

Paralysis of Motor Nerve-Endings by Drugs 147 

Advantage of the Method of Local Protection 149 

Paralysers of Motor Nerves 150 

Exact Localisation of the Action of Curare 1S1 

Action of Drugs in Increasing Excitability of Motor Nerves . . . . 153 

Irritation of Motor Nerve-Endings . . 154 

Action of Drugs on the Trunks of Motor Nerves 154 

,, „ Sensory Nerves 155 

Local Sedatives and Local Ansssthetics 157 

Stimulating Action of Drugs on the Peripheral Ends of Sensory Nerves . . 157 

CHAPTER VII. 
Action of Drugs on the Spinal Cord, pp. 159-182. 

Action on the Conducting Power of the Cord 159 

Action of Drugs on Reflex Action . 163 

Direct, Indirect, and Inhibitory Paralysis of the Spinal Cord by Drugs . . 164 

Indirect Paralysis 164 

Direct ,, 164 

Spinal Depressants and their Uses 165 

Inhibitory Paralysis 165 

Nature of Inhibition 167 

Interference in Nervous Structures 169 

Effect of Altered Rate of Transmission 169 

Opposite Conditions produce Similar Effects 170 

The Same Conditions may cause Opposite Effects 170 

Stimulation and Inhibition merely Consequences of Relation . . . . 170 

Test of the Truth of the Author's Hypothesis regarding Inhibition . . 171 

Explanation of the Action of Certain Drugs on this Hypothesis . . . . 171 

Stimulating Action of Drugs on the Reflex Powers of the Cord . . . 177 

Localisation of the Action of Strychnine by Magendie 177 

Spinal Stimulants . . . . 181 

CHAPTER VHI. 

Action op Drugs on the" Brain, pp. 183-215. 

Functions of the Brain in the Frog 183 

„ „ „ Mammals .184 

Depressant Action of- Drugs on Motor Centres in the Brain . . . . 187 

Irritant „ „ „ .... 188 

Convulsions 188 

Action of Drugs on the Sensory and Psychical Centres in the Brain . . 191 

Drugs which Increase the Functional Activity of the Brain . , . . 192 

Nerve Stimulants 192 

Cerebral Stimulants .... 192 

Drugs which Lessen the Functional Activity of the Brain . . 195 



CONTENTS. xxix 

PAGE 

Hypnotics or Soporifics 196 

Narcotics 200 

Anodynes or Analgesics 201 

Adjuncts to Anodynes 203 

Anaesthetics 203 

Stages of their Action 206 

Uses of Anaesthetics 207 

Dangers of Anesthetics 207 

Mode of Administering Anesthetics 209 

Anesthesia in Animals 210 

History of the Discovery of Anesthesia . . . 21] 

Antispasmodics 212 

Action of Drugs on the Cerebellum 215 

CHAPTBE IX. 
Action of Drugs on the Okoans of Special Sense, pp. 216-231. 

Action of Drugs on the Eye 216 

„ „ „ Conjunctiva 216 

„ „ „ Lacrimal Secretion 217 

Projection of the Eyeball 217 

Action of Drugs on the Pupil 217 

„ „ „ Accommodation 223 

„ „ „ Intra-ocular Pressure . , 224 

Uses of Mydriatics and Myotics 225 

Action of Cocaine 226 

Action of Drugs on the Sensibility of the Eye 227 

„ „ in Producing Visions 228 

„ „ on Hearing: 228 

„ „ on Smell 280 

„ „ on Taste . . ... . 230 

CHAPTEB X. 
Action of Dbucs on Respiration, pp. 232-261. 

Eespiratory Stimulants and Depressants 232 

Comparative Anatomy of the Eespiratory Centre 232 

Action of Drugs on the „ „ 240 

„ „ „ Eespiratory Nerves 244 

Sternutatories or Errhines 245 

Pulmonary Sedatives 246 

Pathology of Cough 247 

Eemedies which Lessen Irritation 249 

Pulmonary Sedatives 250 

Expectorants . 250 

Action of Drugs on the Bronchial Secretion . 252 

„ „ „ Expulsive Mechanism ...... 254 

Adjuncts . . 255 

Arrest of Colds . . '. . . . '256 

Selection of Eemedies in Treatment of Cough 257 

Action of Drugs on the Bronchi '259 

Pathology of Bronchial Asthma 259 

Treatment of „ „ . 260 



xxx CONTENTS. 

CHAPTER XI. 
Action of Detjos on the Circulation, pp. 262-339. 

FAGB 

Arteries and Veins • 262 

Blood-pressure 263 

Painting and Shock ' 264 

Scheme of the Circulation 265 

Circulation in the Living Body 267 

Mode of Ascertaining the Blood-pressure 268 

Fallacies 269 

Alterations in Blood-pressure . . — 270 

Belation of Pulse-rate and Arterioles to Blood-pressure 271 

Effect of the Arterioles on Pulse Curves 275 

Investigation of the Action of Drugs on the Arterioles ..... 277 

Method of Measurement by Bate of Flow 281 

Action of Drugs on Vaso-motor and Vaso-dilating Nerves .... 283 

Action of Other Parts on the Blood-pressure 285 

Keflex Contraction of Vessels . . . .' 285 

Action of Drugs on Reflex Contraction of Vessels 286 

. Comparative Effect of Heart and Vessels on Blood-pressure in Different 

Animals 287 

Influence of Nerves on Blood-pressure 289 

Action of the Heart on Blood-pressure 292 

Causes of Alteration in Blood-pressure and Pulse-rate 293 

Effect of Drugs on the Pulse-rate • . . . 295 

Action of Drugs on the Cardio-inhibitory Action of the Vagus . . . . 295 

Keflex Stimulation of the Vagus 296 

Causes of Quickened Pulse 297 

Action of Drugs on Vagus-Koots 297 

Action on Accelerating Nerves 298 

Stimulating Effect of Asphyxial Blood on the Medulla 298 

Stimulation of the Heart by Increased Blood-pressure 298 

Palpitation 299 

The Heart of the Frog 299 

Action of Drugs on the Heart of the Frog 301 

„ „ its Muscular Substance 305 

Differences between the Heart Apex and the Heart 308 

Action of Drugs on the Vagus of the Frog 310 

Action of Drugs on Inhibition of the, Heart 310 

Theories Regarding the Mode of Action of Drugs on the Heart . . . . 312 

Drugs which Act on the Cardiac Muscle 316 

„ „ „ Motor Ganglia . 316 

„ „ ., Inhibitory Ganglia 317 

„ „ „ Vagus-Ends in the Heart 317 

„ „ ., Vagus-Centre 317 

„ „ „ Accelerating Centre 318 

,, » .. Capillaries 318 

„ „ „ Vaso-motor Nerves 318 

>• .. .. .. Centre . 3 1 9 

Stannius's Experiments ... 319 

General Considerations regarding the Heart . 322 

Regulating Action of the Nervous System . v 324 



CONTENTS.' xxxi 

l'AGE 

Hypothesis regarding the Action of .the Vagus 325 

Inhibition in the Heart * .. . -. . 326 

Therapeutic Uses of Drugs acting on the Circulation ..... 328 

Cardiac Stimulants . 328 

Vascular 330 

Cardiac Tonics 331 

Bisks attending the Administration of Digitalis and other Cardiac Tonics . 335 

Vascular Tonics . 335 

Pathology of Dropsy 336 

Cardiac Sedatives . 338 

Vascular „ 339 

CHAPTER XII. 
Remedies Acting on the Surface op the Body, pp. 340-351. 

Irritants and Counter-irritants 340 

Bubefacients 344 

Vesicants 345 

Pustulants 346 

Caustics 346 

Emollients and Demulcents 347 

Astringents 349 

Styptics . 350 

CHAPTEE XHI. 
Action op Dbugs on the Digestive System, pp. 352-409. 

Action of Drugs on the Teeth 352 

„ „ „ Salivary Glands 353 

Sialagogues 353 

„ Keflex 357 

„ Mixed 357 

„ Specific 357 

Excretion by the Saliva 358 

Refrigerants 360 

Pathology of Thirst 360 

Anti-sialics 360 

Action of Drugs on the Stomach 361 

Gastric Tonics 361 

Appetite • 362 

Action of Drugs on Secretion in the Stomach . 363 

„ „ the Movements of the Stomach 365 

Absorption from the Stomach 368 

Antacids 369 ^ 

Emetics 370 

Anti-emetics and Gastric Sedatives 376 

Carminatives 378 

Action' of Drugs on the Intestines . . . . . . . . 379 V 

Intestinal Movements and Secretion 379 

Paralytic Secretion 380 

Constipation 384 

Action of Drugs On Absorption from the Intestines . . . . . . 386 

Intestinal Astringents 387 



xxxii CONTENTS. 

PAGB 

Purgatives 389 

Action of Purgatives 390 

Uses of Purgatives 394 ' 

Action of Irritant Poisons 395 

Peculiarities in the Action of different Irritant Poisons , . . . 397 

Secondary Effects of Irritant Poisoning 398 

Action of Drugs on the liver . 399 

Hepatic Stimulants 402 

Cholagogues 404 

Adjuncts to Cholagogues 406 

Uses of Hepatic Stimulants and Cholagogues 407 

Hepatic Depressants 407 

Action of Drugs on the Pancreas 407 

Anthelmintics 408 



CHAPTER XIV. 
Drugs Acting on Tissue-Change, pp. 410-421. 

Tonics 410 

Hasmatinics 412 

Alteratives 413 

Antipyretics — Febrifuges '. .... 416 

CHAPTER XV. 
Action or Drugs on Excretion, pp. 422-446. 

Action of Drugs on the Kidneys . . . 422 

Circumstances Modifying the Secretion of Urine 427 

Mode of Action of Diuretics . , 431 

Adjuvants to Diuretics 434 

Action of Drugs on Albuminuria 434 

Lithontriptics 436 

Action of Drugs on the Skin 437 

Diaphoretics and Sudorifics . . . 437 

Excretion by the Sweat Glands . , 439 

Relation between Sweat Glands and Kidneys . , ... 439 

Action of the Skin in Regulating Temperature . . . . 440 

Antihidrotics or Anhidrotics 441 

Pathology of Night Sweats . ... 442 

Action of Drugs on the Bladder 443 

Urinary Sedatives and Astringents 445 



CHAPTER XVI. 
• Action of Drugs on the Generative System, pp. 447-456. 

Aphrodisiacs and Anaphrodisiacs 447 

Aphrodisiacs 449 

Anaphrodisiacs 457 

Emmenagogues 452 

Ecbolics 454 

Action of Drugs upon the Mammary Glands 455 



CONTENTS. xxxiii 

43HAPTBE XVTT. 
Methods of AnMiNisiEEiNa Dkugs, pp. 457-485. 

RAGE 

Application of Drugs by the Skin 457 

Epidermic Application " 457 

Baths . . ' 459 

Cold Bath . * 460 

» Pack 463 

„ Sponging 463 

„ Douches . ' 463 

Local Application of Cold • .■ . . . . . . . .'- . . . 464 

Cold Sitz Bath 464 

„ Foot Bath 464 

„ Compresses . . . ' 464 

Tepid Baths . . . ..... .- 466 

Warm 466 

Hot „ 467 

„ Foot Bath 467 

„ Sitz Bath 467 

Poultices 468 

Medicated Baths . . - 469 

Sea-bathing . . .' . . 469 

Carbonic-acid Bath 469 

Acid Bath 469 

Alkaline Bath 470 

Sulphurous Bath 470 

Mustard Bath , 470 

Pine Bath 470 

Vapour Baths 470 

Calomel Fumigation , . . . . 471 

Air Baths— Turkish Bath 471 

Friction and Inunction 472 

Massage 472 

Inunction 473 

Endermic Application of Drugs 474 

Hypodermic Administration of Drugs 474 

Objections to Hypodermic Injections . . . 476 

Application of Drugs to the Eye . . . . . . . . . . . 477 

Ear, 477 

<> >• Nose 478 

1. » Larynx 479 

» „ Lungs . 481 

„ „ Mouth and Pharynx . . 482 

Masticatories — Gargles 482 

Application of Drugs to the Stomach . . ... . . . . . 482 

Stomach-pump 483 

Gastric Syphon 483 

Application of Drugs to the Intestine 484 

Enemata . . . . . . . 484 

Suppositories 484 

Application of Drugs to the Urethra 484 

„ „ Vagina and.Uterus . . ' . . . . 485 

b 



xxxiv CONTENTS. 

CHAFTEB XVHL 

Antidotes, pp. 486-491. 

PASS 

Antidotes to Poisonous Gases 486 

Acids 487 

Alkalies 487 

„ Alkaloids, &e. 488 



CHAPTEK XIX. 

Antagonistic Action or Deugs, pp. 492-496. 

OHAPTEE XX. 
Dosage, p. 497. 



SECTION n. 

GENEEAL PHAEMACY. 

CHAPTEE XXI. 

Pharmaceutical Peepaeations, pp. 501-534. 

Abstracta — Abstracts . 503 

Aceta —Vinegars 503 

Alkaloidea — Alkaloids 503 

Aquffi — Waters . 505 

Gataplasmata — Poultices 506 

Cerata — Cerates . . . . . . . 506 

Chartse —Papers 506 

Collodia — Collodions 507 

Confectiones — Confections— Electuaries ........ 507 

Decocta — Decoctions 507 

Elixiria— Elixirs 508 

Emplastra— Plasters 508 

Enemata — Injections — Enemas — Clysters 508 

Essentia — Essences 509 

Extracta — Extracts 509 

Glycerina— Glycerita — Glycerines 513 

Infusa — Infusions 513 

Injectiones Hypodermics — Hypodermic Injections 514 

Lamellte— Gelatine Discs 515 

Linimenta — Liniments — Embrocations 515 

Liquores— Solutions . , 517 

Lotiones — Lotions 518 

Masses— Masses 518 

Mellita — Honeys 518 

Misturse — Mixtures . 513 

Mueilagines — Mucilages . . ... . ... . . , 519 



.-CONTENDS. 



• XXXV 



TAUK 



Olea— Oils, Fixed and Volatile 61!) 

Oleata — Oleates ... 621 

Oleoresinffi — Oleoresins 521 

Oxymel . . 521 

PilulsB— Pills 521 

Pulveres — Powders . . 524 

Resinae — Eesins .•.-... . - 524 

Spiritus — Spirits , . 525 

Suppositoria — Suppositories 526 

Succi — Juices . . . » , 526 

Syrupi — Syrups 527 

Tfcbellffl— Tablets 528 

TifcctursB — Tinctures 528 

Triturationes — Triturations 531 

Troehisci — Lozenges 531 

Unguent a — Ointments 532 

Vapores — Vapours — Inhalations 533 

Vina— Wines 534 



■ SECTION m. 

INOEGANIC MATEEIA MEDICA. 

CHAPTER XXn. 
Hydhooen, Oxygen, Ozone, OABBoiir, Sulphur, and the Halogens, pp. 537-564. 

Hydrogen .■ 537 

Oxygen 537 

Ozone . . ■ . . ... . . - . . . . , . 539 

Peroxide of Hydrogen . 540 

Carbon 541 

Sulphur .543 

Sulphuretted Hydrogen 545 

Halogen Elements — General Source and Characters .... . 547 

Mode of Preparation 548 

General Action 549 

Chlorine • 549 

Chlorinated Lime - . .• 550 

„ Soda 551 

Bromine 552 

Bromide of Potassium 553 

„ Sodium 555 

„ Ammonium 556 

„ Lithium . . . ■ 556 

„ Calcium , 556 

„ Zirio (vide p. 678) . . . . 556 

Iodine . . . . . 56? 

Iodide of Sulphur . » ,. . . . . 557 

Action of Iodine . . . 558 

Iodide of Potassium ... . . . 559 



xxxvi 



CONTENTS. 



Iodide of Sodium , 563 

Ammonium . • • "63 

Zinc (vide p. 673) 564 

Silver (vide p. 680) 564 

Mercury, Bed (vide p. 696) 564 

„ Green (rede p. ,696) fi 64 

Lead (vide p. 705) 564 



CHAPTEB XXHI. 
Acids, pp. 565-591. 



General Characters of Acids 
„ Preparations of Acids . 
„ Action , „ 

Sulphuric Acid 

Sulphurous „ 

Hydrochloric Acid . , 

Hydrobromic „ 

Hydriodic Acid (Syrup) 

Nitric „ 

Nitro-hydrochloric Acid 

Acetic 

Phosphorio 

Tartaric 

Citric 

Oxalic 

Boric or Boracic 

Chromic 

Carbonic 

Hydrocyanic 

Lactic 

Oleic 

Arsenious „ (vide p. 719) 

Benzoic „ ,(vide.-p. 964) 

Carbolic „ (vifie p. .813). 

Chrysophanic „ (vide p. 909) 

Gallic „ (vide p. 1033) 

Pyrogallic „ .(vide/p. 819) 

Salicylic „ (vide p..819) 

Tannio „ .(vide.?. 10,31) 



565 
565 
567 
570 
571 
572 
573 
574 
574 
575 
576 
578 
580 
580 
581 
581 
582 
583 
586 
589 
590 
591 
591 
591 
591 
591 
591 
591 
591 



CHAPTER XXIV. 
Metals, pp. 592-643. 



General Classification of the Metals .... 
General Tests fqr Acid Badicals in Metallic Salts 
Metals .of the Alkalis. Their Characters and Reactions 
General Physiological Action of the Alkalis . . 

„ „ „ Alkaline, Group of .Salts 

.1 ii ,. Chlorides „ „ 

„ „ „ Sulphates „ „ 



592 
593 
596 
596 
597 
599 
602 



CONTENTS. 



xxxvn 



Comparative Action of the Alkaline Metals 

Monad Metals, Group I., Potassium, Sodium, Lithium . 

Potassium, General Sources and Eeactions of its Salts 

Preparation of Potassium Salts 

General Action of „ * „i 

Characters, Actions and Uses of Offieinal Potassium Salts 
Sodium, General Sources and Beactions of its Salts 

Preparations of its Salts . - r 

General Impurities, Tests and Action . 
Characters, Actions and Uses of Sodium Salts 
Lithium, Sources and Eeactions -of its Salts . , 
Impurities, Tests and General Action of Lithium Salts . 
Characters, Actions and Uses of Officinal Lithium Salts 
Monad Metals, Group II., Ammonium , 

Nature of Ammonium Salts 

Sources and Beactions 

Impurities and Tests 

Preparation . .. ,. 

General Action 

Characters, Actions and Uses of Officinal Ammonium Salts 



PAGE 

. . 602 

. 603 

. . 603 

604 

. . 605 

007-617 

. . 617 

. 618 

. . 619 

619-630 

. . 630 

. 630 

631-633 

. 633 

. . 633 

. 634 

. . 634 

. 635 

635 

037-643 



CHAPTEB XXV. 

Metals {continued), Class II., Dyad Metals — Gboups I. and II., Metals op 
the Alkaline Earths and op the Earths, pp. 644-661. 

Beactions of the Metals- in Class H 645 

Class II., Group I., Metals of the Alkaline Earths 645 

General Action of „ - „ „ „ . . . . . 645 

Calcium, Beactions, Preparation, Impurities and Tests of its Salts . 646, 647 
Characters, Action and Uses of Officinal Calcium Salts .... 647-653 

Class II., Group I., Appendix — Aluminium 654 

General Sources, Preparation, Beactions, Impurities and Tests of Aluminium 

Salts 654 

Characters, Actions and Uses of Officinal Aluminium Salts . . 654-657 

Cerium, Action and Uses of its Oxalate 657 

Class II., Group II., Magnesium 658 

Sources, Beactions and Preparations of Magnesium Salts .... 658 

Impurities, Tests and Action „ „ , 659 

Characters, Actions and Uses „ „ „ . . . 659-661 



CHAPTEB XXVI. 

Met-als (continued)? The Heavy Metals, Class II., Gboups lH. and IV., 
and Class IV., pp. 662-706. 

General Actions of Heavy Metals 662 

„ „ Class II., Group III., Zinc, Copper, Cadmium and Silver . 665 

Zinc, its Sources, General Beactions and Preparations of Zinc Salts . . 667 

Impurities, Tests and Action of Zinc Salts 668 

Characters, Action and Uses of Officinal Zinc Salts .... 669-674 

Copper, its Sources, Beactions, Impurities and Tests 674 

Characters, Action and Uses of Officinal Salts of Copper . . . 674-676 



xxxviii .CONTENTS. 

PAGE 

Silver, Characters, Action and Uses of its Salts .... 676-680 
Class II., Group IT., Mercury 680 

General Sources and Eeactions of Salts of Mercury , 

„ Impurities, Tests and Action of Salts of Mercury 
Characters, Actions and Uses of Officinal ,, ,, . 

Class IV., Tetrad Metals, Lead and Tin 

General Actions 

lead, its Sources, Eeactions, Impurities .... 

Tests and Action of Lead ....... 

Characters, Actions and Uses of Officinal Salts of Lead . 



. . 680 

. 681 

686-697 

. 698 

. . 698 
. 698 

. . 699 

702-705 



Tin, Action and Uses of its Chloride 706 



CHAPTER XXVII. 

Class V., Pentad Elements — Nitrogen, Phosphorus, Arsenic, Antimont, 
and Bismuth, pp. 707-734. 

Nitrogen and its Compounds 707 

Nitrous Oxide 708 

Phosphorus, its Preparation, Characters and Action .... 709, 710 

Uses of Phosphorus 712 

Arsenic, its Sources and Tests 712 

General Action of Arsenic . 713 

Probable Mode of Action of Arsenic in Phthisis , 717 

Characters, Actions and Uses of Officinal Preparations of Arsenic , 719-721 

Antimony, its Sources and Eeactions 721 

General Action and Uses 722 

Characters, Action and Uses, of its Offioinal Preparations . . . 727-730 

Bismuth, its Sources and Eeactions 730 

General Action and Uses of its Salts 731 

Character, Action and Uses of its Officinal Preparations . . . 732-734 



CHAPTER XXVIII. 
Metals {contMVUed), Class VIII., Iron, Manoanese, pp. 735-755. 

Iron, its Sources and Eeactions 735 

Impurities, Tests and Preparation of its Salts 736 

General Action ■ . ■ . . . . t t 733 
Character, Action and Uses of its Officinal Preparations . . . 740-752 

Manganese _ irgg 

Class VIII., Group II., Gold and Platinum _ 753 

Gold, Preparation and Characters of its Chloride ...... 754 

Platinum, Preparation, Uses and Action of its Chloride . , . 754 755 



CONTENTS. aureix 

SECTION IV. 
OEGANIC MATEELA MEDIOA. 

OHAPTEB XXIX. 
Cabbon Compounds — Fatty Sebies, pp. 759-806. 

PAGE 

Series of Carbon Compounds 759 

General Action of Carbon Compounds • 760 

Bisulphide of Carbon 760 

Hydro-Carbons 761 

Benzin 762 

Petrolatum (Vaseline) 763 

Paraffin, Hard 763 

Soft , . 764 

Alcohols of the Series C 2 H, n+1 OH 764 

General Action , . 764 

Methyl Alcohol 766 

Ethyl Alcohol : General Sources, Preparation and General Impurities . . 767 

Tests and General Action 767 

Effect of Impurities on its Action , . 770 

Chronic Alcoholic Poisoning . 770 

Causes and Treatment of Alcoholism . 772 

Uses of Alcohol 773 

Alcohol as a Stimulant . . 774 

Officinal Alcoholic Preparations 775-778 

Aldehydes, Acetic aldehyde and Paraldehyde 778 

Ketones, Hypnone 779 

Simple Ethers, Ether 780-783 

Saline Ethers .'...' 783 

Ethereal Oil and Hoffman's Anodyne 783 

Acetic Ether . . .'.'.' 783 

Nitrites of Ethyl and Amyl . „ 784 

Nitro-Glycerine— Tablets of Nitro-Glycerine 788 

Liquor Sodii Ethylatis (vide p. 619) 789 

Haloid Compounds 789 

Bromide of Ethyl 789 

Iodide of Ethyl . 790 

Chloral Hydrate, its Preparations and Characters . . . . . , 790 

Its Action . 791 

Treatment of Chloral Poisoning . . 793 

Butyl-Chloral Hydrate 794 

Bromal Hydrate 794 

Bichloride of Methylene 795 

Chloroform, its Preparation, Characters, Impurities and Tests . . . . 795 

Action of Chloroform . . . . . 796 

Bangers of „ 799 

Precautions in using Chloroform . 800 

Uses of Chloroform ... . ... . . , . . 802 

Iodoform . 804 

Methylal (vide Appendix) <• . 806 

Urethane (vide Appendix) , . 806 

Iodol (vide Appendix) . . 806 



xl CONTENTS.' 

CHAPTER XXX. 
Cabbon ..Compounds — Aromatic Sebies, pp. 807-826. 

PAGB 

General Chemistry of the Aromatic Series 807 

General Action „ „ » 811 

Carbolic Acid 812 

Its Action 813 

Uses - 81 5 

Sodii Sulpho-carbolas (vide p. 626) 817 

Zinci Sulpho-carbolas (vide p. 671) . . ...... • . • 817 

Creasote . . . 817 

Eesorcin 818 

Hydroquinone . . • . 818 

Pyrocatechin 819 

Pyrogallic Acid . . . 819 

Salicylic Acid 819 

Naphthalin . . . 821 

i- aphthol. . . . i . . .822 

Eydrochlorate of Bosaniline 822 

Pyridine 823 

Chinoline 823 

Kairin 824 

Antipyrin 824 

Antifebrin . ... . . . . . , 825 

Saccharine 825 



SECTION V. 
VEGETABLE MATEKIA. MEDICA, 

InteoductioN 829 

CHAPTER XXXI. 

Sub-Kingdom I., Phanebogamje. 

DlTISIOH I., ANGIOSPEBMiE ; CLASS I., I)lOOTpaiDO.NES PoLTPETAIJE ; 
. SuB-J&iASS I., THAT.AMTTI.OBa!, pp. 831-875. 

Xanunculacese 831 

Aconite . 831 

Staphisagria . . . . . 836 

Pulsatilla 836 

Adonis Vernalis 837 

Cimicifuga 837 

Podophyllum 838 

Hydrastis. . . . "^ 839 

Tttagnoliaceae 840 

Star-Anise — Illicium 840 

Oil of Anise • 840 

IHenlspermaceae 840 

Menispenmrm 840 

Calumba 840 

Pareira 841 

Picrotoxin 842- 



CONTENTS. xli 

PACK 

Berberidaceee . . * . •. •. 842 

Caulophyllum 842 

Papaveraceae 843 

Eoppy Capsules 843 

Opium . . . 844 

Preparations of Opium 844 

Meconic Aeid 846 

Morphine 846 

Apomorphine 848 

Codeine 849 

Action of Opium 851 

Diagnosis of Opium Poisoning 852 

Treatment „ „ 853 

Circumstances Modifying the Action of Opium 856 

Action of the Alkaloids of Opium . • . . 858 

Uses of Opium • 859 

Khceas— Bed Poppy 862 

Sanguinaria— Blood Boot 863 

Chelidonium — Celandine 863 

Cruciferee . . • 864 

Sinapis — Mustard 864 

Armoracia — Horseradish . ,. 866 

Vlolarleee 866 

Viola, — Pansy ■ 866 

Canellaceae ■ 867 

CanellaAlba - 867 

Polygalaoeae . 867 

Senega ... - 867 

Krameria — Bhatany 868 

Guttlferae 869 

Cambogia — Gamboge . 869 

TernstromlacesB 869 

Tea . • 869 

Caffeine . . .... 870 

Malvaceae 872 

Gossypiuzn — Cotton 873 

Pyroxylin— Gun Cotton . . . 874 

Collodion 874 

Althaea — Marshmallow . . 875 

Steroullaceae (Byttneriacese) 875 

Theobroma — Cacao 875 



CHAPTBB XXXII. 

PHANEEOGAMa: (continued). 

Class I., Dicotyledones Poltpetal^e ; Sub-Class II., DiscrpLORa:, pp. 876-898. 

Xlneee . . . . ■' 876 

Linseed— Flaxseed . . . . 876 

Erytbroxyleee 877 

Coca — ^Erythroxylum - . . . . 877 

Cocaine . . . . . . . - 877 

Action of Cocaine . . . . . . . . , . . 878 



xlii CONTENTS. 

FAGB 

Zjrgophyllaceee 880 

Guaiacum 880 

Geranlaceee • ■ 881 

Geranium — Cranesbill 881 

Rutacese ■ • 881 

Eutese 881 

Oil of Rue 881 

Cusparia 881 

DiosmesB 882 

Buchu ............. 882 

Xanthoxylinas 883 

Xanthoxylum — Prickly Ash 883 

Jaborandi — Pilooarpua 883 

Pilocarpine 883 

Action of Pilocarpine 884 

Aurantiese 887 

Orange 887 

Oil of Bergamoi 889 

Lemon 890 

Bael Fruit 891 

Simarubaceae 892 

Quassia 892 

Bnrseraceee or Amyridacee 893 

Myrrh ,893 

Elemi .....'...,,... 893 

JHellaceae 894 

Azedarach 894 

lUclnese (Aquifoliaceae) 894 

Prinos— Black Alder . 894 

Celastrinae 894 

Euonymus — Wahoo 894 

Rbamnese 895 

Cascara Sagrada — Bhamnus Purshianus ....... 895 

Rhamuus Frangula — Buckthorn , . . . 895 

Ampelldse (Vitaceue) 896 

TJvse — Raisins , . . . . . . 896 

Vinum Xericum 896 

VinumRubrum . . . . 896 

Saplndaceee ...,....•..,.. 897 

Guarana , 897 

Anaoardlacese (Torobinthacote) . . . . , 897 

Mastiohe 897 

Rhus Glabra — Sumach 898 

Rhus Toxicodendron — Poison Ivy 898 



CHAPTER XXXIII. 

, Phanerogams, (continued). 

Class I., Dicottledones Polypetal^: ; Sub-Class III., CALYorrLORai, pp. 899-938. 

lefuminosee . . . .... ... . , . . 899 

Papilionacese . . . ... .....,.,. . . 899 

Glycyrrhiza— Liquorice . .,,..,. , , , .899 



CONTENTS. xliii 

PAUE 

Scoparius — Broom 900 

Tragacanth 900 

Pterooarpus — Santalum— Bed Sandal-wood or Bed Saunders . . 901 

Kino 902 

Balsam of Peru 902 

Balsam of Tolu 903 

Abrus — Jequirity 903 

Physostigma — Calabar Bean 904 

Hamatoxylon — Logwood 908 

Chrysarobinum— Chrysophaoic Acid — Goa Powder .... 908 

Cffisalpinte ' 909 

Senna 909 

Cassia — Purging Cassia 911 

Tamarind 911 

Copaiba — Copaiva 912 

Pi scidia Erythrina — Jamaica Dogwood 913 

Mimoseas 913 

Acacia 913 

Catechu , , . . . 914 

Erythrophloeum — Casca — Sassy 915 

Indigo 915 

Jtosaeese , . . ( 915 

Prunes; 915 

Amygdala Dulcis-^Sweet Almond 915 

. - Amygdala Amara — Bitter Almond ,....,. 915 

Prunum — Prune 917 

Frunus Virginiana — Wild Cherry 917 

Laurocerasus— Cherry Laurel 917 

QuillajesB 918 

Quillaia— Soap Bark 918 

Bubete 919 

Eubus— Blackberry 919 

Bubus Idseus — Baspberry 919 

Boseae 920 

Oil of Bose 920 

Bosa Centifolia — Cabbage Bose— Pale Bose 920 

Bosa Gallica— Bed Bose 920 

Bosa Canina — Dog Bose 920 

Cusso— Brayera . . . . . . - 921 

PomesB 921 

Cydonium — Quince 921 

Myrtaceee 922 

Caryophyllus — Cloves . . 922 

Pimenta — Allspice 923 

Cheken 923 

Oleum Myrti— Oil of Myrtle 924 

Oleum Cajuputi — Oil of Cajuput 924 

Eucalyptus — Oil of Eucalyptus 925 

Granatum — Pomegranate 926 

Papayaceae 927 

Papayotin — Papain - 927 

Cucurbltacese 927 

Colocynth 927 



xliv CONTENT'S. 

PAGB 

Eoballium — JUlaterium • • 928 

Pepo — Pumpkin 930 

Bryonia — Bryony 930 

Vmbelliferae 930 

Campylospermje 930 

Conium ... 931 

Orthospermae 932 

Asafcetida^Asafetida 932 

Galbanum 933 

Ammoniacum . 933 

Eoeniculum — Fennel 934 

Anisum — Anise 935 

Anethum— DUl 936 

Carum — Caraway 936 

Sumbul 937 

Ccelospermse 937 

Coriander 937 

Cornaceee . . . . > 938 

Cornusrr-Dogwood . . 938 



CHAPTEE XXXIV. 

Phanerogams (continued). 

Class II., Dicotsledones G-amofetal.s (ConojjjrhORm), pp. 939-1008. 

Caprifoliacese 939 

Sambucus 939 

Viburnum 939 

Rubiaceee (Cinchonaoese) 939 

Cinohonese , 939 

Cinchona Flava — Yellow Cinchona 940 

„ Bubra — Bed „ 940 

Quinine and its Salts 942 

Cinchonine 943 

Ixorese (Coffere) 948 

Ipecacuanha . . . 948 

Caffea — Coffee 950 

Catechu (Pale) _ 951 

Valerianaceae 951 

Valerian 951 

Composites „ 952 

Pyrethrum . 952 

Absinthium — Wormwood 953 

Tanacetum — Tansy 953 

Santonica — Santonin 954. 

Anthemis — Chamomile 955 

Matricaria — German Chamomile 956 

Eupatorium — Thoroughwort 955 

Taraxacum — Dandelion ggg 

Lactuca — Lettuce 957 

Arnica 957 

Calendula — Marygold 959 



CONTENTS, xlv 



PAGE 



Grindelia , 959 

Inula — Elecampane ...... . ■ , . 959 

Lappa-^Burdock 960 

Campanulaceae (Lobeliacea) 960 

Lobelia , . . 960 

Ericaceae 961 

Uva TJrsi — Bearberry ........... 961 

Chimaphila — Pipsissewa 962 

Oleum Gualtherise — 9il of Wintergreen . 962 

Sapotaceae . 963 

Gutta-percha 963 

Styraeaceae . 963 

Benzoin — Benzoic Acid 963 

OleacesB ...... 965 

Olive Oil 965 

Hard Soap 966 

Soft Soap . . . „v . • ■ ; 966 

Glycerin 966 

Manna - 968 

Apocynaceee . , 968 

Apocynum — Canadian Hemp 968 

Quebracho 969 

Asclepladaceee 970 

AsclepiaB — Pleurisy Boot 970 

Asclepias Incarnata — White Indian Hemp 970 

Hemidesmus 970 

Condurango 970 

Xoganiaceae 971 

Nux Vomica 971 

Ignatia 971 

Strychnine 972 

Curare- , 976 

Gelsemium 977 

Spigelia — Pinkroot — Maryland Pink 978 

Gentlanaceae 979 

Gentian . . . 979 

Chiretta 979 

Convolvulaceae 980 

Scammony 980 

Jalap 982 

Solanaceae . . 983 

Dulcamara 983 

Capsicum 984 

Atropeae • 984 

Belladonna — Atropine 984 

Hyoscyamus 990 

Stramonium 991 

Tobacco , . . . .992 

Scrophulariaceae 994 

Digitalis . • 994 

Leptandra 1001 

Pedalineae 1002 

-Oleum Sesami — Benne oil . . . . . . . ., . . 1002 



xlvi CONTENTS^ 

PASS 

Verbenaeeee . 1002 

Lippia Mexicana » • 1002 

Lablatee »»...... 1002 

Rosemary > » 1002 

Lavender . > 1003 

Peppermint — Menthol. 1004 

Spearmint »•.........•• 1005 

•Thymol 1005 

Hedeoma — Pennyroyal 1006 

Marrubium — Horehound 1007 

Melissa— Balm « • 1007 

Origanum — Wild Marjoram ......... 1007 

Salvia— Sage . » 1008 

Scutellaria— Skull-cap 1008 



CHAPTEB XXXV. 

Phanekogajde (continued). 
Class III., Dicotyledones Monoohlamydej3 (Apeial2e), pp. 1009-1035. 

Cnenopodlaceae 1009 

Chenopodium— Amerioan Wormseed > 1009 

Oleum Chenopodii 1009 

Pbytolaccaoeae 1009 

Phytolacca— Poke berry 1009 

Polygonaceae 1010 

Eheum— Ehubarb 1010 

Eumex— Yellow Dock 1011 

Arlstolochiaceee 1012 

Serpentary 1812 

Asarabacca 1012 

Piperaceae 1012 

Pepper— Piperine 1012 

Cubebs . 1013 

Matico 1014 

Myristlcacese 1015 

Myristica — Nutmeg 1015 

Macis — Mace 1016 

Xiaurlnese 1016 

Cinnamon 1016 

Goto 1017 

Parocoto 1017 

Camphor 1018 

Monobromated Camphor . . , 1019 

Sassafras 1020 

Nectandra— Bebeeru . . 1021 

Santalacese iQ'21 

Oleum Santali , . 102I 

Tbymelaceee 1022 

Mezereon 1022 

Euphorbiaceee 1022 

Cascarilla ... - . . . , 1022 



GOftttEKt&' xltii 

PAGK 

Stillingia . . ■ . . . . 1022 

Croton Oil - . . . . . 1023 

Castor Oil . . . 1024 

Kamala . . < 1025 

Vrtlcaceee 1025 

Ulmeee 1025 

TJlmua , 1025 

Cannabineffi . , . , . , 1026 

■ Cannabis Indica — Indian Hemp . . . ... . . 1026 

i Cannabis Americana — American Cannabis . . . . , .1026 

Hamulus — Lupulus — Hop 1027 

Mores , 1028 

Morus-^Mulberry 1028 

Artocarpeie ... . . . 1028 

Kcus— .Fig » . 1028 

Juglandaceae .„.„.„... , .1029 

Juglans — Butternut 1029 

Hqmamelaceae 1029 

Hamamelis 1029 

Balsamiflorae . . .■<*;. * ,■• • • • • • 1030 

Styrax . . . .""' . / . '/ . ... 1030 

Cupullferee ......... .... 1030 

Querous— Oak . . 1030 

Galls . . . . V 1031 

Tannic Acid . 1031 

Gallic Acid ' 1033 

Castanea — Chestnut . . 1034 

Sallcaceee . . . 1034 

Salix— Salioin 1034 



CHAPTEE XXXVl. 

PniNEKOQAM^: (continued). 

Glass IV., Monocotyledones, pp. 1036-1056. 

Orchldaceae 1036 

Vanilla 1036 

Cypripedium , . . ... . . 1036 

Scltamnaceee (Zingiberaceas) . . . 1036 

Zingiber — Ginger , . . . 1036 

Turmeric 1037 

Cardamoms 1038 

Zrldeae 1038 

Crocus— Saffron 1038 

Iris 1038 

Ullaceae 1039 

Allium— Garlic . 1039 

Convallaria . . 1040 

Squill 1049 

Aloe 1041 

Veratrum Viride . . .1045 



xlviii CONTENTS. 

PASS 

Cevadilla— Sabadjlla— rYeratrine . . . , . ... . • • 1046 
Colehicum , 1049 

MUacese (Smilaceso) . , , 1051 

Sarsaparilla 1051 

Palmacese • ......■ ...*-■ 1052 

Areea 1052 

Aroldese 1052 

Calamus^Sweet Flag - 1052 

Gramlneee ^ 1053 

Wheat— Flours-Bread— Starch 1053 

Conch Grass 1054 

Pearl Barley. 1054 

Malt 1054 

Sugar 1055 

Treacle 1055 

Oatmeal 1056 



CHAPTEE XXXVH. 

Phaneboouix (continued). 

Division II., GraxospEiiKS,' pp. 1057-1065. 

Conlferee , . 1057 

Terebinthina Canadensis — Canada Balsam 1057 

Thus Americanum — Common Frankincense 1057 

Turpentine 1057 

Oil of Turpentine . . . 1058 

Oil of Scotch Fir "... 1059 

Terebene 1060 

Sanitas 1060 

Oleum Succini — Oil of Amber 1060 

Besin . . . 1061 

Larch Bark 1061 

Burgundy Pitch 1062 

Canada Pitch 1062 

Tar 1062 

Oil of Tar .... 1063 

Thuja— Arbor Vital 1063 

' Juniper 1063 

Savin » .... 1064 



CHAPTEE XXXVIII. 

Sub-Kingdom II., Cryptogams, pp. 1066-1073. 

Fllices . 1066 

Male Fern 1066 

Mchenes 1067 

Cetraria — Iceland Moss . . . . 1067 

Litmus . . . . . ......... , . 1067 



CONTENTS. xlix 

PAGE 

rung* ....... 1067 

Muscarine ............ 1067 

Agaricus Albus . 1068 

ErgOt— Ergotin 1068 

TJstilago 1073 

Beer Yeast 1073 

Aleas 1073 

Chondrus— Irish Moss 1073 



SECTION VI. 

ANIMAL KINGDOM. 

CHAPTER XXXIX., pp. 1077-1099. 

Class Mammalia 1077 

Order Bodentia 1077 

Castor 1077 

Order Buminantia 1077 

Musk 1077 

Suet 1078 

Lanolin . 1078 

Curd Soap 1079 

Milk— Koumiss— Kephir 1079, 1080 

Milk Sugar 1080 

Pepsin 1081 

Ox Gall ... 1081 

Keratin 1083 

Order Pachydermata 1084 

Lard 1084 

Order Cetacese 1085 

Spermaceti 1085 

Class Aves . - 1085 

Order Gallinse 1085 

Egg-Albumen and Yolk 1085 

Class Pisces 1086 

Order Sturiones 1086 

Isinglass — Ichthyocolla 1086 

Order Teleosteas— Family Gadidse 1087 

Cod Liver Oil 1087 

Class Inseeta 1089 

Order Hymenoptera 1089 

Honey 1089 

Wax .... 1089 

Order Hemiptera 1090 

Coccus — Cochineal 1090 

Order Coieoptera 1091 

Cantharis — Spanish Flies 1091 

Class Annelida 1095 

Hirudo — the Leech 1095 

c 



CONTENTS. 



APPENDIX. 

PAO» 

Methylal 1097 

Urethane 1097 

Iodol 1099 

Strophanthus hispidus— Strophanthin 1099 

Dead Space 1100 

GENEEAL INDEX 1103 

INDEX OF DISEASES AND BEMEDIES 1177 

BIBLIOGBAPHICAL. INDEX . . 9 ...... . 1239 



ADDITIONS MADE IN 1890 
TO THE BRITISH PHARMACOPOEIA OP 1885. 

PAGE 

Acetanilidum (Antifebrin) (of. p. 825) [1110] 

Acetnm Ipecacuanb.se (cf. p. 949) [1114] 

Adeps LansB (Anhydrous Lanolin) (cf. p. 1078) [1116] 

Adeps Lanse Hydrosus (Lanoline) [1116] 

' Antifebrin.' See Acetanilidum 

' Antipyrine ' (p. 824). See Phenazonum 

' Blaud's Pill.' See Pilula Ferri 

Emplastrum Menthol (cf. p. 1004) [1116] 

Eucalypti Gummi (cf. p. 925) [1116] 

Euonymi Cortex (cf. p. 894) [HOG] 

' Euonymin.' See Extractum Euonymi Siccum. 

Extractum Euonymi Siccum (cf. p. 403) [1106] 

Extractum Hamamelidis Liquidum (cf. p. 1029) [1108] 

Extractum Hydrastis Liquidum (cf. p. 839) [1107] 

' Fehling's Solution.' See Solution of Potassio-Cupric Tartrate 

Gelatinum (cf. p. 1086) [1106] 

Glonoine, Solution of. See Liquor Trinitrini 

Glusidum (cf. Saccharin, p. 825) [1112] 

Hamamelidis Cortex [1108] 

Hamamelidis Folia (cf. p. 1029) [1108] 

Homatropinae Hydrobromas (cf. p. 219) [1114] 

' Huile de Cade.' See Oleum Cadinum 

Hydrastis Ehizoma (cf. p. 839) [1107] 

' Lanoline.' See Adeps Lanse Hydrosus 

Liquor Cocainte Hydrochloratis (cf. p. 877) [1113] 

Liquor Morphinffl Sulphatis (cf. p. 848) [1113] 

Liquor Trinitrini (cf. p. 788) [1115] 

Magnesii Sulphas Effervescens (cf. p. 659) [1105] 

Mistura Olei Bicini [1105] 

Nitroglycerine, Solution of. See Liquor Trinitrini 

Oleum Cadinum [1117] 

Paraldehydum (cf. p. 778) [1113] 

Phenacetinum [1110] 

Phenazonum (Antipyrine) (cf. p. 824) [1111] 

Picrotoxinum (cf. p. 842) [1114] 

Pilula Ferri [1115] 

Pulvis Sods Tartaratse Effervescens [1104] 

■ Saccharin.' See Glusidum 



lii 



CONTENTS. 



' Seidlitz Powder.' See Pulvis Sodte Tartaratas Effervescens 

Sodii Benzoas (of. pp. 78 and 964) 

Sodii Nitris (cf. pp. 331 and 788) . 

Sodii Phosphas Effervescens (of. pp. 626 and 403) 

Sodii Sulphas Effervescens (cf. pp. 625 and 403 

Solution of Potassio-Cupric Tartrate 

Stramonii Folia (cf. p. 991) . 

Strophantus (cf. p. 1099) . 

Sulphonal 

Suppositoria Glycerini . 
Syrupus Ferri Subchloridi 
Tinctura Hamamelidis 
Tinctura Hydrastis (cf. p. 403) 
Tinctura Strophanthi (cf. p. 1099) 
Trochisci Sulphuris (cf . p. 547) 
Unguentum Conii (cf. p. 932) 
Unguentum Hamamelidis (cf. p. 1029) 



[1109] 
[1115] 
[1105] 
[1105] 
[1117] 
[1114] 
[1115] 
[1113] 
[1106] 
[1116] 
[1108] 
[1107] 
[1115] 
[1104] 
[1108] 
[1108] 



MATERIA MEDICA AND THERAPEUTICS. 



B 



INTRODUCTION. 



By Materia Medica we understand a knowledge of the 
remedies employed in medicine. This knowledge may be sub- 
divided into several divisions : Materia Medica proper, Pharmacy, 
Pharmacology, and Therapeutics. 

By Materia Medica proper we mean an acquaintance with 
the remedies used in medicine, the places whence they come, the 
crude substances, plants or animals which yield them, the methods 
by which they are obtained, and the means of distinguishing their 
goodness or purity, or of detecting fraudulent adulteration. 

By Pharmacy we mean the methods by which drugs are 
prepared and combined for administration. 

By Pharmacology we mean a knowledge of the mode of 
action of drugs upon the body generally, and upon its various 
parts. It is of comparatively recent growth, but is now one of the 
most important subdivisions of Materia Medica. 

By Therapeutics we understand a knowledge of the uses 
of medicines in disease. 

Therapeutics may be either etnpirical or rational. By em- 
pirical we mean that drugs are tried haphazard, or with little 
knowledge of their action in some cases, and, being found success- 
ful, are again administered in other cases which seem to be similar. 

Perhaps the best example of the empirical use of a remedy is 
that of quinine in ague. We do not know with certainty what 
the pathological conditions are in this disease, nor how quinine 
acts upon them ; all we know is that it has proved useful in cases 
of ague before, and therefore we give it again. 

Rational therapeutics consists in the administration of a 
drug because we know the pathological conditions occurring in 
the disease, and know also that the pharmacological action of 
the drug is such as to render it probable that it will remove or 
counteract these conditions. 

Bational therapeutics is the highest branch of medicine. Its 
advance is necessarily slow, because it is based upon pathology 
on the one hand and pharmacology on the other, and both 
of these rest upon physiology, which in its turn rests upon 
physics and chemistry. It is only with the development of the 

B 2 



4 INTRODUCTION. 

fundamental sciences that those which rest upon them can grow ; 
and when we consider that chemistry as a science is not much 
more than a hundred years old, and when we see the advances 
it has already made, we cannot but be hopeful for the future of 
therapeutics. 

occasionally we hear the question asked, ' What is the use of 
knowing the action of all sorts of drugs upon the different parts 
of the animal body, and what is the use of knowing the altera- 
tions in the muscles, vessels, or nerves which occur under patho- 
logical conditions, seeing that in many instances such a know- 
ledge cannot be utilised for the treatment of disease ? ' As well 
might we ask, on seeing a half-built bridge, ' What is the use of 
laying the foundations and building the piers, seeing -no one can 
walk across from one end to the other ?•' 

As an example of rational therapeutics, we may take the use 
of nitrite of amyl in certain forms of angina pectoris. The 
obvious symptoms in this disease are intense pain in the region 
of the heart, and fear of impending death. Sphygmographic 
tracings of .the pulse taken during this condition show that the 
tension within the heart and vessels begins to increase as the 
pain comes on, and reaches such a height that the heart can 
barely empty itself. Observations on animals have shown that 
nitrite of amyl lessens the tension of the blood in the vessels ; 
and we therefore give it in angina pectoris with the expectation 
that it will dimmish the tension and remove the pain, and we find 
that it succeeds. 

But this example shows us only the first stage of rational 
therapeutics. We have removed by a remedy the pathological con- 
dition which immediately gives rise to the pain and danger of the 
patient, but the antecedent alterations of the heart, bloodvessels,' 
and nervous system, which led to the occurrence of the pain, are 
unaltered by the remedy. In order that our therapeutics should 
be completely successful, we must seek still further for something 
which will restore the circulation and nervous system to its 
normal condition and bring the patient back to a state of perfect 
health. 

Sometimes we are able to do this. For example, we oc- 
casionally meet with a kind of pain in the cardiac region which 
closely resembles angina pectoris, and is probably a form of 
it. Acting on the general principle that pain is due to irritation 
somewhere, though not necessarily at the place where the pain 
is felt, we seek for the irritant. We find swelling and tenderness 
over the sternum at the junction of the manubrium and the 
body, and we look upon this as the irritant which is exciting 
the cardiac pains. Judging this swelling to be syphilitic, 
we give iodide of potassium ; the swelling subsides, and the 
angina-like pain completely disappears. 

But sometimes it is impossible to remove the cause of the 



INTRODUCTION. 5 

disease, and all that we can do is to alleviate symptoms. 
The organic changes which have occurred in the course of the 
disease may be so great that we can hardly hope that any remedy 
will ever be discovered sufficiently powerful to remove them. We 
must therefore try to prevent them. 

Preventive medicine, or prophylaxis, is daily becoming 
more important, and, possibly before the end of this century, 
medical men will be employed more to prevent people from 
becoming ill than to cure them when disease has become fairly 
established. 

This may at least be the case in regard to the contagious and 
infectious diseases, which attack people as it were by accident, 
and are totally unconnected with their ordinary work or pleasure. 
It is too much to hope that other diseases which depend upon 
hereditary tendencies, overwork, or over-indulgence, will disappear., 
for there can be little doubt that men in the future will, as in the 
past, knowingly sacrifice, not only their health, but their life, to 
ambition, duty, or pleasure. 

The advance of this branch of medicine has been greatly 
aided by the recent increase in our knowledge of the life-history 
of microbes and their action in causing disease. Our power to 
prevent disease will become greater when we know accurately 
the action of various drugs in destroying these microbes or 
preventing their growth. 

Pharmacology has made such rapid advances of late years 
that it is exceedingly difficult for many men who are engaged in 
practice to understand thoroughly either the methods by which 
it is studied, or its results. Many students also, although they 
may be able to pass a good examination in physiology, find it 
difficult to apply their physiological knowledge to pharmacology ; 
and therefore in discussing the action of drugs upon the various 
functions of the body, I have sometimes entered more fully into 
the physiology of those functions than may seem to some at all 
either necessary or advisable. 

In discussing pharmacological questions, we are accustomed 
to speak of the action of a drug on the body or on its various 
parts ; but we must remember the effect produced is not due 
to a one-sided action — that what we actually mean is the 
re-action between the drug and the various parts of the body. 

In some instances we know that the drug itself is changed in 
the body, as well as the function of the body modified by the 
drug ; and even in those cases where the drug itself is eliminated 
from the body apparently unaltered, it is probable that it has 
entered into various chemical combinations within the body 
while circulating in the blood or present in the tissues. 



SECTION I. 

GENERAL PHARMACOLOGY AND 
THERAPEUTICS. 



OHAPTEE I. 

GENEEAL EELATIONS BETWEEN THE OEGANISM AND 
SUBSTANCES AFFECTING IT. 



In discussing the inter-action between the animal organism and 
the substances which act upon it, it may be well to take a slight 
glance first at the substances which compose its environment, 
although these will be afterwards considered more in detail. 

Of the elements composing the earth on which we live we 
at present know about seventy-two whose existence appears well- 
established. They are given in the accompanying table. The 
atomic weights assigned to them cannot be regarded as absolutely 
correct. There are sometimes considerable discrepancies between 
those given by different authorities, and those which are accepted 
to-day may require to be altered again in accordance with the 
more exact knowledge which future observations may supply. 
There are slight differences between several of them as given in 
the British and United States Pharmacopoeias. 







TABLE OF ELEMENTS. 






Element 


Symbol 


Valency or 
Atomicity 


Atomic 

Weight, 

B.P. 


Atomio 
Weight, 

r.s. P. 


Atomic Weight 

very accurately 

determined ' 


♦Aluminium • 


Al. . 


II. & IV. 


27-0 


27-0 


27-009 


♦Antimony \ 
(Stibium)/ 

* Arsenicum . 


Sb. 


in. & v. 


120-0 


120-0 


119-555 


As. 


III. & V. 


75;0 


74-9 


74-918 


•Barium 


Ba. . 


ii. 


137-0 


136-8 


136-763 


Beryllium or "1 
Glueinumj 


Be or G . 


ii. 


9-0 


9-0 


9-085 


♦Bismuth . 


Bi. 


UI.&V. 


209-0 


210-0 


207-523 


*Boron 


. 


B . 


— 


11-0 


11-0 


10-941 


' *Bramme 


. 


Br 


i. 


80-0 


79-8 


79-768 


Cadmium 


. 


Cd 


ii. 


111-8 


111-8 


111-835 


Caesium 


, 


Cs. 


i. 


133-0 


132-6 


132-583 


♦Calcium 


. 


Ca 


n. 


40-0 


40-0 


39-99 


*Cwrbon 


• 


C . 


n. & iv. 


120 


120 


11-9736 


♦Cerium 


, 


Ce. 


IV. 


141-0 


141-0 


140-424 


*Chlorme 


, 


CI. 


i. 


35-5 


35-4 


35-37 


♦Chromium 


. 


Cr. 


n. & iv. 


52-S 


52-4 


52-009 


Cobalt 


• 


Co. 


n. & iv. 


58-9 


58-9 


58-887 



Those marked with ♦ are contained, either simply or in combination, in the 
British Pharmacopoeia. Those printed in italics are non-metallic elements. Their 
atomio weights are given as in the B. P. 

1 From Ira Bemsen's Principles of Theoretical Chemistry. 



10 PHABMACOLOGY AND THEEAPEUTICS. [sect. i. 

TABLE OF ELEMENTS— continued. 







Valency or 
Atomicity 


Atomic 


Atomic 


Atomic Weight 


Element 


Symbol 


Weight, 
B.P. 


Weight, 
U.S. V. 


very accurately 
determined 


Columbium vide 












Niobium 












"Copper (Cuprum) 


Cu. 


II. 


63-4 


63-2 


63-173 


Didymium . 


Di. 


rv. 


145-4 


144-6 


145-4 


Erbium 


ErorEb 1 
orE 

F . 


— 


166-0 


165-9 


165-891 


Fluorine . 


i. 


19-0 


19-0 


18-984 


Gallium 


Ga 


IV. 


70-0 


68-8 


69-9 


♦Gold (Aurum) . 


Au 


i. & in. 


196-5 


196-2 


196-155 


Glueinum vide 












Beryllium 












Holmium . 


. . 





— 








*Hydrogen . 


B . 


i. 


1-0 


1-0 


1-0 


Indium 


In. 


i. & in. 


113-4 


113-4 


113-398 


*Iodime 


I . 


i. 


127-0 


126-6 


126-557 


Iridium 


Ir . 


II. & IV. 


192-7 


192-7 


192-651 


♦Iron (Ferrum) . 


Fe. 


II. & IV. 


56-0 


55-9 


55-913 ■ 


Lanthanum 


La. 


IV. 


139-0 


138-5 


138-526 


*Lead (Plumbum) 


Pb. 


II. & IV. 


207-0 


206-5 


206-471 ' 


*Lithium 


Li. 


I. 


7-0 


7-0 


7-0073 ■ 


♦Magnesium 


Mg 


II. 


24-0 


24-0 


23-959 


*Manganese 


Mn 


II. & IV. 


55-0 


54-0 


53-906 


^Mercury \ 
(Hydrargyrum) / 


Hg 


II. 


200-0 


199-7 


199-712 


Molybdenum 


Mo 




95-5 


95-5 


95-527 


Nickel 


Ni. 


II. & IV. 


58-0 


58-0 


57-928 i 


Niobium or "1 
Columbium/ 


Nb 


V. 


94-0 


94-0 




*Nitrogen . 


N . 


III. & V. 


14-0 


14-0 


14-021 


Osmium 


Os. 


II. & IV. 


198-5 


198-5 


198-494 


* Oxygen 


. 


II. 


16-0 


16-0 


15-9633 


Palladium . 


Pd. 


II. & IV. 


105-7 


105-7 


105-737 


*Phosphorus 


P . 


III. & V. 


31-0 


31-0 


30-958 


♦Platinum . 


Pt. 


II. & IV. 


195-0 


194-4 


194-415 


♦Potassium 1 
(Ealium) / 












K . 


I. 


39-0 


39-0 


39-019 


Bhodium . 


Eh 


H. & IV. 


104-0 


104-1 


104-055 


Bubidium . 


Bb 


I. 


85-3 


85-3 ' 


85-251 


Buthenium 


Eu 


II. & IV. 


104-2 


104-2 


104-217 


Samarium . 


Sm 


— 


150-0 




150-021 


Scandium . 


Sc. 


— 


44-0 


44-0 ' 


43-98 


Selenium . 


Se. 


II. 


78-8 


78-8 


78-797 


Silicon 


Si. 


IV. 


28-0 


28-0 


28-195 


♦Silver (Argentum) 


Ag. . 


I. (? II.) 


108-0 


107-7 


107-7 


♦Sodium(Natrium) 


Na 


I. 


23-0 


230 


22-998 


Strontium . 


Sr. 


II. 


87-4 


87-4 


87-374 


*Sulphur . 


S . 


II. 


32-0 


32-0 


31-984 


Tantalum . 


Ta. 


III. & V. ' 


182-0 


182-0 


182-144 


Tell/wrium . 
Terbium . 


Te. 


n. 


128-0 


128-0 


127-96 


Thallium . 


Tl or Th' 


III. 


203-7 


203-7 


203-715 


Thorium . 


Th 


IV. 


233-0 


233-0 


233-414 


Thulium . 


• 


— 1 


— 







1 Er, Boscoe and Schorlemmer, Treatise on Chemistry, vol i p 54 Eb 
PbWneB, edited by Watts, 12th ed. vol. i. p. 401. E, Ira Bemsen's Principles of 
Theoretical Chemistry. 



CHAP. I.] 



GENEEAL EELATIONS. 



11 





TABLE OF ELEMENTS— continued. 




Element 


Symbol 


Valency or 
Atomicity 


Atomic 

Weight, 

B.P. 


Atomic 
Weight, 
U.S. P. 


Atomic Weight 

very accurately 

determined 


*Tin (Stannum) . 
Titanium . 
Tungsten ■ 
Uranium . 
Vanadium . . 
Ytterbium . 
Yttrium , 
*Zinc . . 
Zirconium . . 


Sn. 
Ti. 
W. 
U . 
V . 
Yb. 

y . 

Zn 
Zr. 


II. & IV. 
IV. 
VI. 

IV. & VI. 

III. & V. 

IV. 

II. 

IV. 


118-0 
49-8 

184-0 

240-0 
51-3 

172-8 
89-8 
65-0 
90-0 


117-7 
48-0 

183-6 

238-5 
51-3 

172-7 
89-8 
64-9 
90-0 


117-698 
49-846 

183-61 

239-8 
51-256 

172-761 
89-816 
64-9045 
89-367 



Nature of the Elements. 

Considerable additions have been made to the number of elements during 
late years. The reason of this is that the spectroscope has indicated the 
presence of metals previously unknown, and by the use of proper means they 
have been obtained in a separate condition. These substances are termed 
elements because we do not at present know how to split them up in such a 
manner as to prove that they are compounds. But it is not improbable that 
they are compounds, just as we now know that potash and soda are com- 
pounds ; although before Sir Humphry Davy split them up into oxygen and 
a metal they were supposed to be elements. Indeed, recently much evidence 
has been brought to show that the substances which we call elements are 
really compounds. 

It is from an examination of the spectroscopic character of the elements 
at different degrees of temperature that Lockyer has been able to obtain 
sufficient data to justify the definite formulation of the hypothesis that 
all the elements we know are really compounds, or, to speak perhaps more 
precisely, are really different forms of aggregation of one kind of matter. 1 
According to this hypothesis the matter of which the universe is composed 
was at one time equally distributed through space, and uniform in kind. 
The atoms then coalesced in various groups of two, three, or more; and 
these, again grouping themselves together still further, formed aggregates of 
more and more complex composition. These aggregates are, it is supposed, 
the elements with which we are acquainted. Most of those complex mole- 
cules are perfectly stable at ordinary temperatures ; and so their composition 
remains constant under the conditions usual at the surface of this earth. 

But when they are subjected to increased temperatures in the laboratory, 
rising from that of the Bunsen lamp to the electric arc, and then to the 
electric spark or to still higher temperatures in the sun, their spectroscopic 
appearances give evidence of decomposition into simpler molecules. When 
the elements are subjected to cold and pressure the molecules which compose 
them come closer together, and we get them forming a solid substance. Heat 
tends, by communicating vibrations to them, to shake the molecules further 
apart, and to produce a liquid condition. Still' greater heat shakes the 
molecules further apart still, and produces a gaseous condition. 

In all those conditions the molecules of the element become more complex 
by reduction of temperature or increase of pressure, and simpler by increase 
in temperature or reduction in pressure. 2 Exceedingly* great heat or elec- 
tricity appears to shake apart still further the constituents of the element, so 
as to resolve it into simpler combinations of the elementary substance of 
which, according to the hypothesis, it is composed. 

This shaking apart of the component elements is known to exist in com- 

1 Lockyer, Phil. Trans. 1874, p. 492 et seq. 

2 According to another hypothesis, bodies are supposed to have molecules of one 
degree of complexity, and the difference between solid, liquid, and gaseous bodies is 



12 



PHAKMACOLOGY AND THEBAPEUTTCS. [sect. i. 



pounds, and to it the name- of dissociation has been given. Thus when 
chalk or limestone is exposed to the action of heat it becomes dissociated 
into carbonic acid and lime, CaCO s = CaO + C0 2 . This process is readily re- 
versible by reversing the conditions. Thus the Erne and carbonic acid which 
are dissociated by heat readily recombine in the cold CaO + C0 4 = CaCO s . 

When matter is solid the molecules of which it is composed are sup- 
posed to be large and close together. When in the state of vapour or gas, 
these molecules are smaller and much further apart. 

Solid, liquid, or densely gaseous matter, when its molecules are agitated 
by heat, gives a continuous spectrum. Gaseous and vaporous matters, when 
their molecules are agitated at lower pressures or higher temperatures by 
heat or electricity, give a discontinuous spectrum consisting of bands or lines. 

Between those extremes we have, as a rule, three other intermediate 
kinds of spectra : first, a continuous spectrum in the red ; next, a continuous 
spectrum in the blue ; next, a fluted spectrum, and after thatthe line spectrum 
already mentioned. 

In all those kinds of spectrum, however, we are supposing that the ele- 
mentary molecules are still' intact ; they are only more or less separated. 

Compound bodies, like simple bodies, give definite spectra. The 
spectrum of a simple metal consists of lines which increase in number and 
thickness as the pressure of the vapour or its quantity in a given space is 
increased. The spectrum of a compound body consists chiefly of channelled 
spaces and bands which increase in the same manner. The greater the number 
of molecules in a cubic inch or cubic millimetre, and the more violently they 
are agitated, the more complex is the spectrum until it becomes continuous. 

The smaller the number of molecules in a given space, the more simple is 
the spectrum, which then consists of a few lines only. 

When a compound is exposed to heat, so as to dissociate it into its com- 
ponent parts the spectroscopic bands characteristic of the compound become 
thinner, and the lines of the metal increase in number, as shown in the 
accompanying diagram where the bands exhibited by calcium chloride in the 
flame of a Bunsen's burner, disappear, and are replaced by lines only, when 



4 - 


11 






' III III 





Fia. 1.— Spectrum of calcium chloride. (1) In the flame of a Bunsen's burner, showing the 
channelled spaces and bands of a oompound. (2) In an electric spark, showing the lines of 
the element calcium. (After Roscoe.) 

an electric spark is used. When an element is treated with more and more 
heat and electricity it likewise gives exactly the same kind of evidence of 
dissociation— bands disappearing, and lines becoming thinner. Besides this, 
new lines make their appearance with every large increase of temperature. 

This behaviour of the element appears to show that it also is a compound, 
but that it is stable under ordinary conditions, and is only dissociated at a 
high temperature. 

, Other proofs of this hypothesis are derived from a comparison of the spectra 
of the elements as observed in our laboratories with their spectra in the sun. 

A comparison «of the two hypotheses shows us that as on the old 
hypothesis each element represents a specjes and is unvariable, its spec- 
trum ought to be always the same in our laboratories and in the sun : and 
the same in sun-spots as in prominences, and the same at all periods of the 
sun's activity. 

supposed to depend on the difference in the free path of the molecule. But accord- 
ing to the new view, the difference in the complexity of the molecule itself is sufficient 
to explain the phenomena. 



qhat. i.] GENEEAL RELATIONS. 13' 

Under the new hypothesis the spectra off metals in our laboratories and 
in the sun should not resemble each other ; they should be different in sun- 
spots and in prominences, because the spot is cooler than the' prominence; 
and they should vary at the time of the sun's activity because the sun is 
hotter at the maximum of the sun-spot period, and therefore there should be 
a greater amount of dissociation amongst the elements at that period. 

As a matter of fact we find that the spectra in our laboratories and in the 
sun do not resemble each other (Fig. 2) ; that those of the same element 



m 



B 



FEEBLE S PARK 



Fig. 2. — Diagram of the spectrum of lithium under various conditions of temperature. 
(After Lockjer, Boy. Sac. Proa. Deo. 12, 1878.) 

m the sun-spot and prominences are as dissimilar as of any two elements ; 
and that the spectra of the elements in the sun do vary with the maximum ? 
of the sun-spot period. 

On the old hypothesis the spectra of prominences should also consist of 
lines familiar to us in our laboratories, because solar and terrestrial elements 
are the. same, while, according to the new hypothesis, the spectra of promi- 
nences should be unfamiliar, because the prominences represent outpourings 
from a body hot enough to prevent the atoms of which our elements are 
composed from coming together. 

As a matter of fact, the lines in the prominences, with the exception of 
those of hydrogen, magnesium, calcium, and sodium, are either of unknown 
origin, or are feeble lines in the spectra of known elements. Spectroscopic 
observation, therefore, leads to the belief that the so-called elements are 
really compounds, the component parts of which are kept apart by high 
temperatures in the sun and stars, but unite when the temperature decreases. 

By the powerful vibrations imparted to them by the electric spark, they 
may be dissociated in the laboratory ; but, as no means has yet been devised 
of separating the components, they again unite to form the original body, 
just as hydrogen and oxygen, into which steam is dissociated by passing it 
through a strongly heated tube, almost instantly combine again to form water 
unless they are separated by means of the more rapid diffusion of hydrogen 
through a porous tube. 

The difficulty in accepting this evidence lies in the fact that we have 
hitherto been unable to isolate the substances into which the elements are 
supposed to be dissociated: as these after their dissociation at once recombine 
and again form the original substance. 

One proof, however, that the supposed components of the element calcium 
may remain permanently separated, is afforded by the fact that in the 
spectra of two stars, Sirius (Fig. 3) and a Lyrse, which are very bright, and 
probably very hot, only one of the ultra-violet lines of calcium is represented. 



1 AFU 
FLfl 



Fig. 3. — Diagram of the speotrum of calcium under various conditions of temperature. In the 
spectrum of Sirius the line K is absent, while it is very strongly marked in the solar spectrum. 

But we have also other evidence of the compound nature of the elements, 
which, although it was not sufficient of itself to force us to abandon our old 
ideas of their simple nature, is yet strongly corroborative of the spectroscopic 
evidence. Thus we find that oxygen is broken up by electricity, and that 
the atoms of which its molecules are composed, rearrange themselves 
so as to form what is to all intents and purposes a new element, ozone, 
having a much closer resemblance to chlorine than to oxygen in its activity, 



14 



PHARMACOLOGY AND THEEAPEUTICS. [sect. i. 



although its compounds with metals appear to be identical with those 
of oxygen. • 





Fig. 4. — Diagram to Illustrate the formation of ozone by electricity, a represents oxygen, through 
which a spark is passing ; & after it has passed. The double rings are intended to represent 
molecules of oxygen, each containing two atom3. As the electric spark passes through the 
oxygen it breads up the first molecule, carrying one atom on to join the second molecule of 
oxygen, and form one of ozone. The atom which is left joins another molecule of oxygen, and 
also forms ozone. (After Lockyer.) 

At a high temperature its atoms are again dissociated, and recombine to 
form ordinary oxygen. When it combines with other substances, the heat 
of combination appears to be sufficient to dissociate the atoms of ozone (Oj), 
so that in the compound we meet with simple oxygen, O. 

When sulphur is simply melted and cooled, it solidifies as a yellow 
brittle substance, but if it is heated to 200° it becomes brownish and thick, 
and if it be suddenly cooled, by throwing it into water, it solidifies as a trans- 
parent reddish plastic and elastic substance. The ordinary brittle and 
yellow, and the reddish plastic sulphur, appear to be quite different sub- 
stances. But if the plastic sulphur be left for some hours, it becomes re- 
converted into ordinary sulphur ; and if either ordinary or plastic sulphur 
be volatilised, the vapour condenses in the form of ordinary sulphur ; but if 
the vapour is quickly cooled, the sulphur, while retaining its ordinary appear- 
ance, may yet undergo a certain change evidenced by its becoming insoluble 
in bisulphide of carbon. On the new hypothesis we explain these phenomena 
by supposing that the different forms of sulphur are 'different compounds, or 
perhaps we should rather say different aggregates, for their components may 
not differ in kind like those of calcium, but only in number like those of 
oxygen or ozone. 

Indeed we are almost driven to such a conclusion by the behaviour of 
sulphur in regard to its vapour density, for only at very high temperatures does 
the specific gravity of the vapour follow the general rule, and at lower tem- 
peratures it is three times as great as it ought to be, indicating that at these 
lower temperatures the molecule of sulphur contains six atoms instead of two. 

Phosphorus also affords us an example of an element which occurs in 
two forms, so different that we should call them distinct bodies, were it not 
that we find that one can be transformed into the other. 

The two forms, red and yellow phosphorus, differ from each other, not 
only in their colour, but in their density, specific heat, readiness of com- 
bustion, and heat of combustion. They differ also in the fact that yellow 
phosphorus is exceedingly poisonous, whereas the red phosphorus is not 
poisonous. They are in many respects, then, different bodies, but we have 
hitherto been content to call them allotropic forms of the same element. 

In combination we find that phosphorus is sometimes pentad and sometimes 
triad ; that its compounds with oxygen are sometimes poisonous, at other times 
not. Thus orthophosphoric acid, H 3 P0 4 , is not poisonous ; pyrophosphorio 
acid, H 4 P 2 0,, and metaphosphoric acid, HPO s , are both poisonous. 

The most striking example, however, is carbon, which we not only find 



chap, i.] GENEEAL EELATIONS. 15 

in three forms, differing enormously from each other, as diamond, charcoal, 
and graphite, but which we find in various compounds playing the most 
varied parts. This we at present explain by saying that carbon unites with 
itself in the formation of the various radicals ; and thus comes to form what ' 
are practically new elements. 

Another example is afforded us by ammonia, the salts of which are just as 
well characterised as those of potash or soda. The amalgam which it forms 
with mercury possibly indicates that we have in it also a real metal, 
ammonium, corresponding to sodium or potassium, though thiB is uncertain. 

The three metals, sodium, potassium, and ammonium (if it exist), agree in 
the readiness with which they are oxidised, so that it is difficult to preserve the 
•.tire metal, although the oxide is stable. They differ, however, in the oxides 
of potassium and sodium being solid, and that of ammonium gaseous. 
Ammonium has not been isolated, and it is put down in the text-books as a 
hypothetical substance, but ammonium salts are tangible enough, and the 
question which we have to keep before us is, whether potassium, sodium, 
and all the other so-called elements, are not in reality compounds like 
ammonium. 

Some people still regard species as immutable, and look upon Darwin's 
hypothesis of evolution as unproven. 

The evidence in favour of the evolution of elements from one simple form 
of matter, is as yet, perhaps, much less strong than that in support of the 
evolution of species ; but the hypothesis has this advantage, that it explains 
certain phenomena which have hitherto been very perplexing. 

It may be at least convenient in discussing the physiological action of 
drugs to bear this hypothesis in mind, and to remember that what we have 
hitherto been accustomed to call elements may be really constituted like the 
so-called organic radicals, with this difference, that we can split up organic 
radicals with tolerable facility, while we cannot do this — at least to any great 
extent — with elements. 

It also shows us that we must as pharmacologists pay attention to 
molecular as well as to empirical composition, and take into consideration 
crystalline form and physical aggregation in all observations regarding the 
relations between elements or compounds and living organisms. It is not 
sufficient, for example, to speak of the action of phosphorus on the organism 
as if this were invariable, for.it varies with the molecular composition of 
the body in the red or yellow form, and isomeric organic substances may be 
utterly different in action. 

Classification of the Elements. 

The vegetable and animal kingdoms are divided into various groups. 
Formerly, men tried to arrange them in linear succession so that there should 
be an unbroken line from the lowest to the highest members of the vegetable 
kingdom, thence to the lowest member of the animal, and onwards up to the 
highest member of the animal kingdom. Such an arrangement as this, 
however, was found to be unnatural. Instead of the highest members of the 
vegetable kingdom being connected with the lowest members of the animal 
kingdom, it is found that the lowest members of each kingdom are closely 
connected and that the divergence becomes greater as development proceeds 
towards the highest members in each kingdom. The doctrine of evolution 
at once rendered this arrangement natural and easily understood. 

Starting from one common point of origin in structureless protoplasm, 
the various organisms became more and more unlike in each successive stage 
of development, their resemblance being only recognisable at all in their 
embryonic condition. 

Various attempts have been made to arrange inorganic substances in 
natural orders. One mode of arrangement is according to their atomic 
weight — as in the following table : — ' 

1 In this and the following Tables the atomic weights have been corrected. 



10 



PHARMACOLOGY AND THEEAPEUTICS. [sect. i. 





a 






ft 






1 






1 




1 




!s 

a 

a 
1 


d 

M 

0) 

a 


t 

a) 

1 


s 

1 


1 

W 
P 


13 

1 


<a 

1 


a 
Si 

a 


1 
a 


! 

5 


o 

a 

V 
-M 

w 

5 


H 


l 




K 


39 


3-5 


Y 


89-8 


2-4 


Ce 


141 


2 


Li 


7' 


6 


Ca 


40 


1 


Zr 


90 


0-2 


Di 


145-4 


3-6 


Gor, 
Be ! 






Ti 


49-8 


9-8 


Nb 


94 


4 


Ta 


182 


36-6. 


9 


2 


V 


51-3 


1-5 


Mo 


95-5 


1-5 


W 


184 


2 


B 


11 


2 


Cr 


62-5 


1-2 


Eh 


104 


8-5 


Ir 


192-7 


8-7 





12 


1 


Mn 


'55 


2-5 


Eu 


104-2 


0-2 


Pt 


195 


2-3 


N 


14 


2 


Fe 


56 


1 


Pd 


105-7 


1-5 


Au 


196-5 


1-5 





16 


2 


Ni 


58 


2 


Ag 


108 


2-3 


Os 


198-5 


2 


m 


19 


3 


Co 


58-9 


0-9 


Cd 


111-8 


3-8 


Hg 


200 


1-5 


Na 


23 


4 


Cu 


63-4 


4-5 


Sn 


118 


6-2 


Tl 


203-7 


3-7 


Mg 


24 


1 


Zn 


65 


1-6 


Sb 


120 


2 


Pb 


207 


4 


Al 


27 


3 


As 


75 


10 


I 


127 


7 


Bi 


209 


3 


Si 


28 


1 


Se 


78-8 


3-8 


Te 


128 


1 


Th 


233 


24 


P 


31 


3 


Br 


80 


1-2 


Cs 


133 


5 


U 


240 


V 


S 


32 


1 


Bb 


85-3 


5-3 


Ba 


137 


4 








CI 


35-5 


3-5 


Sr 


87-4 


2-1 


La 


139 


2 1 


1 





From this it will be seen that the atomic weights of the different elements 
form a series, the members of which in most cases differ from one another by 
1, 2, 3, or 4. There are few exceptions in which the differences are much 
greater, and these probably represent blanks which may yet be Med up as our 
knowledge of the elements increases. This mode of classification, however, 
reminds us of the Linnsean system in plants, and is artificial rather than 
natural. In it, the elements which are placed, close together possess very 
different properties, whereas those which are separated from each other 
present considerable resemblances. 

Newlahd's Tablb. 







Difference 


Member of a Group 
having Lowest Equivalent 


One immediately above 
the preceding 














H = I 


= 1 


Magnesium . 24 


Calcium . . 40 


16 


1 


Oxygen . . 16 


Sulphur . . 32 


16 


1 


Lithium . . 7 


Sodium . . 23 


16 


1 


Carbon . . 12 


Silicon . . 28 


16 


1 


Fluorine . . 19 


Chlorine . . 35-5 


16-5 


1-031 


Nitrogen . . 14 


Phosphorus . 31 


17 


1-062 


Lowest term of Triad 


Highest term of Triad 






Lithium . . 7 


Potassium . 39 


32 


2 


Magnesium . 24 


Cadmium . 112 


88 


5-5 


Molybdenum . 96 


Tungsten . 184 


88 


5-5 


Phosphorus . 31 


Antimony . 120 


89 


5-687 


Chlorine . . 35-5 


Iodine . . 127 


91-5 


5-718 


Potassium . 39 


Caesium . .141 


102 


5-875 


Sulphur . . 32 


Tellurium . 128 


96 


6-062 


Calcium . . 40 


Barium . . 137 


97 


6-062 



CHAP. I.j 



GENERAL RELATIONS. 



17 



The first important attempt at a natural classification of the elements 
•was made by Newlands in 1864. 1 He then arranged them in groups, be- 
tween the members of which there was a close connection in regard to their 
chemical properties, and a curious relation in regard to their atomic weights. 
These presented differences which were generally multiples of the atomic 
weight of hydrogen, and generally equal to, or multiples of, that of oxygen. 

A curious relationship had also been pointed out by M. Dumas 2 between 
the members of the potassium group, their atomic weights being equal to 
multiples of those of lithium and potassium added together. 

7 + 39 = 46 

7 + 78 = 85 



Li + K = 2Na, or in 

Li + 2K = Eb 
2Li + 3K = Cs (133) ' 

Li + 5K = Tl (203-7) 
3Li + 5K = 2Ag 



14 + 117 = 131 

7 + 195 = 202 

21 + 195 = 216 



A similar relation was also pointed out by Mr. Newlands between lithium 
and the calcium group ; as follows : — 

Li + Ca = 2Mg (48), or in figures, 7 + 40 = 47 

Li + 2Ca = Sr „ 7 + 80 = 87 

2Li + 3Ca = Ba (137) „ 14 + 120 = 134 

Li + 5Ca = Pb „ 7 + 200 = 207 

But Mr. Newland's most important table is the following one, in which 
he has arranged the elements in ten series : — 









Triad 




Lowest 


Mean 


Highest 








term 


term 




I. 




Li 7 


+ 17 =Mg24 


Zn 65 


Cd 111-8 




II. 




B 11 








Au 196 


III. 




C 12 


+ 16 =Si 28 




Snll8 




IV. 




N 14 


+ 17 = P 31 


As 75 


Sb 120 


+ 88=Bi 210 


V. 




O 16 


+ 16 =S 32 


Se 78-8 


Tel28 


+ 70 = Os 199 


VI. 




F 19 


+ 16-5 = C1 35-5 


Br 80 


I 127 




VII. 


Li 7 


+ 16 = Na 23 


+ 16 =K 39 


Bb 85-3 


Cs 133 


+ 70 = T1 203 


VIII. 


Li 7 


+ 17 = Mg24 


+ 16 =Ca40 


Sr 87-4 


Bal37 


+ 70 = Pb 207 


IX. 






V 51-3 




W 184 




X. 






Mo 95-5 
Pdl05-7 




Pt 195 





Seven of these series nearly correspond in their first members with those 
of Mendelejeff, to whom and to Lothar Meyer we owe the complete develop- 
ment of this mode of classification. Mr. Newlands also pointed out that the 
eighth element starting from a given one, was a kind of repetition of the first, 
like the eighth note of an octave in music. 4 

Mendelejeff has not only greatly developed this system of classification, 
but has afforded convincing proof of its value by not only predicting the 
existence of an unknown element, but actually describing its physical cha- 
racters and chemical reactions — a prediction the correctness of which was 
proved by the discovery of gallium, and by the agreement of its characters 
and reactions with those which Mendelejeff had foretold. 

The various members of the animal kingdom can all be arranged in a few 
series : Protozoa, Coelenterata, Annuloida, Annulosa, Molluscoida, Mollusca, 
and Vertebrata. These series all differ more or less from one another,, but a 

1 Newlands, Chemical News, July 30, 1864. 
s Dumas, quoted by Newlands, op. cit. 

* The newer atomic weights of Cs, Fl, Mg, and Ba do not correspond so 
exactly as their old ones with the sum of the other elements. 

* Chem. News, Aug. 20, 1864, p. 94. 

C 



18 PHAKMACOLOGY AND THEBAPEUTICS. [sect, u 

certain agreement is observed between their members, and similarly the 
elements may be arranged in series. 

Mendelejeff points out, that if we take those elements having the lowest 
atomic weight, and omit hydrogen, between which and lithium there is a great 
gap, the seven elements, lithium, glucinum, boron, carbon, nitrogen, oxygen, 
and fluorine, may be regarded as typical elements forming a series repre- 
senting the lowest members of seven groups. The next seven elements may 
be arranged in a similar way : — 

Li = 7 : G = 9-4 : B = 11 : C = 12 : N = 14 : = 16 : F = 19 : 
Na = 23 : Mg = 24 : Al = 27 : Si = 28 : P = 31 : S = 32 : CI = 35-5. 

To each group of seven elements Mendelejeff gives the name of a small 
period or series. In each series the characters of the elements vary gra- 
dually and regularly as their atomic weights increase. This variation is 
periodical, i.e. varies in the same way in each series, so that the elements 
which have corresponding places in each series, correspond also to a certain 
extent in their properties, and form similar compounds. The atomicity is 
least in the first, and greatest in the last members of each series. Thus the 
first members of the series form monochlorides, the second dichlorides, the 
third trichlorides, and so on. 

In the accompanying table B represents radical or element, and B' indi- 
cates that the element is monatomic, so that one atom combines with one of 
CI to form a monochloride, BC1. E" indicates that the element is diatomic, 
and so on. 

But a difference is to be observed between the even and the uneven series. 
Corresponding members of even series, such as the fourth and sixth, agree 
with each other, and members of uneven series like the fifth and seventh agree. 
This agreement is greater than between the members of an even series, such 
as the fourth, and those of an uneven series like the fifth, although the fifth 
is more closely placed to the fourth than the sixth is. Thus Ca and Sr 
belonging to the fourth and sixth series have a greater resemblance to each 
other than they have to Zn or Cd, which belong to the fifth and seventh series, 
and these metals on the other hand have a greater resemblance to each other 
than they have to Ca or Sr. The members of even series are less metalloidal 
or more metallic than those of uneven series, e.g. Mn of the fourth series is 
less metalloidal than Br of the fifth series. In the even series the metallic 
or basic character predominates, whilst the corresponding members of the 
uneven series rather exhibit acid properties. The members of the even series, 
so far as we know, form no volatile compounds with hydrogen or alcohol 
radicals, while the corresponding members of the uneven series do form such 
compounds. 

< The last members of the even series resemble in many respects (in their 
lower oxides, etc.), the first members of the uneven series; thus chromium 
and manganese in their basic oxides are analogous to copper and zinc. But 
there are great differences between the last members of the uneven series 
(haloids), and the first members of the next even series (alkali metals). Now 
between the last members of the even series there occur, according to the 
order of atomic weights, all those elements which cannot be included" in the 
small periods. Thus between Cr and Mn in the one series, and Cu and Zn 
in the next, there come the elements Fe, Co, Ni, and in a similar way after 
the sixth series come Eu, Eh, Pd, and after the tenth Os, Ir, Pt. Mendelejeff 
gives the name of a long period to two such series with three intervening 
members, forming seventeen in all. 

From the difficulty of arranging all the elements in this system, it cannot 
be regarded as yet perfect, but the fact that Mendelejeff was able so correctly 
to foretell the properties of gallium, shows that it must contain a large ele- 
ment of truth. At the time that he drew up his table there was a blank in 
the third group of the fifth series. 

The relationships of the metal which Mendelejeff believed would fill this 



CHAP. I.] 



GENEBAL RELATIONS. 



19 



jiff 

g Stf 

S 




Fe = 56 Co = 54 
Ni = 59 Cu* = 63 

Eu = 104 Eh = 104 
Pd = 106 Ag* = 108 

Os = 199 Ir = 193 
Pt = 195 Au*= 196 


S 


rH 

ft 


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ife 00 M I 1 

m » « 7 

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rH W PC| rH rH 

O .1 , 

a l 1 1 1 


0.H00 

g^Srt 
3 


CD 
rH 

a 
o 


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CO t> CM | | 

«, K » O rH g 

1 o " I' 

O S | £ P 


>* . - . 
&M°„3 

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ii 

S3 


iH W3 <M | 00 
CO t> <N I O 

ii ii 7 „ 7 

a, to ;# II CO " 

" rH <j OS ,a rH -~ 
"? II » II ^ 

> S3 1 Eh I 


o.Woi> 

grtSrt 
3 


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II 
O 


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IN t- rj 1 i 
li 11 ° o 
II " B "* o « »-< 

a % i § * 7 s ii a 
n ii m I H g ii 

EH N c- A EH 


o" s " 

g Hrt 
S 


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i-t 

II 

M 


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11 -hi H_ "> " "* J- II 

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1 c «- £ 1 


■r4 

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3 


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II 

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s 


TH TO IN | O 

IN CO rH ,| O 

rH |>. CU 

II II ,, °» .1 
O t- II rH || 

bo -«# fl m 

a ii N ii o s w 
a £ w 1 1 


§• °.3 

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II 

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S 3 1 s 
" ii « ii s? — ii 

m as ! i 


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rH IS 


cQ^iacot^coooi-icq 






pre 

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gfr^ 

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c 2 



29 PHAEMACOLOGY AND THEEAPEUTICS. [sect. i. 

gap will be more easily seen by omitting the even series on either side of it, 
and taking only the odd series with which it will, as already mentioned, the 
more closely correspond. 



Series. 


Group IT. 


Group III. 


Group IV. 


Group T 


3 


Mg 


Al 


Si 


P 


5 


Zn 


— . 


— 


As 


7 


Cd 


In 


Sn 


Sb 



.As it stands between zinc with an atomic weight of sixty-five, and arsenic 
with one of seventy -five, while it is separated from the latter by a blank, its 
atomic weight must be about sixty-eight. As it is atom -analogous with Al, 
its salts should have a similar constitution. It should form an oxide x 2 3 , 
and a sulphide x 2 S s . It will be precipitated from its solution by ammonium 
sulphide. The metal should be easily reduced by carbon or sodium, it should 
have a specific gravity of 5'9, and decompose water at a red heat. As it be- 
longs to an odd series, it should, like zinc, form volatile compounds with 
organic radicals, and form also anhydrous chlorides. 

On the discovery of the metal gallium, it was found to agree in almost 
every respect with the prediction of Mendelejeff, and this fact is not interest- 
ing to chemists only, but also to pharmacologists. For the great object of 
pharmacology is to obtain such a knowledge of the relations between the 
physical and chemical characters of bodies, and their actions upon the living 
organism, that we may be able to predict their actions with certainty, and 
to know the modifications which alterations in their physical and chemical 
characters will produce on their physiological action. 

Mendelejeff s present classification is imperfect, because we find that by 
it the members of some natural groups, such as those of the earthy metals, are 
separated from one another, although they agree in their chemical characters. 

We find also that metals having similar pharmacological actions, as 
copper, zinc and silver, do not fall naturally together in this arrangement. 
But, on the other hand, we find also that by this classification, elements are 
brought .together which do not at first seem to have any resemblance to each 
other, and are yet found by recent investigations to have a physiological con- 
nection. Thus mercury and calcium do not appear to resemble one another, 
yet Prevost has shown that, in acute poisoning by mercury, the calcareous 
matter disappears from the bones, and in the process of elimination by the 
kidneys produces calcification of these organs. 1 

Organic Radicals.— Whether the so-called elements be 
compounds or not, it is certain that several of them have the 
power of uniting with themselves and with others in such a 
way as to form bodies called compound radicals which resemble 
elements in many respects. These groups of atoms may enter 
into and again pass out of combination with other substances, 
just as elements do. 

For example, when compounds of the elements unite, an 
interchange of elements takes place. Thus when calcium oxide 
(CaO) and hydrochloric acid (HC1) combine, the oxygen leaves 
the calcium to combine with the hydrogen and form water, while 
the chlorine leaves the hydrogen and combines with the calcium 
to form calcium chloride. 

CaO + 2HCl = CaCl 2 + H 2 0. 



1 Prevost, Eevuo MMicale de la Suisse Bomande, p. 553, Nov. 15 • t> 605 
Dec. 15, 1882 ; p. 5, Jan. 15, 1883. ' *" ' 



CHAP. I.] 



GENEEAL EELATIONS. 



21 



But when ethylic alcohol (C ? H 6 0) is treated with hydrochloric acid 
(HC1), it is not oxygen which leaves the alcohol and is replaced 
by chlorine. The alcohol does not split up into the group C 2 H 6 
and the element oxygen, but into the two groups OH and C.JI S . 

C 2 H 6 + HC1 = C 2 H a Cl + H 2 ; 
or, as it may also be represented — 

(^^)@) + hci = C5?T) ci+H ©■ 

To the group OH the name of hydroxyl has been given, and 
to the group C 2 H 5 that of ethyl. 

Similarly, when acetic acid (C 2 H 4 2 ) is treated with phos- 
phorus trichloride (PC1 3 ) the three atoms of chlorine leave the 
phosphorus, and are replaced by three hydroxyl (OH) groups. 

3 C 2 H 4 2 + PC1 3 = 3 C 2 H 3 O01 + PO3II3 ; 

or, as it might be represented — 




+© 




+ P 



OH" 

oih 



This mode of representation is awkward and cumbrous, although 
it is clear, and the same reactions may be represented more 
shortly, thus : 

3 C 2 H 3 0. 0H + PC1 3 = 3 C 2 H 3 0. Cl + P . (0H) 3 . 

Here again it is not oxygen, but hydroxyl (OH), which 
breaks off from the acetic acid, just as it did from alcohol ; but 
instead of the group C 2 H 6 (ethyl) being left behind, we have 
another group, C 2 H 3 (acetyl). 

It is evident that such groups of atoms or radicals, as they 
are termed, as hydroxyl, ethyl, acetyl, &c, behave in combina- 
tion just like elements. They are not known in a free state. 

In order to exhibit the valency and probable relationships of 
radicals, they are sometimes expressed by graphic formulas, in 
which the affinities are shown by a — , as well as in the ways 
already shown. 

As the position of the radicals in some compounds, e.g. in 
the organic alkaloids, is probably of great importance in regard 
to their action, although the subject is not well understood at 
present, the most important radicals are given below, with their 
graphic as well as their ordinary formula. 

Hydroxyl, OH, or — 0— H. This is a monad radical, 
consisting of one atom of dyad oxygen, —0—, with one of its 



22 PHAEMACOLOGY AND THEEAPEUTICS. [sect. i. 

two affinities saturated by an atom of hydrogen, and the other 
affinity free. It was at one time called water-residue, as it is 
the residue left after the removal of one atom of hydrogen from 
water, which may be regarded as the hydride of the radical. 

Hydroxyl is an important constituent of alcohols, regarding 
the chemical constitution of which two views may be taken. 
They may either be looked on as water in which one atom of 
hydrogen is replaced by organic radicals, or as compounds 
of the radicals with hydroxyl. Tbe constitution of water and 
alcohol may be represented graphically, K standing for a monad 
organic radical — 

H-O-H water; 

E-O-H alcohol, e.g., (Ethyl} -O-H ; (Phenyl) -O-H 

Ethyl-alcohol. Phenyl-alcohol, or 

Phenol. 

The presence of the hydroxyl group in certain substances, 
and also its position in them, 1 appear to be of great importance 
in regard to their physiological action. 2 , 

By replacing the hydrogen in one atom of hydroxyl by a 
monad, or in two atoms by a dyad element, other radicals are 
formed, e.g. 

Potassoxyl, KO, or — 0— K. 

Zincoxyl, OZnO, or — 0\ 

_o> n - 

When united to carbonyl, hydroxyl forms a very important 

radical carboxyl. 

* 

Carbonyl, CO or — C — , is a dyad radical consisting of 

II 


tetrad carbon, in which two affinities are saturated by dyad 
oxygen, and two left free. It exists in aldehydes, ketones, and 
acids, although in aldehydes it is combined with hydrogen, and 
in acids with hydroxyl, to form other radicals. In ketones both 
its free affinities are saturated by organic radicals, which may 
either be of the same kind or of different kinds. 



E-C-E,e.£r.(Methyl)-C-(iJethyl) (Thenyh-C-(MethyT) 

II ^ ^ II V ^ ^ II 



Acetone. Phenyl-methyl-acetone. 

Aldehyde Group, CHO, or -C-H. When the free affinity 

II 


1 Efron, PflUger's Arcfoiv, xxxvi. p. 467. 

8 Stolnikow, Zeitschr.f.physiol. Ohem., 1884, viii. pp. 235 and 271. 



chap, i,] GENEEAL EELATIONS. 23 

of this group is saturated by a monatomic radical, we get alde- 
hydes; thus — 

(JthyT)-C-H , (^nyj) -C-H 









Ethyl-aldehyde. 


Benzoic aldehyde 




(oil of bitter almonds). 



Carboxyl, CO.OH, or C i}} 0, or -C-O-H. This is 

HI j 



a monad radical. When its free affinity is saturated by an 
organic radical, it forms monad organic acids, in which the 
hydrogen of the hydroxyl is readily replaced by a basic element. 

E_C-H-0,e.^.(lSethyl) -C-O-H (fhlnyT) -C-O-H 

II ^ ^ II II 



Acetic acid. Benzoic acid. 



rMeti^l)_C-0-Na (Ph^nyT)-C-0-Na 

^ II II 



Sodium acetate. Sodium benzoate. 

Carbon forms an immense number of radicals by union 
with itself and with hydrogen, e.g. 

H H 
H H H || 

I I I /C-C\ 

H C- H-C-C- h-c/ n yc- 

I I I ,". 

H HH H H 

Methyl. Ethyl. Phenyl. 

Nitrogen gives origin also to a number of most important 
radicals. 



Nitroxyl, NO a . 

2 , or 
•H 



/H 
Amidogen, NH 2 , or — N^ • 



Imidogen, NH or N^ 



24 PHARMACOLOGY AND THERAPEUTICS, [sect. i. 

Phosphorus, arsenic, and antimony give origin also to a 
number of radicals similar to those of nitrogen. 

PH 2 , or -P^; SbH a , or -Sb^; AsH 2 , or -As<^ H 

/H /H /H 

PH, or -P/ ; SbH, or -Sb^ ; AsH, or -As<^ 

Sulphur also gives origin to some important radicals. 



/y O 

;a\ I ; Sulphin, SO, or -Sf 



Sulphuryl (sulphon), S0 2 , or J>S< I ; Sulphin, SO, or -S<f 



Chemical Reactions and Physiological Reactions.— 

Each element and each of its compounds has chemical re- 
actions special to itself, by which it can be recognised and dis- 
tinguished from all others. The number of these chemical 
reactions is therefore very great, but there are a few reactions 
which are common to a great number of the elements. We 
shall find that something similar occurs in their physiological 
reactions. 

The number of possible actions which may be exerted on the 
body by the elements and their compounds is very great, yet we 
shall find that there are certain physiological reactions which are 
common to so many that their repetition under the head of each 
drug becomes monotonous. 

Chemical Reactions. — Although the chemical reactions 
of the metallic elements are. numerous and varied, yet there 
are certain reactions which are common to a very large number, 
and by these the class of metallic elements may be subdivided 
into sub-classes. Other reactions again are common to a few 
elements only, and by these the sub-classes may be subdivided 
into groups. Other reactions again are peculiar to each 
individual element, and by them it may be distinguished from 
all others. 

Thus, by the use of hydrogen sulphide, or ammonium 
sulphide, we at once divide the class of metallic elements into 
two sub-classes : 

A. Metals which give a precipitate with one or other of these 
reagents. 

B. Metals which give no precipitate with either. 

Physiological Reactions.— It is probable that, if our know- 
ledge of physiological chemistry were sufficient,' we might be 
able to classify physiological reactions according to the chemical 
relation between substances introduced into the organism and 
the various constituents of the organism itself. At present we 



chap, i.] GENERAL RELATIONS. 25 

are quite unable to do this ; but, as albuminous substances form 
an essential part of all living organisms, we may roughly divide 
the elements physiologically, by their relation to albumen, just 
as we do it chemically, by their relation to sulphur, into two 
sub- classes: 

A. Those which precipitate albumen. 

B. Those which do not. 

Just as in the case of sulphides, we might further sub-divide 
sub-class A into two sections : 

(a) Those which precipitate albumen in acid solutions. 

(&) „ „ „ in neutral or alkaline 

solutions. 

Section (b) may be further sub-divided into groups according 
to the kind of albuminous bodies which its members precipitated, 
e.g., myosin, globulin, serum-albumen, albumoses, peptones, &c. 

We might also divide sub-class B in two sections : 

(a) Substances which, though they do not precipitate albu- 
men, have a marked affinity for fatty substances or other con- 
stituents of the organism, and especially of the nervous system 
(p. 144). 

(b) Substances having no such action. 

It is evident that such a classification as this, although it 
might form the groundwork of a system to be perfected at some 
future time, is at present so imperfect that it is generally more 
convenient to divide physiological reactions according to the 
organs affected : e.g., muscles, nerve-centres, respiration, circu- 
lation, secretion, &c. 

A. This group contains substances which paralyse muscles 
and motor nerves. The number of these substances is very great 
(p. 126 et seq., p. 150). 

This large group can again be subdivided into those which 
(a) paralyse muscle, while affecting the nerves but slightly, or 
(6) paralyse the nerves and leave the muscle uninjured. 

B. Another large group is that which acts specially on nerve- 
centres, and has little effect either on muscles or motor nerves. 
This contains sub-groups of substances which affect the brain, 
medulla, or spinal cord by exciting, paralysing, or disturbing the 
functions of each. 

C. Another group is that which affects the secretions, with 
sub-groups of substances affecting the secretions from the sweat 
and mammary glands, salivary, gastric, or intestinal glands, liver, 
or kidneys. 

D. Another group still is that which acts chiefly upon the 
circulation. 

These groups are all more or less distinct, although they, tp 
a certain extent, may run into, or overlap, each other. 

Individual members of the same group may differ very widely 
in their physiological action, even when they all finally paralyse 



2(1 PHABMACOLOGY AND THEEAPEUTICS. [sect. i. 

muscle, nerves, and nerve-centres. For while they may pro- 
duce the same final result, the course of their action will be 
different, and the symptoms they occasion will depend very 
greatly upon the part of the organism which they affect first. 
Thus atropine and curare both completely paralyse motor or 
efferent nerves, but, while a very large dose of curare is required 
to paralyse the cardiac and vascular nerves, a very small dose 
paralyses those going to the muscles, and produces increasing 
weakness, gradually passing into death. On the other hand, 
an enormous dose of atropine is required to paralyse the 
motor nerves of muscles, but very small doses are sufficient 
to affect the nerves of the heart and other involuntary muscles, 
and thus we get rapid circulation, dilated pupil,' and restless 
delirium. 

The physiological action of any drug depends to a great 
extent, not merely on its general affinities for classes of tissues, 
but upon its particular affinity, or power of acting on one tissue 
or organ first. The organ first affected may, through its func- 
tional activity, greatly alter the effects of the drug upon the 
others. 

As an example of this we may take the effects produced by 
very large and by moderate doses of veratrine on the frog. A 
moderate dose will produce great stiffness of the muscles, while 
a very large dose may have comparatively little effect. Yet if 
the large dose were applied directly to the muscles it would act 
more powerfully than the moderate dose. The reason that it 
does not do so in the living body is that the large dose paralyses 
the heart so quickly that the circulation stops, and therefore the 
poison, not being conveyed to the muscles, has no action upon 
them. 

Relation between Isomorphism and Physiological 
Action. — From a number of experiments made by Dr. Blake, 
he concluded that when inorganic salts were injected directly 
into the circulation, the intensity of their physiological action 
increased in proportion to their molecular weight, but only in 
those groups of elements where the salts were isomorphic, or in 
other words, crystallised in the same forms. Thus groups whose 
salts were crystallised in different forms had quite different 
physiological actions. He adopts Mitscherlich's division of the 
elements into nine groups, and considers that the physiological 
action of the different groups differs in kind, whilst that of the 
individual members of the same group agrees in kind but differs 
in degree. Thus he states ' that the salts of the first group 
increase in activity in the order mentioned, silver being the most 
active, and lithium the least. 

1 Blake, American Journal of Science and Arts, vol. vii., March 1874 (corrected 

reprint). 



chap, i.] GENERAL EELATIONS. 27 

These groups are as follows : — 

Group 1. Lithium, sodium, rubidium, thallium, caesium, and silver. 
According to him they produce death by acting on the lungs and impeding 
the pulmonary circulation. None of them affect the nervous system excepting 
cassium ; nor do any affect the pulmonary circulation excepting silver. 

Group 2. Magnesia, ferrous salts, manganous salts, nickel, cobalt, copper, 
zinc, and cadmium are increasingly lethal in the order mentioned. They 
kill by arresting the action of the heart. 

Group 3. Beryllium, alumina, yttria, cerium, and ferric salts both impede 
the systemic and pulmonary circulation. 

Group 4. Calcium, strontium, barium, and lead salts kill by paralysing 
the ventricles of the heart. 

Group 5. Palladium, platinum, osmium, and iridium act on the heart, 
respiration, circulation, and blood. 

Group 6. Ammonia and potash paralyse the heart and cause convulsions. 

Group 7. Hydrochloric, hydriodic, bromic, and iodic acids impede the 
circulation and kill by arresting the circulation. 

Group 8. Phosphoric acid, arsenic acid, and antimony kill by arresting 
the pulmonary circulation. 

Group 9. Sulphuric and selenic acid impede the pulmonary circulation. 

The author's statements regarding the mode of action of the 
elements show that their physiological action has not been fully 
investigated, and his results as to the lethal dose are probably 
only approximate and may want re-investigation ; but while we 
cannot accept at present all his results or conclusions as final, 
yet his last and chief conclusion is one of great interest — viz., 
that in living matter we possess a reagent capable of aiding us 
in our investigations on the molecular properties of substances. 

Relation between Spectroscopic Characters and 
Physiological Action. 

The quickness with which a pendulum oscillates is less or greater accord- 
ing to its length, a long one oscillating slowly, and a short one quickly. The 
vibrations of a string or pipe are also slow or quick, and the note which it 
yields is low or high, according as it is long or short. 

Similarly, according to Lecoq de Boisbaudran, the rate of vibrations of 
molecules, and the wave-lengths of the light which they emit, are determined 
by their weight. When the molecular weight is high, the vibrations of the 
molecules are slow, and the light which they emit has long wave-lengths, and 
is situated towards the red end of the spectrum. When the weight is low 
the vibration of the molecules is rapid ; and the light they emit lies towards 
the violet end of the spectrum. 

In the same family of elements the mean length of the wave of light 
which they emit is a function of their atomic weight, so that for bodies of the 
same chemical type the general form of the spectrum persists, but is gradually 
modified by the mass of the molecules. As the atomic weight diminishes, 
the spectrum will tend to ascend towards the violet, and as it increases the 
spectrum will tend to descend towards the red. 

Until recently, our observations on the spectra of bodies were limited to 
the visible spectrum, but the application of photography now enables us 
to extend our observations both above and below the visible spectrum, and 
to ascertain the presence of definite spectra in the ultra-red and ultra-violet, 
when nothing of the sort is visible to the eye. In most musical sounds 
besides the fundamental note we have a number of harmonics having a much 
greater rapidi,ty of vibration than it. Similarly, in the spectrum there appear 
harmonics as well as the fundamental spectral lines, and so instead of one 



28 PHAEMACOLOGY AND THEEAPEUTICS. [sect. r. 

line or band there may be a number. According to the author already quoted, 
the corresponding harmonics in a series of analogous spectra have mean 
wave-lengths which increase in proportion to the weight of the molecules. 

It might appear, therefore, that a relation might be observed between the 
spectroscopic characters and physiological action of an element, and this 
idea was propounded by Papillon. His idea was, however, to a great extent 
based on the experiments of Eabuteau referred to later on, and just as no 
definite relation can be at present traced between the atomic weight and the 
toxic action of a metal, so no definite relation can be observed between its 
spectroscopic characters and its physiological action. 

Further consideration, however, will show us that this is not at all to be 
wondered at, for in physiological experiments we are not working with the 
same molecules which yield the spectrum. 

In spectrum-analysis, when line spectra are in question, according to one 
view we are in presence of phenomena produced by the chemical atom, 
whereas this atom exists only molecularly combined at lower temperatures. 
According to another view, that put forward by Lockyer, we are in presence 
of phenomena produced by a series — possibly a long series — of simplifications, 
brought about by the temperature employed, and this simplification can 
begin at very low temperatures, and is indeed indicated by Dalton's law of 
multiple proportions. 

Such molecular simplifications and differences are represented by ozone 
and oxygen, ordinary and amorphous phosphorus, the various forms of sul- 
phur and so on, and it is therefore at this lower range of temperature — where 
the phenomena are to be studied by absorption, and not by radiation — that 
we must look for connections between molecular structure and physiological 
action if any such connection exists. 1 

Some of the absorption bands which occur in the spectra of bodies at 
ordinary temperatures may be in the visible spectrum, like those observed in 
alcoholic and aromatic substances ; 2 but others may be quite invisible, and 
only recognisable by the aid of photography in the ultra-red or ultra-violet. 3 

Relation between Atomic Weight and Physiological 

Action. 

From experiments made on the toxic action of the chloride, bromide, and 
iodide of potassium, Bouchardat and Stewart Cooper came to the conclusion 
that a relation existed between the physiological activity of elements and 
their atomic weight, the activity being inversely as their atomic weight, e.g. 
fluorine (atomic weight, 19) being more active than chlorine (atomic weight, 
35-5). 

In 1867, Kabuteau made a number of experiments from which he con- 
cluded that Bouchardat was correct in saying that the physiological activity 
of the monatomic metalloids was in inverse proportion to their atomic weight, 
while that of the diatomic metalloids increased directly with their atomic 
weight : selenium being more active than sulphur. 

He considered also that he had discovered a new law regarding the re- 
lation between the atomic weight and the physiological activity of metals : 
viz., that the activity of metals increases with their atomic weight. He 
afterwards qualified this statement by saying that the poisonous action in- 
creased with the atomic weight amongst elements belonging to the same 
group. Thus potassium (atomic weight, 39) is more poisonous than sodium 
(23), and barium (137) than calcium (40). But it has been shown by Huse- 
mann that lithium is much more poisonous than sodium, and his results 
have been confirmed by Bichet. 

In the following table the lethal activity of various metals is given aa 

1 See Hartley, Phil. Trams., Part II. 1885. 

' Eussell and Lapraik, Journ. Chetn. Soc, April 1881. 

• Abney and Testing, Phil. Trans., 1882, p. 887. 



CHAP. I.] 



GENERAL RELATIONS. 



29 



determined by Bichet, and of the metals belonging to the groups of the alkalis 
and earths as determined by Bichet, by Cash and myself, and by Botkin, jun. 
Where the position of the metals in the tables is different the symbols are 
printed in italics. The most active, Hg, is first ; the least active, Na or Ca, last. 



Kichet 


Brunton 


Botkin, 


Atomic 


Kichet 


Brunton 


Botkin, 


Atomic 


and Cash 


junr. 


Weight 


and Cash 


junr. 


Weight 


Hg 








200 





Cs 


Cs 


133 


Cu 


— 


— 


63-4 


Li 


Li 


Li 


7 


Zn 


— 


— 


65 


Mn 


— 





55 


Fe 


— 


— 


56 


Ba 








137 


Cd 


— 


— 


111-2 


Mg 


— 


— 


24 


NS t 


— 


— 


18 


— 


La 


— 


139 


K 


K 


K 


39 


— 


Di 


— 


145-4 


— 


Be 


— 


9 


— 


Er 





163 


— 


Bb 


Bb 


85-3 


Sr 


Sr 





87-4 


Ni 


— 


— 


58 


— 


Yt 


— 


89-8 


Co 


_ 


— 


58 


Ca 


Na 


— 


40123 


— 


Ba 


— 


137 


Na 


Ca 


— 


23|40 


— 


NH t 


— 


18 











Eichet's experiments were made upon fish, and the substances were 
added to the water in which the animals were swimming. The experiments 
of Cash and myself were made upon frogs, and the substances were injected 
subcutaneously. Botkin's experiments ' were made upon dogs, and the sub- 
stances were injected directly into the circulation. 

It is possible that the differences observed were due to the differences in 
the animals on which the experiments were made, or in the way of applying 
the poison. Botkin's table, so far as it goes, agrees perfectly with Cash's and 
mine, and there is a general correspondence also between Eichet's results and 
ours, although there are several differences in particulars. 

It is thus evident that the relationship between atomic weight and physio- 
logical action is no simple one. But indeed, on looking into the matter more 
closely, we could hardly expect it would be. For the toxic action of an 
element may depend upon its effect on the muscles, nerves, nerve-centres, 
blood, or on the digestive or excretory systems. These differ from one 
another in their composition, and while it is possible that the elements 
belonging to a certain group may have relations varying with their atomic 
weight to individual organs or structures, we can hardly expect those rela- 
tionships to be the same to all organs. 

Thus an element with one atomic weight may prove fatal, by affecting 
the muscular power of an animal, while another with an atomic weight either 
higher or lower, may be still more deadly by affecting the nervous system or 
heart. 

What we want, therefore, is not a general relationship between atomic 
weight and toxic action, but a knowledge of the particular relationships ot 
each group of elements to each organ and tissue of the body. 

Relation of Atomic Weight and Smell. 

The idea has been put forward by Eamsay that the sense of smell is 
excited by vibrations of a lower period than those which give rise to the 
sense of light or heat. These vibrations are conveyed by gaseous molecules 



1 S. Botkin, junr. : ' Zur Frage fiber den Zusammenhang der physiologischen 
Wivkung mit den chemischen Eigenschaften der Alkalimetalle der ersten Grappa 
nach Mendelejeff,' Centralb. filr die med, WissenscJiaft. No. 48 1885. 



30 PHARMACOLOGY AND THERAPEUTICS, [sbot.i.- 

to the surface network of nerves in the nasal cavity. The difference of 
smells is caused by the rate and by the nature of such vibrations, just as 
difference in tone of musical sounds depends upon the rate and on the nature 
of the vibration— the nature being influenced by the number and pitch of the 
harmonics. Just as the eye and ear are capable only of appreciating sight or 
sound vibrations occurring within a limited range, bo the nose is unable to 
appreciate a smell the result of the rapid vibrations produced by substances of 
low molecular weight. Hydrocyanic acid appears to be at the lowest limit, as 
one in five are, according to him, unable to detect its odour. It is fifteen times 
the molecular weight of hydrogen, and he concludes that to produce the sensa- 
tion of smell a substance must have a molecular weight at least fifteen times 
that of hydrogen. The intensity of smell in bodies of similar constitution in- 
creases with the molecular weight ; thus, methyl-alcohol is odourless, but the 
intensity of smell increases with the molecular weight of each succeeding 
member of the alcohol group, until the limit of volatility is reached, and 
they become changed into solids with such a low vapour tension that they 
give off no appreciable amount of vapour at the ordinary tension. 1 

Relation of Atomic Weight to Taste. 

Haycraft considers a that ' quality ' in taste depends upon the nature of 
the atoms found in the sapid molecule. A study of the periodic law demon- 
strates that similar tastes are produced by combinations which contain 
elements such as lithium, sodium, potassium, which show a periodic recur- 
rence of ordinary physical properties. Among the carbon compounds, those 
which produce similar tastes are found to contain a common 'group' of 
elements. Thus organic acids contain the group CO.OH, the sweet sub- 
stances CH e .OH. There is no relation between quality of sensation and 
gross molecular weight, except that substances of either very small or very 
great molecular weight are not tasted at all. 

Connection between Chemical Composition and 
Physiological Action. 

In considering this subject and other subjects allied to it, 
we must carefully distinguish between chemical composition and 
chemical constitution ; between the mere elements of which a com- 
pound is formed and the manner in which these elements are put 
together. Thus the cyanides, or nitriles, and the isonitriles, or 
carbamines, both contain carbon and nitrogen, and contain them 
in equal proportions ; but the manner in which the carbon is 
united with the nitrogen probably differs in the two classes, and 
their physiological action is different. Tneir chemical composition 
is the same, but their chemical constitution is different. 

It was pointed out by Blake in 1841 that a close connection 
exists between the chemical constitution and physiological action 
of salts ; their physiological action on animal organisms appear- 
ing to depend chiefly on the base. Yet the physiological action 
of any salt is not dependent entirely upon the base\ It may be, 
and sometimes is, modified to a very great extent by the acid ; 
moreover, we find that the salts which the same inorganic base 

1 Nature, June 22, 1S82, p. 187. 

2 Ibid., Oct. 8, 1885, p. 562. 



CHAP. I.] 



GENERAL RELATIONS. 



31 



may form with different acids may present very different physio- 
logical actions, as in the case of the carbonate, bromide, and 
cyanide of potassium. The same is the case with organic bases, 
and Richardson, in 1865, drew attention to an example of the 
relation between the action of the base and acid in the amyl 
compounds. He found that amyl-hydride had an anaesthetic 
effect ; the- introduction of oxygen, as in amyl-alcohol or amyl- 
acetate, added spasm to this action ; amyl-iodide produced a 
large excretion of fluid from the body, while amyl-nitrite had 
a great effect on the circulation. Thus, the base remaining 
the same, different acid radicals modified the action of the com- 
pound. 1 

The fact is that sometimes the action is determined chiefly 
by the base (whether it be inorganic or organic), and sometimes 
chiefly by the acid. The action of the whole salt may differ to a 
great extent from that of the substances composing it, and it 
may agree to some extent with other salts, which differ from it 
both in regard to the base and acid composing them ; thus — the 
sulphate of magnesium and the sulphate of sodium are both pur-, 
gative, and in this property they agree not only with the sulphate 
of potassium, in which the base is different although the acid is 
the same, but with the bitartrate of potassium, in which both 
the base and the acid are different. This fact confirms what has 
already been said regarding the necessity for taking into con- 
sideration crystalline form and physical aggregation, as well as 
chemical composition (p. 15). 

Physiological Action of the Constituents of a Drug. — In 
the case of acids and bases, the physiological action of each is 
modified by their union, e.g. when caustic soda and hydrochloric 
acid unite, the caustic action of each is destroyed, and we obtain 
sodium chloride and water, which have different physiological 
actions, as well as different chemical characters, from either the 
acid or the base. 

But if we examine a series of salts of the same base with 
different acids, or of the same acid with different bases, we find 
that both the acid and the base modify the physiological action 
of the compound. 





Different Acids. Different Bases. 


Sodium 


hydrate 


caustic. Sodium ichloride 


neutral in action. 


» 


bicarbonate 


antacid. Potassium 


ii 


muscular poison. 


i) 


sulphate 


purgative. Zinc 


ii 


caustic. 


i) 


benzoate 


antilitMc. Barium 


ii 


muscular poison. 


„ 


salicylate 


antipyretic. Silver 


>» 


inert. 


it 


cyanide 


powerful poison. Iron 


ii 


astringent, 






hcematinic. 


Mercuric 


ii 


corrosive, anti- 
septic. 


This modification is in some cases due to a 


change in the 



Brit. Assoc. Reports, 1865, p. 280. 



32 PHAEMACOLOGY AND THERAPEUTICS, [sect. I. 

physical conditions, and especially in the soluhility of the com- 
pound. Thus the chloride of silver is inert so long as it remains 
in the form of a chloride, because it is insoluble. It thus differs 
much from the corrosive chloride of zinc, while if we were to 
compare the action of the nitrate of silver and zinc we should 
find considerable similarity. 

Another cause of difference is the different proportion of the 
acid to the base. 

Thus the proportion of sodium (Na=23) to the acid radical 
in the following sodium salts is as follows : in the hydrate 
as 23 to 18 ; in the bicarbonate as 23 to 61 ; in the sulphate as 
23 to 96 ; in the benzoate as 23 to 121 ; in the salicylate as 23 
to 137. 

In this connection, too, the degree of saturation of the acid 
by the base must be considered. If, for example, the acid is not 
saturated, part of the action of the compound is due to its acid 
chemical properties ; and if, on the other hand, a weak acid be 
combined with a strong base, this action is partly due to the 
alkaline chemical property. 

Relation between Physiological Action and Chemical 
Constitution. 

An immense step has been made of late years in our 
knowledge of the relation between chemical constitution 
and physiological action by the discoveries of Crum-Brown, 
Fraser, and Schroff, who have shown that by modifying artifi- 
cially the chemical constitution of a drug it is possible to modify, 
also its physiological action. And not only so, but they have 
shown that similar modifications in the chemical constitution 
of various drugs induce similar modifications in the action of 
their derivatives ; thus they have found that by introducing 
methyl into the molecule of strychnine, brucine, and thebaine, 
the convulsive action exerted by these substances on the spinal 
cord was changed into a paralysing one exerted on the ends of 
the motor nerves. Other alkaloids, also, which do not exhibit 
a convulsive action, nevertheless exhibit a paralysing one when 
their constitution is altered by means of methyl ; thus methyl- 
codeine, methyl-morphine, methyl-nicotine, methyl-atropine, 
methyl-quinine, methyl-veratrine, and several others, all exhibit 
this paralysing action (p. 150). 

As a general rule, most of the compound radicals formed by 
the union of amidogen with the radicals of the marsh-gas series 
possess a paralysing action on motor nerves. 

The subject of the connection between chemical constitution 
and physiological action is the most important one in phar- 
macology, and we shall have to return to it in considering the 
actions of various groups of organic substances. 



33 



CHAPTEE IL 

CIRCUMSTANCES WHICH AFFECT THE ACTION OF 
DRUGS ON THE ORGANISM. 

One of the most important circumstances affecting the action of 
any drug is the mode in which it is brought into contact with 
the various parts of the organism. 

Local and Remote Action. — The local action of a drug is 
that which it exerts on the part to which it is applied. Thus 
sulphuric acid has a direct irritant or destructive action, and 
when applied to the skin or mucous membrane will produce 
local redness, inflammation, or sloughing. When swallowed, 
it produces weakness of the circulation, stoppage of the heart, 
and death. 

This effect on the circulation is not due to the direct action 
of the acid upon the heart, the vessels, or the nervous system, 
after its absorption : it is due to the reflex action exerted upon 
them by the irritation of the nerves of the stomach which 
the sulphuric acid produces. This action on different parts 
through the nervous system is termed its remote action, in 
contradistinction to the local action of the acid upon the gastric 
mucous membrane. 

The Interaction of various functions in the body is one 
of the greatest difficulties in the way of our readily understanding 
the action of drugs. 

One function alters another, and the second reacts upon the 
first, so that in some cases it is almost impossible to say precisely 
how far the alteration in any function is due to the direct effect 
of the drug upon it, and how far to some indirect action. Thus 
curare when applied to a wound usually kills without producing 
any convulsion whatever. It paralyses the ends of the motor 
nerves, so that all the muscles in the body become powerless. 
But when it is given by the stomach, and excretion through 
the kidneys prevented, death is preceded by convulsions. These 
convulsions are not caused by any direct irritating action. of the 
curare itself upon the nerve-centres ; they are due to irritation of 
these centres by a venous condition of the blood. This venosity 
of the blood is due to imperfect respiration, produced by paralysis 



34 PHAEMACOLOGY AND THEEAPEUTICS. [sect. i. 

of the respiratory muscles through the action of curare on the 
motor nerves. 1 

The effect of curare is a purely paralysing one, both when 
the animal dies quietly and when it dies with convulsions. In 
both cases it paralyses the motor nerves of the respiratory 
muscles and of the extremities. In both cases it causes death 
by arresting the respiration and producing asphyxia. But in 
the latter case the motor nerves of the extremities being only 
partially paralysed when asphyxia occurs, they respond by con- 
vulsive movements to the irritation of the nerve-centres, which 
the venous blood produces. In the former, the paralysis of the 
limbs being complete, the muscles remain perfectly quiet, not- 
withstanding the irritation of the nerve-centres. 

Convulsions also sometimes occur previous to death from 
narcotic poisons: and in a description of the action of these 
poisons we frequently meet with the phrase, ' coma, convulsions, 
and death.' In such cases the convulsions are also caused by 
the irritation of the nerve-centres by asphyxial blood. 

The drug causes the coma; the coma causes imperfect re- 
spiration ; imperfect respiration renders the blood venous ; and 
tne venous blood causes convulsions. 

Direct and Indirect Action. — The direct action of a drug 
is the effect it produces on any organ with which it comes in 
contact. Thus sulphuric acid applied to the skin, or taken 
into the stomach, will, according to its degree of concentration, 
irritate or destroy the mucous membrane which it touches. 
Its direct action upon them is therefore that of an irritant or 
caustic. 

Curare, when applied to the ends of a motor nerve in a 
muscle, paralyses them. It does this either when the muscle 
is soaked in a solution of curare, or when the curare is carried 
through the substance of the muscle by means of the blood 
circulating in it. 

Paralysis is therefore the direct effect of curare on the motor 
nerves. 

The convulsions which sometimes occur in poisoning by 
curare are caused by its indirect action. It has no stimulating 
effect on the nerve-centres, when applied to them directly or 
caried to them by the blood, but by paralysing the muscles of 
respiration, and thus causing asphyxia, it indirectly irritates the 
nerve-centres, and causes convulsions. 

Selective Action of Drugs. — Drugs sometimes seem to 
affect only one part of the body and to leave the other organs 
unaffected ; although the drugs may be carried equally by the 
blood to every part of the body, they appear to combine with 
some and not with others. Many dye-stuffs will not attach 

■ Hermann, Arch.}. Aitat. U. Physiol, 1807, 64, 650. 



Chap, ii.] ACTION OF DBTJGS ON THE ORGANISM. 85 

themselves to cotton fabrics, but will do so readily to wool or 
silk ; and we find that different tissues, and even different parts 
of the same tissue, have very unequal attractions for stains : 
thus some anilin colours will deeply stain a nucleus, while 
leaving the cell in which it is contained entirely uncoloured. 
Although the different organs of the body contain many sub- 
stances in common, yet their chemical composition varies within 
wide limits, and the products of the tissue-waste are also differ- 
ent. Even in the same organs the cells may have different 
properties, and even individual parts of the same cell may differ. 
Some have a reducing, and others an oxidising action ; some an 
alkaline, and others — as may be ascertained from their action on 
anilin colours l — an acid, reaction (p. 70) . We would therefore 
expect that, just as the tissues exert a selective action upon dye- 
stuffs which we are able to see, they will also have a selective 
action on many organic substances, although this action may 
not be visible to our senses. 

Primary and Secondary Action. — I have already stated 
(p. 5) that the so-called action of a drug is not one-sided : it 
is the reaction between the drug and the organism. While 
drugs are circulating in the body they may modify the chemical 
nature and the physiological functions of various organs. In 
some cases the drug, after doing this, may again leave the organs 
and be eliminated without undergoing any essential change ; but 
in other cases the chemical character of the drug itself under- 
goes an essential change during its sojourn in the body. Some 
organic substances undergo complete combustion, and are con- 
verted into carbonates, while others are converted into substances 
having a powerful physiological action, but perfectly different 
from that of the substance originally introduced into the body. 
These products of the decomposition of the drug may then, 
while circulating in the blood, or during the process of excretion, 
exert upon the organism a marked physiological action quite 
different from that of the original substance. Perhaps one of 
the most marked examples of this is to be found in morphine. 
Morphine lessens the irritability of nerve-centres, producing 
sleep, and having a marked sedative action upon the stomach 
in allaying vomiting, either when introduced directly into the 
stomach or injected into the circulation. This is its primary 
action ; but in the body morphine undergoes certain alterations 
and becomes partly converted into oxy-dimorphine, which 
appears to counteract the soporific action of morphine, and 
probably either oxy-dimorphine or some other product of the 
decomposition of morphine has an emetic action. The effect of 
these secondary products will manifest itself after the original 

' P. Ehrlioh, ' Ueber die Methylenblaureaotion der lebenden Nervensubstanz.' 
Deutsche med. Wochenschrift, 1886, No. 4. Ibid. 1885. 

D 2 



86 PHARMACOLOGY AND THERAPEUTICS, [sect, ft 

dose of morphine has either been eliminated or undergone con- 
version into the products already mentioned; and thus the 
secondary action -will be quite different from the primary, and 
instead of narcosis and quietness of the stomach, there will be 
excitement, and nausea or vomiting, which may require to be 
again counteracted by a larger dose of the original drug. 

It is evident that the relation between the primary and 
secondary effects of a drug will, if this explanation be correct, 
vary very much according to the relative solubility of the drug 
originally administered, and of the products of its decomposition. 
If the products of decomposition be more soluble, and more 
readily eliminated, than the drug itself, they will leave the 
organism before it, and their action will hardly appear ; but if 
they are less soluble, and more slowly eliminated, their action 
may persist for a considerable length of time. 

Relation of Effect to Quantity of the Drug. —The effect 
of drugs varies very much according to the quantity employed. 
Sometimes this is due to the interaction of different parts of 
the body on one another, as already mentioned in regard to 
veratrine (p. 26). Sometimes it is due to the different effects 
upon individual cells or tissues. Thus we find, very generally, 
that any substance or form of energy, whether it be acid or 
alkali, heat or electricity, which in moderate quantity increases 
the activity of cells, destroys it when excessive. 

But varying doses do not always produce opposite effects. 
We sometimes find that exceedingly small and exceedingly 
large doses have a similar effect, which differs from that pro- 
duced by moderate doses. Thus very minute quantities of 
atropine render the pulse somewhat slow ; larger quantities 
make it exceedingly rapid, and very large quantities again 
render it slow. 

Moderate quantities of digitalis slow the pulse, larger quan- 
tities quicken it, and still larger quantities render it slow 
again. We find a similar effect produced by variation in tem- 
perature. Great cold disturbs the mental faculties, so that 
men exposed to it present symptoms which cannot be dis- 
tinguished from those of intoxication. Ordinary temperatures 
do not disturb the functions of the brain, but high temperatures 
do, as we see in the delirium of fever, which in many cases im- 
mediately ceases when the temperature of the patient is reduced 
by cold baths. 

Homoeopathy. — This opposite action of large and small 
doses seems to be the basis of truth on which the doctrine of 
homoeopathy has been founded. The irrational practice of giving 
infinitesimal doses has of course nothing to do with the principle 
of homoeopathy— similia similibus curantur: the only requisite is 
that mentioned by Hippocrates, when he recommended man- 
drake in mania ; viz. that the dose be smaller than would be 



chap, ii.] ACTION OF DEUGS ON THE OEGANISM. 87 

sufficient to produce in a healthy man symptoms similar to 
those of the disease. Now in the case of some drugs this may 
be exactly equivalent to giving a drug which produces symptoms 
opposite to those of the disease ; and then we can readily see 
the possibility of the morbid changes being counteracted by the 
action of the drug, and benefit resulting from the treatment. 
For example, large doses of digitalis render the pulse extremely 
rapid, but moderate ones slow it. 1 The moderate administration, 
when there is a rapid pulse, is sometimes beneficial : this 
might be called homoeopathic treatment, inasmuch as the dose 
administered is smaller than that which would make the pulse 
rapid in a healthy man ; but it might also be called antipathic, 
inasmuch as the same dose administered to a healthy person 
would also slow the pulse. 

Homoeopathy can therefore not be looked upon as a universal 
rule of practice, and the adoption of any such empirical rule 
must certainly do harm by leading those who believe in it to 
rest content in ignorance instead of seeking after a system of 
rational therapeutics. 

Dose. — The amount of a drug, which actually comes in con- 
tact with and affects the tissues, depends upon several conditions 
— (1) the quantity actually given ; (2) its proportion to the 
body-weight; (3) the rapidity of its absorption by the blood 
from the place of introduction ; (4) the condition of the circula- 
tion in various parts of the body, which determines the quantity 
of the drug carried to each ; (5) the rate of its absorption by the 
tissues ; (6) the rapidity of excretion. 

The word dose, as employed in medicine, usually means the 
quantity given at one time, but sometimes this may be very 
different from what actually produces any effect. It is the 
amount of the drug existing in the blood at any given time, 
or rather the proportion of it that actually comes in contact 
with or is absorbed by the tissues, which really acts. We must 
therefore consider more in detail the circumstances which affect 
this proportion. 

Size. — As the action which a drug has on the body is not 
dependent on its absolute amount, but on the proportion it bears 
to the body on which it is to act, an amount which is a small 
dose for one person is a very large one for another. 2 Thus if a 
grain of some active substance be injected at the same time into 
the veins of a full-grown man and into those of a boy of only 
half his weight, it will be distributed through twice as much 
blood in the man as in the boy, and each tissue will only receive 
half as much of it. The dose of a drug must therefore be re- 
gulated by the weight of the patient; and thus women, being 

1 Vide Traube, Med, Centr. Ztg. xxx. p. 94, 1861, and Brunton On Digitalis, p. 21. 
2 Buchheim, Arznevrmttellehre, 3rd edit. p. 54. 



38 PHARMACOLOGY "AND THERAPEUTICS, [sect. I* 

lighter, require a smaller amount than men, and children less 
than adults. Though it would be more exact, it is not always 
convenient, to weigh patients; but in experiments on animals 
we usually weigh the animal carefully, and describe the dose in 
terms of the body-weight. For example, in describing the lethal 
dose of physostigmine we do not say that it is so many grains for, 
an animal, but that it is 0*04 grain per pound weight of a rabbit. 
This relation, however, is not always an exact one, and other 
circumstances must be taken into account. Thus the species 
of the animal must be considered, for the same dose which 
would kill one kind of animal will not kill another. In animals 
of the same species the state of nutrition must be taken into 
account, for two animals of the same species, which would be 
nearly of the same size when equally nourished, may have very 
different weights if the one is fat and the other is lean. But the 
fat is a comparatively inert tissue, and if we give to each animal 
a dose regulated by its body-weight, the vital organs, brain, 
heart, and spinal cord of the fat animal will get a larger share 
in proportion than those of the lean one. 

In testing the action of poisons on frogs, also, it must be 
remembered that a female frog with a quantity of spawn will be 
very heavy, but the spawn, like the fat, is not to be reckoned as 
tissue ; so that a dose given in proportion to the actual weight 
would be much larger than the same proportion given to the 
frog after spawning. 

Mode of Administration. — If a substance be injected into 
the veins, the whole of it mixes with the blood and becomes 
active immediately, and the maximum effect is thus at once 
obtained and will again diminish as the substance is excreted. 
But the case is different if it be injected subcutaneously, and if 
it be given by the stomach or any other mucous cavity the 
difference is still greater ; for as soon as some of it is absorbed 
excretion begins, and thus one portion of the drug is passing out 
of the blood while another portion is being taken in. The 
amount in the blood is, then, only the difference between that ab- 
sorbed and that excreted in a given time (Fig. 6). Absorption may 
be so slow, or excretion so quick, that there is never a sufficient 
amount of the substance in the blood to produce any effect. 
Thus Bernard found that a dose of curare which would certainly 
paralyse an animal when injected into the veins, or even sub- 
cutaneously, would have no effect when introduced into the 
stomach ; ' and showed that this was due to the kidneys ex- 
creting the poison as fast as it was absorbed from the stomach, 
oy extirpating the kidneys, 2 when the animal became paralysed 
art surely as if the poison had been introduced at once into the 



1 Bernard, Leqons sur les Effeta des Substances Toxigv.es, p. 2S2. 
1 Bernard, Revue des Cows Scientifiques, 1865. 



chap, ii.] ACTION OF DEUGS ON THE OBGANISM. 



39 



veins, though not so quickly. Hermann also discovered, without 
being acquainted with Bernard's observations, that curare taken 
into the stomach would produce paralysis if excretion were pre- 
vented by ligature of the renal vessels. 



Pulmonary arteries. >• 
(Absorption.) 

Veins of general surface of - 
body. (Absorption,) 



Liver. m 

(Destruction of drugs.) 

Veins of stomach., 

X Absorption from stomach.) 

Biliary circulation. ,-..— 
(Excretion into intestine.) 

Veins of intestine. — *"" 
(Absorption from 
intestine.) 




Arteries going to nerve- 
centres. 

Pulmonary veins. 
(Excretion.) 

Arteries to muscles. 



Arteries to stomach. 
(Excretion into stomach.) 



Arteries to intestines. 
(Excretion into intestines.) 
Kidney. 



Excretion by kidney. 



Fig. 5.— Diagram to illustrate absorption and excretion. The arrows show the direction of the cur- 
rents. The absorbents from which the blood passes directly into the general circulation are 
represented diagrammatically by the veins of the lungs and of the general body surface in the 
figure. The absorbents by which the drug must pass through the liver, and possibly be partly 
excreted or destroyed, are represented by the veins of the stomach and intestine. The exereting 
channels by which the drug may pass directly from the body without re-absorption occurring 
are represented by the vessels of the lung and by the ureter. Those by which excretion takes 
place into cavities from which much re-absorption may occur are represented by the arteries to 
the intestine and the stomach. 

The absorption of drugs from the stomach and intestines 
may be considerably retarded, and their action diminished, by 
the liver. Before reaching the general circulation, drugs ab- 
sorbed from the intestinal canal must all pass through the liver 
(Fig. 5). In their passage they may be partly arrested and ex- 
creted again into the intestine along with the bile. They may 
be also partially destroyed. A larger quantity of a drug may thus 
be necessary to produce similar effects when introduced by the 
stomach than when injected directly into the circulation or under 
the skin — (1) because it may be absorbed more slowly by the 
vessels of the gastric or intestinal mucous membrane ; (2) because 
a part of it may be arrested in the liver and excreted into the 
intestine along with the bile ; (3) because a part of it may be 
actually destroyed in the liver. 

The more rapid the absorption, or the slower the excretion, 
of any drug, the greater will be its effect. Thus the effect pro- 
duced by the same dose of a medicine will be in proportion to 
the rapidity of its absorption from the different parts to which it 
has been applied, unless the differences be so slight that there 
has not been time for the excretion of any considerable quantity 
from the blood during the process. On this account we must 
diminish the dose of a medicine in order to obtain the 'same 
effect, according to the rapidity of absorption from the place to 
which we apply it. Absorption is quickest from serous mem- 
branes, next from intercellular tissue, and slowest from mucous 



10 



PHARMACOLOGY AND THERAPEUTICS, [sect. 



membranes. The vascularity and rate of absorption from inter- 
cellular tissue is greater on the temples, breast, and inner side 




Pig. 6.— Diagram to illustrate the differences produced in the amount of a drug present in the 
organism by alterations in the rate of absorption and excretion. The lower funnel represents 
the organism. A represents the condition when a drug is rapidly introduced, as by injection 
into a vein. In this case the drug, e.g. curare, comes to be present in large quantities in the 
organism, and produces its full physiological effect. This is represented by the fulness of the 
lower funnel. And it does this notwithstanding the rapidity of excretion, which causes 
the drug to be quickly eliminated and to appear copiously in the urine, as represented by tbe 
fulness of the beaker into which the fluid flows from the lower funnel. B represents the con- 
dition when a drug is slowly absorbed and rapidly excreted, as when curare is given by the 
stomach. In this case the quantity present in the hlood at any one time is very minute, as 
represented by the empty condition of the lower funnel. represents the condition when 
absorption is rather quicker than excretion, as when a dose of morphine is given by the stomach. 
D represents the condition where absorption is moderate but excretion is interfered with, lead- 
ing to accumu! ation in the blood, as where an active drug is given by the mouth and the kidneys 
are much degenerated. 

of the arms and legs than on their outer surfaces, or on the back. 1 
It should not be forgotten that any drug introduced into the 
stomach, but not absorbed into the blood, is as much outside 
the body as if it were in the hand, for any effect it will have on 




too. 7,— Diagrammatio representation of the body, A is a box to represent the tissues. B is an 
inner tube to represent the intestinal canal. It is obvious that anything which is merely in the 
inner tube is outside the box, and, similarly, anything which is merely in the intestinal canal is 
outside the body. 

the system, provided always it have no local action on the gastric 
walls. But if it act directly on the walls of the stomach, it may 
have an effect which it would not have when held in the hand 



Eulenburg, Hypodermatische Injection der Arzneimittel, 3rd edit. p. 65. 



chap. ii.] ACTION OF DEUGS ON THE OEGANISM. 41 

or applied to the skin. Thus mustard, which would produce 
redness and burning of the skin, will cause vomiting when 
swallowed; but opium, which does not act on the stomach 
itself, except by diminishing its sensibility, produces no apparent 
effect until after it has been absorbed. 

By the difference between absorption and excretion under 
different circumstances or in different individuals, 1 the cumu- 
lative action of drugs, the effect of idiosyncrasy, habit, climate, 
condition of body, as fasting, &c, disease, and form of adminis- 
tration, can, to a certain extent, though not entirely, be explained; 
but experiments on some of these points are deficient, and the 
explanations now given are to some extent theoretical. 

Duration of Action of Drugs. — When a soluble drug is 
introduced into the stomach, it will undergo absorption, and the 
whole of it may possibly be absorbed without any portion of it 
even passing into the intestine. After absorption into the blood 
it will either remain in the plasma or form a compound with the 
corpuscles. It will thus be carried to the liver, where part of it 
may be retained (vide p. 39). Such portions as pass through 
the liver will then be carried to the right side of the heart, to 
the pulmonary circulation, and then, passing to the left side of 
the heart, will be distributed to all parts of the body. As ab- 
sorption continues, the quantity of the drug in the stomach will 
gradually diminish, while that in the circulation will increase to 
a certain extent ; this extent, however, will depend upon the 
activity of the eliminating organs. The drug will be carried to 
all parts of the body, both to the eliminating organs and to those 
connected with the other functions of the organism. It will enter 
into combination, more or less firm, with all those organs which 
have any attraction for it, and will more or less modify their 
functional activity. In the processes of tissue-change, which are 
constantly going on, the combination between the drug and the 
organs will be gradually destroyed ; and, being again returned to 
the circulation, it will undergo gradual elimination. The method 
in which elimination occurs will also depend, to a certain extent, 
on the selective action of the eliminating organs ; thus soluble sub- 
stances are usually eliminated most readily by the kidneys, while 
salts of the heavy metals, which form insoluble compounds with 
albumen, are eliminated to a great extent by mucous membranes. 

Cumulative Action. — If a substance be naturally so slowly 
excreted from the body that the whole of the dose in ordinary 
use is not excreted before another is given, the amount present 
in the body will gradually increase, just like the curare in Her- 
mann's experiment, and will produce an increasing or cumulative 
effect. Examples of this are to be found in metallic preparations, 

1 Children absorb more quickly than adults, so opium is more dangerous to 
them. Marx, Lehre von den, Qi/ten, vol. ii.p. 117. 



42 PHABMACOLOGY AND THEEAPEUTICS. [sect, i., 

such as those of mercury or lead, -which are excreted very slowly ; 
or in some of the organic alkaloids, if given in sufficiently large 
and frequent doses. The sparingly soluble alkaloids which 
form stable compounds with the tissues and are thus slowly 
eliminated are more liable to prove cumulative. The size of 
the dose and the frequency with which it must be repeated in 
order to produce a cumulative effect will differ according to the 
rapidity with which the drug is excreted ; for, if excretion be 
rapid, a larger dose or more frequent repetition will be required. 

Sometimes the symptoms of the physiological action of a drug 
instead of increasing gradually may do so suddenly, and it is to 
this kind of action that the term cumulative action is most, 
usually applied. This may sometimes be due to a sparingly 
soluble drug accumulating in the intestinal canal, and being 
suddenly dissolved and absorbed on account of some change 
occurring in the intestinal contents ; at other times it may be due 
to arrest of excretion, as in the case of the two vegetable active 
principles, digitalin and strychnine, to which an especial cumu- 
lative action is ascribed. After moderate doses of these drugs 
have been taken for some time, it is found that instead of the 
effects they produce increasing gradually, as we would expect' 
from a gradual accumulation in the blood, the symptoms of 
poisoning become suddenly developed, in somewhat the same 
way as if the dose had been suddenly increased. It is evident 
that a diminution in the quantity excreted will produce this 
effect as readily as an increase in the quantity taken, and this 
is probably the true cause of the phenomenon. "When digitalin 
has been taken for some time and accumulated to a certain 
extent in the blood, it causes a diminution in the amount of 
urine excreted, and this diminution is either accompanied or 
quickly followed by the other symptoms of poisoning. 1 The 
effect, indeed, seems exactly the same as Hermann would have 
obtained in his experiment if he had only partially compressed 
the renal arteries instead of ligaturing them completely. For 
digitalin appears to diminish the secretion of urine by causing a 
powerful contraction of the renal vessels, 2 and in large doses may 
completely arrest the secretion of urine, 3 and probably also the 
circulation through the kidneys. Strychnine has a similar action 
on the vessels. 4 

Effect of different Preparations. — When a drug is given in 
a soluble form, and in small bulk, it is more quickly absorbed 
and will have greater effect than when given in a less soluble 



1 Brunton, On Digitalis, p. 39. 

2 Brunton and Power, Proceedings of Royal Soc, 1874, No. 153, and Central- 
blattf. d. Med. Wiss., 1874, p. 497. 

8 Chriatison, Edin. Med. Journ., vii. 149. 

* Grfitzner, PflUger's Arohiv, 1876, Bd. xi. p. 601. Gartner, Separat-Abdruck 
a. d. lxxx. Bd. d. k. Akad. d. Wiss. III. Abt., Deo. Heft, Jahrg. 1879. 



chap, ii.] ACTION OF DRUGS ON THE ORGANISM. 48 

form or much diluted. Thus drugs given in solution as tinctures 
will act, as a rule, more quickly than when given in the form of 
pill or powder. 

Effect of Fasting. — When a drug is given upon an empty 
stomach, it is usually absorbed much more rapidly. Thus the 
same quantity of alcohol which would have no effect on a man 
if taken during or after dinner, might intoxicate him if taken 
on 'an empty stomach, and especially if he were thirsty, so that 
absorption occurred rapidly. Curare, although it is usually 
inert when placed in the stomach, is sometimes absorbed so 
rapidly from an empty stomach as to produce a certain amount 
of paralysis. 

Besides the alterations in absorption we have to consider also 
the local action on the stomach itself, and the reflex effects which 
may be produced through the gastric nerves on other organs. Thus 
where we give a drug for its local action on the stomach itself, it 
is administered with the greatest effect during fasting, as it will 
come in contact with all parts of tbe gastric mucous membrane. 
An example- of this is the use of a small dose of arsenic for 
gastric neuralgia or lientery. 

But when we wish to prevent local action on the stomach — as, 
for example, when we give arsenic for its general effect on the 
system, in cases of skin-disease — we administer it after meals, so 
that it may be diluted by the food, and not irritate the stomach 
too much. 

Effect of Conditions of the Stomach. — In some conditions 
of the nervous system, absorption takes place much more slowly 
than others ; indeed, both digestion and absorption appear to be 
sometimes totally arrested. Thus in persons in whom a sick 
headache comes on some time after a meal the contents of the 
-stomach are vomited after a while and the food is found to have 
undergone digestion but not absorption. If the meal be taken 
after the headache has come on it will be found, in some persons 
at least, that the food is vomited almost unchanged, both diges- 
tion and absorption appearing to be arrested. This condition 
exists also in delirium tremens, and in a case of this disease I 
have seen pieces of food thrown up in an undigested condition 
although they have been swallowed, as the patient has informed 
me, three or four days before. It is probable that in these con- 
ditions drugs are also not absorbed, and I think it is not im- 
probable that the harmlessness of large doses of digitalis given 
in cases of delirium tremens is due to the non-absorption of the 
drug. 

Effect of Habit. — The tissues seem to have a certain power 
of adapting themselves to changes in their surroundings. Thus 
salt-water amcebaB will die when placed at once in fresh water, 
but if the fresh water be added very gradually, they may by-and- 
,by become accustomed to live in it.. . Fresh-water amoebae also 



44 PHAKMACOLOGY AND THEEAPEUTICS. [sect, u 

have the power of becoming gradually accustomed to increasing 
quantities of salt gradually added to the water in which they 
live, and which would at once kill them if added suddenly. A 
similar power seems to be possessed by the tissues of the higher 
animals, in regard to some drugs at least. Thus the arsenic- 
eaters of Styria are able to consume — not only without injury, 
but with apparent benefit to themselves — a quantity of arsenic 
Which would prove fatal to one unaccustomed to it. The same is 
the case wiih opium and morphine. With these latter drugs there 
seems to be hardly any limit to the quantity which can be taken 
after the habit has been once established, and after a certain 
dose has been exceeded. 

It is possible, however, that in addition to a process of ac- 
commodation going on in the tissues, there is a slower absorption, 
and perhaps more rapid excretion, going on at the same time ; 
for it is observed in the case of opium that sometimes the effect 
is not only diminished, but the time which elapses before it 
occurs is lengthened when persons have become accustomed to 
the drug. 

In regard to the possibility of very slow absorption we must 
remember the power of the liver to arrest and excrete or to 
destroy poisons, especially as it is chiefly in the case of vegetable 
poisons that their power is lessened by habit, which has much 
less influence on the effect of inorganic substances. The toler- 
ance of some inorganic drugs, and especially of tartar emetic in 
disease or after repeated doses, may be due to fever or the 
drug itself lessening the acidity of the stomach, and consequently 
the action of the drug, which acts most strongly in presence of 
an acid. 

The Effect of Temperature. — Chemical reactions, as a rule, 
go on more rapidly the higher the temperature, excepting when 
very high temperatures are reached and dissociation occurs. 
The effect of drugs upon living organisms may be regarded as 
being to a great extent due to chemical union between the drugs 
and the organism, and therefore we should expect that alterations 
in temperature would greatly affect the action of drugs and that, 
as a rule, we should find that they would act with greater quick- 
ness when the temperature is high unless some other factor 
should be brought into operation by the increasing temperature. 
Experience confirms this expectation, and, as a matter of fact, 
the effect of temperature on the action of drugs is very great. 
At different temperatures the administration of the same drug 
may be followed by different results, and it is probable that a 
great number of the contradictory observations which we find 
in works on Pharmacology are due to this most important factor 
having been neglected in making the experiments. It is of the 
greatest importance to the physician also, as many of the cases 
of disease which he has to treat are accompanied by a rise in 



chap, ii.] ACTION OF DRtJGS ON THE ORGANISM. 45 

temperature which may have a very important effect upon the 
action of the drugs which he administers. 

• The alteration produced in the effect of drugs by warmth, was 
first noticed by Alexander von Humboldt, who observed that 
warmth not only acted as a stimulant to the heart in increas- 
ing the power and rapidity of its contractions, but noticed that 
warmth increased the rapidity with which alcohol destroyed the 
irritability of a nerve, and potassium sulphide that of a muscle. 
Bernard observes generally that poisons act slightly on frogs 
.when cooled down, and become more active the higher the tem- 
perature. The effect of warmth in stimulating the movements 
of protoplasmic structures, such as amoebae and cilia, was in- 
vestigated by Kiihne ; and, in an important research, Luchsinger 
experimented on the influence of warmth on the action of poisons 
on many organs, and found that the ciliary motion in the 
pharynx of the frog became paralysed by chloral, potassium 
carbonate, and tartrate of copper and sodium more and more 
quickly in proportion to the rise in temperature. On cooling 
down the ciliary movement again returned. 

Dr. Cash and I have found that the action of veratrine or 
barium on muscle is very much altered by heat and cold. At 
ordinary temperatures contraction is greatly prolonged, but under 
the influence of either great heat or great cold the contraction 
again becomes nearly or quite normal. 

Many, if not all, muscular poisons act more quickly with 
increased temperature ; and frogs poisoned with chloral, copper, 
manganese, potash, and zinc are paralysed more quickly when 
the temperature is high, than when it is low, whether the alter- 
ations be produced artificially, or be due to differences in the 
season at which the experiments are made. 

Eabbits poisoned with copper or potash also die more quickly 
when placed in a warm chamber than when left at the ordinary 
temperature. 

The terminations of motor nerves in the muscles are also 
greatly affected by temperature. 

Guanidine produces in the frog fibrillary twitchings of the 
muscles, which persist even in excised muscles, but are removed 
by curare, and are therefore in all probability dependent on an 
affection of the terminal ends of the motor nerves in the muscle. 
Luchsinger found that when four frogs are poisoned in this 
way, and one is placed in ice- water, another in water at 18°, a 
third at 25°, and a fourth at 32°, the fibrillary twitchings soon 
disappear from the muscles of the frog at 0°, and only return 
when its temperature is raised to about 18°. In the one at 18° 
convulsions occur, which are still greater in the one at 25°. In 
the frog at 32°, on the other hand, no abnormal appearance is 
to be remarked, and five times the dose may be given without 
doing it any harm. 



46 .PHARMACOLOGY AND THERAPEUTICS, [sect. V 

This poison then resembles veratrine in acting only at ordi- 
nary temperatures, and in its action being abolished by excess of 
heat or cold. 

The effect of temperature on secreting nerves is well marked. 
When the sciatic is stimulated in an animal, the corresponding 
foot usually begins to sweat, but the sweating is very much less 
if the foot is cooled down than if it is warm. A similar action 
is exerted by temperature upon the sweating produced by pilo- 
carpine — a drug which appears to act by stimulating the ends 
of the secreting nerves. When the animal is cooled, this drug 
is much less powerful than when it is warm. 

Overheating appears to have an opposite action, and when 
the foot is heated up to a certain temperature it does not secrete 
nearly so readily, even though the glands themselves are not in- 
jured, and secretion may commence after the lapse of a little time. 

The influence of poisons on the heart of the frog is also 
modified by temperature. Kronecker found that its beats were . 
arrested by ether easily and quickly when the temperature was 
high, but with great difficulty when it was low. Kinger found 
that a small dose of veratrine greatly affects the ventricle at a 
moderate or high temperature, but at a low temperature produces 
no effect. 1 

Luchsinger noticed that when the frog's heart had been 
arrested by passing dilute solutions of chloral, copper, or potas- 
sium carbonate through at 25° C, the pulsations again began 
when the temperature was reduced to 15° C. When, on the 
contrary, the heart had been arrested in a similar manner, at a 
temperature of 5° C, pulsations could then be induced by warm- 
ing it to 15°. 

Some extraordinary observations on the effect of temperature 
upon the action of drugs on the spinal cord have been made by 
Kunde and Poster, who have found that, in a number of frogs 
poisoned with strychnine and exposed to different temperatures, 
raising the temperature diminishes the convulsions, while cold 
increases them if small doses are employed. Baising the tem- 
perature, indeed, may not only diminish but entirely abolish the 
convulsions, while putting a frog in ice may bring them on when 
they would not otherwise appear, and cause them to last for no 
less than twenty-four hours. When large doses are employed 
the opposite effect is produced; raising the temperature then 
increases the convulsions, while cooling the frog down to 0° 
abolishes them. 

An observation similar in some respects, though differing in 
others, has been made on the effect of temperature on the action 
of picrotoxin by Luchsinger. 2 When this poison is given to three 



1 Ringer, Archives of Medicine, vol. vii. Feb. 1882, p. 5. 
! Luchsinger, Physiologische Studien, Leipzig, 18S2. 



chap, ii.] ACTION OF DEUGS ON THE OEGANISM. 47 

frogs, and they are then placed in water at 0°, 15°, and 32°, 
in a few minutes the convulsions occur in the one at 32°, shortly 
afterwards in that at 15°, while the one at 0° remains for a long 
time completely unaffected, and only exhibits signs of convulsion 
when the dose has been very great indeed, or when it is taken 
out of the cold bath. 

The effect of warmth in accelerating death from muscular 
poisons has already been mentioned. 

The power of warmth to preserve life in narcotic poisoning 
was observed by Hermann in relation to alcohol, which rabbits 
bear better when they are somewhat warmed. 1 Its extraordinary 
effect in preventing death in animals poisoned with chloral was 
noticed by Strieker, and more thoroughly worked out by myself 
at his suggestion. 2 Death by chloral appeared from my ex- 
periments to be in a great measure due to continued loss of heat 
from the animal. This seems to be the case also in metallic 
poisoning by copper, manganese, mercury, platinum, potassium, 
thallium, tungsten, and zinc. Its cause appears to be twofold : 
(1) the poisons lessen combustion in the body, and the amount 
of heat produced, as is shown by their diminishing the amount 
of carbonic acid excreted ; (2) besides disturbing the production 
they also disturb the regulation of heat, so that animals poisoned 
by them have less power of resisting the influence of external 
temperature, and therefore the temperature rises more quickly 
when they are put in a warm chamber, as well as sinks more 
quickly when they are exposed to cold. 

All these observations show that the definition of the action 
of a drug, already given (p. 5), must be still further modified, 
and we must define it as the reaction between the drug and the 
various parts of the body at a certain temperature. 

Thomas 3 found that digitalis has sometimes no action on the 
pulse in pneumonia. As the slowing of the pulse produced by 
this drug is to some extent effected through the vagi, it occurred 
to me that its want of action in this disease might be due to the 
paralysis of these nerves by heat. On testing the action of heat, 
however, on the vagus, in rabbits deeply chloralised, I found that 
it was not paralysed at a temperature just sufficient to kill the 
animal. 4 Cash and I, however, have found that though the 
peripheral ends of the vagi are not completely paralysed by high 
temperature, the roots of the vagus in the medulla appear to be • 
so, and probably the want of action of digitalis, when the tem- 
perature is high, is due to this paralysis {vide Digitalis). 

The abnormal effect which opium has in some cases of fever 
— causing excitement instead of sleep — is occasionally most 

1 Hermann, Arch.f. Anat. u. Physiol. 1867, p. 64. 

" Lauder Brunton, Journal of Anatomy and Physiology, vol. viii. 

• Arch.f. Heilk., vol. iv. 329, 1865. 

* St. Bartholomew's Hospital Reports, 1871, p. 216. 



48 PHAEMACOLOGY AND THEEAPEUTICS. [sect, u 

distressing to the physician. It is possible that this may be 
partly due to the temperature, and that the combination of 
tartar emetic with the opium may owe some of its utility to its 
effect in lowering temperature, although not improbably both it 
and another useful combination with chloral also act more per- 
fectly on account of the depressing action on the circulation. 
These are points, however, on which further observations are 
greatly needed. 

Climate. — It is said that the action of narcotic drugs is 
greater in warm climates than in cold, and that smaller doses 
are therefore required to produce a similar effect. If this state- 
ment be true, it may be due to the higher temperature, for 
Crombie has shown that in India the average temperature of the 
body is about half a degree higher than in England. It may, 
however, be due to the slower elimination of the drug by the 
urine ; because in hot climates the secretion of the skin is apt 
to be much greater, and the secretion of urine and elimination 
by it consequently less. 

Time of Day. — In healthy persons fluctuations of the body- 
temperature occur. The lowest temperatures occur at night 
between 10 p.m. and 1 a.m., and in the early morning between 
6 and 8 a.m. The highest temperature occurs between 4 and 5 
in the afternoon. 

The action of drugs may be partially altered by the slight 
variations in temperature which occur within the body, and 
perhaps still more by the variations in tissue-change, of which 
these fluctuations of temperature are the indication. Thus tbe 
necessity for great attention to the administration of stimulants 
in the early hours of the morning in cases of threatening collapse 
has long been recognised. 

Effect of Season. — The action of drugs is altered by the 
changes in temperature due to the seasons. Galen supposed 
that- the quantity of blood in the body was increased in spring, 
and in this country, till within recent years, it was a common 
custom for people to be regularly bled every spring. Purgatives 
were not unfrequently administered also at the same time. 
There are, no doubt, changes corresponding with the seasons in 
the human organisation, although these are better marked in 
the lower animals ; e.g. deer, in which the antlers bud regularly 
in spring and reach perfection just at the breeding season. It is 
possible that the abolition of the practice of bleeding in spring 
and the changes in other plans .of treatment formerly adopted, 
may not be altogether due, as some suppose, to increased know- 
ledge on our part, but rather to the occurrence of a change of 
type not only in diseases but also in slight ailments, and to the 
need for such treatment having disappeared. Formerly, before 
the introduction of coaches, and still more of railways, locomotion 
was difficult and transportation was expensive ; in consequence 



chap, ii.] ACTION OF DRUGS ON THE ORGANISM. 49 

of this, the food consumed by the generality of people was differ- 
ent in character, loaf bread being very little used, and salt meat 
often used for weeks and months together during the winter, 
with comparatively few vegetables. Such a diet might naturally 
lead to a condition of body which would be benefited by bleeding 
and purgatives. 

Effect of Disease. — The direct and indirect, the local and 
remote action of drugs upon the complicated mechanism of a 
mammalian body is so perplexing that the attempt to ascertain 
the precise mode of action of a drug by its mere administration, 
either to a healthy man or to healthy animals, and observation 
of its effect upon them, is hopeless. 

Moreover, the object that we really wish to attain is the 
power to relieve human suffering, and to avert the premature 
death due to disease. But in disease we have new factors; 
changes are produced by it in the functions of the body, and 
the reaction of the diseased organism to the drugs which we ad- 
minister is oftentimes different from that of a healthy one. To a 
man suffering from cholera, for example, enormous doses of drugs 
have been given without the least effect ; and, in the wakefulness 
of fever, the opium which ought to produce sleep may simply 
cause excitement and delirium. 



Use of Experiments. 

As we have seen, the problems put before us are too com- 
plicated to be solved directly, and we must therefore simplify 
them. 

This is done in four ways : — 

1st, by observation of the effects of drugs on animals with 
a simpler organism than our own, such as amoebae 
or frogs ; 

2ndly, by applying the drug to some part of an animal 
body more or less completely separated from the rest, 
such as, for example, the muscle and nerve, or the 
heart of a frog separated from the body ; and 

3rdly, by preventing the drug from reaching one part of 
the body while it acts on the others, as by ligaturing 
an artery, as in Bernard's or Kolliker's experiments on 
curare. 

4thly, by producing artificial changes in the relations of 
the various parts of the body of higher animals, 
either before or after administration of a drug, as, 
for example, by dividing the vagi, in order to ascer- 
tain how far the change produced in the beats of the 
heart by a drug is due to its action upon it through 
these nerves. 



50 PHARMACOLOGY AND THERAPEUTICS, [sect. i. 

Comparative Pharmacology. — It may seem almost absurd 
to those unacquainted with the subject, that so much attention 
should be devoted to experiments on the effect of drugs on the 
lower animals, when our object is, as we have just stated, to 
ascertain their action upon human beings, and their mode of 
employment in the diseases, of man. 

But in the study of Pharmacology, just as in Histology, very 
much is to be learned by comparative studies. In his lectures, 
Ranvier admirably defines General Anatomy as Comparative 
Histology limited to a single organism. He illustrates this by 
showing that the different modes of movement which occur in 
some of the lower classes of the animal kingdom are to be found 
united in the highest. Thus leucocytes of the blood move about 
like amoebae. The epithelium of the respiratory passages is pro- 
vided, like infusoria, with cilia ; and while some muscles have the 
power of rapid contraction, others contract slowly, like those of 
some invertebrata. 1 

We have thus in certain parts of the bodies of the higher 
animals and of man, anatomical elements whose functions are 
performed in a way resembling that of organisms low in the 
scale of existence, and by examining the effects of drugs upon 
these low organisms we acquire knowledge which aids us in deter- 
mining the action of drugs upon similar anatomical elements in 
the human body. 

In his admirable lecture on Elemental Pathology, Sir James 
Paget draws attention to the distinction between the conditions 
of life and the essential properties of living things ; and to the 
fact that, while the various parts of a complicated organism like 
the human body are closely connected together, and made to 
work in harmony for the common good of the organism in 
health, yet each part retains its own mode of life, and may 
sometimes develop to an excessive extent at the expense of the 
rest, and may destroy the organism, and itself as well. We see 
the power which each part possesses of carrying on individual 
life apart from the rest best in lower organisms or in inorganic 
substances, where the parts are less dependent on the welfare of 
the whole. 

Thus, in crystals, a chip which has been broken off is re- 
placed, and the form of the crystal restored, by putting it in a 
solution which will yield it the proper kind of material required. 
When a hydra is cut in two, each part grows into a perfect in- 
dividual : a tail growing to the head part, and a head growing 
to the tail part. When a claw has been broken off a crab or 
lobster, a new one will by-and-by grow ; but if the animal be 
divided in two, unlike the hydra it will die. 



1 Legons d'anatomie ginirale sur le systime musculaire, par L. Ranvier Paris, 
18S0, p. 46. 



ceap. ii.] ACTION OF DEUGS ON THE OBGANISM. 51 

As we ascend in the scale of existence the power of repair 
becomes less perfect. But even in the human being we see that 
the different parts retain their individual life, and if put into 
proper conditions may live, although the original body from 
which they were obtained were to die. Teeth, for example, 
which have been extracted from one person have been trans- 
planted and grown in the jaws of another ; and the transplanta- 
tion of hair, skin, or of periosteum is perfectly practicable. 

Idiosyncrasy. — -In then- onward development from the 
lowest forms of life, man and the higher animals have not 
only permanently retained in their bodies certain parts which 
resemble organisms low in the scale of existence, but every 
now and again a tendency to reversion appears in certain 
individuals, and we thus get anatomical abnormalities and 
malformations. 

These were formerly inexplicable, but the doctrine of evolution 
has thrown much light on their probable causation. 

Now and again we also meet with peculiarities in the re- 
action between drugs and parts of the human body in certain 
individuals. 

Some persons, for example, are like pigeons — only slightly 
affected by opium — and can take enormous doses of it without 
any apparent effect. Others, again, are peculiarly sensitive to 
the action of certain medicines, and a dose of a mercurial 
preparation, which would have but a slight purgative action on 
one, will produce intense salivation in another. 

These personal peculiarities in regard to the action of drugs, 
or idiosyncrasies, as they are termed, have been, _ and are still, 
very perplexing td the medical practitioner. It is probable, how- 
ever, that a more complete study of comparative pharmacology 
will enable us, to some extent at least, to recognise these, and 
thus to avoid the inconvenience which they occasion. 

Experiments upon Healthy Man. — As the action of drugs 
upon animals is to a certain extent different from that on man, 
it is undoubtedly desirable to ascertain the action of drugs by 
experiments upon healthy man. This is all the more necessary 
because by experiments upon animals we are able to discover 
only the ruder differences between drugs, and we cannot ascer; 
tain the finer shades of action, both because it is in man alone 
that these finer differences occur, and because it is he alone who 
can give information regarding slight changes which he can per- 
ceive in his own organism, but which are imperceptible to others 
who may be observing him. There is no doubt that many ob- 
servers of this sort, several of whom have been homceopathists, 
have done good service to medicine by carefully noting and care- 
fully comparing the symptoms produced by various drugs. These 
observations, however, are liable to fallacies, as I will presently 
mention. 

E 2 



52 PHARMACOLOGY AND THERAPEUTICS, [sect. i. 

Fallacies of Experiment upon Man.— But the high de- 
velopment of the nervous system in man, its susceptibility to 
various influences, and the power of expression which man 
possesses— the very qualities which render him such a valuable 
subject for experiment make experiments upon him all the more 
liable to fallacy. Thus we find that in the experiments of Hein- 
rich and Dworzak aconite was found to cause neuralgic pains 
in the face ; but unfortunately these observers have not mentioned 
whether any carious teeth were present, and so we cannot ascer- 
tain whether the neuralgia was due to the action of the aconite 
itself upon healthy nerves, or to alterations in the circulation of 
the alveoli lodging decayed teeth. 

One of the most marked examples of the fallacies occurring 
in experiments upon man, and of the errors to which such 
fallacies may lead, is to be found in the provings which Hahne- 
mann made of cinchona bark, and which led him to formulate 
the doctrine of homoeopathy. Hahnemann, who had suffered 
from ague, 1 for the sake of experiment, took for several days 
4 drachms of good cinchona bark twice a day, and then began to 
suffer from all the ordinary symptoms of intermittent fever. On 
leaving off the drug he soon became quite well. He therefore 
concluded that cinchona bark, which was well known to be a 
remedy for ague, could also produce it. 

Everyone who has an extended experience of ague knows 
well that even when patients have been free from any symptoms 
of the disease for a considerable length of time, they may be 
caused to reappear by various conditions, and more especially by 
anything that irritates the stomach or intestines. I have not 
myself seen a case of ague brought on by the' administration of 
cinchona bark, but I have seen it occur after a succession of 
heavy dinners in a patient who had been long free from it. 
Powdered cinchona is certainly irritant, and Jorg found that 
in two-drachm doses it might cause flatulence, irritation, and 
nausea. Hahnemann took it in double this dose, and in all 
probability the ague which it brought on was simply due to 
gastric irritation, and not to any specific action of the cinchona. 
Had Hahnemann taken any other irritant which disagreed with 
him — say tartar emetic, or perhaps even pork-pie — he might 
have suffered in the same way, and yet pork-pie could hardly be 
said to be a specific for ague. 

Experiments in Disease. — In the present state of medicine 
every attempt which we make to treat disease by the administra- 
tion of medicine partakes more or less of the nature of experi- 
ment, because we can rarely be absolutely certain that the drug 



1 History of Homccopathy. By Wilhelm Ameke, M.D. Translated by Alfred E. 
Drysdale, M.B. Edited by B. E. Dudgeon, M.D. London. Published for the 
British Homeopathic Society, by E. Gould & Son, 59 Moorgate Street. 1S85 



chap, n.] ACTION OP DBUGS ON THE ORGANISM. 53 

will have precisely the effect which we desire. As the phrase is, 
'We try one medicine, and then we try another.' If human 
life were not so valuable, we might pursue a series of systematic 
experiments, and gain valuable information ; but it is impossible 
for a physician to treat the patient who calls upon him for aid in 
any other way than that which seems likely to be the best for 
the patient's welfare. Here again the homceopathists have done 
good service, because by administering to the patient medicines 
in which they believed, but which could neither do good nor 
harm, they have taught us the natural course of some diseases, 
which we could not otherwise have learned. 

Objections to Experiment. — Some people object entirely 
to experiments upon animals. They do this chiefly on two 
grounds. The first is that such experiments are useless, and 
the second is that, even if they were useful, we have no right to 
inflict pain upon animals. 

The first objection is due to ignorance. Almost all our exact 
knowledge of the action of drugs on the various organs of the 
body, as well as the physiological functions of these organisms 
themselves, has been obtained by experiments on animals. 

The second objection is one which, if pushed to its utmost 
limits and steadily carried out, would soon drive man off the face 
of the earth. 

The struggle for existence is constantly going on, not only 
between man and man, but between man, the lower animals and 
plants, and man's very being depends upon his success. 

We kill animals for food. We destroy them when they are 
dangerous like the tiger or cobra, or destructive like the rat or 
mouse. We oblige them to work for us, for no reward but their- 
food ; and we urge them on by whip and spur when they are 
unwilling or flag. No one would think of blaming the messenger 
who should apply whip and spur to bring a reprieve, and thus 
save the life of a human being about to die on the scaffold, even 
although his horse should die under him at the end of the 
journey. Humane people will give an extra shilling to a cab- 
man in order that they may catch the train which will take them 
to soothe the dying moments of a friend, without regarding the 
consequences to the cab-horse. Yet if one-tenth of the suffering 
which the horse has to endure in either of the cases just men- 
tioned were to be inflicted by a physiologist in order to obtain 
the knowledge which would help to relieve the suffering and 
lengthen the life, not of one human being only, but of thousands, 
many persons would exclaim against him. Such objections as . 
these are due either to want of knowledge or want of thought on 
the part of the people who make them. They either do not know 
the benefits which medicine derives from experiment, or they 
thoughtlessly (sometimes, perhaps, wilfully) ignore the evidence 
regarding the utility of experiment. 



54: PHAEMACOLOGY AND THEEAPEUTICS. [sect. i. 

One of the most important objections that has been raised to 
this mode of experiment is that the action of drugs on the' lower 
animals is quite different from their action on man. This 
objection has a certain amount of truth, but is in the main 
groundless. The action of drugs on man differs from that on the 
lower animals chiefly in respect to the brain, which is so much 
more greatly developed in man. 

Where the structure of an organ or tissue is nearly the same 
in man and in the lower animals, the action of drugs upon it is 
similar. Thus we find that carbonic oxide and nitrites produce 
similar changes in the blood of frogs, dogs, and man, that curare 
paralyses the motor nerves alike in them all, and veratrine exerts 
upon the muscles of each its peculiar stimulant and paralysing 
action. 

Where differences exist in the structure of the various organs, 
we find, as we would naturally expect, differences in their re- 
action to drugs. Thus the heart of the frog is simpler than that 
of dogs or men, and less affected by the central nervous system. 
We consequently find that while such a drug as digitalis has 
a somewhat similar action upon the hearts of frogs, dogs, and 
men, there are certain differences between its effect upon the 
heart of a frog and that of mammals. In all it seems to affect 
the muscular substance and cause increased contraction. But 
while the frog almost invariably dies with the heart in a state of 
tetanic contraction, this is not the case with dogs or men, where 
the heart sometimes is found in diastole after death. 

Ipecacuanha or tartar emetic will cause vomiting in man, but 
does not do so in rabbits. The reason of this is that the position 
of the stomach in the rabbit is different from that in man, and 
is such that the animal cannot vomit. In dogs, however, the 
position of the stomach agrees with that of man, and tartar 
emetic or ipecacuanha causes vomiting in both. Belladonna 
offers another example of apparent difference in action — a con- 
siderable dose of belladonna will produce almost no apparent 
effect upon a rabbit, while a smaller dose in a dog or a man 
would cause the rapidity of the pulse to be nearly doubled. Yet 
in all three — rabbits, dogs, and men — belladonna paralyses the 
power of the vagus over the heart. The difference is, that in 
rabbits the vagus normally exerts but little action on the heart, 
and the effect of its paralysis is consequently slight or hardly 
appreciable, the pulse being normally almost as quick as it is 
after the vagus is paralysed. In dogs and men, on the contrary, 
the vagus is constantly exerting considerable restraining power 
over the heart, and the effects of its paralysis at once attract 
attention. 

An example of the apparent difference in the effect of a drug 
on different animals is afforded by nitrite of amyl. If we measure 
the pressure of the blood in the arteries of a rabbit and of a dog. 



chap, ii.] ACTION OF DEUGS ON THE OKGANISM. 55 

and then cause them to inhale nitrite of amyl, we find that the 
small vessels have become widened and allow the blood to pass 
easily out of the arterial system into the veins, so that the 
pressure sinks considerably in the rabbit, whereas it sinks only 
slightly in the dog. The action seems at first sight different ; 
but when we examine it more closely, we find that the heart of 
the dog is no longer beating slowly, but very quickly, so as to 
keep up the pressure, notwithstanding the rapid flow of the 
blood through the widened vessels, while the heart of the rabbit 
was going so fast before that it could not go much more quickly. 
If we cut the vagi in the dog, so that the heart goes as quickly 
as in the rabbit before it begins to inhale, the blood-pressure 
sinks during the inhalation, just as it does in the rabbit. 1 

One of the most marked differences between the action of a 
drug upon lower animals and upon man is to be found in the 
effect of morphine upon frogs and upon pigeons. In frogs it 
causes convulsions ; on pigeons, even in large doses, it produces 
no apparent effect. But although its effects are not appreciable 
to the eye, they exist nevertheless, and on applying the thermo- 
meter it is found that morphine lowers the temperature of pigeons 
many degrees. On comparing the effect of the drug on frogs 
with its effect on man, we see that in the frog the cerebral hemi- 
spheres are very slightly developed indeed as compared with 
man, and in the latter the effects of the drug upon the spinal 
cord are usually completely concealed by the narcotic effect of 
the drug upon the brain. In children, however, and in some 
races of man where the cerebral hemispheres are less developed 
than in Europeans, the convulsant action of morphine manifests 
itself. Occasionally we find individuals who are almost proof 
against the action of morphine, and who take large doses of it 
without any apparent- effect. Whether in these persons it lowers 
the temperature as it does in pigeons is a point which remains 
to be ascertained. 

By means of experiments upon animals, then, we are able to 
ascertain the action of drugs upon those organs of the body 
which are alike in man and animals ; and the very differences 
which exist between the various sorts of animals, help us to 
understand the action of drugs more thoroughly. 

Erroneous Deductions from Experiments. — A great fault 
— and one which is only too common in the works of experi- 
mental pharmacologists — is that of drawing general conclusions 
from limited data. 

One experimenter tries the effect of a drug, let us say tartar 
emetic, upon rabbits. He finds that they do not vomit, and in- 
stead of drawing the only warrantable conclusion, viz. that tartar 

1 Lauder Brunton, ' Action of Nitrite of Amyl on the Circulation,' Journal of 
Anatomy and Physiology, vol. v. p. 95. 



56 PHAEMACOLOGY AND THEEAPEUTICS. [sect. i. 

emetic does not cause vomiting in rabbits, he draws the general 
one — that tartar emetic does not cause vomiting in animals. 
Another tries it upon dogs, and he finds they all vomit. Instead 
of the limited conclusion that tartar emetic makes dogs vomit, 
he draws the general conclusion that it makes animals in general 
vomit. The two observers are equally positive in regard to their 
facts — each is assured that he himself is right, and that the other 
is totally wrong. The reason of the discrepancy is simply that 
the conditions under which the experiments have been performed 
were different, but the observers have not taken these differences 
into account when drawing their conclusions. A third observer 
then comes, perhaps, and by further experiments reconciles the 
apparently contradictory statements. Thus one experimenter 
tries the effect of caffeine upon frogs ; he finds that it produces 
rigor mortis in the muscles. Another tries the same drug, and 
finds no such result. These two observations are completely 
contradictory, until a third tries the effect of the drug upon two 
species of frog, and finds that while the muscles of the rana 
esculenta are but slightly affected, those of the rana temporaria 
are rendered rigid. 1 

These apparent contradictions in the results of different ob- 
servers are exceedingly puzzling to the student, but nothing is 
more instructive to those who are actually working at the subject. 

The utility of apparent exceptions was fully recognised by 
Claude Bernard, who says : ' In physiological studies we must 
always carefully note any fact which does not accord with re- 
ceived ideas. It is always from the examination and the dis- 
cussion of this exceptional fact that a discovery will be made, if 
there is one to make.' 2 

1 Schmiedeberg, Arch. f. exper. Path. u. Pharmalc, Bd. ii. p. C2. 
* Bernard, Ligwides de Vorgawisme, torn. i. p. 258. 



57 



CHAPTEE m. 

ACTION OF DEUGS ON PEOTOPLASM, BLOOD, AND LOW 

OBGANISMS. 

Action of Drugs on Albumin. 

In all living bodies we find that the protoplasm is of a more or 
less albuminous nature. 

Albuminous substances possess a very complex inter-mole- 
cular grouping, and very high atomic weights. Many different 
forms are found in animals, and along with albumins we must 
associate bodies like mucin, which probably have a very im- 
portant relation to it, inasmuch as a body nearly, if not quite, 
identical with mucin forms the nucleus of the red blood-cor- 
puscles in fowls, 1 and a substance of an allied nature also occurs 
in the circulating fluid which represents the blood in the echino- 
dermata. 2 The albumin of serum may be taken as a representa- 
tive of such substances ; it is soluble in water, but, at a certain 
temperature, is coagulated and precipitated. It is coagulated 
also by alcohol, but if the coagulum is quickly placed in water it 
redissolves ; if allowed to remain for some time exposed to the 
action of the alcohol it becomes permanent and insoluble. An 
insoluble precipitate also falls on the addition of tannic acid, 
both lead acetates, and mercuric chloride. The reagents just 
mentioned precipitate all the albumins, even from somewhat 
dilute solutions ; in strong solutions precipitates are also formed 
by silver nitrate, copper sulphate, and zinc chloride. 

When these are added to albumin containing only a small 
quantity of water, as, for example," the white of an egg, they 
form with it a solid mass of albuminate. A small quantity of 
strong potash added to the white of egg produces a solid trans- 
parent jelly of albuminate of potash, and a similar but opaque 
jelly is formed by the use of caustic lime or baryta in the place 
of potash : these albuminates are, however, soluble in water. 

Albumin dissolves in alkalies, and may be partly precipitated 
by neutralising. The alkaline solution is not coagulated by heat, 
and, in fact, the substance present in the solution is no longer 
serum albumin, but a compound of the albumin with the alkali, 
or alkali-albuminate. 

1 Lauder Brunton after Kuhne, Journ. of Anat. and Physiol. Nov* 1869. 
* Sehafer, Proc. Boy. Soc, vol. xxxiv., p. 370. 



58 PHAKMACOLOGY AND THEEAPEUTICS. [sect. i. 

Albumin is precipitated by a small quantity and dissolved 
by excess of most mineral acids, forming witb tbem acid-albu- 
minates ; thus a watery solution of albumin is precipitated by 
concentrated nitric, sulphuric, or hydrochloric acid. It is also 
precipitated by acetic acid along -with a considerable quantity of 
a neutral salt of an alkali or alkaline earth, or of gum arabic or 
dextrin. This precipitation is perhaps best marked with nitric 
acid, but it only occurs with moderate quantities of nitric acid. 
When a minute quantity only of the acid is added, no precipita- 
tion takes place, and the solution remains clear ; but a nitric- 
acid-albuminate containing a small quantity of acid is formed, 
and if the solution is now boiled no coagulum will form. On the 
addition of more acid, however, a second nitric-acid-albuminate, 
insoluble in water, is produced, and a precipitate falls. On the 
addition of more acid still, the precipitate is redissolved, and a 
third nitric-acid-albuminate is formed, soluble in water, and not 
precipitated on boiling. 

The temperature at which albumin coagulates is altered by 
acids and alkalies. Alkalies generally tend to raise the tempera- 
ture of coagulation, and when added in large quantities prevent 
it altogether. 

Very dilute acetic and phosphoric acid, on the other hand, 
tend to lower the coagulating point, although large quantities 
may interfere with coagulation. 

Neutral salts, such as sodium chloride or sulphate, also lower 
the coagulating point. 

The organic alkaloids which have such a powerful action on 
the animal body appear to resemble acids rather than alkalies 
in their effect upon albumin, because, according to Eossbach, 
they lower considerably instead of raising the point of coagula- 
tion. 

Albumin undergoes an extraordinary change in consequence 
of the action of ozone, and becomes, after exposure to it, un- 
coagulable by boiling, and by acids, excepting in large quantities, 
and by metallic salts, with the exception of basic acetate of lead, 
and of alcohol. 

The action of alkaloids upon this ozonised albumin is even 
more remarkable than upon ordinary albumin, for when mixed 
with it in Bmall quantity, they restore its coagulability to the 
albumin, and cause it to coagulate far under the boiling-point. 
When added to the albumin before exposure to a stream of ozone, 
they prevent the albumin being altered by it, in the way which 
it would otherwise be, and it remains coagulable by heat, in the 
same way as if it had not been exposed to the action of ozone at 
all. It is therefore evident that the alkaloids not only increase 
the coagulability of ordinary albumin at a high temperature, but 
that they act upon it at ordinary temperatures (S0°-40° C.) and 
destroy its affinity for ozone. This action will naturally interfere 



ohap. in.] ACTION OF DEUGS ON PEOTOPLASM, ETC. 59 

with the processes of oxidation in protoplasm ; but the methods 
of examining this action will be described later on (p. 69). 

When a solution of pure albumin is added to a mixture of 
guaiac and vegetable protoplasm, it greatly lessens the blue 
colour, which would otherwise be produced. The cause of this 
appears to be that albumins or albuminous substances have 
such an affinity for ozone that they take it up instead of allowing 
it to act on the guaiac. This affinity for ozone is diminished by 
the action of alkaloids. 

This is shown by taking several tubes containing an albuminous solution 
of a certain strength. .Reserving one as a standard, the alkaloids are added 
to the others, and after a certain time has elapsed, so as to allow the alkaloid 
to affect the albumin, a small quantity of lettuce water is mixed with each, 
and then a little guaiac. In the standard one the colour will he least, because 
the albumin not having been acted upon by the alkaloids will interfere with 
the reaction of the lettuce water and the guaiac upon each other. In the 
others a blue colour will appear with greater or less intensity, according as 
the albumin has been more or less affected by the alkaloid. This experi- 
ment, however, is not free from fallacy, because there is to be considered not 
merely the action of the alkaloid upon the albumin, but its action on the 
protoplasm as well, and it is therefore advisable to use it in a quantity which 
is small as compared with the amount of albumin employed. 1 

Action of Drugs on Protoplasmic Movements. 

The amoeba consists of a small mass of structureless proto- 
plasm, without any distinct cell-wall. 

It contains numerous granules and nucleus, with nucleolus, 
as well as one or more vacuoles, which appear to be small spaces 
filled with fluid. 

Some amcebse live in salt water, others in fresh water ; and, 
although it may be impossible with the microscope to detect any 
marked difference between them, they exhibit a great difference 
in their reactions to drugs — the salt-water amcebse being only 
slightly affected by them, while fresh-water amcebse are readily 
susceptible to their action. 

The amceba is nourished by simply adhering to any particle 
of food, closing over it and digesting it, and afterwards opening 
and ejecting the residue. 

This protoplasmic mass is almost constantly altering in 
shape, pushing out projections at one point, and drawing them 
in at another. By this means, also, it moves about from place 
to place, 

Method of Experimentation on Amoebae and leucocytes. — In 

experimenting on amcebse, take a drop of slimy sediment, such as is 
found in the tanks of hothouses, and place it on the covering-glass of a 
microscope ; this may then either be put on an object-glass, and the excess 
of water removed by filter -paper, or, still better, it may be inverted over the 
opening of a Strieker's warm stage. 

1 Bossbach, Yerhandl. d. phys. med, Oes. zu Wilrzburg, N.P., Band iii. p. 346. 



60 PHABMACOLOGY AND THERAPEUTICS, [sect. i. 

"When it is simply laid on the object-glass, a solution of the drug is added 
by putting a drop across the edge of the covering-glasB, and allowing it to be 
drawn gradually underneath by capillary attraction. 

Gases are best applied by means of a Strieker's stage, which is also con- 
venient for experiments on solutions. 

In experimenting on leucocytes with the aid of this stage, a covering-glass 
is applied to the cut surface of a newt's tail, or to the surface of a drop of 
blood, so' that a very minute quantity of blood adheres to it. 

The drug to be tested is kept dissolved in a -65--75 per cent, solution of 
common salt (Na CI). The salt solution of this strength is often called 
simply normal salt solution, and is used instead of water, because water itself 
has a very destructive action on those forms of protoplasm, which are usually 
nourished by saline solutions, like blood or serum. 

A drop of the salt solution containing the drug is placed over the blood on 
the covering-glass, and inverted over the warm stage as already described. 
If the experiment is to continue long, a rim of oil should be drawn around 
the edge of the covering-glass with a camel-hair pencil, so as to prevent 
evaporation. 

The advantage of using such a small quantity of blood is, first, that it 
mixes rapidly and perfectly with the solution ; and secondly, that it does not 
dilute the solution of the drug, and we thus know the strength of the drug used. 

If we used a large drop of blood, we should have to employ a solution of 
the drug twice the strength we desire, so that when a drop of equal size 
was added to the blood, the mixture would contain the proper proportion. 

Amoebae. — The effect of heat and cold upon the movements 
is very marked, cold rendering them slow, or arresting them 
altogether. Heat at first greatly quickens their movements, but 
when raised to 35° C. it causes them to fall into a state of tetanic 
contraction and assume a spherical form. 

This state is one of heat-tetanus, and if the temperature be 
now reduced, the movements will again reappear. 

At a temperature of 40° C. they also become spherical and 
motionless. But their movements do not return when the tem- 
perature is reduced ; they are in a state of heat-rigor, the high 
temperature having coagulated the protoplasm. 

Slight electrical shocks from a coil increase the rapidity of 
the protoplasmic movements ; stronger ones cause tetanic con- 
traction ; and numerous or powerful ones produce coagulation. 

Common salt in very small quantity (a drop of 1 per cent, 
solution slowly added) first quickens the protoplasmic movements 
and then causes sudden tetanic contraction, and the expulsion of 
any food they may contain at the moment, and sometimes even 
expulsion of the nucleus. 

When water is added so as again to dilute the mixture the 
amoebae resume their movements. 

Both acids and alkalies, when very dilute, increase the proto- 
plasmic movements and afterwards arrest them. 

Hydrochloric acid has a more powerful action than a solution 
of potash of a similar strength. It causes the amoeba to contract 
and form a ball with a sharp double contour. In it, twitching 
movements first occur, which expel any food present. It then 
becomes pale and lumpy, and breaks up. 



chap, in.] ACTION OF DEUGS ON PEOTOPLASM, ETC. 61 

Potash causes them to swell up and assume the form of large 
pale vesicles, which quickly burst. 

A constant current of electricity causes contraction and 
imperfect tetanus ; and, if powerful and long kept up, the posi- 
tive pole produces in the amoebae near it the same changes as 
dilute hydrochloric acid, and the negative pole the same changes 
as are produced by an alkali such as potash. 

Oxygen appears to be necessary for their life ; its removal 
by means of hydrogen deprives the amoebae of their power of 
motion, and finally causes contraction and coagulation. 

Carbonic acid alone has a similar action to removal of oxy- 
gen and produces this effect both in the presence and absence 
of oxygen, but takes a longer time to do so when oxygen is 
present. 1 

Leucocytes. — In their appearance and movements leucocytes 
strongly resemble amoebae : they are affected in a similar manner 
by heat, electricity, and drugs. Their resistance to the action 
of drugs varies somewhat in different animals. Those obtained 
from the blood of the newt, for example, are more resistant than 
those of the guinea-pig, and those of the female newt more re- 
sistant than those of the male, to the action of quinine. 2 Heat 
and cold affect the movements of leucocytes in very much the 
same way as those of amoebae. 

The movements of leucocytes, like those of amoebae, are of 
two kinds, viz. movements of the protoplasmic pseudopods, 
while the leucocyte remains in situ. The pseudopods in this 
instance are generally of a waxy look and knoblike form. 

Secondly, movements of migration from place to place ; these 
movements are accompanied, or accomplished, through the 
projection of numerous fine filaments. 

Effect of Drugs.— Cinchona alkaloids — quinine, quinidine, 
cinchonine, and cinchonidine have a remarkable power of arrest- 
ing these movements in the proportion of 1 in 1,500. They 
quickly stop the migratory movements of leucocytes from the 
newt, and in a much larger proportion will arrest the movements 
of the knoblike pseudopods. 

No very marked difference is observed in the strength of the 
cinchona alkaloids, though quinine seems to be somewhat the 
most powerful. 

Sulphate of bebeerine is almost as powerful as the cinchona 
alkaloids. 

Strychnine is very much less powerful than any of the alka- 
loids mentioned. 

Potassium picrate and aesculin have but little action, 3 



1 Kuhne, Protoplasma wnd Contractilitat, pp. 28-53. 

2 Geltowsky, Practitioner, vol. viii. pp. 325-330. 
* Buchanan Baxter, Practitioner, vol. xi. n. 321. 



62 PHAEMACOLOGY AND THEEAPEUTICS. [sect. i. 

Movements of Leucocytes in the Blood-vessels. — In the 

processes of inflammation leucocytes pass in great numbers 
through the walls of the capillaries. 

The effect of quinine in arresting their movements, when 
mixed with them directly, naturally leads one to expect that it 
may arrest their migration from the capillaries, when injected 
into the blood, and this anticipation has been realised in the 
experiments of Professor Binz. 

To observe this phenomenon the brain of a frog is to be destroyed, and 
a little curare injected under the skin, in order to abolish any spinal reflex 
movements. It is then laid on » piece of cork, such as that shown in 
Fig. 8, with a hole at one side, over which a piece of glass is fastened about 




Fig. 8. — Apparatus for examining the mesentery of the frog under the microscope. 

half an inch higher, by means of two other pieces of cork and some sealing- 
wax. On this a piece of sheet cork of the form shown in the figure, and a 
round piece of glass are cemented so as to form a channel, in which the 
intestine lies. The body of the frog is' fixed to the cork, the abdomen 
opened, the intestines drawn out, and the mesentery • fastened with very 
fine pins over the aperture. In half an hour, or two hours, the leucocytes 
pass rapidly through the walls of the capillaries, and afterwards wander 
through the tissues. 

The drug may then be injected into the lymph-sac, or locally applied to 
the mesentery. 

When quinine is applied locally to the mesentery in this 
condition it arrests the movements of the leucocytes, which have 




Fig. 9.— Diagram to illustrate the action of quinine on leucocytes, modified from Binz (Das Wesen 
del- Chininmrkung. Berlin, 1868). The thick lines represent the walls of the blood-vessel, and 
numerous leucocytes are shown both inside it and outside distributed through the adjoining 
tissues, a represents the vessel before, aud 6 after, the local application of quinine. The leuco- 
cytes outside the vessel have their movements arrested, and cannot wander on through the 
tissues, while those inside are not affected and continue to emigrate, c represents the effect of 
quinine injected into the circulation or lymph-sac. The leucocytes inside the vessel are here 
affected first, and their emigration stopped, while those outside still continue to travel onwards. 

already emerged, but does not prevent those which are still 
within the vessels from going out ; they therefore form a dense 
accumulation around the vessel (Fig. 9, b). When injected into 



chap, in.] ACTION OF DEUGS ON PEOTOPLASM, ETC. 63 

the circulation, on the contrary, the leucocytes which are in the 
vessels are prevented from passing from the capillaries, while 
those which have already passed out continue to wander on- 
wards, and thus a dear space is left outside the vessel (Fig. 9, c). 

The quantity of quinine necessary to produce this effect is 
a5 Soi) ^ *° io'oo^ °f the animal's weight. 

If quinine were given to stop the exit of leucocytes from the 
vessels in peritonitis, three or four grammes would be required 
to be given within a short time, to a man weighing 150 lbs. 

In guinea-pigs a dose of quinine sufficient to kill the animal 
does not stop the movements of the leucocytes in its blood, 
which are seen to go on, when a drop of it is examined after 
death. 

Red Blood Corpuscles. — The size of the red corpuscles is 
diminished by carbonic acid, by morphine, or by warmth, either 
applied locally on the hot stage of a microscope, or acting on 
them in the vessels of an animal suffering from fever. 

It is increased by oxygen, hydrocyanic acid, quinine, or cold ; 
and an increase occurs also in eases of anaemia. 1 

The red corpuscles pass out of the capillaries like the white, 
but they do so very slowly indeed, and in small numbers, under 
ordinary circumstances. Excess of sodium chloride in the blood 
causes them to pass out much more quickly ; 2 and rattle-snake 
poison, when locally applied, produces such sudden extravasation 
that it is impossible to follow the process : the whole field of the 
microscope becoming suddenly covered with blood. 3 

Action of Drugs on Infusoria. 

Among the infusoria, like the amcebse, each individual consists of a single 
mass of protoplasm, and not of a number of distinct cells ; but the proto- 
plasm is differentiated. Kound the greater part of the animal it seems to 
be somewhat harder, so as to form a sort of skin, excepting at one place 
which is softer than the rest, serving for the ingress of food and the egress 
of egesta. 

Instead of throwing out pseudopods, the body is either covered entirely 
with cilia or they are arranged round the mouth. Once it has entered by 
the mouth, the food finds its way all through the protoplasm of the body. 

A contractile vesicle exists, which pulsates rhythmically. 

Mode of Experimentation. — For the purpose of examining the 
action of drugs upon infusoria an infusion of hay ia prepared some days 
previously. Two small pipettes are then made, which will deliver drops 
of equal size. 

This is done by heating a piece of glass tubing in the middle, drawing 
it out, and cutting it across by a scratch with a triangular file (Fig. 10). 
With one of these a drop of hay-infusion is placed on the covering-glass, 
which is inverted on a Strieker's stage and examined. In order to ascertain 

1 Manassein, Ueber die Dimensioned, der Blutlcorperchen writer verschiedenen 
Einflussen. Tubingen, 1872. 

2 Prussak, Wiener Akad. SiUungsber.l\i., 1876 (Abth. 2), p. 13. 
' Brunton and Fayrer, Proc. Roy. Soc, February 1875, p. 271. 



64 PHAKMACOLOGY AND THEKAPEUTICS. [sect. I. 

the lethal strength of a drug, a drop of a solution of the poison of a definite 
strength is then mixed with it, and the infusoria are examined again after a 



certain time. 



Fig. 10. — Diagram to show the way o£ making small pipettes. 

If they continue moving, another experiment is made with a stronger 
solution ; but if they have completely stopped, it is repeated with a weaker 
one until the solution is of such » strength that the movements become 
very slight and cease almost immediately after mixing, and cannot be 
restored by the addition of water. As the two drops of fluid were of 
equal size, the lethal strength of the solution is just one half of that which 
was last added. By repeating the experiments in exactly the same way 
with different drugs, their relative poisonous properties are ascertained. 

Heat increases the rapidity both of the rhythmical contrac- 
tions of the vesicle and of the ciliary motion and consequently of 
the movements from place to place of the infusoria. It seems as 
if the cilia were not equally affected by heat, those which pro- 
duce a longitudinal movement appearing to be acted upon more 
quickly than those which cause a movement of rotation. Both 
kinds are first stimulated and then paralysed. 

At temperatures between 25° and 30° G. the contractions of 
the vesicle are greatly quickened, and the animal moves with 
great rapidity in the longitudinal direction. 

Between 30° and 35° its movements are still very rapid, but it seems to 
have lost the power of direction ; all the cilia seem in full action, and the 
movements of the individual are determined simply by their anatomical 
arrangement. 

Above 40° the cilia, which act longitudinally, appear to have stopped and 
the animal rotates, at first very rapidly, then slower and slower until all 
movements cease, and the protoplasm appears to become fluid ; but when 
the heat is still further raised it coagulates. 1 

Cold lessens the quickness of the rhythmical contractions of 
the vesicle, of the ciliary motion and of the movements from 
place to place. Weak electrical currents first quicken the ciliary 
motion and cause movements of rotation, then swelling of the 
protoplasm, slower movements, and finally apparent solution of 
the protoplasm. 

Moderate currents produce a tetanic contraction of the proto- 
plasm and of the cilia, while the contractile vesicle is unaffected. 

Strong currents cause liquefaction of the protoplasm. 

Saline solutions appear rather, if we may say so, to alter 
the conditions under which the infusoria live than to affect the 
protoplasm itself. Strong solutions cause them to shrivel and 



1 Eossbach, ' Die rhythmischen Bewegungserscheinungen der einf achsten Organ- 
ismen,'Verh. d.Wursburgerphysik. med. Gesellsch. A.N.P., Bd. ii., Separat-Abdruck 
S. 23. This work contains a number of exceedingly interesting and valuable 
observations on the subject. 



chap, m.] ACTION OF DEUGS ON PEOTOPLASM, ETC. 65 

then to swell up and become motionless. This effect appears to 
be due to the solution altering the quantity of water which the 
protoplasm contains. 

Weaker saline solutions, on the contrary, quicken their move- 
ments, and, instead of causing them to shrivel, make them swell 
up at once. Chloride of sodium, chloride, bromide, and chlorate 
of potassium, as well as alum, all have this effect. 

Acids in minute quantities cause contraction both of the 
body and of the vesicle. The ciliary motion is at first quickened 
and then retarded ; the rate of contraction of the vesicle is at 
once diminished. 

Moderate quantities cause coagulation of the protoplasm with 
swelling and liquefaction after death. 

Strong acids at once destroy the protoplasm. 

Alkalies in minute quantities cause swelling of the proto- 
plasm, dilatation and slowness of the contractile vesicle. 

Moderate quantities at once arrest the movements, cause 
liquefaction of the protoplasm, and destroy its differentiation, 
the contractile vesicles and vacuoles disappearing. They then 
cause swelling, and finally solution. 

In large quantities they produce immediate liquefaction of the 
whole body. 

Other drugs appear to affect the protoplasm itself, a*id 
arrest its movements without producing any apparent change 
in it. 

The most active are chlorine, bromine, corrosive sublimate, 
iodine, permanganate of potassium, and creasote. 

Quinine is much less powerful than these, though it is much 
more so than most other organic alkaloids. Strychnine has only 
one-fourth the power of quinine. 

Cobra poison at first greatly quickens the movements of 
infusoria and then arrests them, causing just before death a con- 
traction of the protoplasm, which then expands to its ordinary 
size. 

Relations of Motion and Oxidation. 

All animals, from the lowest to the highest, evidence their 
life by motion at one time or another ; and the energy required 
for this motion is maintained by processes of combustion. 

The materials for this combustion, viz. oxygen, and fuel of 
some sort, or food, are derived from the external medium in 
which the animal lives ; and in order to enable these substances 
to be available for each part of the animal body, we must have 
some kind of respiration and circulation going on in it. 

In unicellular organisms, consisting of a single mass of proto- 
plasm, the oxygen is derived from the water in which they swim, 
and both it and the nutritive material derived from the digestion 



•66 PHAEMACOLOGY AND THEEAPEUTICS. [sect. i. 

of enclosed masses are circulated through the protoplasm by 
contractile vacuoles. 

In sponges, where the organism no longer consists of one but 
of several cells united into a community, some of these are fur- 
nished with cilia, in order to send a current containing oxygen 
and food to the other cells having a less favoured position. 

In higher animals, where many cells are built up to form one 
organism, we find a circulatory and respiratory apparatus fully 
developed. 

The medium in which unicellular organisms live is the water 
in which they swim. The medium in which the cells composing 
the main parts of the bodies of higher animals, such as man, 
live, is not the air which surrounds the body, but the intercellular 
fluid in which the cells themselves are bathed. 

As Claude Bernard points out with his usual clearness, the 
cells of the human body and the lowest unicellular organisms 
alike live in a liquid medium. From the layer of fluid surround- 
ing it, the cell takes up the oxygen and food which this layer can 
yield. The supply being exhausted, a unicellular organism can 
move on elsewhere, but the cells in higher animals, being fixed 
and unable to move, require fresh portions of oxygen and of 
aiutritive fluid to be brought to them. 

• This is effected by the slow circulation of the lymph in which 
the cells themselves are bathed and by the supply to the lymph 
<of oxygen and nutritive material from the blood. 

The circulation of the lymph is aided in many lower or- 
ganisms by the motion of cilia, and this is found persisting in 
:some parts of the higher animals, e.g. the central canal of the 
spinal cord. 

Between the blood and the lymph an interchange goes on, 
oxygen passing from the blood to the lymph or intercellular fluid, 
and carbonic acid from the lymph to the blood. 

This interchange of gases between the blood, the intercellular 
fluid, and the cells is termed internal respiration. 

In order to maintain this, a constant current of blood must 
take place ; and when its circulation is locally arrested it becomes 
deprived of oxygen and loaded with carbonic acid, so that the 
•cells in the district in which the stagnation occurs suffer from 
local asphyxia, while the other parts of the body may be perfectly 
healthy. 

When the general circulation is arrested by stoppage of the 
heart, by obstruction of the pulmonary arteries, or by the rup- 
ture of an aneurism draining the blood away, the whole body 
suffers in a similar manner from general asphyxia by the cessa- 
tion of internal respiration. 

If oxygen were simply dissolved in the blood, the quantity 
which would be conveyed to the tissues would be too small for 
their wants, and we therefore have as an oxygen-carrier a sub- 



chap, in.] ACTION OP DRUGS ON PROTOPLASM, ETC. 67 

stance capable of taking up a large quantity of oxygen, of readily 
forming a loose compound with it> and of again giving it off 
readily to oxidisable substances. 

In man and mammals and many of the lower animals this 
substance is haemoglobin containing iron. In some annelids it is 
a green substance, chlorocruorin ; and in the octopus and some 
crustaceans it is a blue body, hsemocyanin, containing copper. 1 

In order to remove carbonic acid taken up from the tissues 
and obtain a fresh supply of oxygen, an interchange takes place 
between the blood and the external air in the lungs; this is 
external respiration. Without any direct influence being ex- 
erted upon the cells of the animal body themselves, they may be 
affected and their nutrition greatly modified by : 

1st. Alterations in the circulation of the intercellular fluid or 
lymph in which they are bathed. 

2nd. In the greater or less rapidity of circulation of blood 
locally. 

3rd. In the circulation generally, from changes in the heart 
and blood-vessels generally. 

4th. Changes in the oxygen-carrying power of the blood, 
either from alterations in its power to take up or give off oxygen. 

5th. Changes in the external respiration. 

All these conditions may be altered by drugs, or at least by 
therapeutic measures. Thus the circulation of lymph in a part 
may be increased by shampooing, and its accumulation in a 
case of dropsy may be removed by incision, by puncture, or by 
drainage. 

The circulation of blood may be arrested locally and gangrene 
induced by the continuous use of ergot. It may be increased by 
the use of local stimulants or irritants. 

The circulation generally may be affected by the large class of 
vascular stimulants and depressants, to be afterwards discussed, 
and sometimes by stoppage of the pulmonary circulation through 
minute emboli. 

Alterations in the oxygen-carrying power of the blood will 
be discussed presently, and those in the external respiration 
subsequently. 

Oxidation of Protoplasm. — The movements of protoplasm 
are intimately connected with processes of oxidation going oh , 
in it. 

By these processes chemical energy is converted into the 
mechanical energy exhibited in the movements, and this is 
sometimes very considerable. 

The oxygen which takes part in these processes is not always 
derived from the surrounding medium at the exact moment when 

1 For further details see Physiological Chemistry, by A. Gamgee, vol. i., 1880, 
p. 130. 

f 2 



68 PHAEMACOLOGY AND THEEAPEUTICS. [sect. i. 

"the movements take place ; it may have been obtained some time 
before, and the movements may continue for a little while after 
all oxygen has been removed. 

It therefore appears that protoplasm has the power of ab- 
sorbing and storing up within itself, in some manner or other, 
oxygen, which it can afterwards utilise for the purpose of liberat- 
ing mechanical energy. 

This storage of oxygen takes place not only in the proto- 
plasm of unicellular organism, but also in the tissues of the 
higher animals, e.g. the muscles. 

The exact way in which storage occurs is not known, but it 
has been well compared by Professor Ludwig to the storage of 
oxygen in gunpowder. The oxygen is there contained in the 
nitrate of potassium, a compound which is readily decomposable 
by the application of heat, and then gives rise to the evolution of 
mechanical energy ; and this it does perfectly well in an enclosed 
Bpace, like a gun-barrel, where no air is present. 

The power of storing up oxygen is very limited, and although 
protoplasmic movements continue for a little while after all ex- 
ternal oxygen has been removed, yet they will not continue long. 

A convenient way of ascertaining this fact has been devised by Ktihne, 
•who adds a small quantity of blood or of haemoglobin solution to a drop of 
water containing protoplasmic organisms or cells placed on a covering-glass. 
This is then observed with a micro-spectroscope. The haemoglobin solution 
exhibits the two bands characteristic of oxy-hsemoglobin. When all the 
oxygen is removed by means of a stream of hydrogen, kept up for some 
time, the spectrum of oxy -haemoglobin passes into that of reduced haemo- 
globin. 

The occurrence of this change indicates the moment when all the oxygen 
has disappeared from the liquid. By reckoning from this moment onwards, 
we are able to estimate the length of time during which the movements 
continue in the absence of oxygen. 

Oxygen-carrying Power of Protoplasm. — Not only does 
protoplasm possess the power of taking up oxygen readily and 
assimilating it to itself, but it has also the power of taking up 
and giving off oxygen to other substances when these substances 
would be unable to take it themselves. 

We may understand this action better by comparing it in a 
very rough way with that of a man whose greater strength 
enables him to seize fruit or break off pieces of sweatmeat and 
give them to his child, which thus enjoys what it could not have 
obtained for itself, however desirous of them it might be. 

.Method of Experimenting'. — Guaiae resin, when finely divided and 
oxidised, becomes of a blue colour. It has, however, only a slight power 
of attracting oxygen to itself from the air, or from water in which the 
oxygen is dissolved, and thus the blue colour is developed slowly. 

On the addition of protoplasm to the water containing the guaiae, the 
blue colour is developed rapidly. The reason of this possibly is, that the 
protoplasm has taken up oxygen from the water and given it over to the 
guaiae. This process reminds us of the action of spongy platinum in causing 
oxidation of hydrogen or formic acid. 



chap, iii.] ACTION OF DEUGS ON PROTOPLASM, ETC. 69 

Ozonising Power of Protoplasm.— It has been supposed 
that, in addition to its power of oxidising such substances as 
guaiac by giving to them oxygen which it has already taken up, 
protoplasm has the power of actually breaking up the molecules 
of oxygen and forming ozone. 

The rapid oxidation which protoplasm causes has been at- 
tributed to this power. A similar action to this is observed 
during the slow oxidation of phosphorus. Phosphorus appears 
to break up the molecule of oxygen, taking to itself one atom 
and freeing another, which unites with two more in order to 
form ozone. 

Action of Drug's on Oxidation. — A convenient way of testing the 
effect of drugs upon oxidation is to use the protoplasm of potato, of lettuce, 
or of dandelion. The most active part of the potato lies just under the 
skin, as is seen by pouring some freshly prepared tincture of guaiac over 
its cut surface. A ring of blue first forms close to the skin, and is always 
darkest there, although it may extend over the whole of the cut surface. The 
ammoniated tincture of the British Pharmacopoeia will not answer. The 
tincture must be made with spirit only. When potato is used, the whole of 
the potato may be pounded with water, or, still better, the peel alone may be 
cut off and rubbed up with water in a mortar and then filtered through 
linen. When lettuce or dandelion is used, the fresh leaves are triturated 




Pig. 11.— Test-glasses for examining the action of drags on oxidation. 

in a mortar with five or ten times their bulk of water, and the solution is 
then filtered. A row of test-tubes or test-glasses having been prepared, 
a measured quantity of water is put into the first. In this glass the 
protoplasm is not mixed with any foreign substance, and it therefore 
serves as the standard with which to compare the others ; and into the 
others is put a similar quantity of solutions of the drugs to be tested. 
Each test-glass is distinguished by a label bearing either a number or the 
name of the drug which it contains attached to it. To each glass a mea- 
sured quantity of the lettuce-water is added and the contents mixed by 
shaking. All are allowed to stand for a period varying from a few minutes 
to some hours. Then a small drop of freshly-prepared tincture of guaiao 
is added to each, mixed by shaking, and allowed to stand for one or two 
minutes ; the glasses are then arranged in the order of depth of colour. 

In this way it is found that many drugs greatly lessen or almost com- 
pletely abolish the oxidising power of protoplasm, so that while the lettuce- 
water in the standard glass assumes a dark-blue colour, that in the others 
exhibits varying shades of blue, or may even retain the creamy-white 
colour caused by the guaiac without showing any blue whatever. 

The colour is deeper and the reaction is more readily obtained when 
the tincture of guaiac is mixed with some substance capable of giving off 
oxygen readily, such as a solution of peroxide of hydrogen in ether, usually 
called ozonic ether. 

A number of experiments made with potato-water by Cash and myself 
showed that oxidation in potato solution was diminished most powerfully by 
strychnine,, then by quinine and coniine; next by morphine, codeine, cin- 
chonine, and atropine, each of which had almost exactly the same action ; 



70 PHAEMACOLOGY AND THEKAPEUTICS. [sect. I. 

next by nicotine, and then veratrine. Aconitine seemed neither to retard 
nor accelerate oxidation, and presented exactly the same degree of coloration 
as the standard solution. Caffeine, picrotoxin, and digitalin appeared some- 
what to hasten oxidation. 1 

Reduction by Protoplasm. — Ehrlich 2 has shown, in an 
interesting manner, the properties of oxidation and reduction 
possessed by protoplasm. Methylene-blue, alizarin-blue, and 
indo-phenol are coloured bodies which become colourless on 
being reduced. After injecting methylene-blue into the veins, he 
found that most of the parenchymatous tissues became coloured, 
the heart, brain, cortex of kidney, the voluntary muscles, &c, 
while the lungs and the liver were normal and only a small 
amount of colouring matter could be obtained by prolonged 
exposure to the air. Ehrlich concluded that the indifferent 
paraplasma of the cells excretes the unchanged matter, while 
the protoplasm, which is greedy for oxygen, excretes the reduced 
colouring stuff. 

Action of Drugs on Blood. 

The haemoglobin of blood has also the power of taking up 
oxygen readily and giving it freely off again. Haemoglobin free 
from oxygen, or, as it is sometimes called, reduced haemoglobin, 
is recognised by the simple band which it gives between D andE, 
when examined spectroscopically. 

Hemoglobin combined with oxygen, or oxyhemoglobin, gives 
two bands, situated in nearly the same portion of the field of the 
spectroscope. These are separated from one another by a clear 
space, and are more sharply defined and darker than the spec- 
trum of haemoglobin. 

The oxygen of oxyhemoglobin may be replaced by other 
gases. Thus: — Carbonic oxide drives out the oxygen from 
oxyhaemoglobin and forms carbonic oxide haemoglobin (CO- 
haemoglobin). This is a comparatively stable compound. It 
presents spectroscopic bands nearly the same as those of oxy- 
haemoglobin, but which are slightly nearer to the violet end of 
the spectrum. This compound, being stable, circulates in the 
blood without performing the functions of respiration. It 
neither takes up oxygen in the lungs nor gives off oxygen to the 
tissues. 

Animals poisoned by CO therefore die of asphyxia, the in- 
ternal respiration being arrested, and their blood remains for a 
long time of a florid colour. 

Hydrocyanic acid appears also to form a compound with 
haemoglobin, which is much less stable than that of carbonic 
oxide. There has been a good deal of discussion about this 

1 St. Bartholomew's Hospital Reports, 1882. 

2 Ehrlich, ' Zur biologischen Verweitung des Methylen-Blau,' Centralblatt f. 
die med. Wissenscha/t. 1885, No. 8. 



chap, in.] ACTION OF DBUGS ON PEOTOPLASM, ETC. 71 

compound, and its existence, indeed, has been denied. The 
spectrum of this compound consists of a single band resembling 
reduced haemoglobin, but nearer the violet end of the spectrum. 

Solutions of haemoglobin when boiled are completely decom- 
posed into haematin and a proteid body or bodies. 

Haematin gives a single band, which differs according as the 
solution is alkaline or acid, and according as the solvent is water 
or ether. 

Acids split up haemoglobin into haematin and a proteid. It is 
sometimes possible to get these to recombine and to again form 
haemoglobin, but this is far from being always the case. 

Methaemoglobin appears either to be a product of the in- 
complete decomposition of haemoglobin or of its excessive oxida- 
tion. Some think that it contains more oxygen than haemoglobin, 
but less than oxyhaemoglobin. Others think that it is a per- 
oxyhaemogldbin containing more oxygen than oxyhaemoglobin. 
At all events the oxygen is more firmly combined in methaemo- 
globin than it is in oxyhaemoglobin. 

This body is distinguished by a spectroscopic band nearly in 
the same place as that of the acid haematin. 

When the solution is made alkaline by ammonia this band 
disappears, and is replaced by another fine one near D. 

Methaemoglobin appears to be converted again into haemo- 
globin by the action of reducing agents and subsequent oxidation. 
When its solution is treated- with reducing agents, it shows the 
spectrum of reduced haemoglobin ; and on shaking this with air 
oxyhaemoglobin is formed, as shown by the appearance of its 
characteristic bands. 

When blood is allowed to stand for a length of time, it 
assumes a brownish colour and gives the bands of methaemo- 
globin. When nitrites are mixed with freshly-drawn blood, they 
impart to it a chocolate colour, and it then exhibits the bands of 
methaemoglobin. 

As the oxygen in methaemoglobin is more firmly combined 
with it than in oxyhaemoglobin, substances such as the nitrites 
interfere with internal respiration, and thus in large doses will 
cause symptoms of asphyxia ; but their action differs from that 
of carbonic oxide in one very important particular, viz., that it 
is altered by asphyxia; whilst that of carbonic oxide is not. 
Eeducing substances are constantly present in the blood and 
tissues, and these accumulate to a greater extent during the pro- 
cess of asphyxia. Carbonic-oxide haemoglobin, being a stable 
compound, remains unaffected by these, and the blood continues 
to circulate unchanged. 

But methaemoglobin, which is produced by the action of the 
nitrites, becomes reduced by these substances and forms the 
normal reduced haemoglobin ordinarily present in venous blood. 
When this reaches the lungs it again takes up oxygen, forming 



72 PHARMACOLOGY AND THEEAPEUTICS. [sect. I. 

normal arterial blood, by which the internal respiration is again 
restored. Thus, unless new supplies of nitrites are constantly- 
added to the blood, the asphyxia they occasion quickly passes 
away. That caused by carbonic oxide, on the contrary, is much 
more permanent. It is not removed by artificial respiration, and 
in order to save the life of the animal or person poisoned by it, a 
quantity of the poisoned blood must be withdrawn from the veins 
and healthy blood introduced by transfusion. 

Oxyhemoglobin 

Haemoglobin 

Carbonic-oxide hsemo- 1 
giobin j 

Sulphsemoglobin 

Ditto, oxygenated 

Methaemoglobin 

Bloodtreatedwithnitrite ] 
of amyl and alcohol ... J 

Acid hrematin (alcoholic ] 

solution) J 

Alkaline hsematin (al- ] 

coholic solution) ) 

Blood treated with 

cyanide of potassium 

or hydrocyanic acid. . . 
Ditto, oxidised 

C D B 5 V 

Fig. 12.— Chart showing the spectroscopic absorption-bands of haemoglobin and its derivatives. 

(After McMunn.) 

A method of ascertaining the effect of drugs on oxidation in 
the blood consists in estimating the rate at which acid is de- 
veloped in it after its removal from the body. 

In this way Binz and his scholars, Zuntz, Scharrenbroich, 
and Schulte, have found that both quinine and sodium nitro- 
picrate stop the formation of acid ; cinchonine lessened it. 1 

The alterations effected in the interchange between blood 
and the air have also been observed by simply allowing the blood 
mixed with the drug to stand for a certain time in a closed 
receiver, partially filled with air, and afterwards analysing the 
gases which the receiver contains at the end of the experiment. 

By this mode of experimentation, Harley 2 found that hydro- 
cyanic acid diminished or arrested the processes of oxidation 
in the blood. Alcohol, chloroform, quinine, morphine, nicotine, 
strychnine, and brucine, all had a similar action, though varying 
in extent, all of them diminishing both the amount of oxygen 
absorbed and of carbonic acid given out. 

Uric acid and snake poison had a contrary effect, increasing 

1 A very complete list of the literature of this subject is given by Binz in his 
work, Das Chinin, Berlin, 1875. 

2 Harley, Phil. Trans., 1805, p. 678. 



"BHflTT 1 ' ■ 

Sf 9HRnr 

■ I "'" ; 
.. . 

Hi_ H 

III,!. I .lil 

EH II s 



chap, in.] ACTION OF DEUGS ON PEOTOPLASM, ETC. 73 

the absorption of oxygen and the evolution of carbonic acid. 
Curare appeared to lessen the absorption of oxygen, but in- 
creased the evolution of carbonic acid. Mercuric chloride 
lessened the • carbonic acid, but increased the absorption of 
oxygen. Arsenious acid and tartar emetic diminished the ab- 
sorption of oxygen, but arsenious acid appeared also to lessen 
the evolution of carbonic acid, while tartar emetic appeared to 
increase it. 

Catalysis. — Fermentation. — Inorganic Ferments. 

There are many examples of chemical reactions which only 
occur between two bodies when a third is present, which may 
nevertheless be found unchanged at the end of the process. 
Notwithstanding the fact that the third body is found unchanged 
at the end of the process, it may have undergone changes during 
the continuance of the process. Thus alcohol is not converted 
into ether and water by boiling alone, but it does undergo this 
conversion by boiling with sulphuric acid. The acid is found 
unchanged at the end of the process, but is changed during it 
into ethyl- sulphuric acid, which, combining with alcohol, again 
yields sulphuric acid along with ether. 

In other cases, however, we cannot show that the substance 
has undergone change. Thus starch is converted into dextrin 
and sugar and cane-sugar into grape sugar by boiling with acids, 
but we do not at present know that the acid has undergone any 
change during the process as it does in the preparation of ether. 
Peroxide of hydrogen is rapidly decomposed by finely divided 
platinum or silver, and finely divided platinum will, on the other 
hand, cause oxygen and hydrogen to unite rapidly. Such 
actions, where the third substance seems to act by its mere con- 
tact with the other substances, and without undergoing change 
itself, are called catalytic. They are probably due to an attrac- 
tion of some kind bordering both on chemical and physical 
between the molecules. 

Thus some organic substances would resist the oxidising 
action of the air for a considerable time, but they are readily 
oxidised by charcoal. It is usually said that the charcoal has 
the power of attracting oxygen and condensing this gas upon its 
surface. It does not unite with the oxygen chemically so as to 
form C0 2 , but merely attracts it, holds it for a while, and then 
gives it off readily to any oxidisable substance. Platinum, 
palladium, rhodium, and iron absorb hydrogen, palladium doing 
* so to an enormous extent, especially when it is in a spongy form. 
The hydrogen is supposed by some to be simply condensed 
within the metal, while others think that the hydrogen and 
metal unite to form a hydride. The hydrogen is given off from 
the metal in a nascent form, and has very strong affinities. 



74 PHAEMACOLOGY AND THEEAPEUTICS. [sect, i, 

Thus palladium-hydrogen readily reduces ferric to ferrous salts, 
the hydrogen taking oxygen from the ferric salt and forming 
water. But when the hydrogen is liberated from palladium or 
rhodium in presence of oxygen, it appears to convert the oxygen 
into ozone, and greatly increases its oxidising power. Thus 
palladium-hydrogen with oxygen colours a mixture of potassium 
iodide and starch paste blue, and oxidises hemoglobin to met- 
haemoglobin and ammonia to nitric acid. Spongy rhodium, or 
iridium saturated with hydrogen, cause formic acid to be oxidised 
to carbonate, calcium formate being changed into calcium car- 
bonate. Exactly the same action is possessed by an organic 
ferment, and in the conversion of the formic into carbonic acid 
the ferment and the spongy rhodium or iridium are alike un- 
changed. Spongy platinum, palladium, rhodium, and iridium 
may thus be regarded as inorganic ferments. 1 

Ferments Organic and Organised. 

The mechanical energy displayed in the movements of proto- 
plasm is supplied by processes of chemical change, and chiefly of 
oxidation. 

By these processes some of the substances contained in the 
protoplasm are destroyed, and their place must be supplied by 
fresh material. This material is obtained from the food, but, in 
order to render it available for the protoplasm, its atoms must 
be more or less disintegrated in order that they may again be 
assimilated. As Hermann very well puts it, the bricks of which 
the old house is built must be pulled asunder before they can be 




Pig. 13. — An amoeba figured at two different periods during movement, 
n, nucleus ; i, ingested bacillus. 

built up again into the new. In the present case, the bricks 
are the atoms of protoplasm in some other organism living or 
dead, which is being used as food by some larger mass of proto- 
plasm, as, for example, a bacillus which has been absorbed by 
an amoeba. (Fig. 13.) , 

In order to render the protoplasm in the bacillus available 
for the nutrition of the amoeba, the atoms of which it is composed 

1 Hoppe-Seyler, Ber. d. deutsch. chem. Gcscllsck., 1883, Feb. 12, p. 117. 



chap, in.] ACTION OF DRUGS ON PEOTOPLASM, ETC. 75 

must be, to some extent, decomposed. This process appears to 
be effected by enzymes or, as they are sometimes called, organic 
ferments. 

Ferments are bodies which split up carbon compounds at 
moderate temperatures and lead to the formation of other carbon 
compounds, most of which are of a simpler constitution than the 
first. 

In this definition we require to introduce the term ' moderate 
temperature,' because excessive heat alone will cause the atoms 
of a complex carbon compound to fly asunder and form simpler 
compounds, as in the process of dry distillation. A less heat 
than this, but aided by the action of powerful chemicals, will 
also produce the same effect. For example, fibrine heated with 
diluted hydrochloric acid under pressure yields peptones; but 
the same change is effected at the temperature of the mammalian 
body by the aid of pepsin. Trypsin from the pancreas effects a 
similar change when mixed with water alone without the aid of 
an acid, though its action is certainly aided by alkalies. Neither 
pepsin nor trypsin are alive, but they contain carbon, and are 
therefore called organic ferments. But this term easily leads 
to confusion with ordinary living or organised ferments, and so 
the term enzymes has been lately introduced to signify ferments 
such as diastase, ptyalin, and pepsin, which, though they con- 
tain carbon and are therefore called organic, are not alive and 
have no definite structure, or, in other words, are not organised. 
The term unformed ferments has also been applied to them. 

By organised ferments we mean minute living organisms, 
which in the course of their life-processes cause decomposition of 
the substances in which they live. They have also been called 
formed ferments. Examples of these are yeast and bacteria. 

The processes of fermentation have been divided by Hoppe- 
Seyler into two kinds : — 

(1) Those in which water is taken up; and (2) those in which 
oxygen is transferred from the hydrogen to the carbon atom. 

The hydration in the first case is produced by the ferment 
acting either (a) like a dilute mineral acid at a high temperature, 
as in diastatic and invertive ferments and in the decomposition 
of glucosides; or (b) like caustic alkalies at a high tempera- 
ture, as in the splitting up of fats or the decomposition of amide 
compounds. These processes of fermentation by hydration are 
chiefly carried on by enzymes. 

The second class of fermentative changes by the transference 
of oxygen from the hydrogen to the carbon, as in lactic and 
alcoholic fermentation and in putrefactive processes, are chiefly 
produced through the agency of organised ferments. The action 
of the latter may be to a certain extent imitated by spongy 
platinum, which absorbs oxygen readily, and readily gives it off 
again to oxidisable substances. Thus acetic fermentation usually 



7C 



PHAEMACOLOGY AND THEEAPEUTICS. [sect, i. 



produced by an organised ferment may be also brought about by 
spongy platinum. 

The products formed by the action of organised ferments 
on the media in which they live are poisonous, to them; and 
when these products accumulate above a certain proportion, 
they kill the ferments. Just as a fire will be smothered in 
its own ashes, or an animal in a confined space will be 
poisoned by the carbonic acid which it has itself produced, so 
the yeast plant, when living in a solution of sugar, is killed by 
the alcohol which it produces, as soon as this amounts to 20 per 
cent. ; and other organised ferments have their lives limited in 
a similar way. 

Action of Drugs on Enzymes. — Although, with the ex- 
ception of a kind of pepsin in the naked protoplasm of JEthalium 
septicum, a species of myxomycetes, 1 enzymes have not been 
shown to be present in the protoplasm of the lowest organisms, 
it is probable that the processes of life in all living beings from 
the lowest to the highest are carried on by their means. A 
ferment, which is evidently of the greatest importance in the 
animal economy, has been recently discovered in the blood by 
Schmiedeberg. He has given to it the name of Histozyme, 
and he believes that its function is to split up nitrogenous sub- 
stances preparatory to their oxidation. 2 The chief enzymes are 
the following : — 

I i Diastase from malt. 

Ptyalin from saliva. 

Diastatic ob J amyloids into maltose A ^? ylo P sin fr ° m P^creas. 
Aklolytic 1 Other ferments having a similar action 

. from other parts of the body. 

From small intestine. 



Inveksive 

Fekments 



Which convert starch and 
amyloids into maltose . 

Which convert maltose 
into glucose . 

I Which convert cane sugar 
into dextros* and levu- 
lose . . . . 
Which decompose gluco- 
sides .... 
Decomposing sugar . 



' Invertin from the intestinal juice. 

„ „ mucus of the mouth. 

„ „ tissue of the testis. 

Emulsin from bitter almonds. 
Myrosin from mustard. 
.Rennet, 
f From stomaoh. 

n 



Proteolytic 

Fekments 



(Which decompose proteids 
and form peptones 



Decomposing fats , . , .., ,„ J . . 

1 From pancreas (Stearopsin). 

Pepsin from stomach. 

Trypsin from pancreas. 

Others from saliva. 

Histozyme. 

The action of drugs on enzymes is ascertained by taking two portions of 
a solution containing the enzyme and the substance to be acted upon. To 
one of these a quantity of the drug to be tested is added, the other acts as a 
standard with which to compare it. If the drug is in solution, a correspond- 
ing quantity of water must be added to the standard solution in order that 
both may be alike. _ They are then placed in a warm chamber and the 
rapidity of digestion is noted. 



1 Krukenberg, Untersuch. a. d. physiol. Inst. d. Univ. Heidelberq, Bd II 1878, 
p. 273. 

8 Schmiedeberg, Arch.f. exyer. Path. u. Pharm., Bd. xiv. S. 379. 



chap, in.] ACTION OF DEUGS ON PKOTOPLASM, ETC. 77 

The effect of some of the more important drugs on the action 
of enzymes will be readily seen from the following table from 
Wernitz, quoted by Meyer. 1 In it the proportion is shown of 
the drugs which arrest in watery solution the action of enzymes ; 
thus, one part of chlorine in 8,540 parts of a watery solution will 
arrest the action of ptyalin upon starch paste, while creasote has 
.no action on it even in saturated solution, and corrosive sublimate 
is so enormously destructive as to arrest its action, even in one 
part in 52,000. 

1 Hermann Meyer, ' Ueber das Milchsaureferment u. sein Vernal ten gegen 
Antiseptica,' Inaug. Diss. Dorpat, 1880. 



78 



PHAEMACOLOGY AND THERAPEUTICS, [sect. i. 



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chap, hi.] ACTION OF DEUGS ON PEOTOPLASM, ETC. 



The different action which the same drug exerta upon formed 
and unformed ferments is of great importance, because upon it 
depends our power to use the drug in the practice of medicine. 
Thus creasote, which appears from the preceding table not to 
destroy the digestive power of ptyalin and to have but a weak 
action upon that of pepsin, has been found by Werneke to destroy 
yeast in a dilution of one part to 500 of water ; and by Bucholtz 
to kill bacteria in a dilution of one part to 1,000 of water. This 
difference enables us to arrest fermentation in the stomach de- 
pending on the presence of low organisms, while the digestive 
action of the pepsin is not interfered with, or only very slightly. 
The following diagram shows the action of drugs on enzymes 
and on the lactic ferment, which is a bacillus. 




Fig. 14.— Diagram to show the different action of drags on different enzymes. The nature of the 
line showing the action of each drug is shown under its name. 



80 PHABMACOLOGY AND THEEAPEUTICS. [sect. i. 

Zymogens. 

As several enzymes act readily in neutral or slightly alkaline 
fluids, it is evident that if they existed free in every part of the 
animal body, they would soon lead to its speedy destruction. 
Accordingly, we find that they do not normally exist free, except 
at the times and places they are required. 

This fact was first discovered by Kiihne in relation both to the stomach 
and pancreas, and was announced by him in the course of lectures which he 
delivered at Amsterdam in 1868-69, which I attended. In my note-books of 
those lectures I find that he stated that there seems to exist ' a pepsin-giving 
substance,' because if a ' slice of stomach is thrown directly into dilute HC1 
of 4 parts to 1,000 of water at 40° C. no digestion takes place,' ' a fact which 
shows that pepsin is not always present in it. In regard to the pancreas, he 
not only recognised the existence of a ferment-yielding body, but described a 
mode of obtaining ferment from it in the following words : — ' Glands which 
have no action on fibrine can be made active by digesting in very dilute acid 
and then neutralising or alkalising, there seeming to exist a, ferment-forming 
substance in the pancreas.' 

Kuhne's discovery of the existence of ferment-yielding bodies does not 
seem to have become widely known, and it was again made independently by 
Liversedge 2 in regard to the amylolytic ferment of the pancreas, and by 
Heidenhain in regard to trypsin. These observers found that when glands 
which did not contain ferment were exposed to the air ferments were formed. 

Heidenhain 3 also investigated more fully these ferment- 
forming substances, and gave to them the name of zymogens. 

The methods by which we obtain ferments from zymogens 
are, therefore, exposure to air and treatment with acids. 



Organised Ferments. 

The chief organised ferments are the yeast-plant, which 
produces alcohol and carbonic acid from grape sugar, and 
various kinds of bacteria, one of which produces butyric, 
another lactic, and another acetic fermentation. Both yeast and 
bacteria belong to the lowest class of plants, the protophytes. 
To this class also belong moulds, the action of drugs upon which 
is sometimes important, inasmuch as moulds give rise to some 
skin diseases. 

Yeasts, moulds, and bacteria have been variously classified 
by different authors, and the classification is apt to undergo 
changes as our knowledge of the life-history of these different 
organisms increases. 

At present it is not certainly known whether the various 

1 Just after this there is unfortunately a blank in my notes, but Professor 
Kiihne has kindly supplied the deficiency, and informs me that he was then speak- 
ing of slices taken from the external surface of the stomach, and therefore containing 
the lower ends only of the gastric glands. 

2 Liversedge (Nov. 1872), Journ. of Anat. and Physiol., Nov. 1873, p. 23. 
• Heidenhain, Pflilger's Archiv, Bd. xi. p. 557. 



chap. in.]. ACTION OF DRUGS ON PROTOPLASM, ETC. 81 

kinds of bacteria, for example, are generically or specifically differ- 
ent, or whether they can, by altered cultivation, be transformed 
into one another or not. 

Koch, who has cultivated them by the dry process on gelatine 
instead of in liquid, and has thus been able to avoid admixture 
of different kinds of bacteria, has come to the conclusion that 
each kind possesses distinctive characters ; but Klein has shown 
that, even when cultivated in this way, bacteria may vary much 
in form. Thus the bacillus anthracis may form torula-like cells, 
from which ordinary bacilli are again produced, 

The numerous names used in treatises on the subject of 
organised ferments are apt to lead to confusion, hence some of 
the names are given here simply for the purpose of reference. 
Thus Brefeld's classification is : — 

(1) ' Phycomycetes = algoid fungi ; (2) Mycomycetes = true 
higher fungi ; (3) Myxomycetes = gelatinous fungi ; (4) Blasto,- 
mycetes = yeast fungi ; (5) Schizomycetes=bacteria. 

The classification into yeasts, moulds, and bacteria which I 
have followed may not be botanically correct, but it is convenient 
for our present purpose. 

" Yeasts. — The yeast-plant, to which various names have been 
given, as torula cerevisiae, saccharomyces, consists of ovoid cells, 
which multiply by budding. The buds may remain attached, 
forming torula-chains, but when they attain the size of the parent 
cell they fall off and begin to multiply anew. When placed in 
saccharine solutions the plant, during the process of growth, 
decomposes the sugar and forms alcohol and carbonic acid, 

In this process oxygen is usually absorbed from the air in 
considerable quantities, but fermentation can occur in saccharine 
solutions even when oxygen is excluded, though under such con- 
ditions the torula grows slowly. When plenty of oxygen is 
present, and the layer of fluid shallow, the torula grows luxuri- 
antly, but there is very little fermentative change ; while, on the 
other hand, when free oxygen is excluded the torula grows 
slowly, but there is marked fermentation. 

Another plant nearly allied to yeast is the mycoderma vini, 
the ferment which changes alcohol into acetic acid. The myco- 
derma is not regarded by Naegeli as a species distinct from 
torula, and it is considered by Grawitz to be the same as the 
fungus found in the aphthous patches which occur about the 
mouth and throat of children suffering from thrush, although 
this fungus is usually said to be an oi'dium. 

To teat the action of drugs on alcoholic fermentation, equal quantities of 
a solution of grape sugar with yeast are introduced into two test-tubes, and 
to one of them a little of the substance to be tried is added. These are then 
inverted over mercury and kept in a warm place for several days. The 
amount of gas developed is then measured, and the power of the drug to 
prevent fermentation is estimated by the diminution in the amount of 
carbonic acid produced, as compared with the standard. 

a 



'82 PHAEMACOLOGY AND THEEAPEUTICS. [sect. i. 

Mould Fungi, or Hyphomycetes. — These form long fila- 
ments or hyphse, which become agglomerated into a mycelium 
or mass of compact tufts. They multiply not only by gemmation, 
but by the formation of spores. 

These moulds vary considerably according to the soil in 
which they grow, and the amount of oxygen present. Thus, if 
the spores of the common white mould, Mucor mucedo, are sown 
in a liquid containing sugar and exposed to the air, they grow on 
the surface, forming branched hyphss without septa, and the 
liquid absorbs oxygen. But if the mycelium be immersed, or the 
oxygen withdrawn, septa develop in the hyphse, and they break 
up into segments which multiply by budding, forming a kind of 
yeast with large cells, and, like the true yeast, decomposing sugar 
into alcohol and carbonic acid. 

They may be trained to thrive on substances on which they 
do not usually grow by gradually altering the composition of 
the soil. Thus, the commonest of all moulds, Penicilliwm 
glaucum, although it does not usually grow on blood, may be 
trained to do so by transplanting it from bread to peptone, and 
then to blood. 

Heat destroys these fungi, but a much higher temperature is 
required to kill the spores than the perfect plant, and in order to 
destroy the spores a temperature of 110 D -115° C, kept up for 
an hour, is requisite. 

The mould-fungi cause some local diseases in the body, and 
especially skin diseases such as favus, tinea tonsurans, tinea 
versicolor, tinea sycosis, onychomycosis, and the madura-foot or 
fungus-foot of India. They also occur in the fur of the tongue. 

Bacteria, or Schizomycetes. — Bacteria are every day be- 
coming more and more important on account of the relation in 
which they are found to stand to various diseases. Anthrax, 
diphtheria, phthisis, and typhoid fever, are probably all due to 
various species of bacteria introduced into the body, and affecting 
various organs in it. It is, therefore, of the greatest possible 
importance that their life-history should be learned, and that we 
should know what the conditions are under which they thrive 
best, and what the conditions are which will destroy their life 
and prevent their development. 

_ They appear to increase in two ways : first, by simple multi- 
plication of their parts, and secondly, by forming spores. 

Bacteria require water, organic matter, and salts, for then- 
life. Some of them also require the presence of free oxygen; 
others do not; hence they have been divided by Pasteur into 
two classes : aerobious and anaerobious. To the anaerobious 
bacteria oxygen is not merely unnecessary but hurtful, and 
even the _ aerobious bacteria, although they require oxygen 
in a certain quantity, are injured or destroyed by it when it is 
in excess. 



chap, in.] ACTION OF DRUGS ON PROTOPLASM, ETC. 83 



Blastomycetes, 01 ) 
Yeasts . / 




Fie. 15. 



(Tornla, 
or Saccharomyces (Fig. 151 
01 Mycoderma. 



Hyphomycetes, or 1 
Moulds . . ) 




Fig. 16. 



/Mucor. 
Penicillium. 
Oldium. 
Achorion. 
Trichophyton 
Microsporcm. 












iWX 



*\\ 




FIG. 17. 



Schizomycetes, 
Bacteria . 



/ Sphaerdbacteria 
(globular cells) 
Microbacteria, or 
Bacteria proper 
(smallj rod-like cells) 

Desmobacteria, or 
Filobacteria (larger 
rod-like or thread- 
like cells) 



1 Micrococcus (1 (a & 6) & 2, Kg- 16). 
J Sarcina (3). 



Bacterium 



Bacillus (straight) 



Spirobacteria 
(twisted or spiral 
cells) . . • 



( Bacterium termo (4). 
(B. llneola(5). 

IB subtilis(6). 
B. anthracis (7). 
B. septicemia. 
B. malaria? (8). 
B. tuberculosis (12). 
B. lepra?. 
Vibrio (wavy) . Vibrio serpens (9). 

Spirocha?ta(Iong,flex- ] gpirochasta. Ober- 
ible, close-wound f meye ri(10). 
spirals) . . . I 
Spirillum (short, stiff, 1 s _ T0 i u t a ns (11). 
open spirals). . J 

e 2 



84 PHAEMACOLOGY AND THEEAPEUTICS. [sect. r. 

The soil which is most favourable to different classes of 
bacteria varies with each class. A struggle for existence goes 
on between bacteria and other organised ferments, and between 
different kinds of bacteria themselves, in the same way as amongst 
higher plants. Just as an abundant crop of one kind of higher 
plants will occupy a whole field and choke other plants, so that 
kind of bacterium which grows most readily in a particular soil 
will choke others and prevent them growing at the same time 
with itself. During their growth they alter the soil or substance 
in which they grow, either by exhausting the nutriment it 
affords, or by forming in it new substanaes which are injurious 
to themselves, and thus they gradually die out. 

But the soil which is no longer suitable for one kind of 
bacterium then becomes suitable . for another, and their spores, 
which may have lain without germinating during the time the 
first kind was growing, now begin to grow actively. 

Thus, if a number of germs of different classes of fungi be 
added at the same time to a saccharine solution, the bacteria 
only will grow and set up lactic fermentation. If a small quan- 
tity of tartaric acid be now added (J per cent.) the yeast alone 
will grow and alcoholic fermentation begins. If more tartaric 
acid be added (4-5 per cent.) the alcoholic fermentation stops, 
and mould begins to grow. In this process neither the bacteria 
nor the yeast are killed by the addition of tartaric acid, which, in 
different proportions, merely renders the liquid more favourable 
for the growth of the yeast and mould respectively, and enables 
them to flourish best,, although the others are still present. 

In fresh grape-juice many germs are present, but the compo- 
sition of the liquid being more favourable to the growth of. the 
yeast-plant than to other fungi, it alone grows. When it has 
converted the sugar into alcohol its growth stops, and bacteria 
may then multiply and convert the alcohol into acetic acid. 
This in turn checks the growth of the bacteria, and mould-fungi 
then find the soil favourable. In their growth they consume the 
lactic acid, and the liquid once more affords a favourable soil for 
bacteria, which may then grow and cause putrefaction. 

The same struggle for existence occurs between the different 
species of bacteria themselves. Thus micrococci may be pre- 
vented from growing by micro-bacteria, and bacilli may be killed 
by bacterium termo when the supply of oxygen is insufficient for 
both. 1 

It is to be noted, however, that in the struggle for existence 
the formation of poisonous products by bacteria- may be, and 
probably is, beneficial to them. No doubt these poisonous 
products check their own growth and finally destroy them ; but 

1 Ziegler's Pathological Anatomy, translated and edited by MacAlister, p. 272. 
This work contains a very lucid and complete account of disease germs. 



chap, in.] , ACTION. OF DRUGS ON PROTOPLASM, ETC. 85 

in the struggle for existence between bacteria and living tissues 
these poisons may be beneficial to the bacteria by killing the 
tissues, and thus giving the bacteria a more ample supply of 
nutriment. 

In investigating any problem it is always best to take the 
simplest case, and if we look at the struggle for existence 
between bacilli and an amoeba, or white blood-corpuscle, we shall 
see that the formation of poisonous products by the bacteria may 
enable them to destroy the amoeba or leucocyte instead of their 
being destroyed by it (Fig. 25, p. 87). 

These poisonous products in fact may prepare the soil for 
bacteria, and this supposition is confirmed by the observations 
of Eossbach and Eosenberger. Eossbach found that when papain 
was injected into the vessels, micrococci developed in the blood 
with extraordinary rapidity, the ferment seeming to have altered 
the blood to such an extent that it became an exceptionally 
favourable soil for the micrococci. A similar result was observed 
by Eosenberger from the injection of sterilised septic blood. In 
tbis blood the bacteria themselves were destroyed, but the 
poisonous substances which they had formed were present, and 
these seemed to have a similar action to the papain. 

The struggle for existence between the Organism and 
the Microbes which invade it.— This has been found by 
Metschnikoff to occur both in the blood and the tissues. In the 
daphne, or water-flea, where the tissues are transparent, he has 
been able to observe the spores of a kind of yeast passing from 
the intestinal canal into the body-cavity (Figs. 18, 19). As they 
pass through they are attacked by leucocytes — sometimes by one, 
sometimes by many. These leucocytes occasionally coalesce 
so as to form a Plasmodium. When they are sufficiently power- 
ful they digest and destroy the spores (Figs. 19, 20, and 21). 
Sometimes the spores may be left sufficiently long intact to 
germinate and give off buds, which become free in the body- 
cavity, and may also, like the parent spores, be attacked and 
digested by leucocytes. 

When there are many spores they destroy the leucocytes 
instead of being destroyed by them (Fig. 25). 

The connective-tissue cells also take up and destroy the 
microbes, and, from the property the cells possess of eating up 
the microbes, Metschnikoff names them phagocytes. 1 He finds 
that bacillus anthracis is eaten up in a similar way by white 
blood-corpuscles ; 2 and Fodor 3 has observed that various kinds of 
bacteria, viz. bacterium termo, bacillus subtilis, and bacterium 
megatherium, as well as the spores of the latter, disappear in 
four hours after they are injected into the blood of living rabbits; 

1 Virchow's ArcMv, vol. xcvi., p. 177. z Idem, vol. xcvii., p. 502. 

» Arch, far Hygiene, Bd. 34, p. 129. 



86 



PHAEMAOOLOGY AND THEEAPEUTIOS. [sect. i. 




Pig. 18.— A piece of the anterior part of the body of a Daphne, with a number of spores, some of 
which are still in the intestinal canal, others are penetrating the intestinal wall, and others 
are free in the abdominal cavity, where they are attacked by leucocytes. 




Pw. 19. 

1. A spore which has penetrated the intestinal wall and entered the abdominal cavity, where font 

leucocytes have surrounded its end. m, the muscular layer of the intestine ; e, epithelial layer ; *, 
the serous layer. 

2. A spore surrounded by leucocytes from the abdominal cavity of a Daphne. 

3. Confluent leucocytes enveloping a spore. 

4. A spore, of which one end is being digested by a leucocyte. 




Fig. 20.— Different stages of the changes undergone by spores through the action of phagocytes. 




Pia. 21.— A germinating spore with leucocyte adherent to It, 



chap. iij.J ACTION OF DKUGS ON PEOTOPLASM, ETC. 87 



/"* 




Fig, 22.— A spore germinating and forming conidia, which drop ofE and become free la 
the abdominal cavity. 



Fig. 23.— (i and 6, two stages in the process of Fig. 24.— A leucocyte enclosing conidla. 

leucocyte eating up two conidia. 




Flo. 26.— A group of conidia which have caused the leucocytes surrounding a spore to dissolve, 
leaving only an empty vesicle and fine detritus. 




Fig. 26.— A connective-tissue phagocyte, containing three fungi-cells. 




Fig. 27.— Leucocyte of a frog from the neighbourhood of a piece of the lung of a mouse infected with 
antnrax about forty-two hours after the piece of lung had been placed under the skin of the 
frog's back. The leucocyte is in the act of eating up an anthrax bacillus. 




Fig. 28.— The same leucocyte, a few minutes later, after It has completely enveloped the baoillnv 



88 PHARMACOLOGY AND THERAPEUTICS, [sept. i« 

but if the animals are weak, or depressed by hunger or cold, 
they have much less power of destroying the foreign organisms, 
and so a longer time elapses before the bacteria disappear. 

When only a small number of pathogenic bacteria, such as 
the bacillus anthracis, is injected into the blood at once, they 
are destroyed in the organism; but when they are in larger 
numbers, they have the best of the struggle, and the organism 
itself is destroyed. It is probable that bacteria are constantly 
entering the organisms of men and animals from the lungs and 
digestive canal, but unless they are excessive in number, and 
virulent in their nature, they are quickly destroyed. 1 

The septic poisoning which occurs from wounds is not due 
merely to bacteria entering the blood from them, but is due 
chiefly to the absorption of the poisons which the bacteria 
have formed in the wound. The dead or enfeebled tissues 
which occur in the wound afford a soil favourable to the growth 
of the bacteria, and for the formation of their deadly products. 
When these are absorbed they not only poison the tissues 
generally, but, by doing so, convert the whole body into a soil 
suitable for the growth and development of bacteria, as is shown 
by the fact that the tissues of animals killed by the injection of 
sepsin decompose very quickly, and swarm with bacteria shortly 
after death. 

Action of Drugs on the Movements of Bacteria. 

Mode of Experimenting-. — In order to test the effect of a drug on 
the movements of bacteria already developed, a drop of the solution contain- 
ing bacteria may be mixed, under the microscope, .with a drop of the solution 
of a drug in the way already described at page 63, and the strength of 
solution necessary to destroy their movements estimated in the same manner. 

In order to combine experiments on the movements, and on the reproduc- 
tion, so as to ascertain whether the bacteria which have been rendered 
motionless by heat or drugs are really dead, or are only torpid, the covering- 
glass in the experiment just described is taken up with a pair of sterilised 
forceps, and dropped into some sterilised Cohn's solution (vide p. 72). It i3 
then put along with the standard solution into a warm chamber, and left for 
a day or two. If the bacteria have been destroyed, it will remain clear like 
the standard solution, but if they have only become torpid, it will be more or 
less opalescent or milky. 

In performing this experiment, great care must be taken that the solution 
of the drug has been sterilised by boiling ; and that the covering-glass, glass 
slide, all the instruments, and indeed everything used in the experiments, 
have been also thoroughly sterilised by heating. 

A temperature of 66° to 70° 0. usually arrests the move- 
ments of bacteria, and if continued for an hour destroys adult 
organisms, though not the spores. A temperature of 100° C. 
usually destroys the spores as well, but this is not always the case. 

If the bacteria are moist, this temperature generally kills 
them, but not if they happen to be dry, and a much higher tem- 

1 Fodor, op. cifc. p. 147. 



chap, in.] ACTION OP DEUGS ON PROTOPLASM, ETC. 89 

perature is then required. They may become dry, before being 
killed, by a little solution containing them having flowed or 
spurted into the higher part of the tube or flask, where the water 
evaporates and leaves them dry before the temperature has been, 
sufficiently raised to destroy them. 

The bacteria grown in different fluids are not all equally 
sensitive to drugs. 

The most destructive substances to bacteria are corrosive sub- 
limate, chlorine, bromine, and iodine. Quinine and the other 
cinchona alkaloids also destroy bacteria, their power diminishing' 
in the following order :— quinine, quinidine, cinchonidine, and; 
lastly cinchonine. 

Bebeerine is nearly as powerful, and potassium picrate is even 
superior to quinine when used with Conn's solution. When 
bacteria are cultivated in beef-tea instead of Cohn's solution, 
potassium picrate is less powerful. 

Sulphocarbolates and strychnine have considerable power, 
though a good deal less than quinine ; berberin and assculin have 
hardly any power to destroy bacteria at all. Sodium hyposulphite 
has very little action ; sodium sulphate has a destructive action, 
but is about ten times less strong than quinine. 1 



Action of Drugs on the Reproduction of Bacteria in 

general. 

The spores of bacteria have an enormous power of resisting 
agents destructive to their vitality, very much greater than that 
of the fully-developed bacteria. Thus it happens that a quantity 
of, an antiseptic, which is quite sufficient not only to prevent the 
spores of bacteria from developing so long as they remain in it, 
but to destroy fully-formed bacteria, will not destroy the vitality 
of the spores or hinder them from germinating as soon as they 
are removed from the influence of the antiseptic and transferred 
to a proper soil. < 

Yet the power to destroy the vitality of the spores completely 
is what is required in an antiseptic, for we wish to destroy the 
infectious material, and prevent it from causing disease, rather 
than to administer substances to an animal which will hinder 
the germs from developing in the blood after their introduction 
into it ; although this may be desirable when infection has 
already taken place. 

It is therefore necessary to test the effect of drugs in destroy- 
ing the germs completely. 

Method of Experimenting. — This is done by adding to a fluid, con- 
taining bacteria and their spores, varying quantities of an antiseptic, and 
allowing the mixture to stand for a longer or shorter time. A drop jf this 

1 Buchanan Baxter, Practitioner, vol. i. pp. 343, 350. 



90 PHAEMACOLOGY AND THEEAPEUTICS. [sect. i. 

fluid is then introduced by a sterilised platinum wire or glass pipette into 
some sterilised Cohn's fluid or beef-tea. This is -watched, to see whether 
bacteria will develop in it or not. If they do develop, it is clear that the 
spores have not been killed by the admixture with the disinfectant in the 
original fluid ; if they do riot develop, then the disinfectant has been sufficiently 
powerful to destroy them. 

The plan usually employed is to take a number of test-tubes, plug their 
orifices with cotton-wool, and destroy any germs that may be attached to 
them by thoroughly heating them to about 300° P. in a hot chamber, or in 
the flame of a Bunsen's lamp. They are then allowed to cool, and a small 
quantity of a liquid (about 5 cc.) in which bacteria readily grow is placed in 
each. This also must be previously thoroughly boiled, in order to destroy 
any germs which may be present in it. The liquid recommended by Cohn 
consists of ammonium tartrate one gramme, potassium phosphate and 
magnesium sulphate of each five grammes, calcium phosphate "05 gramme, 
distilled water 100 cc. This is filtered and boiled before use. To the tubes 
the different agents to be tested are added, the solutions of each having been 
carefully sterilised by boiling, and the pipette used being superheated in each 
case before it is employed. If the drugs are added in solution, a similar 
quantity of boiled water must be added to the first tube, which is to serve as 
a standard. To each of them is then added a single drop of a liquid contain- 
ing bacteria. 

The mouths of the tubes are then stopped with the cotton- wool and placed 
for a few days in a warm chamber at about 40° C. The standard liquid will 
then be found to be opalescent or milky. The' degree of the opalescence in 
the other tubes will be less according to the effect of the drug which has 
been added, in preventing the development of bacteria. 

Where it has completely hindered the development, the solution will 
remain quite clear, and as its strength diminishes, the opalescence will become 
greater until it is equal to that of the standard. 

In performing this experiment it is best to use one definite form of bac- 
terium, instead of a mixture of several unknown kinds. This is referred to 
again in speaking of the experiments of Dr. Koch, who generally employs 
the micrococcus prodigiosus as an example of an organism easily acted upon, 
and the spores of bacillus anthracis, or of a bacillus found in earth, as 
examples of resistant organisms. 

It is found by this mode of experiment that a smaller quantity 
of poison will prevent the development of bacteria than will 
destroy them after they are developed. 

By experiments on the comparative action of different drugs 
on bacteria the results contained in the following table have been 
obtained by N. de la Croix, and these have been to a considerable 
extent confirmed by Koch. 

It will be seen by looking at the table that the exact limit of 
the power of each drug to destroy bacteria is not determined, 
but that two concentrations of each antiseptic are given, one of 
which is sufficient to do it, and the other is insufficient. The 
disinfecting limit therefore lies between the two experiments. 
But the limit of disinfection is not an invariable one for each 
'drug, as its power to destroy bacteria is modified not only by the 
concentration of the solution employed, but by the length of time 
during which it acts, and by the temperature. 



chap, in.] ACTION OP DRUGS ON PROTOPLASM, ETC. 91 



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8)2 PHAKMACOLOGY AND THEEAPEUTICS. [sect. i„ 



Action of Drugs on particular species of Bacilli. 

In these experiments of De la Croix, however, the nature of 
the bacteria experimented on was not determined, and there 
might be a mixture of several sorts. Koch has therefore sought 
to ascertain the action of disinfectants upon definite forms of 
microzymes by cultivating them in pure crops before applying 
the disinfectant. Those which he has chiefly experimented on 
are the red micrococcus prodigiosus, the bacteria of blue pus, and 
the bacillus anthracis. 

The first two do not form spores, and are easily destroyed 
by disinfectants. The bacillus anthracis forms spores, and was 
therefore employed to test the action of disinfectants upon them. 

mode of Experimenting- on the Action of Drugs on Reproduction 
of Bacilli. — In order to avoid admixture with other species, Koch culti- 
vated the first two on slices of potato, instead of in a solution. Upon one 
piece of potato the unaltered microzymes were sown (control specimen), and 
upon the others similar microzymes which had been exposed to the action of 
disinfectants. If the microzymes had been destroyed by the disinfectants, 
no result occurred, but if not, then a crop was obtained which, in comparison 
with the control specimen, was more or less abundant, according as the action 
of the disinfectant had been less or more complete. 

For the cultivation of the anthrax bacillus, Koch used as a soil gelatine 
mixed with some other nutritive substance, usually meat infusion and peptone 
sterilised and spread upon a slip of purified glass, and exposed to such a heat 
as just to solidify it. Koch did not use his solidified blood-serum in these 
experiments. This could be placed under the microscope, and the growth of 
bacilli observed from day to day. Middle-sized test-tubes were then par- 
tially filled with the disinfecting solutions, and silk threads, steeped in a 
fluid containing bacilli and then dried, were placed in them ; from time to 
time a thread was removed from the tubes by means of a previously heated 
platinum wire arid placed on the slide, which was then subjected to micro- 
scopical observation. In this way it was easy to determine what strength of 
solution, and what time of exposure to its action, were required to destroy the 
spores. 

The results of experiments made in this way with carbolic 
acid were very surprising. It was to be expected that carbolic 
acid would readily destroy the spores, but this was not the case. 
A 1 per cent, watery solution had almost no action upon them 
even after they had been exposed to it for 15 days ; 2 per cent, 
slightly retarded their growth, but it did nothing more ; 3 per 
cent, killed the spores in 7 days ; 4 per cent, in 3 days ; and 5 
per cent, in 1 day. 

This comparatively slight action of carbolic acid on spores 
and the long time that it requires to, destroy them show that it 
cannot be relied upon as a universal disinfectant. But it has 
nevertheless great power in destroying microzymes which have 
not formed spores. 

The fresh blood of an animal which has died from anthrax' 
contains only bacilli and no spores. When it is mixed with its 
own bulk of a 1 per cent, solution of carbolic acid, it can very 



<3hap. in.] ACTION OF DEUGS'ON PEOTOPLASM, ETC. 



98 



soon afterwards be injected into an animal without producing 
any marked symptoms. A | per cent, solution will not do this, 
so that the limit lies between *5 and -25 per cent, of the mixture 
(v. p. 97). 

The action of carbolic acid on other fully-developed microzymes, 
or on the spores, is almost j;he .same as on the anthrax bacilli. 

The following table gives the result of Koch's experiments 
with other substances, the figures indicating the number of 
days during which the spores had been submitted to the action 
of the antiseptic previous to cultivation. The black- faced figures 
indicate that the spores were destroyed, and their germination 
prevented by exposure to the disinfectant for that number of 
days ; a * indicates that their vitality was diminished, and that 
the crop from them was scanty ; a f indicates that their growth 
was retarded; *t that it was .both scanty and retarded. The 
disinfectants are divided into three groups. The first contains 
the group of fluids ; the second of solutions in water ; and the 
; third of solutions in alcohol, ether, or oil. 



Geoup I.^FLUIDS. 



. Distilled water . 

.Alcohol (absolute) 

' Alcohol (1 to 1 of water) 

Alcohol (1 to 2 of water) 

Ether 

Acetone 

Glycerine . 

Butyric acid 

French salad oil 

Bisulphide of carbon . 

Chloroform 

Benzol 

Petroleum ether 
^'Turpentine oil . 



7 15 20 35 90 

1 3 5 10- 12 20 30 40 50 65 110 

3 20 30 40 50 65 110 

3 20 30 40 50 65 110 
8* 30 



10 20 30 40 50 65 110 



5 
5' 
3 
5 
30 90 
5 10 20 
3 10 20.100 
5 10 20. 
5 



1* 5 10 



Group II.— SOLUTIONS IN WATEE. 



Chlorine water (freshly made) . 
Bromine (2 p. c. in water) 
Iodine water (1 in 7,000) . 
Hydrochloric acid (2 p. c. in water) 
Ammonia .... 

: Ammonium chloride (5 p. c. in water) 
Common salt (saturated solution) 
Calcium chloride (saturated solution), 

' Barium chloride (5 p. c. in water) 
Ferric chloride (5. p. c. in water) 
Potassium bromiie (5 p. c. in water) 
Potassium iodide (5 p. c. in water) 
Corrosive sublimate (1 p. c. in water) 
Arsenic (1 p. c. in water) . 

, Lime water 

Chloride of lime (5 p. c. in water) 
Sulphuric aeid (1 p. c. in water) 

• Zinc sulphate (5 p. c. in water) 
Copper sulphate (5 p. c. in water) 
Ferrous sulphate (5 p. c. in water) 
Sulphate of aluminium (5 p. o. in.water) 



1 
1 
1 

1 
1 
1 
1 
1 
5 

at 

5 
5 
1 
1 
o 

It 

1 

1 

1 

2 

1 



5 

5 

5 
10 

6 
10 
10 

2 

6 
10 

2*t 

3 

5* 

5* 

6 

5 



10 

10 
10 
10 

20 
45 

25 
25 

10 

15* 
5 
10* 
10* 
10* 

12- 



25 
20 

40 
100 



80 



20*t 
20* 



94 



PHAEMACOLOGY AND THEEAPEUTICS. [sect. i. 



Alum (4 p. e. in water) . _ . . 
Potassium chromate (5 p. e. in water) 
Potassium bichromate (5 p. o. in water) 
Chrome alum (5 p. c. in water) 
Chromic acid (1 p. a. in water) _ . 
Potassium permanganate (5 p. c. in water) 
Do. do. (1 p. o. in water) 

Potassium chlorate (5 p. c. in water) 
Osmic acid (1 p. c. in water) . • _ . 
Boracic acid (5 p. c. in water) not quite dissolved 
Boras (S p. c. in water) . 
Sulphuretted hydrogen water . 
Ammonium sulphide 
Oil of mustard with water 
Formic acid (sp. gr. 1-120) 
Acetic acid (5 p. c. in water) . _ . 
Potassium acetate (saturated solution) 
lead aoetate (5 p. c. in water) . 
Soft (potash) soap (2 p. c. in water) . 
Lactic acid (5 p. c. in water) . 
Tannin (5 p. c. in water) . 
Trimethylamine (5 p. c. in water) . 
Chloropicrin (5 p. c. in water) . _ . 
Benzoic acid (saturated solution in water 
Benzoate of sodium (5 p. u. in water) 
Cinnamio acid (2 p. c. in water 60 and alcohol 

40 parts) .... 
Indol (in excess in water) . 
Skatol (in excess in water) 
Leucin (A p. c. in water) . 
Quinine (2 p. c. in water and 40 alcohol 60 parts) 
Quinine (1 p. c. in water with HC1) . 

Gboot III— SOLUTIONS IN ALCOHOL 

Iodine (1 p. e. in alcohol) 

Valerianic acid (5 p. c. in ether) 

Palmitic acid (5 p. c. in ether) . 

Stearic acid (5 p. c. in ether) . 

Oleic acid (5 p. c. in ether) 

Xylol (5 p. c. in alcohol) . 

Thymol (5 p. c. in alcohol) 

Salicylic acid (5 p. c. in alcohol) 

Salicylic acid (2 p. c. in oil) .... 

Oleum animale (Dippel's oil, 5 p. o. in alcohol) 

Oleum menthse piperita (5 p. c. in alcohol) 

From this table it appears that the ordinary method of sepa- 
rating between formed and unformed ferments by precipitation 
with alcohol and solution in glycerine cannot be relied upon as a 
trustworthy means of separating them, since neither alcohol nor 
glycerine destroys the activity of formed ferments. 

It is remarkable that ether and turpentine oil, which are both 
ozone carriers, should have such a marked action in comparison 
with other fluids. This is in harmony with some recent observa- 
tions of Paul Bert and Eegnard, who found that oxygenated water 
in sufficient quantity destroys the bacteria of anthrax. 

The spores of anthrax bacilli resist in an extraordinary way 
the action of certain substances which usually are fatal to life, as 
hydrochloric acid (2 per cent.), salicylic acid (1 per cent.), cgp 



1 5 
1 2 


12 






1 2 








1 2 








1 2 








1 2 








2 6 








1 2 


6t 


10f 




5 10 


15 






1 5* 








1 2 


5 






1 5 


10* 






1 2 


4 


10 




1 5 








1 4 


10 






1 5 


12 






1 5 


12 






1 2 


5 






1 6 


10 






1 5 


12 






1 2 


6 


12 




1 5 


10 


45 


90 


1 2 


5 


10 




1 3 


5 


10 




1 5 


10 


25 


80 


1 5 


10 


25 


80 


1 5 


10 






l*t 5*t 








1 5 


10 






j, OB BTHEE, OB OIL. 




1* 2* 








1 5 








1 5 








1 5 








1 5 








1 5 


30 


60 


90 


1 6 


10 


15 




1 6 


10 


15 




5 10 


20 


80 




1 v "5 


12 






1 5 


12 







chap, in.] ACTION OF DEUGS ON PEOTOPLASM, ETC. 95 



centrated solutions of chloride of sodium, chloride of calcium, 
metallic solutions, borax, boric acid, chloride of potassium, 
benzoic acid, benzoate of sodium, cinnamic acid, and quinine. 

Action of Drugs on the Development and Growth of Bacilli. — 

In order to test the action of disinfectants on the development and growth 
of bacteria, Koch put into a number of small watch-glasses, or rather 
crystallisation-glasses with flat bottoms, a few drops of blood-serum, or a 
solution of extract of meat and peptone, mixed with varying quantities of 
the disinfectant. Into each of these a silk thread, which had been dipped 
in the fluid containing bacteria and dried, was placed. In one glass serum 
alone, without any disinfectant, was placed, in order to ascertain, by com- 
parison with the growth which takes place in it, how the disinfectant in the 
other glasses had interfered with the growth of the bacilli. 

In experiments of this sort a difference was found between 
anthrax bacilli and other microzymes. A dilution of carbolic 
acid, 1 in 1,250 and 1 in 850, sufficed to prevent the growth of 
anthrax bacilli, while a strength of 1 in 500 was required to 
prevent the growth of others. 

Other species are therefore more resistant than anthrax 
bacilli to the action of carbolic acid. The following table shows 
the strength of various disinfectants required to hinder or entirely 
prevent the development of anthrax bacilli : — 

Solution 
Iodine .... 
Bromine .... 
Chlorine .... 
Osmic acid 

Permanganate of potassium 
Corrosive sublimate . 
. AUyl alcohol . 
Oil of mustard . 
Thymol .... 
Peppermint oil. 
Oil of turpentine 
Oil of cloves 
Arsenite of potassium 
Chromic acid . 
Picric acid 
Hydrocyanic acid . 

The following are abor 

Fluid 
Boric acid 
Borax 

Hydrochloric acid 
Salicylic acid . 
Benzoic acid . 
Camphor . 
Eucalyptol 
Soft soap . 
Quinine . 
Hydrate of chloral 
Chlorate of potassium 
Acetic acid 
Benzoate of sodium 
Alcohol . 
Acetone . 
Chloride of sodium 



Hinders 


Prevents 


1 to 5,000 


— 


1 to 1,500 


— 


1 to 1,500 


— 


1 to 1,500 


— 


1 to 3,000 


— 


1 to 1,000,000 


1 to 300,000 


1 to 167,000 


— 


1 to 330,000 


1 to 33,000 


1 to 80,000 


— 


1 to 33,000 


— 


1 to 75,000 


— 


1 to 5,000 


— 


1 to 100,000 


1 to 10,000 


1 to 10,000 


1 to 5,000 


1 to 10,000 


— 


1 to 40,000 


1 to 8,000 


the same strength 


as carbolic acid 


Hinders 


Prevents 


1 to 1,250 


1 to 800 


1 to 2,000 


1 to 700 • 


1 to 2,500 


1 to 1,700 


1 to 3,300 


1 to 1,500 


1 to 2,000 


— 


1 to 2,500 


— 


1 to 2,500 


— 


1 to 500 


1 to 5,000 


1 to 830 


1 to 625 


1 to 1,000 


— 


1 to 250 


. — 


1 to 250 


— 


1 to 200 


, — 


1 to 100 


1 to 12-5 


1 to 50 No action . 


— 


1 to 64 


. *™~ 



96 PHAEMACOLOGY AND THEEAPEUTICS. [sect. i. 

Influence of the Solvent.— Although a 5 per cent, solution 
of carbolic acid in water has a well-marked destructive action on 
the spores, and a strong destructive action on fully-developed 
anthrax bacilli, a solution of the same strength in oil or alcohol 
has not the least disinfectant action. A similar influence with 
regard to iodine is observable in the previous tables. 

Effect of the Fluid with which Disinfectants are mixed. 
— This is sometimes very marked, especially in the case of free 
iodine, bromine, or chlorine. These in watery solutions are 
powerful disinfectants, but when mixed with fluids which contain 
alkalies, e.g. blood-serum, they are converted into bromides, 
iodides, and chlorides, and their action is very greatly diminished. 
The action of corrosive sublimate, however, and of ethereal oils 
is not altered. 

Influence of Temperature on the Action of Antiseptics.— 
The action of antiseptics is greatly increased by a high tempera- 
ture. Spores of anthrax bacilli exposed to the vapour of carbolic 
acid at 15°-20° C. remain unchanged even after 45 days' expo- 
sure. When exposed to the vapour of carbolic acid at a tem- 
perature of 55° C. the case is very different. Half an hour's 
exposure does not seem to harm them at this temperature, but 
many are destroyed by an exposure of an hour and a half, and 
very few will stand 3 hours' exposure, so that probably an exposure 
of 5 or 6 hours would destroy the whole of them. 

Alterations in Bacteria by Heat and Soil.— By careful 
cultivation through successive generations of a slip taken from 
a wild fruit-tree, the chemical processes of growth may be so 
modified in it that the fruit will lose its acrid character and 
become edible and pleasant. What is true of higher plants is 
true also of lower in this respect, and bacilli are much modified 
by the conditions under which they are cultivated ; for example, 
Pasteur has found that the bacilli of anthrax develop and multiply 
in beef-tea best at 25V40° C. Their development is retarded at 
lower or higher temperatures than these, and is completely ar- 
rested at 15° or 43° C. When cultivated at a temperature where 
development occurs with difficulty, such as 42°-43°, the bacilli 
no longer form resting spores, but only grow into long threads. 

Fresh bacilli injected into an animal rapidly cause death 
from anthrax, but the longer they have been previously kept at 
this high temperature the more does their virulence decrease, 
and at the end of four or six weeks they die. 

When some of the first crop of bacilli are put into fresh beef- 
tea, the second crop retains the degree of virulence of the first, 
and the third crop taken from the second, and again grown in 
fresh beef-tea, has exactly the same morbific power, and so on. 

When the bacilli are cultivated at 35°, the microzymes not 
only multiply quickly, but they form spores of a definite degree 
of virulence, and these spores may be kept unaltered for years in 



chap, in.] ACTION OF DBUGS ON PEOTOPLASM, ETC. 97 

sealed tubes, whereas the threads of developed bacilli die when 
air is excluded. 

When an animal is inoculated with anthrax bacilli whose 
virulence has been diminished by cultivation at a high tempe- 
rature, they produce merely temporary illness instead of death. 
By the growth of these non-virulent bacteria in the body, its 
constitution appears to undergo some alteration, and virulent 
bacteria subsequently injected have a much less powerful action 
on it. If the first injection be made with bacteria having a very 
slight amount of virulence, the animal may still die if injected a 
second time with virulent bacteria, but if inoculated first with 
non-virulent bacteria and a second time with bacteria rather 
more powerful, a slight disturbance is produced by each inocu- 
lation, and a subsequent injection of virulent bacteria no longer 
causes death. 

The changes which are produced by inoculation with modified 
anthrax or with vaccine matter in the blood and tissues, although 
probably very slight, are sufficient to confer on the organism 
immunity from further infection. This is usually permanent, 
although the immunity may dimmish with the course of years, 
unless the advancing age of the animal in itself tends to lessen 
its liability to infection. 

A similar immunity against infection with different bacilli is 
sometimes conferred by age. Thus young dogs are easily infected 
with anthrax, but old ones are not. 

A difference of species also confers immunity. Thus rats 
and field-mice are not liable to infection with anthrax, while 
house-mice are highly so. Algerian sheep also resist infection 
with anthrax, while French sheep do not. 

The experiments of Cash seem to show that it may be possible 
by the action of drugs to alter the blood and tissues in such a 
way as to render the animal proof against infection by pathogenic 
bacteria ; for he has found that by the continued administration 
of minute doses of corrosive sublimate to animals he can render 
them capable of resisting the lethal effects of anthrax subse- 
quently inoculated. 1 This is a direction in which further research 
is likely to yield interesting results. 



Possible Identity of Different Forms of Bacteria. 

It has already been mentioned that we are not quite certain 
whether all the species, genera, or even orders of bacteria are 
natural divisions, or whether the same organism under various 
conditions of nutrition and development may not present such 
different appearances as to be included in different orders and 

1 Cash : Proceedings of the Physiological Society, Dec. 12, 1885. Journal of 
Physiology, vol. vii. 



98 PHAEMACOLOGY AND THEEAPEUTICS. [sect. i. 

under different names. Yet this is a matter of very great im- 
portance in regard to the causation of disease, for if it be true 
that organisms which are usually innocuous may undergo an 
opposite process to that which occurs in anthrax bacilli by cul- 
tivation, and may in certain conditions of soil be changed from 
innocuous into pathogenous forms, we can understand how 
diseases may appear to originate de novo. 

It has been stated by Naegelithat bacteria may be so modified 
by cultivation as to form entirely different fermentative products. 
Thus he says that the bacterium which produces lactic acid 
fermentation in milk may be changed by cultivating it in extract 
of meat and sugar, so that it will no longer produce a lactic but 
an ammoniacal decomposition in milk. He considers also that 
innocuous may be transformed into virulent bacteria, and back 
again into an innocuous form, and Buchner thinks that he has 
succeeded in transforming the ordinary hay -bacillus (bacillus sub- 
tilis) into anthrax bacillus by cultivating it for a number of 
generations in Liebig's meat extract, peptone, and sugar. This 
observation is denied by Klein ' and others, but observations 
which partly support Buchner and partly Klein have been made 
by P. Kohler, 2 who finds that while the ordinary hay -bacillus 
(bacillus subtilis) is not altered in its appearance by repeated 
cultivations, it acquires a progressive virulence which renders it 
so fatal to animals as to resemble the anthrax bacillus in its 
deadly properties. 

H. C. Wood and Formad 3 have also come to the conclusion 
that the micrococci found in diphtheria resemble those on furred 
tongues in all respects excepting in their greater tendency to grow. 
When cultivated successively, they lose their contagious power 
and grow less readily. These authors, therefore, consider that 
circumstances outside' the body are capable of converting the 
slower growing or common micrococcus into the rapidly growing 
micrococcus of diphtheria, which, when cultivated again, reverts 
to the common type. 

Action of Bacteria and their Products on the Animal 
Body. — When bacteria are injected into the animal body, they 
produce different effects according to the original nature of the 
bacteria or bacilli, the conditions under which they have been 
cultivated, and the quantity introduced. There is probably 
another factor of no less importance, which, however, still re- 
quires to be investigated, viz. the condition of the body (p. 97) 
into which they are introduced. In considering the effect of an 
injection into the living body of a solution containing bacilli, we 
must be careful to distinguish between the effect of the bacilli 
themselves, after their introduction into the circulation, upon the 

' Klein, Quarterly Journ. of Microscopic Science, Jan. 1883. 

2 Inaugural Dissertation (Gottingen), 1881. 

* National Board of Health Bulletin, Siipplement No. 17, Jan. 21, 18f>2. 



chap. iii.J ACTION OP DEUGS ON PEOTOPLASM, ETC. 99 

tissues and organs of the body, and the effect of the substances 
which they have already formed in the solution before their 
injection. 

We must distinguish between those two things in the same 
way as we would have to distinguish between the effects of the 
particles of the yeast-plant and the effects of the alcohol which 
it had formed, if we were to inject a solution in which yeast was 
growing into the veins of an animal. The yeast or the bacteria 
would have one effect upon the animal, the alcohol or the septic 
products of the bacteria would have another. 

Solutions of putrid organic matter containing numerous 
bacteria cause high fever and often death. 

The course of the fever depends on the specific nature of the 
bacteria, e.g. septic bacteria, anthrax bacilli, &c. 

It is difficult at present to ascertain exactly how far all the 
following diseases are due to the presence of microbes or their 
products ; but it has been found that micrococci cause erysipelas, 
acute necrosis, gonorrhoea, gonorrhceal ophthalmia, contagious 
ophthalmia, ophthalmia neonatorum, and are present in pyaemia, 
puerperal fever, ulcerative endocarditis, infective myositis, and 
contagious pneumonia. When malignant oedema or traumatic 
gangrene occur, bacilli are usually found. Micrococci are also 
supposed by some to be the cause of vaccinia and of diphtheritic 
inflammation. The bacillus anthracis produces anthrax ; bacillus 
septicaemiae, blood-poisoning ; bacillus malariae, ague and mala- 
rious diseases ; bacillus tuberculosis, phthisis ; bacillus leprae, 
leprosy ; and another bacillus is the cause of glanders. In re- 
lapsing fever the spirochaeta Obermeyeri is found in the blood, 
and is probably the cause of the disease. 

Alkaloids formed by Putrefaction. Ptomaines. — From 
decomposing organic matter substances can be separated which 
have all the characters of alkaloids. 

The alkaloids produced by putrefaction are usually known 
by the name of ptomaines. It was at one time supposed that 
they were different in their chemical nature from the alkaloids 
which occur in plants, and they were supposed to have a much 
greater reducing power than the latter. It was therefore pro- 
posed to distinguish between ptomaines and other alkaloids by 
the addition of potassium ferricyanide : if the alkaloid changed 
this into ferrocyanide, so that a precipitate of prussian blue was 
obtained on the addition of ferric chloride, it was supposed to 
belong to the class of ptomaines ; whereas non-reduction was 
supposed to show that it belonged to the vegetable alkaloids. 
It was soon found, however, that this test was not trustworthy, 
for such important alkaloids as morphine and veratrine produced 
reduction. Later researches, especially those of Brieger, have 
shown that some at least of the so-called ptomaines are identical 
with vegetable alkaloids. 

H 2 



100 PHAEMAC0LOGY AND TSBEAPEUTICS. [sect. i. 

We may indeed now regard alkaloids as products of albu- 
minous decomposition, whether 'their albuminous precursor be 
contained in the cells of plants and altered during the pro- 
cess of growth, or whether the albuminous substances undergo 
decomposition from the presence of microbes, either outside or 
inside the animal body, or by the pimple process of digestion by 
unorganised ferments such as pepsine. 

The alkaloidal products formed by the putrefaction of albu- 
minous substances, vary according to the stage of decay at which 
they are produced. At first the poisonous action of these pro- 
ducts may be slight. As decomposition advances, the poisons 
become more virulent ; but after a longer period they appear to 
become broken up and lose to a great extent their poisonous 
power. 

Muscarine, which is the poisonous alkaloid of some mush- 
rooms, has been made synthetically by Schmiedeberg and Har- 
nack from choline ; and Brieger has obtained from decomposing 
albuminous substances several well-defined chemical bodies— 
dimethylamine, trimethylamine, triethylamine, ethylenediamine, 
choline, neurine, neuridine, muscarine, gadinine, cadaverine, 
putrescine, saprine, and mydaleine, as well as some substances to 
which he has given no name. Muscarine, neurine, and choline 
all have a similar action, their power diminishing in the order 
just mentioned, choline being much weaker than the other two. 
They all produce salivation, diarrhoea, vomiting, dyspnoea, para- 
lysis, and death. Muscarine and neurine in frogs produce com- 
plete stoppage of the heart in diastole ; in mammals they only 
weaken its action. Neurine, cadaverine, putrescine, and saprine 
have no marked physiological action ; but one alkaloid which 
Brieger has isolated from human cadavers in an advanced stage 
of decomposition appears to affect the intestine, causing enormous 
peristalsis, continuous diarrhoea, lasting for days, and extreme 
weakness. Mydaleine, obtained from a similar source, is interest- 
ing, inasmuch as it causes a rise of temperature ; for frequently 
we find in cases of acute disease that the rise of temperature 
coincides with the constipation, and is removed by purgation, so 
that the question arises how far the rise of temperature in such 
cases may be due to the absorption of poison from the intestine. 
Mydaleine causes dilatation of the pupil, enormous secretion of 
tears, saliva, and sweat, vomiting, diarrhoea, paralysis, convulsions, 
twitching, dyspnoea, coma, and death. 

Sepsine, which was isolated by Bergmann and Schmiedeberg 
from putrefying yeast, causes vomiting, diarrhoea, and bloody 
stools ; but Nicati and Kietsch ' have produced choleraic symptoms 
in animals by cultivations of Koch's comma bacillus from which 
the organisms themselves had been removed; and somewhat 

5 

1 Compt. rend., xo. 928. 



chap, in.] ACTION OF DEUGS ON PROTOPLASM, ETC. 101 

similar results were obtained several years ago by Lewis and 
Douglas Cunningham with cholera stools in which any organisms 
present had been destroyed by boiling. 

The extract from putrefied maize has a tetanic and narcotic 

, action, which appears to be due to two different substances. 

These are not present in the same proportion, so that sometimes 

the tetanising action, and at other times the narcotic action, is 

most marked. 

Another alkaloid, resembling atropine in its action, has been 
separated by Sonnenschein and Zuelzer from decomposing animal 
matter ; and this has also been found in the bodies of persons 
dying from typhus fever. 

Another which resembles curare in its action has been separated 
by Guareschi and Mosso ' from putrefying brain. 

Another substance causing tetanic symptoms has also been 
obtained from animal matter. 

Leucomaines. — Gautier, to whom much of our knowledge 
regarding alkaloids produced by albuminous decomposition is 
due, has given the name of leucomaines to alkaloids which are 
not produced by putrefaction due to bacteria, but are formed by 
the decomposition of albuminous matters in the normal processes 
of waste in the living animal tissues. Amongst these he reckons 
various substances formed in muscles and allied to xanthine and 
creatine. 2 

Brieger has shown that during the digestion of fibrin by 
pepsin an alkaloid has been formed, to which he gives the name 
of peptotoxin. 

Absorption and Elimination of Ptomaines and Leuco- 
maines. — It is probable that a considerable production of alkaloids 
takes place in the intestine, both when the digestive processes 
are normal and more especially when they are disordered ; at the 
same time alkaloids are being formed in the muscles, and pos- 
sibly also in other tissues. Were all the alkaloids to be retained 
in the body, poisoning would undoubtedly ensue, and Bouchard 
considers that the alkaloids formed in the intestine of a healthy 
man in twenty-four hours would be sufficient to kill him if they 
were all absorbed and excretion stopped. He finds that the 
poisonous activity of even healthy human faeces is very great, 
and a substance obtained from them by dialysis produced violent 
convulsions in rabbits. When the funcdons of the kidney are im- 
paired, so that excretion is stopped, uraemia occurs, and Bouchard 
would give the name of stercoraemia to this condition, because he 
believes it to be due to alkaloids absorbed from the intestines 
He also thinks that the nervous disturbance which occurs in 
cases of dyspepsia is due to poisoning by ptomaines. That 

1 Les Ptomaines, Turin, 1883. 
Sur les alcalcfides dirivis de la ctestruoticn hacU.-ienne ou physiologig^ue des 

animaux. Paris : G. Masson. 1886. 



102 PHARMACOLOGY AND THERAPEUTICS, [sect. i. 

alkaloids are excreted by the urine has been shown by Bocci, 
■who has found in the urine a substance having an action like 
that of curare. 

Effect of Drugs on the Action of Bacteria in the Animal 

Body. 

So long as bacteria are outside the body, we may use drugs 
of any strength we please to destroy them, but the case is quite 
different when they have once gained entrance and are no longer 
outside but inside the body, because then the nature of the drug 
and the amount we can employ is limited by its effect on the 
organism itself, and we cannot administer very large doses of 
antiseptics leBt we should injure or kill the patient at the same 
time that we destroy the bacteria which are causing the disease. 
All that we can hope to do is to turn the scale, if possible, in 
favour of the organism in the struggle for existence between the 
cells which compose it and the bacteria which have invaded it 
(vide pp. 86 and 89). 

Our hope of doing this rests on the fact that drugs which 
may be injurious both to the tissue and to the bacteria are not 
equally so to each. Thus excess of temperature is injurious to the 
organism, but it is also destructive to bacteria ; and, as Fokker ' 
has pointed out, the febrile reaction which occurs on the intro- 
duction of bacteria into the blood may be a means of destroying 
the mierobes and preserving the animal. There is often a germ 
of truth in apparently foolish plans of treatment, and the old 
practice of treating scarlet fever, small-pox, and measles by warm 
drinks, hot rooms, and abundant clothing may have been a blind 
effort to aid the natural processes of cure, just as the irritating 
ointment of the Middle Ages seems to have been an attempt at 
antiseptic surgery. The extraordinary destructive power of cor- 
rosive sublimate, and the fact that it continues to act in blood- 
serum just as it does in distilled water, seem to indicate that 
it might be used to destroy bacilli in the body, especially as 
Schlesinger has found that it may be injected subcutaneously 
into rabbits and dogs daily for several months without doing 
them any harm, even in doses of 5 milligrammes, 1 cc. of a \ per 
cent, solution. Koch's experiments on this point, by the adminis- 
tration of sublimate after inoculation with anthrax, led to a 
negative result, the animals inoculated with anthrax dying of the 
disease, notwithstanding the injection of the sublimate. On the 
other hand, Cash has succeeded in preventing death from anthrax 
by administering corrosive sublimate for some time previous to 
inoculation (p. 97). 

The extraordinary effect of allyl alcohol, and the less power- 

1 International Medical Congress, 1881. 



chap, in.] ACTION OF DEUGS ON PEOTOPLASM, ETC. 103 

ful but still great action of ethereal oils, indicate, however, that 
we may look forward with hope to the discovery of some organic 
substances which may so hinder the development of bacteria in 
the body after their inoculation, as to allow of their gradual de- 
struction in the organism, and prevent the sickness or death 
which they would otherwise have occasioned. 

In relation to this, the observations of the late Dr. W. Farr 
in his Keport are very interesting : ' Alcohol appears to arrest 
the action of zymotic diseases, as it prevents weak wines from 
fermenting ; like camphor, alcohol preserves animal matter — this 
is not now disputed. But may it not do more? May it not 
prevent the infection of some kinds of zymotic disease ? ' 

Experiments have shown that alcohol itself has but a slight 
power in destroying bacilli, but it is possible that even the slight 
traces of the ethers which are present in wine or spirits may 
have some beneficial action in cases of septic poisoning. 

Antiseptics, Antizymotics, Disinfectants, Deodorizers. 

These classes of remedies are often confounded together. It 
is well, however, to distinguish their meanings : — 

Antizymotics are remedies which arrest fermentation. 

It has already been mentioned (p. 73etseq.) that fermentative 
processes may depend upon either enzymes or organised ferments, 
and that organised ferments maybe subdivided into several classes, 
such as those consisting of yeast, innocuous bacteria, and patho- 
genic bacteria. 

The class of antizymotics includes all substances which arrest 
fermentative processes due to these bodies. It contains two sub- 
classes : antiseptics and disinfectants. 

Antiseptics are remedies which arrest putrefaction. They 
do this by preventing the development, or completely destroying 
the bacilli on which septic decomposition depends. 

Disinfectants are remedies which destroy the specific poisons 
of communicable diseases. Many of those poisons, perhaps all 
of them, belong to the class of microbes, and so disinfectants 
may be regarded as a sub-class of antizymotics. 

Deodorizers or deodorants are remedies which destroy dis- 
agreeable smells. Such smells often accompany the decomposi- 
tion of various organic substances, which septic organisms cause. 
These foul-smelling products may be injurious to health in them- 
selves by acting as poisons ; but they are not to be confounded 
with the bacteria which produce them. Moreover, the disagree- 
able nature of the smell is not always to be relied upon as an 
index of its poisonous nature. M. Gustav le Bon made some 
experiments with hashed meat and water, over which he put 
some small animals. As the meat decomposed, the liquid teemed 
with organisms, was very fatal when injected into an animal, 



104 PHAEMACOLOGY AND THEBAPEUTICS. [sect. I. 

and emitted a very foul smell, which, however, did not seem to 
be very injurious. Afterwards the organisms present in the 
liquid died, and the foul smell became much less disagreeable ; 
but the emanations from the liquid appeared to become much 
more poisonous, although the liquid itself, when injected into an 
animal, had no longer the same virulent power as at first. 

Uses of Antiseptics. — Antiseptics are employed externally 
in order to destroy microbes before their entrance into the body, 
and are administered internally with a like object, or for the 
purpose of at least preventing the free development and multi- 
plication of the microbes. 

They are employed externally in surgical operations, with 
the object of destroying any organisms which might find a nidus 
in the wound, and there give rise to the formation of poisonous 
substances. Both these substances and the bacteria themselves 
will not only have an injurious local action in the wound, but by 
undergoing absorption may prove injurious or fatal to the or- 
ganism as a whole. The antiseptic plan of treatment has been 
empirically practised in a limited manner for a very long period 
without its principle being recognised : for the well-known Friar's 
balsam has antiseptic properties. It is to Lister that we owe 
the introduction of such a mode of treatment, not based upon 
mere empiricism, but upon scientific knowledge. The reason 
why it had fallen into disuse probably was that some of the anti- 
septic substances used for dressing wounds in the Middle Ages 
were irritants as well as antiseptics. Those who employed them 
did not know the reason why they were beneficial, and supposed 
that their virtue was due to their irritating properties. The oint- 
ments were accordingly made more and more irritating : and 
thus more harm than good was done, until they were discarded 
by Ambrose Pare. The antiseptic most commonly employed is 
carbolic acid. Not only are all the instruments to be employed 
disinfected by a watery solution, but the operation itself is con- 
ducted under a spray of the dilute acid, so as to render innocuous 
any organisms which may be present in the air. The wound 
is then covered with an antiseptic dressing. Whenever this 
requires to be removed it must always be done under the spray. 
The reason of these great precautions is obvious : if any germs, 
however few, gain an entrance they will soon multiply and prove 
as deadly as a great number, the only difference being one of time. 

The great danger which may arise from an exceedingly 
minute portion of septic matter renders great caution necessary 
on the part of those who might, by a little indiscretion, convey it 
from one to another. Thus a number of years ago a medical 
man was nearly driven mad by an epidemic of puerperal fever 
which he had in his practice : one patient dying after the other. 
In order to get rid of any infection, he burnt all his clothes and 
went away for three months. During his absence everything 



chap, in.] ACTION OP DEUGS ON PEOTOPLASM, ETC. 105 

went well. On his return the epidemic again broke out : on 
careful investigation he found the only thing he had forgotten to 
burn was his gloves, and these had acted as a reservoir of in- 
fection. The hands, imperfectly cleansed in the first instance, 
had coiiveyed the septic matter into the gloves, and there it re- 
mained, re- infecting the hands every time the gloves were put on. 
In the same way a thermometer may prove a cause of continual 
infection unless the thermometer be carefully washed, and, if 
necessary, disinfected, each time it is used and before it is put 
into the case. In a similar manner it has been found tna,t 
gonorrhceal matter may remain in the vagina and infect several 
persons without the woman herself ever suffering. One of the 
best antiseptics for disinfection in such cases is permanganate of 
potassium. This may be used to wash out abscesses, if there 
is any fear of danger from absorption of carbolic acid ; and also 
as a lotion for ulcers or wounds about the mouth, the urethra, 
or anus, where the carbolic acid might be too irritating ; as is 
evident from Koch's experiment, however (vide p. 92), a solution 
of the strength ordinarily used — one per cent., i.e. four grains to 
the ounce — is not sufficient to destroy the septic organism, 
although one of five times the strength will do so. 

Another way in which septic poisoning may be produced is 
,by the introduction of a catheter into the bladder, where this 
cannot be completely emptied naturally on account either of 
paralysis, enlarged prostate, or stricture. So long as the con- 
tents of the bladder have not come in contact with any foreign 
matter they may remain in the bladder for some time without 
undergoing decomposition, but if a dirty catheter should be 
passed, and thus a few organisms introduced into the bladder, 
decomposition may set up in the urine and septic poisoning 
ensue. A solution of carbolic acid in oil is sometimes trusted 
to for the disinfection of catheters, but, as Koch's experiments 
(p. 96) show that such a solution has little or no antiseptie 
power, the catheters should be disinfected by a strong solution 
of carbolic acid in water, and afterwards oiled before their 
introduction. 

The use of antiseptics internally is limited by the resistance 
of the organism itself, as already mentioned (p. 102). In the 
stomach antiseptics are used for the purpose of preventing decom- 
position, and by thus lessening the production of irritating pro- 
ducts they diminish irritation of the stomach and arrest vomiting. 
Tbose which are chiefly employed for this purpose are creasote, 
carbolic acid, sulpho-carbolates, salicylic and sulphurous acids. 
In the intestine antiseptics are useful in arresting putrefaction, 
and thus preventing the harm caused locally to the intestine 
by the products of decomposition as well as the injury due to 
their subsequent reabsorption. They therefore tend to check 
diarrhcea and dysentery. It is probably to its antiseptic action 



106 PHAEMACOLOGY AND THEKAPEUTICS. [sect. i. 

that currosive sublimate owes its curative power in cases of in- 
fantile dysentery, and it is not improbable that the beneficial 
action of calomel is due to a similar action, for it has been found 
by Wassilieff greatly to retard the decomposition due to low 
organisms . 

The beneficial action of mercurials in such cases may be 
partly due to their antiseptic power not being as greatly diminished 
by admixture with fecal matters as that of other antiseptics. 
After absorption into the blood, antiseptics are chiefly employed in 
febrile conditions, in order, if possible, both to lessen the growth 
o'f the septic organism and to remove the danger to the individual 
which the fever itself would occasion. The principal antiseptics 
used for this purpose are alcohol, eucalyptol, quinine, salicin, 
salicylic acid, and salicylates. Carbolic acid and creasote can 
hardly be used, as their action on the organism is too poisonous, 
but hydroquinone, cresotinic acid, kairin, pyrocatechin, anti- 
pyrin, and resorcin are not markedly poisonous, and are antir 
pyretic. They may thus be useful, and antipyrin is now largely 
employed (vide also Antipyretics). Eucalyptol has sometimes 
appeared to me to be more beneficial in cases of septic poisoning 
ihan quinine ; at any rate, I have seen patients recover under its 
use who had not been benefited by quinine. 

Disinfectants. — These are generally employed in order to 
destroy the germs of disease in the excreta of a patient suffering 
from an infectious disease, or those germs which may be adhering 
to articles of clothing or to furniture or to the walls of a room in 
which the patient has been lying. Probably the most efficient 
and generally applicable to articles of clothing is heat. The heat 
employed is usually from 230° to 250° P., but as a general rule 
it should be as hot as the fabrics will bear without injury, and 
should be continued as long as is necessary to raise the central 
parts of the articles to be disinfected to the temperature of the 
chamber in which they are placed. As the presence of moisture aids 
the destructive action of heat upon septic organisms, superheated 
steam appears to be the best disinfectant under ordinary circum- 
stances. The only disinfectant that seems to be really trust- 
worthy for destroying septic organisms when it is simply washed 
over them is corrosive sublimate : even in a dilution of one to a 
thousand it appears to destroy microzymes and their spores by a 
single application for a few minutes. 

Deodorizers. — Deodorizers are mainly strong oxidizing and 
deoxidizing substances, as chlorine and its oxides, sulphurous 
acid, nitrous acid, ozone, peroxide of hydrogen, permanganate of 
potassium. Charcoal, in addition to oxidizing, absorbs and con- 
denses the foul-smelling gas. Those which are most commonly 
used as deodorizers for the air of rooms are chlorine or its oxides 
set free from chlorinated lime. 

For removing smells from the hands, carbolic acid is to be 



chap, in.] ACTION OF DEUG8 ON PROTOPLASM, ETC. 107 

preferred to others, and for deodorizing faecal matters, perman- 
ganate of potassium, carbolic acid, or charcoal. A mixture of 
eight or nine parts calcined dolomite (magnesia and lime) with 
one or two of peat or wood charcoal is not only an excellent 
deodorizer, but increases the value of the faecal matters as manure. 



Antiperiodics. 

These are remedies which lessen the severity or prevent 
the return of attacks of certain diseases which tend to recur 
periodically. 

The chief of these are : — 

Cinchona bark and its alkaloids : — 

Quinine. Arsenic. 

Cinchonine. Salicylic acid. 

Quinidine. Salicylates. 

Cinchonidine. Salicin. 

Bebeeru bark and its alkaloid : — 

Bebeerine. Eucalyptol. 

Action. — The mode in which antiperiodics act is not at 
present definitely ascertained, nor indeed is the pathology of 
the diseases which they prevent. Bemittent fever, however, has 
been shown to depend upon the presence of a spirillum in the 
blood, and there is considerable evidence for considering that 
malarious conditions are connected with the presence of a bacillus. 
The periodical return of the attacks in such diseases would ap- 
pear, then, to be associated with the growth of successive crops 
of these protophytes, and the action of antiperiodics might be 
explained by supposing that they interfere with the development 
of these pathogenic organisms. 

Uses. — Quinine and cinchona bark are often regarded as 
almost specific in the various affections due to malarious poison- 
ing, i.e. intermittent fevers, periodic headaches, neuralgias, etc. 
In tropical remittent fever of malarious origin, quinine is also 
the best remedy we possess. It must be given in very large doses, 
however, and is less certainly curative than in intermittent fever. 
The other cinchona alkaloids have a similar action to quinine^ 
but are not quite so powerful : they, as also quinine, may be used 
as prophylactics in order to prevent the recurrence of ague in 
persons travelling through or living in malarious districts as 
well as for the purpose of curing malarious conditions already 
present. 

Arsenic is sometimes even more powerful than quinine, but as 
a rule it answers best in malarious conditions which are some- 



108 PHAEMACOLOGY AND THEEAPEUTICS. [sect. i. 

times known as masked or latent malaria, and which manifest 
themselves in neuralgia and nervous or digestive disturbance 
rather than in well-marked ague fits. 

Adjuncts. — Emetics and purgatives aid the action of anti- 
periodics, and sometimes, indeed, can replace them and cure ague 
without their aid. Antiperiodics rarely succeed if the functions 
of the liver are disturbed unless they are aided by emetics or 
purgatives, and especially by cholagogues. 



109 



CHAPTEE IV. 
ACTION OF DEUGS ON INVEETEBEATA. 

The study of the action of drugs on invertebrata has not been 
carried out methodically to any great extent, but it offers a very 
promising field for investigation, and probably in the course of a 
few years may yield very valuable results. 

Action of Drugs upon Medusa. 

This subject has been worked at, almost exclusively by Eomanes ' and 
Krukenberg. 8 At present it has little practical bearing, but it promises to be 
of great service by enabling us to understand better the action of drugs on 
contractile structures generally, and on the heart in particular. 

In medusae the swimming organ consists of a bell-shaped mass of con- 
tractile substance, within which the polyp hangs like the clapper. Around 
the margin of this bell are a number of ganglia connected with one another 
by nervous filaments, and forming a peripheral ring. 



Lithocvst and ganglion M ;; HPolypite. 

Tentacles 9| 9IUII 



Flo. 29.— Medusa (Sarsia), natural size. 



In the normal state of the animal, the bell alternately contracts and dilates 
rhythmically, so that the animal is propelled through the water. 

When the marginal strip containing the ganglia is removed, the bell 
becomes entirely motionless. The bell thus resembles, as we shall see after- 
wards, the ventricle of the frog's heart, both in the relation of ganglia to it, 
and in its rhythmical movements. Oxygen accelerates, and carbonic acid 
slows and finally stops, the rhythmical movements. 

When the bell, paralysed by the removal of the ganglia which supply its 
normal stimulus to motion, is momentarily stimulated by a single induction 
shock, it invariably responds by a single contraction. 

1 Eomanes, Phil. Trans, vol. clxvi. part 1, and vol. clxvii. part 2, 1866 and 1867. 
! Krukenberg, Vergleichend. physiologische Studien, Heidelberg, 1880. 



110 PHAEMACOLOGY AND THEKAPEUTICS. [sect. i. 

When successive shocks are employed at regular intervals the effect of 
each increases until the maximum is reached (Fig. 30, cf. pp. 122 and 123). 




Fig. 30. — Shows the increasing contractions of the tissue of the medusa whien stimulated by repeated 
weak induction shocks of the same intensity. The first two shocks had no apparent effect, and 
the first feeb'e contraction seen in the figure was caused by the third shock. (From a paper by 
Bomanes in Phil, Trans.) 

But if an additional constant stimulus is supplied to it by the addi- 
tion of acid to the water in which it is floating ; by the passage of a constant 
or of an interrupted electrical current through it ; or by alcohol or glycerine 
dropped upon its surface, it commences to beat regularly, rhythmically, and 
continuously. When rhythmical action is thus artificially induced in the 
paralysed bell, its rate is increased by raising the temperature, and re- 
duced by cooling it. Temperatures below 20° or above 85° arrest the rhythm. 

When the marginal strip containing the ganglia is cut off and left attached 
only at one point, a stimulus applied to its end travels along the strip and 
finally causes the bell to contract. The stimuli which pass along may be 



Strip of contractile tissue witS ■ WHmm/M9 ' 

fringe of tentacles H t' 

Fro. 31.— Diagram of a medusa (tiaropsis), about one-third natural size, with a strip of contractile 
tissue cut from the bell, but left attached at one end. 

of two kinds — they may occur separately or together. The first kind is a 
wave of contraction in the contractile tissue of the strip itself. If the stimulus 
is applied to a portion of the strip the contraction will pass along like a wave 
until it reaches the bell, which it excites to contraction. The second is a 
rudimentary form of nervous activity. This may occur along with the con- 
traction wave, and when this is the case it is seen to pass along in front of 
the contractile wave. But it may also occur when no wave of contraction 
takes place. _ Its occurrence is rendered visible by the movements of the 
tentacles which fringe the strip and are much more sensitive than the con- 
tractile tissue of the strip itself. This wave of stimulation without contraction 
passing along the strip will cause the bell to contract on reaching it, provided 
there is a marginal ganglion in the bell, but not if the bell is paralysed. The 
wave of stimulation is more easily excited than that of contraction, so that 
it may occur from stimuli too weak to excite a wave of contraction. The 
passage of stimuli along the strip may be impeded or prevented altogether by 
compressing the strip, by making transverse incisions into it so as to narrow 
the band of tissue by which the wave is transmitted, or by injuring the tissue. 



chap, iv.] ACTION ' OF DEUGS ON INVEETEBEATA. Ill 

by straining. Sometimes the contraction wave may be blocked by the injury 
before the stimulus wave, and sometimes the stimulus wave may be blocked 
before the contraction wave. When the block is only partial it frequently 
happens that two or three waves will pass along the strip up to the block 
without being able to cross it, but after a long time their effect appears to 
penetrate so that a wave at last crosses it. 

As Gaskell has shown, a similar occurrence takes place in the frog's 
heart, and stimuli proceeding from the auricle to the ventricle may also be 
blocked by compression. 

The influence of poisons can be studied either upon the bell containing' 
the ganglia, or upon this marginal strip. 

In healthy medusae chloroform first arrests the spontaneous movements 
of the bell. When now irritated it answers by a single contraction, instead 
of by a series, to such stimulation. 

After the bell has ceased to respond, nipping its margin causes the polyp 
to contract. 

After stimulation of any part of the bell ceases to produce response in any 
part of the organism, the polyp will respond to stimuli directly applied to it. 
Nitrite of amyl also produces effects which in many respects are similar to 
those of chloroform. There are, however, certain exceptions; the first is 
that, before the spontaneous movements are abolished, the rhythm becomes 
quickened, and the strength of the pulsations is diminished. The move- 
ments also die out more gradually than under chloroform, and before they 
entirely cease they become localised to the muscular tissue close to the 
margin. "When the dose is large, spasmodic contractions are produced which 
obliterate the gradual paralysing action of the drug. 

Caffeine first causes an increase in the rate of pulsation, and diminishes its 
strength after a few seconds. This condition passes off, and the spontaneous 
movements become gradually abolished. They still remain for a long time 
sensitive to stimulation, and at first respond by several feeble contractions 
to each stimulus ; afterwards by a single response ; and afterwards they do 
not respond at all. 

As medusas paralysed by removal of the ganglia never respond to a single 
stimulus with more than a single contraction, the increased number of con- 
tractions which at first appear after the application of the stimulus, are pro- 
bably due to increased reflex irritability. 

Caffeine causes the tentacles and polypi to lose their tonus, and become 
relaxed, which is not the case with chloroform. Medusas anaesthetised with , 
chloroform when put into a solution of caffeine also lose their tonus, but their 
irritability is restored, though their spontaneity is not. 

The effects of strychnine differ in different species of medusae. In Sarsia 
it accelerates the rhythmical contractions which occur in groups separated by 
intervals of quiescence. This quiescence finally becomes continuous, and 
during it the animal does not respond to irritation of the tentacle, but does so 
to direct muscular stimulation. 

Veratrine first increases the number and power of the contractions ; after- 
wards it diminishes both. 

Digitalin first quickens them, then renders them regular, causes persistent 
spasms, and produces death in strong systole. 

Atropine causes first acceleration, then convulsions, then feeble contractions, 
and finally death in systole. 

Nicotine causes violent and continuous spasm, with numerous minute 
rapid contractions superimposed upon it. These latter soon die away, leaving 
the bell in strong systole. 

After spontaneous movements have disappeared, the bell no longer 
responds to stimulation of the tentacles, but responds to direct stimulation. 

Alcohol first greatly increases the rapidity of the contractions, so much so 
that the bell has no time to expand properly between them, and they are in 
consequence feeble and gradually die out. The reflex stimulation shortly 
ceases to produce any effect, but muscular irritability is longer maintained. 



112 PHABMACOLOGY AND THERAPEUTICS, [sect, i.,. 

Cyanide of potassium first quickens and then enfeebles the contractions ; 
spontaneous movements rapidly cease, and the bell soon becomes irresponsive 
either to irritation of the tentacles, or to direct irritation. For a long time 
after it has become irresponsive, the nervous connections between the tentacles 
and polyp remain intact, as also do the nervous connections of these organs 
with all parts of the bell. The sensory organs are therefore not paralysed by 
this drug. 

The effects of poisons on medusae were localised by Eomanes in two ways. 
One way was to divide the medusa almost into two halves, connected only by 
a narrow strip of tissue. These halves were plunged into two beakers filled 
with sea-water, pure in one and poisoned in the other. The connecting strip 




Fig. 32.— Diagrammatic representation of the method of localising the action of poisons on medusa. 
One vessel contains normal sea-water ; another contains poisoned sea-w&ter, which is shaded in 
order to distinguish it. 

rested upon the edges of the beaker. When curare was employed as a poison 
in this way, it was found to have an action similar to that which it exerts on 
mammals : apparently paralysing the motor nerves, while it left the sensory 
nerves capable of action. Thus, on nipping the half of a medusa which was 
plunged in the curare solution, it remained absolutely motionless, while the 
other half at once responded by a peculiar contraction to the stimulus. Here, 
also, however, just as in mammals, the sensory fibres are also paralysed by a 
large dose, so that if much poison be used, irritation of the poisoned part will 
have no effect either upon it or upon the unpoisoned part. "When experiment- 
ing in this way with strychnine, Krukenberg found that the excitability of 
the poisoned part was increased, so that when he touched the connecting strip 
lightly with a needle no effect was produced on the unpoisoned half, but the 
poisoned half responded by several energetic contractions. Veratrine had a 
similar action to that of curare, so that irritation of the poisoned half caused 
no movement in it, but caused movement in the unpoisoned half. The irrita- 
bility of the contractile tissue is also diminished so that it no longer reacts so 
readily in the poisoned half to electrical stimuli. 

Nicotine appears to paralyse the ganglionic structures and not the nerves. 

It has already been mentioned that the rhythmical movements of medusse 
depend upon the ganglia : when these are all cut off the movements cease, . 
but if only one be left the movements continue. In the medusa divided into 
two halves, as already described, it is evident that if the ganglia are removed 
from one half, or one half rendered functionally inactive by poison, that half 
will still continue to contract, so long as it remains connected with the other 
half, but will cease to move when it is completely divided from the half 
which still contains ganglia. The effect of nicotine is such as one would 
expect if the poison paralyses the ganglia, for it is found that when one half 
of a medusa is steeped in water containing nicotine, both halves still continue 
to pulsate rhythmically ; so soon as the connecting band of tissue is divided, 
the poisoned half at once ceases to move, while the other half continues to 
pulsate. 

The second way in which Eomanes localised the action of poisons on 
medusae was by applying them to a strip of contractile tissue. He found 
that various poisons applied to the strip, or injected into it, caused a blockage 
of contractile waves, preceded by a progressive slowing of the rate of trans- 
mission along the poisoned part. Chloroform, ether, alcohol, morphine, 
strychnine, and curare, all have this effect. 



chap, iv.] ACTION OF DEUGS ON INVEETEBEATA. 113 

General Results. — The most marked results of experiments 
on medusse are, that the contractile tissue contracts rhythmi- 
cally when stimulated by ganglia. It ceases to do so when the 
ganglia are removed and the contractile tissue left under ordinary 
conditions, hut a constant stimulus, either chemical or electrical, 
applied to it after the removal of the ganglia, will cause it to 
beat rhythmically just a's if the ganglia were present. This 
appears to show that the rhythmical contractile power is a func- 
tion of the contractile tissue and not merely of the ganglia. 
Besides its power of contracting once on the application of a 
single stimulus, or rhythmically from continued stimulation, the 
contractile tissue also possesses the power to conduct stimuli. 
This is seen in the passage of the contraction wave along a strip 
of medusa which, on reaching the bell, causes it to contract. 
When two contraction waves travelling along the contractile 
strip in opposite directions meet one another they arrest each 
other. This mutual extinction may be regarded either as a 
process of inhibition or interference, or as a consequence of ex- 
haustion of the tissue which possibly may be unable to contract 
twice with such a short interval between. 

The power of the contractile tissue to transmit stimuli is 
diminished or destroyed by cutting it more or less completely 
across, by compression, by stretching, by very high or low tem- 
peratures, and by poisons such as chloroform, morphine, nitrite 
of amyl, caffeine, strychnine, curare, and indeed almost any 
foreign substance added to the water in which the strip is im- 
mersed. 

There are, however, two conducting channels, along which 
stimuli may be transmitted ; the first, already mentioned, is the 
contractile tissue; the second is the nervous tissue. The 
passage of stimuli along the second is rendered evident by the 
movements of the tentacles. These nervous or tentacular waves 
and the contractile waves may exist either together or separately. 
The nervous waves are excited by stimuli which are too weak to 
excite contraction waves, and it is to be particularly remarked 
that when this is the case they only travel at half the rate at 
which a contraction wave travels, although, when the stimulus 
is strong enough to excite a contraction wave also, both the 
nervous and the contractile wave travel at the same rate, the 
nervous one being a little ahead of the other. The passage of 
nervous stimuli may also be diminished or completely blocked 
by section or compression just as in the case of contraction waves. 

The transmission of stimuli along nerves is also affected by 
poisons. It appears to be destroyed by anaesthetics, though 
more slowly than that of the contractile tissue. The ganglia may 
be paralysed, e.g. by nicotine, before the transmission of nervous 
stimuli from them is diminished. The contractile tissue alone 
may be paralysed. 



Ill PHAEMACOLOGY AND THEKAPEUTICS. [sect.!.* 



Action of Drugs on Mollusca. 

In the lameiiibranchlata, instead of a chain of ganglia, as in the 
medusae, we have three pairs of ganglia : cerebral at the mouth, pedal in the 
foot, and parietal-splanchnic supplying the bronchial apparatus and viscera. 
The heart has distinct chambers, but apparently consists of protoplasmic 
substance without distinct nerves or ganglia.* The application to it of an 
interrupted current will arrest the rhythmical pulsation and cause stoppage 
in diastole. 1 This effect is prevented by atropine. Warmth up to 104° 
quickens the heart ; when raised higher it destroys reflex movement in the 
animal, and afterwards arrests the heart also. Pure water without salts 
quickly paralyses the muscles and causes death in salt-water molluscs. 
Curare in small doses has no effect, large doses quicken, but do not abolish 
movement, and do not affect the heart. Strychnine somewhat stimulates 
movement, and may cause some local contractions, but never any general 
tetanus. Nicotine acts in a similar way, but in large doses appears to para- 
lyse the muscles and cause death ; it also appears to cause contraction ot 
the vessels, so that the heart becomes more bulky and beats more quickly. 
Veratrine has a similar action. Digitalis has no action, excepting when 
applied to the heart directly, and then it renders the beats slower and some- 
times stops them. Antiarine, like digitalis, has no general action, but stops 
the heart if applied to it directly. Muscarine generally causes muscular 
contractions in the body : first acceleration, quickly followed by retardation 
of the cardiac beats. Sulphocyanide of potassium diminishes reflex action, 
but has little effect on the excitability of the nerves. A small dose somewhat 
quickens the cardiac action ; a large dose stops the heart in diastole, and if it 
is directly applied to the heart the stoppage is permanent. 

Action of Drugs on Ascidians. 

The heart in ascidians consists of a tube open at both ends, and which, by 
its contraction, drives the visceral fluid alternately towards the viscera and 
away from them. Its action does not seem to depend on the nervous 
ganglion lying between the oral and anal sac, or indeed upon nervous 
influence at all. 

The application of an induced current causes it to beat for some time in 
one direction instead of alternately, but does not arrest its pulsations. 2 Ac- 
cording to Krukenberg it is not affected either by atropine or muscarine. It 
is paralysed by veratrine, quinine, and strychnine : these poisons rendering 
the beats gradually weaker and more irregular. No evidences of tetanus are 
to be seen from the action of strychnine. The mode of action of the heart is 
affected by helleborin and nicotine : helleborin increases the number of the 
advisceral beats while nicotine diminishes them. Camphor and strychnine 
have possibly an action in this respect resembling helleborin. 

Action of Drugs on Annulosa. 

In annulosa the nervous system consists of ganglia in each segment 
united together by nervous bundles. These bundles in general appearance 
correspond with the gangliated cord of the sympathetic in higher animals. 
The spinal cord is absent : we might therefore expect that drugs which 
act specially on the spinal cord in vertebrates would not have the same 



1 M. Poster, Pfliiger's Archiv, v. 191. 

* Dew-Smith, Proc. Boy. Soc, March 18, 1875, p. 336. 



chap, iv.] ACTION OF DEUGS ON INVEETEBEATA. 



115 



marked action on annelida, and this appears to be the case. It was found by 
Moseley that strychnine had no action on cockroaches ; ' and leeches, when 
placed in water containing strychnine, become elongated but do not exhibit 
signs of tetanus. Some years ago I noticed that ants sprinkled with insect- 
powder died in violent convulsions, and it occurred to me that possibly sub- 
stances which excite movements of the intestine in the higher animals might 
have a somewhat convulsant action on invertebrates. I therefore tried the 
effect of oil of peppermint on ieeches, and it produced in them violent excite- 
ment. This appears to be of a somewhat convulsant nature : the animal at 
first flying rapidly hither and thither through the water, and afterwards, when 
it becomes quiet and nearly exhausted, there is a constant rhythmical twitch- 
ing movement in the body which appears to last nearly until death. But if my 
idea had been correct, all carminatives should excite convulsions in annulosa. 
This is not the case, for the oils of peppermint, caraway, and anise have no 
apparent effect on black-beetles other than that of making them sluggish. 

Chloroform, ether, and other substances belonging to the alcohol group, 
act as anaesthetics on mammals, temporarily abolishing the functional 
activity of the brain, spinal cord, and medulla. On annulosa they have a 
similar action, although Krukenberg 2 supposed they had a different effect, 
coagulating the muscular substance and rendering it stiff and hard before 
affecting the nerves. The experiment by which he thought this was 




Fig. 33.— Krukenberg's apparatus for investigating the action of chloroform, &c., on annifosa. 
a is a shallow vessel containing a little water. 6 is a beaker containing water, saturated with 
chloroform, or ether, and covered with a piece of millboard c, in which are two holes. Through 
these holes the head and tail of a leech, d, are drawn and fastened by ligatures held by two 
clamps, e is a bell-jar covering the whole. 

proved consisted in applying chloroform to the middle part of a leech 
while the two ends of the animal were protected from the action of the 
vapour. The middle part then became stiff and rigid, but the movements 
of the two ends of the animal were perfectly co-ordinated, so that its 
actions were that of a single animal having a stiff girdle surrounding its 
middle. Ether and alcohol had a similar result. The co-ordination of 
the two ends showed that although the muscles had been rendered rigid 
by chloroform, the nerves which passed through the middle part of the 
body were still functionally active. When the middle part of the body was 
coagulated by the application of hot water, the muscles became rigid but 
the nerves were also destroyed, and the movements of the two ends of the 
animal were no longer co-ordinated, so that they appeared like two dis- 
tinct animals connected by a rigid cylinder. Luchsinger s repeated Kruken- 
berg's experiments, and found that although the muscles were affected by 
the chloroform, yet the nervous system was still more sensitive than the 
muscles. 



1 Moseley, unpublished experiment made in C. Ludwig's laboratory. 

* Krukenberg, Vergleicliend. physiologische Sttidien, Abtg. I., p. 77. 

* Luchsinger und Guillebeau, PflUger's Archill, xxviii., p. 61. 

i 2 



116 PHAEMACOLOGY AND THERAPEUTICS, [sect, i.' 

Atropine has a similar action to chloroform, ether, and alcohol, on the 
muscles of the leech. Veratrine appears to some extent to affect the muscles, 
30 that after contraction they relax slowly. It appears also, however, to 
affect the nerve-centres, and, according to Krukenberg, paralyses more 
especially the sensory centres. Camphor, strychnine, morphine, caffeine, 
copper sulphate, and mercuric chloride act chiefly on the nervous system of 
leeches, although they also affect the muscles when applied for a length of 
time. Caffeine renders the muscles in the leech also rigid. 



117 



CHAPTEE V. 
ACTION OP DKUGS ON MUSCLE. 

Action of Drugs on Voluntary Muscle. 

In the bodies of animals we find the protoplasmic masses or cells 
of which they are composed variously modified, in order to per- 
form special functions. 

In some the power of nutrition is chiefly developed : and 
this we find in glands. In others the power of contractility 
is developed: and this we find in muscles, striated and non- 
striated. 

In the course of special development towards the fulfilment 
of a particular function, the protoplasm of the muscular cells 
undergoes marked changes. But it must always be borne in 
mind that the protoplasmic elements of the body, however dif- 
ferent from one another, always tend more or less to retain all 
the functions which are seen in an organism consisting of a 
single cell, a reference to which may sometimes throw much 
light upon the mode of life of the more highly organised tissues. 

In amoebae or leucocytes the protoplasm contracts in any 
direction and when strongly contracted in tetanus they become 
spherical. 

In muscle the protoplasm is specially modified and contracts 
chiefly in one direction, viz. that of its length, and, indeed, it is 
usually assumed that muscular fibre, either voluntary or in- 
voluntary, contracts in the direction of its length only. 

But the probability of its contraction in a transverse direction 
also is to be borne in mind, and there are some phenomena 
which it is very hard to explain except on the supposition that 
muscle contracts transversely as well as longitudinally. 1 

We distinguish in muscle its elasticity, a physical property ; 
and its contractility, a vital property. 

1 Thus Weber found that when a muscle is loaded with a weight too great for 
it to lift, instead of shortening, it elongates. The usual explanation of this is that 
the elasticity of the muscle then becomes diminished ; but according to Wundt 
the elasticity is not changed. If we suppose that stimulation tends to make the 
muscle contract transversely as well as longitudinally, the explanation is easy, for 
in this case, longitudinal contraction being prevented, the transverse contraction 
tends to elongate the muscle. 



118 PHAEMACOLOGY AND THEEAPEUTICS. [sect. i. 

The word elasticity is applied to the tendency of the body 
both to resist change of its form, and to regain it when this 
change has been effected : so that ivory may be taken as the 
type of a very strongly elastic body. Indiarubber, on the other 
hand, is regarded as a feebly elastic body, because it does not 
strongly resist changes of form, although it tends very strongly 
to regain its original form after such changes. It is, however, 
popularly regarded as the perfect type of an elastic body. In 
talking of the elasticity of muscle, confusion is apt to occur ; it 
is better, then, to avoid the term elasticity and to use the words 
suggested by Marey — extensibility and retractility. The exten- 
sibility of muscle is of two kinds — immediate and supplementary. 
When a weight is attached to it, it extends considerably ; this is 
its immediate extensibility ; it then goes on slowly and gradually 
lengthening for a considerable time, and this is supplementary 
. extensibility. When the weight is removed the retractile power 
of the muscle again becomes evident, and there is immediate 
retractility and supplementary retractility, the muscle at once 
contracting to a considerable extent, and then continuing to do 
so slowly and gradually for some time afterwards. 

The extensibility of a muscle is increased by stimulation, so 
that if a weight be hung on a muscle while it is contracted in 
consequence of stimulation, it will produce a greater extension 
than it would if applied to the same muscle in a state of rest ; 
and if a muscle be loaded with a weight too great for it to raise, 
stimulation, instead of causing contraction, causes elongation. 1 
Heat renders the muscle less extensible and more retractile; 
cold has an opposite effect, rendering it more extensible and less 




Fig. 34.— Ehows the fiction on muscle ot caustic &utia, 1 in z.uuu, once renewed in 25 minutes, followed 
by the action of lactic acid, 1 in 600, once renewed in 25 minutes. (Eruiitou and Cash.) 




Fig. 35.— Shows the action on muscle of caustic potash, 1 in 2,6ou, twice renewed for 13 minutes, 
succeeded by the aotion of lactic acid, 1 in 600, for 18 minutes, and this by the action of caustic 
potash for 17'5 minutes. (Ct Fig. 60, p. 132.) (Brunton and Cash.) 

retractile. Section of the nerve has a similar effect to that of 
cold. Fatigue increases the extensibility. Alkalis (potash or 

1 Vide footnote, ». 117. 



chap. v.J ACTION OF DEUGS ON MUSCLE. 119 

soda), in very dilute solutions, diminish extensibility; dilute 
acids (lactic acid) increase it. By the alternate application of 




Fig. 36.— Shows the action 01 caustic potash, 1 in 1,600, on muscle for 18 minutes, succeeded by the 
action of lactic acid for 24 minutes. 1 is the contraction of normal muscle ; 2, 3, 4, contractions 
of alkali-muscle ; 5, 6, 7, contractions of acid-muscle on stimulation. (Brunton and Cash.) 

alkalis and acids the muscle may be made to yield curves which, 
■ when recorded on a very slowly-revolving cylinder, are similar in 
form to the normal contraction curve recorded on a rapidly- 
revolving cylinder. 1 Fig. 34. 

Irritability of Muscle. — In order to ascertain the irrita- 
bility of muscle itself or the readiness with which it responds 
to various stimuli independently of the nerves within it, the 
muscle is first jpoisoned by curare, and then exposed to various 
conditions, or to the action of drugs. The muscle thus poisoned 
by curare, woorara, woorali, or urari (for the poison has all 
these names), is much less sensitive to the action of fara- 
daic currents. The readiest way of testing its excitability is by 
the making and breaking of a constant current, the strength 
of which can be estimated very exactly by using du Bois Bey- 
mond's rheochord. The excitability of muscles is increased by 
heat and diminished by cold. It is increased by physostigmine 
and diminished by most poisons which paralyse muscle. 2 

Contraction.— "When the ends of the muscle are not kept 
apart by force too great for it to overcome, and it is stimulated 
by heat, mechanical injury, chemical irritants, or electricity, it 
contracts and then relaxes. 

The form of this contraction varies according to the species 
of animal, and the particular muscle tested. 

In cold-blooded animals, as a rule, the contraction is slower 
than in warm-blooded animals. It is not alike in all the muscles 
of the body of mammals. Thus in the rabbit there are two 
kinds of muscles — red and white ; the white muscles contract 
more quickly and relax more quickly than the red ones. The 
muscle usually employed in experiments is the gastrocnemius of 
the frog, freshly prepared, with the nerve and end of the femur 
attached to it. 

1 Brunton and Cash, Phil. Trans., 1884, p. 197. 

1 Harnack and Witkcrwski, Arch. f. exp. Path. u. Pharm. v. 1876, p. 402. 



120 



PHAEMACOLOGY AND THEEAPEUTICS. [sect. i. 



The femur is fixed in a clamp, and the lower end of the 
muscle is attached to a writing lever usually loaded with a 
weight (Fig. 37). The end of this lever writes upon a revolving 



if 


i 


— 



Fig. 37. — Apparatus for registering muscular contraction. It consists of an upright stand on which 
two horizontal bars may be moved by a rack and pinion. The upper bar ends in a clamp, the 
lower carries a delicate lever, the part near the hinge being of metal, and the part beyond of 
light wood tipped with quill or tinfoil, a, a, wires for exciting muscle ; &, muscle ; c, writing 
lever. In the figure no arrangement is shown for exciting the nerve, and for the sake of sim- 
plicity the weight is shown directly under the muscle. In actual experiment, however, the 
weight should be applied close to the axle, or on it, so as to lessen oscillation due to the inertia 
of the lever. 

cylinder (Fig. 38), which is made to rotate with greater or less 
rapidity. The rate of revolution is usually ascertained by 
marking the time upon it by means of an electro-magnet (Fig. 
39) communicating with a clock or metronome, or, when the 
revolution is quick, with a large tuning-fork vibrating 100 times 
or more per second. "When the cylinder is not in motion each ■ 
contraction of the lever makes a straight line upon it (Figs. 40 a 
and 46) ; when the cylinder is moving, the lever describes a 
curve which is more or less elongated, according to the rapidity 
of the cylinder's rotation (Figs. 40 and 41). 

Latent Period of the Muscle. — The mechanical energy 
developed by muscle during its contraction is derived from 
chemical energy liberated by changes in the constituents of the 
muscle itself. These are of the nature of oxidation, and during 
them oxygen is used up, and carbonic acid is liberated. But 
the oxygen is not necessarily present either around the muscle, 
or in the blood circulating through the muscle ; it is stored up in 
some loose form of combination within the muscle. 1 

1 It would appear that this force-yielding substance, or muscle-dynamite, as we 
may call it, is not present, at least in large quantity, in the muscles in a form in 
which it can be at once fired off. There appears rather to exist a substance yielding 
it, or dynamogen, which may be looked upon as corresponding to the zymogen of the 
glands, while the muscle-dynamite may be regarded as corresponding to the fer- 
ments of glands. Irritation of a nerve appears both to liberate muscle-dynamite 



chap, v.] ACTION OP DEUGS ON MUSCLE. 



121 



The form in which it is stored up has been compared by Lud- 
wig to gunpowder, a small quantity of which is fired off at each 
contraction. 

One of the final products is carbonic acid ; but there are 
intermediate products, one of them being sarcolactic acid ; and 
these products tend to cause muscular fatigue. 

Screw 



Brass pin 




Framework 



Clockwork 



Fig. 38.— Revolving cylinder for recording movements. The screws at the top are for fixing ttte-^ 
cylinder in position. The brass pin is for making or breaking a current at a given time in the 
revolution. It does this by striking against a small key. The curve is described by the lever, 
Fig. 37. The abscissa, or zero line, is drawn by a fixed point, and serves to show the height of 
the contraction. 

When they are washed out of the muscle by a current of 
blood, or of simple saline solution, the fatigue of the muscle is 
removed ; and this removal is effected even more perfectly when 
the internal oxidation is rendered more complete by adding per- 
manganate of potassium to the solution, or by the addition of 
minute quantities of potash. A mere trace of veratrine has also 
a similar effect in restoring the muscle after fatigue. 

and to explode it, if we may so term it. The passage of a constant current through 
the muscle appears to liberate the muscle-dynamite from the dynamogen, but 
causes no expulsion except at the moment when the current is made or broken, or 
its strength altered. It must be carefully borne in mind that the idea of a muscle- 
dynamogen is at present simply theoretical, and must be looked upon not as a fact 
but rather as a means of remembering facts. According to A. Schmidt, however, 
the contraction and relaxation of muscle is closely connected with the formation 
and destruction of a ferment. 



122 PHARMACOLOGY AND THERAPEUTICS, [sect. i. 

• We find that the muscle does not immediately respond to a 
stimulus, but that a period elapses between the stimulus and the 
commencement of the contraction, which is on the average about 
the 100th of a second. This is termed the latent period. 

During this period a chemical change is probably going on in 
the muscle, and it is evidenced by an electrical change known 
as the negative variation, or diminution in the natural current 
which passes from the longitudinal to the transverse section of 
the muscle. 

The latent period is altered by fatigue. Loading the muscle 
shortens the latent period, until the load is just sufficient to 
extend the muscle. An increase of load above this, lengthens 
the latent period. Cold lengthens it ; heat shortens it. Small . 
doses of strychnine or veratrine shorten the latent period. Large 
doses of strychnine or veratrine, and also curare, lengthen it. 

Summation of Stimuli. — During the latent period, the 
stimulus applied to a muscle excites chemical changes which 
result in contraction ; but if the stimulus be very small, the 




Electro-magnet. 

(Indiarubber thread to draw 
back the -writing-point when 
released by the magnet. 

Fio. 39.— Electro-magnet (aiter~"Marey) for recording time on a cylinder. When used to record 
time, the current is made and broken alternately by clockwork or by a tuning-fork. It may be 
used also to record the time of irritating or dividing a nerve, or of injecting a poison, &c. 

chemical changes may be so slight that contraction does not 
occur. If the stimulus, however, be repeated several times, the 
changes which it induces in the muscle become sufficient to pro- 
duce at first a slight contraction, and then one greater and 
greater, until the maximum effect is produced — this is called 
summation. It occurs not only in voluntary muscles, but in 
other contractile tissues, such as those of the medusa (vide 
Fig. 30, p. 110). A similar phenomenon occurs also in the heart, 
and has there received the name of ' the staircase.' 

Contraction of Muscle. — In the muscular curve we notice 
(1) the rapidity of its rise, which indicates the rapidity of con- 
traction of the muscle ; (2) its length, indicating the duration of 
contraction ; (3) its height, indicating power of contraction ; and 
(4) slowness of fall, indicating the condition of extensibility. 

The muscular contraction is modified by numerous conditions. 

One of these is the strength of stimulus. 

The stimulus usually applied is electricity, as its strength can 
be more easily regulated, and it does not destroy the muscle so 
readily as mechanical or chemical irritants. 



chap, v.] ACTION OF DEUGS ON MUSCLE. 



123 



"With a weak current, making (closing) has no action on the 
muscle, but breaking (opening) causes contraction. 




Fig. 40. — Muscle curves, showing the different appearances they present according to the rate at 
which the recording cylinder revolves, a is a curve with a very slowly revo'viug cylinder ; 6, e, 
and d are curves with increasing speed of rotation, c is written with a lever pointiug in the 
opposite direction from that with which a and b are recorded, and the curve therefore inclines 
to the other side. 

A moderate current gives contraction both in making and 
breaking, but that of making is comparatively small (Fig. 41). 
With a strong current no difference is observed. 




Fig. 41. — Shows effect of making and breaking shocks. These are normal muscle curves with a 
still quicker rotating cylinder than in Fig. 40a*. The first is caused by irritating the muscle by 
making (closing) a constant current, and the second by breaking (opening) it. 



The more intense the stimulus, the higher and longer is the 
curve. The increase in height is shown in Fig. 42. 




Fig. 42.— Tracing of the contractions of a muscle with stimuli of varying strength. The numbers 
indicate the distance in centimetres of the secondary from the primary coil in the induction 
apparatus. As and Des indicate the ascending and descending direction of the current. 

Cold renders contraction slower, lower, and more prolonged 
(Pig. 48 6). 

Heat renders it quicker, higher, and shorter (Fig. 43 a). 

Fatigue. — Fatigue makes the ascent slow, the height less, 
and the descent slow (Fig. 44). 

Exhaustion of the animal has a similar action ; and dilute 
acids applied to the muscle produce the same effect (Fig. 36). 



124 PHAEMACOLOGY AND THEEAPEUTICS. [sect. r. 

The effect of fatigue is probably due in a considerable mea- 
sure to the accumulation of acid products of muscular waste. 




Fia. 43. — Effeot of heat and cold. In a the muscle has been artificially warmed, and in b it has 

been cooled. 

When these are washed out by passing a weak solution of 
chloride of sodium through the vessels of the muscle, or partially 
removed by kneading, it regains to a great extent its normal 
power of contraction. 




Fig. 44 Effect ol fatigue. 

Oxidising agents, such as permanganate of potassium, added 
to the salt solution, increase its power, and restore the muscle 
even more quickly and completely. 1 

Deprivation of blood has a similar action on the muscle to 
fatigue ; and free circulation of blood tends to remove the effects 
Of fatigue. 

Contracture. — When the stimulation is exceedingly strong, 
the relaxation after contraction may become very slow, and the 
descent of the curve may be divided into two parts. At first it 
descends for a short time pretty quickly, and then falls very 
slowly indeed. This long contraction of the muscle is known as 
contracture. It is very strongly marked in muscles poisoned by 
veratrine or barium. It occurs, though to a less extent, in 
muscles poisoned by salts of calcium and strontium, by ammonia, 
and by the chloride, iodide, nitrite, nitrate, and cyanide of 
ammonium. 2 

The cause of contracture is not known ; it is considered not 
to be a tetanic contraction, because unlike an ordinary tetanised 
muscle it does not give rise to secondary tetanus in another 
frog's muscle, when the nerve of the latter is placed upon it. It 
is, however, an active contraction, not a mere alteration in the 
elasticity of the muscle preventing its relaxation ; for, as Fick 
and Boehm have shown, a much greater amount of heat is 

1 Kroneoker, Ludwig's Arbeiten, 1871, p. 183. 
* Bruntor. and Cash, Proc. Boy. Soc, 1883. 



chap, vj ACTION OF DEUGS ON MUSCLE. 125 

developed during the long-continued contracture than in an 
ordinary contraction. Sometimes, and indeed not unfrequently, 
the contracture, instead of consisting of a single prolonged con- 
traction, appears in the form of a prolonged contraction added 
on to an ordinary contraction before relaxation has had time to 
occur. This gives rise to a peculiar hump in the curve, as is 
well seen in the middle curve in Fig. 49. This appears to show 
that the contracture is really a double phenomenon, like the two 
contractions observed after a single stimulation in the muscle of 




Flo. 45.— Secondary contraction in the muscle of a crayfish. The thick part of the lower line shows 
the time during which the muscle was irritated fay a tetanising current. It will be noticed that 
the secondary contraction occurs after the irritation has ceased, and after the tetanus Caused by 
it has relaxed. It is not a simple continuous rise, but exhibits several wares indicative of a 
kind of rhythm. (After Bichet.) 

the crayfish by Eichet (Fig. 45). How far the contracture may 
depend upon irritation of the muscle by its. own current has yet 
to be determined. 

Tetanus. — If instead of a single stimulation a number of 
stimuli rapidly succeeding each other are applied either directly 
to the muscle itself or to its motor nerve, we get, in place of a 
single contraction, a continued contraction or tetanus. As this 
is due to a fresh contraction of the muscle occurring before the 
previous one has had time to relax, it is evident that the number 
of stimuli requisite to produce this will vary with the length of 
each single contraction in a muscle. Thus in the muscles of the 
tortoise, which contract and relax very slowly, tetanus may be 
produced by 3 stimuli per second, while in the white muscles of 
rabbits 20 may be necessary, and in some muscles of birds 70 
stimuli per second are insufficient. It has been said that with 
as rapid stimuli as 250 per second the tetanus ceases, and after 
a single initial contraction a muscle goes to rest just as if a con- 
stant instead of an interrupted current had been used. Kro- 
necker and Stirling have shown that, with no less than 22,000 
interruptions per second, tetanus is still obtained ; but when such 
extremely rapid stimuli are applied, the muscle still contracts 
about the ordinary rate of 20 per second ; and this is also the 



126 PHAEMACOLOGY AND THERAPEUTICS, [sect. i. 

case when chemical stimuli are applied to the nerve, or when the 
muscle is irritated by the nerve-centres, either voluntarily or by 
artificial stimuli applied to them. It seems therefore probable 
that the number of contractions of the muscles in tetanus are 
not due to the number of stimuli sent down from the nerve 
centres, but that the rate is determined either by the ends of the 
nerve in the muscle or by the muscle itself. 1 

The form of a tetanus curve may be modified very consider- 
ably by the action of drugs : thus substances which diminish 
the contractile power of muscle cause the tetanus curve to fall 
very rapidly notwithstanding the continued application of stimuli 
either to the muscle itself or to its nerve (vide Ammonia). 

Muscular Poisons. — We may distinguish several groups of 
muscular poisons, but at present the classification is difficult, 
and the division into six groups based on that of Kobert, which I 
have adopted, although it possesses some advantages, is far from 
satisfactory, and can only be regarded as temporary. 

Geoup I. — Leaves, the irritability of the muscle unaffected, but 
diminishes the total amount of work it is able to do. 

Group II. — Diminishes the excitability of the muscle as well as 
its capacity for work. 

Group III. — Diminishes the capacity for work, and produces 
majked irregularity in its excitability. 

Group IV. — Alters the form of the muscular curve. 

Group V. — Increases the excitability. 

Group VI.- — Increases the capacity for work. 




Fig. 46.— Tracings showing the gradual loss of contractile power from fatigue in a normal muscle, 
a, and in one poisoned by carbolio acid, 6. Bach section, V—l', 4>c, shows the contractions in 
one minute. (After Gies.) 

The poisons in Group I. do not alter the muscle curve, so 
that if the action of the poison were tested by a single contrac- 
tion only, it would be supposed that the muscle was unaffected ; 
they lessen, however, the amount of work which the muscle can 
yield. 

The amount of work is estimated by the weight which a 
muscle raises multiplied into the number of times it is lifted 
and the height it is raised each time. These are ascertained by 

1 Wedenskii, Archivf. Anat. u. Physiol. Phys. Abthlg. 1883, p. 325. 



chap, v.] ACTION OF DEUGS ON MUSCLE. 127 

registering the contractions on a slowly revolving drum, as in 
Fig. 46, which shows the rapid exhaustion of a muscle poisoned' 
by carbolic acid as compared with a normal one. The rapid 
exhaustion of muscles may also be observed in the form of the 
tetanus curve which, under the influence of such poisons, falls 
much more rapidly in height than that of the normal muscle. 

This group contains a number of drugs having an emetic 
action. 1 These are : apomorphine, asclepiadine, cyclamine, del- 
phinine, sanguinarine, and saponine, copper, zinc, and cadmium. 
Antimony has a somewhat similar action, but only in large doses, 
and after a great length of time. Arsenic, platinum, and pro- 
bably mercury, act in the same way as antimony. 2 Tin, nickel, 8 
cobalt, 3 manganese, 2 aluminium, and magnesium, have little or 
no action on muscle. Large doses of iron are nearly as powerful 
as arsenic, but in small doses it rather increases the amount of 
work the muscle can do. 

Carbonic oxide at the atmospheric pressure does not affect 
muscular contractility, but abolishes it at a pressure of five 
atmospheres. 

Perhaps we may take as a subdivision of this group those 
poisons which lessen the contractile power of the muscle without 




Pitt. 47. — (After Harnack.) Shows the action of lead on muscle, a shows the contraction of a normal 
muscle after eighty stimulations ; &, the irregular contractions of a muscle poisoned by lead 
after ten to fifty stimulations ; c shows the slow relaxation of the muscle after contraction in a 
muscle poisoned by lead after numerous stimulations. 

altering its irritability. When a muscle poisoned by one of these 
is stimulated, it may contract quite as readily as a normal 
muscle, provided the weight that it has to raise is but slight, 
but it cannot raise such a heavy weight as a normal muscle. 
This is tested by loading it with a given weight, and the slightest 
contraction is ascertained by adjusting the lever of the myograph 
in such a way that if raised in the very least it breaks a connec- 
tion in an electrical current and causes a bell to ring. By this 
means contractions quite imperceptible to the eye are readily 
appreciated. Digitalis has an action of this sort, as I found in 
some experiments carried on under the direction of Professor J. 
Eosenthal in 1868, but not published. 

Group II. contains salts of potassium, lithium, ammonium, 

1 Harnack, Archie f. exp. Path. u. Pharm., Bd. ii. p. 299, and iii. p. 44. 

* Kobert, Arch. f. exp. Path. u. Pharm., Bd. xv. p. 22, and xvi. p. 361. 

* Anderson Stuart, Journ. of Aruxt. and Physiol., vol. xvii. p. 89. 



128 PHAKMACOLOGY AND THERAPEUTICS, [sect. i. 

quinine, cinchonine, oil of mace, alcohol in large doses, chloro- 
form, &c. 

Chloral, chloroform, and ether also belong to this group, but 
they might also be reckoned as belonging to Group IV., for they 
slow the ascent, lessen the height, and prolong the descent of the 
curve. Curare has a similar action. 

It is usually stated that curare, while it paralyses motor 
nerves, leaves the excitability of the muscles unaffected, but this 
appears not to be quite correct, for, when very weak currents are 
employed, the muscle loses its excitability by them before the 
nerve, and the contractions of the muscle at the same time 
become unequal. It is perhaps not yet perfectly certain how far 
these appearances are due to the curare, and how far to the 
gradual death of the muscle. 1 

Group III. contains poisons of which lead is a typical 
example. These poisons cause the muscular contractions to be- 
come very unequal, although the stimuli are equal and regular. 
Emetine and cocaine have a similar action to lead. This 
action is probably due only to the gradual death of the muscle. 
It is produced also by ptomaines, and it may occur in muscles 
which are simply dying without being poisoned at all. 2 

Group IV. contains poisons which alter the form of the curve 
to a marked extent. 

The action of veratrine is very peculiar : it does not lessen 
the rapidity of contraction, and even increases the height of the 
curve, but it prolongs the descent to an enormous extent. 




Fig. 48.— Tracing of the contraction curve of a muscle poisoned by veratrine, showing enormous 
prolongation of the contraction, the recording cylinder making many complete revolutions 
before the muscle is completely relaxed. 

This action of veratrine is most marked at moderate tem- 
peratures. 

It is much diminished, and sometimes entirely removed, by 
cold ; and it disappears also when the temperature of the muscle 
is considerably raised. When the muscle which has been cooled 
or heated is again brought back to a moderate temperature, the 
contracture sometimes returns, but occasionally does not, the 

1 Marey, Travaux du Laboratoire, 1878, p. 157. 
» Mosso, Les Ptomaines, Turin, 1883. 



chap, v.] ACTION OF DEUGS ON MUSCLE. 



129 



effect of veratrine on the muscle appearing to be sometimes, but 
by no means always, destroyed by the heat or cold to which the 
muscle has been exposed. 1 

The result of this exceedingly prolonged contraction is that a 
frog poisoned with veratrine is able to jump with considerable 
power, but the extensor muscles, by which the movement is 
executed, remain contracted instead of relaxing. The animal 
• therefore lies extended and "stiff, and is only able very slowly to 
draw its legs up towards the body. After they have been drawn 
up, the flexors in their turn remain contracted for a while, and 
so the animal is unable to jump until some time further has 
elapsed. 

Another remarkable point about the action of veratrine on 
f muscle is, that although a single contraction lasts so long as 
seriously to interfere with the power of co-ordinated movement, 
jet, if the muscle is made to contract a few times in rapid, 
succession, the effect of the veratrine disappears, and it again 
: acts normally. After a short rest the effect of veratrine again 
, reappears. . 

A similar action to that of veratrine is exerted by salts of 
. .barium, which, when locally applied, cause the muscle to describe 




, Fig. 49.— Tracing of the contraction curves of a muscle poisoned by veratrine, showing the 
peculiarly elongated curve at a moderate temperature, and its restoration nearly to the normal 
. by cooling and heating. 

a curve resembling that of veratrine, not only in its form, but in 
the alterations produced by temperature and in its temporary 
disappearance after repeated contractions. A similar action 
is exerted also, though to a less extent, by strontium and 
calcium. Salts of potassium may at first increase the height 
of contraction, but afterwards both moderate and large doses 

1 Brunton and Cash, Joum. of Physiol., vol. iv. p. 1, and Centralblatt f. d. med. 
Wiss., 1S83, No. 6. 



130 PHARMACOLOGY AND THERAPEUTICS, [sect. 7. 

shorten the muscular curve, and lessen its height, so as finally 
to abolish its contractile power altogether. When applied to a 
muscle poisoned by veratrine, barium, strontium, or calcium, 
salts of potassium remove the excessive prolongation of the con- ' 
traction which these drugs occasion, and "restore the muscular 
curve again to its normal. 1 

Although veratrine alters the form of the muscular curve 
so greatly, it does not (excepting in large doses) paralyse the 
muscle, so that when a poisoned muscle is made to contract at 
regular intervals for a length of time, it is able to do as much 
work as a normal one. 

Nearly allied to this is another group of muscular poisons, 
some of which have already been mentioned as a sub-division of 
Group I. It contains : digitalin, digitalein, digitaleresin, digitoxin, 
toxiresin, scillain, helleborein, oleandrin, adonidin, neriodorin, 
and neriodorein. Tanghinia, thevetin, and frynin, or toad 
poison, probably also belong to this class. 

These drugs do not lessen the irritability of muscle, but 
appear to alter somewhat the form of the muscle curve, some- 
what in the same way, but to a less extent than substances of 
the veratrine group. Some of them when applied in a concen- • 
trated form directly to the muscle cause a condition of rigor. 
This is especially the case with caffeine and digitalin. This rigor 
is well marked in the rana temporaria, and only to a compara- 
tively slight extent in the rana esculenta. Although caffeine in 
concentrated solution produces rigor mortis in the muscle, yet in 
very dilute solutions it is a muscular stimulant, and as such is 
included in the sixth group. 

Group V. contains physostigmine, which increases the ex- 
citability of muscle to slight stimuli, but does not increase the 
amount of work it can do ; on the contrary, in large doses it 
diminishes it. 

Group VI. — Poisons belonging to this group in small doses 
increase muscular work, and cause the muscle to recover rapidly 
after exhaustion. Greatin has this power to a great extent; - 
hypoxanthin has it also, though less powerfully. The effect of 
these substances is very interesting, because they are products 
of muscular waste. They also occur in beef-tea, and their action 
appears to show that beef-tea assists muscular power, as well as 
acts as a nervous stimulant. 

Other members of this group are caffeine and glycogen: 
these have great power to increase muscular work. The relation 
of caffeine to hypoxanthin is very interesting. Xanthin, which 
is another substance derived from muscles, differs from hypo- 
xanthin in containing one atom more oxygen. Theobromine, the 
active principle of cocoa, is dimethylxanthine ; and caffeine, the 

1 Brunton and Cash, Proc. Roy. Soc, 1883- 



chap, v.] ACTION OP DEUGS ON MUSCLE. 131 

active principle of tea and coffee, is trimethylxanthine. The 
restorative effects of beef-tea, coffee, tea, and cocoa have long 
been recognised empirically, although their action could not be 
explained. It now seems not at all improbable that it may be 
partly due to their restorative effect on the muscle. 

Massage. — The effect of kneading a muscle so as to remove 
the waste products from it is very extraordinary. 

When the muscles of an uninjured frog are stimulated to 
contraction by the rhythmic application of maximal induction 
currents until they are exhausted and no longer contract, knead- 
ing them, or massage, restores their contractility so that their 
contractions are nearly as powerful as at first, while simple rest 
without massage has very little restorative effect. In man also, 
while a rest of fifteen minutes after exhausting labour had 
very little restorative action, massage during the same period 
increased double the work that could be done. Massage has a 
similar action to very complete and perfect circulation through 
the muscle, in removing the waste products and restoring its 
power. 1 

Propagation of the Contraction Wave in Muscle. — When 
a muscle is irritated at one point, the contraction wave which 
occurs at that point is conducted along the muscle in both 
directions. 

This contraction wave, like that which occurs in the con- 
tractile tissue of the medusa, is independent of the nervous 
system. The completeness with which it is conducted, and the 
quickness with which it subsides at each point, are closely con- 
nected with the rapidity of the conduction, and they are also 
injuriously affected by anything which impairs it. It diminishes 
during the death of the muscle, and it is lessened also by 
fatigue, by cold, and by injury, such as excessive stimulation. 
Certain poisons also lessen it, as cyanide of potassium, veratrine, 
and upas antiar. 2 

Heat increases the rapidity of the conduction. 

Rhythmical Contraction of Muscle. — Ehythmical con- 
traction is frequently regarded as a function of involuntary 
muscular fibre only ; this, however, is not the case, for it is 
observed also in voluntary muscles. Ehythmical contraction 
of involuntary muscle is seen in the trachea, 3 and is well 
marked in the heart and blood-vessels. It is very distinct 
in the intestines and bladder, and becomes still more marked 
after the influence of the central nervous system has been 
destroyed. In the case of the sphincter ani, for example, the 
rhythm is strong and regular, especially after the nerves have 

1 Zabludowski, Central, f. d. med. Wiss., 1883, No. 14, p. 241. 
1 Aeby, XJntersuchungen aber die Forlpflanzungsgeschwindigkeit der Reizungen 
der quergestreiften Muskclfaser. Braunschweig, 1862, p. 52. 
3 Honvath, Pfliiger's Archiv, 1875, vol. xiii. p. 508. 

k 2 



132 



PHAEMACOLOGY AND THEEAPEUTICS. [sect.t 



been divided and the muscle subjected to some mechanical 
distension by tbe introduction of the finger. 

In voluntary muscle the tendency to large rhythmical pul- 
sations is slight, although we see rapid contractions occurring 
in tetanus. 

The number of impulses sent down to the muscles along the 
motor nerves, from the spinal cord, is about 10 per second in 
the dog. If more numerous impulses are sent down from the 
cerebral cortex, or corona radiata, or if more numerous stimuli 
are applied to the spinal cord itself, summation appears to occur 
in the cells of the spinal cord, and only 10 impulses per second 
are sent out. 1 

From the observations of Wedenskii, that irritation of the 
motor nerve of a muscle by exceedingly rapid stimuli still pro- 
duces the same number of contractions in the muscle, it seems 
probable that this, rate of contraction is due to the constitution 




Fio. 50.— Tracing of the contraction curve of a muscle poisoned by veratrine and exposed to a high 
temperature. The poison tends to cause prolonged contraction, and the high temperature to 
cause rapid relaxation of the muscle. The result is a somewhat rhythmical spontaneous con- 
traction. The muscle was only irritated at the very beginning of the first contraction. 

either of the muscle itself, or of the nerve-endings within it. 
Under certain circumstances, however, the voluntary muscle 
may be made to contract with a slow rhythmical movement of 
considerable extent, and closely resembling that of involuntary 
muscular fibre. 

Thus voluntary muscle treated by veratrine tends to renjain 
contracted for a length of time like an involuntary muaole: 
heat has a tendency to cause its relaxation, and sometimes,, as 
is seen in the accompanying figure (Fig. 50), these contending 
influences produce in the voluntary muscle a tendency to marked 
rhythmical contraction. 

A still more remarkable phenomenon has been noticed by 
Kuhne, 2 who finds that when the uninjured sartorius of a frog 
is placed in a solution of 5 grammes NaCl, and 2-5 grammes of 
common alkaline crystallised phosphate of sodium in a litre of 



1 Horsley and Schafer, Proc. Roy. Soc, vol. xxxix. p. 40G. 
= Unters-uchungen cms dem Phr/siologisclien Institute der Universitttt Heidek 
berg. Sonderabclruck, 1879, p. 16. 



chap, v.] ACTION OF DEUGS ON MUSCLE. 133 

water, it begins to contract at once, and after it has been trans- 
versely divided it beats with the regularity of the heart. 

The effect of various substances on the rhythmic action of 
muscle treated in this way has been investigated by Biedermann. 
He finds that the best fluid for the sartorius is 5 grammes 
NaCl, 2-2"5 grammes of Na 2 HP0 4 , -04--05 gramme of 
Nia 2 C0 3 . A low temperature, not rising above 10° C, is 
best. The lower the temperature the slower is the rhythm and 
the more extensive the contraction. Heat quickens the rhythm 
and lessens the contraction. At about 18° to 20° C. the con- 
tractions become rapid and indistinct. When caustic soda is 
used instead of carbonate, the effect is similar, but the muscle 
dies much more quickly. Potassium carbonate and other 
potassium salts only cause pulsations when greatly diluted. 
Lactic acid stops the pulsations;" alkaline NaCl solution again 
restores them. Veratrine and digitalin in a solution of NaCl 
also cause pulsations. 1 

Schonlein finds that, with a certain strength of current inter- 
rupted about 880 times in a second, the muscles of the water 
beetle are not tetanised, but contract rhythmically from two to 
six times in a second. 2 

Biedermann has succeeded in making a voluntary muscle, 
such as the sartorius, contract rhythmically by applying a 
solution of sodium bicarbonate (2 per cent.) to the tibial end, 
and then passing a constant ascending current through the 
muscle. 3 

Pathology of Tremor. 

Bapid alternation of contraction and relaxation, or tremor, 
may be observed to affect either— (a) a few bundles of muscular 
fibres, (6) a single muscle, or (c) groups of muscles. 

The tremors affecting a few bundles of fibres, or fibrillary 
twitchings, may occur in excised muscles, and are probably due 
to some conditions of the muscular fibre allied to those which 
have already been considered (p. 132). They may occur also in 
muscles which still remain in the living animal after the nerve 
has been cut, more especially in the muscles of the tongue after 
section of the hypoglossal nerve, or in the muscles of the face 
after section of the facial nerve. 4 

Tremors affecting groups of muscles occur, in some cases, 
when the limbs are at rest, and cease during voluntary move- 
ment, as in paralysis agitans ; or may cease entirely when the 
limb is at rest, and only come on when the muscles are put in 

1 Sitzungsber. d. Wiener Akad., Abth. lxxxii. p. 257-275. 
! Schonlein, du Bois Beymond's Archiv, 1882, p. 357. 
' Sitzungsber. d. Wien. Akad., Bd. lxxxvii., Abt. iii., March 1883. 
4 They may possibly be regarded as due to disturbance of the normal relations 
letween longitudinal and transverse contraction in muscular substance. 



134 PHARMACOLOGY AND THERAPEUTICS, [sect, i.' 

action, as in disseminated sclerosis and in mercurial tremor. 
As already mentioned, a certain number of motor impulses per 
second are required to keep a muscle steadily contracted. 

It is evident that, if the stimuli proceeding to the muscles 
from the nerve-centre should be too few, tremor, and not steady 
contraction, of the muscle will occur. And the same will be the 
case if any change in the muscle itself should render the duration 
of each single contraction less than usual. 

But in all co-ordinated movements a number of muscleB, the 
actions of which are antagonistic to each other, are brought into 
play ; and it is by the proper adjustment of these antagonistic 
actions that the performance of delicate movements becomes 
possible. Unless the amount of contraction of each of these 
muscles is exactly graduated, there will be a tendency to oscilla- 
tory movement. As the amount of contraction in each muscle, 
or group of muscles, is regulated by the stimuli sent down to 
it from the nerve-centres, it is evident that if the motor cells 
supplying one group of muscles be affected more than those 
which supply the antagonistic or regulating muscles, inco-ordi- 
nation, and possibly tremor, will occur. The pathology of tremor 
is still, however, very obscure. 

Treatment of Tremor. — If tremor should depend upon in- 
sufficient rapidity of the stimuli passing to the muscles from the 
nerve-centres, it is evident that any drug which, like veratrine, 
will increase the duration of each individual contraction, is likely 
to be of use. Acting upon this idea, Dr. Ferris has used vera- 
trine in cases of tremor due to alcoholism, disseminated sclerosis, -' 
and weakness after typhoid fever. Although this treatment was 
successful in all these diseases, it does not seem quite certain 
that the utility of the medicine may not be partially due to its 
action on the spinal cord as well as on the muscles themselves. 
In one case of tremor, occurring at the commencement of general 
paralysis, I have given salts of calcium with the same object with 
the apparent result of arresting the tremor. I had intended 
to use barium, but the tremor ceasing for many months with 
calcium, I have not proceeded to use anything else. 

Connection between Chemical Constitution and 
Physiological Action on Muscle. 

I have already mentioned (p. 29) that one can hardly look 
for a general relation between the atomic weights of metals and 
their lethal activity, so that what we want is really a knowledge 
of the particular relationship of each group of elements to the 
organs and tissues of the body. 

In such an investigation it seems natural to take the muscles 
first, then the motor nerves, afterwards the nerve-centres and 
individual organs. A number of experiments have been made by 



chap. v.J ACTION OF DEUGS ON MUSCLE. 



135 



Cash and myself in order to do this for the alkalis and alkaline 
earths, and we have found that the contractile power of muscle, 
as shown hy the height of the curve, is increased by rubidium, 
ammonium, potassium, and caesium. It is slightly increased or 
unaffected by sodium, excepting in large doses, and is almost 
invariably diminished by lithium. 

The duration of contraction, as shown by the length of the 
curve, is increased by rubidium in large doses, ammonium, 
sodium, and cesium. It is shortened by ammonium, lithium, 
rubidium in small doses, and by potassium. 

The contracture, or viscosity, is increased by rubidium in 
large doses, ammonium, lithium, and sodium. It is diminished 
by rubidium in small doses, ammonium, caesium, and potassium. 

Both ammonium and rubidium have two actions on muscle 
of an opposite character, sometimes increasing and sometimes 
diminishing both the duration of the contraction and of the con- 
tracture, or viscosity, which remains after the ordinary contraction 
has ceased. In the case of rubidium this appears to depend upon 
the dose, but we were not satisfied that it was so entirely in the 
case of ammonium salts. 

In regard to the action of the alkaline-earths and earths, 
we found that the contractile power "of muscle is increased by 
barium, erbium, and lanthanum. It is sometimes increased and 
sometimes diminished by yttrium and calcium. It is diminished 
by didymium, strontium, and beryllium. 

The duration of contraction is increased by barium, calcium, 
strontium, yttrium, and erbium. It is unaffected, or slightly 
diminished, by beryllium, didymium, and lanthanum. 

Contracture is increased by barium, calcium, strontium, 
yttrium, and beryllium. 

The contracture produced by barium is enormous, resembling 
that produced by veratrine. It is, like that of veratrine, dimin- 
ished by heat, cold, and potash, and may be abolished by these 



Increase or diminish 

afteraction or contracture. 

Increase. Diminish. 



Increase or 

diminish altitude. 

Diminish. Increase. 



Shorten or 
lengthen curve. 
Lengthen. Shorten. 



Rb (in small doses) 
Li — 

Na(in moderate doses) . 

. Sr 

Ca 

Rb (large doses) ~— — 
Ba — — 

NH 4 (HC1) — 



agents. It is by no means so well marked when the drug 
is injected into the circulation as when locally applied to the 
muscle. 

The action of some of the more important of those drugs can 



136 PHABMACOLOGY AND THERAPEUTICS, ^sbct.i, 

be graphically represented by a spiral, the terminal members-of 
which are potassium and barium, and these two are, to a certain 
extent, connected by ammonium as an intermediate link. 

The effect of one member of one of these groups may be 
diminished or increased by the subsequent application of another. 
Potassium shortens the elongated curves caused by barium, 
calcium, sodium in large doses, and lithium, and reduces the con- 
tracture which these substances cause. The veratrine-like curve 
of barium is counteracted by almost all the substances which 
produce a shorter curve than itself. 

Action of Drugs on Muscle is Relative and not Absolute. 

In considering the action of drugs on muscle, the first point 
which comes clearly out is that the action of a drug on the 
muscle is not absolute, but merely relative. Thus veratrine and 
salts of barium are not to be regarded as absolute muscle- 
poisons — they are only poisons under certain conditions of 
quantity and of temperature. An exceedingly small dose of 
veratrine, instead of acting as a poison to muscle, acts rather 
as a food, and restores it .when exhausted. Caffeine likewise in 
small doses has a restorative action, while in large doses it is 
a powerful poison. Veratrine and barium in moderate doses 
and at moderate temperatures are powerful muscular poisons, 
but at low temperatures and at high temperatures their action 
is to a great extent, or even completely, abolished. Nay more, 
moderate quantities of barium salts at moderate temperatures 
are poisonous to the normal muscle, but they are restorative to 
the muscle whose composition and functions have been already 
altered by rubidium. Acids and alkalis also produce an effect 
on muscle, but their effect depends upon whether they are applied 
to the normal muscle or to one previously treated with a substance 
having an opposite reaction. 

It is evident, then, that the whole question of the action of 
drugs on muscle is one involving the relation of the drug to the 
muscle at the time of application, and we must expect that if the 
temperature is different from the normal, or if the composition 
of the muscle should vary, the action of the drug will vary like- 
wise. Now the composition of all the muscles in the body is not 
the same, as has been shown by Toldt and Nowak, 1 and the 
composition of the ash obtained by the combustion of different 
animals is also different, as has been shown by Lawes and 
Gilbert. 1 We may therefore expect that muscular poisons will 
not act alike at the normal temperature and in febrile condi- 
tions, nor alike upon all the muscles of an animal ; nor will they 

1 Quoted by Seegen, Wien. Akad. Ber. lxiii. Abt. ii., 11-43. 
' Proc. Boy. Soc, xxxv., p. 344. 



chap, v.] ACTION OP DEUGS ON MUSCLE. , 137 

always have the same action upon different animals— the 
relations being different, the effects will be different. The effect 
of poisons upon muscles will also vary according to the chemical 
composition of the tissue at the time. This composition may 
probably, to a certain extent, be altered by feeding— at least as 
far as regards the proportions of inorganic ingredients. We know 
that the quantity of sodium chloride in the body can be increased, 
for if an animal be fed with a larger quantity of salt than usual, 
it does not at once begin to excrete, but stores it up for two or 
three days, and then the excretion increases. After the ad-* 
ministration of the salt has been stopped the excretion continues 
large for two or three days, and then returns again to the lower 
standard. It seemed probable that similar retention would 
take place with potash, and if this were so, we might expect to 
counteract to a great extent the effect of barium by feeding an 
animal on potash for some time before administering the barium. 
On trying this, Cash and I have found that this is the case to 
a certain extent, and although we have not been able com- 
pletely to counteract the effect of a large dose of barium so 
as to prevent death from a lethal dose, we have been able to 
modify and diminish its action by the administration of potash 
for several days previously, so that the characteristic symptoms 
of barium poisoning do not occur until some hours after they 
would otherwise do so, and thus life is prolonged though not 
preserved. 

Action of Drugs on Involuntary Muscular Fibre. 

Contraction. — Involuntary muscles, with the exception of 
the heart, differ from voluntary not only in their anatomical 
structure but in their functional activity : instead of contracting 
or relaxing rapidly, both their contraction and relaxation are slow. 
We have seen that although voluntary muscle occasionally ex- 
hibits spontaneous rhythmical contractions, yet these occur only 
under exceptional circumstances, and but rarely. Involuntary 
muscle, on the other hand, has a much greater tendency, to 
rhythmical contraction, although it may be regarded as doubtful 
whether some stimulus, however slight, is not required to induce 
this rhythm even in involuntary muscle. It has been already 
mentioned that the contractile tissue of medusa will beat rhyth- 
mically so long as it is connected with motor ganglia. When 
these ganglia are removed, the contractions cease, but will again 
reappear, notwithstanding the absence of the ganglia, if a con- 
stant stimulus be applied to the contractile tissue itself. This 
shows that the conditions for rhythm are contained in contractile 
tissue itself — that the rhythm may be independent of the ganglia 
with which the contractile tissue is connected (p. 113). The same 
appears to be the case with involuntary muscular fibre generally. 



138 PHAKMACOLOGY AND THEEAPEUTICS. [sect. i. 

The ventricle of the frog's heart, containing ganglia, will 
beat rhythmically for a length of time after its removal from the 
body. If the ganglia which lie close to the auriculo- ventricular 
groove be cut off, the rhythmical action will cease just as in the 
medusa when the marginal ganglia are removed; but if a constant 
stimulus be applied to the apex of the heart, as for example by 
passing a constant current through it, or by distending it with 
serum, its rhythmical movement will again commence, mechani- 
cal distension appearing to have upon it the same exciting action 
that a little acid added to the water has upon the nerveless bell 
of the medusa. 

The excitability of involuntary muscular fibre appears to be 
increased by small doses of atropine ; for when the ganglia of 
the frog's heart are removed the apex, instead of stopping im- 
mediately, will give a few beats before it stops if atropine has 
been previously given, and mechanical stimuli cause more beats 
in the atropinised than in the normal apex. 1 

Effect of Stimuli. — Mechanical distension appears to be one 
of the most powerful of all stimuli to excite rhythmical contraction 
in involuntary muscular fibre. 

Luchsinger observed distinct pulsation in the veins of a bat's 
wing twenty hours after the death of the animal, if artificial cir- 
culation was kept up. This appears to show that the power of 
rhythmical contraction resides in the muscular fibres of the veins, 
as it does in the nerveless apex of the frog's heart, and the con- 
tractile tissue of the medusa ; but here also an external stimulus 
appears to be required to induce contraction. "When the pressure 
by which artificial circulation was maintained fell to zero, the 
pulsation stopped, but if it were raised to forty or fifty centi- 
metres of water, so as to distend the vascular wall, rhythmical 
pulsation again commenced. It appears possible, however, that 
when involuntary muscular fibre is perfectly healthy and 
possesses the highest degree of irritability, it may contract 
rhythmically without any extra stimulus. Thus Engelmann 2 
observed that the ureter, in which he could find no nerves at all, 
contracted rhythmically when freshly exposed, although it was 
not distended or subjected to any mechanical irritation ; but if 
artificial respiration has been long kept up, and the animal is 
exhausted, so that the excitability of the ureter is diminished, 
then the effect of minimum distension in increasing its rhythm 
becomes very evident. 

Cold causes the isolated non-striated muscles of animals to 
relax. Heat causes them to contract. 3 

The influence of heat and cold, however, does not seem to be 
constant, and in the non-striated muscle of frogs they have an 

1 Langendorff, Arehwf. Anat. u. Phys. Physiolog., Abtg. 1886, p. 267. 

» PflUger's Archiv, 1869, Bd. 11, p. 251. 

' Luchsinger and Sokolofl, PflUger's Archiv, Bd. 26, p. 465. ■ 



eHAP. v.] ACTION OF DEUGS ON MUSCLE. 189 

opposite connection to thai; just described. It is probable that 
the different results may depend to a great extent upon the 
amount of heat or cold applied, and its relation to the condition 
of the tissues at the time of application ; for mechanical stimu- 
lation has also an opposite effect, according to its amount ; and 
while gentle stimulation of involuntary muscular fibre, such as 
that of the small blood-vessels, causes dilatation, more powerful 
irritation produces contraction. 1 

The influence of various drugs upon involuntary muscular 
fibre, as seen in the contraction of the blood-vessels, will be 
described when considering the circulation. 

The Relation of the Contractile Tissue to the Nerves 
is different in voluntary and involuntary muscular fibre. In the 
latter there are no end plates, but the terminal twigs form 
a plexus around the fibres. The motor nerves of involuntary 
muscular fibre appear to be affected by atropine and its con- 
geners in a similar way to those of voluntary muscle by curare. 
There appears also to be a certain relationship between the atro- 
pine and curare group. Small doses of atropine paralyse the 
motor nerves of involuntary muscle, while very large doses of 
curare are required. The converse is the case with voluntary 
muscle. These effects are usually supposed to be due to a 
definite paralysing action on the nerves themselves. There are 
difficulties, however, in the way of this hypothesis, and a more 
probable one, perhaps, is that these drugs disturb the relations 
between the nerves and the muscular fibres which they excite. 
On the idea of a specific action it seems hard to explain the 
results obtained by Szpilman and Luchsinger, 2 who found that 
atropine produces paralysis of the motor fibres of the vagi sup- 
plying the oesophagus, only in those parts of it where involuntary 
muscular fibre is present. Thus the oesophagus of the frog and 
the crop of birds consist of involuntary muscular fibre, and 
atropine destroys the motor power of the vagus over them. The 
oesophagus of the dog and rabbit contains striated muscular 
fibre, and atropine does not paralyse the motor nerves. The 
oesophagus of the cat contains striated muscular fibres in its 
upper three-fourths, and non-striated in its lower fourth ; atro- 
pine destroys the motor action of the vagus upon the lower 
fourth, but not upon the upper part. 3 

Propagation of Contraction Waves. — Although involuntary 
muscular fibre consists of short cells and not of long fibres like 
voluntary muscle, yet the contraction wave may be propagated 
along a strip of involuntary muscular tissue in both directions 
from the point of irritation, just as in voluntary muscle or in 
the contractile tissue of medusae. This wave is transmitted 

1 Sigmund Meyer, Hermann's Handb. d. Physiol., Bd. 5, Theil ii., p. 476. 
8 Szpilman and Luchainger, PflUger's ArcMv, Bd. 26, p. 459. 
• Ibid. p. 249. 



2 



140 PHARMACOLOGY AND THERAPEUTICS, [sect. i.. 

more slowly in involuntary than in voluntary muscle ; and 
its rate in the involuntary muscle of the heart, though slower 
than in ordinary striated muscle, is quicker than iri unstriated 
muscle, so that in this respect the heart is intermediary between 
the two. 1 

The passage of contraction waves in involuntary muscular 
fibre is affected by the same conditions as voluntary muscle, 
the conduction of the contractile wave being rendered slower by 
fatigue and cold, while it is quickened by heat. 

Cold and fatigue also render the rhythmical pulsations smaller, 
and longer, while heat has an opposite effect. The passage of 
the contraction wave may also be diminished or arrested by 
section or pressure, just as in the contractile tissue of medusae, 
so that instead of each contraction wave passing the block pro- 
duced by the sections or compression, only one out of several, 
or none at all, may pass. The proportion passing the block 
depends upon its completeness. If the tissue forming the 
bridge be dry as well as narrow, the block becomes more com- 
plete, and may be again diminished by moistening. Variations 
in the strength of the stimulus do not affect the passage of the 
contraction wave over the block, so that it would appear that 
the injury caused by the section, along with the narrowing of the 
conduction path, retards the re-establishment of the conductive 
power. 

In experiments made upon the heart of a tortoise cut into a 
strip, it has been found by Gaskell that stimulation of the vagus 
removes the block, quickens the recovery of the tissue, and causes 
every contraction wave to pass. The effect upon the muscle 
therefore seems to be trophic. 

A weak interrupted current applied to the muscle directly 
has the same action as stimulation of the vagus, i.e. it increases 
the conducting power of the muscle. Sometimes, however, both 
the vagus and a weak interrupted current have an opposite effect, 
and diminish instead of increasing the conducting power. 

An artificial rhythm may be induced in a strip of involuntary 
muscular fibre cut from the heart of the tortoise by passing a weak 
interrupted current through it and then stimulating it at one end 
by induction shocks, at intervals of about five seconds. After a 
while, if the induction shocks are discontinued, the muscle still 
continues to contract rhythmically at the same rate. These con- 
tractions, at first weak, afterwards become strong, and may last 
for many hours. Both the conducting and the contractile power 
of the muscle are diminished by muscarine. When a strip of it 
is stimulated by induction-shocks applied to one end, the con- 
traction wave passes quickly along ; but muscarine appears to 

1 Hermann's Handbuch d. Physiologie, Bd. 1, p. 56. 

2 Engelmann, Pflilger's Archiv, 1875, Bd. 11, p. 465 ; Gaskell, Journal of 
Physiology, vol. iii. p. 367. 



chap. v:j ACTION OF DEUGS ON MUSCLE. 141 

block its transmission, so that while the part of the muscle 
between the electrodes contracts at every shock, the rest of the 
muscle contracts only at every second one. A weak interrupted 
current then sent through the muscle may lower its conducting 
power and still further reduce the force of the contractions, and 
not only block the passage of most of the contraction waves from 
the point of excitation, but may even prevent the contraction of 
the excited part itself. 

Atropine has an opposite action and appears to increase the 
conducting power of involuntary muscle, so that when applied 
to a strip of the heart, the conducting power of which has been 
diminished by muscarine,, the contractility is at once increased^ 
and each contraction wave pass'es over the whole muscular strip 
each time that a single point is irritated. Large doses, however, 1 
appear to have a depressant action on the muscle. 

Hypothetical Considerations regarding the Action of 
Drugs on Muscle. 

The modifications which drugs produce in the functions of the animal 
body and of its parts are so numerous and varied that we are unable fully 
to explain them on the basis of our present physiological knowledge. The 
results of pharmacological experiments furnish us indeed with a number of 
additional facts regarding the functions of organs and tissues which will ultl* 
mately lead us to a more correct and thorough knowledge of their physiology'. 
At present, however, we can only explain them hypothetically, and, indeed, in 
many cases we can do little more than guess at the explanation. 

The advantage to be gained from hypothetical explanations is that 
hypotheses not only lead to further experiment, but serve as guides for 
experiments, by which, if false, they may be soon disproved, or, if true, may 
be maintained. 

The disadvantage of hypotheses is that they are sometimes apt to be 
taken for facts, and being made use of as bases for further speculation, may 
lead more and more astray from the truth. While bearing in mind the 
danger of speculation, it may be useful to make some guesses at the mode of 
action of drugs upon the muscle as guides to further research. 

The most striking point about muscle is the motor function which it 
exercises by contracting, and the nature of its contraction must engage our 
attention. Throughout the universe we find that motion of nearly all sorts 
resolves itself into a series of vibrations, and the question arises whether the 
motion of muscle cannot be explained in the same way. 

When a muscle is stimulated it. contracts and relaxes once, describing a 
wave-like curve upon the revolving cylinder. Frequently this first wave is 
followed by a second, and sometimes even by a third, which are usually 
ascribed to the simple elasticity of the muscle. Sometimes we can notice 
that the single contraction wave appears really to consist of two or moie par- 
tially superimposed on each other, and sometimes we may find two distinct 
waves arise from one stimulation. 

When a muscle is in a state of tetanic contraction it appears to the eye to 
be perfectly quiet, yet we know that during this period of apparent rest the 
muscle is in a state of vibration, alternately tending to contract and elongate. 
These vibrations may succeed one another with a rapidity such that the 
muscle appears to the eye to be motionless, while a tracing taken upon the 
revolving cylinder shows distinct successive waves. If the vibrations are 
still more rapid, the waves may disappear, and we get the muscle describing 
a straight line. But even when a muscle is entirely relaxed, its parts may 



142 PHAEMACOLOGY AND THEEAPEUTICS. [sect. i. 

be in a state of vibration quite as continuous as in tetanic contraction. This 
is seen by examining muscular fibre under the microscope. The phenomenon 
which then presents itself was described by Porret and is often known by his 
name. On passing a constant current through a thin muscular slip a con- 
traction is seen when the current is closed. During the whole time of the 
passage of the current, the muscle, to the naked eye, appears to be perfectly 
at rest, but under the microscope its parts are seen to be in constant motion, 
presenting an appearance almost exactly similar to the waving of a field of 
corn on a windy day, or to the motion of rows of cilia. At the same time an 
actual transference of material takes place in the muscle : the end next the 
positive pole growing smaller, and the end next the negative pole growing 
larger. When the current is suddenly reversed, a sudden contraction of the 
whole muscle takes place, and it then returns to apparent rest ; but micro- 
scopic observation shows the same cilia-like motion as before, but in an 
opposite direction. 

This phenomenon reminds one very strongly of the crowding together of 
carriages in a railway train when it is set in motion or stopped by the 
locomotive pushing behind or stopping in front. Wo know that the apparent 
steady movement of the train is due to the backward and forward vibration 
of the piston in the cylinders of the locomotive, and the question occurs 
whether the contraction of the muscle as a whole at the moment of opening 
and breaking the current, is not due to an interference with the rhythmical 
vibration of its parts. The question also arises whether these vibrations are 
not to a great extent dependent upon the molecular weight of its constituents. 
This seems to a certain extent to be indicated by the curious relations between 
the effects of the alkalis, alkaline earths, and certain metals upon muscle. 
Thus Cash and I have found that potassium and calcium neutralise the action 
of each other upon muscle, and if the hypothesis just expressed be correct 
we should expect that metals having a similar molecular weight to a mixture 
of calcium and potassium would have no action upon muscle. This appears 
to be the case. In researches made in Professor Schmiedeberg's laboratory, 
Anderson Stewart found that nickel and cobalt had no action upon muscle, 
and White found that tin also had little or none. On comparing then the 
atomic weights of potassium (39), calcium (40), nickel (59), cobalt (59), and 
tin (118), we get the following relationships : 

K 2 (78) + Ca (40) = Ni 2 (118), or, Co, (118), or, Sn (118.) 
Sodium in large doses lengthens the curve and increases the contracture 
when applied to a normal muscle. It adds to the length of the long curves 
caused by calcium and strontium. Eubidium in large doses produces a long 
curve with enormous contracture almost like that of barium. One would 
naturally have expected that the rubidium and barium would have increased 
each other's effect like sodium, calcium, or strontium ; but the reverse is the 
case, for the abnormal curve caused by rubidium is reduced to the normal by 
the application of barium. If barium be applied to a greater extent than is 
sufficient to antagonise rubidium, it first abolishes the prolonged rubidium 
curve, reducing it to the normal, and then again elongates it, producing its 
own characteristic curve. Calcium and strontium, which also prolong the 
curve, though to a less extent than barium, do not antagonise one another's 
effect — they rather increase it ; but calcium reduces the barium curve to the 
normal before causing its own peculiar curve. At first sight these results 
seem to be independent of any rule, but a curious relation is to be observed 
between the atomic weights of these substances. Thus we have seen that 
rubidium in large doses has the same effect as barium in causing a veratrine- 
like curve, but barium destroys the effect of rubidium before producing its 
own effect. On comparing the atomic weights of these elements we find that 
eight atoms of rubidium have nearly the same weight as five of barium, and 
by subtracting one from the other we get almost no remainder. Thus, 

Ba 137 x 5 = 685 

Eb 85-4 x 8 = 683'2 



chap, v.] ACTION OF DEUGS ON MUSCLE. 14y 

Potassium is, as we know, an important constituent, of muscle, and it 
seems possible that the reduction in the barium-curve which calcium causes 
may be due to their union having resulted in a substance whose molecular 
weight is a multiple of that of potassium. Thus, 

Ba 137 x 2 = 274 - Ca 40 = 234 
K 39 x 6= 234 

The alterations which occur in voluntary muscle from the action of such 
substances as calcium or barium appear to approximate it to some extent to 
involuntary muscle. Voluntary muscle is chiefly characterised by sudden and 
rapid contraction and relaxation. Involuntary muscle usually contracts and 
relaxes slowly. In the slowness of its relaxation, at least, the muscle poisoned 
by barium or calcium approaches involuntary muscle. , 

The power of summation which contractile tissues possess is strongly sug- 
gestive of the idea that rhythmical vibrations of gradually increasing intensity 
are going on within the tissue even before any movement becomes visible. A 
pendulum very gently struck at proper intervals will gradually begin to 
oscillate through a larger and larger arc. If touched on one side while 
oscillating, the effect of the touch will depend upon the time at which the 
touch is applied, for at one period of oscillation it will tend to impede, and at 
another to assist the oscillation. Possibly some unseen rhythm in the muscle 
itself may be the cause of the curious variations in excitability observed in 
dying muscles and in muscles poisoned by lead. Two pendulums connected 
together will swing harmoniously if their rate of oscillation is the same, but 
if one be loaded so as to alter its rate of oscillation they will interfere with 
each other. Possibly the effect of poisons in paralysing nerves may be due 
rather to alteration in the relative rhythms of the nerve and muscle than to 
any specific destructive power on the terminations of the nerve itself. 

The opposite effects which Gaskell has noticed the vagus nerve and a weak 
induced current to produce upon the conducting power of the cardiac muscle, 
sometimes increasing and sometimes diminishing it, may be due to the inter- 
ference or coincidence of rhythm such as are discussed more fully farther on 
under the head of Inhibition. 

It is impossible to say at present what the true cause of the curious 
rhythmical contractions of voluntary muscle is, but if we suppose that there 
is a transverse as well as a longitudinal contraction in muscle, we might 
regard the rhythmical contractions as resulting from the action of these two 
opposing forces. 

It must be borne in mind that the considerations contained in this section 
are purely hypothetical, and their only use is to indicate the direction in 
which we may possibly look for an explanation of the action of medicines on 
muscle. 



IU PHARMACOLOGY AND THERAPEUTICS. Tsect. u 



CHAPTEE VI. 
' ACTION OF DRUGS ON NERVES. 

General Action of Drugs on the Nervous System. 

In low organisms the contractile protoplasm fulfils the func- 
tions of both nerve and muscle, but as we ascend in the scale 
differentiation becomes more and more complete. From their 
original common origin, however, we might expect that the 
poisons which act on the muscles would also act on the motor 
nerves, and vice versa, and we should hardly expect any poison 
to act entirely on the one without affecting the other. This 
is to a considerable extent the case, for very many substances 
paralyse them both. But, as one would also expect from the- 
differentiation they have undergone, muscle and nerve are not 
equally affected in the higher animals. Thus we find that 
although most of the salts of ammonium, and the iodides, 
chlorides, and sulphates of the compound ammonias into which 
methyl and ethyl enter, paralyse both muscle and nerve, yet 
they paralyse the: nerve before the muscle. In some cases the 
nerve is, affected so much before the muscle that at first sight it 
might appear that the nerve alone was paralysed and the muscle 
left unaffected. More careful observation, however, shows us. 
that most of the compound ammonias, and probably most of 
the organic alkaloids, affect muscle, motor nerves, and nerve-; 
centres, and, if their action can be continued long enough, will 
paralyse all three. The symptoms they produce may, however, 
be entirely different, because these depend upon the order in 
which the different parts of the nervous system are affected, as 
has already been pointed out at p. 26. The symptoms pro- 
duced, for example, by strychnine and methyl-strychnine ara 
utterly different, the former causing tetanic convulsions, and 
the latter gradually-increasing torpor, weakness, and paralysis. 
Strychnine stimulates the spinal cord, and methyl-strychnine 
paralyses the motor nerves ; yet if their action continue long 
enough it is found that both of them will ultimately cause 
paralysis of both spinal cord and motor nerves. The final result 
is thus the same in both cases, but the order in which the 
various parts of the nervous system are affected is different. 



chap, vi.] ACTION OF DEUGS ON NERVES. 



145 



In the example just given, the drugs appear to exert a 
selective influence on the spinal cord and motor nerves respect- 
ively, and consequently produce very different symptoms. But 
we find that a number of drugs appear to act upon muscles, 
motor nerves, and nerve-centres, in a given order, although there 
may be slight variations in the action of the individual drugs. 
These substances are .generally found to act as protoplasmic 
poisons, arresting the movements of amoeba and white blood- 
corpuscles, as well as proving fatal to higher animals. 

In the protoplasm of these minute organisms we are unable 
at present to distinguish any evidences of differentiation. As we 
ascend in the animal kingdom we find a differentiation between 



Brain 



Medulla 



Respiratory nerved 



Heart 




spinal cord 



Centre for 
sphincter* 



Sensory and motor nerves 



Pig. 51. — Diagram to illustrate Hughlings Jackson's views of the nervous sj'stem. 

muscle, nerve, and nerve-centre ; and the higher up we ascend 
in the scale the more complex do the nerve-centres become. As 
Hughlings Jackson has well put it, ' evolution is a passage from 
the most simple to the most complex, from the lowest to the 
highest centres.' It is a passage from the most automatic to the 
most voluntary ; but the lowest centres are at the same time the 
most stable, or, as Jackson calls it, the ' most organised centres ' ; 
while the highest centres are the most unstable or least organ- 
ised. This is represented diagrammatically in Fig. 51, where 
the centres for the heart and respiratory apparatus and for the 

L 



146 PHAKMACOLOGY AND THERAPEUTICS. ' [sect, u 

sphincters are represented as very simple in their organisation, 
but very stable, as indicated by the size of the ganglia and thick- 
ness of the nerves in the diagram. The spinal cord is represented 
as more complex, but with thinner lines, in order to show its 
lesser stability ; while the high complexity and small stability of 
the cerebral cortex is indicated by the great number and thin- 
ness of the lines in the figure. According to Jackson, the lowest 
nervous centre extends from the aqueduct of Sylvius to the lower 
end of the spinal cord ; and in this all parts of the body are 
directly represented, so that a discharge of nervous energy from 
any part of it only requires to overcome the resistance in the 
motor nerves . and the muscles, themselves. What he regards 
as the middle motor centres are evolved out of the lowest, and 
re-represent all parts of the body in more complex and special 
combinations. The highest centres evolved out of the middle 
re-re-represent all parts of the body in still more complex and 
special combinations. A discharge from the highest centres, in 
order to act on the periphery, has to overcome the resistance of 
the middle, and lowest centres, as well as of the muscles. 

In the action of such poisons as alcohol, the nervous system 
appears to be paralysed in inverse order of its development : the 
highest centres going first, next the middle, and then the lowest. 
After this comes paralysis of the motor nerves, and lastly of the 
muscles themselves. In the ease of alcohol, the dose required to 
paralyse motor nerves and muscles is so great that, as a rule, we 
can only observe its effect by directly applying the drug to the 
nerves and muscles themselves. To such a process of paralysis 
as this, Jackson applies the term of dissolution. 

In the case of drugs which excite nervous centres, we also 
notice a certain similarity of action. Thus strychnine not only 
causes convulsions by its stimulating action on the medulla 
spinalis, but stimulates also the nerve-centres for the respiration 
and circulation in the medulla oblongata and in the heart itself. 

Action of Drugs on Motor Nerves. 

The readiness with which a muscle responds to a stimulus 
depends both on the condition of the muscle itself, and on the 
terminations of motor nerves within it. A faradaic current 
readily stimulates the nerve-endings, but does not act at all 
readily on the muscle. The making and breaking of a constant 
current, on the other hand, has comparatively slight action on 
the nerves, but a powerful action on the muscle. One of the 
questions which arises most constantly in connection with the 
action of drugs is :— whether or not they paralyse the end of 
the motor nerves in muscle. This question was fully worked 
out by -Bernard, and also independently by Kolliker, in relation 
to curare. 



chap, vi.] ACTION OF DEUGS ON NEEVES. 147 

The same methods of experiment were adopted by both. 
They were twofold, and consisted : 

1. In applying the poison to that part of the body alone which 
seemed affected by it, and seeing whether it produced its usual 
action. 

2. In preventing it from reaching that part, and seeing 
whether its usual effect was then absent. 

The first of these methods consisted in the local application 
of the drug to the muscles and motor nerves themselves (Pigs. 52 
and 53). The second consisted in ligaturing the artery of one 
leg in a frog, so as to prevent the poison from reaching the 
muscles and motor nerves in that leg (Pig. 54) . 

The advantage of the first method, viz. that of local appli- 
cation, is that it allows us to deal with only one organ at a 
time, and the results are therefore less complicated than those 
of the second method. In some respects it is better to begin with 
the second method and work back to the simpler from the more 
complex organs (p. 149). 

Paralysis of Motor Nerve - endings. — Curare produces 
symptoms of paralysis. Paralysis may be due to the action 
of the drug on the muscles themselves, on the motor nerves 
which set them in action, or on the nerve-centres which originate 
motor impulses. In order to decide this, Bernard applied elec- 
tricity to the nerves and to the muscles of a frog poisoned by 
curare administered subcutaneously. He thus found that when 
the nerve was irritated no effect was produced on the muscles ; 
but that when the muscle itself was stimulated, it contracted 
readily. In order to decide whether this loss of irritability in 
the nerve was due to a change in the nerve-trunk, or in the ter- 
minations within the muscle, Bernard employed the first method, 
that of local application. He placed a solution of curare in two 
watch-glasses. In one he immersed the trunk of the nerve (Fig. 




Fig. 52. — Shows the method of applying a drug in solution locally to the trunk of a nerve. 

52), and in the other the muscle, so that the solution penetrating 
between the fibres could reach the nerve-endings (Fig. 53). He 




FiQ. 53.— Shows the method of applying a drug in solution locally to a muscle and the ends 
of motor nerves within it. 

then irritated the nerve attached to both muscles, and found 
that irritation caused contraction readily enough in the case, 

l2 



148 



PHARMACOLOGY AND THEEAPEUTICS. [sect. i. 



Where the nerve-trunk had been steeped in the solution of curare, 
but had no effect when the curare had been allowed to reach the 
nerve-ends by immersion of the muscle in the solution. The 
irritability of the muscle itself to mechanical stimuli, or to the 
making and breaking of a constant current directly applied to 
it, remained quite unaltered, so that the muscular fibre had 
evidently not been affected by the action of the poison. 

The second mode of testing the action of drugs upon motor 
nerves, viz. that of local protection, consists, as has been stated, 
in allowing the drug to be carried to the muscles and nerve-endings 




3FIG.' 54.— Diagram of the mode of experimenting on motor and sensory nerves in the frog. — The 
shaded part shows where the poison has been carried by the cumulation. The unshaded left leg 
shows where the tissues have been protected from the poison by ligature of the artery just 
above the knee. The unbroken lines with arrows pointing to the spinal cord indicate the 
sensory nerves. The broken line with arrows pointing outwards indicates the motor nerve to 
the unpoisoned leg. 

by the circulating blood in one leg of a frog, while it is prevented 
from reaching the other either by ligaturing (Fig. 54) the blood- 
vessels alone, or ligaturing tbe whole leg with the exception of the 
sciatic nerve. After some time has elapsed, the sciatic nerve is 
stimulated on eacb side. If the muscles of the poisoned limb do 
not contract at all or do so more feebly than in the unpoisoned 
limb, it is evident that the poison has paralysed either them or 
the motor nerves. In order to .decide whether the nerves or the 
muscles are paralysed the muscle is next stimulated directly ; if 
it then contracts normally it is evident that the paralysis ob- 
served when the nerve was irritated is due to the action of the 



chap, vi.] ACTION OF DRUGS ON NERVES. 149 

drug on the nerve-endings. If the muscle is, completely para- 
lysed, no definite conclusion can be drawn regarding the nerve- 
endings, but if the muscle shows only partial paralysis, and the 
paralysis is greater when the nerve is stimulated than when the 
muscle is stimulated directly, we conclude that the drug has 
acted upon both the muscular substance itself and the motor 
nerve-endings within it. 

The effect of drugs in paralysing motor nerves is chiefly in- 
vestigated in frogs as the action comes out much more distinctly 
in them. 

Warm-blooded animals may die from paralysis of the motor 
nerves while the nerves still respond readily to faradaic stimuli 
.applied to them, the faradaic stimulus being much greater than 
that normally sent along the nerves from the nerve-centres. 
Thus after an animal has been killed by paralysing it with 
curare, its muscles will still respond readily to electrical stimu- 
lation of the motor nerves. 

A fallacy to be guarded against in experiments on the results 
of preventing a poison from reaching one part of the body is 
that caused by diffusion. Even when the circulation is stopped 
in a frog's leg by ligature of the artery, poison introduced into 
the dorsal lymph-sac may pass down the limb by diffusion and 
affect the parts below the ligature. This may be to a great 
extent prevented by ligaturing the whole limb en masse, at the 
same time carefully excluding the sciatic nerve from the ligature. 
Diffusion may also occur although the circulation has been stopped 
throughout the whole body by removal of the heart and other 
viscera, and the anterior part of the spinal cord may be affected 
before the posterior when the poison is. injected into the dorsal 
lymph-sac. 

Advantage of the Method of Local Protection.:— The 
advantage of this method is that it affords information regarding 
the action of the poison upon other parts of the nervous system,. 
viz. the nerve-centres and sensory nerves, as well as upon. the 
motor nerves. It also gives the order in which the poison affects 
the various nervous structures, and shows whether the quantity 
of poison conveyed to the nerves by the circulation is sufficient 
to paralyse them or not. For some substances, directly applied 
to the ends of the motor nerves, may paralyse them, although 
they do not have this effect when injected into the blood : 
the reason being that the quantity applied to the nerves directly 
may be much greater than that which reaches them through the 
circulation. 

The muscles and ends of the motor nerves being protected 
in the ligatured leg from the action of the poison, while it still 
remains in connection with the nerve-eentres by means of the 
sciatic nerve, this method serves as an index to show what is 
going on in the nerve-centres.. Thus in a frog poisoned by 



150 



PHAEMACOLOGY AND THEEAPEUTICS. [sect. i. 



curare it is found that the ligatured leg moves on irritation 
of the sensory nerves, while all the poisoned parts remain per- 
fectly still. This shows that the afferent nerves are still capable 
of conveying impressions to the spinal cord, and the cord itself 
of reflex action, although the poisoned limbs give no indication 
of the changes which are occurring in the nerve-centres. By- 
and-by irritation of a sensory nerve or root ceases to produce 
any movement even in the ligatured limb. This effect is shown 
to be due to paralysis of the nerve-centres by observing the 
effect of irritation of the nerves in the ligatured limb, for the 
muscles still respond readily to irritation of .the nerve by a 
moderate stimulus. We may conclude with tolerable certainty 
that the motions have ceased in the limbs because the nerve- 
centres have become paralysed. 

Paralysers of Motor Nerves.— Many other drugs have 
an action somewhat similar to that of curare upon the motor 
nerves : — 



ammonium 
ammonium 
ammonium 



Ammonium cyanide. 1 

„ iodide. 

Ethyl ammonium chloride. 1 
Amyl ammonium chloride. 1 

„ „ iodide. 1 

Amyl ammonium sulphate. 1 
Phenyl - di - methyl - ethyl 

iodide. 13 
Phenyl - di - methyl - amyl 

iodide. 13 
Phenyl - di - methyl - amyl 

hydrate. 13 
Phenyl-tri-ethyl ammonium iodide. 13 
Tri-methyl ammonium iodide. 2 
Tri-ethyl „ chloride, 

iodide. 
„ „ sulphate. 

Methyl-tri-ethyl stibonium iodide. 14 
Methyl-tri-ethyl „ hydrate. 14 
Toluyl-tri-ethyl ammonium iodide. 13 
Di-toluyl-di-ethyl „ „ 13 

Toluyl-di-ethyl-amyl „ 
Toluyl-tri-ethyl „ 

Tetra-methyl „ 

Tetra-ethyl „ 

Tetra-methyl „ 

Tetra-amyl „ „ " 

Tetra-ethyl phosphonium iodide. 1 * 
Tetra-ethyl arsonium iodide. 1 ' 
Tetra-ethyl arsonium and zinc double 

iodide. 14 



hydrate. 13 
iodide. 

r » 

iodide. 13 



and cadmium 



Tetra-ethyl arsonium 
double iodide." 

Anchusa. s 

Methyl anilin. 4 

Ethyl „ 4 

Amyl „ 4 

Methyl-atropine. 2 

Methyl-brucine. 2 

Ethyl-brucine. 3 

Camphor. 

Methyl-cinchonine.* 

Amyl „ » 

Chloroxethylene. 

Methyl-codeine. 2 

Collidine. 

Conime. 

Di-methyl-coniine. ! 

Cotarnine. 3 

Cynaglossine. 5 

Di-methyl ammonium chloride.' 
iodide. 1 
sulphate. 1 



Di-ethyl 



Curarine." 

Curare.' 

Dita'ine. 8 

Methyl-delphinine.' 

Echium. 3 

Erythrina corallodendron.* 



chloride. 1 

iodide. 1 

sulphate. 1 



1 Brunton and Cash, Proc. Boy. Soc. 

2 Crum-Brown and Fraser, Trans, of Roy. Soc. of Edinburgh. 
8 Buchheim and Loos, Eckhard's Beitrage, Bd. v. 

4 Jolyet and Cahours, Compt. Bend., lxvi. p. 1181. 

* Diediilin, Med. Centralbl., 1868, p. 211. 

i Preyer, QBttmger Ztschr. f. Chemie, 1, p. 381. 

' Bernard and Kolliker. 

' Hamack, Arch.f. exp. Path. u.Pharm., vii. p. 126. 



chap, vi.] ACTION OF DEUGS ON NERVES. 151 



Guachamacha. 10 
Lobeline. 

Methyl-morphine. 2 
Methyl-nicotine. 2 
Ethyl „ ' 

Ptomaines." 
Methyl-quinine. 3 
„ quinidine. 2 



Methyl-piperidine. 
Saponine. 
Sparteine. 

Methyl-strychnine. 2 , 12 
Ethyl „ 2 

Methyl-thebaine. 2 
Methyl-veratrine.' 
Amyl „ 3 



Although the substances mentioned in the above list have all 
the power of paralysing motor nerves, they do not possess the 
same power as curare. In the case of the salts of ammonium 
and the compound ammonias, the curare-like action is accom- 
panied by a paralysing effect upon the muscular substance and 
on the nerve-centres. When salts of these substances are em- 
ployed, their effect is somewhat modified by their acid radical, 
although this is not the case to the same extent in the salts of 
the compound ammonias, and in the salts of ammonium itself. 
Thus the iodide of ammonium has a much stronger paralysing 
action on the nerves than bromide, chloride, sulphate, or phos- 
phate, and this is observed also, though to a less extent, in the 
salts of the compound ammonias. 1 

Exact Localisation of the Action of Curare. 

The experiments already described have shown that curare 
does not paralyse the trunks of motor nerves (p. 148), nor the 
muscular substance (p. 148), and does paralyse the peripheral 
terminations of the motor nerves within the muscles : but they 
do not show what the exact part of the peripheral terminations is 
on which the drug exerts its action. 

When a nerve enters a muscle it divides and subdivides 
dichotomously until the fibres become single, and, losing their 
myelin sheath, the axis-cylinders enter the muscular fibres. 
There they end in the nerve-plates, from which the ultimate 
branches pass to the muscular substance. 

The paralysis produced by curare may be due to its 
action on : 

(a) The single nerve-fibrillae before they completely lose their 
myelin sheath ; 

(b) The axis-cylinders ; 

(c) The end plates ; 

(d) The ultimate branches. 

As curare acts so much more readily on the nerves passing 

• Harnack, Buchheim's Pharmacologic, 3rd ed. p. 615. 

10 Sachs, Archivf. Physiol., 1877, p. 91 : Schiffer, Deutsch. med. .Wochenschr., 
1882, No. 28. 

"Several authors quoted by Guareschi and Mosso, Les Ptomaines, 1883. 

12 Schroff, Wochenblatt d. Ztschr. d. Aertze zu Wien, No. 14, 1866. 

" Kabuteau, TraiU ilimentaire de Thirapeutique, 4me ed. p. 530 et seq. 

lt Vulpian; Arch.de Physiologie, 1868. i -- : - ... . 



152 PHABMACOLOGY AND THEEAPEUTICS. Isect. i. 

to voluntary than on those passing to involuntary muscles, and 
the most marked anatomical difference between these two kinds of 




Tig. 55".— Curve stowing tlie excitability in different pirts of the sartorial of a frog in a normal and 

curarised muscle, 

muscles consists in the termination of the former in end plates, 
it is natural to suppose that curare acts upoa these plates. 




Pig. 56.— Shows the distribution of the nerves in the gastrocnemius of the froff and the curve of 
excitabi.ity in different parts of the muscle. It will be observed that the excitability is greatest 
in those parts where there ane most nerve-endings. 

Moreover, this supposition appears to receive confirmation from 
the observation of Kiihne — that the end plates undergo a certain 
alteration in poisoning by curare, their outlines becoming more 



chap, vi.] ACTION OF DRUGS ON NERVES. 158 

distinct than in the normal condition. This slightly increased 
sharpness of outline may be regarded as indicating a slight 
physical change, which might, however, be associated with such 
profound chemical changes in the end plates as to destroy their 
power of conducting stimuli from the nerve to the muscle. 

But recent researches by Kiihne and one of his pupils, 
Politzer, appear to render it probable that some of the nerve- 
structures within the muscle retain their functional activity even 
in profound poisoning by curare ; and Politzer supposes that the 
part of the nerve which is acted on by curare is the nerve-fibril 
before it has quite lost its medullary sheath, and that the poison 
destroys the conducting power of the nerve by acting on the 
cement-substance at Ranvier's nodes. The grounds on which 
this supposition is based are that, even in profound poisoning by 
curare, those parts of the sartorius of the frog which contain 
nerve-endings are more irritable than those which contain none 
(Fig. 56), and that the irritability increases or diminishes in 
proportion to the number of nerve-endings, just as it does in 
the normal muscle, although the excitability of all the parts 
containing nerves is less than normal in curare-poisoning. 

That this variation in irritability in different parts of the 
muscle is due to nervous structures, and not to variations in the 
muscular fibres themselves, is shown by the fact that, when the 
excitability of the nerve is depressed by throwing it into a state of 
anelectrotonus, these variations in the excitability of the muscle 
disappear. 

It is just possible that the nervous structures which retain 
a certain amount of excitability in curare-poisoning may be the 
ultimate terminations which pass from the motor plate to the 
muscular fibre : but Politzer appears to throw this possibility 
aside, and considers that the amount of nervous excitability re- 
tained shows that all the parts beyond the last node of Ranvier 
still possess their functions. 

Should Politzer' s supposition — that curare paralyses motor 
nerves by acting on the cement at Ranvier's nodes — be correct, 
it may perhaps serve to explain, not only the difference between 
jts action on motor nerves going to voluntary and those going to 
involuntary muscular fibre, but also the difference between the 
action of curare, or poisons having a similar action, and of 
atropine on the inhibitory fibres of the vagus. 

Action of Drugs in Increasing Excitability of Motor Nerves. 

It is not so easy to prove positively that a drug has increased 
'as that it has diminished the excitability of motor nerves. The 
fact that the nerves of the poisoned leg are found to be more 
excitable than those of the ligatured one in such experiments as 
those just described, does not prove it, for it must be borne in 



154 PHAEMACOLOGY AND THEEAPEUTICS. LSect. r. 

mind that the arrest of the circulation in the ligatured leg 
lessens the excitability of the muscles and the nerves in it. 
This effect of the ligature strengthens the proof that a drug has 
produced paralysis when we find that, in spite of the freer circu- 
lation, the poisoned leg is less irritable than the ligatured one ; 
but it prevents our concluding that the drug has increased ex- 
citability when we find that the poisoned leg responds more 
readily to stimuli than the ligatured one. 

To try whether a drug increases excitability we treat two 
muscles with saline solution, and after ascertaining that their 
excitability is alike we add the drug to be tested to the saline 
solution in which one muscle is steeped, and after some time test 
the excitability again. If the muscle in the poisoned saline solu- 
tion becomes more excitable than the other, we conclude that the 
increase is due to the action of the drug. 

Irritation of Motor Nerve-endings by Drugs. — The peri- 
pheral terminations of motor nerves in muscle appear to be 
irritated by certain poisons, so that the excised muscle exhibits 
fibrillary twitchings. This might be due to irritation of the 
muscular structure itself, but as they are gradually abolished 
by curare they are supposed to depend upon irritation of the 
terminations of motor nerves. The poisons which produce this 
effect are : aconitine, camphor, guanadine, nicotine, pilocarpine, 
pyridine. Physostigmine produces it most markedly in warm- 
blooded animals, but does not seem to cause it in frogs. 

Action of Drugs on the Trunks of Motor Nerves. — Nerve- 
trunks are, as a rule, very much less affected by poisons than the 
end-plates ; but they may, nevertheless, be also acted upon by 
strong solutions of a poison. It appears necessary to apply the 
poison locally to them, and they are probably little if at all 
affected by poisons introduced into the system generally. The 
action of poisons is tested by placing a small piece of gutta- 
percha tissue under the nerve-trunk, usually the sciatic of the 
frog, and applying the poison directly to it, or dipping the nerve 
into a weak solution of common salt, or of sodium phosphate, to 
which the poison has been added, and comparing the poisoned 
nerve with one dipped into a similar saline solution without the 
poison. 

There are two methods of comparison. The first consists 
in using the contraction of the corresponding muscle as an 
index of the functional power of the nerve; the second in 
ascertaining the effect of the poison on the normal electrical 
current in the nerve. 

The motor fibres of a nerve appear to have their excitability 
abolished more readily than that of sensory nerves by changes 
in the body generally, and sometimes also by the local application 
of drugs to them. Thus in wounded nerves the motor function 
may be destroyed, while. the sensory function is little alteredj 



ttup. vi.] ACTION OF DEUGS ON NEEVES. 155 

and where both sensibility and motion have been destroyed by 
a bruise of the nerve-trunk, tbe sensibility may reappear, while 
the motor power does not. In rheumatic neuralgia there is not 
unfrequently motor paralysis with exaggerated sensibility. When 
a solution of physostigmine is applied locally to the nerve-trunk 
for a while, and the nerve is then irritated beyond the point of 
application, it is found tbat it will produce reflex movements of 
the body after it has ceased to do so in the limb supplied by the 
nerve, which shows that the sensory fibres can still conduct im- 
pressions, though the motor fibres cannot. Longer application 
of the poison will destroy the sensory fibres also. When a paste 
of theine is applied to the sciatic nerve, or the nerve is dipped 
in a solution of opium, similar results are observed. 

By dipping nerves in a solution of the poison Mommsen finds 
that atropine diminishes the irritability of the nerves, affecting 
first the intramuscular endings, and afterwards the trunks. 
Alcohol, ether, and chloroform first increase and then diminish 
the irritability. 

Action of Drugs on Sensory Nerves. 

The general action of a drug on sensory nerves is much 
more difficult to ascertain with precision than its effect upon 
motor nerves, because the evidences of sensation we have in the 
lower animals are cries, and movements either of the limbs or 
involuntary muscles, such as the iris, arteries, or bladder, which 
ensue on irritation of sensory nerves. 

In the production of these movements or cries, many struc- 
tures are concerned, viz. sensory nerves, nerve-centres, spinal or 
cerebral motor nerves, and muscles. It is comparatively easy 
to ascertain the local action of the drug upon sensory nerves, for 
in this case these other structures are not affected. By applying 
the substance to one part of the body, either by painting it upon, 
or injecting it under, the skin, and then comparing the effect of 
stimulation produced by pinching or by the application of heat 
or electricity upon that and other parts of the surface, we can 
see whether or not the sensibility of the sensory nerves has been 
affected by the drug. 

But when the drug is absorbed into the circulation, it may 
affect all the other structures already mentioned, as well as the 
sensory nerves, and thus it may be impossible to decide with 
certainty whether these nerves are affected or not. But even 
here definite results are sometimes obtainable, as in the case of 
curare. The method of experimenting is that of local protection, 
arresting the circulation in one leg of a frog by applying a ligature 
to the sciatic artery. The animal is then poisoned with curare, 
or any drug the action of which is to be ascertained. The 
poison is carried by the circulation to all other parts of the body 
excepting the ligatured leg. 



156 PHAEMACOLOGY AND THEBAPEUTICS. [sect. i. 

In the case of curare the motor nerves are paralysed by the 
drug, and it would be impossible to ascertain whether irritation 
of the sensory nerve produced any effect at all, were it not that 
the ligatured limb, retaining its irritability, serves as an index 
to the condition of the nerve-centres. At first it is found that 
pinching the poisoned foot will cause movements in the non- 
poisoned leg. This shows that the sensory nerves retain their 
irritability and transmit, the stimulation up to the spinal 
cord, whence it is reflected down the motor nerves to the non- 
poisoned foot. 

As the poisoning becomes deeper, however, pinching the 
poisoned leg produces much less effect. 

This might be due to paralysis of the spinal cord, but it is 
shown that this is not the case by pinching the ligatured leg just 
above and below the ligature. 

It is found that a pinch just below the ligature causes marked 
reaction, while a pinch just above has little or no effect. 

In this experiment all the structures concerned in the move- 
ment have been alike subjected to the action of curare with the 
exception of the ends of the sensory nerves below the ligature. 
It is thus evident that the diminished reaction from pinching 
above the ligature is due to paralysis of the ends of the sensory 
nerve, in the part of the body to which the poison has had access, 
and which is shaded dark in the engraving (Pig. 54). 

In the experiment just mentioned, the second of the two 
methods already described (p. 147) in the reference to motor nerves 
is employed, and the action of the drug on the ends of sensory 
nerves is ascertained by preventing the poison from reaching 
them; but the first method may also be employed and the 
action ascertained by applying the poison to- the ends of the 
sensory nerves, while the nerve-trunks and nerve-centres are 
protected from its action. Thus, in the experiments of Liegeois 
and Hottot upon the action of aconitine on the sensory nerves, 
they ligatured the vein and injected the poison into the artery of 
a frog's leg; the poison was thus carried to the ends of the 
sensory nerves in the skin, while it was prevented from reaching 
the nerve-centres. In this way they found that irritation of the 
poisoned skin ceased to produce any reflex action, while stimula- 
tion of the trunk of the nerve distributed to that leg still caused 
well-marked reflex action. Normally the terminations of a sensory 
nerve in the skin are much more sensitive than the trunk of 
the nerve; and this experiment therefore proves that -aconitine 
paralyses the ends of the sensory nerves. 

The local action of drugs on the sensory nerves in man is 
ascertained by producing, when applied locally, either diminution 
in pain which may be present at the time, or insensibility,, which 
is usually ascertained by the sesthesiometer. This instrument 
is simply a pair of compasses with blunt points and a scale 



chap, vi.] ACTION OP DEUGS ON NEEVES. 157 

by which the distance of the points from one another can be 
read off. 

"When the sensation is acute, the points are distinctly felt as 
two, even when they are but slightly separated from one another ; 
but when the sensation is blunt, they are felt as one when they 
are at a considerable distance apart. 

In frogs the local action on sensation is ascertained by dipping 
one leg for some time in the solution to be tested, and then 
comparing the effect of irritating corresponding points in the two 
feet or legs by pinching, by the application of acids, or by a faradaic 
current. In this way it has been ascertained that hydrocyanic 
acid has a powerful local action in paralysing sensory nerves. 
Where the drug is very powerful, its action on the nerve-centres 
might complicate the result, if a sufficient quantity should be 
absorbed into the blood. This fallacy may be avoided by arresting 
the circulation entirely through excision or ligature of the heart. 

Local Sedatives and Local Anaesthetics. — Local sedatives 
are substances which diminish, and local anaesthetics are 
substances which destroy, the sensibility of the skin for the time 
being. 

Local Sedatives. Local Anaesthetics. 

Aconite. Extreme cold. 

Atropine. Ice. 

Belladonna. Ether spray. 

Carbolic acid. Carbolic acid. 

Chloroform. Cocaine. 

Chloral. Kawa-resin. 1 
Morphine. 
Opium. 
Veratrine. 

Action. — Their effect in some degree is due to a paralysing 
action upon the terminal branches of the cutaneous nerves. It 
is probably, to some extent, also due to an effect upon the vessels 
and tissues analogous to that which is produced by rubbing or 
scratching, which, as everyone knows, gives temporary relief to 
itching. Sweating also relieves the itching, which is sometimes 
felt just before it begins. 

Uses. — Local sedatives are employed to relieve itching and to 
lessen pain, whether it be due to neuralgia or inflammation. Local 
anaesthetics are employed temporarily to abolish the sensibility 
of the skin, and allow slight incisions or operations to be made 
painlessly. 

Stimulating Action of Drugs on the Peripheral Ends 
of Sensory Nerves. — The peripheral terminations of sensory 
nerves appear to become more sensitive when the supply of blood 

1 Lewin, Ueber Piper methysiicum (Kawa). Berlin, 1886. 



158 PHARMACOLOGY AND THERAPEUTICS, [sect. i. 

to the part is increased. This is markedly seen, not only in 
inflammation, where the part becomes exceedingly tender, but in 
cases where turgescence of the vessels occurs under physiological 
conditions. Besides the class of irritants which act on the peri- 
pheral terminations of sensory nerves so as to cause pain when 
locally applied, there are several drugs which appear to have a 
special irritant action on the ends of sensory nerves when intro- 
duced into the circulation : these are aconite and aconitine, which 
give rise to a peculiar tingling and numbness in the tongue, lips, 
cheeks, and indeed in all parts supplied by the fifth nerve. Vera- 
trine also causes peculiar sensations in the sensory nerves when 
taken internally, but these are felt more in the fingers and toes, 
and in the joints, than in the tongue. 1 

1 Von Schroff, Pharmacologic, 4th ed. p. 584. 



CHAPTEE VII. 
ACTION OP DRUGS ON THE SPINAL COED. 

In the spinal cord we have to distinguish three functions : that 
of conduction, that of reflex action, and that of origination of 
nerve-force! as in the sweat-centres, &c, contained in it. 

The spinal cord transmits sensory or afferent impulses 
upwards to the medulla and brain ; and motor impulses down- 
wards to the muscles, as well as other efferent impulses to the 
glands. It transmits reflex impulses across, either from behind 
forwards, or laterally from one half of the cord to the other. 
Transmission from behind forwards occurs when the impulse 
passes from the sensory to the motor columns on the same side, 
as in the case of reaction of a sensory stimulus on the same side 
of the body. It occurs laterally when the sensory stimulus pro- 
duces motion, not on the same side, but on the opposite side of 
the body. 

Action on the Conducting Power of the Cord. — Its con- 
ducting power for motor impulses is assumed to be impaired 
when it is noticed that any drug causes partial paralysis of the 
hinder extremities of an animal before the anterior extremities. 

It is usually tested by irritating the spinal cord at its upper end, either 
mechanically with the point of a needle, or by a galvanic or faradaic current 
passed through electrodes inserted into it close together, and observing 
whether irritation of the cord itself in this way causes contraction in the 
muscles of the legs. 

When no contraction is produced by irritation of the cord 
itself, while direct irritation of the motor nerves can still produce 
vigorous contraction, it is evident that the cause of the paralysis 
must be that the spinal cord has lost its power to conduct motor 
impulses. 

These experiments may be made in a frog, the cerebrum of which has 
been previously destroyed; and they may be confirmed in warm-blooded 
animals where sensibility has been destroyed by a section of the cord, just 
below the medulla, and respiration is kept up artificially. The spinal cord is 
then exposed, and the anterior columns are irritated in the ways already 
mentioned. 

The power of the cord to conduct sensory impressions is 
ascertained by exposing it under anaesthetics and allowing their 
influence to pass so far off that the animal is capable of giving 



160 PHAEMACOLOGY AND THEEAPEUTICS. [sect. r. 

evidence of sensation. The posterior roots are then irritated 
before and after the injection of the poison into the circulation. 

When it is found that after the poison is injected the irrita- 
tion of the posterior roots which previously caused evidence of 
sensation no longer produces any effect, while irritation of the 
anterior columns still produces motion, the conclusion appears to 
be just, that the poison has paralysed the conducting power of 
the sensory columns of the cord. 

This action appears to be possessed by caffeine, for Bennett 
found that while irritation of the posterior roots of the cord 
caused violent struggles and loud cries in a rabbit before the in- 
jection of caffeine into the circulation, similar irritation, after the 
injection, caused only a slight quiver. That this effect was not 
due to motor paralysis was shown by the fact that irritation of 
the anterior columns caused violent muscular contractions after, 
the injection as well as before it.' 



FIBRE IN 
LATERAL 
COLUMNS 



SENSORY 
ROOT 




Fig. 57.— Diagram to show the effect of chloroform, chloral, and other anaesthetics on conduction of 
painful impressions in the spinal cord. 

Ordinary impressions of touch, temperature, and muscular 
action are transmitted through the posterior roots of the spinal 
cord to the ganglia of the posterior horn of the grey substance, 
and thence upwards by the fibres of the lateral columns. Painful 
sensations, however, appear to be transmitted upwards through 
the grey substance of the cord. The afferent nerves, which trans- 
mit impressions from one part of the cord to another, so as to 
produce co-ordinated reflex movement, are contained in the 
posterior columns of the cord. 

It is evident that any injury or poison which chiefly affects 
the grey matter so as to diminish its conducting power may 
abolish pain while reflex action still persists. This condition may 
be produced by division of the grey matter of the cord, and it 
occurs also at a certain stage of the action of anaesthetics such as 
chloroform and ether. 

The action of drugs on the power of the spinal cord to con- 
duct reflex stimuli both transversely and longitudinally has 
been careful ly investigated by Wundt. He first ascertains the 

1 Hughes-Bennett, Edin. Med. j'ourn., Oct. 1873. 



chap, vn.] ACTION OF DEUGS ON THE SPINAL COED. 1G1 

time which elapses between the application of a stimulus to a 
motor nerve and the contraction of a muscle, the nerve used 
being the sciatic, and the muscle the gastrocnemius of a frog. 
This time, which includes that requisite for the stimulus to 
travel down the motor nerve and to set the muscle in action, he 
terms the direct latency. He next stimulates a sensory root of 
the spinal nerve at the same level and on the same side as the 
motor nerve, taking care that the stimulus does not act on the 
motor nerve directly, but only reflexly through the cord. The time 
between the application of the stimulus and the commencement 
of contraction he terms the total latency. By deducting the 
direct latency from the total latency, he ascertains the time re- 
quired for the stimulus to pass through the grey matter of the 
cord from the posterior to the anterior horn of the same side. 
This he calls the reflex time. 

The time required for transverse conduction is ascertained 
by applying the stimulus to a posterior root on the other side and 
comparing the latency with that of stimulation to a posterior root 
on the same side. 

The time required for longitudinal conduction is ascertained 
by applying a stimulus to the brachial nerve, so that it has to 
travel down the greater part of the length of the spinal cord 
before it can excite the sciatic nerve. By comparing the latent 



POSTERIOR 
ROOT o 



\V/A SECTION Of 
; „ n SPINAL 
U^Uy CORD 



I ) MUSCLE 



Pig. 58.— Diagram to show the method of investigatinjrreflexand transverse conduction In the spinal 
cord. The motor nerve is first irritated.it 1. As the cylinder revolves at a known rate, ai d a 
mark is made upon it by an electro-magnet at the instant the nerve is irritated, the distance 
between this mark and the commencement of the muscle curve indicates the time required for 
the irritation to travel down the motor nerve to the muscle and set it in action. The irritation 
is next applied to the posterior root on the same side ( 2 ). The distance between the commence- 
ment of contraction in this case and in that where the motor nerve was irritated gives the time 
required for simple reflex transmission of the stimulus from the posterior to the anterior horn 
of the cord. The stimulus is then applied 1 o the posterior root on the opposite side at 3, and 
the distance between the commencement of the consequent contraction and that of the curve 
obtained by irritating at 2 gives the time required for transmission across the cord. 

period of excitation in the brachial nerve with that of the sciatic 
on the same side l the length of time required for longitudinal 

1 For convenience sake both the sciatic and the brachial nerves are taken in 
this experiment on the opposite side from the muscle, so that the time of longi- 

M 



1C2 PHARMACOLOGY AND THERAPEUTICS, [sect, t, 

transmission of stimuli in the cord is ascertained. The mode of 
ascertaining the time of ordinary reflex and transverse trans- 
mission in the cord is shown diagrammatically in Fig. 58. 

The differences in the latent period and in the form of the 
muscle curve obtained by irritation of the motor nerve, and by 
simple transverse, and longitudinal reflex stimulation, are shown 
diagrammatically in Fig. 59. Wundt found that when a motor 




Win 59 — Diagram to show tlie difference between the length of the latent period and form ot the 
carve in contraction induced, B, by direct irritation of the motor nerve ; o, by simple reflex from 
irritation of the cord on the same side ; and D, by cross reflex from irritation of the cord on the 
oonosite side to that from which the motor nerve proceeds, as shown in Pig, ,58 i shows com- 
bined transverse and longitudinal reflex ; A indicates the moment at which the stimulus was 
applied in each case. 

nerve was irritated at a point distant from the muscle the xe- 
sulting contraction had not only a longer latent period, but was 
less in height and longer in duration than when the nerve was 
irritated close to the muscle. From a comparison of the curves 
it will be seen that a small portion of grey matter has a similar 
effect upon the stimulus which passes through it that a great 
length of nerve-fibre would have. In all reflex actions, there- 
fore, in the normal animal, the contraction of the muscle has a 
longer latent period, less height, and longer duration than that 
produced by direct irritation of the motor nerve. The increase 
in the latent period, diminution in height, and longer duration 
are greater in the case of transverse than of simple reflex, and 
greater still in the case of combined transverse and longitudinal 
reflex. 

In the normal frog a stronger stimulus is necessary to pro- 
duce reflex contraction than would be sufficient if it were applied 
directly to the motor nerve, and strong and weak stimuli will 
produce strong and weak muscular contractions. The spinal cord 
has a power of summation similar to that already referred to in 
the case of contractile tissue of medusae, so that a stimulus which 
would be powerless to produce a reflex contraction if applied 
once to a posterior root or to a sensory nerve will be effectual if 
repeated several times in close succession. 

Strychnine has an effect on the conducting power of the 
spinal cord which we should hardly expect, and so have other 
convulsant poisons. It increases the excitability so much that 
slighter stimuli than before will produce reflex action, and it 
destroys to a considerable extent the power of summation, so 
that instead of each stimulus producing a contraction in propor- 

tudinal conduction is ascertained by deducting the transverse from the combined 
transverse and longitudinal conduction. 



chap, vii.] ACTION OF DEUGS ON THE SPINAL COED. 1G8 

tion to its strength, all have the same effect — a weak one, which 
is just strong enough to produce an effect at all causing as great 
a contraction as the most powerful. The time required for the 
transmission of stimuli through the cord is enormously increased, 
so that the latent period of ordinary reflex, and still more of 
transverse and longitudinal reflexes, is greatly increased, some- 
times, indeed, to as much as ten times the normal. The retarda- 
tion of transverse conduction is not absolutely greater than of 
longitudinal conduction ; but, as the distance through which the 
stimulus has to pass in the former case is much less than in 
the latter, it follows that strychnine increases the resistance more 
transversely than longitudinally. Morphine in small doses has 
no very marked action upon the cord, but larger doses have an 
action almost exactly like that of strychnine, causing increased 
reflex irritability, tetanic contractions, and prolonged latency. 
Veratrine has a similar action. Nicotine and coniine in small 
doses have a similar action to strychnine, but this is quickly 
masked by the rapid appearance of paralysis. When large doses 
are used, paralysis occurs almost immediately, and is usually 
accompanied by fibrillary twitchings. Atropine has at first an 
action similar to strychnine in causing increased excitability, 
prolonged latency, and tetanic contraction. It differs from 
strychnine in causing more rapid diminution in the irritability 
of the grey substance of the spinal cord and in diminishing the 
conducting power of peripheral nerves. In consequence of this, 
irritation of the sciatic nerve in a frog poisoned by atropine 
causes two contractions, one direct and one reflex, separated from 
each other by a distinct interval, whereas, in a frog poisoned by 
strychnine, these two contractions begin almost at the same 
moment and appear superimposed upon each other. 1 

Effect of Drugs on the Reflex Action of the Cord. — The 
effect of drugs upon the reflex action of the spinal cord is usually 
estimated by the time which elapses between the application of 
a stimulus and the occurrence of reflex action, before and after 
the administration of a drug. Longer time indicates diminished, 
and shorter time increased, excitability of the cord. 

Method of Experimenting:. — Since the spinal cord in mammals quickly 
loses its excitability when deprived of oxygenated blood (as shown by 
Stenson's experiment, p. 164), frogs are used for experiment. The method 
usually employed is called Tiirck's method. The cerebral lobes in a frog are 
destroyed, and after sufficient time has elapsed ib allow it to recover from 
the shock, it is suspended either by the head Or fore -legs, so that the hind- 
legs hang down. A very dilute solution of sulphuric acid, the acid taste of 
which can be little more than perceived by the tongue, is put in a small 
beaker and raised until one foot of the frog is completely immersed in it. 

1 According to W. Stirling, the latent period of reflex action in the spinal cord 
is increased by the chloride and bromide of potassium and ammonium, by lithium 
salts, and by chloral and butyl-chloral ; it- is decreased by the chloride, bromide, 
and iodide of sodium. — Stirling and London' Physiology, 2nd ed., vol; ii. p. 909. 



164 PHAEMACOLOGY AND THERAPEUTICS, [sect. i. 

The time is then counted by means of a metronome, between the immersion 
of the foot in the acid solution and the time when the leg is drawn up out of 
it. As soon as the foot is drawn up, the acid is carefully washed off with 
some fresh water in order to prevent any injury to the skin, and after a 
minute or two, the experiment may be repeated. When the time seems 
constant the drug is injected into the lymph-sac, and the experiment is 
repeated again. The greater or less time which is required for the withdrawal 
of the foot from the acid after the injection of the poison, as compared with 
the time required before, shows the extent to which the reflex action of the 
spinal cord has been diminished or increased by the poison. 

Direct, Indirect, and Inhibitory Paralysis of the Spinal 
Cord by Drugs. — When it is found that the reflex action of 
the cord is greatly diminished or apparently entirely abolished, 
it must not be at once concluded that this is necessarily due to 
the direct paralysing action of the drug itself upon the nervous 
substance of the cord. This may be the case, and is so when 
methyl-coniine is employed, but it may be due to the indirect 
action of the drug upon the heart, weakening the circulation, and 
lessening the function of the cord by interfering with its blood- 
supply. 

In order to ascertain whether this is the case or not, it is usual to take two 
frogs as nearly alike as possible, to destroy the brain in each, and after 
waiting until they have recovered from the immediate shock of the operation, 
to inject into one the drug to be tested, and, at the moment when it stops the 
beating of the heart, to tie a ligature around the heart of the other. The 
persistence of reflex action is then tested in the usual manner, and if it is 
found that it disappears much sooner in the poisoned frog than in the other one 
in which the heart has been ligatured, it is concluded the drug has paralysed 
the substance of the cord itself. 

Indirect Paralysis. — The spinal cord is very rapidly para- 
lysed in mammals if the blood-supply to it is stopped. This is 
readily shown by Stenson's experiment of gently compressing 
the abdominal aorta in a rabbit with the thumb or finger, so as 
to arrest the circulation for four or fire minutes. On releasing 
the animal its hinder extremities are found to be paralysed, and 
this paralysis, though it may be partly due to interference with 
the blood-supply of the muscles and nerves of the lower extremi- 
ties themselves, is chiefly due to the arrest of circulation in the 
spinal cord. The spinal cord in frogs is less rapidly affected, but 
if the circulation be arrested for half an hour or so symptoms 
of paralysis usually begin to appear, the time varying, however, 
with the temperature and other conditions. Indirect paralysis 
is produced by aconitine, digitalin, and large doses of quinine, 
which arrest the circulation. It is frequently difficult to decide 
how far paralysis is due to the action of a drug on the circulation, 
and how far to its direct action on the spinal cord itself. 

Direct Paralysis.— Paralysis of reflex movement is produced 
by a number of substances, some of which produce little or no 
previous excitement ; others, however, markedly increase the ex- 
citability of the spinal cord first, and are thus classed as spinal 
stimulants. 



chap, vii.] ACTION OP DEUGS ON THE SPINAL CORD. 165 

Spinal Depressants.— The following drugs belong to this 
class : — 

Depress without marked previous Excite first and afterwards paralyse, 

excitement. 

Antimony. Ammonia. 

Emetin. Apomorphine. 

Ergot. Alcohol (through circu- 

Hydrocyanic acid. lation. 

Methylconiine. Arsenic. 

Saponine. Camphor. 

Physostigmine. Morphine group. 1 

Turpentine. Carbolic acid. 

Zinc, Chloral. 

Silver. Nicotine. 

Sodium. Potassium salts. 

Lithium. Veratrine. 

Caesium. Mercury. 

Alcohol group 1 (action on 

nervous substance). 

Uses of Spinal Depressants. — Such substances as morphine, 
chloral, &c, which diminish the conducting power of the grey 
matter of the cord for painful impressions, are useful as anodynes, 
though their action in lessening pain is probably often due to 
their effect on the brain as well as on the spinal cord. Spinal 
depressants which lessen reflex action are employed in diseases 
where there seems to be increased excitability of various parts of 
the cord, as evidenced by spasm, either tonic or clonic. They 
are therefore employed in tetanus, trismus neonatorum, chorea, 
writer's cramp, and paralysis agitans. The pathology of many 
nervous diseases is imperfectly known, and as the action of spinal 
depressants is frequently a complex one of combined stimulation 
and depression, some of the drugs included in this class are 
used in paraplegia due to myelitis, locomotor ataxy, and general 
paralysis. 

They are also used as antagonists in cases of poisoning by 
spinal stimulants like strychnine. 

Inhibitory Paralysis. — The higher parts of the nervous 
system have the power of lessening the action of the lower, and 
in the frog this power seems to be especially marked in the optic 
lobes. Irritation of these either mechanically by a needle, chemi- 
cally by a grain of salt laid upon them, or electrically, will lessen 
or entirely abolish the reflex action in the cord ; but this again 
returns when the irritation is removed, or when its influence is 
destroyed by cutting the cord across, below the point of irritation. 
Tbis fact was discovered by Setschenow, and thus parts of the 

1 Schmiedeberg, Arzneimitlellehre, p. 34. 



166 PHAEMACOLOGy AND THEEAPEUTICS. [sect. i. 

optic lobes concerned in this inhibitory action are known as 
Setschenow's centres. 

An inhibitory action appears to be exerted by the cranial 
centres in higher animals also, for McKendrick observed that on 
decapitating a pigeon the body lies comparatively still for a 
second or two, and then violent convulsions set in. If the body 
be held firmly during these convulsions, and a moderately strong 
faradaic current be applied to the upper part of the_ spinal cord, 
the convulsions may be altogether arrested while it continues, 
again commencing when it stops. In this experiment the appli- 
cation of the current to the cut end of the cord is regarded as 
supplying a stimulus in place of that which would normally pass 
downwards from the brain. 

Quinine causes great depression of reflex excitability, and 
this was stated by Chaperon to be due to the action of the drug 
on Setschenow's centres. 




Fig. 60. —Nervous system of a frog, shoving the cerebral and optic lobes, the medulla oblongata, 
and the spinal cord with nerre-roots. The brain is shown on a larger scale at p. 184. 

Almost immediately after injection of quinine into the dorsal 
lymph-sac, the reflex excitability of the frog becomes very greatly 
reduced or almost entirely abolished, but if the spinal cord be now 
cut across at its upper part just below the medulla oblongata, the 
reflex excitability becomes as great, or even greater, than the 
normal. 

This loss of excitability has been ascribed by Binz to the 
action of quinine on the heart, causing weakening of the circula- 
tion, and thus indirectly producing paralysis of the cord. This 
kind of paralysis does occur with large doses and after consider- 
able time, but it is quite different from the inhibitory paralysis 
described by Chaperon, which comes on almost immediately after 
the injection of the drug into the lymph-sac, and disappears 
immediately on section of the cord below the medulla. 

I have repeated Chaperon's experiments, and can fully confirm 
their accuracy. In doing so, however, it struck me that the result 
was most marked when a solution of quinine was concentrated 
and somewhat strongly acid. It therefore appeared probable that 
the inhibition was not due to the direct action of the quinine 
upon Setschenow's centres after it had been carried to them by 
the blood, but only to its reflex action upon them. It irritates 
locally the sensory nerves of the lymph-sac into which it is in- 



chap, vii.] ACTION OF DEUGS ON THE SPINAL CORD. 167 

jected, and this stimulus being transmitted to the optic lobes' 
excites them so that they produce inhibition of that reHex action 
which would usually occur in the cord when the foot is irritated 
by acid. On testing this hypothesis by injecting acid alone into 
the lymph-sac, Mr. Pardington and I found that it also caused 
reflex inhibition like that produced by quinine. We may there- 
fore conclude that there is nothing special in the action of quinine 
upon the inhibitory centres ; it merely acts like other irritants 
on sensory nerves. 1 Probably digitalis and sanguinaria also act 
in a similar way. 

NATURE OP INHIBITION. 

Inhibition and the action of drugs on inhibitory centres play 
a very important part indeed in pharmacology, and on the pre- 
sent hypothesis they are very puzzling. 

By inhibition we mean the power of restraining action which 
some parts of the nervous centres possess. At present it is usually 
supposed that certain parts of the nerve-centres, instead of 
having a sensory or motor function, have an inhibitory one 
peculiar to themselves. It is found, however, that inhibitory 
powers are not confined to Setsehenow's centres, already men- 
tioned (p. 166), but that almost any part of the nervous system 
may have an inhibitory action on other parts, so that it becomes 
almost necessary to abandon the old hypothesis. It is found, for 
example, that not only is reflex action more active in the frog 
when the optic lobes are removed, but that when the spinal cord is 
taken away in successive slices from above downwards, the reflex 
action in the part below goes on increasing. On the old hypo- 
thesis we are almost obliged to assume that each nerve-cell has 
two others connected with it, one of which has the function of 
increasing or stimulating, and the other of inhibiting its action. 
Most of the phenomena which we find can be explained in a 
much simpler way by supposing that nervous stimuli consist of 
vibrations in the nerve-fibres or nerve-cells, just as sound cqnsists 
of vibrations. 





Fig. 61. — Diagram to show increased intensity Fig. 62. — Diagram to show abolition of vibratiua 
of vibration by coincidence of waves. by interference of waves. 

Interference. — In the case of both sound and light we find 
that if two waves should fall upon one another so that their crests 

1 St. Bartholomew's Hospital Beports, 1876, p. 155. 



1G8 



PHAEMACOLOGY AND THEEAPEUTICS. [sect. i. 



coincide, the intensity of the sound or light is increased (Fig. 61), 
•while if they fall on each other so that the crest of one wave fills 
up the trough of the other, they interfere so as to destroy each 
other's effect (Fig. 62) ; and thus two sounds produce silence, or 
two waves of light darkness. This is shown in the case of sound 
by a tube (Fig. 63), which divides into two branches, and these 
again re-unite. The length of one branch may be altered at 



il= 



— s 

E 



Fhj. C3. — Diagram of apparatus for demonstrating the interference of waves of sound. A and B, 
branches of a tube ; c, sliding piece by which the branch B can be lengthened or shortened at 
will ; d, tuning-fork ; B, the ear. 

will, so that the sound travelling through one branch has further 
to go than the other. It may thus be retarded so far as to throw 
it half a wave-length behind the other, and silence is produced. 
If lengthened still further, so as to throw the one sound a whole 
wave-length behind the other, the crests again coincide, and the 
sound is again heard. Increasing the length still further, so that 
the one sound is thrown a wave-length and a half behind the 
other, they again interfere, and silence is again a second time 
produced. This may be repeated ad infinitum, silence occurring 
whenever Ihe one sound falls behind the other by an odd number 
of half wave-lengths. 




I'ig. 64.— Diagram showing the beats or alternate increase and diminution of the wave-heights by 
the interaction of two systems of waves of different wave-lengths. At A, two systems, having a 
relation to each other of 3 to 1, are indicated separately by dotted and complete lines. AtB the 
resultant of the interaction of the two systems is shown. With such a relation as that shown in 
the diagram, and with those of a vibrating rod generally, such as n, Sn, 5n, &c, the interference 
i.f the systems. is not complete, and silence cannot be produced by the interference of sounds. 
(iTom Ganot's Physics.) 

In the case just mentioned, the waves are of the same length, 
but if they are of different lengths, instead of constantly rein- 



chap, vii.] ACTION OF DKUGS ON THE SPINAL COED. 169 

forcing and interfering with others, they may sometimes strengthen 
and sometimes weaken each other. The result is more or less 
rhythmical increase and diminution of action, or as it is termed 
' beats.' This is shown in the accompanying diagram (Pig. 64). 

Instances of rhythm occur in the body, which strongly remind 
us of this condition ; for example, the different rhythms of the 
heart under various conditions. 

Interference in Nervous Structures.— Supposing nervous 
stimuli to consist of vibrations like those of light or sound, the 
action which any nerve-cell would have upon the others connected 
with it would he stimulant or inhibitory according to its position 
in relation to them. If its relation be such that a stimulus 
passing from it to another cell will there meet with a stimulus 
from another quarter in such a way that the waves of which they 
consist coincide, the nervous action will be doubled ; but if they : 
interfere the nervous action will be abolished. If they meet so 
as neither completely to coincide nor to interfere, the nervous 
action will be somewhat increased, or somewhat diminished, ac- 
cording to the degree of coincidence or interference between the 
crests of the wave. 

Thus if the relations of the nerve-cells s, s' and m, m' in the 
diagram (Fig. 65) are such that when a stimulus passes fromja 




Fig. 65.— Diagram to illustrate inhibition in the spinal cord, t, s?, and j" are sensory nerves, m, m\ 
and m" are motor nerves, 8, s', and 8" are sensory cells, m, M', and M" are motor cells in the spinal 
cord, sb is a sensory, and MB a motor cell in the brain. 

sensory nerve s to a motor nerve m, o"ne part of it travels along 
the path s, s, m, m, and another along s, s, s', m, m, or s, s, s',m', m, m, 
at such a rate that the crests of the waves coincide at the motor 
cell m, they will increase each other's effect. If they interfere, 
the effect of both will be diminished or destroyed, i.e. inhibition 
will occur. 

Effect of Altered Rate of Transmission. — But it is evident 
that the coincidence or interference of nervous stimuli travelling 
along definite nerve-paths, will vary according to the rate at 
which they travel, so that when stimuli which ordinarily interfere 
with one another, are made to travel more slowly, one may be 



170 PHARMACOLOGY AND THERAPEUTICS, [sect, l 

thrown a whole wave-length, instead of half a wave-length, behind 
the other : and thus we get coincidence and stimulation, instead 
of interference and inhibition. "When stimuli, whose waves 
ordinarily coincide and strengthen each other's action, are made 
to travel more slowly, one may be thrown half a wave-length be- 
hind the other, and thus we shall have interference and inhibition 
instead of stimulation. 

On the other hand, when the stimuli travel more quickly, the 
one which was half a wave-length behind the other, and interfered 
with it, may be thrown only a small fraction of a wave-length 
behind it. It will thus, to a great extent, coincide and cause 
stimulation, while the one which normally coincides with and 
helps another may, by travelling with increased rapidity, get 
half a wave-length in front of the other, and cause inhibition. 

Opposite Conditions produce Similar Effects. — We see 
then that results, apparently exactly the same, may be produced 
by two opposite conditions, increased rapidity or greater slowness 
of transmission of stimuli. 

The Same Conditions may cause Opposite Effects. — We 
see also that the same conditions may produce entirely opposite 
effects, by acting more or less intensely. Thus, the application 
of cold, or of any agent which will render the transmission of 
stimuli along nervous channels slower than usual, may throw 
one which ordinarily coincided with another a small fraction of 
a wave-length behind it, then half a wave-length, then three- 
quarters, next a whole wave-length, and then in addition to the 
whole wave-length it will throw it, as at first, a small fraction or 
a half wave-length behind, and so on. 

We shall thus have the normal stimulation passing into partial, 
then into complete inhibition, which will gradually pass off as 
the crests of the waves come more nearly together, until they 
coincide, when we shall again have stimulation as at first. As 
the action proceeds, this second stimulation will again pass into 
inhibition. In the same way a gradual retardation of trans- 
mission will cause impulses, which normally interfere, gradually 
to coincide until inhibition gives place to complete stimulation, 
and this again passes into inhibition. By quickening the trans- 
mission and throwing one wave more or less in advance of 
another, various degrees of heat will likewise produce opposite 
effects. 

Stimulation and Inhibition on this Hypothesis are merely 
Consequences of Relation.— Stimulation and Inhibition are 
not due to any particular stimulating or inhibitory centres ; they 
are merely dependent on the wave-length of nervous stimuli or 
the rapidity of transmission, and on the lengths of the paths 
along which they have to travel. Any nerve-cell may therefore 
exercise an inhibitory or stimulating action on any other nerve- 
cell, and the nature of this action will be merely a question of 



chap, vii.] ACTION OF DRUGS ON THE SPINAL COED. 171 

the length and arrangement of its connections, and the rapidity 
with which stimuli travel along them. 

Test of the Truth of the Hypothesis.— If the hypothesis 
be true we ought to be able to convert inhibition into stimulation, 
and vice vend, by either quickening or slowing the transmission 
of stimuli. We can quicken transmission by heat, and we can 
render it slower by cold. 

On this hypothesis we would expect to find that either ex- 
cessive quickening or excessive slowing of the passage of stimuli 
between the cells of the nerve-centres might cause a number of 
stimuli which would ordinarily interfere to coincide and produce 
convulsions. This is what actually does occur, for extreme heat 
and extreme cold both cause convulsions. But it is unsafe to 
lay too much stress upon this point, as the cause of convulsion 
may be very complex. We find, however, as we should expect 
on this hypothesis, that the inhibitory action of the vagus is 
destroyed by cold, 1 



Explanation of the Actions of Certain Drugs on this 
Hypothesis. 

There are certain phenomena connected with the action of 
drugs on the spinal cord which are almost inexplicable on the 
ordinary hypothesis, but which are readily explained on that 
of interference. Thus belladonna when given to frogs causes 
gradually increasing weakness of respiration and movement, until 
at length voluntary and respiratory movements are entirely 
abolished, and the afferent and efferent nerves are greatly 
weakened. Later still, both afferent and efferent nerves are 
completely paralysed, and the only sign of vitality is an occasional 
and hardly perceptible beat of the heart, and retention of irrita- 
bility in the striated muscles. The animal appears to be dead, 
and was believed to be dead, until Fraser made the observation 
that if allowed to remain in this condition for four or five days, 
the apparent death passed away and was succeeded by a state of 
spinal excitement. The fore-arms pass from a state of complete 
flaccidity to one of rigid tonic contraction. The respiratory 
movements reappeared ; the cardiac action became stronger, and 
the posterior extremities extended. In this condition a touch 
upon the skin caused violent tetanus, usually opisthotonic, lasting 
from two to ten seconds, and succeeded by a series of clonic 
spasms. A little later still the convulsions change their character 
and become emprosthotonic. These symptoms are due to the 
action of the poison upon the spinal cord itself, for they continue 
independently in the parts connected with each segment of the 
cord when it has been divided. 

* Horwath, Pfillger's Archiv, 1876, xii. p. 278. 



112 PHAKMACOLOGY AND THE KAPEU TICS, [sect. i. 

This action may be imitated by a combination of a drug which 
will paralyse the motor nerves with one which will excite the 
spinal cord. Fraser concludes that the effects of large doses of 
atropine just described are due to a combined stimulant action of 
this substance on the cord, and a paralysing one on the motor 
nerves. The stimulant action on the cord is masked by the 
paralysis of the motor nerves, and only appears after the para- 
lysis has passed off. He thinks that the difference in the rela- 
tions of these effects to each other, which are seen in different 
species of animals, may be explained by this combination acting 
on special varieties of organisation. In support of his views he 
administered to frogs a mixture of strychnine which stimulates 
the spinal cord, and of methyl-strychnine, which paralyses the 
motor nerves, and found that the mixture produced symptoms 
similar to thoBe of atropine. Notwithstanding this apparently 
convincing proof, it would appear that the paralysis in the frog 
is due to the action of the atropine on the spinal cord, and not 
to a paralysing effect on the motor nerves. For Einger and 
Murrell have found that when the ends of the motor nerves in 
one leg are protected from the action of the poison by ligature of 
the artery there is no difference between it and the unpoisoned 
leg, while if Fraser's ideas were correct the unpoisoned leg ought 
to be in a state of violent spasm. 

A condition very nearly similar to that caused by atropine is 
produced by morphine. "When this substance is given to a frog, 
its effects are exactly similar to those produced by the successive 
removal of the different parts of the nervous system from above 
downwards. Goltz has shown that when the cerebral lobes are 
removed from the frog it loses the power of voluntary motion, 
and sits still ; when the optic lobes are removed it will spring 
when stimulated, but loses the power of directing its movements. 
When the cerebellum is removed, it loses the power of springing 
at all ; and when the spinal cord is destroyed, reflex action is 
abolished. 

Now these are exactly the effects produced by morphine, the 
frog poisoned by it first losing voluntary motion, next the power 
of directing its movements, next the power of springing at all, 
and lastly, reflex action. But after reflex action is destroyed by 
morphine, and the frog is apparently dead, a very remarkable 
condition appears, the general flaccidity passes away, and is 
succeeded by a stage of excitement, a slight touch causing 
violent convulsions just as if the animal had been poisoned by 
strychnine. 1 

The action of morphine here appears to be clearly that of de- 
stroying the function of the nerve-centres from above downwards, 
causing paralysis first of the cerebral lobes, next of the optic 

1 Marshall Hall, Memoirs on the Nervous System, p. 7 (London, 1837). Wit- 
kowski, Archivfiir exper. Path, und Pharm., Band vii. p. 247. 



chap, vii.] ACTION OF DEUGS ON THE SPINAL COED. 173 

lobes, next of the cerebellum, and next of the cord. But it seems 
probable tbat the paralysis of the cord first observed is only ap- 
parent and not real ; and in order to explain it on the ordinary 
hypothesis we must assume that during it the inhibitory centres 
in the cord are intensely excited, so as to prevent any motor 
action, tbat afterwards they become completely paralysed, and 
thus we get convulsions occurring from slight stimuli. 

Ammonium bromide also causes, first, complete loss of volun- 
tary movement and reflex action, but at a later stage in the 
poisoning convulsions. 

On the hypothesis of interference, the phenomena produced 
both by atropine and by morphine can be more simply explained. 
These drugs, acting on the nervous structures, gradually lessen 
the functional activity of the nerve-fibrils which connect the 
nerve-cells together ; the impulses are retarded, and thus the 
length of nervous connection between the cells of the spinal cord, 
which is calculated to keep tbem in proper relation in the normal 
animal just suffices at a certain stage to throw the impulses 
half a wave-length behind the other, and thus to cause complete 
inhibition and apparent paralysis. 

As the action of the drug goes on, the retardation becomes 
still greater, and then the impulses are thrown very nearly, but 
not quite, a whole wave-length behind the other, and thus they 
coincide for a short time, but gradually again interfere, and 
therefore we get, on the application of a stimulus, a tonic con- 
vulsion followed by several clonic ones, and then by a period of 
rest. This explanation is further borne out by the fact observed 
by Fraser, that the convulsions caused by atropine occurred more 
readily during winter, when the temperature of the laboratory is 
low, and the cold would tend to aid the action of the drug in 
retarding the transmission of impulses. 1 

The effect of strychnine in causing tetanus is very remark- 
able ; a very small dose of it administered to a frog first renders 
the animal most sensitive to reflex impulses, so that slight im- 
pressions which would normally have no effect, produce reflex 
action. As the poisoning proceeds, a slight stimulus no longer 
produces a reflex action limited to a few muscles, but causes a 
general convulsion throughout all the body, all the muscles being 
apparently put equally on the stretch. In man the form assumed 
by the body is that of a bow, the head and the heels being bent 
backwards, the hands qlenched, and the arms tightly drawn to 
the body. 

My friend Dr. Ferrier has shown that this position is due to 
the different strengths of the various muscles in the body. All 
being contracted to their utmost, the stronger overpower the 
weaker, and thus the powerful extensors of the back and muscles 

1 Transactions of the Royal Society of Edinburgh, vol. xxv. p. 467. 



174 PHABMACOLOGY AND THEEAPEUTICS. [sect. i. 

of the thighs keep the hody arched backwards and the legs rigid, 
while the adductors and flexors of the arms and fingers clench 
the fist and bend the arms, and draw them close to the body. 1 
The convulsions are not continuous, but are clonic ; a violent 
convulsion coming on and lasting for a while, and then being 
succeeded by an interval of rest, to which after a little while 
another convulsion succeeds. The animal generally dies either 
of asphyxia during a convulsion, or of stoppage of the heart 
during the interval. 

When the animal is left to itself, the convulsions—at least 
in frogs— appear to me to follow a certain rhythm, the intervals 
remaining for some little time of nearly the same extent. 

A slight external stimulus, however, applied during the in- 
terval—or at least during a certain part of it — will bring on the 
convulsion. But this is not the case during the whole interval. 
Immediately after each convulsion has ceased I have observed a 
period in which stimulation applied to the surface appears to 
have no effect whatever. 

It is rather extraordinary, also, that although touching the 
surface produces convulsions, irritation of the skin by acid does 
not do so. 2 

The cause of those convulsions was located in the spinal cord 
by Magendie in an elaborate series of experiments, which will be 
described later on (p. 177). 

Other observers have tried to discover whether any change 
in the peripheral nerves also took part in causing convulsion ; 
but from further experiments it appears that the irritability of 
the sensory nerves is not increased. 3 

According to Eosenthal, strychnine does not affect the rate at 
which impulses are transmitted in peripheral nerves ; he, how- 
ever, states that it lessens the time required for reflex actions. 
Wundt came to the conclusion that the reflex time was on the 
contrary increased. 

In trying to explain the phenomenon of strychnine-tetanus 
on the hypothesis of interference, one would have been inclined 
by Eosenthal's experiments to say that strychnine quickened the 
transmission of impulses along those fibres in the spinal cord 
which connect the different cells together. 

The impulses which normally, by travelling further round, 
fell behind the simple motor ones by half a wave-length, and 
thus inhibited them, would now fall only a small fraction of a 
wave-length behind, and we should have stimulation instead of 
inhibition. 

Wundt's conclusion, on the other hand, would lead to the 

1 Brain, vol. iv. p. 313. 

2 Eckhard, Hermann's Handb. d. Physiol., Band ii. Th. 2, p. 43. 

3 Bernstein, quoted by Eckhard, op. cit. p. 40. Walton, Ludwia's Arbeiten, 
1882. 



chap, vn.] ACTION OF DEUGS ON THE SPINAL COED. 175 

same result by supposing that the inhibitory wave was retarded 
so as to fall a whole wave-length behind the motor one. On the as- 
sumption, however, that the fibres which pass transversely across 
from sensory to motor cells, and those that pass upwards and 
downwards in the cord connecting the cells of successive strata 
in it, are equally affected, we do not get a satisfactory explana- 
tion of the rhythmical nature of the convulsions. By supposing, 
however, that these are not equally affected, but that the re- 
sistance in one— let us say that in the transverse fibres — is more 
increased than in the longitudinal fibres, we shall get the im- 
pulses at one time thrown completely upon each other, causing 
intense convulsion, at another half a wave-length behind, causing 
complete relaxation, which is exactly what we find. 

This view is to some extent borne out by the different effect 
produced by a constant current upon these convulsions, accord- 
ing as it is passed transversely or longitudinally through the 
spinal cord. Eanke found that when passed transversely it has 
no effect, but when passed longitudinally in either direction 
it completely arrests the strychnine convulsions, and also the 
normal reflexes which are produced by tactile stimuli. 

Eanke's observations have been repeated by others with 
varying result, and this variation may, I think, be explained by 
the effect of temperature. 

The effect of warmth and cold upon strychnine-tetanus is 
what we would expect on the hypothesis of interference. With 
small doses of strychnine, warmth abolishes the convulsions, 
while cold increases them. When large doses are given, on the 
contrary, warmth increases the convulsions, and cold abolishes 
them. 1 

We may explain this result on the hypothesis of interference 
in the following manner : — 

If a small dose of strychnine retard the transmission of ner- 
vous impulses so that the inhibitory wave is allowed to fall rather 
more than half a wave-length, but not a whole wave-length, 
behind the stimulant wave, we should have a certain amount of 
stimulation instead of inhibition. Slight warmth, by quickening 
the transmission of impulses, should counteract this effect, and 
should remove the effect of the strychnine. Cold, on the other 
hand, by causing still further retardation, should increase the 
effect. With a large dose of strychnine, the transmission of the 
inhibitory wave being still further retarded, the warmth would 
be sufficient to make the two waves coincide, while the cold 
would throw back the inhibitory wave a whole wave-length, and 
thus again abolish the convulsions. 

The effect of temperature on the poisonous action of guanidine 
is also very extraordinary, and is very hard to explain on the 

1 Kunde and Virchow, quoted by Eckhard, op. cit. p. 44 ; Foster, Journal of 
Anatomy and Physiology, November 1873, p. 45. 



176 PHAEMACOLOGY AND THERAPEUTICS, [sect. I. 

ordinary hypothesis, although the phenomena seem quite natural 
when we look at them as cases of interference due to alterations 
in the rapidity with which the stimuli are transmitted along 
nervous structures. 

Another cause of tetanus that is difficult to understand on 
the ordinary hypothesis of inhibitory centres is the similar effect 
of absence of oxygen and excess of oxygen. When an animal is 
confined in a closed chamber without oxygen, it dies of convul- 
sions ; when oxygen is gradually introduced before the convulsions 
become too marked, it recovers. But when the pressure of oxygen 
is gradually raised above the normal, the animal again dies of 
convulsions. This is evidently not the effect of mere increase in 
atmospheric pressure, but the effect of the oxygen on the animal, 
inasmuch as twenty -five atmospheres of common air are required 
to produce the oxygen-convulsions, while three atmospheres of 
pure oxygen are sufficient. This effect is readily explained on 
the hypothesis of interference by supposing that the absence 
of oxygen retards the transmission of impulses in the nerve- 
centres ; so that we get those which ought ordinarily to inhibit 
one another coinciding and causing convulsions. Increased supply 
of oxygen gradually quickens the transmission of impulses until 
the waves first reach the normal relation, and then, the normal 
rate being exceeded, the impulses once more nearly coincide, 
and convulsions are produced a second time. 1 

The effect of various agents also in arresting or inhibiting 
muscular action suggests the possibility that such inhibition is 
due to interference with vibrations in muscle. The vibrations 
of the parts which occur in the muscle during the passage of a 
constant current have already been mentioned. When a constant 
current is passed for a length of time and then stopped, tetanic 
contraction of the muscle occurs and lasts for some time, but it 
can be at once arrested by again passing the constant current 
through the muscle. 

The idea that coincidence or interference of contractile waves 
in muscle have much to do with the presence or absence of con- 
traction of a muscle has been advanced by Kiihne, in order to 
explain the phenomenon observed by A. Ewald. When the 
sartorius of a frog is stimulated at each end by electric currents 
passing transversely through the ends, the secondary contraction 
which can be obtained from it is strongest in the middle of the 
muscle, while the points exactly intermediate between the middle 
and the end do not produce any secondary contraction at all. 
This absence of secondary contraction Kiihne thinks is due to 



1 For other observations on interference as a cause of inhibition, vide Wundt, 
Untersuchtmgen sur Mechanik cler Nerven und Nervencentren. 1876.' (Stuttgart : 
T. Enke) ; Eanvier, Lemons d'Anatomie Ginerale. Annie 1877-78. (Paris • J B." 
Bailliere et Fils) ; and Lauder Brunton ' On the Nature of Inhibition and the' 
Action of Drugs upon it ' (Nature, March 1883, and reprint). 



chap, vii.] ACTION OP DEUGS ON THE SPINAL COED. 177 

interference^ and the powerful secondary contraction from the 
middle to coincidence of waves. 1 

Inhibition may also be produced by direct irritation of in- 
voluntary muscular fibre. Thus I have noticed, under Ludwig's 
direction, that stimulation of veins as a rule very frequently 
causes dilatation at the point of irritation, and if the mus- 
cular fibre of a frog's heart be injured by pinching at one 
point, that point is apt to remain dilated when the rest is con- 
tracted. Protoplasmic structures appear to be similarly affected, 
and the passage of an interrupted current through the heart of 
a snail will arrest its rhythmical pulsations, although the heart in 
this animal appears to be a continuous protoplasmic structure 
and destitute of nerves. 2 

Stimulating Action of Drugs on the Reflex Powers of 

the Cord. 

The reflex action of the cord is greatly increased by certain 
drugs, more especially by ammonia and by strychnine. The 
action of strychnine was first investigated by Magendie, and his 
research is not only the first example of the systematic investi- 
gation of the physiological action of a drug leading to its thera- 
peutical employment, but is such a model of this method of 
research that it is worth giving in detail. 

He first introduced a little of the upas poison, of which 
strychnine was the essential ingredient, under the skin of the 
thigh of a dog, and found that for the first three minutes no 
symptoms at all were produced. Then the action of the poison 
began to manifest itself by general malaise, succeeded by marked 
symptoms. The animal took shelter in a corner of the labora- 
tory ; and almost immediately afterwards convulsive contraction 
of all the muscles of the body occurred, the for.e-feet quitting the 
ground for a moment on account of the sudden extension of the 
spine. This contraction was only momentary, and almost imme- 
diately afterwards ceased ; the animal remained calm for several 
seconds, and was then seized with a second convulsion, more 
marked and prolonged than the first. These convulsions suc- 
ceeded each other at short intervals, gradually becoming more 
severe. The respiration was hurried, the pulse quick, and it was 
observed that each time the animal was touched a convulsion 
immediately followed. Finally, death occurred at an interval 
increasing with the age and strength of the animal. 

These symptoms suggested to Magendie the following ex- 
planation of the action of the poison. 

It was, he thought, absorbed from the wound into the blood, 

1 Untersuchungen a. d. Physiolog. Inst., Heidelberg, 1879. Sonderabdruck, 
p. 40. 

, 2 M. Foster, Pflilger's Archiv. 

■ N 



178 PHARMACOLOGY AND THEEAPEUTICS. [sect. I. 

by which it was carried to the heart, and thence to all the organs 
of the body. On arriving at the spinal cord, it acted upon it as 
a violent excitant, producing the same symptoms as mechanical 
irritation or the application of electricity. Magendie was not 
content until he had tested his theory by experiment. The first 
question to be settled was whether the poison was absorbed 
or not. 

To test this supposition he applied the poison first to the 
serous membranes, the peritoneum and pleura, from which, as 
he had learned by previous experience, absorption takes place 
with extreme rapidity. The result showed that his supposition 
was correct. The symptoms appeared almost immediately after 
the injection of the poison into the pleura, and within twenty 
seconds after it had been injected into the peritoneum. In order 
to ascertain whether absorption took place from mucous as well 
as from serous surfaces, he isolated a loop of small intestine by 
means of two ligatures, and injected a little of the poison into 
the part between them. In six minutes, symptoms of poisoning 
appeared, showing that absorption had occurred, but they were 
less intense than when the poison was applied to the serous 
surface. 

Further experiments showed that absorption took place from 
the large intestine, from the bladder, and from the vagina ; but 
that it was comparatively feeble and slow. When introduced 
into the stomach along with food, upas invariably caused death ; 
but the symptoms did not appear until half an hour after it had 
been taken. This delay might have been due either to absorp- 
tion from the stomach having taken place very slowly or not 
at all, so that the drug had passed on to the small intestine, and 
thence been absorbed into the blood. To determine this point, 
he isolated the stomach by ligatures applied to its cardiac and 
pyloric orifices, and then injected a little poison into its cavity. 

Under such conditions, symptoms of poisoning were only 
observed after the lapse of an hour. This showed that while 
absorption from the stomach did occur, it was much slower than 
from the small intestine. 

The second question was, Does the poison act through the 
circulation ? If so, reasoned Magendie, the first symptoms of 
the action of the poison will come on more' slowly when it has 
far to travel to the spinal cord from the point of introduction, 
and vice versd. On testing this by experiment, he found that 
when the poison_ was injected into the jugular vein, tetanus 
occurred almost instantaneously, and death took place in less 
than three minutes, for the upas had only to pass through the 
pulmonary circulation and heart to the arteries of the cord. 
When injected into the femoral artery (at D, Fig. 66) the dis- 
tance to be travelled before reaching the cord would be greatly 
increased, for the poison must first pass through the artery itself, 



chap, vii.] ACTION OF DRUGS ON THE SPINAL COED. 179 

through the capillaries, and along the vena cava, traversing the' 
whole distance marked D A B in Pig. 66 before it reached the 
point where it entered the circulation when it was injected into 
the jugular. Under these conditions the action should be slow, 
and experiment showed this to be actually the case, for no 
symptoms appeared until seven minutes after the injection- 
Although these experiments of Magendie's appear to prove com- 
pletely that the upas poison acts through the circulation, a 
number of persons nevertheless considered that the symptoms 
were produced through the nervous system by means of so-called 
sympathy. In order to remove their doubts, Magendie narcotised 
a dog by means of opium, and then divided all the structures of 
one leg with the exception of the artery and vein. Into this 




Eig. 66. — Diagram illustrating Magendie's method of investigating the mode of action of upas 
(strychnine). A, femoral vein ; B, peritoneum ; c, pleura; D, femoral artery; E, f, g, spinal 
cord, to which small arteries are seen passing from the aorta. At p is indicated a point of 
section of the cord. 



almost isolated limb he then introduced a little of the poison. 
This was followed by the usual symptoms almost exactly as if 
the limb had been intact. By pressing upon the vein which 
passed from the limb to the body when the symptoms of tetanus 
appeared he was able to arrest their further development, and by 
releasing the vessel and allowing the circulation to have free 
course the symptoms reappeared. Lest by any chance the 
poison might have acted through nerves or lymphatics contained 
in the walls of the artery and vein, he divided these structures 
also, connecting their several ends by means of quills through 
which circulation then took place. When the poison was applied 
to the severed limb connected with the body only by these quills, 
the same succession of phenomena occurred as when the limb 
was uninjured. Tho possibility of the action being due to 
sympathy between the nervous system and the point of applica- 
tion of the poison was thus completely excluded, and the opera- 
tion of the poison through the circulation triumphantly demon- 
strated. 

The next question was whether the convulsions were 
caused by the action of the drug on the brain or the cord. 

N 2 



180 PHAEMACOLOGY AND THEEAPEUTICS. [sect. r. 

To ascertain its action upon the brain, a little of the solution 
was injected into the carotid artery. The effects produced were 
the same as those of any irritating liquid. The intellectual 
faculties disappeared, the head was laid between the paws, and 
the animal rolled over and over like a ball. These effects passed 
off as the circulating blood removed a quantity of the drug from 
the brain, and were succeeded by the ordinary tetanic convulsions 
when sufficient time had elapsed for it to reach the spinal cord. 
The question whether it really acted upon the cord still remained 
to be put to a crucial test. If its effects were really due to its 
action upon the spinal cord they ought to cease upon the de- 
struction of that part of the nervous system, and to occur when 
the drug was applied to it alone. Tbe cord was therefore de- 
stroyed by running a piece of whalebone down the vertebral 
canal at the moment of injection. When this was done, no 
tetanus occurred. In another experiment, Magendie waited 
until the tetanic spasms had been induced by the upas, and then 
destroyed the spinal cord by slowly pushing the whalebone down 
the vertebral canal. As the whalebone advanced, the tetanus 
disappeared, first in the fore-legs, when the dorsal part of the 
cord was destroyed, and then in the hind-legs, when the whale- 
bone had reached the lumbar vertebrae. 

In another experiment, an animal was narcotised by means 
of opium, and the spinal canal laid freely open. The upas was 
then directly placed on a part of the spinal cord. Tetanus im- 
mediately occurred in that part of the body, and in that part 
only to which the nerves arising from this portion of the cord 
were distributed. When the poison was successively applied to 
other parts of the cord, the convulsions spread to the correspond- 
ing regions of the body. 

The question whether a drug exercises a convulsant 
action through the brain or spinal cord is now frequently 
tested, not by destroying the whole cord as Magendie did, but 
simply by dividing the spinal cord transversely between the occi- 
put and the atlas. Convulsions depending upon stimulation of 
the motor centres in the brain and medulla oblongata then 
cease after section, while those dependent upon the spinal cord 
do not. 

The experiment of dividing the spinal cord transversely about 
its middle is also sometimes performed in order to test whether 
the convulsions are of really spinal origin. If they are, they 
should persist in both the anterior and posterior parts of the 
body, but if they are of cerebral origin, they occur in the anterior 
but not in the posterior part. 

The effect of strychnine and allied substances upon the cord 
is usually ascribed to increased excitability of the nerve-cells, but 
it is not improbably due partly to alteration in the comparative 
rate at which stimuli are' transmitted from one cell to another • 



chap.vii.] ACTION OF DEUGS ON THE SPINAL CORD. 181 

but this subject has already been more fully discussed under 
' Inhibition ' (q.v., p. 173 et seq.). 

Some curious results obtained by Dr. A. J". Spence may be 
explained on the latter hypothesis which would be inexplicable on 
the former. After removing the blood from the body of a frog, 
and exposing the brain, he placed some nux vomica upon it, so 
that it could gradually diffuse along the spinal cord. As it passed 
downwards he observed that, at first, irritation of the fore-feet 
caused spasm only in them ; later it caused spasm of both front 
and hind-feet, while irritation of the hind-feet still produced the 
ordinary reflex ; and later still irritation of the fore-feet caused 
no spasm in the hind-legs while irritation of the hind-feet would 
still cause spasm in the fore-legs. 1 

The action of strychnine on the conducting power of the 
spinal cord has already been discussed. It diminishes or 
abolishes the power of summation, but increases the reflex 
excitability, so that stimuli will produce reflex action which are 
too feeble to do so when the spinal cord is in its normal condition. 
The difference between the reaction to strong and weak stimuli 
is also to a great extent abolished, and both produce tetanic con- 
tractions. This condition, however, is absent for a short time 
after the application of each stimulus, and then strong and weak 
stimuli produce corresponding strong and weak action, much as 
in the normal cord. 2 

The effect of nicotine as a spinal stimulant is very extra- 
ordinary ; for Freusberg found that when frogs had been decapi- 
tated for twenty-four hours, and reflex action was almost entirely 
gone, the injection of a small quantity of the poison increased 
the reflex excitability so much that irritation of the skin caused 
well-marked movements. This increase lasted from one to three 
days, and the bodies of frogs poisoned by nicotine retained a 
fresh appearance for a long time. 

Spinal Stimulants. 

Spinal stimulants are remedies which increase the functional 
activity of the spinal cord. 

Ammonia. Thebaine. 

Strychnine. Gelsemine. 

Erucine. Buxine. 

Absinthe. Calabarine. 

Nicotine. Caffeine. 

The most marked of these are strychnine, brucine, and the- 
baine, which in small and moderate doses greatly increase the 

1 Edm. Med. Journ., July 1866. 

* Ludwig and Walton, Ludwig's Arbeiten, 1882. 



182 PHARMACOLOGY AND THERAPEUTICS. [sect. i. 

reflex excitability, and in large doses cause tetanic convulsions. 
Besides these there are some others, such as opium, morphine, 
and belladonna, which, although they appear at first to have a 
sedative action, when given in very large doses produce convul- 
sions. 

Uses. — The want of an exact knowledge of the intimate 
pathology of diseases of the spinal cord renders the rational use of 
spinal stimulants difficult. They are employed in the cases of 
general debility without any evidence of distinct disease, and in 
paralysis where there is no evidence of inflammation : this 
paralysis may be local, or affect the whole side of the body, as in 
hemiplegia, or the lower half, as in paraplegia. 

When strychnine is given in cases of paralysis until it begins 
to exhibit its physiological action in slight muscular twitches, 
these twitches begin soooner and are more marked in the para^ 
lysed than the healthy parts. 



183 



CHAPTER VIII. 
ACTION OF DEUGS ON THE BRAIN. 

We are able to judge to a certain extent of the order and kind of 
action of drugs upon the different parts of the nerve-centres by 
watching their effect upon the movements of animals after their 
injection. 

Functions of the Brain in the Frog. 

By removal of successive portions of the nervous system 
in the frog, Goltz has shown that the cerebral lobes have the 
function of voluntary movement, so that when they ar.e removed, 
the animal lies quiet, unless acted upon by some external 
stimulus. 

The optic lobes, which correspond to the corpora quadri- 
gemina of the higher animals, have the function of directing and 
co-ordinating movements, but not of originating them, so that a 
frog in which they are uninjured, but from which the cerebral 
lobes have been removed, will remain perfectly quiet, except on 
the application of an " external stimulus, when it will leap like a 
normal frog. 

As the optic lobes have the power of directing and co-ordinat- 
ing movements, when they are destroyed the animal will jump, 
but will be unable to direct its movements. 

The cerebellum has also the power of co-ordination, so that 
when it is removed the animal cannot jump at all, although one 
leg may answer by a kick or other motion to the application of a 
stimulus. But even when all those parts have been removed, 
the frog will still recover its ordinary position after it has been 
laid upon its back. 

The co-ordination requisite for this power of retaining or 
recovering its ordinary position appears to be situated in the 
medulla oblongata, for when this is removed the frog will lie 
upon its back, and will not attempt to recover its ordinary 
position. 

The legs will still respond by movements to irritation applied 
to the foot, but when the spinal cord is now destroyed these 
reflex movements also cease. 

In frogs poisoned by opium, the movements are gradually 



184 PHARMACOLOGY AND THEEAPEUTICS. [sect. i. 

abolished in the order just mentioned, and we therefore conclude 
that opium affects the nerve-centres in the order of their deve- 
lopment, the highest being paralysed first, and the lowest last 
(p. 172). This order is usually not quite the same in higher 
animals, inasmuch as the last centre to be paralysed by opium 
or other anaesthetics is usually the medulla oblongata, and more 
especially that part of it which keeps up the respiratory move- 
ments. As we shall afterwards see, however, the respiratory 
centre is really a lower or more fundamental centre than either 
the brain or spinal cord. 

Functions of the Brain in Mammals. 

In higher animals, such as rabbits and guinea-pigs, the cere- 
bral hemispheres are comparatively much more developed than 
in the frog, and their removal interferes very much with the 
animal's motions. At first it is utterly prostrate, but after some 
time its power of movement returns to some extent, though it 



Effects of removing the part of 
brain included in brackets. 



Voluntary motion lost . 



Cannot direct movements 



Cannot jump 

Cannot recover position when laid 
on its back 




Olfactory nerves. 
Olfactory lobes. 



Cerebral lobes. 
Pineal gland. 
Optic thalamus. 
Optic lobes. 
Cerebellum. 

Rhomboid sinus. 
Medulla oblongata. 



Fig. 67. — Diagram of the higher nerve-centres of the frog. 

remains much less than in the normal animal. As we should 
expect, the weakness is most marked in those parts of the body 
that are most under the control of the cerebrum, and least in 
those whose movements are regulated by the lower centres. 
Thus in rabbits the fore-paws are capable of being used for com- 
plex motions at the will of the animal, such as washing the face, 
holding food, and so on, and in them the weakness caused by 
removal of the cerebrum is much more marked than in the hind 
limbs, which are simply used for progression. After the opera- 
tion the animal can still stand, although it is unsteady, and the 
fore-legs tend to sprawl out. When pinched it bounds forward, 
but, unlike the frog, it is unable to avoid any obstacle in its path. 



chap, viii.] ACTION OF DEUGS ON THE BEAIN. 



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m -PHARMACOLOGY AND THERAPEUTICS, [sect. r. 

If it be pinched at all severely, it not only moves, but will cry 
loudly and plaintively, and this condition is frequently noticed m 
rabbits under chloroform, although they have received no injury 
whatever. The pupils contract on the stimulus of light, and the 
eyes wink if the finger is brought near them. Bitter substances 
cause movements of the tongue and mouth, and ammonia applied 
to the nostrils may cause the head to be drawn back, or the animal 
to rub its nostrils with its toes. 1 

Where the cerebral hemispheres are still more developed, as 
in cats, dogs, and monkeys, their removal causes so much pro- 
stration, and interferes so greatly with motor power as almost 
entirely to destroy equilibrium and co-ordinated progression. 

The motor and sensory centres of the brain have been more 
exactly localised in monkeys by Ferrier, Fritsch, Hitzig, and 
others, and the results of their experiments, especially those of 
Ferrier, agree so well with those of pathological observation in 
men that we may assume that there is a general agreement 
between the position of the centres in man and monkey. 

The motor centres are arranged along the two sides of the 
fissure of Rolando, the order of their arrangement being exactly 
what is required for the purpose of (1) seeing food ; (2) conveying 
it to the mouth ; (3) masticating it ; (4) throwing away the 
refuse ; and (5) advancing to get more 2 (vide Fig. 68, brain of 
monkey). 

The sensory centres he in the posterior and lower parts of 
the brain. The centre for sight is situated in the angular gyrus 
and is marked 14 and 15 in the diagram; that for hearing is 
situated in the superior temporo-sphenoidal and is marked 16 in 
the diagram ; those for smell and taste lie at the tip of the 
temporo-sphenoidal lobe, and the centre for general sensation 
appears to be towards the interior of the brain, in the hippo- 
campal region. 

When the motor centres in the monkey are slightly irritated 
by a faradaic current, a single co-ordinated movement is produced, 
but if the irritation be continued longer, and especially if a 
strong current be used, epileptiform convulsions may occur, suc- 
ceeded by choreic movements after the current has ceased. 
Epileptic convulsions are easily produced by irritation of the 
cerebral cortex in the cat and dog as well as the monkey. It is 
difficult to produce them by cortical irritation in the guinea-pig 
or rabbit, and impossible in birds, frogs, and fishes. 3 

1 Ferrier, Functions of the Brain, p. 38. 

* Lauder Brunton ' On the Position of the Motor Centres in the Brain in regard 
to the Nutritive and Social Functions,' Brain, vol. iv. p. 1. 

* Francois -Franok and Pitres, Arch, de Physiol., July 1883, p. 39. 



chap, vm.] ACTION OF DRUGS ON THE BKAIN^ 187 

Depressant Action of Drugs on the Motor Centres. 

The excitability of the brain may be altered either by 
conditions which modify the nerve-cells or the circulation. A 
deficient circulation greatly depresses the excitability, and it is 
very low when much haemorrhage has occurred. 

One method of investigating the action of drugs on the excita- 
bility of the brain consists in trephining so as to expose the 
cortical substance and then stimulating it by a faradaic current 
before and after the administration of a drug either by inhalation 
or injection. Another method has been employed by Albertoni, 
who first trephines on one side, and having estimated the 
strength of current sufficient to produce an epileptic convulsion 
when applied to a motor centre, he allows the wound to heal, 
and then gives for a length of time the drug on which he wishes 
to experiment. He then exposes the corresponding motor area 
on the other side and observes whether the strength of current 
required to produce an epileptic convulsion is greater or less 
than before. 

The excitability of the motor centres is greatly lowered by 
anaesthetics, so that as anaesthesia becomes deeper, irritation of 
the motor centres has less and less effect, and when anaesthesia is 
very profound, such irritation has no action whatever. 1 The 
motor centres, however, are less affected than the sensory ones 
by anaesthetics, so that they will still react to faradaic irritation 
when the sensation of pain has been completely abolished. 

Alcohol also diminishes the excitability of the motor centres, 
so that the epileptic convulsions which usually follow the appli- 
cation of strong currents to the cortex are less readily produced 
after its administration, as well as after ether and chloroform. 2 
Chloral for a time diminishes the excitability of the brain, 
lengthening the latent period, so that stronger currents or more 
numerous stimuli must be used to produce a result : it will tem- 
porarily abolish the excitability. Cold (not freezing) greatly 
lowers or destroys excitability, and this may be followed 'by a 
period of increased excitability with a shorter latent period. 3 

Bromide of potassium, according to Albertoni, when given for 
several weeks together, greatly diminishes the excitability of the 
motor centres, so that when dogs are thoroughly under its in- 
fluence it is almost impossible to produce epileptic convulsions by 

1 This was observed in the case of ether by Hitzig, Vntersuchungen ilber das 
GeMrn, Berlin, 1874. I have had several opportunities of observing the same 
thing in regard to chloroform when assisting my friend Dr. Ferrier in experiments 
on the brain. 

2 Francois-Francis and Pitres, op. cit. 

' De Varigny, Becherches expirimentaUs sv/r I'excitabiUti ilectrique des eircon- 
volutiom ceribrales et sur lapiriode d 'excitation latente du cerveau. Paris, 1884, 
p. 138. 



188 PHARMACOLOGY AND THERAPEUTICS. [sect.i. 

irritation of the cortical substance. Atropine in small doses 
increases the excitability of the brain in monkeys, but in large 
doses paralyses it. It greatly increases the tendency to epileptic 
convulsions in dogs, so that they can be produced by very much 
slighter stimuli than usual, and strychnine, absinthe, and canna- 
bin have a similar action in this respect. 1 Physostigmine appears 
to increase the excitability of motor centres in the brain ; for 
when guinea-pigs have been rendered epileptic by section of a 
sciatic nerve, the administration of physostigmine greatly in- 
creases the number of fits. 

Irritant Action of Drugs on Motor Centres in the 

Brain. 

.Certain drugs when administered to animals or taken by 
man produce convulsions. The muscular actions which occur 
in these convulsive movements may be induced by (a) irritation 
of the motor centres in the spinal cord, (b) the motor centres in 
the medulla oblongata and pons Varolii, or (c) cerebral cortex. 
These centres may be irritated directly by the action of the drug 
upon them, or they, may be stimulated indirectly by the drug 
causing the blood in them to become venous through its action 
on the respiratory or circulatory organs. Convulsions of this 
sort, although caused by the administration of a poison, are 
really asphyxial, and are similar in character to those produced 
by suffocation. 

Convulsions are usually ascertained to be of spinal origin by 
dividing the cord either at the occiput or lower down in its course 
and finding that they still persist in those parts of the body which 
derive their innervation from the spinal cord below the point of 
section. If they cease in parts of the body innervated by the 
spinal cord alone, but continue in the parts which retain their 
nervous connection with the brain, they are regarded as of cerebral 
origin (v. p. 179). 

It has already been mentioned that irritation of the motor areas 
in the cortex of the brain will produce epileptic convulsions, but 
it is probable that such cortical irritation acts through lower gan- 
glionic centres and especially through the medulla oblongata and 
pons Varolii. Epileptic convulsions can be still more readily pro- 
duced by irritation of this part of the brain than by irritation of 
the cerebral cortex, and may be induced by a slight lesion of the 
pons and medulla by a needle. It is to irritation of this part of 
the brain by venous blood that asphyxial convulsions are due, for 
they can still be induced by suffocation or by ligature or compres- 
sion of all the arteries leading to the brain after all the parts of the 
brain above the pons have been removed, and they cease when the 
spinal cord is divided just below the medulla, or the medulla itself 

1 Franijois-Franck and Pitres, op. cik 



ghap.viii.J ACTION OF DEUGS ON THE BEAIN. 189 

divided at its lower end. It is evident that, if the spinal cord be 
paralysed, the convulsions will not occur though the medulla and 
pons be irritated ; and it has been found that, if its blood-supply 
is stopped at the same time as the circulation in the pons by 
ligaturing the aorta in place of the cerebral vessels alone, convul- 
sions do not occur. Probably the absence of convulsions in slow 
asphyxia is due, at least in some degree, to gradual paralysis 
of the cord by the long-continued circulation of venous blood 
through it. 

The centre for convulsions in the frog appears to be in the 
medulla oblongata. 

Asphyxial convulsions are usually of an opisthotonic charac- 
ter, because, all the muscles being stimulated at once by the action 
of the venous blood on the motor centres, the stronger overpower 
the weaker, and the extensor muscles of the back being more 
powerful than the flexors bend the- spine backwards. Asphyxial 
convulsions only occur in warm-blooded animals and not in frogs, 
where the respiratory processes are slow, and entire stoppage of the 
respiration for a length of time does not render the blood suffi- 
ciently venous to act as a powerful irritant. If any drug therefore 
produces convulsions in the higher animals and not in frogs, the 
probability is that its convulsive action is indirect and the convul- 
sions it produces are asphyxial. .. If, on- the other hand,.it produces 
convulsions in frogs as well as higher animals, its convulsive action 
is in all probability due to the direct effect of the drug upon the 
nerve-centres. In order to ascertain this definitely, however, the 
usual plan is to see (1) whether the convulsions which occur after 
the drug has been injected disappear when artificial respiration 
is commenced, and (2) whether these convulsions are prevented 
by artificial respiration begun before the injection of the drug and 
kept up during its action. But even this does not entirely show 
whether the convulsive action of a drug is direct or indirect, for 
artificial respiration will not prevent asphyxial convulsions . if 
these should depend upon the action of the drug in stopping the 
heart and thus arresting the circulation. If it is found that the 
convulsions occur very shortly after the heart stops, the usual 
plan is - to paralyse the vagus in the heart by atropine, and 
ascertain whether the convulsive action then occurs. If the drug 
still produces convulsions when respiration is kept up and the 
heart is not stopped, it is almost certain that its action is direct 
upon the nerve-centres. 

Experiments to ascertain whether convulsions are asphyxial 
or not may be conveniently made upon fowls, for the venous or 
arterial condition of the blood is readily ascertained by the colour 
of the comb. ' Thus, in fowls killed by cobra poison, the convul- 
sions come oh at the moment the comb becomes livid, and when 
artificial respiration is begun the convulsions disappear as the 
comb again regains its normal colour. It is evident that the 



190 PHARMACOLOGY AND THERAPEUTICS. [sect, i, 

eolour of the comb will indicate' the condition of the blood supply- 
ing the brain, even though a venous condition of it should be due 
to stoppage of the heart and not to failure of the circulation. 

Camphor has a curious exciting action both upon the brain 
and upon the medulla. It produces first rapid succession of ideas, 
great desire to move, hallucinations which are generally agreeable, 
and a wish to dance and laugh. In animals it has a similar 
action, causing wild excitement and constant motion, succeeded 
by clonic epileptiform convulsions, during which death often occurs. 
Usually, if they survive the convulsions, they recover ; but in man 
the convulsive stage may be succeeded by paralysis, coma, and 
death, the parts of the nervous system which are first excited 
being apparently finally paralysed. The action upon frogs is 
different from that on warm-blooded animals, for in them it proT 
daces such rapid paralysis both of the spinal and motor nerves 
that convulsions do not occur. 

Among other drugs having a powerful convulsant action due 
to irritation either of the eortical centres or of the medulla and 
pons are picrotoxin (the active principle of Anamirta cocculus or 
Cocculus indicus), cicutoxine (the active principle of Cicutavirosa), 
and the active principle of the nearly-allied (Enanthe crocata, 
coriamyrtin (from Coriaria myrtifolia) , digitaliresin and toxiresin, 
which are products of the decomposition of the active principles 
of digitalis. 

The method of localising the parts of the brain upon which 
certain drugs exert a convulsant action, consists in extirpating 
some of the motor centres and then giving these drugs, such as 
picrotoxin, cinchonidine, and quinine, 1 which produce epileptic 
convulsions. 2 The results of these experiments are that the 
epileptic convulsions produced by these poisons appear to have a 
twofold origin, (a) in the brain, and (b) in the medulla, the centre 
in the brain being the most sensitive to the action of the poison. 
In consequence of this, when the poison is given after the destruc- 
tion of the motor centres on one side in such quantities as not 
to cause general convulsions, the weakness of the opposite side, 
due to the lesions, becomes still more evident, probably from 
the motor excitability of the sound side being increased. When 
convulsions are produced they are unsymmetrical. Those of the 
sound side are much stronger, are generally clonic, and appa- 
rently arise from irritation of the cerebral centres. Those of the 
paralysed side are much weaker, are more tonic, and apparently 
arise from irritation of the medulla. 



'I have seen a case in which an epileptic convulsion appeared to be caused by 
medicinal doses of quinine. 

« Rovighi e Santini, Publicazioni del R. Inslit. di stud, superiori in Firenze 
Sezwne di scienze fisiche natur. 1882, s. 1. 



CHAP.vrii.] ACTION OF DEUGS ON THE BRAIN. 191 



ACTION OF DRUGS ON THE SENSORY AND PSYCHICAL 
CENTRES IN THE BRAIN. 

'The effect of drugs upon the higher mental functions can only 
be ascertained satisfactorily in man. These functions vary in 
complexity from simple choice to the highest efforts of genius. 

The effect of drugs upon the time required for mental pro- 
cesses is observed by ascertaining, first, the time required for 
the performance before and after the administration of a drug, 
and comparing these two times with one another. 

The processes generally investigated are, (a) the time required 
for simple reaction ; (b) for discrimination ; (c) for decision. The 
simple reaction is ascertained by marking on a chronograph the 
time when a signal is made, such as, for example, the exhibition 
of a coloured flag. As soon as this is seen by the individual 
experimented upon he marks the time upon the same chronograph 
by placing a finger upon a key which is connected with the 
registering electro-magnet. The difference of time between the 
exhibition of the flag and the time registered by the electro-magnet 
is equal to the time required for the transmission of the sensory 
impulse to the brain, for its transmission from the sensory to the 
motor tracts of the brain, for its passage down the motor nerves, 
and the latent period of the muscles. 

The time required for selection is ascertained in the same 
way, but either a red or blue flag may be shown, and the person 
experimented upon has to discriminate between them, and only 
to press when the one previously agreed upon is shown. The 
difference between the time of this experiment and the former 
gives the time required for discrimination. 

The time required for decision is ascertained in the same way 
as the previous one, excepting that a different signal is to be made 
on the appearance of the red and of the blue. 

Simple reaction has been found by Kraepelin ' to be little 
affected by nitrite of amyl : sometimes it is a little quicker and 
sometimes a little slower than normal. It is rendered slower by 
aether and much slower by chloroform, although exceptionally it 
may be quickened by chloroform, probably when used in small 
doses. 

The time required for discrimination is not definitely affected 
by nitrite of amyl, being sometimes increased and sometimes 
diminished. It is generally increased, though it may be dimi- 
nished, by small doses of ether and also by chloroform. 

The time for decision is sometimes increased and sometimes 
diminished by nitrite of amyl. It is increased by ether and also 

1 Kraepelin, Ueber die Einwirkung einiger medicamentosen Staff e auf die Dauer 
hinfacher psychischer Vprgange, 1882. Abstract in Rivista Spepmentale di 
iPrerriatria, anno ix. 1888, p. 124. 



192 PHARMACOLOGY AND THERAPEUTICS. [sect. i. 

by chloroform ; and if the quantity given be great, the increase 
may be very large. 

■ The influence of alcohol upon psychical processes is curious ; 
for while it renders them much slower, the individual under its 
influence believes them to be much quicker than usual. 

Drugs which increase the Functional Activity of the 

Brain. 

Nerve Stimulants. 

These are remedies which increase the nervous activity of 
the cerebro-spinal system. They are subdivided into those which 
act on the cerebrum, or cerebral stimulants, and those which 
affect the spinal cord, or spinal stimulants. Spinal stimulants 
have been already discussed (p. 181) . 

Cerebral Stimulants. 

In popular language, the name of stimulant is generally 
applied to drugs which have the power to increase the activity of 
the brain. From their producing a feeling of comfort and mirth 
they are also called exhilarants. The functional activity of the 
brain, like that of other organs, depends upon the tissue-change 
which goes on in the cells and fibres which compose it, and the 
amount of tissue-change is regulated to a great extent by the 
quantity and quality of the blood supplied to the organ. A free 
supply of blood to the brain may be obtained by general excite- 
ment of the circulation, i.e. more powerful and rapid action of 
the heart and contraction of the vessels in other parts of the 
body driving blood into the brain, or by local dilatation of the 
cerebral arteries allowing blood more ready access to the brain, 
or by a combination of these factors. 

Free circulation through the cerebral arteries may be in- 
duced to some extent by posture : thus, some men can think best 
when the head is low, and almost everyone naturally assumes 
the sitting posture with the head bowed down and held between 
the hands when suffering from the effects of mental depression. 
This posture is not, as is often supposed, merely consequent on 
the depressed condition of the nerve-centres, it is voluntarily 
assumed because it affords an actual sense of relief. In eager 
conversation also the body generally stoops forward and the head 
is held low so as to allow of a free supply of blood to the brain. 1 

This effect of posture on the human brain is admirably shown 2 

1 Lauder Brunton on the Physiological Action of Alcohol, Practitioner, 1876. 
vol. xvi. p. 127. 

* Francois-Franck et Brissaud, Marty's Travaux, 1877, tome iii. p. 147. 



chap, vm.] ACTION OP DRUGS ON THE BRAIN. 198 

by a tracing taken from a patient with an aperture in the skull 
by b rancois-Franck and Brissaud (Fig. 69). 




FlG - 69-- Tracing sh ^i g the inoreas e(J circulation in the brain caused bv inclining the head and 
body forwards The tracing was taken by Brissaud and Francois-Franck, from the parietal regton 
of a woman who had lost a large piece of bone from syphilis? "•"<«" ""» parietal regum 

Local dilatation of the arteries of the brain appears to be pro- 
duced in animals by the movements of mastication (Fig. 70) and 
probably also by savoury food or irritating substances in the mouth. 



AAA 

jOURINC MASTICATION 



Fio. 70. Tracing to show the increased rapidity of circulation in the carotid of a horse dnrlni. 
mastication.. (After Marey.) ^" 

It is probably on this account that so many substances are chewed 
for their stimulant action, such as tobacco, betel nut, cola nut 
and raisins. The effect of smoking is probably to a great extent 
due also to its action on the cerebral circulation through the 
stimulating effect of the smoke on the nerves of the mouth and 
nares, and so is the use of alcohol in sips by men, such as jour- 



Fig. 71.— Pulsations of the fontanelle (F) in an inlant aix weeks old while sucking, ti shows a 
simultaneous tracing of the thoracic respiration. The breast was offered to the child at the 
beginning of the tracing. At the time indicated by the third respiratory wave, which has a 
flattened top, the child began to take the breast. It will be noticed that the line of the tracing 
F rises, indicating increased circulation on the brain. (After Salathc.) a 

nalists, who are engaged in writing. It is probable that tea and 
coffee also cause local dilatation of the arteries supplying the 



1 Mareifs Travaux for 1877, p. 147. 

• SalathS, Marey's Travaux, 1876, p. 354. 



1U PHARMACOLOGY AND THERAPEUTICS, {sect. 1. 

brain. Suction also causes an increased supply of blood to the 

brain (Fig. 71). ' . , , , • « 

The effect of local dilatation of the cerebral vessels is very greatly 
increased, if in addition to it the general circulation is increased 
and the blood-pressure raised by contraction of the arterioles in 
the body generally, or by more vigorous action of the heart. 

General excitement of the circulation is induced by exercise 
short of fatigue, and a brisk walk will sometimes remove a con- 
dition of low spirits. Sometimes the supply of blood to the bram 
is but slightly increased during continuous exercise, as a large 
portion of the blood is then diverted to the muscles, but after 
the exertion is over the excitement of the circulation continues 
for some time, and then the supply to the brain is increased. In 
some persons a cold wind acts as an exhilarant, causing con- 
traction of the vessels, with consequent increase in the general 
blood-pressure and increased circulation in the brain. In persons 
who are debilitated and feeble, on the contrary, the cold may 
have an opposite effect, by depressing the action of the heart. 

Some men can think best when walking about, on account of 
the excitement in the circulation which the exertion produces ; 
but many such people, when they come to a very difficult point, 
will stand still or sit down, so as to allow the blood to flow more 
to the head and less to the muscles. 

Where the circulation is feeble, so that the heart is not much 
stimulated by walking about, men often find that they can think 
better when lying down, or sitting with their head in their hands 
(Fig. 69), so as to gain the advantage of the greater flow of blood 
to the head in these positions. 

Stimulation of the mucous membrane of the nose by smelling 
the vapour of strong ammonia, carbonate of ammonium, or acetic 
acid, raises the blood-pressure generally throughout the body by 
reflexly stimulating the vaso-motor centre, and thus increases 
the circulation of blood in the brain. Smelling salts or aromatic 
vinegar are therefore frequently employed, not only to enable 
people to attend more readily to any subject in which they are 
engaged, and to prevent them from falling asleep, but also to 
arouse them from syncope. 

The action of sipping is a powerful stimulant to the circu- 
lation, for, as Kronecker has shown, the inhibitory action of the 
vagus on the heart is abolished while the sipping continues, and 
the pulse-rate is very greatly increased. A glass of cold water 
slowly sipped will produce greater acceleration of the pulse for a 
time than a glass of wine or spirits taken at a draught. Sipping 
cold water has been recommended to allay the craving for alcohol 
in drunkards endeavouring to reform, and probably its use is 
owing to this stimulant action on the heart. It is sometimes 
said that a single glass of ale sucked through a straw will intoxi- 

1 Salathi, op. cit. 



chap, vni.] ACTION OF DEUGS ON THE BBAIN. 195 

cate a man, although three' times the quantity would not do so if 
taken in large draughts. If this be true, the more rapid intoxi- 
cation caused by sucking is probably due to the conjoined effects 
of the alcohol and of temporary paralysis of the vagus caused by 
the suction, possibly aided by the direct effect of suction on the 
cerebral circulation (Fig. 71, p. 193). 

One of the most typical stimulants is alcohol. In small 
quantities it increases the arterial tension by locally stimulating, 
first the sensory nerves of the. mouth, and afterwards those of 
the stomach, and thus causing reflex contraction of the vessels 
and reflex acceleration of the beats of the heart. This effect 
occurs before its absorption, and is best marked when the alcohol 
is strong, and is but slightly marked when it is diluted. It is 
possible that by inducing local dilatation of the cerebral arteries 
while the heart still continues active, it may have a stimulant 
■ action on the cerebral functions, besides that which it induces by 
merely exciting the circulation generally. 

Any stimulant action on the brain beyond what may be 
explained in this way is very slight, if indeed it exist at all. 
Its further actions are those of paralysis exerted on the nerve- 
centres in the order of their development, the higher centres 
being paralysed first (see p. 146) . 

At or about this point the stimulating action ceases and the 
narcotic action commences. The exhilarating effect of alcohol, 
however, may be most marked just at this point, because just here, 
while the circulation in the brain'generally remains increased, the 
restraining or inhibitory parts of it begin to be paralysed. Thus, 
imagination and emotion are more readily excited and expression 
is free and unrestrained ; external circumstances are less attended 
to, and a boyish or childish hilarity occurs. 

It is probable that some substances, such as strychnine, in- 
crease the mental powers by a direct action on the brain-tissue 
itself, and possibly caffeine may do so also. 

Drugs which lessen the Functional Activity of the 

Brain. 

These drugs are soporifics or hypnotics ; narcotics ; anodynes 
or analgesics ; and ansesthetics. 

Most of the substances belonging to those classes have a 
certain resemblance to one another in their action. Most of them 
stimulate the mental functions when given in very small doses. 
In larger doses they have also a stimulating action at first, i.e. 
while a small quantity only has been absorbed, but later on they 
diminish or abolish the mental faculties. The same drug— as, 
for example, opium or alcohol— in different doses may thus act as 
a stimulant, narcotic, soporific, and anesthetic. 

In a certain stage of their action opium and alcohol do not 

» 2 



196 PHAKMACOLOGY AND THERAPEUTICS. [sect. I. 

merely lessen the functional activity of the brain, but they 
disturb the normal relations of one part to another, so as to 
produce disorder of the mental functions. Bromide of potassium, 
on the other hand, appears simply to lessen the functional activity 
of the brain without disturbing the relation of one part to another. 
We do not know what the causes of this difference in their action 
are, but with some degree of probability we may consider that such 
substances as bromide of potassium, or the normal products of 
tissue-waste, such as lactic acid, simply diminish the functional 
activity of the nerve-cells without disturbing the nervous paths 
by which they communicate with one another, so that we have 
merely a general and even diminution of the mental faculties, as 
in natural sleep. Such substances as alcohol, on the other hand, 
may be supposed not only to diminish the functional activity of 
the cells, but also to disturb the rate at which the impulses pass 
from one cell to another, or to alter the direction in which these 
impulses are sent, so that instead of the mental activity being 
lessened in degree but natural in kind, as after the administration 
of bromide of potassium, we have a disturbance of the functions 
resembling that which we find in delirium or madness. 

Hypnotics or Soporifics. 

These are remedies which induce sleep. Although many of 
them are also narcotic, yet we may distinguish between hypnotics 
and narcotics. Pure hypnotics are substances which in the doses 
necessary to produce sleep do not disturb the normal relationship 
of the mental faculties to the external world. 

In sleep the cerebro-spinal system, with the exception of the 
medulla oblongata, is to a great extent functionally inactive, and 
even the respiratory centre and the vaso-motor centre in the 
medulla, undergo a diminution in their functional activity, so 
that the respiration becomes slower, the vessels of the surface 
dilate, and the arterial tension falls. 

Certain parts of the nervous system may still remain func- 
tionally active, so that, for example, when the nose is tickled 
with a hair, reflex movements of the face or hand may occur 
without awakening the sleeper ; and certain parts of the brain 
may also be active so that dreams occur, which may be afterwards 
remembered as distinctly as real occurrences, or may produce at 
the time various movements of the body. 

But while individual parts may be active, the whole cerebro- 
spinal system is not active together, and thus any co-ordina- 
tion which may occur between either sensations or motions is 
incomplete ; the dreams are incoherent, and the motions do not 
affect the whole body, as is seen in sleeping dogs, where the legs 
make a movement of running, but the animal continues to lie on 
its side. The functional inactivity of the whole or of the greater 



chap, viii.] ACTION OF DEUGS ON THE BEAIN. 197 

part of the cerebro-spinal system is associated with a condition of 
anaemia, and probably depends to a certain extent upon it. At 
the same time it is probable that sleep depends also on functional 
inactivity of the cerebral cells due to accumulation of the products 
of tissue- waste in or around them. 

, The arteries of the brain during sleep are contracted, the brain 
is anaemic, and its bulk is small. On awakening, the arteries 
become dilated, the circulation becomes rapid, and the brain 
increases in bulk. Where parts of the brain are active, as in 
dreaming, increased circulation occurs, but probably this is local 
and not general. 

In considering the circulation of the brain, however, a 
marked distinction must be drawn between the condition of the 
arteries and veins. So long as the blood is in the arteries it is 
available for the nutrition of the nervous structures ; but once it 
is in the veins it is no longer available, and its accumulation 
there will tend to impair nutrition, both by the pressure it exerts 
on the nervous structures, and by its interference with the supply 
of arterial blood. 

In normal sleep the arteries and veins are both contracted, 
and the brain appears anaemic. In the very act of waking the 
brain may slightly contract, and this has been thought by Mosso, 
to whom we owe the observation, to show that sleep does not depend 
upon anaemia of the brain ; but this contraction may be due to 
the removal of venous blood, preparatory to further arterial supply. 

Observations on the brain by trephining appear to show that 
during ordinary sleep, whether it has come on naturally, or has 
been induced by narcotics, such as a small dose of opium, the 
brain is anaemic. During functional activity, either of the whole 
or of its parts, there is arterial dilatation, with a free supply of 
blood. During coma the veins become dilated and the brain con- 
gested. 1 This congestion, however, is utterly different from the 
arterial congestion of functional activity, for in coma the blood, 
though abundant in quantity, is stagnating in the veins, and 
useless for the tissues. 

In order to produce sleep, then, two things are necessary : — 

1st. To lessen the circulation in the brain as much as possible 
by diverting blood from it or quieting cardiac action. 

2nd. To lessen the functional activity. of the organ. 

Blood may be diverted from the brain by dilating the vessels 
elsewhere. In weak conditions of the body, with feeble vascular 
tone, this may occur simply from position, and such persons 
become drowsy when standing or walking about, or when sitting. 
As soon as they lie down, however, the cerebral vessels having 
little or no tone, the blood floods the brain, and they are unable 
to sleep. In such persons, sleep may be sometimes obtained by 

• Hammond, On Wakefulness, 1866, p. 20. 



1U8 PHAEMACOLOQY AND THEEAPEUTICS. ; [seot.u 

raising the head with high pillows. In such cases, also, vascular 
tonics, such as digitalis, by increasing the contractile power of 
the arteries leading to the brain, may enable them to resist the 
increased pressure in the recumbent position, and thus prevent 
the brain being flooded with blood and allow sleep to be obtained. 




3?ig. 72. — Tracings from the brain of a dog after trephining, showing the innuence of position on 
the cerebral circulation. In the upper tracing the vertical line shows when the head of the 
dog was lowered, and in the lower tracing when the head was raised. (Salathe./ - 

The largest vascular area into which the blood may be drawn 
away from the brain is that of the intestinal canal. When the 
vessels in the intestine are contracted, it is almost impossible to' 
obtain sleep. Consequently both man and animals, when ex- 
posed to cold, which acting through the thin abdominal walk 
would cause contraction of the intestinal vessels and drive the 
blood to the brain, instinctively keep the intestines warm by 
curling themselves up before going to sleep, and thus covering 
the abdomen with the thick muscles of the thighs. 

Warmth to the abdomen by means of a large poultice out-; 
side will also tend to produce sleep ; or, in place of a poultice, a .' 
wet compress, consisting of linen or flannel wrung out of cold 
water, and covered with oil-silk, and with two thicknesses of dry 
flannel placed above it, tends greatly to induce sleep and is most 
useful for this purpose, especially in children. 

Warmth to the interior of the stomach has a somewhat 
similar action,- but it differs from warmth to the exterior in 
this, that it may, to a certain extent, stimulate the heart as 
well as dilate the abdominal vessels. Stimulation of the heart ' 
is of course objectionable, as it tends to maintain the activity 
of the brain. 

On this account the food or drink should be tolerably warm, 
but not very hot. Warm milk, either alone, or with bread 
soaked in it, warm gruel, thin corn-flour, or ground rice, sago, 
or tapioca, warm beef-tea or soup, or a glass of hot wine and 
water or spirits and water at bed-time, may all act as soporifics 
by withdrawing the blood from the brain to the stomach. In the 
sleeplessness of fever a wet pack, by restraining the movements 
and by diverting blood from the brain to the body generally, is 
often an efficient soporific. 



Marey's Travaux, 1876, p. 397. 



chap, vin.] ACTION OP DEUGS ON THE BEAIN. 199 

Cold feet also tend to keep up the tension in the vessels 
and prevent sleep, and therefore they ought to be warmed either 
by the use of an india-rubber bag filled with hot water, and 
covered with flannel, or by rubbing them briskly in cold water 
and drying them thoroughly before going to bed, or by both 
means combined. 

Cardiac excitement may be lessened by sedatives, one of 
the most useful of which is cold. After hours of weary tossing 
sleep may sometimes be induced by walking about in a night- 
dress until cool, or by sponging the surface either with cold or 
hot water. 

The chief hypnotics or soporifics are — 

Opium. Hypnone. 

. Morphine. Bromide of potassium. 

Chloral-hydrate. Bromide of sodium. 
Butyl-chloral-hydrate (croton- Bromide of calcium. 

chloral) . Bromide of zinc. 

Hyoscyamus. Monobromo-camphor. 

Cannabis. Hop. 

Paraldehyde. Lettuce. 

Urethane. Lactic acid. 

The most powerful hypnotics that we possess are undoubtedly 
opium and morphine, and they seem to act by depressing the 
functional activity of the brain itself, although along with this 
depression an anaemic condition of the organ sets in. Besides 
their action in producing sleep, even in health opium and mor- 
phine have the power of lessening pain and thus removing the 
effect which painful stimuli have in maintaining a wakeful con- 
dition.. Bromide of potassium and bromide of ammonium in 
large doses have also a hypnotic action, and even in smaller 
doses, when they would not of themselves produce sleep, they 
appear to lessen cerebral excitement, and allow sleep to come on 
when other conditions are favourable. Chloral probably causes 
sleep both by acting on the brain itself and by causing dilatation 
of the vessels generally. It is therefore a useful hypnotic in 
persons suffering from Bright 's disease, in which there is high 
tension of the vessels and consequently a tendency to sleeplessness. 

A combination of hypnotics sometimes answers much better 
than any one singly. Thus morphine or opium alone some- 
times simply cause excitement ; but when chloral is given, either 
along with, or after them, the excitement is quieted and sleep 
occurs. 

A combination also of small quantities, such as five or ten 
minims, of solution of opium or morphine with five grains of 
chloral and ten to thirty of bromide of potassium, is sometimes 
more useful than any one of the three used alone. 

Indian hemp also is sometimes used to procure sleep, and 



200 THAKMACOLOGY AND THEEAPEUTICS. [sect. I; 

lettuce and lactucarium are also said to have a hypnotic action. 
Lettuce certainly does seem to have such an action, hut how 
much of it depends upon the juice and how much upon the 
mechanical effect of the indigestible fibres of the lettuce upon 
the stomach, in drawing blood to it, it would be hard to say. 
Hops are said to be hypnotic, and their combination with lettuce 
in the form of a supper consisting chiefly of beer and salad has 
sometimes a very marked soporific action. 

Narcotics. 

Narcotics are substances which lessen our relationships with 
the external world. They are closely related, as I have already 
stated, to stimulants ; and alcohol in the various stages of its 
action affords us a good example of both stimulant and narcotic 
action. Alcohol at first excites the cerebral circulation and then 
begins to paralyse various parts of the brain in the inverse order 
of their development. 

But this order differs in different individuals ; for in watching 
the growth of children we find that the order of development of 
the nerve-centres in them is not always the same : some talking 
before they can walk, and others walking before they can talk. 
In all, however, the powers of judgment and self-restraint are 
among the last to be completely developed. 

While the circulation of the brain is still active, the restrain- 
ing or depressing effect of present external circumstances, and 
the restraining effect of training, during previous life, which are 
stored up as it were in the inhibitory centres, are lessened. The 
fancy is thus allowed free play and a condition of joyousness and 
volubility like that of a child occurs. The imagination and 
memory fail next in some, while the emotions become prominent, 
and to this follows paralysis or paresis of the power of co-ordina- 
tion. In others the power of co-ordination is impaired before 
the mental faculties are much affected, the speech becomes thick 
and the walking becomes staggering and uncertain. At this 
stage reflex action still persists, but afterwards it is diminished, 
then abolished, and finally paralysis of the respiratory centre 
occurs. The effect of other drugs, such as ether and chloroform, 
is much the same as that of alcohol. 

In the case of opium and Indian hemp, however, there is but 
little excitement of the circulation, and their effects appear to be 
due more to alterations in the relative functions of the different 
parts of the brain. 

Belladonna, hyoscyamus, stramonium, and their allies, have 
a curious effect. They produce delirium of an active character, 
the patient having a constant desire to speak, move about, or be 
doing something, while at the same time he feels great languor. 
It is probable that this effect is due to the combined stimulant 



chap, viii.] ACTION OF DKUGS ON THE BKAIN. 



201 



action of these drugs on the nerve-centres in the brain and 
spinal cord and their paralysing action on tjie peripheral ends of, 
motor nerves. 

Anodynes or Analgesics. 

Anodynes are remedies which relieve pain by lessening the 
excitability of nerves or of nerve-centres. They are divided into 
local or general : — 

Local Anodynes. General Anodynes. 



Anaesthetics in small doses. 

Atropine. 

Belladonna. 

Butyl-chloral. 

Chloral. 

Conium. 

Coniine. 

Gelsemium. 

Hyoscyamus. 

Hyoscyamine. 

Lupulus. 

Lupulin. 

Morphine. 

Opium. 

Stramonium. 



Cold- 
Cold water. 
Ice-bags. 

Warmth — 
Poultices. 
Fomentations. 

Aconite. 

Acupuncture. 

Atropine. 

Belladonna. 

Blood-letting — 
Leeches. 
Cupping. 

Carbolic acid. 

Carbonic acid. 

Cocaine. 

Conium. 

Creasote. 

Gelsemium. 

Hydrocyanic acid. 

Morphine. 

Opium. 

Veratrine. 

Action. — The sensation of pain is due to a change in some 
part of the cerebrum, and is usually excited by injury to some 
part of the body. 

According to Ferrier the hippocampal region is the seat of 
sensation. Pain may be of central origin ; for if these convo- 
lutions should from any cause undergo changes similar to what 
.usually take place in them on the application of a painful 
stimulus to a nerve, pain will be felt, even although no injury 
whatever has been done to the body. Something of this sort 
appears to occur in certain cases of hysteria. 

Conversely, if the changes which ordinarily occur in these 
.convolutions on severe irritation of a sensory nerve are prevented 
from taking place, pain will not be felt, however great the 
stimulus to the nerve may be. 

The sensory nerves of the head pass directly to the brain, but 



202 PHAEMACOLOGY AND THERAPEUTICS. [sect. x. 

all other sensory nerves have to pass fora greater or less distance 
along the spinal cord before they reach the brain. 

The transmission of painful impressions along the spinal cord 
occurs in the grey matter, and the effect of . anaesthetics in pre- 
venting the transmission of painful impressions while tactile 
stimuli are still' conducted has been already discussed, 
i • Pain may be occasioned by irritation applied to nerves any* 
where between the brain and the periphery ; and whatever its 
point of application may be, it is usually referred to the 
peripheral distribution of the nerve. Sometimes irritation 
of a nerve, instead of being referred by the brain to the proper 
spot, is referred to a branch of the same nerve going to a 
different point. 

Pain may be caused by violent stimulation of the peripheral 
distribution of a nerve, of its trunk, of the spinal cord through 
which the fibres pass to the brain, or of the encephalic centres 
themselves. 

Pain may be relieved by (a) removing the source of irritation, 
(b) by preventing the irritation from affecting the cerebrum. 
Thus, if necrosis of the jaw should give rise to intense pain, the 
pain will at once cease on dividing the sensory nerve by which 
the impulses are transmitted to the brain. It may be relieved, 
also, while the source of irritation still remains, by lessening the 
excitability of the peripheral terminations of the sensory nerves 
which receive the painful impression ; or of the nerve-trunks ; or 
of the spinal cord along which the impression travels ; or of the 
cerebral centres in which it is perceived. 

Opium probably acts on them all, diminishing the excitability 
of the cerebral centre, of the spinal cord, and of the sensory 
nerves ; and bromide of potassium is also supposed to affect all 
these structures, though to a much less degree than opium. 

Chloral, butyl-chloral, lupulin, gelsemium, and cannabis 
indica probably act on the cerebral centres. 

Belladonna and atropine lessen the excitability of the sensory 
nerves, and probably this is effected also by hyoscyamus, stra- 
monium, aconite, aconitine, and veratrine. 

Uses.— It is evident that if the nerve-centre by which pain is 
perceived is deadened, the pain will cease wherever its seat may 
be ; and therefore opium and morphine are used to relieve pain 
Whatever may be its cause. Cannabis indica and bromide of 
potassium, having likewise a central action, may also be em- 
ployed, but they are very much less efficient than opium. 
Chloral and butyl-chloral have an anaesthetic action when given 
in very large doses, but in moderate doses their power to relieve 
pain is not so marked as their hypnotic action. Butyl-chloral, 
however, seems to have a special sedative action on the fifth 
nerve, and so has gelsemium : consequently both of them are 
used in the treatment of facial neuralgia. 



chap, viii.] ACTION OF DRUGS ON THE BRAIN. 203 

As cocaine, belladonna, aconite, and veratrine have a local 
action on the peripheral ends of the sensory nerves, they are 
usually applied directly to the painful part in the form of lotion, 
ointment, liniment, or plaster. Local injections of cocaine, mor- 
phine, atropine, or ; ether, in the neighbourhood of the painful 
part, are often of the greatest service. 

Adjuncts to Anodynes.— As pain depends on the condition 
of the cerebral centre by which it is perceived, as well as on 
irritation of sensory nerves, it is obvious that it may vary with 
the condition of these centres, although the irritation remains. 
Thus a decayed tooth does not always cause toothache, and when 
the toothache comes on, it may frequently be removed by means 
of a brisk purgative, even although the tooth be not extracted. 
It is possible that the purgative may act partly by lessening con- 
gestion around the tooth, but partly.also by altering the condition 
of the cerebral centres. When the attention is fixed upon other 
things, also, the pain may be to a great extent, or even com- 
pletely, abolished, as in mesmerism or hypnotism. The sensory 
stimuli, also, which would usually produce pain may be diverted 
voluntarily or involuntarily into motor channels. Thus, during 
the heat of action, the pain of a wound is not felt ; and the pain 
felt during the extraction of a tooth is lessened by the employ- 
ment of violent muscular effort, as in grasping the arms of the 
dentist's chair. Other most powerful adjuncts are electricity 
applied along the course of , the nerves, and counter-irritation, 
especially by means of the actual cautery to the painful part, 
and, when other means fail, stretching the nerve may succeed. 

Cold also, applied to the surface over a painful part, will 
relieve pain, and so may dry heat, applied by a sand-bag or hot 
cloth, or moist heat in the form of a poultice ; for the mode of 
action of these vide ' Action of Iebitants.' 

Pain has been ascribed by Mortimer Granville to vibrations 
of nerves or of the sheaths; and, in order to lessen it, he pro- 
poses to produce vibrations of a different nature : this he does by 
percussing over the painful nerve with a small hammer, worked 
either by clockwork or electricity. For a dull heavy pain he 
uses quick and short vibrations of the hammer, and for a sharp 
lancinating pain he uses large and slow vibrations. 

Anaesthetics. 

Anaesthetics are remedies which destroy sensation. 

It has already been mentioned that both sensation and pain 
require for their perception a certain condition of the cerebral 
centres and of the sensory nerves and spinal cord, by which 
impressions are conveyed to these centres. 

The difference between anaesthetics and anodynes is to a great 
extent one of degree. Anodynes affect more particularly the 



204 PHAKMACOLOGY AND THEBAPEUTICS. , [sect. i. 

cerebral centres by which pain is perceived, or the conducting 
paths by .which painful impressions are transmitted, and thus 
in moderate doses lessen pain without destroying reflex action. 
They only affect the ordinary centres for reflex action when the 
dose is considerably increased. Anaesthetics, on the other handi 
affect the cerebral and spinal centres more equally, and so abolish 
pain, ordinary sensation, and reflex excitability more nearly at 
the same time, though their abolition is by no means completely 
simultaneous. 

According to Eulenberg, in chloroform-narcosis the patellar 
reflex is abolished first, then reflex from the skin, then from the 
conjunctiva, and lastly from the nose. As the anaesthesia passes 
off they return in the inverse order, patellar reflex being the last 
to reappear. A stage of excitement generally precedes the dis- 
appearance of patellar reflex, both in man and animals. 

Narcosis by ether differs from that of chloroform in the much 
greater increase of patellar and other tendon reflexes, both in 
extent and duration. 

Chloral hydrate and potassium bromide have an action like 
chloroform, but much weaker. Like chloroform, they paralyse the 
patellar reflex before the corneal reflex, but butyl-chloral (croton- 
chloral) paralyses the corneal reflex before the patellar. 

In ordinary sleep, reflexes disappear in the same order as in 
chloroform narcosis, but in mesmeric sleep the reflexes are in- 
creased as in narcosis from ether. In hysterical conditions 
diminution of the cerebral reflexes from the nose and cornea 
with persistence of the patellar reflex has been observed. 

The reflex power of the vaso-motor centre is very quickly 
paralysed by chloroform, so that irritation of a sensory nerve 
will no longer raise the blood-pressure. Its reflex power is much 
less affected by ether. 1 

Anaesthetics may be divided into local and general. The 
local are those which abolish the sensibility of the peripheral 
nerves of a particular area. The general are those which act 
on the central nervous system in the way already described, and 
abolish sensation throughout the whole body. 

The chief local anaesthetics are cold, cocaine, carbolic acid, 
iodoform. 

For the purpose of producing local anaesthesia, cold is generally 
applied by means of ether spray, until the part is all but frozen 
and is insensible, when slight operations may be made without 
the patient feeling any pain. The ether may perhaps have itself 
a certain amount of physiological effect in diminishing sensibility 
when applied in this manner. Carbolic acid painted over the sur- 
face also causes it to become white and to lose its sensibility, and 
may thus be used to lessen the pain of opening an abscess. 



* H. P. Bowditoh and C. S. Minot, Boston Med. and Swg. Journ., May 21, 1874. 



chap, vin,] ACTION OF DEUGS ON THE BRAIN. 205 

General anaesthetics are- 
Nitrous oxide. Trichlorhydrin. 
Ether. Bi-chloride of methylene. 
Chloroform. Paraldehyde. 
Bromoform. Bi-chloride of ethidene. 
Tetrachloride of carbon. Bromide of ethyl. 

With the exception of nitrous oxide they all belong to the 
class of alcohols and ethers, and the substitution-compounds 
having an anaesthetic action are probably almost indefinite in 
number. Even alcohol itself produces general, anaesthesia when 
volatilised and inhaled. 

General Anaesthetics may destroy the sensibility of the 
nerve-centres indirectly or directly. Anaesthesia is induced in- 
directly by stopping the circulation in the brain and thus arrest- 
ing the process of oxidation and tissue-change in the nerve-cells 
which are necessary for their functional activity. 

This result may be produced by draining the blood from the 
head into other parts of the body. Thus in some of the hospitals 
at Paris, before anaesthetics were introduced, a plan was some- 
times employed of rendering a patient insensible before an opera- 
tion, by laying him flat on the ground, and then lifting him 
very suddenly to a standing' posture by the united efforts of six 
or eight men (c/. pp. 193, 198). 

Local arrest of the circulation to the brain by ligatures or by 
compression of the arteries has a similar effect. Waller has 
recommended diminution of the cerebral circulation, by the 
combined effects of simultaneous pressure on the carotid arteries 
and vagus nerves, as an easy means of producing anaesthesia for 
short operations. 

Slight anaesthesia, usually accompanied by some giddiness, 
may be produced by taking a number of deep breaths in rapid 
succession. This may be used . in order to lessen the irritability 
of the pharynx in laryngoscopy examinations, and to lessen the 
pain of opening boils or abscesses. The anaesthesia thus pro-, 
duced may perhaps depend on anaemia of the brain, although 
this is not certain. 

Anaesthesia may also be produced by diminishing the internal 
respiration of the nerve-cells through a gradually increasing 
venous condition of the blood. Thus gradual suffocation by 
charcoal fumes or carbon monoxide causes complete insensibility, 
and the inhalation of nitrogen and of nitrous oxide has a similar 
action. 

Anaesthesia may be caused by the direct action of drugs on 
the nerve-cells themselves. Chloroform, ether, and other allied 
substances belonging to the alcohol series appear to act in this' 
way. Although their action is generally exerted through the 
blood by which they are conveyed to the brain when inhaled, yet 



206 PHARMACOLOGY AND THERAPEUTICS. [sect: i.> 

they will also produce a similar action if locally applied to the 
nerve-centres. Thus Prevost 1 found that chloroform applied 
directly to the brain of a frog narcotises it when the aorta is tied- 
When the aorta is again unligatured, so that the current of blood 
can again wash the chloroform away, the narcosis disappears. 
Chloroform and ether when inhaled appear to act. like alcohol, 
producing paralysis of the nerve-centres, commencing with the 
highest and proceeding downwards. The rate of paralysis, though 
the same in order, is more rapid than that caused by alcohol. 

These anaesthetics are, however, not nerve-poisons only ; they 
are protoplasmic poisons affecting simple organisms, such as 
amoebae and leucocytes, and destroying also the irritability of 

muscular fibre. 

This action of anaesthetics and especially that of chloroform 
upon muscular fibre is one of considerable importance in reference 
to the occasional stoppage of the heart and consequent death 
during the administration of anaesthetics. 

The action of anaesthetics may be divided into four 
stages : — 

1st. The stimulant stage. 

2nd. The narcotic and anodyne stage. 

3rd. Anaesthetic stage. 

4th. Paralytic stage. 

Stimulant Stage.— Chloroform and ether, as already men- 
tioned, resemble alcohol in their action, and, like it, in small, 
doses will produce a condition of stimulation and acceleration of 
the circulation passing gradually into one of narcosis, in which, 
the action of the higher nervous centres is more or less abolished, 
while that of the lower centres still remains. 

In small quantities chloroform and ether are sometimes taken, 
either internally or by inhalation, for their stimulant effect. They 
are useful in lessening pain and spasm, as in neuralgia, and 
biliary, renal, or intestinal colic, when given till the stimulant is 
just passing into the narcotic stage. 

Narcotic Stage. — When pushed still further, sensibility 
becomes more impaired, reflex action still continues, and some- 
times, just as in drunkenness, there is a form of wild delirium 
and great excitement. This is much less marked in feeble or 
debilitated persons than in strong men. In the latter, the 
struggles which occur in this condition are sometimes exceed- 
ingly violent, the patient raising himself forcibly from the couch, 
his muscles being in a state of violent contraction, the face livid, 
the veins turgid, and eyeballs protruding. Usually this condition 
quickly subsides and passes into the third stage — that of complete- 
anaesthesia. ; 

1 Prevost, Practitioner July 1881. ■ 



cHAP.vii.] ACTION OF DEUGS ON THE BEAIN. 207 

In order to lessen the pains of labour, anaesthesia is usually 
carried to the commencement of the second stage. 

Anaesthetic Stage.— The third stage diners from the second 
in the function of the spinal cord being abolished, as well as those 
of the brain ; ordinary reflex is consequently abolished, and the 
most common way of ascertaining whether this stage has set in' 
or not is by drawing up the eyelid and touching the conjunctiva. 
If no reflex contraction of the eyelid occurs, the anaesthesia is 
complete. By careful and judicious administration of the anaes- 
thetic this condition may be kept up for a length of time even 
for hours, or days ; but if the inhalation be carried too far, the 
anaesthetic passes into the fourth stage. 

The third stage is the one employed for surgical operations. 

Paralytic Stage. — In the fourth the respiratory centre 
becomes paralysed, respiration ceases, and the beats of the heart 
become feebler and may cease altogether. 



Uses of Anaesthetics. 

Anaesthetics are used not only to lessen pain but to relax 
muscular action and spasm. They are chiefly employed to lessen 
pain in surgical operations, in labour, and in biliary and renal colic. 
They are used to lessen muscular action and spasm in tetanus, 
in poisoning by strychnine, in hydrophobia, and in the reduction 
of dislocations, fractures, and hernia. They are also of assistance 
in diagnosis, by allowing careful examination to be made of parts 
which are too tender or painful to be examined without it, and 
by causing the phantom tumours due to spasmodic contraction 
of the muscles to disappear. 

Dangers of Anaesthetics. — (1) One danger is that just men- 
tioned, of paralysis of the respiration from an overdose. This, 
however, is one of the least of the dangers, and if the enfeeble- 
ment of the respiration be observed in time, it is generally pos- 
sible to save the patient by stopping inhalation, and keeping up 
artificial respiration for a little while if necessary. 

(2) Another danger is from paralysis of the heart by a too, 
concentrated chloroform vapour. This is indicated by a sudden 
stoppage of the heart, paleness of the face, and dilatation of the 
pupil while the respiration may continue. 

If this accident should occur, the body of the patient should 
be inclined so that the head should be lower than the feet, and, 
artificial respiration should be kept up briskly but regularly, the 
expiratory movements being made by pressure on the thorax and 
especially over the cardiac region, so that the mechanical pressure; 
should stimulate the heart, if possible, to renewed action. The. 
vapour of nitrite of amyl may also be administered by holding a 
piece of blotting-paper or cloth on which a few drops have been 
sprinkled before the nose, while artificial respiration is kept up. 



208 PHARMACOLOGY AND THERAPEUTICS. [sect. t. 

The inspiratory movements may be made by crawing the arms 
backwards over the head, as in Sylvester's plan. 

(3) A third danger arises from stoppage of the heart by a 
combination of chloroform-narcosis and shock. This is one of 
the most dangerous conditions. It may occur even during full 
chloroform-narcosis in animals from operations on the stomach ; 
but it is much more common in men from imperfect anaesthesia. 
In very many cases of so-called death from chloroform during 
operations, we find it noted as a matter of surprise that death 
should have occurred as the quantity of chloroform given was so 
small. The reason that death occurred probably was because 
the quantity of chloroform given was so small. Had the patient 
been completely anaesthetised, the risk would have been very much 
less. The reason why imperfect anaesthesia is so dangerous is, 
that chloroform does not paralyse all the reflexes at the same 
time. A very large proportion of the deaths from chloroform 
occur during the extraction of teeth, and we may take this 
operation as a typical one in regard to the mode of action, both 
of the sensory irritation and of the chloroform. When a tooth is 
extracted in a waking person, the irritation of the sensory nerve 
produced by the operation has two effects : — 1st, it may, acting 
reflexly through the vagus, cause stoppage of the heart and a 
consequent tendency to syncope. 2nd, it causes reflex contrac- 
tion of the arterioles, which tends to raise the blood-pressure and 
counteract any tendency to syncope which the action of the 
vagus might have produced. 

In complete anaesthesia all these reflexes are paralysed, and 
thus irritation of the sensory nerves by the extraction of the 
teeth has no effect either upon the vagus or upon the arterioles. 
In imperfect anaesthesia, however, the reflex centre for the arte- 
rioles may be paralysed {ride p. 204), while the vagus centre is 
still unaffected. The irritation caused by the extraction of the 
tooth may then cause stoppage of the heart, and there being 
nothing to counteract the tendency to faint, syncope occurs and 
may prove fatal. 

With nitrous oxide there is very much less danger, inasmuch 
as the nitrous oxide causes a venous condition of the blood, with 
consequent contraction of the arterioles and rise in the blood- 
pressure, so that any tendency to syncope through vagus-irrita- 
tion is efficiently counteracted. 

With ether, also, the danger is very much less, probably be- 
cause it has a more equal effect on the centres (vide p. 204) . 

(4) Another danger is that of suffocation from blood passing 
into the trachea in operations about the mouth or nose, or from 
the contents of the stomach being drawn into the larynx when 
vomiting has occurred during partial anaesthesia. In consequence 
of this, it is better, instead of giving chloroform or ether during 
the whole of an operation on the mouth or nose, to give it 



chap, vni.] ACTION OF DEUGS ON THE BEAIN. 209 

only at the commencement, and to administer along with it, or 
before it, a hypodermic injection of one-sixth to one-third of a 
grain of morphine. The chloroform anaesthesia thus passes into 
the morphine narcosis, and the operation can be finished without 
pain, and without danger. 

To prevent the occurrence of vomiting, it is advisable not to 
give solid food for some hours before an operation, though if 
necessary a little beef-tea or stimulant may be given half an hour 
or so before the administration of the anassthetic. 

Mode of administering Anaesthetics. — In order to obtain 
the first stages of the action of anaesthetics, as in cases of in- 
testinal, biliary, or renal colic, intense neuralgia, or in parturition, 
the best means of administration is one for the account of which 
I am indebted to Mr. W. J. Image, of Bury St. Edmunds. It 
consists of a tumbler, at the bottom of which is placed a piece of 
blotting-paper or linen thoroughly wetted with chloroform or 
ether. The patient holds the tumbler to the nose with his, or 
her, own hand. On account of the form of the tumbler, sufficient 
air always gets in at the sides, and the patient cannot inhale the 
vapour in too concentrated a condition. As soon as the anaes- 
thetic begins to take effect, the hand drops, and the inhalation 
ceases. As the effect again passes off, the patient resumes the 
inhalation. In employing anaesthetics in this way, however, 
great care must be taken that the bottle containing the chloro- 
form is never entrusted to the patient, but is always kept on a 
table at some little distance from the bed, and that the blotting- 
paper or lint in the tumbler is supplied with fresh chloroform by 
an attendant. If the bottle itself be entrusted to the patient, 
as the anaesthetic takes effect and produces stupidity, the stopper 
may fall out, the whole contents of the bottle may be sucked up 
by the pillow, bolster, bed, or bedclothes, and the vapour being 
inhaled, fatal suffocation may ensue. 

Another method of administering chloroform, which is very 
convenient when complete anaesthesia is required for a length of 
time, and when the supply of chloroform is limited, was devised 
by Sir James Simpson: it consists of either a cup-shaped in- 
haler, formed of a wire framework covered with flannel, or else 
simply of a single fold of a pocket-handkerchief thrown over the 
face : the chloroform is dropped upon the flannel or handkerchief 
just under the nostrils in single drops at a time. Another plan 
is to pour some chloroform on to a folded towel or pocket-hand- 
kerchief, and then place it over the patient's face, taking care 
that it does not come so close over the nose as to interfere with a 
free admixture of air with the chloroform vapour. There is this 
difference between ether and chloroform, that whereas it is highly 
inadvisable to give chloroform vapour in a concentrated condi- 
tion, it is requisite to give the ether vapour very strong, in order 
to produce an anaesthetic effect. A combined administration of 



210 PHAEMACOLOGY AND THEEAPEUTICS. [sect, l 

nitrous oxide and ether is now used to a considerable extent : 
the nitrous oxide producing rapid anesthesia, which is kept up 
by the ether. 

Anaesthesia in Animals. 

In the course of many investigations into the action of druga 
on animals it is necessary to perform experiments which would 
be painful unless the animals were anaesthetised. The easiest 
way of doing this with frogs or small animals, such as mice, rats, 
or rabbits, is to put them under a bell-jar with an opening at the 
top. Into this opening a piece of cotton-wool or blotting-paper is 
put, and chloroform dropped on it. The vapour being heavier 
t;han air falls to the bottom, and the animal soon becomes in- 
sensible. The best way of anaesthetising cats, small dogs, or very 
large rabbits, is to put them into a wooden box or tin pail, and 
stretch a towel tightly over the top. An assistant then pours 
some chloroform on the towel and anaesthesia is quickly pro- 
duced. Eats are most readily anaesthetised by completely cover- 
ing the cage, in which they are, with a towel, and dropping 
chloroform upon it. 

Babbits may be very quickly anaesthetised by the plan em- 
ployed by Pasteur. It consists in putting a piece of cloth or 
blotting-paper soaked in chloroform round the animal's nose so 
as to exclude air. At once the rabbit ceases to breathe, and re- 
mains without breathing for about a minute. It then begins 
to struggle, and if the anaesthetic be kept closely applied the 
respiratory movements shortly become steady and regular and 
the animal completely insensible. 

For very large or savage dogs an old packing-case without a 
lid may be simply placed over the animal and held firmly down, 
or one of the sides may be furnished with hinges so as to convert 
the case into a sort of kennel. After the dog is safely housed 
large pieces of blotting-paper or of cloth on which chloroform is 
pourea are pushed through cracks in the top of the case or holes 
specially made for the purpose. The outer ends of the blotting- 
paper or cloth remaining outside, fresh quantities of chloroform 
can be introduced as required until complete anaesthesia is pro- 
duced. Anaesthesia may be maintained for almost any length of 
time that is required, by putting a piece of cloth loosely round 
the animal's nose and dropping chloroform upon it. This re- 
quires careful attention, however, in order to prevent danger from 
an overdose on the one hand, or partial recovery on the other. 
I find the most convenient way of maintaining the anaesthesia 
induced by chloroform in the way already mentioned is to put a 
cannula in the trachea and connect it with a flask containing ether, 
so that the inspired air passes over the surface of the ether, and 
carries a quantity of the vapour with it into the lungs of the 



chap, viii.] ACTION OP DEUGS ON THE BRAIN. 211 

animal.^ By means of a peculiar stopcock, the construction of 
which is indicated in the diagram (Fig. 73), pure air or air 
loaded with ether vapour or a mixture of both may be given. 

The advantages of employing this method and of using ether 
rather than chloroform are that complete anaesthesia may be kept 




Flo. 73. — Diagram of a stopcock by which air or vapour, or two kinds of gas, may be given 
alone, or mixed together in any proportion. 

up for hours together with little or no attention on the part of 
the operator, and without the respiration or blood-pressure being 
seriously affected by the anaesthetic. 

Another plan of maintaining anaesthesia for a length of time 
is to inject some laudanum or liquid extract of opium into a vein 
after anaesthesia has been induced by chloroform. Before the 
effect of the chloroform has passed off, such complete narcosis is 
produced by the opium that no procedure, however painful it 
might otherwise be, will produce the slightest evidence of sensa- 
tion. "When the effect of the anaesthetic or of the opium would 
interfere with the investigation of the action of a drug on the 
circulation or reflex action, the animal may be anaesthetised by 
chloroform, and the crura cerebri divided. The channels by 
which painful impressions are conveyed to the brain being thus 
destroyed no pain can be felt, although the reflex action of the cord 
again returns after the effects of the chloroform have passed off. 

History of the Discovery of Anesthesia. 

This is a subject of considerable interest, and has given rise 
to much discussion. The starting-point of the discovery seems 
to have been Sir Humphry Davy's observations on the pro- 
perties of nitrous oxide, regarding which he said, ' as nitrous 
oxide in its extensive operation seems capable of destroying 
physical pain, it may probably be used with advantage during 
surgical operations.' The property of this gas and also of ether 
vapour to produce excitement when inhaled, caused these sub- 
stances to be used in sport, and during their action bruises 
were frequently received, but not felt. This circumstance excited 
the attention of Dr. Crawford W. Long, of Athens, Georgia, and, 
in 1842, he anaesthetised a patient with ether in order to re- 
move a tumour. He was encouraged to do this by the fact that 
Dr. Wilhite, in a frolic, had rendered a negro boy completely 
insensible without any bad results. Mr. Horace Wells, without 

p 2 



212 PHARMACOLOGY AND THEEAPEUTICS. [sect. i. 

knowing what Dr. Long had done, used nitrous oxide as an 
anesthetic in 1844. His pupil, Mr. Morton, wishing to use it 
also, asked him how to make it, and was referred to a scientific 
chemist, Dr. Jackson. Jackson advised Morton to use sulphuric 
ether, a's it had similar properties to nitrous oxide and was easier 
to get. Acting on this suggestion Morton used ether in dentistry, 
and induced Drs. Warren, Haywood, and Bigelow to perform 
important surgical operations on patients whom he anaesthetised 
by it. From this time onwards anaesthesia has been regularly 
used in medical operations. Shortly afterwards, Sir J. Y. Simp- 
son discovered the use of chloroform as an anaesthetic, and it has 
been chiefly employed in Great Britain, but in America ether has 
always retained its original place. 

Antispasmodics. 

These are remedies which prevent or relieve spasm. 

Spasm is contraction of voluntary or involuntary muscles, 
in a way that is unnecessary or injurious to the organism 
generally. The spasmodic contraction of muscles may sometimes 
be excessive in degree, as in the calves of the legs in cramp, or 
in the fibres of the intestinal walls in colic. Sometimes it is not 
excessive in degree, but are merely out of place, as, for example, 
in the slight twitchings of the face or fingers which occur in mild 
cases of chorea. 

Spasm may affect single muscles, or it may affect groups of 
muscles and the nerve-centres by which they are set in action 5 
these centres may sometimes be very limited in extent, but some- 
times a great number, or indeed most of the motor centres in 
the body, may be involved, as in the convulsions of hysteria. 
Spasm is, indeed, a kind of insubordination in which the 
individual muscles or nerve-centres act for themselves without 
reference to those higher centres which ought to co-ordinate their 
action for the general good of the organism. It may be due, there- 
fore, either to excess of action in the muscles or local centres, or 
diminished power of the higher co-ordinating centres. As a rule 
it is due to diminished action of the co-ordinating or inhibitory 
centres, rather than to excess of action in the motor centres ; it is, 
therefore, a disease rather of debility and deficient co-ordination 
than of excessive strength. 

Cramps in the muscles may come on from their exhaustion by 
excessive exertion, the waste products of their functional activity 
appearing to act as local irritants. This is relieved by the removal 
of these waste products ; as, for example, by shampooing. In the 
intestine, cramp may be due to the presence of a local irritant, 
which ought' in the normal condition to produce increased 
peristalsis, and thus ensure the speedy removal of the offending 
substance. From some abnormal condition the muscular fibres 



chap, vin.] ACTION OF DRUGS ON THE BRAIN. 213 

around the irritant contract excessively, and do not pass on the 
stimulus to those adjoining. Prom this want of co-ordination 
painful and useless spasm occurs. In order to remove it we apply 
warmth to the abdomen so as to increase the functional activity, 
both of the muscular fibres and of the ganglia of the intestine 
(pp. 138, 140). Peristalsis then occurring instead of cramp, the 
pain disappears, and the offending body is passed onwards and 
removed. Or we give internally aromatic oils, which will have a 
tendency to increase the regular peristalsis ; or yet again, we 
may give opium for the purpose of lessening the sensibility of 
the irritated part, or the nerves connected with it, and thus again 
bringing it into relationship with other parts of the body. 
General antispasmodics may act either 

(1) By increasing the power of the higher nervous centres 
to keep the lower ones and the muscles in proper subordina- 
tion, or — 

(2) By lessening the activity of over-excited muscles or lower 
nervous centres. 

On this account we find stimulants and antispasmodics very 
much classed together. Those drugs which stimulate the 
circulation and increase the nutrition of the higher nerve-centres 
and the co-ordinating power, tend to prevent spasm. Thus, 
small quantities of alcohol and ether, by acting in this way, tend 
to prevent general spasm, as in hysteria, nervous agitation, or 
trembling, or remove local spasm, as in colic. 

Camphor, which is frequently used as an antispasmodic, has 
a stimulant action on the brain, spinal cord, circulation, and 
respiration. It is probable that such antispasmodic powers as 
it possesses are due to its exciting the higher centres, and in- 
creasing their inhibitory powers over the lower (p. 214). Bromo- 
camphor has a somewhat similar action. 

Valerian, asafoetida, musk, castor, and other aromatic sub- 
stances, have an antispasmodic action which we do not under- 
stand. It is possible that they affect some part of the brain 
particularly, so as to increase its regulating power, in much the 
same way as camphor. 

Other antispasmodics, such as bromide of potassium, lessen 
the irritability of motor centres. Borneol and menthol have a 
depressing and finally paralysing effect upon motor, sensory, and 
reflex centres in the brain and spinal cord. In this respect they 
differ greatly from ordinary camphor, which has an exciting 
action upon these structures, though they may perhaps be still 
more useful as antispasmodics. 

Other antispasmodics, instead of lessening the irritability of 
nerve-centres, may paralyse the structures through which the 
nerves act. Thus, nitrite of amyl appears to arrest the spasm of 
the vessels in angina pectoris, by causing paralysis of the vessels 
themselves or of the peripheral ends of the vaso-motor nerves. 



214 



PHAEMACOLOGY AND THEEAPEUTICS. [sect. t. 



Adjuvants. — As spasm is usually an indication of deficient 
nervous power, tonics, as quinine, iron, cod-liver oil, arsenic, 
sulphur, cold baths, and moderate exercise, are useful as adju- 
vants. 

It has already been mentioned, that a healthy condition of 
the various parts of the body depends on proper nutrition and 
proper removal of waste. Therefore, when there is a tendency 
to spasm, the diet should be plain, but nutritious. Those condi- 
tions which tend to cause excessive waste should be avoided, such 
as exciting emotions, excessive bodily or mental work, a close 
atmosphere, and late hours. Attention must be paid also to the 
proper removal of all waste, by the use of purgatives, cholagogues, 
or diuretics if necessary. 

Great irritability of the nervous system is usually observed 
in gouty subjects before an attack of gout comes on. It is uncer- 
tain to what this irritability is due, but it may not improbably be 
caused by the retention within the body of the products of tissue- 
waste. Some years ago there was considerable discussion regard- 
ing the active ingredient of bromide of potassium, some attribut- 
ing its antispasmodic action to the bromine, and others to the 
potassium. It occurred to me that possibly its action might be 
partly due simply to its action as a saline leading the patient 
to drink more water, and thus assisting the elimination of the 
products of tissue-waste. I accordingly tried 30-grain doses of 
chloride of sodium in cases of epilepsy. In some it did little or 
no good, but in a few it appeared to have nearly as powerful an 
action as bromide of potassium. 

Uses. — Antispasmodics are used in convulsive diseases. 

The antispasmodics used in hysteria may be divided into 
substances which exert on the higher nerve-centres a sedative, 
tonic, or stimulant action, thus : 



I. Sedatives 



. Alkaline bromides. 
Zinc salts. 



Castor . 

Sumbul . 
► Valerian . 

Asafoetida 
Ammoniac um 
Galbanum 



Derived from the genital organs of 

animals. 
Similar in the nature of their odour 

to the above, though derived from 

plants. 

I Containing sulphur oils. 



II. Tonics 
III. Stimulants, 
whichhaveapower-\ Musk 
ful odour, and pro- 
bably act on the 
higher centres 

through the olfac- 
tory organs, either 
by direct applica- 
tion or during their^ 
elimination (p. 41). 

In epilepsy, laryngismus stridulus, and infantile convulsions, 
bromides of potassium, sodium, ammonium, and calcium, nitrite 
of sodium, salts of silver, zinc, and copper. 

In chorea, arsenic, conium, the salts of copper and zinc. 

In spasmodic asthma, lobelia, stramonium. 

In spasm of the blood-vessels, nitrite of amyl and other 
itrites. 



chap, viii.] ACTION OP DKUGS ON THE BEAIN. 215 



Action of Drugs on the Cerebellum. 

The chief function of the cerebellum appears to be the main- 
tenance of equilibrium. Symmetrical lesions on both sides of the 
organ or division of it down the centre from before backwards, 
cause very little disturbance of the equilibrium, but when a lesion 
is unsymmetrical the equilibrium is disordered. 

According to Ferrier, if the lesion affects the whole of a lateral 
lobe, there is a tendency for the animal to roll over towards the 
affected side. In an animal standing on all fours or lying on the 
ground, we regard the centre of the back as the point of move- 
ment, but in a man standing upright we usually take the face, and 
therefore what we should regard in an animal as rolling towards 
the affected side, would be equivalent hi man to a rotation 
towards the sound side. If the lesion is limited to one part of 
the lateral lobe, it may not cause rotation, but only falling to- 
wards the opposite side. When the anterior part of the middle 
lobe of the cerebellum is injured, the animal tends to fall forward, 
and in walking usually stumbles, or falls on its face. When the 
posterior part of the middle lobe of the cerebellum is injured, the 
head is drawn backwards and there is a continual tendency to 
fall backwards when moving.' 

Injuries of the cerebellum are frequently associated with a 
certain amount of nystagmus, and in all probability the com- 
plete or partial inability to walk or stand which alcohol produces, 
is due to its action on the cerebellum. 

Different kinds of spirit appear to have a tendency to affect 
different parts of the cerebellum, for good wine or beer is said to 
make a man fall on his side, whisky, and especially Irish whisky, 
on his face, and cider or perry on his back. 2 These disturbances 
of the equilibrium correspond exactly with those caused by injury 
to the lateral lobes, and to the anterior and posterior part of the 
middle lobe of the cerebellum respectively. Apomorphine in 
large doses appears also to have an action on the cerebellum or 
corpora quadrigemina, as the animal poisoned by it does not 
vomit, but moves round and round in a circle. 

The action of alcohol on frogs is peculiar and differs from 
that of other narcotics, inasmuch as it appears to affect unequally 
the two sides of the nervous apparatus by which the equilibrium 
is maintained, so that in a certain stage of alcohol-poisoning 
they excite similar manege movements to those which occur after 
division of the corpora quadrigemina on one side. 3 

1 Ferrier, Functions of the Brain, p. 94. 

2 Shorthouse, Baily's Magazine of Sports, 1880, vol. xxxv. p. 396. 

s Wilhelm Wundt : Untersuchungen zur Mechanik der Nerven und Nerven- 
centren. Zweite Abtheilung, 1876. Stuttgart. 



216 PHAKMACOLOGY AND THEKAPEUTICS. {sect. 



CHAPTEE IX. 

ACTION OF DBUGS ON THE OEGANS OF SPECIAL SENSE. 

Action of Drugs on the Eye. 

Action on the Conjunctiva. — Before light can reach the 
retina, it has to pass through the cornea, which is covered by 
epithelium continuous with that of the conjunctiva. Alterations 
in either or both of these textures are therefore very important 
in regard to the integrity of vision. The chief drugs employed in 
the local treatment of diseases of the cornea and conjunctiva are 
warmth, moist and dry, anaesthetics, anodynes, antiphlogistics, 
antiseptics, and astringents. The chief astringents are per- 
chloride of mercury, oxide of mercury, and nitrate of silver. The 
chief antiseptics are perehloride of mercury, quinine, boric acid, • 
and sulphocarbolate of sodium. The chief sedatives are hydro- 
cyanic acid, opium, belladonna, atropine, and cocaine. There 
are two astringents in common use which ought to be avoided, 
these are solutions of lead and of alum. Lead salts are objection- 
able, because if there is any ulceration on the cornea they may 
form an insoluble albuminate and cause permanent opacity. 
Salts of alum are said by Tweedy to be perhaps still more objec- 
tionable, because alum has the power of dissolving the cement by 
which the fibrillae of the cornea are held together, and this is 
very apt to give rise to perforation of the cornea whenever the 
epithelium is removed by injury or inflammation. Tweedy also 
thinks that strong solutions of common salt, ten per cent, or 
more, and solution of permanganate of potassium also dissolve 
the corneal cement and should therefore be avoided in inflamma- 
tion of the conjunctiva or of the cornea. He considers that sul- 
phate of zinc should be avoided, for the same reason, but it is 
largely used by others. The best astringent is probably perehloride 
of mercury, -Jjth to -J^-th of a grain to an ounce of water, and 
coloured with cochineal. The next best is an aqueous solution 
of boric acid, containing 3 to 8 grains of it with 3 to 10 grains of 
sulphocarbolate of sodium per ounce. 

The chief effects which drugs produce on the eye, besides 
those just described, are alterations in the size of the pupil, in 



chap, ix.} ACTION OF DEUGS ON SPECIAL SENSE. 217 

the power of accommodation, in the intra-ocular pressure, in the 
sensitiveness of the retina to impressions, and in the apparent 
colour of objects. 

Action of Drugs on the Lacrimal Secretion.— The great 
power of certain volatile oils, such as those of onion or mustard, 
to irritate the eyes and cause secretion of tears is well known. 
The prolonged action of atropine diminishes the secretion. Ese- 
rine abolishes the action of atropine, and quickly increases the 
secretion. 1 

Projection of the Eyeball.— The non-striated muscular fibres 
which are contained in the orbital membrane and in both eyelids 
push the eyeball forward and draw the eyelids back when they 
contract. Like the dilator pupillae they are innervated by the 
sympathetic, and consequently some degree of protrusion of the 
eyeball is frequently produced by such substances as dilate the 
pupil, and especially by cocaine. Excessive pain, or an asphyxial 
condition of the blood, has a powerful action in producing this 
effect, so that in men subjected to torture in the Middle Ages pro- 
trusion of the eyeballs was noticed; and both in animals and men 
dying from rapid asphyxia the eyeballs may seem as if starting 
from the head. 

Action on the Pupil. — The iris is usually said to consist of 
two muscles, the sphincter, which has circular fibres and contracts 
the pupil, and the dilator, which has radial fibres and dilates the 
■ pupil. All observers are agreed regarding the sphincter muscle 
of the eyes, but some deny the existence of the dilator muscle; 
In the following description, however, I shall take the view which 
is usually accepted. 2 

The sphincter receives its motor nervous supply from the 
third nerve, and the dilator from the cervical sympathetic. The 
nervous centre for the contraction of the pupil probably lies in 
the corpora quadrigemina ; the nerve-centre for the dilatation 
of the pupil lies in the medulla oblongata, but there seems to 
be another dilating centre, situated in the floor of the front part of 
the aqueduct of Sylvius. 3 The contracting -nerves are contained 
in the third nerve, and pass to the ciliary ganglion, and thence 
to the, eye. Along with them motor fibres pass also to the ciliary 
muscle. This muscle when contracted lessens the tension of the 
suspensory ligament on the lens, allowing the latter to become 



1 Maynard, Vmshoto's Archiv, vol. lxxxix. p. 258. 

2 At present it is generally assumed that muscular fibres, either voluntary or 
involuntary, contract only in the direction of their length. If we suppose that they 
can contract either in the direction of their length or their width, the movements 
of the iris might be more readily explained. At present we assume the presence 
of a dilator muscle, which is almost certainly absent in many animals, in order to 
explain phenomena which might be explained just as readily by the supposition that 
the muscular fibres which are present can contract in two directions {see p. 117). 

• Foster's Physiology, 4th ed. 



318 PHAEMACOLOGY AND THEEAPEUTICS. [sect, i, 

more spherical, and thus accommodating the eye for near objects, 
Such accommodation and contraction of the pupil generally ac- 
company one another. The arrangement of the nerves of the eye 
is very diagrammatically shown in Fig. 74. A few of the dilating 
fibres are contained in the fifth nerve, but most of them pass 
down the spinal cord to the cilio-spinal region in the lower cervical 
and upper dorsal part of the cord, and thence through the second 
dorsal nerve in monkeys and probably in man, or through the 
inferior cervical and superior dorsal nerves in the rabbit, into 
the cervical sympathetic, in which they again ascend to the eye. 



Ciliary ganglion 

Muscle for accommodation 

Lens 

Sphincter iridis 

Dilator pupil he 

Vesselsofeye 




Nucleus of third nerve. 
Central origin of sympathetic. 

Sympathetic centre in medulla. 
Sympathetic fibres. 



IjlQ. * 4.— uiagram to show the nervous supply of the eye. a, nerves to the ciliary muscle regu- 
lating accommodation ; 6, nerves to the contracting fibres, and c, nerves to the dilating fibres of 
the iris ; d, vaso-motor nerves to the vessels of the eye. The iris is put apparently behind 
instead of in front of the lens for convenience in showing the passage of nerves to it. 



Along with the dilating fibres others pass to supply the orbital 
muscle at the back of the orbit, which causes protrusion of the 
eyeball, as already mentioned. There are also other fibres from 
the sympathetic (vaso-motor) which supply the muscular coats 
of the arteries of the ciliary vessels. 

The dilating centre may be stimulated directly by venous 
blood circulating in it. In consequence of this the pupils usually 
dilate much when the respiration is imperfect, as during dyspnoea; 
but when the asphyxia becomes complete the centre again be- 
comes paralysed and the size of the pupil diminishes. It may be 
stimulated reflexly by irritation of sensory nerves, so that dilata- 
tion of the pupil has been used as an indication of sensation in 
animals paralysed by curare. It seems to be readily stimulated 
by irritation of the genital organs. This is probably the reason 
why dilatation of the pupil frequently occurs in persons suffering 
from irritation of the genital organs. It is probably also readily 
stimulated by irritation of the intestinal canal, and such irritation 
may be the cause of dilatation of the pupil in children suffering 
from worms, and in cases of poisoning by drugs which irritate 
the gastro-intestinal canal, like aconite. 

The drugs which act upon the iris are divided into two classes : 
Mydriatics which dilate, and Myotics which contract the pupil. 
The most important of these are such drugs as have a local action 



chap, ix.] ACTION OF DEUGS ON SPECIAL SENSE. 219 

on the eye, and they alone are used in ophthalmic medicine. They 
are indicated in the following list by an *. 

Mydriatics. Myotics. 

General anesthetics — General anesthetics— 
chloroform, ether, &c. chloroform, ether, &c. 

*Atropine. *Calabar bean. 
*Belladonna. 

Belladonnine. 

Benzoyltropine. 

Cocaine. 

Daturine. 
*Duboisine. 

Gelsemine locally. Gelsemine internally. 

*Homatropine (oxytoluylic- Jaborandi. 

acid-tropine). Lobeline internally. 

Hyoscyamine. Morphine internally. 

Muscarine locally (?). Muscarine internally. 

„ locally. 

Narcissine. Nicotine locally. 

Piturine. Opium. 

Scopalein. *Physostigmine (eserine). 

Stramonium. Pilocarpine. 

Thebaine. 

Ansesthetics occur in both classes, because they cause con- 
traction towards the commencement of their action, while later 
on they cause dilatation. The probable reason of this is that at 
first they lessen reflex action, so that the reflex dilatation of the 
pupil by stimulation of sensory nerves is abolished. Later on, 
when they begin to paralyse the respiration, the accumulation of 
venous blood causes irritation of the dilating centre and widens 
the pupil. Dilatation of the pupil during the administration of 
ansesthetics is therefore to be regarded as a sign of imperfect 
aeration of the blood, due either to embarrassed or failing 
respiration (p. 218) or failing circulation (p. 207). 

The contraction caused by morphine is also central, and pro- 
bably due to a similar cause. 

It is possible that the local application of drugs to the eyes 
may have an action on the pupil due merely to their effect as 
irritants, and independent of any special action on the iris, for 
E. H. Weber ' found that local irritation at the margin of the 
cornea causes partial dilatation. Irritation in the middle of the 
cornea causes rather contraction of the pupil. Localised irrita- 
tion at the margin of the iris may cause dilatation at that part. 

The reason why muscarine has been found by Binger and 

1 Quoted by Landois. Physiologic, 1880, p. 799. 



220 PHAKMACOLOGY AND THERAPEUTICS, [sect. i. 

Morshead to dilate the pupil when applied locally is probably that 
the solution they used was very irritating, either from its strength 
or for some other reason, while Schmiedeberg and Harnack found 
it to contract the pupil both when given internally and applied 
locally. 

The contraction of the pupil noticed by Eossbach in rabbits 
immediately after the application of atropine, may also have been 
due to local irritation. The occurrence of dilatation in one case 
and of contraction in the other may possibly have been due to the 
solution being dropped into the eye in a different way in the two 
cases. 

The commonest and most important local mydriatic and 
myotic are respectively atropine and physostigmine (eserine). 

From ten to twenty minutes after a solution of atropine has 
been dropped on the eye, the pupil dilates and the ciliary muscle 
becomes paralysed, so that the accommodation for near objects is 
no longer possible, and the eye remains focussed for distant ob- 
jects. When a solution of physostigmine is dropped into the eye, 
the pupil contracts and the ciliary muscle becomes spasmodically 
contracted, so that the eye is accommodated for near objects. 

It is very difficult to explain the mode of action of these 
drugs satisfactorily, and authorities are by no means agreed 
regarding it. That the action is local is shown by the fact that 
when either atropine or physostigmine is applied to one eye its 
action is limited to it and the other remains unaffected. If care 
be taken to limit the application of a solution of atropine to one 
side of the margin of the cornea, local dilatation of the corre- 
sponding part of the pupil may be produced. 

Dilatation of the pupil may be due to 

(1) Paralysis of the sphincter, or 

(2) Excessive action of the dilator, or 

(3) Both conditions combined. 

Paralysis of the sphincter may be due to (a) imperfect action 
or paralysis of the oculo-motor centre in the corpora quadri- 
gemina, (b) to paralysis of the ends of the third nerve in the 
sphincter iridis, or (c) to the action of the drug upon the mus- 
cular fibres of the sphincter itself, or to a combination of two or 
more of these factors. 

Along with the factors just mentioned might be associated 
excessive contraction of the dilator muscle, which may be due to 
stimulation (1) of the sympathetic centre in the medulla, (2) of the 
ends of the sympathetic in the dilator muscle, or (3) of the dilator 
muscle itself. 

Excluding for the present the question of excessive action of the 
dilator muscle and confining ourselves to the causes of paralysis, 
we see that paralysis of the cerebral oculo-motor centre as a 
factor in dilatation of the pupil by atropine is excluded by the 
local action of the drug, by the experiments . of Bernard and 



chap, ix.] ACTION OF DEUGS ON SPECIAL SENSE. 221 

others, which show that dilatation occurs from the local action of 
atropine when the ciliary ganglion is extirpated and all the nerves 
of the eye have been divided, and by the mydriatic action of atro- 
pine even in the exsected eye. We can now limit its action either 
to paralysis of the ends of the oculo-motor nerve, or paralysis 
of the muscular fibres of the sphincter. 

That the ends of the oculo-motor nerve in the sphincter iridis 
are paralysed is shown by the experiment that when the pupil is 
under the full action of atropine, irritation of the third nerve will 
not produce a*ny contraction in it, although the sphincter will still 
contract when stimulated directly. 

Here also we find the same relation between the action of 
atropine on nerves supplying striated and non-striated muscle 
that we have already noticed in the case of the oesophagus (p. 139), 
for in most animals the iris consists of unstriated muscular fibre, 
and atropine causes dilatation ; but in birds the iris consists of 
striated muscular fibre, and atropine causes no dilatation. Para- 
lysis of the ends of the oculo-motor nerve in the iris itself may be 
looked upon as one of the factors in dilatation by atropine, and 
similar paralysis of the fibres supplying the ciliary musele may 
be regarded as the cause of loss of accommodation. 

In addition to this, however, when the dose of atropine is 
large, the muscular fibres of the sphincter themselves become 
paralysed, and fail to contract even when directly irritated. 

The question now arises whether in addition to paralysis of 
the oculo-motor nerve there is not also excessive action of the 
dilator muscle. That such action of the dilator is actually pre- 
sent appears to be shown by the following fact, viz. that the 
dilatation caused by atropine does not appear to be merely pas- 
sive, but occurs with such force as to tear the iris away from the 
lens, and break down inflammatory adhesions which may have 
formed between them. This conclusion has been considered to 
be supported also by the facts : — (a) That when the oculo-motor 
nerve is divided the pupil does not dilate nearly to the same 
extent as it does from the application of atropine. This is shown 
both by a. comparison of measurements of the eye under the two 
conditions and by the observation that after the nerves have been 
divided and partial dilatation produced, atropine causes the pupil 
to dilate still more. And similarly in dilatation due to paralysis 
atropine increases the mydriasis. (6) When the pupil is dilated 
by atropine, section of the sympathetic in the neck lessens the 
dilatation. 

We may consider, then, with tolerable certainty, that dilata- 
tion caused by atropine is due to increased action of the dilator 
as well as diminished action of the sphincter muscles of the iris. 

Contraction of the pupil may be due to 

(1) Excessive action of the sphincter, or 

(2) Paralysis of the dilator. 



222 PHAEMACOLOGY AND THEEAPEUTICS. [sect. i. 

That the contraction caused by physostigmine is not due to 
paralysis of the dilator is shown by the pupil dilating somewhat 
when shaded, even when the drug is exerting a well-marked 
action. Excessive action of the sphincter must therefore be re- 
garded as the cause of the myosis. Such action may be due to 
stimulation (1) of the oculo-motor cerebral centre, (2) of the ends 
of the oculo-motor nerve in the sphincter, or (3) to increased 
action of the muscular fibres in the sphincter from the direct 
effect of the drug upon them. The local action of physostigmine 
upon the eye excludes the cerebral centre, and leaves for our con- 
sideration stimulation of the ends of the nerves and of the mus- 
cular fibres themselves. 

These two structures seem to be specially affected by differ- 
ent drugs— so that local myotics may be divided into two 
classes — 

1st. Those which act upon the peripheral ends of the oculo- 
motor nerve. 

2nd. Those which affect the muscular fibre of the sphincter 
iridis. 

The first class includes muscarine, pilocarpine,' and nicotine, 
wbereas physostigmine belongs to the second. 

Muscarine, pilocarpine, and nicotine, when applied to the 
eye, cause contraction of the pupil and spasm of accommodation. 
Atropine, as we have already seen, not only paralyses the ends 
of the oculo-motor nerve, which these drugs stimulate, but has 
also an action on the muscular fibre itself. Its subsequent ap- 
plication will therefore remove the effect of these drugs, and they 
will not act when atropine has been applied first. As physo- 
stigmine stimulates the muscular fibre itself, it will cause con- 
traction in an eye which is dilated by atropine unless the action 
of the atropine has been carried to such an extent as to paralyse 
the muscular fibre. 

The contraction produced by muscarine in the eye of the cat 
is so great as to reduce the pupil to a mere slit, and is much 
greater than that caused by physostigmine, for muscarine, acting 
only on the ends of the oculo-motor, produces spasm in the 
sphincter without affecting the dilator, while physostigmine, act- 
ing on the muscular fibres, is said to stimulate those of the 
dilator as well as the sphincter, and thus to render the contrac- 
tion less complete. 2 

It has already been pointed out, however, that the action of 
atropine is not confined to the ends of the oculo-motor nerve, but 
affects the muscular fibre itself, and thus it will counteract the 
effect of physostigmine, which it would not do if it acted only on 
the nerves. 

Atropine consists of the combination of a base, tropine, with 

1 Schmiedeberg, Arzneimittellchre, p. 71. 2 Schmiedeberg, op. cit. 



chap, ix.] ACTION OF DRUGS ON SPECIAL SENSE. 223 

tropic acid. Tropine itself has no mydriatic action, but when an 
atom of hydrogen in it is displaced by an acid residue it acquires 
this action. A number of combinations of tropine with different 
acids have been artificially prepared by Ladenberg, who terms 
them tropeines. Amongst these are homatropine, in which the 
tropine is combined with oxytoluylic acid, and also benzoyl-tropine. 
Atropine appears to be identical with daturine. Hyoscyamine is 
also a combination of tropine with tropic acid, but it appears to 
be only isomeric with and not identical with atropine, though it 
seems to be identical with duboisine. 

Action of Drugs on Accommodation. — The accommodation 
of the eye depends upon the ciliary muscle. When the eye is at 
rest the lens is flattened by the elastic tension of the zonule of 
Zinn. During accommodation for near objects the ciliary muscle 
draws the zonule forward and allows the lens to become more 
convex. The ciliary muscle is innervated by the third nerve : 
the centre for it appears to be in the posterior part of the floor of 
the third ventricle. Those drugs which affect the iris, also affect 
the power of accommodation. Their action on the iris and on 
accommodation do not, however, always begin at the same time, 
nor have they the same duration. The action of physostigmine 
and atropine on accommodation usually begins after, and passes 
away long before, the affection of the pupil. 

Action on intra-ocular pressure. — The intra-ocular pressure 
depends greatly on the amount of fluid contained in the vitreous, 
and this in turn is determined by two factors : — 

(1) The amount of fluid secreted by the ciliary body. 

(2) The freedom with which fluid escapes at the angle of the 
anterior chamber. 

The aqueous humour and the fluid which nourishes the 
vitreous and crystalline lens are chiefly secreted by the ciliary 
processes. It ultimately passes out from the anterior chamber of 
the eye by a number of small openings (/, Pig. 75) close to the 
junction of the cornea and iris into the canal of Schlemm 
(c, s, Fig. 75), thence into the anterior ciliary veins. Some of 
it also passes into the perichoroidal space, and out through the 
lymphatics. 

The intra-ocular pressure may be increased by (a) more rapid 
secretion from the ciliary processes, or (b) interference with its 
outward flow from the eye, or (c) by increased quantity of blood 
in the vessels of the iris. It may be diminished by the contrary 
conditions. 

More rapid secretion from the ciliary process probably takes 
place under nervous conditions which are not at present well 
known. Interference with the flow of the aqueous humour^ out 
of the anterior chamber may occur in aquo-capsulitis, in which 
the openings from the anterior chamber into the spaces of 
Fontana are occluded by a coating of inflammatory lymph ; also 



224 PHAKMACOLOGY AND THEEAPEUTICS. [sect. i. 

in glaticoma where these openings are shut by the iris being pressed 
forward against the cornea, as in Fig. 75, and in iritis where the 
iris is much congested and the communication between the 
posterior and anterior chambers is interrupted by complete ad- 
hesion of the pupillary edge of the iris to the anterior capsule 
of the lens (total posterior synechia). The secretion is probably 
diminished by the action of atropine. In glaucomatous states 
where the periphery of the iris lies in contact with the cornea 
the outward flow through the spaces of Fontana may often be 
increased by Calabar bean, which, by causing contraction of the 
circular fibres of the iris, flattens the arch of the iris and, drawing 
it away from the cornea, reopens the contracted angle between 
the cornea and iris, and permits the passage of fluid through the 
spaces of Fontana. 1 

There are few or no experiments on the tension in the vitreous 
humour of the eye, though by the term intra-ocular tension is 
usually intended the pressure in the vitreous humour. The 




Fig. 76.— This diagram ( vhich I owe to the kindness of Mr. J. Tweedy) represents a section througu- 
tlie corneo-scleral region, ciliary body and iris, of a healthy eye (left side), and of a glaucomatous 
eye (right side) : A, cornea ; s, sclerotica ; i, iris ; /, spaces of Fontana ; c s, canal of Schlemm. In 
the glaucomatous eye the ciliary body is atrophied, and the iris lies against the cornea, prevent, 
ing the escape of fluids through the spaces of Fontana and canal of Schlemm. 

degree of intra-ocular tension is usually ascertained by pressing 
the finger secundum artem upon the eye and observing whether it 
is harder or softer than usual, or by pressing upon the sclerotic 
with an ivory point attached to a registering spring, and noticing 
the pressure required to produce an indentation. These methods 
of experiment are valuable clinically, but the tension can be 
more exactly ascertained in animals by passing a small trocar 
into the anterior chamber and connecting it with a manometer. 
The results of experiments even by this method are not entirely in 
accordance. The most recent ones by Graser 2 appear to show that 
the tension depends to a great extent upon the height of the 
blood-pressure generally : contraction of the pupil diminishes, 
and dilatation increases the intra-ocular tension. Eserine causes 
temporary increase at first, but after contraction of the pupil 
comes on, the tension is diminished. Atropine in doses sufficient 



J. Tweedy, Practitioner, Nov. 1883, vol. xxxi. p. 321. 
Graser, Archiv f. exp. Path. u. Pharm., Bd. xvii. Heft 5. 



chap, ix.] ACTION OP DBUGS ON SPECIAL SENSE. 225 

to dilate the pupil increases the tension. The precise effect of 
atropine on intra-ocular tension in man is disputed. From 
clinical observation the truth would seem to be that in a per- 
fectly healthy eye and in ordinary iritis atropine and other 
mydriatics diminish tension, whereas they increase the tension 
when the anterior chamber is shallow from narrowing of the 
iridic angle. In glaucomatous states atropine and other my- 
driatics almost always rapidly increase tension. This action of 
atropine and its allies not only makes them dangerous in cases 
of glaucoma, but where this disease has been impending it has 
been at once brought on by their use. From its power to 
diminish tension eserine is useful in glaucoma. 

Uses of Mydriatics and Myotics. — Belladonna is employed 
locally for its sedative action, to relieve pain and allay irritation 
and inflammation in the conjunctiva, cornea, choroid, or iris. 

Mydriatics and myotics are used not only for their action 
upon the pupil but for their action upon accommodation and 
intra-ocular pressure. 

Mydriatics are employed to dilate the pupil for the purpose 
of facilitating ophthalmoscopic examination,. assisting the detec- 
tion of cataract commencing in the periphery of the lens, or 
allowing the patient to see past the edge of a cataract or corneal 
opacity when this is central in position, and obstructs the vision 
with a pupil of normal size. They are used to prevent prolapse 
of the iris, or to restore it to its normal position when already 
prolapsed in cases of perforating ulcer or mechanical lesion of 
the cornea. They are employed in iritis to afford rest to the 
inflamed tissues of the eye, and to keep the iris as far as possible 
off the surface of the lens and prevent adhesions of its posterior 
surface to the anterior surface of the lens. 

Mydriatics are employed to paralyse the ciliary muscle, and 
thus destroy the power of accommodation in order to test the 
condition of the refractive media of the eye in cases of astig- 
matism, or in cases where the patients either suffer from spasm 
of the ciliary muscle or are unable voluntarily to relax the 
accommodation . 

Myotics are used to counteract the effect of mydriatics which 
have been previously employed, or in mydriasis following a blow 
or paralysis of the third nerve. They are used also to counteract 
deficiency in tone of the ciliary muscle, as in paralysis of ac- 
commodation consequent on diphtheria, asthenopia, a blow on 
the eye, &c. 

Myotics are useful in cases of threatening and commencing 
glaucoma and often even in more advanced cases of glaucoma, 
from their power to lessen intra-ocular tension. As a temporary 
expedient they are often of the greatest service in cases of acute 
glaucoma. So, also, if perchance the instillation of atropine 
have induced glaucoma, myotics will not only counteract the 

Q 



226 PHARMACOLOGY AND THERAPEUTICS, [sect. I. 

mydriasis, but often rapidly restore the intra-oeular tension to 
the normal standard. 1 

Mydriatics and myotics may be employed alternately in order 
to ascertain the presence of any adhesions of the iris,' and to 
break them down if present. 

In glaucoma the intra-ocular tension within the anterior 
chamber is greatly increased, and the increase, according to 
Tweedy, is due to the natural channel of escape for the aqueous 
humour through the spaces of Fontana and the canal of Schlemm 
being obstructed by the iris lying against the cornea. This 
condition is relieved by myotics, which, by causing contraction 
of the pupil, draw the iris away from the cornea, and thus allow 
the fluid to escape through the spaces of Fontana. When the 
anterior chamber of the eye is shallow and the iris is lying close to 
the cornea, so as nearly, though not quite, to obstruct the spaces of 
Fontaaia, atropine may induce an attack of glaucoma by dilating 
the pupil and thus packing the tissue of the iris into the angle 
between it and the cornea, so as to render the obstruction to the 
spaces of Fontana complete. 

Action of Cocaine. — Cocaine, when applied locally to the eye, 
has several actions. It produces local anaesthesia, dilatation of 
the pupil, and relaxation with more or less complete paralysis 
of the ciliary muscle. When two to three drops of a 4-per cent, 
solution are applied to the eye at intervals of five minutes, such 
complete local anaesthesia of the cornea, conjunctiva, and his is 
produced in twenty to thirty minutes as to allow operations to be 
performed on the eye. At the same time the cocaine causes con- 
striction of the superficial vessels, producing blanching of the 
conjunctiva. The dilatation of the pupil is great, is quickly 
attained, and differs from that produced by atropine in the fact 
that the cocainised pupil reacts to light and accommodation. The 
mydriasis is probably due to stimulation of the ends of the sympa- 
thetic in the iris, for cocaine will not produce any mydriatic effect 
after the cervical sympathetic has 'been cut for such a length of 
time as to allow degeneration of the peripheral ends to occur, 
nor has stimulation of the cervical sympathetic any effect in 
increasing the ad maximum cocaine mydriasis. That the third 
nerve is not paralysed is shown by the fact that stimulation of 
it produces contraction in the cocainised pupil. A similar effect 
follows local stimulation of the sphincter pupillse. That the 
action of cocaine is exerted on the peripheral ends and not on the 
centres of the sympathetic is shown by the fact that section of the 
cervical sympathetic does not alter the pupil which is fully dilated 
by cocaine, and cocaine induces mydriasis in an exsected eye. 2 

Action of Drugs on the Retina.— By a comparison of the 
retina of a frog kept in darkness with one exposed to light, it has 



Tweedy, loc. cii. ' Jessop, Proc. Roy. Soc, 1885. 



cSap. ix-1 ACTION OF DEUGS ON SPECIAL SENSE. 227 

been found that light causes not only the internal segments of 
the cones • and rods 2 but also the pigment-cells of the retina to 
contract, so that the external parts of the rods and cones as well 
as the pigment are drawn away from the external towards the 
internal limiting membrane of the retina (Fig. 766). A similar 
effect is produced by heat. 2 The retina of a frog which has been 
tetanised by strychnine in complete darkness has an appearance 





Pig. 76.— Shows the position of the rods and pigment-cells in the retina of the frog : a, after the 
animal has been kept in complete darkness for one or two days ; 6, after it has been exposed to 
diffused daylight for five or ten minutes, after being kept in darkness for twenty-four hours ; 
c, after exposure to light as in b, but for half an hour instead of a few minutes. This also repre- 
sents the position of the rods and pigment-cells in strychnine tetanus. 

similar to that of a retina which has been exposed to full day- 
light, the strychnine haying caused extreme contraction of the 
rods, cones, and pigment-cells (Fig. 76c). A similar effect is 
produced by tetanising the eye itself either by induced currents 
in the dark, or while it is still in the head or immediately 
after its excision. Curare neither hinders this action nor pro- 
duces it. 

Action of Drugs on the Sensibility of the Eye. — The 
sensitiveness of the eye to impressions is increased by strychnine, 
the field of vision becoming larger, and the sight more acute, so 
that objects can be distinctly observed at a greater distance, and 
the field of colour is increased for blue. This action appears to 
be to a certain extfent local, as it occurs more distinctly on that 
side where the strychnine has been injected hypodermically. 
The sense of colour is affected in a remarkable way by santonin, 
which at first causes objects to appear somewhat violet and after- 
wards of a greenish-yellow. The yellow colour has been ascribed 
to staining of the media of the eye by santonin, as it becomes 
yellow when exposed to the light ; others again have supposed 



1 Engelmann (and von Genderen Stort), Pflilger's Archiv, xxxv. p. 498. 
1 Gradenigo, jun., Allg. Wiener med. Ztg., 1885, No. 29. 

« 2 



228 



PHAEMACOLOGY AND THEKAPEUTICB. (sect. i. 



the alteration in the apparent colour of objects to be due, first to 
a stimulation, and then to a paralysis of those constituents of the 
retina by which the violet colour is perceived. 

The sensibility of tbe eye for red and green appears to be 
sometimes diminished by physostigmine. 

Action of Drugs in Producing Visions.— It may be well 
here to mention the effect of some drugs in causing subjective 
sensations of sight, although these probably depend rather upon 
the action of the drugs on the brain, than on the eye itself. The 
centres for sight, according to Ferrier, are the angular gyrus 
(14 and 15, Fig. 68, p. 185), and the occipital lobes. In delirium 
tremens arising from alcoholic excess the patients often complain 
much of visions of the most disagreeable character, which often 
take the form of demons or of animals. 

Cannabis indica produces in some persons, though not in all, 
visions which may be pleasant or laughable. These chiefly occur 
just 'before sleep. 1 

Salicylate of sodium in some persons tends to cause most 
disagreeable visions whenever the eyes are shut, and I have seen 
it have this effect even in such a small dose as five grains. 
Large doses of digitalis may cause subjective sensations of light, 
and after taking nearly one grain of digitalin in the course of 
forty-eight hours I suffered from the centre of the field of vision 
being occupied by a bright spot surrounded by rainbow colours. 
Digitalin when introduced into the eye locally causes at first 
smarting and lacrimation, which soon passes off, but after four 
or five hours, when a light is looked at, a halo is seen surround- 
ing it, which is not improbably due to some opalescence in the 
cornea. 2 

Toxic Amblyopia. — Belladonna taken internally in sufficient 
quantity causes dilatation of the pupil and misty vision. Alcohol, 
tobacco, quinine, and lead all cause failure of the power of vision 
for form and for certain colours, as well as limitation of the field 
of vision either in the centre or the periphery. These symptoms 
are at first functional, but if not relieved they may be the pre- 
cursors of actual anatomical changes. 

Action of Drugs on Hearing. 

The sense of hearing depends on the transmission of sonorous 
vibrations from the air to the auditory nerve by means of the 
membrana tympani and the ossicles of the ear, and upon the 
perception of those vibrations by the brain. 

The centre for hearing, according to Ferrier, is in the 



1 Compare Sohrofi, Pharmacologie, 4th ed. p. 535, and Wood, Materia Medica, 
3rd ed. p. 236. 

2 Lauder Brunton,. On Digitalis, &c. 



chap, nc] ACTION OP DEUGS ON SPECIAL SENSE. 229 

superior temporo-sphenoidal convolution (16, Fig. 68, p. 185). 
It is probable that subjective sounds not depending on disturb- 
ance of the auditory apparatus, such as the sounds of voices, &c, 
heard in delirium or mania, or as the prodromata of an epileptic 
fit in certain individuals, or during intoxication by cannabis 
indica, are due to irritation of these eentres. 

The sense of hearing may be dulled by any interference with 
the passage of the sound into the ear, as by wax in the auditory 
meatus, by disease of the auditory nerve or of the brain itself. 

The hearing may be rendered more acute by the removal of 
any obstacle in the way of transmission of sound to the auditory 
nerve, or by drugs which increase the excitability of the auditory 
nerve or of the brain ; thus the wax may be removed by simply 
syringing ; thickness and catarrh of the Eustachian tube which 
interfere with vibrations in the middle ear may be lessened by 
the inhalation of camphor and ammonia, or by the application 
of a solution of ammonium chloride and sodium bi-carbonate to 
the posterior nares either by the spray or nasal douche. The 
excitability of the auditory nerve or of the brain is increased by 
strychnine, which renders the hearing more acute. 

Subjective noises in the ear, such as humming, buzzing, or 
ringing, are often very troublesome. Bubbling noises may be 
due to mucus in the Eustachian tube. Buzzing or humming 
are probably generally caused by vascular congestion either of 
the external meatus, of the middle ear, or of the Eustachian 
tube. Where the bubbling noises are due to the presence of 
mucus they may be to a considerable extent removed by washing 
out the mucus with a solution of carbonate of sodium applied by 
a nasal douche. Noises in the ears due to hyperemia may be 
lessened or removed by cholagogue purgatives and by hydro- 
bromic acid. Where chronic thickening of the membrane is 
present, relief is usually afforded by iodide of potassium or 
iodide of ammonium, both applied locally and taken internally. 
Subjective noises in the ears are caused by quinine in large 
doses, and also by salicylate of sodium. Both of these drugs 
have their effect upon the ear to a great extent neutralised by 
hydrobromic acid, and ergot ' is said to have a similar power 
to prevent or remove the unpleasant singing. It is uncertain 
whether the singing caused by quinine and salicylates is due to 
their action on the auditory apparatus, or the cerebral centres ; 
but the fact that in larger doses they may cause delirium in- 
dicates that even the earlier symptom of buzzing in the ears 
may be due, in part at least, to their action on the cerebral 
centres. 

1 Schilling; Aertzl. Intelligenzblalt, 1883. 



230 PHAEMACOLOGY AND THERAPEUTICS, [sect. i. 



Action of Drugs on Smell. 

Many drugs, such as musk and ethereal oils, have a marked 
and characteristic smell, due to their effect upon the terminal 
branches of the olfactory nerve. This nerve is soon exhausted, 
so that in a very short time the smell is no longer perceived with 
anything like the intensity it was at first. Such smells as these 
just mentioned cannot be perceived by persons suffering from 
anosmia, but certain drugs, such as ammonia or acetic acid, 
can be recognised by them. The reason of this is that although 
such persons are incapable of perceiving any true smell, the 
nasal branches of the fifth nerve are irritated by pungent vapours, 
and thus produce a certain kind of sensation. The power of 
distinguishing smells seems to be increased by strychnine ; which 
appears at the same time to render such disagreeable odours as 
those of asafcetida, garlic, and valerian agreeable. This effect 
may be due to the action of strychnine on the olfactory apparatus, 
but it is very probably due rather to the action of the drug on 
the cerebral centre for smell, which, according to Ferrier, is 
situated at the tip of the temporo-sphenoidal lobe. The power 
• to distinguish smells is diminished by such drugs as lessen the 
sensibility of the brain, or by those which cause alterations in 
the nasal mucous membrane, as, for example, iodide of potassium 
given in such doses as to produce coryza. 

Action of Drugs on Taste. 

Most of the substances used in medicine have a strong taste, 
and many a very unpleasant taste. 

What is usually termed taste frequently depends on a mixture 
of taste and smell, and if the sense of smell is abolished for the 
time being, the characteristic taste of the substance cannot be 
distinguished. This is the reason why castor-oil, which owes its 
nauseous taste almost entirely to its odour, can be swallowed 
without being so readily distinguished if the nose is held during 
the act of swallowing. In addition to the taste they produce in 
the mouth, certain substances leave an impression termed ' after 
taste ' on the tongue after they have been swallowed or ejected ; 
and this is sometimes quite different from that of the taste of 
the substance itself : thus bitters leave a sweet after-taste in the 
mouth. If quinine is taken in a nearly neutral solution, it 
leaves a persistent bitter taste from the sparingly soluble alka- 
loid being precipitated on the tongue and remaining there for a 
length of time, but if the quinine be taken with excess of acid, 
so as to keep it entirely in solution, and washed out of the 
mouth immediately with a draught of water, it leaves a sweet 
after-taste. 



chap, ix.] ACTION OF DEUGS ON SPECIAL SENSE. 231 

Some substances after their entrance into the blood are 
excreted by the saliva and may cause a somewhat persistent 
taste in the mouth ; this is observable in the case of iodide of 
potassium. 

Iodine appears also to have the power of causing other sub- 
stances to be excreted by the saliva, when they are combined 
with it, and thus Bernard found that iodide of iron was secreted 
by the saliva, though lactate of iron was not ; and I have some- 
times thought that iodine has a similar effect upon quinine, 
because I have very frequently noticed patients complain of a 
persistent bitter taste in their mouth when I have given quinine 
combined with iodide of potassium, although they did not com- 
plain of this when either of the drugs has been given without 
the other. 



232 PHARMACOLOGY AND THERAPEUTICS, [seot.i. 



CHAPTER X. 
ACTION OF DRUGS ON RESPIRATION. 

Respiratory Stimulants and Depressants. 

It is usually supposed by naturalists that in the descent of man 
from some organism low in the scale of existence, he has passed, 
at a remote period, through a stage resembling the Ascidians or- 
Tunicata. In these animals respiration is maintained by water 
being driven through a perforated sac in the meshes of which 
the nutritive fluids of the animal circulate. The contractile 
motions of the sac by which the circulation of fluid is maintained 
probably depend on a nervous ganglion situated between the 
oral and anal apertures as represented in the diagram (Fig. 77). 
We do not know whether or not this ganglion may influence the 
circulation which is maintained by the rhythmical contractions of 
the simple tube which serves as a heart. These drive the fluid 
first in one direction, and then after a while the action of the 
tube is reversed, and its contractions drive the fluid in the oppo- 
site direction. This ganglion in its functions would correspond 
with the medulla oblongata in the vertebrata, and thus the 
medulla oblongata may be looked upon as a lower and more 
fundamental centre than the brain or spinal cord. 

We see this more distinctly perhaps by looking at the two 
diagrams (Figs. 78 and 79) representing an amphioxus and a 
fish. In the amphioxus respiration is kept up in much the same 
way as in the ascidian, the water passing from the pharyngeal 
to the atrial sac and through the atrial aperture or abdominal 
pore. There is no head and no organs of special sense, and so 
we have no brain whatever. But the body is elongated so as to 
remind us of an ascidian, having its ganglion and the part of the 
body-wall containing it so much extended as to remove the anal 
considerably from the oral aperture. The muscles of this 
elongated body require innervation, and thus the ganglionic mass 
is elongated into a cord called the myelon, which represents the 
spinal cord as well as the medulla oblongata. In ascidians then 
we have a mass corresponding to the medulla ; in the amphioxus 
we have a mass corresponding to medulla and spinal cord. 



chap, x.] ACTION OF DEUGS ON EESPIEATION. '233 

In a fish the pharyngeal or branchial sac, instead of opening 
into the atrial sac, opens directly into the surrounding water. 



Body wall 

Serves passing from the 
ganglion 



Pharyngeal sao 

General body-cavity 
Heart 




' Oral aperture. 

Part of body wall containing 

ganglion. 
Branchio-anal or atrial aperture. 

1 Branchial openings in the sep- 
tum between the pharyngeal 
and anal sac. 



Intestine \-J. 



Fig. 77.— Diagram of an Ascidian. 



Oral aperture — — 



Branchial openings | 

3/ — — . 



or pharyngeal sac 
Pharyngeal sac 



Branchial aperture or 
abdominal pore 

Ana} aperture 










Mr Nose. 




Orrl 
aperture "-"" 
Branchial 
apertures 


il 
>4 


wi Brain. 


Nervous 
myelon. 




i 


[Ktf \ cord 




Anal 

apertuie — 


w, 





Fig. 78. — Diagram of Amphioxus. 'riie water enters the 
oral aperture, passes through the openings in the 
pharyngeal sac into another cavity, whence it 
escapes by the abdominal pore. 



Tia. 79.— Diagram of fish. 



We have a head and organs of special sense, and therefore we 
have a large nervous mass or brain. 

In these three members of the animal kingdom, therefore, we 
have the medulla as the lowest or fundamental centre, next the 
spinal cord, and lastly the brain. We might therefore expect 
that notwithstanding the apparently higher position and greater 
nearness of the medulla to the brain than to the spinal cord, 
the medulla would be less readily affected by many drugs than 
the cord or the brain, and this is what we find in the case 
of such drugs as alcohol, ether, or morphine, which appear to 
paralyse the nervous centres in the inverse order of their de- 
velopment — the brain first, spinal cord next, and medulla last. 

There are some drugs, however, e.g. aconite, gelsemium, and 



234 PHAEMACOLOGY AND THEEAPEUTICS. [sect. I. 

hydrocyanic acid, which seem to have a special paralysing action 
on the respiratory centre. 

If we look at the ganglionic mass in an ascidian, represented 
in the diagram, we shall see that it sends some fibres to the 
pharyngeal sac and some to the anal sac. If these two sacs were 
to contract together they would oppose each other's action, and 
thus the passage of water through the branchial apertures would 
be stopped, and respiration consequently arrested. They must 
therefore act alternately, and this alternate action is regulated 
by the ganglion. This ganglion consists of numerous nerve-cells 
and fibres. As some of these have a more special connection 
with the pharynx, the group which they form may be called the 
pharyngeal centre or inspiratory centre. 

Similar arrangements occur in higher animals, and the terms 
used in regard to their nervous system may lead to some confu- 
sion of thought ; thus we speak of the respiratory, of the inspi- 
ratory, of the expiratory, and of the vomiting centres. 

By nerve-centres we simply mean the groups of cells and 
fibres which are concerned in the performance of certain acts. 
They are not necessarily entirely distinct from one another, and the 
same group of ganglionic cells may form a part of several centres. 
Thus in the accompanying diagram (Fig. 80), the respiratory 
centre includes both inspiratory and expiratory centres, and 
the vomiting centre includes some ganglionic groups which form 
part of the inspiratory, and others forming part of the expiratory 
centres, besides other ganglion groups which are concerned with 
the simultaneous dilatation of the cardiac orifice of the stomach. 
On analysing this subject still further we find also that the 
inspiratory centre affects many muscles, and that it does not 
always affect them to the same extent. Thus in men the dia- 
phragm takes a more active share in inspiration during the day 
than the thoracic muscles. During sleep the diaphragm takes 
a much less active part, and may be entirely quiet, while the 
thoracic muscles are more active, and the chest rises and falls 
more than during walking. 

The inspiratory centre might be thus still further divided 
into thoracic inspiratory centre, and diaphragmatic inspiratory 
centre. 

Such subdivisions appear absurd if we imagine that each 
centre represents a distinct nervous mass, and we become puzzled 
to understand how the medulla oblongata can contain so many 
distinct centres in a small bulk. But if we remember that the 
word ' centre ' simply indicates a group of cells and fibres 
connected with the performance of a particular act, and that two 
centres may be formed by the same ganglionic groups and differ 
from one another only by having a few ganglion cells more or 
less which alter the function they perform, no harm is done by 
the use of the term. 



chap, x.] ACTION OF DEUGS ON EESPIEATION. 233 

The act of respiration consists in the alternate enlargement 
and diminution of the thoracic cavity, so that the air is alter- 
nately inspired and expired. 




Vomiting centre. 



Bespiratory centre. 



Fig. 80.— Diagrammatic representation of various groups of ganglion cells, or 'centres' in the 
medu la oblongata. The arrows indicate the directions in which the nerve-currents pass Those 
pointing to the cells indicate sensory, those pointing from the cells indicate motor nerves 

I 

The muscles by which this is effected in ordinary respiration 
are the diaphragm and intercostal and scaleni muscles. The 
diaphragm descends, and the intercostal and scaleni muscles raise 
the ribs during inspiration. 

Expiration is normally a passive act, 1 and is not performed 
by muscular action, but simply by the tendency of the dia- 
phragm and thoracic walls to return to the position of the equi- 
librium from which they had been removed during inspiration, 
and by the contraction of the elastic walls of the air- vesicles dis- 
tended by inspiration. 

When the supply of oxygen is deficient, other muscles are 
called in to aid the inspiration. Expiration appears to be a 
passive act, not merely in ordinary respiration, but even in dys- 
pnoea caused by the absence of oxygen. In some experiments 
by Bernstein 2 the inspiration and expiration were equally 
increased in a rabbit, when the air which it had breathed was 
replaced by hydrogen. But expiratory efforts are required both 
for the production of voice, and for the removal of irritants from 
the air-passages by coughing or sneezing ; and forcible expira- 



1 Bernstein, Archiv f. Anat. u. Physiol., 1882, p. 322. 
* Ibid., op. cit. 



236 PHARMACOLOGY AND THERAPEUTICS, [sect.!, 

tion is produced when an irritant is applied to the mucous mem- 
brane of the nose, of the larynx, trachea, or bronchi. As every 
one who has drunk a bottle of soda-water knows, carbonic acid is 
an irritant of considerable power to these mucous membranes, 
and when it is breathed instead of air or hydrogen the expiration 
becomes much more powerful, and is no longer a passive action, 
but an active one, performed by active muscular exertion. 

The chief respiratory centre is situated in the medulla ob- 
longata close to the end of the calamus scriptorius, at the point 
designated nceud vital by Flourens, because destruction of this 
point arrests the? respiration and causes death. 

It extends equally on both sides of the middle line in the 
medulla, each half regulating the breathing on the same side of 
the body. It has been supposed to be double, and to consist of 
inspiratory and expiratory centres which act alternately, but it 
would appear that in ordinary respiration the inspiratory centre 
only is active. 

When the centre is injured by a puncture, as in Flourens' 
experiment, or when one half of it is destroyed, breathing usually 
stops entirely, but if the respiration be kept up artificially for 
several hours, the normal breathing again becomes established ; 
and the prolonged continuance of artificial respiration has been 
recommended by Schiff in apoplexy. 

When the connection between this centre and the respira- 
tory muscles is cut off by dividing the spinal cord just below 
the medulla, respiration usually ceases entirely, so that at first 
sight it would seem that the respiratory centre is limited to the 
medulla. 

The effects of strychnine show that this is not the case. This 
drug greatly increases the excitability of the respiratory centre, 
and when it is injected into the blood before division of the spinal 
cord, the respiratory movements still continue to some extent 
after the cord has been divided. When it is injected after section 
of the cord, the respiratory movements which had ceased again 
recommence to a slight degree. 

The reason appears to be that the respiratory centre is not 
limited to the medulla, but extends to the upper part of the 
spinal cord, though the spinal portion is of itself too weak to 
keep up the respiratory movements, except when stimulated by 
strychnine. 

The amount of respiratory work which this centre excites 
appears to depend to a great extent, though not entirely, upon 
the condition of the centre itself. 

The distribution of the work is chiefly determined by the 
irritation of one or other of the afferent nerves, and these nerves 
also influence the amount of work. 

The centre is stimulated, and the amount of work it does 
increased by a venous condition of the blood circulating in it. 



chap, x.] ACTION OF DEUGS.ON EESPIEATION. 287 

An arterial condition of its blood lessens or completely abolishes 
its activity, so that when the blood is highly aerated by forced 
artificial respiration, a condition of apncea is produced, in which 
no spontaneous respiratory movements occur. 

_ This condition is much more readily induced when the excit- 
ability of the respiratory centre is lessened by drugs. In an 
animal poisoned by chloral, for example, it is very easy to induce 
it, and it lasts for a long time. 

When the respiratory centre is excited, as by the injection 
of emetine or apomorphine into the circulation, it is difficult or 
impossible to produce this condition. 

It is uncertain whether the stimulation which the venosity of 
the blood produces is due chiefly to the absence of oxygen or to 
the presence of carbonic acid. Possibly it may also be due to the 
products of imperfect combustion in the venous blood. Or all 
these three causes may share in the stimulation, though to what 
extent each does so is not known. 

According to Bernstein, want of oxygen appears to stimulate 
the inspiratory and the presence of carbonic acid to stimulate the 
expiratory centre. 1 

As the blood becomes venous the activity of the respiratory 
centre increases, the respirations becoming quicker and deeper, and 
the accessory respiratory muscles are thrown into action. This 
condition is called dyspnoea. Finally the excitement extends 
to all the muscles of the body and we get general convulsions, 
which have usually an opisthotonic character. The eyeballs 
very often protrude during these convulsions, and the blood- 
pressure rises greatly from stimulation of feympathetic and vaso- 
motor centres in the medulla. 

After the convulsions cease, the animal usually lies motion- 
less, and the heart as a rule continues to beat for a short time 
after the respirations have ceased. 

The excessive venosity of the blood in this condition has 
paralysed the nerve-centres, but if artificial respiration be now 
commenced and the blood becomes gradually aerated, the condi- 
tions just described are again passed through in the reverse 
order : convulsions first reappearing, then dyspnoea, next normal 
breathing, and, if the respiration be pushed far enough, apncea'. 

Asphyxial convulsions only occur in warm-blooded animals, 
and not in frogs, and when we find that any drug produces con- 
vulsions in mammals and not in frogs we usually assume that 
the convulsions are due to asphyxia produced by the action of the 
drug on the respiration or circulation, and not to a direct irri- 
tant action upon the motor centres. If, on the other hand, we 
find that the convulsions occur in frogs as well as in mammals, 
the presumption is in favour of their being due to the direct 
irritant action of the drug on motor centres. 

1 Bernstein, op. cit. p. 324. 



23S PHAEMACOLOGY AND THERAPEUTICS, [sect, u 

Blood becomes venous when the external respiration or inter- 
change of gases between it and the external air is arrested while 
internal respiration continues. 

Internal respiration or interchange of gases occurs between 
tbe blood and the tissues outside the vessels which are consuming 
oxvgen and deriving it from the blood. But the blood although 
fluid is itself a tissue and likewise consumes oxygen, so that it 
will become venous if left to itself in a thoroughly-stoppered glass 

bottle. 

External respiration may be arrested or diminished by — 

(1) Interfering with the access of air to the blood ; or 

(2) „ „ „ ,, ,, blood to the air ; or 

(3) „ „ „ power of the blood to take up 

and give off oxygen. 
The access of air to the blood may be prevented by obstruction 
to the air-passages or alteration in the structure of the lung ; thus 
anaesthetics may obstruct respiration by allowing vomited matters 
to enter the trachea and plug it mechanically. Apomorphine may 
lead to obstruction of the bronchi by profuse secretion from the 
mucous membrane, and large doses of antimony may cause con- 
solidation of the lung. 

Air may be prevented from reaching the blood by any obstruction in the 
respiratory passages. 

The respiratory passages may be obstructed by spasmodic closure of the 
glottis or of the nostrils in rabbits when an irritating vapour is inspired. 
This source of obstruction is easily avoided by putting a cannula into the 
trachea and allowing the vapour to be inspired through it. Another source of 
obstruction is the formation of plugs of mucus or clots of blood in the trachea 
or in the cannula, which has been introduced into it. Occasionally a plug of 
mucus, and sometimes a clot of blood, forms in the tracheal cannula and 
seriously impedes the respiration, whether natural or artificial, without 
being perceived by the experimenter. In order to be sure that such an oc- 
currence has not taken place and vitiated the results, it is always advisable, 
on removing the cannula from the trachea at the end of an experiment, to 
blow through it and see that its lumen is perfectly unobstructed. 

Access of air to the blood may be prevented also by paralysis 
of the muscles of respiration; thus curare will produce it by 
paralysing the ends of the motor nerves, hydrocyanic acid 
by paralysing the respiratory centre, and snake poison by 
paralysing both. 

The blood may be prevented from reaching the lungs by arrest 
of the circulation either local or general, and may thus become 
venous, either locally or generally. 

The venosity of the blood circulating in the medulla may be 
altered locally without any change in the rest of the body. 
Thus if the carotid and vertebral arteries are tied, the blood 
stagnates in the vessels of the medulla, and there becoming venous 
causes dyspnoea and convulsions, which again disappear when the 
ligatures are loosened and the circulation re-established. 



chap. x.j ACTION OF DEUGS ON EESPIEATION. 239 

Dyspnoea and convulsions are likewise produced by alteration 
in the general circulation, e.g. by loss of blood, as is seen when 
an animal is bled to death, or when the supply of blood in the 
arteries is greatly diminished by ligature of the portal vein, which 
causes the blood to accumulate and stagnate in the capacious 
veins of the intestine. 

Stoppage of the heart, either by ligature directly applied to 
it or by the action of drugs upon it, causes asphyxia and convul- 
sions. 

Arrested circulation through the pulmonary vessels by emboli 
has a similar action. This sometimes leads to error in regard to 
the action of drugs when these are injected, as is often done, into 
the jugular vein. 

If they contain solid particles, these mav give rise to embolism 
in the pulmonary arteries and lead to the belief that the drug has 
a tetanising action, when, as a matter of fact, it has nothing of 
the kind. Thus, in making an experiment on condurango, I 
injected an infusion into the jugular vein of a rabbit, and it 
rapidly died with symptoms resembling those of strychnine-poison- 
ing. The cause of this, however, was simply embolism of the 
pulmonary vessels, due to undissolved particles in the infusion, 
and when this was avoided by injecting the drug into the peri- 
toneal cavity, no symptom whatever was produced. Gianuzzi, 
in his experiments on this drug, appears to have fallen into the 
same error as I did at first. 

Altered condition of the blood also gives rise to dyspnoea, as 
is seen in the breathlessness of anaemia, where the blood is unable 
to take up the quantity of oxygen necessary for any exertion, and 
the patient pants violently after any quick movement, such as 
going up stairs. 

Dyspnoea and even convulsions are also caused by nitrites, e.g. 
nitrite of amyl or sodium, which lessen the power of the blood to 
give off oxygen, and by carbonic oxide, which replaces the oxygen 
in the blood. 

It must be remembered, however, that, whatever may be the 
remote cause of dyspnoea, its direct cause is the condition of the 
nerve-cells in the medulla, and if these are unable to take up 
oxygen, and give off carbonic acid to the blood, dyspnoea may 
occur, although the blood itself circulating in the medulla con- 
tains abundance of oxygen. 

In the case of carbonic-oxide poisoning the blood cannot take 
up oxygen from the lungs, although there is abundance of oxygen 
present ; and in a similar way the nerve-cells of the medulla may 
possibly be rendered by certain drugs unable to take up oxygen 
from the blood circulating through the medulla. 

In simple suffocation the internal respiration of the nerve- 
cells in the medulla is arrested by the general venous condition of 
the blood ; in carbonic-oxide poisoning by the oxygen being absent 



240 PHAEMACOLOGY AND THEEAPEUTICS. [sect. i. 

from the haemoglobin ; in nitrite poisoning by the oxygen being 
locked up in methasinoglobin. In all those cases the condition of 
the blood is betrayed to the eye by the appearance of the mucous 
membranes, which in suffocation and in nitrite poisoning become 
dark and livid, and in carbonic-oxide poisoning of a cherry-red 
colour. Perhaps the change is most conveniently seen in the 
comb of a cock poisoned by these substances ; in it the altera- 
tion in the colour of the blood produced by artificial respiration is 
readily observed. The dependence of convulsions upon the blood, 
is also easily observed : the convulsions appearing as the comb 
becomes livid, and again disappearing when artificial respiration 
has been employed, and the colour of the comb becomes bright. 
In poisoning by hydrocyanic acid, however, I have observed that 
convulsions come on while the mucous membranes are still of a 
bright colour, so that we may conclude that they are not due to 
a venous condition of the blood, as in ordinary suffocation. They 
might be due to the formation of a compound between the hydro- 
cyanic acid and the blood, as in poisoning by nitrites or carbonic 
oxide ; but accurate analyses have shown that hydrocyanic acid 
does not displace the oxygen in haemoglobin like carbonic acid; 
nor lock it up in the form of methsemoglobin like the nitrites. 
We are therefore obliged to consider the possibility that the 
dyspnoea and convulsions produced by hydrocyanic acid are not 
due so much to its effect upon the blood circulating in the 
medulla as to an action on the cells of the medulla itself, by 
which it prevents the ordinary internal respiration taking place 
in them. 

Action of Drugs on the Respiratory Centre. 

A useful method of testing the action of the drug itself on the respiratory 
centre is to perform artificial respiration vigorously so as to produce apnoea, 
to allow the respiration to become normal again, then to inject the drug and 
again try to produce apncea. If the drug has excited the respiratory centre, 
apnoea ■will be much more difficult to produce after its injection than before, 
and will last a shorter time ; if it has depressed it, apnoea will be more easily 
produced, and will last longer. 

Apnoea lasting for a short time may be readily produced by taking five or 
six very deep breaths, and the effect of drugs on the respiratory centre may 
be readily tried by anyone in the following way. Laying a watch before 
him, shutting his mouth and holding his nose, let him first ascertain how 
many seconds he can hold his breath after previous ordinary respiration. 
Next let him produce a certain amount of apnosa by six or more deep respira- 
tions, and again ascertain how long he can hold his breath. After repeating 
these observations several times,, let him take the drug to be tested and 
repeat them again, taking care that all the circumstances should be the same 
as before. 

The activity of the respiratory centre is augmented by 
heat, so that the respirations become both quicker and deeper, 
and more respiratory work is done. Strychnine, ammonia, 
atropine, duboisine, brucine, thebaine, apomorphine, emetine,, 



ghap. x.] ACTION OF DRUGS ON EESPIRATION. 241 

members of the digitalis group, salts of zinc and copper, have a 
similar action. 

It appears to be first excited and then depressed by caffeine, 
colchicin, nicotine, quinine, and saponine. 

It is diminished by cold, so that the respirations become 
slow and shallow. Chloral, chloroform, ether, alcohol, opium, 
pbysostigrnine, muscarine, gelsemine, aconite, and veratrine in 
large doses, all have a similar action. 

The action of drugs on the respiratory centre is one of great 
importance, not only as giving us a definite basis on which to 
found a plan of treatment in respiratory diseases, but as helping 
us to preserve life in cases of poisoning — drugs which stimulate 
being antagonised by those which depress the respiratory centre, 
and vice versa. 

The chief afferent nerves, by which the distribution of the 
respiratory movements is altered, may be divided into two classes 
— those having an inspiratory and those having an expiratory 
action. 

The expiratory are the nasal branches of the fifth, the supe- 
rior laryngeal, the inferior laryngeal, and the cutaneous nerves, 
especially of the breast and belly. 

The chief inspiratory are the branches of the vagus. going to 
the lung, but all sensory nerves when slightly stimulated appear 
also to have an inspiratory action. 

The vagus appears, however, to contain both expiratory and 
inspiratory fibres, which are alternately stimulated by the con- 
dition of the lung. Expansion of the lung appears to stimulate 
mechanically the inhibitory or expiratory fibres; while its collapse 
stimulates the accelerating or inspiratory fibres. 

When the expiratory nerves are stimulated, the respiratory 
movements become slower and deeper ; and if the stimulation be 
strong they may stop altogether in expiration, with the diaphragm 
in complete relaxation. 

Stimulation of the inspiratory nerves causes the respiration 
to become quicker and shallower, and at length to stop in 
inspiration, the diaphragm being in a state of tetanic contraction. 

These are the general results, but they are not quite con- 
stant. The reason for this inconstancy may be either that all 
the nerves contain both inspiratory and expiratory fibres, or that 
the same fibres may stimulate either the inspiratory or expiratory 
centres, according to the strength of the stimulus and the con- 
dition of the animal. Thus, when the vagus is divided, the 
stimulus which is conveyed to the respiratory centre being re- 
moved, the respirations usually become very slow; when the 
central end of the divided nerve is irritated they become quick, 
and a very strong current may stop them in inspiration. But this 
is not always so : when the nerve is very much exhausted, irri- 
tation by a strong current may have an entirely opposite effect, 



242 



PHAEMACOLOGY AND THERAPEUTICS, [sect, u 



and cause the respiration to stop in expiration instead of inspira- 
tion. 

The probability that the same nervous fibres may, under dif- 
ferent conditions, excite either inspiration, expiration, or the 
two alternately, is rendered still greater when we consider some 
other experiments ; and the contradictory results which have been 
obtained by various observers in regard to the action of druga 
may depend to a great extent on the strength of the stimulus 
they have used and the state of exhaustion of the animal. Thus 
Langendorf has found that all sensory nerves in the body when 
slightly stimulated have an inspiratory, but when stimulated 
more strongly have an expiratory action. Eosenthal found that 
irritation of the crural nerves caused alternately deep inspiration 
and expiration in animals which were not narcotised. In nar- 
cotised animals, Langendorf, on slight irritation, observed an 
inspiratory effect, indicated by quickening of the respiration or 
slight inspiratory tetanus ; but when the experiment was con- 
tinued long, or the irritation was increased, the contrary or 
expiratory effect was observed, indicated by a slowing of the re- 
spiration. 

On the hypothesis that the various actions of respiration 
depend upon individual centres, inspiratory, expiratory, and in- 



Inspiratory and Expiratory Fibres) 
for voluntas alterations in Hespi- \ 
ration J) 



Cutaneous Nerves of Pace 

■g ("Nasal Branch of Fifth Nerve..! 



Superior Laryngeal Nerve . . .. 
Inferior Laryngeal Nerve 
Larynx ...*.••■.. 



b (.Cutaneous Nerves of the Chest 

Expiratory Fibres of Vagus excited by 
distension of Lung 



Inspiratory Fibres of Vagus excited by 
collapse of Lung 




Respiratory Centre In 
Medulla and Cord 



Spinal cord 



Fig. 81.— Diagram showing the position of the respiratory centre, and the afferent nerves which 
influence it. Inspiratory nerves are indicated by plain, aud expiratory by dotted, lines. 

hibitory, it is exceedingly difficult, or impossible, to understand 
the contradictory results of various experimenters ; but the ques- 
tion seems much less intricate when we regard it as due to the 



chap, x.] ACTION OP DRUGS ON RESPIRATION. 



243 



interference of stimuli passing at different rates in different 
directions, or to different distances, according to the strength of 
the stimulus and the irritability or exhaustion of the nervous 
system. 

In regard then to inhibitory or slowing, and to stimulating or 
accelerating nerves or fibres, it must be carefully borne in mind 
that the same fibres may possibly have either the one or the other 
action, according to the conditions under which they are acting. 

If we keep this carefully in view we may continue to use the 
terms accelerating and slowing or inspiratory and expiratory 
nerves as convenient means of expression. These are shown 
in the accompanying diagram (Fig. 81). 

The movements of respiration are most easily counted, and their depth 
and the relation of inspiration to expiration are best noted by causing 
them to register themselves on a revolving cylinder. Various means of 
doing this have been suggested by different authors. One of the simplest 
consists of a needle pushed into the diaphragm, and connected by a 
thread with one of Marey's levers. Marey's pneumograph consists of a 
cylinder of soft indiarubber, enclosing a spiral spring, whose extremities 
are connected with two pieces of metal which form the ends of the 
cylinder. A band is passed round the thorax of the animal, and attached 
to the ends of the cylinder. The interior of the cylinder is brought into 
communication with one of Marey's levers, and as each respiratory move- 
ment draws the ends of the cylinders wider apart, or allows them to approach, 
the air is rarefied or compressed, and a corresponding movement is trans- 
mitted to the lever. Bert has modified this, and made it more sensitive by 
making the cylinder itself of metal, and its ends of indiarubber. Another 
method — one more ordinarily employed — is to introduce one limb of a 
T-tube into the nostril or trachea of an animal, or connect it with a tracheal 
cannula. The respired air passes through the other end, and the third limb 
is connected with one of Marey's levers. 

In the attempt to find out whether the alteration in respira- 
tion produced by any drug is due to its action on the respiratory 
centre, or on some of the nerves which influence it, we may 
find the following table useful by showing at a glance the chief 
ways in which the respirations may be rendered quicker or 
slower : — 



{Excitement of nerves. 
Greater excitement of 
respiratory centre, 



Stimulation of the vagus. 
Stimulation of optic nerve. 
Stimulation of acoustic nerve. 
Action of brain (voluntary). 
Increased temperature of blood. 
Increased venosity of blood. 
Action of drugs. 



Diminished excite- f Diminished venosity of blood. 



The respiratory 
movements may< 
be rendered slow 
by 



ment of respiratory 
centre. 



Nervous influences. 



Action of drugs. 
, Action of brain (voluntary), 
f Paralysis of vagi. 

Stimulation of superior laryngeal nerves. 

Stimulation of inferior laryngeal nerves. 

Stimulation of nasal nerves. 

Stimulation of cutaneous nerves. 
iStimulation of splanchnic nerves. 

r 2 



244 PHAEMACOLOGY AND THERAPEUTICS., [sect. r. 

If the drug to be experimented on be injected subcutaneously 
or into the veins, the actions on the respiratory centre and on 
the vagi are the chief points which require attention ; but if we 
are experimenting with a vapour, its local action on the nasal,, 
laryngeal, and possibly, also, on the pharyngeal nerves ' must be 
carefully attended to, as it may greatly modify its general action 
on the respiratory centres. Thus Kratschmer has found that 
tobacco-smoke inhaled by a rabbit through its nostrils, or blown 
upward into the nasal cavity from an aperture in the trachea, 
will cause arrest of breathing in a state of expiration from the 
irritating effect of the vapour of the nasal branches of the fifth, 
while it has no such effect when blown into the lungs. Ammonia, 
when inhaled, also arrests the respiratory movements in the 
same way ; but Knoll 2 has observed that if it be blown into the 
lungs while the nostrils are carefully protected from its influence, 
it causes accelerated and shallow breathing, alternating with slow 
and deep respirations, and occasional stoppages in the position 
of expiration, obviously from its action on the different fibres of 
the vagi. 



Action of Drugs on the Respiratory Nerves. 

In experiments regarding the effect of drugs upon the re- 
spiration, the voluntary influence of the brain is excluded by the 
use of ether, chloroform, opium, or chloral, or by section of the 
crura cerebri. In the case of such poisons as cause sickness 
allowance must be made for the effect of gastric irritation. It 
will usually be found that before vomiting occurs the respiratory 
movements are very rapid, but they become slower after vomiting 
has taken place. As the chief afferent fibres from the stomach 
are contained in the vagus, the effect of irritation of the gastric, 
as well as of other fibres contained in these nerves, is prevented 
by their division. Sometimes the action of a drug on the 
peripheral ends of the vagus and upon its roots in the medulla 
may produce exactly opposite effects upon the respiration. Thus 
atropine appears to lessen the excitability of the respiratory 
fibres of the vagus, while it stimulates the respiratory centre. 
Such an action may be to a certain extent inferred from the 
respiration becoming slower almost immediately after the injec- 
tion of the drug into the jugular vein, and while it is still passing 
through the lungs, and by this slowing being quickly succeeded 
by acceleration when the drug begins to circulate through the 
medulla. 

There are two kinds of experiment by which such a conclu- 
sion may be tested. The one is to apply the drug first to the 



Brown-SSquarcl, Archives of Scientific and Practical Medicine, p. 94. 
Sitzungsber. der Wien. Acad., vol. lxviii. Abt. 3, p. 255. 



chap, x.] ACTION OF DEUGS ON EESPIEATION. 245 

medulla by injecting it into the carotid artery, and seeing whether 
acceleration occurs at once and afterwards becomes less when 
the drug has had time to pass round again to the lungs. The 
other way is to divide the vagi before the injection and observe 
the effect. Any alteration in the respiration in the way of either 
quickening or slowing which the drug produced in the uninjured 
animal should remain the same after division of the vagi if 
its effect were due to its action on the medulla, but will be 
absent if it were due to an action upon the peripheral ends of 
the vagi. 

This method was introduced into pharmacological research 
by Von Bezold in his admirable research on atropine, and it is 
the one usually employed. 

There is one fallacy, however, which must not be entirely lost sight of, 
which is, that after division of the vagi the nerves which remain in con- 
nection with the respiratory centre have chiefly a slowing action on the 
respiration; and thus a drug which really renders the respiratory centre 
more susceptible to reflex influences might seem to have a depressing action 
upon it. 

While atropine injected into the jugular vein seems to pro- 
duce first a slowing of the respiration, due to its paralysing 
action on the vagus ends, and afterwards a progressive quickening 
as more of it is carried out of the lungs into the medulla, phy- 
sostigmine, muscarine, and veratrine have an opposite action, 
quickening the respiration at first by their stimulating action on 
the vagus ends, and afterwards slowing it by their action on the 
medulla. 

In the action of veratrine upon the pulmonary branches of 
the vagus we may notice a resemblance to the stimulant action 
which, as already mentioned, it exerts upon the nerves of or- 
dinary sensation. If the sensory branches of the vagus are 
affected by drugs in a somewhat similar way to those of ordinary 
sensation, as the action of veratrine might lead us to imagine, 
we should expect them to be much stimulated also by aconite, 
and, indeed, according to Boehm and Ewers, this is the case. 
The respiratory changes produced by aconite are regarded by 
them as due, in part, to irritation of the peripheral ends of the 
vagus, and disappear on section of the vagi or the administra- 
tion of atropine. 

Sternutatories or Errhines. 

These are drugs which cause sneezing and increased secre- 
tion from the nose when locally applied to it. The drugs must 
be in a pulverised condition. The chief are ; — 

Tobacco (snuff). Euphorbium. 

Veratrum album. Sassy bark. 

Ipecacuanha. Saponine. 



246 PHARMACOLOGY AND THERAPEUTICS, [sect. I. 

Irritation applied to the nose is transmitted by the nasal 
branches of the fifth to the respiratory centre in the medulla 
oblongata, and excites the sudden and forcible expiratory move- 
ments of sneezing. At the same time, however, the stimulus is 
transmitted to the vaso-motor centre, and the blood-pressure 
becomes considerably increased by the contraction of small vessels 
throughout the body, even when no sneezing occurs. When 
sneezing takes place, the pressure is still further increased by 
the muscular efforts which occur in the act. It is probable that 
there is not only general rise in blood-pressure but also that 
local dilatation of the cerebral vessels is reflexly produced by 
the nasal irritation, and thus a stimulant effect is produced on 
the brain. Snuff is therefore employed as a luxury giving a 
feeling of comfort and enabling the snuff-taker to think more 
clearly — ' clearing the head ' as it is often termed (vide p. 193). 

Uses. — Though comparatively little used now, sternutatories 
were formerly employed in failure of memory, deafness, and 
severe persistent headache. From the violent expulsive efforts 
which they induce, they were given also to cause the expulsion 
of foreign bodies from the air-passages, and to hasten the ex- 
pulsion of the child in' cases of lingering labour where no ob- 
struction was present, but where expulsive force was deficient. 
They were given also in order to try and check diseases at the 
commencement, by what was termed ' shock to the system.' 

One curious thing is to be remarked, that stimulation of one 
part of the respiratory tract may arrest abnormal actions in 
another. Thus Marshall Hall has shown that actual sneezing 
may frequently be prevented, after the inspiration by which it 
is usually preceded has occurred, by forcibly rubbing the end of 
the nose or by tightly compressing the nostrils. In a similar 
way irritation of the interior of the nose by snuff will sometimes 
arrest obstinate hiccough. 

Contraindications. — On account of the high blood-pressure 
which they produce their use is by no means free from danger 
in persons affected with atheroma or a tendency to pulmonary 
haemorrhage or apoplexy, as they may cause rupture of a vessel, 
and in those who suffer from hernia or from prolapsus of 
the uterus, they may seriously increase the gravity of these 
affections. 



Respiratory Sedatives. 

These are substances which diminish cough and spasmodic 
difficulty of breathing. ' 

They may be divided into drugs which — 

(1) Tend to remove the irritation which acts as the exciting 
cause of the cough. 



chap, x.] ACTION OF DRUGS ON RESPIRATION. 



247 



(2) Tend to lessen f (a) the afferent nerves in the lungs ; 
irritability of | (6) the respiratory centre. 

Pathology of cough. — Cough consists in a deep inspiration 
followed by a forcible expiration with closed glottis, so that the air 
is driven rapidly through the larynx, carrying with it foreign sub- 
stances, liquid or solid, which may be present in the air-passages. 
As it is a modified respiratory act, the nerve-centre by which the 
muscles employed in it are co-ordinated is situated in the medulla 
oblongata. 

The afferent fibres by which cough may be excited are chiefly 
branches of the vagus. One of the most powerful is the superior 



Pharynx \ Cough very vio- 
I lent.ofteuaccom- 
[ panied by retch- 

CEsophagus j ing or vomiting. 




Liver 



Fig. 82.— Diagram of the afferent nerves by which cough may be excited. These nerves are shown 
passing to the respiratory centre in the following order from above downward— from the audi- 
tory meatus, pharynx, upper part of oesophagus, larynx and trachea, bronchi, lung, costal 
pleura, liver and spleen. 

laryngeal nerve distributed to the glosso-epiglottidean folds and 
to the whole of the interior of the larynx, and this being a 
special expiratory nerve we find that irritation of the larynx and 
also of the trachea is usually characterised by a cough with very 
violent expulsive efforts. Irritation of the mucous membrane of 
the trachea especially at the bifurcation of the bronchi, and 
irritation of the substance of the lung, also give rise to cough ; 
and irritation of the costal pleura and of the oesophagus does so 
also. 1 Irritation of the auditory meatus at the point to which 
the auricular branch of the vagus is distributed will also cause 
coughing ; and cough appears to be also induced by irritation of 
certain parts of the interior of the nose. These are the surfaces 
of the inferior and middle turbinated bones, the most sensitive 



Kohts, Virchow's Archiv, 66, 191. 



248 PHAEMACOLOGY AND THERAPEUTICS, [sect. & 

part being the posterior end of the inferior turbinated bone and 
the portion of the septum immediately opposite. 1 The sudden 
application of cold to the skin on various parts of the body will 
sometimes cause coughing. Probably the cough in this case is 
not due to the stimulus being conveyed directly to the respiratory 
centre by the cutaneous nerves, but to its causing congestion 
of the air-passages, as in Eossbach's experiments (p. 252). The 
congestion then causes irritation of the sensory nerves of the 
bronchi, and occasions cough. 

T have seen irritation of the liver and spleen, induced by 
percussion over them, in a man suffering from chronic enlarge- 
ment due to malaria, likewise cause coughing. 2 In addition to 
those nerves, however, it appears that irritation of the glosso- 
pharyngeal branches distributed to the pharynx, where the 
digestive and respiratory tracts coincide as they cross one an- 
other, may not only excite coughing, but may also act as an 
auxiliary to irritation of the branches of the vagus. The com- 
bined action of the two may thus induce cough, when irritation 
of the vagus alone would not do so. Thus we find that many 
persons begin to cough as soon as they lie down, but that some- 
times by lying round partially on the face, the cough ceases. In 
these persons the uvula is often found to be long and much con- 
gested, and the tickling which it produces as it rests upon the 
pbarynx or pillars of the fauces seems to aid the irritation in 
the respiratory passages, and produce cough. 

Cough due to irritation of those parts of the respiratory 
tract where the nerves are chiefly expiratory, as the pharynx, 
larynx, trachea, and large bronchi, is usually, as might be ex- 
pected, loud, explosive, and prolonged ; while cough due to irri- 
tation of those parts where the nerves are chiefly inspiratory is 
short and hacking (Pig. 82). 

Cough produced by irritation of the pharynx where the, re- 
spiratory and digestive passages cross one another, is not only 
violent, noisy, and barking, but, as we would naturally expect, 
is not unfrequently accompanied by retching or vomiting. 

Pharyngeal irritation may accompany dyspepsia, and it is 
probably the origin of the so-called stomach-cough. Irritation 
of the stomach itself, or of its nerves, causes vomiting, but does 
not produce cough. 

Nevertheless there is a rationale for the common expression 
' stomach-cough.' In some experiments on the reflex origin of 
cough, E. Meyer 3 has noticed that when some part, from which 

1 On Nasal Cough, by John N. Mackenzie, M.D., reprint from The American 
Journal of the Medical Sciences, July 1883. 

2 These observations were made in January and April 1879, but not published. 
Naunyn, in a paper published in the Deutsch. Archw f. Mm. Med. in March 1879 
recorded similar observations. 

■ E. Meyer, Correspondenzblatt d. Schweiser Aerate, No. 1, 1876. 



chap, x.] ACTION OP DRUGS ON RESPIRATION. 249 

cough can be reflexly induced, is already in a state of irritation, 
cough can be brought on with great ease by irritation of a neigh- 
bouring part which would not by itself cause cough. Something 
of this kind appears to occur with the stomach, for although 
irritation of the stomach alone will not cause coughing, yet it 
will do so if irritation of the larynx and trachea are already 
present. Thus I have observed violent spasms of coughing occur, 
along with acidity and heartburn, some time after a meal, in a 
person suffering from congestion of the pharynx, larynx, or 
trachea. The connection between the cough and the acidity was 
shown by the cough ceasing as soon as the acidity was relieved 
by a dose of alkali and the consequent removal of the irritation 
to the stomach, which the acidity had produced. 

Remedies which Lessen Irritation. 

Soothing remedies applied to the pharynx greatly relieve 
cough, although they do not reach so far down as the epiglottis. 
Mucilaginous remedies are very useful for this purpose, and they 
may either be employed alone or as vehicles for the local appli- 
cation of sedatives such as morphine. Thus, a piece of extract 
of liquorice allowed to dissolve in the mouth, a marsh-mallow 
lozenge, a gum-jujube, or a sip of linseed-tea, by covering the 
back of the throat with a mucilaginous coating, will lessen cough 
to a great extent. Such remedies are especially useful where the 
cough depends on congestion of the pharynx and trachea. '> In 
such cases no abnormal sound at all may be heard in ausculta- 
tion, and the cough being due to irritation of the parts supplied 
by the superior laryngeal nerve, has a peculiarly convulsive 
expiratory character often termed ' barking.' 

Other remedies lessen cough by diminishing congestion of 
the respiratory passages, and thus lessening the irritation which 
causes the cough. Many of these also, however, come under the 
class of expectorants (p. 250), inasmuch as the diminished 
congestion is frequently associated with increase of the ex- 
pectoration. Others, again, although they diminish cough, are 
included rather under the head of ' cardiac tonics,' or sedatives. 
Digitalis is an example of this. In the congestion due to 
cardiac disease, and even in that due to bronchitis, digitalis, by 
strengthening the heart and by contracting the vessels, may 
lessen the congestion in the lungs, and give the patient relief. 
Squill and a number of other drugs have an action on the blood- 
vessels similar to that of digitalis. 

Other remedies, such as the vapour of hydrocyanic acid, 
conium, stramonium, and tobacco, have a local sedative action 
on the lung, and may lessen cough ; they also are used in order- 
to diminish local spasm of the bronchioles, and thus to relieve 
spasmodic asthma. 



250 PHABMACOLOGY AND THEEAPEUTICS. [sect. i. 



Pulmonary Sedatives. 

These are remedies which lessen the irritability of the respira- 
tory centre or of the nerves connected with it. The chief drugs 
which diminish the excitability of the respiratory centre are 
opium and its principal alkaloid, morphine. Morphine and 
opium have a double action in lessening cough : they not only 
lessen the excitability of the respiratory centre, but they 
diminish the secretion of mucus in the bronchial tubes, and 
probably thus also lessen the irritation. Hydrocyanic acid has 
also a sedative action on it, but it is by no means so powerful as 
the others. 

Belladonna and stramonium have a rather peculiar action, 
stimulating the respiratory centre, and at the same time appear- 
ing to lessen the excitability of the ends of the vagi in the lungs. 
Atropine has but a very slight and uncertain action on the 
respiratory centre in preventing cough, if indeed it has any at 
all. It has, however, a powerful effect — much more powerful 
than that of opium, — in completely arresting the secretion 
from the bronchial tubes. The cases in which it is useful are 
therefore those where the cough depends upon excessive secre- 
tion; In cases where the mucous membrane is already too dry, 
it would be injurious rather than beneficial. 

When apomorphine and morphine are given together they do 
not destroy each other's action, so that from the combination we 
get increased secretion from the mucous membrane, with dimin- 
ished irritability of the respiratory centre, and consequently 
lessened cough. The cases in which this combination, then, is 
useful, are those where there is difficulty of breathing, continual 
cough, and thick tenacious mucus. When morphine and atropine 
are given together, also, they do not destroy each other's action ; 
and thus dryness of the mucous membrane is produced, along 
with diminished irritability of the centre for coughing. This 
combination is therefore useful in cases of catarrh, emphysema, 
and phthisis, where there is copious secretion of mucus. In 
phthisis it is especially indicated on account of the beneficial 
action of atropine in also lessening sweating. Where the copious 
expectoration depends upon the presence of a cavity, and not on 
excessive secretion from the bronchi, it will not be much affected 
by the use of these remedies. 

Expectorants. 

Expectorants are remedies which facilitate the removal of 
secretions from the air-passages. The secretion may be ren- 
dered more easy of removal, either by an alteration in its 
character rendering it less adhesive and more easily detached 



chap, x.] ACTION OF DEUGS ON EESPIEATION. 251 

from the air-passages, or by increased activity of the expulsive 
mechanism. 

Our knowledge of the use of expectorants is founded chiefly 
on empiricism. We are almost entirely indebted to the recent 
experiments of Eossbach for any precise information as to their 
mode of action. 1 

The secretion from the air-passages, like other secretions, 
depends partly upon the condition of the circulation, and partly 
on the secreting cells themselves. 

• In healthy conditions the increased secretion and increased 
circulation of blood in the mucous membrane go together, but 
just as in the case of the sweat-glands, these two factors may 
occur independently of each other, and secretion may take place 
rapidly when the circulation is diminished and the mucous mem- 
brane is anaemic, and, on the other hand, it may stop altogether 
when the vessels are dilated and the mucous membrane is con- 
gested. The latter happens both in cases of disease and in 
animals poisoned by atropine. 

The secretion from the normal respiratory mucous membrane 
consists of a thin solution of mucin which dries very slowly, and 
is only secreted in sufficient quantity to keep the mucous mem- 
brane moist. It is slightly adhesive, and any particles of dust, 
&c, which may have found their way into the trachea, will stick 
to the walls of the air-passages, and will be gradually moved up 
towards the mouth by the cilia with which the cells of the mucous 
membrane are furnished. Any excess of mucus secreted in 
consequence of irritation will also be moved upwards by the cilia 
in a similar manner. In the ciliated cells of the mucous mem- 
brane we recognise a structure which is frequently met with in 
animals lower down the scale of existence, and the mucous mem- 
brane of the respiratory passages appears to resemble the parts 
of lower organisms, in being very slightly controlled by the 
central nervous system. When not irritated it secretes slowly 
and regularly ; when irritated locally the secretion is increased, 
but irritation of the nerves passing to it, such as the vagus, the 
superior or inferior laryngeal, or the sympathetic, does not cause 
any increase as it does in the case of the submaxillary gland. 
These nerves, however, can influence it indirectly through the 
circulation, for when they are divided an increased dilatation 
of the vessels occurs in the mucous membrane of the trachea, a 
freer circulation of blood occurs, and increased secretion is thus 
indirectly produced. When they are irritated, however, and 
anaemia of the trachea produced, the secretion is not arrested* 
but continues. 

The circulation in the mucous membrane is readily affected 
reflexly by irritation of other parts of the body. When, for 

1 Festschrift der Julius-Maximilian- Universitat eu Wiirzburg, Leipzig. 



252 PHAEMACOLOGY AND THEEAPEUTICS. [bect. i. 

example, a warm poultice is laid for five or ten minutes on the - 
belly of an animal, and then afterwards replaced by ice, the 
mucous membrane of the trachea and larynx becomes m halt a 
minute deadly pale from the contraction of its vessels. Though 
the ice is still allowed to remain on the belly, the tracheal mucous 
membrane quickly changes colour, and to the paleness succeeds 
first slight redness, then deep red congestion, and m five or ten 
minutes lividity. This lividity shows that the congestion is not 
arterial but venous, and that the circulation, instead of being 
quicker is really slower. Along with the increase of congestion 
in the mucous membrane, the amount of mucus secreted in- 
creases. When the ice is removed for half an hour, and again 
replaced by the warm poultice, the bluish-red colour of the 
mucous membrane almost immediately disappears and gives place 
to a rosy colour which is, however, redder than normal. Ice 
again applied will cause a second contraction of the vessels and 
paleness, though much less than before. These experiments 
show how sensitive is the mucous membrane of the trachea to 
reflex stimulation of other parts of the body by heat or cold, and 
enable us to understand more readily how a draught of cold air 
on some part of the body should cause inflammation of the 
respiratory organs. » 

Action of Drugs on the Secretion.— Alkalies, such as car- 
bonate of sodium, injected into the blood, lessen, or in large 
quantity completely arrest, the secretion of mucus from the 
trachea. 

This experimental result is in contradiction to the teaching 
of clinical experience, which shows us that alkalies increase the 
amount of secretion, and render it more fluid. The results of 
clinical observation are quite as certain as those of Eossbach's 
experiments, for we may not only remark the greater quantity of 
expectoration, and its greater fluidity in persons taking alkalies, 
but we may note the alteration which they occasion in the 
amount and nature of the moist rales heard within the lungs. 
This can be observed most readily in persons suffering from 
phthisis, especially round the margin of the cavity. After catch- 
ing a slight cold an extension of consolidation may be remarked, 
in which moist rales readily occur on the administration of dilute 
alkalies. When these are continued until the expectoration has 
been free for a day or two and the rales diminish, acids may be 
given with advantage, so as to dry up the expectoration still 
more. But if the acid is given too soon the expectoration dimi- 
nishes, but the cough increases and becomes troublesome to the 
patient. 

In all probability the difference between the results of clinical 
observation and Eossbach's experiments depends upon the dif- 
ference of dose, the quantity usually given to a patient being 
proportionately much smaller than that which he employed. We 



chap, x.] ACTION OP DEUGS ON EESPIEATION. 253 

are able to observe a similar difference between tbe effects of 
small and large doses in the case of iodide of potassium ; a small 
dose of a grain and a half, taken by a healthy man three times 
a day, will almost certainly cause the nose to run freely, while if 
the dose be increased to ten, twenty, or thirty grains the .excessive 
secretion will almost certainly be arrested. 

The local application of one to two per cent, solution of 
sodium carbonate has very little action. The local application of 
strong liquor ammoniee causes both congestion and increased 
secretion of mucus. Very strong solutions cause a croupous 
exudation from the surface of the mucous membrane. The local 
application of dilute acetic acid (three per cent, solution) has a 
similar action to weak solutions of ammonia : the mucous mem- 
brane becoming redder and secreting more mucus. 

When acetic acid was given internally, Eossbach observed in 
one case that the mucus, which was before watery and clear, 
became gelatinous and opalescent. This result agrees with what 
one finds clinically, that acids dry up the secretion and make it 
harder to expectorate. 

Among astringents Eossbach tried tannin, alum, and nitrate 
of silver; the first two" when locally applied made the mucous 
membrane appear paler by altering the epithelium and rendering 
it opaque, so that the vessels underneath could hardly be seen ; 
at the same time they arrested the secretion of mucus almost 
entirely. A four per cent, solution of nitrate of silver also caused 
opacity of the epithelium, arrest of secretion, and dryness of the 
mucous membrane. There appears to be a difference in the 
action of nitrate of silver on the mucous membrane of the nose 
and on the trachea, as when the inside of the nose is touched 
by it, it causes a profuse secretion, whereas it causes dryness in 
the trachea. 

The vapour of oil of turpentine mixed with air arrests the 
secretion of mucus, whilst a current of air alone, without admix- 
ture with oil of turpentine, will act as an irritant to the mucous 
membrane and increase secretion. Here again, however, a 
marked difference is to be seen in the effect of small and large 
doses, for when a watery solution containing from one to two 
per cent, of oil of turpentine was dropped directly on the mucous 
membrane, it became less vascular, but the secretion was at 
once increased, instead of being diminished, as it was by the 
vapour. 

This action of oil of turpentine is of great cherapeutical 
importance, inasmuch as in many cases of bronchitis we have 
profuse secretion with vascular congestion, a condition likely to 
be removed by the vapour of oil of turpentine. 

Apomorphine, emetine, and pilocarpine, when given internally, 
all cause a ; great increase of the secretion of mucus, but they 
do not alter the vascularity of the mucous membrane. The., 



254 PHARMACOLOGY AND THERAPEUTICS, [sect. i. 

most powerful of all these is pilocarpine, and after it come apo^ 
morphine and emetine. One would therefore expect that pilo- 
carpine would be the best remedy in catarrhal conditions, but 
this is not the case, for its other actions on the salivary and 
sweat glands and on the heart render its^ administration un- 
pleasant for the patient. Sometimes also hi children oedema of 
the lungs has followed its use. Apomorphine, on the contrary, 
has been found by Rossbach to be of the greatest service in 
catarrh of the larynx, trachea, and bronchi, both in adults and 
in children. Ipecacuanha has long been recognised as one of the 
most useful expectorants, but the dose given is often too small. 

Rossbach's experiments have shown that the consequence of 
sudden changes of heat and cold applied to a part of the body is 
congestion of the respiratory mucous membrane with diminished. 
circulation and stagnation of blood in the veins. A similar con- 
dition occurs in many cases of chronic bronchitis, and in them 
we not unfrequently find great benefit from vascular tonics such 
as digitalis, which, in addition to stimulating the vaso-motor 
centre, increase the activity of the heart, and thus tend to main- 
tain the pulmonary circulation. 

In what way cod-liver oil affects the bronchial mucous mem- 
brane it is perhaps hard to say, but there is no doubt whatever 
that it is one of the most efficient expectorants that we possess, 
and in cases of chronic bronchitis it affords more relief than 
any of the ordinary expectorants. It is possible that, being a 
form of fat which is readily assimilated, it is taken up by the 
young epithelial cells of the respiratory mucous membrane, and 
thus enables them to grow and maintain their attachment to the 
mucous membrane, instead of being at once shed in an unde- 
veloped form as pus-cells in the expectoration. 

Action of Drugs on the Expulsive Mechanism.— The 
expectorants which act by increasing the activity of the expulsive 
apparatus may be divided into — 

(1) Those which increase the rapidity of the ciliary motion 
in the tracheal mucous membrane. 

(2) Those which increase the activity of the respiratory 
centre. 

We have no direct experiments or observations on the rapidity 
of the ciliary motion in the bronchial mucous membrane of the 
higher animals, but ammonia has been found to increase its 
rapidity in the mucous membrane of the frog. 

The remedies which increase the activity of the respiratory 
centre are : strychnine, ammonia, emetine, ipecacuanha, bella- 
donna, atropine, senega, and saponine. They are used more 
especially in cases of bronchitis where the expectoration is 
imperfect. 

The chief expectorants have been divided into depressant and 
stimulant. Thoy are as follows :— 



chap, x.] ACTION OP DKUGS ON EESPIEATION. 



255 



Depeessant Expectorants. Stimulating Expectoeants. 



Generally tending to depress 
the heart, lessen blood-pressure, 
and increase secretion. 

Antimonial preparations, 

Tartar emetic. 
Alkalies. 
Ipecacuanha. 

Emetine, 
Lobelia. 

Lobeline. 
Jaborandi. 

Pilocarpine, 
Apomorphine. 
Quebracho. 

Quebrachine 
Potassium iodide, 



Balsams 



Terebin- 
thinates 



Generally stimulating the 
heart, increasing blood-pressure, 
and diminishing secretion. 
Acids. 

(chloride, 
carbonate, 
hydrate 
(Ammonia). 
Nux vomica. 

Strychnine. 
Senega. 

Saponine. 
Squill. 

Benzoin. 
Benzoic acid. 
Balsam of Tolu. 
.Balsam of Peru. 
/Wood tar. 
Terebene. 
Turpentine. 
( Oleum Pini 

Sylvestris. 
Oleum Pini 
VPumilionis. 
Sulphur. 

Saccharine j Syrups, 
substances I Liquorice. 

Adjuncts. — One of the most powerful adjuncts to expectorants 
is an emetic, which frequently will clear the lungs and save life 
in cases of chronic bronchitis with impending suffocation, when 
ordinary expectorants have completely failed. 

One of the emetics most commonly employed in such cases is 
ipecacuanha, either alone or combined with squill, e.g. half a fluid 
ounce each of ipecacuanha wine and oxymel of squills. When 
there is great depression, however, and the circulation is very 
feeble, carbonate of ammonium is to be preferred. 

Another powerful adjunct is warmth and moisture in the 
room in which the patient is living, and this is best secured by 
means of steam brought well into the room from a kettle placed 
upon the hob. The kettle used should either be furnished with a 
very long spout, as in the case of the ordinary bronchitis kettle, 
or a long tube made of a piece of stout brown paper tied around 
with a string may be used to convey steam into the room from 
the nozzle of an ordinary kettle. 



256 PHARMACOLOGY AND THERAPEUTICS, [seot.i. 

Respirators are also serviceable, by preventing the entrance 
of cold air into the trachea. Many persons, forgetting that the 
mouth is part of the digestive tract, and that the nose is the 
proper entrance to the respiratory tract, breathe through their 
mouth ; the consequence is, that the cold air passes down the 
trachea without being previously warmed. In the nose we bave 
a special arrangement for warming the air. The turbinated 
bones present an enormous warming surface, like some recently- 
invented stoves, and moreover, a special arrangement is made for 
allowing a free flow of blood through this mucous membrane by 
its being loosely instead of firmly attached to the turbinated bones. 
Its vessels are therefore capable of great and rapid distension, 
so as to allow the air to be readily warmed in cold weather. 

Most respirators are made simply to go over the mouth, and 
their advantage is that they force people to breathe through 
their nose, or warm the air if they cannot do so, and continue to 
breathe through the mouth. In many persons the same end may 
be gained by forcing them to wear an invisible respirator. An 
instrument is sold bearing this name, consisting of a thin plate 
of metal ; but what is perhaps quite as good, or better, is a sove- 
reign or half-sovereign placed between the lips and teeth. Patients 
are thus forced to keep the mouth shut in order to prevent it from 
falling out, and its value makes them careful about losing it. 

It is often forgotten too that passages and disused rooms are 
nearly as cold as the external air, and many delicate people who 
would never dream of going outside in cold weather will, without 
thinking, walk through cold passages and in rooms without fires. 
Warm clothing, especially over the shoulders, neck, and chest, 
is very useful, and its utility is recognised by the common employ- 
ment of so-called chest protectors made of chamois leather and 
red flannel. 

Other adjuncts are friction to the chest with stimulating 
liniments ; mustard leaves, warm poultices and the application of 
plasters ; the emplastrum calefaciens (B.P.) or emplastrum picis 
cum cantharide (U.S.P.) is especially useful in chronic bronchitis. 

Arrest of Colds. — Catarrhal affections of the respiratory 
passages may be excited by irritants of various kinds, and it is 
probable that these irritants are frequently living organisms. 
The form of coryza usually called hay-fever is probably due to 
irritation of the nasal mucous membrane by pollen-grains com- 
mencing to grow on it and sending pollen-tubes into its substance. 

Other forms of respiratory catarrh, e.g. measles and influenza, 
are probably associated with specific microbes. 

When the respiratory mucous membrane is perfectly healthy 
it is probable that the invading organisms are quickly expelled 
or destroyed (p, 85) so that no injury results. But when the 
resisting power of the mucous membrane is weak, either on 
account of general constitutional tendencies, or from local anil 



chap.x:] ACTION OF DEUGS ON EESPIEATION. 257 

temporary condition of congestion due to a chill (p. 252), the 
microbes may begin to grow and cause great irritation. 

Among the remedies useful in arresting colds we may recog- 
nise antiseptics, which destroy microbes, and also sedatives, 
which remove congestion. 

_ Hay-fever has been treated by Binz with a watery solution of 
quinine in order to stop the growth of organisms in the nose. In 
some cases this treatment is successful. There is a form of cold 
sometimes known as influenza-cold. Like, true influenza it is 
extremely infectious and is easily communicated, not only by one 
member of a family to another, but even by casual visitors. It 
sometimes begins as a cold in the head, passes down the throat 
to the trachea and bronchi, leading to severe bronchitis with 
much depression and occasionally also to gastro-intestinal catarrh. 
Sometimes it begins in the throat and spreads upwards into the 
nostrils and downwirds into the air-passages. It may frequently 
be arrested or rendered less severe by the use of dilute carbolic 
acid applied to the nostrils in the form of spray or by a syringe 
or rasal douche when the cold begins in the head. When the cold 
begins in the throat it may be arrested by the use of a carbolic 
acid gargle, and such a gargle is also useful when the cold begins 
in the head and is spreading down the throat. 

Inhalations of carbolic acid and ammonia appear to be fre- 
quently useful in arresting colds. It seems probable that their 
effect may be due partly to an antiseptic action and partly to their 
lessening congestion. Carbolic acid inhalations appear to be,, 
useful in whooping-cough, probably from an antiseptic action. 

Camphor inhaled and also taken internally is useful in arrest- 
ing colds, though it may be rather hard to give an explanation of 
its modus operandi. 

The sedatives which remove congestion of the nasal mucous 
membrane may be either general or local. Amongst the local may 
be mentioned bismuth, bismuth and morphine, and cocaine ; and 
amongst the general, preparations of opium, especially Dover's 
powder, and aconite. 

Selection of Remedies in the Treatment of Cough. 

Cough, as I have already said, is a reflex act which is per- 
formed hy means of a reflex mechanism, and is adopted for the 
purpose of expelling foreign bodies from the air-passages. It is 
evident that, when the source of irritation may be removed by 
efforts at coughing, these efforts are useful, and require to be sus- 
tained rather than prevented ; but if the irritant cannot be re- 
moved, the effort of coughing is injurious rather than beneficial, 
and the same is the case when the amount of effort is dispro- 
portionately great to the good that it effects. In these cases we 
must try to lessen the cough. 



258 PHAKMACOLOGY AND THERAPEUTICS, [sect. I. 

The source of irritation in the respiratory passages may either 
he free in the lumen of the bronchial tuhes, or may he situated 
in the mucous membrane lining the bronchi, or in the substance 
of the lung itself. Thus we may have foreign substances, such 
as dust, which have been inhaled, or mucus secreted from the 
bronchi, resting on the surface of the mucous membrane, and 
leading to irritation. Such foreign matter may be expelled by 
coughing, and so may purulent matter lying in a cavity, and the 
cough may be useful by expelling them. 

But if the irritation be simply due to a congested condition of 
the bronchial mucous membrane ; to congestion or consolidation 
of the lung-tissue itself; to a caseous or calcareous nodule which 
is firmly embedded in the lung ; or to inflammation of the pleura, 
it is evident that the efforts at coughing will not remove the 
irritant, but will rather tend to produce exhaustion; and con- 
sequently we must either try to remove the source of irritation 
by other means, or to lessen the irritability of the nervous me- 
chanism by which coughing is produced. Where the cough is 
due to irritation caused by indigestion we may give alkalies to re- 
lieve acidity, but we sometimes find that a blue pill and a black 
draught are amongst the most efficient remedies for coughs of 
this character, by the permanently beneficial action they exert on 
the digestion. When there is irritation of the pharynx, as well 
as of the trachea, mucilaginous substances, such as jujubes or 
linseed tea, are exceedingly useful. 

Where cough depends on congestion of the mucous mem- 
brane of the trachea or bronchi, we not unfrequently find that the 
inhalation of cold air, by causing contraction of the vessels, and 
lessening the congestion, will arrest the cough, so that patients 
are able to walk out on a cold frosty morning for a length of time 
without coughing. On coming into a warm room the vessels of 
the respiratory mucous membrane again dilate : the mucous 
membrane becomes congested, and the congestion leads to violent 
and prolonged efforts at coughing. In such cases counter-irrita- 
tion over the neck, upper part of the chest, and between the 
shoulders is useful, probably by causing contraction of the vessels 
(p. 252), and thus lessening congestion. But congestion, not 
only of the trachea and bronchi, but also of the smaller bronchial 
tubes, may be relieved, not only by counter-irritation, but by in- 
ducing secretion. Congestion of the smaller bronchi indicated 
by loud whistling rales all over the chest, is often accompanied 
by great shortness of breath. The inhalation of hot aqueous 
vapour tends to relieve the congestion by inducing secretion, but 
more powerful agents still are antimony, ipecacuanha, and apo- 
morphine. In such a condition as the one just mentioned, where 
secretion is absent and congestion is great, one or other of these 
drugs should be given frequently until secretion occurs freely, as 
indicated by abundant moist rales in the chest. 



chap, x.] ACTION OF DEUGS ON EESPIEATION. 259 

Along with these depressant expectorants, some preparation 
of opium should be given, in order to lessen the cough, which at 
this stage is of no advantage. It is advisable not to stop the 
administration of these expectorants immediately on the occur- 
rence of secretion, but to continue them for some time longer, 
and gradually to lessen their amount. "When secretion has be- 
come copious, either from the administration of depressant ex- 
pectorants or from the natural course of the disease, we have 
resort to such drugs as will tend to cause its expulsion, and also 
to lessen its formation. Amongst those which tend to lessen its 
formation are balsams and terebinthinates (p. 255), and those 
which tend to assist expulsion have already been mentioned (p. 
254). Along with these we generally combine some preparation 
of opium if the cough is disproportionately severe, and in chronic 
bronchitis cod-liver oil (p. 254) is perhaps the most efficient of 
all remedies. 

Action of Drugs on the Bronchi. — The bronchi contain 
muscular fibres in their walls, which appear to maintain a state 
of tonic contraction similar to that of the arteries. The motor 
fibres which supply these muscles are contained in the vagi. 
When one vagus is cut the bronchi of the corresponding lung ex- 
pand, and when the peripheral end of the cut vagus is stimulated, 
the bronchi contract so much as sometimes almost to close com- 
pletely ; but the vagi appear to contain bronchial-dilating fibres, 
as well as bronchial-constricting, so that irritation of the peripheral 
end of a cut vagus may sometimes cause marked dilatation instead 
of contraction, and sometimes primary contraction followed by 
dilatation. The vagi also contain afferent fibres, passing from 
the bronchi to the nerve-centres, and these afferent fibres have 
also a twofold action, so that when the central end of one cut 
vagus is irritated, the irritation may cause either reflex contrac- 
tion or reflex dilatation of the bronchi in the other lung. It is 
probable that there are two cerebro- spinal centres : one produc- 
ing dilatation and the other contraction. Atropine completely 
paralyses either the constricting fibres of the vagus or their ter- 
minations in the bronchi, so -that after a very small dose stimu- 
lation of the peripheral end of the cut vagus no longer causes 
contraction. Ether probably paralyses the cerebro-spinal centre 
for contraction, so that irritation of the central ends of a divided 
vagus causes expansion instead of contraction in the bronchi of 
the other lung. Small doses of nicotine have a powerful effect 
in expanding the bronchi, but the mode of action of the drug has 
not been determined. 1 

Pathology of Bronchial Asthma.— The attacks of dyspnoea 
which occur in spasmodic asthma in all probability depend upon 
spasmodic contraction of the unstriped muscular fibres in the 



' Eov and Graham Brown, Journ of Phys. vol. vi, 

s2 



266 PHAEMACOLOGY AND THBEAPEUTICS. [sect. r. 

bronchi. In some cases no definite cause can be assigned for 
the occurrence of these attacks, though a gouty tendency in the 
patient, or the imperfect elimination of waste products, as in 
renal diseases, increases the tendency to their occurrence. In 
other eases they appear to be occasioned by irritation, either in 
the mucous membrane of the respiratory tract or irritation of 
some other part of the body. Thus they appear sometimes to 
be brought on reflexly, by irritation of the nose by polypi, by 
certain odours, or the inhalation of irritating dust, especially 
pollen of ,grass, or by congestion of the mucous membrane in 
ordinary coryza. Sometimes irritation of the pharynx by en- 
larged tonsils appears to bring them on, and they frequently 
arise from bronchial catarrh. At other times they may occur in 
consequence of indigestion, constipation, of worms in the intes- 
tine, of disease of the uterus or ovaries, or of pregnancy. 

Treatment of Asthma. — In cases where the cause of the 
attacks can be ascertained, the cause is to be removed. Thus in 
gouty patients the free use of water as a beverage, and the ad- 
ministration of iodide and bromide of potassium or of salicylate 
Of sodium may be useful. In renal asthma the diet- must be chiefly 
•farinaceous and fatty, meat and beef-tea being sparingly given, 
>so as to avoid the accumulation of waste products in the system, 
•and caffeine (pp. 433, 434) may be given to aid their elimination. 
The asthma of dyspepsia, and also that of constipation, may 
possibly be due partly to the presence of abnormal digestive pro- 
ducts in the blood, as well as to irritation of the mucous mem- 
brane of the stomach or intestine. In dyspeptic asthma pepsin 
has proved very useful; emetics are sometimes of service, pro- 
Jbably by removing irritating substances (p. 255), and ipecacu- 
anha may possibly have some special action of its own on the 
mucous membrane, in addition to its emetic action. Constipation 
is to be treated by laxatives (p. 388) and cholagogues (p. 404), and 
worms by vermifuges (p. 408). Polypi in the nose and enlarged 
tonsik are to be removed, and for congestion of the mucous mem- 
brane of the nose or throat, carbolic acid lotion may be used 
(p. 257). 

The medicine most usually employed to prevent recurrence 
of the attack is lobelia inflata. The exact mode of action of this 
drug is not known, but the general symptoms produced by it so 
closely resemble those of tobacco that it is often known as Indian 
tobacco, and possibly its action on the bronchial tubes may be 
somewhat the same as those of nicotine. During the attacks of 
■spasmodic asthma more relief is usually afforded by the inhala- 
tion of smoke of various kinds than by any other means. The 
smoke of tobacco, of the leaves of various species of datura:, of 
paper impregnated with potassium nitrate, or with a mixture of 
potassium nitrate and chlorate ; of pastiles and of various powders, 
which probably are principally composed of powdered datura- 



chap, x.] ACTION OF DEUGS ON EESPIEATION. 261 

leaves, mixed with powdered nitre, and perhaps, also, with ipe- 
cacuanha, all prove useful. The action of all these smokes is 
probably the same as that of nicotine, for Vohl and Eulenberg 1 
have shown that the active principles in tobacco-smoke really 
are not nicotine alone, but are the products of the dry distilla- 
tion of tobacco-leaves, consisting chiefly of pyridine, collidine* 
and allied substances, which resemble nicotine in action, and are 
present along with it in the smoke. The same products, but in 
different proportions, are obtained by the dry distillation of other 
organic bodies. The proportion in which the different bases are 
present depends both on the nature of the substances subjected 
to dry distillation, and on the amount of oxygen present during 
the process. When much oxygen is present, bodies of higher 
atomic weight and less volatile than those lower in the series 
are formed, much collidine being produced when tobacco is 
smoked as a cigar, while pyridine is the chief product when it is 
smoked in a pipe. It is probable that the admixture of nitre 
with paper or with powdered leaves acts beneficially by producing 
a different mixture of organic bases than would be produced by 
burning the paper or the leaves alone, and that we must look to 
bodies allied to collidine for the relief of asthma. 

'Arch. Pharm. (2), 1873, vol. cxlvii. 130-166. 



2G2 PHAEMACOLOGY AND THEEAPEUTICS. [sect. i. 



CHAPTEE XI. 
ACTION OF DEUGS ON THE CIECULATION. 

It has already been mentioned that the cells of which higher 
organisms are composed live in the intercellular fluid or lymph 
which bathes them. 

This nutritive fluid is continually being renewed by fresh 
supplies exuding from the blood-vessels into the lymph-spaces 
which surround the cells, the excess being removed by absorption 
either by the veins or by the lymphatics. Besides this, an inter- 
change of gases (internal respiration) and of solids takes place 
by diffusion between the lymph and the blood. 

Wben the circulation stops, internal respiration is arrested, 
and the cells die. But they do not all die at the same time, for 
some are able to live longer without fresh supplies of oxygen 
than others. The order in which they die is (1) the cells of the 
initiative nerve-centres, as the brain ; (2) those of the automatic 
and reflex centres ; (3 ) nerve-fibres (which are modified nerve- 
cells) ; (4) unstriated muscles { (5) striated muscles. 

Arteries and Veins. — It is important in this respect to re- 
member tbat it is only so long as blood is in the arteries that it 
is available for the nutrition of cells. Once in the veins it is 
useless for nutrition ; and were it not that it readily passes from 
the veins into the arteries again, it might as well be outside the 
body for any purposes of nutrition. 

The veins are very capacious, and when dilated to their 
utmost, they can alone hold all the blood the body contains, 
and more. During life they are constantly kept more or less in 
a state of contraction by the action of the nervous system, but 
when they become completely dilated, as after death, all the 
blood flows into them, leaving the arteries empty. It is there- 
fore possible, as Ludwig has well expressed it, to bleed an animal 
into its own veins. Schiff has shown that when the blood-vessels 
relax as they do after section of the medulla oblongata, the whole 
of the blood of another animal as large as the one experimented 
upon must be introduced in addition to its own, in order to raise 
the pressure within the vessels to the normal. Even this is in- 
sufficient to keep up the pressure, for the vessels go on still 
dilating, and the pressure falls, notwithstanding the large quan* 



chap, xi.] ACTION OF DEUGS ON THE CIRCULATION. 263 

tity of blood which is present in them. It is therefore evident 
that the normal action of the vasomotor centres is more than 
equivalent, for .the purposes of circulation, to as much blood 
again as the animal possesses. "Weakened power of these centres 
is to a certain extent equivalent to bleeding, and increased power 
has a similar effect to an increase in the quantity of blood in the 



Blood-pressure.— The continuity of the circulation of blood 
through the capillaries is not maintained by the heart alone : 
the elastic pressure of the arteries on the blood within them plays 
ajnost important part, and indeed during the cardiac diastole the 
circulation is maintained entirely by this elastic pressure. 

If the arterioles or capillaries through which the arterial 
system empties itself into the veins are much contracted, so that 
the blood can flow only slowly through them, the heart may stop, 
and yet the blood-pressure may remain for many seconds almost 
Unchanged. But if the arterioles or capillaries are dilated, the 
arteries quickly empty themselves into the veins, arterial pres- 
sure rapidly falls, and circulation soon stops. 




tm. 83.— Diagram to illustrate the effects of the horizontal and vertical position on the circulation 
of the frog in shock, a, normal ciiculation in the upright position. 6, circu'ation after dilata- 
tion of the veins has been produced by a blow on the intestines. The blood does not reach the 
heart, and it beats empty, so that the circulation stops, c shows the circulation ina horizontal 
position after the veins have been dilated, as in b. The veins are still dilated, but the .blood 
reaches the heart, and the circulation is carried on. Fig. c is perhaps too diagrammatic,' as it 
appears to show an empty space or air in the veins. In reality the veins, being very thic- 
walled, collapse. Fig. 6 is open to the same objection, but if we suppose ourse ves to be look- 
ing at the vein from the front instead of in section, 6 represents almost exactly what I have 
myself seen in repeating Goltz's experiment. 

I use the words arterioles and capillaries as synonymous, 
because it is almost certain that the capillaries do contract. In 
most cases where contraction has occurred in the peripheral 
vessels, it is difficult or impossible to say whether its seat is in 
the capillaries or arterioles. 

The action of the heart is to pump the blood out of the veins 
into the arteries, and this it can only do when the blood reaches 
it. If the veins are much dilated and the animal is in an up- 
right position, no blood may reach the heart, or so little blood 
that its pulsations are practically useless. This is seen in the 
frog when dilatation of the large veins has been renexly pro- 
duced by striking the intestines (Fig. 836). When the animal is 
laid flat, the blood flows into the heart, and then it works nor- 
mally. It is probable that a similar condition occurs in man, as 
one of the factors in shock ; and in this condition, as well as in 
fainting, or failure of the heart's action from the effect of drugs, 



264 



PHARMACOLOGY AND THEEAPEUTICS. [sect, i. 



as chloroform, or other causes, the person should be laid flat, 
with the limbs raised so that the blood may flow out of them 
into the heart, and with the head low (either perfectly level with 
the body or depressed below it), in order to permit of an in-, 
creased supply of blood to the intra-cranial nerve-centres. 

Fainting and Shock. — In fainting there is sudden uncon- 
sciousness, which appears to be caused by sudden arrest of the 
supply of blood to the brain. This arrest may be due to a rapid 
fall in blood-pressure, either from stoppage of the heart, rapid 
dilatation of the arterioles, or sudden removal of pressure from 
the larger vessels. It is possible that these conditions may be as- 
sociated with spasmodic contraction not only of the vessels of the 
face and surface generally, but of those supplying the brain itself. 
Tbe effect of sudden change from a horizontal to an upright pos- 
ture in producing syncope has already been mentioned (p. 205). 
Sudden removal of external pressure from the great vessels acts 
upon both arteries and veins. It removes external support from 
the arteries, and allows them to yield more readily to the in- 
fluence of the blood-pressure, and by their dilatation to lessen it. 
It allows the large veins also to dilate, and blood to stagnate in 
them. Its influence is readily seen when fluid is removed too 
suddenly from the abdomen, and external pressure by a bandage 
hot supplied in its place, as in cases of ascites. 

It is seen, perhaps, even more strikingly, where the bladder 
*has been allowed to become distended and is suddenly emptied. 
The effect of this is shown in Fig. 84. In a the bladder is repra- 



Carotid artery (full) 



Aorta tense 

Veins tense and mode- 1 
ratelyfullf 



Bladder (full) 





e-~ 



" Carotid artery (empty). 



Aorta las. 

Veins lax and full. 



Bladder (empty). 



]?ig. 84.— Diagram to show the effects on the cerebral circulation 'of rapidly emptying the bladder. 

sented as full, and, the pressure within the abdomen being con- 
siderable, the veins are prevented from dilating, the heart is well 
supplied with blood, and the circulation in the brain is active. 
In b, the bladder is represented as empty, and the abdominal 
contents being diminished, so that the intra-abdominal pressure 
is lessened, not only do the aorta and other vessels become lax 
from loss of the external pressure, but the veins dilate, the hear$ 



chap, xi.] ACTION OF DEUGSON THE CIECULATION. 265 

is imperfectly supplied with blood, the cerebral circulation fails, 
and syncope ensues. This occurs more readily just after waking, 
before the vaso-motor centre has recovered its usual tone, so that 
one of the most favourable conditions for its occurrence is when 
a man jumps suddenly into the upright position and empties his 
bladder immediately on waking. The consequence of this some- 
times is that he falls down suddenly, quite insensible, during the 
act of micturition. I have seen one case in which the tendency 
appeared to be increased by the practice of opium-eating, pro- 
bably from the diminished excitability of the vaso-motor centre 
produced by the drug. It is evident that the danger will be in- 
creased if the intervals between the systoles of the heart are pro- 
longed, and it is the combination of the natural tendency to 
syncope, produced by large doses of digitalis, with that caused by 
the sudden assumption of the upright posture, and by the rapid 
emptying of the bladder, which renders micturition in the upright 
posture so excessively dangerous in persons under the action of 
digitalis, and leads so frequently to death. 

It is evident that fainting may be prevented by increasing the 
blood-pressure in the brain locally, or throughout the body gene- 
rally. To increase it locally the head of a fainting person should 
be allowed to lie level with the body, or a little below it, and on 
no account raised even by pillows. A fainting fit may indeed 
often be prevented by sitting with the head hanging between the 
knees. It may also be prevented or removed by such conditions 
as raise the general blood-pressure, e.g. a draught of cold water, 
which causes contraction of the gastric vessels, or a sniff of am- 
monia or acetic acid, which stimulates the nasal nerves, and 
causes reflex contraction of the vessels generally. In some parts 
of India the natives are accustomed to bring persons round from 
a faint by compressing the nostrils and holding the hand over 
the mouth, so as completely to stop respiration. The accumula- 
tion of carbonic acid in the blood irritates the vaso-motor centre, 
raises the blood-pressure, and thus probably tends to bring the 
person round. 

In shock there is no unconsciousness, but the failure of the 
circulation is even more profound than in syncope. Its pathology 
is not perhaps exactly ascertained, but it probably depends to a 
great extent on a paralytic distension of the great veins, as in 
Goltz's experiments. I have found that in shock produced in a 
similar manner in a rabbit the blood-pressure could be raised 
from two inches up to two and a half by the inhalation of am- 
monia. 

Schema of the circulation. — In order to understand the action of drugs 
on the circulation it is absolutely necessary to have a clear idea regarding the 
effect of the heart and capillaries in maintaining the blood-pressure. This 
is best obtained by using a schema which can be easily made from a spray- 
apparatus (Pig. 85). By removing the glass or metal tube from one of these, 



266 



PHAKMACOLOGY AND THEEAPEUTICS. [sect. t. 



and attaching a nozzle with a small stopcock to the india-rubber tube in its 
stead, we obtain a very good schema of the circulation ; and, by imitating on 
it the changes which occur in the heart and vessels, we may form a much 
clearer idea of them than we could otherwise do. The india-rubber ball 
will represent the heart ; the elastic bag, surrounded by netting, will repre- 
sent the elastic aorta and larger arteries; and the stopcock, which regulates 
the size of the aperture through which the air escapes, will represent the 
small arteries and capillaries, whose contraction or dilatation regulates the 
flow of blood from the arteries into the veins. We may judge of the tension 
in the arteries by the distension of the bag, or still better, we may connect 
the tube between it and the stopcock with a mercurial manometer, and 
estimate the tension by the height of the mercurial column which it sustains. 
If we turn the stopcock so as to present some resistance to the escape of air, 
and then compress the india-rubber ball, very little air will issue from the 




Fig. 85.— Simple schema of the circulation, consisting oi a spray-prodncer, Dladder, and mercurial 
manometer. The elastio ball represents the heart ; the elastic bag, covered with netting to 
prevent too great distension, represents the aorta and arterial system, and the bladder represents 
the venous system. 

stopcock even while we are squeezing the ball ; the greater part of it goes to 
distend the bag ; and, when we cease to compress the ball, very little air 
passes through the stopcock. At the next squeeze, the bag becomes a little 
more distended ; and a little more air passes through the stopcock, not only 
while we are compressing the ball, but even when we relax our grasp. At 
each squeeze of the ball, the elastic bag becomes tighter, till it is so tense, 
and contracts so strongly on the air inside, that it can press all the extra 
amount of air, forced into it when the ball was compressed, through the 
stopcock during the time when the ball is relaxed. When this is the case, 
every time we squeeze the ball we see the bag become a little fuller, and air 
issue more quickly from the nozzle. At each relaxation, while the ball is 
refilling, the bag gets a little slacker, and the air passes out of the nozzle a 
little more slowly, but never stops entirely. During the time the ball is 
fi llin g, the valves between it and the bag and nozzle are closed, and cut it 
off from any connection with them. All this time, then, the stream of air 
from the nozzle must be entirely independent of the ball ; it is produced by 
the contraction of the elastic bag, and by it alone. The bag may be stretched, 
and the tension of its walls increased in consequence, in two ways : first, by 
working the ball more quickly or compressing it more completely ; second, 
by lessening the opening of the nozzle, and thus hindering the passage of air 
through it. One trial will, I think, be enough to show how much easier it is 
to alter the pressure by changing the size of the nozzle than by any altera- 
tion in the working of the ball, and to prove that alterations in blood-pressure 



chap. xi/J ACTION OP DEUGS ON THE CIRCULATION. 267 

probably depend much more on alterations in the lumen of the small 
arteries than on changes in the action of the heart. 

But our schema, as it at present exists, is not a perfect representation of 
the heart and vessels ; for it draws its air from an inexhaustible reservoir, 
the atmosphere, and is not obliged each time to use that amount alone which 
it had previously driven through the nozzle ; while the heart can only use 
the blood which has been forced by it through the capillaries and returned 
to it by the veins. In order to make our schema complete, we must connect 
its two ends by tying them into a bladder or large thin caoutchouc bag (such 
as is used, after inflation, as a toy for children), so that the air shall pass 
into it from the nozzle and be sucked out of it by the elastic ball. This will 
represent the veins. If we then repeat the experiment just described, we 
shall find that, when we begin to work the ball and stretch the elastic bag 
representing the arteries, the bladder representing the veins becomes empty 
and collapsed ; and just in proportion as we fill the bag do we empty the 
bladder. If we now stop, the air will gradually escape from the bag to the 
bladder, till the air in both is of equal tension, as at first. 

Circulation in the Living Body. — The phenomena of the 
circulation in the heart and vessels are very much the same as 
in the schema. "When the heart stands still (as when the vagus 
is strongly galvanised), the blood flows from the arteries into- 
the veins until the arteries are nearly empty and the pressure 
■within them falls to zero. If the heart now begin to beat, it 
forces blood into the elastic aorta and arteries at each systole, 
and distends them, just like the elastic bag of the schema ; 
while at the same time it takes blood from the veins, and they 
become empty in proportion as the arteries become full. During 
every diastole of the heart, the distended aorta and other arteries, 
in virtue of their elasticity, contract on the blood they contain, 
and keep it flowing on through the capillaries till another systole 
occurs ; the heart, meanwhile, being completely shut off from 
the aorta by the sigmoid valves (just as the ball of the schema 
was shut off ifrom the elastic bag). In general, the diastole is 
longer than the systole ; so that for the greater part the circula- 
tion through the capillaries is carried on by the elasticity of the 
arteries, and not directly by the heart. The arteries, which we 
have supposed to be at first empty, gradually become distended 
by the heart, just as the elastic bag was by the ball, and exert 
more and more pressure on the blood in them (so that it would 
spout higher ana higher if one of them were cut), till they are 
able during the diastole to press the same amount of blood 
through the capillaries into the veins as had been pumped into 
them during the systole. The more tensely they are stretched, 
the greater is the pressure they exert on the blood they contain ; 
and the amount of this is termed the arterial tension or blood- 
pressure. These two terms mean the same thing, and we use 
one or other just as the fancy strikes us. At each systole, the fresh 
Supply of blood pumped in by the heart stretches them more ; 
that is, the arterial tension rises. Luring each diastole, the 
blood escapes into the wide and dilatable veins, and the arteries 



268 PHAEMACOLOGY AND THEEAPEUTIGS. ■ [sect. i. 

become less stretched ; that is, the arterial tension falls. This 
alternation of rise and fall constitutes the pulse. 

Besides the oscillations which take place in the Hood- 
pressure at each beat of the heart, a rise and fall in the form 
of a long wave occurs at. each respiration.. The wave begins to 
rise just after inspiration has begun, reaches its maximum just 
after the beginning of expiration, and then begins to fall again 
till a new wave succeeds it. The heart-beats are generally quicker 
during inspiration, and slower during expiration. 

The blood -pressure thus oscillates up and down at each 
heart-beat and rises and falls with each respiration, and the 
average between the highest and lowest points is called the mean 
arterial tension or mean blood-pressure. 

Besides the oscillations in blood-pressure due to the pulse 
and to the respiration, there are slowly rising and falling waves 
to which the name of Traube's curves is given. These are due 
to alternate contraction and relaxation of the arterioles and 
capillaries. Bhythmical contraction of the arterioles has been 
observed in almost all parts of the body of rabbits, and probably 
occurs both in the lower animals and in man. 

The blood-pressure is not equal throughout the whole arte- 
rial system. It is greater in the large and less in the smaller 
arteries, in which it becomes diminished by the friction between 
the blood and the arterial walls. It is also modified by gravity, 
so that the position of a limb may alter the pressure in its 
arteries. 



Method of ascertaining the Blood-Pressure. 

The blood-pressure is usually estimated in animals by connecting a large 
artery, such as the carotid or femoral, with a bent tube containing mercury 
by means of a connecting tube, which is filled with a solution of carbonate of 
sodium to prevent coagulation. The pressure is estimated by the height at 
which the mercury stands in the outer limb of the tube. The height may 
either be read off with the eye, or, what is much better, it may be registered 
on a revolving cylinder by means of a long float which rests upon the surface 
of the mercury, and bears on its upper end a brush or pen. This method, 
which is important both in itself and as being the introduction of the graphio 
method into physiology, we owe to C. Ludwig. The apparatus is known as 
the kymograph. 

Tracings may be taken upon paper with a varying speed : it is usual to 
take them upon paper travelling rapidly, so that quick and small oscillations 
due to the cardiac beats may not be lost or obscured by fusion. The great 
disadvantage of this is that it is impossible to use the curves directly : they 
must be reduced, and this is a work requiring much time and labour. When 
taken on a slowly revolving cylinder we get the general results of the action 
of a drug on the blood-pressure shown us at a glance ; and its effects on the 
form and rapidity of the pulse may by a little arrangement be recorded from 
time to time on another cylinder revolving more rapidly. 

This method gives us both the blood-pressure and the oscillations which 
it undergoes on account of the cardiac pulsations and respiration. If we 
wish to get the mean blood-pressure unaffected by these oscillations, it is 



chap, xi.] ACTION OF DRUGS ON THE CIRCULATION. 269 

done by simply narrowing at one point the calibre of the tube containing the 
mercury, either by a stopcock, or by reducing the tube to a capillary bore. 

Fallacies of Mercurial Manometers.— The oscillating mercurial 
( .column does not give the variations in blood-pressure quite truly, because 
the oscillations are compounded of these variations and of the oscillations 
due to the inertia of the mercury itself. In order to obtain the exact form of 
variation we employ Fick's kymograph (Pig. 86), or Eoy's tonometer, in 
which the apparatus is made very light, and all oscillations due to its own 
inertia are as far as possible avoided. 



Writing-point ' 



Piston to lessen oscil- 
lation of point. 

Tube filled with 
glycerine 




Eyringe for altering 
the pressure in the 
I manometer. 



—flat metal tube form- 
ing the manometer. 



(Tube to connect the 
manometer and ar- 
tery. 



Fig. 86.— Pick's kymograph. It consists of a fiat metal tube, bent into a nearly ciroular form, filled 
with alcohol, and connected with the artery by means of a leaden tube, filled with a solution of 
sodium carbonate. When the pressure increases within it, the tube straightens, and when the 
pressure diminishes it bends. These changes are magnified and recorded on a cylinder by a 
light lever. The vibrations of the lever are lessened by a piston, which works in a tube rilled 
with glycerine. 

Fallacies from Anaesthetics. — Even if the instrument be free from 
fallacy, we still have difficulty in ascertaining the real action of the drug on 
the circulation, inasmuch as the blood-pressure is much affected by move- 
ments, and by anaesthetics. If the animal is not anaesthetised we may get 
untrustworthy results from the straining or movements it may make, and if 
it is anaesthetised, the anaesthetic may greatly alter the power of the heart, or 
the sensibility of the nerve-centres either to the direct action of the drug 
upon them, or to its reflex action through the afferent nerves. In order to 
get rid of movement, and at the same time to prevent the vascular centres 
from being much depressed, curare is sometimes used instead of an anaesthetic. 
Perhaps, almost equally good results may be obtained by using ether as the 
anaesthetic, carefully regulating the supply so as to abolish sensation without 
greatly affecting the medulla. The reasons why this is possible are discussed 
at p. 204. In order to regulate the supply of ether, we use a stopcock, by 
which pure ether, or pure air, or an admixture of both in any desired propor- 
tion, can be passed into the lungs (Fig. 73, p. 211). 

Other fallacies arise from the mode of injecting the drug, and this has 
Sometimes led to false results : thus drugs are not unfrequently injected into 
the jugular vein, as it is very conveniently situated for the purpose. In this 
way, however, they are carried directly to the heart, and act much more 
strongly upon it, than they would do if absorbed from other parts of the 
body. In the case of irritant salts, for example, time is not afforded for their 
irritant properties becoming lessened by chemical combination with the con- 
stituents of the blood. If the solution injected contain particles which will 



270 PHAEMACOLOGY AND THEKAPEUTICS. [sect, i, 

not pass through the pulmonary capillaries, or if it is likely to cause coagu- 
lation of the blood, it may plug up the pulmonary vessels and give rise to 
dyspnoea and convulsions. 

Both these objections are avoided when the drug is injected under the 
skin, or into the peritoneal cavity. Absorption from the skin is slower than 
from the peritoneum. In some experiments this is a disadvantage : in others, 
however, it is an advantage. 

Another fallacy sometimes arises from the solution of carbonate of sodium 
used to prevent coagulation. In order to prevent the blood from passing too 
far into the tube connecting the artery with the kymograph, it is usual to 
introduce the solution of carbonate of sodium into the tube by a syringe (vide 
Fig. 86) or otherwise, under a pressure very little less than the usual blood- 
pressure of the animal experimented on. If the blood-pressure be lowered 
much by stoppage of the heart or dilatation of the vessels, the solution of 
carbonate, or bicarbonate of sodium, runs into the arteries and may cause 
convulsions and death. Thus stoppage of the heart by irritation of the vagus, 
or by the action of a drug, may sometimes appear to be followed by results - 
which are not really due to it, but only to the conditions under which the 
experiment has been made. 



Alterations in Blood-pressure. 

In speaking of "blood-pressure, arterial blood-pressure is always 
meant, unless otherwise stated. 

As the blood-pressure depends on the difference between the 
quantity pumped into the arterial system by the heart at one 
end, and the quantity flowing out through the arterioles into the 
veins at the other in a given time, it is evident that — 

The blood-pressure will remain constant when these quan- 
tities remain equal to each other. 

It will rise when — 

(a) More blood is pumped in by the heart. 

(b) When less flows out through the arterioles in a given 

time. 
It will fall— 

(a) When less is pumped in by the heart ; or, 

(b) More flows out through the arterioles ; or, to look at it 

another way : — - 

Heart j more active - Blood-pressure rises. 
Uess „ „ „ falls. 

Arterioles {^tract „ „ rises. 

l dll ate „ „ falls. 

The heart may throw more blood into the arteries, either by 
pulsating more rapidly, or by pulsating more vigorously and 
more completely, so that at each contraction a larger amount of 
blood is expelled. But increased activity can only affect the 
blood-pressure so long as there is a free supply of blood entering 
the heart. If there exist any obstruction to its entrance the 
increased cardiac action will have no effect. Hence obstruction 
of the pulmonary circulation will also lower the blood-pressure. 



-chap, xi.] ACTION OF DEUGS ON THE CIECULATION. 271 

The causes of alteration in the blood-pressure may be tabulated 
as follows :— 

Blood-Pressuve 



May be raised — 

1. By the heart beating 
more quickly. 

2. By the heart beating 
more vigorously and more 
completely, and sending more 
blood into the aorta at each 
beat. 

3. By contraction of the 
arterioles, retaining the blood 
in the arterial system. 



May be lowered — 

1. By the heart beating 
more slowly. 

2. By the heart beating 
less vigorously and completely, 
and sending less blood into the 
aorta at each beat. 

3. By dilatation of the 
arterioles, allowing the blood 
to flow more quickly into the 
Veins. 

4. By deficient supply of 
blood to the left ventricle, as 
from contraction of the pul- 
monary vessels, or obstruction 
to the passage of blood through 
them, or from stagnation of 
blood in the large veins, e.g., 
in shock. 

The influences on the pressure exerted by (a) the number of 
beats, and (b) by the amount of blood sent out by the heart at 
each beat, to a certain extent, though by no means completely, 
counteract each other ; for, when the heart is beating quickly, 
it has not time to fill completely, and so sends out little blood 
at each beat : but, when beating slowly, it becomes quite full 
during each diastole, and sends out a larger quantity of blood 
at each contraction. 

It is evident that the amount of blood which the heart can 
send into the arteries at each beat will depend also upon the 
completeness with which the ventricle relaxes during diastole. 
If the relaxation be incomplete very little blood will enter the 
ventricle, and thus a drug which increases the contractile power 
of the heart may, by unnecessarily prolonging the systole, lower 
the blood-pressure as much as a drug which paralyses the heart 
and prevents the ventricle from expelling its contents. 



Relation of Pulse-rate and Arterioles to Blood-pressure. 

Although we are unable, from the mere fact that the blood- 
pressure rises or falls after the administration of a drug, to say 
whether the result is due to the action of the drug on the heart 
or on the arterioles, yet we can come to some general conclusion 
regarding its mode of action by comparing the alterations which 



272 PHARMACOLOGY AND THERAPEUTICS, [sect. I. 

it has produced in the blood-pressure with those which occur m 
the pulse-rate. For in the normal condition of an animal* when 
all the nerves are intact, a rise in the blood-pressure renders the 
pulse slow by increasing the normal tone of the vagus centre in 
tbe medulla, and a fall of blood-pressure quietens the pulse by 
diminishing the tone. This mechanism tends in the normal 
animal to keep the blood-pressure more or less constant. 

We find, therefore, that when alterations in blood-pressure 
and pulse-rate are depicted graphically, so that a rise in one 
curve indicates a rise in blood-pressure, and a rise in the other 




Fig. 87.— Diagram of a pulse and blond-pressure curve, where tbe alterations are due at first to the 
action of a drug on the heart, as in tbe case of atropine. The unbroken line indicates tbe blood- 
pressure, and the dotted line the pulse. After the injection shown by the vertical line the vagus 
is paralysed, the pulse becomes very rapid, and the blood-pressure rises. At A the vaso-motor 
centre becomes paralysed, the arterioles dilate, and the pressure falls. From a to 6 the action 
of the heart continues nearly uniform, notwithstanding the fall in blood-pressure, but at 6 the 
heart begins to become paralysed, and the pulse-rate and blood-pressure both continue to fall 
steadily till death. 

indicates quickening of the pulse, the two curves run in oppo- 
site directions if the alteration in blood-pressure is due to the 
arterioles, but they run parallel when the alteration is due to 
the heart (Fig. 87). Thus, if the vagi be cut, we find that the 
pulse-rate rises, and in consequence of this the blood-pressure also 
rises. Here the alteration in pressure is due to the heart, and 
the two curves are therefore parallel. If the vagi be irritated the 
pulse-rate falls, and in consequence of this the blood-pressure also 
falls. Here again the alteration is due to the heart, and the two 
curves are parallel. 




Fig. 88.— Diagram of pulse and blood-pressure curves, where the alterations are lue at first to the 
action of a drug on the arterioles. The unbroken line indicates the blood-pressure, the dotted 
line indicates the pulse. The upright line indicates the time of iujectiun of the poison. This 
is followed by contraction of the arterioles and consequent rise of blood-pressure. This rise 
stimulates the vagus roots, and causes slowness of the pulse. At 6 the vagus becomes paralysed, 
the pulse becomes quick, and the pressure rises still higher between A and B. At B the vaso- 
motor centre becomes paralysed, the arterioles dilate, and the pressure falls, notwithstanding 
the rapidity of the pulse. At c the heart itself begins to be paralysed, its beats become slow, 
and both pulse and pressure fall steadily till death. 

If, on the other hand, the arterioles are made to contract the 
pressure rises, but the increased pressure stimulates the vagus 
roots in the medulla and the pulse-rate falls, so that the curves 



chap, xi.] ACTION OF DEUGS ON THE CIECULATION. 273 

run in opposite directions. If the arterioles dilate the pressure 
falls, and the vagus tone being lessened the pulse-rate rises ; so 
the curves are again in opposite directions (Fig. 88). 

An example of this is seen in the accompanying curve (Fig. 89), 
which illustrates the action of erythrophloeum — a substance similar 
in action to digitalis— on the circulation. After the injection of 
the drug the vessels contract, and the blood-pressure consequently 
rises and produces some slowness of the pulse. In a little while 
the vagus becomes paralysed, the pulse becomes quicker, and 





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Jia. 89.— Curve of the pulse and blood-pressure in a cat after division uf the spinal cord at the atlas 
and injection of erythrophloeum. (Prom a paper by Brunton and Pye, Phil. Trans, vol. 167.) 

the pressure rises still further. At a later stage the heart be- 
comes slow, apparently from the action of the drug upon it, and 
the blood-pressure then falls again. At first then, where the 
alteration of pressure depends upon the state of the vessels, we 
have the two curves running in opposite directions, but when 
the alterations depend upon the condition of the heart we have 
them running parallel. 1 It will be noticed that in the latter part 
of the curve, although the blood-pressure and the pulse sink 

1 Although the rise in blood-pressure which accompanies that of the pulse ia 
partly due to the heart, it is very probable that the contraction of the arterioles 
which caused the rise at first is not only continuing but increasing. 



274 . PHARMACOLOGY AND THEEAPEUTICS. [sect. I. 

together, they do hot sink quite parallel ; the pulse falling very 
rapidly and the blood-pressure very slowly. Prom this fact we 
may conclude that the arterioles are still contracted, and this 
affords an illustration of another way in which we judge of the 
effect of drugs upon the arterioles. This conclusion would not 
be warranted by the data contained in Fig. 89 alone. For the 
slowness with which the blood-pressure falls in this experiment 
might possibly be due to the heart beating more perfectly, at the 
same time that it begins to beat more slowly. An examination 
of the original tracings of the blood-pressure shows that this is 
not the case and that the beats of the heart became feeble at the 
same time that they became slow. 

The mutual regulating power of the pulse and blood-pressure 
only exists when the vagi are working normally. If they should 
be paralysed, either by section or by the action of a drug, in- 
creased arterial pressure will no longer slow the pulse ; it may 
even quicken it, and therefore the pulse-rate and blood-pressure 
may, in such a condition, run parallel even though the increased 
pressure should be dependent upon alterations in the arterioles. 

But if the vagi are not paralysed, and we find on comparing 
the curves of blood-pressure and pulse-rate that they run parallel, 
a fall in the blood-pressure and slowness of pulse occurring 
together, or a rise in pressure and quickness of pulse accom- 
panying each other, we may conclude that the alterations in 
such a case are due to changes in the action of the heart. 

If, however, we find that the curves run in opposite directions, 
the pressure rising and the pulse falling, it is highly probable 
that the rise is due to contraction of the arterioles, and that the 
fall of the pulse is caused by the rise of pressure acting as a 
stimulus to the vagus roots. This is, however, not quite certain, 
as it might be due to the action of the drug upon the vagus, and 
the proper method of ascertaining this would be that employed 
by Ludwig, of allowing a quantity of blood to flow out into a 
bladder connected with a blood-vessel, so that the pressure, 
should fall. If the pulse still continued slow in spite of the fall 
of pressure, it would be evident that the slowness was due to the 
action of the drug upon the vagus, and not to indirect action 
through the blood-pressure. By employing a bladder in this 
manner the blood can be quickly introduced again into the 
vessels after the effect of its withdrawal has been ascertained. 

We not unfrequently find that, owing to the action of a drug 
the pulse, which has become slow during the rise of the blood- 
pressure, suddenly becomes very rapid notwithstanding that the 
pressure continues high. This is usually due to paralysis of the 
vagus-ends in the heart, and, when this occurs, the correctness 
of the conclusion which we draw from the occurrence mav be 
ascertained by stimulating the vagus in the neck by a faradaic 
current, and seeing whether any slowing or stoppage of the heart 



chap, xi.] ACTION OF DEUGS ON THE CIRCULATION. 275 _• 

occurs. Frequently we find that after the pulse has become 
quick from paralysis of the vagus, the pressure which the quick- 
pulse had raised begins to fall again from paralysis of the 
arterioles. The pulse may continue quick and weak almost till 
death and then cease suddenly, or it may become gradually slow 
as well as weak from paralysis of the heart itself. 

Effect of the Arterioles on Pulse-curves. — The influence of 
the arterioles upon the blood-pressure in a living animal can be 
to a great extent ascertained by the rapidity or slowness of the , 
fall of the blood pressure during the diastole of the heart. When 
the heart is beating slowly the diastole may be long enough to 
show distinctly the curve which the blood-pressure describes dur- 
ing its descent ; but if the heart is beating quickly the diastole 
may be so short that this curve cannot be exactly obtained. It is 
then necessary to prolong the diastole artificially by stimulation 
of the vagi. 

The reason why the part which the arterioles play in main- 
taining the blood-pressure can be ascertained by the way in 
which it falls during cardiac diastole, natural or artificial, is that 
in the healthy heart the aortic valves close during the diastole so 
as to separate the aorta completely from the ventricle. 

In considering the blood-pressure during the diastole, we may 
therefore disregard the heart entirely, and look upon the aorta 
and its branches as an elongated elastic bag closed at its cardiac 
end, but open at its capillary end. This bag is distended with 
blood, which in consequence of the elastic pressure exerted upon 
it by the arterial walls tends to flow out into the veins. The 
rate at which it does this will depend — 

1st, on the elastic pressure or arterial tension ; and, 

2ndly, on the size or degree of contraction of the arterioles or 
capillaries. 

If we connect a manometer with this elongated bag as in 
Fig. 90, and place on the mercurial column a float by which its 




Fig. 90.— Diagram of the circulation, a, the heart, completely shut off by the valves during 
diastole from b, the arteries, e, the capillaries, d, the veins, e, mercurial manometer. /, a 
float, g, a recording cylinder. 

height can be recorded on a revolving cylinder, it is evident that 
the pressure-curve will fall more quickly to zero when the capil- 
laries are dilated, and more slowly when they are contracted. 
With capillaries of the same size, the rate of flow will vary 

T 2 



276 PHAKMACOLOGY AND THERAPEUTICS, [sect. i. 

with the arterial pressure. If the pressure be high the curve 
will fall more rapidly than when it is low, for the greater blood- 
pressure will drive the blood more rapidly through the open 
arterioles. If we find that with a normal pressure the pressure- 
curve falls more slowly than usual during the diastole, we may 
conclude that the arterioles are contracted ; and if we find that 
the fall is slower, notwithstanding that the pressure is higher 
than usual, the proof that the arterioles are contracted is so 
much the stronger. 

This is what Meyer and I * observed in the case of digitalis, 
where we found, as in the accompanying figure (Fig. 91), that 
the fall of the blood-pressure during the cardiac diastole hi a 
dog is much slower after than before the injection of digitalis 
into the circulation. 

In observations of this sort it must always be borne in mind 
that a great difference exists between the vessels of the intestines 




2?ig. 91.— Tracing showing tlie blood-pressure and form of the pulse-wave before and after the in- 
fection of digitalis -in the dog. The thin line shows the blood-pressure before, and the thick 
one after, the injection. The curve sinks more slowly after the injection, notwithstanding the 
greater pressure in the vessels. 

on the one hand, and those of the muscles on the other. The 
former are readily controlled by the vaso-motor centre, and 
when this is stimulated they contract greatly. Those of the 
muscles appear to be but slightly influenced by the vaso-motor 
centre, so that when it is stimulated they hardly contract at all, 
and indeed the flow of blood through them becomes accelerated 
on account of the contraction of the vessels elsewhere. When 
the vaso-motor centre is stimulated at the same time that the 
vagus is irritated, the blood-pressure appears to fall nearly as 
quickly as when the vagus alone is irritated. It seems possible, 
however, that this result may be really due to some extent to 
actual dilatation of the vessels in the muscles, for stimulation of 
the motor nerves of muscle appears to produce a vaso-dilating 
effect on their blood-vessels (Gaskell and others) . 

The want of power of the vaso-motor centre over the vessels 

1 Brunton and Meyer, Journal of Anatomy and Physiology, vol. vii. 1872, p. 134. 
The experiments described in the paper were performed in 1868. 



chap, si.] ACTION OF DEUGS ON THE CIECULATION. 277 

of the muscles is probably of considerable pathological import- 
ance. John Hunter * noticed, when he was bleeding a lady from 
a vein in the arm, that the blood, which previously had been 
dark and venous, became bright scarlet, like arterial Wood, when 
she fainted, and remained so during the continuance of the faint. 
This seems to indicate that during syncope, although the super- 
ficial vessels are empty and contracted, the arterioles of the 
muscles are dilated like those of an actively secreting salivary 
gland. 

If we find, then, that after the injection of a drug the blood- 
pressure remains constantly high, during stoppage of the heart, 
we may conclude that the vessels of the muscles are contracted 
as well as those of the intestine. Such a condition occurs after 
the injection both of digitalin and of erythrophlceum, in which 
the pressure sometimes remains high for many seconds, or even 
for a minute or more, after the heart has finally ceased to beat 
(Fig- 89). 

Investigation of the Action of Drugs on the Arterioles. 

The arterioles become contracted by the action of the involun- 
tary muscular fibre contained in their walls ; they dilate partly 
by their own elasticity and partly by the pressure of fluid within 
them; 

The capillaries also appear to have the power of contraction. 
Both arterioles and capillaries are induced to contract by the 
effect upon them of the nerves which pass to them from vaso- 
motor centres. The blood-vessels may also dilate actively from 
irritation of vaso-inhibitory nerves. The exact mode of action 
of these nerves is not ascertained; they are generally looked 
upon as entirely separate from vaso-motor, but it seems not im- 
probable that here also the difference between vaso-motor and 
vaso-inhibitory nerves is a mere question of relation, and some 
nerves produce contraction and dilatation according to the point 
where they are stimulated. Thus Dastre and Morat have found 
that the cervical sympathetic, which produces contraction of the 
vessels in the rabbit's ear when irritated between the ear and the 
first thoracic ganglion, causes dilatation instead of constriction 
when it is irritated at a point below the ganglion, in which case 
the stimulus has to pass through the ganglion before it reaches 
the ear. 

In considering the action of drugs on the vessels, we have, 
therefore, to examine — 

1. Their direct effect upon — 

a. The contractile walls of the vessels themselves with their 
a, muscular fibres, 
o, motor ganglia ; 

1 John Hunter's works, edited by Palmer, 1837, vol. iii. p. 91, 



273 PHAEMACOLOGY AND THEEAPEUTICS. [sect. i. 

B. Nerve-fibres 

a, vaso-motor, 

b, vasodilating ; 
c. Nerve-centres 

a, vaso-motor, 

b, vaso-dilating. 

2. Their reflex effect on the nerve-centres just mentioned. 

There are two modes of estimating the contraction of the 
arterioles : 1st, by direct observation and measurement under the 
microscope ; 2nd, by ascertaining the quantity of blood or other 
fluid which will pass through them in a given time. 

Each of these methods may be used in several ways, accord- 
ing as we wish to ascertain the action of a drug— 1st, on the 
contractile walls of the vessels alone ; 2nd, on the walls together 
with the vascular nerves but without the nerve-centres ; and 3rd, 
on the vessels in connection with the nerve-centres. 

The method of direct observation of the arterioles may 
be practised in either frogs or mammals. 

The part of the frog usually selected is the web, the mesen- 
tery, the mylo-hyoid muscle, the tongue, or the lung. The parts 
usually observed in mammals are the wing of the bat and the 
ear of the rabbit. 1 

In observing the effect of various conditions on the lung, it 
is necessary to inflate it. This is easily done by means of a 
small cannula with a bulging end which is tied into the larynx. 
Over the other end is slipped a small piece of india-rubber 
tubing, and by clamping this after the lung has been inflated, 
the escape of air is prevented. 

An apparatus for this purpose is described by Holmgren. 2 
The accompanying engraving (Fig. 92) shows one which I used 
in 1870 for the purpose of investigating the action of heat and 
cold upon the lung. 3 

By means of the india-rubber ball I directed upon the lung 
a stream of air which was previously passed either through hot 
water or through iced water. The pulmonary capillaries, when 
treated in this way, contract under the influence of cold by one- 
third of their diameter. McKendrick, Coats, and Newman, in 
an investigation on the action of anaesthetics on the pulmonary 
circulation, found that chloroform, ethidene, and ether, all stop 
the pulmonary circulation, the action of chloroform being greatest 
■and that of ether least. 4 

In observing the effects of drugs on the vessels alone, it is 
necessary to destroy the influence of the nerve-centres over them. 

1 For observing the vessels of the rabbit's ear one of Bracke's lenses is very- 
convenient. It resembles a telescope in its construction, but has a very short focus. 

2 Ludwig's Festgabe. 

s British Medical Journal, Feb. 13, 1875, p. 204. 
4 Ibid. Dee. 18, 1880. 



chap, xi.] ACTION OF DKUGS ON THE CIRCULATION. 279 

This is usually done in a frog by destroying the brain and spinal 
cord. In the rabbit's ear it is done by dividing as far as possible 
all the nerves going to one ear, then injecting the drug into the 
general circulation and comparing its effect upon the two ears. 




Piu, y2. — Apparatus for ascertaining the effect of heat and cold on the vessels of the frog's lungs. 
A, a piece of cork to which the frog is fastened, is iaid on b, the stage of a microscope, and 
attached by an india-rubber strap, c. D is a small ring of cork covered witha thin circle of glass. 
e is the inflated frog's lung, p is a tube by which a current of air can be directed on the frog's 
lung. It is held in position by a piece of wire, o, which can be bent to any position, z isanask 
containing ice and water. H, a flask containing hot water. K is a three-way stopcock, by which 
a current of air may be sent from the spray-producer, L and M, through either I or H at will, and 
thus cold or hot air may be applied alternately to the lung. 

It is evident, however, that such experiments are not free from 
fallacy, because in them the circulation is dependent on the 
condition of the heart as well as that of the vessels ; and both of 
these may be affected by the drug. 

A better plan, therefore, is to obviate this fallacy by keeping 



280 PHAKMACOLOGY AND THEKAPEUTICS. [sect, i. 

up the circulation artificially, either in the body of the" frog, of 
in the ear of the rabbit. 

A method of maintaining artificial circulation in the rabbit's 
ear while the calibre of the vessels is being measured was in- 
vented by Ludwig, and described by me in the, British Medical 
Journal, 1871. 

In the frog artificial circulation is kept up by putting a 
cannula into the aorta, and another into the vena cava or abdo- 
minal vein after destruction of the brain and spinal cord. The 
aortic cannula is connected with two funnels or bottles, such as 
are used for artificial circulation through the intestine (p. 382). 
These contain either a saline solution or a mixture of saline solu- 
tion with defibrinated blood. To one of them the drug is added. 
The circulation can be rendered quicker or slower at will, by in- 
creasing the pressure under which the fluid flows into the aorta. 
A suitable part of the frog is then put under the microscope, and 
the vessels measured wbile unpoisoned blood flows through them. 
The poisoned blood is then allowed to circulate under exactly the 
same conditions of pressure and the vessels are measured again. 
By this method of observation (iraskell ascertained that very 
dilute alkalies cause great contraction of the vessels, so as some- 
times almost entirely to occlude them and arrest any flow of 
blood through them. Dilute acids counteract this effect and 
cause the vessels again to dilate. 

Cash and I have observed that, in addition to this action, 
dilute acids have a tendency to increase the exudation of fluid 
from the vessels and produce oedema of surrounding tissues. 

In many experiments which have been made on the action of 
drugs on the blood-vessels by direct microscopic measurement of 
their size, before and after the application of the drug, no ac- 
count has been taken of the effect which the application of the 
drug may produce by its local irritating action on the nerves or 
tissues of the part to which it is applied, and by its reflex action 
through the nerves, quite independently of any special action 
which it may have on the vessels. Thus, irritation by the appli- 
cation of alcohol, either alone or as a solvent in tinctures, or by 
a strong saline solution, has an effect similar to that of simple 
irritation by pressure or scratching, and usually causes tempo- 
rary contraction, followed by dilatation of the capillaries. This 
contraction may be more or less prolonged, according to the 
strength of the irritant which is applied. Unless these condi- 
tions are taken into account, observations on the effect of drugs 
applied locally to the web, mesentery, or tongue, are very un- 
satisfactory and generally worthless. 

Perhaps a somewhat better result may be obtained by in- 
jecting the drug into the lymph-sac of a frog, and then observing 
the web. But here also we have the same difficulty, because the 
sensory nerves of the lymph-sac being irritated, reflex stimulation 



chap, xi.] ACTION OF DRUGS ON THE CIRCULATION. 281 



of the vaso-motor centre and consequent contraction of the vessels 
may be induced. 

Method of Measurement by Rate of Flow.— Another 
method of ascertaining the effect of drugs on the vessels is to 
measure the amount which flows out of them in a given time. 
This method may be employed either in the frog or in the higher 
animals. The method of employing it in the frog is to destroy 
the brain and spinal cord, and tie one cannula into the heart or 
aortic bulb, and another into the inferior vena cava. The aortic 
cannula is connected with a reservoir containing saline solution, or 
defibrinated blood, which can be made to pass into the aorta and 
circulate through the vessels at any desired pressure by simply 
raising or lowering, the reservoir ; the fluid flows out through the 
cannula in the vena cava, and the quantity is registered upon a 
revolving cylinder. 

By this method Cash and I have found that potassium 
chloride, contrary to our expectation, causes great contraction 
of the vessels ; that barium and calcium and strontium do so 
also, but to a less extent. The instrument used for this purpose 
consists of a light lever, one end of which is depressed each time 
that a drop falls upon it. An electric circuit is thus broken, and 
the fall of each drop is readily recorded by means of an electro- 
magnetic marker ; at the same time the pressure under which the 
circulation is going on is also recorded by means of a manometer. 
Slowing of the flow indicates of course contraction of the vessels, 
and acceleration indicates dilatation of the vessels. 

The general results of our experiments with several metallic 
salts are shown in the accompanying table. Most of the drugs 
experimented on cause contraction of the blood-vessels, but we 
are unable at present to arrange them in the exact order of their 
strength of action. 

Lithium causes slight contraction. Iron causes slow contraction. 

Potassium (very dilute solutions) causes 
dilatation. 
Ditto (solutions of j^g) causes con- 
traction. 

Barium causes rapid contraction. 

Calcium „ gradual „ 

Strontium „ gradual „ 

Magnesium „ slight „ 

Aluminium (much diluted) has no effect. 
1 per cent, needed to produce any 
effect. 

In experiments made by such methods as that just described 
we reduce the problem of the action of drugs on the blood-vessels 
to a very simple form, although we have still to distinguish 
whether the drug acts directly on the contra 1 ctile walls of the 
blood-vessel or on the nervous elements contained in them. 
There is at present no means of absolutely separating those two 
factors, but it is probable that the nerves die sooner than the 



Copper 


, powerful , 


Zinc , 


» 11 * 


Tin 


i »» » 


Cadmium 


, slight , 


Nickel 


i j» i* 


Cobalt 


ti " i) 


Platinum 


, powerful , 



but none 
is produced by solutions weaker than 

i 
Eooo* 



282 PHARMACOLOGY AND THEEAPEUTICS. [sect. i. 

muscular fibres, and that if the experiments are carried on for 
some time the effect of the drug is chiefly, if not entirely, exerted 
upon the muscular fibres. This is probably the explanation of 
the different effects of chloral on the vessels of the kidney observed 
by Ludwig and Mosso (p. 283). 

In experiments on the flow of blood through the vessels of 
warm-blooded animals, the circulation is kept up in much the 
same way as in the frog. The blood may be used cold, or may 
be kept at the temperature of the body. The cannula is usually 
inserted either into the artery supplying an organ such as the 
kidney, or supplying a single muscle, or it may be put into the 
descending aorta, so that the blood passes through the whole of 
both lower extremities. The flow is measured by the rate at 
which the blood issues from the corresponding vein. 

This method we owe to Ludwig, who, along with his pupil 
Mosso, made a number of experiments on the circulation through 
the kidney. The conclusions arrived at were : — that venous blood 
causes contraction, and oxygenated blood, dilatation of the ves- 
sels; but the dilatation which richly oxygenated blood, circulating 
after venous blood, causes in the vessels is only temporary, and 
they soon return to their normal calibre. Mosso's experiments 
have been repeated by Severini, who used the lung instead of the 
kidneys. He finds that the alternate circulation of oxygenated 
and of venous blood acts in the manner described by Mosso, 
but that when oxygenated blood is passed through steadily the 
vessels contract and the flow through them is diminished ; venous 
blood, on the contrary, when circulated for a length of time causes 
the vessels to dilate and the flow through them to increase. The 
action of venous blood upon the arterioles appears indeed to be 
similar to its action upon other tissues. A small or moderate 
quantity of carbonic acid acts as a stimulus and causes contrac- 
tion, but great interference with the natural process of oxidation 
produces paralysis. 

Nicotine, in the proportion of 1 in 10,000, causes contraction 
of tbe vessels ; but this is also temporary. One per cent., on 
the contrary, immediately causes dilatation. 

Atropine has a very powerful action ; but this differs com- 
pletely according to the dose. One part in 100,000 causes tem- 
porary contraction of the vessels, which soon passes off. One 
in 10,000 causes contraction, which, instead of returning simply 
to the normal, passes into dilatation, and then returns to the 
normal. One in 5,000 has a similar action, but instead of the 
dilatation passing away, and the vessels returning to their normal 
size, the dilatation persists, and the kidney soon dies. 

Chloral causes the vessels to contract and then to dilate ; but 
besides this it has a peculiar action, either increasing rhythmical 
contraction and dilatation of the vessels, when such movements 
are already present, or inducing them when they are absent. It 



chap, xi.] ACTION OF DRUGS ON THE CIRCULATION. 283 

only acts upon the vessels when the blood contains oxygen ; and 
when the blood is saturated with carbonic acid, it has no action 
on them at all. Its action is also altered by the condition of tbe 
kidney. When this organ has been kept for twenty-four hours 
in a cool place, its vessels still retain their irritability ; but small 
doses of chloral, instead of causing contraction followed by dila- 
tation, only produce contraction, and a much larger dose is 
required to produce dilatation. This alteration is due to a 
change in the vessels— either in their muscular walls, or more 
probably in the ends of the vaso-motor nerves — and not to any 
change in the blood ; for it occurs when serum instead of blood 
is passed through the kidneys. When the kidney is dead, chloral 
mixed with the blood, instead of increasing the rapidity of the 
current as in the living organ, or leaving it unaltered, as one 
would expect, greatly diminishes it. Chloral also alters the effect 
of artificial stimulation of the kidney. Faradaic currents or in- 
duction-shocks do not seem to affect the normal vessels, but 
constant currents cause dilatation, which continues while the 
currents are passing and diminishes after they cease. When 
chloral is added to the circulating blood, however, the vessels 
contract during the passage of the current instead of dilating, 
and dilate slightly after the current has ceased. When the 
chloral has acted so far upon the vessels as to dilate them greatly, 
the constant current causes no alteration while it is passing, but, 
after it ceases, dilatation increases still further. 

Action of Drugs on Vaso-motor and Vaso-dilating Nerves. 

The effect which irritation of the vascular nerves produces 
in the living body is also altered by the action of drugs. This 
effect is of two kinds — vaso-motor or vaso-contracting, and vaso- 
dilating. Fibres, having these two different actions on the vessels 
of a part, appear frequently to run together in the same nerve- 
trunk, so that sometimes we get dilatation, at other times con- 
traction of the vessels on irritation of a nerve, and not unfre- 
quently we get contraction followed by dilatation. Such fibres, 
however, are not contained in equal proportions in different 
nerve-trunks. The splanchnics, for example, chiefly contain 
vaso-motor fibres, so that irritation of these nerves causes great 
contraction of the vessels in the intestine, and a rise of blood- 
pressure. The motor nerves of the muscles, on the contrary, 
appear to contain chiefly vaso-inhibitory fibres, so that stimulation 
of the nerve causes dilatation of the vessels in the muscle to 
which it is distributed. Similarly, irritation of nerves distri- 
buted to glands usually causes dilatation of the vessels in them. 
The chorda tympani affords a marked example of this, though 
the same thing is noticed also in the case of the sweat-glands in 
the foot on irritation of the. sciatic nerve. 



284 PHABMACOLOGY AND THEKAPEUTICS. [sect. i. 

Most of these vaso-motor or vaso-inhibitory nerves can be 
stimulated reflexly by irritation of a sensory nerve, as well a8 
directly by irritants applied to the nerves themselves. 

We are not acquainted with many drugs which have the 
power of paralysing the ends of the vaso-motor nerves in the 
vessels apart from an action upon the contractile walls of the 
vessels, or the central nervous system. Arsenic, however, appears 
to be a drug of this kind, and in acute poisoning by arsenic 
Bohm has observed that neither irritation of the splanchnic 
nerves nor of the medulla raises the pressure in the way it 
usually does. Prom this effect Bohm concludes that the motor 
nerves contained in the splanchnics are paralysed, but some other 
observers have not obtained similar results. Hay has found that 
potash has a similar action. The method is not free from fallacy, 
for it is obvious that if the vessels in the intestine should happen 
to be already contracted either from the effect of a drug upon 
them or from any other cause, neither stimulation of the splanch- 
nics nor of the medulla can have any further effect upon them 
or on the blood-pressure through them. For when the vessels of 
the intestine are contracted the blood pours into the veins from 
the aortic system, through the arterioles and capillaries of the 
voluntary muscles, and these are only to a very slight extent under 
the control of the vaso-motor centre in the medulla. Irritation 
of it will therefore have little effect on the general blood-pressure 
when the arterioles of the intestine are already contracted, and 
irritation of the splanchnics is also prevented from having much 
effect. 

It seems probable that curare and poisons which, like it, not 
only paralyse the ends of the motor nerves, but also the ends of 
the vagus in the heart, also paralyse vaso-motor nerves, though 
larger doses are required for this purpose. 

Vaso-dilating fibres appear also to be paralysed by curare, 
for irritation of the motor nerve of a muscle does not cause 
dilatation ' of the vessels in a muscle of an animal deeply poi- 
soned by curare. Stimulation of the spinal cord produces con- 
traction of the vessels of the penis instead of erection in an 
animal poisoned by curare, 2 and stimulation of the chorda tym- 
pani does not cause the same amount of dilatation in a poisoned 
as in a non-poisoned animal, even when the dose of curare is 
small. 3 Small doses of curare, however, and even large doses 
of opium, do not appear to paralyse the vaso-dilating nerves of 
muscles. 

In some experiments which I made on the chorda tympani, I 
got a different result from the usual one in an animal thoroughly 
under the influence of opium. The vessels appeared to contract 

1 Gaskell, Journ. of Physiol 1878-9, vol. i. p. 273. 

s Eokhard, BeitrOge, vol. vii. p. 67. 

* V. Frey, Ludwig's Arbeiten, 1876, p. 98. 



chap, xi.] ACTION OF DRUGS ON THE CIRCULATION. 285 

instead of dilating on irritation of the chorda tympani, so that 
instead of the blood gushing out of the vein, it flowed slowly, 
drop by drop. 

Action of other parts on the Blood-pressure. — It has 
already been mentioned that the blood-pressure rises during 
muscular exertion, as, for example, during the struggles of an 
animal. The cause of this has not been definitely ascertained, 
but it is probably, to a great extent, due to the flow of blood 
through the muscles being mechanically obstructed by the con- 
traction of the muscular fibres and to a more rapid action of the 
heart. 

The flow of blood through those organs which consist of in- 
voluntary muscles, e.g. the intestine, may be also obstructed. 

When physostigmine is given to an animal, the blood-pressure 
is sometimes noticed to rise considerably, and this rise of pres- 
sure was at first attributed to contraction of the arterioles. 
According to Von Bezold and Gotz, however, this is due, to a 
great extent, not to the contraction of the arterioles themselves, 
but to mechanical obstruction of the intestinal vessels by the 
tetanic contraction of the muscular walls of the intestine. 1 

Reflex Contraction of Vessels. — Experiments on the out- 
flow of blood from divided vessels, while the nervous system is 
intact, are sometimes made on frogs for the purpose of ascer- 
taining the direct effect of drugs on the arterioles themselves ; 
but this method is faulty, for the alterations consequent on the 
injection of the drug may be simply due to its local irritant 
action producing reflex contraction. 

Such experiments are usually made by snipping off the toe 
of a frog, then injecting the drug into the lymph-sac and observ- 
ing how many drops of blood exude in a given time from the toe 
before and after the injection. 

It is obvious that if no change occur in the heart, and the 
openings of the divided vessels do not beeome obstructed by clots 
or otherwise, these experiments may give some indication re- 
garding the contraction of the vessels ; but the results are not 
trustworthy unless we can ascertain the condition of the heart. 
A modification of this experiment enables us to some extent to 
do this. The end of a toe on each foot having been snipped off, 
the nerve in one leg is divided and then the drug is injected into 
the lymph-sac. If it be then found that the flow of blood from 
the foot, whose vaso-motor supply has been destroyed by division 
of the nerve, continues unchanged or is even increased after the 
injection of the drug, while that from the other foot is diminished, 
we may conclude that the diminution is due to contraction of 
the vessels caused by the injection of the drug. 

But it is incorrect to assume, as has sometimes been done, 

1 Centralblatt f. d. med. Wiss., April G, 1867, p. 234. • 



286 PHARMACOLOGY AND THERAPEUTICS, [sect, i., 

that this contraction is due to any specific action of the drug, 
either upon the muscular walls of the blood-vessels or upon the. 
vaso-motor centre. There is here a fallacy similar to that already, 
mentioned in respect to direct observation of the size of blood- 
vessels. Any irritation of a sensory nerve by pinching, scratch-, 
ing, heat, &c, may cause reflex stimulation of the vaso-motor 
centre and produce contraction of the vessels, and injection of 
strong saline solutions into the lymph-sac, having a local irritant 
action, will produce a similar effect. 

As an example of this fallacy we may mention certain experi- 
ments with bromide of potassium. In such experiments it was 
found that injections into the lymph-sac were followed by con- 
traction of the vessels of the toes, so that much less blood flowed 
after the injection. When the sciatic nerve was divided on one 
side the flow was not lessened but rather increased in the corre- 
sponding foot, at the same time that it was much diminished on 
the other side where the nerve was intact. This result clearly 
shows that after the injection the vessels in one foot contracted, 
and that this contraction was due to the effect of the injection on 
the vaso-motor centre, inasmuch as it did not occur in the foot 
whose vessels had been withdrawn from the influence of this 
centre by division of the nerves. From this fact the conclusion 
has been drawn that bromide of potassium has a special power 
of contracting blood-vessels generally, and on this conclusion 
theories of its action upon the nervous system have been based. 
Such theories, however, rest on a very untrustworthy foundation; 
for though contraction of the vessels no doubt followed the in-, 
jection of a strong solution of bromide into the lymph-sac, this 
contraction was probably not at all due to any specific action of 
the bromide, but only to the reflex stimulation of the vaso-motor 
centre caused by its local irritant action at the place of applica-. 
tion. If introduced in a dilute solution into the mouth instead 
of in a concentrated form into the lymph-sac, this local irritant, 
action would be absent and probably no contraction of the blood-; 
vessels would be produced. 

Action of Drugs on Reflex Contraction of Vessels. — 
Irritation of a sensory nerve usually produces reflex stimulation, 
of the vaso-motor centre and consequent contraction of the ves- 
sels and rise in the blood-pressure both in the frog and higher 
animals. The chief vaso-motor centre is situated in the medulla 
oblongata, but it is probable that there are many subsidiary 
centres throughout the body. It is probable also that these 
vary in strength and in the amount of independent action they 
possess in different animals. When the influence of the chief 
vaso-motor centre upon the body is destroyed by section of the 
spinal cord just below the medulla, the vessels dilate and the 
blood-pressure falls greatly. This is, however, not always the 
case, for in some dogs I have noticed that after section of the 



chap, xi.] ACTION OF DEUGS ON THE CIECULATION. 287 

medulla, the blood-pressure remained so high that I was under 
the impression that the cord had been imperfectly divided, yet 
after death examination of the cord showed that section was 
complete. 

The vaso-motor centre is paralysed by numerous drugs, 
especially in the final stages of their action, so that its ordinary 
tonic action is destroyed and the blood-pressure falls greatly. 
Its action of responding to a reflex stimulation is also abolished, 
and irritation of a sensory nerve no longer raises the pressure. 
The tonic and reflex action of the centre do not always appear 
to be effected pari passu, — chloral, for example, appearing to 
have a greater power to diminish its reflex action than its tone, 
so that stimulation of a sensory nerve has little or no effect even 
when the blood-pressure has not as yet fallen very low. Some- 
times, indeed, an opposite effect to the usual one may be pro- 
duced and the blood-pressure be lowered still further instead of 
raised by the stimulation. Alcohol also paralyses very markedly 
both the reflex power and the direct excitability of the vaso- 
motor centre, so that neither stimulation of a sensory nerve, nor 
even stimulation of the centre of suffocation, will raise the blood- 
pressure. 1 Both the normal tone and the reflex excitability of 
the vaso-motor centre are greatly increased by strychnine. The 
general- blood-pressure greatly rises after the injection of this 
drug, and the effect of irritation of a sensory nerve upon it is 
increased. It has already been mentioned that in ordinary 
circumstances the subsidiary vaso-motor centres in the cord 
when separated from the medulla cannot of themselves maintain 
the blood-pressure. After the injection of strychnine, however, 
their action is so much increased that they may keep the blood- 
pressure at a high average and may also cause it to rise on 
irritation of a sensory nerve. 

Comparative Effect of the Heart and Vessels on Blood- 
pressure in different Animals. — The influence of these two 
factors — the heart and the vessels — on the blood-pressure varies 
in different animals, and under different conditions; and a 
number of the discrepancies observed by various investigators 
are probably due to this circumstance. Thus, in dogs the effect of 
the heart is very considerable, and when its beats are quickened 
by division of the vagi the pressure rises ; in rabbits, on the other 
hand, the heart, instead of working well under its power as in the 
dog, beats very rapidly in the normal condition, and when the 
vagi are divided the pressure does not rise much, although when 
they are stimulated the pressure falls both in the dog and in the 
rabbit. This different action of the vagus in the dog and rabbit 
is well seen when these animals are poisoned by atropine. This 
drug completely destroys the inhibitory action of the vagus on 

1 Dogiel, Pfliiger's Archiv, 1874, Bd. viii. 



288 PHARMACOLOGY AND THERAPEUTICS, [sect. i. 

the heart ; and when the inhibitory power is completely removed 
we find that only a slight increase in the number of beats takes 
place in the rabbit, the pulse-rate rising one quarter : for ex- 
ample, perhaps from 100 to 125. In the dog, on the contrary, 
the pulse-rate will rise to three times, or even four times, what 
it was before. 

In man the effect of the vagus on the heart is intermediate 
between that of the rabbit and dog : so that if the normal pulse 
is between 70 and 80 in the minute, it rises to between 140 and 
180 when the vagus is paralysed by atropine (Von Bezold). 

This difference between the effect of the vagus on the heart 
alters the effect of drugs on the blood-pressure in different 
animals. 

The difference in the action of drugs on the dog and rabbit 
is well shown in the case of nitrite of amyl. If this be given 
by inhalation to a rabbit, the blood-pressure falls immediately 
and rapidly. If given to a dog the fall may be very slight, at 
least if a small quantity only is used. On counting the pulse in 
the dog we discover at once the cause of the apparent difference 
in the action of the drug on the two animals. Before inhalation 
the pulse of the dog was slow, but alter inhalation its pulse 
became almost as quick as that of the rabbit. In both animals 
the nitrite causes dilatation of the vessels, but in the dog the 
heart begins to beat so much more rapidly than usual that it 
maintains the blood-pressure nearly at the normal, notwith- 
standing this dilatation ; while the heart of tbe rabbit beats so 
quickly, normally, that it cannot maintain the pressure by 
increased rate of pulsation. If the vagi be cut in the dog, so 
ihat the heart beats rapidly like that of the rabbit before inhala- 
tion, the nitrite causes as sudden a fall as in the rabbit. 1 

The numerous factors which have to be taken into considera- 
tion in regard to the blood-pressure, the action and the inter- 
action of different parts of the body upon one another, render 
it by no means easy to understand the effect of drugs on the 
circulation. The differences which we find in the action of drugs 
on different animals seem at first to make matters still worse ; 
but it is through these differences of action that we learn the 
exact mode in which the various factors of the circulation are 
affected by the drug. 

There are at least two other factors which must be borne in 
mind in relation to the difference between rabbits and dogs : 
these are (1) the much greater sensitiveness of the inhibitory 
nerves of the heart to reflex stimulation from the nose as well as 
to stimulation by venous blood, in the rabbit than in the dog ; 
and (2) the proportionately much greater length of the intestinal 
tube in the rabbit, which causes the vessels of the intestines, on 

1 Lauder Bruntcn, Joum. of Anat. and Physiol., Nov. 1870, p. 95. 



Chap. xi.J ACTION OP DRUGS ON THE CIRCULATION. 289 

account of their number, to exercise a greater action, on the 
blood-pressure in it than in the dog. Thus, in the rabbit, a 
slightly irritating vapour will cause the animal to close its nos- 
trils ; and almost immediately the vagus will be excited and the 
heart will stop. This stoppage is probably chiefly due to reflex 
action on the heart through the nasal nerves, though it may be 
partly due to accumulation of carbonic acid in the blood. When 
the spinal cord is divided in the rabbit just below the medulla, 
the pressure sinks enormously: in the dog it also sinks, but 
not to the same extent; and in some cases it sinks so little 
that it is almost impossible to believe that the cord has been 
divided, until examination after death shows that the section 
has really been completed. This effect may be partially due 
to the less power which the dilatation of the intestinal vessels, 
consequent upon the section, has in the dog. It may also, 
however, be partly due to greater development of extra-cranial 
vaso-motor centres in the spinal cord and elsewhere,. than in the 
rabbit. 

Influence of Nerves on Blood-pressure. — Both the quick- 
ness of the heart's beat and the contraction of the arteries are 
regulated by the nervous system ; and it is generally by their 
action on it that drugs alter the blood-pressure, though it must 
be constantly borne in mind that they may also do so by acting 
directly on the muscular walls of the heart and arteries them- 
selves. The parts of the nervous system chiefly concerned in 
regulating the circulation are : 

I. The motor cardiac ganglia which lie in the walls of the 
heart, and are under ordinary circumstances the cause of its 
rhythmical action. 

II. Inhibitory nerves, which render the heart's action slow, 
and, if irritated very strongly, may stop its beatipg altogether, 
and produce quiescence in diastole. The inhibitory fibres have 
their origin or roots in the medulla, and proceed in the vagi to 
the heart. In probably all the higher animals they are normally 
in more or less constant action. In men and dogs they main- 
tain a well-marked action ; and, after they are cut or paralysed, 
the heart beats in the dog three or four times as quickly, and in 
man twice as quickly, as before. In rabbits and cats they act 
less, and their division only makes the heart go one-half or one- 
fourth faster. In frogs they are not in constant action, so that 
their section does not usually quicken the beats of the heart in 
these animals. 

A drug may irritate them, and render the heart's action 
slow — 

1. By acting directly on (a) their roots in the medulla, (b) 
their ends in the heart ; 

2. Indirectly, through its action on other parts, producing 
(a) increased blood-pressure, or (b) accumulation of carbonic 

u 



290 PHAEMACOLOGY AND THEEAPEUTICS. [sect. I. 

acid in the blood, both of which act as irritants to the vagus 
roots ; 

3. Reflexly, through irritation of sensory nerves, e.g. irrita- 
tion of the intestines ; of the sympathetic nerve ; of the depres- 
sor ; or of certain afferent fibres in the vagus. Eeflex irritation is 
only likely to be caused by drugs having a powerful local action. 

Drugs may also paralyse the inhibitory, or the ends of in- 
hibitory, nerves in the heart, and thus quicken the heart. 

Inhibitory ganglia have been supposed to exist in the heart, 
and certain drugs, such as muscarine, are supposed to slow its 
pulsations by their action on these ganglia. They have been 
supposed to be distinct from the ends of the vagus (p. 313), 
although generally when the ends of inhibitory nerves in the 
heart are spoken of, the inhibitory ganglia are included in the 
term. 

III. Quickening Nerves. — These belong to the sympathetic 
system. They have their origin in the brain or medulla, pass 
down through the cervical part of the spinal cord to the last 
cervical and first dorsal ganglion (which in many animals are 
united), and thence through the third branch of the ganglion to 
the heart. Quickening fibres are said by some to run also in 
the cervical part of the sympathetic cord. In the frog the 
accelerating fibres pass from the spinal cord in the anterior root 
of the third nerve into the ganglion on the trunks of the glosso- 
pharyngeal and vagus and thence in the vagus trunk to the 
heart (Gaskell). Unlike the inhibitory nerves, the quickening 
nerves are not normally in constant action in mammals. 

The accelerating centres may be stimulated — 

1. By the direct action of drugs upon them. 

2. Indirectly by the drugs producing a diminution in the 
blood-pressure. Such a diminution acts as a stimulus to them. 




do. 93.— Diagram to show tlie supposed rel ation of motor ganglia In the heart to accelerating fibres. 
A, accelerating fibres proceeding from the cerebrospinal or sympathetic nervous systems to the 
motor ganglia of the heart, tt, motor ganglion, a, accelerating fibres passing from the endo- 
cardium to the motor ganglion, m, motor fibres to the cardiac musole. h, the cardiac muscle. 
tPor the sake of simplicity in this diagram all hypotheses regarding separate motor and 
accelerating ganglia have been disregarded.] 

It is probable that accelerating fibres also pass to the cardiac 
ganglia from the endocardium, for irritation of the interior of the 
heart, either mechanically or by the injection of irritating drugs 



chap, xx.] ACTION OF DEUGS ON THE CIKCULATION. 291 

into it, causes acceleration. The supposed relationship of the 
various accelerating fibres to the cardiac ganglia is shown in the 
accompanying figure (Fig. 93). 

IV. Vaso-motor Nerves, which cause the smaller arteries, 
and probably also the capillaries, to contract. These belong to 
the sympathetic system ; and the most important of them are 
contained in the splanchnics, which when stimulated produce 
contraction of the intestinal vessels. As these vessels can, under 
certain circumstances, hold a?' the blood in the body, the in- 
fluence of the splanchnics over the blood-pressure is very great ; 
and division of them can lower it, or stimulation of them increase 
it, very much. The intestine being much longer in herbivora 
than carnivora, the splanchnics have a greater influence over 
the blood-pressure in the former. The chief centre of the wbole 
vaso-motor system seems to be in the medulla oblongata ; and 
it is generally in constant action, keeping up a certain amount 
of contraction or tone in the vessels. There are also, however, 
subsidiary centres in the spinal cord, and possibly also in the 
ganglia of the sympathetic system. 

The activity of the vaso-motor centres may be increased 
(cf. p. 276), and the vessels made to contract — 

1. By direct irritation of these centres. 

2. By reflex irritation through (a) the cervical sympathetic, 
(b) the vagus, when the brain is intact, and the animal not nar- 
cotised, (c) sensory nerves, including the splanchnics themselves. 
When the medulla is separated from the rest of the body by 
dividing the spinal cord at the atlas, it can, of course, no longer 
exert any influence over the vessels ; they consequently become 
dilated throughout the whole body, and the blood-pressure 
usually sinks very low. If the lower end of the divided cord be 
then irritated, the vaso-motor nerves which pass through it from 
the medulla to the body are stimulated, and the blood-pressure 
rises. 

It is probable that the peripheral ends of the vaso-motor 
nerves in the vessels themselves may be either stimulated or 
paralysed by the action of drugs conveyed to them by the general 
circulation. 

V. Depressor nerves. — Irritation of these nerves is con- 
ducted to the vaso-motor centres, and acts on them in such a 
way as to cause a reflex dilatation of the small vessels, either 
(1) generally throughout the whole body, or (2) locally in one 
particular part of it. 

1. The chief nerve which causes dilatation, especially affect- 
ing the intestinal vessels, is one which runs from the heart to 
the medulla, and is called, from its power of diminishing blood- 
pressure, the depressor nerve. Its fibres seem to be included in 
the vagus in the dog; but in the rabbit it generally runs separate 
from the heart to the level of the thyroid cartilage; here it 



292 PHAEMACOLOGY AND THEEAPEUTICS. [sect. i. 

divides into two so-called roots, one root going to the superior 
laryngeal, and the other to the vagus nerve. These are generally 
called roots, though, as the nerve conveys impressions from the 
heart to the brain, they are, physiologically, really branches. 
There seem to be also depressor fibres in the vagus itself; but 
the vagus contains fibres of many kinds, and, among others, 
some which cause reflex . contraction of the vessels and rise of 
blood-pressure — hence called pressor-fibres. The depressor-fibres 
of the vagus seem to act on the vaso-motor system through the 
medulla itself, while the pressor-fibres affect it through a centre 
in the brain, so that, when the brain is perfect, irritation of the 
central end of the vagus causes increased contraction of the 
vessels and raised blood-pressure ; but, when the brain is re- 
moved or its functions abolished by opium, it causes dilatation 
of vessels and diminished pressure. 

2. When a sensory nerve is irritated, the action of the vaso- 
motor pentre is suspended in the part supplied by the nerve, 
and in 'those which immediately adjoin it, so that their vessels 
become dilated, while at the same time contraction of the vessels 
in other parts of the body is produced. The blood-pressure is 
thus increased generally, and produces in the locally dilated 
vessels a very rapid stream of blood. This fact was first dis- 
covered, and its therapeutics indicated, by Ludwig and Loven. 

The causes of alteration in blood-pressure as well as in the 
pulse-rate, will perhaps be more easily seen from the table on 
the next page. 

Action of the Heart on Blood-pressure. — I have already 
mentioned that we can to a certain extent ascertain whether a 
rise or fall in blood-pressure is due to the heart or arterioles, by 
comparing the pressure-curve with the pulse-curve (p. 271 et 
seq.). If they run parallel the effect may be attributed in great 
measure to the heart. 

But the effect of the heart on the blood-pressure is not so 
simple as that of the arterioles. In the case of the arterioles 
we have to consider only the rate at which the blood will flow 
through them when they are more or less contracted ; but in the 
case of the heart we have to consider not only the rapidity of 
its pulsations, but the amount of blood which is sent into the 
arterial system at each beat. We judge of the amount of blood 
chiefly by the extent to which the blood-pressure oscillates with 
each pulsation. A large quantity of blood will, as a rule, cause 
an extensive, and a small quantity only a slight oscillation. 
When, the heart is beating slowly, so that it has time to fill 
completely during each diastole, the oscillations are large, and 
when it is beating quickly the oscillations are small. 

It is evident that although quick pulsations tend to raise the Hood- 
pressure, they only do so up to a certain point, as beyond that, the heart does 
not get properly filled, and so sends but little blood into the aorta at each 



chap, xi.] ACTION OF DEUGS ON THE CIRCULATION. 293 

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294 PHARMACOLOGY AND THERAPEUTICS, [sect. i. 

beat. But the heart may sometimes be imperfectly filled even when it is 
beating slowly ; this has been shown to occur in the case of the frog by 
Goltz. When a blow or two is struck on the intestines the veins dilate and 
the blood accumulates in them, so that the heart, which is also stopped at 
first, receives no blood when it does begin to beat again. It can therefore 
send none into the aorta, and the circulation remains completely arrested, 
although the heart is beating. 

If the pulmonary capillaries also are contracted the left ventricle will 
receive little blood, and so will send little blood into the arteries, although 
the right ventricle may be much distended. This appears to occur during 
poisoning with muscarine, which causes the lungs to become blanched, 1 the 
right ventricle distended, and the left ventricle and the arterial system empty: 
so that little blood flows from a wound. 2 




a ■ im c 

Fjg. 84. — For description vide p. 263. 

It is difficult, however, to estimate precisely the quantity of blood sent 
into the arteries at each beat, and its relation to the rapidity of the pulse, so 
as to ascertain directly how much the rise or fall of blood-pressure is due to 
the heart ; and therefore this is sometimes estimated indirectly by ascertain- 
ing first how much of the effect of the drug on the blood-pressure is due to 
the arterioles, and then attributing to the heart what is not accounted for by 
their action. 

Sometimes also we may get useful information by compressing the abdo- 
minal aorta as near the diaphragm as possible before and after injection. We 
thus dimmish so greatly the number of capillary outlets by which the blood 
may flow from the arteries into the veins that we greatly lessen, though we 
do not quite destroy, the effect of the arterioles on the blood-pressure. We 
can thus estimate more precisely the action of the heart upon it. 

Section of the spinal cord below the medulla oblongata, by destroying the 
effect of the vasomotor centre upon the vessels, also aids us in estimating 
the action of the heart. 

Another method of ascertaining what share in alterations of the circula- 
tion locally is due to the heart and arterioles respectively, consists in the 
combined use of the manometer and Ludwig's stromuhr or Marey's hsemo- 
dromometer. The manometer shows the general blood-pressure while the 
hffimodromometer shows the rate of circulation in the particular artery 
experimented upon. If the rate of flow increases while the blood-pressure 
remains constant or sinks, it is evident that the arterioles of the particular 
vascular district to which the artery is distributed have become dilated. If, 
on the other hand, the rate of circulation diminishes while the pressure 
remains constant or rises, it is clear that the arterioles have become con- 
tracted. 

This method is only capable of being applied to large arteries such as the 
carotid or femoral. By placing the stromuhr in the femoral artery, Dogiel 
and Kowalewsky found that during suffocation the rapidity of the blood-flow 
diminished while the pressure rose, showing that the peripheral vessels were 
contracted. 3 

1 Lauder Brunton, Brit. Med. Joum., Nov. 14, 1874. 

2 Schmiedeberg and Eoppe, Das Muscarin, p. 57. 
» Pflilger's Archvo, 1870, p. 489. 



chap, xi.] ACTION OF DRUGS ON THE CIRCULATION. 295 

By the use of the stromuhr, Dogiel • haa found that the rapidity of the 
flow of blood m the carotid is first increased and then diminished by alcohol, 
the greatest diminution occurring during complete narcosis. 

Effect of Drugs on the Pulse-rate.— The pulse-rate, i.e. the 
rapidity of the heart's beats, is chiefly regulated by the inhibitory 
fibres of the vagus, although it is affected also by accelerating 
fibres. In the frog the latter, excepting those which pass to the 
motor ganglia of the heart from the endocardium, also run mainly 
in the vagus, which is really the vago-sympathetic (Gaskell). In 
the higher animals they run chiefly through sympathetic channels, 
though to a slight extent also in the vagus. 

If we find that the administration of a drug quickens the 
pulse, we next try to discover the mode in which it has done so. 
A glance at the table (p. 293) will show that there are several 
ways in which acceleration may occur, though the most important 
is either paralysis of the vagus or, at least, cessation of its action. . 
The usual stimulus to the vagus-roots in the medulla which calls 
the nerve into action is the pressure of blood within the medulla ; 
when this is high the vagus-rootB are stimulated, and the pulse 
becomes slow ; when the pressure is low, the stimulus is removed, 
and the pulse again becomes quick. , Alterations in the blood- 
pressure will therefore alter the pulse, and drugs which affect the 
arterioles may quicken or slow the pulse-rate without any marked 
action of their own on the heart or vagus. This has already been 
mentioned when speaking of nitrite of amyl, which, by lowering 
the blood-pressure, and thus lessening the normal stimulus to the 
vagus-roots, greatly quickens the heart in the dog (p. 288). 

In order to ascertain whether irritation of the vagus has been 
caused reflexly or not, we may divide the nerves through which 
we may expect the reflex to have occurred, or we may abolish 
their action on the medulla to a great extent by the use of large 
doses of chloral. 

Action of Drugs on the Cardio-inhibitory Functions of 
the Vagus. 

When speaking in the following pages of the inhibitory action 
of the vagus on the heart I mean its power to affect the rhythm 
of the heart so as to render its pulsations slow or stop them en- 
tirely, and I do not include under the term inhibition, the power 
which the vagus also possesses of enfeebling the cardiac contrac- 
tions, unless when this is expressly stated. 
. We distinguish between (a) stimulation of the vagus-roots by 
any cause whatever, and (b) stimulation of its ends in the heart 2 

1 Pflilger's Archiv, 1874, vol. viii., p. 606. 

* We use the term vagus-ends here for the sake of convenient distinction between 
the central cardio-inhibitory systems in the medulla oblongata and the peripheral 
one in the heart. A fuller explanation of the peripheral cardio-inhibitory apparatus 
will be given further on. 



296 PHAEMACOLOGY AND THEEAPEUTICS. [sect. I. 

by dividing both vagi. Sometimes we inject the drug first, and 
see whether any slowing of the heart which it has produced dis- 
appears on section, or we may divide them before injecting the 
drug, and see whether any change, either in the way of slowing 
or acceleration, occurs after the injection. If the effect of a drug 
in slowing the heart is removed by dividing the vagi, we conclude 
that its action has been exerted on the vagus-roots : if it should 
still persist after their division, we conclude that it has acted on 
the vagus-ends in the heart or on the heart itself. 

Thus aconitine, 1 veratrine, 2 erythrophkeum, 3 and probably all 
members of the digitalis 4 group stimulate the vagus-roots, so 
that the slowing of the pulse they produce is much lessened or 
completely abolished by section of the vagi, and takes place to a 
much less extent when the vagi are divided before the injection. 
That the slowing does not always completely disappear after 
section of the vagi, or is not always completely prevented by 
their previous section, is due to the fact that most of these drugs 
have also an action either on the ends of the vagus in the heart, 
or on the nervous mechanism or muscular fibre of the heart itself. 
Nicotine resembles the substances already mentioned in so far that 
the slowing which it would otherwise produce is somewhat less- 
ened by section of the vagi, but only to a slight extent, its action 
being chiefly exerted on the peripheral cardio-inhibitory system. 5 
Physostigmine chiefly affects the heart itself, and so the slowing 
of the pulse it causes is not abolished by section of the vagi. 6 

Reflex Stimulation of the Vagus.— The vagus-centre may 
be also stimulated reflexly, and slowing or stoppage of the heart 
produced by irritation of sensory nerves. This stimulation occurs 
most readily through the nasal, dental, or other branches of the 
fifth nerve, the nucleus of which is closely connected with that 
of the vagus, or through the sensory branches of the vagus itself, 
but it may also be induced through almost any sensory, and 
some sympathetic nerves, if the stimulus be strong. 

The vagus-centre in rabbits appears to be very readily 
stimulated through the nasal nerves, for the application of any 
strong vapour such as ammonia or chloroform to the nose not 
only induces closure of the nostrils and stoppage of respiration, 
but also complete arrest of the heart's pulsations. . It appears 
also to be very sensitive to venous blood. Stoppage of the heart 
may occur in man from irritation of a sensory nerve, even under 

1 Vide Dissertation on Aconitine under Bshm's direction, by C. Ewers, Dorpat, 
1873. 

» Von Bezold and Hirt, Wilrebwrger physiol. XJntersuch. i. p. 103. 

8 Brunton and Pye, Phil. Trans., 1877, p. 627. 

* Traube and others. 

8 Traube, Med. Centralstg. 1862 and 1863, No. 9; Centralblatt f. d. med. Wiss. 
1863, pp. Ill and 159; Bosenthal, Centralblatt f. d. med. Wiss., 1863, p. 737. 

8 Fraser, Trans, of Boy. Soc. of Edinburgh, 1867, reprint, p. 39; for other 
literature vide Harnack, Arch.f. exjp. Path. u. Pharm., Bd. v. p. 446. 



chap, xi.] ACTION OF DRUGS ON THE OIECULATION. 297 

chloroform anaesthesia, and indeed I believe that in excision of 
the eyeball the heart usually misses one beat at the moment the 
nerves* are divided. 

In dogs, stoppage of the heart and death may occur from 
irritation of the stomach, even when complete anaesthesia has 
been produced by chloroform. Some years ago, when making 
a gastric fistula in a dog, the animal, which was in a state of 
profound anaesthesia from chloroform, suddenly died when the 
stomach was laid hold of with forceps. This occurred in a second 
case just as the cannula was being introduced. On mentioning 
the subject to Professor Schiff, he informed me that he had 
had several cases of a similar sort when using chloroform as an 
anaesthetic, but had none after he began to use ether instead. 
I found also on using ether that no further death occurred. 

Causes of Quickened Pulse. — If, instead of causing a slow- 
ness of the pulse, the drug produces quickening, it may be due 
to paralysis of the vagi, to stimulation of the accelerating nerves, 
or to direct action on the heart itself. We ascertain whether the 
drug has paralysed the ends of the vagus in the heart by inject- 
ing it, and then irritating the vagi in the neck by a faradaic 
current. If we find that we are no longer able to slow or stop 
the heart by stimulation of the vagi, we conclude that the drug 
has paralysed these nerves. This action is well-marked in the 
case of atropine. 

Action of Drug's on Vagus-roots. — We may wish to know, however, 
what the action of the drug has been on the vagus-roots, and it is evident 
that if the ends in the heart are paralysed, no action on the vagus-centre 
could alter the pulsations of the heart any more than nervous stimuli pro- 
ceeding from the cord could move the legs of an animal poisoned by curare. 
Nor can we separate the vagus-centre from the heart by ligature of the 
vessels so readily as one isolates the frog's leg. It can be done no doubt by 
tying the carotid and vertebral arteries and keeping up.an artificial stream 
of blood through the head. Instead of this, however, the simpler method is 
generally adopted of injecting the drug to be tested into the carotid artery, so 
that it will reach the vagus-centre before it gets to the heart, instead of 
injecting it as usual into the subcutaneous tissue or veins, whence it will be 
carried to the heart before it can reach the vagus-centre. 

By experimenting in this way it is shown that atropine stimulates the 
vagus-roots so that when injected into the carotid it causes slowing of the 
heart's action. When it has passed through the cerebral vessels, and returns 
with the blood to the heart it paralyses the ends of the vagus in the heart, 
and therefore the pulse again becomes very rapid, notwithstanding the con- 
tinued stimulation of the vagus-roots. 

We cannot always conclude with certainty that a drug has excited the 
vagus-roots merely because it has caused the pulse to become slower and has 
had no action after the vagi have been divided, for it is possible that the ter- 
minations of the vagus in the heart may be rendered more sensitive than 
usual by a drug, so that they may respond to a slighter stimulus than usual 
or with greater energy to a normal stimulus. Such an action appears to be 
exerted by physostigmine, which in a certain stage of poisoning renders the 
vagus more excitable, so that when irritated in the neck by a faradaic current 
a slighter stimulus suffices to stop the heart after the administration of the 
drug than before. 



298 PHAEMACOLGGY AND THEEAPEUTICS. [sect. i. 

Action on Accelerating Nerves. — We ascertain whether a drug has a 
stimulating action on the accelerating nerves of the heart by cutting both 
vagi and then injecting the drug. If it quickens the heart still further, we 
assume that it does so by stimulation of the accelerating nerves. This 
experiment, however, does not enable us to decide whether the stimulation 
has affected the accelerating nerves passing to the cardiac ganglia from the 
central nervous system or those passing from the endocardium. 

Stimulating' Effect of Asphyxial Blood on the Medulla. — In order to 
prevent fallacies arising from stimulation of the vagus-roots by an asphyxial 
condition of the blood due to the action of the drug upon respiration, it is 
usual to maintain artificial respiration through a cannula placed in the 
trachea. This acts perfectly well in some cases, but if the drug should cause 
violent convulsive actions it may prevent the movements of the thorax 
occurring regularly, and therefore it is sometimes necessary to paralyse them 
by means of curare. 

Moreover, it must be remembered that prolonged stoppage of the heart 
itself will allow the blood in the medulla to become venous and will thus 
irritate the vagus-roots. Prolonged arrest of the heart, therefore, tends by 
this action to prolong it still further, and functional inactivity tends to pass 
into death. This mechanism would render every intermission of the pulse 
very dangerous were it not that the same venous condition of the blood 
which stimulates the vagus-roots stimulates also the vaso-motor centre and 
the respiratory centre. The vaso-motor centre by contracting the arterioles 
maintains the blood-pressure during the prolonged diastole, and excitation of 
the respiratory centre tends to restore the arterial character of the blood. 
The venous condition of the blood also stimulates accelerating centres in the 
medulla (Dastre and Morat). 

Stimulation of the Heart by increased Blood-pressure. — 

It has already been mentioned that increased blood-pressure 
usually renders the beats of the heart slower by the stimulating 
action it exerts on the vagus-roots. When the vagi are divided, 
however, its effect is usually quite different, and a rise in blood- 
pressure after division of the vagi renders the pulse- quicker 
instead of slower, at least generally. An opposite result has been 
found by Marey in the heart of the tortoise, where increased 
pressure rendered the beats slower. The reason of the difference 
observed between the mammalian heart and that of the tortoise 
is probably due to the different development of the nervous and 
muscular structures. The tortoise heart acts more like a single 
simple muscle, and the more resistance it has to overcome the 
more slowly does it work. 

In the mammalian heart the increased pressure appears to 
stimulate the nerves, so that the more resistance it has to over- 
come the more quickly does it work — that is, if the vagi have 
been cut. The sensibility of the nervous system in the heart to 
increased pressure appears to be diminished by atropine, for Schiff ' 
has found that a quantity of this poison slightly larger than will 
dilate the pupil lessens the sensibility of the heart to changes in 
blood-pressure so much that the pressure may be first increased 
to three times the normal and then diminished to one-half, or even 
one-third, without any change in the pulse-rate being produced. 

1 La Nazione, 1872, No. 235. 



chap, xi.] ACTION OF DRUGS ON THE CIRCULATION. 299 

Such an observation suggests that atropine would be useful in 
lessening pain or palpitation of the heart .in persons with high 
blood-pressure or suffering from the effects of cardiac strain con- 
sequent on violent muscular exertion. I have tried it in such 
cases sometimes with apparently great benefit, at other times 
with little result. The cases of failure may, however, have been 
due to the remedy not being pushed far enough, as in them the 
pupil was not markedly dilated. 

Palpitation. — In what I have just said regarding the effect 
of blood-pressure on the heart I have spoken of the total work, 
including in it both the rapidity of pulsation and the amount of 
work done by each beat. This is, perhaps, fair enough ; but at 
the same time we must not forget that there is a distinction be- 
tween the total amount of work done and the nature of the indi- 
vidual contraction, either in the heart of tortoises or mammals, 
or in voluntary muscles. Both voluntary muscles and the heart 
tend to contract rapidly if they have little resistance to overcome,. 
In patients suffering from anaemia and debility, where the blood- 
pressure is low and the resistance to the ventricular contractions 
is consequently small, they are apt to take place with great quick- 
ness, giving rise to a short flapping first sound and a short but 
unsustained apex-beat, while the patient complains of much pal- 
pitation. In such cases increased blood-pressure will tend to 
lessen the palpitation, and digitalis, which contracts the vessels, 
will be useful ; iron also is serviceable by increasing the nutrition 
of the circulatory apparatus of the body generally. The low 
blood-pressure, however, while it increases the tendency to pal- 
pitation, is not the only factor, and is usually accompanied by a 
tendency to disturbance of the cardiac innervation, which is to be 
met by sedatives such as the bromides, or by remedies directed to 
the stomach or other organs from which the disturbing stimulus 
may proceed. 

The Heart of the Frog. 

This is a very convenient object on which to study the action of drugs. 
Their effects upon it are somewhat, though not absolutely, the same as their 
effects on the mammalian heart ; and the frog's heart being simpler in its 
construction it is easier to analyse the exact mode in which drugs act upon 
it. The frog's heart consists of three chambers, one ventricle and two auri- 
cles. But in addition to these, there is what might almost be called a fourth 
chamber, the venous sinus or sac into which the vense cavse open. 

There are three vense cavse, two superior and one inferior, which open 
into the venous sinus. 

The venous sinus itself opens into the right auricle, the opening being 
covered during the auricular systole by a small fold which acts as a valve. 

The left auricle receives the pulmonary veins and discharges into the 
single ventricle the arterial blood which enters it from them, while the right 
auricle does the same with the venous blood it receives from the sinus. 

The septum between the auricles ends inferiorly in two triangular flaps, 
which act as valves between the auricles and ventricle. 



r 300 



PHARMACOLOGY AND THEEAPEUTICS. [sect. i. 



Prom the ventricle issues the common aorta, or aortic bulh, which has at 
its origin from the ventricle a spiral valve to prevent the return of the blood. 
The two auricles beat together, and the aortic bulb and ventricle usually beat 
together, though the bulb is capable of independent pulsation. 



Left auricle and pulmonary veins 

Aortic bulb 
Bidder's ganglia 




Superior venas cavse and vagi nerves. 
Venous sinus and Remak's ganglion. 

Inferior vena cava. 

Ventricle. 



JTIG. 95. — Diagram of the frog's heart. 

The usual rhythm is the following: first the venous sinus, next the 
auricles, then the ventricle and bulb. 

The pulsations of the venous sinus and ventricle alternate with those of 
the auricle. The heart continues to pulsate rhythmically after it has been 
completely removed from the body, so that the motor power of rhythmical 
contraction is evidently contained within itself. Its rhythm is, however, 
regulated by the vagi nerves. These pass along behind the two superior 
cavse to the junction of the venous sinus with the auricle. At this spot, or 




Fig. 96.— View df the auricular septum in the frog (seen from the left side). The nerves are stained 
with osmic acid, n is the posterior, and n' the anterior cardiac nerve ; Ms a horizontal portion 
of thel atter nerve ; 6 is the posterior, and B' the anterior auriculo- ventricular ganglion ; m is 
a projecting muscular fold. [This figure is taken by the kind permission of my friend, M. 
Ran vier, from his Lemons d'Anatomie ghdrale, Annee 1877-78, ' Appareils nervous terminaux,' 
t. 6, p. 79.] 

just over the auricles, between the superior cavse and the pulmonary veins, 
they anastomose to form a single or double ganglion, or a plexus containing 
ganglionic cells, sometimes known as Bemak's ganglion. From hence two 
nerves pass down in the auricular septum, to the base of the ventricle, where 
they end in two ganglia, known as Bidder's ganglia (Fig. 95). These are 
situated at the junction of the wall of the ventricle with the two valvularflaps 
in which the septum ends. They are connected with one another by fibres 
which run transversely, nearly in a line with the auriculo-ventricular groove. 

The posterior or dorsal nerve comes chiefly from the left vagus ; and the 
anterior or ventral from the right vagus. 

Both of these nerves grow thicker as they pass down towards Bidder's 



chap, xi.] ACTION OF DEUGS ON THE CIRCULATION. 801 

ganglia from the presence in them of numerous ganglionic cells ; they also 
send off several branches to the auricle. 

The ventricle itself has not been shown to contain either nerve-fibres or 
ganglionic cells, excepting just at its base, where Bidder's ganglia already 
mentioned are situated, and where branches from them proceed to the 
ventricle. 

Action of Drugs on the Heart of the Frog. 

The effect of drugs may be observed by simply destroying the brain, 
exposing the heart, and either injecting the drug subcutaneously, or into the 
dorsal lymph-sac, or even laying it upon the heart itself. Changes in the rate 
of the pulse and in the mode of contraction of the different cavities of the 
heart are thus readily observed. By exposure and irritation of the vagi the 
effect of drugs upon their action can also be observed. Even when com- 
pletely excised, the heart of the frog continues to pulsate for a length of 
time, and the action of heat, cold, and poisons upon it can be readily demon- 
strated. A simple apparatus for this purpose is shown in Fig. 97. 




Fig. 97. — Instrument for showing the Action of heat and cold and of poisons on the frog's heart. It 
consists of a piece of tin plate or glass three or four inches long and two or three wide, at one 
end of which an ordinary cork cut square is fastened with sealing-wax in such a manner that it 
projects half an inch or more beyond the edge of the plate. This serves as a support to a little 
wooden lever about three inches long, a quarter of an inch broad, and one-eighth of an inch 
thick. A pin is passed through a hole in the centre of this lever, and runs into the cork, so that 
the lever swings freely about upon it as on a pivot. The easiest way of making a hole of the 
proper size is simply to heat the pin red hot, and then to burn a hole in the lever with it. To 
prevent the lever from sliding along the pin, a minute piece of cardboard is put at each side ol 
it, and oiled to prevent friction. A long, fine bonnet-straw, or section of one, is then fastened 
by sealing-wax to one end of the lever, and to the other end of the straw a round pi?ce of white 
paper, cut to the size of a shilling or half-crown, according to convenience, is also fixed by a 
drop of sealing-wax. The pin, which acts as a pivot, should be just sufficiently beyond the edge 
of the plate to allow the lever to move freely, and the lever itself should lie flat upon the plate. 
Its weight, too, increased as it is by the straw and paper flag, would now be too great for the 
heart to lift, and so it must be counterpoised. This is readily done by clasping a pair of bulldog 
forceps on the other end. By altering the position of the forceps the weight of the lever can be 
regulated with great nicety. If the forceps are drawn back as ate, the flagis more than counter- 
balanced, and does not rest-on the heart at all, while the position a brings the centre of gravity 
of the forceps in front of the pivot, and increases the pressure of the lever on the heart. The 
isolated frog's heart is laid under the lever near the pivot, and as it beats the lever oscillates 
upwards and downwards. When used for demonstrating the action of poisons the wooden lever 
should be covered with sealing-wax, so as to allow every particle of the poison to be washed off! 
it, and thus prevent any portion from being left behind and interfering with a future experi- 
ment. By attaching a small point to the end of the straw in place of the paper flag, tracings 
may be taken upon smoked paper fixed on a revolving cylinder. 

The fact that heat accelerates and cold retards the pulsations 
of the heart is one of fundamental importance, both in regard to 
a right understanding of the quick pulse, which is one of the most 
prominent symptoms of fever, and to a correct knowledge of the 
proper treatment to apply when the heart's action is failing. 

It may be shown with the apparatus just described by placing 
a piece of ice under the tin plate. The pulsations will become 
slower and slower, and if the room be not too warm the heart may 
stand completely still in diastole. On removing the ice from the 
plate the pulsations of the heart become quicker. If a spirit-lamp 



802 



PHAEMACOLOGY AND THEEAPEUTICS. [sect. t. 



be now held at some distance below it the heart beats quicker and 
quicker as the heat increases, until at last it stands still in heat- 
tetanus. On again cooling it by the ice, its pulsations recommence. 




Pi8. 98— Ludwig and Coats' frog-heart apparatus, a Is a reservoir for serum. B, a stopcock to 
regulate the supply to the heart. 0, a piece of caoutchouo tubing connecting a and d. d a 
glass cannula in the vena cava inferior, d', another in the aorta, a, a manometer f a' piece 
of tubing closed by a clip, to al low of the escape of serum, a, a fine pen, floating on the mercurv 
in k. h, the frog's heart. J, a sealed glass tube passed through the oesophagus, k, and firml v 
held by a holder, L. H, a second holder to support a. p, a stand with upright rod a a nan 
of akin to coyer the heart and prevent drying. The vagu B nerve is seen oassing to the heart 



chap, xi.] ACTION OF DRUGS ON THE CIRCULATION. 303 



At first they are quick, but they gradually become slower and 
slower. On again applying the spirit-lamp they become quicker, 
and by raising the temperature sufficiently the heat-tetanus is 
converted imto heat-rigor. In this condition no application of 
cold has the slightest effect in restoring pulsation. 

Not_ only the effects of heat and cold, but the effect of 
separating the venous sinus or the auricles from the ventricle can 
readily be shown with this apparatus, as well as the action of 
various poisons. The best for the purpose of class demonstration 
is muscarine. A drop of saline solution containing a little of the 
alkaloid being placed on the heart, it ceases to beat entirely. If 
a drop of atropine solution be now added the beats recommence. 
I have seen them do so on one occasion after they had entirely 
ceased for four hours. 

For the purpose of observing alterations in the strength of the cardiac 
pulsations as well as their rhythm, a convenient piece of apparatus is the one 
devised by Ludwig and used under his directions by Coats (Fig. 98). 

One objection to this apparatus as shown in the engraving is, that the 
blood does not circulate freely through the heart, but this can be overcome 
by closing the tube at f only partially instead of completely, and according 
to the amount of closure the pressure under which the heart worts may be 
regulated. Or the tube f may be lengthened and made to empty itself into 
the reservoir a. The pressure under which the heart works may be regulated 
by the height at which the tube is allowed to discharge. 

Another apparatus is that used by Williams in his researches on digitalin 
(Fig. 99).' It consists of a Y-shaped cannula whose stem is divided by a 



Flask containing 

nutrient fluid 



Valve opening 

towards heart 



Valve opening ) 
from heart ) 




Valve with slit. 



• Recording cylinder. 



— -— i|b~ Manometer. 

SI 



Fig. 99. — Diagram of Williams's apparatus for investigating the action of drugs 
on the heart of the frog. 

longitudinal septum into two halves, each of which is continuous with the fork 
on its own side. The stem is inserted through the aorta into the ventricle of 
■ the heart, which is kept moist by being dipped in a vessel containing serum or 
a dilute saline solution. One fork of the Y is connected with a flask containing 
blood-serum or other nutritive fluid, and the other with a manometer. By 
means of valves these fluids are made to flow only in one direction. These 
valves consist of a piece of glass tubing with a slit on one side ; over this slit 
is loosely tied a piece of thin membrane (gold-beater's skin) which covers about 
three-quarters of the circumference of the tube. This membrane allows fluid 
to pass readily out of the tube from within outwards, but not from without 
inwards, any external pressure causing the membrane to become tightly 
applied to the slit and to close it. 

1 Arch. f. exp. Path. u. Pliarm., Bd. xiii. p. 1. 



304 PHARMACOLOGY AND THEEAPEUTICS. [sect. i. 

A very useM form of apparatus for investigating the action of drugs 
on the frog's heart and on the effect of the vagus upon it is made by com- 
bining the valves in Williams's apparatus with the apparatus of Ludwig and 
Coats. 1 

The apex (as the lower two-thirds of the ventricle is com- 
monly called) contains, as has been mentioned, no nerves, and 
when separated from the rest, either by cutting or by tight liga- 
ture, usually lies perfectly quiet without contracting. When 
irritated by a single induced shock, it answers by a single con- 
traction, just like any other muscular fibre. 

But though the muscular fibres contained in the apex cease 
to contract rhythmically, when the nervous stimulus usually 
supplied by Bidder's ganglia is removed, they still retain a ten- 
dency to rhythmical contraction ; and when subjected to a con- 
stant stimulus of another kind they again commence to pulsate. 
This is seen when the apex is stimulated by supplying it with 
oxygenated blood through a cannula under pressure (the pressure 
supplying the necessary stimulus), or by passing through it a 
constant or interrupted current, or by adding a trace of del- 
phinine to the nutritive fluid with which it is supplied. This 
phenomenon is similar to that which occurs in the bells of 
medusae already described (p. 110), which cease to contract rhyth- 
mically when their marginal ganglia are removed, but recom- 
mence when an additional stimulus is applied to the bell itself, 
by putting it into acidulated water. 

A curious point has been made out by Bowditch regarding 
the excitability of the heart-apex. It has already been men- 
tioned that the amount of compaction of voluntary muscle varies 
with the intensity of the stimulus, and that this is also the case 
with the reflex contraction produced by irritation of sensory 
nerves. The apex when fed with serum usually stands still for 
a long time before it begins to beat, but when in this condition 
may be made to contract by the application of an induction 
shock. The difference between the reaction of an ordinary 
striated muscle and of the apex to such a shock is, that the 
heart, instead of responding by a strong or weak contraction to 
a strong or weak stimulus, either does not contract at all or con- 
tracts with as much force as it can exert. The weakest stimulus 
which will act at all and the strongest have thus exaetly the same 
action, or, in other words, a minimum is also a maximum stimu- 
lus. This condition does not correspond to that which obtains 
in the normal striated muscle when stimulated either directly or 
reflexly. We find, however, a corresponding condition in the 
reflex contraction of the muscle produced by stimulation of 
sensory nerves in an animal poisoned by strychnine (p. 181). 
We noted, however, in discussing the action of strychnine on the 

1 Harnack and Hoffmann, Arch. f. exp. Path. u. Pharm., Bd. xvii. p. 159. 



chap, xi.] ACTION OF DEUGS ON THE CIECULATION. 805 

spinal cord, that, just after exhaustion had occurred from a 
spasm, strong and weak stimuli produced strong and weak con- 
tractions in the muscle. A somewhat similar condition appears 
to occur in the heart, for Mays has noticed that, when the apex 
is supplied with blood which has stood three or four days instead 
of with fresh blood, strong and weak stimuli produce strong 
and weak contractions. 1 

It is obvious that, although the contractions of voluntary 
muscle on reflex stimulation may be analogous to the contrac- 
tions of the apex, yet, in the former case, the alterations occur 
in the nervous centres, while in the apex the changes occur in 
the muscular substance. 

Action of Drugs on the Muscular Substance of the Heart. 

' Since the lower two-thirds of the ventricle or apex, as it is 
usually termed, contains no nerves, it forms a convenient object 
for ascertaining the action of drugs upon the muscular substance 
of the heart itself and has been much used for this purpose. 

Tube for allow- Jr^ ^^%. 

ing escape of W ^ 

fluid from the GL ^S^^^^^ 

heart >S- ^^^0*^ "m. " 



_End for intro- 
duction into 
the heart. 



1TI8. 100.— Perfusion cannula, with the anterior part removed so as to show the septum. 

The apparatus usually employed (Fig. 100) consists of a small cannula 
introduced into the ventricle, which is attached to it by a ligature tightly tied 
round it at the junction of its upper third with its lower two-thirds. The 
interior of the cannula is divided into two by a septum which runs longi- 
tudinally, and the one half is connected with a flask containing the nutritive 
fluid with which it is to be supplied, and the other with a small mercurial 
manometer provided with a float to register its oscillations upon a revolving 
cylinder. 

At first the nutritive fluid is supplied pure to the apex, and 
after a normal tracing has been obtained the substance to be 
investigated is added to it. # . 

When saline solution, a -65 per cent, solution of NaU, is 
employed, the apex usually stops in diastole for a period varying 
from a few minutes to an hour and a half. It then begins to 
pulsate (Fig. 101, a), getting gradually weaker and weaker (Fig. 
101, b and c), and finally stops in diastole. When the heart is 
in this condition its pulsations may be restored by the addition 

> Separat-Abdk. a. d. 7erhandl. d.physiol. Gesellsch. zu Berlin, Jan. 12, 1883. 



306 PHAEMACOLOGY AND THEEAPEUTICS. [sect, i.' 

to the chloride of sodium solution of 1 to 10 per cent, of blood, or 
of serum, or of a solution of the ashes of serum. 

Minute quantities of several poisons such as delphinine or 
quinine, or a mixture of atropine and muscarine, also restore the 






FIG 101 —After Ringer. Tracings showing the effect of simple NaCl solution in weakening the 
pulsations of the apex of the frog's heart. The tracing a was taken soon after the blood was 
replaced by NaCl solution ; 6, after a longer period ; and c after a still longer time. 

rhythmical pulsations after they have ceased in a heart-apex 
supplied with NaCl solution. A minute quantity of Na 2 C0 3 or 
■005 per cent, of NaHO restores or increases the beats for a time ' ; 
afterwards the pulsations become again weaker and the heart 
stops a second time, but it stops in systole and not in diastole. 

Singer has made the remarkable discovery that when the 
saline solution is made with ordinary tap-water the beats become 
prolonged, but the addition of a trace of potash causes them at 
once to assume their normal character, and a frog's heart may 
be kept beating for hours together with saline solution made in 
this way and containing a trace of potash, although the saline 
solution never does this when made with distilled water. The 



S"> 



Fig. 102.— After Ringer. Shows the effect produced upon the beat of the frog's heart fed with NaCl 
solution by the addition of a trace of calcium chloride. The beats in this case are induced by an 
induction shock. 

addition of a minute trace of calcium salt to distilled water pro- 
duces the same effect as tap-water — the contractions become 
larger and longer (Fig. 102) . When potash is then added, the 
length of the contractions becomes diminished to the normal 
without their strength becoming affected, and thus a pure saline 
solution made with distilled water and with the addition of 
minute traces of calcium and potassium will keep the heart 
beating perfectly for hours together. 

Dilute alkalies added to the saline solution have been shown 
by Gaskell to cause a tonic contraction of the muscular fibre of 
the apex, so that it may gradually cease to beat. This con- 
traction may occur whether the apex- is pulsating or not. If it 

1 Gaule, Archiv f. Anat. u. Phys., 1878, p. 295. 




chap, xi.] ACTION OF DEUGS ON THE CIRCULATION. 307 

remains at rest, a manometer connected with it simply shows a 
gradual rise in the mercury until the contraction of the apex is 
complete. If it is heating, the duration of full contraction at 
each systole becomes longer, and relaxation during diastole less 
complete, until no diastolic relaxation occurs and the ventricle 
remains perfectly still in a condition of complete contraction. 

Dilute acids have an opposite action to dilute alkalies, and 
when very dilute acid, e.g. lactic acid, is mixed with the saline 
solution, it produces a condition of complete relaxation. 

Instead of increasing the duration of the systole like alkalies, 
acids first shorten it and then render it less and less powerful, 
until contractions cease altogether and the ventricle remains at 
rest in diastole. 

Dilute acids and alkalies counteract each other's effects on 
the heart, so that after the beats have been very much lowered 
in force by acids, an alkali will first restore it to its original con- 
dition, and then produce its own characteristic effect. The sub- 
sequent application of an acid will undo the effect of the alkali, 
again weakening the beats and again producing dilatation instead 
of contraction. 1 

The three alkalies, potash, soda, and ammonia, have all a 
somewhat similar tendency to increase the tonic contraction of 
the ventricle. When large doses are given they tend to para- 
lyse the muscle, so that it again dilates after a period of tonic 
contraction. The paralysing action of potash is much more 
powerful, and manifests itself much sooner than that of the 
other two. 

The excitability of the muscular fibre is also altered by alkalies. 
Soda and ammonia increase it, so that a faradaic stimulus ap- 
plied to the ventricle has, much more effect after the application 
of soda and ammonia than before. Potash has a different effect 
and diminishes the excitability of the ventricle, although some- 
times the diminution may be preceded by a stage of increased 
excitability. 2 

A number of poisons act on the muscular fibre of the ventricle 
like alkalies, others act like acids. 

Antiarine, digitalin, helleborin, veratrine, physostigmine, 
barium, and probably all the substances belonging to the digitalin 
group, act like alkalies. 

Muscarine 3 acts like an acid, and so apparently do also pilo- 
carpine, 4 saponine, 5 and apomorphine. 

Neutral double salts of copper, chloral, iodal, and , other 
members of the chloral group, 6 are probably to be classed along 

1 Gaskell, Jowrn. of Physiol., vol. iii. p. 48. 

* Binger, Ibid., vol. iii. p. 193. 

* Gaskell, Jowrn. of Physiol., vol. iii. p. 61. 

* Ibid., op. cit. 

* Schmiedeberg, Ludwig's Festgabe. p. 127. 

" Harnack, Archivf. cxp. Path. u. Biwurm.. Bd. xvii. p. 185. 

x 2 



308 PHAKMACOLOGY AND THEEAPEUTICS. [sect. i. 

-with salts of potassium, first exciting and then paralysing the 
cardiac muscle. 

In classifying cardiac poisons, when we say that some act 
like acids and others like alkalies, it must be borne in mind that 
the action though similar is not identical. Although the actions 
may be generally like one another, they may vary very consider- 
ably even in kind, and they certainly vary enormously in degree. 
Thus the action of barium and veratrine may be very similar, but 
veratrine is much the more powerful. We find a similar condition 
in other structures. Thus iodide of ammonium and curarine 
both paralyse the ends of motor nerves, but an enormously 
larger amount of the former is required to produce the effect. 

That there is considerable similarity in kind, however, be- 
tween the action of the vegetable alkaloids and inorganic salts is 
shown by the fact that the action of veratrine may be neutralised 
by potassium chloride. 1 

The irritability of the heart is preserved for very different' 
lengths of time in different gases. Thus Castell 2 found that the 
frog's heart continued to beat in oxygen for 12 hours, in nitrogen 
for 1 hour, in hydrogen for 1£ hour, in carbonic acid for 10 
minutes, in nitrous oxide for 5 or 6 minutes, in carbonic oxide for 
40 minutes, and in chlorine for 2 minutes. 

Differences between the Heart-Apex and the Heart. 

When the heart is tied on to a cannula in the same way as 
the apex, by a ligature round the auricles or even the sinus, so 
that, instead of containing no ganglia at all, it contains either 
Bidder's or Bidder's and Kemak's ganglia, it also remains motion- 




FiG. 103. — Diagram to Bhowthe differ nee in the mode of experimenting with the heart and with the 
apex alone. In a the apex alone its attached to the cannu'a. In o the heart, consisting of 
ventricle and auricles, or of the venous sinus also, is attached to the cannula. 

less in the same way as the apex when supplied with chloride of 
sodium solution, but its rhythmical power is restored by the 
addition of defibrinated blood, of serum, of solution of the ashes 
of serum, by a trace of Na 2 C0 3 , or still better by the addition of 
•005 per cent, of NaHO and a trace of peptone or serum-albumin. 
When supplied with pure serum, it does not beat regularly, 
but its pulsations occur in groups separated by long intervals 
(Fig. 104) . 3 When a little haemoglobin or blood is added to the 

1 Binger, Practitioner, vol. xxx. p. 17. 

2 Hermann's Handb. d. Phys., iv. 1, p. 357. 
* Luciani, Ludwig's Arbeiten, 1872, p. 120, 



chap, xi.] ACTION OF DEUGS ON THE CIKCULATION. 809 

serum, this grouping disappears, and the pulsations become 
regular. 1 

When the heart has been supplied with haemoglobin or blood 
and is beating regularly, the addition of a little veratrine causes 




Fig. 104. — Periodio rhythm of the heart, the pulsations occurring in groups separated 
by intervals of complete quiescence. 

the groups to appear, and a similar effect is produced if the 
blood is not renewed, but allowed to remain in the heart till it 
becomes venous. 2 

This periodic stage does not occur immediately after the heart has been 
tied on the cannula and supplied with serum. It is preceded by an initial 
stage, in which the beats are at first very quick, then slow, and these are 
separated by long pauses. Next comes the periodic stage in which the 
groups occur. It is succeeded by the stage of crisis in which the groups are 
replaced by single pulsations slower and smaller than the normal. 

Atropine and nicotine do not prevent the occurrence of groups. Both of 
them make the groups longer and the pauses shorter. Atropine, however, 
even in small doses, soon kills the heart before it even enters on the stage ot 
crisis. Nicotine, on the other hand, shortens the pauses, and rapidly induces 
the stage ot crisis without destroying the energy of the heart, which is quite 
as great after poisoning by nicotine as in the normal condition. 

Moderate doses of muscarine make the pulsations smaller and slower, the 
groups shorter, and the pauses longer. Sometimes the heart becomes ex- 
hausted before the stage of crisis appears, at other times it does not. Large 
doses of muscarine arrest the movements of the heart. 

The activity of the heart which has been stopped by muscarine is again 
restored by atropine, but muscarine can render the beats smaller and slower, 
even after the previous application of atropine. 

The occurrence of groups appears to be most probably due to 
interference of rhythms — of the ganglionic rhythm with that of 
muscular fibre. 

We find an indication of alternate interference and coinci- 
dence of two rhythms in the alterations which sometimes occur 
in the beats of a ventricle containing its ganglia, but separated 
from the auricles. At first all the beats are of equal strength, 
but soon each alternate beat gets longer and shorter, till some 
disappear and others get much stronger than before (Fig. 105 ; cf. 
Fig. 64, p. 168). 

1 Bossbach, Ludwig's Arbeiten, 1874, p. 92. 
* Ibid., p. 93. 



310 PHARMACOLOGY AND THERAPEUTICS, [sect. i. 

Action of Drugs on the Vagus in the Frog. — When the 
vagi are stimulated by an induced current, the heart usually 
stops in diastole. 




Fig. 105.— Tracing of the pulsations of a ventricle separated from the auricles by section at the 
auriculo-ventricular groove. After Kanvier, Lesons, 1877-78. 

The effect of stimulation may be observed either on the heart 
simply exposed or by means of Ludwig and Coats' apparatus. 
The action of both vagi is not always alike. The right vagus 
has usually a greater power to arrest the heart than the left. The 
action of the Vagus varies also according to the condition of the 
heart, and may produce different effects. It may cause, 1st, 
stoppage of the heart's beats, followed after an interval by slow 
pulsations or by small rapid pulsations, gradually becoming 
larger and stronger ; 2nd, it may cause them to become small 
and slow without actual stoppage — -this is the usual effect of 
irritation of the vagus in the. living body ; 3rd, it may cause the 
pulsations to become simply small and rapid without any stop- 
page ; 4th, it may cause them to become rapid ; 5th, it may 
cause them to become more powerful (Figs. 112 to 115, p. 324). 

It may also act differently on the auricles and ventricle, pro- 
ducing still-stand of the ventricle and rapid pulsation of the 
auricles. These differences are probably due to a great extent 
to the vagus of the frog being really the combined vagus and 
sympathetic. At present the chief point upon which I wish to 
insist is that irritation of the vagus usually causes still-stand of 
the heart. 

When the venous sinus is stimulated, still-stand of the heart 
is produced, which is even more complete and permanent than 
that which follows irritation of the vagus. 

Action of Drugs on Inhibition of the Heart. — The effect 
of certain drugs upon the still-stand produced by irritation of 
the vagus or of the venous sinus is very remarkable. A large 
number of drugs, more especially atropine, curare, coni'ine, and 
nicotine, when injected into the circulation have the power of 
completely destroying the inhibitory power of the vagi as far as 
the rate of rhythm is concerned, so that when their fibres are 
stimulated the heart is not arrested, nor are its beats rendered 
slower, but they are, on the contrary, quickened. 

These poisons again may be divided into two classes : 
Class I. containing atropine and its congeners. 
Class II. containing curare, connne, nicotine, &c. 



chap, xi.] ACTION OF DEUGS ON THE CIRCULATION. 311 

These two classes agree in destroying the inhibitory power 
of the vagus nerve, so that irritation of its trunk will no longer 
produce still-stand or slowing of the heart. They differ in their 
action on the still- stand produced by irritation of the venous 
sinus. Atropine and its allies prevent any inhibition occurring 
when the venous sinus is stimulated, or when muscarine is 
applied to the heart directly. This action affects chiefly the 
rhythm of the heart, for muscarine can still reduce the force of 
the cardiac contractions after the application of atropine. 

Poisons of the second class do not prevent the still-stand of 
the heart occurring on irritation of the sinus, nor do they pre- 
vent muscarine from arresting the beats of the heart. This 
antagonism of atropine and muscarine has hitherto been explained 
on the supposition that muscarine greatly stimulates inhibi- 
tory centres in the sinus or auricle, while atropine paralyses 
them. 

These two classes also agree in leaving unaffected the 
accelerating nerves of the heart. 1 

These complicated effects are very hard to explain on the 
ordinary hypothesis. 

It is. still more strange that although atropine and muscarine 
have such apparently opposite effects, they both agree in ulti- 
mately paralysing the inhibitory function of the vagus. 

Muscarine, as I have already mentioned, arrests the move- 
ments of the heart; but, if the circulation be carried on, this 
arrest is only temporary, and is succeeded by a period, first of 
slowness, then of irregularity, and then of return to the normal ; 
the stage of irritation of the inhibitory centre by the muscarine 
gradually passing into that of complete paralysis. During the 
time when the pulse is still slow in consequence of the action of 
muscarine, irritation of the vagus itself has no power to arrest 
it, or even to increase the slowness, while at that very time 
irritation of the accelerating nerves quickens its pulsations just 
as it would those of a normal heart. 2 When the accelerating 
nerves are thus irritated, there is often not only an increase in 
the number but also in the size of the pulsations, very much as 
Gaskell has observed under other conditions from irritation of 
the vagus in the frog. This action is only to be observed in 
moderate conditions of poisoning. When the poisoning is very 
profound, irritation of the accelerating nerves has a very peculiar 

1 In the frog the accelerating nerves appear to run along with the inhibitory 
fibres in the vagus trunk. In warm-blooded animals these fibres run in separate 
nerves which pass out from the spinal cord along the vertebral artery and reach 
the heart through the sympathetic system. Although the chief accelerating fibres 
pass in these nerves, some are also contained in the vagus trunk, both in warm- 
blooded animals and in frogs. In animals poisoned by atropine, irritation of the 
vagus usually produces acceleration of the pulse. 

, " Weinzweig. From experiments in Yon Basch's laboratory. Archiv f. Amt. 
U. Phys., Phys. Abt., 1882, p. 527. 



812 PHAKMACOLOGY AND THEEAPEUTICS. [sect. i. 

effect, sometimes producing so-called staircases, and sometimes 
a prolonged condition of still-stand, half in systole and half in 
diastole. 

A marked difference is seen between the action of the 
accelerating nerves and the inhibitory fibres of the vagus, 
as the inhibitory action follows very shortly after the irritation 
of the vagus, and usually ceases very shortly after the irritation 
is removed, whereas that of the accelerating nerves does not 
occur until some time after the irritation has been applied, and 
often lasts a good while after the irritation has been removed. 
The two sets of fibres also appear to influence a different period 
of the heart's action, the inhibitory affecting the pause or relaxa- 
tion, wbile the accelerating affect the systole or contraction. This 
condition renders it not improbable that we may have to do here 
with an action of these nerves on two different parts of the heart 
— the ganglia and the cardiac muscle. 

It is quite clear that, in order to get any satisfactory ex- 
planation of these phenomena, we must take into consideration 
not only the rhythmical actions going on in the cardiac ganglia 
and those in the cardiac muscle separately, but also the relation 
to one another of these rhythms both as regards their energy 
and rate. 



Theories regarding the Mode of Action of Drugs upon 

the Heart 

In order to explain the effects of various poisons upon the 
heart, a hypothetical view of its nervous system has been proposed 
by Professor Schmiedeberg, 1 and I have endeavoured to represent 
this in the accompanying diagram (Fig. 106) . 2 It consists of a 
ganglion, m, which keeps up a rhythmical contraction of those 
muscular fibres of the heart to which it is connected by the fine 
nervous filaments, e. This ganglion is connected by an inter- 
mediate apparatus with an inhibitory ganglion, i, which can 
retard or stop the muscular contractions which m produces ; and 
by another apparatus, c, with another ganglion, Q, which quickens 
the contractions, i is connected by an intermediate apparatus, 
a with the retarding fibres, v, of the vagus, and d with the 
quickening nerve, s, of the heart. 

This schema has been adopted by Professor Harnack. 3 
'It has been supposed that motor ganglia are present because 
the apex of the heart of the frog, which contains no ganglia, will 



1 Schmiedeberg, Ltulwig's Arbeiten, 1870, p. 41. 

2 'Experimental Investigations of the Action of Medicines,' Lauder Brunton, 
British Medical Journal, December 16, 1871. 

• Pharmakologische Thatsachen fiir die Physiologic des Froschlmsem, Halle, 
1881. 



chap, xi.] ACTION OP DEUGS ON THE CIRCULATION. 813 

not contract rhythmically if left entirely to itself, whereas the 
ventricle containing ganglia will do so. 1 

It has been supposed that inhibitory ganglia are present, 
because when a little muscarine is applied to the heart it causes 




Fig. 106.— Diagram of the hypothetical nervous apparatus in the heart, m, motor ganglion, r, in- 
hibitory ganglion. Q, quickening ganglion, v, inhibitory fibres ; and s, quickening fibres from 
the head, a, a', b, and c, intermediate apparatus, e, fibres passing from the motor ganglia, m, 
to the muscular substance, v. [For simplicity's sake only one set of motor ganglia has been 
represented, but other similar ones are supposed to be present in other parts of the heart, and 
so connected with this set that they all work in unison. Zt must he remembered that this 
diagram is purely hypothetical : but if this be carefully borne in mind, the sketch will be found 
of service in remembering and comparing the action of different poisons on the heart.] 

it to stop in diastole. This effect is not developed all at once, 
but goes on gradually increasing, and its action in this respect 
seems rather to point to its effect upon ganglia than upon nerve 
fibres. 

It has been supposed that the vagus acts through tbis in- 
hibitory ganglion or ganglia because irritation of the vagus 
arrests the heart in diastole, just as muscarine does ; but it has 
been supposed to be connected by some intermediate apparatus 
with the inhibitory ganglia, because we find that when nicotine 
is applied to the heart irritation of the vagus will no longer 
arrest its beats, but that irritation of the venous sinus, in which 
the inhibitory ganglia have been supposed to be situated, will do 
so at once. 

It has been supposed that the inhibitory apparatus, I, was connected by 
an intermediate structure with the motor ganglia, m, becausephysottigmine 
does not produce the extraordinary still-stand which muscarine does, but it 
counteracts to a certain extent the effects of atropine which muscarine does 
not. Physostigmine in small doses increases the excitability of the vagus, so 
that a slight stimulus applied to that nerve, so slight that it would under ordi- 
nary circumstances be insufficient to affect the heart, will stop it. s In large 
doses it appears to paralyse the vagus. The difference of action between 
muscarine and physostigmine seemed to show that they acted on different 
nerve structures ; while the mutual power of atropine and physostigmine 

* The recent researches of Gaskell have shown that the musoular fibre of the 
heart of the tortoise will contract, although it contains no ganglia. The question of 
muscular rhythm independent of ganglia will be considered further on. 

8 Arnstein and Sustsohinsky, Wilrzburger physiol. JIntemcch. iii. 



314 PHAEMACOLOGY AND THERAPEUTICS, [sect. i. 

to neutralise each other's effects within certain limits indicated that atropine 
acted on the same nerve structure as physostigmine and consequently on a 
different one from muscarine. 1 

When atropine is applied to. the heart it completely removes 
the effect of muscarine and totally prevents any arrest being 
produced either by irritation of the vagus or the venous sinus. 
It has therefore been supposed that nicotine acts upon the in- 
termediate apparatus, a, but that atropine acts either upon i or 
upon b. 

The reason why it has been supposed that quickening 
ganglia exist is, that when irritation is applied to the vagus 
after its inhibitory power has been destroyed by the administra- 
tion of nicotine or atropine it no longer produces slowness or 
still-stand of the heart, but, on the contrary, quickens its pulsar 
tions. But the quickening does not take place immediately, it 
only occurs some timje after the application of the stimulus. If 
it is applied only for a short time, no quickening may take place 
until after its removal, but the quickening once induced remains 
for a considerable time. This seems to indicate that the stimulus 
does not act through nerve-fibres, as these would conduct the 
stimulus directly to the muscle, but rather through, some 
ganglionic apparatus. It has been supposed that this apparatus 
is not identical with the motor ganglia themselves, because if 
the heart is irritated directly, its pulsations at once become 
quickened, and the quickening does not last long after the 
irritation is removed. 

It is evident, however, that though this hypothetical schema 
allows us to explain in a fairly satisfactory manner the action of 
many drugs, yet it can only be looked upon in the same light as 
the hypothesis of cycles and epicycles in astronomy, which was 
useful for a time, and enabled astronomers not only to recollect 
but to predict facts. Its use was only temporary, and the hypo- 
thesis just at the time of its greatest complication gave place to 
one of the greatest simplicity. 

It is probable, indeed almost certain, that the same thing 
will occur in regard to the action of drugs upon the heart, and 
that the whole complication of motor ganglia, inhibitory ganglia, 
accelerating ganglia, vagus endings, and intermediate fibres, 
may resolve themselves simply into a question of the mutual 
relationships- between the rate of rhythm and rapidity of con- 
duction in the muscular fibres, nervous ganglia, and nerve-fibrea 
respectively. Schmiedeberg's hypothetical schema has been 
most useful for several years, but facts which it will not explain 
are beginning to accumulate, and we must look in another 
direction for their explanation. The whole question of the action 
of drugs upon the heart is far from being completely solved, 

■ Lauder Brunton, op. cit. 



chap, xi.] ACTION OP DRUGS ON THE CIRCULATION. 815 

but I shall try, if possible, to indicate the direction in which 
pharmacology is at present looking for an explanation. 

± or this purpose it will be necessary to go still more fully into 
the physiology of the heart than we have already done 

Before doing so, however, it may be advantageous to put in 



Inhibitor; ganglia., 
Motor ganglia 



Cardiao muscle .... 




Pig. 107.— Diagram of the heart and vessels to illustrate the aotion of drugs on the various paHs of 
the circulatory apparatus as given in the following tallies, a, indicates accelerating ganglia. 

a tabular form the action of the most important drugs on the 
various parts of the circulatory apparatus, according to the 
prevalent opinions at present. 1 



' In drawing up this table [see pp. 316-319] I have been greatly aided by the 
admirable paper of Professor Boehm, read before the International Congress in 
London in 1881. 



816 



PHAEMACOLOGY AND THEEAPEUTICS. [sect. 



Cardiac Muscle. 



STIMULATED BY. 



[Stimulation is shown by increased 
energy of contraction, the rate of pulsa- 
tion remaining the same or becoming 
slower.] 
So-called car- /Digitalin. 



diac poisons 
With a larger 
dose the stage 
of stimulation 
is followed by, 

— e c 

staltic action, 
and final ar- 
rest in sys- 
tole. 1 



Digitale'in. 

Digitoxin. 

Erythrophloeum. 

Hellebore'in. 

Nerein (Oleander). 

Scillam. 

Antiarin. 

Strophanthus. 

Thevetine. 

,Theveresine. 

Yeratrine. 

Barium salts. 

Caffeine (produces rigor). 



These do not' 
cause peristal- 
sis, nor arrest 
in systole. 
They excite the 
heart to pulsate 
rhythmically, 
after it has 
been made to 
stand com- 
pletely still in 
diastole by the 
application of 
muscarine. 



Potassium salts, 
Copper double salts. 
Zinc double salts. 



In small 



DEPBESSED OE PARALYSED BY. 

[Depression is shown by diminished 
energy of contraction with final stoppage 
in diastole. The cardiac muscle is shown 
to be paralysed by no longer contracting 
on stimulation, either mechanical or 
electrical.] 

Salicylic acid. 1 

Potassium salts. In large 

Copper double salts, doses. 

Zinc double salts. , 

Quinine (?). 

Saponin (removes the systolic still- 
stand produced by digitalin). 

Apomorphine. 

Emetine. 

Muscarine. 

Pilocarpine. 

Veratrum viride (veratroidine and 
jervine). 



Guanidine. 

Physostigmine. 

Camphor. 

Monobromocamphor. 

Eorneol. 

Arnica-camphor. 

Anilin sulphate. 

Cumarine. 



Motor 



[Stimulation is shown by increased 
rapidity and energy of contraction, which 
is observed, not only when the drug is 
given to an animal, but when it is 
applied directly to the heart.] 

.Alcohol. 
Ether. 
Chloroform. 
Chloral. 

Anaesthetics generally. 
Cyanogen. 
Arsenic. 
Quinine. 
Guanidine. 



Alcohol 
group. 



Ganglia. 

[Depression is evidenced by slower and 
less powerful pulsations, with final stop- 
page in diastole. This stoppage is shown 
to be due to the action of the drug on 
the ganglia, and not on the cardiac 
musole, by the heart contracting on sti- 
mulation, either mechanical or electrical, 
after spontaneous pulsation has ceased.] 

Ergot. 

Antimony (?). The stoppage in 
diastole caused by antimony is 
converted into stoppage in 
systole by helleboreiin. 
Hydrocyanic acid. 
The same drugs that stimulate in 
small doses depress when used in larger 
quantity, or at a later stage of their 
action. 



1 This stoppage of the heart in systole occurs in frogs, but in higher animals 
the heart may stop in diastole. 



chap, xi.] ACTION OP DRUGS ON THE CIRCULATION. 317 



Inhibitory Ganglia. 



STIMULATED BY. 

[Stimulation is shown by the direct 
application of the drug to the heart, 
stoppingits spontaneous pulsations com- 
pletely, while it still contracts on the 
application of a stimulus either mechan- 
ical or electrical.] 

Muscarine. 

Pilocarpine. 



DEPRESSED OB PAEA1YSED BY. 

[Depression or paralysis is shown by 
stimulation, not only of the vagus trunk, 
but of the venous sinus itself, having 
lost all power to slow or stop the heart ; 
and by the direct application of musca- 
rine also having no action.] 

Atropine. 

Hyoscyamine. 

Daturine. 

Duboisine. 

Cocaine. 

Sparteine. 

Saponin. 



Vagus-ends in the Heart. 



' [Stimulation either of the ends of the 
vagus in the heart or of the inhibitory 
ganglia is shown by the injection of a 
drug rendering the pulse slow after 
previous division of the trunks of the 
vagi.] 

Physostigmine (7). 

It is said to render the peripheral 
ends of the vagus more sensitive, 
so that a slighter stimulus will 
stop the heart applied to the 
trunk. 



[Depression or paralysis is shown by 
irritation of the vagus trunk no longer 
producing slowness or stoppage of the 
pulsations of the heart, while the appli- 
cation of muscarine, or irritation of the 
venous sinus, will still cause stoppage.] 

Nicotine. 

Saponin. 

Lobeline. 

Curare, methyl-strychnine, and 
probably large doses of all drugs 
which have the power of paralys- 
ing the ends of motor nerves. 



Vagus Centre. 



[Stimulation is evidenced by slowing 
of the pulse, disappearing on section of 
the vagi.] 

Increased blood-pressure. 
Venous blood. 
Ammonia (in frogs). 
Carbonic oxide. 
Chloroform. 
Chloral hydrate. 
Butyl-chloral. 
Belladonna (atropine). 
Hyoscyamus (hyoscyamine). 
Stramonium (daturine). 
Aconite (acomtine). 
Veratrum viride (veratroidine). 
Tobacco (nicotine). 
Digitalis (digitalin). 
Hydrocyanic acid. 



[Depression is evidenced by a quick 
pulse, which is not rendered slow by irri- 
tation of sensory nerves which usually 
produce slowing of the pulse, e.g. the 
central end of one vagus.] 

Diminished blood-pressure and 
substances which produce it, 
e.g. nitrite of amyl and other 
nitrites. 

Large doses of such substances as 
stimulate it in small doses, vide 
adjoining list. 



318 



PHARMACOLOGY AND THERAPEUTICS, [sect, u 



Accelerating Centre. 



STIMULATED BY. 

[Stimulation is evidenced by the injec- 
tion of the drug after previous section of 
the vagi rendering the pulse still more 
rapid than before.] 

{Venous blood. 
Ammonia. 
Cicutoxine. 
Caffeihe. 
Delphinin. 
Picrotoxin. 



DEPRESSED OB PARALYSED BY. 

[Little or nothing is known about the 
depression of the accelerating centres.] 

Saponin paralyses accelerating 
nerves. 



Capillaries. 



[Stimulation is shown by a rise in 
blood-pressure which remains after sec- 
tion of the spinal cord at the occiput, 
and is produced by the injection of the 
drug after previous division of the cord. 
It is also ascertained by the rate of flow 
through the vessels being diminished by 
the drug when circulation is kept up 
artificially in a frog whose nerve-centres 
have been destroyed, or in a single limb 
of a warm-blooded animal.] 

Alkalies. 

Digitalis and its allies. 

Barium salts. 

Potassium salts. 

Copper. 

Zinc, &c. 



[Depression is shown by a fall of blood- 
pressure to a slight extent, even after 
the spinal cord has been divided, and by 
increased rapidity of flow when artificial 
circulation is kept up.] 

Acids. 
Nitrites. 
Quinine (?) 



Vaso-motor Nerves. 



[It is very doubtful whether they are 
stimulated by drugs, and at any rate it 
is very difficult to ascertain whether 
any stimulation which may occur in the 
arterioles or capillaries is in the termi- 
nations of the vaso-motor nerves or in 
the muscular walls.] 



[Paralysis is shown by the vessels not 
contracting on stimulation of the vaso- 
motor nerves, while they still contract 
on direct stimulation. This has been 
chiefly observed in. the vessels of the 
intestines after irritation of the splanch- 
nic nerves. The effect of irritation is 
ascertained by the alterations in colour 
of the intestines, and also by the altera- 
tionsin the general blood-pressure which 
occur after irritation,] 

Potassium salts. 

Arsenic. 

Antimony. 

Mercury, 

Iron, 



chap.-xi.J ACTION OF DEUGS ON THE CIRCULATION. 319 



Vaso-motor Centre. 



STIMULATED BY. 

[Stimulation is evidenced by a rise of 
blood-pressure, which disappears on sec- 
tion of the spinal cord below the medulla, 
and doeB not occur if the cord has been 
divided before the injection of the drug. 
This rule is only partially true, because 
subsidiary vaso-motor centres occur is 
the spinal cord itself.] 

Salts of ammonium.' 
Potassium (?) 
Caffeine (?) 
Cicutoxine. 
Delphinin. 
Picrotoxin. 
Strychnine. 
Sanguinaria. 
Ergot (cornutine). 
Thebaine. 
Veratrine. 

Belladonna (atropine). 
Hyoscyamus (hyoscyamine). 
Stramonium (daturine). 
Carbolic acid (?) 
Salicylic acid. 
Turpentine. 

Camphor (rhythmically). 
Oil of rosemary, and other ethereal 
oils. 



-Convulsants. 



Digitalin (?) 
Ether (?) 
Chloroform (?) 
Chloral (?) 
Butyl-chloral (?) 



Stimulant action 
doubtful; slight, 
and transient. 



DEPRESSED OR PARALYSED BY. 

[Depression is evidenced by fall in the 
blood-pressure not depending on failure 
of the heart's action. It is also shown 
by the absence of rise in blood-pressure 
on irritation of a sensory nerve.] 

Carbolic acid. 

Lobelia. 

Large doses of most drugs, such as 
those in the adjoining column, 
which stimulate in small doses. 

Depression usually occurs in the 
later stages of the action of such 
drugs even in moderate doses. 



Stannius's Experiments. 



Some of the most important experiments relating to the action of the 
various cavities of the frog's heart were first performed by Stannius, and bear 
his. name. 

"When the venous sinus is separated from the rest of the heart by cutting it 
off with a sharp razor, or by a ligature tightly drawn round it at its junction 



f& 



9 



Ca»W 



few* 




Fig. 108.— «, diagram of frog's heart ligatured at the junction of the venous sinus with the auricles. 
The vena? caT« and sinus are represented with a crenated outline resembling the tracing which 
their beats might give if recorded on a revolving cylinder. The auricle and ventricle being 
motionless would only trace a straight line if connected with a recording apparatus. Their out- 
. line is therefore represented by a straight line, b, diagram of a frog's heart in which sections 
have been made at the junction of the sinus with the auricles, and at the auriculo-ventricu ar 
groove. The sinus and ventricles pulsate, whilst the auricles remain motionless. The beats of 
the ventricle should have been represented as slower than those of the auricle, as in /, Fig. 109. 
c, the same as 6, but with the parts of the heart separated by ligature instead of section. 

with the auricle, it continues to pulsate, but the auricle and ventricle stand 
perfectly still (a, Fig. 108). If now the auricle is separated from the ventricle 



820 PHARMACOLOGY AND THERAPEUTICS, [sect. r. 

by another out (6, Fig. 108), or another ligature be applied (c, Fig. 108), at the 
auriculb-ventrioular groove, the auricles remain motionless, but the ventricle 
begins to beat, so that the venous sinus and ventricle are both pulsating, while 
the auricles are at rest. The venous sinus and the ventricle, however, ho 
longer beat with the same rhythm, and the rate of the ventricular beatB is 
usually much slower (/, Fig. 109). In this remarkable experiment the com- 
plete stoppage of the auricles and ventricle which follows the removal of the 
venous sinus has been supposed to show that the motor centres for the entire 
heart reside in the sinus, and that from them the motor impulses originate 
which keep up the rhythmical pulsations of the organ. But the fact that the 
ventricles begin to pulsate on their own account when separated by another 
cut from the auricle seems to show that they also contain motor centres. 
The hypothesis has therefore been advanced that both venous sinus and 
ventricles contain mt>tor centres, while the auricles contain inhibitory centres. 

So long as the auricles are in connection both with the venous sinus and 
the ventricle, the motor centres in the latter two cavities are supposed to be 
sufficiently powerful to overcome the resistance offered by the inhibitory 
centres, and thus the cardiac rhythm is maintained. When the motor 
centres of the sinus are removed, the inhibitory centres of the auricle are 
supposed to be so powerful as to keep both it and the ventricle in a state 
of rest. 

"When the ventricle is separated from the auricles and their inhibitory in- 
fluence removed, it again begins to pulsate rhythmically. In order to obtain 
a clearer idea of the mechanism of the heart, many variations of the above 
fundamental experiments have been made. 

The chief results of these are the following : — 

First, section or ligature of the venae cavse or of the venous sinus at any 
point before its junction with the ventricle does not affect the action of the 
heart (d, Fig. 109). 

Second, section or ligature of the auricles at any point above the auriculo- 
ventricular groove arrests the movements of the part below them, while that 
connected with the venous sinus still continues to pulsate (e, Fig. 109). 






Pig. 109.— d, diagram of heart with ligature round the venous sinus, e, diagram of heart with liga- 
ture round middle of auricles. /, diagram of heart with ligature in the auriculo-ventricular 
groove. The pulsations of the ventricle are much slower than those of the auricle and venous 
sinus. This is indicated by the larger dentation of the outline of the ventricle. 

Third, irritation of the vagus nerves usually produces stoppage of the 
heart-beats. 

Fourth, ligature or section of the vagi before their entrance into the heart 
prevents their having any action upon it when they are stimulated. 

Fifth, ligature or section of the venous sinus or auricles prevents any action 
of the vagi upon the part of the heart below the ligature or section. 

It is evident that section or ligature of the heart at any point between the 
junction of the sinus and auricles and the auriculo-ventricular groove has 
the same action on the movements of the part below it as irritation of the 
vagus. 

But more than this ; although, as we have seen, the motor ganglia of the 
heart appear to be situated chiefly in the venous sinus, yet irritation of tne 
sinus produces complete still-stand of the heart, even more perfect and 
prolonged than irritation of the vagus. Strong stimulation of the venous 
sinus has therefore the same effect as its removal. The parts whose motions 
have been arrested by section or by irritation, in the experiment just de 





chap, xi] ACTION OF DKUGS ON THE CIBCULATION. 821 

scribed, are not paralysed : this is shown by the effect of stimulation upon 
them. 

"When the auricles and ventricle are standing still after section or ligature 
of the venous sinus, irritation of the outside of the ventricle with a needle has 

9 » k 

Fig. 110.— gr, diagram of heart stopped by a ligature at the junction of the sinus and auricles. The 
o ill side of the ventricle is irritated by a needle, and the even outline indicates that no contraction 
occurs^ A, diagram similar to g, but with the inside of the ventricle irritated by a needle. The 
projections on the outline of the heart indicate that one contraction of the ventricle and three 
or four of the auricles occur. *, diagram similar to g and A, but with the outside of the auricle 
stimulated by a needle. The projections indicate that one contraction of the auricle and one of 
the ventricle occur. 

no action (gr, Pig. 110) ; but if its interior be irritated by a needle (h, Fig. 110) 
the auricle contracts first, then the ventricle, then the auricle again two or 
three times, but the ventricle does not respond. When the auricle is irritated 
by a needle applied to its outside, contraction both of the auricle and ventricle 
ensues (k, Pig. 110). When the auriculo-ventricular groove is irritated by a 
needle there are usually eight or ten contractions in response. When the 
outside of the auricle is irritated by an interrupted current, numerous and 
rhythmical contractions both of auricle and ventricle ensue. 

To sum up these results shortly, we find that either removal of the normal 
stimuli which pass in the direction of the circulation from the venous sinus 
to the auricle and then to the ventricle, or abnormally strong stimulation, 
produces arrest of the rhythmical movements of the heart, or, as it is 
usually termed, inhibition. 

Some exceedingly instructive experiments have been made 
by Gaskell, who, instead of separating the cavities of the frog's 
heart from each other by sections or by a ligature, compresses 
more or less completely the point of junction, so as to impede or 
block (as it is termed) to a certain extent the transmission of 
stimuli from one cavity to another (Fig. 111). 



1 1 r tt t m ** 



Fig. 111. — Diagram to illustrate Gaskell's experiment. At a the jaws of the clamp hold the heart 
without compressing it, and each beat of the auricle is succeeded by one of the ventricle as 

shown by the figure -I . At 6 the heart is compressed, and its rhythm disturbed, so that one 
beat of the ventricle only occurs for several of the auricles. 

He does this by a clamp the two limbs of which are placed one on each 
side of the heart. By means of a micrometer screw their edges can be 
approximated so as either simply to hold the heart without pressure or to 
compress it to any desired extent. When the clamp is placed in the auriculo- 
ventricular groove, the beats of the auricles and ventricle are registered 
separately by levers above and below the clamp with which the auricles and 
ventricle are connected by threads. 

When the heart is simply held by the clamp without compression, each 
beat of the auricle is followed by one of the ventricle ; but when the auriculo- 
ventricular groove is compressed the transmission of stimuli from the auricle 

Y 




322 PHAEMACOLOGY AND THEEAPEUTICS. [sect. x. 

to the ventricle appears to be blocked in somewhat the same way as it is by 
compression in the contractile tissue of medusae, and one beat of the ventricle 
then occurs with every second, third, fourth, or more auricular beats, accord- 
ing to the degree of pressure, and if this be very great the ventricle will cease 
beating altogether. 

The beats of the ventricle are shown in this experiment to be diminished 
or arrested by hindering or blocking the transmission of stimuli to it from 
the venous sinus and auricle. But, as one might expect, a diminution of 
the stimuli themselves has a similar effect as a block to their passage. 
Thus, if the auricle and sinus are heated, but not the ventricle, their rhythm 
is markedly quickened, but the ventricle now beats only once for every two 
or even more pulsations of the auricle, the heat appearing to render the 
impulses proceeding from the auricle and sinus more rapid but more weak, 
If the ventricle be heated as well, it will respond to each beat of the auricle, 
so that the whole heart beats more quickly, but if the ventricle alone be 
heated its rhythm remains unchanged. 

Experiments which are likely to give useful information in regard to the 
action of various drugs on the cardiac muscle and nerves have been made by 
Gaskell by the aid of the clamp already described. 



General Considerations regarding the Heart. 

In ascidians the heart is a mere contractile sac open at both ends, and 
drives the fluid alternately in opposite directions. In snails it is a simple 
sac of protoplasm without differentiated nerves, but it drives the nutritive 
fluid in one direction. In the amphioxus there is no special heart, but only 
numerous contractile dilatations in the chief blood-vessels. In fishes the 
heart may be said to consist of three parts — the auricle, ventricle, and 
arterial bulb. The heart of the frog has already been described, and that of 
mammals requires no description. 

Even the complicated mammalian heart may be regarded as a special 
development of the simple contractile tube endowed with the power of 
peristaltic contraction. The direction in which the contraction occurs is 
probably determined at first by slight differences in the stimuli to which the 
two ends of the tube are subjected, and the direction may be altered by 
altering the stimulus. Thus in the heart of a fish the contraction usually 
proceeds from the auricle to the ventricle and bulb, but by irritating the bulb 
the direction may be reversed so that the bulb contracts first and the auricle 
last, and this reversal of rhythm may persist for some time. 1 In the mam- 
malian heart it is not perhaps so easy to reverse the rhythm by simple 
irritation, and probably some interference with the cardiac nervous system is 
also requisite, but by introducing tincture of opium into the mammalian 
ventricle the rhythm may be reversed so that the beats of the auricle follow 
instead of preceding those of the ventricle. 8 

The cause of rhythmical pulsation in the heart is usually supposed to 
be the motor ganglia which it contains. Of late years numerous researches 
have shown that, although these are very important indeed, yet they are not 
to be looked upon as the exclusive originators of the rhythm. The heart of 
the snail, although it consists of simple protoplasm without nerves, beats 
rhythmically, and when a ligature is tied across the venous sinus in the frog 
the venae cavse and upper part of the sinus continue to beat although they 
possess no special ganglia, while the rest of the heart remains motionless 
although it contains both Eidder's and Retnak's ganglia. From this experi- 
ment one would be inclined at first to say that the Initiation of rhythm 
in the heart is due to the muscular tissue of the venae cavae and sinus, 



' Gaskell, Journ. of Physiol., vol. iv. p. 78. 
• Ijudwig, Physiologie, 1801, vol. ii. p. 88. 



chap. xi.]. ACTION OF DEUGS ON THE CIRCULATION. 823 

and might be inclined to regard the nervous system of the heart as an 
apparatus for merely conducting stimuli from the sinus to the auricles and 
ventricle. 

Other experiments would seem to deprive the nerves even of this function, 
for Engelmann l and Gaskell have shown that when Bidder's ganglia are 
excised, or the nerves cut through as they traverse the auricles, contractions 
still pass from the venous sinus to the ventricle, and continue to do so wh.eji 
the nerves have not only been divided but most of the muscular tissue of the 
auricle has been cut through and only a narrow bridge remains behind. 
This may seem to prove that the muscular tissue of the heart conducts the 
motor stimuli from the venous sinus to the auricle and ventricle, which 
cause them to contract, and may appear to show that the cardiac nerves are 
entirely superfluous. A similar mode of reasoning, however, would lead us 
to say that the ganglia in medusae are also superfluous because the contractile 
tissue will pulsate rhythmically after they have been cut off, if it be placed in 
acidulated water. 

In regard to the conduction of stimuli, the fact probably is that under 
favourable conditions they may be conveyed by the muscular tissue alone 
from the sinus to the ventricle, but under ordinary circumstances they are 
Conveyed in part, at least, by the nerves. 

Ganglionic tissue is more sensitive than contractile tissue, and the stimuli 
which act on the ganglia of the medusa, under the conditions in which it 
lives, are insufficient to excite contractile tissue. When the ganglia are 
paralysed by a poison, the effect is the same as if they were cut off, and 
pulsation is arrested. A similar condition appears to occur in the ventricle. 
The muscular tissue forming the apex of the frog's heart under ordinary 
circumstances will not beat when separated from the rest unless an extra 
stimulus be applied to it. The ventricle containmg Bidder's ganglia will 
usually pulsate rhythmically, and if its apex be dipped in a solution of chloral 
no effect is produced, but if its base be dipped in the solution so that the 
drug acts upon the ganglia, the pulsations are arrested apparently by paralysis 
of the ganglia (Harnack). 

We may consider, then, that ganglia are more susceptible to stimuli than 
muscular fibre, and have the function of making it pulsate rhythmically 
when it otherwise would not. 

It is probable also that they serve to prevent the occurrence of blocks at 
the junction between the different cavities of the heart which might occur if 
the stimuli were transmitted from each cavity by muscular tissue alone. 

When the heart is dying, and when we may fairly assume that its nerves 
are losing their functional activity, such blocks actually take place, and the 
ventricle may beat only once for every two or three or more beats of the 
auricle. 

The cardiac muscle is also without doubt losing its functional activity, 

yet it still retains it to such an extent that each cavity can contract power- 

• fully. The same thing occurs when the heart is poisoned with chloral, iodal, 

or other members of the same group, which, as already mentioned, paralyse 

the cardiac ganglia. 2 

In the present state of our knowledge it is difficult to make any absolute 
statement regarding the function of the cardiac ganglia, but I think we 
may fairly assume them to have two functions, (1) to originate rhythmical 
pulsations in the heart when the muscular fibre alone, although capable of 
independent rhythmical pulsation, would not pulsate under the conditions 
which may be present ; (2) to transmit and receive stimuli from one cavity 
of the heart to the other, and thus prevent the occurrence of blocks at the 
junction of the cavities and consequent irregular action which might occur if 
the stimuli were transmitted only by the muscular fibre. 

1 Pfluger's Archiv, xi. p. 465. 

s Harnack and Witkowski, Arch. f. exp. Path, und Pharm., vol. xi. p. 15, 

y 2 



324 PHARMACOLOGY AND THERAPEUTICS. [sEcr. r. 



Regulating Action of the Nervous System. 

The necessity of some means for regulating the action of the heart ia 
accordance with the wants of the hody is obvious, and in the heart we find 
that such an arrangement exists in relation both, to the strength and rate of 
pulsation. 

The action of the vasru8 upon the heart has long been a matter of great 
dispute, some physiologists holding it to be the motor nerve of the heart, 
while the majority regard it as inhibitory. The reason of this disagreement 
probably is that the right and left vagi have frequently different effects upon 
the heart, and that the effects even of the same vagus may vary according to 
the state of nutrition of the heart, and other circumstances. We find for 
example in rabbits that both the right and left vagi can usually slow or stop the 
heart ; but sometimes the right has much greater power in this respect than the 
left, and in some species of tortoise the left vagus has no inhibitory action 
upon the heart at all, and in the frog during the breeding season the action 
of the vagi is very uncertain. The cause of these different results appears to 
be that the vagus is a very complex nerve, and contains accelerating and 
strengthening fibres which are derived from the sympathetic, as well as in- 
hibitory fibres which are derived from the spinal accessory, and sensory fibres 
which belong to the vagus proper. The results of stimulating the vagus 
trunk will vary according to the proportion of these different fibres which it 
contains, and on the activity of each kind at the time of stimulation. 

A number of experiments made by Gaskell on the heart in situ, and with 
the clamping apparatus already mentioned, by which the beats of the auricle 
and ventricle may be simultaneously recorded, have led him to divide the 
effects produced on the heart by irritation of the vagi into two types : (a) 
affections of the rate of rhythm ; and (6) affections of the strength of the 
contractions. 

The effect of vagus stimulation on the heart of the frog may be divided 
into five classes. 

The 1st class is that which occurs with the heart of the tortoise or frog 
in situ or just after removal from the body. The vagus here causes arrest 
by slowing: the rate of rhythm ; and, in consequence, the first beats which 
occur after the heart again begins to beat are slower than those preceding 
the stimulation. 

In the next classes the vagus produces its effect by weakening: the strength 
of the contractions so that they may become invisible and the heart remains 
still, but after it begins to beat their rate is as quick or quicker than before. 




Pig. 112.— After Gaskell. Tracing showing the action of tlie vagus on the heart. Aur. Indicatesthe 
auricular, and Vent, the ventncu'ar tracing. The part inc lided between the upright lines indi- 
cates the time during which the vagus was stimulated. C. 8 indicates that the secondary coil 
used for stimu'ation was eight centimetres distant from the primarv. The part of the tracing 
tothe left hand shows the regu'ar contractions of moderate height before stimu'ation During 
stimulation, and for some time after, the movements of bith auricle and ventricle are entirely 
arrested. After they again commence tliev are small at first, but soon acquire a much greater 
amplitude thau before the application of the stimulus. 

The 2nd class is an example of this. In it irritation of the nerve produces 
complete stoppage of both auricles and ventricles. This is followed by -con- 



chap, xi.] ACTION OF DRUGS ON THE CIRCULATION. 825 

tractions, which are at first so small as to be hardly visible, but quickly grow 
larger until they are much greater than the normal ; from this they gradually 
decrease to the normal size (Fig. 112). 

The two types of action may occur together, the rhythm becoming slower 
and the contractions smaller. This is seen in Fig. 113. 




Flu. 118.— After Gaskell. Tracing showing diminished amplitude and slowing of the pulsations 
without complete stoppage, during irritation of the va^us. 

The 3rd class is where irritation produces no still- stand of either auricles 
or ventricles, but only great diminution in the size of the beats, followed by a 
gradual increase and subsequent fall similar to that just described. This curve 
is like the first, but differs from it in the absence of the complete arrest 
(Fig. H4). 




Fig. 114. — After Gaskell. Tracing showing diminished amplitude of contraction without slowing op 
stoppage during irritation of vagus. 

The 4th is that where there is no primary diminution, but gradual in- 
crease in the size of the beats, which again sink to the normal (Fig. 115). 

The 5th is where irritation of the vagus does not stop the beats of the 
venous sinus but causes both auricles and ventricle to stop. 

The ordinary inhibitory effect of the vagus is the one which is noticed 
best in well-nourished hearts, and as the heart becomes more exhausted, and 
is dying, the motor power of the vagus becomes more and more pronounced. 
We find a similar occurrence in the case of the splanchnics, which lose their 
inhibitory power as the intestine dies. Nervous structures as a rule die 
sooner than muscle, and the conclusion is not unwarranted that the dis- 
appearance of the inhibitory action of the vagus is due to a gradual death of 
the nervous structures upon which it acts in the healthy heart, while its 
action on the muscular tissue, which has a more prolonged vitality, still 
remains. The actual increase, indeed, in its motor action we may attribute 
to the removal of nervous interference. 

Hypothesis regarding the Action of the Vagus. — Nervous inter- 
ference as a cause of inhibition was clearly pointed out by Bernard, and in 
the case of the heart has been discussed by Banvier with his usual clearness. 

In the grey matter of ifae spinal cord there is ample room for the slowing 



326 



THAEMACOLOGY AND THEEAPEUTICS. [sect.*. 



of nervous stimuli "by transmission along paths of different lengths (p. 169), 
more especially as a small length of grey matter is equivalent to a great 
length of ordinary nerve-fibre (p. 162). _ . 

In the heart we might suppose there was no such provision, hut, as Kanvier 
points out, the ganglion cells in the auricle have one of their fibres wound 




Pio. IIS.— After Gaskell. Tracing showing increased cardiac contractions from irritation of the 
vagus. [In this figure the upper tracing shows the ventricular and the lower the auricular 
contractions.] 

spirally, so as to give a great length in small space, and thus provide for retarda- 
tion and interference of stimuli (Pigs. 116, 117). If we suppose that some of 
the nerve-fibres contained in the vagus trunk pass through these spiral 
ganglia while others pass on directly to the heart, we can understand that 
the different rates of transmission may lead to interference and stoppage *of 
pulsation. Alterations in the rate of transmission along the spiral fibre may 
again convert interference into coincidence of waves and cause acceleration 
and increased action. If these spiral fibres are affected by drugs so that the 
rate of transmission of stimuli along them is altered, we can understand that 
the interference may in some cases be increased, in others diminished, 
and that an increase of interference may readily pass into the opposite 
condition, so that the irritation of the vagus no longer produces stoppage but 
acceleration of the heart, such as actually occurs on irritation of the vagus 
after its inhibitory power has been paralysed by atropine. 

"Wo can understand also how curare and the large class of drugs which 
paralyse the motor nerves may destroy the inhibitory power of the vagus. 

Inhibition in tbe Heart. — But it is probable that interference between 
the nervous structures is not the sole cause of inhibition in the heart ; we 
must look also to the relationship between nervous and muscular rhythms. 
Thus distension of the ventricle frequently diminishes or abolishes the action 
of the vagus, the stimulus which the pressure within the heart exerts on the 
muscular fibre appearing to more than counteract the inhibitory action of 
the nerve. The condition of the muscular fibre too is probably very im- 
portant. Thus, feeding the frog's heart with a. solution containing soda 
appears to paralyse the power of the vagus, which is again restored by 
potash. 1 (Compare their action on the cardiac muscle, p. 307.) 

It is indeed to an action on the muscle rather than on the nerve that we 
must probably look for the explanation of the action of atropine. For the 
heart in snails, though apparently destitute of both ganglia and nerves, is 
arrested by an interrupted current. This effect is prevented by atropine. 

1 lowit, Pflilger's Archiv, xxv. p. 466. 



chap, xi.] ACTION OF DRUGS ON THE CIRCULATION. 



327 




Flo. 1 1 6.— rart of the posterior cardiac nerve, highly magnified, showing the ganglia.' 




Fig. 117.— Spiral ganglion cell from the pneumogastric of the frog. This figure is not taken from the 
cells in the cardiac nerves, as in them the connection between the spiral and straight fibres has 
not been clearly made out, but it is probable that these cells hare a structure similar to theone 
figured ( Ran vier, op. dt. pp. 114- 120). a is the oell-bodv, n the nucleus, r the nucleolus, d nucleus 
of the capsule, /the straight fibre, g Henle's sheath, sp spiral fibre, g' its game, n' nucleus of 
Henle's sheath." 



1 Ranvier, Leq(m$ d'Anatomie G&nfrale, anii^e 1877-78, p. 106, 
1 Ibid., p. 114. 



328 PHARMACOLOGY AND THERAPEUTICS, [sect. t. 

It is exceedingly difficult, or perhaps impossible, with the 
physiological data which we at present possess, to give a complete 
and satisfactory explanation of the action of drugs on the heart, 
but it is evident that while all new discoveries tended for a while 
to render our ideas regarding the cardiac mechanism more and 
more complicated, our increasing knowledge now tends to render 
them more simple. Before long we may hope that systematic 
investigations into the action of drugs on the excitability, 
rhythm, and power to conduct stimuli of the cardiac muscle 
itself, on the action of drugs upcn the rhythm of the ganglia, 
and on the rate of transmission by the nerves, as well as on the 
mutual relations of these various factors, will at last give us a 
clear understanding of this very difficult and complicated subject. 

Therapeutic Uses of Drugs acting on the Circulation. 

The drugs which act on the circulation have been divided 
according to their action into stimulants, tonics, and sedatives. 
Each of these classes has been further subdivided into cardiac 
and vascular, according as its members act on the heart and 
vessels. There are thus six subdivisions in all : cardiac stimu- 
lants, vascular stimulants, cardiac tonics, vascular tonics, cardiac 
sedatives, and vascular sedatives. 



Cardiac Stimulants. 

These are substances which rapidly increase the force and 
frequency of the pulse in conditions of depression. The most 
important are ammonia, and alcohol in its various forms, but 
there are also other substances which are sometimes useful. 

Heat. 

Liquor ammoniaa. B.P. Aqua Ether. 

ammoniae. U.S. P. Chloroform. 

Ammonium carbonate. Spirit of chloroform. 
Sal volatile (spiritus ammonias Spirit of ether. 

aromaticus). Camphor. 

Alcohol. Aromatic volatile oils. 

Brandy. Oil of turpentine. 

Whisky. Heat and counter-irritants to 

Eau de Cologne. the prsecordium. 
Gin. 

Liqueurs. 
Strong wines 
Atropine. 

Cardiac stimulants are used to prevent or counteract sudden 
failure of the heart's action in syncope or shock due to mental 



chap, xi.] ACTION OP DKUGS ON THE CIECULATION. 329 

emotion, physical injury, or poisoning by cardiac depressants, or 
by the bite of snakes, or when the action of the heart becomes 
much depressed in the course of fevers or other diseases. 

Although alcohol after its absorption stimulates the heart, 
yet its effect on the heart is probably, to a considerable extent, 
due to a reflex action on it through the nerves of the mouth, 
gullet, and stomach. Its action is consequently very rapid, and 
begins before there has been time for much of it to be absorbed. 
On this account, however, it must be given in a somewhat con- 
centrated form, and if much dilated, as in the form of weak 
wine or beer, which has little or no local action and can exert 
no' reflex action, it has little or no power as an immediate stimu- 
lant. When given in disease it is best to administer it in small 
quantities frequently, and the rule by which to ascertain whether 
it is doing good or not is : Does it bring the circulation more 
nearly to the normal or not ? If it does so, it is beneficial ; if it 
does not, it is harmful. Thus, if the pulse be too quick, alcohol 
should render it slower; if already abnormally slow, alcohol 
should make it quicker. If too small, soft, and compressible, 
alcohol should render it larger, fuller, and more resistant. There 
are other rules connected with the effect of alcohol on other 
organs which also regulate its use in disease, but these will be 
given further on. 

Ether alone or mixed with alcohol has a stimulant action 
almost more rapid than alcohol itself; and chloroform in small 
doses, and especially when mixed with alcohol, is also a powerful 
stimulant. 

Ammonia has not only a reflex action on the heart like that 
of alcohol, but has powerful stimulating action on the vaso-motor 
centre. Its action when applied to the nose in syncope has 
already been discussed. In cases of snake-bite thirty minims of 
liquor ammonise have been injected directly into the veins. The 
immediate stimulating effect appears to be beneficial, although 
it is doubtful whether life can really be saved by this means. 

Camphor is useful as a cardiac stimulant in febrile conditions 
with a tendency to failure of the circulation, as in typhus and 
typhoid fevers ; in exanthemata, when the rash does not appear ; 
in asthenic pneumonia, and in the typhoid condition depending 
on other diseases. 

Aromatic volatile oils and substances containing them have 
also been used in similar but less severe conditions. 

One of the most powerful of all cardiac stimulants is heat, and 
when the heart's action threatens to fail it may be frequently 
restored by warm fluid taken into the stomach, or by the appli- 
cation of an indiarubber bag l or bottle filled with hot water, or 

1 An indiarubber bag for holding hot water is one of the most useful things an 
invalid can carry about with him; It should have a flannel case fastened by buttona 



880 PHAEMACOLOGY AND THEEAPEUTICS. [sect.i, 

of a bag filled with hot sand or salt, or of a hot poultice to the 
cardiac region. 

It must be remembered that the high temperature of the body 
in febrile conditions acts as a cardiac stimulant; and if this 
stimulus' be removed by the temperature falling, either in the 
natural course of the disease or in consequence of the adminis- 
tration of antipyretics, the heart may fail and collapse, and death 
ensue, unless it be stimulated either by medicines or by the 
application of heat to the cardiac region. 



Vascular Stimulants, 

These are substances which cause dilatation of the peripheral 
vessels, 1 and thus render the flow of blood through them more 
^jrapid. The most important are : 

Heat. 

Alcohol in its various forms. Dover's powder. 
Ether. Acetate of ammonium. 

Nitrous ether. 

Alcohol and ether, by stimulating the heart at the same time 
that they dilate the vessels, render the peripheral circulation 
very vigorous. From its stimulant action on the vaso-motor 
centre, ammonia is less useful than alcohol. 

Vascular stimulants are useful in equalising the circulation 
and preventing congestion of internal organs. Thus, from expo- 
sure to cold generally so that the whole surface of the body is 
chilled, or from a local chill due to a draught, or to the combined 
action of cold and moisture, as in wet feet, congestion of the 
respiratory tract, or of the stomach, intestines, or pelvic organs 
may occur. This frequently evidences itself immediately either 
by rigors or by localised pain. If the congestion be not relieved 
inflammation may occur, but if alcohol be taken either in a con- 
centrated form or diluted with boiling water, the vessels of the 
surface dilate, a warm glow is felt throughout the body, the 
shivering and pains disappear, and frequently all injurious results 
of the chill are averted. If the external cold, however, is very 
excessive, and the exposure is to be prolonged, alcohol must be 

go that it can easily be removed. This allows the heat to come gradually through 
■without burning the skin. For a small gratuity the engine-driver or stoker is 
usually willing to fill the bag with hot water, and the bag can be refilled if necessary 
at each station where there is a sufficiently long stoppage. This is sometimes a 
very great boon to invalids on long railway journeys such as they are often com- 
pelled to make on their way to winter health resorts. 

1 From this definition it will be observed that while cardiac stimulants increase 
the functional activity of the heart, vascular stimulants do not increase the con« 
tractile power of the vessels, nor the aotivity of the vaso-motor centre, but, on the 
contrary, diminish the contraction of the vessels. 



chap, xi.] ACTION OF DRUGS ON THE CIRCULATION. 831 

used with great care, as the blood becomes much more rapidly 
cooled when the cutaneous vessels are dilated than when they 
are contracted ; and in arctic temperatures a person is much more 
readily frozen to death after the free use of alcohol. Dover's 
powder is also a useful vascular stimulant, though less powerful 
and rapid than alcohol. It is of use in similar cases to those 
just described, and may be given after the alcohol to supplement 
and continue its action. 

Slighter cases of chill may be treated by Dover's powder alone, 
and ten grains of it taken at night will often cut short commencing 
coryza, and will frequently prevent slight increase of consolidation 
occurring round a cavity after a chill in persons suffering from 
phthisis. Patients suffering from this disease should not omit to 
take a Dover's powder or some other vascular stimulant at night 
whenever they feel as if they had caught cold, and before any 
local mischief can be detected. 

All nitrites dilate the blood-vessels and thus act as vascular 
stimulants. The one most commonly employed is nitrite of ethyl 
in the form of spirits of nitrous ether. This remedy, taken in 
hot water or along with acetate of ammonium, is a useful vascular 
stimulant, and is often used for the same purposes as Dover's 
powder. 

Camphor is frequently used as a popular remedy instead of 
alcohol or Dover's powder in order to cut short coryza or catarrh, 
about ten drops of the tincture being taken on a piece of sugar. 
Local vascular stimulation is useful in removing chronic inflam- 
mation or consolidation. For a more detailed account of its action 
and uses, vide Irritants and Counter-irritants (p. 343). 



Cardiac Tonics. 

These are drugs which have no perceptible immediate action 
on the heart, but when given for a little while render its beats 
much more powerful, although usually much slower. The most 
important of them are : — 

Digitalis. Convallaria majalis. 

Digitalin. Convallamarin. 

Digitalein. Adonis vernalis. 

Digitoxin. Adonidin. 

Erythrophlceum (Casca) Squills. 

Erythrophlcein. Scillain. 

St'rophanthus bispidus. Helleborein. 
Strophanthin. Antiarin. 

Caffeine. 
Nux vomica. 
Strychnine. 



332 PHAKMACOLOGY AND THEEAPEUTICS. [sect. t. 

All these drugs, as already mentioned, stimulate the cardiac 
muscle and render its contractions slower and stronger. Although 
in large doses they tend themselves to produce irregular and peri- 
staltic contraction of the heart, yet in moderate doses they tend to 
remove irregularity already present. The cases in which they are 
most useful are those in which the left ventricle is unable to drive 
the blood with sufficient force into the aorta. It is evident that 
this inability may depend on simple weakness of the ventricle 
without any valvular lesion, or upon irregular action of the various 
cavities, or upon valvular lesions, or on a combination of two or 
more of these conditions. 

Weakness of the heart may occur in cases of general mal- 
nutrition, as anaemia and chlorosis, or in consequence of acute 
disease such as fevers. It is not necessarily accompanied by 
dilatation, but if it continues for some time the cavities are apt to 
dilate. A considerable amount of dilatation may sometimes occur 
without leading to valvular incompetence, but if it proceeds be- 
yond a certain point the cusps of the tricuspid and mitral valves 
become insufficient to close the dilated orifices, and mitral or 
tricuspid regurgitation is the result. For it must be remembered 
that in the healthy heart the tricuspid and mitral orifices are 
much diminished in size by the contraction. of the muscular tissue 
of the heart at the moment of systole. 

In cases where the mitral valve is thus affected, a systolic 
murmur may be heard at the apex during life, but, should death 
occur, the valves may be found perfectly competent to close the 
mitral orifice in the heart, which is then in a state of more or less 
complete rigor. In all such cases of weakness of the heart, either 
with or without dilatation and functional incompetence of the 
valves, digitalis is of the greatest possible service. I have also 
found erythrophlceum give most satisfactory results in simple 
dilatation without incompetence. 

The form of valvular disease in which cardiac tonics are es- 
pecially useful is mitral regurgitation. In all forms of valvular 
disease there is a tendency to the occurrence, of- compensatory 
hypertrophy, which will enable the heart to do its work in spite 
of the hindrance caused by the disease. Wherever this is suffi- 
cient, so that the circulation is well carried on, notwithstanding 
the valvular defect, cardiac tonics are useless and likely to be 
injurious. Nor should they be given when the compensatory 
hypertrophy is just beginning to take place. But when compen- 
sation is insufficient, cardiac tonics are of the very highest value. 
In mitral regurgitation the blood, instead of being driven entirely 
onwards by the left ventricle into the aorta, is partially driven 
backwards into the left auricle at the very moment that the 
right ventricle is driving the blood into the pulmonary artery and 
lungs. Hence there is a tendency to pulmonary congestion, which 
may lead to haemoptysis. The right ventricle having to work 



cnAP. xi.] ACTION OF DEUGS ON THE CIRCULATION. 333 

against greatly increased pressure tends to dilate, the blood 
accumulates in the venous system generally, and venous con- 
gestion of the stomach leads to loss of appetite, of the kidneys to 
albuminuria, and of the limbs to anasarca. While the venous 
system is gorged, the arterial is correspondingly empty, and it is 
not only the stomach, kidneys, and limbs which suffer by the 
stagnation of the circulation, for a similar condition exists in 
the heart itself. In consequence of this its action may become 
not only weak but irregular, and matters go on from bad to 
worse. 

In such a condition cardiac tonics are of the greatest possible 
service. By increasing the strength of the cardiac muscle they 
not only enable the left ventricle to drive a larger proportion of 
blood into the aorta, but tbey actually tend to lessen the opening 
of the mitral orifice in the same way as in functional incom- 
petence. By rendering the pulse less frequent they allow the 
ventricle to become more completely filled during each diastole. 
The pressure on the lungs, right side of the heart, and venous 
system is diminished, the arterial system becomes correspond- 
ingly filled, the congestion of the various organs is diminished 
and their function correspondingly improved. 

The consequence of this is, that in the stomach we have in- 
creased appetite, in the kidneys diminished albumen, and in the 
limbs removal of anasarca. The heart also benefits by the 
improved circulation in it, its pulsations are more regular and 
powerful, and it will often continue to act well and carry on the 
circulation satisfactorily even after the tonics which first enabled 
it to do so have been discontinued. 

In mitral stenosis cardiac tonics probably are beneficial both 
by lengthening the diastole, and thus allowing more time for the 
blood to run out of the auricle into the ventricle, and by strength- 
ening the auricle itself. Besides this, mitral stenosis is usually 
accompanied by mitral regurgitation, which will be benefited by 
cardiac tonics in the way just described. 

In aortic stenosis digitalis is of little or no use when there is 
sufficient compensatory hypertrophy, but may be useful if the 
heart is becoming feeble. 

There has been considerable difference of opinion regarding 
the use of digitalis in aortic regurgitation, some holding it to 
be useful and unattended with any risk, while others regard its 
administration as attended with considerable danger. In con- 
sidering this question we must bear in mind that the risks which 
a patient runs from aortic regurgitation are not the same in all 
stages of the disease. While the aortic regurgitation is uncom- 
plicated, and the ventricle strong enough to carry on the circu- 
lation, the risk to the patient is that of sudden death by 
Byncope. 

It is easy to understand how this should be the case. When 



834 



PHAEMACOLOGY AND THEEAPEUTICS. [sect. r. 



the aortic valves are healthy the arterial system may be regarded 
as a large-branched tube open only at one end— the capillaries— 
and through these the blood flows so slowly that there is no risk 
of syncope from the blood-pressure falling too low (Fig. 118, a). 

In a case of aortic regurgitation, on the contrary, the arterial 
system is open at both ends, and during the cardiac d'iastole the 
blood is not only running through the capillaries, but is running 
backwards into the left ventricle, so that the conditions are favour- 
able for the blood-pressure falling so low as to induce syncope (Fig. 
118, b). It is evident that anything which prolongs the diastole, 
and thus allows more time for the arterial system to empty itself 
through the capillaries at one end and into the ventricle at the 
other, will increase the risk of syncope, and for this reason digi- 
talis cannot be regarded as free from danger in aortic regurgita- 
tion, The danger may, however, be very considerably diminished 




Fig. 118. — Diagram to illustrate the tendency to syncope in aortic regurgitation. In a the aortio 
valves are healthy and prevent regurgitation. The carotid and its branches are shown as full. 
In b there is aortio regurgitation, the blood flows out of the arterial system through the capil- 
laries and into the heart. The carotid and its branohes are shown as empty. In c the condition 
is the same as In b, but the patient is supposed to be in the recumbent posture, and the carotid 
and Its branohes remain full. 

by keeping the patient in a recumbent posture with the head 
low. The column of blood above the aortic valves being lower, 
there will be somewhat less tendency to regurgitation ; and even 
should the arterial pressure fall much, the brain may still receive 
sufficient blood supply to prevent syncope. 

In cases of aortic disease, where compensatory hypertrophy is 
insufficient, or where the hypertrophied heart is becoming en- 
feebled and dilated so that the mitral valves no longer close the 
orifice, the most urgent risk to the patient is no longer that of 
sudden syncope, but of pulmonary embarrassment, dropsy, and 
all the other consequences of mitral regurgitation. In such cases, 
as well as in those where organic disease of both mitral and 
aortic valves exist simultaneously, we must treat the urgent 
symptoms and give digitalis or other cardiac tonics. 



ghap. xi.] ACTION OP DEUGS ON THE CTKCULATION. 885 

In dilatation of the right heart due to bronchitis or emphy- 
sema, digitalis is frequently useful, though its benefit is less 
marked than in mitral disease. 

Risks attending the Administration of Digitalis and 
other Cardiac Tonics.— The great risk attending the use of 
these drugs is sudden death from syncope. Whenever it is 
necessary to push them to any extent, the patient should be kept 
strictly in the recumbent posture, and not allowed to raise him- 
self quickly even into a sitting position on any pretence what- 
ever, even when there is no aortic complication. The effects of 
sudden change from the lying to the standing position in produc- 
ing syncope have already been mentioned (p. 205), and when the 
patient is allowed to sit up he should be helped up slowly and 
with care. A change from the lying to the standing position by 
the patient getting out of bed is, of course, still more danger- 
ous than simply sitting up in bed, and the most dangerous thing 
of all is for him to get up for the purpose of micturition. The 
reason of this has been already explained (p. 264). 

Such strict precautions are, of course, not required excepting 
when the cardiac tonics have to be given in full doses. But 
when it is necessary to do this they should on no account be 
neglected. 

As digitalis is cumulative in its action, it is often advisable 
after continuing it for several days to leave it off for a day or two, 
and then recommence; and this is a useful precaution when 
giving digitalis to out-patients who are seen at an interval of 
a week or more, even when the dose is comparatively small. 
Another difficulty in the administration of cardiac tonics is the 
gastric disturbance, loss of appetite, and vomiting which they are 
apt to produce. 

In cases where the arterial tension is already abnormally 
high — e.g. in cases of contracting kidney — and the heart seems 
unable to drive the blood into the aorta, the proper treatment, of 
course, is to reduce the abnormally high blood-pressure by purga- 
tives, diuretics, and diaphoretics, and not to attempt to strengthen 
the heart by the use of cardiac tonics. If this be done the pres- 
sure may be raised still further and burst the vessels, giving rise 
to apoplexy. 



Vascular Tonics. 

Vascular tonics are substances which cause increased contrac- 
tion of the arterioles or capillaries. They not only raise the 
blood-pressure, but influence to a considerable extent the quantity 
of lymph poured out into the tissues or absorbed from them, and 
thus modify tissue change. They are of special importance in 
the treatment of dropsy. 



336 



PHAEMACOLOGY AND THERAPEUTICS, [sect. i. 



The most important vascular tonics are :— " 

Digitalis. 

Iron. 

Strychnine. 

Pathology of Dropsy. —Dropsy consists in the. accumulation 
of lymph, either in small lymph spaces in the tissues (oedema, 
anasarca) or large serous cavities (ascites, pleural or pericardial 
effusions). The accumulation is caused by more lymph being 
poured out from the capillaries than can be removed by the 
lymphatics and veins. 

The chief causes of dropsy are — (1) Diminished removal of 
lymph from the lymph spaces or serous cavities. This may be 



Vaso-motor- — 

NERVES > 




Eight leg. 



Left leg. 



Fig. 119. — Diagram of Ranvier's experiment on dropsy. The vena cava is ligatured, and in the left 
leg the trunk of the sciatic has been divided so that hoth the motor and vaso-motor nerves con- 
tained in it are paralysed. On the right side the motor roots of the sciatic alone are divided and 
the vaso-motor left uninjured. There is thus motor paralysis on both sides,-but vaso-motor 
paralysis and dropsy only on the left side. 

due to (a) obstruction of the veins, or (b) of the lymphatics. (2) 
Increased exudation of lymph from the capillaries. This increased 
exudation may be due to (a) changes in the walls of the capillaries 
themselves rendering them more permeable. This appears to be 
the only condition which by itself can produce oedema. There 
are two others, however, which, although by themselves incapable 
of producing oedema, yet, along with others, are of the utmost 



chap, xi.] ACTION OF DRUGS ON THE CIRCULATION. 337 

importance ; these are (b) a watery condition of the blood, and 
(c) vaso-motor paralysis. In many, indeed in most cases of 
dropsy, two or three of these factors are combined. 

Obstruction to the veins, or lymphatics alone, will rarely 
cause dropsy, unless at the same time there is increased transu- 
dation from the capillaries. Thus Ranvier found that ligaturing 
the vena cava of a dog did not produce dropsy in the legs, the 
lymph being removed either by the collateral venous circulation 
or by the lymphatics. On dividing the sciatic nerve on one side, 
however, after ligature of the vena cava, dropsy appeared in the 
corresponding leg, while it remained absent from the other. He 
showed that the dropsy was caused by paralysis of the vaso- 
motor, and not of the motor fibres contained in the sciatic, by 
dividing the motor roots of the sciatic on the other side, leaving 
the vaso-motor roots uninjured. When this was done motor 
paralysis occurred equally in both legs, but dropsy only appeared 
in the one where the vaso-motor nerves had been divided (Fig. 
119). This experiment shows what an important factor the 
loss of vascular tone is in the production of oedema, and we may 
legitimately infer from it that vascular tonics, by increasing the 
contractility of the vessels, will tend to prevent oedema, or remove 
it when it is already present. 

A watery condition of the blood does not of itself increase the 
exudation of lymph, nor does it produce oedema, yet in cases of 
anaemia or chlorosis we very frequently find a tendency to cedetna 
of the ankles, and experiments in Cohnheim's laboratory have 
shown that, although a watery condition of the blood alone causes 
no increased exudation of lymph so long as the vaso-motor nerves 
are intact, yet it does so to a very great extent when the vaso- 
motor nerves are paralysed. 1 

Alteration of the capillaries by inflammation causes increased 
exudation of lymph, and tends to produce a local oedema. This 
oedema is greatly increased if the vaso-motor nerves are paralysed, 
not only attaining a much greater extent, but appearing more 
quickly and lasting longer. I have already mentioned that, in 
experiments on artificial circulation, acids added to the circulating 
fluid not only caused dilatation of the vessels, but increased 
transudation through them, and tended to render the tissues 
cedematous. It is not improbable that some alterations of the 
blood-vessels of the living body which tend to render them more 
permeable may be connected with imperfect oxidation and the 
formation of sarco-lactic instead of carbonic acid. 

Arsenic has this power of lessening oxidation, 2 and it seems 
not improbable that the tendency to produce oedema of the eyelids 
which it possesses may be due to this peculiar action. 

1 Jankowski, Virchow's Archiv, xciii. p. 259. 
* Feitelberg, Inaug. Diss. Dorpat, 1883. 



838 PHAEMACOLOGY AND THEEAPEUTICS. [sect.i. 

It is evident that whatever tends to increase oxidation will 
have an opposite effect, and will tend to prevent any excessive exu- 
dation from the capillaries. In cases of anajmia iron is there- 
fore serviceable, and as the condition of the blood improves the 
tendency to cedema disappears. 

What has just been said regarding the action of acids may 
seem to be in contradiction to the usually received opinion that 
the mineral acids act as vascular tonics. It is quite true that 
small doses of dilute acids, especially when given, as they usually 
are, along with bitters, frequently impart a feeling of strength 
and tone, whereas alkalies are frequently felt to be depressing, 
but in the case of both these classes of remedies this effect is 
probably not due to any direct action on the vessels themselves 
(vide Acids). 



Cardiac Sedatives. 

Cardiac sedatives are substances which lessen the force and 
frequency of the heart's action. 

They are chiefly used, either for the purpose of lessening 
violent action or palpitation of the heart, or of rendering the 
pulse slower in febrile conditions, especially those consequent on 
local inflammation. It has already been mentioned that bella- 
donna diminishes the sensibility of the heart to changes of pres- 
sure, and that sometimes it is useful in palpitation consequent on 
cardiac strain. Simple pressure over the cardiac region appears 
to have the power of lessening palpitation, so that when this 
occurs in consequence of any sudden emotion, there is a natural 
tendency to press the hand over the region of the heart. It is 
impossible to say whether the relief which such pressure certainly 
affords is simply mechanical, or is due to reflex action on the 
heart through the cutaneous nerves. Plasters applied to the 
cardiac region have a beneficial action upon palpitation similar 
to that of the hand, and one of the most commonly used and 
beneficial is belladonna plaster. In irritable-heart of soldiers 
Dr. Da Costa found digitalis better than any other remedy. 1 

In palpitation depending on indigestion, hydrocyanic acid is 
useful. In palpitation due to aortic disease, senega has been 
recommended. It is probable that its efficacy depends upon the 
diminished action of the cardiac ganglia and muscle which its 
active principle, saponine, produces. 

An active circulation of blood is usually advantageous both 
for functional activity and for the repair of damage to an organ, 
but sometimes it may become excessive, and relief may be afforded 
by diminishing it (vide p. 342) . 

1 Amer. Journ. Med. Sci., Jan. 1871. 



CttiP. xi.] ACTION OF DEUGS ON THE CIRCULATION. 839 

The chief cardiac sedatives employed for this purpose are : — 

Aconite. 

Veratrum viride. 
Antimonial preparations. 

It is questionable whether in extensive inflammation of in- 
ternal organs cardiac sedatives are of much service or not. They 
seem, however, to give relief in the feverish condition which accom- 
panies more limited inflammation, such as tonsillitis, otitis, 
&c. In such cases the tincture of aconite is best employed in 
very small doses (one drop) frequently repeated. The introduc- 
tion of this method of using the drug in divided doses is due in 
great measure to Einger, and it has the very great advantage 
that the desired effect can be produced with greater certainty and 
with less risk of an overdose being given. 

Vascular Sedatives. 

Vascular sedatives are substances which, by increasing the 
contraction of the vessels, lessen the flow of blood through them. 
They are chiefly used to lessen local inflammation or prevent 
haemorrhage. One of the most powerful of all vascular sedatives 
is cold. For its use in local inflammation vide p. 343. It is not 
only a vascular but a cardiac sedative, and ice swallowed in con- 
siderable quantity will tend to lessen the action of the heart. It 
is therefore one of tire means to which we chiefly trust in cases of 
haemoptysis. In haematemesis it has the double action of lessen- 
ing the activity of the heart, and of contracting the vessels in 
the stomach. 

The remedies which are chiefly employed in addition to cold 
are :— 

Digitalis. 

Ergot. 

Hamamelis. 

Lead acetate. 

Opium. 



B 2 



840 PHARMACOLOGY AND THERAPEUTICS, [sect. i. 



CHAPTEE XII. 
REMEDIES ACTING ON THE SURFACE OF THE BODY. 

Irritants and Counter-irritants. 

Irritants are substances which, when applied to the skin, 
cause a greater or less degree of vascular excitement or inflam- 
mation. They are employed for the sake of their local action, 
to produce increased circulation in the part to which they are 
applied, and thus to remove abnormal conditions already present 
in it. 

When irritants are employed for the. purpose of affecting 
reflexly a part remote from the seat of application they are named 
Counter-irritants. 

Irritants are subdivided, according to the amount of effect 
produced, into rubefacients, vesicants, pustulants, and escharotics. 

Rubefacients produce simply congestion and redness, which 
may be merely temporary, passing off in a few minutes, or may 
be more permanent, remaining for several days. 

When more powerful, so as to cause exudation between the 
true skin and epidermis, giving rise to vesicles, they are called 
vesicants, or epispastics. 

Wben they do not affect the whole skin alike, but do so un- 
equally, and irritate isolated parts in it, such as the orifices of 
the sudoriferous glands, so powerfully as to give rise to pustules, 
they are called pustulants. 

When they destroy the tissues altogether, forming a slough, 
they are called caustics or escharotics. 

The difference between these sub-classes is chiefly one of 
degree, and not of kind. The weaker ones produce the higher 
degrees of action when applied for a long time, and the stronger 
ones produce the slighter kinds of action when applied for a 
short time. 

It must be remembered that, although inflammation is usually 
associated with increased circulation, the two things are essentially 
different. 

Inflammation is the injury to the tissue ; the increased circu- 
lation is the attempt to repair it. 

Increased circulation occurs wherever we have increased 



chap, xii.] REMEDIES ACTING ON THE BODY. 841 

functional activity, whether this be for the purpose of performing 
a normal function, as in glands during the process of secreting, 
and in muscles during contraction, or for the purpose of repair. 
When repair is going on slowly, the process may be frequently 
quickened by increasing the supply of blood to the part, and this 
is the reason for using friction, and liniments and blisters of 
various kinds, in cases of chronic inflammation in joints or in 
ulcers. 

Sometimes irritation fails to cause absorption, from being too 
weak. In a case of rheumatic gout which I saw some years ago, 
irritating liniments had been applied for some time in vain, until, 
by mistake on the patient's part, so much iodine liniment was 
put on at once as to cause vesication over the whole back of the 
hand, when recovery began immediately. 

In acute inflammation, however, the greatly increased circu- 
lation, along with the heightened sensibility of the sensory nerves 
in the inflamed part, causes much pain, and this is relieved when 
the tension of the . blood in the inflamed part is lessened. We 
notice this very clearly when the finger is inflamed in consequence 
of a prick from a thorn, a bruise, or other injury. When it is 
allowed to hang by the side, the throbs of pain, coincident with 
every pulse-beat, become excruciating, while, if raised above the 




Fig. 120. — Tracings from the radial artery at the Wrist : A before and B after the application of a 
cloth dipped in cold water round the arm. (After Winternitz.) 

head, so that the pressure Of blood in the vessels is less, the pain 
becomes greatly diminished. The tension in the vessels may be 
relieved likewise by causing contraction of the arteries leading to 
the part by a cold compress around the arm (Fig. 120), or by 
dipping the finger in cold water ; but relief is also afforded by a 
warm poultice applied to the finger. At first sight it seems strange 
that heat and cold should both relieve the pain, but a little 
consideration will show that they both relieve the tension in the 
vessels of the inflamed part. Cold does so by causing a reflex 
Contraction of the afferent arteries, and thus diminishing the 
quantity of blood going to the inflamed part. Warmth, on the 
other hand, dilates the capillaries of the collateral circulation, 
and thus diverts the current away from the inflamed vessels. 

The use of counter-irritation as a remedial measure depends 
on the fact that similar alterations to those produced by heat and 
cold on the finger may be produced on the circulation in internal 
organs reflexly through the nervous system. 

When an irritant is applied to any part of the skin, it causes 



812 



PHAEMACOLOGY AND THERAPEUTICS, [sect. 



a local dilatation of the vessels and redness of that part, but 
contraction of the vessels in other parts of the body. Probably 
this contraction takes place with the greatest force in certain or- 
gans having a definite nervous relation to that part of the surface 




FIG. 121. Diagram to show the effects of heat and cold in lessening the pain of inflammation. The 

diagram is supposed to represent the end of the finger. The small star indicates the point of 
irritation, e.g. a prick by a thorn. The line in the centre of each figure is intended to represent 
the nerve' going to the injured part ; and at the side of each figure is an artery and vein con- 
nected by a capillary network. In a the capillary network around the seat of irritation is seen 
to be much congested ; the nerve-filaments are thus pressed upon and pain is occasioned, h re- 
presents the condition of the finger after the application of cold to the arm or hand. In conse- 
quence of the contraction of the afferent arteries the finger becomes ansemic ; no pressure is 
exerted on the nervous filaments, and pain is alleviated, c represents the finger after it has 
been encased in a warm poultice ; the capillary network at the surface of the finger is dilated, 
and the blood is thus drawn away from the seat of irritation and the pain therefore relieved. 



which is irritated. Ziilzer found that when cantharides-collodion 
was painted repeatedly over the back of a rabbit for fourteen days, 
the vessels underneath the skin, and the superficial layers of 



Vessels of thoracic wall 



Vessels of body generally. 




Dilated vessels of lung. 



Fig. 122. — Diagram to show congestion of the lung. The pulmonary vessels are shown dilated, and 
those of the thoracic wall contracted. 



muscles, were congested. The deeper layers of the muscles, the 
thoracic wall, and even the lung itself, were much paler and more 
ansemic than those of the other side. 

It is probable that a similar condition occurs in man, and that 
when we apply a blister to the side we, sometimes at least, cause 
contraction of the vessels in the pleura and lung below, and thus 
relieve pain in the chest in much the same way as when we apply 
cold to an inflamed finger. It has been supposed that the action 
of a poultice or blister was simply to draw away blood from the 



chap, xn.] EEMBDIES ACTING ON THE BODY. 843 

inflamed part. We have seen that the poultice does this in the 
case of an inflamed finger, but in an inflamed lung or pleura the 
quantity which comes to the skin is insufficient to explain the 
relief. It is quite possible, however, that the vessels in the lung 
and pleura adjoining the inflamed district may be dilated by the 
application of a poultice or blister to the side, and thus relief is 
afforded in the same way as by the application of a poultice to the 
finger. It is not easy to say in which of these ways a poultice or 



Dilated vessels of thoracic wall 



Blister 




Taso-motor centre. 



Vessels of body generally. 



Contracted vessels of lung. 



Fig. 123. — Diagram to explain the action of counter -irritation. A blister or other counter-irritant 
is shown applied to the chest-wall. The stimulus which it causes is transmitted up the afferent, 
nerves to the vaso-motor centre ; it is thence reflected down the vaso-motor nerves to the pul- 
monary vessels, causing them to contract, while it is reflected down vaso-dilating fibres to the 
vessels of the thoracic wall and probably of other parts of the body also, causing them to dilate, 
and thus lessening the pulmonary congestion by withdrawing blood from the lungs. (Compare 
with Kg. 122.) 

blister acts in any particular case. Clinical experience seems to 
show that sometimes the blisters relieve acute inflammation by 
causing contraction of the afferent vessels (as represented in the 
accompanying diagram, Fig. 123) and thus lessening the tension 
in the vessels of the inflamed part. If the blister is too near 
to the inflamed part, it may increase instead of diminishing the 
congestion, and thus do harm instead of good. 

As a matter of practice, the rule is usually insisted upon, that 
in a case of pericarditis, for instance, the blister should not be 
put immediately over the pericardium, but at some little distance 
from it. 

Counter-irritation is not only used, however, as a means of. 
lessening congestion and pain in acute inflammation, it is also 
employed with much advantage to cause the re-absorption of in- 
flammatory products. The use of the increased circulation which 
a blister causes in a chronic ulcer is unquestionable, and the rapid 
aosorption of the thickened margins of the ulcer is perceptible to 
the eye. A similar absorption appears to occur in deeper-seated 
organs, such as the lung, on the application of counter-irritation 
to the chest, and painting with iodine liniment is useful in pro- 
moting absorption of liquid effused into the pleural cavity or of 
the product of chronic inflammation of the lung. The mode in 
which the irritation acts is probably the same both in the chronic 



344 



PHABMACOLOGY AND THEEAPEUTICS. [sect. i. 



ulcer and in the lung, i.e. by increasing the circulation through 
the part affected. Where the blister is applied, as in acute peri- 
carditis, to lessen congestion, it is usually placed at a little distance 
from the inflamed part, but where we wish to increase absorption, 
as in consolidation of a part of the lung, we apply the counter--' 
irritant directly over the consolidated part. 



Rubefacients. 

Mechanical, as friction. 

Ammonia. — Solution of am- 
monia, compound camphor 
liniment. 

Alcohol (prevented from evapo- 
rating by oil-silk or a watch- 
glass). 

Arnica. 

Cajeput oil. 

Camphor. 

Capsicum. 

Chloroform (prevented from 
evaporating, like alcohol) ; 
chloroform liniment. 

Ether (like chloroform). 

Iodine and its preparations. — 
Iodide of cadmium, iodide of 
lead. 

Menthol. 

Mustard. 

Oil of turpentine, of nutmeg, 
and many other volatile oils. 

Vesicants. 

Acetic acid (glacial). 
Heat of : 

Boiling water. 

Corrigan's hammer. 
-Cantharides. — Solutions, plas- 
ter, cantharidin. 
Euphorbium. 
Mezereon. 

Volatile oil of mustard. 
Ehus toxicodendron. 



Pustulants. 

Croton oil. 
Tartarated antimony. 

Caustics. 

Actual cautery. 

Acids : — Acetic (glacial). 

Carbolic. 

Chromic. 

Hydrochloric. 

Lactic. 

Nitric. 

Osmic. 

Sulphuric. 
Alkalies :— 

Lime. 

London paste (p. 346). 

Vienna paste (p. 346). 

Potash. 

Soda. 

Ethylate of sodium. 

Alum (burnt). 
Antimony (chloride). 
Arsenic. 
Bromine. 
Soluble compounds of the 

heavier metals ; as : 
Copper sulphate. 
Mercuric chloride. 

„ nitrate. 
Silver nitrate. 
Zinc chloride. 
Zinc sulphate. 



Rubefacients.— One oi" the simplest rubefacients is mere 
friction. This may be made either with the hand, or more 
effectually still, with a rough cloth or a flesh-brush. Friction also 
greatly aids the action of many of the slighter rubefacients. 

Bubefacients may be used for their action upon the skin itseH: 



Chap, xn.] REMEDIES ACTING ON THE BODY. 845 

to relieve itching. They may also be used for their effect on 
deeper-seated structures. 

Friction, with firm pressure, is used in shampooing. Upward 
friction in the limbs will diminish the tension in dropsy, by 
removing part of the fluid from them. It also aids the circula- 
tion of the lymph, and by accelerating the passage of the pro- 
ducts of muscular waste from the muscles themselves into the 
general circulation, it removes to a great extent the sense of 
fatigue after over-exertion (p. 131). When applied along the back 
it soothes conditions of nervous excitement, and tends to produce 
sleep. Friction, along with stimulating liniments, applied to the 
joints after active inflammation has subsided in them, tends to 
remove the swelling and to restore their function. 

Neuralgic pains are frequently relieved by the application of 
rubefacients such as ammonia, chloroform applied by a watch- 
glass, or a mustard-plaster to the painful spot. • 

Conditions of nervous debility are sometimes benefited by 
mustard liniment applied over the spine, and a mustard-plaster 
to the nape of the neck is sometimes useful in nervous irritability 
with sleeplessness. In addition to the action which the mustard 
has on the vessels, it produces a sharp pain, so that it is employed 
also to rouse persons suffering from narcotic poisoning, or from 
coma. 

Mustard-leaves or iodine liniment applied over consolidated 
parts of the lung tend to cause absorption of inflammatory 
products, and are used for this purpose in cases of effusion into 
the pleura or pericardium, of chronic consolidation remaining after 
an attack of pleurisy or pneumonia, or in commencing phthisis. 

Vesicants. — Vesicants are employed locally in chronic ulcers 
and to cause absorption of effusions into joints, or chronic 
thickening about them. When applied around the inflamed 
joints in acute rheumatism, they not only relieve the local affec- 
' tion, but appear to have a curative action on the general febrile 
condition. 

In neuralgia, blisters over the painful point are useful, and 
sometimes, when neuralgia is in the side, or in the breast, it may 
be relieved by applying the blister over the corresponding part 
of the spine where there is usually a spot which is tender on 
pressure. In sciatica, the relief is often greater when the blister 
is applied to the heel, than over the nerve itself. 

In neuralgia also it not unfrequently happens that a slight ap- 
plication of the actual cautery is more efficacious than a blister. 
The most convenient form of this is Paquelin's thermocautery. 

In inflammation of the pericardium or pleura, a blister 
frequently relieves the pain, and it sometimes lessens or cuts 
short the inflammation. Applied over the epigastrium, blisters 
relieve vomiting arising from various causes. 

In