Olmetec Mechanism of Action

Selective angiotensin II receptor (type AT₁) antagonist.
Pharmacology: Pharmacodynamics: Olmesartan medoxomil is expected to block all actions of angiotensin II mediated by the AT₁-receptor, regardless of the source or route of synthesis of angiotensin II. The selective antagonism of the angiotensin II receptors results in increases in plasma renin levels and angiotensin I and II concentrations, and some decrease in plasma aldosterone concentrations.
Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension via the type 1 (AT₁) receptor.
In hypertension, olmesartan medoxomil causes a dose-dependent, long-lasting reduction in arterial blood pressure. There has been no evidence of 1st-dose hypotension, of tachyphylaxis during long-term treatment or of rebound hypertension after cessation of therapy.
Once-daily dosing with olmesartan medoxomil provides an effective and smooth reduction in blood pressure over the 24-hr dose interval. Once-daily dosing produce similar decreases in blood pressure as twice-daily dosing at the same total daily dose.
With continuous treatment, maximum reductions in blood pressure are achieved by 8 weeks after the initiation of therapy, although a substantial proportion of the blood pressure-lowering effect is already observed after 2 weeks of treatment. When used together with hydrochlorothiazide, the reduction in blood pressure is additive and co-administration is well tolerated.
The effect of olmesartan on mortality and morbidity is not yet known.
Pharmacokinetics: 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 tablet was 25.6%. The mean peak plasma concentration was reached within 2 hrs 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 can 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 drugs 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 IV dosing is low (16-29 L).
Metabolism and Elimination: Total plasma clearance was typically 1.3 L/hr (coefficient of variation 19%) and was relatively slow compared to hepatic blood flow (approximately 30 L/hr). 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 hrs of dose administration) and the remainder of the recovered radioactivity was excreted in the feces. Based on the systemic availability of 25.6%, it can be calculated that absorbed olmesartan is cleared by both renal (approximately 40%) and hepatobiliary excretion (approximately 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 (see Contraindications).
The terminal elimination half-life of olmesartan varied between 10 and 15 hrs after multiple oral dosing. Steady state was reached after the 1st few doses and no further accumulation was evident after 14 days of repeated dosing. Renal clearance was approximately 0.5-0.7 L/hr and was independent of dose.