Almobest Mechanism of Action

Amlodipine is a long-action calcium channel blocker (dihydropyridine class) used as an anti-hypertensive and in the treatment of angina.
Pharmacology: ALMOBEST 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 ALMOBEST is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which ALMOBEST relieves angina has not been fully determined but ALMOBEST reduces total ischaemic burden by the following two actions.
1. ALMOBEST 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 ALMOBEST also probably involves dilatation of the main 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 supine and standing positions throughout the 24 hour interval. Due to the slow onset of action, acute hypotension is not a feature of ALMOBEST administration.
ALMOBEST 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.
Use in Patients with Heart Failure: Haemodynamic studies and exercise based controlled clinical trails in NYHA Class II-IV heart failure patients have shown that ALMOBEST did not lead to clinical deterioration as measured by exercise tolerance, left ventricular ejection traction and clinical symptomatology. A placebo controlled study (PRAISE) designed to evaluate patients in NYHA III and IV heart failure without clinical symptoms or objective findings suggestive or underlying ischaemic disease, on stable doses of ACE inhibitors, digitals, and diuretics, ALMOBEST had no effect on total cardiovascular mortality. In this same population ALMOBEST was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.
A randomized double-blind morbidity-mortality study called the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trail (ALLHAT) was performed to compare newer drug therapies: "amlodipine 2.5-10 mg/d (calcium channel blocker) or lisinopril 10-40 mg/d (ACE-inhibitor) as first-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5-25 mg/d in mild to moderate hypertension." A total of 33,357 hypertensive patients aged 55 or older were randomized and followed for a mean of 4.9 years. The patients had at least one additional CHD risk factor, including: previous myocardial infarction or stroke, 6 months prior to enrollment, or documentation of other atherosclerotic CVD (over all 51.5%), type 2 diabetes (36.1%), HDL-C 35 mg/Dl (11.6%), left ventricular hypertrophy diagnosed by electrocardiogram or echocardiography (20.9%), current cigarette smoking (21.9%).
The primary endpoint was a composite of fatal CHD or non-fatal myocardial infarction. There was no significant difference in the primary end point between amlodipine-based therapy and chlorthalidone-based therapy: RR 0.98 95% CI [0.90-1.07] p=0.65. Among Secondary Endpoints, the incidence of heart failure (component of a composite combined cardiovascular endpoint) was significantly higher in the amlodipine group as compared to the chlorthalidone group (10.2% vs RR 1.38, 95% CI [1.25-1.52] p <0.001). However, there was no significant difference in all-cause mortality between amlodipine-based therapy and chlorthalidone-based therapy. RR 0.96 95% CI [0.89-1.02] p=0.20.
In a study involving 268 children age 6-17 years with predominantly secondary hypertension, comparison of a 2.5 mg dose, and 5.0 mg dose of amlodipine with placebo, showed that both reduced Systolic Blood Pressure significantly more than placebo. The difference between two doses was not statistically significant.
The long-term effects of amlodipine on growth, puberty and general development have not been studied. The long-term efficacy of amlodipine on therapy in childhood to reduce cardiovascular morbidity and mortality in adulthood has also not been established.
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.
Biotransformation/elimination: The terminal plasma elimination half-life is about 35-50 hours 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.
Use in the 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.