Organic nitrates
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Organic nitrates
（Handbuch der experimentellen Pharmakologie. Heffter-Heubner, 40）
Springer-Verlag, 1975
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Includes bibliographies and indexes
内容説明・目次
内容説明
Nitroglycerin and other organic nitrates have been used for over a century in the treatment of angina pectoris. Millions of patients, throughout the world, have placed nitroglycerin tablets under the tongue and have experienced rapid and dramatic relief from the chest pain that frequently occurs as a manifestation of disease of the coronary arteries. The empirical observation of the safe use of nitrates for tile alleviation of the symptoms of angina have led to their widespread medical acceptance. The use of organic nitrates preceded any knowledge of their mechanism of action or their ultimate metabolic fate. Thus, more simply stated, although sub- lingual nitrates helped the patients, little was known concerning what these drugs do to the body or what the body does to the drugs. A substantial number of investigators have focused on these questions especially during the last two decades. We now have considerably more insight into the pathways of degradation of organic nitrates and the relationship of the metabolic processes to the biological action of these agents.
Similarly, considerable effort has been expended in understanding the mechanism of action of these agents directly on vascular smooth muscle and on cardiac work and performance. Finally, there is a more substantive understanding of the physiology of the coronary circulation as well as the" pathophysiologic manifestations of myocardial disease.
目次
1 Historical Background.- I. Nitrogen and Its Compounds.- II. Biological Occurrence of Nitrites and Nitrates.- III. The Synthesis of Nitrite and Nitrate Esters.- IV. Discovery of Amyl Nitrite.- V. T. Lauder Brunton, England's Leading Therapist.- VI. SirLauder Brunton and Amyl Nitrite.- VII. The Discovery of Nitroglycerin.- VIII. Early Studies on Nitroglycerin in America.- IX. Nitroglycerin or Glonoin.- X. Nitroglycerin in England.- XI. William Murrell.- XII. Amyl Nitrite and Nitroglycerin in Angina Pectoris.- XIII. Organic and Inorganic Nitrites and Nitrates.- XIV. The Influence of Oil Solubility on Nitrate Ester Response.- XV. Nitrites and Nitrates in Hypertension.- XVI. Extending the Duration of Action of Nitroglycerin.- XVII. Summary.- References.- 2 Chemistry of Organic Nitrates.- I. General Properties.- A. Structure.- B. Physical State.- C. Water Solubility.- D. Spectral Characteristics.- II. Methods of Laboratory Synthesis.- A. Mixed Acid Synthesis.- B. Preparation of Incompletely Nitrated Polyols.- 1. Partial Nitration or Denitration.- 2. Reaction of Alkyl Halides and Silver Nitrate.- III. Chemical Properties.- A. Acid and Base Hydrolysis of Nitric Acid Esters.- B. Reductive Hydrolysis.- C. Acid Decomposition.- D. Explosiveness.- IV. Cautions in Handling.- A. Storage.- B. Isolation.- C. Disposal.- D. Handling of Solutions.- References.- 3 Organic Nitrates: Analytical Techniques.- I. Extraction Procedures.- A. Glyceryl Nitrates.- B. Isosorbide Nitrates.- C. Pentaerythritol Nitrates.- II. Spectrometric Methods.- A. Visible Spectrophotometry.- B. Spectrometric Techniques Outside the Visible Range.- III. Chromatographic Procedures.- A. Column Chromatography.- B. Paper Chromatography.- C. Thin Layer Chromatography.- 1. Glyceryl Nitrates.- 2. Isosorbide Nitrates.- 3. Pentaerythritol Nitrates.- 4. Visualization.- 5. Quantitation.- D. Gas Liquid Chromatography (GLC).- IV. Use of Labeled Products.- References.- 4 Pharmacological Properties.- I. Action on Vasculature.- In Vivo Test System.- II. Cardiovascular Systems.- III. Pulmonary Circulation.- IV. Metabolism of Cardiac Muscle.- V. Actions of Other Smooth Muscles.- VI. Significance of Normal Blood Levels of the Nitrate and Nitrite Ions.- VII. Plasma Levels of Nitrates.- References.- 5 Biotransformation of Organic Nitrates.- I. Isolation and Characterization of Organic Nitrate Reductase.- A. Initial Demonstrations of the Degradation of Organic Nitrate.- B. Role of Liver and Glutathione in the Transformation of Organic Nitrates.- C. Subcellular Localization of Hepatic Glutathione-Organic Nitrate Reductase.- D. Purification and Kinetic Properties of Hepatic Organic Nitrate Reductase.- E. Substrates for Organic Nitrate Reductase.- F. Induction and Inhibition of Organic Nitrate Reductase.- G. Degradation of Organic Nitrates by Plasma.- H. Comparison of Glutathione-Organic Nitrate Reductase to Other Enzymes with Similar Properties.- II. Isolation and Characterization of Organic Nitrate Metabolites.- A. Metabolic Pathway in the Degradation of Glyceryl Trinitrate, Isosorbide Dinitrate, Mannitol Hexanitrate, and Erythrityl Tetra-nitrate.- 1. Metabolism by Liver Homogenates.- 2. Liver Perfusion Experiments.- 3. Absorption and Distribution of GTN.- 4. Plasma Levels, Binding, and Metabolism of GTN.- 5. Conversion of 14C-Glyceryl Trinitrate to 14C-CO2.- 6. Blood Clearance of GTN, Isosorbide Dinitrate, and Mannitol Hexanitrate, from Intact Animals.- 7. Urinary Excretion.- B. Metabolic Pathway in the Degradation of Pentaerythritol-Tetranitrate and Trinitrate.- 1. Absorption, Distribution, and Excretion of Pentaerythritol Tetranitrate (PETN).- 2. Absorption, Distribution, and Excretion of PE-Trinitrate.- C. Degradation of Other Organic Nitrate Esters.- 1. Ethylene Glycol Dinitrate (EGDN).- 2. Propylene Glycol 1,2-Dinitrate (PGDN).- 3. l-Chloro-2,3-Propanediol Dinitrate (CPD).- III. Relationship between Organic Nitrate Metabolism and Biological Activity.- A. Temporal Relationship between Plasma Levels of the Parent Compound and its Metabolites and Biological Activity.- 1. Vasodilatation After Portal and Jugular Vein Injections.- 2. Blood Clearance and Biological Effectiveness.- 3. Plasma Levels After Oral Administration.- B. Biological Activity of Metabolites.- 1. Glyceryl Trinitrate.- 2. Isosorbide Dinitrate.- 3. Pentaerythritol Trinitrate.- IV. Summary and Conclusions.- References.- 6 The Pharmacological and Biochemical Interaction of Organic Nitrates with Sulfhydryls: Possible Correlations with the Mechanism for Tolerance Development, Vasodilation, and Mitochondrial and Enzyme Reactions.- I. Sulfhydryl Reactivity of Organic Nitrates - Introduction.- II. Organic Nitrate-Tolerance.- A. Induction of Tolerance.- 1. In Intact Animals and Man.- 2. Nitrate-Tolerance at the Level of the Blood Vessel.- B. Biotransformation of Organic Nitrate during Induction and Maintenance of Nitrate Tolerance.- C. Dissociation of Sympathetic Compensation from Tolerance to Glyceryl Trinitrate.- D. Mechanism of the Development of Tolerance to Organic Nitrates.- 1. Induction of Tolerance in vitro.- 2. Cross-Tolerance.- 3. Effect of pH on the Interaction between Glyceryl Trinitrate and Tissue Sulfhydryl Groups.- 4. Reversal of Tolerance to Glyceryl Trinitrate.- 5. Working Hypothesis.- III. Sulfhydryl Requirement for Relaxation of Vascular Smooth Muscle.- A. The Effect of Ethacrynic Acid on Vascular Effects of GTN and Other Vasodilators.- B. Vasodilator Potency and Sulfhydryl Reactivity.- C. Working Hypothesis.- IV. Biochemical Actions of Organic Nitrates.- A. Effect of Organic Nitrates on Electron Transport and Phosphorylation in Mitochondria (Sulfhydryl-Rich Organelle).- B. Monoamine Oxidase (MAO) Inhibition by Organic Nitrates.- C. Glyceraldehyde-3-Phosphate Dehydrogenase.- D. Plasma Sulfhydryl Denitration of Organic Nitrates.- E. Hemoglobin and GSH Oxidation by Nitrite.- F. Effect of Organic Nitrates on Adenyl Cyclase.- References.- 7 Physiology and Pathophysiology of the Coronary Circulation and the Role of Nitroglycerin.- I. Normal Physiology.- A. Myocardial Oxygen Supply and Demand.- B. Adrenergic Innervation of the Coronary Arteries.- C. Reactive Hyperemia.- II. Pathophysiology of Ischemic Heart Disease.- Coronary Occlusion.- III. Action of Nitroglycerin in Relieving Myocardial Ischemia.- IV. Use of Nitroglycerin in Myocardial Infarction.- References.- 8 Mechanism of Action of Nitroglycerin: Coronary, Cardiac, and Systemic Effects.- I. Introduction.- II. Action on the Coronary Circulation.- A. Normal Circulation.- 1. Time Course of Action.- 2. Effects of Anesthesia.- 3. Reflex Effects.- 4. Dose Response and Route of Administration.- 5. Summary of Coronary Effects in the Normal Heart.- B. Effects on the Ischemic Heart.- C. Regional and Collateral Coronary Effects.- 1. Effects of Nitroglycerin on Large and Small Coronary Vessels.- 2. Effects of Nitroglycerin on Collateral Vessels.- 3. Effects of Nitroglycerin on Regional Myocardial Blood Flow.- III. Systemic and Cardiac Effects.- A. Systemic Effects.- B. Cardiac Effects.- C. Inotropic Effects.- D. Chronotropic Effects.- IV. Effects of Nitroglycerin on the Ischemic Myocardium.- V. Summary.- References.- 9 Use of Nitrates as Antianginal Agents.- I. Mechanism of Action of Sublingual Nitrates.- A. Effect on Coronary Blood Flow.- B. Effect on Myocardial Oxygen Demand.- II. Sublingual Nitroglycerin as an Antianginal Drug.- A. Therapy of Anginal Attacks.- B. Prophylactic Use.- C. Comparison with Other Sublingual Nitrates.- D. Adverse Effects.- III. Long-Acting Nitrates.- A. Ineffectiveness.- B. Tolerance.- References.- Author Index.
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