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AN INTRODUCTION

CHEMICAL PHARMACOLOGY

McGUIGAN

i » no.

^ AN INTRODUCTION

Chemical Pharmacology

...

Pharmacodynamics in Relation
to Chemistry

HUGH McGUIGAN, PH.D., M.D.

PROFESSOR OF PHARMACOLOGY, UNIVERSITY OF ILLINOIS,
COLLEGE OF MEDICINE

PHILADELPHIA
P. BLAKISTON'S SON & CO.

1012 WALNUT STREET

. II 3 3

9 I*

1 &..

THIC M A i« L K PKKSS YORK: PA

PREFACE

Before the foundation of a science is definitely laid, many facts
must be established, analyzed and correlated. In obtaining
these facts many methods may be used and many fields studied.
This is especially true of the science of pharmacology, the founda-
tion of which rests on anatomy, physiology, chemistry and
physics. It is natural therefore, in the development of pharma-
cology, that research should have proceeded in waves, during
which anatomy, physiology, physics or chemistry, played the
predominant role. The sequence of such waves may be due to
the investigator following the line of least resistance or to the
influence of a dominant character in the science. Finally how-
ever, such waves are spent, and new methods of attack are
developed, often in a new field.

The period of pure physiological methods in which changes in
blood pressure, respiration or heart rate have been recorded, for
the present seems spent, and many are convinced' that chemistry
now offers the most hopeful method for the solution of many
problems of pharmacology.

The changes in blood pressure, respiration, secretion or meta-
bolism, after the administration of drugs are fundamentally due
to a chemical reaction between the drug and the tissue. Physi-
cal changes also result, and it is often difficult to separate the
purely physical from the purely chemical. The fact that we
know little of the chemistry involved in many cases where the
dynamic reaction is most pronounced cannot be used as an argu-
ment against the importance of a study of the Chemical Pharma-
cology. Rather our ignorance of such a reaction should stimulate
chemical investigation concerning many life processes. The
dictum of the great physiologist who said " Ignoramus, Ignora-
bimus," must apparently remain true, until chemical investiga-
tion gives the explanation.

The field of Chemical Pharmacology is so immense that it is
possible to present only a small part of it within acceptable

VI PREFACE

limits. However, much of it is co-extensive with Biological
Chemistry and the aim of this work is to select for emphasis
those chemical reactions, which, in the various branches, have
an especial relation to pharmacology.

The following facts, therefore, have been collected and are
presented from the point of view of pharmacology, in the belief
that students of chemistry, pharmacy, biology, and medicine
should become more familiar with this branch of the subject.
The writer is also of the opinion that in the teaching of pharma-
cology, the chemical side should receive much more attention
than it does at present. In .this way the student will have an
opportunity to review and add to his previous work in chemistry,
and enter the clinical years better equipped and with a fuller
appreciation of the most promising avenue of advance.

In the preparation of this work many sources of information
have been used. Original papers are not quoted because in an
elementary work the student wishes a general survey of the field
and when he attains the stage in which he is able to digest litera-
ture the sources are readily found. The following works among
others have been freely used and contain the original references :
FrankePs Arzneimittel Synthese; The Chemical Basis of Pharma-
cology— Francis and Fortescue — Brickdale; Cushny, Text-book
of Pharmacology; Sollmann, Manual of Pharmacology; Richter's
Organic Chemistry; Mathews, Physiological Chemistry; Henry's
Plant Alkaloids; Barger, Simpler Natural Bases; Kobert's
Lehrbuch der Intoxikationen; Armstrong, Carbohydrates and
Glucosides; Haas and Hill, Chemistry of Plant Products. I
am especially indebted to my colleague in the department,
Harry Victor Atkinson, for help in proof reading and for many
suggestions.

TABLE OF CONTENTS

PAGE

I. INTRODUCTION ' : . 1

Definitions, 1 — Classifications, 1 — Organic drugs, 3 — Composi-
tion of drugs, 4 — Carbon, 4 — Test for hydrogen, 7 — Nitrogen, 7 —
Test for nitrogen, 8 — Nessler's test, 8 — KjeldahPs test for nitro-
gen, 9 — Oxygen, 10 — Ash, 10.

II. PARAFFINS 12

Properties of the hydrocarbons of the paraffin series, 12 — Crude
petroleum, 13 — Liquid petrolatum, 14 — Occurrence in nature, 15
— Synthesis of methane, 16 — Ethane, 16.

III. IMPORTANT DRUGS OF THE METHANE SERIES 17

Tests for methyl alcohol, 18 — Ethyl alcohol, 19 — Alcohol impor-
tance of, 20 — The destructive action on the tissues, 21 — Alcohol

as a food, 21 — The fate of alcohol in the body, 22 — Chemical tests
for ethyl alcohol, 23 — Lieben's iodoform test, 23 — Ethyl acetate
test, 23 — To determine the amount of ethyl alcohol in liquors, 24 —
Propyl and butyl alcohols, 24 — Amyl alcohol or pentyl alcohol,
26— Dihydric alcohols, 28— Glycol, 20— Trihydric alcohols, 29—
Chemical test, 29 — Higher alcohols, 30 — Sulphur alcohols or mer-
captans, 30 — Pharmacology of the alcohols in relation to their
chemistry, 31.

IV. ANESTHETICS, NARCOTICS, SOPORIFICS, HYPNOTICS 32

Anesthesia, 33 — Anesthetics, 35 — Theories regarding the causa-
tion of anesthesia, 36 — The Meyer-Overton theory, 36 — The
theory of Moore and Roaf, 37 — Verworn's theory, 37 — The Hy-
derabad Commission — 1889 and 1890, 37 — Ether anesthesia, 39 —
Ether or ethyl oxide, 39— Chemical tests, 39— Ethyl chloride, 4\—
Hypnotics and analgesics of the methane series, 41 — The chloro-
form group, 41 — Chemical tests, 42 — Phenyl isocyanide test, 43 —
The urethane group of hypnotics, 43 — Veronal, 44 — Chemical
tests, 45 — The sulphone group of hypnotics, 45 — Sulphonal, 46 —
Trional, 46 — Tetranol, 47 — Chemical tests, 47.

V. ALDEHYDES 48

General properties of aldehydes. Reactions, 48 — Tests for for-
maldehyde, 52 — Lieberman's test, 52 — -Rimini's method, 52 —
Phloroglucinol test (Jorissen), 53 — Phenylhydrazin — HC1 method,
53 — Phenylhydrazine hydrochloride and ferrocyanic method, 53 —
Hexamethylenamine, 54 — Acet aldehyde, aldehyde or ethanal, 55 —

vii

Vlll CONTENTS

PAGE

Paraldehyde, 57 — Chloral and chloraldehyde, 57 — Chloral and
chloral hydrate, 58 — The fate of chloral in the body, 59 — To test
urine directly for chloral, 61 — Nessler's solution test, 61 — Chlora-
lose, 61 — Chemical tests, 61.

VI. KETONES 62

Acetone, 62 — Chemical tests, 63 — Legal's test, 63 — Penzoldt's test,
63— Reynold's test, '63— Chloretone, 63.

VII. ORGANIC ACIDS - * 64

Organic acids of methane series, 65 — Acetic acid, 66 — Carbonic
acids, 67 — Urea, 68 — Oxalic acid, 69 — Malonic acid, 70 — Succinic
acid, 71 — Tartaric acid, 71 — Citric acid, 73— Lactic acid, 74 —
Hydrocyanic acid, 75 — Prussian blue test, 77 — Vortmann's nitro-
prusside test, 77 — Picric acid test, 77 — General pharmacology of
the acids, 78.

VIII. lODOFORM AND PHYSIOLOGICAL SUBSTITUTES 79

Lustgarten's test, 80 — Phenylisocyanide test, 80— lodoform sub-
stitutes, 81 — The fate of iodoform in the body, 84 — Bromine com-
pounds, 85.

IX. BENZENE OR BENZOL 86

X. PHENOLS 89

Properties of phenols, 90 — Quinol or hydroquinone or para dihy-
droxy benzene, 92 — Dihydroxy phenols or dihydroxy benzenes, 92
— Pyrocatechol, 93 — Trihydroxy benzenes or trihydric phenols,
94 — Phloroglucinol, 94 — Pyrogallol or pyrogallic acid, 94 — Cresols,
95 — Creosote, 97 — Picric acid, 97 — Tests for picric acid, 97 — Re-
actions of the phenols, 98 — The salol principle, 100 — Friedel and
Craft's Reaction for Toluene Synthesis, 101.

XI. AROMATIC ALCOHOLS, AND PHENOL ALCOHOLS 101

Saligenin, 102 — Aldehydes of the aromatic series, 103 — Benzalde-
hyde, 103 — Ketones of the aromatic series, 104.

XII. ACIDS AND RELATED COMPOUNDS 104

Benzoic acid, 104 — Mesotan, 107.

XIII. ANILINE AND TOLUENE DERIVATIVES 109

Tests for aniline, 112 — Acetanilide, 112 — Antipyrine or phenyl
dimethylpyrazolon, 113 — Pyrazolon, 114 — Antipyrine, 116 —
Pyramidon, 117 — Acetanilide tests, 119 — Tests for antipyrine,

119 — Salicylic acid tests, 120 — Phenacetin, Acetphenetidine, 120 —
Saccharin, 121— Thymol iodide, 122— Phenolphthalein, 123— De-
termination of kidney function, 126.

XIV. NAPHTHALENES (tar camphor) 127

Anthracenes, 128 — Quinones, 130.

CONTENTS IX

PAGE

XV. HETERO CYCLIC COMPOUNDS . . . J- *••;". . 133

XVI. CARBOHYDRATES 134

Monosaccharides, 134 — Disaccharides, 134 — Polysaccharides, 134

— Difference between starches, gums, celluloses and sugars, 135 — •
General tests, 135 — Molisch's reaction, 136 — Starches, 137 —
Tests for starch, 137 — Sugars, 138 — Fermentation, 138 — The uses
of sugars, 138— Cellulose, 139— Tests for cellulose, 140— Crude
fiber, 139— Hemicellulose, 140— Agar, 140— Gums, 141— Tests
for gums, 141 — Pectins, 142 — Method of preparing pectin, 143.

XVII. FATS AND FIXED OILS 144

Classification of oils, 144 — General properties of fats, 148 — Ex-
planation of the cleansing action of soap, 149 — The" characteriza-
tion of fats, 151 — Fat constants, 152— The hydrogen number and
hydrogenated fats, 154 — The Reichert Meissel numbers, 155 —
The acetyl number, 155 — The Elai'din test for fats, 156 — The bro-
mine test, 157 — Maumene" or sulphuric acid test, 157 — Rancidity of
fats, 158 — The significance, uses and fate of fats, 158 — Origin of "
fat in the animal, 160 — Fats from proteins, 162 — The need of
fats in growth, 163— The fate of fats in the body, 163.

XVIII. WAXES 164

Sterols, 165 — Cholesterol, 165 — Tests for Cholesterol, 167 — Schiff 's
reaction, 168.

XIX. VOLATILE, ETHEREAL OR ESSENTIAL OILS 168

Chemical classification, 169 — Aliphatic hydrocarbons in volatile
oils, 169 — Terpenes, 169 — Aromatic terpenes, 171— Aliphatic
alcohols in volatile oils, 173 — Aromatic alcohols in volatile oils,
173 — Differences between fixed and volatile oils, 173 — The general
action of the volatile oils, 174 — Action on the alimentary tract,
174 — Substances excreted combined with glycuronic acid, 175 —
The significance of glycuronic acid in the urine, 175 — Saponifica-
tion, 176 — Stearoptenes, 177 — Thymolis iodidum, 179.

XX. RESINS, OLEORESINS, GUM RESINS, AND BALSAMS 180

Oleoresins, 181 — Gum resins, 182 — Balsams, 182.

XXI. GLUCOSIDES OR COMPOUND SUGARS 183

Pentosides, Galactosides, etc., 183 — Constitution of the glucosides,
183 — Glucosides, 185 — Composition of natural glucosides, 188 —
Ethylene derivatives, 191 — Benzene derivatives, 192 — Phloridzin,
193 — Styrolene derivatives, 194 — Anthracene or anthraquinone de-
rivatives, 195 — Saponin or saponins, 196 — The digitalis glucosides,
196 — Digitalin, 197 — Digitonin, 197 — Convallamarin, 197 — Digi-
talein, 197— Glycyrrhizin, 197— Scillin, 197— Helleborin, 197—
Cyanogenetic glucosides, 198 — Solanin, 198 — Coniferin, 199 —

X CONTENTS

PAGE

Indican, 199— Indoxyl, 200 — Animal glucosides, 201 — The func-
tions, action, and fate of glucosides, 202 — Tests for glucosides, 203.

XXII. BITTER PRINCIPLES 204

Tests to distinguish bitters from other bodies, 204 — Pharmacologic
classification, 204.

XXIII. PHARMACOLOGY OF THE TASTE AND SMELL 205

Chemistry and physics of odors, 207 — Taste, 208 — Glucophore,
212.

XXIV. TANNIC, DIGALLIC ACID OR GALLOTANIC ACID 214

Fate in the body, 216 — Determination, 218.

XXV. NEUTRAL PRINCIPLES 218

Santonin, 219— Tests, 220— Picrotoxin, 220— Tests, 220— H.
Meltzer's test, 220— Langley's test, 221 — Physiologic test, 221 —
Elaterin, 221— Chrysorobin, 221.

XXVI. ALKALOIDS 222

"Nitrogen bases; plant bases or alkaloids, 222 — General characteris-
tics of alkaloids, 224 — Chemistry of alkaloids, 225.

XXVII. AMINES OR SUBSTITUTED AMMONIAS 225

Tests for amines, 226 — Quaternary ammonium bases, 228 — Sources »-
of amines, 229 — The physiological action of the amines, 230 —
Amines with two hydroxyl compounds, 232 — Alkaloids derived
from aliphatic amines, 234 — Epinephrine test, 237 — Arginine, 238

— The fate of arginine in the body, 238 — Ptomaines or putrefactive
alkaloids, 239 — Choline, 242 — Ergot alkaloids, 244 — Ergot amines,
245 — Pyridine alkaloids, 247 — Natural methylated compounds in
the body, 249 — The fate of creatine and creatinine in the body, 249
— Tests, 252 — Nicotinic acid, 255 — Tests for nicotine, 255 — Rous-
sin's test, 255 — Schindelmeiser's test, 256 — Physiological tests,
256— Strychnine, 256— The fate of strychnine, 256— Tests for
strychnine and brucine, 257 — Bichromate test, 257 — Physiologic
test, 257 — Brucine, 257 — Arecoline, 257 — Quinoline, 258 — Quino-
line alkaloids, 259 — Action, 259 — The fate of quinine in the body,
259 — Assay of the alkaloids in cinchona bark, 260 — Tests for
quinine, 261 — Thalleioquine test, Isoquinoline alkaloids, 261 —
Hydrastine and hydrastinine, 262 — Hydrastinine, 263 — Hydras-
tine tests, 263 — Hydrastinine, 264 — Narcotine, 264 — Tests for
narcotine, 265 — Action of cocaine, 266 — The fate of cocaine in the
body, 266 — Artificial cocaines, 267 — Tests for cocaine, 267 — The
pyrrol or pyrrolidine group of alkaloids, 267 — The fate of atropine
in the body, 271— Tests for atropine, 272— Vitali's test, 272—
Scopolamine or Hyoscine, 272 — The glyoxaline group of alkaloids,
273 — Action of pilocarpine, 274 — Fate in the body, 275 — Tests for
pilocarpine, 275 — Phenanthrene alkaloids, 275 — Phenanthrene

CONTENTS XI

PAGE

group, 275 — Apomorphine, 279 — Apocodeine, 279 — The fate of
these alkaloids in the body, 280 — Tests for apomorphine, 280 —
Tests for codeine, 281 — Tests for morphine, 281 — Tests for the-
baine, 282— Papaverine, 282— Tests, 283— The caffeine group, 283
— Guanine, 287 — Adenine, 287 — Murexide test, 288 — Action of
caffeine compounds, 288 — The diuretic action of caffeine, 289 —
Fate of caffeine in the body, Economic use of caffeine, 291— Isola-
tion of alkaloids, 292 — Power and Chestnut's method of assaying
caffeine in vegetable material, 292 — Isolation of caffeine, 293 —
Keller's method, 293 — Unclassified alkaloids, 294 — Veratrine, 294
— Physostigmine or eserine, 294 — Tests, 295 — Colchicine, 295 —
Tests, 295 — Unclassified or alkaloids of unknown composition,
296 — The physiological significance of nitrogen bases, 297.

XXVII. PROTEINS 298

Classification of proteins, 299 — The simple proteins, 299 — Conju-
gated proteins, 300 — Derived proteins, 301 — A. Primary products,
301 — B. Secondary or intermediate protein derivatives, 301 —
Comparison of animal and vegetable proteins, 302 — Amino acids
found in plants, 302 — General properties of proteins, 303 — Color
reactions, 303 — Precipitation reactions, 304 — Hydrolytic products,
304 — General characters of amino acids, 308 — Condensation prod-
ucts, 309 — Condensation with formaldehyde, 311 — The deamini-
zation of amino acids, 312 — Urethane formation or the carbo-amino
reaction of amino acids, 313 — The taste of amino acids, 314 —
Optical properties of amino acids, 314 — The action of amino acids

in the body, 315 — The fate of amino acids in the body, 316 — The
fate of alpha amino acids in abnormal conditions, 319 — Trypto-
phane, 321 — Poisonous proteins, 322.

XXVIII. ENZYMES OR ORGANIC FERMENTS 323

Enzymes used as medicines, 324 — Pancreatic ferments, 324 — The
fate of enzymes in the body, 325.

XXIX. CHLOROPHYLL 328

Relationship of chlorophylls and hemoglobins, 329 — The fate of
chlorophyll in the body, 333 — Other plant colors, 333.

XXX. COLLOIDS 335

Character, or nature, of colloids, 336 — Classification, 338 — Dif-
ferences between the suspensoid and emulsoid colloids, 338 — Gel
formation, 339 — Lyotrope series, 340 — Electric conditions of col-
loids, 341 — Protective power of colloids, 342 — Change in colloids

in gel formation and precipitation, 342 — Surface tension, 343 —
Viscosity and surface tension, 345 — Superficial viscosity, 347 —
Relation of composition to surface tension, 347 — Relation of com-
position to viscosity, 348— Adsorption, 349— Selective adsorption,
349 — Influence of salts on absorption, 349.

Xll CONTENTS

PAGE

XXXL THE REACTION OF LIVING MATTER 350

The colorimetric method, 351 — Electro potential method or gas
chain method, 351 — Method of expressing hydrogen ion concentra-
tion, 352 — Regulating mechanism, 354 — Actual and potential al-
kalinity and buffer value, 355 — Potential alkalinity of blood, 356
— Acidosis, 357 — The determination of the existence of acidosis,
359 — Tolerance to carbonate, 359 — Urinary changes, 360 —
Lowered tension of carbon dioxide in the respired air, 360.

XXXII. PHOSPHORUS 361

The fate of phosphorus in the body, 364 — Arsenic compounds,
364 — Fate of arsenic in the body, 367.

XXXIII. HEAVY METALS 368

Explanation of precipitation, 369 — Colloidal metals, 372.

XXXIV. INORGANIC ACIDS 373

XXXV. SALT ACTION 374

Diffusion, 375 — Osmosis, 375 — Gas pressure in relation to osmotic
pressure, 375 — Difficulties in determining osmotic pressure, 376 —
Relation of osmotic pressure to the boiling point and freezing point

of solutions, 377 — Freezing point method, 377 — To calculate the
osmotic pressure from the freezing point, 377 — Salts in the body,
378 — Salt action in pharmacology, 379.

XXXVI. TOXICOLOGY 379

The isolation of poisons, 379 — Apomorphine, 381 — Methods of
isolating poisons, 382 — The isolation of volatile poisons, 382 —
Preliminary test for phosphorus, 382 — Discussion of results, 382 —
Mitscherlich's test, 383 — Ammonium-molybdate test, 385 —
Ammonium magnesium phosphate test, 385 — The Mitscherlich-
Scherer method for the qualitative and quantitative estimation of
phosphorus, 386 — Tests for detection of phosphorus in oils, 387 —
Acetone, 387 — Aniline, 387 — Oil of bitter almonds or benzalde-
hyde, 387— Test for KCN, 387— Carbon bisulphide, 388— Chloral
hydrate, 389 — Ethyl alcohol, 389 — Methyl alcohol, 390 — lodo-
form, 390— Nitrobenzene, 390— Phenol, 390— Quantitative esti-
mation of phenol, 390 — Creosote (Creosols), 390 — Non-volatile
organic poisons, 391 — Acid extraction Stas-Otto method, 392 —
Metallic poisons, 394 — Arsenic test, 396 — Detection of antimony,
397 — Differences between arsenic and antimony, 398 — Test for
mercury, 398 — Examination of the nitric acid solution, 399 —
Copper and bismuth tests, 399 — Chromium and zinc, 399 — Synop-
sis of metallic poisons, 400 — Sulphuric acid, 401 — Nitric acid
tests, 401— Oxalates and oxalic acid, 402— Alkalies, 403— Fixed al-
kalies, 403 — Potassium chlorate, 403 — Active substances which find
no place in the Stas-Otto method, 403 — Santonin, sulphonal; trional,
404 — Digitalis, 405 — Ergot, 405 — Reagents and solutions, 406.

CHEMICAL PHARMACOLOGY

I. INTRODUCTION

Pharmacology is the science which deals with drugs and the
reactions of living matter brought about by drugs. The term,
"drug" is derived from the Dutch or Anglo-Saxon word, "drugan,"
meaning to dry, and was formerly applied to dried medicinal
plants. At that time materia medica was entirely of plant origin,
at present the term includes all substances used as remedial
agents.

It is often desirable to define foods, drugs, and poisons; but
the distinctions at best are unsatisfactory and arbitrary. Foods
are substances, which, when taken into the alimentary tract are
digested, build up tissue, supply energy, repair waste, and do not
injure health. A poison is anything that, in amounts of fifty
grams or less, injures or destroys life, when taken by mouth.
There is, however, no satisfactory definition of a poison, and
fifty grams is an arbitrary amount; some set the limit at one
gram. Drugs and poisons are relatively little acted on by the
body, are but little digested or hydrolyzed, and as a rule do not
supply energy, and do not repair waste. Some substances, may
be remedies, foods, or poisons, according to the method of adminis-
tration; e.g. egg albumen and peptone, are foods when taken
by mouth, but they are violent poisons if given intravenously.
Iron salts too, when taken by mouth are valuable remedies in
some cases of chlorosis, but they also may exert a toxic action if
given by vein. Some foods such as milk, fish and strawberries
produce most violent toxic symptoms, when taken even in
small amounts, in some persons who are said to have an idiosyn-
crasy for those particular substances.

Classifications. — Drugs may be classified as:

1. Inorganic or mineral

n ~ . Animal

2. Organic ,T , ul

Vegetable

or as was done by chemists about the middle of the 17th Century,
as animal, vegetable, and mineral.

Z CHEMICAL PHARMACOLOGY

When it was discovered that certain compounds are found in
both animals and plants, the distinction between animal and
vegetable chemistry disappeared and to include both the broader
term " organic" was substituted. It was believed then that
" vital force" was necessary for the formation of organic com-
pounds, and that these could not be. produced by the chemist.
In 1828, however, Wohler prepared the organic substance,
""urea" from the so-called inorganic compound, ammonium
isocyanate :

X
NH4 CNO = COC

XNH2
Ammonium isocyanate urea

Since this discovery a sharp distinction between organic and
inorganic compounds cannot be made. Yet, the term " organic"
has survived, and includes not only those substances formed in
plants and animals, but also most carbon compounds. Many
synthetic drugs which contain carbon, are in reality no more
organic than calcium carbonate, but are included in organic
chemistry because of relationship, or of historical interest.

The term vital force or vital activity is still used by physiolo-
gists and pharmacologists especially in discussing absorption and
secretion. It means simply that the known physics and chemis-
try is inadequate to explain all the phenomena, and that the
explanation of some life processes is still unknown.

In addition to carbon, the chemistry of drugs includes other
important elements. Twelve elements are necessary for life
and are consequently found in varying amounts in all organic
matter. These elements are: C, H, N, O, S, P, Na, Mg, Ca, Fe,
Cl, and K. If any of these elements be extracted from living
matter, death results.

If the amount of each element in a substance is determined,
we say that the analysis is ultimate. The elements however do
not exist in a free state in plants or animals, but are combined to
form fats, proteins, carbohydrates, volatile oils, gums, gum resins,
alkaloids, glucosides, salts, etc. These, when they are definite
chemical compounds, are called proximate principles, and the
determination of the amount of these substances is proximate
analysis.

PROXIMATE PRINCIPLES

Proximate principles because of their reaction are divided into
acid, neutral, and basic principles. The following scheme is
illustrative :

Animal

Organic Drugs

Proximate Principles

Vegetable

1. Proteins

2. Lipoids or ether extracts

3. Carbohydrates

Fats

oils

cholesterines

waxes

Celluloses

dextrin

gums

sugars

pectins

starches

glycogen

4. Alkaloids

5. Glucosides — which include saponins and sapotoxins.

6. Volatile, ethereal, or essential oils.

Camphor
menthol

7. Stearoptenes ,

thymol

oleoresins

8. Resins gum resins

balsams

9. Organic acids.

10. Coloring matter or pigments.

f Chlorophyll
carotin
xanthophyll

11. Ash or inorganic residue which remains when drugs or
plants are ignited to constant weight at red heat.

While according to their reaction these bodies are acid, basic,
or neutral; the term " neutral principle " is of ten used in a different

CHEMICAL PHARMACOLOGY

sense. It is applied especially to those neutral physiologically
active bodies that do not belong to a more definite chemical
class; e.g. picrotoxin is a neutral principle and is known only by
that term. Glucosides are also neutral, but are rarely referred
to as such, because the term, "glucoside" is more specific than
" neutral principle. " An alkaloidal salt may be neutral in reac-
tion but is never referred to as a neutral principle, but is always
classified with alkaloids.

Proximate principles, when acted upon by bacteria, yeasts,
enzyme's, heat or chemical agents, give rise to pure chemicals of
simpler composition such as paraffins, alcohols, ethers, acids,
etc., and these form the basis of organic chemistry. Many of
these chemicals are used in medicine, and a knowledge of the
structure of the simple organic bodies is essential for a study of
the more complicated proximate principles, and for the study
of pharmacology. Pharmacology in the last analysis is ap-
plied organic chemistry, or the chemistry and reactions of living
matter, as modified by changes in environment. The cause of
these changes whether due to noxious gases, decomposition
products of foods, impurities in water, bacterial toxins or
other injurious or modifying agent in the widest sense comes
under the term "drug." However, the study of pharmacology
is usually limited to those drugs that are used in therapeutics,
or that are especially valuable in investigative work.

THE COMPOSITION OF DRUGS
CARBON

Carbon in the elemental condition, and in the form of CO, C02
and the carbonates is included in inorganic chemistry. All other
carbon compounds are, for convenience, classified under organic
chemistry.

The word, " carbon" is derived from the Latin, "carbo,"
meaning coal, and the ordinary test for carbon is the carbonizing
action or the becoming coal-like on burning. If we partially burn
a piece of wood, paper, or almost any organic substance it chars.
There is a similar action, if we add strong sulphuric to it. The
acid extracts the water part of the molecule leaving carbon
partially free, or charred. If enough oxygen is present in the

CARBON 5

molecule, or if burning continues, the carbon is completely oxi-
dized and disappears as a gas, CO or C02, but always as C02 if
enough oxygen be present. Most carbon compounds when
taken into the body are oxidized in a similar way, but the oxi-
dative potential of the body is not sufficiently high to oxidize
elementary carbon, nor even such compounds as cellulose.

Not all organic compounds carbonize on heating. If oxalic
acid, COOH. COOH, be heated, it breaks down into C02, CO and
H2O without charring. The reason being that it contains enough
oxygen in the molecule, to completely oxidize the carbon present.
The form in which carbon occurs in the molecule is also an im-
portant factor in determining whether or not it will carbonize on
heating. When present in the form of carboxyl, as it is in the
case of oxalic acid, it is already oxidized and in a bound or

//Q

gaseous form — C\ so that carbonization is impossible

XOH
since it is already past that state. It may break either as

/ft

H— Cf — > H2O + CO in which case, the water is split

XOH

directly from the molecule; or in oxalic acid it may break into
C02 and H20, the H in the acid being oxidized to water by the
oxygen of the air;

COOH

COOH + 0 = 2C02 + H20

There is a general tendency of organic acids, especially when
heated under the influence of strong dehydrating agents, to
break up, giving off C02 or CO from the carboxyl group : e.g.

Formic acid HCOOH + H2SO4 = CO + H2O

Malonic acid heated to 140° COOH
yields acetic acid and C02

CH2 = CH3COOH + C02

COOH

6 CHEMICAL PHARMACOLOGY

In case of aliphatic compounds, the tendency to yield C02 is
greater where two carboxyl groups are attached to one carbon
atom.

COOH

+ CO2

Gallic acid when heated
yields pyrogallic acid and
OH carbon dioxide OH

For these reasons carbonization is not a general test for organic
substances. The formation of CO2 is a more definite test.

The presence of carbon can be shown in those cases that do
not char, if the gas evolved on heating be collected in NaOH or
Ca(OH)2; this results in the formation of a carbonate

2NaOH + CO2 = Na2CO3 + H2O
or Ca(OH)2 + CO2 = CaC03 + H2O

The presence of CO2 in the respired air can be shown this way.
The formation of a carbonate is a general proof of the presence
of carbon whether or not there be carbonization.

Carbon, prepared by heating bone — bone charcoal, or wood —
wood charcoal, in absence of air or oxygen, is used in medicine in
some cases of stomach disease, and in other cases, as an- absorbent
of gases. It will also absorb toxins as in diphtheria, and has
been sometimes applied locally for this purpose. It is used in
chemical analysis as a clarifying agent to absorb colors. When
carbon is wet its value as an absorbent for gases is greatly les-
sened, for this reason, its value when given to absorb gases in
the stomach is questionable.

Carbon dioxide in the body is the specific stimulus of the respi-
ratory centre. It is generated by the oxidation of the carbon of
the food. The fate of carbon and hydrogen is very important
since in the body the oxidation of the carbon and hydrogen of
the food is the exclusive source of heat and therefore of body
temperature. The calorific value of foods in the body is the same
as they yield in the calorimeter, but in the body oxidation pro-

HYDROGEN AND NITROGEN 7

ceeds at about 40°C. while in the calorimeter high temperatures
are necessary to complete the oxidation.

Test for Hydrogen

The presence of carbon and hydrogen together in drugs or
organic compounds can be shown by heating the dried material
with desiccated copper oxide in a glass tube. The copper oxide
is reduced in the presence of organic matter and the free 0
oxidizes the C and H to C02 and H2O. The CO2 is detected in
the usual way with lime water. The water formed will condense
in the cold part of the tube in which the substance is heated.
The formation of water is proof of the presence of hydrogen.
If desired, the water so formed may be collected in sulphuric
acid and weighed as is done in ultimate analysis. Hydrogen in
the free form is not used in medicine.

NITROGEN

Nitrogen as a free gas is characterized by its chemical inertness.
A burning splinter immersed in a vessel containing nitrogen
gas is immediately extinguished. Animals and plants die if
confined in an atmosphere of nitrogen. For this reason, it was
formerly called Azote (against life) . It is a constant constituent
of all plants and in combination is an indispensible food. It is
also essential in the air as a diluent of oxygen, since life in pure
oxygen is impossible. Because of its inertness, the gas has been
used in therapeutics, in the pleural cavity, to collapse one lung
in case of tuberculosis of that organ; the idea being to rest the
lung by collapse and so permit healing, also by preventing move-
ment, to lessen the tendency to spread the diseased condition.
Nitrogen in plants exists mainly in the form of:

1. Proteins 9. Some glucosides

2. Amino acids 10. Mixed compounds, etc.

3. Amines

4. Alkaloids

5. Phosphatides

6. Nitrates

7. Cyanides

8. Ammonia

8 CHEMICAL PHARMACOLOGY

To determine whether or not, a drug or any organic matter
contains nitrogen, the following tests may be used :

Test for Nitrogen

1. In many cases, when an organic substance is burned, an
odor like burnt feathers is given off; this is characteristic of the
presence of N.

2. Lassaigne's test: Organic bodies always contain carbon,
therefore if a small amount of the substance be heated in a dry
test tube to redness, with Na, or K, and the test tube be im-
mediately plunged into water in a beaker, the C and N, if present,
will combine with the Na, or K to form KCN or NaCN, which
may be detected by treating with a mixture of ferric and ferrous
salts, Prussian blue being formed.

Freshly prepared ferrous sulphate with a drop or two of ferric
chloride added, is a suitable reagent. During the operation some
ferrous hydrate is converted into ferric hydrate, which when
acidified with HC1 is converted into ferric chloride. The reac-
tions may be illustrated as follows :

1. 20 + 2N + 2K -* 2KCN

2. 6KCN + FeS04 -> K4Fe(CN)6 + K2S04

3. Fe2Cl6 + FeS04 + SNaOH -» Fe2(OH)6 + Fe(OH)2 +

GNaCl + Na2S04

4. 2Fe2(OH)6 + 3K4Fe(CN)6 + 12HCl-»Fe4{(Fe)(CN)6}3 +

12KC1 + 12H20
Or

1. FeS04 + 2KOH = Fe(OH)2 + K2S04

2. Fe(OH)2 + 2KCN = Fe(CN)2 + 2KOH

3. Fe(CN)2 + 4KCN = K4Fe(CN)6

4. 2Fe2Cl6 + 3K4(Fe(CN)6) = Fe4{Fe (CN)6}« + 12KC1

If the blue or green color does not quickly develop, a drop of ferric
chloride should be added. It often happens that not enough
Prussian blue is formed to give the blue color. The formation
of a green solution is sufficient proof*

Nessler's Test. — Nessler's reagent produces a brown precipitate
of NHg2I. H20 in solutions containing ammonia. If only a trace
of ammonia be present a yellow or reddish yellow color is pro-
duced. This reaction is used to determine ammonia in water.

NITROGEN TESTS 9

3. Kjeldahl's Test for Nitrogen. — Also the estimation of the
amount of nitrogen. This test consists essentially in boiling the
organic substance with strong H2S04 which destroys the organic
matter and converts the nitrogen into (NH4)2SO4; this is then
tested for NH3 which if present, proves the presence of nitrogen.
The method here described is the most used one for determination
of the amount of nitrogen and protein material in drugs, foods,
and other products. It is carried out as follows:

Place 1 to 5 grams of the dry material, accurately weighed in
a Kjeldahl flask of about 500 cc. capacity. Add 30 cc.
H2S04 cone, and about 0.5 gram mercuric oxide, or pure mercury.
The mercury acts as a catalytic agent and hastens oxidation.
Boil over a free flame until the solution is a pale straw color, white
or clear water color. Sometimes the substance, on boiling,
bumps; to prevent this, kaolin, zinc or other finely divided inert
material is added, which prevents bumping by stirring the mix-
ture so that the heat is uniformly distributed and no point of the
glass becomes heated to a much greater extent than the rest.
Many substances foam so much on heating that paraffin or some
other substance is added to lessen this. After the substance
has boiled until it is milky or water color, the flask is removed
and about 0.5 gram of KMn04 added, to complete the oxidation.
The nitrogen is now in the form of (NH4)2S04, which has been
proved by isolation and analysis of the crystals. An excess of
strong NaOH added to this solution liberates NHs, which may be
distilled and caught in a solution of acid of a known strength and
titrated, e.g., (NH4)2S04 + 2NaOH = Na2S04 + 2NH4OH.
If we collect this, say in 50 cc. of N/10 H2S04 we know how much
NHs is present by titrating the excess of the acid with N/10
NaOH. 1 cc. of N/10 H2S04 = .0017 grams NH3 or .0014
grams N. For example: one gram of a substance treated as
above, with H2S04 was made strongly alkaline and distilled into
50 cc. N/10 H2S04. When this distillate was titrated with N/10
NaOH it was found that it took 20 cc. NaOH to neutralize.
Therefore, the nitrogen in one gram of the substance is equiva-
lent to 50 cc. N/10 - 20 cc. N/10 = 30 cc. N/10 acid. Since
1 cc. N/10 acid = .0014 grams N, 30 cc. = 0.042 grams N or
the amount in one gram of the substance and the percentage
is 100 times 0.042 = 4.2 per cent.

10 CHEMICAL PHARMACOLOGY

Since protein contains on the average of 16 per cent. N, it is
customary to multiply the amount of N by 6.25 to obtain the
per cent, of protein (6.25 times 16 per cent. = 100 per cent.).
All protein, however, does not contain exactly 16 per cent, nitro-
gen, so that in some cases the factor 6.25 is not exact.

Various non-essential details in the method are used in some
cases, such as the addition of potassium sulphate to raise the
boiling point and the addition of other catalytic agents.

OXYGEN

Oxygen. — In addition to carbon, hydrogen and nitrogen most
organic compounds also contain oxygen. Because these elements
occur so universally in organic matter, they have been called or-
ganogens. This term has also been used to include the other
essential ingredients of plants. The well known chemical prop-
erties of oxygen in the gaseous form cannot be demonstrated in
organic bodies. There is no simple practical method for its
direct determination. Its quantity is usually calculated in
analyses by the difference between 100 per cent, and the sum of the
percentage of the other elements present, after the other elements
have been determined. Ever since the importance of oxygen
became known, attempts have been made to use it in failing respi-
ration. As a rule, however, it is of little value, because in most
cases the asphyxiation that suggests its use, is really due to a
failure of the heart. Again the hemoglobin of the blood, which
is the oxygen carrier to the tissues, is in most cases saturated,
so that the administration of pure oxygen can aid but little. In
cases of severe hemorrhages or of poisoning carbon monoxide,
nitrites, chlorates, nitrobenzol, etc. which destroy the oxygen
carrying power of the blood, it has been shown that when pure
oxygen is administered the oxygen content of the red cells and
serum is increased somewhat, and this slight increase 'may be
very beneficial. If the gas be administered under tension there
may be sufficient oxygen increase in the blood to cause convul-
sions in animals. Hilarity and other nervous influences have
been observed in man. There is some increase in metabolism
but not sufficient to be of benefit in any given case.

Ash. — If an organic substance contains C, H, N, and O only,
it will leave no residue or ash on burning. Plant drugs leave

ASH 1 1

an ash which contains varying amounts of Na, K, Mg, Ca, Cl, P,
S, Si and Fe, as necessary ingredients. Depending on the soil
on which they were grown, plants may also contain As, Ba, Mn,
I, Zn or any other element, not as essential, but as accidental
elements.

Before testing for these elements, it is necessary to reduce the
plant or drug to an ash. The organic matter must be completely
destroyed because the inorganic elements react only as ions and
ionization is prevented and masked by organic matter.

To aid in the " ashing" some oxidizing agent which can be
driven off by heat may be used, e.g., H202 — HNOs, etc. or, in
case we do not wish to test for K, or Cl, KC1O3 may be used. A
small amount of any of these agents aids oxidation and the reduc-
tion of the substance to a white or grey white ash. The ash of
plants is rarely pure white because of the presence of iron, and
other elements. After the ash has been prepared, it is dissolved
usually in dilute HC1 and tes.ts for the elements made with the
solution. The following scheme will show how to prepare the
ash of plants for analysis.

Weigh out 5 grams of the root, leaves, or whatever is to be
determined, and place in a platinum or porcelain crucible or
dish. Heat it gradually on a thin sheet of asbestos over a Bun-
sen burner. In order to avoid loss by volatilization, tilt the
dish or crucible, and at the beginning keep it covered. The
material first chars, then glows beginning at the top and gradu-
ally extending to the bottom. Carefully regulate the heat to a
dull redness (about 700°C.). If heated higher than this, there
is a loss of alkali chlorides by volatilization and the phosphates
fuse about the particles of carbon, so that this cannot be oxidized
completely. A muffle furnace may be used to complete the oxida-
tion. Finally, when the ashing is complete, weigh and calculate
the amount.

In an actual determination, several weighings are made, and
the substances heated between these weighings, until the weight
keeps constant. We know then that oxidation is complete.

The ash of plants contains considerable carbon dioxide, which
may be found with sodium, potash, or any of the other elements,
in the form of a carbonate and imparts to the ash an alkaline
reaction. The use of plant ash in earlier times for the formation

12 CHEMICAL PHAKMACOLOGY

of soap, is due to this fact. In the analysis of an ash, therefore,
we determine the amount of COz, sand, silica, Fe, Al, Ca, Mg,
and acid radicals, S03, P205, etc. These are in very small
amounts, and while absolutely essential to the life of the plant,
and in the main, essential ingredients of foods, they are not
present in sufficient amount to be important as drugs.

II. PARAFFINS

The paraffins are prepared from crude petroleum or rock oil
(petros-rock) which in turn is the result of the decomposition of
organic matter. Because of their inertness the name paraffin has
been applied (parum-small, affinis-affinity) . The series is known
by a number of names:

1. Fatty or aliphatic because the best known fats belong
chemically to it (aliphos, fat).

2. The limit series because the valences of the carbon atoms are
saturated to the limit.

3. It is called the chain series or acyclic because the carbon
atoms are supposed to be arranged in the form of a chain

in contra-distinction to the ring, or benzene series.

4. Since methane, CH4, is the first member, it is also known
as the methane series. Because methane is found in nature in
marshes, the term marsh gas series is also used. Members of
from 1 to 60 carbon atoms are known.

All hydrocarbon compounds are grouped under three heads,
namely:

1. Fatty or acyclic, or chain-like carbon derivatives.

2. Carbocyclic, or aromatic compounds.

3. Heterocyclic compounds.

Properties of the Hydrocarbons of the Paraffin Series.
Those containing from 1 to 4 carbon atoms are gases; from 5 to 16
liquids; and those containing more than 16 carbon atoms are
solids. This statement refers to ordinary temperatures and

PARAFFINS 13

pressures. All of them may be converted into gas, or all into
solids, if the temperatures and pressure conditions are controlled.

The paraffins are saturated, therefore, they do not absorb
bromine or hydrogen and are not absorbed by sulphuric acid.
They are insoluble in water; the lower and intermediate members
are readily soluble in alcohol and ether. They are noted for
their chemical and pharmacologic inertness. Their action
in the body is mainly physical. However, such light distillates
as naphtha and benzine, are excellent solvents for fats, oils,
lipoids, resins, and their volatility aids absorption. These light
distillates often produce toxic effects that can be ascribed to
their action on the nervous system, probably due to a solvent
action on lipoids. Following their administration, headache,
nausea, giddiness, unconsciousness, muscular tremors, convulsions,
cyanosis and death, have been observed.

The irritant effect of the lighter members may also produce
gastritis and gastro-enteritis. When the boiling point reaches
that of kerosene, the toxicity is greatly diminished. Gastro-
enteritis and narcotic effects similar to alcohol have been ob-
served after kerosene, but no deaths have been reported, although
cases are reported where as much as a liter was swallowed. Liquid
petrolatum has an emollient effect. The solids are inert.

A few hydrocarbons, benzine, gasoline, kerosene, vaseline,
liquid petrolatum, and solid paraffin are used in medicine.
One should carefully distinguish between benzine, and benzene.
Benzine is a light paraffin, a mixture of CeHu and Cy Hie, while
benzene or benzol, CeHe, is an aromatic compound. It (benzol)
has recently had considerable vogue in the treatment of leukae-
mia. Small amounts of it (1 cc. dose) reduce the number of
white cells in the blood, but its continued use is fatal. Kerosene
is used especially in dispensary practice to rid the hair of nits
and lice.

The hydrocarbons above mentioned differ mainly in their
physical properties, but there is some chemical basis for this dif-
ference. The source of all these is crude petroleum.

CRUDE PETROLEUM

This is a most important source of the paraffin hydrocarbons.
When distilled at varying temperatures, the different fractions

14 CHEMICAL PHARMACOLOGY

have a varying and mixed composition, but are approximately as
follows :

Distillation at temperature of: Gives as a resulting substance:
0° Gases, which may be liquified

under pressure, CH4 to C4H^o
18° Rhigolene, C5H12— C6H14

50° and 60° Petroleum ether, or naphtha,

CeHi4 — Grlli 6
70° and 90° Benzine, a mixture of C6H14

and CyHie

90° and 120° Ligroin, C7H16 and C8Hi8

120° and 150° Petroleum benzine, C8H18—

CioH2o
150° and 300° Burning oil distillate kerosene

From the residue left after distillation at 300°, liquid paraffin,
vaseline, and solid paraffin are prepared. These are essentially
paraffins that distil between 300° and 390°C.

LIQUID PETROLATUM

Liquid petrolatum may be obtained from petrolatum after
the fractions distilling under 330° have been removed. The re-
maining liquid, when distilled between 330° to 390°, gives liquid
petrolatum which is purified by treating with sulphuric acid, and
then by caustic soda, and by filtering while hot through some
decolorizing agent, like animal charcoal or Fuller's earth. It
is used in medicine as a cathartic and as a vehicle for other drugs.

Petrolatum, U. S. P. or petroleum jelly, is a soft paraffin or
vaseline obtained from the liquid paraffin distillate. The part
solidifying at 38°-54° is called petrolatum or vaseline.

Paraffin durum, or hard paraffin, is chemically similar to vase-
line, but has a higher melting point, 50°-57°, hence it will cry-
stallize out of the distillate before vaseline. It is prepared in the
cakes of commerce by pressure, and on account of its inertness is
used in the laboratory around the stoppers of acid and alkali
bottles. It has been used by " beauty specialists" to remedy
minor deformities by injecting under the skin, a procedure which
is not recommended.

Light liquid petrolatum (petrolatum levis) is used as a vehicle

PETROLEUM 15

especially for nasal and throat sprays. It is itself an emollient
and as such serves to soothe, and to protect inflamed mucous
membranes, and at the same time mild antiseptics like menthol
or eucalyptol are incorporated with it. A popular nasal spray
or nebula consists of one per cent, each of menthol and eucalyptol
in light liquid petrolatum.

Liquid petrolatum (heavy-Petrolatum ponderosum or gravis)
is used as a cathartic and is very servicable where a cathartic
has to be given continuously as in chronic constipation and
certain diseases of the intestine. It acts mechanically. Any
non-absorbable fluid may act in the same way. It is valuable in
these cases, because it does not cause griping, and does not be-
come inert through continual use. The physical difference be-
tween light and heavy petrolatums is mainly a difference of
viscosity.

The following tables show how the boiling point changes as the
molecular weight increases.

Substance Molecular Boiling

formula point

Methane CH4 -164°

Ethane C2H6 - 84°

Propane C3H8 - 45°

Butane C4H10 1°

Pentane C5Hi2 36°

Hexane C6Hi4 70°

Eicosane C2oH42 330

Penta tria contane C35H72 331

Dimyricyl C6oH122

OCCURRENCE IN NATURE

Methane, or marsh gas, CH4, the first of the series, is found
in marshes and coal mines in varying amounts, and wherever
decomposition of vegetable matter in lack of oxygen occurs.
Mixed with air, methane is known as the fire damp of mines. It
is one of the gases of the intestine, and in smaller amounts may
be found in respired air. It may be prepared synthetically in a
number of ways. These methods have little direct interest in
pharmacology, but since they are fundamental and illustrate how

16 CHEMICAL PHAKMACOLOGY

paraffins may be formed from the elements they are briefly
indicated :

SYNTHESIS OF METHANE

I. Hydrogen sulphide and carbon bisulphide passed through
a red hot tube containing copper, yield CH4.

2H2S + CS2 + 4Cu = 4CuS + CH4

II. By passing carbon monoxide and hydrogen over reduced
nickel at 200°C.

CO + 3H2 = CH4 + H20

III. At 250°C., C02 is also reduced in the presence of finely
divided nickel.

C02 + 4H2 = CH4 + 2H20

IV. Methyl alcohol or wood spirit can be converted into
methane by changing to methyl iodide and then (a) the iodide
nascent hydrogen:

CH3OH + I2 + 2H = CH3I + H20 + HI or (6)

CH3I + 2H = 2CH4 + HI

These and many other methods are used for preparing methane.
Methane itself ^has no uses in medicine. The most important
derivatives of methane from a pharmacological point of view, are
methyl alcohol because of its toxicity and as a source of form-
aldehyde. The latter is used because of its antiseptic action.

ETHANE

This is the second member of the paraffin or methane series.
It occurs in small quantities in natural gas and crude petroleum.
Its derivatives only atfe important. It may be prepared synthe-
tically in a number of ways, which show that it is made up of two
methyl (CH3) groups, as the following reaction shows:

2CH3I + 2Na = CH3.CH3 -f 2NaI

Ethane is also formed when ethylene is treated with nascent
hydrogen :

C2H4 -f- 2H = C2He

or when ethyl iodide is treated with hydrogen
C2H5I + 2H = C2H6 + HI

while ethane is not used in medicine its derivatives are exceedingly
important.

METHANE SERIES

IMPORTANT DRUGS OF THE METHANE SERIES
III. ALCOHOLS

The drugs of the methane series includes alcohols, ethers,
ketones, and many derivatives which are used as narcotics or
hypnotics.

Alcohols are hydroxyl derivatives of the marsh gas series (cf.
phenols) . According to the number of hydroxyls in the molecule
they are classified as:

1. Monatomic or monhydric

2. Diatomic or dihydric, etc.

No gaseous alcohols are known. Up to Ci2H250H with few
exceptions they are neutral, colorless liquids with a pleasant odor
and burning taste. The more important members of the mon-
hydric alcohols with their boiling point and specific gravity are
as follows:

Substance

Chemical
formula

B. P.

Spec. •'
Grav.

Relative
toxicity
(Baer)

Methyl alcohol

CH3OH

66°

0 812

0 8 (?)

Ethyl alcohol

C2H6OH

78°

0 806

Propyl alcohol

C3H7OH

97°

0 817

Butyl alcohol

C4H9OH

117°

0 823

Amyl alcohol

C6HnOH

131°

0.825

Ethyl alcohol is the only one that is used in medicine to any
degree. Methyl and amyl alcohols are of importance because of
their toxicity. The relative toxicity given by Baer does not
hold good for all forms of life. It is only approximate at best.
For man, it is incorrect, methyl being more toxic than ethyl.
As we ascend in the alcoholic series, the members soon become
more solid, and much less soluble, hence less toxic. A drug that
is insoluble in the tissues or fluids of the body is inert. However,
many substances that are insoluble in water dissolve readily in
the body fluids. Next to water, alcohol is the solvent that will
dissolve the greatest number of substances.

Methyl alcohol, or wood spirit, is prepared on a large scale by
the dry distillation of wood. It is important in medicine chiefly

because many cases of poisoning have arisen from its use. Its
2

18 CHEMICAL PHARMACOLOGY

actions in general are the same as ethyl alcohol, and are exerted
mainly on the central nervous system. It seems to have a
selective action on the optic nerve, and blindness often follows
its use; even one dose of about 60 cc. has caused permanent
blindness. Many such cases have been reported recently.
In repeated doses it is much more toxic than ethyl alcohol. It
has been used in patent medicines because it is cheaper than
ordinary alcohol. Its use, however, should be condemned
unhesitatingly.

The main differences in the intoxication of methyl and ethyl
alcohols are: The coma produced by methyl alcohol may last
for several days, as compared with a few hours in case of ethyl
alcohol. Methyl alcohol readily attacks the optic nerve and may
cause the blindness, which is absent in the action of ethyl alcohol.
The oxidation products of methyl alcohol, formaldehyde and
formic acid, are prone to irritate the kidneys and bladder, con-
sequently nephritis and cystitis are frequent after wood alcohol
poisoning. *

Tests for Methyl Alcohol

1. It burns with a luminous flame. In this it resembles ethyl
alcohol. In the body however, it is not so readily oxidized.

2. It dissolves fats, oils, resins, etc. and is extensively used for
this purpose being a better solvent for these than ethyl alcohol.
This greater solvent power for lipoids may be the cause of its
greater toxicity.

3. It is miscible with water in all proportions, the same as
ethyl alcohol.

4. Methyl alcohol may be converted into methyl salicylate
(oil of Wintergreen) as follows:

To some sodium salicylate in a test tube, add an equal volume
of methyl alcohol and concentrated sulphuric acid. Heat gently.
The odor is that of methyl salicylate; which is an important anti-
rheumatic remedy.

/OH /OH

C6H/ + CH3OH = C6H/ + NaOH

XCOONa XCOOCH3

Sodiumsalicylate methylalcohol methylsalicylate.
Oleum betulse (oil of birch) is also methyl salicylate.

ALCOHOL 19

5. Methyl alcohol readily yields formaldehyde on oxidation.
Heat a small copper spiral to redness and drop it quickly into
a test tube containing two or three drops of methyl alcohol.
Note the odor of formalin. This same reaction takes place in
the body when methyl alcohol is taken.

H H

H— C— H-> H— C— OH-+ TL—cf

I H

H H

Methane Methyl alcohol Formaldehyde

An oxidation of the hydrocarbons has not been observed in
the body.

ETHYL ALCOHOL

Ethyl alcohol, C2H5OH, grain alcohol, or alcohol, is the next
higher homologue in the methyl series, and is the result of fer-
mentation of the sugars, of fruits and certain plants. Sugar
and consequently alcohol may be prepared from any plant that
contains starch. The, U. S. P. (IX) requires that the ordinary
commercial alcohol contain not less than 92.3 per cent, by weight
and 94.9 per cent, by volume of C2H5OH. When a specific
kind of alcohol is not mentioned, ethyl alcohol is always
understood.

Alcohol dilutum contains alcohol, one-half, and distilled water
one-half by volume.

Alcohol dehydratum or absolute alcohol is obtained by treating
96 per cent, alcohol with quicklime, and distilling. The lime
holds all but the last traces of water which are taken out with
anhydrous copper sulphate. When rectified again, it contains
0.5 per cent, water in which form it is used commercially, but the
pure absolute alcohol can be obtained by treating the latter with
barium oxide and re-distillation. Absolute alcohol is so hygro-
scopic that as a rule it is not found on the ordinary market.
It contains 0.5 to 1 per cent, water. To prove.the presence of
water in alcohol, drop a small piece of anhydrous copper sul-
phate into 5 cc. of alcohol. Shake and let it stand. If the

20 CHEMICAL PHARMACOLOGY

slightest trace of water be present, a light blue color develops.
Also if a few drops of liquid paraffin be added to the same
amount of alcohol and shaken, a cloudiness due to the formation
of an emulsion by the water, indicates the presence of water.

Whiskey, is prepared from fermented grain, potatoes, or any-
thing containing starch. The starch is hydrolyzed to glucose and
this on fermentation yields alcohol. Whiskey contains about
45 to 55 per cent, alcohol.

Gin, containing about 40 per cent, alcohol, is also made from
grain and in its final distillation, juniper berries, anise seed, etc.,
are added.

Rum, prepared from fermented molasses, contains from 45 to
55 per cent, alcohol.

Brandy, prepared from fermented juices of such fruits as
grapes, apples, peaches, etc. contains about 45 to* 55 per cent, of
alcohol.

Wine, champagne, and beer, are obtained by direct fermenta-
tion and are not distilled. Wine and champagne contain about
8 to 10 per cent, alcohol.

Beer is produced by fermenting malted grain with the addition
of hops, for the taste. It contains from 3 to 5 per cent, alcohol.

Alcohol is important because of: ,

1. Its local irritant action.

2. Its action on the central nervous system.

3. Its destructive action on the tissues.

4. Its supposed food value.

A study of these properties places alcohol among drugs and
poisons rather than among foods.

When alcohol over 60 per cent, is applied to the skin it tends
to unite with the living protoplasm and the reaction produces
redness, itching and a sense of heat. On mucous membranes
and especially on abrasions the irritant action is much greater.
If applied to blood or protein solution, alcohol over 60 per cent,
will cause precipitation on standing. This union with protein
confers astringent properties on alcohol. Alcohol, however,
even in strong solutions (90 per cent.) may be slowly injected
into the blood stream without causing precipitation, since the
circulation causes it to be rapidly diluted. On the cerebrum

ALCOHOL 21

alcohol depresses progressively the psychic, sensory and motor
functions. It attacks the brain functions in the reverse order of
their evolution. The sense of judgment, attention, perception,
reflection, and logical sequence are first to be depressed. The
apparent stimulation being due to depression of the controlling
function. There is no stimulation of the intellectual faculties,
as shown by psychological tests of accuracy, rapidity, or mental
exercise. There is no stimulation of the motor areas of the brain
as shown by response to electrical stimulation of the areas.
There is no stimulation of the medulla as judged by effect on
blood pressure, heart and respiration. There is no stimulation
of the cord as judged from the condition of the reflexes. The
peripheral nerves and nerve endings are depressed and neuritis
may be produced by continued use of alcohol. Bacterial toxins
and heavy metals such as lead and arsenic may cause a similar
neuritis.

The destructive action on the tissues is shown by :

The antiseptic action. The growth of microorganisms is
retarded by all concentrations over 10 per cent. The greatest
effect being manifested by about 70 per cent. This is apparently
due to the fact that stronger solutions cause a precipitation film
on the surface of the organism which retards absorption.

The gastro-intestinal tract especially of the stomach of alco-
holics frequently shows a chronic inflammatory condition.
Nephritis and hepatitis are very common, and neuritis due to
alcohol is relatively frequent.

Alcohol as a food — a great deal can be oxidized in the body and
to that extent it is a food. A dog weighing 25 Ibs. is known to
have oxidized 95 per cent, of 16 grams absolute alcohol in 5J/2
hours. It can also replace fat and carbohydrates to a certain
degree and spare protein waste, but it cannot build up tissue.
Since it is easily oxidized and can supply energy, and prevent
tissue destruction, it may be used as a medicinal food. Its
destructive action on the tissues and its proneness to result in
the formation of a vicious habit, prevent its being classified with
foods.

Offer gives the following experiment on a healthy man to show
the effects of alcohol, as a food :

CHEMICAL PHARMACOLOGY

Gram Nitrogen

Period 1.

Diet alone

Loss, 0.3441

Body nearly in nitro-

genous equilibrium

Period 2.

Diet 100 grams of

Loss, 1 . 1689

Toxic action on tis-

alcohol

sues

Period 3.

Diet 100 grams of

Gain, 0.2335

Tolerance beginning

alcohol

to be established,

and alcohol acting as

a protein-spai in g

foodstuff

Period 4.

Diet alone

Loss, 0.0110

Period 5.

Diet with added fat

Gain, 1.5654

equivalent to 100

grms. of alcohol

The Fate of Alcohol in the Body. — Alcohol is readily absorbed.
Even from the stomach from which absorption is usually slight,
about 20 per cent, of ingested alcohol is absorbed. After ab-
sorption the greatest amounts are found in the blood and central
nervous system. When the blood contains 0.12 per cent, there
is stupor, but as much as 0.72 per cent, has been found in a case of
fatal intoxication. More than six parts per one-thousand in the
blood invariably proves fatal. It is said that if stupor or un-
consciousness after a drinking bout last over 10-12 hours re-
covery rarely takes place. Traces remain in the blood for
twenty-four hours, but over 95 per cent, of the amount ingested
is oxidized. Whether the blood normally contains traces of
alcohol is a disputed question. Traces have been found in normal
blood but there is a question whether or not this was formed
by an abnormal fermentation of carbohydrates in the intestine,
rather than as a normal product of digestion.

B. Fischer reports the following analysis of the alcoholic con-
tent of the organs of a man who died from alcoholic intoxication :

Weight Organ Alcohol

2720 grams Stomach and intestines 30 . 6 grams

2070 grams Blood — heart and lungs 10 . 85 grams

1820 grams Kidneys and liver 7.8 grams

1365 grams Brain 4.8 grams

Ethyl alcohol is recognized by its odor and by chemical tests.

ALCOHOL TESTS 23

Since it distils easily from water solution, if it is in dilute solutions,
as beer, or in colored solutions, as wines, it should be distilled
before testing. The first part of the distillate should be used for
the test.

Chemical Tests for Ethyl Alcohol

1. To a small portion of the distillate add a crystal of potassium
bichromate and a few drops of H2SO4 and warm. The alcohol
is oxidized to the aldehyde and acetic acid with the characteris-
tic odor, and the chromate is reduced giving a green color. Do
not use too much bichromate.

1. K2Cr2O7 + H2S04 = K2S04 + H2Cr207 (H2O + 2Cr03)

2. 3C2H5OH + 2CrO, + 3H2SO4 = 3CH3CHO + Cr2-

(S04)3 + 6H20

2. Lieben's lodoform Test. — To a few drops of dilute alcohol
in a test tube add a crystal of iodine. Warm gently and add
drop by drop KOH until the red color just disappears. Note
the odor. When the sediment has settled examine under the
microscope.

C2H5OH + 41 2 + 6KOH = CHI3 + HCOOK + 5KI + 6H2O.

Bromoform can be prepared in the same way by using bro-
mine instead of iodine. Acetone also gives this test but differs
from alcohol in that it will give it when NH4OH is used instead
ofKOHorNaOH.

3. Ethyl Acetate Test. — Mix equal volumes of alcohol or the
liquid to be tested and concentrated sulphuric acid : About 2 cc.
each. To this add about 0.1 gram dry sodium acetate and heat.
Ethyl acetate is formed if alcohol is present and is recognized by
its odor :

O XOC2H5
1. C2H5 OH + H2SO4 K + H2O

NaHS04

CT
2. CH3COONa + C2H5.O.SO2OH = CH3COOC2H5

There is no evidence that any substance formed in making
these tests is ever formed from alcohol in the body.

CHEMICAL PHAKMACOLOGY

To Determine the Amount of Ethyl Alcohol in Liquors

Place 100 cc. of the liquid in a flask of about 300 cc. capacity.
Add 50 cc. of water. Connect with a condenser and distil over
100 cc. This contains all the alcohol in a water solution. De-
termine the specific gravity of the distillate by means of a pyc-
nometer, Westphal balance, or a delicate hydrometer. Read
the per cent, of alcohol from tables prepared for this purpose.
See U. S. P. IX, page 633. These tables were prepared as fol-
lows: Water has a specific gravity of 1.0000. Absolute alcohol
has a specific gravity of 0.79365, consequently between 0 per
cent, alcohol and 100 per cent, we have a range of sp. gr. of
0.20635. By mixing known amounts of water and alcohol and
carefully measuring the sp. gr. of such mixtures, the tables
were prepared.

Propyl and Butyl Alcohols

Propyl and butyl alcohols are not used in medicine and are of
interest only as impurities in preparations of ethyl alcohol.
Propyl is more powerful in its action than ethyl and butyl still
stronger than propyl. The toxic action increases with increas-
ing molecular weight. This is known as the Rule of Richardson.
There are two propyl alcohols — the normal and the isopropyl.

THERE ARE FOUR BUTYL ALCOHOLS. C4H9OH

B. P.

Specific gravity at 20°

CH3— CH2— CH2— CH2OH

117°

.810

Normal butyl alcohol (primary carbinol)

(CH3)2CH— CH2OH

117°

.806

Isobutyl alcohol (primary isopropyl carbinol)

CH3-CH^CHOH

100°

.808

Normal secondary butyl alcohol (methyl ethyl

carbinol)

(CH3)3COH

83°

.786

Tertiary butyl alcohol (trimethyl carbinol)

BUTYL ALCOHOLS 25

The normal alcohol when oxidized gives propionic aldehyde and
acid, while oxidation of isopropyl alcohol gives acetone.

CH3— CH2— CH2OH -» CH3— CH(OH)— CH3

Primary propyl alcohol (normal) Secondary propyl alcohol (iso-
propyl alcohol)

Normal butyl occurs in traces in fusel oil. It is also produced
by Bacillus butylicus when grown on glycerine and various
sugars, but it has little biological importance. The toxicity of
these and other alcohols on fish has been studied by Picaud who
gives the relative toxicity as follows :

Methyl . 66

Ethyl 1.00

Propyl 2.00

Butyl 3.00

Amyl 10.00

On the isolated mammalian heart Hemmedter found that the
pumping power as measured by the amount expelled in 30 sec-
onds was reduced by the various alcohols as follows:

Methyl 19 cc.

Ethyl 17 cc.

Propyl 79 cc.

Butyl 161 cc.

Amyl 323 cc.

Isopropyl is more toxic than normal, but normal butyl is
more toxic than isobutyl. Alcohols with branched chains are
less toxic than those with straight chains.

Amyl alcohols:

Only primary isobutyl carbinol and secondary butyl car-
binol, are important in pharmacology. Ordinary amyl alcohol
is a mixture of these. Both occur in fusel oil, and are
formed through the life processes of the yeast cell and are
derived from proteins. Consequently where a fermentation
mash contains proteins, as when grain and potatoes are used,
more amyl alcohol is produced, than in the preparation of rum
or brandy where the mash contains less protein. Yeast may

CHEMICAL PHARMACOLOGY

Amyl Alcohol or Pentyl Alcohol

(Amylum-starch)
THERE ARE EIGHT AMYL ALCOHOLS

B. P.

Specific
gravity at
20°

1. Normal primary (butyl carbi-

nol

CHs— CH2— CH2— GHz— CH2OH

138°

.817

2. Isobutyl carbinol (primary)

CHs\

/>CH— CH2— CH2OH

130°

.810

CH/

3. Secondary butyl carbinol (pri-
mary) (active amyl alcohol). .

CHsx
^>CH— CH2OH

128°

.816

CHa — Cxi2

4. Tertiary butyl carbiiiol (pri-
mary)

CH3\
CHsr^C— CH2OH

113°

CH/

5. Methyl propyl carbinol (secon-

CHs\

dary)

/CHOH

119°

CHs— CHz— CH/

6. Methyl isopropyl carbinol (sec-

CH3\

ondary)

CH3v j>CHOH

112°

.819

CH3/

7. Diethyl carbiuol

CHs— CH2v

yCHOH
CHs— CH/

117°

8. Dimethyl ethyl carbinol (ter-

CH3\

tiary)

CHs-^C — OH

102°

CHs— CH/

produce amyl alcohol from its own protein consequently, all
yeast alcohols may contain amyl alcohol. The specific constit-
uent of the protein from which amyl alcohol is prepared appears
to be leucine and isoleucine. Ehrlich, using a pure culture of
yeast, found that when this acted on a sugar solution contain-
ing leucine it readily yielded isoamyl alcohol and isoleucine
yielded amyl alcohol. The reactions are represented as follows:

(1) (CH3)2.CH.CH2CH(NH2).COOH+ H2O = (CH3)2.CH.

CH2CH2.OH + C02 + NH3
Leucine Isoamyl alcohol

(2) CH3.CH(C2H6).CH.(NH2).COOH + H2O = CH3.CH(C2H5.

CH2OH + C02 + NH3
Isoleucine d-amyl alcohol

The amyl alcohols are colorless oily liquids insoluble in water,

AMYL ALCOHOL 27

with a disagreeable characteristic odor and acrid taste. Their
action in general resembles ethyl alcohol but they are about four
times as toxic. They are more locally irritant, and some authori-
ties state that the effect of chronic use is more deleterious than
in the case of pure ethyl alcohol.

Fusel oil is to some extent used in the preparation of essences
and perfumes, and exerts an influence on other perfumes. The
essential oils and aromatic substances develop their finest odors
in alcohol from a special source. In some cases such alcohols are
treated with charcoal which removes most of the fusel oil, the
remaining traces act with other aromatic bodies to produce a
harmony which cannot be reached by any other alcohol. Ehr-
lich points out ^hat "the great variety of the bouquets of wine
and aromas of brandy, cognac, arrak, rum, etc. may be very
simply referred to the manifold variety of the proteins of the raw
materials (grapes, corn, rice, sugar cane, etc.) from which they
are derived."

When oxidized, amyl alcohol is converted into valerianic acid

(CH3)2CH.CH2COOH

which majr be recognized by its odor.

TESTS

1. To test ordinary alcohol for fusel oil constituents: Mix
10 cc. of alcohol with 5 cc. of water and 1 cc. of glycerine and
allow the mixture to evaporate spontaneously from a piece of
filter paper. No odor should be perceptible when the last traces
of alcohol leave the paper. Compare this with a similar solution
to which 1 cc. of amyl alcohol has been added.

2. Warm 1 cc. of amyl alcohol with 2 cc. of concentrated
H2S04. A rose red color is produced.

3. Heat 1 cc. of amyl alcohol with 1 cc. H2S04 and a little
sodium acetate. Amyl acetate is produced which has a strong
smell of pears and is known as pear oil.

4. Heat 1 cc. of amyl alcohol with 1 cc. H2S04 and a
small crystal of potassium bichromate; valerianic aldehyde

CH3(CH2)3C\' is formed. This has a peculiar characteristic

XH
odor.

28 CHEMICAL PHARMACOLOGY

Valeric or valerianic acid (CH3(CH2)3COOH) is the acid cor-
responding to amyl alcohol, just as acetic is the acid of ethyl
alcohol. There are four possible isomerides of valeric acid.
The normal vaLeric acid is N. propyl-acetic acid CH3CH2CH2.
CH2.COOH.

Valerian, which is used in medicine in .cases of hysteria and
other functional nervous trouble contains valerianic acid as the
active or odoriferous principle. The action in these cases is
psychic, and due to the impression made by the odor.

DIHYDRIC ALCOHOLS

These are of no pharmacologic interest except in illustrating
the influence of the change of the molecule on its physical and
physiological actions. The only dihydric alcohol that is used
at all is glycol or ethylene glycol,

CH2OH

I
CH2OH

Do not confuse this with glycocoll (p. 67). The two hydrox-
yls here render the substance more soluble in water and less
soluble in other liquids, hence lessen the physiological activity
(See Meyer and Overton theory of narcosis). The introduction
of OH groups in this series also increases the sweetness of the
substance. Glycerine contains three OH groups and glucose five,
and they are sweeter in about this proportion. This is still more
strongly emphasized under trihydric or triatomic alcohol-
glycerine.

Glycerine, which contains three hydroxyl groups is still less
active, and glucose, which is an hexatomic alcohol, is not toxic.
In fact, sugars are classified as foods rather than drugs.

Ethylene ' glycol is a thick, colorless, syrupy liquid with a
sweet taste (Greek, "glykys" meaning, sweet, and "ol,"
alcohol). It boils at 197.5° and mixes with water and alcohol
in all proportions. It was formerly recommended in the treat-
ment of tuberculosis, but is now considered worthless for this
purpose.

Glycol is formed when choline is heated :

GLYCOL 29

CH3 CH2.CH2OH

\ /

CH3— N— OH • -- > CH3 — N + CH2OH

CH3 CR CH2OH

Choline Tri-methylamine. Glycol
Nitric acid oxidizes glycol to oxalic acid :

CH2OH CHO CHO COOH

CH2OH CH2OH CHO COOH

Glycol glycolaldehyde glyoxal oxalic acid

These products are formed when glycol is oxidized in the body.
Oxalic acid is also formed from cellulose on treatment with caustic
potash, but it is doubtful if any such action occurs in the animal
body.

Glycolaldehyde is one of the products of the oxidation of
dextrose with alkalies and is thought by some to be formed in
the oxidation of sugars in the body.

TRIHYDRIC ALCOHOLS

Of trihydric or triatomic alcohols, glycerine only is important.
It is used extensively in medicine.

CH2OH
CHOH

CH2OH

It has a strong avidity for water, and because of this when applied
to mucous membranes it is irritating. All ordinary fats are
esters of glycerine and a fatty acid. Glycerine is sweeter than
gilycol and is the only trihydric alcohol found in nature.

Chemical Tests

1. Test the solubility of glycerine in water, alcohol, and ether.
The increase in hydroxyl groups, as a rule, decreases the solu-
bility in ether, and increases the solubility in water. Compare
this with other alcohols.

30 CHEMICAL PHARMACOLOGY

2. Taste alcohol, glycol, glycerine, and glucose. The hexoses
are alcoholic compounds. Increasing the hydroxyl groups is in
some way connected with the sweet taste, though not absolutely
essential to the taste, for benzosulphinidum, lead acetate, etc.
which have no (OH) groups may be five hundred times sweeter
than sugar (see p. 210).

3. Heat a few drops of glycerine with a small crystal of KHS04
over a free flame. It is dehydrated with the formation of acro-
lein ("Acer, " acrid, and " oleum," oil).

C8H6(OH)S = C3H40 + 2H20 or C8HB(OH)s = CH2 : CH.CHO

+ 2H2O

Glycerine is used to a considerable degree in medicine. It
was formerly recommended in the treatment of diabetes, as a
sweetening agent to replace sugar. It has been found, however,
to be of little use in these cases. In larger doses (5-20 cc.) it
is a laxative, but may produce gastro-enteritis. It is used in
suppositories as rectal enemata in cases of constipation; as a
vehicle or solvent for many drugs, and especially in the glycerites
of tannic acid, starch, and boroglycerine. It has some power as
a germicide, and is used to preserve vaccine lymph. The use of
it in skin diseases combined with substances like benzoin, for
chapped hands, lips, or other parts is common. It has many
other uses in medicine.

HIGHER ALCOHOLS

Cetyl alcohol, CieHssOH, is found in spermaceti, and myricyl
alcohol, CsoHeiOH, in waxes. These alcohols in waxes corre-
spond to the glycerine of ordinary fats; this is the main differ-
ence between the fats and waxes (q.v.). In waxes the fatty acid
ajso is higher in the series (more C atoms) than the palmitic,
stearic or oleic acids of the ordinary fats.

SULPHUR ALCOHOLS OR MERCAPTANS

The sulphur alcohols correspond to the ordinary alcohols in
which (S) takes the place of (0). Ethyl mercaptan is formed
from ethyl chloride and potassium sulphydrate in alcohol solu-
tion: C2H5C1 + KSH = C2H5SH + KC1

The sulphur confers greater chemical reactivity and also greater

GENERAL ACTION OF ALCOHOLS 31

pharmacological activity on the alcohols. While the OH in
ordinary alcohols is replaceable only with Na, or K, the mercap-
tans react also with heavy metals. The name comes from their
reaction with mercury (mereurium captans) :

2C2H5.SH + HgO = (C2H5S)2.Hg + H2O
The sulphur alcohols are not used directly in medicine, but are
used in the manufacture of some medicinal agents. Ethyl mer-
captan is important because it was the first discovered mercaptan,
and because it forms the basis for the manufacture of the sul-
phone group of hypnotics, of which sulphonal or sulphonmethane
is the most important.

THE PHARMACOLOGY OF THE ALCOHOLS IN RELATION TO
THEIR CHEMISTRY

The relative inertness of the paraffins is markedly activated
by the introduction of the OH groups. The monhydric alco-
hols are pronounced narcotics, which action, seems to depend
on the hydrocarbon radical. Thus, CH4 is inert, CH3OH, nar-
cotic. Further oxidation destroys the CH3 groups, and the nar-
cotic action is lost. Ethane CH3CH3 is inert, ethyl alcohol
CH3CH20H is narcotic, while if both CH3 groups in ethane are
oxidized giving glycol, CH2OHCH2OH, it is inactive. All
hydrocarbons are relatively inert except those that are volatile
liquids and have a solvent action.

Propyl [alcohol, CH3CH2CH2OH, is more toxic than ethyl,
but when two more OH groups are substituted for H, as in
glycerol, CH2OH.CH.OHCH2OH, it loses its soporific and toxic
action. In large doses it may produce restlessness, tremors, and
even tetanus. These actions, however, are less than those of
propyl alcohol, and are apparently more on the motor than on
the sensory side of the nervous system.

As the number of carbon atoms in alcohols increases, the toxic-
ity increases. The six carbon alcohols or aldehydes correspond-
ing to the hexanes are highly toxic, while the corresponding
sugars are foods. Thus, normal hexane CH3CH2CH2CH2CH3
is actively intoxicant, producing excitement followed by deep
anesthesia when inhaled. Glucose, CH2OH (CHOH)4CHO, has
no toxic properties in any amount. Secondary alcohols are
more toxic than primary, and tertiary more than secondary.

32 CHEMICAL PHARMACOLOGY

The action of the alkyl radical of the alcohol is especially
noticeable in the tertiary alcohols where it is found that the
larger the alkyl radical attached to the carbon carrying the
hydroxyl, the more pronounced is the action, e.g.,

4 grams of tri-methyl carbinol (tertiary butyl alcohol)

(CH3)3COH, or
2 grams of dimethyl ethyl carbinol

, or

1 gram of tri -ethyl carbinol (C2H5)3COH have about the
same sleep-producing power. A similar characteristic has been'
observed in other compounds.

CH2OH
Glycol, | the dihydric primary alcohol, is inert, but if

CH2OH

alkyl groups are introduced, in place of the hydrogen attached
to the carbon, substances known as pinacones are formed (Gr.
pinax, pinak tablet). It has been found that 10 grams of methyl
pinacone '

(CH3)2COH (C2H6)2COH

(CH3)2COH °r L5 gramS °f ethyl pmaC°ne' -(C2H6)8COH

have about the same sleep-producing or depressing action.

These examples show clearly the pharmacological action of
alkyl radicals, which are hypnotics or depressants of the central
nervous system, and the greater the molecular weight the greater
the depression produced.

IV. ANESTHETICS, NARCOTICS, SOPORIFICS,
HYPNOTICS

The alkyl radicles are nerve depressants, and affect the cere-
brum especially. According to the degree of depression pro-
duced, several terms are used to define the condition.

Hypnotics, soporifics or somnifacients are used to produce
sleep. Alcohol, ether, or chloroform, in the proper dose may be
used, but more often milder bodies such as chloral, paraldehyde,
the sulphones, veronal, or similar drugs are used.

Narcotics produce a condition of narcosis or coma. The
depressant action is more profound than the hypnotic state and

ANESTHESIA

may be produced by larger amounts of the same drugs. In
addition to the aliphatic narcotics mentioned, urethane and
morphine readily produce narcosis. The aliphatic anesthetics
most used are ether, ethyl chloride, and chloroform. Nitrous
oxide, although not an aliphatic preparation is usually studied
with them. The action of each of these is practically the same
as alcohol, but the stages of the action are more prolonged in
alcohol intoxication. Some stages in general anesthesia pro-
duced by ether or chloroform may be so fleeting that they are
difficult to observe.

Four distinct stages may be observed following the administra-
tion of the aliphatic narcotics and hypnotics.

Dixon gives the stages with the symptoms of ether anesthesia
as follows :

Stage I.

Disorganized
consciousness

and
analgesia

Stage 2.

Excitement
and

Unconscious-
ness

Irritant action of the vapour on the nasal and

bronchial mucous membrane.
Reflex effects — coughing, salivation, respiratory,

cardiac.

Disturbances of judgment.
Loss of memory and self-control.
Emotional tendencies.
Disturbances of special senses.
Analgesia.
Vertigo and ataxia.

Quickened pulse and rise in blood-pressure.
Increased respiration.
Dilated pupils.

Coughing, retching, vomiting.

Delirium varying from shouting to inarticulate

muttering.

Tonic, and clonic muscular spasm.
Reflexes diminished.
Unconsciousness.

Respiration irregular from the struggling.
Pulse accelerated and pupil dilated, both from

excitement.

CHEMICAL PHARMACOLOGY

Stage 3.

Surgical
Anesthesia

Stage 4.

Leading to
Bulbar para-
lysis

Muscular relaxation.

Loss of reflexes.

Breathing regular, often " snoring."

Decrease of respiratory exchange.

Fall of temperature.

Fall of blood pressure.

Pupil small; does not react to light.

Loss of bladder and rectal reflexes.

Paralysis of vaso-motor centre (great fall of

. blood-pressure).
Paralysis of respiratory centre.
Widely dilated pupils.
Great depression of cardiac muscle.

The amount of chloroform in the blood during light anesthesia
is 25 to 35 mgs. per 100 cc. If the concentration is raised to 40-70
mgs. per 100 cc. respiration fails. During light ether anesthesia
there are 100-110 mgs. per 100 cc., and 130 to 140 mgs. in deep
anesthesia. 160 to 170 mgs. per 100 cc. causes failure of respira-
tion. In deep alcoholic coma in man Sweisheimer found that
the blood contained 2.25 parts per 1000 cc. Grehant found that
6 parts alcohol per 1000 cc. blood was invariably fatal to
animals.

Whether the heart or respiration stops first depends on the
method of administration. Large concentrations especially of
chlorine containing anesthetics, if too quickly administered,
paralyze the heart before respiration. When present in the
respired air, in the per cent, given, Cushny tabulates the differ-
ences between ether and chloroform as follows:

Chloroform Ether

0.5-0.7 per cent. 1.5-2.5 per cent. Insufficient to cause anes-
thesia.

1.0 per cent. 3-3.5 per cent. Causes anesthesia on pro-

longed inhalation.

2.0 per cent. 6.0 per cent. Arrests respiration after

sometime.

ANESTHETICS

The amount of anesthetic in 100 cc. of the blood shows the same
proportion and is as follows:

Chloroform Ether

25-35 mgs. 100-140 mgs. Anesthesia

40-70 mgs. 160-170 mgs. Respiratory arrest.

According to the concentration of chloroform in the respired air,
Rosenfeld gives the following series of experiments to show the
effects :

RELATIONSHIP BETWEEN THE PERCENTAGE OP CHLOROFORM IN THE RE-
SPIRED AIR AND THE DEPTH AND RAPIDITY OF THE ANESTHESIA (ROSENFELD,

SPENZER)
(From Meyer & Gottlieb)

Chloroform

Time necessary

Depth of

percentage in

to induce

anesthesia or

Remarks

respired air

anesthesia

narcosis

0.54-0.69

2 hrs.

No narcosis

Somnolence only.

0.96-1.01

30-40 min.

Complete

Blood-pressure at first nor-

mal then gradual fall for

4 hrs. Respiration nor-

mal.

1.16-1.22

30 min.

Complete

Cessation of resphation at

end of 2 hrs.

1.41-1.47

37 min.

Deep

As above after 1 hr.

1.63-1.65

12 min.

Deep

As above after 30 min.

Ether

percentage in

respired air

1.5

2 hrs.

Hardly any

Slight somnolence only.

2.5

Very incom-

Reflexes maintained.

plete

3.2-3.6

25 min.

Complete

Respiration and cardiac

function remained good

for hours.

4.45

15 min.

Complete

Respiration slow and regu-

lar; pulse accelerated.

6.0

Respiration ceased in 8-

10 minutes.

36 CHEMICAL PHARMACOLOGY

THEORIES REGARDING THE CAUSATION OF ANESTHESIA

Both chemical and physical theories have been advanced
to explain the action of ether and chloroform in producing
anesthesia.

1. The Meyer-Overton Theory. — Meyer and Overton think
that anesthesia is due to the solvent action of the anesthetic on
the lipoids of the central nervous system. The anesthetics are
also somewhat soluble in water, and the anesthetic value depends
on the distribution, coefficient, i.e. the ratio of the solubility
in fats (S/F) to the solubility in water (S/W). The most power-
ful anesthetics are very soluble in fats and but little soluble in
water. Meyer studied many aliphatic narcotics and arranged
them in the order of their potency. These are expressed in the
fractions of normal solutions, that will produce the first definite
physiological effect, which he calls the liminal value.

Liminal value in
terms of normal
solution

Distribution SF
Coefficient SW

Trional

0.0018

4.46

Tetronal

0.0013

4.04

Sulphonal

0.006

1.11

Butylchloral hydrate

0.002

1.59

Bromal hydrate

0.002

0.66

Chloral hydrate

0.02

0.22

Ethyl methane

0.04

0.14

Methyl methane

0.4

0.04

Monacetin

0.05

0.06

Diacetin

0.015

0.23

Triacetin

0.01

0.3

Chloralamide

0.04

Chlorhydrin

0.04

Dichlorhydrin 0.002

While this theory is attractive, it merely explains how the
drug gets to the place of action, and Cushny has pointed out
that some benzene derivatives are good lipoid solvents and have a
high distribution coefficient, yet are without narcotic action.
Again cells rich in lipoid substances are not always attacked in
relation to this substance. The peripheral nerves are much less

ANESTHESIA 37

influenced than the central nervous system. Baumann and Kast
give the following table to show that narcotic action depends
on the presence of ethyl radicals.

Action Distribution
Coefficient

Dimethyl-sulpho-me thane very slight . 106

Dimethyl-sulpho-ethane. slight .151

Sulphonal (Diethyl sulphone dimethyl methane) marked 1. 115
Trional (Diethyl sulphone methyl ethyl methane)

more marked 4.46
Tetronal (Diethyl sulphone diethyl methane) more marked 4 . 04

2. The Theory of Moore and Roaf.— They believe that the
action of the anesthetic is due to a loose combination of the anes-
thetic with the cell proteins. A certain concentration of the
anesthetic in the blood is necessary to maintain the combination.
Lipoids may aid in keeping the necessary concentration of the
anesthetic around the living protein, and to this extent the
Meyer-Overton theory may hold.

3. Verworn's Theory. — He accepts the Meyer-Overton theory
to some extent, but believes that the fundamental action is the
prevention of oxidation by the cell. In the last step anesthesia
is an asphyxiation. Due to the presence of the anesthetic the
nerve cells cannot utilize the oxygen that may be present.

Many other theories have been presented but none are entirely
satisfactory. In this connection it should be mentioned that
physiologists have been unable to present a satisfactory theory
to explain natural sleep.

The Hyderabad Commission — 1889 and 1890

Because of the difficulty of handling ether in hot climates
such as India, the Nizam of Hyderabad caused an investigation
to be made of the relative values of ether and chloroform as
anesthetics, especially with reference to the action on the heart.
The commission concluded after numerous experiments that
the only means by which the heart's safety is jeopardized is
through paralysis of respiration. Accordingly respiration always
stops first. This report is both right and wrong. According to

CHEMICAL PHARMACOLOGY

the conditions of their experiments, where the anesthetic in
the respired air is dilute and gradually increased, respiration
stops first. If, however, the concentration in the respired air
is too great at the beginning, or is quickly increased, the heart
may stop first due to direct action on and paralysis of the heart
muscle. It is quite possible, therefore, to have either respiration
or heart stop first, or both at the same time. Consequently,
therefore, in giving an anesthetic, it is necessary to watch both
heart and respiration.

The relative toxicity of ether and chloroform on the heart
was found by perfusing the isolated heart through the coronary
vessels. To stop the heart's action 0.015 per cent, chloroform
or 0.4 per cent, of ether was required. This indicates that
chloroform is about 25 times as toxic as ether. On the respira-
tory center chloroform is about 4 times as toxic as ether.

Ether and chloroform are excreted mainly by the lungs. Ether
is excreted only in this way. Small amounts of chloroform have
been found in the urine and milk, but the statement that some
carbon monoxide is formed from chloroform in the body is
erroneous. Chloroform may be detected in the breath for 24
hours after narcosis. Nicloux gives the following figures to show
the disappearance from the blood.

CHLOROFORM CONTENT OF BLOOD AFTER TERMINATION OF ANESTHESIA

Time elapsed since termination of anesthesia

Per cent,
form i]

of chloro-
i blood

Exp. 1

Exp. 2

0 minutes

0.054

0.0595

5 minutes
15 minutes.

0.0255
0 . 0205

30 minutes

0 018

0 023

1 hour
3 hours

0.0135

0.018
0.0075

7 hours.

0 0015

Ether is eliminated somewhat more rapidly, which explains
the more rapid recovery from ether narcosis.

ETHER ANESTHESIA 39

ETHER CONTENT OP BLOOD AFTER TERMINATION OP ANESTHESIA

Per cent, of ether
in blood

Exp. 1

Exp. 2

0 minutes

0.115
0.071
0.063
0.052
0.025

0.159
0.108
0.080
0.058
0.021
0.004

3 minutes

5 minutes

15 minutes . . . • .

1 hour

2 hours . ....

ETHER OR ETHYL OXIDE

Ether is prepared by mixing alcohol and sulphuric acid and
distilling. The following formula indicates the reaction.

c2H5oH

so4 =

C2H5OH + C2H

H
C2H

>O + H2S04

Ether used for anesthesia is chemically pure ethyl ether.

CHEMICAL TESTS

1. Specific gravity 0.713 to 0.716 at 25°C. Boils at 35°C.
which is below body temperature (37°C.)

To show inflammability of ether apply a flame to 1 cc. of it in
a small dish. Repeat this with chloroform.

2. Shake ether with an equal volume of CS2. The mixture
becomes turbid if the ether contains water, not otherwise. Ether
will dissolve about 10 per cent, water. Anilin violet colors ether
which is adulterated with alcohol, but does not the pure ether.

3. Shaken with J-fo volume of 5 per cent. KOH, no color
should be developed in either liquid in the absence of aldehyde.

4. Ether is miscible with alcohol, benzine, chloroform, benzene,
fixed and volatile oils, and lipoids in all proportions. Test the

40 CHEMICAL PHARMACOLOGY

solubility of oils, fats, lanolin, and other lipoids in ether. Cf. the
Overton-Meyer theory of Narcosis, p. 36.

5. Na will not act on dry ether due to the absence of hydroxyl.

6. Strong acids decompose ether with the formation of ethereal
salts. The action of H2S04 on alcohol is much more complete.
Similarly in the body, ether is excreted unchanged, while alcohol
is almost completely oxidized.

The replacement of the hydrogen hydroxyl in alcohol results
in marked physical and chemical changes. C2H50C2H5 is much
more volatile than C2H5OH. The more volatile a substance the
more quickly it penetrates, consequently it acts more quickly
when taken, into the body.

In the body, alcohol is rapidly and almost completely oxidized.
Ether is not oxidized in the body, but is a catalytic poison, i.e.,
it causes a marked reaction by action in the body without itself
undergoing any change. When oxidized outside the body it
yields the same products as alcohol. Ethers of the marsh-gas
series are always more active than the corresponding alcohol.

CH2OH
Glycerine — CHOH is inert, but when converted into glycerine

CH2OH
ether

CH2— 0— CH2
CH — 0— CH
CH2— 0— CH2

it becomes narcotic. The narcotic action of the alkyl radical
is manifested in other compounds. Phenol CeHsOH which is
antiseptic and stimulating to the motor side of the cord loses its
antiseptic and stimulating action when converted into phene-
tol, C6H5.O.C2H5.

NH3, which is stimulating, loses its convulsant action as the
hydrogen atoms are replaced by alkyls and the quaternary
ammonium bases have a curara-like action.

Urea also becomes depressant when alkyl groups are sub-

NH2 N(C2H5)2

stituted for H, as when C0<^ becomes

XNH2

These examples again show the depressant and hypnotic action
of the alkyl groups.

HYPNOTICS 41

A ETHYL CHLORIDE

Ethyl chloride, C2H5C1, is prepared bypassing HC1 gas through
alcohol in which anhydrous ZnCl2 is dissolved, the ZnCl2 acting
as a catalytic and dehydrating agent. At ordinary temperatures
it is a gas which boils at 12.5°C. It is freed from HC1 by passing
through water.

This compound, like chloroform, illustrates the influence of
introducing Cl into the molecule. It is twice as soluble in water
as in the blood, and is sometimes used as a general anesthetic,
especially in nose and throat work. It has a greater paralytic
action on the heart muscle than ether, but much less than chloro-
form. All anesthetics containing chlorine act strongly on the
heart, as depressants.

Its main use is as a local anesthetic, the action being due to its
rapid evaporation. Freezing with any other agent would have
the same effect.

The most prominent action of the methane group as a whole
is the anesthetic, hypnotic, and analgesic action. The members
of the benzene series on the other hand have a more pronounced
action on the motor side of the nervous system and are antiseptics.

HYPNOTICS AND ANALGESICS OF THE METHANE SERIES

(Hypnos — sleep) (An. without — algos — pain)
These may be divided into:

1. The chloroform group

2. The urethane group

3. The sulphone group

1. The Chloroform Group. — Chloroform, CHC13, is formed by
the action of bleaching powder (a mixture of CaCl2 and CaOCl2)
on dilute alcohol or acetone. The chloroform is distilled off,
washed, and treated with concentrated H2S04 to destroy other
derivatives, and is then rectified. The bleaching powder supplies
chlorine which is an oxidizing agent.

The reactions are complex, and probably as follows :

1. C2H6OH + CaOCl2 = CaCl2 + CH3CHO + H2O

2. 2CH3CHO + 6CaOCl2 = 3CaCl2 + 3Ca(OH)2 + 2C2-

HC130

3. 2C2HC130 + Ca(OH)2 = 2CHC13 + Ca(CHO)2

42 CHEMICAL PHARMACOLOGY

CH3

4. with acetone: />CO + 6CaOCl2 = 2CHC13 +

CH3

2Ca(OH2) + Ca(C2H3O2)2 + CaCl2

Chemical Tests

1. Place 2 cc. of chloroform in a dish and apply flame. Com-
pare with ether and alcohol.

2. Add a few drops of AgN03 to chloroform. No precipitate
if pure. Why? It contains chlorine. Make alkaline and again
heat. Compare with chloral.

3. Evaporate 10 cc. from filter paper on a clean glass slide.
No odor or residue should remain, if pure.

4. A paper dipped in chloroform burns with a green mantle
and HC1 is given off.

5. Test a few cc. of chloroform by boiling with a few drops of
KOH and 0.1 gram of resorcinol. The intense red color is due to
rosolic acid, a derivative of anilin. Chloral gives this same result.

Resorcinol C6H4(OH)2 1:3

Rosolic acid C— C6H4OH

C6H4 = O

In the presence of air, chloroform decomposes slowly into car-
bonyl chloride (phosgene) and HC1.

CHC13 + O = CQC12 + HC1.

The carbonyl chloride is very poisonous. To prevent decom-
position, it should be kept in the dark; and 1 per cent, alcohol
added as a preservative. The action of the alcohol is as follows :

/OC2H5 (ethyl carbonate)
COC12 + 2C2H5OH = C0<^

XOC2H5 -h 2HC1

6. Chloroform is decomposed by passing its vapor through a
hot tube. HC1 is formed which can be recognized by testing
with moist litmus paper, and by the precipitation of AgCl when
passed into silver nitrate solution.

THE URETHANE GROUP 43

7. Phenyl Isocyanide Test. — Add 1-2 drops of aniline and a
few drops of aqueous KOH to the chloroform. Heat gently.
Phenyl isocyanide is produced. This has a characteristic in-
describable repulsive odor. The reaction is:

CHC13 + C6H5NH2 + 3KOH = C6H5NC + 3KC1 + 3H20

Chloral, chloralhydrate, bromoform, iodoform, and carbon tetra-
chloride also give this test. The test is sensitive 1 : 6000.

8. Chloroform will reduce Fehling's solution.

THE URETHANE GROUP OF HYPNOTICS

Urethane: Ethyl carbamate

OC2H5

Urea and alcohol under proper conditions yield urethane. —
/NH2

COC + C2H5OH-»CO<

XNH2 XOC2H5 + NH3

This is soluble in water, a weak hypnotic, and breaks down in

the body to its components, probably by the following mechanism:

/NH2
C0<( + NH3 = C2H5OH + CO

XOC2H5 NNH2

Nearly all substances in the body break down much more

readily into their components than they can be synthesized. In

the formation of urethane, indirect processes must be employed :

Cl
CO -f 2C1 in sunlight->CO<T carbonyl chloride

XC1

Cl Cl

CO<^ + C2H5OH-»CO<^ + HC1.

Cl OC2H5 chloroformic ester

n ,NH2

+ NH3->CO<( Urethane + HC1

'OC2H5 OC2H5

It has been found that the pharmacologic action of the ure-
thanes, like the alcohols, increases with increased molecular
weight, and with the size of mimber of the alcohol radicals, con-

CHEMICAL PHARMACOLOGY

OC2H5

sequently, diurethane, C0<^ is a more powerful narcotic,

OC2H5

than urethane.

Hedonal,

OCH

CH3 which is the ester of

urea and the amyl alcohol methyl propyl carbinol, is more power-
ful than urethane. On account of both the urea and alcohol
content, these drugs are strongly diuretic.

VERONAL

Diethyl malonyl urea, is made from urea, alcohol and malonic
acid, by the introduction of esters of diethyl malonic acid with
urea in the presence of metallic alcoholates. The following
formulae show the principles involved in the formation of veronal,
and the basis for its chemical name :

0<f
X

NH2 NH2

NH2 XOC2H6

Urea Urethane

+ NH3

OC2H5
ethyl
carbonate

.COOH C2H5v /COOH
CH/ + V^ +

XCOOH C2H5/ . XCOOH

Malonic acid Diethyl malonic acid

C2H5

urethane

or ethyl

carbamate

H
HN

C2H5OH

alcohol

= 0

urea

CONR

>CO

2H20

Veronal diethyl malonyl urea

SULPHONE GROUP 45

Chemical Tests

1. Prolonged boiling with sodium carbonate liberates NHs.

2. In a solution acidulated with HNOs Millon's reagent pro-
duces a precipitate soluble in excess of the reagent.

3. The melting point of the crystals is 187°-188°C.

4. The presence of N is shown by fusing with KOH or NaOH
and making the Prussian blue test, p. 8.

THE SULPHONE GROUP OF HYPNOTICS
O OH

Sulphuric acid may be written ">S<\ . The replaceable

hydrogen is not directly attached to the sulphur. When salts
are formed, the replacing metal or radical is also not directly at-

0 ,0— R
tached to the S, but to the oxygen : ^ S<^

</ X0— R

Similarly, in ethyl sulphuric

OC2H5

or phenyl sulphuric 02SC (combined or etheral

XOC6H5

sulphates), the radical is not attached directly to the sulphur
atom. These bodies are inert and phenyl sulphuric acid occurs
normally in the urine up to 0.6 grams per day.

Sulphonic acids are compounds in which the carbon of the
organic radical present is in direct union with the sulphur; the
relation between ethyl sulphuric acid and ethyl sulphonic acid
is shown by the formulae :

C2H50 ,0 C2H. ,0 C^CKZ

o HC

ethyl sul- ethyl sulphonic acid

phuric acid
Where both OH groups of the sulphuric acid are replaced by

radicals, the product is a sulphone : yS02

46 CHEMICAL PHARMACOLOGY

The replaced radical may be methyl, ethyl, or any other alkyl
group.

SULPHONAL

When acetone is mixed with mercaptan in the presence of
HC1 they condense:

,$ — C2H.5

H.SC2H5 = X + H20

O - C_;2iL5

H.SC2H.5

Acetone ethyl acetone-ethyl mercaptol

mercaptan
This can be oxidized by KMnO4 to a sulphone:

202 =

This is acetone diethyl sulphone or sulphone methane or
diethyl sulphone dimethyl methane : The name is shown by the
following steps:

1. H H

C (methane)

H H
2. CH

= 0 (acetone or dimethyl oxymethane)

3. CH.3. .SC2H5

y>C<^ (acetone ethyl mercaptol or dimethyl

CH3 SC2H5 diethyl mercaptol methane)

4. CR3 S02C2H5

yC<^ (dimethyl methane diethyl sul-

CH3 o02C2H5 phone or sulphonal).

TRIONAL

This differs from sulphonal in that one of the CHa groups is
replaced by ethyl C2H5:

consequently it is diethyl sulphone

2C2H6

ethyl, methyl methane. It melts at 76°.

THE SULPHONE GROUP 47

TETRANOL
This has all the replaceable hydrogen occupied by ethyl groups :

/~i TT ^d r*\ TT

and is diethyl sulphone diethyl meth-

\02C2H5 ane'

Since the pharmacological action of hydrocarbon radicals
increases with the size of the molecule, we should expect trional
to be more active than sulphonal. While this seems to be true
for dogs, it does not seem to hold good for human beings. It
should be emphasized that CH.3, or the first of the series, is
nearly always an exception to the rule, both chemically and
pharmacologically.

Sujphones are not true esters, but bodies of remarkable sta-
bility. They cannot be reduced to sulphides by nascent hydro-
gen. However, their stability outside the body is no criterion
of their pharmacological activity; since some of those that are
most stable are physiologically reactive and more or less de-
composed in the body, while some less stable outside the body
pass through it unchanged and are inert pharmacologically.

Ethylene diethyl sulphone:

CH.2-S02C2H5 i ,1 i J302C2H.5 .,

and methylene p^r / are easily

di-ethyl sulphone 2\on ^ TT decomposed

by alcoholic potash, but may be found unaltered in the urine, and
are only slightly active physiologically, whereas, sulphonal,
trional and tetronal, which are unacted on by alcoholic potash,
acids, and many oxidizing and reducing agents, are decomposed
in the body to some extent at least and are actively hypnotic.

Chemical Tests

Test solubility of each in water, alcohol, and ether.

Heat 0. 1 gm. of each separately with an equal amount of char-
coal in a dry test tube. Each one will be reduced to the sulphur
alcohol which is recognized by its odor, which is, similar to
garlic.

Heat another portion of fusion in a test tube alone, S02 is
given off and will bleach starch iodide, or methylene blue
paper.

48 CHEMICAL PHARMACOLOGY

V. ALDEHYDES

Aldehydes are the first oxidation products of primary alcohols.
Primary alcohols contain the group R, CH2OH. Aldehydes

0
contain the group RC<^ . Where R may be H, CH3, C2H5,

or any member of the marsh gas series. In the case of phenol
groups with an aldehyde side chain, almost any complex may take
the place of (R).

Aldehydes may be prepared:

1. By the oxidation of any primary alcohol;

CH3CH2OH + 0 = CH3— C/ + H20

2. C6H5CH2OH + 0 = C6H5— C/ + H20

XH
benzyl alcohol benzaldehyde

3. By dry distillation of a calcium salt, with calcium formate:
Ca(CH3COO)2 + Ca(H.COO)2 = 2CH3CHO + 2CaC03 or

(C6H5COO)Ca + Ca(HCOO)2 = C6H5COH + 2CaC03

The mechanism of the reaction may be represented;

HCOONa

Any other method of oxidizing an alcohol or reducing an or-
ganic acid may yield an aldehyde.

General Properties of Aldehydes. Reactions. — The char-

O
acteristic reactions are due to the group — R — C^ which shows

XH
exceptional chemical reactivity: the H atom in combination

with — C^ can be readily oxidized, by the action of oxidizing
XH

ALDEHYDES 49

reagents. Since they are readily oxidized, aldehydes act as
reducing agents; and when they are added to an ammoniacal
solution in a test tube of silver nitrate the silver is precipitated
as a silver mirror. For the same reason, they reduce Fehling's
solution.

They form addition products readily. This is due to the
C = 0 group which opens up in the form : C — 0 and the free

\ \
valences add anything in the form of H and X as follows :

CH3C<f

XH XH

(a) For this reason, they are easily reduced by nascent hydro-
gen the same primary alcohol from which they were derived
being formed —

0 /OH

CH3C< + H2-^CH3C^H
XH XH

(6) When shaken with a saturated solution of sodium acid
sulphite, a crystalline addition product is formed.

/° I

CH3C<f + NaHS03-»CH3— O-OH

XH XS03Na

On heating this product with acid aldehyde is again liberated.
(c) Aldehydes unite with ammonia to form aldehyde ammonia

CH3C( + NH3 = CH3— C— 0-H
H |

NH2

Similarity with hydroxyl amine, NH2OH, hydrazines, etc.,
addition products are formed, the added product always breaking
or ionizing into H and X. The H adds to the O of the
aldehyde, and the X to the carbon.

50 CHEMICAL PHARMACOLOGY

Caustic alkalies differ from ammonia in their action on
aldehydes. Instead of forming a definite compound they
convert the lower aldehydes into resinous bodies of unknown
composition.

Formaldehyde H — C\ (Methanal) is the aldehyde of

methyl alcohol CH3OH + O = CHOH + H2O. At ordinary
temperatures it is a gas and liquefies at (minus) — 21°C. It
may be prepared easily by heating a copper spiral and dropping
it into methyl alcohol in a test tube. It may also be formed in
the body from methyl alcohol. It can also be derived from hydro-
gen and carbon monoxide under the influence of an electric cur-
rent. At 600°C. it is dissociated into CO and H2. Minute
amounts of it are found in plants where it is highly important, from
a theoretical point of view, in the formation of carbohydrates.
The steps involved may be represented by the following reactions :
(Baeyer)

1. CO2±=»CO + O

2. H2O-»H + OH

3. CO + H2-»CH20

4. 6(CH20)^C6H1206

or carbon dioxide and water may react:

C02 + H20 =CH20'+ 02

In combination with ammonia it forms hexamethylenamine or
urotropine. When it is evaporated on a water bath, it polymerizes
to form paraformaldehyde (CH20)2. Trioxy methylene (CH2O)3
is a white crystalline compound that separates from formalde-
hyde on standing. It liberates formaldehyde again when it is
heated.

Formaldehyde unites with amines, ammonia, sugars, dextrins,
urea, tannic acid, proteins, and many other substances. It
is therefore, a strong antiseptic, a local irritant and a general
protoplasm poison, yet it is surprising how much of it may be
injected intravenously into an animal without killing it. The
reason being that it is oxidized or polymerized rapidly in the body.
Even though it does not kill, it may produce a severe nephritis.
The irritation is probably produced by the union with an amine
group of the proteins.

ALDEHYDES 51

The amine and aldehyde groupings may exist in the living pro-
toplasm simultaneously. Loew explained the difference between
living and dead protoplasm on a rearrangement of such a grouping.
In the living or labile molecule or biogen he assumed the group-
ing to be:

I
-C— NH2

In the dead or stable form

I
— C— N— H

=C— C— OH
H

such a difference of course would be very difficult to prove.

Formaldehyde is valuable in medicine chiefly as an antiseptic,-
disinfectant, preservative and cauterizing agent. A solution of
37 per cent, by weight is known commercially as formalin.

On account of its relative physiological inertness and great
antiseptic powers, in vitro, it was thought that formaldehyde
might be injected into the veins with benefit in cases of tuber-
culosis and other infections. It is now known, however, that it
is rather inert in the body because it is rapidly oxidized, and for
this same reason it possesses relatively little antiseptic action
in the body. In addition it shows no specificity. When the
concentration in the body is sufficient to exert an antiseptic ac-
tion, it will injure the tissues of the body just as readily as the
bacteria within the tissues. Compounds of formaldehyde like
hexamethylentetramine, that are decomposed in the body and
excreted in the urine, are valuable in cases of infection of
the genito-urinary tract and bladder. The concentration of
the aldehyde in the urine is much greater than it is in the
blood.

52 CHEMICAL PHARMACOLOGY

Tests for Formaldehyde

In solutions which are not clear, or in food products which are
to be tested for its presence it is necessary in many cases to distil
and test the distillate from 100 to 200 grams of the substance
which has been acidified with phosphoric acid. Phosphoric acid
is used because it is a non-volatile acid and will not appear in the
distillate.

1. Add to the formalin solution, diluted if necessary, about 1 cc.
of pure milk or a solution of peptone. Add 1-2 drops of 1 per
cent, ferric-chloride solution. Carefully pour this solution into
a test tube containing about 10 cc. of strong H2S04. See that
the two solutions do not mix. At the point of contact a violet
or blue ring will appear. If the solution containing the
formaldehyde is too strong, the result will not be so clear. If
the milk contains less than 1:10,000 formaldehyde, the color
may not appear for some time.

2. To the milk or peptone solution containing the formalin add
double the volume of strong HC1 containing 1 cc. of 10 per cent.
Fe2Cl6 in each 500 cc. of acid. Heat to 80° to 90°C. in a white
dish giving it a rotary motion to cause mixing. A violet color in-
dicates formaldehyde. To test a suspected milk for formalin,
use this same procedure. If the milk has stood for a long time,
it may be necessary to distil it, as a firm combination of the
formalin with the protein prevents the test to some extent.

3. Lieberman's Test. — Mix some of the watery solution of
formalin with a drop of 1 per cent, phenol and pour cautiously,
on some concentrated H2S04 in a test tube. A crimson zone at
point of contact indicates formaldehyde.

The Cannizzaro Reaction. — In the body, if formalin be given
intravenously, there is both oxidation and reduction of it with
the formation of methyl alcohol and formic acid :

/°
2HC/ + H20 = CH3OH + HCOOH

The presence of HCOOH may be shown by collecting the urine,
reducing it with hydrogen and testing for formalin.

4. Rimini's Method. — To 15 cc. of the solution to be tested
add 1 cc. of a dilute solution of phenyl hydrazine hydrochloride,

FORMALIN TESTS 53

then a few drops of 1 per cent, ferric chloride solution and finally
concentrated HC1. A rose red color is given by formaldehyde.
Milk can be tested without distillation by this method, but the
test is more delicate if a distillate is used. Acetic aldehyde or
benzaldehyde do not interfere with the test.

5. Phloroglucinol Test (Jorissen).

Take phloroglucinol 0.1 gram
NaOH 2.0 gram

Aq. q.s. 10.0 cc. Make solution

To 10 cc. of milk or other fluid to be examined, add 2 .cc. of this
reagent by means of a pipette, placing the end of the pipette at
the bottom of the tube in such a manner that the reagent will
form a separate layer. A bright red color, not purple, is formed
at the zone of contact, if formaldehyde be present. Some other
aldehydes, give a yellow color. The red color forms quickly and
soon fades.

6. Phenylhydrazin HC1 Method. — Mix 5 cc. of the solution
to be tested with 0.03 gram of phenylhydrazine hydrochloride and
4 to 5 drops of a 1 per cent, solution of ferric chloride. Keep the
test tube containing this in cold water and add slowly with con-
stant shaking to prevent heating, 1 to 2 cc. of concentrated
H2SO4. A precipitate is formed which can be redissolved by the
addition of either alcohol or H^SCh; giving a red color. The
alcohol extract of anything to be tested will also give the
reaction. This test has been found to give reliable reactions in
a dilution of 1 to 150,000 formaldehyde. Acetic aldehyde or
benzaldehyde, does not interfere.

7. Phenylhydrazine Hydrochloride and Ferrocyanic Method.
This method can be applied directly to aqueous solutions or
aqueous alcoholic extracts. To from 3 to 5 cc. add the size of a
pea of phenylhydrazin hydrochloride and 2 to 4 drops (not more)
of a 5 per cent, to 10 per cent, solution of potassium ferrocyanide
and from 8 to 12 drops of 12 per cent. NaOH. A distinct green
or bluish green reaction is obtained in a dilution of 1-80,000
formaldehyde.

Acetic and benzaldehyde give a color from red to brown and
mask the formaldehyde reaction. It is characteristic only when

CHEMICAL PHARMACOLOGY

a clear green color is obtained. The method is not applicable
where blood coloring matter is present, but can be used with milk
directly.

HEXAMETHYLENAMINE

Formaldehyde reacts with ammonia to form hexamethylen-
amine. The reaction is 6CH2O + 4NH3 = (CH2)6N4 + 6H2O.
This is represented as —

1. CH

.CHo
<CH2

F— CH2

CH:

CH.

CH<

It is a feebly basic crystalline solid, which dissolves readily in
water.

Hexamethylenamine is a valuable remedy in some cases of
cystitis and infections of the urinary tract. It has also been
used in laryngitis, pharyngitis, poliomyelitis, etc. It has but a
slight irritating action, and only when taken in excessive amounts,
does it cause nephritis or other untoward symptom. It is
found on the market under a variety of names such as urotropin,
cystogen, cystamine, hexamine, etc.

It has some solvent action on uric acid, and has been recom-
mended in gout; but the concentrations that dissolve uric acid
never obtain in the organism. It forms a number of additive
products which have been introduced into medicine, such as
amphotropin which is a combination with camphor; cystopurin,
with sodiurn acetate; formurol with sodium citrate; cystazol,

FORMALIN TESTS 55

with sodium benzoate. New urotropin, or helmitol, is anhydro-
methylene citric acid:

CH2 O CO

O -C— CH2— COOH

I
CH2— COOH

None of these compounds have any advantage over hexamethylen-
amine.

1. Mix 0.1 gram each of hexamethylenamine and salicylic
acid. Add 5 cc. H2SO4 and heat moderately. A carmine-red
color is produced.

2. An aqueous solution heated with dilute H2S04 liberates
formaldehyde. If the acid solution is made alkaline with NaOH
and heated gently, NH3 is given off.

3. Test the reaction of urine. Take 5 grains of hexamethyl-
enamine. In 30-60 minutes collect the urine. Note the reaction.
Acidify and distil 10-20 cc. Test the distillate for formaldehyde.
It may not be necessary to distil the urine before testing. Make
the test before distillation and, if in doubt, distil and test.

ACETALDEHYDE, ALDEHYDE OR EtHANAL

CHa — C^ is not used in medicine, but some of its derivatives

paraldehyde, chloral and chloral hydrate are important. From a
purely chemical point of view, acetaldehyde is perhaps the most
important aldehyde. It is a colorless liquid, B. P. 21°, sp. gr. 0.8,
soluble in water, alcohol, and ether, dissolves phosphorus, sulphur,
iodine. It occurs as a by-product in all sugar fermentations.
The following method of preparation illustrates strikingly some
of the characteristic reactions of aldehydes: (after Remsen) :

Place 120 grams of granulated potassium bichromate in a 1 to
2 liter flask A.

(a) Place a stopper with two holes in the flask, and set on
water bath.

(6) Insert a funnel tube in one opening and a condenser in
the other. Elevate the condenser at an angle of 45°, so that it

CHEMICAL PHARMACOLOGY

acts as a reflux. Connect the free end of the condenser by means
of rubber and a glass tube (E) with cylinders F and Gt half-filled
with ether. The glass tubes E and / should dip well into the ether.

Make a mixture of 100 cc. concentrated H2SO4 water 400 cc.
and alcohol 120 cc. Cool the mixture to room temperature and
pour it slowly into the flask.

If the liquid is added too rapidly to the bichromate mixture,
the action may be too violent. Some alcohol may enter the
condenser and flow back again into the flask. The aldehyde is
soluble in the ether. Supply the condenser with water at about

FIG. 1.

30°C. Heat is applied to finish the distillation. After the
reaction is ended, the connections are broken and dry NH3 gas
is passed through the cold ethereal solution of the aldehyde.

Crystals of aldehyde ammonia are deposited. The ether and
the crystals are poured on a filter and the crystals washed with
ether. The pure crystals are then placed in a flask and sulphuric
acid added when aldehyde is liberated. It may be distilled
and condensed in a vessel surrounded by ice.

The reactions involved in the preparation of acetaldehyde are :
CH3CH2OH + 0-+CH3CHO + H2O

PARALDEHYDE 57

If one inhales fumes of acetaldehyde there is a feeling of suffoca-
tion with coughing. In animals its irritative action causes excite-
ment followed by depression, and paralysis of respiration. A
considerable portion of ingested aldehyde is oxidized in the body,
traces escape in the breath and more in the urine. Kunkel
describes a condition of aldehydeismus in people exposed to alde-
hyde fumes. In such cases there is thickening of the adventitia
of the vessels and an increase of connective tissue between the
lobes of the liver.

PARALDEHYDE

(CH3CHO)3. This is the polymer of acetaldehyde. It is
detected only after being reconverted into acetaldehyde.
Graphic formula:

CH3— CH / CH— CH3

i \

0 \ 0

CH3
Paracetaldehyde, or paraldehyde

Paraldehyde is little used in therapeutics because of the per-
sistent disagreeable taste. Formerly it was commonly used in
medicine as a hypnotic. It is used now chiefly in delirium
tremens — where it is often more efficacious than other sedatives.
The dose is 0.5 gram but the patient soon becomes accustomed to
it and if larger doses are given to get the effect, tremors, delirium,
hallucinations and epileptiform convulsions may result.

CHLORAL AND CHLORALDEHYDE

Chlorine is an oxidizing agent. When it acts on alcohol,
chloraldehyde is formed as follows:

1. CH3CH2OH + C12-*CH3CHO + 2HC1

2. CH3COH + 6C1->CC13CHO + 3HC1

58 CHEMICAL PHARMACOLOGY

There are many intermediate reactions in this, but the above
are the essential steps. An important intermediate reaction is
the union of alcohol and the aldehyde to form acetal;

CH3 OH.C2H5 CH3

| XOC2H5

C = O + -»C/ + H2O

XOC2H5.
H OH.C?H5 H

Acetal

Acetal is an uncertain hypnotic and produces unpleasant heart
depression, and patients soon "become habituated to it. By
analogy one would think that water HOH would react with
acetaldehyde to form an addition product, e.g. :

CH3 CH3

| OHH | ,OH
C=0 + = C/ + H20

| OHH | XOH
H H

But there is a general law in organic chemistry that a single carbon
atom cannot hold two OH groups. As a result, another molecule
of water is eliminated and the aldehyde reformed. With
chloraldehyde (chloral), however, the Cl in the molecule so
modifies the action of the carbon atom that it does hold two OH
groups in firm union. Chloral for this reason is the exception to
the rule.

CHLORAL AND CHLORAL HYDRATE (Chloraldehyde)

Chloral is a colorless oily liquid with a pungent odor and acrid
taste, while chloral hydrate is crystalline. Chloral itself is
little used, the hydrate being very commonly used.

Chloral, CC13CHO + H2O = CC13CH(OH)2, chloral hydrate.

Chloral hydrate like aldehydes is irritant to the skin and mu-
cous membranes and is a very disagreeable drug to take. For
these reasons if given in too concentrated a form it may cause
vomiting. The burning or irritant action may be followed by
some local anesthesia. When administered it should be well
diluted with water and a flavoring agent like syrup of orange or
citric acid. After too large a dose there -may be hemorrhages in

CHLORALDEHYDE

the stomach and intestines, and sometimes in nose and lungs.
By its continued use catarrh of the stomach and a skin rash fre-
quently develop. With toxic doses the blood pressure and body
temperature sinks, respiration is weakened, cyanosis, coma, and
edema of the lungs result. All the symptoms of alcoholic in-
toxication may precede these symptoms.

The Fate of Chloral in the Body

Because chloral or chloral hydrate yield chloroform when heated
with KOH, Liebrich explained their hypnotic action, by assum-
ing that they yielded chloroform in the body. Chloral, however,
is not decomposed to any extent in the body. The fate of chloral
in the body is interesting since it is reduced rather than oxidized.
It is well known that both oxidations and reductions occur in
the body, but oxidations are much more frequent, and apparently
more important. The fate of chloral seems to be as follows:

1. Chloral is reduced to the corresponding alcohol, trichlor-
ethylalcohol.

CC13CHO -> CC13CH2OH

2. The alcohol combines with glycuronic acid and the combi-
nation is urochloralic acid, or CsHiiClsOr. This substance
reduces Fehling's solution, but does not ferment with yeast. It
is also decomposed into the alcohol and glycuronic acid on boil-
ing with dilute acids. The combination of trichlor ethyl alcohol
and glycuronic acid may be represented as follows :

COOH

CH.OH CH.OH

CH.OH + CC13-+CH.OH

CHOH CH2 CH.OH

I I /OH

CHO OH CH<"

XO.CH2.CC1
Glycuronic acid

COOH
CHOH
CHX

>H20 + CHOH \

I °

CHOH /

CH^O.CH2.CC13
Urochloralic acid

60 CHEMICAL PHARMACOLOGY

It should be noted in this representation that the glycuronic
acid is formed before the union with the alcohol. As a matter
of fact, such union of the alcohol with glucose may be necessary
for the formation of glycuronic acid in the body (see p. 175,
glycuronic acid) .

1. Heated with KOH, chloral or its hydrate yields chloroform.
Dissolve 0.5 grams chloral hydrate in' 5 cc. of water, add a few
drops of KOH and heat. Note the odor. CC13CHO + KOH
— •> CHC13 + HCOOK. All alkaline hydrates, carbonates, and
borax cause this decomposition.

2. Like all aldehydes, chloral reduces Fehling's solution, and
alkaline silver nitrate solutions.

3. In alcoholic solutions, with NaBr, or KBr, chloral forms
chloral alcoholate

/
CC13CH/ an oily liquid

X)H

4. Chloral triturated with camphor, acetanilide, acetphenetidin,
urethane, phenol, salol, or thymol, produces a liquid. Use equal
parts of chloral and the others, to show this. Such combinations
are incompatible in prescriptions (pharmaceutic or physical
incompatibility) .

5. It is also incompatible with antipyrine with which it forms
Ci3Hi5H203Cl3 (hypnal) and Ci3Hi3Cl3H202 (chloral antipyrine).
Hypnal resembles chloral hydrate in action while chloral anti-
pyrine is inert.

6. A solution of chloral hydrate with a little resorcinol and a
few drops of NaOH gives an intense red (rosolic acid), which is
destroyed by HC1.

7. With ammonium sulphide, chloralhydrate gives an orange
color, changing to brown. The color develops more quickly on
warming.

8. Chloral is sometimes given as a poison (" knock-out drops ") .
In such cases, it is excreted in the urine. To obtain chloral from
the urine, acidify with tartaric acid and distil. To obtain the
whole of the chloral from the urine, it is necessary to distil in
vacuum almost to dryness. Test the distillate for chloral.

CHLORALOSE 61

To Test Urine Directly for Chloral

CAUTION: THIS is DANGEROUS. To about J| of a test tube
full of urine add one drop of anilin, then add 2 cc. of an alcoholic
solution of NaOH. If chloral is present, it will be manifested
by the disagreeable odor of phenyl isocyanide or carbylamine
C6H5NC.

Chloroform also gives this reaction:

CHC13 + C6H5.NH2 = C6H5.NC + 3HC1

This is a very poisonous substance and must be handled with care.
The products should be washed away through a sink pipe in a
draught closet.

9. Pure chloral hydrate does not give the iodoform reaction.

10. Nessler's Solution Test. — Add a few drops of Nessler's
solution to aqueous chloral hydrate and shake. A yellowish
red precipitate forms changing to yellowish green. This is an
aldehyde reaction.

11. Boil an aqueous solution of chloral hydrate with 0.3 gram
solid sodium thiosulphate. A turbid brick red liquid results.
KOH changes this to brownish red.

Chloralose is compound of chloral and grape sugar. It is
made by heating together anhydrous chloral and glucose:

CC13CHO + C6H1206 = CgHiiCljO. + H20

The introduction of the sugar into the molecule makes it act more
like morphine than chloral, and it may produce restlessness,
tremors and hemoglobinuria. Large doses by heightening the
reflexes may produce strychnine-like convulsions. Why such a
combination should so change the action of the original drug is
beyond chemical explanation. All these compounds illustrate
the reactivity of aldehydes.

Chemical Tests

1. Soluble — freely in hot water. Less readily in cold.

2. When hydrolyzed it yields glucose and chloral.

The compounds of bromine and iodine corresponding to chlo-
ral have no uses in medicine.

62 CHEMICAL PHARMACOLOGY

VI. KETONES

When primary alcohols are oxidized they yield aldehydes,
while secondary alcohols yield ketones. Propyl alcohol (pri-
mary) CH3CH2(CH2OH} on oxidation yields CH3CH2CHO,
propyl aldehyde. Isopropyl alcohol (secondary) CH3CH(OH)-
CH3, yields CH3CO.CH3, acetone. Ketones have the general

R
formula ^CO

Ketones are also prepared by the distillation of the calcium salt of
the corresponding acid. The reaction has been most carefully
studied in the distillation of calcium acetate, and the ketone from
this is called acetone. The reaction takes place according to the
following equation:

CH3— COO, CHN

+ CaC03

-
CH3— COO' CH/

ACETONE

Acetone, CH3CO.CH3 is the most important ketone. It is
of importance principally as a solvent, and in the preparation
of chloroform, sulpho-methanum (sulphonal), etc. It has been
used as an anesthetic, hypnotic and anthelmintic, but its use is
now restricted to its solvent action, and the preparation of other
drugs, especially the sulphone group of hypnotics.

It is a pathological constituent of urine, especially in diabetes
and severe forms of cancer (carcinomatous acetonuria). It
has also been found in the urine after poisoning with the following
drugs (toxic acetonuria) phosphorus, carbon monoxide, atropine,
curara, antipyrina, pyridine, male fern, chronic lead poisoning
and in morphinism after discontinuance of the drug.

Secondary alcohols are more toxic than primary. Isopropyl
alcohol in the case of rabbits is about five times as toxic as propyl.
Two grains of isopropyl alcohol in a rabbit produces drowsiness
and sleep. Acetone, however has feeble narcotic properties and
is less toxic than ethyl alcohol. Archangelsky found that dogs
show signs of narcosis when the blood contains 0.5 per cent.
acetone. Smaller doses produce narcosis in rabbits, but the
toxic action is not great. Urine almost always contains some
acetone which is increased in diabetes and protracted fevers,

ACETONE 63

such as typhoid, tuberculosis and pneumonia. It has also been
observed in the urine in various nervous and mental diseases.

Chemical Tests

1. Test solubility of acetone in water, alcohol, ether, chloro-
form and volatile oils. Note the odor.

2. Acetone is formed by the distillation of calcium acetate.

Ca(CH3C02)2 - CH3COCH3 + CaC03

3. Acetone occurs in the urine in diabetes. It yields iodoform
when treated with iodine solution as does alcohol. See tests
under alcohol.

4. LegaPs Test. — To 1 drop of acetone in 5 cc. of water, add
an equal volume of freshly prepared sodium nitro-prusside and a
few drops of NaOH. A red color results which becomes darker
on adding acetic acid. Creatinine gives this same red color
but it disappears on adding acetic acid.

5. Acetone differs from aldehyde as follows:
(a) It does not polymerize.

(6) It does not reduce ammoniacal solutions of silver hydroxide.
(c) It is oxidized only by moderately powerful reagents and
when oxidized yields acetic acid, carbon dioxide and water.

6. Acetone gives Lieben's iodoform test (page 23), even when
NH4OH is used instead of NaOH or KOH.

7. Penzoldt's Test. — Add acetone and a few drops of NaOH
(5 per cent.) to a saturated aqueous solution of ortho-nitro-
benzaldehyde. The mixture becomes yellow, then green on
standing and after 15 minutes a blue precipitate of indigo tin is
formed. When shaken with chloroform indigotin goes into
solution and colors the chloroform blue.

8. Reynold's Test. — Freshly precipitated mercuric oxide is
dissolved by acetone. Add a little mercuric chloride, and an
equal volume of alcoholic KOH to an acetone solution. Shake
thoroughly and filter. To the nitrate add (NH4)2S to form a
layer. A black ring of HgS indicates that some mercuric oxide
was dissolved.

CHLORETONE

Chloretone is acetone chloroform

CH3x CH3x XOH

xOO -f~ OHO13 = /^\

CH/ OH/ XCC13

64 CHEMICAL PHARMACOLOGY

It is produced by the action of caustic alkalies on a mixture
of acetone and chloroform. It is a peculiar camphoraceous
crystalline body, sp. gr. 0.792 at 20°C. It is miscible with water,
alcohol, ether, volatile and fixed oils. Calcium chloride sets it
free from its aqueous .solution. It reduces Fehling's solution.

It is more dangerous than chloral and is therefore little used
except for laboratory animals. The mechanism of the action is
unknown. Anesthetics or hypnotics when taken by mouth
have the disadvantage that they cannot be removed if too much
has been taken. In case of ether and chloroform, if it is seen
that too much is being given, the drug can be removed and the
excess in the body is soon exhaled.

Chloretone is less irritant to the stomach and it has been used
to some extent as a substitute for chloral. It has also some local
anesthetic properties, and has been used in the dressing of wounds,
either in the form of dusting powder or in solution.

The fate of chloretone in the body is unknown. After the
administration of large doses Houghton and Aldrich could not
find it in any of the secretions or excretions and concluded that
it is destroyed in the body.

VII. ORGANIC ACIDS

Organic acids are either the second products of the oxidation
of alcohols, or the third products of the oxidation of hydrocarbons :

I II III IV

C2H6 C2H5OH CH3CHO CH3COOH

ethane alcohol aldehyde acid

The characteristic acid group is carboxyl — COOH. The basi-
city of the acid depends upon the number of the carboxyl groups
in the acid.

When salts are formed, substitution of the carboxyl hydrogen
takes place:

CH3COOH + NaOH = CH3COONa + H2O

The introduction of the COOH group into the hydrocarbon or
alcohol changes the toxicity of the members and of the methane
series but slightly. With the dibasic acid the proximity of the

FOKMIC ACID 65

COOH groups in the molecule seems to have some influence.

f^OOTT
Thus in oxalic • „ „,,. where the carboxyls are closer than in

,
malonic CH2<^ the toxicity is greater.

XCOOH

In the aromatic series, the introduction of a carboxyl lessens
the toxicity. Benzoic acid C6H5COOH is less toxic than benzol.

.COOH

Amino benzoic acid, C6H4<f is less toxic than aniline,

'XNH2

OH
C6H5NH2. Also, salicylic acid, CeH^ is less toxic than

XCOOH
phenol.

Acids of the paraffin series or their salts that are absorbed,
are oxidized to carbonates in the body and increase the alkalinity
of the blood. Aromatic acids are excreted chiefly in combination
with glycuronic, amino acetic, or sulphuric acids.

ORGANIC ACIDS OF METHANE SERIES

Methyl alcohol, when oxidized, gives formaldehyde, and if
oxidation proceeds far enough, formic acid :

CH3OH + 0-+HC/ + H2O
XH

Formaldehyde
0
HC/ + 0-+HCOOH

H Formic acid

Formic acid as such is not important in medicine. It occurs
in nettles and in the sting of insects and is formed in the body
when formaldehyde or any of its preparations are taken. The
rate of formation of acid from aldehyde is so slow in comparison
with the rate of oxidation that it is oxidized to CO2 and H2O
about as rapidly as it is formed. Only under special conditions
may it be found jn the blood or urine. Dakin finds that formic
acid is a constant constituent of the urine during fasting and the

66 CHEMICAL PHARMACOLOGY

quantity is considerably increased after carbohydrate and fat
ingestion and to a lesser extent also after protein ingestion. All
three classes of food substances yield formic acid as an end prod-
uct of metabolism but it is so readily oxidized that it is eliminated
in only small amounts in the urine.

It is the strongest acid of the series and much more toxic than
other members except butyric which also has some narcotic
properties. In presence of metallic rhodium it is spontaneously
decomposed into hydrogen and carbon dioxide. This mechanism
may be of value in the explanation of fermentation by assuming
that yeast produces an organic catalyst that acts similarly.

It has been employed internally in rheumatism, and locally by
allowing bees to sting the involved part. The local hyperemia
so caused is beneficial.

In the presence of alkali, or when introduced into the body,
formic aldehyde shows the phenomenon known as the Canniz-
zaro reaction, i.e. there is both an oxidation and reduction of the
aldehyde;

2HCHO + H20-+CH3OH + HCOOH

ACETIC ACID

Acetic acid is formed from ethyl alcohol in the same manner
that formic acid is prepared from methyl alcohol.

O
C2H5OH + O =CH3C(f + H20

XH
0

CHsC/ 4- O = CH3COOH
XH

It has a wide use in medicine and as a food. Vinegar is impure
acetic acid. In therapeutics the acetates are used as diuretics
and refrigerants. Acetic acid is used as a solvent and preserva-
tive in pharmacy; aceta are solutions of drugs in acetic acid.

Acetic acid is oxidized in the body to C02 and H2O. The
C02 combines with the bases of the body and renders the urine
alkaline. Nearly all organic acids of methane series are oxidized
in this way and are excreted as carbonates. They lessen the H

ACETIC AND CARBONIC ACIDS 67

ion concentration of the blood and act as diuretics, both because
of their alkalinity and their salt action.

However the capacity of the animal body to oxidize acetic
acid is limited and normal human urine contains on the average
between 50 and 300 mgm. per day.

Amino-acetic acid or glycocoll CH2NH2COOH occurs in the
body as a constituent of proteins and the bile acids, and in the
urine of horses as hippuric acid. When benzoates are taken as
medicines, they are excreted combined with glycocoll as hippuric
acid;

C6H5COOH+H2NCH2COOH = C6H5CO.NH.CH2CpOH+H2O

In the same way salicylic acid combines with glycocoll to
form salicyluric acid

,
C.H/

XCO.NH.CH2.COOH

Recent work by Hanzlik throws some doubt on the occurrence
of this reaction in the body. Note that salicyluric acid is in no
way related to uric acid as the name might suggest.

CARBONIC ACIDS

This acid is described both in organic and inorganic chemistry;

/OTT
^\OH' ^ *S not known in the free state, but its salts are

extremely important in medicine. It is thought to exist in
solutions of carbon dioxide and water, and in the blood.
It forms amides and salts like a dibasic acid.

/OH XNH2
CO/ CO/

XNH2
CO/ CO(

/NH2

XOH XOH

XOC2H5

XNH2

Carbonic carbamic

urethane urea

acid acid

/NH2
CO/
XONH4

xONa
CO/
XONa

ammonium carbamate sodium carbonate, etc.

68 CHEMICAL PHARMACOLOGY

The salts of carbonic acid are much used in therapeutics in
effervescent cathartics, as antacids, in baking powders, many
beverages, such as soda water, potash water, champagne, and
other sparkling wines. Effervescent cathartics are essentially a
carbonate or bicarbonate mixed with an organic acid of such a
nature that the salt formed is but little absorbed from the gastro-
intestinal tract, such as the citrates, tartrates, malates, etc.
The C02 liberated masks the taste of many medicines and has a
stimulating action on the gastrb-intestinal tract. Absorption is
hastened by it. It is excreted, much of it by eructation, some
is absorbed and given off by the lungs. It is the normal stimulus
of the respiratory center, but has slight action on the organism
after absorption. This substance is slightly irritating to mucous
membranes and by its action on the stomach may increase appe-
tite. On prolonged application it has an anesthetic action.
Because of this action carbonic acid or effervescent drinks are
used to allay vomiting. Carbon dioxide snow is used especially
for local anesthesia, this being due more to freezing than to
specific action. The hydrogen ion concentration of the blood
can not be altered appreciably by the acid or carbonated drinks,
but can be changed by the soluble carbonates.

The amount of carbon dioxide in the air should not exceed
.03 per cent, but 3 per cent, will produce no immediate toxic
symptoms. It is only when CO2 reaches 5 per cent, that it
produces poisonous symptoms. It is not nearly so toxic as
methylene and many other gases. The toxic effects produced
in crowded rooms, formerly thought to be due to C02, are mainly
due to the heat and moisture, always present in such cases.

UREA
xNH2
Urea = C(X is the diamide of carbonic acid:

CO/
\)H

It is of interest as the basis of veronal, which is diethylmalonyl
urea. A compound of the hydrochloride of quinine and urea,
C20H2402N2HC1. CO(NH2)2 HC1, is used as a local anesthetic.

OXALIC ACID 69

The urine on an average diet contains about 2 per cent, urea,
which acts as a diuretic. According to Fosse, also Bamberger
and Landsiedl, it occurs in very small amounts in higher plants
and has also been reported in bacteria. Plants can use urea as a
source of nitrogen, and microorganisms can convert it into am-
monium carbonate.

XNH2
CO/ + 2H20 <=> (NH4) 2C03

Besides being the main end product of protein digestion urea is
of interest in relation to Wohler's synthesis of ammonium cyanate
into urea, which was the first organic substance artificially
prepared :

NH2

XNH2

OXALIC ACID
COOH
Oxalic acid, | is of importance in medicine only as a

COOH

toxic agent. It is toxic because it removes calcium, which is
necessary for life, and is, therefore, a general protoplasm poison.
Also, because it precipitates calcium, it prevents the clotting of
blood, and prevents rennet from clotting milk.

Its relation to cellulose and the sugars is seen from the fact
that sugars, starches, and cellulose yield oxalic acid when boiled
with nitric acid. Its presence in the urine in some instances
may arise from incomplete oxidation of carbohydrates. Its
relation to CN is seen from the following formula:
CN COOH

| + 4H20 = | + 2NH3

CN COOH

2NH3 + (COOH)2 = (COONH4)2 ammonium oxalate
Oxalic acid is related to formic acid. When sodium formate
is heated rapidly, sodium oxalate is produced:

NaCOolHJ NaOOC

[ + H2
NaCOOIHJ NaOOC

70 CHEMICAL PHAKMACOLOGY

Under proper conditions especially when heated in glycerine,
this reaction may be reversed, and oxalic acid carefully heated
will yield formic acid.

COOH

| -» HCOOH + CO2
COOH

Soluble calcium salts precipitate oxalates as calcium salts.
These salts are, therefore, antidotal to oxalates. Whether or not
any oxalic acid can be oxidized in the body, is a disputed ques-
tion. Marfori claims that 30 per cent, of the amount taken
reappears in the urine while Faust found 100 per cent. Hilde-
brandt, found that 60 per cent, of oxalic acid injected subcu-
taneously in rabbits was oxidized. Dakin found 90 per cent,
oxidized under the same conditions. It appears in the urine as
"envelope" crystals. These may be sufficient to block the tu-
bules and cause nephritis. Glycosuria and indicanuria occur
frequently, after large doses of oxalates. Tomatoes, spinach,
rhubarb, sorrel, and other plants contain considerable oxalate,
and most of this when eaten appears in the urine. In some
cases oxalate poisoning has been caused by these plants.

MALONIC ACID

COOH
Malonic acid, CH2\ is the next higher homologue of

XCOOH

oxalic acid. The use of the cyanides in building up compounds is
illustrated in the formation of malonic acid, which is formed from
monochloracetic acid:

CN. COOH
CH2C1 | |

| + KCN + H2O -> CH2 -> CH2 + KC1
COOH | |

COOH COOH

Malonic add is a crystalline compound, which melts at 132°C.
It is found in nature in the juice of beets, where it occurs as the
calcium salt. It is a constituent of veronal. Barbituric acid

DICARBOXYLIC ACIDS 71

or malonyl urea is obtained from alloxantin by heating it with
concentrated sulphuric acid and from dibrombarbituric acid
by the action of sodium amalgam. Veronal (q.v.) is diethyl
malonyl urea or diethyl barbituric acid.

SUCCINIC ACID

Oxalic, malonic and succinic acid form an homologous series
of dibasic acids:

COOH COOH CH2COOH

COOH XCOOH CH2COOH

oxalic malonic succinic

None of these are used to any extent in medicine. As the
COOH groups become more widely separated in the molecule
the toxicity decreases; hence malonic acid is less toxic than oxalic.
This is still further exemplified in citric and tartaric acids.

Succinic acid occurs in amber, fossil wood, in many plants,
asparagus, etc., in brain, muscle and in the urine after the in-
gestion of plants containing it. It may be prepared from its
elements by forming acetylene from carbon and hydrogen. This
is reduced to ethylene. If ethylene be passed into bromine,
ethylene dibromide is formed :

CH2 CH2Br

| + Br2 = |
CH2 CH2Br

This when treated with an alcoholic solution of KCN forms
CH2CN
CH2CN

which is hydrolyzed to -» CH2COOH.CH2COOH.

TARTARIC ACID

Tartaric acid may occur in levo, dextro, meso, and racemic
forms. It is dihydroxy succinic acid :

. CH2COOH CHOH.COOH

CH2COOH CHOH.COOH

succinic tartaric

acid acid

It was on these acids that Pasteur made his important dis-

72 CHEMICAL PHARMACOLOGY

coveries on the polarization of light by organic substance. He
found that certain crystals dissolved in water turned the polarized
ray to the left. Others turned it to the right; and a mixture of
the two was racemic or inactive (external compensation). On
studying the composition of the organic substances, he found that
the active crystals are mirror images of each other. It has been
found that only those with an asymmetric carbon 'are optically
active. No single base of an organic substance is known that is
optically active without the presence of an asymmetric carbon
atom. However a substance may contain two asymmetric
C-atoms and be inactive. This occurs in the meso form of
tartaric acid, cf . formula III. This is internal compensation.
The importance of this physico-chemical property to living mat-
ter can hardly be estimated. The mould, penicillium glaucum,
ferments dextro, but not levo tartaric acid. Yeast will ferment 1.
fructose, 1. glucose, 1. mannose, or 1. galactose. Dextro epine-
phrine is only about J/i2 as toxic as 1. epinephrine; d. hyoscyamine
is but feebly active in comparison with 1. hyoscyamine. It is
probable that time will greatly emphasize the relationship of
optical properties and life processes.

The levorotatory form is represented in formula (I), the dextro
in (II), and meso tartaric in (III).

(I) (II) (HI)

COOH COOH COOH

I I I

HO— C— H H— C— OH HO— C— H

H— C— OH HO— C— H HO— C— H

I I !

COOH COOH COOH

The central C atoms in (I) and (II) are asymmetric (each
valence has a different element or radical in combination), so
that when both forms are in the same solution, the influence of
one on polarized light neutralizes the other.

Tartaric acid is used in medicine as an expectorant and emetic
in tartar emetic, which is antimonyl potassium tartrate.

/CHOH COOHK
1. 2/ ^H20

XCHOH COO(SbOr

CITRIC ACID 73

2. Rochelle Salt, or sodium potassium tartrate, C4H406K Na
-f 4H2O, is used as a cathartic and antacid.

3. The acid salt of tartaric acid is used in domestic economy
as cream of tartar or baking powder. The essentials of a baking
powder are: something that will liberate C02 slowly and effi-
ciently, and will not leave a harmful or toxic residue in the food.
Cream of tartar fulfills these conditions. The reaction in this
case is:

CHOH.COOK CHOH— COOK

| + NaHC03 = + H20 + C02

CHOH.COOH CHOH— COONa

Cream of tartar sodium potassium tartrate

CITRIC ACID

CH2— COOH
I OH

Citric Acid, Cv occurs in the juice of many

| XCOOH
CH— COOH

plants, especially in lemon juice, where it may reach 5 per cent.
and in gooseberries, 1 per cent. It is also found in raspberries.,
currants, and other acid fruits, and is said to be found in the
milk of animals, probably being derived from the food. It is
formed in the fermentation of glucose by citromycetes pfefferi-
anus. In medicine its use is as a substitute for lemon juice; in
the syrup of citric acid as a vehicle and refrigerant. Magne-
sium citrate is a much used cathartic in iron and ammonium
citrate as a soluble form of iron in citrated caffeine, etc.

Citrophen or citrophenin is a combination of citric acid and
phenacetin :

CH2.CONHC6H4OC2H5

COH.CONHC6H4OC2H5

CH2CONHC6H4OC2H5. It is used as an analgesic and
antipyretic.

The reactions of acetic acid, acetone, and citric acid are inter-

74 CHEMICAL PHARMACOLOGY

esting, and the relationship also shows how the cyanides may be
disintoxicated by the body. Calcium acetate when distilled gives
acetone :

CH3.CO(\ CHN

">Ca = VJO + CaC03

CH3.cocr CH/

If chlorine is conducted through cold acetone, dichlorace-
tone is formed :

CH2C1 CH2CN

I I

C = O + 2KCN-»C = 0 -f 2KC1

I I

CH2C1 CH2CN

Dichloracetone Acetonedicyanide

When this is hydrolyzed it gives acetone dicarboxylic acid; and
this gives citric acid as follows:

CH2COOH CH2COOH CH2COOH

I I /OH | ,OK

CO + HCN = CC + 2H20 -» C(

-| | XCN | XCOOH + NH3

CH2COOH CH2COOH CH2COOH

Acetone dicar- Cyanhydride Citric acid

boxylic acid of citric acid

LACTIC ACID

Lactic acid, from (lac = milk) is but little used in medicine.
It is somewhat used as a local application to tuberculosis ulcers
of the nose and throat, especially on the larynx.
CH3

Lactic acid CHOH is of interest because of its relation to acetic

COOH

and formic acid and to glucose and amino acids derived from
protein. It is formed in the stomach in all fermentations
and dyspepsias when it may reach 0.4 per cent. There
is some doubt whether or not lactic acid exists in the
normal blood. It is present, however, in all cases where

LACTIC ACID 75

there is asphyxiation or reduction of tissue respiration and in
such cases appears in the urine. It occurs especially after
poisoning with phosphorus, arsenic, hydrazines, chloroform, etc.,
i.e., after those poisons which act on the liver causing hyper-
glycemia, reduction of glycogen, and fatty degeneration. It
may also occur in the course of diabetes and wasting diseases,
and is always present in cases of acidosis. Lactic acid since it
contains an asymmetric C atom exists in dextro, levo, and race-
mic or inactive forms. It was first discovered by Scheele in 1780,
who isolated it from sour milk. In the form of sour milk,
it was advocated by Metschnikoff but without any sufficient
reason as a means of prolonging life. Since milk is an important
vitamin containing food, it per se would be of great benefit in
deficiency diseases and some of these benefits may have been
unduly credited to lactic acid. In the destruction of lactic acid
by bacteria, propionic, acetic and formic acids may be formed:

CH3 CH3 CH3 H

| | = C02.H20

CHOH CH2 COOH COOH

I I

COOH COOH

Lactic propionic acetic formic

Zinc lactate Zn(C3H503)2.3H2O is the most characteristic salt of
lactic acid. The acid may be identified by the analysis of this salt.

HYDROCYANIC ACID

Hydrocyanic acid is usually considered with the paraffin acids,
but it is not a derivative of the paraffins. It is of direct interest
to the paraffins because it forms addition products with aldehydes
and ketones. These can be hydrolyzed, enabling the formation
of a product richer in carbon than the initial e.g. :
CH3I + KCN = CH3CN + KI

CH3CN + 2H20 = CH3COOHNH3

The relation of HCN to formic acid is shown by the following:
HCN + H20 -> HCOONH4 (ammonium formate)
It is, therefore, the nitril of formic acid. Hydrocyanic acid 2
per cent., dilute hydrocyanic, is used in medicine as an antemetic
and in cough mixtures, as a depressant of the respiratory centre.
On account of the readiness with which it decomposes, it is not so

76 CHEMICAL PHARMACOLOGY

much used as formerly. It also exists in wild cherry, in amygdalin,
in KCN, Hg(CN)2 and other compounds used more or less.

Because of its toxic action this drug is falling into disuse
It is of considerable importance in toxicology. It is absorbed
even from the skin. It is toxic to all ferments and tissues. It
first stimulates then paralyzes the central nervous system. The
peripheral muscles and nerves are weakened and eventually para-
lyzed. The tissues cannot use oxygen and soon die from asphyxia.
In such cases lactic acid may be found in the blood and urine.
The oxidative processes of the blood are also checked and the color
of the blood is bright red due to oxy hemoglobin as is to the fact
that the tissues from internal asphyxia cannot take oxygen from
the blood. Whether or not such a compound as cyanhemoglobin
is formed is still disputed. It is probably formed and readily
decomposed, though it is harder to reduce than oxy hemoglobin.

Hydrocyanic acid, if it does not kill is changed to sulphocy-
anides in the tissues. This seems to be a simple chemical process
which occurs without the action of living protoplasm. The
sulphocyanate test for hydrocyanic test is based on this fact. It
is as follows:

To a dilute solution of hydrocyanic acid, or a distillate sus-
pected of containing it, add a few drops of a solution of potassium
hydroxide, and twice as much yellow ammonium sulphide.
Evaporate to" dryness on a water bath; dissolve in a little water
and acidify with dilute hydrochloric acid. Filter to remove
sulphur. If the solution contained hydrocyanic acid the filtrate
will give a blood red color on the addition of a drop of dilute ferric
chloride, this is due to the formation of ferric sulphocyanate.

Hydrocyanic acid occurs in many plants, in the form of
glucosides — cyanogenetic glucosides. It is present principally
in the seed, buds, leaves and bark. The cyanide is held to be a
direct product of photosynthesis, and may be of fundamental
importance in the metabolism of the plant and perhaps in the
evolution of life processes. Gautier thinks that prussic acid and
its compounds may be formed in the plant, by the reduction of
nitrates by formaldehyde. This theory agrees with the distri-
bution of both nitrates and cyanides in the plant. The amount
of cyanide in plants varies greatly and may amount to as much
as 0.3 per cent. In many cases free hydrocyanic will be liberated

LACTIC ACID 77

from such plants on chewing — owing to digestion of the glucoside
— and can be detected in this way.

To isolate hydrocyanic acid from a plant or tissue : digest the
finely pulverized substance mixed with water in an incubator or
on a water bath for two hours at a temperature of 40°C. If the
temperature is raised much above this, it will kill the ferment and
prevent the setting free of HCN. Acidify the digest with tar-
taric acid and distil with steam. Test the distillate by:

1. Prussian Blue Test. — Add a trace of KOH, then a few drops
of freshly prepared ferrous sulphate solution and a drop of dilute
ferric chloride solution. Shake well and warm gently. Finally
acidify with dilute nydrochloric acid. A blue color is formed at
once if the quantity of HCN is considerable, if only a minute
amount is present a bluish green color only develops.

2. Hydrocyanic acid gives a white precipitate with AgNOs.

3. Vortmann's Nitro-prusside Test. — To a dilute solution of
hydrocyanic acid add a few drops of potassium nitrate solution,
then a few drops of ferric chloride and enough dilute sulphuric
acid to give a yellow color. Heat to boiling and add enough
ammonium hydroxide to remove excess of iron, filter, and add a
few drops of very dilute ammonium sulphide. A violet color
passing through blue green and yellow, indicates hydrocyanic
acid. It is due to the conversion of the cyanide into potassium
nitro-prusside — K2Fe (NO) (CN)5 which changes color when
ammonium sulphide is added.

Picric Acid Test. — When a solution of hydrocyanic acid is
made alkaline with KOH and heated in a water bath at 50°-60°C.
with a few drops of picric acid, it gives a blood red color due to
the formation of potassium isopurpurate — Cs^NsOeK. Sul-
phides present in decomposing organic matter will also give
this test and sugars under similar conditions will give a red
color due to the formation of picramic acid — which is 2 amino 3,
4, di-nitro phenol CeHt(NH2).(NOa)s.OH. This last is the basis
of Benedict's method for the estimation of blood sugar.

Isopurpuric acid does not exist in the free state, but only as the
potassium salt. Nietzki and Petri (Ber d. deutsch. Chem.
Gesellschaft 1900-33-1788)— think isopurpuric acid (CsHgOeNs)
is dicyano-picraminic acid = 5 oxy. 6 amino — 2, 4 di nitro
isophthalic nitrile : see page 98.

78 CHEMICAL PHARMACOLOGY

Purpuric acid, the formula of which is not definitely known, is
of biological interest in that its ammonium salt,

• CaH^NHONsOe + H2O is the dye stuff murexide. The
murexide test is given by uric acid caffeine, xanthine, theobro-
mine and many nuclein bases (see p. 288).

GENERAL PHARMACOLOGY OF THE ACIDS

The introduction of COOH into the Marsh Gas series gives
rise to acids with relatively slight toxicity. The anesthetic
action of the alkyl radicals is lessened by combination with car-
boxyl. The introduction of carboxyl into the aromatic series
lessens the toxicity of the benzyl group. In addition to the car-
boxyl group the acyl groups exert an action. Acetyl salicylic
acid is more effective as an antipyretic and analgesic than is
salicylic acid. Acetyl atoxyl is said to be less toxic than atoxyl.

The replacement of the hydrogen of the amino group in para-

rnino phenol with an acetyl group, HO^ \NH.COCH3

lessens the toxicity, and gives a compound with greater anti-
neuralgic properties.

Lactyl phenetidine (lactophenin)

C2H5< >NH— CO— CH— CH3

is more soluble, and has a less antipyretic action than phenacetin.
Ecogonine-methyl ester has no anesthetic action but its benzoyl
derivative, cocaine is noted for its local anesthetic effect. Most
artificial cocaines contain the benzoyl group. The toxicity of
aconitine is closely related to the benzoyl and acetyl groups present
in the alkaloid. The mechanism of the action of these and many
other similar compounds is little understood, but the total
action in each case seems to be the algebraic sum of the actions
of the component chemical groups of the drug. In addition
to these there is a molecular action and a hydrogen ion action.
For the effects of the hydrogen ion, see ackjosis, p, 35Q; see also
amino acids, p. 304.

IODOFOBM 79

VIII. 1ODOFORM AND PHYSIOLOGICAL SUBSTITUTES

lodoform, or triodomethane, was the first solid antiseptic known.
It is prepared by the action of iodine upon alcohol or acetone, in
the presence of an alkali or an alkaline carbonate. Its formation
is also used to test for the presence of alcohol or acetone. A solu-
tion of I in KI is added to the solution of alcohol, or acetone, and
warmed, then dilute NaOH or KOH is added, drop by drop
until the color has disappeared. lodoform is formed :

CH3COCH3 + 3KIO = CH3COCI3 + 3KOH
CH3COCI3 + KOH = CH3COOK + CHI3

The potassium hypoiodite KIO is formed when dilute KOH
is added to the I in KI solution : 2 KOH + 2I-»KIO + KI + H2O.
The hypoiodites are easily decomposed into iodides, and iodates :
3 KIO = KIO3 + 2KI. Both the iodate and iodide are usually
formed in the solution with the iodoform, even when KI has
not been added. Strong alkalies cause the formation of the io-
date; and, therefore, if a too strong alkali is added, it interferes
with the reaction. For this reason, sodium carbonate or potas-
sium carbonate instead of the hydrate is sometimes recommended
in making the iodoform test. From alcohol, iodoform is pre-
pared, possibly according to the following reaction :

Ethyl iodide, acetic ether, and other compounds are probably
also produced. The result appears to be greatly influenced by
the temperature, and the relative amounts of the materials used.
Iodine is an oxidizing agent and. the probable mechanism is:

O
C2H5OH + O = CH3C/ + H2O

O 0

CH3C/ + I, = CI3C<f + 3HI
NH XH

CI3C/ + KOH = CHI, + KCOOH
XH

lodoform melts at about 115°C. It is nearly insoluble in
water, but soluble in alcohol, glycerine, carbon bisulphide, ether

80 CHEMICAL PHARMACOLOGY

and in fats. In medicine it is sometimes used in the form of
an ointment.

It is volatile at ordinary temperatures and distils readily in
steam. When it is suspected in organic matter, and its separa-
tion is desired, acidify with tartaric acid and distil with steam.
Extract the distillate with ether and evaporate the ether in a
suitable dish. lodoform remains as yellow hexagonal plates
with a characteristic odor.

Tests: Lustgarten's. — In a test tube warm a little iodpform
solution in alcohol with a few drops of sodium phenolate — made
by dissolving 2 parts of phenol, 4 parts of sodium hydroxide and
7 of water. A red precipitate is formed which settles to the bot-
tom. Pour off the supernatant fluid and dissolve the precipi-
tate in dilute alcohol — a carmine red color results.

Phenylisocyanide Test. — Add a few drops of aniline to a little
iodoform solution in alcohol, then a few drops of alcoholic KOH
solution. When heated gently, phenylisocyanide — C6H5NC is
produced: This is recognized by its very characteristic and
repulsive odor. For reaction see page 43.

lodoform is sometimes used as a disinfecting dusting powder,
and any action it has is due to the liberation of iodine. It has
two serious disadvantages:

1. Its disagreeable and persistent odor.

2. In cases of abraded surfaces, sufficient may be absorbed to
produce toxic symptoms. For these reasons its use is becoming
restricted.

Various other iodine compounds have been devised, with the
idea of securing the iodine effect, without the disadvantages of
iodoform. The following are the most common:

ARISTOL, OR DITHYMOL-DI-IODIDE.

The stearoptene, thymol, from oil of thyme has the formula :

CH3

/\
CH3 CH3

IODINE COMPOUNDS 81

It is a solid crystalline body, which is used in medicine, especially
in the treatment of hook-worm disease. It has also been much
used in biological chemistry as a preservative for urine and other
fluids. Since it combines with iodine-also an antiseptic — it was
thought that a valuable iodine compound could be obtained
without the disadvantages of iodoform. Eichkoff in 1890 pre-
pared aristol or thymol iodide by the action of iodine on thymol
in alkaline solution.

VCH3
XC3H7

This is a chocolate colored powder and contains about 45 per
cent, iodine. It has been used as a dusting powder especially
in soft ulcers, eczema, psoriasis, lupus, burns, infections of ear,
nose and throat and in many other cases where the odor of iodo-
form has been a drawback. Its action is similar to iodoform,
and its only advantage is that it is odorless.

EUROPHEN-OR-DI-ISO-BUTYL ORTHOCRESOL IODIDE.

This is analogous to thymol iodide. It has the formula:

sCiH.9

CeH^;— - CHa

CeHfc— CHa
XC4H9

and is a condensation product of two molecules of isobutyl-ortho
cresol with one atom of iodine. The action is similar to thymol
iodide. It contains about 28 per cent, iodine.

lODOL OR TETRAIODO PYRROL.

I.C — C.I

II II

,C!

CHEMICAL PHARMACOLOGY

was one of the first iodoform substitutes. It is prepared by the
action of iodine on alkaline solutions of pyrrol or indirectly by
the action of KI on tetrachlor-pyrrol.

C4H4NH + 8C1 = C4C144NH + 4HC1

pyrrol tetra-chlor-pyrrol

C4C14.NH + 4KI = CJ4.NH + 4KC1

lodol is a tasteless and odorless powder with an action similar
to iodoform.

Besides the above iodine containing bodies, from which iodine
is liberated readily in the body, others have been prepared, but
since these do not liberate iodine in the body, they cannot be
classified as true iodoform substitutes.

In the iodoform substitutes the iodine is not attached directly
to the benzene ring but replaces the H of the hydroxyl group.
In Loretin, 1 oxy, 2-iodo — 4 sulphonic acid,

SO2OH

4 chlor quinoline

N and vioform 1, oxy, 2-iodo,

and nosophen or tetraiodophenol phthalein C2oHioIi404 and

,OH

Losophan — or tri-iodo di-metacresol — C6HI3

/
\

CH3

IODINE COMPOUNDS 83

and sozoiodol (iodo para phenol sulphonic acid)

XOH
C6H2I/

XS02OH
the I is attached to the ring.

Such compounds are practically undecomposed by the body,
and of little value as antiseptics so far as the iodine content is
concerned. They are therefore not real substitutes for
iodoform.

All phenols have a high antiseptic value, and the introduction
of iodine increases this to some extent. The increase is not
sufficient to warrant approval.

Besides the above iodoform substitutes, organic combinations
of iodine have been prepared for administration internally to take
the place of potassium iodide. Iodides in the form of potassium
or sodium are sometimes too rapidly absorbed, cause irritation
of stomach, skin eruptions and other untoward manifestations.
Many attempts have been made to avoid these complications by
combining the iodine with organic substances that will be slowly
decomposed in the body and slowly absorbed. The combinations
are usually with protein matter, and the composition in most
cases is not fixed or definite as in the iodoform substitutes.

THYREO GLOBULIN is the normal iodine-containing body of the
thyroid gland. The active ingredient of this has recently been
isolated by E. I. Kendall and has the formula:

HI
HI

- N CO

C - CH2 - CH2 - COOH

H or thyro-oxy-indole

IODO-SPONGIN is the iodine compound of the sponge.

IODOALBIN is a compound of iodine and blood albumin, con-
taining approximately 21.5 per cent, of iodine. It passes through
the stomach unchanged, but is decomposed in the intestine.

IODOPIN is iodized sesame oil. As is well known, unsaturated

84 CHEMICAL PHARMACOLOGY

oils may absorb or add iodine — the iodine number. Two prepa-
rations of iodopin are on the market — one 10 per cent, and
one 25 per cent. The action is the same as that of potassium
iodide, but it is claimed that iodism is less likely to develop.

IODO CASEIN is a compound of iodine with milk casein, contain-
ing about 18 per cent, of iodine, in organic combination. Many
other such potassium iodide substitutes have been prepared, but
the principle is the same as the above.

The supposed or claimed advantage of these organic prepara-
tions is that iodism is less likely to develop. By iodism is meant
the untoward symptoms that develop after the prolonged use of
iodides, the most common being catarrh of the respiratory pass-
ages and adnexa, bronchitis, salivation, skin eruptions, eczema,
bullse, pemphigus, purpura, fetid breath, nausea and general
malaise. A dermatitis resembling ivy poisoning is sometimes
seen after iodoform has been used.

The fatal'dose of iodoform or its substitutes is not definitely
known. Barois (Arch, de Med. et de Pharm. Militare, 1890)
records the death of a woman on the 9th day after the injection
of 3 grams of iodoform in ether. Gaillard (Bull, de Chirurg.,
1889) records a comatose condition and apparent death (but from
which recovery took place) after the injection of about 6 grams
iodoform into an abscess, v. Bonsdorff (Jour. Am. Med. Assoc.,
67, 1916, 1052) reports death due to the use of about 40 cc. of
10 per cent, iodoform solution, 10 cc. at a time being injected into
the pleural cavity in a case of tuberculosis in an alcoholic. The
death in this case was probably due to other causes. Much larger
doses than any here recorded have been injected without apparent
injury.

The symptoms of poisoning in addition to iodism are diuresis,
somnolence, hallucinations, delirium, lassitude, diminished re-
flexes, convulsions, paralysis. As in many cases of poisoning,
sodium carbonate in 1 gram doses may be beneficial, because of
its effect on the acidosis which develops.

The Fate of Iodoform in the Body

Iodoform and its substitutes are readily decomposed in the
alkaline fluids of the body, and the iodine is excreted as iodides.
Some decomposition takes place when it is used on wounds as

BROMINE COMPOUNDS 85

a dusting powder. The iodides formed after the administration
of iodoform have been found in the saliva, perspiration, bronchial
secretions, urine and other fluids, just as after the administration
of potassium iodide. lodo albuminates are also formed as after
the use of iodides, and the final excretion of the total iodine as
sodium or potassium iodide,_may be long delayed.

Some iodide undergoes decomposition in the body and free
iodine is said to have been found in the stomach. If this were
absorbed however it must circulate as an albuminous compound
until converted into the inorganic form in which it is excreted.
Free iodine has not been demonstrated out of the acid medium
of the stomach yet many theories which assume its presence,
have been devised to explain skin eruptions, and the inflam-
matory reactions of the mucous membranes.

BROMINE COMPOUNDS

Combinations of bromine similar to iodine have been pre-
pared amongst which are bromopin, analogous to iodipin. Sabro-
mine Ca(C22H4i02Br2)2, the dibrombehenate of calcium, has a
feeble bromide action, because it is stored in the fatty tissues
and liberated slowly, as valerobromide :

^CH.CH.BrCOONa
CR/

which is formed by the action of bromine on valerianic acid ; and
adalin which is bromdiethyl — acetyl urea :

C2H

>CBrCONHCO.NH2
C2H5

As might be surmised Jrom the ethyl groups of this formula such
combinations of bromides are nerve depressants. The bro-
mides are hypnotics, and are used in medicine only to depress
the central nervous system. They are used for this purpose in
chorea, epilepsy, and have also been used in seasickness and in
whooping cough. Since bromides are used to a considerable
extent, bromism often develops. This in the main is similar to

86 CHEMICAL PHARMACOLOGY

iodism, but the skin eruptions and depression are more pro-
nounced. Acne is often very troublesome.

Bromides accumulate in the body; that is, they are not ex-
creted as rapidly as absorbed. This is partly explained by the
fact that the body cannot well distinguish between the bromine
and the chlorine ion, consequently chlorine is excreted and bro-
mine retained. HBr, is sometimes formed in the stomach in-
stead of HC1.

It has been questioned by some whether the depressant effect
of the bromides is due to the presence of the bromine ion or the
absence of the chlorine ion. In favor of the view that it is due
to lessened chloride, it has been found that the depressing action
of the bromides is more pronounced when the chlorides of the
diet are diminished and Loeb has found that fish are depressed
by the administration of bromide, but remain normal if chloride
also is added. However, large doses of bromides depress animals
before the chlorides are much diminished so that while poverty
of chlorides may aid the action of bromides they are not the cause
of it. Bromides are excreted, in the same manner as the iodides.

IX. BENZENE OR BENZOL

Benzene, C6H6, is derived from coal tar. It is the mother sub-
stance of a long series of products, many of which are important
in medicine. Because many of them are odoriferous, the series
is known as the aromatic series. The formula generally given
to the compound is that of Kekule:

CH
CH

The reasons for assigning this formula to it are :
1. All the hydrogen atoms react the same, hence they must be
similarly linked.

BENZENE

2. It acts like a saturated compound— yet if it were an open
chain structure, it could be represented only as a highly unsatu-
rated compound.

3. Under certain conditions it unites with 6 atoms of bromine
to form C6H6Br6. If it were an unsaturated compound related
to hexane, it should unite with eight atoms, since hexane when
saturated has the formula C6Hi4Br6. Hence it seems to be a
closed ring.

4. In favor of this is the fact that when gaseous benzene and
hydrogen are passed through a heated tube containing finely
divided nickel, 6 atoms of hydrogen are absorbed and hexamethyl-
ene is formed. This corresponds with the formula:

CH«

+ 6H =

CH:

That all the hydrogen atoms in benzene are the same, is sup-
ported by the following facts :

1. There is but one mono substitution product of chlorine,
bromine, NH2 etc.

2. The theory calls for 3 possible di-substitution products
and these are known, and only these, e.g. :

(1.2 and (1.6) di-substitution products are the same. Also (1.3)
and (1.5) (1.4) and (2.5) and (3.6) are the same.

CHEMICAL PHARMACOLOGY

3. Three tri-substitution products only are foundx while more
would be expected if the H atoms were different.

adjacent

symmetric

asymmetric

These are all that can be found.

It should be remembered that the existence of the benzene
ring is still theoretical yet all the facts so far can best be ex-
plained on the basis of this theory.

Benzene is a colorless, highly refractive liquid, B. P. 80.5°C.,
Sp. gr. 0.88 at 20°. It is highly inflammable. In commerce
it is not pure, being usually mixed with other hydro-carbons
such as toluene. It is insoluble in water; is a good solvent
for fats, resins, alkaloids, iodine, and other substances, and is
broken up only with difficulty. Under certain conditions it will
yield substitution products. With HNOs it gives nitrobenzene.
C6H6 + HN03 = C6H5N02 + H20. When heated with sul-
phuric acid, it gives benzene sulphonic acid. In the body it is
but slightly acted on, passing through for the most part unchanged.
A slight amount may be oxidized to phenol which is excreted
combined with sulphuric acid. Benzene has been used to a
considerable extent of late in the treatment of leukemias as it
causes a reduction of the number of the leucocytes, the dose being
from 0.5 to 1 cc., four times a day. Frequent examination of the
blood is necessary and too great doses or too prolonged use of it
is decidedly harmful, as it may cause an aplastic anemia. By
this is meant that, while it reduces the number of leucocytes, it
also acts on the bonemarrow in a harmful way so that the normal
production of red cells is lessened or stopped.

While benzene is relatively inactive chemically, the fact that
it is volatile and will dissolve lipoids confers on it a pharmacologic
activity which is due entirely to its physical or solvent action.

PHENOLS 89

This action is manifested on the motor side of the nervous system,
and is stimulating. Members of the methane series act mainly
on the sensory side and are depressant.

X. PHENOLS

1. Phenols (Fr. Phenol, Greek Phaino, — shine. Latin, oleum,
oil.) Hydroxyl derivatives of the methane series are known as
alcohols. Hydroxyl derivatives of the benzene series are called
phenols. Only when the OH is attached directly to a carbon
atom of the ring does the term phenol apply.

2. Since all the H atoms of benzene are the same, only one
monhydroxy phenol is possible, and only one is known. Phenol
is obtained from coal tar, or is made synthetically. It is found in
small quantities in combination in urine, and is derived from
protein.

Phenol is formed from benzene by the action of oxygen in the
presence of a catalyzer like platinum black or aluminum chloride.
Small amounts of it are also formed in the human body from
administered benzene.

Phenol occurs in colorless deliquescent prisms which melt at
42°C. and turn to pink or brown on standing. It boils at 183°C.
and is volatile in steam. One gram of phenol dissolves in 15 cc.
of water at 25°C. It is very soluble in alcohol, glycerine, chloro-
form; ether, carbon disulphide or in fixed or volatile oils. A
water solution is faintly acid to litmus. When heated phenol
crystals melt, forming a highly refractive liquid.

Its solubility is peculiar. When 10 per cent, of water is
added to phenol it liquefies. This is known as phenol liquefra-
tum, and may be regarded as a solution of water in phenol. If
more water be added the solution is destroyed and a clear solution
is not obtained until 15 cc. of water is added for each gram of
phenol. This may be considered as a solution of phenol in water.

Phenol gives a violet coloration, phenolic reaction, with ferric
salts, and a pale yellow precipitate (of tri-bromphenol
C6H2Br3OH) with bromine water.

It is a strong germicide, a general protoplasm poison, and is
excreted from the body mainly as phenyl sulphuric acid or
conjugated sulphate.

90 CHEMICAL PHARMACOLOGY

It is used in medicine mainly for its antiseptic action, and forms
the basis of many synthetic drugs whose actions are antiseptic
and antipyretic. As pointed out under iodoform substitutes,
iodine when attached to the benzene ring is not decomposed in
the body. All phenols are antiseptic but the addition of iodine
increases the antiseptic action. This is the basis for the large
number of iodine compounds on the market.

Properties of Phenols

The phenols have acid properties, but they are weaker than
carbonic acid hence they are not soluble in sodium carbonate and
will not decompose carbonates. Sodium phenolate is not formed
by sodium carbonate but by the use of NaOH. Phenols which
contain strongly negative substitute groups may be sufficiently
acid to decompose carbonates. Picric acid for example, which is
trinitro phenol, is strongly enough acid to do this.

(NO,),

Phenols have alcoholic properties and form ethers, not directly
as with ordinary alcohols, but by use of alkyl iodides, and sodium
phenolate :

+ CH3I -

ONa

Nal

OCIL

Phenyl-methyl-ether

(anisol)
R
Ethers have the general formula /O. In this formula, (phenyl)

R'/

C6H5 = R and (methyl) CH3 = R' The product is a mixed
ether.

The introduction of the OH group into benzene greatly
increases its reactivity, and accordingly increases its antiseptic
toxic properties. The tendency of the aromatic group as a whole

PHENOLS 91

is to stimulate the motor side of the central nervous system while
the paraffin series are depressant. In compounds with a paraffin
side chain the depressant action usually predominates. The
local action of phenols is always anesthetic, this explains the
anodyne action of oil of cloves, eugenol, benzyl alcohol, etc., when
applied to tooth cavities or injected hypodermically. Increase
in the number of OH groups in phenols as in the paraffin series,
lessens the physiological activity.

In case of poisoning by carbolic acid a part is oxidized in the
body to the dihydroxy benzenes, pyrocatechol and hydroquinone.
The dark color of the urine is due to further oxidation of the
hydroquinone with the formation of quinone products. Normal
urine contains considerable free sulphate; after carbolic acid
there is little if any free sulphate, all of it being combined with
the phenol. If such urine is boiled with a mineral acid the
ethereal sulphate is decomposed and the sulphate can then be
precipitated with barium chloride, while the sulphates in the
body combine in this way with phenol. In cases of phenol
poisoning, the injection of sulphates helps but little.

Carbolic acid, in cases of poisoning can be separated from the
tissues by distillation with steam. Long continued distillation
is necessary to remove the last traces. In case of a man dying
15 minutes after taking 15 cc. liquid carbolic acid (Ber. d. Deut.
Chem. Gesell., 16., 1337 1883), Bischoff found

0.171 gram in stomach and intestine
0.028 gram in blood
0.637 gram in liver
0.200 gram in kidney
0.314 gram in brain.

This gives one an idea of how quickly poisons spread through
the body.

Resorcinol, (1.3) or meta dihydroxy phenol,

CHEMICAL PHARMACOLOGY

used mainly for the preparation of eosin, fluorescene, and azo dyes.
It occurs in certain resins, especially galbanum and asafcetida.
Heated with sodium, it yields the blue indicator known as lac-
moid, which turns red with acids. Many other meta and para
'compounds yield resorcinol when fused with KOH. It crystal-
lizes from water in colorless plates or prisms which melt at 118°C.
Formerly resorcinol was much used in some of the skin diseases
and has been injected into the bladder in cystitis and infections
of the genitourinary tract, but it is irritant and likely to be
painful if used in this way. At present it is not much used in
medicine.

Quiuol or hydroquinoue or para dihydroxy benzene (1.4) is
named because it can be obtained from quinone by reduction
with sulphur dioxide and water.

H.OH

O
Quinone

OH
Hydroquinone

It was first obtained by the dry distillation of quinic acid:
C«H7(OH)4COOH + O = C6H4(OH)2 + CO2 + 3H2O

It occurs in nature in combination as a glucoside arbutin, and
uncombined in some leaves and flowers (vaccinum vitis idoea).
The form is colorless and crystalline and melts at 170°C. This
substance has been used as an antipyretic but has been super-
seded by the modern antipyretics.

DIHYDROXY PHENOLS OR DIHYDROXY BENZENES

Three di-hydroxy phenols are theoretically possible, and all are
known and can be prepared from plants. They are, catechol
(1.2), resorcinol (1.3) and hydro-quinone (1.4). .

DIHYDROXY BENZENES

Catechol, pyrocatechol or pyrocatechin or 1.2 hydroxy benzene
occurs in beech-tar.

As the name indicates, (pyros-fire), it is derived from the de-
structive distillation of catechu, which contains protocatechuic
acid : —

OH OH

C02

COOH

It crystallizes in colorless prisms from benzene, and melts at
104°C. It can also be prepared by fusing phenol sulphonic acid
with KOH:

S03H -f KOH

KHS0

It occurs in small amounts combined with sulphuric acid in the
urine of horses and human beings. It is also found in many tan-
nins— the pyrocatechol tannins, especially those of pine and oak
barks (not in oak galls), acacia, cutch, and gambir.

Pyrocatechol has met with little use in medicine. It was
formerly used as an antipyretic, but it is toxic and forms methe-
moglobin readily. This is the parent substance from which
synthetic adrenalin or epinephrine is derived, and itself produces

CHEMICAL PHAKMACOLOGY

an appreciable rise of blood-pressure. Epinephrine is derived
from catechol according to the formula given under epinephrine
(p. 236).

TRIHYDROXY BENZENES OR TRIHYDRIC PHENOLS

I Pyrogallol or pyrogallic acid, 1.2.3, is so-called because it
is formed from gallic acid C6H2(OH);jCOOH (1.2.3.5) by heating.

COOH

gallic acid

pyrogallol

It is also formed by fusing hemotoxylin with KOH. Its
dimethyl ether is found in beechwood creosote. Pyrogallol is
the best known member of the trihydric phenols. It crystallizes
in colorless plates which melt at 132°C. In excess of caustic
alkali it absorbs oxygen readily and is employed in gas analysis
for this purpose. It is used in certain skin diseases and in hair
dyes.

II Phloroglucinol, 1.3.5, trihydroxy benzene, was first
obtained from the glucoside phlorizin. It is also found in the
glucosides, quercitin and hesperidin, and can be produced by
fusing catechu, kino and other resins with KOH. It can be
formed from resorcinol, which illustrates a frequent reaction that
takes place on fusion with alkalies, namely, the replacement of
hydrogen by hydroxyl:

OH + 0 = OHk JOH

Resorcinol — > phloroglucinol.

CRESOLS

Phloroglucinol is a white crystalline body that melts at 219°C.
and tastes sweet. It is not used in medicine but is used in chemis-
try as a reagent with HC1 to detect galactose, pentose, or
glycuronic acid. These give a red color when heated with an
equal volume of HC1 specific gravity 1.09 and a little phloroglu-
cinol is added (Tollen's reaction).

Gallic acid and tannic acid are phenols.

Gallic acid

COOH

on heating gives pyrogallol — see formula p. 94.
Tannic acid is digallic acid.

OH HOOC

The tannins are sometimes divided into the pyrogallol and the
catechol varieties, according to the color they give with ferric
salts. The pyrogallol group gives a dark blue, and the catechol
group gives a greenish color (see tannins).

CRESOLS

Cresols (cresote -f ol) are methyl phenols,
cresols; ortho, meta, and para.

There are three

CHEMICAL PHARMACOLOGY
CH3

CH3

Ortho Meta Para

They occur in the distillate from coal tar and the tars from pine
and beech wood. Like phenols, they react with ferric chloride
to give colored solutions, and with bromine to give precipitates.
They are readily nitrated.

Creosote from beechwood tar consists chiefly of a mixture of
phenols, cresols, and guaiacols.

Guaiacol,

OCH3

so called because it was first obtained

from guaiac resin, is the mono-methyl-ether of pyrocatechin. It
possesses both the properties of an ether and a phenol, gives a
methyl green color with iron salts and is converted into anisol or
phenyl methyl ether on reduction with Zn.

OCH-

Veratrol

OCH3 Anisol

OCH,

is the dimethyl ether of pyrocatechin

and is prepared from the seeds of sabadilla ofncinalis.

PICRIC ACID 97

Creosote (Gr. Kreas, flesh; Soter, preserver) is a mixture of
phenols and cresols and guaiacols, obtained during the distillation
of wood tar.

Creosotum, owing to the presence of phenols, has much the
same action as phenol itself. Due to its anesthetic properties,
creosote on cotton is sometimes inserted in a cavity to allay the
pain of toothache. In addition, it possesses caustic and antisep-
tic properties. Many derivatives, based on the salol principle
(q.v.) have been introduced, as intestinal antiseptics.

Creosote carbonate is one of these. It is a mixture of the
carbonates of the various constituents of creosote, chiefly guaiacol
andcreosol. The formation of this ester greatly lessens the toxi-
city and caustic action of the original mixture, which is said to
be less toxic and more powerfully antiseptic than phenol. It is
a tasteless, odorless powder, well borne by the stomach.

Picric acid or tri-nitro-phenol is the most important nitrophenol
derivative. The introduction of the nitro group into phenols
increases the antiseptic and toxic action.

It is a powerful blood poison, renal irritant and respiratory and
cardiac depressant. The introduction of the nitro groups also
increases the acidity of the phenols. Phenol will not decompose
sodium carbonate but picric acid will. Sodium phenolate is
formed in the reaction, while only by the actign of NaOH is it
formed from phenoL The prolonged consumption of small
quantities of picrate colors first the conjunctiva of the eyes, but
later the entire skin may become yellow. This may be mistaken
for jaundice. Picric acid is changed to picramic acid in the
body, and this colors the urine red. Some is excreted unchanged
in the urine and feces. It produces anuria, strangury, vomiting
and may cause convulsions, like phenol. The red color of pic-
ramic acid has been utilized by Benedict and others as a
method for the quantitative determination of glucose, and the
reaction in the body is probably with glucose. The picramic
acid is not so toxic as picric.

Tests for Picric Acid

I. The material or solution containing it in yellow aqueous,
alcoholic or ethereal solutions have the same color. It is easily
extracted with ether; and is somewhat soluble in water. The
tests are made in water solution.

CHEMICAL PHARMACOLOGY

II. It dyes a thread of cotton, wool or silk yellow.

III. A solution of picric acid warmed to 60°C. with a few drops
of KCN gives a red color due to the formation of isopurpuric acid.
This acid does not exist in the free state but is present in this
test as the K salt. The formulas assigned to isopurpuric
acid are

OH OH

O2N— C

G-NH

O2N— C

C— NHOH

NC— C

C— ON

NO- C

C— CN

N02 N02

Nietzki-Petri Borsche

IV. When picric acid is made alkaline with a solution of sodium
carbonate and a trace of glucose added (1 cc. 0.1 per cent.) and
heated on a water bath or over a free flame a red color due to
picramic acid is developed. This has the formula —

OH • OH

I I

i i

C C

O2N— C6 2C— NO2

HC CH

\4/

6H =

O2N— C6 C— NH2

HC CH

\4/

2H2O

NO2 NO2

Picric acid Picraminic acid or picramic acid.

This color is very similar to that of isopurpuric acid.
Reactions of the Phenols

1. Practically all phenols give a color reaction with Fe2Cl6
varying from greenish to violet. This reaction is known as the

REACTIONS OF THE PHENOLS 99

phenolic reaction. For this reason, phenols are incompatible
with iron salts. (Hydro quinone does not give a color with iron,
which oxidizes it to quinone.)

2. All phenols give Liebermann's reaction: when a phenol
is treated with sulphuric acid and a nitroso compound or a nitrite
is added, it yields colored solutions. When the solution is
treated with an excess of alkali, it assumes an intense blue or
green color.

3. Pyrocatechol, pyrogallol, and phloroglucinol are precipi-
tated with lead acetate. Resorcinol and hydroquinone are not.
(a) They all reduce Fehling's solution on warming.

4. Nearly all phenols reduce ammoniacal solutions of silver
nitrate and salts of mercury and gold to their respective metals.

5. Generally, phenols react with an aqueous solution of NaOH
to form soluble salts, but they are insoluble in Na2CO3.

6. With bromine water, most phenols yield a precipitate of
brominated phenol. The most important reactions are those
with alkalies, ferric chloride and bromine water, and Lieber-
mann's reaction. The fact that phenol gives CeH^ONa, sodium
phenolate with NaOH, but is too weak to decompose sodium
carbonate, distinguishes phenols from acids.

When taken into the body, the phenols are combined and
excreted with sulphuric acid, glycuronic acid, etc. Yet phenol,
when heated in a test tube with sulphuric acid, is not changed to
any extent, because it is less basic than alcohol and does not
form salts so easily.

7. All monhydric phenols give Millon's test. When heated
with Millon's reagent (A solution of mercuric nitrate containing
free HNO3) a red color is produced.

Like the alcohols, phenols contain an hydroxyl group; and
reagents which act on the hydroxyl will act on a phenol:

C6H5OH + CH3COC1 = CH3C0.06C5H + HC1

acetyl chloride

C6H5OH -f PC15 = C6HBC1 + POC13 + HC1

C6H5OH + Na = C6H5ONa + H

Phenols also form ethereal salts or esters which are decomposed
only in alkaline solutions. The irritating action on the stomach
of one or both components of such salt can be avoided in this way

100

CHEMICAL PHARMACOLOGY

and the antiseptic effect retained. This is an important reaction
in medicine; the Nencki salol principle is based on this fact. The
principle is this: To get the antiseptic effect of the phenols, or
derivatives in the intestine or genito-urinary tract, they cannot
be used as such because they are caustic and irritating to the
stomach. In the form of their ethereal salts they pass through
the stomach unchanged but in the neutral reaction of the intes-
tine, these salts are slowly decomposed into their components.
The physiological action of the components is therefore obtained
and the irritation of the stomach avoided. Since Nencki was
the first who used salol with this idea in mind, the principle when
used with any combination is known as Nencki's salol principle:

C6H5(OC.C6H4OH) + H20 = C6H5OH
Phenol salicylate (salol) Phenol

C6H4OHCOOH
Salicylic acid.

The phenols correspond to tertiary alcohols since they yield
neither aldehydes nor acids on oxidation. When, they have
paraffin side chains, these side chains may be oxidized and yield
the same alcohol aldehydes and acids as when they are free: e.g.,
when oxidized with chromyl chloride

CHoOH

COOH

Toluene Benzyl alcohol Benzaldehyde Benzoic acid.

Toluene can be regarded either as methyl benzene or phenyl
methane —

H— C— C6H5
H

AROMATIC ALCOHOLS

101

It is a colorless liquid which boils at 110°C. It is used as a
laboratory antiseptic especially to prevent the growth of bacteria
when the action of ferments is to be determined. It has rela-
tively little action on ferments. It is of direct interest in medi-
cine only as a source of other drugs, such, as benzyl alcohol,
benzaldehyde and benzoic acid. Toluene can be oxidized in the
body to benzoic acid and is excreted combined with glycocoll
as hippuric acid (q.v.).

Friedel and Craft's Reaction for Toluene Synthesis. — When
benzene is treated with methyl chloride in the presence of alumi-
num chloride, which acts as a catalyzer, toluene is formed
according to the following reaction:

+ CH3C1

HC1

Toluene is also formed by the dry distillation of balsam of tolu
or by distilling toluic acid with lime

C6H4(CH3)COOH = C6H6CH3 + CO2.

XL AROMATIC ALCOHOLS, AND PHENOL ALCOHOLS

When a benzene compound contains an hydroxyl group in a
side chain it is known as an aromatic alcohol. There may also
be mixed compounds in which both phenol and alcoholic groups
are present, e. g.\

1. Benzyl alcohol or phenyl carbinol

C6H5CH2OH or

CH2OH

is a type of the aromatic alcohols; while

102 CHEMICAL PHARMACOLOGY

2. Saligenin or salicyl alcohol

CH2OH

C6H4OHCH2OH or

is both a phenol and an aromatic alcohol.

Benzyl alcohol has recently come into vogue as a local anes-
thetic, and benzyl benzoate has been advised in a variety of
internal conditions thought to be due to a spasmodic condition of
smooth muscle. It undoubtedly has some local action, but it
will take some time to evaluate it as a therapeutic agent. It
has the general properties of alcohols.

Saligenin. — Saligenin is found in willow bark in the glucoside
salicin which is a combination of saligenin and glucose (p. 193).
It can be prepared synthetically by the action of formaldehyde
on phenol —

+ HC<f I
XH

CH2.OH
OH

Saligenin is oxidized in the body to salicylic acid. Like all
phenols it has anesthetic properties.

Cinnamyl alcohol, C6H5CH:CH.CH2OH, is another phenol
alcohol, but it differs from benzyl alcohol in that the side chain is
unsaturated. It is a crystalline substance with the odor of
hyacinths, and is present as an ester in the resin storax. It can
also be prepared by heating benzaldehyde and sodium acetate
together, in presence of a dehydrating agent,

C6H5— CHO
benzaldehyde

CH-

COONa
sodium acetate
= C6H5— CH = CH —

-COONa

ALDEHYDES OF THE AROMATIC SERIES

103

It is not used as a medicine, but the aldehyde is added to per-
fumes to give the odor of cinnamon. Other aromatic alde-
hydes used in perfumes are:

Citral or geranial . . . which gives the odor of lemon —

(CH3)2C:CH.CH2.CH2.C(CH3):CH.CHO

Vanillin . . . which gives the odor of vanilla —

XCHO 1

C6H3A)CH3 3

XOH 4

Piperonal . . . which is related to vanillin and coumarin—

OHO 1

CeH3'

xo/

CH:

It possesses the odor of heliotrope to a remarkable degree. In
commerce it is known as heliotropin.

ALDEHYDES OF THE AROMATIC SERIES

Benzaldehyde is found in bitter almonds as the glucoside
amygdalin :

C2oH27NOu -f 2H20 = 6C6H1206 + HCN + C6H5CHO
amygdalin glucose benzaldehyde

Benzaldehyde also occurs in ester combination with benzoic
and cinnamic acid in balsam of torn, peru, and in storax.
Salicylic aldehyde —

Saligenin + O = Salicylic aldehyde

OH
CH2OH + 0

H20

The free aldehyde occurs in the essential oil of spiroea ulmaria
and in the blossoms of meadow sweet and other volatile oils.

104 CHEMICAL PHARMACOLOGY

It is a fragrant colorless liquid B.P. 196° C.; which is readily
oxidized to salicylic acid.

OH
COOH

In the body each of these aldehydes is oxidized to the correspond-
ing acid.

KETONES OF THE AROMATIC SERIES

The only aromatic ketone used to any extent in medicine is
acetophenone, or hypnone or phenyl methyl ketone, C6H5CO.CH3.
It has fairly strong hypnotic properties, due to the methyl group,
but the action is more powerful and possesses no .advantages
over the well known hypnotics of the aliphatic series.

Phenyl ethyl ketone, CeHsCO^Hs, has a more powerful
action than acetophenone but less than the aliphatic series. It
also is oxidized in the body to benzoic acid.

Benzo phenone, Cel^CO.CeHs, has slight hypnotic properties,
but much less than that of the aliphatic ketones.

When fused with KOH it breaks down into benzoic acid and
benzene and we should expect this reaction to take place to some
extent in the body.

XII. ACIDS AND RELATED COMPOUNDS

Benzoic Acid. — Benzoic acid, C6H5COOH, is readily prepared
by oxidation of benzaldehyde. It is found in gum benzoin and
in all balsams. Crystallization takes place from hot water in
glistening flat plates or needles which melt at 120°-121°C. It
reacts readily with alkali hydrates and carbonates to form benzo-
ates. Benzoic acid or the benzoates have very little toxicity.
They are not much used in medicine at the present time, having
been superseded by the salicylates.

When taken into the bo,dy, benzoic acid combines with glyco-
coll (amino acetic acid) to form hippuric acid, and is excreted as

ACIDS AND RELATED COMPOUNDS 105

such C6H5COOH + H2N.CH2COOH = C6H5CO.HN.CH2COOH
(hippuric acid).

Salicylic acid is the most important hydroxy benzoic acid in
materia medica. It occurs as the methyl ester in the oil of
wintergreen (oleum gaultheria) and in the oil of birch (oleum
betulse).

There are some of the free acids in these oils, and also in the
buds of spiraea ulmaria. It can be prepared by the action of
CO2 on sodium phenate at 200°C.

/OH

2C6H5ONa + C02 = C6H/ + C6H5OH

XCOOH

Salicylic acid is a strong antiseptic and has been used in the
preservation of food, wines, beer, etc.

Sodium salicylate is a frequent remedy in the treatment of
acute rheumatism. Its derivatives, salol, and aspirin, are used
for the same purpose.

It was formerly believed that the synthetic salicylic acid
possessed toxic properties and should not be used in medicine.
Recent investigation has shown, however, that the natural and
synthetic salicylates are identical in therapeutic action. The
earlier toxic action was due to impurities.

When the carboxyl (COOH) group is introduced into the
phenol-nucleus, the action of the phenol is greatly modified,
and the toxicity lessened. The extent of the change, however,
depends on the relation of the OH and COOH in the ring. If
they are in the ortho (1:2) position, as in ordinary salicylic acid,
the antiseptic power is about the same as phenol and the anti-
pyretic action is greatly increased. The 1:3 and 1:4 oxybenzoic

106

CHEMICAL PHARMACOLOGY

acids are neither antiseptic nor antipyretic in action. Also the
introduction of a methyl group in place of the hydroxyl hydrogen

As in ortho-methoxy benzoic acid

OCH;

GOGH

greatly lessens the antiseptic and antipyretic action, just as
methoxy quinine is less antipyretic than quinine.

On the other hand, the introduction of the acetyl group,
CH3CO, as in aspirin, does not cause much change in action,
and in some respects improves the salicylate as a therapeutic
agent.

Aspirin is acetyl salicylic acid and is prepared by the action of
acetyl chloride on salicylic acid at high temperatures.

COOH

CH3CO.C1 =

OOCCHa
COOH + HC1

The stomach tolerates it better than sodium salicylate.

Salol is phenyl salicylate. It .is formed by the action of a
dehydrating agent like POC13 on a mixture of phenol and salicylic
acid.

COOIHHOi

COOC6H5 + H20

salicylic
acid

phenol

salol

MESOTAN

107

It is also formed by heating salicylic acid at 200-220°C.

,OH
2C6H4

\COOH

COOC6H5

Salol is used as an intestinal antiseptic, the action being due
mainly to the slow liberation of phenol, in the natural alkalinity
of the intestine. The principle of giving salol to obtain the
action of phenol and salicylic acid in the intestine without their
irritating action on the stomach was first used by Nencki and
is known as Nencki's salol principle (q.v.), p. 100.

Mesotan or the monomethyl ester of salicylic acid is used to a
considerable extent in medicine. It is prepared by the action of
chlor methyl ether on sodium salicylate:

COOi Na

CH;

Cl : -CH.

Sodium salicylate -f- Chlormethyl

ether

COOCH2O.
/x CH3+ NaCl

Mesotan

When used locally in acute rheumatism it may produce derma-
titis, probably by the irritative action of its hydrolytic products.
It readily undergoes hydrolysis as follows :

/OH ,OH /

C6H/ + H20 = C<£{/ -fHC+CH3OH

XX)OCH2O.CH3 XCOOH \

salicylic formal- methyl
acid dehyde alcohol

Mesotan

Nothing definite can be stated about the form in which the sali-
cylates are excreted. It was formerly taught that salicylic acid
combines with amino acetic acid and is excreted as salicyluric
acid (cf. benzoic acid). Recent work does not substantiate

108

CHEMICAL PHARMACOLOGY

this statement. In the earlier work it is thought that the product
isolated as salicyluric from the urine was salicylic acid, mixed with
some impurities.

Cinnamic acid or phenyl acrylic acid, CeHsCHiCHCOOH, is of
interest because many balsams contain it, and it is the most
important phenyl derivative containing an unsaturated side
chain. Leucocytosis in experimental animals is caused by the
use of it, and for this reason it was used for a time in tuberculosis
with the idea of increasing phagocytosis. The clinical results
have not shown any benefit.

It may be prepared by the condensation of benzaldehyde and
acetic acid *or sodium acetate on

iOH2I CH.COOH = C6HBCH.CH.COOH + H2O

C6H5 0^

^H -f acetic acid cinnamic acid

benzaldehyde.

Balsams are resins or oleoresins that contain cinnamic or
benzoic acids, or both these acids. The acid or its preparations
has very few, if any, uses in medicine.

Phenyl quinoline carbonic acid (atophan) or acidum phenyl
cinchoninicum or phenyl quinoline carboxylic acid = 2 phenyl
quinoline 4 carboxylic acid, Ci6HnO2N,

COOH

C6H5

melts at 210 c. with partial decomposition. It is insoluble in cold
water, slightly soluble in cold alcohol, hot alcohol and ether. A
saturated solution in dilute HC1 gives reddish brown crystals
with platinic chloride. It is soluble in ammonia from which it is
precipitated by AgNO3 or lead acetate. It is used chiefly in
gout to increase the uric acid elimination. It does not relieve
the pain and inflammation of an acute attack to the same degree
as the wine of colchicum, or the alkaloid colchicine.

ANILINE BODIES

The ethyl ester of atophan

COOC2H5

109

is known as acitrin.

Novatophan is the methyl derivative of acitrin and is the
trade name for ethyl, 6 methyl phenyl quinolin, 4 carboxylate —

COOC2H5

C6H5

Its properties and uses are the same as phenyl cinchoninic acid.

XIII. ANILINE AND, TOLUENE DERIVATIVES

Aniline is the basis of the modern antipyretics.
When concentrated HNOs acts upon benzene, nitrobenzene
is formed:

C6H6 + HNO3 = C6H5.NO2 + H2O

Nitrobenzene is a pleasant smelling colorless oily liquid with
the odor of bitter almonds, often used to scent soaps, but mainly
in the manufacture of aniline. It soon darkens on exposure to
air. Its boiling point is 208°C. It has a strong poisonous action.
There are on record cases in which from 10-20 drops has caused
death. It changes the blood to a chocolate color but no meth-
emoglobin has been found, but a special absorption band between
C and D (Fihlene's nitrobenzene band) appears. Nitrobenzene
also causes paralyses of the central nervous system. It is ex-
creted as glycuronic acid in the urine. Its use in medicine is

110

CHEMICAL PHARMACOLOGY

limited. When introduced into the body some of it is reduced to
para-ami no phenol.

NH2

This compound is of interest because all of the aniline com-
pounds or antipyretics are supposed to cause a reduction of
temperature due to the formation of this substance in the body.

Nitrobenzene on reduction with nascent hydrogen gives aniline.
This is the characteristic test (see tests for aniline, p. 112):

NO2 + 6H =

NH2 + 2H2O

Aniline is moderately toxic in its action and produces hemo-
globinuria, and an abundance of urobilin. The typical symp-
toms of aniline poisoning are vertigo, asthenia, gastritis,
diplopia, and sometimes exfoliative dermatitis. Since the para-
amino-phenol is less toxic, attempts have been made to use this
substance as the starting point of synthetic antipyretics, rather
than aniline. Phenacetin is the result of such research.

Acetphenetidinum or phenacetin:

OC2H5 OC2H5

NH2

Aniline

NH2

Phenetidin

NHCOCEU
Acetphenetidin

ANILINE BODIES

111

The following reactions occur in the preparation of phenacetin
OH OH

+ HN03

H20

N02

Phenol Para-nitro-phenol

There is also some ortho nitrophenol formed which can be
separated from the para by distillation with steam :
OH ONa

II.

III.

IV.

NaOH

H20

N02
OC2H5

C2H5I =

+ Nal

NO;

OC2H

N02

This~is reduced with hydrogen
to phenetidin.

OC2H5

CH3COOH =

H20

NH2

Phenetidin

NHCOCH3

Paraacetphenetidin or phenacetin

112 CHEMICAL PHAKMACOLOGY

If aniline be taken internally, it is excreted in combination with
glycuronic acid as glycuronate, which will reduce Fehling's
solution. Some aniline may be formed free in the urine. Ani-
line is a weak base and some of it will distil from acid solution.
It gives the following tests :

I. Hypochlorite Test. — To an aqueous solution of aniline
add a few drops of a filtered solution of bleaching powder or
sodium hypochlorite drop by drop. A purple-violet color
changing to red is produced if aniline be present.

II. Chromic Acid Test. — To a solution of aniline in a porce-
lain dish add a few drops of concentrated sulphuric acid and a
few drops of a solution of potassium dichromate. A blue color
results.

III. Bromine Water Test. — Bromine water with aniline
gives a flesh colored precipitate. The test is sensitive to 1 in
50,000.

IV. Phenyl Isocyanide Test. — Aniline contains the NH2
group and will give the phenyl isocyanide test.

A few drops of aniline solution with chloroform and KOH,
when heated, gives the repulsive odor of phenyl isocyanide.
Acetanilide will also give this test. When acetanilide is boiled
with KOH or alcoholic KOH it is decomposed into aniline and
potassium acetate. It will then give the tests for aniline.

V. Ether or chloroform will extract acetanilide from acid
aqueous solution. Acetanilide will give the indo-phenol
test.

Boil acetanilide with concentrated HC1 and evaporate almost
to dryness. Cool and add 5 cc. saturated aqueous carbolic acid
solution, then a few drops of hypochlorite solution. A violet-red
color is produced. Carefully add a layer of ammonium hydrate;
this will take on an indigo-blue color.

Other drugs (phenacetin) give this blue color, which is charac-
teristic of acetanilide only when preceded by the violet-red
color. See indo-phenol reactions (Richter's Organic Chem.,
1911, vol. II, p. 173).

ACETANILIDE

Acetanilide (antifebrine) is formed when aniline is treated
with acetyl chloride or acetic anhydride.

ACETANILIDE

113

CHsCOCl-

-f-HCl

NIL

NH.COCH3

II. The usual method of preparation is by boiling a mixture
of aniline and acetic acid for some hours :

C6H5NH2 + CH3COOH = C6HBNH.CO.CH3 + H2O

Acetanilide is a colorless crystalline substance which melts
at 116°C. It is hydrolyzed to its components rather readily.
This happens in the body, where aniline is converted into para-
amino phenol, which in greater part is excreted combined with
sulphuric and glycuronic acids. Some of it is excreted as oxy-
carbanile,

- OH

These changes reduce the toxicity of aniline. The antipyretic
action is thought to be due to the paramino-phenol.

Antipyrine or phenyl dimethylpyrazolon is -an antipyretic of
importance. It is not an aniline derivative, but is more closely
related to phenyl hydrazine.

Hydrazine, HN2.NH2, is a strong base and extremely toxic.

Phenyl hydrazine, CeHsNH.NH^, is a compound of great
practical importance and is easily prepared by the reduction of
diazo-benzene chloride (benzene diazonium chloride) as follows:

C6H5.NH2 + HC1

HN02 = C6H5N:N.C1 + 2H20
Diazo benzene chloride

When this is reduced with HC1 and stannous chloride
C6H5N:N.C1 + 4H = C6H5NH.NH2HC1

phenyl hydrazine, HC1, is produced which, when treated with
NaOH, the HC1 is removed as NaCl. The technic of carrying

114

CHEMICAL PHARMACOLOGY

out any of these reactions can be obtained from any book on
methods in organic chemistry.

Phenyl hydrazine is a most important reagent for the identifi-
cation of aldehydes and ketones with which it readily combines
to form hydrazones and osazones. With beta-diketones and
/3-ketone esters, it forms ring compounds containing nitrogen,
the so-called pyrazoles and pyrazolones.

Phenyl methyl pyrazolone is formed when phenylhydrazine
is heated with aceto-acetic ether, as follows :

CHs-CO H2N CH3 - C = Nx

| . +| J>N-C6H6

H2C - CO - OC2H5 HN— C6H5->H2C— CCK

+ H20 + C2H5OH

Aceto-acetic ester Phenyl Phenyl methyl

hydrazine pyrazolon

The name pyrazole comes from pyrrole, a feeble basic body
found in coal tar and in the dry distillation of bones (pyros, fire;
oleum, oil) . By the introduction of N into this ring, it becomes
pyrazole.

CHv/CH

N
Pyrrole

Pyrazole

CH
CH

Pyrazolon is:

CH2

C = O

PYRAZOLON 115

1. Phenyl 2.3 dimethyl pyrazolon, or antipyrine, is:
CH3C-=CH

CH3NN^/C = O

C6H5N

The pyrazolons or ketohydro pyrazoles are the pyrazole deriva-
tives known for the longest time and are produced by the
elimination of alcohol from the hydrazones of /3-ke tonic esters.
Phenyl hydrazone aceto-acetic ester, 1.3 Phenyl methyl
pyrazolon #-ketonic esters, are esters in which the ketone group
C = 0 is the ft position with reference to the COOH group.
For example, in aceto-acetic ester:

CH3.CO CH2 COOC2H5

(ft (a)

The CO is in the 6, position, and this reacts with phenyl hydra-
zine to form phenylhydrazone aceto acetic ester:
CH3.C - CH2 - COOC2H5. CH3.C = CH2

\ II

O N C = O

N- — N-C6H5 \/

H2 H NC6H5

This, on loss of alcohol and water,

gives, 1 : 3 phenyl methyl pyrazolon. Aceto-acetic ester reacts
under some conditions as if the constitution were

CH3.C(OH):CH.COOC2H5

This last form is known as the "enol" form (alcoholic), the
other as the " keto " form. By using the enol form, the formation
of phenyl dimethyl pyrazolon or antipyrine can be more simply
explained.
I. CH3 CH3

I , .. H, |

C.\OH . )N.HNC6H5 C - NH.HNC6H5H20

II N II
CH \.Hj + CH

phenyl hydrazine

COOC2H5 COOC2H5
aceto acetic ester aceto-acetic

"enol" form hydrazone

116 CHEMICAL PHARMACOLOGY

II. On heating, this loses alcohol and gives:

-NH

or 1 phenyl.3 methyl pyrazolon.

CO NC6H5

When this is treated with methyl iodide antipyrine is formed :
CH3C=CH CH3C=CH

I I I

HN CO + CH3I = CH3N CO -f HI

\/ \S

NC6H5 NC6H5

phenyl methyl pyrazolon phenyl dimethyl pyrazolon

Antipyrine is classed as an artificial alkaloid and like alkaloids
it unites with acids, hence when prepared in this way it is
combined with HI. The free antipyrine is separated just as
strychnine is extracted from strychnine sulphate — by making
alkaline with NaOH and extracting with ether, from which it is
crystallized.

The structural formula for antipyrine is proved by the synthe-
sis from methyl phenyl hydrazine and aceto-acetic ester.

(I) CH3 CH3 (II) CH3

I \ I /CH3

C. !OH Hi N-NHC6H5 C N -NC6H5

II II Xah

CH + = CH / ->

I I /""

COOC2H5 CO (OC,H6x/

Aceto-acetic ester (enol)

(III) CH3.C= =CH

CH3.N C = 0

NC6H6

PYRAMIDON

117

Antipyrine was discovered in a search for artificial quinine.
It has none of the quinine action on the malarial organism and is
injurious to the hemoglobin, lessening its oxygen carrying power.
It is very useful in the treatment of neuralgic pains, and like
phenacetin is superior to morphine in this condition. It is
eliminated largely unchanged in the urine though some glycuron-
ate is formed.

Pyramidon is said by many to be superior in most respects
to antipyrine.

PYRAMIDON

Pyramidon-dimethylaminoantipyrine is obtained by the fol-
lowing reactions: a solution of antipyrine hydrochloride is acted
on by nitrous acid, the result being nitroso antipyrine.

CH3 CH3

C N.CH3

-N.CH-

= + HNO2

NO-C

H20

CO— N.C6H5 CO— N.C6H6

When this is reduced, amino antipyrine results:

CH3

-N.CH3

NH2- C

CO— N.C6H6

This is isolated by means of its benzylidene derivative, and
when it is methylated by treatment with methyl iodide it gives
pyramidon.

CH3

C N.CH3

(CH^N.C

CO— N.C6H5

118 CHEMICAL PHARMACOLOGY

Pyramidon is a solid, forming in small colorless crystals,
melting at 108°C. It is easily soluble in alcohol, ether and
benzene It is soluble in 11 parts of water. A aqueous solu-
tion saturated at 70°C deposits oily globules of the drug when
it reaches the boiling point. Its aqueous solution gives a slight
alkaline reaction.

Pyramidon is a more powerful base than antipyrine and in
therapeutics the dose required is only one-third the amount of
antipyrine that would be given. This drug has been used both
as an antipyretic and an analgesic, but the latter is the more
important use. Pyramidon may be prescribed in heart disease
and nephritis, as it affects the circulation only slightly. It is not
irritating to the stomach and does not affect the heart, blood, or
kidneys. It is claimed by some that pyramidon increases
nitrogenous metabolism, contrary to most antipyrine derivatives,
and hence should never be prescribed for diabetics. It is useful,
however, in the chronic fevers of tuberculosis, the acute febrile
conditions associated with typhoid fever, erysipelas, and pneu-
monia. In the treatment of all infectious fevers it should be
used with care, as should all other antipyretics.

The dosage is usually from 0.3 to 0.4 gm. (5 to 6 grains)
in tablet form. A single dose is sufficient for twenty-four
hours.

Pyramidon is excreted in the urine, partly unchanged, partly
combined with glycuronic acid and some as uramino-antipyrine,
a combination of urea and antipyrine:

CH3

C— N.CH3

II
NH2.CO.NH— C

CO— N.C6H5

Another derivative, rubazonic acid, C2oHi7N502, occurs in the
urine after standing, and produces a red color due to oxidation.
Its behavior recalls purpuric acid which is formed when uric acid
bases and caffeine are oxidized (murexide test).

TESTS 119

The tests for pyramidon are:
1. Its melting point 108°C.

2 Solubility — soluble in 11 parts of cold water, readily soluble
in alcohol and ether.

3. -Ferric chloride colors the neutral or slightly acidulated
solution a blue violet color.

4. Fuming nitric acid colors pyramidon solutions blue violet.

5. Bromine water gives a gray color to pyramidon solutions.

6. Tincture of iodine colors aqueous solutions of pyramidon
blue.

Acetanilide Tests

1. It melts at 112°-114°C. It is soluble in 190 parts of water,
4 of alcohol and 17 of ether.

2. It gives the phenol isocyanide test as follows: Add 5 cc. 5
per cent. KOH and heat. It gives the odor of aniline. Now
add 1 cc. chloroform and again heat. The odor of the isocyanide
is produced (see p. 43).

3. Bromine water gives a white precipitate with an aqueous
solution of acetanilide.

4. Heated with a little hydrochloric acid, and an equal volume
of 5 per cent, phenol added, and then if an equal volume of filtered
saturated solution of chlorinated lime be added, it acquires a
brownish red color, which becomes a deep blue on the addition
of excess of NH4OH.

5. When boiled with KOH as in test 2, aniline is liberated.
This may be extracted with ether. If, after evaporation of the
ether, a few drops of calcium or sodium hypochlorite be added
a violet or purple color changing to dirty red indicates aniline.

Tests for Antipyrine

1. Antipyrine is precipitated by the alkaloidal reagents.

2. Ferric chloride added to 2 cc. of a dilute solution gives a red
color which changes to yellow on the addition of a few drops of
sulphuric acid.

3. To 2 cc. of 1 per cent, antipyrine add 0.1 gram sodium ni-
trate. The solution remains nearly colorless, but changes to a

120 CHEMICAL PHARMACOLOGY

deep green color due to the formation of iso-nitroso antipyrine on
the addition of 1 cc. dilute sulphuric acid. If the solution be
concentrated, green crystals of nitroso-antipyrine form.

4. Fuming nitric acid added to antipyrine gives a green color.
Heated with excess of nitric acid, it gives a red color.

5. Add a few drops of sodium or potassium nitrite, then sul-
phuric acid, a green to blue color appears. If much antipyrine
be present nitroso antipyrine CnHn(NO)(ON2) will separate
out in crystals.

Salicylic Acid Tests

1. It melts at 156°-159°C.

2. One gram dissolves in 460 cc. of water, or 42 cc. of chloro-
form, or 3 cc. of ether.

3. Its saturated water solution is colored intensely bluish
violet with ferric chloride solution.

4. An aqueous solution warmed with Millon's reagent gives a
deep red color (monohydroxy phenol test).

5. Bromine water precipitates salicylic acid as tribrom phenyl
hypobromite - a white crystalline precipitate (see phenol, p. 89) .

OBr
/OH

C6H4^ + 4Br2 = C02 + 4HBr + Br

XCOOH

PHENACETIN: ACETPHENETIDINE

1. Acetphenetidine melts at 133°-135°C.

2. It is soluble in 1310 cc. of water, 15 cc. of alcohol or 90 cc.
of ether.

3. Boil several minutes with 3 cc. cone. HC1. Dilute with
10 cc. water, filter and cool. A few drops of chromic acid or
chlorine water will produce a green color.

SACCHARIN 121

4. Boil with 3 cc. cone. HC1. Dilute to 10 cc., cool and filter,
and add 2 cc. 5 per cent, phenol, and a little calcium hypochlorite
solution. A carmine red color develops which changes to blue on
addition of ammonium hydroxide.

SACCHARIN

Saccharin is the ortho sulphonated derivative of benzoic acid,
and can be prepared from toluene. The following formulas
indicate the essential reactions:

/CH3

C6H5CH3 + H2S04 = C6H/ + PC15 =

XS03H

/CH3
C6H/ +NH3 =

XS02C1

,CHs /COOH /CO,

C6H/ = C6H/ = C6H/ ^>NH + H20

XS02NH2 XS02NH XSO/

Benzosulphinidum or
saccharin

This substance is not oxidized by the body, and has no food
value. It is used for its sweetening properties only and for hiding
disagreeable tastes. It is 300 to 500 times sweeter than cane
sugar, and has been used in the past as an adulterant of food
products.

It is a white, crystalline powder, acid in reaction with a faint
aromatic odor. One grain dissolves in 290 cc. water or 31 cc.
alcohol, or about 25 cc. boiling water. It is very soluble in
chloroform or ether. It dissolves readily in alkalies. It liberates
C02 from carbonates which forms a salt by replacement of the
imide hydrogen (compare with phenol).

0.2 Gram in 10 cc. of sulphuric acid, when kept at 48°-50°C.
for 10 minutes, gives not more than a trace of color. It will not
reduce Fehling's solution. With ferric chloride it gives no phe-
nolic reaction, or precipitate — absence of phenols and benzoic acid.
It is excreted in the urine unchanged.

122

CHEMICAL PHARMACOLOGY
THYMOL IODIDE

Thymol iodide, or aristol, is a compound obtained by the con-
densation of two molecules of thymol and the introduction of two
atoms of iodine into the phenolic groups :

CH;

This is a reddish yellow bulky powder containing 45 per
cent, of its weight of iodine. It has a slight aromatic odor,
and has been used to replace iodoform as a dusting powder,
but is much inferior to it as an antiseptic. It is insoluble both
in water and glycerol, and is slightly soluble in alcohol, but
is soluble in ether, chloroform, or collodion. The antiseptic
action of all these iodine-containing organic compounds is due
to the liberation of free iodine. The pure product contains
no free iodine since it does not color starch paste. The
amount of iodine in the product and the amount of thymol
iodide can be determined therefore by determining the iodine
content as follows:

Dry over sulphuric acid in a desiccator.

Mix 0.25 gram with 0.3 gram anhydrous sodium carbonate
in a crucible. Cover the mixture with another gram of anhy-
drous sodium carbonate. Gradually raise the temperature to
that of dull redness, and hold at this temperature until the whole
is carbonized completely. This converts the iodide into sodium
iodide. Cool and extract with hot distilled water. Filter and
wash until the filtrate shows no test with silver nitrate (all the

PHENOLPHTHALEIN 123

iodide has been dissolved) . Evaporate the filtrate and washings
to 150 cc. on a water bath, and add an aqueous solution of
KMnO4 (1 : 20) until the hot liquid remains permanently pink.
This converts the I into KIO3. Add enough alcohol slowly to
remove the pink color which is a disturbing factor, make to 200
cc. Mix well, filter through a dry filter, reject the first 50 cc.
and take the next 100 cc. = J^ the whole, for determination.
Add 1 gram of pure KI and acidify distinctly with H2SO4.
Titrate the liberated iodine with tenth-normal sodium thiosul-
phate, adding starch solution near the end, as an indicator.
Each cc. of tenth-normal sodium thiosulphate corresponds to
0.002115 gm. of thymol I. In the reaction the acid added
converts the KIO3 into the bi-iodate KH(IO3)2 and this liberates
iodine from the added potassium iodide according to the formula :

KH(I03)2 + 10KI + 11HC1 = 121 + 11KC1 + 6H20
12)389.94 12)1523.04

10)32.495 10)126.92

3.2495 gm. 12.692 gm. in 1000 mils V.S.

Since in this reaction 12 atoms of iodine are titrated but
only 2 atoms of this or % comes from the thymol, the I. factor
for the thymol is % of 12.692 or in tenth-normal solution % of
0.012692 = 0.002116 gm. iodine per cc. thiosulphate.

PHENOLPHTHALEIN

This phenol derivative has always been important in chemistry
as an indicator. It has recently been used in medicine as a mild
cathartic either by itself or mixed with other substances, as agar.
Kidney function has been determined by its use, but for this
purpose its derivative phenolsulphonephthalein is more com-
monly used.

Formation of phenolphthalein:

When toluene is treated with bromine at ordinary tempera-
tures in the absence .of direct sunlight, bromine may be
substituted for H in the ring, a mixture of ortho, meta and para
brom toluene being obtained:

124

CHEMICAL PHAKMACOLOGY
CH.3 CH.3 CH;

ortho

meta

para

If ortho brom toluene is treated with methyl bromide and
sodium, xylene is formed:

CH3

CH3Br + 2Na

0. xylene on oxidation gives phthalic acid :

2NaBr

CH3

CH,

+ 40

COOH

+ 2H20

COOH

Phthalic acid
When phthalic acid loses water, phthalic anhydride results :

This combines with two molecules of phenol to form phenol-
phthalein:

PHENOLSULPHONEPHTHALEIN

125

,C6H4OH

C6H4

While phenolphthalein is insoluble in water it is dissolved by
the bile in the intestine and develops a mild irritant action. It
is used in medicine almost solely for its cathartic effect. In this
respect it resembles the senna group of cathartics, but has the
advantage of being tasteless, and can be made readily into tablets.

Nosophen, (C6H2I2OH)2C

4)>co,

or tetraiodophenol-

phthalein, is a powerful antiseptic. It is an iodine compound in
which the iodine is attached directly to the ring; consequently,
it is but little if any broken down by the body. When taken
internally it is not absorbed but passes through the system un-
changed, a small amount being absorbed and excreted by the
kidneys unchanged. If the urine is alkaline it has a pink color.
This absorption and excretion may be shown by taking 0.15 gram
phenolphthalein in a capsule, collecting the urine every hour for
three hours and making it alkaline with sodium hydroxide. It
has been used as a dusting powder. Since it contains two
hydroxyl groups, it can form salts" with the heavy metals such
as bismuth, iron, mercury, and zinc.

126 CHEMICAL PHARMACOLOGY

Phenolsulphonephthalein :

C6H4 C6H4OH

/\/
S02 C

O C6H4OH

is a product of the interaction of phenol and sulphobenzoic acid
anhydride :

C6H4

/\
SO2 C02

This phthalein is a bright red crystalline powder slightly
soluble in water and alcohol with a yellow color, but soluble in
dilute alkalies, in which it gives a purer red than phenol phthalein.
It is used in medicine to test the kidney function. When 6
mgm. are injected intramuscularly or intravenously, 60-80 per
cent, of it is excreted by the normal kidneys within two hours.
The amount excreted is determined by making the urine alkaline
and comparing the color with a known concentration of the drug
treated in the same way.

Determination of Kidney Function

Give the patient about 300 cc. water to insure diuresis. In
twenty minutes the bladder should be emptied, and 6 milligrams
of the phthalein injected into a large muscle. The phthalein for
injection can be procured on the market in solution ready for use.
The time of injection is noted, and the urine collected at the end
of one hour and ten minutes and again one hour after the first
collection. Keep the samples separate, and determine the amount
of phthalein excreted immediately or, if this cannot be done,
preserve by the addition of phosphoric acid until the determina-
tion can be made as follows:

Make both samples sufficiently alkaline with 20 per cent. NaOH
to bring out the maximal color. Dilute to 1000 cc. with water

NAPHTHALENES

127

and filter. Compare the color with that produced by 6 milli-
grams of the phthalein in a liter of water or normal urine treated
in the same way. A colorimeter may be used, but sufficiently
accurate results may be obtained by diluting the standard in a
graduated cylinder until the colors are matched.

In normal cases 40 to 60 per cent, of the drug should be
eliminated in the first hour and 20 to 25 per cent, more in the
second hour, making a total of 60 to 85 per cent.

XIV. NAPHTHALENES (Tar Camphor)

Naphthalene occurs in coal tar in larger quantities than any
other hydrocarbon and it is rather easily isolated. It is also
formed when the vapors of many organic compounds are passed
through red hot tubes. The luminosity of coal gas is largely
dependent on its naphthalene content. Distillation takes place
between 170° and 230°. The pure product melts at 79° and
boils at 218°. It crystallizes in large lustrous plates and has a
characteristic odor. Clothing may be protected from moths by
naphthalene which is used in the form of moth balls. On
oxidation, naphthalene and its derivatives may yield phthalic
acid (p. 124), which is used in the preparation phenolphthalein.

+ 9O

COOH

N02
Phthalic acid Nitronapthalene

+ 90

N02 NH2

Nitrophthalic acid Amino napthalene Phthalic acid

128

CHEMICAL PHARMACOLOGY

Napthalene compounds, while extensively used in the manu-
facture of dyes, are but little used in medicine; some are
employed principally as antiseptics and preservatives.

The products most used are the a and 0 napthols :

napthol

These give the reactions of the phenols. The a napthol is far
more toxic than the 0 napthol, and is not employed in medicine.
0 napthol is used mainly in dermatology, and as an intestinal
antiseptic. It has been used in the treatment of hookworm,
and as a food preservative. Its use as a hookworm remedy is
much less important since thymol and oil of chenopodium have
been used.

Beta-napthol combines with benzoic acid to form benzonapthol
and with salicylic acid to form 3 napthol salicylate. Betol
is a proprietary /3 napthol salicylate.

The napthols are eliminated from the body, combined with
glycuronic and sulphuric acids. Most phenols are excreted in
this way.

ANTHRACENES

The anthracenes are a very important group of drugs. Many
of the most used cathartics owe their action to anthracene
derivatives.

Anthracene is a derivative of coal tar, and can also be prepared
synthetically. The dye alizarin, or " Turkey red," is prepared
from it. Crystallization is in colorless plates which melt at 213°
and boil at 351°C.

Its synthesis from ortho brom benzyl bromide and sodium is
shown by the reaction :

ANTHRAQUINONE

129

4NaBr + 2H

Anthracene may also be prepared by the method of Anschtitz,
from benzene, aluminum chloride, and tetrabrom ethane.

BrCH.Br /CH\

CeHe -f- -{- CeHe , — * CcH4x ,Q§R.±

BrCH.Br \CW

Anthracene

This synthesis proves the structure of anthracene to be two
benzene nuclei, united by the groups CH — CH linked to the 2
ortho atoms of the benzene nuclei.

Nitric acid converts anthracene into anthraquinone.

Anthraquinone

The active principles of senna, rhubarb, cascara, aloes, etc.,
consist of the anthracene derivatives, emodin, cathartin, chrys-
ophanic acid, and their compounds.

130

CHEMICAL PHARMACOLOGY
O

Emodin or trioxymethyl anthra-
quinone

Chrysophanic acid or dioxymethyl

anthraquinone

These substances occur in the glucosides of rhubarb. The
digitalis glucosides also are anthracene derivatives.

QUINONES

The quinones are a peculiar class of substances that have no
analogues in the aliphatic series. Benzo quinone was the first
number, and was prepared from quinic acid. There is some
doubt about the formula — two forms being given:
0

and

Formula No. 1 is most generally accepted. The accepted
formula agrees with the fact that quinone readily adds four

QUJNONES

131

bromine atoms, and behaves like a diketone and unites with two
molecules of hydroxylamine with a loss of two molecules of water
to form quinone dioxime:

N— OH

O + 2 NH2OH

+ 2 H20

N— OH

Quinone in the body is reduced to hydroquinone (quinol) which
in turn unites with sulphuric and to some extent glycuronic acid.
Vieth (quoted by May) has. investigated the purgative action
of the synthetic anthra quinones, and his results indicate that the
position of the OH groups has some relation to the activity, and
that the presence of the methyl group has little influence. The
structure of the molecule is indicated as follows:

The purgative action of the products arranged in terms of the
strongest, or anthrapurpurin as 1 is shown in the following table:

This purgative action also gives some indication of the length
of time the substance remains in the intestine — chrysophanic
acid because of its rapid absorption exerts little cathartic action.

132

CHEMICAL PHARMACOLOGY

Substance

Strength
of action

Anthrapurpurin

1—2—7 trihydroxy-anthraquinone

Flavopurpurin
Anthragallol . ....

1—2-6 trihydroxy-anthraquinone
1—2—3 trihydroxy-anthraquinone

Purpuroxanthin
Alizarine-Bordeaux

1-3 dihydroxy-anthraquinone
1—2—3—4 tetrahydroxv-anthraquinone

Purourin . .

1—2—4 trihvdroxv-anthraauinone

Anthra purpurin diacetate has been sold as a purgative, but it
is absorbed to a considerable degree and irritates the kidney.
Anthraquinone acts more like a diketone than a true quinone.
It is readily reduced in the body, and readily forms an oxime
with hydroxylamine (see quinone). Emodin is partly absorbed
and is then excreted in the urine, which turns red on the addition
of an alkali. Sufficient may be excreted in the milk to purge an
infant. In passing through the intestine all these drugs may
produce griping, and since they do not cause evacuation until
they enter the large intestine they are thought to act only on this
part of the tract. . . .

An important derivative of anthracene is acridine:

and phenyl acridine:

HETERO CYCLIC COMPOUNDS

133

These are the basis of a few technically important dye stuffs,
which are amino derivatives of these compounds. These acridine
dyes are among the list of industrial poisons to which the atten-
tion of physicians practicing in industrial communities has been
called by the Bureau of Labor in Bulletin, May, 1920.

XV. HETERO CYCLIC COMPOUNDS

This is a group of nitrogen bases which are of interest chiefly
as being the important nuclei of akaloids. These are pyridine,
quinoline, isoquinoline, and related bodies. They are found to
some extent in the light oil of coal tar, in which they are the basic
constituents.

Pyridine has the formula.

It may be regarded as an ammonia derivative in which the
valences of the nitrogen are occupied by a ring. The alkaloids
have a similar structure. The nitrogen of pyridine, being un-
saturated, can add acids as does ammonia, e.g. :

Cl Pyridine hydrochloride.

Pyridine can be obtained from coal tar, bone oil, and can be
prepared from penta methylene diamine by heating :

134

CHEMICAL PHARMACOLOGY
H2

CB2— CH2— NH
+ ! H
CH2— CH2— !NH2

Piperidine

3H2O

Piperidine + 3. oxygen— > Pyridine + water

There are other ways of preparing pyridine, as by the condensa-
tion of aceto-acetic ether as described under antipyrine formation.

XVI. CARBOHYDRATES

The greatest part of plants consists of compounds of carbon,
hydrogen, and oxygen, called carbohydrates. In most of these
compounds the hydrogen and oxygen are in the same proportion
as in water. They are classified as follows :

1. Monosaccharides, the glucose group, or monoses, simple
sugars, including glucose, fructose, galactose, pentose, etc.
These will not yield simpler sugars on hydrolysis, but break into
smaller molecules. Water and CO2 are the ultimate products,
whether oxidation occurs in the body or in the test tube.

2. Disaccharides, the cane sugar group (bioses, saccharbioses),
include cane sugar, maltose, lactose, etc. On hydrolysis
these break up into simpler sugars, or monosaccharides. The
hydrolytic products are the same in the body as in the test tube.

3. Polysaccharides, the cellulose group (or amyloses amyloids),
which include starches, glycogens, gums, pectins, celluloses, etc.
They are not sugars, but can be hydrolyzed into sugars.

CARBOHYDRATES 135

The carbohydrates are of importance primarily as food, and
secondarily as medicines.

The main carbohydrates used in medicine are: acacia, traga-
canth, starch, flaxseed, cane sugar, fructose, and glucose.

DIFFERENCE BETWEEN STARCHES, GUMS, CELLULOSES AND

SUGARS

1. The products of digestion are different. Starch breaks down
during digestion as follows :

Starch (C6Hi005)x

-Amylodextrin

Maltose Erythrodextrin

Maltose Achrodextrin

Maltose Maltose

Glucose
/\

H2O

There are probably many intermediate products between these
such as other dextrins, alcohol, etc., and probably other sugars
formed, but the final products are, in all cases, carbon dioxide
and water. Often some sugars and dextrins are found in cooking
and this is why cooked food is sweeter than uncooked.

General Tests

1. Examine the various gums, sugars, and celluloses, and make
notes of the physical differences.

136 CHEMICAL PHARMACOLOGY

2. Test the solubility in water and alcohol (see under
mucilages) .

3. Molisch's Reaction. — Treat the carbohydrate in solution
with a few drops of 15 per cent, alcoholic solution of alpha
napthol. Then add slowly, sliding down the side of the tube,
enough H2SO4 to form a layer at the bottom of the tube. A
reddish violet band appears at the line of contact. This reaction
reveals the presence of a carbohydrate even when in combination
with protein. The test is due to the formation of furfurol
(furfural or furfurane aldehyde).

It has the formula C4H3O.COH =

JHCO

O
Furfurol

On oxidation it yields pyromucic acid =

JCOOH

Mucic acid (q.v.) also yields pyromucic acid on destructive dis-
tillation. Furfural results from the oxidation of pentoses and
pentosanes (sawdust, gums, bran, etc.) The name comes from
furfur = bran. It is contained in beer, brandy, fusel oil, etc.,
and was formerly thought to modify the intoxication by fusel
oil, but it is not so considered now. It is a colorless oil, has a
pleasant odor and gives the aldehyde reactions.

(a) To show the presence of furfural : Place about 3 grams of
bran, gum arabic, or any of the above mentioned substances in a
distilling flask. Add 100 cc. 12 per cent. HC1. Distil over
10-30 cc. Let it drop on a filter paper moistened, with aniline
acetate or a mixture of 5 drops colorless aniline and 8 drops
of acetic acid. Note the color; add a few drops of this to a few cc.
of the distillate.

(6) Treat the distillate with a few drops of 15 per cent, alco-
holic solution of a napthol. Compare with Molisch's test.

CARBOHYDRATES 137

STARCHES (C6H10Oo)x

Starches yield maltose and hexose sugars only on hydrolysis.
The vegetable gums and mucilages in addition to hexoses give an
abundance of pentoses.

Galactose is often found among the gum hexoses, consequently
when oxidized with nitric acid gums yield mucic acid (COOH
(CHOH)4COOH).

Starches, dextrins, dextose, levulose, cane sugar, or maltose
do not yield mucic acid on oxidation.

Tests for Starch

1. Add a few drops of iodine solution to a little thin starch
paste. The resultant blue color is due to C6Hio05I. When
heated, the color disappears, to reappear on cooling. The color
can be destroyed by adding anything that has a stronger affinity
for the (I) than has starch, e.g., Ag salts, alkaline hydrates, and
sodium thiosulphate (see decolorized tincture of iodine).

2. Test starch solution with Fehling's solution. No reduction.

3. Boil a solution of starch with a few drops of dilute H2SO4.
Neutralize, or make slightly alkaline with KOH or NaOH,
and again try Fehling's test. This time there is a reduction.
Explain.

NOTE. — Fehling's solution is reduced by anything containing
aldehyde or ketone groups. The reducing sugars are either aldo-
ses or ketoses. The statement is sometimes made that the reduc-
tion is due to the aldehyde and ketone groups, and in the case of
these simple sugars this may be correct, but the fact that chloro-
form, adrenalin and other drugs reduce Fehling's solution renders
the explanation questionable. Fehling's solution on standing
also reduces itself because of the tartrate it contains, and tartrates
contain no aldehyde or ketone groups. A. P. Mathews thinks
that the alkali of the Fehling breaks the sugar into fragments
and these fragments are reducing bodies.

4. Dry starch treated with I in KI solution gives a brown
color.

5. Starch paste when hydrolyzed by saliva or acids fails to
give the iodine reaction.

138 CHEMICAL PHARMACOLOGY

SUGARS

Sugars are predigested foods. The bioses are hydrolyzed into
monoses before absorption. The characteristic sugar group is an
aldehyde or ketone group with one or more

OH O OHO H

I // I II

— G-C or — C— C— C— H

I \ II

H H H H H

hydroxyl groups. Invariably one hydroxyl group is in the alpha
position with reference to the aldehyde or ketone group.

Tests for Sugars

1. All sugars give Molisch's reaction. This is a general test
for carbohydrates. See p. 136.

2. With iodine, starches give a blue color; gums, a port wine
color; sugars, no reaction, and celluloses, no reaction.

3. With Fehling's solution, starches, gums, and celluloses give
no reduction until they are hydrolyzed. Cane sugar does not
reduce it until inverted, while all other common sugars reduce
Pehling's solution directly.

Apply Fehling's test to a solution of cane sugar. Hydrolyze
as under acacia, and again test. Explain and write reaction.

4. Fermentation. — -Pentoses do not ferment with yeast as all
other common simple sugars do. Maltose ferments directly, cane
sugar and lactose only after hydrolysis. To a 2 per cent, solution
of each of these sugars add a small particle of yeast and keep at a
temperature of 40°C. Results?

The Uses of Sugars. — They are used as flavoring and sweeten-
ing agents in medicines, and in strong solutions as preservatives.
Molasses is used in domestic medicine as a laxative. Lactose is
used in the preparation of infant fotjds and as an excipient or
vehicle in pharmacy. Levulose is sometimes given to diabetics
who cannot utilize glucose, but the advisability of this is question-
able since it is perhaps as difficult to oxidize in the body as
dextrose and other sugars. In cases of glycosuria it is often neces-
sary to distinguish between pentosuria, le vulosuria, lactosuria and
glucosuria. To determine this, differences of rotation, fermenta-

CARBOHYDRATES 139

tion, the melting point of the osazone and other tests must be
made.

CELLULOSE

Cellulose is a mixture of complex carbohydrates. Next to
water, it is the most abundant substance in plants where it consti-
tutes the greater part of the cell wall. Because it is not a pure
chemical, it is often called crude fiber. Celluloses are not diges-
tible except by strong reagents and the higher animals digest
but -little cellulose, although some of the lower animals do.
This indigestibility renders cellulose valuable in the treatment of
chronic constipation. In such cases cellulose acts by stimulating
the bowel mechanically. Apparently some indigestible volume
is needed to elicit the normal function of the intestine. This is
one of the reasons why fruits and vegetables are so highly
recommended in cases of chronic constipation.

The celluloses include vegetable fibers, cotton, linen, hemp,
filter paper, etc. They are insoluble in water, alcohol and ether.
While they are indigestible, strong H2SO4 converts them into
dextrin and glucose. Treated with HN03, cellulose yields gun-
cotton, cellulose hexanitrate, which is highly explosive. If the
HN03 is allowed to act a short time only, the tetra and penta
nitrates are formed. These are not explosive, and dissolve
readily in a mixture of alcohol and ether with the formation of
collodion (see collodion and flexible collodion.)

Tests for Cellulose

1. Examine guncotton. Test its' solubility in water and
alcohol.

2. Dip a piece of filter paper in a mixture of 4 volumes of
H2S04 and one of water and immediately wash it off with water.
Let dry and apply the iodine test. Compare the test with the
original paper.

3. Crude Fiber. — The term fiber is applied to those carbo-
hydrate products in drugs or in food which are insoluble in
dilute acids and alkalies. Inasmuch as they are not pure cellu-
lose, they are often designated as crude fiber.

To determine the amount of crude fiber in a food or drug:
Weigh out 2 grams of the dry material. Extract with ether until

140 CHEMICAL PHARMACOLOGY

all lipoids are extracted. Boil the residue with 200 cc. of 1.25
per cent. H2S04 for 30 minutes, using a reflux condenser.
Filter through asbestos, wash with boiling water. Transfer the
asbestos, etc., to the flask again and repeat boiling with 1.25 per
cent. NaOH 200 cc. Boil for 30 minutes, filter through a Gooch
crucible and wash free from alkali with hot water. Dry at
110°C. until the weight is constant. Incinerate and weigh
again. The loss in weight is considered to be crude fiber.

HEMICELLULOSE

Hemi, pseudo, reserve cellulose, or paragalactahe substances
are not well defined and seem to be mixtures of mannans, xylans,
arabans, galactans, or complexes which when treated with hot
dilute HC1 or H2SO4 may yield galactose, rhaminose, mannose,
fructose, arabinose, or xylose, whereas ordinary cellulose does
not, except when treated with strong acids. The seeds of many
plants, especially nut shells and stony seeds, cocoanut rind, and
young plant tissues, contain the reserve carbohydrate, which is
called hemicellulose. It serves as reserve food or supporting
tissue. From its reactions hemicellulose is considered simpler
than cellulose in composition. When boiled with acid the- only
product of hydrolysis is a hexose. Hemicellulose is also dissolved
by dilute alkali and by means of enzymes, and may be converted
into gums. The formation of galactose on hydrolysis suggests
a relationship to the gums.

AGAR

Agar (agar-agar) is a carbohydrate extracted with hot water
from certain marine algae which grow mainly along the eastern
coast of Asia and Japan. The extract is evaporated and the
product sold in bundles of shreds, or as a powder. It consists
practically of the hemicellulose, gelose, (CeHioOs), and dissolves
in 500 parts of water. When boiled with about 500 parts of
water' for 10 minutes, it yields a stiff jelly on cooling. It is used
principally in the preparation of bacterial culture media, and
because of its indigestibility has been recommended as a cathartic.
In this respect it acts like bran and vegetables rich in cellulose.v
Phenolphthalein agar, is agar impregnated with 3 per cent, phenol-

CARBOHYDRATES 141

phthalein to increase its laxative effect. Regulin is another
preparation of agar with cascara.

Agar, because of its cheapness and good jelling properties, has
been employed as a "coagulator" in the manufacture of cheap
jellies. To detect agar in such jellies the product is heated with
5 per cent, sulphuric acid, a little permanganate is added, and
after the material settles, diatoms in large numbers will be found
if agar has been used.

GUMS

Gums are desiccated exudations of certain plants, obtained by
incising the limbs or branches. They are somewhat transparent
carbohydrates, isomeric with starch. Acacia and tragacanth are
the most important. They have a physical action only and are
used mainly as excipients or vehicles (see mucilages and demul-
cents). Their use is objectionable in cases where they are hydro-
lyzed by bacteria and the products remain as irritating
substances. They are but little used externally for this reason.
Pectin or vegetable jelly is closely related to the gums and causes
fruit to set or "gel". Gums lessen the irritation of medicines
and are used in enemata where it is desirable to retain the solution
in the rectum for some time. The taste of acids or salts is also
lessened by being mixed with colloids, as in fruits. Raspberries
contain more acid than currants but taste less acid because they
contain colloid. These effects are due to lessened absorption
and also to protection of the sensory nerve endings by the
colloidal material.

Tests for Gums

1. Test the solubility of gum acacia and tragacanth in water
and alcohol.

2. Mix watery solution of acacia with an equal volume of
alcohol. Result? What has happened? Compare with glu-
cosides under the same treatment. What is the difference?

3. Test a water solution of acacia or tragacanth with Fehling's
solution.

4. Test a water solution of a gum with iodine solution.
Compare results with starch solution. Note differences.

5. To a solution of acacia in a test tube add a few drops of

142 CHEMICAL PHARMACOLOGY

H2SO4. Boil for two or three minutes. Neutralize with KOH
or NaOH and test with Fehling's solution.

6. Compare the taste of a 1 per cent, citric acid in water with
1 per cent, citric acid in 10 per cent, mucilage of acacia.
Explain.

7. Mix a small quantity of cottonseed oil with 3 volumes
mucilage of acacia and shake until an emulsion is formed. Add
alcohol to the mixture and note results. Explain.

8. State the differences between starches, sugars, and gums;
between gums and glucosides; glucosides and alkaloids.

PECTINS

Pectins are carbohydrate bodies whose composition is known
but slightly. They are associated with cellulose in the plant.
It is due to pectin that fruit juices "gel". The phenomenon of
gelling is similar to the setting of gelatin, but the composition of
the gelling body is different in the two cases. In the case of
gelatin it is a protein, while pectin is a carbohydrate.

Pectin is especially abundant in apples, pears, gooseberries
and currants. It is also found in abundance in carrots, beet
roots, etc., as pectose, which as ripening proceeds is converted
into pectin.

The clotting of plant juices is said to be due to an enzyme
pectase, but that it will occur without enzyme action is apparent
from the gelation after prolonged cooking which destroy enzymes.
According to Duclaux and others the clotting of pectin is due to
the presence of calcium salts and the presence of an enzyme is
unnecessary. The clotting therefore would seem similar in
nature to the clotting of blood. According to Freimy (Jour.
Pharm. et chim., 1840, 26, 368) the hardness of unripe fruit is
due to pectose. When this is boiled with dilute acids or alkalies,
pectin, parapectin, metapectin, and pectic acid are formed.
Some of these exist in the plant combined with calcium, in the same
sort of union as that which occurs in gums.

No very characteristic tests for pectins can be given. Methyl-
ene blue and some other substances stain pectins but not pure
cellulose, while crocein, napthol black and orseille, stain cellulose,
but not pectin. Pharmacologically pectins may exert a vitamin
effect, but this is not proven.

FATS AND OILS 143

METHOD OF PREPARING PECTIN

(C. H. Hunt, Science, 48, 201, 1918)

The object in view was to prepare pectin, so that it could be
added to fruit juices which are low in pectin, and so cause a
gelling of non-gelatinating juices: The method was as follows:

Dried apple pomace (60 g.) was boiled with 3 successive
portions (200 cc. each) of H20, and filtered after each boiling.
For each 100 cc. of filtrate, 25 g. (NH4)2S04 were added; the re-
sulting solution was heated to 70°; the pectin separated as a
grayish white flocculent precipitate which was collected on a
filter, dissolved in hot H2O, again precipitated with (NH4)2SO4
and collected on a filter, dried at 60 to 70°, then washed several
times with cold H2O to remove adhering (NH4)2SO4, and again
dried. The product was tested for gelatinizing power "by adding
to a 1 per cent, solution of the pectin 0.5 per cent, solution of
citric acid and 65 g. of sugar. This solution was boiled for 10 to
20 minutes and upon cooling a nice stiff jelly was produced.
The taste did not indicate the presence of (NH4)2S04 and upon
dissolving the jelly in hot H2O only a slight milkiness was pro-
duced when tested for sulphates." If wet pomace be used, in
addition to the 25 ''g. (NH4)2S04 per 100 cc. of filtered extract,
that salt must be added in extra portions 5 g. each until precipita-
tion of the pectin occurs; it may also be precipitated by saturation
of the filtered extract in the cold (NH4)2S04. The (NH4)2S04
method gave a yield of 6.33 per cent, pectin/ the alcohol method a
yield of 6.91 per cent. Concentration of the pectin extract either
at a temperature below the boiling point or by freezing did not
impair the quality of the pectin and reduced the amount of (NH4)2
SO4 required.

XVII. FATS AND FIXED OILS

Fats "and fixed oils are salts of glycerine with fatty acids, the
acids being principally palmitic, stearic, and oleic, or mixtures
of these. The oils are liquid fats. The consistency of fat
depends upon the relative amount of the acids present: if
stearic acid only is present, the fat is hard (e.g., oil of theobroma-
cocoa butter) ; if oleic acid is the principle one present, the fat is
soft or oily (as in all the ordinary fixed oils). Tallow is the fat
from beef and mutton suet, while lard is hog fat. To obtain these

144 CHEMICAL PHARMACOLOGY

relatively pure, the fats are sometimes kneaded in a muslin bag
under hot water. The pure1 fat separates and floats on the sur-
face, while the connective tissue is held in the bag. High heat
decomposes fats with a resultant formation of irritating sub-
stances (acrolein — acrid oil). Vegetable oils are obtained by
expression of the seeds, which, when the fats are solid, are often
heated to liquefy the oil and facilitate the process. The fixed
oils are entirely different from the volatile oils (q.v.).

Fats are sometimes called glycerides, glycerine esters, or etheral
salts. Glycerine with stearic acid alone is called stearin, or
glyceryl stearate; with palmitic acid, palmitin, and with oleic
acid, olein. The combination is represented by the following
formulas — where R represents any fatty acid radical:

CH2OjH HOJOC.R CH2O.OCR

CHO !H HO! OC.R -> CH.O.OCR + 3H20

CH20 |H HOJOC.R CH2O.OCR

Glycerine + fatty acid — > Fat + water

Stearic acid Ci7H35COOH

Stearin C3H5(C18H35O2)3

Palmitic acid C16H3iCOOH

Palmitin , C3H5(C16H3i02)3

Oleic acid Ci7H33COOH

Olein C3H5(C18H3302)3

CLASSIFICATION OF OILS

Oils are divided into drying and non-drying. Some oils which
contain linolenic and linolic acids when exposed to the air absorb
oxygen and become resinous and leave a hard elastic film. This
process is hastened by catalytic agents such as litharge, manga-
nese dioxide and the acetates and borates of leadj manganese, and
zinc. These agents are known as " driers. " Oleic acid does not
absorb oxygen. The drying oils are less viscous and less stable
than the non-drying. This drying and unstable property is due
to the unsaturated fatty acids. The drying vegetable oils are:

FATS AND OILS 145

I. The linseed oil group which includes:

Linseed

Hempseed

Walnut

Sunflower

Poppyseed

Nigerseed

The semi-drying or cottonseed oil group includes:

Cottonseed

Sesame

Beechnut

Maize

Rape

Brazil nut

This group is composed mainly of the glycerides of oleic and
linolic acids.

II. The non-drying or castor oil group includes :

Castor
Croton

The non-drying olive oil group includes :

Olive

Almond

Rape . .

Peanut

Mustard oils

Most animal fats and waxes are non-drying, but the fats of the
rattlesnake and ice bear are drying, while horse fat is semi-drying.

Both animal and vegetable fats and oils are used in medicine.
The most important animal fats are lard or swine fat, suet or
mutton fat, tallow or beef fat, and butter fat.

The relative amount of the various fatty acids in these differ-
ent fats varies widely", not only with the species but also with the
food of the animal. Lard may contain 90 per cent, olein and
melt as low as 28°C. when the diet is cora-meal, or as high as 35°C.
when the animal is fed on oats, peas and barley; the fat in this
case contains less olein than when the animal is corn fed. Fat
10

146 I CHEMICAL PHARMACOLOGY

from different parts of the same animal may vary in melting
point due to differences in composition. Human fat melts as
low as 17.5°C. because it is rich in olein, tallow melts at about
45°C., and suet at 45-50°C. If a fat contains only oleic acid
with glycerine it is an olein or triolein and is a liquid at 0°C.,
while palmitin (tripalmitin) melts at 62°C. and stearin (tri-stearin)
at 71.5°C.

Butter fat is a mixture of palmitin, stearin and olein, and in ad-
dition it contains 6 to 8 per cent, of volatile fatty acids combined
with glycerine. These are butyric, caproic, capryllic, capric,
with traces of lauric and myristic. No other fat except cocoa-
nut oil contains so high a percentage of volatile fatty acids.
This fact aids in the recognition of an adulteration of butter with
other fats as in oleomargarine, which consists chiefly of the higher
fatty acids. Butter is little if at all used as a medicine, but it is
extremely valuable as a food and contains vitamines essential to
normal growth, which few if any other fats can adequately
supply.

Fats and oils are widely distributed in the vegetable kingdom,
chiefly as the glycerides of palmitic, stearic and oleic acids, but
the following fatty acids are frequently found :

I. Isobutyl acetic or caproic CH.CH2.CH2.COOH

Caprylic CH3(CH2)6COOH

Capric CH3(CH2)8COOH

Lauric CH3(CH2)i0COOH

Myristic CH3(CH2) 12COOH

Palmitic CH3(CH2)i4COOH

Stearic CH3(CH2)i6COOH

Arachidic CH3(CH2)i8COOH

Behenic CH3 (CH2) 20COOH

These acids all conform to the general formula

(CnH2n02).

There are other fatty acids of the oleic or acrylic series that
conform to the general formula

(CnH2n_2O2).

FATS AND OILS 147

II. These are Tiglic acid C6H8O2

Oleic Ci8H3402

Elai'dic Ci8H34O2

Iso-oleic Ci8H3402

Erucic C22H4202

Brassidic C22H4202

The most important of these in medicine are oleic and tiglic —
found in croton oil.

III. The linolic series

(CnH2n - 402)

1. open series linolic acid Ci8H32O2

2. Chaulmoogric acid Ci8H3202

a cyclic compound, from chaulmoogra oil, which is used in the
treatment of leprosy.

IV. A linolenic acid series of the general formula

CnH2n_6O2
is also known but not important in medicine.

V. A clupanodonic series with the general formula

CnH2n_8 O2

VI. A ricinoleic oleic series, general formula

CnH2n_203

of which the acid from castor oil is the important representative.
While many of these are unimportant in medicine, they illustrate
because of their unsaturated condition, what is meant by the
iodine number — described below. Unsaturated compounds as
a rule are also more active physiologically than saturated
compounds.

The chief vegetable fats used in medicine are :

Palm oil, which consists almost entirely of palmitin and cocoa
butter, contains about

40 per cent, stearin, 20 per cent, palmitin,

30 per cent, olein, 6 per cent, linolein,

Linseed oil consists mainly of oleins — a mixture of oleic, linolic,
linolenic, and isolinolenic acids.

148 CHEMICAL PHARMACOLOGY

Cottonseed oil consists chiefly of olein, palmitin, and linolein,
with small amounts of linolenic acid.

Olive oil, consists of 72 per cent, of liquid glycerides, made
up of olein 94 parts, linolein 6 parts, and about 28 per cent,
palmitin.

Castor oil consists mainly of the glycerides of triricinolein,
together with ricinisolein, palmitin and dioxystearin.

Croton oil: The composition of croton oil is very complex.
The glycerides of at least 10 acids have been found, namely —
oleic, palmitic, stearic myristic, lauric, valeric, formic, butyric,
acetic, tiglic and croton oleic. It is a violent ^urgative^ a single
drop being a dose. When rubbed on the skin croton oil may also
produce rubefaction and pustulation. It yields about half as
much volatile fatty acids as butter, among these volatile acids are
formic, acetic, and valerianic. While these acids are irritating,
and it was formerly thought that the irritant and purgative
action is due to the irritation caused by the acids liberated on
saponification of the oil, it is now believed that these actions of
croton oil are due to an acrid resin Ci3H1804 contained in the oil.

Most oils are insoluble in alcohol, castor and croton oils are
exceptions to this rule. Croton is somewhat soluble and castor
is soluble in absolute alcohol. Both are soluble in ether.

A distinguishing property of castor oil is its insolubility in
petroleum ether. It is likewise one of the heaviest fats having a
specific gravity of 0.960 as against a range of 0.85 to Q.95 for
other fats.

Fats are extracted from seeds, or tissues after these have been
thoroughly desiccated. They are then placed in extractors and
the fat is drawn out with ether, light petroleum, carbon bisulphide
or carbon tetrachloride. Ether is the usual laboratory solvent.

These solvents extract also cholesterol, lecithin, essential oils,
and the indefinite group of bodies known as lipoids, and the extract
for this reason is known as the ether extract. A process of puri-
fication must be employed if a pure product is desired.

GENERAL PROPERTIES OF FATS

1. The physical properties depend on the composition — oleins
are liquid, stearins are solid, palmitins of a vaseline or tallow
consistency.

ACTION OF SOAP 149

2. Fats are insoluble in water and but slightly soluble in cold
alcohol.

3. They are soluble in ether, benzine, benzene, chloroform,
carbon bisulphide, carbon tetrachloride.

4. Fats can be heated from 200° to 25CrC. without decomposi-
tion. Higher heat may decompose them with the formation of
the irritating volatile product of glycerine — acrolein

CH2 = CH- CHO

This change is hastened by the addition of (KHS04) — potas-
sium bisulphate, and is a test for true fats, or anything containing
glycerine.

5. Lipases hydrolyze fats into fatty acids and glycerine. This
change may also be accomplished by bacteria and by superheated
steam. Acids and alkalies greatly accelerate the reaction. This
hydrolysis is known as saponification.

6. When boiled with alkalies fats are hydrolyzed, and the
combination of the alkali metal with the fatty acid is known as a
soap. Green soap is the potassium or soft soap, and is so-called
because the oils formerly used contained chlorophyll which gave
the soap a green color.

In medicine and pharmacy, antiseptics and other substances
are frequently added to, or incorporated in the soap. These are
the so-called medicated soaps. Cresol, thymol, tar, sulphur,
mercury, salicylic acid, etc. are among the substances added.
Castile soap is made from olive oil and sodium hydroxide; green
soap from linseed oil and potassium hydroxide. Lead plaster is a
lead soap. Resin and sodium silicate are added to soaps mainly
as adulterants. Such soaps hold a great deal of water, hence
weigh more than a pure soap, and this is the principal reason for
the addition.

Explanation of the Cleansing Action of Soap

Ordinary soaps are the sodium potassium salts of fatty acids.
These are weak acids, and their salts are decomposed to some
extent by water just as sodium carbonate is, and soap solutions
are alkaline in reaction for the same reason that sodium carbonate
is alkaline. In water soap is hydrolyzed according to the formula :

150

CHEMICAL PHAKMACOLOGY

1. CH3(CH2)16COONa->CH3(CH-2)16COO + Na+

2. CH3(CH2)16COO ~ + Na+ + HOH ->

Na+ + OH CH3(CH2)16COOH +
Stearate ion Stearic acid

Since stearic acid is insoluble in water, it is removed from solu-
tion, and the NaOH ions react alkaline. The amount of free
alkali depends on the dilution. In strong solution a soap that
will cause just a pink color with phenolphthalein, may be dis-
tinctly alkaline on dilution. These hydrolyzed products readily
emulsify fats, and such emulsion is readily soluble in or removable
by water. This briefly explains the mechanism of soap in wash-
ing. Mathews explains the formation of these colloidal solutions
as follows :

Na+ + 0- - C - (CH2)16 - CH
Sodium ion + stearate ion

1. Na - 0 - C - (CH2)16
Sodium stearate

2. Na - O - C - (CH2)i6 - CH3 +

NaOH+ H - 0 - C - (CH2)16 - CH3

0 II

0
Stearic acid

3. Na+ - O - C - (CH2)i6 - CH3 + 2HO - C - (CH2)16

-O - C - (CH,)i8 - CH3
2HO - C - (CH2)16 - CH3

O
Colloidal soap.

This negatively changed colloidal soap is held in solution by
the great attraction of the positively changed sodium ion, for

PAT CONSTANTS 151

water, and it (colloidal soap) has a great attraction for the fatty
acids of neutral fat or grease. Consequently when put on the
skin, the fats of the skin adhere to the colloidal soap particles
and are held in colloidal solution by the attraction of the sodium
ion for water. Large easily removable aggregates may thus be
formed. Vaseline, liquid petrolatum and other lipoids that do not
form emulsions readily, are for this reason hard to remove.

THE CHARACTERIZATION OF FATS

The following methods are used for the recognition and the
evaluation of fats.

1. The melting point is determined. This shows the general
nature of the fats — whether they are composed mainly of stearin,
palmitin or olein.

2. The acid number. This is the number of milligrams of
KOH required to neutralize the free acid contained in one gram
of the fat. This is determined by dissolving 1 or 2 grams of the
fat in about 20 cc. of a mixture of 1 part alcohol and two parts
of ether. Titrate the solution with N/10 solution of KOH in
alcohol. Alcohol is used here because water does not mix well
with the oil, but causes an emulsion formation, and the end point
is not clear. The acid number gives one an idea of the state of
freshness of the fat.

3. The saponification number or Koettstorfer number. The
saponification number is the number of milligrams of KOH
necessary to neutralize (to form a 'soap), with the fatty acids
derived from 1 gram of fat. Since fatty acids are monobasic one
molecule of potash neutralizes one molecule of acid, but each
molecule of fat required three molecules of KOH — since glycerine
esters or fats are tribasic.

The saponification value is determined by dissolving a weighed
amount of fat — about 2 grams — in a wide mouthed bottle
holding from 250 to 300 cc. Add 25 cc. of half normal alcoholic
KOH. Attach a reflux condenser and heat on a water bath for
30 minutes. Cool and titrate the excess of KOH with semi-
normal HC1, using phenolphthalein as the indicator. Sub-
tracting the acid necessary to neutralize,. from 25 cc. gives the
saponification number.

Since fats are glycerine in combination with monobasic fatty

152 CHEMICAL PHARMACOLOGY

acids, the saponification number will give indirectly the molecular
weight of the pure acid. This relationship is as follows:

Mol. weight Saponification number
Butyrin 302 557.3

Palmitin 806 208.8

Stearin 890 189.1

Olein 884 190.4

4. Unsaponifiable residue = Cholesterol and Phytosterol.
These previous numbers are of value in the calculation of the
molecular weight of acids only when we are dealing with pure
products. The numbers however are of value in determining the
nature of an oil, especially when taken in consideration with other
constants. One of these is the amount of unsaponifiable resi-
due. This residue consists mainly of cholesterols or phytosterols
which are soluble in petroleum ether, while glycerol, and potas-
sium hydroxide are not, and soap only slightly. Accordingly to
determine the unsaponifiable residue, after saponification cool
and filter off the soap — shake the solution with petroleum ether
in a separatory funnel, and evaporate in a desiccator to constant
weight, in a weighed dish. The residue represents the unsaponi-
fiable residue.

The following table gives the amount of unsaponifiable resi-
due in the more important fats.

Per cent, of
Unsaponifiable Matter

Lard 0.30 to 0.40

Castor oil 0.30 to 0.40

Human fat 0.33 to 0.00

Linseed oil 0.42 to 1.00

Olive oil 0.46 to 1.00

Corn oil 1.35 to 2.90

Wheat fat. 4.45 to 0.00

Shark oil 7.00 to 10.00

Sperm oil 37.00 to 41.00

Beeswax 52.00 to 56.00

The isolation and identification of the unsaponifiable residue,
is of importance in establishing whether or not a fat is of animal
or vegetable origin.

IODINE NUMBERS 153

5. The iodine absorption number of fats (Hiibls number). This
is the amount of iodine (per cent.) that a fat will absorb.
It is a measure of the unsaturated fatty acids in the fat. An
unsaturated (ethylenic) compound absorbs iodine after the man-
ner of ethylene:

C^2-tL4 i 12 — ^O2-tl4±2

The resulting compound being saturated.
To determine the iodine number the following solutions are
needed.

1 . 25 grams of pure iodine and 30 grams pure mercuric chloride,
in 500 cc. pure alcohol, free from unsaturated compounds.

2. A decinormal solution of sodium thiosulphate.

3. Potassium iodid 20 per cent, in water.

4. A 1 per cent, solution of starch paste as an indicator.
The determination is made as follows :

Weigh 0.3 gram of the fat in a glass stoppered bottle and dis-
solve in about 20 cc. chloroform and add 25 cc. of the iodine solu-
tion. Stopper the flask and set aside in the dark for 4 hours.
Wash into a flask for titration, with 10 cc. of the KI solution and
titrate with sodium thiosulphate solution. The difference be-
tween the volume of thiosulphate needed and 25 cc. of iodine solu-
tion used will be the amount of iodine absorbed or the iodine
number.

The reactions involved are:

Each cc. N/10 thiosulphate represents 0.0127 gm. iodine

I2 4- 2(Na2S203 + 5H20) = Na2S4O6 + 2NaI + 10H2O

The KI is added to prevent separation of the iodine in the
solid state when diluted with water. The mercuric chloride
forms :

Hg.Cl2 + I2 = Hg.ClI + IC1

The iodine chloride is perhaps the active agent in the addition,
and facilitates the process.

The iodine numbers of pure fats are :

Olein 86.2

Linolein 173 . 6

Linolenin.. . 262.2

154 CHEMICAL PHARMACOLOGY

Iodine Numbers of natural fats :

Linseed oil 175-205

Almond oil 145-150

Olive oil 80-88

Cottonseed oil 108-110

Codliver oil 107

Neat's foot oil 67-73

Palm oil.... 51

Cocoanut oil , 8-9

Tallow 35- 45

Lard 50-70

Butter 26- 38

Japan wax 4-10

Spermaceti 0.4

Unsaturation as evidenced by iodine absorption is a specific
instance or kind of unsaturation and in no sense a general test
for unsaturation. The unsaturation in the case of fats and oils
is ethylenic — i.e. between carbon atoms. In aldehydes, ketones,

R
etc. which contain a carbonyl group /C = O, there is also

unsaturation but iodine is not added to these. If hydrogen be
used, however, it reacts with the carbonyl as also with the
ethylenic linkage.

The reactivity in the one case and not in the other is due to
modification of the unsaturated bonds by attached molecules
or atoms. This may be illustrated by the reactivity of the H
atom in water, alcohol and acid.

H.OH

CH3CH2OH
CH3COOH

The difference in reactivity in each case being due to the modi-
fying influence of the attached radical.

THE HYDROGEN NUMBER AND HYDROGENATED FATS

Under proper conditions hydrogen may be added to fats much
in the same way as bromine. This changes ill-smelling and

ACETYL VALUE 155

tasting, cheap vegetable oils into more palatable products
resembling the more expensive animal fats. The process of hy-
drogenation is of great commercial importance. In some pro-
cesses finely divided metals such as nickel are used as catalyzer,
and some of the metal may remain in the finished vegetable lard.
Nickel may be absorbed from the gastro-intestinal tract; and it
is toxic, hence fats prepared in this way may be interesting from
a pharmacological point of view. The pure products are not
toxic, but if nickel remains in oil the latter may become -toxic.
These hydrogenated fats are important economically.

THE REICHERT MEISSEL NUMBER

This represents the number of cubic centimeters of N/10 KOH
required to neutralize the volatile acids liberated from 5 grams
of fat under certain special conditions. The process of determin-
ing the amount consists in saponifying the fat with an alkali, then
adding an excess of a non-volatile mineral acid, distilling and
titrating the volatile acids. Phenolphthalein is used as the indi-
cator. This method is especially useful in the examination of
butter fat for adulteration.

The Reichert Meissel numbers of the most important fats are :

Linseed oil 0.0

Goose fat 0.2

Tallow 0.5

Olive oil 0.6

Lard 0.7

Palm oil . . . 5-7

Cocoanut oil 6-7

Croton oil 12-14

Butter fat 25-30

No other fat contains as much volatile acid as butter.

THE ACETYL NUMBER

This is a measure of the number of hydroxyl groups in a fat.
The measurement of these depends upon the fact that substances
containing the alcoholic hydroxyl group react with the acetyl
group (CH3CO). The number of OH groups is arrived at by

156 CHEMICAL PHARMACOLOGY

treating the fat with acetic anhydride and heat; when a reaction
takes place as follows :

- CH3 R

W CO - CH3 n'

The acetyl derivative of the fat is stable in boiling water, and
by boiling in water, excess of acetyl anhydride is converted
into acetic acid. The acetylated fat can now be separated by
nitration and washed free from the acid. This acetylated fat
can be saponified according to the reaction:

ROCOCHs + KOH -» ROH + CH3COOK

In this way the amount of potash required for the saponifica-
tiori can be used as a measure of the acetyl groups, and hence of
the hydroxyl groups in the fat.

The number of milligrams of potash required to neutralize the
acetyl derivative of 1 gram of fat, is the acetyl value of that fat.

The following table gives the acetyl value of some common
pharmaceutic products:

Linseed oil ........ ....... 0.4

Olive oil ......... ....... 10.5

Codliveroil ....... ....... 0.5

Spermaceti .............. 4.5

Lard ............. .... 2.6

Tallow (Beef) ............. 2.5-9

Beeswax ............... 15.0

Wool wax . . . . ........... 0.23

Castor oil ............... 0.15

The Elaidin Test for Fats (Gr. Elais— Olive Tree)

This test is distinctive for the oleic series. It depends on the
fact that oleic acid is changed from the cis to the trans form on
treatment with nitrous oxide, or liquid olein is converted into
solid ela'idin — which is an isomeride of olein. Other acids of
this series are similarly transformed.

The Elaidin test is performed as follows:

(I) Place 10 cc. oil in a test tube and add 5 cc. nitric acid sp.
gr. 1.38-1.40 underneath it. Place a small' piece of copper (0.2

TESTS 157

gm.) in the acid. Leave at a temperature of not over 25°C. until
the following day, and observe frequently or

(II) 10 grams of oil are mixed with 5 cc. nitric acid sp. gr. 1.38
and 1 gram of mercury, and the mixture shaken until the mercury
is dissolved. Set aside and shake again after about 20 minutes.
Note the time required for solidification. This reaction is called
the "elaidic transformation."

Depending upon the amount of oleic acid present, the oils
vary in the length of time necessary for solidification.

Olive oil solidifies in about 60 minutes.
Peanut oil solidifies in about 80 minutes.
Sesame oil solidifies in about 185 minutes.
Rape oil solidifies in about 185 minutes.
Lard oil — inside two hours.
Linseed oil gives a red pasty froth.
Hempseed oil remains unchanged.

The temperature of the mixture should not exceed 25 degrees.
At best the reaction gives only an idea of the character of the oil.

The Bromine Test

This test depends on the fact that linolic, linolenic and other
unsaturated drying and semi-drying oils form insoluble addition
compounds with bromine containing 6 or 8 atoms of this ele-
ment, which is insoluble in ether. Linolenic acid having three
double bonds yields a hexabrom derivative. The avidity of the
reaction can be measured also by the heat of bromination, which
runs parallel with the amount of bromine or iodine that a fat will
absorb. To determine the amount of bromine absorbed: 1 to
2 cc. of oil are dissolved in 40 cc. of ether and 2 cc. glacial acetic
acid. Cool to about 5°C. and add bromine drop by .drop until
no more is absorbed.

The precipitate is collected on a weighed asbestos filter and
washed 4 or 5 times with ether, and dried in a steam oven. The
weight is directly proportional to the amount of unsaturated
acids in the fat.

Maumene or Sulphuric Acid Test

Fats of the linolic series on being mixed with sulphuric acid
evolve 'heat while those of the oleic series do not.

158 CHEMICAL PHARMACOLOGY

The difference in degrees centigrade between the initial tem-
perature and the temperature after the addition of sulphuric acid
under special conditions is known as the Maumene Number:
The test is carried out as follows :

Place a beaker of 150 cc. into a beaker of 800 cc. and pack the
space between with cotton. Weigh 50 grams of oil into the smaller
beaker. Place a thermometer in the oil and run in 10 cc. con-
centrated H2SO4 from a burette at the same temperature as the
oil. Stir the oil with the thermometer while the acid is running
in. The temperature rises quickly, and remains at the high point
a sufficient time to permit observation. The maximum point
should be noted. The initial temperature subtracted from the
maximum gives the Maumene number.

RANCIDITY OF FATS

Most fats but especially those containing unsaturated acids
on exposure to the air become rancid and develop a disagreeable
smell and taste. The unsaturated fatty acids are converted into
others containing a smaller number of carbon atoms. Among
the decomposition products aldehydes, alcohols, hydroxy acids
and esters have been found. The actual cause of rancidity is
but little understood. Oxygen, light, and heat, and moisture,
facilitate the process which is probably initiated by enzymes and
bacteria, while free acid is liberated in the process.

Acids may be developed without rancidity as is often seen
in cocoa butter which is frequently acid but rarely rancid.

THE SIGNIFICANCE, USES AND FATE OF FATS

Fat is found in varying amounts in all forms of living matter.
This may not be seen in microscopic sections or when stained with
sudan III, osmic acid and other fat stains but organic substances
when extracted with ether and other fat solvents, always yield
a lipoid residue on evaporation. After anesthesia for an hour
with chloroform, sudan III shows that fat droplets are distinctly
present in the cell, while chemical analysis shows that there is
no greater amount than before the anesthesia. It is differently
distributed after the anesthetic.

In the economy of both plants and animals, fats are connected

SIGNIFICANCE OF FATS 159

with nutrition. They are readily stored and provide a food
reserve which in animals is used in cases of food deficiency.

They act as protectors to the proteins of the body, sparing the
protein from oxidation. They also act as lubricants to the skin
and aid in keeping it soft and pliable. If the lipoid material is too
frequently and too vigorously removed from the skin, as is some-
times done by the excessive use of highly alkaline soaps, the skin
becomes dry and eczematous. In such cases the judicious
use of oils externally is very beneficial. Many fats are used in
emulsions for this purpose. Some fats because they are decom-
posed into slightly irritating materials in the intestines are used
as cathartics.

In the protoplasm fats are distributed very finely as in milk.
None of the ordinary fat tests will detect fat when it is so finely
divided and protected. The fat in the cells in this condition may
also act as a protective to the essential part of the cell. In phos-
phorus poisoning and in- other conditions classed as fatty de-
generations, the fat is run together and so loses its protective
properties. In these conditions there is no increase in the actual
body fat, but simply a redistribution of it. Why one person is
fleshy — or the body retains a considerable amount of fat — while
another, is lean cannot be explained further than that the funda-
mental properties of the protoplasm is different. This may de-
pend on the physiological activity of some endocrine gland either
acting on the seats of oxidation directly or through the nerves.
It is known that basal metabolism is distinctly higher in hyper-
thyroidism, and lower in hypothyroidism, and in other conditions.

Oxidation furnishes the heat necessary for the body and fats
are the heat producing foods par excellence, one gram of fat pro-
duces 9.3 calories. Fats also act as a mantle and since they are
poor conductors they aid in heat conservation by preventing
evaporation and radiation. In cases of obesity this property
may be a hindrance rather than a benefit. Fats also act as pack-
ing material for such organs as the kidney, which is partially
embedded and held in place by a cushion of fat.

In plants fats are found in greatest amounts in the seeds and
propagative organs. Their function here is protective, to pre-
vent desiccation which would prevent germination, they also
serve as nutritive material. Seeds contain lipases which may

160 CHEMICAL PHARMACOLOGY

either hydrolyse the fat into fatty acids and glycerine or syn-
thesize the fats from the same materials.

Regarding the origin of fat in the plant lit tie is definitely known.
In many cases there seems to be strong evidence that it originates
from the carbohydrates. Certain seeds like the almond, and
castor bean, and olive in the green state are rich in carbohydrates
and poor in fats, but as they ripen the carbohydrate decreases
and the fat increases. Glucose, sucrose, mannite, starch and
other carbohydrates, have been observed to change in this way.
Ivanow, in case of flaxseed represents the changes taking place
as follows :

^Glycerine — v

Carbohydrate ^ yFat.

Saturated Unsaturated

fatty acid fatty acid

The reverse change is supposed to take place during germination.
Miller found in case of the sunflower that the cotyledons in the
resting state contained 1 per cent, free fatty acid while in the
seedling there was 30 per cent, fatty acid. These fatty acids
disappear, that is, are used by the plant in the following sequence;
linoleic, linolic, oleic and finally palmitic; that is the more un-
saturated acids are used first. There is some difference of opin-
ion as to the changes in the original fat during germination, but
one acid may be transformed into another.

It has been suggested that starch may arise from oleic acid as
follows :

Ci8H3402 + 27O = 2(C6Hio05) + 6CO2 + 7H20

Fats may also arise from protein, but the proof of this is not
so definite in the plant as in the animal. Fats may also be trans-
ported in the plant from one region to another, similar to fatty
infiltration in the animal.

ORIGIN OF FAT IN THE ANIMAL

1. It may arise from the fat of the food. Proof of this is found
in the fact that when linseed oil, rape oil, mutton fat and the
like are fed to dogs — these fats can be recognized in the fatty
deposits of the tissues of the animal. Experiments have shown

ORIGIN OF FAT 161

that the fat of dogs fed on linseed oil, melts at 0° — while those
fed on suet was solid at 50°C.

2. From carbohydrates; animals have been fed on a carbo-
hydrate diet, and the carbon retention has been shown to be in
the form of fat. For example: Rubner fed a dog weighing 5.89
kg. on starch, sugar, and fat that had a total carbon content of
176.6 grams. During the period the animal excreted 87.1 grams
of carbon, there was thus a retention of 89.5 grams. The fat
of this diet had a carbon content of 3.6 grams. The animal ex-
creted 2.55 grams nitrogen = 16 grams protein — (2.55 X 6.25).
On the improbable assumption that all the carbon of this ex-
creted protein was retained in the body, this would be 8.32 grams
C (16 X 0.52) (52 per cent. C in proteins) so that 8.32 + 3.6 =
12 grams, could originate from other sources than carbohydrate
leaving 89.5 — 12 = 77.5 grams of carbon that could arise only
from the carbohydrate and could be retained only as carbohy-
drate or fat. The greatest possible amount of glycogen that
could be stored from this would be 78 grams or 34.6 C so that there
would still remain 42.9 grams of C that could be stored only as
fat. This calculation is based on the fact that glycogen
is stored equally between the liver and the muscles. The liver
rarely exceeds 4 per cent, of the body weight and only in excep-
tional cases will the liver glycogen = 17 per cent, of the weight
of the organ.

Numerous other fattening experiments have convinced physi-
ologists that fats can be formed in the animal body from carbo-
hydrate. The chemistry of this change is not understood, and
cannot be imitated in the laboratory. See Lusk, Science of
Nutrition, 3d Edition. The following hypotheses have been
proposed in that the process starts with pyruvic acid. Lactic
acid arises from the sugar and may be converted into pyruvic
acid by oxidation. The pyruvic acid unites with an aldehyde to
form higher fatty acids :

I. R CHO + CH3CO COOH = R CHOH CH2 CO COOH.

II. R CHOH CH2 CO COOH + 0 = R CHOH CH2 COOH -f

C02 and

III. R CH2 CH2 COOH.

may also be formed on further oxidation.
11

162 CHEMICAL PHARMACOLOGY

This gives some idea of how higher fatty acids may be formed
in the plants. The glycerol necessary to form fat from the fatty
acid may be synthesized in the plant in a manner unknown to
the chemist. That it may be formed from the elements has been
shown by Friedel and Silva through the following steps :

CH3COOH -+CH3CO.CH3-+

Acetic acid Acetone

CH3.CHOH.CH3 -^CH3.CH:CH2
Propyl alcohol Propylene

CH3.CHC1.CH2C1^CH2C1.CHC1.CH2C1-*
Propylene chloride Trichlorhydrin
CH2OH.CHOH.CH2OH
Glycerol

FATS FROM PROTEINS

It has been shown quite definitely in feeding experiments that
fat may be formed from protein. There has been considerable
difference of opinion on this question. Pettenkoffer and Voit
claiming a distinct formation while Rubner questioned the com-
putation on the basis that they had used the ration of carbon to
nitrogen in protein as 3.68 instead of 3.28 which he believed to
be the correct figure. Cremer, however, showed by experiment
that fat may be formed from protein and his results have been
amply confirmed. His experiment is as follows:

A cat was starved for a number of days. It was then fed 450
grams of meat a day. The animal was kept in a respiration
chamber and the C02 in respiration measured and the excreta
analysed. There was a daily excretion of 13.0 grams nitrogen —
41.6 grams of protein carbon (13 X 3.18). However only 34.3
grams of carbon was eliminated. 7.3 grams or 17.5 per cent, of
the carbon taken in was retained. In 8 days 58 grams of carbon
was retained. If this were stored as glycogen it would make 130
grams, but in the total animal at this time there was found only
35 grams of glycogen. The balance must have been stored as fat.

This subject has also been investigated by Atkinson and Lusk
who have shown by calculations based on respiratory quotients
and heat production as measured by the respiration calorimeter
that fat is produced from protein in the dog after the ingestion
of large quantities of protein.

OEIGIN OF FATS 163

THE NEED OF FATS IN GROWTH

The normal growth of an animal depends upon something in
addition to the requisite number of calories of fats, proteins and
carbohydrates. The fat must be of a certain source and contain a
growth promoting substance "A," or what has been called vita-
mine. All fats do not contain this vitamine. It is especially
abundant in butter fat, beef fat, egg yolk, and cod liver oil.
Animals fed on a diet in which olive oil or almond oil supplies the
fat, do not grow, and soon will die if such diet is continued.
However, even when death is near, the substitution of vitamine
containing fat, immediately restores normal health and growth.
The nature of this substance is not known. The term vitamine,
suggests that they are amines, but such is not the case. The term
vita, McCollum thinks, gives an importance to these essentials;
greater than other equally indispensable constituents of the
diet. He suggests until more definite knowledge is obtained, the
term fat soluble "A" be applied to the vitamine essential growth
promoting ingredient of fats, and to other like substances which
are soluble in water, water soluble "B."

THE FATE OF FATS IN THE BODY

Fats are easily and completely oxidized in the body and are a
great source of body heat. They are absorbed after saponifica-
tion and resynthesized again in the body, probably by an enzyme.
In the dog 10-20 per cent, of the fat of a meal is absorbed in four
hours, about 30 per cent, in seven hours and 86 per cent, in 18
hours. After excision of the pancreas, or disease of it, fat ab-
sorption is markedly retarded but not abolished.

In man the feces contains 0.5 to 1.5 grams of fat in starvation,
while on ordinary diet containing about 120 grams fat, 3 to 7
grams is excreted.

Normal urine contains no fat, but in diseased conditions
variable amounts may be found. The condition is known as
lipuria and may occur after excessive eating of fat, after cod
liver oil, in fat embolism occurring after fractures, in phosphorus
poisoning and other fatty degenerative processes, in prolonged
suppuration, chronic Bright's disease, diabetes, chronic alco-
holism, in wasting diseases, diseases of the pancreas, obesity,
leukemia, and in mental diseases.

164

CHEMICAL PHARMACOLOGY

xvm. WAXES

The waxes are esters of higher monatomic alcohols or sterols
such as cetyl alcohol, C16H33OH, myristic alcohol, C3oH6iOH,
or cholesterol C27H45OH, and one of the higher fatty acids.
Spermaceti is a wax, obtained from a cavity in the head of the
sperm whale, and consists mainly of cetyl alcohol and palmitic
acid or cetyl palmitate. Bees wax consists chiefly of myricil
alcohol and cerotic and melissic acids in ester combination.

Waxes are of both animal and vegetable origin. The surfaces
of all organisms, both plant and animal, are covered with a layer
of wax. The secretion is found in greater abundance in some
plants than others. The function of it is to protect the plant or
animal from over-wetting or over-drying and against changes in
temperature. For these reasons waxes are important in the pro-
tection of the eggs and larvae of insects. It is well known that
wax is a poor conductor of heat as well as electricity.

Lanolin or wool fat, or more correctly, wool wax, consists
largely of monatomic alcohol, cholesterol in the free state. There
is also some of this combined with myristic, cerotic, and lanoceric
acids to form true wax.

The fact that waxes generally have a harder consistency than
fats has given rise to incorrect nomenclature in some cases. For
instance, wool fat, which is in reality a wax, is not usually re-
garded as such, while Japan wax, produced by a species of Rhus,
is actually a fat. True fats are esters of glycerine, but waxes
are esters of higher fatty acids and monatomic alcohols. There
is a great variation in the alcohols and the fatty acids in waxes
as the following list will show :

(COMPOSITION OF THE WAXES — TAKEN PKOM MATHEWS PHYSIOLOGICAL
CHEMISTRY, 1915, p. 80.)

Acids. Saturated.

Formula

Melting point

Wax

Ficocerylic

ClsH26O2

57°C.

Gundang.

Myristic /

CuHasO*

53.8°

Wool.

Palmitic

CieH32O2

62 69

Bees. Spermaceti.

Carnaubic
Cerotic
Melissic
Psyllostearylic

C24H48O2
C26H62O2

C3oH6oO2
CeaH66O2

72.5°
77.8°
91°
94-95°

Carnauba. Wool.
Bees. Wool. Insect.
Bees.
Psylla.

STEROLS

165

II. Acryllic series.

Physetoleic
Doe^lic (?)

deHsoOz
CigHssOz

30°

Sperm oil.
Sperm oil

Lanopalmic

CieHszOs

87-88°

Wool

Cocceric :.....
Lanoceric

CsiHezOs
C3oH8oO4 '

92-93°
104-105°

Wool.

III. Alcohols. Sterols.

Pisan ceryl

CisHs^O

78°

Pisang.

Cetyl (Ethal)

CieHseO

50°

Spermaceti.

Octodecyl

C18H380

59°

Spermaceti.

Carnaubyl

C24H50O

68-69°

Wool.

Ceryl

C2«H54O

79°

Wool Chinese.

Myricyl (Melissyl)

CsoHezO

85-88°

Bees. Carnauba.

Psyllostearyl

CsaHssO

68-70°

Psylla.

Lanolin alcohol

Ci2H24O

102-104°

Wool.

Ficoceryl

CnEbsO

198°

Gundang.

Cholesterol

C27H46O

148 4-150 8°

Wool

Cocceryl

CsoH62O2

101-104°

Cochineal.

Iso-cholesterol -

C26H46O

137-138°

Wool

Waxes are soluble in the ordinary fat solvents, benzene, ether,
chloroform, etc. but are less soluble than the fats.

When heated, waxes give no smell of acrolein, since they contain
no glycerine. They are saponifiable like the fats, but with more
difficulty.

STEROLS

These are solid alcohols, "steros," meaning solid, and "ol"
the chemical ending signifying, alcohol. Cholesterol C27H45OH
was the first discovered member of the group, and the most im-
portant. It is a secondary alcohol, since it oxidizes to a ketone.
Compounds closely related to cholesterol are found in plants,
phytosterols, and also in feces, coprosterols.

Cholesterol can be taken as a type of the sterols, which are
important as constituents of waxes. The relation of the sterols
to waxes is the same as glycerine to fats.

CHOLESTEROL

This sterol was first prepared from gall stones in 1785 by Four-
croy and studied by Chevreul in 1814, who-named it cholesterin
from the Greek chole, bile, and steros, solid. Some gall stones
are almost pure cholesterol. It is also found in brain tissue.
The important source of it is lanolin or wool fat, "lana, "

166 CHEMICAL PHARMACOLOGY

wool, oleum, oil, or adeps lanse hydrosus. This contains some
free cholesterol and some combined with myristic, cerotic, lano-
ceric, and lanopalmitic acids in the form of wax. Wool wax also
contains other sterols, as carnabuyl, and lanolin alcohols.

Cholesterol is insoluble in water and alkalies, sparingly soluble
in cold, but readily soluble in hot alcohol, ether, acetone, chloro-
form, and other organic solvents, slightly soluble in soap solutions
and much more soluble in solutions of bile salts. It is readily
soluble in oleic acid and oils. Solutions of it react neutral. It
is tasteless, odorless, cannot be saponified, and is remarkably
stable toward oxidation. These reasons, and the additional one
that it does not become rancid, recommend its use in ointments,
etc. Because of its penetrative power, it is used as the base to
carry drugs through the skin.

Cholesterol is found to some degree in every cell, probably as a
protective agent. The structure of it is not satisfactorily known.
Mauthner1 assigns to it the following formula :

.
)CH.CH2CH2 - C17H26CH: CH2

H2C CH2
CH(OH)

Windaus2 gives

— CH2 — CH2 —

x
CH3X /\

CH CH

/\/\
H2C CH CH - CH3

H2C CH2 CH

C\
HOH CH2

From these formulas it is seen to be closely related to the
terpenes, which are also important in drug chemistry.

1 Zeit. f. physiologische chemie, 1901, 34, 426.

2 Ber. Deutsche, chem. gesellschaft, 1912, 45, 2421.

CHOLESTEROL 167

This constitution is not yet definitely settled. It is evidently a
terpene compound. The formation of terpenes in the animal
body is hard to explain, and it seems probable that it does not
originate in the animal organism. Animal cholesterol is ap-
parently plant cholesterol, utilized by the body.1 The metabol-
ism of it in the body is as unknown, as is its function, though it
possesses certain definite properties which are pharmacologic
importance. Lecithin accelerates the activity of cobra poison
and cholesterol retards the action of lecithin. Snake venom
added to washed red blood corpuscles suspended in water, will
not cause laking. If, however, a trace of lecithin be added, laking
results. A trace of cholesterol dissolved in methyl alcohol will
neutralize the influence of the lecithin in this case. Since lecithin
and cholesterol exist in all cells and especially in red blood cor-
puscles, it seems that the function of the cholesterol is protective.
Preparation and Tests for Cholesterol

Place 2 grams of wool fat in a 100 cc. Erlenmeyer flask, add
25 cc. of 25 per cent, alcoholic (KOH) and boil under a reflux
condenser for two hours with frequent shaking. This saponifies
the fats but not the cholesterol. Pour the mixture into an eva-
porating dish and evaporate off the alcohol. Dissolve the resid-
ual soap in 50 cc. of hot water and transfer to a 200 cc. separating
funnel, cool and add 50 cc. of ether and shake several times.
The ether dissolves the cholesterol. If separation does not occur
readily, add 5 cc. alcohol and shake again. Run off the soap
solution and collect the ether solution in a dry evaporating dish
and evaporate to dry ness on a water bath.

1. Examine the residue under a microscope on a glass slide for
the characteristic crystals.

2. Cholesterol on oxidation yields pigments. The Lieber-
mann-Burchard test is the most delicate and characteristic.
The test is as follows :

Dissolve a few crystals of cholesterol in 2-3 cc. of chloroform in
1 Recently, Gamble and Blackfan (J. Biol. Chem., 1920, 42, 401-9),
from analysis of the non-saponifiable fraction of the feces of undernourished
children for three days found the excretion of cholesterol larger than the
amount in the food. They interpreted this result as indicating a synthesis of
cholesterol in the body. This is confirmation of an older observation of
Mueller, but does not satisfactorily account for the excretion of a probable
storage from previous feeding.

168 CHEMICAL PHARMACOLOGY

a dry test tube or in the depression of a test tablet. Add about
10 drops of acetic anhydride, shake and add concentrated H2SO4
drop by drop. A transient pink color first develops, which on the
addition of more acid changes to blue and finally to green.

3. SchifPs reaction: A few crystals of cholesterol are placed
on a porcelain dish and treated with a few drops of a mixture of
1 volume 10 per cent, ferric chloride and 3 volumes of concen-
trated H2SO4. It is then evaporated carefully to dryness over a
free flame. A reddish violet residue changing to bluish is
obtained.

4. Crystals of cholesterol on a white surface, when moistened
with a mixture of 5 parts H2SO4 and 1 part water, turn pink.
On the oxidation of a drop of very dilute solution of iodine a play
of colors violet, blue, green, and red, results.

All animal fats contain cholesterol while vegetable fats con-
tain phytosterol, and sitosterol. The isolation and identification
of the unsaponifiable residue, therefore, is of considerable im-
portance, in establishing whether or not a fat is of animal or
plant origin. In food products the more expensive animal fats
are sometimes substituted by or adulterated with, the cheaper
vegetable fats. Recently vegetable fats have been hydrogen-
ated to make them more nearly like animal fats — see p. 154, but
such hydrogenated fats are used only as foods.

XIX. VOLATILE, ETHEREAL OR ESSENTIAL OILS

The sources of the volatile oils are mainly the flowers, fruit
and leaves of many plants. They differ from the fixed oils
chemically, physically, pharmacologically, and economically.

The composition of volatile oils is very variable and not fully
understood. Terpene is the most common constituent. Many
are composed mainly of terpenes either of the aliphatic or aro-
matic series. But mixtures of terpene derivatives which include
alcohols, aldehydes, ketones, acids, esters, ethers, phenols, lac^-
tones, quinones, oxides, nitrogen and sulphur compounds occur.
Some non-terpene hydrocarbons have also been found and in
some oils no terpene has been found (Attar of Roses). The
only common characteristic of the volatile oils as a class is their
volatility. They all contain hydrogen and carbon and most of
them also oxygen. A few contain nitrogen or sulphur or both.

TERPENES 169

The characteristic odor of the oil is associated with the oxygenated
part of the molecule, and especially with the oxygenated aliphatic
terpene.

CHEMICAL CLASSIFICATION
Dumas in 1833, classified volatile oils as follows:

1. Those containing carbon and hydrogen only, like turpen-
tine.

2. Those that contain oxygen, like camphor and eucalyptus.

3. Those that Contain sulphur, like mustard oil or

4. Nitrogen, like oil of bitter almonds. While this classifica-
tion may still be used in a modified form, it is to general to give one
any information regarding the composition of any volatile oil.

ALIPHATIC HYDROCARBONS IN VOLATILE OILS
Heptane C7Hie is the lowest member of this series found in
volatile oils. It has been found in the distillate of the oleoresin
of some California pines. Higher members of this series and of
the olefin series occur quite generally in the wax-like secretions
of leaves, flowers and fruits. They occur mixed with other
homologues and not as pure products. Octylene CgHie has been
found in the oils of bergamot and lemon. A number of terpene
hydrocarbons have been isolated.

TERPENES

Terpenes were formerly defined as hydrogenated derivatives
of cymene and its substituted products (true terpenes). More
recent work however has discovered some olefine terpenes.
These can readily be converted into aromatic terpenes. All
terpenes are unsaturated compounds and can be hydrogeriated
readily and yield addition products with halogens. On exposure
to the air they are oxidized to resins, and this has given rise to
the opinion that natural resins are oxidized products of volatile
oils. As a group they appear to be derived from hydrocarbons
of the composition CsHs. They are classified as:

Hemiterpenes C6Hs

Terpenes CioHie

Sesquiterpenes Ci5H24

Diterpenes C2oH32

Polyterpenes (C6H8)n

These may be divided into two groups:
1. The olefine terpenes.

170 CHEMICAL PHARMACOLOGY

2. The aromatic terpenes.

(a) Monocyclic.
(6) Dicyclic.

The monocyclic are represented by cymene or menthol and the
dicyclic by camphor and camphane.

The most important terpenes of the aliphatic or olefine series
are:

C— CH2— CH2— CH2— CH(

XCH2— CH2OH
Citronellol (Lemon oil)

av ,

,\j — OH — OH2 — OH2 — C^
a/ XCH— CH2OH

Geraniol (Oil of geranium)
v /CH3

"C=CH— CH2— CH2— CCH=

Linalool (Oil of lavender)
,\j — CH —

Myrcene (Oil of lignaloes, etc.)

The nucleus of true terpene /\
is cymene

CH3

or paramethyl isopropyl benzene, which can be derived easily
from some of the volatile oils, stearoptenes and camphors.

CioHieO + P205 -4 C10H14 + H20
Camphor Cymene

C10H16 + 0 -> CioHi4 + H20
Turpentine Cymene

AEOMATIC TERPENES 171

Cymene is a pleasant smelling liquid — specific gravity 0.87
and boils at 175-176°C. On oxidation with dilute HNO3 the
isopropyl end of the ring is first oxidized and para toluic acid is
formed CH3.C6H4.COOH. Further oxidation yields terephthalic
acid COOH.C6H4COOH (1 :4). In the body the methyl end
of the chain is first attacked and cumic acid is formed:

/CH(CH3)2
C6H/

XCOOH
Cumic acid

and excreted as the glycocoll conjugate, cuminuric acid
(CH3)2CH.C6H4CO.NH.CH2COOH

AROMATIC TERPENES

True terpenes have the formula Ci0Hi6. They seem to be
polymerides of the hemi-terpene (C5H8). Two or more mole-
cules of this compound may polymerize to form terpenes or
polyterpenes.

In the destructive distillation of india rubber, or when tur-
pentine is passed through a tube heated to redness, isoprene
(C5HS) which is methyl di vinyl, is formed

•V. :. •'- CHNC/CHV

CH/ CH"

This is a liquid B.P. 37°. It polymerizes readily to the
terpene dipentene,

v x — OH v

2 C— CH = CH2-> ")C— CH/ \C.CH3

O.H.2 OJLL2 O.H.2 - OIl2

Isoprene Dipentene

On treatment with acids, isoprene polymerizes, forming rubber
again, which is considered as a resin.

The terpenes may be considered as being derived from iso-
prene or an isomeric hydrocarbon. The true terpenes all con-
tain the dipentene or cymene nucleus.

172

CHEMICAL PHARMACOLOGY
CH3 CH;

Cymene
nucleus

Dipentene
nucleus

The terpenes being unsaturated bodies, unite with HC1 or
HBr to form addition products. The unsaturated condition
also imparts great reactivity to them. They absorb oxygen
readily and resinify. HN03 or iodine and other oxidizing sub-
stances mixed with them may cause explosions. Weaker oxidiz-
ing may break them down with the formation of acetic, propionic,
butyric, oxalic, and other acids while bromine and iodine convert
them into cymene. One of the easiest ways to prepare cymene
is to treat camphor with P2S5,ZnCl2, or P205 (p. 170).

The main characteristics of this ill-defined group of true
terpenes are:

1. Their composition C10Hi6.

2. Their unsaturated condition.

3. Their great reactivity.

4. Their tendency to polymerize and resinify.

5. On reduction they yield hydroterpenes.

6. On oxidation with potassium, they yield, in many cases,
benzene derivatives.

7. The presence of the cymene ring or nucleus.

8. They boil without decomposition at 155-180°C.

9. When taken into the body, they as a rule, are excreted
combined with glycuronic acid, as conjugated glycuronates.

For convenience of study, the true terpenes have been sub-
divided as follows :

1. The terpenogen group

2. Terpan or men than group

VOLATILE OILS 173

3. Camphan group.

Group I. consists of alcohols, aldehydes, acids, etc., combina-
tions of terpenes from which the hydrocarbon can readily be
prepared.

Group II. Menthol is a prominent member of this group,
and has certain reactions which distinguish it from the first group.
It is not so easily converted into the hydrocarbon.

Group III. Camphor is the typical representative. Cam-
phor yields camphene which is the only solid terpene known.

ALIPHATIC ALCOHOLS IN VOLATILE OILS

Methyl alcohol occurs frequently and has been found in aque-
ous distillates of the oils of cypress, savin, vetiver, orris, etc.
Ethyl alcohol has been observed only in a few instances. N
butyl, isobutyl, isoamyl, n hexyl, heptyl, n octyl, n nonyl and
undecyl have also been found. Various other less known alipha-
tic alcohols have been reported.

AROMATIC ALCOHOLS IN VOLATILE OILS

Benzyl, phenyl ethyl, phenyl propyl, and cinnamic occur;
also salicyclic alcohols, are more or less commonly found.

DIFFERENCES BETWEEN FIXED AND VOLATILE OILS
The chief differences are:

Fixed Oils Volatile Oils

1. Leave a greasy spot on paper. Evaporate completely.

2. Can be saponified. Cannot be saponified.

3. Will not explode when May explode when brought

brought together with ni- together with nitric and

trie acid, iodine, or other other oxidizing agents,
oxidizing agents.

4. Chemical composition — esters Chemical composition,

of glycerine and fatty acids mainly terpenes and deriv-
atives.

5. Almost insoluble in alcohol, Soluble in ether, chloroform,

except castor oil. Soluble benzene, and other oils,
in ether, chloroform, ben-
zene, and in other oils.

174 CHEMICAL PHARMACOLOGY

6. More easily emulsified. Not so easily emulsified.

7. Used in medicine as laxatives, Used in medicine as flavors,

emollients, vehicles for oint- carminatives, stomachics,
ments, liniments, etc. correctives, rubifacients,

deodorants, antiseptics, etc.

8. Are foodstuffs. Are not foodstuffs.

9. Completely oxidized in the Not oxidized but are excreted,

body and excreted as C02 mainly combined with
and H2O. glycuronic acid.

THE GENERAL ACTION OF THE VOLATILE OILS

All volatile oils attack protoplasm and are antiseptic for this
reason. This is a general action of benzene derivatives, and most
volatile oils are such. The volatility of the oil aids in its penetra-
tion and action. When applied to the skin, they produce itching,
redness, some anesthesia, and if volatilization be prevented they
will cause blistering. The turpentine stupe, which is essentially,
oil of turpentine, sprinkled on a woolen cloth wrung out of hot
water, and applied to a part of the body, gives one a good idea of
the local action of volatile oils. Some oils, such as oil of mustard
act after they are broken down into active ingredients, and others
such as menthol have a specific action on the nerves conveying
the sensation of cold. In general however the action resembles
that of turpentine.

Action on the Alimentary Tract

Oils generally have an agreeable taste. They are slightly
irritating and cause a flow of saliva. They are readily absorbed
and may increase the appetite. When swallowed small doses in-
crease moderately the activity of the gastro-intestinal tract and
act as carminatives. Excessive doses produce symptoms of
inflammation with vomiting and diarrhoea.

The oils circulate in the blood for the most part unchanged,
but due to their action on the intestine a leucocytosis may be pro-
duced. If very large doses are taken the central nervous system
is influenced and convulsions may occur. This is readily demon-
strated by giving rabbits large doses of camphor which-acts like a
volatile oil. The harmful effects of absinthe (a volatile oil) are
due to its action on the central nervous system. The continued

GLYCURONIC ACID

175

use of any volatile oil may lead to fatty degeneration of the liver
and kidneys.

Volatile oils are excreted mainly in combination with glycu-
ronic acid — as glycuronates, but this is not characteristic as many
other substances are excreted in this way.

Substances Excreted Combined with Glycuronic Acid. — In ad-
dition to terpenes the following substances, when ingested, may
be excreted as glycuronates:

Isopropyl alcohol

Methylpropyl carbinol

Methylhexyl carbinol

Tertiary butyl alcohol

Tertiary amyl alcohol

Pinacone

Saccharin

Benzene

Nitrobenzene

Aniline

Chloral
Butylchloral
Bromal
Dichloracetone

Phenol
Resorcinol
Thymol
a-and £-
naphthol

Turpentine oil
Camphor
Borneo!
Menthol
Pinene
Antipyrine
Etc.

The Significance of Glycuronic Acid in the Urine

In the normal metabolism of glucose, the aldehyde end of the
chain is first oxidized. Glycuronic acid is formed from glucose
by oxidation of the CH2OH end of the chain. It is thought by
some to be formed in small quantities in normal metabolism,
but this does not seem to be correct, since glycuronic acid
administered parenterally appears in the urine quantitatively
(Biberfeld, 1914). Its appearance in the urine following the
administration of drugs indicates a derangement of carbohydrate
metabolism. The formation of the glycuronic acid may be due
primarily to the drug uniting with the aldehyde end of the
chain which prevents its oxidation.

According to their uses in medicine volatile oils may be classi-
fied as:

176 CHEMICAL PHAKMACOLOGY

1. Flavoring agents or carminatives:

Cloves Peppermint

Coriander Rose

Lavender etc.

Lemon

2. Malodorous oils, used mainly for their psychic effect:

Asafcetida
Valerian

3. Genito-urinary disinfectants. All volatile oils are mildly
antiseptic but those especially valuable here are :

Copaiba

Cubebs

Sandalwood.

Tests

Any fixed and volatile oil may be used. Oil of turpentine is
taken as a representative of the volatile oils and cottonseed as
a type of the fixed oils.

1". Place a drop of each on a piece of glazed paper and note the
difference.

2. Test the solubility of each in water, alcohol, and acetic
acid, chloroform. Repeat this, using croton or castor oil.

3. Add 1 cc. of oil of turpentine to water in a test tube, shake
and let settle. Draw off the water and note the odor. What are
aquae?

4. Saponification. — In an extractor place 200 cc. of cotton-
seed oil and 100 cc. of 10 per cent, alcoholic solution of KOH.
Heat on water bath for 30 minutes, cool and add 15 grams of
NaCl in 50 cc. of water. This converts the soft green soap into
hard soap. Green soap (sapo viridis) was so named because the
vegetable oil from which it was first prepared contained enough
chlorophyll to color it green. Soft soap as now prepared is not
colored green.

5. Heat a little fixed oil with a crystal of KHS04 in a test
tube over a free flame. Note the odor of acrolein (acer,
sharp and oleum, oil). Repeat, using glycerine instead of oil.

CH2OH.CH2OH.CHOH - H20-> CH2:CHCHO

Glycerine Acraldehyde or acrolein

Fats and oils become rancid on standing, especially when ex-

STEABOPTENES 177

posed to light, of if there is a small amount of protein present.
For thi« reason in the preparation of ointments, benzoinated
lard, lanolin, or petrolatum is often substituted.

Lanolin or wool fat, C27H45OH, is cholesterol, a monatomic
alcohol obtained from sheep's wool. It resembles fat in appear-
ance and solubility, and does not become rancid, but is expensive.
It is used in plasters and ointments.

The cholesterols are closely related to the ter penes.

STEAROPTENES

Stearoptenes from their pharmacological action may be con-
sidered as solid volatile oils. When volatile oils are allowed to
stand at low temperatures, they separate into two layers. The
top or lighter layer is known as eleoptene and the lower crystal-
line deposit, as stearoptene. The latter is an oxidized product
of the oil. Camphor, menthol, and thymol are the most impor-
tant stearoptenes. Some unimportant stearoptenes are liquid
at ordinary temperature.

Camphora or camphor is a saturated ketone derived from
cinnamomum camphora. It is said to be saturated because it
will not form addition products. It has the formula — Ci0Hi60.
The form of camphor in white masses of crystalline structure
which have the same solubilities as the volatile oils.
CH2— -CH— -CH2

CH3— C— CH3

CH2 C CO

I
CH3

Camphor-menthol of the National Formulary is a solution pro-
duced by triturating equal amounts of camphor and menthol.
Its uses are as an antiseptic, and as a local anodyne.

Camphor monobromata Ci0Hi5Br.O is a substitution product
of camphor. It occurs as prismatic needles or scales, the solu-
bility being the same as camphor. Borneol camphor: C10H]60 is
a secondary alcohol obtained from ordinary camphor by reduc-
tion.

C9Hi6CO + 2H = C9H16CHOH
Camphor Borneol-camphor

178 CHEMICAL PHARMACOLOGY

Camphor is oxidized in the body to camphorol,
CioH,«0->CioHi6O.OH

This then combines with glycuronic acid and is excreted as
the glycuronate

H] doHisd.OH + C6Hio07 = C10Hi5O O.C6H9O6 + H2O

The camphors are used in medicine chiefly in liniments and
for stimulation of the respiratory and circulatory centres, as
well as the heart muscle in threatening collapse. Externally as
a liniment, camphor irritates the skin and dilates the vessels.
It is used therefore as a rubifacient. It has a mild antiseptic
action and is used to keep away insects. Camphor vapor is a
mild paralyzer of all undifferentiated protoplasm. When taken
by mouth it has a warm bitter taste and carminative action,
much like the volatile oils. Large doses may cause nausea and
vomiting. If large doses are taken it may be absorbed and if so
has a definite stimulant action on the central nervous system,
much like the volatile oils. 10 cc. per kilo of body weight of a
20 per cent, solution of camphor in olive oil given to a rabbit will
produce peculiar bucking spasms in which the animal may turn
a sommersault backwards.

Menthol. — doH220. Menthol is a secondary alcohol de-
rived from peppermint-mentha piperita. It occurs in crystals or
prisms, the solubility of which is the same as the volatile oils.
The dose is about 1 grain, and it is used as an antiseptic, analgesic
and stimulant.

H»C

C— H

C C— H OH

^ __

-H.2 -- \J

CCH3

Menthol

THYMOL 179

Thymol is a phenol from the oil of thyme. It occurs in large
translucent rhombic prisms, its solubilities in general being the
same as the other stearoptenes. It is used especially in the
treatment of hookworm disease, also as an antiseptic and anti-
pyretic.

Thymolis lodidum. — Aristol-thymol iodide is a condensation
product consisting of two molecules of thymol containing iodine
in the phenolic groups. It is a reddish yellow powder and is
used for the same purposes as iodoform, i.e. antiseptic.

Menthol has many of the actions of camphor. It is much used
as a nasal spray, 1 per cent, menthol in light liquid petrolatum,
with volatile oils. When rubbed on the skin it dilates the
vessels as camphor does, but it stimulates the "cold" nerves,
and there is a sensation of numbness of partial anesthesia due
to a paralysis of the sensory nerves, after primary stimula-
tion. For this reason it is sometimes used with benefit in neural-
gias. It is excreted in combination with glycuronic acid as
menthol-glycuronic acid.

CH3 CH3 CH3

I I I

C C C

/V /V S\

HC CH HC C- — C CH

.11 II I I II

HC COH HC COI IOC CH

\s \/ v

C C C

C3H7 C3H7 C3H7

Thymol Dithymol-diiodide (Thymolis iodidum).

1. Note odor and test solubility in water, alcohol, ether and
in fixed oils, of camphor, menthol or thymol.

2. Triturate a small piece of camphor with thymol, chloral,
or menthol.

3. Repeat this with any of the stearoptenes and phenacetin,
acetanilid or antipyrin.

180 CHEMICAL PHARMACOLOGY

Carvacrol is an isomer of thymol. It has the formula

CH3

\OH

CH3 CH3
Carvacrol.

It occurs with thymol in many labiate plants, particularly in
the species origanum and in the oil of thyme it sometimes re-
places all of the thymol. It has the same pharmacological ac-
tions as thymol and can be used instead of it in hookworm disease.
Because of the great demand for thymol in the treatment of
hookworm disease its supply is inadequate. Attempts to produce
thymol synthetically have not been successful from a commercial
standpoint. Carvacrol was first prepared synthetically by Sch-
weitzer (J. Prakt. Chem., 1841, XXIV, 257) and recent work
shows that it may be prepared synthetically from the commercial
point of view. (Hixon and McKee, Journal of Industrial and
Engineering Chemistry, 1918, X, 982).

Besides its use in the treatment of hookworm disease — thymol
is occasionally used as a parasiticide. It has been used in ring-
worm with good results. 5 to 10 per cent, solution in alcohol
being applied directly to the growth. Thymol is excreted com-
bined with glycuronic and sulphuric acids.

XX. RESINS, OLEORESINS, GUM RESINS, AND BALSAMS

Resins are an ill-defined group of amorphous, brittle oxidized
hydrocarbons. They are not pure chemical bodies, but mix-
tures. They are allied to, and probably derived from the vola-
tile oils, and occur as exudations of plants excreted in the course

OLEORESINS 181

of metabolism. Most natural resins consist of a mixture of
peculiar resin acids, which dissolve in alkalies forming resin
soaps. These soaps have detergent properties similar to the
ordinary soaps, and because of their great water-holding power
have been used to adulterate ordinary soaps. The saponifi-
cation value aids in the identification of resins.

Resins are characterized by being insoluble in water and pe-
troleum ether, soluble in alcohol and volatile oils, and when broken
by presenting a smooth shining surface, are amorphous, sticky
and fusible and burn with a smoky flame. They are almost
invariably a mixture of different substances. When resins occur
with volatile oils, they are called oleoresins. When mixed with
gums they are gum resins. Balsams are resins or oleoresins that
contain benzoic or cinnamic acids. The term resin is also used
in chemistry to include such bodies as are formed when a mixture
of alcohol and potassium hydrate are allowed to stand. The
dark colored material that forms and is soluble in the alcohol is
designated as a resin.

The most important resins are those of copaiba, jalap, podo-
phyllum, scammony, guaiacum-wood, gamboge, asafcetida, and
caoutchouc. Amber is a fossil resin and consists of two resin
acids, and a volatile oil. Caoutchouc is prepared from a number
of tropical euphorbiacese, apocinacese, etc. When purified its
formula is (C5H8)n. On distillation it will polymerize spontan-
eously to caoutchouc and also to dipentene. It takes up sul-
phur readily when treated with sulphur chloride (S2C12) in CS2
and the product is vulcanized rubber.

1. Test the solubility of resin in water, alcohol; ether, oil of
turpentine, dilute boiling NaOH and H2SO4.

2. Mix an alcoholic solution of shellac with water; with dilute
alcohol.

3. Mix an alcoholic solution of shellac or resin with mucilage
of acacia. Shake and let stand.

OLEORESINS

These are solutions of resins in ethereal oils. The chief oleo-
resins are aspidium, capsicum, cubeb, lupulin, ginger, and black
pepper. Aspidium is the most important of the group, and is
used in the treatment of tapeworm. It is the principal remedy for
this purpose.

182 CHEMICAL PHARMACOLOGY

Acetone is the solvent used in the preparation of the oleoresins.
It is less expensive and less explosive than ether, and is an ex-
cellent solvent.

1. Evaporate an alcoholic solution of gum turpentine in a
small porcelain dish. Note the odor, and the characteristic
residue. Explain.

2. Compare the appearance of the oleoresins and the resins.
To what is the physical difference due?

3. Place about 25 grams of ginger, pepper, or powdered as-
pidium in a Soxhlet apparatus and extract with acetone. When
the extraction is complete distil off the solvent and examine the
residue-oleoresin. Study the solubility in cotton-seed oil, muci-
lage and water. Shake.

GUM RESINS

Gum resins are mixtures of resins or oleoresins with gums.
Asafcetida, ammoniac, myrrh, gamboge and scammony are the
most important.

Triturate a lump of asafcetida in a mortar with water. Note
the odor and the character of the mixture. Test the influence of
the addition of alcohol. This drug is used in neurasthenic and
hysterical conditions. The influence of it, if it has any, is due to
the odor, i.e. psychic effect.

Boil some of the gum resin with a little H2S04. Neutralize and
filter. Test the filtrate with Fehling's solution. Place 5 grams
of gum in a distilling flask, add 25 cc. concentrated HC1 and distil
from a sand bath. Let the distillate drop on a piece of filter paper
moistened with aniline acetate. A red color indicates the pres-
ence of a pentose, which is converted into furfural by the following
reaction.

C5H1005 - 3H20 -* C4H3O.CHO

Sugar indicates the presence of a gum. Explain the presence and
kind of sugar.

BALSAMS

Balsams are resins or oleoresins that contain benzoic or cinna-
mic acid. The most important are those of peru, tolu, and storax
or styrax. Balsam of copaiba contains neither benzoic or cin-
namic acid and is, therefore, not a balsam. On the other hand
cranberries and other berries of the Ericaceae, contain benzoic
acid but contain no resin.

GLUCOSIDES 183

XXI. GLUCOSIDES OR COMPOUND SUGARS

Glucosides are substances which on hydrolysis yield glucose
or a related sugar, and another substance. In many cases the
composition of the other substance is unknown; usually it is an
aromatic body. The sugar may be rhamnose, galactose, ribose,
arabinose, or any disaccharide that yields a sugar related to glu-
cose. Some glucosides contain only C, H, and O, a few have N,
in addition, and one or two contain sulphur. The part remaining
after the sugar is split off may be alkafbid, e.g. solanine, in which
case the term alkaloidal glucoside would be appropriate. Vege-
table bases however are rarely found in glucosidic combination.
Some of the glucosides are highly toxic, others inert. The
characteristic feature is the yield of glucose or related sugar and
another substance which is not a carbohydrate (different from
gums, starches, sugars polyoses). They are incompatible with
free acids, or ferments, since they are decomposed by these agents.
Some are also decomposed by alkalies. Many have ferments
associated with them in the plant, which are liberated on crush-
ing, and in a water solution hydrolyse the glucoside.

PENTOSIDES, GALACTOSIDES, ETC.

Some writers restrict the term glucoside to compounds yielding
hexose sugars, and designate those yielding pentose sugars, as
pentosides,while those that give galactose on hydrolysis are galac-
tosides. This is a refinement in classification that may or may
not be advisable. Pentosanes, hexosanes, etc. differ from pento-
sides and glucosides in being polyoses and not compounds. On
hydrolysis pentosanes give pentoses only, hexosanes such as cel-
lulose give hexoses only. Other writers taking a wider view
include under glucosides, such polyoses as saccharose, rafiinose,
and gentianose. This is because their combination is ether-like
and, similar chemically to artificial glucosides.

CONSTITUTION OF THE GLUCOSIDES

Chemically, glucosides are ether-like combinations of glucose
with alcohols, acids, phenols, etc. (see table of composition) . Their
constitution is analogous in some respects to acetals or aldehyde
alcohols :

184

CHEMICAL PHARMACOLOGY
H - "If OCH:

R.— C = 0
Aldehyde

+ H

OCH3
Alcohol

OCH,

R.— C/

XOCH3

Acetal.

Since they contain no free aldehyde groups they will not form
osazones and will not reduce Fehling's solution until hydrolysed.

Some glucosides have been prepared synthetically, and the
composition of the synthetic product, gives one an idea of gluco-
sidic composition in general. The best known synthetic glucoside
is the combination of methyl alcohol and glucose. This is pre-
pared by treating a concentrated solution of d. glucose in methyl
alcohol with gaseous hydrochloric acid. Two isomeric products
are. formed. (1) An alpha, glucoside which is dextro-rotatory
+ 157° and dissolves in 200 parts of alcohol and melts at 165°,
and beta, glucoside -which is levo-rotatory — 33° and is soluble in
67 parts of alcohol and melts at 104°C. They can be separated
by their different solubilities.

The formulas assigned to these different glucosides are :

(6)

a-glucoside

jS-glucoside

GLUCOSIDES 185

The a, and Q glucosides are formed simultaneously, the a,
predominating. Equilibrium is established when the mixture
contains about 77 per cent, a, and about 23 per cent, of the 8
isomeride. On standing the |8 form is slowly converted into
the more stable (a) form.

The basis for the assumption of these formulas are :

(I) A single molecule of alcohol reacts with a single mole-
cule of glucose, with the elimination a molecule of water. One of
the secondary alcoholic radicals of the sugar must therefore be
involved.

(II) These glucosides are readily hydrolysed into their con-
stituents. This indicates that the alcohol radical is joined to
the sugar, by means of the oxygen, since if the union were by
means of the carbon atoms direct, they would not be so easily
hydrolysed. (Compare the action and fate of alcohol and ether
in the body.)

(III) The elimination of water is from the (a, and 7) positions,
since other compounds containing R — CHOH.CO. do not yield
glucosides. The (a)» group does not react therefore, and in favor
of the (7) position is the fact that other such combinations are
known; and only combinations containing the (7) group form
glucosides.

From the above, it is seen that there are at least two classes of
glucosides, the alpha and the beta. Maltase splits or hydrolyses
the a group, while emulsin hydrolyses the |8 group.

Burquelot's biological method of investigating plants for glu-
cosides, consists in determining the optical rotation and cupric
reducing power of extracts before and after incubation with
emulsin. A change in these properties indicates the presence
of |8 glucosides, and gives a rough estimate of the amount.

The following table illustrates the hydrolysing action of these
enzymes on the different sugars and glucosides.

186

CHEMICAL PHAKMACOLOGY

Invertin
Saccharose
Raffinose
Gentianose

(7)

(a)

II.

Maltase
Maltose

Methyl-d-glucoside-a
Ethyl-d-glucoside-a
Benzyl glucoside
Glycerine glucoside-a
Amygdalin
Trehalose
Methyl-d-fructoside

CHoOH

H— C— OH

H— C— 0 H

I
HO— C— H

H— C— OH

C = O +H

III.

Emulsin
Aesculin
Amygdalin
Androsin
Arbutin
Aucubin
Benzyl-glucoside
Coniferin
Daphnin
Dhurrin
Gentiopicrin
Glyceryl-glucoside

synigrin
Helicin
Incaratrin
Indican
Lactose
Melatin

Methyl-d-galactoside 8.
Methyl-d-glucoside 6.
Oleuropein
Picein
Prunasin
Prulaurasin

OCH;

Methyl alcohol

Glucose

187

H20

Glucoside

By treatment with methyl-iodide and silver oxide under proper
conditions, alpha, and beta pentamethyl glucosides may be pre-
pared with the formula:

Me.OC— H

CH2OMe

(a) pentamethyl glucoside.

These esters are not acted on by enzymes, but when they are
hydrolysed by acids, alpha and beta, tetra-methyl glucosides
are. formed:

HO— C^-

188

CHEMICAL PHARMACOLOGY

These rapidly change into the same form with constant rotatory
power. The alpha tetra methyl glucoside is not fermentable,
but the beta form can be hydrolysed by emulsin. This enzyme
is especially wide in its action and so far as is known acts only
on beta glucosides.

COMPOSITION OF NATURAL GLUCOSIDES

The natural glucosides are generally colorless crystalline solids
with bitter taste, and levo-rotatory optical power. All natural
glucosides so far isolated are of the beta form. They can all
be hydrolysed by acids though some are very resistant. Emulsin
will hydrolyse a large number of them. Van Rijn (Die Glu-
coside) classifies glucosides according to the plants from which
they are derived. A complete chemical classification cannot be
given, but according to the non-sugar products of hydrolysis,
Armstrong (The simple Carbohydrates .and Glucosides) gives
the following table :

Glucosides

M.p.

Products of hydrolysis

Arbutin
Baptisin

Cl2Hl6O7

CscHszOu

187°
240°

Phenols
Glucose + hydroquinone
Rhamnose 4- baptigenin

Glycyphyllin

CnH24O9

175°

Hesperidin

C5oHeoO27

251°

Rhamnose + 2 glucose -j- hesperetin

Iridin
Methyl arbutin
Naringin

C24H26OlJ

CiiHisOr

208°
175°
170°

Glucose + irigenin
Glucose + hydroquinone methyl ether
Rhamnose 4~ glucose -H narigenin

Phloridzin

C2lH24OlO

170°

Glucose -f- phloretin

Conif erin
Populin
Salicin

CisHzjOg
C2oH2208
CuHisOr

185°
180°
201°

Alcohols
Glucose + coniferyl alcohol
Glucose + saligenin + benzole acid
Glucose -f- saligenin

Syringin

Amygdalin
Dhurrin

Cl7H24O»

C2oH27OuN
Oi4Hi7O7N

191°
200°

Glucose + syringenin
Aldehydes
2 Glucose + d-mandelonitrile
Glucose -f- p-oxymandelonitrile

Helicin

CuHieO?

Glucose -\- salicylaldehyde

Liuamarin

CioIInOsN

141°

Prulaurasin
Prunasin

CuHnOeN
CuHnOeN
GuHieOi

122°
147°
195°

Glucose + racemic mandelonitrile
Glucose + d-mandelonitrile

Samb unigrin

CnHnOeN

151°

Vicianin

Ci9H25OioN

160°

Glucose + arabinose + d-mandelonitrile

GLUCOSIDES

189

Glucoside

M.p.

Products of hydrolysis

Convolvulin
Gaultherin . .

C64H96027

CuHuOt

150°
100°

Acids
Glucose + rhodeose + convolvulinolic
acid
Glucose 4~ methylsalicylate

Jalapin
Strophanthin

^Esculin

C44HS6Ol6

C4oH66Ol9

CieHieO*

131°
205°

Glucose + jalapinolic acid
Rhamnose + mannose + strophantidin
Oxycumarin Derivatives
Glucose + aesculetin

Daphnin

C18H1609
CieHisOio

200°
320°

Glucose + daphnetin
Glucose -J- fraxetin

C22H28Ol4

218°

3 Glucose -j- scopoletin

Skimmin

Frangulin
Polygonin
Ruberythric acid. . .

CisHieOs

C2lH2oO9

C2iH2oOio

C26H28Ol4
C26H28Ol4

210°

228°
202°
258°

228°

Glucose + skimmetin
Oxyanthraquinone derivatives
Rhamnose + emodin
Glucose •+• emodin
Glucose + alizarin
Oxyflavone derivatives

Fustin

C36H26Ol4

C2iH2oOu

218°

Rhamnose + fisetin
Glucose -\- gossypetin

Incarnatrin
Isoquercitrin
Lotusin

C2iH2oOu

C2lH2oOl2

C28H3i016N

242°
217°

Glucose-quercetin
Glucose + quercetin
2 Glucose + HCN + lotoflavin

Quercimeritrin
Quercitrin
Rutin

C2lH2oOl2
C2lH2oOlt

CjyHaoOis

247°
183°
184°

Glucose + quercetin
Rhamnose + quercetin
Glucose -f- rhamnose -j- quercetin

Serotin
Sophorin

C2lH20Ol2

C27HsoOi»

245°

Glucose + quercetin
Rhamnose 4- glucose -J- sophoretin

Xanthorhammin . . .

C34H42O20

2 Rhamnose + galactose + rhamnetin

Glucropaolin
Sinalbin

Ci4H18O9NS2K

C3oH42Ol6N2 S2

138°

Mustard oils
Glucose + benzyl isothiocyanate
Glucose 4" sinapin acid sulphate 4" acrinyl

Sinigrin

CioHiaO9NS2K

126°

isothiocyanate
Glucose 4~ allyl 4~ isothiocyanate +

Aucubin
Barbaloin

Ci3Hi908
C2oHi8O»

KHSO4
Various
Glucose 4~ aucubigenin
d-arabinose 4~ aloemodin

Calmatambia
Datiscein

C19H28Ois

C2lH24Oll

144°
190°

Glucose 4- calmatambetin
Rhamnose 4~ datiscetin

Digitalin
Digi toxin
Gentiin
Digitonin
Gentiopicrin
Gynocardin

CssHseOu

C34H54Oll
C25H28Ou
C54H92O28

CieH2oO9
CnHi9O9N

217°
145°
274°
225°
191°
162°

Glucose 4- digitalose 4~ digitaligenin
2 Digitoxose 4* digitoxigenin
Glucose 4~ xylose 4~ gentienin
Glucose 4- galactose 4- digitogenin
Glucose 4- gentiogenin
Glucose 4- HCN 4- CeHsCh

Indican

CuHnOeN

100°

Glucose 4~ indoxyl

Kampheritrin
Quinovin
Saponarin
Saponins
Vernin . . . .

C27H30O14

CsoEUdOs
CisHuOT

CioHuOsNs

201°

2 Rhamnose 4- kampherol
Quinovose 4- quinovalic acid
Glucose 4- saponaretin
Glucose 4~ galactose 4~ sapogenins
d-Ribose 4- guanine

190 CHEMICAL PHARMACOLOGY

An examination of this table will show that there is little rela-
tion between the known chemistry and pharmacological action.
As a rule, however, the combination of sugar with another radical
increases the action of that radical. This is well illustrated in the
action of chloral, which, when combined with glucose to form
chloralose, is increased and becomes more like morphine in action.
Relatively few glucosides however are used in medicine.

The chief glucosidoclastic enzymes are :

Enzymes Hydrolyses

Emulshr Many natural glucosides

Synthetical /3-glucosides

Prunase . . . . . Prunasin and many other

natural glucosides

Amygdalase Amygdalin

Gaultherase Gaultherin

Linase Linamarin

Myrosin Sinigrin and sulphur glucosides

Rhamnase Xanthorhammin

Emulsin from almonds, hydrolyses, sesculin, amygdalin, andro-
sin, arbutin, aucubin, bankankosin, calmatambin, coniferin,
daphnin, dhurrin, gentiopicrin, helicin, incarnatrin, indican,
melatin, oleuropein, picein, prulaurasin, prunasin, salicin, sam-
bungrin, syningin, taxicatin, verbenalin, etc.

The most important glucosides in medicine are :

Amygdalin Helleborein

Arbutin Jalapin

jEsculin Phloridzin

Coniferin Salicin

Convallarmarin Saponin

Convallarin Strophanthin

Digitalin Scillin

Digitoxin Sinigrin

Pigitophyllin Sinalbin
Digitalein
Digitonin
Aloin

GLUCOSIDES

191

Glychyrrhizin was formerly included in this group, but it is not
a glucoside.

Another classification, of glucosides based on the chemical
groups found in the above is :

1. Ethylene derivatives.

2. Benzene derivatives.

3. Styrolene derivatives.

4. Anthracene derivatives.

The chief representatives of this classification are :
1. Ethylene Derivatives.— Sinigrin CioHi6NS2KO9 -f H2O is
the glucoside of black pepper, mustard, horse radish and tropae-
olum seeds. It is the potassium salt of myronic acid. On
hydrolysis it gives allyl mustard oil, dextrose, and potassium
bisulphate

O— S02— OK

C— S— C6Hn05 + H20 -» C6H1206 + C3H5NCS + KHS04

N— C3H5

Sinalbin C3oH42N2S2Oi5, is the corresponding glucoside found
in white pepper. On hydrolysis it yields mustard oil, glucose,
and sinapin sulphate, which is a compound of choline and sina-
pinic acid and sulphuric acid :

0— S0

C— SC6Hn05

N— CH2.C6H4.OH

Sinalbin

CH:

H20

C7H7O.NCS
Sinalbin mustard oil

OCH.

OH\

Sinapin CH : CH - CO.C2H4O

192 CHEMICAL PHARMACOLOGY

Jalapin C34H56Oi6 is the active principle of scammony, has
been assigned the formula

CH3x

^CH.CHOH.(CroH20)COOH
C2H/

Its decompositions are not definitely known.

Jalapin and Scammonium are identical. This glucoside is
the active principle of scammony (convolvulus scammonia)
and Ipomoea orizabensis. It has the empiric formula C34H56Oi6
and when boiled with dilute acids yields Jalapinolic acid and
glucose:.

CHi-x

C34H56O16 + H2O = ">CH.CHOH.(CioH20)COOH

C2R/ + 3C6H1206

2. Benzene Derivatives. — Arbutin C12Hi607 is the glucoside
found in bearberry (uva ursi). The leaves are used in medicine
and have a diuretic and antiseptic action. The antiseptic action
is due to the hydroquinone liberated. ,

H20

CeHi20<

OH
Arbutin Hydroquinone Glucose

The hydroquinone due to its oxidation imparts a dark color
to the urine.

Amygdalin is one of the best known glucosides and is found in
bitter almond. After hydrolysis with dilute acids, or ferments,
the presence of glucose may be shown with Fehling's solution.

PHLORIDZIN 193

Benzaldehyde may be detected by its odor. The presence
of HCN may be shown by its precipitate with AgNO3 or by the
Prussian-blue test. When the almond is ground with water,
at a temperature below 45°C. the enzyme emulsion contained in
the almond will hydrolyse the glucoside;

O
C20H27NOU + 2H20= 2C6Hi2O6 + C6H5C^ + HCN

XH
Amygdalin Benzaldehyde.

The physiological action of the drug is due mainly to the HCN,
that is liberated in the intestine. Amygdalin is thought to be
a derivative of the nitrile of mandelic acid:

Mandelic acid (Phenylgly collie acid) C6H5CH(OH)COOH may
be obtained by boiling amygdalin with HC1. It may also be
prepared from benzaldehyde by treatment with HCN and hydro-
lysing the resulting hydroxy cyanide :

C6H5CHO + HCN = C6H5CH(OH)CN
C6H5CH(OH)CN + 2H20 = C6H5CH(OH)COOH + NH3

Salicin CisHisOr is the glucoside of Willow bark. On hydroly-
sis, it yields glucose and saligenin.

/OH (1)
C13Hi807 + H20 = C«H/ + C6H1206

XCH2OH (2)
Saligenin

Saligenin is the alcohol corresponding to salicylic acid and on
oxidation will yield salicylic aldehyde and salicylic acid.

194

CHEMICAL PHARMACOLOGY

1. Styrolene Derivatives. — This group contains phenylen-
ethylene or styrolene CeH^CHiCH. Strophanthin and phlorid-
zin are the most important representatives.

Phloridzin C2iH240io.2H20, is a glucoside prepared from the
root bark of the apple, pear, plum, cherry, and various other
members of the rosacese. It is much used in experimental work
and its most pronounced action is the production of glycosuria,
with a simultaneous hypoglycsemia. It is decomposed by dilute
acids into a glucose and phloretin :

C2lH.24Oio2H.20

• Ci5H1406 + C8H1206
Phloretin Glucose

Phloretin has the following formula :
OH -

iCO— CH -

i
.

OH CH3

On decomposition, phloretin yields phloroglucin and phloretinic
acid:

Ci5H14O5 + H20

C6H

Phloroglucin

,OH (1)
^CH(CH3)COOH(4)

Phloretinic acid

Strophanthin. — Several substances have been described under
this term. Strophanthinum or amorphous Strophanthin is
prepared from strophanthus hispidus and Kombe. Ouabain

ANTHRACENES

195

from strophanthus gratus, known also as g. strophanthin-crystal-
line, is considered a purer product than the amorphous forms.
The formula CsoH^O^QH^O has been assigned to it.

Arnand, Kohn, and Kulisch isolated a substance from stro-
phanthus Kombe, which gave the formula CaiH^gO^ which on
hydrolysis yielded strophanthidin Ci9H28O4 and a mixture of
sugars.

4. Anthracene or Anthraquinone Derivatives. — Many of the
anthracene purgatives principles belong in this group. Emodin
and chrysophanic acid occur as glucosides or rhamnosides.
Digitoxin, saponin, and strophanthin may be placed here also,
as in the previous group but the chemistry of these bodies is so
indefinite that a final classification cannot be made.

Chrysophanic acid or dioxy methylanthra-quinon

Ofl

and Emodin or trioxy methyl

anthraquinone
O
CH3 OH

occur in rhubarb, frangula, senna, aloes, etc. The purgative
property of these bodies has been attributed to the anthracene
group, to the ketone or quinone groups, and to various side
chains. Various synthetic bodies of this class have been prepared

196 CHEMICAL PHARMACOLOGY

commencing with aloin. These are not so efficient as purgatives,
as the natural products, because they are too rapidly hydrolysed
and absorbed from the intestine. Drugs used for their direct action
in the intestine should not be rapidly absorbed. It is by reason
of delayed absorption that opium is more efficient in depressing
movements of the intestine than morphine.

SAPONIN OR SAPONINS

The term saponin was originally restricted to the specific
substance obtained from the root of saponaria rubra and S. alba.
The term now includes a series of glucosides of which the empir-
ical formula alone is known. They correspond to the general
formula CgH^NgOio, and are found in many plants as saponaria
officinalis, senega, quillaja, digitalis, sarsaparilla, etc. That
isolated from saponaria officinalis has the formula Ci9H3oOi0.
On hydrolysis, it yields sapogenin, CnH^C^. Solutions of
saponins foam and become soap-like on shaking. When injected
intravenously, they cause laking of the blood." Some are very
toxic and are classified as sapo toxins. Fish are very sensitive
to saponins. One part of saponin in 100,000 of water will kill
fish, but this does not render them unfit for food, since saponin
in this concentration has no action in the gastro-intestinal tract.

THE DIGITALIS GLUCOSIDES

The chemistry of these is not definitely known, and in addition
to the indefiniteness of the chemistry, the nomenclature is con-
fusing. The principles isolated are probably only approximately
pure. Schmiedeberg and Kiliani have done the principal work on
this subject, but the field has just been touched.

Digitoxin is the most important glucoside. According to
Kiliani, it has the empiric formula C34H54On. On hydrolysis,
digotoxin yields digitoxose and digit oxigenin. Digit oxose.

Digitoxose Digitoxigenin

crystallizes in crystals and plates, M.P. 102°C. and is of dextro-
rotatory constitution.

GLUCOSIDES 197

Digitalin, C36RMOu or C^R^Ou, according to Kiliani hy-
drolysis into digitalose, digitaligenin, and dextrose :

dextrose digitalose digitaligenin

Digitonin, CssHg^s or C54H92028. This is a saponin, soluble
in alcohol from which it crystallizes in fine needles m.p. 235°C.
On hydrolyses :

H20 = C3iH5o06 + 2CoHi206 + 2C6H12O6
digitonin digitogenin d,extrose galactose

The commercial digitalins are impure and variable mixtures of
digitalis principles.

Convallamarin, C23H44Oi2, and convallarin, C34H620n, are
two glucosides occurring in convallaria majalis (lily-of-the-valley) .
Convallamarin is soluble in water and alcohol, insoluble in ether
and chloroform, is an acrid glucoside, soluble in water, sparingly
soluble in alcohol, and insoluble in ether and is a saponin-like
glucoside. Little is known of the split products of these glu-
cosides.

Digitalein, C^HasOg, was supposed by Schmiedeberg to be a
pure product but is not now considered a chemical entity. The
same is true of digitophyllin.

Glycyrrhizin, C^HesNds, is the sweet principle of licorice
root. It occurs as the ammonium salt of glycyrrhizic acid,
C44H.62(NH)4N018, and on hydrolysis it yields glycyrrhetin,
C32H47N04, and para saccharic acid, CeHioOs.

This acid reduces Fehling's solution and for this reason gly-
cyrrhizin was formerly thought to be a glucoside.

Scillin, from squill, is a mixture of glucosides, the chemistry
of which is unknown.

Helleborin, CseH^Oe, is found in black hellebore. On hydroly-
sis it gives helleboresin, C3oH3804, and sugar. Helleborein,
C26H.440i5, is another glucoside obtained from the same source.
On hydrolysis it yields helleboretin, Ci4H2oO3, and sugar.

198 CHEMICAL PHAEMACOLOGY

CYANOGENETIC GLUCOSIDES

The cyanogenetic glucosides yield hydrocyanic acid on hydroly-
sis. They are of interest chiefly because they are considered
as the connecting link between the carbohydrates and the alka-
loids and other nitrogen containing compounds. Their composi-
tion differs in different plants. Hydrocyanic acid occurs in
many plants sometimes in the free state but mostly in combina-
tion. The nature of many of the compounds is unknown. Many
are in the form of glucosides and it seems that this is the general
condition of hydrocyanic acid in the plant. However,
nitrogen may occur in glucosides in other forms. The cyano-
genetic glucosides occurs chiefly in the buds, seeds, leaves, and
bark.

With regard to the formation of hydrocyanic in the plant
nothing is definitely known. Gautier supposes that it may be
due to the reduction of nitrates by formaldehyde.

The chief cyanogenetic glucosides are:

Amygdalin Dhurrin

Amygdonitrile (Prunasin)

Sambunigrin Gynocardin and

Prulaurasin Vicianin
Phaseolunatin
Lotusin

SOLANIN

Solanin is an alkaloidal glucoside found in all parts of the
potato plant. Its composition is not definitely known. In its
action it resembles the saponins and is a general protoplasm
poison killing bacteria and hemolyzing red cells in extreme
dilutions. Its salts are amorphous and gummy. It is not
affected by alkalies but acids decompose it into solanidin and
a mixture of sugars including dextrose, rhamnose and galactose.
It dissolves in nitric acid with a yellow color, slowly changing to
red. It gives a green tint with sulphuric acid in alcohol and a
red color with a mixture of sulphuric acid and sodium sulphate.

INDICAN

199

CONIFERIN

Ci6H22O8. This glucoside occurs in various coniferous trees
and in asparagus. On hydrolysis with mineral acids or emulsin
it yields glucose and coniferyl alcohol.

C16H2208 + H20 -> C6H1206 + C10H1203

Coniferyl alcohol.

When coniferyl alcohol is oxidized with potassium bichromate
and sulphuric acid it yields vanillin. Artificial vanillin was
formerly prepared by this method. It is now prepared by the
oxidation of isoeugenol, which in turn is prepared by boiling
eugenol, the chief constituent of oil of cloves. The relationship
is shown by the formulas :

CH = CHCH2OH CHO CH =CHCH3

OCH3
OH

Coniferyl alcohol.

OCH;

Vanillin

OCH
OH
Iso-eugenol

OH
Eugenol

INDICAN

This glucoside occurs in a number of plants, especially indigo
fera anil, I. sumatrana, and I. arrecta. It is decomposed on
hydrolysis into indoxyl and glucose as follows :

> H20

200

CHEMICAL PHARMACOLOGY

Indoxyl
The dye indigo, is formed from indoxyl by oxidation as follows ;

C H O H|C

Indigo blue

V^WJ-JL XJ.VyV>>

r» r»

\j — — V^

Indigo white
The name indican is also applied to a compound of the

formula :

C— OS03K

/CH

ANIMAL GLTJCOSIDES 201

which occurs in the urine in cases of intestinal putrefaction, and
is derived from tryptophane,. in a manner not yet understood.
The relationship is shown by the formula:

C— CH2— CHNH2— COOH

f •

Tryptophane

yCH\

HC C CH

yCH\

HC C

-COH

HC C CH

HC C

Nm/NNH/

^CH/\NH^

Indole

Indoxyl

yCH\

HC C —CO

TTP P P

/C]

OC— C
p p

CH
CH

JLLV^ \j vr

\H/\NH/

— \J \J

VvfTT/ \r<"H
JNrl Orj

Indigo blue

The indigo blue in this case is the same as derived from glu-
coside indican. It is now produced synthetically.

ANIMAL GLUCOSIDES

Glucoside like combinations are found in the animal organism.
The importance of these is not well understood. The term glu-
coside itself it must be remembered is not strictly defined. Thier-
felder isolated a glucoside like substance from the human brain

202 CHEMICAL PHARMACOLOGY

which he called cerebron, a galactoside. On hydrolysis this
yielded cerebronic acid, sphingosine and galactose:

C48H93NO9 2H2O->C25H5oO3 +
Cerebron Cerebronic acid.

C17H36N02 + C6H1206
Sphingosin Galactose.

Cerebron appears to be a mixture of two glucosidic bodies
which have been named Phrenosin (Phren. brain) and kerasin.
Phrenosin yields, sphingosin and galactose kerasin resembles
phrenosin, the differences being mainly that kerasin contains
lignoceric acid C24H4802 instead of cerebronic. The chemistry
of all these bodies is far from complete. Some of the nucleic
acids contain pentosides, and perhaps other glucosides occur in
the brain* substance. The importance of these in the animal
economy for the present cannot be evaluated. That they are
very important can be readily seen when we consider the im-
portance of the nucleins to the life of the cell, and the importance
of the brain tissue in anesthesia, and other drug action, and to
life generally.

THE FUNCTIONS, ACTION, AND FATE OF GLUCOSIDES

The physiological importance of glucosides is not definitely
known. They appear again and again in plants under similar
conditions and it would seem that like the carbohydrates, they are
associated with the metabolism of the plant. As a rule they are
found in greatest amount where metabolism is most active as in
leaves and shoots. Since the time of the maximum amount of
glucosides in plants varies in different plants, their function in
the different plants may also vary. They may be of value as
food stuffs or as reserve food stuffs. Glucosides as a rule are
hydrolysed readily in the upper part of the alimentary tract.
In the case of the digitalis glucosides none reach the large bowel
unchanged. After large doses some of the glucoside has been
found in the liver but not in other organs. The principles have
been found in the urine and faeces, so that both kidney and gut

TESTS FOR GLUCOSIDES 203

take part in the excretion. The hydrolysed products are active
ingredients, though the sugar moiety increases the action. Just
how much of the active part is oxidized in the body is unknown.
The galactoside of the brain is interesting in view of the fact
that all lecithins of vegetable origin are in glucosidic combination.
Galactose, glucose, and pectose," have been identified in these
lecithin glucosides of plants.

Tests for Glucosides

1. Test a 1 per cent, solution of salicin or amygdalin with
Fehling's solution.

2. Acidify another portion of the glucoside with H2S04, boil
for 5 minutes, make neutral or slightly alkaline with NaOH or
KOH, and apply Fehling's.

3. To another portion add some saliva and keep at body tem-
perature for 15 minutes, then test for sugar.

4. Pulverize some bitter almonds in a mortar. Note the odor
of the dry powder. Divide into two parts. Mix one part with
water at 40°C.? and set aside for 15 minutes. Boil the other por-
tion for 5 minutes by adding the boiling water directly to it, and
continuing the boiling. Test both solutions for HCN as follows :
Filter make alkaline with a few drops of KOH, and add a few
drops of freshly prepared ferrous sulphate solution. After al-
lowing it to stand for 4 minutes acidify with HC1. A Prussian
blue color indicates the presence of HCN. See reaction for N
under alkaloids. Difference between the boiled and the unboiled
portions? Bitter almonds contain a ferment-emulsin.

5. To 5 cc. of the fluid extract of licorice, add just enough
1 per cent. Na2C03 to make alkaline. Acidify another 5 cc.
with H2S04. Compare the taste of the two solutions. Acids are
incompatible with glycyrrhiza.

6. Digitalin: Use only a trace of the dry substance^in making
the tests, (a) The solution in H2S04 is yellow. This turns
blood red or violet on adding a drop of HNO3 or Fe2Cl6. (6)
Dissolve a trace of the dry substance in a test tube. Add a
mere trace of Fe2Cl6 with a glass rod. Add an equal volume
of cone. H2S04 without mixing. If digitalin is present there
is a persistent carmine zone at the point of contact. (c)^Place

204 CHEMICAL PHARMACOLOGY

a small piece of the dry substance on a white plate. Add a
drop of Fe2Cle and cone. H2S04 without mixing. A carmine
or violet zone which changes to indigo results (Kiliani). (d)
Physiologic test. This must be taken into consideration with
the above. The slowing and systolic standstill of the frog's
heart is characteristic.

•7. To a portion of a glucosidal solution add 2 cc. of saliva.
Keep it at 40°C. for 15 minutes and test for sugar as in 2.

8. Guignard's test for cyanogenetic glucosides. Strips of
filter paper are dipped in 1 per cent, picric acid solution and
dried; they are now moistened with 10 per cent, solution of
Na2C03 and again dried. In the fumes of HCN, these papers
turn red due to the formation of potassium isppurpurate. If
these papers be suspended over a solution containing HCN
they become red gradually. The rate depending on the amount
of acid present. Hydrogen sulphide gives this same reaction
due to the formation of picraminic acid, and sugar heated in
a solution of alkaline picric acid also gives the red color.

XXII. BITTER PRINCIPLES

Bitters have nothing in common except their bitter taste, and
cannot be classified chemically. All distinctly bitter extractives
other than alkaloids, glucosides, and neutral principles that are
not toxic, are included under the term bitters. The neutral
principles differ from the bitters only in their higher activity and
toxicity.

Tests to Distinguish Bitters from Other Bodies

1. They are not precipitated by alkaloidal reagents — different
from alkaloids.

2. They do not yield sugar on hydrolysis — different from
glucosides.

3. Bitters are physiologically rather inert — different from
neutral principles and alkaloids.

Pharmacologic Classification.— Bitters may be conveniently
placed under four heads :

BITTERS 205

I. Simple Bitters. — These are practically free from tannin
and aromatic oils, and include gentian, quassia, calumba, taraxa-
cum, chirata, pareira, and calendula. The fluid extract and
tincture are the most important preparations.

II. Astringent Bitters. — These contain tannin, which makes
them astringent. Serpentaria, cimicifuga, condurango, and
cascarilla are the chief representatives of this class.

III. Aromatic Bitters. — These contain more volatile oil than
the other classes, and less tannin than the astringent group. The
principal representatives are calamus, aurantii amara cortex,
anthemis, serpentaria, and prunus virginiana.

IV. Compound Bitters. — These are mixtures of. simple bitters.
Blending is said to improve their action. Tinctura gentina com-
posita, elixir aromaticum, tincture amara, and vinum aurantii
compositum belong to this class.

XXIII. PHARMACOLOGY OF THE TASTE AND SMELL

The nerves which mediate taste and smell are the first or
Olfactory (L. Oleo — smell; facio — to make) and the ninth or
glossopharyngeal.

Kant defined smell as taste at a distance, taste and smell being
related. The olfactory is a nerve of special sensation and hard to
investigate because its receptive surfaces are intimately associ-
ated with those of the 5th nerve — a nerve of common sensation.
For this reason true smells, or those substances which stimulate
the olfactory only, are hard to separate from pungent substances
like vinegar which also stimulates the 5th nerve.

For the correlation of odor and structure we are indebted
mainly to Georg Cohn (Die Reichstoffe, 1904) and Zwaar de-
maker (Physiologic des Geruchs, 1895).

Zwaardemaker separates pure odors into nine classes which
have been arranged by Howell (Text Book of Physiology) as
follows :

1. Odores setherei or ethereal odors, such as are given by
the fruits, which depend upon the presence of ethereal substances
or esters.

2. Odores aromatici or aromatic odors, which are typified by

206 CHEMICAL PHARMACOLOGY

camphor and citron, bitter almond and the resinous bodies.
This class is divided into five subgroups.

3. Odores fragrantes, the fragrant or balsamic odors, compris-
ing the various flower odors or perfumes. The class falls into
three subgroups.

4. Odores ambrosiaci, the ambrosial odors, typified by amber
and musk. This odor is present in the flesh, blood, or excrement
of some animals, being referable in the last instance to the
bile.

5. Odores alliacei or garlic odors, such as are found in the
onion, garlic, sulphur, selenium and tellurium compounds. These
fall into three subgroups.

6. Odores empyreumatici or the burning odors, the odors given
by roasted coffee, baked bread, tobacco smoke, etc. The odors
of benzene, phenol, and the products of dry distillation of wood
come under this class.

7. Odores hircini or goat odors. The odor of this animal arises
from the caproic and caprylic acid contained in the sweat.
Cheese, sweat, spermatic and vaginal secretions give odors of
similar quality.

8. Odores tetri or repulsive odors, such as are given by many
of the narcotic plants and acanthus.

9. Odores nauseosi or nauseating or fetid odors, such as are
given byfeces, by certain plants and the products of putrefaction.

Beaunis classified all substances which affect the olfactory
mucous membranes into three groups (Stewart, Text Book of
Physiology), as follows:

1. Those which act only on the olfactory nerves: (a) Pure
scents or perfumes, without pungency. (6) Odors with a certain
pungency — e.g., menthol.

2. Substances which act at the same time on olfactory nerves,
and on nerves of common sensation (tactile nerves) — e.g., acetic
acid.

3. Substances which act only on the nerves of common sensa-
tion (tactile nerves) — e.g. carbon dioxide.

Haller divided odors into :

1. Ambrosial or agreeable,

2. Fetid or disagreeable,

3. Mixed.

CHEMISTRY OF SMELL 207

And in every day life the division is usually made into :

1. Pleasant, or agreeable.

2. Disgusting, or disagreeable.

CHEMISTRY AND PHYSICS OF ODORS

It was formerly believed that before a substance is recognized
as odoriferous, particles must reach the olfactory nerve through
the air. However, odor may be detected when substances are
dissolved in saline, or in the pharmaceutic waters, and taken into
the nostrils.

The concentration of the substances in the liquid is of some
importance, since cumarin, vanillin, oil of rose, etc., and other
substances have different odors in strong and dilute solutions.

Practically, however, volatility is the most essential condition
for production of an odor. Since volatilty is mainly dependent
on molecular weight, chemistry plays an important part. In
chemical compounds, it has been found that certain groups or
radicals give rise to rather distinctive odors. These groups are
called the osmophore groups (osmo — odor; phero — to bear).

Two or more osmophore groups may occur in the same sub-
stance. Investigation of these groups has not gone far enough
to classify odoriferous bodies on their chemical groupings. The
modifying influence of associated groups is not yet understood.
Hydroxyl, aldehyde, ketone, nitrile, nitro and azoimide groups
are all osmophoric, but may produce pleasant or unpleasant
odors, and prediction as to the result is very uncertain. How-
ever, certain facts are established :

1. Homologous derivatives usually have a similar odor.

2. Phenols have characteristic odors.

3. The odor of alcohols is usually pleasant.

4. Unsaturated substances, which are usually chemically
reactive, generally have powerful odors. Triple linked com-
pounds 'are usually unpleasant.

5. If an aldehyde has a pleasant odor, reduction alters the
odor, but does not make it disagreeable.

Drugs that act centrally may stimulate or depress the sensation
of the olfactory nerve; strychnine and caffeine stimulate it,
while chloral depresses. Cocaine applied to the nasal mucous

208 CHEMICAL PHARMACOLOGY

membranes paralyzes the sensation of smell entirely. Marked
changes in the nerve may occur in disease and the sensation of
smell may be entirely abolished (anosmia). Overstimulation
because of the fatigue produced, may also cause this. -

Fatigue of the nerve is quite common. Odors soon give no
sensation when the stimulation is continued, and unpleasant odors,
coal gas, etc., by continued action soon lose their effect.

TASTE

Before a substance can stimulate the taste nerves it must be
soluble in the fluids of the mouth. Accordingly as they affect
the taste, sapid substances have been classified as follows :

1. Sweet

2. Bitter

3. Acid

4. Saline

Regarding the mechanism by which sapid substances stimu-
late the gustatory nerve endings we know but little, but the
stimulus acts on the end organs and not on the nerve trunks.
Nerve trunks in general are not stimulated by any pharma-
cological agent, unless it be applied directly to them; but a sen-
sation of taste is not developed by direct application to the nerve
trunk. Attempts have been made to find a chemical group
responsible for taste, but little progress has yet been made.
Acids and bases owe their characteristic taste to the H, and alka-
lies to the OH ions.

Sternberg ascribes the bitter taste of alkaloids to their cyclic
constitution, but this assertion will not bear analysis. In the
Mendeljef periodic classification of the elements, the sweet
tasting elements boron, aluminum, scandium, yttrium, lanthanum
are found in the third groups, while lead and cerium are in the
fourth. Beryllium, another sweet tasting element, is in the
second, while chlorine which often gives rise to sweet compounds
is in the seventh.

The bitter elements — magnesium, zinc, cadmium and mercury
— are found in the second. Sulphur in the sixth group often
gives rise to bitter compounds.

TASTE 209

The hydroxyl group has often been associated with a sweet
taste. Steinberg (Geschmack and Geruch) has pointed out that
in organic compounds, in order to have a sweet taste the alkyl
groups must not exceed the OH groups, by more than one, or
their combination will be bitter.

Thus Rhamnose: CH3(CHOH)4CHO is sweet,

CH3

(CHOH)3

but methyl rhamnoside CEL is bitter.

I >
GET

OCH3
Again, the sweetness in an homologous series increases with the

CH2OH
increase of hydroxyl groups, e.g. glycol : I

CH2OH

l
is sweet, but not so sweet -as glycerol: CHOH

CH2OH
and glucose:

CH2OH
(CHOH) 4
CHO

is still sweeter. Most substances with the formula (CH20)n
are sweet. That other factors than the OH groups enter into
the production of a sweet taste is shown by the fact that lead
acetate is sweet, yet contains no OH groups; and saccharin,
five hundred times sweeter than cane sugar, contains no OH
groups. Again the corresponding para compound of saccharin
is tastelesss, showing that the architecture of the molecule is
perhaps more important than the chemical grouping. It has been
suggested that the stimulation of the taste buds is a physical
process due to intramolecular vibrations, but we have no way of
testing such a suggestion.

Again in those aromatic bodies containing an OH group the
position of this in the ring and the relation to other groups is
interesting, e.g. :

210

CHEMICAL PHARMACOLOGY
OH OH

OH OH

Pyrocatechol Resorcinol
(bitter) (sweet)

Pyrogallol
(bitter)

NH<

COOH

Anthranilic acid

(sweet)

OC2H5

NH.CO.NH2
Para phenetol or
Dulcin (sweet)

\SO.

Saccharin
(very sweet)

SO2,
CO'

Brom saccharin
(first sweet,
then bitter)

Phloroglucinol

(sweet)

NH2
Amino saccharin

| (very, sweet)

Phthalimide — very similar in com-
position to saccharin — is not
sweet.

N02

Nitro saccharin
(very bitter)

CHEMISTRY OF TASTE 211

This shows that the arrangement of the molecule is of consider-
able importance, but we cannot explain taste in relation to struc-
ture. Saccharin is an orthocompound; resorcin a meta; and
dulcin a paracompound, all of which are sweet. This is further
illustrated by the differences in the taste of optical isomers;
dextro-asparagin is sweet while levo-asparagin is not; and dextro-
glutaminic acid is sweet whereas the levo acid is tasteless.

In a recent study of the chemistry of taste, Oertly and Meyers
(Journal of Am. Chem. Society, 1919, vol. 41, p. 855) have worked
out a theory relating to the aliphatic sweet stuffs. They think
that taste is dependent on two factors, or chemical groups,— a
glucophoric and an auxogmc. They define a glucophore as a
group of atoms which has the power to form sweet compounds
by uniting with a number of otherwise tasteless atoms or radicals.
An auxogluc is defined as an atom or radical which combined with
any of the glucophores yields a sweet compound. Any gluco-
phore will form a sweet compound with any auxogluc.

The following radicals are found to be glucophores in the sense
of their theory :

1. -CO— CHOH(+ H), 4. CH2OH.CHOH-,

2. CO2H.CHNH2-. 5. CH2ONO2-

3. H3-x 6. H3-x H2-y
C — c - C —

HI* HI, HI,

The (+ H) in glucophore 1, simply indicates that the group
must be united with one hydrogen atom at least, in order to
become a glucophore.

In the general formula .H3-x the abbreviation HI is general

C —

HI*

for chlorine, bromine, and iodine. Flourine derivatives may be
included possibly. The small index (x) refers to the number of
halogen atoms in the glucophore. It may vary from one to three,
the number of hydrogen atoms in the glucophore meanwhile
decreasing from two to zero; e.g., methyl iodide has the
glucophore GH2I — . In this case I limits the abbreviation
HI to a single atom of halogen. The index (x) equals one.

212 CHEMICAL PHARMACOLOGY

In respect to the hydrogen, the index is 3 — x which is equal
to two, hence CH2I — agrees with the general formula. Chloro-
form has the glucophore — CC13 which also agrees with the
general formula. The index (y) has the same significance as
(x) but varies from one to two.

The following atoms or radicals seem to act as auxo-
glucs, yielding with glucophores sweet compounds :

(a) H, hydrogen.

(6) The radicals, CnH2n+iO, of saturated hydrocarbons, con-
taining from 1 to 3 carbon atoms. Example CH3CH2 —

(d) The radicals CnH2n-iOn of polyhydric alcohols. Example
CH2OH.CHOH—

The following tables indicate more clearly the significance of
glucophores and auxoglucs.

TABLE I.— GLUCOPHORE CH2OH— CHOH—

Auxogluc Name of Compound Taste

H— Glycol Sweet

CH3— 1, 2-Propanediol Sweetish

CH3CH2— 1, 2-Butanediol Sweetish

CH2OH— Glycerol Sweet

CnH2n-i Polyhydric alcohols All sweet

TABLE II.— GLUCOPHORE, — CO.CHOH — H.

H — Gly collie aldehyde Distinctly sweet

CH3 — Oxy ace tone Sweet j

CH2OH — Gly eerie aldehyde . Sweet and bitter

monomolecular Slightly sweet

bimolecular Sweet

Dioxyacetone Sweet
CH3CHOH — .. Methyl-glyceric

aldehyde,

CH3 (CHOH) 2CHO Sweet and bitter

Methyl-dioxyacetone Sweetish

CnH2n_iOn .... Sugars, e.g. hexoses Sweet

GLUCOPHORES

213

TABLE III.— GLXJCOPHORE, CO2H— CHNH2

Auxogluc Name

H — Amino-acetic acid

CH3 — dl-a-Amino-propionic acid

CH3CH2 — dl-a-Amino-butyric acid

CH3(CH2)2 — dl-a-Amino-n-valeric acid

CH2OH — dl-Serine, a-amino-j3-hy-

droxy propionic acid
dl-a-Amino-/3-hydroxy-bu-
tyric acid

CH3CHOH—

»• — . . d-Glucosaminic acid

Taste
Sweet
Sweet
Sweet
Sweet

Sweet

Sweet
Agreeably sweet

TABLE IV— GLXJCOPHORE CH2ONO2—

CH3_ Ethyl nitrate Sweet

CH3(CH2)2w— . . Butyl nitrate Sweet

(CH3)2CH — . . Isobutyl nitrate Sweet

(CH3)2CHCH2_ Isoamyl nitrate Sweetish

CH2OH — Glycol mononitrate Sweet

3-3

TABLE V. — GLUCOPHORE C

HI,

H— Methyl chloride Sweetish

Methylene chloride Sweetish

Chloroform Sweet

Bromoform Sweetish

lodoform Sweetish

CH3 Ethyl chloride Sweetish

Ethyl bromide Burning

CH2OH — Ethylene chloro hydrine Sweet

214

CHEMICAL PHARMACOLOGY

TABLE VI- — GLXJCOPHORE C

H — . . : Ethylene chloride

Ethylene bromide
Ethylene chloro-iodide

CHs — 2-Chloro-i-iodopropane

CH2OH— . 2, 3-Dichloro-i-hydroxy—

propane

2, Chloro-3-bromo-
propanei-ol

I3-x N2_*

— C
HI, HI,

Sweetish

Sweet

Burning spicy
Sweet

XXIV. TANNIC, DIGALLIC ACID, OR GALLOTANIC ACID
O

occurs in large quantities

C14Hi0O29, or
CO —

OH HOOC

in gall nuts and in all kinds of bark, especially oak. It is the ac-
tive constituent of all vegetable astringents. Its pharmacologic
action is the same as that of metallic astringents and is due to a
union with, and precipitation of, proteins. Tannic acid is soluble
in water, alcohol, or ether. When boiled with H2S04 it is com-
pletely converted into two molecules of gallic acid which shows
that it is a gallic acid anhydride,

COOH

Gallic acid

TANNINS 215

though it is not known which OH group unites with the carboxyl
in the synthesis. All tannins, tannic acid, and gallic acid are
reducing agents, and because of this it was formerly thought
that they were all glucosides. It is now known that not all of
them are e.g. pure tannic acid. Ordinary tannin, is impure tannic
acid and on hydrolysis yields 7-8 per cent, of glucose. The com-
position varies, in some, tannins having been found to be the
penta digallic ester of glucose.

•

CH2— t
CHO— t
CH

/CHO — t "t" represents tannic acid.
(X CHO— t

The composition of many tannins has not been determined.

Tannic acid unites with albumin and is an alkaloidal reagent,
while gallic acid is not. Animal skins properly treated with it
are tanned. Tinctures were formerly detannated by shaking
with finely ground animal hides, but this method has been
given up. Tannin forms inks with iron salts, and for this rea-
son, tannins and iron salts are incompatible. According to
the color of the ink so formed, tannins have been divided into
two classes, first — the pyrogallol class, which gives a dark blue
color, and second — the catechol class which gives a greenish
color.

Tannins differ in the tendency to unite with proteins. A de-
coction of tea is a much more efficient precipitant than a similar
decoction of coffee.

216 CHEMICAL PHARMACOLOGY

On heating gallic acid C02 is given off and pyrogallol
formed. —

OH
OH

COOH

Gallic acid Pyrogallol

All tannins absorb oxygen readily, but pyrogallol does so to a
much greater extent.

Tannic acid is used in medicine for its astringent properties :
externally in cases of local sweating or weeping ulcers, and to
harden the skin. Lead, zinc, and alum salts are used for the same
purpose. In inflammations of the throat, it is used in lozenge
form as an astringent. In cases of diarrhoea it is used in the form
of tinctures of Kino, Krameria, Gambir, Catechu, etc. Its ac-
tion in these cases is due to a combination with the material in
the gut and also to a similar action on the gut wall, which it
protects. It is used as an antidote in cases of poisoning with
alkaloids and heavy metals with which it combines. In such
cases the precipitated material must be removed or the combina-
tion is digested in the body and the action of the alkaloid is
only delayed and not avoided. This delay however may pre-
vent an action by the drug, since such delay may enable the body
to oxidize or excrete it as fast as it is absorbed. In some indi-
viduals, with an idiosyncrasy, tannic acid induces local irritation
and inflammation.

FATE IN THE BODY

When tannic acid is taken internally most of it, in some cases
all, is oxidized. Traces may be excreted in the urine, and feces.
It does not exist in the tissues as such but as the gallate or tannate
of sodium. These are devoid of astringent effects. According
to Harnack, pyrogallol is sometimes formed from gallic acid in
the urine.

TANNINS 217

Tests for Tannin

1. Test the solubility of tannic acid in water, alcohol, ether,
chloroform. Repeat with gallic acid.

2. Add a solution of ferric chloride to tannic acid. Lead ace-
tate added to tannic acid produces a white precipitate; if NaOH
is added to this and the mixture shaken, a pink color is formed.

3. Add tannic acid to a solution of albumin (a) excess albumin;
(6) excess tannic acid; (c) potassium hydroxide. Repeat with
gallic acid.

4. Neutralize a solution of tannic acid with KOH solution.
Add to this neutral solution albumin and compare the result with
that obtained in 3.

5. Add tannic acid to a solution of 1 per cent, quinine bisul-
phate. Repeat with 0.1 per cent, strychnine sulphate.

6. To a 1 per cent, solution of gallic acid add a few drops of 1
per cent. KCN, and there will appear a red color which soon
fades but reappears on shaking (Young's test). Pure tannic
acid does not give this reaction.

7. Boil 1 gm. tannin 15 minutes with 10 cc. of 5 per cent. H2SO4.
Neutralize and apply Fehling's test. What is the result?
Meaning?

8. Permanganate solutions oxidize tannic acid. To 5 cc.
tannic acid solution, add drop by drop KMn04 and note
results. This fact is used in the quantitative determination of
tannin. This is illustrated in the following method — Procter's
Modification of Lowenthals — for the determination of tannin in
tea.

(A) Preparation of Reagents

1. Potassium permanganate. Make up a solution containing
1.33 grams per liter.

2. Tenth-normal oxalic acid. Make up a solution containing
6.3 grams per liter.

3. Indigo carmine. Make up a solution containing 6 grams
of indigo carmine (free from indigo blue) and 50 cc. of concentrated
sulphuric acid per liter.

4. Gelatin solution. Prepare by soaking 25 grams of gelatin
for one hour in a saturated sodium chloride solution, heat until
the gelatin is dissolved, and make up to 1 liter after cooling.

218 CHEMICAL PHARMACOLOGY

5. Mixture. Combine 975 cc. of saturated sodium chloride
solution and 25 cc. of concentrated sulphuric acid.

6. Powdered kaolin.

(B) Determination

Obtain the value of the potassium permanganate in terms of
the oxalic acid. Boil 5 grams of the tea for half an hour with 400
cc. of water; cool, transfer to a graduated 500 cc. flask, and make
up to the mark. To 10 cc. of the infusion (filtered if not clear)
add 25 cc. of the indigo carmine solution and about 750 cc. of
water. Add from a burette the potassium permanganate solu-
tion, a little at a time while stirring, until the color becomes light
green, then cautiously, drop by drop, until the color changes to
bright yellow or, further, to a faint pink at the rim. The number
of cubic centimeters of permanganate used furnishes the value
(a) of the formula given below.

Mix 100 cc. of the clear infusion of tea with 50 cc. of gelatin
solution, 100 cc. of salt acid solution, and 10 grams of kaolin,
and shake several minutes in a corked flask. After settling
decant through a filter. Mix 25 cc. of the filtrate (corresponding
to 10 cc. of the original infusion) with 25 cc. of the indigo solution
and about 750 cc. of water, and titrate with permanganate. The
amount used gives the value b; a — b = c; c equals the amount
of permanganate required to oxidize the tannin. Assume that
0.04157 gram of tannin (gallotannic acid) is equivalent to 0.063
gram of oxalic acid.

XXV. NEUTRAL PRINCIPLES

These are physiologically active substances which are neither
acid nor basic and have no distinguishing chemical properties.
Some are bitter and could, therefore, be classified as bitters,
except for their toxicity and pharmacologic actions. They re-
semble the glucoside closely, but on hydrolysis do not decompose
into sugar; although santonin sometimes contains sugar as an
impurity. The classification of neutral bases, therefore, is in-
definite and includes those chemically nondescript principles of
neutral reaction which are physiologically active. Digitalis,
strophanthus, and even alkaloidal salts from the chemical stand-
point might be included, except that they have chemical proper-

NEUTRAL PRINCIPLES

219

ties that place them in more sharply defined chemical groups.
The chief neutral principles are:

1. Santonin

2. Picro toxin

3. Elaterin

4. Chrysorobin

Santonin, Ci5Hi803, is obtained from wormseed and forms as
crystalline, colorless, bitter, shining leaflets, which melt at 170°C.,
and are soluble in 500 parts of cold water. It is used as an anthol-
mintic, especially for roundworms.

It is the internal anhydride (lac tone) of santonic acid.

0 =

CH3 CH2

Santonic acid

H— OH

H— CH.COOH

CH<

H2 -

H— 0

— CH'

CH3

Santonin

Santonin is a ketone and as such, will react with phenyl hydra-
zine and hydroxylamine. When used as an anthelmintic a
slight amount is absorbed and oxidized to oxysantonin Ci2His04.
Jaffe found this substance in the urine of dogs to the amount of
5 per cent, of the santonin administered. In rabbits only a
small amount could be found. In the rabbit's urine beta-oxy-
santonin was found which is isomeric with alpha-oxysantonin.
After therapeutic doses (0.06 gram) of santonin human urine is
reddish and on the addition of KOH, it becomes carmine.

220 CHEMICAL PHARMACOLOGY

On treatment with lime water, the urine becomes a scarlet or
purple color.

TESTS

1. Santonin heated with an alcoholic solution of KOH gives a
carmine color, which soon fades through yellow to colorless.

2. Santonin heated with concentrated H2SO4 containing a
drop of ferric chloride becomes pink; 10 milligrams of santonin
to 1 cc. of the acid is sufficient.

PICROTOXIN

Picrotoxin, CaoH^Ois is the poisonous principle of cocculus
indicus. It crystallizes in long colorless needles, M.P. 200°C.
It has a very bitter taste, and has a marked action on the medulla
producing spasms that have some resemblance to strychnine
tetanus. Heated to boiling with 20 times its volume of benzene
or chloroform, it decomposes into picrotoxin and picrotin,

CaoHs^is = CisHieOe + CisHisOT

The fate of picrotoxin in the body and the manner of its excretion
is unknown.

TESTS

1. Picrotoxin reduces Fehling's solution. Dissolve a little in
a test tube by the aid of dilute NaOH, and add to dilute boiling
Fehling's solution.

2. If it is warmed with a dilute solution 1 per cent. AgNOa
containing slight excess of ammonium hydroxide a black precipi-
tate of metallic silver will be produced. Where only traces of
picrotoxin are present, the precipitate is colored brown.

3. On oxidation with a trace of H2SO4 on a porcelain dish,
picrotoxin becomes orange red and dissolves to a reddish yellow.

4. H. Meltzer's Test. — One to two drops of a mixture of ben-
zaldehyde and absolute alcohol added to some picrotoxin powder
on a watch glass, will produce a red color when a drop of concen-
trated £[2804 is added. The alcohol here is added as a diluent
because £[2804 produces a brown color with pure benzaldehyde.
20 per cent, benzaldehyde in absolute alcohol is enough.

CHRYSOROBIN

221

5. Langley's Test. — Picrotoxin mixed with about 3 times its
weight of KN03 and moistened with a trace of H2S04 will give
an intense red color when an excess of strong NaOH is added.

6. Physiologic Test. — Typical convulsions are produced in the
frog, but they differ in many respects from those caused by
strychnine. Picrotoxin spasms cease when the medulla is
removed while strychnine tetanus continues after ablation of the
medulla.

ELATERIN

Elaterin, C2oH2806, is the neutral principle of elaterium. It
consists of two substances, alpha-elaterin, which is levo-rotary
and inert, and beta-elaterin, the active dextro-rotary substance.

Elaterin does not exist as such in fruit, but is formed after
expression by a diastatic ferment acting on a glucoside. Little
is known of the chemistry of elaterin or its fate in the body.

CHRYSOROBIN

Chrysorobin is a mixture of neutral principles from Goa
powder. The chief principle is chrysophanolanthranol CisH^Oa,
m.p. 204°, an orange yellow, tasteless, odorless powder, very
irritating to mucous membranes.

According to Tutin and Clewer, chrysophanic acid has the
formula

or dioxmethyl anthraquinone.

Chrysorobin is the anthranol corresponding to chrysophanic acid
and has the formula

222

CHEMICAL PHARMACOLOGY

CH3 OH OH

OH OH

Anthranol is oxyanthracene
OH

Anthranol

Commercial Goa powder contains a mixture of neutral principles,
C30H26O7 and in addition to these described, contains dichrysoro-
bin C3oH2307 and its methyl ester. Aloin and salicin have been
classed as neutral principles but they belong definitely to the
glucosides.

In the body part of the absorbed chrysorobin is oxidized to
chrysophanic acid, but most of it is excreted unchanged by the
kidneys and may cause nephritis. In man slight albuminuria
has been observed after its application to the skin.

XXVI. ALKALOIDS
NITROGEN BASES; PLANT BASES OR ALKALOIDS

These are all synonymous terms and not sharply defined. The
property of N in some compounds to change its valence from 3
to 5, and to unite with acids to form salts is the reason for the
term nitrogen base. The isolation of a number of such bases
from plants, led to the term vegetable alkaloids or " plant bases,"
a term which was formerly restricted to those bases in which the
nitrogen was in combination of pyridine, quinoline, or isoquino-
line. This excluded many nitrogen bases of obvious alkaloidal

ALKALOIDS

223

reactions, including the caffeine or purine bases, which are now
generally conceded to be alkaloids. Alka- loid means an alkali-
like substance. For convenience of study, nitrogen bases or al-
kaloids in the broad use of the term may be divided as follows :

(1) Vegetable alkaloids
derivatives of .

Nature of Nucleus
Group 1. Pyrrole

Group 2. Pyridine

Group 3. Diheterocyclic,
with a common
nitrogen atom

Examples
Hygrine
Stachydrine
Coniine

Atropine,

Sparteine

Strychnine

Papaverine

Pilocarpine

Caffeine

(2) Animal bases or
Alkaloids .

(3) Ptomaines or putre-
factive alkaloids.

(4) Purine Bases

also included under
1.

Group 4. Quinoline
Group5. Isoquinoline
Group 6. Glyoxaline
Group 7. Purine
Group 8. Cyclic or acyclic

derivatives of

aliphatic amines Choline, ar-

ginine

Group 9. Alkaloids of un-
known constitution

Epinephrine — a catechol or

pyrocatechol derivative.

Choline

Muscarine

Betaine

Neurine

Trimethyl amine.

Parahydroxylethylamine and

other ergot amines.

Purine

Hy pox an thine

Xanthine

Guanine

Theobromine

Caffeine

Uric acid

224 CHEMICAL PHARMACOLOGY

(5) Artificial Bases
or synthetic alka-
loids.

Antipyrine
Epinephrine
Cocaine substitutes

In describing these we will not follow this order in detail.
GENERAL CHARACTERISTICS OF ALKALOIDS

1. All alkaloids contain C, H, and N, most of them 0, also.
Those containing 0, are solid and crystalline, while those lacking
O, are liquid and volatile. The liquid and volatile alkaloids may
be regarded as amines, or substituted ammonias and the solid
and crystalline, as amides. See test for N, p. 8.

2. All true alkaloids have an alkaline reaction. The purine
bases are neutral, to litmus.

3. All have a bitter taste.

4. Most of them have marked .physiologic or toxic properties.

5. They form salts by direct addition, as ammonia does.

6. The free alkaloids are relatively insoluble in water and
soluble in ether, chloroform, carbon bisulphide, etc. The salts
have opposite solubilities, they are soluble in water, insoluble
in ether, chloroform, carbon bisulphate and the like.

7. The majority are optically active, and turn the plane of
polarized light to the left. A few, coniine, pelleterine, lau-
danosine, and pilocarpine are dextrorotary.

8. They are precipitated by a large number of bodies, which
because they are much used for this purpose, are called alkaloidal
reagents. The most important are:

1. Iodine in KI (LugoPs solution)

2. Hgl2 in KI (Meyer's reagent)

3. Tannic acid

4. Phosphotungstic acid

5. Gold chloride

6. Platinum chloride

7. Picric acid

8. Picrolonic acid

The shapes etc. of the salt crystals, aid in the identification
of the alkaloid.

9. Many give color changes on being oxidized with nitric
acid, potassium chlorate, potassium bichromate, etc. These
color reactions may be characteristic.

AMINES

225

10. Since all contain N, they will give the tests for N.

11. In cases of poisoning, they leave no characteristic post
mortem change.

CHEMISTRY OF ALKALOIDS

The vegetable alkaloids are related to ammonia and nearly
all are tertiary amines. The basicity of the alkaloids, like am-
monia, is due to the property of nitrogen, changing its valence
from 3 to 5. This is illustrated in the formation of ammonium
chloride.

H + HC1 =

The alkaloids form salts in a similar way.

XXVII. AMINES OR SUBSTITUTED AMMONIAS

Amines are derivatives of ammonia in which the hydrogen has
been replaced by alkyl groups. Depending ori whether one,
two, or three hydrogens are replaced, the amines are named
primary, secondary or tertiary.

/CH3

N^-H

N^H

•vr/_Qjj

J^/_QJJ3

\H '

NxCH3

Methy-

Dimethyl-

Trimethyl

lamine

amine

(primary

(Secondary

(Tertiary

amine)

It is hard to draw a sharp dividing line between the simple
amines and the alkaloids.

Secondary and tertiary amines are also known in which the
N takes part in the formation of a ring. For example, in pyridine

226

CHEMICAL PHARMACOLOGY

the three

or quinoline

hydrogen atoms of N^ — H may be regarded as being replaced

CH— CH
by a group /^-^

= CH— CH

which may be considered a tertiary amine.
H2

Piperidine,

may be classed as a secondary

amine.

Tests for Amines

1. Like ammonia, they form white clouds of finely divided
salts, when brought in contact with HC1 or other volatile acid.
The amines differ from ammonia in being combustible.

2. The amines can be separated from ammonia, if in solution
together, by making strongly alkaline with NaOH or Na2C03.
Then the addition of very fine amorphous mercuric oxide, which
will precipitate the NH3, as follows :

2HgO + NH3 = Hg2N.OH + H20
The precipitate may be separated from the amines by filtration.

AMINES 227

3. Primary and secondary amines will condense with formalde-
hyde while tertiary amines do not. The free bases can then be
regenerated by hydrolysis, and the difference in the distillation
temperature allows separation of primary from secondary.

4. Primary amines all give Hoffman's carbylamine reaction;
secondary and tertiary amines do not.

R - NH2 + CHC13 + KOH = R - N = C + 3KC1 + 3H2O

The disagreeable, indescribable odor is characteristic.

Another method of distinguishing primary, secondary and
tertiary amines is to determine the number of alkyl groups with
which the substance can combine. For example: A substance
having the formula C3H9N. might be:

(a) CsHyNH^ — propyl amine — primary

(6) C2H6

— methyl .ethyl amine — secondary or

(c)

CH3-^N — trimethyl amine — tertiary
CH3X

If when heated with an excess of CH3I a quaternary compound
should be formed in each case, with the primary amine this

would be: C3H7,

>NI or C6H16NI

25v

With the secondary it would be: NIor C5HHNI

with the tertiary: (CH3)4NI or C4Hi2NI

The determination of the amount of iodine added will decide
the question. The titration of the iodine may be done in a
manner similar to that described under thymol iodide.

Other tests for the different amines are as follows :

First. — Primary amines N^-H

228 CHEMICAL PHARMACOLOGY

When primary amines are treated with nitrous acid HN02,
they yield alcohols and nitrogen is evolved:

R.
+HO

>R.OH + H20 + Ns

This reaction is analogous to the reaction of nitrous acid with
ammonia, which yields nitrogen and water:

NH3 + HN02 = H.

Ni.H2 = N2 + 2H2O

HON! O

Second. — Secondary amines. When these are treated with
nitrous acid they yield nitroso amines :

R, R,

>N.HHO - NO = >N - N = 0 + H20

W R/

•

Third. — Tertiary amines either do not react with nitrous acid
or are oxidized by it without the formation of definite products.

QUATERNARY AMMONIUM BASES
Ammonia, NH3, will unite directly with HC1 to form

In a similar way, tertiary amines unite with^alkyl iodide to form
quaternary ammonium iodides or quaternary ammonium bases.
The physiological action of these quaternary bases differs from the
trivalent type. The characteristic action is a paralysis of the
motor nerve ending to striated muscle. This action seems to
depend more on the physical configuration of the molecule than
upon the chemical elements, since phosphorus or arsenic may be
substituted for nitrogen. This paralytic action is also exerted
by alkaloids in which the nitrogen is quinquivalent, such as
curare, methyl strychnine, methyl quinine, methylmorphine,
ethyl brucine, and ethyl nicotine.

AMINES 229

Sources of Amines

Amines occur in nature as the decomposition products of
proteins, and the decarboxylation of amino acids, e.g. :

CH2NH2COOH-»CH3NH2 + C02
CH3CH2NH2COOH-^CH3CH2NH2+ CO2

In this way amines corresponding to all the known amino
acids are thought to have arisen. This process is favored by the
presence of some peptone which serves as a source of nitrogen
for the bacteria and in this way prevents deaminization. They
may also be prepared synthetically; if a concentrated solution
of ammonia be heated in a sealed tube with an alkyl iodide, the
corresponding amine is formed :

NH3 + CH3I-»NH2(CH3) + HI

By further action of the methyl iodide, the other H atoms of
the ammonia may be substituted.

NH3 + CH3I = CH3.NH2.HI

Methylamine hydriodide.
-CH3.NH2 + CH3I = (CH3)2 NH.HI

Dimethylamine hydriodide.
(CH3)2NH + CH3I = (CH3)3N.HI

Trimethylamine hydriodide
(CH3)3N + CH3I = (CH3)4N.I

Tetramethyl ammonium iodide.

Trimethyl amine can also be formed by heating ammonium chlo-
ride with formalin in an autoclave at 120-160°C. (cf. urotropine)

2NH3 + 9CH20 -> 2(CH3)3N + C02 + 3H20

Amines may also be prepared by the reduction of nitro com-
pounds

CH3N02 + 3H2 -» CH3NH2 + 2H20
Nitro methane methylamine

This is a common method of obtaining phenyl amine or aniline

C6H5N02 + 3H2 -> C6H5NH2 + 2H20

Nitro-benzene Aniline

230

CHEMICAL PHAEMACOLOGY

These aromatic amines may also be primary, secondary or
tertiary as in case of the alkyls

Primary

phenylamine or Ani-
line

Secondary

Tertiary

JH,

\
\ H

phenyl phenyl

Methylamine Dimethylamine

Aniline or phenyl-
amine

Diphenylamine

\C!H!

Triphenylamine

The aromatic amines are more active pharmacologically than the
aliphatic.

Amines may also be prepared by reduction of nitrils

CH3 CN + 4H -> CH3CH2NH2
Methyl nitrile

C6H5CN + 4H -» C6H6CH2NH2
Benzo nitrile Benzyl amine

The Physiological Action of the Amines

When ammonia is injected intravenously or when given other-
wise in rather strong solution it stimulates respiration and by
stimulation of the central nervous system may cause convulsions.
As the H atoms of ammonia are replaced by alkyl radicals, the
stimulating action is much diminished, and the extent of the
diminution increases with the molecular weight of the substi-
tuted alkyl.

Alkyl groups are cerebral depressants and the hypnotic action
of alcohol, ether, etc., is due to the alkyl groups. When quater-
nary amine bases are formed, the action becomes paralytic due
to a paralysis of the motor nerve ends in a manner similar to
that effected by curara. The nitrogen atom in the quaternary
amine has little to do with the curara action, since the corre-
sponding phosphorus and arsenic compounds have a like action.

Many amines (substituted ammonias) raise the blood pressure

AMINES 231

after the manner of nicotine and epinephrine. Barger and Dale
have made a rather exhaustive study of the physiological effects
of the amines on the rise in blood pressure, the action on the uterus,
pupil, etc. (Journal of PhysioL, 1910, 41, p. 19) and have com-
pared the action on these locations with that of epinephrine.
Of the aliphatic amines, only the higher open chain primary
amines such as amyl amine, C5HnNH2, and hexyl amine,
C6Hi3NH2, produced a marked rise in blood pressure. Isobutyl
amine, C4H9NH2, is the first to cause any significant rise. The
normal straight chained compounds were more effective than
the isocompounds. Cadaverine, NH2(CH2)5NH2, the only
diamine examined, caused a fall of blood pressure instead of a
rise. Trimethyl amine and tetramethyl amine were inactive,
and of little physiological importance.

A large number of aromatic compounds without a phenolic OH
and containing an amine aliphatic side chain were investigated,
and it was found that only when the amino group in the side
chain is attached to the second carbon from the ring is there a
marked epinephrine — like action. Beta-phenyl ethyl amine
produced all the actions of epinephrine.

Amines with one phenolic hydroxyl group in the ortho position,
such as ortho hydroxyphenyl ethyl amine

CH2.CH2NH2,

are no more active than phenyl ethyl amine itself. The para
compound which is present in ergot (tyramine) and may also be
prepared by heating tyrosin

CH2CH.COOH

NH2
has a similar action.

The pressor or blood pressure raising property in this case
depends on the basic property of the substance, for acetyl p.
hydroxyethyl amine

232

CHEMICAL PHARMACOLOGY

is inactive. The tyrosin ester

CH2.CH2NH CO.CH3

,COOC2H5

CH2.CH

NH<

is also inactive. Methylation or ethylation of the amino group

CH2.CH2NH.R

changes the action but slightly and the alkaloid hordenine, which
is the tertiary base, has a very weak action

CH2.CH.N(CH3)2

Amines with two. phenolic hydroxyl compounds were tested
and their comparative effect on the blood pressure is as follows
(arranged after Percy May Synthetic Drugs) :

Amines with Two Hydroxyl Compounds. — The following
compounds in which the two hydroxyl groups are in the 3-4
position were tested:

(a) DERIVATIVES OF ACETO-CATECHOL (KETONES)

Ratio of

(1) Amino-aceto-catechol, Activity

(HO)2C6H3— CO— CH2— NH2. 1 . 50

(2) Methylamino-aceto-catechol —

(HO) 2CbH3— CO— CH2— NH— CH3.

(3) Ethylamino-aceto-catechol—

(HO)2C6H3— CO— CH2— NH— C2H5. 2.25

(4) Propylamino-aceto-catechol —

(HO)2C6H3— CO— CH2— NH— C6H7 0. 25

(5) Trimethylamino-aceto-catechol chloride —

(HO)2C6H3— CO— CH2— N(CH8),C1.

AMINES 233

(6) DERIVATIVES OF ETHYL-CATECHOL

(6) Amino-ethyl-catechol,

(HO)2C6H3— CH2— CH2— NH2. 1 . 00

(7) Methylamino-ethyl-eatechol —

(HO)2C6H3— CH2— CH2— NH— CH3. 5.00

(8) Ethylamino-ethyl-catechol —

(HO)2C6H3— CH2— CH2— NH— C2H5. 1 . 50

(9) Propylamino-ethyl-catechol —

(HO)2C6H3— CH2— CH2— NH— C3H7 0.25

(10) Trimethylamino-ethyl-catechol chloride —

(HO) 2C6H3— CH2— CH2— N (CH3) ,C1

(11) Amino-ethanol-catechol- —

(HO) 2C6H3CH (OH)— CH2— NH2. ' 50 . 00

(12) Methylamino-ethynol-catechol (adrenaline) —

(HO) 2C6H3CH (OH)— CH2— NH— CH3 35 . 00

The main conclusions of Barger and Dale from their Investiga-
tion of the amines are :

1. An action simulating that of the true sympathetic nervous
system is not peculiar to adrenine, but is possessed by a large
series of amines, the simplest being primary fatty amines. We
describe all such amines and their action as "sympathomimetic."

2. Approximation to adrenine in structure is, on the whole,
attended with increasing intensity of sympathomimetic activity,
and with increasing specificity of the action.

3. All the substances producing this action in characteristic
manner are primary and secondary amines. The quaternary
amines corresponding to the aromatic members of the series
have an action closely similar to that of nicotine.

4. The optimum carbon skeleton for sympathomimetic activity
consists of a benzene ring with a side chain of two carbon atoms,
the terminal one bearing the amino group. Another optimum
condition is the presence of two phenolic hydroxyls in the 3-4
position relative to the side chain; when these are present, an
alcoholic hydroxyl still further intensifies the activity. A phenolic
hydroxyl in the 2 position does not increase the activity.

5. Catechol has no sympathomimetic action.

234 CHEMICAL PHARMACOLOGY

6. Motor and inhibitor sympathomimetic activity vary to
some extent independently. Of the catechol bases those with
a methylamino group, including adrenine, reproduce inhibitor
sympathetic effects more powerfully than motor effects: the
opposite is true of the primary amines of the same series.

7. Instability and activity show no parallelism in the series.

The amines are very slightly toxic and their ultimate fate es-
pecially that of the lower members in the body is perhaps similar
to ammonia, urea and carbon dioxide being the ultimate products.
In some cases various intermediate products are formed. Ewins
and Laidlow found that one-half the amount of p. hydroxy phenyl
amine given by mouth to dogs was excreted in the urine as para
hydroxy phenyl acetic acid. This same conversion of the amine
into the acid occurred when it was perfused through the rabbit's
liver, but when perfused through the isolated heart it was com-
pletely destroyed without the formation of acid. In the vast
majority of the cases, however, little is known of the fate in the
body. In view of the great activity of histamine and its probable
relation to anaphylactic shock and to the toxicity of proteins as
emphasized by Vaughan, many think that a detailed investi-
gation of the fate of the higher amines, especially those like his-
tidine and the more complex peptamine will go far to explain
symptoms now classified as ptomaine poisoning or other equally
vague terms.

ALKALOIDS DERIVED FROM ALIPHATIC AMINES
A number of important alkaloids are aliphatic derivatives or
combinations. The most important in pharmacology are:
1. Epinephrine

2. Arginine

3. The putrefactive alkaloids

Betaine Putrescine

Choline

Muscarine Cadaverine
Tryamine,

_ ii. t -j Histamine,

4. Ergot alkaloids ^

Ergotoxme,

Isoamylamine.

5. Sinapine

6. Hordenine

Epinephrine or the pressor principle of the adrenal glands is
a derivative of para hydroxyphenylethyl amine

AMINES

235

and has the formula
OH—

CH2CH2NH;

CH(OH)CH2.NH.CH3

It was first isolated by Abel in 1879 and 1899 (Zeit. f. Physiol.
Chem., 1898, 28, 318; and Am. Jour. Physiol., 1900, 3, XVII)
and by Takamine who obtained it in crystalline form and from
its decomposition thought he obtained catechol and pyrocate-
chuic acid. These products have been used in the preparation
of synthetic epinephrine. It has since been isolated and analyzed
by others. It has also been prepared synthetically. The natural
product is a slightly yellowish powder, and levo-rotatory. The
synthetic product is optically inactive and resolvable into a
dextro and levo form. Th natural product is twice as effective
as the synthetic judged by its action in raising the blood pres-
sure. The levo form is about 12 times as active as the dextro.
The action on the blood pressure is due to a stimulation of the
sympathetic nerve endings to the heart and blood vessels. Its
action in any location can be predicted if we. know the result of
stimulation of the regional sympathetics. In the intestine and
bronchioles, stimulation of the sympathetics causes a relaxation
and dilation; and in these regions, epinephrine has a like effect.
Because it mimics the action of 'the sympathetics, Barker and
Dale suggest the term sympath-o-mimetic, to describe its action.
The synthesis of epinephrine has been effected by Friedman
as follows :

OH OH

OH + C1.CO.CH2C1

Catechol + Chloracetylchloride

CO.CH2C1
chloracetyl catechol

236

CHEMICAL PHAKMACOLOGY
OH

HNH-CHa

CO.CH2.NH.CH3
Methylamine Methyl ammo aceto catechol or adrenalone

HC(OH)CH2.NH.CH3
Epinephrine.

Epinephrine has been prepared by another method, starting
with pyrocatechuic aldehyde

CHO + HCN -

Pyrocatechuic
aldehyde

CHOH.CN + Reduction

COHH.CH2.NH2 which on methylation

CHOH.CH2.NH.CH2

OH Epinephrine

AMINES 237

This is the accepted formula — others suggested are:

CH2CHOH.NH.CH3 and

CH.NH.CH3
\
CH2OH

In favor of the accepted formula I is the fact that methyl-
amino aceto catechol or adrenalone from which adrenaline may
be prepared by reduction, is formed by the action of methyl
amine on chloracetyl catechol

-CH2.N(CH3)2

Hordenine.

Hordenine, an alkaloid in malt, is very closely related to epine-
phrine in structure, but its action is more like phenol than epine-
phrine. It is only slightly toxic :

1 gram per kilo per os in a dog or rabbit causes some rise in
blood pressure and acceleration of the pulse. It acts both on
sympathetic and para sympathetic endings, and also centrally.
After a fatal dose, which for a dog is 0.3 gm. per kilo intraven-
ously, death occurs from respiratory failure — similar to phenol.

Epinephrine Tests

1. To a dilute solution of adrenaline chloride or an extract of
the gland, add a few drops of ferric chloride. An emerald green
color develops but this is quite transient (phenolic reaction).

2. To a solution add some sodium carbonate. A reddish color
is formed. Alkalies destroy the physiologic effect of the substance
rapidly.

3. Physiological test: 1 cc. 1-10,000 solution injected into the
vein of a mammal will cause a great rise in blood presure.

238 CHEMICAL PHARMACOLOGY

ARGININE

Arginine is physiologically inactive in animals, consequently is
of little interest from a purely pharmacodynamic point of view.
Chemically it is alpha amino guanidine valerianic acid.

NH2

C = NH

N— H

I
H— C— H

H— C— H
H— C— NH2

O = C— OH

All proteins contain arginine, and the head of salmon sperm
yields nearly 90 per cent. Arginine, lysine and histidine have
been called hexone bases, by Kossel, because they contain 6
carbon atoms, and he thought proteins were built up of such
amino acids in a manner similar to the formation of complex
carbohydrates from hexoses. The relationship of proteins to
alkaloids is again apparent here.

The Fate of Arginine in the Body

By the action of so-called carboxylase bacteria, which decar-
boxylate arginine, agmatine is formed :

NH2— C(NH)— NH.CH2(CH2)2CHNH2.COOH =

Arginine.

C02 + NH2.C(NH).NH.CH2(CH2)2.CH2NH2
Agmatine.

Agmatine has also been obtained from ergot and has been
synthesized by Kossel. It is regarded as amino butylene guanid-
ine. According to Dale and Laidlow agmatine contributes but

AMINES 239

little to the activity of ergot. It acts like histamine but is only
1/50 as active. Arginine may also be split in the body by an
enzyme into urea and ornithine, i.e. alpha d-diamino valeric acid.

X2 NH2

NH = CT. I

HO XNH— CH2— (CH2)2— CH— COOH

NH2 NH2

I I

CO + NH2— CH2— (CH2)2— CH-COOH

NH2

This change may also be accomplished by boiling with alkali.
A further decomposition of the ornithin to ammonia and carbon
dioxide may occur.

PTOMAINES OR PUTREFACTIVE ALKALOIDS

Ptomaines or putrefactive alkaloids are products of the putre-
faction of meat. They are basic bodies, usually amines of simple
constitution, such as methyl amine CH3NH2 — dimethyl amine
(CH3)2NH or trimethyl amine (CH3)3N.

Many ptomaines are toxic, others non-toxic. The toxicity
may be due in part to ptomaines directly and in part to associ-
ated unknown toxins.

In their reactions ptomaines may resemble some alkaloid.
This pharmacologic and chemical resemblance may make the
identification of the alkaloids difficult. The similarity, however,
is usually confined to one of the reactions of the alkaloid, and
never extends to all the reactions characteristic of any particular
alkaloid. Ptomaines have been found that show certain re-
semblances to coniine, nicotine, codeine, strychnine, veratrine,
atropine, hyoscyamine and morphine; but as-stated above these
resemblances are frequently confined to one reaction and never
in any case agree with all the characteristic reactions of the
alkaloid.

Ptomaines are of limited importance as medicines, having a
toxicologic interest only. Their great toxicity is probably due

240

CHEMICAL PHARMACOLOGY

to the inability of the body to oxidize them, even in minute
amount.

The most important ptomaines are:

Putrescine

Cadaverine

Choline

Muscarine

Betaine

Neurine

NH2(CH2)4NH2
NH2(NH2)5NH2
N(CH3)3OH

CH2CH2OH
N(CH3)3OH

CH2CHO

N(CH3)3v •

I >0

CH3CCK

N(CH3)3OH

Choline, muscarine, betaine, and neurine are sometimes called
the betaines.

, Putrescine: (from putresco, to rot or putrefy), or tetramethy-
lene diamine —

NH2.CH2.CH2.CH2.CH2.NH2

occurs associated with cadaverine. It was first obtained from
putrefying human internal organs. It has also been found
in the excreta of cholera patients, and in the urine in cases of
cystinuria. Carbohydrate diet lessens the amount excreted in
these cases, while meat diet increases it. This points to protein
as the source of putrescine. Normal feces do not contain it.
The use of salol, sulphur, and other intestinal antiseptics does
not appreciably influence the amount excreted. Garcia, how-
ever, has shown that when cane sugar is added to putrefying
meat and pancreas in vitro, less diamine is formed. The bacteria
forming the diamines apparently live on the sugar in preference
to the protein. Sugar or carbohydrate for this reason has been

AMINES 241

advocated as the preferable diet in many cases of gastro-intes-
tinal putrefactions.

The relation of putrescine to cystinuria is but little under-
stood. It was suggested that putrescine and other diamines
united with cystin to prevent its .oxidation. When diamines
are fed to dogs no cystinuria occurs, and the formula of cystine

H H

H — C— S S C— H

NH2— C— H H— C NH2

I I

O = C— OH 0 = C— OH

does not suggest an origin from the diamines.

The source of putrescine is most probably directly from orni-
thine or a, e, diamino valeric acid.

NH2.CH2.CH2.CH2.CH2.NH.COOH->
ornithine

NH2.CH2.CH2.CH2.CH2.NH2. + CO2
putrescine.

Putrescine has also been prepared synthetically. Addition
or substitution products can be readily formed. The tetramethyl
derivative N(CH3)2(CH2)4N(CH3)2j is much more poisonous
than putrescine, and resembles muscarine in action. The symp-
toms are: nausea, vomiting, salivation, increase then decrease of
respiration, contracted pupils, diarrhoea and collapse. Atropine
will counteract many but not all of these symptoms.

Cadaverine or penta-methylene diamine is found associated
with putrescine and is formed similarly. It is probably formed
from lysine or a, e, diamino caproic acid by decarboxylation :

NH2.CH2,CH2.CH*.CH2.CHNH2COOH—

lysine

NH2.CH2.CH2.CH2.CH2.CH2.NH2. + C02

and is probably identical with so-called animal coniine which
has been isolated from cadavers, it may produce marked in-
flammation and necrosis, and like turpentine and some other

242 CHEMICAL PHARMACOLOGY

drugs, can cause suppuration in the absence of bacteria. With
putrescine it probably causes the cystitis of cystinuria. It is
not very poisonous however , — large doses will kill mice, but it is
relatively non-poisonous to dogs.

By heating pentamethylene hydrochloride piperidine may be
formed which has a definite toxic action:

XCH2.CH2NH

CH2/
\OTT /^TJ

V^X12.^>'J12

H
NH2

HCl->
, NH2

CH2

| | + NH4C1

Piperidine.

By oxidation of piperidine to pyridine the toxicity is again
markedly reduced.

Choline (chole-bile). — Choline is partly amine and partly
alcohol. It is found as a constituent of lecithin, which occurs
especially in nervous tissue, egg-yolk, seeds, and elsewhere. It
is also found in ergot, and in many-plants. Its composition is
shown by its synthesis from trimethylamine and ethylene oxide
in aqueous solution

(CH3)3N + CH2. CH2 yCH2.CH2OH

V + H20 = (CH3)3N(
0 XOH Choline

It is related to muscarine and to neurine :

XCH2.COH XCH:CH2

(CH3)3N< (CH3)3N<.

XOH XOH

Muscarine Neurine

While choline is but slightly toxic, its dehydrated product neurine
is extremely toxic. In the formation of neurine from choline, by
the elimination of a molecule of water, a double-bonded carbon

CHOLINE 243

combination is formed. If this double-bond is changed to a
triple bond by the formation of

(CH3)3

/C-CH
/
XOH

the product is still more toxic. See p. 148 for influence of triple
bond.

The formation of choline from lecithin can be seen from the
formula of lecithin, R and R' being similar to dissimilar acid
radicals :

CH2OR
CHOR'

CH.O— P/ = O

X0— CH2.CH2.N(CH3)3.O.H

Lecithin, however, cannot be regarded as the only source of
choline in plants because it occurs where no lecithin has been
found — as in the seeds of white mustard, sinapin giving rise to
choline as follows :

C16H23N05 + H20 = C5H15N02 + CnH«O8
Sinapin Choline Sinapic acid

Betaine or trimethyl-glycocol

N.(CH3)3
CH2.CO

gets its name because it is found free in the sap of the sugar beet
Beta vulgaris. Betaine is the anhydride of hydroxytrimethyla-
mine-acetic acid:

N.(CH8),.— OH
I
CH2.COO— H

244 CHEMICAL PHARMACOLOGY

The alkaloid stachydrine

/CH-r- CH.CO .
CH2( | )0

XCHr-N.(CH8)/

one of the pyrrolidine alkaloids, is also a derivative of this sub-
stance being a dimethyl betaine of pyrrolidine. Betaine is
physiologically inactive when given by mouth, hypodermically it
acts like choline. It occurs in large amounts in the muscles of
cephalopods and has been isolated from human urine and has
been prepared synthetically. Betaine is excreted unchanged and
cannot therefore act as a food.

Muscarine is a tertiary amine and an aldehyde, while choline
is the corresponding amine with an alcohol. Very few amino
aldehydes or amino ketones are known.

Amino acetaldehyde — CH2NH2.CHO is a very unstable corn-
compound. Muscarine is thought to be the corresponding
trimethyl ammonium base :

CH2— N(CH3)3.OH

CH3X /CH2.CH(OH)2
or CH3~N/
+ H2O CH3/ \)H

The action of muscarine is very similar to pilocarpine or to
arecoline. It causes:

1. A marked slowing of the heart by stimulation of the vagus
endings.

2. A constriction of the pupil, due to stimulation of the third
nerve endings.

3. Marked gastric and intestinal peristalsis 'leading to vomiting
and diarrhoea, also asthmatic respiration.

4. Marked salivation due to stimulation of the endings of
the chorda tympani nerve.

Most of these actions may be neutralized by a small dose of
atr opine.

ERGOT ALKALOIDS

In recent years much has been done to make clear the composi-
tion of the active principles of ergot. These active principles

ERGOT AMINES . 245

consist of alkaloids and amines. The chief alkaloids are ergo-
tinine and ergotoxine. These are readily interconvertible.
Ergotinine is inactive, but its hydrate ergotoxine is active —

C35H3905N5 + H20 -* C35H4106N5
Ergotinine Ergotoxine

Both of these alkaloids on destructive distillation give isobutyl
form amide— (CH3)2CH.CO.CO.NH2.

Beyond this little is known of their constitution. Their fate
in the body is also unknown. Ergotoxine, along with hista-
mine, is responsible for practically the whole action of
ergot in therapeutics. It acts very Inuch like adrenaline
from which it differs by stimulating only the motor myoneural
junctions of the sympathetic nerves while it does not act on the
inhibitors. Dale found that in large doses ergotoxine paralyzes
the augmentor elements only, and that adrenaline after ergo-
toxine often causes a fall of blood pressure. This phenomenon he
called "vaso motor reversal."

ERGOT AMINES
Isoamylamine

CH2 CH2 . NH2
CH

is an ergot amine, and results from the putrefaction of proteins.
It probably arises from leucine,

CH2CH.COOH

CH/ |

by a splitting off of carbon dioxide.

When injected intravenously isoamyline raises the blood pres-
sure. The amount present in ergot is too small to be of any
significance in ergot action. Isoamylamine hydrochloride has
been employed to some extent as an antipyretic.

Beta-iminoazolylethylamine-4-meta-amino, ethyl glyoxaline or
histamine is another ergot amine. It is derived from histidine
by the action of putrefactive bacteria —

246

CHEMICAL

PHARMACOLOGY

CH— NH,
C N^

(

)H— NHV
\CH

: w

V-V .LN

CH2

CH.NH2

CH2

COOH

^H2.NH2

ine or a} amino 0, imino- Histamine /S,
azole propionic acid iminoazole eth

l-amine

Histamine stimulates the uterine muscle directly, and is one of
the important ergot principles. It also stimulates the bronchi-
oles which are highly sensitive; less so, the intestine arteries and
spleen. Its action resembles pituitrine. Histamine dihydro-
chloride, C5H9N3.2HC1, is readily soluble in water, and is used
in the standardization of pituitrine. One part of betaimino-
azolylethylamine hydrochloride (histamine hydrochloride) in
1 : 20,000,000 has the same activity on the isolated uterus of the
virgin guinea pig as 1 to 20,000 solution of standard pituitary
extract.

Histamine is precipitated by phosphotungstic acid, by am-
moniacal silver solutions, and by mercuric chloride in alkaline
solution. On boiling with bromine water it gives a claret color.

Parahydroxy phenyl ethylamine or tyramine :

CH2.CH2.NH2

is of especial interest in medicine as being one of the active in-
gredients of ergot. It has also been isolated from putrid meat.
It gets the name tyramine from the fact that it may be prepared
from tyrosin:

CH— CH?

COOH

NH<

PYRIDINE ALKALOIDS

247

which eliminates CO2 on heating. Tyramine like epinephrine
acts on the sympathetic endings, and unlike epinephrine it
apparently acts more on the constrictor endings and little on
the dilators.

PYRIDINE ALKALOIDS

Pyridine is a colorless mobile liquid, sp. gr. 1.003 at 0°C.
B.P. 115°. • It is an exceedingly stable and chemically inactive
substance with a pungent characteristic odor, and may be heated
with nitric or chromic acid without undergoing change. It is
formed by the destructive distillation of many nitrogenous or-
ganic substances, especially coal tar and bone oil.

Pyridine, CH

like nicotine, is a highly toxic

substance.

In order to name the substitution products, its various
positions are named in relation to the (N) :

Since piperidine is formed from pyridine by reduction, the reverse
change can also be made and pyridine formed from piperidine
by oxidation. In the formation of pyridine, pentamethylene
diamine hydrochloride is converted into piperidine and this in
turn is oxidized to pyridine :

248

CHEMICAL PHARMACOLOGY

,CH

H2C

CH<

NHH

XCH2-CH2-|NH2 HC1

H2CN

CH2
CH2

Pentamethylene-diamine
hydrochloride

+ 30 /

HC/

Piperidine

Pyridine

The toxicity of the pyridine homologues increase with increase
in molecular weight through picoline or methyl pyridine, lutidine
or dimethyl, collidine or trimethyl to parvoline C5NH(CH3)4 or
quatramethyl pyridine, which is eight times as toxic as pyridine.

Pyridine can be formed synthetically, by dry distillation of
pentamethylenediamine. It may be prepared by boiling the
alkaloid piperine with alcoholic potash. The decomposition is
expressed by the formula:

Ci7Hi903N + H20 = C6HnN + Ci2Hi004
Piperine Piperidine piperic acid.

Methyl pyridine may occur in small quantities in the tissues
probably derived from vegetable foods and from pyridine — con-
taining plants, like tobacco. His (Arch f. exp. pharm., 1894,
vol. 22, p. 247, 281) confirmed by Cohn (Zeit. physiol. Chem.,
1894, vol. 18, p. 112) found that pyridine is eliminated in the
urine as methy pyridil ammonium hydroxide

This occurrence of methylation in the animal body is a rare

METHYLATION IN THE BODY 249

and interesting phenomenon. Hoffmeister states that after
feeding an animal tellurium compounds, tellurium dimethide
Te(CH3)2. is excreted in the urine. Methylated compounds as
a rule when introduced into the body are demethylated. Caf-
feine loses successively one, two and three methyl groups. Since
methylation increases the toxicity of pyridine one must feel some
doubt of its methylation in the body.

NATURAL METHYLATED COMPOUNDS IN THE BODY

Creatine is methyl guanidine acetic acid. Creatinine is the
anhydride of this. These are the most important methylated
bodies that occur normally in the urine. Creatine is unquestion-
ably formed from amino acids, but no methylated amino acids
occur in the body and the process of methylation though not
known is perhaps similar to that occurring in plants. Methyla-
tion in plants is a common occurrence and it appears probable that
methyl compounds are formed by Ihe action of ammonia and
formaldehyde :

2NH3 + 3CH20 = 2NH2 : CH3 + C02 + H20

This reaction can be readily carried out in the laboratory.
Formaldehyde has been demonstrated in plants; but its pres-
ence in the animal body, however, has not been proven.
Consequently, if this be the mechanism in plants, there is still
some doubt how methylation takes place in animals.

In the plant, photo chemical reactions must play an important
part in such vital processes.

The Fate of Creatine and Creatinine in the Body
As stated above some of these bodies occur in the urine. The
amount of creatinine in the urine remains constant no matter
how the protein of the diet varies. This led Folin to distinguish
between exogenous metabolism or the metabolism of food stuffs
and endogenous metabolism or that due to the breaking down of
the body protein. Creatinine represents the endogenous metab-
olism. Creatine is destroyed in the tissues. The mechanism
of this oxidation is not known, but it has been suggested that it is
first converted into creatinine and then destroyed. Folin
found, however, that creatinine administered is not oxidized;
but all is eliminated in the urine.

250

CHEMICAL PHARMACOLOGY

Hydrogenation of pyridine results in the formation of piperidine
or hexahydro pyridine or

which has an imide group NH and is a secondary amine.
Piperidine is a colorless oil, with unpleasant odor and strong basic
properties. Pyridine is but slightly toxic and lowers the blood
pressure, but piperidine is very toxic and raises the blood pressure
with general paralysis of central origin. Its total action is much
like coniine, which is propyl piperidine. Large doses exert a
curara action on the motor nerve ends. The action of piperidine
compared with related compounds shows the toxic influence of
the imide group in the molecule.

N NH NH

Pyridine Piperidine Pyrrole

Pyridine is less toxic than either piperidine or pyrrol, and colli-
dine is less toxic than coniine.
CH3

N
Collidine

NH
Coniine

ALKALOIDS 251

Piperidine because it is readily oxidized in the body, does not
give the methyl synthesis that pyridine undergoes in the body.
The principal pyridine alkaloids are:

Coniine from conium maculatum
Nicotine from nicotina tabacum
Atropine from atropa belladonna
Cocaine from Erthroxylon coca
Morphine from Papaver somniferum
Narcotine from Papaver somniferum
Quinine from Cinchona and remija
Strychnine from Strychnos nux vomica
Brucine from Strychnos nux vomica

It is possible to place some of these alkaloids also under other
heads, because they may contain other nuclei. For example
quinine and strychnine also contain the quinoline nucleus, which
is a combination of pyridine and benzene.

The tests for the pyridine nucleus are:

1. Potassium ferrocyanide precipitates the base. This product
is rather insoluble and the pure base can be prepared from it.

2. When the pure base is treated with platinum chloride a
double salt, ^HsN^H^Pt.Cle, is formed. This is soluble in
water, but hydrochloric acid is evolved and a yellow insoluble
compound (C6H5N)Pt.Cl4 is formed.

3. When the free base is warmed with methyl iodide, an addi-
tion product C5H5N.CH3I is formed. When this is warmed with
solid KOH, it gives a very pungent disagreeable odor. This is a
delicate test for pyridine.

Coniine is propyl piperidine and is the alkaloid of conium
maculatum

It is still more toxic than piperidine and is the cause of the poison-
ing of cattle which have eaten the plant or in some cases, browsed

252

CHEMICAL PHARMACOLOGY

on the roots, or drunk water contaminated with the alkaloid.
The drug raises blood pressure by a local action on the peripheral
vessels and slows the heart rate by central vagus stimulation.
In fatal cases death is due to paralysis of the nerves to the respira-
tory muscles. Chemically it is one of the simplest known alka-
loids, one of the few liquid alkaloids, and closely resembles nicotine
in composition and action.

The substance is a colorless oil, boils at 167°C and like nicotine
is readily soluble in water, to which it imparts an alkaline reaction
(note the solubility in water) . It has a peculiar mouse-like odor.
As a rule free alkaloids are rather insoluble in water. Coniine
was formerly much used, but at present is not used in medicine.
It is excreted in the urine.

Tests

1. It gives the pyridine tests p. 251.

2. Test the solubility in water and note reaction and odor.

3. Place a drop of coniine on a watch crystal. Add 2 drops of
concentrated HC1 and evaporate to dryness on a water bath.
Needle like or columnar yellow crystals of coniine hydrochloride
frequently in star shaped clusters are deposited. They are
doubly refractive.

4. Dissolved in concentrated HNO3 or H2SO4 the crystals are
not colored.

5. The alkaloidal reactions especially delicate for coniine are
— iodopotassium iodide (1 :8000) ; phosphomolybdic acid (1 :5000) ;
potassium mercuric iodide (1:8000).

Nicotine, is a more complicated alkaloid than coniine and is
probably a pyridyl-/?, tetrahydro-N methyl pyrrole and may be
represented by

N-CH;

NICOTINE

253

It is a colorless liquid, oily, with a pungent characteristic odor,
boils at 241°C., and rapidly turns brown on exposure to the air.
The drug is very toxic and raises blood pressure much like ad-
renaline but by an action on the peripheral ganglion cells, while
adrenaline acts on the sympathetic endings. Nicotine also resem-
bles coniine in action. Death results frdm a stimulation and
paralysis of the central nervous system.

On standing, due to partial oxidation, a double-bonded com-
pound (nicoteine) may be formed which is more toxic than nico-
tine.

CH3

On further oxidation oxynicotine

CH.

N
«NH.CH3

CH \CH2 and metanicotine,

CH2

much less toxic derivatives, are developed.

254 CHEMICAL PHARMACOLOGY

When nicotine is oxidized with chromic or nitric acid, or po-
tassium permanganate, /3. pyridine carboxylic acid is formed.

COOH (nicotinic acid)

This shows that nicotine is a pyridine derivative with the side
chain in the /3. position.

The blood pressure raising action of nicotine is very great,
small doses injected into the circulation will raise the pressure
as much as adrenaline. There is however, quick paralysis of the
nervous system and a second dose may have no action, or even
cause a fall of pressure or death of the animal. This blood pres-
sure raising seems to be due to the pyrrolidine moiety and not to
the pyridine ring since the action is not shown by pyridine or
nicotininc acid, but is produced by piperidine, pyrrolidine and
N, methyl pyrrolidine.

Nicotine occurs in plants in combination with malic and tartaric
acids. At least three other alkaloids also occur in tobacco.
These are nicotimine, nicoteine and nicotelline. The natural
nicotine is levo-rotatory, synthetic nicotine like most synthetic
products, is racemic. This synthetic product has been sep-
arated by Pictet from the tartrate into the optical antipodes,
and the levo-form corresponded in every way to the natural prod-
uct. The lethal dose of 1. nicotine for guinea pigs, is only one-
half that of the dextro-form, and the toxic symptoms are different
from the dextro (Mayer Verichte, 1905, 38, p. 597).

Nicotine is extremely poisonous. Four milligrams (about
1/10 drop) in man have produced severe toxic symptoms mani-
fested by giddiness, ringing in the ears, disturbance of respiration,
sleeplessness and tetanic spasms. One drop on the tongue of
a small cat will cause death in a few minutes. It is absorbed from
the tongue, eye, or rectum very rapidly. The harmful effects of
tobacco are due to its action on the nervous system, heart and
digestive apparatus. The other rather unknown alkaloids of
nicotine perhaps also play a role.

NICOTINE

255

The end products of oxidation are not well known because of
the small fatal dose, but when minute amounts are inhaled, as
in case of smoking it is probably completely oxidized, though
after toxic doses some excretion takes place by the lungs and
kidneys.

NICOTINIC ACID

The a, /3, and 7 mono carboxylic acids of pyridine, are known

COOH

N
Picolinic acid

N
Nicotinic acid

Isonicotinic acid

These can be obtained by oxidation of the corresponding ethyl
derivatives of pyridine. Their chief interest in pharmacology
lies in the fact which Funk has suggested that a mother sub-
stance of nicotinic acid is the vitamine of rice and is removed by
polishing. Nicotinic acid has been found in the unpurified
product, but the pure acid is inactive in the treatment of
beri beri.

TESTS FOR NICOTINE

1. It gives the pyridine tests page 251. ,

2. When a drop of nicotine and a few drops of cone. HC1 are
evaporated slowly in a watch glass, on a water bath it remains
amorphorus. No crystals, or only a suspicion of crystallization,
occur when the mixture is kept in a desiccator over sulphuric
acid. It differs in this respect from coniine.

3. Roussin's Test. — -Dissolve a drop of nicotine in 5 cc. of dry
ether in a test tube. Add an equal volume of ether containing
iodine in solution. Stopper, shake and set aside — in time ruby
red crystals — Roussin's crystals — appear. Old resinous nicotine
may not give this test until after redistillation.

256 CHEMICAL PHARMACOLOGY

4. Schindelmeiser's Test. — Fresh nicotine with one drop of
formaldehyde free from formic acid, and one drop of concen-
trated sulphuric acid gives a rose red color. If too much formal-
dehyde is used a green color results.

5. Physiological Tests. — Nicotine first stimulates then paraly-
zes all autonomic ganglion cells. When injected into an animal,
the heart and respiration are first stimulated, but are paralyzed
by larger doses. The blood pressure is raised enormously by
the first 4pse — later the drug is inactive because of paralysis of
the ganglion cells.

STRYCHNINE

The chemistry of strychnine is not understood. Perkin and
Robinson (Jour. Chem. Society, 1910, 305) have suggested as a
tentative formula

CH2CH

CH CH
| CH CH2

N C CH CH2
CO N— CH CH2

V \/

CH CH

Strychnine

From a therapeutic point of view the effect of strychnine is
perhaps over estimated. Toxic doses have a pronounced action,
but the actions after therapeutic doses are mild. Respiration is
accelerated, the heart rate is slowed, vasomotor tone is increased,
due to an action on the central nervous system. Brucine has a
similar action but only J£o as strong. Thebaine, one of the opium
alkaloids, has a similar action.

The Fate of Strychnine

The greater part of strychnine is excreted unchanged in the
urine. A small amount is oxidized in the body. This oxidation
has been shown indirectly by injecting strychnine into rabbits,
whose kidneys were removed, thus preventing excretion. It was

STRYCHNINE AND BBUCINE

257

found in this way that in small divided doses much more than the
fatal dose can be given without causing spasms. The difference
in the amount given and the amount excreted is hard to deter-
mine accurately because of the small fatal dose.
Tests for Strychnine and Brucine

Bichromate Test. — Place a trace of strychnine on a white glass
or tile dish. Add a drop of concentrated H2S04, then a small
crystal of potassium bichromate. Draw this crystal over the
plate with a glass rod. An intense purple or violet color
results, gradually becoming red, then yellow, or a blue-violet-red-
orange-yellow play of colors, appears. This is a characteristic
play of colors and is one of the most beautiful and delicate tests
in chemistry.

Physiologic. Test. — One-tenth of a milligram injected into a 30
gram frog will cause a characteristic tetanus in about .10
minutes.

Brucine. — This alkaloid occurs in nux vomica with strychnine :

1. To a little powdered nux vomica, add a few drops of con-
centrated HNOs. The orange color is due to brucine.

2. To a small portion of brucine in a test tube add a drop of
HNO3. A blood red color which turns yellow on heating is the
result. It turns to violet when a few drops of sodium thio-
sulphate (hyposulphite), Na2S203, stannous chloride or colorless
ammonium sulphide are added. Excess of HN03 must be
avoided. The violet color changes to green when NaOH is
added. These changes are given only by brucine.

Arecoline, CsHisNO^ is the chief alkaloid of the nut arecoline
catechu, and occurs together with arecaine, arecaidine and guva-
cine. It is a colorless volatile oily liquid which boils at about
220°C. Arecoline is the methyl ester of arecaidine.
CH CH

H2C

C.COOH H2C

HoC

C.COOCH3

CH5

N.CH3
Arecaidine

N.CH3
Arecoline

258

CHEMICAL PHARMACOLOGY

Arecoline has been prepared synthetically by Wohl and John-
son (Berichte, 1907, 40, p. 4712) commencing with acrolein.
The synthesis is complex.

Arecoline and its salts are highly toxic and resemble nicotine
and pilocarpine in action, while arecaidine is non-toxic. They
act on the nerve endings of the para sympathetic system causing
a marked flow of saliva. It also resembles nicotine in action and
it may be said from its action to be a combination of nicotine and
pilocarpine. Large doses may cause convulsions which soon
pass into paralysis. Some European pharmacopoeias recognize
arecoline as a sialogogue and diaphoretic.

Little is known regarding the fate of these alkaloids in the body.

Quinoline — Quinoline is a colorless oil having a specific gravity
of 1.095 at 20°C. and boiling at 239°. It occurs together with
isoquinoline, in coal tar and bone oil. It may be considered as
a condensation of benzene and pyridine rings.

N Isoquinoline

Both are found in coal tar and bone oil distillates. They are hard
to separate pure and are, therefore, made synthetically. The
formation of quinoline from aniline and allyl aldehyde proves its
formula :

+ OHC-CH :CH2

+H20

QUININE

259

Quinoline Alkaloids. — The important representatives under
this head are the strychnine and quinine alkaloids. Quinoline
itself has antiseptic and antipyretic properties. Compared with
quinine it is, however, feebly antipyretic. The structure of
quinine has not yet been confirmed, but is represented by:

CH<

CHOH— CH-

CH2 CH— CH = CH2
CH2 CH2

— OCH3

Quinine

Action

Quinine is toxic to all kinds of protoplasm, but has a specific
or selective toxic action on undifferentiated protoplasm such as
white cells and malarial plasmodia. Its use in medicine is due
to this action. It reduces heat formation by an action on the
cells where heat is generated, though it to some extent increases
heat loss. This antipyretic action is, however, small in amount.
The action of quinine is thought to be due mainly to the piperi-
dine ring portion of it, which Frankel has called the "Loiponic
acid portion." The vinyl side chain on this ring is not considered
important in its action.

The Fate of Quinine in the Body

70 to 75 per cent, of it is oxidized and disappears. The re-
mainder is excreted in the urine, only traces being found in
the feces. No tolerance for it is gained by the body, and the
rate of oxidation remains the same after prolonged usage.

260

CHEMICAL PHARMACOLOGY

Schmitz (Schmidebergs Arch., 1907, 56, 301) gives the following
experiments to show the excretion of quinine:

Exp. I. 0.817 g. quinine given, 0.217 g. recovered — 26.6 per cent.
Exp. II. 0.817 g. quinine given, 0.244 g. recovered — 29.9 per cent.
Exp. III. 1.226 g. quinine given, 0.346 g. recovered — 29.7 per cent.

When given subcutaneously the excretion is slower.

Day

Quinine given
daily

24-hour
urine, cc.

Quinine
recovered

Per

cent.

Second . . .

1400

0 108

17 Q

Third

1700

0 120

19 8

Fourth

0 605

1400

0 083

13 7

Fifth

1450

0 128

21 1

Sixth

1600

0 076

12 6

Seventh. . .

1500

0 071

11 7

ASSAY OF THE ALKALOIDS IN CINCHONA BARK

The Calisaya bark is most easily worked and is crystallized
most readily by the Keller-Haubensack method: Put 12 grams
of calisaya bark in fine powder in a flask and add 120 grams of
ether. Shake thoroughly and add 10 cc. ammonia hydroxide —
10 per cent. NH3. Shake frequently during 30 minutes. Then
add 15 cc. water and shake thoroughly. Pour 100 grams of the
clear ether extract into another flask and add 40 cc. of 1 per cent,
sulphuric acid. Shake thoroughly and allow to settle. The acid
aqueous solution contains the alkaloidal sulphates. Pour off
most of the ether without losing any of the water solution.
Transfer the acid solution to a separatory funnel and make alka-
line with ammonium hydroxide (6 cc. 10 per cent, solution).
Extract with a mixture of ^ ether and % chloroform, using about
40 cc. of the mixture. Separate this extract and transfer it to a
dry flask. Repeat the extraction with 20 cc. of the ether chloro-
form mixture. Separate and transfer this also to the flask con-
taining the first extract. To get rid of the water filter through a
dry filter into a weighed dry flask and allow to evaporate. The

ISOQUJNOLINE

261

alkaloids will crystallize out. After the solvent has evaporated,
weigh and calculate the percentage of alkaloids in the bark.

Tests for Quinine

A solution of quinine in sulphur, acetic or tartaric acids shows
a beautiful light blue fluorescence. The addition of a small
amount of these acids increases the fluorescence. Solutions of
the alkaloid in hydrochloric or hydrobromic acids are not
fluorescent. Salts diminish it. The fluorescence is best seen by
drawing the solution into a pipette.

Thalleioquine Test. — (Thallos — green) . To 10 cc. of a solution
of quinine bisulphate add a few drops of freshly prepared chlo-
rine or bromine water and an excess of ammonia. Stir. A
characteristic emerald green color develops. Urea, antipyrine
and caffeine, interfere with this test. Morphine, pilocarpine,
cocaine, atropine, codeine, strychnine, phenol, and chloral have
no influence. It is very important that the chlorine or bromine
water be freshly prepared as the presence of HC1 or HBr may
prevent the development of the color.

Isoquinoline Alkaloids. — The most important are papaverine,
hydrastine, narcotine, cotarnine, and berberine.

The formula of none of these is definitely established. Skele-
ton formulae for papaverine and berberine are :

O.CH3

\O.CH;

Papaverine

262

CHEMICAL PHARMACOLOGY

O—

0—

O.CH3

\O.CH3
Berberine

They are of little importance in medicine and their fate in the
body is not well known.

Hydrastine and Hydrastinine. — These are isoquinoline alka-
loids prepared from the root of hydrastis canadensis. On decom-
position, hydrastine takes up water and hydrastinine and opianic
acid are produced:

C21H21NO6 4- H2O = C10HioO5 + CnHuN,
Hydrastine Opianic acid Hydrastinine

CHO

Opianic acid has the formula:

COOH
OCH.

OCH3

Formulas assigned to hydrastinine and hydrastine are:

HYDRASTINE

263

,o—

CH<

CHO

NH.CH3

CH2

OCH3

CH30— //^— COX

\^H/

CH2/

N.CH3

\/\/
CH2

Hydrastinine

C.OH2
Hydrastine

Narcotine, an opium alkaloid, is methoxy hydrastinine and
yields opianic acid on hydrolysis. Hydrastinine has been synthe-
tized by Fritsch and its synthesis throws light on the structure of
hydrastinine. Hydrastinine increases the reflex irritability of
frogs leading to tetanus resembling that produced by strychnine,
and finally to paralysis. In mammals the small amounts slow
the pulse; larger doses cause convulsions and tetanus. The
pulse is slowed by stimulation of the vagus center, and blood
pressure rises for the same reason. It also causes contraction of
the uterus. It is excreted unchanged in the urine.

Hydrastinine. — The hydrolysis of hydrastine changes its action
markedly. Hydrastinine causes but a small increase in blood
pressure. It has no convulsant action but instead is a central
depressant and does not weaken the neart, but stimulates it by
direct action. Its most important action is on the uterus — due to
a direct action on the muscle though there is some action through
the nerves.

Hydrastine Tests

1. Concentrated sulphuric acid dissolves hydrastine without
color until warmed when the solution becomes violet.

2. When dissolved in dilute sulphuric acid, and very dilute
potassium permanganate added, drop by drop, hydrastine is
converted into hydrastinine, and the solution shows a beautiful
blue fluorescence.

3. Froehde's reagent dissolves hydrastine with a rose red
changing to brown color.

264 CHEMICAL PHARMACOLOGY

4. Soluble chromates precipitate insoluble hydrastine chromate
which gives a fleeting red color with sulphuric acid.

HYDRASTININE

1. It crystallizes from light petroleum in colorless glancing
needles which melt at 116°-117°C.

2. It is optically active.

3. It is soluble in alcohol, sparingly soluble in water, forming
yellow fluorescent solutions.

4. It forms salts with hydrochloric acid — which is the form of
the alkaloid used in medicine. The aqueous solutions show a
blue fluorescence. Bromine water gives a yellow precipitate.

Narcotine. — Narcotine is an opium alkaloid; in composition
it is methoxy-hydrastine. It crystallizes from alcohol in color-
less needles which melt at 176°C. When hydrolyzed with dilute
acids it yields opianic acid and hydro-cotarnine.

1f^ TT "\T/"l I TT r\ r^ TT i~\ I f~* TT "\T/~\

v^22Xl23lN wy ~p Xl2w : wio.n.10^5 T V^i2Xli5lN V73

Narcotine Opianic acid Hydro-cotarnine.

2. With dilute HN03 narcotine gives opianic acid and co-
tarnine the constitution of which are
OCH3

C C

s\ /\

HC C.OCH3 CH30— C CH

I II I II

HC C.CO CH30— C C— C = O

V - \/ H

C C

I I

HC —0 HO— C=O

CH3O.C CH

/\/\

O— C C N.CH3 Opianic acid

C CH2

c c

H H

Narcotine

NARCOTINE 265

CH30

I H2

c c

O— C C N— CH3

| II
0— C C CH2

\/\/
C C
H H2
Hydro-cotarnine

In action narcotine resembles morphine but is less hypnotic
and has some strychnine-like action though the hypnotic action
predominates (see page 256). Mohr states that in cats con-
vulsions precede the narcotic stage. It is but little used in thera-
peutics, although it has some antipyretic action.

Tests for Narcotine

1. The alkaloid dissolves in concentrated sulphuric acid with
a greenish color changing to reddish violet and after several days
to a raspberry red.

2. When narcotine is dissolved in concentrated sulphuric acid
and a trace of nitric acid added a red color is produced.

3. A solution of narcotine in sulphuric acid gives a blue color
on warming with gallic acid (Labat).

Cocaine is' the alkaloid of coca leaves. It is a white crystal-
line solid that melts at 98°C. The hydrochloride is the most
important salt. The formula of cocaine is.

H2C- -CH- -HC— COOC.Hs

N— CH3 CH—OOC— C6H5

I i

H2C -- CH - CH2

Cocaine or methyl benzoyl ecgonine

On hydrolysis cocaine gives methyl alcohol, benzoic acid and
ecgonine :

266 CHEMICAL PHARMACOLOGY

CH2 CH— CH.COOH

I
N.CH3

Ecgonine

Cocaine can be prepared from ecgonine by benzoylation and
methylation ; and ecgonine has been synthetically prepared from
tropine, but so far the synthetic product has not been separated"
into its optical isomers. The natural product like most natural
alkaloids is levorotatory. A dextrotatory (isococaine) isomeride
of 1. cocaine has been prepared from coca leaves, but this is now
thought to be formed from the 1. cocaine by the action of alkalies.
L. cinnamyl cocaine CioH^sC^N is the chief alkaloid of the
Java cocoa leaves. The d. isomeride does not occur in the coca
leaves but has been prepared synthetically.

Action of Cocaine

The chief action of cocaine is its local anesthetic effect. This
is due to its general protoplasm action, though it acts more
strongly on the sensory nerves than on motor ends. The effect
is due to the benzoyl group. Large doses first stimulate, then
paralyze the central nervous system, chiefly in a descending di-
rection. The heart muscle is directly stimulated by small doses
and paralyzed by larger doses. The striated muscles are also
stimulated by a direct action. There is a marked mydriasis,
formerly thought to be due to stimulation of the sympathetics
locally, but later work questions this location. The toxic dose
of cocaine varies enormously. Swabbing the tonsils with 4
per cent, has proved fatal in some cases while over 1.5 grams have
been taken per os with recovery.

The Fate of Cocaine in the Body

Neither man nor dog eliminates in the urine more than 5 per
cent, of the cocaine ingested, and since the urine contains no
ecgonine it is thought to be profoundly changed in the organism.
In the oxidation in the body it is thought to be first decomposed
into ecgonine, benzoic acid and methyl alcohol, and these are

NARCOTINE 267

then oxidized. Proells could not detect cocaine in cadaveric
material after 14 days.

ARTIFICIAL COCAINES

A large number of artificial cocaines have been prepared. All
these contain a benzoyl radical. The most important artificial
cocaines are :

Anesthesine, or para amino ethyl benzoic acid:

NH2< V-CO.O C2H£

Pro-cocaine or novocaine is the hydrochloride of the diethylamine
derivative of anesthesine or para amino benzoyl di-ethyl amino
ethanol and has the formula.

NH C >CO.O.CH2CH2N(C2H5)2HC1

A number of other substitutes have been prepared.

Tests for Cocaine

1. Heat a few milligrams of cocaine with a few drops of alco-
hol and concentrated H2S04. Note the odor of ethyl benzoate.

C6H5COOH + C2H5OH = C6H5COOC2H5 + H20

2. Boil a solution of cocaine with a drop of H2S04 and add a
drop of Fe2Cl6. Ferric benzoate is precipitated.

3. Physiological tests: Local anesthesia and dilation of the
pupil, when applied locally.

THE PYRROL OR PYRROLIDINE GROUP OF ALKALOIDS

1. This includes, in addition to pyrrol and pyfrolidine, hygrine,
a derivative of n. methyl pyrrolidine :

CH2.CH -- CO.CH2.CH3

and kuskhygrine from the leaves of erythroxylon coca.

268

CHEMICAL PHARMACOLOGY

2. Stachydrine from stachys tuberifera has the formula.
CH2 CH2

CO CH CH2

I \/
0 N (CH3)2

which is a dimethyl betaine of pyrrolidine.

The atropine and cocaine group of alkaloids may be considered
in this group or in the tropane group. They may be regarded
as a combination of a piperidine and a pyrrolidine nucleus, which
is tropane

OH 2 OH OH2

pyrroli- N-CH3 piper- CH2
dine idine

CH<

-CH-

-CH.

Tropane

Pyrrol — (pyros, fire-ol., oil) is a constituent of coal tar, and a
product of the distillation of bones. It has the formula: C4HsN
or

CH CH

It is more toxic than pyridine or piperidine. It resembles
benzene in action.

Blood coloring matter, chlorophyll and protein decomposition
products contain a pyrrol nucleus. The derivatives of pyrrol are
classified according to the scheme

NARCOTINE 269

On reduction with hydriodic acid and phosphorus, pyrrol
yields pyrrolidine:

CH2 CH2

which is a much stronger base than pyrrol.

Pyrrol has been synthesized in several ways. It has been
formed by the interaction of succin-dialdehyde and ammonia :

H .OH

+ NH3 CH2.CH/
0 XNH2

/H X

CH2— C/ + NH3 CH2.CH(

\0 XOH

")NH + NHe + 2H2o

Pyrrolidine has also been formed by heating penta-methylene
diamine with hydrochloric acid.

,CH2 CH2NH

yV^J-X^ . V^JlJL^i^ XJL AA J.A2\

^C CH

NH2 + HC1 ->

H2C CH2 + NH4C1

Pictet (Ber. deut. chem. Gesells, 1907, 40, 3771) thinks that alka-
loids in plants are formed by the breaking down of complex nitro-
genous substances, such as protein and chlorophyll, and by a
condensation of these substances with others, as in the syntheses
above. He is of the opinion that methylation within the plant
can be accomplished by the action of formaldehyde on amino or
hydroxyl groups:

ROH + CH20 = HO CH3 + 0
or RNH3 + CH20 = RNHCH3 + 0

270

CHEMICAL PHARMACOLOGY

It should be noted that methyla^n in the animal body is of rare
occurrence (see p. 249). Various alkaloids may then be formed
by other changes, for example, by heat. The secretion of alka-
loids by plants may, according to Pictet, be a means of getting
rid of nitrogen which cannot be used in metabolism. It is a
curious fact that these alkaloids, though highly toxic to animals,
are not toxic to the plants themselves. The theory that alkaloids
are necessary compounds in the plant and are secreted to protect
the plant from animals does not agree with the fact that plants
grow just as well when moved into other latitudes, yet the content
of alkaloid is much diminished.

Methyl pyrrol can be changed to pyridine by heat :

N.CH3 N Pyridine.

Fate of Pyrrol in the Body

Pyrrol and its derivatives appear to be easily destroyed in the
body.

TROP1NE ALKALOIDS WITH DIHETERO CYCLIC NUCLEI
Tropane Alkaloid.— Tropane has the formula:
CH2 CH CH2

NCH3

GIL

CH.

CH-

/
CH2

This substance contains a piperidine ring and a pyrrolidine
ring, consequently there may be some duplication in the classi-
fication. The tropane alkaloids would include:

I. The atropine group — atropine, hyoscine, hyoscyamine.
II. The cocaine alkaloids — cocaine and tropo cocaine.
III. The pomegranate alkaloids — pelletierine, isopelletierine,
etc., from punica granatum.

ATROPINE 271

IV. Cytisine from cytisus laburnum, lupinine from lupinus-
luteus and niger, etc.

Tropine differs from tropane in that one of the H. ions of tro-
pane is replaced by hydroxyl:

H2C CH CH2

| | XCH2OH

NCH3 CHOH + C6H5.CH/

| XCOOH

H2C CH • CH2

Tropine Tropic acid

Atropine is a combination of tropic acid and tropine. When
other acids are used tropeines are formed.

Atropine :

N.CH3

,
C/

CH2OH

\n/ \p IT

O6Xl5

CH2 CH CH2

The main actions of atropine are stimulation of the central nerv-
ous system and paralysis of the peripheral para sympathetic
nerve endings. In these actions the tropine part of the ester
is the more important. This is proved by the fact that other
acids may be substituted for tropic acid. The only other acid
that has yielded an ester of practical importance is mandelic
acid, which is

Homatropine, C5H7N(CN3)C2H4O.CO.CHOH.C6H5

The action of homatropine is practically the same as atropine
but it is less toxic. It is used especially in eye work, since the
dilation of the pupil caused by it lasts only a few hours,
while that caused by atropine may last for days.

The tropines derived from benzoic and cinnamic acids exert
no mydriatic action.

The Fate of Atropine in the Body

Atropine is readily absorbed and excreted. After adminis-
tration it has been found in most all tissues and fluids. It has

272 CHEMICAL PHARMACOLOGY

been found in the milk and in the total blood. It is decomposed
to tropine and oxidized in the body, though some may escape
unchanged in the urine. It is very resistant to putrefaction and
has been found in bodies after two years.

Tests for Atropine

1. Boil a small amount with dilute H2SO4. This gives an
orange flower odor which changes to that of bitter almond. The
solution gives a green color when a trace of potassium bichro-
mate is added.

2. To a trace of atropine in a test tube add 10 drops of H5S04
and heat until it becomes brown or until white fumes appear.
Then add 2 volumes of water. During the heating there will be
a sweetish odor resembling tuberose, which is characteristic
(Gulichno). The odor is strengthened by adding a little KMn04
(Reuss). This test is sensitive to 10 milligrams.

3. VitalPsTest. — Put 1 or 2 mgms. of atropine in an evaporating
dish and dissolve in it a few drops of fuming nitric acid and
evaporate to dryness high above the flame or on a water bath ;
cool and touch the spot with a drop of alcoholic solution
of KOH. The color will be violet, changing to cherry red. Vera-
trine also gives this test, hence it is characteristic only in the ab-
sence of veratrine.

4. Atropine dilates the pupil and gives a dry sensation to the
mouth and eliminates vagus action on the heart, thus causing a
very rapid rate of heart. These tests can be recognized with
certainty in presence of veratrine.

Scopolamine or Hyoscine, Ci7H2i04N, is a tropane alkaloid
whose composition is so closely allied to atropine and hyoscya-
mine that the same reactions are given. With mercuric chloride
atropine gives a yellowish red precipitate of mercuric oxide,
while hyoscyamine gives a white precipitate.

When warmed with barium hydroxide, scopolamine is hydro-
lyzed yielding tropic acid and a base C2Hi302N — named
pseudo-atropine, oscine, oxytropine or scopoline.

Hyoscine resembles atropine in its action on the nerve termi-
nals, but has practically no action in stimulating the central
nervous system. The main action is a feeling of fatigue and
drowsiness. It has been often used to produce " twilight sleep."

GLYOXALINE 273

THE GLYOXALINE GROUP OF ALKALOIDS

This includes pilocarpine, isopilocarpine and jaborine, which
may be a mixture of pilocarpine and isopilocarpine. There are
other unimportant members such as pilocarpidine. The only
one of interest in medicine is pilocarpine.

Glyoxaline is metameric with pyrazole and may be regarded
as a pyrrol nucleus in which one methine radical has been replaced
by nitrogen. It is formed when ammonia acts on glyoxal in
presence of formaldehyde; sufficient formaldehyde may be
formed from the glyoxal without the extra addition of it.
CHO NH3 CH— N .

+ +0 :CH2 -> CH + 3H20

CHO NH3 CH—

Glyoxaline

The purine group of alkaloids contain a glyoxaline nucleus and

may be regarded as a glyoxaline ring condensed with pyrimidine.

2 CH— - N 1

S \

3 N CH 6

,W \ /

4 C= =C 5

9 N NH 7

^CH /

Glyoxaline may also be prepared by oxidizing benzimidazole
with permanganate.

H COOH.C— N

H COOH.C— NHX

Glyoxaline dicarboxylic acid

H. C— N .

|! ^CH + 2C02

H. C— NH/

Glyoxaline
Compare with the given formula for purine, p. 283.

274 CHEMICAL PHARMACOLOGY

Pilocarpine is a colorless oil, freely soluble in water, alcohol and
chloroform and but slightly soluble in ether and light petroleum.
It readily forms crystalline salts with acids and the nitrate is the
most important. It is readily soluble in water. The alkaloid of
commerce is derived from the leaves of pilocarpus jaborandi, a
South American plant. It has been prepared synthetically, and
based on this synthesis Jowett and Pinner consider pilocarpine

C2H5— CH— CH— CH2— C N— CH3

to have the formula

CO CH2 CH CH

\/ \S

O N

Iso-pilocarpine is probably a stereoisomeride.

Action of Pilocarpine

Pilocarpine is a strong stimulant to all glands, especially the
sweat, salivary, bronchial, lachrymal, gastric, and intestinal.
The smooth muscles of the alimentary tract, the urinary bladder,
spleen and bronchi are stimulated . The muscles of the blood
vessels are not influenced, but when given intravenously the
heart is slowed by an action on the vagus endings. When taken
by mouth, the heart rate may be increased. This action has not
been satisfactorily explained; it may be secondary. There is
some stimulation of the central nervous system, followed by
paralysis after large doses. The whole action of pilocarpine
resembles that of muscarine, but it is much less poisonous.

Pilocarpine is used in medicine almost totally for its diaphoretic
action, especially in cases of dropsy and similar diseases. Iso-
pilocarpine and pilocarpine have a similar but weaker action.
Pilocarpic acid is inactive. Very large or toxic doses of pilocar-
pine cause profuse sweating, flow of nasal secretion, tears, pallor,
slow heart, and arrythmias, vomiting, diarrhosa, contracted
pupil, tremors, cloudiness of the cornea, tracheal rales, and edema
of the lungs. The part played by the glyoxaline ring has not
been determined.

Atropine is antidotal in all cases and a small dose will neutralize
the effects of a large dose of pilocarpine,

PHENANTHBENE GROUP 275

Fate in the Body

A large part is excreted unchanged in the urine. There may
be some in combination (Curci) .

Tests for Pilocarpine

1. The general alkaloidal reagents especially delicate for
pilocarpine are iodo-potassium-iodide, phosphomolybdic acid, and
'phospho tungstic acid.

2. Pilocarpine nitrate melts at 176°-178°.

3. A solution of pilocarpine in formalin sulphuric acid when
warmed becomes yellow-brown-red.

4. In a test tube add a crystal of potassium bichromate to 2 cc.
chloroform with pilocarpine and 1 cc. hydrogen peroxide; shake.
Depending on the amount of pilocarpine the chloroform is blue
violet, dark or indigo blue.

5. Physiological tests: These are constriction of the pupil,
slowing of the heart, profuse sweating and an edematous con-
dition of the lungs.

PHENANTHRENE ALKALOIDS

Phenanthrene is an isomer of anthracene and occurs with it in
coal tar.

Phenanthrene Phenanthraquinone

3/~ ~\2 1 CO CO

/ \

/" "\ /" \

89 \_ _/ \ /

Phenanthrene Group. — The most important representatives
of the group are morphine, codeine, thebaine, and apomorphine.
On distillation with zinc dust these alkaloids yield pyrrol,
pyridine, quinoline, and phenanthrene; consequently, they may
be placed under either of these headings.

Phenanthraquinone is obtained from phenanthrene by oxida-
tion with glacial acetic and chromic acids. According to Amoss,
morphine is a derivative of tetrahydro-dioxy phenanthrene to
which a morpholine is added. To morpholine he assigned the
formula:

276

CH2
CH,

CHEMICAL PHARMACOLOGY

CH-
CH-

Morpholine

CH;

CH30\

\
CH-

CH3
Morphine

-N— CH3
CH2

\/ V

CH
CH2

\/
CH.OH

Codeine (Knorr)
CH2

V \s

NPH

^ /<\

H°ll 1

CH30\ /\

CH2 HO^
/ jUHj

V \/ x
CH /

^ • rfxlN-

CH2

PTT
\/\/ 2

N/ \/

i CH2CH2

\ //

Apomorphine

COCH3
Thebaine (Knorr)

CH2 N— CH3

/\/\/\

CH CH2

CH2
C— H

0— C CH2

/\/
H C

H OH
Codeine (Pschorr)

THEBAINE 277

CH2 N— CH3

\x\

CH CH2

CH2

CH30\/\/\/

C— H

I
0 C CH

H C

OCH3
Thebaine (Pschorr)

Roser and Howard (Berichte, 1886, 19, 1596) think the re-
lationship of morphine, codeine and thebaine may be shown as
follows :

CH3O

C16H14ONCH3
Morphine

C16H14ONCH;

Codeine

CH30'

;C16H12NO.CH3

Thebaine

In accordance with this view it has been found that the prin-
cipal decomposition products of all three are similar. Codeine
is methyl morphine. The graphic formulas are now known
with certainty, but among others the following have been pro-
posed for morphine:

278

CHEMICAL PHARMACOLOGY

CH2

CH N—

CH2

O-

CH;

-C CH2

CH2 N— CH3

^/\
CH CH2

CH2

C— H

0 C CH2

H C

H OH
Pschorr's formula

H OH

Knorr's later formula

CH2

\x v

\/ \/ \

I CH /

O CH2-
\/

CH3
CH CH2
\ /

/\
/ \

H OH .

Bucherer's formula modified by Knorr

APOMORPHINE 279

The principal pharmacological actions of morphine are :

1. A marked depression of the central nervous system, com-
mencing above and descending. The perception to pain and the
sensitivity of the respiratory center, seem more depressed than
other functions.

2. Depression of the blood pressure and slowing of the heart
due to an action on the medullary centers.

3. A decrease in the peristalsis of the alimentary canal, pre-
ceded in some animals by stimulation.

4. A marked constriction of the pupil, due apparently to the
removal of a central action. The constriction disappears in the
paralytic stage, and in some animals in which morphine causes
stimulation or excitement rather than depression (cat, horse
and others) the pupil is dilated at all stages.

5. The cord is stimulated with all these drugs, and the reflexes
exaggerated. Morphine applied directly to the cord will cause
convulsions, and some of the morphine alkaloids stimulate only.
Dixon (Manual of Pharmacology, 1906, p. 137) because of these
differences arranges the morphine alkaloids as follows with the
percent of these alkaloids in opium

Morphine (most narcotic) 10. 0 per cent.

Papaverine 1.0 per cent.

Codeine 0.5 per cent.

Narcotine 6.0 per cent.

Thebaine 0.3 per cent.

Laudanine (most convulsant) trace

Apomorphine. — When morphine is heated in a sealed tube with
strong HC1 at 140°C. it loses a molecule of water and apomor-
phine is formed. This change it has also been asserted, occurs
when morphine salts or their solutions are exposed to light, but
no proof of this has been advanced.

Solutions of apomorphine have a green color and the entire
physiological action of morphine is changed by the loss of water
from the morphine molecule.

Apocodeine. — Ci8Hi902N has been prepared by the action of
zinc chloride solution on codeine hydrochloride. It is supposed to
bear the same relation to codeine that apomorphine does to

280 CHEMICAL PHARMACOLOGY

morphine. Dott (Pharm. Journal, 1891, III, XXI, 878, 916,
955, 996) claims that it is not a pure compound, but a mixture
of chlorocodeine apomorphine, amorphous bases, and codeine
(Knorr and Raabe, ibid., 1908, 41, 3050).
The chief actions of these apo-compounds are:

1. Apomorphine causes vomiting by a strong stimulation of
the vomiting center, and

2. Also stimulates: the secretory centers for saliva, perspira-
tion, etc. It has a paralytic action on skeletal and heart muscle.

3. Apocodeine paralyzes all ganglion cells, and is toxic to all
forms of motor nerve endings.

The Fate of These Alkaloids in the Body

Morphine is partly oxidized and a part is unchanged and ex-
creted by the alimentary tract. This is a different method of
excretion from most alkaloids which are excreted in the urine.
Faust found that 70 per cent, of that administered to a non-
immunized animal was excreted, but when tolerance is established
the oxidizing power of the tissues is increased. The excretion
into the alimentary tract begins soon after administration, as
shown by the fact that morphine has been found in the vomitus
soon after hypodermic administration. Codeine is excreted
much in the same way as morphine but tolerance is harder to
establish and more is excreted unoxidized. When injected
intravenously Marquis found 15 per cent, of the morphine de-
posited in the liver in 15 minutes and some retained in the central
nervous system. A slight amount is excreted in the urine in
combination with glycuronic acid. Morphine resists putrefac-
tion and has been found in putrefying material after 15 months.

Tests

•Apomorphine. — The solutions have a green color.

1. To a dilute solution add a few drops of HC1 or H2SO4, then
neutralize with Na2CO3 and add a drop of an alcoholic solution
of iodine. The emerald green color which is produced becomes
violet when shaken with ether.

2. Dissolve a trace of apomorphine hydrochloride in water and
shake. A green color appears. Add a trace of ferrous sulphate
and shake. The solution gradually turns blue and finally black.

APOMOBPHINE 281

On the addition of alcohol the blue color returns (different from
codeine and morphine).

3. Dissolve a trace of apomorphine in concentrated H2SO4 and
add a drop of concentrated HN03; a violet color changing quickly
to red and yellowish red is formed.

4. Physiologic test: 0.01 gram apomorphine hydrochloride
hypodermically in a dog causes vomiting in a few minutes.

Codeine. — 1. To a little of the dry alkaloid in a crucible add a
few drops of concentrated H2S04 and heat. A greenish color
which changes to violet-red results. Morphine gives none, or
only a slightly yellow color, except when heated, then it is brown.
HNO3 changes the reddish violet color of codeine to yellow and
purple.

2 Codeine with H2SO4 heated, with a drop of nitric acid added,
gives a blood red color.

3. Codeine with H2SO4 gives no color; add a drop of formalin
and a violet color is produced. Morphine gives an intense purple.

4. Codeine with H2SO4 with a trace of ferric chloride added
gives a violet blue color.

Tests for Morphine

1. 1 gram of morphine is soluble in 3340 cc. of water, -210 of
alcohol, 6250 of ether, or 1220 of chloroform.

2. A saturated aqueous solution of morphine is alkaline to
litmus.

3. Concentrated sulphuric acid produces either no color or
only a red or yellow tint when added to a morphine solution.
On heating a brown color is developed. Concentrated sulphuric
acid containing 0.1 per cent, formalin gives a purple color.

4. Concentrated nitric acid with morphine produces an orange
red color fading to yellow.

5. Ferric chloride added to a neutral solution of morphine,
made by adding dihite H2S04 to morphine, produces a blue
color.

6. lodic acid test: When morphine in dilute sulphuric, is
shaken with a few drops of iodic acid and chloroform, iodine is
liberated and dissolves in the chloroform producing a violet color.
Other reducing substances may give this test.

7. Prussian blue test: When morphine is added to a dilute

282

CHEMICAL PHARMACOLOGY

mixture of ferric chloride and potassium ferricyanide, a deep blue
color appears. When considerable morphine is added a precipi-
tate may be produced.

8. When morphine is added to silver nitrate with an excess of
ammonium hydroxide a gray precipitate of metallic silver is
formed.

Thebaine. — 1. Thebaine gives a blood red coloration which
gradually becomes yellowish red with concentrated sulphuric
acid.

2. With nitric acid thebaine gives a yellow color.

3. Chlorine water dissolves thebaine. If ammonia be added
to the solution it becomes red-brown.

Papaverine occurs in opium to the extent of 0.5-1 per cent.

H,CO— C

H3CO— C

HC CH
HC CO.CH<

OCH3
Papaverine

It crystallizes in colorless poisons which melt at 147°C. It is
insoluble in water, soluble in ether 1 to 260 and freely soluble in
chloroform. Ether partially extracts it from tartaric acid solu-
tion, and completely extracts it from alkaline solutions. Chloro-
form extracts it easily from either acid or alkaline reaction.

CAFFEINE 283

Tests

1. When pure, cold sulphuric acid does not color papaverine,
it becomes violet when heated. Impure solutions may be violet
without heating.

2. Concentrated nitric acid dissolves papaverine with a dark
red color.

3. Papaverine gives a purple color, changing to black and
green, when dissolved in sulphuric acid containing iodic acid.

4. With iodine in alcohol, papaverine yields a characteristic
crystalline periodide.

THE CAFFEINE GROUP

Caffeine and related drugs are important from the standpoints
of biochemistry, pharmacology, and as foods. They occur
especially in tea, coffee, cocoa, kola, gurana mate* and in numerous
other plants in small amounts. The most important drugs of
this group are:

Purine, or the nucleus of the group.
Caffeine, or 1.3.7 — trimethyl xan thine.
Theobromine, 3.7 — dimethyl xanthine.
Theophylline, 1.3 — dimethyl xanthine.
Xanthine, 2.6 — dioxy purine.
Hypoxanthine 6— oxy purine.
Guanine 2 — amino. 6 oxy purine.
Adenine 6 amino purine.

Uric acid 8 — hydroxy xanthine, or 2, 6, 8 trioxy purine.
1 N = 6 CH

7
-NH.8

\CH
N *
9

The word purine is a portmanteau word, a combination of
purum uricum.
N(CH3)— CO NH— - CO

I I I

CO C— N(CH3)V CO C -- N(CH3)

I II \

N (CH3)— C- -W N (CH3)— N

Caffeine Theobromine

284 CHEMICAL PHARMACOLOGY

CH— N— CO NH— CO

CO C— NHN

CH3— N— C N^

Theophylline

NH— CO

I I

HC C— NHV

II II >H
N— C— N^

Hypoxanthine

N=C— NH2

CO C— NH

I
II

NH— C— N

Xanthine

NH— CO

H2N— C C— NH

N—
Guanine

NH— CO

HC C— NH

II II
N— C— N

Adenine

CO C-NH,

NH— C— NH'

Uric Acid

:CO

Purjne or the nucleus of the group is of interest only in showing
the chemical relationship of the whole group to uric acid. Purine
has been prepared from uric acid, and this in turn from simpler
well known compounds. The sodium salt of uric acid when
treated with phosphorus oxy chloride, yields hydroxy di chlor
purine.

;C.OH

Cl.C C— NH,

N— C— N

When this is acted ,on by phosphorus trichloride, it gives trichlor
purine

C1.C C^-NH

II II

N— C— N '

;ci

CAFFEINE GROUP

285

and when this is treated with hydriodic acid, diodo-purine is
N^C.T

I.C C— NH

N— C-N ^

formed, which when reduced by zinc dust and water gives purine
(p. 283). _

According to Fischer purine may occur in the body, but can-
not be detected on account of its ease of decomposition in the
body.

The establishment of the formulae of uric acid and related
substances has been a slow growth. The suggestions for the
synthesis came principally from a study of the products of
hydrolysis of uric acid. Among these products were urea, para-
banic acid, alloxan, allantoine, etc., depending on the oxidatizing
agent. After numerous attempts, the following steps were
successful in establishing the synthesis and formula of these
bodies.

Sf/i

N\ i
XH

H0i(

NH— (

(ID

O + CH2 = CO CH2 + H20

N' liiOiCO NH— CO

urea + malonic acid = malonyl urea or barbituric acid.

NH— C HONiOi
C=OC!H2+j

NH— C^
C CrN.OH

NH— CO NH— CO

Barbituric acid + Nitrous acid = iso-nitroso-malonyl urea

286

CHEMICAL PHARMACOLOGY

(III) Reduction of iso-nitroso NH
malonyl urea gives:

CHNH2

NH CO

amino barituric acid

(IV)

,0
NH— C^ NH-

C* C H NH2 + KCNO + HC1 = C CHNHCO

NH-

-C = O

NH C = ONH2

amino barbituric acid pseudo uric acid

(V) Pseudo uric acid loses water on treatment with dilute
mineral acids and gives uric acid.

x.O ,Q

0 = 0 (

j '

^HNH, ->
\3 = 0

^ = 0 (

1 NH
\,

NR- (

^!- OFT IS

NR - (

"VNTH

CO + H20

pseudo uric acid

uric acid or 2.6.8. trioxy
purine

By reduction, the purin base has been prepared from uric acid,
as shown above.

Caffeine occurs especially in tea and coffee and similar stimu-
lant food stuffs, in the following amounts:

Tea 1-4.8 per cent. Kola nuts 2.5-3.6 per cent.

Coffee .... 1-1 . 5 per cent. Mate 1 . 2-2 . 0 per cent.

Gurana 3 . 0-5 per cent

It occurs partly free and partly combined as caffeine chlorogenate.
Caffeine has also been prepared synthetically by the action of

CAFFEINE GROUP 287

methyliodide on theophylline. It crystallizes in slender silky
needles which melt at 234°. It is soluble in water 1 : 46, alco-
hol 1 : 66, and in chloroform 1 : 8. Its solubility in water is
increased by heat, citric acid, benzoates and salicylates, bromides,
antipyrine and a number of other substances. Combinations,
such as caffeine sodiosalicylate and caffeine sodiobenzoate, pre-
pared by mixing caffeine with such solutions and evaporating the
mixture, are used in medicine. The object is to increase solu-
bility and to make the preparations available for hypodermic use.
Theobromine is the chief alkaloid of cocoa beans and is found
in small quantities in Kola nuts and leaves and in tea leaves. It
has also been synthesized. Caffeine may be separated fairly
well from theobromine by extraction with cold benzine in which
theobromine is insoluble.

Hypoxanthine, and guanine (6 oxy 2 amino purine) occur to-
gether in a number of plants, especially, curcubita pepo, hordeum
sativum. Hypoxanthine occurs free to some extent in animal
tissues, especially muscles, more is found in the combined state.
Xanthine is found in tea leaves, and the juice of beet root;
theobromine, in theobroma cocoa; caffeine, in tea and co'ffee.
Uric acid is not found in plants. The murexide test makes the
recognition of the purine base an easy matter, but the identifi-
cation of the individual members is a difficult task. Hypoxan-
thine and xanthine when administered to man increase the uric
acid to about 55 per cent, of the theoretical amount.

Guanine is uually prepared from guano — hence the name. It
occurs commonly in animal organisms and has been found in
small quantities in yeast, sugar cane, and beet root. It has also
been synthesized. Its main interest in pharmacology is its re-
lation to the more important caffeine drugs. In the urine of
pigs xanthine, hypoxanthine, with smaller amounts of adenine
and guanine preponderate in amount over uric acid. The tissues
of these animals are deficient in guanase, and the pig sometimes
suffers from " guanine gout". Nitrous acid converts guanine
into xanthine. This may also be accomplished by boiling it with
hydrochloric acid.

Adenine occurs in beet root, yeast, tea, and other plants and in
the animal organism especially in the pancreas. Adenase converts
it into hypoxanthine C5H3N4NH2 + H2O = C5H5N5O + NH3.

288 CHEMICAL PHARMACOLOGY

Murexide Test

Put 3 or 4 milligrams of caffeine in a white evaporating
dish. Add a few cc. of saturated chlorine or bromine water and
evaporate to dryness on a water bath. To the yellow residue
add a drop of NH4OH. A bright purple color is produced. Nitric
acid may be used to oxidize the caffeine instead of the chlorine
water, but it is not so efficient. HC1 with a crystal of KC103 may
also be used. This decomposes the purine bases to alloxan
which, on reduction yields alloxantine:

CO— - NH NH - CO CO - NH

C = 0 CO CO &— -^C CO

II .1 II

CO - NH NH - €0 CO - NH

Alloxan Alloxantine.

Alloxantine in presence of ammonia forms ammonium pur-
purate or murexide. — NH^Cg^NsOe + H20

O
NH - C CO - NH

C = 0 C\NH/C CO

NH C = O CO — NH

Purpuric acid

2. Caffeine is also precipitated by the alkaloid reagents.
These tests are not characteristic.

3. The melting point is 235-237°. It is soluble in 46 parts
of water, 5.5 of chloroform, and in 530 parts of ether.

Action of Caffeine Compounds

Caffeine is used mainly as (1) a diuretic, and (2) as a stimulant
to respiration and circulation, (3) for its influences on muscle,
and (4) for its action on the nervous system. Theophylline has
less action than caffeine on the central nervous system and heart
but is a stronger diuretic, this diuretic action is said not to last
as long as that produced by theobromine, which is a less powerful
diuretic. Theobromine also acts less on the central nervous

CAFFEINE 289

system than caffeine. The other compounds have varying
actions, but these are not important in medicine.

1. The Diuretic Action of Caffeine. — Caffeine compounds are
the diuretic drugs par excellence. Many laboratory exercises on
this point fail because they do not consider the fundamentals of
urine secretion or the condition in which caffeine acts best as a
diuretic. First, the kidneys cannot secrete water unless water
is present. While the blood normally contains over 90 per cent,
water, this water is apparently in combination with colloid mate-
rial and only free water can be secreted. In those clinical cases
where caffeine compounds act to the best advantage, the tissues
are water logged either because of inadequacy on the part of the
heart, or change in the proteins, or salt retention. Caffeine
under these conditions causes a diuresis either by causing a
greater elimination of the free water or by liberating some of the
combined water. In normal animals the change caused by
caffeine on diuresis is so small that, as a class experiment, it is
unsatisfactory. Only as much water as is taken in can be poured
out, and in normal conditions this pouring out or urination pro-
ceeds at a constant rate and is hastened but little by diuretics.
To make a laboratory experiment show the real action of caffeine
on the kidneys, the animal should be given a large volume of
liquid a short time before the caffeine is administered.

The action of caffeine is direct on the kidney because:

1. There are no secreting nerves to the kidney. Diuresis
occurs after section of all nerves and on the isolated kidney, and
after degeneration of the nerves.

2. The fluids in the tissues are not changed.

3. The kidney increases in volume, when secreting:

, (a) The action therefore is local but may be either on the ves-
sels— a circulatory action, or

(6) It may be an action on the secreting cell. Opinion at
present favors, a direct action on the secreting cell:

4. Rost1 has found that the flow of urine is increased only
when considerable caffeine passes into the urine.

5. Richards and Plant2 have shown that diuresis may occur with
caffeine even when there is no change in kidney volume.

1 Schmidebergs Archiv., 1895, vol. 36.

2 Jour, of Pharmacology, 1915, p. 485.

290 CHEMICAL PHARMACOLOGY

Fate of Caffeine in the Body

In the body caffeine loses its methyl groups— first becoming
dimethyl — then monomethyl xanthine. Then xanthine is formed
and this may be broken down into urea. Of the monomethyl
xanthines, 7 monomethyl is formed in greatest quantity. Of the
dimethyl xanthines, paraxanthine — 1, 7 dimethyl xanthine is found.
Both of these may be found in the .urine after the ingestion of
caffeine. While this is true for man there is some difference in
the order in which the methyl groups are lost, in different
animals. In the dog all three dimethylxanthines appear in the
urine after larger doses of caffeine, although theophylline 1.3
dimethylxanthine predominates; while in the rabbit under the
same conditions and in man, paraxanthine or 1.7 dimethylxanthine
predominates. The monomethyl xanthines are also excreted in
different proportions in the various species of animal, but in man
and the rabbit heteroxanthine — 7 methyl xanthine prevails.

Only about 10 per cent, of the ingested caffeine appears in
the urine in the form of the above decomposition products. The
rest is oxidized in the body to urea and other end products, car-
bon dioxide and water. After the ingestion of 1 to 1.5 grams
caffeine daily uric acid elimination is increased (Benedict) . This
is apparently due to a conversion of caffeine to uric acid, though
it might also be due to a stimulation of the kidney to secrete the
normal uric acid of the blood.

The tolerance that is acquired from the prolonged uses of tea
and coffee, is in great part due to the body acquiring the ability
to oxidize these alkaloids more rapidly than at the beginning.
This is not the only explanation, however, for large quantities
may still be obtained from the tissues.

Purin metabolism is especially interesting in relation to gout,
in which an apparent deficiency of the oxidation of uric acid or
an increased formation, or a change in combination exists. It
has been found that when dogs, pigs or rabbits are fed nucleic
acid, 90-95 per cent, of it can be recovered as allantoine, 3 to 6
per cent, as uric acid and 1 to 2 per cent, as purin bases. It
may be that in perverted metabolism more than the usual amount
of purin bases is converted into uric acid. There. is no increase
in the uric acid content of the blood after the ingestion of foods

CAFFEINE 291

rich in purines except in cases of renal insufficiency, for this
reason gout is looked upon as a beginning nephritis (Denis).

In normal cases the oxidation of purin bases takes place as
follows — hypoxanthine — » xanthine — >• uric acid — > allantoine. It
has been taught that allantoine was oxidized to C02 and urea,
but at present it is believed by many that allantoine is the end
product of purine oxidation. The human organism cannot oxi-
dize allantoine, since allantoine injected hypodermically in man
has been completely recovered.

It has been also found that 60 to 90 per cent, of uric acid ad-
ministered hypodermically can be recovered in the urine. Some
have found as much as 99 per cent, of that administered. Uric
acid is oxidized with much greater difficulty in man than in
monkeys, dogs, cats, rabbits or pigs. In fact no adequate evi-
dence exists that the tissues of man can oxidize uric acid. Urea
is formed from uric acid in vitro by a variety of oxidizing agents
and allantoine is hydrolysed by boiling water into allanturic acid
and urea, so that its resistance to oxidation in the body is difficult
to understand.

Economic Use of Caffeine

Owing to the daily use of caffeine compounds in the form of
tea and coffee, frequent cases of chronic poisoning are seen.
The symptoms, mainly those of dyspepsia, are: epigastric
uneasiness, depression, succeeded by nervousness, restlessness
and excitement, tremors, disturbed sleep, anorexia, headache,
vertigo, confusion, palpitation, constipation and hysterical dis-
turbances. These symptoms are relieved by the gradual re-
moval of the drug. No acute fatal case of caffeine poisoning is
recorded and the fatal dose is not known, but it is over 10 grams.
To avoid the symptoms of chronic poisoning and to allow the
use of tea and coffee in susceptible individuals, numerous at-
tempts to remove the caffeine from tea and .coffee have been
made. Some manufacturers have placed the blame for the
nervous symptoms on the volatile oil content — the 'so-called
caffeol — but this is insufficient to cause the symptoms, and the
caffeine content is quite sufficient to explain all the untoward
symptoms.

292 CHEMICAL PHARMACOLOGY

TO ILLUSTRATE IN GENERAL THE ISOLATION OF

ALKALOIDS

POWER AND CHESTNUT'S METHOD OF ASSAYING CAFFEINE IN
VEGETABLE MATERIAL1

Ten grams of the finely ground material, previously moistened
with a little alcohol, are extracted for about 8 hours in a Soxhlet
apparatus with hot alcohol. The alcoholic extract is then added
to a suspension of 10 grams of heavy magnesium oxide in 100 cc. of
water, contained in a porcelain dish, the flask being rinsed with
a little hot water, and this liquid added to the mixture. The
mixture is allowed to evaporate slowly on a steam-bath or water-
bath, with frequent stirring, until all the alcohol is removed and
a nearly dry, powdery mass is obtained. This is mixed with
sufficient hot water to enable it to be brought on a filter, which
preferably should be smooth, and, after thoroughly cleaning the
dish by means of a glass rod, 'to which a piece of rubber tubing
is attached, the contents of the filter are washed with successive
portions of hot water until about 250 cc. of filtrate is obtained.
To the filtrate, contained in a flask of one-liter capacity, is added
10 cc. of a 10 per cent, solution of sulfuric acid, which causes the
liquid to become much lighter in color, and with some kinds of
material, such as Ilex leaves, a considerable precipitate is pro-
duced. In some cases, as with tea and guarana, it was found
necessary to use 20 cc. of the above-mentioned acid in order to
prevent the formation of an emulsion on subsequently extracting
with chloroform. After the addition of the acid, a small funnel
is placed in the neck of the flask, and the liquid, which is at first
gently heated until any frothing ceases, is kept in a state of
active ebullition for half an hour. This treatment is for the
purpose of hydrolyzing any saponin that may be present. After
being allowed to cool, the liquid is passed through a double
moistened filter into a separatory funnel, the flask and filter
being washed with small portions of about 0.5 per cent, sulfuric
acid. The clear acid filtrate is then shaken with 6 successive
portions of chloroform of 25 cc. each, which usually separates
sharply and quickly, but, if not, can be made to do so by gently

1 The Journal of the American Chemical Society, Vol. xli, No. 8, August,
1919.

CAFFEINE 293

rotating the separately funnel, or, if necessary, by the use of
somewhat larger portions of chloroform. The united chloroform
extracts are brought into another dry separatory funnel and
shaken with 5 cc. of a 1 per cent, solution of potassium hydroxide,
which serves to remove coloring matter. After complete sub-
sidence of the chloroform solution it is passed through a small,
dry filter into an Erlenmeyer flask, the alkaline liquid remaining
in the separatory funnel being subsequently washed with two
successive portions of chloroform of 10 cc. each. These washings
of the alkali are passed through the previously mentioned filter,
and, after washing the latter with a little chloroform, they are
added to the first chloroform solution. The chloroform is finally
removed by distillation from a water-bath the residual caffeine
brought by means of a little chloroform into a tared beaker, and,
after the solvent has been allowed to evaporate spontaneously,
the caffeine is dried for half an hour in a water-oven and weighed.
On heating for another half an hour there is usually a further
slight diminution of weight, and this second weighing may be
considered to represent the correct amount of caffeine, which,
when multiplied by ten, denotes the percentage. As so obtained
the caffeine is nearly colorless, and possesses a^quite satisfactory
degree of purity.

ISOLATION OF CAFFEINE

The most important source of caffeine is tea and coffee. To
separate and estimate the amount of caffeine in tea and coffee :

Keller's Method. — Take 6 grams of tea leaves and place them
in a separatory funnel. Add 120 grams of chloroform. Shake
and in a few minutes add 6 cc. 10 per cent, solution of NH3.
Shake repeatedly during a period of 30 minutes. Let stand for
3 to 6 hours or until the solution is clear and the leaves have
absorbed all of the water. Filter through a paper moistened
with CHC13 and collect 100 grams in a small weighed flask.
This represents 5 grams of the tea. Evaporate the chloroform
over a water bath. Pour 3-4 cc. of absolute alcohol on the resi-
due and heat on the water bath to drive off the alcohol. The
residue represents chlorophyll, fat, caffeine, etc., or CHC13 ex-
tract. To purify this add 10 cc. 30 per cent, alcohol, heat on
a water bath. The caffeine passes into solution. The coloring

294 CHEMICAL PHARMACOLOGY

matter forms in lumps and can be filtered off. Pass the solution
through a filter and wash the filter with 10 cc. of water. Evapor-
ate the filtrate on a small weighed evaporating dish to dryness
on a water bath. The residue is nearly pure caffeine. Calculate
the per cent, in the original tea. The tea is thus assayed.

High heat decomposes organic substances, hence a water bath
is used in this assay. The ammonia liberates the free alkaloid
which is readily soluble in the chloroform. The ammonia also
combines with tannic acid, the amount of which depends on the
variety of the tea.

This method may also be used for coffee and cola preparations.
There are other much more refined and elaborate methods for
estimating caffeine, than this one.

UNCLASSIFIED ALKALOIDS

Veratrine is a mixture of alkaloids of unknown composition.
The effects of veratrine resemble closely those of aconite (qv).
In addition the muscles are stimulated and relaxation greatly
prolonged. The chief tests are :

1. Concentrated sulphuric acid added to veratrine gives an
intense yellow color, which changes to orange and finally cherry
red.

2. Concentrated hydrochloric acid gives a cherry red color
only after heating 10-15 minutes on a water bath.

3. VitaK's test: Dissolve veratrine in a few drops of fuming
nitric acid and evaporate to dryness on a water bath, a yellow
residue remains which when moistened with alcoholic potash gives
an orange red or red violet color.

Atropine, hyoscyamine, scopolamine and strychnine also give
this test.

4. Physiological test : When 0.5 -cc. of 0.1 per cent, veratrine
is injected into the lymph sac of a frog, a muscle preparation
prepared after 30 minutes shows an enormously increased relaxa-
tion period.

Physostigmine or Eserine. — C^H^iC^Ns is an alkaloid found
in calabar bean. Its composition is unknown. It has a con-
siderable use in medicine and resembles muscarine and pilocarpine
in action but has a greater effect on parenchymal tissue. Its
chief actions are :

COLCHICINE 295

1. Marked constriction of the pupil and spasm of the ciliary
muscle, seen as a rule only when applied locally.

2. A powerful stimulation of the muscular mechanism of all
muscles innervated by the parasympathetic system especially
the gastro-intestinal system.

3. A stimulation of the vagus endings to the heart.

4. Some initial stimulation followed by depression, of the
medullary centers and spinal cord.

TESTS

1. Light and heat cause solutions to turn red on standing.

2. If a physostigmine salt is evaporated to dry ness and am-
monium hydroxide added a bluish green residue remains.

3. Nitric acid dissolves physostigmine forming a yellow
solution.

4. If a solution of physostigmine is shaken with an excess of
NaOH solution, a red coloring matter rubroserine is formed.
Crystals separate on standing which become greenish blue.

5. A solution of eserine dropped in the eye of a rabbit or cat
causes constriction of the pupil. Atropine will remove the
constriction.

Colchicine. — This is an alkaloid of unknown composition. It is
found in all parts of meadow saffron, and is used in the treatment
of gout. When hydrolysed with H2S04 it yields colchicein and
methyl alcohol

C22H25N06 + H20 = C21H23N06 + CH3OH
colchicine Colchiceine

In toxic doses it causes acute intestinal pain with nausea
vomiting and diarrhrea. The lethal dose is about .0012 gram
per kilo of body weight. Death is due to vasomotor paralysis.

Tests

Unless the aqueous solutions have a yellow color colchicine is
absent. It may be confused with dilute sols, of picric acid.

1. Precipitation occurs by the general alkaloidal reagents.

2. Concentrated nitric acid dissolves colchicine with a dirty
yellow color changing to red and finally yellow. Addition of
NaOH produces an orange red or orange yellow color.

296 CHEMICAL PHARMACOLOGY

3. Concentrated sulphuric acid dissolves colchicine with an
intense yellow color. A drop of concentrated nitric added to
this produces a green, blue, violet and finally yellow color, an
excess of KOH will now produce a red color.

Unclassified or Alkaloids of Unknown Composition. — The
most important are the aconite alkaloids:

Aconitine : Acetylbenzoylaconine

C21H2703N(OAc) (OBz) (OCH3) 4
Bikhaconitine : Acetylveratroylbikhaconine

C2iH27ON(OAc)(OVe)(OCH3)4
Indaconitine : Acetylbenzoylpseudaconine

C21H27O2N(OAc)(OBz)(OCH3)4
Japaconitine : Acetylbenzoyljapaconine

C21H2903N(OAc)(OBz)(OCH3)4
Pseudaconitine : Acetylveratroylpseudaconine

C21H27O2N(OAc) (OVe) (OCH3) 4
Ac = acetyl; Bz = benzoyl; Ve = veratroyl.

The Quebracho Alkaloids.

Aspidosamine, ................ C22H28O2N2.

Aspidospermatine, ............ C22H2s02N2.

Aspidospermine, .............. C22H3oON2.

Hypoquebrachine, ........ .... C2iH26O2N2.

Quebrachamine

Quebrachine, . . . .............. C2iH26O3N2.

Ergotoxine.

Ergotoxine,. ... ............... C35H4iO2N5 .

Ergotinine, ...................

The Colchicine Alkaloids.

Colchicine, .................... C22H25O2N ,

Colchiceine, ............ ....... C21H23O6N.KH2O.

Yohimbinine, ................. CssH^OeNs

Yohimbine, ............. ...... C22H3006N2

Cytisine, ..................... Cn

The amount of any known alkaloid can be determined by
dissolving it in an excess of normal acid and titrating the excess

ALKALOIDS 297

of the acid, just as ammonia is titrated. We know that 1 cc. of
each normal solution is equivalent to 1 cc. of every other normal
solution. If we titrate NH4OH with H2S04 the reaction is as
follows : t

H2S04 + 2NH4OH = (NH4)2SO4 + 2H2O
Ice. of normal H2SO4 = therefore . 014 grams N or
1 cc. of N/10 H2SO4 =' .0014 grams N or

.0017 grams NH3

The factors for the various alkaloids differ depending on the
molecular weight of the alkaloid, but 1 cc. n/10 H2SO4 always
represents .0014 N in the alkaloid just as it does in ammonia, but
while the molecular weight of NH3 is 17, that of atropine is 289.19.
Hence, the amount of atropine equivalent to 1 cc. n/10 H2S04
is 17 : 289.19 :: .0017 :X = .029-.

The amount of each alkaloid represented by 1 cc. n/10 H2S04
is as follows :

iitf./ Aconitine 0.0645

Atropine 0.0289

Brucine 0.0394

Cocaine 0.0303

Coniine 0.0127

Morphine + H20 0.0303

Physostigmine 0. 0273

Pilocarpine 0.0208

Quinine 0.0324

Strychnine 0.0334

Combined alkaloids of Cinchona 0 . 0309

Combined alkaloids of Ipecac 0.0240

THE PHYSIOLOGICAL SIGNIFICANCE OF NITROGEN

BASES

Since many of these bases are exceedingly reactive in animals
one wonders what role they play in the life of the plant. Three
views are held regarding this:

1. They are the end product of plant metabolism rendered
harmless to the plant and correspond to the urea and uric acid,
of animals. This view is generally accepted.

298 CHEMICAL PHARMACOLOGY

2. They are protective materials, against the attack by ani-
mals and parasitic fungi.

3. They are nutritive or plastic material used by the plant
in metabolism.

In favor of the first view is the fact that the purine bases
generally are formed in places of great cellular activity, and
their disappearance is never aecompanied by a simultaneous
increase in albuminous substances. Again Kerbosch has pre-
sented evidence to show that narcotine is formed from protein
during the germination of poppy seeds. Caffeine and- theobro-
mine are generally held to be decompositive products of protein.
The difference in plants and animals in this regard is that animals
have a mechanism for the elimination of these waste products
while in plants there is no such elimination.

The view that they -are protective against animals and fungi
has little to recommend it since plants grow just as well in lati-
tudes where no alkaloid or much less is formed.

There is little evidence to show that they are nutritive since it
has been shown that in the germination and early growth of
potatoes, nux vomica, thorn apple, and other seeds there is no
change in the alkaloid content. Certain lower forms of plant
life, that do not contain alkaloids, can utilize atropine, cocaine,
morphine in their growth. Strychnine is toxic to some, quinine
to others.

XXVII. PROTEINS

The name protein comes from the Greek word Protos, first,
and in the animal body they are of the first importance. In
plants, carbohydrates constitute the greater part, with some pro-
tein, while in the animal, the greater part of the living matter is
made up of protein with some carbohydrate always associated.

Proteins, fats and carbohydrates, are organic materials, and
are always associated with life. Some authors hold that the pro-
tein molecule in life is in a labile form, probably due to the pres-
ence of aldehyde and nitril groups. When life ceases, there is
an intramolecular rearrangement, to the stable or dead form.
The vibration or movement of the protein molecule is life.
Whether this movement ever can be analysed or imitated the

PROTEINS 299

future only can tell. Progress in pharmacology, however, must
consist to a great degree in a study of chemical protein reactions.

CLASSIFICATION OF PROTEINS

Owing to the complexity of the proteins, and to the fact that
their chemistry is still to a great extent unknown, and still the
subject of research, the nomenclature is continually changing.
The American Society of Biochemists and the American Physio-
logical Society, have agreed on the following classification :
I. Simple proteins.

II. Conjugated or compound proteins.
III. Derived proteins.

THE SIMPLE PROTEINS

These on hydrolysis yield only monoamino acids. They are
subdivided into:

A. Albumins. — These are soluble in water and dilute saline
solutions. They are coagulable by heat in neutral or acid solu-
tion. They are not precipitated by saturation with NaCl, or
MgSO4. Unless the reaction be acid they are precipitated by
saturation with ammonium sulphate. They are rich in sulphur
and yield no glycocoll on hydrolysis.

. The typical albumins are egg white, serum albumin, lact
albumin, legumelin of the pea and leucosin of the wheat and
other cereals. Traces of albumin are found in all seeds.

B. Globulins. — These are insoluble in water but soluble in
dilute saline. In neutral solution they are precipitated by sat-
uration with magnesium sulphate or half saturation with am-
monium sulphate. They can be separated from the albumins
by dialysis. They are found associated with albumins. The
albumins and globulins are the only proteins that are coagulated
by heat; but many vegetable globulins differ from those of animal
origin in that they are coagulated by heat with difficulty. Serum
globulin and edestin are the chief representatives. They are
the commonest form of the reserve protein of plants.

C. Glutelins. — These are insoluble in water and neutral saline,
but dissolve in dilute acid or alkali. Only two are known,
glutenin found in wheat and oryzenin in rice. They are hard to
prepare pure and have been but little investigated.

300 CHEMICAL PHARMACOLOGY

D. Prolamines or Gliadins. — These are vegetable proteins
found in cereal grains only. They are insoluble in water or
saline, soluble in 70-90 per cent, alcohol, soluble in dilute acids
or alkalies. On hydrolysis they yield a considerable amount
of proline — hence the name prolamine. Gliadin, hordein, zein
are the chief representatives.

E. Albuminoids. — These are insoluble in water, or in dilute
acid, alkali, or saline. Elastin, keratin, and collagen are the
chief members. They are found on connective tissue, skeletal
tissue, hair epidermis especially. On hydrolysis these are lacking
in certain amino acids such as cystein, tyrosin and tryptophane.

F. Histones. — These are strongly basic, soluble in water and
dilute acid, and insoluble in ammonia. They are characterized
by being precipitated by ammonia. They are related to the
protamines, but are more complex than these. They have been
prepared mainly from bird's blood corpuscles and the thymus
gland.

G. Protamines. — These are strongly basic. They are the
simplest proteins known, and usually associated with nucleic
acid. They are soluble in ammonia and yield large amounts of
diamino acids sturin, salmin, clupein, etc., on hydrolysis.

No compounds of this kind have been isolated from plants.

CONJUGATED PROTEINS

These are combinations of simple proteins with a non-protein
group, which is usually acid in character. This group is some-
times called the prosthetic group (prosthesos — additional). The
group is subdivided as follows :

A. Hemoglobins or Chromoproteins. — In these the prosthetic
group is colored. The representatives are hemoglobin, hemocy-
anin, phycoerythrin, and phyocyan.

B. Glyco or glucoproteins, represented by mucin, ichthulin,
rnucoids. The prosthetic group is a carbohydrate.

C. Phosphoproteins. — Compounds of a simple protein with an
unidentified phosphorus containing prosthetic group — casein and
vitelljm are types.

D. Nucleoproteins. — These are perhaps the most important
conjugated protein. They are combinations of protein with

PROTEINS 301

nucleic acid, and are found in the nucleus and chromatin.
Nuclein and nucleolustone.

E. Lecitho proteins, the prosthetic group is lecithin or a phos-
pholipin. English chemists do not recognize this group. They
probably exist, though none has been isolated.

F. Lipoproteins. — The existence of this group is also doubtful.
They are supposed to be combinations of proteins and a higher
fatty acid.

DERIVED PROTEINS

This group includes products formed from the simple proteins
by hydrolysis.

A. Primary Products

(a) Proteans. — These are the incipient or first products formed
on digestion. Edestan, myosan.

(6) M eta-proteins. — These are products of the further action
of acids and alkalies on proteins. They are soluble in weak acids
and alkalies but precipitated on neutralization. Acid and
alkali albumins are examples.

B. Secondary or Intermediate Protein Derivatives

(a) Proteoses. — These are hydrolytic cleavage products of
proteins that are soluble in water, and not coagulated on heating.
They are completely precipitated by saturation with ammonium
sulphate."

(6) Peptones. — These hydrolytic product's are not precipitated
by ammonium sulphate. They give the biuret reaction and are
diffusible.

(c) Peptides or Polypeptides. — These are compounds of
amino acids of known composition, such as leucyl glutamic acid.
Many are synthetic. They are called di, tri, tetra — etc. accord-
ing to the number of amino acids in the molecule. They are not
coagulable by heat, are diffusible, and may or may not give the
biuret reaction.

302 CHEMICAL PHARMACOLOGY

The English Biochemists classify proteins as follows:

I. Simple Proteins

1. Protamines

2. Histones

3. Globulins

4. Albumins

5. Glutelins

6. Gliadins. (Prolamins) (Soluble 70-90 per cent, alco-
hol; insoluble in water).

7. Sclero-proteins. (Forming the skeletal structure of
animals) .

8. Phosphoproteins. Caseinogen.

II. Conjugated Proteins

1. Chromoproteins

2. Nucleoproteins

3. Gluooproteins.

III. Hydrolyzed Proteins

1. Metaproteins

2. Albumoses or proteoses

3. Peptones

4. Polypeptides

COMPARISON OF ANIMAL AND VEGETABLE PROTEINS

The general properties of these are the same, but there are
some striking individual differences : With the exception of
diamino trihydroxy-dodecanic acid, a hydrolytic product of
casein, all the products of hydrolysis of animal protein have been
found in plant protein.

Vegetable proteins as a rule yield more glutaminic acid,
proline, arginine, and ammonia than animal proteins.

Prolamins or alcohol soluble proteins are found only in plants.
None have so far been found' in animals.

AMINO ACIDS FOUND IN PLANTS

Leucine has been found in the sprouts and buds of the horse
chestnut.
Iso-leucine in the residue of molasses.

GENERAL PROPERTIES OF PROTEINS 303

Arginine in etiolated pumpkin seeds, in conifer seed, and in
lupin seed.

Phenyl-alanin in germinating lupin seeds.

Tyrosine has been isolated from a number of growing shoots.

Tryptophane in the seedlings of several species of legumes.

Proline is obtained on the hydrolysis of a number of vegetable
proteins, but has not been found free in any plant.

GENERAL PROPERTIES OF PROTEINS

The following are some of the more prominent properties of
the group:

I. Proteins are colloids (some have been prepared in crystalline
form). They will not diffuse through a membrane.

II. The ultimate elements are present in a certain proportion
varying only within narrow limits.

C 50.6-54.5 per cent.

EL... '. . . . 6.5- 7.3 per cent.

N ... 15.0-17.6 percent.

S 0.3- 2.2 per cent.

P 0.4- 0.85 per cent. '

0 21.4-23.5 per cent.

III. Proteins give precipitation and color reactions. The
color depends upon certain chemical groups or complexes within
the protein molecule, while the precipitate is due to a new com-
pound formed with the reagent. Heavy metals and the alka-
loidal reagents precipitate the proteins.

Color Reactions

1. Millon's reaction depends upon the presence of a mono-
hydroxy benzene nucleus group.

2. The xantho-proteic (xanthos-yellow) reaction is given by
all proteins containing the benzene nuclei in the molecule.

3. Adamkiewicz's reaction is given only by bodies which con-
tain the indol groups.

4. The biuret reaction has some relation to the amine group
linked to carbon.

CONH2 CSNH2 C(NH)NH2 CH2NH2 etc.

304 CHEMICAL PHARMACOLOGY

Precipitation Reactions

The following reagents cause precipitation of most proteins.
Exceptions may be seen under the classification of proteins :

1. Alcohol.

2. Boiling or heat.

3. Mineral acids.

4. Solutions of salts of heavy metals.

5. Excess of the salts of the alkalies.

6. Potassium ferro-cyanide in acid reaction with acetic acid.

7. Tannic acid in acid reaction with acetic acid.

8. A solution of phosphotungstic or phosphomolybdic acid,
after acidification with a mineral acid.

9. Iodine in potassium iodide (Lugol's solution).

10. Picric acid.

11. Precipitins.

Hydrolytic Products

(IV) When hydrolysed proteins split into definite complexes,
albuminoses, peptones, polypeptids, amino acids, etc., which are
constant for the same, but vary for each protein.

Twenty-one amino acids have been prepared from protein.
They are as follows:

A-Mono-amino — mono-carboxylic fatty acids:

H H H

H— C— NH2 H— C— H H— C— H

I I I

0=C— OH H— C— NH2 H— C— H

I I

O=C— OH H— C— NH2

C2H5N02 C3H7N02 0=C— OH

C4H9NO2

Glycocoll Alanine (a-amino

(a-amino acetic (a-amino butyric

acid) propionic acid)

acid)

AMINO

ACIDS

H— C— H

CH3 CH3

\/
C— H

H— C— H

H— C— NH2

H— C— H

1
O=C— OH

1
H— C— NH2

0=C— OH

C6HnN02

(a-amino
valerianic
acid)

C5HnN02
Valine
Iso-propyl
acetic acid)

305

CH3 CH3

\ /

CH3

H— C— H

1
H— C— H

\/
C— H

H— C— H

1
H — C — H CHg

C— H

H— C— H

H— C— NH2

H— C— H

0=C-OH

O=C— OH

H— C— NH2

C6H13N02

(a-amino normal
caproic acid)

C6H13N02

Leucine

(a-iso

butyl

a-amino

acetic

acid)

C6Hi3NO2

Iso-leucine
(ethyl, methyl
a-amino propionic
acid)

306

CHEMICAL PHARMACOLOGY

H H

H— C— OH H— C— SH

H— C— NH2

I
O=C— OH

C3H7N03
Serine
(B-hydroxy
a-amino
propionic
acid)

H— C— NH2

0=C— OH
C3H7NS02
Cysteine
(B-thio, a-amino
propionic acid)

H— C— S — S— C— H
NH2— C— H H— C— NH2

0=C— OH 0=C— OH

C6H12N2S204
(Cystine)

B. Mono-amino dicarboxylic acids

O=C— OH 0=C— OH

H— C— H

H— C— NH2

H— (

>-H

0=C— OH

H— (

;— NH2

O=C— OH

C4H7NO2
Aspartic acid
(a-amino
succinic acid)

C5H9NO2
Glutamic acid
(a-amino glutaric
acid)

AMINO ACIDS

307

C. Isocyclic amino acids
C— OH
HC CH

.HC CH

\/
C

I
H— C— H

H— C— NH2

0 = C— OH
C9HnN03

Tyrosine
(/3-para-hydroxy-
phenyl, a-amino
propionic acid)

HC CH

H— C— H
H— C— NH2

0 = C— OH
C9HnN02

Penyl alanine (/3-phenyl
a-amino-, propionic acid)

D. Heterocylic amino acids
CH H NH2O

HC C C— C— C— C-

I II II II I
HC C C H H

V \/ \

CH NH H

CiiHi2N2O2 (Tryptophane)
(a-amino, /3-indole
propionic acid)

H2C CH2 O

I I II

H2C C— C— OH

NH H

C6H9NO2 (Proline)
(a-pyrrolidine carbox-
ylic acid)

308 CHEMICAL PHARMACOLOGY

HC— N H2C CHOH

^CH

C— NH H2C C— C— OH

I \/\

HC— H NH H

H— C— NH2

I
0=C— OH

C6H9N3O2 C5H9NO3

Histidine Oxy-proline

(a-amino, fl-imidazole (The position of the hydroxyl

propionic acid) is uncertain)

E. Mono-carboxylic, diamino acids

NH2 NH2

C=NH H— C— H

N— H H— C— H

I I

H— C— H H— C— H

I I

H— C— H H— C— H

H— C— H H— C— NH2

I !

H— C— NH2 O— C— OH

I
O=C— OH

C6H14N402 C6H14N202

Arginine Lysine

(a-amino, d-guanidine (a, e, amino, caproic

valerianic acid) acid)

GENERAL CHARACTERS OF AMINO ACIDS

I. Reaction. — The mono-carboxylic mono-amino acids are

amphoteric to litmus. The diamino acids, and arginine and

AMINO ACIDS 309

histidine are alkaline, and in solution absorb CO2. The mono-
amino dicarboxylic acids are acid to litmus.

II. Solubility. — As a rule they are soluble in water. Tyrosine
is but slightly soluble in cold but is soluble in hot water. They are
soluble in dilute acids and alkalies. They are insoluble in ether.

III. Combinations. — Since amino-acids contain both NH2
and COOH group they will unite with both acids and bases. The
NH2 group unites with acids as does ammonia. The COOH
group unites with NaOH etc. to form salts of -the amino acid.
Through the amino group they unite with salts of the heavy
metals, such as Cu, Pt, Ag, Hg etc. to form such combinations as
- CH3.CH2.CH.NH2CuCl2.COOH. These salts are insoluble in
water.

IV. Condensation. — Amino acids may condense or unite with
each other to form polypeptides. The amino group of one uniting
with the carboxyl group of another. Such combinations are two
molecules of glycocoll or glycyl-glycine :

NH2CH2CO.NHCH2GOOH and
Leucyl — asparagine :

COOH

)CH.CH2.CH(NH2)CO.NH.CH

CH2

CONH2

A great number of such polypeptides have been prepared and
are named di, tri, penta, etc. according to the number of amino
acids in the combination. The most complex of these so far
synthesized contained 18 amino acids, and contained three
leucine and 15 glycocoll groups. It was 1-leucyl-triglycyl-l-
leucyl - triglycyl - 1 - leucyloctoglycylglycine. NH2CH (C4H9) CO.
(NHCH2CO)3.NHCH(C4H9)CO.(NHCH2C03).NHCH(C4H9)
CO. (NHCH2CO) 8NHCH2COOH .

CONDENSATION PRODUCTS

The alpha amino acids readily condense by the elimination of
water from the OOOH groups:

310 CHEMICAL PHARMACOLOGY

CH2 NH H HO| OC CH2 NH OC

+ 2H2O

CO OH HHN CH2-* CO— HN— CH.

Beta amino acids condense through loss of ammonia with the
formation of unsaturated acids :

NH2|CH2 CH|HiCOOH = NH3 + CH2 : CH.COOH
B. amino propionic acid acrylic acid

Amino acids through the loss of water yield inner anhydrides
which, because of the similarity to lactones, are called lactams:

CH2 CH2 CH2 CO CH2 CH2 CH2 CO

NH(H OH) HN

Amino butyric acid — > lactam of aminobutyric acid

Lactones are the inner anhydrides of gamma and delta hy-
droxy acids, i.e., instead of the amino group in amino acids a
hydroxyl group may be substituted. Such condensations as
these may explain the formation of alkaloids in plants. Thus
when solutions of leucine are evaporated diketo condensation
imides are formed :

(CH3)2=CH— CH2— CH.NH— C

I
0=C— NH-CH— CH2— CH=(CH3)2.

Leucinimide (Diisobutyl-diketopiperazine)

This gives rise to diketo piper azine from which piperazine may
be prepared:

NH CH2— CH2

/\ / \

HN NH

H2C CO \ /

| | CH2— CH2

CO CH2

\/ piperazine

NH
Diketo piperazine

LACTIM UKIC ACID 311

From the pharmacological point of view, lactams are interesting
preparations producing strychnine like convulsions in animals.
This is a common characteristic of ring compounds. The amino
acids themselves are devoid of visible action. Such molecular
rearrangements may be the cause of many obscure reactions in
indigestion, uremias, gout, etc.

The precipitation of urates in gout according to some (Gudzent)
is due to uric acid changing from the lactam to the lactim form.
The lactim form of uric acid is :

N = C— OH

I !

HOC C— NH

COH

N C N

Cf. formula p. 284.

Piperazine has been advocated in the treatment of gout, but
it is without influence.

Condensation with Formaldehyde

Ammonia condenses with formaldehyde to form hexamethylene
tetramine. The product formed in this case is N4(CH2)6.

The amino acids also condense with formaldehyde according
to the formula.

NH2 N = CH2

O I O

II I II

R— C— C— OH+HC = 0 = R— C— C— OH+H20

H H H

Methylene amino acid

This methylene derivative has no basic properties and can be
sharply titrated with alkali. This is the basis for the Sorensen
titration method for the titration of amino acids in a mixture.
This is perhaps one of the mechanisms in the formation of
amino acids in plants and animals. Erlenmeyer and Kunlin1

'Ber. deut. chem. Gesells. 1902-35-2438.

312 CHEMICAL PHARMACOLOGY

were able to synthesize formyl derivatives of alanine and glycine
by the interaction of ammonia and glyoxylic acid, and since both
of these occur in plants, the probability of such formation in the
plant is suggested.

CHO CH2NH CHO

2 | +NH3 |

COOH COOH+H2O+CO2
Glyoxylic acid Formyl-glycine,

CH2 NH CHO CH2NH2

| +H20 -> +HCOOH

COOH COOH

Formyl-glycine Glycine

THE DEAMINIZATION OF AMINO ACIDS

In the preparation of amino acids from protein, the usual
method is to boil the protein with acid for hours. This fact
shows the stability of the amino groups in acid solution. The
slight amount of nitrogen that is evolved is in the amide condi-
tion, that is, in the form of R.CONH2. Amino acids are also
quite stable in alkaline solution. Arginine decomposes to orni-
thin and urea, and cystine and cysteine lose considerable of their
sulphur, but as a rule little decomposition occurs.

Oxidation may cause deaminization through splitting off
ammonia. Various oxidizing agents like hydrogen peroxide,
and potassium permanganate, cause, in vitro, the deaminization
as follows:

CH3 CH3

! I

H— C— NH2 + O t? C=O + NH3

0=C— OH . O=C— OH

Alanine Pyruvic acid

Where deaminization takes place in the body is not known.
It seems that all tissues, perhaps due to a ferment, have deaminiz-
ing properties. It is thought by some that since no amino acids,
or only a trace, can be demonstrated in the blood, that deaminiza-
tion takes place in the intestine. There is no direct proof that

CARBAMINO REACTION 313

the intestine possesses this property to a greater extent than any
other tissue.

URETHANE FORMATION OR THE CARBAMINO REACTION OF
.; AMINO ACIDS

Chloroformic ester reacts with ammonia to form urethane or
amino ethyl-formate — or the ethyl ester of carbamic acid.

, ,

CO/ + NH8 = CO/ + HC1

XOC2H5 XOC2H5

Ammonium carbamate is formed as follows :

O O

II II

HO— C— OH + 2NH3-»NH4— C— O— NH2

+ H20
Carbonic acid

Urethane is the ethyl ester of ammonium carbamate, and a
reaction of this kind is known as the carbamino reaction.

Ammonium carbamate is the intermediary compound in the
formation of urea in the body.

XNH2
NH2 - COONH4 C0 + H20

XNH

Ammonium carbamate, urea or carbamide.

Carbamate salts, differ from carbonates in their solubilities,

/OCa
2CO<f or calcium carbamate being soluble in water.

XNH2

When boiled however calcium carbonate is formed and NH3 is
driven off. This difference iirthe solubilities is used to advantage
in determining the composition of mixtures of amino acids. If in
a solution containing amino acids the CO2 formed is equivalent

f^O
to the N, or -4^ = 1 the relation is that of mono-amino acids.

If diamino acids or polypeptids are present the ratio is less than 1.

314 CHEMICAL PHARMACOLOGY

The Taste of Amino Acids

There is nothing distinctive in the taste of amino acids. Glyco-
coll as the name indicates is sweet. Alanine and glycoleucine
are also sweet. Leucine is tasteless and iso-leucine is bitter.
Taste in relation to chemical structure is not weir understood.
See p. 205.

OPTICAL PROPERTIES OF AMINO ACIDS

The alpha atom of amino acids is asymmetric, consequently
the acids are optically active. The presence of the asymmetric
C atom does not necessarily confer optical activity, but no opti-
cally active organic substance is known without the asymmetric C
atom. Like most natural products many amino acids are levoro-
tatory; proteins also are levorotatory and on hydrolysis the
rotation increases, so that the rate of digestion can be measured
by increase of optical activity.

Knowing the formula of a compound it is impossible to tell
what direction the rotation may be, and when one group is sub-
stituted for another prediction of the change can not be made.

It is possible by substituting one group for another to transform
an optically active compound into its optical antipode. This is
known as Walden's inversion. In several cases it has been
possible to start with a substance and by a reaction cycle obtain
the optical antipode and again the original substance Walden
treated 1. Chlorsuccinic acid with moist silver oxide and obtained
1. malic acid. This on treatment with phosphorus pentachloride
was converted into d. chlorsuccinic acid, which was converted
into d. malic acid which on treatment with phosphorus pentach-
loride yielded 1. chlorsuccinic acid.

These transformations are diagrammed in the following scheme :

AgOH

1-Chlorosuccinic acid > 1-Malic acid

|PC1,

AgOH

PC15

d-Malic ackh— d-Chlorosuccinic acid

With alanine, and nitrosyl bromide — Emil Fisher worked out
the following reaction cycle:

OPTICAL PROPERTIES

315

NOBr

d-Alanine

NH3

d-Bromopropionic acid<

4-Bromopropionic acid
NH3

1-Alanine

The significance of optical activity in so far as amino acids
are concerned, and in general, is little understood. A knowledge
of the cause of these facts would do much to advance the under-
standing of drug action.

The facts that certain moulds can ferment dextrotartaric
acid and not levo; that yeast will ferment such sugars as d-
mannose d-glucose, or d-fructose, but will not ferment 1-fruc-
tose, 1-glucose, 1-mannose, or 1-galactose; and that dextrohyos-
cyamine, dextro-epinephrine, etc. are so much more potent than
the levo forms, are full of suggestions and when understood may
do much to clarify vital activities.

Regarding the formation of optical bodies little is known,
but in plants photo chemical reactions seem to play an important
role. Cotton (Am. Chem. Phys., 1896, VII, 8, 373) found that
the dextro and levo forms of tartaric acid absorb d. circularly
polarized light at different rates, which suggest a method of
their formation.

The Action of Amino Acids in the Body

The amino acids are utilized in the body as foods. This use
may be in the building up of protein in the body, and repair of
used protein. Amino acids may also be to some extent converted
into carbohydrate and consequently into fat and will exert the
action of these food stuffs. The following formulas show the
possibility of carbohydrate formation from amino acids :

COOH

COOH
CH2

C6H120

H20

CHNH2

COOH
Aspartic acid

CH2OH

2CO2
/?. lactic acid

Dextrose

316

CHEMICAL PHARMACOLOGY

COOH COOH

CH2 —

CH<

CH3

HOH CH2OH

CHNH2 + HOH-+ CHOH

COOH
Glutamic acid

COOH

Glyceric acid

Two molecules of glyceric acid forms glucose on reduction: —
Glyceric acid— >gly eerie aldehyde-»glucose

When fed to glycosuric dogs, many amino acids, like protein,
increase sugar excretion, and are converted into sugar. It is
probable that carbohydrates may be used to some extent in
the formation of amino acids, though this is not definitely prov-
en. The only nitrogen containing carbohydrate of the body
is glucosamine. This is found especially in chitin which forms
the external skeleton of orthopods. It can also be prepared
from cartilage and ovalbumin.

Besides their function in metabolism, amino acids exert a
specific stimulating action on metabolism. A similar action
however is exerted by all food stuffs and is known as the specific
dynamic action. When for example, an animal is starving and
the energy metabolism is represented by 100 calories and we wish
to keep the animal at this level by feeding protein, it will be
necessary to feed 140 calories, or fat 114 calories or carbohydrate
106 calories. The excess of heat generated above the 100 per
cent, is the specific dynamic action. Lusk (1912) thinks that
in the case of proteins this is due to the mass action of the
amino acids on the cell protoplasm which they stimulate.

The Fate of Amino Acids in the Body

The amino acids derived from protein hydrolysis are readily
oxidized in the body and ultimately excreted as urea, CO2 and
H2O. Stolte found that when injected intravenously into rab-
bits, the nitrogen of glycine and leucine is almost totally excreted
as urea, while that of alanine, cystine, aspartic acid and glutamic

FATE OF AMJNO ACIDS 317

acid are less readily catabolized, and phenyalanine and tyrosine
led to no immediate urea excretion.

Traces of unchanged amino acids may be found in the normal
urine. The presence of glycine has been definitely established, and
it may reach as high as 1 per cent, of the total nitrogen output.

Tyrosine, leucine, and glycocoll are regularily found in the urine
in cases of acute yellow atrophy of phosphorus poisoning and in
other conditions. Cystine is found in cases of cystinuria, a
disease of metabolism not well understood. In these cases, the
diamines, putrescine and cadaverine, formed by putrefaction in
the intestine may also be found.

In the normal catabolism of the amino acids, the first step in the
formation of urea is thought to begin with the alpha position :

R.CH2CHNH2COOH + O2 = RCH2COOH + CO2 + NH3

Many examples of this kind of reaction are known, e.g., leucin
on oxidation gives iso-valeric acid

CH3v

))CH.CH2CHNH2COOH + O2 =
CH/

CH3,

)CH.CH2COOH+ C02 + H20
CHS

Iso-valeric acid

In cases of alkaptonuria tyrosin undergoes a similar change to
form homogentisic acid

OH HO

CH2 +CO2+NH3
COOH

COOH
Tyrosin homogentisic acid

318 CHEMICAL PHARMACOLOGY

Homogentisic acid in turn is oxidized by the normal organism,
and this may be the usual mechanism of tyrosin catabolism. In
alkaptonuric cases homogentisic acid is either not oxidized or at
a much slower rate than in the normal.

Alanine is oxidized in the body as follows,

CH3CH.NH2.COOH + 0 -> CH3CHO + C02 + NH3

When oxidized in vitro by hydrogen peroxide or potassium
permanaganate the amino group is replaced by oxygen and a
ketonic acid is formed :

CH3 CH3

I
H— C— NH2 0 ±> C = O+NH3

| +

COOH COOH

This reaction may be reversed by reducing agents. By reduc-
tion of the alpha ketonic acids hydroxy acids may be formed, in
this case lactic acid

CH3

CH.OH

I
COOH

is formed, and this indirect method may explain the production
of lactic acid in the body. Lactic acid is found chiefly in cases
of tissue asphyxia due to excessive exercise, or deficient supply of
oxygen.

The reversibility of the alanine — lactic acid reaction, and the
relation of lactic acid to carbohydrates, suggests the possibility
of a synthesis of amino acids from carbohydrates and ammonia
in the body. Embden obtained evidence of this synthesis by
perfusing a liver with glycogen and found that alanine was
formed. Many other examples of alpha ketonic acids being
formed from alpha amino acids. It is assumed that alpha
ketonic acids are essential products in the oxidation of alpha
amino acids, and hydroxy acids are formed from these by reduc-

FATE OF AMINO ACIDS 319

tion and are not directly derived from the amino acids (see Dakin,
Oxidations and reductions in the animal body).

The ultimate fate of alpha amino acids and alpha ketonic acids
in the body is the same but, in the process of catabolism the
ketonic acid may undergo three types of change:

1. It may be oxidized to a lower fatty acid:

R.CH2CO.COOH + O = R.CH2COOH + CO2

2. It may be reduced with formation of an hydroxy acid :

R.CH2.CO.COOH+H2 = R.CH2CHOH.COOH

3. Its ammonium salt may be reduced to the corresponding
amino acid:

R.CH2CO.COONH4H-H2 = R.CH2.CH.NH2COOH4-H2O

These three types have been imitated in vitro.

The Fate of Alpha Amino Acids in Abnormal Conditions

In cases of diabetes, in which there is a reduction of the ability
of the tissues to oxidize carbohydrates, and perhaps some other
bodies, amino acids may give rise to sugar and aceto acetic
acid.

The following table from Dakin (oxidations and reductions in
the animal body) shows this:

Increased glucose Acetoacetic acid
excretion when formation when
Substance given to diabetic perfused through

animal surviving liver

Gly cine +

Alanine -f

Valine ?

Leucine +

Aspartic acid +

Glutamic acid +

Phenylalanine ? +

Tyrosine -f

Histidine + +(?)

Lactic acid -f —

320 CHEMICAL PHARMACOLOGY

Since carbohydrates can be formed from amino acids, it follows
that alcohols may also be formed. Their actions in the forma-
tions of alcohols appears to be as follows :

oxidation

R.CH2.CH.NH2.COOH -> R.CH2.CO.COOH -»

a, Ketonic acid

reduction

CO2 + R.CH2CHO -> R.CH2.CH2 OH

Aldehyde Alcohol.

The fate of cystine, the only sulphur containing amino acid
is of interest since sulphur is important in pharmacology.
In normal conditions this acid is completely oxidized and the
sulphur eliminated in the form of sulphate. In certain individ-
uals the ability to oxidize cystine is lacking and it appears in the
urine. Such persons appear normal, and do not suffer from the
condition. It is an inherited condition and is more frequent in
males than females. The cause of this anomaly of metabolism
is not known.

Taurine, CH2.NH2.CH2SO3H, which is found in the bile
combined with cholic acid, as taurocholic acid, appears to be a
derivative of cystine or cysteine:

COOH COOH CH2.NH2

CHNH2 -» CH.NH2 -» CH2(S03H)

Taurine.

CH2(SH) CH2(SOaII)

Cysteine Cysteic acid

Because of the relation to the active principles of ergot, ad-
renalin etc. the fate of tyrosine, phenylalanine and tryptophane
are of especial interest. These are normally completely oxidized
in the organism. This is contrary to the fact that most aromatic
bodies are not readily oxidized. In cases of alkaptonuria
tyrosin and phenylalanine may be converted into homogentisic
acid:

FATE OF AMINO ACIDS

COOH COOH COOH

CHNH2

CH2

321

Tyrosine

Homogentisic acid Phenyl-alanine

The normal organism oxidizes homogentisic acid readily, but
but alkaptonurics have not this power.

Tryptophane. — Little is known of the mechanism of the fate
of this body in the human organism. It apparently undergoes
complete oxidation. When fed to dogs, it causes an increase in
the excretion of kynurenic acid.

/
HC

!.CH2.CHNH2.COOH

NH
CH

Tryptophane

COH

\c/

So.

COOH

1
/c\

^•CH

CH N

Kynurenic acid

322 CHEMICAL PHARMACOLOGY

\ *

In this reaction an additional C atom has entered the indole
ring.

The fate of histidin in the body is of especial interest because
of its relation to the active principles of ergot. When CO2 is
split off from histidin, histamine or @ imido azole ethyl amine,
or ergamine is formed.

C— NEL C— NEL

II ^CH || \CH

C 1ST C N *.

\ | + C02

CH2 — > CH2

I I

CH.NH2 CH2NH2

COOH

Histidin /3-imino azole ethyl amine

(histamine or ergamine)

The effects of ergamine differ in different animals. In dogs
and cats it causes a condition resembling anaphylactic shock
due to dilation of the peripheral vessels. While in the rabbit
it tends to constrict the vessels. It acts directly on the vessel
wall and may have some action on the neuro-muscular junction.
According to some authors, histamine is the same as vasodilatin.
Such substances as histamine, epinephrine, and perhaps many un-
known hormones may be intermediate products in the catabolism
of amino acids.

POISONOUS PROTEINS

These are protein substances, and have been termed vegetable
agglutinins; they coagulate milk and blood. They resemble
bacterial toxins and have been found in a number of higher plants,
and are therefore called phytotoxins. The most important are
Ricin — from the castor bean (Ricinus communis). Abrin, from
the seeds of abrus precatorius— Crotin, from the seeds of croton
tiglium. Robin from the leaves and bark of the locust, Robinia
pseudoacacia, and Curcin from the seeds of Jastropha curcus.
The general properties and actions of these substances are
similar. Ricin is found in ricinus communis along with castor

ENZYMES 323

oil, but the oil itself does not contain ricin. It is the most power-
ful of the phytotoxins. One thousandth of a milligram
per kilo is fatal to a rabbit when given hypodermically. The
ricin agglutinates the corpuscles and also precipitates serum.
Death occurs several days after a subcutaneous injection, with
but few symptoms other than loss of appetite, and towards the
end diarrhoea and vomiting. Post mortem examination shows
congestion and inflammation of the gastro-intestinal tract with
ecchymoses; blood in the serous cavities; punctiform hemorrhages
beneath the serous surfaces and extravasations in various organs.
Microscopical examination shows foci of necrosed tissue in the
spleen, liver, intestine stomach and other organs. The whole
picture is much the same as that caused by diphtheria toxin.
The poisons are eliminated through the intestinal mucosoa, which
accounts for^the great amount of gastro-intestinal injury. An
immunity can be developed against these toxins, and antitoxins
can be prepared.

Abrin contains two poisons, a globulin and an albumose, of
which the former is more powerful. Crotin is less powerful than
ricin or abrin, but the action is similar. Robin and curcin are less
known than the others. Curcin differs from all the others in
having no hemagglutinative action.

XXVIII. ENZYMES OR ORGANIC FERMENTS

Nothing definite is known of the chemistry of enzymes. The
word means literally "in yeast" (from the Greek "en", in; and
"zyme", leaven. They are complex organic substances, capable
of rendering food available for the cell. Because of their colloidal
nature and the difficulty of obtaining enzymes in a pure condition,
their chemical nature is unknown. They are formed within the
living cells, although in certain cases, the cells do not secrete the
complete enzyme, pro-ferments or zymogens, which are trans-
formed into active enzymes outside of the cell, being first formed.

Enzymes differ from catalysts in their sensitivity to heat and
light. All enzymes are destroyed at 100°C. and most of them at
60°C. Each enzyme acts best at a definite temperature which is
the optimum temperature. For the digestive enzymes this is
about 40°C. The destructive action of heat is perhaps due to a
coagulation of the proteins of the enzyme.

324 CHEMICAL PHARMACOLOGY

Regarding light, there seems to be two kinds of action:

(a) Those produced by ordinary light in presence of oxygen.
This is greatly accelerated by the presence of fluorescent sub-
stances such as eosin, quinoline red etc., which though not under-
stood yet offers hope of therapeutic value in many diseases.

(6) Ultra-violet light independent of oxygen destroys diastase
and other enzymes. In this connection we might add that
various rays of light and emanations are now used with consider-
able effect in cancer and other diseases the causes of which are
unknown.

The colloidal nature of enzymes is shown by lack of diffusibility
and by their precipitation by other colloids. Enzymes are
adsorped readily by many finely divided inert particles such as
charcoal, infusorial earth, etc. This adsorption is a phase of
precipitation, and in this case is electrical.

The addition of salts, drugs, etc. influence enzyme action;
those substances hastening it being called accelerators, those
depressing it being called depressants or paralysers.

If enzymes are injected subcutaneously into an animal, an
antienzyme -may be formed, which neutralizes the activity of an
enzyme in a manner similar to toxin and antitoxin.

ENZYMES USED AS MEDICINES

The digestive ferments diastase, pepsin, and trypsin have been
used to some extent in medicine. The value of these in most
cases is questionable, for the reason that it is doubtful if defici-
ency of the natural digestive enzymes ever occurs. The term
" Amylaceous dyspepsia" has been used to indicate cases of
dyspepsia supposedly due to incomplete digestion of starches.
However, for all practical purposes, starches are digested in the
intestine, and it has never been shown that there is any deficiency
of the diastatic intestinal ferments. Diastase preparations as
medicines would therefore seem superfluous. The pepsin of the
stomach is almost always capable of digesting proteins, providing
the reaction is acid, and the deficiency is not in pepsin but a lack
of acid. The treatment therefore, except in rare cases, is acid
medication not the administration of pepsin. However, while
pepsin in the majority of cases is superfluous it is not injurious.

Pancreatic Ferments. — The value of these in medicine is even
more problematical than pepsin. When given they are adminis-

FATE OF ENZYMES 325

tered in a capsule or in a salol coated pill, to avoid digestion in
the stomach. To get such preparations through the stomach
without digestion, and at the same time, have them in a form
that will be liberated in the intestine is very difficult. It is
doubtfuUf any of the preparations that pass through the stomach
undigested are liberated in the intestine. If they are not liber-
ated they are useless, and if liberated, superfluous.

THE FATE OF ENZYMES IN THE BODY

Since the chemistry of the enzymes is unknown, the exact fate
cannot be determined. The protein part, or impurity, suffers
the fate of all protein in the body. The enzymes may be used
over again in the body to some extent. They are also excreted
in the urine and faeces.

Under hydrolytic enzymes, we find a group of fat-splitting
enzymes called lipases or steapsins. This group was found by
Green (1890) and subsequently confirmed by Connstein, Hoyer,
and Wartenberg, who found that castor-oil seeds contain an
enzyme that hydrolyses the fats present. In the tissues of the
body, this fat-splitting role of lipase which brings about the
separation of neutral fat in the presence of an excess of water is
reversible and builds up fat, when allowed to act upon a mixture
of fatty acids and glycerol in a medium poor in water. Diastase,
which hydrolyses starch to maltose and dextrose, is. one of the
commonest of enzymes, and occurs in practically all living matter.

Under fermenting enzymes may be mentioned the alcoholic
fermentation of glucose, levulose, mannose, etc., by zymase,
which probably occurs also in animal tissues, this supposition,
however, requires more evidence than has yet been shown. It
is thought that traces of alcohol found in the blood may have
been formed in the intestine by bacterial action.

Coagulating enzymes, are represented by rennin, which curdles
milk; thrombin, which coagulates blood; and pectase, which coagu-
lates soluble pectic bodies.

The oxidizing enzymes are divided into (a) those which oxidize
alcohols to acids, and (b) those which set free oxygen from hydro-
gen peroxide or other peroxides. These are the peroxidases or
catalases.
Life processes of all kinds are accompanied by enzyme action.

326

CHEMICAL PHARMACOLOGY

Growth, repair, ripening of fruit, decomposition, etc., have been
explained by enzyme activity. Enzymes are not held to originate
an action, but simply to accelerate those already in progress.
Whether the facts justify this opinion remains to be determined.

Enzymes are classified according to the substance acted on as
follows :

Coagulating enzymes (thrombin rennet).

Pepsin, trypsins, erepsins, amidases, catalases, etc.

The most important are arranged in tabular form as follows :

FEBMENTS ACTING ON CARBOHYDRATES

Name of Enzyme

Substances on which
Enzyme acts.

Products of the
reaction

Invertin or sucrase

Cane sugar

Dextrose and levulose

Amylase or diastase

Starch and dextrins

Maltose

Glucase or maltase

Dextrins and maltose

Dextrose

Lactase

Lactose mycose or

Dextrose and galactose

Trehalase

Trehalose

Glucose

Cytase

Hemi-cellulose

Mannose and galactose

Pec base

Pectin

Pectates and sugars, ara-

binose

Caroubinase

Caroubin

Caroubinose

Invertase which hydro-

Raffinose to

Levulose and melibiose

lyses

Maltase which hydro-

lyses

Maltose (malt sugar)

Dextrose

Inulase which hydro-

lyses

Inulin to

Levulose

FERMENTS ACTING ON FATTY SUBSTANCES

Steapsin or lipase

Emulsin

Myrosin
Betulase
Phytase

Fatty substances | Glycerin and fatty acids

FERMENTS ACTING ON GLUCOSIDES

Amygdalin and other

Potassium myronate

Gaultherin

Phytin

Glucose, oil of bitter al-
monds, and hydrocy-
anic acid

Glucose and allyl iso-
sulphocyanate

Oil of wintergreen

Glucose

Inosite and phosphoric
acid

FERMENTS
FERMENTS ACTING ON PROTEINS. — Continued

327

Name of Enzyme

Substance on which
Enzyme acts

Products of the
reaction

FERMENTS ACTING ON PROTEINS

Rennet

Plasmase
Pepsin
Trypsin
Trypsin

Papain

Caseinogen

(Casein, Hammarsten)
Fibrinogen

Albuminoid substances
Albuminoid substances
Albuminoid substances

Albuminoid substances

Casein

(Para casein)
Fibrin

Proteoses, peptones
Proteoses, peptones
Polypeptides and amido
acids

Polypeptides and amido
acids
Erepsin contained in the intestine which hydrolyses

Proteins to Potypeptides and amino

acids
Bromelin contained in the pineapple juice which hydrolyses

Proteins to

Polypeptides and amino
acids

FERMENTS CAUSING — MOLECULAR DECOMPOSITION

Zymase or alcoholic di-

Starches. Alcohol and

astase

carbonic acid. Vari-

ous sugars CO2 lactic

Lactic acid bacteria

Lactose

acid etc.

Butyric bacteria, etc.

Lactose

Butyric acid

FERMENTS ACTING ON PROTEINS TO CAUSE CLOTTING

Rennin (Chymosin)

which curdles milk

Thrombin

which coagulates blood

Pectase

which coagulates soluble

pectic bodies

Laccase

Uruschic acid

Oxyuruschic acid

Oxidin

Tannin, anilin, etc.

Unknown products of

Coloring matters of

oxidation

cereals

Malase

Coloring matters of

Unknown products of

fruits

oxidation

Tyrosinase

Tyrosine

CO 2 parahydroxy ethyl-

amine, NHs etc.

Oenoxidase

Coloring matter of wine

CO2 parahydroxy ethyl-

amine NH3 etc.

Oxidases which oxidize

alcohols to

acids e.g., action of My-

coderma aceti, etc.

328 CHEMICAL PHARMACOLOGY

FERMENTS ACTING ON PROTEINS. — Continued

Name of Enzyme

Substance on which
Enzyme acts

Products of the
reaction

FERMENTS ACTING ON UREA

Urease

Urea

Ammonia and CO2

DEAMIDIZING ENZYMES

Nuclease
Guanase
Adenase

Splits nucleic acid
Converts guanine
Converts adenine

Purin bases, etc.
Xanthine
Hypoxanthine

OXIDIZING FERMENTS

Oxidases
Catalase

Causes oxidation of or-
ganic substances
Decomposes hydrogen
peroxide

Water, oxygen

XXIX. CHLOROPHYLL

Chlorophyll (Gr. chloros, green — phyllon, leaf). Plant colors
have no physiological action and if used in medicine, it is for
their esthetic or psychic effect. But the relation between chlor-
ophyll and hemoglobin is of great .biological significance.

The name chlorophyll was first applied by Pelletier and Caven-
tou to the green coloring matter of plants. By the use of the
spectroscope it has been found that chlorophyll of the green leaf
instead of being one simple color, contains at least seven different
pigments.

The reactions in the formation of chlorophyll are not well
understood. Light is essential. The presence of iron and mag-
nesium is necessary. Starch and sugar may or may not be
essential. This point is still under investigation; as is also
the chemistry of the substances which immediately precede
chlorophyll and from which it is formed. Lecithins and proteins
seem to take part in its formation. The chemistry is complex
and not definitely known, but is sufficiently understood to
show a definite chemical relationship between chlorophyll and
hemoglobin.

CHLOROPHYLL 329

RELATIONSHIP OF CHLOROPHYLLS AND HEMOGLOBINS

There are several different chlorophylls, just as there are dif-
ferent hemoglobins. The hemoglobin of different animals varies
slightly in composition but all are closely related chemically.

By the action of glacial phosphoric acid containing HI on
hematin or hemochromogen, hsemopyrrol, C8Hi3N, a colorless
oil which in air gradually changes to urobilin is formed. Uro-
bilin is also produced by the action of the same reducing agents
on the chlorophyll derivative, phyllocyanin. This shows a close
relationship between chlorophyll and haemoglobin.
There are two well known chlorophylls:

,COOCH3

Chlorophyll (a) C32H29N3Mg~-COOC2oH39

/CO
NET

,COOCH3
and chlorophyll (6) C32H28O2N4Mg(^

XCOOC20H39
(Willstatter and Isler)

When these are treated with alkalies, two groups of products are
formed :

1. Phyllins, which contains magnesium and

2. Porphyrins, which are free from magnesium.

On oxidation with chromic and sulphuric acid, Marchlewski, also

Willstatter and Asahina, think the pyrrol group | / N

r^ r*S'

\^j' - \j

exists in the chlorophyll molecule since the pyridine derivatives

CH3.C OX

yNH Hsematinic acid imide, and

COOH.CH2.CH2C GO/

CH3.C CO,

/NH Methylethylamaleinimide are formed.

CH3.CH2C CO/

CH3.C.COOH

Haematinic acid has been obtained

COOH.CH2.CH2.C COOH

330 CHEMICAL PHARMACOLOGY

from hemoglobin and the imide of this obtained from chlor-
ophyll again establishes a relationship between chlorophyll and
hemoglobin. Hematin and hsematoporphyrin also yield hae-
matinic acid imide.

Pyrrol is an important nucleus in many biological compounds,
being found in alkaloids, nicotine, cocaine, and others, and
in proteins. In fact, proteins may be looked upon as containing
an alkaloidal nucleus.

The structure of the pyrrol derivatives is indicated as follows :

A\ TIO r^ IT (Q
p) JtlvJ \u ±1 (p

a) HC C H (a

Besides these mentioned, the following derivatives of haematin
are of biological importance.

-C- C—

CH3. C CH CO CH3

V \/

NH NH

Isohemopyrrol Kryptopyrrol or a

]3-ethyl a' $' dimethyl pyrrol methyl /? ethyl 0-

methyl pyrrol

(HI) (IV)
CH3. C C C2H5 CH3. C C CH2.CH2-COOH

CH3 C C CH3 C C

\/ V

NH NH

Phyllo pyrrol or a methyl Isophonopyrrol carboxylic acid
/3-ethyl a' &' dimethyl or /3-propionic acid a' ft'

pyrrol dimethyl pyrrol.

The bile acids are derivatives of hemoglobin and also contain
pyrrol nuclei which are derived from the hematin of blood. When
blood is dropped into acetic acid containing some NaCl and the
solution heated to 95°C. the hydrochloride of haematin, haemin

COLORING MATTERS 331

crystallizes out. When haemin is treated
with HBr, a dibrom compound is formed and iron is lost. When
the dibrom compound is hydrolysed hsemato porphyrin is formed
which is a dibasic acid of the formula :

/OH

XCOOH

Hematoporphyrin

The intermediate reaction is not known. When hematophyrin
is reduced by heating with'methyl alcoholic potassium hydroxide
in pyridine solution, hemoporphyrin C33H3604N4 is formed, which
on heating with soda lime forms aetioporphyrin C3iH36N4.
Willstatter thinks this is the mother substance from which both
chlorophyll and hematin are derived.

HC=CH

I I
CH3 — C-CEL ,G—C

\\ > N^ ||

C2H5-C-C/ //C~CH

CTT /~i ft/ \r^ r^ r\ u
2Xl5 ^ VA. ,\j \j — v>2Xl5

PTT /^ r1/ \r^ r< r^tr

v-*l.J.3 \j ^\ \~s v^ v^Xl3

CH3
Aetioporphyrin.

HC=CH

CH3— C-CH

COOH

CH3
HaBmoporphyrin.

332 CHEMICAL PHARMACOLOGY

The folto wing skeleton formulae has been suggested by Werner
to show the relationship between chlorophyll and haematin.

/C— — C

:N N(

XC
Chlorophyll Haematin

In addition to chlorophyll plants contain many other related
pigments such as carotin, the yellowish red pigment of carrots,
which is found with chlorophyll in many plants. It has the
molecular formula C^Hse- Xanthophyll C^HseC^ and carotin,
both neutral substances, are closely i elated and on reduction
xanthophyll can be converted into carotin. Tucoxanthin
C4oH54O6 isolated from brown algae has basic properties and forms
blue salts with HC1 and H2S04.

Besides the colors mentioned, there are yellow colors known
as flavones and xanthones as well as anthocyanin, which give
blue, red, and violet tints ; and many others, which have as yet
only a remote interest in the chemistry of drugs. Chlorophyll is
the only one that has been investigated in detail.

While chlorophyll and hemoglobin are related chemically,
their functions are quite dissimilar. The chief function of hemo-
globin is as a carrier of oxygen, while chlorophyll participates in
both metabolism and assimilation. Chlorophyll contains no
iron, while the main function of hemoglobin depends on this
element.

The following diagram shows the relationship of chlorophyll,
hemoglobin and bile pigment (after Mathews, p. 423) :

The great difference between plants and animals is that in the
plant, reduction and synthesis are the predominant chemical
processes, while in the animal, oxidation and hydrolysis predomi-
nate.

HEMOGLOBIN
I. II.

Hemoglobin

Globin Hematin

C32H32N403Fe(?)

Hematoporphyrin Bilirubin

333

III.

Chlorophyll

i
Phyllocyanin

Phylloporphyrin

C32H36N406(?) C32H36N406(?) C32H36N402

Biliverdin

C32H36N408

i
Urobilin

C32H40N407(?)

Hemopyrrols Hemopyrrols Hemopyrrols

C8H13N (etc.) C8H13N (etc.) C8H13N (etc.)

Hematic acids
C8H805C7H9N02 C8H9N04

The Fate of Chlorophyll in the Body

We known nothing definitely about the transformations of
chlorophyll in the alimentary tract. Neither chlorophyll nor
hsematin are absolutely essential in the diet, since the animal
body is apparently able to construct respiratory pigments from
the split products of protein. Those containing the pyrrol ring
are probably used in this synthesis.

Other Plant Colors

Litmus results from the fermentation of the CH-

lichens Rocella and Lecanora. These lichens con-
tain orcinol, partly free and partly as orsellic
acid and combinations. By special treatment
with ammonia and potassium carbonate, litmus
is formed. The concentrated salt mixed with Orcinol

334 CHEMICAL PHARMACOLOGY

chalk or gypsum, constitutes commercial litmus. Little is known
of the chemistry of this substance, which contains several colors,
azolitmin, erythrolitmin, and erythrolein. The first named is the
most important and is soluble in water, but insoluble in alcohol.
The others are insoluble in water and soluble in alcohol. When
orcinol is exposed to the air and ammonia it changes to orcein,
C28H24N2O7, which is a reddish brown amorphous powder, the
chief constituent of archil, which is also known as cudbear or
persio. It is sometimes used to color medicines.

Gurcumin, curcuma, Ci4Hi4O4 or tumeric is the coloring prin-
ciple in the root of curcuma longa. It dissolves in alkalies to
form brownish red salts.

Hemotoxylin Ci6H]406 + 3 H2O is the coloring matter of
logwood, sometimes used in medicine for its astringent effects.
It reduces Fehling's solution, dissolves in alkalies with a violet
color (and therefore may be used as an indicator). When fused
with KOH it yields pyrogallic acid and resorcinol.

Red saunders is the heart wood of pterocarpus santalinus.
When extracted with alcohol, it gives a red solution and is used to
color the compound tincture of lavender.

Coccus (cochineal) is the coloring matter of the cochineal bug.
Besides its use in pharmacy, it is particularly valuable in chemis-
try as an indicator and is employed especially in the titration of
ammonia and the carbonates.

Carmine is prepared by extracting the cochineal with water
and precipitating with alum and lime or cream of tartar.

Crocus or saffron is made of the stigmas of crocus sativa.

Caramel is partly burnt sugar.

Annato is the pulp surrounding the seeds of Bixa Orallana, a
South American Plant. Annato and saffron are also used to
color butter and oleomargarin.

Alkanet is the root of alkanna tinctoria. This is red with acids
and blue with alkalies.

Indicane C7H6NCOC6HiiO5 is a glucoside found in a number of
plants, as indigo fera anil
I. arrecta
I. tinctoria

I. summatrana and many other plants. When boiled
with a mineral acid, indicane breaks up into glucose and indoxyl.

INDICAN 335

.COH
C7H6NCOC6Hii05 = C6Hi2O6 + C6H/ _)CH

^NR/
Indican Indoxyl

When indoxyl is exposed to the air it is oxidized and gives a
deep blue coloring matter indigo

./co\

Indigo blue

It was formerly supposed that plant indican was identical with
urine indican the latter being so named, because of this supposed
identity. The two are not . identical, however, although both
may give rise to indoxyl; plant indican through hydrolysis, and
urinary indican by oxidation of indol.

.
Indol C6H/ CH is also formed in the intestine as the

result of putrefaction. It is oxidized most probably in the liver
to indoxyl and this is eliminated as the potassium sulphuric ester.
C(OS02OK)

/ \

G6H4v / CH. This ester is known as urine indican

\ / and on oxidation gives indigo blue and

XNH acid potassium sulphate.

XXX. COLLOIDS

In all reactions of chemical pharmacology, one of the reacting
bodies is a colloid. The word colloid was first applied to
bodies that had the properties of glue (Gr. kolla, glue; eidos,
appearance). More recent study has widened the original
scope of this word. Graham, in 1861, divided substances into
crystalloids and colloids, classifying them on the following
basis; those substances that would diffuse through an animal
membrane or parchment paper he called crystalloids, and those
that would not do so, colloids. Sodium chloride, sugar, alka-

336 CHEMICAL PHARMACOLOGY

loidal salts and the like are crystalloids, while gums, starches,
resins and proteins are colloids.

Besides the property of non-diffusion through membranes,
colloids are amorphous, viscous, and when sufficiently concen-
trated, form gels. The pseudo solution of the colloid to distin-
guish it from a true solution is called a sol. According to the
liquid in which the colloid is suspended (water, alcohol, etc.) the
sol is called hydrosol, alcosol, and the gel, hydrogel, alcogel.

Graham also found that under some conditions, non-colloidal
matter might become colloidal. He discovered that by adding
an excess of dilute hydrochloric acid to a dilute solution of sodium
silicate he obtained a clear solution instead of a precipitate of
silicic acid. When such a solution was dialyzed, the sodium chlor-
ide was washed out and the ordinarily insoluble silicic acid
remained in a colloidal condition. A similar method is used at
present to prepare colloidal iron.

Colloidal matter under some conditions can also be crystallized ;
hemoglobin and egg albumen have been obtained in crystalline
form. At the present time, therefore, the opinion is that the
colloidal condition is not entirely due to the kind of matter, but
also to the condition under which the matter is found, and the
size of the particles. In proper solvents, perhaps any form of
matter may be amorphous or crystalline. Even such a typical
crystalloid as sodium chloride in benzene may be colloidal, while
under other conditions the typical colloid, albumen, may be
crystalline. These extreme cases, however, should not minimize
the difference between crystalloids and colloids as they are found
in nature.

CHARACTER, OR NATURE, OF COLLOIDS

Enzymes are colloids, and the study of artificial enzymes has
done much to explain the nature of colloids. Bredig found that
if an electric spark produced by a current of 8-12 amperes at 30
to 40 volts is passed through pure water between two platinum
wire electrodes, the metal disintegrates and the water becomes
first, yellow, and then a brown or black color. The liquid filters
easily, no particles are visible under the microscope, and ap-
parently the platinum has gone into solution. The physical
constants, however, do not show a true solution. The freezing

COLLOIDS 337

point, boiling point, or osmotic pressure is but little changed,
whereas if an equivalent quantity of a salt is added, these constants
are definitely changed. Instead of being in true solution, the
platinum is in a pseudo solution or a state of extreme division
(dispersion) that may be seen by the aid of the ultra microscope.
The size of these particles has been estimated at 0.00001 milli-
metre. These particles in colloidal solutions are known as the
disperse phase of the colloidal solution. The water is the con-
tinuous phase. Gold, silver, copper, and other metals have been
prepared in pseudo solution. These solutions, when allowed to
stand, do not respond to the laws of gravitation; the solution is
rather permanent, due to the fact that the particles carry an
electric charge. The evidence to support the theory that the
particles are changed electrically is :

1. The method of preparation. The current that causes the
disintegration of the metal, and carries it into solution, would
probably remain on it.

2. The particles will wander in the stream if a current of electri-
city is led through the solution.

3. Electrolytes will precipitate colloids. This is well shown by
the action of Na2SO4 or MgSO4 on the colloidal iron, or by the
action of HC1 on colloidal arsenic sulphide and by the fact that
colloidal platinum can not be kept for any length of time if
electrolytes are present in the water.

4. Colloids of opposite electrical sign precipitate each other.
Practical application is made of this in the use of aluminum
cream A1(-OH)3 and colloidal iron, Fe(OH)3 to precipitate the
proteins of blood, in blood sugar determinations.

5. Non-electrolytes such as sugar will not precipitate colloids
in water solution. Alcohol, however, which is also a non-electro-
lyte will cause precipitation but this is due to a changed solvent.

The chief electro-negative colloids are arsenious sulphide,
antimony sulphide, gold, copper, and nearly all metals, as well as
most proteins, in neutral or slightly alkaline solution, lecithin
and phosphatides, the carbohydrates, gum, starch and glycogen,
and nucleic acid and soaps.

The electro-positive colloids are ferric hydrate, aluminum
hydrate, basic proteins, histones and protamines, proteins in acid
solution, and oxyhemoglobin.

338 CHEMICAL PHARMACOLOGY

Classification. — The colloidal solution of a metal like platinum
is vastly different in viscosity from a solution of gum or protein.
The classification of colloids, which is based mainly on this dif-
ference of viscosity of their solutions, is as follows :

1. Suspensoids, or inorganic.

2. Emulsoids, or organic.

As the names indicate, suspensoid colloids resemble a suspen-
sion of solid matter in a liquid, while emulsoids resemble emul-
sions. Colloids differ from simple suspensions or emulsions in
being charged electrically. The particles of colloid all bear the
same kind oi electricity, hence repel each other. This keeps them
in solution. The electrical charge also acts against the force of
gravity, and there is but little tendency to form a deposit or
precipitate until the charge is neutralized. Only inorganic col-
loids belong to the suspensoid class. They may be prepared first,
by the use of an appropriate electric current under water, or,
second, by the reduction of dilute solution of metals by reducing
agents such as formaldehyde, third, when hydrogen sulphide is
passed through a solution of arsenious acid, arsenic trisulphide
may remain in colloidal solution. Some other metals act in the
same way. Some of the suspensoid colloids are used in medicine.

Colloidal preparations of silver are used in medicine especially
in the treatment or prevention of gonococcus infections of the
eye and mucous membranes. Colloidal gold is employed as a
diagnostic aid in syphilis, tuberculosis, etc. Copper has been
advocated in the treatment of carcinoma, etc. Platinum, in
the form of platinum black, has been used to a considerable ex-
tent by laboratory workers. The chief suspensoid colloids are:

Fe.Ag.

colloidal metals — Cu.Au.
Pt.Al.

kaolin, antimony sulphide, arsenious sulphide.

DIFFERENCES BETWEEN THE SUSPENSOID AND EMULSOID

COLLOIDS

The emulsoid colloids make up the greater part of living ma-
terial. They are solutions of a liquid in a liquid ; in other words,
the disperse phase as well as the solution is liquid. This ac-

COLLOIDS 339

counts for their having a greater viscosity than suspensoids.
Solutions of liquids in liquids have no sharp boundary lines as
might be expected between solids and liquids, and they have
little, if any, electrical properties. When free from electrolytes,
they do not travel with the electric current, and are not as sus-
ceptible to electrolytes as suspensoids, which are precipitated by
traces of electrolytes. Emulsoids are precipitated only after
the addition of considerable quantities of electrolytes. Traces
of electrolytes seem to aid fluid solution, presumably by adding
their Qharge to the colloid.

Emulsoids are precipitated by suspensoids. Colloidal iron
has been used for this purpose to remove the blood proteins in
blood sugar analysis. The excess of the suspensoid is removed
at the same time by the addition of an electrolyte like MgSO4
or Na2S04. However, where there are large amounts of emul-
soid present, it forms a coating on the suspensoid particles and
prevents their complete precipitation by the electrolytes. This
is the chief objection to this method for blood-sugar work.

The difference between emulsoid and suspensoid colloids is
probably due to a difference in the affinity of the two substances
for the solvent. Suspensoids have practically no affinity for
the solvent, and readily fall out of solution when their electric
charges are, removed. Emulsoid colloids which are hydrophyUc
require an excess of the neutralizing salt to overcome the union'
of the colloid and the water. Such colloids are called hydro-
phyl because they have an affinity for water. This is strikingly
illustrated in the change of viscosity in water caused by a small
amount of colloid. A 1 per cent gelatine increases the viscosity
of water 29 per cent.

GEL FORMATION

In an ordinary solution of an emulsoid colloid, the solvent or
water is the continuous phase. It is possible to think of a small
body going through the solution, passing around the isolated or
dispersed particles as a ship would sail around small islands.
When these colloids gel, a molecular arrangement of the disperse
phase takes place, and a network is formed. The water now
appears to be the disperse phase, as it is enmeshed in a cellular
network of colloid. One could think of a body being able to
pass along the network from any portion of it to any other over

340 CHEMICAL PHARMACOLOGY

a continuous route. This netlike structure can be substantiated
by the use of the microscope.

When gelling occurs, the colloid acts more like a solid than a
liquid. Gelatin and agar-agar form gels readily, but on heating
they will liquefy, and again, on cooling, set or gel. Such sub-
stances are called reversible gels. Protoplasm, on heating, forms
an irreversible gel. If a gelatin or agar gel is allowed to stand
for some time, it contracts and some water is liberated. This proc-
ess of contraction with the liberation of liquid is called syneresis.
Blood, on clotting, may show the same phenomenon, which is
well known in the preparation of bacterial media also. This
phenomenon may be of great importance in pharmacology. The
water holding capacity of protoplasm is changed in a similar
way, and the diuresis following ,the administration of alkalies
and salts has been explained on such a basis. It is well known
that the water holding capacity of gelatin and fibrin is modified
enormously by the presence of salts.

LYOTROPE SERIES

Colloids, according to the affinity of the disperse phase for the
dispersing medium may be classified as lyophile, where there is
a marked affinity of the disperse phase and the medium and
lyophobe, where no such affinity is shown. When water is the
dispersing medium, the terms hydrophile and hydrophobe are
also used.

In the lyophobe series, which is synonymous with stfspensoid,
the physical properties of the sol are very little different from
those of the dispersing medium, while the physical properties
of the lyophile markedly change those of the medium. Much
greater concentrations of electrolytes are necessary to precipi-
tate the lyophile series of colloids. According to Pauli, both
ions of an electrolyte play a role in the precipitation of colloids.
While one ion precipitates, the other may have a solvent effect.
Cations as a rule act as precipitants, while anions are solvents,
the total action being the algebraic sum of these actions. From a
series of experiments, the relative efficiency of the ions in causing
precipitation, etc., has been arranged from the least to the most
effective. This series is known as the lyotropic series. The
following table shows the relative action of the various ions.

COLLOIDS 341

Rations — - Mg NH4 K Na Li
Anions

Fluoride + + +

Sulphate + + + + +

Phosphate.. + + +

Citrate + + +

Tartrate + + +

Acetate — — • + +

Chloride - + + +

Nitrate. - + +

The action of the ions in this series is so nearly the same se-
quence in many other reactions in which they can react only
indirectly that their action in most cases is thought to be on the
solvent or dispersing medium rather than on the colloid. The
sequence does not follow any chemical order as valence, atomic
weight, or the like; for example,

1. In the hydrolyses of esters by acids,
anions SO4< (H2O) < Cl< Br
kations H20< Li < Na<'K < Rb <Cs

In this case, SC>4 retards action, in all others the ions accelerate.

2. In the hydrolyses of esters by bases,
anions I > N03 > Br > Cl> H2O<S04
kations Cs> Rb > K > Li H20

It is seen here that the ions that accelerated the acid hydrolysis
retard basic hydrolysis.

3. The surface tension of aqueous solutions,
H2O < I < NO3<C1 < S04 <C03

All these ions increase surface tension. A similar influence is
exerted on viscosity.

ELECTRIC CONDITIONS OF COLLOIDS

As we have seen, there are various reasons for believing that
colloids are electrically charged: (1) they migrate in an electric
current; (2) oppositely charged colloids precipitate each other.

The proteins are amphoteric, but are more acid than basic.
The isoelectric point, i.e., the reaction in which they .will not
migrate in the electric current, is:

342 CHEMICAL PHARMACOLOGY

Serum albumin 4.7

serum globulin 5.4

casein 1 4.7

oxyhemoglobin 6 . 74

It may be that all colloids to some degree at least are amphoteric.

PROTECTIVE POWER OF COLLOIDS

The presence of colloids in a solution greatly lessens the action
of electrolytes. Suspensoid colloids are also protected by the
presence of emulsoid colloids of the same sign; suspensoids mixed
with emulsoids can be evaporated to dryness and the residue
redissolved in water. Without the emulsoid, the colloidal nature
of the suspensoid would.be destroyed. Colloidal mercury and
silver can be made more stable by admixture with emulsoid
colloids. This protective power is used in medicine to disguise or
lessen the taste of acid and bitter medicines. Solutions of gly-
cyrrhizae, acacia, etc., are used as vehicles because of this pro-
tective action on the nerves of taste.

CHANGE IN COLLOIDS IN GEL FORMATION AND PRECIPITATION

Just as there is no sharp line between crystalloids and colloids
so there is no sharp line between pharmaceutical emulsions and
emulsoid colloids. The emulsions of the pharmacist are, perhaps,
electrically charged to some extent, and this helps to hold them
in solution. The emulsifying agents used are usually gum
acacia or tragacanth which produce very viscous solutions which
settle very slowly. The magma of magnesia which is mainly
magnesium hydroxide resembles colloidal iron or iron hydrate.
Under a variety of conditions, all emulsions or emulsoid colloids
" crack" or precipitate. The cause of these changes may be:
(1) spontaneous; (2) heat or cold; (3) changes in the volume or
composition of the solvent; (4) the action of enzymes; (5) other
colloids; (6) electrolytes.

1. Spontaneous change. Just as any electrically charged
body may lose its charge and become neutral, so a colloidal solu-
tion after a time may crystallize, precipitate, or otherwise lose its
colloidal character.

SURFACE TENSION 343

2. Cold is especially liable to destroy pharmaceutical emul-
sions. Emulsoid colloids are also less stable on freezing. Heat
above the coagulative point of an emulsoid coagulates it. Heat
will also demagnetize iron.

3. The effect of changes in the volume of a solvent is well
illustrated when a dilute solution of gelatin or agar is evaporated
to a small volume. It gels. If the solution is changed by
adding alcohol, the gelatin or agar is precipitated, in the first
instance there is no intramolecular change other than the abstrac-
tion of water and when this is again added, the emulsoid character
is restored. In such a case, the change- is reversible. In the
second there is an intramolecular change aside from the changes
in the solvent and this change is irreversible.

4. The action of enzymes. The clotting of blood and the
curdling of milk are types of irreversible gel formation. The
mechanisms of these actions are not well understood, but are due
to an electrical neutralization of the colloids, in all probability.

5. Suspensoid colloids are especially susceptible to the action
of electrolytes. The action here is due to the neutralization of
the charges on the suspensoid by the electrolyte. Emulsoids are
but little influenced by small amounts of electrolytes, due to their
characteristics being less well defined, but are precipitated by
larger amounts of the salts. That the electrical charge of the
emulsoid plays some part in the precipitation is seen in the series
of effectiveness of the anions in the salting out of non-electrotytes.

SURFACE TENSION

A substance in a gaseous state tends to increase its volume,
while substances in the liquid state tend to contract into the
smallest volume, or volume with the least surface area. The
surface in this condition, in all liquids behaves as if stretched.
This stretch or pull on the surface film is the result of unbalanced
molecular forces. In any liquid the molecules have a definite
attraction for each other. This attraction has been estimated at
10,000 to 25,000 atmospheres. A molecule in the center is sub-
ject to the same force from all sides, and consequently there is
no movement one way or the other. Below the surface layer,
the molecules exert an attraction for those above them in the
surface layer, while those on the top are, not attracted by the

344 CHEMICAL PHARMACOLOGY

atmospheric gases, and bend or curve in the direction of the pull
from within, hence tend to assume the spherical form. The
thickness of this film, or the range of the molecular attraction
has been estimated at about 6 X 10~8 millimetres.

This stretch or pull on the surface layer interferes with the
movements of the molecules, and for this reason confers on the
liquid some of the properties of a solid, since in the solid state,
freedom of movement in the molecules is limited. Various meth-
ods have been devised to measure surface tension, the most
practical being the following. The average weight of a drop of
the fluid falling from a standardized pipette or stalagmometer is
taken. The surface tension of water is considered as unity, and
that of any other fluid, like blood or serum, is calculated by di-
viding the weight of the liquid by the number of drops, and com-
paring this with water under the same conditions.

Surface tension of liquid = sp. gravity of solution multiplied

by number of drops of water

number of drops of solution

There are other methods, more accurate and correspondingly
more complicated than this one. The above formula gives the
surface tension in relation to water. Since water has a tension
of 73 ergs, per square centimeter, the formula, to read in ergs.,
should be :

no. of drops of water X density of liquid

— 7-.— — p — rr - X 73 dynes

number of drops of liquid

The surface tension of liquids in dynes per centimeter is

water 73

alcohol.- 22

ether 16

Surface tension undoubtedly plays an important role in many
biological reactions. In phagocytosis or the taking up of bac-
teria by cells, substances (toxins?) which change the surface
tension modify the phagocytic power. The dumping of bacteria
and opsonic index, shows a change in the surface tension of bac-
teria; similarly anesthesia may in the last analysis be due to
changes in surface tension.

VISCOSITY 345

The following experiment by Rhumbler (Arch. Entwichlungs-
mech, 1898 (VII), 249) is interesting in this regard:

If one tries to pierce a drop of chloroform under water with a
fine glass rod, it is very difficult or impossible. If now the rod
be coated with shellac it is sucked into the chloroform. The
shellac in this case changes the surface tension in a manner
similar to the changes that may occur in bacteria by toxins
or between nervous and muscular tissue by an anesthetic.

VISCOSITY AND SURFACE TENSION

The distinctive character of solids is that the relative position
of the molecules is fixed and can not be changed except by the
expenditure of a relatively great force. The characteristic of a
liquid is its tendency to flow. The molecules can be moved with
relative ease; in gases, the fluidity is much greater than in liquids.
In liquids, although the particles move relatively easily, the
fluidity is not perfect. The particles adhere to each other so
that when a thread of the liquid moves, it drags some of the other
particles with it, and is in turn held back by them. There is
thus a movement of the different layers past each other in the
direction of the flow. This shearing, or internal friction, or
property of the particles to adhere to each other, is viscosity.
It is exerted only during movement. Ether, water, oils, balsams
and waxes are examples of fluids possessing progressively greater
viscosity.

The suspensoid colloids, which are solid particles suspended
in a liquid, have little intimate relation with the liquid in which
they are suspended, and hence have little viscosity, while the
emulsoid colloids, which are liquids in liquids, have the properties
of liquids, and thus a greater viscosity than the suspensoids.

Surface tension is a surface phenomenon only. It is due to
the attraction or pull of the molecules on each other; it is exerted
at all times, but is only manifest at the boundary surfaces of
liquids, because here the balance of force is upset. The force
of attraction of the molecules of a fluid for each other is exerted
at a very short range only — about 6 X 10~8 millimetre. All
molecules in a liquid this distance below the surface will be
attracted with an equal force in all directions but the layers of
molecules in the surface fluid will be attracted only by those

346

CHEMICAL PHARMACOLOGY

below, without a balanced pull from above. Hence they will
tend to pack together and assume the spherical form, since
potential energy always tends to become a minimum. The sur-
face, therefore, contracts as much as the conditions will allow.
The strength of the pull of the molecules on each other will de-
pend entirely on the kind or chemistry of the molecule. In the
case of viscosity, this depends more on the physical state of the
molecules.

The tendency of liquids to assume this spherical form can be
shown :

1. In Hammerschlag's method of determining the specific
gravity of the blood; mix benzene and chloroform until it is of the
same specific gravity as the blood. Then place a drop of blood
in the mixture and the blood will assume a spherical form.

2. Alcohol and water is made to the same density as olive oil.
Drops of olive oil in this will neither rise nor sink, but will
assume a globular form.

3. If conditions are imposed so that the liquid can not assume
the spherical form, it will assume the smallest surface area that
conditions will permit, as Van der Mensbrugge's experiment
shows: "A loop of fine silk is taken and tied to a wire ring. If the
whole be dipped into soap solution, so as to produce a film, the
loop floats in the film; the silk thread forming its boundary is
quite loose, and can be readily moved into any shape by means of

FIG. 2. — Mensbrugge's Experiment.

a fine needle wetted with the soap solution. (A) The film inside
the loop is now broken by touching it with a bit of filter paper cut

SURFACE TENSION 347

to a fine point. The loop is immediately drawn to a circular
form by the tension of the film surrounding it, and can be felt to
resist attempts to change its shape by the needle. (B) The
soap solution should be prepared by the method of Boys (1912,
p. 170), from pure sodium oleate, with the addition of about 25
per cent, of glycerol."

Substances that lower the surface tension always collect on the
surface. They are never uniformly distributed through the
liquid ; float two small pieces of wood parallel to each other and a
few millimetres apart. Now let a drop of alcohol fall between
them. They will suddenly fly apart. The reason for this is that
the surface tension of alcohol is less than that of water, and the
drop of alcohol weakens the surface tension film between the
small pieces of wood so that it breaks and they fly apart. In
the same way, a film of water on a glass slide breaks when a drop
of alcohol or ether is added. Camphor placed on water darts
about over the surface, because it lowers the surface tension
unequally at different points and the rupture of the surface film
causes it to move.

Superficial Viscosity. — This is different from, and independ-
ent of surface tension, which, as we have said, is a constant stress
at the boundary of liquids. Surface viscosity is a sort of surface
friction which is manifest only when there is something to disturb
or rupture the film. If a liquid assumes a globular form, it is due
to surface tension, independent of viscosity. Pure water has a
large .surface tension, but no viscosity. It will not foam on
shaking. A solution of saponin has a marked superficial vis-
cosity, but no marked surface tension above that of water. A
magnetic needle placed on the surface of the saponin solution,
because of the viscosity is not changed in position by the earth's
magnetic directive force, while it will be changed in a water
solution. A saponin solution foams on shaking superficial
viscosity holding the bubble together while the surface tension is
tending to break it. Oil has a small surface tension but a large
surface viscosity.

RELATION OF COMPOSITION TO SURFACE TENSION

The surface tension of a liquid decreases with the rise of tem-
perature; hence comparisons should only be made of liquids at

348 CHEMICAL PHARMACOLOGY

the same temperature. As might be expected, the surface tension
varies enormously with composition, but no definite rule can be
made, nor from chemical composition can predictions of surface
tension be made with certainty. In a homologous series like the
paraffin series, increase in CH2 does not appreciably change sur-
face tension. Water has a surface tension of 73 dynes, alcohol
= 22, and ether =16. Here it would seem that the introduction
of C2H5 decreases surface tension. Isomeric compounds have the
same surface tension only when they have similar constitutions.

Salts increase the surface tension of water, as do. gum arable,
starch and plum gum. On the other hand, gelatin glue, egg
albumen, dextrin, cherry gum, and traces of fatty acids, soaps,
bile acids, tannic acid and resins lower it.

Since the same chemical substance may be a suspensoid in one
dispei sion medium and an emulsoid in another, we find that the
same substance may lower surface tension in water and raise it in
alcohol, and vice versa. Thus the dye, Night Blue, lowers the
surface tension of water and raises it for alcohol.

RELATION OF COMPOSITION TO VISCOSITY

As a rule, viscosity or internal friction increases with molecular
weight. An iso c6mpound always has a larger coefficient of
viscosity than the normal compound. In many cases, the mole-
cular viscosity can be calculated from known viscosity constants.
Thus the viscosity constant of

H = 44.5

C = 31.0

hydroxylO =166.0

carbonyl O =198.0
Cl in monochlorides = 256 . 0

I in monoiodides = 374 . 0

Double linkage = 48 . 0

Ring grouping = 244 . 0

There is a relation between chemical constitution and viscosity,
although water and alcohol present exceptions to any relation yet
discovered. In suspensoids. the viscosity is little different from the
water-dispersing medium. There is also little chemical union
here, it being merely a physical suspension. Colloids, however,

ADSORPTION 349

show a marked viscosity, which depends upon the amount of the
colloid. One per cent, gelatine increases the viscosity of water
29 per cent.

ADSORPTION

Adsorption is the term applied to surface absorption. This
process has long been used by chemists to clarify liquids, especi-
ally for polariscopic work. If a solution contains color, or is
otherwise opaque, it has been the custom to add powdered char-
coal, shake, and filter the solution. The coloring material in
most cases adheres to the surface of the particles of charcoal.

Filter paper also adsorbs certain colloids. If a piece of filter
paper is dipped into a solution of Congo red, it soon accumulates
enough of the dye on the surface so that the solution becomes
visibly lighter in color. Fuller's earth and kaolin also absorb
coloring matter and alkaloids in the same way. Bunsen recom-
mended freshly precipitated ferric hydroxide as an antidote in
arsenic poisoning. He thought that a compound of basic ferric
arsenite was formed; 4Fe2C>3, As20s, 5H2O. Recent work shows
that this is an adsorption compound.

Charcoal condenses and absorbs gases, and for this reason has
been used in treatment of gas accumulation in the stomach and
intest.ines. The gas is adsorbed. Similarly, palladium and
platinum adsorbs hydrogen. In the gas chain method of deter-
mining hydrogen ion concentration, spongy platinum holds so
much hydrogen that it acts as an hydrogen electrode.

Selective Adsorption. — Colloidal materials in many cases, for
unknown reasons, exert a selective adsorption. Sea weeds, for
example, select iodine from the sea water out of all proportion to
the amount present. In the same way, plants take up potassium
as compared with sodium. Adsorption in all these cases may be
preliminary to chemical combination or chemical action; similar
to the adsorption of pepsin by fibrin. If a thread of fibrin is
introduced into a solution of pepsin, most of the ferment is soon
adsorbed by the fibrin.

Influence of Salts on Absorption. — Salts seem to have a marked
influence in some cases. Bone black does not absorb diptheria
toxin in water, but it is readily absorbed from saline or Ringer's
solution. Bone black adsorbs sugar in neutral solution, but not
when acicjified with acetic acid.

350 CHEMICAL PHARMACOLOGY

The explanation of adsorption is not easy. It is a surface
phenomenon, and is increased by increase of surface. In colloidal
solutions, the surface is enormous. It has been calculated that
in a red colloidal solution of gold containing 0.5 grams of gold in
a liter, the surface amounts to 8 square meters. Although col-
loidal solutions of the same sign may adsorb each other as in the
case of Congo red and filter paper, the kind of electric charge on
the solid does influence adsorption. When colloids of the same
sign are adsorbed, it may be that they are amphoteric.

Acid dyes are in general adsorbed by electro positive colloids
like clay and colloidal iron, while basic dyes are adsorbed by
electronegative colloids like kaolin, sulphur, charcoal, silk, cotton,
etc.

XXXI. THE REACTION OF LIVING MATTER

Living matter is alkaline in reaction, but becomes acid after
death. To determine the reaction during life therefore, it is
necessary to use an indicator that will act in the living body with-
out killing it. Such indicators are neutral red and cyanamine,
the former being an orange red color in alkaline reaction and
pink in acids. Cyanamine is red in alkaline and blue in acids.
Acid fuchsin does not stain alkaline protoplasm, but stains it
red when the protein reacts acid. When the circulation stops,
protoplasm becomes acid. This may be shown in the following
experiment: Inject a frog with a solution of acid fuchsin. After
it has penetrated all the tissues, tie off the circulation of one leg,
and stimulate the muscles of this leg. On removal of the skin
from the muscles on the ligated side, it will be found that they
have become red due to acid formation. It is known that lactic
acid develops during muscular contraction, in the absence of
sufficient oxygen.

In order to determine the reaction of tissues by the use of a
stain, several conditions must be fulfilled: (1) The stain must
penetrate the tissue fluids. (2) It must not kill the tissues,
since the reaction changes after death. (3) Since the tissues
have oxidation and reduction properties, the stain must not be
influenced by the oxidation and reduction processes of the body.

The alkaline reaction of the body is due to excess of OH
ions. Acid reaction is due to H ions. The concentration of

REACTION OF LIVING MATTER 351

these ions present in the body fluids may be determined by a
number of methods.

1. The Colorimetric Method. — Solutions of acids of known
strength in which complete ionization has taken place, or where
the degree of ionization is known, in terms of a normal solution,
are colored by some indicators in intensity directly as the con-
centration of the ions. This being the case, one may determine
the hydrogen ion concentration of a solution by comparing it,
when treated with an indicator, with the color solutions produced
by the same indicator in solutions of known hydrogen ion con-
centration. This is most easily done by using tubes of the same
bore, and containing the same amount of fluid as the control
and the same amount of indicator by using a series of tubes of
known but varying PH concentrations as controls the unknown
concentration can be found by matching its color with a control
tube. ' Such control tubes sealed and with different PH values can
be obtained, sealed from Hynson Westcott and Co., Baltimore.

2. Electro Potential Method or Gas Chain Method. — When
a metal is dipped in a solution of one of its salts an electromotive
force is set up at the surface of contact. The voltage developed
depends on the strength of the salt solution. These electrode
potentials are susceptible of direct measurement, consequently,
two solutions of different concentration having the same ions in
common have different electrical potentials. When such1 solu-
tions are connected by a conductor, a current flows from the
stronger toward the weaker. The strength of this current
depends upon the relative concentration of the two solutions.
In the case of an acid it is in direct ratio of the hydrogen ions.
It has been found that a ten fold difference in the ionic concen-
tration of solutions with common ions is equal to a voltage of 58
millivolts. Since the logarithm of 10 is 1, the factor obtained by
dividing the voltage by .058 will give the logarithm of the dilu-
tion. To determine the hydrogen ion concentration of blood or
other fluid by this method therefore the difference in the concen-
tration of a known solution as compared with the concentration
of H ions in the blood may be represented by the formula;

e = K log Cone. Hi/Cone. H2
Where e = the difference in the potential determined by

352 CHEMICAL PHARMACOLOGY

measurement. K = .058 volts when common logarithms are

E.M.F.

used, consequently ' ' is equal the number of ten-fold

dilutions or PH.

In an actual determination of PH there are many technical
difficulties to be observed and overcome. While every ten-fold
dilution makes a difference in potential of 58 millivolts an actual
determination if made in a chain consisting of —

HHC1 n/10|HCl n/100|H would show only 0.019 volts.
This is due to a contact potential at the junction of the acid
solutions developed by the difference in speed of H. and Cl ions
and which acts in opposition to the electrode potentials. To
obviate this error, a neutral conducting solution is placed between
the acid solutions. Such a solution is KC1. The ions of this
solution have about the same speed, but in opposite directions,
consequently neutralize the effect of each other. When such
a chain is connected we get a voltage of 0.058 at 20°C.

H|HC1 n/10|KCl|HCl n/100|H

Again in actual practice instead of using two hydrogen electrodes,
as in the above, a standard calomel electrode is used for the known
solution. The normal calomel electrode has a voltage of 280
millivolts above the normal hydrogen electrode. Consequently
the electromotive force E, developed by this when assembled
with an unknown hydrogen cell (C) would be:

E = 0.280 - .058 log C or
E - 0.280 . 0 . 1 _
0.058 • ~logC =1°gc = PH'

If a normal tenth normal calomel electrode be used it has a volt-
age of .337 above the normal hydrogen electrode, consequently
0.337 is used instead of 0.280 in the above formula.

, METHOD OF EXPRESSING HYDROGEN ION CONCENTRATION

. The hydrogen ion concentration of body fluids is very close
to that of water. It would be cumbersome to express frequently
a dilution of one molecule of dissociated H . in ten million litres of
water by 0.000.000.1. In biologic work we have to deal mainly
with such dilutions. The adoption of a more convenient method
of expression is therefore advisable.

HYDKOGEN ION CONCENTRATION 353

Since the ionization constant of water is H times OH = 10~14
or H = 10~7 and OH = 10~7, and since the factor 10~14 is always
constant, when H increases, OH decreases.

Thus if H = 10-1, OH = 10~13, and theoretically if H = 10°
OH = 10-14=1 gram molecule OH in 10.000.000.000.000 litres.
The older methods of expressing H ion concentration retained the
constant 10~7 and until recently the acidity or alkalinity of body
fluids was expressed:

2 times. 10~7

1 times 10~7

or 0 . 5 times 10~7 etc.

Following the suggestion of Sorensen it is customary to express
the reaction by the reciprocal or cologarithm of the number.
In reality this is the logarithm of the dilution in terms of normal
solution. Thus potential of H when H = 10~7 is expressed
PH = 7, and H = 1Q-10, PH = 10. This method of expression
is brief but confusing until one gets accustomed to translating the
numbers, and knowing that the greater the value of PH the lesser
the acidity, and thinking in terms of logarithms and remembering
that PHi PH2 PH3 etc. differ by powers of 10.
Thus:

PHi = n/10 acid or PH - 1

PH2 = n/100 acid PH = 2

PH8 = n/1000 acid PH = 3

PH6 = n/1,000,000 acid PH = 6
PH8 = n/1,000,000 alkali PH = 8
PBii = n/1000 alkali PH = 11

PH12 = n/100 alkali PH = 12

PHi3 = n/10 alkali PH = 13

PH14 = n/1 alkali PH = 14

Since the numbers refer to negative logarithms the higher the
number the fewer H ions in a given volume, while the OH ions
increase. This is quite comprehensible when we recall that H
times OH is always 14 or 10~14. If PH is 14, it follows that OH
must be O and if PHi is N/10 acid P(OH)! must be N/10 alkali.
Some confusion may also raise in translating such expressions
as PH = 2 X 10~6 into the more modern figures. One readily
sees that in terms of normal solution 2 X 10~6 is twice as strong

354 CHEMICAL PHARMACOLOGY

as 10-6 but that PH = 5.70 (Log. 2 = - 0.3 hence 6-0.3 =
5.70) = n/500.000, is not so obvious.
Similarity :

0.35 X 10~7 = n/28.580.000 or PH = 7.45
0.91 X 10-1 = PHx= 1.04

0.98 X 10-3 = PH = 3.01

Since normal metabolism and therefore, normal health, depend
on the maintenance of the normal alkalinity, pharmacology is
concerned with the regulating mechanisms and the changes in
the alkalinity that may be produced by drugs.

REGULATING MECHANISM

The blood always contains a mixture of C02, NaHCO3, NaH2-
PO4 and Na?HPO4. All of these dissociate so weakly and
normally occur in such quantities that the reaction is constantly
kept close to PH = 7.2. The normal ratio of NaH2PO4 : Na2-
HP04 is stated by Michaelis and Garmendia to be 1 : 5.1
molecules. If these were the only salts present in a solution of
water in the proportion of Ice. n/10 NaH2P04 and 2.5 cc. n/10
Na2HPO4 we would have a PH of 7.0. The carbonates modify
this to the PH found in the blood. .While the salts which main-
tain the normal PH are fairly well known the reason why these
salts are found in the necessary concentrations is not known. It
should be emphasized that there is a wide margin of safety within
which they may vary without materially changing the PH. For
example if m/3 solutions of Na2HP04 and NaH2P04 are mixed in
the following amounts PH =

Na2HP04 NaH2P04 PH =

Ice. 32 cc. 5.11

1 16 5.42

1 - 1 6.62

2 , 1 6.92
4 1 7.22
8 1 7.52

16 1 7.82

32 1 8.12

BUFFER VALUE 355

The lungs and the kidneys play an important part in the regu-
lation of the H ion concentration, e.g., CO2 is excreted by the
lungs. It is continuously formed in digestion. Alkaline salts
are constantly taken in the foods, especially vegetable foods.
NH3 is formed from the digestion of proteins. Acid salts are
formed and these act as diuretics. Hence, under normal con-
ditions formation and excretion take place at such pace that the
body holds a reserve or potential alkalinity.

It is thus possible to give an account of the mechanism as it
exists or to state reactions as they probably occur. The basic
cause, or why, is still beyond the scope of science.

Under some conditions this mechanism fails and acidosis
develops. A knowledge of the normal mechanism enables us to
modify and treat the acidosis. The importance of this may be
realized since it has been shown by Henderson and Palmer that
the acid formation in the human organism corresponds to be-
tween 600 and 700 cc. n/1 acid solution daily.

ACTUAL AND POTENTIAL ALKALINITY AND BUFFER VALUE

Sodium bicarbonate reacts slightly alkaline to litmus. This
alkaline reaction is explained by the fact that in water we have
H and OH ions. When NaHC03 is dissolved in water we also get
Na, H, OH and CO3 ions. Consequently there will be a shifting of

the balance. Since the constant of carbonic acid, — TT <^r\ -- ig

Jbl2LAJ3

, Na times OH . . , .

very small and the constant of -- r -- is large, the carbonic

acid will be suppressed and the constant of NaOH will tend to
be established. This full constant cannot be reached because

, , AT vnr. . .... , Na X H X C03 v

the NaHC03 also has a constant -- AT ^^^ - = K and in

NaHCO3

this case only a certain number of Na + ions can remain in the ionic
state in the presence of NaHC03. The whole solution, therefore,
strikes a balance at a strength which reacts slightly alkaline to
litmus. This balance point is known as the actual alkalinity of
the solution. This is the PH of the solution as represented by
the colorimetric or gas; chain method.

If we titrate a solution of sodium bicarbonate with an acid,
the acid removes the OH ions, but when these are removed,

356 CHEMICAL PHAKMACOLOGY

others are formed from the bicarbonate which will keep forming
OH ions in the attempt to form the balance until the whole is
neutralized by the acid, in the following way.

NaOH

Na times OH ~

This titratable alkalinity is known as the total or potential
alkalinity.

POTENTIAL ALKALINITY OF BLOOD

The weak alkaline condition of the blood is guaranteed by a
mixture of H2CO3, NaHCO3, NaH2PO4. These (buffers) are all
very weakly dissociating substances and may be considered in
the blood in a balanced state.

NaHCO3 " * N2H P04 "

Where K and K2 are constants, and the sum of these constants
in terms of H ions is about PH 7.1 to 7.8

H2C03 _
NaHCO3 ~

If acid be added to this directly or indirectly, as in cases of acido-
sis, it liberates H2C03. This will either break into CO2 and H2O,
and K kept constant; or it will tend to act with Na2C03 if such
be present and restore the constant in that way. If enough acid
be added or developed, the whole alkali reserve may be exhausted.
The phosphates are balanced in the same way. According to
Michaelis and Garmendia, the ratio of

NaH2P04 1 _, - .
-^ H pQ = g-j Molecules.

Since the normal blood always contains C02, NaHC03 and
Na2 HPO4 in this balanced state, the H ion concentration at any
one time cannot be determined, by titration, because as fast as
the actual alkalinity is removed, the potential alkalinity is con-
verted into actual. Consequently, the titration alkalinity is the
sum of actual and potential.

This difference between the actual and total alkalinity of the
blood, is known as the "buffer" value, and NaHC03 and Na2-
HPO4 are the buffers, NaHCO3 especially. The value of this
buffer is illustrated by comparing the effect of acid added to a
liter of water, and to a liter of NaHC03. The reaction of a solu-

BUFFERS 357

tion of pure NaHC03 is very weakly alkaline. Water is neutral.
A drop of acid added to a liter of water will definitely acidify it.
When added to a solution of NaHCO3, however, it will not change
the actual alkalinity, and will not exceed the acidity of CO2 until
all of the NaHCO3 has been decomposed. The amount of acid
required to do this will depdnd on the amount of the NaHC03 in
solution, in other words on the buffer value of the solution. The
carbonates are the chief biologic buffers, and the constant in
blood plasma of

^^ - 1/20
NaHC03 "

Now PH, or CH as it is sometimes given, is directly proportional
to this ratio. And any condition in which the ratio of these in
the plasma is greater than %Q may be looked on as an acidosis.
Since CO2 is the principal reagent used by the organism to
regulate the reaction, it is evident that H ion concentration and
CO2 concentration run parallel. Hence knowing the one we can
calculate the other. Hasselbach (Biochemische Zeitschrift, 1912,
vol. 46, p. 403) thinks that the hydrogen ion concentration is the
real stimulus of the respiration rather than CO2. However,
while many accept the view that C02acts because of the hydrogen
ion concentration of its solutions, the question of a specific
action of molecular CO2 has not been satisfactorily answered.

ACIDOSIS

By acidosis is meant the poisoning of the organism with acids,
due directly to neutralization or depletion of the alkaline reserve
or potential alkalinity. A better term would be hypoalkalinity.
Acute poisoning by acids due to corrosion or local action of acids
does not come under the term acidosis. Most cases are due to
faulty metabolism, and in such cases oxybutyric acid, diacetic
acid, lactic acid and acetone are formed and may be found in the
urine. Acidosis occurs especially in diabetes when as much as
250 grams of acetone bodies may be produced in a day. The
normal excretion in adults is from 3 to 15 milligrams per day.
Until quite recently (1907) diabetes was the only disease in which
acidosis was known to occur. We now know that it is present
also in certain nephritic cases, in cholera, in certain intoxications
in children, starvation, phosphorus poisoning, etc. It often

358 CHEMICAL PHARMACOLOGY

happens that these acetone bodies are present in the urine when
there is no symptoms of acidosis. The presence of acetone
bodies in the urine develops after the reserve alkalies or buffers
have been somewhat depleted. This form of acidosis is called
a ketosis or poisoning by ketone. No special names are given
to the other acidoses. This depletion may also be caused by the
introduction of weak acids into the body either by mouth or
parenterally, and this method of pioducing the symptoms is
largely responsible for the term acidosis.

The symptoms of acidosis are mainly those of asphyxia, labored
respiration, air hunger, cyanosis, coma, and convulsions. Death
is due to respiratory paralysis. These occur before the blood at-
tains an acid reaction. It requires three hundred times as much
acid to render blood acid, as it does to acidify water. This is
because of the potential alkalinity or buffer value, due to the
proteins, carbonates and phosphates in the blood which neutralize
acids. The treatment of acidosis is the administration of sodium
carbonate, and even in the last stages this is often effective.

In uremia and diabetes, the acidosis may reach a degree suffi-
cient to produce coma. Fasting, high fat diet, arsenical and
phosphorus poisoning, and heavy metals may cause an increase
in the H ion content of the blood, but not sufficient to produce
coma.

Why depletion of the alkaline reserve should cause death while
the blood is still alkaline is like many other whys — hard to answer.
We know, however, that certain conditions are necessary for life.
These are the presence of certain essential chemical elements and
in addition a balance of these elements. Loeb has shown that
the ova of fish living in sea water, die in an isotonic, solution of
sodium chloride sooner than they do in distilled water. In this
case the poisonous action of the sodium can be neutralized by
traces of calcium. A similar, but perhaps more complex, reaction
occurs in the human body when the alkaline reserve is depleted,
i.e., after abnormal loss of the Na+, K+, Mg++, and other
positive ions. When the balance is destroyed other elements
like potassium, or hydrogen act more as poisons.

Acidosis is a problem still under investigation and for a clear
statement of the problem, the student is referred to the little
book by Sellards, Harvard University Press — 1917.

ACIDOSIS 359

THE DETERMINATION OF THE EXISTENCE OF ACIDOSIS

Formerly the presence of acetone bodies in the urine, was the
only diagnostic test used. This, however, is a relatively late
sign, and in order to be of much value an earlier indication is
needed. It was thought, therefore, that in the development of
acidosis the blood would become less alkaline, and attempts were
made to titrate the blood with a standard acid. But while this
method is theoretically sound, it has been found unsatisfactory
for several reasons: (1) It is hard to remove the coloring matter
of the blood to allow a satisfactory titration; (2) large volumes
of blood are required ; (3) the proteins of the blood interfere with
acid titration; and the " buffers" in normal cases vary to a
greater degree than the possible range of a true acidosis. Acidosis
is a question of the tissues, hence the blood may not be a true
indication of the body state as a whole.

The methods now used to detect acidosis are:

1. Increased tolerance to sodium bicarbonate.

2. Urinary changes:

(a) Increased acidity and acetone bodies. (6) Increase in
ammonia, (c) Changes in the fixed bases.

3. Lowered tension of carbon dioxide in the respired air.

4. Lowered carbon dioxide content of blood = lessened amount
of carbonate in the blood.

5. Lowered alkalinity of the blood = increased hydrogen ion
concentration.

1. Tolerance to Carbonate. — The normal individual cannot
take more than 5 grams of sodium bicarbonate a day without the
urine becoming alkaline. In case of acidosis the sodium bicar-
bonate is apparently depleted. The tissues absorb and retain
as much as 100 grams per day before the urine becomes alkaline.
It has been proven in these cases that the retention is not due
to defective kidney function.

2. Urinary Changes. — (a) Increased acidity and acetone
bodies. Acetone bodies indicate mainly disturbance of carbohy-
drate metabolism and may have no reference to acidosis. Again
acidosis may develop in diabetes without the presence of acetone
bodies in the urine.

(6) Increase in ammonia. When the fixed bases of the body

360 CHEMICAL PHARMACOLOGY

are used to neutralize the acids formed in acidosis there is some
break-down of protein with the formation of ammonia to aid in
the neutralization and to make up the alkaline deficit. It was
therefore thought that the free ammonia excretion in the urine
would be a measure of the acidosis. But in primary disturbances
of protein metabolism the ammonia coefficient may be high, and
it may be low in acidosis. This may be because ammonia in
some cases is converted into stable salts and in other cases urea
may be decomposed yielding ammonia.

(c) Change in the fixed bases of the urine, sodium, calcium,
magnesium and potassium are somewhat used to neutralize the
acids formed in acidosis. The excretion of these, therefore, in
the urine may be increased. Since, however, it is the depletion
of these in the tissues that gives rise to the symptoms of acidosis,
their amount in the urine may be lower, at the height of the
attack. The determination of these bases, therefore, to be of
value must extend over a number of days. Since the determina-
tion is tedious and time consuming it is little used.

3. Lowered Tension of Carbon Dioxide in the Respired Air.
The normal venous blood carbon dioxide exists under a tension of
about 6 per cent. (42.6 mms. Hg.) practically 40-50 millimeters.
An extreme fall of the carbon dioxide is virtually pathognomic
of acidosis. In four cases of uremia Sellards found 10 to 24 mms.

The CO2 content of the alveolar air is practically the same as
that of the venous blood 37.6 mm.: 42.6 mm. Hg. and more
closely approaches the content of the arterial blood. For this
reason, analysis of the respired air has been used to aid in the
diagnosis. The principle is based on the fact that alkaline
solutions absorb COa in proportion to the strength of the solution.
The reaction does not go on to completion and is reversible.

2 NaHCOs <=* Na2C03 + H20 + CO2
or expressed in another form —

= a constant (about 1/20). (Isolated plasma only)

Since H2CO3— »H2O + C02, and the CO2 readily penetrates the
alveolar tissue, a measure of the CO2 in the alveolar air, is prac-
tically a measure of the buffer value of the blood.

4. Carbon Dioxide Capacity of the Plasma (alkali reserve).
Method of Van Slyke and Cullen — Principle*— The plasma from

PHOSPHORUS 361

oxalated blood is shaken in a separatory funnel filled with a CCV
air mixture approximating the composition of the alveolar air
which has a CO2 tension equivalent to that of arterial blood. In
this way the sample of blood plasma combines with as much
CO2 as it is able to hold under normal tension. A measured
quantity of this saturated plasma is then acidified within a
special pipette, and its CO2 is liberated by the production of a
partial vacuum. The liberated CO2 is then measured under
atmospheric pressure and the volume corresponding to 100 cc.
of plasma calculated.

This method is the most useful clinically because of the ease
with which it can be carried out and because it directly measures
the alkali reserve of the blood under conditions simulating the
conditions in the body.

The H ion concentration of the blood varies so little that it
is of less value in the diagnosis of acidosis than the measurement
of the alkali reserve.1

XXXII. PHOSPHORUS

There are two forms of phosphorus, yellow and red or amor-
phous. The red .form is not used in medicine, being inert. The
yellow is the medicinal variety and it is In the metallic state. It
appears as a translucent, nearly colorless solid, of a waxy lustre,
with the consistency of beeswax.

Phosphorus is very slightly soluble in water, and its solubility
in alcohol is 1 :350; it is easily oxidized and burns when exposed to
the, air. On this, acount, it should be cut and handled under water.

In the body it is rather insoluble, and is active only in the finely
divided metallic, state. A large mass may pass through the
body unchanged, but in the finely-divided state or in solution
in oil, it is readily absorbed and highly toxic, 0.05 to 0.1 gram has
proved fatal to man.

Phosphorus exists in the blood as such and- its actions are due
to the element and not to the oxygen or hydrogen compounds.
As soon as it is oxidized, it loses its specific action. The chief
toxic action is to cause fatty degeneration in various organs.
In therapeutic doses, it is used to stimulate bone formation and
growth.

This substance resembles arsenic in many of its reactions.
For details, see Hawk's Physiological Chemistry, 6 Edition, p. 325.

362 CHEMICAL PHAEMACOLOGY

PH3, or phosphine, corresponds to AsH3, or arsine. PH3 has
basic characters like NH3 and unites with acids to form salts
of the general formula PH4X (phosphonium) . These salts are very
weak and are decomposed by water into PH3 and HX. Arsine,
AsH3, and stibine, SbH3, do not possess this basic property.
The H atoms in phosphine c'an be replaced by alkyl groups to
form

H~D ~D

/rt /\\

— H or R— R or P— R or

mono dialkyl tertiary quaternary

alkyl phosphine alkyl phosphoniun

phosphine phosphine base

Only the tertiary phosphine and the quaternary phosphonium
compounds are formed by the action of alkyl halides RI on PH3.
The mono and di alkyl phosphines are obtained by heating phos-
phonium iodide, PH3I, with an alkyl iodide and zinc oxide. These
quaternary phosphonium bases, like those of arsenic, antimony,
etc., exert a strong curare-like action in animals. They are
strongly basic, and when heated, decompose into a hydrocarbon
Cn H2n -+- 2 and oxygen compound;

(C2H5)4 P.OH = C2H6 + (C2H5)3 PO

An ammonium base under the same conditions would decom-
pose into an alcohol and trialkyl base :

2H5 = NR3 + C2H6OH

2-H.5

XOH

Oxidizing agents oxidize phosphorus to phosphoric acid.

In cases of poisoning with phosphorus, the metal will distil
from an acid solution and can be detected by its phosphorescence
in a dark room. This phosphorescence is due to the process of
oxidation of the metal. Oxidizing agents, like potassium perman-
ganate and hydrogen peroxide in dilute solutions are used as
antidotes in phosphorus poisoning.

PHOSPHORUS 363

Ag forms a compound with P, Ag3P. This test is used in
cases of suspected poisoning with P. A piece of filter paper
moistened with AgN03, suspended over a solution containing
P turns black if phosphorus is present, due to the formation
of silver phosphide Ag3P. Other substances like H2S in the
solution will also cause a blackening of the AgNO3 paper, and
the test for P is valuable only in proving its absence. Copper
also forms compounds with P. The formula of the copper
phosphide is not definite, probably Cu3P or Cu2Pe. In cases of
acute poisoning with phosphorus, the administration of dilute
copper sulphate 0.5 gram in 100 cc. may be of value in preventing
the absorption of P. which is still in the gastro-intestinal tract.
In addition, the copper solution will also act as an emetic.

The name phosphine may lead to confusion at times, for an
acridine dye, Philadelphia Yellow, is also known by the same
name. Acridine, Ci3H9N, is prepared from ortho-amino-diphe-
nyl-methane;

/CH2.CDH5 ^N v

-u

XNH2 CH

o. amino diphenyl acridine

methane

Phosphine, or Philadelphia Yellow, is a beautiful yellow dye
which forms red colored salts, and is a mixture of the hydro-
chlorides of asymetrical diamido-m-tolyl acridine. It is obtained
as a by product in the manufacture of rosaniline. Its formula is;

NH2.C6H4

NH2
Phosphine

364 CHEMICAL PHARMACOLOGY

It is a protoplasm poison, especially for protozoa, but has been
used without success in malaria.

The Fate of Phosphorus in the Body

The fate in the body is obscure. It is highly probable that
it is oxidized to some extent in the body. It is hard to tell this
from direct chemical examination because the phosphates vary
normally, more than a toxic dose of phosphorus- could change the
phosphate content of the urine. Some may be excreted by the
lungs; but the statement that the breath may become phosphores-
cent is not given much weight : Unknown organic combinations of
phosphorus have been found in the urine.

ARSENIC COMPOUNDS

Metallic arsenic is non-toxic, while its compounds are all
toxic. White arsenic, As203, which is an anhydride of arse
nious acid, As2O3 + 3H20 = 2H3As03, is the most important
compound. Arsenious acid, however, cannot be isolated
since on evaporation of its solution arsenic trioxide is again
obtained. This is also known as white arsenic. A 1 per
cent, solution of this in 2 per cent, potassium bicarbonate
solution is known as Fowler's solution, and is a favorite prepara-
tion in medicine. AsI3, arsenious iodide, is also used in medicine
in the form of liquor arseni et hydrargyri iodidi. This is a
1 per cent, solution each of AsI3 and red mercuric iodide HgI2
in water. Sodium arsenate, Na2H.AsO4.7H20 is used to some
extent.

Atoxyl, sodium arsinalate, or sodium p amino-phenyl arsenate
is a compound formed when anilin and arsenic acid are heated
together

/OH
CeHsNHa + As(OH)3 = C6H5NH2 - 0 - As=0

\OH

p. amino-phenyl arsenate
/OH

NH2C6H4 - As=0 = + H20
\OH

p. amino-phenyl arsenic acid

ARSENIC 365

The sodium salt of this is atoxyl. The Na replaces an hydroxyl H.

/OH
Acetyl atoxyl CH3.CO.NH.C6H4.-As=O is also employed.

\OH
Arsacetin is the sodium salt of this, or

/OH
CH3CO.NH.C6H4 - As^O

\ONa

/OH

///OH

Arsenic acid has the formula H3AsO4 or As^

When two of the OH. groups are replaced by methyl groups, we
have cacodylic acid: —

CH3

Cacodylic acid is formed when potassium acetate is distilled with
arsenious acid: —

As203 + 4CH3COOK -> (CH3)2 = As -- O -- As = (CH3)2

+ 2K2CO3 + 2CO2

cacodyl oxide

Cacodylicoxide when treated with HC1 yields cacodyl chloride:
(CH3)2 = As - O - As = (CH3)2 + HC1 = 2(CH3)2 As - Cl.
On oxidation this yields cacodylic acid :

/CH3 /CH3

As— CH3 + 2H20 + 20 -> 2 As— CH3
\C1 || \OH

/Cl
As— CH3
\CH3
Sodium cacodylate is the most important salt of cacodylic acid.

0 = As-CH

366

CHEMICAL PHARMACOLOGY

If the three hydroxyl hydrogens of arsenic acid are replaced by
Na, sodium arsenate is the product. This, acted upon by
methyl iodide in alkaline solution, yields sodium methyl arsenate
or arrenhal.

/ONa
O = As— ONa + CH31

\ONa
Sodium arsenate

/CH3

0 = As— ONa
\ONa
arrenhal

Arsphenamine or salvarsan "606" dioxy diamino arseno benzol
The number "606" refers to the laboratory research number.
This substance is a derivative of arseno benzene,

C6H5 - As = As - C6H5,
which is analogous to azo benzene,

C6H5 - N = N- C6H5.
The following reactions illustrate its preparation:

(I) When phenol and arsenic acid are heated together a conden-
sation takes place in the para position:

HHa--As=0 =

==O + H2O

p. phenol arsenic acid
When this is treated with nitric acid, a nitro derivative is formed :

OH< > As= =0+ HON02 =

\)H

ARSPHENAMINE 367

On complete reduction, this yields a condensation product:

(2) OH

/OH
As = O + 2 OH

\OH

A «

xTLO

NH<

OH salvarsan OH

Arsphenamine or salvarsan is a light yellow crystalline powder
and yields a solution in water with an acid reaction. When given
intravenously, the solution should be well diluted and slightly
alkaline.

Neo-arsphenamine or neo-salvarsan, (914) is a soluble prepa-
ration of salvarsan. Jt is sodium di-amino dihydroxy arseno-
benzene methanal sulphoxylate;

XAJO

NHS

NH(CH20) OSNa

It is prepared by precipitating a salt of arsphenamine with
sodium methanal sulphoxylate and dissolving the precipitate
in alkalies. It is an orange yellow powder of peculiar odor and
is unstable in the air.

Fate of Arsenic in the Body

Arsenic is absorbed rapidly and excretion by the urine begins
in about seven hours and lasts several days, though it may con-

368 CHEMICAL PHARMACOLOGY

tinue for three months. It is excreted mainly through the kid-
neys. Since it irritates the kidneys the amount of urine in toxic
cases is greatly diminished.

Regarding the retention of arsenic by the various organs, the
liver retains the most, but the kidneys, spleen and muscles all
may contain arsenic. Only traces are found in the brain. It has
been detected in the cancellous bones of the skull and vertebrae
after it has disappeared from .all the other organs. The poison
is probably combined in the organs as arseno-nucleins: Since
the nucleins are the most active seats of life it probably kills by
an action here.

Binz and Schultz thought that the action of arsenic was due
to an alternate reduction and oxidation of it in the tissues.
Arsenious acid being oxidized to arsenic acid and the reverse
reaction occurring also. In this way oxygen is alternately
withdrawn from and supplied to the protoplasm. If such a
process takes place it must be very gradual otherwise we cannot
explain why arsenious acid is so much more powerful than arsenic
acid.

Gautier thought arsenic to be a normal constituent of the
thyroid gland, but there seems to be no basis for this, and what
Gautier found must have been taken as medicine or otherwise.

For a complete report on the Chemistry of the Organic Com-
pounds of Arsenic and Antimony — see Organic Compounds of
Arsenic and Antimony by Gilbert T. Morgan, Longmans Green
and Co. 1918.

XXXIII. HEAVY METALS

We include under the term heavy metals, antimony, mercury,
iron, lead, copper, zinc, silver, bismuth, aluminum, gold, plat-
inum, manganese, cadmium, nickel, cobalt, tin, thallium, van-
adium, tungsten, uranium, etc. Of these, only the first twelve
are of importance in medicine, the others being of toxicologic
interest only. Phosphorus and arsenic are important, but; they
are not usually classified with heavy metals.

The metals themselves are inactive, and it is only in the form
of soluble salts that they exert any action. It must be remem-
bered, however, that the solubility in albumen may be different
from that in water, although usually only those salts that are
soluble in water are active.

HEAVY METALS 369

Heavy metals have two actions: (1) local, and (2) general,
or the action after absorption.

The salts of the heavy metals form combinations with proteins,
and local action is due to this combination. According to the
reactivity, strength, and extent of the combination, the salts of
the heavy metals may be astringent, irritant, styptic, caustic or
corrosive. Since the same salt in different concentrations may
exhibit all these actions, it is impossible to classify metals under
these heads. From a practical standpoint, however, they may
be classified as follows :

1. Styptics — ferric chloride, dried alum.

2. Astringents — alum, lead acetate, basic lead acetate, zinc
oxide, bismuth subnitrate, ammoniated mercury.

3. Astringent and corrosive — iron salts, zinc sulphate, zinc
acetate, copper acetate, silver nitrate, lead nitrate, lead iodide.

4. Corrosive — mercury salts, zinc chloride, tin chloride, anti-
mony chloride, copper sulphate.

As a rule, the greater the ionization, the greater the action.

The salt formed by the union of a metal with protein is a pro-
teinate, e.g., argenti proteinas or protargol. It is not of constant
composition, but varies with the kind of protein and the amounts
of the protein and metal used. Thus the salts are not true chem-
ical compounds. The precipitate when formed may redissolve,
or go again into solution if too much of the reagent or of the
protein solution is added. This is especially true in the case of
lead salts, and is readily understood in the light of the phenome-
non of precipitation.

Explanation of Precipitation

Proteins are emulsoid colloids. Colloids remain in solution
because they are electrically charged, either negatively or posi-
tively. Proteins belong to the class* of colloids, which are usu-
ally negative, and remain in solution as long as they retain this
charge. Because the charge is the same throughout, and as like
charges repel each other, the protein remains in solution but
when the charge is neutralized, precipitation occurs. According
to the cause, precipitation may be due to:

1. Spontaneous precipitation.

2. Gelatinization.

370 CHEMICAL PHARMACOLOGY

3. Coagulation by enzymes and heat.

4. The addition of electrolytes.

5. Other colloids of opposite sign.

Examples of these changes in drug chemistry are:

1. The spontaneous decomposition of a solution of silicic acid
or water glass.

2. The precipitation of gelatin or agar due to loss of water by
evaporation. Their solution may be considered as hydrophylic
compounds. Evaporation necessitates an internal rearrange-
ment and a loss or neutralization of the charge. These charges
are reversible, an addition of water again causing the formation
of a colloidal solution.

3. Heat coagulation, and the changes caused by enzymes are
well known in the coagulation of white of egg, and the souring
of milk. These coagulations are irreversible.

4. The precipitates formed by electrolytes are divided into
two groups (reversible and irreversible), depending on the na-
ture of the precipitate or coagulate.

Salts of Ba.Sr. and the heavy metals form precipitates which
are irreversible.

The difference between reversible and irreversible precipitates
is due to a fundamental change and molecular rearrangement in
the case of the irreversible; while in the reversible there is merely
a neutralization of the electrical charge. Accordingly, proteins
may be precipitated in three forms:

1. Unaltered, i.e., by salting out or neutralization of the
charge — reversible.

2. As albuminates, by coagulation \ . ...

3. Insoluble salts of metals /

Both ions of a salt are important in precipitation. Which of
the two is more important depends on the nature of the colloid
to be precipitated. For example: colloidal iron is a positive
colloid, and is much used to remove" proteins from the blood.
The positive charge on the iron salt is neutralized by the negative
charge on the protein and both are precipitated. Colloidal iron
is also precipitated by a solution of MgSO4, or Na2SO4 or almost
any salt. In this case it is the negative ion or anion which acts
to neutralize the positive charge of the iron.

In the precipitation of proteins, however, the same explanation

COLLOIDS 371

holds; but since the proteins are negatively charged it is the posi-
tively charged ion or cathion that is more important as a protein
precipitant. Since the precipitation is due to a neutralization, it
follows that if the colloid is negative the precipitating ion is always
the cathion, if positive, the anion.

Bivalent ions are more active in causing precipitation than
monovalent, and polyvalent more powerful than bivalent. The
valence of the ion of the -same sign as the colloid has no influence
on the action.

Aside from the neutralization, there are, of course, especially
with the heavy metals, proteinates formed that can not be
explained on this simple basis. These salts, while not so definite
as the heavy metal combinations with sulphates, carbonates, etc.
are of the same nature.

The action of heavy metals when taken internally is due to the .
chemical local action of the metal on the stomach and intestine.
The nature of the acid in the salt is of importance, as is also the
nature of the precipitate, slimy or granular.

Nitrates are more irritant than acetates because the nitric acid
liberated in the reaction is a more powerful irritant than acetic
acid.

When the precipitate is granular, the acid liberated penetrates
to the tissue below more readily than when the precipitate is
slimy in nature. Corrosive sublimate, for these reasons, pene-
tiates deeper and is more corrosive than lead acetate.

Local reactions of the heavy metals when taken internally are;
loss of appetite, pain and discomfort, nausea, vomiting, purging,
congestion, hemorrhages. These are all the result of the irritant
and corrosive action of the metal. Ulcers may result after a
time due to bacterial action on the dead tissue.

The action after absorption is also the result of a combination
of the metal with the protein.

There is little difference in the action of the metals after ab-
sorption. Iron is just as toxic as arsenic when it is introduced
into the blood, but it is not absorbed rapidly from the stomach;
consequently it is not ordinarily toxic.

The toxic action of the heavy metals on the central nervous
system is manifested by delirium, hallucinations, mania, stupor,
and coma. Convulsions indicate that the motor areas, basal

372 CHEMICAL PHARMACOLOGY

ganglia and spinal cord are affected. Peripheral neuritis occurs
especially with lead and antimony, not differing from the neuri-
tis caused by alcohol, arsenic or toxins.

The astringent action of the heavy metals is due to several
factors :

1. The metal and protein unite to form an albuminate, and the
resultant liberated acid has an astringent effect.

2. The metal may be absorbed locally and exert a constricting
action on the local vessels.

3. Insoluble salts like cerium and bisrnuth cover and protect
the surface mechanically.

Absorption of heavy metals is slow, with the exception of salts
of mercury. Mercury is the only volatile metal and volatility
aids absorption. Whether the volatile character of the free
metal conveys any properties on the ion in the salt is not known.

The matter of excretion of heavy metals may be described as
follows; the body stores up the metals in the liver, spleen and
other organs, slowly eliminating it from them. This is done by
the kidneys and intestine, thus showing the reason that nephritis
is a prominent symptom. Heavy metals are also excreted into
the gut, and have a specific action on the gastro-intestinal tract.
This effect is more marked with arsenic, phosphorus and anti-
mony than with the heavy metals. By whatever course they
enter the body, there is always an inflammation of the gastro-in-
testinal tract throughout its extent, as much of the metal leaves
the body by this route.

COLLOIDAL METALS

The colloidal metals especially used in medicine are gold, cop-
per, platinum and silver. These are simply finely divided metals
having an electrical charge, which is positive. They are suspen-
soid colloids.

The methods for preparing colloidal metals are:

1. The disintegration of heavy metals by means of an electric
current strong enough to cause sparks under water. The metal
is used as electrodes.

2. Reduction of dilute solutions of the salts of the metals by
various reducing agents. They are prepared in water free from
electrolytes as they can not be kept for any time in the presence of
salts.

INORGANIC ACIDS 373

The method of preparation by an electric current, and the effect
of electrolytes in causing precipitation, together sustain the
opinion that colloids bear electric charges. This properly differ-
entiates true suspensions from suspensoid colloids. True suspen-
sions will settle out on standing at rest, while suspensoid colloids
are little influenced by gravity and remain suspended.

The basis for the use of colloidal metals in medicine is that
traces of copper and other heavy metals in water in a vessel of
one of these metals, contain none of the metal detectable by
chemical means, yet they prevent the growth of, and sometimes
kill, unicellular organisms. When the metallic surface is in-
creased as in the colloidal solutions, a greater chance is given for
this action, and the colloidal solutions can be injected into tumors
or applied to mucous surfaces. The value of colloidal metal
solutions is still problematical, for while solutions such as argenti
proteinas unquestionably is efficient in some infections of the
eye, it is probably less efficient than a 1 per cent, solution of
silver nitrate.

XXXIV. INORGANIC ACIDS

The inorganic acids of importance in pharmacology are boric,
hydrochloric, sulphuric, nitric and phosphoric. Chromic and
hydroflouric acid are of small importance.

The acids when used as such owe their action to the hydrogen
ion, and are protoplasm poisons. Protoplasm, which is essen-
tially alkaline in reaction, cannot contain life if this alkalinity is
neutralized by acids. If strong acids come in contact with pro-
toplasm, they may disintegrate it, hence they are corrosive poi-
sons. For this reason, strong acids, when applied to the skin,
destroy the epidermis. Acids, because of this corrosive action,
are sometimes used to destroy warts. The corrosive action is
more marked when the acids are applied to mucous membranes ;
even a small quantity of a strong acid in the eye may destroy the
sight. The mucus membrane of the mouth, esophagus and stom-
ach may be destroyed if such acids are swallowed. In dilute
solutions, they are absorbed rapidly, and are neutralized, and
exist in the blood in the form of salts.

The process of neutralization differs in different animals.
Herbivora, because of their food, have a greater reserve of fixed

374 CHEMICAL PHARMACOLOGY

alkalies, mainly sodium and potassium, which are first used to
neutralize any acid that may be taken. When these alkalies are
used below a certain level, proteins are broken down and ammonia
is formed to neutralize the acids. Carnivorous animals, on
the other hand, are accustomed to the development of acids
from their protein food, and as their food contains a limited quan-
tity of fixed alkali, the normal process of neutralization is the
formation of ammonia. Hence carnivorous animals, because
they can more readily form ammonia are in a better position to
protect themselves from the neutralizing influence of acids.
Herbivorous animals consume large quantities of organic salts
of the alkalies in their food, and have a greater immediate reserve
of these salts than carnivorous animals, but the mechanism to
form ammonia quickly is lacking, which is always at work in the
carnivora, and, in case of poisoning, requires only a little speeding
up. Herbivora, then, are more easily poisoned with acids than
carnivora. The absorption of dilute acids in dogs does not mater-
ially change the available alkali of the blood, while in rabbits,
the same amount of dilute acid causes a reduction of from twenty
five volumes to two volumes per cent, in the carbonic acid in the
blood. When this occurs, respiration becomes deep, labored
and rapid, afterwards, weak and shallow, and finally ceases.
The heart continues to beat after respiration has ceased.

The acids are excreted by the kidney in the form of salts. If
any considerable quantity has been taken, the body conserves its
alkali reserve and the salts are excreted as acid salts.

To counteract the effect of acids, alkalies are used : Since most
alkalies themselves are corrosive, one must exercise care in their
use. The most available is sodium bicarbonate or baking soda.
This may be used without much danger. Lime water can also
be used, but its neutralizing power is little since calcium oxide
is soluble only in about 800 parts of water, If sodium carbonate,
or sodium hydroxide be used, very dilute solutions can be used
without injury, but if stronger solutions are used they exert a
caustic action perhaps more harmful than the acids.

XXXV. SALT ACTION

By salt action in pharmacology, we understand those actions
which are not specific but which may be elicited by any salt,

SALT ACTION 375

and are due fundamentally to processes of osmosis, diffusion, and
dialysis. The effects of sodium chloride on red blood corpuscles
are an example of salt action. If the salt is iso-tonic, no action
takes place, while if. it is hyper tonic, crenation occurs. If the
salt is hypotonic, the cell will absorb water and a swelling or
edematous condition results. If the salt is applied to the nerve
in hypertonic solutions, it will" cause a twitching of the muscle
through its action on withdrawing water from the nerve.

Ion action differs from salt action in that the action is specific.

+
Thus, KCN is a pronounced poison because it ionizes into K and

CN. The CN is a violent poison. The same amount of CN
in potassium ferro cyanide which does not ionize but remains as a
salt is without action.

Diffusion. — When two or more gases are brought together with
no physical barrier to separate them, they soon form a homogene-
eous mixture; e.g., when gas is liberated in a room, it soon spreads
throughout the whole space and mixes uniformly with the oxygen
and nitrogen of the air. This process of mixing is called diffusion.

Osmosis.— If two miscible liquids are placed in the same vessel,
in a short time they will diffuse or mix uniformly just as gases.
This process is due to the movement of the molecules and is slower
in liquids than in gases. If the liquids are separated by a mem-
brane and the diffusion occurs through the membrane, the proc-
ess is known as osmosis. Not only water but salts and crystal-
loids generally will pass through the membrane. Colloids diffuse
through a membrane very slowly.

If the process of osmosis is used to separate one substance from
another, as in the separation of crystalline substances from
colloids, the process is known as dialysis.

GAS PRESSURE IN RELATION TO OSMOTIC PRESSURE

It has been proved that the osmotic pressure, or osmotic
suction, of a crystalloid is the same as would be exerted by the
same number of particles of a gas if it were confined in the same
space. To illustrate; if a gram molecular weight of any gas
oxygen H2 = 2 grams O2 = 32 grams N2 = 28 grams is confined
in a liter volume at 0° (zero) centigrade, it will exert a pressure
of 22.32 atmospheres, or the converse of this a gram molecular

376 CHEMICAL PHARMACOLOGY

weight of any gas at ordinary pressures occupies a volume of
22.32 litres. This is in accordance with the gas law; Pressure
times volume = pressure times Volume, or Pv = pV.

Crystalline substances do not pass into the gaseous state
without decomposition, but when in solution they exert the same
pressure as they would if they were in a gaseous state in the same
volume. For instance, the gram molecular weight of cane sugar,
CitHnOirj, is 342 grams. If this amount of cane sugar is dis-
solved in water and made up to 1 litre, it will exert a pressure of
22.32 atmospheres. An ion exerts the same influence as a
molecule, consequently, if a substance which contains two ions in
the molecule is completely ionized, the pressure will be doubled,

as in a very dilute solution of sodium chloride. In the case of

+ +

sodium sulfate, which ionizes into Na — Na — S04, complete
ionization would make the pressure three times the molecular

pressure. In sodium phosphate, Na2H P04, in complete ioniza-

+ + +
tion Na — Na — H — P04 the complete pressure would be four

times the molecular. Calculation of osmotic pressure of solutions
that do not ionize is an easy task. All that is necessary is
to know the molecular weight of the substance and the concentra-
tion. For example:

I. To calculate the osmotic pressure of 5 per cent, cane sugar
solution. 342 grams in 1 liter or 34.2 per cent. = 22.32 atmos-
pheres. 5 per cent. = ^~^ times 22.32 atmospheres.

o4.Z

II. 5 per cent, solution of NaCl — assuming no ionization —
58.5 grams in 1 liter or 5.85 per cent. = 22.32 atmospheres

5 per cent. == ~K~QK times 22.32 atmospheres.

If there is a certain percentage of ionization however the osmotic
pressure will be increased accordingly.

DIFFICULTIES IN DETERMINING OSMOTIC PRESSURE

The pressure exerted by a molecular solution is so enormous
that it is hard to get a semi-permeable membrane that will stand
the strain. Before the theoretic level is reached, most mem-
branes rupture. The nearest approach to a semi-permeable

SALT ACTION 377

membrane that would stand the strain was devised by Pfeffer.
He used a porous clay cell and filled it with a solution of copper
sulfate and set it in a solution of potassium ferro cyanide. As
the two solutions permeated the porous clay they met and formed
a precipitate of copper ferro cyanide, which functions as a semi-
permeable membrane. Most animal membranes and collodion
tubes are only partially semi-permeable. Salts will pass in both
directions and while they answer for the ordinary purposes of
dialysis they cannot be used to determine or measure the extent of
osmotic pressure. In biological work the osmotic pressure is
not determined directly, but indirectly, from the freezing point.

RELATION OF OSMOTIC PRESSURE TO THE BOILING POINT AND
FREEZING POINT OF SOLUTIONS

The rise in the boiling point of a water solution of a substance,
provided the substance does not change on heating, bears a
direct relation to the number of molecules or ions in the solution.
An ion exerts the same influence as a molecule. Since most
biological fluids contain proteins, and change in physical proper-
ties on heating, the boiling point method cannot be used.

Freezing Point Method. — This method is available in biological
work. It is simple and convenient. Each mol-ion added to a
liter of water depresses the freezing point 1.85°C. This depres-
sion of the freezing point is designated by A. Solutions with the
same freezing point have the same osmotic pressure. To calculate
the freezing point of a pure substance in water, we must know its
formula and the per cent, of the solution. For example; to calcu-
late the freezing point of 1 per cent. NaCl. A molecular solution
of sodium chloride is 58.5 grams to the liter, or 5.85 per cent.
This depresses the freezing point 1.85°C. 1 per cent, solution

depresses it KQ K of 1.85° C. or. 316°C. This assumes no ioniza-

Oo.O

tion. In actual work it is found that A = 0.589 which shows a
high per cent, of ionization. The freezing point of a 1 per cent,
solution of cane sugar, since a molecular solution of sugar — 342
grams in the liter or 34.2 per cent, is ^4-2 of 1.86°C. or -0.054°C.
To Calculate the Osmotic Pressure from the Freezing Point.
The osmotic pressure of a molecular solution is 22.32 atmospheres
or 16,986 millimeters of mercury. This height of mercury is

378 CHEMICAL PHARMACOLOGY

equivalent to a temperature reduction of 1.86°C. The osmotic
pressure of 1 per cent, cane sugar is therefore 16,986 : 1.86 :.054 :

0 054
X . or j ' times 16,986 = 493 millimetres of mercury.

SALTS IN THE BODY

Certain salts are necessary for life, but the amount of these is
small (see p. 2). They exist in the body mainly as ions. The
freezing point of mammalian blood is .526; (varies from .480 to

.605) ; hence the osmotic pressure is ^-Q= times 22.3 atmosphere

l.oo

or about 7.25 atmospheres. This is due almost entirely to
salts, sugar and urea. The proteins contribute but a small part
to the total osmotic pressure.

The average freezing point of serum is -0.6°C. 0.95 per cent.

NaCJ has this same freezing point and is, therefore, iso-osmotic

or isotonic. The osmotic pressure calculated from this is T~o^X

l.oO

22.32 = 7.24 atmospheres.

Calculated on the percentage basis and assuming no ionization,
a molecular solution of NaCl = 58.5 grams in a litre or- 5.85
per cent. = 22.32 atmospheres. .95 per cent. NaCl should equal

of 22.32 atmospheres = 3.62 atmospheres. Assuming no

ionization, the osmotic pressure here is just one half of that found
by direct determination, hence normal saline must be completely
ionized.

The action of sodium chloride when injected into the circulation
is not noticeable on the blood pressure or circulation. A solution
of KC1 of the same osmotic pressure causes a pronounced depres-
sion of the heart. Since Cl, as judged from the action of NaCl,
has no action, the action obtained from KC1 must be due to the
K ion. This illustrates the difference between salt action and
ion action. Isotonic saline solutions can exert no salt action,
and if an action results, it must be an ion action. Both ions
usually have some action, but in most salts one of the ions is
much more powerful pharmacologically than the other. K in
the KC1 is the important ion, but in the case of KCN the CN
ion is so much more toxic than the K that the action of KCN is

TOXICOLOGY 379

attributed almost entirely to the CN ion. Some drugs are not at
all dissociated in the body and therefore the only action they
exert is the molecular or salt action. Ether, sugar and alcohol are
not ionized. They exert only a salt action. Some of these,
however, may be broken down in the body and their cleavage
products may form ionizable compounds. Alcohol and sugar
yield C02. This may react with the fixed bases of the body to
form carbonates, Na2CO3, etc. The carbonates may be hydro-
lyzed to form NaOH which ionizes into Na + OH. While
alcohol contains the group OH, it does not ionize and it exerts
only a molecular action unless broken down.

SALT ACTION IN PHARMACOLOGY

Salts have the same importance in pharmacology as in physiol-
ogy, but in addition, many salts used as drugs owe most of their
action to osmosis, dialysis, and diffusion. This is especially
true of the cathartic salts. Because these are not absorbed from
the gut, the physical properties above enumerated suffice to
explain their action. In most cases when salt is administered
some is absorbed, and may either be excreted into the gut again
or by the kidneys. When excreted by the kidneys, salts exert
osmotic effects on the convoluted tubules. Some are reabsorbed
from the tubules, others such as sodium sulphate, are but little
reabsorbed and hence act as better diuretics than the chloride.
The diuretic action of these salts can be seen best when they are
injected into the circulation. Other instances of the osmotic
effects of salt might be cited, but none more impressive.

XXXVI. TOXICOLOGY
THE ISOLATION OF POISONS

For analytical purposes, poisons may be divided into groups
as follows:

Group I. — Volatile poisons which distil with steam from acid
solution without decomposition, and can be detected in the
distillate. They are arranged in the order of their boiling point —
which is about the order in which they would appear in the
distillate :

380 CHEMICAL PHARMACOLOGY

Yellow phosphorus Chloral hydrate 97°

lodoform — m.p 119°

Hydrocyanic acid 26° Benzaldehyde 179°

Carbon disulphide 46° Phenol 180°

Acetone 57° Aniline 183°

Chloroform 61° Creosote 200°+

Methyl alcohol 67 . 4° Nitrobenzene 208°

Ethyl alcohol 78°

Group II. — Non-volatile organic substances which can be ex-
tracted from extraneous matter with hot alcohol, after acidifica-
tion with tartaric acid. The principal members of this group
are:

The alkaloids, neutral principles, some glucosides and bitters,
synthetic organic drugs such as the sulphone hypnotics, the
antipyretics, phenacetine, acetanilide, antipyrine, pyramidone,
etc. After separating protein, fats, gums, resins, etc. that may
be mixed with these drugs in cases of poisoning, non- volatile
poisons may be subdivided into groups based on analytical
methods. One of the methods is the Stas-Otto process which
consists in extracting the liquid in a separatory funnel with
immiscible solvents. Those extracted with ether when the
solution is acid are:

A. Acetanilide Colchicine Picro toxin
Antipyrine Picric acid Salicylic acid
Caffeine Phenacetin Veronal

B. Those extracted with ether when the solution is made
alkaline with sodium hydroxide:

Aniline Codeine Pilocarpine

Antipyrine Coniine Pyramidone

Atropine Hydrastine Quinine

Brucitne Narcotine Scopolamine

Caffeine Nicotine Strychnine

Cocaine Physostigmine Veratrine

C. Those extracted with ether, in a solution made alkaline with
ammonia. The solution from the sodium hydroxide extract, is
first made slightly acid, and then alkaline with ammonia. Ether
will extract from this alkaline solution apomorphine and traces
of morphine.

TOXICOLOGY 381

D. Those extracted by chloroform. After the ether extract
from the ammoniacal solution has been removed, chloroform
will extract the following, if present:

Antipyrine
Caffeine
Morphine
Narceine

Group III. Metallic Poisons. — These may be found in the
residue after the extraction of the organic poisons, or an original
portion may be used to test for them. Before testing for these,
all organic matter must be destroyed. The most important
metallic poisons are:

Antimony Cadmium

Arsenic Chromium

Barium Lead

Bismuth Mercury
Tin

Group IV. — Poisons not in groups and for which special direct
tests must be made — the most important are:

(a) The mineral acids— HN03, HC1, H2SO4.

(b) Oxalic acid.

(d) Chlorates.

(e) Miscellaneous organic:

Cantharidin Opium

Cytisine Santonin

Digitalis — glucosides Saponins

Solanin

Ergot principles Sulphonal

Pilocarpine Trional

Ptomaines Toxalbumins —

Abrin

Crotin

Curcin

Ricin

Robin

382 CHEMICAL PHARMACOLOGY

METHODS OF ISOLATING POISONS

The tests made with pure substances, give one but little
conception of toxicology. The isolation of poisons, from stomach
contents or from the liver, and the preparation of these for
testing is more important than the tests, and much more difficult.

THE ISOLATION OF VOLATILE POISONS

The volatile poisons include those that are volatile in steam in
acid solution. The acid used must be non-volatile, especially
suitable is tartaric, but dilute sulphuric or phosphoric may be
used. Note that this group does not contain the volatile alka-
loids— nicotine, coniine, sparteine. Because the solution is
acid, salts of the alkaloids are formed, and these are not volatile.
Before distilling, certain preliminary tests are made. These
may shorten or obviate the necessity of much work.

Preliminary Test for Phosphorus
Scherer's test.

This is founded on the fact that phosphorus in a solution of
silver nitrate, acidified with nitric acid, forms silver phosphide
(Ag3P).

The vapor of phosphorus will give this test with filter paper
moistened with the silver nitrate solution. Hydrogen sulphide
will also darken silver nitrate so a control test must be made along
with the preliminary test, as follows: (See Fig. 3.)

Place some of the solution to be tested in a distillation flask,
with a cork stopper. Moisten a strip of filter paper about
6-10 cm. along, and 1 cm. in width, with the silver nitrate solu-
tion, and insert this in a V-shaped slit in one side of the cork,
moisten another, similar piece of paper, with lead acetate, and
place this in a slit in the other side of the cork. Be sure that the
papers do not touch each other. Place the cork in the flask,
and set the flask on a water bath at -about 50°C.

It is advisable to protect the papers from light, since light
colors the silver to some degree.

Discussion of Results

(a) If the silver paper only is darkened phosphorus may be
present.

TOXICOLOGY

383

(6) If both papers are darkened HsS is also present, and in
either case the test for phosphorus should be made. Any
volatile organic reducing substance such as formaldehyde or
formic acid ma,y also darken the papers.

(c) If neither paper is darkened, phosphorus is absent and
further tests for phosphorus need not be made. The preliminary
test is more important therefore in establishing the absence of
P. than its presence.

FIG. 3. — (After Autenrieth- Warren.)

FIG. 4.

Principal Test for Phosphorus

I. Mitscherlich's Test. — In examining animal material such as
stomach and contents, liver, spleen, kidney, etc. It is ground to
a fine pulp in a mortar, a little clean sand may be used, and
placed in a flask of suitable size, sufficient water is added to give
it a mash like consistence. The flesh present may be cut with
scissors to about the size of peas before grinding. If the pre-
liminary test does not rule out P. set up a distillation apparatus
as in Fig. 4.

The glass tube in this case should be about 130 cm. long, 45
high and about 8 mm. internal diameter. The lower end of the
tube from the condenser should dip one or two centimeters under
water in the flask C to collect any gases like HCN that may come
over in the distillate. If yellow phosphorus is present a character-

384 CHEMICAL PHARMACOLOGY

istic phosphorescence appears in the tube — and may be seen
best in a dark room or when the distilling apparatus is covered
with a black cloth. The phosphorescence is due to oxidation of
the phosphorus. It may be prevented or masked by alcohol,
ether, formaldehyde, formic acid, chloroform, chloral hydrate,
benzin, petroleum, turpentine, ethereal oils, hydrogen peroxid,
mercuric chlorid, phenol, creosote, hydrogen sulphide, and putre-
factive products. When the presence of P. is established by the

FIG. 5. — (After Kippenberger.)

phosphorescence, it is advisable to let the apparatus cool^and
change the distillation to the regular Liebig condenser, see Fig. 6.

In heating organic matter in a flask over a free flame, there is
danger of breaking the flask, consequently some advise the
heating on a water bath or on an oil bath. Again in heating the
flask in presence of oxygen some of the phosphorus may be
oxidized to P2O5 which is not volatile, and to prevent this some
advise distillation from an atmosphere of CO2, see Fig. 5.

To test for phosphorus in the distillate, add an excess of
chlorine water, or fuming nitric acid and evaporate to dryness

TOXICOLOGY

385

on a water bath. This oxidizes the phosphorus to H3PO4.
Acidify with a few drops of HN03 and dissolve in 10 cc. water.
Use 5 cc. for each of the following tests.

Fia. 6. — (After Autenreith- Warren.)

I. Ammonium Molybdate Test. — Add 5 cc. of the solution to be
tested to 5 cc. ammonium molybdate solution and warm on a
water bath at 40°C. A yellow precipitate of ammonium phospho-
molybdate is formed.

FIG. 7. — (After Kippenberger.)

II. Ammonium Magnesium Phosphate Test. — Add an equal
volume of magnesia mixture to 5 cc. phosphate solution. Be sure
the solution is slightly alkaline. Ammonium magnesium phos-
phate is precipitated (NH4) Mg.PO4.6H20.

The precipitate is formed slowly and is facilitated by shaking.
Let stand over night if necessary.

386

CHEMICAL PHARMACOLOGY

In an elementary course in toxicology where the object is
training in principles only, quantitative work is unnecessary,
yet in many cases quantitative work is of more value as an aid to
correlation and assimilation, than qualitative work.

The Mitscherlich-Scherer Method for the Qualitative and
Quantitative Estimation of Phosphorus. — A weighed portion of
the substance to be analyzed, is placed in flask and acidified with
H2SO4, and a little ferrous sulphate added. This last is added to

FIG. 8.— (After Autenreith- Warren.)

prevent oxidation of the P. Before heating the air is expelled
from A, by CO2, from the Kipp generator E. The C02 is washed
with water in F. C contains water, and D contains a silver nitrate
solution. The stop-cock B permits the entrance of air, if desired
to increase the phosphorescence. When this has been seen no
more air is admitted.. The P collected in C is oxidized with bro-
mine water or HNO3, on a water bath and evaporated to dryness.
The P. is oxidized to phosphoric acid. This is precipitated with
magnesium mixture, filtered, dried, ignited and weighed as
magnesium pyrophosphate,

TOXICOLOGY 387

The P. in the silver nitrate in D as Ag3P is heated with nitric
acid which oxidizes the P. The silver nitrate is precipitated and
removed as AgCl by the addition of NaCl. This is filtered off,
and the filtrate treated as the contents of C and added to C.

This method will detect .00006 gram of yellow phosphorus.

Detection of Phosphorus in Oils

Straub's Test. — Copper sulphate in contact with phosphorus,
forms copper phosphide Cu3P2(?) and at the same time tends to
oxidize the phosphorus. Because of this copper sulphate is
used in the treatment of phosphorus poisoning.

Test.— In a test tube shake equal volumes of oil containing
phosphorus and 1 per cent, copper sulphate. A black emulsion
is formed, or a black ring at the junction of the liquids when the
emulsion settles.

ACETONE

Acetone is not an important poison. To test for its presence
in the distillate use tests, "page 63.

ANILINE
For tests see page 113.

OIL OF BITTER ALMONDS OR BENZALDEHYDE

See pages 76 and 104. Pure benzaldehyde is not poisonous,
but it occurs in oil of bitter almonds in the form of the cyan-
hydrin of benzaldehyde

/H
C6H5 - C— OH

\CN

This is readily hydrolyzed by KOH into -> KCN + H2O +
C6H5CHO. (Benzaldehyde.)

Test for KCN. — To 2 cc. oil of bitter almonds or the same
volume of the distillate add 10 cc. KOH 5 per cent., heat gently,
add a few drops of freshly prepared ferrous sulphate containing
a drop or two of ferric chloride. Prussian blue is formed. See
test for nitrogen, page 8. To test for benzaldehyde : add KOH
to the original solution. Extract with ether in a separatory fun-
nel, remove and evaporate the ether on a water bath at 40°C.

388 CHEMICAL PHARMACOLOGY

If benzaldehyde is present it is deposited as globules. Heat
these globules with 10 cc. 5 per cent, potassium dichromate and
dilute sulphuric acid under a reflux condenser. The benzalde-
hyde is converted into benzoic acid. Cool the liquid and again
extract with ether. Evaporate the ether. Benzoic acid remains,
its melting point is 120°-121°C. When dissolved in dilute
NaOH, ferric chloride produces a flesh colored precipitate.

CARBON BISULPHIDE

Carbon bisulphide distils slowly with steam and is found
but little in the first third of the distillate.

I. Lead Acetate Test. — CS2 is not precipitated by lead until
after decomposition. Add an equal volume of lead acetate to
CS2 shake — no reaction. Now add an excess of KOH and boil.
A black precipitate of Pb.S will appear (cf. H2S).

II. When an aqueous solution of carbon bisulphide is heated
with an alcoholic solution of NH4OH — ammonium sulphocyanate
is formed together with ammonium sulphide. Evaporate
nearly to dryness on water bath to expel (NH4)2S. Dissolve in
dilute HC1. When ferric chloride is added to this a deep red
color due to iron sulphocyanide appears. .05 gram of CS2
will give this test.

The reaction is: »

1 4NH3 + CS2 - (NHO CNS + (NH4)2S

2. FeCl3 + 3(NH4)CNS = Fe (CNS)3 + 3NH4C1

III. Xanthogenate Test. — When CS2 is shaken with 3-4 times
its volume of saturated alcoholic KOH it gives potassium xantho-
genate as follows:

/
CS2 + C2H5OK C = S]

OC2H5

This is a yellow compound, when this is acidified with acetic
acid and copper sulphate added, a black precipitate of cupric
xanthogenate is formed.

TOXICOLOGY 389

SK S

Cu + K2SO4

\J Vy2J.J.5 J 2

xanthogenate then decomposes into cuprous
nd ethyl xanthogen disulphide, as follows:

/ /

2 C = S + CuS04 = (S = C

\ \

O C2H6 O C2H5

The cupric xanthogenate then decomposes into cu
xanthogenate and ethyl xanthogen disulphide, as follows
OC2H5 OC2H5 OC2H5

s = c s = c s = c

\ • \ \

s s

\ I + I

Cu = S S— Cu

s s = c s = c

/ \ \

s-c \ \

' \ OC2H6 OC2H5

OC2H5

Ethyl Cuprous

Cupric — > xanthogen + xanthogenate

xanthogenate disulphide

Chloroform: Tests see p. 42.

Introduce 5 cc. chloroform into flask a (Fig. 7) ; heat on a water
bath and blow current of air through the flask and through the
heated tube c. This decomposes the chloroform vapor with
formation of HC1, which can be demonstrated by collecting it in
the U tube d. which contains a one per cent, solution of AgNOs-

CHLORAL HYDRATE

Chloral hydrate distils very slowly with steam. The solution
should be distilled for a long time and quite completely in order
to get most of it over. It is decomposed by distillation. For
tests, see page 60.

ETHYL ALCOHOL

This would be present in the same distillate as methyl alcohol.
It is quite impossible to separate them but tests for each may be
made. For tests see page 23.

390 CHEMICAL PHARMACOLOGY

METHYL ALCOHOL

This would be all distilled over when one third of the original
volume is distilled. For tests see page 18.

IODOFORM

lodoform distils readily with steam giving a milky distillate
which may be recognized by its odor. For tests and reactions
see page 80.

NITROBENZENE

C6H5NO2. The boiling point of this oily liquid is 208°C.
which is higher than that of phenol (183°C.) consequently most
of it will appear in the last part of the distillate: It is nearly
insoluble in water but very soluble in ether and if only traces are
present, the distillate should be shaken with ether, the ether
evaporated at about 40°C. and tests made on the residue. For
tests see page 110. Convert it into aniline, by reduction with
hydrogen and then make the aniline tests, page 112.

PHENOL

Phenol boils at about 180° and distils readily with steam. The
distillate may 'be cloudy and is recognizable by its odor, though
this may be masked by putrefactive odors. Traces of phenols
are formed in all putrefactions. For tests see page 99.
Quantitative Estimation of Phenol

An excess of saturated bromine water precipitates phenol in
aqueous solution as tribromophenyl hypobromite — C6H2Br3OBr.

Method. — Place an aliquot part of the liquid under examina-
tion in a stoppered flask. Add bromine water from time to time
and shake until the supernatant liquid has a red brown color and
bromine vapor is visible above the liquid. Let ,s;tand 2-4 hours
and filter through a weighed Gooch crucible. Dry in a desiccator
over H2SO4 to constant weight. The weight of the dried precipi-
tate multiplied by 0.2295 gives the amount of phenol, since
C6H2Br40 C6H5OH 94.05

409.86 94.05 409.86

= .2295

1 CREOSOTE (Creosols)

See page 96. Creosotes are methyl phenols and distil over
similar to carbolic acid. Some commercial creosotes contain

TOXICOLOGY 391

phenol. The tests are in many cases similar to phenol and hard
to distinguish from it.

1. With pure creosote iron chloride gives a green color, while
with phenol it gives a blue-purple color.

2. HNO3 when added to creosote gives picric acid, HN03 does
not form picric acid directly with phenol.

3. When equal volumes of colloidon and creosote are shaken
together there is no visible change while with phenol, a gelatinous
coagulum is formed.

NON-VOLATILE ORGANIC POISONS

Before non-volatile organic poisons can be extracted from
stomach contents, organs, etc. the proteins, fats, carbohydrates
and resinous material must be removed. As an aid to their
removal and to lessen the likelihood of removing poisons with
these materials, the organs are cut, or ground so that no piece is
larger than a pea. The finely chopped material is then placed
in a flask of suitable size and three times the volume of absolute
alcohol which has been redistilled from tartaric acid is added.
The alcohol has been redistilled to remove basic material which
often is present in commercial alcohol. Just enough tartarjc
acid is added to acidify the mixture. The whole is extracted on
a water bath for 30 minutes using a reflux condenser. Cool the
flask and contents, in order to help solidify fats present, and
filter through cheese cloth if much solid material is present.
Wash with absolute alcohol, and filter through paper to remove
fat and solid matter. Wash again with alcohol. Evaporate the
filtrate in a glass or porcelain dish on a water bath to a syrupy
consistency, and thoroughly mix with about 100 cc. water.
This precipitates resins. Filter, wash with water and again
evaporate to a syrup. Mix thoroughly with 150 cc. absolute
alcohol. This precipitates proteins, albumoses, peptones, dextrin-
like bodies, some inorganic salts — while the tartrate salts of the
poisons are dissolved. Filter and wash with alcohol. Again
evaporate off the alcohol and dissolve the residue in about 50 cc.
of water. This should be relatively clear and free from proteins,
fats, carbohydrates and resins, but if not the above processes
should be repeated until a clear solution is obtained. This is
the most important part of the analysis, as upon the removal

392 CHEMICAL PHARMACOLOGY

of all foreign matter depends the success of the tests which follow.
At all stages the solution should he acid — but a large excess of
acid should be avoided as its presence interferes with the tests.
When the solution is, so prepared it is ready for the Stas-Otto
method of extraction. This method consists in extraction of
the poisons with immiscible solvents first with acid alcohol, then
changing the solvent to water solution; and then successive
extractions of the prepared liquid with ether and chloroform in
acid and alkaline reactions as given below.

Acid Extraction — Stas-Otto Method. — Place a portion, or all,
of the prepared acid extract in a separatory funnel. Add an
equal volume of ether, shake well, allow to settle and remove the
ether into an evaporating dish. Repeat the extraction 3 or 4
times. Unite all extracts and allow to stand for 30 minutes. If
water separates out, it may be removed by filtering through
a dry filter. A dry filter will absorb and retain considerable
water. Evaporate the ether at a temperature of 40°C. Since
only a small residue may be expected after evaporation,
it is best not to have this spread over a large surface. To avoid
this let the ether extract drop from a separatory funnel into a
small evaporating dish at a rate about equal to the evaporation.
In this way whatever residue remains is on a small surface and
more easily examined. The completion of the evaporation may
be carried out on a water bath at a higher temperature if the
residue remains too moist for examination.

Even when none of the first group of poisons is present, some
little residue may remain which consists of tartaric acid, lactic
acid, resins, etc. which are not completely removed in the process.

The residue may contain any of the following poisons.

Acetanilide Caffeine

Antipyrine Picrotoxin

Phenacetine Picric acid

Salicylic acid Veronal .

Colchicine

Also traces of mercuric cyanide: .

Cantharidin

Digitalin

Veratrine

TOXICOLOGY 393

and Atropine may occur in this extraction. An examination of
the general appearance, taste, odor, color, etc. of the residue should
be made. Then a microscopic examination for crystals should be
made. Since usually only one of the poisons of the group is
expected, tests for the most likely should be made first.

II. After the acid solution has been extracted with ether, it is
made alkaline with sodium hydroxide. The alkali liberates most
alkaloids from this salts, and these are then readily extracted
with ether. Morphine, apomorphine, and narceine are more
soluble in the water alkaline solution than in ether, consequently
are not extracted, with ether. Note this exception to the general
alkaloidal solubilities. The water solution should be saved for
further investigation. The ether extract from alkaline sodium
hydroxide should be examined for:

Page Page

Aniline 112 Narcotine 265

Antipyrine 119 Nicotine 255

Atropine 272 Physostigmine . 295

Brucine 257 Papaverine 283

Caffeine. . > 288 Pilocarpine 275

Cocaine '. 267 Pyramidone 119

Codeine 281 Quinine. 261

Coniine 252 Scopolamine . 272

Hydrastine 263 Strychnine 257

Thebaine ' 282

Veratrine. 294

The figures refer to pages in the text where the tests are
given.

III. The alkaline sodium hydroxide solution, after extraction
with ether, is slightly but distinctly acidified with tartaric or
sulphuric acid. Then made alkaline with ammonia, and ex-
tracted in a separatory funnel with ether, and afterwards with
chloroform.

A. The ether extract may contain, apomorphine and traces of
morphine.

B. The chloroform extract may contain morphine, narceine
and antipyrine and caffeine that was not previously removed.

394 CHEMICAL PHARMACOLOGY

METALLIC POISONS

To detect poisonous metals, in animal or vegetable matter,
it is first necessary to destroy or remove the organic material
after which the tests are made in the same way as in inorganic
chemistry. In toxicological analysis therefore a most important
part of the process is the removal of the organic material.

Method

Various methods may be used, the principle in all is essentially
the same. The Fresinius v. Babo method is taken as the type.
Since all the organic poisons are also destroyed when the organic
matter is being destroyed, one may work either with an orig-
inal portion of the material or with the residue that remains
after the organic poisons have been removed. A portion of
the material is mixed to a fluid mass and placed in a large
flask Fig. 9.

About 30 cc. concentrated HC1 is added per 100 cc. mate-
rial, and 1-2 grams of KClOa added. The flask is heated on
a boiling water bath in a hood. Nascent chlorine is evolved
which destroys the organic matter. When the flask is hot, it
is frequently shaken and a trace of KClOs added from time to
time until the solution is a pale yellow color and longer heating
produces no further change. Fat is Very resistant to oxidation in
this way, yet isseasily oxidized in the body.

When oxidation is complete dilute with hot water and add a
little sulphuric acid to precipitate possible barium, filter and
evaporate in a porcelain dish on a water bath nearly to dryness
to remove excess of acid. The decomposition of some KClOa
may give a brown color at this point. If necessary filter, wash
with water and evaporate again almost to dryness. Dissolve
in water, and filter. There will be some insoluble white residue
wholly unaffected by the action of chlorine (see test for Ba) .

Examination of Filtrate

This should have only a faint yellow color, and be slightly acid.
Place in a flask and heat on a water bath. While heating saturate
the solution with H2S from a Kipp generator. The gas should
be run for 30 minutes in the hot solution, and again for 30 min-
utes after the flask has cooled, then the flask is tightly stoppered

TOXICOLOGY

395

and allowed to stand for several hours— preferably over night —
and filtered. The filtrate may contain chromium or Zn. The
precipitate may contain As, Sb, Sn, Cu, Hg, Pb, Bi, Cu, Cd.

FIG. 9. — (After Autenreith.)

Examination of the Precipitate

The precipitate is thoroughly washed with hydrogen sulphide
water, then the moist precipitate is dissolved in about 25 cc. of
a mixture of equal parts of ammonium hydroxid and yellow
ammonium -sulphide and heated to boiling — filter and wash
several times with some of the hot ammonium — sulphide mixture :
The filtrate may contain As, Sb, Sn, or Cu. The precipitate
Hg, Pt, Bi, Cu or Cd.

396 CHEMICAL PHARMACOLOGY

Examination of the Filtrate

Evaporate the solution to dryness on a water bath — cool,
moisten with HNOs and again evaporate to dryness. Then mix
the residue with 3 times its volume of a mixture containing 2 parts
sodium nitrate and 1 part sodium carbonate. Evaporate this
mixture to dryness and add it little by little to a crucible contain-
ing a little sodium nitrate heated to redness. The heating is
continued until the whole is fused. If copper is present the melt
is gray or black. Sodium arsenate, sodium pyroantimonate and
sodium stannate may also be present. When the crucible is
cold, add a little hot water and wash into a flask. If sodium
stannate is present a little sodium bicarbonate is added to
precipitate the tin as stannic oxide. Filter. The filtrate may
contain As as sodium arsenate and the residue will contain
sodium pyroantimoniate (Na2H2Sb2Q7), stannic and copper
oxides.

Arsenic Test

Acidify the filtrate with arsenic free sulphuric acid. Evaporate
over a free flame, and add sufficient sulphuric acid to expel nitric
acid. Heat until copious white fumes of sulphuric acid appear.
Arsenic if present is in the form of arsenic acid and is tested in the
Marsh Apparatus, see Fig. 10 (Autenrieth, Warren).

Place 30 grams of arsenic free zinc in flask A. Pour 15 per
cent, arsenic free sulphuric acid on the metal. The flask should
be kept cool during the analysis by keeping it surrounded with
cool water and by generating hydrogen slowly. If the tempera-
ture gets too high S02 is formed and this in presence of hydrogen
is reduced to H2S, which interferes with the test. All joints of
the apparatus should be tight to avoid escape of AsH3 and also to
prevent explosions. Air should be completely expelled before
igniting also to prevent explosion, to determine whether the air is
expelled catch some of the escaping hydrogen in a test tube and
test from time to time until it ignites without detonation. It
may require 10 minutes to expel the air. When lighted and
before adding the solutions to be tested, one should test to see
that no arsenic is present in the chemicals. If the hydrogen is
arsenic free, the solution to be tested is gradually introduced into
the sulphuric acid — zinc flask, A, through' the funnel — at the

TOXICOLOGY

397

same time the tube C. is heated to redness just back of the
constriction D. If the solution contains As, a shining metallic
arsenic mirror is deposited, just beyond the point of ignition.

2. If the flame is removed from C. and a cold porcelain dish
pressed down on the arsine-hydrogen flame a brownish black
spot is formed upon the dish. This spot dissolves readily in sodium
hypochlorite solution. Antimony spots will not dissolve.

3. If the hydrogen flame is extinguished, and the end of the
tube dipped into a dilute silver nitrate solution, arsine produces
a black precipitate of metallic silver.

FIG. 10.

4. Arsine produces a yellow stain on a piece of filter paper
moistened with cone, silver nitrate solution. A drop of water
added to this changes the yellow spot to black. This is Gutzeit's
test.

Detection of Antimony

The insoluble residue after fusion may contain Cu, Sb, or Sn.

1. Test for Cu. — Dissolve in dilute HC1. The solution may
be colored light blue, excess of NH4OH pioduces a deep blue
color. Potassium ferrocyanide gives a deep red precipitate.

Test for Tin. — The insoluble residue is dissolved in HC1 as
in testing for copper. The tests for tin depends on the fact
that tin chloride is a reducing agent.

1. Add a few drops of mercuric chloride. If tin is present it

398 CHEMICAL PHARMACOLOGY

reduces this to calomel which precipitates. When heated this
precipitate is changed to metallic mercury.

Test for Antimony

Dissolve in dilute hydrochloric acid by aid of heat. Introduce
into Marsh gas apparatus and test in the same way as for arsenic.

1 . Differences between Arsenic and Antimony. — The antimony
mirror in the Marsh gas apparatus is deposited on both sides of
the flame. The metal in contact with the heated flame fuses
to the glass and is silver white. It sublimes with difficulty.
Arsenic volatilizes readily.

2. Nitric acid dissolves both antimony and arsenic mirrors.
When neutralized with ammonium hydroxid, silver nitrate
precipitates silver arsenate Ag3AsO4 which is reddish, with
antimony there is no reddish precipitate.

3. The spot produced on a cold porcelain surface when held
to the Marsh gas flame by arsenic is not heavy, is brown and
lustrous, and dissolves readily in sodium hypo chlorite.

The antimony spot is heavy velvet like, not lustrous and is
insoluble in hypochlorite.

Detection of Metals Whose Sulphides are Insoluble in Ammonium

Sulphide
This group includes:

Bismuth Copper

Cadmium Lead

Mercury

1. Treat these sulphides on the filter with dilute nitric acid.
All dissolve except mercury — save the filtrate for further work.

Test for Mercury. — Dissolve the sulphide with hot dilute HC1
containing a crystal of potassium chlorate. Filter, evaporate
to dryness on a water bath, and dissolve in 5 cc. 5 per cent. HC1,
filter and test filtrate for mercury, as follows :

1. To a portion add a few drops of stannous chloride. The
mercuric chloride is reduced to calomel which is precipitated.
Excess of stannous chloride especially if heated reduces the calo-
mel to metallic mercury.

2. Place a few drops of the solution to be tested on a piece of
clean copper. A gray spot with silver luster is deposited if

TOXICOLOGY 399

mercury is present. Wash with water, alcohol, and ether, dry
and place the copper in a small test tube. Heat over free flame.
Mercury sublimes and collects in metallic globules on the cool
sides of the tube. A crystal of iodine placed in the warm tube
vaporizes and scarlet mercuric iodide is formed.

3. Dilute potassium iodide added to a solution of HgCl2 pre-
cipitates the red iodide HgI2.

Examination of the Nitric Acid Solution

This may contain Pb, Cu, Bi and Cd nitrates.

Evaporate to dryness and dissolve in a little hot water, add
dilute sulphuric acid. Lead precipitates — filter. The sulphates
of Cu, Bi and Cd are soluble. Test the filtrate for these.

Copper and Bismuth Tests. — Add excess of ammonium hy
drate, if Cu is present it produces a blue color. If Bi is present,
it is precipitated as Bi(OH)3. Filter dissolve ppt. in dilute HC1.
Pour into 50 cc. water. A white precipitate of BiOCl proves the
presence of bismuth. If cadmium be present, it will give a
yellow precipitate with hydrogen sulphide. If present with
copper, add solid KCN to the blue color, until the color dis-
appears.

Then pass hydrogen sulphide. The copper remains in solu-
tion. As K4Cu2(CN)6 while yellow CdS is precipitated.

CHROMIUM AND ZINC

If present these are found in the H2S filtrate.
Detection of Zn

Make one half of the filtrate alkaline with ammonium hydrate
and add ammonium sulphide. This will precipitate Zn, but
there may be a precipitate even if no Zn is present, because
solutions from animal matter contain traces of iron, alkaline
earths, phosphates, etc. Add acetic until faint acid reaction;
this dissolves phosphates except ferric phosphate. Filter, wash
with water, dry and ignite in porcelain crucible. A drop of
ammonium nitrate aids oxidation — cool. Add dilute sulphuric
acid, boil and filter. This converts Zn into ZnS04 — divide the
filtrate into two equal parts.

(a) Add dilute NaOH to precipitate iron which may be present

400 CHEMICAL PHARMACOLOGY

as ferric phosphate. Filter, add a few drops of ammonium sul-
phide. This precipitates ZnS as a white flocculent precipitate.
(b) Add ammonium hydroxide and filter to remove ferric
phosphate. Acidify filtrate with acetic acid. Zn if present can
be precipitated with hydrogen sulphide as a white precipitate.

Detection of Chromium

Evaporate a portion of the hydrogen sulphide filtrate almost to
dryness, add about 1 gram each of sodium carbonate and potas-
sium nitrate — dry and add .a little at a time to a hot crucible
containing fused potassium nitrate. Heat until fusion is com-
plete. This oxidizes chromium to chromates. Cool and dis-
solve in water, and filter. The filtrate is yellow if chromium is
present, acidify with acetic acid and add a little lead acetate;
yellow lead chromate is precipitated.

Detection of Lead, Silver and Barium

The residue from the fusion with potassium chlorate may con-
tain lead, silver or barium. The residue is dried in an air oven,
and ground in a mortar. Then 3 times the amount of a mixture
of potassium nitrate and sodium carbonate is added and the
mixture fused in a crucible adding a little potassium nitrate to
complete the fusion. This destroys fats and other organic
matter. Cool and dissolve in water. Transfer to a flask and
pass C02 through the flask. The precipitates lead as the car-
bonate. Filter, the precipitate may contain lead and barium
carbonate and metallic silver and silver oxide. This silver gives
the precipitate a gray color. Wash with water and dissolve in
dilute nitric acid. Evaporate to dryness and dissolve in hot
water. Add HC1 and heat, this precipitates silver, filter and
add H2S to precipitate lead. Filter and heat to expel the excess
of H2S. Add dilute H2S04 to precipitate barium. The con-
firmatory tests need not be given.

SYNOPSIS OF METALLIC POISONS

The material is boiled with dilute hydrochloric acid (about
12 per cent.) and potassium chlorate added until a pale yellow
solution results. This destroys organic matter and dissolves the
heavy metals. A little sulphuric acid is added and the solu-
tion filtered.

TOXICOLOGY

401

Filtrate may contain — As, Sb, Sn, Cu,
Hg, Pb, Bi, Cu, Cd, Cr, Zn.
Add H2S

Precipitate may — con-
tain— Pb, Ag, Ba.

Precipitate — Dissolve precipitate with
yellow ammonium sulphide and am-
monium. Filter.

Filtrate contains — Cr
and Zn.

Filtrate contains —
As, Sb, Sn, Cu.

Residue — Hg, Pb,
Bi, Cu and Cd.

SULPHURIC ACID

Sulphates are present in small amounts in all vegetables and
animal matter. The appearance of the tongue and stomach as
well as the amount after sulphuric acid poisoning should settle
any case of doubt. The tongue may be dark or boiled looking
due to the formation of methemoglobin, hematin, etc.

I. The finally divided stomach and tissues reacts strongly
acid. When extracted with water and filtered, the filtrate is acid.

II. The barium chloride gives a precipitate which is insoluble
in HC1. The amount of H2SO4 may be determined by igniting
the precipitate, and weighing in a weighed crucible or by titra-
tion of the water extract as under HC1.

III. When the water extract is evaporated on a water bath
and then over a free flame white fumes of SO 2 are evolved. A
particle of sugar, or any organic matter added to this heated
solution will be carbonized.

Nitric Acid. — Nitrates occur only in traces in foods and or-
ganic matter. In a case of poisoning with nitric acid, the parts
of the body touched by it are yellow — xantho-protein test. If
taken in dilute form nitric acid is excreted in the urine as nitrates.

Tests

I. The water in extracts gives the tests for mineral acids.

II. It distils after it reaches a certain concentration. The

402 CHEMICAL PHARMACOLOGY

protein material in the distillation flask is yellow — xantho-pro-
tein. If distillation is carried far enough, the brown vapors of
nitrogen peroxid appear.

III. Brucine test: Mix part of the distillate with an equal
volume of a solution prepared by mixing 1 gram brucine in 5 cc.
dilute sulphuric acid and 95 cc. water. Pour this mixture care-
fully on concentrated sulphuric acid in a test tube. If nitric
acid is present, a black ring is formed between the solutions.

IV. Saturate the liquid to be tested with ferrous sulphate. Pour
this upon concentrated H2SO4. A black zone appears between
the liquids.

V. Nitric acid evolves red brown vapors of NO2 when clean
metallic copper is added.

OXALATES AND OXALIC ACID

Extract the finely divided material with 3-4 volumes of hot
absolute alcohol acidified with HC1. Cool to about 10°C. and
filter through dry paper. Fats and proteins are removed. Add
20 cc. water to prevent the formation of ethyl oxalate and evapo-
rate the alcohol. The residue may again be extracted with
alcohol and evaporated. Make alkaline with ammonia, filter
if there is a precipitate and to the clear filtrate add calcium
chloride solution. A precipitate of octahedron crystals or en-
velope shaped crystals of calcium oxalate results. These should
be examined under the microscope. If it is desired to determine
the amount of oxalic present, this may be done by igniting the
precipitate in a weighed crucible as CaO.

CaO:H2C2O42H2O : : 56 : 126
56 : 126 = 0.444

Consequently the Weight of the precipitate multiplied by 0.444 =
gives the amount of oxalic acid.

To get purer crystals of calcium oxalate, for identification, it
is sometimes advised to extract the water solution from the
alcohol filtrate with ether, and use the residue after evaporation
for the test. This gets rid of some interfering bodies which may
be present in the alcohol extract.

TOXICOLOGY 403

ALKALIES

The tissues after alkali intoxication react blue to litmus and are
soft and greasy, if poisoning has occurred from ammonia it may
be recognizable by its odor. To detect ammonia, or to estimate
the amount, it will be sufficient to extract with water, filter —
add 20 cc. strong NaOH and distil. The distillate reacts alkaline
and the amount may be titrated with N/l NaOH, using cochineal
as the indicator.

FIXED ALKALIES

Extract with water, filter. The filtrate reacts alkaline, the
fingers moistened with it feel slimy. The amount may be
titrated with N/l acid using phenolphthalein as the indicator
and alcoholic extract of the tissues shaken with freshly precipi-
tated washed mercurous chloride gives a black compound, which
is soluble in nitric acid.

POTASSIUM CHLORATE

I. Extract the tissues with water and filter, add excess of silver
nitrate and filter if there is a precipitate; add a little sul-
phurous acid and heat. If chlorate is present this decomposes
it with the formation of a chloride, which gives a precipitate with
the excess of AgN03 in the solution:

AgC103 + 3H2S03 = AgCl + 3H2S04

Add dilute HNO3 — silver sulphite dissolves, if present, silver chlo-
ride is insoluble.

II. Chlorates liberate chlorine from hydrochloric acid and the
gas will liberate iodine from potassium iodide.

(a) Heat a solution containing a chlorate with concentrated
HC1 — free chlorine is given off. Pass the gas into a solution of
potassium iodide; free iodine is liberated and can be. separated
by dissolving in chloroform.

Chromic acid and bichromates also liberate chlorine from
hydrochloric acid.

ACTIVE SUBSTANCES WHICH MAY CAUSE POISONING, BUT

WHICH ARE HARD TO DETECT, AND WHICH FIND NO

PLACE IN THE STAS-OTTO METHOD

Cantharidin is the vesicating principle of Spanish fly.
Chemically it is the anhydride of cantharidic acid.

404

CHEMICAL PHARMACOLOGY

C CH2 - COOH

/ \/
H2C C— 0|H =

| CH2
H2C \C-CO !OH

\ /
C
H2
Cantharidic acid

H
C

CH2— COOH

H2C C— O

| CH2|
H2C \C-CO

\ /
C
H2
Cantharidin

H20

It occurs as small, colorless glistening crystals which melt at
214°-218°C. and sublimes at higher temperatures in white
needles. The pharmacopeia gives a method for the extraction
of the active substance from Spanish fly. There is no chemical
test for it. The physiological test consists in dissolving a little
of the substance in a fatty oil and rubbing it on a spot on the arm
or chest. A blister will be formed in a short time if cantharidin
be present.

SANTONIN, SULPHONAL, TRIONAL

These substances are not extracted under the conditions of the
Stas-Otto process. They are not soluble in acid ether solution.
Extract the tartaric acid solution of the organs with hot alcohol,
filter. If a colored solution results add a little animal charcoal
and heat again. Filter while hot, cool and extract the acid
solution several times with chloroform. Evaporate the chloro-
form which may contain sulphonal, trional, santonin.

1. Santonin, see page 220.

2. Sulphonal, see also page 46.

3. Trional, see page 46.

Cytisine is an alkaloid of unknown structure, CnHi4ON2,
found to the extent of 1.5 per cent, in the ripe seeds of Golden
Chain — Cytisus Laburnum. Cytisine forrns large colorless
rhombic crystals which melt at 153°. It causes convulsions
similar to strychnine, but it is also irritating to the gastro-intesti-
nal tract, and for this reason may cause vomiting, and it also
stimulates the vomiting center directly. Cytisine also resembles
nicotine in action. In the tartaric extract in the Stas-Otto

TOXICOLOGY 405

method, it can be extracted with chloroform in alkaline solu-
tion of NaOH.

Test I. — Ferric chlorid colors cytisine and salts blood red. The
color is discharged by hydrogen peroxid which changes to blue when
heated on water bath.

Test II. — Nitrobenzene containing dinitro-thiophene pro-
duces a reddish violet coloration.

Digitalis. — Nothing is known regarding the fate of digitalis in
the body, consequently extracts of the tissues cannot be tested
chemically for it. It has been claimed that more of it accumu-
lates in 4he heart than in other tissues. This has been shown by
physiological tests; no test for the drug as a whole is at hand.

Digitonin when dissolved in sulphuric acid, gives a red color
with bromine water.

Digitoxin. — I. This dissolves in concentiated HC1, with a
brownish green coloration, which is unchanged by the addition
of bromine.

II. Kiliani's test. Digitoxin dissolved in a little glacial acetic
acid containing a trace of ferric sulphate. When superimposed
on strong sulphuric acid containing a trace of ferric sulphate
gives a dark ring. On standing the acetic acid layer becomes a
deep indigo blue.

Digitalin. — This dissolves in concentrated sulphuric acid with
an orange yellow color, which changes to red on addition of
bromine water, or ferric chloride, or after an hour with the
addition of these' oxidizing agents.

ERGOT

Ergot contains a red pigment — sclererythrin — which is charac-
teristic of ergot. This cannot be found in tissues poisoned with
ergot, but the material containing ergot, like flour, bread, etc.
will give the following test.

Test I. — If flour containing ergot be treated with a very
dilute solution of anilin violet, the stain is absorbed by the
damaged particles of the grain, while the normal particles are
not stained.

Test II. — Extract the flour with 10 to 15 times its volume
of 40 per cent, alcohol heated to 40°. Filter and add basic lead
acetate to the filtrate. Filter. Press the precipitate between

406 CHEMICAL PHARMACOLOGY

filter papers warm and add a few drops of saturated borax solu-
tion. If ergot be present a red violet color appears.

REAGENTS AND SOLUTIONS

Ammonium Molybdate Solution for Phosphates. — Dissolve
50 gm. of molybdic acid in 72 cc. cone, ammonia and 136 water;
slowly and with constant stirring pour the solution into 245 cc.
of nitric acid, cone., and 574 cc. of water. Keep this mixture in
a warm place for several days. Decant and preserve in glass
stoppered bottles.

Barfoed's Reagent is prepared by dissolving 45 grams of neutral
cupric acetate crystals in 900 cc. of water and filtering. Add
6 cc. of 10 per cent, acetic acid to the filtrate and dilute to a
liter. A portion of the reagent when heated on the water bath
should show no reduction.

Benedict's Qualitative Reagent for Glucose.

Copper sulphate 17.3 gm.

Sodium citrate 173. 0 gm.

Sodium carbonate, anhydrous 1000.0 gm.

Dissolve the copper sulphate separately in about 150 cc. of
water and add slowly to the filtered solution of the other two in
about 800 cc., and make up to 1000 cc.

Esbach's Reagent. — Dissolve 10 grams of picric acid and 20
grams of citric acid in 1 liter of water.

Fehling's Solution

A. Copper sulphate 69 . 28 gms.

Water 1000.00 cc.

B. Potassium and sodium tartrate 346.0 gms.

Potassium hydroxide. 100.00 gms.

Water to 1000.00 cc.

Mix equal volumes of A and B, and' then add four volumes
water just before using. This mixed solution does not keep well.

Froehde's Reagent is a solution of molybdic acid in sulphuric
acid prepared by dissolving 0.5 gram of molybdic acid in 100 cc.
of hot, pure concentrated sulphuric acid. The solution should be
colorless and it does not keep long.

Gold chloride is used in a 3 per cent, aqueous solution.

TOXICOLOGY 407

Iodine Solution, aqueous (Lugol's). — Dissolve five grams of
iodine and ten grams of potassium iodide in about 20 cc. of water.
When completely dissolved add a sufficient quantity of distilled
to make the product weight 100 grams.

Iodine solution ; alcoholic, about 1 gram of iodine in 100 cc. of
alcohol (95 per cent.).

Mayer's Reagent (mercuric potassium iodide solution) is
prepared by dissolving 1.36 grams of corrosive mercuric chloride
in 60 cc. of distilled water, and 5 grams of potassium iodide in
10 cc. of water. Mix the two solutions and then add sufficient
water to measure 100 cc.

Millon's Reagent. — Dissolve 100 grams of mercury in 200
grams of strong nitric acid, by the aid of heat finally, and after
cooling dilute the solution with twice its volume of water.

Nessler's Reagent. — Place 35 grams of potassium iodide and
50 grams of mercuric iodide, both finely powdered, in a 500 cc.
volumetric flask and add about 200 cc. of water: Now add to this
mixture in the flask; with constant shaking, 250 cc. of a cooled
20 per cent, solution of sodium hydroxide. Then make up to
500 cc. Set aside in a warm place for several days and decant
the clear liquid for use. *

Phospho-tungstic acid solution is prepared by adding a little
20 per cent, phosphoric acid to an aqueous solution of sodium
tungstate.

Platinum chloride is used in a 5 per cent, solution.

Sodium Hypochlorite Solution. — Prepare a solution of calcium
hypochlorite from bleaching lime and then precipitate the
calcium by adding an excess of sodium carbonate — allow to
settle and use the clear supernatant liquid.

Magnesia Mixture. — Dissolve 52.5 grams of crystallized
magnesium sulphate and 105 grams of ammonium chloride in
about 300 cc. of water and add 180 cc. of concentrated ammon-
ium hydroxide. Dilute to 600 cc. Filter off turbidity which
may develop on standing.

INDEX

Abrin, 323, 381
Acetal, 58, 184
Acetaldehyde, 55
Acetanilide, 112, 120, 380, 392
Acetic acid, 66

Acetoacetic acid, formation by ami-
no acids, 319-320

Aceto-catechol, activity of deriva-
tives of, 232-233
Acetone, 62-63, 380, 387
Acetphenetidin, 111, 120
Acetyl atoxyl, 365
Acetyl number, 155
Acid number of fats, 151
Acid taste, 208
Acidosis, 357-^359

detection of in body, 359
Acids, pharmacology of, 78
Aconitine, 296
Acridine, 132, 363
Acrolein, 30
Adenase, 287
Adenine, 283-287
Adrenaline, 245
Adrenalone, 236
Adsorption, 349
Aetioporphyrin, 331
Agar, 140

Agglutinins, vegetable, 322
Agmatine, 238
Atenine, 304, 312
Albuminoids, 300
Albumins, 299
Alcohol, absolute, 19

action of, 20

amyl, 26

as a food, 21

butyl, 24-25

cetyl, 30

Alcohol, dihydric, 28

fate of in body, 22

myricyj, 30

pharmacology of in relation to
chemistry, 31

propyl, 24-25

toxicity of various, 25

trihydric, 29
Alcohols, 17

Aldehydes, 48-49
Alkalies, 381, 403
Alkalinity, actual and potential, 355

of blood, 356
Alkaloidal factors, 297
Alkaloids, 223-298

chemistry of, 225

general characteristics of, 224

isolation of, 292

utilization by plant life, 298
Alkanet, 334
Alkaptonuria, 320-321
Alkyl groups, physiological action

of, 230

Alkyl radicals, depressive action of, 32
Alizarine-Bordeaux, 132
Allantoine, 290-291
Alloxan, 288
Alloxantine, 288
Aloes, 195
Amber, 181
Amines, 225-228
Amines, physiological action of, 230-

231
Amino acids, metabolism of, 315

occurrence in plants, 302

occurrence in the urine, 317

optical properties, 314

pathology of, 319-322

properties of, 308-309
Ammoniac, 182
Ammonium molybdate solution, 406

409

410

INDEX

Amygdalin, 193-198

Analgesics, 41

Anesthesia, stages of ether, 33-34

theories of, 36
Anesthesine, 267
Anesthetics, 32
Aniline, 110, 230, 380-387
Aniline tests, 112
Animal glucosides, 201
Anisol, 90
Annato, 334

Anthracene derivatives, 195
Anthracenes, 129
Anthragallol, 132
Anthranilic acid, taste of, 210
Anthranol, 222
Anthrapurpurin, 132
Anthraquinone, 129
Antimony, 381, 395-397, 401
Antipyrine, 113, 117, 119, 380-381,

392

Apocodeine, 279
Apomorphine, 276, 279
Arbutin, 192
Arecoline, 257-258
Arginine, 234, 238, 303, 308
Aristol, 366
Aromatic alcohols, 101
Arrenhal, 366
Arsacetin, 365
Arsenic, 381, 395-398, 401

compounds, 364

fate in body, 367-368
Arsphenamine, 366
Asafcetida, 176, 182
Ash, 10-11

Aspartic acid, 306, 315
Aspidium, 181
Aspidosamine, 296
Aspidospermatine, 296
Aspirin, 106
Astringents, 214, 369
Atophan, 109
Atoxyl, 364
Atropine, 239, 244, 251, 271-272,

368, 380
Attar of Roses, 169

Balsams, 180-182

Barbituric acid, 285-286

Barfoed's reagent, 406

Barium, 381, 394, 399-401

Bear fat, 145

Beer, 20

Bee's wax, 164

Benedict's sugar reagent, 406

Benzaldehyde, 100, 103, 193, 380,
387

Benzene, 13, 87-89

Benzine, 13, 14

Benzoic acid, 104, 105

Benzyl alcohol, 101-102

Benzyl amine, 230

Berberine, 262

Betaine, 234

Bikhaconitine, 296

Bile pigments, 333

Bismuth, 381, 395, 398-401

Bitter principles, 204

Bitter taste, 208-214

Bitters, pharmacologic classifica-
tion of, 205

Black pepper, 181

Blood pressure, effect of amines on,
231

Boiling point, changes with mole-
cular weight, 15

Borneol-camphor, 177

Brandy, 20

Bromine compounds, 87

Bromine test for fats, 158

Bromopin, 86

Brucine, 251, 257, 380

Brucine, ethyl, 228

Buffer value, 355

Cacodyl oxide, 365
Cacodylic acid, 365
Cadaverine, 231, 234, 240-241
Cadmium, 381, 395, 398, 401
Caffeine, 287, 380-381, 392

INDEX

411

Caffeine, action of, 288

assay of, 292

economic use of, 291

diuretic action of, 289

fate of, 290

group, 283

isolation of, 293
Camphor, 178-179
Camphor monobromata, 178
Camphorol, 179
Cantharidin, 381, 392, 403-404
Caoutchouc, 182
Capsicum, 182
Caramel, 334
Carbamate, 313

Carbamino, reaction of amino acids,
Carbon disulphide, 380, 388
Carbohydrate tests, 137
Carbohydrates, 135
Carbolic acid, distribution of in

body, 92

Carbonic acid, 67-68
Carminatives, 177
Carmine, 334

Carnivora, poisoning of, 374
Carvacrol, 181
Castor oil, 149
Castor oil group, 146
Catechol, 93-94, 233, 235
Celluloses, 136, 140
Central nervous system, toxic ac-
tion of heavy metals on,
371

Cerebron, 199
Cerebronic acid, 199
Chaulmoogra oil, 148
Chloral, 57-61
Chloral, fate of in body, 59

in urine, 61

Chloral hydrate, 380, 389
Chloraldehyde, 57-58
Chlorates, 381, 403
Chloretone, 63-64
Chlorocodeine, 280
Chloroform, 34-35, 41-42, 380
Chlorophyll, 269, 328-335

fate in the body, 333

Chlorophylls and hemoglobins, re-
lationship of, 329

Cholesterol, 153, 166-169

Choline, 234, 240, 242

Chromium, 381, 399-401

Chromoporteins, 300

Chrysophanic acid, 131, 196, 222

Chrysorobin, 219, 222

Cinchona bark, 260

Citric acid, 73-74

Cloves, 177

Clupanodonic acid series, 148

Coca, 265, 267

Cocaine, 251, 265-267, 380

Cocoanut oil, 147

Codeine, 239, 276, 278-279, 281, 380

Coffee, caffein in, 286

Colchiceine, 295-296

Colchicine, 295-296, 380, 392

Colliding 250

Colloidal copper, gold, platinum and
silver, 372

Colloidal metals, 372

Colloids, 335-350

Colloids, changes in during precipi-
tation, 342

Colloids, electrical condition of, 341

Colloids, protective power of, 342

Colormetric method, 351

Coniferin, 200

Coniferyl alcohol, 200

Coniine, 239, 250-252

Convallamarin, 197

Copaiba, 182-183

Copper, 177, 395, 397-399, 401

Coriander, 177

Corrosive salts, 369

Cottonseed oil, 149, 177

Cranberries, 183

Creatine, 249

Creatinine, 249

Creosote, 98, 380, 390

Cresols, 9&-97
Crocus, 334
Croton, 322, 381
Croton oil, 149
Crude fiber, 140

412

INDEX

Cubebs, 177, 182
Cudbear, 334
Curara, 228, 230
Curcin, 322, 381
Curcumin, 334
Cyanogenetic glucosides, 198
Cysteic acid, 320
Cysteine, 306, 320
Cystine, 306
Cystinuria, 241
Cytisine, 271, 381, 404

Ergot, derivatives of, 245
Ergot alkaloids, 234
Ergotinine, 296
Ergotoxine, 234, 245, 296
Esbach's reagent, 406
Eserine, 294
Ethane, 16
Ether, 34, 36-39
Ethyl alcohol, 19, 380, 389

tests for, 23-24
Ethyl chloride, 41
Eugenol, 200
Europhen, 82

Dhurrin, 198

Diastases, 324

Diffusion, 375

Digallic acid, 214

Digitalein, 198

Digitalin, 197

Digitalis, 197, 381, 392, 405

Digitoxin, 197

Disaccharides, 135

Dithymol-di-iodide, 81-82

Diuresis, 289

Drug, definition of, 1

Drugs, classification of, 2-4

Dulcin, taste of, 210

Ecgonine, 266
Elaidic acid, 148
Elaidin test for fats, 157
Elaterin, 219, 222
Electro-potential method, 351
Emodin, 131, 133, 196
Emulsoid, 338-339
Enolforms, 116
Enzymes, 323-328

fate in body, 325
Epinephrine, 231, 234-237

stimulation of sympathetics by,
235-236

tests, 237
Ergot, 231, 244-245, 320, 381, 405

Fat, appearance after anesthesia,
159

butter, 147

formation from protein, 163

formation of from carbohy-
drate, 162

from carbohydrate, 161-162

from fat, 161-162

human, 147

in urine, 164

influence of diet on, 146

wool, 165
Fats, constants of, 152

fate of, 160

fate of in the body, 164

hydrogenated, 155

melting point of, 152

properties of, 149-150

rancidity of, 159

significance of, 160
Fatty acids, fats and oils, 144
Fehling's solution, 138, 406
Fermentation, 139
Ferments, table of, 326-328
Fixed and volatile oils, differences

between, 174
Flavopurpurin, 133
Flavoring agents, 177
Food, definition of, 1
Formaldehyde, 50-54
Formic acid, 65

INDEX

413

Fowler's solution, 364
Frangula, 196
Froehde's reagent, 406
Furfural, 137
Fusel oil, 27

Galactose, 138

Galactosides, 184

Gallic acid, 95, 216

Gallotanic acid, 214

Gamboge, 182-183

Gas chain method, 351-352

Gas pressure, relation to osmotic

pressure, 375-377
Genito-urinary disinfectants, 177
Gel formation, 339
Gin, 20
Ginger, 182
Gliadins, 300
Globulins, 299
Glucose formation by amino acids,

319-320
Glucophore group, definition of, 211

list of, 211-214
Glucoproteins, 300
Glucosides, 184-204

action of, 202

animal, 199

composition of, 189

cyanogenetic, 198

fate of, 202

functions of, 202

table of, 191

tests for, 203-204
Glutamic acid, 306, 316
Glutelins, 299
Glyceric acid, 316
Glycerine, 29, 312
Glycocoll, 304
Glycol, 28-29
Glycolaldehyde, 29
Glycuronic acid, 176
Glycyrrhizin, 198
Glyoxal, 29

Glyoxaline, 273
Goa powder, 222
Gold chloride, 406
Gout, 290

Guaiacum-wood, 182
Guanidine derivatives, 238
Guanine, 283-287
Gum resins, 181-183
Gums, 136, 142
Gynocardin, 198

Hsematin, 332

Haematinic acid, 329

Haemoporphyrin, 331

Heart, effect of alcohols on, 25

Heavy metals, 368-372

Helleborin, 198

Hematic acid, 333

Hematoporphyrin, 331

Hemicellulose, 141

Hemoglobins, 300, 333

Hemotoxylin, 334

Herbivora, poisoning of, 374

Hetero-cyclic compounds, 134

Hexamethylenamine, 54

Hexone bases, 238

Hippuric acid, 106

Histamine, 234, 246, 322

Histidine, 238, 245-246, 308, 322

Histones, 300

Homogentisic acid, 317-318, 321

Hordenine, 237

Hyderabad Commission, 37

Hydrargyri iodidi, 364

Hydrastine, 262-264, 380

Hydrastinine, 262-264

Hydro-cotarnine, 265

Hydrocyanic acid, 75-77, 380

Hydrogen, 7-8

Hydrogen ion concentration, 352-

354

Hydroquinone, 93
Hygrine, 267
Hyoscine, 272
Hyoscyamine, 239

414

INDEX

Hypnotics, 41, 43, 45
Hypoquebrachine, 296
Hypoxanthine, 291

Indaconitine, 296
Indican, 200, 334
Indigo Blue, 201

white, 201
Inks, 215
Inorganic acids, pharmacology of,

373-4

Indoxyl, 201, 335
Iodine number of fats, 154-155

solution, 407
lodoalbin, 84

lodoform, 80-81, 85-86, 380, 390
lodol, 82
Indole, 202, 335
lodopin, 83
lodo-spongin, 84

Irritant action of heavy metals, 371
Isoamylamine, 234
Isomerism, 24
Isopurpuric acid, 78

Jalap, 182
Jalapin, 193
Japaconitine, 296

Kerosene, 14

Ketones, 62

Kidney function, 127

Kola nuts, caffeine in, 286

Kuskhygrine, 267

Kynurenic acid, 321

Lactams, 310

Lactic acid, 74-75, 315

Lactims, 310
Lanolin, 165, 178
Laudanine, 279
Lavender, 177, 334
Lead, 381, 395, 398-401
Lecithin, 243
Lecithoproteins, 301
Lemon, 177
Leucine, 26, 302, 305
Lignoceric acid, 199
Ligroin, 14

Linolic acid series, 148
Linseed oil group, 146
Lipoproteins, 301
Losophan, 83
Lotusin, 198
Lupine, 271
Lupulin, 182
Luqor arseni, 364
Lyotrope, 340-341
Lysine, 238, 308

Magnesia mixture, 407

Malodorous oils, 177

Malonic acid, 70

Mandelic acid, 194, 271

Maumene or sulphuric acid test, 158

Mayer's reagent, 407

Menthol, 179-180

Mercaptans, 30

Mercury, 381, 398, 401

Mesotan, 108

Meta-proteins, 301

Methane, 15-16

Methyl alcohol, 18, 380, 390

Methylated compounds, 249

Methylation in animal body, 249,
270

Meyer-Overton, Theory of anes-
thesia, 36

Millon's reagent, 407

Mineral acids, 381, 401

Monosaccharides, 135

Moore and Roaf, Theory of anes-
thesia, 37

INDEX

415

Morphine, 239, 251, 276, 281, 381

methyl, 228

pharmacology of, 279
Mucic acid, 137
Murexide, 79

test, 288
Muscarine, 234, 240

pharmacological action of, 244
Mustard oil, 192
Myronic acid, 192
Myrrh, 183

Naphthalenes, 120

Naphthols, 129

Narceine, 381

Narcotine, 251, 264, 279, 380

Neo-salvarsah, 367

Nessler's reagent, 407

Neurine, 240, 242

Neutral principles, 219

Nicotine, 239, 247, 251-254, 380

Nicotine, ethyl, 228

Nicotinic acid, 255-256

Niger, 271

Nitric acid, 401-402

Nitrobenzene, 380, 390

Nitrogen, 7-9

Nitrogen bases, 223-298

Nitrophenols, 112

Nosophen, 83, 126

Novacaine, 267

Nucleic acid, 290

Nucleo proteins, 300

Odors, chemistry of, 207-208

classification of, 205-207

physics of, 207-208
Oils, classification of, 145-146

drying, 145

non-drying, 145

essential, 169

ethereal, 169

solubility in alcohol of, 149

Oils, malodorous, 177

Oleic acid series, 147

Oleoresins, 181-182

Olive oil, 149

Olive oil group, 145

Opianic acid, 262-263

Opium, 381

Opsonic index, 344

Optical activity, 71-72

Oxalic acid, 69

Organic acids, 64

Ornithine, 238, 241

Osmophore groups, 207

Osmosis, 375

Osmotic pressure, relation to
boiling point, 377-8

Osmotic pressure, relation to freez-
ing point, 377-378

Oxalates, 402

Oxalic acid, 381

Oxygen, 10

Palm oil, 148

Pancreatic ferments, 324

Papaverine, 261, 282

Paraffins, 12

Paraldehyde, 57

Paralytic action of alkaloids, 228

Pectin, preparation, 144

Pectins, 143

Pelletierine, 270

Pentosides, 184

Peppermint, 177

Peptides, 301

Peptones, 301

Peru, balsam of, 183

Petrolatum, liquid, 14

Petroleum, 13

Petroleum ether, 14

Pharmacology, definition of, 1

Phenacein, 112, 121, 380, 392

Phenanthrene, 275

Phenetidin, 111-112

Phenol, properties of, 91-92

Phenols, 90, 380, 390

416

INDEX

Phenols, reactions of, 99-102
Phenolphthalein, 124
Phenolsulphonephthalein, 127
Phenyl-alanine, 303-307, 321
Phloretin, 195
Phloridzin, 189, 194
Phloroglucinol, 95

taste of, 210
Phosphine, 363-364
Phosphoproteins, 300
Phosphorus, 361-363

isolation of, 380-387
Phosphotungstic acid solution, 407
Phrenosin, 199
Phthalic acid, 125
Phthalimide, 210
Physostigmine, 294-295, 380
Phytosterol, 153
Phytotoxins, 322-323
Picolinic acid, 255
Picramic acid, 78, 99
Picric acid, 98-99, 380, 392
Picrotoxin, 219-222, 380, 392
Pilocarpine, 244, 274-275, 380-381
Pilocarpine, action of, 274
Piperazine, 310
Piperic acid, 248
Piperidine, 135, 226, 242, 247-248,

250, 268
Pituitarine, 246
Plant bases, 223-298
Platinum chloride, 407
Podophyllum, 182
Poison, definition of, 1
Poisons, isolation of, 379-389
Poisonous proteins, 322
Polysaccharides, 135
Potassium cyanide, 387
Precipitation of colloids, 369-371
Pressor substances, 231
Prolamines, 300
Proline, 303,. 307-308
Protamines, 300
Proteans, 301
Proteins, 298-304

coagulated, 301

color reactions of, 303

Proteins, comparison of animal and
vegetable, 302

composition of, 303

conjugated, 300

derived, 301

English classification, 302

hydrolytic products of, 304

precipitation reactions of, 304
Proteoses, 301
Proximate principles, 2
Prulaurasin, 198
Ptomaines, 239, 381
Purin metabolism, 290
Purine, 283-287
Purpuric acid, 288
Purpuroxanthin, 133
Putrescine, 234, 240
Pyramidon, 118-119, 380
Pyrazolon, 115
Pyridine, 134

alkaloids, 247-249, 251
Pyrocatechol, 94
Pyrocatechol, taste of, 210
Pyrogallic acid, 9o
Pyrogallol, 95, 216

taste of, 210
Pyrrol, 250, 269, 330
Pyrrolidine alkaloids, 267
Pyrollidine, 268-269
Pyruvic acid, 312

Quaternary ammonium bases, 228-

231

Quebrachamine, 296
Quebrachine, 296
Quebractio alkaloids, 296
Quinine, 251, 259-261, 380
Quinol, 93
Quinoline, 258

alkaloids, 259
Quinones, 93, 131

Rattlesnake fat, 146

Reaction of living matter, 350-361

INDEX

417

Reichert Meissel number, 156
Regulating mechanism of blood

reaction, 354
Resins, 181-182
Resorcinol, 42, 92-93

taste of, 210
Rhubarb, 196
Ricin, 322, 381
Ricinoleic-oleic series, 148
Robin, 322, 381
Rose, 177
Rosolic acid, 42
Rum, 20

Sabromine, 86
Saccharin, 122

taste of, 210

taste of derivatives of, 210
Salicylic acid, 106, 380, 392

tests, 121
Saligenin, 103, 194
Saline taste, 208
Salol, 101, 107
Salol principle, 101
Salt action, 374

pharmacology of, 379
Salts in body, 378
Salvarsan or "606," 366-367
Sambunigrin, 198
Sandalwood, 177
Santonic acid, 219
Santonin, 219-220, 381, 404
Saponification, 177

number of fats, 152
Saponins, 196, 381
Scammonium, 193
Scammony, 182-183
Scillin, 198
Sclero-proteins, 302
Scopolamine, 272, 380
Scopoline, 272
Senna, 196
Serine, 306
Silver, 400-1

Sinapic acid, 243

Sinapin, 192, 243

Sinigrin, 192

Smell, pharmacology of, 205

Soap, cleansing action of, 150-152

Soaps, medicated, 150

Sodium hypochlorite solution, 407

Solanine, 199, 381

Sorensen titration of amino acids,

311

Specific dynamic action, 316
Spermaceti, 30
Sphingosin, 199
Stachydrine, 244, 268
Starches, 136, 138
Stearic acid, 151
Stearoptenes, 178
Sterols, 166
Storax, balsam of, 183
Strophanthin, 195
Strychnine, 239, 251, 256-257, 380

methyl, 228

Stryolene derivatives, 194
Styptics, 369
Succinic, acid,
Sugars, 136

tests for, 139

uses, 139

Sulphonal, 46, 381, 404
Sulphones, 45
Sulphuric acid, 401
Surface tension, 343-348
Suspensoids, 338-339
Sweet taste, 208-314
Sympathetic nerves, stimulation of,

235
Sympathomimetic action, 233

Tannic acid, 96, 214-217

Tannins, 215

Tar camphor, 128

Tartaric acid, 71

Taste, 208-214

pharmacology of, 205
theory of, 211-214 J

418

INDEX'

Taurine, 320

Tea, determination of tannins in,

218

caffein in, 286
Tellurium, 249
Tension of carbon dioxide in respired

air, 360-361
Terpenes, 170-173
Tetranol

Thalleioquine test, 261
Thebaine, 276, 279, 282
Theobromine, 283-287
Theophylline, 283-287
Thymol iodide, 122-123
Thymolis iodidum, 180
Thyreoglobulin, 84
Tiglic acid, 148
Tin, 381, 397, 401
Tolu, balsam of, 183
Toluene, 101-102
Toxicology, 379
Trional, 46, 381, 404
Tropane, 268, 270
Tropic acid, 271
Tropine, 271
Tryptophane, 303, 307
Tyrosine, 231, 307, 317, 321
Tryptophane acid, 321.
Tyramine, 231
Turpentine, 177

Ulcers, 371

Unsaponifiable residue of fats, 153
Unsaturated compounds, physiolo-
gical activity of, 148
Urea, 68-69, 313
Urethane, 43

Uric acid, 283-287,. 291
Urinary changes in acidosis, 360

Valerian, 177

Valine, 305

Vanillin, 200

Vaso-motor reversal, 245

Verworn's Theory of anesthesia, 37

Veratrine, 239 272, 294, 380, 392

Veronal, 380, 392

Vicianin, 198

Vioform, 83

Viscosity, 345-348

Vital activity, 1

Vitamine, 164

Volatile oils, action of, 175

Volatile oils, classification of, 170

Walden's inversion, 314
Wax, Japan, 165
Waxes, 165
Whiskey, 20
White arsenic, 364
Wine, 20

. X

Xanthine, 283-287, 291
Y

Yohimbine, 296
Yohimbinine, 296

Zinc, 399, 401

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