Antihypertensive Agents: Handbook of Experimental Pharmacology, cartea 39

1 Antihypertensive Drugs.- I. Introduction.- II. Requirements for an Antihypertensive Agent.- III. Combinations of Antihypertensive Drugs.- IV. Trends in Antihypertensive Therapy.- V. National Preferences of Treatment Schemes.- VI. Experimental Hypertension.- References.- 2 The Chemistry of Antihypertensive Agents.- I. Early Antihypertensives.- II. Adrenergic Neuronal Blockers: Guanethidine and Similar Compounds.- A. SU 4029 and Guanethidine.- B. Modification of the Guanethidine Structure.- III. Rauwolfia Alkaloids.- IV. Ganglionic Blockers.- V. Clonidine, ST 155, 2-(2, 6-dichlorophenylamino)-2-imidazoline and Analogs.- VI. The Chemistry of the Veratrum Alkaloids.- VII. Compounds Acting Directly on Vascular Smooth Muscles.- VIII. The ?-Adrenolytics (?-Adrenergic Receptor Blocking Agents).- IX. Fusaric Acid.- References.- 3 Ganglion-Blocking Drugs in Antihypertensive Therapy.- I. Introduction.- II. Characteristics of Individual Drugs, Generic, and Brand Names, Routes of Administration, and Dosages.- A. General Remarks.- B. Quaternary Ganglionic Blockers.- C. Nonquaternary Ganglionic Blockers.- III. Pharmacokinetics.- A. Methonium Compounds.- B. Mecamylamine and Pempidine.- C. Other Drugs.- IV. Mode of Action.- A. Principles of Ganglionic Transmission.- B. Drug-Induced Ganglionic Blockade.- C. Nonselective Interference with Sympathetic and Parasympathetic Transmission.- D. Effects on the Cardiovascular System.- E. Tolerance to Antihypertensive Activity.- F. Pharmacologic Effects Unrelated to Ganglionic Blockade.- V. Side-Effects.- A. General Remarks.- B. Side-Effects Due to Blockade of the Autonomic Nervous System.- C. Side-Effects Unrelated to Ganglionic Blockade.- VI. Present Role of Ganglion-Blocking Drugs.- References.- 4 The Pharmacology of Rauwolfia Alkaloids.- I.Introduction and History.- II. Absorption, Metabolism, and Distribution of Reserpine.- III. Effects of Reserpine on Levels of Catecholamines and Serotonin in Tissues.- A. Sympathetically Innervated Tissues.- B. Tissue Chromaffin Cells.- C. Adrenal Medullary Amines.- D. Peripheral Serotonin.- E. Central Nervous System.- IV. Effects of Reserpine on Uptake, Storage, Synthesis and Catabolism of Catecholamines and Serotonin.- A. Effect of Reserpine on Uptake of Amines.- B. Effect of Reserpine on Amine Storage Mechanisms.- C. Effect of Reserpine on Retention of Amines by Isolated Storage Particles.- D. Effect of Reserpine on the Synthesis of Catecholamines and Serotonin.- E. Effect of Reserpine on Catabolism of Catecholamines and Serotonin.- F. Recovery of Amine Stores After Reserpine Treatment.- V. Effect of Reserpine on Other Neurotransmitters and Auracoids.- A. Acetylcholine.- B. Histamine.- C. Tryptamine.- VI. Effects of Reserpine on Function of Peripheral Tissues.- A. Effect of Reserpine on Adrenergic Mechanisms.- B. Effects of Reserpine on Cardiac and Smooth Muscle Function.- C. Reserpine-Induced Supersensitivity.- VII. Effects of Reserpine on Central Nervous Function.- A. The Sedative and Tranquillizing Activity of Reserpine.- B. Extrapyramidal Effects of Reserpine.- C. Effect of Reserpine on Body Temperature.- D. Electrical Activity of the Brain.- E. Effects of Reserpine on Reflexes and Centrally Maintained Autonomic Nervous Tone.- F. Recovery from the Central Actions of Reserpine.- G. Interaction Between Reserpine and Other Centrally Acting Drugs.- VIII. Endocrinological, Metabolic and Structural Effects of Reserpine.- A. Effects of Reserpine on Endocrine Systems.- B. Electrolyte Metabolism.- C. Tissue Metabolism.- D. Structural Effects.- References.- 5 Adrenergic Neuron Blocking Drugs.- I. Introduction to Adrenergic Neuron Blocking Agents.- A. General Pharmacology.- B. History of Development.- C. Therapeutic Use in Hypertension.- II. Distribution of Neurin Blocking Agents in Tissues Following Their Administration to Animals and Man.- III. Interactions of Neuron Blocking Agents with Adrenergic Neurons.- A. Retention by Adrenergic Neurons.- B. Mechanism of Uptake into Adrenergic Neurons.- C. Storage in Adrenergic Neurons.- D. Release from Adrenergic Neurons.- IV. Interactions of Neuron Blocking Agents with Norepinephrine in Adrenergic Neurons.- A. Capacity to Release Norepinephrine from Nerve Endings and Simultaneously to Inhibit the Release of Norepinephrine Elicited by Sympathetic Neuronal Activity.- B. Effect on the Norepinephrine Content of Adrenergically Innervated Organs and the Adrenal Medulla.- C. Effects on Synthesis and Degradation of Norepinephrine in Adrenergic Neurons.- D. Effect on the Uptake of Norepinephrine into Adrenergic Nerves, Storage of Norepinephrine in and Release from Intraneuronal Granules, and Disappearance of Norepinephrine from Adrenergic Nerves.- V. Hypotheses Regarding the Mechanism of Neuron Blockade.- A. Subcellular Pool Depletion Hypothesis.- B. Membrane Depolarizing and Stabilizing Hypotheses and Local Anesthetic Action.- C. Cholinergic Link Hypothesis and the Possible Role of Ca-Ion.- D. Amphetamine Receptor Site Hypothesis.- E. MAO Inhibition Hypothesis.- F. False Transmitter Hypothesis.- VI. Absorption, Metabolism and Excretion of Neuron Blocking Agents.- A. Guanethidine.- B. Bretylium.- C. Bethanidine.- D. Debrisoquin.- E. Guanoxan.- VII. Actions of Adrenergic Neuron Blocking Agents in Tissues and Organs.- A. General Sympathomimetic Action.- B. General Potentiation of the Responses to Norepinephrine and Closely Related Pressor Amines and Inhibition of Tyramine and Other Indirectly-Acting Phenethylamines.- C. Vascular Smooth Muscle.- D. Cardiac Muscle.- E. Neuromuscular Junction.- F. Influence on Frequency-Response Curves for Several Nerve-Smooth Muscle Preparations.- G. Actions on Excitable Membranes of Nerve Trunks.- H. Effects at Synapses.- I. Central Nervous System.- J. Additional Biochemical Effects.- K. Structural and Ultrastructural Changes in Neurons.- L. Effects on the Interaction Between Sympathetic and Parasympathetic Nervous Systems.- M. Effects on Degeneration Phenomena Following Section of Post Ganglionic Sympathetic Nerves.- N. Effects on Plasma Volume and Kidney Function.- O. Mast Cells and Platelets.- P. Effects on Extraneuronal Uptake of Norepinephrine.- VIII. The Amine Pump in Peripheral Adrenergic Nerves.- A. Some Problems Discussed.- B. The “Amine Pump Receptor”.- IX. Authors’ Perspective.- References.- 6 False Transmitters as Antihypertensive Agents.- I. Catecholamine Metabolism.- A. Ring Hydroxylation.- B. Decarboxylation: Dopa Decarboxylase.- C. Aliphatic Side-Chain Hydroxylation: Dopamine-?-Hydroxylase.- D. N-Methylation: Phenethanolamine-N-Methyl Transferase.- E. Amine Oxidation: Monoamine Oxidase.- F. m-O-Methylation: Catechol-O-Methyltransferase.- II. Catecholamine Storage and Release.- III. Uptake of Amines Through the Cell Membrane.- IV. False Transmitters and Sympathetic Transmission.- V. False Transmitters and Blood Pressure.- A. Methyldopa.- B. Dopa and m-Tyrosine.- C. ?-Methyl-m-Tyrosine.- References.- 7 The Pharmacology of Clonidine and Related Products.- I. Introduction.- II. Chemistry.- III. Principal Pharmacological Properties.- IV. Effects on the Sympathetic System.- A. ?-Sympathomimetic Effect.- B. Effects onCatecholamines.- C. Influence on Noradrenaline Levels and Metabolism at Peripheral Sites.- D. Effects on Postganglionic Sympathetic Fibers.- E. Centrally Mediated Decrease in Sympathetic Tone as the Cause of Hypotension.- F. Sites of Action in the Central Nervous System.- G. Effects of Clonidine on Centrally Mediated Increases in Sympathetic Tone.- H. Effects of Clonidine on Centrally Mediated Depressor Responses.- J. Effects of Clonidine on Cardiovascular Reflexes.- K. Evidence for Activation of a Central ?-Sympathomimetic Mechanism as the Cause of the Sympatho-Inhibitory Effect of Clonidine.- L. Discrepancies Between the Decrease in Blood Pressure and the Reduction in Sympathetic Nerve Activity.- M. Interferences Between Clonidine, Neuroleptic and Antidepressant Agents.- V. Effects on the Parasympathetic System.- A. Increase in Vagal Tone.- B. Effects on the Action of Acetylcholine and Vagal Stimulation.- C. Effects on Parasympathetic Postganglionic Fibers.- D. Interactions with Cholinolytic and Cholinergic Agents.- VI. Effects on Angiotensin and Plasma Renin Activity.- VII. Effects on 5-Hydroxytryptamine and Histamine.- VIII. Clonidine and Cyclic Adenosine 3,5-Monophosphate Formation.- IX. Baroreceptor Mechanisms.- X. Hemodynamic Effects.- A. Bradycardia.- B. Cardiac Output.- C. Stroke Volume.- D. Ventricular Volumes.- E. Atrial and Left Ventricular End-Diastolic Pressures.- F. Blood Volume.- G. Heart work.- H. Myocardial Performance.- J. Total Peripheral Resistance.- K. Pulmonary Circulation.- L. Coronary Circulation.- M. Cerebral Circulation.- N. Renal Blood Flow.- O. Splanchnic Blood Flow.- P. Gastric Blood Flow.- Q. Bone-Marrow Blood Flow.- R. Peripheral Circulation.- S. Changes in Vascular Reactivity.- T. ECG.- XI. Effects on Respiration.- XII. Effects onGastro-Intestinal Tract.- XIII. Effects on Secretions.- XIV. Effects on the Kidney.- XV. Effects on the Eyes.- XVI. Sedative Effects.- XVII. Antinociceptive Action.- XVIII. Water Intake.- XIX. Food Intake.- XX. Hypothermic Effect.- XXI. Glycemia.- XXII. Spinal Reflexes.- XXIII. Neuro-Endocrine Effects.- XXIV. Aggressivity.- XXV. Actions on Neurons in the Central Nervous System.- XXVI. Effects of Clonidine on Excitation and Excitation-Contraction Coupling.- XXVII. Influence on Monoamine Metabolism in The Brain.- XXVIII. Metabolism.- XXIX. Related Compounds.- XXX. Conclusion.- References.- 8 Drugs Acting on Arteriolar Smooth Muscle (Vasodilator Drugs).- I. Introduction.- II. Hydralazines.- A. Pharmacodynamics.- B. Pharmacokinetics.- C. Some Hydralazine Derivatives.- III. Nitroprusside.- A. Pharmacodynamics.- B. Pharmacokinetics.- C. Therapeutic Use.- IV. Diazoxide.- A. Pharmacodynamics.- B. Pharmacokinetic Studies.- C. Therapeutic Use.- D. Adverse Reactions.- E. Combination With Other Drugs.- V. Minoxidil.- A. Pharmacodynamics.- B. Pharmacokinetics.- C. Therapeutic Use.- D. Adverse Reactions.- VI. Guancydine.- A. Pharmacodynamics.- B. Pharmacokinetics.- C. Therapeutic Use.- D. Adverse Reactions.- VII. Prazosin.- A. Pharmacodynamics.- B. Pharmacokinetics.- C. Therapeutic Use.- D. Adverse Reactions.- References.- 9 Antihypertensive Effect of Diuretics.- I. Introduction.- II. Acute Haemodynamic Response to Diuretics (1–7 days).- III. Chronic Haemodynamic Response.- IV. Characteristics of the Hypotensive Response.- V. Interaction Between Diuretics and Other Antihypertensive Drugs.- VI. Mode of Antihypertensive Action.- VII. An Abnormality of Sodium Regulation in Hypertension?.- VIII. Summary and Conclusions.- References.- 10 The Pathophysiology of Adrenal Inhibitors withRespect to their Antihypertensive Activity.- I. Introduction.- II. Adrenocortical-Related Hypertension (Mineralocorticoid Hypertensive Syndromes).- A. Hyperaldosteronism.- B. Excessive DOC Secretion.- C. 18=OH=DOC Hypersecretion.- D. Concurrent Hypersecretion of DOC and 18=OH=DOC.- E. The Problem of Hyporeninemic Hypertension (Low-Renin Essential Hypertension) — Mineralocorticoid Syndrome.- III. Inhibitors of Steroid Secretion.- A. In vitro Studies.- B. Metyrapone (Metopirone) (Fig. 7).- C. Aminoglutethimide (Elipten) — A—G (Fig. 8).- IV. Inhibitors of Corticosteroid Secretion of Potential Interest in Hypertension.- A. o, d’-DDD (Fig. 11).- B. Heparinoids.- C. GPA-2282 (Fig. 12).- D. SU-9055 and Related Compounds.- E. SKF-12185 2(p-aminophenyl)-2-phenylethylamine (SKF-12185) (Fig. 14).- F. Monamine Oxidase Inhibitors.- V. Competitive Inhibitors of Mineralocorticoids.- VI. Reserpine and Pharmacologically Related Drugs.- VII. Concluding Remarks.- References.- 11 Interference with the Renin-Angiotensin System and Their Effects on High Blood Pressure.- I. Components of the RAS.- A. Renin (EC 3.4.99.19).- B. Angiotensinogen (Renin Substrate).- C. Angiotensin-I-Converting Enzyme (CE) (E.C.3.4.15.1).- D. Structure of AII.- E. Angiotensinases.- II. Pathophysiological Significance of the RAS.- A. Experimental Hypertension in Animals.- B. Hypertension in Man.- III. Interference with the RAS.- A. The Renin-Substrate Reaction.- B. Immunological Interferences.- C. Inhibitors of Angiotensin-I-Converting Enzyme (CEI).- D. AII Antagonists at the Receptor Site.- E. Conclusions and Outlook.- References.- 12 Veratrum Alkaloids with Antihypertensive Activity.- I. Introduction.- II. Botanical Origin and Chemistry.- III. Pharmacological Actions of Small Doses of the HypotensiveCeveratrum Alkaloids.- A. Circulation.- B. Respiration.- C. Emetic Action.- IV. Therapeutic Use.- A. Circulatory Action.- B. Action on Renal Function.- C. Side Effects and Toxic Actions.- D. Indications.- V. Summary.- References.- 13 The Clinical Pharmacology of Antihypertensive Drugs.- I. Introduction.- II. The Guanidinium Adrenergic Neuron Blocking Drugs.- A. The Fate of these Drugs in Relation to their Use in Therapy.- B. The Effects of Guanethidine on Sympathetic Reflexes and Cardiovascular Control in Man.- C. The Spectrum of Clinical Effects.- III. Methyldopa.- A. Introduction.- B. Pharmacokinetics.- C. Mechanism of Action.- D. Hemodynamic and Renal Effects.- E. Relative Efficacy.- F. Side-Effects and Toxicity.- IV. Clonidine.- A. Pharmacokinetics.- B. Mechanism of Action.- C. Hemodynamic Effects in Man.- D. Renin Release and Catechol Amines.- E. Relative Efficacy.- F. Summary.- V. Beta-Adrenoreceptor Blocking Drugs.- A. Introduction.- B. Pharmacokinetics and Metabolism.- C. Relationship of Plasma Concentration to Effect.- D. Efficacy in Hypertension.- E. Combinations with Vasodilators and Other Drugs.- F. Adverse Effects.- G. Hemodynamic Effects and Mechanism of Action.- VI. The Direkt Peripheral Vasodilators.- VII. Diuretic Drugs.- A. Hypertension Associated with Low Plasma Renin Activity.- B. Role of Plasma Volume in Determining the Blood Pressure of Patients Receiving Inhibitors of Sympathetic Reflexes.- References.- 14 Table of Antihypertensive Drugs.- Author Index.