Hanclbuch cler experimentellen Pharmakologie Begrundet von A. Heffter Erganzungswerk . Vierter Band General Pharmacology J. A. Clark-Edinburgh Reprint Springer-Verlag Berlin Heidelberg GmbH 1970 ISBN 978-3-662-27158-2 ISBN 978-3-662-28641-8 (eBook) DOI 10.1007/978-3-662-28641-8 Softcover reprint of the hardcover 1s t edition 1970 Das Werk ist urheberrechtlich geschiitzt. Die dadurch begriindeten Rechte, insbesondere die der "Obersetzung, des Nach druckes, der Entnahme von Abbildungen, der Funksendung, der Wiedergabe auf photomechanischem oder iihnlichem Wege und der Speicherung in Datenverarbeitungsanlagen, bleiben, auch bei nur auszugsweiser Verwertung, vorbehalten. Bei Vervielfiiltigungen filr gewerbliche Zwecke ist gemiB § 54 UrhG eine Vergiitung an den Verlag zu zahlen, deren HOhe mit dem Verlag zu vereinbaren ist. Library of Congress-Catalog-Card Number 75-105699 Die Wiedergabe von Gebrauchsnamen, Handelsnamen, Warenbezeichnungen usw. in diesem Werk berechtigt auch ohne beoondere Kennzeichnung nicht zu der Annahme, daB solche Namen im Sinne der Warenzeichen-und Markenschutz Gesetzgebung als frei zu betrachten waren und daher von iedermann benutzt werden dilrften. Titelnummer 1173 HANDBUCH DE R EXPERIMENTELLEN PHARMAKOLOGIE BEGRDNDET VON A. HEFFTER ERGANZUNGSWERK HERAUSGEGEBEN VON W.HEUBNER UND J. SCHOLLER PROFESSOR DER PHARMAKOLOGIE PROFESSOR DER PHARMAKOLOGIE AN DER UNlVERSITlT BERLIN AN DER UNIVERSITIT KOLN VIERTER BAND GENERAL PHARMACOLOGY BY A. J. CLARK-EDINBURGH WITH 79 FIGURES SPRINGER-VERLAG BERLIN HEIDELBERG GMBH 1937 Preface. The author's general aim has been to survey as wide a field of evidence as possible and this had involved excursions into subjects of which he has little first hand knowledge. This width of range also has necessitated a somewhat arbitrary selection of evidence and has prevented full discussion of any indi vidual problem. The author trusts that he has not misrepresented anyone's results or opinions, and if this has occurred, he can only plead in excuse the peculiar difficulty of giving a brief and yet accurate account of evidence of such a wide variety. The diagrams reproduced in the article have all been redrawn and in many cases the original figures or diagrams have been modified as, for instance, by recalculating dosage on the logarithmic scale. The original authors therefore have no direct responsibility for the diagrams in their present form. The author desires to thank Messrs Arnold and Co. for permitting the repro duction of Figs. 9 and 23 from similar figures which appeared in his book "The Mode of Action of Drugs on Cells"; portions of other figures from this book also have been reproduced in modified form. The author also desires to thank Dr. J. M. ROBSON for help in correction of the proofs. Edinburgh, July, 1937. A. J. CLARK. Contents. I'age Int.roduction . . . . . . . . . . . 1 (!hapter ]: Methods of General Pharmacology.. . . . . . . . . . . . .. 4 General Considerations p. 4. - Selection of Material p. 5. - Employment of Physico-chemical Methods p. 5. - The Mathematical Interpretation of Biological Data p. 6. - Favourable Factors in Pharmacological Measurements p. 7. - Curves Relating Exposure to Drugs with Biological Effect p. 7. - Classes of Curves p. 8. - Discussion p. 9. Chapter 2: The Cell as a Physico-chemical System. . . . . . . . . . . . . 10 The Structure of Protoplasm p. 10. - The Cell Surface p. 12. - Cell Permeability p. 12. - Structure of Plasmatic Membrane p. 14. - Cell Organisation p. ]5. Chapter 3: General Characteristics of the Cell-Drug System . . . . . .. 17 Dimensions of Molecules and Cells p. 17. - The Number of Molecules in Single Cells p. 19. - The Number of Enzyme Molecules per Cell p. 19. - Lethal Doses of Drugs per Cell p. 20. - Effective Doses of Drugs per Cell p. 21. - Minimum Active Doses of Drugs per Organism p. 22. - Minimum Active Dilutions of Drugs p. 22. - Intracellular Administration of Drugs p. 23. - Types of Action of Drugs on Cells p. 25. - Discussion p. 25. Chapter 4: Reactions between Drugs and Active Proteins. . . . . . . . . 26 Symplex Compounds p. 26. - Combination of Haemoglobin with Oxygen and Carbon Monoxide p. 27. - Antagonism of Oxygen and Carbon Monoxide p. 29. - Discussion p. 30. Chapter 5: The Action of Drugs on Catalysts and Enzymes . . . . . . . . 31 Poisoning of Inorganic Catalysts p. 31. - General Characters of Enzymes p. 33. - Enzyme Activity p. 34. - General Characters of the Poisoning of Enzymes p. 34. - Diphasic Actions of Enzyme Poisons p. 36. - The Rate of Action of Enzyme Poisons p. 37. - Relation between Concentration of Poison and In hibitien of Enzyme p. 37. - Discussion p. 40. Chapter 6: Action of Heavy Metals on Enzymes in vitro and in vivo . . . 4() Action of Heavy Metals on Saccharase p. 40. - Concentration-action Relations of Heavy Metals and Enzymes p. 42. - The Action of Metals on Living Cells p. 44. - Relation between Metal Concentration and Action on Cells p. 44. - Minimum Lethal Concentrations of Heavy Metals p. 44. - Relative Toxicity of Metals p. 46. - Course of Reaction between Metals and Cells p. 47. - Diphasic Actions of Metals on Cells p. 48. - Discussion p. 49. Chapter 7: Action of Various Enzyme Poisons in vitro and in vivo. . . . fi() The Action of Dyes on Enzymes p. 5-0=. - Aciion of Quinine on Enzymes p. 51. - Action of Quinine on Cells p. 52. Action of Cyanide on Enzymes and Cells p. 52. - Diphasic Actions of Cyanide p. 55. - Phenol Compounds p. 55. - The Action of Narcotics p. 56. - Action of Narcotics on Enzymes p. 56. - Action of Narcotics on Cells p. 59. - Theories of Narcotic Action p. 60. - Discussion p. 61. Chapter 8: Concentration-action Relations I. . . . . . . . . . . . . . 61 (1) Classification of Concentration-action Curves. . . . . . . . . . . . . . 62 Relations Depending on Mass-action p. 63. - All-or-None Effects p. 64. (2) Concentration-action Relations Attributable to Mass-action Laws . . . .. 6fi The Mode of Action of Acetylcholine p. 66. - Amount of Acetylcholine Acting on Cells p. 69. - Individual Variation p. 70. - Site of Action of Acetylcholine p. 70. - Influence of Temperature on Acetylcholine Response p. 72. - Speci- Contents. v Page ficity of Acetylcholine Action p. 72. - Possible Nature of Acetylcholine Re· ceptors p. 73. - Acetylcholine Esterase p. 74. - Concentration-action Re lations of Adrenaline p.74. - Dosage of Adrenaline p.75. - Concentration action Relations Found with Various Hormones p. 76. - Insulin p. 76. - Thyroxin p. 77. - Posterior Pituitary Principles p. 77. - Sex Hormones p.77. - Various Alkaloids p. 78. - Nicotine p. 78. - Physostigmine p. 79. Other Alkaloids p. 79. Chapter 9: Concentration-action Relations II 79 (3) Linear Relations; Action of Narcotics. . . . 79 (4) All-or-None Responses. . . . . . . . . .. . 83 Instrumental Errors p. 83. - Distortion by the Cell of some Chemical Relation p. 83. - Obligatory All-or-None effects p. 84. - All-or-None Cellular Res ponses p. 85. - Concentration-action Curves with Guinea Pig's Uterus p. 86. - Drugs Producing All-or-None Effects p. 87. - Discussion p. 89. Chapter 10: Quantitative Pharmacology and the Theory of Humoral Trans- mission. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 Introduction p. 90. - Quantitative Data p. 91. - Rate of Action p. 92. - Concen tration-action Relations p. 93. - Specific Antagonisms p. 95. - Discussion p. 96. Chapter 11: Kinetics of Drug Action . . . . . . 96 Sources of Error in Kinetic Measurements . . 96 ( 1) Kinetics of Reactions in Heterogenous Systems 97 (2) Kinetics of Cell Reaction . . . . . . . . . . 98 Delays in Drug Action Due to Diffusion to Cell Surface p. 98. - Penetration of Cells p. 100. - Delay in Biological Response p. 102. (3) Maximum Rate of Drug Action . . . . . . . . 104 Chapter 12: The Rate of Action of Drugs on Cells 105 (1) Curves Relating Time and Graded Action. . . . 105 The Shapes of Time-action Curves p. 107. (2) Curves Relating Time and All-or-None Effects ............... 108 Kinetics of Protein Precipitation p.ll0. -Precipitation of Protein by Phenol p. 111. (3) Time Action Curves as Expreasions of Variation .............. 112 Calculation of Time-action Curves p. 114. - Time Relations of Toxic Action of Copper on Algae p. 115. (4) Implications of Monomolecular Theory .................. 118 Quantitative Measurements of Drug Uptake p. 118. - Drug Actions as Chain Processes p. 119. (5) Mortality Curves . . 120 (6) Action of Radiations 121 Discussion p. 122. Chapter 13: Time-concentrations Curves 123 (1) Form of Curves and Possible Significance. 123 (2) Time-concentration Curves of Nerve Paralysis. 133 (3) Time-concentration Curves with Various Drugs 135 (4) Time-concentration Relations in Disinfection. . 136 (5) Toxic Vapours . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 Deviation of Narcotics p. 139. -- Time-concentration Curvea of Anaesthetics p. 140. - Time-concentration Curves of Hydrocyanic Acid p. 141. - Irritant Gases p. 141. - Discussion p. 142. Chapter 14: Individual Variation of Response to Druga .......... 142 Methods of Measurement of Individual Variation p. 142. - Skew Variation in Biological Material p. 144. - Normal Equivalent Deviation p. 146. - Errors in Construction of Characteristic Curves p. 148. - Uniformity of Population p. 148. - Errors of Sampling p. 149. Chapter 15: Relation between Various Types of Curves Expressing Response of Cells to Drugs. . . . . . . . . . . . . . . . . . . . . . . . . . 150 (1) Concentration-action Curves as Expressions of Individual Variation . . . . . 150 Virus Infections p. 151. - Discussion p. 153. VI Contents. (2) Characteristic Curves as Expressions of Chemical Processes. . . . . . . . . 154 (3) Correlation between Concentration-action Curves and Characteristic Curves. . 156 Examples of Skewed Characteristic Curves p. 156. - All-or-None Effects p. 161. - Discussion p. 162. (4) Drug Responses and Individual Variation ................. 163 Chapter 16: Special Problems Relating to Variation of Populations .... 165 Uniformity of Population p. 165. - Influence of Sex, Age and Weight on Response to Drugs p. 166. - Seasonal Variations in Sensitivity p. 169. - Variation in Human Populations p. 169. - Hypersensitivity and Idiosyncrasy p. 171. - Margin of Safety with Massive Doses p. 173. - Disinfection, etc. p. 175. Chapter 17: Quantitative Aspects of Drug Antagonism and of Drug Syner- gism ................................ 176 Introduction p. 176. - The antagonism of cyanides by narcotics p. 177. - Selective Antagonisms with Haemoglobin p. 180. - Antagonism in Enzyme Poisoning p. 181. - Acetyl Choline-Atropine Antagonism p. 184. - Adrenaline Ergotoxine Antagonism p. 186. - Synergists of Adrenaline p. 187. - Compari son of Antagonisms found with Enzymes and with Hormones p. 188. Chapter 18: Qualitative Aspects of Drug Antagonism ........... 190 Introduction p. 190. - Antagonism of Adrenaline p. 191. - Chemical Structure of Acetyl Choline Antagonists p. 191. - Acetyl Choline Antagonism in Different Tissues p. 193. - Analysis of Drug Actions by Drug Antagonisms p. 196. - General Theory of Drug Antagonisms p. 198. Chapter 19: Alternative Theories of Drug Action ............. 199 Monomolecular Theory p. 199. - The Potential Theory of Drug Action p. 200. - Phasic response of cells p. 201. - Arndt-Schulz Law p. 204. - Drug Responses as Expression of Individual Variation p. 204. - Weber-Fechner Law p. 205. - Discussion p. 205. Chapter 20: Quantitative Aspects of Chemotherapy ............ 206 Introduction p. 206. - Action of Metallic Compounds p. 207. - Action of Non-metallic Compounds p. 212. - Drug-resistance p. 213. - Discussion p. 214. Chapter 21: Conclusion 215 Index of Authors . 218 Index of Subjects ... 223 Introduction. Pharmacology may be defined as the study of the manner in which the func tions of living organisms can be modified by chemical substances. The subject actually developed in a narrower field because its chief original aim was to provide a scientific basis for therapeutics. This study required as its basis an adequate knowledge of the functions of the normal organism (physiology) and the derangements of these by disease (pathology), hence pharmacology developed later than the other medical sciences. The first task of the young science was to sift the traditional beliefs of thera peutic practice and to discover how much of this was based on fact and how much was merely a legacy from mediaeval superstition. The energy of pharmaco logists during the second half of the nineteenth century was largely expended on this task which was both wearisome and thankless. Neither the clinicians nor the drug manufacturers were grateful to the pharmacologist who hampered their freer flights of fancy by captious criticism. On the other hand the physiologists regarded the pharmacologists as mere collectors of uncorrelated data. The present situation is very different because it is now recognised that many if not most of the functions of the body are regulated by drug action and hence the manner in which drugs exert their action on cells has become one of the most important fundamental problems in physiology. The discovery of hormones first suggested that the activities of the body were regulated by chemical agents, and the significance of this advance was recognised by ERNEST STARLING who at the Naturforscherversammlung at Stutt gart concluded a famous address on the then new subject of hormones with the following words (quoted from HEUBNER, 19341): "Jedes physiologische Problem ist in letzter Linie auf ein chemisches zuriickzufiihren. Hier reichen sich Physiologie und Pharmakologie die Hande, und die alteste unter den Forschungen, die in Verbindung mit der Heilkunde erscheinen, namIich jene, welche sich mit der Wirkung del' Arzneikorper befaBt, wird uns vielleicht die Handhabe zur Au£klii.rung der fundamentalen Lebensprobleme Iiefem." As HEUBNER (1934) says: "Man darf wohl sagen, daB STARLINGS prophetische Worte ill der seither verflossenen Zeit Erfiillung gefunden haben: mehr und mehr haben sich die Probleme der Physiblogie auf chemische reduziert, grol3er und groBer ist die Zahl eigentiimIicher und hOchst wirksamer Suhstanzen geworden, die wir als unentbehrIiche Werkzeuge im Getriebe des lebendigen Korpers kennengelemt haben; sind wir doch fast schon so weit, als das WesentIiche bei der tl'bertragung einer Nervenerregung auf das Erfolgsorgan die Produktion eines Pharmakons ansehen zu diirfen." The development of organic chemistry also has had important consequences, since today the number of organic compounds with possible pharmacological actions is practically unlimited. This has opened new fields in therapeutics but also has opened unpleasant new possibilities in toxicology because all kinds of new compounds are being introduced into industrial and domestic use. Hence accurate knowledge of the possibilities of cumulative poisoning and of drug idiosyncrasy has become of increasing importance. 1 HEUBNER, W.: Klin. Wschr. 13, 1633 (1934). Handbuch der Pharmakoiogie. Erg.-Werk, Bd. IV. 1 2 Introduction. Partly as a result of these advances in organic chemistry human society is relying more and more on drugs for the control of parasites and pests. The remarkable development in chemotherapy which has followed the pioneer work of EHRLICH is the chief of such advances, and the discovery of prontosil justifies the hope that, after many decades of fruitless endeavour, corresponding advances are commencing in the control of bacterial infections. The disinfectants, trypano cides, spirochaeticides and anthelmintics form a large and important section of modern therapeutics, and apart from therapeutics agriculture is relying more and more on insecticides and fungicides for the protection of crops. Finally one must recognise the unfortunate fact that poison gases have proved to be weapons of great efficacy in warfare, and apart altogether from the study of poison gases as offensive weapons, it is necessary for medical science to study the means of prevention and cure of poisoning by war gases. The mode of action of drugs upon organisms is therefore to-day of ever in creasing importance, and this subject is of such outstanding importance in physiology that the question is now raised whether pharmacology has any claims to be regarded as a separate branch of science or whether it should not be con sidered a special branch of physiology or biochemistry. The objection to this view is that although all the other biological sciences use drugs as useful agents to produce desired effects, yet none of them are prepared to study the action of drugs in a systematic manner. The bacteriologist for instance is satisfied when he discovers that the addition of a small quantity of dye to a medium will inhibit the growth of certain bacteria, but usually he is not interested in studying the manner in which the dye produces this remarkable specific action. The physiologist is content to know that a fraction of a microgram of acetyl choline will produce actions simulating the effect of parasympathetic activity and that this effect is abolished by similar quantity of atropine, but is disinclined to study the possible physico-chemical mechanisms by which these remarkable actions and antagonisms can be produced. For these reasons the writer believes that there is a need for a science which devotes itself primarily to the study of the mode of action of drugs. This science can most conveniently be designated "general pharmacology". It must borrow its methods largely from physical chemistry, biochemistry and physiology, but its task is a distinctive one, namely to discover the mode by which chemical agents alter the functions of living cells. The study of the mode of action of drugs on cells is of course dependent on our knowledge of the physical chemistry of cells, and this subject owes much to the works of ROEBER (1902)1 and BECHHOLD (1911)2 who were some of the first authors to give a systematic account of the physico-chemical properties of cells. ARRHENIUS (1915)3 was one of the first to attempt a general interpretation of drug action by means of the laws of physical chemistry. Ris conclusions are subject to the general criticism that he attempted to explain reactions occurring in complex colloidal systems by laws derived from the simplest homogeneous systems. This fact does not however lessen the importance of his work as a pioneer in a field that had previously been neglected. STORM VAN LEEUWEN (1923) 4 described in a systematic manner the variety of relations between drug con centration and biological response that can be observed with intact animals and 1 HOEBER, R.: Physikalische Chemie der Zelle und Gewebe. Berlin: Engelmann 1902. 2 BECHHOLD, H.: Die Kolloide in Biologie und Medizin. Dresden: Steinkopff 1911. 3 ARRHENIUS, S.: Quantitative Laws in Biological Chemistry. London: Bell and Sons 1915. 4 STORM VAN LEEUWEN, W.: Grondbegins. d. alg. Pharmacol. Den Haag: Wolters 1923.