Amedin Mechanism of Action

Pharmacology: Pharmacodynamics: Amedin is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle. The mechanism of the antihypertensive action of Amedin is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which Amedin relieves angina has not been fully determined but Amedin reduces total ischaemic burden by the following 2 actions: Amedin dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.
The mechanism of action of Amedin also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischaemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina). In patients with hypertension, once-daily dosing provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24-hr interval. Due to the slow onset of action, acute hypotension is not a feature of Amedin administration. In patients with angina, once-daily administration of Amedin increases total exercise time, time to angina onset, and time to 1-mm ST segment depression and decreases both angina attack frequency and glyceryl trinitrate tablet consumption. Amedin has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable for use in patients with asthma, diabetes, and gout. Haemodynamic studies and exercise based controlled clinical trials in New York heart association (NYHA) class II-IV heart failure patients have shown that Amedin did not lead to clinical deterioration as measured by exercise tolerance, left ventricular ejection fraction and clinical symptomatology. A placebo controlled study (PRAISE) designed to evaluate patients in NYHA class III-IV heart failure receiving digoxin, diuretics and ACE inhibitors has shown that Amedin did not lead to an increase in risk of mortality or combined mortality and morbidity with heart failure.
Pharmacokinetics: Absorption, Distribution, Plasma-Protein Binding: After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6- to 12-hrs post dose. Absolute bioavailability has been estimated to be between 64% and 80%. The volume of distribution is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
Biotransformation/Elimination: The terminal plasma elimination half-life is about 35-50 hrs and is consistent with once-daily dosing. Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.
Elderly: The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life in elderly patients. Increases in AUC and elimination half-life in patients with congestive heart failure were as expected for the patient age-group studied.