New Neuromuscular Blocking Agents: Basic and Applied Aspects PDF
Preview New Neuromuscular Blocking Agents: Basic and Applied Aspects
Handbook of Experimental Pharmacology Continuation of Handbuch der experimentellen Pharmakologie Vol. 79 Editorial Board G. V. R. Born, London' A. Farah, Rensselaer, New York H. Herken, Berlin' A. D. Welch, Bethesda, Maryland Advisory Board S. Ebashi . E. G. Erdos' V. Erspamer . W S. Feldberg G. B. Koelle' 1. R. Vane' P. G. Waser New Neuromuscular Blocking Agents Basic and Applied Aspects Contributors S. Agoston . K. Biro ' W. C. Bowman' A. A. Bunatian V. V. Churyukanov . D. Colquhoun ' A. F. Danilov . A. Deery D. Duncalf . V. P. Fisenko . F. F. Foldes' A. 1. Gibb . A. L. Harvey R. Hughes· E. Karpati . D. A. Kharkevich . N. V. Khromov-Borisov A. A. ~imenis . I. G. Marshall' M. D. Mashkovsky . R. D. Miller H. Nagashima . D. S. Paskov . J. P. Payne' M. Riesz . V. A. Shorr A. P. Skoldinov . 1. B. Stenlake . G. A. Sutherland ' G. Szab6 L. Szpomy ' E. Tassonyi ' M. B. Tyers· L.Vimlati· L. P. Wennogle L. N. Yakhontov Editor D. A. Kharkevich Springer-Verlag Berlin Heidelberg New York Tokyo DIMITRY A. KHARKEVlCH, M.D., D. Sc. Professor and Chairman of the Department of Pharmacology Academician of the USSR Academy of Medical Sciences First Medical Institute Department of Pharmacology 2/6 Pirogovskaya Street, Moscow II9435, USSR With 128 Figures ISBN-13: 978-3-642-70684-4 e-ISBN-13: 978-3-642-70682-0 DOl: 10.1007/978-3-642-70682-0 Library of Congress Cataloging-in-Publication Data. Main entry under title: New neuromuscular blocking agents. (Handbook of experimental pharmacology; vol. 79) Includes bibliographies and index. I. Neuromuscular blocking agents - Physiological effect. 2. Myoneural junction - Effect of drugs on. 1. Agoston, Aleksandar. II. Kharkevich, D.A. (Dmitni Aleksandrovich) III. Series: Handbook of experimental pharmacology; v. 79. [DNLM: I. Neuromuscular Blocking Agents - pharmacodynamics. 2. Neuromuscular Junction - drug effects. 3. Neuromuscular Junction - physiology. WI HA51L v. 79/QV 140 N532) QP905.H3 vol. 79 [RM312) 615'.1 s [615'.77) 85-20809 This work is subject to copyright. AIl rights are reserved, whether the whole or part of the material is concerned, specifically those of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photocopying machine or similar means, and storage in data banks. Under § 54 of the German Copyright Law, where copies are made for other than private use, a fee is payable to "Verwertungsgesellschaft Wort", Munich. © by Springer-Verlag Berlin Heidelberg 1986 Softcover reprint of the hardcover 1st edition 1986 The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product Liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutica1literature. 2122/3130-543210 List of Contributors S. AGOSTON, Research Group of the Institutes of Anesthesiology and Clinical Pharmacology, University ofGroningen, University Hospital, Oostersinge159, 9713 EZ Groningen, The Netherlands K. BIRO, Pharmacological Research Center, Chemical Works of Gedeon Richter Ltd., P.O. Box 27, 1475 Budapest 10, Hungary W. C. BOWMAN, Department of Physiology and Pharmacology, University of Strathc1yde, Royal College, 204 George Street, Glasgow Gl 1XW, Great Britain A. A. BUNATIAN, Department of Anesthesiology, National Research Centre of Surgery, USSR Academy of Medical Sciences, 2 Abrikosovsky per., Moscow 119874, USSR V. V. CHURYUKANOV, Department of Pharmacology, First Medical Institute, 2/6 Bolshaya Pirogovskaya Street, Moscow 119435, USSR D. COLQUHOUN, Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, Great Britain A. F. DANILOV, Department of Pharmacology, Sechenov Institute of Physiology and Biochemistry, USSR Academy of Sciences, 44 M. Thorez Prospect, Leningrad 194223, USSR A. DEERY, Department of Anesthesiology, Montefiore Medical Center and Albert Einstein College of Medicine, 111 East 210th Street, Bronx, NY 10467, USA D. DUNCALF, Department of Anesthesiology, Montefiore Medical Center and Albert Einstein College of Medicine, 111 East 210th Street, Bronx, NY 10467, USA V. P. FISENKO, Department of Pharmacology, First Medical Institute, 2/6 Bol- shaya Pirogovskaya Street, Moscow, 119435 USSR F. F. FOLDES, Department of Anesthesiology, Montefiore Medical Center and Albert Einstein College of Medicine, 111 East 210th Street, Bronx, NY 10467, USA A. J. GIBB, Department of Physiology and Pharmacology, University of Strathc1yde, Royal College, 204 George Street, Glasgow Gil WX, Great Britain VI List of Contributors A. L. HARVEY, Department of Physiology and Pharmacology, University of Strathc1yde, Royal College, 204 George Street, Glasgow G 1 lXW, Great Britain R. HUGHEs, Clinical Investigation Department, The Wellcome Research Labora- tories, Langley Court, Beckenham, Kent BR3 3BS, Great Britain E. KARpATI, Pharmacological Research Center, Chemical Works of Gedeon Richter Ltd., P.O. Box 27, 1475 Budapest 10, Hungary D. A. KHARKEVICH, Department of Pharmacology, First Medical Institute, 2/6 Bolshaya Pirogovskaya Street, Moscow 119435, USSR N. V. KHROMOV-BoRISOV, Pro Korablestroitelei 23-1, 214 Leningrad 199226, USSR A. A. J}.IMENIS, Biological and Medical Research Division, Institute of Organic Synthesis of the Latvian SSR Academy of Sciences, 21 Aizkraukles Street, Riga 226006, USSR I. G. MARSHALL, Department of Physiology and Pharmacology, University of Strathc1yde, Royal College, 204 George Street, Glasgow G 1 1XW, Great Britain M. D. MAsHKOVSKY, Department of Pharmacology, All-Union Chemical Pharmaceutical Research Institute, 7 Zubovskaya Street, Moscow 119815, USSR R. D. MILLER, Department of Anesthesia, University of California, School of Medicine, San Francisco, CA 94143, USA H. NAGASHIMA, Department of Anesthesiology, Montefiore Medical Center and Albert Einstein College of Medicine, 111 East 210th Street, Bronx, NY 10467, USA D. S. PASKOV, 5 Razlatiza Street, 1463 Sofia, Bulgaria J. P. PAYNE, Research Department of Anesthesia, Royal College of Surgeons of England, Lincolns Inn Fields, London WC2, Great Britain M. RIEsz, Pharmacological Research Center, Chemical Works of Gedeon Richter Ltd., P.O. Box 27, 1475 Budapest 10, Hungary V. A. SHORR, Department of Pharmacology, First Medical Institute, 2/6 Bolshaya Pirogovskaya Street, Moscow 119435, USSR A. P. SKOLDINOV, Department of Organic Chemistry, Institute of Pharmacology of the USSR Academy of Medical Sciences, 8 Baltijskaya Street, Moscow 125315, USSR J. B. STENLAKE, Department of Pharmacy, University of Strathc1yde, Royal College Building, 204 George Street, Glasgow G 1 1XW, Great Britain G. A. SUTHERLAND, Division of Anesthesia, Royal Infirmary, Castle Street, Glasgow G4, Great Britain G. SZABO, Postgraduate Medical School, Central Research Division, P.O. Box 112,1389 Budapest 62, Hungary List of Contributors VII L. SZPORNY, Pharmacological Research Center, Chemical Works of Gedeon Richter Ltd., P.O. Box 27, 1475 Budapest 10, Hungary E. TASSONYI, Postgraduate Medical School, 2nd Department of Surgery, P.O. Box 112, 1389 Budapest 62, Hungary M. B. TYERS, Neuropharmacology Department, Glaxo Group Research Ltd., Ware Hertfordshire, SGl2 ODJ, Great Britain L. VIMLATI, Postgraduate Medical School, 2nd Department of Surgery, P.O. Box 112, 1389 Budapest 62, Hungary L. P. WENNOGLE, Neurosciences Cardiovascular Research, Ciba-Geigy Corp., Summit, NJ 07901, USA L. N. Y AKHONTOV, Department of Organic Chemistry, All-Union Chemical Pharmaceutical Research Institute, 7 Zubovskaya Street, Moscow 119815, USSR Preface The problems associated with the pharmacologic and physiologic regulation of neuromuscular transmission and of the morphofunctional organization of neuromuscular junctions have attracted a wide range of investigators. Numerous handbooks, monographs, and reviews are devoted to this subject. At the same time, many fundamental and applied aspects of this trend continue to progress succesfully. In recent years, new experimental and clinical data on the structure and function of neuromuscular junctions have been gained, and new, more perfect neuromuscular blocking agents have been designed. It is these data that the present handbook mainly deals with. A considerable number of chapters have been written by authors from eastern Europe. This was done intentionally since much of their work has previously been published only in their own languages, and is thus inaccessible to most Western readers. This is why some of the data included in the volume are not quite the latest, but they contain fruitful ideas or important results and are of value for further progress in the pharmacology of neuromuscular transmission. Naturally, the methodological level of the investigations differs, depending on when they were carried out. The handbook contains a number of selected chapters on the pharmacology of neuromuscular junctions; they comprise data otherwise insufficiently reviewed or not dealt with at all. They furthermore reflect the up-to-date state of the problem and probable directions of further developments in this field. D. A. KHARKEVICH Contents CHAPTER 1 Neuromuscular Blocking Agents: General Considerations D. A. KHARKEVICH . . . . . . . . . . . . . . . . CHAPTER 2 The End-Plate Acetylcholine Receptors: Structure and Function L. P. WENNOGLE. With 6 Figures A. Introduction 17 I. Scope of Review 17 II. Perspective of the Junctional Acetylcholine Receptor. 18 III. Some Particularly Interesting Questions 19 B. Molecular Properties of the Acetylcholine Receptor 19 I. Purification 19 II. Subunits and Stoichiometry 21 III. Physical Properties 22 IV. Reconstitution, Flux, and Planar Lipid Bilayers 22 C. The 43K Protein 24 Receptor Mobility. 25 D. Multiple Binding Sites and Multiple Affinity States 25 I. Multiple Sites for Ligand Interaction 26 II. The Three-State Model 26 III. The Agonist Binding Site. 30 IV. Noncompetitive Blocking Agents 30 E. Three-Dimensional Structure 32 I. Biochemical Characterization . 32 II. Transmembrane Orientation 42 III. Model. 44 F. Biochemical Control Over Receptor Activity: Phosphorylation, Methylation, and Glycosylation . 45 G. Summary and Conclusions 45 References. 46 XII Contents Pharmacodynamics and Pharmacokinetics of Neuromuscular Blocking Agents CHAPTER 3 On the Principles of Postsynaptic Action of Neuromuscular Blocking Agents D. COLQUHOUN. With 4 Figures A. Introduction . . . . . . . . . . . . . . . . . . . . . 59 B. Mechanisms of Action and Experimental Criteria for Them. 60 I. Range of Conditions of Tests 60 II. Measurement of Binding . . . . . 60 III. Measurements of Response . . . . 62 IV. Tests for Competitive Antagonism. 64 V. Tests for Noncompetitive Mechanisms 67 C. The Mechanism of Action of Agonists. . . 68 I. Structure of the Receptor Ion Channel 68 II. Opening of the Ion Channel by Agonists 69 III. The End-Plate Current. . . . . . . . 74 IV. Desensitization . . . . . . . . . . . 76 D. Nondepolarizing Neuromuscular Blocking Agents: Tubocurarine and Similar Drugs . . . . . . . . . . . 78 I. Numbers of Binding Sites. . . . . 78 II. Depolarization by Tubocurarine. . 79 III. Inhibition of Equilibrium Responses 79 IV. Binding of Tubocurarine and Similar Agents 81 V. Evidence Concerning Nonequivalence of Binding Sites 82 VI. Kinetics of Competitive Action . . . . . . . . . 90 VII. Ion Channel Block by Nondepolarizing Antagonists . 91 VIII. Competitive Block Under Physiological Conditions. . 93 E. Nondepolarizing Neuromuscular Blocking Agents: Miscellaneous Agents of Low Specificity . . . . . . . . . . . . 94 I. Some Drugs and Possible Mechanisms . . . . 94 II. Block (Selective or Otherwise) of Ion Channels 94 III. Reduction of Single-Channel Conductance . . 96 IV. Enhancement of Desensitization . . . . . . . 96 V. Other Mechanisms: Correlations with Lipophilicity . 98 F. Depolarizing Blocking Agents. . . . 99 I. Some Possible Modes of Action . . . . . 99 II. Sodium Channel Inactivation . . . . . . 100 III. Changes in Intracellular Ion Concentration 102 IV. Desensitization, Channel Block and "Dual Block" 103 G. Conclusions 105 References. . . 106 Contents XIII CHAPTER 4 On the Hydrophobic Interaction of Neuromuscular Blocking Agents with Acetylcholine Receptors of Skeletal Muscles D. A. KHARKEVICH and A. P. SKOLDINOV. With 11 Figures A. Introduction . . . . . . . . . . . . . . . . . . 115 B. The Effect of Hydrophobic Radicals on the Mode of Action 115 I. N-I-Adamantyl Derivatives. . . . . . . . . . . . . 115 II. Quaternary Ammonium Compounds with Adamantyl Radicals in Various Parts of the Molecule . . . . . . . . . . . .. 122 III. Alterations of the Mode of Action Evoked by Gradual Increase in Hydrophobicity. . . . . . . . . . . . . 124 C. The Effect of Hydrophobic Radicals on the Activity . . . . .. 129 I. The Role of the Initial Mechanism of Action . . . . . .. 129 II. The Role of the Stereochemical Structure of Cationic Groups 132 D. The Effect of Hydrophobic Radicals on the Main Pharmacologic Action 134 E. Conclusions 136 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 CHAPTER 5 Prejunctional Actions of Cholinoceptor Agonists and Antagonists, and of Anticholinesterase Drugs. W. C. BOWMAN, A. J. GIBB, A. L. HARVEY, and I. G. MARSHALL. With 8 Figures A. Introduction ......................... 141 B. Cholinoceptor Agonists and Antagonists, and Anticholinesterase Drugs 142 I. Repetitive Antidromic Nerve Activity . . . . . . . . . . . . 142 II. Tetanic Fade and Rundown of Trains of Nerve-Evoked Responses 148 III. Is There Feedback Control of Transmitter Release? 159 IV. Summary and Conclusions 163 References. . . . . . . . . . . . . . . . . . . . . . 165 CHAPTER 6 On the Comparative Sensitivity of Acetylcholine Receptors of Various Groups of Skeletal Muscles to Neuromuscular Blocking Agents D. A. KHARKEVICH and V. P. FISENKO. With 7 Figures A. Introduction . . . . . . . . . . . . . . . . . . . . . . 171 B. On the Order of Skeletal Muscle Relaxation in Humans Under the Influence of Neuromuscular Blocking Agents 171 I. Investigations on Anesthetized Patients . . . . . . . . 171 II. Investigations on Volunteers . . . . . . . . . . . . . 173 C. Factors Which May Affect the Sensitivity of End-plate Acetylcholine Receptors to Neuromuscular Blocking Agents. 174 I. Structure of Skeletal Muscles. . . . . . . . . . . . . . . . 174
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