Alzor CCB Mechanism of Action

Angiotensin II Receptor Blocker/Calcium Channel Blocker.
Pharmacology: Pharmacodynamics: Mechanism of Action: Olmesartan medoxomil plus Amlodipine combination is a combination of an angiotensin II receptor antagonist, Olmesartan medoxomil, and a calcium channel blocker, amlodipine besilate. The combination of these active ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.
Pharmacokinetics: Olmesartan medoxomil plus Amlodipine combination: Following oral intake of Olmesartan medoxomil plus Amlodipine combination, peak plasma concentrations of olmesartan and amlodipine are reached at 1.5 - 2 h and 6 - 8 hours, respectively. The rate and extent of absorption of the two active substances from Olmesartan medoxomil plus Amlodipine combination are equivalent to the rate and extent of absorption following intake of the two components as separate tablets. Food does not affect the bioavailability of olmesartan and amlodipine from Olmesartan medoxomil plus Amlodipine combination.
Olmesartan medoxomil (active ingredient of Olmesartan medoxomil plus Amlodipine combination): Absorption and distribution: Olmesartan medoxomil is a prodrug. It is rapidly converted to the pharmacologically active metabolite, olmesartan, by esterases in the gut mucosa and in portal blood during absorption from the gastrointestinal tract. No intact Olmesartan medoxomil or intact side chain medoxomil moiety have been detected in plasma or excreta. The mean absolute bioavailability of olmesartan from a tablet formulation was 25.6%.
The mean peak plasma concentration (Cmax) of olmesartan is reached within about 2 hours after oral dosing with Olmesartan medoxomil, and olmesartan plasma concentrations increase approximately linearly with increasing single oral doses up to about 80 mg.
Food had minimal effect on the bioavailability of olmesartan and therefore Olmesartan medoxomil may be administered with or without food.
No clinically relevant gender-related differences in the pharmacokinetics of olmesartan have been observed.
Olmesartan is highly bound to plasma protein (99.7%), but the potential for clinically significant protein binding displacement interactions between olmesartan and other highly bound co-administered active substances is low (as confirmed by the lack of a clinically significant interaction between Olmesartan medoxomil and warfarin). The binding of olmesartan to blood cells is negligible. The mean volume of distribution after intravenous dosing is low (16 - 29 L).
Biotransformation and elimination: Total plasma clearance of olmesartan was typically 1.3 L/h (CV, 19%) and was relatively slow compared to hepatic blood flow (ca 90 L/h). Following a single oral dose of 14C-labelled Olmesartan medoxomil, 10% - 16% of the administered radioactivity was excreted in the urine (the vast majority within 24 hours of dose administration) and the remainder of the recovered radioactivity was excreted in the faeces. Based on the systemic availability of 25.6%, it can be calculated that absorbed olmesartan is cleared by both renal excretion (ca 40%) and hepato-biliary excretion (ca 60%). All recovered radioactivity was identified as olmesartan. No other significant metabolite was detected. Enterohepatic recycling of olmesartan is minimal. Since a large proportion of olmesartan is excreted via the biliary route, use in patients with biliary obstruction is contraindicated.
The terminal elimination half-life of olmesartan is between 10 and 15 hours after multiple oral dosing. Steady state is reached after the first few doses and no further accumulation is evident after 14 days of repeated dosing. Renal clearance is approximately 0.5 - 0.7 L/h and is independent of dose.
Amlodipine (active ingredient of Olmesartan medoxomil plus Amlodipine combination): Absorption and distribution: 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 absorption of amlodipine is unaffected by the concomitant intake of food.
Biotransformation and 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 metabolites excreted in the urine.