Alzor HCT Mechanism of Action

Angiotensin II Receptor Blocker/Anti-Hypertensive/Diuretic.
Pharmacology: Mechanism of Action: Olmesartan and Hydrochlorothiazide is a combination of an angiotensin II receptor antagonist, Olmesartan Medoxomil, and a thiazide diuretic, hydrochlorothiazide. The combination of these ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.
Once daily dosing with Olmesartan and Hydrochlorothiazide provides an effective and smooth reduction in blood pressure over the 24 hour dose interval.
Olmesartan Medoxomil: Olmesartan Medoxomil is an orally active, selective angiotensin II receptor (type AT1) antagonist. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension. The effects of angiotensin II include vasoconstriction, stimulation of the synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by blocking its binding to the AT1 receptor in tissues including vascular smooth muscle and the adrenal gland. The action of Olmesartan is independent of the source or route of synthesis of angiotensin II. The selective antagonism of the angiotensin II (AT1) receptors by Olmesartan results in increases in plasma renin levels and angiotensin I and II concentrations, and some decrease in plasma aldosterone concentrations.
In hypertension, Olmesartan Medoxomil causes a dose-dependent, long-lasting reduction in arterial blood pressure. There has been no evidence of first-dose hypotension, of tachyphylaxis during long-term treatment, or of rebound hypertension after abrupt cessation of therapy.
Once daily dosing with Olmesartan Medoxomil provides an effective and smooth reduction in blood pressure over the 24 hour dose interval. Once daily dosing produced 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.
The effect of Olmesartan Medoxomil on mortality and morbidity is not yet known.
Hydrochlorothiazide: Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity and increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II and therefore co-administration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with thiazide diuretics.
With hydrochlorothiazide, onset of diuresis occurs at about 2 hours and peak effect occurs at about 4 hours post-dose, whilst the action persists for approximately 6-12 hours.
Epidemiological studies have shown that long-term treatment with hydrochlorothiazide monotherapy reduces the risk of cardiovascular mortality and morbidity.
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 from a tablet formulation was 25.6%.
The mean peak plasma concentration (C_max) 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 coadministered 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).
Hydrochlorothiazide: Following oral administration of Olmesartan Medoxomil and hydrochlorothiazide in combination, the median time to peak concentrations of hydrochlorothiazide was 1.5 to 2 hours after dosing. Hydrochlorothiazide is 68% protein bound in the plasma and its apparent volume of distribution is 0.83 - 1.14 L/kg.
Biotransformation and elimination: Olmesartan Medoxomil: 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 varied between 10 and 15 hours after multiple oral dosing. Steady state was reached after the first few doses and no further accumulation was evident after 14 days of repeated dosing. Renal clearance was approximately 0.5 - 0.7 L/h and was independent of dose.
Hydrochlorothiazide: Hydrochlorothiazide is not metabolised in man and is excreted almost entirely as unchanged active substance in urine. About 60% of the oral dose is eliminated as unchanged active substance within 48 hours. Renal clearance is about 250 - 300 mL/min. The terminal elimination half-life of hydrochlorothiazide is 10 - 15 hours.
Olmesartan and Hydrochlorothiazide combination: The systemic availability of hydrochlorothiazide is reduced by about 20% when co-administered with Olmesartan Medoxomil, but this modest decrease is not of any clinical relevance. The kinetics of Olmesartan are unaffected by the co-administration of hydrochlorothiazide.