Local Anesthetics

1 Some Aspects of the History of Local Anesthesia.- A. Introduction.- B. Freud, Koller and the Early History of Cocaine.- C. Structure and Synthesis of Local Anesthetics.- D. Epinephrine and Local Anesthesia.- E. Toxicity of Local Anesthetics.- F. The Nervous Impulse and the Action of Local Anesthetics.- G. Pharmacokinetics of Local Anesthetics.- H. Summary and Conclusions.- References.- 2 The Action of Local Anesthetics on Ion Channels of Excitable Tissues.- A. Introduction.- B. Physiological Basis of Generation of the Action Potential.- I. Role of Ion Channels.- II. Kinetic Properties of Sodium Channels.- III. Gating Currents.- IV. Pharmacological Dimensions of the Sodium Channel.- C. The Action of Local Anesthetics on Sodium Channels.- I. Distribution of Local Anesthetics and the Mechanism of Their Blocking Action.- II. The Modulated Receptor Hypothesis: Past and Present Formulations.- D. Current Questions in Local Anesthetic Action.- I. Location of Local Anesthetic Binding Site(s) in the Sodium Channel.- II. Factors that Determine Rates of Action and Potencies of Local Anesthetics.- III. The Number and Nature of Local Anesthetic Binding Sites.- E. New Kinds of Local Anesthetic Agents.- F. Effects of Local Anesthetics on Potassium Channels.- G. Conclusion.- References.- 3 Structural Elements which Determine Local Anesthetic Activity.- A. Introduction.- I. Scope of Review and Methodology.- II. Measurements of Anesthetic Action.- B. Structure and Physico-Chemical Properties of Local Anesthetics.- C. Resolution of Structural Contributions to Potency.- I. Aromatic Groups.- II. Amide, Ester, and Ether Bonds.- III. Intermediate Alkyl Chain.- IV. Terminal Amine.- V. Stereoisomers.- VI. Onset and Duration of Action.- D. Comparisons of Nerve Blocking Actions with Antiarrhythmic Actions of Local Anesthetics.- I. Sensitivity of Nerve Versus Muscle.- II. Different Inactivation Gating in Nerve and Heart.- III. Factors Determining Potency in Heart.- IV. Relevance to Cardiotoxicity.- V. Importance of Intermediate, Open and Inactive Channel Blocking.- E. Models for Local Anesthetic Receptors.- I. Kinetic Models of Local Anesthetic Action.- II. Physico-Chemical Models.- III. Anesthetic Action and Channel Structure.- IV. Molecular Substrate for the Block Recovery Process.- References.- 4 Mechanisms of Differential Nerve Block.- A. Introduction.- B. Historical Discussion.- I. Differential Tonic Block.- II. Origins of the Dominant Paradigm.- III. Synthesis: The Size Principle.- C. Confirmations, Extensions, Clarifications, and Contradictions.- I. Confirmation and Extension of the Size Principle.- II. Contradictions of the Size Principle; Importance of Additional Factors.- D. Summary and Conclusion.- I. The Notion of Functional Specificity.- II. A Distributed Model of Conduction Safety.- References.- 5 Pharmacokinetics of Local Anesthetics.- A. Introduction.- B. Factors Affecting the Interpretation of Local Anesthetic Blood Concentrations.- I. Units of Expression.- II. Sampling Site.- III. Plasma Protein Binding.- C. Metabolism.- I. Ester Type Local Anesthetics.- II. Amide Type Local Anesthetics.- D. Pharmacokinetics in Man.- E. Factors Affecting Pharmacokinetics of Local Anesthetics.- I. Lung Uptake of Local Anesthetics.- II. Age.- III. Other Drugs.- IV. Disease.- V. Other Factors.- F. Pharmacokinetics in Experimental Animals.- References.- 6 Toxicity and Systemic Effects of Local Anesthetic Agents.- A. Effects on the Central Nervous System.- B. Effects on the Cardiovascular System.- I. Cardiac Effects.- II. Peripheral Vascular Effects.- C. Effects on the Neuromuscular Junction.- D. Miscellaneous Effects.- E. Other Toxicological Effects.- F. Treatment of Systemic Toxicity.- G. Local Tissue Toxicity.- H. Summary.- References.- 7 The Role of Local Anesthetic Effects in the Actions of Antiarrhythmic Drugs.- A. Introduction.- B. Electrophysiology of Cardiac Fibers.- I. Description of the Cardiac Action Potential.- II. Fast Responses and Slow Responses.- III. Excitability, Refractoriness, and Responsiveness.- C. The Effects of Local Anesthetics on Cardiac Fibers.- I. Effects on Fast Inward Sodium Current.- II. Effects on Action Potential Duration.- III. Effects on Phase 4 Depolarization and Normal Automaticity.- D. Antiarrhythmic Effects of Local Anesthetic Agents.- I. Classification of Arrhythmias.- II. Arrhythmias Due to Altered Impulse Initiation.- III. Reentrant Rhythms.- E. Conclusion.- References.- 8 Central Effects of Local Anesthetic Agents.- A. Introduction.- B. Routes of Entry of Local Anesthetic Agents into the CNS.- C. Behavioral Pharmacology of Local Anesthetic Agents.- I. Animal Studies of Locomotor Activity, Behavior and Correlative Neural Activity.- II. Effects of Local Anesthetics on Conditioned Behavior.- III. Behavioral Effects of Local Anesthetics in Man.- D. Effects of Local Anesthetics on Electrical Activity of the Brain.- I. The Convulsant Properties of Local Anesthesia.- E. Anticonvulsant Properties of Local Anesthetics.- F. Temporal and Spatial Effects of Local Anesthetics at Regional CNS Sites.- I. The Amygdaloid Complex as the Initial CNS Target of Local Anesthetics.- II. Anatomy and Function of the Amygdaloid Complex.- III. Other CNS Structures Affected by Local Anesthetics.- G. The Mechanisms Underlying Local Anesthetic-Induced Seizures.- I. Local Anesthetic Induced Disinhibition of Neuronal Pathways.- II. The Interplay of Local Anesthetics and Putative Neurotransmitters and Neuromodulators.- H. Central Nervous System Metabolic Effects of Local Anesthetics.- I. Summary.- References.