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Full text of "A manual of pharmacology and its applications to therapeutics and toxicology"

A MANUAL 

of 



PHARMACOLOGY 

and its applications to 
THERAPEUTICS AND TOXICOLOGY 



By 
TORALD SOLLMANN, M. D. 

Professor of Pharmacology and Materia Medica in the School of 
Medicine of Western Reserve University, Cleveland 



ILLUSTRATED 




PHILADELPHIA AND LONDON 

W. B. SAUNDERS COMPANY 

1917 



Copyright, 1917, by W. B. Saunders Company 



PRINTED IN AMERICA 

PRESS OF 

W. B. 8AUNDER8 COMPANY 
PHILADELPHIA 



N. THE 
OR ANY 
IN THE 

:NGTHS. 



PREFACE 



In the process of revising the "Text-Book of Pharmacology," it became 
apparent that the extensive development and applications of Pharma- 
cology justified a somewhat more ambitious treatment of the subject. 

Pharmacology comprises some broad conceptions and generalizations, 
and some detailed conclusions, of such great and practical importance 
that every student and practitioner of medicine should be absolutely 
familiar with them. It comprises also a large mass of minute details, 
which would constitute too great a tax on human memory, but which can- 
not safely be neglected. It is the ambition of this book to present both 
types of information without confusion. The matter in the larger print 
aims to give a connected and concise statement of the essentials of pharma- 
cology. The smaller print need not be considered by the reader who 
wishes to obtain merely a general knowledge of pharmacology. It con- 
tains more detailed data for consultation. Side headings have been intro- 
duced liberally to facilitate this use. The bibliographic references are 
intended to put the investigator on the track of further details. 

The volume can, therefore, serve both for study and reference. 
There may be some question as to the general advisability of combining 
text-books and reference books; but in Pharmacology this appears to be 
necessary, since every student may need more detailed information at any 
time. 

These objects necessitated a complete rearrangement, and fairly 
extensive enlargement of the book, and as the work progressed, it appeared 
plain that it meant not merely a revision, but the making of an entirely 
new book. 

With this enlargement of the text, it became necessary to practice the 
utmost economy of matter, in order to bring the contents within a single 
volume. This and other considerations prompted the separation of the 
Laboratory Guide In Pharmacology, which will be issued as a companion 
volume. The illustrations have also been omitted wherever the text could 
be understood without them. A further economy was effected by cur- 
tailing the discussion of the drugs of slight importance, thus leaving more 
space for the relatively few really important drugs. This is in line with 
the modern movement for the restriction of the " Materia Medica." 

I am greatly indebted to my friend, Dr. R. A. Hatcher, for valuable 
help in reading the proofs. 



CONTENTS 



PAGE 

PHARMACOGNOSY 17 

IMPORTANT PLANT CONSTITUENTS 18 

PHARMACEUTIC STANDARDS 22 

PHARMACEUTIC METHODS 23 

Pharmaceutic Assaying, 29. 

CLASSES OF PHARMACEUTIC PREPARATIONS 30 

Watery Solutions, 30 Alcoholic Solutions, 32 Preparations Made by 
Extraction, 32 Mixtures, 35 Solid Preparations, 36 Dosage Forms, 37 

SOLUBILITIES 41 

INCOMPATIBILITY 43 

METROLOGY 45 

GENERAL TOXICOLOGY 49 

Outline of Toxicologic Analysis, 51 Treatment of Poisoning, 54. 

PRESCRIPTION WRITING 59 

Prescription Latin, 63. 

COLORING AND FLAVORING 65 

Coloring, 65 Flavoring, 66. 

THE TREATMENT OF DISEASE 70 

The Chemical and Physical Basis of Pharmacology, 75 The Manifesta- 
tions of Pharmacologic Actions, 78 Classification of Drugs According to 
Selective Action, 80 The Administration of Drugs, 84 Conditions 
Influencing Absorption, 88 The Excretion of Drugs, 90 Dosage (Po- 
sology), 90 Conditions Influencing Drug Actions, 92. 

FERMENTS AND NUTRIENTS 96 

Digestive Ferments, 96 Lactic Acid Ferments, 98 Medicinal Foods, 
99 Diabetes Foods, 100 Cod Liver Oil, 101 Parenteral Alimentation, 
102. 

EMOLLIENTS 102 

Olive Oil and Other Bland Fatty Oils (Olea Pingua), 105 Lard and Simi- 
lar Animal Fats, 105 Woolfat-lanolin, 106 Petrolatum and Other 
Petroleum Products, 106 Waxes, 108 Compound Ointment Bases, 
1 08 Cerates, 108 Glycerin, 109. 

DEMULCENTS OR MUCILAGINOUS SUBSTANCES 109 

Demulcent Teas, no Gelatin, in Starch, in Indifferent Dusting 
Powders, 112 Poultice Masses, 112 Plasters, 113 Mechanical Pro- 
tectives, 113. 

PHENOMENA COMMON TO LOCAL IRRITANTS, CORROSIVES AND ASTRINGENTS . 114 
Fixed Caustic Alkalies, 125 Ammonia, 126 Alkaline Salts and Soaps, 
127 Alkaline Sulphids, 128 Hydrogen Sulphid, 128 Sulphur, 129 
Ichthyol, 130 Thiosinamin, 130 Caustic Acids, 131 Dilute Acids, 
132 The Haloids, 133 Ipdin, 133 Bromin, 134 The Local Actions of 
Metallic Salts, 134 Tannins and Vegetable Astringents, 136 Astringent 
Styptics, 139 Strength of Most Useful Solutions of Astringents and 
Antiseptics, 140. 

IRRITANT VOLATILE OILS AND RELATED DRUGS 141 

Olfactory Stimulants, 142 Hysteric Sedatives or Antispasmodics, 142 
Oil of Turpentine, 143 Terpin Hydrate, 144 Eucalyptol, 144 Rube- 
facient Volatile Oils, 145 Liniments, 146 Juniper Oil, 146 Ecbolic and 
Toxic Volatile Oils, 146 Volatile Oils and Oleoresins Employed in Ure- 



I o CONTENTS 

PAGE 
thritis and Cystitis, 148 Balsams, 149 Insecticides, 150 Mustard 

,ILE ORGANIC IRRITANTS 151 

Cantharidin, 152 Chrysarobinum, 154 Poison Ivy, 155 Physical 
Counter-irritants, 156. 

DRUGS EMPLOYED FOR THEIR LOCAL EFFECTS ON THE ALIMENTARY CANAL . 157 
Stomachics, 157 Simple Bitters, 158 Astringent Bitters, 159 
Aromatic Bitters, 160 Carminatives, 160 Vegetable Cathartics, 161 
The Anthraquinon or Emodin Cathartics, 166 Cascara Sagrada, 167 
Senna, 168 Rhubarb, 169 Aloes, 169 Phenolphthalein, 171 Bile, 
171 Castor Oil, 172 Ricin, 173 Abrin and Jequirity, 174 Cathartic 
is, 174 Jalap, 175 Resin of Podophyllum, 175 Colocynth, Ela- 
terin, and Bryonia, 176 Croton Oil, 177 Colloid and Emollient Laxa- 
tives, 178 Evacuant Enemas, 178. 

ANTHELMINTICS 179 

Aspidium or Male Fern, 180 Chenopodium Oil, 181 Pelletierin, 182 
Santonin, 183 Vermicides for Thread Worms (Oxyuris), 184. 

CONVULSANT POISONS 184 

Strychnin and Nux Vomica, 185. 
PICROTOXIN GROUP 199 

CAFFEIN, THEOBROMIN, AND OTHER METHYL-XANTHINS 200 

Caffein Beverages, 214. 

THE MORPHIN GROUP 217 

HYDRASTIS 245 

COTARNIN 247 

CANNABIS 249 

Lactucarium; Dried Lettuce Juice, 250 Lupulin and Hops, 250 Loco 
Disease, 250. 

COCAIN GROUP; LOCAL ANESTHETICS 251 

Action of Cocain on the Eye, 253 Systemic Actions, 254 Acute Cocain 
Poisoning; Etiology, 257 Chronic Cocain Poisoning, 257 Use of Cocain 
as a Local Anesthetic'.in Minor Operations, 258 Catarrh, Hay Fever and 
Asthma, 258 Use of Cocain in Larger Operations, 258 Use of Cocain as 
a Cerebral Stimulant, 260 Cocain Substitutes, 260. 

DRUGS ACTING PERIPHERALLY ON THE AUTONOMIC-SYMPATHETIC SYSTEM . . . 263 
The Parasympathetic and Sympathetic Systems, 263 Pharmacology 
of the Sympathetic Division, 264 Pharmacology of the Parasympathetic, 
Cranio-sacral or Restricted Autonomic Division, 265 Drugs with Par- 
tial Autonomic Reactions, 265 Location of Action, 266 The Response 
of the Uterus to Autonomic Poisons, 270 Gall-bladder, 271 Ureter, 271 
The Nature of Antagonism, 272 Optical Isomers, 273 Autonomic 
Phenomena of the Intestine, 274. 

ATROPIN 276 

Bronchial Muscles and Glands, 279 Circulation, 280 Temperature, 
282 Gaseous Metabolism, 282 Actions on the Eye, 282 Paralysis of 
Secretions, 286 Glycogenolysis, 288 Atropin in Diabetes, 288 He- 
patic Actions and Coagulability of Blood, 288 Action of Atropin on 
Peristalsis, 288 Biliary and Renal Colic, 289 Urinary Bladder and 
Incontinence of Urine, 289 Uterus, 289 Curare Action, 289 Anodyne 
Action, 289 Atropin Poisoning, 290 Racial and Acquired Tolerance, 
291. 

HYOSCYAMIN 292 

PROTOCATECHYL TROPEIN 292 

SCOPOLAMIN OR HYOSCIN 293 

PlLOCARPIN 297 

PHYSOSTIGMIN 301 



CONTENTS 1 1 

PAGE 

MUSCARIN 303 

MUSHROOM POISONING 305 

CHOLIN 305 

NEURIN 307 

BETAIN 307 

QUATERNARY AMMONIUM BASES 307 

Tetra-methyl Ammonium Chlorid, 307 Tetra- Ethyl Ammonium Chlo- 
rid, 308 Methyl-Ethyl Ammonium Compounds, 308. 

NICOTIN 308 

Acute Nicotin or Tobacco Poisoning, 311 Habitual Use of Tobacco, 313. 

LOBELIA 317 

CONIUM 317 

GELSEMIUM 317 

SPARTEIN 318 

CURARE 319 

GUANIDIN 322 

EPINEPHRIN 322 

Suprarenal Testing, 338. 

UZARA 339 

COTOIN(METHYL-TRIOXY-BENZOPHENONE) 339 

PITUITARY EXTRACTS 339 

Active Constituents, 340 Circulation, 340 Clinical Use in Shock and 
Collapse, 342 Respiratory Center, 342 Uterus, 343 Use in Obstetrics, 
343 Urinary Bladder, 343 Intestines, 343 Lacteal Secretion, 344 
Saliva, 344 Pancreatic Secretion, 344 Cerebrospinal Fluid, 344 
Pupils, 344 Toxic Effects, 344 Standardization, 345 Anterior Pi- 
tuitary Lobe, 345. 

THYROID PREPARATIONS 345 

PARATHYROIDS 351 

PINEAL GLAND 351 

PANCREAS PREPARATIONS IN DIABETES 352 

SECRETIN 352 

PHLORHIZIN 353 

KIDNEYS 354 

RED BONE MARROW 354 

PRESSOR AND DEPRESSOR PRINCIPLES IN ANIMAL EXTRACTS 354 

THYMUS 355 

NUCLEOPROTEINS, NUCLEINS, AND NUCLEIC ACIDS 355 

YEAST ("F^;x MEDICINALIS") 355 

SEXUAL GLANDS 356 

ORCHITIC EXTRACTS 356 

OVARIAN EXTRACTS 356 

CORPUS LUTEUM (LUTEIN) 356 

MAMMARY GLAND *. . . . 357 

ERGOT 357 

Actions, 359 Actions of Pure Ergotoxin, 361 Histamin, 362 Tyra- 
min, 363 Phenylethylamin, 364 Indolethylamin, 364 Paraphenylen- 



I j CONTENTS 

PAGE 

diamin, 364 Ergotinic Acid, 364 Hordenin, 364 Ptomain Poisoning, 
ite Ergot Poisoning, 365 Chronic Ergot Poisoning, " Ergotism," 
365 Deterioration, 366 Bio-assay, 366. 

ECBOI.H - < >\N TOCICS) AND EMMENAGOGUES 367 

I M KIM SHD \n\i- AND HEMOSTATICS 367 

Vnu KM MS 368 

. \NAIM1YI. AXIS 369 

Anaphy lactic Shock, 369 Anaphylactoid Intoxications, 373. 

NITRITES, NITROGLYCKKIN, AND OTHER ALKYL NITRATES 375 

Tin: DniiTALis GROUP 382 

Digitalis Actions on the Circulation, 385 Gastro-intestinal Actions of 
Digitaloids, 396 Gall-bladder, 396 Suprarenal Secretion, 396 Local 
Actions, 396 Therapeutic Uses of Digitalis, 397 Chronic Digitalis Poi- 
soning in Animals, 403 Toxic Effects in the Clinical Use of Digitalis, 403 
Acute Digitalis Poisoning, 404 Administration, 405 Recapitulation of 
Other Digitaloid Drugs, 407 Bio-assay of Digitaloid Drugs, 409. 

('Am - 412 

MI-.M-AI 413 

CAMPHOR 413 

Toxic Effects, 415 Camphor Isomers, 416 Camphoric Acid, 416. 

MENTHOL 417 

SAI-OMNS (SAPOTOXINS; SAPO-GLUCOSIDS) 417 

; \ 420 

SNAKE VENOM . 421 

CHOLESTEROL 421 

ACONITE 422 

VERATRIN (CEVADIN) 428 

VEKATRUM 432 

Protoveratrin, 434 Jervin, 435 Rubijervin, 435. 

COLCHICUM 435 

Therapeutic Use in Gout, 436 Colchicum Poisoning, 436 Colchicin De- 
rivatives, 437 

Ai'oMOKi'nix ' 438 

The Emetic Action of Apomorphin is Central, 438 Other Evidence that 
Emesis is Central, 438 Hypnotic Action and Use in Acute Alcoholism 
and Hysteria, 440 Phenomena of Nausea, 440 Accidents in the Thera- 
peutic Use of Apomorphin, 441. 

;>KIN 441 

A>iM!)ospERMA (QUEBRACHO) 442 

IPECACUANHA AND IPECAC 442 

Comparative Action of Emetin and Cephaelin, 445 Psychotrin, 445 

Ipecacuanhic Acid, 445. 

TiiKkAi'Kinc USE OF NAUSEANT EXPECTORANTS 446 

Y ACTING EMETICS 446 

Cupri Sulphas and Zinci Sulphas, 447 Mustard, 447 Antimony, 447 
is as an Undesirable Side Action, 447 Therapeutic Use of Emetics, 

447- 
Tin-; PHARMACOLOGY OF HEAT REGULATION 448 

Reactions which Raise the Temperature (Pyretics), 451 Reactions which 

Lower the Temperature (Antipyretics), 445 The Treatment of Fever, 

459- 
(Ji IMN 461 

Quinin Derivatives, 467 Absorption, Fate and Excretion, 468. 



CONTENTS 13 

PAGE 
ETHYL-HYDROXYCUPREIN 469 

CUPREIN 470 

ACETANILID, ACETPHENETIDIN AND ANTIPYRIN 470 

ANTISEPTIC BENZOL DERIVATIVES 476 

Benzol, 477 Toluol, 478 Phenol, 478 Toxicology, 481 Phenol- 
camphor, 482 Phenolsulphonates or Sulphocarbolates, 482 Cresols, 
483 Polyatomic Phenols, 484 Resorcinol, 485 Uva Ursi, 485 Pyro- 
gallol, 485 Picric Acid, 486 Nitrobenzol, 486 Anilin, 487 Creosote 
and Guaiacol, 487 Tar, 489 Thymol, 490 Naphthalin, 490 Naphthpl, 
491 Quinolin, 491 Benzoic Acid and Benzoates, 492 Cinnamic Acid, 
495 -Salicylic Compounds, 495 Salicyl Derivatives, 502 Acetylsali- 
cylic Acid (Aspirin), 503 Methyl Salicylate, 504 Phenyl Salicylate, 504 
Phenyl-quinolin-carboxylic or Phenyl-cinchoninic Acid (Atophan), 
505 Quinic Acid, 507 Saccharin, Benzosulphinid or Glusid, 507 
Methylthionin Hydrochlorid or Methylene Blue, 508 Other Coal-tar 
Dyes, 509. 

MISCELLANEOUS ANTISEPTICS 510 

Formaldehyd, 510 Formaldehyd Compounds, 513 Hexamethylena- 
min, 513 Chlorin, 517 Para-toluene Sodium Sulphochloramid, 519 
Sulphur, Dioxid (Sulphurous Acid), 519 Sodium Sulphite and Thiosul- 
phate (Hyposulphite), 519 Ozone, 520 Hydrogen Peroxid, 521 Per- 
oxids of Metals, 521 Organic Peroxids, 252 lodoxybenzoic Acid, 522 
Potassium Permanganate, 522 Boric Acid and Borax, 523 lodoform, 
524 General Consideration of Antiseptics, 525. 

SERUMS AND VACCINES 527 

Diphtheria Antitoxin, 528 Normal Horse Serum, 531 Hemostatic 
Tissue Extracts; Kephalin, 531 Tetanus Antitoxin, 531 Antimeningo- 
coccus Serum, 532 Antipneumococcic Serums, 533 Hay Fever Serum, 
533 Vaccine Virus, 533 Antirabic Vaccine, 533 Tuberculin Prepara- 
tions, 534 Typhoid Vaccine, 534 Gonococcus Vaccine, 535. 

THEORIES OF NARCOSIS 535 

ALCOHOL 541 

Food-value of Alcohol, 552 Centra-indications, 553 Acute Alcohol 
Poisoning, 553 Antagonism of Alcohol and Caffein, 554 The Habitual 
but Moderate Use of Alcohol, 554 Chronic Alcoholism, 554 Peculiari- 
ties of Alcoholic Beverages, 557 Wines, 558 Higher Alcohols, 559 Iso- 
amyl Alcohol, 559 Methyl Alcohol, 559 Acetone (Dimethyl-ketone), 
561 Denatured Alcohol, 561 

ETHER AND CHLOROFORM GROUP 561 

Choice of the Anesthetic, 577 Preparation of Patient for Anesthesia, 
581 The Administration of Anesthetics, 582 Causes of Death Under 
Anesthesia, 585 Poisoning by Swallowing Chloroform, 586 Treat- 
ment of Accidents, 586 Idiosyncrasy, 587 Impurities, 588 Origin 
of Chloroform, 588 Induction of Anesthesia during Sleep, 588 Related 
Anesthetics, 588. 

ALIPHATIC HYPNOTICS 590 

Chloral Hydrate, 592 Other Chlorinated Hypnotics, 595 Paraldehyd, 
596 Sulphonal (Sulphonmethanum), 597 Trional, 598 Tetronal, 598. 

HYPNOTIC UREA DERIVATIVES 598 

Veronal (Diethyl-Barbituric Acid), 599 Bromural, 600 Urethanes, 600 
Ethyl Carbamate, 600. 

THE SYSTEMIC ACTIONS OF GASES 601 

Nitrous Oxid, 60 1 Carbon Dioxid (Carbonic Acid), 604 Carbonic 
Oxid (Carbon Monoxid, CO); Illuminating Gas, 608 Oxygen, 610 Oxy- 
gen Deficiency, 613. 

HYDROCYANIC ACID AND CYANIDS 613 

PHYSICAL FACTORS OF SALT ACTIONS 618 

Colloidal Solutions, 619 Osmosis, 624 Electrolytic Dissociation, 630. 






CONTENTS 



PAGE 

- CELLS 633 

>ns of ! , 638 Physiologic or Normal Saline Solutions 

-Osmotic Exchanges in the Body, 643. 

ra 6 4 8 

Sodium Sulphate, 652 Sodium Phosphate, 652 Pyrophosphates, 653 
iK-sium Compounds, 654. 

658 

KS 662 

CLIMATE 664 

DIURETICS 665 

SODIUM CHLORID 667 

UREA 674 

SACCHARUM LACTIS (MILK-SUGAR) 675 

MI M Su.i> 675 

LITHIUM SALTS 677 

Rriunn M AND CESIUM 678 

MI M COMPOUNDS 678 

CLASSIFICATION OF EXPECTORANTS 68 1 

Sedative Expectorants, 682 Irritant (Stimulant) Expectorants, 682 
Anodyne Expectorants, 682 Simplification of Expectorants, 683 
Expectorant Vehicles, 683 Cough Mixtures, 683. 

CALCIUM SALTS 683 

STRONTIUM 690 

OXALIC ACID AND OXALATES 691 

FLUORID ION 692 

BARIUM 693 

BROMIDS 694 

Organic Bromin Compounds, 699. 

IODIDS 699 

Sui.rnocYAMDs (RHODANATES) 706 

NITRATES 707 

CHLORATE 707 

BROMATES . . . ! 709 

METHEMOGLOBIN FORMATION 709 

THE REACTION OF THE BODY (REMOTE EFFECTS OF ACIDS AND ALKALIES) . 710 

DII.UTE HYDROCHLORIC AND OTHER ACIDS 718 

SODIUM BICARBONATE AND OTHER MILD ALKALIES 721 

CRAIE SOLVENTS 726 

Uric Acid and Its Salts, 726. 

<)kr, ASK ACIDS AND THEIR SALTS 729 

ACETATES 730 

CITRATES 730 

LACTATES 731 

\TES 731 

-. AND THEIR SALTS 732 

;; Mil u.s 734 

ARSENIC COMPOUNDS. 735 

ic COMPOUNDS 743 

iylate, 745 Sodium Arsanilate (Atoxyl), 746 Salvarsan 
ami Neosalvarsan, 748. 

MM AND TELLURIUM 755 

IUM 755 

756 



CONTENTS 15 

PAGE 

URANIUM 757 

BISMUTH 759 

IRON 762 

MANGANESE 772 

CHROMATES 772 

ALUMINUM 773 

Baking Powders, 774. 

CERIUM 774 

YTTRIUM AND ZIRCONIUM 775 

BERYLLIUM SULPHATE 775 

THORIUM 775 

RADIO-ACTIVE METALS 775 

SILVER 780 

GOLD AND PLATINUM 782 

TIN 782 

COPPER 782 

ZINC 784 

CADMIUM 785 

NICKEL AND COBALT 785 

MERCURY 786 

Peculiarities of Calomel, 791 Cathartic Action of Calomel, 791 Mer- 
cury in Syphilis, 793 Mercury in Tuberculosis, 797. 

LEAD 799 

Acute Lead Poisoning, 800 Absorption, 800 Retention, 800 Excre- 
tion, 801 Chronic Lead Poisoning, 801. 

THALLIUM 806 

PHOSPHORUS 806 

Phosphorus Poisoning, 807 Therapeutic Uses, 811. 

PHOSPHORUS COMPOUNDS IN NUTRITION 812 

Lecithin, Glycerophosphates, Hypophosphites, Etc., 812 Lecithin, 814 
Phytin, 816 Glycerophosphates, 816 Hypophosphites, 8 1 6. 

APPENDIX 819 

Appendix A. Tabulation of Average Doses 819 

Appendix B. Check-list for the Study of Preparations 823 

Appendix C. Bibliography 826 

INDEX . . 889 



A MANUAL 

OF 

PHARMACOLOGY 



PHARMACOGNOSY 

Definitions. Pharmacognosy deals with the origin and the anatomic 
and chemic structure of crude drugs. 

Materia Medica is an older, obsolescent title, which was used to include also the 
actions, uses and dosage. Organic Materia Medica is limited to the drugs derived 
directly from the vegetable and animal kingdoms. 

Importance of Pharmacognosy. An accurate knowledge of this 
branch is necessary to the pharmacist to insure the quality of his wares. 
It is much less important to the physician. However, it is useful to 
know the appearance, odor, taste, solubility, and perhaps the origin, at 
least of the more important drugs. 

Vegetable Drugs. The crude organic drugs are derived mainly from 
plants, either wild or cultivated; collected at the proper season to insure 
the maximum activity; and properly dried or otherwise prepared. 

Parts Used. The active principles are often diffused throughout the 
plant; but they are generally more abundant in one particular part, 
which is then used. The parts are designated by their usual botanic 
names. The following are the most important, with some characteristic 
examples. 

Root (Radix). The underground part of the plant, generally devoid 
of chlorophyl (green coloring matter), and which does not produce leaves 
(Dandelion, Belladonna, Ipecac, Rhubarb). 

Tuberous Roots. Roots swollen with accumulation of reserve food 
material (Sweet Potato, Aconite, Jalap). They are often called tubers; 
but true tubers (Potato) are similar formations on rhizomes. 

Conn. A thickened underground stem (Colchicum). 

Bulb. Very fleshy, closely crowded leaves, enfolding the underground 
base of the stem (Onion, Squills). 

Rhizome. Underground stems which bear leaves (Podophyllum, 
Hydrastis, Ginger, Aspidium). 

Wood (Lignum}. The wood of trees, in fragments, chips or coarse 
powder (Quassia, Hematoxylon, Sandal wood). 

Bark (Cortex). The outer layer of the stem (Cinchona, Cascara, 
Wild Cherry), or of the root (Sassafras, Cotton-root). Sometimes only 
the inner bark is collected (Ceylon Cinnamon, Elm). 

Leaves (Foliof Digitalis, Uva Ursi, Belladonna, Senna. 

Herb (Herba or Species}. The smaller leafy and flowering or fruiting 
stems (Peppermint, Cannabis Indica, Savin). 



I g MANUAL OF PHARMACOLOGY 

Flowers (Florcs). Chamomile, Arnica. Unexpanded flowers are: 
Cloves. Santonica. 

Fruit (Frnctus). The ripened ovary, with any persistent parts of the 
Hower, and containing the seeds (Pepper, Cardamom, Hops, Colocynth, 
Anise). 

Seed (Semen). The essential part of the fruit (Nux Vomica, Strophan- 
thus, Physostigma, Mustard, Linseed). 

Microscopic Structure of Plants. This differs from the animal cells, 
especially l>y the thick cell walls, and by the frequent presence of proto- 
plasmic enclosures, starch, fats, calcium oxalate, protein crystals, etc. 
The cell walls are chiefly responsible for the shape and physical properties 
of the cell. They consist primarily of cellulose, variously modified 
l>y certain allied substances (lignin in wood, suberin in cork). These 
all insoluble in ordinary solvents and in the alimentary canal of man. 
They are therefore so much useless "ballast' ; in the administration of 
the drugs. The processes of pharmacy consist largely in isolating the 
active constituents from this useless material. 

Pharmacognostic Importance of Microscopic Structure. The appearance, size and 
arrangement of the cells and their inclosures (starch grains, etc.) is often the most 
important aid in identifying a drug, particularly when in the form of powder. The 
pharmacopeias therefore include microscopic descriptions, whenever these are important. 



Elementary and Proximate Constituents. The elementary or ultimate, 
constituents of plants, as of animals, are mainly C, H, O, and N. The 
chemical compounds formed from these are called the proximate principles 
or constituents of the plant. These belong to the chemical groups of 
proteins, fats, carbohydrates, tannins, resins, alkaloids, glucosids, acids, 
terpenes, etc. Plants also contain inorganic salts. 

Cellulose. This is found in the cell walls. It exists in almost pure 
form in cotton. It is chemically an isomer of starch, having the ele- 
mentary formula (CeHioOo),,. It is insoluble in all the ordinary solvents, 
and is not affected by boiling water. It dissolves without change in 
Schweitzer's reagent (ammoniated solution of copper sulphate). In 
older cells it is often modified by the introduction of allied molecules: 

<1 (lignin) or cork (suberin). Cork is very resistant to reagents and 
impermeable to water, and hence protects the plant against evaporation 
and chemic injury. The cellulose may also undergo a retrograde meta- 
morphosis into gum or pectin. 

Starch (CeHioOoV This is produced as one of the first stages in the 

milation of CC>2. It occurs in the form of granules, usually showing 
a laminated structure around a center (hilus). The character of this 
lamination, as well as the average shape and size of the granules, are 
important in distinguishing between different plants. 

Starch can be easily recognized by the blue color which it gives with 
iodin. It is insoluble in all the ordinary solvents, but with boiling water 
swells and forms a peculiar colloidal solution (paste). 

Gums. These are colloidal carbohydrates, swelling or dissolving 
in water to viscous adhesive fluids (mucilages or pastes'). They are pre- 
cipitated by alcohol. They are formed in the plant by the transformation 
of cellulose and cell contents, especially as the result of pathologic proc- 
esses. Pectins are closely related substances, occurring in fruits, and 



PHARMACOGNOSY ig 

causing the boiled fruits to set into jelly. Gums and pectins do not color 
with iodin; they reduce copper only after inversion. 

Sugar. The various forms of sugars have a wide distribution in the 
vegetable kingdom. Some reduce copper in alkaline solution; others 
do so only after inversion. All turn the plane of polarized light. They 
are soluble in water; much less so in alcohol. The most important types 
are: 

Glucose (Dextrose and Levulose), C 6 Hi 2 O 6 ; Maltose and Saccharose, 
Ci 2 H 22 On; Mannite C 6 Hi 4 O 6 . 

Glucosids. These are ester-like combinations of sugars with various 
other substances, frequently with phenols. Acids or appropriate ferments 
hydrolyze them into sugar and the other substance. Many do not con- 
tain nitrogen. Most glucosids are neutral or weakly acid; a few are 
alkaloidal. They are widely distributed in plants, and include active 
principles such as the digitalis constituents, saponins, tannins, etc. 

Saponins. These are neutral, non-nitrogenous substances distin- 
guished by foaming with waters, emulsifying oils, and laking red blood 
corpuscles. Many have the formula C n H 2n -8Oio. Some are glucosids. 
Those which are markedly toxic are sometimes called sapotoxins. The 
saponins are also of wide occurrence. 

Tannins. This term is applied to a group of phenol derivatives, 
distinguished by giving a bluish or greenish color with ferric salts. The 
greater number also form insoluble compounds with other metallic salts, 
with alkaloids, proteins, etc. This precipitation leads to an astringent 
action. 

Tannins occur in many plants, especially in the leaves and bark, and 
in pathologic formations (nut-galls). They are non-nitrogenous; some are 
glucosids. They are soluble in water and in alcohol; but since they form 
insoluble compounds with so many substances, they often occur in plants 
in granular form. 

The tannins have been classified by their chemic composition. More convenient 
is the older classification into: 

1. Physiologic Tannins. Occurring in normal plant tissues; giving a green color 
with iron; yielding pyrocatechin on dry distillation. Most of these tannins form with 
connective tissue an extremely insoluble and impermeable compound, and are therefore 
used in tanning. 

2. Pathologic Tannins. Occurring in pathologic tissues (galls); giving a blue color 
with iron (changed to green by acid) ; yielding pyrogallol on dry distillation; unsuited for 
tanning. 

Phlobaphens. Tannins are easily decomposed into resin-like substances called 
phlobaphens. These exist naturally in plants, but are usually formed as artificial de- 
composition products in all extracts. They are dark-colored, soluble in alcohol and 
in alkaline liquids, insoluble in water. 

Tannins and phlobaphens, as well as most other plant constituents, are easily con- 
verted into a group of substances called liumins. These do not exist in living tissues, 
and arise on the death of the cells, by the action of air and moisture. They cause the 
brown color which plants assume on drying; they are also. present in the brown bark. 

Tannins, phlobaphens, and humins form a series, without sharp demarcation. They 
are not subject to the action of bacteria, and in this way protect plants against putre- 
faction. 

Alkaloids. These comprise many of the most active and important 
plant constituents. They may be defined as natural nitrogenous organic 
bases (generally tertiary amins); i.e., they are organic substances, contain- 
ing nitrogen, of basic character, combining with acids without the elimina- 
tion of hydrogen, forming well-defined and usually crystalline salts. The 



2Q MANUAL OF PHARMACOLOGY 

sal IN with halogens are called hydrochlorids, hydrobromids, etc. (not 
rhlorids. etc.). 

The names of alkaloids are often spelled with a final e, to distinguish them from 
neutral principals ^thus morph/w, an alkaloid; saliciw, a glucosid). This distinction 
her arbitrary, and is not followed here. 

/" Ike . I . 'k .ili>uls. This is an achievement of the igth century (Morphin, 
n'er, 1805 to 1817; Strychnin, 1818; Quinin and Caffein, 1820; Nicotin, 1829; 

333)- 

rmce. Only a few alkaloids occur in the animal kingdom, the most important 

:ple hem- epinephrin, the active principle of the suprarenal gland. Alkaloidal 

principles arc aUo formed by the action of bacteria, and are called ptomains. Amongst 

the higher plants the occurrence of alkaloids is very common, the same plant containing 

usually several alkaloids, which are often formed from one another. They are often 

found in all parts of the plants, but sometimes they are strictly localized in certain 

jxiriions. Amongst seeds, e.g., in aconite, in the central part; in physostigma in the 

Vdons; in datura, hyoscyamus and atropa, in the layer beneath the epidermis; in 

nu\ vomica, both strychnin and brucin occur in the endosperm, brucin alone in the 

embryo. 

The alkaloidal content of plants varies considerably according to the climate, culture 
and other conditions. Individual plants also show considerable variations (Sievers, 
They can also be improved by selective breeding, although this is technically 
rather difficult (Sievers, 1916). 

Some alkaloids contain oxygen, others do not. Those containing oxygen are solid 
and comparatively non-volatile, whereas those free from oxygen (nicotin and coniin) 
are liquid and volatile. 

Properties of Alkaloids. All alkaloids have certain properties in com- 
mon: bitter taste, alkalinity to litmus, nitrogen reaction; generally pro- 
found physiologic action, without postmortem lesions. 

Solubility Characters. Free alkaloids are soluble in ether, chloroform, 
and oils, much less soluble in alcohol, and comparatively insoluble in 
water. Alkaloidal salts, on the other hand, have just the opposite solu- 
bility: They are soluble in water and alcohol, insoluble in chloroform and 
ether. With the alkaloidal salts, the combined acid plays a prominent 
r61e in the solubility. 

Precipitation Reactions. Alkaloidal salts are precipitated by compound 
solution of iodin, mercuric-potassic iodid (Mayer's reagent); phospho- 
molybdic acid; picric acid; gold chlorid, platinic chlorid, etc. Many also 
precipitate mercuric chlorid, potassium bichromate, tannin, etc. 

Color Reactions. Many alkaloids give characteristic colors with con- 
centrated acids, with or without the addition of oxidizing or reducing 
agents. 

Che mi c Constitution. The structure of many alkaloids is well under- 
stood; others are still obscure. The greater number are fairly complex 
derivatives of pyridin (coniin, nicotin); pyrrolidin (cocain, atropin); 
quinolin (quinin, cinchonin, strychnin, brucin); iso-quinolin (hydrastin, 
narcotin, cotarnin, berberin); morpholin or phenanthren (morphin, codein, 
thebain). 

Neutral or Bitter Principles. This class comprises a heterogeneous 
rolled ion of substances, which have not been assigned to other classes. 
The principles usually have a bitter or sharp taste, and are usually crys- 
talline and non-nitrogenous. A number are lactones, i.e., derived from 
alcohol-acids, by the elimination of H 2 O. 

Resins. These are also a heterogeneous collection; including solid, 
non-volatile, amorphous substances of obscure composition, generally non- 
oitrogenous. The distinguishing character is their insolubility in water, 
and solubility in alcohol, most fat solvents (except petroleum ether) and 



PHARMACOGNOSY 21 

strong alkalies. The resins are contained in special vessels, from which 
they are usually obtained as exudations after incising the plant. 

Mixed Resins. When the resins occur mixed with essential oils, they 
are natural oleoresins; when mixed with gums, gum-resins. If they contain 
aromatic acids (cinnamomic, benzoic, etc., or essential oils), they are called 
balsams. 

Resinoids. These are artificially isolated principles soluble in alcohol 
and insoluble in water. They are generally mixtures, often containing 
true resins. 

Volatile Oils (Essential Oils). These are odorous principles, of the 
physical characters of fatty oils, from which they differ by being volatile 
and soluble in alcohol. They are responsible for the odor of plants. 
Chemically, they are mixtures of esters, aldehyds, alcohols, ketones, and 
especially the terpens (Kremers, 1898). 

The constituents may separate on cooling, the liquid part being called eleopten, 
the solid stearopten. Camphors are analogous substances, but solid at ordinary tempera- 
ture. Rubber (caoutchouc and gutta-percha) is also related to the terpens. 

Plants also contain many other alcohols, aldehyds, organic acids> 
aromatic derivatives, etc. 

Fats and Fixed Oils. Typical fats (esters of fatty acids and glycerin) 
are abundant especially in seeds, occurring within the cells as drops or 
crystals. The fats are greasy liquids or soft solids; when heated, they 
undergo decomposition, denoted by acrid acrolein vapors. They are in- 
soluble in water or glycerin, sparingly soluble in alcohol, and freely soluble 
in ether, chloroform, benzin (petroleum ether), carbon disulphid, turpen- 
tine, etc. (fat solvents'}. 

Waxes. These are more solid substances with the solubility charac- 
ters of fats. Chemically, they are esters of fatty acids with alcohols other 
than glycerin. 

Proteins. These are, of course, represented in all vegetable cells, but 
are especially abundant in seeds, sometimes as crystals (aleuron). Several 
classes of the proteins are peculiar to plants. 

Chlorophyl. This, the green pigment of plants, is insoluble in water, 
soluble in alcohol and fat solvents. It is allied to blood pigment, but con- 
tains no iron. It is readily changed and discolored by reagents. 

The chlorophyl occurs in the cells as granules (chloroplasts) , made up of a colorless, 
spongy, protein groundwork, containing in its meshes the chlorophyl pigment. The 
latter consists really of a mixture of green and yellow colors (chlorophyl and xantho- 
phyl). These chlorophyl granules are found mainly in the higher plants, and serve in 
the presence of light to assimilate CO 2 , and consequently to form starch, etc. During 
the process of drying, especially if this occurs slowly, the pigment is acted on by acids, 
etc., developed under these conditions, and undergoes various changes, usually be- 
coming brown. 

Other Pigments. Plants are rich in colors, belonging to various 
chemic groups, often unidentified. Many alter with changes of reaction. 
The brown coloring matter of barks, etc., is allied to the tannins and 
phlobaphens. 

Enzymes. Different plants contain almost every imaginable kind 
of ferment, a few being used in medicine. 

Extractive Matter. This term is applied to the mixture of unidentified 
organic constituents; especially to the colloidal smeary mass which remains 
after evaporating any extract from which the important constituents 
have been removed. 



22 MANUAL OF PHARMACOLOGY 

Mineral Salts. These are fairly abundant in plants, constituting 
; he a-h which remains on incineration. Ca and K are especially important. 

in to In- combined largely with the protoplasm, and exist partly 
.irtly as crystals. Growing tissues are always richer in salts than those 
fully developed. 



PHARMACEUTIC STANDARDS 

Objects. Pharmacy deals with the preparation and compounding 
of drugs for the purpose of administration. It has for its objects the 
separation of the active principles of drugs, their combination, and the 
putting of them in a pleasant form. 

The Need of Pharmacy. The necessity for such an art will be readily understood. 
Drugs may be divided according to their origin into mineral, vegetable, and animal 
drugs. The last two are often too bulky to be conveniently used, and the substances 
whirh determine their action are often in such a condition that they can not readily 
;iar:iu-d in the body, and so can not develop their action. Often, one drug alone 
does not meet all the indications in a disease, and when several are given it is necessary 
to combine them in such a way that they may not interfere with one another, either 
chemically or mechanically. Lastly, having chosen and prepared the drugs in a proper 
manner, and having decided how to combine them, it is highly desirable to give them 
in such a form as will be least objectionable to the taste, smell, or sight of the patient. 

Official Drugs. A certain degree of uniformity in the strength and 
preparation of pharmaceutic products is absolutely indispensable. Ac- 
cordingly, practically all civilized countries have standards established 
by law, to which drugs and preparations in the shops must conform. 
The book in which these standards are published is usually called the 
Pharmacopeia. Preparations listed in these official books are termed 

;cial." A Pharmacopeia, therefore, is an official book of standards 
for official drugs. 

International Uniformity. The first effective step in this direction was taken by 
i;rus>el> Conference of 1906, the "International Conference for the Unification of 
the Formulas for Potent Medicines." This conference drew up a list of the potent drugs 
for which uniformity was most important, and established standards of strength for 
them and their preparations. These have been adopted essentially by most of the 
civili/.ed nations. These formulas of the Conference are designated as "I. A." (Inter- 
national Agreement) by the B.P.; as "P.I." (Protocol International) by the U.S. P. 

Scope of the Pharmacopeias. These usually aim to include only 

mdard drugs," i.e., those of established value, including some, however, 
which have little to recommend them except extensive use. Proprietary 
drti j -it/rally excluded, on the plea that it might be difficult to inforce 

their compliance with the official standard. There is also a healthy 
tendency to restrict the admission of complex mixtures. 

Galenic Preparations. "Galenicals" are, strictly speaking, medicines 
i after the formulas of Galen. The term is now used to designate 

;dard preparations containing one or several organic ingredients, 
with pure chemic substances. 

Proprietary Drugs. Drugs which are protected by a monopoly 
by patents, trade marks, secrecy, etc. are generally not admitted into 
the pharmacopeias, and are therefore non-official. They are thus not 
subject to legal control, and are often advertised under extravagant, 
misleading and false claims. However, some of the most valuable drugs 
are proprietary, and many are marketed in a strictly ethical manner. 



PHARMACEUTIC METHODS 23 

Patent Medicines. This term is used to cover proprietary drugs that are advertised , 
directly or indirectly, to the laity. They are not usually patented, as the name would 
imply; most manufacturers preferring to rely upon secrecy to impose on the public. 
The medical profession is generally opposed to patent medicines as a class, and to lay 
advertising in particular. "The impossibility of controlling the irresponsible claims 
which are usually made in advertisements to the public, the well-known dangers of 
suggesting by descriptions of symptoms to the minds of the people that they are suffer- 
ing from the many diseases described, the dangers of the unconscious and innocent 
formation of a drug habit, and the evils of harmful self-medication, including the dangers 
of the spread of many infectious and contagious diseases when hidden from the physician, 
and similar well-known considerations, are the reasons for discouraging, in the interest, 
and for the safety, of the public, this reprehensible form of exploitation" (N.N.R.). 

The United States Pharmacopeia. The U.S.P. IX (ninth revision) was 
issued in September, 1916. It furnishes mainly the standard definitions, 
tests and formulas. It is a legal standard. 

The U.S.P. was first published in 1820, and is revised every ten years, by a Pharma- 
copeial Revision Committee, appointed by the United States Pharmacopeial Conven- 
tion, which consists of delegates from pharmaceutical and medical organizations. 
The current committee of revision consists of 50 members, mainly pharmacists, and is 
divided into 15 subcommittees, and headed by an executive committee. 

The British Pharmacopeia. The B.P., fifth edition, was issued in 
1914. It resembles the U.S.P. in scope and arrangement. 

The B.P. is published by the General Medical Council, and revised at irregular 
intervals. 

National Formulary (N.F.). This is a collection of formulas for less important 
preparations, issued by the American Pharmaceutical Association. It is also a legal 
standard. 

New and Non -official Remedies (N.N.R.). This contains descriptions of the 
characters, actions and uses of those proprietary drugs that are marketed in a proper 
manner. It is issued by the American Medical Association and revised annually by 
its Council on Pharmacy and Chemistry. 

Dispensatories. These are commentaries which enlarge and explain 
the official texts, and generally also describe unofficial preparations. 
The National Dispensatory and the U.S. Dispensatory are principally 
used in the U.S. The British Pharmaceutical Codex (B.P.C.), and 
Hager's Praxis are similar works. 

Useful Drugs. This is a small manual issued by the American Medical 
Association, which contains only the most useful drugs with such informa- 
tion as is of especial interest to physicians. 

Physicians' Epitome of U.S.P. and N.F. This is another A.M.A. 
publication, giving a brief but critical abstract of all U.S.P. and N.F. 
preparations. 



PHARMACEUTIC METHODS 

IN the making of pharmaceutic products very different methods must 
be used, depending upon the physical and chemic nature of the crude 
drug, and upon the character of the desired product. 

These may be roughly classified into those used in the making of many 
different preparations general methods and those used in only a very 
limited number of cases special methods. 

The methods can be best understood when studied in the order in 
which they are usually applied to the drug. 



24 MANUAL OF PHARMACOLOGY 

PREPARATORY PROCESSES 

Desiccation or Drying. This is usually the first operation to which 
tin- v rude drugs arc Mibjected after their collection. It serves a three- 
fold purpose: It reduces the bulk, assists preservation, and facilitates 
comminution. 

Formerly the drying was done by spreading or hanging the drugs in airy lofts. At 
are usually placed on perforated trays in special drying closets and heated 
artiiu-ially 'steam, etc.). They are often cut into smaller pieces before this drying. 
The decree of heat must not be so high as to injure the sometimes very unstable in- 
gredients. The U.S.P. designates 32 to 39C. as "gentle heat." 

Comminution. The next step is comminution, or reducing of the sub- 
stance to smaller pieces. 

This is usually done by machinery. Crude vegetable drugs are first sliced or 
chopped, often before drying. They are then bruised by pounding in a mortar and 
finally ground, the finer grades of powders often several times, the grinding surfaces 
being brought closer together each time. The mills for this purpose are constructed 
on the same general principles as flouring mills, employing stones, rollers, etc. The 
details of the process used depend upon the physical character of the drug. A fibrous 
material like licorice root requires a different process from a friable substance like gum 

( )n the small scale, drug mills, constructed more or less on the principle of the coffee- 
mill, are used for fibrous, and mortar and pestle for friable drugs. Mortars are made 
of iron, wedgewood, porcelain, and glass. 

Pulverization is comminution to a powder. 

Trituration is the process of rubbing (not pounding) a substance to a 
powder in a mortar. 

Some points deserve special mention. Often a substance will not 
powder by itself, but will do so when mixed with another substance 
e.g., sugar of milk. This is called "pulverization by intervention." Some- 
times it is well to moisten the drug e.g., camphor with alcohol, nux 
vomica with steam, etc. 

Fineness of Powder. In the process of percolation, presently to be described, it is 
often essential to use a powder of a certain degree of fineness. The powders are there- 
ied, and are classified according to the size of the meshes of the sieve through 
which they pass, thus: 

No. So = 80 meshes to linear inch, very fine. 
No. Oo = 60 meshes to linear inch, fine. 
No. 50 = moderately fine. 
No. 40 = moderately coarse. 
No. 20 = coarse. 

Since the different structures in a crude drug do not powder with equal readiness, 
ntial that the whole of the drug to be powdered should be passed through the 

he different portions will not have the same composition. 

Levigation. This is employed to obtain very fine powders of insoluble substances, 
h\ making them into a thick paste with water, and rubbing this between polished 

Elutriation is used to separate fine insoluble powders by suspending them in water 
and decanting. 

PROCESSES OF SEPARATION 

the separation of the desired ingredients from the inert material 
'Methods are in vogue, depending upon the nature of the active con- 
stituents. If volatile constituents are to be separated, this may be readily 
done by the application of heat distillation and sublimation. If they 



PHARMACEUTJC METHODS 25 

are not volatile, the separation is usually effected by exposing the drug 
to the action of some solvent in which the desired principles are soluble, 
and the rest, as far as may be, are insoluble. In certain cases some 
mechanical means are sufficient, as in the separation of fixed oils from 
seeds, etc., by pressure. 

Separation by Means of Heat. This may be done whenever the sub- 
stances to be separated have a different boiling-point, and are not them- 
selves destroyed by the necessary degree of heat. The methods used 
must vary according to whether the fixed or the volatile portion is desired, 
and, if the latter, according to whether it is liquid or solid. 

Desiccation, Torrefaction, Carbonization, Ignition. With all these, 
the object is to drive off some volatile constituent from a solid, the fixed 
residue being the portion desired. 

When the heat employed is of such degree as not to change the chemic 
composition, the process is spoken of as desiccation. 

Torrefaction. The process of roasting; the object being to employ such a degree 
of heat as will alter some of the constituents without affecting others. The roasting 
of coffee is a familiar example. 

Carbonization. -The heating of organic substances under exclusion of air. The ob- 
ject is to destroy the chemic composition without oxidation; carbon results in the pro- 
cess (vegetable or animal charcoal). 

Ignition. This is the process of heating a substance strongly, usually in a crucible, 
with full access of air, so as to effect complete oxidation; nothing but the ashes remain. 

Evaporation consists in vaporizing the solvent from a solution, the 
object being the concentration of the dissolved substance. 

Since the rapidity of the evaporation, aside from the quantity of heat applied, 
depends upon the extent of the liquid exposed to the air and to the heat, dishes as flat 
as possible are chosen. For ordinary pharmaceutic and chemic purposes, those made 
of porcelain are of most frequent service. Vessels made of glass, iron, platinum, etc., 
find application in special cases. The heat may be applied directly, say by means of a 
Bunsen flame, only a piece of wire gauze or a plate of asbestos or iron being interposed. 
This method can be used only when there is no danger of injuring the solution by exces- 
sive heat, either the substance being incapable of change, or the solvent sufficient in 
amount so that the temperature can not rise much beyond its boiling-point. If this is 
not the case, some method must be used of regulating the amount of heat applied, and 
this is done by applying the heat indirectly through a bath. This consists of an outer 
vessel filled with water (steam), oil, sand, or air. 

The rapidity of evaporation may be considerably increased by stirring, thus exposing 
a constantly renewed surface to the air. 

In cases where the evaporation must be carried on at a temperature below the boiling- 
point of the solvent, this may be done either by evaporation over H 2 SO4, or in a vacuum, 
or by passing a current of dried air through the liquid. 

The evaporation which occurs from the surface of a liquid exposed to air at ordinary 
temperature is called "surface evaporation." It varies in quantity with the amount of 
surface exposed and with the temperature and dryness of the air. 

When very inflammable liquids (ether) are being evaporated, this should be done 
on a large water-bath, and the Bunsen flame should be protected by wire gauze. 

Sublimation. The process of separating a volatile from a non- volatile 
solid by heat. 

This may be done in a distilling apparatus, provided that the cooling 
tube has sufficient lumen to prevent its clogging by the condensation 
of the sublimate. The apparatus is, however, usually modified. A 
simple illustration of this process is the old method of manufacturing 
benzoic acid from gum benzoin, a paper hood being used as condenser. 

Distillation. The process of separating a volatile liquid from a less 
volatile liquid or solid. (The difference between sublimation anddistilla- 



26 MANUAL OF PHARMACOLOGY 

lion consists in this, that the product is solid in the former, liquid in the 

lath 

.listilhition is such a ready and simple means of separation that one 

mi-t have been discovered at a very early time, such does not appear to 

\\V find the first record of it in the writings of the fourth century 

The typical apparatus used for distillation consists of three parts. 
The still (retort or flask), the vessel in which the vapor is generated. 

condenser (straight or spiral), the apparatus in which the vapor is 
cool' 

The receiver, for receiving the condensed product. 

The alembic is the old-time still, and differs from the retort in having a chamber 
(helm or hood) where the vapor is partly condensed. By fitting the helm on the body 
with a flange joint a very wide opening can be secured, which is of use in cleaning. 

. ; ,M/ distillation is the process of separating a mixture of liquids of different 
boiling-points by distillation. 

:ir!i:r distillation is the name applied to the process of heating a substance so 
strn:. decompose it, and collecting the volatile products arising from this de- 

composition: i.e., in the case of organic bodies, tar. 

.Solution. This consists of incorporating a solid into a liquid in a state 
of "molecular subdivision." 

That is. the molecules of the solid diffuse themselves in the liquid and become so 
widely separated that no solid particles are by any means discernible. In other words, 
the solid is liquefied and its molecules intermingle with those of the solvent. 

i pie solution is one occurring in the manner described, the change in the solid 
being physical. When a chemic change takes place, the process is called chemic solution 
(such as the solution of a metal in an acid). 

A solvent is capable, under given conditions, of dissolving but a limited amount of 
a given solid. A solution which contains as much of the solid as the liquid can dissolve 
under these conditions is called a saturated solution. The condition which has the 
i-st inlluence upon solubility is the temperature. A liquid can usually dissolve 
the more of the solid, the higher the temperature. There are, however, a few exceptions 
to this rule. 

If a solution saturated at a high temperature is allowed to cool, the priginally dis- 

< 1 substance will be in excess of saturation. Under certain conditions it may still 

un in solution at the lower temperature, this being a supersaturated solution. 

Ordinarily, however, the excess will separate, usually in crystalline form. This process 

is called crystallization. It is frequently used as a means of purification. 

iition which contains less of the solid than it is capable of dissolving is an un- 
att-d solution. A solution which is saturated with one substance is still capable 

u-rs, though not as much as if it were the pure solvent. 

Solution is effected by placing the solvent in contact with the substance to be dis- 

1. The process may be hastened by applying heat, or by exposing the largest 

ible surface to the action of the solvent. The latter may be done by using the sub- 

a pulverized condition, and by constant stirring. With circulatory solution 

the substance is suspended near the surface of the solvent. As this takes up the sub- 

-pecific gravity, and hence sinks to the bottom, a new portion of 

liquid taking its place . The same object may be secured by a process analogous 

ition, the powder being placed in a funnel partly occluded by a pledget of 

cotton, etc.. and the solvent allowed to percolate through it. 

The simple solution of a substance always causes a depression of temperature. 
Hut if a chemic change occurs, the temperature may be raised. 

The process of solution applied to crude drugs has for its purpose the 

separation of the active ingredients from the insoluble inert material. 

The obi' >lissolve out the greatest possible amount with the least 

ible menstruum. This accomplishes two results: We obtain a 

strong extract, and we waste neither drug nor menstruum. There are a 



PHARMACEUTIC METHODS 27 

number of methods of accomplishing this, each with its advocates. They 
are combinations of two extremes: maceration and percolation. Neither 
of these is commonly used alone in this country, the practice being to com- 
bine the two. 

Maceration is by far the simpler process. It consists in simply leaving 
the solvent in contact with the drug under suitable conditions for a suffi- 
cient length of time. 

When maceration alone is employed, a given quantity of the drug is put in a bottle 
or other suitable vessel with a definite proportion of the solvent (called menstruum) 
and left a certain time, usually a week or two. The liquid is then strained off, the residue 
(marc) is expressed and the mixed extract filtered. The details of the process are 
influenced by the fineness of the powder, the time of maceration, and the temperature. 

Different names are given to the process according to the temperature at which if 
is carried out. Maceration proper = room temperature; 30 to 4oC. = digestion' 
boiling = decoction. Possible injury to some constituents by heat, or evaporation o{ 
a constituent or of the solvent, are objections to the application of heat in certain cases. 

This process of maceration is the one almost exclusively employed in Europe; and 
it offers certain advantages, not the least being its simplicity and the constant results 
which it gives. Its main disadvantages are the required time and the loss of the extract 
retained in the insoluble residue or "marc." Certain drugs are physically unfit for 
percolation, since the moistening causes them to form into a tough mass, as good as 
impenetrable to the solvent. 

The loss of menstruum does not, of course, weigh when an aqueous solvent is used 
and only small quantities are prepared. Hence maceration is used in making infusions 
and decoctions. 

Percolation consists in passing a solvent through a thick layer of the 
powder to be exhausted. This exposes a large surface of the latter; the 
nearly saturated solvent flows off and fresh unsaturated portions contin- 
uously replace it, insuring very rapid solution. 

The principle of the method is to pack the powder intp a tall vessel, 
with an opening at the bottom, and to let the solvent trickle through it. 
Usually the process is combined with a short previous maceration. 

The U. S. Pharmacopeia defines percolation as consisting in "subjecting a substance 
or a mixture of substances, in powder, contained in a vessel called a percolator, to the 
solvent action of successive portions of a certain menstruum, in such a manner that 
the liquid, as it traverses the powder in its descent to the receiver, shall be charged with 
the soluble portion of it, and pass from the percolator free from insoluble matter." 

The details are as follows: 

The powder (the fineness of which depends upon the nature of the drug and is 
directed for each case by the Pharmacopeia) is moistened in a jar with some of the 
menstruum. This moistening is for the purpose of swelling the drug, for if this took 
place in the percolator, the drug would become so firmly impacted that the menstruum 
could not penetrate through it; or it could even burst the percolator. The moistened 
powder is then passed through a coarse sieve and transferred to the prepared percolator, 
which it should fill about two-thirds. 

The choice of the shape of the percolator depends upon the nature of the drug. 
Should the drugs have a tendency to swell particularly if they are in fine powder or if 
weak alcohol menstruum is used, a conical percolator is employed; otherwise, the 
cylindrical. The size corresponds to the quantity of the powder. 

Arrangement of Percolator. The percolator is prepared in the folio wing manner 
(Fig. i): Into the small end there is inserted a cork perforated by a short glass tube 
which projects about i cm. inside the percolator. The outer end of this tube is attached 
to a piece of rubber tubing, about one-fourth longer than the percolator, and this to a 
U-shaped glass tube. This is held to the percolator by a rubber band in such a way 
that it can be raised and lowered. The percolator is then set in the stand. A pledget of 
absorbent cotton is loosely packed in the neck of the percolator and this is covered by 
a layer of clean sand, and over this goes a well-fitting disk of filter-paper. Then the 
moistened drug is pressed in and this is the part of the process which requires the 
greatest skill and judgment, and on it depends the success of the product. It should be 
done very evenly, else the menstruum will choose the path of least resistance and some 



28 



MANUAL OF PHARMACOLOGY 




FIG. i. Method of percola- 
tion (Thornton). 



portions of the powder will be entirely exhausted whilst others are still scarcely affected. 
The lirinnos of the packing is also of great importance; if not firm enough, the men- 
struum will run through too rapidly and the percolate will consequently be weak. If 
too lirm it can not run at all; and if any swelling occurs the percolator will be broken. 
Drugs in co;ir>e powder should be packed more firmly than fine powders. An alcoholic 
menstruum requires firmer packing than a watery one. 

The {Kicking being completed, the menstruum is poured on until it stands an inch 
or two above the drug; the percolator is then covered and set aside for maceration 
for a specified time, the tube being raised so that no liquid flows out. When the time 
of maceration is completed, the tube is lowered and fixed 
at such a level that the outflow occurs at the rate of 2 to 
15 drops per minute. New menstruum is poured on in 
the measure that the old flows out. Care should be taken 
always to maintain the layer of liquid above the powder; 
else cracks may appear in the latter, necessitating re- 
packing. 

The process is continued, in the case of tinctures, until 
a certain volume of percolate is obtained. The quality of 
the percolate will, of course, depend upon the care and skill 
of the operator, and the product is apt to vary. Macera- 
tion would, therefore, be a better process for tinctures. 

This difficulty is avoided in the case of extracts, for 
here the percolation is continued "until the drug is ex- 
hausted;" i.e., until the active ingredients have become 
completely dissolved out. This is recognized by testing 
the last portions of the percolate in the appropriate man- 
ner, such as Mayer's reagent for alkaloids, water for resins, 
etc. It may here be remarked that a drug is usually 

more rapidly exhausted of its active ingredients than of its coloring-matter, so that the 
last portions of percolate may be colored and yet devoid of activity. 

The choice of a menstruum must be determined by the nature of the constituents. The 
object is, to extract all the active ingredients and the minimum of inactive. Alkaloids 
and resins require strong alcohol; gums, weak alcohol; licorice, alkaline alcohol; san- 
guinaria and ergot, acidified alcohol; gentian and quassia, water plus alcohol enough to 
keep. 

Pharmaceutic Solvents. The most useful are the following: 

Water or Glycerin. Dissolve salts (including those of alkaloids), 
sugar, gums, tannin, acids, and alkalies, etc. 

Dilute Acetic Acid. Especially for alkaloids. 

Alcohol. Dissolves alkaloidal salts, neutral principles, resins, volatile 
oils. Precipitates gums and most inorganic salts. 

Ether, Chloroform, Acetone. Dissolve free alkaloids, neutral principles, 
resins, volatile and fixed oils, and fats. 

Petroleum Benzin. Solvent properties as the preceding, except resins. 

- 1 romatic Spirits of A mmonia. Dissolves resins and organic acids. 

In the case of very volatile menstrua, such as ether, chloroform, or petroleum ether, 
some means must be employed to collect and return the evaporated solvent. One of the 
best apparatus of this kind is the familiar Soxhlet extractor. 

Expression. The process of separating a liquid from a solid by 
pressure. 

Its principal employment in pharmacy is for the recovery of tinctures from the 
"marc," i.e., the liquid retained by the drug residue after maceration and percolation. 
It is also a process of separating fixed oils. 

The drug is put in a coarse strong cloth and subjected to pressure in a press. These 
are of various patterns; screw, lever, hydraulic, or centrifugal. The pressure must 
be applied gradually to prevent the bursting of the cloth. Small quantities can often 
be pressed sufficiently by putting them into a cloth and tightly twisting the end. 

Straining or Colation. The process of separating solid coarse particles 
from a liquid by pouring it through a cloth or strainer. 



PHARMACEUTIC METHODS 2Q 

Filtration. The process of separating solid particles (fine or coarse) 
from a liquid by pouring it through a finely porous material, such as 
filter-paper. 

The usual material for nitration is pure unsized paper, "filter-paper," which is made 
of various grades white and gray and of varying texture and thickness according to 
the purpose for which it is to be used. 

There are two principal methods of folding a filter plain and plaited. These two 
filters have different uses. The plaited filter offers a much larger surface for filtration 
and is therefore more rapid; it is the form usually employed in pharmacy. The plain 
filter, on the other hand, facilitates washing and removal of the precipitate, and is of 
more frequent use in chemistry. 

Other materials are sometimes employed instead of paper. A very useful filter for 
large quantities of liquid is made from felt. A plug of glass-wool or asbestos placed in 
the tube of the funnel is especially useful for strong acids or alkalies. A cell of porous 
clay is also employed, as in the various forms of the Chamberland filter. With this 
a vacuum is indispensable. 

Dialysis. This is sometimes used to separate crystalloids (alkaloids, 
salts, etc.) from colloids (extractives). 

Decolorization. It is often desirable to remove the coloring-matter from a solution. 
This may sometimes be accomplished by choosing appropriate solvents. More often, 
however, the solution is filtered through recently calcined animal charcoal. This very 
often retains some of the active constituents as well as the coloring-matter. 

Clarification. The process of rendering turbid mixtures clear and transparent, by 
removing the suspended solid. When filtration does not suffice, the object is accom- 
plished by agitating the mixture with insoluble powders (talcum, phosphate of lime, 
aluminum hydrate) or by adding egg- albumen and boiling; or sometimes by the cen- 
trifugal machine. 

Sterilization. The destruction of bacteria and their spores is accom- 
plished by the various customary methods. 

Glass and metal utensils may be sterilized by dry heat of 160 to i7OC. for two hours; 
by superheated steam of 115 to i2oC. for fifteen minutes; heating in a current of steam 
for thirty minutes or boiling for fifteen minutes, especially in o. i per cent, sodium bicar- 
bonate. Kills all non-spore-bearing organisms. 

Solutions that are not- readily decomposed by heat may be boiled in a current of steam 
for one-half or better one hour. 

Solutions that are readily decomposed by heat are either prepared aseptically or filtered 
through porcelain. 

Emulsions in glycerin or oil are prepared aseptically, the solvent being first sterilized 
by heat. 

PHARMACEUTIC ASSAYING 

Different samples of vegetable drugs may vary widely in the quantity of active 
constituents which they contain. These variations are most undesirable from a thera- 
peutic standpoint, especially when they occur in potent, so-called "heroic" drugs. 
Inorganic drugs or other definite chemic compounds are not subject to this variation; 
but in many cases the removal of the last traces of innocuous impurities would greatly 
increase their cost without adding to their therapeutic usefulness. The pharmacopeia 
has therefore aimed to furnish quantitative methods of estimation, assays, wherever 
possible, and to establish practical standards to which medicinal substances must 
conform. With inorganic drugs, it states the largest permissible quantity of innocuous 
impurities (usually less than 2 per cent.). With crude vegetable drugs, it states the 
lowest permissible percentage of active ingredient, wherever practical methods for their 
determination are available. Assayed galenic preparations are directed to be diluted 
so as to contain a definite proportion of active constituents, corresponding to the 
minimum permitted in the crude drug. These preparations should therefore be pre- 
ferred to the crude drug whenever accurate dosage is desired. 

The assay of inorganic drugs involves the well-known methods of ordinary quan- 
titative analysis, volumetric processes being preferred. Special tests are furnished for 
determining the permissible limits of accidental impurities, and the presence of harmful 
substances, such as metals. 



30 MANUAL OF PHARMACOLOGY 

ies of volatile oils are assayed for their most important ingredient. Fats and 
lor their "iodin absorption" and " saponification values;" resins 
for the "add number;" some vegetable products for their ash. These tests serve 
mainly for identifu at ion and the exclusion of willful adulterations. 

in is as>ayed for its digestive power for proteins, pancreatin for starch. In 
IK drills, such as Jalap. Scammony, or Guaiac, the proportion of ether- or alcohol- 
ile matter is determined. 

most important class of assays refers to drugs containing alkaloidal principles, 
utili/.ing the method of immiscible solvents, as in toxicologic analysis. This rests on 
ict that free alkaloids are generally soluble in chloroform or ether, whilst their salts 
are insoluble in these, but soluble in water. In principle, alkaloids are extracted by 
chloroform or ether, or a mixture of both, in alkaline reaction. This solution is then 
shaken in a separator with acidulated water, which converts the alkaloids into salts and 
them, leaving the impurities behind. For further purification, the watery 
solution is again rendered alkaline and extracted with chloroform or ether. This, 
on evaporation, leaves the fairly pure alkaloid which may be weighed; or titrated, by 
I vmg it in a known amount of acid, and titrating back with alkali. Each cubic 
centimeter of acid corresponds to a definite quantity of each alkaloid. It is important 
to observe the directions minutely to obtain reliable results. The process for extracts 
and fluidextracts differs merely in details (the percolation being omitted, etc.). Tinc- 
tures are first concentrated by evaporation. 

This method estimates the sum of all the alkaloids present in the drug, and suffices 
when the important one predominates very largely over the others. When this is not the 
case, it is necessary to confine the assay to the particular alkaloid desired, generally a 
very difficult matter. In Hydrastis, advantage is taken of the comparatively greater 
solubility of hydrastin in ether; in Opium, of the comparative insolubility of the morphin 
in this solvent. In Nux Vomica, the brucin is removed by oxidizing it with nitric acid. 
Bio-Assay. Drugs which depend for their activity on neutral principles are un- 
fortunately unsuitable for chemic assay; there being no reliable chemic method for 
estimating the constituents of Apocynum, Cannabis Indica, Convallaria, Digitalis, 
Ergot, Scilla, etc. Attempts have been made to supply this deficiency by physiologic 
standardization estimating the strength of a preparation by comparing its effects on 
animals with those of a standard product. A just fatal dose is generally the best cri- 
terion for quantitative work. Individual differences of susceptibility and absorption in 
different animals can be largely eliminated by using an extensive series of animals. 
The expense and labor is scarcely warranted by the results, except in a very few cases, 
for instance with Digitalis. Qualitative physiologic tests of drugs of very uncertain 
activity, such as Cannabis Indica or Ergot, are more simple. The U.S. P. describes the 
most important bio-assays, but leaves their employment optional with the manufacturer 
(except in the case of Cannabis). 



CLASSES OF PHARMACEUTIC PREPARATIONS 

The pharmaceuticals are grouped into certain definite classes, estab- 
lished by long usage, such as Waters, Spirits, Tinctures, Extracts, Pills, 
Plasters, Ointments, etc. The student should learn to distinguish clearly 
between these preparations, according to the definitions given below. 

WATERY SOLUTIONS 

These include the Waters, Liquors, Mucilages and Syrups. Their 
advantage lies in the fact that water is a cheap solvent of very wide 
applicability, itself devoid of any therapeutic property. In the case of 
vhich are insoluble in it, it can not of course be employed. 
The greatest drawback lies in the fact that watery solutions of organic 
substances tend to spoil rapidly by the development of bacteria and infu- 
soria. Solutions of chemic substances are less subject to this change, as 
they do not furnish a pabulum, and are often themselves antiseptic. 

Aquae, Waters (singular, Aqua; abbreviated, Aq.). Clear aqueous 
solutions of volatile substances. Two very dissimilar classes of prepara- 
tions come under this heading: 



CLASSES OF PHARMACEUTIC PREPARATIONS 31 

Aquae Aromaticae, Aromatic Waters, U.S.P. (Flavored Waters). 

Saturated solutions of volatile oils (Aqua Cinnamomi, etc.). These are 
alone included under Aquae in the B.P. They are prepared either by 
distilling the plant or oil with water (B.P.); or by triturating the oil with 
an absorbent substance (talc, etc.) until it is finely subdivided, and then 
extracting this with water. 

The quantity of active substance in them is just large enough 
to give them a pleasant flavor without imparting to them any noticeable 
therapeutic properties. The absence of alcohol makes them good sol- 
vents for salts, which are generally insoluble in this liquid. Hence their 
main use is as a pleasant vehicle (a vehicle being the substance which 
serves for the conveyance of another substance). 

The dose of flavoring waters is practically unlimited (15 c.c., 4 drams, 
U.S.P.) ; except Aqua Amygdelae Amarse, 4 c.c. 

Waters, as a rule, do not keep well. Their keeping qualities may be improved by 
adding to them some of the oil of which they are solutions. This floats on the surface, 
and in this way excludes air and bacteria, and at the same time insures permanent 
saturation. 

The second class of Waters (included under Liquores by the B.P.) are 
fairly strong solutions of gases (ammonia, etc.) prepared by passing the 
gas into water. Their doses are relatively small. 

Liquores (Liquor, Liq.) ; Solutions. Aqueous solutions of solid chemic 
salts or hydrates, made either by dissolving the pure salt directly in water 
by trituration or heat; or, more often, by chemic decomposition (simple 
and chemic solution). (The British Pharmacopeia includes solutions of 
gases under this heading.) 

The advantage of the solutions consists mainly in the convenience of 
measuring the relatively large volumes of the solution against weighing 
the small quantity of salt. Water is chosen as the solvent because salts 
are but little soluble in alcohol, and because the therapeutic qualities 
of the latter are not desired. 

Solutions, when used for special purposes, receive special names, thus : 
Injectiones (Hypodermicae; Urethrales), Collyria (Eyewaters), Lotiones 
(Washes), Gargarismag (Gargles), etc. 

Injectiones Hypodermicae (B.P.) (Inject. Hyp.). These are watery solutions of 
active drugs, intended for subcutaneous administration, and of such strength as to be 
used in the dosage of 0.3 to 0.6 c.c., 5 to 10 minims. They are sometimes preserved 
sterile by the addition of phenol or salicylic acid. Manufacturers also market a 
variety of unofficial hypodermic solutions in aseptic ampouls, i.e., small sealed glass 
vials containing a single dose of the sterilized solutions. 

Mucilagines, (Mucilago, Muc.); Mucilages. Aqueous solutions of 
gummy substances. They are used as vehicles and demulcents. Since 
gums are insoluble in alcohol, mucilages are incompatible with this sub- 
stance. They should be recently prepared because they are very apt to 
mold. 

Mucilages are made by either hot or cold process: the former being solution by 
heat, the latter by percolation. Heat should be used only when necessary (tragacanth), 
as it usually causes discoloration of the product. 

Syrupi (Syrttpus; Syr.) ; Syrups. Dense saccharine solutions of medic- 
inal substances. The syrup serves mainly as a vehicle and preservative. 
The dose of flavoring syrups is practically unlimited (15 c.c., 4 drams, U.S.P.). 



MANUAL OF PHARMACOLOGY 

mpe -vrun is practically a saturated solution of cane-sugar, containing 85 Gm. 
- [>. (66.7 Gm. of sugar in 100 Gm. of syrup, B.P.). Syrups are usually 
pri . p ; king an infusion, and dissolving in this the sugar, either by heat or 

by prro.lation, aro.nlini; to whether or not the drug is injured by a high temperature. 
I,", s , modifications may be introduced. Some syrups are prepared by mixing 

the t1uide\tr.u t and syrup. //</< v is sometimes used instead of cane-sugar, making a 
.lions railed mcllit,i. If acetic acid is added to this, we have oxymellita. 
Confections (Conffctio; Conf.) are thick medicated jams. 

They wore formerly very popular, but have now been almost abandoned. Electuaries 
were similar but somewhat thinner preparations. 

Elixiria (Elixir; Elix.} ; Elixirs. Sweetened aromatic alcoholic liquors, 

! a> flavoring vehicles, similarly to the syrups. Their content in 
alcohol (about 25 per cent.) is apt to lead to abuses, which must be kept 
in mind. 

The official Aromatic Elixir is flavored with orange peel, lemon, cori- 
ander and anise. This, mixed with licorice, constitutes Elixir Adjuvans. 

Glycerites (Glyceritum, U.S.P.; Glycerinum, B.P.; Glyc.}. Solutions 
in glycerin. Glycerin is a good solvent for many substances. It keeps 
well. and is useful especially for external application on account of its 
adhesiveness. Glycerin is also less irritant than alcohol and devoid of 
the pharmacologic action of the latter agent. 

ALCOHOLIC SOLUTIONS 

Alcohol is a specific solvent of certain substances (volatile oils, alka- 
loids, resins). In prescribing, these should not be mixed with an aqueous 
solution. Alcohol is also a good preservative; but it has distinct thera- 
peutic qualities, which may or may not be useful. 

Spirits (Spiritus, genitive Spiritus; Sp.}. Alcoholic solutions of vola- 
tile drugs. They are all fairly strong. They are prepared by simple or 
chemic solution or by distillation. Flavoring spirits contain 10 per cent. 
of the respective volatile oils. Their dosage is 2 c.c., 30 minims, U.S. P. 
(0.3 to 1.2 c.c., 5 to 20 minims, B.P.). Spirits other than flavoring vary 
in strength and dose. 

PREPARATIONS MADE BY EXTRACTION 

In these, only a part of the crude drug is dissolved. They comprise 
the aqueous Infusions and Decoctions; and the alcoholic Tinctures and 
Fluid and Solid Extracts. 

Infusions (Injnsiim; Inf.}. Aqueous solutions of the soluble principles 
of vegetable drugs, obtained by brief maceration in hot or cold water. 

Decoctions (Decoction; Dec.). Analogous preparations, in which 
the ingredients have been boiled with water for at least fifteen minutes. 

Infusions and decoctions are especially useful when it is wished to 
-<>me principle which is more soluble in water, or when the ther- 
itic effect of alcohol or the mechanical incompatibility of alcohol 
with salts is to be avoided. There are some inconveniences connected 
with their use: They take a long time to prepare. Like all watery solu- 
spoil quickly, and must, therefore, be made fresh. The decoc- 
tion can only be used if there are no delicate constituents to be destroyed 
by boiling. 

The solvent being so very cheap and having no action, it is usual to 
make decoctions considerably weaker than tinctures. In prescribing 



CLASSES OF PHARMACEUTIC PREPARATIONS 33 

infusions or decoctions of potent drugs, the proportion should always be 
stated by the prescriber. When the strength is not stated, the pharmacist 
is supposed to use 5 per cent, of the drug. The dose of non-poisonous 
infusions and decoctions lies between 15 and 120 c.c. (J^ to 4 ounces). 

Type Formulas (U.S.P.). Infusa. 1,000 c.c. of boiling water are poured on 50 
Gm. of the coarsely comminuted drug, the vessel is covered tightly, and allowed to 
stand for half an hour in a warm place. It is then strained with expression, and enough 
water is poured through the strainer to make the infusion measure 1,000 c.c. 

Decocta. 50 Gm. of the coarsely comminuted drug and 1,000 c.c. of cold water are 
boiled in a covered vessel for fifteen minutes, cooled to about 4oC., strained and 
expressed, and cold water added through the strainer to make the decoction measure 
1,000 c.c. 

Preservatives. The amount of preservative which must be added to a watery solu- 
tion to insure its keeping qualities must vary with its nature, and in the same direction 
as the amount of "extractive." The proportions generally necessary are: Alcohol, 
20 to 25 per cent.; glycerin, 10 per cent.; sugar, 66 Gm. to too c.c. of finished product. 
Alcohol, 20 per cent. + glycerin, 5 per cent. 

A bibliography of the deterioration of drugs and pharmaceutic products is given 
by Eberhardt and Eldred, 1914. 

Tinctures (Tinctura, TV.). Alcoholic or partly alcoholic solutions of 
the useful constituents of such drugs as are not wholly soluble in the mens- 
truum. 

Exceptions of this definition are tincture of iodin, tincture of chlorid of iron, and 
tincture of tolu, in which the solution is complete. 

The drug-strength of the tinctures varies from 0.4 to 50 per cent.; 
but those containing potent drugs conform to an international standard 
of 10 per cent. 

The tinctures are in many respects the most useful therapeutic prepa- 
rations: The dose is relatively large and uniform (about 2 to 4 c.c. 
for the non-toxic); the quantity of solvent is sufficiently large to keep the 
principles in solution; the use of heat in the preparation is avoided. 

The greater number of tinctures are prepared by percolation; a few 
by maceration. The menstruum is alcohol or alcohol and water; acetic 
acid or glycerin are added in a few cases; aromatic spirit of ammonia 
is used in the ammoniated tinctures. 

Type-process for Percolation Tinctures (U.S.P.). The powdered drug is moistened 
with the menstruum, transferred to a percolator without pressing, and allowed to stand 
covered for six. hours. It is then packed firmly, and menstruum poured on to more 
than cover the powder. When the liquid begins to drop, the lower orifice of the per-, 
colator is closed, and the maceration prolonged for twenty-four hours. The percola- 
tion is then allowed to proceed slowly, gradually adding sufficient menstruum to the 
percolator until the percolate measures the required volume. 

Type-process for Maceration Tinctures (U.S.P.). The drug is macerated in a 
moderately warm place with the menstruum, using four-fifths of the final volume. 
This is continued, with frequent shaking, for at least three days. _ It is then filtered, 
the filter being washed with menstruum sufficient to make the required volume. 

Detannated tinctures are tinctures from which the tannin has been removed (as by 
powdered skin). They do not precipitate with iron salts. 

Ethereal tinctures are made with ethereal spirit, a mixture of 7 parts of ether and 3 
parts of alcohol. 

Green Tinctures. Since some drugs are supposed to lose part of their activity by 
drying and keeping, a class of tinctures made from the freshly collected green drugs has 
been introduced under the name of Tinctura? Herbarum Recentium. The directions 
are to macerate 500 Gm. of the fresh herb with 1,000 c.c. of alcohol for fourteen days, 
to express and filter. These preparations are justly unpopular. They are of very 
inconstant strength, since the natural moisture of plants is variable. Again, they can 
be prepared only in the localities where the plants are native and where there often 
3 



34 



MANUAL OF PHARMACOLOGY 



are no reliable facilities for their manufacture. These remarks apply equally to the 
.) of the British Pharmacopeia, made by using i part alcohol and 
^ part> i>f tin- freshly expressed juice. 

Wines (Vhmni; Vin.). These are tinctures in which wines have been substituted 
for alcohol. They have a more pleasant taste, but inferior keeping qualities, and are 
now very little used. 

: (Acet.) are medicated vinegars, prepared by maceration with dilute acetic 

Fluidextracts, U.S.P.; Liquid Extracts, B.P. (Fluidextractum; 
Fldext. -Extnictum Liquidum; Ext. Liq.}. These are liquid alcoholic 
extracts 100 c.c. representing approximately 100 Gm. of the drug. The 
menstruum is in certain cases modified by the addition of glycerin, acetic 
acid, i-tc. They are the most concentrated fluid preparations, and were 
supposed to possess considerable advantages, but many are of doubtful 
value. 

The simple ratio of drug-strength has no special advantage in therapeutics, and 
has led to serious abuses such as the practice of preparing tinctures, infusions, etc., 
by the dilution of the fluidextracts. This is highly reprehensible, since these dilutions 
often differ materially from the orthodox preparations. 

Concentration may sometimes be desirable to reduce the bulk of the dose, but it is 
often secured at the cost of efficiency. The heat which must necessarily be used in 
their preparation is never beneficial. Precipitates are apt to form on standing, and while 
these are often inactive, they may contain the active principles. They are also 
much more subject to precipitation on mixture with other liquids, and the dose is usually 
so small that they require some such admixture. 

Fluidextracts are usually prepared by percolation, the first four-fifths 
of the percolate being set aside, the remainder evaporated to the consist- 
ency of a soft extract, dissolved in the reserved portion, and menstruum 
added to make the required volume. 

Type -processes for Fluidextracts. The following are described by the U.S. P. : 

Type A. The powdered drug is moistened and macerated with the menstruum as 
described under tinctures, the maceration being prolonged to forty-eight hours. The 
percolation is then started, and continued by the addition of menstruum, until 850 
c.c. of percolate have been collected for 1,000 Gm. of drug. This is reserved and 
percolation continued, with additional menstruum, until the drug is exhausted. These 
later percolates are evaporated to a soft extract, below 6oC., dissolved in the reserved 
portion, and diluted with menstruum to make 1,000 c.c. 

Type B. This is employed when two successive menstrua are used, the first con- 
taining glycerin, acid, etc. In this case, the powdered drug is moistened and macerated 
with the first menstruum. The percolation is then started, and continued with the 
plain alcoholic menstruum. Otherwise, the process is identical with Type A. 

Type C. Fractional or Divided Percolation. This is used for drugs containing con- 
stituents that are volatile or injured by heat. It may also be used in place of Type A. 

The drug is divided into three portions of 500 Gm., 300 Gm. and 200 Gm. The first 
portion is then moistened and macerated, as usual. The first 200 c.c. of percolate are 
reserved; and the percolation then continued, collecting five additional portions of 300 
c.c. each. 

The second 300 Gm. portion of drug is moistened with the first 300 c.c. percolate 
of the preceding percolation; and macerated and percolated, as usual. The first 
300 c.c. of percolate are reserved; and the percolation continued with the successive 
portions of the percolate from the first drug, until exhausted. These weaker percolates 
are collected in 200 c.c. portions. 

The third 200 Gm. portion of the drug is moistened with the first 200 c.c. percolate 
of the second drug, macerated and percolated with the successive weak portions of the 
percolate of the second drug, until 500 c.c. are obtained. This is mixed with the reserve 
portions of the two first drugs. 

Type D. In this, the drugs are exhausted with water and preserved by the subse- 
quent addition of alcohol. 1,000 Gm. of the ground drugs are mixed with 5,000 c.c. 
of hoiling water and macerated for two hours. They are then transferred to a per- 
colator, gradually adding boiling water until the drug is practically exhausted. The 



CLASSES OF PHARMACEUTIC PREPARATIONS 35 

percolate is evaporated on a water-bath to the specified volume. It is then cooled, 
and sufficient alcohol added to make 1,000 c.c. 

Solid Extracts (Exiractum; Ext., U.S. P. Extractum Siccum; Ext. 
Sice.; B.P.}. Must not be confused with the fluidextracts. They are 
solid or semisolid preparations obtained by evaporation of solutions of 
the medicinal principles of drugs. Some of the solid extracts are dry, 
others of a "pilular" consistency, i.e., like a pill-mass. They are con- 
venient for administration in solid form, e.g., in pills, ointments, plasters, 
etc. Nearly all the potent, and most of the other, extracts are adjusted 
to four times the strength of the fluidextracts. 

"Powdered Extracts" are dried, and mixed with sufficient diluent 
(milk-sugar) to give them the same strength as the solid extracts. Most 
extracts are prepared by percolating and subsequent evaporation; the 
last and weaker portions of the percolate being evaporated first, to avoid 
the deleterious actions of prolonged heat on the main portion. Some of 
the extracts are obtained by evaporating the fluidextract. The menstruum. 
is sometimes water, or alcohol, or a mixture of both; acetic acid being 
added in some cases. The finished product is assayed, if possible, and 
adjusted to a definite standard by the addition of sugar of milk. 

Artificial resins are precipitates obtained by mixing alcoholic solutions 
with water. Where they constitute the active principle, this is a conven- 
ient method of isolating it in a concentrated although somewhat impure 
form. Their strength is fairly constant. They are practically identical 
with the eclectic "resinoids. " 

Oleoresins (Oleoresina, Oleores], are extracts containing the resinous 
and oily constituents of the drug obtained by evaporating ethereal, acetone 
or alcoholic percolates. 

MIXTURES 

Mixtures, in the wider meaning of the word, are fluids resulting from 
the mixture of fluids with other fluids or with solids. They comprise: 
Linimenta, Misturae, Emulsa. 

Liniments (Linimentum, Lin.}. These are solutions of irritant drugs 
in oily, soapy or alcoholic solutions, intended to be rubbed on the skin as 
counterirritants. 

Mixtures (Mistura; Mist.}. In the narrow meaning of the term, 
these are generally suspensions of a solid in a liquid, sometimes by the 
use of a gummy substance; for heavy powders can not be evenly distrib- 
uted in a light liquid without this aid. The B.P. also includes some 
emulsions under this title. 

Emulsions (Emulsum, Emtd.}. These are mixtures of a milky appear- 
ance, made by suspending fats, oils, or resinous substances in aqueous 
liquids by the intervention of some viscid, usually gummy, substance. 

The object of emulsification is to break up the insoluble oil into the 
finest particles and to envelop each of these in a coating of the emulsi- 
fying agent, which will keep them from reuniting. 1 This allows of dilution, 
of the admixture of other substances, and it facilitates absorption. 

Milk is a natural emulsion in which the butter-fat is kept in emulsion by the casein. 
It may be taken as a type to which artificial emulsions must conform. The globules 
must be uniform and of about the same size as those in milk. 

Emulsions may be divided into the following classes: 

J See also Roon, 1916, Physical significance of emulsions. 



36 MANUAL OF PHARMACOLOGY 

\iilnriil emulsions, such as are found ready formed in nature. Instances of these 
are milk, the yolk of e^. and some plant juices. 

tinm-resin <nul sent ,-niitl\ins; that is, emulsions made from such substances as con- 
tain their mvn emulsifier. Examples of such gum-resins are ammoniac, asafetida, and 
myrrh. Tin- drugs arc reduced to a coarse powder and water is added gradually. Seeds 
which yield such emulsions are poppy, hemp, and almond. 

///. artificial emulsions an emulsifier must be added. Quite a num- 
ber of substances may be used for this purpose, the principal ones being 
gum acacia, tragacanth, yolk of egg, Irish moss, soap bark, and extract 
of malt. The substance most commonly used is gum acacia. This 
emulsifier is incompatible with large quantities of alcohol, borax, tincture 
of iron, or glycerin. It may be used by either the Continental method, 
where a nucleus is first formed from gum, oil, and water, and to which the 
remainder of the water may then be added; or by the English method, 
where a mucilage is first made, to which the oil and water are added in 
alternate small portions. 

The Continental method deserves the preference. To form a nucleus there should be 
used for each part of oil Y to 3^ part of acacia and i part of water. Stir the oil with the 
acacia in granular powder, then add the water at once. The mixture of the oil and the 
gum must not be allowed to stand too long before adding the water, otherwise it will 
cake. In the English method the acacia, the amount of which should be half that of the 
oil, is rubbed up with an equal volume of water and then small portions of oil and 
water are added alternately. If this addition should be done too rapidly, there is danger 
that the emulsion will separate or "crack." This does not necessarily spoil it, for it 
may be re-emulsionized by adding it to a fresh portion of acacia and repeating the 
process. 

In making medicated emulsions the ingredients should be mixed in the folio-wing 
order: First the nucleus, then the flavoring, then the syrup, and, lastly, the water in 
which the solids have been dissolved. 

In yolk emulsions, the yolk of egg is used in place of the nucleus in the Continental 
method. The yolk is triturated in a mortar and the oil and water are added alternately 
in small portions. One yolk suffices for from i to 2 ounces of oil. The yolk emulsions 
are incompatible with the same substances as gum emulsions and do not keep nearly 
as well. 

Soap bark has saponin for its emulsifying agent. It is not incompatible with any 
of the above-named substances, but possesses very decided therapeutic properties, 
which preclude its use in many cases. It is used in the proportion of i part of the 
tincture to 8 parts of the oil: Place the tincture in a dry bottle, add the oil in portions, 
and shake after each addition. Finally add the water. Crude saponin (0.3:1 oo of oil) 
can also be employed. 

Extract of malt emulsifies its own weight of oil. It is used as the nucleus in the 
Continental method. 

Solutions of alkalies may also be used for emulsification, since they form soaps, but 
they are usually not desirable. 

SOLID PREPARATIONS 

These comprise the Powders and the various dosage forms, Pills, etc., for 
internal use; and Ointments, Plasters, for external applications. 

Powders (Puhns; Pulv., Gen., Pulveris) are finely powdered drugs 
intended for either external or internal administration. 

When intended for internal use, they are generally folded in papers 
(chartulcE; chartul.). It must be borne in mind that hygroscopic (deli- 
quescent) substances, such as potassium acetate or citrate, can not be 
prescribed as powders, nor such substances as become a fluid when 
mixed (e.g., camphor and chloral). 

In making compound powders, one should begin with the smallest ingredient and 
add the others in the order of their amount, triturating thoroughly after each addition. 



CLASSES OF PHARMACEUTIC PREPARATIONS 37 

In dividing the powder, it is not always necessary to weigh out each powder. The object 
is often accomplished with sufficient accuracy by flattening the powder on a piece of 
paper, squaring off the edges, and dividing into a number of equal parts by means of 
a spatula. In the case of more bulky powders, such as Seidlitz powders, measures are 
used. 

When intended for external use, as for dusting-powders, extreme fineness is the 
main desideratum. They should in this case be mixed with a spatula and not in 
a mortar, since the former insures greater smoothness. 

Triturations (Trituratio; Trit.). These are powders obtained by triturating the 
active substances with some inert material such as sugar of milk. Their advantage 
lies in the greater ease in weighing out a comparatively large amount of substance. 
When no special directions are given, triturations are made of a strength of 10 per cent. 
The trituration of elaterin is the only one official. 

Eleosacchara are triturations of volatile oils with sugar in the proportion of i : 30. 
They are used for the purpose of flavoring other powders. 

Effervescent (Eff.) Salts. These are dried salts, mixed with sodium 
bicarbonate and tartaric acid, etc., so as to evolve carbonic acid when they 
are dissolved in water. This aids in disguising the taste. 

DOSAGE FORMS 

Pills, capsules, tablets, lozenges, cachets, etc., are used to divide the 
drug into definite doses, to avoid the inconveniences of dry powders, and 
to reduce the bulk. Care must be used in prescribing the dosage forms 
so as not to make them too large to be swallowed. 

The administration of drugs in compact solid form delays solution and 
absorption. This is especially true of old pills, in which the excipient may 
become so impervious that they pass unchanged into the feces; but it 
applies also to many tablets. A mere delay in solution may be an advan- 
tage if an intestinal action is to be procured; but difficultly soluble sub- 
stances (salol, bismuth, etc.) should not be administered in these compact 
forms. Corrosive substances are also unsuited for solid administration. 

Pills (Pilula; PH., U.S.P.}. These are denned as spherical or elongated 
masses of medicinal substances, of such size as to be convenient for 
swallowing; that is to say, containing up to 5 gr. (0.35 Gm.) of active sub- 
stance. If the pill is of larger si.?e, it is called a bolus. Very small coated 
pills are spoken of as granules. The quantity of drug in the official pills 
is adjusted so as to make the average dose two pills. 

Pill-Masses (Massa; Mass., U.S.P. Pilula; PH., B.P.). These are 
soft solid preparations of such consistency that they can be formed into 
pills. 

A pill consists of the active ingredient and of the excipient (cohesive). 
In order to make pills, the substance is first made into a mass by means 
of this excipient. The mass must be sufficiently soft to admit of mold- 
ing, but on the other hand it should be sufficiently consistent not to lose 
its shape. It should neither harden nor soften nor crumble on keeping. 

The quantity of drug in the B.P. pills is adjusted so as to make their dose, with few 
exceptions, 0.25 to 0.5 Gm., 4 to 8 gr. (The exceptions are Pil. Phosphori; Pil. Ferri; 
Pil. Plumbi c. Opio; Pil Saponis Co.). 

Excipients. Syrup, glycerin, acacia, vegetable extracts (Extr. Gen- 
tianae), and a great variety of other substances are used, according to the 
characters of the active drug. The choice may usually be left to the 
pharmacist. 

Liquid Excipients. Glycerite of acacia or tragacanth, thick flour paste, glycerin 
syrup, confections, or extracts. 



38 MANUAL OF PHARMACOLOGY 

Solid Excipients. Acacia, tragacanth, starch, althea, licorice powder, soap. 

For chemicals which are destroyed by organic substances the best excipient is formed 
by a mixture of petrolatum and kaolin. 

Absorption Influenced by Excipients. These, being colloidal, all delay absorption 
somewhat. For iodid pills, Rieben, 1907, found the greatest delay with waxy and oily 
rxdpients, the least with vegetable extracts and syrups. Silver-foil coating produced 
considerable delay. 

Preparation of Pills. The ingredients are first triturated to a fine powder. In 
case crystalline salts are used, these must be desiccated. The excipient is then 
added in small portions and thoroughly triturated with the powder until the proper 
consistency is obtained. If accidentally too much excipient is added this can be 
remedied by the addition of some inert powder, such as starch, gum acacia, or powdered 
licorice-. 

The mass having been formed by thorough trituration, it is placed on a glass or 
porcelain slab marked with equal divisions. It is well to put a little dusting-powder 
on the slab to prevent the mass from sticking to it. The best dusting-powders are 
starch, lycopodium, or licorice, according to the color of the pill-mass. This mass is 
then rolled out by means of a broad spatula into a cylinder of uniform diameter, and 
this is cut with a sharp knife into the requisite number of equal parts. These are formed 
into spherical shape by rolling them between the thumb and the first two fingers. The 
finish may be rendered more perfect by placing the pills with a liberal amount of dust- 
ing-powder in the lid of the pill box and gently rolling them with the ball of the thumb. 

Pill-coatings. Pills are often coated with sugar, gelatin, chocolate, 
etc., to disguise their taste while being swallowed. The coatings tend to 
interfere somewhat with absorption. 

In coating with sugar, the pills are moistened with a thick syrup and rapidly rotated 
and dried in a current of warm air until they acquire a sufficiently thick coating and a 
fine polish. The latter is often enhanced by a little wax. For a gelatin coating they 
are dipped into a strong hot solution of gelatin, which is allowed to harden in the air. 
When it is desired to exclude the air from the pills, they are sometimes varnished by 
dipping them into an ethereal solution of tolu. This is the official process for keeping 

Ehosphorus pills. A still finer polish may be given to pills by coating them with silver 
:af, which is done by shaking them in a box with silver foil. 

Enteric Pills. These are pills coated with some substance (keratin, 
salol, stearic acid, or f ormaldehyd-hardened gelatin), supposed to protect 
them from the gastric juice, but which dissolves in the intestines. They 
would be useful when the drug is intended to act only after passing the 
stomach. Unfortunately, they fail to accomplish their purpose, for soluble 
drugs diffuse through them rapidly (Linossier, 1911). 

Improved directions for the salol-coating of pills are given by Peacock, 1915; for 
stearic acid by Toplis, 1915. The latter claims that the stearic coating apparently 
fulfils its purpose. 

Keratin (a protein derived from horn, goose quill, etc.) was tried extensively; but 
it is totally unsuitable, since commercial specimens are largely soluble in artificial 
gastric juice (Puckner, 1911). 

Formaldekydized Capsules. These are prepared by immersing the filled capsules 
in water containing i per cent, of absolute formaldehyd, and drying. The capsules 
should become insoluble in acid-pepsin solution, but remain soluble in 0.5 per cent, 
sodium carbonate. The degree of insolubility is governed by the duration of the im- 
mersion. If they are to be used on the next day, the immersion should last six minutes; 
but these will have become quite insoluble in the carbonate after they have been kept 
a week With immersion of thirty seconds, the capsules will be properly hardened only 
after storing them for two weeks; but they will preserve their proper solubility in 
carbonate for one year (Scoville, 1915). 

Capsules. These are small containers, usually of gelatin, intended to 
be filled with the drug and swallowed. Those used for powders are hard, 
and consist of a body and a cap. In filling these capsules, the powder is 
divided into the requisite number of parts, forced into the body with a 



CLASSES OF PHARMACEUTIC PREPARATIONS 



39 



spatula, and the caps placed on. Soft capsules are used for oils, etc. 
These are sealed with a drop of melted gelatin. These soft capsules 
may be made to hold as much as 4 Gm. Hard capsules should not hold 
more than 0.3 Gm. or at most 0.5 Gm. A somewhat larger amount may 
be used by making the powder into a pill-mass. The purpose of capsules 
is to disguise the taste of the substance. 

Capacity of Capsules for Dry Powders. The capsules are marketed by numbers, 
which have about the following average capacity (Caldwell, 1913); probably differing 
somewhat, however, for the various makes: 



Size of capsules 


Capacity in 
minims 


Average capacity for most powders 


In grains 


In grams 


3 
2 


5-3 
6-5 


3-0 
4.0 


0. 20 
0.25 


I 


8.4 


5-5 


o-35 


O 
00 


IO.O 

15-5 


7-5 

IO.O 


o. 50 
0.65 



Parke, Davis & Co. state the capacity of their capsules as: No. o, 12 minims; 
No. i, 9 minims; No. 2, 6 minims; No. 3, 4J^ minims; No. 4, 3 minims; No. 5, 2 minims. 

Wafers are thin sheets formed of a dried flour-paste, in which the powder is enveloped. 
They are immersed in water and swallowed. They possess the advantage that larger 
quantities of the drug (up to i Gm.) may be administered. 

Cachets are wafers, molded into concave circular forms. 

Troches or Lozenges (Trochicus, Troch.}. These are made by punch- 
ing or cutting out circular or oblong disks from a mass made up from the 
active substance, sugar, and mucilage or fruit base. These are then dried 
in the air. They are usually intended for solution in the mouth, and are 
most popular for throat medication. They are, however, sometimes used 
instead of pills. 

Tablets (Tabella, Tab.). These are small disks composed of medicated 
powders. Tablet triturates are prepared from the powdered drug and milk- 
sugar or sugar, made into a paste with alcohol, and pressed into molds. 
Compressed tablets are formed by strong dry compression. These forms 
are used similarly to pills, and dissolve more readily, especially the tritu- 
rates. By suitable choice of ingredients, they may be made very accept- 
able to children (Tabellce Dtilces, "Candy medication" Fantus, 1912- 
1914). 

Variability of Commercial Tablets. Commercial tablets are often very unreliable. 
Variations of 10 per cent, may be excusable, but Kebber, 1914, found that nearly a 
fifth of the samples bought varied by 20 per cent, or more; and this even with toxic 
substances. 

Hypodermic tablets are similar to the tablet triturates, especial care 
being exercised to secure quick solution. 

Lamellae (B.P.) (Lam.} are thin gelatin disks, softened with glycerin, and impreg- 
nated with substances acting on the pupil. They are intended to be placed under tha 
eyelids. 

Suppositories (Suppositorium, Supp.}. These are suitably shaped 
masses of solid, medicated usually fatty substances, intended for introduc- 
tion into the rectum, vagina, or urethra (Fig. 2). They take the place of 
ointments for local treatment where these can not be readily applied. 



4O MANUAL OF PHARMACOLOGY 

Suppositories are made by incorporating the medicinal substance 
into a suitable base, and mokling into masses of suitable shape and size 
The ideal base is one which, whilst solid at the ordinary temperature, is 
nu-lted by the heat of the body. Such is cacao-butter (Oleum Theobro- 
maii- 1 . \ilya-rinated gelatin or a soapy base is also sometimes used, 
espeeially with urethral suppositories for which cacao-butter would be 
too brittle. Rectal suppositories are usually made with sufficient base 
igh i or 2 Gm.; vaginal, 4 Gm. 

Urethral suppositories are pencil-shaped, pointed at one end, and measure 7 or 14 
i-m., weighing 2 or 4 Gm. 

Theobroma suppositories are made either by the hot or cold process. The hot 
process consists in melting cacao-butter at a temperature not exceeding 3SF. and 
adding the active substances, then pouring the mixture into cold molds. In the cold 
proce-i* the active substances are triturated with grated cacao-butter with the addition 
of a small amount of castor-oil, sufficient to make it into a suitable mass, which is 
then rolled out and divided as for pills. They may also be formed by pressure. 




FIG. 2. Different forms of suppositories (H. Blair). Natural size: The largest is for use in 
the vagina; the cylinder is a urethral suppository or bougie; the others are various shapes and sizes 
of recta! suppositories. 



Suppository capsules, whether of gelatin or of cacao-butter, largely defeat the object 

for which suppositories are employed. They are, however, much more convenient to 

prepare than the suppositories, and may suffice when the object is merely internal medi- 

: i . ( ;i ycerin is made into a suppository by means of a very hard soap formed from 

stearic acid and sodium carbonate. 

Ointments (Unguent urn, Ung.} are soft fatty masses intended for external 
application. They consist of the active ingredient and the base. 

Ointments are prepared by fusion, mechanical admixture, and chemic reaction. 
In mixing ointments by fusion, that constituent of the ointment which has the highest 
mi-king point is first melted, and the others are then added in the order of their melting- 
points. Tlii' active substance is added last, to obviate the prolonged action of heat 
upon it. The mechanical admixture is usually done on a slab or in a mortar. It is 
needless to say that powders must be in the finest stage of subdivision. If the quantity 
of powder is large, it is usually first mixed with some of the melted ointment. 

Ointment Bases.. The base of ointments is formed by lard, by petrolatum, by 
lanolin, or by various mixtures, of which the "simple ointment," consisting of 4 parts 
of lard and i part of white wax, is the most important. The base must" vary according 
to the object for which the ointment is employed, whether absorption, protection, or 



SOLUBILITIES 41 

local action is desired. Petrolatum (vaselin), which consists of the less volatile parts of 
petroleum, is simply protective, or useful as a vehicle for substances intended to have a 
mere local action, since it is not absorbed. Lanolin (Adeps Lanae Hydrosus) consists 
of a mixture of cholesterin-like substances obtained from sheep's wool. It is very readily 
absorbed, does not become rancid, and mixes with its own weight of water. This latter 
property is of great advantage when it is desired to use crystalline salts in ointment 
form, since these can be incorporated in the form of solution, making a much smoother 
ointment. Lard is the cheapest ointment material, It penetrates well; but an im- 
portant objection to it rests upon the fact that it becomes rancid very rapidly. This 
tendency can be greatly diminished by the incorporation of antiseptic substances. 
Official Benzoinated Lard is an attempt in this direction. 

Emollient or soothing, and antiseptic ointments, should not be absorbed, and are, 
therefore, best made with petrolatum. Stimulating and absorbent ointments are 
intended to penetrate, and therefore require lard or lanolin. With astringent ointments, 
the base should vary according to the intended depth of action (Corlett, 1910). 

Oleates (Oleatum, Oleat.}. These are solutions of metals or alkaloids in oleic acid. 
They are used similarly to ointments. 

Cerates (Ceratum, Cerat.). These are preparations similar to oint- 
ments but of a firmer consistency. They are generally made from a mix- 
ture of wax and petrolatum, in the same manner as ointments. 

Plasters (Emplastrum; Emp.). These are made by spreading on a 
thin cloth or leather support a mass or base which is hard at an ordinary 
temperature, but is softened and rendered adhesive at the temperature 
of the body. They are applied as adhesive or for counterirritation. A 
rubber composition is the base for most modern plasters. 

Plasters are now usually obtained from manufacturers, and are but rarely made 
to order. The typical old plaster, had for its base diachylon, Burgundy pitch, or other 
resins. Diachylon is a lead soap made by precipitating soap with lead acetate. This 
alone, or with the addition of a little rubber and petrolatum forms the base of the other 
official plasters. The* base is fused and the active ingredients incorporated into it by 
stirring. 

To spread the plaster, the cloth, cut to the proper size and shape, is tacked on a 
board and the mass is heated and spread evenly with a trowel or spatula. A margin 
^2 in. wide must be left to allow of handling. To avoid the rather excessive irritation 
resulting from the confinement of the secretions of the skin, plasters are now frequently 
made porous. Isinglass plaster is made by spreading a thick solution of isinglass on 
silk. 

Chartae are medicated papers, i.e., pieces of paper covered or impreg- 
nated with a medicinal substance. Charta Sinapis is used as a plaster, 
Charta Potassii Nitratis for fumigation. 

Collodia (C allodium, Collod.}. Solutions of pyroxylin (gun-cotton) 
in a mixture of ether and alcohol, or in acetone. By the evaporation of 
the solvent they form a film on the skin, and thus act like plasters. Col- 
lodia must not be brought near fire. 

Poultices (Cata plasma, Catapl.). These are used mainly for the 
purpose of supplying heat. It is often necessary to give a patient direc- 
tions for preparing them. Linseed poultices may be taken as a type: 
Pour a cup of linseed meal into 2} -2 cups of boiling water, stirring con- 
stantly. Spread the mush thickly on a piece of flannel, fold so as to form 
a sack, and apply as hot as can be conveniently borne. Other pasty mate- 
rials (flour, clay, etc.) are also used. 



SOLUBILITIES 

It is well to have a general idea of the solubility of the substances 
usually prescribed. The subjoined compilations will be found useful in 



42 MANUAL OF PHARMACOLOGY 

this connection. A knowledge of analytic chemistry and of incompati- 
bilities can be utilized here, for a substance appearing as a precipitate is, 
of course, relatively insoluble. 

GENERAL SOLUBILITY OF COMMONLY USED SALTS IN WATER 

I. Arranged by Acids. 

Group A : Salts Mostly Soluble. 

1. Acetates and Nitrates: all soluble (except bismuth subnitrate). 

2. Halogen group ( = iodids, bromids, and chlorids): Soluble, except 
Ag;Hg (ous);Pb; Bi. 

3. Sulphates: Soluble, except Pb, Sr, Ba; Ca sparingly soluble. 

4. Tartrates and Citrates: mostly soluble. 

Group B : Salts Mostly Insoluble. 

i. Ar senates 
Arsenites 
Carbonates 



Hydrates (Ca sparingly soluble) 
Oxids 



Insoluble, except those of 
alkali metals. 



Oxalates 

Borates 

Phosphates 

n. Arranged by Base. 

The salts considered in this table are: Acetates (Ac), Halogens (H), 
Oxids (O), Sulphates (SO 4 ), Phosphates (PO 4 ), Oxalates (Ox), Carbonates 
(CO 3 ), Sulphids (S), Nitrates (NO 3 ), Citrates (Ci). Hydrates agree 
with oxids. 

Those of the above salts which are not mentioned with the respective 
base are insoluble. 

1. Alkali Metals ( = Na, K, NH 4 ): all soluble. 

2. Lithium: Soluble, except O and CO 3 , sparingly soluble, and PO 4 , 
insoluble. 

3. Mg, Al: Soluble: NO 3 , Ac, H, Ci, SO 4 , S. 

4. Ca, Ba, Sr: Soluble: NO 3 , Ac, H, Ci, S; sparingly: O. 

5. Zn, Mn, Ni, Co, Fe \ Soluble: NO 3 , H, Ci, SO 4 (mercuric iodid 
Hg (ic), Cu, Sn I is insoluble). 

6. Ag: Soluble: NO 3 , SO 4 . 

7. Pb: Soluble: N0 3 , Ac. 

8. Bi, Sb: Only soluble in form of double organic salts, e.g., Bismuth 
and Ammonium Citrate; Antimony and Potassium Tartrate. 

9. Mercurous: Insoluble. 

Strength of watery solution, in which commonly used salts may safely 
be prescribed. (It must be remembered that where several salts are 
prescribed in the same mixture, the solubility of each is apt to be lowered.) 

The following table gives the amount of very commonly used drugs 
which can be safely prescribed in water enough to make 100 c.c. These 
should be memorized: 

50 per cent., or grams: ( = 5iv in water q. s. 5 j) Tannin; Antipyrin; Ace- 
tate, Citrate, Salicylate, Iodid or Bromid of 
Potassium or Sodium; AgNOa; ZnSO 4 ; Chloral; 
Cocain Hydrochlorid. 



INCOMPATIBILITY 



43 



5 per cent., or grams: ( = 25 grains in water q. s. 5 j) Alum ; Carbolic Acid ; 
Borax; KC1O 3 ; NaHCO 3 ; HgCl 2 ; Tartar Emetic; 
Quinin Bisulphate; Citrated Caffein; the major- 
ity of the soluble salts of alkalies, earths, and 
metals. 

smaller quantities: Boric Acid, 4; Morphin Sulphate, 4.5; Quinin 
4/00.1 per cent. Hydrochloric!, 3 ; Quinin Sulphate, 0.13; Strych- 
nin Sulphate, 2. 

HI. Solubility in Different Media. As a general rule, inorganic sub- 
stances are more soluble in water than in alcohol. 

Basic alkaloids are insoluble in water, more soluble in alcohol. 

Alkaloid al salts are soluble in either alcohol or water. 

Gums are soluble in water, insoluble in alcohol. Resins and essential 
oils are the reverse. 

(In making mixtures, it must be remembered that spirits, tinctures, 
and fluidextracts all contain alcohol.) 

Glycerin stands intermediate between alcohol and water as a solvent. 

The following substances are: 

1. Practically insoluble in water: lodin, calomel. 

2. Soluble in water, but almost insoluble in alcohol: Alum, NEUCl, 
KClOs, tartar emetic, ZnSC>4, Borax. 

3. Much more soluble in glycerin than in water: Boric acid, alum, car- 
bolic acid, HgCl2. 

Terms Used in Defining Solubility. The following terms (Wilbert, 
1909) are employed in " Useful Drugs" to describe the approximate solu- 
bility, which is often sufficient for prescribing. Substances that are solu- 
ble in less than i part of solvent = very soluble. From i to 10 parts of 
solvent = freely soluble. From 10 to 100 parts of solvent = soluble. 
From 100 to 1,000 parts of solvent = slightly soluble. From 1,000 to 
10,000 parts of solvent = very slightly soluble. From 10,000 to 100,000 
parts of solvent = nearly insoluble. More than 100,000 parts of solvent 
= practically insoluble. 

Official Solubilities. The U.S.P. and B.P. state the solubility of 
articles, as grams of substance to cubic centimeters of solvent; i.e., a 
solubility of i :io means that i Gm. of substance requires 10 c.c. of sol- 
vent for solution, at the standard room temperature, 25C., 77F., 
U.S. P.; i5.5C., 6oF., B.P. The standards given in this book are those 
of the U.S.P. In percentage solutions, 10 per cent, signifies that 100 c.c. 
of solution contain i Gm. or c.c. of the substance. 



INCOMPATIBILITY 

This is a subject usually very confusing to the student, since it consists of what 
appears at first sight a vast array of details. However, it rests only upon an applica- 
tion of the ordinary chemic reactions, and when the latter have been mastered, the sub- 
ject is comparatively easy and simple. It may be laid down as a general rule that sub- 
stances are incompatible if they are used in testing for each other or if they form antidotes. 

In the following compilation it has been attempted to arrange the incompatibilities 
into general groups. 

In this generalization, it is not feasible to take account of individual exceptions. 
Care has been taken to err on the safe side. It is much more important for the physician 
to remember that mercuric chlorid is generally incompatible with alkaloids, than it is 
to know that it may be prescribed with some. 



44 MANUAL OF PHARMACOLOGY 

Definitions. Incompatibility is said to exist when the constituents of 
a mixture interfere with one another in a way not intended by the prescriber. 

If an intrrk-rence is intentional, it is called an intentional incompatibility. 
: rlu-nnVal change occurs, the incompatibility is called chemical. 

When it consists in a precipitation of the substance by a change in 
the solvent, or when a chemic incompatibility does not interfere with 
the active substance, but produces an unsightly appearance, it is phar- 

:itic. 

If the interference is with the solubility, or if liquefaction or deliques- 
cence occurs, the incompatibility is mechanic. 

When without causing any chemic changes it interferes with the 
physiologic action of the ingredients, it is therapeutic. 

Chemic Incompatibility. This may result in explosion, precipitation, 
or the production of new substances with undesired properties. 

Explosives. Powerful oxidizing agents are apt to explode when mixed 
in concentrated form with easily oxidizable substances. 

The most important oxidizing agents are: Chromic acid; Concentrated 
nitric acid and nitrates; Permanganates; Chlorates; Peroxids. 

The most important oxidizable substances are: All organic substances; 
Sulphur, sulphids, sulphites, and hyposulphites; lodin and iodids; 
Phosphorus, phosphites, and hypophosphites ; Reduced iron. 

Explosions may also result from mixing iodin with ammonia or turpen- 
tine; and chlorin with ammonium chlorid. 

Explosions will occur only when the substances are dry or at least con- 
centrated, and when they are heated or percussed. 

Dilute solutions may be mixed without danger if not heated. Glycerin, 
phenol, and in some cases alcohol, behave like dry solids. 

Permanganate of potash or chromic acid or nitrate of silver will de- 
compose organic substances even in solution, but in this case without 
explosion. 

Powders may be mixed without concussion, but even this should be avoided, since 
conditions favorable to explosion may arise after they leave the hands of the dispenser. 

Pills containing these easily decomposed substances are best made with inorganic 
excipient (clay and vaselin). 

Substances containing loosely combined oxygen may explode on concussion or 
heating when no reducing substances have been added; this is due to their containing 
dust or other organic matter. They should therefore be handled with care. 

Gradual Evolution of Gas. This occurs especially on mixing acids 
with carbonates or sulphids; also when mixing strong acids with alcohols 
(= esters), or with chlorate (= Cl); also, on mixing strong HC1 and HNO 3 . 

Incompatibility by Precipitation. Alkalies precipitate earths, metals 
and alkaloids from their salts. Under alkalies may be included oxids, 
hydroxids, carbonates, phosphates, borates, arsenates and arsenites. 

Chlorids, bromids and iodids precipitate salts of Ag, Pb, and some 
alkaloids. lodid also precipitates mercuric salts, redissolving in an excess. 

Sulphates precipitate Pb, Ca and the other earthy metals, except Mg. 

Salicylates, phenol and tannin precipitate or color iron salts. Tannin 
also precipitates most other metals, alkaloids, and some glucosids and 
neutral principles. Salicylates precipitate quinin. 

Salts of metals are precipitated by alkalies, sulphids, tannin and pro- 
teins. _ They precipitate some alkaloids and acacia. Mercuric salts are 
often incompatible with other metals. Silver and lead salts are precipi- 
tated by chlorids, bromids, and iodids. Silver salts are also incompatible 



METROLOGY 45 

with organic substances. Iron salts are colored by tannin, salicylate and 
phenol. 

Calcium salts are precipitated by alkalies, phosphates and sulphates; 
Magnesium salts by alkalies and phosphates. 

Alkaloidal salts and synthetic bases (antipyrin, etc.) are precipitated 
by alkalies, tannin, iodin, potassium-mercuric iodid, and some by iodids 
or metallic salts. 

Acacia is precipitated by alcohol, borax, Tr. Ferri Chlor. 

Production of Substances with Undesired Qualities. Iodids liberate 
iodin on the addition of acid and oxidizing agents, including H 2 O2, ni- 
trites, salicylic acid, etc. They oxidize mercurous to the dangerous 
mercuric salts. 

Chlorates liberate chlorin with concentrated acids. 

Chloral liberates chloroform with alkalies. 

Glucosids (f.i., glycyrrhizin) are destroyed by acids. 

Pharmaceutic Incompatibilities. Alcohol should not be added to: 

Acacia, gelatin, proteins, emulsions, strong salt solutions. 

Water should not be added to: 

Alcoholic liquids in general (such as tinctures, spirits, fluidextracts) ; 

or to Ethereal liquids (oleoresins), or oils. 

(Phenol should not be mixed with collodion.) 

Liquefaction occurs when chloral is rubbed with camphor, menthol, 
phenol, salol, etc. Any of these, when rubbed together, or with coal-tar 
antipyretics, are apt to liquefy. 

Especially Incompatible Drugs. The following are most likely to give 
incompatibilities, and any combinations should therefore be scrutinized 
with special care: Acids, alkalies and carbonates; permanganates; iodids. 
Mercury, iron, silver and lead salts; tannin; alkaloids. 



METROLOGY 

A ready working knowledge of weights and measures is indispensable 
in prescribing. 

Formerly every country, even every State, and some cities, had their own system 
of weights and measures, resulting in endless confusion and loss of time. This state of 
affairs still exists to some extent. In the United States and Great Britain no less than 
five different systems are in common use. It is a hopeful sign that the United States 
and British Pharmacopeias and the U. S. government medical services employ the metric 
system. This system originated in France near the close of the last century. It has 
been adopted in science to the exclusion of all others, and possesses a number of ad- 
vantages which should cause all other systems to be discarded. This is the ultimate 
tendency, and the student is urged to learn the doses and practice prescription-writing 
in the metric system. Since, however, the common systems are still used in many 
hospitals and journals, these must also be mastered, and the conversion of the systems 
practised. 

The Metric System. This is based on the decimal system, and has for 
the unit the measure of length, the meter (M.). 

This was intended to be a natural unit, viz., the ten-millionth part of the distance 
from the pole to the equator of the earth at a particular meridian. Subsequent measure- 
ments have given a slightly different value to this distance. The meter is therefore an 
arbitrary standard the length of a platinum bar, the original of which is preserved in 
Paris. 

The meter is divided into 10, 100, and 1,000 parts, called respectively 



46 MANUAL OF PHARMACOLOGY 

decimeter (dm.), centimeter (cm.), and millimeter (mm.). The thousandth 
part of a millimeter is a micron (p) 

The contents of a cube whose edges measure a decimeter, or 10 cm., 
form the unit of capacity, the liter (L.). The thousandth part of this is a 
cubic centimeter (c.cm., or, briefly, c.c. ; also termed a " milliliter " or " mil ") . 
The unit of weight is given by the weight of a liter of distilled water at 
4C. in vacuo: this is the kilogram (Kg.). A thousandth part of this is a 
gram (Gm.). A quantity ten times the unit is expressed by prefixing 
the Greek numeral Deca; one hundred times, Hecto; one thousand times, 
Kilo. The tenth part of the unit is expressed by prefixing the Latin 
numeral deci; one-hundredth, centi; one- thousandth, milli. 
Thus: 

1,000 Gm. = Kilogram (Kg.) 1 
100 Gm. = Hectogram (Hg.) 
10 Gm. = Decagram (Dg.) 
i ' Gm. = Gram (Gm.) 

o.i Gm. = decigram (dg.) 
o.oi Gm. = centigram (eg.) 
o.ooi Gm. = milligram (mg.) 

In quantities including several denominations only one unit is used: 
thus, 1.234 Kg. would be read as 1,234 Gm.; 0.002 Gm. as 2 mg., etc. 
The quantities are always denoted by Arabic figures placed before the 
appellation. Fractional parts are always converted into decimal fractions. 

Milliliter. The U.S.P. and B.P. designate the cubic centimeter as milliliter, and the 
B.P. further employs the following divisions and abbreviations. Their use does not 
seem advisable, as they tend to introduce complications and confusions that may 
retard the final adoption of the metric system. 

Liter (Lit.) = 1,000 Gm. of water at 4C. 

Milliliter, Mil, Ml. = i Gm. of water at 4C. 
Decimil, Dl. = o.i Gm. of water at 4C. 

Centimil, Cl. o.oi Gm. of water at 4C. 

In continental Europe the liquid measure is very little used in pharmacy, liquids 
being usually weighed. 

Common Systems of Weights and Measures. 2 The denominations are 
the following: 

APOTHECARIES' OR TROY WEIGHT 

(USED IN PRESCRIPTIONS) 

Grain (gr.) 

[Scruple (3) = 20 gr. ] 
Dram 3 (3) [ = 3 9] = 60 gr. 
Troy ounce (5) = 83 = 480 gr. 
[Troy pound =125 = 5,760 gr.] 
i^j of water under standard conditions 4 measures 504.83 minims.) 

AVOIRDUPOIS OR IMPERIAL WEIGHT 

(A SYSTEM USED IN COMMERCE) 

Grain = same as Troy grain. 

Ounce (oz.) = 437 /-^ grains. 

Pound (lb.) = 16 oz. = 7,000 grains. 

Ton = 2,000 lb. 

1 Some authors begin all the abbreviations with capitals; others employ capitals for the units; 
gram, liter and meter, and their multiples; and small letters for fractions (as in the above lists) 
the latter plan has some advantages. 

2 Those in square brackets are practically obsolete. 

3 Also spelled drachm. 

At 4C. and in vacua. 



METROLOGY 47 

UNITED STATES APOTHECARIES' OR WINE MEASURE 

(USED IN UNITED STATES FOR BOTH PRESCRIPTION AND COMMERCIAL PURPOSES) 

Minim (TH, or min.) (approximately equal to i drop or to i grain of water more exactly, 

0.95 grain). 

Fluidram (fl3) = 6o11l. 

Fluidounce (fl5) = 8 fl 3 = 48oTTl (fl 5 j of water under standard conditions 1 

weighs 456% grains). 

Pint (pt., or Octarius, O) = i6fl5 = 7,68om. 
Quart (qt.) = 2 pts. = 32 fl3- 

Gallon (gal., or Congius, C) = 8 O = 128 fig = 6i,44om. 
A gallon holds 231 cubic inches. 

Another system of liquid measure is in use in Great Britain, and must 
not be confused with the American system. It is the 

IMPERIAL MEASURE 

UNITED STATES SYSTEM 

Minims (min.) 0.96 Tfl, 

Fluidrachm (fl.dr.) =60 min. . =0.96 fl3 

Fluidounce (fl.oz.) = 8 drachms =0.96 fl5 

Pint (O) =20 fluidounces =1.2 O 

Gallon (C) = 8 pints =1.2 C 

In writing the apothecaries' measure in prescriptions, the figures are 
written in the Roman system and placed after the appellation. Thus, 
gr. xx, not 20 gr. The ones are always dotted, and the last one is formed 
like a j: thus 5iij, 5 vj, etc. The fl. before the sign is often omitted with 
liquids. 

Fractions are written as common fractions: gr. ^Q, not gr. o.i. 

Popular Measures. These are formed of utensils commonly found in 
the household, and are, of course, very inexact. They should be displaced 
by graduated medicine glasses, which can now be obtained very cheaply. 
Spoons are supposed to be filled so that the fluid stands level with the rim. 

The usually accepted equivalents of these measures are: 

i drop (gtt.) = i minim 2 = 0.05 c.c. 

i teaspoon = i fl 3 3 =4 c.c. 4 

i dessertspoon = 2 fl 3 = 10 c.c. 

i tablespoon = 4 fl 3 (M5) = 15 c.c. 

i wine-glass = 2 fl5 5 c - c - 

i tea-cup = 4 fl5 =125 c.c. 

i tumbler = 8 fl5 =200 c.c. 

i knifepointfui (tableknife) =15 to 30 gr. =1.0 to 2.0 Gm. 

The units of temperature may also be treated in this place. 

The scientific scale is the Centigrade or Celsius. In this the range between the 
freezing-point of water (oC.) and its boiling-point (iooC.) is divided into 100 parts. 
In the inconvenient and unscientific Fahrenheit scale, in common use, the freezing-point 
of water is 32F., the boiling-point 2i2F., and the range, therefore, i8oF. 

Each degree Centigrade therefore =18 5Koo = %F. 

Each degree Fahrenheit = %C. 

The conversion of one scale into the other may be done by the following rules: 
To convert degrees Centigrade into Fahrenheit: multiply by % and add 32. 
To convert degrees Fahrenheit into Centigrade: subtract 32 and multiply by %. 
Normal Temperature. The U.S. P. has adopted 25C., 77F., for solubilities, specific 

1 At 4C. and in vacuo. 

'As a matter of fact, the size of a drop varies greatly according to the nature of the fluid and of 
the container; there may be from 50 to 150 to a fluid drachm. The International Protocol author- 
ized a standard dropper, designed to deliver exactly 20 drops per cubic centimeter of water. 

'Really from \~> to 2 fl3. 

4 As a matter of fact, the actual capacity of teaspoons averages 5 c.c., when filled level (Wilbert, 
1905). 



4 S MANUAL OF PHARMACOLOGY 

gravity, calibration, etc., except for the specific gravity of alcohol, which is taken at 
15.0 V I In li.!'. used i5.sC., 6oF., for metric determinations; i6.7C. for imperial 
measuri-s. 

Advantages of the Metric System. These will now be manifest. 
The metric system is widely used, and is understood throughout the 
civili/.cd world. 

2. There is a simple relation between linear, solid, and liquid measures. 

3. The decimal feature determines great ease in multiplications, since 
only a change of a decimal point is required to change one denomination 
into another. It is also much easier to write the quantities. 1 Calculations 
involving specific gravity are also much more easily made. 

4. The adherents of the common system claim that it is more conven- 
ient for dosage. There may be some truth in this, for the grain, minim, 
and dram happen to be more convenient doses than the gram or cubic 
centimeter. This advantage, however, is insignificant. 

Equivalents of Metric and Common Systems. Doses and formulas 
may be calculated from one system into the other. For this, it is only 
necessary to remember that i Gm. = 15.4 gr. However, this always 
entails the possibility of some error in reckoning, which may have serious 
consequences. The student is therefore advised to learn the dosage 
in both systems, and to construct prescriptions directly in whichever system 
is chosen. If a transposition must be made, the following approximate 
equivalents (which should be thoroughly memorized and practised) are 
sufficiently exact for prescription purposes; and being simpler, they are 
less apt to lead to arithmetical errors, than the exact equivalents. 



i Gm. 

I C.C. 

i milligram 

i Liter 

i Kilogram 



APPROXIMATE EQUIVALENTS 
= 15.5 grains or minims. 



= %4 grain. 
= i quart (+). 
= 2.2 Ib. 



i gram or minim 

i dram 
i ounce 
i pint 



= 0.065 Gm. or c.c. 

= 4-0 (-) 
= 30.0 ( ) 
= 0.5 Liter (-) 



Dosage Equivalents. In memorizing "average doses" even this de- 
gree of approximation is needlessly complicated. The following table 
gives the most convenient figures: 



i Gm. 


Above 
IS gr. 


o.i to 0.75 
Gm. 


I ^ to 12 

gr. 


2 to SO 

mg. 


J-io to i 


Below 2 

mg. 


Below Ho 
gr. 


350 
1 2O 


(125) 

(45) 


0.750 
0.500 


(12 gr.) 
(8) 


0.050 
0.030 


(i) 


O.OOI5 
O.OOI 


(Mo) 
(Mo) 


25 
IS 


(43) 


0.300 
0.250 


(5) 
(4) 


0.015 
O.OIO 


(M) 
(M) 


0.00075 
0.0005 


(Mo) 

(M20) 


IO 


UM3) 


0. 200 


(3) 


0.008 


(M) 


0.0004 


(Meo) 


4 
3 

2 


(*3) 

(45 gr-) 
(3 gr.) 


0.150 
0.125 
C . IOO 


(2) 


0.005 

0.004 

0.003 


(H 2 ) 
Ks) 

(Mo) 


0.0003 
0.00025 

O.OO02 


(Moo) 
HBO) 

(Moo) 




(lD gr ' } 




o .002 


(Mo) 


O.OOOI5 


(Moo) 



vimple will make this clearer: Take 40 Gm.: in the United States system this must be 
n iiU K ffi XVIJ : tH S ^ uld '* ^ necessary to calculate five times this quantity, one multi 
ition will suffice with the metric system: 5 X 40 = 200 Gm. But with the Apothecaries' 
rtion would be much more complicated: 

. S X 3J 3U gr. xvij = gv 3* gr. Ixxxv 

ihis must be reduced: 



gr. Ixxxv = 



3J gr. xxv 



Answer = Jvj 3iij gr. xxv 



GENERAL TOXICOLOGY 



49 



i meter =39.370 inches. 

= 3 ft. 3.370 inches. 
= i yd. 3.370 inches. 



EXACT EQUIVALENTS 

SPACE 

i inch = 0.0254 M. = 2.54 cm. 
i ft. =30.227 cm. 
i yd. =91.440 cm. 



i c.c. =16.23 TP,. 
i L. =33-8i5 fl5- 

= 2.113 pts. 

= 0.2642 gal. 



i L. =1.760 pints. 
= 0.2209 gallons. 



i mg. = J^ 4 gr. 

i Gm.= 15.432 gr. 

= 0.03527 oz. Av. 

= 0.03215 3 Troy, 
i Kg. = 2.2046 Ib. 



CAPACITY (UNITED STATES) 

i Tfl. = o. 06161 c.c. 
i S3 = 3-7 c.c. 
i fl3 =29.574 c.c. 
i pt. = 0.4731 L. 
i gal. = 3-7854 L. 

CAPACITY (BRITISH) 

i pint =0.5679 L. 
i gallon =4-5435 L. 

WEIGHT 

i gr. =64.8 mg. = 0.0648 Gm. 

1 3 = 3.888 Gm. 

i oz. Av. = 28.3495 Gm. 

i % Troy =31.1035 Gm. 

i Ib. = 0.4536 Kg. 



GENERAL TOXICOLOGY 

Toxicology is the science of poisoning. The details of the actions and 
symptoms will be considered in connection with the individual poisons; 
but certain matters of general application may be discussed here. 

Definition of Poison. A poison (from potion, a draught), by the broad- 
est definition, is a substance the administration of which is injurious to 
health. However, injurious mechanical, physical, or bacterial agencies 
are not commonly classed as poisons; nor are the substances which 
produce injurious effects only in very large doses (say over 50 Gm.). 
It is very difficult to give a definition which will not be ambiguous 
in some cases (see,/.*'., the collection of definitions by Murray and Frame, 
1914). The following covers most of the points which must be con- 
sidered in classing a substance as a poison: 

A poison is any substance which, acting directly through its inherent 
chemic properties, and by its ordinary action, is capable of destroying life, 
or of seriously endangering health, when it is applied to the body, externally, 
or in moderate doses (to 50 Gm.) internally. 

Etiology of Poisoning. Poisoning may result through criminal or 
suicidal intent, or through accident. 

The statistics of the relative frequency of the different forms of poisoning vary 
from year to year, and with each country. A classified list of deaths from poisoning in 
the U. S. registration area is given by Wilbert, 1916. Suicidal poisoning is probably the 
most frequent, nearly a half of the suicides in the United States being due to poisoning. 

It is calculated that here five-sixths of all suicidal cases are due to phenol. There 
is, however, a fashion in poisons, as in other things. This is greatly fostered by the 
notoriety which the newspapers often give to these cases. 

Symptoms of Poisoning and Classification of Poisons. Suspicion of 
poisoning is aroused if a person, previously in good health, manifests 
rather suddenly marked pathologic symptoms, which become rapidly 
worse. The suspicion becomes more firm, if the phenomena appear a 



^O MANUAL OF PHARMACOLOGY 

short time after swallowing some substance which may perhaps have an 
unusual odor or taste; 1 if they agree in character with those produced by 
some group of poisons, and if they do not agree with any other disease. 

With reference to these symptoms several classes of poisons are quite 
well defined. 

1. Irritants. These produce inflammation; if they are taken by the mouth, there 
H pain throughout the alimentary canal, vomiting, purging, delirium, coma. Most 
poisons are to some extent irritant, so that these symptoms are almost universally 
present. The irritants can be subdivided into corrosives, which produce a direct de- 
struction of tissues; and simple irritants, which do not. If corrosives are taken by 
the stomach, the vomit is often bloody. 

2. Nerve Poisons. These act on the neuromuscular apparatus, and include most 
of the poisons which are fatal in minute doses. They are subdivided into : Convulsants, 
which cause spasms; Somnifacients, causing sleep and coma; and Cardiac poisons, 
which stop the heart. 

3. Blood Poisons. Those which alter the hemoglobin or blood corpuscles. These 
include the toxic gases, the nitrites, etc. Their action is generally characterized by 
cyan i' 

It must not be supposed that the action of a poison is confined generally to one 
class of structures or functions. All functions suffer directly or indirectly, and whatever 
the class to which the poison belongs, the final cause of death is, in almost all cases, a 
paralysis of respiration, preceded by the phenomena of asphyxia. In virtue of the 
latter, or through other causes, the urine often contains sugar. 

The irritants, and especially the corrosives, produce lesions which can be demon- 
strated at AUTOPSY. With other poisons the postmortem examination is generally 
negative. The SPECTRUM OF THE BLOOD shows characteristic changes with some 
poisons. These are also apt to cause ecchymotic discolorations of the skin. Anti- 
septic poisons delay the putrefaction of the body, so that mummification may result. 
Convulsive poisons quicken the onset of rigor mortis. 

Duties of the Physician in Cases of Poisoning. These are twofold: 
to save life or suffering, and to forward justice. The former object requires 
the removal of the poison, the administration of chemical antidotes, and 
the treatment of the symptoms. 

For the detection of the poison, and to aid in fixing the guilt on the proper 
person, the physician must carefully observe the symptoms, take pos- 
session of any suspected material, medicine, vomit, etc., and in case of 
autopsy, preserve the stomach and its contents, the intestines and contents, 
blood, liver, kidneys, and portions of other organs, separately, without 
antiseptics, 2 in clean, hermetically closed, glass vessels, which should be 
sealed with wax. 3 An exact written record of all the observations should 
be made as soon as possible. 

The symptoms in cases of suspected poisoning are very rarely sufficient 
to affirm the presence or nature of a poison, although they may be of great 
aid to the analyst. The final proof rests generally as the results of the 
chemic examination. 

So much depends on this analysis, that it should never be undertaken by anyone 
who has not had extensive experience in this class of work, and who has not the neces- 
sary facilities. It lies entirely outside of the scope of the practising physician. The 
hitter should, however, be familiar with the general outline of the process used for isolat- 
ing poisons; and with such chemic tests as may be quickly applied. These tests are 
often valuable for diagnostic and therapeutic purposes. The physician is also expected 
to give expert testimony on toxicologic questions, and to do this intelligently, he must 

1 It may appear strange that poisons which possess a pronounced and disagreeable taste could 
be used for criminal poisoning, except with infants; but a moment's thought will show that if a 
liquid is taken unsuspectingly, the taste is not noticed until a large amount has been swallowed. 

' Even glucosid and alkaloid poisons can be isolated for a long time (160 to 270 days) from 
putrefying masses. Some poisons, however, disappear rapidly (Phosphorus, Cyanid, Picrotoxin, 
Phenol, etc). Strychnin and morphin are very persistent. 

3 In emergency, a rare or specially marked com, or a key, may serve to impress the seal. 



GENERAL TOXICOLOGY 51 

have at least an elementary knowledge of toxicologic analysis, such as is furnished in 
the following section. 

Some poisons can be demonstrated much better by tests on animals than by any 
chemic tests. For this object, they should be isolated in as pure a form as possible, 
by the methods laid down in this section. The application of these life tests, which 
have not hitherto received the attention that they deserve, falls peculiarly into the 
province of the scientifically trained physician. 

OUTLINE OF TOXICOLOGIC ANALYSIS 1 

Precautions. The first duty of the analyst is to guard the material confided to 
him from the wilful or accidental introduction of poisons. For this purpose, precaution 
must be taken that no other person has access to the material; and every reagent and 
apparatus must be tested personally. 

As a rule, the different organs must be kept strictly separated throughout the analysis. 
It will depend on circumstances whether the analysis of the individual organs is made 
at the same time, or successively. If the latter is decided on, the largest organ, or that 
most likely to contain the poison, is examined first. It may be advisable, however, 
to mix a weighed quantity (one-fourth or one-third) of the comminuted organs, and to 
use this mixture for the first analysis. 

Since the material to be analyzed is usually limited in amount, and can not be 
replaced, the examination must be arranged in such a way that as many tests as possible 
can be made successively on a single sample of the material. An economy of time and 
material is also secured by obtaining, as quickly as possible, some idea of what poisons 
may be present. This may be done by some easy preliminary tests, or by using so- 
called "group-reactions" which, if negative, will exclude a number of substances. The. 
symptoms may also have furnished some important hints, but should never prevent the 
complete examination of the substance. 

During the isolation and the preliminary search for the poison, only the most im- 
portant tests should be applied. When the poison has been isolated, however, it should 
be subjected to every known test. A sample of the isolated poison should be preserved, 
in stable form. 

Preliminary Examination. The systematic examination is begun by a 
careful inspection of the portions of the alimentary canal. These are 
opened, and extended on an inverted evaporating dish, mucous surface 
upward. Pathologic lesions are looked for, as also particles of the poison 
which may be adherent. A magnifying lens should be employed. (Gran- 
ules of arsenic have often been isolated in this way.) The contents of 
the alimentary canal, or vomited matter, are subjected to a similar close 
inspection. The odor should be carefully observed. During this exami- 
nation, the reaction to litmus paper should be noted (caustic acids or 
alkalies). 

Each organ is then hashed, carefully weighed, and replaced in hermetically sealed 
jars. 2 

Isolation of the Poison. No routine schema of analysis will fit all 
cases, since each presents its own problems. However, the following 
illustrates the usual procedure. 

Division of Material. Ordinarily, each organ, after comminution, is divided into 
the following portions carefully weighed: One-third is reserved for control; one- 
twentieth for preliminary tests. The remainder is divided into four parts, used respect- 
ively for the search for volatile, fixed organic and inorganic poisons, and for reserve. 
If the quantity of material is very scanty, two equal portions will suffice : one is reserved 
for preliminary tests, easily decomposable poisons, and control; the other is examined 
successively for easily volatile poisons, for fixed organic poisons, and for metals. 

Volatile Poisons. A portion of the material is acidulated with tartaric 
acid (adding water if necessary), and distilled from a flask or retort con- 

1 This section should be studied in connection with the practical exercises. Gadamer's "Lehr- 
buch der chemischen Toxicologie" is an excellent reference book. 

2 As soon as the absence of volatile poisons has been proven, the contents of the jars may be 
covered with 95 per cent, alcohol. 



52 MANUAL OF PHARMACOLOGY 

nectt'd with a Liebig's condenser. 1 It is advisable to pass a slow current 
of live steam through the mass. The distillation is continued until about 
two-thirds of the liquid have been collected. The distillate is collected 
in three portions. The odor is noted (volatile oils, chloroform, ether, 
:.l the characteristic tests applied for phosphorus, phenol, cyanids, 
ali-ohol, 2 chloroform, chloral, etc. 

Phosphorus. A preliminary test for this element must be made with silver 
nitrate and lead acetate papers before the distillation is begun. If this test indicates 
iN presence, the condenser is set vertically downward, and the distillation is carried on 
in a darkened room. All air is expelled from the apparatus by a stream of carbon 
dioxid. This is then shut off, and replaced by live steam, the flask being heated at 
the same time. If phosphorus is present, a luminous ring appears in the tubes 
<>r condenser, shifting its position when the heat applied to the flask is altered (Mitscher- 
m el hod). The appearance of this phenomenon proves the presence of phosphorus 
absolutely. 

There are, however, quite a number of substances the presence of which interferes 
with the formation of this ring. Almost any volatile substance may do so; turpentine, 
chloroform, ether, alcohol; and alcohol is often present, as it is usually given as an 
antidote. 

The absence of the ring does not, therefore, prove the absence of phosphorus. The 
distillate will contain phosphorus in the lower stages of oxidation, as phosphorous or 
hypophosphorous acid. The best way to prove phosphorus in this is to add some bromin 
\\.iter to the distillate and to evaporate to dryness. This results in phosphoric acid, 
which may be demonstrated by magnesia mixture or ammonium molybdate. The 
quantitative determination of phosphorus is not important; because if it is present at 
all, it is present as a toxic agent. 

Cyanids. The presence of mere traces of hydrocyanic acid in the distillate is no 
proof of poisoning, since these may have been introduced in the way of food (almonds 
or other seeds). A quantitative estimation, by means of silver nitrate, may be necessary. 
The qualitative proof also requires two further precautions: 

With the method which we have given, ferrocyanids might also be decomposed and 
give rise to hydrocyanic acid; and since ferrocyanids are not toxic, this would lead 
to wrong conclusions. To eliminate this, the original liquid is filtered and the Prussian 
blue test applied to it directly. Mercuric cyanid does not yield its hydrocyanic acid in 
this treatment. If it is suspected, the material must be treated with hydrogen 
sulphid. 

Distillation from Alkaline Solution. It is sometimes recommended to add water to 
the residue in the retort, to make it alkaline with sodium carbonate, and to distill again. 
The distillate contains ammonium, amines, chloroform (if chloral was present), and the 
volatile alkaloids. This step may generally be omitted, as these poisons are discovered 
in other parts of the process; or a small sample may be heated in a test-tube with sodium 
carbonate, and the odor noted. 

Extraction of Fixed Organic Poisons. The extraction, separation and 
purification of these poisons are based on their special solubility in certain 
solvents. As a rule, they are all fairly soluble in acidulated water and 
alcohol. The neutral principles are removed from the acid watery solu- 
tion by ether or chloroform. The alkaloids are dissolved by these sub- 
stances only after the addition of an alkali. 

In brief outline, the suspected material is first extracted with boiling 
acidulated water and alcohol. The acid watery extract is then treated 
with ether, which dissolves neutral principles and various impurities, but 
which leaves the alkaloids. These are extracted later by fresh ether, after 
rendering the solution alkaline. 

Various methods are in use. The most practical is that of Stas-Otto, slightly 
modified: 

i. The poisons are first brought into solution by boiling the material, if solid, with 
about 5 parts of water for fifteen minutes (or the residue remaining after the distillation 

1 See below for special arrangement to be used when phosphorus is present. 

1 Alcohol is only important if it is present in large amounts. Smaller quantities may be present 
accidentally or as antidote. 



GENERAL TOXICOLOGY 53 

of the acid solution may be used). The mixture is cooled and strained. This removes 
fat, coagulable proteid, fiber, etc. 1 

2. The strained solution is evaporated at a low temperature to a syrupy con- 
sistency, and boiled with twice its volume of alcohol, for fifteen minutes. The evapo- 
rated alcohol is replaced. It is then filtered, and the filter washed with alcohol. This 
removes salts, non-coagulable proteids, etc. 

3. The alcoholic filtrate is diluted with an equal volume of water and filtered. 
This removes resins, fats, etc. (The residue may be examined for cathartic resins and 
croton oil.) (For further purification, the filtrate may be again treated by 2 and 3.) 

4. The filtrate, which should have an acid reaction, is now shaken in a separatory 
funnel with 10 c.c. of ether. This is drawn off, and the same process is repeated twice. 
The ether removes neutral principles, picric acid, and salicylic acid. It is filtered and 
allowed to evaporate in a glass capsule, and the residue is purified and tested for these 
acids, for caffein, cantharidin, colchicin, digitalin, picrotoxin, and the coal-tar anti- 
pyretics. 

5. The watery solution, remaining from the extraction with ether in the last para- 
graph, is now made fairly alkaline with sodium carbonate (to liberate the alkaloids) and 
again extracted with ether, as in the last paragraph. From this alkaline olution, the 
ether removes all alkaloids except morphin. The ethereal layer is filtered and evaporated, 
the residue is purified, and tested, first by potassium mercuric iodid, then for physo- 
stigmin, apomorphin, nicotin, coniin, veratrin, strychnin, brucin, atropin, cocain, codein, 
narcotin, emetin, and aconitin. 

6. To isolate the morphin, the watery liquid remaining in the last paragraph, 
is made acid, then alkaline by ammonia, and shaken at once with acetic ether, or with 
hot amyl alcohol. 

7. To test for oxalic acid, the original substance is partly dried, extracted with 5 
c.c. of hydrochloric acid and 20 c.c. of boiling alcohol, for half an hour, filtered, evapo- 
rated, extracted with. water, and tested by Ex. 10, No. 25. Santonin and Meconic Acid 
must also be extracted by special methods. 

Dragendorflf's Method. In this, a more extensive separation of the poisons is 
obtained, by multiplying the solvents and operations. The preliminary treatment is as 
per i, 2, and 3. The acid solution is then exhausted successively by petroleum ether, 
benzol and chloroform; and then in alkaline solution by the same sequence of solvents, 
and finally by amyl alcohol. 

Kippenberger's Method. This possesses the advantage of separating the poisons 
in purer form from the start, but it involves technical difficulties. It depends on the 
insolubility of the tannates of proteins in glycerin, whilst the organic poisons are soluble 
in this medium. The solid material (say 100 Gm.) is digested for two days at 4OC. 
with 10 Gm. tannin, i Gm. tartaric acid, and 100 Gm. glycerin. The mass is expressed; 
the residue is washed with tannic glycerin. The fluids are diluted with water, heated 
to 5oC., and filtered. The filtrate is then extracted twice with petroleum ether, which 
removes mainly fats. The glycerin layer is then extracted as in the Stas-Otto method 
(4 and 5), but using chloroform in place of ether. 

For the purification of the alkaloids, the residue, left by the evaporation of the 
chloroform, is dissolved in acidulated water, neutralized, and at once precipitated by 
iodin-potassium-iodid. The precipitate is collected on a small filter, washed with cold 
water dried, and dissolved in hot acetone. The filtered acetone solution is treated first 
with alkali, then with acid, then with water; the acetone is expelled on a water-bath, 
and the remaining watery solution is decolorized by sodium hyposulphite. The solution 
is then made alkaline with sodium carbonate and extracted with ether or chloroform. 

Physiologic Tests. The poisons isolated by these methods are often not sufficiently 
pure to give the typical chemic tests; furthermore, certain of the tests are closely simu- 
lated by ptomains. This holds true also of the physiologic tests, i.e., the effects on 
animals. The only way to distinguish with certainty between these is to use both the 
chemic and the physiologic tests. For, as far as is known, there are no ptomains 
which give both the chemic and physiologic tests of one alkaloid. 

The physiologic tests can generally be obtained with fairly impure preparations. 
They are most typical in the case of strychnin, atropin, physostigmin, aconite, digitalis 
group, picrotoxin, veratrin. cantharidin, croton oil. The subject is elaborated in 
Fuehner's "Nachweiss von Giften." 

Isolation of Fixed Inorganic Poisons. The residues of the preceding 
operations may be used for the search of these poisons. The usual 

1 It is understood that the remaining mass should be washed, in every instance of nitration or 
straining. 



^4 MANUAL OF PHARMACOLOGY 

methods of inorganic analysis are followed; but it is superfluous to test 
for non-poisonous constituents. 

The absence of many metallic poisons can be quickly shown by Reinsch's test. 
This does not, however, dispense from further tests. Only an outline can be given 
bere: 

A : Destruction of Organic Matter and Solution. Method of Fresenius and Babo. 
Organs or syrupy residue, plus 30x3 c.c. to 500 c.c. of arsenic-free HC1 (i : 2) in liter flask: 
heat lukewarm. Add 4 to 6 Gm. KC1O 3 in 0.5 Gm. portions, till dissolved. Evaporate 
to about too c.c. (no free Cl). Dilute to 400 c.c. Add 2 c.c. dilute H 2 SO4. Stand over- 
night. Filter. Filtrate = B. Residue = A". 

Filtrate B. Pass through filter, add water to just 500 c.c. Use 50 c.c. for Marsh's 
test (see L). If As is present, use balance for quantitative (see C). If not, evaporate 
small sample, dissolve in 10 c.c. water, add NH 4 OH: blue = Cu. 

C. Heat balance of nitrate B to 8oC. and pass arsenic-free H2S 1 for two or three 
hours, until cool. Heat again, and repeat. Stopper and set aside in warm place for 
twenty-four hours. Precipitate may contain As, Sb, Hg, Cu, Pb. It may be used 
for the quantitative estimation of As, or for further identification by D. Filtrate = I. 

D (HS precipitate of C). Wash with H^S water, warm with 4 c.c. ammon. sulphid, 
4 c.c. ammonia, 8 c.c. water. Filter. Filtrate = E. Insoluble = F. 

E (Filtrate of D). Evaporate to dry; heat with HNO 3 till pure yellow; heat to expel 
HX() 3 ; add Xa 2 CO 3 and NaNO 3 ; fuse; extract with boiling water; add 2 Gm. NaHCO. ; . 
Filter. Filtrate contains As and may be used for quantitative. The insoluble = Sb. 
(Apply tests.) 

F (Insoluble of D). Oxidize residue and filter in capsule with HC1 and KC1O 3 ; 
filter; dilute; heat; pass H^S; filter; wash precipitate with warm HNO 3 . Filtrate = C. 
Precipitate = H. 

G (Filtrate of F). Add 10 drops dilute H 2 SO4 - , evaporate; take up with water. 
Residue = Pb. Filtrate = Cu. (Apply tests.) 

H (Precipitate of F). Oxidize with aqua regia; evaporate; filter; dilute; test forHg. 

I (Filtrate of C). Use half for zinc, half for chromium. 

ZH: Neutralize with KOH; acidulate with H 2 C3O 2 ; precipitate with H 2 S; wash 
precipitate with H 2 C 3 O 2 in H 2 S water (1:5); incinerate, precipitate and filter; dissolve 
in dilute H 2 SO 4 , plus a little HNO 3 ; evaporate dry; dissolve in H 2 O; test for Zn. 

Cr: Evaporate to just moist; mix with KNO 3 ; dry; fuse; dissolve; test for chromate. 

K (Residue of A). Fuse with KXO 3 , Na 2 CO 3 , and NH 4 NO 3 . Suspend in H 2 O; 
pass CO 2 ; boil; filter. Dissolve precipitate in dilute HNO 3 . Test this solution for 
Ag, Ba, and Pb. 

Marsh's Test (see B). Produce hydrogen in flask by acting on pure zinc with 
arsenic-free HC1; pass through CaCl 2 , through tubes drawn out at several places. Heat 
to redness at the thick portion of a segment. (This blank test should be continued for 
six hours.) If no mirror appears, introduce the suspected solution. Black mirror 
occurs with arsenic or antimony. They may be distinguished as follows: 

ARSENIC ANTIMONY 

Mirror beyond heated portion. Mirror at heated portion. 

Garlic odor on heating in air. No odor. 

lyes in hypochlorite. Not. 

Easily volatilized when heated in hy- 
ilro^en. Not easily volatilized 

Heated in air, yields easily volatilized Amorphous white residue, not easily 

white crystals. volatilized. 

Heated in H 2 S, yellow, insoluble in Red (black on strong heating); 

HC1. soluble in HC1. 

Diqpolved in HNO 3 , evaporated, plus No color in cold; black (metallic Ag) 

AXO,, plus vapor of NH 3 , red or yellow on heating, 
precipitate. 

TREATMENT OF POISONING 

Whilst every case of poisoning demands to be treated by itself, yet 
certain general principles are all but universally applicable. These are 
the more important since the nature of the poison is so often unknown. 

1 H*S purified by passing through water, calcium chlorid, and a tube, 30 cm. long, filled with 
alternate layers of glass-wool and iodin crystals. 



GENERAL TOXICOLOGY 55 

The first peculiarity of poisoning to deserve especial attention is 
the rapid course. This demands that whatever measures are taken, 
they must be taken quickly. The physician should therefore be thor- 
oughly familiar with the general rules of treatment, so that no hesita- 
tion or delay occurs. On this account also, the antidote nearest to 
hand should be used in preference to one which can only be obtained 
with delay, even if the latter should be theoretically preferable. 

The treatment of poisoning is directed against the cause and the 
symptoms. The former consists in removing the poison, or in render- 
ing it harmless. Since neither of these objects can usually be attained 
absolutely, both are generally attempted at once. 

Removal of the Poison. The measures directed to this end must 
vary with the site to which the poison was applied. 

On the skin and on accessible mucous membranes this will be accom- 
plished by a thorough washing with water. This will also be useful by 
diluting the poison. If the poison is only sparingly soluble in water 
(as phenol) alcohol may be employed. Soap may be useful, but should 
be avoided if the poison is an alkali. The appropriate chemical antidote 
should also be added to the wash water (for acids or bromin: Soap or 
Linimentum Calcis; for alkalies: vinegar or lemon juice). The poisons 
which are important in these situations are all irritants, and the further 
treatment consists in the application of oils or salves. 

If the poison has been applied hypodermically or to wounds, the systemic 
effects may be lessened by preventing or retarding the absorption of the 
poison. The absorption can often be delayed sufficiently so that the drug 
is excreted as fast as it is absorbed, and doses which would otherwise 
be, fatal may then cause no effect. The best means for this purpose is a 
firm ligature applied centrally to the wound. Where this is. not feasible, 
sucking, cautery, or excision may be resorted to. 

If an irritant poison has been taken by the mouth, the oral cavity and 
the pharynx demand the same treatment as would the skin. 

With gaseous poisons, the treatment consists in free ventilation of 
the lung, using artificial respiration, and oxygen, if necessary. 

Removal from the Alimentary Canal. This is always the first step 
in the treatment of a case of poisoning by mouth, unless the symptoms 
are already so far advanced as to make it useless. Even if the poison 
has been administered some time before the treatment is begun, or if it 
has been given hypodermically, the alimentary canal should be cleansed, 
since many poisons (notably morphin) are excreted by this channel, 
and then again reabsorbed. The only contraindications to the emptying 
of the alimentary canal are: extensive corrosion, and advanced strychnin 
poisoning. Great caution and careful judgment are required in these 
cases. 

The measures for the removal of poisons from the alimentary canal 
consist in emptying the stomach and intestine. 

A cathartic, however, need only be administered after the acute manifestations are 
past. Oily cathartics should usually be avoided, and enemeta are useless. The best 
purgatives in poisoning are the cathartic salts (15 to 30 Gm. of Magnesium sulphate). 

Evacuation of the Stomach. Vomiting often occurs spontaneously, 
but even in this case, more active measures are generally required. These 
consist in the administration of emetics, or in lavage. 

Lavage always deserves preference, if it can be used. It cleanses 



56 MANUAL OF PHARMACOLOGY 

the stomach much more effectually, particularly of small insoluble ad- 
herent particles; it is less depressant to the patient; and it permits the 
convenient use of chemic antidotes. It is indispensable with depressant 
poisons which paralyze the vomiting center (such as deep morphin or 
chloral poisoning). 

The complicated stomach pump has been generally abandoned for the more con- 
venient stomach tube. In emergencies, 6 feet of rubber gas tubing, with a funnel 
attached, answers very well. The tube should not be forced down, but should be gently 
pushed to the pharynx, where the pharyngeal muscles will grasp it and push it further. 
Cart- should be taken to avoid overdistention of the stomach; it is much better to use 
small quantities of fluid frequently. If there is much pain, 0.05 per cent, to o.i per 
cent, of cocain may be added to the wash water; against organic poisons, a 0.5 : 1,000 
solution of potassium permanganate may be used. If there is trismus, or the patient 
resists, the tube may be passed through the nose. 

Emetics have the advantage of greater convenience, and avoid 
struggling. They should be repeated every fifteen to thirty minutes, 
if necessary. 

Apomorpkin. [5 mg. (grain H i* 1 * P er cent, solution = 0.5 c.c. 
or 1U x] hypodermically. This is the only emetic which can be given by 
the skin, and is therefore particularly useful if the patient resists. It is 
very prompt and certain, but rather more depressing than the following 
emetics: 

Copper Sulphate or Zinc Sulphate. These act promptly and with a 
minimum of depression, but should not be given if the poison is a corrosive. 
Zinc sulphate is less irritant than the copper, and nearly as efficient; 
2 Gm. may be given in a glass of water. The dose of copper sulphate 
is 0.5 Gm. at once, or three doses of 0.3 Gm., fifteen minutes apart. If 
it is ineffective it must be removed by lavage. 

Ipecac. A teaspoonful of the powder in water, or a tablespoon of the wine. Un- 
certain, and produces considerable depression. 

Mustard. A teaspoonful stirred in a tumbler of warm water. This is the most 
uncertain of these emetics, but useful in emergencies. 

Neutralization of the Poison Chemical Antidotes. The object of 
these is, to render the poison incapable of acting, or of being absorbed. 
They accomplish this by enveloping the poison with an impenetrable 
coating, or by precipitating it, or by destroying it. Since these antidotes 
are hindered in their action by the. presence of food, and since the pre- 
cipitates are not perfectly soluble, it is well to combine them with lavage 
or emesis, adding the antidotes to the wash water, or giving them in 
the interval between vomiting; they must be repeated frequently. 

Demulcents (raw eggs, acacia, boiled starch or flour, milk, ad libitum). 
-These act by lessening absorption; by allaying inflammation; and in 
the case of metals, by precipitation. 

Precipitants. The most universally applicable of all precipitants 
is tannin (a teaspoonful of tannic acid, or preferably, very strong hot 
tea, ad libitum). The efficiency will be increased by the addition of 
sodium acetate or bicarbonate, and diminished by alcohol and acids, 
since the precipitates are soluble in these media. 

From the experiments of Kiefer (1892), on tannin, and Sollmann (1901), on tea, 
it may be deduced that these are useful against: Apomorphin, Cinchona alkaloids, 
Hydrastin, Strychnin, Veratrin, Digitalis, Antipyrin, Colchicin; and the metals: Pb, 
.\K, Al, Co, Cu, Ni, Ur, Zn, Fe. 



GENERAL TOXICOLOGY 57 

Scarcely useful against: Cocain, Brucin, Aconitin, Lobelin, Nicotin, Pilocarpin, 
Codein, Muscarin, Physostigmin, Solanin. 

Practically useless against: Atropin, Coniin, Morphin, As, Sb, Hg. 
Of other, specific precipitanls, the following should be remembered : 

For 

Alkaloids. Tincture or compound tincture of iodin, 15 drops in half 
a glass of water. 

Metals (especially mercury). Raw eggs. 

Arsenic. 'Arsenic antidote (see Index). 

Barium. Sulphates (Glauber's or Epsom salt). 

Oxalates. Calcium (limewater, chalk, whiting). 

Phosphorus. Copper sulphate or Oxidized (old) Turpentine. (The 
former envelopes the phosphorus with an insoluble coating of metallic 
copper. Turpentine forms the insoluble turpentine-phosphoric acid.) 

Antidotes Which Destroy the Poison in the Alimentary Canal. 
(These, for the most part, will not be useful after the poison is absorbed.) 

Acids. Alkalies (burnt magnesia, soap, chalk, baking soda). 

Alkalies. Weak acids (vinegar, lemon juice). 

Organic Poisons (Alkaloids, Glucosids, etc.} and Phosphor us. Oxidizing 
agents, especially Potassium permanganate, i Gm. (one-fourth teaspoon- 
ful) in a quart of water. Care must be taken that no undissolved crystals 
are administered; H 2 O 2 . (In case of snake bite, the powdered permanga- 
nate may be rubbed into the wound, after free incision.) 

Hydrocyanic Acid. The above, also arsenic antidote, hydrogen per- 
oxid, and hyposulphite of sodium. 

Antidotes Which Destroy Absorbed Poisons. To be effective, these must be given 
hypodermically or intravenously. The best known examples of this class are the anti- 
toxic sera. The following are also useful: Sodium hyposulphite against hydrocyanic 
acid; and sodium carbonate against mineral acids. 

Removal of Poisons after Their Absorption. This can be attempted by increasing 
the excretions, but is usually not very successful. The elimination by the alimentary 
canal has been discussed. The principal remaining channels are the urine and sweat, of 
which the former is by far the more important. 

Diuretics. Water, especially as weak tea or carbonated drinks; theobromin; potas- 
sium acetate (irritant diuretics should be avoided). 

Diaphoretics. Hot drinks; heat; pilocarpin (if not contraindicated by pulmonary 
edema). Diuresis and diaphoresis often fail, partly because they act too slowly, partly 
because not all poisons are eliminated by these channels. 

Infusion of Normal Saline Solution (i Liter of 0.9 percent, injected under the skin 
of the sub-clavicular region) increases elimination by all channels. Bleeding may be 
resorted to in some cases. Up to a liter of blood may be drawn, a double quantity of 
salt solution being injected. 

Symptomatic Treatment. The symptoms produced by poisons can 
often be lessened or removed by the use of drugs having an opposite action. 
It is not to be supposed that these physiologic antidotes really lessen the 
action of the poison, although they cover its symptoms. But by tiding 
the patient over the dangerous period, and by preventing exhaustion, 
they are often potent means of saving life. It must be remembered, how- 
ever, that large doses of the antidotes often cause effects similar to those 
of the poison, which may add to the fatality of the latter. They must 
therefore be used in appropriate small doses. 

It is not purposed to enter in this place into the special physiologic 
antidotes, but we shall take up only those measures which are generally 
useful. 

These measures are directed, in the order of their importance, to: sup- 



58 MANUAL OF PHARMACOLOGY 

porting the respiration, heart, and vasomotor tone; to lessen cooling, pain, 
convulsions and coma. 

Respiration. This is usually the first function to fail, and accelerates 
the other actions of the poison through the convulsant. and paralytic effects 
of asphyxia, and by preventing the destruction of poisons through oxida- 
tion. For these reasons, it is well not to wait with the supporting measures 
until the respiration has actually failed, but to begin as soon as it shows 
signs of weakening. The measures consist in direct or reflex stimulation 
of the respiratory center; in artificial respiration; and in the administra- 
tion of oxygen. 

. Rejlcx stimulation of the respiratory center is the quickest, but can not 
be kept up as long as the direct stimulation. It may be secured by the 
administration of ammonia, by inhalation of ammonia water or smelling 
salts, or by aromatic spirits of ammonia (half a teaspoonful in a glass of 
water); the alternate application of heat and cold (whipping with wet 
towels); friction with alcohol, or camphorated oil; hypodermic injection 
of brandy, whiskey, or ether; mustard plasters. 

Direct Stimulation of the Respiratory Center. By strong hot coffee, 
strychnin (0.002 Gm.) or atropin (o.ooi Gm.). The respiration may also 
be raised by improving the circulation. Saline infusion is also very 
effective. 

Artificial Respiration. This should be resorted to whenever the above 
measures are ineffectual. 

Any of the commonly used methods (also rhythmical stimulation of the phrenic 
nerve) may be used. It should be remembered that very prolonged and violent artificial 
respiration may injure the lungs. It should also be remembered that artificial respira- 
tion is apt to induce apnea, so that the patient does not breathe spontaneously simply 
because there is not enough CO in the blood to stimulate the respiratory center. If 
the heart is strong, the artificial respiration should therefore be intermitted occasionally 
for a short time. 

Oxygen. This will be useful in every case of failing respiration, and 
particularly if an asphyxiant gas is the cause of the poisoning. 

Heart. Attempts to revive or even to support the poisoned heart 
directly have not been very successful. The best results are obtained by 
the injection of normal saline, possibly with the addition of some epi- 
nephrin (1:100,000). Digitalis is usually unsuccessful. Strong rhythmical 
pressure (rate of 100 per minute) over the cardiac region of the chest, may 
be helpful. A dilated heart can sometimes be revived by withdrawal of 
blood. 

Vasomotor Stimulation. This is usually accomplished by the reflex 
stimulants mentioned under respiration. Lowering of the head and ban- 
daging the extremities is often sufficient. 

Cooling. This is prevented by the application ot external heat; pain 
by morphin, or if local, by cocain; convulsions are controlled by the 
cautious inhalation of chloroform; coma by reflex stimulants, coffee, and 
atropin. 

Methods of Administering Antidotes. Physiological antidotes should 
be given hypodermically or intravenously, if possible. This obviates the 
loss of the antidote through vomiting, and the action is more prompt and 
more certain. 

If the circulation is very low the absorption of hypodermic injections may also be 
very slow. It is therefore well thoroughly to massage the site of the injection, and if 
the circulation has almost stopped, to employ vigorous rapid rhythmical compression. 



PRESCRIPTION WRITING 59 

of the heart (this maintains a fairly efficient artificial circulation even after the heart 
has stopped beating). 

Resume of the General Treatment of Poisoning. Promptness is of 
vital importance. The physician should be familiar with antidotes; he 
should have these antidotes readily accessible; he should plan his treat- 
ment on his way to the patient. If he finds the condition of the patient 
dangerous, he should at once proceed to relieve the symptoms. Otherwise 
he should first administer the chemical antidote and evacuate the stomach; 
apply heat; attend to the respiration, to pain, to any other symptoms; give 
a diuretic, and, finally, a cathartic. 

Antidotes for First Aid. Every physician (and every drug store) should keep the 
following antidotes together, in a special satchel ("Antidote-Bag") so that they can be 
readily transported. The dose should be written on each container. Amyl nitrite 
pearls; Apomorphin tablets, 2 mg.; Atropin tablets, i mg.; Caffein Citrate; Chloro- 
form; Cocain hydrochlorid tablets, 0.03 Gm. (2 to 4 per quart); Tincture iodin; Copper 
sulphate, powdered; Lime Water; Magnesia, calcined; Potassium permanganate, i 
per cent, solution (to be diluted ten times); Sodium sulphate; Spir. Ammon. Arom.; 
Strychnin sulphate tablets, 2 mg.; Whiskey; also a hypodermic syringe in good order, 
and a stomach-tube with funnel. 

The following should be demanded at the house of the patient: Boiled water; 
Coffee (strong, hot, and black); Eggs; Hot-water bags; Milk; Mustard; Salad oil; Salt; 
Soap; Starch, boiled; Tea, Vinegar. 



PRESCRIPTION WRITING 

Parts of the Prescription. A prescription is an order for medicine, 
sent by a physician to a pharmacist. It consists of the following parts 
(in this order) : 

i. Superscription. The heading 



The 1^ stands for recipe, take thou. The stroke is generally considered an ancient 
invocation to Jupiter; but probably it is simply a sign of abbreviation (McGuigan, 1913). 

2. Inscription. The ingredients and their amounts. 

3. Subscription. The directions to the dispenser. 

4. Signature. The directions to the patient. 

The prescription should also bear the signature of the physician, the 
date, and the name of the patient. 

The Inscription may consist of but one ingredient. If several are used, 
they should be placed in the following order: 

Basis: the principal substance. 

Adjuvant: the substance which is used to aid the action of the basis. 

Corrective: whose purpose it is to modify or correct an undesirable 
action of the basis. 

Vehicle: the indifferent substance used to dilute the active ingredients. 

The following is the type of a complete prescription: 

Superscription 

Inscription: Basis. 



Subscription 



Adjuvant. . 
Corrective. 
Vehicle . . 



GM. vel C.C. 

45 



Tincture Aconiti o 

Spiritus Athens Nitrosi 15 

Liquoris Ammonii Acetatis 15 

Elixiris Aromatici 30 

Misce 



Signature 

S. Teaspoonful every hour in half a 
glass of water. 

Dr. X 

Jan. i, 1905. 

For Mr. V 



6O MANUAL OF PHARMACOLOGY 

The names of the ingredients and the directions to the pharmacists 
are generally written in Latin, usually with abbreviations; but they may 
be written in English. With liquid mixtures, the directions to the phar- 
macist may often be confined to M. (misce, mix). 

The directions to the patient (signature abbreviated Sig. or S., for 
"signa," sign) are always written in English, so that the patient can read 
them. The directions should be made as complete as possible, and should 
include everything which it is necessary for the patient to know. The 
habit of giving verbal instructions to patients and of having the medicine 
labeled "use as directed" can not be too much discouraged. Aside from 
the fact that human memory is extremely apt to fail, the patient or rela- 
tives, when the prescription is given to them, are usually in a more or less 
excited frame of mind, and can not be relied upon to remember what is 
told them. Medicines intended for external application should be plainly 
labeled to that effect, and when a medicine contains poison, it should be 
so labeled, except when there is special objection to this. 

The custom of having prescriptions "refitted" obtains in many locali- 
ties. Whereas it is often impossible for the physician to put a stop to this 
practice, it is absolutely necessary that he should prevent such prescrip- 
tions being refilled which contain narcotics or other drugs likely to cause 
a habit. He can attain this result by writing "non repetatur" under the 
prescription. The druggist refilling this will do so on his own responsi- 
bility. (The law prohibits the refilling of prescriptions containing mor- 
phin or cocain, with their derivatives. A prescription must be written 
each time that these are to be dispensed.) 

When the patient is very poor, it is often customary to invite the drug- 
gist to charge him the lowest terms by writing P. P. (Pauperissimus) 
under the prescription. It is, of course, not just to do this if the physician 
himself receives a regular fee. 

Forms of Administration. If the medicine is to be used internally, 
it may be prescribed as: 

Solution. If the ingredients are soluble in water, alcohol or glycerin. 

Mixtures or emulsions, i.e., suspended by acacia, if insoluble in water. 

Powder. If the substance does not have a very bad taste. These are 
preferred to the following preparations if the dose is bulky, or if the sub- 
stance is to be dissolved in water before swallowing. 

Pills, Capsules, Etc. If the substances are solid or semisolid, and pos- 
sess a disagreeable taste; or if they are to act locally on the alimentary 
canal. 

If the medicine is intended for external use, it may be prescribed as: 

Plaster. If the action is to be prolonged and superficial. 

Ointment. If the action is to be deeper, or briefer. 

Lotions or Injections, Eye-waters, Gargles, Etc. If it is soluble in water. 

Liniment. If it is soluble in oil or alcohol. 

Size of Prescriptions. Fluids should be prescribed so as approximately 
to fill the bottles in current use (15, 30, 60, 125, 150, 200, 400 c.c.) 
(y%, i, 2; 4; 6; 8 and 16 ounces). 

For drop doses and eye- waters, the usual amount is 15 to 30 c.c. (% to 
i5); for teaspoon doses, 30 to 125 c.c. (i to 45); for gargles and injections, 
60 to 1 50 c.c. (2 to 65); lotions, 120 to 200 c.c. (4 to 85); tablespoon doses, 
150 to 400 c.c. (6 to i65)- Pills are prescribed in numbers of 5 to 25; 
powders, i to 12; ointments, 10 to 30 Gm. (% to i5). 



PRESCRIPTION WRITING 6 1 

The Need of Practice in Prescription Writing. 1 The subject of prescription writing 
seems to possess almost insurmountable difficulties for the student. There is, perhaps, 
no other subject in the whole course of study which he finds more discouraging and 
finishes with less satisfaction. Nevertheless the principles upon which it is based are 
few, simple, and easily memorized. When asked for them, the student usually has no 
difficulty in answering the questions. The difficulties appear when he tries to put these 
principles into practice. But it is the same with any other art: nothing but practice 
will give expertness. 

The prescription is usually a fair indication of the physician's training, 
knowledge and character. The student who would master this subject 
must not rest content with doing the few exercises which can be given him 
in class. As he studies each drug, or as he reads up the treatment of dis- 
eases, he should himself compile such prescriptions as the subject suggests. 
This will not only aid him in prescription writing, but in pharmacology 
and therapeutics as well. It is only in this way that he can acquire the 
necessary self-confidence and skill. In this home practice, method and 
detail should be cultivated, for in these lies the secret of the art. The 
following rules may prove helpful: 

Routine Construction of Prescriptions. When writing a prescrip- 
tion for a given condition, put down, first, the name of the best 
remedy. Ask yourself whether there is any other drug which may be em- 
ployed to aid or usefully modify this. Put this down also. 

Then consider in which form the medicine should be administered, 
whether as liquid, powder, salve, etc. This will usually determine 
which preparation of the ingredient is to be employed. Put this down 
also. 

Then ask yourself what may be added to render the mixture agreeable 
to the patient. Add the vehicle. When this is written, all the ingredients 
will be represented. 

Now look over these carefully and see that there are no incompatibili- 
ties and that the constituents are soluble if the mixture is to be a liquid. 
Write the directions to the dispenser. Assure yourself that the prescrip- 
tion is grammatically correct (especially the endings). 

Decide how many days the mixture is to be taken, and how many doses 
a day (on the basis of sixteen hours to the day). Decide whether the dose 
of the total mixture is to be a teaspoonful, tablespoonful, etc. By multi- 
plying the total number of doses with the size of the single dose, ascertain 
the approximate size of the mixture. Round this off to a convenient 
figure. Multiply the single dose of each ingredient by the total number 
of doses (again reducing the quantities to round numbers, unless the 
constituent is very active). 2 Check the doses. Write the directions to 
the patient. Consider whether a non repetatur is advisable. Affix your 
signature, the date, and the name of the patient. This finishes the 
prescription. Look over the result carefully in the same order. 

It would seem almost superfluous to mention that it is extremely 
essential in writing prescriptions to use as legible handwriting as possible. 
It is astonishing, in view of the dire results that may follow, how often 
this self-evident rule is disregarded. The same remarks apply to abbrevia- 
tions. While it is justifiable to employ abbreviations even extensively, 
it is necessary to make these in such a way that they can not possibly be 

1 The author has found it very useful in class practice in prescription writing, to make some of 
the students in turn work out the prescriptions on the blackboard, and to subject these to the 
criticism of the class. 

2 One may also write the quantities for a single dose, and state in the subscription the number 
of doses desired: "Pac tales doses no. XX" (make 20 such doses. } 



62 MANUAL OF PHARMACOLOGY 

misinterpreted. It is, therefore, advisable to employ the official abbrevia- 
tions which are given under the "Preparations." 

An efficient aid in acquiring practice in writing prescriptions is to 
look over a druggist's prescription file, when this may be done. 

The copying of a prescription, ingredient for ingredient and dose 
for dose, is as much empiricism as the use of any other ready-made com- 
pound. The physician should be well enough educated to devise his own 
prescriptions and to select such ingredients as will best suit the special 
needs of the case in hand. 

Simplicity in Prescription Writing. Formerly the ingredients of a 
prescription were almost numberless. This was in the time of empiricism, 
and was simply an application of the idea that in a large mixture of sub- 
stances there would probably be one which would do good. This was the 
so-called "shot-gun prescription." At present the tendency in prescription 
writing is to make the prescription as simple as possible. This avoids 
the chances of incompatibilities, and, what is more important, makes the 
action of the medicine more easy to watch and control. Especially, 
one should avoid to combine, in the same prescription, drugs which differ 
markedly in quickness of action, absorption or elimination; or habit- 
producing drugs with others that will presumably be used for long periods. 

If the prescription includes a number of mixtures, each containing several ingredients, 
such as the numberless preparations now put on the market by many firms, the result 
is, of course, as much a "shot-gun" prescription as if the prescriber had enumerated all 
the ingredients. 

Posology (Doses). The dosage of drugs must be adapted to the 
individual patient. The Pharmacopeias state "Average Doses" (adult) 
for each preparation that is likely to be used internally; but these are 
not intended to be binding on physicians. They are, however, convenient 
approximations for memorizing. The metric and apothecaries' doses 
in the U.S. P. are not intended as mathematical equivalents, but represent 
rather the quantities that would be used by prescribers in these systems. 

The doses of crude drugs are given mainly as a basis for calculating 
the preparations. 

Maximal Doses. The pharmacist is supposed to check the quantities 
of the ingredients, and not to dispense a prescription containing an 
unusual dose of a powerful poison without convincing himself that the 
physician prescribed this intentionally. While this does not in any 
way lessen the responsibility of the physician, it is a safeguard which 
deserves all encouragement. To avoid delay, it is customary to mark 
such large doses in such a way that the pharmacist will have no doubt 
that they are intentional. Thus: 

Tr. aconiti, 3j or 5j!; or 3j Q- R- (quantum rectum), the last being 
the best. 

Most foreign pharmacopeias (but not the U.S.P. or B.P.) give tables 
of "Maximum Doses;" not with the purpose of restricting the physician, 
but as a guide to the pharmacist. The latter is not permitted to dispense 
doses larger than these, unless the physician indicates specifically (as 
explained above) that the larger doses are intentional. The maximum 
doses in this book are taken from the compilation of the U.S.P. Digest, 
1912, pp. 40-42. 



PRESCRIPTION WRITING 63 

PRESCRIPTION LATIN 

It is customary, but not compulsory, to write the inscription, and often 
the subscription in Latin. A slight knowledge of the rules of grammar 
of this language is therefore desirable. It is supposed that this is possessed 
by the student, and the following is intended merely to recall some of the 
more important facts. 

Advantages of Latin. The use of the Latin names of drugs is generally urged 
because they are more definite and concise, and less liable to change than common 
names; and because they serve to keep the patient in ignorance of the nature of the drugs. 
This is sometimes very desirable,/.?., to guard against drug habits. However, the official 
English names are equally definite; and as either names are usually abbreviated, there 
is little difference. As a matter of fact, less than 5 per cent, of the U.S. P. "Latin" 
names are really Latin (Oldberg, 1910). 

In the directions to the dispenser, Latin has no advantage, except in the brevity of 
the customary abbreviations. . Indeed, unusual Latin terms are apt to lead to mistakes. 
The discarding of Latin in prescription writing is being actively discussed (Fantus, 
1916). 

Grammatic Rules. The superscription, R (recipe: "take thou"), 
requires the name of the substance to be in the genitive, if the quantity 
is given, the quantity itself being in the accusative (the latter is, of course, 
very rarely written out in full). When the quantity is not given, the name 
of the substance is to be placed in the accusative. Adjectives agree with 
their nouns in gender, number, and case. 

These rules will generally be understood by translating into English: 
e.g., Take thou of tincture of aconite i ounce. 

The following rules for the formation of the genitive case will be found valuable 
("Mann's Manual"): 

RULE i. All nouns ending in a., farm the genitive in as; as Quinina, Quininse. Excep- 
tions: Aspidosperma, Physostigma, and Theobroma form the genitive in atis. Folia 
is plural; genitive, foliorum. 

RULE 2. AH nouns ending in us, um, os, on, form the genitive in i; as Coniunv 
Conii. Exceptions: Rhus, gen. Rhois; Flos. gen. floris; Erigeron, gen. Erigerontis. 
Fructus, Cornus, Quercus, Spiritus, do not change. 

RULE 3. All other nouns of whatever termination make the genitive in s, or is. Elixir, 
gen. Elixiris. 

Some lengthen the termination thus: 

as, genitive atis; as Acetas, Acetatis. 

is, " idis; as Anthemis, Anthemidis. 

o, onis; as Pepo, Peponis. 

x, cis; as Cortex, Corticis. 

There are a few exceptions. Asclepias, gen. Asclepiadis; Mas, gen. Maris; Phosphis, 
Sulphis, etc., gen. itis; Mucilago, gen. Mucilaginis; Solidago, gen. Solidaginis; Pulvis, 
gen. Pulveris, etc. 

The following words do not change in their genitive: Azedarach, Buchu, Cannabis, 
Catechu, Condurango, Cornus, Curare, Cusso, Fructus, Digitalis, Hydrastis, Jaborandi, 
Kino, Matico, Quercus, Sassafras, Sago, Sinapis, Spiritus, Gambir, Sumbul. 

The accusative is rarely employed. It is formed according to the following rules 
(Mann): 

RULE i. Nouns singular ending in a, are feminine, and make the accusative singular 
in am and the plural in as. Example: Drachma, ace. sing. Drachmam, pi. Drachmas. 

RULE 2. Those ending in um or us, make the accusative singular in um. The accusa- 
tive plural of those in us is os, and of those in um is a. Those in us are masculine, those 
in um are neuter: 

Congius, ace. sing. Congium; ace. pi. Congios. 
Granum, ace. sing. Granum; ace. pi. Grana. 

RULE 3. Those whose genitive ends in is, form the accusative in em, plural es. 



64 MANUAL OF PHARMACOLOGY 

Attention is also called to the fact that adjectives change their endings, 
a fact which the student is apt to forget. 

The following prepositions are frequently used, and command the fol- 
lowing cases: 

ad to accusative. 

ana 1 of each genitive. 

cum with ablative. 

in into accusative. 

The following Latin words and phrases occur frequently in prescrip- 
tions (adapted from Mann) : 

ad to, up to 

ad libitum at pleasure 

adde add (thou) 

ana (aa) of each 

aqua bulliens boiling water 

" fontana spring water 

" fervens hot water 

" destillata distilled water 

bene well 

bis in dies twice daily 

cape, capiat take, let him take 

charta a paper (medicated) 

chartula v a small paper for a powder 

cibus food 

cochleare magnum a tablespoon 

" parvum a teaspoon 

cola, colatus strain, strained 

collyrium an eye wash 

congius (C.) a gallon 

cum with 

dilute, dilutus dilute (thou), diluted 

dimidius one-half 

divide (Div.) divide (thou) 

dividendus to be divided 

dividatur in partes requales let it be divided into equal parts 

dosis a dose 

extende supra spread upon 

fac, fiat, fiant (ft.) make, let be made, let them be made 

fac tales doses make such doses 

filtra filter (thou) 

gargarisma a gargle 

gutta, guttze (gtt.) a drop, drops 

haustus a draught 

hora an hour 

hora somni just before going to sleep 

hora decubitus at bed time 

in dies daily 

instar like (with genitive) 

lac milk 

libra (Ib.) . . a Troy pound 

mane primo very early in the mornine 

magnus large 

misce (M.) mix 

more dictu as directed 

non repetatur do not repeat 

numerus, numero (Xo.) a number, in number 

octarius (O.) . . a pint 

ovum an egg 

pars a part 

partes aequales (P. ae.) equal parts (governs genitive) 

parvus small 

1 From the Greek. 



COLORING AND FLAVORING 65 

pilula (pil.) a pill 

pro re nata (p.r.n.) according to circumstances, occasionally 

pulvis (gen., pulveris) a powder 

quantum sufficit (q. s.) as much as is necessary 

quaque hora every hour 

(cum) semisse (ss.) and a half 

signa sign 

sine without 

si opus sit if necessary 

solve, solutus dissolve, dissolved 

solutio a solution 

statim immediately 

talis such 

tritura triturate 

tere simul rub together 

ter in die (t.i.d.) three times a day 

vitellus the yolk (of an egg) 



COLORING AND FLAVORING 
COLORING 

Liquid prescriptions intended for internal administration should be 
clear if possible. It might be well to mark all such prescriptions "filtra." 
The appearance may often be materially improved by the addition of some 
coloring-matter, and this may also prove useful through its suggestive 
element and by hiding the nature of the medicine from the patient. The 
nature of the coloring-matter must vary according to the nature, and 
especially the reaction of the mixture. The usual colors for internal use 
are red, brown, and yellow. Anilin dyes should be avoided, except methy- 
len blue and gentian violet for external preparations. 

The most useful dyes are the following: 



Red Brown 



Yellow 



For alkaline or neutral fluids: 


Tr. Cardamomi 


Fldext. Glycyr- 


Tr. Hydrastis 




Co. 


rhizae 






Liq. Carmini 


Elixir Adjuvans 




For acid fluids: 


Tr. Persionis 


Caramel 


Tr. Hydrastis 








Tr.Curcumae 


For powders: 


Carmine 







PREPARATIONS RED COLORS 



Coccus, Cochineal, U.S. P., B.P. The dried female insect of Coccus Cacti. 

Tr. Cocc., B.P. 10 per cent. Dose, 0.03 to o.i c.c., 5 to 15 minims, B.P. 

Carminum, Carmine. A precipitate obtained from decoction of cochineal by alum 
or cream of tartar. Soluble in alkalies, brightened and precipitated by acids. Also 
soluble in alcohol. Contains carminic acid. Used in powders, etc. (i :5oo). 

*Liquor Carmini (Liq. Carm.). A glycerinated extract of carmine. Pink to deep 
red in alkaline solutions, precipitated by acids. Used in the proportion of about i 
per cent. 

(*7>. Cardamomi Co. (Tr. Card. Co.). An aromatic alcoholic (50 per cent.) vehicle, 
colored with cochineal. Used undiluted (see Index). 

*Tr. Persionis (Tr. Persion.); Tinct. of Cudbear (a lichen allied to litmus). Red in 

1 The preparations of each class are generally arranged alphabetically under the crude drugs. 
The important preparations, which the student is expected to study, are marked.* In addition 
to these, he should glance over the corresponding crude drugs. 



66 MANUAL OF PHARMACOLOGY 

neutral or acid, purplish in alkaline solutions. Used in the proportion of about 1.5 



or cent 

ilum Rubrum (Santal. Rub.), U.S.P.; Pterocarp. Lign., B.P., Red Saunders. 
The heart-wood of Pterocarpus santalinum. Used in Tr. Lavand. Co. 

PREPARATIONS BROWN COLORS 

Caramel is a concentrated aqueous solution of carbonized sugar. Commercial 
caramel is generally made by heating glucose with a little alkali, until the sweet taste is 
destroyed and a uniform dark mass results. It is probably a complex mixture. Cara- 
im-1 from cane-sugar according to Stolle, 1899, is a single substance, Ci 2 HigO 9 , formed 
tiy the elimination of two molecules of water from sucrose. Caramel is being tried in 
diabetes, being apparently well tolerated (Grafe, 1914; Umber, 1915). 

*Fldext.Glycyrrhiz(e and *Elix. Glycyrrh. (see Index). 

PREPARATIONS YELLOW COLORS 

Crocus, Saffron, has been used as abortifacient; but it apparently lacks this action 
and is practically non-toxic (Cevidalli, 1914). 

*Tr. Curcuma (Tr. Curcum.) (Turmeric) precipitates with water, but sufficient 
remains in solution to impart a yellow color. Used in ratio of i per cent. Curcuma 
changes to reddish brown in alkalies. 

*7>. Hydraslis (Golden Seal) is used similarly (see Index). 

FLAVORING 

This subject, although often neglected, is quite important. It not 
only humors the patient and secures more conscientious compliance 
with the prescrip'tion, but also often aids absorption and digestion just 
as condiments do in foods. 

Patients often fail to take a disagreeable medicine, and the physician should always 
be on the lookout for such cases. It is scarcely necessary to say that he should approxi- 
mately control the amount taken by judging as to the quantity left in the container, as 
he should also, in general, control the medicine dispensed by the druggist as to its 
appearance and taste. 

Some patients carry the deceit further and pour away the appropriate amount of 
the medicine, and if the physician does not obtain the anticipated results, it may be 
well to prescribe some test medicine, such as salol (0.3 Gm.), or potassium iodid (0.3 
Gm.), which can be detected in the urine. 

Improving the Taste of Liquid Medicines. This may be done by 
dilution; sweetening; demulcents; aromatics; alcoholics; acids; bitters; 
and drugs which paralyze the taste-endings. Several of these means are 
often combined. 

Simple Dilution. This is often most effective for salts, alkalies, 
chloral and other hypnotics; and in general, substances with disagreeable 
but not very marked taste. These should be taken in a half-glass or 
glass of water, milk, tea, or carbonated water. 

The Most Important Flavors. The following will be found to be gener- 
ally sufficient: 

To disgiiise bitter taste: Aromatics (Tr. Cardamomi Co. ; Elixir Aromatic ; 
Syr. Aurantii); for children, Glycyrrhiza, Aq. Anisi, Syr. Tolutanus. 

To disguise acrid taste: Aromatics as above; also syrups, acacia, 
acid flavors (Syr. Aurant.). 

To disguise salty or alkaline taste: Dilution with simple or carbonated 
or aromatic water or milk. 

To disguise oily taste: Aromatics (Oil or Spirit of Peppermint, lemon, 
orange, wintergreen or almond, according to personal preference). 

For insipid drugs: Aromatics and acids (Syr. Aurantii). 



COLORING AND FLAVORING 67 

PREPARATIONS SUGARS AND HONEYS 

*Saccharum (Sacch.), U.S. P., 1 Saccharum Purificatum (Sacch. Pur.), B.P.; Sugar 
(Cane or Beet), CiaH^On. Very sol. in water (i :o.5), slightly in ale. 2 (i : 170). Used 
for sweetening powders, for the administration of volatile oils (eleosacchara), and the 
preparation of syrups, elixirs, etc. 

*Sugar Substitutes. -In cases where sweetening is desired and sugar is excluded, 
particularly in cases of diabetes, the artificial synthetic product saccharin may be 
substituted. It is about 300 times as sweet as sugar, but the taste is not exactly the 
same. The dose for a cup of coffee or tea is about ^ to i gr. Glycerin is another sweeten- 
ing substance which does not contain sugar, and is sometimes employed in place of 
saccharin. A principle of quite a different kind is the glucosid of glycyrrhiza. This 
acts only in alkaline liquids. It has no taste if the liquid is made acid. 

Many other substances have a sweet taste. Attempts to connect this with the 
chemic structure (Haycraft, 1882; Sternberg, 1898) have not been very successful. 

*SaccIiarum Lactis (Sacch. Lact.), U.S. P., B.P.; Sugar of Milk (Lactose); CiaH^On- 
HaO. White, hard, crystalline masses, or white powder, feeling gritty on the tongue; 
odorless; faintly sweet taste. Freely sol. in water (i 14.9); almost insol. in ale. 

Glucosurn (Glucos.), U.S. P., B.P., Glucose (Syrupy). The product obtained by the 
hydrolysis of starch, consisting chiefly of dextrose and dextrins. Colorless, or slightly 
colored, thick, syrupy liquid. Very sol. in water, sparingly sol. in ale. 

Syr. Glucos, B.P. Glucose i, syrup 2. 

Mel, U.S.P. Honey. 

Mel Depuration (Mel Depurat.), U.S.P., B. P. Clarified Honey. 

Oxymel, B.P. Honey with % acetic acid. Dose, 2 to 8 c.c., '% to 2 drams. 

Rosa Gallica (Rosa Gall.), U.S.P.; (Ros. Gall. Pet.), B. P. Rose Petals. 

Conf. Ros. Gall., B.P. 25 per cent, of fresh Rose Petals. 

Mel Rosa, U.S. P.; Honey of Rose. Fldxt., i; Honey ; 7. Dose, 4 c.c., i dram, U.S. P. 

Fldext. Ros., U.S. P. Dose, 2 c.c., 30 minims, U.S.P. 

Svr. Rosa (Syr. Ros.), B.P. Dose, 2 to 4 c.c., % to i dram, B.P. 

Rhceados Pctala, B.P. Red Poppy Petals. 

Syr. Rhcead., E.P.Dose, 2 to 4 c.c., Y^. to i dram, B.P. 

PREPARATIONS FLAVORING SYRUPS 

*Syrupus (Syr.), U.S. P., B.P. ; Syrup. A strong aqueous solution of sugar containing 
85 Gm. of sugar in 100 c.c. of syrup, U.S.P. (66.7 Gm. in 100 Gm. of syrup, B.P.). 
Miscible with water or alcohol. It is more commonly employed in the form of the 
flavored syrups. Their dose is ad libitum. 

*Syrupus Acidi Citrici (Syr. Acid. Cit.), U.S.P. A i per cent, solution of citric acid, 
flavored with sugar and lemon peel. 

Limonis Cortex (Limon. Cort.), U.S.P., B.P. Lemon peel (fresh). 

Ol. Limon., U.S.P., B.P. A volatile oil obtained by expression from the fresh, ripe 
peel of Citrus medica var. Limonum. Dose, 0.2 c.c., 3 minims, U.S.P.; 0.03 to 0.18 
c.c., H to 3 minims, B.P. 

Syr. Limon, B.P. About 50 per cent, of lemon juice, flavored with lemon peel. 

Tr. Limon. Cort., U.S.P. 50 per cent. 

Tr. Limon., B.P. 25 per cent. Dose, 2 to 4 c.c., ^ to i dram, B.P. 

Aurantii Amari Cortex (Aur. Amar. Cort.), U.S.P.; Aurant. Cort.. Sice., B.P.; Bitter 
Orange Peel. The dried rind of the fruit of Citrus Aurantium amara. Dose, i Gm., 
15 gr., U.S.P. 

Aurant. Cort. Rec., B.P. The fresh peel. 

Fldext. Aur. Amar., U.S.P. Dose, i c.c.; 15 minims, U.S.P. 

Inf. Aurant., B.P. 5 per cent. Dose, 15 to 30 c.c., % to i ounce, B.P. 

Inf. Aurant. Co., B.P. 25 per cent., with lemon and cloves. Dose, 15 to 30 c.c.; 
^ to i ounce, B.P. 

01. Aur., U.S.P. Dose, 0.2 c.c., 3 minims, U.S.P. 

Spir. Aur. Co., U.S.P. 20 per cent, of orange oil, with oils of lemon, coriander and 
anise. 

1 "U.S.P. " stands for preparations official in the United States Pharmacopeia; " B.P. ," British 
Pharmacopeia; "N.N.R.," New and Non-official Remedies; "N.F.," National Formulary; 
"B.P.C.," British Pharmaceutic Codex. 

1 The following abbreviations will be used in connection with solubilities. Ale. = alcohol: 
glyc. = glycerin; eth. = ether; chlorf. = chloroform. The figures refer to the parts solvent 
required to dissolve i part of drug (f.i., i : 0.5 = i part of drug dissolves in 0.5 parts of solvent). 
The solubilities refer to 2SC. (room temperature), unless otherwise stated. 



68 MANUAL OF PHARMACOLOGY 

*Syrup. Aiiranlii (Syr. Aur.), U.S.P.; (Syr. Aurant.), B.P.; Syrup of Orange. 
Flavored with orange peel. The U.S.P. contains ^ per cent, of citric acid. Dose, 
. % to i dram, B.P. 

[mar., U.S.P., 20 per cent. Tr. Aurant, B.P., 25 per cent. Dose, 4 c.c., 
; drum, 1. S.I'.; 2 to 4 c.c., ^ to i dram, B.P. 
Aurant., B.P. 
:ntii Dulcis Cortex (Aur. Dulc. Cort.), U.S.P. From Citrus Aurantium sinensis. 

Aurant. Cort. Ind., B.P. 

Aq. Aur. Flor., U.S.P.; Aq. Aurant. Flor., B.P.; Orange Flower Water. A 50 per 
cent. U.S.P. (33 per cent. B.P.) dilution of the Stronger Water. 

i sir. Flor. Fort., U.S.P. The saturated aqueous distillate prepared by distilling 
the fresh flowers of Citrus Aurantium amara with water. 

Syr. Aur. Flor., U.S.P.; Syr, Aurant. Flor., B.P.; Syrup of Orange Flowers. Dose, 
2 to 4 c.c., V-2 to i dram. 

*Klixir Aromtitinnn (Elix. Arom.), U.S.P. (Simple Elixir). Syrup containing about 
25 PIT cent, of alcohol and flavored with aromatics (Comp. Spir. Orange). 

Fldcxt. Arom., U.S.P. From Pulv. Arom. Dose, i c.c., 15 minims, U.S.P. 

Pith\ Arom., U.S.P. Cinnamon, Ginger, Cardamon and Myristica. Dose, i 
Gm., 15 gr., U.S.P. 

S\-r. Annual., B.P. Flavored with orange and cinnamon. Dose, 2 to 4 c.c., > to i 
dram, B P. 

Glycyrrhiza (Glycyrrh.), U.S.P.; (Glycyrrh. Rod.), B.P. The dried rhizome and roots 
of Glycyrrhiza glabra typica, Spanish Licorice; or of Glycyrrhiza glabra glandulifera, 
Russian Licorice. Dose, 2 Gm., 30 gr., U.S.P. 

*Elix. Glycyrrh., U.S.P. (Elix. Adjuvans). Fldext. i; Elix. Arom. 7. 

Ext. Glvc'vr'rlt., U.S.P. Commercial Extract of Glycyrrhiza (licorice). 

Ext. Glycyrrh. Pur., U.S.P.; Ext. Glycyrrh., B.P. An evaporated watery, pilular 
extract. 

*Flnidexlractiim Glycyrrhiza (Fldext. Glycyrrh), U.S.P.; Ext. Glycyrrh. Liq., B.P. 
A watery extract of Glycyrrhiza (licorice root), preserved with 25 per cent, of alcohol. 
The U.S.P. contains some ammonia to dissolve the sweet glucosid, Glycyrrhizin. This 
is precipitated by acids, which are therefore Incompatible. It is miscible with water or 
alcohol. Mixed in the proportion of i : 7 with syrup or elixir, it is a good vehicle for 
quinin etc. Dose, 2 c.c., 30 minims, U.S.P.; 2 to 4 c.c., % to i dram, B.P. 

Glycyrrhizin belongs to the saponins, although it does not have the typical formula 
and does not hemolyze (Robert, 1915; he also describes a new chemic test). The bark 
likewise contains resins. Composition: Houseman, 1916. 

*Syr. Glycyrr. Fldext. i; Syrup 7. 

Glycyrrhizin um A-mmoniatum (Glycyrrh. Ammon.), U.S.P. Dark brown or brown- 
ish-red scales, without odor, and having a very sweet taste. Freely sol. in water and 
sol. in ale. Dose, 0.25 Gm., U.S.P. 

*Syr. Tolulanus (Syr. Tolut.), U.S.P.; (Syr. Tolu.), B.P. Prepared from Tolu 
Balsam. Dose, 15 c.c., 4 dram, U.S.P.; 2 to 4 c.c., % to i dram, B.P. 

I'.inillinum, U.S.P.; Vanillin, Methylprotocatechuic aldehyde (C 6 H 3 -OHOCH 3 -COH 
4:3:1). Fine, white, crystalline needles; odor and taste of vanilla. Sol. in water 
(i: 100); freely sol. in ale., glyc. or eth. Dose, 0.03 Gm., % S r -> U.S.P. 

AROMATIC WATERS, SPIRITS AND OILS 

Aromatic Waters. These are miscible with water or alcohol. Their 
dose is ad libitum. 

. ! romatic Spirits. These are used in alcoholic and oily liquids, in the 
proportion of 2 per cent. They are immiscible with water. 

Aromatic Oils. These may be used for flavoring alcoholic or oily 
liquids, in the proportion of 0.2 per cent. However, the spirits are gen- 
erally preferred. 

Aromatic Tinctures. These are used similarly to the Spirits. None 
of the simple tinctures are especially important. 

Some flavors, such as Gaultheria, etc., have also more important ac- 
tions, and will not be discussed here. 

Aq. Anis., U.S.P., B.P. Anise Water. Dose, 15 c.c., 4 drams, U.S.P. 
Sp. Anis., U.S.P., B.P. 10 per cent. Dose, 2 c.c., 30 minims, U.S.P.; 0.3 to 1.2 
c.c., 5 to 20 minims, B.P. 



COLORING AND FLAVORING 69 

Ol. Anis., U.S.P., B.P. The volatile oil. Dose, 0.2 c.c., 3 minims, U.S.P.; 0.03 
to 0.18 c.c., % to 3 minims, B.P. 

Anisum (Anis.), U.S. P.; Anis. Friicl., B.P. The dried ripe fruit of Pimpinella 
Anisum. Dose, 0.5 Cm., 8 gr., U.S.P. 

Fceniculum, U.S.P. (Fennel seed). The dried, ripe fruits of cultivated varieties of 
Foeniculum vulgare. Dose, i Gm., 15 gr., U.S.P. 

Aq. Fcenic., U.S.P., B.P. Fennel Water. Dose, 15 c.c., 4 drams, U.S.P. 

01. Fcenic., U.S.P. The volatile oil. Dose, 0.2 c.c., 3 minims, U.S.P. 

Aq. Aneth., B.P. Dill Water. 

01. Aneth., B.P. Volatile oil. Dose, 0.03 to 0.18 c.c., % to 3 minims, B.P. 

Anethi fructus, B.P. Dill Fruit. From Peucedanum graveolens. 

Aq. Carui, B.P. Caraway Water. 

01. Cari, U.S.P.; Ol. Carui, B.P. Volatile oil. Dose, 0.2 c.c., 3 minims, U.S.P.; 
0.03 to 0.18 c.c., ^ to 3 minims, B.P. 

Carum, U.S.P.; Carui Fruct., B.P. The dried fruits of Carum Carvi. Dose, 

1 Gm., 15 gr., U.S.P. 

01. Ajowan, B.P. Volatile oil of fruit of Carum copticum. Dose, 0.03 to 0.18 c.c., 
% to 3 minims, B.P. 

Cinnamomum Zeylanicum, U.S.P.; Cinnam. CorL, B. P.; /-Ceylon Cinnamon. The 
dried bark of cultivated trees of Cinnamomum zeylanicum. Dose, 0.25 Gm., 4 gr., 
U.S.P. 

*Aqua Cinnamomi (Aq. Cinnamom.), U.S.P., B.P. Cinnamon Water. Dose, 
15 c.c., 4 drams, U.S.P. 

01 Cassia, U.S.P., 01. Cinnam., B.P. A yellowish or brown volatile oil distilled 
from the bark of Cinnamomum Cassia, U.S.P.; zeylanicum, B.P. Dose, 0.2 c.c., 3 
minims, U.S.P.; 0.03 to 0.18 c.c., % to 3 minims, B.P. 

Pulv. Cinnam. Co., B.P. (Pulvis Aromaticus). Equal parts of Cinnamon, Cardamon 
and Ginger. Dose, 0.6 to 4 Gm., 10 to 60 gr., B.P. 

Sp. Cinnam., U.S.P., B.P. 10 per cent, of oil. Dose, 2 c.c., 30 minims, U.S.P.; 
0.3 to 1.2 c.c., 5 to 20 minims, B.P. 

Tr. Cinnam., U.S. P., B.P. 20 per cent, of the bark. Dose, 2 c.c., 30 minims, U.S.P. ; 

2 to 4 c.c., % to i dram, B.P. 

Cinnamomum Saigonicum, U.S.P. The bark of an undetermined species of Cinna- 
momum. Dose, 0.25 Gm., 4 gr., U.S.P. 

Oliveri Cort., B.P. The bark of Cinnam. Oliveri. 

Tr. Oliver. CorL, B.P. 10 per cent. Dose, 2 to 4 c.c., ^ to i dram, B.P. 

*Aqua Mentha Piperitce (Aq. Menth. Pip.), U.S.P., B.P. Peppermint Water. 
Dose, 15 c.c., 4 drams, U.S.P. 

Aqua Menthce Viridis (Aq. Menth. Vir.), U.S.P., B.P. Spearmint Water. Dose, 
15 c.c., 4 drams, U.S.P. 

Sassafras, U.S.P. The bark of the root of Sassafras variifolium. Dose, 10 Gm., 
2% drams, U.S.P. 

Oleum Sassafras (Ol. Sassaf.), U.S.P. A yellow or reddish yellow volatile oil 
distilled from Sassafras root. Dose, 0.2 c.c., 3 minims, U.S.P. 

*Aqua Rosce (Aq. Ros.), U.S.P., B.P.; Rose Water. A 50 per cent, dilution (33 
per cent., B.P.) of Stronger Rose Water. 

Aqua Rosa Fortior, U.S.P. Prepared by distilling the fresh flowers of Rosa cen- 
tifolia with water. 

01. Ros., B.P. (Otto of Rose). The volatile oil of the fresh flowers of Rosa damascena. 

01. Graminis Citrati, B.P. Oil of Lemon Grass. Dose, 0.03 to 0.18 c.c., ^ to 3 
minims, B.P. 

01. Coriandri (Ol. Coriand.), U.S.P., B.P. Volatile oil. Dose, 0.2 c.c., 3 minims, 
U.S.P.; 0.03 to 0.18 c.c., % to 3 minims, B.P. 

Coriandrum, U.S.P.; Coriand. Fruct., B.P.; Coriander. The dried ripe fruit of 
Coriandrum sativum. Dose, 0.5 Gm., 8 gr., U.S.P. 

*Tinctura Cardamomi Composita (Tr. Cardam. Co.), U.S.P., B.P. 2 per cent, of 
Cardamom, with Cinnamon, Caraway and Cochineal, in 50 per cent, alcohol, U.S.P. 
Dose, 4 c.c., i dram, U.S.P.; 2 to 4 c.c., % to i dram, B.P. 

Tr. Card., U.S.P. 15 per cent, in 50 per cent, alcohol. Dose, 2 c.c., 30 minims, 
U.S.P. 

Cardamomi Semen, U.S.P., B.P.; Cardamom Seed. The dried seeds of Elettaria 
Cardamomum. Dose, i Gm., 15 gr., U.S.P. 

Tr. Lavand. Co., U.S.P., B.P. (Compound Spirit of Lavender). Lavender, Rose- 
mary, Cinnamon, Clove, Myristica, Red Saunders, in 75 per cent. Alcohol, U.S.P. 
Dose, 2 c.c., 30 minims, U.S.P.; 2 to 4 c.c., % to i dram, B.P. 



JQ MANUAL OF PHARMACOLOGY 

Spir. Lavand., 5 per cent, of oil, U.S. P.; 10 per cent., B.P. Dose, 2 c.c., 3 minims, 
U.S.P.; 0.3 to 1.2 c.c., 5 to 20 minims, H.P. 

S.!'.. K.I'. A volatile oil distilled from the fresh flowering tops of 
i. A'.sr, 0.2 c.c., 3 minims, U.S. P.; 0.03 to 0.18 c.c., l -> to 3 minims, B.P. 

ERIODICTYON (YERBA SANTA) 

The leaves of this plant disguise bitter taste (not sweet, salt or acid taste). It is, 
however, therapeutically objectionable. It probably renders alkaloids insoluble, and 
as for ordinary bitters, it is extremely probable that the therapeutic action is connected 
with the bitter taste. One c.c. of the fluidextract covers the taste of 0.012 Gm. of 
quinin sulphate or 1.5 Gm. of quassia. 

Similar properties are found in the following plants: Gymnema sylvestre; Bulme- 
nia dulcifica, and Phrynium Danielli. Gymnema contains gymnemic acid, which 
destroys bitter and sweet taste, not acid or salt. 

PREPARATIONS 

Kriodictyon, U.S. P. (Yerba Santa). The dried leaves of Eriodictyon californicum 
(Composition, Tutin, 1910). Dose, i Gm., 15 gr., U.S. P. 

Fldext. Eriodict., U.S. P. Dose, i c.c., 15 minims, U.S. P.; precipitated by water. 



THE TREATMENT OF DISEASE 

Development of Therapeutics. If we cast a glance at the history of therapeutics, 
the treatment of disease, we are met with some very singular facts. Some of these will 
serve to explain errors which have long adhered and which still adhere to the subject. 

We may imagine one of our remotest ancestors brought face to face with disease. 
How mysterious must have seemed to him the phenomenon that to-day he is strong, 
active, and full of life, and to-morrow, without any cause apparent to him, he is weak, 
listless, and about to die! What strong hold it must have taken upon his untutored 
imagination! How earnestly he must have sought for means to remedy it! Here he 
happened at once upon two apparently very different methods: a spiritual and a 
material. On the one hand, overpowered by the mysteriousness of the process, he lost 
himself in superstition. He deemed the disease due to malevolent spirits which could 
be appeased by prayers and incantations. This formed the principal materia medica of 
prehistoric ages, as it does of the modern savage. It still survives in a modified form 
in "Christian Science." 

On the other hand, chance and the observation of animals revealed to him that certain 
material products were also efficient. As long as he limited himself to actual observa- 
tion, the results were usually good. However, he soon began to search for more of these 
remedial agents. In this search we must remember the total ignorance which then 
.existed regarding the nature of the action both of the disease and remedy. In this 
darkness he was only too glad to be guided by any ray of light, without having the means 
to examine whether the light came from a beacon or was only an ignis fatuus. With 
the fantastic, half logical incongruity so characteristic of the untutored mind he as- 
sumed the most extraordinary relations. 

It is interesting to observe a little closer the principles which guided the blind savage 
in his search for remedies. Having found that most active medicines had a bitter or 
disagreeable taste, he came to regard any such substance as beneficial. Thus arose a 
host of simples which are now stowed away to molder in the attic of science, and which 
might well be disregarded were it not that some zealot occasionally disturbs their well- 
rqxr. ;ind attempts to launch them as something new. 

Xor did this love of the disgusting die out with the stone age. It was prolonged 
far into the middle ages. To it we can probably trace the employment of feces and 
urine, of smoked snake, and of others still worse. 

At a later period of the middle ages it was tried to combine the spiritual and the 
material treatment. It was thought that the Deity alone could cure disease, but that 
He had given man material remedies, and in His wisdom He had put a seal upon them 
by which man might know them. Thus arose in due time what is called the doctrine 
lures." According to this, the use of a remedy was suggested by a fanciful 
resemblance in shape or color to some organ; e.g., the liverwort, the lungwort, bloodroot, 



THE TREATMENT OF DISEASE 71 

etc. These are survivals of this custom. Even a name was sufficient. Silver was used 
in lunacy because it was dedicated to Luna. 1 

On the other hand, alchemists had arisen with their pertinacious search for the 
philosopher's stone, which was to convert all metals into gold, and cure all diseases. 
In this search they gave their nostra extensive trial on sick and well. 

The school of spagirists was founded toward the end of the fourteenth century and 
reached its zenith of power with Paracelsus. They insisted upon the mystical virtues 
of antimony, arsenic and silver and chemicals in general, and stood opposed to the 
old Galenists, who used only organic drugs. Notwithstanding their mysticism, 
which savors of quackery, we must thank them for the discovery of some of our most 
valuable medicines. 

Thus, a mass of materials, rubbish and otherwise, was added to the various simples, 
etc. Having so well-stocked an armory, the physician of that day felt that he was not 
doing his duty unless he gave his patient the benefit of it all, and the "shot-gun" 
prescription flourished at its best. 

The Homeopathic Doctrine. A natural reaction against this excessive drugging set 
in, and had for one of its first results the establishment of homeopathy by Hahnemann, 
near the end of the eighteenth century. The Hahnemann system was by no means new. 
For the most part it had its roots much further back. It was the natural result of the 
then existing theory of "vitalism." 

Hahnemann believed that disease depends upon a perversion of the purely spiritual 
vital powers and is entirely immaterial in its nature. Logically, a thing spiritual could 
not be combated by material remedies, and, hence, Hahnemann turned to a spiritual 
power which he believed to be bound up in plants and liberated by dilution. The 
activity would therefore increase with the dilution, and be the greater, the smaller the 
dose (doctrine of potency). This liberation of the principles exactly turned their action 
around, so that the action of his dilutions was, he stated, exactly the opposite of that 
of the concentrated drug, and could be used for the relief of such symptoms as the latter 
produced: Similia similibus curantur. This was the first tenet of Hahnemann. The 
second was that the nature of the disease being unseizable, it was not subject to treat- 
ment, but that only its symptoms can be treated. Hence, homeopathy, in so far as 
it follows the principles of its founder, has no place for the medical sciences, such as 
physiology, anatomy, pathology, or chemistry. Any one with an indexed book of 
symptoms and their remedies would be able to practice it without an elaborate study 
or preparation. ' 

In marked contrast to the above is the third dictum: that the medicinal treatment 
must be supported by dietetic and hygienic measures. 

The claims of homeopathy as a rational system hinge on the proof of the similia 
similibus theory and of the doctrine of potentiation by dilution. Most of its advocates 
seem to deny altogether the relevance of scientific testimony, and to base themselves 
purely on the slippery ground of empirical experience. Others, however, whilst they 
carefully neglect the great body of scientific experience which disproves their theory, 
seem very glad to avail themselves of the few experimental facts, which, through a 
variety of logical contortions and sophistications, can be twisted into a specious support. 
Hahnemann himself seems to have started from the observation that large doses of 
drugs produce the opposite effects from moderate doses. The correctness of this principle 
may be granted, -for most cases. But it is a very unwarranted feat of logic to assume 
that infinitesimal doses must again cause effects opposite to those of moderate dosesl 

The more recent discovery of the effect of dilution on electrolytic dissociation, on 
ionization, has also been seized upon as illustrating homeopathy quite disregarding 
the fact that the action depends on the number of ions rather than on the degree of 
ionization; and the further fact, that the majority of the substances employed in 
homeopathy are not electrolytes at all! These few examples of inconsistencies may 
suffice. 

Hahnemann's system was the natural outgrowth of his time. At 
present it is an anachronism, as his pupils are the first to acknowledge in 
practice, if not in words. But in his time Hahnemann accomplished con- 
siderable for medical science. He called attention to the importance of 
diet, etc., when this was only too much neglected; but perhaps the prin- 
cipal use of homeopathy has been to show to rational medicine the fact 
that disease tends to recovery without any medical interference. 

1 It would appear that the native Chinese materia medica is largely based on the doctrine of 
signatures. 



72 MANUAL OF PHARMACOLOGY 

Therapeutic Nihilism. This was, indeed, the next step which medicine 
took total emancipation from all drugs. This dates from the establish- 
ment of the Vienna school by van Swieten, in 1745. The strongest advo- 
cate of nihilism was Skoda (1805-1881), the founder of the methods of 
percussion and auscultation. Such nihilism was absolutely necessary at 
that time, just as periods of skepticism are necessary in philosophy, and 
mark steps in progress. The accumulated refuse was so great as to bury 
the good. The only way was to empty out the whole and begin anew. 
This was a necessity then, but now consistent nihilism is as obsolete as 
the "Shot-gun" prescription. He who proclaims it, simply proclaims his 
own ignorance and want of critical faculty. 

The Rise of Rational Therapeutics. The reestablishment of thera- 
peutics, founded now upon reason, was thus aided by the very man who 
had attempted to destroy it. For he established physical methods of 
diagnosis, and demonstrated the effects of disease as they had never been 
demonstrated before, making it possible also to demonstrate the effect 
of remedies. 

Then followed the isolation of active principles (led by the discovery 
of morphin in 1817), thus substituting the definite for the indefinite drugs. 
Finally followed animal experimentation, by means of which modern 
pharmacology has developed. 

Services of Pharmacology. This has made possible a much more 
exact knowledge of the action of drugs, without which their employment 
would be a matter of mere chance. It also made available much more 
accurate methods of observation, and furnished standards by which thera- 
peutic trials must be conducted. It" led to the introduction of the great 
number of synthetic drugs, some of great usefulness, because it pointed 
out the directions in which new drugs could be sought with most success. 
It furnished the means of trying their actions and probable usefulness on 
animals, when their use on man would not be justified without these 
preliminary trials. It has also contributed to the development of experi- 
mental pathology, and has thus laid the foundation of experimental thera- 
peutics the experimental investigation of the action of drugs in disease. 

Psychotherapy. Rational therapeutics is now on a firm basis. But, at the 
same time, the mystic has also been further developed, not only in homeopathy, but also 
in the many forms of suggestion. The value of suggestive therapeutics proper cannot 
be denied. It is a strictly scientific method of treatment, and is employed in its milder 
forms by every physician as " the personal influence " and the " faith in doctor and medi- 
cine." It often constitutes all there is of merit in those medical fads which have 
accompanied medical science since the oldest time. 

Vis Medicatrix Naturae. It is most important to the rational treat- 
ment of disease that the physician should understand that he cannot 
directly make a patient well. That is exclusively nature's task. Physi- 
ologic functions tend to run their normal course, or to return to it 
if they have been disturbed. "Nature," therefore, tends very strongly to 
bring the organism back to its normal conditions, or life would long since 
have disappeared from the globe. The task of the physician consists in 
directing his treatment in such a manner as to remove obstacles from 
nature's path. 

Just as the surgeon can not cause the union of a broken bone, but can only put it in 
the most favorable condition for nature to perform this union I.e., set it so the phy- 
sician cannot cure heart disease. He may either remove the condition which causes 
it, if still present, or remove by digitalis, etc., the factors which retard the cure; but in 



THE TREATMENT OF DISEASE 73 

any case he must rely upon nature to perform the last, the really important act: viz., 
the permanent return to normal. 

That nature not only puts the final touch upon every reparative process, but that 
she may take every step as well i.e., that a patient may get well without any medical 
interference is too well known to require further discussion. The ways in which these 
processes of repair take place constitute one of the departments of pathology and 
medicine. 

The Field of Therapeutics. In the light of the above, it might well be asked: If 
nature is thus able to effect cures; if the greater number of diseases tend to spontaneous 
recovery, what is the function of the physician? Can he do anything but harm if he 
attempts to meddle with the processes of nature? If he undertakes to aid, does he 
not really meddle? We must, in examining this question, lay the emphasis in the 
above sentence on "nature tends to effect a spontaneous cure." But nature is essentially 
blind in her workings. She works by general laws, which often do not take account of 
individual cases. Though we must recognize that her processes are generally in the 
right direction, they may be greatly at fault quantitatively. Nature may do too much 
or too little. It is now conceded that fever, pain, inflammation, etc., are protective 
mechanisms; but when the fever becomes so high as to be in itself dangerous to life; when 
the pain is intolerable and constant, and persists after it is no longer needed; when 
inflammation spreads; then it is evident that the originally salutary process is becoming 
the reverse. That the processes of nature are often insufficient is evident from the fact 
that they do not in all cases effect a cure. Nature may sometimes be absolutely wrong; 
e.g., in the desire for solid food in typhoid. 

It is, then, the duty of the physician judiciously to modify the natural tendency, 
if he possesses the means of doing so. But he must do so wisely, or it were better not 
at all. He must understand the diseased condition; he must understand nature's way 
of meeting the difficulty; he must judge in what ways nature may be supported; and, 
finally, he must thoroughly understand the means at his command for the purpose 
i.e., pharmacology. As long as he is not clear in regard to these factors, he is merely 
groping in the dark, as likely at least to do harm as good. In this case expectant treat- 
ment is alone justifiable. 1 

We see how from the above we can deduce a number of methods 
of treatment. 

Preventive or Prophylactic Treatment. This aims to protect the body 
from disease. It comprises individual and community hygiene. 

Etiologic, Causal or Curative Treatment. The cure of disease is 
scarcely possible while the original cause persists. The physician must 
therefore always aim to discover and remove that cause. If this can be 
done, the conditions will generally return to the healthy normal unless 
anatomic lesions have already occurred. The chances for complete recov- 
ery are therefore the better, the earlier effective treatment is instituted. 
However, even considerable anatomic deficiencies can be compensated 
by the fact that the organism has large "factors of safety" (Meltzer). 

Symptomatic, Functional or Alleviative Treatment. When the cause 
of the diseased condition can not be attacked, it is often possible to remove 
its functional manifestation or symptoms. This may be useful in some 
cases, objectionable in others. 

In striking the symptoms one very often also strikes the disease. The symptoms 
in themselves may be so objectionable or lead to such secondary results as to make their 
removal desirable. Pain, cough, and fever are all purely symptoms, and yet no one 
would refuse to treat them simply because unable to remove the root of the disorder. 
The derangement of function may be immediately threatening to life, /.?'., cardiac 
dilation; or it may add to the tax on the diseased organs, f.i., the edemas of valvular 
disease. The faulty functionation may also be relieved by increasing other compensat- 
ing functions, /./., diaphoresis in renal disease. 

On the other hand, the symptoms may be very deceptive a chill will not require 
external heat; a referred pain will not be relieved by local application of iodin to the 
place where it is felt. In removing the symptoms the physician also deprives himself 
of the only index to the treatment of the underlying disorder. He must constantly 

1 In this connection see S. J. Meltzer's essay on the Therapeutics of Self-Repair; Am. J. Med. 
Sc., July, 1908. 



74 MANUAL OF PHARMACOLOGY 

be on his guard against believing himself successful when he has succeeded in removing 
one or several of the symptoms of the disease. In many cases the symptom may itself 
iutary; in which case it would not do to remove it (e.g., cough when there is hyper- 
mucus; a certain amount of pain when rest is indicated in fracture), 
.ircely be added that it is not ethical to persuade a patient that he is being 
cured when he is in fact only being relieved of the symptoms. 

Restorative or Roborant (Strengthening or Tonic) Treatment 
Disease generally impairs the vitality and resistance of the organs directly 
involved, and of the body at large. This is corrected by rest and efficient 
nutrition of the diseased organs and of the entire patient; and by correcting 
any other abnormal conditions (digestive disturbances, suppurations, 
t.-u.) which may be present, and which are added drains on the vitality 
of the patient. 

Expectant Treatment. This is the absence of any real attempt 
at treatment beyond hygiene, rest, diet, and other similar general 
measures; with the object of leaving the powers of nature frSe play. This 
should be employed in all cases where no better treatment is known; 
but, as has been said, it is usually within the province and power of the 
physician to support nature in her endeavor. 

The expectant treatment must also be used when it is desired to let 
the disease progress to a certain point, if this is necessary for diagnosis. 

Empiric and Rational Therapeutics. The treatment of disease has 
developed by two different methods, or perhaps more accurately, attitudes 
of mind. The Empiric method follows merely the dictates of experience, 
without concerning itself about the reasons of these. 

It is typified by the patent medicine slogan; "it has cured others and will cure you." 
While in the present state of our science it is still necessary to employ it only too 
often, it requires scarcely a thought to see how of ten it may be not only useless, but even 
injurious. Conditions which resemble each other very closely superficially may really 
be diametrically opposite, and may require very different treatment. The objection 
to the empiric method is not that it rests upon experience, which is the basis of all 
science, but that it does not endeavor sufficiently to distinguish whether the experience 
is real or deceptive. It is, of course, an equally grave error to go to the opposite ex- 
treme, and to base treatment on theories and deductions inadequately supported by 
observation. 

Rational or scientific therapeutics should employ observation, experi- 
ment and scientific reasoning, checking each against the others. 

A real science of therapeutics, by which it would be possible to foretell the exact 
results is still largely a vision. The numerous physiologic and pathologic variables 
render predictions uncertain. The personal factor plays a large role; and the due 
appreciation of this "the art of therapeutics" is therefore very important. How- 
ever, the best results can only be secured by the critical application of all the known 
scientific facts. 

Pharmacal and Non-pharmacal Therapeutics. A distinction is some- 
times made between "drugs" and "physiological agents"; including under 
the latter physical measures, such as heat or cold, bathing or climate, 
rest, exercise and massage, diet, etc. The distinction is convenient, 
but not fundamental. The use of drugs is no more "unphysiological" 
than the use of abnormal heat or cold, or of special diets, etc. The me- 
chanisms of their action are not essentially dissimilar. Each is in- 
tended to produce definite changes of functions. One or the other 
may be better adapted to secure this end; and the physician should not 
hesitate to employ whichever is best suited. 

Physiologic Processes Normally Controlled by Pharmacologic Agents. The body 
normally produces a variety of pharmacologically active substances, as direct or by- 



CHEMICAL AND PHYSICAL BASIS OF PHARMACOLOGY 75 

products of its metabolism, and uses them as aids in regulating its own activity. The 
CO2 control of the respiration and the various other hormones and internal secretions 
are familiar examples in mammalian physiology (Starling, 1908). The use of drugs is 
therefore not an unphysiologic proceeding. 

THE CHEMICAL AND PHYSICAL BASIS OF PHARMACOLOGY 

Scope of Pharmacology. The term Pharmacology in a general sense 
covers all scientific knowledge pertaining to drugs, i.e., to substances 
which may be used in the treatment of disease. Materia Medica, Phar- 
macognosy, and Pharmacographia have the same meaning when they are 
used in a general sense. 

More commonly, however, the term "pharmacology" is used in a more 
restricted sense, as a synonym for pharmacodynamics. It concerns itself 
with the actions of drugs on living structures; or with the reactions occur- 
ring between drugs and living structures. It is therefore in a sense a 
branch of physiology on the one hand, of chemistry on the other; and is 
thus essentially a division of biology. It has important practical relations; 
on the one hand, with toxicology (the science of poisons) ; on the other hand, 
with therapeutics (the treatment of disease). 

The Nature of Pharmacologic Action. The processes of life are essen- 
tially conditioned on chemical and physical changes in the constituents 
of the cells. Foreign chemic substances may enter into these reactions, 
and thus modify them more or less profoundly, with corresponding changes 
of function. These are termed drugs or poisons, according to whether 
they are useful or harmful in a given case. Some of the reactions are 
comparatively simple, analogous to those produced on isolated proteins. 
Others, however, occur only in living substance. Our limited knowledge 
of the chemical details of the living cell does not permit any deep insight 
into the nature of the action of these substances, except in a few directions. 
They suffice to show that the mechanism of the action of different drugs 
is not uniform, but is sometimes along chemical, and sometimes along 
physical lines. No sharp division can be drawn. 

Physico-chemical Conditions of Life. The living cell may be considered as a very 
complex laboratory, where chemic decompositions and syntheses, reductions and oxi- 
dations, etc., are constantly going on. These chemic changes lead to transformations 
of energy which find their final expression in the phenomena of life. The vital mani- 
festations of the cell are, therefore, inseparably connected with physico-chemic trans- 
formations, which require for their occurrence the existence of certain chemic and phys- 
ical conditions. The chemic essentials .are: the presence of substances capable of 
liberating energy, and the conditions suitable for their reactions, such as a proper tem- 
perature, alkalinity, presence of ferments, etc. The physical conditions of life are: 
A viscid medium, containing colloid proteins, salts, fats, and water. 

Ordinary Chemic Reai'intns. In the simplest cases the actions occur on dead tissues, 
and resemble those produced on substances of known composition; this is the case with 
strong acids, alkalies, wetals, etc. 

Obscure Chemic Reactions. In many cases, particularly with alkaloids, glucosids and 
toxins, the action is confined to the living cells; for most of these, no adequate explana- 
tion can be offered. It is very probable that many of these produce chemic changes in 
the protoplasm; but the evidence is suggestive rather than conclusive. 

From the complicated structure of the protein molecules we conclude that it must 
be capable of a very great number of reactions, a conclusion which is confirmed by the 
large number of substances which arc utilized by the cell. We find an expression of 
these chemic changes in the final excretory products of the cell; but we are very ignorant 
of the reactions by which these final changes are produced. When we find, therefore, 
that a chemic substance possesses actions for which there is no adequate physical 
explanation, we presume that it enters into chemic reactions with the protoplasm. 



y6 MANUAL OF PHARMACOLOGY 

This has been expanded especially in the side-chain theory of Ehrlich.^ This assumes that 
the poisons combine with certain groups (receptors) of the cell which are essential for 
it< metabolism. 

Evidences of Chemic Actions. The theory of chemic combination is confirmed by the 
fact that most of the poisons (not all) are altered in the body; although it does not 
follow that the action is due to this particular change. The toxicity is often parallel 
t> tin- chemical reactivity or lability of the poison. Other indications of chemic reac- 
tion are, that these poisons often accumulate in the cells; and that the effects generally 
increase with the dose. This would be expected with chemic reactions, but could also 
occur on physical grounds. In any case, the combination is often very loose and un- 
stable, for the poison can often be removed by simple solvents (f.i., antipyretics and 
fuchsia stain by alcohol, P. Ehrlich). Indeed, the organism recovers promptly from 
most poisons when these are washed out, unless secondary changes have occurred. 
In some cases, the action seems to be produced only whilst the poison is passing into 
or out of the cell (Straub; Kuyer and Wijsenbeck, 1913). /The action is then probably 
on the plasma membrane. The relation between the action and chemic constitution 
of poisons also speaks for chemic reactions, but may in some cases be explained by cor- 
responding alterations of the physical properties. Compounds between alkaloids 
and proteins have been described; but it is not certain whether these are real combina- 
tions, or merely adsorption products (Eddy and Gies, 1907). 

Modifications of Ferments. Catalytic reactions, which are so important to the cell, 
may be modified by chemic reagents, without as well as within the cell. This explains 
the asphyxiant action of cyanids. 

Changes in the Cell Membrane. Since most cells are in contact with surrounding 
fluids, they must be protected against changes of composition by a limited permeability 
of their surface layer, the cell wall or plasma membrane. This apparently contains 
lipoid and protein constituents. It may, therefore, be altered by fat-solvents, or by 
agents which either precipitate or liquefy proteins. This explains, at least partly, the 
effects of lipclytic narcotics; hemolysis by these, by alkalies and saponins; the actions of 
various ions, especially Ca, etc. 

Osmotic Changes. Cells are generally much more permeable to water than to 
dissolved substances. This leads to osmotic phenomena the withdrawal or absorption 
of water when the cells come into contact with solutions of higher or lower salt con- 
centration. This explains the actions of many otherwise nearly indifferent salts, e.g., 
saline catharsis and diuresis. 

Surface Forces. The physical structure of protoplasm is such as to present large 
surfaces, and therefore gives peculiar opportunity for the development of the surface 
forces, which are very important for various vital functions. These are greatly modi- 
fied by a variety of substances, including the lipoid solvents, salts, etc. 

Colloid Phenomena. Many chemical and physical conditions depend on the colloid 
character of protoplasm. The state of aggregation of colloids, and hence their reactions, 
are easily modified, especially by salts, acting both by their chemic properties and elec- 
tric charges. This is another important element in salt-action. 

Dependence of the Pharmacologic Action on the Chemic Constitution. 

As a general rule, drugs having a similar constitution, possess similar 
actions; and definite changes in the molecule as in homologous series, 
or the introduction of new groups often produce definite modifications 
in the pharmacologic effects. This should be expected, since the physical 
as well as chemical properties change with the constitution. This relation 
has a wide general application; but its application to details has been dis- 
appointing, because we have not sufficient knowledge of the chemic con- 
stitution and reactions to take account of the numerous variables. 

It must be remembered, for instance, that the action is not so much determined by 
the elementary composition of the substance, but rather by the manner in which the 
elements are combined. Isomeric compounds have often very different actions. 
Apparent exceptions result also from the different penetrability of cells to substances 
which, could they be introduced into the cell, would cause similar effects. Other mani- 
festations of selective action also come into play. 

Attempts to construct a general theory of pharmacologic action on chemical lines 
have merely shown that this is impossible. The data which we possess had therefore 
to be gathered empirically without much guidance. 



CHEMICAL AND PHYSICAL BASIS OF PHARMACOLOGY 77 

The Importance of the Chemic Radicals or "Side-chains." A sub- 
stance, to produce chemical pharmacologic actions, must be capable of 
combining with protoplasm and then of altering its properties. These 
two functions -combination and action (analogous to amboceptor and 
complement, P. Ehrlich) may be united in the same group; but more 
commonly they are distinct ("haptophore" and "toxiphore" groups), so 
that one may be modified without the other. Often several groups are 
present which may enter different combinations under different condi- 
tions. It is evident that these may introduce great variations in the 
actions. 

Morphin, f.i., produces its hypnotic action by "anchoring" or combining with its 
phenyl-hydroxyl. When this group is closed, f.i., by the methyl radical, as in codein, 
it anchors in a different way, to different cells; and the convulsant action becomes more 
prominent. The introduction of acid radicals into the amido-group renders this more 
stable and less toxic; but the same acid radicals when introduced in the OH group 
(f.i., as in heroin) increases the toxicity, by providing a new combining group. In 
these cases, the new groups act only by altering the combining properties of the active 
group. In other cases, the new group may itself be active. 

The Construction of Synthetic Compounds. The recognition of these 
laws of the modifications produced by the different radicals is of practical 
importance. It permits the prediction, with considerable probability, 
of the effects of new drugs; and it points the way to modifications 
which will emphasize desirable quantities and eliminate those which are 
undesirable. This has lead to the introduction and improvement of 
many new remedies. Really new properties can not, of course, be predicted 
by known properties. Their discovery is generally accidental. Accord- 
ingly, synthetic chemistry has introduced relatively few new principles, 
but endless modifications; some useful in the ways indicated; many 
others needless and detrimental. It is very easy to introduce minor 
changes in composition which do not alter the actions of the original 
drug materially, but which are commercially profitable by evading the 
patent and trade mark laws. This needless multiplication is confusing and, 
therefore, undesirable. 

Distribution of Drugs Within the Body. Drugs are not distributed 
uniformly, but accumulate especially in certain cells, according to their 
permeability and physical and chemical affinities. This influences their 
action; either by bringing them in contact with reactive tissues, or by 
storing them in places where they may be inactive. The distribution 
has been studied in relatively few cases, especially for inorganic poisons; 
but the data are not sufficient to permit generalizations. The distribution 
appears to be altered by disease; e.g., degenerating tissue takes up more 
iodid, etc. 

Storage Places. The poisons disappear quite rapidly from the blood, the greater 
part within a few minutes. The chlorids, bromids, and related ions accumulate in all 
organs, but mainly in the skin and blood. The thyroid stores a relatively high per- 
centage of iodin as iodothyrin. The bones retain the earthy metals and fluorid. The 
heavy metals are deposited as loose organic compounds, especially in the liver and spleen; 
mercury as a loose globulin compound; arsenic as a more stable nuclein combination 
(Yamossy, 1905). The iron deposits serve as a reserve stock of this metal. Little is 
known about the distribution of organic posions, mainly for want of suitable assay 
methods. 

Chemic Changes in Drugs. The majority of poisons are more or 

altered in the body, and generally rendered less harmful. This 

is effected by the oxidation, reduction, hydration or dehydration, or other 



MANUAL OF PHARMACOLOGY 

decomposition of the poison, or by the storage of the poison in certain 
organs, or by its combination with other substances which render it harm- 
le->. This process of disintoxication is of great practical importance. 
It makes it necessary to administer the drugs continuously, in order to 
maintain their effect; it often requires the use of continuously increasing 
doses as the power of disintoxication becomes more developed; and were 
it not for the power of the body to destroy or remove poisons, and thereby 
to recover from their action, all therapeutic use of drugs would be 
impossible. 

Decomposition by Digestion. The digestive juices destroy many organic poisons 
by hydrolytic cleavage; especially the proteins, toxins and antitoxins, and the glu- 
cosids. On the other hand, they are necessary to saponify and liberate the active con- 
stituents of insoluble esters, e.g., phenyl salicylate. The acidity of the gastric juice 
is important for the solution of bases. It also often splits off acyl groups. 

Decomposition in Tissues. Strychnin and many other poisons are partly oxidized 
in the body, and the toxic effect is, therefore, reduced if the poisoned animal is placed in 
an atmosphere of oxygen. Morphin is largely destroyed, especially by those accustomed 
to its use. Reid Hunt (1905) has shown that feeding with thyroid markedly diminished 
the toxicity of acetonitril, by preventing its conversion into cyanid. The resistance to 
morphin is also modified. It has been claimed that excision of the thyroids increases 
the toxicity of a number of other poisons; but Lerda and Diez, 1905, obtained negative 
results with caffein, strychnin, urine, and tetanus and diphtheria toxin. Organic com- 
pounds of metals (cacodyl, etc.) only develop the metal action after oxidation. Many 
organic acids (citric, etc.), alcohol and formaldehyd, are oxidized, and thus disintoxi- 
cated. Hexamethylenamin is activated by the liberation of formaldehyd in acid urines. 
The benzol ring is very resistant, most of the changes occurring in the side-chains. 

Disintoxication by the Liver. This is believed to be especially active in disintoxi- 
cation, partly by destroying, but particularly by storing poisons, so that the same dose 
is much less effective (perhaps one-half) when given by the mesenteric, than by the 
jugular vein. This has been demonstrated for curare, strychnin, morphin, cocain, 
veratrin, quinin, atropin, and the metals. Perfusion of alkaloids, glucosids, toxins, 
barium, etc., through excised liver, also decreases their toxicity (Woronzow, 1912). 
Liver emulsions seem to be less active. They did not destroy strychnin, but attacked 
caffein (Petron, 1905). Experiments with Eck's fistula gave rather negative results 
(Rothberger and Winterberg, 1905). 

Other Organs. Perfusion through excised muscle also produced disintoxication, but 
weaker than the liver, with chloral, atropin, physostigmin, curare and alcohol, not with 
muscarin and ricin (Woronzow, 1912). Excision of the spleen is said to increase the 
toxicity of most alkaloids, but not all. The phagocytes accumulate and thus disin- 
toxicate poisons, especially colloids. The serum of atropin-resistant animals destroys 
atropin. 

Disintoxication by Combination. Phenols and other aromatic compounds are ren- 
dered less toxic by combining with sulphates; many metals by the proteins; toxins by 
antitoxins; acids by alkalies; aldehydes, camphor, chloral and ethereal oils by glycu- 
ronic acid; cyanids by sulphur; benzoic and salicylic acid by glycocoll; etc. The extent 
of the disintoxication will depend upon the activity of the metabolic processes which are 
concerned, or on the amount of neutralizing substance present in the body. 

Quantitative Relation of Concentration and Action. The ratio is generally not in 
simple proportion. There is usually a "minimal threshold," all concentrations below 
this being apparently ineffective. At the other extreme, once the "maximal response" 
has been reached, further increase of concentration can produce no further effect. Be- 
tween these points, every increase of concentration increases the action; the increment 
being the greater the lower the original concentration. For instance, when the con- 
centration of ouabain was doubled from 0.00125 to 0.0025, the action was increased 4.6 
times; when the concentration was doubled from 0.005 to - 01 ) the action increased only 
1.28 times (Sollmann, Mendenhall and Stingel, 1915; the paper also discusses the reasons 
for the phenomenon). 

THE MANIFESTATIONS OF PHARMACOLOGIC ACTIONS 

Modifications of Functions. Since protoplasm is essentially identical 
in all cells, the action of pharmacologic agents must also be essentially the 



MANIFESTATIONS OF PHARMACOLOGIC ACTIONS 79 

same in all situations; but just as quantitative differences exist in the cell, 
so does the pharmacologic action show quantitative differences and selec- 
tive properties. Of these we shall have more to say presently. As a 
general rule, the most conspicuous changes occur in the most conspicuous 
function of the cell partly because these are the most readily appreciated, 
but partly also because specialized functions are the most complex and 
hence the most sensitive. 

Pharmacologic agents can in no case create new functions in a cell or 
tissue; they can only modify existing functions, or at most make evident 
functions which have previously been latent. The functions of a cell may 
be increased or diminished, resulting in stimulation or depression. Since 
there are also structures the stimulation of which would lead to an inhibi- 
tion of other structures, an actual increase of function is sometimes dis- 
tinguished as an excitation. A very violent stimulation passes usually 
into injury; such injurious stimulation is called irritation. Moderate, but 
prolonged, stimulation also passes into depression, either by the disap- 
pearance of food substances (exhaustion), or by actual injury to the struc- 
ture (fatigue). If the depression is so great that the given function has 
disappeared, the condition is called paralysis; if all the functions are 
abolished, there is death. 

The greater number of pharmacologic agents produce at first a stimu- 
lation, which is followed in larger doses by a depression. In this respect 
the differences between the different poisons are again mainly quantitative. 

The so-called "stimulants" produce a very strong and prolonged 
stimulation, the depression being produced only by relatively large doses. 
The "depressants," on the other hand, cause only a slight stimulation, 
which passes readily into depression. Indeed, with some depressants, no 
stimulation whatever exists. It is very rare that a depression precedes 
a stimulation; when this occurs, the action is presumably on different 
structures. 

Selective Action. The actions of drugs are generally much greater on 
some tissues than on others; i.e., they are selective. The difference may 
be almost or quite absolute, so that the drug acts specifically on one class of 
cells. This "monotrop" action is especially important in parasiticides, 
and is the ideal of modern " chemo-therapy" the treatment of infections 
by chemic agents. Antibodies also illustrate a strictly monotropic selec- 
tive action. With most drugs the differences are merely quantitative or 
relative; a number of structures being affected with various degrees of 
predilection, which may sometimes shift with changing conditions. The 
actions on the central and peripheral nervous systems generally belong 
to this relative type. 

Mechanisms of Selective Actions. These may consist in differences of 
penetration; of the chemic affinities of the cell; or of sensitiveness of the 
functions. The details are known only in a few cases. 

Selective Absorption. A drug may act upon a cell without actually 
penetrating into it; for instance, by exciting the nerves supplying the cell, 
or more directly, by withdrawing water from the protoplasm; but as a 
general rule, the poison must be absorbed into the cell or cell-membrane, 
before it can produce any action. In order that this absorption may take 
place, the drug must be soluble in the cell contents, and particularly in 
the cell envelope. The solubility of a substance in protoplasm is not nec- 
essarily the same as in water. Indeed, it varies for each kind of cell, 



80 MANUAL OF PHARMACOLOGY 

and consequently the penetrability of different cells for a given substance 
may vary greatly. 

Whilst the renal cells, for instance, are very permeable for sulphates, the intestinal 
cells are but slightly permeable. It is in virtue of this peculiarity that cells are capable 
of preserving their own composition, notwithstanding considerable changes in the fluids 
in which they are bathed. This fact also explains why a given substance acts much 
more <tn>ngly upon one cell than upon another. 

These differences are illustrated strikingly by the distribution of dyes in living and 
dead tissues; or indeed, in unorganized materials. Their behavior has been extensively 
studied, but as yet without leading to secure general conclusions. 

The differences in absorption may be due partly to the cell envelope, partly to the 
cell contents. Lipoid solvents generally penetrate better than other agents, because 
of their affinity for the lipoid constituents of the cell membrane. Other agents probably 
form " solid solutions " with some of the cell constituents; others are attracted by chemic 
differences e.g., the basic stains by the acid character of the nuclear chromatin. 
Absorption and surface forces probably play an important part. 

The distribution is often modified by conditions reaction, oxygen, the presence 
of a second substance, etc. Important differences arise also in diseased conditions, 
e.g., iodids are taken up in higher concentration by degenerating tissues. 

Effect of Concentration. The amount of a drug absorbed into a cell 
varies generally with the concentration of the drug in the surrounding fluid 
This concentration is greatest at the place where the poison enters and 
leaves the body, i.e., in the alimentary canal, liver, and kidneys. Differ- 
ences of blood supply also come into play. The influence of concentration 
is most readily seen with locally acting drugs. 

Chemic Differences. The various cells differ in their chemic proper- 
ties, and therefore in their reactions. This is seen most definitely with 
the antibodies, precipitins, cytolysins, antitoxins, etc., which are supposed 
to fit especially into certain cells, "as a key is fitted to a special lock." 
Something of the same kind doubtless applies at least to some of the ordi- 
nary poisons, which can unite only to certain side-chains or certain con- 
stituents; but little is known of the details. Similar combining properties 
may make a poison innocuous to certain cells, by leading to its destruction, 
or binding it into a harmless form. On the other hand, the decomposition 
may serve to liberate or form an active substance /.., formaldehyd from 
hexamethylenamin in acid urines. 

Functional Differences. The cause of selective action lies often in the 
cells themselves, the more delicate functions being damaged more readily. 
Hence a poison which acts indifferently on all tissues produces always the 
most conspicuous effect on the central nervous system. 

The sensory nerve fibers are uniformly more sensitive than the motor fibers. The 
heart of the king-crab limulus furnishes a good illustration. Its structures fail in the 
same order (ganglion, motor nerve-plexus, muscle) in respect to all kinds of injurious 
agencies, alkaloids, anesthetics and other drugs; heat and cold, etc. (Meek, 1908). 

Certain cells also accommodate themselves more readily to altered conditions. 

CLASSIFICATION OF DRUGS ACCORDING TO SELECTIVE ACTION 

Poisons which alter all tissues, and which therefore produce effects at 
the place where they are applied, are termed "locally-acting'' 1 drugs. 
They may produce similar chemic changes in dead tissues. These usually 
cause inflammation when applied to living tissues, and are then called 
irritants (including simple irritants, corrosives, and astringents). Others 
lessen inflammation mechanically (emollients and demulcents). 

Others act chemically on all living structures, without changing dead 
tissues; these are termed "protoplasmic poisons." 



MANIFESTATIONS OF PHARMACOLOGIC ACTIONS 8 1 

Poisons which act selectively on a few structures are called "muscle- 
nerve poisons." They may affect end-organs (sensory endings, gland cells, 
or striped, smooth or cardiac muscle); or the nerve-endings; or ganglia; or 
any part of the central nervous system. 

Nerve trunks are so resistant that they are only affected when the poison is applied 
to them directly. The access of drugs to them is restricted, in intact animals, by their 
limited blood supply. The nerve fibers are also protected by the slight permeability 
of their sheath. 

Pharmacologic Groups. Various systems of classifying nerve-poisons 
have been devised. None is really satisfactory, because most drugs pro- 
duce several effects which, by their interaction, complicate the subject so 
that no simple system will apply. With some drugs, however, one phar- 
macologic, chemic or physical feature predominates so greatly that they 
can be separated as fairly distinct groups. However, this is more or less 
arbitrary and artificial. 

Variations in Symptoms. The selective action of drugs is rarely absolute; even 
strychnin, a highly selective poison, acts as a general protoplasmic poison when it is 
directly applied in sufficient concentration. However, some one action often predomi- 
nates so greatly over the others, that it may be considered as characteristic for the drug. 
Even in this case, the poison as a rule acts selectively on several structures. This 
accounts for the great variability which is often seen in the action of the same drug 
under different conditions. Thus, atropin stimulates the vagus center, but paralyzes 
the endings: it may therefore cause either a quickening or a slowing of the pulse. 
Again, through the opposed action of small and large doses, strychnin, e.g., may cause 
either a stimulation or a paralysis of the vasomotor center. Another frequent cause 
of variable actions lies in the indirect actions of a drug. A drug which causes con- 
vulsions will thereby tend to stimulate the vasomotor center, although its direct action 
on this center may be depressant. 

These variable actions and interactions make the effects of many 
poisons appear very complicated, although they prove quite simple on 
analysis. This analysis is very important for a proper understanding of 
the action, but it is still more important to remember the complex effects 
which result, for it is with these that the practicing physician has to deal. 

Often the pharmacologic action in this sense is not the therapeutic action. A very 
important pharmacologic action of morphin, for instance, is a stimulation of the spinal 
cord; but no one would think of employing the drug therapeutically for this purpose, 
since this action is entirely overshadowed by its other effects. 

For this reason it would not be a good plan to classify the drugs strictly according to 
their pharmacologic actions. On the other hand, a therapeutic classification, although 
useful in some respects, is not favorable to a study of the underlying actions of the 
drugs, and tends to empiricism. The best principle of classification yet devised is that 
of Buchheim, 1 according to which drugs are grouped according to their principal 
pharmacologic characters, taking account of all the important actions, as well as of the 
chemic properties, 2 and in many cases also of the therapeutic uses of the drugs. This 
is the general plan adopted in this volume. 

Definitions of Pharmacologic Terms. Some rather loosely used 
pharmacologic terms may be defined in this place, in the sense in 
which they are generally employed in this volume: 

Local actions: produced at the place where the drug is applied; Remote 
actions: occurring in distant parts of the body (may be either systemic 
or reflex); Systemic effects (sometimes called general action): produced 

1 Buchheim may be considered the founder of modern pharmacology, by the establishment 
of the first pharmacologic laboratory, at Dorpat in 1856. 

2 Drugs of very different chemic character often appear to have identical actions. Thus the 
action of strychnin resembles that of tetanus toxin, arsenic that of cholera, barium that of digitalis. 
In some cases the action may be supposed to be really identical, but in others the resemblance is 
merely superficial. 

6 



82 MANUAL OF PHARMACOLOGY 

after the absorption of the drug into the circulation; Direct effects (sometimes 
called primary) : produced by the direct action of the drug on the tissue 
concerned; Indirect effects (sometimes called secondary), are not produced 
by the action of the drug on the tissue concerned, but by the intervention 
of some other structures on which the drug acts (e.g., asphyxial convulsions 
are an indirect effect of asphyxiant poisons); Reflex effects are indirect 
actions arising from local irritation; Immediate effects (also sometimes 
called primary) are the effects resulting at once; Late effects are those occur- 
ring later; if they are preceded by other (immediate) actions, they are 
properly called secondary actions. Side actions are actions which are not 
desired in the therapeutic use of the drug. 

Localization of Action. The effects of drugs on patients, or in cases 
of poisoning, are by far too complex to furnish any real insight into the 
actions which are involved. To attain the object of pharmacology 
the explanation of the action of drugs it is indispensable to simplify 
the conditions as much as possible, and to make the functions, which 
are to be studied, accessible to measurement, and if feasible, to graphic 
representation. The methods of experimental physiology are employed 
for this purpose. 

The Study of Isolated Structures. To eliminate the complications 
which arise from a simultaneous action on several structures or from 
indirect actions, the tissues to be studied are generally isolated. The 
most certain method is the actual anatomic isolation of the structure. 
Drugs of known antagonistic actions may also be utilized, but they are 
more apt to lead to erroneous conclusions. 

The anatomic isolation may be accomplished by employing unicellular organisms 
if the action on undifferentiated protoplasm is to be investigated; or by excising the 
tissue (as muscle, etc.) from the body; or by applying the drug to the exposed tissue 
(e.g., to a sympathetic ganglion); or by severing the connection with other tissues which 
might be affected (as by section of a nerve) ; or by restricting the action of a drug to a 
given part, by cutting off the circulation. In some cases it suffices to confine the ob- 
servation to the structure to be studied. 

One or the other method of isolation may be employed, according 
to circumstances; that giving reliable results with the least difficulty of 
technic being naturally preferred. Complete isolation is in many cases 
superfluous. If the question is, for instance, whether an observed 
stimulation is on a central or on a peripheral structure, it suffices to divide 
the nerve: on an efferent chain, this will abolish the effects of a central 
stimulation, whilst those of a peripheral stimulation will persist. With 
an afferent chain the conditions would be reversed. By making sections 
at various levels of the chain, the location of the action may be accurately 
determined. When the structures to be investigated are inaccessible 
to the scalpel, one may substitute drugs which are known to paralyze 
these structures selectively (curare for the endings in striped muscle; 
nicotin for ganglia; atropin for endings of the vagi or sympathetic, etc.). 
The site of a paralysis is similarly located by successive stimulation. 
The stimulation is accomplished by electricity or by appropriate drugs 
(epinephrin for sympathetic endings; muscarin for vagus endings; pilo- 
carpin for glands; barium for smooth muscle, etc.). 

A few examples will make this general method clear: 

i. Strychnin. It is noted that strychnin produces a tetanus. This implies a motor 
stimulation somewhere. The sciatic nerve is cut; it is found that the convulsions 
disappear in the leg but persist in the rest of the body. The action must therefore be 



MANIFESTATIONS OF PHARMACOLOGIC ACTIONS 83 

central. The cerebrum and medulla are successively, excised; the convulsions persist, 
and must, by exclusion, be located in the cord. This is confirmed by destroying the 
cord, which causes the complete disappearance of the tetanus. 

2. Curare. This produces a complete muscular paralysis. Stimulation of the 
sciatic elicits no response. The paralysis must therefore be peripheral. Direct stimu- 
lation of the muscle is effective. This excludes all the possible structures except the 
nerve trunk and endings. The nerve of another preparation is laid into the curare 
solution, and after a time, is stimulated; a contraction results, so that the nerve trunk 
is not paralyzed. The action must therefore be on the endings. 

If a peripheral structure is stimulated or paralyzed, it is impossible 
to decide by this method whether there is not also a central action, 
for the peripheral effects would obscure the central. A stimulation 
of the cord, for instance, could cause no effect if the drug had paralyzed 
the motor endings. In these instances, it is necessary to confine the 
action of the drugs to the centers, which requires a more complicated 
technic. 

The Study of the Effects of Drugs on Intact Normal Animals. A complete con- 
ception of the actions of a drug can be obtained only by supplementing the study of its 
effects on isolated structures, by careful observation and analysis of the symptoms 
which it produces in intact mammals. The effects on metabolism, and the histologic 
lesions, etc., can only be studied in this manner. Indeed, these experiments are often 
undertaken before the more difficult investigations on isolated structures; for they 
furnish valuable hints of the direction which the latter should take. When circum- 
stances permit, it is advisable to proceed from the lower to the higher classes of animals, 
and finally to man. Opportunities for observing the effects of drugs on man are frequent 
in cases of poisoning, and should not be neglected; but intentional experiments with 
drugs on man are to be undertaken only with the greatest caution, with doses which do 
not exceed the therapeutic maxima; and, as a rule, only after the effects have been 
thoroughly studied on animals. 

The Effect of Drugs in Disease. The action of drugs is not always the 
same in disease as in health. The differences are, however, as a rule 
quantitative rather than qualitative. Since the drugs are in practice 
employed most extensively in disease, their action in these conditions is 
of the greatest importance. As a general rule, it is possible to explain, 
and even to predict, the action of drugs in disease from their action on 
normal tissues. However, the actual test must always be made. 

Animal experiments are as yet of limited value in this connection, and we are forced 
to rely mainly on observations on patients. To make these of any value it is in the 
first place necessary that the observations be made very accurately and that all psychic 
factors be excluded; it is further necessary that the existing pathological condition be 
correctly known. These requirements are unfortunately not fulfilled in many cases, 
which accounts in part for the differences which are occasionally noted between the 
clinical and the experimental data. These exceptions will be discussed in the text. 

In the case of all the older drugs, clinical tests have been made so abundantly that 
further observations would seem superfluous. This is by no means the case. Accurate 
observations in the light of our advancing knowledge, and employing the improved 
methods of diagnosis and observation, are always needed. 

It is also highly desirable that every physician should obtain his knowledge of the 
therapeutic action of drugs at first hand. He should utilize every case under his care for 
this purpose, and conduct his treatment as if it were a critical experiment, the interests 
of the patient being, of course, paramount. The conclusions will be greatly simplified 
if but one drug is used at a time. 

Chemic Investigations. Since the action of drugs depends so largely upon their 
chemic constitution, the latter is a legitimate subject of pharmacologic inquiry. The 
study of the fate of the drug in the body, of the mechanism of its absorption, excretion, 
and storage, is also indispensable. These involve the methods of quantitative chemic 
analysis. 

Transfer of Results of Animal Experimentation to Man. The utilitarian aim of 
pharmacology is to supply the science of medicine with a rational and scientific basis 



84 MANUAL OF PHARMACOLOGY 

for the practice of therapeutics and for the study of toxicology. It was shown in the 
preceding section that these objects can be attained only by experimentation on lower 
animals. This brings up the fundamental question: To what extent can results observed 
ti animals be transferred to man? The same question applies to all other fields of 
experimental medical research, and has been abundantly answered by their results. 
A similar physiology implies a similar pathology and pharmacology. In the great 
majority of cases, similar structures are affected in the same way by a given drug, no 
matter in what animal they are studied. Where differences exist, they can usually be 
explained by differences of physiologic function, as will be discussed under " Racial 
Idiosyncrasy." Those which are not yet explained must be referred to our ignorance. 
The differences in animals, physiologic and unexplained, are now generally recognized 
so that suitable species can be chosen for experimentation. They can furthermore 
be eliminated by using the drug on several species: // a given poison affects all species 
alike, it may be concluded that Us action on man is also the same. If it produces different 
effects, but if these can be explained by differences in physiology, the effects on man will 
be similar to those produced on the species the physiology of which resembles most 
closely that of man. 

Value and Limitations of Experimental Pharmacology. It will be seen that great 
care must be used in applying the results of experimental pharmacology to man. The 
neglect of this precaution, the drawing of far-reaching conclusions from a few limited 
experiments, threw discredit on pharmacology in its earlier days, and is still seen all too 
frequently. Pharmacology can not be held responsible for this misapplication of its 
data by half-trained enthusiasts. Its scope is limited primarily to its own results and not. 
to their application, although it may legitimately suggest the latter. It should not be 
made to replace the science of therapeutics, but should only aim to place well-studied 
tools in the hands of the latter. If this limitation is realized; if the therapeutist will 
carefully study the results of pharmacology and will utilize and interpret them in the 
light of bedside experience, then pharmacology will be of very great value to medicine. 

One very important service is rendered by pharmacology through the examination 
of new remedies. The development of synthetic chemistry especially has resulted in 
the discovery of a very large number of new substances of some therapeutic value. The 
number is indeed so large, that all could not be given a thorough trial on patients. Most 
of these substances possess some value, but many differ from each other by very in- 
significant details. In this case, pharmacology can select the most promising drugs of a 
type, and by their thorough study, indicate those which are worthy of trial by the 
clinician. 

THE ADMINISTRATION OF DRUGS 

The effects of a given drug or poison are not always uniform, but vary 
with conditions; such as the dose; the absorption and elimination; the 
method and time of administration; the simultaneous presence of other 
substances; the age, sex and race of the patient; the existence of disease, 
etc. A knowledge of these variations is very important. 

Methods of Administering Drugs. The channel by which a drug is 
introduced into the body, or the place to which it is applied, must vary 
with the object to be secured whether the action is to be local or systemic; 
the desired rapidity of absorption; the necessity of avoiding irritation of 
certain organs, etc. 

Local Application. Drugs may be used locally either to protect a sur- 
face, or for reflex effect, or as antiseptics, or as stimulants. They may be 
applied to the skin in various vehicles: If it is desired to secure the absorp- 
tion of the remedy or its deep penetration, vegetable or animal oil must 
be used, preferably adeps lanae hydrosus (lanolin). The influence of the 
ointment base, however, varies for different substances (Sauerland, 1912). 
Where the local effect alone is required, the mineral fats (petrolatum or 
vaselin) may be employed. The remedy may also be placed in aqueous 
solutions (washes), especially if intended for an antiseptic; or it can be 
used in powder form. Caustics may be used either as solids or liquids. 
Counterirritants are used as liniments, i.e., dissolved in oil, turpentine, or 
alcohol. 



ADMINISTRATION OF DRUGS 8$ 

Absorption from Skin. Local application to the skin can be used for 
producing general effects, but it is only employed in those cases (mercury 
with some patients) where the stomach has to be avoided and sub- 
cutaneous administration is not practical. The principal objection to 
the administration of drugs by the surface of the skin consists in the 
uncertain absorption, an exact dosage being in consequence impossible. 
The absorption is greatest where the skin is most delicate; in the 
axilla, loins, and the inner surfaces of the extremities. Absorption is 
aided by friction and cleanliness. 

Watery solutions are not absorbed from the skin, unless the drug is caustic. The 
reason for this non-absorption lies in the fact that the stratum corneum of the epidermis 
is practically non-permeable to solutions. Absorption must take place through the 
glandular structures of the skin, and these are filled with fatty matter, which prevents 
the penetration of watery solutions, but not, of course, of other fats. However, when 
the skin has been macerated for several hours it may absorb some salt. It also ab- 
sorbs HoS and other gases. 

It must be borne in mind that the application of solutions to open 
wounds or abraded surfaces is practically the same as subcutaneous injec- 
tion, and absorption occurs in this case very readily. 

Local medication may be used also on other surfaces than the skin, if 
they are accessible; e.g., mucous membranes. They are usually applied as 
aqueous solutions (injections, washes, and gargles). 

Calaphoresis. This process has been employed in dentistry to facilitate the pene- 
tration of cocain, but it has not as yet found very extensive adoption in medicine and 
surgery. It is a process by which the molecules are carried from the + to the pole. 
The solution to be introduced must possess a higher conductivity than the liquid of 
the tissues. 

Sprays. Vapors and finely "atomized" sprays are inhaled for their 
local action on the respiratory mucous membranes. They must not be 
too irritant. 

To reach the lower air passages, they should be inhaled deeply with the nostrils 
closed, the mouth wide open, and the tongue protruded. Even so, the numerous 
branching surfaces prevent the spray from reaching any but the larger bronchi 

(Semmola). 

Inhalation. This method is used only for gaseous medicines, such as 
anesthetics or oxygen. 

When giving drugs by inhalation, it must be borne in mind that the 
effect does not depend upon the quantity given, but the concentration of 
the gas and the time during which it is administered. The rich capillary 
area of the alveoli is one of the best absorbing surfaces, so that the action 
is very rapid. The lungs also absorb fluids and dissolved substances 
rapidly, if these are introduced through the trachea. 

Oral Administration. This, the most ancient method, is still the stand- 
ard one. Its advantage lies in its great convenience and in the absence 
of local irritation. Nevertheless, certain drugs do give rise to disturb- 
ances of digestion. This can be avoided by giving them in such a form 
that they will not be dissolved in the stomach (pills), or by giving them at 
a time when the stomach is filled with food. Absorption is, of course, de- 
layed in these cases. Pills should never be employed for insoluble powders 
or for corrosive drugs which require dilution. 

Absorption from Alimentary Canal. The absorbing power of the stomach 
is relatively low, even for water and soluble substances (Hirsch, 1892); so 



86 MANUAL OF PHARMACOLOGY 

that the main absorption does not occur until the drug has reached the 
small intestines. The effects, with gastric administration, are therefore 
relatively slow. The passage is quickest if the drug is taken fasting in 
water; somewhat slower with milk, soup or wine; slowest after eating, es- 
pecially when administered dry (Moritz, 1898). 

The conditions in the small intestines are very favorable for absorption, 
being aided by the long sojourn, the extensive surface, the folds and villi, 
the segmental movements, etc. 

The relative rdle cf the stomach and intestine in absorption varies for different drugs 
and animals. Strychnin, e.g., is absorbed from the stomach with dogs and cats, but 
not with rabbits and guinea pigs; whereas sodium salicylate and iodid give just the 
opposite result. Inoye and Kashiwado (1905) have shown that atropin and rhubarb 
are not absorbed from the dog's stomach, whilst salol is absorbed. The data as to man 
are insufficient. 

Certain drugs are more or less destroyed in the alimentary tract, 
/.'., toxins and antitoxins, so that oral administration is relatively ineffi- 
cient. Glucosids are also partly destroyed, so that the oral dose must be 
larger. On the other hand, drugs which require the action of the diges- 
tive juices for their solution (resins, oils, etc.) are more efficient by mouth 
than by other channels. The oral route is of course the only one for drugs 
intended to act locally on the upper parts of the digestive tract. 

Rectal Administration. The stomach and small intestine may be 
avoided by giving the drugs per rectum, either in the form of enema or 
suppositories. The rectum is a fairly good absorbing surface for many 
soluble substances; so that the effects are often greater or more prompt 
than with oral administration (/.?'., for salts, narcotics, etc.). The ab- 
sorbed drug also avoids the passage through the liver, and the consequent 
destruction. 

Encmata, when introduced for the absorption of the medicine, should be as small as 
possible, but not so strong as to produce local irritant effects. One or 2 ounces is usually 
the proper quantity, the rectum being first cleansed with warm water. When enemata 
are employed for their mechanical effects, the amount must, of course, be much greater 
i or 2 pints. These should be raised to the body temperature. 

Conjunctiva, Urethra and Vagina. These are very good absorbing 
surfaces, so that systemic effects often follow local application (vagina; 
Menges, 1906). Iodid is also absorbed from the uterine cavity (Higuchi, 
1908). 

Subcutaneous or Hypodermic Administration. The injection of solu- 
tions through a hollow needle into the loose subcutaneous tissue. It has 
the advantage of being quicker and more certain in its effects, and the 
dosage is more exact than can be secured by any other method. The 
principal objection to it lies in the fact that while it is not very painful 
with some medicines, it is very much so with any irritating substance. 
There is also a tendency to abscess formation. This is frequently due 
to deficient asepsis, but certain substances (protoplasmic poisons) pro- 
duce abscess formation even with the most rigorous asepsis. 

Hypodermic injections are generally made into the forearm, arm, thigh, 
or nates. For very bulky injections, e.g., for antitoxin or for saline solu- 
tion, the loose areolar tissue of the subscapular or mammary region is chosen. 
The subcutaneous dose may often be made somewhat smaller than the 
oral dose. The rapidity of absorption from hypodermic injections may be 
hastened by massage, by distributing the injection over several places, 
and by dissolving the drug in a small amount of fluid. The concentration 



ADMINISTRATION OF DRUGS 87 

in salts should not exceed that of the blood, or the injection will be pain- 
ful. Normal saline solution is the least irritant solvent for alkaloids. 
Subcutaneous injection is naturally inadmissible, if local effects in other 
parts of the body are desired (e.g., for stomachics, cathartics, locally acting 
emetics, etc.). 

Hypodermic injection was probably first practiced by E. Rynd, 1844, but was in- 
troduced practically by Alex. W. Wood, in 1853. Pravaz invented his syringe in 1853, 
for the injection of aneurisms (Macht, 1916). 

Intratmiscular Injections. These are made by thrusting the needle 
through the skin deep into the substance of the gluteal or lumbar muscles. 
The absorption is more rapid than with subcutaneous administration 
(Meltzer and Auer, 1904), and the irritation and tendency to abscess for- 
mation are less. Auer and Meltzer, 1911, advise the sacro-spinal muscles 
in preference to the gluteal, as giving better absorption with less pain 
and other complications. 

Subnasal Injection. Injection under the mucous membrane of the nasal septum 
gives extremely rapid absorption, the efficiency approaching intravenous injection 
(Pilcher, 1914, 1915). 

Intraperitoneal and intrapleural injections are used in experimental technic, and 
resemble subcutaneous injections, the drug being absorbed more rapidly. Intra- 
peritoneal injections in man have been made by Schmidt and Meyer (1905), but are not 
recommended. The pleura absorbs through the parietal and pulmonary surface; 
but the absorption is less than from the peritoneum (Naegeli, 1913). In both mem- 
branes, it occurs by the blood rather than lymph. Gravity plays a part, the absorp- 
tion being rather better with pelvis down position (Dandy and Rowntree, 1914). 

Intrapericardial Injections. Solutions are quite rapidly absorbed from the pericardial 
sac into the heart-muscle. Gunn and Martin, 1915, suggest that this could be utilized 
in epinephrin-resuscitation. 

Injections into the trachea are very rapidly absorbed .through the 
alveolar capillaries, and act more like intravenous injections. They also 
cause asphyxia, and are not used intentionally. Tracheal sprays are 
used for local effects. 

Inlracerebral injections (i.e., into the substance of the brain) have been used experi- 
mentally. The injections are at once conveyed to the ventricles and produce local and 
mechanical effects often different from the systemic action of the drug. 

Subdural Injections. These are used if the drug is to act directly on 
the spinal cord, especially for spinal anesthesia. The technic is that of 
lumbar puncture, some cerebro-spinal fluid being withdrawn before the 
injection is made. The procedure is dangerous, since the poison may 
produce local effects or be conveyed directly to the medulla. 

The absorption of quinin and atropin from the cerebro-spinal fluid is almost as rapid 
as if they were injected into a vein. It occurs probably by the blood (Dixon and 
Halliburton, 1912). Irritation of the meninges does not modify the absorption (for" 
salvarsan, Stollman and Swift, 1915). 

Intravenous Administration. This is often used in pharmacologic 
experiments. Clinically, it has been tried in recent years (F. Mendel, 
1908). Its dangers restrict its application mainly to emergencies when 
an immediate action is necessary (strophanthin), or where other methods 
are not applicable (salvarsan). 

Intravenous injection was tried rather extensively in the seventeenth century, but 
its modern application dates f rom Landerer, 1881 (history, Epstein, 1915; Macht, 1916). 

\Yhile it is the quickest way of securing the action of the substance, the slight opera- 
tion required is some objection. There are also more serious dangers. Air may be 



gg MANUAL OF PHARMACOLOGY 

introduced into the vein, and while the presence of a small bubble of air in the circula- 
tion of a man is not as dangerous as in that of a rabbit, it may lead to very serious 
results. The action of drugs injected intravenously may be quite different than when 
taken by other channels. They act upon the heart more directly and with less dilution. 
Many substances also have the property of clotting the blood, and unless the adminis- 
tration be very skilfully done, the result might be disastrous. 

CONDITIONS INFLUENCING ABSORPTION 

The time required for absorption into the body and into the cells 
varies from a few seconds (e.g., hydrocyanic acid), to several weeks 
(e.g., lead). The rapidity of absorption depends upon the nature of the 
drug, the place of administration, and a number of accessory factors. 

Place of Administration. Absorption of drugs may occur from the alimentary 
canal or from other mucous surfaces; from subcutaneous tissue or serous cavities; from 
the alveoli of the lungs (gases and volatile substances) ; a limited number of substances 
may also be absorbed from the intact skin. The influence of the place of administra- 
tion has been discussed. 

Solubility. Only soluble drugs can be absorbed (except the small 
quantities taken up by phagocytosis); but the solubility in the protein 
containing fluids of the body is not necessarily the same as the solubility 
in water. The solubility may also be modified by chemic changes in the 
digestive canal. 

Solid Substances. These are practically unabsorbable from the alimentary tract, 
although Koellicker and many others, on feeding rabbits with carbon, found particles 
in the prevertebral and mesenteric ganglia. 

There is always considerable uncertainty in the absorption of solid substances, even 
when they are soluble. They should therefore be avoided unless a very slow action is 
desired. Free dilution is favorable to absorption. 

Influence of Colloids, Etc. Oil, gums, extractives, kaolin and other 
colloids hinder absorption, partly by adsorption of the drug, partly by 
hindering its access to the absorbing surface. The presence of food in the 
alimentary canal has a similar action. The isolated active constituents 
(alkaloids, etc.) are preferred if a quick systemic action is desired, whilst 
the galenic preparations (extracts, tinctures, pills, etc.) are used for 
local effect. In case a crude drug contains several active ingredients, 
the employment of the isolated constituents will give more definite results. 
On the intact skin, absorbable oils facilitate the absorption of other sub- 
stances dissolved in them; alcohol usually has a similar favorable effect in 
the stomach. 

Fuller's Earth on Alkaloids. Fuller's earth (hydrous aluminum silicate) has a 
high adsorbing power, especially for alkaloids varying, however, in degree with differ- 
ent samples. (Lloyd, 1916.) The proprietary brand "Alkresta" is being especially 
investigated. McGuigan, 1914, found that this mixture with strychnin is insoluble in 
acid fluids, and develops the bitter taste quite slowly; and that it delays and dimin- 
ishes the tetanic action in frogs. Fantus, 1915, finds that the combination is not dissolved 
in the stomach, but dissociates gradually in the intestines. He also investigated the 
suitability of the earth as alkaloidal antidote, and found it very limited. It is somewhat 
improved by the addition of tartaric acid or acid sodium phosphate; it is highest 
against mprphin, cocain, nicotin and ipecac; and least efficient against strychnin, aconitin 
and colchicin. The effects of Kaolin and related substances were also investigated by 
Friedberger and Tsuneoka, 1913. 

Sabbatani, 1913, found considerable antagonism between strychnin and colloidal 
carbon (caramel) when mixed in vitro. The intravenous injection of the carbon also 
furnished some protection against the oral administration of strychnin; but this was too 
uncertain for practical application. 



CONDITIONS INFLUENCING ABSORPTION 89 

v. Paulucci, 1915, showed that fatty substances (including petrolatum) diminish 
the toxicity of strychnin, both hypodermically and with direct application to the nerve 
centers. 

Concentration. The absorption varies generally in the same direc- 
tion as the concentration, especially for hypodermic injections; but the 
relation is not a simple one. Absorption tends also to increase with the 
extent of absorbing surface (e.g., by making multiple hypodermic injections). 
This seems to be less important in the intestines (Sollmann and Hanzlik, 
1911-1913). 

Changes of the Absorbing Cell. In the alimentary canal, injury to the absorbing 
cell may either facilitate or hinder absorption; astringents tend to have the latter effect, 
corrosives and simple irritants the former. 

Sollmann and Hanzlik have found that phenol, alcohol, iodid, and probably other 
substances tend to inhibit their own absorption; so that the absorption, at first very 
rapid, is promptly slowed. 

Circulation. The rapidity of absorption is proportional to the ra- 
pidity with which the drug is removed; just as a burning lamp- wick absorbs 
the oil more quickly (Mialhe). It therefore increases with the rapidity 
of the circulation and of the lymph flow. Active hyperemia (hot air; 
Klapp, 1901) and hemorrhage hasten absorption; while it is delayed by 
venous stasis, passive congestion, deficient heart action, vasoconstriction, 
catarrh, etc. Increase of lymph flow, by moderate distention and massage 
also quickens absorption. Excessive distention diminishes absorption by 
slowing the local lymph flow (Hamburger, 1907). 

Absorption in Absence of Circulation. Considerable absorption occurs when the 
circulation has stopped. Thus, strychnin and morphin are absorbed by frogs with 
ligated hearts, producing interesting modifications in their actions (Meltzer, 1911- 
1913). Abel, 1912, and Abel and Turner, 1914, believed that the solutions in cardiec- 
tomized frogs are circulated by the lymph hearts; but Meltzer, 1914, Joseph, 1914, 
and Githens and Meltzer, 1915, affirm that general effects from the local injection of 
strychnin, fuchsin or epinephrin may occur even when all the lymph hearts are definitely 
excluded, the absorption occurring through the lymph spaces. 

The absorption in frogs is delayed by destruction of the spinal cord 
(Filippi, 1912). Considerable absorption occurs also in dead animals 
(Sollmann and Hanzlik, 1913), probably by diffusion. 

Absorption by Blood and Lymph. Most soluble substances are absorbed from the 
alimentary canal by the blood, rather than the lymph. This also holds for the serous 
cavities; methylen blue injected into the peritoneum or pleura, for instance, appears in 
the urine before it is seen in the thoracic duct (Starling and Tubby). A few drugs, how- 
ever, take the lymphatic path. Tetanus and diphtheria toxin, and perhaps other 
toxins, are absorbed from the local injections by the nerve sheaths, and reach the central 
nervous system along these (Meyer and Ransom, 1903; Meyer, 1915; C. W. Field, 
1907). These toxins are more active on hypodermic or intramuscular than on intra- 
venous injection, since apparently they reach the nerve centers in more concentrated 
form by the lymph than by the blood. 

Sojourn in Blood. This is generally very short. 

It must not be forgotten that a drug, after it has been absorbed into the circulation, 
needs still to penetrate into the cells. This intracellular absorption depends upon the 
nature of the poison (selective absorption), and to some degree on its concentration. 
As a rule, it is a very rapid process: Masoin (1903) found the time which elapses before 
just toxic doses disappear practically completely from the blood, after intravenous in- 
jection, to be for Arsenic, nine-tenths to thirty seconds; Tetanin, twenty seconds; 
Cyanids, two to six minutes; Diphtheria toxin, four minutes; Antitoxin, several hours. 



QO MANUAL OF PHARMACOLOGY 

THE EXCRETION OF DRUGS 

Channels of Excretion. This occurs mainly through the urine and 
feces, and with volatile drugs through the lungs. The sweat and, indeed, 
all the secretions play a minor part. The relative importance of the dif- 
ferent channels varies for each drug, the reasons being but little understood. 
The rapidity is proportional to the circulation and to the functional ac- 
tivity of the excretory organs, and may be increased by the factors which 
stimulate these. 

The excretion of certain drugs appears to be limited by their existing in the body 
in the form of combinations. The elimination of these is favored by substances which 
displace them from the compounds. This is probably the explanation of the increased 
excretion of iodids on the administration of chlorids, and possibly of the favorable effect 
of iodids in chronic poisoning by metals. 

Excretion by Sweat. A considerable number of drugs are thus excreted (iodids, 
bromids, borates, phenol, salicylates, antipyrin, methylen blue, As, Hg). The quan- 
tities are too small to make them significant for elimination, but they may help to ex- 
plain exanthemata. 

Excretion by Saliva. This is rather limited, and is only important for the haloids 
(iodids) sulphocyanates, K and NH 4 , Hg and Pb, menthol and guaiacol, hexamethyl- 
enamin, and some alkaloids (morphin and quinin). The excretion generally begins 
within twenty minutes and may last over nine hours (Howe, 1912). 

Passage into Cerebro-spinal Fluid. Inorganic substances are excreted into this 
only in a slight degree; iodids and bromids are generally present. Many organic sub- 
stances pass into it much more freely: Alcohol, chloroform, acetone and hexamethyl- 
enamin occur constantly in about one-third the concentration of serum (Hald, 1911). 

Passage to Fetus. The more important drugs which have been demonstrated are: 
ferrocyanid (Mayer, 1871); chloroform, ether, CO, ethyl bromid, atropin, morphin, 
scopolamin, chloral, salicyl, quinin, benzoic acid, phlorhizin, alcohol, nitrate, urea, 
methylen blue, As, Hg, KI, KBr (Kehrer, 1907). 

DOSAGE (POSOLOGY) 

Definition. Drugs are administered to produce a desired effect, 
and the dose must be sufficient for this purpose, and neither too small, 
nor too large. Since the effect is influenced by numerous conditions, 
it is impossible to state the exact doses for any drug; experience is the 
only safe guide. However, the doses vary under ordinary conditions 
only within narrow limits, so that it is feasible to state the customary or 
average dose, as is done in the U.S.P. and in this book. This is convenient 
as a starting point. 

The "maximum dose" signifies the largest dose which can be safely used in ordinary 




is used in physiologic experiments on animals. 

Variations According to Administration. The different methods of 
administration, by altering the rapidity of absorption, produce quantitative 
differences in the effects, and therefore in the dosage. Since these vary 
with each drug, they must be determined by observation. General 
ratios of oral, rectal and hypodermic doses, supposed to apply more or 
less to all drugs, are dangerous (Hatcher, 1910; Hatcher and Eggleston, 
1914). 

The same dose acts the more profoundly, the more rapidly it is introduced; mainly 
because there is less excretion and destruction before the full dose has entered; also be. 
cause it reaches the heart and other centers before being distributed through the body- 



DOSAGE (POSOLOGY) 91 

This must be taken into account in fixing the minimal fatal dose. Extremely rapid in- 
travenous injection may simulate a higher fatal dose, if death occurs during the injection; 
because in this case really more poison may have been administered than was necessary 
for death (I. Simon, 1905). 

Action and Dose. With some drugs, the fatal and active dose are far apart (atro- 
pin); with others, they are close together (strychnin). The distance varies with the 
delicacy of observing the active dose, and for different actions of the same drug. 

Daily Dose. The single doses are usually calculated on the assump- 
tion that sufficient time is allowed to elapse between the doses for the 
greater part of the drug to be excreted. This constitutes a periodic 
medication. The exact time varies of course with the nature of the drug, 
but in most cases the drug is administered three or four times a day; so 
that the daily dose is about three or four times the single dose. If a con- 
tinuous action is desired, correspondingly smaller doses are given at shorter 
intervals. 

Repetition of Dose. Cash, 1908, found that doses of indaconitin, repeated at 
sufficiently close intervals, gave imperfect summation of the temperature action; but 
if the interval exceeded two hours, with doses less than one-half fatal, the later doses 
produced actually less effect. 

Variation of Dosage. The doses ordinarily stated in text-books 
apply only to adults of average size, and to oral administration. 

Effect of Weight. Other things being equal, the effect of a given dose 
is inversely proportional to the weight of the individual (exclusive of 
the adipose tissue). It is rarely necessary to make allowance for the 
weight in adults (twenty to sixty years), but it may be used for calcu- 
lating the doses for children. 

Body-Surface. This is regarded by some as a more accurate although less con- 
venient index of the dose (Moore, 1909; Dreyer & Walker, 1914); but the subject is in 
dispute (Kisskalt, 1915). 

Calculation of Doses for Children. In most cases, the adult dose is 
reduced in simple proportion to the weight of the child either by direct 
calculation, or by the use of empiric rules based on averages, as described 
below. The dosage so obtained is generally sufficiently exact. It is 
inadmissible only with extremely young children; and with drugs the 
action of which is influenced specifically by age. 

Clark's Rule. Multiply the adult dose with the weight of the child 
(in pounds) and divide by 150 (the weight of the average adult). This 
rule gives the most exact results. 

Cowling's Rule. Multiply the adult dose with the age of the child at 
the next birthday, and divide by the adult age, taken as twenty-four. 
F.i., the dose for a child of three years would be ^4 = % of the adult 
dose. This rule is simple, easily remembered, and gives data agreeing 
sufficiently well with the average weight curve; more accurately than 
Young's Rule. The results are rather too low, below four years and above 
fifteen years, but the error is on the safe side. 

Young's Rule. Multiply the adult dose with the age of the child (in years), and di- 
vide by the age plus 12. F.i., the dose for a child of three years would be ^5 = Y^. 
As compared with Cowling's Rule, it gives somewhat higher doses below twelve years, 
and somewhat lower above this age. 

Fried's Rule for Infants. Divide the age in months by 150 and multiply it by the 
adult dose;/.?'., for a baby of five months, the dose would be 



The dose for aged people is generally taken as somewhat less than 



92 MANUAL OF PHARMACOLOGY 

that for adults. Above sixty years, the adult dose is reduced to four- 
fifths or two- thirds; and in extreme senility, to one-half. 

Specific Influence of Age on Drug-action. These (i.e., apart from the 
difference due to weight) are known definitely only for a few drugs. 
Children are especially susceptible to morphin and nicotin, and compara- 
tively tolerant to cathartics, strychnin, iodids, iron, belladonna, calomel, 
digitalis and spartein (A. Jacobi, 1907). Old age is generally less resistant 
to drugs,; purgatives and emetics are especially debilitating. The fre- 
quent existence of atheroma makes it dangerous to use drugs which raise 
the blood pressure, directly or indirectly. 

Influence of Sex. Women usually require somewhat smaller doses 
than men (one-half to four-fifths). The greater susceptibility is in large 
part due to the lesser weight, but in part also to the anatomic and func- 
tional peculiarities. The influences of sex are of course most pronounced 
with drugs which act on the generative organs. Pregnancy also modifies 
the action of drugs, and contraindicates the use of irritant cathartics 
(because of the danger of inducing abortion) and of irritant diuretics 
(on account of the tendency to nephritis), etc. 

CONDITIONS INFLUENCING DRUG ACTIONS 

The time of administration also influences the action of drugs. Hyp- 
notics and Cathartics, for instance, are most effective when their action 
coincides with the natural time of sleep and defecation, and if the ex- 
ternal conditions are favorable. Stomachics are best given shortly before 
meals. Drugs which are to be absorbed rapidly are given on an empty 
stomach, whereas irritants are administered just after meals, when the 
stomach is protected by food; etc. 

Idiosyncrasy. This term (from i'Stos, one's own, and GVVK. pasts, a blend- 
ing) is applied to peculiar, exceptional reactions to the effects of 
drugs. The differences are generally quantitative, and may concern 
the main action, or the side actions, especially skin eruptions. They 
may be inherent in the remedy, or may be due to extraneous causes, 
or they may be referred to the constitution of the patient. In the latter 
case, they may be due to anatomic or to functional peculiarities. They 
may be congenital or acquired, temporary or permanent. Neurotic 
patients are especially liable to show unusual effects. (Many apparent 
instances of idiosyncrasy are doubtless due to differences in the strength 
or constituents of drugs.) 

Impurities in Drugs. Qualitative abnormalities in the effects of drugs are usually 
due to the exaggeration of a side action; but in some cases they may be referred to the 
presence of impurities. It is rather doubtful, however, whether these impurities have 
the importance which is often assigned to them. Whilst it is undoubtedly desirable that 
drugs should be as pure as it is practical to make them, minimal amounts of foreign 
substances can not be said to be very objectionable, unless they are particularly poison- 
ous. The pharmacopeias have taken a wise stand in this matter by permitting the 
presence of small amounts of such innocuous impurities which it would be very difficult 
and costly to remove. 

Increased Susceptibility. This may be due to very rapid absorption, 
or slow elimination; to the presence of synergistic agents in the body; 
or to increased functional susceptibility. 

Anaphylaxis. This is a striking type of highly increased susceptibility; but it seems 
to be confined to proteins. It has been suggested that the peculiar irritative reactions 



CONDITIONS INFLUENCING DRUG ACTIONS 93 

to iodids, volatile oils, etc., are also anaphylactic; but this is not the case (H. N. Cole; 
Zieher, 1912; Glueck, 1913). One striking difference is that the hypersusceptibility 
to ordinary drugs can not be transferred passively. 

Cumulative Action. This is said to exist when the continuation of 
a given dose of a drug produces greater effects than the first doses. It 
may be due to an actual accumulation of the drug, absorption being 
greater than the capacity for excretion (lead); or it may be due to the 
summation of effects, when the changes brought about by the first doses 
persist (digitalis); the drug may use up some substance required for its 
disintoxication (phenol); or there may be general decrease of resistance. 

Inconstant absorption is a frequent cause of apparent cumulative action. Succes- 
sive doses of the drug may lie unabsorbed in the alimentary canal, to be finally taken 
into the system in toto when the conditions are favorable to absorption. This explains 
that the greatest individual variability to toxic doses exists precisely for those drugs 
which are absorbed with the greatest difficulty. 

Irregularities of Excretion (nephritis, etc.) are also favorable to the development of 
cumulative effects. 

"Education." It is sometimes noted that effects are more easily reproduced after 
they have once been induced. This is seen particularly in drugs acting upon the central 
nervous system. It is found, e.g., that the susceptibility to strychnin increases with 
its administration, and it would seem that this is caused by the central nervous system 
becoming educated to the stimulating actions and responding to them more readily. 

Tolerance. This may be due to non-absorption, to rapid elimination, 
to the neutralization or destruction of the poison, or to anatomic pecu- 
liarities. Many cases can not be explained in this manner, and must 
be assumed to be functional (the "histogene-tic" immunity of Behring). 
The tolerance is rarely absolute, so that it is scarcely correct to speak 
of "immunity." (Critical review of the literature of tolerance, Heger 
and Zunz, 1914.) 

Habituation. Tolerance may be congenital, or it may be developed 
by the repeated administration of the poison. This habituation may be 
functional (alcohol, caffein, nicotin); or it may be due to diminished ab- 
sorption (arsenic) or increased elimination (atropin in cats) ; or to increased 
destruction of the poison (morphin); or to the production of antibodies 
(toxins). The tolerance is usually limited, not absolute. With some 
poisons, it develops a craving and serious abstinence symptoms, if the 
drug is suddenly withheld. 

It is interesting that functional habituation, when acquired for a par- 
ticular drug, may hold also for other drugs having a similar action. A 
habitual drunkard, e.g., is resistant to the general anesthetics; morphinists 
are said to be more tolerant to cocain (Chouppe, 1889); etc. 

Hausmann, 1907, and Santesson, 1912, give re views of the recent data on habituation. 

Antitoxin formation is a conspicuous instance of acquired tolerance. It was sup- 
posed to be confined to proteins, but seems to exist also toward certain glucosids 
(toadstools, and poison ivy, Ford, 1909; snake venom, Faust, 1911). It does not occur 
with alkaloids or any of the simpler poisons. 

Acquired Immunity in Protozoa. This has a practical as well as theoretic bearing 
on chemotherapy, and has been investigated by Ehrlich, 1909, and Neuhaus, 1910. 
These organisms acquire immunity for several groups of poisons metals and dyes 
the tolerance induced by one drug applying to other chemically related drugs, but not 
to the other groups. The immunity, when once induced, is transmitted unlimited 
from generation to generation. It is probably due to diminished affinity of the proto- 
plasm for the poison. With alkaloids, Prowazek, 1910, found that different individuals, 
even in the progeny of a single parent, show varying resistance to the same alkaloid. 
He also found that lecithin protects against the alkaloids. 

Racial Idiosyncrasy in Animals. Different species of animals often vary in their 
reaction. This can usually be explained by differences in the physiologic functions. 



94 MANUAL OF PHARMACOLOGY 

For instance, the cerebral actions are usually the more pronounced, the more highly 
the central nervous system is developed; whereas spinal actions predominate in the lower 
vertebrates. Rodents are incapable of vomiting and are, therefore, not affected by 
i motics. Atropin quickens the heart of the dog, but not that of the rabbit, because it 
acts by paralyzing the vagus, which is not tonically active in the rabbit. The dog-fish, 
which is more or less resistant to nephrotoxic poisons, normally excretes urea and 
probably other metabolic products mainly by the intestines and bile (Denis, 1913). 

Natural resistance is often due to the destruction of the poison, f.i., that of atropin 
by the serum of rabbits, etc. The destructive mechanism may be greatly increased by 
habituation;/.i., with morphin. Differences of absorption and excretion also come into 
play. 

There are still a number of differences which can not yet be explained on a physiologic 
basis. These must be referred to our ignorance of the physiologic differences which are 
involved. The hedgehog has a high unexplained resistance to many poisons; morphin, 
atropin, nicotin, cyanid, cantharides, arsenite, diphtheria and tetanus toxins; not for 
strychnin (Strubell, 1909; Willberg, 1913). 

Even the same organs in different classes of animals may show unexplained differ- 
ences. Thus, Gunn, 1909, claims that apocodein, quinin, and yohimbin, which cause 
vasodilation in mammals constrict the blood vessels in frogs both peripherally. 
Characteristic differences in epinephrin are well known; but the mechanism of these is 
explained by differences in innervation. 

Individual Idiosyncrasy in Animals. In animals, as well as in man, peculiarities 
exist in different individuals of the same species. Qualitative differences are seen particu- 
larly in the action of Cannabis on dogs. 

Instances of quantitative differences are very numerous: 

In a large series of experiments with toxic doses of drugs on animals the author has 
found that there is a fair degree of uniformity in the proportion of animals which die 
with a given dose. Thus, certain limits can be found inside of which, out of five animals 
three will always die. These limits vary from 0.5 per cent, (strychnin) to 25 per cent, 
(ergot), but are usually comprised within from 5 per cent, to 10 per cent. 

On the other hand, the susceptibility of any one animal is subject to greater possible 
variations; e.g., with a given preparation of digitalis, 0.6 mg. per gram will always kill 
three guinea pigs out of five. But in a large series of experiments, a number of animals 
will be found which will die of doses as small as 0.4 mg., while others will die only when 
0.9 mg. is reached. Whether these comparatively immune animals always enjoy this 
immunity, or whether the condition is only temporary, as well as the influence of age, 
sex, etc., has not been determined. 

These individual differences are still more striking if, instead of observing the toxic 
doses i.e., the sum total of the effects we direct our attention upon some one particu- 
lar action, e.g., the amount of slowing of the heart or the variation of blood pressure. 
The differences in this respect are so great qualitatively that it is undoubtedly unsafe 
to draw conclusions from a single experiment, and it is absolutely impossible in these 
cases to establish any quantitative standard. 

Seasonal Variations. The susceptibility of animals to a number of poisons varies 
considerably with the season. With cold-blooded animals, this would be referred 
mainly to differences of temperature; but considerable variations exist also in mammals. 
Guinea pigs, f.i., are more resistant to ouabain, and less resistant to acetonitrile and 
diphtheria toxin during November to January than in the spring and summer months 
(Haskell, 1912). 

Temperature. This has a marked effect in cold-blooded animals; digitalis, veratrin, 
nicotin, strychnin, tetanus toxin, chloral, and alcohol, for instance, are rendered more 
active, morphin and curare, less active, by raising the temperature The temperature 
quotient of strychnin was investigated by Schlomovitz & Chase, 1916. 

The influence is especially marked with poisons that have to undergo a transfor- 
mation in the body. At 37C., the susceptibility of frogs to atoxyl is increased 12 
times, that for colchicin 50 times, above ordinary room temperature. With muscles, 
the activity of drugs increases in a mathematical ratio with the temperature within 
certain limits (Veley and Waller, 1910). 

The temperature relations of digitaloids are fully discussed by Sollmann, Men- 
denhall and Stingel, 1915. An indication of this influence in man is seen in the modifi- 
cation of the action of antipyretics by fever. (In mammals, cooling generally increases 
the fatal effect by adding its direct depressant action.) 

Diet. This has a marked effect on the resistance of animals to many poisons 
(Hunt, 1910; Opie and Alford, 1914); but little is known of this in man. The calcium 
content is important in influencing cutaneous irritation (Luithlen, 1911, 1912). Barium 
is better absorbed from a Ca-poor diet (Alsberg and Black, 1912). 



CONDITIONS INFLUENCING DRUG ACTIONS 95 

Influence of Pathologic States. The effects of drugs in disease may 
differ materially from those on healthy animals. The pathologic condi- 
tions may lessen absorption (diarrhea) or increase it (corrosion) ; they may 
hasten the destruction of the poison (alcohol produces less intoxication in 
fever) ; or they may alter the effects entirely. Some of these modifications 
are readily explained by the functional or anatomic changes of disease; 
others are obscure. 

The antipyretics reduce the temperature in hyperpyrexia, but do not effect it when 
it is normal; digitalis is an efficient diuretic in cardiac disease, but not in health; it 
affects the normal cardiac muscle, but has little action on a fatty heart, etc.; the anti- 
septics and antitoxins are active only in infections, etc. Numerous other instances 
may be found in the papers of Salant, 1911, and Wallace, 1912. 

Pathologic conditions which modify absorption and excretion are of particular prac- 
tical importance: Suppression of urine, as by nephritis, may lead to toxic symptoms 
from drugs or doses which are ordinarily harmless. The general reduction of vitality, 
the "lowered resisting power" which is so common in many diseases is similarly import- 
ant. As an instance of such modifications, the investigations of Lusini and Sebastiani, 
1906, may be quoted. They found the absorptions of poisons hastened immediately 
after hemorrhage but not later. The toxic symptoms were not modified. The resist- 
ance was found lowered to a varying degree for different poisons: Most for strychnin, 
less for veratrin, and not at all for physostigmin. 

Inflamed Vessels. These react abnormally. Eskin, 1914, found constrictor drugs 
generally less and dilator drugs more effective. Epinephrin often produced dilation, 
whilst caffein, which normally dilates, constricted the inflamed vessels of rabbit's ear. 

Diseased intestines allow a much more rapid diffusion of proteins, toxins and ferments 
than healthy intestine (Mayerhofer and Pribram, 1909). 

The distribution of the drugs in the body may be different in disease and health. 
This is best illustrated by fluorescein (see Index). 

The Combined Action of Drugs. The effects of drugs are also influ- 
enced by the unusual conditions induced by the simultaneous administra- 
tion or presence of other drugs. A quantitative change may occur either 
in the sense of increasing the efficiency (synergism), or of diminishing it 
(antagonism). There may also be qualitative changes. In other cases, 
new actions are developed by the reaction of the drugs on each other, with 
the production of new compounds. For instance, the presence of acids 
renders the basic salts of bismuth soluble and toxic; oxidizing substances 
may liberate iodin from iodids; the iodids also decompose calomel and 
render it irritant. 

Antagonism of action is employed in the treatment of poisoning; or 
sometimes to remove undesired side effects. When it interferes with 
desired effects, it constitutes "therapeutic incompatibility" 

Combination Therapy. Synergism is utilized to secure the summa- 
tion of the desirable effects of several drugs, whilst the side actions are 
not increased or may even be neutralized. The efficiency itself may be 
increased, especially when the drugs attack a given cell or function 
simultaneously by several different mechanisms. Chemo- therapy has 
furnished some illustrations of this (Ehrlich, 1909). Formerly, combina- 
tions of drugs were very popular, but on the empiric principle of the shot- 
gun mixture that of many ingredients, some at least might fit the 
disease. Such indiscriminate mixtures are not scientific. It is better to 
employ the fewest possible drugs, until it has actually been shown that 
combinations give superior results in the particular condition. In giving 
several drugs of similar actions, the dosage of each must be correspondingly 
reduced. 

Variations of Combined Action. When several drugs are administered 
together, each may act independently, as if it were present alone. The 



96 MANUAL OF PHARMACOLOGY 

result would then be a simple algebraic summation of the effects, either 
synergistic or antagonistic. In many cases, however, the combined 
action is greater or smaller than would be calculated (potentiated and 
deficient summation). The relations may differ entirely according to 
dosage. 

F.L, stimulants are antagonistic to depressants only in small doses. Large doses 
(if ton become synergistic, the depression being greater than if the depressant were used 
alone. Instances of this are atropin and pilocarpin on embryonal growth, Sollmann, 
1904; caffein and alcohol toxicity, Pilcher, 1912; atropin and physostigmin toxicity, 
Fraser; Fothergill gives other interesting examples of antagonism. 

Sometimes, an action develops only in the presence of another drug;/./., pilocarpin 
provokes the action of minute doses of atropin on the intestine; or the point of attack 
may be shifted by the second drug. Instances will be found in the chapter on " Auto- 
nomic Poisons." The ratio of ions in the medium surrounding the cell influences the 
effects of drugs very materially. 

Instances of Synergism. The best-studied examples are from the group of narcotics. 
The simple lipolytic narcotics (alcohol, ether, chloroform, etc.) show practically only 
simple summation; but the addition of the alkaloidal narcotics (morphin and scopola- 
min) gives considerable potentiation (Knell, 1907; Fuehner, 1911; Kochmann and pupils, 
1913). Bromids give simple summation with lipolytic and alkaloidal narcotics (Klam- 
mer, 1913). The different opium alkaloids potentiate each other in interesting ways 
(Straub, 1913; Macht). The organic local anesthetics do not usually potentiate (Schmid, 
1913), but show marked potentiation with potassium (Zorn, 1913). Fuehner, 1912, has 
worked out the summation of hemolytic agents. 

Mechanisms of Potentiation. There are several possible explanations, but few 
positive data. Qne drug could modify the penetration of another. Fuehner, 1913, 
showed that this is true of the solubility coefficient of the narcotics; or it might alter 
the chemic affinity, either by acting as an amboceptor, or by closing the combining 
groups of the cell or of the drug (antitoxins) ; or it might attack the cell from a different 
point. 

Mansfield and Hamburger, 1915, believe that magnesium potentiates urethane; 
and that ether potentiates chloral or morphin, by favoring the distribution of these 
agents in the nervous system; for they find that the augmented action of the combi- 
nations persists after the magnesium is neutralized by calcium; or after the ether has been 
eliminated. 

Those interested in summation and antagonism should read Chapter VIII of 
Verworn's "Erregung und Laehmung." 

Buergi's Law. Buergi, 1910-1912, proposed a universal explanation of synergism; 
but his generalization is doubtless too sweeping. He announced that potentiation 
occurs, always and only, when two drugs have different points of attack in the cell; 
because two different receptors could take up more poison in a given time than could 
a single receptor from the double quantity of a single drug, Fuehner, 1912; Issekutz, 
1913; Zorn, 1913, and others have pointed out numerous important exceptions to this 
"law." It is certainly not universally applicable. 



FERMENTS AND NUTRIENTS 
DIGESTIVE FERMENTS 

Nature of Ferments. The digestion of food in the alimentary canal is 
accomplished mainly by the secretion of organic ferments or enzymes; 
colloid substances of unknown composition, whose presence accelerates 
chemical changes. Commercial ferments are more or less purified ex- 
tracts, rich in protein, and dried or preserved by glycerin. 

Our knowledge of the nature of ferments is very incomplete. Like colloids, they 
possess electric charges (Michaelis, 1909). Emil Fischer found their action on sugars 
to depend on their optic activity. Several workers have shown that the cleavage 
ferments may, under proper conditions, produce syntheses (Taylor, 1904). The term 
'fermentation" is derived from fermentum, leaven; and this probably from fervere, 
to boil. It was originally applied to all effervescence. 



FERMENTS AND NUTRIENTS 97 

Conditions of Action and Deterioration. The digestive ferments are 
specifically adapted to the hydrolytic cleavage of the various food products 
(amylolytic, proteolytic, lipolytic, etc.). Their activity is greatly influ- 
enced by various conditions, especially by temperature (40 to 45C. being 
optimal for mammalian ferments); by acid or alkaline reaction; by salts, 
etc. Solutions are quite unstable. They are destroyed rapidly about 
5oC., immediately by boiling and more gradually by any excessive con- 
ditions, and by putrefaction. Pepsin is much more resistant to destruc- 
tion than trypsin, but both deteriorate even in neutral solutions, trypsin 
often in a few days. Dilute watery solutions deteriorate quickly even at 
ordinary temperature; and even dry "pancreatin" is unstable (Long and 
Muhlmann, 1914). Pepsin can also be completely destroyed by shaking 
(Shaklee and Meltzer, 1909). 

Incompatibilities. Solutions of ferments are therefore incompatible 
with excess of acid and alkali (Long and Muhlmann, 1914) or salts; with 
many antiseptics; with excess of alcohol; and with all protein-precipitants. 
Pepsin in neutral or alkaline solution is destroyed by sodium chlorid 
(W. H. Hamburger, 1915). 

Mixtures of ferments digest each other more or less rapidly according 
to their reaction. Pepsin, in the presence of weak acids, destroys trypsin 
and amylopsin completely; but trypsin has little effect on pepsin under 
ordinary conditions (Long and Muhlman). "Compound Digestive Elix- 
irs," supposed to contain pepsin with pancreatin, etc., are therefore prac- 
tically worthless (J. A. M. A., 1907, v. 48, p. 434). 

Administration of Ferments in Digestive Disorders. This has not 
realized the early expectations, one reason being that digestive disturb- 
ances are rarely due to deficiency of ferments. It is also difficult to ad- 
minister ferments so that they could develop their actions. This is prob- 
ably possible only with pepsin and perhaps with diastase. The latter, if 
thoroughly mixed with food, could act in the fundus of the stomach for 
an hour or so (Cannon) before the mass becomes acid (Gruetzner, 1905). 
It is almost inconceivable that trypsin should reach the intestines un- 
changed, since it would certainly be exposed to the digestive action of the 
gastric juice. However,' there are some data which suggest that the 
administration of fresh pancreas by mouth improves the absorption of 
fat and proteins in dogs deprived of natural pancreatic secretion (Sand- 
meyer, 1895; Pratt, 1909). The action of papain is too feeble at body 
temperature to deserve consideration. 

Pepsin and possibly diastase may therefore have a limited value in a 
few cases; but little could be expected from the other ferments. Appar- 
ently favorable results may often be explained by the other treatment 
with which they are usually combined. 

Other Uses. A more rational field for ferments is in the preparation 
of predigested foods, especially for rectal alimentation. Rennin and 
Pepsin are used for curdling milk. Pepsin has been employed to dissolve 
diphtheritic membranes. Trypsin injections were tried against cancer 
(J. Beard, 1905; Shaw-Mackenzie, 1906), but proved disappointing. _ They 
produce local lesions and toxic effects resembling peptone-poisoning 
(Kirchheim, 1911). Papain and takadiastase act similarly (Kirchheim, 



Intravenous Injection of Ferments. This produces toxic symptoms resembling 
those of Albumoses (Hildebrandt, 1890). Smaller doses give rise to the formation of 
specific antibodies. Normal serum and other native proteins are also markedly re- 



7 



9 8 

sistant to protolytic ferments (Levne and Stookey, 1903). This resistance is de- 
stroyed by heating to 7oC., and is connected especially with the albumen fraction 
(Cathcart, 1904). 

PREPARATIONS FERMENTS 

* Pepsinum (Pepsin), U.S.P., B.P. A proteolytic extract obtained from the mucous 
membrane of the stomach of the pig (or sheep or calf, B.P.). Capable of digesting not 
less than 3,000 parts of coagulated egg-albumen (U.S. P.), (2, 500 parts, B.P.), when the 
test is made according to the official directions. Various processes are used in its 
manufacture. White or yellowish scales or powder, slight odor and taste; acid reaction. 
Sol. in water (1:50); nearly insol. in ale. Solutions are incompatible with alkalies, 
salts, metals, and tannin. Dose, 0.5 Gm., 8 gr., U.S. P.; 0.3 to 0.6 Gm., 5 to 10 gr., B.P. 
Numberless proprietary preparations are advertised, but without material advantage. 

Glycer. Pepsin., B.P. 10 per cent, of pepsin; 1.15 per cent, of hydrochloric acid. 
Dose, 4 to 8 c.c., i to 2 drams, B.P. 

Pepsin. Sacch. 1:10 of milk-sugar. 

Liq. Seriparus, N.F., B.P.C.; Liquid Rennet. Extracts of the fourth stomach of 
calves; used to coagulate unboiled milk (i: 100 to 300, 38C., iooF.) for the prepara- 
tion of junket and whey. 

* Pancreatinum (Pancreat.), U.S. P.; Pancreatin. A mixture containing enzymes, 
consisting principally of amylopsin, trypsin and steapsin, obtained from the fresh 
pancreas o! the hog or of the beef. It converts not less than 25 times its own weight 
of starch into sugars. However, commercial pancreatins generally contain little or no 
proteolytic ferment, and very uncertain amounts of diastase. The amylopsin acts 
best in a faintly alkaline (0.025 P er cent. NaHCOs) or neutral medium, and is destroyed 
by very weak acidity (0.006 per cent. HC1) (Long and Muhlman, 1914). Trypsin also 
acts best when alkaline (0.2 to i per cent. Xa2COs) but is somewhat active with very 
weak acidity. Excess in either direction is detrimental. It acts best on fibrin or casein, 
feebly on cooked albumen, and scarcely at all on raw albumen (Long and Muhlmann; 
Sugimoto, 1913). Pancreatin occurs as a cream-colored, amorphous powder, having a 
faint, peculiar odor. Slowly sol. in water; insol. in ale. Dose, 0.5 Gm., 8 gr., U.S. P. 

Liq. Pancreat., B.P. An alcohol-glycerin extract. Dose, 4 to 8 c.c., i to 2 drams, 
B.P. 

Pidv. Pancreat. Co., X.F., B.P.C. Pancreatin mixed with 4 parts of sodium bi- 
carbonate; is used for the artificial digestion of milk (1.5 to 500, 38 C., iooF., for half 
an hour). 

Papain. The dried milk-juice of the unripe fruit of Carica Papaya. Extracts are 
marketed under proprietary names. It is supposed to digest proteins in acid, alkaline 
and neutral media; its activity, however, is variable, and always much less than pepsin. 
The digestion is more rapid at 80 to 95C. (Pozerski, 1909; some of its peculiarities 
were studied by Mendel and Blood, 1910). Dose, o.i to i Gm. 

Extractum Malti (Ext. Malt), U.S. P. A watery, pilular extract of malt, prepared 
at 55C., and evaporated at this temperature to the consistence of a thick honey. 
Contains diastase, and therefore digests starch; but the diastatic power of the commercial 
extracts is very weak. 1 It is more properly nutrient, being rich in carbohydrates. 
Dose, 15 c.c., % ounce. Many liquid malt extracts are practically strong beer. 

Mailum, U.S P.; Malt. The grain of barley, Hordeum sativum, partially germi- 
nated artificially, and then dried at a temperature not exceeding 55C. It is capable 
of converting not less than five times its weight of starch into sugars. 

Diastasum, U.S. P.; Diastase. A mixture containing amylolytic enzymes obtained 
from an infusion of malt. It converts not less than fifty times its weight of potato starch 
into sugars. A yellowish-white, amorphous powder or in translucent scales; odorless 
and tasteless. Diastase gradually loses its amylolytic power on keeping; is diminished 
by the presence of acids or alkalies. Sol. in water; almost insol. in ale. Dose, 0.5 
Gm., 8 gr., U.S.P. 

Diastatic ferments are also obtained from other sources, animal and vegetable; 
Taka diastase, for instance, from a Japanese mould. Their diastatic action is also 
weak and unreliable. 2 

LACTIC ACID FERMENTS 

These were introduced by Metchnikoff, with the idea of acidifying the intestines, 
and thereby preventing intestinal putrefaction, which he held responsible for premature 
senility. They had only a brief popularity. Even if the theory of old age were ac- 

i Rep. C.P.C., J.A.M.A., July n, 1908. 

s Rep. C.P.C., J.A.M.A., July n, 1908; July 6, 1912. 



FERMENTS AND NUTRIENTS 99 

cepted, there is no evidence that these organisms check intestinal putrefaction. To the 
contrary, they usually succumb to the putrefactive bacteria. The commercial prep- 
arations were of uncertain composition (Heinemann, 1909). The more reliable are 
listed in X.X.R. Metchnikoff's Bacillus bulgaricus is in no way superior to the 
Streptococcus lacticus which produces the ordinary souring of milk. 

MEDICINAL FOODS 

Limitations. The administration of food in the guise of medicine is 
sometimes advantageous; but medicinal foods, are subject to the ordinary 
law of dietetics, and therefore can not accomplish the wonders which are 
often claimed for them. The proprietary foods have been enormously 
overestimated, and therefore have probably done more harm than good. 
The ultimate value of any food depends mainly on the amount of calories 
which it can yield, and on its supplying at least a minimum of proteins. 
In these respects, the medicinal foods are all inferior, for they can not be 
administered practically in sufficient quantity to supply the needs of the 
body. They have a place as adjuvants to other foods, permitting the 
introduction of more food than the patient could otherwise be induced to 
take. This may be needed for superalimentation; when digestion is low, 
as in fevers or convalescence; or to tide the patient over some temporary 
crisis. Aside from the special diabetes foods and cod liver oil, their value 
is largely psychic. The better medicinal foods, it is true, are free from 
indigestible portions, and are pleasantly flavored; those which contain 
meat extractives would stimulate the flow of gastric juice; but all these 
properties are possessed by milk, eggs, cereals and soups. A few are more 
concentrated; but this has no advantage in feeding the sick, since water 
must be supplied in one form or another. 

Predigested Foods. The value of these is doubtful, even .if they are 
well utilized; for digestive disturbances involve more commonly the motor 
functions and absorption than the chemical functions. The continued 
use of predigested foods often produces irritation. Their main field is in 
rectal alimentation. 

Utilization of the Products of Artificial Digestion. It has been questioned whether 
this is as effective as that of the products of natural digestion. The work of Abder- 
halden and others has shown that nitrogen equilibrium can be maintained in animals 
on a diet of the products of acid-hydrolysis of proteins, if these are sufficiently varied 
to secure a proper balance of the various amino-acids, etc. (Rep. C.P.C., 1912). 

Animals with their digestive canal excised can be kept alive by intravenous injection 
of amino-acid mixtures, but not by peptones, proteoses, ammonium or urea (Henriquez 
and Anderson, 1914). 

Dry "Peptones." The dried products of the artificial digestion of meats, usually 
consisting mainly of albumoses. Their taste is disagreeable and they often cause 
irritation. Intravenously they are toxic, lowering the blood pressure and rendering 
the blood non-coagulable (see Index). In "Erepton," N.N.R., the digestion has been 
carried to the stage of amino-acids. 

Liquid Predigested Foods. As found on the market, these are flavored solutions 
containing small amounts of predigested proteins (% to 6 per cent.) and of sugars and 
other carbohydrates (J^ to 15 per cent.), with 12 to 19 per cent, of alcohol, and often 
with large quantities (up to 30 per cent.) of glycerin (details in Rep. C.P.C., J.A.M.A., 
May u, 1907). Their protein content averages less than that of milk (3.5 per cent.), 
and in energy value, on the basis of calories, they are vastly inferior. Their daily dose 
(50 to 150 c.c.) yields but 55 to 300 calories, including their alcohol; and this is only 
one-thirtieth to one-fifth of the minimum daily requirement, even of resting patients 
(1,500 calories, yielded by two quarts of milk). To increase their dose to that required to 
maintain nutrition would mean the ingestion of an amount of alcohol equivalent to 
about a pint of whisky per day. 

No liquid food should be given consideration unless it contains, exclusive of alcohol 
and glycerin, at least as much food value as milk; and at least one-fourth of this should 



100 MANUAL OF PHARMACOLOGY 

ho in the form of nitrogenous constituents. Those complying with this requirement are 
enumerated in N.N.R. Kven these can only be considered as adjuvants and vehicles. 

Meat and Beef Juices. When prepared extemporaneously by expression of fresh 
or slightly broiled meat, these contain from 2.5 to 9 per cent, of coagulable proteins, 
and 2 to 4 per cent, of other proteins and nitrogenous extractives. They have there- 
fore a moderate value as sources of nitrogen. The commercial preparations are supposed 
to be concentrated; in fact, however, they are very inferior, containing but 0.2 to 3 per 
cent, of coagulable proteins; others are reinforced by the addition of defibrinated blood, 
sugar, glycerin, etc., which are of doubtful utility (Rep. C.P.C., J.A.M.A., Nov. 20, 
1009). 

Bouillon and Meat Extracts.'* Bouillon (beef-tea) is prepared by boiling meat with 
water; the extracts by evaporating the solution to a semisolid consistency. The co- 
agulable proteins are removed by this process, the extract containing the salts of the 
meat, the flavoring substances and meat bases (xanthin and creatin products) and a 
certain amount of non-coagulable protein, in the form of gelatin, albumoses, etc. In the 
small amounts in which they are used, these preparations contain a very insignificant 
quantity of nutriment. They are, however, valuable as stimulants. They owe their 
action largely to the odorous principles which they contain, and which are excellent 
stomachics (Wolff, 1912). 

The potassium salts have also been invoked to explain the action, it being claimed 
that they stimulate the heart in moderate doses and paralyze it in large doses. But 
the dose required to produce the former effect is very much larger than would be admin- 
istered in beef-tea. 

Beef extracts of the Liebig type (pasty consistency) contain 60 to 80 per cent, of 
solids, of which 3 to 18 per cent, are soluble proteins, i to 5 per cent, insoluble proteins, 
12 to 25 per cent, meat-bases, and 13 to 30 per cent, ash (McGill, 1899). They are used 
to flavor soups, etc. 

Insoluble Meat Powders. Tropon, Sozon, etc., are employed to thicken soups. 
Their usefulness is very limited. 

Casein Powders. Include nutrose, N.N.R. (sodium caseinate); and some adver- 
tised to the public with most extravagant claims (Sanatogen, J.A.M.A., May 6, 1911, 
etc.). It is difficult to understand in what ways these could be superior to ordinary 
cottage-cheese. 

Dextrose, N.N.R. Prepared artificially by the action of dilute acids on starch; 
is sometimes used as nutrient (to 180 Gm., 6 ounces daily); and as an addition to saline 
infusion liquids (o.i per cent.). 

Rapidity of Oxidation of Sugars. In man, the respiratory quotient shows that 
saccharose, lactose, levulose and lactose begin to be oxidized within five or ten minutes 
after their ingestion. With glucose and maltose, oxidation begins only after 20 or 30 
minutes (Higgins, 1916). 

DIABETES FOODS 

Gluten flours should be practically free from carbohydrates; but many are 
fraudulent (J.A.M.A., 1913, 60 1922; Street, 1913). Those acceptable are enumerated 
in N.N.R. Other "Diabetes Flours" consist of casein, etc. 

Levulose, N.N.R., and inulin are sometimes tolerated better than other sugars, 
(v. Noorden, 1910; Goudberg, 1913); but the difference is usually not important. In 
pancreatic diabetes and phosphorus glycosuria the levulose is deposited as glycogen, 
whilst dextrose is not (E. Neubauer, 1909). H. B. Lewis and Frankel, 1914, conclude 
that inulin is quite useless. It is not digested, although some is burned by the intestinal 
bacteria. None is converted into utilizable carbohydrate, even in phlorhizin animals. 

Grafe, 1914, finds promising results with caramelized sugar. It is all absorbed and 
completely tolerated even in severe diabetes. It does not increase the blood-sugar, 
and the respiratory quotient shows that it is utilized in the diabetic as well as normal 
organism. 

Mannit is also employed as sweetener, being assimilated without causing glycosuria; 
doses above 20 to 30 Gm. are laxative. (For normal assimilation limits of various 
carbohydrates, see Macleod, 1913 and 1914; Jacobson, 1913.) 

Hediosit, N.N.R. An artificial sugar, the lacton of a glucoheptonic acid; was intro- 
duced by Rosenfeld, rgrr, as sweetening agent and food, but has failed to realize the 
original expectation. When administered by mouth, 25 to 85 per cent, is excreted un- 
changed by the urine and feces. The fate of the remainder has not been established, 
l-ar^e doses produce diarrhea and other digestive disturbances. Its excretion is 
diminished in nephritis, resulting in retention (Kohshi, 1912; Kramer, 1912; Lenel, 
1914). 



FERMENTS AND NUTRIENTS IOI 

Jambul. The fruit, leaf, or bark of Syzygium Jambulana, Eastern Asia. It contains 
an essential oil, tannin, and probably a glucosid. It has been recommended in diabetes 
mellitus in doses of 0.3 to 0.5 Gm. of the fruit (5 to 8 grains). Efficiency doubtful. 

COD LIVER OIL 

This is employed as nutrient in tuberculosis, rickets, diabetes and other 
wasting diseases. It has a very high food value, a tablespoonful yielding 
about 130 calories. 

Animal experiments support the clinical conclusion that it favors 
nutrition and growth more than other fats. The reasons for this superior- 
ity are obscure, but it is not shared by fat-free extracts. 

The oil may cause distaste, eructations and diarrhea. These are 
often avoided by starting with small doses, gradually increased. It 
is generally administered two hours after meals. Indigestion and fever 
contraindicate its use. 

Superiority over Other Fats. Cod liver oil was adopted into medicine in the early 
decades of last century from the Norwegian fishermen, who prepared it by very crude 
methods, involving putrefaction. These oils, therefore, contained free fatty acids 
(Buchheim, 1874), bile constituents (Naumann, 1865), cholesterin, putrefactive alka- 
loids (asellin, morrhuin, etc.; Gautier and Mourges), traces of iodin (about as much as 
oysters), and other impurities. All of these have been credited with the effects; but 
these substances are eliminated in the modern sanitary processes, without decreasing 
the usefulness of the oil; whilst "oil-free," "tasteless" extracts, wines, etc., are useless 
(Rep. C.P.C., J.A.M.A., Oct. 9, 1909). 

The easier emulsification of the oil is probably a peculiarity of its characteristic 
fats, which are largely glycerids of jecoleic and therapic acids. Lipanin was a mixture of 
olive oil with 6 per cent, of oleic acid, based on Buchheim's suggestion that free acids 
aid emulsification. It has not establshed itself clinically. The digestibility of different 
animal fats is discussed by Langworthy and Holmes, 1915. Mottram, 1915, attributes 
the superiority to the high percentage of unsaturated fatty acids, which approaches 
more closely the form in which fat is supposed to be utilized in metabolism 

Specific Influence of Fats on Growth. Osborne and Mendel, 1913 and 1914; Mc- 
Collum and Davis, 1913; and Mendel, 1915, investigated this on rats maintained on 
artificial diets that kept up their body- weight, but did not allow further growth. Growth 
resumed when butter-fat, beef-fat egg- yolk lipoid or especially cod liver oil were added 
to the diet; whereas lard and olive or almond oil were ineffective. This fat-soluble 
growth-promoting substance "A" is widely distributed in plants, occurring also in 
leaves (McCollum, Simmonds & Pitz, 1916). Fat- free extracts of cod liver oil do not 
share this specific nutrient effect of the oil (Street, 1915). 

The growth-promoting action of butter-fat is not due to contamination with nitrogen 
or phosphorus compounds (Osborne and Wakeman, 1915). It is confined to the portion 
of the fat with low melting-point is not destroyed by steam (Osborne and Mendel, 1915), 
and as it exists in butter, is very stable under ordinary conditions of storage (Mendel and 
Ooborne, 1916). Another, a water-soluble growth-promoting substance "B" (Funk and 
Macallum, 1914), is also of wide occurrence in animal and vegetable foods (McCollum 
el al., 1916). 

Vitamins. These are somewhat analogous but probably not identical substances, 
that counteract the harmful effects of certain limited dietaries. Eyknian discovered 
that polyneuritis resembling beri-beri can be induced in fowls by an exclusive diet of 
polished rice. Funk, 1911, found that this can be prevented by small amounts of a 
substance separated from rice polishings, which he calls a vitamin. Its exact nature is 
not yet known, but it is probably a fairly simple substance. Similar principles can be 
prepared from yeast, etc. 

PREPARATIONS COD LIVER OIL 

* Oleum Morrhua (Ol. Morrh.), U.S.P., B.P.; Cod Liver Oil (Ol. Jecoris Aselli). 
A fixed oil from the fresh livers of Gadus Morrhua and other species. Occurs as a pale 
yellow thin oil, having a peculiar fishy, but not rancid odor, and a bland fishy taste. 
It thickens on exposure to air. Dose, 10 c.c., 2% drams, U.S.P.; 4 to 15 c.c., i to 4 
drams, B.P. 



IO2 MANUAL OF PHARMACOLOGY 

* Emulsum Olei Morrtnue (Emul. Ol. Morrh.), U.S. P. A 50 per cent, emulsion, 
made with acacia, sweetened with syrup and flavored with wintergreen. Dose, 15 c.c., 
4 drams, U.S.P. 

PARENTERAL ALIMENTATION 

Rectal Feeding. This becomes necessary when alimentation by 
mouth is inadmissible. However, only sugars are well absorbed by this 
channel; fats, undigested proteins, milk and casein poorly. 

The absorbability may be increased by pancreatic predigestion (Reach, 1901). 
Even with peptonized milk, the average daily absorption of nitrogen is only 1.14 Gm., 
i.e., practically insignificant (Adler, 1915). The absorption of fats from enemas is 
negligible (Nakashima, 1914). Judged by the urinary nitrogen, practically no 
protein is absorbed from milk or eggs, unless the peptonization is carried to the 
amino-acid stage. Dextrose is well absorbed and utilized, being capable of diminishing 
acetonuria (Bergmark, 1915). 

Rectal alimentation suffices for only a limited time, varying with the previous con- 
dition of the patient, especially as regards adipose tissue. The food is introduced 
into the rectum in the form of enemata. These must be made as non-irritant as possible; 
i.e., they must not be too concentrated. They must be warmed and injected very slowly 
in small quantities of 6 to 8 ounces (200 c.c.) at each injection, repeated at intervals of 
six to eight hours. The constituents must of course all be in the liquid form. The 
best medium is milk, pancreatized for twenty-four hours, with 5 per cent, of dextrose 
added (Bywaters and Short, 1913); and in this the sugar probably plays the main part. 

Small enemas are carried by antiperistalsis to the cecum, but not into the ileum; 
with larger injections, some of the material passes into the small intestine (Cannon). 

Subcutaneous Feeding. The hypodermic injection of nutrient solutions has been 
tried with limited success. Dextrose has given the most promising results. Even 
large doses are well utilized and have no detrimental effects on nitrogen metabolism 
(Underbill and Closson, 1906; Berendes, 1911); but are capable of diminishing ace- 
tonuria (Bergmark, 1915). Only a small proportion is excreted into the alimentary 
tract (Kleiner, 1911). A 5 per cent, solution may be given under the skin, or 10 per 
cent, intravenously, up to 1,000 c.c. per day (Kausch, 1911). 

Saccharose is partly utilized (Mendel and Mitchell, 1905; about one-third, Japelli 
and d'Errico); but mainly excreted unchanged (Mendel and Kleiner, 1910; Heilner, 
1911). It is not available for feeding (Mendel, 1914). Roehmann, 1915, claims 
that the blood, after intravenous saccharose injections, sometimes develops ferments 
that invert it to dextrose and levulose, and even convert these into lactose. Abder- 
halden and Brohm suggest that the utilization may be explained by partial excretion 
into the alimentary canal, where it is converted, and reabsorbed in usable form. 
Lactose, dextrimand glycogen are also not available. In normal animals, lactose in- 
jected into the blood disappears rapidly into the tissues and urine; after nephritis or 
in nephrectomized animals, it is retained in the blood (O. Schwarz and Pulay, 1915). 

Oil can be utilized hypodermically; 10 to 100 Gm. per day of olive oil being slowly 
injected with the same technic as is used for the injection of antitoxic serums. The 
absorption, however, is so slow that these injections are almost worthless (Winternitz, 
1903; Henderson and Crofutt, 1905). 

Intravenous Feeding. This has been accomplished successfully in animals, by a 
mixture of protein cleavage products, dextrose, sodium acetate and salts (Hendriquez 
and Anderson, 1913). Serum protein is well utilized (Austin and Eisenbrey, 1912), 
but the dangers (anaphylaxis, etc.) preclude its clinical use as nutrient. 

Fat introduced in emulsion intravenously is also burned (Murlin and Riche, 1915); 
and so, of course, is dextrose. 



EMOLLIENTS 

Definition of Emollients and Demulcents. These are drugs which 
soften, "relax," protect, and "soothe" the parts to which they are applied; 
in other words, drugs which lessen irritation. The term emollient is re- 
stricted more to those used on the skin, demulcent to those applied to mucous 
membranes. No very sharp distinction can be drawn between these, and 



EMOLLIENTS 103 

many belong to both classes; but, as a rule, the fats are used as emollients, 
the gums as demulcents. 

These substances lessen the action of all chemic, mechanical or bac- 
terial irritants; diminishing pain, reflexes, catarrh, and all manifestations 
of irritation. They also delay and diminish absorption, particularly 
from the stomach, but also from the intestine, subcutaneous tissue, etc. 
In this way they diminish the systemic effects of absorbable poisons, whilst 
they prolong their local actions. 

Mechanism of Action. Colloids and fats are practically indifferent 
and inabsorbable for cells, so that they do not produce any direct effects 
on them; but through their adhesive character, they form an extra cover- 
ing to the surfaces to which they are applied, and thus hinder the access 
of irritant agents. Their action consists, therefore, in mechanical pro- 
tection, and is strictly local. Fine insoluble adhesive powders (talcum, 
bismuth) act similarly. 

Explanation. The oils prevent the penetration of water-soluble substances, the 
gums that of fats and resins. Gums also lessen the effects of crystalloids, although they 
do not impede their diffusion. They produce this effect by increasing the viscidity 
of the solution, thereby interfering with its transportation (von Tappeiner, 1902). 
Adsorption probably also plays a part, for dissolved substances are condensed on the 
surfaces of fine powders and thus removed from the solution. 

One sees a beautiful illustration of these facts in the natural lubricants of body- 
coverings. Whilst the skin is normally covered with a thin layer of oil, the mem- 
branes of the interior of the body are moistened with mucus, which is a typical gummy 
demulcent. 

Emollient Drugs. These comprise the true fats and oils (glycerids 
of fatty acids), woolfat, petrolatum, and glycerin. They are employed 
mainly on external surfaces, to soften and protect the skin, ulcers, burns, 
and other superficial wounds; as vehicles (salves) for the application of 
medicaments to the skin or, more rarely, for systemic effects (mercurial 
inunctions). Internally, the true fats serve as nutrients. Larger amounts 
than can be digested stimulate peristalsis and act as intestinal lubricants 
and laxatives. For external use, the liquid or semifluid fats (oils, lard, 
woolfat, glycerin) should be chosen if a deep effect is desired for softening 
the skin or for inunction. The effects of petrolatum and of the harder 
"cerates" and plasters are more superficial and prolonged. 

Penetration of the Skin. Oils penetrate the epidermis much more 
readily than watery solutions. Rubbed into the skin, they enter the 
sebaceous glands and eventually can be demonstrated microscopically 
in the lymph channels. True fats are gradually oxidized and disappear; 
but the mineral fats remain for a long time in the subcutaneous tissue, and 
thus produce chronic irritation and fibrosis. The animal and vegetable 
fats therefore deserve preference when penetration is desired (Sobieranski; 
Juckuff; Meyer; see "Ointments" in Index). 

Paraffin Prothesis. The persistence of the mineral fats in the subcutaneous tissue 
has been utilized for the correction of deformities (e.g., of the nose), by injecting sub- 
cutaneously a mixture of paraffins melting at about 4oC. There is some danger of 
embolism, and the results are not permanent, the paraffin being gradually replaced by 
scar-tissue (Heidingfeld, 1910). 

Protection of the Skin. The oily emollients and glycerin soften the 
stratum corneum, and render the skin more pliable and resistant to injuri- 
ous agencies. They reinforce in this manner the natural fat of the skin 
and prevent roughness and "cracks" from wind, cold weather, sun- 
burn, skin diseases, etc. 



104 MANUAL OF PHARMACOLOGY 

Rancidity. Fats turn "rancid" on keeping, especially if they are ex- 
posed to air, light, and heat, and if they contain protein impurities. The 
change consists in oxidation with the development of free volatile fatty 
acids. Rancid fats are disagreeable and irritating, and therefore unfit 
for medicinal use. Lanolin and the petroleum products are free from this 
objection. 

OLIVE OIL AND OTHER BLAND FATTY OILS (OLEA PINGUA) 

Uses. The expressed oils of olive, cottonseed, almond, sesame, etc., 
are essentially similar. For internal use, olive oil is preferred because of 
its more agreeable flavor. These oils are employed externally to soften 
the skin and crusts in eczema and psoriasis; as dressing for burns; as 
vehicles for liniments, etc.; and by rectal injection, to soften fecal concre- 
tions (150 to 500 c.c., 5 to 20 ounces, of the cheaper cottonseed oil, warmed. 
Hertz claims that oil is less effective than water for this purpose). In- 
ternally, olive oil is used as nutrient, laxative, and in hyperchlorhydria 
(15 to 50 c.c., Yi to 2 ounces before meals). Kennedy and others have 
claimed beneficial results in biliary colic, using large doses (150 to 500 c.c. 
in four to eight portions within three hours). Its effects, if any, have not 
been explained; it does not increase the flow of bile, and the concretions 
found in the feces when olive oil and epsom salt are given, are not gall- 
stones, but simply soap (magnesium oleate). 

These oils are insoluble in water or glycerin, very sparingly in alcohol, 
freely in chloroform, ether, volatile oils, or fats. 

Fats are useful antidotes in corrosive poisoning. 

Influence on Digestion. Neutral fats allay gastric peristalsis, diminish gastric 
secretion and acidity (Pawlow; Cowie and Munson, 1908; Chiari, 1915), and lessen 
the pyloric tone. They leave the stomach slowly and in small portions; a fatty meal 
requiring seven hours for complete passage into the duodenum. The digestibility of 
animal fats is discussed by Langworthy and Holmes, 1915. The length of gastric 
sojourn increases with the melting-point of the fat, Feyer, 1913. In the duodenum, 
fats check the gastric discharge and stimulate the flow of pancreatic juice and the evacua- 
tion of the gall-bladder (Klee and Knuepfel, 1914). 

Subcutaneous injections of fats as nutrients were proposed by Leube, 1895. They 
can be administered indefinitely without irritation or other disturbance, and are grad- 
ually absorbed by the lymph. However, the absorption of plain fats is too slow to 
be of practical value (Winternitz, 1903; Y. Henderson and Crofutt, 1905). Somewhat 
better results were obtained with fats emulsified by lecithin (Mills and Congdon, 1911). 
The injection of free fatty acids would be toxic. Fats are also oxidized when emulsions 
are injected into a vein (Murlin and Riche, 1915). 

Oleic Acid Anemia. The continued administration of large doses of oleic acid, by 
mouth or hypodermically, to animals, produces hemolysis and severe anemia (Faust, 
1906 and 1908; Polano, 1909; Adler, 1911). Similar effects produced by the injection 
of extracts of tapeworm (bothriocephalus) are also due to oleic acid-cholesterin esters 
(Faust). The saturated higher fatty acids are also hemolytic (Shimazono, 1911). 
The hemolysin of bacterium putidum is oxydimethyl thiol-erucic acid, a typical un- 
saturated fatty acid (Burckhardt, 1910). 

PREPARATIONS FATTY OILS 

* Oleum Olivce (Ol. Oliv.), U.S.P., B.P.; Olive oil (Sweet Oil). A pale yellow or 
greenish-yellow fixed oil, expressed from the ripe fruit of Olea europaea. Slightly sol. 
in ale. Dose, 30 c.c., i ounce, U.S.P. 

Oleum Gossypii Seminis (Ol. Gossyp. Sem.), U.S.P.; Cottonseed Oil. -Fixed oil, 
expressed from seeds of cultivated varieties of Gossypium. Slightly sol. in ale. On 
account of its cheapness, it is especially adapted for external use. It is inferior for inter- 
nal administration; it can not be readily emulsified or saponified, since the free fatty 
acids have been removed in the process of purification. 



EMOLLIENTS 10$ 

Gossypol. Feeding with "cottonseed meal" (not the oil) sometimes produces toxic 
effects. These are due to the gossypol, a crystalline substance, first isolated by March- 
lewski, 1899. It is soluble in gasolin. It maybe rendered harmless by various methods 
of oxidation, precipitation or extraction (Withers and Carruth, 1915). 

Ol. Sesami, U.S.P., B.P.; Oil of Sesame (Teel Oil, Benne Oil). Expressed from 
seeds of Sesamum indicum. 

Ol. Arachis, B.P. (Peanut Oil). 

Ol. Amygdala Expressum (Ol. Amygd. Exp.); Ol. Amygd., B.P. (Oil of Sweet 
Almond). Fixed oil from bitter or sweet almond. 

Ol. Lint, U.S.P., B.P.; Linseed Oil. Expressed from Linseed. Disagreeable odor. 
Employed mainly in veterinary practice and in liniments. "Boiled" oil must not be 
used. Dose, 30 c.c., i ounce, U.S. P. 

Acid. Oleic, U.S.P., B.P. Mixture of fat acids consisting chiefly of CnHssCOOH. 
Yellowish or brownish-yellow, oily liquid; peculiar lard-like odor and taste. Practi- 
cally insoluble in water; completely miscible with about 85 per cent, alcohol; soluble in 
chloroform and in fixed and volatile oils. Used as solvent for metallic oxids and alka- 
loids, intended to be absorbed from the skin. 

Acidum Stearicum (Acid. Stear.) U.S. P. Mixture of fat acids consisting chiefly of 
CnH-^COOH obtained from tallow or other fats. Hard, white, or yellowish-white, 
somewhat glossy, solid, odorless, having a slight, tallow-like odor, tasteless. Melts 
above 56C. Sol. in ale. (1:21); almost insol. in water. Used in glycerin supposi- 
tories. 

*0l. Theobromatis (Ol. Theobrom.), U.S.P., B.P.; Oil of Theobroma (Cacao 
Butter). A yellowish- white solid fat from the roasted seeds of Theobroma Cacao. 
It melts at the temperature of the body. It is used mainly for making suppositories, 
and as a lubricant in massage. Not to be confused with: 

Oleum Cocos; cocos-oil. The expressed oil of the cocoanut, the fruit of the palm, 
Cocos nucifera. It is a whitish fat, soluble in alcohol, used especially in soap-making. 

Ol. Chaulmoog., B.P.; Chaulmoogra Oil (Gynocardia Oil). A fatty oil 
expressed from seeds of Taraktogenos Kurtzii. Favorable, but temporary results 
are reported in leprosy. The action, if any, is unexplained. Dose (oral), 0.3 to 
0.6 c.c., 5 to 10 minims, gradually increased to 2 to 4 c.c., ^ to i dram, B.P. As it 
becomes very nauseating, it has been given hypodermically, 0.3 to 0.8 Gm., 5 to 
10 drops. Heiser, 1914, advises a mixture of 60 parts, each, of Chaulmoogra and 
camphorated oil, with 4 parts of resorcin. 

Injections are made weekly, beginning with i c.c. and increasing gradually. He 
claims very constant improvement and sometimes apparent cure. The oil is but- 
tery, of greenish color, and peculiar odor and taste. It contains 18 per cent, of 
gynocardic acid, which has also been used in doses of 0.03 to 0.02 Gm. (^ to 3 
grains). Power, 1915, finds that the genuine (Taraktogenos) oil consists largely of the 
glyceryls of a new type of fatty acids, mainly chaulmoogric acid, CisflszOz. 

Ung. Chaulmoog., B.P. 10 per cent. 

LARD AND SIMILAR ANIMAL FATS 

These are employed as soft ointment bases. They all have the in- 
convenience of rapidly turning rancid. This is delayed by antiseptics, 
as in Benzoinated Lard. 

PREPARATIONS FATS 

* Adeps Benzoinatus (Adeps Benz.), U.S.P., B.P.; Benzoinated Lard. Lard digested 
with Benzoin. In this process it takes up a certain amount of the latter, and acquires 
the antiseptic and stimulant properties of balsams, besides increasing its own keeping 
qualities. 

Adeps, U.S.P.; Adeps Prcep., B.P.; Lard. The purified internal fat of the abdomen 
of the hog. Insol. in water; very slightly sol. in ale.; melts between 36 and 42C. 

Scvitm Prceparalum (Sev. Praep.), U.S.P., B.P.; Suet. The internal fat of the 
abdomen of the sheep, purified by melting and straining. 

See. Benz., B.P. 

Butyrum, Butter, is sometimes used as an ointment basis. Since it can not be salted 
for this purpose, it keeps very poorly. 

Other Animal Fats. Other animals also yield fats which are popularly supposed to 
have special advantages dog fat, goose grease, etc. There appears to be no reason 
for preferring them to the more easily obtainable lard. 



106 MANUAL OF PHARMACOLOGY 

WOOLFAT-LANOLIN 

This differs chemically from ordinary fats in that the fatty acids are 
not united to glycerin but to cholesterin and isocholesterin and smaller 
quantities of other alcohols. 

Crude woolfat or suint was used by the ancients, but was too disagree- 
able, until a purified product was introduced by Liebreich as "lanolin." 
Even this has a rather unpleasant odor and disagreeable sticky consist- 
ency, but it does not readily turn rancid. Since its composition resem- 
bles that of the natural skin-fat, it was believed that it would be more 
readily absorbed; but this does not seem to be the case. Its chief advan- 
tage lies in the property of forming salve-like emulsions with up to two or 
three times its volume of water, so that watery solutions may be incor- 
porated with it. This is attributed by Liefschuetz and Unna (E. Unna, 
1912) to traces of free isocholesterin and oxycholesterin. It also emul- 
sifies other fats and petrolatum. Anhydrous woolfat is too sticky for use. 
It is employed after the admixture of 30 per cent, of water (Hydrous Wool- 
fat), or better with the further addition of an equal weight of petrolatum 
or other fat. It is not absorbed from the intestines (Bloor, 1913). 

PREPARATIONS WOOLFATS 

* Adeps Lance Hydrosus (Adeps Lan. Hyd.), U.S. P., B.P.; Hydrous Woolfat (Lano- 
lin). Contains from 25 to 30 per cent, of water. A yellowish- white, or nearly white, 
ointment-like mass, having not more than a slight odor. Miscible with about twice 
its weight of water. 

Adeps Lan., U.S. P., B.P.; Woolfat. The purified fat of the wool of sheep freed 
from water. A light-yellow, tenacious, unctuous mass, not more than a slight odor. 
Miscible with about twice its weight of water. Sparingly sol. in ale., readily in 
chlorof., eth., acetone, etc. Melts between 38 and 42C. 

PETROLATUM AND OTHER PETROLEUM PRODUCTS 

Properties. These were introduced under the name of Vaselin by 
Chesebrough, 1871. They are obtained from petroleum by distilling off 
the more volatile products, chilling, purification by filtration through 
bone-black, etc. They consist of hydrocarbons of the methane and 
related aliphatic series. According to the process of preparation, they 
occur of various consistencies, from the waxy "paraffin" (employed for 
hardening ointments), through the buttery "petrolatum" (a typical 
emollient), to the "liquid paraffin" (used especially for laxative and sprays) . 
The color, from deep yellow to almost pure white, does not affect the action. 

Notwithstanding the chemical difference, they resemble the fats in 
physical character and therapeutic application. They have the advan- 
tage that they are chemically indifferent, do not undergo deterioration, 
can not become rancid or irritant, and do not react with drugs, such as 
oxidizing or reducing agents. They are not so well adapted for inunction. 

Liquid Petrolatum as Laxative. Mineral oils are not absorbed (except 
perhaps doubtful traces; Bradley and Gasser, 1912); but are eliminated 
unchanged by the feces (Randolph, 1885; Hutchison, 1899; Bloor, 1913). 
They can not, therefore, act as nutrients. By softening the feces, they are 
mildly laxative, and are used as such in intestinal stasis (A. D. Schmidt, 
1905; Lane, 1913). Sometimes they do not mix well with the feces, the 
oil leaking from the anus. Occasionally they are followed by nausea and 



EMOLLIENTS 107 

regurgitation (Bastedo, 1914). Any of the "liquid paraffins" (Petro- 
latum Liquidum Album) may be employed there being no therapeutic 
difference between the light or heavy Russian or American oils (Bastedo, 
1915). Their composition is perhaps also similar. The usual dosage 
is from 10 to 30 c.c., one-half hour before meals; or a single dose of 30 to 
60 c.c. before retiring. The "light" oil is preferred for sprays (Wilbert, 
1914) ; the more viscid oils for laxatives. 

The Russian oil is non-fluorescent, and consists mainly of naphthenes; 
the American oil contains members of the methane series, and is generally 
fluorescent. The history and composition is discussed in the J.A.M.A., 
1914, 62 : 1740; and by Hilton, 1914. 

Composition of Liquid Petrolatums. All crude petroleum oils are complex mixtures 
of hydrocarbons, the composition varying quantitatively according to their origin. 
These differences are eliminated in refining, so that the composition of the thoroughly 
refined, colorless products is probably similar, whether the product is derived from 
Russian or from American oils. The liquid petrolatums consist mainly of naphthenes 
(C n H 2 n) and polynaphthenes (C n H 2 n-2 and C n H 2n _4). They do not contain true 
paraffins (CnH^n+s); so that the term "Paraffin Oil" is a misnomer. The irritant 
olefin hydrocarbons and the benzenes of the crude oils are absent from the refined. 
Certain ingredients, which give the fluorescence and rancid taste, are more difficult 
to eliminate from some oils than from others (Brooks, 1916). 

Criteria of Availability. Brooks considers the physical qualities, the color, odor, 
taste and viscidity or specific gravity as much superior to all chemic tests. 

PREPARATIONS MINERAL FATS 

* Petrolatum (Petrolat), U.S. P.; Paraffinum Molle (Paraff. Moll.), B.P.; Petrolatum, 
Soft Paraffin (Petroleum Jelly, Vaselin). A purified mixture of semisolid hydro- 
carbons obtained from petroleum. An unctuous mass, varying in color from yellowish 
to light amber, having not more than a slight fluorescence; without .odor or taste. 
Insol. in water; scarcely sol. in cold or hot ale.; freely sol. in fats and fat solvents. 
Melting-point, 38 to 54C., U.S. P.; 40 to 46C.; B.P. The color may be specified by 
adding "Album" for white, "Flavum" for yellow. 

* Petrolatum Liquidum (Petrolat. Liq.), U.S. P.; Paraff. Liq., B.P.; Liquid Petro- 
latum, Liquid Paraffin. A mixture of liquid hydrocarbons. A colorless, transparent, 
oily liquid free from fluorescence, odorless, and tasteless when cold; insol. in water or 
ale. Dose, 15 c.c., 4 drams, U.S. P.; 4 to 16 c.c., i to 4 drams, B.P. Heavy Liquid 
Petrolatum (Heavy Liquid Paraffin, Heavy Mineral Oil) is a very viscous liquid. Light 
Liquid Petrolatum (Light Liquid Paraffin, Light Mineral Oil) is almost free from 
viscosity. 

Paraffinum (Paraff.), U.S.P.; Paraff. Dur., B.P.; Paraffin, Hard Paraffin. A puri- 
fied mixture of solid hydrocarbons. Colorless, or white, more or less translucent mass, 
without odor or taste; insol. in water or in ale. Melts at 50 to S7C., U.S. P.; 50 to 
6oC., B.P. 

Toxic Effects of Petroleum Products. ; Gasolin (Petroleum benzin). The inhalation 
of the vapors causes headache, nausea, giddiness, inebriation, unconsciousness, muscu- 
lar tremors, convulsions, dyspnea, cyanosis, and death (Buegi and Burgl; Wolf, 1911). 
Chronic poisoning results in dulness, pain in limbs, trembling, muscular weakness and 
other nervous disturbances (Rambousek), and pulmonary hemorrhages (Jaffe, 1914). 
The symptoms of acute and chronic poisoning, as they occur in the rubber industry, 
are described by Alice Hamilton, 1915. 

Concentrated vapors cause purely paralytic symptoms in frogs, but in mammals 
they seem to have only a weak anesthetic action. If they are inhaled to the exclusion 
of air, they will cause an asphyxial anesthesia. Before this sets in there are very char- 
acteristic convulsions (Sollmann, 1904). The animal struggles violently, then falls 
on its side and claws the air with all fours, as if running. The pupils are widely dilated. 
Reflexes absent. The spasms are intermittent, and between them the dog is perfectly 
limp, except that the toes, tail and eyelids continue to twitch. The respiration is nr#t 
stimulated, then weakened. There is paralysis of the vagus, then a depression of the 
cardiac muscle, and later of the vasomotor center. Either heart or respiration may stop 
first. 



108 MANUAL OF PHARMACOLOGY 

Gasolin is, therefore, unsuitable as an anesthetic even for animals; although it has 
been tried with man (Felix, 1888). It is said to be used as an intoxicant. Its oral 
administration does not produce gastroenteritis. It is absorbed slowly from the ali- 
mentary tract, and excreted mainly by the lungs (Jaffe, 1914). 

I'rlrolcittn (Coal oil). When petroleum is swallowed, it produces narcotic effects 
similar to those of alcohol, with strong gastroenteritis. It is toxic in proportion to its 
conum of the more volatile products. No fatal case has thus far been reported, 
although as much as a liter has been swallowed. Coal oil applied to the skin or con- 
tinuous handling of unpurified paraffin is a moderate irritant, and may lead to dermatitis 
(Joseph, 1896), acne and other eruptions, and papillomas (see "Tar"). 

WAXES 
These are used in pharmacy mainly to stiffen ointments (as in cerates). 

PREPARATIONS 

Cera Flaw (Cer. Flav.), U.S.P., B.P.; Yellow Wax, Beeswax. The purified product 
of the hive bee, Apis mellifera. Melts between 62 and 6sC. Sparingly sol. in ale.; 
sol. in eth., chlorof., and oils. 

Cera Alba (Cer. Alb.), U.S.P., B.P.; White Wax. Bleached beeswax. 

Cetaceum (Cetac.), U.S. P., B.P.; Spermaceti. A fatty substance, obtained from the 
head of the sperm whale, Physeter macrocephalus. Consists mainly of ester of cetylic 
alcohol and palmitic acid. 

Resina (Res.), U.S. P., B.P.; Rosin (Colophony). The residue left after distilling 
off the volatile oil from turpentine, the concrete oleoresin obtained from species of Pine. 

COMPOUND OINTMENT BASES 

These are survivals of older formulas, without serious advantage 
over the simpler bases. Typical ointments melt at the temperature of 
the body. 

PREPARATIONS COMPOUND OINTMENT BASES 

Unguentum (Ung.), U.S.P.; Ointment (Simple Ointment). 2 parts White Wax, 
8 parts Benz. Lard. 

Ung. Para/., B.P. Hard Paraff., 27 per cent.; Soft Paraff., 70 per cent; Beeswax, 
3 per cent. 

Ung. Aq. Ros., U.S.P., B.P. (Cold Cream). Expressed Almond Oil, thickened with 
Spermaceti and White Wax, flavored with Rose Water, and containing 5 per cent, of 
Sodium Borate, U.S.P. 

Ung. Ceta., B.P. Spermaceti, 20 per cent.; White Beeswax, 8 per cent.; Liq. 
Paraff., 72 per cent. 

Ung. Lance Co., B.P. Lard, 40 per cent.; Woolfat, 40 per cent.; Paraff. Oint., 
20 per cent. 

Ung. Res., B.P. Resin, 26 per cent.; Yellow Beeswax, 26 per cent.; Olive Oil, 
26 per cent.; Lard, 22 per cent. 

CERATES 

These are stiffer ointments, containing sufficient wax so that they 
do not melt at body temperature. They are also superfluous survivals. 

PREPARATIONS CERATES 

Ceratum (Cerat.), U.S.P. ; (Simple) Cerate. Three parts of White Wax and 7 parts 
of Benz. Lard. 

Cerat. Res., U.S.P.; Rosin Cerate (Basilicon Ointment). Rosin, 35 per cent.; 
Yellow Wax, 15 per cent.; Lard, 50 per cent. 



DEMULCENTS OR MUCILAGINOUS SUBSTANCES ICX) 

GLYCERIN 

Therapeutic Uses. This acts both as emollient and demulcent. It 
is used to soften the skin, to prevent chapping, internally in coughs, 
etc. Concentrated glycerin abstracts water, so that the soothing action 
is preceded by smarting. It should therefore be diluted with two or 
three volumes of water (rose water for lotions). Roth has shown (with 
Cataplasma Kaolini), that glycerin does not abstract water from the 
intact skin, because of the impermeability of the stratum corneum. 

Undiluted glycerin injected into the rectum causes evacuation in a 
few minutes, without pain if there are no abrasions (5 to 10 c.c., i to 
23; or the official suppository). Similarly, it provokes uterine con- 
tractions if introduced into the cervical canal. Large doses (100 to 150 
Gm. per day, in divided portions) have been employed to kill intestinal 
trichinae. 

Pharmaceutic Uses. Glycerin has many uses in pharmacy, as a 
vehicle and solvent for salts; sweetening agent, to preserve ferments 
and vaccines; to keep pill masses or extracts moist, etc. As a sweetening 
agent in diabetes it has been replaced by saccharin. 

Nutrient Value. Glycerin has been tried as a substitute for cod liver oil. It is 
transformable into glycogen and sugar; but its nutrient value is rather doubtful, since 
larger quantities lessen gastric secretion (L. Kast, 1910) and provoke diarrhea. Like 
other intestinal irritants, it produces increased elimination of uric acid (Abl, 1913). 

Toxic Effects. These have never been reported in man, but they occur in animals 
when large doses are given, by any channel. The symptoms are convulsant and para- 
lytic, probably through a direct action of glycerin on the central nervous system. The 
blood corpuscles are laked, especially if the glycerin is injected hypodermically. This 
is probably an osmotic effect, the glycerin remaining for a time unabsorbed, and in high 
concentration at the place of injection; and the corpuscles being laked during their 
passage through this area (Filehne). 

On muscle-nerve preparations, glycerin acts similarly to veratrin. 

PREPARATIONS GLYCERIN 

*Glycerinum (Glycerin), U.S.P.; (Glycer.), B.P; Glycerin, C 3 H 5 (OH)3. A liquid 
obtained by the hydrolysis of vegetable or animal fats, purified by distillation. Clear, 
colorless liquid, of a thick, syrupy consistence, sweet to the taste. Miscible with water 
or ale.; insol. in eth., chlorof. or oils. Dose, 4 c.c., i dram, U.S. P.; 4 to 8 c.c., i to 2 
drams, B.P. 

* Suppositor ia Glycerini (Supp. Glycerin), U.S. P.; Supp. Glycer., B.P.; Glycerin 
Suppositories. Each suppository contains 3 Gm. of Glycerin, solidified by sodium 
stearate, U.S. P.; 70 per cent, of Glycerin, solidified by Gelatin, B.P. 

Glycerites are solutions of medicinal substances in glycerin. 



DEMULCENTS OR MUCILAGINOUS SUBSTANCES 

These comprise gums and other colloid substances, which form viscid 
solutions with water, and are insoluble in alcohol. They are used to 
emulsify oils; to suspend insoluble powders; to mitigate the taste and local 
effects and to delay the absorption of other drugs; and to allay inflamma- 
tions of mucous membranes, especially in bronchitis, gastritis, enteritis 
and diarrhea. The effects are strictly local, but in the respiratory passages 
they reach far into the bronchi. Gums and proteins (raw eggs, milk, 
flour) are employed for their protective action against irritant poisons. 
They are also precipitant chemic antidotes for metals. 



110 MANUAL OF PHARMACOLOGY 

Mucilages and similar drugs (salep, Irish and Iceland moss) were 
formerly considered efficient carbohydrate nutrients; but it has been 
shown that they are very imperfectly digested, and for the most part 
eliminated unchanged by the feces (Mendel, 1908; Swartz, 1911). 

Demulcents as Flavors. Gums and similar substances markedly diminish the char- 
acteristic taste of all substances, acid, salt, and sweet, as well as bitter. They act by 
enveloping the substance and forming a protective layer over the mucous membrane, 
and in this way preventing the access of the substance to the taste organs. This, of 
course, diminishes absorption as well as taste. One can very readily convince himself 
of this "corrective" action by mixing a i per cent, solution of citric acid with water and 
with a thin starch paste. The latter will taste very much less sour. Colloid substances 
of this kind are present in fruits as pectin bodies, and have a very marked influence upon 
their taste. The raspberry, for instance, actually contains more acid than the currant 
and but little more sugar, its less sour taste being due to the greater amount of these 
pectin substances present in it. 

PREPARATIONS GUMS 

*Acacia (Acac.), U.S.P.; Acacias, Gummi (Acac. Gum.), B.P.; (Gum) Acacia (Gum 
Arabic, Gum Senegal). The dried, gummy exudation of Acacia Senegal, and of other 
African species of Acacia. More or less spheroidal tears, or angular fragments; whitish 
to light amber colored; translucent; very brittle; nearly inodorous; taste insipid, muci- 
laginous. Insoluble in ale.; slowly soluble in twice its weight of water, forming a muci- 
laginous liquid, which is acid to litmus. Incompatible with ale., borax or metallic salts. 

* Mitcilago Acacia (Mucil. Acac.), U.S. P., B.P.; Mucilage of Acacia. 35 per cent., 
U.S.P., 40 per cent., B.P., dissolved in cold water. Dose, 15 c.c., 4 drams, U.S. P. 

Syr. Acac., U.S.P 10 per cent. 

Gum Ind., B.P. A gummy exudation from the stem of Anogeissus latifolia. 

Mucil. Gum. Ind., B.P. 25 per cent. 

* Tragacantha (Trag.), U.S. P., B.P.; Tragacanth. The spontaneously dried gummy 
exudation from the stems of Astragalus species. Swells in water to a gelatinous mass, 
without dissolving. Used in pill excipients, emulsions, etc. 

Mucil. Trag., U.S. P., B.P. 6 per cent, in diluted glycerin, U.S. P.; 1.25 per cent, in 
water, B.P. 

Glycer. Trag., B.P. 20 per cent. 

Puh. Trag. Co., B.P. Tragacanth, Acacia, Starch and Sugar. Dose, 0.6 to 4 Gm., 
10 to 60 gr., B.P. 

Dextrin. Prepared by heating starch with nitric acid. Presents all the characters 
of gum arabic, and forms the principal ingredient of commercial mucilages. A good 
formula for this is the following (Sykes): Mix 180 Gm. of dextrin with 180 c.c. cold 
water; add 240 c.c. boiling water and boil five minutes, stirring constantly. Add hot 
water q.s. 400 c.c. When cold, add 30 c.c. of dilute acetic acid, 10 drops of phenol and 
30 c.c. of glycerin, previously mixed. 

DEMULCENT TEAS 

Drugs containing mucilages are used as decoctions, ad libitum, mainly 
in folk medicine. 

PREPARATIONS DEMULCENT TEAS 

Althaa U.S.P. ; Marsh Mallow Root. The root of Althaea officinalis deprived of 
the brown, corky layer and small roots. 

Amygdala Dulcis (Amygd. Dulc.), U.S.P., B.P.; Sweet Almond. The ripe seeds of 
Prunus Amygdalus dulcis. 

Emul. Amygd., U.S.P. (Milk of Almond). An emulsion made by rubbing 6 parts 
of blanched sweet almonds with i part of acacia, 3 parts of sugar, and enough water to 
make 100 parts. 

Mist. Amygd., B.P. 12.5 per cent. Dose, 15 to 30 c.c., % to i ounce, B.P. 

Puh. A mygd. Co., B.P. Sweet Almond, Sugar and Gum Acacia. 

Cctrariti; Iceland Moss, a Lichen. A gelatinous decoction (i 120) is prepared after 
previous extraction with cold water, to remove a bitter principle. 

Chondrus, U.S.P. (Irish Moss, Carrageen). The dried plant of the seaweeds Chon- 
drus crispus and Gigortina mamillosa. Yields a demulcent jelly with boiling water. 



DEMULCENTS OR MUCILAGINOUS SUBSTANCES III 

Cydonium. Quince Seed. 

Ispaghula, B.P. Dried seeds of Plantago ovata. Dose, 3 to 10 Gm., 45 to 150 gr 
B.P. 

Dec. Ispagh., B.P. 1.5 per cent. Dose, 15 to 60 c.c., J^j to 2 ounces, B.P. 

Salep. The tubers of an orchid. 

Sassafras Medulla. Sassafras Pith. 

Triticum (Trit.), U.S.P.; Agropyron (Agropyr.), B.P.; Triticum, Couch Grass. 
The dried rhizome and roots of Agropyron repens. Dose, 8 Gm., 2 drams, U.S. P. 

Fldext. Trit., U.S.P.; Ext. Agropyr. Liq., K.P.Dose, 10 c.c. 2^ drams, U.S.P.; 
4 to 8 c.c., i to 2 drams, B.P. 

Dec. Agropyr., B.P. 5 per cent. Dose, 15 to 60 c.c., % to 2 ounces, B.P. 

Ulmus, U.S.P.; Elm (Slippery Elm). The bark of Ulmus fulva. 

GELATIN 

Uses. This is employed in pharmacy as a coating for pills, for making 
gelatin capsules, etc., and in the form of glycerinated gelatin as a base for 
suppositories. In the form of soups and jellies it is used as a nutrient, 
being easily digested and capable of replacing from one-fourth to two- 
thirds of the protein of an ordinary diet, especially if the carbohydrates 
are ample (Murlin, 1907). Subcutaneous injections of gelatin have been 
given to increase the coagulability of the blood, especially in aneurism. 
Their efficiency is doubtful. They have the serious objections of severe 
pain and danger of infection, since ordinary gelatin solutions are often not 
sterile, and may even carry tetanus. 

Gelatin as Styptic. The efficiency of gelatin is affirmed ^by some and denied by 
others. Burton-Opitz, 1906, found that it increased the viscosity of the blood on intra- 
venous injection. Cmunt, 1912, claims the same effect hypodermically. Dastre and 
Floresco, 1897; and Grau, 1910, describe increased coagulability of the blood, lasting 
for several days. Zibell, 1901, and others are inclined to attribute the action to Ca, of 
which gelatin contains about 0.6 per cent. The contradictory data do not permit any 
definite conclusions. The gelatin was originally used subcutaneously (100 to 200 c.c. 
of sterile i to 5 per cent, solution, injected slowly into the thigh, not near the aneurism, 
every ten to fifteen days, until 10 to 20 injections have been given). The treatment 
is quite painful, and may raise the temperature to io3F. Wood (1902) claims that the 
gelatin is just as effective, only somewhat slower, when given by mouth, and recom- 
mends eating 3 or 4 ounces of flavored 10 per cent, jelly, three times a day. 

PREPARATIONS GELATIN 

* Gelatinnm (Gelat.), U.S. P., B.P.; Gelatin. The purified, air-dried product ob- 
tained by the hydrolysis of animal tissues, as skin, ligaments, and bones, by treatment 
with boiling water. ' Insol. in cold water, but swells and softens when immersed in it, 
gradually absorbing from five to ten times. its own weight of water; sol. in hot water, 
acetic acid or glycerin; insol. in ale. Watery solutions of 2 per cent, or over solidify 
on cooling. Precipitated by phenol or tannin; not by dilute solutions of metallic salts. 

Gelatinum Glycerinatitm (Gelat. Glycerin.), U.S. P. Equal parts of Gelatin and of 
Glycerin. Used for making bougies, etc. 

STARCH 

Uses. Dry starch is used as a dusting powder. By boiling with 
water, starch is converted to a colloid condition, starch-paste. This is 
used as an emollie'nt, in the form of the glycerite; in poultices; and to 
secure the retention of enemas (teaspoonful, rubbed smooth with a little 
cold water and poured into a cup of boiling water). It is a chemical anti- 
dote to iodin. It is also employed as a nutrient, especially as "arrow- 
root,'" the starch of Maranta, which has a somewhat finer flavor than, the 
official corn starch. 



112 MANUAL OF PHARMACOLOGY 



PREPARATIONS STARCH 

* Amylum, U.S.P., B.P.; Starch. Prepared from maize, U.S. P.; from wheat, rice 
or maize, B.P. 

Glycer. Amyl., U.S.P. 10 per cent, of starch. 
Glycerin. Amyli, B.P. 20 per cent, of starch. 

* Barley-water is used as a demulcent decoction; and for diluting cow's milk for 
infants, to prevent the precipitation of solid masses of casein in the stomach. It is 
prepared by boiling for twenty minutes 10 parts of washed pearl barley with 150 parts 
of water and straining. (B.P.C.) 

INDIFFERENT DUSTING POWDERS 

These are very fine ("impalpable"), insoluble, non-irritant powders, 
such as talcum, chalk, starch, lycopodium, etc. They form a protective 
covering, prevent friction, absorb secretions by capillary action, and are 
therefore drying. Purified Talcum and Terra Silicea are also used for 
clarifying turbid solutions. 

PREPARATIONS INDIFFERENT DUSTING POWDERS 

* Talcum Purificatum (Talc. Purif.), U.S.P. ; Purified Talcum. A purified, native, 
hydrous magnesium silicate. A fine, white or grayish-white powder; odorless and taste- 
less. Insol. in water and dilute acids or alkalies. 

Terra Silicea Purificata (Ter. Sil. Purif.), U.S.P. (Purified Kieselguhr, Purified 
Infusorial Earth). A form of silica (SiO2) consisting of the frustules and fragments of 
diatoms, purified by boiling with diluted hydrochloric acid, washing and calcining. 

* Lycopodium (Lycopod.), U.S.P.; Lycopodium. The spores of Lycopodium clava- 
tum. A light yellow, very mobile powder, nearly inodorous and tasteless. Insoluble 
in water. 

POULTICE MASSES 

Poultices or cataplasms are used to convey heat, and to macerate the 
skin. A variety of pasty materials may be used. The most common are 
linseed, starch, bread and clay. * Linseed poultice is prepared by stirring 
i part of ground linseed into 3 parts of boiling water, to which a little 
baking soda may be added, to render it fluffy and less irritant. Clay or 
Kaolin poultice is much heavier, but can be sterilized if desired. The rate 
of cooling of different poultice masses has been investigated by Pilcher, 
1908. They do not differ materially. Whole linseed may be made into 
a demulcent decoction against bronchitis. 

PREPARATIONS POULTICES 

* Linum, U.S.P.; Lini Sem., B.P.; Lini Sent. Contus. (crushed or ground, "meal"), 
B.P.; Linseed, Flaxseed. The ripe seeds of Linum usitatissimum. 

Cataplasma Kaolini, N.F. Essentially a thick mass formed of about 2 parts of 
kaolin and i part of glycerin, together with a little boric acid (4.5 per cent.) and flavor- 
ing oils. It is spread hot in a thick layer and left in place for twelve to forty-eight hours. 

Kaolinum, B.P.; Kaolin. Native aluminum silicate (china clay; bolus alba), 
powdered and freed from gritty particles by elutriation. When added directly to blood, 
kaolin is hemolytic; and toxic when injected intravenously (FriedbergerandTsumeoka, 
1913)- 

Kaolin in Diarrheas. Bolus alba, willow charcoal and silica are being used as 
adsorbents in watery diarrheas and dysentery. In acute bacterial dysentery, large 
doses are given, 45 Gm. three times daily, stirred into hot tea (after a preliminary 
cleansing by calomel). Smaller doses suffice in chronic dysentery (Stoerk, 1915). 
Hess, 1916, reports good results from Fuller's earth in infantile diarrhea. It is easily 
administered in the food, or by a spoon; giving i to 2 tablespoons three times daily 
(Charcoal, H. Strauss, 1916). 



PHENOMENA COMMON TO LOCAL IRRITANTS 113 

The application of dry Kaolin to the nose and throat is being tried, with apparent 
success, to remove the bacteria of diphtheria carriers (Rappaport, 1916). 

PLASTERS 

These serve similar purposes as emollients; for the slow conveyance 
of drugs to or through the skin; and for mechanical support. They are 
somewhat irritant, partly by preventing evaporation from the skin, and 
partly by the small quantities of volatile oils contained in the resins from 
which they are often prepared. The official plaster-masses are unimport- 
ant, since the commercial plasters are usually made by private formulas 
from some rubber mixture. " Court plaster" is made of isinglass (Ichthy- 
ocolla), a variety of gelatin prepared from the swimming bladder of the 
sturgeon. 

PREPARATIONS PLASTER MASSES 

Emplastrum Elasticum (Emp. Elast.), U.S. P.; Rubber (Adhesive) Plaster. A mix- 
ture of rubber, pitch, wax and an absorbent powder (starch, etc.), spread on cloth. 

Emplastrum Resince (Emp. Res.), U.S. P., B.P. (Rosin Adhesive Plaster). Lead 
plaster with rosin and yellow wax, U.S. P.; hard soap instead of wax, B.P. 

Emplastrum Plumbi (Emp. Plumb.), U.S.P., B.P. ; Lead Plaster (Diachylon Plaster). 
A soap made by boiling lead oxid with olive oil and lard, U.S. P.; with olive oil, B.P. 

Emp. Saponis (Emp. Sap.), B.P.; Soap Plaster. Similar to preceding, with greater 
proportion of soap. 

MECHANICAL PROTECTIVES 

Certain substances which are used for this purpose may be mentioned 
in this place. 

PREPARATIONS MECHANICAL PROTECTIVES 

* Collodium (Collod.), U.S.P., B.P.; Collodion. A 4 per cent, solution, U.S.P., 
2.1 per cent. B.P., of Pyroxylin (gun-cotton) in a mixture of 3 vol. of ether and i vol. 
of ale. Should be kept in a cool place remote from fire. Clear, or slightly opalescent, 
syrupy liquid; colorless, or slightly yellowish and having the odor of ether. Highly 
inflammable. Collodion dries rapidly into a firm film, which is used to protect small 
wounds. The film cracks easily and contracts considerably, exerting pressure on the 
tissues. Similar solutions may be prepared with acetone or other solvents. 

* Collodium Flexile (Collod. Flex.), U.S.P., B.P.; Flexible Collodion. Collodion 
rendered flexible by the addition of a little Castor Oil and Camphor, U.S.P.; Castor 
Oil and Canada Turpentine, B.P. It does not contract or crack, but does not adhere 
quite so well. 

Pyroxylinum (Pyroxylin), U.S. P., B.P.; Pyroxylin (Soluble Gun-cotton). Obtained 
by acting on cotton with a mixture of nitric and sulphuric acids. Consists chiefly of 
cellulose tetranitrate, Ci2Hie(ONO2)4O6. Slowly sol. in 25 parts of a mixture of 3 
vol. of ether and i vol. of ale. ^equal vol. of 90 per cent. ale. and eth., B.P.); Sol. in 
acetone. Celloidin, N.N.R., is a purified form. Ordinary gun-cotton is a hexanitrate. 

* Gossypium Purificatum (Gossyp. Purif.), U.S. P.; (Gossyp.), B.P.; Purified (Ab- 
sorbent) Cotton. The hairs of the seed of Gossypium herbaceum freed from adhering 
impurities and deprived of fatty matter (so as to make it absorbent) and often sterilized. 
Consists of almost pure cellulose (CeHioOs). Used in bandaging, etc., either as such, 
or as gauze (Tela, Carbasus), lint (Lintum), etc., or impregnated with antiseptics, 
astringents, etc. 

Calcii Sulphas Exsiccatus (Plaster of Paris, Burnt Gypsum), CaSO + ^H 2 O. 
A fine white powder, which sets into a stone-like mass when mixed with half its weight 
of water. Used in bandaging. The "setting" takes place in fifteen to twenty minutes. 
It may be delayed to an hour by the addition of 5 per cent, of glycerin, or hastened by 
the addition of sodium silicate. Plaster of Paris must be kept dry. 

Liquor Sodii Silicatis (Waterglass). A colorless syrupy liquid, of alkaline properties, 
but not corrosive. Contains about 20 per cent, of sodium silicate. Forms a solid 
glassy mass on exposure. Used in bandaging. 
8 



114 MANUAL OF PHARMACOLOGY 

Actions of Sodium Silicate. When given by the mouth or skin, this acts like a 
typical mild alkali without showing any specific features. It is readily absorbed from 
tin- alimentary canal, and excreted by the urine. Injected intravenously it causes 
agglutination of blood corpuscles, and consequently intravascular clotting. Silicates 
.irv normally present in all tissues, but in very small amount (Siegfried, 1901). They 
are constantly present in hairs and feathers (H. Schulz, 1901). 



PHENOMENA COMMON TO LOCAL IRRITANTS, CORROSIVES 
AND ASTRINGENTS 

Uniformity of Irritant Phenomena. The local actions of drugs are, as 
a rule, simple and uniform, since they can occur ordinarily in only a few, 
situations, especially the skin and mucous membranes. These agree 
closely in structure and functions. There are therefore many phenomena 
which hold true of all local irritant poisons. These may be studied once 
for all, and present only minor modifications in individual cases. 

Chemical Basis of Irritation. The majority of local poisons produce 
the typical phenomena of inflammation ("irritation"), by causing necrosis 
of protoplasm through coagulation, liquefaction, etc. Many of these 
reactions are purely chemic or physical, and can be reproduced in 
the test-tube with proteins. Remembering the extreme sensitiveness 
of protoplasm to reagents, it will be readily understood that almost all 
substances even water may be irritant under suitable conditions. 

Degrees of Cutaneous Irritation. The general phenomena of irritation 
can be studied very typically on the skin. They are identical with the 
familiar changes produced by scalds or burns of increasing severity. 

Rubefaction. The first degree of irritant action is shown in an arterial 
and capillary hyperemia, at first active, later passive. This constitutes 
the "dermatitis ery thematosa " of the dermatologists. Or, speaking 
pharmacologically, it constitutes rubefaction, and the agents which pro- 
duce it are therefore called rubefacients. The dilation involves at first the 
most superficial vessels, but progressively also those of the deeper sub- 
cutaneous tissue, partly directly and partly by reflexes. 

The congestion is accompanied by sensory stimulation by itching, 
burning or pain. The intensity of the pain depends upon the rapidity, 
rather than on the degree of the irritation. It is often succeeded by more 
or less anesthesia. 

If the irritant action does not go any further, resolution takes place 
without leaving any lesions, simply by a return of the vessels to normal. 
The pain may outlast the congestion. The upper layers of the skin are 
usually desquamated. 

If the action is stronger than rubefaction, it may pass into vesication 
or pustulation. 

Vesication. This occurs if the inflammatory action results in the 
formation of an exudate greater in amount than can be carried off by 
the lymphatics. Every hyperemia is accompanied by an increase of 
exudation, but up to a certain amount, as in rubefaction, this is readily 
reabsorbed. When this limit is exceeded, an actual, visible, effusion 
results. This liquid will accumulate in the parts of the tissues offering 
the least resistance to distention. In the case of the skin, it penetrates 
readily through the lower layers of the rete Malpighii, but is arrested by 
the impermeable stratum corneum. It is therefore confined between the 
upper and lower layers of the rete Malpighii, and separates them, in this 



PHENOMENA COMMON TO LOCAL IRRITANTS 115 

way causing blisters or vesicles. The agents which produce these are 
called vesicants or epispastics. 

The vesicles appear as small points which gradually coalesce into a 
large blister. The fluid is at first clear, but later becomes turbid by leuco- 
cytes. The sensory stimulation is stronger than in rubefaction. 

Resolution takes place in these cases without loss of tissue, by the 
formation of a new stratum corneum from the remaining rete Malpighii. 
The area may remain pigmented for years. 

If the overlying and separated layers of epidermis are removed, there 
is much chance of infection, the lower layers of the rete Malpighii offering 
but little resistance. In this way there may be a loss of substance from 
secondary infection. 

Suppurative and Inflammatory Necrosis. If the vesicant is allowed to act after the 
blister has been formed, the infiltration will become purulent, with deeper destruction 
of the skin, and healing with scar formation. This degree of action should be avoided. 

Aseptic Pus Formation. A few drugs possess a specific chemotactic power on leuco- 
cytes; so that their injection (hypodermic or into serous cavities) leads to the collection 
of pus, even when asepsis is perfect. Turpentine, croton oil, petroleum, mercury, silver 
nitrate, digitoxin, cadaverin, aleuron suspensions, etc., are the principal examples. 
Turpentine also stimulates the chemotactic action of b. coli extracts (Hamburger, 



Pustulation. This occurs if the irritant does not penetrate the epidermis, but only 
the cutaneous glands, especially if thje acid secretion of these glands dissolves or liberates 
the irritant agent. Discrete and later confluent pustules are formed, which heal with 
more or less "pitting." They produce severe sensory irritation, but are now rarely 
used. The principal pustulants are croton oil and tartar emetic. 

Influence of Systemic Conditions of Cutaneous Irritation. Luithlen, 1911, found 
that the local reaction to croton oil is increased by feeding with acids or oxalates and 
diminished by calcium. Different diets also modify the susceptibility. These systemic 
influences may be connected with the great variations in the susceptibility of different 
individuals to cutaneous irritants; and with such skin diseases as eczema, 'which do not 
seem to be explainable by local irritation. There are also, however, local differences 
in susceptibility, and if an irritative reaction has once been induced, the skin remains 
hypersensitive for some time. 

Dermatitis from Systemic Drugs. Many drugs cause a dermatitis^ when they are 
given by mouth (belladonna, arsenic, iodoform, quinin, salicin, antipyretics, iodids 
and bromids, digitalis, chloral, chloroform, etc.)- This is sometimes due to changes 
in the cutaneous circulation, sometimes to the excretion of the drug by the skin. It 
may take the form of scarlatinal, desquamating, urticarial or papular rashes or acne. 

Corrosion, cauterization, or direct destruction of tissue results if the 
agent (cauterizant or escharotic) acts chemically on the protoplasm, as do 
strong acids or alkalis, iodin or bromin, some metallic salts, etc. This 
leads to the production of a scab or "eschar;" and resolution by scar 
formation. 

Areas of Corrosion. The chemic destruction of tissue is generally pre- 
ceded by inflammatory necrosis. Chemic cauterization therefore shows 
three areas: The first, situated at the depth and periphery of the ulcer, is 
simply an area of inflammation and hyperemia. Then follows a layer of 
necrotic tissue, the result of the inflammatory action; and last, a layer in 
which the chemic cauterization results in solution of the cells which have 
already been killed by the inflammatory process. These three hypere- 
mia, inflammatory necrosis, and chemic solution are to be considered 
as successive stages in the same action; and by proper dilution, the second 
or first degree of action may be obtained without the succeeding stages. 

The Eschar. This (scab) is formed after corrosion by the coagulation 
of the inflammatory exudate and by the chemical products (albumi nates, 
etc.) of the interaction of the corrosive agent with this exudate and with 



Il6 MANUAL OF PHARMACOLOGY 

the killed cells. According to whether the proteins are dissolved (as by 
alkalies) or precipitated (as by most metals), the scab will be soft or hard. 
This has an important bearing on the penetration of the corrosive agent: 
if the scab is soft, the chemical will penetrate it, and will spread and extend 
deeply. On this account the alkalies, for instance, are not practical for 
the purpose of cauterization. If, on the other hand, the scab is solid, it 
prevents deeper penetration, so that the action can be easily confined 
to the desired areas. 

Astringent Action. Agents which have a strong precipitant action 
produce a relatively mild irritation; and if their concentration is not too 
high, their primary inflammatory effect does not proceed to necrosis; on 
the contrary, it leads to diminution of any existing inflammatory process. 
This "astringent" (drawing together) action is characterized by visible 
contraction of the tissue; blanching and wrinkling of mucous membranes; 
and diminished exudation, or secretion of mucus, according to the place 
of application. These agents also possess a peculiar "astringent" taste. 
The effects are probably due to precipitation and hardening of the cement 
substance of the capillary endothelium, producing contraction and de- 
creasing the permeability of the capillaries; and thus counteracting the 
essential phenomena of inflammation (congestion and exudation). 

Astringents are used therapeutically to check diarrhea, reduce in- 
flammation of mucous membranes, promote healing, and to arrest 
hemorrhage (by coagulating the blood). 

The principal astringents are: metallic salts, tannins, dilute acids, 
and strongly hypertonic solutions. 

Explanation of Astringent Action. The manner in which this astringent action is 
brought about is only imperfectly understood. All astringents produce precipitation 
of proteins, and this insoluble protein precipitate seems to be the cause of the astringent 
action. To explain this action it has been assumed that these precipitates form a 
lining along the capillary walls, and in this way add an additional coat, as it were, to 
each capillary. It seems, however, much more likely that they act by coagulating the 
ordinary semifluid cement substance between the endothelial cells, and that this pre- 
vents the nitration of fluids, and more especially the emigration of cells. The silver 
"staining" of endothelia by silver nitrate is a visible illustration of this fixation of the 
cement substance. The diminished mucus secretion is perhaps due to a similar super- 
ficial coagulation of the cell envelope. The blanching and puckering (produced only 
by the more concentrated solutions) points to a direct stimulation of the arterial and 
other muscular tissue. The absorption of already formed effusions, following the use of 
astringents, may possibly be explained by osmostic laws: By precipitating the proteins of 
these effusions, they lower their molecular concentration, and render them more 
diffusible. Not all protein precipitants are astringents. The precipitant action must 
be of a special kind. It must be produced very quickly, and the precipitate must be 
practically impermeable to the precipitant. Otherwise the precipitant action would 
extend so deeply as to lead to extensive necrosis, and would thus continue the in- 
flammatory process. 

Quantitative Estimation of Astringent Action. This has been measured by Motolese, 
IQIO, by noting the degree in which the extensibility of frogs' lungs is reduced after 
immersion in the astringent solutions (Dreser's method). With i per cent, solutions, 
the order was: silver nitrate > tannin > lead subacetate > picric acid > lead acetate > 
alum > zinc sulphate. 

Astringent Effects are Strictly Local. Since astringents are precipitated 
by proteins, they can not be absorbed nor exist in the blood or tissues, 
in effective form. It is therefore absolutely irrational to expect a remote 
action from astringents. The very facts of their action exclude such 
a possibility. Before this was well understood it was tried to obtain 
astringent action throughout the body by external application or by 



PHENOMENA COMMON TO LOCAL IRRITANTS 1 17 

giving astringents by the mouth. The want of success confirmed what 
has just been said. 

Astringents on Peristalsis. In the intestinal canal the astringents 
form a deposit along the lumen of the intestine, and in this way diminish 
absorption, and also the penetration of other irritant substances, in this 
way lessening peristalsis. 

Irritation of Mucous Membrane. Differences in detail are seen when 
irritants are applied to other surfaces than the skin; for instance, to the 
mucous membranes. These are readily explained by anatomic peculiari- 
ties. There will, for instance, be less tendency to vesication, since the 
epithelium is not impermeable, as it is in the skin. The oral mucous 
membrane presents a transition; it blisters, but less readily than the skin. 
Pustulation can not occur since this depends upon the cutaneous glands. 
On the other hand, the mucous glands will be stimulated to an increased 
activity, producing "catarrhal" conditions. 

Gastroenteritis. The effects of irritants on the alimentary tract present 
some special features; the effects being stomachic, carminative, nauseant 
or emetic; diarrhea, dysentery; abortion; corrosion and perforation; 
according to the nature and degree of their action. 

Respiratory Passages. If an irritant poison is volatile, its main effects 
may fall upon the respiratory passages. The general phenomena will 
be those of acute laryngitis, bronchitis, or pneumonitis. Similar effects 
follow the aspiration of non-volatile irritants. 

Local Irritation of Wounds and Ulcers. The effects are more marked 
than on the intact skin. Even the milder irritants destroy the superficial 
cells, especially if diseased; but the deeper cells multiply more rapidly, 
partly through direct stimulation and partly through the hyperemia. 
Mild irritants therefore promote healing. Astringents, balsams, quinin, 
salts and even water have this therapeutic action. 

Hypodermic Injection of Irritants. These produce more or less pain, 
and often aseptic abscesses. The danger of infection is also considerable 
if the tissues are killed by the irritant. With intramuscular injection, 
the pain is less severe. 

Antiseptic Action. All irritants are somewhat antiseptic for they de- 
stroy the protoplasm of the bacteria just as they do that of the tissue cells. 

Concentration. The degree of the local action depends upon the con- 
centration, rather than on the absolute quantity of the irritant. 

A small quantity of concentrated acid will do much more damage than 
much larger quantities diluted; as a gram of MgSO 4 in solid form 
introduced into a solution,, may precipitate all its globulin, whilst an 
unlimited quantity may be added in 5 per cent, solution, without any such 
effect. 

Specific Differences Between the Different Irritants. These affect 
the strength of their action in different situations. Some, for instance, 
seem to act especially on the alimentary canal, and to a very small 
extent on the skin. This is probably connected with differences of 
absorbability. A drug which can not penetrate the skin, can not, of 
course, act upon it. It will be remembered that the epidermis is im- 
permeable to most substances. In order to penetrate, these must be 
either fatty, like croton oil or turpentine; or they must actually destroy 
the epidermis, like caustics. 

Irritant Effects after Absorption. None of the irritants acts indiscrimi- 
nately on the body at large. Many are not absorbed; and even when 



Il8 MANUAL OF PHARMACOLOGY 

absorption occurs they are too greatly diluted to have much effect, 
except at the place of their absorption and excretion; i.e., the liver and 
kidneys. Other tissues are involved only if the administration is long- 
continued, as in alcohol or lead poisoning. Such chronic intoxications 
lead to increase of connective tissue, arteriosclerosis, cirrhosis, etc. 

Drug Nephrites. These are produced by all absorbable irritants and 
often occur acutely. The inflammation may involve all the renal tissues; 
or it may be predominantly glomerular or parenchymatous, according 
to the poison. Continued administration leads to interstitial nephritis. 

The inflammation is characterized by albuminuria, casts, and the 
histologic lesions. The urine flow is increased in the early stages, and 
decreased later (Schlayer and Hedinger, 1907). The excretory efficiency 
is diminished (Eisenbrey, 1911, 1913), as estimated by the phenolsulphone- 
phthalein test of Geraghty and Rowntree, 1911. The changes in nitrogen 
and chlorid excretions are complex (Austin and Eisenbrey, 1911). The 
nitrogen excretion is decreased in tubular nephritis (uranium), not in 
glomerular (arsenic). Retention of nitrogen in the blood occurs, especially 
in tubular nephritis (Foster, 1915). Renal Glycosuria may occur (E. 
Franck, 1913; Pollak, 1911); also hepatic edema (Opie, 1912), and some- 
times slight myocardial changes (Walker, 1911). Hemorrhagic nephritis 
is seen with cantharides, turpentine, formaldehyd, etc. Edema occurs 
only with uranium, at least in animals. The restoration of the blood- 
volume after saline injections is delayed in uranium, chromateand tartrate 
nephritis (Bogart, Underbill & Mendel, 1916; Boycott, 1913 and 1914; 
Chisholm, 1914). 

Experimental Nephrites. These have been extensively investigated (bibliography in 
R. M. Pearce, 1910). 

Tubular nephritis with little or no primary glomerular injury is produced by uranium, 
chromate, mercuric chlorid and aloin. The anatomic changes in the early stages of 
uranium and chromate nephritis are confined essentially to the tubules, especially the 
convoluted; they consist of granular and fatty degeneration and necrosis. Mercury 
acts similarly but mainly on the ascending loops of Henle, with deposition of lime salts. 
The glomeruli are at first unaffected but later show thickening of the capillary walls, 
and vascular disturbances can be shown by physiologic methods. 

Glomerular Nephritis. This, generally with some secondary involvement of the 
tubules, is produced by arsenic, cantharides and snake venom. Diphtheria toxin acts 
on all the structures; and many other irritants act diffusely. The anatomic changes 
vary according to the poisons. Arsenic produces little or no anatomic change, except 
dilatation of the capillary tufts, filling Bowman's capsules. Physiologic methods, how- 
ever, show serious vascular injury. The cantharides changes involve both the glomeru- 
lar tufts and space. The capsules are filled with desquamated cells, whose origin is 
disputed. There is also functional vascular injury. The functional changes are not 
proportional to the anatomic. 

Chronic^ Nephritis. This is difficult to produce experimentally, the acute experi- 
mental lesions usually ending in rapid and complete recovery. Positive results have 
been obtained by Ophiils with lead, by Dickson with uranium, and by Klotz, 1914, with 
infections. 

Reflex Effects of Irritants. Stimulation of sensory areas acts reflexly 
on the vasomotor, cardiac, respiratory and other centers, producing 
changes in the circulation, respiration and other functions. These vary 
according to the place, extent, speed, intensity and kind of the stimulation. 
As "counter-irritation" they are used extensively in therapeutics. 

The Respiratory Reflexes. These are of special therapeutic impor- 
tance. _ They differ according to the state of the center: if the respiratory 
center is depressed, as in collapse, morphin poisoning, anesthesia, asphyxia, 



PHENOMENA COMMON TO LOCAL IRRITANTS 1 19 

etc., moderate counter-irritation produces marked stimulation; and if the 
collapse is not too deep, natural respiration may be restored. 

// the respiration is normal, mild cutaneous irritation may either slow or quicken the 
rate. If the irritation is strong, the respiration is always slowed. Sudden and extensive 
stimulation, as by cold douches, produces momentary standstill, followed by deep 
inspirations. 

Consciousness. This is also often revived by counterirritation,/./., in 
fainting or light coma. The usual measures for this purpose are dashing 
with cold water, slapping with wet towels, or inhalation of dilute ammonia 
vapor (smelling salts or aromatic ammonia). 

Circulation. Mild cutaneous stimulation (f.i., blowing on the skin) 
tends to produce widespread vasoconstriction and therefore some rise of 
blood pressure (Gruetzner and Heidenhain, 1877). The vasoconstriction 
involves mainly the cutaneous vessels, except those which are dilated by 
direct contact with the irritant. The renal vessels are also constricted, 
whilst those of the brain are dilated (Wertheimer; Roy and Sherrington). 
The cutaneous vasoconstriction tends to raise the internal temperature. 
The heart rate is quickened (Naumann). 

Vasomotor Reflexes. Mild stimulation of sensory nerves generally produces a 
slight depressor action; stronger stimuli cause a pressor effect, increasing with the 
intensity of the stimulation (Stiles and Martin, 1915). % 

With stronger stimulation of the skin, the vasoconstriction is soon followed by dilation, 
fall of blood pressure and of internal temperature. The effects may be less than with 
mild irritation. 

Gastro -intestinal Irritation. Sollmann, Brown and Williams (1907) have shown 
that irritation of the stomach or peritoneum has practically no effect on the blood pressure 
in anesthetized animals, even when the anesthesia is light. There is generally a marked 
increase of respiration, and sometimes a slight and momentary rise of blood pressure, 
but no fall is noticed for several hours. This holds true both for mild irritants, such as 
peppermint, mustard or moderate heat; and for strong corrosion by formaldehyd, 
concentrated acids, or actual cautery, even when these measures produce perforation. 

Irritation of the Mouth and Larynx. This produces very much more marked effects 
(Sollmann) ; even contact with 5 per cent, acetic acid causes struggling, convulsive rise 
of blood pressure and dyspneic respiration. 

Reflex Shock. Violent and extensive corrosion may produce immediate "shock," 
which may be promptly fatal. This appears to consist essentially in profound inhibi- 
tion of the nervous system. Since it is not produced in anesthetized animals, at least 
with anything like the same rapidity, it must be due to psychic factors apprehension, 
pain and others rather than to reflexes in the ordinary sense. However, long- 
continued irritation of the viscera gradually produces, even in anesthesia, a condition 
(surgical shock), which is allied to, if not identical with, acute traumatic shock. 

Metabolism. Mild stimulation of extensive skin areas (salt-water baths)_ increase 
metabolism. Paalzow found increased oxygen consumption and carbon dioxid excre- 
tion on applying sinapism to animals; Zuntz and others have demonstrated increased 
nitrogen excretion. 

"Derivative" Action. The application of irritants often subdues in- 
flammation in deep-seated organs. This counterirritation was formerly 
supposed to act simply by mechanical withdrawal of the blood from the 
inflamed area to the area of "counterirritation." This explanation is 
certainly incorrect. It is now believed that the circulation in the distant 
organs is modified by reflexes along homologous nerve paths in a sense 
a reversal of the "referred pain" which occurs in definite skin areas when 
the corresponding viscera are irritated (Head). This would explain the 



120 



MANUAL OF PHARMACOLOGY 



old empirical observations that the counterirritation, to be most effective, 
must be applied at a definite place for each internal inflammation 
(Figs. 3<* and 36). 

Cold applied to one hand constricts the vessels of both hands, and heat dilates them 
(G. N. Stewart, 1913; Hewlett, 1913). Irritation of the hand by mustard does not in- 
crease the local blood flow, as would be expected from the rubefaction (Wood and Weis- 
man, 1912; Hewlett, 1913). 

Influence of Pain on Inflammation. Bardy, 1914, confirms Spiess and Bruce that 
inflammatory phenomena depend mainly on sensory disturbances (pain, reflex hyper- 
emia, etc.). The reflex, however, is quite peripheral. For instance, mustard conjunc- 
tivitis is prevented by local anesthetics or by division of the peripheral nerves, but not 



Phthisis. 
Pericarditis or pleurisy. 

Flying blister or sina- 
pism, in pleurisy or 
pneumonia. 

Vomiting 



Chronic thickening 
after perityphlitis. 



Acute rheumatism. 




Laryngitis, hysteric 
aphonia. 

Pericarditis. 



Ovarian irritation. 



Gout. 

FIG. 30. Diagram of the body showing some of the points where blisters or sinapisms are usually 
applied. Front view (Brunton.). 

by section of the ramus ophthalmicus. It is prevented by nicotin, so that the reflex 
must involve the ganglia. Central anesthetics, ether or morphin, also prevent the 
inflammation. Other substances having a similar effect are: calcium chlorid, antipyrin, 
quinin, salicylates, atophan, bromids, etc.; and substances yielding available oxygen. 
(Amberg, Lrevenhart and McClure, 1916.) 

Changes hi the Blood. Irritation of the skin produces changes in the blood which 
may have some influence on inflammation: Winternitz, 1896, found at first leucopenia, 
then leucpcytosis. Van den Velden, 1912, claims that the coagulability of the systemic 
blood is increased by a number of local irritant and especially vasoconstrictor processes 
(ice to the skin; astringents or epinephrin to the mouth; cocain to the nose; turpentine 
inhalation, etc.). 

Relief of Pain by Counterirritation. This is partly explained by 
homologous reflexes; but largely also by the diversion of the attention 
of the patient from the disease-pain, to the usually more bearable sen- 
sations of the counterirritant. 



PHENOMENA COMMON TO LOCAL IRRITANTS 



121 



Therapeutic Indications of Cutaneous Irritation. This is employed 
mainly in the following conditions: 

1. In certain skin diseases, for the local effects alkalies, sulphur, 
chrysarobin, etc. 

2. To promote diaphoresis alcohol, frictions, heat, etc. 

3. For reflex stimulation of the central nervous system, in fainting, 
collapse, narcotic poisoning, accidents of anesthesia, etc. ammonia 
inhalation, heat or cold. 

4. To alter the distribution of blood, to prevent colds mustard; to 
relieve congestion of viscera poultices, vesication; or to promote the 
absorption of exudates iodin, vesication. 



Epistaxis, cerebral con- 
gestion, delirium, and 
tendency to coma, or 
constant wakefulness, 
in fever, headache, 
giddiness, tinnitus au- 
rium. 

Hemoptysis. 

Intercostal neuralgia. 



Rheumatic gout. 




Headache, giddiness, tinnitus 
aurium, ophthalmia. 



Flying blister or sinapism, in 
pleurisy or pneumonia. 



Dysmenorrhea, spinal irrita- 
tion, leucorrhea. 



> Sciatica. 



Sciatica. 



FIG. 36. Diagram of the body showing some of the points where blisters or sinapisms are usually 
applied. Back view. (Brunton.) 

Counterirritation is, as a rule, useful only in chronic inflammation. 
In acute inflammation there is always a danger of increasing the process 
or of causing it to extend to neighboring organs. 

5. To diminish pain, especially in neuralgic and rheumatic affections 
turpentine and other volatile oils, capsicum, chloroform. 

6. As a general tonic, in the form of salt-water baths or alcohol frictions. 
Therapeutics of Cauterization. Cauterization the destruction of 

tissue is sometimes employed for severe counterirritation, but particularly 
to remove tissue: (i) In cases of poisoning, snake-bite, etc.; (2) for the 
removal of pathologic tissues, tumors, warts, etc. ; (3) indolent granulations, 
etc.; (4) to cause cicatricial contraction of hypertrophied mucous mem- 



122 MANUAL OF PHARMACOLOGY 

branes (nose, etc.); (5) for removing the nerves of teeth; and (6) to remove 
superfluous hair. 

In many cases the chemic cautery has been replaced by galvano- and thermocautery, 
which are more prompt and permit a more exact limitation of the cauterized area. On 
the other hand, the slower effect of chemic caustics is of advantage in permitting a 
graduation in the strength of the action, or in confining it to certain tissue elements. 
Pathologic formations, being less stable, are in this way more profoundly altered than 
normal tissue. 

The caustics may be applied in solid form (sticks, or fused at the end of a probe), in 
paste, or in solution the first being the most strictly localizable, the last the most dif- 
fuse. In the latter case, or when the eschar liquefies, the surrounding tissue should be 
protected by court-plaster. 

General Toxicology of Irritants. The phenomena produced by irritant 
poisons depend in the first place upon the part of the body with which 
they are brought into immediate contact. The most prominent symptoms 
arise from the skin, alimentary canal, or respiratory organs; the last only 
in the case of very volatile poisons. Later symptoms may appear in 
the urinary organs. 

The extent of the action depends upon the concentration of the poisons, 
the time during which they act, and the extent of surface with which 
they come into contact less upon their absolute amount. If taken 
by the alimentary canal, their action will also be modified by the presence 
of food. 

Cauterization of the Skin. This may be accidental or criminal. In the latter case 
it is usually by sulphuric acid ("Vitriol"). The results are the same as in the case of 
extensive burns. The diagnosis offers no difficulty. The character of the stains is that 
described in the next section. Sufficient of the corrosive can generally be collected 
from the clothing, etc., to establish its identity by chemic means. The treatment is 
precisely like that for burns, after previous neutralization and removal of the corrosive 
agent. Salves and oils are useful especially the Linimentum Calcis (Carron Oil, i.e., 
equal parts Linseed Oil and Lime-water). 

Caustics in the Eye. These are best washed away by liberal application of water. 

Caustic Poisoning by the Alimentary Canal. The introduction of 
caustics by the mouth is generally accidental or suicidal. The effects are so 
painful, appear so promptly, and the lesions are so persistent, that they 
would scarcely ever be used in criminal poisoning except possibly in 
infanticide. They are sometimes taken by mistake for syrup or other 
medicine, and may be swallowed before the difference is noticed. How- 
ever, certain organic irritants, usually insoluble, such as croton oil, 
do not produce their action for some time. 

The phenomena vary according to whether the irritant produces 
an actual cauterization a destruction or solution of the tissues; or whether 
it causes only inflammation. 

Irritants Which Do Not Destroy the Tissue. To this class belong 
elaterium, croton oil, and most of the other organic irritants, such as 
volatile oils, formaldehyd, etc. 

The symptoms are those of a violent gastroenteritis: nausea, vomiting, 
and diarrhea. If the poison acts only when dissolved, and is insoluble 
in the stomach, as is croton oil, the nausea and vomiting may not be 
present, but only the diarrhea. The symptoms will appear correspond- 
ingly late. The abdomen is usually distended and extremely painful, 
especially upon pressure. As a result of the gastroenteritis, there is 
extensive dilatation of the splanchnic area, and consequently withdrawal 
of blood from other parts of the body. This produces marked changes 



PHENOMENA COMMON TO LOCAL IRRITANTS 123 

in the circulation. The pulse will be soft, small, and quick. The lowered 
circulation reacts upon other organs, and most conspicuously upon the 
central nervous system. There is great anxiety, vertigo, delirium, convul- 
sions, then collapse, and finally coma and death. This picture is common 
to the entire series of irritant poisons. 

Abortion. The hyperemia is not confined to the intestine, but extends 
to all the abdominal organs, which therefore partake in the inflammation, 
although they do not come into direct contact with the irritant. The most 
important organ involved in this is the uterus, and the organic irritants 
have been used to procure criminal abortion. Oil of savin, of tansy, 
and of pennyroyal enjoy a special reputation in this connection, but any 
other irritant produces the same result. The ecbolic effect is only 
secondary to the gastroenteritis, and the latter is very often fatal without 
accomplishing the object for which it was produced. 

The postmortem appearances are those of gastroenteritis, and in cases 
of suspected criminal abortion this must be of sufficient extent to explain 
the fatal issue. The pathologic condition consists in an intense congestion 
of the entire alimentary canal, often with inflammatory exudate into the 
lumen of the intestine. The congestion may be so violent as to produce 
ecchymoses. If these are present, the vomit and stools will be tinged 
with blood during life. Destruction of tissue is quite rare. It may, 
however, occur from gangrene due to the interference with the circulation. 

The Fixed Caustics. The most important are the mineral acids; 
oxalic acid, which, however, stands apart on account of its specific toxic 
action; the organic acids, which are, generally speaking, corrosive in 
proportion to their volatility; the alkalies and their carbonates; the haloid 
substances, bromin, chlorin, and iodin. Phenol and the metals are also 
to some extent corrosive, but not usually sufficiently so to produce perfora- 
tion. The alkalies and bromin produce the most extensive destruction 
of tissue, because of their deep penetration. With them, the scar forma- 
tion is also the most extensive. 

Corrosive effects occur especially in those situations which are in pro- 
longed contact with the caustic: the lips; mouth and pharynx; esophagus 
at its beginning and end, and where it crosses the left bronchus; 1 and the 
stomach, especially the pyloric end 2 (because the caustic follows the lesser 
curvature and accumulates at the pylorus). The firm closure of the py- 
lorus furnishes more or less protection to the intestines. 

Characteristic Appearance of the Corrosions and Stains. These are of 
diagnostic importance, since they may be recognized about the mouth 
during life: 

Alkalies cause transparent swelling of the epithelium, which will detach 
as a gelatinous mass, exposing the scarlet-colored inflamed area beneath. 3 
The other corrosives, which precipitate proteins, produce at first a grayish- 
white opaque stain. This persists in the case of the metallic poisons. 
The acids, however, change the hemoglobin in the neighboring area into 
the dark acid-hematin, and the color of the stain consequently becomes 
dark or black. Nitric acid is an exception: its stain takes on a yellow 
color. This differs from that of picric acid by being changed to orange 
by alkalies, whilst the picric acid stain remains unaltered. Bromin pro- 

1 E. v. Hoffmann, Atlas of Legal Medicine, W. B. Saunders, 1898. Figs. 186 and 187. 
2 ib. Pig. 187. 
* ib. Plate 46. 



124 MANUAL OF PHARMACOLOGY 

duces a characteristic light brown or orange stain; iodin stains a mahogany 
color. The silver stain turns black after a time. 

Removal of Stains. The stains of iodin and silver are frequently a 
source of annoyance in their therapeutic exhibition. They can be readily 
removed: The iodin by ammonia water or by thiosulphate; the silver by 
potassium cyanid, or by painting first with iodin and then with ammonia. 

Symptoms of Corrosive Poisoning. These begin in the mouth, with 
burning pain, dysphagia, and loss of tissue. The taste of many of these 
substances is characteristic acid, alkaline, metallic, astringent, etc. 

The further symptoms are those of gastroenteritis, similar to those 
described under non-corrosive irritants, but generally more severe. The 
vomiting and diarrhea are more frequently bloody. In the case of acids 
the vomited blood is frequently very dark in color on account of the for- 
mation of acid hematin. This is the so-called "coffee-grounds" vomit. 
The pain is very much more marked with corrosive poisons. The destruc- 
tion of the tissue gives rise to reflexes which may take the form of " shock." 
The absorption of the chemic products of corrosion may produce fever; 
or the temperature may be lowered by collapse. If perforation occurs, 
the clinical picture turns into that of peritonitis. 

Death. This may occur from shock before the local symptoms have 
time to develop; or it may follow after one or two days of more gradual 
collapse; or it may result later from peritonitis; or finally, after recovery 
from the acute effects, the formation of scar-tissue in the corroded areas 
may lead to stenosis and thus to gradual starvation. 

Postmortem Examination. This shows the characteristic stains and corrosions in 
the mouth, esophagus, stomach and duodenum; with the metallic corrosives, the cecum 
and large intestines may show the principal changes 1 since many metals are excreted in 
these situations. The other abdominal organs are also hyperemic. 

When the action has not progressed to actual corrosion, there is often very marked 
hyperemia and ecchymosis. The color is frequently much darker than corresponds to 
the amount of congestion, especially in the case of acids (due to acid-hematin). 2 

Treatment of Poisoning by Corrosives. The first measure is dilution, 
since the action is proportional to the concentration. The drinking of 
water in abundance and the washing out of the stomach are therefore 
important. If corrosion is already advanced, it is not advisable to pass 
the stomach-tube. The further treatment consists in the administration 
of demulcent substances, as mucilage or boiled starch; or proteins, as white 
of egg; or milk. The proteins are especially useful against the metallic 
poisons, since they form rather insoluble albuminates. 

The pain usually requires the exhibition of narcotics in free doses. 
Most of the irritant poisons can be treated by chemic antidotes; in the case 
of alkalies, by acids (vinegar, lemon juice, or any acid diluted to i to 5 per 
cent.); in the case of acids, by means of alkalies; preferably magnesium 
oxid; or in emergencies by soap. (The free alkalies are usually too caustic, 
and the carbonates involve danger of rupturing the corroded stomach by 
the evolution of carbon dioxid gas. Potassium compounds are objection- 
able because of the danger of toxic absorption from the corroded mucosae. 
In case of necessity any alkali may be used, such as whitewash or chalk.) 

Iodin, chlorin or bromin may be neutralized by sodium bicarbonate. 

Volatile Caustics. These comprise ammonia, chlorin, bromin, the 
fuming mineral acids, the gaseous acids, such as sulphurous, nitrous, etc.; 

1 ib. Plate 43. 

2 ib. Plates 34, 35 and 33. 



FIXED CAUSTIC ALKALIES 125 

and certain organic acids acetic, formic, etc. Also other organic sub- 
stances, such as formaldehyd; and the volatile oils, especially the oil of 
mustard. 

When swallowed, these produce the symptoms already described, the 
actions being, however, more rapid and extending more deeply. When 
inhaled, they irritate mainly the respiratory passages and other exposed 
mucous membranes, causing coryza, conjunctivitis, bronchitis, pulmon- 
ary edema, pneumonia, etc. Through the irritation they produce pro- 
found nervous effects, at first mainly stimulant. The respiration stops 
at first in expiration, the glottis closes spasmodically, and the bronchial 
muscles contract. This is a conservative mechanism, and explains why 
fatal poisoning is not more common. During this stage there is cardiac 
inhibition through vagus stimulation, and also dilation of peripheral 
vessels. The inhalation irritants may prove promptly fatal by spasm or 
edema of the glottis; or the course may be slower, passing through bron- 
chitis, pneumonia, etc. (cf. L. Lewin, 1908). The irritation may also 
involve the esophagus and stomach, with protracted hemorrhagic gastritis 
(Loeper et al., 1915). The inhalation of irritant vapor is especially 
deleterious to asthmatic individuals. 

Bronchodilator drugs (atropin, etc.) have a limited efficiency against 
the acute respiratory distress of irritant gases (Symes, 1915). 

The effects of small quantities of volatile irritants in the air has an eco- 
nomic importance, in view of their escape from chemical factories, etc. 
There can be little doubt that even a small proportion tends to produce 
bronchitis, and to diminish the resistance to infections (Ronzani, 1908: 
low concentrations of Cl, SC>2, NO2). They may possibly cause cachectic 
conditions; but it is difficult to assign the limits between which these 
poisons are harmless, objectionable, and dangerous. 

Nitric Peroxid (Nitrous Acid, NC^). This constitutes the brown vapors arising from 
the action of nitric acid on metals. It is also produced in large amount in the combus- 
tion (not in the explosion) of nitroglycerin and gun-cotton. The acute phenomena are 
relatively slight, but they are followed after six or eight hours by sudden bronchitic 
attacks with extreme dyspnea, pulmonary edema, and often death within forty-eight 
hours (F. C. Wood, 1912). 

This gas is therefore especially dangerous. 

FIXED CAUSTIC ALKALIES 

Members. These comprise NaOH and KOH, which corrode even 
the skin; the carbonates of sodium and potassium which are not caustic, 
but which irritate the mucous membranes violently; and quicklime, which 
on account of its limited solubility, is caustic only when used in substance. 

Manner of Action. The free alkalies combine with the tissue elements to form alka- 
line albuminates, or with the fats to form soaps, and in this way produce a destruction 
of substance. They are also very hygroscopic, and withdraw water from the cells, 
which contributes to the necrosis. The scab which they produce is very soft, and the 
compounds which they form are very soluble; consequently the alkalies penetrate very 
deeply, are very painful, their action continues for several days, and leads to extensive 
scar formation. It is therefore difficult to circumscribe their effects. This is only 
partly remedied by mixing them with the non-diffusible quicklime as in the " Vienna 
Paste" a mixture of equal parts of KOH and CaO, stirred into a thick paste with alcohol. 

Actual and Potential Alkalinity. The "actual" or immediately effective alkalinity 
of a solution depends on the dissociated OH ions; but as these combine with the tissues, 
further OH ions are split off ("potential") alkalinity), which continue the action. The 
total effect, therefore, depends upon the total quantity of OH ions which can be split 
off under the conditions of the body (Dreser, 1910). This can be estimated by ap- 
propriate indicators. 



126 MANUAL OF PHARMACOLOGY 

Poisoning by Caustic Alkalies (Lyes). This is quite common. Half 
an ounce of potassium carbonate or an ounce of the liquors would gen- 
erally be fatal. Sodium carbonate is less toxic. On account of the deep 
action, stricture of the esophagus is a frequent sequel, and the fatality is 
fairly high. 

PREPARATIONS CAUSTIC ALKALIES 

* Potass! I Hydroxidum (Pot. Hydrox.), U.S. P.; Potassa Caustica (Potass. Caust.), 
B.P.; Potassium Hydroxid (Caustic Potash, Potassium Hydrate); KOH. White flakes 
or masses or pencils; odorless; caustic. Very sol. in water (i :o.g), freely sol. in ale. 
(i :3). Used as caustic, to remove warts, etc.; and to soften epidermis (2 per cent.). 

* Llq. Pot. Hydrox., U.S. P.; Liq. Potass., B.P. 5 per cent. Sometimes used inter- 
nally as alkali. Dose, i c.c., 15 minims, U.S.P.; 0.6 to 1.8 c.c., 10 to 30 minims, B.P.; 
freely diluted. 

Potas. Carbonas (Pot. Carb.), U.S.P., B.P. (Salts of Tartar); K 2 CO 3 . White granu- 
lar powder; odorless; strongly alkaline taste. Very deliquescent. Very sol. in water 
(i 10.9), practically insol. in ale. Dose, i Gm., 15 gr., U.S. P.; 0.3 to 1.2 Gm., 5 to 20 gr., 
B.P. 

Sod. Hydrox., U.S.P. (Caustic Soda); NaOH. Dry, white flakes, or fused masses or 
pencils. Very sol. in water (i :o.g) and ale. 

Liq. Sod. Hydrox., U.S.P. (Solution of Soda). 5 per cent. Dose, i c.c., 15 minims, 
U.S.P. 

* Sodii Carbonas Monohydratus (Sod. Carb. Monohyd.), U.S.P.; Na 2 CO 3 + H 2 O. 
A white, crystalline, granular powder; strongly alkaline taste. Freely sol. in water 
(i : 3) and inglyc. (i 17); insol. in ale. Used as lotion (0.5 per cent.). Is nearly twice as 
strong as the ordinary crystallized carbonate. Dose, 0.25 Gm., 4 gr., U.S.P. 

* Sod. Carb., B.P.; Sodium Carbonate (Washing Soda); Na 2 CO 3 + 10 H 2 O (equiva- 
lent to 37 per cent, of Na 2 CO 3 ). Freely sol. in water (i -.2). Dose, 0.3 to 2.0 Gm., 
5 to 30 gr., B.P. 

Sod. Carb. Exsic., B.P.; Na 2 CO 3 . Dose, 0.2 to 0.6 Gm., 3 to 10 gr., B.P. 

Calx, U.S.P., B.P.; Calcium Oxid (Lime, Quicklime); CaO. Hard, white or grayish- 
white masses, or a white powder; odorless; caustic taste. Slightly sol. in water (i : 840); 
sol. in glyc.; insol. in ale. When sprinkled with about half its weight of water, calcium 
oxid becomes heated, and is gradually converted into a white powder (calcium hy- 
droxid or slaked lime). When this is mixed with about 3 or 4 parts of water, it forms 
a smooth magma (milk of lime). 

Calc. Hydr., B.P. (Slaked Lime) ; Ca(OH) 2 . White powder. 

* Liquor Calcis (Liq. Calc.), U.S.P., B.P.; Solution of Lime (Lime-water). A satu- 
rated solution of Ca(OH) 2 , containing about o. 14 per cent. Clear colorless liquid; odor- 
less; alkaline taste. Incompatible with carbonates or "hard" water. Used as antacid, 
against diarrhea and externally against burns. It is often added to milk (i 14). Dose, 
15 c.c., 4 drams (about 0.02 Gm. of the hydroxid), U.S.P.; 30 to 120 c.c., i to 4 ounces, 
B.P. 

Liq. Calcis Saccharatus (Liq. Calc. Sacch.), B.P. (Syrup of Lime). Contains about 
2 per cent, of CaO. Antacid, and antidote for phenol poisoning. Dose, 2 c.c., 3 
minims. 

* Linimenlum Calcis (Lin. Calc.), U.S.P., B.P.; Lime Liniment (Carron Oil). A 
mixture of equal volumes of lime-water and oil (olive, B.P.; linseed, U.S.P.). Applied 
to burns, on cloths, frequently renewed. 

AMMONIA 

This differs from other alkalies by its volatility and deeper penetration. 

Use as Counterirritant. It passes through the stratum corneum of 
the epidermis without injuring it, and, acting upon the lower layers of 
the skin, produces blisters. It is sometimes used for this purpose instead 
of cantharides, especially in nephritis, where the latter can not be employed. 
It is, however, more painful. 

It is frequently used in more dilute form as liniment for counterirrita- 
tion, when a deep action is desired. 



ALKALINE SALTS AND SOAPS 127 

The Inhalation of Ammonia. Free, or in the form of aromatic spirit, 
or of carbonate, this is used for reflex stimulation in fainting, etc. Care 
must be used, since too high concentrations of the vapor may produce 
bronchitis or pneumonia. 

Poisoning by Swallowing Ammonia. This presents the same phe- 
nomena as other caustic alkalies except that the respiratory passages are 
more involved by the inhalation of the vapor. 

Five to 10 Gm. of the official solution would be toxic; 30 Gm. are generally fatal, 
although recovery has occurred from 60 Gm. 

Inhalation of Ammonia. This produces the effects described under volatile irritants. 
For man 0.5 to i : 1,000 become insupportable. 

For "Preparations" see Index. 

ALKALINE SALTS AND SOAPS 

The soluble bicarbonates, basic phosphates, borates, sulphids and 
soaps, act as mild alkalies, since their watery solutions undergo hydro- 
lytic dissociation, with the liberation of OH ions. 

Actions and Uses. By their alkalinity, they dissolve mucus, soften 
the epidermis and hair, and emulsify and dissolve fats. They are there- 
fore employed in catarrhal conditions; in skin diseases (seborrhea, acne, 
ichthyosis, psoriasis, and epidermal proliferations) ; to facilitate the pene- 
tration of antiseptic remedies into the skin (in scabies, favus, ringworm) ; 
to emulsify cutaneous remedies (mercury, tar, sulphur) ; as lubricants for 
liniments (soap liniment); as cleansing agents (detergents), especially in 
the form of soaps and borax; and as depilatories (especially the sulphids). 

Laxative Action. In the rectum, soap secures prompt evacuation. 
It is used for this purpose as warm soap-suds enemas; or solid, formed into 
a suppository. 

The Detergent Action of Soaps. This is due to the mechanical effect of the foam, 
the emulsification of the grease, and the softening of the epidermis, so that the super- 
ficial layers are readily removed with the adherent dirt. 

Potassium soaps are the more energetic. They are semiliquid (soft soap); sodium 
forms hard soaps. 

Alkaline Baths. In skin diseases, these are best administered at bedtime. Any 
of the alkaline salts can be used; such as sodium carbonate or bicarbonate, potassium 
carbonate, or borax, in the proportion of about 100 Gm. per bath; for lotions, 2 per cent. 

Hemolytic Action. Alkalies, and especially soaps, are hemolytic. These also sen- 
sitize pneumococci to serum-lysis (Flexner, 1913). 

Phagocytosis. This is stimulated by soaps, even in fairly high concentrations; 
but excessively strong solutions are detrimental (Hamburger and de Haan, 1913). 



PREPARATIONS SOAP 

* Sapo, U.S.P.; Sapo Dums (Sap. Dur.), B.P.; Soap (White Castile Soap). Pre- 
pared from sodium hydroxid and olive oil. A white solid; sol. in hot water and ale. 

Sap. Animal., B.P.; Curd Soap. Hard soap prepared from animal fat. 

* Sapo Mollis (Sapo Moll.), U.S.P.; (Sap. Moll.) B.P.; Soft Soap (Green Soap, 
Sapo Viridis, Sapo Kalinus). Made from potassium hydroxid and vegetable oil (cot- 
tonseed, U.S. P., olive, B.P.). A soft, unctuous, yellowish mass. 

* Liniment urn Saponis, (Lin. Sapon.), U.S. P.; Soap Liniment (Opodeldoc). An 
alcoholic solution of 6 per cent, of soap, 4.5 per cent, of camphor, and i per cent, of 
rosemary oil. 

* Lin. Sap., B.P. Similar to the preceding. 

* Lin. Sapon. Moll.. U.S. P. (Tincture of Green Soap). 2 parts of the soap, i part 
of alcohol, flavored with lavender oil. 



128 MANUAL OF PHARMACOLOGY 

ALKALINE SULPHIDS 

When applied to the skin, the sulphids (K, Na, Ca) soften the stratum corneum, 
much like the alkalies, and they are used in the same conditions. Their action on hair is 
iven greater, so that they are valuable as depilatories, especially calx sulphurata. 
When taken by mouth, they act as irritants and corrosives, through the liberation of 
sulphuretted hydrogen and free alkali. 

Toxic Doses. These produce the systemic effects of hydrogen sulphid. Death has 
occurred from 12 to 15 Gm. Smaller doses have little systemic action, as they are 
rapidly oxidized. They are excreted in the urine mainly as sulphates; but there seem 
to be also some organic sulphur compounds. 

A small amount of some volatile sulphur compound is also excreted by the lungs, 
giving the peculiar H 2 S odor to the breath, and causing some expectorant action. 

When injected intravenously, the sulphids produce violent convulsions, followed by 
depression of the medullary centers. This is due to a direct action. Outside of the 
body, sulphids form a peculiar compound with hemoglobin, but this does not occur 
during life, in mammals. 

Therapeutic Uses. The sulphids are only used externally, in skin diseases (psoriasis, 
acne, etc.); and as parasiticides in scabies (solution of the skin and eggs of the mite). 

The sulphids have been proposed as an antidote for hydrocyanic acid, since they 
would form sulphocyanids, which do not have the hydrocyanic acid action. This has 
not been tested. It is possible that the reaction goes on too slowly to be of value. 

PREPARATIONS SULPHIDS 

Calcii Sulphidum Crudum (Calc. Sulphid. Crud.), U.S.P.; Calx Sulphurata (Calx 
Sulphur), B.P.; Crude Calcium Sulphid, Sulphurated Lime. A mixture containing 
about 55 per cent, of CaS. A pale gray or yellowish powder; faint odor of hydrogen 
sulphid; nauseous alkaline taste. Very slightly sol. in cold water; more readily sol. 
in boiling water with partial decomposition; insol. in ale. Used as depilatory, mixed 
with an equal quantity of starch and made into a paste. Internally it is used against 
boils and other suppurations. Its efficiency is doubtful. Dose, 0.06 Gm., i gr., U.S. P.; 
16 to 60 mg., Y to i gr., B.P. 

Vlemingkx's solution is a solution of calcium polysulphids, used in scabies (i :i), 
and as a bath in skin diseases (2 drams per gallon). 

Pot. Sulphurat., U.S.P.; (Potass. Sulphur., B.P.); Sulphurated Potash (Liver of 
Sulphur). A mixture composed chiefly of potassium polysulphids and potassium 
thiosulphate. Freely sol. in water (i : 2). Used in baths (30 to 200 Gm., i to 6 ounces, 
per bath). 

HYDROGEN SULPHID (H 2 S) 

This gas is extremely toxic, much more so than is commonly realized. 

Actions. These are partly local and irritant, due to its acid character; and partly 
central somewhat resembling asphyxia. In vitro, it forms a firm compound (sulph- 
hemoglobin) with the blood pigment. Thick layers have a brown color. Thin strata 
appear a dirty green, which 'is responsible for the postmortem discoloration. Lewin 
believes that the effects are due to the interference of the compound with oxygenation; 
however, it is generally believed that only traces are formed during life (E. Meyer, 
1898) and that the sulphid is directly toxic to the nervous system. 

Occurrence. Hydrogen sulphid is formed in putrefaction, particularly of sewerage. 
"Sewer gas" consists essentially of CO 2 , NH 3 , CH 4 , and 2 to 8 per cent, of H 2 S. Small 
quantities are also formed in intestinal putrefaction, giving rise to diarrhea and possibly 
to some of the symptoms of "intestinal autointoxication." It may be removed by the 
administration of bismuth salts, and its further formation checked by cathartics and 
intestinal antiseptics. 

Concentrations in the Respired Air. 0.02 per cent, produces symptoms, particu- 
larly irritation of the conjunctiva and bronchial mucosa; 0.05 per cent, produces 
asphyxial symptoms; hyperpnea, nausea, giddiness, headache, cerebral excitement, and 
finally narcosis; 0.07 per cent, produces death after about an hour under coma, often 
with convulsions; 0.2 per cent, is fatal to dogs in one and one-half minutes. The after- 
effects resemble those of carbon monoxid. Edema of the lungs and pneumonia are 
common sequels (Lehmann, 1892). 

H 2 S is partly excreted by the lungs. The urine is also said to contain sulphids. 



SULPHUR 



129 



It is readily detected in air by its odor and by blackening lead or silver-paper. In 
case of death, it may be recognized by the blackening of a silver coin laid on the skin. 
Sulphur Springs. Hydrogen sulphid is contained in small quantity in a number of 
mineral waters (sulphur springs). These are recommended for a variety of obscure 
disorders rheumatism, gout, diabetes, etc. When these waters are administered 
for some time, they cause diuresis and diaphoresis, irritation of the urinary passages, 
intestinal irritation, and muscular pains. Their therapeutic effects are probably to be 
referred to their laxative, diuretic and diaphoretic actions, although the general hygienic 
conditions must contribute largely to the results, as with other mineral waters (Boecker, 
1895)- 

SULPHUR 

Uses. Sulphur is employed as a parasiticide in itch; as a mild cutane- 
ous irritant in skin diseases (sulphur ointment) ; and internally as a laxative 
for softening the stools, especially in hemorrhoids (as Compound Licorice 
Powder, or mixed with an equal amount of Potassium bitartrate). Like 
other intestinal irritants, sulphur somewhat increases the elimination of 
uric acid (Abl, 1913). 

Manner of Action. Sulphur itself is inactive, but by contact with 
proteins and alkalies it is slowly converted into the active sulphids. This 
process is so gradual that the action is always mild and protracted, unless 
the finely divided "precipitated " sulphur is used. Ordinary or " washed " 
sulphur therefore deserves preference. Sulphur is somewhat soluble in 
ointment bases, and this facilitates its action (Sabbatani, 1913). Sulphur 
is also burned for fumigation, the disinfectant action being due to the 
formation of SOa. 

Formation of Sulphids. This is effected on the skin by the cutaneous secretions. 
Xo change occurs in the stomach; but a considerable amount (to 10 per cent.) is con- 
verted into H 2 S in the intestine, as may be readily seen from the increased secretion 
of sulphate by the urine. The conversion was formerly referred to the alkalies of the 
intestine; but Heffter (1904) points out that the alkali exists as bicarbonate, which 
can not affect the conversion. He showed that it is produced by proteins of all kinds 
(even after these are boiled). The hydrogen sulphid is formed most abundantly in 
the large intestines (Taegen, 1912). (Frankl, 1911, claims that the effects are due to 
the formation of sulphites). 

Colloid Sulphur. A new modification of sulphur in "colloid solution" produces 
H 2 S much more rapidly, also on intravenous injection; and thus causes typical H>S 
poisoning without other visible effects (Sabbatani, 1908, 1913, 1914). 

Alopecia. Sulphur (2 to 4 per cent.) is used in the seborrheic form, as also other 
irritants (salicylic acid, i to 2 per cent.; mercuric chlorid, o.i to 0.4 per cent.; beta- 
naphthol, i to 2 per cent.; pilocarpin, 0.15 per cent.; cantharides; resorcin (i to 2 per 
cent., discolors the hair). These agents may be dissolved in water, glycerin or oils, or 
applied as ointments (Dore, 1914). 

PREPARATIONS SULPHUR 

* Sulphur Sublimatum (Sulph. Sublim.), U.S.P.; (Sulphur Sublim.), B.P.; Sublimed 
Sulphur (Flowers of Sulphur). A fine, gritty, light yellow powder, of slight odor, and 
faintly acid taste. Insol. in water; nearly insol. in ale.; slightly sol. in fat solvents and 
oils; freely sol. in carbon disulphid. For fumigation, it is used in the ratio of 2 pounds 
per 1,000 cubic feet. It contains some free acid and other impurities, but is sufficiently 
pure for medicinal use, although the Washed should be preferred. It enters into all 
the B.P. preparations, whilst those of the U.S. P. are made from Washed Sulphur. Dose, 
4 Gm., i dram, U.S.P.; 1.2 to 4 Gm., 20 to 60 gr., B.P. Sulphur also enters into Pulvis 
Glycyrrhizae Co. (see Index). 

* Sulphur Lotum (Sulph. Lot.), U.S. P.; Washed Sulphur. This is prepared by wash- 
ing the preceding with ammonia water to remove the acid. Its properties are similar 
to the preceding, but it is tasteless and odorless. Dose, 4 Gm., i dram, U.S. P. 

Sulphur Pracipitatum (Sulph. Praec.), U.S.P.; (Sulphur Praec.), B.P.; Precipitated 
Sulphur (Lac Sulphuris, Milk of Sulphur). This is prepared by precipitating sulphur- 



130 MANUAL OF PHARMACOLOGY 

ated lime with acid. An amorphous pale yellow powder. It is a much finer powder 
than sublimed sulphur and is therefore rather more active; but its dose is the same. 

* Unguent u in Sitlphitris (Ung. Sulphur.), U.S. P., B.P.; Sulphur Ointment. 15 per 
cent, of sulphur, U.S.P.; 10 per cent., B.P.; in benzoinated lard. 

Conf. Sulphur., B.P. 45 per cent, of Sulphur, n per cent, of Potass. Bitart. Dose, 
4 to 8 Gm., 60 to 120 gr., B.P. 

Troch. Sulphur., B.P. 0.3 Gm. of Sulphur. 

ICHTHYOL 

Uses. Peculiar value has been attributed to the incompletely oxidized sulphur 
occurring in organic compounds. The pioneer product of this kind is ichthyol, which 
contains 10 per cent, of sulphur as sulfons, mercaptans and sulphids. It is weakly anti- 
septic and mildly irritant. Taken internally, it produces gastro-intestinal irritation, 
with diarrhea. Its influence on metabolism is in dispute. It has been used locally to 
cause absorption of swellings and effusions, in contusions, burns, etc., and especially in 
gynecologic practice. It has also proven useful in skin diseases, acting somewhat like 
sulphur. Internally, it has been endorsed against the greatest variety of diseases of 
digestion, respiration, genito-urinary tract, tuberculosis, etc. These claims bear the 
stamp of exaggeration. 

Ichthyol Substitutes. The disagreeable odor and taste of ichthyol can not be dis- 
guised by flavors, but can be removed by combination: Ichthalbin, a compound with 
albumen, has been recommended for internal administration; Ichthyoform, an almost 
insoluble compound with formaldehyd, as antiseptic dusting powder. 

The commercial success of ichthyol has led to the substitution of a number of syn- 
thetic products, formed by saturating mineral oils with sulphur. Thiol and Tumenol are 
the principal products of this class. They seem to have the same actions as ichthyol, 
and are tasteless. Linseed oil saturated with sulphur has long been used in domestic 
medicine under the name of Harlem Oil. 



PREPARATIONS ICHTHYOL 

Ichthyol, N.N.R. (Ammonium Sulpho-ichthyolate). A mixture prepared by sulph- 
oning the tar-like distillate obtained from bituminous shales found in Tyrol, and which 
contain the fossil remains of fishes. A dark brown syrupy liquid of characteristic 
empyreumatic odor and burning taste; of faintly acid reaction. Miscible with glycerin, 
oil or fats; incompletely soluble in ale. Insoluble in water (Hostmann, 1915). Dose, 
internally, 0.2 to 2 c.c. (3 to 30 minims) mostly in simple suspension in water, or pepper- 
mint water, sometimes in the form of pills or capsules; locally, in vaginal, uterine or 
rectal suppositories; in 0.06 to 0.18 c.c. (i to 3 minims) bougies or i to 3 per cent, solu- 
tion for gonorrheal treatment. 

The compounds and substitutes are described in N.N.R. 

TmOSINAMIN 

Uses. This is allyl-sulphocarbamid, prepared by heating volatile oil of mustard 
(allyl thiocyanate) with alcoholic solution of ammonia. It was introduced by Hebra 
and Unna, 1892, and has been credited with causing the absorption of exudates, lym- 
phatic swellings, scar- tissue, etc.; and with the cure of lupus. The administration must 
be continued for weeks, and combined with massage and other adjuvant measures. It 
is therefore difficult to judge whether it has any value. The clinical opinions are con- 
tradictory, and no satisfactory explanation has been offered for its reputed effects. It 
probably does little, if any good, and it may produce toxic systemic effects, although it 
is usually well borne, except for the bitter taste and garlic eructations. 

Toxic Effects. In man, i Gm., or 0.2 Gm. on repeated use, have caused headache, 
nausea, vomiting, lassitude and fever (J.A.M.A., 56 1835, 1911; Charteris, 1910; Seifert, 
Nebenwirk., 1915, p. 182). These may set in suddenly after it has been used for a time 
uneventfully. In animals, Tyrode, 1910, found impaired respiration, eventually cessa- 
tion, and death; sometimes pulmonary edema and hyperemia (Lange, 1892). The circu- 
lation is not affected in mammals, but high concentrations paralyze the frog's heart. 
Smaller doses produce severe changes in metabolism, with loss of nitrogen and rapid 
emaciation; and fatty degenerations of parenchymatous organs, especially the heart 
and kidneys. Normal connective tissue showed no changes. 



CAUSTIC ACIDS 13! 

Other Ally I Compounds. Allyl acetic acid, allyl urea and dimethylallylamin are 
indifferent; allyl iodid is strongly irritant; allyl formate produces necrosis of the liver 
and kidneys; allyl amin is highly toxic. The effects are described by Piazza, 1915. 

PREPARATIONS THIOSINAMIN 

Thiosinamina, N.N.R.; Thiosinamine; (NH ? )- CS- NHCHy CH : CH 2 . Colorless crys- 
tals, of slight garlic odor and bitter taste. Slightly sol. in water, with decomposition; 
dissolves in ale. or glyc. The oral dose is 0.03 to o.i Gm. in capsules. It is usually 
administered by hypodermic injection (which need not be made at the site of the lesion), 
daily to every third day, 0.05 to 0.2 Gm., in 15 per cent, alcohol or 10 per cent, glycerin. 
Since the solvents produce local irritation, Fibrolysin may be substituted (Mendel, 1905). 

Fibrolysin, N.N.R. (Liq. Thiosinam. Sodio-Salicylatis). 15 per cent, of a double 
salt of thiosinamin and sod. salicyl. Dose, a 2 c.c. vial, corresponding to 0.2 Gm. of 
Thiosinamin. 

CAUSTIC ACIDS 

Members. The most typical acids in regard to the local action are sulphuric and 
hydrochloric acid. Nitric acid produces the same effects, but differs from these in its 
chemic action, producing xanthoproteic acid from the proteins. The sulphurous acid 
has also a marked corrosive power. Hydrofluoric acid has a specific toxic action, pene- 
trates very deeply in virtue of its volatility, and is especially strongly corrosive, pro- 
ducing obstinate ulcers. Its inhalation from air containing 0.02 per cent, produces 
acute catarrhal irritation. Of the organic acids, those of the fatty series act similarly, 
but are weaker. The trichlor-acetic acid is the most corrosive of these. The volatility 
of most of the fatty acids makes them more penetrating than the mineral acids. Oxalic 
acid occupies a place by itself on account of its specific toxic action, produced probably 
by the precipitation of the calcium. 

The compound acids such as ethyl-sulphuric, etc. act like organic acids. The 
aromatic acids act partly as acids, but this action is greatly obscured by their collapse 
action. 

The irritant action of the acids is also shared to some extent by the acid salts, acid 
tartrates, acid sulphates, etc. 

Manner of Action. This varies to some extent with the constituents of the tissues. 
But, on the whole, it consists, with concentrated acids, in withdrawal of water; in the 
formation of acid albumins; in softening of the connective tissue and epithelium; and 
in special situations, in solution of calcareous material. 

All the concentrated acids have an affinity for water, and withdraw this from the cells. 
This affinity is so strong in the case of concentrated H 2 SO4 that not only the formed 
water is withdrawn from the tissues, but the elements H and O are split off from their 
chemic combinations with carbon, leading to carbonization. 

All acids convert proteins into acid-albumins, which are insoluble in moderately 
strong, but soluble in concentrated or very weak acids. Upon this precipitation of 
proteins depends their astringent and styptic action. 

The connective tissue undergoes a rather peculiar change. It is not dissolved, but 
is softened and rendered more soluble in boiling water. (This explains why meat be- 
comes more tender on keeping.) The concentrated acids have a similar effect upon 
epithelium. Without actually dissolving it, they soften it in such a manner that it is 
readily detached. Dilute acids, on the other hand, harden it. 

Poisoning by Concentrated Acids. This presents the usual phenomena 
of caustic poisoning. It is extremely painful. The " coffee-grounds " vomit 
is characteristic. Scar formation and stenosis are frequent. 1 The prog- 
nosis and toxic dose depend upon the concentration, and the parts affected. 
The treatment has been discussed. Sulphuric acid poisoning is the most 
common. 

Continued exposure to the vapors of acids, such as occurs in certain 
trades, gives rise to chronic bronchitis. They also attack the teeth 
and from these the necrosis may spread to the jaw, as with phosphorus. 

Uses. Because of the intense pain, deep penetration and extensive scar formation, 
acids are not desirable cauterizants. Nitric and Iri-rhlor-acclic arid form relatively 
firm eschars, so that their action is more circumscribed and less painful. Sulphuric 
1 See v. Hoffmann's Atlas of Legal Medicine. Plates 33, 34. 35, 36 and 37. 



132 MANUAL OF PHARMACOLOGY 

acid has been made into a paste with various inert powders (charcoal, sawdust, lead 
sulphate, etc.) to localize its action, but is still painful and difficult to control (Pusey, 
1913). Lactic acid has a relatively mild action on normal tissues. Chromic acid may 
cause poisoning when used as a caustic. 

Antiseptic Action. The destruction of proteins makes acids efficient antiseptics 
Even quite dilute solutions, such as the gastric juice, suffice to limit the growth of bac- 
teria. The concentrated acids destroy them outright. 

PREPARATIONS CAUSTIC ACIDS 

Acidum Hydrochloricum (Acid. Hydrochlor.), U.S.P., B.P.; Hydrochloric Acid 
(Muriatic Acid). About 32 per cent, of HC1. Colorless, fuming liquid. Pungent 
odor. The commercial acid (strength = 30 per cent, to 33 per cent.) has a golden yellow 
color due to Fe and free Cl. Since it often contains As, it should not be used in 
internal medicine. 

Acidum Lacticum (Acid. Lact.), U.S. P., B.P.; Lactic Acid. A liquid containing 
Lactic Acid (optically inactive alphahydroxypropionic acid, CH 3 CHOH.COOH) and 
lactic anhydrides. A colorless, or slightly yellow, syrupy liquid, nearly odorless, acid 
taste, absorbing moisture on exposure to air. Miscible with water, ale. or ether. 
Dose, 2 c.c., 30 minims, U.S. P.; i to 2 c.c., 30 to 60 minims, B.P. Used as caustic, 
especially for dissolving diphtheritic membranes. 

* Acidum Nitricum (Acid. Nit.), U.S. P., B.P.; Nitric Acid. About 70 per cent, of 
HNOs. Fuming liquid, very caustic and corrosive. Peculiar somewhat suffocating 
odor. Used as a caustic for warts (glass rod) ; against hyperhydrosis of feet (i to 2 ounces 
to pail of water); as disinfectant (will corrode metal vessels or pipes). 

Commercial nitric acid contains about 60 to 64 per cent.; the "fuming" acid is almost 
absolute HNO 3 , saturated with NO 2 . 

Acid. NitrohydrochL, U.S. P.; Nitrohydrochloric acid (Nitromuriatic acid, Aqua 
Regia). A strong solution containing hydrochloric acid, nitric acid, nitrosyl chlorid and 
chlorin. Made by mixing 18 c.c. of nitric acid with 82 c.c. of hydrochloric acid. A 
golden-yellow, fuming, and very corrosive liquid; strong odor of chlorine. Dose, 0.2 
c.c., 3 minims, U.S. P., diluted. 

Acid. Nitrohydrochl. Dil., U.S. P. Nitric acid, 10 c.c.; Hydrochloric acid, 45.5 c.c.; 
Water, 194.5 c.c. Colorless or pale yellowish liquid. Faint odor of chlorine. Dose, 
i c.c., 15 minims, U.S. P., diluted. On account of the free chlorin, it may be supposed 
to have a stronger local irritant action than HC1. It is popularly supposed to "stimu- 
late the liver," but its action does not differ in kind from that of other acids. 

Acid. Nitro-hydrochl. Dil., B.P. Nitric acid, 24 c.c.; Hydrochloric acid, 32 c.c.; 
Water, 200 c.c.; kept fourteen days before use. Dose, 0.31 to 1.2 c.c., 5 to 20 minims, 
B.P., diluted. 

Acidum Osmicum, Osmic Acid, OsC>4. Intraneural injections are used to produce 
degeneration of nerves for the relief of persistent neuralgias (Billroth and Neuber, 
1885). The treatment is best applied by injecting % to i c.c. of a fresh i to 2 per cent, 
solution directly into the, preferably exposed, nerve. The result is sometimes imme- 
diate, but more commonly it is not complete until after one or two weeks, or it may 
even fail entirely. If successful, the effects persist at least for several months, when it 
may become necessary to repeat the injection. They are rarely if ever permanent. 
The local reaction is always painful but not serious. It is probably not advisable to 
use osmic acid in the presence of renal disease (Eastman, 1906). 

Acid. Sulphuricum (Acid. Sulph.), U.S. P., B.P.; Sulphuric Acid. About 95 per cent. 
of H 2 SO 4 . An oily, colorless liquid, acquiring a brown color if exposed to dust. Very 
intensely corrosive, charring organic substances. Miscible in .all proportions with 
water or ale. with the evolution of much heat. (Such mixing must be done very cau- 
tiously by slowly pouring the acid into the water, under constant stirring.) The Com- 
mercial Sulphuric Acid (Oil of Vitriol) is very apt to contain arsenic, and should not be 
employed in medicine. 

Acidum Trichloraceticum (Acid. Trichloracet.), U.S. P.; Trichloracetic Acid. A 
monobasic organic acid, CC1 3 COOH. Colorless, deliquescent crystals, having a 
slight, characteristic odor. Very sol. in water or ale. Used in substance or strong 
solution, especially against warts, less painful than nitric acid. 

DILUTE ACIDS 

Local Effects. Dilute acids produce a mild irritation, and at the same time harden 
the epithelium, without destroying it. They differ from the volatile organic irritants 
in that they do not penetrate so deeply, and do not cause nephritis. 



IODIN 



133 



They may be used in the form of baths, in the strength of about 30 c.c. (i ounce) of 
concentrated acid to the bath (30 gallons). Or they may be applied as lotions. In 
this case the volatile acids are preferred, because their action is deeper. Formic acid 
has a special reputation. It is used in the strength of about 4 per cent, or 5 per cent. 
in alcohol. 

This stimulation of the skin without destruction of epidermis is used to increase the 
amount of sweat; and acids, usually in the form of vinegar, are therefore used for 
sponging in fever. On this account they have received the name of "refrigerants." 
On the other hand, they are used in excessive secretion of sweat (sweating feet) to harden 
the epidermis. For this purpose 5 or 10 c.c. of concentrated hydrochloric acid are put 
in a basin of water and the feet placed in this until they become painful. This is done 
about twice a week. 

The irritant action of the volatile acids is sometimes employed to produce reflex 
stimulation of the central nervous system by inhaling vinegar, etc. 

Acidum Formicum. Formic Acid, 



THE HALOIDS 

These comprise bromin, iodin, dilorin, and the hypochlorites. 

Their corrosive action is determined by their entering very easily into chemic reac- 
tion with all kinds of organic substances, taking from them hydrogen and forming 
hydrobromic, hydrochloric, and hydriodic acids, which have the ordinary acid actions. 
If water is present they set free oxygen in the form of ozone, by combining with the 
hydrogen of the water; this is also a strong irritant. The halogens furthermore enter 
directly into the protein molecule. 

Chlorin is discussed under the disinfectants. 

IODIN 

Uses. The tincture or solution, painted on the skin, produces a mild 
but deep and persistent irritation which can be easily graduated by suc- 
cessive applications. This irritation is used to secure the correction of 
chronic inflammations and the absorption of inflammatory exudates 
(pleura, joints, etc.); also as an antiseptic; and formerly for securing ad- 
hesive inflammation of serous cavities and cysts. The internal uses are 
discussed under "lodids." 

Antiseptic Action. This is used especially for disinfecting wounds, and 
for preparing the skin for operations (Woodburg, 1907). For the latter 
purpose, the official tincture is painted over the operative field on the pre- 
ceding day, and again just before operating. The action is attributed 
to the formation of antiseptic compounds with the tissues (Schumacher, 
1915). Bacterial tests from the skin have given equivocal results; 
clinically, the results are excellent, even dirty wounds healing rapidly. 
Experimental results with infected wounds were also good, the iodin being 
effective within five hours after infection, i.e., until the bacteria have 
spread too deeply (Brunner, 1915). The stain may be removed by warm 
concentrated solution of sodium thiosulphate (Snoy, 1911). Sometimes 
there is severe irritation (Herzog, 1914). 

Local Phenomena. Applied to the skin iodin produces a mahogany color, smarting, 
erythematous inflammation, infiltration of subcutaneous tissue, desquamation of the 
epidermis in large shreds; if repeated, vesication results. The effects on mucour 
membranes are more severe and may produce corrosion. Its action is chemical, since 
it precipitates proteins as easily dissociated compounds. It is absorbed from the skin 
fairly readily, and excreted mainly in the urine as iodid. 

Employment as Counterirritant. Iodin is used especially in chronic pleural effusions, 
chronic rheumatism, diseased joints, enlarged lymph glands, lymphangitis, etc. It has 
also been employed in erysipelas, painting the tincture from the periphery toward the 
center, five or six times daily (Ferrari, 1911); but Wood warns that the action must be 
graded very mildly, or it will produce extensive necrosis. 



134 MANUAL OF PHARMACOLOGY 

Injections into cysts, hydrocele, empyema, etc., produce at first increase of the fluid, 
then adhesive inflammation. The injections are very painful, and have often caused 
serious poisoning. They are now displaced by surgical procedures. 

Toxic effects from iodin absorption from cysts consist in cyanosis, salivation, vomiting, 
skin eruptions, high fever, and collapse. The urine is scanty and albuminous. The 
intoxication may persist for several days and then end with sudden death. 

The toxic effects of swallowing iodin are successively: gastric uneasi- 
ness; disagreeable metallic taste; violent vomiting; abdominal pain; and 
sometimes purging. The vomit has the color of iodin, or is blue if starch 
is present. 

The fatal dose corresponds to about 2 or 3 Gm.; but recovery is said to have occurred 
after 10 Gm. 

The treatment of iodin poisoning consists in evacuation; demulcents 
(eggs, milk, oils, and cooked flour or starch, which form loose compounds 
with iodin); dilute alkalies (NaHCO 3 ); and 5 per cent, sodium thiosul- 
phate (''Hypo"). The last binds the iodin: 2Na 2 S 2 O3 + 2! = 2NaI 4- 
Na 2 S 4 O6 (Sabbatani, 1913). The further treatment would be symptomatic. 

Circulation. Perfusion of excised frog hearts with dilute iodin solutions produces 
irregularities, followed by depression. Stronger solutions result in diastolic arrest. 
Intravenously, it depresses the circulation greatly in cats, not in dogs (Salant and 
Livingston, 1916). 

Toxic Effect in Mammals. Boehm, 1876, found that the intravenous infection of 
0.04 Gm. per Kg. is fatal. Symptoms set in only after 6 or 8 hours, with exhaustion, 
dyspnea, and death in 12 to 24 hours. Necropsy shows bloody pulmonary and pleural 
exudate and renal congestion and hemorrhages, 



PREPARATIONS IODIN 

lodum, U.S.P., B.P.; Iodin, i. Bluish black, friable scales, of distinctive odor and 
acrid taste. Very slightly sol. in water (i : 2950); sol. in ale. (i : 12. 5), or glyc. (i : 80); 
freely sol. in fat solvents or aqueous solutions of iodids. Dose, 5 mg., Jl2 *> U.S. P., 
diluted; maximal, 30 mg., % gr. 

* Tr. lodi, U.S. P.; Tincture of Iodine. 7 per cent, iodin; 5 per cent. KI; in ale. 
Dose, o.i c.c., iJ- minims, U.S. P., diluted; maximal, 0.3 c.c., 5 minims. The KI in 
the tincture makes it miscible with water and insures against loss of strength on keeping 
(Wetterstroen, 1908). (When iodin is administered in milk, it is largely converted into 
iodid and albuminates), 

* The principal incompatibilities of iodin are: alkaloids; alkalies and carbonates; 
tannin; turpentine and volatile oils. 

* Tr. lodi Fort., B.P. 10 per cent, iodin, 6 per cent. KI. 

Tr. lodi Mil., B.P. 2.5 iodin, 2.5 per cent. KI. Dose, 0.12 to 0.3 c.c., 2 to 5 
minims, B.P., diluted. 

Liq. lodi Co., U.S. P. (Lugol's Solution). 5 per cent, iodin, 10 per cent. KI, in water. 
Dose, 0.2 c.c., 3 minims, U.S. P., diluted. 

Ung. lodi, U.S. P., B.P. 4 per cent, each of Iodin and KI, in lard base. 

BROMIN 

This is a reddish brown, very volatile and intensely corrosive liquid. Only a few 
instances of swallowing bromin are recorded. In one of these (Snell, 1850), death oc- 
curred seven and one-half hours after taking an ounce. The antidotes would be eggs 
and starch. 

Inhalation of bromin vapors is very irritant to the respiratory organs, i : 1,000,000 
of air is already disagreeable; 10 : 1,000,000 is said to be dangerous. 

THE LOCAL ACTIONS OF METALLIC SALTS 

Mechanism of Action. Metallic salts combine with proteins to form more or less 
difficultly soluble compounds containing varying amounts of the metal and proteins. 



METALLIC SALTS 



135 



The acid of the metallic salt is thus set free. If, for instance, a solution of ferric chlorid 
is added to egg-albumen, the result is an albuminate of iron, and free hydrochloric acid. 
This free acid will exert its own irritant action. 

The local effects of metallic salts, therefore, rest on two factors: the precipitant action 
of the metal, and the irritant action of the liberated acid. Both influence the total 
effect. 

Corrosive and Astringent Metallic Salts. Some of the metal albuminates are almost 
insoluble in water; some are soluble in excess of protein, especially when neutral salts 
are present; others are not. If the precipitate is soluble, there is no obstacle to the 
penetration of the metal, and its action, irritant or caustic, is deep. If, on the other 
hand, the precipitate is insoluble, as in the case of lead salts, penetration can not take 
place; the irritation is confined to the surface, and an astringent action results. In 
regard to this, the metals stand in about the following order: The most astringent is 
lead; then comes aluminum; then iron; then zinc, copper, silver, and tin, which stand 
about on a level; the most caustic is mercury. As to the liberated acids, the strongest 
caustic action appears in hydrochloric acid; then comes nitric acid; then sulphuric; 
then phosphoric; the weakest of all are the organic acids acetic, citric, and tartaric. 

By proper combination, then, between the metals and the acids, one may obtain 
any grade of action from pure caustic to pure astringent. 

The most typical caustic would be mercuric chlorid, the most typical astringent, 
lead acetate. 

The strength of action will, of course, also depend upon the concentration in which 
the salt is used, and this is often limited by its solubility. The chlorid of silver would, 
theoretically, be a stronger caustic than the nitrate, but since it is not soluble, it can not 
be used^in the same concentration. 

It must not be forgotten that the irritant action, the astringent action, and the 
caustic action, are merely degrees of the same process. The astringent action always 
precedes the caustic action; and, consequently, by proper dilution, one may obtain 
astringent effects from salts which are ordinarily purely caustic. For instance, silver 
nitrate can be so graduated in strength as to have a purely astringent action, without 
any caustic effect whatever. 

It is, therefore, impossible to establish a perfectly definite classification between the 
metallic salts. An approximation to it is given in the following table: 

Mainly Caustic: All Hg salts; ZnCl 2 ; SnCl 4 ; SbCl 3 ; tartar emetic; CuSO 4 . 
Both Caustic and Astringent: Fe salts; ZnSO 4 ; ZnAc-.*; CuAc 2 ; AgNO 3 ; 

Pb(N0 3 ) 2 ; PbI 2 . 
Mainly Astringent: Alum; PbAc 2 ; Pb 2 OAc 2 ; ZnO. Bi subnitrate; white 

precipitate. 

The Caustic Action of Metallic Salts. This was formerly used quite extensively, but 
it has now been largely abandoned. Most are not sufficiently powerful for this purpose; 
others, again, are too toxic, being absorbed in sufficient amount to produce poisoning. 
To the latter class belong arsenic, antimony, and mercury. Zinc chlorid and antimony 
chlorid (Butter of Antimony) are very active caustics, but rather too diffluent. Their 
scab is so soft that their action can not be kept within bounds. In fact, of all the metallic 
caustics, silver nitrate in the form of sticks (Lunar Caustic), and to a less extent copper 
sulphate, are alone used to produce a purely caustic action. Arsenic, were it not for 
its toxicity, would be a very useful corrosive. Its action is so slow that it can be very 
readily limited. It was believed to destroy only pathologic formations, leaving healthy 
tissue intact. This would be easily understood, from the fact that the former are 
much less staple. Silver nitrate is also quite easily controlled, since its action may be 
stopped at once by washing with NaCl, which converts it into AgCl. 

Astringent Efficiency. The most actively astringent metallic salt, lead 
acetate, can not be used internally, nor for any length of time externally, on 
account of the danger of chronic poisoning. Next in activity comes alum, 
and especially the burnt alum (alum which has been roasted, so as to de- 
prive it of its water of crystallization, and which therefore acts not only 
as a metallic astringent, but mechanically by withdrawing water). Next 
to alum, come the soluble zinc salts, the sulphate, the acetate, and the 
sulphocarbolate. Then, after these, insoluble zinc salts, oxid and car- 
bonate. Of other insoluble metallic salts the subnitrate of bismuth and 

* Ac = Acetate. 



136 MANUAL OF PHARMACOLOGY 

the oxalate of cerium are most commonly used. Then come the caustic 
salts in proper dilution. The most important is silver nitrate. Then 
the iron salts in dilute solution; iron sulphate, about 5 per cent.; ferric 
chlorid, about 3 per cent. 

In actual use, these different astringents are frequently combined. 
Whether this has any advantage is somewhat difficult to say. Better 
results could perhaps be secured by using only one astringent, since its 
action could be much more exactly controlled. 

Therapeutic Applications. For use on open wounds, ulcers, abscesses, 
etc., for the astringency and a mild nutritive stimulation leading to repair, 
silver nitrate is the most useful. Next to this, the soluble zinc salts; then 
alum. They are used in strengths of from ^ per cent, to 5 per cent. The 
insoluble astringents may be used as dusting-powders, or in the form of 
ointments 5 per cent, to 20 per cent. It must not be forgotten that 
absorption is fairly free from open surfaces, and calomel, bismuth, lead, 
etc., must be used with caution. Zinc oxid is quite safe, and is one of the 
most useful. 

The mucous membranes which are easily accessible to the local action 
of astringents are those of the mouth, conjunctiva, nose, genito-urinary 
tract, and rectum. The same salts as in the case of open wounds can be 
used, as also tannin. They are employed in somewhat weaker solution, 
as gargles, washes or injections. The usual strength is from ^ to i per 
cent. For vagina or rectum, double this; in the conjunctiva and nose, 
perhaps one-fourth of this. The strength, as with all local medication, must 
be adjusted to the anatomic peculiarities of the surface: It should be 
very different for the cornea and for the plantar surface of the foot. In 
the case of the genito-urinary tract, irritation is particularly undesirable. 
For this reason non-irritant protein compounds of silver have become 
popular. 

Astringents cause actual constriction of the mucous membranes, and 
may in this way bring about the complete disappearance of small polypi. 

In the alimentary canal the astringents are useful mainly in lessening 
the reflexes resulting from inflammation; i.e., the vomiting and diarrhea. 

Against vomiting, especially when caused by ulceration, bismuth sub- 
nitrate or subcarbonate seems to be the most useful. These act not only 
in virtue of their astringency, but also somewhat after the manner of 
inert dusting-powder, affording an artificial protective covering to the 
walls of the viscus by adhering to them. Silver nitrate is also some- 
times used in doses of about i eg. (% grain), dissolved in water and 
given three times a day. 

Their action on diarrhea is entirely similar. Bismuth is again pre- 
ferred; silver nitrate is often very useful in the summer diarrhea of infants. 

Further details will be found under the respective metals. 

TANNINS AND VEGETABLE ASTRINGENTS 

Actions and Uses. The tannins are a group of widely distributed vege- 
table principles, which percipitate proteins and are therefore astringent; 
and which give blue or green compounds with iron salts. They act more 
mildly than the metals; and being practically non- toxic they are especially 
suited for use in the alimentary canal. They do not decrease peristalsis 
directly, but do so indirectly, by allaying the underlying inflammation. 
Their employment in diarrhea dates back beyond the fourth century 
B. C. 



TANNIN 



137 



The official "tannic acid" is derived from nut-galls. Free tannin 
would be too irritant to the stomach; so that its action must be slowed, 
by the presence of extractives, as in the crude plant extracts (Gambir, 
Krameria, Kino); or by delaying its solution through combination with 
proteins (Tannalbin) ; or by esters, which are but slowly decomposed in 
the intestines. 

In the course of its absorption, tannin is decomposed into the non- 
astringent gallic acid, pyrogallol, etc. 

Varieties of Tannin. Ordinary "tannin" or gallo-tannic acid is derived chemically 
by the elimination of a molecule of H 2 O from 2 molecules of gallic acid (Tri-hydroxy- 
benzoic acid, C6H 2 .(OH) 3 .COOH). The numerous other varieties are of different 
composition, in many cases unknown. Some are compounds of gallic acid with sugar 
or with phlorhizin. Their gross classification has been discussed under the general 
"Chemistry of Plants." 

Constipative Action. This has been studied on cats with the X-ray method by Hesse, 
1913. In the absence of diarrhea, tannalbin has no effect on the intestinal movements 
beyond a slight delay in the emptying of the stomach; nor had it any influence on the 
diarrheas produced by milk-feeding or senna; and but little on the catharsis of castor oil. 
However, it arrested certain dietetic diarrheas (bread), and that produced by the colon- 
action of colocynth. Its action is therefore not on peristalsis, but on the inflamed 
mucosa. 

Pharmacologic Peculiarities. Tannins form more or less insoluble compounds with 
many metals, alkaloids, glucosids, etc., and are therefore useful as antidotes. They also 
precipitate proteins, gelatin and connective tissue (leather), and thus act as astringents, 
styptics, and antiseptics (mainly by depriving the bacteria of food). The different 
tannins are not equivalent in these respects. Some (which are perhaps misnamed), 
such as those of coffee and ipecac, are practically non-precipitant. Others present dif- 
ferences in the firmness and solubility of the precipitate, which, when better known, 
may prove of therapeutic importance. 

Fate. In the stomach, tannin precipitates the proteins in the form of tannates, 
which are decomposed by further digestion, again setting free active tannin. In the 
intestine, a part of the free tannin combines with the alkali to form the non-precipitant 
alkali tannates. The further fate is imperfectly known; but all of the tannin, even if 
injected intravenously, undergoes decomposition into gallic and pyrogallic acid and 
other decomposition products, before being excreted. These appear both in the urine 
and feces (E. Rost, 1897; the older contradictory statements were based on faulty tests 
for tannin). Only the insoluble tannates (Tannigen, Tannalbin, etc.) pass in part un- 
decomposed into the feces. The decomposition must, therefore, take place to a large 
extent in the intestines. With oral administration, the urine contains at most i per 
cent, of the gallate of the tannin. 

The use of tannin as antidote has been discussed under "General Toxicology." 

The insolubility of tannin compounds has been utilized in securing a more prolonged, 
local action of the kations. It will be remembered that this is one reason for the more 
lasting local effects of galenics as compared with alkaloids. It has been suggested to 
prepare such combinations artificially, but these have not come into general use. 

The effect of the continued administration of small amounts of tannins has consider- 
able importance, because they are contained in a number of beverages; as tea and certain 
wines. A mild astringent action may be locally tonic and beneficial; but larger 
quantities prove actually irritant, and may lead to gastroenteritis. 

Even small amounts of tannin interfere somewhat with absorption. This is largely 
due to their precipitating proteins. But these combinations are again decomposed in 
the alkaline intestine, so that the interference is not large. 

In the actual experiments of Biberfeld (1903) on the absorption of normal saline 
solution from a Vella fistula, this was accelerated by o.oi per cent, of tannin; 0.04 per 
cent, had no effect; o.i to i per cent, delayed absorption. 

On the whole, one may say that the small quantities of tannin ordi- 
narily taken with the food and drink are not injurious; but that large 
quantities (excessive tea drinking) are certainly deleterious. The tannin 
of coffee is scarcely astringent, and therefore lacks this action. 

Effects of Larger Doses. These produce irritation and corrosion, 
especially if the stomach is empty; pain, vomiting, diarrhea or obstipation. 



138 MANUAL OF PHARMACOLOGY 

Incompatibility. Tannins are incompatible with alkaloids, alkalies, 
iron and many other metals; also with proteins and gelatin. 

PREPARATIONS TANNIC AND GALLIC ACIDS 

* Aciditm Tannicum (Acid. Tann.), U.S.P., B.P.; Tannic Acid (Tannin, Gallotannic 
' Acid, Digallic Acid) ; HCi4H 9 p 9 . A tannin obtained from nut-gall. Very sol. (i : i), in 

water glyc. and ale. Almost insol. in eth. or chlorof. Watery solutions gradually spoil 
on keeping, although they still color iron. Incompatible with alkalies, alkaloids, salts 
of iron and most other metals, proteins and gelatin. Dose, 0.5 Gm., 8 gr., U.S. P.; 0.3 
to 0.6 Gm., 5 to 10 gr., B.P. Locally, for urethra, i to 2 per cent.; vagina, 5 per cent.; 
enema, i to 2 per cent.; rectal irrigation (cholera) Y to ^ per cent.; skin and ulcers, 
5 to 20 per cent., or the Glycerite. 

*Glycer. Acid. Tann., U.S.P., B.P. 20 per cent. 

Ung. Acid. Tann., U.S. P. 20 per cent. 

Supp. Acid. Tann., B.P. 0.2 Gm., 3 gr. (against hemorrhoids). 

Track. Acid. Tann., U.S.P. 0.06 Gm., i gr. 

Troch. Acid. Tann., B.P. 0.03 Gm., % gr. 

* Tamutlbin (N.N.R.). Albumin tannate, containing about 50 per cent, of tannic 
acid (Gottlieb, 1896). Light brown, odorless and tasteless, powder, practically insolu- 
ble in water and gastric juice. Dilute alkalies (intestinal and pancreatic juice) liberate 
the tannin slowly. Used in diarrhea, especially of children. Dose, i to 4 Gm. (15 to 
60 gr.) in powder or tablets, followed by water; infants, 0.3 to 0.5 Gm. in gruel. 

Other Artificial Tannin Compounds of N.N.R. are: Tannigen, Diacetyltannin (H. 
Meyer, 1894); insoluble in stomach, soluble in intestine; also Tannopin, Tannoform, 
Eugallol, Gallogen, Protan. 

Acidum Gallicum (Acid. Gall.), U.S.P.; C 2 H 2 (OH)3CO 2 H + H 2 O. Occurs in many 
plants, usually with tannic acid. It does not precipitate alkaloids, albumin, or glue. 
Sol. in water (i : 87); freely sol. in ale. (i : 4.6) or glyc. (i : 10). Dose, i Gm., 15 gr., 
U.S. P. Externally, i per cent., as weak astringent. 

TANNIN DRUGS 

These are very numerous, and many might well be dispensed with. 
Gambir (Catechu) would fulfill all indications. 

Acacia Cortex, B.P.; Acacia Bark. The dried bark of Acacia arabica and decurrens. 
Astringent and demulcent. 

Dec. Acac. Cort., B.P. 6 per cent. Dose, 15 to 60 c.c., % to 2 ounces, B.P. 

Belts Fruct., B.P. The fresh fruit of Aegle Marmelos. 

Ext. Belce Liq., B.P. Dose, 4 to 8 c.c., i to 2 drams, B.P. 

Butea Sem., B.P. The seeds of Butea frondosa. 

Butea Gum., B.P. (Bengal Kino). The inspissated juice of Butea frondosa. 

Galla, U.S. P., B.P.; Nut-gall. An excrescence on the young twigs of Quercus in- 
fectoria and other allied species of Quercus (Oak), induced by the punctures on the leaf- 
buds and by the deposited ova of a wasp, Cynips tinctoria. Contains 50 to 60 per cent, 
of tannin, 2 to 5 per cent, of gallic acid. Dose, 0.5 Gm., 8 gr., U.S. P. 

Ung. Gall., U.S.P., B.P. 20 per cent. 

Ung. Gall. C. Opio. B.P. The preceding, with 7.5 per cent, of powdered Opium. 

Catechu, B.P.; Catechu (Pale); identical with Gambir, U.S. P. A dried extract of 
the leaves of young shoots of Uncaria Gambir. 

* Tr. Catechu, B.P. 20 per cent., with Cinnamon. Dose, 2 to 4 c.c., ^ to i dram, 
B.P. 

Pulv. Catech. Co., B.P. Catechu, 40 per cent.; Kino and Krameria, each 20 per 
cent.; Cinnamon and Nutmeg. Dose, 0.6 to 4 Gm., 10 to 60 gr., B.P. 

Troch. Catech., B.P. 0.06 Gm., i gr. 

Catechu Nigrum (Catech. Nigr.) B.P.; Black Catechu. An extract from the wood 
of Acacia Catechu. 

Embelia (Embel.), B.P. The dried fruit of Ribes Embelia and robusta. Dose, 
4 to 16 Gm., 60 to 240 gr., B.P. 

Gambir, U.S.P.; Gambir (Pale Catechu); identical with Catechu, B.P A dried 
extract prepared from decoctions of the leaves and twigs of Ourouparia Gambir. Con- 
tains 33 to 47 per cent, of catechu-tannic acid. Dose, i Gm., 15 gr., U.S. P. 



ASTRINGENTS 



139 



* Tr. Gambir Co., U.S. P. (Compound Tincture of Catechu). 5 per cent, in 50 per 
cent, alcohol; flavored with cinnamon. Dose, 4 c.c., i dram, U.S.P. 

Hamamelidis Cortex, B.P.; Hamamelis Bark (Witch Hazel Bark). The dried bark 
of Hamamelis virginiana. 

Tr. Hamam., B.P. 10 per cent, of bark. Dose, 2 to 4 c.c., % to i dram, B.P. 

Hamam. Fol., B.P.; Hamamelis Leaves. Fresh or dried. 8 per cent, of tannin 
(Straub, 1899). 

Ext. Hamam. Liq., B.P. 50 per cent, of dried leaves. Dose, 0.3 to i c.c., 5 to 15 
minims, B.P. 

Ung. Hamam., B.P. 10 per cent, of the preceding. 

Hamatoxyli Lignum, B.P.; Logwood. The heart- wood of Hsematoxylon campechi- 
anum. 12 per cent, of Haematoxylin. 

Dec. Hamatox., B.P. 5 per cent. Dose, 15 to 60 c.c., J^ to i ounce, B.P. 

Kino, U.S.P., B.P.; Kino. The dried juice from the trunk of Pterocarpus Marsup- 
ium. 75 per cent, of Kino-tannic acid. Dose, 0.5 Gm., 8 gr., U.S. P.; 0.3 to 1.2 Gm., 
5 to 20 gr., B.P. 

Tr. Kino, U.S.P. , B.P. 10 per cent. Dose, 4 c.c., i dram, U.S.P.; 2 to 4 c.c., 
Yz to i dram, B.P. 

Pulv. Kino Co., B.P. 5 per cent, of opium. Dose, 0.3 to 1.2 Gm., 5 to 20 gr., B.P. 

Kino Eucalypti (Kino Eucalyp.), B.P. (Eucalyptus Gum, Red Gum). An exuda- 
tion from the stem of Eucalyptus species. Dose, 0.3 to 1.2 Gm., 5 to 20 gr., B.P. 

Troch. Kino Eucalypti, B.P. 0.06 Gm., i gr. 

Kramer. Rod., B.P.; Krameria (Rhatany). The dried root of Krameria species. 

Ext. Kramer., B.P. A dry extract. Dose, 0.3 to i Gm., 5 to 15 gr., B.P. 

Tr. Kramer., B.P. 20 per cent. Dose, 2 to 4 cc., ^ to i dram, B.P. 

Inf. Kramer., B.P. 5 per cent. Dose, 15 to 30 c.c., ^ to i ounce, B.P. 

Troch. Kramer., B.P. 0.06 Gm., i gr. 

Myrobalanum, B.P., Myrobalans. The dried immature fruit of Terminalia Chebula. 
Dose, 2 to 4 Gm., 30 to 60 gr., B.P. 

Ung. Myrobal., B.P. 20 per cent. 

Ung. Myrobal C. Opio., B.P. The preceding with 7.5 per cent, of Opium. 

Sappan, B.P. The heart- wood of Caesalpinia Sappan; similar to Logwood. 

Dec. Sappan., B.P. 5 per cent. Dose, 15 to 60 c.c., % to 2 ounces, B.P. 

Diarrhea Mixtures. These are generally "shot-gun" prescriptions . of which the 
following are types: 

Mist lira Contra Diarrhaam, N.F. (Sun Cholera Mixture). Equal parts of Tincture 
of Opium, Capsicum, Rhubarb, Camphor, Peppermint. Dose, to one teaspoonful. 
Or, Tr. Opium, Tr. Catechu, Tr. Rhubarb, Sp. Peppermint, Bismuth subnitrate. 
(History, Raubenheimer, 1916). 

ASTRINGENT STYPTICS 

All the metallic salts, the irritant as well as the astringent, and also 
the vegetable astringents, act as local styptics ; i.e., lessen local hemorrhage. 
They do so mainly by the formation of precipitates which occlude the 
lumen of the small vessels, just as it is occluded ordinarily by fibrin. 
(Whilst the majority lessen the formation of fibrin, this is offset by the 
precipitation.) Besides this precipitation, they also act by injuring the 
vessel walls in such a way as to produce thrombosis. This is claimed 
especially for zinc chlorid. 

It is scarcely needful to mention that astringents will act only at the 
place to which they are applied. It is necessary that they come into 
actual contact with the bleeding vessels. They can not act through a large 
clot of blood, and if such exists, it must first be removed. At one time 
they were used internally with the idea of producing astringent action in 
remote places; iron was given by the mouth to check bleeding in the uterus. 
This was entirely irrational. Their action can not even extend beyond the 
stomach, since they are precipitated or decomposed in the intestine. 

The indications for the use of styptics are to lessen bleeding, especially 
capillary oozing. They are sometimes injected into hemorrhoids, and 
have even been injected into aneurisms. Their injection into larger 
vessels is dangerous, as it may produce embolism. 



140 



MANUAL OF PHARMACOLOGY 



The most useful of the metallic styptics are the iron salts, especially 
the ferric chlorid and ferric sulphate. The ferric chlorid is used either 
as the solution, or tincture, quite largely diluted with water. Cotton may 
be steeped in this, forming " styptic cotton." Next comes alum, especially 
the burnt alum. Then the tannins in any form. 

Besides these, any substance which gives a precipitate with proteins will act as a 
styptic in the same manner; e.g., dilute acids in concentrations which need not be at 
all caustic (vinegar and lemon juice). Quite a number of purely mechanical measures 
favor the formation of clot; for instance, ordinary cotton or Pengawhar Djambe (this 
also contains tannin). Cobwebs also form a popular and very effective measure for 
producing the same result, but are unfortunately very septic. One may obtain the 
same effect by fine powders which have a strong attraction for water. In case of emer- 
gency powdered or granulated sugar is a good styptic, and at the same time antiseptic. 
Other styptic measures are position, raising the limb and keeping it quiet so as to reduce 
the local congestion; local pressure; depression of the vasomotor center by narcotics; 
direct constriction of the vessels by the application of cold, or by drugs, such as cocain, 
suprarenal extract, hydrastinin, etc. 

STRENGTH OF MOST USEFUL SOLUTIONS OF ASTRINGENTS AND ANTI- 
SEPTICS 1 





Touching ulcers, 
gargles, rectal and 
vaginal injections 


Urethral in- 
jections and 
eye washes 


Baths (Gm. per 
bath, 200 liters 
30 gallons) 


Neutral Salts: 
Sodii chloridum 


1% 


O.Q% 


4 Kg. 


Alkalies: 
Sodii bicarbon 






100 Gm. 


Sodii carbonas 


0.2 tO I % 


0.2% 


100 Gm. 


Potassii carbonas 






100 Gm. 


Sulphids: 
Pot. sulphurat 






50 to 150 Gm. 


Acids (Mineral) 


0.5% 


0-5% 


30 c.c. (i ounce) 


Haloids : 
lodin 


O.I tO I % 






Metallic Salts: 
Zinc sulphate or phenolsulphonate. 
Mercuric chlorid 


1.5 to i% 
0.05 to o . i % 


O. 2 tO O.4% 

0.02<5% 




Liq. plumbi subacet. dil 


Full strength 


Full strength 




Silver nitrate 


0.5 to 5% 


0.2 to 0.5% 




Tr. ferri chloridi 


10% (of Tr.) 






Alumen and alum, salts 


i to 3% 


o. 25% 




Cupric sulphate 


i% 


0.5% 




Lead acetate 


i% 


0.5% 




Tannins: 
Tannic acid 


i to 3% 


0.5 tO 2% 




Miscellaneous: 
Boric acid, or borax 


4% (sat'd) 


2% (Y 2 sat'd) 




H 2 O 2 . . 


} to % of aqua. 


3^3 of aqua. 




Pot. permangan 


i to 2% 


0.4% 




Glycerin 


20% 


10% 




Phenol 


i% 


0.2% 




Thymol, essential oils 


Saturated, watery 


Saturated, 




Alkaloids: 
Morphin 




watery 

0.2% 




Hydrastinin 




0.1% 




Most alkaloids for eve. . . 




o . =; to i % 





1 (i percent. = 5 grains per ounce.) When several are combined, the dose of each must be 
correspondingly decreased. 



IRRITANT VOLATILE OILS AND RELATED DRUGS 141 

Baths. Usually taken in the evening before going to bed. Metal-lined tubs must 
be avoided for medicated baths. 

Gargles. No toxic substance should be used, especially with children, on account 
of the danger of swallowing. The metallic salts attack the teeth, so that they can not 
be employed for a long time. 

Urethral Injections. Always have the patient urinate just before injecting, to remove 
bacteria. Let injection remain at least one minute, then let flow out, but patient should 
not micturate immediately after. 



IRRITANT VOLATILE OILS AND RELATED DRUGS 

General Statement. Most volatile (or "essential") oils are complex 
mixtures, generally containing terpenes and oxidized aromatic derivatives. 
The balsams and resins, which contain volatile oils, may be included in 
the group. These oils occur in numerous plants, and determine their use 
as flavors, aromatics, carminatives, antiseptics and irritants. Their 
chief application is for their local effects, consisting in deep irritation with 
a minimum of tissue destruction. The sensory stimulation is followed by 
some anesthesia. They exert a favorable influence on chronic inflamma- 
tions; partly by their mild antiseptic and irritant action, and partly by 
chemotactic attraction of leucocytes. In acute inflammations they are 
more apt to do harm. Their antiseptic action is, in practice, relatively 
weak, since they are but slightly soluble in water. 

After their absorption they are excreted mainly in combination with 
glycuronic acid. They irritate the kidneys and produce diuresis. 

Central effects are only seen in poisoning, and agree broadly with 
those of camphor, which really belongs to this group. These effects are 
more or less convulsive, followed by narcosis; on direct application, stimu- 
lation of cardiac muscle; and curare action on the muscle-nerve endings. 

The Flavoring and Aromatic Oils are considered in another place. 

Composition. A convenient tabulation of the constituents of volatile oils is given 
by Rippetoe and Wise, 1912. The terpenes are aromatic, cyclic compounds of the 
general empirical formula, CioHie- Related to them are the semi- terpenes (CsHg); 
sesqui-terpenes (Ci B H2 4 ); and di-terpenes (C2oH 32 ). Other constituents are oxidation 
products of these and aromatic phenols, ketones, aldehydes, acids and their compounds. 

The Antiseptic Effects. These have been investigated especially by Robert, 1906; 
Bruning, 1906; Geinitz, 1912; and Rippetoe and Wise, 1912. 

Chemotactic Action. The value of volatile oils (particularly those enumerated as 
urinary antiseptics) in chronic inflammations of all sorts has been abundantly proved 
by clinical observations and laboratory experiments. They also lessen aseptic inflam- 
mations at points remote from the site of their application, by decreasing the formation 
of exudates and by hastening their absorption. The explanation probably lies in a 
chemotactic attraction for leucocytes (Lemiere, 1891; Borissow; Hamburger, 1912). 
In this way they withdraw these cells from the inflamed area into the blood (Winternitz, 
1901). 

Excretion. Terpenes are for the most part excreted in the urine in combination 
with glycuronic acid (Matzel, 1905), sometimes after partial oxidation. 

Systemic Actions of Volatile Oils. The principal central effects of volatile oils 
are reflex. With the ordinary doses, no direct action whatever can be observed. 
Large doses act on the nervous centers, especially the brain and medulla. These are 
first stimulated, then depressed. The details have been investigated especially by 
Rimini, 1900; Hildebrandt, 1901 and 1902; Matzel, 1905; and Geinitz, 1912. The de- 
gree of stimulation varies for the different oils. Turpentine has scarcely any effect, 
whilst absinthe, thujon, fenchon, carvon and camphor produce violent epileptic con- 
vulsions. The depression is more uniform: The majority (valerian, fennel, chamomile, 
eucalyptus, mint, rosemary, sabinol, citral, turpentine) diminish the reflex excitability, 
so that large doses will entirely prevent strychnin convulsions in rabbits. The effective 
doses are, however, entirely too large to make it possible to employ this action in man. 



142 MANUAL OF PHARMACOLOGY 

The Cnrarc-actions have been studied by Hildebrandt and by Matzel; the cardiac 
effects by H. Schwalb, 1912. 

According to d'Ormea (1903), the intravenous injection of volatile oils causes a 
peculiar dilation of the cerebral vessels, the volume of the brain increases, whilst the pres- 
sure in the circle of Willis falls. This effect is strongest with absinthe, weak with 
anise or lemon. Camphor has a similar effect. The general blood pressure also falls 
in most cases, but quite independently of the changes in the cerebral circulation. 

If volatile oils are injected hypodermically, they produce at first the reflex action, 
and in a more marked degree than when they are applied to the surface of the skin. 
Later their systemic, and still later the renal, actions take place. 

Isolated Intestinal Segments are stimulated by oil of anise, turpentine and chenopo- 
dium, in concentrations of 1:50,000 to 1:25,000. Higher concentrations of all 
volatile oils depress the movements (Muirhead & Gerald, 1916). 

Hemolytic Action of Terpenes. Ishizaka, 1914, found that this varied mainly with 
the surface tension; but that the alcohol or ketone character also has an influence. 
Some form methemoglobin. 

OLFACTORY STIMULANTS 

Odorous substances produce pronounced reflex effects. Pungent and aromatic 
drugs cause in this way a prompt medullary stimulation, increasing the respiration 
and blood pressure, and slowing the pulse. They are especially useful in fainting. 
They are employed by inhalation. Tinctura Lavandulce Composita (U.S. P., B.P.) and 
Aromatic Ammonia are used for this purpose. 

Any pungent substance will answer in an emergency; the burning of a feather under 
the nose of the patient is a standard household measure. 

Substances which produce sneezing (sternutatoria or errhines) act in a similar manner, 
but have rather passed out of fashion. They are sometimes useful as local counter- 
irritants in nasal catarrh (snuff). 

HYSTERIC SEDATIVES OR ANTISPASMODICS 

Actions and Uses. Asafetida, valerian, and some other malodorous 
drugs have been used since antiquity as sedatives in hysterical and simi- 
lar nervous conditions. They are often effective, presumably by olfac- 
tory and psychic reflexes. Asafetida is also carminative, and has been used 
by mouth and enema (emulsion) in tympanites; but it imparts its odor 
to the excreta and eructations. Very large doses (^ ounce) have been 
taken without other noticeable effects. Large doses of valerian produce 
systemic action, but it is very doubtful whether these occur with the ordi- 
nary doses. Valerian was formerly used as a perfume, and as a spice for 
meat, and asafetida is said to be similarly employed in Persia. 

PREPARATIONS HYSTERIC SEDATIVES 

* Asafetida (Asafet.), U.S.P.; Asafetida (Asafet.), B.P.; Asafetida. The gum- 
resin obtained by incising the rhizome and roots of Ferula Asafetida. Characteristi- 
odor; bitter and acrid taste; forms milk-white emulsion when triturated with water. 
Constituents: 3 to 9 per cent, volatile oil; 20 to 30 per cent, gum; 45 to 70 per cent, 
resin. The alcoholic preparations yield turbid mixtures with aqueous liquids. Dose, 
0.25 Gm., 4 gr., U.S. P.; 0.3 to i Gm., 5 to 15 gr., B.P.; best as pills. 

Pil. Asafet., U.S.P. 0.2 Gm., 3 gr. Dose, 2 pills, U.S.P. 

Emul. Asafet., U.S.P. (Milk of Asafetida, Asafetida Mixture). Made by rubbing 
4 parts of asafetida with 100 parts of water. Dose, 1.5 c.c., 4 drams, U.S.P. Used 
especially as enema against tympanites. 

Tr. Asafet., U.S.P., B.P. 20 per cent. Dose, i c.c., 15 minims, U.S.P.; 2 to 4 c.c., 
Y% to i dram, B.P. 

Sp. Amman. Fet., B.P. An alcoholic distillate of Asafetida, mixed with Ammonia. 
Dose, 1.2 to 2.5 c.c., 20 to 40 minims, repeated; single, 4 to 6 c.c., 60 to 90 minims, 
largely diluted, B.P. 

Valeriana (Valer.)., U.S.P.; Valer. Rhiz., B.P.; Valerian. The dried rhizome and 
roots of Valeriana officinalis. Dose, 2 Gm., 30 gr., U.S.P. Contains % to 2 per cent. 
volatile oil, valeric and other organic acids; tannin and resins. The oil consists of esters 



IRRITANT VOLATILE OILS AND RELATED DRUGS 143 

of valeric (Valerianic) acio, especially with borneol. These are the bearers of the action, 
free valeric acid and its salts being quite ineffective. The fresh root is also ineffective', 
the esters being formed only during drying, by the action of oxidases (Kochmann' 
1904). The juice of the fresh plant also produces different effects from the dried valerian 
(Pouchet and Chevalier, 1905). The esters again deteriorate by oxidation on keeping. 
Certain synthetic esters are said to be more stable (Kionka, 1902). 

Tfte Injection of Valerian. This produces the usual effects of volatile oils (Pouchet 
and Chevalier, Kionka, 1904); in small doses, psychic exaltation and rise of blood 
pressure form cardiac and vasomotor stimulation; in larger doses, central sensory and 
motor depression. 

Excised Uterus. This is stimulated by Valerian oil (Pilcher, 1916). 

Tr. Valer., U.S.P. 20 per cent. Dose, 4 c.c., i dram, U.S.P. 

* Tinctura Valeriance Ammoniata (Tr. Valer. Ammon.), U.S.P., B.P. 20 per cent.; 
with Sp. Ammon. Arom., U.S.P.; with ammonia and aromatics, B.P. Dose, 2 c.c., 
30 minims, U.S.P.; 2 to 4 c.c., ^ to i dram, B.P. 

Valer. Ind. Rhiz., B.P. From Valeriana Walachii. 

Tr. Valer. Ind. Ammon., B.P. Dos-', 2 to 4 c.c., % to i dram, B.P. 

Synthetic Valerian Esters (N.N.R.). Bornyval (borneol isovalerate) ; Validol 
(mixture of menthol); and Valyl (valeryldiethyl-amin) . Side actions, Seifert, Neben- 
wirk, 1915, p. 99. 

Valer ates (Valer ianates). These have very little value. They are given in doses 
of 0.06 to i Gm. (i to 15 gr.), generally in capsules. They are colorless crystals of a 
valerianic odor, readily soluble in water; Zinci Valeras, U.S.P., P.P.; Ammonii Valeras, 
U.S.P. 

Minor Drugs of this group. Sumbul (Musk-root), Moschus (Musk), Castoreum, 
Cataria (Catnip); and Symplocarpus (Skunk-cabbage). 

tfysfhits, U.^.P.; Musk. The dried secretion from the preputial follicles of Moschus 
moschiferus. Dose, 0.25 Gm., 4 gr., U.S.P. 

Tr. Moschi, U.S.P. 5 per cent. Dose, 4 c.c., i dram, U.S.P. 

Sumbul, U.S.P. (Musk-root). The rhizome and roots of Ferula Sumbul. Dose, 
2 Gm., 30 gr., U.S.P. 

Ext. Sumbul, U.S.P. A pilular extract. Dose, 0.25 Gm., 4 gr. 

Fldext, Sumbul, U.S.P. Dose, 2 c.c., 30 minims, U.S.P. 

OIL OF TURPENTINE 

Actions and Uses. Applied to the skin, this produces simple reddening 
and burning, and is used as a counterirritant; undiluted, or mixed with 
i to 5 parts of oil in liniments. It is often used as "Stupes," i.e., flannel 
wrung out of hot water, and then out of warm turpentine, and applied 
for ten to thirty minutes. In susceptible individuals it may cause severe 
eruptions, and if left on for several hours, blistering. 

Oil of turpentine is used externally in bronchitis, neuralgic and rheu- 
matic pains, and to relieve meteorism. It causes more severe irritation 
on mucous membranes. 

Inhaled or taken internally it diminishes bronchial secretions (Rossbach 
and Fleischmann). It was used for this purpose (a teaspoonful inhaled 
from a pint of hot water) in chronic bronchitis. It is now displaced by the 
more pleasant terpene hydrate and pine-needle oil. Its use as anthelmintic 
(2 to 15 c.c.) and as diuretic and urinary antiseptic has also been discon- 
tinued. 

Absorption, Fate and Excretion. Oil of turpentine is readily absorbed from the skin, 
lungs and intestines. It circulates for a time unchanged in the blood, and is excreted 
mainly in the urine as terpenals, paired with glycuronic acid. The urine has the odor 
of violets. Neither turpentine, nor eucalyptol nor menthol, is excreted by the lungs 
or sputum (Falk, Hofbauer, 1915). 

Systemic Actions. These do not occur with small doses. 

Turpentine Poisoning. Half an ounce has been fatal to children, 6 ounces to adults. 
The symptoms in man are those of gastro-intestinal irritation; nausea and vomiting, 
colic and diarrhea, wild excitement and delirium, ataxia, painful micturition, hema- 
turia, albuminuria, and glycosuria, skin eruptions, coma. 



144 MANUAL OF PHARMACOLOGY 

The Treatment. This comprises evacuation, demulcents and coffee. 

Inhalation. Fatal poisoning has been reported from inhalation of varnish in a 
confined space (Drescher, 1906); largely by exclusion of air (Wolf, 1911). There is 
rapid breathing, palpitations, vertigo, stupor, convulsions, and other nervous disturb- 
ances; pain in chest, bronchitis and nephritis. The latter may also occur on chronic 
exposure. 

PREPARATIONS TURPENTINE 

* Oleum Tcrebinthinee (Ol. Tereb.), U.S.P.; Oil of Turpentine (Spirit of Turpentine) 
The volatile oil recently distilled with water, below iooC., from the concrete oleoresin 
(Turpentine) obtained from Pinus palustris and from other species. It consists mainly 
of pinen, CioHie, with small quantities of other terpenes and traces of organic acids. 
A thin, colorless liquid, of characteristic odor and taste, becoming stronger and more 
unpleasant by age and exposure to air. Practically insol. in water, sol. in 3 vol. of 
ale. and in all proportions of oils. The rectified oil should be employed for internal use. 

*Ol. Tereb. Reel., U.S.P.; Ol. Tereb. Rectif., B.P. Rectified (by distillation with 
XaOH, U.S. P.) Dose, 0.3 c.c., 5 minims, U.S. P.; 0.12 to 0.6 c.c., 2 to 10 minims, B.P.; 
anthelmintic dose, 12 to 15 c.c., 3 to 4 drams, B.P. 

Emul. 01. Tereb., U.S. P. 15 per cent. Dose, z c.c., % dram, U.S. P. 

Lin. Tereb., U.S. P.; Turpentine Liniment. Cerat. Res., 2; Ol. Tereb., i. 

Lin. Tereb., B.P. Ol. Tereb., 65 per cent.; Camphor, 5 per cent.; Sap. Moll, and 
water. 

Lin. Tereb. Acel., B.P. Ol. Tereb;, 53 per cent.; Lin. Camph., 45 per cent.; Ac. 
Acet. Glac., n per cent. 

*Ol. Pint Pumilionis (Ol. Pin. Pumilion.), U.S.P., Oil of Dwarf Pine Needles; 
Oleum Abictis (01. Abiet.), B.P., Oil of Siberian Fir. Colorless or faintly yellowish 
volatile oil, of pine-needle odor, distilled with steam from the fresh leaves of Pinus 
montana, U.S. P.; of Abies sibirica, B.P. Contains 1-pinene, other hydrocarbons, and 
esters. Resembles oil of turpentine, but has more agreeable odor, and is employed as 
inhalant in bronchial affections. 

Terebinthina Canadensis (Tereb. Canad.), B.P.; Canada Turpentine. An oleoresin 
obtained from Abies balsamea. 

TERPIN HYDRATE 

This is used to lessen cough and expectoration in phthisis and in chronic 
bronchitis, acting similarly to oil of turpentine, and being less irritant, less 
disagreeable and non-toxic. It is also sometimes employed as diuretic 
and urinary antiseptic, but is not very effective. 

Lepine, 1887, claimed a diuretic effect from 0.2 to 0.4 Gm. Matzel, 1905. took 4 
Gm. daily without any effect; the urine was not albuminous. It was excreted as paired 
glycuronic acid. 

PREPARATIONS TURPENTINE DERIVATIVES 

* Terpini Hydras (Terpin. Hyd.), U.S.P.; Terpin Hydrate, Ci Hi 8 (OH) 2 + H 2 O). 
Prepared by hydrating oil of turpentine with alcohol and nitric acid. Colorless prisms, 
odorless, of slightly aromatic and somewhat bitter taste. Slightly sol. in water (i : 200) ; 
freely sol. in ale. (1:12.5). Dose, 0.25 Gm., 4 gr., U.S.P.; o.i to i Gm., i^ to 15 gr., 
in powders or capsules. The N.F. Elixir contains i gr. to the drachm, in a vehicle of 
alcohol and glycerin. 

Terebenum (Tereben.), U.S.P., B.P.; Terebene. Dipentene and other hydrocarbons, 
obtained by the action of concentrated sulphuric acid on oil of turpentine. Colorless, 
thin liquid; rather agreeable odor; aromatic, somewhat terebinthinate taste. Slightly 
sol. in water; freely sol. in ale. (1:3). Dose, 0.25 c.c., 4 minims, U.S.P.; 0.3 to i c.c., 
5 to 15 minims, B.P., on sugar; or by inhalation. 

EUCALYPTOL 

Eucalyptol (Cineol, Cajeputol), doHi 8 O, is obtained chiefly from oil 
of eucalyptus, but occurs also in other volatile oils, such as cajuput. 
It is a mild local irritant, used especially in bronchitis, as inhalation 
(teaspoonful in hot water), or internally (5 to 10 drops on sugar); and in 



IRRITANT VOLATILE OILS AND RELATED DRUGS 145 

coryza (spraying with 3 to 5 per cent, solution in liquid petrolatum). 
The oil of eucalyptus may be substituted. 

Eucalyptol ifnparts to the urine the same violet odor as does oil of turpentine, which 
it closely resembles in action. It has been used in malaria, but is greatly inferior to 
quinin. 

PREPARATIONS EUCALYPTUS AND CAJUPUT 

Eucalyptus, U.S.P. (Blue Gum Leaves). The dried leaves of Eucalyptus Globulus. 
Dose, 2 Gm., 30 gr., U.S.P. 

Fldext. Eucalypt., U.S.P. Dose, 2 c.c., 30 minims, U.S.P. 

* Ol. Eucalypt., U.S.P., B.P. A volatile oil distilled from the fresh leaves of Eucalyp- 
tus species, yielding not less than 70 per cent, of eucalyptol. Colorless or pale yellow 
liquid. Dose, 0.5 c.c., 8 minims, U.S.P.; 0.03 to 0.18 c.c., 3^ to 3 minims, B.P. 

Ung. Eticalypt., B.P. 10 per cent, of the oil. 

* Eucalyptol, U.S.P.; Eucalyptol (Cineol), CioHi 8 O. An organic compound ob- 
tained from the volatile oil of Eucalyptus Globulus and from other sources. A color- 
less liquid; characteristic, aromatic and distinctly camphoraceous odor; a pungent 
spicy taste, and producing a cooling sensation in the mouth. Very sol. in ale. or oils 
practically insol. in water. Dose, 0.3 c.c., 5 minims, U.S.P. 

Oleum Cajuputi (Ol. Cajup.), U.S.P., B.P. A volatile oil distilled . from the fresh 
leaves and twigs of several varieties of Melaleuca Leucadendron. Used mainly as 
counterirritant. Dose, 0.5 c.c., 8 minims, U.S.P.; 0.03 to 0.18 c.c., K to 3 minims, 
B.P. 

Sp. Cajup., B.P. 10 per cent. Dose, 0.3 to 1.2 c.c., 5 to 20 minims, B.P. 

RUBEFACEENT VOLATILE OILS 

A large number of drugs containing volatile oils have been used as 
ingredients of liniments, but without serious advantage. With some 
of the tinctures (arnica, witch hazel) used in domestic medicine, the 
alcohol is perhaps the main active ingredient. Thymol, menthol, and 
camphor, and some of the volatile oils that are discussed in other connec- 
tions could be classed with the rubefacients. 

The oils of cloves, cinnamon, and creosote are employed in dentistry 
to destrov the nerves and to disinfect the cavities of carious teeth. 



PREPARATIONS 

Arnica, U.S.P.; Arnic. Flor., B.P.; Arnica. The dried flower-heads of Arnica 
montana. Contains a volatile oil, small quantities of volatile acids, and an acrid 
bitter principle (Arnicin). Used externally. 

Tr. Arnic., U.S.P. 20 per cent, in 50 per cent, alcohol. Dose, i c.c., 15 minims, 
U.S.P. 

Tr. Arnic. Flor., B.P. 10 per cent. Dose, 2 to 4 c.c., K to i dram, B.P. 

Caryophyllus, U.S.P., B.P.; Cloves. The dried flowerbud of Eugenia aromatica. 
Dose, 0.25 Gm., 4 gr., U.S.P. 

Inf. Caryoph., B.P. 2.5 per cent. Dose, 15 to 30 c.c., ^ to i ounce, B.P. 

*Ol. Caryoph., U.S.P., B.P.; Oil of Clove. The volatile oil, consisting mainly 
(82 per cent.) of eugenol. Dose, 0.2 c.c., 3 minims, U.S.P.; 0.03 to 0.18 c.c., l -> to 3 
minims, B.P. 

Eugenol, U.S.P. An unsaturated, aromatic phenol (CeHs.CsHg.OCHsOH) obtained 
from oil of cloves and from other sources. Dose, 0.2 c.c., 3 minims, U.S.P. 

Ol. Cedrela. Cedarwood Oil. 

Aqua Hamamelidis (Aq. Hamam.), U.S.P.; Liq. Hamam., B.P.; Hamamelis Water, 
Solution of Hamamelis (Witch Hazel, Extract of Witch Hazel). A saturated aqueous 
distillate obtained by distilling with steam or water the bark, twigs and smaller stems 
of Hamamelis virginiana and adding about 15 per cent, of alcohol, U.S.P. Clear or 
colorless or slightly yellowish liquid having a characteristic aroma and taste. 

Ol. Origani. Origanum oil. 

Ol. Pimenl., U.S.P. (Oil of Allspice). A volatile oil distilled from the nearly ripe 



146 MANUAL OF PHARMACOLOGY 

fruit of Pimenta ofiicinalis yielding not less than 65 per cent, of eugenol. Dose, 0.2 
c.c., 3 minims, U.S.P. 

Ol. Rosmarini (Ol. Rosmar.), U.S.P., B.P.; Oil of Rosemary. Distilled from the 
fresh flowers of Rosmarinus officinalis. Dose, 0.2 c.c., 3 minims, U.S.P. 

Sp. Rosmarin., B.P. 10 per cent. 

Ol.'Succini. Oil of Amber. 

Ol. Thymi, U.S.P.; Oil of Thyme. Distilled from the flowering plant of Thymus 
vulgaris. Dose, 0.2 c.c., 3 minims, U.S.P. 

LINIMENTS 

Cutaneous irritants are usually employed in the form of liniments; i.e., in solution 
or suspension in oil or alcohol. The proportions in which they are used are about the 
following: 

Ammonia Water 

Tr. Belladonna or Opium. 

Spirits Chloroform 

Spirits Ether 

Spirits Camphor 

Tr. lodin 

Tr. Aconite 

Tr. Capsicum .} 

Tr. Cantharides 

Turpentine s i : 10 

Sp. Sinapis 

Essential Oils 

Croton Oil 

Creosote 

JUNIPER OIL 

This is closely allied to turpentine (containing pinen, CioHie, and 
cadinen, Ci 5 H 2 4) ; but it has a much more agreeable flavor. It is distilled 
from the "berries," the fruit, of the conifer, Juniperus communis. In the 
form of "Holland Gin" or its official substitute, the Spir. Juniperis Comp., 
it is an old-fashioned diuretic (Cow., 1912) in cardiac and hepatic dropsies. 
It is supposed to act by mild irritation of the kidneys. Its use in nephritis 
therefore requires caution. It also has some reputation as emmenagogue. 
Overdoses produce poisoning, similar to Savin. 

PREPARATIONS JUNIPER 

Ol. Juniperi (Ol. Junip.), U.S.P., B.P.; Juniper Oil. Distilled from the ripe fruit of 
Juniperus communis. Dose, 0.2 c.c., 3 minims, U.S.P.; 0.03 to 0.18 c.c., ^ to 3 minims, 
B.P. 

Sp. Junip., U.S.P. 5 per cent. Dose, 2 c.c., 30 minims, U.S.P. 

Sp. Junip., B.P. 10 per cent. Dose, 0.3 to 1.2 c.c., 5 to 20 minims, B.P. 

Sp. Junip. Co., U.S.P. 4 per cent, of Juniper oil, with Caraway and Fennel oils, 
in 70 per cent, alcohol. Similar to "Holland Gin." Dose, 10 c.c., aVjj drams, U.S.P. 

ECBOLIC AND TOXIC VOLATILE OILS 

Actions. Many volatile oils are popularly employed as emmenagogues 
and ecbolics: turpentine, juniper, savin, rue, pennyroyal, tansy and apiol. 
They produce pelvic congestion through intestinal irritation. A mild 
degree of this action may be useful in delayed and painful menstruation, 
as after exposure to cold. Abortion occurs only with toxic doses; indeed 
fatal doses are not always effective. Prochnow, 1911, also finds a slight 
direct action on the excised uterus. Macht, 1913, finds the contraction 
inhibited, never stimulated. 



147 

Savin (Sabina) and Arbor Vitse (Thuja) also contain volatile oils similar to turpen- 
tine but much more toxic. Savin oil contains pinen, cadinen and sabinol, CioHuOH. 
Thuja contains pinen, fenchon, and thujon (isomers of camphor, and having similar 
actions (Hildebrandt, 1902; Matzel, 1905). Poisoning has often occurred from their 
use as abortifacients. 

Toxic symptoms from oil of savin are those common to volatile oils: Burning, nausea, 
vomiting, colic and diarrhea, sometimes bloody; severe congestion of the pelvic organs, 
increased menstrual flow and sometimes abortion; hematuria and painful micturition; 
unconsciousness, convulsions and coma. Death may occur in a few hours, but more 
often after several days. Six drops are said to have produced toxic effects (Lewin). 

Fatty degeneration of the liver and of other organs (Heffter, 1895; Lindemann, 
1899) is produced by large doses of these oils, especially by pulegon, the active constitu- 
ent of pennyroyal; and also by the oils of sassafras, rosemary and thyme. 

Apiol. Two drugs are known under this name: "Green Apiol," or Oleoresin of 
Parsley Seed (N.N.R., Oleores. Apii), a green oily liquid. Dose 0.3 to i c.c., 5 to 15 
minims; and "Apiol" proper, N.N.R., "Crystallized Apiol," "Parsley Camphor," 
a crystalline aromatic derivative extracted from the oleoresin, dose, o.i to 0.3 Gm., 
2 to 5 gr. It has been studied by Heffter, 1895. Overdoses (0.6 to 0.8 Gm.) produce 
arythmia, incoordination, digestive disturbances and fever. Fatal poisoning, with 
intestinal symptoms, icterus and uremia, is reported by Brenot, 1916. 

The Apiols are administered in capsules, as emmenagogues and antipyretics. The 
actions of the different apiols do not seem to be identical (Lutz, 1910). 

Tansy. The leaves and tops of Tanacetum vulgare have been used mainly as an- 
thelmintic against Ascaris and Oxyuris, internally, 0.5 to 2.5 Gm. as infusion, twice a 
day; or as enema of 15:200. Half an ounce to an ounce of the oil (which con- 
tains thujon) has produced death after two to four hours, with convulsions and uncon- 
sciousness. 

Pennyroyal. The leaves and tops of Hedeoma pulegioides are used as carminative, 
5 to 10 Gm., i to 2 ounces, as infusion. Ol. Hedeomce (U.S.P.) 0.2 c.c., 3 minims; a 
teaspoonful has produced convulsions. Its active constituent, pulegon, CioHieO has 
been studied by Lindemann, 1899; Falck; and Matzel. 1905. 

Absinthe. The herb Artemisia Absinthium, contains a volatile oil, whose chief 
constituent is thujon, Ci H 16 O. This produces effects similar to camphor (Hildebrandt, 
1901 and 1902; Matzel, 1905). The liqueurs "absinthe" and "vermouth" contains this 
oil and also anise, fennel, and others; it is doubtful what part each of these and the alco- 
hol (50 per cent.) plays in the toxic complex. In mammals, the liqueur produces trem- 
ors and epileptiform convulsions (Magnan, 1871). In man overindulgence causes 
similar effects and is also said to lead to mania. 

Nutmeg Poisoning. This is by no means rare. In man severe symptoms have 
occurred from one to one and one-half nutmegs, or from a teaspoonful of powdered 
mace. The effects appear in one to six hours, and are mainly narcotic, varied by ex- 
citement and delirium, with some motor stimulation and local irritation; they usually 
end in recovery in twenty-four hours. Nutmeg is also ecbolic. Similar effects occur 
in animals. Hepatic necrosis has been demonstrated in cats (Dale, 1909). Cushny 
and Wallace, 1908, showed that the narcotic effect is produced by "myristicin" the 
high-boiling portion of the volatile oil. The oil has been investigated chemically by 
Power and Solway, 1908. 

Senecio. The alkaloids (senecin and senicionin) of S. Jacobea and vulgaris produce 
in cattle toxic effects resembling those of volatile oils: Hemorrhages in abdominal organs, 
especially the liver; fatty changes, necrosis, congestion, and hepatic cirrhosis (Cushny, 
1911.) The fluidextract (10 to 20 drops) has been used as emmenagogue. It has a 
slight depressent effect on the excised uterus (Pilcher, 1916). 

Helenium Autumnale. This contains a neutral bitter principle (Reeb, 1910), 
which is strongly irritant to mucous membranes. Systemically, it stimulates respira- 
tion and directly paralyzes cardiac and other muscle. It is not hemolytic (Lamson, 
1913)- 

PREPARATIONS ECBOLIC AND TOXIC VOLATILE OILS 

Petroselini Fructus, U.S. P.; Parsley Fruit. The dried ripe fruit of Petroselinum 
sativum. 

Oleores. Petrosel., U.S.P. (Liquid Apiol). Evaporated ethereal extract of Parsley 
Seed. Dose, 0.5 c.c., 8 minims, U.S.P. 

Myristica, U.S.P., B.P. (Nutmeg). The ripe seeds of Myristica fragrans. Dose, 
0.5 Gm., 8 gr., U.S.P. 



148 MANUAL OF PHARMACOLOGY 

Ol. Myrisl., U.S.P., B.P. Distilled from the preceding. Dose, 0.2 c.c., 3 minims, 
U.S.P.; 0.03 to 0.18 c.c., K to 3 minims, B.P. 

Sf>. Myrist., B.P. 10 per cent. Dose, 0.3 to 1.2 c.c., 5 to 20 minims, B.P. 

VOLATILE OILS AND OLEORESINS EMPLOYED IN URETHRITIS AND 

CYSTITIS 

Members. The oil of Sandalwood and the oleoresins of Copaiba 
and Cubeb, and Matico are used mainly as urinary antiseptics in gonor- 
rhea; Buchu as a diuretic in catarrhal cystitis. 

Manner of Action. The oleoresins are natural mixtures of resins 
and volatile oils rich in .terpens and terpen alcohols. The terpens are 
excreted as glycuronic compounds, which have a slight but distinct 
antiseptic action on the urine. This is much less than that of hexamethy- 
lenamin; but it has the advantage that it is not affected by the reaction 
of the urine (Jordan, 1911); and probably they are specifically more effect- 
ive for certain bacteria. The gonococci are not killed (Bruck, 1913); 
but the control of the putrefactive bacteria presumably puts the mucous 
membrane in a better position for resistance. The resin-acids are mildly 
irritant. The urinary passages are thus kept under the continuous in- 
fluence of the antiseptic terpens, and stimulated to repair by the resins. 
The combination seems to be more effective than either the oils or the 
resins administered separately. 

Side Actions. The gastro-intestinal tract is also irritated, resulting in 
anorexia, colic, eructations, and diarrhea. These unpleasant effects are 
less with sandal oil, which therefore deserves preference; and they may be 
further avoided by the use of the santalol esters, which are only dissolved 
in the intestines. Skin eruptions, scarlatinal rashes, etc., occur in some 
patients, either directly or from the digestive disturbance. Excessive 
doses of the oils produce more pronounced irritation of the entire urinary 
tract, with kidney pain, albuminuria, and vesical tenesmus. Albuminuria 
may be simulated by the precipitation of the resin-acids with nitric acid; 
to be distinguished by the addition of alcohol, which dissolves the resins. 
Glycosuria may also be simulated by the glycuronic acid. 

Therapeutic Uses. These drugs are employed mainly in subacute or 
chronic gonorrhea, as adjuvants of the local treatment. They should not 
be used in the acute stage, since they would increase the irritation. They 
are best administered in capsules, on a full stomach, to avoid gastric 
irritation. Cubeba is sometimes used in bronchitis; and Buchu as a 
diuretic. 



PREPARATIONS VOLATILE OILS USED AGAINST GENITO-URINARY 
INFLAMMATION 

Buchu. U.S.P. (Buchu Fol., B.P.); Buchu. The dried leaves of Barosma betulina 
(also of B. serratifolia, U.S. P.). Contains volatile oil, glucosid, bitter principle, etc. 
Dose, 2 Gm., 30 gr., U.S. P.; best as infusion. 

Inf. Buchu., B.P. 5 per cent. Dose, 30 to 60 c.c., i to 2 ounces, B.P. 

Fldexf. Buchu, U.S.P. Dose, 2 c.c., 30 minims, U.S.P. 

Tr. Buchu, B.P; 20 per cent. Dose, 2 to 4 c.c., ^ to i dram, B.P. 

* Copaiba (Copaib.), U.S.P., B.P. (Balsam of Copaiva). An oleo resin derived from 
South American species of Copaiba. Contains volatile oil and resin (copaivic acid). 
Pale yellow to brownish yellow, more or less viscid liquid, either without fluorescence 
or with only a slightly greenish fluorescence; having a peculiar aromatic odor, and a 
persistent, bitter and acrid taste. Insol. in water, partly sol. in ale., freely sol. in oils. 
Dose, i c.c., 15 minims, U.S.P.; 2 to 4 c.c., % to i dram, B.P.; in capsules or pills (with 



IRRITANT VOLATILE OILS AND RELATED DRUGS 149 

magnesia). The various "Lafayette," "Chapman" and similar mixtures are un- 
desirable. 

01. Copaib., B. P. Distilled from the preceding. Dose, 0.3 to 1.2 c.c., 5 to 20 
minims, B.P. 

Cubeba, U.S. P.; Cubeb. Fruct., B.P.; Cubeb. The dried, full-grown, unripe fruits 
of Piper Cubeba. Contains volatile oil and resin (cubebic acid). Dose, i Gm., 15 
gr., U.S.P.; 2 to 4 Gm., 30 to 60 gr., B.P. 

Oleores. Cubeb., U.S.P. An evaporated alcoholic extract. Dose, 0.5 Gm., 8 gr., 
U.S.P. 

OL Cubeb., U.S.P., B.P. The distilled oil. Dose, 0.5 c.c., 8 minims, U.S.P.; 0.3 
to 1.2 c.c., 5 to 20 minims, B.P. 

Tr. Cubeb., B.P. 20 per cent. Dose, 2 to 4 c.c., }- to i dram, B.P. 

Troch. Cubeb., U.S.P. 0.02 Gm., 3 gr. 

Kava Rhiz., B. P. From Piper methysticum. 

Ext. Kava Liq., B.P. Dose, 2 to 4 c.c., % to i dram, B.P. 

Matico. The leaves of Piper angustifolium. 

Sabal, U. S. P. (Saw Palmetto). The partially dried, ripe fruit of Serenoa serrulata. 
Statements as to presence of alkaloids and volatile oils are contradictory. Has been 
used as nutritive tonic, alterative, in respiratory diseases, digestive disturbances, as 
aphrodisiac, etc. Of very doubtful value. Dose, i Gm., 15 gr., U.S.P. 

Fldext. Sabal., U.S.P. Dose, i c.c., 15 minims, U.S.P. 

* Oleum Santali (OL Santal.), U.S.P., B.P.; Sandal Oil. Distilled from the wood of 
Santalum album. A pale yellow, somewhat thick liquid; peculiar aromatic odor, 
spicy taste. Readily sol. in ale. Dose, 0.5 c.c., 8 minims, U.S.P.; 0.3 to 1.8 c.c., 
5 to 30 minims, B.P. 

Santal Oil Derivatives. Sandal oil consists chiefly (90 per cent.) of santalol, CuH^eO, 
a mixture of two sesquiterpen alcohols. It is used in the form of its carbonic ester 
(Carbosant, Santalolis Carbonas, N.N.R.), and of its salicylic ester (Santyl, N.N.R.). 
These are oily liquids, almost without odor or taste. Dose, 0.5 c.c., three times daily. 

BALSAMS 

Balsams (Peru, benzoin, tolu, storax) are oleoresins containing cin- 
namic and benzoic acids. The oils act as antiseptics; the oils and resins 
are mildly irritant, stimulating repair; and the resins furnish local protec- 
tion and thus allay inflammation. The balsams are therefore employed 
in chronic inflammations of mucous membranes (bronchitis) and of the 
skin (eczema and pruritus); and to promote the healing of ulcers and 
wounds. Myrrh acts similarly. The balsams are also used locally against 
scabies, destroying the acarus and their ova. Peru balsam is employed 
locally and internally for tuberculosis (for intravenous use, see " Cinnamic 
Acid"). Its internal administration is of doubtful utility, as is also the 
internal use of other balsams in bronchitis. Even large doses of the bal- 
sams do not produce albuminuria (Stockman, 1891). 

PREPARATIONS BALSAMS 

Benzoinum, U.S.P., B.P.; Benzoin (Gum Benjamin). A balsamic resin obtained 
from Styrax Benzoin and other species growing in the East Indies. Dose, i Gm., 15 
gr., U.S.P, 

Tr. Bens., U.S.P. 20 per cent. Dose, i c.c., 15 minims, U.S.P. 

* Tinctura Benzoini Composita (Tr. Benz. Co.: Tr. Benzoin. Co.), U.S.P., B.P.; 
Compound Tincture of Benzoin (Friars' Balsam, Turlington's Balsam). 10 per cent. 
of Benzoin, with Aloes, Storax, and Tolu, in alcohol. Dose, 2 c.c., 30 minims, U.S.P.; 
2 to 4 c.c., J<j to i dram, B.P., as stimulant expectorant; as inhalant, teaspoonful to 
cup of boiling water; externally, mixed with glycerin or water, as lotion for chapped 
hands. The original formula was much more complex. 

* Balsamum Pcruvianitm (Bals. Peruv.), U.S.P., B.P.; Balsam of Peru. A balsam 
obtained from Toluifera Pereirae, Central America (not from Peru) ; of ten adulterated. 
Dark brown, viscid liquid of agreeable vanilla odor and persistent bitter acrid taste. 
Freely sol. in ale. Dose, 0.3 to i Gm., 5 to 15 minims, B.P. Externally on lint; in 
scabies, inunction of 2 to 3 Gm., four to six times in the day. 



MANUAL OF PHARMACOLOGY 

Styrax, U.S.P.; Styrax Praep., B.P.; Storax. A balsam obtained from the wood and 
inner bark of Liquidambar orientalis. Dose, i Gm., 15 gr., U.S. P. 

Balsamum Tolutanum (Bals.Tolu.), U. S. P.,B. P.; Balsam of Tolu. A balsam ob- 
tained from Toluifera Balsamum. A yellowish-brown or brown, plastic solid, becoming 
brittle when old, dried, or exposed to cold; pleasing, aromatic odor, resembling that of 
vanilla; mild, aromatic taste. Sol. in ale. Dose, 0.3 to i Gm., 5 to 15 gr., B.P. 

Tr. Tolu., U.S.P. 20 per cent, in alcohol. Dose, 2 c.c., 3 minims, UJS.P. 

Tr. Tolut., B.P. 10 per cent. Dose, 2 to 4 c.c., % to i dram, B.P. 

(* Syr. Tolut., U.S.P., B.P.; see Index.) 

PREPARATIONS AROMATIC RESINS 

Ammoniacum, B.P. Gum resin exuded from stem of Dorema species. Dose, 0.3 
to i Gm., 5 to 15 gr., B.P. 

Mist. Ammoniac, B.P. 3 per cent. Dose, 15 to 30 c.c., ^ to i ounce, B.P. 

Galbanum. Gum-resin from Ferula galbaniflua. Dose, 0.3 to i Gm., 4 to 15 gr., 
B.P.C. 

Mastiche, Mastic. Resinous exudation from Pistacia Lentiscus. An ethereal solu- 
tion is used as a skin- varnish (Merck's Rep., 27:324). 

Myrrha, U.S. P., B.P.; Myrrh. Gum-resin from Commiphora species. Dose, 
0.5 Gm., 8 gr., U.S. P.; 0.3 to i Gm., 5 to 15 gr., B.P., as carminative. Was used by the 
ancients as incense in religious ceremonies; and by the Egyptians in embalming, in 
combination with spices. 

* Tr. Myrrh., U.S. P., B.P. 20 per cent, in alcohol. Dose, i c.c., 15 minims, 
U.S. P.; 2 to 4 c.c., % to i dram, B.P. Used especially as mouth wash (i : 25) in stomati- 
tis and pharyngitis; as a lotion, 1:5 or 10. 

PREPARATIONS RESINOUS DRUGS 

Echinacea. The root of Echinacea angustifolia (Purple Cone Flower). It contains 
resins, and no alkaloids (Heyl and Staley, 1914). Several proprietary preparations 
have been praised for sialagogue, diaphoretic, antiseptic, stimulant, and general altera- 
tive effects (Lloyd, 1904; Madden, 1905); but no good evidence of its value has been 
published and the claims appear extravagant (J. A. M. A., Nov. 27, 1909). Dose, 
i to 2 Gm., 15 to 30 gr. 

Grindelia, U.S. P., B.P. The dried leaves and flowering tops of Grindelia camporum 
(also Grindelia squarrosa, U.S. P.). Contains an amorphous resin (probably the active 
principle), sugars, proteins, tannin, and a very small quantity of volatile oil, no saponin 
or alkaloid (Power and Tutin, 1905). It is said to relax the muscular coats of the bronchi 
and diminish the excretion of mucus. It is therefore used in asthma and bronchitis, 
Dose, 2 Gm., 30 gr., U.S.P. 

Fldext. Grindel., U.S.P.; Ext. Grindel. Liq., E.P.Dose, 2 c.c., 30 minims, U.S.P.; 
0.6 to 1.2 c.c., 10 to 20 minims, B.P. Also employed locally in ivy poisoning. 

Pyrethrum, U.S.P.; Pyreth. Rad., B.P. (Pellitory). The dried root of Anacyclus 
Pyrethrum. Chewed as sialogogue and against toothache. Dose, 2 Gm., 30 gr. 
U.S.P. 

Tr. Pyreth., U.S.P., B.P. 20 per cent. 

INSECTICIDES 

Certain volatile oils, or drugs containing them, are used to kill or repel noxious 
insects, such as Mosquitoes, Roaches, Flies, etc. "Insect Powder" (the powdered 
flowers of Pyrethrum species Persian Powder and of Chrysanthemum cinerariae- 
folium Dalmatian Powder); Eucalyptus, Menthol, Erigeron, Cedar, and Lavender 
may be cited. (Roach powders commonly contain borax; arsenic is efficient, but danger- 
ous; White Hellebore is also poisonous.) Naphthalin and Camphor are used against 
moths. 

Pediculosis. The experiences of the war have greatly revived the interest in insecti- 
cides against these parasites. Mercury, staphisagria, phenol, etc., are effective 
against limited infections; but they are too toxic and irritant for extensive application. 
Naphthalin and volatile oils stupefy and paralyze the parasites, but they are likely to 
recover subsequently. Acids are definitely fatal. Sulphur dioxid is effective (Knaffl- 
Lenz, 1915). 



NON-VOLATILE ORGANIC IRRITANTS 15! 

MUSTARD OIL 

Actions and Uses. The volatile oil which is developed from black mus- 
tard on contact with water, produces a more prompt, more violent, and 
more penetrating irritation than the other volatile oils. Mustard prepara- 
tions are extensively used for counterirritation, but care must be taken to 
stop the application when marked tingling is felt, or there may be vesication 
and even ulceration. Internally, mustard is used as a condiment; larger 
doses (i to 4 5 in a tumbler of warm water) produce vomiting; still larger 
doses cause violent gastro-intestinal irritation. Boiling water prevents 
the development of the oil by destroying the ferment. 

Composition. Volatile oil of mustard (allyl iso-thiocyanate, C 3 H 6 NCS) is derived 
from black mustard by the action of a ferment, myrosin, on the glucosid sinigrin 
(potassium myronate). The latter itself is not irritant. Mustard seed also contains 
about 25 per cent, of bland fixed oil. 

White mustard contains a similar ferment and glucosid, sinalbin, which yields an 
analagous oil, acrinyl iso-thiocyanate. Much less volatile oil is liberated than with 
black mustard. White mustard seeds have a cathartic action, due to the liberation of 
H 2 S on contact with water. Large doses may produce sulphid poisoning, with cyanosis, 
etc. (van Leesum, 1916). 

Similar sulphur-containing oils are formed in other cruciferous plants, such as horse- 
radish, radish, cress; and in onion, garlic, etc. 

Plants containing mustard oil (Bursa pastoris) stimulate the contractions of the 
excised uterus (Groeber, 1915). 

PREPARATIONS MUSTARD 

Armoracia Radix, B.P. Fresh Horseradish Root. 
Sp. Armor. Co., B.P. Dose, 4 to 8 c.c., i to 2 drams, B.P. 

Sinapis Alba (Sinap. Alb.), U.S. P.; White Mustard. The ripe seeds of Sinapis 
alba. Dose, as emetic, 10 Gm., 2^ drams, U.S.P., of the powder, in tepid water. 

* Sinapis Nigra (Sinap. Nig.), U.S. P.; Black Mustard. The ripe seeds of Brassica 
nigra. Dose, as emetic, 10 Gm., 2% drams, U.S. P., of the powder, in tepid water. 
Powdered mustard is applied as a poultice, mixed with 5 to 10 parts of flour and enough 
water to make a paste; it may also be sprinkled on the surface of the ordinary linseed 
poultice. It is used in footbaths for preventing colds (i to 2 ounces to a gallon); and in 
general baths for infantile coma (large tablespoonful to small bath). 

* Emplastrum Sinapsis (Emp. Sinap.), U.S. P.; Mustard Plaster (Charta Sinapis, 
Mustard Paper). A mixture of de-oleated black mustard and rubber, uniformly mixed 
and spread on paper, cotton cloth or other fabric. Mustard plaster is moistened 
thoroughly with warm (not hot) water, and applied to the skin for fifteen to thirty 
minutes. 

* Oleum Sinapis Volatile (Ol. Sinap. Vol.), U.S.P., B.P.; Oil of Mustard. A volatile 
oil produced synthetically or obtained from the seed of Brassica nigra, consisting chiefly 
of allyl iso-thiocyanate (C 3 H 5 SCX). Colorless or pale yellow, strongly refractive liquid, 
having a very pungent and acrid odor and taste. Dose, 0.008 c.c., % minim, U.S. P. 
It may be used as counterirritant in V{ to 2 per cent, solution in 50 per cent, alcohol 
(Herzfeld, 1909). 

Lin. Sinap., B.P. 3.5 per cent, of Ol. sinap., 5.5 per cent, of Camphor. 



NON-VOLATILE ORGANIC IRRITANTS 

A number of fixed organic drugs also act as local irritants. The most important of 
these is cantharidin. Capsicum, euphorbia, poison ivy, and croton oil, the "acrid 
principles" of certain fresh plants, especially of the family of Ranunculaceae, etc., may 
be counted in this group. They owe their activity to neutral, resinous, or oily princi- 
ples. Some benzol derivatives chrysophanic acid, resorcin, pyrogallol, etc. have a 
slimilar action, so also do some of the toxins and the poison of bees (Faust, 1910). 



152 MANUAL OF PHARMACOLOGY 

CANTHARIDIN 

Actions and Uses. Cantharides (Spanish Flies) are used for vesica- 
tion and for prolonged counterirritation in pleurisy, neuralgic and rheu- 
matic pains, etc. The irritation is active, but the penetration slow, so 
that the effects are gradual, with only moderate pain, and without involv- 
ment of the deeper layers of the skin. The blisters therefore heal readily 
and without scar. On mucous membranes and open wounds, the effects 
are more severe, leading to local necrosis, and slowly healing, suppurating 
ulcers. Internally, cantharis is highly toxic by gastroenteritis and neph- 
ritis; even the absorption from a large blister may cause severe irrita- 
tion of the kidneys and urinary passages. It is therefore contraindicated 
in nephritis, and should never be used internally, although it was formerly 
employed as a diuretic. 

Origin of Cantharidin. Cantharidin is a crystalline principle, the anhydrid of 
cantharidic acid. It combines readily with alkalies, forming soluble salts. These 
produce the same local and systemic actions. Cantharidin is contained in a number of 
insects, especially beetles. A similar substance exists also in some caterpillars. It is 
present in varying amount, even in the same species. It was isolated by Robiquet in 
1812 from the Spanish "Fly" (a beetle Cantharis or Lytta vesicatoria). It is con- 
tained in the soft parts, particularly the blood. 

Cantharis was recommended by Hippocrates in dropsy and amenorrhea; it was very 
popular in the days of heroic medication. 

Absorption and Excretion. Cantharidin is readily absorbed from all surfaces even 
from the skin. It is excreted mainly by the kidneys (Eliaschoff) ; but since it irritates 
the gastro-intestinal tract when injected hypodermically, some must be excreted by 
this channel. 

Symptoms of Poisoning. When cantharis is taken by mouth, it produces success- 
ively: burning in the mouth, thirst, difficulty in swallowing, swelling and blistering 
of the tongue; salivation, nausea, vomiting, colic, and sometimes bloody diarrhea and 
tenesmus. The gastro-intestinal symptoms may be less pronounced in rapid poison- 
ing. Kidney pain, burning in urethra, frequent micturition, albuminuria, casts, 
hematuria, painful erections, abortion. Weak and slow pulse, chill, syncope and col- 
lapse. Recovery may occur in about five days, the urine returning to normal. Toxic 
effects have been produced by 0.6 Gm.; death by 1.5 to 3.0 Gm., but recovery has also 
occurred from much larger doses. Of Cantharidin, 10 mg. is said to be fatal. 

Central Actions. When injected into the circulation, Cantharidin affects the central 
nervous system, producing short stimulation, excitement, and increased reflexes, fol- 
lowed by paralytic symptoms, coma, etc. 

This central action is not often seen, being obscured by gastroenteritis or nephritis. 

The Treatment of Poisoning. This would consist of gastric lavage, demulcents, 
opiates, alkalies and plenty of fluid, heat to the gastric and renal region, and warm 
baths. No oils or fats should be given. 

Cantharidin Nephritis. The kidneys are extremely sensitive to Cantharidin. Small 
doses act entirely on the glomeruli, which are enormously dilated; numerous leucocytes 
are found in Bowman's capsule. The urine becomes albuminous within half an hour 
after subcutaneous injection. The smallest doses increase its amount, while larger 
doses diminish it. The epithelium of the convoluted tubules is only affected by larger 
doses, and rather late in the course of the poisoning. The interstitial tissue escapes 
entirely in the acute intoxication, and is but slightly changed even in the subacute form 
(Miirset, 1886; Lyon, 1904; Richter and Roth; Schlayer and Hedinger, 1907; Pearce, 
1913). The excretion of phthalein is delayed (Eisenbrey, 1913); the non-protein 
nitrogen of the blood is increased (Folin, Karsner and Denis, 1912). 

Hepatic Changes and Edema. These are seen in dogs, with fatal doses. Opie, 
1912, found fibrinous clots in the lymph nodes of the hepatic region, around the injured 
cells, and considers their obstruction responsible for the edema. In their absence, 
the lymph flow is increased independent of the renal changes. 

Racial Tolerance. The hedgehog, chicken, and duck are remarkably tolerant to 
the nephritic action (Ellinger, 1900). This is not due to differences in the absorption, 
nor to destruction of the poison, for the Cantharidin is found in the urine, just as it is 
in susceptible animals. Nor are these animals immune to other nephritic poisons. 
The immunity to cantharides is also only partial; even a single injection of a large dose 



NON-VOLATILE ORGANIC IRRITANTS 153 

causes chronic nephritis. But taking the fatal dose for man (30 mg. by stomach) as the 
unit, that for the same weight of hedgehog lies about 3,000. For the dog and cat it is 
about 2.5 (i mg. per kilo); for the rabbit, about 45. 

This immunity to the nephritic action does not confer immunity to the local action 
on the skin. In this respect, the hedgehog is even more susceptible than the rabbit, 
which latter animal is almost immune to the cutaneous action. The nephritic action 
is lessened by rendering the urine alkaline (Ellinger, 1905). In the rooster, cantharidin 
causes changes in the comb, analogous to those produced by ergot. Frogs are not 
susceptible. 

Other Vesicants. When cantharis is contraindicated e.g., in cases 
of inflammation of the urinary passages it is usually replaced by ammonia 
water or chloroform, which also produce a vesicant action if their evapora- 
tion is prevented, as by covering the point of application by a thimble. 
These are rather more rapid in action, but much more painful than fly 
blister, and are, therefore, avoided, if possible. lodin, croton oil, and 
mustard have also been used, but act too deeply. 

Contraindications to Vesication. Blisters in general are contraindi- 
cated in people of feeble condition, since they may then lead to ulceration. 
When they are employed for counterirritation, they should not be applied 
directly over the inflamed part, but at some distance from it. They 
might otherwise render the inflammation more violent. 

Alopecia. Cantharis is used in the treatment of baldness, in the form of tincture, 
very greatly diluted with alcohol. 

Treatment of Impotence. Many drugs have been employed for this purpose, but 
our knowledge concerning them is still very meager. Cantharis is one of the most cer- 
tain, acting through reflex irritation from the urethral mucous membrane. It is, how- 
ever, quite dangerous, since effective doses are apt to set up considerable nephritis. 
Many essential oils act in the same manner, and are at once less dangerous and less active. 
Here belong, e.g., damiana, ginseng, mint, garlic, etc., and possibly camphor. Strychnin 
is thought to be effective by raising the tone of the spinal centers. Phosphorus and 
arsenic enjoy some reputation. If they are effective at all, it must be through improve- 
ment in the general condition of the patient. Alcohol, morphin, cannabis, and other 
narcotics act as aphrodisiacs by stimulating the imagination. Yohimbin has a specific 
action. The best treatment for impotence consists, of course, in the removal of the 
cause and improvement in the general health of the patient by appropriate hygiene. 

PREPARATIONS CANTHARIDES 

CantJtaris (Canthar.), U.S. P.; Cantharides (Spanish Flies, Russian Fb'es). The 
dried beetle, Cantharis vesicatoria. Contains cantharidin, 0.4 to i per cent, (not less 
than 0.6 per cent., U.S. P.) volatile and fixed oil, etc. Maximal dose, 0.05 Gm., i gr. 

Cerat. Canthar., U.S.P. (Blistering Cerate). 35 per cent, of Cantharides. 

* Emplastrum Cantharidis (Emp. Canthar.), U.S.P.; Cantharides Plaster. Pre- 
pared by spreading Cantharides cerate upon rosin plaster, leaving a margin around the 
edges. Each square centimeter of spread plaster should contain o.i Gm. of cantharides 
cerate. It requires from six to ten hours to raise a blister, according to the thickness 
of the skin, its content in fat, and probably also individual susceptibility. Since can- 
tharidin is insoluble in water, it is well that the skin be rather greasy, to facilitate its 
absorption. The plaster adheres very poorly, and must usually be fixed with adhesive 
plaster. When the blister has appeared, the plaster should be carefully removed with- 
out rupturing the vesicle. The latter is then pierced and dressed with an ointment. 
This prevents further pain, irritation, or infection. By a "flying blister" is meant a 
series of small blisters raised along the course of a nerve by the application of 
successive plasters. 

Collod. Canth., U.S.P. (Blistering Collodion, Vesicating Collodium). 6 per cent. 
Cantharides in Flexible Collodion. 

Tr. Canthar., U.S.P. 10 per cent. Dose, o.i c.c., i}/2 minims. Maximal, 0.5 c.c. 
8 minims. May be added to liniments to prolong their local action; in hair lotions, i : 50. 

Canthar idinum, B.P.; CioH^Cu. Obtained from various species of Cantharis and 
of Mylabris. Colorless, glistening crystals; no odor. Very slightly sol. in water or ale., 



154 MANUAL OF PHARMACOLOGY 

more sol. in chlorof., ether or oils. Cantharidin, 0.05 to i mg. in a drop of oil, and 
covered with simple plaster, may be employed as a blister. 

The cantharidal preparations of the B.P. are now made of Cantharidin. 
The proportions are adjusted on the basis that i part of Cantharidin is 
equivalent to about 200 parts of Cantharis; so that the activity of the new 
preparations is about the same as that of the old. 

Acet. Cantharidin, B.P. 0.05 per cent, (equiv. to 10 per cent, of Cantharis). 

Collod. Vesic., B.P. 0.4 per cent, (equiv. to 50 per cent, of Cantharis). 

* Emplastrum Cantharidin (Emp. Cantharidin), B.P. 0.2 per cent, (equiv. to 35 
per cent, of Cantharis). See "Emp. Canthar." 

Emplastrum Calefaciens (Emp. Calefac.), B.P.; Warming Plaster. 0.02 per cent. 
(equiv. to 4 per cent, of Cantharis). 

Liquor Epispasticus (Liq. Epispast.), B.P.; Blistering Liquid. 0.4 per cent, (equiv. 
to 50 per cent, of Cantharis), in acetone menstruum. 

Tr. Cantharidin., B.P. o.oi per cent., equiv. to i)4 P er cent . of Cantharis (^ of 
U.S.P.). Dose, 0.12 to 0.3 c.c., 2 to 5 minims, B.P. 

Ung. Cantharidin., B.P. 0.033 P e ? cent., equiv. to 7 per cent. Cantharis (% of the 
old preparation). 

PREPARATIONS CAPSICUM AND SIMILAR IRRITANTS 



, U.S.P.; Capsic. Fruct., B.P.; Capsicum (Cayenne Pepper, African Pepper), 
ripe fruits of Capsicum fastigiatum, U.S. P.; Capsicum minimum, B.P. 



Capsicum, 
The dried 

The action is due to about 0.02 per cent, of a crystalline neutral principle, capsaicin 
(i: 100,000 produces lasting burning of the tongue, Nelson, 1910). Capsicum is used 
internally as a condiment and carminative, and externally to produce prolonged counter- 
irritation for rheumatism, etc. (20 per cent, ointment; or equal parts of tincture and 
of soap-liniment). Dose, 0.06 Gm. i gr., U.S. P. 

Emp. Capsic., U.S. P.; Capsicum Plaster. Prepared by brushing oleoresin of cap- 
sicum upon the surface of rosin plaster so as to form a thin coating, leaving a margin 
around the edges. 

Oleores. Capsic., U.S.P. Evaporated ethereal extract. Dose, 0.03 Gm., % gr., 
U.S.P. 

* Tr. Capsic., U.S.P. 10 per cent. Dose, 0.5 c.c., 8 minims, U.S.P., diluted. 

* Tr. Capsic., B.P. 5 per cent. Dose, 0.3 to i c.c., 5 to 15 minims, B.P. 

* Ung. Capsic., B.P. 25 per cent. 

Euphorbium. The dried juice of Euphorbia resinifera, consists of a gum-resin. 
The active constituent is the resinous euphorbon which resembles the active resin of 
croton oil (Boehm, 1915). The drug is rarely used (in liniments, 10 per cent.; plasters, 
3 per cent.). 

Mezereum, U.S.P. The dried bark of Daphne species. The active constituent is 
the anhydrid of mezerinic acid. There is also a glucosid daphnin. The fluidextract 
is rarely used as an addition to liniments or plasters; also in Fldext. Sarsap. Co. 

Piper, U.S.P.; Black Pepper. The dried unripe fruit of Piper nigrum. (White 
pepper is the ripe fruit, deprived of its outer pericarp.) Contains the crystalline alka- 
loid piperin, a volatile oil, and a pungent resin. Dose, 0.5 Gm., 8 gr., U.S.P. 

Oleores. Piper, U.S.P. Evaporated ethereal extract. Dose, 0.03 Gm., % gr., U.S.P. 

Piperin (piperyl-piperidin). Has been used as an antipyretic and carminative, 
o.i to 0.5 Gm , 2 to 8 gr., in capsules. 

Pulsatilla. The herb of Anemone Pulsatilla and A. pratensis; Europe. Should 
not be kept over one year. Active ingredient, Anemonin. The drug is very irritant, 
and is almost obsolete, but has been used against asthma, hemicrania, etc., in doses 
of o.i to 0.4 Gm. It has a depressant action on the excised uterus (Pilcher, 1916). 

Arisaemia (Indian Turnip; Jack-in- the-Pulpit). The fresh corm of this plant is 
very irritating 'or "acrid" when chewed. This is probably due to the mechanical 
effect of its sharp calcium oxalate crystals (Lazenby, 1915). 

CHRYSAROBINUM 

This is strongly irritant to the skin and mucous membranes. It is 
employed as ointment (5 to 25 per cent, daily) against psoriasis and para- 
sitic skin diseases, ringworm, etc. It stains the skin (keratin) and linen 



NON-VOLATILE ORGANIC IRRITANTS 155 

a brownish-violet color. This can be removed by chlorinated lime. 
Caution must be used lest it reach the eyes and produce violent conjunc- 
tivitis (or rather keratitis; Igersheimer, 1912) and corneal opacity. It is 
absorbed from the skin, and excreted partly as chrysophanic acid, which 
is easily formed by its oxidation, especially in alkaline solutions. The 
urine is, therefore, colored red by alkalies. A part is excreted unchanged, 
and causes renal irritation, casts and albuminuria. By mouth, it produces 
(0.18 Gm.) vomiting, diarrhea, renal pain and hematuria. 

Chrysarobin has a strong affinity for oxygen, abstracting it from the tissues. This 
is supposed to be the basis of its action, the oxidation product, chrysophanic acid, 
being relatively inactive. The oxidation occurs only in watery suspensions in the pres- 
ence of alkali. Fats, therefore, diminish its activity (Schamberg, Raiziss and Kolmer, 
1915)- 

PREPARATIONS CHRYSAROBIN 

Araroba, B.P. (Goa Powder, Crude Chrysarobin). A substance found in cavities 
of the trunk of Andira (Vouacapoua) Araroba. 

* Chrysarobinum (Chrysarob.), U.S.P. B.P.; Chrysarobin. A mixture of neutral 
principles extracted from Goa powder; chiefly chrysophanolanthranol, CisHnOs. 
An orange-yellow, macrocrystalline powder, tasteless, odorless, and irritating to the 
mucous membrane. Very slightly sol. in water, slightly sol. in ale. (1:385); partially 
sol. in fats. A saturated ethereal solution of chrysarobin is used in the treatment of 
warts. It is painted on daily, the dead tissue being pared off. Dose, 0.03 Gm., % g r -> 
U.S.P. 

Ung. Chrysarobin, U.S.P. 6 per cent, in Benz. Lard. 

Ung. Chrysarobin, B.P. 4 per cent, in Soft Paraffin. 

Scarlet Red, Medicinal, N.N.R. (Rubrum Scarlatinum, toluylazo-naphthol). This 
is used as 4 to 8 per cent, ointment, to stimulate the growth of epithelium, on clean 
granulating wounds, especially burns, and on clean ulcers. (Schmieden, 1908; Mora- 
wetz, 1909; Dobrowolskaya, 1912, report the results as no better than without the dye.) 
The application is described in N.N.R. Its use is in the experimental stage. The 8 
per cent, ointment often produces irritation and even erosion and sometimes systemic 
effects (violent gastroenteritis; Lyle, 1912). O. Sachs, 1911, claims that a number of 
other anilin dyes also stimulate epithelial growth. Amidoazotoluol is being advocated 
as less staining (Hayward; Beck, 1913). It is used in the same strength. 

POISON IVY 

Actions. Contact with certain species of Rhus, common along 
roadsides, on fences, in woods and swamps, etc., produces typical derma- 
titis, passing through the successive stages of hyperemia and itching, to 
violent vesication, edema, and suppuration, according to the specific sen- 
sibility of the individual ; many persons are practically immune, although 
a sufficient quantity of the isolated toxicodendrol has never failed to 
produce the dermatitis. The active ingredient of all the species is a 
glucosid toxicodendrol. It is so highly active that K.ooo m g- has caused 
severe vesication (Pfaff). These small amounts may easily be conveyed 
by dust, etc., to some distance, although toxicodendrol itself is non- 
volatile. (Warren, 1913, could not find the poison in the pollen, as has 
been claimed.) Similarly, it may be conveyed by the hands or clothing 
from one person to another, as if it were contagious. The dermatitis 
has a latent period of one to nine, usually four to five days, apparently 
independent of the dose. Internally and hypodermically it produces 
local irritation and nephritis, but the toxicity is relatively low (critical 
bibliography, Ford, 1913). 

Toxic Species. The most important are: Rhus vernix, synon. venenata (Poison 
Sumach, the most powerful); Rhus Toxicodendron (Poison Oak); Rhus radicans and 



156 MANUAL OF PHARMACOLOGY 

diversiloba (Poison Ivy) ; Rhus pumila (a Southern species) all common in North 
America; the Japanese lacquer tree (Rhus vernicifera). Other toxic species are men- 
tioned by L. E. Warren, 1909. The common sumach, Rhus glabra, does not have this 
action. 

Nature of the Toxicodendrol. Pfaff, 1897, showed that the toxicity is not due 
to a volatile alkaloid, as claimed by Khittel, 1858; nor to a volatile acid (Maisch, 1866); 
but that it is caused by a fixed oily substance. Acree and Syme, 1907, isolated this as 
a tar or wax, and showed it to be a glucosid, dissociable into rhamnose, gallic acid and 
fisetin. It is soluble in alcohol and oils and is precipitated by lead acetate, from which 
it is dissolved by ether. It is not destroyed by heating an hour at iooC. (v. Adelung, 
1912, 1913). The toxicodendrol occurs in the lacteal vessels, which terminate in fine 
hairs (Schwalbe, 1902). 

Artificial Immunity. Ford, 1907, found that repeated hypodermic injections of 
increasing doses of the fluidextract induced resistance to the local necrosis and to the 
nephritis; and that the serum of these animals conferred passive immunity on others. 
v. Adelung, 1913, was not successful in producing immunity to the isolated toxico- 
dendrol. 

Congenital Tolerance. The congenital variations in susceptibility are very marked, 
many persons being immune to ordinary contact, although the immunity is probably 
never absolute. The tolerance is sometimes lost, and one attack seems to leave the 
skin more sensitive to others; but Ford mentions that Syme gradually acquired tolerance. 
Perspiration seems to facilitate infection. 

Treatment of Ivy Poisoning. This is best accomplished by thorough scrubbing with 
mild soap, then thoroughly rubbing in a hot solution of potassium permanganate (2 
per cent, for ordinary skin, i per cent, if the skin is delicate or broken); and applying a 
paste of castile soap. The permanganate stain may be removed by 5 per cent, oxalic 
acid, or by sulphurous acid; but these must be used cautiously. Salves or oils must 
not be used since, by dissolving the toxicodendrol, they would spread the infection. 
They become indicated only in the later stages, when the poison has become completely 
removed. Rubber gloves protect against infection. 

Lead acetate (saturated alcoholic solution) precipitates the toxicodendrol; but the 
compound dissociates easily, so that the applications, to be effective, must be made 
frequently. Other popular remedies are: copper or iron salts; the expressed juice of 
"Touch-me-not" (Impatiens fulva); and fluidextract oiGrindelia Robusta (diluted with 
4 to 8 vol. of water and used as a lotion). 

Other Plants Producing Dermatitis. These comprise a number of tropical trees 
belonging to the same family Lithrea caustica; Anacardium (active principle, cardol, 
an oily substance) ; Semecarpus. Primula, chrysanthemum, arbor vitae, and many other 
plants (Vanilla beans, Claveric, 1908); the fruit of the ornamental Ginko tree (Starr, 
1913), affect sensitive persons in the same manner. 

Primula Dermatitis. This is produced by direct contact with the common Chinese 
house plant, Pr. obconica, and a few other species. Nestler describes toxic crystals in 
the resinous secretion of the leaves. The treatment consists in cleansing with alcohol 
or ether, and the application of Zinc Ointment (O. H. Foerster, 1910; Rost, 1914). 

Hypericum. Ray, 1914, stated that cattle feeding on a Tunisian species (H. 
crispum) developed dermatitis of non-pigmented portions of the skin, and inflammation 
of the mucous membranes exposed to light. The phenomena are due to a fluorescent 
substance. Rogers, 1914, claims analogous effects for the common St. John's wort, 
Hypericum perforatum. Similar symptoms are also said to be sometimes produced by 
buckwheat. 

The action of fluorescent dyes on plants is discussed by Gicklhorn, 1914. 

PHYSICAL COUNTERIRRITANTS 

Irritation of the skin is easily produced by physical agencies, which are often pre- 
ferred to the chemical irritants. The effects and indications are similar. They can 
only be enumerated here; heat and cold, in the form of applications, baths, heated air, 
or cautery. Friction, generally combined with massage. Electricity, radiotherapy and 
phototherapy. 

Antiquated are: Acupuncture (pushing needles through the skin to the underlying 
organs, said to be popular with the Chinese); scarification (small incisions with knife 
or needle); setons (a string carried through a fold of skin and left to suppurate). 

Venesection, cupping and leeches also act by altering the distribution of the 
blood. 



STOMACHICS 157 

DRUGS EMPLOYED FOR THEIR LOCAL EFFECTS ON THE ALI- 
MENTARY CANAL 

STOMACHICS 

Bitter, aromatic and "sharp" drugs have been used since ancient times 
as "tonics," and in various functional dyspepsias. They were supposed 
to increase the appetite and improve digestion, and thus favor nutrition. 

Classification. Simple bitters generally contain some "bitter principle" 
neutral substances, often crystalline, non-nitrogenous, sometimes glu- 
cosidal, and without pronounced systemic actions. In aromatic bitters 
these are mixed with volatile oils. The astringent bitters contain tannin. 
Condiments, which also contain aromatic oils or other sharp principles, 
form the transition to carminatives. These are employed to secure the 
expulsion of gas from the alimentary canal. 

Efficiency in Health and Disease. About a tenth of the medicines 
mentioned by Hippocrates belong to this class, and they have always 
played a prominent role in folk medicine. 

Modern scientific investigations (Moorhead, 1915) have confirmed that 
the bitters may improve deficient appetite, and the flow and quality 
(acidity) of the gastric juice, in conditions of poor health (anemia); al- 
though they have no effect on normal individuals (Carlson and co-work- 
ers, 1914 and 1915). 

The aromatics and condiments probably act by mild direct irritation 
of the gastric mucosa, the beneficial effects being due to the hyperemia 
and motor stimulation. 

Effect in Experimental Cachexia. In dogs provided with a Pavvlow gastric pouch, 
and rendered cachectic by repeated large hemorrhages, Moorhead, 1915, found that the 
administration of bitters improved the appetite and the gastric deficiency, although not 
quite to normal. The animals consumed more food and the gastric juice became, more 
abundant and more acid. The increase of appetite occurred whether the bitters were 
given by mouth or by stomach; the increase of secretion was confined to oral use.. The 
improvement occurs with the first administration so that it is not due to the establish- 
ment of a habit. Possibly the bitter taste enhances the taste of food, by contrast. 

Experiments on Normal Individuals. Carlson and co-workers, 1914 and 1915, could 
find no beneficial effects in normal men or dogs. Therapeutic doses of bitters, however 
given, have no immediate or delayed effect on gastric secretion. When taken by 
mouth (or large doses introduced directly into the stomach) they inhibit the normal 
hunger contractions and the sensation of hunger, just as do other irritant or disagreeable 
substances. 

Gastric Secretion. Carlson, 1915, tested the effects on a man with gastric fistula, 
and on dogs with Pawlow miniature stomachs. The bitters were placed in the mouth, 
or directly in the stomach, etc., before, with, or without food, etc. However, the 
experiments were varied, the results were uniformly negative. This disposes of the 
rather contradictory results of older investigators as to direct secretion (Buchheim and 
pupils, 1849; Reichmann, 1888; Korczynski, 1901; Hoppe, 1905) and "psychic juice" 
(Borisoff, 1904; Bonanni, 1905; Strasheko, 1905). 

The introduction of irritant substances into the mouth also fails to provoke gastric 
secretion in man (Carlson, 1915). 

Absence of "Taste" in the Stomach. Albertoni and Tullio, 1912, found on a human 
subject that the direct introduction, through a gastric fistula, of bitter or sweet 
substances or bouillon, produced only the same immediate sensation as saline; but 
bouillon, bread or alcohol provoked speedier secretion of acid and, taken with food, 
afforded a more satisfactory sensation. 

Influence on Pancreatic Secretion. The presence of any irritant in the intestine 
stimulates the flow of pancreatic juice (Gottlieb, 1894). The effect of bitters is some- 
what different: They have no effect on the pancreatic or bile flow; the intestinal juice 
is first diminished, then increased (Reichmann, 1888; Jodlbauer). 

Effect on Absorption. Bitters hasten the absorption of sugar and peptone from the 



158 MANUAL OF PHARMACOLOGY 

stomach (Brandl, 1893), but seem to delay it somewhat from the intestine (Rieder, 
1910). 

Sojourn of the Food hi the Stomach. According to Heubner, this is shortened 
In small, delayed by large, doses. 

Effect on Digestive Ferments. Most of the bitters have no effect on digestion in 
vitro. 

Antiseptic Action. Bitters and aromatics are antiseptic, and may therefore influence 
digestion favorably by limiting putrefaction and abnormal fermentation. 

Leucocytosis. A further action of stomachics (both bitters and aromatics) which 
may be concerned in their therapeutic action, is that they increase the leucocytes of the 
blood. (Hirt, 1856, Binz, 1875, Pohl, 1888). The theory has been advanced that 
these leucocytes play a role in intestinal absorption. (Hofmeister, 1887). 

Therapeutic Uses of Stomachics. These are employed: 

1. To increase appetite, from whatever cause this be deficient. 

2. To improve digestion in all kinds of "atonic" dyspepsias, with 
motor or secretory deficiency. They tend to remove the anorexia, op- 
pression, constipation, hypochondria, etc. In subacute or chronic gas- 
tritis, the astringent bitters may be more useful, otherwise they are rather 
objectionable. Tannin must be especially avoided when the bitter is to 
be prescribed with iron, since this makes an unsightly mixture. Tannin- 
free are the simple bitters and the majority of the aromatic bitters. 

3. As tonics in anemia, convalescence, phthisis, etc., to hasten recon- 
struction. 

4. As antemetics. 

5. To modify or improve the taste of food or medicines; also to obscure 
a "bad taste in the mouth." 

Administration. It is believed that stomachics should be administered 
about a half an hour before meals. They are generally more pleasant, 
and therefore more effective, if they are judiciously blended, as in the 
aromatic and compound bitters (Tr. Gentianae Co.; Tr. Cardamomi Co.). 
Overdoses produce nausea and so defeat their object. 

SIMPLE BITTERS 

These are practically free from aromatic oils or tannin, and can there- 
fore be mixed with water. The tinctures are strongly alcoholic. 

Certain pure alkaloids, such as Quinin or Strychnin, may be used as 
simple bitters. 

PREPARATIONS 

Berberis, B.P. The dried stem of Berberis aristata. The rhizome and roots of B. 
aquifolium were formerly official in the U.S.P. The pharmacology has been studied 
by Hildebrandt, 1907. 

Tr. Berber., B.P. 10 per cent. Dose, 2 to 4 c.c., % to i dram, B.P. 

Calumba, U.S. P.; Calumbaj Radix, B.P.; Calumba (Colombo). The dried root of 
Jateorhiza palmata, U.S. P.; Jateorhyza Columba, B.P. Resembles gentian but can 
be mixed with iron. Contains several alkaloids (Calumbanin, jateorhizin, and pal- 
matin), related to berberin. Biberfeld, 1909, found that these differ only quantitatively 
in action, paralyzing the central nervous system, especially the respiratory center, and 
lowering the blood pressure through cardiac and vasomotor depression. Dose, 2 Gm., 
30 gr., U.S.P. 

Inf. Calumb., B.P. 5 per cent. Dose, 15 to 30 c.c., ^ to i ounce, B.P. 

Tr. Calumb., U.S.P. 20 per cent, in 60 per cent, alcohol. Dose, 4 c.c., i dram, 
U.S.P. 

Tr. Calumb., B.P. 10 per cent. Dose, 2 to 4 c.c., % to i dram, B.P. 

Chirata, B.P. The dried plant of Swertia Chirata. 

Inf. Chirat., B.P. 5 per cent. Dose, 15 to 30 c.c., ^2 to i ounce, B.P. 

Tr. Chirat., B.P. 10 per cent. Dose, 2 to 4 c.c., % to i dram, B.P. 



STOMACHICS 159 

Gentiana, U.S.P.; Gentiana Radix, B.P.; Gentian. The dried rhizome and roots of 
Gentiana lutea, Switzerland. One of the most useful of the bitters; mentioned by 
Pliny. The bitter principles are the crystalline glucosid gentiin, and the amorphous 
gentiamarin. The fresh drug contains the crystalline glucosid gentiopicrin, which 
disappears in drying. There is also a small amount of tannin, not enough to be astrin- 
gent, but sufficient to be incompatible with iron. Dose, i Gm., 15 gr., U.S.P. 

* Extractum Gentians (Ext. Gent.), U.S.P., B.P. A watery pilular extract, used 
largely as pill excipient. Dose, 0.25 Gm., 4 gr., U.S.P.; 0.12 to 0.5 Gm., 2 to 8 gr., B.P. 

Inf. Gent. Co., B.P. 1.25 per cent., with Bitter Orange and Lemon peels. Dose, 
15 to 30 c.c., % to i ounce, B.P. 

* Tinctura Gentiana Composita (Tr. Gent. Co.), U.S.P., B.P. 10 per cent, of 
Gentian, with Bitter Orange Peel and Cardamom, in 45 per cent, alcohol. Dose, 4 c.c., 
i dram, U.S.P. ; 2 to 4 c.c., % to i dram, B.P. 

Pareira. The root of Chondodendron tomentosum. Contains bebeerin, isobe- 
beerin, and other alkaloids (studied by Faltis, 1912; Scholtz, 1913). Commercial 
"Bebeerin sulphate cryst." is isobebeerin. It is isomeric with codein, and like this, 
has narcotic actions (Scholtz and Koch, 1915). Dose of Pareira, 2 Gm., 30 gr. 

Picrorhiza, B.P., The rhizome of Picrorhiza Kurroa. Dose, 0.6 to 1.2 Gm., 10 to 
20 gr.; antiperiodic dose, 3 to 4 Gm., 45 to 60 gr., B.P. 

Ext. Picrorh. Liq., B.P. Dose, i to 4 c.c., 15 to 60 minims, B.P. 

Tr. Picrorh., B.P. 25 per cent. Dose, 2 to 4 c.c., % to i dram, B.P. 

Quassia, U.S.P.; Quassia Lignum, B.P.; Quassia. The wood of Picraena excelsa 
(also of Quassia amara, U.S.P.). Dose, 0.5 Gm., 8 gr., U.S.P. 

Inf. Quass., B.P. i per cent. Dose, 15 to 30 c.c., ^ to i ounce, B.P. 

Tr. Quass., U.S.P. 20 per cent. Dose, 2 c.c., 30 minims, U.S.P. 

Tr. Quass., B.P. 10 per cent. Dose, 2 to 4 c.c., ^ to i dram, B.P. 

Taraxacum, U.S.P.; Tarax. Rod., B.P.; Taraxacum (Dandelion). The dried rhi- 
zome and roots of Taraxacum officinalis, U.S.P.; the fresh root, B.P. (Composition, 
Power and Browning, 1912). Dose, 10 Gm., 2% drams, U.S.P. 

Ext. Tarax., U.S.P. A pilular extract; used as pill excipient. Dose, i Gm., 15 gr., 
U.S.P. 

Fldext. Tarax., U.S.P. Dose, 10 c.c., 2% drams, U.S.P. 

Succ. Tarax., B.P. The juice, preserved with 25 per cent, of alcohol. Dose, 4 to 
8 c.c., i to 2 drams, B.P. 

Xanlhoxylum, U.S.P. (Prickly Ash). The dried bark o'f Xanthoxylum ameri- 
canum or X. Clava-Herculis. Contains berberin. Dose, 2 Gm., 30 gr., U.S.P. 

Fldext. Xanthox., U.S.P. Dose, 2 c.c., 30 minims, U.S.P. 

ASTRINGENT BITTERS 

With these, tannin is a prominent ingredient, whilst volatile oils are 
present only in small quantity, if at all. The preparations can be mixed 
with water. 

PREPARATIONS 

(* Tr. Cinchona Co., U.S.P., B.P., see Index.) 

Cascarilla, B.P. The dried bark of CrOton Eluteria. 

Inf. Cascarill., B.P. 5 per cent. Dose, 15 to 30 c.c., J to i ounce, B.P. 

Tr. Cascarill., B.P. 20 per cent. Dose, 2 to 4 c.c., ^ to i dram, B.P. 

Cimicifuga, U.S.P. (Black Cohosh, Black Snakeroot; Macrotys). The dried 
rhizome and roots of Cimicifuga racemosa (Constituents, Finnemore, 1910). Dose, 
i Gm., 15 gr., U.S.P. 

Ext. Cimicif., U.S.P. A powdered extract, i Gm. representing 4 Gm. of the drug. 
Dose, 0.25 Gm., 4 gr., U.S.P. 

Fldext. Cimicif., U.S.P. Dose, i c.c., 15 minims, U.S.P. 

Condurango. The bark of Marsdenia Condurango. Used as astringent bitter 
especially in gastric ulcer and carcinoma. 

Fldext. Condur. Dose, i to 1.5 c.c., 15 to 25 minims. 

Cusparia (Angostura Bark). The bark of Cusparia febrifuga. Contains alkaloids, 
chiefly cusparin (Troeger and Mueller, 1915). Dose, 0.6 to 2.5 Gm., 10 to 40 gr. 

Serpentaria, U.S.P.; Serpent Rhiz., B.P.; Serpentaria (Virginia Snakeroot). The 
dried rhizome and roots of Aristolochia Serpentaria or reticulata. Dose, i Gm., 15 gr., 
U.S.P. 

Tr. Serpent., B.P. 20 per cent. Dose, 2 to 4 c.c., % to i dram, B.P. 



l6o MANUAL OF PHARMACOLOGY 

AROMATIC BITTERS 

These contain both aromatic oils and bitter principles, but no tannin. 
Their alcoholic preparations can not be mixed with water without tur- 
bidity. 

PREPARATIONS 

(Aur antii Amari, Cortex, see Index.) 

Anthemidis Flares, B.P. (English or Roman) Chamomile Flowers. The dried flower- 
heads of Anthemis nobilis. 

Ol. Anthem., B.P. The distilled oil. Dose, 0.03 to 0.18 c.c., J^ to 3 minims, B.P. 

Betel, B.P. The dried leaves of Piper Betle. 

Calamus (Sweet Flag). The rhizome of Acorus Calamus. 

Matricaria, U.S. P. (German Chamomile). The dried flower-heads of Matricaria 
Chamornilla. Volatile oil and bitter principles. Used as infusion, internally as 
stomachic, carminative, and diaphoretic; externally as counterirritant. Dose, 15 Gm., 
4 drams, U.S.P. 

Panax, Ginseng. The root of Panax quinquefolium, very highly valued by the 
Chinese, belongs to this series. So do other species of Panax and Aralia. 

Numerous other bitters are used in domestic medicine, but they are not worth 
mentioning. 

CARMINATIVES 

This class comprises certain aromatic oils exerting an irritant action 
upon the stomach and intestine, being somewhat specific in causing the ex- 
pulsion of gas rather than of fluid or solid contents. Since they are also 
antiseptic, they are especially useful in abnormal fermentation, removing 
at once the discomfort caused by the gas, and checking the growth of 
the bacteria which give rise to it. They also form useful additions to laxa- 
tive mixtures, since they diminish the "griping." Charcoal is also classed 
as a carminative. 

PREPARATIONS CARMINATIVES 

* Carbo Ligni (Carb. Lig.), U.S.P., B.P.; Wood Charcoal. Black, tasteless and odor- 
less, very fine powder. Dose, i Gm., 15 gr., U.S.P. , to 4 Gm., 60 gr. 

When freshly heated, charcoal condenses gases and dissolved substances in its pores, 
therefore acting somewhat as a catalyst in facilitating oxidations and other chemic 
reactions. It has been used as a dressing for infected wounds. Internally, it is some- 
times employed in flatulence, with the idea that it will absorb the gases. It is prob- 
ably useless since moist charcoal has this property only to a very slight degree. It is 
also used as an antidote, especially for alkaloidal poisons (Wiechowski). Animal 
charcoal, Carbo animalis, U.S.P., Bone-black, is used in chemical industry for de- 
colorizing. It has been employed in dysentery, similar to Kaolin. It adsorbs and 
therefore hinders digestive ferments in vitro; but this seems to be compensated by 
increased secretion (Strauss, 1916). It also adsorbs and inactivate^ toxins (R. Kraus 
& Barbara, 1915). 

Colloidal Carbon (caramel) is harmless, even on intravenous injection. }t antag- 
onizes alkaloids (strychnin) when mixed in vitro, and even somewhat when the strychnin 
is given by mouth, and the carbon by vein; but this antagonism is too uncertain for 
practical application (Sabbatani, 1913 and 1914). 

Mentha Piperita, U.S.P.; Peppermint. The dried leaves and flowering tops of 
Mentha piperita. Dose, 4 Gm., 60 gr., U.S.P. 

(* Aq. Menth. Pip., see Index.) 

Ol. Menth. Pip., U.S.P., B.P. The distilled oil, containing at least 50 per cent, of 
menthol. Colorless liquid, characteristic odor, pungent aromatic taste. Dose, 0.2 
c.c., 3- minims, U.S.P.; 0.03 to 0.18 c.c., 2^ to 3 minims, B.P. 

* Spiritus Mentha Piperita (Sp. Menth. Pip.), U.S.P., B.P.; Spirit (Essence) of 
Peppermint. 10 per cent, of the Oil; the U.S.P. is tinged green by maceration with 
Peppermint. Dose, 2 c.c., 30 minims, U.S.P.; 0.3 to 1.2 c.c., 5 to 20 minims, B.P.; 
in water. 



VEGETABLE CATHARTICS l6l 

Mentha Viridis, U.S. P.; Spearmint. The dried leaves and the flowering tops of 
Mentha spicata. Dose, 4 Gm., 60 gr., U.S.P. 

(Aq. Menth. Vir., see Index.) 

Ol. Menth. Vir., U.S. P., B.P. The distilled oil, containing at least 40 per cent, of 
carvone. Dose, 0.2 c.c., 3 minims, U.S. P.; 0.03 to 0.18 c.c., j to 3 minims, B.P. 

Sp. Menth. Vir., U.SP. 10 per cent, of oil, colored by maceration with spearmint 
herb. Dose, 2 c.c., 30 minims, U.S. P.; diluted. 

Zingiber, U.S. P., B.P.; Ginger. The dried rhizome of Zingiber officinale. The 
chief active ingredient is a volatile oil. Dose, i Gm., 15 gr., U.S.P., as powder or in 
water. 

Similar to Ginger are: Galanga, Zedoaria, and Asarum. 

Fldcxt. Zingib., U.S.P. Strong alcohol. Dose, i c.c., 15 minims, U.S.P. 

Oleores. Zingib., U.S.P. An evaporated ethereal extract. Dose, 0.03 Gm., % gr 
U.S.P. 

Syr. Zingib., U.S.P., B.P. 3 per cent., U.S.P.; 2.5 per cent., B.P. Dose, 15 c.c., 
4 drams, U.S.P.; 2 to 4 c.c., ^ to i dram, B.P. 

* Tinclura Zingiberis (Tr. Zingib.), U.S.P., Tincture of Ginger. 20 per cent, in 
alcohol. Dose, 2 c.c., 30 minims, U.S.P. 

* Tr. Zingib. B.P.; 10 per cent. Dose, 2 to 4 c.c., ^ to i dram., B.P. 

VEGETABLE CATHARTICS 

Manner of Action. Cathartics or evacuants are drugs which produce 
defecation. They may do so by simply increasing the bulk of the intesti- 
nal contents (petrolatum, agar, etc.); or by preventing the absorption of 
water (salines); or by irritating the small or large intestine, as most 
of the vegetable cathartics. The cathartics differ from other irritants 
in that their irritation is relatively mild and is confined more specifically 
to the intestines. This may be explained by selective action, or more 
simply by the alkaline reaction of the intestines favoring their solution 
or decomposition. This solution must not be too rapid or the drugs 
will be largely absorbed or decomposed before reaching the lower intestine. 
The isolated principles are therefore less useful, and sometimes less effective 
than the galenic preparations in which they are protected by the ex- 
tractives, gums, etc., of the drug. 

Liberation and Solution of the Cathartic Constituents. Castor oil and croton oil 
become active only when their fatty acids are liberated; croton oil contains some free 
acid and is, therefore, pustulant also on the skin. The emodin cathartics often contain 
glucosidal compounds, which must be split before the action occurs. The group of 
"resins" are insoluble in water, but are decomposed and dissolved by alkalies and bile. 

Influence of the Bile on Cathartics. The bile seems to be necessary for the activa- 
tion of many of the resinous cathartics, the following being relatively or quite ineffective 
in its absence: gamboge, podophyllum, convolvulin, jalap, and scammonium (Buchheim 
and Stadelmann). The bile acts presumably by increasing the solubility. Rhubarb, 
senna and calomel are active in the absence of bile (Valeri, 1910). Aloe seems to act 
quite well without bile in animal experiments; but clinically it has been claimed that 
it is ineffective in biliary obstruction. 

Efficiency on Hypodermic Administration. The anthracene and resinous cathartics 
also increase peristalsis if they are injected subcutaneously or intravenously; the resin- 
group is even more active by this channel. The action, however, is even then a local 
one, the constituents being excreted into the intestine. The cathartics are not admin- 
istered in this manner, in practice, since the injection would be painfully irritant; the 
effects are also more easily controlled when the drugs are given by mouth. 

Absence of Toxic Effects. Only very excessive doses of the drastic cathartics 
produce serious effects through gastroenteritis. A relatively mild irritation suffices for 
active catharsis. None of the vegetable cathartics are at all corrosive; and even toxic 
doses cause necrotic changes only as the result of excessive inflammation. The irrita- 
tion is confined to the intestinal tract; the stronger cathartics escaping absorption, 
whilst the milder laxatives would scarcely be irritant even if absorbed. There is con- 
sequently no danger of nephritis. 



1 62 MANUAL OF PHARMACOLOGY 

Location of Action. This is of practical as well as scientific interest, 
because it often determines the choice of the cathartic. The older inves- 
tigations have only a limited value, because they generally involve opera- 
tive procedures which are apt to render the intestinal movements abnormal 
or to arrest them altogether. Cannon's method of observing these move- 
ments in intact animals by means of the Roentgen-rays has opened the 
way for more reliable observations. This method has been applied to 
pharmacologic problems especially by Magnus, 1909 and by his pupils. 
Their results have been confirmed in man (J.i. Meyers-Betz and Gebhardt, 
1912). They have shown in this way that Senna acts mainly on the large 
intestine, increasing the defecation-reflex. Castor oil stimulates peristalsis 
in the small intestine. Colocynth stimulates the movements of the small 
intestine and leads to intestinal effusion. Magnesium sulphate quickens 
the passage through the small intestine, and prevents the absorption of 
fluid and the concentration of the contents of the large intestine. Calomel 
increases peristalsis both in the small and large intestine. 

The Normal Course of the Food through the Alimentary Canal. The following 
description (Magnus) applies specifically to cats fed with 25 c.c. of potato mash, mixed 
with 5 Gm. of bismuth subnitrate (to render it opaque to the Roentgen-rays) and 
observed with the fluoroscope. The phenomena are similar with other food and in 
other animals, including man (Cannon, 1911). 

Passage through the Stomach. Immediately after feeding, the stomach is entirely 
filled, with a fundus dilated and resting. In the pyloric antrum, regular powerful 
peristaltic waves are observed, sweeping the contents against the pyloric sphincter. 
In a quarter of an hour, the food begins to be expelled into the duodenum, small portions 
at a time, the expulsion being completed in two or three hours; meats and especially 
fats are discharged more slowly. 

Passage through the Small Intestine. This exhibits three motor processes: (i) 
The pendulum movements, which produce an alternating "rythmic segmentation" 
of the contents; kneading and mixing the chyme, and exposing it to a large absorbing 
surface. (2) True peristaltic waves, appearing from time to time, and propelling the 
entire contents of the loop slowly for a few centimeters in a descending direction. (3) 
Peristaltic "rush," sudden waves of contraction sweeping the contents swiftly through 
long segments. This is seen especially under pathologic conditions, such as poisoning. 

In cats the passage of food into the cecum begins in two and one-half to three hours 
and is completed in seven to eight hours after the feeding. The passage is hastened 
by cellulose, delayed by fats, and especially by meats (some two hours). In man the 
usual time of appearance in the colon is four to six hours. The chyme as it reaches the 
colon is still semifluid. 

Passage through the Large Intestine. The colon is divided functionally into two 
portions. The proximal portion effects the concentration of the chyme by a churning 
process; groups of powerful ascending (antiperistaltic) waves sweeping the contents 
against the ileo-cecal valve. Extensive absorption of fluid occurs during this process, 
and as the contents becomes solidified, fragments are separated from the lower portion 
by annular contractions of the intestinal muscle. These masses then wander very 
slowly toward the rectum. The passage through the large intestine occupies about the 
same time as that of the small intestine, in man about six hours. 

Defecation Reflex. This is started by the arrival of the mass in the rectum. It is 
greatly influenced, however, by the sensitiveness of the rectum and by the habits of the 
patient. It is here that the delay in constipation mainly occurs. 

Total Tune for the Passage of Food. In man the journey from the mouth to the 
rectum is made in about nine hours; the further delay in the rectum depends on the 
habits of the individual. 

Peculiarities of the Cathartics. These are largely explained by the 
mechanism, the location and the severity of the action. 

Time of Action. A cathartic which acts on the large intestine can not 
produce any effect until it reaches this place. Even then the response 
will depend on the habits of the patient. These become less important 



VEGETABLE CATHARTICS 163 

with the more irritant cathartics. The usual time of response, for the 
more important cathartics, is as follows: 

Salines, one-half to one hour on empty stomach; two to four hours if 
in bed. 

Castor oil, one to two hours on empty stomach. 

Jalap, three hours or less. 

Senna, four to five hours. 

Rhubarb or Phenolphthalein, four to eight hours. 

Cascara or Aloes, eight to twelve hours. 

Podophyllum, ten to sixteen hours. 

Colic and "Griping" is proportional to the severity of the irritation. 
It is due partly to increased peristalsis, partly to direct irritation, as 
evidenced by abdominal tenderness. It may be mitigated by belladonna 
and carminatives. 

Consistency of the Stools and Elimination of Fluid. The consistency 
varies from the soft but formed stools of the milder laxatives, to the watery 
stools of the "hydragogue" cathartics, the salines and drastics. The more 
rapid passage of the intestinal contents leaves less time for the absorption 
of fluid, so that the stools always contain more water. Some of the 
cathartics also prevent the absorption of fluid by osmosis (salines) ; or by 
imbibition (agar) ; and some perhaps by inhibiting the absorbing power of 
the epithelium (castor oil, calomel). The fluid in these cases comes 
really from the food rather than from the body. Even large doses of the 
anthracen cathartics (senna, cascara, etc.) do not increase the secretion of 
intestinal fluid (Thiry, Brieger, Flemming). On the other hand, the 
irritant cathartics (colocynth, jalap, etc.) actually produce effusion into 
the small intestine. The practical results, as concerns the water supply 
of the tissues, is the same in either case; whether these are deprived of 
fluid by effusion or by non-absorption. 

Effects on the Local Circulation. All catharsis must be accompanied 
by some hyperemia, were it only by the increased intestinal movement. 
The irritant cathartics produce a more violent intestinal congestion, which 
extends also to the pelvic organs, and thus increases the menstrual flow. 

The Systemic Circulation. This is affected indirectly by the splanch- 
nic dilation; and by the withdrawal of fluid from the blood. Both 
factors tend to lower the blood pressure moderately. The heart rate is 
slowed reflexly. 

C. H. Xeilson and Hyland, 1913, made a clinical study of these effects after full doses 
of salts and compound jalap powder. The latter gave somewhat greater results. 
The average decrease of the systolic pressure was 17 per cent.; of the diastolic pressure, 
8 per cent.; of the pulse pressure, 24 per cent.; of the heart rate, 14 per cent. The 
conditions generally returned to almost normal within a day. Individual cases, es- 
pecially of arteriosclerosis, gave much greater falls (from 180 to 100 mm.), sometimes 
with the appearance of arythmias and increased heart rate. 

Influence on Dropsies. Cathartics favor the absorption of dropsies 
by carrying off liquid from the body; in ascites, the emptying of the intes- 
tines also removes some of the pressure from the veins, and thus tends 
to the removal of the edema by improving the general circulation and 
the urine flow. 

Elimination of Waste Products. Cathartics are employed in neph- 
ritis to relieve the kidneys of a part of their work, by eliminating fluid, 
and presumably some of the metabolic products, through the stools. 



164 MANUAL OF PHARMACOLOGY 

Uric Acid. Abl, 1913, claimed that cathartics increase the elimination of endogen-' 
ous uric acid. Stehle, 1915, found no change with laxatives, but only with drugs that 
stimulate the digestive glands. 

Effects of Cathartics on Bile; Cholagogues. The stools, with moderate 
catharsis, have usually a darker color, suggesting an increased bile content. 
This is not due to increased secretion of bile, as was supposed by the older 
therapeutists; but to the more rapid passage of the intestines, leaving less 
time for the reabsorption and decomposition of the bile. The dark color 
of calomel stools is due partly to mercurous sulphid. The only really 
effective stimulant of bile formation is the administration of bile or bile 
salts; salicylates (5 Gm. per day) and olive oil are perhaps also very slightly 
effective. 

Experimental Investigations of Cholagogues. The older experiments on animals 
with biliary fistulas, gave contradictory results, because they did not extend over 
sufficient time to discount the natural variations in bile flow. Reliable experiments on 
a human patient were made by Pfaff and Balch, 1897; Van Hengel, 1913; and Ignatowski 
and Monossohn, 1914. The last-named found the bile secretion increased by feeding 
animal protein, and especially fat. Sodium salicylate was less effective, and bile-acids 
least. Weinberg, 1911, experimented in Pawlow's laboratory with dogs provided 
with gastric and biliary fistulas. He found the order of efficiency to be: bile > soap > 
albumose> hydrochloric acid > olive oil. No effect was obtained with glycerin, egg 
albumen, saccharose, dextrose, water, normal saline or sodium carbonate. Okada, 
1915, found marked increase with salicylate, chloral, salol, potas. bitart., bile salts, 
acids, and large doses of alcohol. A slight diminution was caused by atropin; no 
effect by calomel or sod. bicarb. Food increased the secretion, but the nature of the diet 
was generally unimportant; fats, egg white, albumose and meat extracts produced 
some increase; starch and sugar were indifferent. Volborth, 1915,- reports diminished 
filling of the gall-bladder after milk or oil; increased filling after acid or bile. 

Evacuation of Gall-bladder. Klee and Knuepfel, 1914, found that this is stimulated, 
in animals, by eating, entrance of the chyme into the intestine, injection of Witte's 
peptone; and especially by the administration of olive oil. No effect was produced by 
soap or hydrochloric acid. Weinberg, 1911, also observed this effect of oil. 

Autonomic Drugs on Gall-bladder. Lieb and McWhorter, 1915, found that the 
muscles of the gall-bladder receive augmentor impulses from the parasympathetic, 
inhibitory from the sympathetic. The autonomic drugs act correspondingly: Pilo- 
carpin, barium and strophanthin stimulate; atropin, epinephrin, nitrites and bile salts 
relax. The rhythmic movements are increased during digestion; or on the introduction 
of acid into the duodenum (Okada, 1915). 

Sphincter of Biliary Papilla. Reach, 1914, states that the tone of this is increased, 
and the bile flow correspondingly hindered, by morphin, epinephrin, pilocarpin and 
atropin. 

Therapeutic Indications. Cathartics are used chiefly for the following 
indications: 

To relieve constipation cascara, rhubarb, phenolphthalein, small 
doses of salts. 

To soften the stools, in hemorrhoidal and other rectal diseases; and to 
prevent straining in aneurism, hernia, and apoplexy petrolatum, cascara, 
podophyllurn, sulphur. 

To cleanse the intestines in digestive disturbances, diarrheas and other 
intestinal putrefactions calomel, castor oil, rhubarb, cascara, aloes. 

To facilitate the absorption of dropsies; to relieve the kidneys in 
nephritis; to lower the temperature in fevers; to relieve internal conges- 
tions, especially of the brain calomel, large doses of salines, compound 
jalap powder; in emergencies, croton oil or elaterin. 

Cathartics are perhaps the most ancient method of internal medication, and were 
for a long time practically the only method. Even the Greeks used the same word, 
ct>apna.Keiv, both for internal medication in general and for the use of cathartics in 
particular. The present English word physic is similarly applied. 



VEGETABLE CATHARTICS 165 

Contraindications. All inflammatory conditions of the abdominal 
organs (peritonitis, gastroenteritis, etc.) preclude the administration of 
intestinal irritants. Pregnancy and menstruation are contraindications 
to the use of the stronger cathartics, since the hyperemia may lead to 
abortion or excessive menstrual flow. General debility, tendency to 
collapse, threatened intestinal hemorrhage, and toxic spasm of the intes- 
tine, are further contraindications. Cathartics should not be used in 
intestinal obstruction or intussusception. 

Habitual Constipation. In this condition ("chronic intestinal stasis"), 
cathartics should be used as little as possible; the condition being treated 
most effectively by the removal of the cause and the cultivation of proper 
hygienic and dietetic habits; aided by the mechanical laxatives, petrola- 
tum, agar or enemas. Small doses of salts, cascara or similar aperients 
may be needed. The irritant cathartics should be avoided. 

In using cathartics the rule should always be to employ the mildest remedy which will 
accomplish the result. One reason for this is that soft, not liquid, stools are desired; 
but, further, a "habit " is quite readily acquired so that the intestines will require stronger 
and stronger stimuli, and the usual cathartics gradually lose their efficiency. If the 
treatment has been begun with mild measures, stronger ones are left for later use if 
necessary. The habitual use of very irritant cathartics is also quite apt to engender a 
chronic enteritis. 

Therapeutic Classification. The cathartics may be classified accord- 
ing to their clinical characters, i.e., mainly by the degree of their effects. 
This can not be done rigidly, because the effect varies with the dose; 
moreover, the names are defined somewhat differently by individual 
authors. 

The following table gives a useful clinical classification: 

1. Laxatives or Aperients. Increase peristalsis only moderately, pro- 
ducing somewhat more frequent stools, of almost normal consistency, 
and this without causing notable irritation. They are active in doses of 
10 Gm. or over. 

Fruits, Manna, Agar, etc.; mechanical means (massage, enemas, etc.); 
Sulphur, Magnesia, Carminatives, Bile, Bland Oils (Olive, Cottonseed, 
Petrolatum, etc.). 

(Small doses of Cascara, Senna, Castor Oil, Rhubarb, and Ipecac are 
also laxative.) 

2. Purgatives. Increase peristalsis actively, causing more frequent 
semifluid stools. 

(A) Simple Purgatives. Active in doses of 0.2 to i Gm. These cause 
more or less colic and irritation: 

Aloes, Rhubarb, Senna, Cascara, Phenolphthalein, Castor Oil, Calomel, 
small doses of drastics. 

(B) Saline Purgatives. Active in doses of about 10 Gm. Rather pro- 
fuse, watery stools, with practically no irritation or griping: 

Sulphate of Magnesium or Sodium, Sodium Phosphate, Magnesium 
Citrate, Potassium Bitartrate, Rochelle Salt, etc. 

3. Drastics. Produce watery stools, with much irritation. Large 
doses are apt to set up an enteritis: 

Elaterium, Colocynth, Jalap, Scammony, Gamboge, Podophyllutn, 
Croton Oil, the stronger Mercurials, and Antimony Sulphid. 

4. Hydragogues. All which produce watery stools, i.e., the salines and 
drastics. 

5. Cholagogues. Were supposed to increase the bile flow: 



1 66 MANUAL OF PHARMACOLOGY 

Aloes, Rhubarb, Mercurials, Podophyllum, Euonymin, Sod. Salicylate 
or Phosphate, Acid. Nitrohydrochlor. Dilut., Bile. 

Pharmacologic Classification. The cathartics may also be divided 
into the following groups: 

1. Those which act mainly on the colon and rectum, inhibiting colon 
antiperistalsis, and provoking the defecation reflex. This includes the 
drugs containing emodin and other anthraquinon derivatives: Senna, 
Cascara, Rhubarb, Aloes, and perhaps also Phenolphthalein and Bile. 

2. Those which stimulate the peristalsis of the small intestine and 
inhibit the antiperistalsis of the colon, but without producing much 
irritation or effusion. This includes Castor Oil and probably Calomel 
and Sulphur. 

3. Those which, in addition to these actions, cause marked intestinal 
effusion and irritation. This comprises Colocynth, Jalap, and presumably 
the other drastic resinous cathartics, Podophyllum, Elaterin, Gamboge, 
Croton Oil, etc. 

4. The saline cathartics, which retain water by osmosis. 

5. The colloid cathartics, which retain water by imbibition: Agar, 
Fruits, Manna, etc. 

6. Emollient cathartics, such as Petrolatum or Olive Oil. 

7. Enemas and similar local measures. 

THE ANTHRAQUINON OR EMODIN CATHARTICS 

Active Constituents. Senna, Rhubarb, Cascara, Aloes and related 
drugs contain glucosidal compounds which are themselves inactive. In 
the alkaline intestine they are hydrolyzed or oxidized, yielding various 
oxymethyl-anthraquinons (Buchheim; Tschirch and pupils, 1899), which 
produce the cathartic action. The pure substances would be too irritant, 
but their action is graded by their slow liberation, and by the presence of 
colloid extractives. The most common of these substances are emodin 
and chrysophanic acid. Numerous isomers of these are possible (15 for 
emodin alone). The special characters of the different drugs is probably 
due to differences in these isomers; in the stability of their glucosidal com- 
bination; and to the presence of other associated substances (tannin in 
rhubarb). The action of these drugs never progresses to inflammation. 
They are often more effective when given in divided doses (three times 
daily), than when given in a single dose. 

Emodin is partly absorbed and is excreted into the urine and milk 
(laxative effects on sucklings). 

The structure of these anthraquinons is shown by the following formulas: 
CH CH CH CH CO CH 





CH HC\ /\ /\ /CH 



CH CH CH CH CO CH 

Anthracen, CnHio Anthraquinon, CiiHsO* 



C(CH 2 ) CO C(OH) 
r-TT 

\^1L 



CH 




VEGETABLE CATHARTICS 

C(CH 2 ) CO C(OH) 



I6 7 



HC 



HC 



C 



;CH 



CH CO C(OH) 

Dioxymethylanthraquinon . 
Chrysophanic acid, CjsHioCh 



C(OH) CO C(OH) 

Trioxymethylanthraquinon. 
Emodin, dsHioOs 



Ernodin is probably the most important of these principles. It is present in the 
amount of 0.8 to i per cent, in senna; 2.6 per cent, in frangula; 0.6 per cent, in cascara; 
0.8 per cent, in Cape aloes; and 1.5 per cent, in rhubarb (Tschirch and Hiepe). 

Coloration of Urine. The drugs containing emodin color the urine yellowish-brown 
when it is acid, reddish or violet when alkaline. It may be advisable to acquaint the 
patient with this fact. 

Other drugs which change the color of the urine are: Logwood (Hematoxylon) does not 
color acid urine, but produces a reddish or violet color in alkaline urine. Santonin 
gives a yellow color to acid urine, with a yellow foam; if the urine is made alkaline it 
gives a very pronounced pink. Picric acid gives reddish-brown color in both acid and 
alkaline urine. The various coal-tar products give a brownish-black color. Methylen 
blue imparts a green color. 

Manner of Action. The older work (Buchheim; Tappeiner and Brandl, 
1889) showed that their action is mainly on the large intestine, which re- 
acts by increased movement also to intravenous injection; and that there 
is no increase of intestinal secretion. The X-ray experiments of Magnus 
with senna show that the effects consist chiefly in increase of the local 
defecation reflex, and inhibition of the colon antiperistalsis. 

Experiments of Magnus (1909). Senna does not affect the course of the chyme 
through the stomach and small intestine. The first effect occurs when the senna reaches 
the colon, so that its action must be strictly local. Here it inhibits antiperistalsis and 
thus prevents the concentration of the feces. At the same time, it starts the defecation 
reflex. It thus leads to the expulsion, first of the solid contents already present in the 
rectum, and then of the more fluid contents of the upper colon. 



CASCARA SAGRADA 

Cascara is used chiefly in habitual constipation. It softens the stools 
without noticeable irritation. The susceptibility is not lost with use; on 
the contrary, the establishment of regular habits usually permits it to be 
gradually withdrawn. By its bitter taste, it acts also as stomachic. It 
may be given as the fluidextract, 15 drops three times daily; or in a single 
dose, a half teaspoonful, in the evening. This causes a single soft stool in 
the morning. In the Aromatic Fluidextract, which is much more pleasant, 
some of the bitter and cathartic principles have been destroyed (Wenzell 
1886) by an alkali (magnesia). It may be given in twice the dose. 

It is generally stated that the fresh bark is emetic, through the presence of a fer- 
ment, which gradually disappears as the bark is aged. R. H. True, and Klugh, 1909, 
did not find any emetic effect from the unaged bark. 

In the excised intestine, cascara increased the rate, but lessened the intensity of the 
contractions (Flury, 1912). The tone is increased by small, and lowered by large doses, 
also intravenously (Ott and Scott, 1908). 

When cascara is administered hypodermically (as with the proprietary "Peristaltin"), 
its constituents are rapidly absorbed and excreted by the kidneys, producing renal 
irritation, but not catharsis (Chistoni, 1914). 

Cascara sagrada ("Sacred Bark") was used by the early settlers, but was little 
known to the profession till introduced by Bundy, 1877. Johnson and Hindman, 1914, 
review its history, composition and bibliography. 



1 68 MANUAL OF PHARMACOLOGY 



PREPARATIONS CASCARA 

Cascara Sagrada (Case. Sagr.), U.S.P., B.P.; Cascara Sagrada (Cascara; Rhamnus 
Purshiana). The dried bark of the trunk and branches of the shrub Rhamnus Pur- 
shiana, stored at least one year. The active principles are: Cascarin, which is a cathartin 
or emodin principle; isoemedin, bitter resins, etc.; no chrysarobin or chrysophanic acid 
(Jovvett, 1904. This author claims that emodin is not the main active constituent). 
Dose, i Gm., 15 gr., U.S.P. 

* Ext. Cascar. Sagr., U.S.P. ; Ext. Case. Sagr. Sice., B.P. A powdered extract, i 
Gm. representing 4 Gm. of drug, U.S.P. Dose, 0.25 Gm., 4 gr., U.S.P. 

* Fldexl. Cascar. Sagr., U.S.P.; Ext. Cascar. Sagr. Liq., B.P. Dose, i c.c., 15 minims, 
U.S.P.; 2 to 4 c.c., ]4 to i dram, B.P. 

* Fldext. Cascar. Sagr. Arom., U.S.P. (Aromatic Cascara). A watery extract, with 
the bitter principles partly destroyed by maceration with magnesia; preserved with 
25 per cent, of alcohol, flavored with glycyrrhiza, aromatics and saccharin. Dose, 
2 c.c., 30 minims, U.S.P. 

* Syr. Case. Arom., B.P. 40 per cent, of Liquid Extract, flavored with orange, cin- 
namon and syrup. Dose, 2 to 8 c.c., % to 2 drams, B.P. 

Frangula, U.S.P. (Buckthorn Bark). The dried bark of Rhamnus Frangula. Dose, 
i Gm., 15 gr., U.S.P. 

Fldext. Frangul., U.S.P. Dose, i c.c., 15 minims. 

SENNA 

The effects are more extensive and more irritant than with the other 
drugs of the group, so that it is better suited for acute than for chronic 
constipation. There is considerable griping, which may be corrected 
by carminatives, or by the previous extraction of the resins with alcohol 
(as in the Fluidextract). 

PREPARATIONS SENNA 

* Senna (Senn.), U.S.P.; Senna Folia (Senn. Fol.), B.P.; Senna. The dried leaflets 
of Cassia acutifolia or angustifolia. Introduced by the Arabians. Constituents: 
senna-emodin, senna-isoemodin, senna-chrysophanic acid, and other anthraquinon 
derivatives, free and in glucosidal combinations (Tutin, 1913; Tambach, 1913). Dose, 
4 Gm., i dram, U.S.P., as cathartic; as laxative, i to 2 Gm., 15 to 30 gr., infused in a 
cup of hot water. Many of the laxative nostrums ("Castoria;" "Fig Syrup;" various 
"Teas") owe their activity mainly to senna. 

A preparation for hypodermic use is marketed as "Sennatin." Betke, 1914, 
claims good effects in postoperative ileus. 

Conf. Senn., B.P. 10 per cent, of powdered Senna. Dose, 4 to 8 Gm., i to 2 drams, 
B.P. 

Jnf. Senn., B.P. 10 per cent., with Ginger. Dose, 15 to 30 c.c., % to i ounce, 
repeated; single, 60 c.c., 2 ounces, B.P. 

Inf. Senn. Co., U.S.P. (Black Draught). Average dose, 120 c.c., 4 ounces, U.S.P., 
contains about 7 Gm. of Senna; 15 Gm. of Magnes. Sulph., with Manna and Fennel. 

Fldext. Senn., U.S.P. Dose, 2 c.c., 30 minims, U.S.P. 

Mist. Senn. Co., B.P. 25 per cent, of Magnes. Sulph. in Inf. Senn., with aromatics. 
Dose, 30 to 60 c.c., i to 2 ounces, B.P. 

* Syrupus Senna (Syr. Senn.), U.S.P. 25 per cent. Flavored with coriander. 
Dose, 4 c.c., i dram, U.S.P. 

* Syr. Senn., B.P. About 40 per cent., with coriander. Dose, 2 to 8 c.c., % to 2 
drams, B.P. 

Tr. Senn. Co., B.P. 20 per cent., with caraway and coriander. Dose, 2 to 4 c.c., 
^ to i dram, repeated; single, 8 to 15 c.c., 2 to 4 drams, B.P. 

* Pulvis GlycyrrhizcE Compositus (Pulv. Glycyrrh. Co.), U.S.P., B.P. (Compound 
Licorice Powder). Greenish-yellow to greenish-brown powder; odor of fennel. Aver- 
age dose, 4 Gm., i dram, U.S.P.; contains about 0.7 Gm. of Senna, 0.3 Gm. of Sulphur 
and a little Fennel pil. Dose, 4 to 8 Gm., i to 2 drams, B.P. 

Senna. Fructus (Senn. Fruct), B.P.; Senna pods. The dried ripe fruits of Cassia 
acutifolia or angustifolia. 

Cassia Fructus (Cass. Fruct.), B.P. The ripe fruits of Cassia Fistula. 



VEGETABLE CATHARTICS 169 

Cassia Pulpa (Cass. Pulp.), B.P.; Cassia Pulp. An evaporated watery extract of 
the preceding. 

RHUBARB 

This contains a considerable quantity of tannin as well as cathartic 
principles. The astringent action predominates with smaller doses 
(0.05 to 0.3 Gm.) and these are used as astringent bitter in gastric catarrh, 
and in diarrhea. Larger doses (i to 5 Gm.) are laxative with little colic. 
They may be employed in chronic constipation, but the astringent action 
makes it inferior to cascara. It may cause skin eruptions. 

Constituents (Tutin and Clewer, 1911). The cathartic principles are mainly a 
resin, non-glucosidal, but yielding on hydrolysis various anthraquinon derivatives, which 
also exist partly free: rhein, emodin, aloe-emodin, chrysophanic acid, etc. The astrin- 
gent principles are glucosidal compounds of tannin (rheotannic acid), and gallic acid. 
There is also a large amount of calcium oxalate. 

PREPARATIONS RHUBARB 

Rheum, U.S.P.; Rhei Rhiz., B.P.; Rhubarb. From Rheum officinale and probably 
other species growing in China and Thibet. (The species of Rhubarb cultivated in this 
country are devoid of cathartic properties.) Rhubarb has been used since antiquity 
in China, and by the Roman physicians. Dose, i Gm., 15 gr., U.S.P.; 0.2 to 0.6 Gm., 

3 to 10 gr., repeated; single, i to 2 Gm., 15 to 30 gr., B.P. 

Ext. Rltei., U.S.P., B.P. A powdered extract, i Gm. representing 2 Gm. of drug, 
U.S.P. Dose, 0.25 Gm., 4 gr., U.S.P.; 0.12 to 0.5 Gm., 2 to 8 gr., B.P. 

Fldext. Rhei, U.S.P. Dose, i c.c., 15 minims, U.S.P. 

Inf. Rhei, B.P. 5 per cent. Dose, 15 to 30 c.c., ^ to i ounce, B.P. 

Mist. Rhei et Soda, N.F. Sod. bicarb., 3.5 per cent.; Fluidext. Rhubarb, 1.5 per cent.; 
Fluidext. Ipecac, 0.3 per cent.; Sp. Peppermint, Glycerin, and Water. Dose, 4 c.c., i 
dram. 

Pil. Rhei Co., U.S.P. Each pill contains 0.13 Gm. of Rhubarb, o.oi Gm. of Aloes. 
Dose, two pills, U.S.P. 

Pil. Rhei Co., B.P. Pill-mass containing 25 per cent, of Rhubarb, 20 per cent, of 
Aloes, 14 per cent, of Myrrha. Dose, 0.25 to 0.5 Gm., 4 to 8 gr., B.P. 

Puh. Rhei. Co., U.S.P., B.P. 25 per cent, of Rhubarb, 65 per cent. Magn. Oxid., 
10 per cent, of Ginger, U.S.P.; the B.P. formula is almost the same. Dose, 2 Gm., 
30 gr., U.S.P.; 0.6 to 4 Gm., 10 to 60 gr., B.P. 

Syr. Rhei, U.S.P. 10 per cent, of Rhubarb; i per cent, of Pot. Carb.; flavored with 
Cinnamon. Dose, 10 c.c., 2^ drams, U.S.P. 

Syr. Rhei, B.P. 7 per cent., with Coriander. Dose, 2 to 8 c.c., ^ to 2 drams, B.P. 

* Syr. Rhei Aromaticus (Syr. Rhei Arom.), U.S.P.; Aromatic Syrup of Rhubarb. 
15 per cent, of Tr. Rhei Arom.; o.i per cent. Pot. Carb. Dose, 10 c.c., 2^ drams, U.S.P. 

Tr. Rhei, U.S.P. 20 per cent.; flavored with Cardamon. Dose, 4 c.c., i dram, 
U.S.P. 

* Tinctura Rhei Aromatica (Tr. Rhei Arom.), U.S.P. 20 per cent, flavored with 
Cinnamon, Clove and Nutmeg. Dose, 2 c.c., 30 min., U.S.P. 

* Tinctura Rhei Composita (Tr. Rhei Co.), B.P. 10 per cent.; flavored with Carda- 
mon and Coriander. Dose, 2 to 4 c.c., 3^ to i dram, repeated; single, 8 to 16 c.c., 2 to 

4 drams, B.P. 

ALOES 

General Statement. The inspissated juice of the leaves of various 
species of Aloe from the West Indies, Africa, etc., furnishes the different 
commercial varieties of aloes, which differ somewhat in composition and 
action. They contain anthraquinon derivatives, especially aloins (10 
to 1 6 per cent.). These are glucosids which are probably inactive them- 
selves ; but which yield emodin and other active anthraquinon derivatives 
on cleavage. This cleavage occurs in the intestine ; it is favored by alkalies 
and perhaps also by bile and by iron salts. Aloin may be used as such, 



170 MANUAL OF PHARMACOLOGY 

but is generally considered less satisfactory than aloes. Aloe is intensely 
bitter, so that it must be administered in pills. Very small doses may be 
used as stomachic. Moderate doses are simply laxative, but somewhat 
apt to gripe, and are therefore commonly combined with belladonna or 
carminatives (myrrh, etc.). They do not lose their efficiency on contin- 
ued use and would be suited to habitual constipation, but have no 
advantage over cascara. Aloes are believed to produce considerable 
congestion of the pelvic organs and are therefore contraindicated in 
hemorrhoids, menstruation and pregnancy. On the other hand, they 
may be used as emmenagogues. They are especially valuable for correct- 
ing the constipative action of iron medication. 

Hypodermic Administration. Aloin is also effective subcutaneously, being excreted 
into the large intestine; but this method is too painful (H. Meyer, 1890). 

Aloin Nephritis. In rabbits, hypodermic injection (2 c.c. per kilogram of 5 per cent., 
repeated on two to three successive days) produces a tubular nephritis. The anatomic 
lesions have been investigated especially by Miirset (1885); they are practically the 
same in acute and chronic poisoning, and consist mainly in degeneration of the epithe- 
lium of the convoluted tubules. This loses its striations and staining qualities, and the 
nuclei disappear. The glomerular epithelium is but slightly altered, and the glomerular 
vessels show no lesions. The urine may be increased or diminished and contains pro- 
teins, leucocytes, casts, crystals, and blood. 

Metabolism. There is also an increased protein metabolism, resulting in rise of 
urea in mammals, of uric acid in birds. The latter may therefore develop gout. Dogs 
show some fever (Berrar, 1913). 



PREPARATIONS ALOES 

* Aloes, U.S. P., B.P.; Aloes. The dried juice of the leaves of Aloe species: Aloe 
Perryi, yielding Socotrine Aloes; Aloe vera, yielding Curacoa Aloes; Aloe ferox, yielding 
Cape Aloes (Natural history of the commercial aloes, Wilbert, 1903). Aloe was used 
by the Greeks and probably by the Egyptians. Brown, opaque, glassy masses; aromatic 
odor; nauseous bitter taste. Parti}' sol. in water; completely sol. in ale. Dose, 0.25 
Gm., 4 gr., U.S. P.; 0.12 to 0.3 Gm., 2 to 5 gr., B.P.; best as pills. 

Dec. Aloes Co., B.P. i per cent, of Ext. Aloes, with Myrrh, Aromatics and Liquorice. 
Dose, 15 to 60 c.c., % to 2 ounces. 

Ext. Aloes, B.P. A powdered watery extract. Dose, 0.06 to 0.25 Gm., i to 4 gr., 
B.P. 

Pil. Aloes, U.S.P. 0.13 Gm., 2 gr. of Aloes, with Soap. Dose, two pills, U.S. P. 

Pil. Aloes, B.P. 58 per cent., with ^Soap and Caraway Oil. Dose, 0.25 to 0.5 Gm., 
4 to 8 gr., B.P. 

Pil. Aloes et Asafet., B.P. 20 per cent., each, of Aloes, Asafet., and Soap. Dose, 
0.25 to 0.5 Gm., 4 to 8 gr., B.P. 

(Pil. Aloes et Ferr., see Index.) 

Pil. Aloes et Myrrh., B.P. 44 per cent, of Aloes, 22 per cent, of Myrrh. Dose, 
0.25 to 0.5 Gm., 4 to 8 gr., B.P. 

Tr. Aloes, U.S.P. 10 per cent, of Aloes, with Glycyrrhiza. Dose, 2 c.c., 30 minims, 
U.S.P. 

* Aloinum (Aloin.), U.S.P., B.P.; Aloin. A pentosid or mixture of pentosids 
obtained from aloes (usually from Curacoa, W. Hills, 1908), varying in chemical 
composition, physical and chemical properties according to the source. A yellow 
microcrystalline powder, practically odorless, intensely bitter taste. Sol. in water and 
ale. Dose, 0.015 Gm., % gr., U.S.P.; 0.03 to 0.12 Gm., % to 2 gr., B.P. 

Pil. Aloin. Bellad. et Strychn. (Pil. Laxativas Co., U.S.P. VIII). Each contains: 
Aloin, 13 mg. (^ gr.); Strychnin, 0.5 mg. (^28 gr.); Ext. Belladonn., 8 mg. (K S r -); 
Ipecac, 4 mg. (^" 6 gr.). Dose, Two pills. 

Nataloin. This differs from the other aloins in composition, and is more difficultly 
hydrolyzed (H. Meyer). 

Synthetic anthracen derivatives with laxative action have been prepared, but have 
little practical importance (purgatin, anthrapurpurin diacetate; exodin, methyl esters 
of diacetyl-hexaoxy-anthraquinon) . 



VEGETABLE CATHARTICS 1 71 

PHENOLPHTHALEIN 

This is a mild tasteless purgative, acting probably on the large intestine. 
It is but little absorbed from the alimentary canal, and is ordinarily non- 
toxic even in large doses. It may be used in habitual constipation, 
and has been exploited under several proprietary names (purgen, laxans, 
etc.). Phenoltetrachlorphthalein, 0.4 Gm. dissolved in 20 c.c. of neutral 
olive oil, has been suggested as a subcutaneous purgative (Abel and 
Rowntree, 1909; Rowntree, 1910). Phenolsulphonephthalein is used to 
test the excretory efficiency of the kidneys (Abel and Rowntree, 1909; 
Rowntree and Geraghty, 1910; Chesney, Marshall and Rowntree, 1914). 

Action. The purgative effect of this familiar indicator was discovered by v. Vamossy, 
1900. It appears to be connected with the quinon structure. It has been investigated 
experimentally by v. Vamossy, 1902; Tunnicliffe, 1902; Fleig, 1908; Abel and Rown- 
tree, 1909, etc.; and clinically by Dornblueth, 1903, and many others. Animals are 
rather less susceptible than man. Ott and Scott, 1908, found evidence that it acts 
directly on the muscle of the excised intestine. (Fleig and others attribute the action 
to increased intestinal secretion, but the evidence is not satisfactory.) It acts also on 
hypodermic or intravenous administration, reaching the intestine through the bile. 
The blood pressure is scarcely affected, even when large doses are injected into a vein 
(Tunnicliffe; Abel and Rowntree, etc.); the kidneys are not irritated, nor are there any 
other systemic effects. Phenolphthalein itself does not produce local irritation, but 
its soluble salts are highly irritant. It is not bactericidal (Abel and Rowntree). 

Absorption, Fate and Excretion. Phenolphthalein is insoluble in acids, but gives a 
pink solution with alkalies. It passes the stomach unchanged. It is partially dis- 
solved in the alkaline intestine, but very little is absorbed, almost the entire quantity 
(over 85 per cent.) appearing unchanged in the feces (Vamossy). After large doses, 
traces are found in the urine (Fleig; Elmer, 1909), which is then colored violet-red by 
alkalies (Gruebler, 1906). 

After hypodermic administration, it is excreted by the urine, feces, saliva, tears, 
etc. The excretion is very rapid, beginning within fifteen minutes and ending in 
twelve to eighteen hours. In the urine it exists partly free, partly conjugated. The 
body-fluids dissolve it more readily than water (Fleig). It is excreted into the intestine 
mainly by the bile, and is to some extent reabsorbed in the large intestine (Abel and 
Rowntree). (The fate of the phthaleins is also discussed by Kastle, 1906.) 

Toxic Effects. Only a few doubtful cases are on record (Holz, 1905; Best, 1906; 
Zabel, 1911; Orland, 1913, etc.). These presented phenomena of intestinal irritation, 
always ending in recovery. Hydrick, 1914, claims that even 0.05 to 0.15 Gm. produce 
quite constantly a slight albuminuria, lasting one to three days. On the other hand, 
very large doses have often been given without bad effects: to man, several grams by 
mouth, 0.5 Gm. subcutaneously; to dogs, 1.25 Gm. per kilogram. 

Administration. Phenolphthalein may be taken in the evening, as 
powder, capsules, or lozenges, in doses of o.i to 0.2 Gm., i^ to 3 gr.; for 
bed-ridden patients, 0.5 Gm., 8 gr.; for children, 0.03 Gm., Y^ gr. These 
smaller doses soften and regulate the stools for several days, with little 
or no colic. Large doses are hydragogue. 

PREPARATIONS PHENOLPHTHALEIN 

* Phenol phthaleinum (Phenolphthal.), U.S.P., B.P.; Phenolphthalein (Dihydroxy- 
phthalophenone), (C6H 4 OH) 2 CO.C6H4CO. White crystalline powder, odorless and 
tasteless. Almost insol. in water, sol. in ale. (1:13). Dose, 0.15 Gm., 2^ gr., U.S. P.; 
0.12 to 0.3 Gm., 2 to 5 gr., B.P. 

Phenolsulphonephthalein, N.N.R. The preceding, with CO replaced by SO 2 . Dose, 
6 mg., as test of kidney function (for details, see X.N.R.). 

BILE 

The administration of bile or bile salts ^sodium glycocholate and tau- 
rocholate) stimulates the secretion of bile (Pfaff and Balch, 1897), increases 



172 MANUAL OF PHARMACOLOGY 

peristalsis (Stadelmann, 1896); acts as antiseptic (Limbourg), and facili- 
tates the digestion of fat. They have been advocated in obstructive 
jaundice and in biliary fistulas; but their effects are not very pronounced. 
Added to enemas, bile is used as a laxative against impacted feces and 
against ascaris, but has little advantage over soap. 

Peristalsis. On excised small intestines, or large, bile or bile salts produce mainly 
depression (Ott and Scott, 1909; d'Errico, 1910); but the large intestines may be stim- 
ulated (Schuepbach, 1910). In man, evacuation is assured especially by enemas, but 
also by oral administration (Glaessner and Singer, 1910). 

Excised Uterus. Bile and bile salts, in moderate concentrations, increase the con- 
tractions of the pregnant, not of the virgin uterus. High concentrations inhibit (Can- 
toni, 1914). 

Toxic Actions. Bile is non-toxic by mouth, but when injected into the circulation 
(Meltzer and Salant, 1905, 1906; Bunting and Brown, 1911) it produces severe nervous 
and cardiac depression (Brandenburg, 1903; Glur, 1909) and hemolysis. It is also 
directly toxic to muscle and nerve. J. H. King and H. A. Stewart claim that the pig- 
ments are mainly responsible for the circulatory effects. However, bile-acids are highly 
toxic. Small doses stimulate the vagus center; larger doses depress the heart directly, 
with slow irregular pulse and low blood pressure. They also produce depression of the 
medullary centers, coma and paralysis; and hemolysis and cell destruction. 

Bile Salts in Gonorrhea. Loehlein, 1909, introduced the local injection of bile 
salts in the acute stage for destroying the gonococci. V. Hofmann, 1912, found that i 
to 2 per cent, had little effect; 5 to 10 per cent, gave better but only temporary results- 
These were improved by following with silver injections, or by using a soluble silver- 
bile acid compound. 

PREPARATIONS BILE 

Pel Boms, U.S.P.; Oxgall. The fresh bile of Bos taurus. 

Pel Bovimtm Purificatum (Fel Bov. Pur.), B.P.; Purified Ox Bile. An evaporated 
alcoholic extract. Dose, 0.3 to i Gm., 5 to 15 gr., B.P.; as enema, 1:50. 

* Extractum Fellis Bovis (Ext. Fel. Bov.) U.S.P.; Extract of Oxgall (Purified Oxgall). 
An alcoholic extract of bile, evaporated and mixed with starch; i Gm. representing 
8 Gm. of Oxgall. Very bitter yellow powder. Dose, o.i Gm., i% gr., U.S. P., in pills 
or formaldehyd-hardened capsules. As enama 2%. 

Bile Sails, N.X.R. The various commercial preparations are used as pills, generally 
0.05 to 0.5 Gm., % to i gr.; or better as suppositories, in the same dosage. 

CASTOR OIL 

This consists mainly of the triglycerid of an unsaturated fatty acid, 
Ricinoleic acid. The neutral fat is not active, but becomes so when it is 
saponified in the intestine. The cathartic effect is due mainly to motor 
stimulation of the small intestine. The intestinal secretion is not in- 
creased, the fluid character of the stools being due to the quicker passage 
of the feces. 

With the usual dose, ^ to i ounce, the response is certain and complete, 
resulting in a few hours in one or two extensive semifluid stools, with but 
little hyperemia or irritation, there being little or no colic. The evacua- 
tion is so complete that there may be some after-constipation. It is es- 
pecially suited to the treatment of acute constipation or acute diarrhea 
from dietetic errors, ptomain and other poisoning, etc. It is less useful 
for continuous use, since this may produce gastric disturbance. There is 
some pelvic congestion, so that it is avoided during menstruation and 
pregnancy. 

Mechanism of Action. This has been studied with x-ray by Magnus, 1908, and his 
observations have been confirmed on man. The pure oil delays slightly the passage 
through the stomach (as do other neutral oils). Rancid oil hastens the gastric expulsion. 
In the small intestine, the segmenting movements and peristalsis are greatly increased, 



VEGETABLE CATHARTICS 173 

so that the expulsion may be completed in two hours instead of the normal eight hours. 
In the colon, the normal antiperistalsis is allayed, so that the feces escape concentration. 
The propulsive movements of the colon are not much increased, but the passage of the 
fecal material is hastened by its thinner consistency. 

In China it Is used as an article of diet. The properties of Castor Oil were known 
to Herodotus; but Croton Seeds were first described in the middle of the sixteenth century. 

Administration. It is best given on an empty stomach an hour before breakfast. 
The taste may be somewhat disguised by wetting the mouth with hot coffee or milk, 
and giving the oil floating in these liquids, so that it will not be so adherent. The 
after-taste may be mitigated by peppermint or bread. It is sometimes preferred in 
emulsions: N.F., 33 per cent.; B.P. (Mistura), 40 per cent., flavored with orange flower 
and cinnamon. The soft gelatin capsules are the only tasteless method; but since the 
ordinary size contains only i c.c., it is difficult to administer an effective dose. (For 
other methods, see J.A.MA., 60:1174.) 

PREPARATIONS CASTOR OIL 

* Oleum Ricini (Ol. Ricin.), U. S. P.; Castor Oil. A fixed oil expressed from the 
seed of Ricinus communis. An almost colorless viscid oil, of faint but characteristic 
odor and taste, extremely disagreeable to many persons. Sol. in an equal volume of 
ale. Dose, 15 c.c., 4 drams, U.S. P.; 4 to 30 c.c., i to 8 drams, B.P.; for infants, a 
teaspoonful. Also used as hair tonic, diluted with i to 10 vol. of alcohol. 

Mist. Ol. Ricin, B.P. A 37.5 per cent, emulsion. Dose, 30 to 60 cc., i to 2 
ounces, B.P 

RICIN 

Occurrence, Clinical Symptoms and Treatment. This toxin is contained in the 
castor seeds, but does not pass into the oil. Similar phyto-toxins occur in croton seeds 
(Crotin) ; and in jequirity seeds (Abrin) ; in the bark of the locust tree, Robinia pseud- 
acacia (Robin); and in the seeds of some leguminous plants (Phasin). The last is 
but weakly toxic (Review of Literature, Ford, 1913). The ricin is responsible for the 
toxic effects on eating the castor seeds; five or six of these are fatal to a child, twenty to 
adults; three or four seeds may cause violent gastroenteritis, with nausea, headache, 
persistent vomiting, colic, sometimes bloody diarrhea, thirst, emaciation, and great 
debility. The symptoms usually do not set in until after several days. More severe 
intoxications cause small frequent pulse, cold sweat, icterus, and convulsions. Death 
occurs in six to eight days, from the convulsions or from exhaustion. The fatality is 
about 6 per cent. This small fatality is due to the destruction of the poison in the 
alimentary canal. The treatment would be evacuant and symptomatic. Three to 
ten days are required to complete recovery (Critical Review and Bibliography, Ford, 



Effects on Animals. The actions can be best studied on rabbits, by hypodermic or 
intravenous injections. Even with the latter, there is an incubation period of at least 
twelve to eighteen hours before symptoms appear. These correspond to those de- 
scribed for man. They are partly local gastroenteritis; and partly central paralysis 
of the respiratory and vasomotor centers. The local inflammation also occurs on 
other mucous membranes to which the poison may be applied, especially the conjunctiva. 

The autopsy findings are very characteristic. They consist in swelling and reddening 
of Peyer's Patches and mesenteric lymph glands, internal hemorrhages and diffuse neph- 
ritis. Cruz, Flexner, Mueller and others have shown that these lesions are not due to 
thrombosis, but to direct action on the tissues. The site of the injection is boggy. 

Frogs have a much higher resistance than mammals; but this is weakened by 
their temperature. The phytotoxins have no direct effect on muscle or nerve. 

Action on Blood. In vitro, ricin hemolyzes and agglutinates the corpuscles of nearly 
all warm-blooded animals (Stillmark, 1888). The agglutination does not seem to occur 
in the body, but is of great importance as an immunity phenomenon. Leucocytes, 
epithelial and other cells (except those with thick membranes, as yeast) are also ag- 
glutinated; as likewise the stroma of laked corpuscles (Elfstrand). The presence of 
serum hinders the effect. 

The agglutination has been referred to precipitation of the nucleoalbumins (Stassano) 
or other proteins, such as those of serum (Kraus, 1902). All kinds of colloid precipitates 
carry down ricin, and it is adsorbed by solid proteins and lipoids. 

Nature of Ricin. This appears to be a true protein; for a preparation of ricin has 
been obtained, which is a typical albumin, and which is so active that 0.0005 mg. is 
fatal to a kilogram of rabbit; i.e., i part of the ricin is fatal to 2,000,000 parts of rabbit; 



174 MANUAL OF PHARMACOLOGY 

the fatal dose for man would therefore be about 0.035 mg., or 1/2,000 grain (Osborne, 
Mendel and Harris, 1905; Osborne, 1909). The agglutinating action is also very 
powerful. 

The attempt is also being made to separate the agglutinin (which is adsorbed by 
blood corpuscles) from the cytotoxin, which is destroyed by peptic digestion. Jacoby, 
1902, believes that they have certain groups in common. 

Antiricin. Injections of the phytotoxins produce typical antitoxins, so that an 
immunized animal can survive 5,000 ordinary fatal doses of ricin. Some of the basic 
work of Ehrlich was done with ricin and abrin. He showed (1891) that the immunity 
starts in five to six days, and lasts six or seven months. The resistance of the corpuscles 
is unchanged, the antiricin being contained in the pseudoglobulin fraction of the serum 
(Jacoby, 1902). It contains antitoxin, antiagglutinin (probably identical) and precipi- 
tin. Madsac and Walbum found that this combination obeys the same laws as diphtheria 
antitoxin. The toxicity of ricin is modified rather complexly by lecithin (Lawrow, 1913). 

ABRIN AND JEQUHUTY 

Abrin, a toxalbumin from Jequirity bean (abrus precatorius), resembles ricin so 
closely in its action that the difference was established only when it was noticed that 
immunity against one did not constitute immunity against the other. Hausmann, 
1902, has studied it by the methods of Jacoby. The literature was reviewed by Ford, 



Poisoning. When the whole beans are swallowed, no toxic effects result, since the 
shell is so hard that the poison does not dissolve. But if the powder is taken, it pro- 
duces effects similar to ricin. Its toxicity is greatly increased by heating the animals 
(Lesne and Dreyfus, 1913). 

Use hi Ophthalmology. The action on the eye is much stronger than with ricin, 
producing ophthalmitis. This has been used therapeutically (Weeker, 1882), to clear 
corneal opacities. This is dangerous, unless standardized preparations are used, and 
excessive effects checked bv an antiserum. 

CATHARTIC RESINS 

General Statement. Jalap, Colocynth, Podophyllum, Elaterin and 
similar drugs contain active principles which are for the most part resinous 
(i.e., soluble in alcohol, but slightly soluble in water), often glucosids; 
on chemic manipulation (probably hydration) these yield resinous acids. 
The latter are much less active. 

The effects of these resins are highly irritant, producing considerable 
colic (sometimes vomiting), and several watery stools, in one or two 
hours with jalap and most of the others; but with podophyllum only after 
twelve to twenty-four hours. They are used especially in dropsies 
(Compound Jalap Powder); small doses of podophyllum also as laxative 
in habitual constipation. The others tend ultimately to produce con- 
stipation. Colocynth, and presumably the others, stimulate peristalsis 
in the small intestine, inhibit antiperistalsis in the colon, and lead to 
the effusion of fluid from the whole intestinal canal. 

The resins require the presence of bile, presumably to secure their 
solution. They are therefore inactive in obstructive jaundice. They 
produce griping, and are therefore often prescribed with belladonna 
and aromatics. If they are not removed by catharsis, they may produce 
severe enteritis. 

The principles are not as effective when given pure as when they are mixed with some 
extractive, as in the crude drugs and "resins" (alcoholic extracts precipitated by water), 
or as preparations of the crude drug. This is due, in some cases, to their being some- 
what soluble, and therefore absorbed in the stomach. 

Subcutaneous Administration. This produces diarrhea with podophyllin and 
colocynthin, but is not available because it also produces nephritis, local irritation and 
abscesses. 



VEGETABLE CATHARTICS 175 

Mechanism of Action. This has been studied on colocynth by the X-ray method 
by Padtberg, 1909, under Magnus. Similar observations have been made with jalap 
on man: the gastric movements may be slightly increased but often remain normal. 
In the small intestine the peristalsis is so much quickened that the contents may be 
completely expelled in half an hour instead of the normal eight hours. This is ac- 
companied by the effusion of considerable fluid into the lumen. In the large intestine 
the propulsion is only slightly increased; but the stools are rendered still more liquid 
by the inhibition of antiperistalsis, and by the secretion of additional mucus. Padtberg, 
1911, found that the colocynth peristalsis and effusion are arrested by morphin and 
opium, although these do not ordinarily act directly on the intestine, but on the stomach. 

JALAP 

This is perhaps the mildest member of the group. It produces watery 
stools within three or four hours, with little intestinal irritation, without 
gastric disturbance or much prostration. It has little taste and is 
therefore easily administered. It is used in ascites, cerebral congestion, 
hypertension; and as adjuvant to anthelmintics. Scammony is closely 
related to jalap. 

Constituents. These have been studied by Power and Rogerson, 1909 and 1912. 
The "resin" is a complex substance, which can be separated by solvents into several 
glucosidal portions: Jalapin (convolvulin, jalapurgin) and Scammonin (orizabin). 

PREPARATIONS JALAP GROUP 

Jalapa U.S.P., B.P.; Jalap. The dried tuberous root of Exogonium purga. At 
least 7 per cent, of resin, U.S. P.; 10 per cent., B.P. Dose, i Gm., 15 gr., U.S.P.; 0.3 
to 1.2 Gm., 5 to 20 gr., B.P. 

* Pulvis Jalapa Composilus (Pulv. Jalap. Co.), U.S. P., B.P., Compound Jalap 
Powder. i part of Jalap, 2 parts Pot. Bitart. (flavored with Ginger, B.P.). Dose, 
2 Gm., 30 gr., U.S.P.; 0.6 to 4 Gm., 10 to 60 gr., B.P., stirred into water. 

Tr. Jalap., B.P. 1.5 per cent, of resin. Dose, 2 to 4 c.c., % to i dram, B.P. 

Tr. Jalap. Co., B.P. 8 per cent, of Jalap, 1.5 per cent. Scammon. Res., i per cent. 
Turpeth. Dose, 2 to 4 c.c., K to i dram, B.P. 

Resina Jalapa (Res. Jalap.), U.S. P.; Jalap. Res., B.P. Prepared by precipitating 
an alcoholic extract of Jalap with water. Dose, 0.125 Gm., 2 gr., U.S. P.; 0.12 to 0.3 
Gm., 2 to 5 gr., B.P. Maximum dose, i Gm., 15 gr. 

Scammonii Radix (Scam. Rad.), U.S.P.; Scammon. Rod., B.P.; Scammony Root. 
The dried root of Convolvulus Scammonia, yielding not less than 85% of resins. Used by 
the ancients. The constituents are similar to Jalap. They have been investigated by 
Power and Rogerson, 1912. Dose, 0.25 Gm., 4 gr., U.S. P. 

Pulv. Scammon. Co., B.P. Scammon. Res., 50; Jalap., 35; Ginger, 15. Dose, 
0.6 to 1.2 Gm., 10 to 20 gr., B.P. 

Res. Scamm., U.S.P., Scammon. Res., B.P. Prepared by precipitating an alcoholic 
solution with water. Dose, 0.2 Gm., 3 gr., U.S. P.; 0.25 to 0.6 Gm., 4 to 8 gr., B.P. 

Ipom<K(B Radix (Ipom. Rad.), B.P.; Orizaba Jalap Root (Mexican Scammony 
Root). The dried root of Ipomceas orizabensis. 

Kaladana, B.P. (Pharbitis Seeds). The dried seeds of Ipomcea hederacea. Dose, 
2 to 3 Gm., 30 to 45 gr., B.P. 

Pulv. Kalad. Co., B.P. Similar to Pulv. Jalap. Co. Dose, 0.6 to 4 Gm., 10 to 60 
gr., B.P. 

Tr. Kalad., B.P. 20 per cent. Dose, 2 to 4 c.c., > to i dram, B.P. 

Kalad. Res., B.P. Dose, 0.12 to 0.5 Gm., 2 to 8 gr., B.P. 

Tiirpethum, B.P.; Turpeth. The dried root and stem of Ipomrea Turpethum. 
Dose, 0.3 to 1.2 Gm., 5 to 20 gr., B.P. 

RESIN OF PODOPHYLLUM 

This acts very slowly, generally only after twelve to twenty-four hours 
or longer, producing several soft stools. Larger doses (20 mg., % gr. or 
more) act as a hydragogue cathartic; but it is chiefly employed in small 



176 MANUAL OF PHARMACOLOGY 

doses (5 to 10 nig., Ho to ^ gr) as a laxative in chronic constipation, often 
combined with aloes or calomel. 0.3 to 0.5 Gm. has been fatal. 

PREPARATIONS PODOPHYLLUM 

Podophyllum, U.S.P., Podoph. Rhiz., B.P.; Podophyllum (Mandrake, May Apple 
Root). The dried rhizome and roots of Podophyllum peltatum (yielding not less than 
3 per cent, of resin, U.S. P.). Active constituents, resin and a crystalline principle, 
podophylo toxin. Podophyllum was used by the Indians. 

Fldext. Podoph., U.S.P. Dose, 0.5 c.c., 8 minims, U.S.P. 

Tr. Podoph., B.P. 3.65 per cent, of resin. Dose, 0.3 to i c.c., 5 to 15 minims, B.P. 

* Resina Podophylli (Res. Podoph.), U.S.P.; Podoph. Res., B.P.; Resin of Podophyl- 
lum (Podophyllin). Prepared by precipitating an alcoholic extract of Podophyllum 
with acidulated water. Amorphous greenish-yellow powder, of slight peculiar odor and 
faintly bitter taste. Very irritating to mucous membranes, especially of the eyes. 
Sol. in ale. A very similar resin is prepared from the East Indian species P. Emodi 
(literature, Scoville, 1909). Dose, 10 mg., }/ gr., U.S. P.; 16 to 60 mg., ^ to i gr., B.P.; 
as pill. Maximum dose, o.i Gm., ij^ gr. 

Podoph. Ind. Rhiz., B.P. The dried rhizome and roots of Podophyllum Emodi. 
Corresponds practically to Podophyllum, also in the strength and dose of its preparations. 

Tr. Podoph. Ind., B.P. 

Podoph. Ind. Res., B.P. 

Stillingia, U.S.P. (Queen's Root). The dried roots of Stillingia sylvatica. Contains 
pungent resin and volatile oil. Used mainly in domestic medicine in purgative mixtures, 
also as nauseant and emetic. Dose, 2 Gm., 30 gr., U.S.P. 

Fldext. Stilling., U.S.P. Dose, 2 c.c., 30 minims, U.S.P. 

Leptandra (Culver's Root). The rhizome and roots of Veronica Virginica. Con- 
tains an amorphous bitter principle, and not a crystalline glucosid, as formerly reported 
(Power and Rogerson, 1910). "Leptandrin" is a resinoid. The preparations are 
pharmacologically inert, but were supposed to be cholagogue without producing intes- 
tinal irritation. Dose, i Gm., 15 gr. 

Juglans (Butternut). The root bark of Juglans cinerea, collected in autumn. 
Used as rather mild laxative. Dose of extract, i to 2 Gm., 15 to 30 gr. 

Iris (Blue Flag). The rhizome and roots of Iris versicolor. Power and Salway, 
1911, could not find any active principle, although the drug and the resinoid "iridin" 
were formerly considered cathartic and diuretic. Dose, i Gm., 15 gr. 

Iridis Rhizoma (Orris Root). The rhizome from several cultivated species of iris, 
has a violet odor. It is used in sachets and tooth powders. 

COLOCYNTH, ELATERIN AND BRYONIA 

A number of plants of the cucumber family (Cucurbitaceae) yield these 
drastic drugs. They are of complex composition, each containing several 
active principles, resinous and alkaloidal. They produce continuous 
watery stools, with intense irritation and hyperemia (mechanism described 
above). They are less used than formerly, when they were frequently 
employed to reinforce the action of other purgatives as in the Compound 
Cathartic Pills. Colocynth is excreted by the kidneys and milk, and 
should therefore not be used by nursing women. Elaterin is one of the 
most powerful cathartics, sometimes used in uremia. Large doses cause 
dangerous prostration. 

The toxic dose of Colycynth is 0.6 to i Gm.; fatal, 4 Gm. Of elaterin, the toxic 
dose is 5 mg.; fatal, 0.6 Gm. 

PREPARATIONS COLOCYNTH, ETC. 

Bryonia. The root of Bryonia alba and dioica. Bryonin and Bryonidin are com- 
plex mixtures. The purgative action is due to npn-giucosidai resins and alkaloids 
(Power, 1912). Dose, 0.6 to 4.0 Gm. (10 to 60 grains). 

Cambogia, U.S.P.; Gamboge. A gum-resin obtained from Garcinia Hanburii. 
The resin (70 to 80 per cent.) contains garanolic acids, which form readily soluble com- 



VEGETABLE CATHARTICS ifj 

pounds with alkalies, and thus become active in the intestine. The effects resemble 
those of colocynth; 4 Gm. are fatal. It is rarely used, in pills. Dose, 0.125 Gm., 2 
gr., U.S.P., 0.03 to 0.25 Gm., B.P. 

Colocynthis, U.S.P.; Colocynlhidis Pulpa (Colocyn. Pulp.), B.P.; Colocynth (Bitter 
Apple). The dried pulp of the fruit of Citrullus Colocynthis. The action is due to at 
least two constituents, an alkaloid and a resin. Colocynthin and colocynthidin are 
merely impure mixtures (Power and Moore, 1910). Dose, 0.06 Gm., i gr., U.S. P., 
in pills. Maximum dose, 0.4 Gm., 6 gr. 

Ext. Colocyn., U.S. P. A powdered extract, i Gm. representing 4 Gm. of drug. 
Dose, 0.03 Gm., J^ gr., U.S.P. Maximum dose, 0.06 Gm., i gr. 

Ext. Colocyn. Co., U.S.P. Ext. Colocyn., 16 per cent.; Aloes, 50 per cent.; Scammon. 
Res., 14 per cent.; Cardamon, 5 per cent. Dose, 0.25 Gm., 4 gr., U.S.P. 

Ext. Colocyn. Co., B.P. A dry extract from Colocynth, Aloes, Scammony and Car- 
damon. Dose, 0.12 to 0.5 Gm., 2 to 8 gr., B.P. 

Pit. Colocyn. Co., B.P. Colocynth, 20 per cent.; Aloes, 35 per cent.; Scammon. 
Res., 35 per cent. Dose, 0.25 to 0.5 Gm., 4 to 8 gr., B.P. 

PH. Colocyn. et Hyoscy., B.P. Pil. Colocyn. Co., 2; Ext. Hyoscy., i. Dose, 0.2 
to 0.5 Gm., 4 to 8 gr., B.P. 

Pilulee Cathartica Composites (Pil. Cathart. Co.), U.S.P.; Compound Cathartic 
Pills. Each pill contains: Comp. Ext. Colocynth, 0.08 Gm.; Calomel, 0.06 Gm.; Jalap 
Resin, 0.02 Gm.; Gamboge, 0.015 Gm.; a total of seven active ingredients. Dose, 
two pills, U.S.P. 

* Elaterinum (Elaterin.), U.S.P.; Elaterin. A neutral principle obtained from Ela- 
terium, a substance deposited by the juice of the fruit of Ecballium Elaterium (a sub- 
stance used in antiquity). White, hexagonal scales or prismatic crystals; odorless, and 
having a slightly acrid, bitter taste. Insol. in water; slightly sol. in ale. (1:325). 
Dose, 3 to 6 mg., ^ to ^{Q g r - repeated in five hours if necessary, but not daily (U.S.P., 
3 mg., ^20 gr.). The dose of elaterium is 6 to 30 mg., % to ^ gr. 

Elaterin consists of two crystalline substances, the levorotary a-elaterin, which is 
inert; and 60 to 80 per cent, of the active dextrorotary /3-elaJerin. Commercial elaterin 
varies in composition and activity (Power, 1912). Elaterin does not exist as such in 
the fruit, but is formed during the expression by a diastatic ferment, acting on a gluco- 
sid (Berg, 1909). 

Davis, 1913, advises elaterium in hepatic cirrhosis to provoke watery stools (5 to 
15 mg. at night; first day, two or three doses). This rarely causes nausea or pain, but 
may act during the night. 

Trit. Elaterin., U.S.P. 10 per cent. Dose, 0.03 Gm., % gr., U.S.P. 

CROTON OIL 

This contains, besides ordinary fats, about 10 per cent, of "croton- 
resin," the active component (Dunstan and Boole, 1895). The old 
"crotonolic acid" was an impure mixture of this resin with inactive fatty 
acids. The resin produces the local and systemic effects of the oil (Robert 
and Hirscheydt, 1890; Boehm, 1915). It is destroyed by boiling with 
alkalies. 

Croton oil is the strongest of all cathartics, 3^ to i drop producing 
burning in the mouth and stomach, often vomiting, and after one-half to 
three hours, several extensive fluid evacuations, with much colic and tenes- 
mus. It is used only in extreme cases of constipation (lead), and in un- 
conscious patients (uremic and apoplectic coma). It should not be given 
to weak patients, nor if the gastro-intestinal canal is inflamed. Toxic 
doses produce collapse. Twenty drops have been fatal, but recovery is 
said to have followed J^ ounce presumably because of vomiting. The 
treatment would be evacuant, demulcent, opiates and symptomatic 
(directed against the enteritis and collapse). 

Applied externally, croton oil produces irritation, proceeding to pustulation and 
even sloughing. When diluted with 2 to 10 parts of olive oil, it may be used as counter- 
irritant. 



178 MANUAL OF PHARMACOLOGY 

PREPARATIONS CROTON OIL 

* Oleum TigliL, U.S.P.; Oleum Crolonis (Ol. Croton.), B.P.; Croton Oil. A fixed 
oil expressed from the seeds of Croton Tiglium. A pale yellow or brownish-yellow, 
somewhat viscid and slightly fluorescent liquid, having a slight, fatty odor. Slightly 
sol. in ale. Dose, 0.05 c.c., i minim, U.S. P.; 0.03 to 0.06 c.c., % to i minim, B.P.; 
on a lump of sugar, slice of bread or lemon. With unconscious patients, a small drop 
may be placed at the back of the tongue, and repeated every hour to three doses. 
Maximum dose, 0.05 c.c., i minim. 

Lin. Croton., B.P. 12 per cent., in equal volume, of Ol. Cajup. and alcohol. Pro- 
duces severe inflammation. 

COLLOID AND EMOLLIENT LAXATIVES 

These act mainly by retaining water in the intestine through imbibi- 
tion, and thus modifying the bulk and consistency of the feces, so that 
these are more easily expelled. They are useful in habitual constipation, 
especially if aided by the occasional administration of cascara. A gar is 
typical of this class. In fruits (prunes, grapes, tamarinds, etc.) this colloid 
action is supported by the organic acids and sugars. Manna acts through 
its difficultly absorbable sugar, the action being largely osmotic. Petro- 
latum is not absorbed and therefore softens and lubricates the feces. Olive 
oil, in so far as it escapes digestion and absorption, acts in the same manner. 

Agar-agar. This is prepared from various Japanese marine algae. It consists 
mainly of the hemicellulose "gelose," which gelatinizes with water. It is tasteless 
and has been used for culinary jellies, but is not digested (8 to 27 per cent, is utilized 
in man; Saiki, 1906; Swartz, 1911; herbivorae utilize about 50 per cent.; Lohrisch, 
1908). It was introduced as a laxative by A. Schmidt, 1905. J. L. Morse, 1910, 
advises the chopped shreds, % to i ounce for adults; i or 2 teaspoons for children; part 
with the breakfast cereal, part with sauce or cream at another meal. For children, 
it may be boiled with oatmeal, or made into a jelly (i : 200 boiling water). It is not very 
effective, and usually requires the addition of cascara or phenolphthalein (Bastedo, 1914). 

PREPARATIONS AGAR, ETC. 

A gar, U.S. P.; Agar-agar. The dried mucilaginous substance extracted from 
marine algae growing along the eastern coast of Asia. Thin, translucent, membranous, 
agglutinated pieces, yellowish-white or brownish- white; odor slight; taste mucilaginous. 
Dose, 10 Gm., 2^ drams, U.S.P. 

Manna, U.S. P.- The dried saccharine exudation of an Ash-tree, Fraxinus Ornus. 
Contains mannit, about 90 per cent. Dose, 15 Gm., 4 drams, U.S. P., to 60 Gm., 2 
ounces, as infusion. 

Tamarindus, B.P.; Tamarind. The fruit of Tamarindus indicus. It owes its ac- 
tivity to organic acids, especially citric. It is used as a laxative, in doses of 4 to 30 Gm. 
(i to 8 drams). 

EVACUANT ENEMAS 

Rectal injections or clysters increase the peristalsis of the large and 
small intestines in response to the mechanical stimulation. The effect 
is enhanced by the addition of irritants. 

Enemata have an advantage over cathartics taken by mouth, 
in that they may be made absolutely non-irritant, and may therefore 
be used in conditions in which the other cathartics are positively contra- 
indicated. If the purpose of the enema be merely to soften hardened 
scybala, they would be used warm, in copious quantities, preferably 
with soap; or as decoctions of mucilaginous substances. 

To secure the maximum motor effect, the injection must be used 
cold, and in fairly large quantity: Adults a pint, quart, or more; children 



ANTHELMINTICS 



179 



according to age (at a year, an ounce, and about % ounce more for each 
year). Water and bland oils are also often used by high injection. 

The irritants which are most commonly used in clysters are: Soap; 
castor oil; molasses, i :8; salt, 1:16; turpentine, 1:20 (emulsified with 
egg-yolk) ; bile, i : 50. 

Enemata also have other uses: For local effects on the rectal mucous 
membrane (astringents, etc.); for the removal of parasites; and as a method 
of introducing medicine and nourishment. 



ANTHELMINTICS 

General Statement. Anthelmintics (anti, against; helminthos, worm) 
are remedies used against intestinal parasites. 

An active peristalsis will tend to remove intestinal parasites, as well 
as the other intestinal contents. Active cathartics are therefore necessarily 
Vermifuges i.e., drugs which expel parasites. But these parasites, 
when in good condition, are endowed with remarkable faculties of main- 
taining their position in the intestines by traveling in the direction 
opposite to peristalsis, or by fixing themselves to the intestinal wall 
by means of suckers or hooks, or by their serrated margins, etc. It 
therefore becomes necessary to lower their vitality. This may be done 
to some extent by appropriate diet. But this is rarely sufficient, and it 
is generally necessary to employ drugs which will paralyze them Vermi- 
cides. Since the latter necessarily present some danger to the host 
as well, it is desirable that they should be used in the smallest doses. 
For this reason it is well to give them their maximum efficiency by preced- 
ing them with a course of diet which lowers the resistance of the parasite 
without affecting the host. The vermicides but rarely kill the parasites; 
these usually recover if they remain in the intestine. It is therefore very 
necessary to follow the vermicide by an active cathartic, a saline, jalap, 
or calomel. Oily cathartics must be avoided, since they favor the absorp- 
tion of most anthelmintics. 

Preliminary Dietary Measures. A limitation of the proteins of the diet is generally 
regarded as injurious to the parasite, but care must be taken not to carry this so far 
as to weaken the resistance of the patient. Carbohydrates may be allowed in any 
amount. Mechanical irritants vegetables rich in fiber; the seeds of strawberries, 
blackberries, or figs; the husks of grain, etc. are very useful. So are "sharp" articles 
of diet condiments, especially those of the mustard group, strongly salted meat, etc. 
At the time when the vermicide is taken, the intestinal canal should be fairly empty, 
so that the parasite will not be protected by the contents. The remedies are therefore 
usually given before breakfast, and no food is taken for several hours after. This un- 
fortunately increases the tendency to the absorption of the poison, and to the local 
irritation. Vomiting may occur and render a repetition of the whole cure necessary. 
It has been attempted to circumvent this difficulty by combining the principles with 
tannin, but this lessens their action. The best that can be done is to inclose them in 
gelatin capsules. 

Vermicides. The substances which are toxic to intestinal parasites are in general 
toxic to all forms of protoplasm. The class of intestinal antiseptics are all to some 
extent vermicidal, but can scarcely be introduced in sufficient amount to kill the 
parasites without injuring the host. Special qualities are necessary for this end : The 
remedy must be absorbed to the smallest possible extent, since its absorption would not 
only render it deleterious to the patient, but would also prevent its reaching the lower 
portions of the intestine and acting on the parasites found there. On the other hand, 
it must be capable of penetrating the resistant, often chitinous, covering of these worms. 
This combination can only be secured with volatile poisons, whose vapors permeate the 
intestinal canal and penetrate into the parasites before there is time for an extensive 



l8o MANUAL OF PHARMACOLOGY 

absorption. From this volatility of the active principles, it follows necessarily that 
these drugs are not very stable; the more so since these principles also undergo chemic 
changes very readily. This uncertain activity has thrown mistrust on the whole 
class of anthelmintics. The pharmaceutic extracts or isolated principles share this 
instability, although to a less degree. 

Finally, it is more than probable that these parasites, as most other forms of life, 
show peculiar susceptibility to certain poisons. There is some hope that further research 
will bring forth specific vermicides. At present, the following data have been gathered 
largely from empirical observations: 

Specific Vermicides. The most efficient for Tapeworms are Male 
Fern (especially for Bothriocephalus) ; Pelletierin (especially for Taenia); 
and Kosotoxin; for Round Worms, Santonin, Chenopodium and Spigelia. 
Thread Worms are treated most efficiently from the rectum by enemata. 
Thymol (see Index) and Chenopodium are used for Hook-worm. Aspid- 
ium is also said to be effective against Hook-worm. 

It may be well to mention that the vermicides are under no circum- 
stances absolutely safe. They should never be given unless the parasites 
or their eggs are actually demonstrated in the feces. This is also the time 
when treatment offers the greatest chance of success. 

ASPIDIUM OR MALE FERN 

Composition. The anthelmintic action resides in several closely 
related substances, complex methane derivatives of phloroglucin and 
its homologues, with butyric radicles in ketone combination (Boehm, 
1897). The most important is probably the amorphous filicic acid. 
Analogous compounds occur in several other anthelmintic drugs (Rotlerin 
in Kamala; Ascaridol in Chenopodium; Tanacetin in Tanacetum; Koso- 
toxin in Cusso). 

The Active Constituents of Aspidium (Poulsson, 1891; Boehm, 1897) are: Amorphous 
filicic acid (CssHUoOn); Aspidinin; Albaspidinin; Flavaspidic acid (weak); Aspidin 
(probably from other species). The amorphous filmaron (C^YL^Ois; Kraft; Jacquet; 
1904) is perhaps an impure filicic acid (Scnmiedeberg). The inactive constituents are: 
the crystalline filicic acid or filicin (CssHssOn), and aspidinol. The crystalline filicic 
acid is the lacton of the active amorphous acid, the two being readily converted into 
each other. This probably explains the deterioration on keeping the root. All these 
substances are so closely related, and change so readily into each other that our knowl- 
edge is very confused; even the elementary formulae are in dispute. Aspidium also 
contains volatile and fixed oil, tannin, etc. Filicic acid is decomposed in the body, 
yielding trimethylphloroglucin. Filicinic acid is an inactive artificial reduction product 
of filicic acid or aspidin. 

Actions. Active filicic acid probably paralyzes the muscles of the 
parasites; at least it has this action in rain-worms, without affecting the 
nerves (W. Straub, 1902). This has been utilized for the standardization 
of filix preparations (Yagi, 1914). In frogs, it paralyzes the central 
nervous system, the heart and skeletal muscles; in mammals, it produces 
local gastro-intestinal irritation; followed by tetanic convulsions with 
simultaneous central and cardiac paralysis. 

Administration. Aspidium is used against tapeworms and hook- 
worm. Its reputation dates from the ancients. The oleoresin is admin- 
istered in capsules of }/% to 2 c.c., or emulsions, as described. If a cathartic 
is given, if no oil is taken and if the patient is vigorous, the ordinary 
doses cause little disturbance. If unsuccessful, several weeks should 
elapse before another administration. 

Phenomena of Poisoning. This may occur even with moderate doses 
(Sidler Huguenin, 1898); and larger doses are dangerous. Four grams 



ANTHELMINTICS l8l 

of the oleoresin have produced severe poisoning, but 20 Gm. have been 
given without toxic effects (Drenkhaw, 1911). The milder symptoms 
consist in colic, diarrhea, headache, dizziness, dyspnea, yellow vision, 
and sometimes temporary blindness. Severe cases showed delirium, 
violent muscle-cramps, syncope, tonic convulsions and coma; often glyco- 
suria, albuminuria and casts, and icterus; death occurs by respiratory 
paralysis. 

Recovery is slow, often with permanent blindness (Stuelp, 1904). 
This occurs also in animals. It is due to spasm of the retinal vessels, with 
subsequent optic atrophy (Harnack, 1912). 

The treatment would be evacuant, demulcent and symptomatic. 

PREPARATIONS ASPIDIUM 

Aspidium, U.S.P.; Filix Mas, B.P. (Male Fern). The rhizome and stipes of Dryop- 
teris Filix Mas and marginalis; using only such portions as have retained their green 
color. Dose, 4 Gm., 60 gr., U.S.P. 

* Oleoresina Aspidii (Oleores. Aspid.), U.S.P.; Exl. Filicis Liq., B.P. (Oleoresin of 
Male Fern). An evaporated ethereal extract (containing at least 20 per cent, of filicin, 
B.P.). Greenish oily liquid, often containing a crystalline sediment which should be 
incorporated before dispensing. Disagreeable taste and odor. Dose, 2 Gm., 30 gr., 
U.S.P. (Caution; not repeated on same day); 45 to 90 minims, B.P.; in capsules or emul- 
sion. Maximum dose, 15 Gm., 4 drams. 

Amorphous Filicic Acid, N.N.R. 0.5 to i Gm., Filmaron Oil, N.N.R., 10 per cent., 
10 c.c. 

Cusso, B.P.; Kousso (Brayera). The pistillate flowers of Brayera anthelmintica. 
(The male flowers are powerfully emetic, and, therefore, useless as vermicides.) Con- 
tains kosotoxin, related to filicic acid (Leichsenring, 1894; Lobeck, 1901). Dose, 
8 to 16 Gm., 2 to 4 drams, B.P., as infusion. 

Kamala (Rottlera). The glands and hairs from the fruit-capsules of Mallotus 
Phillipinensis. Contains Rottlerin, related to filicic acid (Telle, 1907; Semper, 1910. 
Dose, 10 Gm., 2^9 drams. 

CHENOPODIUM OIL 

The oil distilled from American Worm-seed has again come into promi- 
nence as an anthelmintic, especially against round worm and hook-worms. 
It appears to be highly efficient and relatively safe, although large doses 
are toxic. Its effects on the worms are similar to santonin, viz., peripheral 
stimulation, followed with large doses by paralysis (Trendelenburg, 1915). 

Ascaridol. This is the principal active constituent. It is a very unstable com- 
pound of peroxid type (Alsberg, 1913). 

Efficiency. Bruening, 1906, 1912, found that chenopodium oil has a high toxicity 
for ascaris, and a low toxicity for mammals. In hook-worm, Schueffner and Verwoort, 
1913, found it clinically fully equal to thymol, and superior to beta-naphthol or eucalyp- 
tol. Bishop and Brosins, 1915, consider it more efficient than thymol, with the 
further advantage of easier administration. In the Orient, according to Heiser, 1915, 
the clinical results have been superior to other hook-worm remedies. It was also highly 
effective against ascaris, tapeworms and whipworms. 

Administration. The oil does not kill, but merely paralyzes the worms, so that it 
must be given with a cathartic, usually castor oil. Oils do not increase, but rather 
diminish, the toxicity (Salant and Bengis, 1915). 

Dosage against Ascaris. For children, 5 to 10 drops of the oil are given on sugar 
two or three times a day for two days, and followed by a tablespoon of castor oil (Levy, 
1914)- 

Dosage against Hook-worm. The patient is allowed a light supper and no break- 
fast. The treatment starts in the morning with 50 Gm. of magnesium sulphate; two 
hours later, 16 drops of the oil on a teaspoon of granulated sugar; the same dose is re- 
peated twice with two-hour intervals. The last (third) dose is followed after two hours 
by 2 tablespoons of castor oil with 50 drops of chloroform. The treatment is repeated 
weekly until the castor oil stools are free from ova. For children below fifteen years, 



1 82 MANUAL OF PHARMACOLOGY 

the dosage is approximately i drop per year (Schueffner and Verwoort, 1913; Levy, 
1914). 

Bishop and Brosins, 1915, advise even simpler technic, requiring no dietary prepara- 
tion. The oil is used in capsules of 0.5 c.c. For adults, three doses, each of i c.c., are 
given at intervals of two hours. Castor oil, 2 ounces, is administered four hours after 
the last dose. For convenience in collecting the stools, the treatment is usually started 
in the evening. The course is repeated every three to five days, until the parasites have 
disappeared from the feces. The dosage for children is i drop per year, on sugar. The 
treatment may be contraindicated during fever or acute gastro-intestinal inflammations. 

Absorption and Excretion. The oil is absorbed from the ligated stomach and 
especially from the small intestine. The excretion occurs partly by the lungs (Salant 
and Livingston, 1915). 

Toxic Effects in Man. These are rare, and generally attributable to gross over- 
dosage. The symptoms consist in nausea, vomiting and abdominal pain; headache, 
drowsiness, deafness and tinnitus; ataxia and depression. Fatal cases show coma, 
tachycardia and convulsions (Levy, 1914; Seifert, Nebenwirk., 1915, p. 140). The 
treatment would consist in purgatives and stimulants (Motter, 1914). 

Toxic Effects on Animals. These have been studied especially by Salant and his 
co-workers, 1910-1916. The toxicity varies greatly, even with intravenous injection. 
It is increased by starvation, diminished by abundant diet. Cumulative effects have 
also been observed. 

Intact animals first show depression of the higher centers, then convulsions. There 
is a cardiac fall of blood pressure and organ volume, with slowed heart and decreased 
vagus irritability. Somewhat larger doses also decrease the rate and amplitude of the 
respiration, independently of the circulation. Peristalsis is diminished, by intravenous 
injection, as well as in the excised intestine. The depression is antagonized by barium, 
but not by pilocarpin. Renal irritation is also evidenced. Caffein antagonizes the 
respiratory depression, epinephrin and digitalis the cardiac depression (Salant and 
Livingston, 1916.) 



* Oleum Chenopodil (Ol. Chenopod.), U.S.P.; Oil of Chenopodium (American 
Worm-seed). A volatile oil distilled from Chenopodium ambrosioides anthel- 
minticum. Dose, 0.2 c.c., 3 minims, U.S.P. 

PELLETIERIN 

This is a mixture of alkaloids obtained from Pomegranate bark. It 
acts much more powerfully on Tasnia than on Ascaris (v. Schroeder, 1884; 
also effects on higher animals). Decoctions of the bark have been used as 
tapeworm remedy since the Romans; but the large amount of tannin (20 
or 25 per cent.) often causes vomiting, so that the alkaloids are preferred. 
These are generally given in the form of the tannates to avoid gastric 
irritation, employing the usual precautions. The ordinary dose often 
causes mild toxic symptoms: vertigo, dimmed vision, great weakness and 
cramps in the legs, formication, convulsive trembling, etc. Toxic doses 
produce promptly mydriasis, partial blindness, violent headache, vertigo, 
vomiting and diarrhea, profound prostration, sometimes convulsions 
(Landis, 1889). 

PREPARATIONS PELLETTERIN, ETC. 

*Pelletierin<B Tannas (Pellet. Tann.), U.S.P., B.P.; Pelletierin Tannats. A mixture 
of the tannates of alkaloids obtained from the bark of the root and stem of the Pome- 
granate. Tanret, 1878, found two active, liquid volatile alkaloids, Punicin and Iso- 
punicin. There are, further, two less active alkaloids, Methylpunicin and Pseudopuni- 
cin. The commercial alkaloid is of rather variable composition. The tannate occurs 
as a light yellow, odorless, a*iorphous powder, of astringent taste. Slightly sol. in 
water (i 1240), sol. in ale. (i : 16). Dose, 0.25 Gm., 4 gr., U.S. P.; 0.12 to 0.5 Gm., 
2 to 8 gr., B.P.; suspended in water. 

Granatum, U.S.P. ; Pomegranate. The dried stem and root of Punica Granatum. 
Dose, 2 Gm., 30 gr., U.S.P. 



ANTHELMINTICS 183 

Decoct. Granat. 20 per cent. Dose, 15 to 60 c.c., J^ to 2 ounces. 

Fldext. Granat., U.S. P. Dose, 2 c.c., 30 minims, U.S.P. 

Areca. The fruit of Areca Catechu. Contains vermicidal volatile alkaloid (Are- 
colin). Areca is used only in veterinary medicine. Arecolin stimulates peristalsis 
(Paetz, 1910). Arecolin hydrobromid has been used locally, ^ to i per cent., as miotic 
(smarting). 

Pepo, U.S.P. ; Cucurbita Semina Pr&parata (Cucurb. Sem. Praep., B.P.; Pumpkin 
Seed, Melon Pumpkin Seed. The dried (fresh, B.P.) ripe seeds of Cucurbita Pepo 
(maxima). Dose, 30 Gm., i ounce, U.S.P.; 100 Gm. bruised to a cream with water or 
milk, B.P. 

Pumpkin or Melon Seeds, fresh or at least not over a year old, are eaten in % ounce 
doses, on the day preceding the regular treatment. They are not sufficiently active 
themselves, but serve to support other measures. They were investigated chem- 
ically and pharmacologically by Power and Salway, 1910; but none of the constit- 
uents had any action on the host or parasites. Weinblum, 1912, found neither alka- 
loids nor glucosids, and also considers the action very unreliable. The fresh "milk" of 
the cocoan-ut is also said to be anthelmintic. 

Spigelia, U.S.P.; (Pink Root). The dried rhizome and roots of Spigelia marilandica. 
It is said to stupefy round worms. It contains a bitter acrid resin; a poisonous alkaloid; 
volatile oil, etc. Little is known of its action. Toxic effects, which are rare, resemble 
those of pelletierin. Dose, 4 Gm., 60 gr., U.S.P. 

Fldext. Spigcl, U.S.P. Dose, 4 c.c., i dram, U.S.P. 

Butea Semina, B.P.; Butea Seeds. The seeds of Butea frondosa. Used in India 
as anthelmintic. 

Pitlv. Butea Sent., B.P. Dose, 0.6 to 1.2 Gm., 10 to 20 gr., B.P. 

SANTONIN 

General Statement. Santonica has been a favorite remedy against 
round worms since Dioscorides. It is also used against pinworms if these 
have ascended beyond the reach of enemas. It does not seem to kill the 
ascaris, either in the intestine or in vitro, but they attempt to escape from 
it and thus flee into the large intestine, whence they are evacuated by a 
purgative. Santonin is insoluble, non-irritant and almost tasteless, and 
is therefore easily administered to children. It may be mixed with some 
sugar, and combined with calomel or castor oil, which does not increase 
its absorption. To children of two to five years, 0.03 Gm., ^ gr., may be 
given every hour for two or three doses, according to age, and then not 
repeated for at least three days. The adult dose would be three times as 
much. It should not be given on an empty stomach, since this would 
favor absorption. 

Santonin is the lacton of santonic acid. It is dissolved in the intes- 
tine as sodium santoninate, and the greater part is eliminated unchanged 
in the feces. A small amount is absorbed, oxidized, and the derivatives 
(especially the crystalline Santogenin, Jaffe, 1890) are excreted by the 
urine. An unknown derivative imparts a bright yellow color to the urine 
when acid, changing to pink when alkaline. 

Doses but little above the ordinary cause " yellow vision," persisting 
for some hours, without other bad effects. Overdoses produce serious 
poisoning. Santonin should therefore only be sold on prescriptions. The 
Troches, by their resemblance to candy, are especially liable to produce 
accidental poisoning. 

Action on Worms ; Relation to Structure. This has been studied by Trendelenburg, 
1915, on rain-worms, leeches and ascaris. It consists in strong stimulation (increased 
tonus and contractions) of the muscle, persisting after removal of the ganglia. The 
effect is highly specific, since it is not produced in anything like the same degree by other 
substances (although some alkaloids have a weak action); nor does santonin stimulate 
vertebrate muscle. It is connected with the lactone structure, as is also a depressant 
effect on the isolated frog heart. The convulsant effect on mammals, on the other hand, 
does not depend on the lactone, but on the naphthalin nucleus. 



184 MANUAL OF PHARMACOLOGY 

The Phenomena of Severe Intoxication. These are vomiting, colic 
and diarrhea, painful micturition, hematuria, headache and vertigo, weak- 
ness, somnolence; finally convulsions (which may be unilateral), and fall 
of temperature (Binz, 1877; Harnack, 1901). 

The Treatment. This would consist in evacuation; chloroform in- 
halation against the convulsions; and stimulants against collapse. 

Fatal Dose. In children, 0.06 Gm., i gr., has produced serious poisoning, and two 
such doses have been fatal; in other cases, 0.18 Gm., 3 gr., caused only light symptoms, 
and recovery has occurred after 0.72 Gm., n gr. By adults, 0.5 to i Gm. and more 
have been taken without damage (Lewin). 

The Color of the Urine. This may be confused with that of emodin (rhubarb, etc.). 
The emodin colors can be shaken out with ether, or precipitated by lime or barium 
water, whilst the santonin color can not. 

Uric Acid Elimination. This is increased by Santonin, as by other intestinal irri- 
tants (Abl, 1913). 

Xanthopsia. Doses as small as o.i Gm. may cause "yellow vision" i.e., white 
light has at first a violet, then a yellowish-green hue, and these colors tint the entire 
field of vision. The power of seeing in dim light is also lessened. It has been demon- 
strated that these effects are peripheral (Knies, 1894), and the theory is advanced, 
based on some experimental data, that santonin impairs the reproduction of the visual 
purple and violet, which are at first used very rapidly. There is no truth in the state- 
ment that it discolors the media of the eye (Filehne, 1900). 

Colored vision also occurs, but more rarely with amyl nitrite, picric or chromic 
acid, and digitalis (de Schweinitz, 1899). 

PREPARATIONS SANTONIN 

* Santoninum (Santonin.), U.S.P., B.P.; Santonin, CisHigOs. The inner anhydrid 
or lacton of santonic acid obtained from Santonica. Colorless crystals (turning yellow 
on exposure to light) ; odorless and nearly tasteless when first placed in mouth, but after- 
ward developing a bitter taste. Very slightly sol. in water, sol. in ale. (1:43). Dose, 
0.06 Gm., i gr., U.S.P.; 0.06 to 0.2 Gm., i to 3 gr., B.P.; in powder, with a little sugar. 
Maximum dose, 0.2 Gm., 3 gr. 

Santonin has been used in epilepsy and in diabetes, but with little success. 

Santonica, "Levant Worm-seed" (really the unexpanded flowerheads of Artemisia 
pauciflora), also contains cineol, but this has no action on ascaris (Bruening, 1912). 

Troch. Santonin., B.P.; Santonin Lozenges. Each contains 0.06 Gm., i grain. 

VERMICIDES FOR THREAD WORMS (OXYURIS) 

These are usually treated most efficiently by the rectal injection of 
various irritants. The rectum is first washed with injections of iron, 
tannin, or bitters (quassia,) to limit the secretion of mucus, and is then 
irrigated with solutions or emulsions of salt (5ss to pt.), aloes (3j to pt.), 
or turpentine (3ij to pt.), etc. Mercury salts are sometimes used as in- 
jection or suppository, but are dangerous. 



CONVULSANT POISONS 

Convulsions may be caused by direct stimulation of the muscles (ver- 
atrin) ; or of efferent motor nerves (physostigmin, aconitin) ; ftr by reflexes 
from strong afferent stimulation; or by stimulation of the motor centers 
in the cord, medulla or brain, either directly by the drug, or as a result of 
asphyxia, etc. These produce different types of convulsions. Spinal 
convulsions, as typified by strychnin and caffein, are generally symmetrical 
and when fully developed, tetanic (i.e., the contractions are maintained). 
Medullary convulsions (picrotoxin, camphor, asphyxia) are more irregular, 



STRYCHNIN 185 

asymmetrical and clonic (rapid intermissions). Cerebral convulsions 
(absinthe) are of the epileptic type, irregular, often involving only limited 
groups of muscles. 

Convulsions are usually the result of extreme stimulation of the motor 
centers, and as such are mainly of toxicologic interest. Smaller doses of 
these drugs, however, may be used for therapeutic stimulation; their 
action often extending to other nervous centers, and exciting the respira- 
tory and vasomotor centers. 

STRYCHNIN AND NUX VOMICA 

General Statement. Strychnin, the main alkaloid of Nux Vomica, has 
considerable therapeutic and toxicologic importance. It increases the 
reflex excitability of the spinal cord and of the medullary centers. The 
action is chiefly on the dorsal gray matter of the cord. 

Therapeutic doses produce a " bitter" and, therefore, tonic effect on the 
alimentary canal; improved tone and nutrition of muscle; and a limited 
amount of respiratory and vasomotor stimulation. 

Toxic doses cause characteristic tetanus, violent changes in blood 
pressure, and spasmodic respiration. Death occurs from asphyxia and 
from the paralysis which succeeds the stimulations. 

Actions closely resembling those of strychnin are produced by a num- 
ber of other alkaloids, which have little practical importance. The 
actions of tetanus toxin are very similar. 

Description of the Motor Effects. The principal symptoms of strych- 
nin poisoning in all vertebrate animals are referable to modified and in- 
creased reflex excitability of the spinal cord, culminating in symmetrical 
convulsions and tetanus. The motor reflexes are modified so that smaller 
stimuli are effective; and the response even to slight stimulation, is maxi- 
mal, tetanic, and tends to spread to all the muscles. There is also a 
reversal of inhibitory into augmentory reflexes, so that the reciprocal 
action of antagonistic muscles is disturbed. 

The symptoms in man correspond to those in the lower vertebrates. 
With small doses, there is merely a greater response to stimulation, and 
the muscles feel somewhat more taut. As the dose is increased to 6 or 
7 mg. in men, 5 or 6 mg. in women (Hartenberg, 1913), this tightening 
becomes more sensible, especially in the neck and jaws; the movements 
become rather abrupt; and slight twitchings may appear in the individual 
muscles, often in the little finger. (In case of paralysis from a high lesion 
(apoplexy), the paralyzed muscles may be the first to react since they are 
removed from the cerebral inhibitory impulses.) 

Convulsant Effects. With toxic doses, these symptoms are promptly 
succeeded by sudden convulsions, usually following some stimulation; 
or the premonitory symptoms may be absent. The attack may start 
with a loud cry, which is usually caused mechanically, by the convulsive 
movement of the air, rather than by pain. The convulsions involve all 
the voluntary muscles of the body, including the diaphragm. The move- 
ments are at first rapidly intermittent, but become promptly tonic, 
resulting in a typical tetanus. Since all the muscles are contracted, the 
convulsions are symmetrical, and the body assumes the position corre- 
sponding to the stronger muscles, which in most situations are the extensors. 
Accordingly, the body is arched backward (opisthotonus), so that the 



1 86 MANUAL OF PHARMACOLOGY 

patient may touch the ground only with the head and heels. 1 The legs 
are adducted and extended, the feet curved inward. (A frog may be held 
horizontally by the feet.) The arms are either strongly flexed over the 
chest, or rigidly extended, with the fis.ts balled. The jaws are fixed, and 
foam gathers at the mouth. The fixed diaphragm and the tense thoracic 
and abdominal muscles arrest respiration. The skin and mucosae are, 
therefore, cyanotic and congested; the eyes protruded, evolved; and the 
pupils dilated. The pulse is small and tense, often imperceptible. The 
patient remains perfectly conscious, and suffers severe pain from the vio- 
lent contractions. The asphyxia may be fatal in the first attack. More 
commonly there is a: 

Remission. The tetanus lasts perhaps a minute, then the muscles 
relax, and the patient passes into a greatly depressed, almost paralytic 
condition, still perfectly conscious and very anxious and oppressed, with 
dry throat and thirst, sometimes sweating. This intermission lasts at 
most ten or fifteen minutes, when there is another attack, usually again 
following some slight stimulation. If this is not fatal by asphyxia, it is 
again followed by remission, and so on, the whole sequence being repeated. 
The remissions, however, become progressively shorter, the spasms 
become weaker and the paralysis more prominent. 

Death occurs usually in the interval after the second to fifth attack, 
from exhaustion and general depression. It may be preceded by asphyxia! 
coma. 

Recovery may occur from sublethal doses, or under appropriate treat- 
ment, the convulsions and depression disappearing gradually. Animals, 
however, have been observed to relapse into fatal convulsions several 
hours after apparently complete recovery (Sollmann), so that patients 
should be watched. 

Dependence of Convulsions on Reflex Stimulation. In the lighter grades of strychnin 
poisoning, the convulsions occur only on reflex stimulation. In the severe grades, they 
are often apparently spontaneous; but even here they are really reflex, due to slight and 
accidental sensory stimulations. This is shown by the fact that convulsions do not 
occur spontaneously if all sensory impressions are prevented from reaching the spinal cord, 
as by dividing all the -posterior roots in frogs (Hermann Meyer, 1846); together with 
the medulla (Hering, 1893; Verworn, 1900); or by placing the frog in a very weak 
cocain solution (Poulsson, 1889). 

Different Forms of Stimulation. Practically all kinds of sudden 
sensory stimulation may provoke the convulsions. The skin is especially 
sensitive, even to the slight jars produced by heavy walking. Sudden 
light and sound are also dangerous. Gradual stimulation is much less 
effective (as with all reflexes), so that a patient may support considerable 
but deliberate manipulation, as for instance artificial respiration; when a 
slight, but abrupt or unexpected touch would cause an attack. 

Stimulation of the exposed intestines does not cause convulsions, since these are poor 
in sensory fibers. 

Chemical stimulation (the application of dilute acids) not only fails to produce 
tetanus, but even the normal reflex is greatly diminished (Schlick, 1890). The absence 
of tetanus is easily explained because the slow penetration of the acid leads to a gradual 
instead of abrupt stimulation. The various explanations of the diminished reaction 
are mainly hypothetical (Baglioni, 1900 and 1909; Sano, 1908). 

Simple and Crossed Reflexes. The effects of strychnin are relatively greater (i.e., 
the threshold is lowered more) for the crossed or leg-arm reflexes than for simple un- 
crossed reflexes, apparently because the excitability in simple paths is normally 

1 The opposite position, body bent forward, constitutes "emprosthotonus." 



STRYCHNIN 187 

already so high that it can not be materially increased by strychnin. Therefore, 
the strychnin increase of excitability is better marked in the more difficult complex 
paths, where several synapses interposed; or when the normal threshold has been raised 
by ether or asphyxia (E. L. Porter, 1914, 1915). The excitability is increased for 
single induction shocks, as well as for interrupted stimuli (van Leeuwen, 1913). 

The Modification of the Short Reaction of Ordinary Reflexes into the Prolonged Con- 
traction of Strychnin Tetanus. It might be supposed that the strychnin tetanus is due to 
the summation of repeated stimuli; each muscular contraction, by the movements of the 
tendons and joints, sets up a fresh reflex, these rapidly succeeding stimuli fusing into 
a tetanic contraction which persists until the nerve centers are exhausted (Baglioni, 
1900). However, there is good evidence that this is not necessary, but that the tetanus 
is in fact a true multiple response to a single stimulus: For it occurs also if all reflexes 
but the original single stimulus are excluded; f.i., tetanus occurs in a leg with a single 
stimulus of its divided sensory nerves, the remainder of the animal being curarized 
(Veszi, 1913; Buchanan, 1912; Henkel, 1913). The spinal stimuli, in strychnin tetanus, 
reach the muscles at the rate of 50 per second (Fahrenkamp, 1914). 

Elrington, 1914, concludes that the strychnin action consists in greater sensitiveness 
of the central receptor cells; not in greater spread of the impulses, or in greater intensity 
of the afferent impulses. 

Reversal of Reciprocal Innervation. -The modification of the reflexes 
by Strychnin is not merely quantitative, but also qualitative. Sherrington 
(1905 to 1909) showed that in a normal animal, the contraction of a muscle 
is accompanied by the automatic relaxation of its antagonistic muscles. 
The reciprocal reflex is destroyed by such substances as strychnin and 
chloroform. With strychnin, all reflex stimulations result in simultaneous 
contraction of all the muscles, including the antagonist; whilst with chloro- 
form, they result in simultaneous relaxation. (The vasomotor system 
presents analogous phenomena, Bayliss.) The work of de Barenne 
(quoted under "Localization") shows other qualitative changes in the 
functions of the sensory cells. 

Location of the Tetanizing Action. The distinction between the pos- 
sible sites of convulsant action furnishes interesting illustrations of the 
general methods of experimental pharmacology. Most of these experi- 
ments can be carried out more conveniently on frogs ; but they can also 
be demonstrated on mammals. 

The Action is Localized in the Spinal Cord. This can be easily shown 
by exclusion: (a) The peripheral motor apparatus is excluded by section 
of the nerve trunk, which arrests the convulsions in the corresponding 
muscles (Johannes Mueller, 1844). Conversely, no convulsions will 
occur if strychnin is injected directly into a muscle say the leg; provided 
that the leg is first ligated so that the poison can not reach the general 
circulation, (b) If this experiment is modified so that the nerve is not 
included in the ligature, the absence of convulsions will also prove that 
strychnin does not affect the peripheral sensory apparatus (Magendie, 
1819). 

(c} The brain and medulla oblongata are not essential to the convulsions, 
for these occur in frogs in which these centers have been destroyed. 
(d) The posterior root ganglia are also not concerned; for typical tetanus 
can be obtained, by direct stimulation of the cord, when all the posterior 
roots have been cut in frogs (Hermann, 1846; Verworn, 1901); and in dogs 
even when the afferent fibers from these ganglia have completely degener- 
ated after section (Sherrington, 1898). Nor does the localized application 
of strychnin to the exposed posterior root ganglia produce any effects 
(de Barenne, 1910). 

(e) Action on the Spinal Cord. It is evident, therefore, that the 
strychnin action is located somewhere within the spinal cord. The 



1 88 



MANUAL OF PHARMACOLOGY 



next question, whether it acts on the sensory or on the motor tracts, or 
on both, has not been conclusively answered, although it has been the 
subject of much ingenious investigation. At present, it appears that 
both the motor and sensory portions of the cord must be poisoned, to 
obtain the typical strychnin convulsions. 

Methods of Anatomical Isolation. The basic experiments in this direction weie 
made by Hermann Meyer in 1846: after cutting away the entire posterior columns of 
the spinal cord, he found that strychnin does not produce tetanus, even if the remaining 
cord is touched. If the ablation is confined to a part of the cord, the corresponding 
muscles do not participate in the convulsions. This seems to indicate that the action 
is located in the posterior and not in the anterior columns. However, as pointed out 
by Verworn, 1900, the proof is not conclusive, for the operation produces too much 
shock, and besides, destroys all the physiological relations of the motor cells. Similar 
objections apply to all anatomical methods, so that these can not furnish conclusive 
evidence. It was therefore necessary to have recourse to physiological means. 

Localized Application of Strychnin to the Spinal Cord. Houghton and Muirhead, 
1895, basing themselves on the earlier and imperfect work of A. J. Spence, 1866, at- 
tempted to utilize the fact that impulses from the sen- 
sory cells of the cervical segments of the cord to the 
motor cells of the caudal segments, and vice versa. By 
destroying the circulation and applying strychnin 
locally to the exposed cord it is therefore possible to 
make impulses pass either through a poisoned sen- 
sory cell to an unpoisoned motor cell; or through an 
unpoisoned sensory to a poisoned motor cell. In Fig. 
4 the strychnin is supposed to be restricted to the 
cervical half of the cord. 

The path goes through a poisoned sen- 
sory to an unpoisoned motor cell; the path 
through an unpoisoned sensory to a poisoned 
motor cell. When the foreleg is stimulated in this 
frog, the hindleg participates in the convulsions. 
When the hindleg is stimulated, there is no convulsion. 
Analogous observations have been made on mam- 
mals (Ryan and McGuigan, 1911); on frogs with the 
sensory paths paralyzed by phenol (Baglioni, 1900); 
and on the excised nervous system of toads (Bag- 
lioni, 1909). 

These results were interpreted as proof that 
strychnin acts essentially on the sensory mechanism of the cord, and that the motor 
cells were at best unessential: for convulsions appeared whenever the impulse passed 
through a poisoned sensory cell, even though the motor cell be unpoisoned; whereas 
no convulsions appeared when the sensory cells were not poisoned, even though the 
motor cell was poisoned. 

However, these results are obtained only when the cervical cord is poisoned. If 
the strychnin is applied to the lumbar cord, the convulsions do not spread at all to the 
cervical segments, but remain confined strictly to the poisoned area (McGuigan and 
Becht, 1914). Furthermore, if the entire animal is poisoned by small doses of strychnin, 
the same phenomena are observed as in the Houghton-Muirhead experiement; namely, 
minimal stimuli applied to the forelegs produce general convulsions, whereas the same 
stimuli applied to the hindlegs produce only local contractions. The Houghton- 
Muirhead phenomenon may therefore be explained by the more easy spreading of 
impulses in the caudal than in the cephalic direction. (The entire subject is reviewed 
by. McGuigan, Keeton, and Sloan, 1916.) 

Barenne, 1911 to 1913, adduced some new facts. By strictly localized applica- 
tion of strychnin to the exposed spinal cord of frogs and dogs he finds: 

1. When the application is restricted to the ventral surface of the cord, no percep- 
tible symptoms are produced. 

2. When it is restricted exclusively to the dorsal surface, there is no tetanus; but 
instead, a characteristic syndrome, comprising sensory disturbances (paresthesias), 
increased reflexes, and incoordinate asymmetrical twitchings. These "dorsal symp- 
toms" are sharply localized on the skin according to the level and side of application 
to the cord; the skin areas being identical with the "dermatomata" defined by 
anatomic-physiologic isolation methods. They occur even after the division and 
degeneration of the posterior root fibers. 




FIG. 4. Diagram of Houghton- 
Muirhead experiment. 



STRYCHNIN 3:89 

3. Typical tetanus occurs only if both the sensory and motor tracts are poisoned. 
F.i., if the strychnin is applied dorsally to the arm region, and ventrally to the leg re- 
gion, then stimulation of the leg causes only normal reflexes (unpoisoned sensory to 
poisoned motor); stimulation of the arm causes tetanus of the legs (poisoned sensory 
to poisoned motor) in which the arms do not participate (poisoned sensory to unpoisoned 
motor). This experiment (which was confirmed by Beritoff, 1913)- would indicate 
that both thse ensory and motor cells must be poisoned, to obtain the typical tetanus. 

Motor Cortex. The cerebral motor centers react to the direct application of strych- 
nin (and also to picrotoxin) by increased excitability to electric stimulation, and even 
by rhythmic spontaneous movements, identical with those which would be induced by 
electric stimulation. The action is not abolished by deep anesthesia (Bickeles and 
Zbyszewski, 1913). It is localized in the gray mattter, for it disappears on ablation 
(Baglinoi and Magnini, 1909). 

The "silent area" of the brain does not respond to the local application of strychnin 
(Amantea, 1913). 

Psychic Centers. These are evidently not affected by strychnin, since consciousness 
is not disturbed until the onset of asphyxial coma. 

Practical Significance of the Location of Strychnin Action. The loca- 
tion of the tetanizing action of strychnin in the spinal cord is not only of 
experimental interest, but also of practical importance. It explains, for 
instance, why strychnin convulsions are abolished by curare, since curare 
blocks impulses from the cord to the muscles. Also, that strychnin has 
a stronger action on a paralyzed limb in those cases of paralysis in which 
the lesion is above the cord, for cutting off of the spinal cord from the brain 
always increases its reflex excitability. 

The fact that strychnin in small doses increases the tone of muscles is 
also due to its heightening the reflex excitability of the spinal cord. Not 
only the convulsive centers, but other spinal centers are put in a condi- 
tion more favorable to reflexes. It is in this way that strychnin is useful 
in impotence or in paralysis of the bladder or other sphincters, when these 
are due to lowered activity of their respective spinal centers. 

Indirect Results of the Motor Actions. The increased activity of the 
muscles brings about several secondary results, such as pain, asphyxia, 
increased metabolism, disturbance of temperature, tendency to rise of 
blood pressure and quickening of pulse; early postmortem rigor. The 
asphyxia in turn produces its characteristic phenomena. 

Pahi. Strychnin convulsions are extremely painful, just as any other form of muscle 
cramp. 

Metabolism. The increased muscular tone or convulsions result in increased 
consumption of oxygen and output of carbon dioxid, and increased use of glycogen. 
The increase of gaseous metabolism is observable even with therapeutic doses (Edsall 
and Means, 1914). The asphyxia will also cause hyperglycemia and glycosuria. 

Effect of Convulsants on Temperature. All convulsant poisons (santonin, picro- 
toxin, strychnin) produce characteristic changes in heat regulation. Small doses 
cause increased heat loss and a slightly smaller heat production. Larger doses 
cause increased metabolism, through muscular action, and hence increased heat 
production, which is accompanied by a further increase of heat loss. Paralytic 
doses diminish the heat production very greatly. The temperature is accordingly vari- 
able: Small doses tend to lower it; moderate convulsive doses would increase it; 
paralytic doses lower it greatly. The heat loss is particularly conspicuous in small 
and young animals, whilst larger animals tend to show a rise of temperature, with 
moderate doses. 

Lactic Acid. Strychnin and other convulsions cause the appearance of lactic acid 
in the blood, provided that the glycogen store is adequate (Lusk, 1916). 

Nux Vomica. The preparations of Nux Vomica, and its second alka- 
loid, Brucin, act essentially lie strychnin. 

Brucin. The action of brucin is much weaker than that of strychnin, the ratio 
varying with different animals. The paralytic and curare effects are relatively stronger 



190 MANUAL OF PHARMACOLOGY 

(resembling methyl-strychnin), so that Brucin is less useful therapeutically (cf. Dixon 
and Harvey, 1908). 

Brom-Strychnins. The two mono-brom-strychnins act similarly to strychnin, but 
are only }> or }^ as effective. Dibrom-strychnin is also convulsant, but in frogs it 
produces mainly the curare effect (C. R. Marshall, 1912). 

Other Spinal Convulsants. Spinal tetanus, in every respect similar to that of 
strychnin, is produced by caffein, thebain (an opium alkaloid), gelsemin, calabarin and 
hydrastin, etc. It is also a late phenomenon in morphinized frogs. Tetanus ioxin 
likewise increases spinal tetanus, the minor differences being due mainly to peculiarities 
of absorption (Froehlich and Meyer, 1915). 

The Convulsant Action of Sulphonated Dyes; Inhibitory Action of Cerebrum. Acid 
Fuchsin (Barbour and Abel, 1910), and other water-soluble, neurophilic sulphonated 
dyes (Macht, 1912), produce strychnin-like convulsions in frogs. In normal frogs, the 
tetanus occurs only after a long latent period (up to twenty hours), and requires rela- 
tively large doses. If the anterior third of the cerebrum is removed (either before or 
after the injection), the convulsions occur much more promptly (within thirteen min- 
utes), and very much smaller doses (}^Q to Mo) suffice. The anterior cerebrum therefore 
exercises a strong inhibitory effect on the convulsant action of these drugs (much less, 
if any, on other convulsant poisons). With the cerebrum intact, the latent period is 
also shortened by voluntary fatigue. 

Cardicctomized Frogs. Joseph and Meltzer, 1911, found that the late convulsant 
action of acid fuchsin, and of morphin, could be greatly hastened, and that a very much 
smaller dose would suffice, in frogs in which the heart had been tied, the circulation of 
the blood being thus arrested. According to Abel, 1912, this interesting observation is 
explained by the peculiar distribution of the poison. The ligation of the heart prevents 
the dissipation of the poison in the body, and the anterior lymph hearts drive the solution 
directly into the communicating vessels of the central nervous system. This is there- 
fore exposed to a much more concentrated solution. At the same time the interrup- 
tion of the normal circulation, and the partial asphyxia, increase the sensitiveness of 
the nervous system to convulsants; for the outbreak of these is hastened even if the 
heart is excised after the drug has been injected. Meltzer, however, does not accept 
this explanation. 

Carbon Dioxid. This also greatly hastens the convulsions, when its tension in the 
air exceeds 20 per cent. (Joseph, 1915). The gas also lowers the threshold for strych- 
nin convulsions (Pilcher and Sollmann, 1915). 

Therapeutic Use of Strychnin in Paralyses. Strychnin and nux 
vomica are used to preserve muscular nutrition in paralysis from func- 
tional neurites and higli lesions; to raise the tone of the rectal and vesical 
sphincters in incontinence of urine or feces; to improve the effects of 
cathartics, especially in atonic constipation. It is also used (but is of 
doubtful value) in sexual impotence. Most of these uses have been dis- 
cussed in the text. 

Paralytic Disorders. It should be remembered that strychnin only increases the 
excitability of existing structures. It must therefore be useless in organic lesions of the 
cord. In spastic paralysis, and in inflammatory conditions, it would be contraindicated. 
Moderate doses (i to 2 mg., three times a day) may be useful in functional depression 
of the cord (lead poisoning, or sometimes in diphtheritic paralysis); but its main indi- 
cations are for maintaining the muscular tone, and thereby preventing muscular 
atrophy whilst awaiting the repair of cerebral lesions (apoplexy); but it must be re- 
membered that large doses of strychnin may bring apoplectic attacks in predis- 
posed patients. The trophic effect should be supported by massage and electricity. 
Strychnin is also said to lessen the pain of some older paralyses. 

Incontinence of Urine. Strychnin would be useful only if the incontinence is due to 
atony of the sphincter; if due to overaction of the detrusor urinae, the indication would be 
for atropin. 

Sexual Impotence. The spinal stimulation of strychnin would be useful theoret- 
ically; in fact, however, the condition requires either suggestion or systematic general 
tonic treatment. The reputed specific nerve tonics (phosphorus, etc.) act mainly as 
general tonics; whilst others (damiana, zinc, yohimbin) act mainly by suggestion. 

Medullary Actions of Strychnin. These are analogous to its effects 
on the spinal cord, consisting in a more or less violent and convulsive 



STRYCHNIN 19! 

exaggeration of the reflex excitability, particularly of the respiratory and 
vasomotor centers, followed by paralysis with toxic doses. These effects 
are more or less modified by the coexistence of asphyxia. 

These medullary stimulations are very marked and violent with con- 
vulsive doses. With therapeutic doses, they are so slight that they can 
not be demonstrated with certainty, either clinically or experimentally. 
The therapeutic use of strychnin as a respiratory or circulatory stimulant 
therefore rests on a very insecure basis. It was doubtless due mainly to 
the uncritical transfer of the results of convulsive doses to therapeutic 
doses. 

Therapeutic Doses on the Circulation. These produce either no effect 
whatever, or a very slight (10 to 20 mm.) rise of blood pressure, fairly 
well sustained. The rise is rather more marked in the diastolic pressure. 
Direct observation of the vasomotor center may also, but exceptionally 
show a slight and doubtful stimulation ; but in asphyxia, the same doses (0.05 
mg. per kg.) cause intense vasomotor stimulation (Pilcher and Soll- 
mann, 1915). These effects (aside from asphyxia) are so inconstant and 
small that they could be accidental. The cardiac contractions are not 




FIG. 5. Convulsive doses of strychnin on blood pressure. 

changed. Clinical observations on the blood pressure and heart rate, in 
health and in various diseased conditions (cardiac diseases, fevers, etc.), 
give similarly negative or inconclusive results, even when rather large 
doses (Ko gr. every hour) were used (Cabot, 1904; Parkinson and Row- 
lands, 1913 and i9i4;Neuburgh, i9i5;Lucas, 1914). Thepositiveresults|of 
Cook and Briggs, 1903, and of Marvin, 1913, must therefore be viewed 
with suspicion. 

Convulsive Doses. Whilst small doses of strychnin have but little 
effect on the circulation, convulsive doses cause very conspicuous changes; 
especially a large rise of blood pressure, due to central vasomotor stimula- 
tion, produced mainly by the direct action of strychnin on the center; 
but aided by the convulsions and asphyxia. This is followed by vaso- 
motor depression. 

These effects are synchronous with the convulsions: the typical course is shown in 
Fig. 5. With the onset of the irregular spasms at (b) the mean pressure rises (central 
vasomotor stimulation), the heart being slowed and strengthened (central vagus stimu- 



IQ2 MANUAL OF PHARMACOLOGY 

lation). During the tetanus (c), the pressure is very high (intense stimulation of vaso- 
motor center), the heart beats are faster and smaller (reflex vagus depression, mainly 
through muscular exertion). As the tetanus disappears (d) the pressure falls below 
normal (central vasomotor paralysis), and the heart beats become very slow (intense 
vagus stimulation, mainly asphyxial). The phenomena b to d are repeated during 
each spasm. 

As death approaches, and the respiration stops permanently, the pressure remains 
low, and the heart beats rapidly but weakly (total paralysis of vasomotor and vagus 
centers), and finally stops. 

This description applies almost equally well to the effects of convul- 
sions produced by any other cause; and particularly to asphyxia (see 
Fig. 6). These are both present in strychnin poisoning, and must be con- 
tributory factors. However, they are not the main cause of the rise of 
blood pressure; for this occurs when convulsions are excluded by complete 
curarization ; and when asphyxia is prevented by artificial respiration. 
Only the portion (d) of the tracing is due entirely to asphyxial vagus 
stimulation. 

Vasomotor Center. Pilcher and Sollmann, 1915, found that the vasomotor center is 
greatly stimulated by convulsive doses, independently of the convulsions or asphyxia. 
Very large doses (above i mg. per kg.) depress and paralyze the center. 

The Vein pressure which is also unchanged by therapeutic doses, rises during tetanus, 
indicating cardiac insufficiency (Capps and Matthews, 1913). 

Vascular Areas. During the strychnin rise of pressure, all the splanchnic vessels 
contract, while those of the skin (Wertheimer and Belezenne, 1897) and cerebrum (Roy 




and Sherrington, 1890) dilate. The vessels, of the pia mater and retina are constricted 
(Hirschfelder, 1915). 

Vasomotor Convulsions. In curarized animals, the rise in blood pressure occurs 
spasmodically (S. Mayer, 1872), and can be brought on by reflex stimulation, just like 
the convulsions in ordinary animals. The dose required to produce the convulsant 
and the vasomotor action are also identical. This supports the view that the action 
of strychnin on the medullary centers is essentially identical with its action on the spinal 
centers. 

Vasomotor Reversal. According to Bayliss, 1908, contraction of the vessels through 
the vasomotor center is always brought about by stimulation of the vasoconstrictor 
nerves and simultaneous automatic inhibition of the vasodilators the reciprocal in- 
nervation of Sherrington. Bayliss claimed that this is modified by strychnin and chloro- 
form in exactly the same sense as with skeletal muscle; and there is the same antagonism 
between the two drugs. The vasoconstrictors are so much more powerful than the 
dilators, that under strychnin, every reflex stimulation will cause a rise of blood pressure; 
under chloroform, a fall through inhibition. Langley, 1912, however, failed to confirm 
the "reversal" of depressor fibers by strychnin; small doses simply increase the response 
of the pressor fibers and large doses (10 to 20 mg. per rabbit) produce transient paralysis 
of the depressor response, but never "reversal." 

Heart. Amongst clinicians, the opinion prevails very widely, that strychnin is 



STRYCHNIN 



193 



a "cardiac stimulant." This clinical terra does not necessarily imply that the drug 
stimulates the heart directly; but merely that it improves the pulse. (The expression 
is used so loosely, that the student is advised to discard it altogether.) 

As a matter of fact, strychnin has no effect whatever on the heart in therapeutic 
doses with living animals. Convulsant doses cause some stimulation of the ventricles 
(Wiggers, 1916). (Cameron claims increase of cardiac tone in animals with 0.03 mg. 
per kilogram; but this lacks confirmation.) 

When perfused directly through the excised heart, the effects are first stimulant, 
then depressant (Hedborn, Igersheimer, 1905); but the necessary concentration could 
not be maintained in vivo. 

Respiration. In animals, therapeutic doses of strychnin increase res- 
piration mainly by acceleration (Cushny, 1913). This is due to increased 
excitability of the center, and indirectly to the increased movements. The 
increase of respiration is not always conspicuous, on account of the 
variable excitability of the respiratory center. Clinically, it is practically 
absent (Newburgh, 1914; Edsall and Means, 1914; Higgins and Means, 
1915, 4.5 mg. hypodermically). It is presumably greater when the ex- 
citability is partly depressed, as in anesthesia or morphin poisoning 
(Biberfeld, 1904). 

With toxic doses, the respiration is spasmodic, arrested during the teta- 
nus; accelerated immediately after; and depressed during the intermissions. 

Therapeutic Use of Medullary Stimulation. The supposed circulatory 
and respiratory actions of strychnin led to its use in collapse (fainting, 
trauma and hemorrhage; fevers; depressant poisons, alcohol, anesthetics, 
coal-tar derivatives, snake venom, etc.) and in exhaustion of the respira- 
tory center (pneumonia, phthisis). It is probably inefficient. In any 
case, it should be remembered that it would be only a temporary remedy, 
useful to tide the patient over a crisis; it could not in itself produce any 
permanent improvement in the central nervous system. It would 
merely raise the reflex excitability; and it is doubtful whether the perma- 
nent maintenance of this artificially raised irritability is ever .of benefit. 

Traumatic Shock. Profound surgical shock involves a complete paralysis of the vaso- 
motor center, associated with depression of the heart, and presumably of the vessels 
themselves. The poor circulation causes the prompt degeneration of the nervous 
centers, in which they can not respond to strychnin or any other stimulant (Sollmann 
and Pilcher, 1914). Even epinephrin, transfusion or other mechanical means, whilst 
they may temporarily restore the blood pressure, can not restore the nervous centers 
(Crile). Excessive hemorrhage presents the same conditions. 

Minor Degrees of Collapse and Especially in Hemorrhage, in Fevers, and in Intoxica- 
tions. In these, the increased excitability of the vasomotor center might somewhat 
counteract the lowered blood pressure, and enhance the effect of other stimulant 
measures (saline infusion, etc.). Moderate doses of strychnin (2 mg.) are used, pref- 
erably hypodermically. However, the clinical studies of Newburgh, 1914, and Lucas, 
1914, were entirely negative. Its effects are certainly much less pronounced than those 
of the reflex vasomotor stimulants (ammonia, alcohol, ether, camphor). These reflex 
stimulants are more useful especially for fainting and temporary myocardial insufficiency. 

In Heart Disease proper strychnin is generally contraindicated, unless it be to ease 
the dyspnea; even this effect could be secured better by caffein. Newburgh, 1914, found 
no effect from 3-io to Ho grain in broken compensation. 

Depressant Effects of Toxic Doses of Strychnin. The medullary and 
spinal functions all show a curious mixture of stimulant and depressant 
response to strychnin; the stimulation predominating during the con- 
vulsions, the depression during the intermissions. The paralytic effects 
gradually increase as death approaches, the respiratory center, vasomotor 
center, vagus center, and the cardiac muscle failing in about this order. 
Exhaustion and asphyxia as well as the direct depressant action of 
strychnin, are important factors in this paralysis. 
13 



194 MANUAL OF PHARMACOLOGY 

Contributory Factors in Strychnin Paralysis. That exhaustion is an important con- 
tributory factor is shown by the fact that life may be greatly prolonged by preventing 
the convulsions through chloral or curare. The prolongation of life by artificial res- 
piration shows the contributory action of asphyxia. However, animals die from large 
doses of strychnin, when exhaustion and asphyxia are both excluded, in the manner 
indicated. Indeed, the direct depression seems generally to be the main factor (Heub- 
ner and Loewe, 1913). 

There seems considerable reason to believe that in the frog the paralysis of the cen- 
tral nervous system is caused largely by the failure of the circulation through cardiac 
paralysis; but this is not the sole cause, for the heart is often still beating when the re- 
flexes have disappeared. In the case of mammals death usually occurs before the heart 
has stopped. 

Importance of Treating the Paralysis. It is important to bear in mind 
that the convulsions are not in themselves the dangerous element in 
strychnin poisoning. Death is rather due to paralysis. Remedial meas- 
ures must therefore be directed not only against the convulsions, but 
also against the subsequent paralysis. 

Tetanus alone is not such a dangerous condition. Thus, tetanus quite as violent 
as that of strychnin has been produced, e.g., by camphor, without being fatal, and the 
very severe convulsions of traumatic tetanus may last for weeks, whereas large doses of 
strychnin may kill after a single twitch or even without any signs of convulsions 
(death may then, however, be due to cardiac paralysis). 

Special Senses. Strychnin (2 to 3 mg.) increases the sharpness and field of vision 
for all colors (Dreser, 1894), and also the olfactory sense. The sense of touch is little, 
if at all, affected. These actions are central. In the eye it acts probably also on the 
retinal ganglion cells, the effects being obtainable unilaterally by injection into the tem- 
ples or under the conjunctiva. It has been employed to arrest the progress of optic 
atrophy amaurosis (Nagel 1 ), sometimes with temporary improvement; % to i c.c. of 
a Yi P er cent - solution (2.5 to 5 mg.) being injected into the temple. 

Bitter and Tonic Actions. Strychnin is extremely bitter (perceptible 
in dilution of i : 400,000 to i : 100,000, according to the sensitiveness of 
the observer) . It shares the stomachic effect of other bitters, and is therefore 
used to improve appetite and digestion in nervous dyspepsias, chronic gastric 
and intestinal catarrhs, hyperemesis, seasickness, etc., and thus favor nutri- 
tion. The increased tone of the muscles creates a feeling of vigor which con- 
tributes to the "tonic" effect. To enhance the local action, the tincture of 
nux vomica (i c.c. diluted, before meals) is often preferred to the alkaloid 
(i to 2 mg). It is often combined with other tonics (Elixir Ferri, Quininae 
et Strychninae Phosphatum). If the bitter effect alone is desired, the dose 
of the tincture may be reduced to i or 3 drops, which is too small to pro- 
duce any central effects. 

In seasickness it has been employed as a prophylactic in conjunction with atropin 
(Skinner, N. Y. Med. Jour., December, 1893; Girard, 1906). 

Drug Habit. The bitter and tonic effects of strychnin make it a useful adjuvant in 
the treatment of chronic alcoholism and other drug habits. 

Diabetes Insipidus. Strychnin is said to be occasionally effective in reducing the 
polyuria. There is no pharmacologic explanation for this action, if it exists. 

Peristalsis. Strychnin is often used as an addition to other cathartics ("Aloin, 
Belladonna and Strychnin") with the idea of improving their action, especially in atonic 
constipation. It stimulates the Auerbach ganglia on direct application (Langley and 
Magnus, 1907). It has not been shown whether this action would occur in its thera- 
peutic use. Hypodermically, it probably has no direct effect in ordinary doses, whilst 
toxic doses weaken or arrest peristalsis (Pollak, 1910). Any results may perhaps be 
explained by increased tone of the spinal centers which influence intestinal move- 
ments and defecation. For this purpose, the extract of Nux Vomica is generally used 
(15 mg. in pills). 

Other Peripheral Actions. Strychnin, when used systemically, has practically no 
peripheral action on muscle, nerve, or glands except the bitter effect. 

1 Cf. Derby, 1902, Boston Med. & Surg. Jour., 20, 508. 



STRYCHNIN 195 

The local application of strong solutions paralyzes most nervous and muscular tissues; 
for instance, the heart muscle, superior cervical ganglion, striped muscle endings. 
The last effect (curare action, Lapicque, 1913) also occurs weakly in living frogs. 
Small doses seem to sensitize the neuro-muscular junction, lowering the threshold to 
indirect stimulation, and delaying fatigue (Hammett, 1916). The curare effects are 
stronger in brucin; and methyl-strychnin may be counted in the curare group. After 
death, strychninized forgs cease to respond to sciatic stimulation much earlier than 
normally (Githens and Meltzer, 1912). 

Action on Invertebrates. Strychnin acts as a weak protoplasmic poison on ameboid 
cells, yeast, etc. Higher invertebrate animals are also relatively insusceptible. Many 
insects are quite immune, others are only slightly injured (Juchenack and Griebel, 
1910). 

Absorption. Strychnin is promptly absorbed, mainly from the intes- 
tine. In rabbits, none is absorbed from the stomach proper; it is not 
known whether this is also true for man. 

Gastric Absorption. Rather variable results have been obtained by different in- 
vestigators when strychnin was placed in ligated stomachs. Generally, alcoholic 
solutions are absorbed readily, aqueous solutions scarcely at all. These results seem to 
depend partly on the ligation; for from unligated stomachs (Pawlow's pouch) aqueous 
solutions are well absorbed, better than alcoholic (Ryan, 1912). 

Excretion. A part of the strychnin is excreted unchanged, mainly by the urine. 
Small quantities occur also in the saliva, milk, sweat, bile, and feces. The excretion 
starts within five minutes after absorption (Ipsen, 1892); and is practically completed 
within forty-eight to seventy-two hours (Bukunin and Majone, 1906), although 
traces may be found even after five days (Plugge, 1885; Hale, 1909; Kuenzer, 1914). 
In the remarkable case of a patient who had swallowed 15 grains and recovered, Hewlett, 
1913, recovered 4% grains from the first stomach washings, and a total of i% grains 
from the urine, mainly between the first and tenth hour. Traces were present on the 
fourth, none on the fifth day. 

Destruction. At least a fourth, and often much more, of the administered strychnin 
can not be recovered from the excreta (Kobert), and is presumably destroyed in the 
tissues (perhaps mainly in the liver; not in the alimentary canal, Hatcher, 1904). 
Kratter, 1882, however, believes that none of the alkaloid is destroyed in' mammals. 

Influence of Absorption and Channel of Administration on Effect. 

Since the capacity for the excretion and perhaps the destruction of strych- 
nin is relatively great, the effect of the same dose will vary considerably 
with the rapidity of its absorption. Hypodermic injections are therefore 
two to eight times more active than oral administration; intravenous 
injections are two to three times more active than hypodermic. The 
effects of rectal administration approach more closely to hypodermic 
than to oral administration. The toxicity of strychnin is slightly reduced 
by the administration of large quantities of fluid (Kleiner and Meltzer, 
1912). Colloids have a marked retarding effect (Hatcher, 1904.) 

Even very large doses may produce no symptoms, if the experiment is arranged so 
as to make their absorption very gradual; for instance, by injecting it into the ligatured 
limb of a guinea pig. A considerable quantity will be gradually absorbed through the 
ligatured tissue; and if the ligature is released, after several hours, the effects will be 
correspondingly small. 

Distribution in Body. In fatal cases, the strychnin is found mainly in the blood, 
liver and kidneys, in frogs especially in the spinal cord, but there is no evidence that 
strychnin is bound by spinal cord emulsions (Dixon and Ransom, 1912). 

W. Koch and Mostrom, 1911, found that phosphatids increase the solubility of basic 
strychnin; but this is probably a simple solution phenomenon, and has nothing to do 
with its selective action on the nervous system. Lombardi, 1913, also finds that the 
toxicity of strychnin is somewhat diminished when it is first digested with brain sub- 
stance; but not if the brain of a strychnin-poisoned dog is used. 

Influence of Age. Children are said to be comparatively unsusceptible 
to strychnin. In old people with atheromatous arteries, large doses 
might lead to apoplexy. 



196 MANUAL OF PHARMACOLOGY 

Increased Susceptibility on Continued Administration. The continu- 
ous use of strychnin does not lead to tolerance; on the contrary, the 
repetition of its action "educates" the nervous system to respond more 
readily, so that the effects are apparently slightly increased. 

After the repeated administration of equal tetanic doses to frogs, the spasms occur 
earlier and last longer (Mostrom and McGuigan, 1912). In mammals, the experiments 
of W. Hale, 1909, gave rather inconclusive results, some indicating increased suscepti- 
bility, others slight tolerance. 

Susceptibility of Different Animals. This varies greatly. With subcutaneous 
administration, man, cats, and dogs require about the same dose, 0.75 mg. per kilogram, 
to produce a fatal effect; rabbits are slightly more susceptible. Guinea pigs and frogs 
require about six times, and snakes eighteen times, this dose. With the frog, the spasms 
appear with one-sixth the fatal dose; with the guinea pig they only set in when at least 
95 per cent, of the fatal dose has been given. The differences for oral administration 
a ? e even greater. Some birds are almost insusceptible to oral poisoning, the fatal dose 
for chickens by mouth being 30 to 40 mg. per kilogram; subcutaneously, 3 to 5 mg. 
Temperature on Convulsions in Frogs. Smaller doses suffice to produce tetanus when 
the temperature is either below or above the ordinary (55 to 75F.). In the cold, the 
tetanus appears later, but lasts longer (Githens, 1913). The rapidity of onset, with 
large doses, rises with the temperature according to van't Hoff's law (Schlomovitz and 
Chase, 1916). This, however, may depend on absorption. 

Toxicology of Strychnin. The symptoms and course of strychnin 
poisoning have been sufficiently described under the convulsant effects. 

Toxic Dose. In man, 5 to 10 mg. may exceptionally produce convulsive effects, 
more pronounced with 20 to 30 mg. These doses may even be fatal. The ordinarily 
fatal dose, by mouth, would probably be about 100 mg. With efficient treatment, 
patients ma> be saved after 250 mg.; and even doses of a gram and over are said to have 
been treated successfully (Hewlett). The fatal dose of Nux Vomica lies about 0.75 
to 3 Gm. 

Time of A ppearance of Symptoms and of Death. These depend upon 
the mode of administration, the condition of the stomach, and other 
factors influencing absorption. With oral administration, the symptoms 
generally appear in fifteen to thirty minutes; the convulsions sometimes 
only after an hour or later. Death occurs usually in one to three hours, 
but the time may be as short as ten minutes, or as late as nine to twenty 
hours, or even later. 

Differential Diagnosis of Strychnin Poisoning. Strychnin tetanus 
may be confused with traumatic tetanus, spinal meningitis, epilepsy, 
or hysteria. Traumatic tetanus is characterized by previous malaise and 
slow development. The convulsions begin in the jaw. The muscles 
remain rigid in the intermission. The course is comparatively slow. 
Strychnin tetanus may also begin in the jaw, but this is not so conspicuous. 
In rare cases of strychnin poisoning the muscles also preserve their rigidity 
during the interval, so that the diagnosis is sometimes difficult. When 
in doubt, strychnin treatment should be used, as it is beneficial in all 
similar conditions. The course of the case will clear up the diagnosis. 

In spinal meningitis the diagnosis maybe made by the fever and history. 
Epilepsy differs by the loss of consciousness; the reflexes are normal. 
In certain cases of hysteria the diagnosis may be impossible. Such cases 
should also be treated as for strychnin. 

Postmortem Phenomena. Death by strychnin is characterized by early 
and often persistent rigor. This, however, is common to all forms of 
convulsions, and is presumably due to the increased production of acid. 
The anatomical appearances are those of asphyxia and violent convulsions: 
venous congestion, often hyperemia of the central nervous system, and 
small hemorrhages; in a few cases hyperemia of the alimentary tract. 



STRYCHNIN 197 

Identification of Strychnin. Strychnin may be identified in the sus- 
pected material, vomitus, or tissues (after isolation and purification) 
by its taste, convulsant effects on frogs, and chemical tests (violet and 
cherry color with bichromate-sulphuric acid). It is very resistant to putre- 
faction, and may be demonstrated in putrefying organic matter after a 
year or longer (e.g., Sundrick, 1884). 

Treatment of Strychnin Poisoning. 1 This comprises the prompt 
administration of chemic antidotes (permanganate, iodin, tannin) ; evacua- 
tion by emetics or stomach-tube (under chloroform); suppression of the 
convulsions by chloroform and chloral or ether; and artificial respiration. 
Absolute quiet of the patient is imperative. 

Chemic Antidotes. Potassium Permanganate is probably the most effective, if it 
is given sufficiently early, since it destroys the strychnin. One gram (^ teaspoonful) 
should be dissolved in a quart of warm water, carefully decanted, and administered in 
tumbler doses at short intervals. Iodin (15 drops of tincture in ^ glass of water) or 
tannin (teaspoon in 3^ glass of hot water) merely delay absorption, but this is dis- 
tinctly useful. Tea or coffee should be avoided, since the caffein is synergistic. Char- 
coal, or better caramel or Fuller's earth, are useful by absorbing the strychnin and 
delaying its absorption (Sabbatani, 1914; Fantus, 1915); but their efficiency is limited. 

Evacuation. Emesis by zinc or copper sulphate or mustard may be tried, or apo- 
morphin (although the depression is therapeutically objectionable). Gastric lavage 
should be done if the patient is thoroughly under chloroform otherwise it may start 
a fatal convulsion. Diuresis and catharsis are probably of little use. Hatcher, 1915, 
obtained fair results in animals with large quantities of hot water, or the intravenous 
injection of 2 per cent. sod. sulphate. 

Physiologic Antidotes. Chloroform, chloral, paraldehyd, ether, etc., 
suppress the strychnin convulsions. By preventing their painful and 
exhaustive effects, they conserve the energy of the patient so that he may 
more successfully resist the strychnin depression. They also lessen the 
danger of tetanic asphyxia, and are therefore the most useful antidotes. 

Chloral is given in doses of 2 Gm. (J^ dram), with the addition of another gram 
(15 grains) after half an hour or longer, as necessary. There is always the danger in 
giving this, that its paralytic effects may coincide with those of the strychnin, and thus 
increase the danger. For this reason chloroform or ether is preferred, since their action 
can be better controlled. Ether has the advantage that it is not liable to the dangers 
of late chloroform poisoning. Githens and Meltzer, 1911, advise the intratracheal 
insufflation of air and ether, combined with intravenous injection of Ringers' solution. 
Bickeles and Zbyszewski, 1913, found differences in the antispasmodic action of the 
various narcotics; amylen hydrate being especially effective, veronal very little, and 
chloral between. 

Morphin is theoretically objectionable, since its action on the spinal cord is syner- 
gistic to strychnin. It has been employed, however, and its analgesic action at least 
would be useful; but chloral and chloroform should be preferred. Other depressants 
which have been used, but are of doubtful efficiency, are bromid, nicotin, and pilo- 
carpin. 

Epinephrin counteracts the cardiac depression, on local application (Januschke, 
1910); but systemically, it increases the convulsive effects, so that there is no thera- 
peutic antagonism. 

Artificial Respiration. This prevents or suppresses the convulsions, 
and may save life if it is carefully maintained until the patient is out of 
danger. The effect is probably due mainly to the removal of the syner- 
gistic effects of asphyxia. 

There are, however, some conflicting theories and data: Osterwald, 1900, claimed 
that strychnin spasms are diminished by excess of oxygen in the air, and vice versa. 

1 The student should review the general "Treatment of Poisoning" and the "Exercises on 
Chemical and Physiological Antidotes." 



198 MANUAL OF PHARMACOLOGY 

This might suggest that the result is due to destruction of the strychnin by oxygen; 
but there is no other evidence for this view. Meltzer and Gies, 1903, found that the 
mere rythmic movements of the chest were also important, for these prolonged life 
even when the animals were in an atmosphere of pure hydrogen. They suggest that 
this is due to a reflex inhibitory effect on the convulsive centers. It is also conceivable, 
that it might be due to removal of carbon dioxid. Paradoxically, however, Ryan and 
Guthrie, 1908, find that the inhalation of carbon dioxid also arrests strychnin convul- 
sions, in frogs and mammals. 

It is claimed as a result of animal experiments that the application 
of external heat also decreases the strychnin mortality. 

PREPARATIONS STRYCHNIN 

Strychnina, U.S.P., B.P.; C 2 iH 22 N 2 O2. An alkaloid obtained from mix vomica and 
other plants of the Loganiaceae. Colorless, transparent crystals or white, crystalline 
powder. Very slightly sol. in water (i : 6420); slightly sol. in ale. (i : 136). Dose, 1.5 
mg-, Ho g r - U.S.P.; i to 4 mg., %4 to ^5 gr., B.P. 

* Strychnina Nitras (Strych.Nit.), U.S. P.; C 2 iH22N 2 O2.HNO 3 . Sol. in water (i : 42); 
slightly sol. in ale. (i : 150). All strychnin salts occur as colorless crystals or white 
powder; intensely bitter, even in dilute solutions. They are incompatible with alkalies, 
iodids and bromids (slow precipitation), tannin, arsenates and arsenites. Dose (of all 
Strychnin Salts), 1.5 mg., J^Q S r - U.S. P.; i to 4 mg., % 4 to J^g gr., B.P. Maximum 
dose, o.oi Gm., % gr. 

Strych. Sidph., U.S.P.(C 2 iH22N 2 O 2 ) 2 .H 2 SO 4 + H 2 O. Sol. in water (i : 32) and in 
ale. (1:81). Dose, etc., see "Strych. Nit." 

* Strych. Hydrcchl., B.P.; C 2 iH 2 2N 2 O 2 .HCl + 2H 2 O. Sol. in water (i : 60). Dose, 
etc., see "Strych. Nit." 

Inject. Strych. Hyp., B.P. 0.75 per cent. Dose, 0.3 to 0.6 c.c., 5 to 10 minims, B.P. 

Liq. Strych. Hydrochl., B.P. i per cent. Dose, 0.12 to 0.5 c.c., 2 to 8 minims, B.P. 

Elix. Ferri, Quin. el Strychn. Phosph., N.F. The dose (4 c.c., i dram) contains 
(about): Strychnin, ij^ mg., %Q gr.;Quinin, 45 mg., % gr.; Ferric Phosphate, 90 mg., 
i^ gr. 

Syr. Ferr. Phosph. c. Quin. et Strych., B.P. (Easton's Syrup). Ferrous Phosphate, 
1.7% per cent.; Quin. Sulph., 1.5 per cent.; Strych., 0.57 percent. Dose, 2tO4 c.c., % 
to i dram, B.P. 

Nux Vomica, U.S.P., B.P. (Strychni semen, P.I.). The dried, ripe seeds of Strychnos 
Nux Vomica, East Indies; yielding not less than 2.5 per cent, of total alkaloids, U.S. P.; 
not less than 1.25 per cent, of strychnin, B.P. Dose, 0.06 Gm., i gr., U.S.P., 0.06 to 
0.25 Gm., i to 4 gr., B.P. Maximum dose, 0.25 Gm., 4 gr. 

The constituents are strychnin, brucin, tannin, fat, etc. 

The drug was unknown to the ancients, and was probably introduced by the Arabs. 
The first good description occurs in 1540. Strychnin was discovered in 1818. 

The bark contains the same principles in less amount, but relatively more brucin. 
It was formerly found in commerce under the name of "false angostura." Several 
arrow poisons are also derived from the genus Strychnos, especially the Upas Tieute" 
from Java. Some of the strychnos species do not contain any active principle. 

Nux vomica contains a small quantity of a third alkaloid, igasurin, which has not 
been very greatly studied, but which seems similar to strychnin. 

Ext. Nuc. Vom. Liq., B.P. 1.5 per cent, of strychnin. Dose, 0.06 to 0.18 c.c., 
i to 3 minims, B.P. 

* Extractum Nitcis Vomica (Ext. Nuc. Vom.), U.S.P.; Ext. Nuc. Vom. Sice., B.P. 
A powdered extract; i Gm. representing about 4 Gm. of drug, 10 per cent, of total 
alkaloids, 5 per cent, of strychnin. Dose, 15 mg., 3^S r -> U.S.P.; 16 to 60 mg., 34 to i 
gr., B.P., as pills. Maximum dose, 60 mg., i gr. 

* Tinctura Nucis Vomictz (Tr. Nuc. Vom.)., U.S.P., B.P.; Tincture of Nux Vomica. 
10 per cent, of drug, 0.25 per cent, of alkaloids, 0.125 per cent, strychnin, in about 75 
per cent, alcohol. Miscible with water and ale. Incompatibilities as for Strych. Nit. 
Dose, 0.5 c.c., 8 minims, U.S.P.; 0.3 to i c.c., 5 to 15 minims, B.P. Maximum dose, 
2.5 c.c., 40 minims. 



PICROTOXIN GROUP 



PICROTOXIN GROUP 



199 



General Statement. The pharmacologic group of which picrotoxin 
is the main representative produces a conspicuous stimulation of the medul- 
lary centers, with characteristic convulsions, slowed pulse, etc. There 
is also some stimulation of the spinal cord. These effects are followed by 
paralysis. The actions are not utilized therapeutically, but are of some 
toxicologic as well as scientific interest, since the members of the group 
have often caused poisoning. 

The Principal Members of the Group. These comprise picrotoxin from Coccuius 
indicus (the seed of Anamirta) paniculata ("Fish-berries;" used for poisoning fish, the 
flesh of which becomes toxic; also for adulterating beer; and in "knockout drops." 
The external use against pediculi has given rise to toxic effects); Cicutoxin from the 
rhizome Cicuta virosa "Water Hemlock," an umbeliferous plant eaten by mistake for 
parsley, etc. (the American species, Cicuta maculata and bulbifera, are also toxic). 
Cicutoxin is a complex pyrone- derivative, occurring as an unstable resinous substance 
(C. A. Jacobson, 1915). Some of the decomposition products of digitalis (digitaliresin, 
toxiresin) are also counted in this group. 

Less important members are: Coriamyrtin (from Coriaria myrtifolia); and Tut-in 
(from Coriaria species of New Zealand) (C. R. Marshall, 1910). W. W. Ford, 1910, 
found that tutin combines with nervous structures, thereby losing its toxicity; but no 
tolerance is acquired. > 

Chemic Nature. Most of the substances are non-alkaloidal, non-nitrogenous 
"neutral principles," more soluble in alcohol than in water. Some are glucosids. 
Picrotoxin itself consists of a mixture (or perhaps a feeble combination; Sielisch, 1912) 
of nearly equal parts of picrotoxinin and picrotin (Cervello, 1911; structural formula, 
Angelico, 1912). These are closely allied chemically and have identical actions, but 
picrotoxinin acts far stronger. Coriamyrtin seems to vary. That first isolated by 
Riban was very soluble, while Merck's is almost insoluble, but probably more active 
(Marshall, 1912). 

Picrotoxin Convulsions. The characteristic effects on the frog, and the localiza- 
tion of the convulsions in the medulla, are described in the "Laboratory Exercises." 
In mammals, also, the convulsions are not modified by destruction of the hemispheres 
(Gruenwald, 1909; Morita, 1915) or section below the optic thalami (Pollock and Holmes, 
1915). Spinal Tetanus may often be observed in frogs after the medulla is destroyed, 
the spinal stimulation having previously been masked by the more intense stimulation 
of the higher centers (Luchsinger, 1878). The convulsions are not so much dependent 
upon reflex stimulation so that they are probably in part due to a direct stimulation. 
According to Baglioni, 1909, the action is located in the sensory cells. 

Symptoms of Picrotoxin Poisoning in Mammals. The effects of convulsive but 
non-fatal doses were described by J. Crichton Brown, 1875, as: Salivation and vomiting 
(central; Eggleston and Hatcher, 1915); then quiet and apathetic; then restless and 
apprehensive; then trembling of legs; lies on side, with efforts to stand; progressively 
stronger twitching of face and neck muscles; head drawn back. Then, suddenly, 
generalized clonic convulsions; clonic champing of jaws; closing of eyelids; marked 
frothing at mouth; involuntary urination; pupils dilated during the convulsions. The 
clonic spasms change imperceptibly to running movements, become slower, and finally 
cease. The animal remains quietly on its side, and then, after some efforts, regains the 
erect position. After a time, varying with the dose, the convulsions may recur. 

Respiration. This is stimulated before the convulsions; becomes irregular during 
the initial twitching and arrested during the clonic spasms (Pollock and Holmes, 1915). 
These authors point out the similarity of the respiratory, convulsive and circulatory 
changes with those of epileptic attacks (Pollak and Tread way, 1913). The threshold 
of the respiratory center to CO2 is lowered by Coriamyrtin (Wieland, 1915). 

Spasms of the laryngeal muscles lead, with the frog, to distention of the body with 
air and to a characteristic cry similar to that sometimes heard with strychnin. \Yith 
digitaliresin, toxiresin, and oleandresin, the convulsions are preceded by immobility. 

Circulation. In the early stages, the blood pressure may rise from stimulation of 
the vasomotor center. About three to eight seconds before the convulsions, the blood 
pressure falls, remaining low until asphyxia sets in (Pollock and Holmes, 1915). 

Vagus Center. The heart is greatly slowed, and may even cease for a time. After 
division of the vagi, the heart will return almost to normal. There is, however, some 



200 MANUAL OF PHARMACOLOGY 

depression of the cardiac muscle involved in this slowing. Later there may be a quick- 
ening, partly due to stimulation of the accelerator center and partly to paralysis of the 
vagus center and to fatigue of its endings. 

The vomiting, salivary, and sweating centers are also excited. The sweat may, 
however, be suppressed by vasomotor constriction. 

Aulonomic Centers. Gruenwald, 1909, pointed out that picrotoxin produces the 
symptoms of parasympathetic stimulation: Contraction of pupils, salivation, vomiting, 
plowed pulse, contraction of urinary bladder, erection, etc. These effects are central, 
for they do not occur after section of the nerves. They are not hindered by 
decerebration. 

Uterine Spasms. These have been observed, and depend probably on stimulation 
of the spinal cord, since they cease upon destruction of this organ. 

Paralysis. With larger doses, all the stimulant effects give way to paralysis. 

Ilcmolylic Action. Picrotoxin, cicutoxin, and phytolacca decandra are said to act 
similarly to saponin. 

Excretion. This occurs by the urine; picrotin is partly unchanged; the picrotoxinin 
is decomposed (Chistoni, 1912). 

Toxic Dose. According to Lewin, 0.03 to 0.24 Gm. of cocculus is toxic, 2.4 Gm 
fatal. Of picrotoxin, 20 mg. are toxic. The fatal dose is not known. 

The Symptoms of Poisoning in Man. These consist in burning sensation, nausea, 
salivation, cold sweat, pallor, colic, vomiting, diarrhea; pulse slowed or quickened; 
palpitation; shallow respiration. These are rapidly followed by confusion, stupor and 
unconsciousness. After one-half to three hours, trembling, clonic and tonic convulsions. 
These generally pass into paralysis and death by asphyxia, after several hours. 

The postmortem findings are those of asphyxia. The poison disappears rapidly 
during putrefaction (within one or two weeks); so that the toxicologic analysis must be 
made promptly. The characteristic effect of the isolated poison on the frog constitutes 
the best test. The intensely bitter taste (discernible in dilutions of i : 80,000) may arouse 
suspicion. 

Treatment. The chemic alkaloidal precipitants would not be efficient. The best 
treatment would be emetics (if vomiting has not occurred), permanganate, chloral, 
chloroform, and external heat. The combined administration of chloral, morphin, 
and minimal doses of atropin has recently been recommended as the result of animal 
experiments. 

Therapeutic Uses. The medullary stimulation produced by the group might be 
expected to have many therapeutic uses; in fact, however, they have not been found 
available, perhaps because the effective doses are too near to the toxic. Picrotoxin 
(0.5 to 2 mg.) has been used in the night sweats of phthisis, and in epilepsy, but with 
very doubtful results. Powdered cocculus has been used against pediculi, but is 
dangerous. 

Solubility. Picrotoxin is soluble in about 8 parts of alcohol, or 240 parts of water. 



CAFFEIN, THEOBROMIN, AND OTHER METHYL-XANTHINS 

Members. -This group comprises the various methyl derivatives of 
xanthin (dioxypurin). These occur in several plants; as products of 
metabolism in animals; and may also be obtained synthetically. The 
most important are caffein (trimethylxanthin), the principal alkaloid of 
coffee, tea, kola, guarana, mate, etc.; theobromin (3.7 dimethylxanthin) 
from cacao; and theophyllin (1.3 dimethylxanthin), which is usually pre- 
pared synthetically. Xanthin itself, and all its other methyl derivatives, 
produce the principal actions of the group. 

Nature of Caffein. Caffein is capable of forming salts, and is, therefore, an alka- 
loid; but it is so feeble a base that it does not turn litmus, and the salts are dissociated 
by water. Its solubility is also peculiar. It was isolated from coffee in 1820 by Runge, 
Pelletier and Caventou, and Robiquet. Its identity with the alkaloid of tea (some- 
times called Thein) was surmised by Berzelius, and confirmed by Jobst and Mulder in 
1838. Commercial caffein is now produced almost exclusively from tea. 

Occurrence. Caffein occurs in plants of at least six families, which are scattered 
over many portions of the globe. It is rather remarkable that these plants have nearly 
all been discovered and consumed by the natives as stimulants. These plants often 



CAFFEIN AND OTHER METHYL-XANTHINS 



2OI 



contain volatile products or tannin, which slightly modify their effects. Theobromin 
is often associated with the caffein; in cacao, the theobromin predominates. 

The chemical structure and derivation of the purin derivatives have been eluci- 
dated by Emil Fischer. The most important are as follows: 



1. X C 8 

I I 

2. C C 5 N 7 



3 . X C 4 N, 

Purin (the numbers indicate the posi- 
tions in which radicles may be intro- 
duced). 

HN CO 

I I 
OC C NCH 3 

>CH 

CH 3 N C N 
Theobromin 

CH 3 X CO 



HN CO 

OC C NH 

>CH 
HN C N 

Xanlhin 



CH 3 N CO 
OC C NH 



CH 



CH,N C X 

Theophyllin 



OC C NCH 3 
>CH 
CH 3 N C N 

Caffein 

Principal Actions. i. Increase of the reflex irritability of the central 
nervous system from above downward; leading to stimulation of the psy- 
chic areas (insomnia, etc.); of the medullary centers (respiratory, vaso- 
motor and vagus) ; and with large doses to heightened reflexes and tetanic 
convulsions. With toxic doses, the stimulation * is accompanied by 
paralysis. 

2. Increased ease of muscular contraction, progressing to loss of elas- 
ticity and to rigor; this affects all forms of muscle to a varying degree. 
The heart rate is thereby quickened. 

3. Vasodilation by a direct action on the vessels with moderate doses; 
this combines with the cardiac stimulation to quicken the circulation. 

4. Diuresis results through the interaction of several factors. 
Caffein is used as a psychic, muscular and respiratory stimulant; and 

as a cardiac tonic and diuretic. Theobromin and theophyllin are probably 
more effective when the peripheral actions are desired. 

Psychic Functions. In man, moderate doses of caffein (to 0.3 Gm.) 
produce a quicker and clearer flow of thought; disappearance of drowsiness 
and fatigue; more sustained intellectual effort; more efficient appreciation 
of sensory impressions, and more perfect association of ideas (Kraepelin, 
1872; Diet! and Vintschgau, 1878; Ach, 1900; Hollingsworth, 1912). 
The central actions of theobromin are relatively much weaker than those 
of caffein (Filehne, 1886). Theophyllin is intermediate (Dreser, Pouchet, 
Thomas). 

With larger doses, these effects pass into wakefulness, excitement, and the other 
unpleasant reactions described under the toxicology. 

The lower mammals react by restlessness and excitement. The cat is said often 
to become frantic. Frogs do not exhibit any symptoms referable to the brain. 

Use as Antidote in Narcotic Poisoning. Caffein is often used as an 
antidote against acute poisoning by morphin (Bennett, 1874); alcohol 



202 MANUAL OF PHARMACOLOGY 

(Binz, 1878); paraldehyd (Schroeder, 1887); chloral (Airila, 1913, Soll- 
mann). The psychical actions are directly antagonistic, the mental 
and muscular coordination being immediately improved, although the 
effect is not lasting. The respiration and circulation may also be some- 
what stimulated, but the effects easily become additive, so that with fatal 
alcohol poisoning, caffein is actually deleterious. With morphin, the con- 
ditions are probably more favorable. 

As a stimulant antidote, the caffein is usually administered as a very strong, hot, 
black coffee, to secure the synergistic stimulant action of the heat and oils. Strongly 
boiled tea, through its tannin, would be a chemical antidote in poisoning by corrosive 
metals. Coffee has not this precipitant effect. 

Mutual Antagonism of Alcohol and Caffein. This has been studied especially by 
Pilcher, 1912. He found that with the smaller doses, each drug tends to act qualitatively 
as if present alone. In alcohol sleep, small doses of caffein cause awakening, restore 
the reflexes, and diminish the fall of temperature. With larger doses, there is a qualita- 
tive change in the direction of greater depression. Light alcohol coma is intensified 
by moderate or large doses of caffein; the reflexes are further depressed. With toxic 
doses, the fatality is greatly increased if both drugs are present, mainly by their deleteri- 
ous action on the heart. 

Medullary Centers. These are moderately stimulated by caffein, 
similarly to strychnin. There are, however, some important differences: 
With caffein the stimulation is on the whole weaker for toxic doses, but 
rather stronger and much more prolonged with therapeutic doses; and 
there is little or no subsequent depression, even with toxic doses. The 
most conspicuous effect is on the respiration. The stimulation of the 
vasomotor and vagus centers is interfered with by other factors, as de- 
scribed under "Circulation." 

Respiration. In man, the respiration is only moderately increased 
(Edsall and Means, 1914), or scarcely affected by oral therapeutic doses 
(Newburgh, 1914; Taylor, 1914); unless cardiac dyspnea is improved by 
the circulatory effect. With hypodermic injection of 0.15 to 0.25 Gm., 
there is definite evidence of respiratory stimulation. The CO 2 tension is 
markedly lowered, inducing a lowered threshold of the respiratory center. 
The rate and depth of the respiration, and the minute- volume are increased. 
There is also increased gas metabolism, and sometimes bronchial dilation 
(Higgins and Means, 1915). 

Anesthetized animals respond by increased rate (Binz, 1878; and gen- 
erally also increased depth of the respiration (Heinz, 1890; Impens, 1899). 
The latter is probably due to partial awakening from the anesthesia; for 
with decerebrated animals, the increase is confined to the rate, the depth 
being unchanged or more shallow (Cushny, 1913). Inhibitory reflexes are 
less effective. 

Use in Asthma. Coffee somtimes gives relief in asthmatic attacks. The action is 
probably partly psychic, partly bronchial; for in guinea pigs, it relaxes the bronchial 
spasm produced by peptone or muscarin (Pal, 1912). Bronchial dilation is also some- 
times observed in man (Higgins and Means, 1915). F. Meyer, 1915, concludes that 
caffein acts mainly by stimulating the respiratory center to greater effort. He con- 
siders it less efficient than atropin, epinephrin or nicotin. 

Spinal Cord. Ordinary doses of caffein heighten the reflexes (Wood, 1912; Leeu- 
wen, 1913). Toxic doses produce convulsions of spinal origin (Bing, 1901), which agree 
in all essential respects with those of strychnin; except that the tetanus is neither as 
violent nor as prolonged. The exhaustion in the intervals is also less pronounced. The 
tetanus may produce death by fixation of the respiratory muscles. The convulsant 
dose is relatively large, and it is therefore doubtful whether it has ever been observed 
in man. Ordinary toxic doses produce only tremor. In frogs, the tetanus is not in- 



CAFFEIN AND OTHER METHYL-XANTHINS 203 

creased or hastened by removal of the cerebrum (difference from morphin; Githens, 
1914). 

The paralytic action of large doses can be shown in frogs by protecting the muscles 
from rigor; i.e., by ligating a leg exclusive of the nerve. Caffein will then destroy its 
reflexes. 

Skeletal Muscle. Ordinary doses of caffein increase the functional 
activity of skeletal muscle so that it contracts more readily and more 
completely and powerfully, and is less easily fatigued (Wood, 1912). 
This improvement can be demonstrated by the ergograph, as well as in the 
excised or curarized frogs' muscle (Fig. 7). It is, therefore, at least hi 
large part, peripheral. Larger doses depress the musgle, and eventually 
cause it to go into rigor, even in the living animal. 

The Stimulant Phase. A smaller stimulus suffices to produce contraction (Paschkis 
and Pal, 1886). The latent period is shortened. The height and rapidity of the con- 
traction are greater, and a larger weight can be lifted (Robert, 1881). Fatigue is less- 
ened, and a greater amount of work can be performed (Dreser, 1890), so long as the 
load and stimulation are optimal; but with excessive load or stimulation, caffein dimin- 
ishes the total work (Golowinsky, 1915). The other methylxanthins affect muscle 
qualitatively like caffein (Golowinsky). 




FIG. 7. Effect of caffein on gaslrocnemius muscle of frog, normal tracing; 

after five minutes in i : 10,000 caffein solution; . . . in I : 1,000 solution. 

The Depressant Phase. As the dose or concentration is increased, these effects are 
reversed. The contraction becomes less powerful, and the curve resembles that of a 
fatigued muscle; i.e., it is lower and more drawn out. This lengthening shows first in 
the relaxation (Buchheim and Eisenmenger; Golowinsky), eventually also in the con- 
traction. The elasticity is lessened. The muscle is exhausted more rapidly by tetanus. 

Similar muscular effects are produced by xanthin (Paschkis) and creatin (Dreser). 

Resemblance to Fatigue. The successive increase and diminution of the muscular 
functions by caffein resembles the successive phenomena of work and fatigue; and sug- 
gests that a part of these may be due to the accumulation of the xanthin products which 
are formed in metabolism; but other products which accumulate during work also in- 
fluence the muscle similarly to fatigue (Lee, 1906). 

Caffein Rigcr. This was observed by Voit, 1866, and then investigated by Johann- 
sen, and by Schmiedeberg, 1872. Its occurrence in the living body can be demonstrated 
by hypodermic injection in certain species of frog (the European Rana temporaria, 
and the ordinary American laboratory frog, R. pipiens); while another European frog 
(R. esculenta) is less susceptible to the rigor, and therefore succumbs to spinal convul- 
sions. In both cases, the frog becomes rigidly extended; but the rigor (as distinguished 
from tetanus) persists after division of the sciatic nerve (Johannsen) and occurs after 
curare. The heart may continue to beat strongly for some time. Mammals also show 
some stiffness after large doses of caffein, but actually rigor results only if the alkaloid 
is injected directly into an artery. The coagulant action is possessed by other xanthins, 
being strongest with xanthin itself, and progressively weaker with theobromin, theo- 
phyllin and caffein (Filehne, 1886; Dreser). 

The muscle in caffein rigor is inexcitable and appears white, bloodless, stiff and con- 
siderably swollen and shortened, and is acid to litmus (Ransom, 1911). 

Microscopic Changes. If the caffein is applied to a teased muscle under the micro- 
scope, the contents of the fiber are seen to move; the cross-striations disappear, and the 
longitudinal striae become more prominent. The sarcolemma becomes detached. The 
fibers shorten by half (Johannsen). 



204 MANUAL OF PHARMACOLOGY 

These changes have been studied by Secher, 1914, through perfusion with dilute 
solutions of xanthin and the various methyl-xanthins, which all produce similar effects. 
The histologic changes increase with the concentration, to disorganization (caffein, 
i : 2,000). Short of disorganization, the changes are reversible. The disorganized 
fibers also eventually regenerate, provided their nuclei are intact. Hardening and true 
rigor is confined to the destroyed fibers. Similar changes are produced by chloroform and 
other poisons, and in other vertebrates, although mammals require higher concentrations. 

Perfusion of the muscle with saline or blood, if undertaken soon after the onset of 
the rigor, restores the plasticity but not the excitability (v. Fiirth). 

Coagulation of Muscle Extracts, Rigor may also be produced in living animals by 
the injection of a number of other substances in sufficient concentration; for instance, 
by chloroform. All of these, as well as caffein, favor the coagulation of muscle extracts 
(v. Fiirth, 1896). However, there need not be any relation between rigor and this 
coagulation; for certain substances coagulate muscle extracts even more actively, but 
are incapable of producing rigor during life. 

Muscular E/ccts in Man. Morse showed by the ergcgraph that moderate doses of 
caffein (o.i to 0.6 gm.) increase the muscular work. In the first hour this may be 
raised four or five times; the effect then lessened, but extended over two to seven hours. 
Practically all subsequent experimenters have confirmed the increase, although it 
was not always as great (Hellesen, 1904). Sometimes the increase was mainly in the 
height of contraction (Kraepelin); with others, in the number (Rossi). This indicates 
that the action is both on the muscle substance (height) and on the motor centers 
(fatigue). Rivers and Weber, 1907, found it quite variable, and sometimes followed 
by a decrease. Schumburg showed that the effect is less when the experiment is made 
fasting on an exhausted muscle. The increase of efficiency is due partly to a lesser 
feeling of fatigue (Rivers and Weber), but it is at least in part peripheral, since the effi- 
ciency is also increased when the muscle itself is stimulated electrically. 

Use of Caffein Against Fatigue. The psychic and muscular action of 
caffein are popularly used against fatigue. This will be discussed under 
the "Caffein Beverages." 

Use in Headache. Fairly large doses of caffein (0.5 Gm. = 7^2 grains) 
are rather effective against certain forms of headache, such as migraine, 
neuralgia, fatigue, etc. It may be combined with acetanilid. It does not 
prevent the depressant effects of the latter; but rather increases its tox- 
icity (Hale, 1909; Salant, 1912); it also increases the toxicity of alcohol 
and barium chlorid by its circulatory action. Caffein is also useful in 
some cases of nervous dyspepsia. 

Smooth Muscle. The effect of caffein on smooth muscle consists in a longer and 
more persistent contraction curve. Larger doses prolong the period of relaxation. 
The tone seems to be affected differently in various muscles. The arteries are relaxed 
by relatively small doses; whereas the caffein has a tonic effect on the pelvic portion 
of the ureter (Lucas, 1907). It has very little effect on the uterus (Rohrig); and none 
on peristalsis (Nasse, 1866). . 

Other Peripheral Actions. Caffein has no action on peripheral nervous 
structures when it is used systematically (Aubert, 1872); nor does it 
cause any local irritation. 

It has a paralyzing action only when it is applied in a very strong paste directly to 
the nerve (Pratt). It does not act on any ganglia, nor on any glands other than the 
kidney; nor on red corpuscles, nor on fibrin formation. Small doses increase the move- 
ments of leucocytes in shed blood, whilst higher concentrations kill them. 

Lower Organisms. The actions of caffein on these are not characteristic (Brunton, 
1882: oxidation of guaiac; Haskins, 1903: gas formation by yeast; Bokorny, 1894, and 
Korentschewsky, 1903: amebae; Romanes, 1867: medusae; Sollmann, 1906: adult and 
embryonic fish; Pickering, 1893: embryonic chick's heart; Ransom, 1912: germination 
of seeds). 

Metabolism. The results of different investigators have been con- 
tradictory, but it appears that caffein causes a rather small and variable 
increase in urea and CO 2 . Both effects are probably indirect; the urea 



CAFFEIN AND OTHER METHYL-XANTHINS 205 

being explained by the diuresis, the CO^ by the increased movements. 
This also explains the slight rise of temperature. 

The earlier investigators claimed diminished urea excretions (J. Lehmann, 1853; 
Bocker, 1854, and others), with varying results as to CO 2 . The earlier work has not 
been confirmed, and may possibly be explained by imperfect methods. (However, 
Farr and Welker, 1912, describe decreased N elimination after theophyllin in health and 
renal disease; whilst Endilyi claims an increase of N after theophyllin or theobromin. 
The contradictions probably depend on differences of diuresis.) C. J. Lehmann, 
Voit, Roux and others have demonstratedincreased urea excretion after caff ein; Reichert, 
increased heat production; Heerlein, 1892, Edsall and Means, 1914, and Higgins and 
Means, 1915, found increased CO 2 and 62 metabolism, with therapeutic doses. Salant 
and Phelps, 1910, and Salant and Rieger, 1914, found slight changes in the excretion of 
creatin and creatinin. 

Temperature. The rise was demonstrated by Binz and Peretti, 1878. It is very 
slight in normal animals (i to i.sC.). It is perhaps rather more effective in preventing 
the fall of temperature which occurs in light narcosis, but is ineffective in deep narcosis 
(Pilcher, 1912). The rise is much greater in thyroidectomized dogs (Karelkin, 1914). 

Glycosuria. During the caffein or theobromin diuresis, there is commonly a slight 
hyperglycemia and glycosuria, especially in rabbits fed on carbohydrate food. How- 
ever, it occurs also in fasting animals (E. Hirsch, 1915). It may be induced by oral 
administration, and occurs also in cats, but not in dogs (Salant and Knight, 1909). 
The phenomenon, which occurs also with other diuretics, has not received a satis- 
factory explanation (Miculicich, 1912). It is not renal, for sugar appears in the urine 
only when there is a considerable rise of blood sugar (Hirsch). The hyperglycemia 
indicates increased glycogenolysis, which resembles that produced by piqure (Nishi, 
1909). Like this, it is generally (but not always; Jarisch, 1914) prevented by section 
of the splanchnics, excision of the suprarenals (A. Mayer, 1906) and by nicotin (Hira- 
yama, 1911). It must therefore be usually central, perhaps through increased reflex 
irritability; but under certain conditions it is also peripheral (Jarisch). 

Digestion. The effects will be discussed under the beverages. 

Circulation. Caffein acts on the heart and blood vessels, peripherally 
and centrally. The effects are therefore quite complex and vary with the 
dose and other conditions. The predominant action of therapeutic and 
moderate physiologic doses consists in vasodilation, combined with suffi- 
cient cardiac stimulation to maintain the blood pressure, or even to raise 
it somewhat. Both actions should combine to favor the blood flow, and 
would therefore be useful in circulatory diseases; the diuretic action being 
a further desirable feature. On the other hand, the effects of caffein are 
not so powerful nor so lasting as those of digitalis ; and its side actions often 
interfere with its use. The other methyl-xanthins act very similarly to 
caffein, and the same description probably applies to all. 

Stages of Action. -The effects in animals may be divided into the im- 
mediate effects of intravenous injection, the more persistent effects of 
moderate (stimulant) doses; of larger depressant doses; and fatalities 
(Sollmann and Pilcher, 1911; Wood, 1912; Salant, 1913; Pilcher, 1912). 

Intravenous Injection of Caffein. This produces a fairly severe fall of blood pressure, 
with prompt recovery. The acute fall of pressure is presumably due to depression of the 
myocardium by the concentrated drug. It does not occur with other methods. of ad- 
ministration, and therefore has little practical importance. It is not characteristic for 
caffein, but occurs with many other drugs. The organ volume (oncometer) falls with 
the pressure (indicating that the action is cardiac). Direct observation of the heart 
shows dilation with diminished excursions. The heart rate is quickened and the vaso- 
motor and respiratory center are stimulated by the low pressure. 

Stimulant Doses. Small and moderate doses (to 20 mg. per kilogram) 
generally produce a slight (10 to 20 mm.) rise of blood pressure, usually 
with more or less increase of the heart rate. The tone of the hearths 
increased and the amplitude of its excursions may be greater. This, 



2O6 MANUAL OF PHARMACOLOGY 

and the faster rate, raise the output of the heart. The vein pressure is 
not changed (Capps and Matthews, 1913). The blood flow is increased 
(Landgren and Tigersted, 1892; Loewi, 1905). The volume of the 
splanchnic organs (Phillips and Bradford, 1887; Albanese, 1881; Gottlieb 
and Magnus, 1901; Loewi, 1905) and of the cerebrum (Roy and Sherring- 
ton, 1887) increases. This oncometric change is more marked and more 
persistent than that of the blood pressure, and therefore indicates a marked 
vasodilation. It has been claimed that the dilation is more powerful 
in the kidney than in other organs (Phillips and Bradford; Loewi); but 
in fact it seems to be about equal at least in the splanchnic area (Sollmann 
and Pilcher). The vasodilation is peripheral, since the perfusion method 
shows that the vasomotor center is actually stimulated. Ordinarily, the 
peripheral dilation is more powerful than the central constriction; but 
under some conditions the constriction may predominate, so that the 
oncometer falls with the rising pressure. This, however, is very excep- 
tional. The older conception of a powerful and constant constriction was 
based on slender and indirect evidence (mainly on the experiments of 
Wagner, 1885, and Schroeder, 1886). Vinci, 1895, found that caffein 
gave a much larger rise of blood pressure (presumably cardiac) in animals 
which had been weakened by anemia or starvation. 

Depressant Doses. Doses of caffein above 40 mg. per kilogram progressively lower 
the blood pressure, until a level of 60 to 85 mm. is reached, with doses of about 140 mg. 
per kilogram. This level is then maintained until death approaches. If the original 
pressure was low, it may not be further lowered. The tone of the heart is decreased, 
so that it gradually dilates, and the amplitude of the excursions and the output are 
diminished. The oncometer falls with the blood pressure, so that cardiac depression 
is the dominant element. It is accompanied, however, by a progressive and finally 
complete vasomotor paralysis, when epinephrin, splanchnic, and other forms of vaso- 
motor stimulation become less and less effective. (Epinephrin still causes a relatively 
small rise through cardiac stimulation.) The vasomotor center can be shown (by the 
perfusion method) to be stimulated even after very large doses; but this stimulation 
can not become effective against the peripheral paralysis. 

Fatal Doses. Death occurs by acute cardiac failure. Caffein serves to lower the 
resistance of the heart, so that the fatal dose may vary greatly in different animals. 

Factors Involved in the Circulatory Actions of Caffein. These may be summarized 
as follows: Cardiac stimulation or depression, according to the dose and rapidity of 
injection. 

Increased heart rate, not due to vagus depression. (If the vagus is intact, there may 
be slowing through central stimulation, but with large doses the heart escapes from the 
vagus tone.) 

Vasodilation, through peripheral depression of the vasoconstrictor mechanism. 

Central vasoconstrictor stimulation generally ineffectual, also convulsive stimula- 
tion. 

Cardiac irregularities, with large doses. 

Direct Action on Blood Vessels. These tend to dilate when excised organs are per- 
fused with caffein (Beco and Plumier; Cow, 1911). The effect is not very great with 
caffein alone, since the vessels are already dilated after death; but very little caffein 
suffices to counteract the constrictor effect of epinephrin (Sollmann and Pilcher). The 
caffein must therefore act on or beyond the structure stimulated by epinephrin; i.e., 
on the receptive or muscle substance. 

Special Vessels. The Coronary Vessels are not affected directly by caffein or theo- 
bromin (Bond, 1911; Rabe, 1912); but in intact animals there is increased blood flow 
and some passive dilation with therapeutic doses when the blood pressure rises (F. 
Meyer, 1912). Toxic doses generally dilate (Sakai and Saneyoshi, 1915; Macht, 1915). 
The Lung Vessels are first constricted, soon ceding to dilation (Berezin, 1914). Macht, 
1914, observed dilation of excised pulmonary artery. Theobromin was practically 
negative. Baehr and Pick, 1913, found no effect with caffein on lung perfusion. The 
Liver veins are dilated (Berezin, 1914). The vessels of the pi a mater and retina are 
dilated during life (Hirschf elder, 1915). The dilation of the eye-vessels may raise the 
intra-ocular tension even with falling systemic blood pressure (Wessely, 1915). 



CAFFEIN AND OTHER METHYL-XANTHINS 207 

The Heart Rate. When the vagi are intact, small doses of caffein may cause some 
slowing through stimulation of the vagus center (Swirski, 1904) and increased vagus 
excitability (Fredericq, 1913). This slowing does not occur in all animals. With larger 
doses, or always if the vagi are paralyzed, the rate is markedly quickened. With the 
vagi divided, 2 mg. per kilogram increases the rate by 25 per cent.; 20 mg. per kilogram 
by 33 per cent.; 30 to too mg. by 50 per cent. Beyond this there is no further increase, 
but the heart shows arythmia and irregularity. The quickening is evidently not due to 
vagus depression, since it occurs after section of the vagi or atropin (Johannsen, 1869, 
and others). The vagus tone is indeed lost after large doses (Aubert, 1872, and others), 
and the response to vagus stimulation is uncertain; but direct central vagus stimula- 
tion may still cause marked slowing. 

Nor is the quickening due to stimulation of the accelerator mechanism. The 
effect occurs after excision of the stellate ganglia and in the excised mammalian heart. 
Swirski, 1904, found that when the caffein quickening had reached its maximum, a 
further increase would be obtained by stimulating the accelerator. (Large doses 
destroy the response to accelerator stimulation, Fredericq, 1913.) Cushny showed that 
the details of the cardiac curve are different in caffein and accelerator stimulation. 
Dixon, 1903, found that caffein quickens the heart after apocodein, which paralyzes 
the accelerator endings. Pickering, 1893, observed it in the embryonic chick's heart 
before the nervous structures had become developed. The quickening must therefore be 
due to increased contractibility of the muscle substance itself. 

Frog's Heart. Small doses increase the rate (Voit, 1860), excursions (Wagner, 1885), 
pulse volume, and especially the absolute force or maximal resistance (Dreser, 1887). 
The diastole is shortened more than the systole. 

Large doses cause slowing and weakening (Maki), with diastolic tendency (Faval). 
The heart beats for some time after the skeletal muscles are in rigor (Wagner). The 
final arrest may be either in systole (Johannsen, 1869) or diastole (Faval). 

With hypodermic injection, the stimulant dose is 5 mg.; the depressant 25 mg. 
(Wagner). Dropped on the exposed heart, .1 : 10,000 is stimulant, and i :ioo depressant 
(Sollmann). 

The terrapin's heart responds similarly to the frog's (Beyer, 1885). 

Excised Mammalian Heart. When studied by modifications of the Langendorff 
method, caffein and the other xanthins produce increased rate, amplitude, and force of 
the cardiac contraction, and generally quickened coronary flow (Hedbom, 1899; O. Loeb, 
1904; Beco and Plumier, 1906; Lifschitz, 1907; Plavec, 1909). The increased amplitude 
is first in the systole, then also in the diastole; but the cardiac tone is not increased 
(Plavec). The stimulation is greatest with theophyllin, then theobromin, then caffein. 
The coronary vasodilation is also greatest with theophyllin, but least with theobromin. 
This indicates that the increased flow is not simply due to the increased contractions. 

These experiments seem to refer only to stimulant concentrations, and they may be 
considerably modified by changing the conditions (Lifschitz, 1907; Plavec, 1909; Bock, 
1900). 

Mammalian Heart in Situ. The effects of the various doses were studied by Pilcher, 
1912, with the results described under the general discussion of the circulatory effects. 

Experimental Heart-block. In complete block, caffein increases the strength of the 
ventricular contraction. Larger doses produce ventricular extrasystoles and tachy- 
cardia. The strength of the auricles is temporarily quickened (Egmond, 1913). 

Circulatory Effects in Man. These correspond with what would be 
expected from animal experiments. With doses to 1.5 Gm., the acute 
effects are inconstant and generally slight. The heart rate may be slowed 
or quickened or unchanged (literature, Sollmann and Pilcher; Wood, 
1912). Palpitation is common, but apparently largely subjective. The 
blood pressure may rise (Wood, 1913); or fall (Mirano, 1906); or remain 
unchanged (Lucas, 1914; Newburgh, 1914). The volume of the human 
arm is diminished (Hewlett, 1913). The blood flow tends to improve by 
increased systolic output. 

Unman Blood Flow. Hypodermic doses of 0.3 to 0.5 Gm. in resting men, produce a 
definite increase of the total blood flow (Keogh-Lindhard method). The improvement 
occurs by increased systolic output. It does not occur during work. Means and 
Newburgh, 1915, attribute the rest effect to increased venous return to the heart, by 
some action outside of the heart. During work, the venous return is adequate even 
without caffein, and is not materially increased by the drug. 



208 MANUAL OF PHARMACOLOGY 

Blood Pressure. In advanced myocarditis, full and continued doses of caffein (about 
i Gm. per day) cause a progressive and permanent lowering of blood pressure, reaching 
a total of 10 to 50 mm. This is parallel to the diuresis, and to the relief of the edema 
and other symptoms (L. Taylor, 1914). Theobromin does not lower the pressure, 
although it is otherwise equally or more efficient. 

Therapeutic Effects on Circulation. The methyl-xanthins are used as 
cardiac stimulants in syncope, and especially in cardiac dropsies. They 
lack the permanent, tonic action of digitalis, but are useful as adjuvants 
or when a quick effect is desired. In Taylor's myocarditis series, the 
results were excellent in one-half, moderate in one-fourth, and unsuccessful 
in one-fifth. Theobromin is effective on the first day, if at all, so that 
its usefulness can be determined more quickly than with caffein. Further- 
more, the side actions of caffein interfere with its employment, especially 
in excitable patients. Theobromin therefore deserves preference. 

In hypotension and infectious diseases, caffein fails to improve the 
circulation (Newburgh, 1914; Lucas, 1914). 

Clinical Side Actions. Effective doses of caffein, especially in cardiac 
cases, produce palpitation, insomnia, nausea, vomiting, headache, vertigo, 
restlessness, anxiety and sometimes delirium. Theobromin is relatively 
free from these objections, but they may arise (Seifert, Nebenwirkungen, 
1915, p. 128). They are also produced by theophyllin (Widmer, 1914; 
Seifert, I.e., p. 131). The side actions occur much more violently, and 
with much smaller doses (0.3 Gm. of caffein per day, or even less) in 
patients with interstitial nephritis (L. Taylor). 

Effects on the Urine. The most important therapeutic effect of caffein 
consists in a considerable diuresis. The increase concerns mainly the 
water of the urine. The absolute quantity of solids is also increased, but 
less than the water, so that their percentage is lowered. The efficiency 
varies with conditions, especially with the amount of water in the body 
(Widmer, 1914) ; the diuresis is most abundant in dropsical conditions, and 
fails entirely with dry food. It is much greater in wet-fed rabbits than 
in dogs. It fails also in glomerular nephritis, but is effective in tubular 
nephritis unless the vessels are involved. The albumin in nephritis may 
be increased. Theobromin and especially theophyllin are more effective. 
This difference is explained in part by the relatively larger doses which 
can be taken without prohibitive side actions. 

Mechanism of the Diuresis. No agreement has been reached on this 
subject. The increased renal circulation resulting from the simultaneous 
cardiac stimulation and vasodilatation must be a powerful factor, and may 
in itself suffice to explain the diuresis. This does not exclude the possi- 
bility of stimulation of the secretory epithelium; but the direct evidence 
for this is weak. This theory of secretory stimulation, which is still 
widely accepted, was advanced by von Schroeder, mainly because he 
could not explain the diuresis by the blood-pressure changes; but he was 
ignorant of the dual and complementary action of caffein on the heart 
and vessels. At present, its main supports are the occasional failure of 
complete agreement, in minor details, of the circulatory and urinary 
changes; and the perfusion experiments of Richards and Plant, 1915. 

Relation of Caffein Diuresis to Circulation. Schroeder, 1886 and 1887 (and inde- 
pendently, Langaard) found that morphinized rabbits often fail to respond to caffein. 
Assuming this to be due to vasoconstriction, he administered chloral to paralyze the 
center, or divided the renal nerves, and now found caffein uniformly effective. This 
appeared to show that the diuretic effect was opposed by the circulatory effect of caffein, 



CAFFEIN AND OTHER METHYL-XANTHINS 2OQ 

namely, vasoconstriction. However, it is now known that caffein ordinarily causes 
vasoduation, and not vasoconstriction; and von Schroeder's results have not always been 
confirmed by later observers (Loewi, 1905). It appears that chloral heightens the re- 
sponse to caffein, but von Schroeder himself showed that the same result is attained by 
paraldehyde in doses which certainly did not paralyze the vasomotor center. The 
synergism may perhaps be explained as a simple summation of the vasodilator effect 
of the two drugs (Albanese, 1900). The combination of caffein with salines also gives 
a greater diuresis than either alone; whilst a mixture of the several methyl-xanthins only 
gives simple addition (Schlosser, 1913). 

When the diuresis is compared with the changes in the oncometer (Phillips and 
Bradford, 1887; Gottlieb and Magnus, 1901; Loewi, Fletcher and Henderson, 1905), 
they are found to exhibit a remarkable parallelism. During the intravenous fall, the 
urine flow ceases; as the oncometer recovers, the urine resumes, to reach its maximum 
with the rise of the oncometer, after which both shade gradually back to the normal. 
After large doses of caffein, there is neither dilation nor diuresis; 

If the conditions are otherwise unfavorable to diuresis, as in dry-fed animals or when 
the kidneys have been injured, the caffein dilation may fail to result in diuresis (Loewi; 
Phillips and Bradford). Other discrepancies have occasionally been noted (Gottlieb 
and Magnus, 1901), but they are exceptional and usually insignificant; especially in 
view of the statement of Loewi that the blood flow may be increased (as judged by the 
arterial color of the blood in the renal vein) even when the kidney volume is kept con- 
stant by encasing it in plaster. 

The restitution of blood after hemorrhage is not modified by the caffein diuresis, so 
that there is no sign of altered permeability of the vessels (Gaisboeck, 1911). The vis- 
cosity of the blood is said to be diminished (Loria, 1912). 

Perfusion of Excised Mammalian Kidneys. Munk, 1887, adding caffein to the per- 
fusing blood, found a large increase of ureter flow and a moderate increase of vein flow. 
This result is certainly exceptional (von Schroeder, 1887; Robert, 1886; Sollmann and 
Hatcher, 1907). It would naturally be explained by the vasodilator action; but Rich- 
ards and Plant, 1915, report increased urine flow even when the perfusion flow is kept 
constant. This would mean that a diuretic effect occurs apart from circulatory changes. 
Further observations are desirable. 

Changes in the Size of Excised Kidney Cells and Absorption of Saline Solutions. 
Sections of kidney treated with caffein absorb less fluid from hypotonic salt solutions 
than do control sections (Filehne and Biberfeld, 1902); but the change is small and in- 
constant (Sollmann and Hatcher, 1907). Histologically, the epithelium of the convo- 
luted tubules tends to swell slightly in caffein solution (W. W. Williams, 1907). 

Intra-mtam Staining. Sobieransky found that caffein (and saline) diuresis prevents 
the intra-vitam staining of the tubular nuclei by indigocarmin. Assuming that the 
staining is due to reabsorption, he argued that this reabsorption was paralyzed by caf- 
fein; and extending this, he argued that the diuresis is due to failure to reabsorb the 
glomerular fluid. There is no secure basis for either assumption, and the absence of 
pigment would be the natural result of the flushing of the kidneys by the diuresis. 

Ureter Peristalsis. Lucas, 1907, found that caffein has a tonic effect on the pelvic 
portion of the ureter. This would have but little influence on the urine flow, since this 
is not influenced even by a considerable negative ureter pressure (Sollmann). 

Perfusion of Frogs' Kidneys. Cullis claims that if the perfusion is arranged so that 
the caffein acts only on the glomeruli, the effects are unsatisfactory; if it is confined to 
the tubules, it increases the perfusion flow and starts the urine. This result would in- 
dicate that the action of caffein is on the tubules; but it is opposed to the findings in 
mammalian nephritis; and the conditions are too complex to be satisfactory. 

Renal Irritation by Caffein. Ordinary doses of caffein give no indications of injury 
to the kidney cells; in nephritic patients, however, large doses may be followed by 
marked albuminuria. Animals also respond to large doses (40 mg. per kilogram), 
especially when long continued, by definite nephritic changes: albuminuria of 1.4 per 
1,000; leucocytes, epithelium and casts in the urine. The kidneys show dilated vessels, 
cloudy swelling, to vacuolar degeneration and necrosis of the epithelium, and slight 
interstitial swelling. These histologic changes may be present even when the urine 
appears normal. Dogs are more subject than rabbits, but the lesions are usually only 
transitory, disappearing a few days after discontinuance. No lesions are perceptible 
with doses of 5 to 10 mg. per kilogram, corresponding to 5 to 10 grains in man (Vinci, 
1914). 

Caffein in Experimental Nephritis. Hellin and Spiro, 1897, found caffein ineffective 
in glomerular and general nephritis, but quite effective in pure tubular nephritis. This 
has been confirmed by Schlayer and Hedinger, 1007; and by Pearce, Hill and Eisenbrey. 
1910; and these further showed that the failure of diuresis is accompanied by failure 



210 MANUAL OF PHARMACOLOGY 

of the oncometric reaction. This is important evidence that the diuretic action is exerted 
on the glomcrular circulation and not on the tubular epithelium. 

In uranium nephritis, diuretics, including caffein, are effective during the early 
polyuric stage; but they become ineffective when the anuric stage is reached, although 
the circulatory response may be well preserved (MacXider, 1912; Boycott and Ryflfel, 
1913). This depends on the intactness of the renal epithelium (MacNider, 1914). In 
the subacutely fatal form, caffein and the other methyl-xanthins did not prolong life 
(Christian, 1914). The phenolphthalein excretion was rather improved, but the nitro- 
gen retention in the blood was not materially affected (Christian, 1913; Christian and 
O'Hare, 1913; Fitz, 1914). 

For chromate mphritis, on the other hand, theobromin and theocin were distinctly 
harmful, since they diminished the phthalein output and the animals died more promptly 
(O'Hare, 1915), although the nitrogen excretion was unchanged, and the elimination of 
urine and chlorid was increased (Fitz, 1914). Finally, the kidneys ceased to react 
(fatigue?). This is especially marked if the caffein has been preceded by several injec- 
tions of saline (Mosenthan and Schlayer, 1913). 

Failure of Caffein Diuresis. Aside from glomerular and general nephri- 
tis, there are a number of other factors which may interfere with diuresis. 
The quantity of water in the tissues is very important; and also the water 
in the food, which is the ultimate source of the water of the urine. There 
is, consequently, a conspicuous difference between dry-fed and wet-fed 
rabbits (von Sobieranski, 1895; Loewi, 1905); and presumably the limited 
water intake of dogs accounts in part for their lesser diuresis response 
(Sobieranski). Schroeder, 1887, found the water content of the rabbits' 
blood decreased by 10 per cent, after an effective diuresis. The same fac- 
tor is active in the poor diuresis of hemorrhage (Michaud, 1904), and in 
the superior diuresis in dropsy (Hofmann, 1880); but other factors may 
cooperate. On the other hand, when an effective water diuresis has been 
secured by excessive continued water administration (Sollmann and Hof- 
mann, 1905) or in diabetes mellitus (Meyer, 1905), there is no further 
increase when caffein is added. 

The Diuretic Response in the Normal Human Subject. This is comparatively small. 
Raphael, 1904, found the daily urine increased (under otherwise constant conditions) 
by 0.5 Gm. caffein sodium salicylate, 42 per cent.; 0.5 Gm. theobromin sodium salicy- 
late, 2 per cent.; 1.5 Gm., 14 per cent.; 3 Gm., 53 per cent. This was much less than the 
increase secured by the consumption of an extra liter of water or beer (100 per cent.); 
whilst a liter of mUk increased the urine by 153 per cent. 

Interference by Vasoconstriction and Vagus. Whilst the vasomotor stimulation 
has not ordinarily the importance attributed to it by von Schroeder, it may sometimes 
be sufficiently powerful to overcome the peripheral dilator effect. At all events, the 
diuresis is aided by the hydrocarbon narcotics. Curare is also said to aid the diuresis 
(Cervello and LoMonaco). 

Corin, 1886, claimed that the vagi exert an inhibitory influence, which Anten, 1901, 
attributed to a direct inhibitory influence of these nerves on the secreting cells. Atropin 
would therefore increase the diuresis. These claims need confirmation, before they can 
be accepted. 

1- 'allure in Repeated Administration. It is a common clinical experience 
that caffein often becomes ineffective after a time (LeNoir and Camus, 
1903). This is not surprising when it is remembered that the factors 
which favor and impair the diuretic response are apt to vary from time 
to time. The disappearance of the edema, for instance, would decrease 
the response. 

In experiments, it is also noted that repeated injections become less and less effective 
(Phillips and Bradford, 1887; Loewi, 1905). This, however, is simply due to the fact 
that the depressing dosage is gradually attained. 



CAFFEIN AND OTHER METHYL-XANTHINS 211 

Relative Efficiency of the Xanthin Derivatives. Caffein has now been 
largely supplanted, as a diuretic, by theobromin (diuretin), and more 
lately by theophyllin (theocin), which are credited with a much more 
powerful action. With theobromin, this is not surprising, since the cus- 
tomary dose is four times as large as with caffein; with theophyllin, the 
superiority is genuine. Both are superior to caffein in producing less of 
the nervous side actions. Theobromin also acts much more promptly, 
i.e., within a day, whilst caffein requires four days to reach its full effi- 
ciency. Exceptionally, caffein succeeds where theobromin fails (Chris- 
tian, 1915). 

No reliable quantitative experiments on the relative diuretic action of the various 
xanthin derivatives have been made the much-quoted experiments of Ach being based 
on too few animals to have much value. The attempt to correlate the diuretic and 
muscular action (Schmiedeberg) is therefore premature. Mendel and Kahn, 1913, 
found that most of the newer methylated xanthins are not diuretic. 

Differences in the Members of the Group. Caffein has the most 
powerful central nervous action, with relatively weak peripheral effects. 
The strongest diuretic action is produced by theophyllin (theocin), which 
also causes the most marked cardiac stimulation and coronary dilation. 
Its central effects and its action on muscle approach those of caffein. 
Theobromin (diuretin) acts most powerfully on muscle; its effect on the 
heart and urine are intermediate. It causes very little central stimula- 
tion. (The toxicity of theobromin to isolated muscle is 1^3 that of caffein 
(Veley and Walker, 1910).) 

The pharmacology of theobromin was first investigated by Mitcherlich, 1859, and 
further by Filehne, 1886. It was used experimentally as a diuretic by von Schroeder, 
1887, to avoid the supposed vasoconstriction of caffein. He found it effective without 
chloral; and the action on oral administration extended over twenty hours presumably 
because its insolubility caused slow absorption. This led to its clinical introduction 
by Gram. 

The Composition of the Urine. von Schroeder, 1886, showed that the 
urine in caffein diuresis is more diluted (its molecular concentration may 
fall below that of the blood; Dreser, 1892) ; but that the absolute quantity 
of the solids urea as well as salts is increased. Entirely similar changes 
occur in other forms of diuresis, so that they are not characteristic of 
caffein, and throw no light on its actions. The urinary protein in nephritis 
is ordinarily not increased. 

Different investigators disagree as to which of the solids is most increased, the salts 
(LeNoir and Camus, 1903), or the urea (Anten). Presumably this varies with circum- 
stances. In rabbits, the salts may be increased without diuresis (Katsuyama, 1898 
and 1901); and this may also occur when caffein is given in human diabetes (E. Meyer, 
1905). On the other hand, Sellei, 1912, describes theophyllin diuresis with little change 
in the specific gravity or solids. In rabbits, theophyllin increased the K and Na, but 
not parallel with each other or with the diuresis (Bock, 1911). The cfilorid-retaining 
mechanism is broken down in rabbits (Pototsky, 1902; Loewi, 1902), but not in dogs or 
man (Sollmann, 1903; Haskins, 1904; Sollmann and Hofmann, 1905; Saccone, 1911). 

Sollmann and McComb, 1899, found that caffein did not increase a physiologic 
albuminuria and Emerson, 1902, saw no increase of albumin in acute or chronic nephritis 
under theobromin. Pouchet and Chevalier, 1903, claim that large doses of theophyllia 
injure the glomerular and tubular epithelium. 

Astolfani, 1905, states that caffein, in common with other diuretics, increases 
hippuric acid synthesis, when benzoic acid is administered. 

The secretion of milk is not affected by caffein (Ott and Scott, 1912). 

Therapeutic Use of Diuretic Action. The methyl-xan thins are em- 
ployed mainly for the removal of cardiac effusions. The diuresis is pro- 



212 MANUAL OF PHARMACOLOGY 

portional to the effusion, sets in promptly, and ceases when the drug is 
withdrawn. It is therefore especially useful for two or three days at the 
beginning of the more slowly acting but more permanent digitalis treat- 
ment. Caffein is the least active of the series. It may be given in the 
doses of 0.3 Gm. (5 grains) of citrated caffein, in watery solutions, three 
times a day, but Taylor found at least 0.5 Gm., four times daily, neces- 
sary for a full effect. 

Theobromin (i Gm. or 15 grains of theobromin-sodium-salicylate, or 
diuretin, in water, four times a day) has the advantage of producing a 
better diuretic effect with the least side effects. Taylor found that a 
daily dose of 30 grains produced very little effect; 40 grains a moderate 
diuresis; but 80 grains (5 Gm.) were required to secure the maximum 
efficiency. This quantity, when divided into four doses, was well tole- 
rated. It has also been used intravenously, 20 c.c. of 5 per cent., Neuhof, 
1913 ; but it is doubtful whether this is justified. Theophyllin (theophyllin- 
sodium-acetate, or theocin) is the most powerful, but has been charged 
with sometimes causing renal irritation. Its dose is 0.3 Gm. = 5 grains, 
three times per day, administered in hot tea. 

In renal or hepatic effusions, the efficiency is less certain. In acute or 
chronic parenchymatous nephritis, there is often no response whatever, 
while chronic interstitial nephritis usually responds (J. Miller, 1912); but 
unless the dosage is very small and carefully watched, the toxic side ac- 
tions may set in, and the renal condition grow worse. Theophyllin and 
theobromin may cause renal irritation; it would therefore be better to 
avoid the methyl xanthins when the kidneys are acutely irritated. In 
anuria, the methyl xanthins are generally ineffective. Christian et al., 
1915, state that diuretics are generally ineffective in chronic nephritis, 
unless there is edema. They would therefore be of little use against 
nephritic toxemia. 

Absorption, Fate and Excretion. Caffein is readily and completely 
absorbed: none appears in the feces even after large doses. Only a small 
fraction is excreted unchanged in the urine. This excretion starts and is 
mainly completed promptly, but traces may continue for two or three days 
(Salant and Rieger, 1912). A somewhat larger fraction loses a part of 
its methyl groups, and appears in the urine as di- and mono-methyl- 
xanthins. It is not known whether this is effected by oxidation or hydroly- 
sis. The remainder up to 80 per cent. is completely oxidized to urea. 
Practically none of the caffein is converted into uric acid (which is largely 
the fate of hypoxanthin and of xanthin) . 

Theobromin undergoes changes similar to caffein, but a larger fraction 
(32 per cent.) escapes decomposition. The greater part leaves as hetero- 
xanthin. 

Quantitative Excretion. The quantity of caffein which is excreted unchanged varies 
with the dose and with different animals, being only i per cent, in carnivora, less than 
8 per cent, in man, and 6 to 20 per cent, in rabbits (Rost, 1895; Salant and Rieger, 1912). 
The relative quantity of the various mono- and dimethyl-xanthins also varies in differ- 
ent animals, representing 10 to 40 per cent, of the caffein (Albanese, 1895; Bondzynski 
and Gottlieb, 1895, Krueger and Schmidt). The literature has been summarized by 
Bloch, 1906. The demethylation is retarded by alcohol (Salant and Phelps, 1912). 
Emory and Salant, 1909, report experiments on the decomposition of caffein in the 
liver. A trace appears in the stomach, intestines and in the bile (Salant and Rieger). 
The gastro-intestinal excretion is higher when the kidneys are excised (Salant and 
Rieger, 1913). The loss of methyl groups occurs in pretty much all organs (J. Schmidt, 
1910). 



CAFFEIN AND OTHER METHYL-XANTHINS 213 

Toxicology. The fatal dose of caffein is so large (presumably about 
10 Gm.), 1 that no fatal case of poisoning is on record; but doses above 
i Gm. may produce alarming symptoms, and even therapeutic doses may 
cause unpleasant side actions. 

With larger doses, the pulse is full and hard, quickened or slowed, with palpitation 
and precordial distress (sometimes anginal attacks). The head is heavy, throbbing, 
confused; often intense headache and great anxiety. Restlessness and excitement, 
insomnia (sometimes mild delirium, aphasia, fever). Vertigo, nausea, general discom- 
fort, fatigue, weakness (sometimes burning in the throat, gastric distress, heat flashes, 
perspiration, insensible pharynx, swollen tongue, ringing in the ears, flashes in eyes). 
Tremors of jaws, hands and feet, and muscular stiffness. Quickened, embarrassed 
respiration. Increased micturition (sometimes ardor urinae and erection). 

In very severe cases, there is vomiting (sometimes violent diarrhea and tenesmus); 
violent choreic tremors. Collapse, with small, irregular arrhythmic pulse, cold extremi- 
ties, dilated pupils. Consciousness is usually intact, but there may be delirium. 

Toxic Effects on Animals. The symptoms in animals correspond fairly to those 
observed in man: restlessness and increased reflexes; increased respiration, vomiting 
and diarrhea; muscular weakness. Then: clonic or tetanic convulsions, during which 
respiration may stop, with or without resumption; exhaustion and increasing paralysis; 
death in one to four hours. The fatal dose lies about 0.15 Gm. per kilogram. Dogs 
and cats are somewhat more susceptible than rabbits and guinea pigs. The dose by 
mouth is but little larger than the intravenous dose, except in rabbits (Salant and 
Rieger, 1910, 1912). Young mice are more resistant than old. The effects in birds 
are similar (Brill); in frogs they are modified by the onset of rigor. The toxicity is 
diminished by temperature above 98F. At 45F. the muscular effects predominate; 
while the convulsions become more prominent as the temperature is increased (Salant, 



Recovery is usually complete within a day, even when the symptoms 
were violent. Some restlessness and weakness may remain for a time. 
It is claimed (Kunkel) that large therapeutic doses have been followed 
by nephritic urine, but on the other hand, daily doses of 1.25 Gm. have 
often been given without detriment (Becher, 1884). Idiosyncrasy toward 
caffein is marked, as every one knows. Children and nervous and weak- 
ened individuals appear to be relatively more susceptible. Overdoses 
should be avoided, especially in myocarditis. 

Treatment. This would consist in evacuation and narcotics bromid, 
alcohol, chloral, or morphin. The principal indication would be to reas- 
sure the patient. 

Theobromin and theophyllin, in excessive doses or in susceptible in- 
dividuals, may produce toxic effects similar to caffein: headache, nausea, 
vomiting, epileptic spasms, albuminuria, gastric hemorrhage, etc. (Robert, 
Schmiedeberg, Seifert). These manifestations are, however, rare. In 
epileptic patients, large doses of theophyllin are said to have produced 
attacks (Schlesinger, 1905). Chevalier, 1914, claims that some commer- 
cial theobromins contain toxic impurities; this requires more confirmation. 

PREPARATIONS CAFFEIN GROUP 

* Cajfeina, U.S.P., B.P.; Caffein (Thein); C 8 Hi N 4 O2 + H 2 O. A feebly basic alka- 
loid, usually prepared from tea. White, silky, needle-crystals; odorless; bitter taste. 
Sol. in water (1:46) and in ale. (1:66). Its solubility in water is greatly increased by 
heat, citric acid, benzoates or salicylates, bromids, antipyrin and a number of other 
substances. Incompatible with tannin. Dose, 0.15 Gm., 2\ gr., U.S. P.; 0.06 to 0.3 
Gm., i to 5 gr., B.P.; in capsules. Maximum dose, 0.5 Gm., 8 gr. 

* Caffeina Citrata (Caffein. Cit.), U.S.P.; (Caffeina Citras.), B.P.; Citratecl Calk-in; 
Caffein Citrate. An unstable compound of uncombined caffein and citric acid, containing 

1 The doses refer to pure caffein; the corresponding doses of citrated caffcii; '\vice as 

large. 



214 MANUAL OF PHARMACOLOGY 

not less than 48 per cent, of caffein. White powder, odorless; slightly bitter, acid taste. 
Citrated Caffein gives a clear syrupy solution with a little water, but precipitates on 
dilution. The precipitate redissolves on the further addition of water, the solubility 
being about 1:32. Incompatible with carbonates. Dose, 0.3 Gm., 5 gr., U.S. P.; 
0.12 to 0.6 Gm., 2 to ip gr., B.P., in water. The free acid renders this unsuitable for 
hypodermic use. Maximum dose, i Gm., 15 gr. 

Caffeina Citrata Ejferuescens (Caff. Cit. Eff.), U.S.P.; Caffeince Citras E/ervescens 
(Caffein. Cit. Eff.), B.P.; Effervescent Caffein Citrate. A granulated mixture of Sodium 
Bicarbonate and Tartaric and Citric Acid, with about 2 per cent, of Caffein. Dose, 
4 Gm., i dram, U.S.P.; 4 to 8 Gm., i to 2 drams, B.P. 

* Caffeina Sodio-benzoas (Caff. Sod. Benz.), U.S.P. A mixture of about 50 per cent, 
caffein with sodium benzoate. A white powder; odorless and of a bitter, aromatic 
taste. Freely sol. in water (1:1.1), sol. in ale. (1:30). Dose, 0.3 Gm., 5 gr., by mouth; 
hypodermic, 0.2 Gm., 3 gr., U.S.P. ; the most suitable compound for hypodermic use. 
Maximum dose, i Gm., 15 gr. 

Theobr&mina, Theobromin. A dimethylxanthin prepared from Cacao seeds (Theo- 
broma Cacao) or synthetically. Very slightly sol. in water. 

* Theobromince Sodio-salicylas (Theobrom. Sodio-Sal.), U.S.P.; Theobrom. el Sod. 
Salicyl., B. P.; Theobromin-sodium-salicylate (Diuretin). Sodium Theobromin 
(CyHT^OaNa) and Sodium Salicylate, in approximately molecular proportions. Not 
less than 46.5 per cent, of theobromin. White, odorless powder; sweetish saline and 
somewhat alkaline taste. Freely sol. in water (1:1); slightly sol. in ale. It gradually 
absorbs carbon dioxid from the air^with the liberation of theobromin, becoming partially 
insoluble in water. It must therefore be protected against exposure to air, and is 
incompatible with acids; also with chloral. It should not be given with meals, to avoid 
precipitation by the gastric acid. Dose, i Gm., 15 gr., U.S.P.; 0.6 to 1.2 Gm., 10 to 20 
gr., B.P.; well diluted. Solutions do not keep. 

Other Theobromin Salts. The following are listed in N.N.R., but have no special 
advantage: Sodio-acetate (Agurin); Sodio-formate (Theophorin). 

* Theophyllina (Theophyll.), U.S.P.;- Theophyllin (Dimethylxanthin, Theocin); 
C 7 H 8 N4O2 + H 2 O. White crystalline powder; odorless; bitter taste. Sol. in water 
(i: 100) and ale. (1:80). Dose, 0.25 Gm., 4 gr., U.S.P., three times a day, in warm tea. 
After two or three days, it should be replaced by theobromin. 

TheophyllincK Sodio-acetas, N.N.R. (Soluble Theocin). Contains 60 per cent, of 
the alkaloid. It dissolves in 23 parts of water. 

Guarana, U.S.P. A dried paste consisting chiefly of the crushed seeds of Paullinia 
Cupana, yielding not less than 4 per cent, of caffein. Dose, 2 Gm., 30 gr., U.S.P. 

Fldext. Guaran., U.S.P. 4 per cent, of Caffein. Dose, 2 c.c., 30 minims, U.S.P. 

CAFFEIN BEVERAGES 

Caffein is an important article of popular consumption, in the form of 
coffee, tea, and other beverages. The usual per capita consumption in 
the United States is about 10 pounds of coffee and i pound of tea (Graham, 
1912). A cup of coffee or strong tea contains about o.i Gm. (i^ grains) 
of caffein. Its effects are somewhat modified by the associated products 
(the volatile products causing more psychic stimulation, the tea-tannin 
and coffee oil deranging digestion); but essentially the actions are those 
of the alkaloids. They consist in increased mental and physical efficiency, 
psychical stimulation, comfort, and relief from muscular and mental fatigue 
and from their attendant unpleasant sensations. These effects may be very 
useful in certain conditions, as in those exposed to severe hardship, hunger, 
fatigue, etc., but ordinarily they are mere luxuries pleasant, but super- 
fluous. They may do no harm if the consumption is kept within bounds; 
but nervous individuals, who are the most apt to be injured by caffein, 
are most likely to exceed these bounds. The bad effects are usually not 
very serious, and disappear promptly if the habit is discontinued. They 
consist in nervousness, tremor, palpitation, insomnia, headache, and diges- 
tive disturbances. 

The habitual consumption of caffein confers a very limited tolerance. 
Its withdrawal does not produce any marked abstinence symptoms. 



CAFFEIN AND OTHER METHYL-XANTHINS 



215 



Coffee and chocolate are useful flavors and extemporaneous vehicles, 
especially for castor oil and cod liver oil. 

Coffee (Caffea) consists of the dried seed of Coffea Arabica, Rubiaceae. The con- 
stituents of the "green bean" are caffein, fat, coffalic and chlorogenic acid, saccharose 
etc. The chlorogenic acid gives a green color with iron, similar to tannin, and in its 
impure form it was formerly called "Caffeotannic acid." Gorter, 1910, has found it in 
about 100 plants. On oxidation it yields caffeic acid. It differs from tannins in that 
it does not precipitate proteins, and is therefore not astringent. The percentage of 
caffein varies in different specimens from % to 2% per cent., usually about 1.2 per cent. 
(Koenig). It exists mainly as caffein-potassium chlorogenate (Gorter, 1908). 

In the process of roasting (i.e., heating the seed to 200 to 25OC.) a small amount of 
caffein is volatilized; but since about 10 per cent, of water is driven off, the percentage 
of caffein is actually a trifle higher (1.25 per cent.). The main change in roasting con- 
sists in the production of aromatic, brown and oily products. This oil (Caffeol or 
Caff eon), according to Erdmann, 1902, and Grafe, 1912, consists of 50 per cent, of fur- 
furol alcohol, and small quantities of valerianic acid, phenol, pyridin, and a nitrogenous 
aromatic substance. It is probably derived mainly from the hemicellulose. 

The beverage, coffee, is a decoction made with 6 to 10 per cent, of the drug. Prac- 
tically the entire caffein (perhaps ^f ) is thus extracted; so that a cup of strong coffee, 
prepared from 15 to 17 gm., contains about o.i to 0.12 gm. of the alkaloid. 

The use of coffee arose in Arabia and Egypt about the middle of the fifteenth cen- 
tury. Coffee and tea were introduced into Europe about the last quarter of the seven- 
teenth century, about the same time as the potato, cinchona, tobacco and chocolate. 

Action of Coffee Oil. The volatile aromatic constituents produce 
local irritation and reflex stimulation, in the same manner as the condi- 
ments. The hot water contributes to this effect; and possibly the greater 
reactivity induced by the caffein heightens the reflex response (Schmiede- 
berg). The local irritation stimulates peristalsis, and with excessive use, 
tends to nervous dyspepsia. It is doubtful whether the quantities taken 
in the beverage cause any direct central stimulation. 

Wilhelm, Rorer, and Reichert could not obtain any effects with coffee distillates. 
J. Lehmann, Archangelsky, Hare and Marshall, and Erdmann found, with small doses: 
Pleasant stimulation; increased respiration; increased heart rate, but fall of blood pres- 
sure; muscular restlessness; insomnia; perspiration; congestion. Large doses: incfeased 
peristalsis and defecation; depression of respiration and heart; fall of blood pressure and 
temperature; paralytic phenomena. 

The intravenous injection of coffee is more toxic than the corresponding caffein. 
This is presumably due to the potassium (Aubert). By mouth, however, the potassium 
(0.44 Gm. KC1 in 20 Gm. coffee) is not sufficient to produce any effect. 

Decaffeinated coffee does not produce the cardiac or diuretic effects of coffee or caffein 
(Busquet and Tiffeneau, 1912). The caffein-content of commercial decaffeinated 
coffees and other coffee substitutes is given by Street, 1916. 

Tea (Thea) consists of the dried leaves of Thea sinensis, Theacea:. Constituents: 
Caffein (1.4 to 3.5 per cent., usually 2 to 3 per cent.); tannin (10 to 30 per cent.); traces 
of theobromin, theophyllin, xanthin, adenin, and volatile oil. The black and green 
teas differ only in the treatment to which the leaves are subjected a fermentation with 
the black variety, which mainly alters the color and flavor; the green tea is rather more 
rich in volatile oil. The beverage is a i to 4 per cent, infusion. A cup of strong tea 
prepared from 5 Gm. of leaves, contains about o.i Gm. of caffein (Aubert). A quick 
infusion extracts practically all the caffein, but only a part of the tannin (which is espe- 
cially abundant in the finer sorts). The customary brief infusion is therefore commend- 
able, since the tannin is deleterious to digestion, by precipitating proteins and album- 
oses, by lessening absorption, and by irritating the gastric mucosa. 

The tea-distillate is credited by Archangelsky with actions similar to those of caffeol. 
Lehmann and Tendlau found it inactive. 

Cola (Kola, the seed in Cola acuminata, Sterculiaceae). Tin's is used extensively 
by the natives of Africa, the fresh and often germinated seed being chewed. The dried 
seed, which has been introduced as a popular "tonic," contains caffein (ij-i to 3)2 P er 
cent., usually 2% per cent.); theobromin (Ho P er cent.), tannin (Kola red); fat, sugar, 
etc. 

In the fresh nut, the caffein is combined with a glucosidal tannin ("Kolatin," Goris, 



2l6 MANUAL OF PHARMACOLOGY 

1907). This compound, which was formerly termed "Kolanin," is partly decomposed 
in drying, by an oxidase, into free caffein, glucose, and Kola red (Chevrotier and 
Vigne, 1907). 

Guarana. A dried paste, prepared by the Indians of South America, consists chiefly 
of the dried and pounded seed of Pauljinia cupana, Sapindaceas. It contains 4 to 5 
per cent, of caffein, tannin, etc. Mate (Paraguay tea) consists of the leaves of Ilex 
paraguayensis. It contains 0.13 to 1.85 per cent, caffein (2 per cent., Bertrand and 
Devuyst, 1910), 10 to 16 per cent, of tannin, etc. It is used in South America for 
preparing a beverage. 

Cacao is consumed extensively as a beverage and in the form of chocolate. (The 
latter is a mixture of melted cacao and sugar, often with the addition of flavors, starch, 
etc.). It contains theobromin, instead of caffein, and therefore acts less on the nervous 
system. It is also rich in fat, which is nutrient. A part (about half) of this fat (Oleum 
Theobromatis or Cacao Butter) has been removed from the commercial powdered cacao. 

The name Cacao should not be confused with Cocoa (the palm yielding the cocoa 
nut), nor with Coca, the source of cocain. 

Cacao consists of the fermented, dried and often roasted seeds of Theobroma Cacao, 
Sterculiaceas. Constituents: Theobromin (ij^ to 4% per cent., usually i^ per cent.); 
a trace of caffein; 50 per cent, of fat; starch, tannin, etc. The theobromin is liberated 
from a glucosid during the fermentation. 

The fat is generally considered rather indigestible, but Neumann, 1906, showed 
that it is digested as well as other fats. 

Chicory. The roasted root of this plant is used as an adulterant and substitute 
for coffee. It probably contains similar empyreumatic substances, but no caffein. 
Schmiedeberg, 1912, considers it a harmless stimulant, stomachic and antiseptic; 
while Horwith, 1908, believes it liable to disturb digestion. Still less is known about 
roasted malt and other cereals which are used as coffee substitutes. 

Phenomena of Chronic Caffein Poisoning. These have been described 
most commonly in excessive tea drinkers. A good analysis of the effects 
is given by Bullard, 1886. The first symptoms are usually dyspeptic 
epigastric uneasiness after meals, and a general lowering of the mental 
and physical tone. This is succeeded by restlessness and nervous excita- 
bility, tremors, and disturbed sleep, soon followed by anorexia and by 
headache, vertigo, confusion. Constipation is very common, but not 
more so than in individuals who are not addicted to tea. Palpitation, 
generally associated with irregularity, becomes distressing, and is often 
accompanied by dyspnea. In the severer cases, these symptoms become 
aggravated and continuous. Neuralgias, sensory and hysterical disturb- 
ances are common, but it is not easy to say whether these are the cause or 
effects of the caffein habit. Children who 'drank coffee were found by 
Taylor, 1912, to average below the normal weight, height and strength. 

The quantity of tea required to develop these symptoms varies greatly with the 
individual. The daily average consumption of Bullard's patients was five cups, which 
corresponds to about 0.6 Gm. or 8 grains of caffein. The susceptibility is much greater 
in youth, anemia, weakness, insufficient food, exhaustion, and in "nervous" individuals. 

Differences between Tea, Coffee and Cacao. The effects of excessive 
coffee consumption differ only in minor details from tea; whilst tea tends 
to constipation, coffee is laxative. Both interfere with digestion, but in 
different ways: the coffee through the irritant effects of its volatile oil; 
the tea through the coagulant action of the tannin. It may therefore be 
observed that different individuals are more injured by one or the other. 
The caffein itself probably contributes to the digestive derangement, 
through its vasodilator action. This may account for the common tend- 
ency to hemorrhoids. Cacao may disturb the digestion through its rich- 
ness in fat, but the other symptoms are not common; partly because there 
is less inclination to its excessive use. 

The acute effects on digestion deserve special mention. Cushny states that coffee 
and tea retard the action of the ferments considerably (in test-tube experiment), whilst 






THE MORPHIN GROUP 217 

caffein slightly accelerates the action. The secretion of gastric juice has been investi- 
gated by Pincussohn, 1006, using dogs with the Pawlow gastric pouch. Coffee gave 
a considerable but brief increase of quantity and acidity. "Malt coffee" (the type of 
the coffee substitutes prepared by roasting cereals) has a similar, but weaker action. 
Tea and ordinary cacao decrease the secretion; but cacao in which the fat has been re- 
duced to 15 per cent, causes some increase. 

Chronic Caffein Poisoning in Animals. Salant and Rieger, 1910, found that the 
continued administration of doses which did not cause acute effects, eventually pro- 
duced emaciation, often ending in death. The stomach and, to a less degree, the intes- 
tine showed inflammatory changes. 

On the other hand, they found that habituation increased the tolerance to acute 
poisoning, the fatal dose being 15 to 80 per cent, larger than ordinary. Gourewitsch, 
1907, also claims a "histogenetic" habituation. 

Mice kept continuously under caffein were found to exhibit less than the normal 
activity, but showed a normal gain in weight (Nice, 1912). 



THE MORPHIN GROUP 

Members. The morphin group comprises opium and most of its 
alkaloids: Morphin, codein, narcotin, papaverin; also the esters formed 
by replacing the H of one or both of the hydroxyls of morphin: Methyl 
morphin (codein); diacetyl morphin (heroin); ethyl morphin (dionin), etc. 
These resemble each other in their pharmacologic actions, but present 
minor differences which are of practical significance. Since morphin is 
the most important member, it will be considered first. 

Central Nervous System. The most important actions of morphin 
are on the central nervous system. It depresses the brain, especially its 
higher functions. The medullary centers are first stimulated, then de- 
pressed. The reflexes and the spinal functions are mainly stimulated. 
The effects are broadly identical in all vertebrate animals, although the 
dosage varies greatly, and the symptoms show considerable differences in 
the relative prominence of certain phenomena and in the time required to 
produce the successive actions. 

Narcotic Action. The descending depressant action of morphin is well 
illustrated by the frog, in which the development of the symptoms corre- 
sponds very closely to those produced by progressive removal of the brain. 
This is also the general course in mammals; but with these the symptoms 
are more confused. The difference is explained by the more rapid action 
of the drug, and by the more intimate correlation of the nervous centers. 

Effects of Morphin on Frogs. After doses of 20 to 50 mg. the symptoms start with 
diminution, and then absence, of voluntary movements, but the animal reacts normally 
when stimulated. (This corresponds to ablation of the hemispheres.) The frog sits 
quietly in the normal position; he will climb up an inclined plane and give the croaking 
reflex when stroked. When placed in a tumbler filled with water and inverted in a 
large vessel of water, it will leave the glass to seek the air. As the narcosis deepens, 
it will remain under the glass. Placed on the table, its leaps become more and more 
clumsy, and it does not avoid obstacles in jumping (corresponding to excision of the 
corpora quadrigemina). Then the animal fails to leap even when stimulated (paralysis 
of cerebellum) ; but when turned on its back, it will resume its normal sitting position. 
This reaction also becomes more and more delayed, and can be obtained only by rein- 
forcing the stimulation through pinching, etc., until finally it fails altogether (paralysis 
of medulla oblongata). The reflexes are weakened, but present. The respiration is 
decreased. 

Morphin Tetanus in Frogs. After the frog has remained in this depressed condition 
for some time (a few minutes to several hours; the shorter, the larger the dose), the 
respiration becomes spasmodic, resembling superficially the Cheyne-Stokes type; then 
the spinal reflexes return; and the frog passes gradually into a tetanus of the strychnin 
type, located in the spinal cord. The delayed appearance of this tetanus is due to the 



2l8 MANUAL OF PHARMACOLOGY 

slow absorption of the effective dose, for it appears at once on intravenous injection 
(Stockman, 1891). The convulsions occur more promptly if the heart is tied off (Gith- 
ens and Meltzer, 1911), presumably because thus more of the morphin reaches the 
nervous axis (Abel, 1912). The onset is also hastened, and the necessary dose reduced, 
by cold, and by removal of the cerebrum, which inhibits convulsions. The results are 
more prompt if the medulla is not destroyed (Githens, 1913). 

McGuigan and Ross, 1915, find that the previous injection of morphin sensitizes 
frogs to strychnin, so that strychnin tetanus develops more quickly provided that a 
latent period of one-half to two hours elapses between the morphin and strychnin 
injections. They believe that the tetanizing action is due to an oxidation product of 
morphin, since an artificially oxidized morphin tetanizes more rapidly. Along the same 
lines, they explain the usual absence of tetanus in mammals by assuming rapid destruc- 
tion of the tetanizing substance. The explanation involves some unproven assumptions. 

Death. The tetanus is mixed with paralytic phenomena, the animal lying lax be- 
tween the spasms. Eventually the paralysis becomes permanent and ends in death. 
The heart is still beating at this stage and is indeed little affected directly. Death may 
also occur during a spasm. The convulsive stage may be absent with very large or 
very small doses. 

Recovery. If recovery occurs, the depressed functions recover in inverse order to 
their appearance (Witkowski, 1877. This paper also gives the older bibliography of 
the experimental work with morphin). 

Invertebrates do not show typical morphin effects. 

Narcotic Symptoms in Human Subjects. The first effect, produced 
by doses too small to elicit any other symptoms (5 mg.), consists in dimin- 
ished sensibility to lasting impressions; especially such as give rise to pain, 
cough, fatigue, hunger, discomfort, and other disagreeable sensations. 

Somewhat larger doses (10 mg. or more) depress the attention and thus 
weaken the appreciation of other external impressions. A sudden stimulus 
may evoke a normal or exaggerated reflex response ; there is even increased 
acuteness of perception of external impressions (Kraepelin, 1892); but 
persistent or gradual stimuli are neglected. The stimuli are evidently 
transmitted to the brain, but do not fix the attention. The faculties of 
concentration,. of judgment and of memorizing (Weygandt, 1903) are all 
seriously disturbed, constituting a narcosis. 1 Through this exclusion of 
external stimuli, the patient is quieted, and then passes through a dreamy, 
apathetic, drowsy state, into natural sleep. Exceptionally, the disturbed 
balance of the brain leads to excitement (especially in cats) and even to 
delirium. 

Larger doses cause a much more extensive depression, the sleep becom- 
ing so profound that the patient can be aroused only incompletely and 
with difficulty. Eventually the coma and insensibility are complete. 

Relative Analgesic Action of Opium Alkaloids. Morphin is decidedly 
the strongest hypnotic and analgesic member of the group. 

Analgesic Experiments on Man. Macht, Herman and Levy, 1916, have investigated 
the influence on the sensory threshold by a quantitative method. They find the effi- 
ciency highest with morphin; then comes papaverin; then codein; narcotin, narcein and 
thebain are practically not analgesic. However, narcotin has a considerable poten- 
tiating action on morphin. 

With hypodermic injection, 5 mg. of morphin produced no measurable analgesic 
effect; with 10 mg., the analgesia was marked in two subjects; the third responded by 
hyperesthesia, especially to larger doses, although all the other narcotic effects were 
present. With codein, 20 to 25 mg., the analgesia was only slight; with papaverin, 
40 mg., it was as strong as with 10 mg. of morphin, but slower and shorter; with narcotin, 
8 mg. was ineffective; 20 to 40 mg. produced first some hyperexcitability; then slight 
analgesia. Narcein and thebain, 10 mg., were ineffective. With a mixture of equal 
parts of morphin and narcotin, containing 3^ mg., the analgesia was almost as great 

1 Narcotics are substances which have the property of stupefying: Opium, alcohol, cannabis, 
atropin and similar drugs. 



THE MORPHIN GROUP 2IQ 

as with 10 mg. of morphin alone. This combination was also effective in the subject 
who resisted morphin. 

Excitant Effects in Man. Some Eastern races, especially the Malays, 
as also some individuals of other races, particularly women, are apparently 
more excited than depressed by morphin. This also can be explained by 
diminished restraint, rather than by direct stimulation. The same ex- 
planation probably holds true also for the flights of imagination which fill 
the period preceding the sleep. 

Effects of the Other Members of the Group. Codein and diacetyl- 
morphin are less quieting, and perhaps more excitant and convulsant than 
morphin. Codein does not inhibit, but rather increases the convulsions of 
camphor, etc. (Januschke and Masslow, 1915). 

Imagination. It is self-evident that an unrestrained imagination will take very 
different directions, according to the individual. In some it will tend directly to sleep; 
in others, it may even prevent sleep; in some it will be highly unpleasant, whilst others 
will seek to repeat the experience and thus fall easy victims to the morphin habit. The 
aphrodisiac effects, which occur in some, and the anaphrodisiac action in others, depend 
upon this action on the imagination. 

Special Senses. These are not affected directly. They may appear disturbed 
through the impaired attention, or through the heightened reflex irritability. 

Symptoms in the Lower Mammals. The effects are almost purely depressant 
(apathy, stupor, analgesia, sleep and coma) in the dog, rabbit, guinea pig, white rat, 
mouse and sparrow. The acute reflexes are heightened, but firm pressure, which would 
be much more painful in normal animals, elicits no response. Dogs exhibit a peculiar 
clumsiness and incoordination in their voluntary movements. They stand and walk 
unsteadily, and often drag their hind legs ("Hyenoid walk" Cl. Bernard). These 
motor symptoms resemble those of ablation of the motor areas. On the other hand, 
one often sees convulsions, tremors or choreiform twitchings of the limbs. The ex- 
citability of the motor areas to electric stimulation is not altered even by the largest doses 
(Hitzig, 1873). The respiration may at first be very rapid, but is eventually depressed. 
Vomiting and defecation occur early. 

In the cat (and also with the horse, ass, beef, sheep, pig and goat and sometimes in 
dogs) the coma is preceded by more or less excitement. The cat particularly exhibits a 
violent mania, races about as if in extreme terror, with prominent eyes and widely 
dilated pupils, scratching and clawing wildly. Sometimes there are even convulsions. 
These symptoms have been interpreted as stimulation. In fact, however, the psychic 
functions are depressed; the animal does not avoid obstacles in its career; marked anal- 
gesia is present. The excitement is apparently due mainly to terror, to which the 
nausea contributes greatly, and which is^not inhibited by the normal restraining im- 
pulses (since these are dulled by morphin) . The excitant effect on cats is also produced 
by codein and thebain; whilst papaverin and narcein are mainly depressant (G. H. 
Miiller, 1908). 

Relative Toxicity for Different Animals. The tolerance for morphin differs remark- 
ably. Man is by far the most susceptible, the fatal dose man for being no greater than 
that required for a frog of but 1 -2ooo the weight. Pigeons, goats, rabbits and pigs 
require nearly 100 times the human dose, per kilogram; dogs and cats about 15 times; 
horse and cow two to four times. 

Respiratory Center. Morphin and its derivatives depress the excita- 
bility of the respiratory center. The spontaneous rhythm and the 
response to asphyxia, and to reflexes are all lowered. There is also a 
marked decrease of the cough reflex; this action probably involving a 
somewhat different mechanism and depending partly on the analgesic 
effect. 

Very minute doses (2 mg. of morphin for man) lessen the cough reflex 
without producing any other noticeable change. Somewhat larger, but 
still non-narcotic doses (3 to 15 mg. of morphin), diminish the excitability 
for carbon dioxid, and to a lesser degree for other afferent impulses (Y. 
Henderson and Scarbrough, 1910). The threshold to CO 2 is raised (Hig- 



220 



MANUAL OF PHARMACOLOGY 



gins and Means, 1915). The respiratory rate may be slowed (Gscheidlen, 
1869), or slightly quickened (Higgins and Means, 1915). With the smaller 
of these doses, the depth and efficiency of the respiration is somewhat 
increased, especially if it has been superficial. Dyspneic respiration is 
quieted, and "air hunger" relieved. Toxic doses cause very marked 
decrease of excitability, rate, depth, and efficiency; periodic respiration 
(Filehne; B arbour, 1914), resembling the " Cheyne-Stokes type" (Fig. 8); 
and finally arrest of respiration, before the heart is seriously injured. 

Codein, heroin, and all other morphin derivatives produce the same 
effects (Issekutz, 1911). 

Codein has the material advantage of relative freedom from undesir- 
able side action and is therefore preferable in cough. Heroin has no real 
advantage; it is at least as liable as morphin to induce habit formation; 
and it is much more toxic (Harnack, 1899). Morphin is much more 
effective than its derivatives in quieting dyspnea. 




FIG. 8. Cheyne-Stokes respiration (HCN poisoning, dog). 

Some of the minor opium alkaloids stimulate the respiratory center; 
so that opium is rather less depressant to the respiration than would be 
expected from its morphin content (Macht, 1915). 

Rate and Depth of Respiration. The effect of morphin, as of most drugs acting on the 
respiratory center, is mainly on the rate. With small doses, the depth is affected only 
secondarily, namely, increased in the attempt to compensate for the slowed rate, espe- 
cially if the respiration was previously superficial (Issekutz, 1911). The effects, there- 
fore, resemble those of section of both vagi: this suggests that the effect might be due to 
blocking of the normal augmentor vagus impulses; but this is not the correct explana- 
tion, for morphin does not block the response to electric stimulation of the vagi, and it 
also causes a further slowing after both vagi have been divided (Cushny, 1913). 

In the dog, the hypodermic injection of morphin first causes a quickening of respira- 
tion (perhaps through nausea) followed in fifteen minutes by the typical slowing (Mayor, 
1908). In the fr ogs, the slowing is succeeded by quickening, just prior to the convulsive 
stage. A secondary quickening is also seen in rabbits (Filehne, 1879; Cerna, 1892) but 
never in man. 

Decreased Excitability of Respiratory Center. This is shown by the fact that apnea 
is more easily produced, and more lasting (Filehne, 1879; Cushny and Lieb, 1915). 
The blood becomes more venous, the oxygen content being decreased and the carbon 
dioxid increased (Filehne and Kionka, 1895). Asphyxia produced by the inhalation of 
carbon dioxid or deprivation of oxygen in normal animals increases the depth and rate of 
respiration. Under morphin, this response is of the same type, but very much decreased 
(A. Loewy, 1890; Lindhard, 1911; Cushny, 1913; Cushny and Lieb, 1915). Afferent 
inhibitory respiratory reflexes are rendered more effective; but acute augmentor re- 
flexes are not materially altered (Cushny). The response to persistent irritation (cough) 
is of course diminished. 

Since the reactions of the center to reflexes and CC>2 stimulation preserve the normal 
type, Cushny and Lieb ascribe the action of morphin to slowing of the intrinsic rhythm 
of the respiratory center. The hydrocarbon narcotics (urethane), on the other hand, 
depress mainly the asphyxia! reflex. 

Morphin Derivatives on Respiration. Heroin was introduced by Dreser, 1898, with 
the claim that therapeutic doses lessen the cough reflex and slow the respiration; but 



THE MORPHIN GROUP 221 

that the inspirations are deepened and more powerful, so that the alveolar air is more 
effectively ventilated. Independent workers, however, have shown that there is no real 
difference from morphin (Cushny, 1913). The deepening of the respiration is not con- 
stant (Santesson; Lewandowsky; Harnack, 1899), but is seen only with small doses, 
when the slowing is excessive or when the respiration has been shallow (Fraenkel, 1899). 
Appropriate doses of codein, dionin, and even morphin produce practically the same 
effect (Fraenkel; Issekutz, 1911). In man, the respiratory effects of 5 mg. of heroin 
correspond almost quantitatively to those of 15 mg. of morphin (Higgins and Means, 



Dreser also claimed that heroin did not alter the excitability of the center to carbon 
dioxid, but lessened the reflex excitability (to stretching of the lungs). Impens, under 
Dreser, likewise claimed the carbon dioxid threshold unaltered by heroin (and dionin), 
but raised by codein, and, of course, still more by morphin. Winternitz, 1899, found 
just the opposite result, the threshold being raised by heroin, but not by codein or dionin. 
The difference is probably insignificant: none of the derivatives raise the threshold as much 
as morphin, and they are, therefore, less effective in relieving dyspnea. 

Separate and Combined Opium Alkaloids on Respiration. This subject has been 
investigated by Macht, 1915. He finds the effects of morphin on rabbits and dogs 
essentially as described. Small doses (o.i mg. per kilogram) markedly slow the rate, 
but somewhat increase the minute-volume and alveolar ventilation; but the response 
of the center to COa is somewhat decreased. Full doses (i to 5 mg. per kilogram) 
diminish the rate, minute-volume, alveolar ventilation, and response to CO 2 

Small Doses of Codein (i to 2 mg. per kilogram) generally slow the rate, without much 
change in the minute-volume, alveolar ventilation, or CO2 response. Convulsive doses 
(20 mg. per kilogram) increase the ventilation and COa response. Narcotin and 
papaverin increase the COa response, although the rate may be slightly slowed. N ar- 
cein, thebain and cryptopin produce either no effect, or slight stimulation of the res- 
piratory center. 

Combination of the stimulant alkaloids with morphin gives simple summation of 
their respiratory action; i.e., their stimulation partly counteracts the morphin depres- 
sion. This is true for opium as well as for artificial mixtures. It also holds for the 
perfused-respiratory center. 

Bronchial Muscles. These are slightly relaxed by therapeutic doses 
of morphin, and more powerfully by papaverin and narcotin (Pal, 
1913; Macht, 1915); whereas large doses of morphin, codein, dionin and 
especially heroin, narcotin and thebain, produce marked constriction. 
Higgins and Means, 1915, observed bronchial constriction in man with 
15 mg. of morphin or 5 mg. of heroin. The relaxation may play a part in 
the relief of bronchial spasm (asthma); whilst the constriction may con- 
tribute to the asphyxia of toxic doses. 

The effects are peripheral, for they occur on excised bronchial muscle (relaxation, 
Trendelenburg, 1912) as well as in pithed (constriction, Jackson, 1914 and 1915) and in 
intact animals (relaxation with small, constriction with large doses; JBrodie and Dixon, 
1903). The constrictor action is not antagonized by atropin, and must therefore be on 
the muscle or myoneural junction. It can be overcome by powerful dilator (sympa- 
thetic) stimulation (epinephrin, hordenin, Jackson, 1914 and 1915). 

The combination of morphin and narcotin in dilator concentration gives less dila- 
tion than either alone (Macht, 1915). This is similar to the behavior of the coronary 
artery. 

Bronchial Secretion. Unless there is nausea, the secretion of mucus 
appears diminished; particularly in bronchitis. This may be explained 
largely by the suppression of cough, permitting a longer sojourn of the 
mucus in the bronchi, with consequent removal of its water by absorp- 
tion and drying; but there may also be a central depression, analogous to 
that of the salivary secretion, for a decrease of tracheal secretion has been 
demonstrated in animals (Rossbach, 1882). 

Circulation. Therapeutic doses of morphin or its derivatives do not 
affect the circulation seriously. In man, there is generally an (indirect) 
increase of pulse rate immediately after an injection; this is quickly fol- 



222 MANUAL OF PHARMACOLOGY 

lowed by persistent moderate slowing, with increased fulness and force 
(stimulation of vagus center). The blood pressure, after a short rise, may 
remain level (Anderes, 1913), or falls slightly (Guinard, 1895), through 
the slowing, and perhaps through incipient depression of the vasomotor 
center. The cutaneous vessels are markedly flushed. 

With toxic doses, the fall of blood pressure is more marked (central 
vasomotor depression), and the pulse becomes weak, varying in rate, and 
often arythmic (stimulation of vagus center and disturbed cardiac 
conduction). 

The heart muscle suffers indirectly, by the low blood pressure and 
asphyxia (hence danger in cardiac insufficiency, especially when com- 
bined with dyspnea). Ordinarily the circulation remains fairly good, 
until death occurs by paralysis of respiration. Direct depression of the 
heart is produced only when morphin, or especially its derivatives, are 
perfused directly through the heart. 

Hering, 1915, believes that the increased vagus tone resulting from 
large doses may indirectly produce ventricular automatism, or even 
fibrillation, especially in pathologic hearts tending in that direction. 

Vagus Center and Cardiac Conduction. Dogs show the same phenomena in more 
marked degree. The preliminary acceleration is due to nausea. The typical slowing 
does not occur after section of the vagi, and is therefore central. It occurs with very 
small doses, increases with larger doses, and passes into arythmia (van Egmond, 1911; 
Anderes, 1913). Electrocardiograms also show central vagus stimulation (Einthoven; 
Cohn, 1913); and sinus-auricular and auriculo-ventricular heart-block, separate or com- 
bined, removable by atropin (Eyster and Meek, 1912, 1913). The reflex excitability 
of the vagus center is also increased (Jackson and Ewing, 1914). 

The effect on the pulse rate is inconstant in cats, absent in rabbits (Egmond). 
Anderes found constant slowing in rabbits, the vagus stimulation being partly central, 
partly peripheral through decrease of the negative thoracic pressure. 

Cardiac Muscle. On the Langendorff excised mammalian heart, morphin and all its 
derivatives first increase the rate and amplitude; this is followed by decrease, and finally 
systolic standstill (Vinci, 1907). The rate of the perfused, atropinized frog's heart is 
quickened by dilute, slowed by more concentrated solutions of all the papaveraceous 
alkaloids; morphin being the least deleterious (Hale, 1909). Lippens, 1908, found 
peronin highly toxic for the turtle's heart. Narcotin is the most toxic of the opium 
alkaloids, for the heart (Macht, 1915). Papaverin lowers the cardiac tone (Pal); 
this is followed by considerable tachycardia (Renon and Desbouis, 1914). 

Cardiac Ganglia. These show degenerative histologic lesions, similar to those of 
alcohol or chloroform (Lissauer, 1914). 

Coronary Circulation. This is quickened, by dilation of the coronary vessels, by 
most of the opium alkaloids. The action is most marked with narcotin and papaverin, 
slight with morphin, very slight with codein, heroin or pantopium, and absent with 
narcein and thebain (Macht, 1915). 

Vasomotor Effects. These have not been satisfactorily investigated. Gscheidlen, 
1869, found that the center is not completely paralyzed even in advanced poisoning; 
stimulation of the spinal cord still gives a rise. The venous pressure is not changed by 
moderate doses, slightly lowered by toxic doses, indicating vasodilation (Capps and 
Matthews, 1913). 

Cerebral Circulation. The effects are small and inconstant with ordinary doses. 
Huerthle, 1889, found sometimes an increase, sometimes a decrease, of the flow. Alip- 
randi, 1905, describes a brief constriction, followed by lasting dilation. Frankfurther 
and Hirschfeld, 1910, describe an initial increase of brain volume, followed by decrease, 
the latter probably due to the fall in general blood pressure. 

Circulation of the Skin; Diaphoretic Action. The cutaneous vessels are 
specifically dilated (through the vasomotor center) even by small doses. 
The skin is reddened, warm, and the perspiration increased. This ac- 
tion is utilized, in the form of Dover's powder (Pulvis Ipecac et Opii, 
0.5 Gm. at night) for the "abortion" of colds. In susceptible individuals, 



THE MORPHIN GROUP 



223 



the cutaneous dilation may give rise to exanthemata. With toxic doses 
the skin becomes pale (vasodilation of the splanchnic area), and cyanotic 
(asphyxia). 

Other Poisons which may Produce Erythema on Systemic Administra- 
tion are: atropin, quinin, chloral, veronal, benzol derivatives (antipyrin, 
atophan, salicylates, aspirin, etc.) iodids, bromids, sera, etc. 

W heals. The local application of solutions of morphin or any of its esters to the 
scarified skin results in the production of an urticarial wheal. Similar wheals are pro- 
duced by histamin, peptone, emetin, and calcium chlorid (Sollmann and Pilcher). 

Effect on Pupils. In man (not in animals) even small, scarcely anal- 
gesic doses constrict the pupils. The miosis is due to a stronger con- 
strictor (oculomotor) tone; for it disappears when the oculomotor endings 
are paralyzed by atropin; whilst it is scarcely affected by cocain, which 
stimulates the sympathetic endings. The action is central, for it is not 
produced by local application. It has been suggested that morphin de- 
presses the inhibitory impulses which normally keep the oculomotor tone 
in abeyance (Meyer and Gottlieb). There is a fairly lasting rise of intra- 
ocular pressure (Myashita, 1913). Ethyl-morphin produces a shorter 
rise. 

The oculomotor center (pupillo-constrictor) appears to be normally in a state of partial 
inhibition through a variety of sensory impulses. When these are diminished as by 
sleep, narcosis, and in a specific manner by morphin the oculomotor tone increases, 
and the pupils contract. When the inhibitory impulses are reinforced as by emotion, 
electric stimulation of the cerebral cortex, asphyxia, etc. the oculomotor tone is 
diminished, and the pupils dilate. That this type of mydriasis is not due to stimulation 
of the sympathetic (dilator) center, is shown by the fact that it occurs after division of 
the cervical sympathetic nerve (Braunstein, 1894). 

Pupil Changes in Animals. In cats, the pupils are dilated, in conformity with the 
general excitement. In dogs, the effect is variable, but generally dilator. 

Conjunctiva} Reaction to Ethylmorphin (Dionin). The direct applica- 
tion of a i to 5 per cent, solution or ointment produces burning pain, 
hyperemia, and acute edema of the lids and conjunctiva, which disappears 
without any ill effects. This reaction is used in ophthalmology for the 
removal of old inflammatory products. 

The edema, which is ascribed to vascular congestion, appears in a few minutes and 
lasts for several hours. There is also some more persistent local anesthesia. The pupils 
are at first constricted, and the intraocular tension is raised (Toczyski, 1912). The 
edema does not occur in rabbits, but readily in dogs or cats (Axenfeld, 1905). 

Benzoly-morphin (peronin) is said to act in the same way; but the effect does not 
occur with morphin, codein, heroin, or any of the natural opium alkaloids. 

Spinal Cord. Morphin and all the members of the group increase 
the spinal reflexes. 

Large doses, in frogs, produce convulsions which are indistinguishable 
from those caused by strychnin. Mammals generally die from the res- 
piratory depression before the convulsant stage can develop; but the 
smaller mammals may exhibit muscular stiffness and tremors. Con- 
vulsions are sometimes seen, even in man, when toxic doses (3 grains) are 
taken (A. Gordon, 1915; Keen). In dogs, the intraspinal (subarachnoid) 
injection of morphin produces marked convulsions (McGuigan and Ross, 



The convulsant action is especially strong in one of the minor opium alkaloids, 
thebain, so that this is generally placed in the strychnin group. 



224 MANUAL OF PHARMACOLOGY 

The spinal stimulation would seem to contraindicate the use of mor- 
phin in convulsant conditions of spinal origin, as in strychnin poisoning. 
Practically, however, the analgesic effect may offset this disadvantage; 
nor does the theoretical objection hold against convulsions that are not 
spinal. 

Sensory Nerves. Opium and its alkaloids have no action whatever 
on the sensory endings, or on the peripheral sensory nerves, for the site of 
application is no more affected than other regions of the body (Jolly and 
Hilsmann, 1874). Their local use is therefore irrational. Any apparent 
success is largely psychical; although there may be some central analgesia, 
since morphin is readily absorbed from wounds and mucous membranes, 
and to a slight extent even from the unbroken skin. With the time- 
honored "Lead and Opium Wash," the precipitate formed by the lead with 
the gums and meconic acid furnishes a soothing protection. (The mor- 
phin is not precipitated by the lead.) 

Curare Action. All the members of the group, when applied directly to a muscle 
preparation, exert a weak and slow curare action: If the motor nerve is stimulated 
with a tetanizing current, the muscle responds with a series of rapid separate con- 
tractions, instead of a fused tetanus. Larger doses paralyze the muscle-nerve endings 
completely. Diacetyl morphin acts more powerfully than morphin or codein; but the 
action is too weak to be observed in intact mammals (Hale, 1909). 

Protopin Group. The curare and rnuscular actions were first described by v. Engel, 
1890, for the protopin group certain unimportant alkaloids (protopin, crytopin, 
chelidonin, homochelidonin, and chelerythrin) which occur in opium, but especially 
in other Papaveraceous plants (Sanguinaria or Bloodroot; and Chelidonium or Celan- 
dine; Bocconia, etc.). These alkaloids share also the depressant morphin action on the 
heart (Hale). They are said to paralyze the sensory endings like cocain. The respira- 
tion is stimulated. 

Sanguinaria also contains sanguinarin (Reports, Council Pharm. and Chem., 1911, 
60) and other alkaloids (Kozniewski, 1910). Chelidonium contains berberin. Both 
drugs are irritant. Sanguinaria has been used as a nauseant (o.i Gm.). The fresh 
juice of ghelidonium is applied in folk medicine to remove warts. 

Chelidonin. Central Actions. H. Meyer, 1892, found that it produces, in frogs, a 
descending depression of the central nervous system, nmilar to morphin, but without 
spinal stimulation. Mammals also respond by analgesia and sleep, without marked 
depression of reflexes. Larger doses cause coma, without nausea or vomiting; finally, 
the vasomotor center becomes paralyzed. 

Peripheral Actions of Chelidonin. These have been investigated especially by Hanz- 
lik, 1915. Like other isoquinolin alkaloids (narcotin, papaverin), it depresses all kinds 
of smooth muscle. The effect appears to be directly on the muscle substance, since 
it antagonizes not only pilocarpin, histamin and epinephrin, but even barium; whilst 
these do not remove chelidonin depression. It is relatively non- toxic; and when its 
therapeutic dosage has been ascertained, it may have a clinical field in asthma, colic, 
and other spasms of smooth muscle. 

Meyer also found that it paralyzes skeletal muscle and sensory and motor endings. 

Morphin on Urinary Bladder. Morphin, in toxic doses, produces spasm of the 
vesical sphincter (either through depressed inhibition or analogous to pyloric spasm), 
leading to distention of the bladder and constant but ineffective desire for micturition. 
This sometimes occurs in the therapeutic use (Czapek and Wassermann, 1914). In 
guinea pigs the distention may rupture the bladder (Tappeiner, 1899). 

Uterus. Morphin probably tends to delay the progress of labor, by its psychic 
sedative action, largely by preventing the reinforcement of labor pains by the con- 
traction of the abdominal muscles (Barbour and Copenhaver, 1916). It has practically 
no effect on the normal uterine contractions in animals, in situ (Barbour, 1915); when 
applied directly to the excised uterus, the tone is somewhat increased (Barbour and 
Copenhaver, 1915); but this would have no clinical bearing. 

Effects on the Digestive System. Morphin tends to produce nausea 
and vomiting, and thus disturbs digestion. The effect is independent of 
the mode of administration, the action being central. The severity varies 
greatly in different individuals. In some cases it is so serious, and accom- 



THE MORPHIN GEOUP 225 

panied by so much depression, as to preclude the use of the drug. It may 
sometimes be lessened by bromid or by atropin (I. Simon, 1907). 

Larger doses are antemetic. 

Morphin is one of the most efficient drugs for checking peristalsis. 
Small doses suffice for this purpose. The action is evidently peripheral, 
but its mechanism is complex, involving several factors, one or the other 
of which may predominate under certain conditions. The known factors 
are closure of the gastric sphincters, delaying the entrance of food into 
the intestines; decreased responsiveness to defecation reflex; and a direct 
sedative action on irritated (not on normal) intestine. With opium, there 
is also the direct depression of intestinal tone by the isoquinolin alkaloids 
(papaverin, etc.). 

Of the individual opium alkaloids, morphin acts most powerfully on 
the alimentary canal. However, the minor alkaloids, especially papa- 
verin, narcotin and codein, are also constipating, with less narcotic action 
(Gottlieb and v. d. Eeckhout, 1908; Zehbe, 1913; Hess and Neukirch, 
1913; Macht, Herman and Levy, 1916). These differences, and the de- 
layed absorption, may explain the clinical preference for opium when the 
constipative effect is desired. 

Nanseant and Emetic Action. This is essentially central (Eggleston and Hatcher, 
1915). It may conceivably be aided by reflexes from the gastric spasm; for atropin, 
appears to diminish the emetic tendency. There is no evidence of local gastric irrita- 
tion, although the alkaloid is rapidly excreted into the stomach. Vomiting occurs more 
readily with hypodermic than with intravenous injection; probably because the latter 
depresses the vomiting center too rapidly. 

The emesis is produced by absolutely pure samples, and is therefore not due to 
contamination with apomorphin (even prolonged boiling does not convert morphin 
into apomorphin; Feinberg, 1913). 

Relative Emetic Action of Opium Alkaloids. Morphin is more nauseant and emetic 
than the other isolated alkaloids. Opinions differ as to the position of the combined 
alkaloids. Eggleston and Hatcher, 1915, believe that the emetic effect of pantopon and 
narcophin is more powerful than would correspond to their morphin content. As nar- 
cotin alone is not emetic, it would be conceived as sensitizing the center to morphin. 
Macht, Herman and Levy, 1916, incline to the opposite conclusion. 

Salivary Secretion. The nausea, as usual, is accompanied by salivation. In the 
absence of nausea, the mouth is dry and the patient thirsty, from depression of the 
salivary center (V. E. Henderson, 1910). 

The appetite is diminished, through the lesser perception of hunger, and through the 
gastric derangement. 

Gastric Secretion. Morphin starts the gastric secretion in the empty stomach (there- 
fore contraindicated in gastric ulcer), but is said to diminish the secretion when the 
stomach contains food (Chiari, 1915). It also increases the pancreatic secretion. 
Opium increases gastric secretion, but causes a lasting decrease of pancreatic flow 
(Bickel and Pincussohn, 1907; O. Cohnheim and Modrakowski, 1911). In chronic 
morphinism, gastric secretion is said to be abolished (Hitzig). 

'Antemetic Action. Dogs, after a primary emesis, do not respond to irritant emetics 
or apomorphin. This has been attributed to paralysis of the vomiting center; but it 
could also be explained by the firm contraction of the cardial sphincter (Magnus, 1908); 
for morphin, codein, or heroin are antemetic in doses which are not narcotic, whilst 
chloral or urethane, to prevent vomiting, must be exhibited to full narcotic action 
(v. Issekutz, 1912; Ruth, 1913). Papaverin is not antemetic (Ruth). 

Constipation Action in Milk Diarrhea. A new light has been shown on morphin- 
constipation by R. Magnus, 1906 and 1908, who tested its effect on experimental diar- 
rhea. A very suitable quasi-physiological form of diarrhea can be maintained in cats 
by an exclusive milk diet. This diarrhea is very effectively stopped by morphin. The 
remedial action is equally pronounced when the intestinal nerves have been divided so 
that the action is certainly peripheral. On the excised intestine, however, morphin in- 
creases peristalsis (except with enormous doses), indicating that its constipating effect 
is not due to peripheral intestinal depression. (The excised intestine has also been 
studied by Popper, 1913.) 



226 MANUAL OF PHARMACOLOGY 

Gastric Toniis. To solve this riddle, Magnus investigated the passage of the ali- 
mentary contents by the Bismuth tf-ray method of Cannon. He now observed that 
morphin acts exclusively on the stomach, producing prolonged contracture of the sphinc- 
ter antri pylori, as also of the pyloric and cardiac sphincters. As a result, the food re- 
mains for hours in the fundus, the complete evacuation occupying twenty-five hours 
instead of the normal three hours. The intestines thereby are granted a very large 
amount of physiological rest, the food entering very slowly and gradually, being more 
perfectly macerated and digested, and presumably relatively aseptic. This furnishes 
the whole explanation of the constipating action in milk-diarrhea; for the same method 
shows that the movements of the small intestine are scarcely affected by the morphin, 
whilst those of the large intestine, as also the defecation of enemata, are quite unaffected 
by the drug. (Schwenter, 1912, using a similar method, describes relaxation of the 
large, and probably also of the small, intestines.) Xor has morphin any constipating 
action in experimental diarrhea from certain irritant cathartics, viz., senna, castor oil, 
or magnesia. 

Entirely analogous phenomena are observed in the dog (Magnus; E. Zunz, 1909), 
and in the human subject. They are probably a highly important factor in 'the thera- 
peutic effect. Magnus himself, however, suggested that morphin may possibly have 
further indirect actions on peristalsis, by modifying intestinal secretion or absorption. 

Colocynth Diarrhea. This surmise was confirmed by the results of his pupil, Padt- 
berg, 1911, in colocynth diarrhea. This drug produces exudation and increased move- 
ments throughout the alimentary tract. Both effects are antagonized by morphin 
(and much more by opium), even when the food is already in the intestine. The action 
of morphin in colocynth diarrhea is therefore different from its action in milk, senna, 
castor oil or magnesia diarrhea, in which morphin would not affect the progress of the 
food after this has reached the intestine. 

Other Opium Alkaloids on Colocynth Diarrhea. Takahashi, 1914, found that codein 
acts similarly to morphin, but weaker. Mixtures of morphin and codein act stronger 
than either alone (potentiation), so that constipation occurs by combining one-fourth 
of the minimal active dose of morphin with one-fortieth to one-four hundredth of the 
minimal active dose of codein. Equal parts of the two alkaloids constitute the best 
ratio. The other alkaloids do not seem to contribute, but rather to interfere; so that 
Pantopium, for instance, is inferior. Codein also potentiates the gastric spasm, but only 
with much larger doses than are needed in colocynth. When used alone, the codein 
does not produce gastric spasm. 

Observations on Man. The results are rather inconstant; but those of 
Zehbe, 1913, with the x-ray method are fairly representative for normal 
subjects. The time of the total sojourn of the food was nearly doubled 
by the opiates; more by opium and pantopium than by morphin and nar- 
cophin. That in the stomach and small intestines was each delayed by 
about a third. The main effect, however, was on the colon and rectum. 
The defecation-reflex is delayed or suppressed (Stierlin and Schapiro, 1912; 
Schapiro, 1913; Mahlo, 1913). 

On the other hand, Pancoast and Hopkins, 1915, observed the main 
delay in the small intestines; but little in the colon; the defecation-reflex 
was not observed. The effects, however, are extremely inconstant in dif- 
ferent individuals. Small doses were more effective than large. Hypo- 
dermic and oral administration produced the same results. 

Older Explanations. Prior to the conclusive experiments of Magnus, the constipat- 
ing action was explained either by a peripheral depression of the local reflex (the cells 
of Auerbach's and Meissner's plexus) ; or central stimulation of the inhibitory splanchnic 
fibers (Nothnagel, 1882). Neither theory was satisfactory. The apparent results of 
Nothnagel were probably accidental (Magnus, 1910) and need not be discussed. 

Other Opium Alkaloids on Peristalsis. Whilst the phenanthren alkaloids (morphin, 
thebain and codein) increase the pendulum movements of excised intestine, these are 
said to be decreased by the isoquinolin alkaloids (papaverin, narcotin and narcein) 
(Popper and Frankl, 1912 and 1913). Pal, 1913, claims that the latter also remove 
spastic contractions of the stomach and intestines clinically. 

Cathartic Action. Large doses produce catharsis in dogs and some other animals, 
but not commonly in man. The action is presumably due to local irritation. 






THE MORPHIN GROUP 227 

Bile Flow. Large doses of morphin increase the tone of the sphincter of the biliary 
papilla, and thus hinder the flow of bile (Reach, 1914). The musculature of the bile- 
bladder is not affected (Lieb and McWhorter, 1915). 

Metabolism. The output of CC>2, and to a lesser degree of urinary 
nitrogen, are materially decreased, mainly by the muscular quiet; in pro- 
longed experiments also by the digestive derangement. The CC>2 content 
of the blood rises, through the defective respiration. The urine often 
contains reducing substances, partly morphin-glycuronic acid (P. Mayer, 
1899), partly glucose from the asphyxia. The flow of urine is said to be 
decreased (Ginsberg, 1912). The body temperature is lowered through 
lessened heat production. 

Lessened COz Output. That this is due to muscular depression is shown by the fact 
that cats exhibit an increase (Boeck and Bauer, 1874), and this is also the result in other 
animals with the more stimulant members of the group, as codein. In man, however, 
the oxygen consumption is not altered, whilst the CO 2 production is decreased. The 
paradox is not explained (Higgins and Means, 1915). 

Ratio of Urea to Total Nitrogen. This is not altered. 

Morphin Gh'cosuria. A peculiar reducing substance in human urine is described 
by Spitta, 1908. 

Tempfrature. The fall (which is sometimes preceded by a slight rise) may be as 
great as 2C. with large doses; the extent depending, however, more upon idiosyncrasy 
than upon the dose. The cooling is particularly great if the animal is kept in cold sur- 
roundings. With small doses, the fall may be explained by increased heat loss from 
cutaneous vasodilation; but with large doses it is due mainly to diminished heat produc- 
tion, and finally to circulatory collapse. The heat production may be reduced by 80 
per cent, in extreme cases, reaching its minimum in the third hour. The heat loss is 
diminished (up to 20 per cent.), partly through the effort of the heat centers to compen- 
sate for the diminished production, partly through the depressed circulation (Reichert, 
1901). 

Leucocytes. These are diminished in acute and chronic morphin poisoning (Cloetta, 
1903). The injection of morphin inhibits the migration of leucocytes ' in inflamed 
frog's mesentery (Ikeda, 1916). 

Regulation of Blood Volume. Morphin hinders the transfer of injected saline solu- 
tion from the blood to the tissues (Bogert, Underbill and Mendel, 1916). 

Absorption, Fate and Excretion. Morphin is rapidly absorbed from 
all mucous surfaces, and from the abraded skin; but scarcely, if at all, 
from the intact skin. It disappears from the blood, being partly fixed in 
the organs, and largely destroyed, so that only a fraction can be recovered 
at autopsy. A part is excreted unchanged, especially by the alimentary 
tract. The saliva and gastric juice show its presence in a few minutes. 
Some of this excreted morphin is reabsorbed hence the indication of 
emptying the stomach in morphin poisoning, even after subcutaneous 
administration. The intestinal secretion proceeds somewhat more slowly. 
In acute poisoning with large doses, administered hypodermically to dogs, 
one to two-thirds of the morphin can be recovered from the feces. The 
urine participates in the excretion to a smaller degree. The destruction 
is much more complete in habituated animals, thus accounting partly for 
the increased tolerance for morphin. 

Some of the morphin is said to be excreted by the milk and to cause 
morphinism in sucklings. It also passes through the placental circulation 
to the fetus, sometimes killing the latter in utero (Jung, 1914). 

The investigation of the fate of morphin is of great scientific, as well as of practical 
toxicologic interest. Unfortunately it is beset with considerable difficulties. The 
methods of isolation are complicated, and the more or less firm combination and partial 
alteration of the morphin in the body render its quantitative isolation in pure form 
practically impossible. Marquis, 1896, believes that it exists in the tissues in three 
different forms. 



228 MANUAL OF PHARMACOLOGY 

Disappearance from the Blood. The morphin usually ceases to be demonstrable 
within twenty minutes, although it is not destroyed by the blood (Cloetta, 1903). It 
must therefore have passed into the tissues. 

Presence in the Tissues. These contain only a fraction of the morphin for the most 
part mere traces. The largest quantity is usually found in the liver and in the contents 
of the alimentary canal (Kauzmann, 1868; Marquis, 1896). The brain of poisoned 
animals is very poor in morphin, although in vitro, brain substance fixes the alkaloid 
much .better than liver pulp (Cloetta, 1903) (Localization in rabbits; van Rijn, 1908). 

Excretion by the Urine. The statements in regard to this are very contradictory. 
Kauzmann found it qualitatively in less than two up to thirty-six hours; negative in 
fifty hours. Recent investigators agreed that it can be demonstrated only after large 
doses, and then merely in traces. However, Kaufmann-Asser, 1913, finds that dogs 
and rabbits excreted by urine 3 to 23 per cent, of the morphin in acute poisoning; and 
to 39 per cent, in chronic poisoning. 

Excretion by Milk. -Contrary to the usual statement, Koldewijn, 1910, found that 
this does not occur (in cows and goats). 

Excretion by Saliva. Rosenthal, 1893, showed its presence in man, after 0.05 
Gm. per day. 

Gastric Excretion. This was discovered by Marme, 1883. Alt, 1889, demonstrated 
morphin in the stomach (by lavage) in two and one-fourth minutes after hypodermic 
injection; the excretion rose for five minutes, then remained steady for twenty-five to 
thirty minutes, and was arrested in an hour. He also showed the benefit of gastric 
lavage after hypodermic injection. This indicates that part of the excreted morphin 
is ordinarily reabsorbed; Leineweber, 1883, and Bongers, 1895, also observed the gas- 
tric excretion. This is increased by the presence of hypertonic solutions (10 per cent. 
NaCl) in the stomach. Heroin behaves similarly (Langer, 1912; Kleiner, 1913). The 
gastro-intestinal excretion of morphin is greatly diminished by vegetarian diet in dogs 
(Valenti, 1914). 

Excretion by Intestine. Marquis found morphin in the large intestine one hour after 
intravenous injection; in the small intestine only after two hours. The large intestine 
contains the larger amount. This indicates that morphin is excreted by the mucosa 
of the whole alimentary tract. With oral administration, the morphin may reach the 
intestine directly, within half an hour (Kauzmann). The bile may contain traces in 
twenty-five minutes, but is generally negative (Kauzmann). The intestinal excretion 
is increased by intestinal irritants (quillaja, senega, alcohol), even when the morphin 
has been administered hypodermically (McCrudden, 1910). 

Quantity Excreted in Feces. Faust, 1900, found that non-habituated dogs excreted 
by the feces 66 per cent, of the morphin which had been injected hypodermically 
(Cloetta, 1903, recovered 23 to 32 per cent.) With repeated injection, as the animals 
became habituated, the feces contained less and less morphin (twenty-six per cent, 
after twenty-one to twenty-four days; 8 per cent, after twenty-nine to thirty-two 
days; none after forty days); although the later doses were up to 50 times as large as 
the earlier doses. It is evident, therefore, that the power of the organism to destroy 
morphin is greatly enhanced by habituation. 

Quantity of Morphin Recovered from the Tissues. Cloetta, 1903, succeeded in re- 
covering about one-third of the injected morphin from the entire bodies of non-habitu- 
ated rats and pigeons killed in five to twenty-four hours after the injection of large 
doses of morphin. The same quantity was recovered from animals which had been 
habituated, but left without morphin for two days prior to the final injection (to per- 
mit the complete elimination of retained morphin). This indicates that the destruc- 
tion is not a rapid process, even in habituated animals. 

Destruction of Morphin in the Body. The facts described in the preceding section 
leave no doubt that the morphin is largely destroyed; but as to the place and manner 
of this destruction, the evidence is incomplete. It indicates that the morphin may be 
destroyed in various organs, and more actively in habituated animals. 

Tauber, 1890, could not demonstrate any destruction on perfusing morphin through 
excised liver or kidney. Cloetta, 1903, claims the disappearance of one-sixth to one- 
third of the morphin digested with oxygenated emulsions of lung, liver, and especially 
brain; no destruction with filtered extracts; so that the action is not due to soluble 
ferments, but presumably oxidative. The destruction is increased in habituated 
animals. Albanese, 1909, found practically no destruction by liver pulp, from either 
normal or habituated animals; but marked destruction during abstinence following 
habituation. Other organs showed similar but weaker destruction. Dorlencourt, 1913, 
again claims that morphin is destroyed by liver in vitro, and that this is increased by 
habituation. (Theories of decomposition, Spitta, 1908). 



THE MORPHIN GROUP 22Q 

Fate In Chick-embryos. If morphin is injected into fertilized eggs, which are then 
incubated, no destruction of morphin or its derivatives occurs if the embryo dies 
before it is half developed. If development is completed, heroin is destroyed abso- 
lutely; morphin very largely, codein and dionin not at all. The destruction therefore 
takes place only after a certain development, perhaps of the nervous system, has been 
reached. The alkyl groups protect the morphin against oxidation, just as they do in 
the adult organism, while the acetyl groups are evidently easily separated (Grueter, 
1916). 

Fate in Frogs. In these, the destruction is very small, and no tolerance is acquired. 
The excretion is very slow, extending over eight days, and occurs exclusively through 
the alimentary tract (B. Frenkel, 1910). 

Fate of Codein. This behaves quite differently from morphin: about 
80 per cent, is excreted unchanged, mainly in the urine, but somewhat 
also in the feces (Tauber, 1892). Repeated administration does not 
increase its destruction, nor does it appear to produce tolerance in 
animals (Bouma, 1903). 

Heroin. The greater part is excreted unchanged in the urine; some 
also in the feces. A part is destroyed and this destruction is greatly 
increased in habituation (Langer, 1912). 

Odorous Substances. The substances which give the characteristic odor to opium are 
excreted largely by the urine, and also in the breath, sweat and milk. 

Toxicology. Acute Symptoms of Morphin and Opium Poisoning. 
Suicidal and accidental poisoning by morphin or opium is common, and 
familiarity with its successive symptoms is therefore important. The 
following description of the morphin effects applies equally to opium (with 
ten times the dose); except that the symptoms do not appear quite (but 
almost) as promptly. 

Moderate Therapeutic Doses (5 to 15 mg.; }/{% to ^ gr. of morphin). 
The symptoms set in promptly (five to ten minutes after hypodermic, 
fifteen to thirty minutes after oral administration). They begin with 
slight flushing of face, sensation of warmth and comfort; lassitude, giddi- 
ness, dreamy state, with free imagination but confused intelligence; mouth 
dry and thirsty. 

The patient becomes sleepy; skin pale; respiration and pulse slowed; 
pupils constricted. Nausea and vomiting are exceptional with this 
dosage. 

In a short time the sooner, the larger the dose a natural sleep sets 
in, lasting six to eight hours or more; the patient commonly awakens 
refreshed. 

Intravenous Injection. If the injection accidentally enters a vein, there 
is tinnitus, tachycardia, fainting, but usually rapid recovery. 

Larger Therapeutic Doses (20 to 30 mg.; ^ to 3^ gr.). The initial 
symptoms are the same. Sleep occurs more promptly and is more pro- 
found. On awakening there is usually some confusion, nausea, anorexia, 
and constipation. 

Toxic Doses (100 to 300 mg.; \\^ to 5 gr.). The initial symptoms are 
as described. The somnolence deepens rapidly into sleep and coma; 
severe symptoms being generally conspicuous in five to ten minutes after 
hypodermic, or fifteen to forty minutes after oral administration; rarely 
delayed for one or two hours. 

In the earlier stages of the coma, the patient can be partially aroused 
to a confused consciousness, but relapses promptly into lethargy. 

As the coma deepens (i.e. almost always within two hours, and often 



230 MANUAL OF PHARMACOLOGY 

in half an hour after taking the poison), the patient can not be roused, the 
reflexes disappear, the muscles relax, the jaw drops. The miosis becomes 
extreme ("pin-point pupil"); the skin pale, with cold sweat, finally 
cyanotic; fall of temperature; respiration very slow, irregular, often 
Cheyne-Stokes; pulse slow, feeble and often irregular. Convulsions are 
rare in adults, more common in infants; they are sometimes violent, but 
rarely if ever tetanic. 

The respiration stops before the heart. The pupils almost always 
dilate as the terminal asphyxia sets in. (With heroin, death is due to the 
convulsions; Langer, 1912.) 

The time of death is usually seven to twelve hours; sometimes in two 
hours or even less. Survival over twelve hours indicates a good prognosis. 

Autopsy findings are not characteristic. There are only the common asphyxial 
lesions: Cerebral and meningeal congestion, sometimes with serous effusion; lungs hypere- 
mic and sometimes edematous; general venous congestion; rarely intestinal or cerebral 
ecchymoses. 

Ordinary Fatal Dose. With morphin, this is 0.2 to 0.4 Gm. (3 to 6 gr.) ; 
with opium, 3 Gm. (45 gr.). There is, however, considerable idiosyn- 
crasy, and 60 mg. (i gr.) of morphin must be regarded as dangerous. 
With 250 mg. (4 gr.) the prognosis is unfavorable, even under treatment, 
although patients have been saved after 4 Gm. (60 gr.) of morphin. 

Recovery. This may occur even after asphyxial convulsions. The 
respiration and pulse improve, the coma becomes lighter, and passes into 
a very prolonged sleep, often lasting for one or two days. On awakening, 
the patient is troubled with headache, constipation and digestive disturb- 
ances, often vomiting, itching, impotence of the bladder; exceptionally 
excessive depression. Sometimes the recovery is interrupted by a serious 
relapse, perhaps through the reabsorption of morphin from the intestine. 

Idiosyncrasies. Infants are highly susceptible to morphin; as to older 
children, there is difference of opinion. The female sex, and patients 
weakened by disease, succumb relatively easily. On the other hand, large 
doses are well tolerated in diabetes, in delirium tremens and in tetanus. 
In fever, morphin is sometimes exciting; in neurotic patients it may cause 
insomnia and delirium, instead of sleep. Nausea and vomiting are very 
pronounced in some individuals. Urticaria has been observed. Itching 
of the skin, especially of the nose, is a rather common symptom in poison- 
ing. These idiosyncrasies should be remembered in the therapeutic use 
of the drug. 

Death has been reported from almost incredibly small doses. Lewin 
cites two fatalities in children from 0.3 mg. (J-^oo g r -) f opium. In 
adults, 0.2 Gm. (3 gr.) of opium (% gr. of morphin), is credited with a 
death. The great variation in the susceptibility of different animals has 
been described, man being by far the most susceptible. 

Hyper susceptibility of Infants. Young animals are said to be more sus- 
ceptible than adults, with the exception of cats. Doebeli, 1911, from a 
clinical and experimental investigation, concludes that the hypersensi- 
tiveness, both in the human and in animals, applies only to the age be- 
fore weaning, older children following the ordinary rule. This, he finds, 
is also the opinion of most pediatrists. The special susceptibility of suck- 
lings is perhaps explained by the observation of Hunt, 1910, that a milk 
diet greatly increases the toxicity of morphin (for mice). The hypersus- 
ceptibility exists only for the narcotic action, and is, therefore, insignificant 
for codein. 



THE MORPHIN GROUP 33! 

Influence of Thyroid and lodids. Hunt, 1905 and 1907, found that feeding with 
thyroid or iodids increases the susceptibility of mice, rats and guinea pigs to morphin. 
Githens and Meltzer, 1913, find in rabbits that iodid increases the morphin depression 
but lessens the tetanic effect, and therefore the fatality. 

Diagnosis of Morphin or Opium Poisoning. A prompt diagnosis is 
very important for proper treatment. The coma is the most conspicuous 
symptom, and its gradual development is characteristic. In advanced 
poisoning, it may be difficult to distinguish the morphin coma from other 
forms. The symmetrical pin-point pupils are important, but it must be 
remembered that these dilate as death approaches (asphyxia). The odor 
is characteristic of opium poisoning. 

Differential Diagnosis of the Origin of a Coma. 1 Those forms of coma which 
might be confounded with morphin are mainly alcoholic (chloral), uremic and diabetic, 
epileptic and apoplectic. 

One of the most important points is furnished by the pupils. If these are dilated, 
the coma is probably alcoholic, but may be diabetic. With pin-point pupils the coma 
is either from opium or pontine apoplexy. If the latter, they are very often unequal, and 
on lifting the arms, one may often detect a paralysis. 

The pupils respond readily to light in epileptic coma, not in the others. 

The smell of the breath furnishes presumptive evidence of <z/c0/w/-poisoning, but it 
is not a definite proof, since this substance is often given as an antidote, and is so often 
present in quantities which would not cause a coma. The smell is, however, usually 
characteristic of opium, uremia and diabetes, but not of morphin. Uremia would also 
be characterized by albumin in the urine. 

There are yet other forms of coma which may be confused with these, but no rules 
can be laid down for them. The history is often of the greatest importance. 

Treatment of Acute Morphin and Opium Poisoning. The first indi- 
cation is to empty the stomach, and this no matter whether the drug has 
been taken by the mouth or hypodermically. If narcosis has already set 
in, emetics may act too slowly, and it may be necessary to employ a stom- 
ach-pump. The best chemic antidote is potassium permanganate, about 
0.5 Gm. per liter (5 gr. per quart) by lavage; orally, a o.i Gm. (i^ gr.) 
in a tumbler of water. Tannin is not very effective. The patient should 
be kept awake as far as possible and in constant movement, since this con- 
tributes to the better tone of the medullary center. Reflex stimulants 
may be employed, such as cold ablutions, the inhalation of ammonia in 
the form of smelling salts, hypodermic injections of ether, etc. Caffein, 
especially in the form of strong, black, hot coffee, is the best physiologic 
antidote. Atropin may be valuable if the dose of 1.5 mg. (%Q 8 r -) is not 
exceeded. The patient should be kept warm. If the breathing shows 
signs of failing, artificial respiration should be supplied. 

When the danger is over, the constipation which usually follows should 
be relieved by cathartics and enemata. 

Permanganate. De Buscher (1904, 1905) has found this effective in rabbits, even 
when it was administered three hours after the morphin; it was much less successful 
with dogs. It was quite ineffective if the morphin was given subcutaneously. Nothing 
could be expected from the hypodermic injection of permanganate, since this would be 
destroyed before entering the circulation. 

Atropin. This has been used extensively and somewhat indiscriminately in- the 
treatment of morphin poisoning. It is a very dangerous remedy in this condition. The 
most conspicuous antagonistic actions of these two poisons are on the pupil, heart-rate, 
psychic processes, secretions, etc. in short, upon functions which are of very subor- 
dinate importance in dangerous cases of poisoning. Any useful antagonism must 
be sought in their actions on the circulation, respiration, and metabolism. A careful 
study will show that the effects of morphin and atropin on these functions are antag- 
onistic only with certain stages; whilst more severe grades are actually synergistic. 
1 Coma.: A condition of insensibility from which the patient can not be aroused. 



232 MANUAL OF PHARMACOLOGY 

The later paralytic effects of atropin coincide with those of morphin; whilst in the last 
stages of morphin poisoning the centers are too greatly depressed to respond to the slow 
and weak stimulation of atropin. The usefulness of this antidote exists therefore only if 
moderate doses of atropin are given in moderate morphin poisoning (or vice versa). This 
conclusion is supported by several series of experiments on animals. As a practical 
deduction, the atropin should be given hypodermically in the dose of 1.5 mg. 0^ gr.) 
and this should not be repeated. It is fair to state, however, that this is not the universal 
opinion. For instance, Roch, 1907, advises 2 mg., frequently repeated, until the pupils 
begin to dilate. 

Cocain. A general antagonism exists also between morphin and small doses of cocain, 
especially as regards the effects on temperature and metabolism. Larger doses are 
synergistic, and as the susceptibility to cocain is variable, the hypodermic dose of o.oi 
Gm. (Y gr.) should not be exceeded. 

Acute Heroin Poisoning. Animals are killed by the convulsions; if these are pre- 
vented by etherization, almost double the fatal dose may be survived (Langer, 1912). 

Chronic Opiumism. Etiology; Early Effects. Opium, Morphin and 
Heroin habits are unfortunately very prevalent and together with the 
Cocain habit (and to a much lesser extent of "Hashish") they constitute 
one of the terrible scourges of modern times. All these drugs produce at 
first a feeling of well-being, relief and contentment, of stimulation and 
freedom of imagination, and of ease and facilitation of mental effort. 
These agreeable actions vary in degree in different individuals, and there- 
fore all do not fall their victims -with equal readiness; women and neurotic 
and dissipated individuals are especially in danger, if they become ac- 
quainted with the effects of these drugs. The majority of the heroin and 
cocain addicts begin the use through curiosity or dissipation (Drysdale, 
1915, Mclverand Price, 1916); but "Patent medicines" (cough, consump- 
tion, diarrhea, and catarrh "cures," etc.) are responsible for many cases. 
Physicians must also be on their guard in prescribing these drugs, even in 
acute conditions. Mclver and Price found that most cases of mor- 
phinism arise from the medicinal use. The continued use of opiates will 
lead to the habit, or disease, in practically every one, and is therefore excus- 
able only in exceptional conditions, such as hopeless, painful diseases 
(cancer, etc.). Petteys believes that the habit becomes firmly established 
when the drug has been used daily for a month. 

Historical. Whilst the therapeutic use of opium dates back of Hippocrates, its 
habitual use seems to be of more recent origin. The first authentic records fall in the 
beginning of the sixteenth century. It would seem that its use is much older in India 
than in Turkey, and that the Mohammedans learned it through the conquest of the 
former country. Their acquaintance with cannabis indica is of much earlier date. 
The existence of the opium habit was at .first confined to the Orient; its introduction 
into Europe and America is of very modern date it began in the United States about 
1860. 

Prevalence of Opium and Cocain Habit. It is impossible to secure reliable statistics ; 
but some idea may be gained from the fact that of about 600,000 pounds of opium, or 
its equivalent in morphin, and of coca leaves corresponding to perhaps 150,000 ounces 
of cocain, which are imported annually into the United States, at least half, and more 
probably nine-tenths, are used by habitues. The alarming increase of the habit may be 
judged by this, that whilst the population in the past fifty years has increased 13*3 per 
cent., the importation of opium has increased 350 per cent. (H. Wright, 1910); and in 
addition, the cocain and heroin habits took their rise only within this period. In Ten- 
nessee, registration showed o.i per cent, of the population to be afflicted with drug habits 
(Wilbert, 1915). From this and other data, he estimates the number of drug addicts 
in the United States as not over 200,000. The applications to the city institutions of 
Cleveland for relief of opium, morphin, heroin and cocain habits in consequence of the 
Harrison Law, amounted to about o.oi per cent, of the population. Of the sixty-six 
cases, forty-eight used opium or morphin; twenty-nine heroin, seven cocain (Drysdale, 
1915)- 



THE MORPHIN GROUP 233 

Opium Habit in Children. This is unfortunately not at all rare. It is usually 
started by the indiscriminate employment of paregoric and other soothing syrups. 
They present the typical symptoms. Withdrawal of the medicine is followed by 
restlessness, wakefulness, and every indication of suffering and distress. The treat- 
ment would be mainly hygienic. 

Forms of Opium Habit. The drugs are introduced by all possible 
channels: by the mouth, hypodermically, by smoking, by suppositories; 
and heroin, like cocain, by snuffing. The effects are very similar in all 
cases. 

Smoking. This is mainly practised in the Orient; but the International Opium Com- 
mission estimates that there are in the United States probably over 100,000 opium 
smokers, outside of the Chinese. 

Smoking opium (chandoe) is prepared by the Chinese, by a complicated process of 
roasting, and repeated extraction and evaporation. Its morphin content is about the 
same as that of ordinary opium. It has been claimed that the opium smoke does not 
contain morphin (e.g., Hartwich and Simon, 1903); but Pott, 1912, has proved that 
morphin is indeed the active constituent. It has been said that Orientals are less in- 
jured by opium; but this is mainly because, in smoking, smaller quantities are consumed, 
with longer intermissions. The hypodermic method is now becoming the more popular, 
and with it, the Chinese present the same phenomena as Europeans (A. S. Rochester, 
1909). The Chinese government has been making serious and successful efforts to 
suppress the opium evil. 

Heroin Habit. This has become very common, especially in the form 
of "snuffing" (J. Phillips, 1912; bibliography, Farr, 1915). It exhibits 
all the phenomena of the morphin habit, and its cure presents similar 
difficulties and dangers (Manguat and Blondel, 1903; Sollier, 1905; 
Fauntleroy, 1907; Duhem, 1907; Mclver and Price, 1916). Fatalities 
from overdosage are also more common. The quantities consumed daily 
average 0.6 Gm. (Mclver and Price), may reach i Gm. (Wholey, 1912) or 
even 2.8 Gm. (Comar and Buvat, 1904); so that considerable tolerance is 
acquired. Snuffing causes rhinitis. 

Codein Habit. Codein is not nearly so apt to induce a habit, although 
this has been reported (Pelz, 1905; Petteys). Little is known about habit 
from the other morphin derivatives. 

Later Phenomena; Tolerance; Degeneration. The more or less un- 
pleasant immediate after-effects of morphin have been described under the 
toxicology. These also vary in intensity in different individuals; in many, 
the famed dreams of the opium eater degenerate into frightful nightmares. 
As the use of the drug is continued, an increased tolerance to it becomes 
gradually established. The desired effects are weaker and evanescent, 
unless the dosage is progressively raised. This, however, exaggerates 
the unpleasant after-effects. Most habitues use the drugs as stimulants, 
rather than for pleasurable effects (Bishop, 1913). Moreover, any at- 
tempt to stop the drug results, not only in violent craving, but also in more 
serious and even dangerous "abstinence symptoms." The patient now 
takes the drug, not because he desires it, but because he can not do without 
it. The organism, accustomed to working under the influence of morphin, 
revolts against its withdrawal. When these drug habits have taken a 
thorough hold, they cease to be mere vices, and become real diseases, with 
physical, as well as mental and moral degenerations. 

The Acquired Tolerance. This may reach a remarkable degree, so that 
extraordinarily large doses can be taken daily without producing acute 
poisoning, and are even necessary to prevent the withdrawal symptoms. 
This immunity to morphin is, however, never absolute, and death from 



234 MANUAL OF PHARMACOLOGY 

overdoses forms the most frequent "excitus letalis" of the morphinists. 
The tolerance is lost if the drug is discontinued. 

The tolerance is explained partly by a very considerable increase in the 
power of the organism to destroy morphin; but since the destruction pro- 
ceeds more slowly than the absorption, there must also be an acquired 
tolerance to the action of morphin. No "antitoxin" is formed. 

The daily consumption of morphin: This is generally about i Gm. (Mclver and 
Price, 1916); but as much as 5.5 Gm. (85 gr., or one and two-thirds of the ordinary 
bottles) has been reported. Even larger doses are claimed by patients; but their state- 
ments are generally unreliable, since they are made in the hope that the drug will be 
withdrawn more gradually. 

Bishop, 1913, states that the tolerance persists unimpaired after seven months of 
abstinence. In animals, at least, it disappears in a few days. 

Tolerance in Animals. This can be induced in dogs (Faust), rabbits, goats, rats, 
and pigeons (Cloetta, 1903). Frogs seem to become more susceptible. 

The Explanation of Acquired Tolerance to Morphin. This has been the subject of 
many investigations and theories. Marme, 1883, aimed to show that morphin is trans- 
formed in the body into oxydimorphin, to which he attributed actions precisely the re- 
verse of morphin. It would thus explain both the tolerance, and the abstinence symp- 
toms. This theory has only historical interest, since Donath, 1886, and Marquis, 1896, 
have shown that oxydimorphin is not formed; and moreover, the properties of this sub- 
stance do not agree with the assumption of Marme. 

Another theory which may be dismissed is the formation of an antitoxin. Hirsch- 
laff, 1 902, claimed that the serum of habituated animals is protective; but his experi- 
ments are discredited by the negative results of Morgenroth, 1903, and Cloetta, 1903. 

The increased destruction of morphin (Faust) and of heroin (Langer) in habituated 
animals must be a factor in the protection, but can not explain it completely. The 
experiments of Cloetta and of Ruebsamen, 1908, incidate that this destruction is a rela- 
tively slow process, so that the tissues must in the meantime be exposed to a large amount 
of morphin. van Egmond, 1911, found that habituation to the toxic effect does not 
diminish the susceptibility to the central vagus stimulation. In further contrast to 
the vagus, the respiratory center and the pupil acquire marked tolerance in dogs (not 
in rabbits, van Dongen, 1915). Langer, 1912, also states that the acquired tolerance 
of dogs to the narcotic action of heroin does not extend to its convulsive effects. This 
persistence of some of the effects proves that the disappearance of others can not be 
due to destruction of the alkaloid. 

Biberfeld, 1915, found no difference in the lipoid content of the brains of normal and 
habituated animals. 

Crossed Tolerance. Dogs habituated to morphin also show marked tolerance toward 
heroin and codein, as regards the respiratory effects; slight as to equilibrium; none as to 
heart or peristalsis. They have not acquired toleration toward cannabis or chloral 
(.H. B. Myers, 1915). 

The later consequences of opium habit are insidious, but none the less 
dangerous. For years, victims of the habit may appear quite normal to 
superficial observers, but closer attention would even then reveal signs of 
the disease. Especially characteristic is the variability of moods de- 
pressed or stimulated according to the interval since the last dose. 

The physical phenomena relate at first to the digestive tract: obstinate 
constipation, alternating later with equally obstinate diarrhea; loss of 
appetite alternating with voracious hunger and thirst, and polyuria. 
These disturbances of digestion, as well as the more direct action of the 
drug, are not long in showing their effects upon the rest of the body. The 
patient loses weight rapidly and suffers from marasmus and cachexia. 1 

The skin becomes hard, pale, dry and rough. The nails, teeth and 
hair are also diseased. The condition of the integument is rendered still 

1 These are two ill-defined terms. The former, marasmus, signifying a continued low condition 
of the nutrition and a wasting of the flesh without apparent organic cause. Cachexia also indicates 
a wasting of the body, with some striking change in the features, which are usually pinched and 
yellow. 



THE MORPHIN GROUP 235 

worse by the local effects of the injection when the drug is used hypoder- 
mically. The whole skin may be mottled with scars and marks of recent 
or older injections, and abscesses are often produced through want of 
cleanliness. Even when the drug is used by the mouth, the entire skin 
often acquires a peculiar waxy appearance. 

The pupils are almost invariably contracted; the eyes lose luster; so 
that an opium user may often be recognized from his appearance. The 
pupillary and accommodation movements are affected. The heart is 
irregular. Albuminuria, glycosuria, and amenorrhea are frequent. The 
sexual functions are lessened (functional impotence, sterility), but usually 
return on withdrawal (Wholey, 1912). Fevers resembling simplex, inter- 
mittent, and typhoid, are often seen. The motor-nervous system shows 
considerable change: nervous tremors, increased reflex irritability, etc. 
These conditions sooner or later weaken the resisting powers of the patient, 
so that he falls an easy prey to some other ailment, and thus rarely reaches 
old age. However, the habit may persist for over thirty years (Mclver 
and Price). 

The effects on the character of the patient are even more deplorable? 
This sinks progressively to the lowest level of unscrupulous cunning and 
cowardice. It is very doubtful whether the testimony of an opium user 
can ever be accepted, even in instances which do not affect him. He 
becomes absolutely incapable of any effort. Duty no longer appeals to 
him, and in order to escape it, or, still more, in order to obtain his drug, he 
will resort to any lie or any trick, no matter how dishonest. He will prom- 
ise everything and fulfil nothing. Were he not so cowardly and disinclined 
to, or rather incapable of, any effort, he would be fit for any crime. His 
condition is all the more unhappy since he fully realizes it and sees himself 
in his true colors. He makes grand plans, and, at the same time, knows 
that he can never summon the energy even to begin them. Add to this 
the fact that he is a social outcast, and it is difficult to imagine a more 
unhappy condition. To the physician he should appeal as a sufferer, as 
one afflicted with a form of insanity; one who, like any other insane patient, 
should be treated with unflinching firmness, but with the most considerate 
kindness. Only in this way will it be possible to help him. He is himself 
devoid of the necessary will power, and this must to some extent be sup- 
plied by his physician and attendants. 

Abstinence Symptoms. The withdrawal of morphin from those accus- 
tomed to its use leads to a train of very severe effects, the severity being 
proportional to the rapidity with which the drug is withdrawn and to the 
dose which has been used. Prominent throughout is uneasiness and rest- 
lessness, with almost uncontrollable craving for the drug, passing sometimes 
into a true mania. Besides this, the first symptoms consist in spasmodic 
yawning and sneezing; coryza and lachrymation ; and hoarseness. The 
pupils dilate again. Most conspicuous are muscular twitchings and vio- 
lent pains or "cramps," sometimes in the abdomen, more commonly in 
the legs; also headache and other neuralgias. The extremities are cold, 
the head congested. Insomnia is a very constant symptom; the patients 
are very irritable and excitable, and this condition may culminate in 
delirium or acute mania, often suicidal. Women often have hysteric 
attacks. The digestion is profoundly disturbed, presenting the symptoms 
of a violent functional gastroenteritis. The most dangerous phenomenon 
is sudden collapse, ushered in by irregular and weak pulse, alternating 
between extremes of rapidity and slowness, cold sweat, and general pros- 



236 MANUAL OF PHARMACOLOGY 

tration; and often ending fatally by heart-failure. This collapse, if severe, 
demands the prompt injection of a moderate dose of morphin, which 
generally causes the symptoms to disappear. 

The abstinence symptoms are practically absent if the patient is 
rendered delirious by scopolamin (Wagner and Riewel, 1905). This sug- 
gests that they are mainly of psychic origin. 

Abstinence Symptoms in Animals. 'According to Valento, 1914, these show cir- 
culatory disturbances, arrhythmia, tachycardia, low blood pressure, etc.; and he states 
that these effects are produced acutely when abstinence blood is injected into normal 
animals. He finds, further, that the blood retains this property long after the morphin 
has been stopped, which speaks rather against an analogy with the human absti- 
nence symptoms. 

Treatment of Opium and Other Drug Habits. The prime indication, 
as in all diseases, is the removal of the cause, the withdrawal of the drug. 
This must be done under medical supervision, best in special institutions, 
for the patients have neither the will power, nor the physical resistance to 
carry it through unaided; attempts at self-treatment are generally unsuc- 
cessful, and always dangerous. In fact, the closest surveillance of the 
patient is indispensable, both to prevent clandestine continuance of the 
habit, and to control the abstinence symptoms. The main object, there- 
fore, is to withdraw the drug without danger or too great discomfort to 
the patient. When the drug has been completely stopped, even for a few 
days, the desire for it disappears, and the patient may be considered cured, 
although still in need of tonic treatment. Unfortunately, the seductive 
memories remain, and when occasion offers, sooner or later, relapses are 
all too common, often within a few weeks. These remarks apply equally 
to cocain and other serious drug habits; and the treatment of these is 
identical. 

Methods of Withdrawal. 1 Attempts at "insensible withdrawal," by 
very gradual diminution of the dose, amounts to useless and protracted 
agony; the sensations of the patient gauge the dose with surprising ac- 
curacy, and their patience reaches its end long before the drug. 

Rapid withdrawal is much better, and generally succeeds if the patient 
can be supervised. With this method, the drug is reduced as rapidly as 
can be borne by the patient without producing very violent reaction. 
It is better to begin by reducing the number, rather than the size of 
the doses. Profuse catharsis is a very effective adjuvant. The with- 
drawal may be completed within ten to fourteen days. Very hot baths 
relieve the restlessness and insomnia; salicylates the "pains" (Mclver 
and Price, 1916). The treatment is effective and not excessively difficult 
(Drysdale, 1915). 

Sudden complete withdrawal is both cruel and dangerous. It can be 
made more pleasant by substituting another habit-drug, but this accom- 
plishes nothing more than the deceit of the patient, and is no better than 
the many advertised "Morphin Cures" which are thinly disguised solu- 
tions of morphin. 

.The Scopolamin Treatment of Drug Habits. This permits the sudden 
and complete withdrawal of morphin, cocain, or alcohol from habitues, 
without the usual unpleasant results. It depends, apparently, on the 
maintenance of a mild delirium or "twilight sleep" which renders the 
patient more or less unconscious of the withdrawal. According to the 
experience of Wagner and Riewel, 1905, the cure can be completed in a 

1 Puller descriptions of the standard methods are found in the J.A.M.A., 64: 1022, 1915. 



THE MORPHIN GROUP 237 

> 

very few days, and is as complete as with any of the more difficult 
methods. 

Details. The treatment consists in absolute withdrawal of the drug, and in adminis- 
tering hypodermically a mixture of scopolamin hydrobromid, 0.3 mg. (J^oo 8 r -); 
atropin sulphate, o.i mg. (%QQ gr.), strychnin sulphate, 0.4 mg. (Kso g r -)> and water 
1.5 c.c. (25 minims). The first dose, which is usually without results, is repeated in 
one-half to two hours, and again in one and one-half hours, and then every one-half to 
two hours, until the full scopolamin effect is indicated by dry throat, flushed face, dilated 
pupils, restlessness, and mild delirium. The patient is maintained continuously in this 
state for three or four days, by repeating the injection every two to six hours, reducing 
the individual dose to half, if possible. Constant, careful and skilled watching of the 
patient is indispensable. If the pulse (which remains ordinarily of normal character, 
with a rate of 60 to 70) should fall below 505 or rise above 1 10, the treatment is inter- 
mitted, and some strychnin and a very little morphin are given. 

The second day usually produces some abstinence symptoms (violent attacks of 
sneezing and some gastro-intestinal phenomena), but these are rarely of sufficient 
severity to require special attention. 

The patient can be about the room throughout the treatment, and receives "fever 
diet." The delirium is usually mild and busy, the patient being mainly engaged in 
picking imaginary insects, etc. 

At the end of the third day the injections are stopped, to see whether craving for 
the drug will return. Should this occur, the treatment is continued for another day. 
This is rarely required. 

The Lambert-Towns Method, described by A. Lambert, 1909 and 1913, seems to in- 
volve the same principles, since it uses essentially Hyoscyamus and Belladonna. (De- 
tails in J.A.M.A., 1911, v, 56, p. 503; v. 60, p. 1933.) Collapse sometimes occurs 
(Wholey, 1915). 

Pilocarpin has also been employed. 

Sceleth, 1916, advises a method including scopolamin, pilocarpin and ethylmorphin. 

The After-treatment. This is important with all methods. The patient 
should receive tonics, nutritious food, and rest for several weeks. Insom- 
nia is rather troublesome at first, and should be relieved by giving chloral 
and bromid for two or three nights. The bowels should be kept clear, both 
before and after the treatment. 

The " recovered" patient must be protected as much as possible against 
pain and other circumstances which would tempt him to the resumption 
of the drug. Psychotherapy may be useful to prevent recurrence. 

Legislation Against Drug Habit. The real cure of drug habits lies in the enforce- 
ment of appropriate legislation. The Harrison Law, if properly enforced, should suffice 
to suppress the opium and cocain habits almost completely. It is asserted that it has 
already reduced the sales of the affected drugs to half (Wilbert, 1916). 

Therapeutic Uses. Morphin and Opium are used mainly to lessen 
pain, to procure sleep, to check peristalsis, to suppress cough, to ease dyspnea, 
to facilitate anesthesia, and to secure muscular quiet. These indications 
arise in a great variety of diseases; and since the action of the opiates is 
certain and highly effective, their field of usefulness is extensive and im- 
portant. However, they must be used with discretion. It should be 
remembered that the relief is generally only symptomatic and may some- 
times interfere with the natural processes of repair, or obscure the observa- 
tion of the progress of the disease. 1 The danger of habit formation re- 
stricts their employment in neurotic individuals and in chronic diseases 
(except when these are hopeless). The habit danger can be somewhat 
avoided if the morphin is administered only by the physician, with some- 
what impressive formalities of asepsis, and not intrusted to the patient 

1 Cushny, 1914, aptly points out that the avoidance of opiates for fear of obscuring the diagnosis 
is a confession of deficient diagnostic technic; it should not be necessary to make the .diagnosis at 
the expense of exhausting pain. 



238 MANUAL OF PHARMACOLOGY 

himself. The side actions (constipation, nausea, gastric disturbance, and 
occasional excitement) may also interfere with the usefulness. Even with 
these restrictions, however, the range of usefulness of the opiates is still 
very wide. 

Pain. Morphin surpasses in efficiency all other analgesics, particularly 
for persistent pain. It is generally aimed to dull, rather than to abolish 
the sensibility; and for this purpose relatively small doses suffice. Mor- 
phin by hypodermic injection is to be preferred, 5 to 15 mg. (J^ 2 to Y 
gr.) according to severity, and repeated as necessary. Local application 
is irrational, although it is still somewhat used. (H. C. Wood, Jr., 1916). 

Insomnia. Morphin should be avoided, if possible, especially in ner- 
vous insomnia and in psychic excitement. It may be needed if the insom- 
nia is caused by pain, cough, or dyspnea; and small doses (5 mg. or 
^ 2 gr.) may be employed to reduce the dosage, and thus the side actions, 
of other hypnotics (/./., the circulatory depression of chloral). 

Diarrhea. Opiates are very effective in arresting the excessive peris- 
talsis in acute intestinal catarrh. If the intestines are first cleared of 
toxic and irritant material by a cathartic, the rest afforded by opiates 
favors the subsidence of the inflammation. Tincture of Opium by mouth 
(0.5 c.c. or 10 drops) deserves the preference. If the opiates are given 
while the materies morbi are still in the intestine, they may do harm, even 
when they give symptomatic relief. 

Opium is also useful in the constipation and colic of lead poisoning, 
by relaxing the intestinal spasm. In peritonitis it relieves the pain, both 
directly and by lessening peristalsis; but the disguise of the symptoms may 
be objectionable surgically. In biliary and renal colic, Morphin (15 mg. 
or % gr.) is given hypodermically, to lessen the suffering (usually with 
i 'mg. atropin, which relaxes the ducts). 

Cough. The opiates check cough by lowering the reflex irritability 
of the respiratory center. Small doses suffice for this purpose by mouth, 
Morphin 5 mg. or ^ 2 gr. ; Tr.Opii ^ c.c. or 10 drops; Codein 30 mg. or 
]/2 g r -5 Heroin 5 mg. or 3-^2 g r - (children above one year, % mg. or f 20 
gr. ; below one year, % mg. or ^40 gr.);Dionin 15 mg. or ^ gr. Codein 
deserves preference, since it produces the desired effect with less side ac- 
tions, and without habit formation. 

The use of opiates for this purpose, as in bronchitis and phthisis, re- 
quires judgment. They are indicated when the cough is mainly irrita- 
tive ; and contraindicated when it is required for the expulsion of excessive 
mucus. Even then, however, they may be needed to produce sleep. 

Asthma and' Dyspnea. Morphin (15 mg. or }/ gr., hypodermically) 
often relieves this condition, by quieting the patient, allaying the "air 
hunger" and perhaps by lessening reflex irritability. It should be 
avoided if possible. In nervous asthma, it tends to form a habit. In 
respiratory dyspnea, the reduction of respiration may be dangerous. In 
cardiac asthma, the increase of carbon dioxid in the blood may injure 
the cardiac function and establish a vicious circle. The use of caffein 
or atropin would be preferable; but it may be justifiable to resort to 
morphin, especially for relieving the anxiety. 

Colds. The diaphoretic action is utilized for aborting colds; generally 
as Pulv. Ipecac et Opii, 0.5 gm. or 7^ gr. 

Anesthesia. Morphin in safe doses does not induce complete insensi- 
bility, but it is an efficient synergistic to other ansthetics (10 mg. or % 
gr., hypodermically, see under "Ether," also under " Scopolamin.") 



THE MORPHIN GROUP 239 

Morphin is similarly useful for distracting the patient's attention from 
operations under local anesthesia. 

Hemorrhage. Morphin favors the arrest of hemorrhage by quieting 
the patient, thus keeping the blood pressure low, and permitting the for- 
mation of the clot. It is especially valuable when the hemorrhage is in 
inaccessible situation, f.i., the pulmonary hemorrhage of phthisis. The 
depressant effect on the respiration enjoins caution in the use of larger doses, 
especially in severe hemorrhage, cardiac disease, and other debilitating 
conditions. 

Convulsions. Since morphin increases reflex excitability, it can not 
compare with ether, chloral or chloroform for suppressing tetanus or other 
spinal convulsions; but its analgesic effect may justify its use as an ad- 
juvant. The depressant action on the respiratory center must be borne 
in mind (Dreyfus, 1914). 

Psychic and motor exaltations, e.g., delirium tremens or atropin poisoning, are con- 
trolled only by very large doses, the danger of which offsets the problematic benefit. 

Diabetes. Large doses of opium, morphin or codein appear to benefit 
some otherwise intractable cases; but the ultimate results are not brilliant. 
The effects are probably indirect, by slowing the absorption of sugar from 
the alimentary tract. 

Experimental Glycosurias. The opium alkaloids have no effect on the hypergly- 
cemia resulting from the conversion of hepatic glycogen (epinephrin or piqure) ; but they 
have an inhibitory action on alimentary hyperglycemia (Klercker, 1914). This indi- 
cates that the action is on the alimentary canal, presumably by the gastric delay slow- 
ing the digestion and absorption of the carbohydrates, and thus preventing the sud.den 
flooding of the organism with sugar (Macleod, 1914). Morphin delays the disappear- 
ance of injected dextrose from the circulation of dogs, although it facilitates its excre- 
tion by the urine (Kleiner and Meltzer, 1916). It must therefore hinder the passage 
of sugar from the blood into the tissues. 

Clinical Evidence. Good clinical observers claim that the thirst, polyuria, glyco- 
suria, and itching of the skin are all markedly diminished. Part of this action must be 
attributed to the analgesic effect, while the influence on the glycosuria is probably due 
to its action on digestion, and is produced in the same way as by a limitation of the diet 
or by nauseants. As a matter of fact, opiophagic diabetics die faster than others. 
Codein has been used instead, but without any marked advantages. 

Emesis. Morphin is employed as an ant-emetic, but the doses which can be safely 
prescribed are often ineffective. 

Dosage of Opiates for Children. This is best adjusted to the weight: 
with children above ten months, the weight (in pounds) is divided by 150; 
below ten months, by 300. The adult dose is multiplied by the factors 
thus obtained (Doebeli, 1912). 

Recapitulation of the Chief Differences of the Morphin Derivatives. 
The action of all morphin derivatives are quantitatively identical, so 
long as they involve only changes in the outlying side-chains (R. Stockman, 
1891). Even the quantitative differences are not of very great practical 
importance. 

Morphin. Produces the strongest narcotic, analgesic, hypnotic and 
intestinal effects, and the weakest stimulation. It causes the greatest 
derangement of digestion; and, with heroin, is most apt to induce a 
habit. 

Codein (Methyl-morphin) is less narcotic, less constipating, and less 
apt to induce a habit or tolerance. It has some advantage in the treat- 
ment of cough. Bastedo uses 15 to 30 mg., but Fraenkel, 1899, claims that 
at least 40 to 60 mg. are required to affect cough. This dosage is some- 



240 MANUAL OF PHARMACOLOGY 

what quieting, but not narcotic, and scarcely analgetic. Larger dosage 
produces restlessness instead of quieting. The susceptibility is the same 
for all ages (Doebeli, 1911). 

It increases the spinal reflexes more than morphin (v. Schroeder, 1883). Frank- 
further and Hirschfeld, 1910, claim a greater dilation of the cerebral vessels (without rise 
of blood pressure). 

Dionin (Ethyl Morphin) seems to stand intermediate between morphin 
and codein, in all respects. Mering advises it in cough. Lindenmayr, 
1912, uses it in colds, 0.05 Gm. before retiring. It sometimes causes 
itching of the skin (Seifert, Nebenwirk., 1915, p. 61). It has a special 
action on the conjunctiva (edema). 

Heroin (Diacetylmorphin) approaches still more to morphin, of which 
it shares all the disadvantages, and over which it has no serious advantage. 
Bastedo finds it inferior to codein (Side actions, Seifert, Nebenwirk., 
1915, p. 69>. 

Thebain is so markedly convulsant that it may be placed in the strychnin group 
(Cl. Bernard; Stockman and Dott). ' 

Structure of Opium Alkaloids. These belong to two groups, those con- 
taining a phenanthren nucleus (morphin and its esters) ; and those derived 
from isoquinolin (papaverin, narcotin, narcein). The difference in the 
nuclei is shown in the diagram. 

x\ 




Phenanthren nucleus Isoquinolin nucleus 

Structure of Morphin and its Derivatives. -Morphin is a complex deriva- 
tive of phenanthren. It contains two OH groups (one phenolic, the other 
alcoholic) in which substitutions can be made, either by alkyl or acid 
radicals. 

The more important alkyl esters are the monomethyl (Codein), di- 
methyl (Thebain) and ethyl (Dionin). Heroin is the di-acetyl derivative. 

The nature of the radicals whether acid or alcoholic, aromatic or aliphatic is not 
of great importance. Replacement of a single H (codein, dionin) diminishes the nar- 
cotic actions and increases the respiratory and tetanic action, and the toxicity for ani- 
mals. When both OH groups are replaced by acids (heroin) the narcotic action is 
stronger than for codein, the tetanic action is weaker than with morphin. 

Comparative Activity of the Two Groups. The alkaloids of both the 
phenanthren and isoquinolin are more or less narcotic and convulsant. 
The essential differences are in the peripheral actions: whilst the phen- 
anthren alkaloids produce but few peripheral actions, the isoquinolin 
group causes extensive depression, as described under "Papaverin." 

Convulsant-narcotic Series. In general, the narcotic actions on the brain, on the 
one hand, and the stimulant action on the cord and medulla on the other, are in inverse 
ratio; morphin being the most narcotic and least convulsant, and thebain the most 



THE MORPHIN GROUP 241 

convulsant and least narcotic; the other morphin esters and the isoquinolin alkaloids 
being intermediate. Claude Bernard arranged them in the order of: Morphin, codein, 
narcotin, papaverin, laudanosin, thebain. Buergi, 1914, places them as: Morphin, 
papaverin, codein, narcotin, narcein, thebain. 

Mcconic Acid. This has no effect in the doses which would be administered in 
opium. Larger doses produce narcosis, muscular fibrillation; medullary convulsions; 
diarrhea; curare action (Barth, 1912). 

Papaverin. This was recommended as an analgesic by Baxt, 1869, and Macht, 
1915; but its central effects are insignificant (Pal). Its toxicity is low. Bouchet 
claims that i Gm. produced no effects on man. Its important peripheral actions have 
been investigated mainly by Pal, 1913, 1914. He finds that it relaxes the tonus of all 
smooth muscle, especially when this has been spasmodically contracted, and this without 
paralyzing the contractility of the muscle; f.i., he claims that it inhibits intestinal 
tonus without interfering with normal peristalsis or producing constipation; that small 
doses lower abnormally high blood pressure, whilst it requires much larger doses to 
lower the normal pressure. Macht, 1916, claims that it lowers blood pressure, mainly 
by peripheral vasodilator action, especially in the splanchinic area. The coronary 
circulation is increased. Small doses slow the heart, with tendency to stronger con- 
tractions. Popper claims that the isoquinolin alkaloids relax the longitudinal coat 
of the intestines; the phenanthrens the circular coat. Macht, Herman and Levy, 
1916, find that 40 mg. hypodermically in man, produces marked analgesia with some 
vasodilation, fall of blood pressure and slight constipation. 

Papaverin and narcotin are toxic to protozoa; Pick and Wasicky, 1915, have there- 
fore suggested the trial of papaverin against amebic dysentery. 

Therapeutic Use of Papaverin. Pal advises its use in gastric and intestinal spasms 
and colics, and in spastic constipation (30 to 80 mg. by mouth or hypodermic; 5 to 30 
mg. by vein several times). Stoerk, 1915, employs it against the tenesmus of bacterial 
dysentery (0.06 Gm., three times daily, continued as long as required). It has also 
been tried with less reason, in hypertension, angina pectoris; vomiting, gastric crises; 
asthma and pertussis (Pal; Popper, 1914; L. Levy, 1914). It is a local anesthetic, and 
has been used on the cornea as solution of 4 to 10 per cent. Macht, 1916, finds that 
papaverin relaxes the tone of the ureter, without inhibiting the peristalsis. Gerathy 
and Macht, 1916, use its injection by ureteral catheter, against the colic of ureteral 
calculi. - ' 

Commercial papaverin contains considerable cryptopin, to which most of its chemical 
tests are due (Pictet and Kramers, 1910). In general, however, the quality of commer- 
cial opium alkaloids is satisfactory (Warren, 1915). 

Fate of Papaverin. It is probably extensively destroyed in the body, since neither 
papaverin nor any immediate decomposition products have been recovered from the 
organs or excreta after its hypodermic administration (Zahn, 1915). 

Tetra-Hydro-Papaverolin. Laidlaw, 1910, found that this inhibits the tone of un- 
striped muscle, dilates the bronchioles and blood vessels, and lowers blood pressure, 
whilst at the same time stimulating the heart. It is relatively non-toxic. Marshall, 
1912, tried it clinically in arteriosclerosis, but found it practically inefficient probably 
therefore it is too easily oxidized. 

Narcotin. The peripheral actions appear to be similar to papaverin, but weaker 
(Pal, 1914). Macht, 1915, found, contrary to Straub, that it is quite toxic to the heart, 
respiration and other functions. 

Xarcein. The peripheral actions resemble narcotin (Pal, 1914). 

Differences between Morphin and Opium ; Opium Alkaloid Mixtures. 

Whilst the actions of opium are essentially those of its principal alka- 
loid, morphin, there are various differences, especially quantitative. 
These are due partly to the mechanical action of the gums and resins, which 
must delay absorption, and thus increase the local and diminish the cen- 
tral actions. In the main, however, the differences are due to the pres- 
ence of the minor alkaloids, which modify the effects of morphin; for 
similar differences exist in mixtures of the alkaloids, natural (Pantopium) 
or artificial (Narcophin, Laudanons). 

The precise differences between the actions of morphin, opium and the 
mixed alkaloids are still under dispute. The statements of different (and 
sometimes of the same) observers are so contradictory that it is often 
impossible to judge them (Literature, E. Buergi, 1914). 



242 MANUAL OF PHARMACOLOGY 

Claimed Therapeutic Advantages. It is asserted that opium and the 
alkaloid mixtures, for a given degree of analgesic and cough sedative 
action, cause less depression of respiration and less nausea; that their 
action, though slower, is more prolonged; and that they are sometimes 
effective in patients in whom morphin has failed. It is also believed that 
opium and pantopium are more efficient in checking diarrhea; whilst at 
the same time, it is stated that pantopium is not as constipating for normal 
individuals. 

Before considering these actions in detail, it is necessary to describe the nature of 
the commercial products which have been largely used in the investigations. 

Pantopon (Pantopium Hydrochloricum), N.N.R. This consists of the isolated alka- 
loids of opium in their natural proportions. It was introduced by Sahli, as an improve- 
ment over the opiates. Discounting the early extravagant claims, it has the advantage 
that the absence of gums and resins insures prompter absorption and makes it much 
more suitable for hypodermic injection. The pharmacologic data on pantopium are 
reviewed by Earth, 1912; Schwentner, 1912; Watkyn-Thomas, 1913. Severe poison- 
ing from 0.04 Gm. is reported by Voigt, 1911. The side actions are quoted by Seifert, 
Nebenwirk., 1915, p. 81. 

Artificial Mixtures. Since it is unlikely that all the alkaloids are therapeutically 
useful, and that they occur naturally in the optimal proportions, there exists a field for 
artificial mixtures. Faust, 1912, introduced mixtures of the principal opium alkaloids 
under the name of "Laudanons." The proportions appear to be merely arbitrary. 
A more scientific attempt has been made by W. Straub in the introduction of Narcophin. 

Narcophin. W. Straub and Caesar, 1912, investigated the modifications produced by 
a large variety of mixtures of opium alkaloids. They found narcotin the most important 
alkaloid in the combination; claiming that doses of narcotin, which were ineffective 
alone, modified the actions of morphin, so as to increase the toxicity and narcotic effect, 
and at the same time diminish the respiratory depression; that a mixture of equal parts 
of the two alkaloids was the optimal proportion and fully represented* the advantages 
of opium; that the other alkaloids of opium had less effect and introduced complex 
modifications which render them undesirable. These claims have been both confirmed 
and contradicted, clinically and experimentally. Meissner, 1913 and 1914, failed 
to confirm the synergism in the most important effects, viz. the respiratory and psychic; 
Straub's reply, 1913, is not quite convincing. Under the circumstances, judgment 
must be suspended. 

Potentiation of Toxic Action. Issekutz, 1912, found that the toxicity of mixtures of 
morphin and its esters corresponds to simple addition, but that mixtures of these with 
the isoquinolin alkaloids shows marked potentiation. This has been confirmed by 
W. Straub and Caesar, 1912, who claim that doses of narcotin, which are in themselves 
inactive, double the toxicity of morphin for mice. This synergism may be considered 
as established; but it has little bearing on the therapeutic use. 

Analgesic Action. The statements are contradictory, as might be expected from the 
difficulty of making quantitative observations in a subjective condition. As yet, the 
claims of superior analgesic or narcotic action are not fully established. The sedative 
action on cough comes under the same category. 

Straub claims a marked increase of narcotic action by narcotin, in that the morphin 
excitement of cats is prevented. (This, however, is a very variable condition, which is 
greatly influenced by external conditions.) Macht, Herman and Levy, 1916, also claim 
a synergistic decreased sensitiveness to cutaneous pain in human subjects. On the other 
hand, it is very suggestive that the clinical doses of narcophin and pantopium are strictly 
equivalent to their morphin content. Zeelen, 1910 and 1911, found only simple sum- 
mation in the narcotic (and tetanizing) action of the various opium alkaloids. Meissner 
also failed to confirm Straub. 

Respiratory Action. Straub asserts that the respiratory center in rabbits (as judged 
by response to CC>2 stimulation) is much less depressed by narcophin than by morphin. 
This is contradicted by Meissner. Straub's statements appear self-contradictory, since 
he also claims that the toxicity, which generally depends on respiratory depression, is 
increased. However, Macht, 1915, confirms that the minor opium alkaloids stimulate 
respiration, and thus antagonize somewhat the morphin depression. 

Circulation. The data are scanty. Macht, 1915, finds that morphin-narcotin mix- 
tures dilate the coronary vessels much less than either alkaloid alone; and that Pantopon 
and Laudanon have practically no effect on the coronary circulation. 

Gastric Disturbance. It is quite generally asserted that the combinations are less 
liable to produce nausea and vomiting; but quantitative differences of this kind are diffi- 



THE MORPHIN GROUP 243 

cult to judge, clinically. It is possible, though not proven, that there may be a slight 
difference, since morphin itself stimulates the vomiting center more than any other 
opium alkaloid. 

Constipating Action. This has been discussed under morphin. 

The synergism of morphin with scopolamin and with the anesthetic and hypnotics 
will be discussed in connection with those drugs. 

PREPARATIONS OPIUM 

* Opium, U.S.P., B.P. (Meconium, Thebaicum). The dried milky juice exuding 
from the incised unripe seed-capsules of the poppy, Papaver somniferum. Brown 
masses or powder, of peculiar odor and bitter taste. Contains a number of alkaloids, 
the most important being morphin (about 10 per cent.). Dose, 0.06 Gm., i gr., U.S.P. 
(equivalent to 6 mg. or 3^o S r - morphin); 0.03 to 0.12 Gm., K to 2 gr., B.P. Maximum 
dose, 0.2 Gm., 3 gr. 

Opium was mentioned by Theophrastus, third century B.C. An interesting account 
of its history is given by Macht, 1915. The history of the opium preparations is also 
interesting (Wilbert, 1916). Laudanum is said to have been originated by Paracelsus 
(1493-1541) but as a solid aqueous extract; paregoric by Le Mort of Leyden, early in 
the eighteenth century. Sydenham's laudanum (Vinum Opii) is derived from a formula 
of Sydenham (1624-1689). Tr. Opii Deodorati was originated by Robiquet (1780- 
1840), and Robt Hare, 1827; Mist. Glycyrrh. Co. by Dr. B. J. Barton of Philadelphia, 
about 1814. 

The opium poppy is cultivated in Asia and Egypt; it can also be raised in the United 
States, but the cost of labor renders the production of opium unprofitable. The capsules 
(especially before ripening, Caesar and Loretz, 1902) and seed also contain the alka- 
loids. The seeds yield 50 per cent, of a bland fixed oil which may be used like olive oil. 

The usual percentage of the other alkaloids is: Codein, 0.2 to 0.7 per cent.; The- 
bain, 0.15 per cent.; Narcein, 0.02 to 0.7 per cent.; Narcotin, 1.3 to 10 per cent.; Papa- 
verin, i per cent, (absent in some sorts; Van Italie and Kerbosch, 1910). The develop- 
ment of these alkaloids in the growth of the plants is interesting (Kerbosch, 1910). 

Opium also contains a number of other minor alkaloids; meconic acid (2.5 to 5.5 
per cent.), lactic acid; gums, resins, fats, odorous principles. No starch or tannin. 

*Opii Puhis (Opii Pulv.), U.S. P.; Powdered Opium. Light brown powder, yielding 
10 per cent, of anhydrous morphin. Dose, 0.06 Gm., i gr., U.S.P. 

Opium Deodoratum (Opium Deod.), U.S.P. Opium exhausted with petroleum ether, 
to remove some of the odorous principles. It is similar to the secret "improved" 
opiums. 

Opium Granulatum, U.S.P. This is employed in manufacturing. 

Ext. Opii Liq., B. P. 0.75 per cent, of morphin, 3.75 per cent, of the Dry Extract, in 
20 per cent, alcohol. Dose, 0.3 to 1.8 c.c., 5 to 30 minims, B.P. 

Ext. Opii, U.S.P.; Ext. Opii Sice., B.P. A powdered extract, i Gm. representing 
2 Gm. of the drug, or 20 per cent, of morphin. Dose, 0.03 Gm., % gr., U.S.P.; 16 to 60 
mg., J4 to i gr., B.P. Maximum dose, 0.15 Gm., 2^ gr. 

Lin. Opii, B.P. Equal parts of Tr. Opii and Lin. Sapon. 

Lotio Opii Et Plumbi, N.F.; Lead and Opium Wash. Lead acetate, 4.5 Gm.; Tinct. 
opium, 9 c.c.; Water, q.s., 250 c.c. 

* Mistura Glycyrrhizce Composita (Mist. Glycyrrh. Co.), U.S.P. (Brown Mixture). 
The adult dose, 10 c.c., 2% drams, of this mixture contains 1.2 c.c. of Paregoric or 5 mg., 
Y\<i gr- of opium; and 2.5 mg., ^4 gr., of Tartar Emetic; also a little Sp. Aether. Nit. 
It is a popular expectorant, but needlessly complex. 

(Pil. Plumb. C. Opio, see Index.) 

Pil. Sap. Co., B.P. 20 per cent, of Opium. Dose, 0.12 to 0.25 Gm., 2 to 4 gr., B.P. 
Pulv. Cret. Arom. C. Opio, B.P. 25 per cent, of Opium. J)ose, 0.6 to 4 Gm., ro 
to 60 gr., B.P. 

* Puhis Ipecacuanha Et Opii (Pulv. Ipecac et Opii), U.S.P.; Pulv. Ipecac. Co., B.P. 
(Dover's Powder; Opii et Ipecac. Pulv. Co., P.I.). Contains 10 per cent, each of 
Opium and Ipecac with Milk-sugar, U.S.P., or Potass. Sulphate, B.P. (This was in- 
troduced by Thomas Dover, 1742, as a diaphoretic in gout.) Dose, 0.5 Gm., 8 gr., 
U.S.P.; 0.3 to i Gm., 5 to 15 gr., B.P. Maximum dose, 1.5 Gm., 20 gr. 

(Pulv. Kino Co., see Index.) 

Pulv. Opii Co., B.P. 10 per cent, of Opium, with aromatics. Dose, 0.3 to i (1m., 
5 to 15 gr., B.P. 

(Supp. Plumbi Co., B.P., see Index.) 

*7Y. Opii, U.S.P., B.P.; Tincture of Opium (Laudanum). 10 per cent, of opium, 
or i per cent, of morphin, in diluted alcohol. Miscible with water or alcohol. Dose, 



244 MANUAL OF PHARMACOLOGY 

0.5 c.c., 8 minims, U.S. P.; 0.3 to i c.c., 5 to 15 minims, repeated; single, 1.2 to 1.8 c.c, 
20 to 30, B.P. Maximum dose, 2 c.c., 30 minims. 

Tr. Opii Amman., B.P. o.i per cent, of Morphin, with Anise oil, Benzoic acid and 
Ammonia. Dose, 2 to 4 c.c.; *> to i dram, B.P. 

*Tinctura Opii Camphorata _(Tr. Opii Camph.), U.S.P.; Tr. Camphor. Co., B.P. 
(Paregoric; Opii Tinctura Benzoici, P.I.). 0.4 per cent., each, of opium, benzoic acid, 
camphor, and anise oil, U.S.P. The B.P. contains the same ingredients with 0.5 per 
cent, of opium. The preparation is used especially for children. Dose, 4 c.c., i dram, 
U.S. P.; 2 to 4 c.c., ) to i dram, B.P. 4 c.c. contains 16 mg., ^ gr., of opium or 1.6 
m*?" Mo gr., of morphin, U.S.P.*j(2o mg., Y$ gr. of opium or 2 mg., ^ gr. of morphin 
B.P). 

* Tinct. Opii Deodorati, U.S.P. Same strength and dose as the Tincture; has less 
odor, having been extracted by petroleum ether. Similar to McMunn's Elixir and other 
nostra. 

(Ung. Gall. C. Opio, B.P., see Index.) 

(Ung. Myrrh. C. Opio, B.P., see Index.) 

Pantopon (Pantopium Hydrochloricum), N.N.R. A purified mixture of opium 
alkaloids, containing 50 per cent, of morphin. Sol. in water. Dose, 5 to 20 mg., 
3- to ^ gr., by mouth or hypodermically. 

Narcophin; Morphin-Narcotin meconate. About 33 per cent, of morphin. Sol. 
in water. Dose, three times that of Morphin. 

Sanguinaria, U.S.P. (Blood Root). The dried rhizome and roots of Sanguinaria 
canadensis. Dose, 0.125 Gm., 2 gr., U.S.P. 

Tr. Sanguin., U.S.P. 10 per cent., in acidulated 60 per cent, alcohol. Dose, i c.c., 
15 minims, U.S.P. 

PREPARATIONS MORPHIN 

* Morphin and its salts occur as odorless, bitter white powders or colorless crystals. 
They are incompatible with alkalies, tannins, iodids and other precipitants of alka- 
loids. Dose, 8 mg., % gr., U.S.P.; 8 to 30 mg., % to % gr., B.P. The rectal dose is 
the same; the hypodermic about two-thirds of the oral. Maximal single dose, 30 mg., 
% gr. The actions begin in about five minutes on hypodermic administration. Solu- 
tions are said to decompose rather readily when heated above 6oC. (Welmans, 1908). 

Morphina, U.S.P., CnHigNOg + H 2 O. Very slightly sol. in water (1:3,340); 
slightly sol. in ale. (i : 210); sol. in lime-water (i : 100). 

Morph : Acet., B.P., CnHisNOs^HsOa + 3H 2 O. Freely sol. in water (i =2.5). 
Loses acetic acid on exposure to air. 

* Morphines Hydrochl oridnm (Morph. Hydrochl.), U.S.P., B.P., Ci 7 Hi 9 NO 3 .HCl+ 
3H 2 O. Sol. in water (i -.17.5} or ale. (1:52). 

*Morph. Sulph., U.S.P., (CnHi9NO 3 )2.H 2 SO 4 + sH 2 O. Sol. in water (i : 15.5); 
slightly sol. in ale. (i : 565). 

Morph. Tart., B.P., (CnH^NOaKC^Oe + 3H 2 O. Sol. in water (i : n). 

Inj. Morph. Hyp., B.P. 2.5 per cent, of tartrate. Dose, 0.3 to 0.6 c.c., 5 to 10 
minims, B.P. 

Liq. Morph. Acet., B.P. i per cent. Dose, 0.6 to 3.6 c.c., 10 to 60 minims, B.P. 

Liq. Morph. Tart., B.P. i per cent. Dose, 0.6 to 3.6 c.c., 10 to 60 minims, B.P. 

Supp. Morph., B.P. 0.017 Gm., ^ gr. 

Tr. Chlorof. El Morph. Co., B.P. Chlorof., 7.5 per cent.; Morph., i per cent.; Acid. 
Hydrocyan. Dil., 5 per cent.; with Capsicum, Cannabis Indica and Peppermint. 
Dose, 0.3 to i c.c., 5 to 15 minims, B.P. Used in colic. 

Troch. Morph., B.P. 2 mg., }^Q gr. 

Track. Morph, Et Ipecac., B.P. 2 mg., Ho gr., of Morphin; 6 mg., % Q gr.,oi Ipecac, 

PREPARATIONS MORPHIX DERIVATIVES 

These resemble the morphin salts in physical characters and incom- 
patibilities; they are further incompatible with strong acids or alkalies. 

Aethylmorph. Hydrochlor., U.S.P. (Dionin), Ci 7 Hi7NO(OH)(OC 2 H 5 ).HCl + 2H 2 O. 
White or yellowish, odorless, microcrystalline powder. Freely sol. in water (i :8); 
sol. in ale. (i 122). Dose, 15 mg., Y gr., U.S.P.; Locally, 10 to 20 per cent. Maximum 
dose, 50 mg., % gr. 

Diacetylmorphina, U.S.P. (Heroin), CnHn^HsOa^NO. Very slightly sol. in 
water (i : 1,700); sol. in ale. (i :3i). Dose, 3 mg., %Q gr.. U.S.P. 

* Diacetylmorph. Hydrochl., U.S.P., Diamorph. Hydrochl., B.P. (Heroin Hydrochlorid), 



HYDRASTIS 



245 



CnHi7(C 2 H 3 O 2 ) 2 NO.HCl + H 2 O. Freely sol. in water (1:2); sol. in ale. Dote, 
3 mg., Ko gr-, U.S.P.; 2.5 to 8 mg., % 5 to % gr., B.P. Maximum dose, 10 mg., % gr. 

Codeina, U.S.P., B.P., Ci 7 Hi 8 (CH 3 )NO3 + H 2 O. Slightly sol. in water (i :i 2 o); 
freely sol. in ale. (i : 2). Dose, 30 mg., % gr., U.S.P.; 16 to 60 mg., % to * g r - B.P. 

* Codein. Pkospk., U.S.P., B.P., C ]8 H 2 iNO 3 .H 3 PO 4 + 2H 2 O. 67 per cent, of anhy- 
drous codein. Freely sol. in water (1:2.3); slightly sol. in ale. (1:325). Dose, 
30 mg., ^2 g r -, U.S.P.; 16 to 60 mg., % to I g r -> B.P. Maximum dose, o.i Cm., ij gr. 

Syr. Codein. Phosph., B.P. 0.5 per cent. Dose, 2 to 8 c.c., ^ to 2 drams, B.P. 

Codein Sulph., U.S.P., (Ci 8 H2iNO3)2.H 2 SO4+ sH 2 O). Sol. in water (i 130); very 
slightly sol. in ale. (i : 1,280). Dose, 30 mg.; J- gr., U.S. P. 

Papaverin. Sulph., N.N.R., (C2oH 2 iO 4 N) 2 .H 2 SO 4 . Sol. in water or ale. Dose, 
30 to 80 mg., H to 1 14 gr. 



HYDRASTIS 

Hydrastis (Golden Seal) has few, if any, rational indications. It is 
employed empirically as a bitter stomachic; to check internal hemor- 
rhage; and locally in catarrhal conditions, especially of the geni to-urinary 
tract. 

Constituents. Hydrastis contains at least three alkaloids: Berberin, 1.5 to 4 per 
cent.; Hydrastin, at least 2.5 per cent. (U.S. P.), and Canadin, a derivative of berberin. 
There is also some resinous matter, etc. 

Hydrastin. This is an isoquinolin derivative, closely related to some of the minor 
opium alkaloids, Narcotin, Laudanosin and Papaverin. Narcotin is methoxy-hydras- 
tin, an H of hydrastin being replaced by OCH 3 . 

Hydrastin - Ci 9 H 14 NO 4 .H(OCH 3 ) 2 
Narcotin - Ci 9 Hi 4 NO 4 .(OCH 3 ) 3 

By oxidation both give analogous artificial alkaloids, which are somewhat important: 
C 2 iH 21 N0 6 + H 2 -f O = C 10 H 10 6 + CuH 12 NO 3 H 

Hydrastin Opianic acid Hydraslinin 

C 22 H 23 NO 7 + H 2 O + O = C 10 H 10 O 5 + C U H 12 NO 3 OCH 3 

Xarcotin Opianic acid Cotarnin 

Berberin, C 20 HivNO 4 (structure, Faltis, 1910) is an intensely yellow and bitter alka- 
loid, of wide occurrence, which gives the color and taste to a large number of "golden" 
roots and barks (Berberis, Xanthoxylon, Coptis, etc.). 

Actions of Hydrastis. An extensive study of hydrastis and its alkaloids was made by 
Bunge, 1895. This gives the literature to that time. Of later papers, mention may be 
made of .those of Fellner, 1906; Williams, 1908; and Laidlaw, 1910. The effects of the 
drug and of its different alkaloids are qualitively similar. 

Central Nervous System. Hydrastin produces convulsive effects analogous to 
those of strychnin. These are also obtained with the fluidextract. The derivatives 
hydrastinin and cotarnin have a purely depressant action, producing death by respira- 
tory paralysis (Laidlaw). There is no narcosis. 

Circulation. From the experimental results, it seems that the effects 
of hydrastis and its alkaloids and derivatives on the circulation are too 
uncertain to be therapeutically useful. The clinical evidence also ap- 
pears insufficient to establish their value. Frey, 1909, found that hydras- 
tinin had no effect on pulmonary hemorrhage. It is possible that these 
drugs may have a more pronounced influence on uterine hemorrhage, 
through their action on the uterine muscle. 

Very discordant results have been described. Williams obtained no effects with 
hypodermic or oral administration, even with very large doses. Intravenously the 
fluidextract, hydrastin and berberin produced the same results; considerable fall of 
blood pressure, followed with small doses by a slight and short rise. With large doses, 
the pressure remained low. These effects were predominantly cardiac (myocardio- 
grams and oncometer); this overshadowed any possible vasomotor changes. 



246 MANUAL OF PHARMACOLOGY 

. The vasomotor center is not directly affected by moderate doses of hydrastis, hydras- 
tin, berberin, hydrastinin or cotarnin; but may be stimulated indirectly through 
respiratory depression, convulsive phenomena or cardiac arrest (Pilcher and Sollmann, 



With toxic doses, there is vasomotor paralysis, and paralysis of vagus endings. 
Excised organs show some vasodilation. 

On the scarified skin, hydrastin (1:1000) produces some blanching (Sollmann and 
Pilcher). 

Hydrastin is related to the protopin group, and therefore depresses the cardiac 
and skeletal muscle, and has a weak local anesthetic action. 

Hydrasti nin also causes some primary fall but a larger rise (about 15 mm.) main- 
tained for over fifteen minutes; the heart rate is slowed. This rise is also predominantly 
cardiac, but there is a stimulation of the arterial muscle, not prevented by paralyzing 
the nerve endings with ergotoxin. Kurdinowski. 1904, interprets its actions rather 
differently. 

Uterine Actions. Fellner, 1906; Kehrer, 1907, and Lieb, 1914, showed that hydrastis, 
hydrastin, hydrastinin and cotarnin increase the tonus and excite rhythmic contrac- 
tions of the uterus, both in the excised organ and in living animals. This has been con- 
firmed by the subsequent workers; also for the surviving human uterus (Ruebsamen 
and Kligermann, 1912). High concentrations relax (Wendling, 1915). Berberin has 
similar effects (Marek, 1911). La Torre, 1912, examined histologically the uteri of 
animals treated with hydrastinin. The muscular layers were contracted and thickened, 
compressing the larger vessels, and thereby probably decreasing the blood supply of the 
mucosa. Laidlaw found the stimulant action of hydrastinin and cotarnin constant in 
the excised organ, but varying with conditions during life. These actions resemble 
those of the pituitary and ergot principles; but hydrastis does not act on the intestine, 
and very slightly on the bladder. Synthetic hydrastinin appears to be rather more 
stimulant than the natural alkaloid (Wendling, 1915). 

The bronchioles are not markedly affected in pithed animals (D. E. Jackson, 1914). 

Action of Berberin and Canadin. Berberin acts as a simple bitter in small doses. 
Its bitter taste and the yellow stain which it produces on linen, render it objectionable 
in the therapeutic use of hydrastis. Berberin is about seven times as active as hydras- 
tin on the circulation; and as hydrastis contains about one and one-half times as much 
berberin, about 85 per cent, of the circulatory effect is due to this alkaloid. Large 
doses lower the temperature, increase peristalsis, and kill by central paralysis (Curci 
1892). It is not excreted, being probably oxidized completely (Berg). 

Canadin resembles morphin somewhat in its action. It is present in too small a 
quantity to be of practical importance. It occurs also in xanthoxylum, where its actions 
have been studied by Laidlaw, 1913. 



PREPARATIONS HYDRASTIS 

Hydrastis, U.S.P.; Hydrast. Rhiz., B.P. (Golden Seal). The dried rhizome and roots 
of Hydrastis canadensis, yielding not less than 2.5 per cent, of hydrastin, U.S. P. Dose, 
2 gm., 30 gr., U.S.P. 

Hydrastis was employed by the Indians, mainly as a pigment, but also as medicine. 
It was introduced by the eclectics about the end of the eighteenth century. The plant 
is becoming rare, but is easily cultivated (Henkel and Klugh, 1908). 

Ext. Hydrast., U.S.P. A powdered extract with 10 per cent, of hydrastin, i Gm. 
representing 4 Gm. of drug. Dose, 0.5 Gm., 8 gr., U.S.P. 

* Fldext. Hydrastis, U.$.P.; Ext. Hydrast. Liq., B.P. 2 per cent, of hydrastin; % 
alcohol, ^LO glycerin, U.S.P. Dose, 2 c.c., 30 minims, U.S.P.; 0.3 to i c.c., 5 to 15 min- 
ims, B.P. 

Glyccr. Hydrast., U.S.P. About 1.25 per cent, of hydrastin. Dose, 2 c.c., 30 minims, 
U.S.P. 

Tr. Hydrast., U.S.P. 20 per cent. Dose, 4 c.c., i dram, U.S.P. 

Tr. Hydrast., B.P. 10 per cent. Dose, 2 to 4 c.c., % to i dram, B.P. 

Ilydrastina, U.S.P., C2iH 2 iNO 6 . White prisms. Almost insol. in water. Dose, 
10 mg., Y & gr., U.S.P. 

Hydrastin. HydrochL, U.S.P., C 21 H 2 iNO6.HCl. White powder. Very sol. in water 
or ale. Dose, 10 mg., % gr., U.S.P. Maximum dose, o.i Gm., i% gr. 

Hydrastinin. HydrochL, U.S.P., CnHnNO 2 -HCl. Light yellowish needles or 
powder. Very sol. in water or ale. Its aqueous solution, especially when highly 
diluted, shows a blue efflorescence. Dose, 30 mg., % gr., U.S.P. 



COTARNIN 247 



COTARNIN 

Cotarnin Salts (marketed under the names of "Stypticin" and "Styp- 
tol") are used to arrest bleeding, especially in menstrual disorders. 

The clinical reports, on which their employment rests, are often superficial and 
sometimes contradictory. The mechanism of the reputed actions has not been cleared 
by experimental investigations. This obscurity necessitates a more extensive discus- 
sion than the importance of the subject would otherwise justify. 

Cotarnin was introduced by M. Freund, 1893, on the basis of its chemical similarity 
with the more expensive hydrastinin. This chemical relation was discussed under 
hydrastis. 

Clinical Uses. Cotarnin has been employed systemically in various forms of 
uterine hemorrhage; in other internal hemorrhages; and locally in superficial bleeding. 

Uterine Hemorrhage. The most favorable results are reported in menstrual menor- 
rhagia, endometritis and congestive hemorrhage resulting from malposition (Gott- 
schalk, 1895 and 1899; Katz, 1903; Vieth, 1903; Boldt, 1904; K. Abel, 1905; Aarons, 
1907; Offergeld, 1915). Cotarnin is said to shorten the duration of the periods and to 
lengthen the intervals (Elischer, 1004). The response is prompt if adequate doses are 
injected (Offergeld, 1915). Some observers claim that it also acts as a "uterine seda- 
tive," meaning that it lessens the pain of dysmenorrhea (Gottschalk; Katz; K. Abel; 
Jacoby, 1906; Lockyer, 1907) ; but the claim rests mainly on loose statements of patients, 
and others have failed to observe any anodyne effect (Handfield- Jones, 1907; Offergeld, 
1915). All agree that it does not provoke uterine pain or contraction. It is conceded 
to be ineffective against postpartum hemorrhage, and probably also against bleeding 
resulting from abortion, tumors and other gross anatomic lesions. 

Other Internal Hemorrhage. Positive results have been reported in bronchial hemor- 
rhage and tubercular hemoptysis (Lavialle and Ruyssen, 1898; Hussa, 1912); in hema- 
turia of urethritis, catheter injuries, etc. (Kaufmann, 1905); in intestinal hemorrhage, 
etc. 

These statements, however, are not sufficiently substantiated, in view of the diffi- 
culty of predicting the spontaneous cessation of such hemorrhages, and the history of 
other "internal hemostatics." The claims are flatly contradicted by at least one of the 
warmest advocates of Cotarnin (Vieth). 

Local Hemorrhage. The topical application of cotarnin in substance or strong solu- 
tion (10 to 50 per cent.) to superficial wounds apparently produces a local vasoconstric- 
tion with prompt arrest of bleeding. This has been used successfully especially in 
tooth extraction (Munk, 1899; Marcus; Sigrist, 1913), epistaxis; and in nasal and genito- 
urinary operations. Its effects would be more lasting than those of epinephrin, and 
devoid of the coagulant action of the astringents. It is said to be effective even in 
hemophilia (Hulisch, 1899). This local effect of strong solutions is quite distinct from 
the systemic administration; for Marcus states specifically that the latter was ineffec- 
tive, either prophylactically or remedially, in tooth extraction. 

The local styptic effect has also been confirmed experimentally (K. Abel, 1905). 
Ammonium phthalate likewise acts as a local styptic, and this may contribute to the 
local effects of Styptol; although it can play no part in the systemic action (Offergeld, 

1915)- 

Experiments on Mechanism of Action. The numerous investigations so far made 
have yielded little of practical value. They show that cotarnin has a low toxicity. 
Very large doses produce some lassitude, ataxia, general depression, and finally death by 
paralysis of respiration. The narcotic action is not pronounced. Intravenous injec- 
tions produce brief, inconstant and usually slight changes in the circulation, which can 
play no part in the therapeutic action. The contractions of the excised uterus are 
stimulated, but the clinical data show that this does not occur with therapeutic doses. 
Perfusion of excised organs have failed to show any peripheral or central effects on the 
systemic vessels. The local styptic action is obtained with high concentrations, and 
can not therefore apply to the systemic administration. There remains the possibility 
of a specific constrictor effect confined to the uterine vessels. The only direct evidence 
for this consists in the histologic observations of la Torre, which require confirmation on 
living tissue. 

General Symptoms. K. Mohr, 1905. found that o.i to 0.2 Gm. per kilogram, in 
rabbits, dogs or cats produced only some lassitude and drowsiness. Larger doses had a 
pronounced sedative action, especially in cats and dogs. Ataxia was also pronounced. 
With fatal doses, these effects were followed by some excitement, then progressive 



248 MANUAL OF PHARMACOLOGY 

paralysis till death. Toward the end, the respiration became very slow and shallow, 
sometimes interrupted by asphyxial convulsions. 

Laidlaw, 1910, on guinea pigs, describes indefinite depression of the central nervous 
system and death by paralysis of the respiratory center. Relatively small doses slowed 
the respiration, without change of depth. 

Fatal Dose. This ranges from about o.i Gm. per kilogram for guinea pigs (Laidlaw) 
to 0.3 to 0.4 Gm. per kilogram for rabbits, and even higher for dogs and cats (Mohr). 

Uterine Contractions. Kehrer, 1907, found that cotarnin stimulates the uterus, 
both excised and in situ, pregnant or non-pregnant; increasing the contractions and 
tonus. This has been confirmed for the excised organ by all subsequent workers 
(Laidlaw, 1910; Ruebsamen and Kligermann, 1912; Lieb, 1914). The results in situ are 
contradictory. Kehrer's stimulant effects were obtained with cats. With a pregnant 
rabbit, Mohr, 1905, obtained no stimulation. Laidlaw, 1910, also found the results on 
living rabbits negative, whilst the excised organ responded. La Torre, 1912, observed 
no histologic evidence of contraction, such as is seen after ergot and hydrastinin. 
Chiappe and Ravano found that the pregnancy of guinea pigs was not affected by toxic 
doses; and that even fatal doses produced no abnormalities. 

The clinical data are in harmony with these negative results. All reporters agree 
that cotarnin never provokes uterine pains, even in late pregnancy; that it does not 
hasten the involution of the uterus; and that it has no influence on postpartum 
hemorrhage. 

Mohr claimed that cotarnin depresses the excitability of the uterus to hypogastric 
stimulation; but his conclusion appears to be based on a single very imperfect experiment 
with enormous doses, and must therefore be rejected. 

It appears, from all this, that cotarnin stimulates the excised uterus, on local con- 
tact; but that, with systemic administration, the uterus does not respond, at least in 
rabbits; and certainly not with therapeutic doses in the human. 

Other Smooth Muscles. Offergeld quotes contraction of the intestines and bladder; 
but Laidlaw found the bladder irresponsive. 

Systemic Circtt/a/iow. Intravenous injection produces variable changes in the 
blood pressure; sometimes a fall; or a momentary fall followed by a slight rise (Kehrer, 
1907; Laidlaw, 1910; Lieb, 1914). If the vagi were divided, the rise is more prominent 
(Pilcher and Sollmann, 1915). The vasomotor center is not affected directly, but may 
be stimulated by the slowed respiration (Pilcher and Sollmann); and this probably 
accounts for the rise. The fall of pressure appears to be cardiac; for the Langendorff 
heart is slowed and weakened (Laidlaw). Kehrer and Heinz also consider the fall 
cardiac. 

This diminished output of the heart has been credited with being the cause of the 
hemostatic effect; but this is most improbable. There is no evidence that it occurs 
with therapeutic doses; and even with the experimental doses, it is too slight and espe- 
cially too evanescent, to influence a persistent hemorrhage. 

Direct Action on Systemic Arterioles. All the earlier investigators (Falk, Marfori 
and Ronsse) affirm that cotarnin has no effect on the arterioles, with systemic admin- 
istration. This has been confirmed by the negative results of perfusion experiments 
(Laidlaw, leg). The positive results of direct contact with strong solutions have no 
bearing on this. Cotarnin does not produce the gangrene changes characteristic of 
ergot (Mohr). 

Coagulation of Blood. This is not affected, whether the cotarnin is added directly 
to the blood, or injected into the animal (Laidlaw; Marfori). 

Uterine Vessels. Many of the clinical authors explain the action of cotarnin by a 
special action on the uterine vessels, a stimulation of their vasomotor nerves, etc. 
(K. Abel, 1905). This appears to be pure assumption. More recently, however, La 
Torre, 1912, reports histologic evidence of contraction of the larger uterine vessels in 
animals treated with cotarnin. Since postmortem appearances usually give a very 
imperfect picture of the changes during life, this evidence requires confirmation by 
physiologic methods. 

Dosage and Administration. The cotarnin salts may be used by mouth or hypo- 
dermically, the latter being much more efficient. The intramuscular dose is 0.25 to 
0.5 Gm., as 10 or 20 per cent, solution, repeated daily as needed. The injections are 
not irritant. By mouth, the dosage is from 0.05 to o.i Gm. four to five times daily. 
Smaller doses are inefficient. In menorrhagia, it may be started several days before the 
expected period. 

Side Actions. None have been reported from oral administration or from hypo- 
dermic injections of 0.5 Gm. Offergeld found some lassitude with 0.7 Gm. and a single 
case of temporary collapse with 0.65 Gm. by intramuscular injection. 



CANNABIS 249 

PREPARATIONS COTARNIN 

Cotarnince Hydrochloricum (Cotarn. Hydrochl.), U.S.P. (Stypticin), Ci 2 Hi 3 ON.HCl. 
Odorless, bitter, yellow, crystalline powder. Very sol. in water or ale., yielding 
yellow solutions. Dose, 0.06 Gm., i gr., U.S.P. 



CANNABIS 

The tops of the hemp plant are somewhat of a pharmacologic curiosity. 
They contain resinous constituents (cannabinol) which produce a peculiar 
psychic exaltation. It is employed as an intoxicant in the Orient. 
Therapeutically, it is used empirically (Extract o.oi Gm., ^ gr.) as an 
adjuvant to other drugs in nervous headaches, and as a coloring agent 
for corn remedies. The drug is of uncertain activity, and has no rational 
indication. 

Intoxicant Action in Man. The oriental use of Cannabis ("Hashish," Bhang, 
Charas, etc.) antedates history. It was introduced in Western medicine about the 
middle of the nineteenth century. When used as an intoxicant, the tops or resins are 
made into a confection or smoked with tobacco. Effective doses (2 gr. of solid extract 
of the Indian or American drug) produce after about an hour a state of partial inebriety 
and confusion, with happy and humorous tendencies. Ideas pass rapidly but discon- 
nectedly, so that the time seems very long. The subject often has hallucinations of 
double personality. The exaltation, which seems to be much more marked in orientals, 
is succeeded by some irritability, dozing, and complete recovery in five or six hours. 
The effects are modified by individual disposition and surroundings (Hamilton, Lescohier 
and Perkins, 1913). It is stated that the drug is not fatal even in very large doses, but 
experience on dogs certainly shows that it presents some danger. The habit to which 
it gives rise shows less effect upon the alimentary canal and less marasmus than does 
morphin, but more often psychic alterations, dulness, or mania. The clinical side 
actions are described by Seifert, Nebenwirk., 1915, p. 149. 

Effects on Animals. Dogs (Dixon, 1899) also show a decided narcotic effect. After 
a preliminary ataxia, excitement, and nausea, the animals usually fall into a deep and 
prolonged sleep, during which the sensation of pain is much diminished, whilst the re- 
flexes persist. Some animals show acute mania; a fatal ending is not rare from doses 
which are ineffective in other animals, the same preparation being used. Considerable 
idiosyncrasy exists, and the action is fairly independent of the dose. The effects can 
not be obtained by hypodermic administration (on account of_the non-absorption of 
the resin). 

Rabbits seem absolutely insusceptible to the narcotic action of cannabis. 



PREPARATIONS CANNABIS 

Cannabis, U.S.P.; Cannabis Indica, B.P.; Cannabis, Indian Hemp (Hashish, Bhang, 
Guaza, Gangja, Charas, Momeka, etc.). Dose, 0.06 Gm., i gr., U.S.P. 

The dried flowering or fruiting tops of the pistillate plant of Cannabis sativa. The 
B.P. requires that it be grown in India; the U.S.P. permits any origin, but provides 
that the activity must be confirmed by testing its narcotic effects on dogs (Houghton 
and Hamilton, 1907; U.S.P. IX). This is necessary since different samples vary greatly, 
and are liable to deteriorate rapidly. If the Indian drug is preferred, Cannabis Indica 
may be specified; if the American, Cannabis Americana. American grown Cannabis 
produces identical effects (Houghton and Hamilton, 1907 and 1908), but is generally 
only half as active (Eckler and Miller, 1912). The preparations, however, are brought 
to the same degree of activity. 

The active ingredient is a resin, cannabinol (Fraenkel, 1903), C 2 iH 30 O2, which presents 
the appearance of a thick reddish yellow oil, soluble in petroleum ether, etc. (not identical 
with the commercial "cannabinol"). This changes by oxidation to an inactive black 
pitch. The change accounts for the deterioration which the drug and its preparations 
undergo in keeping. The deterioration can be prevented by excluding the air (Marshall, 
1909). Cannabis also contains a volatile oil (terpenes), paraffin, pitch, etc., which are 



250 MANUAL OF PHARMACOLOGY 

not concerned in its action. There is no specific alkaloid, but the extracts may give 
alkaloid reaction from the formation of cholin and triamethylamin. These are also 
not connected with the action. The fresh extract has a beautiful green color (if prepared 
without excessive heat), due to chlorophyl. The active principle is completely extracted 
by alcohol, but is insoluble in water. 

The pretended Isolated Principles on the market under various names are generally 
quite inactive (S. A. Matthews, 1908). 

*Ext. Cannabis, U.S.P.; Ext. Cannab. Ind., B.P. A pilular alcoholic extract. 
Dose, 10 mg., % gr., U.S.P.; 16 to 60 mg., y to i gr., B.P. Maximum dose, o.i Gm., 

i^gr- 

Fldext. Cannab., U.S.P. Dose, 0.05 c.c., i minim. U.S.P. 

Tr. Cannab., U.S.P. 10 per cent, of drug. Dose, 0.5 c.c., 8 minims, U.S.P. Maxi- 
mum dose, 1.25 c.c., 20 minims. 

Tr. Cannab. Ind., B.P. 5 per cent, of extract. Dose, 0.3 to i c.c., 5 to 15 minims, 
B.P. 

LACTUCARIUM DRIED LETTUCE JUICE 

This was introduced by Dr. Coxe of Philadelphia in 1799 as a sedative. Lettuce 
had some reputation as a hypnotic in ancient times, but it is probably undeserved. 
Kelterborn took 12 Gm. of Lactucarium without any effects. No active principle has 
been determined. 

PREPARATIONS LACTUCARIUM 

Lactucarium, U.S.P. The dried milk juice of wild lettuce, Lactuca virosa. Dose, 
i Gm., 15 gr., U.S.P. 

Syr. Lactucar., U.S.P. 5 per cent. Dose, 10 c.c., 2^ drams, U.S.P. 
Tr. Lactucar.. U.S.P. 50 per cent. Dose, 2 c.c., 30 minims, U.S.P. 

LUPULIN AND HOPS 

These act as bitters, and have some popular but exaggerated reputation as hypnotics. 
Hops are the dried pistillate flowers of Humulus Lupulus. The active principles are 
contained in small glands, which can be separated as a powder, and constitute the 
Lupulin. 

Two acids (a- and fi-lupulinic acids) are present. They stimulate the respiratory and 
vagus centers; this is followed by depression. They also depress the cardiac muscle. 
Lupulin contains a further, unknown, constituent which is insoluble in water and a strong 
cardiac poison. Power, Tutin and Rogerson, 1913, also found a trace of alkaloid. All 
these, however, are not active when administered by the stomach, and are therefore 
not concerned in the action of the drug. 



PREPARATIONS HOPS 

Humulus (Humid.) , U.S.P.; Hops. The dried strobiles of Humulus Lupulus. 
Dose, 2 Gm., 30 gr., U.S.P. 

Lupulin. Dose, 0.5 Gm., 8 gr. 

LOCO DISEASE 

Horses, cattle and sheep on the Western stock ranches are subject to this peculiar 
disease, which bears some resemblance to drug habits. The symptoms consist in motor 
incoordination, forced movements, misjudgment of distance, stupidity, apparently 
hallucinations. In the chronic form there is emaciation. Death is preceded by coma 
and convulsions. 

The cause of these conditions is obscure. It is generally attributed to feeding on 
certain leguminous plants ("loco weeds" especially Astragalus). C. D. Marsh, 1909, 
claims to have reproduced the condition (nervous symptoms, etc., with exudative 
meningitis, anemia, etc.) experimentally by very long-continued feeding with these 
plants; but H. T. Marshall, 1914, considers the results inconclusive, and believes that 
there is no distinct loco disease; and that the name covers a variety of conditions mal- 
nutrition, parasitism, etc. unconnected with the loco weed. 



COCAIN GROUP; LOCAL ANESTHETICS 251 



COCAIN GROUP ; LOCAL ANESTHETICS 

Actions and Uses. The alkaloid cocain is important mainly as a 
local anesthetic, paralyzing the sensory nerve fibrils on direct application. 
With dilute solutions, its action may be confined to these; but higher con- 
centrations paralyze all other nerve fibers, and, indeed, they kill all proto- 
plasm. Dilute solutions also produce local vasoconstriction and dilate 
the pupil through stimulation of the sympathetic pupillo-dilator mechan- 
ism, both central and peripheral. 

When cocain is absorbed in sufficient quantity, it produces complex 
systemic actions, involving stimulation and paralysis of various parts of 
the central nervous system. These are mainly of toxicologic and scientific 
interest. Its continued use leads to the formation of a habit, resembling 
morphinism. 

Analogous local anesthesias are produced by a variety of synthetic 
bases, which may be used as substitutes for cocain. 

Historical. Cocain is derived from the leaves of Erythroxylon Coca, a tree indigen- 
ous to Peru, Chili and Bolivia. The leaves were chewed from time immemorial by 
the natives to relieve hunger and fatigue, and to produce a psychic stimulation, some- 
what after the manner of caffein. It is now cultivated in other tropical countries. 

In Europe, trials with the leaves gave disappointing results. The discoverers of 
cocain (Woehler; Niemann and Lessen, 1860) incidentally described its anesthetic 
action on the tongue, but without realizing its significance. As late as 1880, a British 
medical commission reported on the drug as merely a poor substitute for caffein 
(further details, J. U. Lloyd, 1911, "History of Vegetable Drugs," and 1913, J. Am. 
Pharm. Assoc., 2:1242). In the same year, Anrep subjected cocain to a thorough 
pharmacologic investigation; and in 1884, the Vienna oculist Roller introduced it as a 
practical local anesthetic. Its importance was then at once recognized. 

Peripheral Nerves. Local Anesthesia. Local contact with cocain 
paralyzes all forms of nervous tissue, without preceding stimulation. 
The susceptibility of the various nerve fibers presents marked and char- 
acteristic quantitative differences. Sensory fibers are especially easily 
attacked; and by using appropriate dilutions, the paralysis can be confined 
strictly to them. With sufficient concentration, the paralysis is as com- 
plete as if the nerve fibers had been severed with a knife. If the alkaloid 
is washed away, or absorbed, the nerve recovers its functions promptly 
and completely (but very strong solutions may produce neuritis and per- 
manent paralysis). 

Since these effects are strictly local it follows that the cocain must be 
applied in such a way that an effective concentration will reach the nerve 
supply of the part which it is desired to affect. This may be accomplished, 
according to circumstances, by painting a solution on mucous membranes 
(from which it is very readily absorbed) ; or by injecting it into or under 
the skin (infiltration and subcutaneous anesthesia) ; or around or into the 
nerve trunk (peri- or intraneural anesthesia); or around the spinal nerve 
roots (subdural or spinal anesthesia). The intact skin is practically 
impermeable to cocain. 

Duration of Local Action. The onset and duration of the anesthesia 
varies with the concentration of the solution, and the method of its appli- 
cation. Roughly speaking, it starts in a few minutes and lasts perhaps 
ten to thirty minutes, with a single application. 

Local Anemia. As the cocain is absorbed and thus removed from the 
site of application, its local action ceases and its systemic and toxic effects 



252 MANUAL OF PHARMACOLOGY 

start. Since cocain is rapidly destroyed in the body, the systemic toxicity 
increases with the rapidity of absorption. It is therefore desirable and 
often necessary to delay the absorption. This may be done by restricting 
the local circulation. Cocain itself tends to do this by producing a local 
vasoconstriction an advantage which is not shared by its substitutes. 
This vasoconstriction should be reinforced by the addition of epinephrin. 
In suitable situations, the circulation may be slowed by bandages, or 
arrested by temporarily clamping the arterial blood supply. The anemia 
also favors anesthesia directly; ligation of a large artery in itself produces 
anesthesia of the nervous end structures. 

When a large quantity of dilute cocain solution is injected under pres- 
sure, as in the infiltration anesthesia, the cocain action is reinforced by 
anemia, pressure, and edema. 

The Selective Action of Cocain on Motor and Sensory Fiber. When a % to 2 per 
cent, solution of cocain is injected into a mixed nerve, or into the subdural canal, the 
selective action is very marked, so that there is complete anesthesia, without motor 
impairment. If the contact is prolonged, by stopping the circulation, or if stronger 
solutions are employed, the motor fibers also become paralyzed, so that the difference is 
merely quantitative. A similar difference in the susceptibility of motor and sensory 
structures exists also for the alcohol group, aconitin, phenol, and hydrocyanic acid; and 
even for the centrally acting narcotin, ether, etc. It is therefore a characteristic of 
nervous tissue rather than of cocain. 

Cocain is Less Effective in Inflamed Tissues. This may be explained by the hypere 
mia, resulting in more rapid absorption. 

Peripheral Paralysis of Special Sense Nerves. Cocain abolishes not only the sensa- 
tion of pain, but other special sensations, if it is suitably applied. Here also there is 
some selection. In the skin, it paralyzes the sense of pain and touch, but has little or no 
effect on temperature sensation. In the nose, it abolishes the olfactory sense. On the 
tongue, it destroys the taste for bitter substances, but has less effect on sweet and sour 
taste, and none on salty taste. 

Selective Action on Other Nerves. When cocain is applied to the appropriate 
nerves, it is found that the centrifugal vagus fibers are paralyzed before the centripetal; 
vasoconstrictor fibers before vasodilator; bronchial constrictors before the dilators, etc. 
(Dixon, 1904). 

Visceral Pain. The abdominal viscera are sensitive to pain in normal animals; but 
the sensation is abolished by cocain, even when small doses (0.7 mg. per kilogram) are 
injected at a distance; for instance, into the pectoral muscles (Kast and Meltzer, 1906- 
1909). This special anesthesia lasts about half an hour. The insensitiveness of viscera 
in surgical operations under cocain anesthesia is thus explained. The effect is probably 
central, for the animals are greatly quieted, although general sensation is not impaired. 

Motor Endings. Large doses of cocain paralyze these in frogs. This curare action 
would not be seen in intact mammals. 

Smooth Muscle. This is generally first stimulated, then depressed, regardless of 
innervation (constituting a fundamental distinction from epinephrin). Cardiac muscle 
and the salivary glands are not stimulated (Kuroda, 1915). 

Site of Action. Cocain can paralyze the nerve fibers anywhere in their course, 
wherever it is brought into contact with them. When it is applied to mucous mem- 
branes or hypodermically, it doubtless selects the portions peripheral to the main 
trunks, the thinner sheath of the terminal fibrils facilitating its penetration. It is 
therefore unnecessary to assume a selective action on the histological sensory endings. 

Penetration. It is quite possible that its selective action on different nerve fibers 
may also depend, in part, on differences in penetration. On this account, the free 
cocain base is more effective than its salts, in equal concentration, since the base is more 
soluble in the lipoids of the nerve sheath. Free cocain, however, is not sufficiently 
soluble in water for practical use. O. Gros, 1910, therefore advises an extemporaneous 
mixture of molecular quantities of novocain hydrochlorid and sodium bicarbonate. 

Nature of Action. Of this, little is known, except that it is purely functional. X<> 
structural changes are discoverable in the nerve fibers. 

Synergisms. The mixture of cocain with its related bases (novocain, etc.), or with 
antipyrin or nitrites, gives simple summation of the anesthetic effect (A. Schmid, 1913); 
mixtures with potassium salts give potentiation by 75 per cent.; potassium also poten- 
tiates novocain, but not stovain or alypin. Kochmann, 1914, therefore advises to make 



COCAIN GROUP; LOCAL ANESTHETICS 253 

cocain solutions in a medium of 0.5 per cent, potas. sulphate and 0.9 per cent. Nad. 
Epinepkrin also increases the anesthetic power of cocain {H. Braun) by direct synergism 
(Esch). Conversely, cocain increases the epinephrin constriction, even in very small 
concentrations (Fischel, 1915). The Tropacocain, however, deprives epinephrin of its 
synergistic and constrictor action (Kochmann, 1914). 

Local Vasoconstrictor Action. The application of cocain to mucous membranes, 
particularly the inflamed conjunctiva, produces distinct local vasoconstriction, with 
blanching, astringent sensation, and actual contraction of vascular formations, such as 
polypi. The cocain substitutes do not possess this action; many of them dilate the 
vessels. 

The analysis of the constrictor action of cocain has given contradictory results. 
Since the action is local, it must be peripheral. However, direct perfusion of the vessels 
is either ineffective or produces dilation, never constriction; nor does cocain counteract 
the dilator effect of nitrites (Kuroda, 1915). The constriction can not be explained by 
anesthesia, since other local anesthetics do not constrict. 

General Toxicity to Protoplasm. Cocain is a typical, if rather weak, protoplasmic 
poison, paralyzing all sorts of cells, without producing any gross chemical changes. It 
is toxic to the lower forms of animal life (infusoria, etc.); but has little effect on bacteria, 
or on ferments. 

ACTIONS OF COCAIN ON THE EYE 

When cocain is applied to the conjunctiva, it produces local anesthesia 
(which may not extend to the iris); local anemia (which extends to the 
iris, but not to the retina) ; and submaximal dilation of the pupil by 
peripheral sympathetic stimulation. The mydriasis occurs also on sys- 
temic administration. The accommodation is impaired, but the light 
reflex is preserved; there is some exophthalmos. The intraocular pressure 
is usually lowered, but may be increased. The mydriasis and its associated 
phenomena are not produced by most of the cocain substitutes. 

Injury. Cloudiness and even ulcers of the cornea sometimes follow 
the application of cocain; they are explainable by the drying, and the irri- 
tation of dust and other foreign matters which are not perceived on account 
of the anesthesia and the abolition of the winking reflex. The protoplas- 
mic toxicity may have a part in their production. 

The Cocain Mydriasis. This differs in important respects from the atropin mydria- 
sis; with atropin, the dilation is greater; the light reflex is lost; the intraocular tension is 
always raised; exophthalmos is absent. The pupil does not react readily to pilocarpin 
or muscarin, whilst these constrict the cocain pupil easily. 

These differences point to a different mode of action. In effect, atropin paralyzes 
the oculomotor (constrictor) endings, whilst cocain stimulates the sympathetic (dilator) 
mechanism; for when the sympathetic fibers have degenerated (eight days after extir- 
pation of the superior cervical ganglion) ordinary doses of cocain cease to be effective 
(Limbourg, 1892; Schultz, 1899). Dilation may still occur, however, with large doses 
or under special conditions. Simple (postganglionic) division of the sympathetic does 
not immediately abolish the cocain reaction; the stimulation must therefore involve 
the endings; but since the dilation is not as strong, it would seem that, ordinarily, the . 
pupillo-dilator center is also concerned (Schultz, 1898). 

Under ordinary conditions, the cocain pupil continues to respond to oculomotor 
stimulation, showing that the constrictor mechanism is not paralyzed. Prolonged 
application of a 5 per cent, solution, however, also paralyzes the oculomotor endings. 
In birds' eyes cocain produces no dilatation, whereas in frogs it is very marked. 

Cycloplegia. This begins in five or ten minutes. The maximum is reached in 
thirty minutes and lasts ten to fifteen minutes; the normal is restored in one and one- 
quarter to two hours. The accommodation is merely disturbed by a drop of 6 per cent, 
solution ; high concentrations paralyze it completely. The mydriasis develops somewhat 
more slowlyjand is more lasting (Horovitz, 1912). C. Wood, 1893, advises the addition of 
cocain to homatropin, to paralyze accommodation. 

Intraocular Pressure. This may be unchanged, or" raised or lowered (Tourriere, 
1913). The reduction is probably due to the local vasoconstriction, which would 
tend to lessen the lymph flow into the chambers. This is partly counteracted by the 
mydriasis, which leads to obstruction of the lymph channels by the relaxed ciliary 



254 MANUAL OF PHARMACOLOGY 

muscles (see "Atropin"). This obstruction may predominate, and the pressure may 
thus be increased, especially in glaucoma (Myashita, 1913). 

Eucain and alypin act similarly. Holocain is said to have provoked acute glaucoma 
(Gjessing, 1915). Tropacocain and acoin are probably inactive (Bollet and Curtil, 
1911). 

Retinal Vessels. These are strongly constricted (Hirschfelder, 1915). This may be 
responsible for the occasional occurrence of optic atrophy (Harnack, 1912). 

SYSTEMIC ACTIONS 

These are rather variable and complex, depending largely upon the 
dose. Whilst all structures are first stimulated and then paralyzed, the 
susceptibility to the poison is not uniform. Indeed, some portions of the 
nervous system show only stimulation, death occurring before the paralysis 
of these structures is reached. 

Stimulation of Higher Functions. The first effect is a well-marked 
stimulation of the higher parts of the brain (caffein action). This is 
shown in animals by increased movement (sometimes " circus movements "). 
In man there is some psychic stimulation and wakefulness. A greater 
endurance against fatigue and hunger is also noticed. 

How far this may be due to a stimulation after the manner of caffein, or to a narcosis* 
after the manner of morphin, is impossible to state. It is not at all unlikely that both 
play a part. In regard to the sensation of hunger, it is also probable that local anes- 
thetization of the stomach aids in the effect. 

The resistance to fatigue can be demonstrated with the ergograph. 

Another evidence of the stimulating action of cocain is furnished by the fact that 
animals to which it has been administered are more difficult to put and to keep under 
chloroform or other anesthetic. Mosso, 1887, and Airila, 1913, find that 10 to 40 mg. 
of cocain, hypodermically, wakens dogs or rabbits from deep chloral sleep. The stimu- 
lation is greatest with excitable individuals, and may seriously interfere with operations. 

Inco ordination, Narcosis, Convulsions. This stage of stimulation 
may be very short or even absent. With somewhat larger doses it may be 
succeeded by depression, first of the coordinating functions. The move- 
ments lose their purposive type and become choreic. There is then a 
general narcosis after the manner of morphin. 

This is followed by convulsions. If the paralysis is rapid, the convul- 
sive stage may not appear. 

The Seat of the Convulsions. This has not been exactly determined. They, like 
the other effects, are probably descending, and the different convulsive centers may be 
affected in succession. In some stages at least they seem to reside exclusively in the 
hind brain. In dogs, they appear to be confined to the cerebral cortex, for Feinberg 
and Blumenthal, 1887, claim that they do not occur after ablation, nor in new-born 
animals, in which the cortical motor centers are not yet excitable. Rabbits deprived 
of the hemispheres do not show the clonic convulsions or respiratory effects; but they 
do exhibit tonic convulsions and "running movements." Their resistance to toxic 
doses is increased (Morita, 1915). 

Central Phenomena hi Frogs. These show at first symptoms of stimulation by 
increase of the voluntary movements and exaggeration of the reflexes, sometimes leading 
to convulsions. This is followed by paralysis of the whole central nervous system. 

Spinal Cord. In frogs from which the brain has been removed, cocain causes at 
first an increase of the reflexes, then convulsions, and finally total paralysis. In intact 
animals this effect is obscured by the action on the higher centers of the nervous system. 

The results of applying cocain directly to the cord will be considered later. 

Respiration. This is at first accelerated. During the spasms it is 
irregular. The volume then diminishes. It may assume the Cheyne- 
Stokes type. Respiratory paralysis is the usual cause of death. This is 
also the first center to fail when the cocain is applied locally to the fourth 



COCAIN GROUP; LOCAL ANESTHETICS 



2 55 



ventricle. Excised bronchial muscle is somewhat dilated (Trendelenburg, 
1912). 

Emesis. The vomiting which frequently occurs in cocain poisoning 
is perhaps due to the medullary stimulation, but its mechanism has not 
been fully investigated. 

Circulation. The effects of cocain on the general circulation are 
partly central, partly peripheral. They vary according to the dose, as 
shown diagrammaticaUy in Fig. 9. They are also influenced by indi- 
vidual susceptibility. 

The typical effects are as follows: 

Very small doses diminish the pulse rate, by stimulation of the vagus 
center (Vulpian, 1884). There is a quick rise of blood pressure from stimu- 



Resjnralbry Center. 
Vaso-motorCenfer 
Vaoas Center. 

dcce\rdb>r Center 

Heart Jllascte. 

Pulse Rate 

Blood Pressure. 



Doses. 



Laraje Doses. 



FIG. 9. Diagram of the Actions of Cocain on Respiration and Circulation. (A^rise of the curve 
signifies an increase or stimulation ; a fall, the reverse.) 

lation of the vasomotor center; this is followed by a temporary fall due to 
the slowing. 

Moderate doses quicken the pulse, mainly by central and peripheral 
depression of the vagus (v. Anrep, 1880) with some stimulation of the 
accelerator center (Mosso, 1887). The pressure rises (v. Anrep) from stimu- 
lation of the vasomotor center (Berthold, 1885), aided by the faster heart 
rate. The vasomotor factor is predominant, for the rise is practically 
absent if the cord is cut. 

Large doses cause a great fall of pressure and slow and weak pulse (v. 
Anrep), from the depression of the medullary centers (collapse) and of the 
cardiac muscle. 

Actions on Heart Rate. This demands some further discussion: The slowing from 
small doses does not occur if the vagi have been cut, so that it is of central origin. The 
quickening from moderate doses is also less marked if the vagi have been divided, so 
that it is probably due in part to a depression of the vagus center. The vagus ganglia 
are also depressed, for electrical stimulation of the vagus trunk is only partly successful 
(v. Anrep, 1880). In the frog these ganglia can be paralyzed completely by the local 
application of cocain, but in the intact mammal the paralysis is not complete. Some 
quickening occurs, however, even when the vagi have been divided, but none is seen 
if the accelerators have also been cut. The final slowing is due to a direct paralysis of 
the muscle, for it is accompanied by weakening of the contraction, and it occurs after 
atropin, and in the excised heart. 



256 MANUAL OF PHARMACOLOGY 

The Excised (Langendorff) Mammalian Heart. This has been investigated by 
Hedbom, 1899; Kochmann and Daels, 1908; and Prus, 1913. Low concentrations slow 
and strengthen the contractions; higher concentrations cause slowing and weakening; 
fatal concentrations give diastolic arrest. Kuroda, 1915, observed no stimulation in 
excised hearts of mammals or frogs. 

The excised frog's heart is stimulated by small concentrations (Mosso, 1890), and 
depressed by high concentrations. The terrapin's heart is similarly affected (H. G. 
Beyer, 1885). 

The effects on blood pressure have been described mainly by Ott, 1874; v. Anrep, 
1880; Vulpian; Mosso, 1800, and Reichert, 1891. The comparative effects of cocain i 
and novocain have been investigated on dogs by Kamenzove, 1911. 

Splanchnic Circulation; Influence on "Shock." The intravenous injection of cocain 
has a very pronounced effect on the splanchnic circulation. The intestines appear 
unusually pale. Handling of the viscera and other measures of "shock" which cause a 
splanchnic dilation and consequent fall of blood pressure in normal animals, have less 
or no effect after cocain. Burning and stimulation of the sciatic, which cause a rise of 
pressure normally, are also ineffective (Crile, 1901). Fere, 1906, on the other hand, 
claims that local anesthesia (by cocain, its substitutes, or freezing) does not abolish the 
depressant reflexes (decrease of muscular work, of sharpness of vision, etc.); these occur 
from procedures which would ordinarily be painful, even when the sensation of pain is 
eliminated. 

Cerebral Circulation. This is increased by cocain, and still more by novocain 
(Frankfurther and Hirschfeld, 1910). The vessels of the retina and pia mater are 
constricted (Hirschfelder, 1915). 

The urine flow is generally diminished, but sometimes increased, depending mainly 
on the vasomotor effect. 

Temperature. Cocain causes a rise of temperature, due essentially 
to increased heat production, and this largely from muscular excitement 
(see chapter on "Heat Regulation"). , 

Effect on Metabolism. In rabbits, large doses of cocain cause rapid loss of weight. 
The quantity of urine, its specific gravity, and particularly the urea, are diminished, 
whilst the incompletely oxidized (extractive) nitrogen is increased. During recovery, 
the quantity of urine returns promptly to normal or above; the disturbances of the 
nitrogen metabolism persist for some time (Maestro, 1904). 

The effects of repeated injection on dogs have been investigated by Underhill and Black, 
1912: Doses of 10 mg. (per kilogram) produce no change in fat or nitrogen metabolism; 
15 mg. gave a slight impairment of fat utilization, and considerable decrease of body 
weight; 20 mg. markedly decreased the nitrogen and fat utilization. The nitrogen 
balance may become negative. Lactic acid excretion was markedly increased in well- 
fed dogs, but not in starvation the increase being probably due to the muscular activ- 
ity. The ammonia output bore little relation to the lactic acid. 

Blood-sugar. This is not changed (cats, 15 to 35 mg. per kilogram), except as a 
result of excitement (Schaer, 1915). 

Fate of Cocain. This is partly destroyed in the organism, but mainly 
excreted unchanged in the urine (contrary to the results of Wiechowski, 
1901). 

Rifatwachdini, 1913, recovered 42 to 85 per cent, from the urine of rabbits after 
acute poisoning, and all in chronic poisoning. None was present as ecgonin; but if 
ecgonin itself was injected, 25 per cent, was recovered from the urine. Cocain left 
for several hours in a ligatured limb was not destroyed. 

Destruction of Cocain in Vitro ; Sterilization. Long-continued boiling 
decomposes cocain into benzoyl-ecgonin and methyl alcohol. It was 
therefore believed that solutions could not be sterilized by boiling. In 
fact, however, the decomposition on boiling half an hour, is insignificant 
(Merck, 1907; Holbrook, 1912); and even longer boiling only decreases the 
activity, for the decomposition products are merely inactive and not toxic. 

Benzoyl Ecgonin. This was found by Stockman, 1886, to resemble caffein in its 
central and muscular action. It had no effect on sensory nerves or the pupil. 



COCAIN GROUP; LOCAL ANESTHETICS 257 

ACUTE COCAIN POISONING; ETIOLOGY 

This is of special importance, since cocain poisoning is not a very 
uncommon occurrence in the therapeutic employment of the drug. Very 
large amounts are sometimes used in a most careless manner for local 
anesthesia, and since the absorption is fairly rapid, serious and even fatal 
results may follow. The susceptibility varies enormously, due partly to 
the uncertainty of the absorption; partly to the rapidity of destruction; 
and partly to the varying intensity of the effects. In some cases 2 drops 
of a 4 per cent, solution (= 0.005 g m -) m the conjunctival sac caused 
serious collapse, whilst very much larger doses produced no effect in other 
cases. The ordinary fatal dose is considered by Kunkel to be about 1.2 
gm. (18 gr.); but death has been reported from as little as 0.08 gm. (i^ 
gr.). The toxicity is greatly lessened by the addition of epinephrin. 

Symptoms with Slow Absorption. The symptoms vary according to 
the rapidity of absorption. 1 If this occurs relatively slowly, there is 
confusion, laughter, vertigo, motor excitement; quickened pulse and pal- 
pitation; irregular respiration; pallor, chill, with sweat and rise of internal 
temperature; dilated pupils and exophthalmos; nausea, vomiting and 
abdominal pain; great anxiety; disturbance of cutaneous sensation (worms 
under skin, etc.), finally delirium, dyspnea and Cheyne-Stokes respiration, 
convulsions, unconsciousness; and death by collapse and asphyxia. 
Recovery may be followed by more lasting psychic depression and 
melancholia. 

With rapid absorption of large doses (especially from mucous mem- 
branes) severe symptoms may develop without warning: fainting, extreme 
pallor, brief convulsions, and death, sometimes in a few minutes. 

Treatment. If the drug has been taken by mouth, one should 
promptly 'resort to evacuation and chemic antidotes. If the symp- 
toms have developed, the head should be lowered, and the collapse 
treated by sinapism to chest and abdomen; and by caffein, or aromatic 
ammonia. The convulsions should be allayed with chloroform, chloral, 
and artificial respiration. Amyl Nitrite has been recommended. 

CHRONIC COCAIN POISONING 

This bears considerable resemblance to the morphin habit. It is 
unfortunately on the increase, especially amongst negroes, prostitutes, and 
the criminal classes (see under "Morphin Habit"). 

The immediate effects consist in a sense of elation and increased mental 
and physical vigor. The excitement may rise to delusions and mania. 
These stimulant effects are succeeded by depression, tremors, with pale face, 
and sunken and unsteady eyes (Owens, 1912). 

The chronic effects are similar to those of the morphin habit, with 
more severe psychic disturbance insomnia, hallucinations, apathy, 
melancholia, suicidal mania. (For Cocain Psychoses, see Vallon and 
Bessiere, 1914.) The pupils are inconstant. A very considerable toler- 
ance is acquired, so that the daily hypodermic consumption often reaches 
2.5 Gm., sometimes even 10 Gm. (Grode, 1912). Animals do not become 
tolerant (Grode, 1913). Chouppe, 1889, claims that morphinists are 
relatively tolerant to cocain. Sudden withdrawal leads to abstinence 
symptoms very similar to those of morphin. 

1 Fuller description in Seifert, Nebenwirk., 1915, p. 51. 
17 



258 MANUAL OF PHARMACOLOGY 

With cocain snuffing, where smaller amounts are used in intermittent 
debauches, the chronic effects, the craving and the abstinence symptoms 
are proportionately less marked. Such patients show a characteristic 
ulcer ation of the nasal fossae (Owens; also present in heroin snuffing, 
Phillips). 

The treatment of cocain habit coincides exactly with that of the 
morphin habit (which see) ; it is said to be more difficult to cure. 

USE OF COCAIN AS A LOCAL ANESTHETIC IN MINOR OPERATIONS 

The direct application of cocain abolishes the sensation of pain more 
or less completely in about five minutes, the anesthesia lasting for about 
half an hour; the duration increases with the concentration. Solutions 
of 2 to 5 per cent., or the trace of the powder on the point of a probe, are 
applied to the surface of mucous membranes, or injected under the skin. 
Stronger solutions are dangerous and offer no advantage. Application 
to the surface of the skin is useless, since the drug is not absorbed by this 
channel. Mucous surfaces, on the other hand, absorb it readily. It is 
desirable to limit the local circulation, e.g., by a constricting rubber band. 
The vasoconstrictor action of the cocain may be heightened by the addi- 
tion of epinephrin (i :ioooo to i :iooooo). 

In eye, nose, and larynx operations the abolition of reflexes and the 
diminution of hemorrhage are very useful side actions. 

In connection with its action on the eye, it must be remembered that it does not 
ordinarily anesthetize the iris when applied to the cornea. However, the iris may also 
be anesthetized by applying one or two drops of a 10 per cent, solution to the cornea 
every two or three minutes, for ten minutes; keeping the conjunctiva moist by frequent 
winking, to prevent epithelial sloughing (Gifford). 

CATARRH, HAY FEVER AND ASTHMA 

Cocain is also useful in the treatment of diseases which appear to be due to heightened 
irritability of the peripheral endings, such as hay fever and asthma. In these the cocaini- 
zation of the nasal mucous membrane is often specific. The astringent action renders 
it effective in acute coryza. 

One per cent, cocain ointment has been recommended in herpes zoster; it is said not 
only to relieve the pain, but to put a stop to the disease. 

Cocain is also useful locally in hemorrhoids, producing contraction and diminish- 
ing pain. It has been taken by the stomach to prevent vomiting and dyspeptic 
pain. 

The danger of the formation of the habit interferes with its use in all these conditions; 
indeed many cases of cocain habit were started by proprietary catarrh "cures." 



USE OF COCAIN IN LARGER OPERATIONS 

This demands the most economical utilization of the alkaloid, to avoid 
systemic poisoning, by securing the maximum effect from the smallest 
dose. 

The infiltration method (Schleich, 1892) involves the injection of 
very dilute solutions (Hoo to % per cent.) under considerable pressure, 
directly into the place where the next incision is to be made. It is espe- 
cially useful for anesthetizing the skin for extensive incisions. It is rather 
too painful for inflamed tissues. 



COCAIN GROUP; LOCAL ANESTHETICS 



2 59 



The object is to produce a local edema, which supports the action of the cocain by 
causing local anemia and by compressing the nerve filaments. The injections can be 
made with an antitoxin syringe with a long needle, by means of which the solution is 
first injected into (not under) the epidermis, so as to raise a blister. The needle being 
left in place and gradually pushed deeper, the entire field of operation is saturated with 
the solution, 30 to 500 c.c. being used. The usual solution (Sol. II) contains % Q P er 
cent, of cocain and per cent, of sodium chlorid. In inflamed tissue, the cocain may be 
doubled (Sol. I); or if the field is extensive, it may be reduced to J^oo P er cent. (Sol. 
III). Bevan, 1915, speaks highly of novocain infiltration. He employs up to 100 or 
200 c.c. of a solution with 0.25 to 0.5 per cent, of novocain, to which % to i c.c. of epi- 
nephrin, i : 1000, has been added. 

In the paraneural method the solution, of a strength of % to 2 per cent., is injected 
in the neighborhood of the nerve trunk. The results are uncertain. 

Intraneural Method (Nerve Blocking). In this, a ^2 to 2 per cent, 
solution is injected directly into the nerve trunk. 

If the injection is made quickly and directly into the nerve tissue, the procedure is 
quite painful. A few drops should first be injected under the nerve sheath. When these 
have caused a local anesthesia, the needle should be pushed deeper and more of the solu- 
tion injected, until the anesthesia is complete. In this way the pain is relatively slight. 
Anesthesia requires fifteen to twenty minutes, and is not always completely successful. 

The combination of all the above methods is perhaps most useful. 
The skin and superficial muscles are anesthetized by infiltration. The 
deeper structures are exposed, and the smaller nerves are treated by the 
paraneural, the larger by the intraneural methods. In this way, surpris- 
ingly small quantities of cocain suffice (8 mg. for amputation of shoulder 
joint!). 

Influence on Shock. The complete, blocking of nerve impulses obtained in this way 
tends to prevent surgical shock. No method of local anesthesia can, however, prevent 
the psychic shock and pain, the nervous dread of the patient, the removal of which is one 
of the most valuable features of general anesthesia; but it may at least be lessened by 
morphin (0.015 Gm. hypodermically) half an hour before the operation. It may at times 
be justifiable to operate without the knowledge of the patient, which is quite feasible 
by the use of cocain (Crile). 

Spinal Anesthesia. The subdural injection of cocain, or other local 
anesthetics, anesthetizes the sensory nerve roots at their emergence from 
the spinal cord. This abolishes sensation in their entire peripheral dis- 
tribution for about one and one-half hours (one-half to two hours), with- 
out loss of consciousness or motor functions. The method was demon- 
strated by Corning of New York in 1885, and introduced into practice 
by Bier, 1899, but it was temporarily abandoned, and did not come into 
vogue until about 1904. The injection is performed by lumbar puncture, 
withdrawing a little cerebro-spinal fluid, and introducing ^ to i c.c. of 
2 per cent, cocain solution; or more commonly, corresponding quantities 
of its substitutes: Tropocain, 5 per cent., novocain (not above 0.15 Gm.) ; 
stovain (not above o.i Gm.; beginning with one-half or two- thirds of these 
doses). Epinephrin and strychnin may be added. 

The anesthesia extends to the level of the nerve roots reached by the 
cocain, the aim being to confine it to the lower half of the body. If it 
should extend to the fourth ventricle, it will result in paralysis of the res- 
piration. Alarming symptoms and fatalities from this cause are not in- 
frequent (Seifert, Nebenwirk., 1915, p. 105), and the method is more 
dangerous even than chloroform. The fatality is probably over 1:500 
(Bevan). It has also been fatal to the fetus in utero (Jung, 1914). Minor 
accidents are not uncommon. Cord injuries are sometimes produced; 
severe headache may last for days or weeks. Further, the technic is 



260 MANUAL OF PHARMACOLOGY 

difficult, disagreeable to the patient, and the anesthesia is often unsuccess- 
ful. Spinal anesthesia should therefore not be employed (Hohmeier and 
Koenig, 1910), unless inhalation anesthesia is directly contraindicated 
(Anesthesia Commission, Journ. Amer. Med. Assoc., 1908). It is espe- 
cially useful in pulmonary disease, arteriosclerosis, bladder and rectal 
cases, impending uremia, and diabetics; emergencies after a full meal. 
It is not justifiable to use it for operations above the costal margin (F. L. 
Richardson, 1913). Bevan, 1915, can see no justification for spinal anes- 
thesia under any conditions. 

Phenomena of Spinal Anesthesia. These occur in the following order: Loss of knee- 
jerk; of plantar and cremasteric reflex; ascending analgesia; later, ascending loss of motor 
power. The upper limit is usually quite abrupt. Subjectively, there is an ascending 
feeling of warmth, swelling and heaviness. Occasional toxic effects are pallor, nausea, 
vomiting, sweating, feeble pulse, relaxation of sphincters, dyspnea. The most frequent 
after-effects are headache and insomnia. 

Fall of Blood Pressure. This is a very common phenomenon of spinal anesthesia. 
Smith and Porter, 1915, found that it is due to paralysis of the splanchnic fibers in the 
cord, not in the medulla. Epinephrin with tropacocain or novocain caused even a 
greater fall. Measures to restore the pressure were only temporarily successful. As 
the effects of the anesthetic began to wear off, sciatic stimulation produced a fall, in- 
stead of the normal rise. 

To prevent the spreading of the solution E. Erhardt, 1908 and 1912, has proposed to 
increase its viscidity by gum arabic. Bulk of solution (dilution) favors spreading 
(Smith and Porter, 1915). 

The combined action of stovain and strychnin on the cord has been investigated by 
Aron and Rothman, 1909; and Simon, 1915. The two drugs are not antagonistic; and 
strychnin does not render stovain any safer. 

Intravenous Injection of Cocain. The action of cocain is sufficiently selective so that 
a marked, though incomplete general analgesia, without disturbance of consciousness 
or motor functions, can be produced by intravenous (Ritter, 1909; Harrison, 1911) or 
intra-arterial (Ransohoff, 1909) injection. However, these methods are both unsatis- 
factory and dangerous (Bevan, 1915). 

USE OF COCAIN AS A CEREBRAL STIMULANT 

Cocain has been employed to combat fatigue, and as a general tonic. It has no ad- 
vantages and many disadvantages as compared with other stimulants, especially caffein 
and strychnin. The danger of habit formation should suffice to condemn it. That the 
harm has not been greater may be attributed to the unreliability of the coca preparations 
which are generally employed. 

COCAIN SUBSTITUTES 

A large number of substances have been introduced as substitutes 
for cocain. Some of these (Novocain, Stovain, Eucain) may have a slight 
advantage by combining an equal anesthetic activity with somewhat 
lower toxicity and much greater stability; but practically these advan- 
tages are not very serious and scarcely justify the introduction of these 
numerous products. Moreover, Stovain and Eucain produce far more 
irritation than cocain, and stovain may permanently injure the nerves. 
Orthoform or Anesthesin, on account of their limited solubility, are only 
slightly toxic and produce a slow and prolonged anesthesia when applied 
in substance to superficial or gastric ulcers, etc. 

The substitutes have in general the same incompatibilities as cocain. They resemble 
it more or less in their chemic structure. 

Structure of Cocain. Cocain is the methyl-benzoyl ester of ecgonin, 
a base closely related to tropin, the corresponding base of atropin, both 
being pyrrolidin derivatives. 



COCAIN GROUP; LOCAL ANESTHETICS 



261 



The relation is shown by the structural formulas : 
H 2 C CH CH 2 



N(CH 3 ) 

CH CH 2 

Tropin 




H 
OH 



OH 



-CH 2 



X 



COOCH 3 



).COC 6 H 6 



Ecgonin 



Cocain 



Relation of Structure to Actions. Ecgonin itself produces only the least important 
of the actions of cocain, viz., the hepatic degeneration. The other actions are only 
developed by the entrance of both radicals. The methyl may be replaced by any other 
alkyl radical, without changing the actions of cocain. The benzoyl radical, however, 
can not be replaced by other aromatic acids (possibly with a few exceptions) nor by 
fatty acids without great impairment of the local anesthetic action. Indeed, the pres- 
ence of the benzoyl group gives the anesthetic properties to other alkaloids, and may be 
considered as the hook by which the molecule attaches itself to the protoplasm of the 
sensory cell. It is present in most of the cocain substitutes. The required conditions 
for the development of a local anesthetic action seem therefore to be: a base with a 
structure analogous to ecgonin, containing a benzoyl and an alkyl radicle in certain 
relations. 

Advantages and Disadvantages of Cocain. The valuable features of cocain consist 
in its strong, prompt and comparatively certain action; it is the best studied and the most 
familiar product of its class; the vasoconstriction lessens hemorrhage (but may be objec- 
tionable in snaring polypi); the dilation of the pupil may be a convenience in ophthalmic 
operations; it is practically free from local irritation; it acts through intact mucous 
membranes. Some of these features, viz., vasoconstrictor and mydriatic actions may 
be given to the substitutes by the addition of epinephrin or atropin. 

The Disadvantages of Cocain. These consist in the instability of its solutions; in 
the occasional collapse; and in the habit formation. 

The Relative Advantages of the Substitutes. These have been the subject of much 
discussion which indicates that they are not very striking. The comparative exper- 
iments of Le Brocq, 1909, and of Dreyfuss, 1910, favor novocain; but it is only one-third 
as strong. Stovain, holocain and alypin cause some local injury. Quinin is weaker than 
cocain, but much more lasting. Extensive compilations of the anesthetic efficiency and 
toxicity of the cocain substitutes are given by Closson, 1914, and especially by Koch- 
mann, 1914. The latter found the "value factor" anesthetic power -r toxicity great- 
est for a combination of novocain and potas. sulphate. 



PREPARATIONS COCAIN 

Coca Folia. The dried leaves of Erythroxylum Coca and E. truxillense, shrubs 
indigenous to Peru and Bolivia, and cultivated in tropical countries. Ceylon coca 
contains mainly cocain; Java coca contains only other ecogonin derivatives (Jong, 
1911). 

Cocaina, U.S. P., B.P., Cnl^iNO* Colorless prisms or crystalline powder, of 
slightly bitter taste followed by anesthesia. Slightly sol. in water (1:600); freely sol. 
in ale. (1:6.5), chlorof., eth.; sol. in oils (1:12 olive oil). Used especially in ointments. 
Dose, 15 mg., % gr. 

* Cocain. Hydrochl., U.S.P.; B.P., Ci 7 H 2 iNO 4 -HCl. Colorless, transparent prisms; 
or flaky, lustrous leaflets, or white, crystalline powder. Very sol. in water (1:0.4); 
freely sol. in ale. (1:3.2); sol. in glyc.; practically insol. in oils. Incompatible with 
alkalies, sodium borate (not boric acid), silver nitrate and calomel. Solutions decom- 
pose on keeping (a 15 per cent, solution in Dilute Alcohol is said to be permanent; 
Wintersteiner, 1906). Contrary to older statements, they are not materially decom- 



262 MANUAL OF PHARMACOLOGY 

posed by boiling. Dose, 15 mg., ^ gr., U.S.P.; 6 to 16 mg., ^10 t 2<gr., B.P. Maxi- 
mum close, 50 mg., % gr. 

Inject. Cocain. Hyp. 5 per cent. Dose, 0.3 to 0.6 c.c., 5 to 10 minims, B.P. 

Lam. Cocain., B.P. 1.3 mg., 3^o S r - 

Ung. Cocain., B.P. 4 per cent. 

Troch. Kramer, el Cocain., B.P. 60 mg. of krameria; 3 mg. of cocain. 

PREPARATIONS COCAIN SUBSTITUTES 

Betaeucaina Hydrochloridum (Eucain. Hydrochl.), U.S.P. (trimethyl-benzoxy- 
piperidin), CisHaiNC^-HCl. White, crystalline powder; odorless. Sol. in water (1:30 
and ale. (1:35). Dosage, locally, one to two times that of cocain. The anesthetic 
effect is perhaps slightly slower and weaker, and the irritation considerably greater, 
than with the same concentration of cocain. The pupils are not dilated; the tissues are 
rendered hyperemic. The toxicity is four-tenths that of cocain. Toxic doses cause 
convulsions, central vagus stimulation, and direct cardiac depression, with fall of blood 
pressure (Seifert, Nebenwirk., 1915, p. 64; case and bibliography, Orr, 1916). 

Benzamin. Lad., B.P. (Beta-eucain Lactate), CisNaiNC^'CaHeOs. Freely sol. 
in water (1:5) and ale. (1:8). Dose, 8 to 30 mg., % to ^ gr., B.P. 

Orthoform New, N.N.R. (amino-oxybenzoate of methyl). White tasteless powder, 
scarcely soluble in water (the hydrochlorid is soluble). Not absorbed from skin or 
mucosae. It is said to have repeatedly caused local inflammatory reaction (Seifert, 
Nebenwirk., 1915, p. 79; McCleave, 1914). Dose, 0.5 to i Gm., 8 to 15 gr. ; locally as 
dusting powder or oinment. 

Anesthesin, N.N.R. (ethyl-aminobenzoate) is very similar (side actions, Seifert, 
Nebenwirk., 1915, p. 44). 

* Novocain, N.N.R. (aminobenzoyl-diethyl-amino-ethanol hydrochlorid). Color- 
less needles, sol. in equal weight of water, or 30 parts alcohol. The nitrate is compatible 
with silver salts. Dosage, locally, one to three times that of cocain. Anesthetic and 
irritant action perhaps slightly less. No effect on pupil. 

Novocain is probably safer than cocain. Occasionally, however, toxic effects occur 
even with small doses (o.oi to 0.13 Gm.); while in other cases up to 3 Gm. have been 
used safely. There is no definite ratio between the toxicity of novocain and cocain, 
since this depends enormously on the rate with which they enter the circulation; especi- 
ally in the case of novocain. This is due to the great rapidity with which novocain 
leaves the circuation, being fixed and probably destroyed in the liver. Epinephrin 
diminishes the toxicity, even by intravenous injection, probably by cardiac stimulation 
(Hatcher and Eggleston, 1916). 

The details of the clinical toxic effects are described by Seifert, Nebenwirk., 1915, 
p. 78; lumbar, p. 107. Renal irritation is not uncommon after local use of 5 to 10 per 
cent; but disappears in a few days (Morian, 1915). 

Stovain, N.N.R. (benzoyl-ethyldimethyl-aminopropanol hydrochlorid) . Colorless 
scales, extremely soluble in water, or in 5 parts alcohol. Dosage, locally, as for 
cocain. Anesthetic action slightly stronger, irritant action (hyperemia) much greater, 
toxicity two-thirds that of cocain. No effect on pupil. 

It has been used especially for spinal anesthesia, in combination with strychnin 
(T. Jonnescu, 1909). The immediate danger may be somewhat less than with cocain, 
although it is not negligible. The local injury is much greater. Spiller and Leopold, 
1910, and Consoli, 1913, have observed degenerations in the nerve roots and cells, after 
subdural injection of stovain. The immediate paralysis is more extensive than with 
cocain, involving muscular movements (Santesson, 1906) and spinal reflexes (Adler, 
1906). On the circulation, it causes in dogs, quickened pulse and fall of blood pressure 
(Kamenzove, 1911). The kidneys are also rather irritated, especially if albuminuria 
was previously present (Schwartz, 1907; Chiaie, 1913). The liver is not affected 
(side actions, Seifert, Nebenwirk., 1915, p. 91; lumbar, p. 109). A comparative study 
of the local anesthetic actions of stovain and its homologues has been made by Symes 
and Veley, 1911. 

Alypin, N.N.R., which resembles stovain in structure, is used especially in the 
urethra. It is more irritant than cocain. Several cases of sudden collapse and 
asphyxia, after its injection, have been reported (Ritter, 1912; Lichtenstein, 1914; 
lumbar, Seifert, Nebenwirk., 1915, p. 104). 

Tropacocain Hydrochlorid, N.N.R., (benzoyl-pseudo-tropein) ; occurs in Javanese 
coca, but the commercial is synthetic. Colorless needles, readily soluble in water. 
Dosage, locally, one or two times that of cocain. Anesthetic action about the same; 
irritation greater; toxicity one-half that of cocain; less mydriatic; more stable (side 



PERIPHERAL AUTONOMIC SYSTEM 263 

actions, Seifert, Nebenwirk., 1915, p. 97; lumbar, p. 112). It is used especially for 
spinal anesthesia (Stanley, 1916). 

Holocain, N.N.R., (phenetidyl-acetphenetidin hydrochloric!). Colorless crystals, 
soluble in 50 parts water. Dosage, for eye, i per cent. Anesthetic action about as 
strong as cocain, but more rapid (anesthesia in half a minute) ; more toxic, but stated 
not to injure or anesthetize cornea. No effect on vessels has been reported (Gjessing, 
1915). 

Yohimbin, C22H 28 N2O3- HC1. An alkaloid isolated by Spiegel, 1896, from the 
bark of Yohimbehe tree (Apocynaceae; West Africa). Fourneau and Page, 1914, con- 
sider it identical with quebrachin. Local anesthetic, about same strength but more 
lasting than cocain. Less toxic, but much more irritant. Mydriasis, without loss of 
accommodation. Vessels dilated. Intestines excised or in situ, and bladder stimu- 
lated by small, depressed by large, doses (A. Loewy and Rosenberg, 1914). Solutions 
are unstable. 

When it is given by the mouth or hypodermically in moderate doses, it produces a 
general vasodilation in the skin, mucous membranes, and particularly in the sexual organs. 
In consequence of the latter, and perhaps by a direct action of the spinal centers, it pro- 
duces erection. It does not seem to stimulate the production of spermatozoa or sexual 
desire. The effect is not produced by therapeutic doses in man (5 mg. or ^ 2 gr.), 
although it has been promoted as an aphrodisiac. The reports of clinical improve- 
ment after several weeks are probably explainable by suggestion. Yohimbin has also 
been proposed for lowering abnormally high blood pressure; but Lawrence, 1912, found 
that it may produce a further rise, with dangerous symptoms. 

Larger doses produce psychic excitement, cerebral congestion, vertigo, gastric dis- 
turbance; and in rabbits, marked injury of the renal epithelium (Huebner, 1912). 
Toxic doses produce general stimulation and subsequent paralysis of the nervous cen- 
ters, particularly in the medulla; and complex effects on the cardiac muscle (F. Mueller, 
I 97! J- Tait, 1910). The coronary vessels are not affected (Rabe, 1912); or they are 
dilated (F. Meyer, 1912). Death occurs by respiratory paralysis (for literature, see 
Strubell, 1906). 



DRUGS ACTING PERIPHERALLY ON THE AUTONOMIC-SYM- 

PATHETIC SYSTEM 

A variety of poisons act peripherally upon the several portions of the 
involuntary or "vegetative" nervous system, in a more or less specific 
manner. It appears advisable to premise their individual consideration 
by a more general exposition, so as to obtain an intelligent grasp upon their 
various relations, and an insight into what is known of their action. 
Much light has been thrown upon these in recent years, and our concep- 
tions have been largely revolutionized. 

Anatomic and Physiologic Relations. The "autonomic" system (in the wider sense 
in which the term was introduced by Langley) has certain physiologic and anatomic 
peculiarities. Physiologically, it includes all the functions which are subject to involun- 
tary nervous control the smooth and cardiac muscles and the glands. Their relation 
to the central nervous system is peculiar, in that they are capable of functionating auto- 
matically, and by local neuro-muscular reflexes, when all connections with the cerebro- 
spinal axis are severed (hence "Autonomic"). On the other hand, their functions are 
normally regulated, augmented or inhibited, by central tonic impulses of varying 
intensity. 

The chief anatomic peculiarity of these autonomic nerves is, that they all pass through 
a relay ganglionic cell, situated outside of the central nervous axis. These cells are 
partly scattered but mostly collected into the "sympathetic ganglia." A given nerve 
fiber has but a single relay cell, although it may pass through a number of ganglia. 

THE PARASYMPATHETIC AND SYMPATHETIC SYSTEMS 

Physiologically, and especially pharmacologically, as also in its embryologic develop- 
ment, the autonomic system as a whole has two fairly sharply denned divisions, which 
correspond, anatomically, on the one hand, to the nerves having their origin in the roots 
of the midbrain, medulla oblongata, and sacral cord (the cranio-sacral or parasympa- 



264 MANUAL OF PHARMACOLOGY 

Ihetic system, also often called the autonomic system in the restricted sense); and on the 
other hand, those arising from the dorsal and down to the fourth or fifth lumbar nerve 
roots (the sympathetic system). The relay cells of the sympathetic system are situated 
in the sympathetic ganglion-chain (including the cervical and splanchnic ganglia); 
those of the cranio-sacral system are scattered more peripherally, near their end organs. 

Distribution and Function. The two divisions are antagonistic, a given organ 
usually receiving its innervation from both divisions, one being augmentor, the other 
inhibitory. 

The parasympathetic division, for instance, supplies the vagus (cardio-inhibitory, 
intestinal and bronchial augmentor), oculomotor (pupillo-constrictor), chorda tympani, 
etc. 

The sympathetic division supplies the vasoconstrictors, pupillo-dilator, intestinal 
inhibitory, cardiac accelerator, etc. 

The innervation of the sweat glands occupies a peculiar position; anatomically, it 
is purely sympathetic, but it reacts pharmacologically as if it, were purely parasym- 
pathetic. The uterus is also exceptional; its sympathetic innervation responding to 
both classes of poisons. It must be remembered, however, that the anatomic evidence 
of the origin of the autonomic nerves is in some respects inconclusive. 

Pharmacologic Reactions: Xicotin. Pharmacologically, the most 
prominent characteristic of the whole autonomic system is its reaction 
to nicotin: this alkaloid paralyzes all the ganglionic synapses of both the 
parasympathetic and the sympathetic nerves (often after a fleeting pri- 
mary stimulation). This paralysis is so specific, that it has proved of great 
value for locating the site of these synapses, especially in the hands of 
Langley. Nicotin, whether it is applied locally or systemically, abolishes 
the response to stimulation of the preganglionic fibers, whereas the post- 
ganglionic fibers respond normally. 

Deprivation of calcium increases the excitability to the augmentor 
impulses of both divisions (see "Calcium Ions"); most of the other drugs 
which affect the autonomic system restrict their action exclusively to one 
or the other of the two divisions: Epinephrin, ergotoxin and cocain act 
exclusively on the sympathetic divisions; atropin, pilocarpin, muscarin, 
cholin, and physostigmin act exclusively on the parasympathetic division. 
Still others act only on certain parts of one or of both divisions. 

Anisotonic Solutions. Hypertonic solutions (Ringer's) inhibit the tone of smooth 
muscle, increase the response to inhibitory drugs, and lessen the response to stimu- 
lants. Hypotonic solutions have the opposite effect (Dale, 1913). 

PHARMACOLOGY OF THE SYMPATHETIC DIVISION 

Epinephrin, the alkaloid of the suprarenal gland, produces a pure periph- 
eral stimulation, restricted exclusively to the sympathetic system, but 
involving the entire distribution of this system (with the exception of 
the sweat glands). In other words, the effects of typical doses of epine- 
phrin on a given organ correspond precisely to the stimulation of its 
sympathetic nerve supply (Levandowsky, 1899; Langley, 1901; Elliott, 
1905). This has been aptly described by the term " sympathomimetic 
action" (Barger and Dale, 1910). The action of epinephrin is there- 
fore augmentory or inhibitory, according to whether the sympathetic 
impulses are augmentory or inhibitory, as follows: 

The Principal Sympathetic Reactions (e.g., the Effects of Epi- 
nephrin). The augmentory reactions consist in constriction of most of the 
arteries and consequent rise of blood pressure; stimulation of the cardiac 
accelerator; dilation of the pupil; contraction of the plain muscle of the 
orbit; flow of sympathetic saliva and of tears, not readily abolished by 
atropin; erection of hair, etc. 



PERIPHERAL AUTONOM1C SYSTEM 265 

Inhibitory Reactions concern the tone and rhythm of the contractions 
of the stomach, intestine, biliary and urinary bladder (cat), and of the 
virgin uterus of the cat. 

Peculiarities of Species. Certain of the sympathetic reactions vary with the species 
of animals, being augmentory in some, and inhibitory in others (urinary bladder, anal 
sphincter). The sympathetic reaction of the uterus varies according to its physiological 
state; in the cat, the virgin uterus is inhibited, whilst the pregnant uterus is stimulated. 

All these peculiarities are reproduced exactly in the reaction to epinephrin, thus 
furnishing the most striking illustrations of its sympathomimetic action. 

Other Drugs with Sympathomimetic Action. Similar actions are possessed by a 
large number of primary and secondary amins, the simplest being the primary fatty 
amins, amylamin, etc.). There are quantitative differences between these. The rela- 
tive effect on the different sympathetic distributions does not go parallel; nor is there any 
parallelism between augmentory or inhibitory innervations. The intensity and speci- 
ficity increase as the amins approach the structure of epinephrin (Barger and Dale, 
1910). 

Cocain increases the peripheral excitability of the sympathetic system 
without being directly stimulant. 

Peripheral Sympathetic Paralysis : Ergotoxin. The active alkaloid of 
ergot (in large doses) destroys the response of the augmentory sympathetic 
impulses, but does not affect the inhibitory sympathetic impulses (Dale, 
1906). It therefore prevents,/.?'., the vasoconstrictor action of epineph- 
rin, but does not abolish the inhibitory action of epinephrin on the intes- 
tine or uterus. 

PHARMACOLOGY OF THE PARASYMPATHETIC CRANIO-SACRAL AND 
RESTRICTED AUTONOMIC DIVISION 

The action of drugs on this system is confined mainly to its augmen- 
tory functions (with the important exception of the vagus). These, in 
their entire peripheral distribution, are paralyzed by atropin; and stimu- 
lated by pilocarpin, muscarin, cholin and anaphylotoxin. Physostigmin 
heightens their irritability, perhaps without being directly stimulant. 
(These statements must be restricted to typical doses.) 

Atropin is therefore antagonistic to all the other drugs named. If a 
sacro-cranial function is exposed simultaneously to the depressant action 
of atropin and to the stimulant action of one of the other drugs named, 
the end result depends on the nature and quantity of the drug, and upon 
other conditions. Physostigmin, for instance, is a more powerful antago- 
nist of atropin than is pilocarpin; however, larger doses of the stimulants 
tend to become depressant, so that the atropin action tends to appear 
predominant. 

The centers of the parasympathetic system are stimulated by picro- 
toxin. 

Principal Results of Parasympathetic Stimulation (Pilocarpin, etc.). 
These consist in: slowing of the heart; constriction of the pupil; bronchial 
spasm; contraction of intestine and uterus; increase of practically all 
centrally innervated secretions (sweat, saliva, mucus, gastric, pancreatic, 
etc; not urine, bile, milk, nor the internal secretions). These are the main 
effects of pilocarpin, muscarin and physostigmin. 

Craniosacral depression (atropin) produces precisely the opposite 
results. 

DRUGS WITH PARTIAL AUTONOMIC REACTIONS 

The preceding presentation is somewhat schematic, and includes only 
the typical effects, as they are currently conceived. When the doses and 



266 MANUAL OF PHARMACOLOGY 

other conditions are varied, many of these drugs depart more or less from 
the schema, as will be discussed later. This indicates that the physio- 
logical divisions, which are the basis of the pharmacologic divisions, are not 
as absolute as the schema would imply. In accordance with this, there are 
a number of drugs (for instance, apocodein and pituitary extract; the 
latter, however, is probably a mixture), which do not fit anywhere in the 
schema, but whose actions involve isolated functions of one or both 
divisions. 

LOCATION OF ACTION 

The precise site of action of the autonomic drugs is not yet 
satisfactorily decided. It is currently assumed that they act on the 
"myoneural junction," or upon a "receptive substance" (Langley, 1905), 
which is believed to be interpolated between the anatomical nerve-end- 
ings and the reactive substance of the cell (the contractile elements of the 
muscle, or the secretory elements of the gland cells). It would perhaps 
be equally or more exact to say that they act upon that property of the 
cells which excites or initiates their peculiar functions. 

The essential evidence for this view is the fact that these poisons pre- 
serve their action after severance and anatomic degeneration of the post- 
ganglionic nerve fibers, showing that their action is peripheral to the ner- 
vous structure. On the other hand, the specificity of the reactions, and 
their correspondence with the physiologic innervation, indicates that the 
action is not directly on the contractile or secretory substance. If epi- 
nephrin, for instance, acted directly upon the contractile elements of smooth 
muscle, it would be difficult to understand why it should throw them into 
contraction in some situations, relax them in others, or in others again, 
leave them entirely unaffected. Anatomically, these muscles are all alike; 
their physiologic properties are also identical, they respond alike to mus- 
cular poisons, such as barium; the only difference between them lies in 
their innervation. This difference of innervation is reproduced exactly by 
epinephrin; and since the degeneration-experiments show that the poison 
does not act upon the nervous elements themselves, it follows that both 
the nervous impulse and epinephrin must act upon the same substance or 
property of the muscle. 

It is idle to speculate upon the nature of this receptive substance, or receptive prop- 
erty, until we know somewhat more of the real nature of the nervous impulse, of stimu- 
lation, and of excitability. The term "myo-neural junction" has the advantage that 
it does not commit one to any unproven hypothesis. 

Anatomic Localization of Depressant Effects. The anatomic methods 
of localization are quite simple, since the problem concerns a purely effer- 
ent path. The nerve would be stimulated in various sites in its course; 
the paralysis would be located just central to the highest point which 
gave a positive response. 

For instance, after nicotin, stimulation of the preganglionic fibers of 
the vagus (say in the neck), does not slow the heart; stimulation of the 
postganglionic fibers (in the sinus) causes slowing. Nicotin has therefore 
paralyzed the ganglia. 

After atropin, stimulation of the sinus is also ineffective; the paralysis 
must therefore be peripheral; the heart-muscle is evidently not paralyzed, 
since it is beating vigorously. The paralysis must therefore be just cen- 
tral to the muscle, i.e., in the endings or myo-neural junction. It must be 



PERIPHERAL AUTONOMIC SYSTEM 267 

remembered, however, that this does not exclude the possibility of an 
additional more centrally located paralysis; for instance, so far as this 
evidence goes, atropin might have paralyzed the vagus ganglia in addition 
to the " myo-neural " junction. Further, the precaution must be taken 
to employ a sufficient dose of the poison, for a slight paralysis may often 
be overcome by a powerful stimulation. 

Anatomic Localization of Stimulant Effects. This would also be very 
simple, involving the division of the nerve (or its equivalent, the applica- 
tion of the drug to excised organs or structures). For instance, pilocar- 
pin and muscarin contract the pupil of the excised eye, and physostig- 
min increases its excitability to stimulation of the postganglionic oculo- 
motor. Their action is therefore postganglionic. It is again possible that 
the drug may stimulate an additional, more centrally located structure. 

To distinguish between anatomic endings, myo-neural junction, and 
muscle substance, the nerve is allowed to degenerate, as just described. 

Pilocarpin, /.*'., remains effective after the anatomic endings are degenerated, and 
when therefore electric stimulation of the nerve is ineffective. However, if a still 
longer time elapses after the division of the nerve, pilocarpin also becomes ineffective. 
It is therefore generally assumed that the myo-neural junction also degenerates, but 
more slowly than the anatomic endings. However, it is also conceivable that pilo- 
carpin acts on the anatomic nerve-endings, and that the degenerating endings remain 
excitable to pilocarpin longer than they do to electric stimulation. This proof of myo- 
neural action is therefore not conclusive. 

The evidence from degeneration may also mislead if the drug, instead of stimulating, 
raises the excitability of the reacting cell. In this case, the drug would produce no visi- 
ble effect after degeneration of the endings, for this would exclude extraneous stimulation, 
and the increased excitability would therefore not be apparent. This increased excita- 
bility of the myo-neural junction is supposed to be the action of physostigmin on the 
oculomotor mechanism. 

Localization by Antagonistic Action. The anatomical localization, al- 
though simple in theory, is often technically difficult, and it is beset with 
the limitations which have just been pointed out. It has therefore been 
attempted to supplement and extend it by pharmacologic evidence, based 
on antagonistic actions. The matter was at first conceived as very 
simple, namely as strictly analogous to anatomic localization; a drug 
paralysis being considered as equivalent to anatomic division or excision; 
and a drug stimulation as the equivalent of electric stimulation. The 
action of a few drugs having been localized (with more or less probability) 
by anatomic means, it was thought that the actions of others could be 
localized by simply "matching" them against these standards. In 
localizing action by antagonism, a stimulant poison was paired with a 
depressant poison of known action, f.i., atropin. If stimulation resulted 
(as with physostigmin) it was concluded that the action must be peripheral 
to that of the atropin; if there was no stimulation (as with pilocarpin), 
it was assumed that it must be central to that of atropin. 

Unfortunately, there has been a good deal of cumulative evidence 
(well summarized by Magnus, 1908) that matters are not so simple, and 
that localization by antagonism has limitations so serious that it can be 
utilized only in relatively few cases. The difficulty is that the phar- 
macologic stimulation and paralysis are not strictly equivalent to the ana- 
tomic. In pharmacologic antagonism, the tissue is still in the body and 
exposed to both poisons; and the resultant effect is rarely, if ever, the simple 
algebraic sum of their separate actions. One drug may modify the effects 
of another qualitatively, as well as quantitatively. Moreover, a drug 



268 MANUAL OF PHARMACOLOGY 

paralysis is not an irreversible process, as is anatomic division or excision. 
The numerous instances of mutual antagonism prove that a function 
which has been completely abolished (paralyzed) by one drug may be 
revived by another. For instance atropin can abolish the physostigmin 
miosis; but physostigmin can also remove an atropin mydriasis the result 
depending upon the relative dosage. 

Localization by antagonism is therefore conclusive only if the antagon- 
ism is not mutual and if it involves absolutely distinct structures; for 
instance, atropin abolishes the action of cevadin (veratrin) on the cardiac 
vagus; whilst cevadin does not interfere with the atropin action. Evi- 
dently, the cevadin action must be central to that of atropin. 

Mutual Antagonism. When two drugs are mutually antagonistic, it 
is natural to assume that they act on the same structure. This is doubt- 
less often the case; but there are instances in which this simple assumption 
offers difficulties; for in some cases, the point of attack of a drug appears 
to be different in the presence of an antagonist. This is practically im- 
portant; for it is probable that disease may produce similar modifications. 
The following instances are adduced by Magnus, 1908: 

Physostigmin and Curare on Striped Voluntary Muscle. Physostigmin produces 
fibrillary twitchings of the voluntary muscles. These persist after section of the motor 
nerve (sciatic). They are therefore peripheral (Harnack and Witkowski, 1876). They 
are suppressed by curare, which paralyzes the endings; on the other hand, physostig- 
min removes the curare paralysis (Pal and Rothberger). Magnus found that the 
physostigmin fibrillations can not be produced when the motor nerve has been cut and 
allowed to degenerate completely (but whilst the muscle fibers still respond to direct 
stimulation). This would seem to localize the physostigmin action strictly in the end- 
ings; and the case would be a typical instance of mutual antagonism, both poisons 
acting on the nerve-endings. 

This conclusion appeared to be opposed by the antagonism of nicotin and curare on 
striped muscle. Langley, 1906, showed that certain muscles of the fowl are thrown into 
tonic contraction by nicotin, and that this is removed by curare. This peculiar nicotin 
action, however, persists after degeneration of the nerve; hence nicotin, and therefore 
also curare, must act upon the intramuscular "receptive substance." But if curare 
paralyzes an intramuscular structure, its action could not be removed by physostigmin, 
which stimulates an extramuscular structure. 

The two phenomena are reconcilable by the assumption that the curare attacks the 
receptive substance in the presence of nicotin, and that it attacks the nerve-endings in 
the presence of physostigmin; in other words, that the point of attack of curare is deter- 
mined by its antagonist; in other words, that we are dealing with two distinct and un- 
related paralytic actions of curare, manifested under different conditions, one on the 
extramuscular, the other on the intramuscular structure. The nicotin-tonus effect 
appears to be a distinctive reaction, which has probably nothing to do with ordinary 
muscular contraction; so that the curare block, f.l., with ordinary sciatic stimulation, is 
probably the same in all animals (i.e., in the nerve-endings). 

Langley, 1913 and 1914, investigated the nicotin effects on frogs' muscle. He found 
the nicotin-tonus action quite distinct from the nicotin-twitchings. The twitchings, 
f.i., are prevented by a definite concentration of curare, whatever the concentration of 
the nicotin; whereas, to prevent the nicotin-tonus, the concentrations of the two drugs 
must be kept proportional. 

Peculiarities of Fowls' Muscle. The tonus action is particularly characteristic in 
fowls' muscle, which also shows other related peculiarities (Edmunds and Roth, 1908). 
In these animals, not only the nicotin, but also the physostigmin actions persist after 
degeneration of the nerve; the physostigmin action is not removed by atropin, whilst 
it is so removed in mammals. Barium produces only an increase of muscular tone in a 
normal fowl's leg; but in a denervated leg, or after nicotin, barium causes a strong 
contraction. 

Atropin-Pilocarpin-Physostigmin on the Pupil. When the pupil has 
been dilated by atropin, stimulation of the short ciliary, i.e., of the post- 
ganglionic fibers of the oculomotor nerve, is ineffective, whilst direct 



PERIPHERAL AUTONOMIC SYSTEM 269 

electric stimulation of the iris sphincter .contracts the pupil. Atropin 
therefore paralyzes either the nerve-endings or the myoneural junction. 
Pilocarpin and physostigmin both constrict the normal pupil. When the 
endings of the short ciliary are made to degenerate, pilocarpin is still 
effective (Anderson), but physostigmin is now ineffective. The pilocarpin 
therefore acts on the receptive substance or muscle; the physostigmin 
would be supposed to act on the extracellular nerve-endings. 

From this, one might suppose that pilocarpin should be a more power- 
ful antagonist of atropin than is physostigmin. In fact, however, the 
opposite is the case, so that the point of attack of atropin seems to be 
shifted more centrally by the physostigmin, as if it were determined by its 
antagonist. 

However, in this case also another explanation is possible, perhaps 
more probable. The weak point in the argument is the localization of the 
physostigmin action. There is some evidence that physostigmin acts 
by increasing the excitability of the oculomotor mechanism, and not 
by direct stimulation; for it lowers the threshold for stimulation when 
it does not stimulate directly. If this be true, the failure of physostigmin 
after nerve degeneration would not argue against its action being on the 
receptive substance; for degeneration of the' nerve endings might interfere 
with the physostigmin action simply by eliminating the possibility of 
extraneous stimulation. (If this view is correct, physostigmin should be 
rendered active through the presence of pilocarpin even after nerve degen- 
eration; but the experiment has not been tried.) 

Conflict of Sympathetic and Parasympathetic Actions. Langley and Dickinson, 
1890, showed that the effects of nicotin on the pupil and nictitating membrane are the 
resultant of simultaneous stimulation of the sympathetic and cranial innervation. In 
cats, the sympathetic usually predominates (dilation of pupil and retraction of mem- 
brane). Pilocarpin, on the other hand, causes constriction (oculomotor stimulation), 
which is also unaffected by complete denervation (Anderson). However, it acts also 
on the sympathetic, for the nictitating membrane retracts. Both drugs therefore act 
on both systems. 

Both drugs act after degeneration of the nerves, in the body; but with the excised 
iris, only the augmentor (oculomotor) response persists. To explain this contradiction, 
Dale and Laidlaw, 1912, assume that the sympathetic stimulation in denervated ani- 
mals is brought about by increased secretion of epinephrin, to which the denervated 
sympathetic endings are especially susceptible. 

The other examples adduced by Magnus appear more conclusive: 
Pilocarpin and Atropin on Intestine. Magnus has worked out an 
anatomic method for localizing the action of poisons on the intestinal 
movements, as will be explained presently. He could thus show that the 
ordinary atropin action is located in Auerbach's plexus, whilst the pilo- 
carpin stimulation is peripheral to this plexus. Nevertheless, the two 
drugs are mutual antagonists. Moreover, the pilocarpin stimulation is 
prevented by doses of atropin but one-hundredth as large as the minimum 
dose which has any effect on the unpoisoned gut. 

Apparently therefore the point of attack of atropin is shifted by the 
presence of pilocarpin. There is another possibility, however; for it is 
conceivable that atropin might inhibit the pilocarpin action, not by depres- 
sing the cells, but by preventing their combination with pilocarpin in 
some way. This seems to be nearer the truth, for Bayliss and Starling, 
1901, showed that atropin, whilst it completely inhibits the pilocarpin 
stimulation, does not prevent the response to stimulation of the extrinsic 
motor or inhibitory nerves of the intestine, or to the pinching reflex. 



270 MANUAL OF PHARMACOLOGY 

Threshold of Sympathetic Stimulation. It is also possible, however, that the differ- 
ences are only quantitative; for there exist considerable differences in the threshold 
of the different functional fibers of sympathetic nerves (Gruber, 1915). 

Atropin and Pilocarpin on the Vasomotor Mechanism. This furnishes a strictly 
analogous example: Brodie and Dixon found that atropin removes the pilocarpin 
vasoconstriction, without impairing the response to electric or other stimulation of the 
vasoconstrictor nerves. 

Bladder and Uterus. Similar conditions are found in the Urinary Bladder (the 
response of which to autonomic poisons has been studied by Langley, 1912) and in the 
uterus of the rabbit. In the latter, pilocarpin produces violent contractions, which are 
arrested by atropin, whilst hypogastric stimulation continues effective. 

THE RESPONSE OF THE UTERUS TO AUTONOMIC POISONS 

This presents some very interesting problems of antagonism, especially 
in the cat (Cushny, 1910). 

Spontaneous Movements. The surviving uterus placed in oxyge- 
nated Ringer's fluid continues to perform rhythmic movements for hours 
(Kehrer, 1908). These vary with the physiologic condition of the 
organ, being most lively in early pregnancy. In advanced pregnancy they 
are slower and separated by longer pauses; but they are extensive. They 
can be influenced through the uterine nerves and by the drugs which act 
upon these (Cushny, 1906). 

The nerve supply of the uterus is derived from the sympathetic, chiefly through the 
hypogastric; and from the parasympathetic through the pelvic nerve. Of these, the 
hypogastric is by far the more important. The response to hypogastric stimulation 
differs according to the animal and pregnancy. Rabbits respond by contraction; so 
also do pregnant or recently pregnant cats; in non-pregnant cats, the same stimulation 
inhibits contraction and lessens the muscular tone. There are occasional exceptions 
to this; but in any case, it may be assumed that the augmentor or inhibitory response 
is due to the different functional condition of the muscle. In guinea pigs, the uterine 
effects of poisons resemble their intestinal actions (Sugimoto, 1913). 

Action of Autonomic Poisons on the Uterus. Pilocarpin, Nicotin, and 
Epinephrin. These always produce the same effect on the cat's uterus 
as hypogastric stimulation: augmentation in the pregnant; inhibition in 
the non-pregnant. They would therefore seem to act on the same neuro- 
muscular path. Their reaction to atropin, however, is different: 

Atropin by itself stimulates the movements in small doses; whilst larger doses 
cause arrest. Its main interest lies in the antagonisms: Atropin abolishes the pilocarpin 
effect, whether this be augmentory or inhibitory; but it does not alter the reaction to 
nicotin, to epinephrin, or to electric stimulation of the hypogastric nerve. This is 
in harmony with the specific predilection of atropin against pilocarpin, of which several 
instances have just been given. 

Ergotoxin, on the other hand, abolishes the augmentory effects, both of pilocarpin 
and of epinephrin; it therefore appears to differentiate between the effects, rather than 
between the drugs. 

Still another phenomenon is presented by the physostigmin and atropin antagonism: 
Physostigmin has a purely augmentor action, whatever the state of the muscle; this is 
abolished by atropin, but the antagonism is one-sided (contrary to the experience in 
other organs) : further quantities of physostigmin remain ineffective. 

The uterus is the only instance in which physostigmin, pilocarpin, and 
atropin act on the same nervous (sympathetic) path as epinephrin, and is 
thus a transition to the sweat glands in which the sympathetic innervation 
responds to the craniosacral poisons, and apparently not to the sym- 
pathomimetic epinephrin. 

Reaction of Different Uteri to Epinephrin. The response to this drug, and to sym- 
pathetic stimulation, varies in different animals and functional states, as shown in the 
following table (adapted from Gunn and Gunn, 1914). 



PERIPHERAL AUTONOM3C SYSTEM 271 

Uterus Responds 
By contraction By relaxation 

Rabbit Pregnant or non-pregnant 

Cat Pregnant Non-pregnant 

Guinea pig and rat Pregnant or non-pregnant 

Monkey Non-pregnant 

Dog Non-pregnant 

Human . Non-pregnant (also tubes). 

Other Drugs Acting Peripherally on the Uterus. Infundibular extract produces 
maximal contraction (Frankl-Hochwart and Froehlich, 1009), in all animals, pregnant 
or non-pregnant; also in human uterus, but not in the tubes (although these are con- 
tracted by epinephrin (Gunn, 1914). 

Quinin increases the contractions (Kurdinowski-Kehrer, 1906). Cinchonin, 
cinchonidin and quinidin contract even more powerfully than quinin (Hale, 1915). 

Morphin in small doses is stimulant, in larger doses depressant (Kehrer). 

Scopolamin has no effect. 

Histamin or beta-imidazolylethylamin (a constituent of ergot, also formed by the 
action of bacteria on histidin) is powerfully stimulant (Barger and Dale, 1910). Other 
related amins, peptone, and anaphylotoxin act similarly. Hydrastin, hydrastinin and 
cotarnin are stimulant (Kehrer, 1907). The actions of a number of other drugs are 
described by Pilcher, 1916. 

Purified Organ Extracts. Fawcett, et al., 1915, examined aqueous extracts, after 
removal of the nucleo-proteins and coagulable proteins. Pituitary, pineal, thyroid, 
parathyroid, thymus, adrenal glands, pancreas and spleen were found to contain sub- 
stances that stimulate cat's uterus. The stimulation was inhibited by epinephrin. 
The effects on intestinal muscle differed; when stimulated, it was also inhibited by 
epinephrin. 

Difference between Uterus in Situ and Excised. With non-pregnant cats, the 
uterus in situ is inhibited by nicotin, cytisin, hydrastinin, indolethylamin and pilo- 
carpin. Excised uteri, on the other hand, are generally stimulated by these drugs. 
It seems from this that there is both sympathetic (inhibitory) and parasympathetic 
(augmentory) stimulation. The sympathetic effect predominates during life, but does 
not survive excision. Dale and Laidlaw, 1912, believe that the sympathetic stimulation 
is not direct, but through increased epinephrin secretion. 

Practical Importance of the Uterine Actions. The stimulation of 
uterine contractions is useful for arresting postpartum hemorrhage. Ergot 
particularly is employed for this purpose, hydrastis and cotarnin have also 
been used, but they seem to be less effective. Pituitary extract is used to 
initiate or strengthen uterine contraction. 

Nicotin (tobacco infusion), pilocarpin and quinin are sometimes used 
by the laity as abortifacients; effective doses, however, are dangerous. 

Reflex Increase of the Movements. This is secured by irritation of the intestine 
(Kehrer, 1910), especially, by drastic cathartics and irritant volatile oils. These should 
therefore be avoided in pregnancy. They also have a reputation as abortifacients, but 
are highly dangerous. 

Central Action on the Uterus. These are relatively unimportant. The motor 
center in the lumbar cord is stimulated by anemia and asphyxia. 

GALL-BLADDER 

Lieb and McWhorter, 1915, found that this is augmented by vagus and inhibited 
by Sympathetic stimulation. Epinephrin therefore relaxes, whilst physostigmin and 
pilocarpin stimulate, and this stimulation is removed by atropin. It is also stimulated 
by strophanthin and barium; relaxed by bile salts and nitrites. Okada, 1915, states 
that the normal rhythmic movements are greatly increased during digestion, and by 
the introduction of acid into the duodenum. 

URETER 

The movements and tone of the excised ureter are stimulated by the parasympathetic 
stimulants and paralyzed by atropin; they are also stimulated by epinephrin. Ergo- 



272 MANUAL OF PHARMACOLOGY 

toxin reverses the epinephrin stimulation, but has no effect on the parasympathetic 
stimulants. Nicotin produces an initial stimulation and subsequent paralysis. Papav- 
erin relaxes the tone, without inhibiting the peristalsis (Macht, 1916). 

THE NATURE OF ANTAGONISM 

Until there is a clearer understanding of the chemical and physical changes which 
condition the actions of the antagonistic poisons, we can conceive the nature of their 
antagonism only in terms of crude analogies: 

1 . We may suppose that the stimulant and depressant drugs each act upon different 
chemic constituents. In this case, the combined effect would be a simple summation 
of their separate actions. This might be the explanation of the action of atropin and 
physostigmin on the oculomotor junction. 

2. Both poisons may act upon the same constituent. In this case the end result 
would depend upon the relative affinity of the two poisons for this constituent. This 
offers several possibilities. 

(o) The two drugs may have approximately the same affinity in this case the end 
effect would depend purely upon the relative quantity. 

(b) One drug may have a much greater affinity than the other; this might apply, 
for instance, in the case of atropin and pilocarpin on the pupil, where a small quantity 
of atropin suffices to abolish the effects of a large quantity of pilocarpin; whilst a large 
quantity of pilocarpin is needed to overcome even a trace of atropin. The case may be 
somewhat analogous to the combination of oxygen and carbon monoxid with hemo- 
globin. 

(c) The efficiency of the one may be so much greater than that of the other, that the 
antagonism is practically irreversible. Atropin, f.i., completely prevents the action 
of physostigmin on the uterus. 

3. One poison might influence the penetration of another, and in this way alter its 
distribution, and thus again entirely change its point of attack. This has been shown by 
Ehrlich for certain dyes; and similar conditions have been shown to prevail for mus- 
carin and atropin, by Straub; and for morphin and chloroform by Fuehner. 

With these possibilities in mind and remembering that they are based 
merely on crude analogies, it is clear, at least, that antagonism is a highly 
complex subject. We must be content, for the present, with the empiric 
facts: That the point of attack of the poisons is not absolutely specific: 
that it may shift according to conditions, dose, time of action, etc.; that 
the effect of the same drug on different structures, and even on the same 
structure, may be aug'mentory or inhibitory, or both; that a poison may 
present mutual antagonism to two poisons which act on different structures; 
that the antagonistic dose may be much smaller than the minimal effec- 
tive dose under ordinary conditions; that the removal of a drug (pilo- 
carpin) stimulation by a depressant (atropin) need not be accompanied 
by paralysis to electric stimulation, whilst in other cases they go hand in 
hand. The schematic presentation which has been given may serve as 
the thread of Ariadne through this labyrinth; but after all, it is still more 
important to grasp the individual facts which have a practical application. 

Quantitative Antagonism of Atropin and Pilocarpin Salivary Secretion. This has 
been investigated by Cushny, 1915, on dogs with salivary fistulas. It was found that 
the antagonistic dose was the same for different dogs. The ratio also remained the 
same (about i part of atropin to 9.5 of pilocarpin) whether the two drugs were injected 
simultaneously~or some time apart; and that it remained unaltered whatever total dose 
was injected. This agrees with the laws of mass action, rather than with those of 
chemical combination. 

Relation of Action to Intracellular Penetration, Storage, and Destruction. Ac- 
cording to W. Straub, 1907, the effect of most alkaloids is proportional to their 
concentration within the cell. With muscarin, however, he found the relation quite 
different: Here the effect appears to depend upon the concentration outside the cell; or 
rather, on there being a higher concentration outside than inside the cell. 

The experiments were made by placing the frog's heart into a muscarin solution. 
The quantity of poison remaining in solution, and the quantity which could be extracted 



PERIPHERAL AUTONOMIC SYSTEM 273 

from the heart were then tested on aplysia-hearts. Hearts laid in a muscarin solution 
show a primary diastolic standstill, followed by spontaneous recovery in a few hours. 
The maximal diastolic action occurs when very little muscarin has passed into the 
muscle; whilst at the time of "recovery," all the muscarin has passed into the heart. 
If now the recovered heart is placed into a fresh muscarin solution, it is again arrested, 
with spontaneous recovery. This may be done repeatedly; but the action becomes 
shorter and shorter, and finally nil. That is, the heart becomes completely refractory 
to even the highest concentrations of muscarin. If the muscarin concentration is 
increased very slowly, the heart does not respond. The presence of atropin appears 
to delay the penetrat