Aforbes Mechanism of Action

Pharmacology: Pharmacodynamics: Amlodipine 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 this drug is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has not been fully determined but it reduces the total ischemic burden by the following actions: 1. Amlodipine 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.
2. The mechanism of action of amlodipine also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischemic 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-hour interval. Due to the slow onset of action, acute hypotension is not a feature of amlodipine administration.
In patients with angina, once-daily administration of the drug increases total exercise time, time to angina onset, and time to 1 mm ST segment depression and decreases both angina attack frequency and nitroglycerin tablet consumption.
Amlodipine 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.
Hemodynamic studies and exercise-based controlled clinical trial in NYHA Class II-IV heart failure patients have shown that amlodipine did not lead to clinical deteriorations 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 amlodipine did not lead to an increase in risk of mortality or combined mortality and morbidity in patients with heart failure.
In a follow-up, long term, placebo controlled study (PRAISE-2) of amlodipine in patients with NYHA III and IV heart failure without clinical symptoms or objective findings suggestive or underlying ischemic disease, on stable doses of ACE inhibitors, digitalis, and diuretics, amlodipine had no effect on total cardiovascular mortality. In this same population amlodipine was associated with increased reports of pulmonary edema.
Pharmacokinetics: Absorption, distribution, plasma protein binding: After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hours 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.
The bioavailability of amlodipine is not affected by food intake.
Biotransformation/Elimination: The terminal plasma elimination half-life is about 35-50 hours and is consistent with once-daily dosing. Amlodipine is extensively metabolized by the liver to inactive metabolites with 10% of the parent compound and 60% of the metabolites excreted in the urine.