Amlodipine

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.