New Neuromuscular Blocking Agents : Basic and Applied Aspects

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 . . . . . . . . . . . . . . . .

1 Neuromuscular Blocking Agents: General Considerations.- 2 The End-Plate Acetylcholine Receptors: Structure and Function.- A. Introduction.- I. Scope of Review.- II. Perspective of the Junctional Acetylcholine Receptor.- III. Some Particularly Interesting Questions.- B. Molecular Properties of the Acetylcholine Receptor.- I. Purification.- II. Subunits and Stoichiometry.- III. Physical Properties.- IV. Reconstitution, Flux, and Planar Lipid Bilayers.- C. The 43K Protein.- Receptor Mobility.- D. Multiple Binding Sites and Multiple Affinity States.- I. Multiple Sites for Ligand Interaction.- II. The Three-State Model.- III. The Agonist Binding Site.- IV. Noncompetitive Blocking Agents.- E. Three-Dimensional Structure.- I. Biochemical Characterization.- II. Transmembrane Orientation.- III. Model.- F. Biochemical Control Over Receptor Activity: Phosphorylation, Methylation, and Glycosylation.- G. Summary and Conclusions.- References.- Pharmacodynamics and Pharmacokinetics of Neuromuscular Blocking Agents.- 3 On the Principles of Postsynaptic Action of Neuromuscular Blocking Agents.- A. Introduction.- B. Mechanisms of Action and Experimental Criteria for Them.- I. Range of Conditions of Tests.- II. Measurement of Binding.- III. Measurements of Response.- IV. Tests for Competitive Antagonism.- V. Tests for Noncompetitive Mechanisms.- C. The Mechanism of Action of Agonists.- I. Structure of the Receptor Ion Channel.- II. Opening of the Ion Channel by Agonists.- III. The End-Plate Current.- IV. Desensitization.- D. Nondepolarizing Neuromuscular Blocking Agents: Tubocurarine and Similar Drugs.- I. Numbers of Binding Sites.- II. Depolarization by Tubocurarine.- III. Inhibition of Equilibrium Responses.- IV. Binding of Tubocurarine and Similar Agents.- V. Evidence Concerning Nonequivalence of Binding Sites.- VI. Kinetics of Competitive Action.- VII. Ion Channel Block by Nondepolarizing Antagonists.- VIII. Competitive Block Under Physiological Conditions.- E. Nondepolarizing Neuromuscular Blocking Agents: Miscellaneous Agents of Low Specificity.- I. Some Drugs and Possible Mechanisms.- II. Block (Selective or Otherwise) of Ion Channels.- III. Reduction of Single-Channel Conductance.- IV. Enhancement of Desensitization.- V. Other Mechanisms: Correlations with Lipophilicity.- F. Depolarizing Blocking Agents.- I. Some Possible Modes of Action.- II. Sodium Channel Inactivation.- III. Changes in Intracellular Ion Concentration.- IV. Desensitization, Channel Block and “Dual Block”.- G. Conclusions.- References.- 4 On the Hydrophobic Interaction of Neuromuscular Blocking Agents with Acetylcholine Receptors of Skeletal Muscles.- A. Introduction.- B. The Effect of Hydrophobic Radicals on the Mode of Action.- I. N-1-Adamantyl Derivatives.- II. Quaternary Ammonium Compounds with Adamantyl Radicals in Various Parts of the Molecule.- III. Alterations of the Mode of Action Evoked by Gradual Increase in Hydrophobicity.- C. The Effect of Hydrophobic Radicals on the Activity.- I. The Role of the Initial Mechanism of Action.- II. The Role of the Stereochemical Structure of Cationic Groups.- D. The Effect of Hydrophobic Radicals on the Main Pharmacologic Action.- E. Conclusions.- References.- 5 Prejunctional Actions of Cholinoceptor Agonists and Antagonists, and of Anticholinesterase Drugs.- A. Introduction.- B. Cholinoceptor Agonists and Antagonists, and Anticholinesterase Drugs.- I. Repetitive Antidromic Nerve Activity.- II. Tetanic Fade and Rundown of Trains of Nerve-Evoked Responses.- III. Is There Feedback Control of Transmitter Release?.- IV. Summary and Conclusions.- References.- 6 On the Comparative Sensitivity of Acetylcholine Receptors of Various Groups of Skeletal Muscles to Neuromuscular Blocking Agents.- A. Introduction.- B. On the Order of Skeletal Muscle Relaxation in Humans Under the Influence of Neuromuscular Blocking Agents.- I. Investigations on Anesthetized Patients.- II. Investigations on Volunteers.- C. Factors Which May Affect the Sensitivity of End-plate Acetylcholine Receptors to Neuromuscular Blocking Agents.- I. Structure of Skeletal Muscles.- II. Blood Circulation in the Skeletal Muscles.- III. Temperature of Skeletal Muscles.- IV. Acid-Base Equilibrium.- V. Lability of Neuromuscular Junctions.- VI. Site and Mode of Action of Neuromuscular Blocking Agents.- VII. Chemical Structure of Neuromuscular Blocking Agents.- D. Conclusions.- References.- 7 Antimuscarinic and Ganglion-Blocking Activity of Neuromuscular Blocking Agents.- A. Antimuscarinic Activity.- I. Introduction.- II. Comparative Characteristics of Antimuscarinic Activity of Neuromuscular Blocking Agents.- III. Mechanism of Antimuscarinic Action of Neuromuscular Blocking Agents.- IV. Some Other Possible Mechanisms of Cardiovascular Side Effects of Neuromuscular Blocking Agents.- V. Conclusions.- B. Ganglion-Blocking Activity.- I. Introduction.- II. Comparative Characteristics of Ganglion-Blocking Activity of Neuromuscular Blocking Agents.- III. Conclusions.- References.- 8 The Interaction of Neuromuscular Blocking Agents With Human Cholinesterases and Their Binding to Plasma Proteins.- A. Introduction.- B. Determination of Cholinesterase Activity.- C. Determination of Protein Binding.- D. Hydrolysis of Neuromuscular Blocking Agents by Cholinesterases.- E. Inhibition of Human Acetyl- and Butyrylcholinesterase by Neuromuscular Blocking Agents.- F. Binding of Neuromuscular Blocking Agents by Plasma Proteins.- G. Summary and Conclusions.- References.- 9 On the Effect of Neuromuscular Blocking Agents on the Central Nervous System.- A. Introduction.- B. Intravascular Administration of Neuromuscular Blocking Agents.- I. The Effect on Conditioned Reflexes.- II. The Effect on the Electroencephalogram.- III. The Effect on Interneuronal Transmission in the Afferent Pathways.- IV. The Effect on the Brain Stem.- V. The Effect on the Spinal Cord.- VI. The Effect on Reflex Responses of the Arterial Pressure.- VII. The Interaction of Neuromuscular Blocking Agents with Other Neurotropic Drugs.- C. Conclusions.- References.- 10 Biodegradation and Elimination of Neuromuscular Blocking Agents.- A. Introduction.- B. Ester Hydrolysis.- I. Suxamethonium.- II. Pancuronium.- III. Vecuronium.- C. Azo Fission.- Fazadinium.- D. Hofmann Elimination.- Atracurium.- References.- On the Relationship Between the Chemical Structure and the Neuromuscular Blocking Activity.- 11 Methods for the Experimental Evaluation of Neuromuscular Blocking Agents.- A. Introduction.- B. Evaluation of Neuromuscular Blocking Activity.- C. Evaluation of Toxicity.- D. Conclusions.- References.- 12 Steroid Derivatives.- A. Introduction.- B. Neuromuscular Blocking Activity.- I. Androstane Derivatives.- II. D-Homoazaandrostanes and Androstenes.- III. 4-Azaandrostanes.- IV. Miscellaneous Azasteroids.- V. Pregnane Derivatives.- VI. Conessine Derivatives.- VII. Cholane and Norcholane Derivatives.- VIII. Miscellaneous Steroids.- C. Onset and Duration of Neuromuscular Blocking Effect.- D. Conclusions.- References.- 13 The Derivatives of Carboxylic Acids.- A. Introduction.- B. The Derivatives of Truxillic Acids.- I. Bisquaternary Ammonium Derivatives of Basic Esters of Truxillic Acids.- II. Bisquaternary Ammonium Salts of ?-Truxillic Acid Aminoalkylamides.- III. Bistertiary Ammonium Salts of ?-Truxillic Acid Aminoalkylamides.- C. The Derivatives of Cinnamic and Benzoic Acids.- I. Cinnamic Acid Derivatives.- II. Benzoic Acid Derivatives.- D. The Derivatives of Aliphatic Dicarboxylic Acid Esters.- I. Neuromuscular Blocking Action.- II. Hydrolysis by Cholinesterases.- E. Conclusions.- References.- 14 Quinuclidinium Compounds.- A. Introduction.- B. Some Chemical Peculiarities of Quinuclidine.- C. Relationship Between the Structure and Neuromuscular Blocking Activity.- D. Pharmacology of Qualidilum.- E. Conclusions.- References.- 15 Derivatives of Terphenyl..- A. Introduction.- B. The Molecular Complementarity of the Nicotinic Acetylcholine Receptors and Dicationic Neuromuscular Blocking Agents.- C. Conformational Properties of Dicationic Neuromuscular Blocking Agents.- D. The Structure of Cationic Heads.- E. Directed Synthesis of Tercuronium.- F. Conclusions.- References.- 16 Delphinium Alkaloids.- A. Introduction.- B. Neuromuscular Blocking Activity.- C. Conclusions.- References.- Preclinical Pharmacology of New Neuromuscular Blocking Drugs.- 17 Bisquaternary Steroid Derivatives.- A. Introduction.- B. Chandonium and Its Analogs.- I. HS-342 and HS-467.- II. Chandonium Iodide.- III. New Derivatives.- C. Pipecuronium Bromide.- I. Introduction.- II. Action on the Neuromuscular Junction.- III. Other Pharmacologic Actions.- IV. Distribution, Excretion, and Metabolism.- D. RGH-4201.- I. Introduction.- II. Comparative Neuromuscular Blocking Effects.- III. Cardiovascular and Other Pharmacologic Actions.- IV. Pharmacokinetics.- V. Clinical Studies.- E. Conclusions.- References.- 18 Vecuronium (ORG-NC-45).- A. Introduction.- B. Mechanism of Action.- C. Potency and Time Course of Action: Cumulative Effects.- D. Pharmacokinetics.- E. Antagonism of Blocking Action.- F. Unwanted Effects.- I. Histamine Release.- II. Anticholinesterase Activity.- III. Ganglion Block.- IV. Block of Muscarinic Receptors.- V. Inhibitory Action on the Postganglionic Cardiac Vagus.- VI. Noradrenaline Release and Reuptake Block.- VII. Cardiovascular Effects.- G. Influence of Acid-base Balance.- H. Interactions with Other Drugs.- J. Conclusions.- References.- 19 The Derivatives of ?-Truxillic Acid.- A. Introduction.- B. Bisquaternary Salts of Aminoalkylester Derivatives: Anatruxonium, Cyclobutonium, Truxilonium, and Pyrocyclonium.- I. Neuromuscular Blocking Action.- II. Assessment of Side Effects.- III. Toxicologic Study.- C. Bisquaternary Salts of Aminoalkylamides: Dipyronium and Amidonium (in collaboration with E. Yu. Lemina).- I. Neuromuscular Blocking Action.- II. Assessment of Side Effects.- III. Toxicologic Study.- D. Bistertiary Salt of Aminoalkylamide: Pyrocurinum.- I. Neuromuscular Blocking Action.- II. Assessment of Side Effects.- III. Toxicologic Study.- E. Conclusions.- References.- 20 Adamantyl Compounds.- A. Introduction.- B. Diadonium.- I. Neuromuscular Blocking Action.- II. Assessment of Side Effects.- III. Toxicologic Study.- C. Decadonium.- I. Neuromuscular Blocking Action.- II. Assessment of Side Effects and Toxicity.- D. Conclusions.- References.- 21 Tercuronium..- A. Introduction.- B. Pharmacology of Tercuronium.- I. Neuromuscular Blocking Action.- II. Side Effects.- C. Toxicity of Tercuronium.- D. Conclusions.- References.- 22 Dioxonium..- A. Introduction.- B. Experimental.- I. Neuromuscular Blocking Activity.- II. Mechanism of Action.- III. Peculiarities of Effect on Repetitive Administration.- IV. Possible Side Effects.- V. Pharmacokinetics.- VI. Toxicology.- C. Conclusion.- References.- 23 Fazadinium Dibromide..- A. Introduction.- B. Azobisarylimidazo[1,2-a]pyridinium Dihalides.- Structure-Activity Relationships.- C. Animal Pharmacology of Fazadinium Dibromide.- I. Neuromuscular Blocking Properties.- II. Termination of Action.- III. Selectivity of Action.- D. Pharmacokinetics and Metabolic Fate of Fazadinium.- E. Conclusions.- References.- 24 Atracurium.- A. Introduction.- B. Neuromuscular Blocking Activity.- I. Chick Isolated Biventer Cervicis Preparation.- II. Anaesthetised Cats, Dogs and Rhesus Monkeys.- C. Changes in Acid-Base Balance.- D. Other Actions of Atracurium.- I. Effects on Autonomic Mechanisms.- II. Cardiovascular Effects.- III. Histamine Release.- E. Drug Interactions.- I. Premedicants.- II. Anaesthetics.- III. Hypotensive Drugs.- IV. Drugs Used for Resuscitation.- V. Antibiotics.- VI. Neuromuscular Blocking Agents.- F. Breakdown Products and Related Substances.- G. Cholinesterase Inhibition.- H. Conclusions.- References.- Clinical Pharmacology of New Neuromuscular Blocking Drugs.- 25 General Principles and Methods of Evaluation of Neuromuscular Blocking Agents in Anesthesiology.- A. Introduction.- B. Screening of Neuromuscular Blocking Agents in Conscious Subjects.- C. Assessment of Neuromuscular Blocking Agents in Anesthetized Subjects.- I. Pharmacodynamic Effects.- II. Pharmacokinetics.- D. Summary and Conclusions.- References.- 26 Neuromuscular Blocking Agents of Different Chemical Structure.- A. Introduction.- B. Bisquaternary Adamantyl-Containing Ester.- Diadonium.- C. ?-Truxillic Acid Derivatives.- I. Pyrocurinum.- II. Anatruxonium.- III. Cyclobutonium.- IV. Truxilonium.- D. Bisquaternary Derivative of Terphenyl.- Tercuronium.- E. Bisquaternary Derivative of Cyclic Acetosuccinylaldehyde.- Dioxonium.- F. Quinuclidine Derivative.- Qualidilum.- G. Combined Use of Neuromuscular Blocking Agents with Identical Modes of Action.- I. Diadonium plus Tercuronium.- II. Diadonium plus Tercuronium plus Diadonium.- III. Summary.- H. Conclusions.- References.- 27 Pipecuronium Bromide (Arduan)..- A. Introduction.- B. Clinical Pharmacodynamics.- I. The Neuromuscular Blocking Effect.- II. Effects on Heart Rate.- III. Hemodynamic Effects.- C. Clinical Pharmacokinetics.- I. Pharmacokinetics in Normal Patients.- II. Pharmacokinetics in Patients with Impaired Renal Function...- D. Clinical Use.- I. Intubation.- II. The Reversal of Pipecuronium Block with Anticholinesterases...- III. The Use of Pipecuronium in Patients with Impaired Cardiovascular Function.- IV. The Use of Pipecuronium in Patients with Impaired Renal Function.- V. Interaction Between Pipecuronium and Other Drugs Used in Anesthesiology and Surgery.- E. Conclusions.- References.- 28 Vecuronium (ORG-NC-45)..- A. Introduction.- B. Neuromuscular Blocking Characteristics.- I. Potency.- II. Duration of Action.- III. Cumulative Effects.- IV. Endotracheal Intubation.- C. Pharmacokinetics and Pharmacodynamics.- I. Comparison with Pancuronium.- II. Renal Failure.- D. Cardiovascular Effects.- I. Patients Without Cardiovascular Disease.- II. Patients Undergoing Coronary Artery Bypass Surgery.- III. Patients Undergoing Resection of a Pheochromocytoma.- E. Antagonism.- F. Conclusions.- References.- 29 Fazadinium Dibromide.- A. Introduction.- B. Clinical Pharmacology of Fazadinium.- I. Neuromuscular Blocking Properties.- II. Selectivity of Action.- III. Placental Transfer.- C. Conclusions.- References.- 30 Atracurium.- A. Introduction.- B. Quantitative Assessment.- I. Neuromuscular Blocking Activity.- II. Cardiovascular Effects.- III. Use with Volatile Anaesthetics.- C. Pharmacokinetics.- I. In Vitro Degradation.- II. Pharmacokinetic Profile.- D. Comparative Studies with Other Neuromuscular Blocking Agents...- I. Suxamethonium.- II. Tubocurarine and Dimethyltubocurarine.- III. Pancuronium and Vecuronium.- IV. Histamine-Releasing Potential of Atracurium, Dimethyltubocurarine and Tubocurarine.- V. Incremental Dosage of Atracurium and Vecuronium.- E. Specialised Uses.- I. Obstetric Anaesthesia.- II. Paediatric Anaesthesia.- III. Routine Anaesthesia in Elderly and Severely Ill Patients.- IV. Patients in Renal Failure.- V. Patients with Coronary Artery Disease.- VI. Infusion for Long Procedures Including Cardiopulmonary Bypass.- F. Conclusions.- References.- Antagonists of Neuromuscular Blocking Agents (Pharmacology and Clinical Use).- 31 Galanthamine..- A. Introduction.- B. Pharmacology of Galanthamine.- I. Anticholinesterase Activity.- II. Effect on Neuromuscular Transmission.- III. Antagonism Against Nondepolarizing Neuromuscular Blocking Agents.- IV. Effect on the Central Nervous System.- V. Effect on the Cardiovascular System.- VI. Effect on Respiration.- VII. Effect on Smooth Muscles.- VIII. Effect on the Superior Cervical Ganglion and Adrenals.- IX. General Effects and Toxicity.- X. Distribution: Pharmacokinetics of Galanthamine in Animals and Healthy Volunteers.- XI. Teratology and Embryotoxicity.- XII. Mutagenesis.- C. Clinical Application of Galanthamine.- I. Clinical Application as a Decurarizing Agent.- II. Treatment of Diseases of the Central and Peripheral ...