Amlobloc Duo Mechanism of Action

Pharmacology: Losartan: Losartan and its principal active metabolite block the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor found in many tissues, (e.g., vascular smooth muscle, adrenal gland). Both Losartan and its principal active metabolite do not exhibit any partial agonist activity at the AT1 receptor and have much greater affinity (about 1000-fold) for the AT1 receptor than for the AT2 receptor.
Amlodipine: Amlodipine 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 ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Amlodipine 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.
Pharmacokinetics: Losartan: Losartan is an orally active agent that undergoes substantial first-pass metabolism by cytochrome P450 enzymes. It is converted, in part, to an active carboxylic acid metabolite that is responsible for most of the angiotensin II receptor antagonism that follows Losartan treatment. Losartan metabolites have been identified in human plasma and urine. In addition to the active carbolxylic acid metabolite, several inactive metabolites are formed.
Following oral and intravenous administration of 14C-labeled Losartan potassium, circulating plasma radioactivity is primarily attributed to Losartan and its active metabolite.
In vitro studies indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of Losartan to its metabolites. Minimal conversion of Losartan to the active metabolite (less than 1% of the dose compared to 14% of the dose in normal subjects) was seen in about one percent of individuals studied, the terminal half-life of Losartan is about 2 hours and of the metabolite is about 6-9 hours.
The pharmacokinetics of Losartan and its active metabolite are linear with oral Losartan doses up to 200mg and do not change over time. Neither Losartan nor its metabolite accumulates in plasma upon repeated once-daily dosing.
Following oral administration, Losartan is well absorbed (based on absorption of radiolabeled Losartan) and undergoes substantial metabolism; the systemic bioavailability of Losartan is approximately 33%. About 14% of an orally administered dose of Losartan is converted to the active metabolite. Mean peak concentrations of Losartan and its active metabolite are reached in 1 hour and in 3-4 hours, respectively. While maximum plasma concentrations of Losartan and its active metabolite are approximately equal, the AUC of the metabolite is about 4 times as great as that of Losartan. A meal slows absorption of Losartan and decreases its Cmax, but has only minor effects on Losartan AUC or on the AUC of the metabolite (about 10% decreased). Biliary excretion contributes to the elimination of Losartan and its metabolites. Following oral 14C labeled Losartan, about 35% of radioactivity is recovered in the urine and about 65% in the feces. Following an intravenous dose of 14-C labelled Losartan, about 45% of radioactivity is recovered in the urine and 50% in the feces. Both Losartan and its active metabolite are highly bound to plasma proteins, primarily albumin, with plasma-free fractions of 1.3% and 0.2%, respectively. Plasma protein binding is constant over the concentration range achieved with recommended doses.
Amlodipine: After oral administration of therapeutic doses of Amlodipine, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability has been estimated to be between 64% and 90%. The bioavailability of Amlodipine 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. Ex Vivo 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 half-life of about 30-50 hours.
Steady-state plasma levels of Amlodipine are reached after 7 to 8 days of consecutive daily 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 the area under the plasma concentration time curve (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.