home000A - "Essentials of Pharmacology" by Oldham, Kelsey, and Geiling (book, 1947)

"Essentials of Pharmacology" by Oldham, Kelsey, and Geiling

(book, 1947)

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Written by : Frances Kelsey, Dr. Fremont Ellis Kelsey (born 1912) Geiling

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• ,,ES1S1 ENTIALS OFPH:ARMACO LOG'Y...l.•sentials OfarBY•FRANCES K. OLDHAM, M.Sc., PH.DRe1earch A.Jso,iaJe i,1 Pharmarology \,The Univ1r1ilyo f Chi,4goANDF. E. KEISEY, PH.D.A11oria1P1 rofe1soro f PharmarologyThe Un1v1r1itoyf Chi,dgoANDE. J\f. K. GEILING, PH.D., M.O.Frank P. Hixo11 DiJli"guished Servi re Prof e11or andCl1airr,1aonf lht Deparl"1e11oJf Pharma,ology 'The University of Chicago•Philadelphia London Montreal 1•J.B. LIPPINCOTT COMPANY•COPYRIGHT, 1947J. B, LIPPINCO'IT COMPANYTHIS BOOK lS FULLY PROTECTED BY COPYll?GHTAND WITJl TllE EXCEPTION OF BRIEF E.XCl:RPTS FOR.REVJtW NO PART OF rt ).(AY BE REPRODUCED INANY FORP.{ .wrrl{OUT Wll.llTEN PERMISSION Fll.Ol{THE PUBLISHERS,•PRINTED IN THE UNITED STATES OF AMERICA•I• • • •I ..'~~"'°1"'°1~.,q;icQlMQMQ'IC.C~~ll:,Oi.qi,cQl~~MQMQ~'-.Q'-.Q"AQ'I'-... "\ ' ,, . ,,., I ••~• ' ' -.I. ~ 4.,_, .1 ... ·, ' .... #,,• ) ' .... ...... , ----·~ ... ~ , ..I\ ' ,... f, 'I "--- ~ ";' ,• ' 1 Preface .v. J ..I ::ur ---:;\~. J ·... ,' "i (.J • 'I .,- , I ·~·- ,.. - ,"-..'"'"' ,..---~,JI•"'This book is intended to serve as an introducto'"rytext inpharmacology. 1\Iuch of the detailed documentary materialnecessary for the more advanced student or the research,vorker has been omitted, and scant mention has been madeof such drugs as nicotine, strychnine and muscarine, whichare of considerable importance from the viewpoint of pharmacodynamicsbut are little used in present-day medicine.On the other hand, the general principles of pharmacologyhave been stressed wherever possible, and efforts have beenmade to indicate what appear to be the coming trends • •in the field.The first course in pharmacology in medical schools is usuallygiven after preparation of the student in anatomy, bacteriology,biochemistry, physiology and pathology. Experi~mental pharmacology draws freely on all these sciences for itsmaterials and methods, turning to the clinical sciences forhelp in those researches requiring the use of human subjects.Pharmacology has also built a place for itself in otherprofessional fields such as dentistry, nursing, pharmacy andveterinary medicine. Futthermore, popular knowledge ofthis science is becoming more and more widespread as theresul~ of such dramatic advances as insulin;- the ''sulfa''drugs, penicillin and the new antimalarial agents.At the end of each chapter, there. is a list of importantpreparations of the drugs discussed and a fairly extensivebibliography. The preparations are compiled from the Pha;~macopoeia of the United States, Thirteenth Revision, 1947;from the British Pharmacopoeia, 1932, including AddendaI-VII; and from New and Nonofficial Remedies, 1947. Wehave followed the U.S.P. XIII usages of English names fordrugs and the metric system for dosag~. For practical pur-V•I• VI 'poses, the references have been largely limited to recentarticles, written in English and published in readily availablejournals.We are grateful to a number of colleagues who have readand offered criticisms of various chapters. In particular weare indebted to Dr. M. E. Davis of the Department of Obstetricsand Gynecology, to Dr. J. G. Allen, Dr. A. S. Alving,Dr. E. B. Bay, Dr. A. T. Kenyon, Dr. C. P. Miller, Dr. \V. L. ,Palmer, Dr. H. T. Ricketts, Dr. S. Rothman and Dr. C. L.Spurr of the Department of l\.Iedicine and Dr. ,v. H. Talia•ferro of the Department of Bacteriology and Parasitologyof the University of Chicago; to Dr. J. J. Jacoby of the Departmentof Surgery of Ohio State University and Dr. F. F.Snyder of the Department of Obstetrics and Gynecology ofHarvard Medical School. \Ve are also indebted to our assocl• •ates in the Department of Pharmacology, Dr. J.M. Coon, Dr.K. P. Dubois and Dr. J. R. do Valle, Guggenheim Fellow inPharmacology and Proressor of Pharmacology at Sao PauloUniversity, Brazil, for many constructive suggestions. \Vealso wish cto acknowledge the invaluab1e assistance of l\fr.Wallace Tourtellotte, Research Assistant in Pharmacology.TUE AUTHORS••1.2.3.4 .•,.•• I •ContentsSection OneGENERAL PRINCIPLES..Historical Development of PharmacologyGeneral Principles of Pharmacology • •Sources of Drugs • • • • • • •Drug Metabolism • • • • • • •l\Iechanism of Action . • • • • •Detennination of Toxicity . - • • •Control and Dispensing of Drugs • • •Introduction . • • • • • • .. •••••••••Pharmacopoeias and Other References .• Laws and Regulatory Agencies . • •Drug Assay • • • • • • • • • •Prescription Writing . • • • • • •Administration of Drugs • • • • • • •Introduction . • • • • • • • • •Oral Administration' • • • • • • •Rectal Administration • • • • • •Parenteral Administration • • • • •Inhalation • • • • • • • .. .. •Local Application • • • • • • • • , ._Section Two 'FUNCTIONAL DRUGS\•• • 1• • 8• • 8• • 9• • 11• • 13• • 16• • 16• • 16• • 18• • 20• • 23• • 2S• • 2S• • • 26• • 28• • , 28.. • 31• • 31•5. General Anesthesia . . . . . ~ . . . . . 36Introduction . . . . . . . . . . . . 36' ,-,'• '' , ,,, • •j ••' .I l •Vl•l•l• Contents •General Anesthesia (continued)Inhalation Anesthesia . . . . . . . . . 39Intravenous Anesthesia . . . . . . . . 48Rectal Anesthesia . . . . . . . . . . SOCurare . . . .. . . . . . . . . . . . 50Oxygen Therapy . . . . . . . . . . 52Preparations . . . . . . . . . . . . 546. Regional Anesthesia . . . . . . . . . . . S 7Introduction . . . . . . . . , . . . 57Topical Anesthesia . . . . . . . . . . 58Injection Anesthesia . . . . . . . . . 58 •Regional Anesthetic Agents. . . . . . . 61Refrigeration Anesthesia . . . . . . . 68Preparations . . . . . . . . . . . . 687. Hypnotics and Sedatives . . . . . . . . . 71Introduction . . . . . . . . . . . . 71Barbiturates . . . . . . . ., . . . . 72Chloral Hydrate . . . . . . . . . . 'JSParaldehyde . . . . . . . . . . . . 76Sulf onal . . . . . . . . . . . . . 7 7Bromides . . . . . . . . . ✓• • • • 77• Antiepileptic Drugs . . . . . . . • . 78Preparations . . . . . . . . . . • • 828. Antipyretic Analgesics . . . . . . . . . • 86Introduction . . . . . . . . . • • • 86Salicylates . . . . . . . . . • • • 87Antipyrine and Aminopyrine . . . • • • 90Acetanilid and Acetophenetidin ~. • • • • 9lCincophen and Neocincophen • • • • • • 9ZPrepara li•o ns . . . . . . . • • • • • 949. Morphine ~d Alli•e d Drugs . . • • • • • • 97 _,Morphine .. . . . . . • • ., • • • • 97Morphine Derivatives . . . • • ~. • • tOS. .lsonipecaine :. . . . . : -~#' 'r ,. , • 101Methadon . . . . . . . . ~ , • l •Preparatio• ns • • • • • • • , l••I • Contents lX'10. Central Nervous System Stimulants • • • • • 113Introduction . ~ • • • • • • • • ♦ • • 113• Strychnine • • • • • • • • • • • • 113Picrotoxin . • • • • • • • • • • • • 114'l\fetrazol • • • • • • • • • • • • • 116Nikethamide . • • • • • • • • • • • 117Caffeine • • • • • • • • • • • • • 118Amphetamine and Related Compounds . • • 119l\liscellanrous Preparations . • • • • • • 121• Preparations . • • • • • •• 121 • • • • •11. Autonomic Drugs . • • • • • • • • • • • 125.,Introduction . • • • • • • • • • • • 125Sympathomimetic Drugs • • • • • • • 128Sympatholytic Drugs . • • • • • • • • 135Preparations . • • • • • • • • • • • 1.3612. Autonomic Drugs . • • • • • • • • • • • 139Parasympathomimetic Drugs 139 •• • • • • •Parasympatholytic Drugs • • • • • • • 148Preparations . • • • • • • • • • • • 15213. Histamine and Antihistamine Drugs • • • • • 156Introduction . • • • • • • • • • • • 156Histamine • • • • • • • • • • • • 1S6Antergan and Neoantergan. • • • • • • 158Diphenhydramine and Tripelennamine . • • 160Preparations . • • • • • • • • • • • 16114. Heart Drugs . . . . . . . . . . . . . 163Introd11ction . . . . . . . . . . . . 163Digitalis and Related Preparations . . . . 163 •Quinidine . . . . . . . . . . . . . 169Xanthine Derivatives . . . . . . . . . 170 •Nitrites a.pd Organic Nitrates . . . . . . 171 .' Papaverine . . . . . . . . . . . . 172Drug Therapy of Hypertension . . . . . 173Preparations . . . . . . . . . . . . 1 7 4..'Contents1S. Diuretics. • • • • • • • • • • • • • • 181Introduction . • • • • • • • • • • • 181Crystalloid Diuretics . • • • • • • • • 182Xanthine Diuretics • • • • • • • • • 183Mercurial Diuretics • • • • • • • • • 184•Preparations . • • • .. • • • • • • • 18616. Blood, BJood Derivatives and Blood Substitutes . 189Introduction . . , . . , . . . . . . 189,Vhole Blood . . . . . . . . . . . . 189 'Blood Derivatives . . . . . . . . . . 191Blood Substitutes . . . . . . . . . . 193Preparations . . . . . . . . . . . . 19 5•17. Drugs Affecting the Blood and the Blood.FormingOrgans • • • • • • • • • • • • • • • 199Introduction • • • • • • • • • • • • 199Iron Preparations • • • • • • • • • • 200Liver and Stomach Extracts . • • • • • • 200Pteroylglutamic Acid ("Folic Acid") • • • 202Radiation Therapy . • • • • • • • • • 204Radioactive Phosphorus . • • • • • • • 204Nitrogen Mustards • • • • • • • • • 206Phenylhydrazine • • • • • • • • • • 207Arsenic. • • • • • • • • • • • • • 207Urethane • • • • • • • • • • • • • 208Anticoagulants • • • • • • • • • • • 208✓ Coagulants • • • • • • • • • • • • 210Preparatio• ns • 211 • • • • • • • • • • •18. Drugs Affecting the Gastr<rlntestinal Tract. • • 218Introduction • • • • • • • • • • • • 218Antacids • • • • • • • • • • • • • 218Choleretics • • • • • • • • • • • • 220Cathartics . • • • • • • • • • • • • 220Antidiarrheal Agents • • • • • • • • • 223•••• • Contents 'XIDrugs Affecting the Gastro-Intestinal Tract (continued)11iscellaneous Preparations . • • • .. • 223Preparations . . . . . . . . • . . • 22S•19. Oxytocics . . . . . . . . . • . • . • 233>Introduction . . . . . . . . . . . . 233Ergot . . . . . . . . . . . . . • 234Posterior Pituitary . . . . . . . . . . 23 7Quinine . . . . . . . . . . . . , 239l\1iscellaneousO xytocics . . . . . . • 239Abortifacients . . . . . . . . . . . 240Preparations . . . . . . . . . . • • 24120. Endocrins . . . . . . . . . . . . . . 244Anterior-Pituitary Hormones . . . . . • 245Gonadotropins . . . . . . . . . . • 24 7Sex Hormones . . . . . . . . . . • 249Adrenal Cortex . . . . . . . . . . • 2S5Preparations . . . . . . . . . . : . 2 S 721. Endocrins (Continued) . . ,. . . . . . . . 261Posterior Pituitary . . . . . .. . . . . 261Insulin . . . . . . . . . . . . . . 265Thyroid . . . . . . . . . . . . . 270Parathyroids . . , . . . . . . . . . 274Lipocaic . . . . . . . . . . . . . 276Thymus . . ... . . . . . . . . . . 277: ,, heparations . . . . . . . . . . . . 27722. Vitamins . . . . . . . . . • . . . . . 281Vitamin A . . . . . . . . . . . . . 284 'Vitamin B-Complex . . . . . . . . . 285Vitamin C . . . . . . . . . . . . . 290Vitamin D . . . . . . . . . • . . . . 291Vitamin E . . . . . . . . . . . . . 293Vitamin P . . . . . . . . . . . . . 294Vitagens l '. • • • • • • • • • • • • 295Preparations . . . . . . . . . . . . 296••,-'Xl•l•23.••' lContentsDiagnostic Agents • • • •Phthalein Derivatives. •Phtbaleins . • • • • •Radio-Opaque SubstancesBiological Products • •Preparations . • • • •'• • • • • • • • 303• • • • • • • 303• • • • • • • 304• • • • • • • 306 •• • • • • • • 309• • • • • • • 309===--~-=-=-----'=-==============24.25.~Section ThreeCHEMOTHERAPEUTIC AGENTS'Local Anti-Infectives • • • • • • • •Introduction • • • • • • • • • •Acridine Derivatives • • • • • • •Mercury and Silver Preparations . • •Halogens • • • • • • • • • • •Peroxides • • • • • • • • • • •Alcohols • • • • • • • • • • •Phenols. ~• • • • • • • • • • •Acids • • • • • • • • • • • •Detergents • • • • • • • • • •Nitrofurazone • • • • • • • • •Preparations . • • • • • • • • •Intestinal Anthelmintics • • • • • • •Introduction • • • • • • • • • •Carbon Tetrachloride and Tetrachloroethylene• • • • • • • •Hexylresorcinol . • • • • • • • •Oil of Chenopodium • • • • • • •Santonin • • • • • • • • • • •Thymol • • • • • • • • • • •Betanaphthol • • • • • • • • •Methlrosaniline Chloride • • • • •Aspidium . . • • • • • • • • •Miscellaneous Agents , • • • • • •Preparatio• ns . • • • • • • • • •• • 313• • 313• • 315• • 317• • 319• • 319• • 320• • 320• • 321• • 322• • 322• • 323• • 327• • 327• • 329• • 330• • 331• • 331• • 332• • 332• • 333• • 333• • 333• • 336 ,,,•I •••Contents Xlll6. Amebacides . . . . . . . . • . . • . • 338Introduction . . . . . . . . . . . . 338Emetine . . . . . . . . . . . . . 339Iodoquinoline Derivatives . . . . . . • 341. Arsenicals . . . . . . . . . . . . • 342Preparations . . . . . . . . . • • . 343:7. Antisyphilitic Drugs . . . . . . . . . . . 345Introduction . . . . . . . . . . . . 345Arsphenamines . . . . . . . . . . . 346Arsenoxide5 . . . . . . . . . . . . 35 l1fiscellaneous Agents . . . . . . . . . 353Preparations . . . . . . . . . . . . 3 S 5'ZS. Antimalarial Drugs . . . . . . . . . . . 358Introduction . ,. . . . . . . . . . . 358Quinine . . . . . . . . . . . . . 3 60 ~Quinacrine . . . . . . . . . . . . 363Chloroquine . . . . . . . . . . . . 365Paludrine . . . . . . . . . . . . . 365Pamaquine . . . . . . . . . 1• • • 366Pentaquine . . . . . . . . . . . . 367Preparations . . . . . . . . . . . . 36829. Sulfonamides . . • • • • •Introduction . . . .Sulf athiazole . . . .• •• •• • . . . . \ 371. . . 371. . . . 3 77• • •• •,Sulf adiazi11e . . . . . . . . . . . . 3 79Miscellaneous Sulfonamides . . . . . . 380 ,Preparations . . . . . . . . . . . . 384 '30. Antibiotics • • • • • • • • • • • • • • 387Introduction • • • • • • • • • • • • 387Penicillin • • • • • • ~ • • • • • • • 390Streptomycin . • • • • • • • • • ' • • 396Tyrothricin • • • • • • • • • • • • 397Bacitracin . • • • • • • .. • • • • • 398l .••\•Xl•V' -ContentsAntibiotics (continued)Miscellaneous Antibiotics . . . .' . . • 398Preparations . . . . . . . . . . . . 39931. ?\fiscellaneous Chemotherapeutic Agents. . . . 403Antimony Compounds . . . . . . . . 403Gold Compounds . . . . . . . . . • 404Melarsen Oxide . . . . . . . . . . . 405Surrunin . . . . . . . . . . . . . 405Cyanine Dyes . . . : . . . . . . . 405Diamidines . . . . . . . . . .. . . 406Para-Aminobenzoic Acid . . . . . . . . 407Chaulmoogra Oil . . . . . . . . . . 407Sulf ones . . . . . . . . . . . . . 408 IMandelic Acid and f\.fe thenamine . . . . \ . 409Vaccines and Sera . . . . . . . . . . 409Preparations . . . . . . . . . . . . 410'I••IHistorical Development ofPharmacologyPharmacology is a compound word derived from theGreek terms pharmakon meaning medicine or drug andlogos, a discourse or study. The science of pharmacologyhas been defined by Schmir.deberg as "an experimentalscience which has for its purpose the study of changesbrought about in living organisms by chemically actingsubstances (with the exception of foods) whether usedfor therapeutic purposes or not.'•1 Modern experimental pharmacology is one of our newestdisciplines, as far as university organization is concerned,yet it had its beginnings in antiquity. Ever since man'sadvent on earth, one of his main concerns has been thealleviation of pain and suffering, consequently, each succeedingperiod of history has had its own system of healingbased, in part at leastt on the scientific concepts of the"'time. Early man sought a reason for pain and for diseaseprocesses; he ascribed them to the presence of evil spiritsor consid~red them as punishments from the gods for wrongshe had done. The first remedies, accordingly, were intendedto drive away the evil spirit or to punish the individual forwrongs done and were chosen for their disagreeable tasteor odor. '-... ' •In ancient times, as today, much suffering and diseaseran their course or came to spontaneous remission regardlessof the therapy used. Such recoveries gave an apparentvalidity to many remedies that were . actually worthless. •1J••2 Historical Development of PharmacologyOn the other hand, some substances employed by fortuitot13 .circumstances were of specific value in certain diseasesand are part of our armamentarium today. Among the mul•titudinous recipes listed in Eber's papyrus, an Egyptianrecord of 15S0 B.C., are such drugs as castor oil, colchicumand opium, which are still in use. .In the Egyptian period and even in the early Greek ·pe-, riod, medicine was a part of religion and philosophy. Theconcept of disease as a pathologic process going on withinthe body, rather than as a visitation from the gods, wasformulated for the first ti.me by Hippocrates (460-370 B.C.)and marks the beginnings of scientific medicine. Accurateobservation of the course of iJJness made it possible to classifyand appraise the use of drugs. Unfortunately, the scientificprinciples of Hippocrates were not to be fully carriedout until the dawn of the Renaissance many centuries later.\Vith the decline of Greek culture, the quest for freshknowledge ,vas forgotten. Although medicine among theearly Romans was an honored and important field, underthe influence of Galen (A.D. 131·201) it degenerated intoa dogmatic system of polypharmacy. Instead of furthering•....ob5ervation and analysis of actual processes, Galen soughtthe answer to medical problems in pure theory. Throughoutthe late Roman and medieval periods, Gale.n's theorieswere accepted and medical progress ceased.,. \Vith the Renaissance, however, the Hippocratic spiritwas revived. Free thought and critical inquiry led Paracelsus(1493-1541) to attack the Galenic system of po)ypharmacy.He introduced simplicity in prescription writingand recommended the use of chemical substances ratherthan the mixed vegetable preparations of Galen:-The treat~ment of syphilis with mercurials was inaugurated by Paracelsus.The first official pharmacopoeia was printed in Flor.ence in 1497. . . . .The revolt against Galen1c med1c1ne did not, howe,.,erlead at once to the establishment of truly Hippocratic in~..•Historical Development of Pharmacology 3quiry. Freedom of _thought and individual scientific efforthad, by the seventeenth century, led to a curious anomaly.\Vhile medical science was progressing, popular medicinewas retrogressing. The same century that saw the use' of~ the royal touch to cu,r,e the kin.g's evil, ·a'nd the exp!oitationof many useless remedies also sa,v H[arvey's 1CP10cha'I observationof the circ:uJa,tiono f the blood and l\Ialpighi's in•troduction of microscopic anatomy and the beginnings o(animal experimentati'o 1n ..These discoveriesi[' n the! field of scie:n'lificm 1ediclne, togetherwith the beginnings of modern chemistry and physics,formedt he f erme·n•to ut, of which ,vas t,o com1e modern ex-perimentalpharmacology. Throughout the eighteenth cen•tuty men of science endeavo1edt o classi'yf :and to correlatethe new knowledge; it became the age of theories and sys.tems. The0phi1e de Bordeu enunciated a theory of endo•crine secretions, poistulalinglt hat each or,gan ,serves as afactory ior its specifi,ch: untor, which is abso,rb1ed into thebloods tream an[dc arried,t o distant orga,ns\. Villiam \Vith4Vering introduced digjt:ilis, after identifying it :as the activeingredient in a recipe obtained from an old woman of 'Shropshire, thu,s esitablisbing th,e rationale f10r ,another bit -of successful folk-medi,cin,e.The organized advance.men.ot f mode·rn ph;armacalogybegan with the nineteenth century~ \Vith the developmentof organic chemistry,, isolation and identilication of theactive princip1les 01f1 crude drugs becam1e,p o,ssible,a ll!ongthe earliest being the isolation of morphin 1e by Serttirner• 1n 1804. Physiolo1g1ic problems could now fo'r the first timebe approached fr1om the .standpoint of 1chemistry andphysics, an appr,oach which marked th1e end of vitalism ..U. nderstanding of the transmission of infection and of thellacteriologic nature of many diseases op1e,ne 1d new fields1 for therapeutics. T1he introduction of aniesthesirale 1dt o greatand rapid progr,ess, in, the clinical and experimental fields~Up to 1850, the French were leaders in sc:ientific medical....BERLIN
[...]
y...,.., Utrecht New YOtl. tlbcrlcld GlNpW ~ SwH•o 1"\ Iloo,>t.t tW!e. ~Forty Chairs of Pharmacologyh ave been held by pupil! ()f Oswald Schmiedebcrgi n many different countries. Thoseamed above have been chosen to illustr.ate lbe inlfm.ational character of the school developed by him. A more completest is given in his "Festschri!t" volume of the Archiv. f. l'at.h. u. Pharmakol., 1908, supplementary volume,•-,::,..-.~. .. I.J.>. ...0. ., n- ·S-l) t1 (1) < n-, .g8 n,;,~0- i ..,B EU8- 0• ·~ I'-•. 'Historical Development of Pharmacology 5progress. Fran~ois itagendie studied the action of strychnineon dogs and made the first clear-cut scientific observationof the action of drugs on anin1als. Claude Bernard, investigated carbon-monoxide poisoning and explained themechanism of its action. Caventou and Pelletier, pharmacistsand skilled chemists, isolated as chemical entities suchimportant alkaloids as strychnine, veratrine, brucinc andquinine. The importance of toxicology as a branch of researchwas developed by Orfila, a Spaniard living in France.-ln the second half of the nineteenth century, the centerof activity shifted to Germany with its two importantschoots of physiology-Johannes l\Iiiller's at Berlin andErnst \Veber's at Leipzig. Carl Binz;- a pupil of l!iiller,became famous for his lectures on pharmacology and hisfundamental work on cyanide poisoning and on quinine.Rudolph Buchheim, a pupil of \Veber, established in thebase!_I'lenot f his home the first laboratory of experimentalp~armaoology. His work so impressed the university au.thorities that he was invited to establish the first chair •of pharmacology 'at, the University of Dorpat in 1849,with adequate laboratory space in the Anatomical In•st•1 tute.Oswald Schmiedeberg was a pupil of both Buchheimand the well-known physiologist Carl Ludwig. Schmiedeberg,a man of robust constitution and indefatigable energy,who attracted students from all over the world is regardedas the founder of modern pharmacology.The first full~time university professorship of pharma.cology in the United States was created in 1890 at theUniversity of Michiga.n and was held by John J. Abel.~Victor G. Vaughan, the dean at the medical school at AnnArbor, chose Abel to fill this position on the recommenda-• • t1on of Schmiedeberg. Vaughan, in his book "A Doctor'siiemories,"* tells the story of how Abel came to Michigan:• Bobbs.l\1errlll Company, New York, 1926.6 Historical Development of Pharmacology- "\Vhen in 1890 we decided to have a real chair of pharma ..co logy with laboratory instruction, I wrote to ProfessorOswald Schmiedeberg, the dean of that science.at that timein Strasbourg. He replied at length and advised me not totake a German, since he thought it a doubtful procedure toinstall a foreigner into a professorship. He said that he hadin his laboratory two Americans, but that one of them wasmore German than American, and he recommended theother. Besides, he said that the man he was recommendingwas not on}y an American but a graduate of l\1ichigan Uni~ ,versity. In this way John J. Abel became our first professorof pharmacology, as a real science." Thereafter in 'rapidsuccession, departments of pharmacology were estabJishedin many other universities in the United States.Prior to Dr. Abel's appointment, materia medica andtherapeutics were taught in thi.s country by physiciansengaged in private practice. Abel introduced Scbmiedeberg'steaching methods, by lectures, demonstrations and discussionsin pharmacology and by devoting considerable timeto research. He further advanced the teaching of pharmacologyby the inauguration of student experiments and byinsisting on preliminary instruction in related departmentsin order that students would have a better backgroundfor their studies in pharmacology.Early workers in the field of experimental pharmacologywere limited to observation of responses to the action ofdrugs by living animals or by isolated organs and tissues., These methods remain Qf great importance in modern~,pharmacology for such procedures as biologic assay, thescreening of new chemical compounds for their toxicityand possible therapeutic value and the isolation of pharma-~ cologically active agents as chemical entities. In addition,technologic advances in the fundamental sciences have madeossib1e more basic approaches through studies of enzy.p t'c reactions whicb collectively make up the living cell:0~1the enhancement or inhibition of these reactions by- I I•Historical Development of Pharmacology 7physical or chemical means. Such studies into the mechanismof drug action require, for example, the use of biochemicalprocedures for measurements of enzyme activityand the effects of drugs on the economy of the body;. methods of physical chemistry are used for studies on dialysis,adsorption and diffusion of drugs; analytic and or•ganic chemistry contribute methods {or the analysis ofbiologic materials for drugs and drug metabolites; andfinally nuclear physics has recently provided the very usefulprocedures of isotope-tracer technics ,vhereby the me•tabolism of a drug can be follo,ved th:---··-1.... ... :. ._ ,:t- =-the body.'I\ -•2•General Principles ofI PharmacologySOURCES OF DRUGSDRUO METABOLISMMECHANISM OF ACTIONDETERMINATION OP' TOXICITYSOURCES OF DRUGSThe discovery of the pharmacologic action or therapeuticusefulness of a substance can be made in several ways.The activity of most of the older drugs in our therapeuticarmamentarium was found by pure chance. For the mostpart, the crude plant extracts formerly making up themajority of drug preparations have been subjected to study,and pure crystalline preparations have been obtained. Asthe composition of these purified substances is determined,new compounds with minor modifications in structure canbe synthetized with a view to obtaining even better thera•peutic agents.Another approach is by the system introduced and practicedso successfully by the Germans of trying a large numberof chemicals in a screening test designed to uncover agiven •pharmacologic activity. This procedure is responsiblefor the discovery of such widely used drugs as quinacrine,the sulfonamides and the arsenicals.A third procedure is to undertake a deliberate methodicalsearch for a medicinal use for a give'? prep~ration. However,the types of possible phar~colog1~ .action _are so varied,d the tecbnics for determ.1rung act1v1ty so time-consuming::d expensive, that few substances indeed have received0 •• •\ •Drug Metabolism 9corμplete evaluation. The literature is replete with instancesin ,vhich immensely valuable compounds were well knownfor years before their pharmacologic action was discovered.The development of a theoretical background for pharmacologyhas now reached the point where it is possibleat times to relate chemical structure to pharmacologic action ,and to predict with some success the activity of newly syn•thesized compounds. Certain series of compounds, notablythe barbiturates, the local anesthetics and the sulfonamides,have been so thoroughly investigated that reasonably accu.rate predictions of the activity of a closely related analoguecan be made from a consideration of its chemical structure.Even under the best of conditions, however, extensive animalexperimentation is required before a drug can receive evenlimited trial in man.DRUG METABOLISMMany of the quantitative and some of the qualitativedifferences in the pharmacologic action of two closelyrelated drugs are due to differences in their metabolism in ,the body. Absorption, distribution in the various tissuesand fluids of the body, persistence in the body1 inactivationby adsorption, activation or inactivation by enzymaticchange, and the rate and route of excretion are all factorswhich must be considered in the evaluation of any given- drug. Such properties as diffusibility, solubility and d~greeof ionization of a drug may have a profound influence indetermining the penetration or fixation of the drug by thecell, which, in turn, determines the efficiency with which itexerts its action. ,Absorption. The factors controlling the rate and theextent of absorption of drugs are poorly understpod. Solubil.i ty in water or in lipids is often but not always the deter- ,m1nant. The absorption of a drug may be strikingly differentin different species of animals. For this reason it is1';,..l,,l •• -l .... ,irable to use as many species as possible in study'•,,10 General Principles of Pharmacologying the absorption characteristics of new compounds. Formost drugs there are one or more pref erred routes of admin•istration which give the desired intensity and duration ofthe response.Intermediary Metabolism. The variation in the rate ofthe intermediary metabolism of a given drug in differentspecies of animals may be even greater than the varia.tion in absorption. Furthermore, the intermediate or endproducts of metabolism may be quite different in differentanimals, thus accounting, at least in part, for the variableresponse. Hence, investigative pharmacology requires aknowledge of the enzyme systems which may be involvedin the metabolism of drugs.For a drug to be effective it must reach the site of its, action. The pattern of distribution of the drug in the tissuesmay vary from one species of animal to another. Pathologicor physiologic states may also effect the distribution andtherefore the efficacy of a drug. Furthermore, the metabolicchanges produced in a drug by the action of one ormore of the many enzymes in the body may either increaseor decrease its pharmacologic potency. Finally, a drug maybe noneffective if combined as an adsorption complex withsome normal constituent of the body such as serum or tissueproteins or bone.Excretion. The rate of excretion of a drug from the bodyis important in determining the duration of its effect. Inaddition, the route of excretion often affords a convenientway to obtain a therapeutically useful localized concentrationof the drug in the excretory channel. However, in somecases, toxicity may be partly dependent on the excretioncharacteristics of a given drug because of this concentration.Furthermore, pathologic changes in the excretory organ maymarkedly decrease tolerance to the drug. -Drug Tolerance: Accumulation and Sen~itization. Re~l)eated administration of a_ drug fr~q~ently !s accompaniedby either a decrease or an increase 1n 1ts action., A decrease,•1\-fechanism of Action • 11' is referred to as ''drug tolerance'' and may be due either toa change in the rate of metabolism of the drug or a changein the reactivity of the cell involved. An increase in response, is presumptive evidence that the rate of removal of the drugfrom the body (excretion plus detoxification} is less thanthe rate of administration, and is ca1led "the cumulativeeffect." This phenomenon is distinct from that of ''drugsensitization," which is characterized by the sudden appearanceof toxic symptoms. These syn1ptoms usually disappearpromptly when the drug is discontinued, but may reappearwith even very small doses.MECHANISl\I OF ACTIONDrugs may exert their effects on a physical basis, e.g., theaction of bismuth subcarbonate in coating the intestine toprevent irritation; or on a chemical basis, e.g., neutraliza- ,tion of gastric acidity by sodium bicarbonate. However~ themajority of drugs are pharmacologically active by virtueof an interference with some enzymatic process essential tothe normal economy of the affected cell. This inter! erencemay be either by an increase or by a decrease in the rate ofa metabolic reaction. Enzymatic reactions are readily in.fluenced by enzyme, substrate, and coenzyme concentrations,pH, temperature, and the presence of activators orinhibitors. Consequently, a drug affecting any of these£actors may elicit a pharmacologic response. For example,cocaine and ephedrine inhibit the destruction of sympathin,, by combining with the enzyme ami12e oxidase ,· hence, certainof the pharmacologic effects of these two drugs can 'be attributed to the action of sympathin. Similarly, theaction of physostigmine and the fluorophosphates is-thoughtto be due to an inactivation of clioline esterase by reversibleand irreversible combination respectively, resulting ina prolongation of the effects _of the acetylcholine liberatedat the nerve endings.Seve-ral chemotherapeutic agents have been shown to b~•12 General Principles of Pharmacology•ef!ective by virtue of a similarity to an essential metaboliteof the invading organism, with a resultant competitive inhi•bition of reactions in which that metabolite is concerned.For example, the action of sulf anilamide can be completelyneutralized by the presence of small additional amounts ofthe essential metabolite, para-aminobenzoic acid. Othersulfonamide drugs apparently interfere with the normalutilization of other metabolites as well, e.g., riboflavin,nicotinic acid and thiamine. Other examples of antagonismare desthiobiotin, ,vhich interferes with the utilization ofbiotin, pantoyltaurine with pantothenic .a. cid, 6,7-dichlororiboflavinwith riboflavin, and pyrithiamine with thiamine.The principle of biochemical antagonism has recentlybeen applied in the search for drugs other than chemotherapeuticagents. Examples of these include imidazoJe andderivatives which act as antihistamine substances, andpteroyltriglutamic acid, which interferes with pteroylglutamic-acid metabolism in tumor tissue.Certain other drugs exert their action by supplying anessential constituent of the cell. Examples of this type ofaction are the vitamins, hormones and the essential min:crals, amino acids and fatty acids. Synthetic compounds,vhich can substitute for the natural ones in metabolic reactionsare also included in this group, such as menadione,diethylstilbestrol and metacholine.Drug Combinations. Formerly it was the custom to usemedicines composed of a large number of supposedly activeingredients. This "polypharmacy" was perhaps inevitable,in the past, but now drug combinations are only prescribedwhen there are specific indications. Two or more drugswhen used together may have a synergistic or an antagonis~tic action. By synergistic action is meant the productionof an effect which is more intense or more prolonged thanwould be obtained with eit~er drug used a~one. This term• lso used' in a more limited way to des1gnate those in-s1tsa nac es in which the effect • h dd't' • 1S1more t an a 1 1ve, 1.e., the•• lDetermination of Toxicity 13Iresponse is greater than the algebraic summation of theeffects of the drugs ,vhen used alone. This latter definitionalso applies to the term potentiatio11S. ynergistic action canbe illustrated by the following drug combinations: mor.phine-scopolamine, procaine epinephrine, sulf adiazine-sulf amerazine,pentaquine--quinine. Antagonistic actions can beillustrated by the following pairs of drugs: pentobarbitalpicrotoxin,bromide-amphetamine, atropine-physostigmine,para-aminobenzoic acid-sulfonamide. Further details aregiv~n in the appropriate chapter of this text.• DETER1\1INATION OF TOXICITY...._, ,Before attempting therapeutic use of a new drug, or ofa new sample of a familiar drug of unkno,vn purity obtainedfrom natural or synthetic sources, it is necessary to knowits toxicity. This property of a drug is. usually expressedas "median lethal dose" or LD~0. It is the amount of drugper unit of body weight which, for a given species, will killhalf the animals when administered to a group. ,vhen adrug is given by inhalation, this property may be expressedas LCT50 , or the concentration of the drug in the inspiredair, times the duration of exposure, whicl1 will kill SO percent of a group of animals. The rate and duration of admin.istration and the species of animal used must be reportedalong with the numerical value obtained.1 Individuals from any strain, no matter ho\v carefully bred,may differ in their resistance to a drug. The various personalsusceptibilities or "individual lethal doses" are sodistributed in any population that their logarithms fall onthe normal bell-shaped frequeJ1cy or error curve. As a result,if varying doses of a drug are given to groups of animalsand the log dose is plotted against per cent mortality, thelatter on the "probability scaleu of special probability co.ordinate paper, the points fall roughly on a straight line.T~e intersection of this line with the SO per cent mortality'>rdinate gives the logarithm of LD50 •••,-... I•14 General Principles of PharmacologyOwing to the variation between individuals, it is necessaryto use a reasonably large number of animals in each group.Five groups of twenty or thirty animals should be sufficientfor determining the LDr;o of an unknown drt1g. The approximatetoxicity must, of course, be determined by preliminaryobservations on smaller groups and doses for the assay,so chosen that mortalities near O or 100 per cent are avoided.Analysis of the potential toxicity of a drug requires itsadministration in both short-term (acute) and long-term(chronic) experiments. Acute-toxicity experiments are ofconsiderable value in the rough "screening" of large numbersof ne,v, closely related drugs, in order to select themost promising one for the more elaborate and more costlychronic-toxicity studies. These latter are necessary becauseof the frequent cumulative action of drugs, and because ofthe possibility of a delayed toxic action, when histologicallyor functionally indetectable damage may result in a majorbreakdown of some organ or function long after the drughas been discontinued.BIBLIOGRAPHYBernheim, F.: The Interaction of Drugs and Cell Catalysts,Minneapolis, Burgess, 1946.Clark, A. J.: The Mode of Action of Drugs on Cells,Baltimore, Williams & Wilkins, 1935.Clark, A. J.: General Phar1nacology-Supplement IV toHeffter's Handbuch der experimentellen PharmakoJogie,Berlin, Springer, 1937.Gold' H.: 'Cornell Conferences on Therapy, New York J • , Macmillan, 1946.Green, D._: Currents in Biochemical Research, New York,Intersc1ence, 1946.Gunn, J. A.: Cellular immunity: congenita! and acquiredtolerance to nonprotein substances, Phys1ol. Rev. 3: 41,1923. . d . BHurst, H.: Biophysical factors 1n rug action, rit. ~f.Bull. 3: 132, 1945.•I•- Bibliography 15Sl1aw, F. H.: The approach to therapeutics through tl1emode of action of drugs on ceJJs: 1\-I. J. Australia 32:649, 1945.Smith, A.: Medical Research-A Symposium, Philadelphia,Lippincott, 1946.Woolley, D. W.: Recent advances in the study of biologicalcompetition betl>veen structurally related com~ounds, Physiol. Rev. 27: 308, 1947.VanWinkle, W., R. P. Her,vick, H. 0. Calvery andA. Smith: Laboratory and clinical appraisal of ne,v •drugs, J.A.l\f.A. 126: 958, 1944 .••3"Control and Dispensingof DrugsIINTRODUCTIONPH.Altlt:ACOPOEIAS, ETC.LAWS AND REGULATORYAGE:t{CIES'\DRUG ASSAYPRESCRIPTION WRITINGINTRODUCTION• The safe use of pharmacologic agents is a practical problemjnvolving the co-operat' ion of several groups of individ.uals. Because of this divided responsibility, certain generallyaccepted practices and official rules of procedure havebeen evolved. Before a new drug can be sold on the openmarket, it must be subjected to adequate experimentation,not only in regard to its activity and possible therapeutic. advantages but more particularly to its toxicity and potentialityfor producing more harm than good. In addition,the manufacture and distribution of all drugs must receivesome degree of public control in order to insure the reliabilityand uniformity of the final product. This chapterincludes a discussion of the official standards for drugs,the laws governing them and the agencies for enforcementof these laws, a consideration of the problems of drug assayand a short presentation of the essentials of prescriptionwriting.PHARMACOPOEIAS AND OTHER REFERENCESThe Pharmacopoeia of the United States of America(U.S.P.) was first published in 1820._ The thirteenth editionbecame official on April 1, 1947. Since the passage of the16• •..J•Pharmacopoeias and Other References 17Food and Drug Act of 1906, the Pharmacopoeia has beenrecognized in courts of law as being the ultimate standardof reference for those drugs that are listed in it. The mono~graph on each 'drug includes a description of its chemicaland physical properties; chemical or biologic tests for itsidentification, quality and purity, with stated limits of theamount of contamination with inactive or toxic substances;and the size of an average single dose for an adult. For •practical reasons, only those drugs are included that arc oftherapeutic usefulness or pharmaceutical necessity and thatare more or less widely used in medical practice within theUnited States or its possessions. Listing is restricted toactive principles rather than mixtures or complex prepara•tions. English names for drugs and the metric system fordosage are given preference over Latin names and theapothecaries' system. --..The National Formulary (N.F.) was first published in1888, 68 years after the appearance of the fifst edition ofthe U.S.P. It is currently in its eighth edition, which becameofficial on April 1, 1947. The N.F. is compiled by theAmerican Pharmaceutical Association and has as its purposethe function of serving as a "steppingstone" to andfrom the U.S.P. for those drugs which are not used widelyenough to be included in the U.S.P. but which neverthelessare in some demand in certain sections and especially ifthey are listed in foreign pharmacopoeias or have been listedin the U.S.P. Further.more, to increase the usefulness ofthe book, elixirs, fluidextracts, solutions, syrups, tinctures,pills, emulsions, mixtures and powders, and preparationsbelonging to the so-called ''elegant pharmacy'' are included.Originally, this compilation had no legal standing, but the'Foo? and Drug Act of 1906 and the Food, Drug and Cosme:1c Act of 1938 give both the National Formulary and theUnited States Pharmacopoeia the same official position .. The Bri:ish Pharmacopoeia (B.P.) was first published1" London 1n 1864. It is currently in its sixth edition (1932)\ •I ,•II18 Control and Dis' pensing of Drugs•,vith seven supplements covering changes in later years. Itis in statutory force in most parts of the British Empire.The United States Dispensatory (U.SD.) was first publishedin 1833. It is a privately owned, non'official compilationand includes all items in the U.S.P., the N.F., and theB;'P., as well as many nonofficial drugs less frequently used.At the time the U.S.D. was first published, the U.S.P. badbeen in existence for 13 years but had received almost noacceptance by the medical or pharmaceutic professions. Furthermore,the U.S.P. had at tha·t time no legal standing andthe U.S.D. was considered by far the more useful book, since• it contained information on many more drugs. It is now 1nits twenty-fourth edition. Somewhat comparable volumes arethe English !\.1artindale's Extra Pharmacopoeia and the GermanGehe's Codex.New and Nonofficial Remedies {N.N.R.) is an annualpublication of the Council on Pharmacy and Chemistry ofthe American Medical Association. The ''New and NonofficialRemedies" has no legal standing but items are sub•mitted to the Council for consideration and if their standardsare met, the item is "accepted.I'' Products and ac•cepted only so long as they conform to the standards ofthe Council both with reference to the quality of the productand the claims made for it in advertising by the manufacturer.No advertising in any of the American MedicalAssociation's journals is permitted for nonaccepted items.Accepted Dental Remedies (A.D.R.) is the publication,comparable to the N.N.R., compiled by the Council on Den•tal Therapeutics of the American Dental Association. Likethe N.N.R., it accepts items on condition of maintenanceof quality by the manufacturer and restriction of the advertisingmaterial to adequate and reasonable statements.LAWS AND REGULATORY AGENCIESPrior to the passage of the Virus, Serum and Toxih Actof 1902 and the Food and Drug Act of 1906, there \Vere,Laws and Regulatory Agencies 19practically no restrictions on the manufacture or sale ofmedicinal products in the United States. In 1906 the firstcomprehensive national food and drug law ,vas enacted byCongress. This law was superseded by the present Food,Drug and Cosmetic Act of 1938. This act prohibits themovement iQ. interstate commerce of adulterated and misbrandedfood, drugs, devices and cosmetics. It has been ofinestimable value in protecting the American public and hascontributed markedly to the improvement of the quality and• honest labeling of the nation's foods, drugs and cosmetics.The Food and Drug Adm1nistration is charged with theresponsibility of enforcing the provisions of the act. ThisFederal agency also enforces the Caustic Poison Act of1927, ,vhich safeguards the distribution and sale of certaindangerous caustic or corrosive acids, alkalies and othersubstances in interstate and foreign commerce. This actnames twelve materials which are classified as dangerous,'caustic or corrosive substances.The \Vheeler-Lea Act of 1938 is concerned mainly withthe prevention of unfair trade practices involving the useof misleading or extravagant claims in advertising and isadministered by the Federal Trade Commission, which cooperateswith the Food and Drug Administration.The United States Post Office has the power to prosecutefirms and individuals for- fraudulent use of the United States mails.The United States Public Health Service administers theVirus, Serum and Toxin Act of 1902. This act provides forthe maintenance of potency and purity of biologic products.Licensing power is vested in this agency.The Harrison Narcotic Law of 1914, with subsequentamendments, regulates the importation manufacture produ~t•1 on, compounding, sale, dispensing 'a nd giving aw'a y ofopium or coca leaves or any compounds or preparations.hereof. The l\1arihuana Act of 1937 regulates the impor~ation, manufacture, production, compounding, sale; deal20Control and Dispensing of Drugsing in, dispensing, prescribing, administering and givingaway of marihuana. Both of these acts are enforced bythe 'Bureau of Narcotics of the United States TreasuryDepartment.DRUG ASSAYThe determination of the relative purity of a drug samplehas a different purpose from the determination of the rela-' tive purity of ordinary chemicals. This purpose is boundup with the use to which the drug is put. Not only must itnot contain toxic contaminants, but it must possess the• therapeutic activity of the drug even in those instances 1nwhich nothing is known about the actual chemistry of theone or more compounds and the proportion of each whichmust be present in order for the drug to exert this therapeuticeffect.Synthetic Chemicals. For the most part, these drugs canbe identified with sufficient precisiory and specificity. However,occasionally the compound is of such a nature thathighly toxic substances may be formed during manufactureor storage. In such cases a simple test may be devised todetect such contaminants. For example, every package oftribromoetbanol solution (avertin) is accompanied by apparatusand chemicals to detect the presence of hydrobromicacid in the product. If this test is positive, the drug mustbe discarded since it is proof that sufficient decompositionhas occurred to make the use of the preparation undesirable.The complex nature of some synthetic drugs makes iteconomically unsound to insist on chemical purity, yet thepossible contaminants may be much more toxic than is permissible.Thus, in the case of the arspbenamines and arsenaxides,onJJr government Jjcensees may manuf.actu.re thedrugs, and all lots must go through the hands of theNational Institute of Health, where the toxicity is assayedon rats and the "expiration date" {the date beyond whichthe contents cannot be expected, beY.ond reasonable doubt,to retain stability) clearly printed on the package ••'', DrugAss:i.y 21Drugs of Plant or Animal Origin. If the active componentsof the crude drug have been isolated and identified,the problem of assay is usually relatively simple. If they'have not been identified, ho1,vever, or if chemical-assay •procedures are impractical, recourse must be had to biologicassay (bioassay), in ,vhich the drug sample is comparedquantitatively :with a standardized preparation of the same• drug with regard to a particular pharmacologic effect. Thestrength or activity of the standard preparation is generally'fixed by agreement among workers or by law. In a fewcases, such as parathyroid hormone and antipernicious ..anemia preparations, standard preparations are not avail ..able and the strength is determined by the amount of mate .. ~rial required to elicit a certain pharmacologic response. Theadvantages of a standard preparation include a reduction ininaccuracies due to variations in animal susceptibility and, to differences in the technics of the assaylsts.Official U.S.P. Methods of Biologic Assay. A few ofthese procedures are given in abbreviated form as illustra ..tions of the principles of biologic assay. Strict observanceof details, many of which are not repeated here, is usuallynecessary to obtain a valid assay.1, TINCTURE or DIGITALIS. The amount of a dilutedtincture of unknown potency required to kill etherized catswhen injected intravenously is compared with the biolog•ica1ly equivalent amount of a standard tincture preparedfrom'tbe U.S.P. Reference Standard, At least six cats mustbe used with each preparation, the injections should be madeat 5-minute intervals and the dose should be such that •between 13 and 19 injections are required to cause cardiacarrest. An error of 20 per cent is permissible. One U.S.P.digitalis unit represents the potency of. 0.1 gram of theU .S.P. Reference Standard.2. lNsu1.1N INJECTION. The blood•sugar-lowering effectsof the unknown solution and of a standard solution arecompared, using rabbits as the test animals. Groups of three•,22 IControl and Dispensing of Drugs. \rabbits each are used for three concentrationso f both 'theunknown and the standard. Three analyses are done atintervals after the injection and the average depression ofblood sugar used for the calculations. In order to minimizethe effect of animal variation, the procedure must be repeatedwith the same rabbits several days later. The rabbitsused in the first part of the assay for the standard preparationmust be used in the second part for the unknown, andvice versa. The standard solution is prepared from theU.S.P. Zinc-Insulin-Crystals Reference Standard, the potencyof which is 22 units per milligram. The concentrationof the nnal solutions are adjusted so as to contain 40, 80. or 100 U.S.P. insulin units, with a variation of 5 per centor less.3. PosTE~roR-PITUITARYIN JECTION. Dilute acetic-acidextracts of cleaned, dried and powdered posterior lobes obtainedfrom the pituitary body of cattle or swine are compared,vith extracts of the Reference Standard. Suitabledilutions of the unknown and the standard extracts areadded alternately to a special saline bath in which is suspendedone horn of a virgin guinea-pig uterus. The con-~ tractions produced by both solutions must be approximately. equivalent and submaximal. One U.S.P. unit is the amountof activity contained in 0.5 mg. of the U.S.P. PosteriorPituitary Reference Standard. A variation of 20 per centis permissible.4. ~IVER EXTRACT. There is no satisfactory method forthe biologic assay in animals of liver, stomach or otherpreparations intended for the treatment of Addisonian perniciousanemia. The products available are specificallyapproved by the TJ.S.P. Antia.nemia Preparations AdvisoryBoard. Details concerning the source, the method of manu ..f acture, etc., and clinical data from the treatment of suscep.tib]e human patients in relapse must be supplied. OneU.S.P. unit is defined as that amount of . an otherwiseacceptable product which will produce a satisfactory clin...• •Prescription Writing 23ical and hematopoietic response jn Addisoni.an perniciousanemia when administered daily.PRESCRIPTION \VRITINGA prescription is an order for a medicine written by aphysician and given to his patient. It is to be filled by apharmacist. The physician is legally responsible for anyerrors but the pharmacist is co-responsible if a prescriptionis filled for a fatal dose of a drug. Prescriptions are neces•sary because of the great variety of therapeutic agents andbecause of the necessity for individual treatment. The sizeof the individual dose, the frequency of administration, thelength of treatment and the form or vehicle in ,vhich thedrug is given, as well as the actual composition of the medicine,will vary from patient to patient. ,There is an increasing amount of governmental restrictionon the dispensing of drugs and specific rules must be folIowed,especially in the prescribing of narcotics. In theseinstances, the prescription must contain the name, addressand age of the patient as well as the physician's full nameand his narcotic license number. \Vhen unusual amountsof narcotic are prescribed, justification must also appearon the prescription., In writing a prescription, the prescriber should keep inmind the number of days the medicine ,vill be taken, thetotal daily dose, the size' of the individual dose, the stabilityof the drug, the cost, the sizes of standard containers andavailable dosage forms, and pharmaceutical (physical),"chemical and therapeutic (pharmacologic) incompatibilities.A prescription contains the date and usually the name; ,ad~ress and age oi the patient; the superscription, usuallywr1tt,~n as ~, a:1 ~bbreviation of ''re~pe" meaning "take~ou ; the i1tscription, or body of the prescription, consist•1ng. of the name an.d the amounts of the basis (primaryactive drug], the ad;uvant (secondary active drug, if any),the correctsve (an agent to counteract some of the u.ndesir-'•, r'I-24 Control and Dispensing of Drugs-able side actions of the other drugs, if any), and the vehicle(medium in which the other agents are dispensed); thesu/Jscriptio1otr, directions to the pharmacist regarding thepreparation of the medicine; the signatura, or order to thepharmacist to label the medicine ll'ith the instructions for 1its use which follow. Fina1ly, the prescription must- besigned by the prescriber. It 1s common practice to haveforms with the physlcian's name, address and office hours.Formerly, all prescriptions were written in Latin with theapothecaries' system of weights and measures. The trendtowards the more convenient use of English terms and themetric system is well illustrated by their adoption in the194 7 editions of the United States Pharmacopoeia, the •National Formulary, and New and Nonofficial Remedies., A description of certain pharmaceutic: preparations anddosage farms is presented in Chapter 4.BIBLIOGRAPHYde Beer, E. J.: The calculation of biological assay resultsby graphic methods-the all-or-none type of response,J. Pharmacol. & Exper. Therap. 85: 1, 1945.Burn, J. H.: Biological Standardization, London, OxfordUniv. Press, 1937; Philadelphia, Blakiston, 1940.Eggleston, C.: Essentials of Prescription Writing, Philadelphia,Saunders, 1942.Green, F. H. K.: Clinical evaluation of ne,v remedies inBritain, Brit. Med. Bull. 2: 58, 1944.Herrick, A. D.: New Drugs, New York, Revere PublishingCompany, 1946.Lyman, R. ~-: A~e~ican Pharmacy. VoJumes I and II,Philadelphia, L1pp1ncott.New and ~onof!ici:i-t Remedies. Published Annually.Philacf ef pnia, Lt pp1ncott.Solomon, C.: Prescription Writing and FormuJary, Phifa.deJphia, Lippincott, 1935.United States Dispensatory, 24th ed., 1947, Philadelphia,Lippirtcott.Waud, R· ':·: Th~ _use of Latin and the me:ric system inprescription wr1t1ng, Canad. M. A. J. S6. @S, 1947."'•4Administration of DrugsINTRODUCTIONORAL ADMINISTRATIONRECTAL ADMI~ISTRATION•P AllENTERAL ADMINISTRATIONINHALATIONLOCAL APPLICATIONlNTRODUCTION> The pharmacologic activity of drug~ is of ten profoundlyinfluenced by the route, rate, duration and frequency ofadministration, and by such factors as the age, weight, sex,race and temperament of tlie subject. Various pathologicstates and certain physiologic states, such as menstruation,pregnancy and lactation, may affect the absorption, intermediarymetabolism or excretion of a given drug and thusnecessitate giving special consideration to the dosageschedule.The selection of the proper dose of a given drug forchildren is usually made with the aid of one of the severalformulas which have been developed for the purpose. Theseare to be considered only as a general guide, not as inflexibler.u les. The ones in most common use are: ' ,Clark's Rule.D f child wci~ht of child d fose or = 150 X ose ..-or adult.Cowling's Law.D f . age at next birthdayose or child = 24 X dose for adult.Bush's Law.Dose for child='ageX S100I•X dose for adult.•I26 Administration of DrugsYoung's Law.Dose for child== age X dose for adult. ,age+ 12The choice of the dose and the route·of administration fora drug in a particular circumstance depend on the proper•ties of the drug in question and the type of response desired.All other things being equal, the oral route is the methodof choice. Ho,vever, since some drugs are destroyed in thegastro-intestinal tra'c t, and others are not absorbed or do notpenetrate to the site of action, alternate routes are essential.The advantages and disadvantages of the various routes ofadministration are dealt with in this chapter.ORAL ADMINISTRATIONA large variety of pharmaceutic preparations are availablefor th-e dispensing of drugs intended for oral administration. Aromatic waters are saturated aqueous solutions of '\'ola-1tile oils or other aromatic or volatile substances. They haveno therapeutic action since the concentration of the activeingredient is very low. They are used as flavored vehiclesfor water-soluble drugs, usua]Jy diluted with at ]east anequal volume of water.Syrups are nearly saturated aqueous solutions of sugar,with or without flavoring agents. Alcoholic solutions of\Yater-insoluble drugs may be added to syrups. Their chief/ use is as a vehicle for flavoring agents.Infusions are aqueous extractions of crude drugs of animalor vegetable origin. Decoctions are similar except thatthey are prepared by extraction with boiling ,vater.Spirits are solutions of volatile substances in alcohol.Elixirs are sweetened aqueous solutions containing flavor.ing materials and from 4 to 40 per cent alcohol. The alcoholcontent is just sufficient to keep the volatile oils or themedicinal agent in solution. The sugar content of elixirsis lower than that of syrups.Vinegars are dilute acetic-acid extracts of crude drugs.,,.Oral Administration 27<Tinctures are alcoholic or aqueous alcoholic extracts ofdrugs. ~' Fluidextracts are concentrated liquid extracts of drugs.In all cases, the amount of active ingredient in 1 cc. is equivalentto the amount in 1 gram of crude drug. Alcohol isinvariably present either to aid in the extraction or to actas a preservati•v e.Pills are globular or ovoid dosage forms of dry preparationsintended for oral administration. They arc made witha. moistening agent or excipient, usually liquid glucose orsyrup. Pills are generally coated to keep them from stickingtogether and to improve their appearance.. Troches are solid preparations, usually with a candy orglycerogelatin base, intended to be allowed to disintegrateslowly when placed in the mouth. ,.Tablets are molded or compressed solid medicinal substances,usually with lactose or lactose and sucrose as thebase and alcohol or alcohol-water as the excipient. Theymay or may not be coated.' Enteric Coating. Pills and tablets may be given a specialtype of coating which is resistant to the gastric juices butwhich dissolves more or less readily in the intestinal tract.This is of special advantage for those drugs ,vbich aredestroyed in the stomach or which produce undesirablelocal effects in the stomach.The chief advantage of oral administration is its convenience.The action of practically all drugs is slower andn1ore variable when they are given by mouth than when they1 are given by other routes. l\Iany drugs cannot be eff ectivelyused by !mouth because of their instability in, orpoor absorption from, the gastro-intestinal tract, becausetheir pharmacologic action is too fleeting or because thedesired efiect can be achieved by a distribution of the drugsin the body obtainable only by some other route of administration.The absorption of drugs given by mouth may alsobe affected by the presence or absence of food or a1cohol •~ - ' ' ~\\1 .• '28' , , Administration of Drugsthe digestive enzymes and hydrochloric acid or bile salts in' the gastro-intestinal tract. Furthermore 1 oral administrationis sometimes obviously impracticable, as with moribund orunco-operative patients. -Drugs given by mouth generally pass through the liverby way of the portal circulation before tntering the systemiccirculation. Other routes o{ administration, including therectal to a more or less variable degree1 result in a 'directabsorption into the systemic circulation. Since many drugsare either destroyed or temporarily stored in the liver, thisby-passing may result in a greatly increased sensitivity toa given amount of a drug. Consequently, the dose for oraladministration may be much higher than for other routesof administration. •RECTAL ADl\flNISTRATIONThe rectal route is usetuJ for local or for systemic admin•istration as a supplement or alternati\'e to the oral routewhen a drug cannot be given by mouth because the patientis unable to swallow or to retain oral preparations. Drugsmay be given as suppositories or as r~tention enemas. Inthe latter case, the volume should be kept as low as is consistentwith the irritant qualities of the more concentratedsolutions. Certain drugs, such as tribrornoethanol and etherin-oil, are regularly given by this rotate; the salicylates,caffeine, morphine, mercurial diuretics and digitalis havebeen so administered but other routes are generally preferred. As supportive measures, saline and glucose solutionsare often given by rectum. The chief di.sadvantages are thatthe procedure is unesthetic anq liable to result in proctitis., l\f any drugs cannot be given in this way because of theirirritant local action.1 PARENTERAL ADMINISTRATIONParenteral administration is the administration of drugsunder one or more layers of the skin or mucous membranes.In general, it offers the advantage of s~curing quicker andIParenteral Admjnistration 29more certain effects than the oral or rectal route, with moreexact dosage~response relations.Solutions of drugs for parenteral use must be made witha pyrogen-free vehicle. Pyrogens are substances capable .o..f.causing a rise in body temperature. Pyrogens of bacterialorigin may be found as contaminants of sterile distilledwater. They are not destroyed by autoclaving ancf may 6eformed as a result of bacterial contamination of the still ordistillate prior to the sterilization process. An official pro ..cedure for the demonstration of the absence of pyrogens insolutions intended for parenteral injection is described inthe United States Pharmacopoeia. Three rabbits are used, 110 cc,/Kg. of the solution to be tested are injected intra• \venously into each1 and the subsequent body-temperature t\rise must not exceed 0.6° C. in any animal or a total of ;1.4 ° C. for all three animals. ..,Parenteral solutions should be sterile whenever possibleand must be given with aseptic precautions. This frequently~ necessitates the use of trained personnel and is one of thedisadvantages of this route of administration.Subcutaneous injections are made under the skin intothe subcutaneous fat. The drug enters the blood streamfairly rapidly by diffusion through the capillary walls.Massage significantly accelerates the rate of absorption. ,The rate of absorption may be decreased by the inclusionin the injected solution of a vasoconstrictor, such as epi ..nephrine. Irritant drugs cannot be administered subcuta ..neously because of the danger of sterile abscess formationind sloughing. This route is suitable for the injection ofpotent, nonirritating drugs, such as morphine, atropineind ergonovine.Intradermal (intracutaneous) injections are used forprod.u cing regional anesthesia of the ~kin' for the adminis• trat1on of smallpox vaccine, and for diagnostic skin reactions.The agent is introduced between the layers of.t.h • J,,·•,I30 Administration of Drugs•Intramuscular injections are suitable for aqueous solu•tions as well as for insoluble or immiscible preparations.In general, the rate of absorption is intermediate betweenthat of oral administration and intravenous injection. Inorder to obtain an unusually slow rate of absorption, thedrug may be given dissolved in peanut oil or beeswax orcombined with a nonantigenic protein, such as protamine.Absorption can also be slowed by the inclusion of a vasoconstrictorin the solution to be injected or 'by the localapplication of cold packs.- Intravenous injection is the most rapid method of intro-ducingdrugs into the blood stream. Only drugs which donot precipitate in the blood can be used. Fairly irritantpreparations can be given because of the rapid dilutionby the blood. Precautions must be taken, however, to preventleakage of such solutions around the venipunctureinto the subcutaneous tissue.Intraperitoneal injections are used in laboratory animalsbut seldom in human patients. The danger of puncturingthe intestine or other viscera is slight but absorption is irregular,particularly if the circulation is impaired. Further•more, irritant drugs may produce peritoneal adhesions.Intramedullary Injections. Drugs injected into the bonemarro,v spaces are taken up in the circulation about asrapidly as by intravenous injection. This route bas alsobeen used for the infusion of fluids. In adults, sternalpuncture is preferred and, in infants, puncture of the femuror tibia. There is some danger of fat embolism, osteomye-,litis or periostitis.Intracardiac Injections. The heart can be entered readilyby a sharp, direct thrust of the needle after first passingthrough one of the intercostaI spaces. On a few rare occasions,the intracardiac injection of epinephrine has restoredcardiac activity after conl;plete standstill. Success in thesecases was probably due as much or more to the mechanicalstimuJation of the 'puncture as to the drug.'Parenteral Administration 31Intra-arterial injections are rarely used except for diagnost1•c purposes.Subarachnoid (intrathecal, intraspinal) injections may beused for obtaining high loca1 concentration of a drug as inthe treatment of infections of the central nervous system orfor the production of spihal anesthesia.INHALATIONDrugs are rapidly taken up by the blood stream throughthe pulmonary epithelium. Amyl nitrite and the volatileanesthetics are examples of volatile drugs commonly usedby inhalation. Recently, technics have been evolved wherebysolid drt1gs can be dispersed in air in particles of a suitable~ize. If the droplet of drug solution, as in an aerosol, orthe speck of solid drug, as in a smoke, is larger than Smicrons, the particle will usually be filtered out by the noseand throat. If it is smaller than 0.3 micron, it will usuallybe exhaled rather than fixed on the surface of the alveoliand absorbed. Because of this limitation, relatively preciseapparatus is needed and this method has only limited appli- .cation. It has been applied with variable success for theadministration of the sulfonamides and the antibiotics andfor drugs used in the treatment of asthma. It offers few, ifany, advantages over intravenous therapy, since absorptionis almost instantaneous.LOCAL APPLICATIONDrugs may be applied directly to the skin or to mucousmembranes. For the application of drugs to the skin, thevehicle and method of application are often more importantthan the drug used.Aqueous solutions are useful in the treatment of acuteinflammation of the skin, where oozing and crusting occurfollowing the damage to the capillaries. These solutions are"oplied as "dermatologic wet dressings.,, A ,vetted linen......,c_l oth is applied to the area and the cooling effect, produced~ '.I•y32 Administration of Drugs~ .by the evaporation of water, is suffi~ient to produce local 1vasoconstriction and so reduce inflammation. The clothshould, therefore, never be covered tight]y as jn a surgicalwet dressing, and it should be replaced as soon as it is dry.The solution should be at room temperature in order toprevent reactive hyperemia. Usually it contains a mildantiseptic or an astringent agent. •Dusting powders are used for their moisture.absorbingeffect. They should not be used in oozing dermatitis. •Lotions are aqueous solutions in which dusting powdersare suspended. Addition of glycerol decreases the rate of.evaporation of water and insu.res the formation of a con•tinuous adherent layer of the po.wder after drying.Ointments are greasy protective substances used asvehicles for drugs in subacute and chronic inflammatoryprocesses. There are three groups of ointments: plain fa.ttysubstances of animal, vegetable or mineral origin, and oil•in-water and water-in-oil emulsions. Those of the first groupare immiscible with water. Ointments of the second groupcontain emulsifying substances, such as wax:, cetaceum orcholesterol or its derivatives and are miscible with water,forming stable emulsions. These emulsions are permeableto sweat and have some cooling effect due to a slow evap·oration of water, as in ''cold cream." They are used oninflamed, dry skin and also when aqueous solutions of drugsare to be incorporated into ointments. Oil.in-water (socalledgreaseless bases) are rather unstable and their practicabilityis not established. Drugs incorporated in .oint•ments usually penetrate into deeper layers of the skin thando those incorporated in the aqueous solutio,ns, dustingpowders or lo~ons. . This is I?ro~ah1y . due to the partialsuppression of insensible perspiration with accumulation ofwater in the skin and resultant maceration.Pastes are mixtures of powders and ointments. Becauseof their powder content,_ they have a dz;•ing effect . .,,, .r-:are less occlusive than 01ntmen'ts and therefore druts : ✓ ~'' \'•' Local Application 33t' fil)rated into pastes a~t less intensively than if incorporated,into ointments.Plasters are solid preparations containing a mixture' ofrubber with solvents or diluents as a base. Medicamentsincorporated into plasters penetrate deeply into the skin.• ,SKINFew drugs are administered for systemic effects by applicationI to the skin. Free mercury, ,vhen rubbed into hairfollicles and sweat and sebaceous ducts is effectively absorbed.Fat-soluble hormones and vitamins have been shownto be appreciably absorbed through the skin. They are notordinarily\ given in this way, however, except that occasionallytestosterone is applied percutaneously in relatively highdoses and estrogens have been applied by inunction overmammary tissue. Salicylic-acid compounds have been ap•plied percutaneously, and although there is some slightsystemic absorption, the effects obtained are chiefly local.Fat-soluble compounds of toxicologic interest are known tobe appreciably absorbed by percutaneous contact, e.g.,phenol, nicotine and nitroglycerin.Volatility and fat solubility are the two common characteristicswhich. seem to determine percutaneous penetration.The horny layer of the epidermis (stratum corneum) is.readily penetrated by nearly all substances since it is asort of rough network of horny lamellae with large holes.The stratum granulosum and stratum lucidum represent thechief b.:,.rrier to skin absorption. Such water-soluble in.. 'organic substances as do penetrate the skin under special• circumstances probably do so by entering the follicularand glandular pores. This type of penetration is favored bythe concomitant use of substances -which lower surfacetension,Galvap.ic currents can substantially increase the penetra., tion of some ionizable drugs. • The process is referred to as''electrophoresis" or "iontophoresis.'' ,•34 Administration of DrugsORAL 1\1U COSAAbsorption through the stratified squamous epitheliumunder the tongue is largely conditioned by the fat-water distributioncoefficient of a compound. Very few drugs have ahigh enough coefficient to penetrate directly through thlsmucosa. Glyceryl trinitrate and the steroid hormones, suchas testosterone and desoxycorticosterone, have been effectiveJygiven in this way.NASAL l\f UCOSAThe columnar epithelium of the nasal mucosa is penetratedwith reasonable ease. Pituitrin is occasionally givenin this way during the management of diabetes insipidus.Immunization to tetanus and diphtherja. has been accomplishedclinically by this route.OrHER MucosAE•Drugs may be absorbed from the conjunctival sac, thevagina, the urethra or the .bladder. These routes are notused, however, for the administration of systemically actingdrugs, although occasionally systemic toxic reactions followthe application of drugs intended for local effects, e.g., Jatropine in the eye for pupillary dilation and ciliary muscleparalysis; mercury bichloride in the vagina as an ill.advisedcontraceptive measure; local anesthetics in the urethra.Drugs such as quinine and nicotine may be reabsorbed fromthe urinary passages, absorption being increased by analkaline urine.BIBLIOGRAPHY 'Calvery, H. 0., J. H. Draise and E. P. Lang: The n:ietab~olism and permeability of normal skin, Physiol. Rev.26: 495, 1946.Draise, J. H., G. W'!o~ar~ and H. 0. _c_alvery: Methodsfor the study of 1rr1tat1on. and tox1c1ty of substances, a,pplied topically to tl1e skin and mucous membranesJ. Pharmacol. & Exper. Therap. 82:377, 1944. '/~'IlI•,,I,Bibliography 35Gaddum, J. H.: Principles of administration in chemotherapy,Brit. M. Bull. 4: 280, 1946.Hopkins, J. G.: Some newer bases for use in cutaneoustherapy, J. Invest. Dermat. 7: 171. 1946. ,Lane, C. H., and I. H. Blank: Vehicles in topical dermatologictherapy: their functions and physicochemicalcharacteristics, Arch. Dermat. & Syph. 54 : 650, 1946.Loewey, F. E.: Histamine iontophoresis in general andindustrial practice, Brit. J. Phys. 1fed. 8: 115, 1945.MacKee, G. M., M. B. Sulzberger, F. Herrmann andR. L. Baer: Histologic studies of percutaneous penetrationwith special reference to ..t.h e effect of vehicles,J. Invest. Dermat. 6: 43, 1945.MacKenzie, J. W. A.~ Absorption of drugs from therectum, Arch. Dis. Childhood 17~18 :28, 1942-1943.MacQuigg, R. E.: New t~chniques for parenteral fluidand drug administration: 1. Muscular intubation, Sur•gery 18: 592, 1945.Prigal, S. J.: The production of aerosols from medicatedsolutions, J.A.M.A. 131: 398, 1946.Quilligan, J. J., Jr., and H. Turkel: Bone marrow infusionand its complications, Am. J. Dis. Child. 71: 457,1946.Rothman,' S. : The principles of percutaneous absorption,J. Lab. & Clin. Med. 28: 1305, 1943.Schwidetsky, 0.: History of needles and syringes,Anesth. & Analg. 23: 34, 1944.T~cantins, L. M., and J. F. O'Neill: Complications of1ntra-osseus therapy, Ann. Surg. 122: 266, 1945.Walton. R. P.: Sublingual administration of drugs,J.A.M.A. 124: 138, 1944.II,, 5•General AnesthesiaINTRODUCTIONINHALATION ANESTHESIAINTRAVENOUS A'.NESTIIESIARECTAL ANESTHESIACURAREOXYGEN THERAPYI PREPARATIONSIINTRODUCTIONThe term anesthesia was coined in 1846 by Oliver \VendellHolmes to signify a state of "insensibility, more particu•JarJy .. ~ to objects of touch." Tbe term may be used todescribe either a general or a local effect. General anes·thesia implies a loss of consciousness, a loss of pain sense(analgesia) and general muscular relaxation. These effectsare produced by depression or narcosis of the centralnervous system. •Development of General Anesthesia. The history ofgeneral anesthesia dates back to very ancient times. Suchsubstances as rnandragora, wines and other alcoholic prerrarations, opium, hyoscine (scopolamine) and cannabis(hashish, bhang, marihuana} were used to effect someloss of consciousness or analgesia for the crude surgery'of ancient and medieval times. Stunning the patient, bilateralcompression of the carotid arteries to produce cerebralanoxia and hypnotism or mesmerism were other proceduresused in an attempt to induce some degree of anesthesia.It was not until the advent of modern anesthesia in themiddle of the nineteenth century, however, that the criesand struggles of the patient, with the resulting handicap ,to the surgeon during an operation, could be satisfactorilyeliminated. The physicist, Sir Humphrey Davy, noted'36 y ,., ,,'Introduction 37Iearly as 1800 that nitrous oxide would produce unconscio~snessand abolish pain sense, but practical application of thisagent in surgery was not made at that time.Ether was first used as an anesthetic by Crawford W.Long m 1i42, aiter he had omietved that inuulgence in''ether frolics" to the point of intoxication would of ten resultin loss 'of consciousness and abolition of pain sense. ShortlyI, after this, a dentist, Morton, in Boston, upon the suggestionof his teacher, Jackson, tried ether to produce anesthesiaduring dental extractions and found it to be quite satisf actory.He was the first to give a successful public demonstra-, tion of the value of ether in general surgery, and from thistime on the use of ether as an anesthetic became widespread.Previously, another dentist, \Vells, bad used nitrous oxideduring dental extractions, but his attempted public demonstrationof its value failed quite completely, and it was•, not until 1868 that nitrous oxide was introduced into clinicalpractice. Chloroform was first introduced as a generalanesthetic by an Edinburgh obstetrician, James Simpson,in 1847.The intravenous injection of drugs to produce generalanesthesia was first used clinically in 1874 by Ore, whoemployed chloral hydrate. Although various other agentswere tried, this method was considered too dangerous to.attract widespread interest until the introduction of theultra-short-acting barbiturates, hexobarbital and thiopental,in 1933 and 1934 respectively.The rectal administration of drugs to produce general anesthesiawas tried as early as 1847, using ether. This method\Vas soon abandoned, however, because of irritation of therectal mucosa. In 1913, Gwathmey reintroduced the technicof r~ctal anesthesia, using a nonirritating mixture of ether "and olive oil. This became quite widely used, especiallyfor obstetric analgesia. In 1926, tribromoethanol (avertin)• ,vas introduced for rectal anesthesia. It is now used almost '~"1,l>lya s a basal anesthetic.I'\•I38 General AnesthesiaTheories 0£ Narcosis. The mode of action of generalanesthetics is not understood, although various theorieshave been advanced. The early belief was that anesthesiawas caused merely by asphyxia. Claude Bernard was thefirst to suggest an alternate explanation, that anesthesia isdue lo a reversible coagulation of the constituents of thenerve cells. The Meyer-Overton theory assumes that theaction of anesthetics is due to the fact that they are solublein, and are taken up by, the lipids of nerve tissue, the anestheticpotency depending on the relative solubility of theagents in fats and water. The l\foore and Roaf theory is anextension of the !\feyer-Overton theory. It postulates thatanesthesia is due to that part of the drug which leaves thelipids and combines with the protoplasm. The lipid materialholds the anesthetic in contact with the protein and in thisway aids in the production of narcosis. Recovery is due tothe reversible nature of the combination of the narcoticwith the cell protoplasm. According to Lillie's theory, anestheticsproduce their effects by modifying cellular mem•branes, making them more resistant to changes of permeability.Since variations of permeability are essential io.. stimulation, the irritable tissue is thus rendered temporarilyinsensitive. Verworn's theory assumes that the depressionof the neuron is due to suppression of the power of tbe cell 'to use oxygen, inasmuch as narcosis is accompanied bydiminished oxygen utilization. Recent studies by Quastel onthe effects of narcotics in decreasing the oxygen consumptionof brain tissue in vitro have revived interest in thistheory .The administration of anesthetics causes a decrease in theelectronegativity of the brain cortex so that in the stage ofdeep surgical anesthesia the brain cortex is electropositive.According to Burge's electrical theory of narcosis, the Jossof negative potential is due to the blocking of the passageof negative charges into the cortex through sensory fibers,.....\Introduction , 39while motor fibers are left free to conduct the negativecharges away, thereby rendering the cortex electropositive.INHALATION ANESTHESIAAdministration. A number of gases and pighly volatileliquids are used to produce general anesthesia. These areadministered either by dropping the liquids on an appropriatemask which permits the inhalation of vapors or bythe use of gas machines which deliver the gases and vaporsinto a face piece or an endotracheal tube. The early gasmachines discharged the exhaled breath into the room air,a procedure now called the semiclosed method. New developmentshave made the so-called closed system more popular.In the closed system the exhaled breath passes into agas reservoir, usually a rubber bag, and is rebreathed. Therebreathed gases pass through a canister containing sodalime, which removes the exhaled carbon dioxide. Oxygen. is added at a rate of about 300 cc. per minute to replacethat which is used up by the patient. This method permitsthe reuse of the exhaled anesthetic agent, thus effecting aconsiderable economy. It is more physiologic, since theinhaled gases/are warmed and humidified. It also minimizesthe dangers of anesthetic explosions and it provides a suitableapparatus for the administration of pure o:,cygen whennecessary.Stages of Anesthesia. The sequence of events followingthe administration of the various inhalation agents is quali~tively very similar ,and consists essentially of a graduallyincreasing depression of the central nervous sy?tem beginningwith the higher cerebral centers. A number of charac-, teristic signs occur during the administration of the anestheticand reappear in reverse qrder as the anesthetic is~ithdrawn (see page 40). On the basis of these signs it1s common to describe four stages of anesthesia, the first ,stage being one of analgesia, the second of excitementor delirium, the third of surgical anesthesia and the fourth,\,•40 General Anesthesiaof respiratory paralysis, which leads to death unless appr~priate resuscitative measures are taken. The anesthetistmust be able to recognize the depth of anesthesia in orderto insure that it is adequate for the surgical procedure inquestion and also to avoid the danger of giving an over•dose of the anesthetic. ,
[...]
In the first stage of anesthesia, the patient is consciousbut there is a variable degree of mental disorientation. Painsensibility is diminished, so that this stage is often usedin obstetric analgesia to provide relief during the intermit- •tent tabor pains. If the anesthetic agent is irritating, theremay be coughing and voluntary breath-holding, and the ,Inhalation Anesthesia 41•patient may have a sensation of choking or suffocation. Ifthe agent is nonirritating, the patient may have pleasantflights of fancy and a sensation of giddiness, well.being andfreedom from care.Loss of consciousness ushers in the second stage of anesthesia.With skillful administration, this stage may bepassed through uneventfully. Often, however, the patientexhibits signs of excitement or delirium, which vary frommuttering and shouting, muscular tension and purposelessmovements, to violent attempts to escape. There may be irregularbreathingl breath•holding, coughing, salivation, swallo,ving movements, retching and vomiting. The blood pressuterises, the pulse accelerates, the pupils dilate and theeyes move about. There is exaggerated response to sensorys' timuli, such that a loud noise, a touch or a movement of anextremity may precipitate a bout of violent activity.During the first plane of the third stage, the respiration• is full and rhythmic. The eyeball activity is greatest at the. beginning of this plane but disappears by the time thesecond plane is reached. The pupils are usually normal butthe eyelid reflex. diM.ppears. During the emergence fromanesthesia, swallowing occurs at the upper border of the firstplane of the third stage, while vomiting marks the lower' limit of the second stage. The second plane is the one inwhich most surgical operations are performed. There ismoderate muscular relaxation, and the general condition ofthe patient is good. The respiration remains unchanged andthe pupils begin to dilate unless this reaction is modified by~preanesthetic n1edication. The dilation may be due to adirect paralyzing effect of the anesthesia or to hypoxia. Ifmorphine has been given, the pupils remain miotic until thethird plane is reached. If scopolamine or atropine is giventogether ,vith morphine, a mydriatic effect may predominate.ln the third plane, respiration decreases in volume becauseo! intercostal paralysis. The pupils become increasinglydilated even if morphine has been given, and the lacrimationI •TADI-E 1CHARACTERISTICS OF THE 1fAIN INHALATION ANESTIIETICS • -VINYL ZTlllaITDII CDLOIOFOIMFormula Csllis> O CllClsNlTltO'UI OJtJD&N10r:rDYL1KI.Cll:a = Cll2CYCLOl'ZOl'AKIc11:a= e nCll.:a = Cll > OC:1111CH2c1G-e112• • • wLiq. b. p. 34 6• Liq, b. p. 61 • Ga1 Ga Ga, Liq. b. p. 28•rbyalcal char.Sp. Gr, of vaporcompared w1tb air•Stab1lit12.56 4.10 1.52 0.90 1.45 2.42•Rclallvdy ,table Unatable In llaht Stable- In 1teel Stable - In 1teel Stable - In at eel Unnabte afterand heat. c11inder1. c1llnder1. cylinder• opening.S - I I P IlnAamm1blllt1 lnftammabte and Nonlnflammable NonlnfiamU1abte. 1118:ammabloan d Infl:immable and Inflammable.explosive Support• combu• ellplo1lve explo1IYetlonInhalation- I hal I c,pca Inhalation- Inhalatlon- opel! n at on closed open open Inltalatlon-cloacd Inbalatloa open1cm1elo,cd ecmlclo~d ,e.mlclosed closedclosed clo1ed closed.Admlnl1tratlonAnetlhctlc Induction S-7% Induction 1·2% Induction 90% Inductlon 80% Malnlmance 7½- l\lalntenance 4%concentration :M1111tcnan3c.o6'% Mainttnance 0,5% Malntc111ne11 Malnttnance :TO% 13%60 90o/"-InductionSubJtctlnSlow 15-30 min.War111tb,J1'1ddl•ne,,, 1u1Ioc.atlonRapid S-8 rnln.More plea,anttban ether~Id 1°4 mln.1laratlonRapid 3-8 mln.M 1ldl.r unplca~ntodorRapid 1·3 min.l'l,a1antRapid 2-3 min.M1ldl:r unplca,antodorEitcittment rre!tntne~p. lrrc11:11larPup1lt ddattdLlltle t.llCltementSurrlc.al 1tareMu1calu relax. Excellent ExcellentOx11t111tl0n CO<l-d eyt.no•I• Coo<llatePrnent,but11&Ntd UncommOGover q1,11cldyNOtHIPoorPoorPoor Il.vcommo11GoodGoodLittle or none.P11,edonrqu1ekl1.CoodCoad•~.i:,.N)~ i~~ [liS'I' ,y - •./ (ETJll.ll CJII.OllOJ'O•K NJT•OUS oxm• ETBYLIUfK CYC'LO.tR.OPANJi VINYi, HBE1Toxicity Slow, derf. ln Slow,dccpin,tage Irregu1arandatim• Normal res~. in Normal resp. and Normal or slowedRcapiratory stag-e II . III, Resp. de- ulated in III, s.Qge DI. Slow, slowing in III, in III.Apnea, wbcn pressed. partial asphyxia! reg., 11haUow hkc Ap.uea - when Apnea - controlledpushed. stimulation, thenA51e-ep. ·a1 • 'f pushed- easily with O:z. Resp.Respirato~fail- fadurc. !ph)'XI stun. 1 controlled by arti• failure before c:irurelate. ucus 0, reduced. .6cw respiration culatory.obstruct10D.Laryngeal spasm.Resp. Irritation ,, Salivation and Little irritation. No irritation. 1'0 ,rnutton. Slight irritation Mucus secretion.mucus marked.Marked salivation Shght irritation I~Circubtion B.P. normal in Vasomotor dcpres• Asphyxial rise of Stightdro~inB.P. Little effect in Myocardial damage e.Sta~ III. Good sion • B.P.insta,eIII. Shghtbr 7cardia 1taf III. in dogs ~c1rc:ulat1onu ntil Early fall in B.P. C1rculator7 ailure in III. Car ·acirrei\11ari• a-.late. Fails after Myocardial damage secondary to t1es apt to occur 0resp. Cutaneous andcard~carrest asphyxia. = ~vessels dilated. >Stomach and gut Relaxation Relaxation Relaxation Blight Relaxation &lirht. Relaxation alightesrJlmarked very marked - ;.Li1cr daauge Litlle or nODe Delayed poisoning None None None wsthanwith ("t>~ Central nect"o&is chloroform V., ... •~Kidner Little di.sturbance.1 Anuria and oli• None None NoneAnuria and oh- gUriaearltcrthanf.uria after pr1>- with etherongcd use. Fati infiltrationan degenerationPostoperative nau• Frequent Sameuether A little Present but much Present but less Small per centaca a.od vomiting leas than with than with ether.etherOperation forwhich suitableLong-major Brief or lightanesthesiaAnalgcaia(obatet.)Long in absenceof anoxemiaInduction1:!f-majorinductionLonf- zmjor -an inductionLess than ½-1 hr.'It'44 General Anesthesiareflex is abolished, giving a dull, lusterless appearance to theeyes. In the four th plane, the respiratory volume is markedlydecreased and the pupils are completely dilated. Theintercostal muscles are paralyzed, and respiration is carriedon entirely by diaphragmatic contractions, and is irregularand inefficient.The depth of anesthesia depends on the concentration ofanesthetic reaching the central nervous system. This isdetermined by the partial pressure of the anesthetic inthe inspired air, the respiratory volume, the permeabilityof the alveolar membrane, the circulation time and the cir- ,culatory volume of the various organs and tissues.Desirable Properties of General Anesthetics. Idea11ya,1 general anesthetic should be a nonirritating substance freefrom any d.isagreeabJe odor. It shou1d produce a rapid,pleasant induction and permit a rapid recovery. It shouldprod11ce adequate muscular relaxation and should not in•crease capillary bleed.ing. It should have a wide margin ofsafety and be of adequate potency so that sufficient oxygencan be a~ministered. It should be easy to administer andshould cause little change in the normal physiology of thebody. Finally, it should be easily and cheaply manufactured,nonexplosive and should not decompose on standingor during storage. The properties of the more importantinhalation anesthetics are summarized in Table 1.Anesthetic Explosions. One of the hazards of anesthesia 'is the occurrence of explosions, especially with ether, ethyleneand cyclopropane, which form explosive mixtures withoxygen. The sources of ignition include static sparks, cauteries,open flames and motors and/ other electrical devices.-Static sparks may be prevented by maintaining a highhumidity or by the grounding of all apparatus Used. Thedanger of explosion ma~ ~e ~mi~ed by_ using the closed- ,•rcuit method of administration, 1n which the explosiveCgIa s es are confined in .t he apparatus and not regularly reteasedinto the room air.,\'Inhalation Anesthesia 45Preoperative Preparation of the Patient. The anesthetistshould determine in advance the most suitable anestheticagent and method for each patient, basing his selection onthe physical condition of the patient and on the nature andduration of the ope.ration. The -patient should receive mentalpreparation in ,vhich his fears are allayed with reassuranceand encouragement. He should receive adequate sedationon the night preceding the operation to permit restful sleep.About an hour before the operation he should be premedicated,vith such agents as morphine or related compoundsto decrease metabolism and to allay pain and apprehension,barbiturates to produce sedation, atropine to reduce thebronchial and salivary secretions or scopolamine to reducesecretions and to produce amnesia. Basal na1cosis may beproduced with such agents as tribromoethanol or barbitutates.Basal narcosis or basal anesthesia is a condition ofunconsciousness or very light anesthesia insufficient for• surgical procedures. It is often induced before bringing thepatient to the operating suite so that he is una\vare of anyof the events concerning his operation. It permits themaintenance of surgical anesthesia with smaller doses ofanesthetic drugs than would ordinarily be required.Postoperative measures include the administration of nar~,cotics for severe pain, the use of intravenous fluids to combatdehydration and shock, the administration of antispasmodicsto allay distention and oxygen therapy to prevent hypoxia.GENERAL ANESTHETIC AGENTSEther is probably the most widely used and safest generalanesthetic. It produces a depth of anesthesia sufficient to• give complete muscular relaxation while high concentrationsof oxygen are maintained. Its disa.dvantages include theun?lea~nt and slow induction, irritation of the respiratoryep1thel1um and high incidence of postoperative nausea andvomiting. If liquid ether is aspirated into the respiratory..... ft.. ft- -.pilled in the eye, very severe irritation results .•I,••46 General AnesthesiaEther produces a number of undesirable effects, includingdepression of liver function, irritation of the kidneys, elevationof blood sugar and acidosis. Tbe so-called "ether convulsions''are probably not caused by ether, since they may, occur during anesthesia with other agents. The cause ofthese convulsions is not definitely known. A number of factorsare probably involved, including acute toxemia, hyperthermia,acidosis, hypoxia and carbon-dioxide retention.Cyclopropane was introduced clinically by ,vaters in1930, after preliminary studies by Lucas and Hendersonhad suggested its value as a general anesthetic. It produces_a rapid and pleasant induction, and adequate muscularrelaxation can be secured while h.igh concentrations of oxygenare administered. Its chief disadvantages are its explerI siveness and the occasional production of cardiac arrhythmiasduring deep anesthesia. The arrhythmias can usuallybe stopped by the addition of a small amount of ether vaporto the gas mixture. Bronchiolar spasm may be encounteredduring the administration of this agent. Because of itscostliness, it is almost always administered by the closed,carbon-dioxide-absorption technic. ~ _Nitrous oxide is the least toxic of the general anesthetics., Its disadvantage lies in the fact that deep anesthesia cannotbe produced unless the oxygen concentration is reduced toa dangerously low level. Nitrous-oxide--0:xygen anesthesiais almost always accompanied by some degree of hypoxia.As a supplement to other anesthetics, such as tbiopentalsodium or tribromoethanol, it is of considerable value. Theuse of nitrous--0xide-oxygen anesthesia for short dental prercedures is very common but is .not without hazards.Ethylene was introduced as an anesthetic by Luckhardtand Carter in 1923. In spite of its unpleasant odor, it pro•vides a rapid and pleasant induction and is comparatively, nontoxic though its explosiveness in anesthetic mixtures ispotentially dangerous. It is probably the anesthetic of choicefor poor.risk patients but does not usually provide sufficient',,Inhalation Anesthesia 47muscular relaxation for intra.abdominal operations. It is asatisfactory analgesic agent in obstetrics.Vinyl ether was introduced in 1929 by Leake, who predictedthat a chemical agent related to both ether andethylene ~hould pos£>eSSde sirable anesthetic properties. Itsaction is very rapid and the usual signs of deepening anesthesiamay not be noted, so that precautions must be takento avoid overanesthetization. It often produces troublesomesalivation and may cause liver damage if administered for 1a long period or if hypoxia occurs during the procedure. Itis used primarily for short surgical procedμres, for the inductionof anesthesia and during labor.Trichloroethylene has recently been introduced as ageneral anesthetic, being more widely u5ed in Great Britainthan in the United States. It is apparently quite toxic andmay cause cardiac arrhythmias. Its use is generally restrictedto minor surgical procedures of short duration. It'should not be administered by the closed method since itdecomposes in the presence of soda lime, giving rise totoxic products.Ethyl chloride is a potent general anesthetic agent. Itproduces a very rapid induction, and has been used princi~pally for this purpose. Its toxicity resembles that of chloroform.It has largely been replaced as an induction agentby vinyl ether because of its toxicity. \Vhen sprayed uponthe skinJ it produces local anesthesia by cooling. .,,,Chloroform is now generally considered to be too toxicfor routine use, but its nonexplosibility and its relatively lowvolatility make it a useful agent where open flames cannotbe avoided, and in hot climates, while the ease with whichit can be administered is of value when hospital facilities arenot available. It is a potent agent and can produce completemuscular relaxation in the presence of high concentrationsof oxygen. Low concentrations of chloroform sensitize theheart muscle, as a consequence of which stimulation or theinjection of ~pinephrine -may result in acute ventricular... -•j}•...48 General Anesthesiafibrillation. High concentrations and rapid induction depressthe heart to a dangerous degree and may lead to cardiacarrest. Resuscitation after chloroform overdosage is difficultsince the circulation usually fails at the same time as respira~tion, whereas with other agents the heart generally continuesto beat for some time after the cessation of respiration. Afurther disadvantage of chloroform is the frequent developmentof postanesthetic liver and kidney damage, especiallyin debilitated patients. There is some indication that thismay be minimized by a high-carbohydrate diet or by theadministration of choline or methionine.Miscellaneou's anesthetic agents whose clinical value hasnot been adequately determined include a series of com•pounds related to both ether and cyclopropane which havebeen prepared and studied by Krantz and his associates.These are ethyl cyclopropy1 ether (cyprome ether), propylcyclopropyl ether (cypreth ether) and its unsaturated analogue,known as cyprethylene ether. Other compounds studiedby this group include isopropeny1 vinyl ether (propethyleneether), an isomer of cyprethylene ether, and n-propylmethyl ether (metopryl), an isomer of ethyl ether.Combined Anesthesia. Frequently, surgical anesthesia1 is effected by the use of several drugs and/or several methodsso that the dose of each drug is minimal. An exampleof combined anesthesia would be adequate premedication, aregional block with procaine for analgesia and musclerelaxation, intravenous thlopental sodium for unconsciousness,nitrous-oxide•oxygen for analgesia and unconsciousness,and the provision of increased oxygen supply for thepatient during the operative procedure.INTRAVENOUS ANESTHESIAIntravenous anesthesia offers the advantages of rapidinduction, simplicity of administration and absence ofexplosion hazards. Its disadvantages include all those inher•ent in intravenous therapy while the very simplicity of itsIIIntravenous Anesthesia 49administration may lead to its use by persons who are notqualified to recognize the danger signals of anesthesia.Intravenous anesthesia is confined almost exclusively tothe use of thiopental sodium (pentothal). Hexobarbital{evi?al} i~ \l'5ed to a cettaln extent, and recently two newultra-sl1ort-acting barbiturates, kemitha1 and thioethamyl,have been introduced. Such agents as morphine, paraldehyde,alcohol and the longer-acting barbiturates have beenused in the past but are considered unsafe.Thiopental sodium, an ultra-short-acting barbiturate (seeChapter 7}, ,vas introduced clinically by Lundy in 1934.Its present popularity is due in no small measure to theexperiences gained during its widespread use in World \Var '11. It may be used alone, in combination with the weakerinhalation anesthetics, with regional anesthetics, or as abasal anesthetic in apprehensive patients. It is rapidlydestroyed in the body and if administered slowly, fairlysatisfactory "moment to moment control" can be attained.The mechanism of its detoxication has been in doubt, butrecent evidence indicates that it, like the short-actingbarbiturates, is destroyed in the liver. A moderate degreeof liver damage does not constitute a contraindication to' ifs use, since the duration of anesthesia is not prolonged.Laryngeal spasm may occur if the vocal cords are irritatedby the presence of foreign material. The use of thiopentalis therefore contraindicated in operations about the nose,mouth and throat, during which blood may run down and• • 1rr1tate the vocal cords. Oxygen should be administeredduring thiopental anesthesia because of the respiratoryd~pr~ssion which the drug produces. The use of 50 per centnitrous oxide and SO per cent oxygen reduces the quantityof thiopental necessary for a surgical procedure, and at thesame_ t1m; provides the recommended increase of oxygen inthe 1nsp1red atmosphere. Thiopental is contraindicated1or should be used with extreme caution in patients withrecent ~evere hemonhage or who are suffering from shock'•I50 General i\nesthesia ----------------------'or toxemja, since the tolerance to thiopenta1 'is greatlyreduced in these conditions. It should be administered inconcentrations of 2.5 per cent or less, since the use of moreconcentrated solutions may cause venous thrombosis.RECTAL ANESTHESIA •The administration of anesthetics by rectum is seldomresorted to at the present time, since the method is cumbersomeand the variations in the rate of absorption make theend results unpredictable. The first preparation to receiveconsiderable use was G,vathmey's oil-ether mixture, a solutionof ether in olive oil. This mixture was later modifiedfor obstetric aAesthesia by the" addition of magnesium sulfate,which was thought to act synergistically with the ether.Even in such mixtures, however, the ether may be irritatingto the rectal mucosa.More recently a solution of tribtomoetbanol in amylenehydrate (avertin, bromethol) has been used. When firstintroduced it was used to produce general anesthesia. Thenarrow margin of safety between anesthetic and toxic dosesJed to abandonment of its use for this purpose, and it is nowemployed largely as a basal anesthetic, especially in chil·dren. Its chief toxic effect lies in its profound depressantaction on the respiratory center. The shorter-acting bar•biturates, such as pentobarbital, amytal and thiopental, arealso used rectally as basal anesthetics. ParaJdehyde basbeen administered by this route to produce obstetric analgesiabut it is too unreliable to be acceptable.CURARECurare is a crude drug of indefinite composition obtained ;from a number of South American plants. Its predominantpharmacologic action is paralysis of voluntary muscle, anaction shown by CJ.:iude Bernard in 1844 to originate at theneuromuscular junction. It has long been known and usedby the natives of South America as an arrow poison.,.curare 51Although curare was used clinically in 18S9 in anattempt to control tetanus convulsions, its use was abandonedbecause of the uncertain supply and the variablepotency of the drug. In 1938, however, intocostrin, a purifiedand standardized preparation, became available andwas used successfully to secure skeletal-muscle relaxationduring the shock therapy of mental disorders. It was firstused to secure muscular relaxation in anesthesia by Griffithand Johnson in 1942 and in the following years its usebecame widespread. It must be remembered that curare isnot an anesthetic agent in itself and is used only as anadjunct to anesthesia.Curare preparations currently in clinical use include intocostrin,20 units per cc., and d-tubocurarine chloride, 3mg./ cc. The activity of 20 units of intocostrin is equivalentto that of 3 mg. of d-tubocurarine. The latter is apparentlythe active principle of curare. It was first isolated by Kingin 1935 and its structural formula has been tentatively 1 identified.Curare is a useful adjunct to such anesthetics as thior,en\.a\, nittou!i oxide and cyclopropane <:iince it inducessatisfactory muscular relaxation without the use of dangerouslyhigh concentratio.ns of anesthetic. The usual proce ..dure is to administer intravenously from 40 to 100 units of• mtocostrin or from 6 to 1 S mg. of d.tubocurarine chloridewhen the patient is in light surgical anesthesia. Muscularrelaxation usually occurs in about 2 minutes. The effectspersist for from 15 to 30 minutes or longer; additional injectionsmay be given ag required. The dosage should bereduced by at least one-third if used with ether since thisagent has a curare-like action in itself. Curare preparationsabo\isb many oi the conventional signs for estimating thedepth of anesthesia and unless adequate precautions aretaken either over- or under-anesthetization may occur.Overdosage with curare results in paralysis of the respirawtory muscle, hence facilities for artificial respiration with•'• •••52 General Anesthesia /oxygen should always be available ,Yhen curare preparationsare used. Neostigmine is a pbarmacologic antidote to curareand may be admi11istered if signs of respiratory, embarrass•ment appear. The undesirable parasympathomimetic effectsof neostigmine can be controlled \vith atropine. Neostigm1' neis rarely necessary, ho,vever, since the treatment of choiceis artificial respiration '\\'ith oxygen until adequate respira•tory activity returns.l\Iyasthenia gravis patients are particularly sensitive tocurare; the drug has been used as a diagnostic aid ,vhenthis condition is suspected. It should be used in minuteamounts, however, lest respiratory paralysis occur. It hasalso been used to relieve spastic states and to facilitatebronchoscopy and tracheal intubation.Recently, a synthetic preparation with a curare-like effecthas received preliminary cJinical trials in Great Britain.This compound, cz, ~' dihydroxy, (2 methyl) phenoxypropane,known as myanesin or B.D.H. 312, appears to exert"----<~ 0- 1H2-CH-,H 2CH3OH OHits muscular-relaxing action by a depressant action on thereflex excitability of the spinal cord. It appears to be muchless toxic than curare, and intercostal paralysis· does notoccur with doses producing full abdominal relaxation.Erythroidine, an alkaloid with a curare-like action, ispresent in various species of erythrina. Altl1ough a satisfactorysubstitt1te for curare, it appears to have had littleclinical use. Its action is Jess prolonged than that of cur.ire.OXYGEN THERAPYOxygen alone, or mixtures of oxygen with carbon dioxideor an inert gas such as helium are of great value in thetreatment of \1arious types of anoxia or hypoxia, includingI•Oxygen Therapy 53re' anoxemia which may develop during the ad1ninistration: general anesthetics. \Vhile the term anoxia is generally;ed, the term hypoxia is more accurate since the lack of{ygen is relative, not absolute.The f ollo\ving four classes of anoxia are generally rec{nized:l. Anox.ic anoxia (anoxen1ia), due to a. low oxygen tenonin the alveolar air and the blood, with a resultant~auction in the saturation of the hemoglobin with oxygen.his may arise during anesthesia, at high altitudes, duringJimonary infections, from shallow respirations or f tom,ngenital malformations of the heart and blood vessels.2, Anemic anoxia, in which the blood oxygen tension is)rmal but there is a deficiency of functioning hemoglobin.his may occur with the anemias, hemorrhage or with agentshich interfere ,vith oxygen transport by hemoglobin, such; carbon monoxide, chlorates, nitrites and coal-tar derivaves.3. Stagnant anoxia, in which the tissues receive insuffi'.ent oxygen because of a slowing of the circulation as in1ock and conditions of impaired venous return.4. Histotoxic anoxia, in which the tissue cells are poiJnedand cannot utilize oxygen, as in poisoning by cyanidesnd other cellular depressants.Symptoms of ano.xia include dyspnea f o]lowe.d by slow,:tbored breathing and coughing; tachycardia or, later, alow bounding pulse and an increased blood pressure folowedby a terminal fall; gastro-intestinal disturbancesncluding abdominal cramps, nausea and von1iting andlfarrhea; und cerebral changes manifested by irritability,estlessness, headache, confusion and delirium. The pres- -'.nee of cyanosis is a useful though not altogether reliablendex of oxygen want since it depends on the amount of·educed hemoglobin in the peripheral capillaries and on theJcgree of vascular dilation or constriction. Five grams ofreduced hemoglobin per 100 cc. blood are necessary for-IJ" . ' t54 General Anesthesiacyanosis to be apparent. A patient with severe aneniia maydie of oxygen want but never be cyanotic.Indications for oxygen therapy include operations onanernic and toxic patients; any condition interfering withpulmonary function; poisoning by depressant drugs, suchas Inorphine, barbiturates and general anesthetics; severetoxemias; coronary thrombosis and decompensated heartdisease and surgical and traumatic shock.Oxygen may be administered by means of a face mask,by nasal catheter or by placing the patient in an oxygentent or specially constructed oxygen chamber. If given bythe catheter technic, the oxygen should be humidified;otherwise it will irritate the respiratory passages. If administeredin a closed circulation, provisions must be made forremoval of the carbon dioxide. If an oxygen tent is used,,provision must be made to cool the tent atmosphere, andthe oxygen concentration in the tent should be determinedfrequently. Oxygen must not be administered in the presenceof open flames, cautery or electrjc motors because ofthe fire hazard.PREPARATIONSEther U.S.P. Anesthetic ether B.P.Cyclopropane U.S.:P.; B.P.Nitrous oxide U.S.P.; B.P.Ethylene U.S.P.; B.P.Vinyl ether U.S.P.Trichloroethylene U.S.P.Ethyl chloride U.S.P.; B.P., Chloroform U.S.P.; B.P.Thiopental sodium U.S.P. Soluble thiopentone B.P.Hexobarbital soluble N.N.R. Hexobarbitone B.P.Tribromoethanol U.S.P.; B.P.Tribromoethanol solution U.S.P.; B.P. A solution of tri•bromoethanol in amylene. hydrate containing 100 Gm.of tribromoethanol in 100 cc.J1•I •Preparation_Oxygen U.S.P.; B.P.Intocostrin N.N.R.D-tubocurarine chloride N .N .R.BIBLIOGRAPHYGENERAL•55Adriani, J.: The Pharmacology of Anesthetic Drugs,Springfield, 111., Thomas, 1942. .Adriani, J.: The Chemistry of Anesthesia, Springfield,Ill., Thomas, 1946.Keys, T. E.: The History of Surgical Anesthesia, NewYork, Schuman, 1945.Mousel, L. H., D. Stubbs and J. Kreiselman: Anestheticcomplications and their management, Anesthesiology7 :69, 1946.Weiss, W. A., and L. H. Mousel: Preoperative and postoperativesedation, Surg. Clin. North America 25: 1057,1945.INHALATION ANESTHESIAClement, F. W.: Nitrous Oxide-Oxygen Anesthesia__:11cKessen-Clement Viewpoint and Technique, Philadelphia,Lea, 1945.Cole, F.: Explosions in anesthesia-a review of the literature,Surgery 18 : 7, 1945.Guedel, A. E.: Inhalation Anesthesia, New York, Macmillan,1937.Livingstone, H. 1f.: The present status of ethyleneoxygeneanesthesia, Ann. Surg. 122: 1071, 1945.1 Waters, R. M.: Cyclopropane a personal evaluation,Surgery 18: 26, 1945.INTRAVENOUS ANESTHESIAAdams, R. C.: Intravenous Anesthesia, New York Hoeber,1944. '•Adams, R. C. : Principles of intravenous anesthesia ,vith )g4;~thal sodium, Surg. C\in. No~th Ame tit.a ZS~ 788,CURAREBerfger, F. ~-, and W. Bradley: 11uscle-relaxing action0 myanes1n, Lancet 1 : 97, 1947.'•{ ,56 General AnesthesiaBerger, 11. N ., and W. Bradley: The pharmacological1>roperties of d :JJ di-h}•droxyI-r-(2 methyl-phenoxy)•J)ropane (111yanesi11), Brit. J. Pharn1acoJ. 1: 265, 1946.Cullen, S. C. : Curare in anesthesia, Surgery 18: 45, 194?Gray,T. C., and J. Halton: A milestone in anesthesia,( d-tubocurarine ch Ioride), Proc. Roy. Soc. Med. 39: 400, 11946.lVIclntyre, A. R.: Curare, Its History, Nature and Clin·ical Use, Chicago, Chicago Univ. Press1 1947.OXYGEN TIIERAPYAndre,vs, A. H., Jr.: l\,Ianual of Oxygen Therapy Techniques,Chicago, Yr. Bk. Pub., 1943. .Barach, A. L. : Principles and Practices of Inhalat1onatTherapy, Philadelphia, Lippincott, 1944 .III• 6IRegional AnesthesiaINTRODUCTIONTOPICAL ANI:STHESIAINJECTION ANESTHESIAREGION AL ANESTHETIC AGENTSREFRIGERATION ANESTHESIAPREPARATIONSINTRODUCTION' Regional (local) anesthesia consists of loss of pain in acircumscribed area of the body without loss of.~consciousness.It may be produced by the application of cold, pressureon the nerve trunks or by tissue an~mia; by suchagents as phenol or quinine; or by drugs which depresssensory nerves sttch as cocaine and its various syntheticsubstitutes, either applied locally to mucous surf aces orinjected by mea11s of a hypodermic syringe (Table 2).TABLE 2•LOCAL ANESTHETIC AGENTS GROUPED ACCORDINGTO THEIR CLINICAL USE• I AGENTS SUITABLE FORTOPICAL ANESTlIESlAONLYAGENTS SUITABLE FORINJECTION A~IAONLYAGENTS SUITABLE FORTOPICAL AND INJECTIONANESTIIESIACocaineTutocainc(also subcutaneous)FbenacaineElhylaminobcnzoateButacaineDiotbancAmylsineDut} klminobenzoatcnutesin picratcOrtbofonnProcaineApothesineLarocaine57TetracaineAmydricaine (too toxic forspinal)l!ttetycaineDibucaine•t58 • Regional AnesthesiaTOPICAL ANESTHESIA,No local anesthetic agent is absorbed in effective concentrationsthrough the skin, with the exception of phenol,which is now considered too toxic to be used clinicaUy.Cocaine and some of its synthetic substitutes, such asphenacaine, tetracaine and butacaine, are absorbed throughmucous membranes and are of value in eye, nose and throatwork or in urology. Some preparations as butyl aminobenzoate,butesin picrate, ethyl aminobenzoate and orthoformare highly insoluble and may be applied to openwounds or burns since they penetrate the tissues very slowly.Cocaine should never be used in conditions permitting rapidabsorption because of its high systemic toxicity.INJECTION ANESTHESIAProcaine and related compounds are the most widely usedagents for injection anesthesia. Alcohol and quinine saltsfind limited use because of their irritating properties,although they possess the advantage of a prolonged anes•lhetic action which may be useful in the relief of ,n eural-g1• c pai•n .Injection anesthesia may -be effected by local infiltration,field block or nerve block. In infiltration anesthesia, the •anesthetic agent is injected intracutaneous1y and subcuta•neously at the desired site of incision or in a painfuJ,area.In field block, injections are made around the site ofincision, cutting off the nerve supply to the area withoutrendering it edematous as in local infiltration. In nerveblocktechnics, the nerve supplying the field of operationis blocked by the accurate placement of the anesthetic agent' in or arouna "ine nerve 'trwiK a"t some &stance lrom fneoperative field. Special forms of nerve block include peri•dt,ral anesthesia, in which the spinal nerves are blockedby agents placed in the peridural space, and spinal or intra•dural anesthesia, in which the agents are placed in thesubarachnoid space. The former results in a slower onset•'I'Injection Anesthesia 59,of anesthesia since the agent must penetrate the perineuralsheath before reaching the nerve trunk. Since the spreadof the anesthetic drug is more limited than with spinal,there is less danger of producing respiratory depression orparalysis. With intradural anesthesia, the onset is rapid,the reaction more intense but upward diffusion of the drugthrough the cerebrospinal fluid may lead to respiratorydepression and failure because of paralysis of the intercostaland phrenic nerves.Spinal anesthesia may be used for all operations belowthe diaphragm. If the drug is permitted to ascend to ahigher level, respiratory paralysis may occur. It offers theadvantages of maximal muscular relaxation and little orno postoperative vomiting. It should not be used in nervousor apprehensive patients, in children or in very old patients,in the presence of degenerative heart diseases or of, veryhigh or low blood pressure, in patients with deformities ofthe spine, in the presence of infections in the region ofinjection, and in patients with diseases of the centralnervous system.The choice injection site in spinal anesthesia is the thirdor fourth lumbar interspace. The height to which anesthesiaascends depends upon the a1nou11t of anesthetic injected,the force with which it is injected, the specific gravity of,the injected fluid and the position of the patient. Thespecific gravity of normal spinal fluid is about 1.007. Solutionsfor spinal anesthesia which have a higher specificgravity than 1.007 are called hyperbaric; those with lowerspecific gravity are called hypobaric; if the specific gravityof the solution is equal to that of the spinal fluid, it iscalled isobaric. After injection into the spinal canal isobaricsolutions do not tend to shift position. If the pati;nt is nothorizontal, however, hyperbaric solutions run downward andhypobaric solutions float upward in the spinal fluid.C:u~al a1:esthesia is a special t:ype of peridural anes4thes1a in which the anesthetic agent is introduced through•••60•Regional Anesthesia•-·····•·- •• Spinal Cord- ---···-·- ~uhar-ic:11noul Sr-ice-··-··•····_,{)ura J.Jatcr-•··········SP n"II Nene Root(w11h1n the sulmracbno,d®-..·. Uonc Root of the Vertebral________ Ep1dur:il Sp:ic:eI- lntervt'rtcliral Foramcn...., ___ N~le ,n I'os,t,on {or Poro;,Btoi-k. The drug affects the -~--- Nttdlc an Position for Ep,d.,,~a~.rth~s,a Diffuses to some down 1n the space betfllcea the and the dura, affect111g sc,enl .. ~.~-~~~~---1'ecdle ,n Position for S/ltnal A11,drug bas 1otunatc contact with before the protecting conncctlYe en,elops them The ane~tbcs,this m;inncr 1s intense a11d may sprud Spinal anesthesia 1s a~nerve roots, not of the apinal cord_ .......: •.i "2~....,,,,~ ·-····-· Bone--Sacral Com=. w,th throuah the sacral hiatus------·-··- Nttd!e in Pos.iuon for Cotldol form of peridurill anesthesia}. ,cct~ enters the epidural spac.e caudal anesthesia, a form of a11estbcs1a.,._l '• Injection Anesthesia 61the sacral1hiatus into the caudal canal. It is used in obstetricsand for surgery of4 the perinea! region. Both caudaland spinal anesthesia can be administered either by singleor by repeated doses. For the latter purpose, a specialneedle or catheter is generally left in place and fresh solutioninjected as conditions demand, i.e., tl1e so-called continuousspinal or caudal anesthesia.Saddle-block anesthesia is a special type of spinal anesthesiain ,vhich the effect of the drug is limited to thelo\Vest spinal nerves and anesthesia is produced in the perinea!area. It has the advantage of producing minimalchanges in the cardiovascular system and of having noeffect on respiration and on uterine contractions.REGIONAL ANESTHETIC AGENTS~ I• IThe· ideal drug for regional anesthesia should be stable, ,,water-soluble, no11irritating to tissues or nerves and of lo,vsystemic toxicity. It should provide an adequately longperiod of anesthesia with a prompt onset, and on recoveryexcessive sensitivity (hyperesthesia) or distorted sensations(paresthesias) should not be present. Finally, it should becapable of withstnndi11g sterilization and should be rela- _,,lively ir1expensive.The injection of a regional anesthetic agent does not result•1n an immediate paralysis of all nerve fibers. The autonon1icfibers are affected first, then the sensory, and finally tl1emoto:· According to Gasser and Erlanger, the size of theconstituent fibers is the most important factort the smalJestfibers being the most susceptible. Pain is the first sensationto disappear, followed by cold> warmth, touch, joi11t anddeep pressure. Recovery results in the return of sensationsin the reverse order.Potentiation of Local Anesthetics. The addition of a •vasoc..onstrictor such as epinephrine to . local anestheticagents results in an increased duration of anesthesia and a'lo,,·cred threshold concc11tration since absorption of the••I/,62 Regional Anesthesiadrug is retarded by the vasoconstriction. Epinephrineismost commonly used for this purpose (see Chapter 11).The addition of alkali to local anesthetic agents increasestheir efficiency to the extent that the free bases penetratetissues more readily than their salts. However, the use ofthe free base would only be of advantage in topical anes•thesia. The free bases, although more potent, are so insolu•ble as to be impractical for injection anesthesia, and thelocal anesthetics are generally marketed as the hydrochloridesalt. Since their activity is due to the liberation offree base by the tissue fluids, it is difficult to obtain a properdegree of anesthesia in an acutely inflamed area or whereveran acid reaction i.n the tissues is encountered .Biologic Assay. Various technics are used for testinglocal anesthetic agents. Cocaine or procaine usually serves asthe standard of reference. Topjcal anesthesia can be assayedby the duration of loss of sensation occasioned by placingthe agent on the mucosa of the human tongue, in the rabbit'scornea or on the frog's skin. Infiltration anesthesia. may beTABU: 3COMPARATIVE TOXICITY OFVARIOUS LOCAL ANESTHETIC AGENTS•SUBCUTANl:OUS LD50 FORCUINEA PIOS IN Y.G./KG.(TOTAL SAFE DOSE:J i"ORJ IUY,A NS) ______________ , __________ fProcaine (novocaine) ................. .Eucaine (Beta-eucaine) ............... .l.\.fetyc.a ine (neothe.sin) ................ . Laroca1ne ..... ' • • . . . . . .. • ........... .Amylocaine (stova!ne) ................ .Tutocaine .•. • • • • • • • • • • .. • • • • • • • • • • • • • •Butacaln~ ................ .,... .......... .Amydricaine (alypin) • • • • • • •• • • • • • • • • • •• Coca in~ ••• • • • • • • • • • • • • • • • • • • • • • • • • • • • •Phenacalne (hoiocaine) • • • • • • • • • • • • • • • •Tetra.caine (pontocaine) • • • • • • • • • • • • • • • •Dibucaine (nupercaine, percalne) • • • • • • • •43031030020020019070 ,oso- so• 3010IlRegional Anesthetic Agents 63tested by raising an intradermal wheal in human beings orguinea pigs. Rabbits are usually used for the study of spinalanesthesia. Toxicity is generally determined by injectingthe agent subcutaneously into laboratory animals. Bieterhas shown that the subcutaneous LD50 for guinea pigs,expressed as mg./Kg., is equivalent to the total safe dose inmg. for human beings; values for the more commonly usedagents are presented in Table 3. The LD 50 may be greatly• increased by prior administration of barbiturates.Toxicity. Toxic reactions from local anesthetic agentsmay result from idiosyncrasy, from rapid absorption fromthe site of injection, or from accidental intravenous injection.Symptoms include excitement, apprehension andanxiety, dizziness, severe headaches, convulsions and fall inblood pressure. Death is due to cardiovascular collapse. and respiratory failure. Prophylactic measures include slowinj~tion, the use of dilute solutions, aspiration to insur~that intravascular penetration has not occurred, the additionof epinephrine or other suitable vasoconstrictors todecrease the rate of absorption, and the administration ofpressor drugs, such as ephedrine, to combat the fall ofpressure which occurs in spinal anesthesia following paral-. ysis of the sympathetic nerves. The administration of ashort-acting barbiturate an hour or so before anesthetizationdoes much to reduce the central stimulation.Treatment of acute symptoms of poisoning include immediateinterruption of administration, intravenous barbituratesto control convulsions, injections of epinephrine tocombat the fall in blood pressure, and the use of oxygenand artific.ial respiration to combat/respiratory depression.In _spinal anesth~a, withdrawal of a small volume of spinalfluid may result 1n the removal of appreciable quantities ofthe drug. If the injection was made in an extremity a!ourniquet should be applied proximal to the injection site,1n order to stop further absorption of the drug.64 Regional Anesthesia•Metabolism. Local anesthetic agents are hydrolyzedchiefly by the liver; the variations in their toxicity areproportional to the rate at ,vhicJ1 they are metabolized• One of the products of l1y<lrolysis of procaine and relatedcompounds is para-aminobenzoic acid, ,vl1ich may interfere8•1GCOllle•,vith the activity of concomitantly administered sulfonamides(see Chapter 29). ,Chemistry. Because of the toxicity of cocaine and itstendency to produce habituation, numerous compounds havebeen synthesized in the hope of developing a Jess dangerousanalogue. The structtrres of the more important of theseand their rel,,!--. "- ----!-- """" .,.1-,,,....,._ .,1,.,.,..,.,. n,1. ••• •--- · -•.•,,.I.Regional Anesthetic Agents 65of active local anesthetic agents are sho,vn on this page.The lack of specificity for local a11esthetic action is ,veilillustrated by the diverse nature of the synthetic compounds,although it can be seen that the most ,videly developedclass is that of the alkamine esters of benzoic or para-aminobenzoicacid. Alterations in the lengtl1 of the alkyl chain orin the nature of the substitutions on tl1e amino group resultin only minor changes in pharn1acologic action.~~N V\==:/"'-1 C-O-CH 3OHOld orthoform\ Elhylommobe11zoeo tNuperca,ne0 CH 0- 11 125CH=-CH-C-0-CH-CH-Cti -N2 2 2 \C2H5•Phenoco1ne•Cocaine is an alkaloid obtained from the leaves ofErytl1rox31lo1i coca, a tree indigenous to Peru, Chile andBolivia. For centuries, the Indians of South America havechewed coca leaves mixed with an alkali, such as limeor charcoal, to allay hunger and to increase endurance.The alkaloid \vas fttst isolated by Gaedecke in 1855 and 1becan1e know11 as erythroxylin. It was rediscovered in 1859b?' Niemann, ,vho n~med it cocaine. Its anestl1etic properties,1rere f1t5t noted by \Vohler in 1860, but it was not ~~....._ - ..... , J ,. •••. --II\'\l66 Regional Anesthesia1introduced clinically until 1884, when Koller demonstratedits usefulness as a topical anesthetic in ophthalmology.In 1885, Halsted used cocaine for nerve-block anesthesiaand in the same year Corning used it experimentally as aspinal anesthetic.in dogs. It was introduced for this purposein patients by Bier in 1898 and its adoption immediatelybecame widespread until its toxicity was realized, where-• upon it soon was replaced by Jess toxic substitutes.The use of cocaine is now limited to surface application.It should not be used where repeated administration is nee•essary, since this may lead"' to habit formation, which ischaracterized by alternate periods of elation and depression,loss of appetite and weight, insomnia and moral degenera•tion. Sensory hall~cinations are common. Cocaine is fre•quently taken by addicts as a snuff, which may lead to nasalabscesses.The acute toxic effects of cocaine are those of centralstimulation, followed by depression, and stimulation of thesympathetic nervous system. The latter effect is apparentlydue to a suppressive action on the amine oxidase (see Chapter11) and is manifested by such effects as pupillary clila·tion, vasoconstriction and tachycardia. Cocaine has apyretic action, possibly due to a direct action on the temperature-regulating center.Procaine (novocaine) was prepared by Einhorn in Germanyin 1905. It is much less toxic and almost as effectiveby injection as cocaine, although it is not so rapidly ab·sorbed from mucous surfaces. It is probably the most widelyused agent for injection anesthesia. It does not possess thehabit-forming properties or the sympathomimetic action ofcocai• ne.Procaine is detoxified rapidly by the liver and may beadministered jntravenously if injections are given slowly andhigh dilutions of the drug are used. Intravenous procainehas recently been used in the treatment of painful burnsand injuries and in childbirth. It aooarentlv affect,; the••Regional Anesthetic Agents 67/nerve endings in the painful region in concentrations toolow to affect those in other parts of the body. Intrqvenousprocaine has also been used in the treatment of serum sicknessand to protect the heart in cyclopropane anesthesia., l\1uscle aches and sprains may of ten be dramatically and. • permanently relieved by the local infiltration of procaine.Procaine is used for infiltration anesthesia in concentrationsof 0.25 to 1.0 per cent combined with epinephrine(1: 100,000 to 1: 200,000). Approximately from 2 to 4 cc.of a 5 per cent solution are usually used for spinal anesthesia.Dibucaine (nupercaine) is a quinoline derivative preparedby Uhlmann in 1929. It combines the qualities of cocaineand protaine in that it is effective both for topical andinjection anesthesia. It is more toxic than cocaine but itsanesthetic properties are correspondingly greater. It is usedin concentrations of from 1 in 2,000 to 1 in I,000 for infiltrationanesthesia, and in l_in 1,500 solution for spinal anes-,, thesia, the average dose being from 10 to 15 cc.Metycaine was first prepared by McElvain in 1927. Likedibucaine, it is effective both topically and by injection.It is somewhat more toxic than procaine. It is applied tomucous surfaces in concentrations of from 2 to 10 per centand is used in 0.5 to 1 per cent solutions in infiltration anesthesia.It has also been used as a spinal anesthetic.ITetracaine (pontocaine) has recently been used quiteextensively for spinal and caudal anesthesia. It is muchmore toxic than procaine, but gives a prolonged period ofanesthesia. Spinal anesthesia may be achieved with from2 to 4 cc. of a O.S per cent solution.Eucaine (Beta-eucaine) and amylocaine (stovaine) aremainly of historical interest. Eucaine was one of the earliest?>caine substitutes being synthetized by Vinci in 1897. It1s somewhat less toxic than cocaine but is fairly irritatingto the tissues. It is no longer included in the United StatesPharmacopoeia. Amylocaine was synthesized by Fourneau• •''/...,68 Regional Anesthesia ••in 1904 and still finds some use, particularly in Europea, sa spinal anesthetic. It is irritating, however, and highly toxic.•REFRIGERATION ANESTHESIARefrigeration anesthesia was introduced by Allen in 1941.It is applicable only to the extremities. Surgery may beeffected with a minimum of shock and blood loss. It is ofparticular value for amputations of severely traumatizedor gangrenous limbs. Absorption of toxic products is pre•vented by the application of a tourniquet, and pain is 11lleviatedby a rapid cooling of the limb to from 2 ° to 8 ° C. byapplication of ice or by a refrigeration machine. At thistemperature, the activity of the tissues is suspended andthe spread of infections halted; hence, amputation can bedelayed for several days if necessary. Refrigeration withouttourniquet has on occasion saved a badly infected limbthat would other,vise have had to be amputated.PREPARATIONSCocaine U.S.P.; B.P.Cocaine hydrochloride U.S.P.; B.P.'Procaine hydrochloride U.S.P.; B.P. Procaine borate N.N.IlProcaine nitrate N.N.RTetracaine hydrochloride U.S.P. Ametbocaine hydrochlorideB.P •Phenacaine hydrochloride U.S.P.Ethyl aminabenzoate U.S.P. Benzocaine B.P.Ethyl aminobenzoate ointment U.S.P.; S per cent ethylaminobenzoate in white ointment.Butacajne svJf.ate U.S.P,Butyl aminobenzoate U.S.P.Amylocaine hydrochloride B.P.Amydricaine hydrochloride N .N .R.Amylsine hydrochloride N .N.R.Apothesine hydrochloride N .N .R.Diothane hydrochloride N .N.R.• •,,jI•I Preparati•o nsLarocaine hydrochloride N .N .R.?\1etycaineh ydrochloride N .N .R.Dibucaine hydrochloride N.N.R.Tutocaine hydrochloride N .N .R.Monocaine hydrochloride N.N .R.Butesin picrate N .N .R.Orthoform N.N.R.•BIBLIOGRAPHYGENERAL69IAllen, F. M.: Intravenous obstetric anesthesia-pre~liminary report, Am. J. Surg. 70: 283, 1945.Bro,vn, H. O., J. M. Thomson and J. E. Fitzgerald: Ananalysis of 500 obstetrical cases with continuous caudalanesthesia using pontocaine, Anesthesiology 7: 355,1946. •Burn, J. H.: The testing of local anaesthetics, Brit. l'.{.' Bull. 4: 82, 1946.Fraser, R. J.: Continuous spinal or lumbar ana~sthesia,Canad. M. A. J. 54: 363, 1946.Gasser, H. S., and J. Erlanger: The role of fiber size inthe establishment of a nerve block by pressure orcocaine, Am. J. Physiol. 88: 581, 1929. .Gordon, R. A.~ Intravenous novocaine for analgesia in. burns, Canad. M.A. J. 49: 478, 1943.Hershey, S. G.: Imperfections of spinal anesthesia, NewYork State J. Med. 45 : 1761, 1945.Hirschfelder, A. D .. and R. N. Bieter: Local anesthetics,Physiol. Rev. 12: 190, 1932.Johnson, K., and C. R. A. Gilbert: Intravenous procainefor obstetrical anesthesia, Anesth. & Analg. 25: 133,1946. 'Knoefel, P. K., R. P. Her,vick and A. S. Loevenhart':The prevention of acute intoxication from local anesthetics,J. Pharmacol. & Exper. Therap. 39: 397, 1930.Lul!, C. B., and R. A. Hingson: Control of Pain in Childbirth,Philadelphia, Lippincott, 1945. ·itaxson, L. H.: Spinal Anesthesia Philadelphia Lippincott,1938. • 'f<I'70 l Regional Anesthesia'Pitkin, G. P.: Conduction Anesthesia, Philadelphia, Lippincott,1946.State, D., and 0. H. Wangensteen: Procaine intrave•nously in treatment of delayed serum sickness, J.A.M.A. 130: 990, 1946. .REFRIGERATION ANESTHESIAAllen, F. M.: Reduced temperatures in surgery-I. Surgeryof limbs, Am. J. Surg. 52: 225, 1941.Crossman, L. W., and F. M. Allen: Shock and refrigeration,J.A.M.A. 130: 185, 1946.Kanaar, A. G.: Refrigeration in the treatment of trauma,,vith revie\v of crymotherapy, Anest. & Analg. 25: 177,228, 1945.Melick, D. W.: Relrigera.tion anesthesia, Am. ]. Surg,70: 364, 1945.- J •••7. •H)'pnotics and SedativesINTRODUCTION SULFONALBARBITURATES • BROMIDESCHLORAL HYDRATE ANTIEPILEPTIC DRUGSPARALDEHYDEINTRODUCTIONHypnotics are drugs used to induce sleep when ~eeplessnessis not due to a definite stimulus, such as pain, dyspneaor itching, which prevents sleep or awakens the patient.Sedatives are drugs which allay excitement and reducemotor activity without necessarily inducing sleep. Hypnotics 'in small doses usually have a sedative action,,The-choice of hypnotics depends to a large extent on thenature of the insomnia. The patient may have difficulty in •falling asleep but once asleep may rest soundly. In suchcases a drug acting promptly but with a short duration ofaction will suffice. A longer-acting drug is indicated forpatients who fall asleep readily but awaken during thenight and fall asleep again with difficulty or for patients whoexperience periods of wakefulness during the night. Suchtypes of insomnia are usually due to some emotional disturbanceand wherever possible the underlying cause shouldbe treated without recourse to drugs. Hypnotics should beprescribed only if the emotional tension is transitory, suchas anxiety preceding.,-a surgical operation or grief at a bereavement,or if the lack of sleep is seriously impairing thepatient>s health and welfare. • 11-•72 Hypnotics and Sedatives \Hypnotics, with the exception of morphine, do not relievepain though they may dull the consciousness of pain per•ception sufficiently to permit sleep. Ioeally, a hypnotic shouldhave no subsidiary effects on the circulation, respiration ormetabolism. It should cause no pre-excitement or post•depression and should rapidly produce a natural sleep fromwhich the patient awakes refreshed and relaxed. The efficacyof a hypnotic is enhanced if, in addition, sleep-inducingconditions such as a quiet and darkened room, adequatewarmth and the absence of exciting stimuli are provided.BARBITURATESBarbituric-acid derivatives were introduced into medicinein 1903 when the hypnotic action of diethyl barbituric acid(barbital, veronal) was established by Fischer and vonMering. Since that time, hundreds of derivatives have beenstudied, partly because of the ease with which such com•pounds can be prepared and tested and partly because ofthe great demand for barbiturates not onJy as hypnotics butalso as sedatives, anticonvulsants, basal anesthetics andgeneral anesthetics.Chemistry. Barbituric acid (malonyl urea) is prepared bythe condensation of urea with malonic add: 1Urea MalonicAcidIMalonyl Urea(Barbituric acid)The replacement of both hydrogen atoms in position 5 byalkyl or aryl groups results in compounds with a hYPnotic 'action. If the substituting groups are chemically stable, the•IBarbiturates ' 73•(compounds appear to be stable under the metabolic con,ditionsof the body and are long-acting. If the groups containbranched chains or double bonds, they are apt to be n1ore• rapidly destroyed in the body and thus are short-acting.Replacement of the oxygen in the 2 position by sulfurresults in compounds known as thiobarbiturates which haveexceptionally short periods of action. Thiopental sodium(pentothal) is an example of this group. Substitution in thel and 3 positions may result in compounds having a convulsantaction.'\The substituted barbituric acids ate not very soluble inwater but are fairly stable. The sodium salts are readilysoluble in water but the solutions are not very stable and _may form toxic decomposition products. \Vhen barbituratesare used intravenously, fresh solution of the sodium saltsshould be prepared.Pharmacology. Therapeutic doses of barbiturates havelittle action bther than depression of the higher brain cen•ters. In toxic doses they also depress the spinal cord. Athigher dosage levels they may have :i mildly depressant,action on smooth muscle and on the kidney. The heart isnot affected by therapeutic doses, but may be secondarilya.ffected by toxic doses ,vhich cause profound respiratorydepression and peripheral vasodilation.In vitro, the barbiturates have a depressant effect on the/r.arbohydrate metabolism of the brain, probably through aninterference with oxidation-reduction reactions of flavoproteinby the cytochrome system. Since the oxidation of succinateis not affected, antagonism of barbiturate-induceddepression by large doses of succinate is theoretically pos•sible. In practice, the metabolism of succinate by the liveris so rapid that usually inadequate amounts are availableto the brain, and the administration of succinate to bar.biturate.poisoned animals or man has for the most partyielded erratic results. '•'I'I'••'- J ,74 Hypnotics and SedativesClassification. Barbiturates can be conveniently classi-• .fled according to duration of hypnotic action. Barbiturates'with a long action include phenobarbital (luminal) andbarbital ( veronal} ; with an inter1nediatea ction, amytal, dial,probarbital (ipral), alurate and neonal; with a slzort action,nostal, ortal, pentobarbital (nembutal), phanodorn, pernoston,seconal, sandoptal and vinbarbital; and with an ttltrashortaction, effective only when given intravenously, hexo-'barbital (evipal) and thiopental sodium (pentothal).Clinical Uses. The most common use of barbiturates isfor the treatment of insomnia .. Their use as basal and generalanesthetics is discussed in Chapter 5. They are effectiveantidotes for convulsant poisons, pentobarbital and arnytalbeing probably the most useful drugs for this purpose.Amytal has found special use in psychiatry to produce astate comparable to hypnosis (amytal interview) in •whichthe patient will talk freely and be susceptible to suggestions.The use of phenobarbital in the treatment of epilepsy isdiscussed under antiepileptic drugs in this chapter.Toxicity and Antidotes. Acute barbiturate poisoning,either from accidental overdosage or from suicidal attemptsis one of the most common forms of drug toxicity encounteredin present-day practice. The symptoms are nonspecific.Usually there is confusion, ataxia, vomiting, motor excite-, • ment followed by coma, shallow, rapid respiration, fixedmiotic pupils, thready pulse, low blood pressure and absenceof reflexes. The specific antidote for barbiturate poisoning ispicrotoxin. It should be given in small repeated doses or bycontinuous infusion at the rate of approximately 1 mg. perminute until the wink teflex returns. The dosage can thenbe reduced but the drug should not be discontinued untilconsciousness returns since it is rapidly detoxified by thebody, following which severe depression may again set in.Supportive '.measures include gastric lavage and intravenousfluids to promote diuresis and thus assist in the removal ofthe drug. Artificial respiration may be necessary if therespiration is greatly depressed.•',•' Barbiturates 75,tAmphetamine sulfate, by intravenous injection, has alsobeen used in the treatment of acute barbiturate poisoning.It is less liable to cause convulsions than is picrotoxin andis usually more readily available.A particular danger of barbiturates is that a single dosemay lead to a mental dulling and a disorientation as to timeand place; consequently, the patient may take additionaldoses, and accidental intoxication may ensue. Repeated useof barbiturates may lead to habituation; a marked cravingfor the drug may be developed but true abstinence symptomsdo not follow its withdrawal. It is debatable whether prolongedu.s e of the barbiturates lead.s to chronic poisoning ~though there is considerable evidence to indicate that thisis the case. Degenerative changes have been reported inanimals given barbiturates over long periods and clinicalreports suggest that mental deterioration may occur in manafter long-continued administration. /Occasionally individuals are hypersensitive to barbituratesor may display side-actions or excitement and delirium afterther~peutic doses. Dermatologic lesions are not infrequentand are manifested as wheals or an angioneurotic edema orIby skin rashes which resemble measles or scarlet fever. Theselesions, occur more frequently with long-acting than withshort-acting barbiturates. \The dangers of promiscuous use of barbiturates has led 'to their being available only ()n a physician,s,prescription inmany states. As a further precaution, it is advisable to.limitthe amount prescribed to a minimum and to designate theprescriptions are nonrefillable. .CHLORAL HYDRATEH/ cc1.-c-0:a',l'oa ' '••'' 76 ' IIypnotics and SedativesChloral hydrate was introduced into medicine by Liebreichin 1869. It achieved immediate popularity as a hyp·notic, morphine being the only other such drug a,•ailable at• that time. It still remains one of the safest, best and leastexpensive hypnotics. It acts rapidly because of its readysoJuhility and produces a natural sleep of short duration.Chernically related substances with similar though somewhatweaker hypnotic effect include butyl chloraJ hydrateand chloro-butanol (chloretone). The latter compound isis also a mild local anesthetic, antiseptic and preservative.Disadvantages of chloral hydrate include its pungent odorand bitter taste and its habit-forming tendencies. It is somewhatirritating to mt!cous membranes unless adequatelydiluted with water. It should not be used in patients withgastritis. In therapeutic doses, it is probably not toxic to theheart though it should be used with caution in the presenceof heart disease. The fatal dose of chloral hydrate 1s usuallyconsidered to be about 10 Gm. though fatalities have resultedfrom considerably less. Toxic effects include' cardiac an<!respiratory depression. Treatment consists of the use of- central nervous system stimulants, intravenous fluids andgood nursing care. Introduction of chloral as a hypnotic "'asdue to the fact that Liebreich thought it was decomposed inthe body to chloroform and formates, a reaction known tooccur in the presence of alkalis. It is now known to circulateunchanged in the body and to be excreted conjugated withglucuronic acid as urochloralic acid.PARALDEHYDE(CHiCHO)a•Paraldehyde was introduced as a hypnotic by Cervelloin 1882. It is a remarkably safe and rapidly acting drug: Itschief use is in mental institutions to tranquillize eJtcited1 patients. It has recently been used for preoperative sedationand to produce analgesia and amnesia in childbirth. It isBarbiturates 77usually administered orally or rectally. It can be administeredintravenously to obtain a prompt effect but this routeis not without danger of emboli formation or direct depressionof the heart. Intramuscular injection may cause localirritation and tissue damage.The disadvantages of paraldehyde include its disagreeabletaste and the fusel-oil-like smell it imparts to the breath. Itis excreted in part by the lu.ngs and should be avoided inbronchitis and pneumonia since it stimulates bronchial secre-'tions. \Vhile the drug is of very low toxicity, deaths from'idiosyncrasy have been reported. It should be carefullystored since it tends to decompose with the formation ofperoxides and an increase in acidity.....SULFONAL' CHa SOi C2 H&"-c/ I/ " CH3 S02 C2 Hr;'Sulfonal (sulfonrnethane) introduced in 1888, is nowlittle used except in institutional practice. It is particularlyuseful to sedate cases of chronic mania because of its prolongeddepressant action. It is absorbed and excreted slowlyand is cumulative with repeated dosage. Toxic effects includedepression, ataxia, gastro-intestinal upsets, and kidney irritation.The urine may be a cherry-red color, due to thepresence of hernatoporphyrin. 'Trional (sulfonethylmethane) is related chemically tosulfonal. It is more rapidly absorbed and excreted, andsomewhat less toxic.I BROl\IIDES~Bromides' were first introduced into medicine in 1840to replace potassium iodide in the treatment of syphilis.They proved ineffective for this purpose but in 1853 theirvalue 1n the treatment of epilepsy was recognized by Locock.,-••,•I •' • ~' 78 Hypnotics and Sedatives•Their usefulness as hypnotic agents is limited by the factthat their full effect does not develop with a single dosewhile administration over prolonged periods may lead tochronic bromide intoxication (bromism). Both inorganic(sodium, potassium and ammonium salts) and organic prepiarations (bromural{ carbromal) are available. The latter aregenerally less toxic, less effective hypnotics and are moreexpensive. A number of patent headache remedies and coldcures contain bromides and are not infrequently the cause ofbromism through self-medication.Symptoms of brom.ide poisoning include headache, rest·lessness, diminished power of concentration, mental confu.sion and delirium. Bromide rashes occur rather frequentlyand are probably due to an idiosyncrasy toward the drug.The effect of bromides is determined by the degree of substitu tion of bromide ions for chloride ions in the body.Decrease of sodium-chloride intake wi11 increase the rate ofsubstitution. Symptoms of toxicity will usually appear beforea 40 per cent substitution is attained. Treatment ofbromism consists of the oral or intravenous administrationof sodium chloride to displace the bromide ion by chloride.ANTIEPl.L EPTIC DRUGS, ~Antiepileptic drugs are agents used in the treatment ofepilepsy. They are frequently referred to as anticonvulsantsthough they· do not necessarily control convulsions otherthan those of epilepsy. Epileptic seizures are usually classifiedinto three main types on the basis of clinical mani-~ f estations and electt'bencephalographic records.GRAND-MAL seizures are characterized by convulsions andby the rapid rhythm of the brain waves.PETIT-MAL seizures consist of temporary lapses of consciousnesswith immobility or with slight muscular twitching'or jerking, usually confined to the eyelids or the brow.The brain records generally show alternating slow andfast rhythms. ,,.J - lAntiepileptic Drugs 79PsYCHOMOTOR ATTACKS are characterized by periods ofamnesia during which the patient may perform irrational 'acts. The brain waves are abnormally slow and, unless thepatient also suffers from grand- or petit-mal attacks, convulsio~s rarely occur. •In view of the great differences among the various typesof seizures, it is not surprising that none of the existingtherapeutic agents is universally satisfactory in the treatmentof epilepsy.\Vith the exception of petit mal, which occurs chiefly inchildren and which frequently disappears spontaneously,the treatment of .epilepsy usually has to be continued indefinitely.The inherent toxicity of a new antiepileptic maytherefore not be recognized immediately and a compoundshould not be deemed nontoxic until it has been usedcontinuously over a period of years. The drug of choiceshould have no hypnotic, sedative or depressant action. Its.h ould not affect adversely the mentality of the pa-tient or interfere with his normal activity. The dosage should bedetermined by the patient's response, and the drug shouldbe withdrawn if no apparent benefit is derived from it.Furthermore, tl1e preparation should be easy to administer,not unpleasant to take and should be relatively inexpen-s1• ve.Bromides as Antiepileptics. The inorganic bromides' have been used in the treatment of epilepsy since 1853 butare rapidly being superseded by newer preparations whichare less toxic and more effective. The main disadvantageof the bromides is that they tend to hasten the mental de•terioration of the patient; in addition, brom.ism frequentlyoccurs on prolonged administration. The organic bromidepreparations are of little value in the treatment of epilepsy.Phenobarbital (luminal) was first used for epilepsy inGermany in 1912: It was introduced into America shortlyaftenvards but did not receive wide use until after World\Var I when domestic manufacture of the drug became pos-\' ,,..II'••80 Hypnotics and Sedatives,sible. It is usually administered orally in tablets but ifnecessary can be injected intravenously or intramuscularlyin the form of the sodium salt. There is some disagreementas to whether it impairs the mentality after prolongedmedication. It usually has a sedative and depressant effectcausing the patient to feel drowsy and dull. The suddenwithdrawal of phenobarbital frequently results in the precipitationof a series of epileptic seizures so that if another~ drug is to be substituted, phenobarbital should be wjtb.drawn gradually over a period of weeks.The barbiturate mebara1 or prominaJ (N-metbyl, ethylphenylbarbituric acid) is sometimes used in place ofphenobarbital, especially in Europe. It is less toxic thanphenobarbital and is said to have a less depressing effect.••(DiphenylhydantoinIDiphenylhydantoin sodium (dilantin) was introduced in ,• J937 by Putnam and l'\,Ierritt a.fter a systematic evaluationof the anticonvulsant activity of a Jarge number of drugs byanimal experimentation. It is structurally analogous to thebarbiturates, being derived from glycolyl urea instead ofma1onyl urea. In therapeutic dosage, it has a relatively weakh.ypn.atic and sedative action. It is most effective in grand•mal and psychomotor seizures and relatively Jneffective inpetit mal. It is frequently administered along with phenobarbital,a combination of the two drugs being of ten moreeffective than either alone. Even with therapeutic doses,annoying toxic symptoms may occur so that a~mini.strationshould be under careful medical supervision. Toxic effectsIAntiepileptic Drugs 81•,•include muscular inco-ordination, gastro-intestinal upsets,, skin rashes, hyperplasia of the gums, and occasionallyhirsutism. Ordinarily the drug tends to have a stimulatingrather than a depressing effect and occasionally may causehallucinations and delirium.\N-Methyl, phenylethylhydantoin (mesantoin, phenantoin)has recently been introduced for the treatment ofgrand-ma! seizures. It appears to lack some of the undesirableattributes of diphenylbydantoin, such as the production' of muscular inco-ordination or gum hyperplasia. However,CH -N-C=OIH-N Ithere is evidence that some patients develop tolerance tothe drug.Nirvanol (phenylethylhydantoin) was introduced about1919 as a hypnotic and sedative. It was later widely usedin the treatment of chorea. It is little used now because ofits toxic manifestations, which include a rise in temperature,skin lesions, edema and eosinophilia.ITridione-Trimethad{one ( tridione). Tridione is a member of aseries of drugs ,vhich possess hypnotic, analgesic and anticonv~lsant properties. Preliminary clinical reports indicatethat it may prove of considerable value in petit mal and•~'I,'••82 • Hypnotics and Sedativespsychomotor seizures. It is of little value in the treatmentof grand mat, and may even be barmf ul in this condition.Its most outstanding toxic effects are the production ofphotophobia and disturbances of color vision. Other toxicsymptoms include gastric upsets, skin eruptions, light- 1headedness and drowsiness. Recently, blood changes havebeen reported following the use of trimethadione, includingfatal cases of aplastic anemia, indicating that the drugshould be used cautiously, until its toxic and therapeuticpotentialities are more fully evaluated.Miscellaneous Agents. Petit mat is occasionally sue~cessfully treated with stimulants such as caffeine andamphetamine sulfate. The production of acidosis or ofketosis and the administration of glutamic acid have alsobeen advocated but the regimens are usually distastefulto the patient and the results for the most part are disappointing.PREPARATIONSBarbital U.S.P.; B.P. 300 mg.•Barbital tablets U.S.P.; B.P. Usually contain 300 mg. bar·bital.Barbital sodium (soluble barbital) U.S.P.; B.P.Barbital-sodium tablets U.S.P.; B.P. Usually coi:itain 300mg. barbital sodium.Phenobarbital U.S.P.; B.P. 15-100 mg.Phenobarbital sodium (soluble phenobarbital) U.S.P.; B.P._Phenobarbital tablets U.S.P.; B.P .. Usually 15, 30 and·100 mg.Phenobarbital-sodium tablets U,S.P.; B.P, Usually 30 and_ 100 mg.Elixir of phenobarbital U.S.P. Contains not less than 0.37• Gm. or more than 0.43 Gm. phenobarbital in 100 cc.Pentobarbital sodium U.S.P.; B.P. 100 mg.Pentobarbital-sodium tablets U.S.P. Usually 30, 50 andtoo mg.•Preparations 83~Pentobarbital-sodium capsules U.S.P. Usually 30 and 100mg.Alurate N .N .R. 65 mg. ,Amytal N.N.R. 100-300 mg.Dial N .N .R. , 100-300 mg.Probarbital N.N.R. 120-250 mg.·Neonal N.N.R. 50-100 mg.Nostal N.N.R. 100-300 mg.Ortal N.N.R. 200-400 mg.Pernoston N.N .R. 200 mg.Phanodorn N.N.R. 200 mg.Sandoptal N.N.R. 200 mg.Seconal N.N.R. 100-200 mg.Vinba.rbitaNl .N. R. 100-200 mg.Chloral hydrate U.S.P.; B.P. 0.6-1.2 Gm.Butylchloral hydrate N .N .R. 0.3-1.3 Gm.•Chlorobutanol( chlorbutol) U.S.P.; B.P. 0.6 Gm.•\•Paraldehyde U.S.P.; B.P. ~-8 cc.Sulfonmethane N.F.; Sulphonal B.P. 0.3-1.2 Gm.Sulfonethylmethane N.F.; ?\lethylsulphonal B.P. 0.3-1.2Gm.Pota5":>iubmro mide U.S.P.; B.P. 1 Gm.Sodium bromide U.S.P.; B.P. 1 Gm.Tablets of potassium bromide B.P. Usually conta, in 0.3 Gm.potassium bromide.Bromural N.N.R. 0.6 Gm.Carbromal N.N.R.; B.P. 0.3-1 Gm. 'DipJienylhydantoin sodium U.S.P. 0.1 Gm.Diphenylbydantoin sodium capsules U.S.P. Usually 30 and100 mg.Trimethadione N.N.R. 0.3 Gm..BIBLIOGRAPHYGENERALFisher, J. \V.: The emerge11cy narcotic treatment of themental case, Practitioner 152: 108l 1944.,\•,'••' I,IHypnotics and SedativesfI IGrabfield, G. P.: The use of hypnotics, J.A.lvt.A. 107:1381, 1936.Reitman, F.: Pharrnaco•hypnosis treatment of neuroses,Practitioner 149: 175, 1942. '?ice, R. V.: The synthetic organic hypnotics, J. Am.•• Pharm. A. (Scient. Ed.) 33 :289, 1944.Solomon, M.: Insomnia, M. Clin. North America 29: 178, .1945.BARBITURATESDorsey, J. F.: The picrotoxin treatment of barbituratepoisoning, J. N erv. & Ment. Dis. 99: 367, 1944.Freireich, A. W., and J. W. Landsberg: Amphetamine(benzedri11e) sulfate for acute barbiturate poisoning,J.A.M.A. 131: 661, 1946.Hambourger, W. E.: A study of the promiscuous use ofthe barbiturates, th~ir use in suicides, J.A.M.'A. 112:1340, 1939 .Hambourger-, W. E.: The promisc11ous use of the barbiturates.Analysis of hospital data, J.A.l\I.A. 114: 2015,1940.Tatum, A. L.: The present status of the barbiturateproblem, Physiol. Rev. 19: 472, 1939.PARAI.DEHYDE• Kane, H. F., and G. B. Roth: The relief of labor painsby the use of paraldehyde and benzyl alcohol, J.A.~{.A.107; 1710, 1936.BROMIDES• Gundry, L. P.: Bromide intoxication: report of fifteencases, J.A.1'.1.A. 113: 466, 1939. .Kane, H. F., and G. B. Roth: Hazards of bromidism in" proprietary and uncontrolled hypnotic medicatjon,Council Report, J.A.M.A. 115: 933, 1940. -Kracke, R. R., and W. R. Platt: Bromide 'intoxicationfrom prolonged self medication with B.C. HeadachePo,vder: report of t,vo cases, J.A.1\f .A. 125: 1071 1944,ANTIEPlLEPTIC DRUGSDeJong, R. N.: Effect of tridione in the control of psy•chomotor attacks, J.A.M.A. 130: 565, 1946.Stern, L., L. Eisenbud and J. Klatell: Analysis of oralreactions to H • • • • • • ~ ~ • ...... • • -- • r.-r. .,- 1~1943.• Bibliography 85, ~Everett, G. M., and R. K. Richards: Comparative anticonvulsiveactio11 of 3, 5, 5-trimethyloxazolidine-2, 4-dione (tridione), dilantin and phenobarbital, J. Pl1ar-, macol. & Exp er. Therap. 81 : 402, 1944.Grinker, J.: Experiences \.vith luminal i11 epilepsy, J.A.1\1.A. 75: 588, 1920.Kozol, H. L.: Epilepsy: treatment \vith new drug: 3-methyl 5, 5-phenyl-ethyl-hydantoin (phenantoin), Am.J. Psychiat. 103: 1S4, 1946.Lennox, W. G.: The treatment of epilepsy, M. Clin.North America 29: 1114, 1945.Lennox, W. G.: The petit mal epilepsies. Their treatment,vith tridione, J .A.M.A. 129: 1069, 1945.i{erritt, H. H., and T. J. Putnam: A new series of anticonvulsantdrugs tested by experiments 011 animals,Arch. Neurol. & Psychiat. 39: 1003, 1938.Robinson, L. J.: Evaluation of continued tl1erapy with_ phenytoin sodium, Am. J. Psychiat. 99: 231, 1942.Waelsch, H., and J. C. Price: Biochemical aspects ofglutamic acid therapy for epilepsy, Arch. Neural. &Psychiat. 51: 393, 1944.Waelsch, H., and J. C. Price: Aplastic Anemia and Tridione,Editorial, J.A.M.A. 132: 26, 1946.',•••8Antipyretic AnalgesicsIN?RODUCTIONSALICYLATESAN'IIPYIUNE ANDAMINOPYRZNE'IACETANILlD AND ACETOPHENETIDINCINCJIOPEN ANDNEOCINCHOPHENPREPARATIONS IINTRODUCTIONAnalgesics are agents which relieve pain without producingloss of consciousness. Their site of action may be onthe peripheral pain receptors, on thf.! afferent sensory nervesor on the pain centers either in the hypothalamus or in thecortex. The peripherally acting analgesics include the localanesthetics and possjbJy the counterirritants, although thereis some evidence that the pain~relieving action of the latteris a central effect. Drugs which depress the hypothalamicpain centers usually depress the temperature~regulating cen·ter as well, and hence are known as antipyretic analgesics.The analgesics which act on the pain centers in the cortexinclude morphine and allied drugs as well as hypnotics which• alter the reactions to pain wjthout greatly raisjng the pain,threshold. Conversely1 analgesics may have a hypnotic effecthy depressing painful stimuli and permitting a relaxationconducive to sleep.Antipyretics are agents which lower the temperature infebrile conditions without materially affecting the normaltemperature, at least in therapeutic doses. Antipyresis canbe effected by physical means such as cold sponges andbaths; by specific chemotherapeutic agents such as the sulfonamidesand antibiotics; by drugs which slow the circu'• Introduction 87'lation or cause peripheral vasodilation; or by centrally actingdrugs which depress the temperature~regulating center.Antipyresis per se is neither necessary nor desirable unlessthe temperature becomes alarmingly high or the patient istoo uncomfortable. In such cases the preferred method oflowering the temperature is by physical means. Hence, al- "'though the antipyretic analgesics were for the most l)artintroduced into medicine for their antipyretic action, theyare now used almost exclusively for- their analgesic action.Certain drugs, such as dinitrophenoi, cocaine, the centralnervous system stimulants and bacterial toxins, have apyretic effect similar to that observed after "heat puncture"of the thalamus. The elevation in temperature so producedcan be lowered by antipyretic drugs, affording a convenientmethod of assay of antipyretic potency.It is generally believed that the heat loss in antipyresis iseffected by blood dilution, capillary dilation and increasedsweating, while in febrile states the reverse situation obtains.In support of this theory, a lowered blood osmotic pressurehas been shown to follow the administration of antipyreticsin fever.COOHI~ OHSalicylicAcidSALICYLATEScoo Na.SodiumSalicyl:i.teCOOCH3 I~ OHllMethylSalicylateCOOHI~ OCOCH3#Acety lsalicylicAcid, The salicylates are the best known and the most widelyused analgesics because of their low cost, their comparativelylow toxicity and their effectiveness in the alleviation of thepai? of headache and neuralgias. The chief members of thisscr1;s i1:c:lude salic)•lic acid, sodii,11i salicylate, acetylsali•cyl,c ac,d (aspirin) and methyl salicylale (oil of winter~\•,II••' ,,•88 Antipyretic Analgesics 'green). Although salicylic acid itself was first introducedinto medicine in 1875, decoctions of willo1-bva rk wereu sedas f ebrif uges for centuries before it was known that theireffectiveness was due to the glucoside salicin, which yielihsalicylic acid on hydrolysis. Salicylic acid is irritating to thegastric mucosa and frequently causes nausea and vomiting.It has been replaced for internal use by sodium salicylateand acetylsalicylic acid, introduced in 1899 and 1908, re•spectively. Externally, salicylic acid is used as a keratolyticand mild antiseptic in dermatologic preparations. lfethylsalicylate is a liquid extremely irritating to mucous me~branes. It is used as a counterirritant; applied to the skin,it relieves the pain of sprains and afflictions of the joints.Salicylate Therapy of Rheumatic Fever. Since theintroduction of salicylic acid into medicine, the salicylateshave proved to be the most effective drugs for the treatmentof rheumatic fever. Even in Jaw doses these drugs relievethe symptoms of acute rheumatic fever, but it is question•able whether they actually cut down the number of sub-,sequent attacks or affect the prognosis as far as the heart is.concerned. Since the cause of rheumatic fever is still olrscure, the use of the salicylates in this disease is at presentempirical.1Sodium salicylate and acetylsalicylic acid are the twomost commonly used drugs in rheumatic~fever therapy. Itis now generally believed that the best results are achievedby maintaining a plasma-salicylate level of at least from25 to 35 mg. per cent, which requires doses of about 10 Gm,per day. Such high doses usually cause some toxic symptoms,but the treatment need not be discontinued unless'these become too severe. Administration may be eitheroral, rectal or intravenous. \Vhen sodium salicyl;ite is givenorally, sodium bicarbonate may be given to neutralize theacidity and reduce the gastric irritation. However, unless· minimal amounts of bicarbonate are used, the salicylate--.plasma level will be reduced because of an increased urinary'\• ISalicylates ----------~-----------,,,. l 89excretion of salicylates. Acetylsalicylic acid usually causesless gastric upset than sodium salicylate. Since high plasma' concentrations are rapidly obtained after oral administration,intravenous administration of salicylates is unnecessaryunless the patient is unable to retain oral doses.Salicylate Toxicity. Salicylate toxicity may be chronic,acute or of the nature of an allergic response.Chronic salicylate poisoning or salicylis111i,s not infrequentlyencountered during the therapeutic use of salicylates.The chief symptoms include headache, dizziness, tinnitus,blurred vision, nausea and vomiting, diarrhea and profuseperspiration. More severe symptoms include hyperpnea,hematemesis and mental disturbances.Acute salicyJate poisoning most often results from theaccidental ingestion of oil of wintergreen or the consumptionof a large dose of acetylsalicylic acid for suicidalpurposes. The symptoms include hyperpnea, hyperpyrexia,ketosis and mental disturbances. Autopsy frequently showswidespread hemorrhages. The fatal dose is variable, patientshaving been known to survive as much as 30 cc, of oil ofwintergreen and 80 Gm. of aspirin, while as little as 4 cc. ofoil of wintergreen proved fatal to a one-year-old child.Treatment consists of gastric lavage to remove any unabsorbeddrug and the administration of fluids.Allergic responses to salicylafes are occasionally manifested,especially in asthmatic subjects. The symptoms,which on occasion may be quite alarming, include angioneuroticedema or' the face and glottis and skin rashes.The possibility that salicylate therapy may produce hemorrhagesby a reduction in blood prothrombin has recentlyreceived some attention both clinically and experimentally., It is well known that acetylsalicylic acid may cause gastricbleeding, especially in sensitive individuals. It was firstthought that this action was due to an irritant effect sincegastroscopic examination may reveal irritation and engorgementof the mucosa around small, undissoJved particles of• •I••'90 Antipyretic Analgesicsthe drug. Recent work, however, suggests that the salicylatesmay actually cause hemorrhage by' an increase in clot•ting time. Link and his associates found that dicumero1th, etoxic substance in spoiled sweet clover1 causes a prothrom•bopenia in vivo but not in vitro. They suggested that salicylicacid, one of the breakdown products of dicumeroilnthe body, might be responsible for the prothrombin reduction.Studies on patients have shown that prolonged sali•cylate therapy does cause the prothrombin level to fall,though there is some difference of opinion as to whether thisfall reaches a dangerous level. Since serious hemorrhage, shave been known to occur during salicylate therapy, it basbeen suggested that patients whose prothrombin level isappreciably lowered receive prophylactic doses of vitamin K.ANTIPYRINE AND Al\:IINOPYRINE0 0 /CH3 11 II/c C-H ,,} /c c~N '#N II N II 'CH'N 'N3C CI I I ICH3 CH3 CH3 CH3Antipyrine AminopyrineAntipyrine and Aminopyrine. The introduction of sali·cylic acid into medicine stimulated the search for othersynthetic antipyretics. The antipyretic properties of thepyrazolone antipyrine (phenazone) were accidentally dis- •covered by Knorr in 1884, and a few years later the re•lated compound aminopyrine (pyramidon) ,vas introduced.~ This drug is probably the most effective of the antipyreticanalgesics and at one time was used in many proprietaryI• - Antipyrine and Aminopyrine 91, pain~relievingp reparations. In 1932, Kracke showed thatthe condition agranulocytosis, first described in Germanyin 1922, was associated ,vith drug-therapy and the follow,ing year aminopyrine was shown to be one of the chief' offending agents. Following this discovery, the1 use ofaminopyrine was forbidden or greatly restricted in manycountries,Agranulocytosis is characterized by a marked fall inleukocyte count, fever, severe sore throat with ulcerations •of the mouth and throat and occasionally of the vagina, andprostration. If untreated, death frequently results fromsecondaryi nfection. The condition seems to be in the natureo! an allergic response since attacks frequently bear norelation to dosage or duration of therapy. \Vhile most fre~quently associated with aminopyrine, it has also followedthe use of such preparations as the sulfonamides, arsenicals,_. gold salts, thiouracil and cinchophen. Treatment consists~f immediate withdrawal of the drug and administration ofPenicillin prophylactically or therapeutically to combat anysuperimposed infections. Adequate nutrition should bemaintained and the patient should be protected f ram possiblesources of infection. Pentneucleotide, pyridoxine, liverextract and blood transfusions have been tried but theirvalue has not been established.tACETANILID AND ACETOPHENETIDINOC2H5•~A'•\ NHCOCH 3Acetanllld,NHCOCH3Acetophenetidin\II\92 Antipyretic AnalgesicsAcetanilid (antifebrine} was introduced in 18.,8. 6, andacetophenetidin (phenacetin) a year later. \Vhen first in•troduced, these drugs were largely used as antipyretics,while acetanilid was also used as an antiseptic on openwounds ~nd ulcers. The large doses employed proved quitetoxic ; when used in analgesic doses, these drugs ate relativelyharmless. Both are metabolized in the human bodyto para,aminophenol, ,vbich is probably the active agentbut which is too toxic for clinical use, as are also the two''mother substances,'' aniline and phenol.Acetanilid and acetopbenetidjn are commonly used invarious proprietary remedies, of ten in combination withother drugs, such as bromides. Repeated use of these preparationsmay give rise to habituation and chronic poisoning,characterized by cyanosis, anemia, cardiac weakness andmental confusion. In acute poisoning, there is a rapid fallin body temperature accompanied by symptoms of collapse.Acetanilid and, to a lesser degree, acetophenetidin, producemethemoglobinemia and occasionally sulfhemogiobinemia,which accounts for the cyanosis. It is doubtful whether themethemoglobinemia per se is an important factor in theirtoxicity. In some species of animals, little or no methemo-globinemiais produced./ICINCHOPHEN AND NEOCINCHOPHENc?oH . cooC2H5~ CH....-:~ ~3•/2~N '==,-Cincbopben Neocincboph!n•Cinchophen (atophan) was introduced into medicine in1908. It is used mainly for the treatment of gout and rheu-'\' .Cinchophen and N eocinchophen 93matic fever and for the relief-of pain. It was a commqningredient of patent ''cold cμres'' and arthritis remedies,until its dangerous properties were realized. Although theetiology of gout is not fully understood, cinchophen and itsderivative neocinchophen (tolysin) give symptomatic relief. and at the same time the uric.acid excretion is increased, and the painful uric-acid tophi are reduced or eliminated.The increase in uric-acid excretion has been shown to bedue to a selectively increased permeability of the kidney.The value of cinchophen and probably also of the somewhatless toxic neocinchophen is greatly limited by the productionof liver damage in susceptible individuals, whichmay terminate in fulminating yellow atrophy. Jaundicefollowing the use of cinchophen was first reported in 1923,and by 19361 191 cases had been reported in the literature.Symptoms may develop after very small doses or after thedrug has been taken over long periods of time ,vith apparentimpunity, or they may develop weeks after the drug hasbeen discontinued. This unpredictable toxicity of cinchophenand related drugs has caused many physicians tobelieve their potential hazard far outweighs their usefulness 'and has led to the deletion of cinchoJ?hen from the UnitedStates Pharmacopoeia.l\.Iild symptoms of cinchophen poisoning resemble thoseof salicylism. A curious property of some cinchophen preparationsis that of producing gastric ulcers in dogs. Thisdoes not indicate that cinchophen is an important cause ofpeptic ulcers in man, since the experimental doses are rela- 'lively enormous. It does, ho\vever, provide a method for theexperimental study of ulcer. formation.Colchicwn in the Treatment of Gout. Colchicum is theoldest known remedy for gout: and is probably still the drugof choice in the treatment of this disorder. It is preparedfrom the seeds or the corm of the autumn crocus, Colchicun,autu11itt?lc, the active agent being the aJkaJoid colcJ1icine.The poisonous properties of the autumn crocus \Vere de- '••I•I'\94 Antipyretic ,Analgesicsscribed by Dioscorides, while its value in the treatment ofgout was recognized by the Arabians in the 1\:1:iddJAe ges.The mechanism of its action is not known; it does not affectthe uric-acid output. It will relieve the pain of acute attacksor abort impending attacks of gout. It is extremely toxic,causing gastro--intestinal irritation and rJ.nal damage.Colchicine arrests mitosis in the metaphase and bas ,proved a useful tool in histologic studies, while its ability tocause doubling of the chromosomes has led to the developmentof giant•size .flowers. It has been tried clinically toarrest neoplastic growths. Results ha.,·e been disappointing,however, and several fatalities have followed its use.When applied locally to the epidermis, colchicine producesdegenerative cellular changes which lead to cell death.Similar changes are produced by the resin podophyllum,f ormer1y used as a drastic cathartic. Both podophyJJurnand colchicine have recently been shown to be of value inthe treatment of condylomata acuminata.PREPARATIONSSodium salicylate U.S.P.; B.P. l Gm.Sodium-salicylate tablets U.S.P.; B.P. Usually available as0.3 and 0.6 Gm. tablets.Acetylsalicylic acid U.S.P.; B.P. 0.3 Gm.Acetylsalicylic-,acid tablets U.S.P. Usually available as60 mg. and JOO mg. tablets.Phenets,a l ( acetyl-paraminophenol salicylate) N .N. R. 0.3-1 Gm.Salysal (salicylic ester of salicylic acid) N.N.R. 0.3-0.6 Gm.Ethyl sa1icy1ate ]\T.N.R. 0.3-!J.6 cc.Sal-ethyl carbonate (carbonic-acid ester of ethyl salicylate)N .N .R. 0.3-1 Gm.Phenazone (antipyrine) B.P. 0.3-0.6 Gm.·Tablets of phenazone B.P.Aminopyrine U.S.P.; amidopyrine B.P. 0.3 Gm.Aminopyrine tablets U.S.P. 0.3 Gm. tablets.•• ,,,.•••Preparations 95AcetanilidU .S.P. 0.2 Gm.AcetophenetidinU .S.P.; phenacetin B.P. 0.3 Gm.Acetophenetidinta blets U.S.P.; tablets of phenacetin B.P.Usually available as 0.12, 0.2 and 0.3 Gm. tablets.CinchophenN .F.; B.P. 0.3-1 Gm.NeocinchopheUn .S.P. 0.3 Gm.Neocinchophenta blets U.S.P. Usually available as 0.3 and0.5 Gm. tablets.Colch;cine U .S.P. 0.5 mg.Colchicine tablets U.S.P. Contain 0.5 mg. colchicine.Tincture of colchicum B.P. Contains approximately 0.03per cent colchicine. _,,,.Liquid extract of colchicum B.P. Contains approximately0.3 per cent colchicine..Liquid extract of colchicum corm B.P. Contains 0.3 percent colchicine.BIBLIOGRAPHY ,GENERALAssociation for Research in Nervous and Mental Disease,XIII, Pain. Baltimore, Williams & Wilkins, 1943.Dilling, W. J.: Modern th'erapeutics VIII, sedatives andanalgesics, Practitioner 144: 189, 1940.Gammon, G. D., and Starr., I.: Studies on the relief ofpain by counterirritation. J. Clin. Investigation 20:13, 1941.Hanzlik, P. J.: Actions and Uses of the Salicylates andCinchophen in 1iedicine, Baltimore, Williams & Wilkins,1927.\Vay!1e, E. J.: 11:odern therapeutics, XVIII, counter-irritationand counter-irritants, Practitioner 14S: 422, 1940. •\Voolle~,. V. J.: 1!odern therapeutics, XIV, antipyretics, 'Pract1t1oner 145: 132, 1940.SALICYLATES• Cobttrn: A. F.: S~licylates therapy in rheumatic fever;43~5t19~4te 3cl1n1que, Bull., Jol1ns Hopkins Hosp. 7~:•fI ,IlI•96 ' Antipyretic AnalgesicsJFashena, G. J. and J. N. Walker: Salicylate intoxication;studies on the effects of sodium salicylate on prothrom•bin time and alkali reserve, Am. J. Dis. Child. 68:369, 1944.Hamill, P.: The therapeutics and toxicology of acetylsalicylicacid, Practitioner 142: 314, 1939\.Sable, H. Z.: Toxic reactions follo,ving salicylate therapy,Canad. M.A.]. 52: 153, 1945.ANTIPYJUNE AND AMfNOPYRINEKracke, R. R.: Relation of drug therapy to neutropenicstates, J. A.M.A. 111: 1255, 19.38.AcETANILm AND AcETPHEN£TIDINLester, D.: Formation of methemoglobin I; species dif•ferences ,vith acetanilide and acetophenetidine, J. Pharmacol.& Exper. Therap. 77: 154, 1943. .Payne, S.: Acetanilid poisoning; a clinical and experimentalstudy, J. PharmacoI. & Exl}et. Therap. 53: 401,1935.Gross, M. : AcetaniJid; a Critical Bibliographic Rev1elv,Ne,v Haven, Hillhouse Press, 1946.CINCHOPHEN"Bartels, E. C.: Successful treatment of gout, Ann. Int,Med. 18: 21, 1943.Palit.er, W. L., and P. S. Woodall: Cinchophen; is there)a safe method of administration? J.A.M.A. 107: 7(1),1936.Present status of cinchophen and neocinchophen, J.A.M.A. 117: 1182, 1941.Simonds, J. P.: Mode of origin of experimental gastriculcer induced by cinchophen, Arch. Path. 26: 44, 1938.,CO'LCHICUMBauer,,W., and F. Klemperer: The treatment of gout,New England J. Med. 231: 681, 1944._ Bro,vn, W. 0., and L. Seed: Effect of colchicine on humantissues. Am. J. CJin. Path. 15: 189, 1945.King, L. S., and M. Sullivan: The similarity of the effectof podophyllin and colchicine and their use in thetreatment of condylomata acuminata, Science 104: 244,1946.''' r•'•9Morphine and Allied DrugsMORPHINE•1 MORPHINE DERIVATIVESlSONIPECAINE\..MEl'HADON'PREPARATIONSMORPHINElNIRODUCTION •Morphine, the most important constituent of opium, wasfirst isolated by Sertiirner in 1804. It is a member of thephenanthrene or morphine group of opium -alkaloids, towhich also belong the naturally occurring codeine andthebaine and a number of synthetic derivatives such asheroin, dilaudid and dionin. The isoquinoline or narcotinegroup of opium alkaloids includes narcotine, narceine andpapaverine. Generally speaking, the predominant action ofthe morphine alkaloids is on the central nervous system,while that of the narcotine group is on smooth muscle.Opium is obtained from the dried latex of the poppy,Papaver sontniferutn. The pharmacologic activity of opium1 is due almost entirely to its morphine content. It is inferiorlo morphine as an analgesic since it acts less rapidly becauseof slower absorption. Although it causes more gastric irrita~tion, it has a greater constipating action, and opium prepa-.• rations, especially camphorated tincture of opium (paregoric)are still widely used in the treatment of diarrhea.Par~g~ric _also· has an expectorant action, which is almostnegl1?1ble1 n morphine and is useful in the treatment of a dry,b:i.cking cough. Dover's powder, a mixture of ipecacuanha91IV•,I • \\98 Morphine and Allied Drugsand opium, is included in the British Pharm' acopoeiaI.t isa powerful diaphoretic and expectorant, used in the treat•ment of coughs and colds. Opium preparations have beenapplied locally for the relief of pain but it is doubtful iithey are of any value in this respect. Pantopon (omnopon},an artificially prepared mixture of the chief opium alka·loids, can, unlike opium, be administered hypodermically.It offers no special advantages over morphine. 'PHARMACOLOGYCentral Nervous System. The action of morphine on thecentral nervous system varies in different species and tosome extent in djfferent individuals, In man, the characteris·tic effects are depression of the cortical and subcorticalstructures and of the medulla, and stimulation of the cord., The cortical depression fs manifested by an inattentivenessto external stimuli, a dulling of pain sensation, a feeling• of well-being and a tendency to sleep. These reactions arethe basis of the clinical usefulness of the drug. Respirationis slowed and the cough reflex is depressed. The depressingeffect of morphine on respiration is one of the serious draw·backs to its general clinical use. It is a matter of dispute asto whether the effect is due to a primary depression of therespiratory center or secondarily through an increase inthe pH of the blood or a reduced need for oxygen becauseof the decrease in general metabolism. Stimulation of thecord is usually mild in man but may be quite marked incertain animals. Morphine convulsions are strychnine-like.in character; there is some evidence that they result from, stimulation of certain higher centers as well as centers ofthe spinal cord.In the cat family, morphine regularly produces a markedcerebral stimulation instead of the depression character,' istically found in man. In some human subjects, however,the drug causes a wild excitement, ,vhich is either due to adirect stimulating action or to the depression of inhibitoryl•• -, Morphine 99 __________ ___,;:.,_ ___________mechanisms. This reaction is more commonly encounteredin women and children than in men.Autonomic Nervous System. Some of the effects ofmorphine, such as those on pupillary size, on heart rate. ~ and on the gastro-intestinal tract, are suggestive of stimulationof the parasympathetic nervous system. There is alsoexperimental evidence to indicate that morphine inhibitsthe action of choline esterase and acts synergistically withparasympathomimetic drugs. This has led to the suggestionthat the actions of morphine are mediated through stimulationof cholinergic synapses. Morphine may cause ahyperglycemia, which is thought to be due to a stimulationof the adrenals leading to a release of epinephrine.Sensory Nerve Endings. Morphine has no effect onsensory nerve endings, any apparent effect being due tothe systemic action of the drug following its absorption.Circulation. The effect on the circulatory system of therapeuticdoses of morphine is not very marked in man or ,in laboratory animals. There is usually a moderate slowing ...of the heart, which may be preceded by a brief increase inrate. The blood pressure may fall slightly; intravenousinjection of larger doses may result in circulatory collapse.The effect on the blood vessels is variable though dilationof the vessels of skin and muscles and constriction of visceralvessels are the most usual phenomena. The actionseems to be due largely to a direct action on the bloodvessels with the vasomotor center playing a minor role.Eye. In man, and in some but not all animals, morphinecauses a constriction of the pupil, which in its extreme formresults in the upin-point" pupil characteristic of morphinepoisoning. The mechanism of action is not wholly understood;it is probably not entirely a central effect since itcan be ab?lished by sectioning the optic nerve .• Bronch1oles. Constriction of the bronchioles has beend~n:onstrated in animals but large doses are required toelicit the e.fiect. \Vhile there is no evidence that bronchiolarI,,,\J f• •100 Morphine and Allied DrugsIconstriction occurs in man, morphine should be used with,caution in asthma when sensitivity may be increased.Intestinal Tract. 1\forphine has a marked constipatingaction due to a delayed emptying of the stomach, decreased-activity of the stomach muscμlature and spasn1s of the1 pyloric sphincter. Furthermore, while the tone and theactivity of intestinal musculature may be increased, therate of passage of the contents is decreased. Vomiting mayoccur because of an initial stimulation of the vomitingcenter.Urinary Tract. Morphine causes a retention of urine duein part to spasm of the vesical sphincter. It also has anantidiuretic effect, ivhich is apparentJy mediated throughstimulation of the neural lobe of the hypophysis and releaseof the antidiuretic (pressor) hormone.METABOLISM•The chief route of morphine excretion is by the urine,in which it appears both free and in conjugated form ••Traces of morphine are found in the feces and perspirationand possibly also in milk and saliva. A certain amount '1 5destroyed in the body, probably by the liver. It has beenshown that the addicted or tolerant dog destroys considerablymore morphine than the normal dog and excretes asmaller fraction in the conjugated form, a situation whichprobably also obtains in man.I CLmrcAL UsESMorphine is the most effective agent for the relief ofpain, but because of its addicting properties it should, ~ngeneral, only be used when a nonaddicting analgesic wiJJ_ not suffice. It will relieve all types of pain, such as thatfrom coron~ry occlusion, biliary or renal colic, migraine,pleurisy and severe injuries.Although morphine relieves the pain of biliary and renalcolic by its c;,:ntral analgesic action, it tends to aggravate•Morphine 101the condition by, its spasmodic action. It may be used toarrest severe diarrhea and to ease the pain of acute abdominalconditions, provided the diagnosis has been completedand concealment of the pain will not mask the truecondition of the patient. It is frequently used postopera.tively --to allay distention. l\i1orphine will relieve restlessaness and anxiety when these effects are caused by pain andnot by such other factors as fear, hysteria. or cerebralhypoxia. It should be used with caution in head injuries,however, since it causes an undesirable rise in cerebroaspinal-fluid pressure and may mask signs of cerebral dam•age. Caution is also indicated if the respiration is embar ..rassed since it may contribute a further depression and- if the drug is administered to old persons and children,who usually tolerate it poorly.~I orphine, usually ,vith atropine, is frequently administeredfrom 1 to 2 hours preoperatively to sedate the patientand reduce the amount of anesthetic required. In emergencies,morphine can be given intravenously shortly beforethe operation is started. Intravenous morphine mayalso be used to prolong anesthesia towards the end of a!loperation. iiorphine may prolong the induction period withinhalation anesthetics because of the respiratory depressionit causes. It will also diminish the pupillary reflexand may contribute to postoperative nausea and vomiting.In obstetrics, morphine with scopolamine is often given✓ to produce "twilight sleep," a state of analgesia and amnesia.The danger of asphyxiation of the child is increasedby its use, ho,vever, and in the case of premature babies,morphine is contraindicated. \Vhcther the harmful effectsarc clue to the direct action of morphine upon the fetus,~r v.·.hether the labor mechanism is chiefly involved, result.1ng 1n delay in the emptying of the uterus, has been difficultto determine from clinical observation alone. RecentexperimentJ.1 analvsis bv c......... ..,,,1 h\s associates in rab-I,,\I-102 Morphine and Allied Drugsbits, however, revealed a striking prolongation of laborwith increased Incidence of stillbirths following morphine.TOXICITY ,Acute morphine poisoning may occur from accidental 1or criminal overdosage or in individuals who tolerate thedrug poor1y. It is characterized by extreme miosis~ (;'pin•point" pupils) , markedly slowed respiration, cold, clammyskin and coma. Treatment consists of prolonged artificialrespiration, if possible with oxygen. The patient should notbe exhausted by stimulant drugs or physical means such as"walking the floor." Morphine re•e>c:cretedin to the stomachcan be removed by gastric lavage and reahsorption fromthe bowel can be prevented by colonic lavage; the amountof morphine removed by these means is insignificant, how•ever, except when the drug has been taken by mouth. Supportivetreatment includes the use of intravenous glucoseand the maintenance of body temperature. Good nursingcare is of the utmost importance.The subcutaneous injection of morphine is 6rdinar1Jyfollowed by a rapid response. When the circulation is inadequate,as in shocked patients, especially those exposedto cold, absorption may be delayed and the continued painmay lead to the administration of one or more additionaldoses of morphine. \Vl:ten shock treatment is institutedand the circulation improves, the several doses of morphinemay be absorbed simultaneously and may act as one mas·sive dose. The symptoms and treatment of this delayedpoisoning are those of acute morphine poisoning. Prophy•Jactic measures include intramuscular injection with mas~sage of the site of administration in all shocked or hypotensivepatients. If circumstances permit, the intravenousadministration of small doses of the drug will insure rapiddevelop[Jlent of the full effects and will obviate the dangerof delayed poisoning. ,•)Morphine 103Addiction. The main drawback to the use of morphinelies in its addicting properties. The development of drugaddiction depends to a great extent on the psychogenicmake-up of the individual and the masterfulness of thedrug. It is characterized by a development of toleranceto:ward the drug and the appearance of deranged physio'...logic processes fallowing the withdrawal of the drug incontrast with the mere psychic craving which follow,s thewithdrawal of habit-farming drugs.-i:he' development of tolerance to morphine depends onthe size of the dose and the frequency of administration.Generally speaking, it will develop within three weeksof daily administration of ordinary analgesic doses. Dosesmust then be progressively increased in order to producethe desired effect. Furthermore, tolerant individuals ,canwithstand doses far greater than those which would betoxic to the nontolerant individual.The diagnosis of physiologic dependence to morphinerests on the development of withdrawal symptoms. Thesesymptoms vary according to the individual, being directlyrelated to the severity of the addiction. Symptoms includerestlessness, vomiting, mydriasis, tremors, gooseft.esh, anorexia,yawning, lacrimation, perspiration, rhinorrhea andfever. Collapse and even death may occur in severe cases.Immediate alleviation of symptoms results from the administrationof morphine.The U. S. Public Health Service maintains a narcotic 1farm at Lexington, Ky., where patients may apply voluntarilyfor treatment of drug addiction. Convict addicts areconfined and treated in the Federal Prison at Leavenworth.The complete treatment of addiction comprises two stages:disintoxication and rehabilitation. The former can be accomplishedby slow, rapid or sudden withdrawal' of thedrug, with or without attempts at substitution with ·othernarcotics. Rehabilitation consists of psychiatric treatmentusually· disappointing because of the basic inade-..1.I.ttII'•104 itorphine and Allied Drugs\quacies in the personality of the addjct. Jntensjve studiesare being carried out under the direction of the Committeeof Drug Aqdiction of the National Research Council by theU. S. Public Health Service and a number of collaboratinginstitutions, ,vith a view to determining the exact nature ofaddiction and to obtaining nonaddicting morphine substitutes.As yet, no comparable analgesic agent has beendeveloped which does not have addicting tendencies. Amongthe most promising derivatives studied are 1netapon (methyldihydromorphinone)and deso11io,phine (dihydrodesoxymorphine-D). Desomorpbine has an effective analgesic .actionin very small doses but its action is of shorter durationand less reliable than that of morphine, while its addictingproperties are comparable to those of morphine. l\,fetaponis an excellent analgesic for the control of chronic pain;tolerance and dependence are developed more slowly than, with morphine and are apparently lost quite rapidly duringshort periods of abstinence. It jg not satisfactory for pre•anesthetic medication, however, since it has only a slight1 hypnotic effect and occasionally causes severe respira•• tory depression when used in conjunction with inh.alationanesthetics.The production, manufacture and distribution of addict•ing drugs is regulated by the Harrison Narcotic Act, passedin 1914, and its several amendments. The act covers "opiumand coca leaves, and compounds, manufactures, salts, derivativesor preparations thereof. 11 ~uch drugs can onlybe prescribed by physicians possessing a narcotics license,which must be renewed yearly. All prescriptions must bemade on officia.I narcotic order forms and must bear the• physician's license number. They are not refillable. Certainpreparations containing only small amounts of restricteddrugs are'exempt, as are preparations for external appJica·tion only, except for those containing cocaine. E:J"emptpreparations include those containing no more than 2 grains, of opium, ¼ grain of morphine, ¾ grain of heroin or lr, •IMorphine , 105grain of codeine in 1 ounce. International problems of opium-- regulation are governed by the Hague Convention of 1912and the Geneva Conventions of 1925 and 1931.,The Leagueof Nations maintained an Opium Advisory Committee,which met annually to discuss opium control. This functionhas been assumed by the United Nations organization.1\fORPHINE DERIVATIVES----,<N-CH 3 ,--~ ' H2>----cf--CH2 ~~=:.( HOH 0 OHMorphineIOHCodeine(Methyl morphine),:-----,(N-CH 3.r---< 'cHz'>--~CH 2~'F==( HOHOionin(Et hy !morphine)•N,-CH 3---<.. CH2---<r--~ CH2)==.( ~OH O 0, Dilaudid(Dihyd ro m orphinone)N, CH3,---< CH2,--,<~---c---CH 2~'?=< Ho-b-CH 3 110Heroin{Oiace tyl morphineJ'••',- ••106 Morphine and Allied DrugsCodeine was first isolated from opium in 1832 by Robi•quet and came into general clinical use in 1880. It is preparedcommercially largely by the methylation of mor•, , phine, only small amounts being obtained from opium dur•ing the extraction of morphine. It is used mainly for therelief of cough and of moderately severe pain. It has defi-•nitely weaker analgesic, respiratory, depressant, emeticand intestinal effects than morphine. It is less addictivethan morphine, though, in some cases, withdrawal symptomsmay be as severe as those following the withdrawal of mor•phine. Codeine causes less euphoria than morphine and ismore costly in addiction~sustaining amounts. There is across tolerance between the two drugs, large doses of codeinerelieving the withdrawal symptoms of morphineaddicts. ,Dihydromorphinone hydrochloride (dilaudid) was intro-ducedinto Germany by Krehl in 1926. Its analgesic potency.is about four times that of morphine though its duration ofaction is shorter. While it is an efficient substitute for mor•phine, it has no therapeutic advantages and has equal orgreater addicting properties.Heroin (diacetylmorphine, diamorphine) was introducedinto Germany in 1898 by Dreser. At first considered to be anonaddicting substitute for morphine and codeine, it waslater found to be more addictive than morphine and itsmanufacture and importation is prohibited in the UnitedStates.Ethylmorphine (dionin) has an analgesic action inter•mediate between tbat of codeine and morpbjne and bassimilar addicting properties. It is used chiefly in ophthal·mology in' inflammatory conditions. It stimulates the vascu1arand lymphatic circulations by a dilating effect on thevessels and has a local anesthetic action on the conjunctiva!sac.,,\•IsonipecaineISONIPECAINECH3 I/N,H2C CH2 >---Y c-oc2H5--- 11\ 0Isonlpecaine107• Isonipecaine (demerol meperidine) is one of the mostsuccessful substitutes for morphine. It was synthetized inGermany in 1939 by Eisleb and Schaumann, who weresearching for new compounds with an atropine-like action.They found that this substance had, in addition to parasympatholyticproperties, a direct spasmolytic effect onsmooth muscle similar to that of papaverine and a central, analgesic and sedative effect like that of morphine. Thedrug is known in Germany as dolantin; in Great Britain theofficial name is pethidine.Isonipecaine relieves all types of pain, being only slightlyless effective than morphine. The dose is approximately tentimes that of morphine but the drug is much less toxic andis quite rapidly metabolized in the body. It is much lessliable to cause addiction than morphine but since it doespossess addicting properties it has recently come under thescope of the Federal narcotic law. ..\ Isonipecaine has a relaxing action on the gut musculaturebut does not delay the passage of the gut contents anddoes not have the constipating action of morphine. It isprobably more efficient than morphine for the relief of•,•'•I108 l\jorphinc and Allied Drugsbiliary and urinary colic since it has a direct spasmolyticeffect in addition to a central analgesic action.• It is alsoof value in the tteatment of asthma because of its relaxingaction on the bronchioles. It has recently been introduced...,f. or preancsthetic medication and for obstetric analgesia.It is said to be superior to morphine since it causes littleor no respiratory depression, it decreases salivary secretionand does not markedly interfere with the pupillary reflex,and jt is said to cause Jess postoperative nausea. and vomit•ing than morphine. It has been claimed to hasten labor bya direct relaxing action on the uterine cervix. It must becombined \vith barbiturates or scopolamine if amnesia aswell a.s analgesia is desired.l\1ild toxic actions foIIo,vingt he use of isonipec:iinein cludegiddiness, dryness of the mouth, nausea and vomiting,siventing, headache and anxiety. J\..fores evere toxJc effectsrcsemlJle tl1ose of atropine poisoning.Recently, a new synthetic analgesic developed in Ger•many has given promising clinical results in a limited serjesof cases. The drug is the hydrochloride of 1, 1~diphenyl.l•(2:.dimethylaminopropyl)-2-butanone and is lc.nown as meth·, adon, amidone, dolophine or 10820.• JMethadon 109Its analgesic action is quite similar to that of morphinebut it apparently causes less gastro~intestinal distress and. respiratory depression. It is not as satisfactory as morphineas a preanesthetic agent since it causes little or noeuphoria and leaves the patient apprehensive. There is no, information yet as to whether prolonged use leads to toleranceor addiction, and until these question~ are answered,cautious use of the drug is advisable.PREPARATIONSPowdered opium U.S.P.; B.P. Granulated opium U.S.P.Co~ta,ins approximately 10 per cent anhydrous morphine.60 mg.Opium tincture (laudanum) U.S.P.; B.P. Contains approximately1 per cent opium. 0.6 cc.Camphorated opium tincture (paregoric) U.S.P.; B.P.Contains approximately 0.04 per cent anhydrous morphine.4 cc. .l\1orphine sulfate U.S.P.; B.P. ?vlorphine hydrochloride,B.P. l\Iorphine tartrate B.P. 10 mg.l\Iorphine-sulfate tablets U.S.P. Usually available in 51 B,10, 15, and 30 mg. amounts.)forphine injection U.S.P. Usually contains 10, 15, 20 or30 mg. morpl1ine salt in 1 cc.Codeine B.P. 30 mg.,Codeine phosphate U.S.P.; B.P. Codeine sulfate U.S.P.30 mg.Codeine-phosphate tablets U.S.P.; B.P. Codeine sulfatetablets U.S.P. Usually available in 15, 30 and 60 mg.:lll\OUUls,D~hydromorphinone hydrochloride U.S.P. 2 mg.Dih;·d_romorphinonc•hl:drochloride tablets U.S.P.a\o·a1lablei n 1, 2 and 4 mg. amounts.~thylmorpl1ine hydrochloride U.S.P. IS mg.Ust1ally'\,-,I,_1_10_ __ Mo_r.p.!h,.i.n_e. ..a.:n:d.: .=A..ll.i:e.:d:: .n::::r..t.:g:.~s: __---·I'Diamorphine hydrochloride B.P. (Diacetylmorphine orheroin). 2-8 mg.i1eperidine hydrochloride N.N.R. 0.05-0.1 Gm.BIBLIOGRAPHYGENERALIndispensable use of narcotics, J.A.M.A. 119: 338, 1942., MORPHINEAdams, E.W.: Drug addiction, New York, Oxford, 1937.Adams, E. W.: Studies on drug addiction, Pub. HealthRep., Supplement 138, Washington, U. S. GovernmentPrinting Office, 1938.Adams, E. W.: The Pharmacology of the opium alka·loids, Parts 1 and 2, Pub. Health Rep., Supplement No.165, Washington, U. S. Government Printing Office.Beecher, H.K.: Delayed morphine poisoning in battlecasualties, J .A.M.A. 124: 1193, 1944.Bodo, R. C., F. W. Cotui and A. E. Benaglia: Studies onthe mechanism of morphine hyperglycemia; the roleof the adrenal glands, J. Pharmacol. & Exp er. Therap.61 : 48, 1937.Gross, E. G., and V. Thompson : The excretion of a com·bined form of morphine in tolerant and nontolerantdogs, J. Pharmacol. & Exper. Therapy. 68: 413, 1940 •.Lee, L. E., Jr.: Studies of morphine, codeine and theirderivatives, XVI, clinical studies of morphine, methyldihydromorphinone(metopon) and dihydrodesoxymor·phine-d (desmorphine), J. Pharmacol. & Expe~. Therap.75: 161, 1942.Mengert, W. F.: Morphine sulfate as an obstetric analgesic,a clinical analysis, Am. J. Obst. & Gynec. 44: 888,1942.McCrea, F. D., G. S. Eadie and J. E. Morgan: The mech·anism of morphine miosis, J. Pharmacol. & E:xper.Therap. 74: 239, 1942.Oberst, F. W-: Studies on the fate of morphine, J. Pharmacol.& Exper. Therap. 74: 37, 1942.Oberst, F. W.: Free and bound morphine in the urine ofmorphine addicts, J. Pharmacol. & Exper. Therap. 69:240, 1940 ••IBibliography 111Pearman, R. 0.: Intravenous use of morphine. sulfate,Am. J. Surg. 61: 423, 1943.Presman, D., and S. Schatz: A critical analysis of the useof intravenous morphine, Anesthesiology 4: 53, 1943.Schmidt, C? F., and A.E. Livingston: The action of morphinean the mammalian circulation, J. Pharmacol. &Exper. Therap. 47: 411, 1933.Slaughter, D.: New concepts of morphine analgesia,Anesthesiology 5 : 508, 1944.Snyder, F. F., and E. M. K. Geiling: Action of morphinein obstetric analgesia, Am. J. Obst. & Gynec. 45: (5()4,1943.IsoNtPECAINEBatterman, R', C., and C. K. Himmelsbach: Demerolnewsynthetic analgesic-a review of its present statusand comparison with morphine, J .A.M.A. 122: 222,1943.von Eisleb, 0., and O. Schaumann: Dolantin, ein neuartigesSpasmolytikum und Analgetikum ( chemischesand pharmakologisches), Deutsche Med. Wchnschr.65: 967, 1939.Himmelsbach, C. K.: Studies of the addiction liabilityof "demerql" (D-140), J. Pharmacol. & Exper. Therap.75: 64, 1942.Himmelsbach, C. K. : Further studies of the addictionliability of demerol {l-methyl-4-phenyl-piperidine-4-carboxylicacid ethyl ester hydrochloride), J. Pharmacol.& Exper. Therap. 79: 5, 1943.Noth, P.H., H. H. Hecht and F. F. Yonkman: Demerol-a new synthetic analgetic, spasmolytic and sedativeagent, 111 clinical observations, Ann. Int. Med. 21: 17,1944.Roby, C., and \V. R. Schumann: Demerol (S-140) andscopolamine in labor-a preliminary report. Am. J.Obst. ~ Gynec. 45: 318, 1943.Rovensttne, E. A., ar;id R. C. Batterman: The utility ofdem~rol. as a subst1tu~e for the opiates in preanesthetic. med1cat1on, Ancsthcs1ology 4: 126, 1943.Yonkman, F. F., f · H. Noth and H. H. Hecht: Demerol:a nc,v synthetic analgetic, spasmolytic and sedative i~:• 1, phaTmacologic studies, Ann. Int. Med. 21 ~ 7,112 1\f orphine and Allied DrugsMETHADONScott, C. C., K. G. Kohlstaedt and K. K. Chen: Comparisonof the pharmacologic properties of some ne,vanalgesic substances, Anesth. & Anaig. 26: 12, 1947.Scott, \V. W., H. I\f. Livingstone, J. J. Jacoby and G. R.Broberg: Early clinical experience ,vith dolophine (No.10820), Anes th. & Analg. 26: 18, 1947._.r • 'IIOCentral Nervous SystemStimulantsINTRODUCTIONSTRYCHNINEPICROTOXINMETRAZOLN1KETilAl.lIDECAFFEINEAMPHETAMINE AND RELATED COMPOUNDSMISCELLANEOUS PREPARATIONSPREPARATIONSINTRODUCTIONCentral nervous system stimulants may act primarilyas spinal stimulants (strychnine), mcdullary stimulants(picrotoxin, n1etrazol and nikethamide) or cerebral stimu•lants (caffeine and amphetamine). In large doses, theyind11ce convulsions, which, with the exception of the metrazol-induced con\·ulsions used in shock therapy of mentaldisorders, arc o( toxicologic importance only. In smallerdoses, they act as analeptics or restoratives and are capableof antidoting depression.STRYCHNINEStrychnine, the principal alkaloid obtained front the seedsof Strycl111o1s1 ux vo,nica, was first isolated by Pelletier andCa\'cntou in 1818. It acts chiefly on tl1e spinal cord, increasingreflex c..,:citability. It l1as therefore no direct stimulatoryaction but sensitizes the nervotlS system to external stimuli.It l1as little or no clinical value as a central nervous systemstimulant since n1ost depressants act primarily by depressionof the n1cdullary centers and strychnine stimulates ,'the medulla only in con\·ulsivc <loses. On tl1e other hand,l?c depressant <lrugs are antidotes to strychnine poisoningsince these drugs usually depress the spinal cord beforedc1)rcssing the n1c<lulla.T he stimulatory action or strychnine... ,,, 113 •I '\•,I • •114 Central Nervous System Stimulants'\on the higher centers is usually not very marked, thoughin some individuals it sharpens visual and auditory acuity.Strychnine poisoning not uncommonly results from criminalactivities or accidental ingestion of strychnine-containingplants or medicinal preparations. 1 Consciousnessisretained despite severe tonic convulsions which aff'ecta llmuscles of the body. In the human, the body is archedback jn the position of opisthotonus. The convulsionsa reprovoked by external stimuli, hence the patient must bekept completely quiet and in a darkened room, and noattempt should be made to pass a stomach tube or otherwiseto disturb the patient. Short-acting barbiturates,administered intravenously, are probably the most effectiveantidotes. Death from strychnine poisoning usually resu~tsfrom respiratory failure due to exhaustion of the respira•tory center.The manner in which strychnine increases reflex e::r:dta•bility is not fully understood. It has been found that smalldoses of strychnine inhibit the action of choline esterase,the enzyme which destroys acetylcholine. This suggests thatthe mode of action of strychnine might be somewhatanalogous to that of physostigmine with the primary effectbeing located in the central nervous system rather than inthe autonomic nervous system.• Brucine, an alkaloid obtained during the preparation of • strychnine, has very weak strychnine-like pharmac0Jog1cproperties. Preparations of nux vomica, strychnine or brucineare used largely as tonics; they stimulate the appetitebecause of their bitterness and increase the flow of salivaryand gastric secretions. Strychnine is frequently included in,.,..proprietaryca thartics, allegedly to increase the tone of theintestinal musculature.PICROTOXINPicrotoxiJ'li s a. g]ycoside obtained from the seed of Anamirtapaniculata, a climbing plant indigenous to Malabar,•' Picrotoxin 115., Iand the East Indies. The fruit of this plant, known as fishberry, levant berries or Cocculus indicus, is used by nativesto stupefy fish.-Small doses of picrotoxin stimulate the medulla and prob•ably also the cortex. The spinal cord is stimulated to alesser extent. Picrotoxin acts as a pharmacologic antidote ,to drugs which depress the respiratory center and is theagent of choice in the treatment of severe barbiturate de•pression (see Chapter 7). It is contraindicated in morphinepoisoning, however, because morphine appears to sensitize 'the cord to picrotoxin so that convulsions appear beforerespiratory stimulation is apparent.The value of picrotoxin as an antidote to depressant drugswas first demonstU1ted experimentally in 1875. During thefollowingy ears it was used to a limited extent clinically tocombat overdoses of hypnotics and general anesthetics butdid not gain widespread recognition until its efficacy in barbituratepoisoning was demonstrated by Maloney, ~itcli and -Tatumin 1931. Picrotoxin has also been used to produce _convulsions in the shock treatment of mental disorders. Itis effective in lower doses than metrazol and is said to causeless apprehension. However 1 the onset of convulsions is .oft en delayed and 't he action of the drug is less predictablethan that of metrazol. In the past, picrotoxin has beenadded to beer for its bitter and intoxicating properties. Ithas also been used externally as an antiparasitic agent. Itsextreme toxicity makes these uses dangerous. •Overdoses of picrotoxin lead to a depression of the centralnervous system anq. the sequence of events in picrot_oxin,poisoning is convulsions, confusion and unconsciousnes.s • In using pic:rotoxin as a respiratory stimulant, care shouldbe taken to avoid convulsions, which may lead to furtherdepression of the center. Pjcrotoxin can be. effectively antidotedby intravenously adntlnistered barbiturates .••116' •Central Nervous System StimulantsMETRAZOL, Metrazol (leptazol, cardiazol) was introduced into Ger•many by Schmidt, Hildebrandt and Krehl in 1925 as awater.soluble substitute for camphor, which was held inconsiderable repute on the Continent as a respiratory andcardiac stimulant. It ,vas first known as cardiazol, a somewhatmisleading name, since the drug in therapeutic dosesltas little or no effect on the coronary flow, the heart rate'or the blood pressure. Its chief pharmacologic action isICH2 CH2 CH2 ...'' I °"N N/ CH2 CH2 IIc~ 'N NMetraiol \stimulation of the medullary centers. It is an effective anti•dote to respiratory depressants though i~ferior to picrot,oxinin severe barbiturate poisoning. Like picrotoxin, it shouldbe avoided in morphine poisoning because of the danger ofinducing spinal convulsions.Metrazol has been used extensively in the drastic shocktreatment of certain mental diseases, principally schizo•phrenia and depressive psychoses. The use of convulsant • drugs in mental disease was initiated by de l\feduna 1nI 1933. He reasoned that since schizophrenia and epilepsyseldom occurred together, there was a biologic incompatibilitybetween the two disorders. He sought, therefore,to induce epiJeptiform convulsions in schizophrenic pa~tients1at firSt by the intramuscular injection of camphor andlater by the intravenous injection of metrazol, which producedmuch more prompt and reliable convulsions. Althoughde l\f eduna's hypothesis is not generally accepted as correct,the treatment has proved of considerable value, althoughr••' r• I!\-Ietrazol ',117it has recently been -largely replaced by the simpler andprobably safer electrical convulsive therapy. 1\ietrazol convulsionsusually occur within one minute after the intravenousadministration of the drug. They are mainly clonicin nature and of comparatively short duration because ofthe rapid destruction of the drug by the liver. Because o(the severity of the convulsions, metrazol should not beadministered in the presence of cardiovascular or pulmonarydisease or spinal injuries. The patient may be pro-• tected from fractures or dislocations of the extremities orspine by the 'administration of purified preparations of _curare, which greatly diminish the contractions of the skel~tal muscles. •Triazol 156 (azoman, hexazole) has somewhat similarpharmacologic properties to metrazol and has been quiteextensively used in Europe for convulsant therapy. It isTriazo11S6effective in smaller doses than metrazol and can be giveneither _intravenouslyo r intramuscularly. It is said to causeless apprehension in patients.• NIKETHAuiIDE0 /C2Hs 0 '' IIC N, . C-OH~ C2Hs ' ~ i NNil...tthamide NicoUnicA dd. ...'••f118 Central Nervous System Stimulants -•Nikethamide (coramine) was introduced into Germany1n 1924 as a substitute for camphor~ Jt'is much less effectiveas an analeptic than picrotoxin or metrazol and is oflittJe value in the treatment of severe respiratory depression.It may increase the rate of coronary blood flow, andit is claimed to be of value in combatting postoperativedepression and traumatic shock by maintaining the intra~muscular pressure and venous blood pressure and flow. It iscomparatively nontoxic, and up to 30 cc. of the 2S per centsolution have been given without ill effects. 'Nikethamide is related chemically to nicotinic acid and,like the latter, is capable of allevjating the symptoms ofpellagra and black tongue (see Chapt~r 22).CAFFEINE• H3C N C=OI I /CH 30 C C N, H I 11 N~CH C-N C 3 •CalieincCaffeine is an alkaloid which may be prepared syntheticallyor obtained from various plant sources, including• , coffee seeds, tea leaves, mate, guarana and kola. The maulcomniercia1 source of caffeine is damaged tea.Caffeine is a mild cerebral stimulant, its action-on thelower centers being inconsequential. It tends to facilitatemental and muscular effort and to diminish drowsiness a.ndmotor fatigue. It has been suggested that caffeine increasesthe capacity for muscular activity by decreasing the thresh~old for .response to acetylcholine at the neuromuscular junction.Caffeine frequently relieves the pain of mild head·aches, possibly by lowering the cerebrosoinaJ-Buizd, ressure.••' ,1INikethamide 119•It· is of questionable value as an antidote for depressantpoisons, except in cases of mild alcohol or mild morphinepo•1 son• 1ng. 1Caffeine is comparatively nontoxic. Excessive doses leadto insomnia and nervousness, while its diuretic action is of•some disadvantage in its use as a stimulant. The relatedcompounds, theobromine and theophylline, have qualita•tively similar stimulatory actions. Much larger doses arerequired, however, and these drugs are more widely used asdiuretics, since their comparative freedom from centraleffe-cts makes them more useful than caffeine. The innoc- uousness of caffeine is attested to by the wide consumptionof caffeine-containing drinks for their palatability and.mildly stimulating properties. The average cup10£ tea or ,coffee contains approximately 0.1 Gm. of caffeine. Excessiveuse of these beverages may be harm£ ul in patients susceptibleto peptic ulcer since caffeine has been shown to stimulatethe flow of gastric juices in man.AMPHETAMINE AND RELATED COMPOUNDSThe shortcomings of the camphor substitutes, metrazoland nikethamide, encouraged the se~rch for more effectivecentral nervous system stimulants and led to the introductionof amphetamine and of various sympathomimeticamines with analeptic properties. Of the latter group ofcompounds, amphetamine (benzedrine) was the first toreceive extensive clinical use. This drug was first introduced ~as a nasal decongestant (see Chapter 11). Its markedstimulatory action on the central nervous system soon becomeapparent, and in 1935 the nonvolatile sulfate salt was ..~ed success£u lly as an analeptic in amytal anesthesia, Itis now used widely in the treatment of narcolepsy and invarious psychogenic depressive states.:he establishment of the value of amphetamine as a~timulant_ led to studies of related compounds and to the1ntroduct1on of d-desoxyephedrine (methedrine, pervitin).....•/I•' ' ••I 120,CE>ntral Nervous System Sti111ulantsand of dexedrine, the dextrorotatory component of the racemicamphetamine. Dexedrine elicits more marked centraleffects than its levorotatory isomer or the ~acemic mixture,although its peripheral effects -are less marked. Comparativestudies indicate that the central nervous system stimulanteffect of these drugs is not correlated with their,sympa thomimetic activities. .,. 'In the normal subject, amphetamine usually gives a feelingof increased well-being, mental stimulation, lessenedfatigue and even euphoria. In a few individuals, depressionof mood occurs. The stimulating effects of the drug Jed toits' indiscriminate use in the form of "pep pills/' which wereespecially popular with students on the eve of examinations •. Several fatalities were reported following such unsuperviseduse, and, as a result, restrictions have been placed on itssale in many areas.Amphetamine sulfate has been ,videly advocated for the,, treatment of obesity, since it depresses the appetite andmaintalns the patient's feeling of weJl-being despite a lowcaloric intake. However, directly the drug is withdrawn,the appetite returns in full and unless a new food patternhas been established the patient generalJy is un,villing toadhere to his former diet. Furthermore, there is a dangerof habit formation, especially since the type of patientrequiring amphetamine will be one prone to become habituatedto the drug. It has also been used as an adjunct topsychotherapy in the treatment of chronic alcoholis~- ,.Toxic manifestations of amphetamine overdosage includeirritability, anxiety, insomnia, dizziness, headache and nausea.Se-..•eracl ases of collapse, evidently due to idiosyncrasy,have been reported. Tolerance may develop after pro--•..l.o nged medication; however, moderate doses have beentaken over a period of years for the treatment of' narco- • lepsy, without any apparent ill effects. • .Dexedrine and d-desoxyephedrine may be used in placeof amphetamine when central stimuJation is required. They -I•••Amphetamine and Related Compounds 121~ Iare effective in somewhat lower dosage. D-desoxyephedrinewas developed in Germany, where it was used quite exten ..\sively by the army and the air force to produce a temporarystate of alertness.11ISCELLANEOUS PREPARATIONSAlpha-lobeline, the principal alkaloid of Lobelia i1z.flataI. Linne (Indian tobacco), and various cyanide preparations•' have been recon1mended as respiratory stimulants in nar-' cotic poisoning and in asphyxia neonatorum because of ,their stimulatory action on the carotid body. Tl1eir effectsare unreliable and fleeting, however, and are obtained only\vith nearly toxic doses.Ammonia water and camphor have long enjoyed a popularreputation as stimulants. Ammonia water, when givenorally, or when its vapors are inhaled, stimulates the vasomotorcenter reflexly by stimulation of the chemoceptors ofthe carotid body, but its action is evanescent. The value ofcamphor as a respiratory or cardiac stimulant is doubtfuland quite unreliable.PREPARATIONSStrychnine sulfate U.S.P. 2 mg., Strychnine~sulfate tablets U.S.P. Usually of 0.6, 1.0, 1.2,1.5 and 2 mg. amounts.Strychnine hydrochloride B.P. 2 mg.Solution of strychnine hydrochloride B.P. Contains 1 percent strychnine.Picrotoxin U .S.P. (Dose determined by needs of the, pa .tient.) ' ,Picrotoxin injection U.S.P. Usually available in ampuls containing3 mg. picrotoxin in 1 cc. isotonic sodium chloride .l\Ietrazol. N :N .R. ; leptazol B .P. 0.06-0.3 Gm.Injection of Jeptazol B.P. Contains 10 per cent 1eptazo1., Injection or nikethamide B.P.; N.N.h. 25 per cent solutionQf nikethamide in distilled water. 1-4 c;c, ,•,I••••• • I122 Central Nervous System Stimulants'Caffeine U.S.P.; B.P. 0.2 Gm. I • ~Citrated caffeine U.S.P. A mixture of approximatelye qua1amounts by weight of caffeine and citric acid. 0.3 Gm.Caffeine and sodium benzoate. U.S.P.; B.P. A mixture ofapproximately equal amounts ~y weight of caffeinea ndsodium benzoate. 0.5 Gm.I,Caffeine and sodium-benzoate injection U.S.P. Usuallyavailable as capsules containing 0.25 Gm. and O.S Gm. -• J - m 2 cc .Amphetamine sulfate B.P.; N.N.R. 5-10 mg.BIBLIOGRAPHYGENERAL•Burn, J. H.: Analeptics and sympathomimetic substances,Brit. M. ]. 1 : 599, 1939.Hazleton, L. W.: The present status of analeptics, J. Am.Pharm. A. (Scien. Ed.) 33: 65, 1944.Lim, K. T., and F. F. Snyder: The effect of respiratorystimulants in the ne,vborn infant, Am. J. Obst. &Gynec. 50: 146, 1945.STRYCHNINEAikman, J.: Strychnine poisoning in children, J .A.1f.A.95: 1661, 1930.Anderson, W. F. : The tonic action of strychnine, Brit.M. J. 1 : 360, 1944.Drusser de Barenne, J. G.: The mode and site of actionof strychnine in the nervous system, Physiol. Rev.• 13: 325, 1933 .Travel!, J., and H. Gold: Mechanism of action of strychnineon respiration, J. Pharmacol. & Exper. Therap.53: 169, 1935.PICROTOXINMaloney; A. H., ~- H .. Fitch and .A. ~- Tatum: Picrotoxin'asan antidote xn acute po1son1ng by the shorter• acting barbiturates, J. Phatmacol. & 4Xper. Therap.41 ! 465. 1931.'-,, Bibliography 123METRAZOLBennett, A. E.: Preventing traumatic complications in- convulsive shock therapy by curare, J.A.11.A. 114: 322, r. • 1940.Ebaugh, F. G.: A review of the drastic shock therapies-_;.'}t .~ t£ .. e«t.we."lt d t.~ P.,o/.c.lw.~. . E) _1.t1.t1J.-.ut.-M£d18: 279, 1943.de l\feduna 1 L.: New methods of medical treatment ofschizophrenia, Arch. N eurol. & Psychiat. 35 : 361, 1936.Walk, A., and W. Mayer-Gross: Observations on convulsiontherapy with triazol 156, J. 1'1:ent. Sc. 84: 637,1938.NtKETBAMIDEGunther, L., H. Engelberg and L. Strauss: Intramuscularpressure, II, the venopressor mechanism in shocklil~e conditions and the effects of various drugs, Am. J. "' ,M. Sc. 204: 271, 1942. .Smith, D. T., G. Margolis and L. H. Margolis: Theblack-tongue curative effect of pyridine-~-carboxylicacid diethylamide (coramine). J. Pharmacol. & Exper.Therap. 68: 458, 1940.CAFFEINEFoltz, E. E., A. C. Ivy and C. J. Barborka: The influenceof amphetamine (benzedrine) sulfate, d-desoxyephedrinehydrochloride (pervitin) and caffeine upon ,vorkoutput and recovery when rapidly exhausting work isdone by trained subjects, J. Lab. & Clin. l\lfed. 28: 603,1942-1943.Huidobro, F. and E. Amenbar: Effectiveness of caffeine(1, 3, 7, trimethylxanthine) against fatigue, J. Pharma!.col. & Exp er. Therap. 84: 82, 1945.Roth, J. A., A. C. Ivy and A. J. Atkinson: Caffeine and"peptic" ulcer: relation of caffeine and caffeine-contain•ing beverages to the pathogenesis, 'diagnosis and man•agement of "peptic 0 ulcer, J.A.M.A. 126: 814, 1944 .•AMPHETAUlNE AND RELATED PREPARATIONS •Albrecht, F. K.: The use of benzedrine sulfate in obesity,Ann. Int. 11:ed. 21 : 983, 1944. ,Bakst, H. J.: Daily use of benzedrine sulfate over aperiod of 11ine years-report of a case, U. S. Nav. l\{.Bull. 43: 1228, 1944. -'•\• l \... •'1_24_ ___Ce_ntr_al _Ne_rv_ou_s S ystem Stimulants _..::. ___________Davidoff, E.: A comparison of the stimulating effect ofamphetamine dextroamphetamine and dextro-N-metbylamphetamine (dextro-desox3rephedrine), 1:1. Rec. 156:422, 1943,Ivy, A. C., and F. R. Goetzl: D-desoxyephedrine, a review.War Med. 3: 00, 1943.Ivy, A. C., and L. R. Krasno: Amphetamine (benzedrine)sulfate a revie\v of its pharmacology, \Var. !lied. 1:15, 1941.Norman, J.1 and J. T. Shea: Acute hallucinosis as a complicationof addiction to amphetamine sulfate: reportof a case, N e,v England J. 1'led. 233: 270, 1945.Reifenstein, E. C., Jr., and E. Davidoff: Intravenous benzedrinesulfate as an antagonist to intravenous solubleamytal, Proc. Soc. Exper. Biol. & 1'Ied. 38: 181, 1938.Smith, L. C.: Collapse with death fo1Jo,ving the use ofamphetamine sulfate, J.A.M.A. 113: 1022, 1939. •Tainter, M. L., L. J. Whitsell and J. M. Dille: The'analeptic potency of sympathomjmetic amines, J. Pharmacol.& Expe1-. Therap. 67: 56, 1939.••I I• •Autonomic DrugsINTRODUCTIONSYMPATiiOMIMEIIC DRUGSEPINEPHRINEEPHEDRINESYNTHETICSYMPHATHOMIMETIC AMINESSYMPATHOLYTIC DRUGSPRJ:PARATIONSINTRODUCTIONA number of drugs of wide clinical importance are classifiedas autonomic drugs because their action more or lessresembles that produced by stimulation or inhibition ofeither sympathetic or parasympathetic nerves. The actionof these drugs can be 'most readily interpreted in terms ofthe chemical-mediation theory of nerve transmission across• l a synapse. In brief, it is believed that impulses travelingalong preganglionic fibers of both parasympathetic andsympathetic nerves cause the release of acetylcholine, ,vhichtrans1nits the impulses across the synapse to the postganglionicfibers. Impulses traveling down the postganglionicfibers of most sympathetic nerves liberate syrnpathin 1 a •substance similar if not identical with epinephrine (adrenaline)1 while those traveling down postganglionic fibers ofparasympathetic nerves liberate acetylcholine. Acetylcholine,liberated either at the synapses or at the nerve endings1 •is normally rapidly destroyed by an enzyme, acetylcbolineesterase (choline esterase), while sympathin is probablysimilarly destrO}'ed by amine oxidase.us• •I'••lI]26 Autonomic Drugs • )SCHEl\1:ATIC ILLUSTRATION OF THE ACTION OFAUTONOMIC DRUGSADRENERGIC CHOLINERGICrpregangJionic fiber(medullated)~prrganglionic 6bcr(medulratcd)ganglion 1 -~ --~ At the ganglia of either branch·AcetyJcholine is the chemical mediator;nicotine mimics the action of aret}JcboJjne; •curare i.nhibits the action of acctylcholine;physostigmine, ncostigrninc, atropine ormusc3tinehave no cff ect.' react.1ng cells~ \•, postganglionic fiber(noru:nedulutro)postganglionic fiber(nonmedulbttd)Sympatbin (epinephrine?) is the chemical Mediator.Ephedrine potetitiatcs by inhibition af amine ox.idasc.Epinephrine acts directly on the sensitive area. of the reacting cell.Etgotamine may partially block the stimulant action in toxic doses.,Ace(y! choline Is the cbemica! mtdi.1tor.Physostigroine, ncostigminc, potentiate by inhibition of choline esterase.Acetylcholine, musca.rine, act dir~y on the sens.itlve area cl the reacting ttll,Atropine inhibits the tesponse to all but dittct stitnul3. tion of ~Jtac!~g cell.l••,., ,.,••Introduction,127Acetylcholine is also liberated_ at the endings of certainpostganglionic sympatl1etic nerve fibers (notably the nervesto the sweat glands and pilomotor muscles in human beings).Nerve endings at which acetylcholine is liberated are describedas cholinergic, in distinction from those at ,vhich\. sympathin' is liberated, which are said to be adrenergic.As a result of the action of acetylcholine at the ganglionic,synapses of both branches of the autonomic nervous systemas well as at the postganglionic nerve endings of all para-• sympathetic and certain syn1pathetic fibers, there are twodistinct groups of responses to acetylcholine administration. _The effects initiated at the ganglionic synapse are similarto those obtained with injections of _nicotine and are dtscribedcollectively as the nicotinic action of acetylcholine.The effects initiated at postganglionic cholinergic nerveendings are similar to those obtained by the injection -0fmuscarine and are described collectively as the muscarinicaction of acetylcholin~. The nicotinic effects can be abolishedby curare, the muscarinic by atropine. .The chemical-mediation theory of transmission of nerveimpulses was expanded in 1936 by Dale and his co-,vorkers,who demonstrated the presence of acetylcboline at the endplates of motor nerves to voluntary muscles. The action of •acetylcholine at these end plates is nicotinic in nature, beingabolished by c~rare. Recentlyt considerable attention hasbeen paid to the possible role of acetylcholine in synaptictransmission in the central nervous system.Drugs which when injected elicit responses /simulating •those of stimulation of adrenergic nerve fibers are kno\vnas sympathomimetic drugs. Drugs which elicit responsessimulating inhibition of adrenergic nerve fibers are known~ sympatholytic drugs. Similarly, drugs whose actionsimulates the muscarinic effect of acetylcholine are de•~cr~b«:<a1s parasympathomimetic drugs, while those which1nh1b1t this effect are described as parasympatholytic drugs.It shnulrl hP. realized that because of the close interrelation-./Ir 128 Autonomic Drugsship of the two branches of the autonomic nervous system, supplying any given organ, stimulation of one branch maylead to a compensatory stimulation of the other· thus vari- able and unpredictable 'e ffects may ensue. Likew' ise, inhibitionof one branch may be tantamount to stimulation ofthe other, since the normal counteracting mechanism basbeen abolished. Furthermore, parasympathomimetic drugsmay, especially'in larger doses, have nicotinic actions whichproduce sympathomimetic as well as parasympathomimeticeffects. Finally, in addition to their effects on the autono1nicnervous system, autonomic drugs frequently have also acentral effect which may at times overshadow their peripheraleffects.SYMPATHOMI1'fETIC DRUGS•Sympathomimetic drugs can be classified pharmacologicallyas true sympathomimetic drugs which stimulate theeffector mechanism directly and pseudosympathomimetics,which act by preserving sympathin, presumably by blockingthe amine oxidase. The first group includes epinephrine,phenylephrine (neosynephrine), kephrine and cobefrine; thesecond, ephedrine, amphetamine, propadrine and paredrine.EPINEPHRINEEpinephrine (adrenaline) is the active principle of theadrenal medulla. It is prepared commercially either syntheticallyor from glands obtained from the slaughterhouse.The naturally obtained product is levorotatory; the dextrorotatoryform has little physiologic activity. Optically inac- •tive or racemic epinephrine is about one-half as active1 physiologically as levorotatory epinephrine.Actions. The effect of epinephrine on any given organis similar to that of stimulation of postganglionic adrenergicfibers supplying that organ and hence may be excitatory orinhibitory, depending on the organ, the species of anim~I andother factors, such as presence or absence of certain sex,I•'1• I,I -•I •S)·mpathomimetic Drugs I 129' hormone;. Effects of therapeutic significance include con- ,traction of arterioles, cardiac stimulation, dilation of the 'coronaries relaxation of the bronchioles and dilation of thepupil. Other effects~nclude con.traction of ~e r~di~l -~uscleof the\iris ' augmentation of salivary secretion, 1nh1b.1 t1ono f the small intestine, excitation of the retractor penis, constrictionof the spleen, inhibition of the nonpregnant andexcitation of the pregnant human uterus.Adminis' tration. Epinephrine is ineffective by mouthexcept in occasional hypersensitive patients. Solutions ofepinephrine in jsotonic solution of sodium chloride aremarketed for use in nasal sprays. Recently, a suspension ofepinephrine, containing 1 part epinephrine in 500 parts ofvegetable oil, has been introduced with a view to prolong ..ing the action of the drug by slowing absorption. Diluteaqueous solutions of epinephrine are quite unstable andcommercial preparations frequently contain sodium bisulfite ,as a preservati•v e.•Toxicity. Symptoms of overdosage with epinephrine includenausea 1 pallor, feeling of oppression and fear, throbwbing headache, vertigo, tachycardia and hypertension. The' use of too concentrated solutions may lead to local tissuenecrosis, especially in sensitive individuals. Severe toxicmanifestations include acute pulmonary edema, acute cardiacdilation and acute ventricular fibrillation. In personswith cardiovascular disease, and occasionally in apparentlynormal individuals, death or permanent mental imp<1iirmentmay result from a cerebral accident. Treatment is symp- ~tomatic, the symptoms usually passing off in a few hours. .Epinephrine should be avoided in aged or hypertensive• patients and in cases of heart disease. It is contraindicatedin light chloroform or in cyclopropane anesthesia because ofthe danger of initiating ventricular fibrillation. Hyperthy•roid ~atients have an increased sensitivity to epinephrine,especially as regards the cardiovascular response and itshould be avoided, or used cautiously in such cas~s. ThisIt130 Autonomic Drugs. -!_ncreased response to epinephrine formed the basis of one ofthe earlier clinical tests for hyperthyroidism (Goetsch'stest).Therapeutic Uses.' CIRCULATORY EMERGENCIES. Epinepb-'rine increases the heart rate and the force of contractionand raises the blood pressure by peripheral vasoconstriction.,, It is thus of value in circulatory emergencies when a com•petent circulatory system becomes suddenly depressed, asin drowning accidents, carbon-monoxide poisoning, overanesthesia,etc. Epinephrine is administered parenterallyin doses up to 1 cc. of a 1: 1000 solution. Administration iseither subcutaneous, intramuscular, intravenous or intracardial,depending on the severity of the condition.Epinephrine is of doubtful value in shock. It is believedthat in shock the arterioles are already maximally contractedand such effect as epinephrine might have on thecapillaries would not cause any great shift in the bloodaway from the abdominal regions and mig.bt have the dis•advantage of increasing tissue hypoxia.Asthma. Epinephrine dramatically relieves asthmaticparoxysms by relaxation of the smooth muscle of the bron•chioles and by vasoconstriction of engorged bronchial mucosae.Its disadvantages, however, are its short action, itsineffectiveness orally, and its tendency to cause dryness andirritation of mucous membranes. A more pro1anged effectcan be obtained ,vith intramuscular injection of oily suspen•sions. (Subcutaneous injection of such preparations maylead to local irritation or scar formation.) Inhalation ofepinephrine in the form of a fine mist should be undertakenonly under medical supervision because of the dangers ofthe strength of the solution used ( 1 : 100).Local Vasoconstrictiou. Epinephrine is usually addedto procaine and a number of other local anesthetics in orderto delay absorption, thus increasing the duration and intensity~of anesthesia as well as decreasing the systemic· effectsof the drug. Furthermore, the risk of hemorrhage is lessenedrI • ..Sympathomimetic Drugs 131by the comparative bloodlessness of the field. In thesepreparations the concentration of epinephrine varies from~ 1 : 100,000 to 1 : 200,000.Epinephrine in 1: 1000 solution may be used to shrink thenasal mucosa in acute rhinitis but because of the brevity of' its action and its tendency to produce ''after~congestion" itis n!)t the drug of choice in this condition. It is also usedin the treatment of allergic responses, such as urticaria,angioneurotic edema, anaphylaxis, serum sickness, nitritoidreactions and hay fever. For these conditions up to 1 cc. ofthe 1: 1000 solution may be injected subcutaneously. ,Epinephrine sprayed on raw and bleeding surfaces mayprevent excessive loss of blood by hemorrhage. However,the possibility of systemic toxicity from the large absorptive, area should not be overlooked.Introduction of epinephrine in the c.onjunctival sac issometimes effective in the alleviation of glaucoma, the pupillarydilation and the constriction of the vascular bed reducingthe ocular tension. However, in some cases, especiallyin acute glaucoma, there may be a dangerous rise oftension. Epinephrine finds further use in ophthalmology,often in conjunction with atropine, in breaking up adhesionsof the iris to the lens by dilation of the pupil.Standardization of Epinephrine. A U.S.P. referencestandard is available. The official method of assay is basedupon the ris~ of blood pressure in the anesthetized dog.Chemical methods are available but are less sensitive andless specific.EPHEDRINEThe alkaloid ephedrine was first isolated in 1887 by theJapanese chemist, Nagai, from ·a Chinese shrub, 1fa-huang(E~hedra e~z,isetina). It is obtained commercially fromvarious sp~cres of Ephedra or produced synthetically. Thenatura:ly ~solated product is levorotatory. The syntheticephedrine is usually racemic and is only about half as active, I I,'•-1---3-~2-- ------.....;;:.,_, ✓• Autonomic Drugs _____Ias the natural ephedr:ne since the dextrorotatory Cormispractically inert pharmacologically.Ephedrine augments the effects of injected epinephrine orof sympathetic stimulation. It has been suggested that thiseffect is due to an inhibition of the destruction of sympathinby amine oxidase. Hence the sympathomimetic effect ofephedrine would be due to a prolongation of the life ofsympathin continually liberated at the nerve endings.Ephedrine has essentially the same uses as epinephrine.It has the advantages of being effective by mouth, morestable and longer acting. Its disadvantages include theslower onset of its effects, the lessened effect of repeateddoses (tachyphylaxis) and its pronounced stimulatory effecton the central nervous system. Like epinephrine, ephedrinetends to have a marked effect on the heart and should beavoided in cardiovascular diseases. Ephedrine is of somevalue in the treatment of myasthenia gravis, its use in thtscondition predating that of neostigmine. While the mechanismof action in this condition is not wholly understood,recent work indicates that transmission of impulses alongmotor nerves is improved by ephedrine.Toxic symptoms of overdosage or hypersensitivity aremanifested by sympathetic stimulation as ,veil as by centralnervous system stimulation suggestive of a convulsantpoison. Dysuria and urinary retention are at times noted,and in fact strangury may be an annoying feature in theclinical use of ephedrine and other sympathomimetics.SYNTHETIC SYMPATHOMIMETIC AMINESThe numerous pharmacp1ogic effects of ephedrine andepinephrine are a distinct disadvantage clinically whenundesirable side-effects limit their usefulness. Efforts havebeen made, therefore, to synthesize related compounds whichwould be useful for a particular purpose and be relativelyfree from other effects. Such compounds are convenientlyref erred to as sympathomimetics 1 though in many instances,>....\,,,..CHOHICH2INHCH3,Sympathomimetic DrugsCHOH C' H2 N'H CH3CHOHI~HCH3NHCH3C::::.Q C'H 2I133NHCH3£pjnephrJne Neosynephrine Ephedrine Kephrlne~H~-OHCHOHIYHCH3NH2Cobef rineCH2IiHCH 3NH2PciredrineCHOHICHCH3 INHePropadrineyH3(~H2)4CHCH 3 INH2CH2ICHCH3 I... NH2AmphetamineCH2IIycH 3(yH2)3CHCH3 INHCH3Phedracine Pri\line Tua.mlne Octin,CH2 ICHCH 3 INHCH3Methedrlne,'...CHCH3 ' ... CH •I 2NHCH3•Vonedr1neCH2ICHCH 3 I ~NHCH3 , . •Paredrlnol ••\••I134 Autonomic Drugsthey retain little of the sympathomimetic patterns of epinephrineor ephedrine. Literally hundreds of such com•pounds have been prepared and a number of them havebeen adopted for clinical use. In order to evaluate these' newer drugs, one should consider how they measure up tothe qualifications for a particular use. Thus, a pressor drugused to maintain or restore the blood pressure during orafter a surgical operation should be effective by intravenousor intramuscular injection; it should rapidly produce asustaineU rise in blood pressure and should have no untowardeffects on the cardiovascular system. Epinephrinegives a rapid and marked rise in blood pressure but itsduration is short and it may be fallowed by a precipitousfall. Ephedrine has a some,vhat more gradual and long~rIastingeffect but it is not so effective on repeated inject~nand has undesirable stimulating effects on the central nerv•ous system. Among the newer drugs, phenyiephrine (neo•, synephrine), paredrine, phedracine, paradrino1 (veritol,pholedrine) and the aliphatic a.mine oenethyl are said tohave prolonged pressor effects with little cardiac or centralnervous system stimulation, and are reported to be effectiveon repeated injection. Unfortunately, none of these drugsis effective for more than half an hour. 1\Iethedrine (d·desoxyephedrine) is claimed to have a much more Iastingeffect, though its cortical-stimulatory action may counteractpostoperative sedation.In selecting a drug for a nasal decongestant, a prolongedeffect, without a period of after-congestion and freedom.__ from central nervous system or cardiac stimulation areprime prerequisites. A volatile substance makes for ease ofadministration in the form of an inhalant. The drug shouldbe able to penetrate rnucus, should not interfere with thenasal cilia and should not produce any local irritation. Oilypreparations are to be deprecated because of the interfer•ence wjth ciliary movements and because of the danger oflipoid pneumonia. Epinephrine causes too much after-con•• •' Sympathomimetic Drugs( I,135gestion and ephedrine too much central stimulation to besatisfactory nasal decongestants. Amphetamine {benzedrine),vooedrine, and the aliphatic amine, tuamine, arevolatile bases dispensed as inhalants. Amphetamine has apronounced central~stimulatory effect and gives rise tonervousness and insomnia unless used very sparingly. Naph~azoline (privine) has a very intense and prolonged vasoconstrictor.action which, however, may be followed by anannoying congestion which limits its use. Phenylephrine•and propadrine have a more prolonged action than ephedrineand appear to be relatively free from central-stimulatoryeffects but must be applied by sprays or as nose drops.Drugs used to enhance or prolong the effect of local anestheticsinclude cobefrine and phenylephrine, ,vhich possessthe local vasoconstricting effect of epinephrine but are saidto be less toxic and to cause fewer side-effects, such ascentral nervous system and cardiac stimulation. However,they are less efficient vasoconstrictors than epinephrine andhigher concentrations are therefore required. Kephrine isa local vasoconstrictor, less powerful but more prolongedin action than epinephrine. It is used locally to controlcapillary bleeding.The aliphatic amine, octin, has a spasmolytic action, prcsun1ablydue both to a direct action on smooth muscle andto a stimulation of inhibitory sympathetic fibers. It hasbeen recommended for the relief of spasm of the intestinal,biliary and genitourinary tracts.SYl\:IPATHOLYTIC DRUGSSeveral drugs, such as ergot, yohimbine and certain diox-'ane derivatives have a depressant action on the sympathetic 'nervous system. These drugs are too toxic for routineclinical use,'and, therefore, in combating overactivity of thesympathetic nervous system recourse has to be made eitherto sympathectomy or to parasympathetic stimulation. ·Theneed for a safe sympatholytic is apparent in view of the\' . •I\\•136 Autonomic Drugs ,.,various conditions whose basis may well be an autonomicimbalance, .such as hypertension, Reynaud's disease, mega.colon and certain nervous conditions., In 1939 a study was made in Germany of the sympatho.Iytic properties of a number of imidazoline derivatives. Oneof these compounds, 2-benzyl-4,5-imidazoline or priscoIh, asbeen used clinically in Europe, apparently with promisingresults. 1 A similar but probably ~ore potent compou~d,N, N-dibenzyl-~-chloroethylamine or dibenamine, is beingstudied in this country with a view to determining its cJinicalvalue and its usefulness in physiologi,c and pharm.acoJogicinvestigations., PREPARATIONSEpinephrine U.S.P.; adrenaline Il.P. 1Epinephrine solution U.S.P. A 1: 1000 solution of epineph•rine hydrochloride in distilled water.Solution of adrenaline hydrochloride B.P. A 1: 1000 solutionof adrenaline hydrochloride in physiologic saline.Epinephrine injection U.S.P. Sterile solution of epinephrinehydrochloride in water for injection. It is usually avail•able as 1. cc. of 1: 1000 solution; 10 cc. of 1: 1000 solution;30 cc. of 1 : 1000 solution. 1 mg.Epinephrine inhalation U.S.P. 1: 100 solution of epineph•rine in distilled water.Suspension of epinephrine in oil, 1 : 500 N.N.R. A suspen•sion of epinephrine U.S.P. in vegetable oil. 0.2-1.5 cc.Ephedrine hydrochloride U.S.P.; B.P. Ephedrine sulfateU.S.P. 25 mg.Ephedrine-sulfate tablets U.S.P.; B.P. Usually available in,15, 25, 30, and 45 mg. amounts.Racepbedrine N.N.R. Racemic ephedrine. 30-50 mg.,Racephedrine sulfate and hydrochloride N.N.R. 30-50 mg.Phenylephrine hydrochloride N.N.R.Amphetamine N .N .R.VonedrineN .N.R.,• PreparationsTuamine N .N .R.Tuamine sulfate N.N.R.Naphazoline hydrochloride N.N.R.Propadrine hydrochloride N .N .R.BIBLIOGRAPHYGENERAL137IBurn, J. H.: The relation of adrenali11e to acetylcholine inthe nervous systen1, Pl1ysiol. Rev. 25: 377, 1945.Loe,vi, 0.: The l1umoral transmission of nervous impulse,Harvey Lectures 28: 218, 1932-1933.tfyerson, A.: Hun1an autonomic pl1armacology, XII,theories and results of autonomic drug administration,J.A.M.A. 110: 101, 1938.SYMPATHOMIMETIC DRUGSBrunner, R. S., and G. de Takats: The use of neosynephrinein spinal anesthesia, Surg. Gynec. & Obst.68: 1021, 1939. IBumgardner, J. S .. L. D. Abernethy and F. B. Zimmerman:Vonedrine; clinical study of a ne,v nasal decongestant,Laryngoscope 54: 408, 1941.Butler, D. B., and A. C. Ivy: Method of application ofdrugs to the nasal m ucosa.-a com parjson of nasaldrops, sprays and inhalers, Arch. Otolaryng. 39: 109,1944.Cohen, A. E., and '11. L. Waterstone: Epinephrine hypersensitivity,J. Allergy 11: 393, 1939-1940.Edgeworth, H.: A report of progress on the use of ephedrinein a case of myasthenia gravis, J.A.M.A. 94: 1136,1930.Elmes, P. C., and A. A. Jefferson: Action of pholedrineand neosynephrin in raising the blood pressure, Brjt.ir. J. 2: 65, 1942.Feinberg, S. ?vi., and S. Friedlaender; Nasal congestionfrom frequent use of privine hydrochloride, J.A.lI.A.,128: 1095, 1945.Gu~n, J. A.: The pharmacological actions and therapeu•tic uses of some compounds related to adrenaline, Brit.11. J. 2: 155. 214,, 1939.'•; •138 Autonomic DrugsHartung, W. H.: Inactivation and detoxication of pressoramines, Ann. Rev. Bioche'm, 15: 593, 1946.Keeney, E. L., J. A. Pierce and L. N. Gay: Epinephrinein oil, a ne,v, sio,vly absorbed epinephrine preparation,Arch. Int. Med. 63: 119, 1939.Kully, B. M.: The use and abuse of nasal vasoconstrictormedications, J.A.M.A. 127: 307, 1945. 'LeCompte, C. B.: Some clinical experiences ,vith (oenethyl)2-methyl-amino-heptane as a vasopressor sub•stance, Anesth. & Analg. 25: 168, 1946. .Sterling, A. : Dangers attending the clinical use of ep1•nephrine in bronchial asthma, M. Clin. North America24: 1851, 1940.Sympathomimetic agents-A symposium, Indust. &Engin. Chem. 37: 116, 1945.SYMPATBOLYTIC DRUGSChess, D., and F. F. Yonkman: Adreno1ytlc and sym·patholytic act~ons of priscol (benzyl-imidazolioe), Proc.Soc. Exper. Biol. & Med. 61 :127, 1946. .Nickerson, M., and L. S. Goodman: Pharmacologicalproperties of a new adrenergic blocking agent: N, N•dibenzyl-~~chloroethylamine ( dibenamine), J. Pharmacol.& Exper. Therap. 89: 167, 1947.12tAutonomic DrugsPARASYl:lPATHOMIME'IICDRUGSCHOLINE DERIVATIVESPHYSOS'IlGMINE ANDNEOSTIGMINEDI-ISOPROPYL FLUOROPHOS•PHATEPILOCAlU'INEMUSCARINE ANDAllECOLINETHERAP~UTIC USES OFPARASYMPA.THOMIMETICDRUGSPARASYMPATHOLYTIC DRUGSBELLADONNA.ALKALOIDSSYNTHETIC PARASYMPATHO-"LYTICDRUGSTHERAPEUTIC USES O'F PARA•SY.MPATEOLYTIC DRUGSATROPINE POISONINGPREPARATIONS•PARASYMPATHOI\fIMETIC DRUGSParasympathomimetic drugs include the choline deriva- ~tives, such as acetylcholine, methacholine (mecholyl) andcarbachol; physostigmine (eserine); neostigmine (prostigmine)and pilocarpine. Clinically, these drugs are used tostimulate a depressed parasympathetic system or to antagonizean overactive sympathetic nervous system and to improvethe transmission of impulses at the myoneuraljunction of skeletal muscle. There is evidence that in somecases their therapeutic action may be due to an effect onthe central nervous system.Acetylcholine was first studied pharmacologically in1906 by Hunt and Taveau, who were attempting to identify• 139\••,140 At1tonomic DrugsCHOLINE DERIVATIVES0JICH-C-O_;CH3 I 20n'\,)•CH2CH - 2 , ...CH -N-CH3 f 3, I+ CH3-r-cH 3 _'CH3CH3Methacholinethe substance responsible for the blood-pressure-Joweringactivity of the adrenal gland after the epinephrine had beenextracted. They succeeded in isolating choline but in insuffi·cient quantities to account for the observed effects. In thebelief that the choline ,vas the end product in the breakdownof a more active compound, these investigators tested acetylcholineand observed its very potent blood-pressure-loweringeffect. Their suggestion that acetylcholine was present in theI adrenal gland, however, was met with considerable scepticism.The compound was later studied by Dale, who•J Parasympathoniimetic Drugs 141observed the remarkable similarity between the effects ofacety1choline and of stimulation of parasympathetic nerves 'and who first suggested that this drug might play the roleof a parasympathetic hormone. The first direct evidenceof such an ac1tion was presented in 1921 by Otto Loewi, whostimulated the vagus of an isolated frog heart and on perfusing a second heart with the Ringer's fluid from the stimu ..lated heart obtained a slowing similar to that produced bystimulation of the vagus. However, no slowing was observedif the second heart was atropinized. Loewi suggested that, the heart is not stimulated directly by the vagus but bya substance which he called Vag1,sstoff, which" is liberatedby vagus stimulation. The behavior of this substance wasshown by Loewi and others to be similar to that of acetylcholine.In 1929 Dudley and Dale isolated acetylcholinefrom animal tissue (spleen). Later workers, using refinedtcchnics of bioassay, have shown the presence of acetylcholineat nerve endings, ganglionic synapses and in thecentral nervous system, giving strength to the conceptionthat acetylcholi11e plays an important role in the transmissionof nerve impulses across the synapse and at the neuromuscularjunction .The well-established parasympathetic stimulatory actionof acetylcholine is of no therapeutic value because of theinstability of the drug and its evanescent action. A numberof more stable choline derivatives, however, find wide,, clinical application. • 'Methacholine (mecholyl, acetyl-~-methylcholine) wasfirst studied pharmacologically in 1911 by Hunt and Taveau,who were endeavoring to find a drug which would give amore persistent blood.pressure-lowering effect than acetyl~ol~ne. The compound did not arouse any widespread clin•1cal interest, however, until some twenty years later followingthe work of Simonart. It is the drug of choic~ in thetreatment of peripheral vascular disease, in which it givessymptomatic relief by improving the circulation. It is suf.-- --II '142 Autonomic Drugsficiently stable to be administered orally or subcutaneously,and it can be applied local1y by iontophoresis. It has a verypowerful effect on the heart and should not be given intravenouslybecause of the danger of cardiac arrest. Unpleasantbut less dangerous effects include the precipitation ofasthmatic attacks in patients subject to asthma, dyspneaand substernal pain, epigastric discomfort, vomiting anddisturbances in accommodation. These symptoms are c,o mmonto all parasympathomimetic.s and can be promptlyrelieved by the injection of atropine. .1\fethacholine bas amuch less pronounced nicotin.ic action than acetylcholine,though it is questionable whether the absence of a nicotineaction is of great clinical significance since it would only beobtainable by undesirably large doses. ACarbachol (doryl, lentin, carbaminoylcholine), the mostpowerful choline derivative known, was synthetized in Germanyin 1932. Under the name of lentin it became popularin that country for the treatment of gastro-intestinal disordersin animals. Because of its toxicity, it is seldom usedexcept in the treatment of glaucoma when the eye does notrespond to pilocarpine, physostigmine, methacholine or neo•stigmine. It is poorly absorbed from the conjunctiva! sacbut absorption is improved when it is mixed with petrolatumor zephiran. It may cause blurring of vision andoccasionally pain. It gives effective relief in the pain ofperipheral vascular disease and by subcutaneous injection,its effects outlast those of methacholine. However, thelatter is safer and it is to be preferred unless the patientis under constant medical supervision. Carbachol is said tohave much less effect on the heart and blood vessels thanmethacholine. It hasJ however, a much more pronouncednicotine-like action.Choline Derivatives with Parasympatholytic Effects.Swan (1943) prepared a series of choline derivatives havinga surface-tension-lowering effect in the belief that su':11derivati••~ might have enhanced or altered pharmacolog1c•Parasyrnpathomimetic Drugs 143properties due to their greater penetrability. Such compoundshave a mydratic and cycloplegic action on the eye incontrast to the myotic and cyclotonic action associated withparasymp:ithomimetic drugs. The action is apparently similarta that of atropine and is due to a. paralysis of tJieparasyn1pathetic systen1 rather than a simulation of thesympathetic. One such drug, the dibutyl carbamate ofdimethyl ethyl-~-hydroxyethyl ammonium sulfate ( dibutolinesulfate), has been tried' clinically as a cycloplegic. It isclaimed to be a rapidly acting drug giving a short period ofvisual disability ,vith negligible systemic effects. Disadvantagesinclude irritation with continued use and disturbn11ceof• the corneal epithelium due to the surface activity of• tl1e drug..,..PHYSOSTIGMINC AND N'EOSTIGMINEII H\ 0N-C-0/CH3 N NI ICH3CH3PhysostigmineCH O C1H3\ 3 II '--N!. CH1N-c-o I 1 3CH CH~ 3 . ,.,JNcostigmlne, Pl1ysostigmine (eserine) is obtained from the seed ofPliysostig11zav e1ze1zosu,,tzh,e Calab:i.r bean. Neostigmine(prostigmine) is a synthetic drug introduced in 1931 as aresult of the work of Stedman and his associates. Both co111-pounds O\Ve their parasympathomimetic action to an inhibitionof choline esterase and thus to a prolongation of the lifeof the acetylcholine at cholinergic nerve endings.A new series of parasympathomimetics, the fiuorophosph:ites, were developed in the course of studies on toxic, agents in "-·arfarc. Their activity and the duration of theireffects is due to an irreversible inhibition of cl1olinc esteraseIl• \_144_ ______A_ut_on_om_ic Drugs __;:~------ -•Dt·ISOP.ROPYL FI.UOROPHOSPHATE 'II 0p,..........CH-0 FCH3Di-isopropyl Fluorophospbatein contrast to the reversible inhibition of physostigminea ndneostigmine. Their effects last, therefore, until adeqwteamounts of choline esterase are built up again. Furthermore,their action, in therapeutic doses, is apparently nicotinic,rather than muscarinic. One of these drugs, di•isoprdpyl.ftt1orop!1ospl1ate(D FP), has had limited clinical use. Itappears to be best suited for the treatment of glaucomabecause of its long duration of action. It is too toxic to beof much value in the treatment of myasthenia gravis.GH3-C H-C2 HPILOCAnPINEfO=C\ /CH2 H~ j H0 NPilocarpine •.,,•pi]ocarp.ine is an alkaloid obtained from the leaves ofthe shrub Pilocarpus jaborandi. It has a specific parasym• '••Parasympathomimetic Drugs 14SIIpathomimetic effect, the exact mechanism of which is notfully understood. Its action on sweat and salivary glands isespecially marked.MlJSCARINE AND .ARECOLlNE) ,?CH--CH -CHOH-CH-C• -~ 2 I \HMuscarineCH -N-CH3 I, 3OHCH3NICH3o·IIC-OCH3ArecolinoMuscarine is an alkaloid present in the mushroom, Ama-\ nita 1nuscaria. It was first isolated and studied pharmaco.logically by Schmiedeberg in 1869. \Vhile at present of n~clinical importance, it has had extensive use experimentallyin the differentiation of smooth-muscle innervation since itsaction is at cholinergic nerve endings only and not., likeacetylcholine, at both cholinergic nerve endings and at autonomicganglia.JJ Arecoline is an alkaloid, obtained from the betel nut,,vhich bas a parasympathomimetic action. Its only use isin veterinary medicine in the treatment of gastro-intestinaldisturbances.II TllE.RAP.EUTIC USES OF PARASY!.[PATlfOMIMETIC DRUGSI. Peripheral effects.LocAL VASODILATION. The vasodilator effect of parasym-1;>athomimetic drugs has several clinical applications. Theprevention or overcoming of vascular spasm gives symp..tomatic relief in peripheral vascular disease (e.g., Raynaud'sdisease, intermittent claudication, chronic ulcers, et~.).f••I146 Autonomic Drugs --------------~---···---.rMethacholine has been used with good results in these conditions,either orally, subcutaneously or locally, by iontransfer. Carbachol is also effective but too toxic for routineuse, l\fethacholioe by iontophoresis has also been used inthe treatment of arthritic pain and pelvic inflammation,relief being due to hyperemia, which may last from 4 to 8hours. Recently, neostigmine has been used for the treat•ment of delayed menstruation. It is believed that the inhibitionof the destruction of acetylchoJine, effected by neostigmine,leads to the vasodilation and hyperemia of theuterus, ,vhich is thought to be one of the determining factors• in the onset of the menstrual bleeding. If the patient ispregnant, bleeding rarely ensues, hence injection of neostigminehas been suggested as a test for early pregnancy butthe possibility of inducing abortion limits its usefulness.Neostigmine has also been tried with promising results inthe treatment of atrophic rhinitis. Application by nasalspray causes an increased blood flow to the nasal mucosa,with reduction in the encrustation and of the associatedfetid odor.SINUS TACHYCARDIA. Stimulation of the vagus by parasympathomimeticdrugs frequently brings about the arrest• of attacks of sinus tachycardia when carotid pressure isineffective. Neostigmine and methacholine are useful drugsin this connection. They do not, however, affect the heart•rate if the tachycardia is associated with obvious organicdisease.OPHTHALMOLOGY. Parasympathomimetic drugs are importantadjuncts in the treatment of glaucoma; the con•traction of the ciliary body facilitates drainage through thecanal of Schlemm, while vasodilation may also assist inthe removal of fluid. Physostigmine is perhaps the mostwidely used drug for this purpose, though, piJocarpine,neostigrnine and methacholine are also effective. Carbacbol(usually as a 0.75 per cent solution) has been used succe:5·fully jn cases not responding to the usual treatment, while•, •I'Ir • Parasympathomimetic Drugs 147preliminary studies indicate that di-isopropyl fluorophospbateoffers the advantage of a prolonged action. Since thedrugs are applied locally, the danger of systemic toxic effectsis greatly reduced. Parasympathomimetic drugs, especiallyphysastigmine,a re a.1sau sed ta restore accomnwda.tion afterthe use of short-acting parasympatholytic drugs.STIMULATION OF THE GASTRO-INTESTINAL TRACT. The parasympathomimeticdrugs, especially methacholine, neostigmineand carbachol have been used in the relief and in the•prevention of postoperative distention and urinary retention.The beneficial effects of the drugs are due to their stimulationof peristalsis by increas,i6g the intestinal tone and theircontraction of the bladder and relaxation of the trigoneand sphincter. ,II. Conditions in Which Parasympathetic Stimulation isnot Involved.l\!YASTHENIA GRAVIS. Neostigmine is probably the bestdrug avaiJable for the symptomatic treatment of myastheniagravis. This condition is believed to be due to a disturbancein the transmission of impulses at the myoneural junctionof volW1tary muscle. The dramatic improvement frequentlyafforded by neostigmine and also by physostigmine has beenexplained both by the inhibition of the choline esterase andby the antagonism of a hypothetical curare-like substance.Undesirable parasympathomimetic effects, such as salivation,perspiration, bradycardia and gastro-intestinal upsets,are abolished by the concomitant administration of atropine.Neostigmine can also be used as a diagnostic test formyasthe11ia gra.vis since in this disease a remarkable toleranceto the drug is developed, and the usual parasympathon1imeticeffects of neostigmine are elicited only bylarge doses.RELIEF OF l\IuscLE SPASM. Neostigmine has been recentlyreported to be of value in the relief of muscle spasms dueto poliomyelitis, rheumatoid arthritis and allied conditions.•r/••..I•148 Autonomic Drugs -It has been suggested that relief is clue to a central effectof the dru' g leading to inhibition of muscle tone in' additionto the inhibition of choline esterase at the myoneurajlu nction.As in the treatment of myasthenia gravis, undesirableparasympathomimetic effects are abolished with atropine.PARASYMPATHOLYTIC DRUGSDepression of the parasympathetic nervous system isobtained clinically by the use of the belladonna alkaloidsor by synthetic substitutes. In general, the synthetic substitutesdo not display the variety of actions of the naturallyoccurrjng alkaloids. Tbey do not, therefore, have as wide a• field of application, but, on the other hand, their use inconditions for ,which they are effective is attended by fewerundesirable side effects.BELLADONNA .ALKALOIDSCH -CH ·CH2 O H ,</f/ l I tllr=\ N-af ..c-o-c ~ ~' I 3 I ICH-CH- CHz CH2&Atropine Scopolamfne(d, I, hyoscyamine)The belladonna or solanaceous alkaloids, atropine, byoscyamineand scopol<J,mine (hyoscine) are obtained Crom anumber of solanatPous plants including Atropa belladonna(the deadly nightshade), Datura stramonium (Jimsonweed)and Hyocya111usn iger (henbane). Atropine rarely if everoccurs in nature and is formed by the racemizatio.a of thenaturally occurring /-hyoscyamine. Since the phannacolog~cactivity 1s invested in the levorotatory form, atropine , JSappro;timately half as active as hyoscyamine. Scopolam1neis the most active of the belladonna alkaloids, partly be•cause bf its greater solubility, which permits more rapidpassage to the site of action.•Parasympatholytic Drugs 149IThe belladonna alkaloids have a depressant 'action onsmooth muscles and -glands innervated by postga11glioniccholinergic nerve fibers. In larger doses they also have adepressant action on autonomic ganglia. The parasympatho~Jytic effect is not due to a suppression of acetyJcboJjneformation but to failure of the liberated Jl,Cetylcholine tostimulate the atropinized cell.The belladonna alkaloids, in addition to their characteristicperipheral effects, also have a central action; atropineand hyoscyamine at first stimulate and then depress thecentral nervous system, while the action of scopolamine is•predominantly depressant.I• ' SYNTllETIC PARASYMPATllOLYTJC DRUGSCH2-CH--CH2 0 H'I I 11 '-0 N-CH HC-0-C--C ~, ,/. I 3 I 1 uCU-CH-- CH OH2IEucatropine HomatroplncSyntropanThe manifold eff ccts elicited by atropine stimulated thesearch for synthetic substitutes with a more specific action.Preparations used in ophthalmology include homatropine 1eucatropine and E3 (dimethylaminoethyl benzilate ethochloride),which was recently introduced in England. Thesedrugs act more promptly and have a much more evanescenteffect oa the eye than atropine. In addition, they are considerablyless toxic and can be used on patients sensitiveto atropine. Other compounds, such as homatropine methylbromide(novatrine), syntropan and transentin, are' used•I\ ,I•f•\'150 Autonomic DrugsIas antispasmodics, their effectiveness being due apparentlyboth to a parasympathetic-depressant action and 'to adirect action on the muscle. These drugs have less effectthan atropine on the eye, the salivary secretion and theheart rate. Isonipecaine, which is related chemically toatropine, is used chiefly for its morphine-like action. (SeeChapter 9.)/THERAPEUTIC USES OF PARASYMPAI'HOLYnc DRUGSI. Peripheral ActionsOPHTHALMOLOGY. Parasympatholytic drugs cause a re•Ia.~ation of the circular constrictor muscle (mydriasis) andof the ciliary body (cycloplegia). \Vith atropine the effectsmay last for days and are not readily antagonized byphysostigmine; hence, for routine eye examinations shorteractingdrugs such as homatropine and eucatropine are usu•ally preferred. Atropine is of advantage when prolonged restis indicated, as in some inflammatory conditions. It shouldnot be used, however, if glaucoma is present or suspectedsince the relaxation of the ciliary body may impede drainageof the ocular fluid by blocking the canal of Schlem.Dl,RELIEF OF SuooTH-i1usCLE SPASM. Atropine and a num•ber of synthetic substitutes are useful in the treatment ofgastro-intestinal spasm, especially in cases in which theunderlying cause is thought to be overactivity of the para•sympathetic nervous system. Atropine is included in \nanyproprietary cathartics, allegedly to prevent griping. It isalso used occasionally for the relief of biliary and urinarycolic. Atropine is one of the most effective drugs in thetreatment of enuresis in children, since it decreases theirritability and increases the capacity of the bladder.The belladonna alkaloids were among the first remedies£or bronchial asthma, inhalation of smoke from burningJimson weed being a popular and fairly effective remedy.While atropine relaxes bronchial spc1~m~ and reduces se•'•I'I'Parasympatholytic Drugs 151cretions ' large doses are required, with attendant un. desi.r - able side effects; consequently the use of sympathom1met1csis now pref erred.HEART BLOCK. Atropine occasionally restores the norn1alsinus rhythm in transient or intermittent heart block,presumably by its inhibitory action on the vagus.Arurnst OF SECRETIONS. Atropine is usually administeredpreoperatively to reduce bronchial and salivary secretionsduring anesthesia, though some operators claim that th_eresultant thick viscous mucus is as likely to cause complicationsas the more readily removed watery secretion whichoccurs without premedication .....II. Central ActionsScopolamine (0.3-0.6 mg. intramuscularly) relieves therigidity and tremor of postencephalitic Parkinson's disease.The action is thought to be a central one since the efficacyof the atropine-like compounds in this disease is relatedto their central-depressant action. ,Scopolamine (0.6 n1g.) combined with morphine (8 mg.)has been used widely since its introduction as an obstetricanalgesic by von Steinbilchel in 1902. A condition ofamnesia and anesthesia results (''twilight sleep"), the patientremains more or less conscious but does not recalllater the unpleasant circumstances of the event. This procedurehas now fallen into disfavor in many clinics becauseof unfavorable influences on uterine contractions, the dangerof markedly depressing the respiration of the child,and the fact that the relief of pain is often inadequate.Atropine or scopolamine is frequently administered withmorphine to counter3ct the respiratory depression of morphine.Scopolamine appears to be the drug of choice sinceit produces greater psychic depressipn and respiratorystimulation than atropine in equivalent dosage. The opti.mun1 ratio is 1 part of scopolan1ine (or atropine) to 25parts 0£ n1orphine.-I'f I1S2 Autonomic DrugsScopolamine, taken orally, is an effective prophylacticfor seasickness and airsickness, probably because of bothits central~depressant and its antispasmodic actions.IATROPINE Po1s0NrnG \Atropine poisoning occurs frequently in children fromthe ingestion of belladonna plants or atropine-containingmedicines. It may a.Isa occur accidentally during treatment;for example, sufficient atropine may occasionallybe absorbed from the conjunctiva to give rise to systemictoxic effects. Both peripheral and central effects are apparent.The pupils become widely dilated. The skin is hot,dry and flushed a.nd the temperature rises because of theinhibition of sweat secretion and the motor restlessne~.Excitement may be marked and mental derangement mayoccur, followed by depression and collapse. Gastric lavageshould be instituted if the poison was taken by mouth;barbiturates may be given to control the convulsionsw, hilethe peripheral symptoms may be treated with pjlocarpinein 10 mg. doses subcutaneously, repeated until the mouthbecomes moist. If depression has set in, stimulants and artificialrespiration may be necessary./ PREPARATIONS1\.1ethacholinec hloride U.S.P. 0.2 Gm. oral, 10 mg. sub·cutaneous. •'l\fethacho1ine-chloride capsules U.S.P. Contains 0.2 Gm.Methacholine-chloride injection. Contains 10 mg. in 1 cc.Physostigmine salicylate U.S.P. and B.P. 2 mg.Neostigmine bromide U.S.P. 15 mg.Neostigmine methylsuliate U.S.P. 0.5 mg. subcutaneousor jntramuscular. 'Neostigmine-methy1su1fatien jection U.S.P. Usually availabelas 0.2 S and 0.5 mg. per cc.Pilocarpine nitrate U.S.P. and B.P. S mg., Carbachol U.S.P.; B.P. (Carbaminoyl choline chloride)2 mg. oral; 0.25 mg. subcutaneous.• (Prepm-ationslCarbachol injection U.S.P. 0.25 mg. in 1 cc.Carbachol tablets U.S.P. Usually 2 mg. tablets.Belladonna extract U.S.P.; B.P. 15 mg.• J 153Belladonna tincture U.S.P.; B.P. Approximately 0.03o/oalcoholic solution of the alkaloids of belladonna leaf.Liquid extract of belladonna B.P. Contains 0.75% alkaloids.Atropine U.S.P.; B.P .. 0.4 mg.Atropine sulfate U.S.P.; B.P. 0.5 mg.Atropine-sulfate tablets U.S.P. Usually 0.3, 0.4, 0.5, 0.6and 1.2 mg.Scopolamine (hyosclne) hydrobromide U.S.P.; B.P. 0.5 mg.Scopolamine stable N.N.R. An aqueous solution of purescopolamine protected against decomposition by the additionof 10% of mannite.Hyoscyamus U.S.P.; B.P. Dried leaf, wi~h or without thetops, of Hyoscya,nus niger Linne. 0.2 Gm.'Hyoscyamus tincture U.S.P.; B. P. Approximately 0.004%(0.005% B.P.) alcoholic solution of alkaloids of hyoscyamus.2-4 cc.Dry e:ttract of hyoscyamus B.P. Contains 0.3% of alkaloiosof hyoscyamus. 16-60 mg.Liquid extract of hyoscyamus B.P. Contains approximately0.0S % alkaloids of hyoscyamus.Eucatropine hydrochloride U.S.P. Used in ophthalmology asa 5% so1ution.Homatropine hydrobromide U.S.P.; B.P. Homatropine hydrochlorideN.N.R. Used in ophthalmology as 1 % solu'tions.Homatropine methylbromide N.N.R. 2.5 mg.Syntropan N.N.R. 50 mg.BIBLIOGRAPHYPARASYltPATHOUIME?'ICS, •Alles, G. A.: The physiological significance of cholinederivatives, Physiol. Rev .. 14: 276, 1934. •/\•''I •154 Autonomic DrugsFof, M. J., and W. H. Spankus: The value of neostigminein acute anterior poliomyelitis, J.A.?ri.A. 128:720, 1945.Henderson, V. E. and 1{. H. Roepke: Drugs affectingparasympathetic nerves, Physio1. Rev. 17: 373, 1937.Leopold, I. H. and J. H. Comroe, Jr.: Use of diisopropylfluorophosphate (''DFP") in treatment of glaucoma,Arch. Ophthal. 36: 1, 1946.Moll, H. H.: The :\ction of parasympathetic-mimeticdrugs in asthma, Quart. J. Med. 33: 229, 1940.O'Brien, C. S. and K. C. S,van: Carbarninoy1cho1inechloride in the treatment 0£ glaucoma, Simplex. Arch.Ophth. 27: 253, 1942.Simonart, A. : On the action of certain derivatives ofcholine, J. Phartnacol. & Exper. Therap. 46; 157, 1932.Soskin, S., H. Wachtel and O. Hechter: Prostigminemethyl-sulfate for delayed menstruation; a therapeutictest for early pregnancy, J.A.M.A. 114: 2090, 1940.Swan, K. C. and N. G. White: Choline esters with atropine-like action, J. Pharmacol. & Exper. Therap. 80:285, 1944. • • Tractenberg, I. and W. 0Jjver: The use of prost!gminin abdominal and vaginal operations for the relief ofpostoperative distention and urinary retention in aseries of 96 consecutive cases. Am. J. Surg. 53: 284,1941.Viets, H. R.: Myasthenia gravis, J.A.M.A. 127: 1089,1945.Waldman, S. and S. N. Moskowitz: The treatment ofattacks of sinus tachycardia ,vith prostigmin, Ann. Int.Med. 20: 793, 1944. • • White, A. C. and E. Stedman: On the ph_ysost1gm1oe· Jlike action of certain synthetic urethanes, J. Pharmacol.& Exper. Therap. 41: 259, 1931.\Vinkelstein, L. B.: Prostigmine methylsulfate and de•layed menstruation, Am. J. Obst. & Gynec. 44:231,1942.PARASYl!PATHOLYTICSGraham, D.P.D. and J. A. Gunn: The comparative ac·tivities of atropine, l•hyoscyamine, hyoscine and hornatropineon mammalian srnooth muscle, Quart. J.Pharro. & Pharmacol. 17: 88, 1944 .•• Bibliography 155Henderson, V. E. and M. 0. S,veeten: The effect ofatropine on tl1e gastro-intestinal canal and its glands.Am. J. Digest. Dis. 10: 241, 1943.Loman, J., P. G. Myerson and A. Myerson: Experimentalpharmacology of post-encepl1alitic Parkinson's disease,Arc~ Neurol & Psychiat. 47; 399, 1942. -11artin, J. E.: '.Atropine glaucoma, Brit. ir. J. 1: 631, 1943.~Iorton, H. G.: Atropine intoxication, its manifestationsin infants and children, J. Pediat. 14: 755, 1939.Phelps, ~i. L.: The role of the alkaloids of ,the belladonna.plants in clinical anestl1esia, Anestl1esiology3: 71, 1942. ,,Wangeman, C. P. and 1f. H. Ha,vk: The effects of tnorphine,atropine and scopolamine on liuman subjects,Anesthesiology 3: 24, 1942 .•,,,,,~•\'I•' ''• J- •13Histamine and AntihistamineDrugs •INTRODUCTIONHISTAMINEANTERGAN AND N.EOANTI:RGANDIPlIENHYDRAMINE ANDTRIP.ELENN A!.tlNEPREPAR,\TIONS\INTRODUCTIONThe probable role or histamine in inducing many of thesymptoms or anaphyJactic shock and other alJergic disordershas prompted the search for preparations antagonistic tohistamine. The antihistaminic agents discussed in this chapterare a newly introduced series of drugs which appar~ently interfere with the activity of histamine, possiblybecause of a competitive action with histamine at its site, of action. Their action is not comparable, there! ore1 withthat of pharmacologic antagonists to histamine such asepinephrine and certain antispasmodics.The antihistamine drugs are such recent additions to •therapeutics that their usefulness and their limitations can4not as yet be adequately appraised. However, the greatdemand for simple and effective relief from allergic dis-, orders has already evoked widespread interest in the avail•able compounds and will undoubtedly lead to the introduc•tion of newer and possibly more effective agents.HISTAMINE •Histamine was first prepared synthetically by \Vindausind Vogt in 1907 from iminazolyl-proprionic acid. In 1910,156•\I, (•IHistamine 151, it was isolated from ergot simultaneously by Barger and, Dale and by Kutscher and in the same year Ackermannprepared synthetic histamine by the action of putrefactiveorganisms on the amino acid histidine. This reaction ,isresponsible for the formation of histamine in the gastr<?intestinaltract but probably little or none of the so-formedhistamine is absorbed.1NH-CHCHiNH-C-CH 2-cH2 NH2HJstamineI'The phar1nacodynumic and toxicologic actions of histaminevary considerably among the different species of ani~mals. In the human being the main effects of histamineinjection include stimulation of the bronchial, intestinal,venous and arterial smooth muscles, dilation of the arteriolesru1d capillaries accompanied by an increased capillarypermeability and a fall in blood pressure, and stimulationof the salivary, gastric and pancreatic glands. The similaritybetween these effects and the characteristic reactionsof anaphyla."<is ,vas first observed by Dale and Laidlawin 1910, while in 1926 Le,vis and Grant suggested that thevascular reactions in the skin follo,ving various injuriesand urtica.rial reactions were due to the liberation of histamineor a histamine.like substance ("H" substance) sincethey resembled so closely the effects of subcutaneously injectedhistamine. The possibility that histamine plays arole in the animal economy was further strengthened by ,the isolation of histamine f ram various tissues of the bodyby ,\bel and Kubota in 1919 and Best, Dale, Dudley andThorpe in 1927, and by various subsequent investigators.The belief that histamine plays a role in allergic disordershas led to various attempts to neutralize the his-I••1S8 Histamine and Antihistamine Drugs• • ' tam1ne as a therapeutic measure. On the assumptionth atpatients suffering from allergies are hypersensitiveto histamine,small doses of histamine have been administered •with a view to effecting desensitization. The results havebeen inconclusive, however, leading to the suggestionth atnegative results were due to the nonantigeniclty of histamine.Hence, attempts have been made to produce his·tamine antigens by conjugating histamine and variousprotejns, in particular, despeciated horse-serum globulin(histamine-azoprotein). Antibodies have apparently beenproduced in animals by this means but clinical results havenot been encouraging. Histaminase, an enzyme capable ofdestroying histamine in vitro, appears to have no effectin vivo although at one time it ,vas widely advocated as atreatment for allergic disorders. With the reclnt introduc,tion of substances which apparently act by interferencew ithhistamine at its site of action, a new approach to the treat•meot of allergic disorders bas been presented.' It shouJd• be remembered, however, that the· effect of these drugs JStransient and symptomatic relief only is secured. Further•more, the effect of these drugs on the development of im·munity has not been determined. 'Histamine is employed clinically in the histamine testof gastric function. This test is based on the fact that while\ • • histamine normally stimulates the acid-secreting cells, it JSineffective in promoting acid secretion in certain types ofachlorhydria, especially that associated with perniciousanem•i a.\ANTERGAN AND NEOANTERGAN,An.tergan(2339RP) - Neo:1ntergan(2786:R.P)•, •Antergan 'and Neoantergan 159A systematic search for substances antagonistic to histaminewas first undertaken in 1937 by Bovet and Staub,working in Fourneau 1s laboratory in France. These investigatorsfirst studjed a number of sympatholytic and antispasmodicdrugs which had been shown earlier by Fourneauand other workers to inhibit some of the actions of histamine./Various phenolic ethers and ethylenediamine preparationswere studied but found to be too toxic for therapeuticuse. However, in 1942 Halpern prepared a series of ethylenediaminecompounds closely related to those studied byBovet and Staub. One of these compounds, dimethylaminoethylbenzylanilinc(antergan or 2339RP) has been usedtherapeutica1Jy in Europe for the relief of various allergicdisorders, apparently with promising results. Subsequently,Bovet and his associates introduced another ethylenediaminederivative N-p-methoxybenzyl-N-dimethylaminoethyl. aminopyrine (neoantergan or 2786RP), which they claim isbetter tolerated than antergan. These compounds have hadlittle clinical use in America so that a comparison cannotbe drawn between them and the antihistaminic substances •, developed in this country.Recently, Halpern has reported the development of twonew compounds, 301S and 3277, which are much more effec--tive antihistamine agents than antergan or neoantergan.3015 3277Preliminary therapeutic tria.Is indicate that these drugscause some dro,vsiness but no symptoms of digestive into!-,era.nee.''160 Histamine and Antihistamine DrugsDIPHENHYDRAiIINE AND TR1£ELENNAMINEDipbenbydraminHe ydrochloride(Benadryl)TripelennaminHey drochloride(Pyribenzamine)Diphenhydrami1le hydrochloride (benadryI, ~-dimethylaminoethylbenzhydrylether hydrochloride) was introducedin 1945 by Loew and his associates after a study of theantihistamine activity of a number of benzhydryl alkamineethers. The experimental criteria of activity was reductionof bronchial constriction in guinea pigs that had been ex·posed to atomized histamine solutions. Other antihistaminiceffects observed include antagonization of the bronchostrlctionin sensitized guinea pigs subjected to anaphylacticshock and suppression of the fall of blood pressure followingsmall doses of histamine in anesthetized dogs. Dipbenhydra-,mine also possesses musculotropic and neurotropic activitysince it antagonizes the spasmogenic effects of barium andof acetyicholine on the guinea-pig intestine, though in •. doses larger than those required to abolish the spasmogemc1 action of histamine. 'Diphenhydramine has given promising results in the treatmentof urticaria, angioneurotic edema, seasonal allergicrhinitis, serum reactions and drug sensitivities. It hasproved of less value, however, in the treatment of asthmaand nonseasonal allergic rhinitis. Its chief drawback isthat it produces a state of drowsiness in many patients,which may lead to confusion and loss of judgment, thoughoccasional cases of excitement and delirium after its usehave been reported. Other toxic symptoms include g,a stro--intestinal upsets, dryness of the mouth and hot flushes.Tripelennamine hydrochloride (N'pyridyl-N'benzyI-Ndimethyletbylenediaminehydrochloride, pyribenzamine) wasI Diphenhydran1ine and Tripelennamine 161\introduced by l\Iayer and his associates in 1945 after a surveyof the antihistamine activity of a series of pyrjdinederivatives. Its pharmacologic and therapeutic propertiesare essentially similar to those of diphenhydramine, thoughit is said to cause fewer toxic reactions and is apparentlymore effective in both seasonal and nonseasonal allergicrhinitis. It has also been used locally in the form of a 2per cent ointment for the relief of itching of allergic origin.PREPARATIONSHistamine phosphate U.S.P.; B.P. 0.3 mg~ intra.muscu.Jar.Histamine-phosphate injection U.S.l.>. Contains 1 Gm. in '1000 cc.• Diphenhydramine hydrochloride (benadryl) N.N.R. 50 mg,Tripe1ennamineh ydrochloride (pyribenzamine) N .N.R. 50mg.REFERENCESGENERALFeinberg, S. I\1.: Histamine and antihistaminic agents,their cxperin1ental and therapeutic status, J.A.M.A.132: 702, 1946.HIS'tAMlNEIAbel, J. J., and S. Kubota: On the presence of histatnine(~•iminazolylethylamine) in the hypophysis cerebri andother tissues of the body and its occurrence among the .bydrolytic decomposition products of proteins, J. Phar•ma.col. & Exper. Tl1erap. 13: 243, 1919.Best, C. H., and E. W. A-fcHenry: Histamine, Physio1.Rev. 11: 371, 1931.~est, C. H., H. H. Dale, H. \V. Dudley and W. V.Tltorpe: Tl1c nature of the vaso-dilator constituents ofcertain tissue extracts, J. Phy,siol. 62: 397, 1927.Dale, H. H., and P. P. Laidla,v: The physiological actionof ~·imin.izolylethylamine, J. Physiol. 41 • 318 1910-1911. • '. Dragstcd~, C. A.: The significance of liistamine in ana·pl1ylax1s, J. Allergy 16: 69, 1945.l)ltt1dy,. I-I. 1?·B,.. Zol1n a?d R. Chobot: Histamine azo•1>rotc111c: l1111c.eilv aluation, J. ~l)ergy 18: 1, 1947.II162 • Histamine and Antihistamine Drugs,Fell~ N., G. Rodney and D. E. Marshall: Histamine-proteincomplexes: synthesis and imrnono1ogicin vestigation,1. Histamine-azoprotein, J. Immun. 47: 237, 1943.Le,vis, T., and R. T. Grant: Vascular reactions of theskin to injury, part VII, notes on the anaphylactic skin, reaction, Heart 13: 219, 1926.ANTERGAN AND NEOANTE;RGANDews, P. B., and J. D. P. Graham: The antihistaminesubstance 2786RP, Brit. J. Pharmacol. 1 :278, 1946.Halpern, B. N. : Les antihistaminiques de synthese, essaisJde chimiotherapie des etats aJJergiques, Arch. Int.Pharmacodyn. 68: 339, 1942.DIPHENHYDRAMINE AND TRIPELENNAUINEArbesman, G. E., G. F. Koepf and A. R. Lenzner: Clinicalstudies ,vith n'pyridyl, n'benzyl, dimethyl ethylene.diamine monohydrochloride (pyribenzamine), J. Allergy17: 275, 1946. ~ .Feinberg, S. M., and T. B. Bernstein: Tripelenna~ine"pyribenzamine'' ointment for the relief of itching,J.A.M.A. 134: 874, 1947. .Friedlaender, A. S.: The use of a histamine antagonist,beta-dimethylaminethyl benzhydryl ether hydrochloride,in allergic disease, Am. J. M. Sc. 212: 185, 1946• .Loew, E. R., M. E. Kaiser and V. Moore: Synthetrcbenzhydryl alkamine ethers effective in preventing fatale..""Cperimentaals thma in guinea pigs exposed to ato20mizedhistamine, J. Pharmacol. & Exper. Therap. 83: 1 ,1945.Mayer, R. L.: Antihistaminic substances ,vith specialreference to pyribenzamine, J. Allergy 17: 153, 1946.O'Leary, P. A., and E. M. Farber: Evaluation of be_tadimethylaminethylbenzhydryl ether hydrochlonde\ (benadryl) in the treatment of urticaria, sclerode~~aand allied disturbances, Staff .11e'e tings Mayo Cl101c21 : 295-297, 1946.Wells, J. A., H. C. Morris, H. B. Bull and C. A. D~ag-, stedt: Observations on the nature of the antagonismof histamine by ~-dimethyJaminethyl benzhydry1 ether(benadryl), J. Pharmacol. & Exper. Therap. 85: 122,1945.•,•14Heart Drugs•INTRODUCTIONDIGITALISA ND RELATEDPREPARATIONSQUINIDINEXANTHINE DEIUV ATIVESNITRITES AND ORGANICNITRATESPAPAVERINEDRUG THERAPY OFHYPERTENSIONPREPAUATIONSINTRODUCTION\The heart drugs include substances acting directly on theheart, such as the digitalis group, quinidine and probablythe :xanthine derivatives; and substances acting on the coro ..nary vessels, such as the nitrites, nitrates and papaverine,In a br:oader sense, the term also includes preparations·which act mainly on the peripheral vascular system, such asthe sympathomimetic amines (chap. 11) and posteriorpituitary (chap. 21), which are used to maintain or elevatethe blood pressure; parasympathomimetic drugs (chap. 12),which slow the heart by vagal stimulation and which arethere( ore of value in the treatment of paroxysmal tachy ..cardia ; diuretic drugs ( chap. 15), which relieve the heartby ridding the body of exces.s fluid ; morphine and isonipe ..caine (chap. 9), which relieve the pain and dyspnea ofsevere heart disease; oxygen (chap. 5), which relieves thehypoxia of congestjve heart failure; and drugs used in thetreatment of essential hypertension, ,vbich are included inthe present chapter. \• •DIGITALIS AND RELATED PREPARATIONSDigitalis and related preparations a.re the most widelyused d~gs in diseases or disorders of the heart. The digitalis163•,'I164 Heart Dr' ugsor foxglove plant was known to the herbalists in the sixteenthcentury, who used it as an external remedy. It!rational medicinal use was not developed until 1785, when\Villiam \Vithering, an English physician, published theresults of 10 years' observations on the use of foxglovaesa diuretic in dropsy. His investigations were promptedb ythe acquisition of a secret cure from an old woman in Shro~shire. Although this remedy was composed of twenty ingredients,\Vithering soon found the therapeutically effectivesubstance to be digitalis. Actually he considered its efficacylay in its diuretic effect, although he did observe the effectsof the drug on the heart. A few years later, however, theprimacy of cardiac action of digitalis was recognized byboth Cullen and Ferriar. The introduction of digitalisproved to be a revolutionary development since previouslyonly comparatively ineffective drugs such as camphor andvalerian were ,available for cardiac patients.Chemistry of the Cardiac Glycosides. The cardiac actionof digitalis is due to glycosides, which are conjugation productsof sugars and nonsugars. The nonsugar moieties a~eare known as aglycones or genins. A similar pharmacologicactivity is found in a number of other plants in which theactive agents are either glycosides or alkaloids, and in thevenom of toads. The latter generally contains two classesof digitalis-like principles, the bufagins 1 which resembleaglycones, and the bufotoxins, which are conjugation prod·acts of bufagins and suberyl-arginine.Glycosides, bufagins and bufatoxins all contain the ster•oid nucleus in common with cholesterol, the sex hormones,adrenal-cort{cal hormones and the vitamins D. The cardiacactivity is associated with the unsaturatep butyro-Iactonering attached to C17• The carbohydrate portion of the gJy.coside bas no cardiac action itself but greatly jncreases theactivity of the aglycone. , '•' Digitalis and Related Preparations 16SGENERAL STRUCTURE OF THE CARDIAC GL YCOSIDESWhile cardiac glycosides ar; widespread in nature, theofficial sources of therapeutic prep.arations are limited tot,vo species of digitalis (D. purpurea and D. lanata), twospecies of strophantbus (S. ko11tbe and S. gratus), andUrgi1iea maritima or squiil. It is of interest to note that. plants containing cardiac glycosides have long been used inthe preparation of arrow poisons. These include Stroplza1ithusko1nbe and S. gratus, Thevetia 1ierifolia and Antiarist oxicaria ( u pas tree) . 1IOHaQlycone•0!i"ugf~t\orl icula( s)A number of cardiac glycosides have been isolated andidentified chemically. These do not necessarily representthe g1ycosldes as they exist in the living plant or animalbut are more probably derived from the native glycosidesby the loss of one or more sugar molecules. Digitoxin,gitoxin and gitaJin have been isolated from Digitalis purpurea.On complete hydrolysis they yield the aglyconesdigitoxigcnin, gitoxigenin and gitalige11in. Three glycosides ,Ihave been isolated from D. la,1ata1 lanatoside-A, lanatoside-Il and lanatoside-C, which on partial hydrolysis yielddigitoxin, gitoxin and digoxin, respectively. The variousspecies of Strophanthus yield strophantbins, which arerelated but not identi~al; they are usually designated bythe initial of the specific name of the species from whichthey are obtained, thus, K-strophanthin is obtained fromS. ko11:be and G-strophanthin or ouabain from S. grati,J.Urgiuca ,1iariti11zyai elds a Ct)'Stallinc fraction scillaren-Aand an amorphous fraction, scillaren-B, v. .h ich is probablya 1nixture of two or more glyco~idcs. ,\ ,·aricty of squill, the' '166 • I Heart Drugs ,red sq~i~l, is used widely as an ingredient of rat poisons.In. add1t1on to the sciliarens, it contains a substance highlypoisonous to rats.The use of galenical preparations of cardiac glycosidesis being rapidly superseded by the use of the crystallineglycosides or of highly purified preparations. These havethe advantage of stability, injectability and more accuratedosage. They are generally more rapidly absorbed whengiven orally and cause less gastro-intestinal irritation, inpart because of the absence of nonabsorbable glycosides andof the much smaller doses required.Phannacologic Actions. All the cardiac glycosideps roduceessentially similar pharmacologic effects. l\f arkeddifferences in rates of absorption and in dissipation of theglycosides account for the quantitative differences in theiraction. Following the administration of these drugs, theforce of systolic contraction is increased, the diastolic sizeof the heart is reduced, the cardiac output increased and thevenous pressure reduced. The heart rate is usually slowed,in part because of vagal stimulation, but the degree ofslowing is usually not significant in cases of normal sinusrhythm. The conduction time is slowed, the P-R intervalbeing prolonged. The mechanism of action underlying theseeffects is not wholly understood. \Vbile many investigatorsbelieve that the primary action is directly on the heartmuscle, it has also been suggested that the cardiac changesare secondary to changes in the peripheral circulation,namely, a relief of venous engorgement by a redistributionof the blood. The diuretic action of digitalis is secondaryto an improvement in, circulation. Digitalis is of no valueas a diuretic in the absence of heart disease.Therapeutic Uses. Digitalis and reJated preparations arcof particular value in the treatment of congestive heart fail·ule. The pulse rate is decreased whiJe the cardiac output'is increased. The edema is relieved by diuresis, and dyspneaand cyanosis disappear as the circuJation improves. The1••Digitalis and Related Preparations 167• \cardiac glycosides are also of value in the treatment ofauricular fibrillation and flutter. In the former, beneficial~effects are achieved by the depressant action on the ven- -tricular rate and conduction, which prevents the developmentof congestive failure and produces conditions favorableto the return of a normal auricular rhythm. In cases ofauricular flutter, normal rhythm may be restored by aprolongation of the refractory period. In some cases, theflutter may be converted to fibrillation, with a slowed ventricularrate.Administration. Preparations t>f digitalis and squills aregenerally administered orally. A number of purified digitalispreparations are suitable for intravenous or intramuscularinjection but parenteral administratjon is on1y justified incases of emergency. The Stropbanthus glycosides are poorlyabsorbed from the gastro•intestinal tract. Their~use is usuallyrestricted to intravenous therapy, especialJy in patientswho tolerate digitalis poorly.The full effects of cardiac glycosides develop slowly evenafter intravenous injection. The glycosides are taken uprapidly by all tissues of the body and are excreted veryslowly. Because of the slow excretion, repeated doses tendto lead to a cumulation of the active principles in the bodyand to the development of toxic symptoms. l-Ience, forclinical purposes, an adequate concentration is built up inthe body with an initial series of large doses, or, rarely, asingle, massive oral or intravenous dose, a procedure knownas digitalization. \Vhen the desired therapeutic effects havebeen attained, the patient is put on a maintenance dose,which is actually dependent on the amount metabolizedper day but which is determined ciinica.lJy by the amount - necessary to secure therapeutic effects \Vithout toxic symp•' toms. Thus the maintenance dose of powdered digitalism:iy vary betn·cen 0.2 Gm. per week and 0.2 Gm. per day.Toxicity. Sympto1ns of overdigitalization include loss ofappetite, nausea, vomiting and occasionally diarrhea, visualIII168 \ , Heart Drugs,•disturbances,i ncluding colored vision double visiono r tem- • 1porary blindness, and headache. The pulse is usually markedlys1owed. There may be paroxysmal tachycardia withcomplete or partial heart block, eltrasystoles ·or ventricularfibrillation, which is the probable cause of death in fatalpoisoning. In the normal individual, digitalis causes adecrease in cardiac output and an impairment of circulation.It has been employed fraudulently to induce symptomssimulating heart disease.Animal experiments have indicated that prolonged administrationof digitalis frequently produces degenerativeo rhemorrhagic lesions in the cardiovascular and central nervoussystems suggestive of local ischemia. It has not beenestablished that such lesions occur in man. However, it is.of jnterest to note that recent studies in man havt! indicatedthat digitalis administration leads to a reduction in the clottingtime of the blood which may predispose to thrombosis 1and emboli formation.Patients receiving digitalis are unusually sensitive toepinephrine and to intravenous calcium. These drugs shouldbe avoided or used with extreme caution during digi~talistherapy. • Standardization of Digitalis and Related Preparations.Preparations of digitalis are assayed biologically. TheUnited States Pharmacopoeia{ Digitalis Reference Standard,which is equipotent to the International Digitalis Standard,contains 1 unit of activity in 0.1 Gm. The official methodof assay employs the etherized cat as the test object (seeChapter 3). The main criticisms of this method are that itis a measure of the toxicity of the preparations, which is n~tnecessarily related to their therapeutic effect, and that itemploys jntravenous injection, eliminating the factors ofdegree and rate of absorption, which are of great ~ignificancein oral therapy. Numerous attempts have been made tointroduce reliable chemical methods of assay f !)r digitalispreparations. The most reliable method is based on the•'••Digitalis and Related Preparations 169BaJjet reaction, which depends on the presence of the activehydrogen in the unsaturated lactone group characteristic ofcardiac glycosides. Some workers pref er to sta.udardizepreparations on patients but this method requires extensiveclinical facilities to provide a uniform group of patients.The purified glycosides, digo::tin, oubain and lanatosidc-C,• being apparently chemical entities, can be identified bychemical and physical means. Preparations of these com•pounds, however, must be standardized biologically againstthe respecti<res tandard preparation since the amounts pres. ..cnt in the accepted dosage f or1ns are too small for adequatephysical or chemical identification. Digitoxin must beassayed biologically against the U.S.P. Digitoxin ReferenceStandard.QUINIDINEQuinidine, the dextrorotatory isomer of quinine, was firstused for the treatment of cardiac arrhythmias by Frey in1918. For many years, cinchona preparations were claimedto act as heart "tonics," but it was not until 1914 that thematter was investigated critically by \Venckeback. Hedemonstrated conclusively the value of quinine in the treat~m.ent of paroxysmal auricular fibrillation. Subsequently,Frey showed that quinidine was superior to quinine byvirtue of its greater effect on the heart and its lesser toxicityin therapeutically effective dosage.Quinidine is widely used in the treatment of auricularfibrillation and auricular flutter. It apparently has a directdepressant action on the heart muscle1 causing an increasein the refractory period and a decrease in irritability andin the rate of conductivity. Since the effect is usually greateron the rate of conducyvity than on the refractory period,the effect of quinidine IS to extinguish the rapid self-perpet.uating ring of excitation, the ''circus movement'' responsiblefor the injtjation of the rapid rhythm. Quinidine is aJso of- value in the treatment of paroxysmal ventricular tachy ..••\f'•I.170 • Heart Drugscardia, postoperative thyroid tachycardia, extrasystoles andparoxysmal auricular tachycardia.Quinidine is rapidly metabolized and eliminated from thebody and there is little danger of cumulative poisoningunless large doses are given at very frequent intervals.Toxicity. Since some individuals are sensitive 'to quini•dine, the initial dose should be small. The more seriouscomplications of quinidine therapy include collapse withcardiorespiratory failure; ventricular fibrillation, which maybe prevented by the concomitant administration of digitalis;and 1he dislocation of emboli following resumption of thenormal beat in chronic auricular fibrillation. Rarely, theremay be severe gastro-intestinal upsets which make oraladministration impracticable. In such cases, quinine pre~arations may be given parenterally; since quinidine salts,because of their insolubility, can only be injected withlarge volumes of fluid. Recently an injectable form ofquinidine, quinidine hydrochloride with urea and anti•pyrine, has been described which is said to produce muchmore prompt effects than oral quinidine and to have analmost equal duration of action. However, intravenous' injection of quinidine is dangerous and is rarely justified.\XANTHINE DERIVATIVESThe xanthine derivatives have already been discussed asdiuretics ( chap. 1 S) and central~nervous stimulants ( chap.10). Their value in the treatment of heart disease is dueboth to their diuretic action and to their stimulatory effecton the myocardium. There is some disagreement as towhether the latter effect is due to a direct action on themyocardium or whether it arises secondarily from anincreased coronary flow.The xanthines have been used since 1895 in the treatmentof a~ina pectoris, though their value has frequentlybeen questioned. Theobromine and theopbylline preparationsappear to be the most effective. AminophyllineI•••'' I• ' ..Xanthine Derivatives 171(theophylline ethylenediamine, euphyllin) is probably .themost widely used preparation because of its ready solubility.There is also experimental evidence to indicate thatethylenediamine enhances the vasodilator effect of theophyllinewithout having any such effect of its own.The xanthines in larger doses cause nausea, heartburnJand gastric irritation. More disturbing symptoms includeheadache, giddiness, nervousness and palpitation. Deathshave been reported from the intravenous administration ofaminophylline so that the oral or intra.muscular route •should be used wherever Pt>ssible. However, ,intravenousadministration has of ten proved to be a lifesaver in paroxysmaldyspnea. The use of xanthines in hypertension hasno reliable clinical basis. Any fall in blood pressure thatthese drugs may produce is of short duration and of a "minordegree.NITRITES AND ORGANIC NITRATESNitrites and organic nitrate preparations are used chieflyin relieving angina pectoris by their dilating action on thecoronary arteries. In view of their direct relaxing action onthe smooth muscle of the vascular system and of the bronchioles,they have also been used in the treatment of hypertensionand of bronchial asthma, respectively. Their valuein hypertension is questionable since their depressant effectis unpredictable and not sustmned and tolerance frequentlytlevelops after repeated administration.The beneficial effect of amyl nitrite in angina pectoris wasfirst observed by Lauder Brunton in 1867. This drug is a\'olatilc con1pound which is dispensed in thin-walled gla.ss -ampoules ("pearls") enclosed in a protective cloth envelope.The effects on inhalation are imrnediate but evanescent.irorc prolonged though less rapid effects are produced bysodium nitrite taken by mouth, and by some organic nitratessuch as erythrityl tctranitrate and mannitol hexanitratc. Itbas been suggested that the activity of the latter compounds•I•\'I•• -172 Heart Drugs'is due to their degradation in the body to nitrites. However,the rapidity of the onset of their action followingintravenous injection and the high degree of potency ofsome of these preparations suggest that their activity isvested in the intact moJecuJe. ... 'Toxic reactions to nitrites and )litrates include a throb-,bing headache, weakness, giddiness and faintness. Cyano.sismay be present because of the formation of methemoglobinby the nitrite ion. A number of organic nitrate preparations,'such as glycery1 trinitrate, erythrityl tetranitrate andrnannitol hexanitrate, are explosive and should be storedand handled with care .PA.PAV ERINEICH30CH30 N ~ OOH~~ CH oc 2 3Papaverine is a member of the narcotine group of mor•phine alkaloids ( chap. 9). It was first isolated by l\ferck in1848. \Vhiie its central effects are much less marked than•those of morphine, it does have a mild sedative action 1ntherapeutic doses. It is apparently free from addictingpropertie• s. ,The chief pharmacologic action of papaverine is inhibitionof the contractions and relaxation of the tanus of smoothmuscle. It was first used clinically by Pal in Vienna in 1914in conditions ol smooth-muscle hyperexcitability, such asgastro•intestinal spasm and biliary colic. Pal also suggestedits value in angina. pectoris, but its subsequent use by anumber of investigators yielded for the most pa'rt disappoint ..ing re~;rJ}ts, possibly because of inadequate dosage. Duringthe p~i;;t 10 years interest in the use of papaverine in heartII•• --Papaverm• eIconditions has been revived. It has been shown that insuitable oral or intravenous dosage, it effectively dilates thecoronary arterie""s and relieves the arterial spasm accom~panying acute vascular occlusion. In addition, Elek. a~dKatz have reported that the drug depresses the conduct1v1tyof the heart and eliminates or reduces premature systoleswithout depressing the myocardium.DRUG THERAPY OF HYPERTENSIONA variety of drugs have been recommended for the treat.' ment of hypertension either on the basis of a long-standingpopular reputation or because of their pharmacologic actionin Jo\vering blood pressure. The results have usuaJJ_v beendisappointing and as yet no drug is available which regularlyproduces a sustained lowering of blood pressure inhypertensive patients without producing toxic symptoms.On occasion, however, subjective improvement may be attainedwithout reference to any alteration in the bloodpressure, which may justify continuation of the treatment.IPreparations used in the treatment of hypertension includen1iscellaneous plant and animal extracts of questional1levalue, such as extracts of mistletoe, garlic, watermelonseeds and extracts of liver, spleen and pancreas; sedatives, 'sucl1 as barbiturates and chloral hydrate; vasodilators, suchas 11itritcs, nitrates and parasympathomimetic agents; xantl1incderivati\·es; and thiocyanates.Thiocyanates. Thiocyanates have been used in Germanyin the treatment of hypertensive patients since 1900. Elsewhere,thclr toxicity ,vas generally considered a barrier totheir use until Barker in 1936 demonstrated that the toxiceffects could be obviated if the blood level of the drug wasnot permitted to exceed lS mg. per 100 cc. The therapeuticrange is generally _considered to be from 5 to 12 mg. per 100cc. Both sodium and potassium salts have been used. Tbio•cyanatcs arc normally present in the body in much higherconcentration than any other known depressive substance .•', •174 Heart Drugs 1,This has led to the suggestion that they play·a physiologicrole in the regulation of blood pressure. 'The mode of action of thiocyanates in lowering the bloodpressure is not understood. The action is not readily observedin experimental animals. Claude Bernard in 1857demonstrated a depressing action of the thiocyanates onthe heart but this depression apparently only occurs withnear.lethal doses. A • depressant action on the adrenalmedulla with suppression of epinephrine secretion has beensuggested. Toxic effects include dermatologic lesions, nausea,heartburn, and mental disturbances, such as hallucinations,slurred speech and unsteady gait. ... ✓In effective thiocyanate therapy, the fall in blood pressuredevelops slowly, usually after several weeks of treatment.Because of their toxicity and unreliability, tbiocya•nates should be tried only under strict medical supervision,which must include a check of the blood level of the drug.Thiocyanates may be of value in the prevention or aUe•viation of migraine if given in the prebeadache stage of anattack. They are of no value after the onset of a headache,presumably because of the slowness with which they act,No thiocyanate preparations are included in the Unit:dStates or British Pharmacopoeias or in New and NonoffiaalRemedies.PREPARATIONS(For xanthine preparations, see Chapters 10 and 15,)Digitalis U.S.P. Digitalis leaf B.P. Dried leaf of Digitalispurpurea Linne. ,Powdered digitalis U.S.P. 0.1 Gm. equivalent to 1 U.S.P.digitalis unit.Powdered digitalis B.P. 0.1 Gm. equivalent to 1 intern.a·tional standard digitalis unit.Digitalis tincture U.S.P. Contains 1 U.S.P. digitalis unit ,per cc.••Preparations 175,. ,Tincture of ~igitalis B.P. Contains 1 international standarddigitaJis unit per 1 cc.Fresh infusion of digitalis B.P. 0.05 international standardunit in 1 cc. 30-120 cc.Digitalis injection U.S.P. Usually contains 1 U.S.P. unit ofdigitalis in either 1 or 2 cc.Digitalis tablets U.S.P. Digitalis capsules U.S.P. Usuallycontain 50 and 100 mg. powdered digitalis.Digalen N.N.R. Cardioactive principles of digitalis in tab-•lets or injectable solution.Digifolin N.N.R. Contains therapeutically desirable constituentsof digitalis in more absorbable form than wholeleafpreparations. Suitable for oral or parenteral administration.Digipoten N.N.R. !\fixture of digitalis glycosides in solubleform, with an activity equal to that of digitalis leaf ofstandard quality.Digitalin "German" N.N.R. A mixture of glycosides ob-~ tained from digitalis seeds, considerably more potent thandigitalis.DigitoI N.N.R. Fat-free tincture of digitalis.Digitan N.N.R. Purified extract of digitalis, in which 85 percent of the inactive ingredients have been removed.Digitoxin U.S.P. 0.1 mg.Digitoxin injection U.S.P. Usually 0.2 mg. in 1 cc. and0.4 mg. in 2 cc. ,Digitoxin tablets ,U.S.P. Usually 0.1 and 0.2 mg. tablets.Digitaline Native1le N.N.R. (digitoxin).Gitalin (amorphous) N.N.R. 0.5 mg.Lanatoside-C U.S.P. 0.5 mg.Lanatoside-C injection U.S.P. Usually available as 0.4 mg .• 1n 2 cc. and 0.8 mg. in 4 cc.Lanatoside-C tablets U.S.P. Usually 0.5 mg. tablets.Digoxin U.S.P. 0,5 mg. ,Digoxin taplets U.S.P. Usually 0.25 mg. tablets.Digoxin injection U.S.P. Usually 0.5 mg. int cc .I•,J '176 Heart DrugsDigilanid N.N.R. A mixture of lanatosides-A -B and ~Cb. , ,o ta1ned from D. lanata in the same proportions in whichthey occur in the crude drugs. 0.4-0.8 mg./ Tincture of stropbanthus B.P. Activity equivalent to thatof 0.42 per cent solution of international standard ouabainor 0.33 per cent solution of anhydrous ouabain. 0.12-0.3 cc. •Ouabain U.S.P.; G-strophanthin B.P. Glycoside obtained{rom seed of Strophanthus grati,s. 0.25 mg. (intra•venously). -Ouabain injection U.S.P. Usually available as 0.2S mg. and0.5 mg. ouabain per cc.Scilla B:P. Bulb of Urginea scilla (Urginea 11uzritima),1 (Urginea indica was acceptable as a war emergency\ measure.) 0.06-0.2 Gm. •Vinegar of squill B.P. 10 per cent solution of squill in diluteacetic acid.'- Syrup of squill B.P. Contains approximately 4.5 per centsquill.Oxymel of' squill B.P. Contains approximately 5 per centsquill.Tincture of squill B.P. Contains approximately IO per centsquill. IScillaren N.N.R. A mixture of the glycosides scilJaren-Aand scil!aren-B in the proportions in which they exist infresh crude squill. Administered orally. 0.8-1.6 mg.Scillaren-B N.N.R. The amorphous glycoside of Sci/lanzaritima. Administered intravenously. 0.5 mg.Quinidine sulfate U.S.P.; B. P. 0.2-0.4 Gm.Quinidine-sulfate tablets U.S.P. Usually 0.1, 0.2 and 0.3 Gm.Sodium nitrite U.S.P.; B.P. 60 mg.Sodium-nitrite tablets U.S.P. UsuaJly 30 and 60 mg.Amyl nitrite U.S.P.; B.P. 0.2 cc. (inhalation).ErythrityJ-tetranitrate tablets U.S.P.; B.P. Usua]Jy 15 and30 mg. 30 mg.1\iannitol be.xanitrate N.N.R. 15-60 mg.l\\ \Preparations 177Spirit of glyceryl trinitrate B.P. Contains approximately1 per cent glyceryl tl'initrate in a]cohol. 0.05 cc. (inhalation).Glyceryl trinitrate tablets U.S.P.; B.P. Usually 0.3, 0.4,0.6 and 1.2 mg. 0.4 mg.Papaverine hydrochloride U.S.P. 0.1 Gm.Papaverine~hydrochloride injection U.S.P. Usually 30 mg.in 1 cc. 0.1 Gm. (intravenous).BIBLIOGRAPHYGENERALGold, li.: Pharmacologic basis of cardiac therapy, J.A.M.A. 132: 547, 1946.Levy, R. L.: The drug tl1erapy of cardiac arrhythmias,J.A.M.A. 115: 848, 1940.DIGITALIS AND RELATED PREPARATIONSCushny, A. R.: The Action and Uses in Medicine of Digitalis,London, Longmans, 1925.Stoll, A. : The Cardiac Glycosides, London. Pharm.Press, 1937.Withering, Wi1ljam: An Account 0£ the Foxglove andSome of Its 11:edical Uses, Birmingham, 1785.Bell, F. K., and J. C. Krantz, Jr.: A chemical evaluationof digitalis, J. Pl1arma.col. & Exper. Thera.p. 83: 213,.1945.Carroll, F. D.: Visual symptoms caused by digitalis, Am.J. Ophth. 28: 373, 1945.Clitnenko, D. R. : Pharmacodynamics of the cardioactiveprinciples of Urginea maritima (Squill). J. Am. Pharni.A. 27: 596, 1938.Elderfield, R. C.: The chemistry of the cardiac glyco- ,sides, Chem. Rev. 17: 187, 1935.De G:aff, A. C.: Clinical comparison of the cardiac glycos1des,N e,v York State J. 1vled. 45: 1803f 1946.Gold, H., M. Cattell, N. T. Kwit and M. Kramer: Therelative activity of digitalis preparations in the frog,t~e cat, and man, and its bearing on the problem of 'bto-assay and so-called deterioration, J. Pharmacol. &Exper. Therap. 73: 212, 1941 .••'178 Heart Drugs- Hedley, 0, F.: The fraudulent use of digitalis to sim~tatheart disease, Ann. Int. Med. 18: 154, 1943.~Herrmann, G. R., G. 11. Decherd and W-; F. McKinleyDigitalis poisoning, J.A.M.A. 126; 7(1), 1944. 'Hueper, W. C.: Some toxic aspects of digitalis therap~Ne,v York State J. Med. 45: 1442, 1945.Jacobs, W. A.: The chemistry of the cardiac glucoside:Physiol. Rev, 13: 222, 1933.Kisch, B.: Strophanthin, Ne'rV York, Brooklyn l{edictPress, 1944.Macht, D. I.: Experimental studies on heparin and itjnflllence on toxicity of digita1oids, Congo red, cob~venom and other drugs, A.nn. Int. Med. 18: 772, 194~Movitt, E. R.: Digitalis and other cardiotonic drugiOxford Medical Publications, 1946.Sto11, A.: The genuine cardiac gJucosides, J. Am. Pharn:A. 27: 761, 1938.de Tak.its, G., R. A. Trump and N. C. Gilbert: The effecof digitalis on the clotting mechanism, J.A.M.A. 1Z5840, 1944,QUINIDlNECarter, J. B.: Uses and abuses of quinidine, M. ClinNorth America 29: 215, 1945. .Le,\tis, T.: The value of quinidine in cases of aur1culafibrillation and methods of studying the clinical reaction, Am. J. M. Sc. 163: 781, 1922. ,:Sagal!, E. L., C. D. Horn and J. E. J;. Riseman: Stud1e:on the action of quinidine in man, 1, measurement o.the speed and duration of the effect folJ01ving oral an<intramuscular administration, Arch. Int. Med. 71: 4~1943. ' •XANTHtNE DD.IVATIVESBoyer, N. H.: Aminophyl1ine and related xanthine derivatives,present status and therapeutic claims, J.A.M.A. 122: 306. 1943.Gold, H., N. T. K,vit and H. Otto: The xanthines (th!o·bromine and aminophylline) in the treatment of cardi.zcpain, J.A.M.A. 108: 2173, 1937.LeRoy, G. V., and J. H. Speer: A comparison of the ~oro-aary vasodilator activity o! certain a1ky1 xa.ntb1nes,J. Phannacol. & Exper. Tberap. 69: 45, 1940 .•'Bibliography 179A-{c1Iahon,A ., and R. A. Nussbaum: The use and abuseof theophyJline and its derivatives, Soutl1ern ?.I. J.33: 1127. 1940.Merrill, G. A.:' Aminophylline deaths, J.A.:t-cI.A1. 23: 1115,1943.Smith, F. 1I., H. W. Rathe and W. D. Paul: Theophyllinein the treatment of disease of the coronary arteries,Arch Int. 11e: d. 56: 1250, 1935.NI'IRlt'ES AND ORGANIC NITRATll:SCrandall, L. A., Jr., C. D. Leake, A. S. Loevenl1art andC. W. Muehlberger: Acquired tolerance to and crosstolerance bet,veen the nitrous and nitric acid esters andsodium nitrite in man, J. Pharmacol. & Exper. Therap.41: 103, 1931._,,._.__Marshall, C. R.: The mode of action of nitric esters,J. Pharmacol. & Exper. Therap. 83: 106, 1945.Weaver, J.C., J. H. Wills and H. C. Hodge: The effect ,on the blood pressure of normal persons and hypertenwsive patients of glyceryl trinitrate, sodium nitrite.erythrol tetranitrate and mannitol h~anitrate, Am ..Heart J. 28: 601, 1944.Weiss, S., and L.B. Ellis: Influence of sodium nitrite onthe cardiovascular system and on renal activity inhealth, in arterial hypertension and in renal disease,Arch .. Int. Med. 52: 105, 1933.PAPAVERINEElek, S. R., and L. N. l(atz: Some clinical uses of papaverinein heart disease, J .A.M.A. 120: 434, 1942.~acht, D. I.: On the relation bet,veen the chemicalstr1;cture of the opium alkalo_ids and their physiologicalaction on smooth muscle with a pharmacological andt~erapeutic study of some benzyl esters, 1, on the relationoi the chemical structure of the opium alkaloidsto their action on smooth muscle, J. Pharmacol. &Exper. Therap. 11: 389, 1918. 'de Takats. G.: The use of papaverine in acute arterial ",occlusions, J.A.l\.I.A. 106: 1003, 1936.''•••180 Heart Drugs•Dnuo TtrERAPY OF HYPERTENSIONBarker, M. H., H. A. Lindberg and M. H. Wald: Furtherexperiences ,vith thiocyanates, clinical and experimental observations, J.A.M.A. 117: 1591, 1941.Evans, W., and D. Loughnan: The drug 1treatment ofhypcrpiesia, Brit. Heart J. 1: 199, 1939.Forster, R. E.: The medical use of thiocyanates in thetreatment of arterial hypertension, Am. J. M. Sc. 206:668, 1943.Kapernick, J. S.: The blood pressure in essential hypertension;effect of several reputedly hypotensive drugs,Am. Heart J. 25: 610, 1943.Nelson, E. E.: Thiocyanates, Internat. M. Digest 41: 245,1942. ••I 15Diuretics,INTRODUCTIONCRYSTALI.OID IURETICSI:MERCURIALD IURETICSPREPARATIONSI'.,. XANTHINE DIURETICSINTRODUCTIONDiuretics are drugs which increase the excretion of urineby the kidney. Diuresis may be effected by an increase ing1omerular filtration or a decrease in tubular reabsorption,•- either by a direct action on the kidney (xanthine and mer:--...--.curial diuretics) or indirectly by alterations in the osmoticpressure or electrolyte balance of the plasma (water, crystalloiddiuretics). The main uses of diuretics are to reduceedema, to hasten the excretion of ingested poisons, to removeaccumulated metabolic products and to render the urinemore dilute in order to prevent the precipitation of drugsin the kidney tubules.Edema (dropsy) is the accumulation of an ultrafiltrate "~ of blood plasma in the intercellular spaces and in serouscavities. Edema may result from a decrease in t9e osmoticpressure of the plasma or from an increase in capillarypressure. It usually disappears when the underlying dis ..orders are treated. If the symptoms are severe, diureticsmay be used for temporary relief. If the underlying causeof the edema is a lowering of the blood osmotic pressure,as in glomerulonephritis or malnutrition, diuresis may beinduced by transfusions of whole blood, plasma or serumalbumjns, or gum-acacia solution and the administration ofa high-protein-low-salt dieL If the edema is due to anincreased capillary pressure, as in congestive heart failure181•I182 Diuretics •or cirrhosis of the liver, saline, xanthine or ~ercurial diureticsare indicated. If the accumulation of fluid in the~est seriously embarrasses the work of the heart or lungs,1t should be removed by paracentesis.Diuretics are not effective in the presence of severe car•diac or renal damage since urine formation requires ade,quate blood pressure and blood flow and also a functioningkidney. Injudicious use of diuretics may lead to dehydrationor to chloride depletion. In such cases, anuriaor oliguria may arise because of the lack of salt to aid inthe excretion of water. Hence, edema will persist despitethe use of additional diuretics. Occasionallyi, f diureticsa reused during or shortly after digitalis therapy, they maycause a mobilization of digitalis in the body and precipitatedigitalis poisoning.C.RYSTALT,OIDD IURETICSWater is an effective diuretic agent and has even beenused for the treatment of severe edema. It requires in itspassage through the kidneys a certain amount of salt, whichit abstracts from the tissues. This, in turn, leads to theexcretion of additional water since the isotonicity of theblood must be maintained. In the normal individual,excessiJe fluid intake may lead to salt depletion.The most effective saline diuretics are those with stableions and those which are more or less foreign to the body; •thus the order of effectiveness is potassium, ammonium,sodium, and nitrate, chloride, bicarbonate, acetate an_dcitrate. Potassium nitrate, introduced by \Villis in 1679, 1sthe most effective saline diuretic though doses of 12 Gm.or more a 4ay are required. / sotonic saline is the mo5tsatisfactory agent for producing a profuse diuresis in orderto counteract stone formation, to irrigate the urinary tract· in infections or to hasten the excretion of toxic substances.1Substa.nces such as urea and parenterally administeredsucrose, which are readily filtered by the glomeruli but••Crystalloid Diuretics 183poorly reabsorbed by the tubules, cause a diuresis by inhibitingthe tubular absorption of water. Urea is probably theleast toxic diuretic agent, but large doses are required andits bitter taste is objectionable to many patients. Sucroseis used to reduce cerebral edema since it does not pass thecerebrospinal barrier. A characteristic foamy swelling ofthe convoluted tubules has been described • in man and1 laboratory animals fallowing large doses. ,vhile the effectof these lesions on renal function is not lc.nown, it is probablyinadvisable to give sucrose in the presence of renaldamage or to give repeated injections of sucrose at closeintervals.XANTHINE DIURETICSCH3N co CH N-··CO I /CH 33I 1 I H OC C OC1 C N/N'CH!-~ N/CH I ll N',. l°CH3 CH3N -cCaffeine TheophyllineHN-COocI CI /CH3 NI ll 'cHCH3N C N~- Theo bromineTheo~hyll~ne and tbeobromine a.re among the oldest andsafest diuretics. Caffeine is a less effective diuretic agentand has a mo!e marked central-stimulating effect, which isusually undes1r~ble. 'J;heophylline causes a greater diuresisthan theobromme. Its action is not so long-lasting,· how--- rir ---••-'•184 Diuretics •ever, and it has a much more irritating effect on the gastrointestinaltract. It is better tolerated and more readilyabsorbed if given in combination with other preparations,such as theophylline and sodium citrate, and aminophylline(theophyJJine ethy1enediamine). The latter preparationhalso used as a coronary dilator and in the treatment ofasthma. •The manner by which the xanthines effect their diureticaction is not wholly understood. It appears most likely thatthey act on the glomeruli, increasing the rate of gJomerularfiltration. They also have an indirect action through their, effect on the heart, since they strengthen the beat andthereby improve the circulation. The xanthines are not aseffective as the mercurial d.iuretics. It has been suggestedthat their action is limited by a physiologic stimulation ofthe posterior pituitary leading to a compensatory secretionof the antidiuretic (pressor) hormone.l\.1ERCURIAL DIURETICSO=C-r-1f II,c~H5, c c-o-Hg.. 21 IO~C-NHCtfCH3'--CONHCH2CHCH2H9,.0H-acH2COONO.Merbaphen MersalylThe diuretic action of mercury compounds has beenknown for centuries, but its usefulness was always overshadowedby toxic manifestations. The modem use of mer•curial diuretics dates from 1886 when Jendrassik in Hun·gary reported the value of mercurous chloride ( calomel) .inthe treatment of cardiac edema. The cathartic propertiesof the drug limited its use and mercurials were virtuallyabandoned until 1920, when Saxl and Heilig introduced thefirst organic mercurial diuretic, merhaplten (novasurol).This compound had been developed a few years earlier asan antisyphilitic. , It proved to be quite toxic as a diuretici••Il\fercurial Diuretics 185and ~as \soon replaced by less toxic and more efficientpreparations, such as mersalyl (salyrgan) and 11iercuri1,(novurit). In these compounds the mercury is present in aside chain, while in merbaphen the mercury is united directlyto the benzene ring. The diuretic activity of mercurialdiuretics is due largely if not entirely to the actionof liberated mercury on the renal tubules, leading to adtcreased absorption of water.Since the xanthine diuretics apparently act mainly on theglomeruli and the mercurials on the tubu]es, it was not long. before the two were combined with a view to obtaining amore effective diuretic agent. The first such preparation 'was mercurophylli,ie (mercupurin), which was introducedin 1927. It contains theopbylline and the free acid of mercurin(mercuri compound). Meralluride (mercuhydrin) isa similar type of compound. The addition of theopbyllineto organic mercurials not only incfeases the efficacy ofthese preparations but also decreases the local necrosis andinflammation at the site of injection and, in some instances,reduces their toxicity.Mercurial diuretics can be administered intravenously,intramuscularly, orally or rectally. Their efficacy is enhancedif they are preceded by acid-forming salts, such asammonium chloride' or nitrate. By injection, 1 or 2 cc. of a10 per cent solution may be given once or twice a weekover long periods of time without any apparent damage tothe kidney. Occasionally, however, there may be idiosyncrasiesor untoward reactions so that it is advisable to giveonly a small dose at first. Mercurials given rectally in theform of suppositories are not very reliable and may causeirritation of the bowel. Oral administration is fairly effec- ,tive, the drugs being administered in enteric-coated pills.If they do not prove effective by this route, intramuscularor intravenous injection should not be attempted for severaldays lest delayed absorption f ram I the bowel lead to toxic~ymptoms. l\1ercurials should not be given if,there is severe• ' •••186 Diuretics 'renal damage since slow excretion may give rise to chronicmercury po•1 son• mg.Toxicity. Toxic reactions to mercurial diuretics includedyspnea, substernal oppression, cyanosis, sweatingb, radycardiaand syncope. Sudden death may occur, due apparentlyto a direct action of mercury on the ventricularm usclecausing fibrillation. Some protection to the heart is said tobe offered by small doses of magnesium sulfate. Late toxiceffects are characteristic of chronic mercury poisoning(mercurialism) and include stomatitis, salivation, colitisand degeneration of the kidney tubular epithelium.PREPARATIONSUrea U.S.P.; B.P. 20-40 Gm .. -Ammonium chloride U.S.P.; B.P. 3-6 Gm.Potassium acetate U.S.P.; B.P. 1-4 Gm.Potassium citrate U.S.P.; B.P. 1-2 Gm.Potassium nitrate B.P. 0.3-1 Gm.' 'Theophylline U.S.P.; B.P. 0.2 Gm._ Theophylline tablets U.S.P. Usually 100 and 200 mg. tablets.Aminophylline U.S.P.; B.P. 0.1--0.2 Gm. • Aminophylline injection U.S.P. Usually available contalll·ing the following a.mounts of tbeopbylline ethylenedia•mine: 0.25 Gm. in 10 cc.; 0.5 Gm. in 2 cc.1 and 0.5 Gm •• in 20 cc.Aminophylline tablets U.S.P.. Usually 0.1 and 0.2 Gm. tablets.Theophylline and sodi11na1c etate U.S.P.; B.P. 0.2 Gni.Theophylline and socliwn-acetate tablets U.S.P. Usually0.1 and 0.2 Gm. tablets.Tbeobrom.ine and sodium acetate U.S.P.; B.P. o.s Gm.Theobromine and sodium-acetate tablets U.S.P. Usually0.1 and 0.2 Gm. tablets .., Theocalcin N.N.R. Mixture of calcium theobromioe andca1,ciums. alicylate. 0.5-1 Gm. •Preparations 187Mersalyl and theophylline injection U.S.P.; injection ofmersaJyl B.P. Contains approximately 0.1 Gm. of mer-- salyl and 0.05 Gm. of theophylline per cc. 1-2 cc., 1Iercurophylline injection (mercupurin) U.S.P. 0.5-1 cc.l\!eralluride-sodium solution N.N.R. 1-2 cc.BIBLIOGRAPHY ,GENERALMarvin, H. M.: The therapy of dropsy, J.A,M.A. 114:757, 1940.Poll, D., and J. E. Stern: Untoward effects of diuresis(with special reference to 'mercurial diuretics), Arch.Int. Med. 58: 1087, 1936.Smith, H. W.: The physiology of the kidney, New York,Oxford, 1937. 'CRYSTALt.om DWRETICSAnderson, W. A. D., and W. R. Bethea: Renal lesionsfollowing administration of hypertonic solutions' ofsucrose, J.A.M.A. 114: 1983, 1940.'Schemm, F. R.: A high fluid intake in the managementof edema, especially cardiac edema, Ann. Int. Med.21:937, 1944. 'MERCURIAL DIURETICSBarker, ~f. H., H. A, Lindberg and M. E. Thomas: Sud•den death and mercurial diuretics, J.A.M.A. 119: 1001,1942.Batterman, R. C., A. C. De Graff and J. E. McCormack:The effectiveness and safety of mercupurin adminis•tered orally in the treatment of congestive heart fail•ure, J.A.M.A. 124: 1243, 1944.Brown, G., L. Ftiedfeld, 1\..1K. issin, W. Modell and R. M.Sussman: Deaths immediately following the intra•venous administration of mercupurin, J.A.M.A. 119:1004, 1942.Atodell, W. : The optimal dose of mercurial diuretics,,Ann. Int. 11:ed. 20: 265, 1944.Pines, I.,. A. Sanabria and R. T. Hernandez Arriens:Afercur1al diuretics-the addition of magnesium sul-••'\,188 Diuretics' • . •phate to prevent the toxic effects of their intravenousadministration, Brit. Heart J. 6: 197, 1944.Ruskin, A., and G. R. Herrmann: Studies in combined• diuretic therapy, J. Lab. & Clin. 11ed. 29: 486, 1944.Wexler, J., and L.B. Ellis: Toxic reactions to the intravenousjnjection of mercurial diuretics, Am. Heart J.27: 86. 1944.\l•16, _,IBlood, Blood Derivativesand Blood Substitutes•INTRODUCTION\VHOLE BLOOD•IBLOOD DERIVATIVESBLOOD SUBSTITUTESPREPARATIONSINTRODUCTIONI'..•This chapter includes a discussion of blood, blood derivativesand blood substitutes which are administered paren,terally to maintain the circulating blood in shock due to 1hemorrhage, trauma or burns or to correct hypoproteinemia.Amino-acid preparations, which are administered primarilyto supply nutrition, are discussed in the chapter on vitamins.·, The increased demands for transfusion fluids during thesecond \Vorld \Var stimulated development of more economicalmethods of utilizing blood and led to the fractionationof plasma into albumins, used in shock, hypoproteinemia ,and edema1 and a miscellaneous assortment of clinically usefulsubstances, such as gamma globulins, isohemagglutinins,fibrin foam and thrombin. These miscellaneous substancesare also included in this chapter.•I\VHOLE BLOOD\Vhile the use of blood transfusions dates back to theseventeenth century, the procedure was not put on a safe189••ii •\•190 Blood, Blood Derivatives and Blood Substitutesbasis until the recognition in 1900 of the existenceo f variousblood groups and the introduction in 1914 of the relativelynontoxic anticoagulant sodium citrate.Transfusion of whole blood is the treatment of choiceinhemorrhage since it maintains the normal blood volume. 'prevents hypoxia and shock and maintains the blood-plasm~proteins. It is also of value in the treatment of shock fron:burns, especially if anemia has developed. For immeiliatttreatment, plasma or saline is probably preferables incetb 1fluid, rather than the cellular elements, is lost.\Vhole blood retains its usefulness for from 3 to S week:or more if suitably preserved. The prothrombin,h oweveir ,destroyed in a few days' time, hence in hemorrhage due t1hypoprothrombinemia, f resb blood should be used. Sodiullcitrate is generally used as an anticoagulant, the final con• centration usually being 0.25 per cent. This concentratzowill not result in toxic symptoms unless large volume0sblood are injected very rapidly. Calcium gluconate is aeffective antidote to citrate intoxication. Glucose is frtquently added to citrated blood since it has been shown tprolong the lite of the red blood cells. - .All blood for trans! us ions should be typed both as regarcthe Landsteiner groups and the Rh factor. \Vhenever possble, the patient should receive blood of the same type ash:own. Universal group-0 type of blood may be used witholtyping cases of emergency. Such blood may produce uitoward effects in patients with type~A or type-B blood sineanti-A and anti-B agglutinins and hemolysins occasionallappear in high titer in group-0 donors and 1ead to hemal!5of the recipient's cells. These agglutinins may be neutralizeby the addition of /\ and B group-specific substances, tht,, minimizing the danger of reactions. With regard to the Rfactor, Rh-negative males should not receive repeated traD!fusions of Rh~positive blood and Rh-negative women shoul, never receive Rh-positive blood.II ' ,•'',. II'Whole Blood 191\Immediate symptoms of hemolytic reactions due to thetransfusion of incompatible blood include chills, feve, r, nausea,vomiting and defecation and lumbar pain. Renal com-plications may develop later, and if death res'u lts it isusuaJ]y due to uremia. Treatment for transfusion accidentsis symptomatic. 'Blood should be taken only from healthy donors, sinceblood transfusions have been responsible for the transmissionof diseases, including malaria, syphilis and infectiousjawtdice. Care should be taken to avoid air embolism, whichmay occur as a result of faulty technic either in withdrawing' or in administering blood. Filtration should be carried outimmediately before injection in order to remove any particlesthat may cause emboli.Occasionally, allergic reactions may follow the administrationof whole blood and also of plasma and serum. Symptomsinclude urticaria, edema and asthma. In some cases., ,these are due to allergens in the blood of the donor, henceblood for transfusion should be taken only from fastingindividuals .•BLOOD DERIVATIVESPlasma and Serum. The use of plasma became widespreadduring World \Var II since it offered certain practicaladvantages over whole blood. It can be stored for atleast 2 years in a liquid, frozen or dehydrated state. It ismuch less bulky than whole olood and, if pooled plasma isused, large volumes can be administered without crossmatching.It is of special value in cases of shock fromsevere injury, burns or infections accompanied by loss ofplasma from the circulating blood. It is of less value in theloss of large volumes of blood by hemorrhage .. Plasma is of great value in nutritional hypoproteinemia,in plasma loss in ascites and in conditions of impaired protejnsynthesis. However, large volumes are required tocombat effectively a low plasma-protein level since plasmacannot be given in concentrated form. .192 Blood, Blood Derivatives and Blood Substit~fes.,.Plasma, like whole blood, should be filtered before bein11administered, especially since particles of fibrin frequent!;settle out, leading to the danger of emboli formation or tothe blocking of the transfusion needle. ,Serum may be used in place of plasma. It has the advantageof not requiring an anticoagulant and of being freefrom fibrin. However, the red blood cells are wasted duringthe preparation of serum.Red Blood Cells. During the manufacture of plasma, thered blood cells are usually salvaged and stored in a smallquantity of plasma. These may be given in concentratedsolution in cases of anemia, especially if cardiac insufficiencyexists and unnecessary fluid is to be avoided. They can alsobe administered after resuspension in saline or glucose solution.Dried red-blood-cell powder has been used as a dress•ing material in poorly healing wounds but its value has notbeen adequately established.• Human Albumin. Human albumin can be used to raisethe osmotic pressure of the blood. Its only advantage overplasma lies in the fact that it can be given in highly concen·trated solution, which is of value in patients who maybecome edematous from excessive volumes of parenteralfluids. 'Miscellaneous Plasma Fractions. Gamma globulins, aby~product of the fractionation of the plasma proteins, haverecently proved of value in preventing or attenuating r:iea-·sles and infectious hepatitis. This preparation is rapidlyreplacing the use of convalescent serum, pooled normal ad~ltserum and placental extract for the passive immunization ininfectious diseases since it is considerably more potent in itscontent of immune bodies.Fibrin foam and tbrombin is a useful hemostatic agent forthe control of local bleeding, especially during brain sur•gery. The fibrin foam is a porous matrix on which thethrombin, obtained from prothrombin by human tbrombo•plastin, is absorbed. Gelatin has recentlv been shown to•f•I'I•Blood Derivatives• 193serve the same p'urpose as fibrin and bas the advantages ofbeing more readily obtainable and more easily handled technically.,Fibrin film prepared from fibrinogen and thrombinconsists of a thin rubbery sheet which is used in neurosurgeryas a dural1substitute or for the prevention of adhesionsof the meninges to the brain.Isohemagglutinins prepared from plasma are availablecommercially for the typing of blood. -BLOOD SUBSTITUTES • ICrystalloid Preparations. Crystalloid preparations are ofvalue in replacing lost electrolytes, but they diffuse too rapidlyto be of any great use as supportive agents in the treatmentof hemorrhage or shock. However, sodium chloride,usually in isotonic solution, or Ringer's solution, is oftenadministered routinely to replace fluid lost during surgicalprocedures, while many advocate the use of saline solutionsfor the early treatment of burns. Excessive amounts, how•ever, may lead to edema and delayed wound healing.Other crystalloid preparations are used chiefly for purposesother than blood replacement. Thus, sodium lactateor sodium bicarbonate may be administered to correctacidosis, while glucose solutions are occasionally administeredto relieve edema but more often to correct ketosisor disturbances in carbohydrate metabolism.The use of crystalloid solutions as diuretic agents and forthe treatment of cerebral edema is discussed in Chapter 15 •Colloidal Solutions. During botlrWorld \Var I and World\Var II, tl1e heavy demand for transfusions stimulated thesearch for effective blood substitutes and led to the introduc•• • t1on of solutions of various colloidal preparations in isotonicsaline. Such substances to be of value must be capable offorming solutions of a viscosity and osmotic pressure ap•proximately equal to that of normal circulating blood; theymust remain in the blood stream for a sufficient period to,-194 Blood, Blood Derivatives and Blood Substitutesgive a sustained effect; they must be nonantigenic; and theymust not cause any deleterious effects.While in peacetime the demand for such substanceissgreatly reduced, they do offer the advantages of being inexpensive,convenient to store and easy to prepare and theycan be given without typing or cross-matching. However,at best they are poor alternatives for blood, plasma or serum.Gum acacia as a 6 per cent solution was widely usedduring the first '\Vorld '\Var, especially by the British Army.·However, it was later shown to be removed very slowlyf romthe body, being stored largely by the liver and to a lesserextent by the spleen a.nd kidney. It has been said to lead toliver or kidney damage, and while this effect may be due toimpurities, the use of acacia as a transfusion fluid has beenvirtually abandoned. Recently, it has been advocated forthe relief of edema in nephritis.Gelatin was introduced by Hogan in 191S, but it soonbecame overshadowed by gum acacia. Its value has recentlybeen reinvestigated and it has been shown that suitablegelatin as a 4 per cent to 8 per cent solution produces f•e wuntoward effects, It may, however, cause a conglomera~onof red blood cells, ,vhich interferes with subsequent typingof the blood ; hence, a sample of blood for typing purposesshould be obtained prior to the injection. .Gelatin supplies a number, but not all, of the essentialamino acids, but it is doubtful if it can contribute appre·ciably to the production of tissue protein unless supple•mented with other amino-acid preparations.Isinglass or "fish gelatin" in 7 per cent solution was suggestedearly in the recent war as a substitute for animalgelatin since it was thought that impure gelatin preparati~nsmight result in tetanus or anthrax infection or might give, rise to sensitization. However, with carefully manufacturedgelatin, such complications apparently do not arise. Onedisadvantage of gelatin solutions is that they gel at 20° C.. .., ,Blood Substitutes 19Sand hence must be heated prior to administration in coolor temperate surroundings.Other colloidal substances which have received limitedexperimental and clinical trials include pectin, polyvinylalcohol and bovine albumin and plasma. Pectin is a col.loidal carbohydrate and is presumably nonantigenic. However,there is some indication that it may act as a reticulo•endothelial irritant. Bovine blood approximates human blood• as regards total protein but contains more fibrinogen. Whileit provides a cheap and readily available source of serumand of albumin, the use of these products is attended bysuch a high incidence of reactions that it has, for the timebeing at least, been abandoned.PREPARATIONSCitrated normal human plasma U.S.P. Sterile plasma obtainedfrom pooling approximately equal amounts of theliquid portion of citrated whole blood from eight or morehuman donors certified free of disease transmissible byblood transfusion (50 cc. of 4 per cent sodium citrate inisotonic sodium chloride per each 500 cc. blood). It maybe dispensed as liquid plasma, frozen plasma or driedplasma. 500 cc.Norn1al hu1nan serum U.S.P. Sterile serum obtained by- pooling approximately equal amounts of the liquid portionof coagulated whole blood from eight or more humandonors-certified free from any disease transmissible byblood transfusion. 500 cc.Anticoagulant sodium-citrate solution U.S.P. B.P. Contains2S Gm. sodium citrate (Na 3C6H50 7·2H20) .and 9 Gm.sodium chloride in 1,000 cc.Anticoagulant acid citrate-dextrose solution (A.C.D. solution)U.S.P.Solutia~ of sodium citrate with dextrose B.P. Each ltOOO cc.contains 30 Gm. sodium citrate and 30 Gm. dextrose .•-•,196 Blood, Blood Derivatives and Blood SubstitutesInject~n of sodium chloride and acacia B.P. Contains9 Gm. sodium chloride and 17 Gm. acacia in 11000 cc., Ringer's solution (isotonic solution of three chlorides)U.S.P. Contains between 0.84 and 0.88 Gm. NaC1; 25-25mg. KCI and 30-36 mg. CaC12·2H20 in 100 cc.Lactated Ringer's solution U.S.P. • ,• Isotonic sodium-chloride solution U.S.P. Contains between'. 0.88 and 0.92 Gm. NaCl in 100 cc.Physiologic solution of sodium chloride B.P. Contains9 Gm. Na Cl in 1,000 cc. 'Sodium lactate injection U.S.P.Dextrose injection U.S.P. ,,D.e.x trose and sodium-chloride injection U.S.P .BIBLIOGRAPHY/ GEN~RALAbbott, W. E.: A review of the present concepts on fluidbalance, Am. J.M. Sc. 211: 232, 1946.Bradasch, G. A.: Comparative value of various parenteralfluids, Anesthesiology S: 1, 1944.Jane,vay, C. A., W. Berenberg and G. Hutchins: Indica~tions and uses of blood, blood derivatives and bloodsubstitutes, M. Clin. North America 29: 1069, 1945.WHOLE BLOODAllen, J. G., D. E. Clark, T. T. Thornton and W. E.• Adams: The transfusion of massive volumes of citratedwhole blood and plasma in man-clinical evidence of• its safety, Surgery 15: 824, 1944.tDenstedt, O. F., D. E. Osborne, H. Stansfield and I. Rochlin:The survivaf of preserved red cells after transfusion,Anesthesiology 5: 237, 1944.Evans, E. I., and I. A. Bigger: The rationale of ,vholeblood therapy in severe burns, Ann. Surg.122: 693, 1945.Hirsh, ]. : The story of blood transfusion; its civiljan and. military history, Mil. Surgeon 88: 143, 1941. 'McGraw, J. J., Jr.,. E .. K. Vaubel, J. Reiche!, Jr., andJ. Elliott: Compl1cat1ons of blood transfusion, Surg.Clin. North America 25: 1042, 1945.• BibliographyRappaport, E. M.: Hepatitis following blood or plasmatransfusions, observations i11 thirty-tl1ree cases, J.A. \M.A. 128: 932, 1945.Tisdal, L. H., D. M. GarJand and A. S. Wiener: A criticalanalysis of the value of the addition of A and B group'specific substances to group O blood for use as universaldonor blood, J. Lab. & Clin. Med. 31: 437, 1946.Unger, L. J., M. Weinberg and M. Lefkon: The Rh fac-1 tor as applied to the operation of blood banks, Am. J.Clin. Path. 16: 498, 1946. ,Wiener, A.' S.: Blood groups and Blood Trans£ usion,Springfield, 111., Thomas, 1943.Witebsky, E., N. C. Klendshoj and P. Swanson: Preparationand transfusion of safe universal blood, J.A.M.A. 116: 2654, 1941.BLOOD DERIVATIVESAnderson, M. W., N. W. Barker and T. H. Seldon: Aclinical evaluation of po.vdered red blood ceJ]s in the _treatment of ulcers of the extremities associated withvascular disorders, Am. Heart J. 32: 754, 1946. ~Bailey, 0. T., F. D. Ingraham, 0. Swenson, J. J. Lowreyand E. A. Bering, Jr.: Human fibrin foam \Vith thrombinas a hemostatic agent in general surgery-experi•mental studies and clinical use, Surgery 18: 347, 1945.Binder, 11. L.1 and A. Klein: Concentrated red-cell transfusions,Am. J. M. Sc. 208: 95, 1944. -Blum, L. L.: Isoagglutinin and agglutinogen contents ofpooled plasma-their role in transfusion reactions, Am. 1J. Clin. Path. 14: 112, 1944.Cohn, E. J.: Blood proteins and their therapeutic value,Science 101: 51, 1945.Jenkins, H. P., E. H. Senz: H. W. Owen and R. W.Jam polis: Present status of gelatin sponge for the controlof hemorrhage, \vith experimental data on its usefor ,vounds of the great vessels and the heart, J.A.M.A.132: 614, 1946. • Lozner, E. L., S. Lemish, A. S. Campbell and L. R. Ne,v-., h?u~er: Preservat~o:1 of normal human plasma in the ,l1qu1d state; V. cl1n1cal, chemical and physicocbemicalstudies during three years of storage at room temperature,Blood 1: 459; 1946~•I#I I198 Blood, Blood Derivatives and Blood Substitutes,Miller, E. B., and L. H. TisdaJI: Reactions to 10,000pooled liquid human plasma transfusions, J.A.M.A.128: 863, 1945.Stead, E. A., Jr., E. S. Brannon, A. J. Merrill and J~ V.Warren: Concentrated human albumin in the treatmentof shock, Arch. Int. Med. 77: 564, 1946.Stead, E. A., Jr., E. S. Brannon, A. J. Merrill and J. V.Warren : Cl1emical, clinical and immunological studieson the products of human plasma fractionation (a series..-·of 23 papers), J. Clin. Investigation 23: 417, 1944.BLOOD SUBSTITUTESAmberson, W. R.: Blood substitutes, Biol. Rev. 12: 48, '1937.Andersch, M., and R. B. Gibson: Studies on the effectsof intra.venous injections of colloids-I, deposition ofacacia in the liver and other organs and its excretionin urine and bile, J. Pharmaco}. & Exper. Therap.52: 390) 1934.Brunschwig, A., S. Nichols and R. Bigelow: Intravenous"gelatin for nutritional purposes-clinical and experimentalstudies, Surg., Gynec. & Obst. 82: 2SJ 1946.Johnson, J. B., and L. H. Ne,vman: Intravenous injectionof acacia--clinical and physiologic effects on patients,vith nephrotic edema, Arch. Int. l\fed. 76: 167,1945.Koop, C. E., and L. Bullitt: Gelatin as a plasma substitute,the effect of gelatin infusion on the subsequenttyping and cross-matching of the blood, ,vith a methodof eliminating the phenomenon of pseudoagglutination,Am. J. M. Sc. 209: 28, 1945.Popper, H., B. W. Volk, K. A. Meyer, D. 0. Kozoll andF. W. Steigmann: Evaluation of pectin and gelatinsolutions used in the treatment of shock: histologicchangPS produced in the human being,. J. Lab. & Clin.Med. 30: 352, 1945. ,Patek A. J.J Jr., F. E. Kenda]l, J. Victor 1 A. Lowell,H. )Colcher and D: Seegal: Venous thrombosis afterinfusion ,vith gelatin solutions containing 1nercurialpreservati,·es, Am. J, M. Sc. 212: 561, 1946.' . -C\''17•Drugs Affecting the Blo6and theBlood-Forming OrgansITRODUCTION:ON PREPARATIONSCVER AND STOMACHEXTRACTSIEROYLGLUTAMICA CJD(FOLIC ACID)ADIATION THERAPY•RADIOACTIVE PHOSPBORlNITROGEN MUSTARDSPHENYLHYDRAZINEARSENICURETHANEANTICOAGULANTSCOAGULANTSPREPARATIONSINTRODUCTIONThe drugs discussed in this chapter include those uhe treatment of diseases of the erythropoietic tissue:ytbemia vera and anemia) and of the leukopoietic:the leukemias, Hodgkin's disease and lymphosarcon:vell as drugs affecting the coagulability of the blood irrhe use of blood itself or of blood substitutes in acute>rrhage or shock is discussed in Chapter 16. 'l\Iany of the drugs used in the treatment of disea:he erythropoietic and leukopoietic tissues have me1~alliative action, improving the comfort of the patientJut necessarily prolonging his life. It is important tcin mind that there may be remissions in these disease~\Vithout treatment, which may lead to an unduly entb199I'I •200 Drugs Affecting Blood and Blood-Forming Organstic appraisal of newly introduced drugs. lVIany of the drugs• discussed are unpleasant to take and may cause severetoxic reactions but the severity and the poor prognosis ofthe diseases usually justify their use and stimu]ate thesearch for more effective compounds.\IRON PREPARATIONS 'Preparations containing iron in a form available to thebody have long been used in the treatment of hypochromicanemias due to iron deficiency in the body. Symptomsresulting from this deficiency include anemia, weakness andlassitude, which are promptly relieved by adequate oraldoses of inorganic iron preparations. Ferrous iron is effectivein smaller dosage than ferric and causes less gastricirritation. The addition of copper, manganese or cobalt witha view to enhancing the iron utilization is probab]y of littleor no value, \Vith the possible exception of anemia in infantsfed cows' miJk exclusively, since the dietary requirementsof these elements is so small.Iron compounds are comparatively nontoxic, the primaryeffects of overdosage being gastro-intestinal cramps anddiarrhea. In solution form, they may cause a black deposit'on the teeth which can be readily removed by a toothbrushor avoided if the preparations are taken through a straw.The manner in which iron restores the blood hemoglobinand the metabolism of iron in the body are not wholly·understood. Work with radioactive iron has shown that theamount of iron absorbed is apparently related to ,the needsof the body for iron. It is not excreted to any appreciableextent by the body. Parentera] administration of jron offersno,advantages and may cause local pain, gastro•intestin.aleffects and occasionally nephritis. .LIVER AND STOAfACH EXTRACTS 1IPernicipus anemia, a form of anemia due . to def~ctiveerythrocyte maturation, was first described 1n detail by',.•Liver and Stomacl1 .t:xtracts 201' Thomas Addison in 1849. The treatment of this condition,however,r emained unsatisfactory unti'l . 1926, when Minotand l\furphy reported successful results with addition ofraw liver to the diet. Tl1eir work was prompted by that of\Vhipple and his associates, who had demonstrated in dogsthe hlnnd-te.genez:at.ing ?to11ertie~ of a diet rich in liver.Following the dramatic report of Minot and Murphy, effortswere made to isolate the active antianemic principle orprinciples of liver. As yet, this goal has not been reached;however, extracts have been sufficiently purified so that therequirement of pernicious-anemia patients are approximately1 mg. per day, while the corresponding requirementof ,vhole liver is from 200 to 400 Gm.Purified liver extracts are generally administered intramuscularly.Orally, n1uch larger doses are required. Intramuscularinjections are more reliable in severe perniciousanemia since the gastro-intestina] disturbances which accompanythis disease may interfere with absorption fromthe alimentary tract. Intravenous therapy, while possible,offers. no advantages. A sensitivity, apparently allergic innature, may develop to parenteral liver injections. Desensitizationmay be effected by the administration of smalldoses. Otherwise, the patient must be placed on oral livertherapy or on desiccated stomach preparations. Occasion•~lly, changing to another brand of liver extract may suffice,especially if the species of animal from which the new preparationis made is also different.In 1928, Castle, who was interested in the gastric disturbancesof pernicious anemia, reported that the disease couldbe controlled by the administration of beefsteak incubated•1n normal gastric juice. He suggested that the disease might?e due either to the absence of an intrinsic factor presentin normal gastric juice, to the absence of an extrinsic factor 'normally supplied in the food, or to a failure of absorptionof the products of interaction between the two factorswhich in the normal individual are stored in the body a~ .II•202 Drugs Affecting Blood and Blood.Forming Organs,the antipernicious-anemia factor or factors. Castle1s workled to the int' roduction of desiccated hog stomach (ventricu-~ Jin) for the treatment of pernicious anemia. The activityof this preparation may he due to an unidentified intrinsicfactor or to the adsorption on the mucosa of a Jiver principlepreviously formed by the interaction of extrinsic andintrinsic substances. Its chief value lies in the treatmentof patients sensitive to liver extracts.The site of formation of the intrinsic substance in thehuman being is thought to be in the fundus glands but thefailure of pernicious anemia to develop after total gastrectomyhas led to the suggestion that there may be an extra-gastric: source as welJ • 1 unless one assumes a long periodof storage.Standardization of Antianemia Preparations. Since perniciousanemia has been observed only in man, there is nomethod af assay of antianemia preparations using laboratoryanfmals. Standardization must be carried out on untreatedpernicious-anemia patients in a state of relapse. AU.S.P. unit is the minimal amount which1 when given daily,will cause an adequate hematopoietic response. It is neces-~ sary to distinguish between ''oral'' units and "injectable"units since much smaller doses are effective by injection.PTEROYLGLUTAl\iIC ACIDN=C-OHI IH N-C C-N=C2 II It IN-C-N=C-Ct\-NH ~--0IIC-NH-CIH -CH -CH -COOH 2 2COOH \..__ _ ----i ___ ___,,, \.._ ___ y,,...-~, ,.__ ____ ,_ __ y' _____ _J- y , Pterolc acid ·Pa.ra-a.mino- Glut<1mic\ • "be~zoivc,-_c_ci__d_ __ ~_c_i_d_ J~-----P-t e-7r o_y_l_gt_ Ql. m..,iu C a.CIdPteroylglutamic acid, ''folic acid," is a synthetic productprepar ed by Angier and his associates in 1945. It has givenPteroylglutamic Acid 203promising clinical results in the treatment of various typesof macrocytic anemia, including pernicious anemia, nutritionalmacrocytic anemias and sprue. It also, acts as anessential metabolite for the growth of certain bacteria, includingLactobacillus casei and Streptococcus lactis. Its clinicaluse preceded the disclosure of its chemical nature, andin the interim it became known as both "folic acid" and"synthetic L. casei factor'' because of its similarity to folicacid isolated in nearly pure form from spinach by Mitchell,Snell-and ,villiams and to the L. casei factor isolated fromliver by Skokstad. It is probably identical with the lattercompound and can be classed as a member of the vitaminB complex. 'The relationship of pteroylglutamic acid to the antiperniciousanemia factor in liver extract is not fully understood . • The activity of liver extract is out of all proportion to its1 pteroylglutamic acid content; in addition, pteroylglutamicacid is equally potent by mouth and by injection and canbe tolerated by persons who have developed a sensitivity toliver extract. It does not appear to be so effective as liverextract in prevention or treatment of neurologic complicationsin pernicious anemia. Pteroyiglutamic acid is evidentlynot the ''extrinsic factor'' of Castle since it is effectiveparenterally, in low dosage and also in cases in whichthe intrinsic factor is absent or greatly reduced.' The advantages of pteroylglutamic acid lie in its cheap•ness, its effectiveness by the oral route and tl1e apparentnondevelopment of sensitivity on repeated administration:Thymine, a constituent of nucleic acid, has been shownto have a hematopoietic effect in pernicious anemia andsprue when given in very large doses. Spies has suggestedthat pteroy1glutamic acid may act as an enzyme or a coenzytnein the synthesis of thymine or a thymine-like compoundin the body.'••204 Drugs Affecting Blood and Blood• Forming Organs' ...RADIATION THERAPYRadiation therapy was first introduced for the treatmentof blood dysc:rasias by Pusey in 1902 and Senn in 1903. Itis of established value in such condjtions as polycythemiavera, chronic leukemias, lympbosarcoma, Hodgkin's disease,multiple mye]oma, endothelioma and Ewing's tumor. Itseffects are palliative only, mainly by relieving pain andpressure symptoms f ram enlarged lymph glands or spleenor from infiitrations of neoplastic growths. The radiationmay be directed towards the neoplasm itself or towardsthe spleen, long bones and chest. Recently "spray 11 radiationhas come into ,vide use. In this procedure, the whole •body, except for the chest and genital organs, is exposed toa low intensity of radiation. The treatments may be givenat frequent, regular intervals or a short, intensive treatmentmay be given and the patjent allowed to remain untreateduntil a recurrence of symptoms develops. The most commonuntoward effect of radiation therapy is radiation sicknesscharacterized by anorexia, nausea and vomiting. The white•,,.,,blood-cell count must be followed closely during treatment• since Ieukopenia may develop from excessive radiation.. ,Ex'cessive total body roentgen therapy may lead to ~everehemorrhages. Recently, Allen has reported that the bleedingis apparently associated with an increased output of heparinor heparin-like compounds in the body. His studies indicatethat administration of toluidin blue (an antiheparin substance)will control the bleeding by inactivating the heparin, .even though the platelet count may have been considerablyreduced. Preliminary clinical studies suggest that this dyemay a1so control petechi.al hemorrhages and thrombocytopenicpuerpera 1 but is ineffective in treatment of prothrombindeficiency and in hemoplu1ia.RADIOACTIVE PHOSPHORUS \'Radioactive phosphorus (f 32 ) was first inq:pduce? intomedicine in 193 6 for the treatment of blood dyscr3Slas by•• •- ••" IRadioactive Phosphorus -Ij205Lawrence and bis associates: In many respects, its effectsIare similar to those of radiation therapy but it has severaladvantages. It is administered intravenously or occasionallyorally and is quickly concentrated in rapidly growing tissues, ,1 and especiaJly in tissues with a high phosphorus contentwhich metabolize phosphorus rapidly; furthermore, it does ,not cause radiation sickness, its penetrating powers arelimited, and its duration of activity is sufficiently long forall practical purposes and yet short enough to be relativelyfree from long-range harmful effects. At first, its \\Se wastrestricted by the limited supplies available but with therecent developments in atomic research, it has become availableat fairly low cost. However, at this writing, officialrestrictions on the distribution of the substance limit itsuse to such research centers as are equipped with suitableapparatus. (The principles of alJocation and distribution ofradioactive isotopes are presented in Science 103: 697 ,, 1946.)Radioactive phosphorus is probably the treatment ofchoice in advanced cases of polycythernia vera, long periodsof remission being secured by a single course of therapy.It slo\VS the rate of erythropoesis and improves the physicalcomfort of the patient, but probably does not prolong life.Its effects develop slowly and the erythrocyte count is usu~ ...,, nlJy not appreciably reduced until six 1,vee1casf ter initiationof therapy. Hence, if the symptoms are severe, the patient'may have to be bled in order to secure more prompt relief.Phlebotomy alone is of ten adequate treatment for mildforms of the disease.Radioactive phosphorus is about as effective as radiationtherapy and arsenic preparations in the treatment of chronicmyelogenous leukemia but does not cause such a rapidreduction in the size of enlarged lymph nodes or spleen.It may1hf:. combined \Vith either 1orm of treatment if symp~oms o~ pressure effects are severe. Radioactive phosphorus1s of little or no value j11 acute or subucute forms of this•(\'-•'•- \,209 Drugs Affecting Blood and Blood-Forming Organs'disease, or in the lymphatic leukemias, in Hodgkin's disease,in reticuJar-cell sarcoma and in lymphosarcoma.' I .., ~ • Undesirable effects of radioactive phosphorus therapyinc]ude Jeukopenia, thrombocytopenia and anemia due tothe depressant action on the bone marrow. The dosage ofthe drug is regulated by blood and marrow examinations and- by general clinical observations. With adequate precautions,toxic effects can be avoided or minimized. The usual singledose of p32 is one millicurie, a course of treatment includingfrom 3 to 7 suc:h doses .. Up to 15 millicuries may beused in a course of treatment for polycythemia vera. ~,NITROGEN MUSTARDSs(CH2 CH2 CICH, CH2 ClDis (fJ cbloroethyl) Sulfide(Mustard)<CH2 CH2 ClH~C-NCH:i CH.2 Cl 'Methyl Bis (~ cbloroetbyl).Amine(A Nitrogen ~lustard)The clinical value of the nitrogen mustards was first sug-'gested by toxicity studies undertaken both by German andAmerican scientists to determine their possible use as chemicalwarfare agents. It was found that certain ~chloroethylcompounds of this series were most toxic to areas of rapidgrowth, such as the hematopoietic system and the intestinaltract. As a result, they have been tried in the treatment ofneoplastic diseases, lymphosarcoma and leukemia. The mostencouraging effects have been obtained jn the treatment ofHodgkin's disease though the results are apparently no• better than those obtained by radiation therapy. Resultsinleukemia have been disappointing.Toxic effects of the nitrogen mustards include moderatelymphopenia, neutropenia, thrombocytopenia, anemia, occasionalbleeding tendencies and nausea and vomiting. Theactivity of the nitrogen mustards decreases very rapidl;r .after solution in water1 hence freshly prepared solutions inJ...• 'Nitrogen Mustards 207pl1ysiologic salit1e are immediately injected intravenously,usually about 0.1 mg. per Kg. A course of treatment consistsof four such injections given on successive days. Cautioushandling is necessary to prevent contact of the drug withthe skin of the patient or doctor wiqt ensuing discomfort orvesication. Severe tissue damage may occur if leakage ispermitted around t~e injection site.Numerous analogous con1pounds of this series have beenstudied but· only those ~-chioroethyl compounds ,vhich canform a cyclic onium cation are capable of exerting thetypical actions described above.\ PHENYLHYDRAZINEPhenylhydrazine and the less toxic acetyl phenylhydrazineare useful in the treatment of polycythemia vera be•cause of their destructive action on the red blood cell.Phenylhydrazine was first introduced clinically in 1918 byEppinger and Kloss. Too large doses may precipitate hemolyticcrises from massive destruction of red cells, but, ifused in moderation, these drugs constitute an inexpensiveand easily administered form of treatment. They probablydo not cause liver or kidney damage, provided the dosageis carefully controlled. They are best administered by capsuleand should be handled with caution since they may'give rise to severe dermatitis. Acetyl phenylhydrazine was• introduced as an antipyretic under the name of pyrodinbut proved too toxic.ARSENICThe ability of inorganic arsenic compounds to lower theleukocyte count in chronic myeloid leukemia was first studiedcriticaJly in 187B by Culter and Bradford. Little use/ has been ~ade of these preparations since the introductionof roentgen therapy; however, there is little question as totheir value either as adjuvants to roentgen therapy or as' the sole therapeutic agent in leukemia and in the earlyIJ\\ I208 Drugs Affecting Blood and Blood•Forming Organs. 'treatment of polycythemia vera. The commonly used prep-~ aration is arsenic trioxide, either in the form of a solution of. 1 ,arsenious oxide or a solution of potassium arsenite (Fowler'ssolution). Injudicious use of these compounds may Jead tosymptoms of chronic arsenic poisoning, including po1yneu-, ,' ritis, keratosis and cirrhosis. 'URETHANENH2IC=OIO-C2 HsUrethane (ethyl carbamate) has recently been used inEngland in the treatment of leukemia. The therapeuticeffects appear to be essentially similar 1 to those obtainedwith roentgen therapy. They include a fall in total white- •cell count, a tendency for the differe.ntial count to approach, a more normal pattern, diminution in the size of the spleenand of enlarged lymph nodes and a rise in hemoglobin.Toxic effects are sJight, consisting of gastro-intestinal upsetsand drowsiness. The therapeutic action of urethane maybe associated with its inhibitory effect on mitosis which hasbeen demonstrated ,vith plant and animal cells.ANTICOAGULANTS~ Anticoagulation therapy using heparin or dicumarol isa recently introduced method for the prevention of thrombiand ~mboli, especially in conditions of accidental or surgi- Jca1 trauma. It is of no benefit if the b1ood clots havealready formed except that it may prevent their furtherextensi•o n.Heparin is an anticoagulant substance present in thetissues of the body. It ,vas isolated f_rom the liver byliowell and Holt in 1916. Its exact che:111canl ature has notbeen determined. It may not be a single substance but•I••'' ' ' Anticoagulants ,i 209rather a mixture of compounds having a mucoitin-polysulfuric-acid structure. Heparins from various animal sources\ have simil~- chemical properties but differ in their anti ..coagulant activity.Heparin apparently Jorms a strong thrombin-inactivatingcomplexw: ith a co~factor present in serum albumin. It iseffective both in vitro and in vivo after parenteral injection.It acts almost immediately but its effects usually last only3 or 4 hours. It is usually given intravenously but recentlya more prolonged action has been obtained by subcutaneousinjection of heparin in a gelatinous base which releases the, drug slowly.Various units of potency and methods of assay have ,been suggested for expressing the activity of heparin extracts.Probably the best standard is that of the cry_stallinebarium salt of heparin prepared by the Connaught laboratoriesof the University of Toronto. The proposed unit isdefined as 0.01 mg. of this salt .IOHCH20 0-.. 0 ' .Dicumarol. _Dicumarol ,vas first isolated from spoiled sweet clover byLink and his associates in 1941. It is the causative agent ofa hemorrhagic disease of cattle ,;sweet-clover disease''which is. due primarily to a prothrombin deficiency. F~rfommerc1al purposes, dicumarol is prepared syntheticallyfrom acetylsalicylic acid.~he °:ode of action of dicumarol is not yet understood.It 1S bel1ev~dt~ inhibit productjon of prothrdmbin possibly\,• ,••~ 210 Drugs Affecting Blood and Blood•Forming Organs,by interference with the enzyme system responsible for itselaboration. It is effective in vivo but not in vitro,Dicumarol offers the advantages over heparin of being 'effective on oral administration and of being relativelyinexpensive. However, there is usually a delay of about 48hours before its effect is apparent. Furthermore, its action ,may persist for several days and cumulative poisoning mayoccur with hemorrhages as the main toxic effect. It can bereadily antidoted wjth large doses of vitamin K preparationsor by blood transfusions. During the administration of" dicumarol, the prothrombin level should be followed dailyand should not be permitted to fall below from 10 to 30 percent of the normal. Dicumarol should not be given to patientswith hemorrhage tendencies or with liver or kidneydisease. \Vhen an immediate yet protracted anticoagulanteffect is desired, dicumarol may be given together with \heparin, the heparin being discontinued as soon as a satis•factory prothrombin JeveJ has been reached.•0II0COAGULANTS0IIVitamin K1 Vitamin K2 Menadione. (From Plants} (From. Micto•organisms) (Synthetic)Vitamin K Preparations. The existence of an antihemorrhagicfactor in green plants was first demonstrated byDam in 1929. He showed that chicks raised on a deficientdiet developed hemorrhagic manifestations which could bealleviated by the addition of alfalfa to the diet. The active'· principle was isolated simultaneously by Dam and by Doisyin 1939. Subsequently, Doisy isolated a second anti•hemorrhagic principle from putrified fish meal. This prin•cip1e apparently does not occur jn plants and is known as•• Coagulants 211vitamin K2, while the original principle is known as vitaminK1. Both these substances are lipid in nature and are notabsorbed from the gastro-intestinal tract in the absence ofthe bile salts. A number of synthetic naphthoquinones havebeen found to have vitamin-K-like properties, and, of these,menadione (2-methyl-naphthoquinone) and the water-solu.ble. menadione sodium bisulfite have been accepted for clinicaluse.Vitamin K preparations prevent hemorrhages by raisingthe prothrombin level of the blood. In massive dosage (from40 to 60 mg.), they effectively antidote dicumarol over•dosage and are probably of greatest value in this condition.They ,vill correct hypoprothrombinemia due to such conditionsas obstructive jaundice in which the normal absorptionof the vitamin K of the diet is interfered with. They may beof value in hemorrhagic states associated with hepatic diseaseprovided the liver can utilize the administered drug. Theywere at one time widely advocated as prophylactic andcurative agents in hemorrhagic disorders in the newborn.However, the present concensus appears to be that thesedisorders are not necessarily related to the prolonged prothrombintime characteristic of the first week of life andthat their incidence is not significantly reduced by the administrationof vitamin K preparations.PREPARATIONSFerrous sulfate U.S.P.; B.P. 0.3 G~.Ferrous sulfate tablets U.S.P. 'Usually contain 0.3' Gm.~ferrous sulfate.Exsiccated ferrous sulfate U.S.P.; B.P. Contain not lessthan 80% ferrous sulfate. 0.2 Gm.Reduced iron B.P. Contains not less than 90ro metallic iron.0.06-0.5 Gm.Ferric ammonium citrate U.S,P.; B.P. 1 Gm.•'212 Drugs Affecting Blood and Blood-Forming OrgansFerric ammonium citrate capsules U.S.P. UsualJy contai110.5 Gm. Ferric ammonium citrate.Iron and quinine sulfate B.P. Contains approximately 13%iron and 15% anhydrous quinine. 0.3~1 Gm.Pills of ferrous carbonate (Blauds' pills) B.P. Each pilJcontains not less than 60 mg. FeC03• 5 pills.Saccharated iron carbonate B.P. 0.6-2 Gm.Injection of iron B.P. Contains double salt of citrate ofiron and ammonium. (Intramuscular). 1-2 cc.Syrup of ferrous iodide B.P. Contains 5% FeI 2 • 2-8 cc.Compound syrup of ferrous phosphate (Parrish's syrup)B.P. Contains 0,9% anhydrous ferrous phosphate. 2-8 cc.Syrup of ferrous phosphate with quinine and strychnine(Easton's syrup) B.P. Contains 1.8% anhydrous ferrousphosphate, 1.09% anhydrous quinine and 0.0246% strychnine.2 .. 4 cc.Citrated ferrous chloride B.P. 0.2-0.3 Gm.Ferrous lactate N .N.R. 0.06-1.3 Gm.Liver extract U.S.P.; B.P. l U.S.P. unit.Liquid extract of liver B.P. EaclI cc. equivalent to 8 Gm.raw liver. 30 cc.Liver solution U.S.P. 1 U.S.P. unit.Liver injection U.S.P. Usually contains l and 2 U.S.P.units in 1 cc. jnjected intramuscularly. 1 U.S.P. unit.Powdered stomach U.S.P. 1 U.S.P. unit.Liver with stomach U.S.P. 1 U.S.P. unit.Extralin N.N.R. A liver-stomach concentrate administeredorally. Contains 1 U.S.P. unit in,.6 Gm.Potassium arsenite solution U.S.P. Arsenical solution B.P.(Fowler's solution) approximately 1 % solution of arsenictrioxide with potassium bicarbonate. 0.2 cc.Menadione U.S.P. Menaphthone B.P. 1 rng.Menadione tablets U.S.P. Usually 1 and 2 mg. tablets.Menadione sodium bisultite U.S.P. intravenous or intramuscular.2 mg. ,•Bibliography , 213, • • IMenadione sodium bisulfite injection. U.S.P. usually con ..tains the following amounts of menadione sodium bisul ..fite: 2 mg. in½ cc.; 4 mg. in 1' cc.Vitamin K1 N.N.R. 4-10 mg.BIBLIOGRAPHYlGENERALA Symposium on tl1e Blood and Blood-forming Organs, ,1Madison, Univer. Wisconsin Press, 1939.Abt, H. L. : The treatment of leukemia, Med. Clin. NorthAmerica 28: 187, 1944.Forkner, C. E.: Leukemia and Allied Disorders, NewYork, Macmillan, 1938.Kracke, R. R.: Diseases of the Blood and Atlas of Hematology,2nd ed., Philadelphia, J. B. Lippincott,· 1941.Pxaegel, B. L., and J. F. Ross: The diagnosis and treatmentof anemia, Med. Clin. North Atnerica 30: 1042,1946.Vaughan, J. M.: The Anae1nias, Ne,v Yorlc, Oxford,London, Humphrey Milford, 1936.' IRON THERAPYIHahn, P. F., W. F. Bale, E. 0. Lawrence and G. H.Whipple: Radioactive iron and its metabolism in anemia,J.A.M.A. 111: 2285, 1938.Heath, C. W.: Iron in nutrition-requirements for iron,J .A.M.A. 120 : 366, 1942.Henderson, V. E., and G. H. W. Lucas: On the absorptionof iron, Am. J. Digest. Dis. 11: 244, 1944.LIVER AND STOMACH PREPABATIONSCastle, W. B.: Observatit>ns on the etiologic relationshipof achylia gastrica to pernicious anemia; 1. The effectof the administration to patients with pernicious anemiaof the contents of the normal human stomachrecovered after the ingestion of beef muscle, Am. J. 1f.Sc. 178: 748, 1929.Fox, H. J., and W. B. Castle: Observations on the etio•logic relationship of achylia gastrica to pernicious ane ..mia; IX. Difference in site of secretion of intrinsicfactor in the hog and in the human stomach, Arn. J.M. Sc. 203: 18, 1942.•214 Drugs Affecting Blood and Blood-Forming Organs1\.IcSorley, J. G., and L. S. P. Davidson: Sensitivity toliver extract, Brit. M. J. 1: 714, 1944. ~ _Minot, G. R., and W. P. l\f urphy: Treatment of perni~cious anemia by a special diet, J.A.l\f.A. 87: 470, 1926.Sch,vartz, S., 0.: Pernicious anemia, Med. Clin. NorthAmerica 28: 214, 1944.Schwartz, S. 0., and H. Legere: Treatment of liver extractsensitivity, Blood I: 307, 1946.Subbarow, Y., A. B. Hastings and 11. Elkin: Chemistryof anti-pernicious anemia substances of liver, Vitaminsand Hormones 3: 237, 1945.PTEROYLGLUTAMIC AcmAngier, R. B., et al.: Synthesis of a compound identical,vith the L. casei factor isolated from liver, Science102: 227, 1945.Angier, R. B., et al.: The structure and synthesis of theliver L. casei factor, Science 103: 667, 1946.Berry, L. J., and T. D. Spies: The present status of folicacid, Blood l : 271, 1946.Doan, C. A.: Folic acid (synthetic L. casei factor) anessential panhematopoietic stimulus experimental andclinical studies, Am. J. 1!. Sc. 212: 257, 1946.Mitchell, H. K., E. E. Snell and R. J. Williams: Theconcentration of "folic acid,'' J. Am. Chem. Soc. 63:2284, 1941.Spies, T. D., W. B. Frommeyer, Jr., C. F. Vilter andA. English: Anti-anemic properties of thymine, Bloodl : 185, 1946.Stokstad, E. L. R. : Some properties of a gro,vth factorfor Lactobacill1,s ca.rei, ]. Biol. Chem. 149: 573, 1943.RADJOAC:rJV.E PHOSPHORUSErf, L. A.: Radiophosph~rus as the treatment of choicein primary polycythem1a, Am. J. 1{. Sc. l: 363,\1946.Hempelmann, Jr., L. A., E. H. Reinhard, C: V. Mo?re, o. S. Bierbaum and S. 1'-f~ore:. Hematolog1c compl1ca~tions of therapy ,vith radioactive phosphorus, J. Lab.& Clin. :rtfed. 29: 1~0, 1944.•,- \Bibliography ' 215La,vrence, J. H., K. G. Scott and L. W. Tuttle: Studieson leukemia ,vith the aid of radioactive phosphorus,N e,v Internat. Clinics 3: 33, 1939.Reinhard, E. H., C. V. i1oore, 0. S. Bierbaum andS. l\foore; Radioactive phosphorus as a therapeuticagent; A review of the literature and analysis of theresults of treatment of 155 patients witl1 various blooddyscrasias, lymphomas and other neoplastic diseases,J. Lab, & Clin. Med. 31: 107, 1946.vVarren, S.: The therapeutic use of radioactive phos-'photus, Am. J. M. Sc. 209: 701, 1945. -._Warren, S.: Availability of radioactive isotopes-announcementfrom headquarters, Manhattan project,Washington, D. C., Science 103: 697, 1946.NITROGEN MusrAIU>s• Gilman, A., and F. S. Philips: The biological actions andtherapeutic applications of the B-chloroethyl aminesand sulfides, Science 103 ~ 409, 1946. ,Goodman, L. S., M. W. Wintrobe, W. Dameshek, M. J.Goodman, A. Gilman and ~1. T. McLennan: Nitrogenmustard tl1erapy-use of methyl-bis (beta-chloroethyl)amine hydrochloride and tris (beta-chloroethyl) aminel1ydrochloride for Hodgkin's disease, lymphosarcoma,leukemia and certain allied and miscella11eous disorders,J.A.11:.A. 132: 126, 1946.Jacobson, L. 0., C. L. Spurr, E. S. Guzman Barron,T. Smith, C. Lushbaugh and G. F. Dick: Nitrogenmustard therapy; studies on the effect of metl1yl-bis(beta-cl1loroethyl) amine hydrochloride on neoplasticdiseases and allied disorders of the hemopoietic system,J.A.i\1.A. 132 ~263, 1946.Rl1oads, C. P.: Nitrogen mustards in the treatment ofneoplastic disease, J.A.M.A. 131: 656, 1946.PHENYI.HYDRAZINEGriffin, H. Z., and E. V. Allen: The control and complete' ren1i_ssion of polycythemia vera follo,ving the prolongedadministration of pl1enylhydrazine hydrochloride, Am.J. 11. Sc. 185: 1, 1933.216 Drugs AffectjngB lood and B1ood•ForminOg rgansGriffin, H. 2., and H. M. Conner: The unto,vard effectsof treatment by phenylhydrazine hydrochloride, J.A.1\:f.A. gz: 1505, 1929. 'Stealy, C. L., and H. S. Sumerlin: Polycythemia vera,final report on a case under continual treatment withphenylhydrazine hydrochloride for eleven years, J.A. ,M.A. 126: 954, 1926.URETHANE'Paterson, E., A. Haddo\v. I. A. Thomas and J. 11. Watkinson:Leukaemia treated ,vith urethane compared,vith deep x-ray therapy, Lancet 1: 677, 1946.ARSENICKandel, E. V., and G. V. LeRoy: Chronic arsenical poisoningduring the treatment of chronic mye1oid 1eu·kemia, Arch. Int. Med. 60: 846, 1937. IANTICOAGULANTS 'Allen, J. G., and L. 0. Jacobson: Hyperheparinemia:cause of the hemorrhagic syndrome associated ,vithtotal body exposure to ionizing radiation, Science 105:388, 1947.Barker, N. W., H. E. Cromer, M. Hurn and J. ?v!. Waugh:The use of dicumarol in the prevention of postopera•tive thrombosis and embolism ,vith special reference todosage and safe administration, Surgery 17: 207, 1945.Bauer, G.: Heparin therapy in acute deep venous thrombosis,J.A.M.A. 1'31: 196, 1946.Evans, J. A., and R. J. Boller: The subcutaneous use ofheparin in anticoagulation therapy, J.A.M.A. 131: 879,1946.Jorpes, J. E.: Heparin in the Treatment of Thrombosis,New York, Oxford, 1947.Link, K. P.: TJie anticoa~lant 3, 3-m~thylenebis (4-hydroxycoumar1n)Federat1on Proc. 4. 176, 1945.Loe,ve, L., and P: Rosen?I31tt: !i-ne,v practi~al met~odfor subcutaneous adm1n1strat1on of heparin-preliminaryreport. Am. J. M. Sc. 208 : 54, 1g44_ ., p t s H R J R Guyther and C. E. Brarnbel: ·D1cu•eme:r~l i~ ac-~te· co~onary thrombosis, J.A.M.A. 130:398,1946.' •.tl 1 bliography 217Quick, A. J.: The anticoagulants effective in vivo withspecial reference to heparin and dicumarol, Physiol.Rev. 24: 297, 1944.Rosenbloom, D., and J. J. Crane: Massive hematuria dueto dicumarol overdosage, J.A.M.A. 132: 924, 1946.,COAGULANTSCrpmer, H. E., and N. W. Barker: The effect of largedoses of menadione bisulfite ( synthetic vitamin K) onexcessive hypoprothrombinemia induced by dicumaro1,Proc. Staff Meetings, Mayo Clinic 19: 217, 1944.Potter, E. L.: The effect on infant mortality of vitamin Kadministered during labor, Am. J. Obst. & Gynec. 50:235, 1945.Richards, R. K., and S. Shapiro: Experimental and clinicaJstudies on the action of high doses of hykinone andother menadione derivatives, J. Pharmacol. & Exper.Therap. 84: 93, 1945.'18Drugs Affectingthe Gastro-Intestinal TractINTRODUCTIONANTACIDSCHOLERETICSICATHAnTICSANTIDIARRHEAL AGENTSMISCELLANEOUS PREPARATIONSPREPARATIONSINTRODUCTION•Drugs discussed in this chapter include antacids, chol.eretics, cathartics, antidiarrheal agents and miscellaneouspreparations which are either little used or whose therapeuticvalue has not been fully established. Other drugsof ten administered for their effect on the gastro-intestinaltract include opium and morphine, used to treat diarrheaand to relieve severe abdominal pain; antispasmodics suchas papaverine, the parasympatholytic agents and the aliphaticamine, octin, which are used in the treatment ofgastro~intestinal and biliary spasm; posterior pituitary,used to stimulate the intestinal musculature and to allaydistention; and the anthelmintics, amebacides and certainsulfonamides which are used in infections of the gastro-in~,,testinal tract.••ANTACIDSAntacids are -drugs which reduce the acidity of the gastricsecretion. They are u~ chiefly ~ the t~e.atm~nt ofpeptic ulcer. While the etiology of this cond1t1on 1S not -. 218Antacids 219fully understood, it is generally believed to be due to theirritant and digestive action of hydrochloric acid and prob-, ably also of pepsin on a susceptible area of the gastricmucosa. This view has been supported recently by Dragstfdtand his associates, who have reported striking im-¾provement !n patients with chronic refractory ulcers folIo,ving section of the vagus. The results to date indicatethat the operation leads to reduced secretion a11d motility,relief of pain and healing of the ulcer.Antacids either act by a direct neutralization of thehydrochloric acid of the stomach or by adsorption of excesshydrogen. ions leading to a higher pH and a resultantdecrease in peptic activity. Included in the first group aresodium bicarbonate, magnesium oxide, tribasic calciu~and magnesium phosphates, and magnesium and calcium,, carbonates. Calcium carbonate is one of the most widelyused preparations because of its cheapness and its nonpurgativeaction. Excessive use of soluble, absorbable preparationssuch as sodium bicarbonate m.ay lead to systemicalkalosis.Adsorbent preparations are colloidal in nature and includealuminum hydroxide, aluminum silicate, colloidalmagnesium silicate and aluminum phosphate gel. Thesesubstances are also said to have a protective, lining actionon the mucosa which may relieve the pain and promotehealing of the ulcerated area. The colloidal preparationstend to have a constipating effect and should thereforebe supplemented by noncolloidal magnesium preparationswhich have a faxative action in adequate dosages. Thecolloidal preparations may also interfere with the absorptionfrom the gastro~intestinal tract and, with the excep-' tion of aluminum phosphate, may lead to a depletion ofphosphorus from the bones due to the combination inthe intestinal tract of aluminum and phosphorus.Gastric mucin has been used to a limited extent in thetreatment of gastric ulcer. Its activity may be due to aprotective coating action or to an absorbent action ..•220 1 Drugs Affecting the Gastro-Intcstinal TractDetergents such as sodium alkyl sulfate and sodiumlauryl sulfate inactivate pepsin in vitro but thefr action invivo is disappointing. These preparations have pot as yetproved of value in the treatment of gastric ulcer.I• CHOLERETICSCholeretics are substances which increase the output ofbile. The most important are bile salts and related prepara•t1• ons. •The bile salts when given by mouth are absorbed fromthe intestine and re•excreted by the liver in the bile,thus entering the same cyclic process as endogenous bilesalts. They are of value in promoting the absorption of fatsand fat.soluble vitamins f ron1 the intestinal tract whenthe normal biliary output is reduced or absent.Dehydrocholic acid (dechoJin), an oxidation product ofcholic acid derived from natural bile salts, and its sodium .salt, sodium dehydrocholate, have a ltydrocholeretic action.They increase the volume of the biliary secretion by in•creasing the water content without increasing the outputof the bile salts. These preparations are of some value in''flushing out" the biliary tract but should be avoided incases of complete biliary obstruction. Tbey have a milddiuretic action and potentiate the action of mercurialdiuretics. These preparations may be employed in cholecystographyto hasten the appearance of the shadow and thesubsequent removal of the dyestttff from the biliary tract.Cho1ecystagogues are substances which cause evacuationof the gallbladder, either by the contraction or ,its mus·,culature (fats and cholecystokinin) or by relaxation of thesphincter of Oddi (nitrites and antispasmodics).CATHARTICSCathartics ar~ used to relieve constipation or to hastenthe evacuation of toxic substan:es from _the ~owel. Ca•·th t· ction depends usually on increased 1ntest1nal move.m::t~c ~duced either by increased bulk of the intestinal•Cathartics 221contents or by irritation of the intestinal musculature.Cathartic drugs vary considerably in the degree to whichthey act and are sometimes classified in approximate orderof increasing activity as aperients, laxatives, cathartics, ecco•protics, purgatives, physics, hydragogues and drastics. Theyare more. conveniently. classified according to their methodof action or their chemical nature.Cathartics have been exploited by the patent-medicineindustry probably more tl1an any other group of drugs, and- many cases of chronic constipation and of bowel irritationhave resulted from their indiscriminate use. Indications fortheir use include the elimination of poisons, the medicalinduction of labor, the presence 1 of painfully hard stools,~ tl1e presence of certain anorectal lesions, during late pregnancyand early puerperium, and to prevent straining atstool in extreme hypertension, aneurysm, abdominal herniaor recent coronary occlusion. The use of cathartics to relievegastro•intestinal symptoms of unknown cause cannotbe too emphatically condemned.Drugs which act by jncreasing the bullt of the gastrointestinalcontents:1. Saline cathartics consist of poorly absorbable saltsthat hold water in the gut by osmotic force, thus increasingthe bulk and fluidity of tl1e intestinal contents. They includesodium, magnesium and potassium sulfates, citrates,tartrates and phosphates. If given in hypertonic solution,these salts draw\ water from the body tissues, hence their ,cathartic action is slower and tissue dehydration may occur.The latter effect may, however, be of value in edema. Isotonicsolutions are less irritating to the stomach and are /passed more rapidly through the pyloric sphincter thanhypertonic solutions. The palatability of the saline catharticsmay be improved by prescribing them in the form ofeffervesc:nt preparations. ~Occasional cases of magnesium poisoning have been reporteddue to unusual absofl>tion of magnesium sulfate. The••222 Drugs Affecting the Gastro-Intestinal TractIcharacteristic symptom is profound depression. Calciumsalts are effective- antidotes •2. Plant colloids include insoluble gums, such as plantagoseed (psyllium seed) and agar, which take up watera~d swell to give considerable bulk, and bran, ,vhich containsa high proportion of indigestible celluloses and hemicelluloseswhich have a water-binding action. Bran mayalso act by irritating the mucous membane of the intestinaltract and should not be used in such conditions as colitis.3. Emollients include bland oils, such as liquid petrolatumand olive oil. It has been suggested that these substancescoat the intestine with an oily film which interfereswith the absorption of waier and thus increases the bulkand fluidity of the intestinal contents. Prolonged use ofliquid petrolatum may lead to the loss of the fat-solublevitamins, to loss of weight due to poor absorption of foodstuffs'from the intestinal tract and to pruritus ani due toan interference with anal hygiene by leakage of oil fromthe anus.Drugs which act by irritation or stimulation:1. Irritant oils include castor oil and croton oil. Theactivity of castor oil is due to its hydrolysis in the intestineto the mildly irritating ricinoleic acid. Croton oil containsa violently irritating resin and is seldom used except inveterinary medicine.2. Anthracene cathartics, such as senna, rhubarb, cascaraand aloe, owe their activity to polyhydroxyanthraquinones,present usually as glycosides. Such preparations wereformerly thought to have. a tonic effect on the intestinal--mu45culalur~.3. Cathartic resins include such preparations as euphorbiumjalap, ipomoea, elaterin, podophyllum, gamboge andcoloc;,nth in which the active ingredient is often a glucoresin.These substances are seldom used nowadays because• • • of the severity of their action.J ,Cathartics 2234. , Miscellaneous irritants include phenolphthalein andrnercurous chloride ( calomel). Phenolphthalein is frequentlyincluded in proprietary cathartics because of its tastelessnessand its low toxicity. It may cause a skin rash in sensitiveindividuals. ~lercurous chloride should be followed by anothercathartic if effective results are not obtained followingits administration since the insoluble mercurous ion may bechanged in the intestine to the soluble mercuric ion and leadto symptoms of mercury poisoning (mercurialism), such assalivation, stomatitis and nephritis.ANTIDIARR.HEAL AGENTS\Nonspecific agents used in the treatment of diarrhea •include adsorbents, such as activated charcoal, bentoniteand kaolin, or substances such as bismuth subnitrate orsubcarbonate, ,vhich are thought to farm a protective coat• _ing over the mucous membrane of the intestinal tract. Bismuthsubnitrate is occasioQally decomposed in the intestinewith the formation of the more toxic nitrite. Adsorbentsare of value in the treatment of poisoning by mercuricchloride and alkaloids. Huge quantities are necessary foreffective results, and with kaolin preparations partial orcomplete intestinal obstruction may occur.MISCELLANEOUS PREPARATIONSEmetics are drugs which produce vomiting. In smalldoses they act as expectorants, increasing the secretion of ,1fluid from the respiratory tract. Emetics act either locallyby irritating the stomach or centrally by stimulating thevomiting center in the medulla. The locally acting emeticsinclude zinc sulfate, copper sulfate, alum and mustard. Cent~ally acting emetics include ipecac, antimony and potas~s1um tartrate (tartar emetic) and apomorphine.l\Iost emetics are irritating to the stomach and if noteffecti1:e promptly must be rem~ved by ston1ach pump. Furthermore,emesis in a semiconscious patient may lead to.. /•224 Drugs Affecting the ,Gastro-Intestinal Tractentrance of vomitus into the respiratory tract. Hence thetendency is to replace emetics in modern practice by thestomach pump. Apomorphine, which is prepared from mor.phine by the abstraction of one molecule of \Vat~r, is probablyone of the safest and most effective emetics. Given byhypodermjc injection, it acts promptly in very small dosageand is nonirritating to the stomach. ,In small doses, emetics increase sweating {diaphoreticaction) atfd increase the secretion of fluid from the respira.tory tract (expectorant action). Expectorants are of valuein the treatment of inflammatory conditions of the lungsand of the air passages by aiding in the removal of mucusor exudates. Other types of expectorants include salineexpectorants, such as ammonium chloride or carbonate,citrates and iodides, and irritant expectorants, such as terpinhydrate, cresote and squill, which arc said to stimulaterepair proce:ses by irritation of the mucous membrane.Carminatives are substances which relieve gaseous dis.tension of the stomach or intestines. They include sodiumbicarbonate and a number of flavoring agents, such ascaraway, capsicum, cardamon, cinnamon, clove, ginger andpeppermint, in which the active agent is a volatile oil.Bitters are substances used to increase salivary and gastricsecretions and to improve the appetite. Their actionis probably largely psychic, although they may act reflexlyby stimttlating the taste buds. They are effective in verysmall doses. Preparations include compound tincture ofgentian, tincture of nux vomica, and quinine and its salts.The are rarely prescribed in modern practice.H fdrochloric acid in dilute solution may be prescribedwhett the normal hydrochloric acid of the stomach is reducedor absent. Its effectiveness is probabJy due to its actionin liberating ga~tro-intestinal hormones, rather than to anyeffect on the free acidity of the gastric juice.Pancrea~in is a preparation containing the enzymes trypsin,amylase and lipase. It is obtained f rem the fresh•• • I l\Iiscelianeous Preparations 225" pancreas of cattle and hogs. It is used both in the preparationof predigested foodstuffs and in the treatment of digestivedisorders, especially in patients in which the normalpancreatic secretion is deficient. 1Gastro-intestinal Hormones. The control of the digestiveprocesses appears to be due at least in part to humeralagents liberated from the mucosa of the intestinal tract bythe· stimulus of eating. A number of active preparationshave been prepared and studied, some of which show promiseas therapeutic agents.Enterogastrone is a partially puri.fied preparation ob- .tained from the upper intestine which inhibits gastric secretionand motility. Ivy and his associates have shown thatenterogastrone has a protective action against experimentalulcers 1in dogs and have reported encouraging preliminaryclinical results in the treatment of peptic ulcer in man.Secretin is the humeral agent responsible for stimulating, the flow of pancreatic juice. It is liberated from the inactiveprosecretin by the action of hydrochloric acid in the upper,duodenum. It ha~-limited value in the diagnosis of pancreaticdisease. It is effective only on intravenous injection.Cholecystokinen is an agent obtained f!om intestinalextracts which produces evacuation of the gallbladder byc,ausing it to contract. It may prove of diagnostic value in_ gallbladder disease.PREPARATIONSANTACIDS'l\lagnesia magma (milk of magnesia) U.S.P. 1\Iixture ofmagnesium hydroxide B.P. Approximately 8 per centsolution of magnesium hydroxide. Antacid, 4 cc. Laxative,15 c:c.1\lagnesium carbonate U.S.P.; B. P. Antacid, 0.6 Gm. Laxat1•ve, 8.0 Gm. • .icagnesium oxide (light and heavy) U.S.P.; B.P. Antacid,0,25 Gm. Laxative, 4.0 Gm. ·,226 Drugs Affecting the Gastro-Intestinal TractMagnesium trisilicate U.S.P.; B. P. 1.0 Gm.Tribasic calcium phosphate N.N.R. Calcium pbospate B.P.1-5 Gm.Tribasic magnesium phosphate N.N.R. 1-5 Gm.Dried aluminum hydroxide gel U.S.P. 0.6 Gm.Aluminum hydroxide gel U.S.P. Contains approximately4 per cent A120 3 , chiefly as hydrous oxide of aluminum.8 cc. -Aluminum phosphate gel N.N.R. 15-30 cc.Gastric mucin N.N.R. 2.5 Gm. •CHOLERETICSOx-bile extract U.S.P.; B.P. 0.3 Gm.Ox-bile extract tablets U.S.P. Usually contain 0.3 Gm.extract of ox bile.Dehydrocholic acid N.N.R. 0.25-0.S Gm.Sodium dehydrocholate N.N.R. Available as a 20 per centsolution for intravenous injection. 5-10 cc.CATHARTICSMagnesium sulfate (Epsom salt) U.S.P.; B.P. 15 Gm.Magnesium citrate solution U.S.P. Contains about 1.6 percent magnesium citrate in flavored carbonate solution.200 cc. •Compound effervescent powders (Seidlitz powders) U.S.P.Blue paper contains 2.5 Gm. sodium bicarbonate and 7.SGm. potassium and sodium tartrate; white paper contains2 .16 Gm. tartaric acid.Sodium phosphate U.S.P. B.P. 4 Gm.Effervescent sodium phosphate U.S.P. Contains 20 per centsodium phosphate. B.P. Contains SO per cent sodiumphosphate.Sodium hipho:;phate U.S.P.; B.P. 0.6 Gm.-4.o Gm,Sodium sulfate (Glauber's salt) U.S.P.; B. P. 15 Gm.Effervescent sodium sulfate B.P. Contains SO per cent sodiumsulfate.Preparations 227Agar B.P.; U.S.P. Dried mucilaginous substance extractedfrom various species of Gelidium and closely related algae.4 Gm.Plantago seed (psyllium seed) N.N.R. Dried seed fromvarious species of plantago. 4-15 Gm.l\Ietamucil N.N.R, Contains approximately 50 per centpowdered psyllium seed. 4-7 Gm.Liquid petrolatum U.S.P.; liquid paraffin B.P. 1S cc. ,Liquid petrolatum emulsion U.S.P. Contains 50 per centliquid petrolatum. ,,Olive oil U .S.P.; B.P. 30 cc.Castor oil U.S.P.; B.P. Oil from seeds of Ricuzus com,n1,nis.15 cc.Senna U.S.P.; B.P. Dried leaflets of Cassia acutifolia orC. angustifolia. 2.0 Gm.Senna pod }3.P. Used for preparing fluid extract of senna.2.0 Gm.Senna fluid extract U.S.P.; B. P. 1 cc. represents 1 Gm.I... senna.Senna syrup U.S.P.; .B.P. Contains 25 per cent fluid extractof senna. 8 cc. ,Confection of senna B.P. Contains 10 per cent senna.4-8 Gm.Concentrated infusion of senna B.P. Contains 80 per centsenn~ pod. 2-8 cc.Fresh infusion of senna B.P. Contains 10 per cent sennapod. 15-60 cc.Compound mixture of senna (black draught) B.P. 30-60 cc.Rhubarb U.S.P.; B.P. Dried roots and rhizome of variousspecies· of rheum. 1 Gm. _Compound powder of rhubarb B.P. (Gregory's powder).Contains 25 per cent rhubarb with·light and heavy magnes•1 umc arbonate. 0.6-4 Gm.•ICo~pound rhubarb pill B.P. Contains 2S per cent rhubarb . ·with aloes, myrrh, hard soap and flavoring matter. 0.25-0.5 Gm. J-J/ 228 Drugs Affecting the Gastro-Intestinal ,Tract•Aromatic rhubarb tincture U.S.P. Contains 20 per centrhubarb.Aromatic rhubarb syrup U.S.P. Contains 15 per cent aromatictincture of rhubarb. 10 cc. ,Compound tincture of rhubarb B.P. Contains 10 per centrhubarb. 2-4 cc.Cascara sagrada fluid extract U .S.P. ; B .P. 1 cc. representsl Gm. cascara sagrada. 1-4 cc., Aromatic cascara sagrada fluid extract U.S.P. Elixir of~cara sagrada B.P. 1 cc. represents 1 Gm. cascara sagrada.2 cc.Cascara sagrada extract U.S.P. 1 Gm. of extract represents3 Gm. cascara sagrada. 0.3 Gm.Cascara sagrada extract tablets U.S.P. Usually contain 0.12,0.2 and 0.3 Gm.Dry extract of cascara sagrada B.P. 0.12-0.S Gm.Aloe U.S.P.; B.P. Dried juice of leaves of various species ofaloe. 0.25 Gm. ,.Aloin U.S.P.; B.P . .1\,fixture of active principles of aloe.15 mg.Pill of aloes B.P. Contains 58 per cent aloe. 0.25-0.5 Gm.Pill of aloes and asefetida B.P. Contains 30 per cent aloe.0.25-0.5 Gm.Pill of aloes and iron B.P. Contains 20 per cent aloe. 0.25-0.S Gm.Jalap B.P. Drjed tubercles of lpo,noea pwga.Powdered jalap B.P. 0.3-1.2 Gm.Compound powder of jalap B.P. Contains 30 per cent pow•dered ja1ap. 0.6-4 Gm.Ipomoea B.P. Dried root of Ipomoea orizabensis. 0.3-,1.2 Gm.Scammony resin B.P. Mixture of resins from ipomoea.0.03-0.2 Om.Podophyllum B.P. Dried rhizome and roots of P. peltatus.,f0.12-0.6 Gm.>II Preparations .\.229Indian podophyllum B.P. 1 Dried rhizome and roots ofP. ..e_ modi. 0.12-0.6 Gm. ., Resin of podophyllum B.P. l\-1:ixturoe r resin obtained fromP. peltatus or P. emodi. 15-60 mg.Colocynth B.P. Dried pulp of fruit of Citrullus colocyntlzis.o.12-0.3 Gm. .Compound extract of colocynth B.P. Contains colocynth,aloes, scammony resin, curd soap and cardamon. 0,12-0.5 Gm.,Pill of colocynth and hyoscyamus B.P. Contains colocynth• • (12.S per cent), aloes (ZS per cent), scammony resin(25 per cent), dry extract of hyoscyamus (12.S per cent),curd soap, oj1 of c]ove and glucose solution. 0.25-0.S Gm.Phenophthalein U.S.P.; B. P. 0.06 Gm.ANTIDIARRHEAL AGENTSActivated charcoal U.S.P.Kaolin B.P. Native aluminum siJicate. 15-60 Gm. - Bentonite U.S.P. Native, colloidal, hydrated aluminum sili-• cale.Bentonite magma U.S.P. Contains 5 per cent bentonite.Bismuth subcarbonate U.S.P.; B.P. 1 Gm.M1SCELLANI:OUS AGENTS•Zinc sulfate U.S.P.; B.P. 0.65-2.0 Gm.Cupric sulfate U.S,P.; B.P. 0.3 Gm .•Alum U.S.P.; B.P. Either potassium aluminum sulfate orammonium aluminum sulfate. Astringent, 0.3-1 Gm.Emetic, 2-4 Gm.Black mustard U.S.P. Dried seeds of various species of1 brassica. 10 Gm. •Tpecac (uanha) U.S.P.; B.P. Dried rhizome and roots ofCepltaelis ipecacua/11,a or C. acumi11ata. Yields not less1 than 2 per • cent of \vater-soluble alkaloids of ipecac.0.5 Gm.f'••••L•230 Prugs Affecting the Gastro-Intestinal Tractr ,Ipecac fluid extract U.S.P.; JJ.P. _Contains approximately1 2 per cent ether-soluble alkaloids •of ipecac. 0.5 cc.Ipecac syrup U.S.P. Contains 7 per cent fluid extract ofipecac. En1etic, 8 cc. Expectorant, 1-Z cc. . ~Antimony potassium tartrate (tartar emetic) U.S.P.; B.P.Emetic, 30 mg. Expectorant, 3 mg. .Apomorphine hydrochloride U.S.~.; B.P. Emetic, 5 mg.Expectorant, 1 mg.Anise oil U.S.P. 0.2-0.3 cc.Caraway U.S.P.; B.P. 0.6-2 Gm.• Cardamom seed U.S.P. ;-B.P. 0.6-2 Gm. •Compound cardamom tincture U.S.P.; B.P. Contains carda•mom seed, cinnamon and caraway. 4 cc.Cinnamon U.S.P.; B.P. 0.3-1.2 Gm.Cinnamon oil U.S .P. .; B.P. 0.1 cc.Clove U.S.P.; B.P. 0.32-0.65 Gm.Ginger U.S.P.; B.P. 0,6 Gm.Ginger fluid extract U.S.P. 0.6 cc., Peppermint U.S.P.Peppermint oil U.S.P. 0.06-0.3 cc.•Compound gentian tincture U.S.P.; B.P. Contains gentian,bitter orange peel and car&amom seed. 4 cc.Tincture of nux vomica B.P. 0.~2 cc. _Diluted hydrochloric acid U.S.P.; B.P. Contains approxi•mateiy 10 per cent hydrochloric acid. 4 c~ (well diluted).Pancreatin U.S.P.; B.~. 0.5 Gm.BIBLIOGMPHY.ANTACIDSCollins E. N.: Use of aluminum hydroxide and othernonabsorb11.ble antacids in treatment of peptic ulcer,J.A,M.A. 127: 899, 1945. .Ehrtna.nn, R.: Drugs in tht: treatm_ent of peptic ulcer andhypersecretion, Am. J. Digest. Dis. 12: 154, 1945. .Kirsner, J. B., and R A. ~olff _: The ~e~ect of_ s_od1urnalkyl sulfate on the peptrc act1v1tyI\\(• BibJiography 231>tents and on the healing Qf gastric u]cer in man, Gastroenterology2: 93, 1944. •Nelson, E. E.: Gastric antacids, Internat. M. Digest 40:, 376, 1942.Steigmann, F., and A. R. Marks: Inhibition of pepticactivity in t11e treatment of peptic ulcer, Am. J. Digest.Dis. 11: 173, 1944.Tl1ornton, T. F., Jr., E. H. Storer and L. R: Dragstedt:Supradiaphragmatic section of the vagus nerves effecton gastric secretion and motility in patients with pepticulcer., J.A.M.A. 130: 764, 1946.CHOLERETICS •...., ,IIvy, A. C.: Cholecystagogues, choleretics and cholepoietics,Gastroenterology 3: 54, 1944.\ CATHARTICS-Bethea, 0. W.: The use of cathartics, J.A.M.A. 107: 1298,1936.-..F antus, B.: Useful Cathartics, Chicago, A. M. ~-, 1927.Gray, H., and M. L. Tainter: Colloid Jaxatives availablefor clinical use, Am. J. Digest. Dis. 8: 130, 1941.Micks, R. H.: Modern therapeutics. IX-the use andabuse of aperients, Practitioner 144: 285, 1940.l\iorgan, J. W.: The harmful effects of mineral oil (liquidpetrolatum) purgatives, J.A.M.A. 117: 1335, 1941.... Nelson, E. _E.: The treatment of constipation, Internat.l\'.I. Digest 42: 308, 1943. 'ANTIDIARRHEAL AGENTS1Iiller, G. E.: Bismuth subnitrate poisoning with methemoglobinemia,Gastroenterology 4: 430, 1945.Emery,.Jr., E.,S.: The use of adsorbents in gastro-intestinaldiseases, J.A.M.A. 108: 202, 1937. ~.' !\1.ISCELLANI:OUS l?REPARATIONS -. .....Bro, ..· n, C. L.: The use of expectorants J A M A 109 •268, 1937. ' • • • ' •Carlson,. A. J.,J . Van de Erve. J. H. Le,vis and S.J . Orr:Contr1but1ons to the physiology of1 the stomach; XVI.rl--••'232 • • Drugs Affecting the Gastro-Intestinal TractI rThe action of the so-called stomachics or bitters' on thehunger mechanism, J. Pharma col. & Exper. Therap.6: 209, 1914.Frankel, E.: Hydrochloric acid therapy in achlorhydria,Am. J. Digest. Dis.12: 15, 1945. _Ivy, A. C.: Internal Secretions of the Gastro-intestinal'tract-Glandular Physiology and Therapy, Chicago,A. M. A., 1942. ,Ivy, A. C.: The prevention of recurrence of "peptic" ulcer-an experimental study, Gastroenterology 3: 443, 1944.Van Liere, E. J., and D. W. Northup: The effect of carminativeson the emptying time of the normal human' stomach, J. Pharmacol. & Exper, Therap. 76: 39, 1942.INTRODUCTIONERGOT•POSTERIOR PITUITARY•19OxytocicsQUINlNE,}1.IISCELLANEOUS OXYTOCICSARBORTIPACIENTSPR.EPARATIONS \INTRODUCTION •\Oxytocics (ecbolics) are drugs used to initiate or enhanceuterine contractions. The most widely used drugs of this ,cl'a ss include the ergot alkaloids, posterior pituitary andquinine. In conservative obstetric practice, they are usedonly at the end of the third stage of labor and during thepuerperium to control postpartum bleeding and possiblyto hasten the involution of the uterus. On occasion, theymay be used to induce labor, if the spontaneous contrac•tions of the uterus appear ineffectual. Their routine use .,for initiating or hastening labor for the convenience of thephysician, however, is not without danger, since sustainedcontractions may result which may cause injury or deathto the fetus or rupture of the uterus with possible fatal• results to the mother.Oxytocics are occasionally used for the temporary reliefof excessive uterine bleeding in the nonpregnant patient orr to hasten or complete therapeutic abortions. In cesareansections, posterior pituitary extracts or ergonovine injectedinto the uterine musculature causes a shrinkage of the musculaturethat facilitates surgery and decreases bleeding.Oxytocics are rarely successful as abortifacients in earlypregnancy, though they are frequently used illegally forthis purpose.' 233'.. I'I,••234 • Oxytocics ',ERGOTErgo~ is a fungus, Claviceps pz,rpura, nrhlch infects variousgrains. The official (N.F.) source of ergot is the driedsclerotium of the fungus developed on rye plants. A numberof alk~loids have been isolated from ergot, all of which havelyserg1c acid as a basic nucleus. The most important ofthese a1ka1oids are the Ievorotatory compounds ergotoxine( 1906) , ergotam ine ( 1918), ergonovine ( 193 S) and ergosine( 1936) and their respective dextrorotatory isomers, ergotinine(1878), ergotamine (1920), ergometcinine (1935) andergosinine (1936). The Jevorotatory compounds havemarked pharmacologic activity while the dextrorotatorycompounds are relatively inert. Recent work by Stoll andhis associates indicates that ergotoxine is not a pure compoundbut a mixture of ergokryptine, ergocornine and ergocristinein varying amounts.The ergot alkaloids have the common property of stimu.lating smooth muscle directJy. Ergotoxine and ergotaminealso have a sympatbolytic effect when used in large doses.This action is limited to excit.atory effects of sympathinor epinephrine.For many years, it was believed that all the oxytoclcactivity of ergot was vested in the water-insolublea lk.aioids,ergotoxine and ergotamine. However, in 1932, 1\Ioir showedthat aqueous extracts of ergot had a definite uterus-stimu ..lating effect when given by meuth, and by 1935 four labora ..tories working independently succeeded in isolating fromsuch extracts an alkaloid known officially in the UnitedStates as ergonovine, and in Britain as ergotnetrine. Ergota ..mine and ergotoxine have very similar pharmacologic andtoxicologic properties, though the latter has had little clinicaluse since it appears to be a somewhat more toxic and a,. Jess reli~bJe 1zterine stimulants. Ergotamine is usually givenby intramuscular injection sin~ it is erratica!Jy abso~bedwhen given by mouth. Erg~novme ~as _fewer sid_e -r_eact1onsthan ergotamine or ergotoxme and 1t 1s nontoxic 1n doses•, • '••J - IErgot\ 235far exceeding those of its therapeutic use. In contrast to,ergotamine, ergonovine in therapeu/tic doses does not causean elevation of the blood pressure. It can be given bymouth, intramuscularly or intravenously. It has a promptoxytocic effect even when given by mouth in contrast with ,, ,that of ergotamine, whose onset of action is too slow foruse • • 1n emergencies. .Some authorities question the advisability of giving oxy- 'tocics before the placenta is delivered in case hourglasscontractions are produced, necessitating manual removal ofthe placenta and increasing the danger of puerperal, fever. ,In hospital practice, however, the danger of such complicationsis minimal and it is customary in the Chicago LyipginHospital to inject 0.2 mg. of ergonovine intravenously assoon as the head is delivered. A prompt contraction of theuterus follows, which assists in the separation and deliveryof the placenta, reducing the duration of the third stage oflabor and decreasing the blood loss by as much as 7 5 percent. The effect of this dose will last f ram 4 to 6 hours,following which postpartum bleeding can be controlled withfurther doses of ergonovine, ergotamine or liquid extractof ergot. Use of ergot preparations in the puerperium isalso said to hasten involution of the uterus, reduce lochia]secretions and limit the spread of uterine infections, thoughl\Ioir, in a recent review, has questioned the efficacy of thedrug in these respects.Recently, Stoll and his associates have synthetized alysergic-acid derivative, methergine. Like ergonovine, meth- •ergine bas an oxytocic effect but little or no sympatholyticeffect. This compound is of interest because of the possi- .bility of replacing the _limited supply of ergonovine by asynthetic substitute. '•Use of Ergotamine in Migraine. Ergotamine tartrate(gynergen) usually provides prompt relief in many casesof migraine. It has been suggested that the pain of mi. 'graine is associated either with spasm or with dilation of- • ,•\-I.I236 Oxytocics \ I\the vessels of the scalp and the dura mater and that ergot•amine gives relief in the latter instance by producingvasoconstriction. Ergonovine is much less effectiv.e.i. n.. thisrespect. A new compound, dihydroergotamine (DJI.E. 45),• formed ,by the hydrogenation of ergotamine, has recentlybeen reported to be as -effective as ergotamine in the treatmentof migraine. It has little or no uterus-stimulatingactivity and is much less toxic than ergotamine.Ergot Poisoning. Ergot poisoning (ergotism) may resultfrom the injudicious clinical use of ergot preparations orfrom the ingestion of ergot-infested rye. Epidemics of ergotjsmfrom the latter cause were formerly quite common,especially in European countries. Two types of chronicergotism are differentiated, the gangrenous type and tbespasmodic convulsive type. The gangrenous type, whichis due to vascular spasm, is characterized by severe painand cyanosis in the extremities, which may be followedby dry gangrene. In the l\Iiddle Ages this type of poisoningwas known as the "fire of St. Anthony" or "holy fire." Inthe convulsive type of ergotism, twitchings and epileptif ormconvulsions occur, frequently followed by delirium, blind•ness, deafness, paralysis and insanity. Since this type ofpoisoning is not observed in communities in which thediet is rich in diary products, it has been suggested thatit is associated with a vitamin A deficiency.Ergot preparations should be used cautiously, especiallyif repeated administration is necessary, because of the dangerof causing gangrene. The treatment, should this occur,is not very satisfactory though it has been claimed thatrelief may be afforded by the vascular antispasmodic actionof papaverine. Ergonovine is apparently free from thegangrene-producing action of ergotamine a.r:d ergotoxine.Standardization of Ergot Crude ergot preparations areassayed either by biologic or chemical procedures. Thechemical methods in general ten~ to ~ive valu:s that are,too high because of the fact that inactive alkaloids may be• ''Ergot 237'carried along in the extraction process. The most commonlyused method for the bioassay of ergot compares the abilityof the unknown preparation to cause darkening of the cock's. comb with that of a solution of ergotoxine ethanesulfonate.All the pharmacologically active alkaloids are measured bythis method. The Clark-Broom method is based on the , Iantagonism of the stimulant effect of epinephrine on theisolated rabbit uterus. This method determines only alkaloidswith a sympatholytic effect, such as ergotoxine andergotamine, and is therefore not applicable to ergonovine.POSTERIOR PITUITARY...The value of posterior-pituitary extracts in obstetrics\Vas first demonstrated by Blair Bell in--1909 and by Hofbauerin 1911, following the discovery by Dale in 1906 ofthe direct stimulating action of posterior-pituitary extractson the isolated uterus. In 1928, Kamm and his associateswere able to separate an oxytocic fraction (pitocin) and~presser fraction (pitressin) from posterior-pituitary ex.tracts(pituitrin) (see Chapter 21). -~There is much experimental evidence to indicate that theresponse.. of uterine smooth muscle to posterior pituitaryand its various fractions 1depends upon the species ofanimals, the phase of the menstrual or estrus cycle,whether the uterus is gravid or nongravid, the stage ofpregnancy and whether observations are made on the uterusin situ or on strips of uterine muscle suspended in a salineb~th. In brief, the nonpregnant human uterus in situ respondsto posterior-pituitary extracts, and especially to thepressor fraction, at all stages of the menstrual cycle, theresponse being son1ewhat exaggerated just before and duringmenstruatio,,n. In early pregnancy the uterus is comparativelyunreactive to posterior pituitary and to theseparate principles. In late pregnancy and during parturi- •tion and the early puerperium, the uterus is very sensitiveto the oxytocic fraction of the pituitary extracts, becoming -•,'• 238 Oxytocics \Increasingly less responsive as the puerperium progresses,though its reactivity can be prolonged or restored if adequatedoses of estrogens are given. ,Pitressin is much more effective than pitocin in elic'itingcontractions in isolated strips of the pregnant and thenonpregnant human uterus. Pitocin, however, contracts theisolated virgin guinea-pig uterus while any action of pitressinin this respect is due to the presence of the contaminatingoxytocic fraction, neither fraction being as yet completelyseparated from the other. The specific action ofthe oxytocic hormone on the isolated virgin guinea-pjguterus forms the basis of the official method for the bioassayof posterior.pituitary extracts.In the normal parturient patient, posterior pituitary or itspressor fraction in therapeutic doses Hoes not produce anyapprecl,able effect on the blood pressure. In the patient witheclampsia or pre-eclampsia, however, there is a marked risein blood pressure and a decrease in urine volume, condi•tions which might predispose to an eclamptic attack. Be-causeof this and because the pressor fraction appears moreprone to cause posterior•pituitary "shock," the use of theoxytocjc fraction is to be preferred in obstetrics to the useof pitressin, or to pituitary extract containing approximatelyequal amounts of both the presser and oxytocic--fractions.Posterior•pituitary preparations are usually given intramuscularly.In emergencies when a prompt effect is desiredthey can be given intravenously, but a single dose shouldnot exceed 0.2 units.A clinical disadvantage of posterior pituitary is theevanescence of its oxytocic action, which usually does not ..last for more than 10 rninutes. Various attempts have been ,made to delay the absorption of posterior pituitary and thusprolong its effect. Hofbauer introduced the application ofthe drug to the nasal mucosa but the absorption is difficultto control and overdoses may ensue. Pitocin tannate in oil,pituitary and thymus•gland combinations (thymophysin and :••\ '. . - Posterior P1tu1tary 239thytuitary) and solution of posterior-pituitary sulfonate(pitsulfonate) have all had clinical trials# The first two' preparations are probably without virtue. While the clinicalreports on pitsulfonate are not extensive, it does appearto have an increased duration of action and is less likelyto cause tetanic contractions than ordinary pituitary extracts.,\ QUININEQuinine, especially in combination with castor oil, baslong been popular for the induction of labor. Its oxytociceffect is unreliable and probably only in about half ofthe cases does it actually stimulate uterine contractions.Furthermore, quinine may pass through the placental 1barrier and cause toxic effects in the fetus; cases of death,blindness or deafness have been reported. Occasionally, too,the mother may have an idiosyncracy to quinine or displayevidences of cinchonism. Danger of toxic symptom.s is minimizedif the dose is limited to 0.6 Gm. and restricted topatients at or beyond term. l\1ore effective contractions maybe obtained by following the quinine with small doses ofposterior pituitary.- l\!IISCELLANEOUS OXYTOCICS•There is some evidence that estrogens increase the motilityof the uterine musculature. Clinical results are notvery encouraging, probably because the effect is slow, nochanges being evident for 24 hours or more. There is someevidence that the preliminary administration of estrogenssensitizes the ut~rus to ergot or pituitary, causing them tobe more effective in producing therapeutic abortions earlyin pregnancy when the uterus is normally refractory tothese drugs.Calcium bas been shown to be essential for uterine con,tractions, and the administration of calcium preparationseither alone or with an oxytocic, has been reported as bein~,• ••240 Oxytocics' successful in the stimulation of1 the uterus in primary inertia.• . '~There bas been cons1derab]e djff erence of opinion withregard to the action of epinephrine on the uterus, Certainlyvar1• at1• ons •1 n response occur, depending on the specieso fthe animal studied, the presence or absence of pregnancyand the experimental technics employed. Because theearlier work suggested that epinephrine abolished the spontaneouscontractions of the uterus, the drug has been usedclinically for the treatment or contraction rings duringpregnancy. More recent work, however, indicates that epi• •nephrine is probably of little or no value in such condi•tions; any apparent muscular relaxation being fo 11owedbyincreased motor activity. Furthermore, undesirable sideeffects from epinephrine may contribute to the patient'saZready weakened condition. Recently, there have been re•ports in the German literature of a new oxytocic "varon,"obtained by methylating the two phenolic-OH groups ofepinephrine. This drug is claimed to liave an oxytocic effectbut little or no pressor action.ABORTIFACIENTSA wide variety of drugs have been used to bring onabortions. Usually employed by the laity, these drugs are,generally speaking, neither safe nor efficacious. The simplestof such drugs allegedly act by pelvic congestion andinclude the drastic purgatives and uterine stimulants. Particularlydangerous are the proprietary abortifacient pastessuch as 1'utra.-je1," 11interruptin," "provocol" and ''anti•gravid," which act by killing the fetus. They consist principallyof soft soap and are deposited in the uterus bymeans of a special appJjcator. They may produce localeffects such as inflammation, necrosis or prolonged bleedingas well as systemic effects including embolism, hemoJy.sis (ll~ generalized septicemia. ,,'Preparations 241'' ( PREPARATIONSPrepared ergot B.P. Powdered and defatted ergot. 0.3-1Gm •.Liquid extract of ergot JJ.P. When fres12Jyp reparetJ, tJJlscontains· not less than 0.06% of total ergot alkaloids,calculated as ergotoxine. 0.6-J.2 cc. .Ergotamine tartrate U.S.P. O.S mg. by injection; 1 mg.orally . 'Ergotamine-tartrate tablets U.S.P. Usually O.S and 1 mg.tablets. 'Ergotoxine ethanesulfonate B.P .. 0.5-1 mg.Ergonovine maleafe U.S.P. Ergometrine B.P. 0.1--0.S mg.\' Ergonovine-maleate tablets U.S.P. Usually 0.2 and O.S mg. ,tablets. 'Ergonovine maleate injection U.S.P. Usually 0.2 mg. orI0.5 mg. in 1 cc. , - 1 •P..o. sterior-pituitary injection U.S.P.; B.P. Contains 1 unitper 0.1 cc. 0.2-1 cc.Ampuls pjtocin N.N.R. 1 cc. contains 10 oxytocic units.0.3-1.0 cc.Ampuls pitressin N.N.R. 1 cc. contains 20 pressor units.0.3-1,0 cc.Pitressin tannate in oil N.N.R. 1 cc. contains S pressorunits. 0.3-1.0 cc.Quinine hydrochloride U.S.P.; B.P. Quinine sulfate U.S.P.;B.P. 0.12--0.6 Gm.\IBIBLIOGRAPHYGENERALDavis, ?\I. E.: Post-partum hemorrhage Am. J. Surg.48: 154, 1940. ' ;Davis, ·lI. E., F. L. Adair and S. Pearl: The,prcsent'!tj~s , of oxytocics in obstetrics, J.A.1-1.A. 107: 261,Eastmil_?, N. J.: The induction of labor, Am. J. Obst. &Gynec, 35:721, 1938. ·•242 OxytocicsMoir, C.: Oxytocic drugs and their use, J. Obst. &Gynaec. 51: 247, 1944.Reynolds, S. R. M.: Physiology of the Uterus, Neiv York,Hoeber, 1939. 'ERGOT 'Barger, G. : Ergot and Ergotism, London, Gurney andJackson, 1931.Hartman, M. M.: Parenteral use of dihydroergotamine inmigraine, Ann. Allergy 3: 440, 1945.Lennox, W. G.: The use of ergotamine tartrate in migraine,New England J. 11ed. 210: 1061, 1934.Moir, C.: The action of ergot preparations on the puerperaluterus-a clinical investigation ,vith special referenceto an active constituent of ergot as yet unidentified,Brit. M. J. 1: 1119, 1932.lvioir, C., and C. S. Russell: An investigation of theeffect of ergot alkaloids in promotjng involution of thepostpartum uterus, J. Obst. & Gynaec. 50:94, 1943.Nelson, E. E., and H. 0. Calvery: Present status of theergot question, Physiol. Rev. 18: '297, 1939.Velkoff, A. S., and A. D. Ferguson: Bilateral dry gan•grene of both lo,ver extremities due to ergot, Am. J.Obst. & Gynec. 44: 331, 1942.White, A. C.: A comparison of some oI the ergot alkaloids;III. General pharmacology, Quart. J. Pharm. &PharmacoJ. 17: 95, 1944.POS'IEIUOR PITUITARY •De Lee, J. B.: The use of soJution of posterior pituitaryin modern obstetrics, J.A.M.A. 115: 1320, 1940.Moir C.: The effect o( posterior lobe pituitary gland fractionson the intact human uterus. J. Obst. & Gynaec.51: 181, 1944., Sullivan, C. L., and R. J. Heffernan: Convulsions followingthe intravenous administration of pituitary ex•' tract, Am. ]. Obst. & Gynec. 44: 675, 1942. ~-l\,frSCEI.I.ANEOUSBroiv11 W. E., and V. M. Wilder: The response of theh11,n~n uterus to epinephrine, Am. J. Obst. & Gynec.4$ :-659, '1943. \•IBibliography•243Hart, B. F., and V. Noble: Calcium and quinine in laborand post partum hemorrhage, Am. J. Obst. & Gynec.45 : 692, 1943.Murphy, D. P.: The effect of estrogenic substance uponuterine motility during labor-a study of 42 patients,vith the Lorand Tocograph, Surg., Gynec. & Obst. 77:433, 1943.Woodbury, R. A., and B. E. Abreu: Influence of epineph•rine upon the human gravid uterus, Am. J. Obst. &Gynec. 48 : 706, 1944.MIORTIFACIE?-i'ISLe,vin, L.: Die Fruchtabtreibung durch Gifte und andere,Mittel (ein Handbuch fiir Arzte, Juristen, Politiker,N ationalokonomen), Berlin, Stilke (publisher), 1925.Straus, R., and N. de Nosaquo: Effects of an abortifacientpaste (''utra-jel") report of a death from its use andof an experimental study of its effects on rabbits andrats, Arch. Path. 39: 91, 1945. •Weilerstein, R. W.: Intrauterine pastes, J.A.M.A. 125:205, 1944.II••20EndocrinsAN'.I'ERIOR-Pl'.I'UITARHYO Rl!ONESGON ADOTROPI.NSSEX lIORMON~SANDROGENSGSI'ROGENSPROGESTINS IAD.RENAL CORTEXPREPARATIONS -Endocrins (hormones} are autopharmacologic substancesnormally elaborated by the endocrine or ductless glands.Use of glandular preparations is largely restricted to substitutionor replacement therapy occasioned by surgicalinterference, congenital deficiency or disease. In some cases,only crude extracts are available. In others, the activeprinciples have been isolated as chemical entities, whileepinephrine, thyroxin, the sex hormones and a numberof the adcenal-cortica1 steroids can be prepared synthetically.In addition, a number of synthetic preparations areavailable which are not identical with the natural hormonesbut which resemble them in some or all of their pha,rmacologicactivities. Such compounds include the sympa•thomimetic amines ( chap. 11) ; a variety of compoundshaving an activity simulating that of the sex hormones; andprobably also desoxycorticosterone, which produces severalof the physiologic effects of adrenal-cortex extracts.Endocrins of known cl:Jemical constitution, such as thy·roxin, epinephrine and the sex hormones, can be assayedby chemical methods. In general, however, hormones arenot assayed by such procedures either because their com•position is not established or because they are present insuch minute quantities that physical or chemical identifica•244I• Endocrins ' ----------------------· \tion is not possible. In such cases, biologic assay is necessary.International or United States Ph{;U"macopoeialstandard preparations are available for most of the hormones,the strength of the endocrine preparations beingusually expressed in terms of units of activity.Endocrine preparations, with the exception of the thyroidand some of the steroid hormones, are ineffective by mouthbecause of their rapid destruction by the digestive juices _or by the liver. The action of most hormones is slow inonset and is sustained over some period of time. Notableexceptions are epinephrine and posterior-pituitary extracts,which elicit prompt, short-acting effects . ..,In recent years, drugs having an antagonistic action towardsendocrine glands have attracted considerable experimentaland clinical attention. Alloxan has a selective toxicaction on the beta cells of the islet tissue of the pancreasleading to a permanent diabetes mellitus. Thiourea andrelated drugs interfere with the formation of the thyroidhormone and lead to a depression of basal metabolism innormal or hyperthyroid subjects. The relationship betweenthe hormones themselves is a matter of considerable practicaland theoretical importance. Thus, small doses of crudeanterior lobe extracts stimulate the production of insulin(pancreatropic effect) while large doses cause degenerativechanges in the islet cells leading to diabetes ( diabetogeniceffect). In addition, certain drugs may stimulate the for ..mation or release of endocrins. Recent evidence suggeststhat yohimbine stimulates the anterior lobe of the pituitarygland, while the antidiuretic effect of a number of drugshas been.thought to be mediated indirectly through an increasedoutput of the antidiuretic hormone of the neurallobe. ~ANTERIOR-PITUITARY HORl\IO.NESAnterior-lobe preparations have fe,v therapeutic applicationsor uses at the present time despite the important\246• Endocrins,physiologic role of this gland. Clinical use is limited bythe lack of suitably potent preparations and by the hazardsof undesirable side effects. These undesirable effects mayresult not only through the action of contaminating principlesin impure preparations, but also from the peculiarreciprocal relationships between the pituitary and the otherglands, and by the development of allergic phenomena andantibody formation due to the protein nature of theanterior-pituitary principles.A number of active principles have been isolated in ahigh degree of purity from the anterior pituitary. Theseinclude the growth, thyrotropic, adrenocorticotropic andgonadotropic substances. Growth hormone preparationshave had some use in the treatment of dwarfism, but sincethey have usually been used in conjunction with other drugs,such as thyroid extract, it is difficult to assess their realvalue. The t!zyrotropic principle will relieve the symptomsof hypothyroidism of pituitary origin; however, it is ofdiagnostic interest only since such conditions respond readilyto thyroid medication. The lactogenic hormone, prolactin,has been isolated in crystalline form. It stimulates thesecretion of milk after the mammary glands have been suitablyprepared by the sex hormones and has been used clinicallyfor this purpose. Though its efficacy is questionable,its use has been reportedly attended with little or no unde•sirable effects. No anterior-lobe preparations have beenaccepted for inclusion in the U.S.P. or N.N.R. The N.F.contains whole pituitary, which must be given by mouthand is therefore almost certainly without effect.Standardization of Anterior-Pituitary Preparations:International Standard preparations have been established •for the thyrotropic and lactogenic hormones. One unit ofthyrotropic activity is present in 0.2S mg. of the standard.Several assay methods are used which are based on thestimulation of the thyroid of the .immature or hypophysec•tomized animal. One unit of Jactogenic activity is present\Anterior-Pituitary Hormones 247' I •in 0.1 mg. of the prolactin standard. The usual assay procedurefor prolactin is based on stimulation of the cropgland in pigeons.GONADOTROPINS \, Gonadotropins are substances which stimulate the gonadsand indirectly affect the secondary sex organs by increasingthe output of the sex hormones. Sources of gonadotropinsinclude the pituitary gland, human pregnancy urine, menopausalurine, and the serum of pregnant mares. Gonadotropicsubstances are also found in the urine of patientswith chorionepithelioma and bydatidiform mole. None ofthe gonadotropins have been identified chemica!ly thoughthey are believed to be protein in nature.The pituitary is thought to elaborate at least two gonadotropicsubstances: the follicle-stiniulating ltormone (FSH),whose gametogenic activity stimulates the development ofthe ovarian follicles and the seminiferous tubules, and theluteinizi,tg hor1no1ie (LH), whose interstitial-cell stimulatingeffect leads to the formation of the corpus luteum andthe secretion of the male sex hormone. At present, therapywith pituitary gonadotropins is still in the experimentalstage because of the difficulties of obtaining sufficient quan•tities of the purified preparations and the uncertainties con•terning the true nature of the defects in patients treatedwith such preparations.The gonadotropic substance in human pregnancy urineis believed to be elaborated by the chorion and is known asclzorionicg onadotropin.I t is demonstrable in the urine soonafter implantation of the egg. It differs from pituitarygonadotropin in that it has little or no follicle-stimulatingeffect on the Qvaries of primates and in fact may even causedegenerative changes. It does, however, stimulate the testisand its chief clinical use is ip rases of cryptorchidism inwhich nondescent of the testis is not due to a mechanicalobstruction. \Vhile there have been reports on the success£ ul248 Endocrinsuse of chorionic gonadotropin in ovarian hypofunction andmenstrual disorders, there is little evidence to support theuse of the preparation in gynecologic practice. The combineduse of pituitary and chorionic gonadotropins is saidto induce a synergistic stimulatory action onth e ovariesbut reports on the clinical efficacy of such a combinationare conflicting. 1In species below primates, chorionic gonadotropin basa stimulatory action on the ovaries. This action forms thebasis of the Aschheim-Zondek and the Friedman tests forpregnancy. In the Aschheim-Zondek test, urine is injectedinto mice on three successive days. The animals are thenkilled and the ovaries examined. The presence of blood·filled follicles or corpora Iutea indicates that the subjectfrom whom the urine was obtained is pregnant. The Friedmantest uses rabbits. The urjne extract is injected into theear vein and 24 hours later the ovaries are examined bycJaparotomy.The presence of ovulated or hemorrhagic /olliclesis indicative of pregnancy. Positive responses will begiven in these tests in other conditions in which chorionicgonadotropin is excreted, such as chorionepithelioma.Equine gonadotropin obtained from the serum of preg~nant mares has both follicle-stimulating and lutei9izing ac•tivity, though whether these two effects are vested i11 thesame or in separate principles is still undecided. Equinegonadotropin bas been prepared in a high degree of purity.It has a prolonged action since it is metabolized very slowlyin the human body and is not excreted by the kidney. \Vhileexperimental findings would indicate its usefulness as atherapeutic agent in hypo-ovarianism, clinical trials have,for the most part, been disappointing. Hamblen and hisco-workers believe that more promising results are obtained'' with a cyclic form of treatment in which equine gonadotropinis given during the first ha_If of the me;1st~ual cycleto cause follicle growth and ovulation and chor1on1c gonadotropinif: given during the second half to promote Iuteinization.I• Gonadotropins 249Standardization of Gonadotropins. International Stand- , .ard preparations are available for the assay of both chor1-onic and equine gonadotropins; 0.1 mg. of the InternationalStandard of chorionic gonatlotropin and 0.2 5 mg. of theInternational Standard of equine gonadotropin contain oneunit of chorionic and equine gonadotropin respectively.Assay procedures may be based either on direct morphologicchanges in the gonads or on secondary changes in theaccessory sex organs provided it can be shown that thesechanges are not directly caused by c.ontaminating sub- .stances. This can be done by means of control experimentswith castrated animals .• SEX HORMONESThe sex hormones can be classified into three groups,a1zdroge11ess,t roge,tsa nd progestins, which are remarkably• similar in chemical structure but divergent in biologicactivity. \Vhile androgens are, for the most part, elaboratedin the testis and estrogens and progestins in the ovary, thevarious types are by no means peculiar to one sex only.Furthermore, these substances are produced not only bythe gonads but also by the adrenal, placenta and .possiblyelsewhere in the body.The naturally occurring sex hormones are relativelyinactive by mouth. A number of synthetic substances possessingandrogenic. estrogenic or progestational activityhave been developed which are active by mouth. Suchpreparations are less rapidly destroyed by the liver thanthe naturally occurring sex hormones.ANDROGENSAndrogens are substances possessing masculinizing activity,vhicl1 leads to the development and maintenance ofsecond.i.ry sex characteristics in the male. The naturallyoccurring an<lrogens include testosterone, first isolated frombull testicles jn 1934 and now prepared synthetically, and250Naturcflyoccurring-EndocrinsH 011androgens o= /)NaturallyoccurrfngestrogensTestosterone Androsterone OehydroandrosteroneOHOHOHHOEstradiolDiethylstilbestrol ,,, Hexestrol Benzestrol ~- SyntheticestrogensNaturallyoccurringprogesteronesSyntheticprogesterooesHI<~~ C =C C--~ ~HO ITri ph enylethyl ene Ethi nyl es trad1olHOProgesterone Pregnanediol0(Inactive urinary excretionproduct of pro gesferone)O=Preg nen f no lone(Eth inyl testosterone)o b -= STRUCTURAL 'FORMULAS OF THE SEX HORMONES'Sex Hormones 2S1the less active androsterone and dehydroandro:sterone.These latter are found in the urine and may be of adrenalcorticalorigin.Androgens are used mainly for replacement therapy incastration and eunuchoidism. A prolonged effect may beobtained by parenteral administration of testosterone propionatein oil. l\fethyltestosterone is effective by mouth butlarge doses are required. Testosterone itself can also beused in the form of subcutaneously implanted pellets or asan ointment. Continued dosage of and.rogenic preparationsleads to a restoration 0£ secondary sex characteristics, suchas gro,vth and distribution of hair, pitch of voice and growthof external genitalia, and to a general improvement in thewell~being of the patient. Androgen therapy does not restoreimpaired testicular function; on the contrary, further depressionmay occur due to a suppressive action on thegonadotropic hormones of the anterior pituitary. Its use is,therefore, questionable in cases of delayed maturity inwhich normal physiologic function might be ultimatelyestablished; in such cases, stimulation with gonadotropicpreparations should be first tried.Androgen therapy has been recommended for a varietyof disorders in women, such as dysmenorrhea, functionaluterine bleeding and menopausal symptoms. Its value inthese conditions is questionable in view of its masculinizingilction, ,vhich may lead to hirsutism and alterations in thepitch of the voice. ...Standardization of Androgens. The international unitof androgenic activity is the activity contained in 0.1 mg.of the International Standard preparation of androsterone.Androgen preparations are assayed biologically by compar•ing their gro,vth•promoling action on the capon's comb ,viththat of the standard.ESTROGENSEstrogens 3re substances which,i..- ~ , __ !_ .in addition to their•252 Endocrins 'distributed in nature and have been obtained from both, plant and animal sources; The most important of the naturallyoccurring estrogens are the f o11icu1ahro rmonesw hichdevelop and maintain the secondary~s ex characteristicsi nthe female. The main physiologic source of these hormonesis the ovary; during pregnancy, however, the placenta prob•ably assumes the chief burden of secretion. Commercially,' the main source of natural estrogens is the urine of preg•nant mares.Estrogens are normally inactivated by the liveri probablyby conjugation. Liver damage or inanition retards thisinactivation, and may lead to manifestations of excessiveestrogen activity. The tolerance for estrogens is greatlyincreased during pregnancy, at which time as much as 1,000times the ordinary dose has been given without untowardeffects.Natural Estrogens. Three natural estrogens are availablein crystalline form for therapeutic use: estradiol, obtainedfrom ovaries and pregnancy urine; estriol, obtainedfrom placental tissue and pregnancy urine; and estrone,obtained from the urine of pregnant mares. Preparationsof highly purified noncrystaJJine estrogens from pregnanthuman or pregnant mare urine are also available. Theactivity of these preparations, known as solutions of estro·.gens, is almost entirely due to estrone.Synthetic Estrogens. In addition to the natural estrogens,a number o{ synthetic products with qualitativelysimilar biologic effects have been introduced for clinicaluse. These preparations have the advantages of cheapnessand of being active by mouth, probably because they areless rapidly metabolized by the liver than the natural estrogens.For the same reason, they are more toxic than thenatural estrogens. Their toxicity is not of great clinicalimportance since untoward reactions, chiefly gastro-intestinalupsets, are minimal in therapeutic doses.'•Sex Hormones , 253,The introduction of synthetic estrogens was the outcomeof a series of investigations undertaken in 1933 by Doddsand his co-workers who were the first to demonstrate thatestrogenic activity' was not confined to substances with asterol nucleus. Of the several hundred substances shown topossess estrogenic activity, only-"a few have found clinicaluse. These include diethylstilbestrol, hexestrol, benzestrol( octofollin) and triphenylethylene. Another compound,vhich should perhaps be classified as a synthetic estrogenis ethinylestradiol, a modified natural sex hormone. It isprobably the most active estrogen known; it is effective bymouth, although its metabolism by the liver is apparentlyas rapid as that of free estradiol. The activity of triphenylethyleneand related compounds is actually enhanced bypassage through the liver suggesting their breakdown intomore potent compounds.Biologic Effects. Biologic' effects of estrogen includehyperplasia of the vaginal epithelium with cornificationof the superficial layers; proliferation of the myometriumand endometrium; increase in weight and blood supply ofthe uterus; growth of the mammary gland and suppr~_sionof the secretion of pituitary gonadotropin.Therapeutic Uses. Clinically, estrogens are used asreplacement therapy in primary disorders of, defects in orinsufficiency of ovarian function, for the relief of vasomotorand nervous disturbances of natural or surgical menopause,and for the relief of senile or menopausal vaginitis. Beforethe introduction of sulfonamides, the estrogens found wideuse in the treatment of gonorrheal vaginitis in children sincethey produce a. cornifi.ed epithelium and an acid reactionin the vagina unsuitable for the gro,vth of bacteria. Estrogenshave been used for the suppression of lactation, theiraction possibly being due to a reduction of the secretiono( the lactogenic hormone by the anterior pituitary.In 1941, Huggins showed that carcinoma of the prostatecould be at least temnorariJv :ttTM.t~rl l,\1 r~c:t.-~ tinn T n•254 •Endocrinscas~s in which surgical castration is impractical, physioIog1ccastration with estrogens by virtue of an inhibitoryeffect on the pituitary gonadotropins has been reported togive promising results. Estrogen therapy also relieves post•castration symptoms in the male, which frequently resemblethose of the menopause.Estrogens as Carcinogenic Substances. Large doses ofestrogens have been shown to increase the incidence of can-• cer 10 susceptible strains of animals, \Vhile cancer of theprostate is apparently greatly stimulated by the male sexhormone. \Vhile the causal relationship between cancer and' the sex hormones in humans has not been established, manyinvestigators feel that prolonged use of these substancesis contraindicated in persons suffering from cancer or whohave a familial history of cancer. For this reason alone,the indiscriminate use of proprietary cosmetics containingestrogens may lead to serious consequences and is certainlyun,varranted.Standardization of Estrogens. International Standardpreparations of estrone and estradiol monobenzoate areavailable, each containing one unit of activity in 0.1 micro·grams. It is not feasible to assay against a standard anyestrogen other than that of which the standard is composedbecause of differences in rates of penetration and of metab·olism of the various estrogens. The chief assay methods arethe examination of vaginal smears in rats and mice and the,veight increase of tl1e uterus of castrated rats.PROCESTINSProgestins are substances producing progestationalchanges in the uterus which are suitable for implantationof the ovum and for maintenance and development of theembryo. Progesterane is a naturally occurring progestin.It is elaborated by the corpus Iuteum during the secondhalf of tbe menstrual cycle and also, during gestation,by the pl.!!centa. The adrenals and probably also the testis•Sex Hormones 255•are other sour~es .. of this hormone. It is quite similar chemicallyand to a certain extent biologically to the hormonesof the testis and adrenal cortex. It is apparently metabolizedto pregnandiol, a physiologically inert product whichis excreted in the urine and which is believed to be an indexof corpus luteum activity. Commercial preparations are forthe most part prepared synthetically from stigmasterol.Progesterone is inactive by mouth and is .usually administeredintramuscularly in oil. A synthetic progestin, pregneninolone(ethinyltestosterone) is active by mouth, but dosesfrom five to ten times the parenteral dose of progesteroneare required.Data concerning the clinical value of progesterone therapyare still inconclusive. Its use appears to be warranted incases of habitual or threatened abortion in early pregnancy' when corpus luteum insufficiency is suspected. It bas alsobeen used in cases of dysmenorrhea because of its allegedquieting action on the uterine musculature and in cases offunctional bleeding resulting from overactivity of estrogensin the absence of corpus luteum activity.Standardization of Progestins. The International Standardpreparation of progesterone contains one unit of activityin 1.0 mg. The assay procedure is based on progestationalchanges in the uterus of the immature or ovariectomizedrabbit.0ADRENAL CORTEX011;c--C-c.Hzc.iCorticostuone Deso%) corticostcrone,\t least thirty steroids have been isolated from the adrenalcortex, manf of which have no apparent biologic activity.'I-•f256 Endocrins-Among the physiologically active compounds are the corti.costerone and the desoxycorticosterone groups of com•pounds and the sex hormones. In addition, the amorphous~ fraction remaining after the known steroid hormones have ,been extracted will prolong the Jife of adrenalectomizedanimals, indicating the presence of further unidentifiedprinciples.The main use of adrenal-cortical extracts is in the treat•rnent of Addison's disease and other adrenal Insufficiencies.In such conditions, sodium chloride and water are rapidlylost by the body, ,vhile potassium is retained. These changesin electrolyte balance lead to debydrationJ reduction ofblood-plasma volume and bemoconcentration. In addjtion,there are serious disturbances in carbohydrate metabolism.Absorption of glucose from the gastro~intestinal tr..act isimpaired, glucose metabolism is increased and glycogenstores become depleted. Symptoms include weakness andfatigability, loss of weight and increased pigmentation ofthe skin.l\1ild cases of adrenal insufficiency can be controlled bythe administration of sodium chloride. l\iore severe casesrequire supplemental treatment with adrenal-cortical extractsor with the synthetic preparation, desoxycorticosterone,which is available as the acetate. Adrenal-corticalextracts are usually prepared from fresh beef adrenals andvary greatly in their activity. Desoxycocticosteconeh as theadvantage of being less expensive and more easily standardized.It has, however, little or no effect on the carbohydratemetabolism, which is apparently controJied by the corticosteronegroup of hormones. Furthermore, it may lead to a• dangerous retention of water, which may result in byperten~sion, cardiac damage or edema of the lungs and other tissues.Adrenal•cortical extracts are active by mouth, but theireffects by this route are unpredictable and Jarge amountsare required so that they are usually administered by intra ..muscular, subcutaneous or occasionally by intravenous in ..•'••Adrenal Cortex 257jection. Desoxycorticosterone' is ,not active by ·mouth. Itcan be implanted in the form of pellets to give a prolonged'effect. A 12S mg. pellet of desoxycorticosterone acetate may ~satisfactorily control the symptoms of adrenal insufficiencyfor a year or more; patients require supplementary inj~ctionsof adrenal-cortical extracts in cases of emergenoessuch as those induced by intercurrent infections. Furtherimprovements in the treatment of adrenal insufficiency canbe expected with the introduction of synthetic corticosterone-like compounds, capable of improving the carbohydratemetabolism and muscular efficiency. ,Assay 0£ Adrenal-Cortical Preparations. Adrenal-corti- •cal preparations are assayed on adrenalectomized animals., No official standard is available as yet. Potency is frequentlyexpressed in terms of the dog unit, which is defined ,as the minimurn. daily dose per kilogram of body ,veightnecessary to maintain a dog for a period of from 7 to 10 dayswithout loss of body weight and elevation of nonproteinnitrogen level in the blood.PREPARATIONSChorionic gonadotropins N.N.R. 200-500 units.Testosterone propionate U.S.P. 25 mg. intramuscular.I\Icthyltestosterone U.S.P. 5-10 mg. oral or sublingual.?\lelhyltestosterone tablets U.S.P. Usually S and 10 mg.tablets.Estrone U.S.P. Oestrone B.P. 1 mg.Estrogenic substances (water soluble) N.N.R. Largelysodium estrone sulfate 1-3 mg.Estrogenic substances (tvater insoluble) N.N.R. Largelyestrone 1.000-10.000 units.Estradiol U.S.P. 0.2 mg.Est.radio] benzoate U.S.P. Oestradiol monob enzoate n. P.1 mg.Diethylstilbestrol U.S.P. Stilboestrol B.P. 0.5 mg.258 EndocrinsDiethyJstilbestrol tablets U.S.P.; B.P. Usually 0.1, o.sa nd1.0 mg. tablets.Diethylstilbestrol capsules U.S.P. Usually available containingfollowing amounts of diethylstilbestrol, 0.1, o.sand 1.0 mg.Benzestrol N.N.R. 2-5 mg.Hexestrol N.N.R. 2-3 mg.Ethinyl Estradiol N.N.R. 0.5 mg.1\'Iesti1bol N.N.R. 0.5-1.0 mg.Progesterone U.S.P. 5 mg. intramuscular.Desoxycorticosterone acetate U.S.P. Dose determined byneeds of patient.Adrenal cortex extract N.N.R.BIBLIOGRAPHYGENERALGlandular Physiology and Therapy, A. M. A., Chicago,1942.Greene, R. : The materia medica of endocrinology, Prac,.titioner 154: 157, 1944. ,Sevringhaus, E. L.: Endocrine Therapy in General Practice,Chicago, Yr. Bk., Pub. 1945.ANTERIOR-PITUITARY HORMONESEvans, H. M.: The hypophJ•sea1 grolvth hormone itsseparation from the hormones stimulating the thyroid,gonads, adrenal cortex and mammary glands, A. Res.Nerv. & Ment. Dis. 17; 175, 1938.Friedgood, H. B.: Endocrine function of the hypophysis,N e,v York, Oxford, 1946.Rynearson, E. H. : Hormones of the anterior lobe of thepituitary body-a clinical review, J.A.M.A. 12S: 5, 1944.Smith P. E.: •Relations of the activity of the pituitaryand 'the thyroid glands, Harvey Leet. 25: 129, 1929-1930.Van Dyke! H. B. : The ~hysiolo~ and _Pharmacology oft11e Pituitary Body, Chicago, Univ. Chicago Press, 1936,Winson, S. G.: The lactogenic effect of prolactin in thehuman being, Atn. J. Obst. & Gynec. 46:- 545, 1943. - --I•' •'• I' Bibliography 259 .,Young, F. G.: Functions of the pituitary' gland (anteriorlobe), Practitioner 154: 129, 1945. .I/GoNADOTROPINS ''Davis M. E., and A. A. Hellbaum: Present status ofgon~dotropic therapy in gynecologic practice, J. Clin.Endocrinol. 3: 517, 1943. 'Goldzieher, 11. A.: Treatment of menstrual disorders ,vithprolactin, J. Clin. Endocrinol. 5: 132, 1945.Gusman, H., and 1\1. A. Goldzieher: Synergism bet,veenpituitary extracts and chorionic gonadotropins, Endocrinology29: 931, 1941. 1Hamblen, E. C., and C. D. Davis: Treatment of hypoovarianismby tl1e sequential and cyclic administrationof equine and chorionic gonadotropins-so-called onet,vo cyclic gonadotropic therapy-summary of 5 years' .results, Am. J. Obst. & Gynec. 50: 137, 1945.Zondek, B., and F. Su Iman: The mechanism of action andmetabolism of gonadotropic hdrrnones in the organism,Vitamins & Hormones 3: 297, 1945.SEX HORMONESBurro,vs, H. : Biological Actions of Sex Hormones, Chicago,Ca1nbridge Univ. Press, 1945.Dodds, E. C.: Hormones in cancer, Vitamins & Hormones2: 353, 1944.Dodtls, E .. C.: Possibilities \O the realm of synthetic estrogens,Vitamins & Hormones 3: 229, 1945. ,Fergusson, J. D., and W. Pa.gel: Some observations oncarcinoma of the prostate treated ,vitl1 oestrogens asden1onstrated by serial biopsies, Brit. J. Surg. 33: 122,1945.Fluhmann, C. F.: Clinical use of extracts front the ovariesand of synthetic products having similar actions, •J.A.l\f.A. 12S: l, 1944.Freed, S. C.: The treatment of pre-menstrual distress, ,vithspecial consideration of tl1e androgens, J.A.l\f.A., 127:377, 1945.Grcenl,ill, J. P.: The use and potency of synthetic estrogens,Am. J. Obst. & Gyncc. 44: 475, 1942.Jla.111l>lcnE! . C.: E11docrine therapy in gynecology andobstctr1cs, 1\m. J. Obst. & Gynec. 45: 147, 1943 .•••,260 • EndocrinsHeckel, N. J.: Evaluation of sex hormones in the treat•ment of benign prostatic hypertrophy, carcinoma of theprostate and other diseases of the genito-urinary system,J. Clin. Endocrinol. 41: 166, 1944.Huggins, C.: Endocrine control of prostatic cancer, Sci-, ence 97: 541, 1943.l\forgan, T. N.: The male sex hormones,1Practitioner 154:149, 1944#Solmssen, U. V.: Synthetic estrogens and the relation bet,veen their structure and their activity, Chern. Rev.37: 481, 1945. IStoddard, F. J.: The abuse of endocrine therapy in gynecology,J.A.11.A. 129: 508, 1945.Thompson, W. 0.: Uses and abuses of the male sex hormone,J.A.l\1.A. 132: 185, 1946.ADRENAL CORTEXGoldzieher, M. A.: The Adrenal Glands in Health andDisease, Philadelphia, Davis, 1945. lGrollman, A.: The Adrenals, Baltimore, Williams &Wilkins, 1936 .,. Reichstein, T., and C. W. Shoppee: The hormones of th~adrenal cortex, Vitamins & Hormones 1 : 345, 1945.Swingle, W. W., and J. W. Remington: The role of theadrenal cortex in physiological processes, Physiol. Rev.-I ' 24: 89, 1944.Thorn, G. W.: Clinical use of extracts from adrenal cortexand of synthetic products having similar actions,J.A.M.A. 125 : 10, 1944.\Villiams, R. H., J. L. Whittenberger, G. W. Bissell andA. R. Weinglass: Treatment of adrenal insufficiency,J. Clin. Endocrinol. 5: 163, 1945. •,•I •• 21Endocrins •( Continued)INSULINTHYROIDPARATHYROIDSLlPOCAICTHYMUS ••PREl'ARATIONS\ POSTERIOR PITUITARYCommercial posterior-pituitary preparations consist ofboth the neural- and the intermediate-lobe hormones sincethe t\VO lobes cannot easily be ~eparated in most speciesand since their active principles have quite similar chemicalproperties. The neural-lobe hormones consist of the oxytociclzor1none (pitocin) and the pressor /1or11ione( pitressin),which is generally thought to be identical with the a,itidiureticltormone. The intermediate-lobe hormone is kno,vn •as intermedin. In animals which lack an intermediate lobe(birds, cetaceans and the armadillo) intermedin is present inthe anterior lobe, while the pressor and oxytocic hormonesare present in the neural lobe. Although the pressor and theoxytocic hormones have been obtained as highly pure prep•arations, there is considerable evidence to indicate that inthe body the various activities associated with the two puri ..fied hormones are actually vested in a single molecule.Intennedin. The intermediate.Jobe hormone has no knownpb}·sioJogic or pharmacologic activity in man. In lowervertebrates (fish, amphibians and reptiles); it cattSes a dis•persion or pigment granules in the skin chromatophores.There is little evidence to indicate, ho~·ever, that it plays a- role in pigmentary changes in higher vertebrates. It bas261r 262' •Endocrins ..._ 'J Ibeen suggested that pigmentary degenerationo f the retinamay involve the intermediate-lobe hormonesb, ut McDonaldand AdJer in a series of weII-contro11eedx perimentsw ereunable to find any support for this theory. It has beenadvocated in the treatment of vitiligo, but it is probableth atany apparent imptovement is due to a nonspecificir ritanteffect. An increased. excretion of intermedio has been reportedin pregnancy and various pathologic conditionsb, utthese results are undoubtedly due to the nonspecificn atureof the assay procedure used, since they cannot be confirmedwhen a hypophysectomized animal is used as the test object.Neural-Lobe Hormones. PharmacoJogic effects evokedby injection of posterior-lobe extracts include an increa..cein blood pressure in the anesthetized mammal; suppre5.5ionof urine secretion; stimulation of the gut musculature;• constriction of blood vessels; increase in blood sugar j stimulationof the uterine musculature; and a fall in blood pres•sure in the fowl. In 19281 Kamm succeeded in separating. the posterior lobe into two extracts with different effects.One fraction, the oxytocic, causes uterine stimulation and afall in blood pressure in the bird, ,vhiie the other, the pressor,causes antidiuretjc and pressor effects, diminished cardiacoutput, probably due to coronary constriction, and stim·• ulation of the gut. Both fractions have been shown to raJSethe blood sugar and to antagonize the effect of insulin. Asyet the fractions have not been prepared completely freefrom each other; commercial preparations of the separatefractions contain about 90.per cent of one and 10 per centof the other. Both fractions contain appreciable amounts( of the intermediate-lobe hormone.Clinical Use of Posterior-Lobe Extracts. The use ofposterior pituitary as an oxytocic drug is discussed in Chapter19. Preparations of posterior pituitary or of the pressorfrac!ion are used in the treatment of diabetes insipidus.Thjs condition is believed to be caused by a decreased secre•ti.,,n of the antidiuretic (pressor) hormone due to lesions' ...• Posterior Pituitary -263in the neural lobe of the pituitary gland or in the supraoptico-hypopbyseal tracts. It is characterized by the excretionof large volumes of urine of lo'Y specific gravity accompaniedby an abnormally great thirst, ..w. hich is probably'secondary to the polyuria. Such patients may excrete 10 to20 liters of urine per day. Administration of posterior pituitarycauses a return to normal of the urine secretion and ofthe water· intake. The antidiuretic effect is believed to be9ue to an increased absorption of water by the kidneytubules and a decreased absorption of salt. It has beensuggested that the role of the hormone in the body is tomaintain an equable water balance, acting in an antagonisticfashion to the adrenal cortex and to a diuretic substance inthe anterior lobe. Removal or destruction by disease of theentire pituitary does not lead to the development of diabetesinsipidus, while removal or destruction of the anterior lobealleviates diabetes insipidus. ,The most satisfactory preparation for the treatment ofdiabetes insipidus is pitressin tannate in oil. It was intro- •duced by Greene and January in 1941 in an attempt toobtain a more prolonged effect than that afforded by aqueous.solutions of posterior pituitary. The effect of pitre~intannatc in oil lasts from 45 to 60 hours following a single•injection or S units, while a similar dose of ordinary postcrior•pituitary extract is effective for only some 4 to 6hours. Intranasal absorption of posterior pituitary is alsoquite satisfactory; pituitary po\vder may be applied as asnuff or pledgets of cotton soaked in posterior-pituitary solutionmay be inserted in the nostrils. Overdosage of posteriorpituitary may lead to a dangerous retention of water.The vasoconstrictor action of posterior pituitary has ledto its use as a styptic. It is of particular value in operationssuch as prostatic resections and tonsillectomies, in whichexcessive bleeding may occurt obscuring the operative fieldand contributing to surgical shock. If the drug is too rapidlyabsorbed there may be gastro-intestinal cramps and evacua-•1>•Endocrinstion of the bowels. The use of posterio( pituitary is con~a.indicated in heart disease because of its coronary--constricting1actionand in pregnancy becauseo f its oxytocice fJecLThe addition of epinephrine or ephedrine may antagonizethe effect of pituitary on the coronary 'vessels and has afurther advantage of prolonging tbe pressor effect of pos-•terior pituitary. /Posterior pituitary, because of its stimulating action onthe bowel musculature, has been used for the treatment ofpostoperative paralytic ileus and to allay distention. Fairlylarge doses are required to produce this effect. It.has beendemonstrated experimentally that large doses of posteriorpituitary may give rise to gastric ulcers because of localischemia caused by vasoconstriction. There js some clinicalevidence to indicate that gastric ulcers have followed theuse of posterior pituitary. , .Hypersensitivity to Posterior-Pituitary Extracts. Occa·siona1 cases of hyPersensitivity to posterior.pituitary preparationshave been reported. Symptoms include pallor, rapidpulse, fall io b]ood pressure, air hunger, sense of impendwgdeath and, in some cases, edema and unconsciousness. Rapi~relief may be obtained with epinephrine injections.Standardization of Posterior Pituitary. An InternationalStandard preparation of posterior pituitary is available forassay purposes. It contains 1 unit of activity (pressor,antidiuretic, oxytocic and intermedin) in 0.5 mg. The officialUnited States and British methods of assay cover only orf·tocic activity and are based on the production of contra~·tions in the excised uterus of the virgin guinea pig. Oxytoe;cactivity can also be assayed by the fall of blood pressure 10the fowI. The pressor (antidiuretic) hormone can be assayedby the rise of blood pressure in the anesthetized cat or dogor by the production of antidiuresis in the rat, mouse or dog.Assays for the intermediate-lobe hormones should be basedon m~lanopbore•dispersing activity in the hypopbysecto-~ animal, since a number of substances will ca.use a,•{ I •'J(lI' Posterior 'Pituitary 26S ,•dispersion of pigment granules in the normal animal byvirtue of a stimulatory action on the pituitary. IINSULINInsu\m is a simple protein elaborated by the i5let U":>:lueof the pancreas which affects the intermediary metabolismof carbohydrates and lipids and relieves the symptoms of, diabetes mellitus. It is prepared commercially from the pancreas'es of cattle and of hogs. It was one of the first hormonesto be prepared in crystalline form. '\\Thile its chemical structurehas not been fully established, over 95 per cent of thenitrogen has been accounted for in the form of ami;:io acids,\Vith a'high prop6rtion containing sulfur. Zinc is an essentialpart of the molecule, and the addition of zinc or ofcertain other heavy metal salts greatly facilitates crystallizatiort.Insulin is inactive by mouth because of its largemolecular size and its sensitivity to digestion by pepsin,trypsin and acids. Parenteral administration results in arapid lowering of the blood sugar, increased deposition ofglucose in the liver and muscles, increased respiratory quotientand decreased excretion of ketone bodies.The relationship of the pancreas to diabetes mellitus wasfirst established experimentally in 1889 by von Mering and!ti inkowski, who showed that depancreatized dogs developedsymptoms essentially similar to those of diabetesmellitus i'n man. In. 1922, Banting and Best, in l\'.lacleod'slaboratory, succeeded in preparing a pancreatic extract ,vhichalleviated the diabetic symptoms of such animals, thus fullyestablishing-the endocrine function of the gland. The active• '-principle was called insuli1i by Banting and his associates,a name suggested by Sharpey.Schaefer. in 1916 when theexistence of such a substance was hypothetical. The experimenmlwork led to the preparation of insulin extracts suitablefor clinical purposes by Collip and to the isolation of thehormone in crystalline form by Abel and his co.workers in1927. ·••••I'•'266 EndocrinsClinical Uses of Insulin. DIABETE1S\ IELLrrus. The chiefuse of insulin is in the treatment of diabetes mellitus adisorder caused by inadequate endogenous insulin prod~ction.Tbe major problem in tbe treatment lies in tryingto duplicate by injection the fupction of the normal pancreasin supplying insulin accordin~ to the varying demands ofthe body. Amorphous or crystalline insulins are rapidlyabsorbed into the blood stream on subcutaneous injection,causing marked fluctuations in blood sugar and necessitatingfrequent dosage. Early efforts to delay absorption by theuse of oily suspensions or by the concomitant injection oflocal vasoconstrictors were not very successful. In 1935,however, Hagedorn and his associates prepared a slowlyabsorbed preparation, protamine insulinate, by combininginsulin with a protamine obtained from fish sperm. Thiswas soon replaced by the even more effective protamine zincinsulin made by Scott and Fisher by adding zinc to insulinbefore the addition of protamine. This compound or c~mpl~is very satisfactory in cases of mild diabetes in whic'h asingle daily injection suffices to control the disease by arelatively constant action throughout the 24-hour period(see page 267). In more severe cases, doses sufficientlylarge to control the daytime blood glucose may lead to ahypoglycemia at night when the carbohydrate intake isreduced. In some cases, a satisfactory compromise can be. reached by two morning injections, one of regular insulinand one of protamine zinc insulin. Since the jnjection oftwo preparations requiring different dosage tends to beconfusing to the patient, efforts have been made to modifythe pratamine zinc insulin to contain a proportion of t.heinsulin in readily absorbab1e form. Such preparations canbe prepared by adding equal or greater amounts of regularinsulin to the protamine zinc insulin or by modifyingordinary protamine zinc insulin so that its protamine andzinc content is lowered. The exact chemical nature of theresulting products is not known but their action js inter'•IInsulin '267•mediate in promptness, intensity and dur~ation of actionbetween protamine zinc insulin and ordinary insulin. .Other insulins with a retarded action, incl,ude globininsulin, a combination of insulin and globin prepared frombeef hemoglobin, and histone insulin, insulin combined withhistone from the thymus. The duration of action of thesepreparations is intermediate between protamine zinc insulinand ordinary insulin. However, since their onset of actionis as delayed as that of protamine zinc insulin, they will notcontrol the postprandial hyperglyc4:mia of severe cases ofdiabetes mellitus. Globin insulin is a clear acid solutionMILK~~-L-...J...---ll.-..J-_...Ji.-..J..-L-_,L-L-...L-J..--L.--1HOURS O 2 4 6 8 10 12 14 16 18 f0 22 2.4, . Twenty-four hour blood-sugar curves on the same patient withdi~erent forms of insulin. All food was withheld other thatt milk,which was given every 2 hours. (PZI = protamine zinc insulin;G.I. ==_g lobini nsulin; C.I. = crystalline insulin; P + C = mixture ofprotarn1I!e zinc insuhn and crystalline insulin. The dosage of eachpreparation is expressed in units.)MFrom H. T. Ricketts: Certain Aspects o[ the newer insulins, Illinoised. J. 87: 1331 1945.,which is precipitated by tissue fluids. Sin~ its duration of~ffect ~epe~ds upon the degree to ,vhicb it is p~ecipitated,~ts a~tion 1s less \predictable than that of protamine zincinsulin. Furthermore, some patients complain of a burning ., 'J•268 - , EndocrinsIsensation on injection, though local reactions are said tobe less frequent than with protamine zinc insulin._ '"'\\Vhile insulin alleviates the symptoms of diabetes ratherthan curing the underlying disorder, there is considerableevidence to indicate that the islet cells of the pancreas havesome regenerative powers. Brush has introduced a newregimen in tbe treatment of diabetes of recent onset in ·c1u1.dren. \Vhen treatment is begun, insulin is administered tothe limit of tolerance. After about 10 days of such dosagelevels, shock develops, presumably because of the increasedsecretion of endogenous insulin as a result of functionalrecovery of the islet cells. The daily insulin 'requirement\ then progressively decreases until a stable level is reached,usually after some 20 or 30 days of treatment. 'Insulin dosage should always be expressed in terms ofunits and should be based on the needs of the patient. Mild Icases can usually be controlled by diet alone. In moresevere cases, the initial dose should be fairly low (10 to 20units, once or twice a day, depending on the preparationused) and gradually adjusted so that the patient's bloodsugarlevel is kept between 100 and 150 mg. per cent.Extremely severe cases may require 80 or more units. Whilemost diabetics can be ~ontrolled by one of the modifiedforms of insulin, ordinary insulin should be available foremergency intravenou~ use, for the rapid relief of severehyperglycemia or for the treatment of diabetic coma.Shock Treatment of Mental Disorders. Insulin has beenused for the shock treatment of schizophrenia and certainother mental disorders since 1932. Its value was accidentallydiscovered by Sakel1 who noted a marked improvement inthe mental condition of his patients following an attempt totreat withdrawal symptoms in morphine addicts with insulin.Treatment consists of daily injections of insulin, start.. .,ing with from 10 to 20 units and gradually increasing thedoslge until unconsciousness is produced. The treatment.requires careful medic~ and nurs~g care .and for this reason'• Insulin 269r, has been largely replaced by simpler technics employingmetrazo1 or electric convulsions.Malnutrition. Insulin is used to stimulate the appetitein malnutrition and during convalescence. Small doses aregiven three times daily beiore mea1s, ,until a satisiactmygain in weight is achieved. It has been postulated that theimprovement in appetite following insulin results. fromincreased hunger sensations due to hypoglycemia and hypermotilityof the stomafb or from improved digestion due toincreased gastric and biliary secretion. It is possible, howeverJ,tliat the improved appetite ~ a psychologic effect.Insulin Resistance and Insulin Sensitivity. Occasion ..ally, patients manifest a resistance to insulin which maybe idiopathic in nature or associated with infection, fever,liver disease or overactivity of the thyroid, adrenal or pitui ..tary glands. In severe cases, patients may fail to respond toI ✓doses greater than 1,000 units. In addition to insulin resist ..ance, some individuals are remarkably resistant to theeffects of hypoglycemia per se. In such cases, unconscious~ness cannot be induced in insulin-shock therapy despite agreatly lowered blood glucose. •Insulin hypersensitivity may be manifested by a localreaction or a severe generalized reaction resembling anaphylacticshock. Hypersensitivity may be due to theinsulin itself, to extraneous pancreatic substances, or toadded sub.stances, such as protamine. Desensitization canbe effected by very small doses at frequent intervals. ,Becauseof the possibility of insulin sensitivity, all diabeticI • patients should be first treated with small doses of the drug.• Granulomas or fatty hypertrophy may develop at the siteof insulin injection. The former are nonspecific inflammatory. reactions ,while the latter is specific to insulin,· the' condition being known as insulin lipohypertrophy. Theopposite condition, namely, atrophy of the subcutaneousfat, also occurs. These disfiguring complications· are not '-270 Endocrins 'I ~common but when present may result in poor absorptionof insulin. 'Standardization of Insulin. The International Standardpreparation of insulin is a crystalline zinc-insulin preparationwhich contains 22 units of activity per milligram. TheU.S.P. method of assay is based on the lowering of the bloodsugar in rabbits. The official British method is based on theproduction of convuJsions in mice.Hyperinsulinism. Excessive insulin results in a proportionaldecrease in blood glucose, giving rise to a characteristicset of symptoms, ref erred to as hyperinsulinism. Thiscondition may arise from an overdose of insulin or fromhypersecretion Jrom t.be islet tissue and is characterized byweakness, fatigue, disorientation and unconsciousness.Treatment consists of the intravenous administration ofglucose if the patient is comatose or the administration ofcarbohydrates by mouth if the condition is less severe.Recently it has been shown that diabetes can be inducedexperimentally by the intravenous injection of the drugalloxan, which has a selective toxic action on the islet cellsof the pancreas. Attempts to treat islet-cell tumors with thisdrug have not as yet proved very successful, though someamelioration of symptoms has been reported. The effect of--a11oxano n the pancreas is in contrast to that of tbiou.rea onthe thyroid; both {lrugs suppress the overactivity of an endocrineq;gan, but whereas thiourea acts by interfering with themanufacture of the thyroid hormone, alloxan has a necrotiz-• ing effect on the cells which elaborate insulin. Except 1n• small doses, the action of alloxan is therefore irreversible.J<THYROID.. ~-'The thyroid gland exercises a general stimulatory effect, on the oxidative processes of the body. • Its activity is in 1turn regulated by the thyrotropic hormone of the anteriorpituitary- i1iid hypothyroidism is characterized by a low•ered b-asal metabolic rate and increased f atigability. l\fore"\.••'Thyroid 271severe states result in myxedema in adults or cretinismin children. \The iodine•containing amino, acid t/Jyroxin is the only,,.compound with appreciable activity that has been isolatedfrom the thyroid. Thyroxin was first isolated in 1915 byI--OH0CH2I,....CH-NH 2 'COOHThyroxin'II \,I•Kendall but its chemical constitution was not determineduntil 1927 when Harington and Barger succeeded in prepar.ing it synthetically. There is still doubt as to whether •thyroxin is the form ·of the circulating hormone or whetherIt represents a degradation product. The presence of anunidentified active compound is suggested by the fact thatthe physiologic activity of the gland is related to its totalorganic iodine content rather than to its thyroxin-iodinecontent. • ,...••272 EndocrinsIt was early suggested that thyroxin in nature is derivedf!olll tyrosin and di-iodotryosine. Support ior this hypothe-'sis has been given by the studies o{ Chaikoff and 'his associateswith radioactive iodide. These workers reported thatwhen radioactive iodide was introduced into the body, subsequentanalyses of the thyroid showed it to be distributedin the inorganic iodide, di-iodotryosine and thyroxin fractionsrespectively, the amount present in the thyroxin fract.i on becoming progressively greater as the time interval ' increased.The formation of thyroxin is probably not confined tothe thyroid gland since studies with radioactive iodidehave shown thyroxin may be formed in comp1etely thyroidectomizedanimals. Thyroxin has been produced in vitronot only by adding iodine to blood proteins, but also toother proteins rich in tyrosine, such as casein. Increasingthe iodination of casein until the iodine content is about 7per cent causes an increasing physiologic activity in thepreparation. However, when the iodine content is furtherincreased, the physiologic activity is decreased.Therapeutic Use. Thyroid preparations are used almostentirely for the treatment of hyopthyroidism. The usuaJform of medication is by tablets of desiccated glands\administeredora]ly. Thyroxjn itself has littJe or no clinical appJi.cation. It is not used orally because df the unpredictability,of its absorption and although, unlike crude thyroid preparations,it can be given intravenously, this route is rarelyif ever indicated. Patients under thyroid treatment shouldbe observed closely for the development of hyperthyroidsymptoms, which include nervousness, tachycardia and lossof weight. The maximal effects of thyroid therapy are notobtained until several weeks after institution of therapy.Thyroid extracts have been used in the treatment ofobesitv and also to produce an increased sense of well-being.1 Becau;e of the dangers of hyperthyroidism, however, their,,,use 'for these purposes is dangerous except under strict'••''Thyroid 273!medic.al supervision and even then it is of questionable\ soundness. The danger of the uncontrolled use of thyroidpreparations has led to their being available in many regionsonly, on a doctor's prescription.Standardization of Thyroid Preparations. Thyroid preparationsare standardized by their content of iodine, inthyroid combination. The United States Pharmacopoeiarequires that thyroid • contain not less than 0.17 per centand not more than 0.23 per cent of iodine in such a combination.'# Drug,, Therapy of Hyperthyroidism. The fact thatcertain· groups of sulfur-containing compounds will on re.pealed administration lead to enlargement of the thyroidand to hYPothyroid symptoms was first demonstrated in1942 by three groups of scjentists, working independently.The' hypothyroidism produced by srich compounds wasshown to be due to an interference with the formation of~ thyroxin by inhibiting the conversion of inorganic iodide todi•iodotyrosine and thyro~in. The thyroid enlargement wasshown to result from stimulation of the thyroid by thethyrotropic: hormone of the anterior pituitary in responseto the reduction in thyroid activity, a condition which hasbeen described as ''hyperplasia of frustration.'' The clinical_significance of such drugs for the treatment of hyperthyroid~• ism was immediately realized and thiouracil \vas found tobe the best suited of the available compounds for therapeuticpurposes.While thiouracil represents a considerab1e advance inthe therapy of hyperthyroidism, it is a toxic agent andhas caused a number of deaths. The most severe toxic effect • 15 the occasional development of agranulocytosis. Lesssevere reactions include gastro-intestinal disturbances,~dem~ of the legs, enlargement of the submaxillary glands,, Jau~dice and skin rashes. Search is continuing for a lesstoxic drug than thiouracil, 6--propyl thiouracil being oneof the more promising compounds.,,... -•274 , IEndocrins -•-~iouracil has been used in the treatm~nt of hyperthyro1d1Smwhen operative relief is not feasibJe or desirable.• It ' will not relieve exophthalmic conditions· , in fact, since)such conditions are believed to be caused by the thyrotropichormone, they may conceivably be aggravated by thiouracil.Thiouracil can be used for preoperative treatment in thyroidectomy,especially in patients who do not respond to orwho do not tolerate iodides. It does not produce such adesirable operative field as iodides, howe9'er, since it causesa hyperemia and softening of the gland. The full effects ofthiouracil may require several weeks of treatment as it doesNH-C=Ol IS=C CHI IINH-CHTblouradl 6-Propylthlouracilnot affect the stores of thyroxin in the body but only theformation of additional thyroxin.Recently, radioactive iodide has been used in the treatmentof hyperthyroidism and adenocarcinoma of the thyroid.Because of the affinity of the thyroid for iodide, theradioactive material becomes concentrated in the gland andeffects an internal radiation. Toxic reactions are similarto those of acute roentgen~ray sickness and include nausea,vomiting, malaise and fever.,PARATHYROIDSThe internal secretion of the parathyroid gland plays animportant role in the metabolism of calcium and phosphorus.The exact nature of its action is not, however,fully understood. Hypoparathyroidism may occur idiopath•ically or can be ascribed definitely to diseasP o~r to acci4).L' .'''t• IIIIII,tIfI►....>•Parathyroids 27Sdental removal of the glands during thyroidectomy. Thecondition is characterized by a lowering o~ the serum-·calcium level, a rise in the inorganic phosphate level and adecrease in phosphate excretion. The symptoms includeincreased neuromuscular excitability leading to tetany,brittleness of the skin, dryness of the hair, formation ofcataracts and occasionally cardiac disturbances and psychoses.'A parathyroid extract capable of combatting the effectsof parathyroid insufficiency was first prepared by Collip in192S. The active principle frequentJy referred to as parathormonehas not been isolated, though chemical studiesindicate it to be of protein nature. Its physiologic actionhas been variously explained as tieing due either to anincreased mobilization of calcium from the bones or to anincrease in the excretion of phosphate by the kidney leadingindirectly to a rise in blood calcium. Convincing experimentalevidence has been presented in support of botharguments and it may well be that a dual effect is involved.Parathyroid extracts are of limited value in the treatmento~ hYPoparathyroidism because tolerance develops aftersome weeks and the hypocalcemia is no longer affected.Furthermore, parathormone is inactive by mouth, beingdestroyed by the digestive juices. For prolonged treatmentof hYPoparathyroidism or other bypocalcemic conditions,activated sterols must be used. The value of these prepara-•t1ons ,vas first demonstrated by Holtz, in Germany, in1933. The most widely used compound is dihydrotachyslerol,also known as A.T. 10 (antitetany compound No. 10),which is closely related chemically to calciferol (vitamin\D2) but which has little or no antiracbitic activity. VitaminD preparations can also be used to maintain the bloodcal~ium level but large doses are required. The activatedsterals can be given by mouth. Their action develops slowly, ,ho~ever, and parathormone must be used in acute tetany. ',It is frequently supplemented with intravenous injections'\276...Endocrins'of calcium gluconate or chloride. During the treatment ofparathyroid deficiency, the serum ca1cium must be followedu.nuJa stable level is reachedi n order to detect the developmentof hypercalcernia, which may cause serious if notfatal damage. .Hyperparathyroidism. This may result either from adenomaor hypertrophy of the parathyroids or from overdosesof parathormone. Symptoms include muscular weaknessand pathologic changes in the bones, due to a withdrawalof calcium. The serum-calcium level is very high and theserum-phosphorus level low unless .kidney damage is present.Increased amounts of calcium and phosphates are excretedin the urine, which may result in formation of urinarycalculi or deposition of calcium in the pyramids leading torenal insufficiency. .Standardization of Parathyroid Extracts. The U.S.P.unit of parathyroid activity is equivalent to one one-bun•dredth of the amount required to raise the calcium contentof 100 cc. of the blood serum of normal dogs 1 mg. within16 to 18 hours after administration.LIPOCAICThe depancreatized animal undergoes characteristic fattychanges in the liver that eventually lead to death despitethe administration of insulin. These changes can be pre;ventedby the addition of raw pancreas to the diet. Dragstedtand his associates have prepared a fat-free extract ofthe pancreas, which exerts the same effect as fresh pancreasin daily doses of from 60 to 100 mg. These investigatorsbelieve the effect is of an endocrine nature and have designatedthe active principle lipocaic. Preliminary clinicaltrials indicate this preparation may be of value in disturb·ances of fat metabolism in diabetic patients. Clinical ex•perience is not sufficient, however, to indicate whether Jipo•caic has a place in the treatment of human disease.•\ •• 277•,Thymus• THYMUSNo definite endocrine function has been determined forthe thymus gland. It has long been known that somemyasthenia gravis patients have characteristic tumors inthe thymus known as thymomas. Recently, surgical removalof the thymus has been reported to afford some measure ofrelief to these patients. This has led to the suggestion thatthe thymus gland is in some way related to the metabolismof acetylcholine in the body.PREPARATIONSPosterior•pituitary injection U.S.P.; pituitary (posteriorlobe)extract B.P. Aqueous extract containing 10 unitsper cc. 0.2-2 cc.Ampuls pitocin N.N.R. Contain 10 oxytocic units per cc.0.3-1 cc.Ampuls pitressin N.N.R. Contain 20 pressor units per cc.0.3-1 cc.Pitressin tannate in oil N.N.R. 5 pressor units per cc.0.3-1 cc.Insulin injection U.S.P. Contains 40, 80 or 100 U.S.P. insu.~ lin uni ts per cc.Injection of insulin B.P. 20, 40 or 80 units per cc.• Protamine zinc insulin N.N.R. 40 or 80 units per cc.Protamine zinc insulin injection U.S.P.; B.P. 40 or 80 unitsper cc.Zinc insulin crystals N.N.R. Contain not less than 22 unitsper mg. 'Crystalline zinc insulin injection N.N.R.-Globin insulin with 2inc NN.R. 40 or 80 units per cc. ' 'Thyroid U.S.P. Contains not less than 0.17 per cent or morethan 0.23 per cent iodine in thyroid combination and mustbe iree from iodine in inorganic or any form of combinationother than that peculiar to the thyroid gland. 60 mg.Thyroid tablets U.S.P. Usually in 15, 30, 60 and 120 mg.amounts.•'•'278 Endocrins ••Thyroid B.P. Contains 0.1 per cent i~ in combinationas thyroxine (limits 0.09-0.11) and not more inorganiciodine than 10 per cent of the content of total iodine.Thyroxin U.S.P. 0.5 mg. intravenously.Thyroxine soclium B.P. 0.1-1 mg.Thyroxin fraction N.N.R. Partially purified disodium saltof thyroxin. For oral adII]inistration only.Parathyroid injection U.S.P. Each cc. must contain apotency of not less than 100 U.S.P. units. 25 U.S.P. units' intramuscularly.POS'IERIOR Pl'IUI'IARY~Adler, F. H., and P. R. McDonald: Studies on pigmentarydegeneration of the retina: the role of themelanophore hormone of the pituitary gland in pigmentarydegeneration of the retina, Tr. Am. Ophth.Soc. 39: 49, 1941.Blotner, H. : Pitressin tannate in oil in the treatment ofdiabetes insipidus, J.A.M.A. 119: 995, 1942.Court, D., and S. Taylor: Slowly acting pituitary prep~arations in diabetes insipidus, Lancet 1: 265, 1943.Fisher, C., W. R. Ingram and S. W. Ranson: Diabetesinsipidus and the neuro-hormonal control of ,vater balance;a contribution to the structure and function ofthe hypothalamico-hypophyseal system, Ann Arbor,Mich., Ed,vards, 1938.Geiling, E. M. K., and F. K. Oldham: The site of formationof the posterior lobe hormones, Tr. A. Am. Phys.52: 132, 1937. \Greene, J: A., and L. E. January: Efficacy of pellets of •posterior hypophysis and of pitressin in oil in diabetesinsipid us, Proc. Soc. Exper. Biol. & Med. 44: 2171 1940.Jones, G. M.: Diabetes insipidus--clinical observationsin forty-two cases, Arch. Int. Med. 74: 81, 1944.Pickford, --M.: Control- of the secretion of anti diuretic 'hormone from the pars nervosa of the pituitary gland,Physiol. Rev. 25: 573, 1945. • ..Smith B., Jr., J.M. Coon, P. Fourt and E. M. K. Ge1l1ng:A p'roposed modification in the official method for theassay of posterior pituitary solution, J. Am. Pharm. A.30: 151, 1941.• -•Preparations 219INSULINAbel, J. J., E. M. K. Geiling, C. A. Rouiller, F. K. Bell and 10. Wintersteiner: Crystalline insulin, J. Pharmacol. &Exper. Therap. 31: 65, 1927.. Adlersberg, D., and H. Dolger: Insulin mixtures in t}1etreatment of diabetes: variable versus fixed ratios of• insulin and protamine zinc insulin, J.A.M.A. 128: 414,1945.Bailey, 0. T., C. C. Bailey and W. H. Hagan: Alloxandiabetes in the rabbit: a consideration of morphologicand physiologic changes, Am. J. M. Sc. 208: 450, 1944.Banting, F. G., and C. H. Best: The jnternal secretion ofthe pancreas, J. Lab. Clin. Med. 7: 251, 1922.Brunschwig, A., J. G. Allen, F. 1\1. 0\vens, Jr., and T. F.Thornton: Alloxan in the treatment of insulin-producingislet-cell carcinoma of pancreas, J.A.M.A. 124: 212,1944.Brush,lJ· ¥· : I~itial stabilization of the diabetic child,Am. . D1s. Ch1ld. 67: 429, 1944.Eaton, J. C.: Clinical trial of globin insulin and otherinsulins with delayed action, Lancet 2: 269, 1944.del Fierro, R. S., and E. L. Sevringhaus; Clinical use ofnew types of modified protamine zinc insulin, Ann. Int.11:ed. 22: 667, 1945.Goldner, 11:. G.: Insulin lipohypertrophy, J. Clin. Endo~crinol. 3: 469, 1943.Greco, J. B., A. 0. Lima and J. R. Can,;ado: The treatmentof under,veight ,vith insulin, Am. J. M. Sc. 204:~ 258, 1942.Hagedorn, H. C., B. N. Jensen, N. B. Krarup and I. Wodstrup:Protamine insulinate, J.A.M.A. 106: 177," 1936. .1Iartin, W. P., H. E. Martin, R. W. Lyster and' S.Strouse: Insulin resistance crjtical survey of the literaturewith the report of a case, J. Clin. Endocrinol. ,1: 387, 1941.Reiner, L., E. H. Lang, J. W. Irvine, Jr., W. Peacockand . R._ D. Evans: T11e absorption rates of insulin,glob1n insulin and protamine zinc insulin labelled ,vithradioactive iodine, J. Phannacol. & Exper. Therap.78: 352, 1943. •Ri1ck~tt~, H •. T.: Certain aspects of the newer insulins,"" ll1no1s 1Ied. J. 87 : 133, 194S.-- , ,, 280 , Endocrins'/ .Weitz, M. A.: lnsulin hypersensitivity with desensitization-report of a case, J. Allergy 14: 220, 1943.THYROIDChapman, E. M. and R. D. Evans: The treatment of·hyperthyroidism lvith radioactive iodine, J.A.1tf.A. 131:86, 1946. IHarrington, C.R.: The thyroid gland-its chemistry andphysiology, Ne,v York, Oxford, 1933.' Harrington, C. R.: Thyroxine; its biosynthesis and itsimtnunochemistry, Proc. Roy. Soc., London, 132:223,1944-1945.Reineke, E. P., and C. W. Turner: The recovery of crys•talline thyroxine from iodinated casein, J. Biol. Chem.149: 555, 1943.Soskin, S., and R. Levine: Recent advances in physiol·ogy of the thyroid and their clinical application, Arch.Int. Med. 74 : 375, 1944.Williams, R. H.: Thiouracil treatment of thyrotoxicosis,• 1, the results of prolonged treatment, J. Clin. Endo·crinol. 6: 1, 1946.Williams, R. H., H. M. Clute, T. J. Anglem and F. R. ,Kenney: Thiouracil treatment of thyrotoxicosis, II,toxic reactions, J. Clin. Endocrinol. 6: 23, 1946.PARATHYR.O IDS 'SheJJjng, D. H.; The Parathyroids in Health and in Dis•ease, St. Louis, Mosby, 1935.Rose, E.: Hypoparathyrodism. Clinics, 1: 1179, 1943.Sevringhaus, E. L.: Activated steroJs and calcium saltsin the treatment of parathyroid tetany, Am. J. M. Sc.203 : 726, 1942.) LIPOCAICDragstedt, L. R.: Some physiologic problems· in surgeryof the pancreas, Ann. Surg. 118: 576, 1943.I • THnros•Blalock, A., A. M. Harvey, f. ~- Ford and J. L. Lilien·tha1 Jr.: The treatment of myasthenia gravis byrem~val of the thymus gland, preliminary report, J.A.M.A. 117: 1529, 1941. .,\•••22VitaminsVIT-AMINA VITAMIN B COMPLEX•VITAMIN CVITAMINDVITAMINEVITAMINPVITAGENSPREPARATIONSIVitamins are protective agents which are required forno;mal growth and reproduction and ,vhose deficiencyleads to characteristic clinical symptoms which can be alleviatedby administration of the deficient vitamin. Theydiffer from the hormones in that they are of exogenousorigin, the body's needs being normally supplied by ingestionof the active principles or their precursors.Vitamins evoke few pharmacologic effects other th~alleviation of symptoms characteristic of deficiency of thevitamin in question. They.. are effective in relatively smallamounts. The symptoms of hypervitaminosis are not asapparent as those of excess hormone formation or administration;most preparations are comparatively nontoxiceven in high dosage.It should be borne in mind that vitamins have beengreatly exploited by commercial interests and that the idealsource of vitamins is an adequate diet. Vitamin preparationsshould, therefore, be used only where prompt reliefo.f h. ypovitaminosis is indicated, when demand for vitamins 'ts increased, or ,vhere conditions necessitate a restrictionof tlie diet. Indiscriminate use of vitamins should be dis••,••, -,•282 Vitamins 'IIcouraged. There is evidence that excess of one vitaminmay lead to an increased requirement for a second) althoughthe interrelationship bet,veen the vitamins is as yet poorlyunderstood. Combinations of vitamins or crude preparationsare often more efficacious than individual vitamins sincerarely does a deficiency in a single vitamin exist. The use ofpreparations of vitamin B complex in particular is usuallymore desirable than the use of a single crystalline vitaminbelonging to the complex. Finally, it must be recognized thatour knowledge of the vitamins is as yet jncompletea nd thatunknown factors may be supplied in the relatively crudepreparations.Vitamins are prescribed either at supplementary or attherapeutic levels. Supplementary doses should be restrictedto cases in which the diet is unavoidably inadequate or inwhich the vitamin requirements are increased as in preg•nancy, lactation, fever or severe physical exertion. In suchcases, multip]e vitamin preparations such as he:xavitamintablets, dried yeast, crude liver preparations or rice polishings,containing approximately the daily requirement ofvarious vitamins are given. Therapeutic doses of single ormultiple vitamin preparations are usually from three tote!) times the supplementary doses and are prescribed incases of proven or suspected vitamin deficiency. The FederalTrade Commission has held to be misleading any therapeuticclaims for supplementary levels of vitamins. Suchdosages would be of value only in the very mildest of defi•ciency states and furthermore might tend to give the patienta false sense of security so that he may neglect a satisfactorydiet. The range of dosage for supplemental and therapeuticlevels of vitamins is set forth in Table 4.Thif chapter is restricted, for the most part, to the discussionof the use of vitamins in well-tecognized deficiencystates.~ Reference is made elsewhere to the use of pteroylglutan1icacid in macrocytic anemia, para-aminobenzoic acidin Rickettsial diseases, vitamin D preparations in hypopara-••'•, •V. .1tamxns 283thyroidism1 and vitamin K preparations as coagulants. Themode of action of none of the vitamins is fully understood.Some vitamins are known to be an essential component ofcertain enzymes; others may act as "promoters" of enzymaticreactions.The importance of vitamins to the growth and developmentof micro-organisms and of malignant growths shouldnot be overlooked. There is evidence to indicate that certaindiseases may be limited by vitamin deficiencies or encouragedby the presence of certain vitamins.Certain other protective agents are recognized whoseeffect on normal growth and development is as essential asthat of the vitamins. These substances have been variouslydescribed as vitagens, dietary factors or vitamins and includecholine, inositol, certain fatty acids and the essentialamino acids. As yet the therapeutic application of thesesubstances is largely experimental, but as knowledge oftheir metabolism is advanced, they will undoubtedly come .to play as important a role as the vitamins.Vitamins for therapeutic purposes are supplied as crudeextracts or as synthetic pTeparations which may be eitheridentical with the natural vitamin or which may possessvitamin-like activities. Preparations of known compositioncan be assayed by chemical or physical methods. Othersare assayed biologically. The older biologic assay methodsare based on the use of laboratory animals depleted ofthe vitamin to be assayed. When deficiency symptoms appear,the preparation to be assayed is added to the deficientdiet and its efficacy in restoring the health of the animalis compared to that of a standard preparation in similarlyprepared animals. Recently the nutritional requirementsof certain micro-organisms have been shown to provide asensitive method of assay that can be completed rapidly andthat involves the use of only minute amounts of the activeprinciples.A number of these methods have been adoptedby the U.S.P.•/,284 VitaminsVITAMIN A2CH==CH-CJ =-CH-Gi=CH-C=CIH -CROH-- ,CH3 CH3 CH3ViwnmAVitamin A is a fat-soluble vitamin, obtajned commerciallyfrom fish-Jiver oiJ. The dietary sources of vitamin A includegreen, leafy and yellow vegetables, dairy products and Jiver.In plants and dairy products, the vitamin A activity is due •largely to the presence of provitamins, particularly beta- ,carotene, which can be converted into vitamin A or storedin the body if there is no immediate need for additionalvitamin A. Excessive intake of these substances or a failureof the liver to convert them to vitamin A may lead to carotinemia.While the condition is apparently harmless, theyelJow tinting of the blood, skin and conjunctiva whichaccompanies it may be confused with jaundice. Animalsgiven massive doses of vitamin A develop characteristicsymptoms which include loss of weight, internal hemorrhagesand fractures of the bones of the e:ttremities. Thereis some evidence that hypervitaminosis A may occur inhumans, though potent preparations are not as yet readilyavailable.At present, there is no evidence that vitamin A prepi-ations have any therapeutic action other than that of•• -l\ t Vitamin Arelieving vitamin A deficiency. Signs of vitan1in A de.ti~ciency ,vhich are relieved by the administration of thevitamin or one of its precursors include metaplasia ofmucous epithelium, characteristic skin lesions, night blindness,and defec_ts in tooth development in children. The useof vitamin A preparations in excess of normal r~quirernentsto reduce the incidence of respiratory or other infections . ' 1s of no proven value.Assay of Vitamin A Preparations. Although vitamin Acan be assayed spectrophotometrically, the official U.S.P.method of assay is a biologic one since it has been claimedthat spectrophotometric methods can be influenced byadulteration. The British,recognize both biologic and physicalmethods of assay but stipulate that the biologic methodhas priority if discrepancies exist between the two methods./ The U.S.P. official method of bioassay for vitamin Aconsists of comparing the unknown preparation with acod•liver oil preparation standardized for its vitamin Apotency in regard to its ability to produce weight gains inrats rendered avitaminic by a vitamin A deficient diet(vitamin A test diet U.S.P.). The U.S.P. unit of vitamin Aactivity is identical with the International unit, being the -specific activity of 0.6 micrograms of pure beta-carotene.VITAl\1IN B COI\f PLEX IThe vitamin B complex includes a number of water- ,soluble vitamins, the richest sources of which include yeastand liver. It is probable this group contains many as yetunidentified protective agents. The substances identified todate vary greatly in their chemical structure and in theirphysiologic roles. They have all been prepared synthetically.T~e term vitamin B (antineuritic' vitamin) was firstappl1e~ to th~ V{_ater~solublteh ermolabile principle isolatedfrom r1ce ~ol1shings and yeast which alleviated the symp.toms of beriberi. The isolation from similar sources of a secondwater-soluble principle which differed from vitamin Bin,'286 Vitamins•\being thermostable and which relieved the symptoms of' pellagra 1ed to the separation of "water-soluble vitamin B'1into two fractions, vitamin B1 (thermoJabile) and vitaminB2 (thermostable). The subsequent discovery that vitaminB2 consisted of not one but several substances led to theconti_nued acceptance of vitamin B1 for the antineuriticvitamin (later identified as thiamine) and the use of B2,Ba, B4, etc., for additional activities as they were disco.v.ered. As the chemical structure of these compounds becomesestablished, and as synthetic preparations become available,they are generally referred to by their chemical namesrather than as one of the B vitamins. Only those membersof accepted therapeutic value are discussed in this section.N-CH Cl-(Pyrimidine Nucleus) (Thiazole Nuclew)Thiamine HydrochlorideThiamine. Thiamine or vitamin B1 is of considerablehistorical interest since the demonstration of its antiberberiaction led to the formulation of ~e present-day conceptof vitamins. It was first isolated in crystalline form in1926 by Jensen and Donath and its empirical formula determinedby Windaus in 1932. Its structural formula andsynthesis were reported by \Villiams and Cline in 1936. Itis known in Europe as aneurin. Sources of thiamine includepork, dried yeast and rice husks ... Live yeast contains muchthiamine but the organisms apparently prevent its beingavailable to man. The body does not store thiamine to anyappreciable extent, although the appearance of deficiencysymptoms may be delayed for several weeks or even months'Vitamin B Complex 287after depletion has occurred. Any complicating conditions,such as pregnancy, illness or undue exertion, may, however,lead to mild symptoms of thiamine deficiency, such as generalfatigue, loss of appetite, poor memory and musclecramps, or to more severe symptoms, including degenerativechanges in the nervous system, edema and cardiac hypertrophy.The term beriberi is usually reserved to describethese severe symptoms, which arise in the Orient due tothe consumption of polished rice. Essentially similar clinicalfindings, however, are presented by the Korsakoff syn.drome, alcoholic polyneuritis, Wernicke's disease and otherpolyneuritides due to faulty nutrition. These conditionsmay be treated with crystalline thiamine or \vith substances. rich in vitamin B1 ,vhich have the probable advantage ofcontaining other members of the vitamin B complex, sinceit appears probable that other avitaminoses are also present. ,Thiamine is best administered orally. Fatal anaphylacticshock has occurred fallowing its intravenous injection, and ,sensitivity may develop after prolonged parenteral use.Standardization of Thiamine. The U.S.P. official method ,of assay for vitamin B1 preparations involves the use ofrats rendered polyneuritic by a te' st diet. Crystalline thiaminehydrochloride is the official standard preparation, 3micrograms containing one unit of activity. Thiamine hydrochlorideand other products from which certain interferingsubstances are absent may be assayed by a fluorometricprocedure.I•1H2(CHOH) 3 CH20HN N'/It o. . -.•I288 Vitamjns• Ribofla,.,in. Riboflavin, known also as vitamin G or lacto•fla.vjn, is widely distributed throughout the p1ant and animaJkingdoms. The most important food sources include milkand meats. It was isolated in 1933 in three different labora•tories, at ll1hich time its identity with lactochrome, a yellow,water-soluble, green.fluorescing pigment of whey, first in•vestigated in 18179w, as realized. Riboflavin was first syn•thetized in 1935 by Kuhn and Karrer.Riboflavin is used in the treatment of riboflavin deficiencyor ''ariboflavinosis," the symptoms of which include g1ossi•tis, cheilosis and photophobia and other ocular disturbances.It is also used to treat the riboflavin deficiency in conditionsin which multiple vitamin deficiencies undoubtedly exist,such as pellagra, black tongue and beriberi. No untowardeffects have been reported following large doses of riboflavin.Standardization of Riboflavin. A U.S.P. Riboflavin ReferenceStandard is avajJab1e. Preparations are standardizedby a microbiologic assay employing Lactobacillus casei asthe test organism.I COOH I CONH2~ ~N· NNicotinic Add NicotinalnideNicotinic Acid. Nicotinic acid (niacin, antipellagra vita·!min, P.P. [pellagra-preventing] factor) is the most importantfactor 1in the prevention of pellagra. Rich food sourcesof this vitamin include meats and ,vhole wheat products.Nicotinic ~cid was first prepared by the oxidation ofnicotine in 18731 Jong before its vitamin activity was recog•nized. Its efficacy in curing black tongue and pellagra wasdemonstrated by Elvehjem and by Spies respectively in1937~ Although nicotin1c acid is several • , • ..,..!•timesJ ess...,,...toxic than nicotine, it was felt the .. ' '•-,, ' ',Vitamin B Complex 289'be p~judicial to its use, hence the term niacin has beengenerally adopted. Nicotinic acid is probably present in, the livinglanimal i~ the form of its amide, nicotinamide. rNicotinic acid and nicotinamide are used mainly for theprevention and treatment of pellagra. Nicotinic ,acid frequentlycauses a disagreeable but not serious flushing of theskin of the face and neck and extremities. Nicotinamidedoes not produce the effect, although it is about twice astoxic to animals as nicotinic acid.Standardization of Nicotinic Acid or Nicotinamid, e:The official U.S.P. method of assay for nicotinic acid and• nicotinamide is a microbiologic procedure, using Lactobacillusarabi,iosus as the test organism and the U.S.P:Nicotinic Acid Reference Standard as a basis of compari•son of activity.,•'CH20HHO-'I"!,CH3......,.~NPyrldoxfnfll'. Pyridoxi.n..e . Pyridoxine (vitamin B6 ) was first isolatedin 1938 by five different groups of ,vorkers. Its chemicalstructure was elucidated and its synthesis accomplished in1939 by two groups of workers, one in Germany and onein the United States. It is widely distributed in nature, the '·main food sources being grain, egg yolks and milk.The clinical value of pyridoxine has not been fullyestablished. It appears to promote the recovery of pellagrinswho are not completely cured with nicotinic acid and thia-•mine. It has recentlx been introduced for the preventionan~ th; treatment of radiation sickness, the severity of~hi~ 1s believed by some investigators to be due to deficienciesof the vitamin B complex. Deficiency of pyridoxine•\290 Vitaminsin rats leads to ''rat acrodynia" characterized by degenerativechanges in the cardiac and striated muscles and changes'in the nervous system. This has led to its use in such con•~ditions as paralysis agitans and pseudohypertrophimc us~cular dystrophy, with promising results being reported insome cases.VITMfIN C •I o, I ~ OHIC C C C C CHII I I I I I '0 OH OH H OH HAscorbicA cidVitamin C (ascorbic acid, cevitamic acid) is a watersolublevitamin widely distributed in nature. The importantfood sources are fruits and vegetables, especially citrusfruits, tomatoes and potatoes. It is rapidly destroyed byheat and by oxidation. It was isolated from lemon juiceby King and Waugh in 1932 and identified as the reducing,compound "hexuronic acid'' isolated earlier by Szent-Gyorgyifrom the adren~l glands and vegetable sources. Itsconstitution was demonstrated and synthesis accomplishedin 1933 by several workers. Synthetic vitamin C is nowconsiderably more economical than that isolated from nat- 1- ural sources.Ascorbic acid is the specific curative agent in scurvy, acondition due to a deficiency of this vitamin. It is probablethat this disease is widespread in a subclinical or borderlineform characterized by restlessness, irritability and gen•eral run-down feeling. 1'Iore marked symptoms includecapillary fragility, manifested by petechial hemorrhages inthe skin and swollen and bleeding gums. The underJyjngpathology appears to be a change in the intercellular matrixof the connecti•v e tI•S Sue.Vitamin C 291Adequate ,vitamin C is necessary to insure healing ofbone' fractures and wounds. However, there is no evidencethat administration of vitamin C is of value if the bodysupplies are normal. It is said to have a detoxicant actionon various toxic substances, such as lead and arsenic com.pounds, on bacterial toxins and on substances producinganaphylaxis.Ascorbic acid can be administered orally or intravenousJy.It is apparently nontoxic even in large doses.Standardization of Vitamin C Preparations. The U.S.P.unit of vitamin C is equivalent to the international unitand represents the activity of 0.05 mg. of the U.S.P. Ascor•hie Acid Reference Standard. Preparations are assayed bychemical means based on the reducing ability of ascorbicacid. A biologic test is available, based either on the preventionor on the cure of scurvy in the guinea pig.'tiOVITA1\1IN DHOErgosterol,7-Dehydro-cholestero\ 'CHI 2tCH~1\ "~ I ,VilQmln 0~J••••I•292 Vitamins-Vitamin D (antirachltic vitamin) consists o( a group off at~solubJe substances which occur in j,hysio1ogica1a1cJt•iv eform only in animals. Plants contain "provitamins D,"including ergosterol and 7-dehydrocholesterol, which canbe converted into active vitamin D by ultraviolet lighLFood sources of vitamin D include eggs, milk and milk prod:ucts. Sunlight is an important factor in converting provitafI!jos to an active form in the human or animal body,the skin providing a rich store of provitamins. Commer•,cially, vitamin D is obtained from the liver oil of marinefishes, which is usually rich in both vitamins A and D, andby the irradiation of ergosterol or 7-dehydrocholesterolwhich yield vit.amin D2 (drisdo1, calciferoJ, viosteroJ,;i cti•vated ergosterol) or vitamin D3 (activated 7•dehydrocholesterol)respectively. At least six different vitamins Dare present in fish.Jiver oils. There appear to be quitemarked differences in the responses of various species ofanimal to a given vitamin D and also in the response of agiven species to various vitamins D.Vitamin D preparations are used chiefly in the preventionand cure of inf an tile rickets, spasmophilia (inf' antiJe tet•any), and osteomaJacia or rickets of the adult, which occurslargely in pregnant and lactating women. These diseasesresult from faulty calcium and phosphorus metabolism dueto vitamin D deficiency. The characteristic symptoms ofthese conditions are decalcification of the bone leading tobrittleness and deformities and extreme muscular weakness.Large doses of vitamin D have been reported by several in~vestigators to be of value in the treatment of lupus vulgaris.Vitamin D in massi\-·ed oses has been recommendedi n thetreatment o( arthritis and has unfortunately been used quitewidely in this condition without medical supervision. Itstherapeutic value has been shown to be questionable, andnumerQJJs reports have appeared concerning the toxic effectsof large doses of vitamin D, including gastro-intestinalupsets, weakness, skin eruptions and occasionally metastatic' • •Vitamin C 293calcification, especially in the kidneys and blood vessels.The use of vitamin D and activated sterols in the treatmentof hypoparathyroid tetany is discussed in Chapter 21.Standardization of Vitamin D Preparations. The U.S.P.official method of assay of vitamin D preparations involvesthe use of rats given a rachitogenic diet. The preparationsto be assayed are compared ,vith the standard preparationin regard to their healing effect on the racbitic metaphysisby means of the "line test.'' In this procedure the leg bonesare removed from the animal, cleaned and immersed in· asilver-nitrate solution, which converts the calcium phosphateto silver phosphate. The criterion of healing is thepresence of a new line of calcification through the racbiticmetaphysis. The standard preparation is the U.S.P. ReferenceCod-Liver Oil, standardized for its vitamin D potency.The U.S.P. and the international unit of vitamin D is equivalent'to 0.025 microgram pure crystalline vitamin D2 •IVITA1\1IN ECH3••a.-TocopherolVitamin E is a fat-soluble vitamin widely distributed ln· , •foodstuffs. Commercially, it is available in concentratedform in ,vheat-germ oil or as synthetic alpha-tocopherol.No form of vitamin E deficiency has been established inhuman beings, a fact which has been attributed to its widedistribution and its unusual stability. In rats, vitamin E isI- •294 Vitamins, . 'essential to the processes of reproduction; in its absence,there is degeneration of the seminiferous epithelial cells inthe male, and degenerati\re changes of embryos in the pregnantfemale, resulting in resorption of the embryos or inabortion. This has led to its use in the treatment of sterilityand threatened or habitual abortion in human beings.Its value is questionabJe but its use has been justified on thegrounds that it is nonto~c and that alternative treatmentis usually ineffectual.Laboratory animals on a vitamin E deficient diet developnutritional muscular dystrophy and lesions of the nervoussystem. Consequently, vitamin E has been used in thetreatment of muscular dystrophy and degenerative diseasesof the nervous system. The results, however, have not beenvery encouraging, and all clinical uses of vjtamin E mustbe considered only experimental at this time.- VITAMIN PVitamin P has received little attention and not much iskno,vn as to its role as an essential nutritive element. Itis present in citrus fruits and probably in many other plants.It appears to be a flavone derivative. Its physiologicaction is concerned with main tenaace of the walJs of b1qodvessels and, in its absence, there is increased capillaryfragility.HOHO0II0IOH·>-OH ·IRutla• ' IVitamin P 295...._ Recently, a flavone glucoside, rutin, has been shown tohave a much greater vitamin P activity than that of many1 of the available crude preparations. Rutin ,vas first isolatedin 1924 from tobacco but buckwheat has now been foundto be a better source. Rutin is apparently nontoxic. It hasbeen tried clinically in states of increased capillary fragilitybut as yet no verdict can be given concerning its therapeuticvalue.VITAGENSAnimal 'experiments have shown that choline, methionine,inositql and choline-containing phospholipids play an importantrole in the transport of fat from the li¥er. Deficienciesof these lipotropic factors lead to fatty infiltration andcirrhosis of the liver. Choline has been found to be particularlyeffective in reversing pathologic changes inducedby choline deficiency which may follow, for example, a highintake of cystine while inositol is effective in combattingchanges induced by a high intake of cholesterol.These findings stimulated the therapeutic use of theselipotropic substance;, in liver disease in human beings, themost promising results having been obtained by the use ofinositol and either choline or methionine.Fatty acids containing more than one double bond cannotbe synthetized by the body. Since both linoleic andar~chidonic acids are essential, they must be supplied in .the dJet. The amounts required are so small it is doubtfulwhether a deficiency is ever observed in man, with the possibleexception of very young infants maintained on a lowfat diet. In such instances, eczema may occur, apparentlyreferable to a deficiency in the essential fatty acids.Certain amino acids must be included in the diet sincetheir synthesis cannot be accomplished by the body. Specificdeficiency of one or more of the essential amino acidsis practically impossible when the total protein supply isadequate. One possible exception is arginine deficiency. A296 Vitaminsdeficiency of this amino acid, produced experimentallyinman, showed a specific effect on the production and motilityof spermatozoa ,vhich was corrected by arginine supplements.Recently, synthetic mixtures of the essential amino addsor of simple peptids and amino acids (casein digests orhydrolysates) have been used to provide the protein nitrogenrequirements when normal feeding is interfered with.These preparations may be administered orally, intrave•nously or subcutaneously. Intravenous injection of hydrolysatesoccasionally causes febrile reactions or nausea and\ vomiting. The incidence of nausea and vomiting can bereduced by siow administration.I•TABLE 4DAILY DOSE OF VITAMINSAt Supplemental and Therapeutic LevelsVITAMINSUPPLDR.NTALLEVELTm:ltAPEUUC U:VELAB1 (thiamine)B2 (riboflavin)Nicotinic add and nicotinaln.ideBo (pyridoxine)C (ascorbic acid)D1 E (tocopberoJ)S,000 units1-2 mg.2-Jmg10-251'IS400 units?25,~200,000 units20-100 mg. ~S-20mg.100-500S-lOmg.100-SOOmg,l,S00-2,SOOu nits30-100mg.PREPARATIONS(For dosage, see Table 4)•Oleovitamin A. U.S.P. Contains vitamin A from naturalsources. Each grain contains not less than 50,000 or morethan 65,000 U.S P. units of vitamin A and not morethan 1,000 U.S.P. units of vitamin D.Oleovitamin A capsules U.S.P. Contain 5,000 or 25,000U.S.P. vitamin A units per capsule.'•'• -Preparations 297Concentrated solution of vitamin A B.P. Contains 50,000I.U. of vitamin A per gram. .Concentrated oleovitamin A and D U.S.P. Contains bet,veen50,000 and 65,000 U.S.P. units vitamin A and between10,000 and 13,000 U.S.P. units vitamin D per gram. ~Oleovitamin A and D U.S.P. Contains between 850 and1,100 U.S.P. units vitamin A and 85 and 110 U.S.P. unitsof vitamin D.Concentrated oleovitamin A and D capsules U.S.P. Contain5,000 U.S1.P. units of vitamin A and 1,000 units of vitaminD per capsule. ,Concentrated solution of A and D B.P. Contains 50,000 I.U.vitamin A and 5,000 I.U. vitamin D per gram.Vitamj.nisedo il B.P. Contains 1,000 I.U. vitamin A and100 I.U. vitamin D per gram.Emulsion of vitaminised oil B.P. Contains 50 per cent vita- ,minised oil.Cod~livero il U.S.P. Contains not less than 850 U.S.P. unitsvitamin A and 85 U.S.P. units vitamin D.Cod-liver oil concentrate N.N.R. Contains between 50,000and 65,000 U.S.P. units vitamin A and between 5,000 and6,500 U.S.P. units vitamin D.Cod-liver oil B.P. Contains not less than 600 units vitaminA activity and 85 units antirachitic activity.Emulsion of cod-liver oil U.S.P.; B.P. 50 per cent emulsionof cod-liver oil U.S.P.; B.P.Halibut-liver oil U.S.P. Contains not less than 60,000 U.S.P.units of vitamin A and 600 U.S.P. units of vitamin D.Halibut-liver oil capsules U.S.P. Contain 5,000 or 25,000U.S.P. units of vitamin A per capsule.Halibut-liver oil B.P. Contains not less than 30 000 units 1 . . 'v1tam1nA and between 2,500 and 3,000 units vitamin D.Burbot-liver oil N.N.R. Contains not less than 4,480 U.S.P.• units vitamin A and 640 U.S.P. units vitamin D per gram.Shar~-liv:r oil N.N.R. Contains not less than 16,500 U.S.P.units vitamin A and 40 units vitamin D per gram.,\•I298 Vitamins )• Percomorph.Iiver oil N.N.R. A mixture of fixed oils fromvarious percomorph fish. Contains not less than 60,000U.S.P. units of vitamin A and 8,500 U.S.P. units of vita~min D per gram.Carotene N .N .R.Carotene in oil N.N.R. Conta.ins not less than 7,500 U.S.P.vitamin A units per gram. ,Liver-B-vitamins injection U.S.P. Each cc. contains nJtfess than 0.08 mg. riboflavin, o.s mg. nicotinic acid and12 mg. choline.Dried yeast U.S.P. Contains not less than 0.12 mg. thiaminehydrochloride, 0.04 mg. riboflavin and 0.25 mg. nicotinicacid per grarn.Dried yeast tablets U.S.P.Triasyn B capsules and tablets U.S.P. Contain not lessthan 2 mg. thiamine hydrochJoride, 3 mg. riboflavin and20 mg. nicotlnamide.Rice polishings U.S.P. 'Rice-polishings extract U.S.P. Contains not less than 20U.S.P. units vitami,;i B1, representing approximately 14.SGm. rice polishings.Thiamine hydrochloride U.S.P. Ane~rine hyclrochloride B.P.• • Thiamine-hydrochloride tablets U.S.P. Available conta1n1ng3, S and 10 mg. thiamine hydrochloride.Thiamine-hydrochloride jnjection U.S.P.Adsorbate of vitamin B1 ; B.P. Contains 100 units antineuriticactivity per gram.Nicotinic acid (niacin) U.S.P.; B.P.Nicotinic-acid tablets U.S.P. Available containing 25, SO,and 100 mg. nicotinic acid.Nicotinamide U.S.P.; B.P.Nicotinamide tablets U.S.P. Available containing 25 andSO mg. nicotinamide.Nicotinamide injection U.S.P.Riboflavin U.S.P.; B.P.•I,•IPreparations 299Riboflavin tablets U.S.:P. Available containing l and 5 mg.riboflavin.Riboflavin injection U,S.P.Pyridoxine hydrochloride N.N.R. Accepted for purposes ofstandardization and experimentation only.Ascorbic acid U.S.P.; B.P.Ascorbic-acid tablets U.S.P.; B.P. Contains 25, SO and 100mg. ascorbic acid.Sodium-ascorbate injec:tion U.S.P. ,Synthetic oleovitamin D (viosterol in oil). Contains notless than 10,000 U.S.P. units of vitamin D per gram aseither activated ergosterol or activated 7-dehydrocholesterol.Calciferol (vitamin D2 ) B.P. Contains 40,000 I.U. antirichiticunits per mg.Vitamin D2 (Drisdol) N.N.R. -Solution of calciferol 13.P. Contains 3,000 I.U. per gram.Concentrated solution of vitamin D B.P. Contains 10,0001.U. per gram.Hexavitamin tablets U.S.P. Each tablet contains not lessthan 5,000 V.S.P. units l'itamin A, 400 units vitamin D,75 mg, ascorbic acid, 2 mg. thiamine hydrochloride, 3 mg.riboflavi' n and 20 mg. nicotinamide.Amigen N.N.R. A hydrolysate of casein prepared by enzymaticdigestion. ,Parenamine N .N .R. A hydrolysate of casein prepared byacid digestion.BIBLIOGRAPHY, GENERAL 'The ;Biologica~ Action of the Vitamins, A/Symposium,C~1c~g~, Univ. Chicago Press, 1942.In~1scr1m1nate administration of vitamins to workers in1~dustry, Council on Foods and Nutrition and the CounThcilo!l ln?ustrial l!ealth, J.A.M.A. 118: 618, 1942.e V1tam1ns- A Symposium, Chicago, A.M.A., 1939.'\300 VitaminsGordon, E. S., and E. L. Severinghaus: Vitamin Therapyin General Practice, Chicago, Yr. Bk. Pub., 1940.Methods 1 of Vitamin Assay, Ne,v York, Interstience,1947. 'Jeghers, H.: Vitamins in present-day treatment, ?If. Clin.North America 29: 1294, 1945.Jolliffe, N. : The preventive and therapeutic use of vita•mins, J.A.l\f .A. 129: 613, 1945.Molitor, H.: Vitamins as pharmacological agents, Feder·ation Proc. l: 309, 1942.Pett, L. B. : The use and abuse of vitamins, Canad. M.A. J.52 : 488, 1945.✓ Rosenberg, H. R.: Chemistry and Physiology of the Vita•mins, New York, lnterscience, 1942.VITAMIN AJosephs, H. W.: Hypervitam.inosis A and carotenemia,Am. J. Dis. Child. 67: 33, 1944.Moore, T., and Y. L. Wang: Hypervitaminosis A, Biochem.J. 39: 222, 1945. 'THIAMINEIBean', W. B., T. D. Spies and R. W. Vilter: A note onirradiation sickness, Am. J. M. Sc. 208: 46, 1944.Field, H., Jr., and '\V. D. Robinson: The absence of reactionsfollo,ving therapeutic doses of nicotinic acidamide, Am. J. M. Sc. 199: 275, 1940.Laws, C. L.: Sensitization to thiamine hydrochloride,• J.A.M.A. 117: 176, 1941.Mann, I.: Ariboflavinosis, Am. J. Ophth. 28: 243, 1945.Oppenheim, A., and B. Lih: PeroraJ administration ofvitanfin B6 (pyridoxine hydrochloride) in the treatment• of radiation sickness, Radiology 47: 381, 1946.Reingold, I. M., and F. R. Webb: Sudden death folJo,vingintravenous injection of thiamine hydrochloride,J.A.M.A. 130: 491, 1946.Williams R. R.,' and T. D. Spies: Vitamin B1 (thiamin)and its 'use in medicine, Ne1v York, Macmillan, 1939.•IBibliography 301VtTAM.lN D IBauer, J. M., and R. H. Frey berg: Vitamin D intoxicationwith metastatic calcification, J.A.M.A. 130: 1208, 1946.Covey, G. W., and H. W. Whitlock: Intoxication resulting{ram the administration of massive doses of vitaminD with report of five cases, Ann. Int. 1\,fed. 25: 508,1946.Gaumond, E., and J. Grandbois: Vitamin D2 in the treatmentof lupus vulgaris, Canad. M. A. J. 56: 205, 1947.VITAMIN EMason, K. E.: Pl1ysiological action of vitamin E and itshomologues,. Vitamins & Hormones 2: 107, 1944.f\iinot, A. S., and H. E. Frank: Serum tocopherol-its relationto failure of vitamin E therapy for pseudohypertrophicmuscular dystrophy, Am. J. Dis. Cl1ild. 67: 371,1944.Shute, W., and E. Shute: The prevention of prematurelabour, J. Obst. & Gynaec. Brit. Emp. 52: 570, 1945.VITAMIN pGriffith, J. Q., Jr., J. F. Couch and M.A. Lindauer: Effectof rutin on increased capillary fragility in man, Proc.Soc. Exper. Biol. & 11:ed. 55: 228, 1944.Scarborough, H.: Observations on the nature of vitamin Pand the vitamin P potency of certain foodstuffs, Bio~chem. J. 39: 271, 1945. \VITAGENSBeatns, A. J.: The treatment of cirrhosis of the liver withcholine and cystine, J.A.?i.f.A. 130: 190, 1946.Be~t, ~- H., and C. C. Lucas: Choline chemistry andsJgn1ficance as a dietary factor, Vitamins & Hormones1: 1, 1943.Gyporgy, P.: E}Cperimental hepatic injury, Am. J. Clin.ath. 14: 67, 1944.Hahnsen, A. E., and G. 0. Burr: Essential fatty acids anduman nutrition, J.A.M.A. 132: 855, 1946.Hech~, H. '!J.·: Reactions to intravenously administered ~!1~94~16ds (casein hydrolysates), Am. J. M. Sc. 212:' ••(302 Vitamins 'Holt, L. E., and A. A. Albanese: Observations on aminoacid deficiencies in man. Tr. A. Am. Physicians 58: 143,1944.Madden, S: C., S. H. Bassett, J. H. Remington, F. J. C.Martin, R.R. Woods and F. W. Shull: Amino acids intherapy of disease-parenteral and oral administrationcompared, Surg. Obst. & Gynec. 82: 131, 1946.Riegel, C., C. E. Koop, R. P. Grigger, J. E. Rhoads andL. Bullitt: The protein requirements of surgical patientsduring the postoperative period, S. Clin. of NorthAmerica 25 : 1096, 1945. -' 'I-I)• '23Diagnostic AgentsPHTHALEIN DERIVATIVESPHTllALEINSRADIO•OPAQUE iiUBSTANCESBIOLOGIC PRODUCTS •PREPARATIONS., This chapter is devoted mai.nly to a discussion of variousdrugs used chiefly or wholly for securing information regard-...ing the function and structure of various organs or tissues.It also includes a summary of a number of biologic productswhich are used to determine susceptibility to infectiousdiseases or to allergies.To be of practical value, tests employing drugs for diagnosticpurposes should be simple to perform and to interpret,and the agents used should not give rise to serious untowardre"a ctions. Information concerning the technics and theclinical value of the many liver- and kidney-function testsnow in use may be found in the review articles which are- listed in the bibliography. •PHTHALEIN DERIVATIVES,Jn •1909, Abel and Rowntree examined a series of phthaleinswith a view to finding a purgative suitable for subcutaneousinjection. In the course of this work they reportedthat f ollo,ving parenteral administration phenoltetrachlorphthaleinwas excreted only in the bile, while phenolsulfon-,303 --'304 Diagnostic Agents•phthalein (phenol red) was excreted almost exclusiveliynthe urine. These findings were promptly adopted byRo,vntree and his a'.ssociates as a means of t~sting liverand kidney function respectively. Rowntree's liver-functiontest involved determination of the amount of the dye excretedin the stools during the 48-hour period subsequentto its intravenous injection. Rosenthal later showed that theliver function could be more conveniently tested by foJJowingthe rate of disappearance of the drug from the bloodstream. This investigator also examined a further series ofphthalein dyes for their value i.n indicating hepatic damageand found that pbenoltetrabromphthalein sodium sulfonate(sulfohromophthalein sodiu.mU .S.P., bromsulphthaJein)w asthe most suitable for the purpose.PHTHALEINSTh 1923, Graham and his associates began a series ofstudies on radio-opaque bromo- and iodophenoJphthaleinderivatives ,vhich could be used simultaneously for cbole-cystography and for the determination of hepatic funct•i on.Of these, sodium tetraiodophenolpbtha1ein (iodophthaleinsodium U.S.P.) and sodium phenoltetraiodophthalein (phentetiophthaleinsodium N.N.R.) are most commonly used.In general, the phenolphthalein compounds are relatively ,free from toxic symptoms. Sodium iodophthalein may causegastro-intestinal upsets, dizziness and a fall in blood pressure.It should be used with caution in cases of heart andkidney damage.Sodium fluorescein (sodium resorcinalphthalein) is usedas a diagnostic agent in ophthalmology. It stains diseasedareas of the cornea a bright fluorescent green, while foreignbodies appear in a green ring. Fluorescein has also beenused to determine the 1ine of demarcation of gangrenousareas. ':fhe dye is injected intravenously and areas with anadequate blood supply promptly show a greenish color under, ultraviolet light.'IIBrBr•,PhthaleinsPhthal einsOHc,0c/\\0Phe nolpht ha I ei nOH OHBrSu I I obrom oph1 holtinSodium0IIlONaC10NaC~ \\ 'OH OHc,0s/II\\0 0Phenolsulf onphthaleinONaClodo p hthalelnSodium•0Fluorescein Sodium '305••••'p•306rIDiagnostic AgentsRADIO-OPAQUE SUBSTANCESBAIUUM SU, LFATE•Barium sulfate was introduced in Germany in 1910 as acontrast medium for roentgen examinations of the gastrointestinaltract. It is nontoxic because of its extreme insolu•bility and is very inexpensive. A number of fatal cases ofbarium poisoning have been reported due to accidental sub•stitution of soluble salts, especially barium sulfide. To avoidsuch errors, it is recommended that when barium sulfate isprescribed, the title of the drug be written out in full.Previous to the introduction of barium sulfate, insolublebismuth salts were used in roentgen examination of thegastro-intestinal tract. They are still used to a limited extent,the subcarbonate being preferred to the subnitrate becauseof its lower toxicity.THORIU?i{ DIOXIDEThorium dioxide is an intensely radio-opaque substancewidely used as a contrast medium in the form of a stabilizedcolloidal solution (thorotrast). On intravenous injection, itis rapidly taken up by the cells of the reticulo-endothelialsystem and it is, therefore, of particular value in roentgen•ography of the liver, spleen and blood vessels. It has alsobeen injected into the lacteal ducts in mammographic studies, Jbut its use is accompanied with a high incidence of irritatingeffects.• The chief danger in the use of thorotrast lies in the fact• that it remains in the body for an indefinite period of time,during which it emits radioactive disintegration productswhich may give rise to late toxic manifestations of a seriousnature.IODINE PREPARATIONSIodized Oils. A number of radio-opaque preparations areavaiJabJe which consist of iodine addition products of veg~tible oils. These preparations are nonirritating and can be'•l Radio-Opaque Substances 307injected into various cavities of the body, such as the urinaryand genital tracts, bronchi, fistulous tracts and thespinal canal. They are removed slowly from closed cavitiesand may give rise to foreign-body reactions. If injectedunder considerable pressure, oil embolism may result. Themost common toxic symptoms associated with the use ofiodized oils are those of iodism, including swel1ing of theparotid and submaxillary glands and skin eruptions. Allergicresponses, occasionally fatal, have also been reported.Pa1ztopaquew as introduced in the United States in 1942as a contrast medium in myelography. It consists of amixture of isomeric esters, with ethyl iodophenylundecylic\acid apparently the principal one. It is more fluid than theiodized oils and can be more readily injected into andaspirated out of the spinal arachnoid space.IWater.Soluble Iodine Compounds. In addition to cer~tain phthalein compounds, a number of radio-opaque solubleorganic iodine compounds are used for visualization of theurinary and.biliary tracts. They should be avoided in renal ,or hepatic insufficiency, tuberculosi! and other severe illness.Untoward effects occasioned by these preparations includeflushing of the skin, nausea, skin eruptions and disturbancesof respiration.lopax (uroselectan), neo-iopax (uroselectan, iodoxylum),metliiodal (skiodan, abrodil), iodopyracet (diodrast, neo•skiodan) and kippuran are effective contrast substances foruse in intravenous pyelography or for retrograde pyelogra•phy. The first of these substances to be used clinically wasiopax, which was introduced for intravenous pyelography by?Wick in 1929 to replace the more toxic sodium iodideintroduced by Rowntree and his associates in 1923. Largedo~es of these preparations may lead to suppression of~rin? formation. lodopyracet is also used in roentgen examJnat1onsof the biliary tract and blood vessels. For the latterpurpo~e, ~ concentrated solution is available. The technic,however, 1s quite complicated and not without danger.I ,I\•308 Diagnostic Agentslodoalpltionic acid (priodax) ,vas introduced in Germanyin 1940 under the name of biliselectan as a medium forcholecystography. It is claimed to cause fewer gastro-intes-I1•Iodine Compound's0 •,1CH2\S03NDMethiodal sodium•CO-NH-CH 2-COONoHippu,anI0IIINaoor....1.·ICOONa' •N, . 'CH3Neo-iopa)( \•Rl I•OHlI IIodoalphionic odd(I-•tinal upsets than iodophthalein. Furthermore, it is excretedlargely by the kidneys and therefore does not cause confusingshadows in the hepatic flexure. Iodoalphionic acid isknown in Great Britain as pheniodol .•• •Biologic Products 309BIOLOGIC PRODUCTSA number of biologic products ,ate available for the 'diagnosis either of the presence of or the susceptibility toa given disease. A summary of the nature, source and usefulnessof these preparations is presented in Table 5.Other biologic products are used in diagnosis and treatmentof hypersensitivity reactions. These include proteinsfrom animal and plant sources, extracts of animal furs,feathers and hairs, and pollen extracts. None of thesepreparations has been recognized by the United StatesPharmacopoeia. However, a number are listed in New andNon•official Remedies, from which further details can beobtained.PREPARATIONSSulfobromophthalein sodium U.S.P.Sulfobromophthalein-sodium injection U .S.P. Usually avail•able 1S0 mg. sulfobromophthalein in J cc. I.V. 2-5mg./Kg. .. .,Iodophthalein sodium U.S.P. Iodophthalein B.P. I.V. 0.3Gm. per 10 Kg. Oral 0.5 Gm. per 10 Kg.Phenolsulfonphthalein (phenol red) U.S.P.Phenolsulfonphthalein injection U.S.P. Usually available•as 6 mg. in l cc. I.V. or intramuscular 6 mg.Phenoltetrachlorphthalein N.N.R. I.V. 5 mg./Kg.Phentetiothalein sodium (phenoltetraiodophthalein Na)N.N.R. I.V. 40 mg./Kg.Fluorescein sodium U.S.P. Soluble fluorescein B.P.Barium sulfate U.S.P.; B.P.Iodized oil U.S.P. An iodine addition product of vegetableoils containing from 38 to 42 per cent combined iodine.Iodised oil B.P. Iodine addition prQ.guct of poppyseed oil.Contains from .39 to 41 per cent combined iodine.Lipiodol 40 per cent iodine N.N .R. •Lipiodol radiologique ascendant N.N.R. Contains 10 percent iodine.I,l'UPAJtATIONSDiagnostic diphtheria toxinU,S.P.. I(Sthlck test tonn)Scarlet fever streptococcustoxin U.S.P.(Dick test t.o.iin)Scarlet fever streptococcusantitoxin U.S.P.Old tuberculinU .S.P.;B .P.(Tubttt11lin-K.oth)( Concentratedt1 1bttculin)( Crude tubemilln)~uri6ed protein derivativeof tuberculin U.S P.(P.P.D.)Ttlcblbellac ztnct N."N".R.<TABU S -BIOLOGIC TOXINS FOR. IMMUNl'l'Y TESTSSO'CraCBCorynebat:ltrium diphthlrilu cultures.Culture of auitablc &rains of hemolylicstreptococd.Blood serum or plasm.a of' healthyanimal inimunlzed against tomproduced by bactetia which causesarlet fever. ..Solutiono f gro\Vthp roducts of cultureof litycobacterium tuberculosis.A3 above, except non protein culturemedium is ustd.I•mJ:CT OJ' INnACUTAlttO'OS m]ECIIOMLocal skin nadJon inrucaus su.,aptlb.ility todipbthe~Local .skin mdiom lnclicate .susctpt.ibillty toscarlet fever. Can be used In larger a!ld r&peateddos~ for active immunization.Injection into site of rash will result in local dis,.appearance of rash if due to .scarlet fever. C3.nalso be used to produce temporary pasl>iveimmunity,Inflammation at site of Injection Indicates patienthas been inlectcd with tubercle bacilli at sometime.Saline dlgest of Trichinella f.ir11ae. ( Immtdia.te or delayed local reaction lndlcatestrltb.inosl.s.~ <_:.(N -0t:1 ~-~ ::r. n~ ('1) ::,!ii"\Preparations 311Iodobrassid N.N.R. Iodine addition product of rapeseedoil.Iodopyracet injection U.S.P. Diodrast.Iodoxyl B.P. Neo•iopax N.N.R. 15 Gm. in 20 cc. solutionintravenous.Hippuran N.N.R.l\1ethiodal sodium N .N .R.Iodoalphionic acid N .N .R. 3 Gm.BIBLIOGRAPHY(Diagnostic Agents)GENERALEggleston, C., and H. Gold: Drugs used in clinical diagnosis-revie\v of recent literature, Am. J. M. ~c. 208:661, 1944.Pear]mutter, M.: Drugs used in clinica] diagnosis; II. Re~vie\v of recent literature, Am. J. M. Sc. 212: 613, 1946.Mateer, J. G., J. I. Baltz, D. F. Marion, R. A. Holland and, E. M. Yagle: A comparative evaluation of the newerliver function tests, Am. J. Digest. Dis. 9: 13, 1942.11:cGhee, L. C., and J. E. Martin: Limitations of renalfunction determination, Ann. Int. Med. 132 : 1626, 1940.Teitalbaum, M., A. C. Curtis and S. M. Goldhamer: Thecomparative vaJue of several liver function tests, Ann.Int. Med. 22 : 653, 1945. ,Weir, J. F.: Tests of liver function, M: Clin. North' Atnerica 9743, 1945.IPHTHALEIN DERIVATIV£SAbel,.J. J., and L. G. Rowntree: On the pharmacologicalaction of some phthaleins and their derivatives, withespecial reference to their behavior as purgatives, J.~Pharmaco1. & Exper. Therap. 1: 231, 1909-1910.Graham, E. A.: The story of the development of cholecystography,Am. J. Surg. 12: 330, 1931.Hat~eld,. C. A., R. A. Buyers and A. A. \i\Talkling: Fluoresce1n-1ts use in determining the viability of strangulatedintestine, Surg. Gynec. & Obst. 81: 530, 1945.Rosenthal, S. M.: An improved method for using phenol-&tetrachlorphthalein as a liver function test, J. Pharmacol.Exper. Therap. 19: 385, 1922.'I312 Diagnostic Agents..Rosent~al, S. M., and E. C. White: Studies in hepaticfunction; VI-A. The pharmacological behavior of certainphthalein dyes, J. PharmacoJ. & Exper. Therap.24: 265, 1925.Ro,vntree, L. G., and J. T. Geraghty: An experimentaland clinical study of the functional activity of the kidneysby means of phenolsulphonephthalein, J. Phar-,macol. & Exper. Therap. 1: 579, 1909-1910.Ro,vntree, L. G., S. H. Hur,vitz and A. L. Bloomfield:An experimental and clinical study of the value olphenoitetrachlorphthalein as a test for hepatic function,Bull. Johns Hopkins Hosp. 24: 3277, 1913. 'Wirts, C. ,v., and A. Cantarow: A study of the excreti~nof bromsulphthalein in the bile, Am. J. Digest. D1s.9: 101, 1942. •RADIO-OPAQUE Su.BSTANCESDangers of the injection of iodized oils report of the'Council on Pharmacy and Chemistry, J.A.M.A. 99: 1932,1946. •Bernstein, P.: Hysterosaipingography, a routine aid ingynecological diagnosis, Am. J. Obst. & Gynec. 48: 444, 1~44.Eisen, D., and J. Goldstein: Lipiodol intravasation <f'ur1nguterosalpingography ,vith pulmonary complications,Radiology 45 : (5()3, 1945.von Lichtenberg, A.: The principles of intravenous urog- •raphy, J. Urol. 25: 249, 1931.Mahon, G. S. : Reaction follo,ving bronchography ,vithiodized oil, J.A.M.A. 130: 194, 1946.Reeves, D. L., and R. M. Stuck: Clinical and experimentalresults ,vith thorotrast, Medicine 17: 37, 1938.Quinby, W. C., and G. Austen: Suppression of urine complicatingpyelography, New England J, Med. 221 :814, 193?,Spier, J., L. W. Cluff and W. D. Urray: Aplastic ane~zafollo,ving administration of thorotrast, J. Lab. & Chn,Med. 32: 147, 1947.Unfug, G. A.: A comparative clinical jnvestjgation ofcholecystrographic preparations, Radiology 46: 489,' 1946.Weber, H. M.: The present status of contrast myelographyAm. J. l\f. Sc. 206: 678, 1943. •Yater, W. M., and F. 0. Coe: Ten years' experience ,vith, thorotrast hepatosplenography, Ann. Int. 1!ed. 18: 350,?943.<•· 24,Local Anti-Infectives•INTRODUCTIONACRIDINE DERIVATIVES, MERCURY AND SILVER PR.EPARATIONSIHALOGENSPEROXIDESPREPARATIONSALCOHOLSPHENOLSACIDSDETERGENTSNITROFURAZONEINTRODUCTIONIThis chapter deals with a heterogenous collection of preparations,vhich are said to counteract infection when applied \locally to the skin, mucous membranes and superficialwounds (antiseptics) or to inanimate objects (disinfectants).The activity of these preparations is due in some cases to adirect lethal effect on the pathogenic organisms (bacteriocides,germicides, fungicides or mycocides) and in othersto an arresting of their growth or activity (bacteriostats,germistats, fungistats or mycostats).The rational use of anti-infectives dates from the latterhalf of the nineteenth century. Pasteur's demonstration thatputrefaction and fermentation were due to living microbescame to the attention of the British surgeon Lister, who wasconcerned with the high mortality from infection followingsurgical procedures. Stimulated by Pasteur's discoveries,Lister introduced the use of phenol to sterilize operatingequi•p ment, as a spray for decontamination of the atmos•. phere and as a wet dressing for wounds. Despite the dramaticresults accomplished by these procedures, the irritat- ,I•-,314 Local Anti•lnfectivesing properties of phenol led to the abandonment of its useand to its replacement by aseptic techoics. The interestin antiseptics was revived during \Vorld War I, when it, became necessary to treat an overwhelming number ofseverely infected wounds under field conditions. After thewar, however, interest in these preparations was negligible,in large part because of disappointingr esults followingth e.earlier extravagant claims. -\Vith the introduction of the sulfonamides and the antibiotics,it appeared that, at last, the problem of localantisepsis had been solved. Unfortunately, ho\\'ever, as aresult of the widespread and often indiscriminate local useof these agents occasioned by the war, the inadequacies, and dangers of the local use of the sulfonamides and alsoof penicillin soon became apparent· (see Chapters' 29 and30) . This led to a re-examination of the older preparations,especially of the acridine derivatives, and to a search fornew preparations, of which propamidine seems the mostpromising (see Chapter 31). 'The efficacy of antiseptics and germicides is greatlyinfluenced by the conditions under which they are used.Important factors include the concentration of the drug;. the duration of exposure and the nature of the solvent; thespecies of organism; the phase of its growth and thepresence of serum, pus or blood. Thus, young cells areusually more susceptible than old ones, while spores orcapsulated forms are, as a. rule, very resistant. Organicsubstances, especially proteins, may lead to protective filmsaround the organisms or to interference with the antiseptic.However, the activity of acrifiavine, for example, may beincreased by the presence of serum because of the fact thatthe dye is a more effective antiseptic in an alkaline medium.The strength of an antiseptic or of a disinfectant is con-• ventionally expressed by its phenol coefficjent. This repre•sents the ratio of its germicidal power to that of phenol, bothbeing tested under identical conditions. The test, however,'✓ Introduction 315is only reliable in determining the efficacy of water ..s olublecompounds related chemically to phenol. It is performedon a synthetic medium, using Stapl1ylococcus aureus (oroccasionally E. typliosa) as the test organism. Hence itdoes not take into account the effect of the presence oforganic matter, nor does it yield information concerning theirritant effects of the compound on normal tissues. Severalother methods have therefore been devised to obtain a- bro' ader range of inforniation. These include toxicity studieson tissue culture cells or on chick embryos; determinationof inhibiting effects on the respiration of liver tissue in vitroor on the phagocytic activity of leucocytes; and the examinationof skin washings for the presence of bacteria foil owingapplication of the preparation. _ -As yet, no ideal antiseptic has been developed. Such a , .substance should possess high efficiency and low toxicity.It should be capable of penetrating into skin, pus, cellulardebri~, and so on. It should not irritate, blister or burn the- normal tissue nor should it interfere with the natural healingprocesses. Finally, it should be effective against a wide ,,range of pathogenic organisms.ACRIDINE DERIVATIVES2,8-diomino-I 0-methylacridinium, chloride2 ,8- diominoacrldineIIAcri.flavine was first thought to be 2,8-diamino-lO~meth- 1ylacridinium chloride. It is 'now known ta consist of avari_ablem_ ixture of this compound and 2,8-diaminoacridine.Acr1fJaV1nwe as shown by Ehrlich in 191Z to be trypano,•316 Local Anti•Infectivescidal, hence it is also known as trypaflavine. Its bacteriocidalaction was demonstrated by Browning in 1913 and itbecame ,videly used for wound antisepsis in ,vorld \Var I.It is probably the least effective and the most toxic of theacridine derivatives in present-day use.Proflavine is 2,8-diaminoacridine. It was first made availableas the bisulf ate salt, which required neutralization withsodium bicarbonate or a buffering salt. It is now availableas the Jess acid monosulfate. It has been used successfullyas a fine dusting powder on suppurating wounds but shouldbe used sparingly on relatively clean wounds, otherwisecoagulation necrosis may be produced.5-aminoacridine or monacrine was introduceclby Albertin 1942. It has essentially the same properties as acrifiavineand proflavine. It is almost co1orJessa nd does not thereforestain clothing. Both monacrine and difiavine (2,7-diamino-• acridine) are said to be more effective against gram.negativeorganisms than the other acridines.During \Vorld \Var II, the use of acridine dyes combinedwith sulfonamides was advocated because of their allegedsynergistic action. However, such preparations, when usedlocally, owe their activity almost entirely to their acridinecomponent and at the same ,time present the same hazardsas does' the local application of the sulfonamides.The acridines inhibit the growth of a wide variety ofpathogenic bacteria. They are active in the presence of• serum proteins and are relatively nonirritant in effectiveconcentrations, though high concentrations may have dam•aging effects on normal tissues. They possess a low systemic• toxicity and probably do not interfere with phagocytosrs.They have been injected intravenously as systemic antiinfectivesbut their value is questionable. Their disadvan•tages include their affinity for fabrics, such as surgicaldressings and clothing and the instability to light of thethe colored compounds .•••l\.Iercury and Silyer Preparations 317- 1\IERCURY AND SILVER PREPARATIONS',_Inorganic Mercury Compounds. In 1881, Koch reportedthat solutions of mercuric bicbloride possessed a powerfulgermicidal activity, destroying even bacterial spores. Al.though Geppert, in 1889, demonstrated conclusively thatthis preparation ,vas bacteriostatic rather than bacteriocidal,Koch's views persisted and mercury compounds havelong received an undeserved popularity as sterilizing agents.The value of mercurials as disinfectants and antisepticsis limited by their corrosive effect on metals, their i~ritanteffect on tissues, their inactivation by organic matter andtheir high toxicity to man and animals. Of the inorganicpreparations, only the soluble salts of the bivalent formare effective. The bichloride (corrosive sublimate) has been ,most widely used. Other preparations include the cyanideand the iodide.The action of inorganic mercurials is thought to be due 1to the precipitation of the bacterial proteins by mercuryions with the formation of a mercury proteinate. The combinationis believed to take place at the sulfhydryl groups.Organic Mercury Preparations. Organic mercury compoundsare less toxic and less effective anti-infectives than' the inorganic mercury compounds. They are of som~ valuewhen applied prophylactically to fresh wounds and are.widely used as preservatives in biologicals which are to beadministered parenterally. It should be emphasized, however,that neither inorganic nor organic mercury preparationsare ~ble to destroy spores. The action of organicmercurials may be due to the action of the molecule as a~ whole rather than to the liberation of mercurial ions. \Organic mercurials used as anti-infectives include thephenyl mercuric compounds (borate, picrate and nitrate),merbromin (mercurochrome), nitromersol (metaphen) andmerthiolate. Merbromin was introduced in 1919 by Youngand his associates as a germicide for the genitourinary tract. .'318 Local Anti-InfectivesIts popularity immediatly became widespread and it waseven used intravenously for the treatment of septicemiaI .. ater, more critical studies showed its value to be quitelimited. •Simple Silver Salts. Silver salts, such as the nitrate,lactate and picrate, are astringent and corrosive as well asantiseptic and germicidal. Their activity is due largely tothe liberation of silver ions and possibly to the liberationNaOBr'HOH0 ~ ,9I ,,1COONaMerbromin-0IHgMetaphenIIMerthiolateof silver, which is germicidal in very minute amounts.· Silvernitrate as a 1 to 2 per cent solution has been used propbylac•tically against gonorrheal ophthalmia neonatorum since1881, when Crede demonstrated its value.Prolonged use of any silver preparation may result inpermanent pigmentation of the skin (argyria).Colloidal Silver Preparations. Colloidal silver prepara·tions lack the astringent and corrosive properties of thesilver salts. They consist of indefinite mixtures of metallic~silver, silver oxide and various silver-protein compounds.The strong silver-protein preparations, such as protargol,are intermediate in their germicidal action between thesilver salts and the mild silver protein compounds. Theycontain 8 per cent silver and are used in concentrations offrom 0.1 to 10 per cent. Mild silver-protein preparationscontain from 19 to 23 per cent silver, but they are less active1IMercury and Silver Preparations 319\germicides' and irritants than the strong preparations. Theyare used in concentrations of from 5 to SO per cent.HALOGENSCompounds liberating chlorine by hydrolysis, organiccompounds containing highly active chlorine groups, andsolutions of gaseous chlorine are germicidal, probably bothby the formation of chloramines by replacement of thehydrogen in free amino groups of the bacterial proteins andby an oxidizing action. These preparations are used in thepurification of water or sewage, in ·the disinfection of dairyequipment and for bleaching purposes. The more stablepreparations, such as Dakin's solution (alkaline solutionoI sodium or potassium hypochlorite) and the chloramines,can be applied to infected wounds. 1Iodine and certain iodine-containing compounds arewidely used as antis~ptlcs and disinfectants. TinctLre of-1 iodine is used almost routinely as a skin antiseptic at thesite of surgical operations. Iodine-containing compounds,such as iodoform and iodochlorhydroxyquinoline (vioform),have been used on wounds in the form of dusting po,vders.'They liberate iodine slowly and lack the irritant action of,..tincture of iodine. The use of iodine prepar:ations as amebacidesis discussed in Chapter 26.PEROXIDES" Hydrogen peroxide has a mild germicidal action due t~ ~the liberation of oxygen. This is greatly accelerated by thepresence of organic matter and by the enzyme catalasewhich is present in all living cells. The rapid evolution ofgas makes the injection of hydrogen peroxide into clo~ed,.,. cavities or abscesses dangerous.. Zinc peroxide consists of a mixture of zinc r>eroxide ~ ,zinc carbonate and zinc hydroxide. Like all metallic peroxides,it liberates oxygen more slowly than does hydrogenI• •I320 • Local Anti-Infectives i-----------r------------ Iperoxide. It is of vaJue in the treatment of infectioncsa usedby anaerobic organisms.I Sodium peroxide forms an alkaline and caustic solutionwith ,vater. It is used largely by dentists as a bleachingagent. Incorporated into soap, it is used in the treatment1 of acne.Potassium permanganate also exerts its antibacterial, activity by oxidation. It has been used for wound dressingsand for the treatment of gonorrhea but its staining qualitiesare undesirable. It can be used in the disinfection of water,but it imparts a disagreeable taste and the residual manganesecompounds may produce toxic effects.,lIALCOHOLSEthyl alcohol is a fairly effective germicide' because of its,•dehydrating, coagulating and cleansing action. The optimumconcentration is 70 per cent by weight. 'Isopropyl alcohol is a more powerful germicide thanethyl alcohol and has the further advantage of being amore efficient cleansing agent because of its lower surface• _tension and greater fat-solvent activity. It is most acti~ein full strength and is not so corrosive for metal instrumentsas 70 per cent ethyl alcohol. Neither ethyl nor isopro_pylalcohol is capable of destroying spores even after prolongedexposure.• Glycol vapors, particularly those of propylene and tr1-ethylene glycol, have recently been shown by Robertson a~dhis associates to be effective germicides for the control ofair-borne diseases. \Vhen suitable practical technics havebeen evolved for dispersal of the vapors and for the control0£ their concentration, they should prove useful in the disinfectionof closed spaces, such as hospital rooms, schoolrooms,barracks and theaters.PHENOLSThe phenols exert their germicidal activity by coagulationof bacterial proteins. They are effective against many'_.._ I~ Phenols 321•Ispores and are used, for the most part, for sterilizing inani 4, mate objects. They are irritant when applied to tissues ingermicidal concentrations and penetrate poorly. They arereadily absorbed from wounds, mucous surfaces and theintact skin and may give rise to systemic poisoning characterizedby central nervous system depression. They alsoproduce local anesthesia of the exposed area.Hexylresorcinol was introduced by Leonard in 1927. Itis used as an antiseptic in a l: 1,000 solution in glycerin andwater (S.T. Ji), and as an anthelmintic in solid form (seeChapter 2S). Its germicidal effect is due in large part toits surface-tension-lowering effect.The cresols are several times as germicidal as phenolitself and somewhat less toxic. They have a very disagreeableodor and are relatively insoluble in water. Their toxicityand local irritant action may be reduced by esterifica ..tion. One such compound is the acetic-acid ester of metacresol,metacresylacetate or cresatin. It is used in pure formor diluted with oils or alcohol.ACIDSRadical alteration of the hydrogen-ion concentration willeffectively kill most micro.organisms. However, strong acidsand alkalis are too corrosive to use on living tissues, \Veakacids, such as boric, benzoic and salicylic acids, have mildantiseptic properties, due both to their effect on the pH 9fthe medium and to a specific toxic action of the undissociatedmolecule# They are also of value in restoring thenormal acidity of infected areas of the skin, thereby assist- 'ing the natural defense mechanisms. Salicylic acid has the \added advantage of being a keratolytic agent, producinga slow and painless destruction of the epithelium which aidsin the removal of deep infections. Thus \Vhitfield's oint•"!ent, used widely in fungus infections and ringworm, conSlStsof a mixture of 3 per cent salicylic acid and 5 per centbenzoic acid in a bla:rid base.322 ' Local Anti-Infectives'DETERGENTSThe detergents include the common soaps and the so.called synthetic detergents. They exert their anti-infectiveaction in large part by the simple removal of the microorganisms.They lower the surface tension of the water,enabling it to surround and wash away the adhering organismsas well as grease and dirt particles. The removaJo f thegrease and the softening of the film in which the organismsare embedded makes the emulsification and washing offeasier. In addition to their cleansing action, the detergents,possess in many cases a direct toxic action, on the bacteria.This may be intensified by the addition of other germicides,' such as mercuric chloride, but usually the concentration istoo low to be of any value if the preparation is to remainnontoxic.The action of the common soaps is enhanced by theircontent of free alkali and the appearance of considerablymore alkali when the soaps are hydrolyzed. This alkalinity 'may be important in determining the degree of direct germicidalaction of the soap. In addition, it promotes morerapid desquamation and thereby aids in the removal ofpathogenic agents from the skin.The most effectjve synthetic detergents are the cationiccompounds, including benzaikonium chloride (zephiranchloride, a mixture of alltyl dimethyl benzyl ammoniumchlorides}, phemerol chloride and cetyI pyridinum chloride.These preparations consist essentially of ammonium saltswith organic groups substituted for the hydrogen atoms.They are in general more effective against gram-positive thanagainst gram-negative organisms. Their activity is greatJyreduced by the presence of soap or other anionic detergents.NITROFURAZONEJt has been known for many years that a number of com•pounds containing the f utan nucleus possess antiseptic prop.erties. However, a' systematic investigation of compounds~-------------N--itr-o-fu-r-az-o-n-e 323• of this type was not undertaken until 1944, when Doddsand Stillman demonstrated that the presence of a nitrogroup at 'position 5 greatly increased the antibacterial activity.One such compound, 5-nitro 2-furaldehyde semicarbazone(nitrofurazone) bas been recently introduced underthe name of furacin as a dressing for wounds and chroniculcers. It is apparently effective against both gram-positiveand gram-negative organisms and is claimed to have little0 N I ;,--I CH=N-NH-CONH2 o 2Nit rofu razone•or no effect·o n normal tissues. A number of cases of sensi-•tivity have been reported following its use. These may wellhave been due to the ointment-like base in which the compoundwas incorporated and which has since been changed.PREPARATIONSAcriftavineB .P. Acriflavineh ydrochloride N.N.R. Usually.used as l: 1,000,solution..Acriflavinbe ase N .N. R.Proflavine sulfate B.P. .1:roflva ine sulfate ( 2 ,8-diami~oacridinium monohydrogensulfate) N.N.R.lierc1ur!c chloride B.P. ~As a disinfectant, 1: 11000-2,000so ut1on. As an antiseptic, 1 : 6,000.Mercuric cyanide N.N.R.!\Iercuric oxycyanide B.P.l\Iercuric iodide B.P.Potassium mercuric iodide N N R /l,i er br?m1•n N.N.R. Usually u• se•d •a s a 2-5 per cent solution..1.,Ierth10IaNte.N .R.y• • ' 'Local Anti-Inf ecti vesNitromersol N.N.R.Merphenyl borate, merphenyln itrate and' merphenypl icrateN.N.R. 'Silver nitrate U.S.P.; B.P.Toughened silver nitrate (lunar caustic) U.S.P.; B.P.Silver lactate N.N .R.Silver picrate N.N.R.Mi]d silver protein U.S.P. IStrong silver protein B.P.; N.N.R.Surgical so1ution of chlorinated soda. (Dakin's solution) B.P.Chloroazodin U .S.P.ChJoroazodin solution U.S.P.Chloramine-T. N .N. .R. Chloramine B.P.Dichioramine-T. N.N.R.Hyclorite N.N.R.Succinchlorimide N.N.R. (for water disinfection).Halazone N.N.R. (for water disinfection).Iodine tincture U.S.P. Contains 20 Gm. iodine, 24 Gm.sodium iodide in 1000 cc.Strong solution of iodine B.P.Weak solution of iodine B.P.Iodoform H.P.Hydrogen peroxide solution U.S.P.; B.P. Approximately 3per cent solution.Sodium peroxide N.N.R.l\1edicinal zinc peroxide U.S.P. Contains zinc peroxide, zinccarbonate and zinc hydroxide., Potassium permanganate U.S.P.; B.P.Alcohol U.S.P.; B.P. Approximately 92 per cent ethylalcohol by weight.Isopropyl alcohol N.N.R.Phenol U.S.P.; B.P.Cresol U.S.P.; B.P. A mixture of isomeric cresols obtainedfrom coal tar. •~ Cresatin N.N.R. •l • ' Boric acid U.S.P.; B.P. (j••'Preparations 325Boric-acido intme'n t U.S.P.; B.P. Contains approximately10 per cent boric acid.Benzoic acid U.S.P.; B.P.Salicylic acid U.S.P.; H.P.Ointment of salicylic acid B.P. Contains approximately 2per cent salicylic acidPhemerol chloride N .N .R.Benzalkoniumc hloride U.S.P.Nitrofurazone N.N.R.•BIBLIOGRAPHY; GENERALGarrod, Lawrence P.: Principles and practice of localchemotherapy, Brit. M. Bull. 4: 275, 1946.Huqter, A. C.: The evaluation of antiseptics, J.A.M.A.121: 25, 1943.McCulloch, E. C.: Disinfection and Sterilization, PhilaMdelphia, Lea, 1945.ACRIDINE DERIVATIVESAlbert, A., S. D. Rubbo, R. J. Goldacre, M. E. Davey andJ. D. Stone: The influence of chemical constitution onantibacterial activity, Part 11-a general survey of theacridine series, Brit. J. Exper. Path. 26: 160, 1945.Heggie, J. F., G. B. R. Warnock and R. W. Nevi11: 1'Neutralproflavine sulfate" ( n1onosulfate of 2: 8-diaminoacridine),its local action infected wounds involvingbone, Brit. M. J. 1 : 437, 1945.~fartin, G. J.: Acridine antiseptics, Medicine 23: 79, 1944.I \l\fERCURY AND SILVER CO!.lPOUNDSOrganic mercurial compounds as bactericidal agents{ Council report) , J .A.M .A. 115 : 2083J 1940.Bre\ver, J. H.: The antibacterial effects of the organicmercurial compounds with special reference to theiruse as germicides for the sterilization of surgical and~ental instruments, J.A.M.A. 112: 2009, 1939.Hill, W. R., a_nd D. M. Pillsbury: Argyria, the Pharmacologyof Silver, Baltimore, Williams & Wilkins, 1939.'I\ •326 Local Anti-Infectives~ Young, H. : A new germicide for use in the genito.uri•nary tract: ''mercurochrome-220,'' J.A.M.A. 73: 1483,1919.PEROXIDESFreeman, B, S.: The use of zinc peroxide in malignantlesions, J.A.M.A. 115: 181, 1940.'ALCOHOLSArcher, G. T. L.: Bactericidal effect of mixtures of ethylalcohol and ,vater with special reference to sterilization ,of the skin, and a note on the comparable effects ofether, Brit. M. J. 2: 148, 1945.Hamburger, M., Jr., 0. H. Robertson and T. T. Puck:The present status of glycol vapors in air sterilization,Am. ]. M. Sc. 209: 162, 1945.DEl'ERGENl'SMedical Uses of Soap-A Symposium, Phila<le]phia,Lippincott, 1945.Morton, H.: "Germicidal" soap, J.A.M.A. 124: 119S1, 944'.1°'tmAN D1mIVATlVESIDodd, M. C., and W. B. Stillman: The in vitro bacterio·static action of some simple furan derivatives, J. Phar- •ma col. & Exp er. Therap. 82: 11, 1944.Downing, J. G., M. C. Hanson and M. Lamb: Use of ,5-nitro-2-furaldchyde semicarbazone in dermatology,J.A.M.A. 133: 299. 1947. 1••1-25I'Intestinal AnthelminticsINTRODUCTION THYl.lOLCARBON TETRACHLORIDE AND BETANAPHTHOLTETRACHLOROETHYLENE l.lETHYLROSANILINEHEXYLRESORCINOL CHLORIDEOIL 011 CHENOPODIUl\lSANtONlNASPIDIUl\lMISCELLANEOUSA GENTSPREPARATIONSINTRODUCTIONIAnthelmintics are drugs used to rid the body ,.of worms.They are sometimes classified as vermicides, which have a, direct lethal action on the worm, and vermifuges, causing.evacuation of the worms without exerting a direct lethaleffect. , /itost parasitic worms are found only in the gastro-intes-. tinal tract, notable exceptions being the schistosoma, filariaand trichinella, which are tissue invaders. The prime requisitesfor an intestinal anthelmintic are low toxicity whenapplied locally to mucous surfaces and either low toxicityafter absorption or the property of nonabsorbability fr9mthe gastro-intestinal tract. J\.Iany of the drugs discussed inthis chapter would, if absorbed, cause serious toxic effectsor death with much lower doses than those required for eradicationof the parasites. Hence, the mechanism of the chemo-. therapeutic action of these agents is not a specific differentialtoxicity towards the host and the parasite but is amatter of -localization of the. drug on or within the parasite.,••I'• • •328 Intestinal AnthelminticsIn practice, a certain amount of absorption of these drugsfrom the gastro•intestinal tract invariably occurs. The possibilityof toxic effects can be minimized, however, by cer.tain precautionary measures. Thus, the presence of alcoholand of fatty foods in the gastro-intestinal tract may increasethe absorption of the anthelmintic to a dangerous degree;therefore, these must be avoided for a day or two before thedrug is given. 1\1any of the anthelmintics have a deleteriousaction on the liver and especially on a glycogen-depletedliver, hence the state of nutrition of the patient may havea marked influence on the toxicity of these drugs. Bestresults are usually obtained if the patient is allowed a lightmeal 12 hours before the drug is to be given. .Anthelmintics should always be followed promptly bypurgation. This serves the dual function of sweepingo utthe dead or dying worms and removing the potentially toxic •antheimintic. In general, saline purgatives are recommended.Most anthelmintics are fat.soluble, and oiJy purges are saidto facilitate their absorption, but this is probably on1y truein the case of absorbable oily purgatives, such as olive oil.While each anthelmintic exerts some deleterious actionon all of the common worms, it is usually particularly effectiveagainst one species. Stool examinations should be made,therefore, to identify the particular parasite or parasitespresent so that the most effective agent may be chosen.A single administration of an antbelm.intic is not alwayssufficient to eradicate the infestations completely. If successivedoses of anthelmintics are required, they should beadequately spaced th. avoid cumulative poisoning-:. The effec·tiveness of the treatment may be determined by demonstra• Ition of egg-free stools after an appropriate period of time.With tapeworms, cures cannot be expected unless the beadis removed.In severe helminth infections, the use of anthelminticsshould be supplemented or even in some cases preceded bysupportive measures including the use of iron or blood transIntroduction• 329fusions if anemia exists, the administration of adequatefoods and vitamins and the use of antibiotics or sulfona- 1mides if secondary infection exists. It should also be real- 'ized that worm eradication must usually be carried out ona family, institutional or community basis since infestationsare rarely confined fo one individual and reinfection mayreadily occur. In the case of mass treatment, jt is importantto use a preparation that can be administered eff ecUvelywith a minimal amount of supervision and that isrelati,v ely nontoxic and comparatively inexpensive.CARBON TETRACHLORIDE ANDTETRACHLOROETHYLENECl Cl t CI-C-CI 'cIc11• Cl•Cld \Cl ·• CarbonT etrachloride Tetrachloroethylene,.-- Carbon tetrachloride '\Vas introduced in 1921 by Hall, whodemonstrated its effectiveness in helminth infestations indogs and horses an~d suggested its use in human b~ings. Itsvalue in the treatment of hookworm disease in humanbeings was immediately established and because of its effi~cacy and cheapness it soon became widely used. It soonbecame appare~t, however, that carbon tetrachloride pro-.duced severe liver and kidney damage if sufficient amounts• were absorbed. Extensive μperimental and clinical studiesindicated that its toxicity could be greatly reduced if thepatient were given a carbohydrate- and calcium.rich dietand were ,varned to abstain from alcohol and fatty foods.~Ieanwhile, in 1925, Hall and Shillinger demonstrated thattetrachloroethylene was almost as effective an antheJminticas carbon tetrachloride and much less toxic. This drug has,',•330 Intestinal Anthelminticsnow almost entirely replaced carbon tetrachloride as ananthelmintic. As far as is known, no fatalities have followedits use, the occasional toxic reactions being limitedto giddiness, nausea and vomiting. Rarely, a soporifice ffectis produced.Tetrachloroethylene or carbon tetrachloride apparentlynarcotize rather than kill the hookworms, hence their administrationmust be followed promptly by a saline cathartic.These drugs are contraindicated in the presence ofascaris infestations since they cause a primary stimulationof these worms which may lead to the formation of obstructingmasses in the intestine or to migration of worms into thebiliary or pancreatic duct, stomach or esophagus.HEXYLRESORCINOLOHI OH • 'CH2-CH2-CH~CH~CH2-CH3•HexylresorcinolHexylresorcinol is one of the safest and most widely usedanthelmintics. It is used chiefly in the treatment of ascarla·sis but is also of some value in the eradication of dwarftapeworms, hookworms and pinworms. It lvas introducedas an antiseptic in 1927, its anthelmintic properties beingfirst established by Lamson in 1930. It owes its effect to ablistering action on the cuticle of the worm. Its efficacy isgreatly reduced by the presence of protein material in thegastro-intestinaJ tract, hence, purgation or lasting shouldprecede its use.•Hexylresorcinol 331When used as an anthelmintic, hexylresorcinol is administeredin crystalline form, usually in capsules or coatedpills, since it may cause a burning sensation in the mouth,followed by anesthesia and ulceration of the oral mucousmembrane., OIL OF CHENOPODIUM,Oil of chenopodium is a volatile oil obtained from Amer-• ican wormseed (Chenopodium a1nbro.sioides). It owes itsanthelmintic properties to an organic peroxide, ascaridol.It is of greatest value in the treatment of tapeworm andwhipworm. It is said to be more effective on the Old Worldhookworm but less effective on the American species than 'carbon tetrachloride or tetrachloroethylene.Oil of chenopodium is quite toxic and commonly givesrise to dizziness, nausea, ringing in t.l}e ears and occasionallyto deafness. In fatal cases, convulsions and coma occur.Children and debilitated persons are especially susceptible.Its toxicity is due both to a local irritating action on thegastro.intestinal and urinary tracts and to a central depres~sant action on the respiratory and circulatory centers.SANTONINCH3- O= ,->---C-CH3o-b oSantonin is a crystalline principle obtained from variousspecies of Artemisia (Levant wormseed), the anthelminticproperties of which have been recognized for centuries. It is .I•I•I•332 Intestinal Anthelminticsmost effective in the treatment of ascariasis; it does not killthe worms but renders them easily removable with a purge.• However, it is quite toxic, causing vomiting, c:olic anddiarrhea, hallucinations and convulsions. The urine is sometimescolored yellow or green. Disturbances in color visionare common, especially ''yellow vision" (xanthopsia).THYMOLH3C , ~ O~CH3# CH\CH3Thymol is a crystalline phenol derivative prepared syn-• thetically or obtained frorn the volatile oils of a number ofdifferent plants. It was first used in the treatment of hook~worm infections by Bozzolo in 1879 in It.a1y. It ls littleused now because of its toxicity. Symptoms of poisoninginclude gastro-intestinal upsets, ringing in the ears, dizzinessand muscular weakness.BETANAPHTHOLOHBetanaphthol was introduced for the treatment of hook~,vorm in 1906. It is little used now as an anthe1minticexcept in the treatment of fascio1opsiasisb ecauseo f its tox•i ceffects, which inc1ude gastro-intestinal upsets and centralnervous system stimulation. Hemolysis of red blood cellsbas also been reported following its use.Betanaphthol has a marked germicidal effect. Its greatestuse is in the treatment of parasitic skin diseases usually inthe form of an 0.5 to S per cent ointment. It is also usedas an intestinal antiseptic.',Methylrosaniline Chloride 333IV METHYLROSANILINE CHLORIDEMethylrosaniline chloride (gentian, methyl, crystal violet)is a mixture of hexa-, penta- and tetra-methyl-p-rosanilinechlorides. It ,vas first introduced as an antiseptic but has 'recently been used effectively as an anthelmintic in strongyloidiasisand oxyuriasis. Untoward effects are usually ofa temporary nature and include nausea, vo1niting, diarrheaand abdominal pain. It is generally administered in entericcoatedpills, which minimize the gastric irritation causedby this drug.Methylrosaniline chloride is also used as an anti-infectivein pyogenic skin infections, in fungus infections and inburns.ASPIDIUMAspidium is a crude drug obtained f ram the EuropeanAspidium (male fern) or American Aspidium (marginalfern). It has been used as an anthelmintic for centuries.It is of particular value in the treatment of teniasis, beingprobably the most effective agent available against tapeworms.It narcotizes rather than kills the worms, hencemust be followed by a purge. It is occ.asionally absorbed insufficient quantities to cause severe toxic effects, includingdizzinesst headache, convulsions, hallucinations, visual disturbancesand kidney damage. It is usually administerednowadays as the oleoresin, which is considerably less toxic \than the crude drug. •MISCELLANEOUS AGENTS'I.Phenothiazine was introduced as a veterinary anthelmm•t1• c 1• n 1933. It was first used in the treatment of threadwormand roundworm infections in human beings by?\-Janson-Bahr in 1940. However, subsequent workers were?~t so ent_husiastic concerning its efficiency, ,vhile its tox-1c1ty, particularly its destructive action on red blood cells,I334 ~ Intestinal AntheJminticshas led to its virtual abandonment in the treatmenot fhuman helminth infestation. In animals, overdosage has ledto paralysis.Leche de higuer6n is the crude fresh latex of certainspecies of fig trees of the South and Central AmericasI. t isused effectively in those countries as a vermicide, especiallyin ascariasis ancl trichuriasis. Its activity is apparently dueto the presence of a proteolytic enzyme, ficin, which digeststhe worm. Preparations of 1eche de higuer6n rapidly Jose• their effectiveness unless refrigerated. Some potency may~I "N ~II # sPhenothiozinebe retained, however, if sodium benzoate is added as a,preservative.Other proteolytic enzymes which have been sag·gested as anthelmintics include papain, obtained from thepapaya, and bromelin, obtained f ram pineapp1e juice. Thelatter has been shown to be effective against ascaris in vitrobut not in vivo. The use of enzyme preparations as anthel•mintics should be avoided in cases in which bowel lesionsare known or suspected to exist.Pelletierine tannate is a mixture of the tanna.tes of sev•eral alkaloids obtained from pomegranate, whose use in the,treatment of tapeworm .is mentioned in the writings ofDioscorides. Pelletierine is little used nowadays because ofthe frequency with which it produces severe toxic eff~cts,including gastro-intestinal upsets, muscular cramps, dizzinessand visual disturbances. Occasiona1 cases of permanentblL.'ldness have been reported f olJowing its use. ,,!I'I , Common Parasitic Intestinal Helminths 335TABLE 6COl\IMON PARASITIC INTESTINAL HELMINTHSORGANISM DISEASENemathelmintbes(Roundworms)A1icylos' tomdau odenale(Old World bookworm)•'N ecator a1nericanus(Americanh ookworm)Ascarisl u,nbricoides(Roundworm)E11terobiuvse r,nicularis(Pinworm, seatworm, oxuris)Strongyloides tercoralis(Eel worm)Trichuris trichiura(Whipworm)AnclyostomiasisN eca toriasis, uncinariasisAscariasisIEnterobiasis, oxyuriasis•Strongyloidiasis•TrichuriasisPlatyhelminthes(Flatworms)Diphyllobothriu1l1a:t unt(Dwarf tapeworm)H ymenolepis nana(Fish tapeworm)Te1iias agi1ia.ta(Beef tapewonn)Tenia solium(Pork tapeworm)Fasciolopsibs uski(Large intestinal fluke)DiphyllobothriasisHymenolepiasis nanaTeniasis saginataTeniasis soliumFasciolopsiasis••336 Intestinal Anthelmintics• PREPARATIONS/Tetrachloroetbylene U.S.P. 3 cc. -Tetrachloroethyiene capsules. Usually contain 0.2, 1.0 and2.5 cc.Carbon tetrachloride B.P. 2-4 cc.Hexylresorcinol U.S.P. 1 Gm.Hexy1resorcino1p ills U.S.P. Usually 0.1 and 0.2 Gm.Oil of chenopodium B.P. 0.2-1 cc.Santonin B.P. 0.06-0.2 GmThymol U.S.P.; B.P. 1-2 Gm.Betanaphthol U.5.P.; B.P. 0.12 Gm.Methylrosaniline chloride U.S.P. 60 mg.Aspidium U.S.P. Male fern B.P. 4-8 Gm.Aspidium oleoresin U.S.P. 4 Gm. Extract of male fern B.P.2-6 cc.Pelletierine tannate B .P. . 0.12--0.5G m. •BIBLIOGRAPHYGENERALCraig, C. F., and E. C. Faust: Clinical Parasitology,Philadelphia, Lea, 1945.Einhorn, H. E., and J. F. Miller: Intestinal be1minthia•sis: clinical survey of six hundred and eighteen cas~sof infection with common intestinal helminths in ch1l~1 dren, Am. J. Trop. 11:ed. 26: 497, 1946.Faust, E. C.: The chemotherapy of intestinal parasites,J.A.'1!.f.A. 117: 1331, 1941.CARBON TETRACllLORit)E AND TEI'RACIILOR.OETHYLENEHall, l\f. C. : The use of carbon tetrachlorid for theremoval of hook-worms, J.A.M.A. 77: 1641. 1921.Lamson, P. D., G. H. Gardner, R. K. Gustafson, E. D.Maire, A. J. McLean and H. S. \Velis: The pharmacoI·ogy and toxicology of carbon tetrachloride, J. Pharma·col. & Exper. Therap. 2Z: 215, 1923. ,Lamson, P. D., B. H. Robbins and C. B. Ward: Thepharmacology and toxicology of tetrachloretfiylene,Am. J. Hyg. 9: 430, 1929 .• • ..Bibliography • 337A{ost, H., J. 11. Hayman and T. B. Wilson: Hookworminfections in troops returning from the Pacific, Am, J., M. Sc. 212: 347, 1946. •Sandground. J. H.: Coma follo\ving medication l-Vithtetrachlorethylene, J.A.M.A. 117: 440, 1941.liEXYLRESORCINOLEinhorn, N. H., J. F. l\1iller and L. Whittier: Ascariasisclinical survey of one hundred and t\venty~five cases ofinfection with Ascaris lunibricoides in children, Am. J.Dis. ChiJd. 69: 237, 1945.Lamson, P. D.1 E. L. Caldwell, H. W. Bro\vn and C. B.Ward: Hexylresorcinol in the treatment of humanascariasis, Am. J. Hyg. 13: 568, 1931.Trim, A. R.: Experiments on the mode of action of hexylresorcinol as an anthelmintic, Parasitology 35: 209,1943-1944.' - OIL OF C11ENOPODIUM\·Smillie, W. G., and S. B. Pessoa: A study of the anthelminticproperties of the constituents of tl1e oil of chenopodium,J, Pharmacol. & Exper. Therap. 24: 359, 1925.'METHYLROSANILINE CHLORIDEEv~ns, H. L., and H. Moore: A comparison of gentian~1olet a~d hexylresorcinol in the treatment of pin,vorm1~festat1on, J. Pediat. 20: 627, 1942.Wright, W. H., and F. J. Brady: Studies on oxyuriasisXXII-the efficacy of gentian violet in the treatmentof pinworm infestation, J ..'-.\ .1\:f.A1. 14: 861, 1940.M. ISCELLANEOUS PREPARATIONS /Ber~ovitz, 2., R. C. Page and E. ). de Beer: Phenothia~ztne experimental and clinical study of toxicity andanthelmintic value, J.A.I\{.A. 122: 1006, 1943.Fafsth E. C., and L. F. Thomen: Parasitical properties0& t e proteolytic enzyme ficin, Proc. Soc. Exper. Biol.!,Ied. 47 : 485 1941i{ 0 1•·t ~r, H., C. W'. i:tus•h ett and S. Kuna: Some toxico-~o~cal and pharmacological properties of the proteo~... 'ilt~2o~1ef,fi4cinL, Je. ,P harmacol. & Exper. Therap.I•,'tINTRODUCTION~ EMETINE•26Arneb acid es • rIODOQUINOLINE DERIVATIVESARSENICAI.SPREPARATIONSINTRODUCTIONAmebacides are drugs lethal to amebae. They are usedprincipally in the treatment of infections of Entameba histol>•lica,a mebiasis. The choice of drugs and the successo fthe treatment are governed largely by the loca'tion of theparasites, the duration of the disease, the presence or absenceof secondary bacterial infections and the generalhealth of the patient. •In its mildest form, amebiasis consists of the presenceof Entameha liistolytica in the lumen of the large intestinewith or without some penetration or ulceration of themucosa. It has been estimated that from 1 o to 20 per centof the population of the United States harbor the parasitein this form and act as symptom-free carriers of the disease.If the bowel involvement is more severe, symptoms of dys,entery or chronic diarrhea develop, the so-called amebic. dysentery or amebic colitis. If untreated, this stage mayprogress to amebic hepatitis or the more severe amebicabscess through secondary invasion of the ·liver. ~forerarely, there play be invasion of the lung or the brain.The vegetative form of the parasite responsible for the ,pathogenicity of the disease does not survive long outsidethe body and is destroyed by gastric acidity. The encystedform is quite resistant in moist surroundings and is responsiblefor the transmission of the disease. Itrmay be destroyed338IIntroduction 339by heat, drying, chlorine, iodine or de't ergents, or may beremoved by filtration .. Three types of compounds are the main therapeuticagents used in the treatment of amebiasis: emetine, iodo,quinoline derivatives and arsenicals. None of these agentsis effective against all stages of the disease, so that a course• of treatment consists of the alternate use of two or morepreparations. This has the further advantage of reducingthe possibility of drug,fastness, which may develop withthe prolonged or repeated use of a single drug. Amebicabscesses usually require surgical drainage and if secondarilyinfected, one of the sulfonamides or antibiotics shouldbe used. The general health of the patient should be sus~tained by an adequate diet with vitamin supplements whennecessary. The anemia which is frequently present in long ..standing infections responds well to liver e."ttract and iron.Unless treated early, amebiasis may prove very difficult tocure. Chronic cases of amebic dysentery may be complicatedby coexisting bacterial infections; in some of thesecases, dramatic improvement has followed the use of penicillinand the sulfonamides.It should not be forgotten that chronic sufferers of amebiasistend to get discouraged by long series of unsuccessfultherapy. Every effort should be made to,vards reassuringthem, and towards providing suitable occupational therapywhiJe treatment is in progress.IEMETINE~me tine is an alkaloid obtained f ram ipecacuanha, thedried root of Cephaelis ipecacuanlza or acumi11ata. Ipeca.,cuanha or ipecac was brought to Europe from Brazil-in1658 for the treatment of dysentery. Since it was not until1905 that it was shown to be effective only in amebic andnot i~ bacillary dysentery, it is not surprising that duringthe in.tervening centuries it was greeted with alternateenthusiasm and disappointment.\...340 AmebacldesIn 18 l i, Pelletier obtaine~ an active alkaloidal fractiofrom crude ipecac. This was later shown to consist of~least four alkaloids, of which emetine is the most impo1tant. Emetine djd not replace ipecac in the treatment ,amebiasis for many years after its isolation, largely becausof the mistaken notion that it represente-'1 the emetic but nothe parasitical activity of the crude drug. In 1911, howeve1Vedder demonstrated the amebacidal action of emetineb.:in vitro studies, and the following year Rogers reported thsuccessful treatment of amebic dysentery and hepatitis witlintramuscular injections of soluble emetine salts. ,Emeline is a toxic drug and shou]d be admimstered ~nl)under hospital supervision. It produces depression, mus•cuJar weakness, nausea and diarrhea. It has a direct ton,action on the heart which may result in cardiac irregulari•'ties and a fall in blood pressure. Its dangers are mini•mized, however, if the patient is .kept in bed during treat•ment and if the therapeutic dose is not exceeded. Emetineis only slowly excreted from the body, which resuJts in accu•mutation of the drug in the body during the course of treat•ment, with the attendant possibility of late toxic effects.Emetine is the only effective amebacide for the treatmentof amebic hepatitis or amebic abscess. It is of little valuein the treatment of intestinal amebiasis, however, for whileit may temporarily relieve the symptoms it only rarely com·pletely eradicates the parasites. It is without effect on encystedstages of the parasites.A number of insoluble emetine preparations have been.introduced which can be ta.ken orally. These drugs offerlittle, however, since they are more erratic in action than'parenteral emetine and cause more gastro-intestinal disturb·ances. Emetine and bismuth iodide (E.B.I.) is probably themost wide]y used of such preparations and may owe someof its effectiveness to its iodine content. Ipecac is still used, to some extent because of its availability and lower cost.Gastro-intestina1 upsets from its use may be reduced by thel 'I••fEmetine • 341•administration of opium or of tannic~acid preparations. Bismuthsubnitrate or subcarbonate, either alone or in combinationwith emetine, has had some use in the treatment ofintestinal amebiasis, but it is probably because they actlargely as protectives and demulcents on the inflamed mucousmembrane of the colon.IODOQUINOLINE DERIVATIVESso3H Cl IVI ~ VII ~ /4 I ~NOHChlniofonOHViotorm1 : IOHOilo do-OXyquinoline.The iodoquinoline derivatives are the safest and mostefficient agents available for the treatment of intestinalamebiasis. They are of no value, however, in the treatmentof amebic hepatitis or amebic abscess. Their efficacy is dueto liberated iodine, which has a lethal effect on both encystedand vegetative forms. In therapeutic doses, toxic effectsare rare, though many patients experience a profuse diarwrhea, especially during the first few days• of treatment.Occasionally, sufficient iodine may be absorbed to givesymptoms of iodism1 of ,vhich skin eruptions and salivationare the most common manifestations. Liver damage hasbeen demonstrated experim.entally and the iodoquinolinederivatives should be avoided in cases of hepatic impairment.Chiniofon (yatren) was introduced as an amebacide in1921. It is marketed as a mixture of chiniofon, its sodiumsalt and sodium bicarbonate. It can be administered orally •in tablet form or rectally as a retention enema. It has beenadvocated as a prophylactic agent for individuals requiredto spend short periods of time in regions in which amebiasisis endemic.•342 AmebacidesrIodochlorohydroxyquinoline (vioform), like chiniofon,was first introduced, as an iodoform substitute for woundantisepsis. It is more irritating to mucous surf aces thanchiniofon and cannot be given rectally. It is more likely tocause nausea, vomiting and diarrhea.Diiodo-oxyquinoline (diodoquin) is the most recentlyintroduced of this series, having been overlooked for manyyears because of its extreme insolubility. Animal experimentsindicate that it is poorly absorbed and relatively nontoxic.Ho,vever, absorption does occasionally occur in bothanimaJs and man and toxic symptoms characteristic of iodinepoisoning have recently been described following therapeuticdoses . .Blood levels of iodine may increase ten or a hundred·(old during its use.ARSENICALS10HO=As\OH~~ I NH-co-CH3NH-CO-NH 2 OHcarbasone Acetarsone•The organic arsenicals, like the iodoquinolines, are onlyeffective in treating intestinal amebiasis. Their activity isdue to their arsenic content. They may give rise to symptomsof ;irsenic poisoning, including liver and kidney damage,fever, diarrhea and skin eruptions. They should notbe used in the presence of liver or kidney disease.Carbarsone, introduced as an amebacide in 1932, is pro~ ~ably the safest of these preparations. It is given by mouthor as a retention enema. Acetarsone {stovarsol) was intro--.t duced as an amebacide in 1923. It is seldom employed nowbecause of its toxicity.\• • • - Preparations 343PREPARATIONS •Ipecacuanha U.S.P.; B.P. 0.5 Gm.Emetine hydrochloride U.S.P.; B.P. 60 mg.Emetine-hydrochloride injection U.S.P. Usually available'in ampuls containing the following amounts of emetine 'hydrochloride: ZO mg. in 1 cc.; 30 mg. in 1 cc. ; 60 111g.in 1 cc.Emetine and bismuth iodide B.P. 0.06-0.2 Gm.Chiniofon U.S.P.; B.P. 0.5-1.0 Gm.Chiniofon tablets U.S.P. Contain 0.25 Gm. chiniofon.Iodochlorohydroxyquinoline N.F. 0.5 Gm.Diiodo-oxyquinoline N .N .R. 0.5 Gm.Carbarsone U.S.P. 0.25 Gm.Acetarsone N.N.R. Acetarsol B.P. 0.25 Gm.BIBLIOGRAPHYGENERALAdams, A. R. D.: Amoebiasis with special reference totreatmet1t, Tr. Roy. Soc. Trop. Med. & Hyg. 38: 237,1945.Albright, E. C., and E. S. Gordon : Present status of theproblem of amebiasis, Arch. Int. !\1ed. 79: 253, 1947.•Amebiasis: War Dept. Tech. Bull. 159, War l\icd. 7: 390,1945. .Craig, C. F.: The Etiology, Diagnosis and Treatment of 1Atnebiasis, Baltimore, Williams & Wilkins, 1944.Hargreaves, W. H.: Chronic amoebic dysentery-newapproach to treatment, Lancet 2: 68, 1945.No~h, P.H., and J. W. Hirshfeld: Amebic abscess of theli--:er ,vith secondary infection: local treatment ,vithpenicillin, J.A.M.A. 124: 643, 1944.Ochsnei:, A., and 11:. DeBakey: Amebic hepatitis andhepatic abscess, Surgery 13: 460 (Marcl1), 612 (April), r1943.. ' EMETINEHa1rdgro~e, 11., and E. R. Smith: Effects of emetine ont 1e electrocardiogram, Am. Heart J. 28: 752, 1944.••• ,344 Amebacides I•✓Rogers, L.: The rapid cure of amoebic dysentery andhepatitis by hypodermic injection of soluble salts ofemetine, Brit. M. J. 1 : 1424, 1912.Iot>OQUINOLINESDavid. N. A. V., N. M. Phatak and F. B. Zener: Iodochlorhydroxyquinolineand diiodohydroxyquinoline;animal toxicity and absorption in man, Am. J. Trop.Med. 24: 29, 1944.Hummel, H. G.: A critical appraisal of the newer amebicidesand the results of treatment of amebiasis withdi-iodohydroxyquinoline (diodoquin), Am. ]. Digest."Dis. 6: 27, 1939.Silverman, D. N., and A. Leslie: Toxic effects of diodoquin,J.A.M.A. 128: 1080, 1945 .•• AAsENICALS•Epstein, E.: Toxicity of carbarsone, J .A.M.A. 106: 769,1~~ 'Reed, A. C., H. H. Anderson, N. A. David and C. D.Leake: Carbarsone in the treatment of atnebiasis,J.A.M.A. 98: 189, 1932 .'l .',•I27Antisyphilitic DrugsINTRODUCnoN ARSENOXIDESMISCELLANEOUS AGENTSPREPARATIONSM,ARSPHENAMINES•INTRODUCTION \\The drugs discusse<J in this chapter are used principallyfor the treatment of syphilis. They are also effective inother spirochetal infections, such as yaws, relapsing feverand Vincent's angina, while some of the arsenic preparationsare 'used in other parasitic infections, notably trypanosomiasisand, to a lesser extent, amebic dysentery and malaria.The clinical evaluation of a new antisyphilitic drug in•valves many factors, some of which, such as the incidenceof late relapse following treatment, may require years ofobservation of la;ge numbers of patients. For example, whilepreliminary studies indicate that penicillin shows considerablepromise of becoming one of the most useful drugs: in this field, several years must elapse before its true rolein the treatment of syphilis can be established.Syphilis was first described in the fifteenth century butsuccessful treatment was not available until the introductionof arsphenamine (usalvarsan") by Ehrlich in 1909.Previously, mercury and the iodides had long been used butthese drugs merely aided in the healing of open syphiliticlesions without exerting any curative action. ,The research work culminating in the discovery of arsphenaminclaid the foundation for modern chemotherapy.Ehrlich's work was stimulated by • the earlier studies ofHeubel on the fixation of lead by certain tissues of the .. 'I•346 Antisyphilitic Drugsbody and by his own observations on the differentials tainingcapacity of various dyes: From these experimentsh econceived the idea of developing drugs ,vbich are specificallyattracted to the pathogenic organism rather than to thetissues of the host in the hope of exerting a toxic effect onthe invading organisms without affecting adversely thetissues of the host. Ehrlich applied the term "chemoreceptors"to those hYPothetical groups in the parasite ~esponsiblefor fixation of the drug and expressed the relative tox-,icity of the drug to the parasite and to the host as the''chemotherapeutic index." This term is still retained toexpress the ratio of the minimum effective dose to the maximaltolerated dose. \It should be pointed out that Ehrlich's work in developingnew antisyphilitic ,agents was greatly aided by three contemporaryadvances in the field of syphilology, namely, thetransmission of syphilis to experimental animals by l\fetsch-• nikofI and Roux in 1903, the discovery of the causativeagent, Treponema pallidu1n by Scbaudinn in 190S and thedevelopment by Wassermann in 1907 of a blood test forsyphilis. Finally, the recognition by Hata, the Japanesechemist who collaborated with Ehrlich, of the incorrectness• of the accepted structural formula for atoxyl, an orgarucarsenica1 introduced in 1904 for the treatment of trypanosomiasisand relapsing fever, led to the determination ofits rea1 nature and to the synthesis of related compounds,\culminating in the development of the arsphenamines.ARSPHENAMINESArsphenamine (sa1varsan, 606, old arsphenamine} wasthe six hundred and sixth of a series of compounds preparedby Ehrlich and his associates. After its spirocheto.cldal action was demonstrated, Ehrlich named it salvarsan,"saviour of mankind." \Vhen manufacture was commencedin the United States during World War I 1 the drug wasofficially designated 85 arsphenamine. '•I•347Arsphenamine is a semicrystalloid preparation marketedas the soluble dihydrochloride salt. Before injection, solutionsof the drug must be made alkaline, since injection ofacid solution results in intravascular precipitation of thedrug. Tlie alkalinfzed solution, consfstfng of a mixture ofA,==AIOHArsphenam1ne Nea 0 rsph1n omineAs==As As==As_?~ NH•CHiOS02 No,.. rH..N ~ I ~ I NH • k AqOZ 2 :ZOH OH OHSu lforsphenom•l n S1I ver orsph eno m1n•1As B As-Bi=AsOHBlsmorsen•♦ formula l'()t defiNlely estobtlshed •the mono. and disodium salts, must be injected intravenouslybecause of its irritating propertfes.Following the injection of arsphenamine, arsenic appearsin the urine within a few hours. The maximal excretionoccurs from 24 to 48 hours after administration, but arseniccan be demonstrated in the urine for many days. A largefraction of the dose is excreted in the bile and appears inthe feces. ••I ,(348 Antisyphilitic ·Drugs J.,.._ .The treatment of syphilis with the arsphenamineuss uallyrequires weekly injections for a period of from 6 monthsto 2 years. l'rfany patients fail to complete such a schedule.Consequently, the intensive treatment methods, using thearsenoxides or penicillin, are proving increasinglym orepopular. The arsphenamines are too slowly detoxified bythe body to be used in these procedures. ,Neoarsphenamine (neosalvarsan, 914) was also devel-, oped by Ehrlich. It differs from arsphenamine in that itcan be used immediately after solution Jn water. However,solutions oxidize even more rapidly than those of arsphenamine,hence they should be injected within 20 !11inutes.Neoarsphenamine is always injected intravenously. It issomewhat less active than arsphenamine and somewhathigher doses and a more prolonged period of treatment areusually necessary.Sulfarsphenamine was introduced into the United States{n 1922 by Voegtlin and Johnson. It is acid in reaction,about as active as neoarsphenamine, and is extremely resistantto oxidation by air. It can be injected intramuscularly,which is of particular value in the treatment of children.Silver arsphenamine was developed in Germany byKolle. It is of the same order of activity as neoarspbenamine.It is Iess likely to produce toxic reactions but argyriamay result from its long-continued use. It need not bealkalinized before use but solutions must be injected within20 minutes since they deteriorate both by oxidation andby precipitation of the silver by the carbon dioxide in the air.Bismarsen (bismuth arsphenamine sulf onate) is a watersolubleorganic preparation containing approximately 13 percent arsenic and 24 per cent bismuth. It was prepared byRaiziss in 1927. It must be administered intramuscularlysince it is very toxic when given intravenously. It is a reJa.tively weak and slow-acting drug but is of value whenintravenous medication -is impossible or contraindicated.-.•Arsphenamines • 349•Mode of Action of the Arsphenamines. It is generallybelieved that the arsphenamines themselves do not possessany spirochetocidal action but that their activity is due totheir oxidation products, the arsenoxides, which are fixedby the tissues of the body and by the parasites. The degreeof fixation is dependent on the organic part of the molecule,some compounds being adsorbed more readily than others.This portion of the molecule is also responsible for thedifferential absorption by the spirochetes, thus accountingfor,, the variations among the chemotherapeutic indices ofthese compounds.The lethal effect of the arsenoxides is believed to be dueto their reaction with sulfhydryl compounds of the cell inwhich they become adsorbed. This is supported by thechemical reactivity between arsenoxides and compoundspossessing free sulfhydryl groups and by the antidotal actionof sulfhydryl compounds, such as cysteine, glutathione anddithioglycerol ("BAL") against toxic doses of arsphenaminesand arsenoxides.Toxicity of the Arsphenamines. General reactions toarsphenamines include the nitritoid crisis and the JarischHerxheimerreaction, skin lesions, blood dyscrasias, central• nervous system disturbances, gastro-intestinal upsets andrenal injuries. Local irritation and necrosis may occur fromintramuscular injection of irritating preparations while suddencollapse and death usually follow the accidental injec- , .•t1on of unneutralized arsphenamine.The nitritoid crisis is characterized by the sudden onsetof flushing of the face, edema of the tongue and lips, nauseaand vomiting, profuse perspiration, fall in blood pressureand a feeling of anxiety. This syndrome is referred to asthe nitritoid crisis because of the similarity of the effects tothose produced by the administration of nitrites. They areP;obably due to the formation of minute pulmonary embolisince they rarely occur from the J.soef crystalloid arsenicalssuch as oxophenarsine and may be minimized by slow ad-I••350 Antisypbi1iuc· Drugs'ministration of the drug. Severe cases may be followed bycomplete collapse and death. Epinephrine is a great helpin combatting this reaction and may on occasion be lifesav1•ng.The J arisch-Herxheimer reaction may appear from 2 to3 hours after the injection is completed. It consists of anintensification of secondary eruptions and, in late syphilis,may occasionally result in death by coronary occlusion, byasphyxia in cases of gumma of the larynx or by cerebralhemorrhage. The reaction may be avoided by preliminarytreatment with srnall doses of arsphenamines or by preparatorytreatment with bismuth or mercury preparations andpotassium iodide.The arsphenarnines can produce almost any form of ,dermatitis, due in part to overdosage and in part to sensi•tization. Desensitization in these cases is not successful andshould never be attempted since minute amounts of any ofthe organic arsenicals can cause a recurrence. The most• severe reaction is exfoliative dermatitis. Another reactionis known as "erythema of tbe ninth day." It occurs withinthe first 2 ,veeks after the first injection of arspbenam•1 ne ,• • and is characterized by erythema, malaise and a ~1se 1ntemperature.Blood changes are severe though relatively infrequentcomplications during the administration of arsenica1s. Theyare due to depression of the bone marrow and include aplasticanemia, granulocytopenia and tbrombocytopenia. Jaundicemay occur during the CO)lrse of treatment. In somecases, this has been proved to be due to infectious hepatitis,transmitted by improperly sterilized syringes. Toxic en•cephalopathy is a rare but serious complication of arsenictherapy. Gastro-intestinal upsets are frequent and manypatients complain of a garlic or ether odor f oJJowing injectionof arspbenarnine and neoarsphenamine. It can beavoided if the patient holds his nose and breathes throughhis mouth.f•r\rsphenamines 351''BAL'' in the Treatment of Arsenic Poisoning. "BAL"(British Anti-Lewisite1 dithioglycerol 1 2-3 dimercaptopropanol)was introduced by British scientists during WorldWar II as an' antidote for the arsenic-containing chemicalwarfareagent, Lewisite. It has recently been used in the'CH2 - CH - CH2I I I•\SH SH OHtreatment of arsenic and mercury poisoning and in antidotingthe toxic effects of therapeutic arsenicals 1 antimonials,mercurials and gold compounds. Since its action is to removethe drug from the living cell, it also reduces the therapeuticeffects of these preparations.Overdosage with "BAL" leads to acidosis and hyperglycemia,increased depth and rate of respiration, tremors,tachycardia and, finally, tonic and clonic convulsions. Thedrug is marketed in a benzyl benzoate peanut-oil solutionfor intramuscular injection and in combination with glucoseas BAL-glucoside for intravenous medication.Control of Arsphenamines and Arsenoxides. The distributionof trivalent arsenicals in the United States issupervised by the United States Public Health Service.itanufacture may be carried out in licensed laboratoriesonly and the arsenic content and toxicity in animals ofeach drug lot must be determined. Essentially similar regulationsare in force in Great Britain.ARSENOXIDESOxophenarsine (mapharsen, mapharside "arsenoxide") isthe arsenoxide of arsphenamine and presumably the activemetabolite of the latter drug. It was tested as an antisyphiliticagent by Ehrlich but he considered that its toxici•t y precluded its clinical use. In 1932, however, Tatum andCooper restudied the drug and recommended its clinical~~- .•- , ;.352 Antisyphilitic DrugsOxophenarsinei s a pure chemicalc ompounda vailableincrystalline form. It is relatively unstable even in the drystate, decomposition being accompanied by a brownishd iscolorationand an increase in the toxicity. It does1 1otr e•quire alkalinization. It must be given intravenously. It isten times more active than arsphenamine but less toxic intherapeutic doses. It is detoxified more rapidly than ars-'phenamine and is sometimes administered at more frequentintervals.'OHOx ophenorsineOHDich1orophenorsineThe toxrc reactions f oilowing the use of oxophena:rsine- are, in general, similar to, though less frequent than, those• fallowing the arsphenamines. The Herxheimer reaction z.slikely to occur more frequently and be more serious thanwith the arsphenamines but the nitritoid reaction is seldomseen. Pain in the arm frequently occurs, due to spasm ofthe injected vein.The greater effectiveness of oxophenarsine and the rapid•ity of its action have Jed to the almost exclusive use oi th~. compound in the intensive arsenotberapy of syphilis. Thismode of treatment consjsts of continuous intravenous ad-' ministration or repeated injections at frequent intervalsover periods varying from 5 to 20 days. The shorter periodsof treatment are accompanied by a higher incidence ofuntoward reactions. The so-caJled "l•day treatment" consistsof intensive chemotherapy and fever therapy over 24Arsenoxides 353-hours. The incidence of untoward reactions is very high,however, and the therapeutic results are poor.Dichlorophenarsine (chlorarsen, phenarsine) was introducedfor the treatment of syphilis in 1941. It is rapidlybroken down in the body to oxophenarsine. It offers theadvantage of greater stability in storage; its use and effectivenessare otherwise identical to that of oxophenarsine.•MISCELLANEOUS AGENTS1oNaAs=O~ \OH•NH-CH2 - C.O -NH 2Tryparsomide'Tryparsamide is a pentavalent arsenical originally intro' -duced by Jacobs and Heidelberger of the Rockefeller Insti~lute in 1919 for the treatment of trypanosomiasis. Its spiro- •chetocidal action is ,veak and it is used only in syphilis ofthe central nervous system. Its use is based on the beliefthat it, in contrast to most of the trivalent arsenicals, readilypenetr'\_tes the meninges.Tryparsamide, in common with many pentavalent arsen•icals, has a tendency to produce visual disturbances becauseof a specific toxic effect on the optic nerve. Gastro-intestinaldisturbances and nitritoid reactions occur, as with otherarsenicals. The relatively low potency of the drug explainsthe low incidence of Herxheimer reactions.Tryparsamide remains the drug of choice in the treatmentof late trypanosomiasis.•••354 ~\ntisyphilitic Drugs ~Bismuth. Bismuth preparatjons were jntroducedf or thetreatment of syphilis in 1921 by Sazerac and Le\'aditi. Theynre relatively weak spirochetocides and are usually usedalternately ,v-ith the arsenicals to prevent cumulative poison4ing by the Jatter. ,A great number of bismuth preparations are on themarket. These differ pha~macologically only in respectsattributable to the different rates of absorption of theelement from the site of injection. The usual dosage isequivalent to JOO mg. of bismuth per ~eek.Toxic effects with bismuth compounds are rare and seldomcall for discontinuance of the drug. Stomatitis, diarrbeJ,nlbuminuria and dermatitis may occur. Usually after si."ot rmore injections of bismuth, a bJue line appears on the gumsand may extend to the buccal mucosa. While this may becosn1eticallyu ndesirable, it is of no serious significancen nddoes not justify discontinuation of treatment. All bismuthpreparations arc much more toxic intravenously than intra•muscularly. Furthermore, accidental intravenous injectionsof the oily preparations present the danger of formation olpulmonary embo1i. If an artery is penetrated, a Jocal arterialembolus may develop. ,Oral bismuth preparations includesobisminol and bistrimate.M~rcury bas been used in the treatment of syphilis since149S, but its toxicity is high. Before the introduction of the ,Jess toxic bismuth preparations, mercury preparations wereused in conjunction with arsenicals. Now, however, they areonly used topically for prevention of infection, ca lorn el oint•ment being the most efficient prophylactic agent available.Sodium or potassium iodide are useful adjuncts in thetreatment of late syphilis. The iodides seem to promoteresolution of the gummatous lesions, thus e."tposingt hespirochetes to the action of other drugs or to the naturaldefense mechanisms of the body. The use of iodides is,• however, still empirical.Miscellaneous Agents 355Fever Therapy. The apparent intolerance of spirochetesto liigh temperatures has led to the use of fever therapyin the treatment of syphilis, especially in neurosyphilis.1 Ideally, a temperature of 106° (! should be reached andmaintained over a period of, time, during which antisyph•ilitic drugs may be administered. Fever may be produced• by malaria, by the injection of foreign proteins and vaccinesor by physiCTllm eans. While fever therapy is of establishedvalue, the medical supervision and nursing carerequired tend to limit its use. Furthermore, it is contraindicatedin the presence of diseases of the cardiovascular andresp•i ratory systems.PREPARATIONSArsphenamine U.S.P. 0.3 Gm. intravenous.Neoarsphenamine U.S.P.; B.P. 0.45 Gm. intravenous.Sulfarsphenamine U.S.P.; B.P. 0.45 Gm. intramuscular.Silver arsphenamine N.N.R. 0.2 Gm. intramuscular.Bismarsen N.N.R. o.2 Gm. intramuscular.Oxophenarsine hydrochloride U.S.P. 0.045 Gm. intravenous.Dichlorophenarsine hydrochloride U.S.P. 0.045 Gm. intravenous.Tryparsamide U.S.P.; B.P. 2 Gm. intravenous.Sodium iodide U.S.P.; B.P. 0.3 Gm.Potassium ,iodide U .S.P. ; B .P. 0.3 Gm.Bismuth potassium tartrate U.S.P. 0.1 Gm. intramuscular.Bismuth-potassium-tartrate injection U.S.P. \Vater solutionor oil suspension. 0.1 Gm. intramuscular.~ismuth subsaljcylate U.S.P. ,Bismuth-subsalicylate injection U.S.P. Usually 100 mg. or•120 mg. in 1 cc. •Bismuth sodium tartrate B.P.; NN.R.Bismo-cymol N.N.R.Bismuth ethylcamphorate N.N.R..Iodobismitol with benzocaine N.N.R.Quinine bismuth iodide N.N.R.,356 Antisyphilitic DrugsSobisminol mass N N .R.Iodob[smuthite sodium N.N.R.Sodium potassium bismutbyl tartrate N.N.R.Thio-bismol N.N.R. (sodium bismuth tbioglycollate}l\Iercuric salicylate N.N.R.irercury benzoate N.N.R. 'l\fercuric oxycyanide N.N.R.l\iercuric succlnimide N.N.R.Solution coJloidal mercury sulfide N.N.R.BIBLIOGRAPHYGENERAL•,Ehrlich, P., and S. Hata: The Experimental Chemotherapyof Spirilloses, London, Rebman Ltd., 1911.Moore, J.E.: The iiodern Treatment of Syphilis, Spring·field Ill., Thomas, 1943.Reynolds, F. '\V., and J. E. Moore: Syphilis-a revie,v ofthe recent literature, Arch. Int. Med. 78: S92, 733, 1945-1946.' ARSPHENAMINESCannon, A. B., ]. K. Fisher, J. J. Rodriguez, G. F. Beattieand E. H. Maechling: Blood and urine arsenic levelsof patients ,vith eariy syphilis under intensive arsenotherapy,Am. J. Syph., Gonor. & Ven. Dis. 30: 144, 1946.Eagle, H., and H. J. Magnuson: The systemic treatmentof 227 cases of arsenic poisoning (encephalitis, derma•titis, blood dysc:rasias, Jaundice, fever) ,vith 213-dimercaptopropanol(BAL)> Am. J. Syph., Gonor. & Ven.Dis. 30: 420, 1946.Probey, T. F., E. W. Norris, A. V. Diebert and E. V,Price: Sulfarsphenamine in the therapy of syphilis-acomparative study of the toxic manifestations of neoarsphenamineand sulfarsphenamine, Pub. Health Rep.59: 733, 1944.Beerman, H., and J. H. Stokes: The trivalent arsenicatsin syphilis, Part II, treatment reactions, Am. ]. M:Sc. 202: 6J6, 1941.-.,.Bibliography 357~,Voegtlin, C.: The pharmacology of arsphenamine (salvarsan)and related arsenicals, Physiol. Rev. 5: 63,1925.i\RSENOXID.ESBeerman, H., and V.-S. Wammock: Dichlorophenarsinehydrochloride in the treatment of syphilis, Am. J. Syph.,Gonor. & Ven. Dis. 31: 150, 1947.Tatum, A. L., and G. A. Cooper: An experimental studyof mapharsen (meta-amino parahydroxy phenyl arsineoxide) as an antisyphilitic agent, J. Pharmacol. & Exper.Therap. 50: 198, 1934.MISCELLANEOUS\.Beerman, H., and B. Shaffer: Reactions to tryparsamide-a review of ten years' experjence, Brit. J. Ven. Dis.16: 145, 1940.Eagle, H.: The relative toxicity and therapeutic activityin experimental syphilis of bismuth subsalicylate, bismosoland biliposol, Am. J. Syph., Goner. & Ven. Dis.30: 549. 1946.Fleming, W. L., and M. H. Wolf: The relative prophylacticeffectiveness against syphilis of ointments containingcalomel in different particle size, Am. J. Syph.,Gonor. & Ven. Dis., 30: 47, 1946.Kendell, H. W.: Fever-chemotherapy, Clinics 4: 1614,1946.Kolmer, J. A., H. Brown and A. M. Rule: Studies in thebismuth therapy of syphilis, 1, A comparative study ofthe toxicity and therapeutic activity of bismuth com.p«;>undsc ommonly employed in the treatment of syph-111s, Am. J. Syph., Gonor. & Ven. Dis. 23: 7, 1939.Worms! W.: Prophylaxis of syphilis by locally appliedche~1cals methods of examination, results, and sugg~st1ons for £urther experimental research, Brit. J. Ven.D1s. 16: 186, 1940. .,•28Antimalarial DrugsINTRODUCTIONQUININEQUINACRINECut.ORO QUINEPAtUDRINEP.Al!AQUINEPENl'AQUlNEPREPARATIONS•INTRODUCTION•The chemotherapy of malaria dates back to the seven•teenth century when Jesuit missionaries observed that thePeruvian Indians treated fevers with decoctions of cinchonabark. Until 1926 extracts of cinchona bark or its alka·loids remained the only specific means of treating malariadespite the attempts 1 of German chemists during \Vorld\Var I to produce a synthetic su~stitute. Subsequently,however, they introduced both pamaquine and the moreuseful quinacrine in 1926 and 1932, respectively. No fur•ther advances "'ere made in the field until World ,var 11,when the loss of quinine supplies from the Dutch EastIndies and the alleged toxicity of quinacrine led to a vastprogram of experimental and clinical research on anti• ......malarials by American and British scientists which advancedour understanding of the treatment and prevention of malariaand culminated in introduction of three new drugs: chloro•quine, paludrine and pentaquine.The three most important species of plasmodia capableof infecting human beings are P. falciparum, P. vivax andP. malariae, the causative agents of malignant tertian,benign tertian and quarta.n malaria, respectively. The .first58-- •Introduction 359of these, P. falciparum, is the most virulent and is alsothe most responsive to chemotherapy. Infections of P. 1nalariaeare relatively infrequent.f Vivax malaria is a debilitating disease characterized bychronicity and by a low mortality rate. With the possibleexception of pamaquine and its homologues, no drug treatmentis completely effective for prophylaxis or for cure,although a suppression of the clinical signs and symptomsof the disease may be obtained with one of several drugs ofrelatively low toxicity. This suppressive action can be putto use to achieve a type of prophylactic effect; althoughan individual may become infected, all signs and symptomsof the disease can be suppressed until the drug is withdrawn.In the interval, the subject is unaware of havingcontracted. malaria and, in addition, immune processes mayadvance to the point of being able to cope with the infectionafter discontinuance of the drug.There are several possible explanations for the lack of acurative action by quinine, quinacrine, chloroquine andpaludrine in vivax malaria. It may be due to a quantitativeeffect, in that the drugs are simply not sufficiently potentto kill 100 per cent of the organisms. Again, the unevendistribution of these drugs in the body may afford protectionagainst the actioti of the drug on the parasites in thoseparts of the body in ,vhich the concentration of the drug islow. However, experiments with the intentional inoculationof malaria for therapeutic purposes in patients with syphilisof the central nervous system have shown both of theseexplanations to be unlikely. Infections induced by theinoculation of, blood from an infected donor, in contradistinctionto those induced by sporozoite inoculation, arereadily cured by any of the so-called "suppressive drugs."Hence, the pre-erythrocytic forms of the parasite, develop-• • 1ng 1n a naturally acquired infection from the inoculatingsporozo•1 tes, are resistant to these drugs. This resistancemay 1be either by these forms possessing pathways of me• ,,' 360 Antimalarial Drugs ,. tnbolism alternate to those interruptabie by the drug in thecrytl1rocytic forms, or by their lacking the ability to concentratethe drug from the surrounding medium in effectiveatnounts. Experiments with avian malaria have shown theexistence of pre-crythrocytic forms of the parasites (cryptozoites),as ,veil as other types of exo-erythryocytic forms,but these have ne\·er been conclusively demonstrated in man.QUININE IQuinine is the chief alkaloid in cinchona bark. It wasfirst isolated by Pelletier and Caventou in 1827 and hasrecently been prepared synthetically but the procedure iseconomically impractical. The metabolism and the therapeuticeffectiveness of the four predominant cinchona alkaloidsquinine, quinidine, cinchonine and cinchonidine-isessentially the same except for the slightly greater rate ofdegradation of cincbonidine in the human body with resultantlo,ver blood concentrations. A relatively crude preparationof cinchona bark, containing all four of these alkaloids,'is avaiJable under the name "Totaquine." It hasno advantage over the pure alkaloids except its lower eost.Quinine is rapidly absorbed from the gastro-intestina1tract or from intramuscular injection. It may be usedintravenously if given slowly and in high dilution. Intramuscularinjections may be followed by painful sterileabscess formation, and cardiovascular collapse has resultedfrom its intravenous use. Therefore, it should be given by,the oral route unless the patient is moribund or for somereason unable to absorb the drug. ,Animal experjments indic.ate that quinine is distributedvery unevenly in the body. The liver, spleen, lung and kidneyconcentrate the drug in highest amounts. The blood,muscle and nervous tissue retain relatively little of it •. Plasma and red blood cells contain approximately equalamounts, but the ,vhite blood cells concentrate the drugto from two to ten times the plasma value. Urinary excreQuinine361tion accounts for less than 10 per cent of the administereddose: At least part of the remaining 90 per cent is oxidizedin the liver to the carbostyril derivative, which is thenexc~eted in the urine. It is only about one third as activeas quinine in experimental malaria but is correspondinglyless toxic.NQuinineCorbostyrllDerivativeo f quinine ,,The establishment of the chemical structure of this metaboliteof quinine suggested the synthesis of analogous compoundsin which the susceptible point of oxidation wouldbe blocked by the addition of a more resistant group. Suchcompounds are still in the developmental stage but someof them show greatly enhanced activity against experimentalmalaria. One of these, SN 10,275, is retained by the bodyapproximately fifty times as long as quinine.The rapid metabolism of quinine makes it a noncumulativedrug. Consequently, full antimalarial action (withplas~~ concentrations of 5 mg. (1 liter or higher) can beobtained early in the course of treatment. iraintenance ofthis action requires frequent administration of the drug,lJ,•362 Antimalarial Drugsoptimal results being obtained when the drug is given every4 ~ours. The dosage schedule does not have to be loweredduring the course of treatment a.nd toxic symptoms can bequickly alleviated by cessation of administration of thedrug. These toxic symptoms are collectively known as''cinchonism,, and consist of ri.nging in the ears, headache,blurred vision, photophobia, edema and skin rash. Id.iosyn•crasy to quinine is not uncommon. High doses of quininehave been known to cause blindness (quinine amblyopia),apparently due to a spasm of the retinal arterioles.ClaSN 10.275Quinine has a central antipyretic effect and \vas forme.widely used as an antipyretic. It has some chemotherapeulaction in bacterial infections but is little used in these co1ditions because of its inefficacy and its unpleasant side ac_tions. Ethylhydrocupreine { optochin), a synthetic compouncclosely related to quinine, was shown by lforgenroth in 1911• to be effective against pneumococcat infections. Its systeIIllCuse was abandoned when it was found to cause damage tothe optic nerve, though it may be applied locally in thetreatment of pneumococcal infections of the eye. Hydroxyethylapocupreineis a much less toxic compound and mighthave found wide use in the treatment of pneumonia but forthe advent of the more effective sulfonamides.Quinine has a curare-like action on skeletal muscle (seeChapter 5) and like curare has been used for the diagnosisof myasthenia gravis since small doses accentuate the con•Qu1..n 1ne 363'dition. It is of questionable value in the relief of spasticconditions.Quinine may occasionally give dramatic relief of itching,its mode of action being unknown. The oxytocic action ofquinine is discussed in Chapter 19 and its local anestheticaction in Chapter 6. The use of quinidine as a heart drugis discussed in Chapter 14. Quinidine is rarely used in malariathough it is of some value in patients sensitive to quinine.Until recently, quinine was the drug of choice for thetreatment of all types of malaria. Its low toxicity and itsrelative abundance, coupled with its long history of usefulness,assure its continuation as a valuable adjunct. Newerdrugs, especially quinacrine, chloroquine and paludrine aresuperior in many respects but their toxic potentialities arenot so thoroughly understood and their very newness militatesagainst their complete acceptance. However, malignanttertian malaria, caused by P. fa.lciparum, yields completelyto these newer drugs, whereas quinine is of relativelylittle value in this infection. Blackwater fever, acommon complication of falciparum malaria, seems to occurinfrequently when the infection is treated promptly andadequately with quinacrine, chloroquine or paludrine.' QUINACRINE•c~-o• ~H3 C2H5H-N-CH-CH -CH--CH -t/ 2 ·2 2 \ °' C2H5Cl_Quinacrine (mepacrine> atabrine) is a yellow-orange alka!otd whose acid salts are freely soluble in water. The drugts almost invariably given by mouth since its parenteral usemay be accompanied by local irritation at the site of injec-••364 Antima1arial Drugstion, or by syncope if it is given intravenously. When givenby mouth, gastric irritation may be severe, leading to nauseaand vomiting. This is best controlled by giving the drugnf ter meals., Quinacrine is rapidly absorbed from the intestinal tractand is stored in the tissues for a considerable period. Distributionof the drug in the body is very uneven, more or lessparalleling that of quinine except that blood and plasmaconcentrations are very low. Suppression of the early signsnnd symptoms of the disease is usually obtained with a concentrationof 25 μ.g. of quinacrjne per liter of plasma, requiringthe daily administration of 0.1 Gm. of quinacrine hydrochloride.Since the concentration of this drug in the whiteblood cells is several hu.ndred times that of the plasma,analyses obtained with whole blood are apt to give misleadingresults.Qttinacrine is a cumulative drug. Less than S per centof the administered drug Is excreted, although traces of thedrug can be found in the urine for 1 or 2 months after thelast dose. Qtiirtacrine is deposited in the skin and nails,persisting for weeks or months after discontinuance of thedrug. This slow excretion and metabolism account for theaccumulation of the drug in the body during a period ofcontinual administration and explain the necessity for largeinjtial doses in order to achieve full suppressive or therapeuticeffects as early as possible. For the treatment of anacute attack, usually 1.0 Gm. of quinacrine hydrochloride' is given in divided doses the first day, followed by 0.3 Gm.per day for 6 days.Quinacrine is remarkably free from serious toxic effects,although it may produce several minor or subjective symptoms.The yellow pigmentation of the skin, due to thedeposition of quinacrine or its metabolites and not tojaundice, is cosmetically undesirable. Gastro-intestinal upsetswith nausea or vomiting and diarrhea, are nol uncommon'. Manifestations of allergic reactions may be encoun...,Quinacrine 365tered, but these are rarely of sufficient severity to 'warrantwithdrawal of the drug. Toxic psychoses, aplastic anemiaand' atypical lichen planus are other relatively infrequentcomplications.CHLOROQUINEyH3H-N-CH-CH -CH -CHCl~ '~NChloroquine (SN7618) was introduced in 1944. Absorptionof this drug from the gastro-intestinal tract is rapid andcomplete and from 10 to 20 per cent of the total dose isexcreted in the urine. Chloroquine is as persistent in thebody as quinacrine but exerts a suppressive action with aplasma concentration as low as 5 to 8 μg. per liter, thus permittingadequate suppression of the symptoms of the diseasewith a dosage schedule of only one dose of 500 mg. or less ofchloroquine diphosphate per week. Chloroquine provides themost rapid rate of parasite clearance from the blood and thelongest latent period between attacks. It also has the advantageof being a colorless compound and thus does not causethe yellow pigmentation of the skin caused by quinacrine.Chloroquine may produce the same signs and symptomsof toxicity as quinacrine, but their incidence is less. l\Iild• prur1tus may also occur.PALUDRINEPaludrine was introduced in 1945 by a group of English1• n,rest•1 gators. It has a suppressive action similar to that of• • • quinine, qu1nacrine and chloroquine with the further advan•tage of exceptionally lo,v toxicity and cheapness of manu.facture Its action is less rapid than that of the other sup•I,-•' 366 Antimalarial Drugs ,pressive drugs1 full suppression of the disease being notordinarily obtained for 3 or 4 days after treatment is begun.The usual therapeutic dose is 100 mg. per day; however,doses of 1000 mg. produce no sings or symptoms of toxicity.Paludrine is readily absorbed following oraJ administra•lion. About one third of the dose is excreted through the1CH3NH-C-NH-C-NH-CHfl II \CHNH NH 3bile and the intestinal mucosa and appears in the feces.A smaller amount is excreted in the urine. The drug is notcumulative with ordinary doses; however, weekly ad.ministration of the drug seems adequate to suppress infections.Like quinacrine and chloroquine, it is a curative agent inP. Jalciparum infections but is without effect on the reJaJlSerate in P. vivax infections. Hawking has shown that paludrineper se is inactive; it is converted in the body to anunknown metabolite which is the active antimalarjaJ agent.CH -03PAMAQUINEN ,c2H5H-N-CH-CH -CH -CH-N• J 2 2 2 \C HCH3 2 5Pamaquine was introduced by Fischl in 1926 as the resultof the study of thousands of compounds in experimentalavian malaria. The chemotherapeutic index of this compound,in birds indicated that it would be a most valuableand safe drug; unfortunately, it proved to possess unex•pectedly high toxicity in mammals, including man. It foundr, Pamaquine 367-some use, however, in the public-health aspects of malaria,since it has a peculiar gametocidal effect in low, relative]ynontoxic doses which are ineffective against the asexualforms which are responsible for the symptoms and continuationof the disease in man. Thus, the effective use of thedrug in all infected human beings within a given area wouldprevent the infection of the mosquito vectors and thereforelimit the spread of the disease. Although theoreticallypossible, this procedure is impractical except in rare instances,such as under military control.Pamaquine appears to have a definite effect in loweringthe relapse rate in P. vivax infections when it is given indangerously high doses and in conjunction with quinine.The toxic effects so produced are usually so serious as toprevent this use of the drug but nevertheless it was the firstdrug, and until the discovery of pentaquine the only onepossessing any curative action in P. vivax infectionsThe absorption, intermediary metabolism, excretion, usageand toxic symptoms of pamaquine are essentially the sameas those of pentaquine. It is now certain that pa' maquinewill be completely replaced by pentaquine or one of itsanalogues.CH -o 3•PENTAQUINE1cH3~ CHN /\~H-N-CH -CH -CH -cH 2-cH 2-N 32 2 2 \Hl!any hundreds of compounds related to pamaquine havebeen synthesized and tested in the search for a less toxicagent which might retain the curative power of pamaquine.At. present, the most promising of these analogues is pentaquine_(SN13,276). A given dose of pentaquioe is about halfas toxic, and half again more active, than the same dose of•'•368 Antimalarial Drugspamaquine. This improvement in the chemotherapeuticratio is sufficient to make the drug a most useful addition toour list of antimalarial agents. From 40 to 80 mg. of penta..quine monophosphate is the daiJy dose; the lower amountalmost never produces toxic symptoms and is very effectivein producing a complete cure in old cases of P. vivaxi nfe.c.tions which have been kept under control with one of thesuppressive drugs.Pentaquine is always used with quinine. It has now beendemonstrated experimentally as l\'ell as clinically that thereis a definite synergistic response to the administrationo f acombination of these drugs. Pentaquine is always given bymouth and it is rapidly and completely absorbed from theintestinal tract. It is not a cumulative drug but the natureand extent of its degradation in the body is not known, Onlysmall amounts are excreted. The usual course of treatment• is 14 days. A second or third course may be ne~essary 1nrecent heavy infections.The toxic symptoms of pentaquine include abdominalpain with nausea and anorexia, anemia, leukopenia, fever,cyanosis due to methemoglobinemia, and jaundice. Acute1 intravascular hemolysis, long, persistent postural bypoten•sion and syncope may occur at dosage levels of 180 mg. ofpentaquine monophosphate per day. There is some evidenceof a synergism in toxic action with the development ofagranculocytosis when pentaquine and the sulfonamides areused concurrently.PREPARATIONSQuinine bisul!ate U.S.P.; B.P. l Gm.Quinine bisulfate tablets U.S.P.Quinine dihydrochloride U.S.P.; B.P., t Gm.Quinine hydrochloride U.S.P.; B.P. 0.6 Gm.Tablets of quinine hydrochloride B.P. 0.6 Gm.Quinine sulfate U.S.P.; B.P.• '••,Preparations 369Quinine-sulfate tablets U.S.P. Usually 0.12, 0.2 and 0.3Gm. tablets.Totaquine U.S' .P. A mixture of cinchona alkaloids containingnot less than 10 per cent anhydrous quinine and between70 and 80 per cent of total anhydrous crystallizablecinchona alkaloids. 0.6 Gm.Totaquine capsules U.S.P. Usually 1201 200 and 300 mg.capsules.Totaquine tablets U.S.P. Usually 120, 200 and 300 mg. tablets.Quinacrine hydrochloride U.S.P. l\fepacrin hydrochlorideB.P. 0.1 Gm.Quinacrine-hydrochloride tablets U.S.P. Usually 50 and 100mg. tablets. •l\fepacrine methanesulfphonate B.P. 0.05 to 0.1 Gm. intra•muscular.Pamaquine B.P. 0.025 to o.osG m.BIBLIOGRAPHYSeries of papers on clinical studies on quinacrine, chloroquine,paludrine and pentaquine, special number ofJ. Clin. Investigation (in press, fall, 1947).Bang, F. B., N. G. Hairston, W. Trager and J. Maier:Treatment of acute attacks of vivax and falciparummalaria~ A comparison of atabrine and quinine, Bull.U.S. Anny ti. Dept. 7: 75, 1947.Butler, 1{. G.: Atypical lichen planus tropicalis, Arch.Dermat. & Syph. 55: 535, 1947.Fitzhugh, 0. G., A. A. Nelson and H. 0. Calvery:Chronic toxicity of quinacrine, J. Pharmacol. & Exper.Therap. 85: 207, 1945.Ha,vking, F.: Activation of paludrine in vitro, Nature159: 400, 1947.Keis:>:• F. E., F. K. Oldham, \V. Cantrell and E: l\I. K.Ge1}1ng: . An~imalarial activity and toxicity of a meta•bolic denvat1ve of quinine, Nature 1S7: 440, 1946.•370 • Antimalarial DrugsKelsey, F. E., F. K. Oldham and E. 1{. K. Geiling:Studjes on antimalarial drugs-the metabolism of qui•nine and quinidine in birds and mammals, J. Pharmacol.& Exp er. Therap. 85: 170, 1945.Loeb, R. F.: Activity of a ne,v antimalarial agent, chloroquine(SN7,618), J.A.M.A. 130: 1069, 1946.Loeb, R. F.: Acti,·ity of a ne,v antimalarial agent, pentaquine ( SN 13,276), J .A.iI.A. 132: 321, 1946.Most, H., C. A. Kane, P. H. Lavietes, I. M. London, E. F .Schroeder and J, M. Hayman: Combined quinine-plasmochintreatment of vivax maJ.iria: Effect on relapserate, Am. J. ?vi. Sc. 212: 550, 1946.Oldham, F. K., and F. E. Kelsey: Studies on antimalarialdrugs--the distribution of atabrine in the tissues of thefo,vl and rabbit, J. Pharmacol. & Ex_per. Therap. 83:288, 1945.Scl1affer, A. J., and R. A. Le,vis: Atabrine studies in thefield: I. The relation of serum atabrine level to break•through of previously contracted vivax malaria, Bull.Johns Hopkins Hosp. 78: 265, 1946.\Viselogle, F. Y.: A Survey of Antimalarial Drugs,1941-1945, Ann Arbor, Mich., Ed\.vards, 1946.•INTRODUCTIONSULPA' 'IHIAZOLE29SulfonamidesSULFADIAZINEMISCELLANEOUS SULFONAMIDESPREPAllATIONSINTRODUCTIONThe antibacterial activity of sulfanilamide was first ob~served by the Trefouels in Fourneau's laboratory in Francein 193S. This .finding resulted from a study of the inter•mediary metabolism of the recently announced dyestuff"prontosil," which had been synthesized in 1932 and wasshown by Domagk early in 1935 to have a remarkable curativeeffect in experimental hemolytic streptococcal infections1• n m•i ce. ..,The discovery of the activity of the sulfonamide drugsgave. the first real impetus to the study of chemotherapysince the work of Paul Ehrlich. The lack of success in thesearch for active antibacterial agents had slowly built upa philosophy that bacteria, being relatively simple forms oflife, could never be expected to respond to chemotherapy ascompletely as the more complex parasitic micro•organisms.Since 1935, developments in the field of bacterial chemotherapyhave been rapid. Not only have many new and• important therapeutic agents been introduced but also considerableprogress has been made in understanding themechanism of action of these drugs. In a few isolatedcases, these new theories have been responsible for thesynthesis of new and active drugs and further progress maybe expected to yield even more important chemotherapeuticagents.371•372 SulfonamidesMechanism of Action. The sulfonamidesa re activeb acteriostaticagents in infections produced by a variety ofbacteria, including hemolytic streptococci, meningococci,gonococci, pneumococci, staphyJococci and H. inftuenzae.Soon after the discovery of the antibacterial activity of thesulfonamides, it was found that the extracts of bacterialcultures, or yeast, contain a substance capable of neutral•izing the effect of these drugs. This substance was shown••To2 COOHNH2Sulfonilamide• p- aminobenzoicacidby Woods in 1940 to be p-aminobenzoic acid. The cJosestructural relationships between these two compoundssuggested a possible mechanism of action. If it be supposedthat p-aminobenzoic acid is an ''essential metabolite,"i.e., required by the cell for its continued growth andmultiplication, then the presence of sulfanilamide or oneof its derivatives in the media would tend to block, bycompetitive inhibition, the reaction utilizing p-aminobenzoioacid. It has since been shown that p~aminobenzoic acid isrequired for the growth of certain micro-organisms and fspresent in most, ii not all, Jiving cells. Following the .eJuci'I\' Introduction 373dation of the chemical structure of pteroylglutamic acid,and the proof that it contains p-aminobenzoic acid, it wassuggested that the reaction which is inhibited by the sulfonamidesmight be the synthesis of pteroylglutamic acidfrom its components. In substantiation of this hypothesis,it has been observed that certain micro-organisms which ,require pteroylglutamic acid as a growth factor are unaffectedby the sulfonamides.The variations in activity among the sulfonamides maybe explained in several ways. First, substitutions in the acidamide portion of the molecule so affect the electronegativecharacteristics of the acid group that the resulting compoundis more nearly identical, from the standpoint ofionization characteristics, to p-aminobenzoic acid. Second,these substituting groups may potentiate the activity bycompeting with other "essential metabolites" in enzymaticreactions, as, for example, sulfathiazole with riboflavin,sulfapyridine with niacin, and sulfadiazine with thiamine.Finally, differences in the clinical usefulness of these compoundsis dependent largely on such factors as solubility ofthe drug and its metabolic products, distribution in thetissues of the body, inactivation by adsorption on blood •and tissue proteins and the rate of excretion of the drug.There is also sufficient variation in the toxicity of thesedrugs to warrant special consideration of possible toxicreactions with each individual drug. Thus, the choice ofa sulfonamide may vary not only from one infection toanother, but also from patient to patient. Too much emphasiscannot be placed on the necessity for careful examinationof the patient before these drugs are prescribed. •Sensitization and Developed Resistance. Indiscriminateor too frequent use of the sulfonamide drugs may lead to thedevelopm~nt of an allergic type of reaction whereby skinrashes, pbotosensitivity or, more rarely, acute granulocyto.penia or anemia may result from subsequent use of the drug.Furthermore, it is becoming increasingly evident that the••374 Sulfonamidesjnadequate use of one of these drugs in a given infectiontends to result in the appearance of a strain of the infectingorganism which is resistant to further treatment with thedrug and which is also frequently possessed of even greatervirulence than the orjginal strain. For these reasons, theuse of the sulfonamides either in the local treatment ofwounds and bums or for routine prophylaxis is to be con•demned.Certain strains of generally susceptible bacteria are foundto be less sensitive than others to the action of the sulfonamides.In some cases, these may be examples of developedresistance, while in others, where there is no possibj]jtyo fprevious exposure of the bacteria to the drug, the resistancemust be natural, not acquired. The detection of sulfona•mide resistance, and an approximation of its magnitudec, anbe made in the laboratory, and such tests should be made in,nll cases in which the drug fails to suppress the infectionwithin 3 or 4 days of adequate administration.Metabolism. \Vith certain exceptions, the sulfonamidesare rapidly absorbed when given by mouth. These drugsare all relatively insoluble in water but for parenteraladministration the sod1um saJts may be used: Highly concentratedsolutions may be so obtained but the high alka·linity (pH 10 or above) makes them too irritant except forintravenous use.In order to exert a maximal effect on the invading organ·isms, the decision to use one or more of the sulfonamidesin a given case should be implemented by the administra·tion of a large crpriming'' dose in order to more or lesssaturate the body with the drug. This should be followedby regular day and night doses at whatever intervals maybe required to maintain a relatively constant concentrationof the drug in the blood and tissues. The size of the initialdose and the frequency of maintenance doses will varyac,ording to the rate of excretion of the drug. This isreflected by the blood concentrations of the ·drug which canII'I !jI>1I...-.. .._. .,• Introduction 375be determined by chemical analysis. Urinary analysis maybe necessary in new patients before the administration ofthe priming dose in order to determine whether or not thepatient may have been receiving one of these drugs in therecent past and accordingly does not need, and may not beable to tolerate, a large initial dose.TAM,E 7INFLUENCE OF pH ON SULFON.UfIDE SOLUBILITYSOLUBILITY I AS MG,% 1 IN AQUEOUSBUfi'El<. SOLUTIONSSULl'ON AMID'!!!I•pKS.S pH6.S pH 7.5Sul!atbiazole ................ , .... 98 108 235Acety1suUathlazol.e.. .........•.. , 7 9 29Sulfadiazine.. ..................... 13 28 20()Acetylsulaf diazine • • I I ♦ • • 'I ♦ • • ♦ • ♦ • e 20 75 S12Sulf alllerazine ........... " ........ 35 45 170Acetylsulfatnerazine. ..... , ........ 38 57 272SuJfametbazuie 69 i6 140 • • • • • • • • • • • • • • • • • • •Acetylsulfametbazine •............. 90 107 240?:.lodifiedf rom D. R. Gilligan, S. Garb, C. Wheeler and N. Plummer:J.A 11.A. 122: 1160, 1943.Generally speaking, the sulfonamides are eliminated fromthe body through the urine. The rapid rate of excretion,the relatively large amounts involved, and the low aqueoussolubility, all tend to favor precipitation of microcrystalsof these drugs in the kidney tubules. This crystalluria is themost frequent hazard,._encountered in sulfonamide therapy.In those £ ew cases in v.·hich actual blockage of the tubulesoccurs1 death may result from kidney damage and anuria.The solubility of the sulfonamides and of their metabolicproducts is greatly increased in slightly alkaline solutions(see Table 7). This prompted the formerly widespreadpractice of administration of sodium bicarbonate along376 Sulfonamideswith the drug in order to alkalinize the urine. Clinicalexperience, however, has shown that easily tolerated amountsof bicarbonate do not actually influence the acidity of the_ urine sufficiently to affect the solubility of the drugs. Inpractice, maintenance of a large volume of fluid output isthe method of choice. The volume of urine excreted per dayshould be kept over 1,500 cc. This may be difficult to obtainin moribund patients, in patients with diarrhea, or in verywarm climates. Recently the practice has been introducedof giving two or more of the sulfonamide drugs at the sametime, since a saturated solution of such a mixture containsconsiderably more sulfonamide than a saturated solutionof either drug alone.The only chemical changes that are made in the sulfonamidemolecules \o any exte.nt by the body are referable tothe p-arnino group. This may be esterified, usually TI,jth anacetate group, resulting in the formation of an acetylsulfon•amide. This is of practical importance because the acetylderivative is without therapeutic effect, yet its solubilityin urine may be either more ( e.g., acetylsulfadiazine) orless (e.g., acetylsulfathiazole) than that of the parent com•pound. The degree of acety1ation varies from one speciesof animal to another as well as from one drug to another.' Toxic Effects. The sulfonamides are one of the mostimportant groups of therapeutic agents but they are not• without serious toxic potentialities. In addition to the poSSI·bilities of drug sensitization and kidney damage alreadydiscussed, there is a group of minor or moderately severesigns and symptoms which may occur but which do not callfor stopping further administration, as well as a group ofmore severe signs and symptoms which demand immediatemeasures as well as a careful evaluation as to whether the,disease or the drug presents the greater hazard to thepatient. In the first group are nausea and vomiting, ':ithor without stomatitis, abdominal cramps, flatulence or d1ar•rhea; dizziness, psychoses, ocular and auditory disturbances,'Introduction 377which may be of special importance to ambulatory patients;painful joints, cyanosis, acidosis, mild hemolytic anemiaand hematuria. Drug rash or drug fever may also occur.Drug fever is sometimes hard to detect since its onset maybe simultaneous with the decrease in fever resulting fromthe suppression of the infecting organisms by the drug.The more serious signs and symptoms include leukopeniawith granulocytopenia, acute hemolytic anemia, anemiawith azotemia, leu.kocytosis, purpura hemorrhagia and jaundice.None of the toxic manifestations seem to be influencedby the administration of p-arninobenzoic acid; the treatmentis based on measures designed to increase the amountof urine formation in order to prevent kidney damage andto aid in the excretion, and such supportive measures asmay be indicated.SULFATH!AZOLEAt the present time, the choice of a sulfonamide usuallylies between sulfathiazole and sulfadiazine. Sulfathiazolewas first synthesized in a number of laboratories in 1939.It is much more effective than the earlier sulf anilamide orsulfapyridine. It is the sulfonamide of choice in the treatmentof mixed infections since it appears to be activeagainst a greater variety of organisms. It is also thoughtto be more active than sulfadiazine and its homologues instaphylococcal and gonococcal infections. This may or maynot be true; in any case, penicillin is now the drug of choicefor these infections. Sulfathiazole has been widely used as aurinary-tract antiseptic because of its polyva1ent action andits rapid urinary excretion.The metabolism of sulfathiazole is characterized by rapidabsorption and excretion. The initial dose is usually from4_ to 6 grams, subsequent maintenance doses are 1 gram?1ven at least every 4 hours. This is usually adequate, but1: ~ be increased if due regard is taken of the poor solubilityof this drug in the urine.378 SulfonamidesSulfathiazole is fairly evenly distributed in the body tissueswith the exception of the cerebrospinafl luid,w heret he .concentration attained is only 10 per cent that of the blood.The high activity of orally administered sulfathiazolei nmeningitis suggests, however, that penetration of the drugS11lfono1d1 •1,fHPr 11111l,0ICHfONH ~ N•N-0--S°z~NaS03 •"" S03NaNe0"'1)fO!IIOsilSullo111lom,d1HeN-0-SOzNH7D ~N-Q-so.;at-0~!falh1<1zolt S11lfod1oz1111Sul0f1 1\lfOZ~ S11lrome1~0:iotSulfapyrozmS11Ho;uonldl111is somehow increased when the meninges are infected, ashas been shown in the case of penicillin.In man, the amount of sulfathlazole in the blood andin the urine in the acetylated form is from 10 to 30 per cent. ...From 60 to 80 per cent of the total unacetylated drug presentin the plasma may be adsorbed on the plasma albumins./Sulfathiazole 379•This adsorption, however, appears to be readily reversible,since the drug is completely excreted by the kidney ,vithin24 hours after the last dose. This rapid clearance is anadvantage in those cases in which severe toxic symptomssuddenly appear. ,The incidence of toxic reactions to sulfathiazole is gen•erally higher than is the case with sulfadiazine. Nauseaoccurs in about one third of the cases and allergic man if estations,such as skin eruptions (from 8 to 10 per cent), drugfever (from 5 to 6 per cent), and conjunctivitis (4 percent), are more frequent ,vith sulfathiazole than with anyother commonly used sulfonamide. Special precautions mustbe taken to insure an adequate flo,v of urine because of thelow solubility of the drug.SULFADIAZINESulfadiazine is the most ,videly used sulfonamide drug.It is nearly if not equally as effective as sulf athiazole, andthe incidence and severity of toxic manifestations are appre•ciably less. Sulfadiazine was synthesized in 1940 and wasrapidly adopted as the drug of choice for the treatment ofpneumococcal pneumonia, in place of the much more toxicsulfapyridine.In addition to its relatively low toxicity, sulfadiazineoffers the convenience of longer persistence in the body,making the maintenance of constant blood levels of the drugsomewhat easier. As with all the sulfonamides, a priming _dose is necessary (from 2 to 4 grams) with maintenancedoses of 1 gram every 4 to 6 hours. A blood concentrationof 15 mg. per cent or higher is desirable in severe infections,while one of from 5 to 10 mg. per cent is usually satisfac•tory in mild infections. The drug is not completely absorbedfrom the intestinal tract but the fraction that is absorbed,from 60 to 80 per cent, is quite constant. It diffuses intothe spinal fluid in concentrations of from 50 to 75 per cent_ of the blood level, and into pleural and ascitic fluid in con•~ I'380 Sulfonamidescentrations o( from 60 to 80 per cent of the blood level., The concentration attained in the tissues is approximatelyequal to that of the blood. From 1 to 20 per cent or theblood sulfadiazine is acety1ated and from 20 to 40 percent of the urinary sulfonamide is acetylated, indicatingpartial tubular reabsorption of the free drug. About halfof the sulfadiazine present in the blood is adsorbed on theplasma albumins. Excretion is complete alter from 48 to12 hours.Although acetylsuJfadiazine is more soluble than acetylsulfathiazole, the relative solubilities of the parent compoundsare reversed (see Table 7). The chief disadvantageof sulfadiazine is this low solubility, since it favors theproduction of concretions in the kidney. A large number ofcompounds have been synthesized and studied in an attemptto find one retaining the high effectiveness and low toxicityof sulfadiazine but with a greater solubility. These researcheshave been partly success! ul, but the problem Isactually of little importance as Jong as a large fluid outputcan be maintained.All the toxic manifestations of the sulfonamides, as aclass, have been reported f ono wing the use of suJfadiazine.Although the incidence is quite low, several deaths havebeen reported in the literature and precautionary measuresshould be taken with every patient receiving a long courseor a relatively high dosage schedule.MISCELLANEOUS SULFONA?rIIDESThousands of compounds have been synthesized for studyjn this field, Some have had brief periods of popularity inthe past and are now almost completely discarded. Othersare still in an investigative phase and may well supplantthe currently used ones as further experience is gained. Thecompounds discussed in this section are examples of bothcategor•i es.•lliscellaneous Sulfonamides 381Prontosil is the complex organic dye reported by Domagkin 1935 to be effective against hemolytic streptococcal infec•tions. This patented preparation was used widely in themonths immediately following this announcement but itsuse was greatly curtailed by the discovery that sulfanila•mide was the active portion of the molecule. A derivativeof prontosil, neo-prontosil (Prontosil-S, Azosulfamide) offersthe distinct advantage of being freely water-soluble. It isperhaps unfortunate that patent restrictions on this class ofcompounds prevented further investigations of their propaerties and therapeutic values. Prontosil is not an officialdrug and finds little or no use today in the United States.Sulfanilamide is the least active of the sulfonamides. Itsone advantage is that it bas relatively high solubility inwater. Saturated aqueous solutions contain approximately800 mg. per cent at 25° C., while human serum at 37° C.can hold in solution nearly 2,000 mg. per cent. The drugis almost never used today for systemic administration.Its use for local application, originally promoted because of .the ease with which high local concentrations could besecured, is gradually falling into disfavor because of thedanger of inducing sensitization in the host and resistancein the infecting organisms.Su1£apyridine' was introduced by \Vhitby in Englandin 1937, particularly for the treatment of pneumonia. Itis irregulaly and of ten poorly absorbed from the intestinaltract. Excretion is slow and from 4 to 5 days may be re•quired for its complete elimination. The incidence I ofnausea and vomiting and anemia is greatest with sulfapyridine.The erratic absorption and the high toxicity ofthis drug has resulted in its almost complete replacementby other sulfonamides.Sulfamerazine (sulfamethyldiazine) has much the sameproperties as suifadiazine. It has the advantage of greatersolubility, especially in acid urine, and thus is less apt tocause kidney damage. It is more rapidly absorbed and more----I382 Sulfonamides •slowly excreted, thus giving hlgher and more prolongedblood levels and need only be given at 8- rather than at 4!or 6-hour intervals as is the case with sulfadiazine.Sulfamethazine (sulfadimethyldiazine) is almost identicalin its action to su1farnerazine except that its solubilityin acid urine is even greater. Neither of these methyl derivativeshas received nearly as much clinical trial as sulfadiazine,but there is some evidence that, despite their greater1solubility, kidney damage may occur.Sutfapyrazine is an isomer of sulfadiazine. Its absorptionfrom the intestinal tract is limited. ,vith sma11d oses,a 1mostcomplete absorption occurs while larger doses do not giveproportionately higher blood JeveJs, thus affording an automaticsafety mechanism against pverdosage. The activityand toxicity of sulfapyrazine approximates that of sulfadiazine.Sulfacetamide is used as a urinary.tract antiseptic. Absorptionand excretion are rapid and complete. Since tubu•lar reabsorption is negligible, high concentrations are easilyobtained in the urine with relatively low, nontoxic doses.The antibacterial activity is not as great as that of sulfathiazoJein equivalent concentrations; however, the high.,safe concentrations readily obtained with sulfacetamide(from 50 to 100 rng. per cent) are as effective, if not moreso, than the lower safe concentrations of sulfathiazole (from5 to 10 mg. per cent).The drug is about fifteen times as soluble in water assulfatbiazole and about one hundred fifteen times as solubleas sulfadiazine; consequently, intrarenal precipitation doesnot occur. Furthermore, sulfacetamide has the advantageof bejng sufficiently soluble even in acid urine to permit itsuse with such acidifying agents as may be desirable to maintainthe necessary degree of urinary acidity for optimalantibacterial action.Sulfaguanidine was introduced in 1940 by Marshall andhis associates as an intestinal antiseptic. Its absorption fromI 'l\1iscellaneous Sulfonamides .383the intestinal tract is relatively poor; hence, it exerts a highdegree of local antibacterial action. However, sufficient absorptionmay occur to produce severe toxic effects, especiallywhen the drug is used under conditions which prevent themaintenance' of high urinary volumes. The drug offers nospecial advantages over succinylsulfathiazole or sulf athia ..' zole as an intestinal antiseptic.Succinylsulfathiazole (sulfasuxidine) is not absorbedfrom the intestinal tract in significant amounts. Accordingly,it is only used in the treatment of infections of theintestinal tract. In itself it is almost without antibacterialactivity; however, a small fractio~ is slowly hydrolyzed togive free sulfatbiazole, which is the active antibacterialagent. The dosage of succinylsulf athiazole is very large;from 20 to 60 grams may be given at intervals of 4 hoursfor several days. It is gradually being supplanted by sulfa"thiazole used as such, since the effectiveness is about thesame and much smaller doses are required.Sulfamylon (marfanil, homosulfanilamide, mesudin, sulfabenzamine)is a sulfonamide which is superfici11lly verysimilar in structure to sulfanilamide. However, the pharmacologicproperties of the two compounds are quite different.The antibacterial activity of sulfamylon is not affected bythe addition of p-aminobenzoic acid to the medium nor is itaffected by the presence of pus or necrotic tissue. It is recommendedin the German literature for use in the localtreatment of wounds when mixed ,vith nine parts of sulfanilamidewhere it may be of value against Clostridiu11iwelchii and Cl. septicum, and against streptococcal strainswhich are resistant to ordinary sulfonamides.Sulfamylon ,is of no value for systemic administrationbecause of its extremely rapid excretion in the urine. It isfreely soluble in water. No toxic symptoms have beenreported following its use.Sulfonamide or Antibiotic? The question of whether touse sulfonamides or antibiotics f_or the treatment of infec••384 Sulfonamides•tion which are amenable to both is frequently difficulttoanswer. The chief advantages offered by the sulfonamidesare oral administrationa, slightly longer history of successful clinical use and considerably less expense. The anti•SuI f amyol nSult onilomidebiot.ics off er the advantages of generally greater activitywith negligible toxic effects. Both classes of drugs havebeen introduced too recently to permit a complete and finalevaluation of their relative merits.PREPARATIONSSulfathiazole U.S.P. 2 Gm. •Sulfthiazole tablets U.S.P.; B.P. Usually 300 mg. and S00mg. tablets.Sulfathiazole sodium U.S.P.; B.P. 2 Gm.Sterile sulfathiazole sodium U.S.P. 2 Gm. intravenous.Sulfadiazine U.S.P. i B.P. 2 Gm.Sulfadiazine tablets U.S.P.; B.P. Usually 300 mg. and 500mg. tablets.Sulf adiazine sodium U.S.P.; B.P. 2 Gm.Sterile sulfadiazine sodium U.S.P. 2 Gm. intravenous.Su1fanilamide U.S.P.; B.P. 2 Gm.,• I, Preparations 385Sulfanilamide tablets U.S.P. i B.P. Usually 300 mg. and500 mg. tablets.Sulfapyridine N.N.R.; B.P. Tablets of sulphapyridine B.P.Soluble sulf apyridine B .P.Sulfamerazine U.S.P. 2 Gm.Sulfamerazine tablets U.S.P. Usually 0.5 Gm. tablets.Sterile sulfamerazine sodium U.S.P. 2 Gm. intravenous.Sulfapyrazine N.N.R.Sulphacetamide B .P.Soluble sulphacetamide B.P.1 Sulfaguanidine U.S.P.; B.P. 2 Gm.Sulfaguanidine tablets U.S.P.; B.P. Usually 300 mg. andS00 mg. tablets.SuccinylsulfathiazoleU .S.P. 2 Gm.Succinylsulfathiazole tablets U.S.P. Usually 300 mg. and500 mg. tablets.•BIBLIOGRAPHYCouncil report: Dangers from the external use of sulfonamides,J.A.M.A. 128: 1024, 1945.Beyer, K. H., H. F. Russo, E. A. Patch, L. Peters andK. L. Sprague: The formation and excretion of acetylatedsulfonamides, J. Lab. & Clin. Med. 31: 65, 1946.Bratton, A. C., and E. K. Marshall, Jr.: A ne\V couplingcomponent for sulfanilamide determination, J. Biol.Chem. 128: 537, 1939.Collins, E. N •) and J. S. Hewlett: Succinylsulfathiazole(sulfasuxidine) in treatment of chronic ulcerative colitis:Report 55 cases followed two years; its value byretention enema in early cases, Gastroenterology 7 : 549, 11946. • 'Do\vling, H. F., H. L. Hirsh and M. H. Lepper: Toxic!eactions accompanying second courses of sulfonamides1n patients developing toxic reactions during a previouscou:se, Ann. Int. Med. 24: 629, 1946.Dowling, H. F.,H. H. Hussey, H. L. Hirsh and F. Wit•h~l~: Penicillin and sulfadiazine compared with sulfa•d1az1ne alone, in treatment of pneumococcic pneumonia.,Ann. Int. Med. 25: 950, 1946.I•386 SulfonamidesFrisk, A. R., G. Hagerman. S. Helander and B. Sjogren:''Sulpha•combination"-A new chemotherapeutic principle,Brit. l\f. J. 1: 7, 1947.Gilligan. D. R.: Comparative studies of the chemicalchanges occurring in sulfonamide drugs during therapyin man, J. Clin. Investigation 24: 301, 1945.Grand, 1-I. J. H., J. B. Stanbury, E. W. Ekermeyer andJ. D. Purvis, Jr.: Rheumatic fever: statistical analysis0£ incidence during suifadiazine prophylaxis( U. S.Nav. 1\fed. Bull. 462 : 1793, 1946.Kracke, R. R.: The effects of sulfonamide drugs on theblood, Am. J. Clio. Path. 14: 191, 1944.Lees, R.: Treatment of sulphonamide-resistant gonorrhoea,vith penicillin, Brit. M. J. 1 : 005, 1946.l\fitchetl, G. A. G., W. S. Rees and C. N. Robinson:l\Iarfanil and marfanil prontalbin, Lancet l : 627, 1944.O'DonneJI, C. H., J. L. Posch and J. W. Hirshfeld: Astudy of the values of local sulfathiazole in operative,vounds in the prophylaxis of infection, Surg. Gynec. &Obst. 82: 323, 1946.Rothman, P. E.: Recurrence of infection follo,ving ther~apy ,vith sulfonamide compounds and penicillin, .Am. J.Dis. Child. 72: 415, 1946. ,Woolley, D. W.: Recent advances in the study of biologicalcompetition bet,veen structurally related compounds,Physiol. Rev. 27: 308, 1947 .••INTRODUCl'IONPENICILLIN ,,STREPTOMYCIN••-30AntibioticsTYROl'HRIClNBACITRACINMISCELLANEOUS ANTIBIOTICSPREPARATIONSINTRODUCTIONIn its broadest sense, the term ''antibiotic" describes anysubstance capable of destroying life or living matter. However,it is now generally used in a more restricted sense todescribe antimicrobial agents produced by molds, bacteriaor actinomycetes. The present chapter deals with antibioticagents of established therapeutic value.The development of antibiotics as chemotherapeuticagents may be said to have been initiated by the Englishbacteriologist Alexander Fleming in 1929, although fromthe time or Pasteur sporadic attempts were made to utilizeas a therapeutic weapon the known antagonism betweencertain micro-organisms. Fleming, while studying staphylococcusvariants, noted a transparent zone surrounding amold contaminant of a culture plate or staphylococcus.Properly interpreting this clear zone as evidence of lysisof the bacteria by a diffusible substance produced by themold, he prepared cell-free filtrates of broth cultures of thismold and demonstrated their antibacterial activity. Theactivity was lost so rapidly from the filtrate that he wasunable to obtain adequate quantities for complete studies;however, he did demonstrate the relatively low toxicity ofthe substance and its activity against a number' of pathogenicbacteria. Since the mold belonged to the genus Penicilliun,,he adopted the name upenicillin" for the active. --.,._ 387•I•II388 Antibioticsagent in the filtrates. In 1940, Florey and hls associateswere able to produce stable preparations of peniciJJjnb ysterilizing a neutralized filtrate and were thus able to proceedwith more extensive experimental laboratory andclinical investigations. l\Ieanwhile, in 1939, Dubos in theUnited States demonstrated antibiotic activity in culturefluids obtained from certain soiJ bacteria and in 1942\Vaksman announced the first of a series of antibiotics to beisolated in his laboratory from various actinomycetes.It is of interest to recall that in 1922 Fleming noted thata bacteriocidal substance which he named "1ysozyme"w aspresent in the tissues and secretions of animals and in eggwhite. This substance was later studied as .a possiblechemotherapeutic agent by Florey and bis associates but"·as found to have little activity in vivo. Fortunately, their.studies on penicillin proved more fruf tful and the successfulclinical trials with this substance in 1941, together withthe stimulus provided by the demands of war, led to a rapiddevelopment of this newest field of chemotherapy.Antibiotics are highly selective in their action i hente thenature of the infective organism should always be determinedin order that the most effective antibiotic may 'beused. It ls a1so essential that the antibiotic be administeredin adequate dosage since resistant strains may developduring the course of therapy if submaximal doses are used•There is considerable variation in the ability of variousstrains and species of micro-organisms to develop resistanceto antibiotics as well as variation among the antibioticsconcerning their ability to foster the development of suchresistant strains. This is illustrated by the data in Table8. After thirty transfers into media containing progressivelyhigher concentrations of the antibiotic, a strain ofgonococcus increased its resistance to a po.int where thebacteria could tolerate three hundred fifty times the orig-.,, inal maximum tolerated concentration of penicillin. How• '~ • , ever, when streptomycin was used in place of penicillin, only)•Introduction 389three or four transfers were necessary to increase the resistanc~of this strain to a point where the organisms grew in asaturated solution of the drug. Furthermore, the streptomycin-resistant strains persisted for longer than 14 weeksand showed an enhanced virulence, while the penicillinresistantstrains were less virulent and soon reverted totheir original sensitivity., TABLE 8J.U.XD{Ul,I CONCENTRATION(mnTS PER CC.) 01!' DRUGPERMJTTING GROWTH BI.FOR!. NUMBERANTIBIODC OllGANIS?d: AND AFTJ:R TR.ANSn:RS IN 01!'DRUC-CONTAINING :MEDJA ntANsnRSI Br.FORE APllJlgonococcus 0.06 21 30Penicillin • 36 137meningococcus 0.3 41 305,000 147Strcptorn cin 1go n~coccus &-40 75,000 4Y men1ngococcus 1-40 75,000 3From C. P. Miller: J.A !\i.A. 130: 485, 1946, with subsequent data bypersonal communication.The use of antibiotics as chemotherapeutic agents is ofsuch recent origin that an impartial appraisal of their use~fulness is not always possible. The low toxicity of penicillinand its effectiveness in certain infections unaffected by sulfonamideshas made it a most valuable addition to thera-. peutics. Streptomycin and tyrothricin have as yet receivedless extensive use; but they appear to be of definite value,the former primarily in the treatment of diseases due to&:am.negative organisms and the latter as a local anti•infecti~e, while early clinical reports on bacitracin indicate thatthis_ ~n~ibiotic may be of special value i~ the treatment ofperuc1ll1n-and sulfonamide-resistant surgical infections.390 AntibioticsPENICILLINPenici]Jjn is obtained commercially from the molds Peni•cilli1111i notat11m or P. clirysogen111n by a variety of procedures.The rapid development of the large-scale productionof penicillin is a tribute to the co-operative efforts of theEnglish group of ,vorkers with a number of governmental,university and commercjaJ laboratories in this country. Thisinvolved not only continued improvements in the technicalaspects of production of this mold metabolite but also in thesearch for the n1ost suitable strains of Penicillium and eventhe creation of ne,v strains by artificial mutation to increasethe yield of the drug.Chemistry. Penicillin is no,v kno,vn to exist in severalforms \vhich differ chemically in the side chains attached tothe basic nuclear structure. These are identified in theUnited States as penicillin F, G, Kand X. In Great Britain,penicillins F, G and X are known as penicillin I, II and IIIrespectively. The four forms have approximately equal bacteriostaticactivity when tested in vitro. However, penicillinK has very little chemotherapeutic activity in vivo. This isthought to be due to the greater adsorption of peniciJlin Kon serum and tissue proteins, the adsorbed fraction beinginactive against most, if not all, organisms. This inactivationby adsorption explains both the re]ative ineffectivenessof penici]lin K in vivo and also the lower blood concentrationobtained v.·ith a. given dose of this penicillin type, sinceby biologic assay only the active penicillin is measured.Lo,v recoveries may also be obtained in in vitro tests whenserum or tissue proteins are added to the media. The recognitionof the comparative inactivity in vivo of penicillin Khas served to explain a number of disappointing results inpenicillin therapy, since some of the earlier commercialpreparations were shown to have contained appreciableamounts of this penicillin.The penicillins are organic acids. On acid hydrolysis,they yield several degradation products, including a d-amino•Penicillin 391'acid, penicillamine or d-~-~-dimetbyicysteine. Syntheticpenicillins have been produced in minute yield by condensationof penicillamines with 2 -benzyl-4- methoxymethy lene-5 ( 4 )-oxazolone, ,vhile further compounds ,vith antibioticactivity have been obtained by substituting other d-amino~-mercapto acids for penicillamine. The constitutional formulaof penicillin has not been fully established but it seemsmost probably to involve a ~-lactam structure.PenicilTFi,n A 2-pentenylnenicillRin:·C H -CH -CH=CH-CH -" ' 3 2 2PenicilriGn , benzylpenicilliRn=; - ~~-.;/~ CH2 -PenicilliXn . P-hydroxybentylpenicillinR; = HO--< ---- PenicillinK , N-heptylpenicillin· R: CH -( CH ).- CH -' 3 25 2Probable BasJc Formulae of Penicillins.Crystalline preparations of penicillin are odorless andtasteless. Amorphous preparations are yellow and have abitter taste, which may be objectionable when they are used1oca1Jyi n the mouth and throat. Only the solid crystallinef?rm may be stored without refrigeration. Aqueous solutionsof penicillin are unstable; however, they may be usedas llluch as a month after preparation if they have beenkept refrigerated and are sterile and neutral or slightly acid .. ~ertain micro-organisms are capable of inactivating penicillinbecause of the presence of an enzyme, penicillinase.Penicillinase is of practical importance both in determiningthe therapeutic effectiveness of penicillin and in testing thesteriJity of commercial preparations of the drug. It permits392 Antibiotics 'the selective destruction of penicillin in cultures of pharmaceuticpreparations, or of infected fluids such as b]ood orpus from patients under treatment.' This is a necessaryprerequisite for demonstrating the absence of penidllinsensitivemicro.organisms since the organisms will not growand hence cannot be detected in the presence of thedrug. Furthermore, assay of the penicillinase content ofinfecting organisms may be of value in explaining or detectingpenicillin-resistant forms or a usually sensitive speciesof bacteria.Metabolism. The sensitivity of penicillin solutions to acid,coupled ,vith the high content of penicillinase of the intestinalbacteria, produces erratic results when penicillin isgiven by mouth; hence, during the period when the use ofpenicillin was restricted, the drug was administered onlyparenterally. ,vith abundant supplies now available, theconvenience of the oral route has favored its more extensiveuse and a number of procedures have been utilized to improvethe absorption of penicillin from the gastro-iqtestinaltract. Since penicillin is sensitive to alkaline solutions as• well as to acid, simultaneous administration of sodiumbicarbonate or similar alkaline agents is of no value inprotecting the drug from destruction. However, approxi•mately 20 per cent absorption may be obtained if the penicillinis given admixed ,vith a buffering agent such as sodiumor calcium citrate, magnesium hydroxide or an aluminumpreparation. Some success has also been obtained withenteric-coated capsules and with penicillin-in-oil for oral use.Maintenance of optimal blood concentration is advisablefor adequate control of systemic infections. This requiresfrequent administration of the drug, since penicillin 1is rap-,idly excreted by the kidneys. Methods for continuous intravenousor intramuscular infusion have been devised andmay be used in severe infections. The drug is, however,most often given intramuscularly in aqueous solution at. I\ ,Penicillin 393intervals of from 2 to 6 hours throughout the day and night.Recently, preparations of penicillin in peanut oil and beeswaxhave been introduced for intramuscular or subcutaneousinjections. These' afford a convenient way of insuring anadequate blood concentration of the drug for from 12 to 24hours with a single injection. Similarly, delayed absorptionfrom intramuscular injections may be obtained by the localapplication of ice bags or by a' dmixture of the penicillinwith plasma proteins or with a vasoconstrictor such asepinephrine. •Penicillin may also be given by inhalation both for localand for systemic effects. \Vhen penicillin is administered asan aerosol, it is rapidly absorbed into the circulation toproduce blood levels comparable with those obtained byintramuscular or intravenous administration.• Attempts have been made to decrease the rate of excre-. tion of penicillin by the kidneys in order to obviate thenecessity for frequent administration and to attain higherblood concentrations. Penicillin appears in the glomerularfiltrate but the greater bulk (80 per cent) is secreted by thekidney tubules. This tubular excretion can be retarded by ,the administration of such substances as diodrast, paraaminohippuricacid, benzoic acid, sodium benzoate or caronamide.The use of adequate amounts of these substanceswill decrease the excretion rate to as little as one third ofthe ordinary rate. Renal excretion is also greatly reducedi•n nephritis and other forms of impaired renal function.Penicillin readily diffuses into the body fluids and tissues,with the exception of the cerebrospinal and synovial fluids,the humors of the eye, and probably also the pleural cavity.For the treatment of infections in those areas which arenot easily reached by systemically administered penicillini~ local injection may be necessary. This has been. particularlysuccessful in cases of empyema when the infectingorganism is sulfonamide-resistant. In such cases, response to394 Antibiotics . (1.n trap1eural injections of penicillin is usually prompt, ands1nce the drug does not readily diffuse out of the cavity,injections need only be made at 24- or 48-hour intervals.\\1hile there is some evidence that penicillin can penetratethe cerebrospinal barrier in meningitis, intratbecal injectionsof penicillin are generally administered in this condition toinsure adequate concentrations of the drug reaching thecausative organisms. Such injections, ho,vever, may beaccompanied by unusual toxic symptoms such as canvul-s•1 onso r syncope. •Penicillin finds ,vide use in the local treatment of boilsand carbuncles and other localized infections when it canbe injected directJy into the diseased area. The drug is notrapidly lost by diffusion and local concentration remainshigh. Dramatic improvement can be expected in from J2to 48 hours, or not at all.Activity. The use of penjcil}Jn is especially effective in_ infections caused by grampositive organisms, includingStapl1ylococcz,s aureus and albus, Streptococcus hemolyticusand viridans, pneumococci, clostridia and Corynebacterium .dipl1tl1eriae. Gonococci and meningococcia re also suscept•i -ble, but, in general, gram-negative forms are resistant topenicillin. Penicillin has given promising results in thetreatment of early syphilis and because of its lack of toxicityis probably the method of choice for the short-termtreatment of this disease. However, final evaluation of theresults of penicillin treatment of syphilis must await thecompletion of long-term studies on the permanence of cure.Penicillin appears to be effective in other spirochetal diseases,such a.s Vincent's angina, yaws and probably alsorelapsing fever.The average penicillin concentration required to inhibitbacterial growth in vitro may vary from 0.01 to O.S ormore unjts per cc. In vivo, maximal results are usuallyobtained with blood concentrations of from .0.04 to 0.ZIlPenicillin J9Sunits per c~ Higher concentrations may be necessary incertain infections, particularly syphilis, diphtheria, gasgangrene and subacute bacterial endocarditis.The mechanism by which penicillin exerts its action isnot understood. It is kno,vn to differ from that of the sulfonamides,hence cross•re~istance is not to be expected.Penicillin is not markedly inhibited by the presence of blood,pus or the products of tissue degeneration, nor do the localanesthetic agents interfere with its action. It affords somedegree of protection against meningococcus endotoxin, increasesthe requirements of the body for nicotinic acid, andhas an inhibiting action on urease, although these actionsare probably not directly related to its bacteriostatic andbacteriocidal activity.Toxicity. Penicillin is the least toxic of the chemotherapeuticagents. 1'Ialaise with chills and fever and headacheare rare and minor symptoms. Intramuscular or subcutaneousinjection may be accompanied by local pain which,however, is preventable by the addition of a local anestheticto the penicillin solution before injection. Allergic mani•festations are present in about 10 per cent of the cases.They usually consist of rash, angioneurotic edema andasthma, or of muscular twitchings or even convulsions. Thevery. effectiveness of the drug results in a high incidenceof Herxheimer reactions in syphilitic patients inadequatelypretreated with one of the slower-acting agents.Standardization of Penicillin. The international unit ofpenicillin is the activity contained in 0.6 micrograms ofpure sodium penicillin G. Assay is generally effected bycomparing the growth inhibitory effects of the standard andunknown on a penicillin.sensitive organisn1. The internationalunit is essentially equal to the origin.al Oxford unit,which ,vas defined as the amount of penicillin necessary toform a zone of inhibition 24 mm. in diameter in a cultureof particular strains of Staphylococcus aureus.396 AntibioticsSTREPTOMYCINS!reptomycin is an antibiotic substance formed by certainstrains of the fungus Streptomyces griseus in a suitablemedia. It was first isolated by \Vaksman in 1944 and isnow available in crystalline form. It is usually dispensed ina relatively pure state as the hydrochloride or su1fates alt.For systemic use, streptomycin must be administeredparenterally, since it is not appreciably absorbed on oraladministration. Intramuscular injection is safer and asefiective as intravenous. Pain at the injection site may beminimized by the addition of procaine to the streptomycinsolution.Streptomycin is usually injected as a 10 per cent solutionin isotonic saline or distilled water. The solution is relativelystable. The average dose is 0.4 Gm. of streptomycinrepeated at 4-hour intervals.Streptomycin is readily absorbed following intramuscularinjection. It is apparently excreted by glomerular filtrationonly and not by tubular excretion and therefore remainsin the blood stream for a longer period than penicillin. Itdoes not diffuse readily into the cerebrospinal fluid.Streptomycin is effective against a number of gram.negativeorganisms, including Escherichia coli, Pasteurella t1!Jare11sis,H emoplzilus inftuenzae, Psei,dotnonas aeruginosa,Bacillus protei,s, Ebertlzella typhosa and Brucella abortusand melitensis. It appears to be of particular value in sulfonamide-and penicillin-resistant infections of the urinarytract and is the most effective chemotherapeutic agent avail•able for the treatment of tularemia. Animal experimentshave indicated its etTectivenessin the treatment of tuberculosisand preliminary results in human beings have been• encouraging.If large doses of streptomycin are administered over atong period of time, symptoms of vestibular disturbanceincluding dizziness, tinnitus and deafness may occur. Mjldertoxic symptoms, which may be due to impurities, include,'Streptomycin 397•skin rashes, joint and muscle pains and nausea and vomiting.A histamine-like reaction has been reported following" streptomycin injection but this has been shown to be dueto a contaminant. There is some evidence that renal irritationmay occur with large doses.Standardization of Streptomycin. Assays of streptomycinare based on the inhibition of growth of a standardstrain of E. coli as determined by the dilution method. Theofficial streptomycin unit ('tS'' unit) is defined as the activityof 1 microgram of pure crystalline streptomycin base.TYROTHRICINTyrothricin is a mixture of at least two antibiotic substances,gramicidin and tyrocidin. The former, though presentin lesser amounts, is responsible for most of the activityof tyrothricin since tyrocidin is largely inhibited by thepresence of serum proteins and cephalin. Tyrothricin wasfirst isolated in 1939 by Dubos from the gram-positive soilorganism Bacillus brevis. At that time he named the prep~aration gramicidin but altered this to tyrothricin the foil owingyear when he recognized the presence of more than oneactive agent.Tyrothricin is effective against a variety of gram-positiveorganisms, including Streptococcus hemolyticus, faecalis,pyogenes and Stapliylococcus aureus. However, its therapeuticusefulness is limited by its toxicity, parenteral administrationcausing hemolysis of the red blood cells. It is usedlar'g ely for the local treatment of wounds, sinuses or superficialulcers infected with gram-positive organisms. It hasalso been used in veterinary medicine for the treatment ofbovine mastitis. The antibacterial activities of gramiciclinand tyrocidine appear to be related to their detergent properties.The optimum therapeutic concentration appears tobe approximately 500 micrograms per cc.Recently, Gramicidin.S has been isolated from a B. brevistype of organism by a group of Russian workers. It appears- ,398 -Antibioticsto be more effective on gram•negative organisms than grami•cidin but equally as toxic. Gramicidin•S, gramicidin andtyrocjdin are all polypeptides.BACITRACINBacltracin is an antibiotic isolated by Johnson, Ankerand l\feleney in 1943 from a strain of the B. si,btilis groupof organisms. It received its name because the bacillus wasisolated from a compound fracture in the leg of a youngpatient named l\largaret Tracey. In vitro experiments indic.1ted that it possessed bacteriocidal action largely againstgram.positive organisms, though gonococci and rneningococciwere also susceptible. In vivo, it proved active againsthemolytic streptococcal infections in mice and gas-gangreneJ.!lfections in guinea pigs. •Bacitracln has had as yet limited clinical trial. Recently,l\feleney and Johnson have reported its effectiveness in anumber of surgical infectjons which were resistant to penicillinand sulfonamides. It is apparently nontoxic and nonirritatingwhen applied locally and its action is not inhibitedby the presence of pus or micro-organisms. It is now beingproduced commercially so that further clinical studies willbe f ortbcoming.Subtilin, another antibiotic obtained from the B. si,btilisgroup, was isolated by Jansen and Hirshmann in 1944. Inaddition to its in vitro activity against a number of bacteria,it has recently been shown to be active in vitro againstE,zdameba histolytica, Trypanosoma equiperdum and Leisltntaniadonovani. Its activity is apparently due, at least inpartt to its detergent properties.iIISCELLANEOUS ANTIBIOTICSA number of other antibiotic substances have been testedfor their therapeutic value. Some of these, such as pyocyanineand pyocyanase obtained from Pseudomonas p;•oc;•a•'•Miscellaneous Antibiotics 399nea, actinomycin A and B from Acti1ioniyces a11tibioticus,gliotoxin from Trichoderma lig11oru111f,u magatin fromAspergillus JunJ.igatus, citrinin from Penicillium citri,zumand streptothrycin from Acti110111ycelsa vendulae, are tootoxic to be of practical importance. Patulio, obtained fromPenicilliu11pia tulu111e, njoyed brief popularity as an allegedcure for the common cold, but well•controlled experimentsshowed the early claims to be unfounded. It is apparentlyjdentical with claviform obtained from P. clavijo,111 andclavacin from Aspergillus clavatz,s and is too toxic forparenteral use.PREPARATIONSPenicillin calcium U.S.P.; B.P." Penicillin sodium U.S.P.; B.P.Penicillin dental cones U.S.P. Usually contain 1)000 and5,000 units of penicillin, with or without a sulfonamidepreparation.Injection of penicillin B.P. \Penicillin injection in oil and wax U.S.P.; B.P. Contains100,000, 200,000 and 300,000 units per cc.Penicillin ointment U.S.P.; B.P. B.P. preparation contains500 units per Gm.Penicillin ointment for the eye B.P. Contains 1,000 unitsper Gm.1 Sterilized penicillin cream B.P.; penicillin cream B.P. Contain500 units per Gm.Penicillin tablets U.S.P. Usually 20,000 and 25,000 unittablets. - Penicillin troches U.S.P.; B. P. Usually contain 500 l 000• I J and 20,000 units ,Tablets buffered penicillin N.N.R.Streptomycin N .N .R.Tyrothricin N.N.R.400 , AntibioticsBIBLIOGRAPHYGENERALKolmer, John A.: Penicillin Therapy, Including Tyrothricinand Other Antibiotic Therapy, Ne,v York, Appleton-Century, 1947.Herrell, W. L.: Penicillin and Other Antibiotic Agents,ed. 2, Philadelphia, Saunders, 1947.Waksman, S. A.: Production and nature of antibioticsubstances, Harvey Leet. 40: 77, 1944 -1945.Dubas, R. J.: Utilization of selective microbial agents intl1e stud}' of biological problems, Harvey Leet. 35: 223,1939-1940.PENICILLINAbraham, E. P., E. Chain, C. M. Fletcher, A. D. Gardner,N. G. Heatley, M. A. Jennings and H. W. Florey:Further observations on penicillin, Lancet 2: 177, 1941.Beyer, K. H., W. F. Venvey, R. Woodward, L. Petersand P.A. Mattis: The enhancement of the plasma concentrationof penicillin in dogs by the simultaneousadministration of para-aminohjppuric acid, III, Arn. J.M. Sc. 209: 608, 1945.Chain, E., H. W. Florey, A. D. Gardner, N. G. Heatley,l\1, A. Jennings, J. Orr-E,ving and A. G. Sanders:Penicillin as a chemotherapeutic agent, Lancet 239: 226,1940.Eagle, H. : The therapeutic activity of penicillins F, G,K and X in experimental infections ,vith pneumococcusType I and Streptococc11psy ogene.r, ]. Exper. Med. BS;175, 1947.Fleming, Sir Alexander: Penicillin, Its Practical Application,Philadelphia, BJakiston, 1946.Goerner-, J. R., A. J. Geiger and F. G. Blake: Treatmentof subacute bacterial endocarditis ,vith penicillin: reportof cases treated 1-vithout anticoagulant agents,Ann. Int. Med. 23: 491, 1945.Heller, Jr., J. R.: Results of rapid treatment of early syphilisJ.A.M.A. 132: 258, 1946.Levy, II, L., and N._ McKrill: ~~suits in the treatm;ntof subacute bac:ter1al endocard1t1s, Arch. Int. Med. 17:367, 1946.• Bibliography 401l\feJeney, F. L.: Penicillin in the treatment of establishedsurgical infections a systematic study of 744 including82 septicemias, Ann. Surg. 124: 962, 1946.1\1:endellT, . H., and P. H. Prose: Severe allergic reactionsto penicillin, Am. J. M. Sc. 212: 541, 1946. ..1.forginson, W. J.: Toxic reactions accompanying penicillintherapy, J.A.M.A. 132: 915, 1946.Rake, Geoffrey, and A. P. Richardson: Pharmacology ofpenicillin, Ann. New York Acad. Sc. 48: 143, 1946.Richardson, A. P., I. Miller, C. Schumacher, W. Jambor,F. Pansy and D. Lapedes: Physiological disposition of' penicillin G and K in dogs, Proc. Soc. Exper. Biol. &Med. 63: 514, 1946.du Vigneaud, V., F. H. Carpenter, R. W. Holley, A. H.Livermore and J. R. Rachele: Synthetic penicillin,Science 104: 431, 1946.Walker, A. E., and H. C. Johnson: Penicillin in Neurosurgery,Springfield, Ill., Thomas, 1946.Walker, A. E., and H. C. Johnson: The chemical study ofpenicillin, Science 105: 653, 1947.Walker, A. E., and H. C. Johnson: The changing characterof commercial penicillin-with suggestions as to theuse of penicillin- in syphilis, J.A.1\1.A. 131: 271, 1946.STREP'IOMYClNAdcock, J. D., and R. A. Rettig: Absorption, distributionand excretion of streptomycin, Arch. Int. Med. 77: 179,1946 .•Farrington, R. F., H. Hull-Smith, P. A. Bunn 1 andW. McDermott: Streptomycin toxicity, reactions tohighly purified drug on long►continued administrationto human subjects, J.A.M.A. 134: 679, 1947.Hinshaw, H. C., W. H. Feldman and K. H. Pfuetze:Treatment of tuberculosis with streptomycin-a summaryof observations on one hundred cases, J.A.M.A.132:778, 1946. ·Miller, C. P., and M. Bohnhoff: Streptomycin resistanceof gonococci and meningococci, J.A.11.A. 130: 485, 1946.~filler,. C. P:• and 11:. ~ohnhoff: Development of streptomyc1n•res1stant variants of meningococcus, Science105: 620, 1947.402 Anboiotics - Pulaski, E. J.: Streptomycin in surgical infections: II.Infections of the genito-urinary tract, Ann. Surg. 124:392, 1946.Reimann, H. A., A. H. Price and W. F. Elias: Streptomycinfor certain systemic infections and its effect onthe urinary and {ecal flora, Arch. Int. 1!ed. 76: 269, •1945.Waksman, S. A., and A. Schatz: Streptomycin-origin,nature, and properties, J. Am. Pharm. A. 34: 273, 1945.TYROTIDUCINFranks, A. G., W. L. Dobes and J. Jones: Tyrothricin"in treatment of disease of skin, Arch. Dermat. & Syph.53: 498, 1946.Gause, G. F .• and M. G. Brazhnikova: Gramicidin S.,origin and mode of action, Lancet 2: 715, 1944.Henderson, J.: The status of tyrothricin as an antibioticagent for topical application, ]. Am. Pharm. A., s~ Ed.35: 141, 1946.BACil"RAClNAnderson, H. H., G. G. ViIJela, E. L. Hansen and R. K.Reed: Some physical and biologic properties of subtilinand other antibiotics, Science 103: 419, 1946.Johnson, B. A., H. Anker and F. L. l\.feleny: Bacitracin:a ne,v antibiotic produced by a member of the B. sub·tills group, Science 102: 376, 1945.Meleney, F. L., and B. Johnson: Bacitracin therapy-thefirst hundred cases of surgical infections treated Jocally,vith the antibiotic, J.A.M.A. 133: 675, 1947.31MiscellaneousChemotherapeutic AgentsANTIMONY COMPOUNDSGOLD COMPOUNDSMELARSEN OXIDESURA.MINCYANINE DYESDIAMlDINESPARA-AMINOBENZOIC ACIDCHAULMOOGRA OILSULFONESI\fANDELIC ACID ANDMETHENAMINEVACCINES AND SERAPREPARATIONSANTIMONY COMPOUNDSOrganic antimony preparations are used in the treatmentof schistosomiasis, filariasis, Ieishmaniasis and lymphogranulomainguina1e. They are of some value in the treatmentof trypanosomiasis but are inferior to the arsenicals in thisrespect. Both trivalent and pentavalent antimonials are inuse at the present time; inorganic antimony salts are notused therapeutically.Potassium antimony! tartrate (tartar emetic) and sodiumantimonyl tartrate were first used in the treatment of schistosorniasisin 1915. Prior to their introduction emetine wasthe drug of choice in this condition but its use had provedfar from satisfactory. The main disadvantage of the antimonytartrates lies in the fact that they must be giveni_!ltravenously because of their irritant properties, and acourse of treatment usually requires hospitalization withinjections on alternate days for 3 weeks. Recently, an intensive1- or 2-day treatment by continuous drip has givenpromising results.403'404 Miscellaneous Chemotherapeutic Agents •In 1929, the less toxic compound stibophen (fuadin, neo•antimosan) became availab1e. This drug can be administeredintramuscularly and injections can be given more frequentlythan those of the more toxic potassium or sodium antimonyltartrate. Other trivalent antimonials include antimony thiog1ycoJ1amideaz1d the more so1ubJe and somewhat Jesstoxic antimo~y thioglycollate and anthiamatine or antimonylithium thiomalate. Pentavalent antirnonials includestibosan ethylstibamine (neostibosan) and urea stibamine.\Vhile relatively Jess effective than the trivalent antimoniaisin the treatment of schistosomiasis, they have given promis•ing results in the treatment of filariasis and leishmaniasis.In filariasis, the adult ,vorm but not the microfilaria appearsto be affected, hence treatment must he prolonged.Characteristic toxic effects of a.ntimonia]s include salivation,abdominal cramps, vomiting, a hard, unproductive'cough, constriction of the chest, bradycardia, dizziness anda,JJapse. There are often transient changes in the e1ectrerca' rdiogram, the most characteristic being a decrease inamplitude in the T wave.GOLD COl\f POUNDSGold compounds are used in the treatment of Lupuserythematosus and of rheumatoid arthritis. They were for•merly used in the treatment of pulmonarJ" tuberculosis but ,proved of doubtful value and high to,ricity. Gold sodiumthiosulfate (sanocrysin) is probably the most widely usedcompound. ..Gold compounds are administered intramuscularly or .intravenously. They must be used cautiously because ofI their toxicity, manifestations of which include skin reactions,gastro-intestinal upsets, blood dyscrasias and liver and kid4ney damage. Sma.11d oses should be administered at firstsince many patients display an idiosynacrasy towards goldcompounds. ./••' Melarsen Oxide 40SI MELARSEN OXIDE,# NH2NH--\~NNH2Melarsen oxide is a trivalent arsenical which, like theparent pentavalent compound, melarsen, has recently beenshown to be effective in both early and late stages of Africansleeping sickness. It is said to be much less toxic thantryparsamide.SURAMINSuramin (naphuride, germanin, Bayer 205), a nonstainingcomplex urea derivative ,vas introduced in Germany in1920 for the treatment of trypanosomiasis. Its compositionremained secret until 1924, when Fourneau synthesized acompound of apparently identical chemical structure andtherapeutic activity which he called moranyl or Fourneau309. It is of value only in the treatment of the early stagesof the disease, being valueless after the central nervoussystem has become involved. For treatment of the latestages of sleeping sickness, tryparsamide remains the drugof choice.' Suramin forms a complex with plasma protein whichgreatly delays excretion of the drug from the body. Sincethe trypanocidal activity is not affected, a single dose of, the drug will exert a chemotherapeutic effect for several/ months.CYANINE DYES •Certain cyanine dyes have recently been shown by Bieterand by \Velch to exert a. curative action on experimentalf1larial infections in rats. The adult worms are affected,~406 l\.fiscellaneousC hemotherapeuticA gents'·the preparations being active both in vivo and in vitro.The mode of action is suggested as being a depression ofenzyme systems concerned with oxidative metaboJism.DIAl\fIDINESThe guaaidine derivatives synthalin and synthalin B,vere tried in 1926 and 1928 for the treatment of diabetesmcllitus because of their blood-sugar-lotrering power.In 193S it was reported that these compounds were effec~tive in e."tperimental trypanosomiasis and since tryano-someswere known to require relatively large amounts ofglucose to maintain their growth, it was assumed the proto-zoicidalaction of these compounds was due to their effect onthe blood sugar. Since these two compounds were too toxicfor practical purposes, however, a further series oI guaui•dines and diamidines were prepared and tested by Yorkeand his colleagues. It was soon apparent that the chemotherapeuticactiv.ity of these compounds was quite unrelatedto their action on the blood sugar. The most suitable compoundsfor clinical use include stifbamidine ( 4-4'-diamidinostilberte),propamidine ( 4-4'-diamidine-diphenoxypropane)and pentamidine (4-4'-diamidine,diphenoxypentane). Thesesubstances are as effective as tryparsamide or suramin inearly cases of T. gambiense infections and have the advantage0£ being much less to:uc. They are apparently alsoeffective as prophy1actic agents. However, they are of JjttJevalue in cases with central nervous system involvement. Inthe treatment of leishmaniasis, stilbamidine has been themost wjdely used of the diamidines#The diamidines have a marked bacteriostatic effect inaddition to their antiproto.zoal activity. This activity isreported not to be inhibited by the presence of pus or bodyfluids. Propamidine bas been used for the local treatmentof infected wounds or burns. lt apparently does not inter•fere with wound healing if used in 0.1 per cent concentration.It does not, l1owevera, ffect Proteus or Ps. pyocyanea.Diamidines 407To'x icity. Immediate but not dangerous effects of intra ..venous injection of the diamidines include a sharp fall inblood pressure, accompanied by breathlessness, tachycardia,dizziness and gastro.intestinal upsets. These effects can beminimized by slo\v injection or by the use of the morepainful subcutaneous or intramuscular injections. Othereffects occasionally noted include rigor, granulocytopeniaand itching. Trigeminal-nerve neuritis has also been reported.It is supposedly due to toxic degeneration of thecells of the chief sensory nucleus in the pons.Solutions of stilbamidine are unstable and contain toxicproducts of an unknown nature which give rise to a delayedform of poisoning characterized by nausea and vomitingfollowed by coma and death. In the solid form, stilbamidine•is apparently quite stable. •PARA-Ai1INOBENZOIC ACIDPara-aminobenzoic acid (PABA), a member of the vitaminB complex, has recently been shown to be effective inthe treatment of a number of rickettsial diseases, includingtyphus fever, Rocky Mountain spotted fever and tsutsugamushifever. It has been suggested that the drug stimulatesthe metabolism of the host cell, permitting it to overcomethe invading organism. Sulfonamides appear to have aworsening effect in these conditions, due possibly to theirsuppression of the utilization of the naturally occurringpara-aminobenzoic acid. Para-aminobenzoic acid is usuallyadministered in a bicarbonate solution to minimize gastricupsets. Because of the rapid metabolism of the drug, freq9entadministration of large (from 2 to 8 Gm.) doses isnecessary.CHAUL1100GRA OILChaulmoogra oil (hydnocarpus oil) has been used forcenturies in the treatn1ent of leprosy, but authorities stillI408 1\IiscellaneousC hemotherapeuticA gentsdisagree as to its effectivenessT. he active5 1genatsr e thoughtto be the fatty acids known as chaulmoogrica nd hydnocarpicacids. Preparations are administered intramuscularly,since oral administration is usually accompaniedb y gastrointestinalupsets. \Vhile cures have been reported followingits use, some observers ha\•e maintained these have beenobtained only in mild cases which occasionallyh eal spontaneously.SULFONESI A number of sulfones, including promin, diasone andpromfzofe, have given promising results in the treatment ofexperiment.11t uberculosis in the guinea pig. They havebeen tried clinically in the treatment of tuberculosisa nd ofleprosy but t1ieir effects have been hard to evaluate becauseof the slow progress of these diseases. The drugs appear tobe more toxic in man than in guinea pigs.~t~OH(CHOH)4C>ISO NDI 3Ntl'9H2 0H(CHOH)4fHS03NaNHPrornizo1eOHlHSO Noj z ' NH II•• -Mandelic Acid and ~iethenamine 409l\IANDELIC ACID AND l\1ETHENA1\1INE•~ CHOH-COOH /1" CH2 c12C~Mandelic AcidNCH/"2CH2 / ~N"" /NCH2MethenamincMandelic acid and metbenamine were formerly widelyused as urinary antiseptics but have now been largely replacedby the sulfonamides and streptomycin. Both drugsare administered orally. l\1ethenamine owes its activity tothe liberation of formaldehyde, which occurs only in acidsolution. Mandelic acid is also effective only in an acidmedium; hence, if the urine is neutral or alkaline, acidifyingagents such as ammonium chloride or nitrate should beadministered concomitantly with these drugs.VACCINES AND SERA•A number of infectious diseases may be prevented ortreated by biologic products which combat the invadingorganisms or their toxins by building up the immune reactionsof the host. These include vaccines, which induceactive immunity by stimulation of antibody formation by_the host and serums, which confer passive immunity bytheir antibody content.Vaccines are preparations of attenuated or dead bacteriaor viruses or of bacterial toxins or toxoids. They includesmallpox, rabies, cholera, plague, typhus and typhoid vaccines,diphtheria and scarlet-fever toxins and diphtheria andtetanus toxoids. /Serums include human immune globulin obtained frompooled human placental blood and placentae and used in410 Misce}Ianeous Chemotherapeutic Agentsthe prevention and modification of measles,· human measlesand scarlet fever immune sera obtained from patients convalescingfrom measles and scarlet fever, respectively, andused in the prevention and treatment of these diseases;antibacterial sera, such as antipneumonococcic and antimeningococcicsera, which are obtained from the blood ofimmunized animals and which are believed to attack thepathogenic bacteria directly; and antitoxins, such as diph- •theria, scarlet-fever, gas-gangrene and tetanus antitoxins,which are obtained from immunized animals and act byneutralizing the toxins of the invading organisms. Officialpreparations of vaccines and sera are listed at the end orthis chapter. Details ol dosage and adm.inistration may beobtajned from the Unjted States Pharmacopoeia or from Newand Nonofficial Remedies, which al.so includes a number ornonofficial preparations.The injection of foreign serum may result in an anaphy•Iactoid or allergic reaction known as serum sickness. Signsand symptoms include urticaria, edema, joint pains, high 'fever and prostration. A more severe type of reaction developsin some patients who have previously recei\•eds erum,and who have developed a sensitivity or in patients whoare naturally .sensitive to a given serum. Immediate treatmentincludes the injection of epinephrine or of one of theantihistamine drugs. In some cases, desensitization can beaccomplished by repeated injection of small doses of theserum.PREPARATIONSAntimony potassium tartrate (tartar emetic) U.S.P.; D.P.0.03-0.12 Gm. intravenous.Sodium antimonyltartrate B.P. 0.03-0.12 Gm. intra.venous.Antimony~sodium-thioglycolatein jection U.S.P. 0.05-0.lGm. intramuscular or intravenous.\ Stibophen B.P.; N.N.R. 0.054-0.32 Gm. intramuscular.Ethylstibamine N.N.R. 0.05 Gm. intramuscular or intravenous.',Preparations 411IGold sodium thiosulfate N.N.R. 5-50 mg. intravenous orintramuscular. •Triphal N.N.R. Sodium aurothiobenzimidazole carboxylate.5-75 mg. intravenous.Surantlns odium U.S.P. 1 Gm. intravenous.lfandelic acid N .N .R. 3 Gm.Syrup of ammonium mandelate N.N.R.IvlethenamineU .S.P. Hexamine B.P. 0.5 Gm.?.Iethenamine tablets U.S.P. Usually 0.3 and 0.5 Gm.Cholera vaccine U .S.P.Diphtheria and tetanus toxoids U.S.P.Alum precipitated diphtheria and tetanus toxoids U.S.P.Diphtheria antitoxin U.S.P.; B.P.Diphtheria toxoid U.S.P.Alum precipitated diphtheria toxoid U.S.P.Diphtheria prophylactic B.P.Bivalent gas-gangrene a.ntitoxin U.S.P. Obtained from animalsimmunized against Clostridium perjringens andC. septicum toxins.Trivalent gas-gangrene antitoxin U.S.P. Obtained from animalsimmunized against C. perjringens, C. septicum, andC. oede1natietis(N ovyi) toxins.Pentavalent gas-gangrene antitoxin U.S.P. Obtained fromanimals immunized against C. perfringens, C. septicum,C. oedematiens (Novyi), C. bifermentans (Sordelli) andC. histolyticum toxins.Gas-gangrene antitoxin (oedematiens) B.P., gas-gangreneantitoxin (perfringens) B.P., gas-gangrene antitoxin(vibrion septique) B.P.Human immune globin U.S.P. A sterile solution of antibodiesobtained from human placental blood and placen.tae pooled from at least ten healthy women.Plague vaccine U .S.P.Rabies vaccine U.S.PScarlet fever streptococcus antitoxin U.S.P.Scarlet fever streptococcus toxin U.S.P.412 Miscellaneous< ?hemotherapeutAicg ents -Smallpox vaccine U.S.P. Vaccine lymph B.P.Tetanus and gas-gangrene antitoxins US.P. Obtained fromanimals immunizeda gainst C. tetani, C. perjringensa,n dC . .repticum toxins.Tetanus antitoxin U.S. P. .; B.P.Tetanus toxoid U.S.P.; B.P.Alum precipitated tetanus toxoid US.P.Typhoid and paratyphoid vaccine U.S.P.; B.P.Typhoid vaccine U S.P.Epidemic typhus vaccine U.S.P.Yellow-fever vaccine U.S.P.• BIBLIOGRAPHYANTIMONIAl.S•Bro,vn, H. W., N. D. Thetford: Further studies on treatmentof filariasis due to ,vuchereria bancroft with lithiumantimony thiomalate, Am. J. Hyg. 44: 379, 1946.Brady, F. J., A. H. La,vton, D. B. Cowie, A. L. Andre,vs,A. T. Ness and G. E. Ogden: Localization of trivalentradioactive antimony follo,ving intravenous administrationto dogs infected ,vith Dinofilaria immitis, Am. J.Trop. Med. 25: 103, 1945.Alves, W., and D. M. Blair: Schistosomiasis-intensivetreatment ,vith antimony, Lancet 1: 9, 1946.Khalil, M., and M. H. Betache: Tre.atment of bilharziasiswith a new compound "Fouadin''; report on 2041 cases, ,Lancet 1 : 234, 1930.Schroeder, E. F., F. A. Rose and H. lvfo st: Effect of antimonyon the electrocardiogram, Am. J. M. Sc. 212: 679,1946.Gor.oComroe, B. I.: The use and abuse of gold therapy inrheumatoid arthritis, J.A.M.A. 128: 848, 1945.MELARSENWeinman, D.: The treatment of African sleeping sickness,vith two new trivalent arsenical preparations(melarsen oxide and 70 A), Am. J. Trop . .l\1ed. 26: 95,1946.I•Bibliography 413SURAMINDewey, H. ~!., and A. W ornall: Studies on suramin Antrypol; Bayer 205)-5. Tl1e combination of the drug \viththe plasma and other proteins, Biochem. J. 40: 119, 1946.CYANINEDYES\Vetch, A. D., L. Peters, E. Bueding, A. Valk, Jr., andA. Higashi: A ne,v class of antifilarial compounds,Science 105: 486, 1947.IlIA'MIDlNESRosenberg, E. F.: The diamidines in chemotherapy: Asurvey of recent developments with a note regardingtherapeutic trials in patients with rheumatoid arthritis,Ann. Int. Med. 25: 832, 1946.Heathcote, R. St. A.: The diamidines: their pharmacolo¥ical actions and their therapeutic uses in some tropicaldiseases, J. Trop. Med. Hyg. 49: 1, 33, 1946.p ARA•AMlNOBENZOIC AcmSmith, P. K.: The use of para-aminobenzoic acid in~ndemic (murine) typhus, J.A.M.A. 131: 1114, 1946.Flinn, L. B., J. W. Howard, C. W. Todd and E. G. Scott:Para-aminobenzoic acid treatment of Rocky Mountainspotted fever, J.A.M.A. 132: 911, 1946.Greiff, D., H. Pinkerton and V. Moragues: Effect ofenzyme inhibitors and activators on the multiplicationof typhus rickettsiae: 1. Penicillin, para-aminobenzoicacid, sodium fluoride, and vitamins of the B group,J, Exper. Med. 80: 561, 1944.hicCoy~ G. W.: Chaulmoogra oil in the treatment of_leprosy, Pub. Health Rep. 57: 1727, 1942. . .Tierney, N. A.: Effect of para-aminobenzoic acid intsutsugamushi disease, J.A.M.A. 131: 280, 1946.VACCINES AND SERA,Derow, M. A., and S. B. Hooker: Active immunizationagainst some common communicable diseases, M. Clio.North America 29: 1238, 1945.Kolmer, J. A., and L. Tuft: Clinical Immunology, Bio,th.erapy and Chemotherapy, Philadelphia, Saunders, 1942.Parish, H.J.: A half-century of serology, Proc. Roy Soc.1Ied. 38: 1, 1944.
' Index•AAbel, John J ,, 4, S-6, 1S7, 26S, 303Abortifacients2, 33, 240Abortion, 2SS, 294Abrodtl, 307AcceptedD ental Remedies( A.D .R.),description of, 18Acetanilirid, escription of, 91-92Acetar.;one3, 42Acetophenetidind, escription of, 91-92Acetyl phenylhydrazint, 207Acetylcholine1,2 5, 126, 139-140,1 41esterase1, 25Acetylsalicyliac cid, 87, 209Acidosis, 193Acids, 321Ackerman, 157Acridine derivatives, 314-316Acriftavine, 315Activated charcoal, 223Adenocarcinoma, of the thyroid,274Addison, Thomas, 201Addlsonian pernicious anemia, 329. Addison's disease, 2S6symptoms of, 2S6Adler, 262A.D.R. (Accepted Dental Remedies),18Adrenal, 249cortex, 255cortex e.~tracts, 244,cortical preparations, assay of,257Adrenalin, see EpinephrineAgar, 222Agitans, paralysis, 290Aglycones, 164-165 1Agranulocytosis, 273de,s, cription of, 91Airsickness, 1S2Albert, 316Albumin, bovine, 195human, 192Albuminuri.a, 354Alcohol, etbyl,320isopropyl, 320Alcohol.ism, chronic, treatment, IZOAlkalis, 321Allen, 681 204Allergies, treatment of, 158Alloxan, 2451 270Aloe, 222Alpha-lobeline, 121Alpha-tocopberol1 293Alum, 223Aluminum hydroxide1 219phosphate gel, 219silicate, 219Alurate, 74Amanita muscaria, 145Amebacides, 319description of, 338-344preparations of, 343Amebiasis, 338American Dental Association, 18American Medical Association, 18American Pharmaceutical Association,17Amidone, 108Amine oxidase, 11, 125, 126, 132Amino acids, 26S, 283, 295, 2965-Aminoacridine, 316Aminophylline, 170-171Aminopyrine, 90-91Ammonia. water, 121Ammonium, 182Amphetamine, 128, 133description of, 119-121sulfate, 75415toxic effects, 120Amylase, 224I416Amyl nitrite, 171Amy1ocaine6, 7Amytal, 74inteh'i'ew, 74Anal~sia, 36Analgtsics, 86-96antit,yretic, 86-96&licylates, 87-90.AnamirtCJ /,anictdata, 114Anapbylactic .shock, 269Anaphyla.xis, 157Androgens, Z49, ZSlstandardlzation of, 251tbenipy, 2S1Androsterohe, 2SlAnetnia,22-23,329,33~acute he?llolytic, 371aplastic, 3SO, macrocytlc, 203pernJciow, JS8, 200-203Anemic ano:rla, 53Anesthesia, caudal, SfJ--606,1closed system, 39combination of, 48curare, s0-s2cyclopropane, use of procaine, 67definition of, 36field block, 58historical development, 36-37infiltration, 58use of procaine, 67inbafatiott of, administration, 39-48injection, 5s-61intradural, 58intravenous, 4S-SOmi.sce1Janeous agents, 48nerve-block tecbnies, 580xygen thetaPY1 S2-54peridural, 58postoperative me~u~, 45preane&theticm edication, 41preoperative preparation oI thepatient, 4Srectal,SOIndexAnesthesia (contm~d)refriguation 1 68'regional, description of, 57-,osaddle--block6, 1signs of, chart, 40spinal, 58, 59spinal, byperbarics oiuUon5, 9bypobarlc solution, -59isobaric solution, 59stages of, J!)-44analgesia, 39 ,,,.delirium, 39respiratory paralysis, 40surgical, 39theory or llllrcosis3, 8topical, 58Anesthetic agents, ;fS-48biological assay, 62--63chemistry of, 64-6Scomparative toxicity, 62L.D 110, 63local, chart of, 57metabolism, 64regional, 61-68Anesthetic explo!>iollS4,4Anesthetic preparations, ~8, 69Anesthetics, desirable properties of,44general, preparations of, 54-55inhalation, comparative charac•terisUcs, 42-43Aneurin, 286Angier, 202Angina pectoris, 170, 171Angina, Vincent's, 345Aniline, 92Anker, 398Anoxem.ias, ee Anon•c anon•a .Anoxia, descrlption of, SJstagnant, 53 •symptoms of, 53-~4Anoxic anoxia, SJAntagonism, iUusmtions of, 11-JJAntergan, 158-159Anterior lobe ....'•\ •IIndex 417\nterior pituitary, adrenocorticotropicsubstance, 246gonadotropic& Ubstance2,4 6growth hormone preparations,246standardizationo f, 246thyrotropic substance, 246 •hormones, 2451 246Anthelrn.intic3s2, 7intestinal, 327-33 7Antacids2, 18-220Antianemiap reparations, standardizationof, 202Anllbiotics3, 14, 329, 339description of, 387-402dosage of, 388inhalation of, 31preparations of, 399resistance to, 389Anticoagulant, 190, 2os.-210Antidianheal agents, 223Antidiuretic hormone, 261Antiepllepticd rugs, 7&-82AnUfebrine9, 2Anti-lnfectivesl, ocal, 313-326preparations of, 323-325Antimoniak, 351toxic effects, 404trivalent, 404Antimony, 223compounds, 403-404Antineuritic vitAmln, 285Anlinoznycin3, 99Antipyretic analgesics, 86-96preparations of, 94-95.synthetic, 90Antipyrine, description of, 90-91Antirachitic vitamin, 292Antiseptics, 313-314Antisyphilitic, 184 • /AnUtetany compound, No. 10, 275Antitoxins, 410Anuria, 375Apexient.s, 221Apomorpbine, 223, 224Aqueous solutions, Jt-32Ara.Jen, 365Aw:olin, 145Arginine deficiency, 295Argyrla, 318,348Ariboflavinosls, 288Aromatic waters, 26Arrhytbmias,cardiac,46 147,169Arsenic, 207-208poisoning, 208therapy, 350trioxide, 208Arsenicals, 339,342, 351agranulocytosis, 91Arsenoxides, 348control of, 351lethal effect, 349Arsphenamine, 345description of, 346-348Arspbenamines, control of, 351mode of action, 349toxicity of, 349Artemisia, 331Arthritis, 292rheumatoid, 404Ascariasis, 330, 332, 334Ascaridol, 331Ascarsis infestations, 330Aschbeim-Zondek, pregnancy test,248Ascorbic acid, 290U.S P., Reference Standard, 291Aseptic techniques, 314Aspidium, 333Aspirin, 87A&Say, see Drugs, control ofAsthma, bronchial, lSO, 171treatment of, 130A.T. I0,27S ,Atabrine, 363Atophan, 92Atoxyl, 346At,opa belladonna, 148Atrophine, 29••,418Atropine, 41, 52, 127, 1421 148poisoning, 108, 152used in arnst of secretiom, 151Autonomic drugs, 125-155action of, 126preparation of, 136-137Auricular fibrillation, 167, 169Auricular flutter, 169Avertin1 37, 50Azoman, 117BBacilliu brevis, 397Bacltradn, 389description of, 398Bacterlocides, 313Bacteriostats, 313BAL, 349, 351overdosage, 351Baldoni, 4BAL-glucoside, 351Baljet reaction, 169 ~Banting, 265Barbital, 72, 74Barbiturates, 72-73antidotes, 74-75clinical uses, 74dosage, 73intermediate action, 74long action, 74pb•armacology of, 73preparations of, 82-83prescription of, 75short action, 7 4toxicity. 74-75dennatologic lesions, '15' dosage, 75ultra-short action, '14Barbituric acid, cheJJllStryo f1 72Barger, 157, 271Bariurn sulfate, 306BariUDl sulfide, 306Barker, 173» Basal anesthesia, 4SBasal narcosis, 4.SIndex ~I•Bayer, 205, 405Beefsteak, use in pernicious anemia,201Bell, Blair,' 237Belladonna alkaloids, 148Benadryl, 160Bentonite1 223,Benzalkoniu'Jn chloride, 322Benzedrine, see AmphetamineBenzestrol, 253Benzoic acid, 321Beriberi, 285, 288Best, 265B.D.H. 312, 52Bernard, Claude, 4, S, 38, 50, 174Best, 157Beta-carotene, 2S4Betanaphtbol, 332Beta-eucaine, 67Betel nut, 145Bier, 66~Bieler, 63, 405Bile salts, 220Biliary colic, 172Biliselectan, 308Binz, Carl, 4, SBioa.ssay, see Biologic assayBiochemical antagonism, examplesof1 12Biologic assay, 21official U.S.P. methods, 21-23Biologic toxins, 310Bismarsen, 347,348Bismuth, 354arspbenaznine sul{onate, 348iodide, 340salts, 306subcarbonate, 223, 341subnitrate, 223, 341Bitters, 224Black tongue, 118, 288,.Blackwater fever, 363Blood, 189-195derivatiyes of, 189-195dysc.rasias,3 49preparations,•419--------~I~n=d=~=----------·~Blood (conlinutd)pressure,1 74 •substitutes, 18~195sugar, chart of, 267types, 190Bock,4Boils, 394de Bordeu, theory of endocrine se•cretions, 3Boric acid, 321Bovet, 1S9Bouolo, 332B.P. (British Pharmacopoeia), 17-18Brad.ford2, 07Bradycardia, 404,British AnU-Lewisite, 351British Pharmacopoeia. (B .P .) descriptionof, l~-18,Bromides, as antiepileptlcs, 79description of, 77-78toxicity of, 78Bromelin, 334-Bromelhol, 50Bromism,b romide intoxication,~ 7,,8,.Bromsulphthalein, 304Bronchiolar spasm, 46Bronchoscopy, SZBrool:Jl, 237Browning, 316Brucine, use of, 114BrUcke, 4Brunton, Lauder, 4, 171Brush, 268Buchheim, Rudolph, 4, SBuf3,gins, 164Bufatoxins, 164Bureau of Narcotics, 20Burge, 38Burns, treatment 0£1 190, 333Bush's law, 25Butacaine, 58Butesin picrale, 53Butyl aminobenzoate, 58Butyl •. • 1 bydrate. 76'CCaffeine, 183description of, 118-119Calabar bean, 143Calcifcrol, 275, 291, 292Calcium, 23~240carbonates, 219gluconate, 190, 276Calomcl, 184, 223ointment, 354Camphor, 121U5C in convulsive therapy, 116-117Canal of Schlemm, 1S0Cancer, 254Carbachol, 146description of, 142Carbaminoylcholine, 142Carbarsone, 342Carbon tetrachloride, 329Carbostyril, 361Carbuncles1 394•Carcinoma, of pro~tate, 2S3Cardiac edema, 184glycosides, 165-167Card!azol, 116Carminatives, 224Carotinemia, 284Carter, 46Cascara, 222Casein, 272Casile, 201-202 1 203Castor oil, 2, 222, 239Castration, 251, 2S3Cathartic resin'i, 2.22Cathartics, 220-223antbra.ccne, 222salinc1 221-222Caudal anesthesia, description of,59, 60, 61Caustic Poison Act 192 '/, 19Cavcntou,4,S, 113,300Central nervous system, stimulants,113-124420Cephailis ipecacwnlsa, 339Cervello, 76CetaQ:um, 32Cetyl pyridinum, chloride, 322Cevitamic add, 290Chaikoff, 272Chaulmoogra oil, 4-0tCheilosis, 288Chemoreceptor5, 346ChcmotherapeuUc agents, miscel•la.neou!, 40J-413p.rep.irntion., ol, 410-412Chemotherapeutic inda, 346Chemotherapy, 34Sbacterial, 371Chenopodiuma mbrosioidts3, 31' Chenopodium, oil of, 331Chinofon, 341,342Christison, Robert, 4Cbloro-butanoJ, 76Chloral hydrate, 37description of, 7S-76toxic effects, 76,. Chloramines, 319Chloretone, 76Chlorarsen, 353Chloroform, descripUon of, 47Chloroquine, JSB, 365Cholecystagogues2,2 0Cbolecystography, 220,304,308Cboiecystokinen, 225Cholera, 409Choleretics, 220\ Cholesterol, 32, 164, 29SCholine, 140,283,295derivatives, with pat35YtllpathoIyticeffect.51, 42-143esterase, 111 12 5Cb.orea, 81, Chorionepithelioma, 247Chotionic gonadotropin, 247Cinchona bark, 358Cinchonidine,360Cinchonine, 360Cinchonism3, 61IndexCinchopben,a granulocytosis9, 1description of, 92, 93Cinhosis cf the liver, 29SCitrin.in, 399 IClark, 237Clarke's rule, 2SClavacln, 399Clavice/s purpura2.,3 4Claviform, 399Cline, 286Cloetta, 4CJostrid.ia3,9 4-Coagulants, 283Cobcfrine, 128, 133Coca, 19Cocaine, 57, 81, 104-description of, 65-66toi:ic effects, 66Cocculw indicus, 115Codeine, 97description of, 105-106Colchicine, 93Colcliicum, Zdescription of, 93Co!clsicuma utumMle, 93Colitis, amebic, 338Collip, 275Colloidal solutions, 193-194Colocynth, 222Coma,diabetic,268\Convulsions, epileptic, grand mal,78petit maI, 78psychomotor attacks, 79Convulsive therapy, electrical, 117Cooper,351 ,Copper sulfate, 223Coratnine, 118Corning; 66Corpus luteum, 247, 254 Cort1• costerone,2 55, 256Coryne'bacterium dipbtberiu, J~4Cowling's law, 25Crcd~. 318Crt:satia, 321,,,• •Index 421•Crtsols, 321Cretinism2, 71Croton oil, 222Crude liver, 282Ctyptorchidism,2 47Cryptozoites3, 60Crystalloid diuretics, 182-183preparations, 193Crystal violet, 333Cullen, 164Culter, 207Curare, 127description of, .S0-52effect on myasthenla gravb patients,52preparation of, Stuse in convulsive therapy, 117Cushny, 4Cyanine dyes, 405-406Cycloplegia1, S0Cyclopropane, 48description of, 46Cypretbylene ether, 48Cysteine, 349Cystine,295DDak.in'es olution, 319Dale, 127, 140,141,157,237Darn, 210Datura stramonium, 148Davy, Sir Humphrey, 36Dec.holin, 220 •Decoctions, 26Dehydro-androslerooe, 2517-Dehydro-cbolesterol, 291, 292Dehydrocholic acid, 220Demerol neperidine, 107DermatiUs, 350, 3S4Dermatologic wet dressings, 31Desomorphine, 104Desoxycorticosterone, 34, 244, 2S5-257D-dcsoxycpbedrin~, 119Detergtnts. 322Detergents (continiud)synthetic, 321Dexedrine, 120D.H.E. 45, 236Diabetes insipidus, 34description of, 262Diebetes meWtus, 245, 265,406description of, 266Diebetic coma, 268Diacetylmorpbine, 105-106Diagnostic agents, 303,312chart of, 310preparations of, 309-311Dial, 74Diamidines, 406toxicity of, 4072,7.Di,.minoacridine, 3162,S•Diaminoacridlne, 315, 3162,8•Dia.mino-10•methylacrldiniumchloride, 31SDiamorphine, 105-106Diarrhea, 223, 354cluonic, 338Diascorides, 94Diasone, 408Dibenamine, 136Dibuca.ine, 61Dibutoline, sulfate, 143Dichlorophenarsine, 352, 3S3Dick test toxin, 310Dicumerol, 90, 20S.-210Diethylstilbestrol, 253Digitalis, 163-169administration of,• 167as diuretic, 164, 166biologic assay of, 21sta.ndardizaUon of, 168-169therapeutic uses, 166-167toxicity, 167-168Dicitalis laMta, 165, Digitalis purs,urea1, 65Digitalization, 167Digiloxin, 165Digonn, 165Dihydrocbloride salt, 347\ f422 IndexDihydroergotamJne, 236Dibydrode$0X)'Jl]orphine~1D0,4Dihydromorphlnone hydrochloride,J06Dihydrotachysterol, 27SDi-lodo-oxyquinoline, 342Di-Jodotryosine, 2'12Di-isopropyl tluorophosphate, 144Diiantin, 80·Dilation, effect o[ anesthesia, 41Dilaudid, 97, 105-1062..J Dimercaptopropano1, 351Dimetbylatninoethylbenzylaniline,159Dimetbylaminoethyl benzilate etho.chloride, 149Dinitropbenol, 8'1Diodoquin, 341, 342Diodrast, 307Dionln, 97, 105-106Dioscorides, 334Diphenbydramlzzeh ydroch?oride,160Dipbenylhydantoin, description of,80toxic. effetts, 80-81Dipbtheria,J4,J10,39S,410Disinfectants, 314Ditbiog[ycerol, 349, 351Diuresis, 181Diuretics, 181-186preparation., of, 186-187Dodds, 2S31 323Doisy, 210• Dolantin, .see lsonipecaineDolophine, 108Domagk, 371, 381Donath, 286Dorpat, University of, 5Doryl, 142Dosage, calculation of for children,25-26Dover's powder, 97Dragstedt, 219, 276Drastics, 221Dreser, 4, 106Dried yeast, 282Drisdol, 292Dropsy, 181Drug, drug,colnbinations, 12-13l\fe~bolism, see Me~bolismadtnini!tration of, 2S-34inhalation, 31 _local application, 31-34rnisci>llane{)musu cosa,3 4nasal mucosa, 34oral, 26-28oral mucosa, 34parentual, .28-31rectal, 28application on sl:ln, 33anliepileptic, 78-82antihi.stamin~, 1S6-162antimalarial, 35~70antisyphilltic,345-357preparations of, 3$5-3S6autonomic, 125-lSScholine derivatives, 140preparation or, 152-153control of, as.say of syntheticchemicals, 20, 21drug as.say, 20-2.:,histamine, 156-162injections,i ntra-arteria1,3 1intracardiac, 30intracutaneous, 29intradermal, 29intramedullary, JOintramuscular, 30intraperitoneal, JOintraspinal, 31intratbecaJ, 31intravenous, 30subarachnoid, 31subcutaneous,t oJaws and regulatory agrndes, 18-20parasympatbolytic, 127, 148-152therapeutic uses 1 ,.Index 423Drug, drugs (continued)parasympathomimetic, 127, 130-148ftuorophosphates, 143therapeutic uses of, 145-146plant or anbn,t origin, 21preparation of antimalarial, 368-369treatment of erytropoietic tissue,199-211treatment of heart, 163-177treatment of leuk.opoietic tissue,190-211sourceso f, 8-9sympatholytic, 135-136sympathomimetic, 127, 128--135synthetic, 20sensitivitit5, 160Dubos, 388, 397Dudley, 141, 157Dusting powders, 32Dyscrasias, 204Dysentery, 338amebic, 340, 345ba.dllary, 339Dysmenonhea, 251, 255Dyspnea, 53Dystrophy, muscular, 294pseudohypcrtropic muscular, 290EEber's papyrus, 2EB.I., 340Ecbollcs, 233-240Eccoproctics, 221Eclar...)Sia, 238Eczem, a, 295Edcina, 410 •angioneuroUc, 160description of, 181-182Eisleb, 107Einhorn, 66Elaterin, 222Electrophoresis, 33 , •Elek, 173 -.._Elixirs, 26Elvehjem, 288Eh.rlich, 315, 345, 351, 371Emboli, 208Embolism, 30Emollients, Z22Emetics, 223-224Emeline, 339,341,403Empyema, 393Emulsions, 32Encephalopathy, toxic, 350Endocarditis, 395Endocrins, biological assay of, 245definition of, 244, 245preparations of, 257-258, 277-278Endotbelioma, 204Enema, see Drugs, rectal administrationEntameba histolytica, 338Enteric coating, see PillsEnterogastrone, 225Enuresis, 150Ephedro. equisetina, 131Ephedrine, 63, 126, 128,133,264description of, 131-132toxicity of, 132, 134Epilepsy, 116desc.ription of seizures, 78grand mal, treatment of, 81petit mal, treatment of, 81-8,2psychomotor seizures, treatlnentof, 82use of bromides, 77Epinephrine, 29, 41, 61, 63, 125-126, 128,134,168,234,240,244-245, 264, 350admioistl"3.tion of, 129description of, 128--129standarditalion of, 131therapeutic uses, 130toxicity of, 129 . \use in asthma, 130circu1atory emergencies, 130 _.local anesthetics, lJ0-131.•424 • IndexEpinephrine (continutd)treatment of a!Jergi'c~ ponses,.131Epival, 74Eppinger, 207Ergometrine, 234Ergomctrinine, 234Ergonovine,29, 233, 2J4ErgOSllle2, 34Ergoslnine, 234Ergosterol, 291, 292Etgot, 135, 234-237poisoning, 236standardization of, 2J6-2J'IErgotamine, 126, 234-236tartrate, 235Ergolinine, 234Ergotism, 236Ergotome, ZJ4Erlanger, 61Erytbema, 3S0Erytbrityl tetranitrate, 171, 172Erythrocyte maturation, defective,200-202Erytbroicline, 52Erythro.:ryJins, ee CocaineErythro%y1on coea, 65Eserine, 143Estndio1, 2S2Estriol, 252Estrogens, JJ, 239, 249biological effects, 253carcinogenic substances, 254commercial soun:e, 252de!Wption of, ~St, 252natural, 252~lution of, 252standardization of, 2S4synthetic, 252therapeutic wes, 253Estrone, 252Estrus, 251EtbinylestradioJ,2 53Etbinyltestosterone,2 ssEthyl aminobemO&te5,8-IEthyl chloride, d~cription of, 47, Ethyl eyclopropy1 ether, 48Ethyl iodopbcnylundecyliacc id,3 07Ethylene, d~ption of, 46Ethylenediamine, 171Ethylhydrocupreine, 362Ethylmorphine, 105-106Ether convulsions, 46description of, 45first u_ce3, 7Eucaine, 67Eucatropine, 149Eunuchoidism, 251Euphorbium, 222Eupbyllin, 171E\\ing's. tumor, 204Expectorants, 224Extrasystoles, 168FFasclolopsia.sls3,3 2IFederal Trade Commission, 19, 282Fennentation, 313Ferriar, 164Ferric iron, 200Ferrous iron, 200Fever therapy, 35SFibrillation, ventricular, 169-170Fibrin, 192, 193Ficin, 334F.ilaria, 327Filariasis, 403, 404Fire of St. Anthony, 236Fzschl,366Fascher, 72FJ.Sher2, 66Fi5h liver oil, 284a5 source of vitamin D, 292Fitcb, 115Flavoring agents, 26, 224iIF1eming, Alexander, 387, 388Florence, official pharmacopoeia, 2Florey, 388l FloUl"ens, 4Fluidextrads, 27 ,' •••I IndexFluorescein, 304Food and Drug Act 1906, 17, 18-19Food and Drug Administration, 19Food, Drug and Cosmetic Act, 1938,17, 19Folic acid, 202, 203Follicle-stimulatingh ormone, 247Follicular pores, 33Foumeau,67,159,309,371 140SFowler's solution, 208Foxglove, 164Frey, 169Friedman, pregnancy test, 248F.S.H., see Follicle-stimulating hormone,247Fuadin, 404Fumagatin, 399Fundus glands, 202Fungicides, 313Fungistats, 313Furacin, 323GGitoxin, 16SGlandular pores, 33Glaucoma, 142, 144, 146, 150Gliotoxin, 399Globin insulin, 267Glometulonephritis. 181Glossitis, 288Glucose, 190Glutamic acid, 82Glutathione, 349Glycerol, 32Glyceryl trlnitrate, 34, 172Glycol, triethylene, 320vapors, 320Glycosides, 164-169, 222cardiac, 165-167crystalline, 166pbarmacologic actions, 166Goetsch, 130Gold c.ompounds, 3S1, 404toxicity, 404Gold salts, agranulocytosis, 91Gold sodium thiosulfate, 404Gonadotropin, chorionic, 247425'Ga.edetke, 6SGaglio, 4Galen, 2Gamboge, 222equine, 248Gonadotropins, description of, 2471Gamma globulins, 192Gangrene, 23 6gas, 39SGas-gangrene, 410Gasser, 61Gastric mucin, 219Gastric ulcers, 264248standardization of, 249'Gonads, 249Gonococci, 372, 394Gonorrhea, 320Gottlieb, 4~ Gout, treatment of, 92-93Graham, 304Castro-intestinal tract, 21S.-2251 306 Gramicidin, 397stimulation of, 147Gehc's Codex, 18Gelatin, 192-193, 194Geneva Convention, 105 ,Genitourinary trut, 317Gentian, 333Geppert, 317Gennanin, 405Germ.lcldcs3, 13Gc~~~13Grant, 157Granulocytopenia, .3SO3, 77Granulomas, 269Greene, 263Griffith, StGuanidi~, 406Guedel, 40Gum acacia, 194Gunn, 4Gwathmey, 37, 50•'•' '426I -~ l' ·-- } ~.,- "\r ._I • • ! v' I•' > ,·· "Index\• \_ I ·.,, \\'Gynergen~.~J! \ ' ~ - llcxestrol, 253• " < -. "IIexobarbital, 37, 49, 74\\, H , • • Beiuronic atid, 290Hagedorn, 266 ... l Hexylresorcinol, 321, lJO \Hague Convention, lOS ,. Hildebrandt, 116Halogens, 319 , .. " r .. :--Hippocrates, concept of disease, 2Hall. 329 ' : -: • ~ IDppuran, 307, 308Ha1pern, 159 .. ,. • Hifflimann, 398Rllsted, 66 Histaminase, IS&Hamblen, 248 Histamine, 1S6-1S9Harington, 271 '- effects of, 157-158Harnack, 4 gastric-f Wlcdon test, 158Harrison Narc::otic Act 1914, 19-20, azoprotein, 1S8104 preparatiotis of, 161Harvey. 3 Hlstone insulin, 267Hata, 346 Historical development, of anc,-Hay, lr!attbew, 4 thcsia, 36-37Htart block, 151, 168 of pharmacology, 1-7Heart drugs, 163-177 ' Hlstotoxic anona, SJpreparations of, 174-177 Hodgkin'& disease, 199, 204-206Heldelberger, 353 Hofbauer, 237, 238Heilig, 184 Hoffter, 4Helmholtz, 4 Hofmeister, 4Helminth infect.ion, 328 Hopn, 194infestations, 329 Holmes, Oliver Weadell, 36Helminths, preparations of, 336 Holt, 208Hemoconcentration, 256 Holtz, 275Hemolytlc crisis, 207 Homatropine, 149Hemolytic reactions, 191 methyl-bromide, 149Hemophilia, 204 Hookworm, 329Hemorrhage, treatment of, 190 Hormones, see Endocrins, 244Hero.orrbagia, purpura, 377 adrenal-cortical, 164Henbane, 148 anterior pituitary, 245, 246Henderson, 46 g&tro-intestin.al, 225Henle, 4 intermediate-Jobe, 2611 162}feparin, 204, 208--210 ~ural-lobe, 2611 262He~tic function, 304 sex, 164He~titls, amehic, 338 structural formulas of, 250infectious, 1!>2 Howell, 208Heroin, 97, 105-106 Huggins, 253Herxheiiner reaction, 352, 353, 395 Hunt, 139, 141 \Heubel, 34S Hydatidifonn mole, 247Heubner, 4 Hydnocarpu.s ail, 407Hexavitarnio tablets, 282 Bydragogues, 221gexazole, 117 HydrochloricI•'Index 427Hydrogen ..P.-, eroxid3e,1 9Hydrolysates, 296Hydroxyetbylapocupreine, 362Hyoscine, 148H;yocyamusn iger, 148Hyoscyamine, 148Hypettalcemia., 2 7 6Hyperinsulin.ism, description of,270treatment of, 2)0Hyperparathyroidism, 276-Hyperplasiit of frustration, 273Hypertension, 136,171, 173-174drug therapy of, 173-174Hyperthyroidism, 130drug therapy of, 273Hypervitarninosi.s, 2S1Hype.rvitamioosis A, 284Hypnosis, 74Hypnotics, 71-85Hypocalcemia., 275Hypochromic anemias, 200Hypoglycemia, 266Hypo-ovarianisro, 248Hypoparatbyroidism, 274, 282HyJ)oproteinemia, nutritional, 191Hypoprothrombinemia, 211Hypothyroidism, 246c:harac:teristico:sf , 270, 271Hypoxia, 41, 53IIminazolyl-proprionic acid, 1S6Immunity tests, 310Intlutnz~, 372Inius.ions, 26Injection anesthesia, 58-61Inositol, 283, 29SInsomnia, treauncnt of, 74types of, '11lntocostrin, 51lnsttlio, 245, 262biologic assay ol• 21-22clinical USt!S, 266..1 • .cripUon of, 26SInsulin (contmue4)dosage, 268lipohypertrophy, 269resistance, 269sensitivity, 269standardization of, 270use in malnutrition, 269Intermedin, description of, 261, 262International Digitalis Standanl,168Intravenous anesthesia, 48-SOIodoalpbionic acid, 308Iodocblotohydro.xyquinoline, 319,342Iodophtbalein sodium, 304, 30SIodopyracet, 307, 308lodoxylum, 307Iodides, 34SIodide, sodium .and potassiWX13,5 4Iodine, compounds, water soluble,307 •preparations, 306-308 ~tincture of, 319radioactive, 212lodisxn, 307, 341Iodofonn, 319lodopbenolpbtbalein, 304lodoquinoline, 339derivatives, 341Iontophoresis, 33lopax,307,308Ipecac,233,339,340Ipecacuanha, 339Ipomoea, 222lpral, '14•lron preparations, 200lschetnia, 168Isinglass, 194Isohernaggh.1.tinin1s,9 3lsoniPecaine, 150description of, 107-108toxic effect, 108Isomtric esters, 307Isato~ic saline, 182Ivy, 225•428\ Jackson, 3'1Jacobs, 3S3Jalap, 222Jansen, 3981January, 263Jariscli-Herxhcimer, .349, 350Jaundice,93,2?3,284,350,377J endrassik, 184J CD5'!D1 286Jimson weed, 148Johnson, 51,348,398KKa.mm, 237, 262Kaolin, 223Kaner, 288Katz, 173Kemithal, 49Kendall, 271Kephrine, 128, 133$Ketone bodies, 26SKing, 51, 290Kloss, 207Knorr, 90Kobert, 4Koch, 317Kolle, 348Koller, 66Kolllker, 4Korsakoff syndrome, 287Kracke, 91Krantz, 48Krebl, 106, 116Kubota, 15?Kuhn, 288Kutscher, lS?LLactation, 282suppression or, 253Lactobacill,u casei, 203Lactochrome, 288I,actoflavin, 288Lactogenic hormones, a.ssay or, 246Laidlaw, 157IndexLamson,330Landsteiner, 190Lawrence, 205Laxatives, 221LCTcsod,e finition of, 13LD:101 see Median Lethal DoseLeake, 47Lecbe de higuer6n, 334Leishmaniasi!4, 03, 404,4 06•L.H., see Luteinizing hormone, 247Lentin, 142Leonard, 321Leprosy, 407Leptazol, 116Leukemia, 199Leukocytosis, 37'/Leukemia.,, chronic, 204-206lymphatic, 206Leukopenia, 204,377Lcvaditi, 354Lewis, IS?Lewisite, 3S1Liebrcich, 76LiJU", 38Link, 90, 209Lipase, 224Lipocajc, 276Lister, 313Liver, cirrhosis of, 182extract, 22-23, 200-201function test, 304'source of vitamin B-cmnp!ex, 28$Lobelia mftata. Linnl, 121Local anesthetic agents, chart of, 57Local anesthesia, see Anesthesia,regionalLocock, 77Loew, 160Loewi, Otto, 141Long, Crawford W., 37Lotions, JZLucas, 46Ludwig, Carl, 4, 5Luckhardt, 46LuminaJ, 14, see • _: •,""I, IIndex 429Lundy,49Lupus erythematosus, 404Lutemization, 248Luteinizingh ormone, 247Lymphogranulomai nguinale, 403Lympbosarcoma, 199,204-206Lysozyme, 388MMacrocytic anemia, 282Magendie, Fran~is, 4, SMagnesium carbonates, 219oxide, 219phosphates, 219po•1 SO•w .ng2,2 1silicate, colloidal, 219Magnus,4Malaria, 345avian, 360, 366description of, 358malignant tertian, 358vivax, description of, 3S9,prophylaxis treatment of, 359Malnutrition, 181during convalescence, 269Maloney, 11SMalonyl urea, 72Malpighi, 3Mandelic acid, 409l\fannitol hexanitrate, 171-17 2Manson-Bahr,333tlapbarsen, 3S1Mapbarside, 351hiarfori, 4Maribuana Act 1937, 19-20hiarshall, 382•l{artindale's Extra Pharmacopoeia,18?.fa!.titis, bovine, 397)fayer, 161 •?-IcDonald, 262l\IcElvain, 67!oteaslcs, 192:t.Iebual, SO?iledl~is~ of action, 11-13Mechanism of action (continued)enzymatic reactions, 11Mecholyl, 141Median Lethal Dose, definition of,13determination of, 13-14de Meduna, 116?tfegacolon, 136Melarsen oxide, 405Afeleney, J 98Menadione, 211sodium bisulfite, 211~leningococcl, 3 72, 394Meningococrus endotoxin, 395l\1enopause, 251Menstruation, 146Mental disorders, shock treatment,268treatment of, electric convulsions,269Mepacnne, 363Meralluride, 185Merbaphen, 184-18.SMerbromin, 317,318Merck, 172Mercubydrin, 185l')lercupurin, 185I\lercurials, 351diuretics, 184-186administration of, 185-186toxicity, 186I\lercuric chloride, 321• Mercuric cyanide, 31 iiodide, 317•Mercurio, 185?tlercurochrome, 317~fercuropbylllne, 185I\lercurous chloride, 1&4, 2231.lercury, 345bichloride of, 317• • 1norgan1d compounds, 317organic compounds, 317in treatment of syphilis, 354Merritt, SOMmalyl, 184-185'430lt!erthlolate, 317, 318l\Iesantoin, 81•IndexMorpbine,29,41, ,2,86,15I,2J8.addiction lo, 103Metabolism, absorption of dl'IJA 9-10and allied drugs, preparaUon cf,drug tolerance, 10-11"the cumulative effect," 11excretion of drugs, 10in local anesthetic agents, 64intermediary metabolism ofdrugs, 10preceding operation, 45MetacresoI, 321Metacresylacetate, 3Zl1\-fetapben3, 17, 3181\fetaplasia of mucous epithelium,2BSMetapon, 104Metastatic calcification, 292Metbacboline, 142description of, 140-142l\!ethadon, description of, 106-109Methedrine, 119, 133Metbemoglobinemia, 92l\'.(etbenamine,'1 09Ivfethiodal, J07, 308Methionine, 29S~Iethocboline, toxic effects, 142Methyl, 333$3licylate, s,Methyld.thydro'tnorpbinone, 1041t1etbylmorpbine, 105' 2-Metbyl-naphthoquinones, 211Metby)rosanilinec hloride, 333~fethyltestosterone, 2S1Metrazol, 115-117, 269description of, llS-11 ~l\{etscllnikoff3, 46Metycaine, 6'1ti{eytr, 4].feyer-Overton theoty. 38J.tigra.ine,1 74, 235-236~finkowski, 265:trtinot, 201?Ylitchel2l,0 3Mitscherlicb, 4109-110bronchiolar corutricUon,9 9-100clinical uses of, 100-102convulsions, 98description of, 97-1071derivatives, 105-108effect on autonomic nervous sys- •tem, 99'effect on central nervous system,98effect on cin:ulatioa, 99 ,effect on eye, 99effect on intestinal tr.act, 100eifect on urinary tract, 100pharmacology of, 98preceding operation, 45metabolism of, 100tolerance to, 103toxicity of, 1ozMoir, 234, 23SMonacrine, 316MonosuJfate, 3161\-!oore and Roaf theory, 38Z\!oranyl, 405Morgenroth, 362Mori.shima, 41\forton, 37•1\-losso4,Mucoitin-polysulfuric-acld structure.209Muller, J ohatmes, 4school of physiology, SMurphy, 201Muscarine, l2~, l4S •l\..fuscies pasm, trt.atment of, 141Mustard, 223Myanesi.n, 52Myasthenia gravis, 132, 144, 147,277, 362l\iycocides, 3131\fycostats, 313Mydria.si.s1,5 0'•\•(•Index 431Myelography, 307•l,lyeloma1 multiple, 204-205Myxedcma, 271NNagai, 131Naphthoquinones, 211Naphuride, 405. Narceinc, 97Narcolepsy, 119Narcosis, 38theory of, 38Narcotic farm, 103Narcotine, 97Narcotics, 23license, 104National Formulary, 24description of, 17National Institute of Health, 20National Research Council, 104Necrosis, 349Nemathelminths3, 35Nembutal, 74Neoantergan, 158-159Neoantimosa.n4, 04Neoarsphe11amin3e4, 7 , 348Neoclnchophen9, 3Neo•iopax, 307, 308Neonal, 74Neoprontosil3, 81Neosalvarsan3, 48Neo-skiodan, 307Neostigmine5, 2, 132, 142-143Neosynephrlne1, 28, 133Nephritis, 194Neural-lobe hormones, descriptionof I 262Neurosyphilis3, 55New and NonofficialR. emedies,2 4description of, 18N.F., set National FormuluyNiacin, 288Niemann, 6SNicotinic acid, 117, 288, 289standardization of 1 .. . 289 ~Night blindness, 285Nightshade, 148Nicotinamide, 288, 289Nicotine, 33, 127Nikethamide, description of, 117-118 •Nirvanol, 81Nitrates, organic, 171-172toxic reactions to, 172Nitrites, 171-172toxic reactions to, 172Nitritoid crisis, 3495-Nitro 2-furaldehyde semicarbazone,323Nitrofurazone, 322, 323Nitroglycerin, 33Nitrous oxide, 37description of, 46•Nitrogen mustards, 206-201toxic effects, 206, 207N-methyletbylphenyl barbituricacid, 80N-methyl, pbenylethylhydantoin,81N.N.R., see New and NonofficialRemediesNostal, 74Novocaine, see ProcaineNovasurol,' 184,Novatrine~ 149Novurit, 18SN-p-methoxybeniyl-N-dimetbylamino-ethylaminopyrine,159Nucleic acid, 203Numbered formulas606, 346914, 3482339RP, 158-159Nupercaine, 67Nux vomica, 114Octin, 133; 218Octofollin, 2530432Oil of wintergreen, 87-88Ointments,3 2Oleoresin, 333Omnopoo, 98Opbtbabnia, gononbeal neona~torutn, 318OpbthaJmoJogy1, 50, 304use of drugs in, 146Opium, 2, 19,218,341alkaloids, 97Opium Advisory Committee, 105Optochin, 362Osteom:ilacla, 292O!tl!omyelitis, 30Oral administration of drugs, 2'1Ore, 37Orli.la, 4, SOrta!, 74Ortboform, $8•Ouabaln, 165Oxophenal'!ine,J49,3Sl, JSZtoxlc reactions to, 3S2Oxytocic hon:none, 161Oxytocics, 233-240preparations of, 241use in ch'i ld birth, 235Oxygen therapy, S2-54o~yuriasis, 333pPABA,407Pal, 172Paludrine, 358description of, 36S, 366Pamaquine, 358description of, 366, 367use in vivax malaria, 367p.Amlnobenzoic a.cid, 372Pancreas, 245fa.t.ftte extract of, 276Pancreatln, 224-225pant0paque, 307Pantopon, 98PapaiD, 3.34Papavtr somniferum, 97.., . ...IndexPapaverine,97, 172-173,218Para-aminobenzoic acid, 64, 281,' 407Paracelsus, ZParacentcsis, 182Paraldcbyde, description of, 76-77as rectal anesthesia, 50Parasympathomi:m~tldcr ugs, 13~148Parathormone, 275Parathyroid, 274extracts, 275standardintion of, 276Paredrine, 128, 133Pattdrli,oJ, JJJParegoric, 97✓Parente.ral administration of drug,,28-31Parkinson'sd l.seaseJ, SZParoxysmal dyspnea, 171Pastes, 32Pasteur, 313, 387Patulin, 399Pectin, 195'Pella.gra, 118, 286, 288Pelletier,4,S,113,340,360Ptl1etjer1ne tannate, JJ4Pcnicillin,314,34S,348,387administration of, 392-393chemistry of, 390, 391description of, 390metabolism of, 392standardization of, 395toxicity, 395Penicillamines, 391Penicillinase, 391Penicillium chrysogenum, 390no#atum, 390Pentamidine, -406Pentaquine, 358description of, 36~-368toxicity, 367-368Pentobarbital, 74Pentothal, 74Peptlds, 296,,IIndex 433Periostitis, 30Pem.oston'1, 4Peroxides, 319, 320Pervitin, 119 ,Petecbial hemorrhages, 204Pethidine, see IsonipecainePhagocytosis, 316Phanodorn,74Pharmacology, definition of, 1historical development, 1-7Pharm, acopoeia, first official, 2of U.S.A. (U.S.P.), descriptionof, 16-17Pharmakon, definition of, 1Phedracine, 133Phemerol chloride, 322Phenac:aine, 58Phenacetin, 92Phenantoin 1 81Phenarsine,3S3Pbenazone, 90Pheniodot, 308Phenobarbital, 74use in epilepsy, 79-80Phenol, 33, S 7, 581 92, 313coefficient, 314. description of, 320, 321Phenol red, 304Phenolphthalein, 223, 304, 305Phenolsulfonpb.tbalein, 303-305Phenoltetrabromphthalein sodiumsulfonate, 304Phenoltttrachlorpbthalein, 303Phenothiazine,333,334Phentetiophtbalein sodium N.N,R.,304Phenylepbrine, 128Phenylethylhydantoin, 81Phenylhydrazine,207Pblebototny, 20SPbo5pbolipid.s, 295Photophobia, 82, 288Phthalci.n derivatives, 303, 304, JOSPhysQJtlgma vmenomm, 143lSO•Pbysostigmine (continued)description of, 142-143Picrotoxin, '14antidote, 11Sdescription of, 114-115use in shock treatment, 115Pills, description, 2'1enteric coating, 27Pilocarpine, 142Pilocarp-ujsa borondi,1 44Pitocin, 23 7-238, 261tannate, 238Pitre~n, 237-238, 261tannate, 263Pitsulf onate, 239Pituitary extracts, 24SPituitary gland, neural lobe, 245Pituitary, posterior, 261, 265Pituitrin, 34, 237Pla.centa, 249Plague, 409Plant colloids, 222Plasma, 191-192, 195Plasmodia falciparum, 3S8malariae, 358vivax, 358Plasters, 33Platelet count, 204Platyhelminths, 335Pneumococci, 372, 394 ,Pneumonia, pneumococcal, 379Podopbylluni, 222Pobl,4 •Poison, convulsant, antidote, 74Polycythl'mia anMDia, 199vera, 199, 204, 205Polybydroxanthraquinones, 222Poliomyelitis, 147Polyneuritides, 287Polyvinyl alcohol, J9SPomegranate, 334Pontocaine, 67•l>ortal circulation, 28l'o.surior-lobe utr.u:ts., clinical u26l\''\434 IndexPosterior pituitaey, 233, 237-230Cltracts, 24Shypersensitivity to, 264injection, biologic assay of, 22standardization of, 264use in operati.oll!, 263Potassium. 182antimonyl, 403hypochlorite, 319pennanganate, 320tartrate, 223Potmtiation, definition of, 12-13Pregnancy, 282tests, 248 •Pregnandlol, 25SPregnant mares, scrum of, 247Prcgneninolone, 255Preparations of amebacides, 343• anesthetics, 54-SS• anesthetic, 6&-69antibiotics, 399•antimalarial drugs, 36S-J69antipyrctic analgesics, 94-9Santlsyphilitic drug5, 3S~S6autonomic drugs, 13£>-137, 152-153barbiturates, 82-83blood, 195-196chemotherapeutic agents, miscellaneous,4lo-412diagnostic agents, 309, 311diuretics, 186-187drugs affecting blood and blood-, fonnlng organs, 211-213gastro-intestinal tracb. 225-2301 endocrins, 257, 258heart drugs, 174-177belininths, 336histamines, 16!local anti-infectives, 323-325tnorphine and allied drugs, 109-1100xytocics, 241--~410•Pnparations of amebaddes (cont.). stimulants, central nervous system,121-122sulfonamides, 384-385vaccines, 409vitamins, 29£>-299rrcscription, 23 'adjuvant of, Z3basis of, 23corrective of, 23-24description of, 23-24inscription of, 23 -"signatura of, 24subscription of, 24superscription of, 23vehicle of, 24PreMOr hormone, 261Priodax, 308Prisco!, 136Privine, 133Procaine, 58, 130, 396description or, 66Progesterone, 254therapy, 255Progestins, 249desuiption of, 254standardization of, 25SProflavine, 316Prolactin, 246Promin, 408Prominal, 80Promizole, 408Prontosil, 371, 381Propadrlne, 128, 133Propantidine,314,406Propy) cyclopropyl ether, 48Propylene, 320l-Propy) thiouracil, 273, 274Prostate, carcinoma of, 253Prostigmine, 143Protamine, 30, 269insulinate, 266-zinc insulin, 261Protargol, 318Proteus, 406\ . \IIndex 435Prothrombin1, 90, 209-:ZlOdeficiency2, 04Prov1tamins, 284ProvitaminsD , 292Psychlatry, use of amytal, 74P!}chosesd, epre~ive, 116Psylhum seed, 222,Pteroylglutamica cid, 202-203, 282,373Purgation3, 28Purgatives2, 21, 303Pusey, 204Putnam, 80Putrefaction, 313Pyelography3, 07Pyocyanea4, 06Pyocyanase, 398Pyocyanine3, 98Pyra1nidon9, 0IPyrazolonca ntlpyrine, 90Pyribcnzaminc,1 60-161Pyridine derivatives, 161Pyridoxine, 289Pyrodin, 207Pyrogens, 29Q!Uastcl3, 8!uinacrine,3 58description of, 363, 364metabolism of, 364toxic effects, 364luinidine, t69-17o, 360, 363toxicity of, 170luininc, 57, 239amblyopia, 362action of, 360description of. 360-361dosage, 362metabolism of, 361RRabies, 409R :idi.a.tion sickn~ 2041 289Radioactive phosphorus, 204-206toxicity, 206Radio-opaque substances, 304Raizis.s, 34&Rat. acrodynia, 290poisons, 166Raynaud's disease, 136, 145Rectal administration of drugs, 28Red blood cells, 192Refrigeration anesthesia, 68·Relapsing fever, 345, 394Reymond, DuBois, 4Rheumatic fever, sallcylate therapy,8aRheumatoid arthritis, 147RH factor, 190Rhinitis, atrophic, 146seasonal allergic, 160Rhubarb, 222Ribofiavine, description of, 2S7, 288standardir<ttion of, 288Rice polishings, 282Rickets, 292Rickettsial diseases, 282Ringer's fluid, 141Ringer's solution, 193Roaf. 38Robertson, 320Robiquet, 106Rockefeller Institute, 353Rocky ?\.fountain spotted fever, 407Roentgenography, 306Roentgen-ray sickness, 274Roentgen therapy, 204, 207Rogers, 340Rosenthal, 304Roundworm, 333,335Roux, 346Rowntree, 303, 307Rutin, 294, 295sSaddle-block anesthesia, 61Sakel, 268Sandoptal, '14,436Salicylatcs, 87-90to:ticity of, 88Salicylic acid, 87, 321Salicylic.acid compounds, 33Salicyllsm, 89Saline diuretics, 182Salvarsan1 345Salyrgan, 185Sanocrysin, 404Santesson1 4S.'.lntonin3, 31S:ul, 184Sazerac, 354Scarlet fever, 310, 410Schaudinn, 346Schaumann, 107Schick test toxin, .310Schillinger, 329Schlstosoma, 327Scbistosomiasis4, 03Schlzoph.reni'!, JJ6, 268Schlem'ln, canal of, 150Schmidt, 116Schmiedeberg, 4, 145definition of pharmacology, 1influence on American phuma•cology, 5-6Scbwann, 4Scopolamine4, 1, 148, 151Scott, 266Scurvy, S,Ylllptomosf , 290Seasickness, JS2Seconal, 74Secretin, 225Sedation, preoperative, 45, 76Sedatives, 71-85Septicemia, 318Senn, 204 •Senna, 222Sera, 409antimeni:ngocoecie4,1 0antipneUlDODOCOCcic, 410preparation ct, 410Serturner, 97isolation of morphlne, 3IndexSerum, 191-192sidotess, 410Sel: hormones, 244c!assific:atioonf , 249-257Sharpey•Scbacfer, 26SShock, anaphylactic, 287Shock treatment, mental disorders,268 -Silver arsphenamine, 347,348Silver preparation, colloidal, 318Silver s.1lt.5,3 18Sunonart, 141Simpson, James, 4 7 •Sinus tachycardia, 146Skiodan, 307Skin, application of drugs on, JJ1esions, 285 Iparasitic diseases, 332pyogenic infections, 333Skokstad, 2035l~pi.ng sicluiess, 405SmalJpo:r, 409SN7618,365SN 10,275,361,362Snell,203Snyder, 101Soaps, 321Sobhninol, 354Sodium, 182antimony] tartrate, 403bicarbonate, 193, 219citrate, 190Sodium debydrocholate, 220Sodium .fluoresce.in3,0 4, 305lactate, 193peroxide, 319rtsorclnolphtbalein, 304Sodium salicylate, 81tctraiodophenolphthatdn, 304Sodium thiopental, 46, 49, 74Spasni, gastro-intestinal, 150, 172Spasmophilla, 292Spies, 203, 288Spin.al anesthesia, 58,Spirochetal • ~IIlIIndex 437Sprue, 203 ,Squill, 165-166S.T. 37,321Staphylococci3, 7ZStaphylococcusa lhus, 394, aweus, 31S, 3941 39SStaub, 1S9Stedman, 143Steroids, adrenal cortical, 244Stibophen, 404Stilbamidine, 406StigmasteroI, 255Stillman, 323Stimulants, central nervous system,113-124preparations, 121-122cerebral, 113medullary, 113spinal, 113Stockman, 4Stoll, 234, 235Stomach extracts, 200-202Stomatitis, 354Stovaine, 6 7Stovarsol, 342Stratum comeum, 33granulosum, 33lucidum, 33Streptococcus, 310he1nolyticus3, 72, 394lactis, 203viridans, 394Streptomyces griseus, 396Streptomycin, 388description of, 396d~ge, 396standardization of, 397toxicity of, 396use against gram-negative organisms,396Streptothrycin, 399Strongyloidiasis, 333Stropbant.bin.s, 165 •si,op1,a.m1,u, cratw, 165kombl, 16SStrychnine, description of, 113-114poisoning, 114Strychnos nux tJomica, 113Styptic, 263Subtilin, 398SuccinylsuUatbiazole, 383Sucrose, 182-183Sullacetarolde, 382Sulfadiazine, description of, 379,380dosage, 379Sulfadimethyldiazine, 382Su1faguanidine1 382Sulfamerazine, 381Sulfametharlne, 382Sulf amethyldiazine, 381Sulfamylon, 3831 384Sulfanilamide, 371,381,384biochemical antagonism of, 12chemistry of, 378Suliapyra.zine, 382Sulfapyridine, 377, 381Sulfarsphenamine, 347,348Suliasuxidine, 383SulfathiazQle, description of, 377dosage, 377metabolism of, 377toxic effects, 3 79Sulihemoglobinemia, 92Sulfobromophthalein .sodium U.S.P .,304,305Sulfonal, description of, 77toxic effects, 77Sulfonamides, agranulocytosis, 91developed resistance to, J73..J74dosage of, 374evaluaUon of, 3S3, 384inhalation of, 31mechanism of action, 372metabolism of, 374preparations of, 384-385sensitization, 373-374solubility of, 375toxic effects, 376Sul!o _nes4, 08Sulionethylmethane, 77I•'438 IndexSul! O.tlmrthan~, 'J'JSulfonamides, 64,314,316.329, 339,371-386Suppositories, see Drugs, rectal ad~Tel.any (ctmtinJJUJ)hypoparatbyroid, t9JTetraC3ine, 53, 67Tetracblorortbyl~ne, 329Theb:une, 9~•'ministrationSutalb.in, 405Swan, 142Sweet-dover disease, 209Swic.Jc3, 07Theobromine, 119,170,183Theophylline, 119, 1701 1711 183-SympathiD, 11, 12s, 126, 1JZ, 234SymJ)aU,oJyticd rog:s,l JS-136Sympathomimc~ 132-133amiD~ 244Synergism, definition of, !Z-13illustrations of, 13Synthalin, 406Synthalin B, -406Syntropan, 149Sypbilts, 2,34S-3S?,3941-day'trutment,352tmltmtn! c,J, 3fBSyphilo1ogy, 346Syru~, 26Systenuc absorption, 33dmllation. 28Sreat~Gyazgyi, 290TTachyeardi.a, 53, 272, 351extra.systoles,l 70paroxysmal, 168ventricular, 169-170TachYJ>bylnis, 132Tllllnic..add, 341Tapewurms, 328,331,333Tartar emetic, 223Tart.rate emetic, 40JTatom, 115,351.Taveatt, 139, 141Teniasi&3,3 3Testosterone, 33, 34, 249Tetanus, 34, 410Teiany, acute, 275con'V1llsions.S, tinfantile, 292184, 18Sethylenedia.mine, 184Thennoiabilc, 286Thermost.'lb'k, 286Thiamine, 286sources of, 286, 287standardization of, 28'1Thioba.rbiturale!, 73Thiocy.anates, 1,3-174toxic etiects, 174Thioethamyl, 49Thiopcntal, 37Thiouracil, 273, 2746graJ11J}ozy!OJh, 9JTbiourea, 245, ZiOThorium dioxide, 306Tborotrast, 306Tho.lJ)e. 15'1Threadworm, JJJTl}rombi, 208Thrombin, 192-193Thrombocytopenia, 3SOpue,pera, 20,JTbrombo-plastia, human, 192Thymine, 20JTbyxnol, 332Tby1J1omas, 271ThyroopbysiD, 238Thymus, 267endocrine function, 27'1Thyroid, 270-274preparations, control o(, 273standardization of, 273tberapeutic uses, 2'12tac6yca.rdiap, ostoperatit't,1 70IIndex - ' 439• Tbyroxin, 244,271Thytuitary, 239Tinctures, 27Tolysin, 93Topical anesthesia, 58Totaquine, 360•Toxicity, d termination of, tJ-14in local a ,esthetic agents, •3Tracey, Margaret, 398'Tracheal intubation, S2Transentin, 149Trefouels, 371Treponema. pallidutn, 346Triazol, 156, description of, 11,Tribasic caJclum, 219Tribrotnoetbanol, 3 7, 46, 50Trichinella, 327Trichlnosis, 310 /Tricbloroetbylene, description of, 47Trichuriasis, 334Tridione, description of, 81Tri.rnetbadione, 81Trional, 77Tri• -.nnamine hydrochloride,160-161Triphenylethy1cne, 253Troch~ 27Trypaflav: 316•Trypan• .1. 1asis, 'l4S, 353, 403, 40.STrypa~..a~de, 353, 405Try~• , 224~sutsugamushi fever, 407Tuarnine, 133Tuberculos.is, 310,396,404,408Tularemia, 396Typhus, 407,409Typhoid, 409Tyrocidin, 397Tyrosin, 272Tyrothricin, 389description of, 397toxicity of, 397use again.st gram.positive organ;sms, 397Ttil,ilight slttp, 101, 151uUlcers, chronic, 14Srefractory, 219Ulcers, peptic, 119, 2181 225United Nations, 105United States Dispensatory( U .S.D.), description of, 18United States Post Office, power ofprosecution, 19United States Pharmacopoeia, 24Unlted States Public Health Service.19, 103, 351University of Toronto, Connaughtlaboratories, 209Urea, 182-183Uremia, 191Urginea mantima, 165Urine, human pregnancy, 247m.enopausal ' 1 24?Uroselectan, 307Ui:ticaria, 160, 410U.S.D. see United States DlspensatoryU.S.P. see Pharmacopoeia of U.SA .VVaccines, 409preparation of, 409Vagusstoff, 141Van SteinbucheliD, 1S1Varon, 240Vaughan, Victor G., 5-6Vedder, 340Venous thrombosis, SOVentricular nbrillation, 168tachycardia, 169-IiOVentriculin, 202Verona), 72, 74Vermicides, 327Vermifugcs, 321Verworn, JSVinbarbital, 74Vincent's angina, 345,394Vind, 61Vmega.rs, 26440 IndexVinyl ether, description of, 47Vioform, 319, 341, 342VJosterol, 292Virthow, 74Virus, Scrum and Toxin Act, 1902,18VltagcM, 283, 295-296Vitamins, 281-302aMay of, 283dosage, daily, 296supplemental, 281therapeutic, 281, 282preparations, 296-290relation to growth of micro.organism,, 283Vitamin A, deficiency of, 285prepo.ra.tion,a, ssay of, 285!IOUrc.e Of, 284Vitamin B, chemistry of, 286Vitamin B-complex, 285-200Vitamin B1, 286Vitamin B2, 286Vitamin Be, 280Vitamin C, 290standardization of, 291Vitamin D, 282, 291-293standardization of, 293Vitamin D2, 27S, 291,293Vitamin Da, 291Vitamin E, 293, 294Vitamin G, 288Vitamin K, 283preparations, dosage, 211Vitamin P, 294, 29SVitamin P.P., antipellagra, 288Vitiligo, 262Voegtlin, 348Vogt, 156Vonedrine, 133von Mering, 72, 265wWaksnian, 388, J96~~-tl~l"P. 4,Wassennann, blood tt"st, 346Waters, 46\Vaugh, 290\Veber, Ernst, 4school of physiology,SWelch, 405Wells, 37\Venckebaclc, 169Wcmickc's disease, 287Whetler-Lea. Act 19381 19\Vhit6cld's ointment, 321Whitby, 381Whipple, 201\Vhipworm, 331\Villiams, 203, 286WJ.fli.s1, 82\Vindaus, 1S6, 286\Vithering. \Villiam, 164•introduction of dig:$talfr3, ,Wohler, 6S\Voods, 372Wormsttd, 331XXanthine derivatives, 170-171 •Xanthine diuretics, 183-184Xanthopsia, 332Yatren, 341Yaws. 345, 394ytYeast, source of vitamin B-complex,28SYellow vision, 332Yobimbine, 135, 24SYorke, 406Young, 317 .Young's Jaw, 26z•Zephiran chloride, 322 'Zinc-Insulin-CrystalsR eferenceStandard, 22Zinc, peroxide, 319gulfate, 2Z3,..-

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