Modern Inhalation Anesthetics

The most important development in studies of the metabolic effects of anes­ thetics has been the recent demonstration that anesthetics may alter the rate of transport of metabolites across biologic membranes. The membranes affected include cell membranes as well as mitochondrial membranes. Inhalation anesthe­ tics generally have little effect on glycolysis but may sigrllficantly alter oxidative phosphorylation and mitochondrial oxygen consumption. The direct effects of anesthetics on cell metabolism may be overshadowed in vitro by secondary effects anesthetics exert on endocrine balance, organ blood flow, and changes in oxygen and carbon dioxide tensions. References ALBERS, C., BRENDEL, W., USINGER, W.: Kreislaufrespiratorischer Stoffwechsel undAtmung in Athernarkose. Arch. expo Pathol. Pharmakol., Naunyn-Schmiedeberg's 226, 278 (1955). ALEXANDER, S. C., COHEN, P. J., WOLLMAN, H., SMITH, T. C., REIVICH, ~L, MOLEN, R. A. U.: Cerebral carbohydrate metabolism during hypocarbia in man. Studies during nitrous oxide anesthesia. Anesthesiology 26, 624 (1965). ANDERSEN, N. B.: Effect of general anesthetics on sodium transport in the isolated toad bladder. Anesthesiology 27, 304 (1966). - Synergistic effect of cyclopropane and epinephrine on sodium transport in toad bladder. Anesthesiology 28, 438 (1967). ANNAMUNTHODO, H., KEATING, V., PATRICK, S. J.: Liver glycogen alteration in anaesthesia and surgery. Anaesthesia 13, 429 (1958). APRAHAMIAN, H. A., VANDERVEEN, J. L., BUNKER, J. P., MURPHY, A. J., CRAWFORD, J. D.: The influence of general anesthetics on water and solute excretion in man. Ann. Surg. 100, 122 (1959).

Section 1..- Foreword and Commentary.- Section 2..- The Chemistry of Modern Inhalation Anesthetics.- I. Introduction.- II. Halothane.- A. Synthesis.- 1. ICI Process.- 2. Hoechst Process.- 3. Miscellaneous Processes.- 4. Synthesis of Optically Active Halothane.- 5. Synthesis of Isotopically Labeled Halothane.- B. Chemical Reactions of Halothane.- 1. Thermal Decomposition.- 2. Reactions with Metals.- 3. Reaction with Base.- 4. Photochemical Reactions.- 5. Halothane Azeotrope.- III. Methoxyflurane.- A. Synthesis.- B. Synthesis of Isotopically Labeled Methoxyflurane.- C. Chemical Reactions of Methoxyflurane.- 1. Thermal Decomposition.- 2. Reactions with Metals.- 3. Reaction with Bases.- 4. Reaction with Acids.- 5. Photochemical Reactions.- IV. Fluroxene.- A. Synthesis.- 1. Air Reduction Process.- 2. Miscellaneous Processes.- B. Chemical Reactions of Fluroxene.- Fluroxene Azeotropes.- V. Teflurane.- A. Synthesis.- B. Chemical Properties.- 1. Reaction with Base.- 2. Photochemical Stability.- VI. Roflurane.- VII. Flammability.- VIII. Foaming in Halogenated Anesthetics.- References.- Section 3.0 Clinical Monographs.- 3.1 Halothane.- I. Development of Halothane and Early Clinical Trials.- II. Physical and Chemical Properties of Halothane.- III. Methods of Assaying Halothane Concentration.- IV. Methods of Administration: Anesthetic Circuits and Vaporizers.- A. Anesthetic Circuits.- B. Vaporizers.- V. Uptake and Distribution of Halothane — Clinical Considerations.- VI. Anesthetic Requirement of Halothane.- VII. Effects on Physiological Systems.- A. Nervous System.- B. Cerebral Circulation and Metabolism.- C. Respiratory System.- D. Circulatory System.- E. Liver.- F. Other Systems.- VIII. Clinical Considerations.- A. Specific Applications.- B. Miscellaneous After-effects.- IX. Concluding Remarks.- References.- 3.2 Methoxyflurane and Teflurane.- I. Pre-Anesthetic Medication.- II. Techniques of Administration.- A. Open Drop Technique.- B. Semi-Closed System.- C. Closed System.- D. Non-Rebreathing System.- E. Penthrane Analgizer.- III. Other Drugs Used in Conjunction with Methoxyflurane.- IV. Methoxyflurane and Muscle Relaxants.- V. Induction Techniques.- VI. Types of Surgery Suitable for Methoxyflurane Anesthesia.- VII. The Use of Methoxyflurane for Obstetrical Analgesia and Anesthesia.- VIII. Contraindications and Precautions.- IX. Summary and Critique.- X. Teflurane.- XI. Chemical and Physical Properties.- XII. Pharmacology.- XIII. Miscellaneous Findings.- XIV. Clinical Use of Teflurane.- XV. Summary and Conclusions.- References.- 3.3. Fluroxene.- I. Flammability.- II. Azeotrope.- III. Methods of Estimation.- IV. Bio-transformation.- V. Cardiovascular Effects.- VI. Central Nervous System Effects.- VII. Respiratory Effects.- VIII. Gastro-intestinal, Hepatic, and Renal Effects.- IX. Clinical Considerations.- X. Applications.- XI. Conclusion.- References.- Section 4.0. Comparative Action on Vital Systems of Man.- 4.1. Central Nervous System.- A. Stages and Planes of Anesthesia.- B. Clinical Observations.- C. Anesthetic Agents.- 1. Ethers — Diethyl Ether (Ether).- 2. Halogenated Agents.- 3. Other Anesthetics.- Summary.- References.- 4.2. Autonomic Nervous System.- I. Introduction.- II. Afferent Nervous System.- 1. Baroreceptor Effects.- 2. Chemoreceptor Effects.- III. Central Nervous System.- IV. Peripheral Nervous System.- 1. Preganglionic Effects.- 2. Ganglionic Effects.- 3. Nerve Ending.- V. Effector Sites.- VI. Biochemistry.- VII. Concluding Remarks.- VIII. Summary.- References.- 4.3. Circulatory Effects of Modern Inhalation Anesthetic Agents.- I. Introduction.- A. Hemodynamics.- B. Regional Blood Flow.- C. Cardiac Arrhythmias.- D. Catecholamines.- E. Myocardial Function.- II. Halothane.- A. Hemodynamics.- 1. Cardiac Output.- a) Extra-Anesthetic Factors.- b) Adaptation.- c) Effects of Induction.- d) Oxygen Consumption.- e) Hemorrhage.- f) Halothane-Ether Azeotrope.- 2. Arterial Pressure.- a) Extra-Anesthetic Factors.- b) Adaptation.- c) Effects of Induction.- d) Halothane-Ether Azeotrope.- 3. Heart Rate.- a) Extra-Anesthetic Factors.- b) Adaptation.- c) Induction.- d) Mechanism.- e) Halothane-Ether Azeotrope.- 4. Stroke Volume.- a) Adaptation.- b) Induction.- 5. Total Peripheral Resistance.- 6. Central Venous Pressure.- B. Regional Blood Flow.- 1. Pulmonary Circulation.- 2. Coronary Blood Flow.- 3. Renal Circulation.- 4. Splanchnic Circulation.- 5. Cerebral Circulation.- 6. Peripheral (Limb) Circulation.- 7. Microcirculation.- C. Myocardial Function.- D. Arrhythmias.- 1. Incidence and Types.- 2. Hemodynamic Effect of Atrial Arrhythmias.- 3. Effect of CO2.- 4. Administration of Epinephrine.- 5. Injection of Other Cardiovascular-active Agents.- 6. Adrenergic Block.- 7. Mechanism of Arrhythmias.- E. Catecholamines.- 1. Plasma and Tissue Catecholamine Levels.- 2. Norepinephrine Release and Reuptake.- 3. Response to Catecholamines.- 4. Adrenergic Blockade.- F. Blood Volume.- G. Blood Viscosity.- III. Methoxyflurane.- A. Hemodynamics.- 1. Cardiac Output.- 2. Arterial Pressure.- a) Extra-Anesthetic Factors.- 3. Heart Rate.- a) Extra-Anesthetic Factors.- 4. Stroke Volume.- 5. Total Peripheral Resistance.- 6. Central Venous (Right Atrial) Pressure.- B. Regional Circulation.- 1. Pulmonary Circulation.- 2. Coronary Blood Flow.- 3. Renal Blood Flow.- 4. Peripheral (Limb) Flow.- 5. Microcirculation.- C. Myocardial Function.- D. Arrhythmias.- 1. Incidence and Types.- 2. Effect of Increased C02.- 3. Administration of Epinephrine and Other Agents.- E. Catecholamines.- 1. Plasma Levels.- 2. Response to Norepinephrine; Disposition of Norepinephrine.- 3. Response to Adrenergic Blockade.- F. Miscellaneous Effects.- IV. Fluroxene.- A. Hemodynamics.- B. Regional Circulation.- C. Myocardial Function.- D. Arrhythmias.- V. Teflurane.- A. Hemodynamics.- B. Arrhythmias.- VI. Halopropane.- A. Hemodynamics.- B. Arrhythmias.- C. Catecholamines.- D. Miscellaneous Effects.- VII. Nitrous Oxide.- A. Hemodynamics.- B. Regional Circulation.- C. Catecholamines.- D. Myocardial Contractility.- VIII. Miscellaneous Agents.- References.- 4.4. Liver. C. Trey (see page 502).- 4.5. General Anesthesia and the Kidney.- Indirect Circulatory Effects.- Sympathetic Nervous System.- Endocrine System.- Direct Effects of Anesthetics on Renal Function.- Summary of Anesthetic Effects on Renal Function.- Nephrotoxicity.- Summary.- References.- 4.6. Respiratory System.- I. Physiologic Changes During Anesthesia.- II. Depth of Anesthesia.- III. Resting Ventilation.- IV. Ventilatory Response.- V. Other Drugs.- VI. Surgical Stimulation.- VII. Recovery.- Summary.- References.- 4.7. Metabolic Effects of Anesthetics.- I. Direct Effects.- II. Indirect Effects.- III. In Vivo Changes.- Summary.- References.- 4.8. Endocrine System.- Summary.- References.- 4.9. The Action of Inhalation Anesthetics on the Gastrointestinal Tract.- I. Introduction.- A. Potential Spectrum of Gastrointestinal Activity.- II. Esophagus.- A. Physiology.- 1. Pharyngoesophageal Sphincter.- 2. Esophagus.- 3. Gastroesophageal Sphincter.- B. Pathophysiology.- 1. Nausea, Retching and Emesis.- 2. Regurgitation.- 3. Eructation.- 4. Clinical Considerations.- C. Pharmacology.- D. Special Clinical Considerations.- III. Gastric Emptying.- A. Physiology.- B. Pharmacology.- IV. Secretion.- A. Salivary Secretion.- B. Gastric Secretion.- V. Absorption.- VI. Motility.- A. Physiology.- B. Preanesthetic Medication.- C. Pharmacology.- 1. Gastric and Intestinal Contractile Activity.- 2. Gastrointestinal Transit.- VII. Gas.- Summary.- References.- Section 5.0. Absorption, Distribution and Excretion.- 5.1. Kinetics.- A. A Simple Analogue.- B. Quantitation of the Analogue.- C. Comparison with Experiment.- D. The General Pattern of Distribution.- E. The Effects of Different Inspired Tensions.- F. The Effects of Different Solubilities.- G. The Approach to Equilibrium for Specific Agents.- H. The Use of “Overpressure”.- J. The Effects of Changes of Ventilation and Circulation.- K. Elimination during Recovery.- L. The Effects of Processes not Represented by the Simple Analogue.- References.- 5.2. Biotransformation.- I. Introduction.- II. Chloroform.- III. Diethyl Ether.- IV. Halothane.- V. Methoxyflurane.- VI. Trichloroethylene.- VII. Fluroxene.- VIII. Other Anesthetics.- IX. Enzyme Systems.- X. Implications of Metabolism.- References.- Section 6.0. Mechanism of Anesthesia.- 6.1. Molecular Aspects.- References.- 6.2. Neurophysiological Aspects.- I. Experimental Work on the Cat.- A. Halothane.- 1. The EEG Recording.- 2. The Arousal Response.- 3. Evoked Potentials.- a) Along the Specific Primary Pathways.- b) Along the Non-specific Pathways.- 4. Effect of Halothane on the Recruiting Response.- 5. After-discharges.- 6. Effect of Halothane on the Metrazol (Pentylene Tetrazol) Threshold.- 7. Reactions to Dental Stimulation.- B. Methoxyflurane.- 1. The EEG Recording.- 2. Reticular Arousal Response.- 3. Evoked Potentials.- a) Changes in the Evoked Potentials along the Specific Primary Pathway under the Effect of this Drug are seen as.- b) Non-specific Pathways.- 4. Effect of Methoxyflurane on the Recruiting Response.- 5. Effects on the After-discharges and the Metrazol (Pentylene Tetrazol) Threshold.- 6. Responses to Dental Stimulation.- II. Primate Investigations.- A. Halothane.- a) Before the Drug.- b) Effects of Inhaling 0.5% Halothane.- c) Effects of 1% Halothane.- d) Effects of 2% Halothane.- e) After Stopping Inhalation of Halothane.- B. Methoxyflurane.- a) Before Anesthesia.- b) Inhalation of 0.25% of Methoxyflurane.- c) Inhalation of 0.5% Methoxyflurane.- Conclusions.- References.- 6.3. Effects of Anesthetics on Metabolism of Brain.- I. Introduction.- II. Oxygen and Oxidations.- A. Physiological Considerations.- B. Anesthesia.- C. Non-Volatile Anesthetics.- D. Volatile Anesthetics.- E. In Vitro Studies.- III. Glucose.- A. Glucose Uptake during Narcosis.- B. Brain Level of Glucose.- C. Glycogen Levels.- D. Effects on Glucose Metabolism in Sympathetic Ganglia and Perfused Brain.- IV. High Energy Phosphates.- V. Amino Acid and Protein Metabolism.- VI. Phospholipids.- VII. Acetylcholine.- A. Surface Release.- B. Brain Content.- C. Enzyme-Related Studies.- References.- Section 7..- Exploratory and Newer Compounds.- I. Aim.- II. History.- 1. Chemical Structure.- 2. Purity.- 3. Flammability.- 4. Chemical Inertness.- Chronological List of Some Key References in the Development of Fluorinated Anesthetics.- Patent List of Fluorinated Anesthetics.- References.- Section 8..- Comparative Aspects of Anesthesia in Animals.- I. Inhalation Anesthetics.- II. Tracheal Intubation.- III. Complications and Species Differences of Tracheal Intubation.- IV. Systems for Veterinary Anesthesia.- V. Intravenous Anesthetic Agents.- VI. Non-Barbiturate Injectable Drugs.- Urethan.- VII. Preanesthetic Medication and Drugs for Restraint.- A. Narcotic-Analgesics.- B. Neuroleptanalgesia.- C. Atropine Sulfate.- D. Tranquilizers.- E. Cyclohexamines (Dissociogenic Agents).- F. Rompun.- References.- Section 9..- Toxicity of Impurities.- I. Hydrocarbons.- II. Ethers.- III. Halogenated Compounds.- IV. Nitrous Oxide.- References.- Section 10.0.- Interaction of Drugs.- I. Chemical Reactions.- II. Transport Phenomena.- III. Interaction at Receptor Site.- IV. Interaction at Several Sites.- V. Altered Drug Metabolism.- VI. Effects of Temperature.- VII. Patient Factors Affecting Drug Action.- References.- 4.4. The Liver.- I. Clinical and Biochemical Assessment of Liver Function.- II. The Diagnostic Approach to Liver Disease.- III. Systemic Effects of Liver Failure.- IV. The Treatment of Patients with Fulminant Hepatic Failure before and during Anesthesia.- V. Post-Operative Acute Hepatic Failure.- VI. Toxic and Drug Injuries to the Liver.- VII. Viral Hepatitis.- VIII. Chronic Hepatitis.- IX. Alcoholic-Associated Liver Disease.- X. Anesthesia for Patients with Liver Disease.- References.- Author Index.