Angizaar/Angizaar-H Mechanism of Action

Pharmacology: Angizaar: Mechanism of Action: Angiotensin II is a potent vasoconstrictor, stimulant of aldosterone secretion and an important component in the pathophysiology of hypertension. Both losartan and its principal active carboxylic acid metabolite, (10-40 times more potent by weight than losartan) 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 (eg, vascular smooth muscle, adrenals). Losartan does not inhibit ACE (kininase II), the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin.
Pharmacodynamics: Losartan 100 mg inhibits the pressor effect of angiotensin II infusion by 85% at peak with 25-40% of the inhibition persisting for 24 hrs. Predictably, plasma renin activity and angiotensin II concentrations increase and aldosterone concentrations fall. Single-dose losartan has no effect on glomerular filtration rate, renal plasma flow and filtration. Multiple-dose studies have shown no effects on renal or systemic prostaglandins, lipids or plasma glucose concentrations.
The effect of losartan is evident to a substantial degree within 1 week of continued administration, but it may take 3-6 weeks for the maximal effect to occur in some patients. The effect of losartan is maintained on prolonged administration and there is no rebound effect on abrupt withdrawal. There is no change in average heart rate during treatment.
Angizaar-H: Losartan is an angiotensin II receptor antagonist with antihypertensive activity mainly due to the selective blockade of angiotensin I receptors and consequently, reduced pressor effect of angiotensin II.
Hydrochlorothiazide, a diuretic, affects electrolyte absorption at the level of distal convoluted tubule and increases the excretion of sodium and chloride in approximately equivalent amounts by its inhibitory effect on Na⁺Cl^- symport located in the luminal membrane.
Pharmacokinetics: Losartan is well absorbed on oral administration and undergoes substantial first-pass metabolism by cytochrome P-450 enzymes to form an active carboxylic acid metabolite, E-3174. Peak concentrations of losartan and its major active carboxylic acid metabolite are achieved in 1 hr and 3-4 hrs, respectively. The systemic bioavailability of losartan is about 33%.
Food does not have any effect on the AUC of losartan or its active metabolite. Pharmacokinetics of losartan and its active metabolite are linear with doses up to 200 mg. There is no accumulation on repeated dosing. Plasma concentrations of losartan and its active metabolite are similar in the young and elderly hypertensives.
The elimination half-life of losartan is 2 hrs and that of its major active metabolite is 6-9 hrs. Both losartan and its active metabolite are highly protein bound. Losartan is excreted both in the bile and urine. Following oral administration of losartan, approximately 35% of this radioactivity is recovered in the urine and about 60% in the feces.
Renal Insufficiency: The plasma concentration of losartan is not altered in patients with creatinine clearance >30 mL/min. AUCs are 50% greater in patients with low creatinine clearance and doubled in patients on hemodialysis. Losartan or its active metabolite cannot be removed by hemodialysis.
Hepatic Insufficiency: The plasma concentrations of losartan and its active metabolite are higher and the total plasma clearance is lower in patients with hepatic insufficiency.
Angizaar-H: On oral administration, hydrochlorothiazide is fairly and rapidly absorbed from the gastrointestinal tract. Its diuretic action begins within 2 hrs, peaks in about 4 hrs and lasts about 6-12 hrs. Hydrochlorothiazide was reported to have a bioavailability of about 65-70% and plasma half-life of about 5-15 hrs. It is bound to red blood cells. Hydrochlorothiazide is mainly excreted in the urine without undergoing metabolism. At least 61% of Angizaar-H is eliminated unchanged within 24 hrs.