Antihypertensive Agents

ISBN-13: 9783642663116 / Angielski / Miękka / 2011 / 779 str.

M. E. Conolly;J. Conway;D. Garrlen

Opis

Between 1950 and 1960, remarkable advances were made in the develQpment Qf antihypertensive drugs, but since then, prQgress has been less rapid. This dQes nQt mean that no. new drugs have been intrQduced: Qn the cQntrary, their number has increased sharply; but since the advent Qf the beta-adrenergic blQckers no. new pharmacQdynamic principle has been discQvered that CQuid be applied widely as an antihypertensive. This has nQt been fQr want Qf effQrts, because many attempts have been made to. find new ways and means Qf influencing blQQd- pressure regulatiQn Qr the mechanisms invQlved in the pathQgenesis Qf hypertensiQn. HQwever, the results Qf these endeavQrs have mQstly been disapPQinting. Even thQugh high blQQd pressure can be treated mQre satisfactQrily tQday than many Qther diseases, the success achieved in cQmbating Qne Qf man's mQst frequent ailments shQuld nQt induce cQmplacency, but rather stimulate research tQwards further imprQvements. The present standstill affQrds an QPPQrtunity to. review the field Qf antihy- pertensive agents, fQr it is unlikely that fundamentally new drugs will appear in the near future. AlthQugh greater knQwledge has been gained Qf the mechanisms Qf blQQd-pressure regulatiQn and Qf the pathQgenesis Qf hypertensiQn, these ad- vances have had no. direct cQnsequences in the search fQr new therapeutics.

Spis treści

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 on Catecholamines.- 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 on Gastro-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 with Respect 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 Hypotensive Ceveratrum 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.