Amlodipine

ISBN-13: 9783540566984 / Angielski / Miękka / 1993 / 277 str.

Winifred G. Nayler

Opis

"Those who choose to increase their knowledge still further by reading ... will discover an exciting new world. " NOEL WHITTAKER, in "Making Money Made Simple" 1989. The development of calcium antagonists has recently been described as representing "one of the major advances in cardiovascular thera peutics of the latter half of the twentieth century" (Braunwald, 1990). However, although the development of these drugs started in the mid nineteen sixties it is only recently that their real potential has begun to be appreciated. Even now the calcium antagonist saga is not complete, since new compounds continue to appear and new therapeutic applica tions emerge. Based on the experience gained in the clinics in which these drugs have been used recognition is being given now to the need to improve upon the prototypes of the group. Such improvement is resulting in the development and production not only of long-acting formulations of the prototypes (nifedipine, verapamil and diltiazem) but also of new calcium antagonists with improved tissue selectivity, potency and duration of action. To those of us who are interested in this field such a development is both exciting and rewarding. As far as the clinicians who prescribe these drugs are concerned the long-acting nature of some of the newer calcium antagonists should make the satisfactory management of their patients an achievable goal."

Spis treści

1. The Calcium Antagonists: Are Different Drugs Needed?.- The Need for Tissue Selectivity.- Potency.- Duration of Action.- Plasma Biochemical Profile.- Ancillary Properties.- Side-Effect Profile.- In Summary.- 2. Calcium and Its Relevance to Biological Systems.- The Measurement of Intracellular Free (Ionized) Ca2+.- The Range of Intracellular Ca2+.- Mechanisms Involved in Signalling Ca2+-Dependent Events.- Calcium, Calcium Antagonists and the Release of the Neurotransmitter, Noradrenaline (Norepinephrine).- Tissue Distribution of Ca2+-Selective Channels Containing Binding Sites for the Calcium Antagonists.- In Summary.- 3. Cell Membrane Transport.- The Topography of the ? and ? Subunits of the Na+-K+ Pump.- The Na+:Ca2+ Exchanger.- The Sarcolemmal Ca2+ ATPase.- The Ion Conducting Channels of the Sarcolemma.- The Voltage-Dependent Ca2+ Channel.- The Ca2+ ATPase of the Sarcoplasmic Reticulum.- The Ca2+ Release Channels of the Sarcoplasmic Reticulum.- In Summary.- 4. The Voltage-Activated, Calcium Antagonist-Sensitive Calcium Channels: Their Structure, Composition and Calcium Antagonist Binding Sites.- The Calcium Conducting Channels.- The Voltage-Activated Calcium Conducting Channel.- The L-Type of Calcium Conducting Channel.- The Alpha1 Subunit of Skeletal Muscle. Is it Different?.- The Voltage-Sensor of the Alpha1 Subunit.- The Localization of the Dihydropyridine Binding Region of the Alpha1 Subunit.- The Localization of the Phenylalkylamine Binding Sites of the Alphai Subunit.- The Density of the Dihydropyridine Binding Sites in Ventricular Myocytes Relative to the Number of Functional L-Type Calcium Channels.- The Activation of the L-Type Ca2+ Channels in Cardiac Muscle.- Amlodipine-induced L-Type Ca2+ Channel Inactivation.- In Summary.- 5. The Chemistry of the Calcium Antagonists.- First and Second Generation Phenylalkylamine-Based Calcium Antagonists.- First and Second Generation Benzothiazepine-Based Calcium Antagonists.- First and Second Generation Dihydropyridine-Based Calcium Antagonists.- Relevance of the Second Generation Dihydropyridine-Based Calcium Antagonists.- Is There a Third Generation of Calcium Antagonists?.- In Summary.- 6. Amlodipine — A Long-Acting Second Generation Calcium Antagonist With an Unusual Binding Profile.- The Chemistry of Amlodipine.- Proof of the Calcium Channel Blocking Activity of Amlodipine.- Electrophysiological Studies Demonstrating the Inhibitory Effect of Amlodipine on the Activity of the Voltage-Activated Ca2+ Channels.- Does the Degree of Ionization Influence the Calcium Channel Blocking Activity of Amlodipine?.- Manipulations of the Amlodipine Molecule Which Affect its Potency as a Calcium Antagonist.- Which is the Active Enantiomer of Amlodipine?.- Location of the Amlodipine Binding Site.- The Receptor Binding Properties of Amlodipine.- The Pharmacokinetics of Amlodipine, Relative to Other Calcium Antagonists.- In Summary.- 7. The Pharmacokinetic Properties of Amlodipine.- Rate of Absorption.- Bioavailability.- Plasma Levels.- Metabolism and Elimination.- Volume of Distribution.- In Summary.- 8. The Vascular Selectivity of Amlodipine.- The Tissue Selectivity of Amlodipine.- Vascular Selectivity of Amlodipine Relative to That of Nifedipine.- The Vascular Selectivity of Amlodipine, Relative to Other Calcium Antagonists.- Negative Inotropy of Amlodipine Relative to That of Nifedipine. 77 Evaluation of Data Relating to Tissue Selectivity of Calcium Antagonists.- Time Course of the Inhibitory Effect of Amlodipine on Ca2+-Induced Contraction of Vascular Smooth Muscle: A Comparison with the Time Course of Nifedipine.- The Relative Coronary Dilator Effect of Amlodipine.- The Vascular Selectivity of Amlodipine Relative to its Effect on Atrioventricular and Nodal Conducting Tissue.- Evidence Relating to the Prolonged Duration of Action of Amlodipine.- Physiological Basis of the Vascular Selectivity of Amlodipine.- In Summary.- 9. Conditions Which Affect the Pharmacokinetic Profile of Amlodipine.- Effect of Age.- Effect of Renal Impairment.- Effect of Hepatic Disease.- Interaction With Other Drugs.- Effect of Food.- Rationale for the Different Behaviour of Amlodipine.- In Summary.- 10. Calcium Antagonists and the Kidney.- Calcium Antagonists and the Kidney.- Effect of Calcium Antagonists on Renal Blood Flow.- Effect on Glomerular Filtration Rate.- Effect on Sodium Excretion.- Effect of Amlodipine on Mesangial Cell Proliferation.- Other Properties of Calcium Antagonists Which May Be Applicable to their Efficacy as Protective Agents for the Kidney.- Use in Transplant Associated Acute Renal Failure.- The Acute and Chronic Effects of Calcium Antagonists on Kidney Function in Hypertensives.- The Natriuretic Effect of the Calcium Antagonists.- In Summary.- 11. Calcium Antagonism and the Ischaemic Heart: Is Calcium Antagonism Relevant?.- The Ischaemic Myocardium.- The Biochemistry of the Ischaemic Myocardium.- The Depletion of the Energy-rich Phosphate Reserves (Adenosine Triphosphate and Creatine Phosphate) and Their Precursors.- Membrane Receptors and Ischaemia.- The Pharmacological Management of the Ischaemic Heart.- Clinical Data Relating to the Efficacy of Amlodipine as a Cardioprotective Agent.- In Summary.- 12. Calcium Antagonists and the Stunned Heart — Are Vascular Selective Antagonists Protective?.- What is “Stunning”?.- The Characteristics of the “Stunned” Heart.- Molecular Basis of Myocardial Stunning.- Abnormal Ca2+ Homeostasis.- Calcium Antagonists and the Stunned Heart: Are Long-Acting Vasoselective Antagonists Useful Under These Circumstances?.- Clinical Relevance of Calcium Antagonists for the Management of the Stunned Myocardium.- In Summary.- 13. Amlodipine and the Hibernating Myocardium: Could it be Beneficial?.- The Diagnosis of Hibernating Myocardium.- “Acute” and “Chronic” Hibernation.- Clinical Conditions Under Which the Myocardium Hibernates.- The Metabolic State of the Hibernating Myocardium.- Comparison of “Hibernating” and “Stunned” Myocardium.- Therapeutic Management of the “Hibernating” Myocardium.- In Summary.- 14. Calcium Antagonists and the Treatment of Hypertension.- Hypertension: Should it be Treated or Ignored?.- The Properties of an Ideal Antihypertensive Agent.- Ca2+ and Smooth Muscle Contraction.- Calcium Antagonists as Antihypertensive Agents.- Vascular-Selective Calcium Antagonists as Anti-Hypertensive Agents.- The Antihypertensive Properties of Amlodipine.- Effect on Cardiac Output.- Rate of Onset of Response.- Effect of Amlodipine on Circadian Variations in Blood Pressure.- Effect on Blood Plasma Profile.- Efficacy in Elderly Patients.- Effect on Renal Function.- Effect of Amlodipine on Ventricular Hypertrophy.- Organ Protection.- Effect of Amlodipine on Platelet Aggregation in Hypertensives.- Amlodipine in Combination with Other Antihypertensive Agents. Which Combinations are Safe?.- Effect of Amlodipine on Insulin Resistance.- Calcium Antagonists and the Management of Diabetic Hypertensives.- Effect of Amlodipine on Sodium Excretion.- Relative Potency of Amlodipine as an Antihypertensive Agent.- Effect of Amlodipine on Pulmonary Resistance Arteries.- In Summary.- 15. The Antiatherogenic Potential of the Calcium Antagonists, Including Amlodipine.- The Aetiology of an Atherosclerotic Lesion: An Overview.- Atherosclerotic Lesions and Myocardial Infarction: Which Lesions are Dangerous?.- The Lipoproteins.- The Macrophages.- The Occurrence and Distribution of Atherosclerotic Lesions.- Lesion Progression and Classification.- Syndromes Associated With Coronary Artery Atheroma.- Restenosis After Percutaneous Transluminal Coronary Angioplasty (PTCA).- The Role of LDL in the Atherogenic Process.- Strategies Designed to Control the Formation or Cause the Regression of Atherosclerotic Lesions.- Calcium Antagonists as Antiatherogenic Agents.- In Summary.- 16. Amlodipine and the Coronary Circulation: Is it a Useful Antianginal Agent?.- The Pathophysiology of Angina Pectoris.- Calcium Antagonists and the Management of Patients with Angina Pectoris.- Mode of Action.- Experimental Studies Demonstrating the Direct Coronary Dilator Effect of Amlodipine.- Evidence of a Coronary Dilator Effect of Amlodipine in Intact Animal Studies.- Basis of the Coronary Dilator Effect of Amlodipine: Are Ca2+ Channels Involved?.- Clinical Evidence of the Usefulness of Amlodipine in the Management of Patients with Inadequate Coronary Perfusion.- Amlodipine, Atherosclerosis, Ischaemia and Abnormal Coronary “Irritability”!.- Comparison of the Antianginal Efficacy of Amlodipine with Other Drugs.- Comparison with Diltiazem.- Comparison with Nadolol — a Long-acting Beta-adrenoceptor Antagonist.- Amlodipine Added to Existing Beta-adrenoceptor Antagonist Therapy: Is this Beneficial?.- Withdrawal From Amlodipine Therapy: Are There Problems?.- In Summary.- 17. Calcium Antagonists and Heart Failure.- Definitions.- The Pathophysiology of Congestive Heart Failure.- The Contractile Proteins.- Abnormal Calcium Homeostasis.- Energy Supply.- Excess Catecholamine Secretion.- Beta1 Adrenoceptor Down Regulation.- The Pharmacotherapy of the Failing Heart.- The Use of Digitalis.- The Role of the Diuretics.- Angiotensin Converting Enzyme Inhibitors.- The Calcium Antagonists and the Failing Heart. Prototypes: Verapamil, Diltiazem, Nifedipine.- The Second Generation Vasoselective Calcium Antagonists: Are They Useful Under These Conditions?.- The Pharmacokinetics of Amlodipine in Patients with Congestive Heart Failure.- In Summary.- 18. The Side-Effects of Calcium Antagonist Therapy. Is Amlodipine Different?.- What Constitutes a Side-Effect?.- The Side-Effects of the First Generation Calcium Antagonists (Verapamil, Nifedipine and Diltiazem).- Side-Effects of the Second Generation Antagonists.- Withdrawals Due to Side-Effects.- In Summary.- 19. The Future of Calcium Antagonism.- The Future.- The Present.- References.