New Neuromuscular Blocking Agents

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 Nervous Systems.- III. Application in Some Other Diseases.- D. Conclusions.- References.- 32 Chinothylinum..- A. Introduction.- B. Experimental Findings.- I. Anticholinesterase Activity.- II. Acetylcholine-Potentiating Activity.- III. Decurarizing Activity.- IV. Toxicity.- C. Clinical Findings.- D. Conclusion.- References.- 33 4-Aminopyridine Hydrochloride (Pymadin).- A. Introduction.- B. Actions on Excitable Membranes.- C. Actions on Neuromuscular Transmission.- I. Evoked Acetylcholine Release.- II. Spontaneous Acetylcholine Release.- III. Repetitive Nerve Stimulation.- D. Actions on Other Peripheral Synapses and Neuroeffector Junctions.- E. Actions on the Spinal Cord and Brain.- F. Actions on Endocrine Glands.- G. Actions on Muscle.- H. Cardiovascular System.- J. Clinically Useful Effects.- I. Human Pharmacokinetics.- II. Use of 4-Aminopyridine in Clinical Anaesthesia.- III. Experimental Clinical Use.- K. Conclusions.- References.- Subject Index V.V. Maisky.