Pharmacology: Pharmacodynamics: Mechanism of Action: Amcardia is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions intovascular smooth muscle and cardiac muscle. Experimental data suggest that AMCARDIA binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac 2 muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels.
AMCARDIA inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. AMCARDIA is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
The precise mechanisms by which AMCARDIA relieves angina have not been fully delineated, but are thought to include the following: Exertional Angina: In patients with exertional angina, AMCARDIA reduces the total peripheral resistance (afterload) against which the heart works and reduces the rate pressure product, and thus myocardial oxygen demand, at any given level of exercise.
Vasospastic Angina: AMCARDIA has been demonstrated to block constriction and restore blood flow in coronary arteries and arterioles in response to calcium, potassium epinephrine, serotonin, and thromboxane A2 analog in experimental animal models and in human coronary vessels in vitro. This inhibition of coronary spasm is responsible for the effectiveness of AMCARDIA in vasospastic (Prinzmetal's or variant) angina.
Pharmacokinetics: Pharmacokinetics and Metabolism: After oral administration of therapeutic doses of Amlodipine besilate, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64 and 90%. The bioavailability of AMCARDIA is not altered by the presence of food.
Amlodipine besilate is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine. Elimination from the plasma is biphasic with a terminal elimination half-life of about 30-50 hours. Steady-state plasma levels of Amlodipine besilate are reached after 7 to 8 days of consecutive daily dosing.
The pharmacokinetics of AMCARDIA are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose. Elderly patients and patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40-60%, and a lower initial dose may be required. A similar increase in AUC was observed in patients with moderate to severe heart failure.