Pharmacology: Mechanism of Action: Amlodipine is a dihydropyridine calcium antagonist that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels.
Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6) and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of dissociation with the receptor binding site, resulting in a gradual onset of effect. Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and a decrease in blood pressure.
Pharmacokinetics: After oral administration of therapeutic doses of amlodipine, peak plasma concentrations are reached between 6-12 hrs. Absolute bioavailability has been estimated to be between 64% and 90%. Amlodipine's bioavailability is not altered by the presence of food. Amlodipine 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. Studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Elimination from the plasma is biphasic with a terminal elimination t½ of about 30-50 hrs. Steady-state plasma levels of amlodipine are reached after 7-8 days of consecutive dosing.
The pharmacokinetics of amlodipine is 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 area under the curve (AUC) of approximately 40-60%, and a lower initial dose may be required.