Torlos-50 Mechanism of Action

Pharmacology: Mechanism of Action: Angiotensin II [formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II)], is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex. 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). There is also an AT2 receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. 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. In vitro binding studies indicate that Losartan Is a reversible, competitive inhibitor of the AT1 receptor. The active metabolite is 1 0 to 40 times more potent by weight than Losartan and appears to be a reversible, non-competitive inhibitor of the AT1 receptor.
Neither Losartan nor its active metabolite Inhibits ACE (kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin); nor do they bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Pharmacodynamics: Losartan inhibits the pressor effect of angiotensin II (as well as angiotensin I) infusions. A dose of 100 mg inhibits the pressor effect by about 85% at peak with 25-40% inhibition persisting for 24 hours. Removal of the negative feedback of angiotensin II causes a doubling to tripling in plasma renin activity and consequent rise in angiotensin II plasma concentration in hypertensive patients. Losartan does not affect the response to bradykinin, whereas ACE inhibitors increase the response to bradykinin. Aldosterone plasma concentrations fall following Losartan administration. In spite of the effect of Losartan on aldosterone secretion, very little effect on serum potassium was observed.
The effect of Losartan is substantially present within one week but in some studies the maximal effect occurred in 3-6 weeks. In long-term follow-up studies (without placebo control) the effect of Losartan appeared to be maintained for up to a year. There is no apparent rebound effect after abrupt withdrawal of Losartan. There was essentially no change in average heart rate in Losartan-treated patients in controlled trials.
Pharmacokinetics: Absorption: Following oral administration, Losartan is well absorbed and undergoes substantial first-pass metabolism. The systemic bioavailability of Losartan is approximately 33%. 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 (area under the curve) 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 (~10% decrease). The pharmacokinetics of Losartan and its active metabolite are linear with oral Losartan doses up to 200 mg and do not change over time.
Distribution: The volume of distribution of Losartan and the active metabolite is about 34 liters and 12 liters, respectively. 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. Studies in rats indicate that Losartan crosses the blood-brain barrier poorly, if at all.
Metabolism: 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. About 14% of an orally-administered dose of Losartan Is converted to the active metabolite. In addition to the active carboxylic acid metabolite, several inactive metabolites are formed. In vitro studies indicate that cytochrome P450 2C9 and 3A4 are involved in the biotransformation of Losartan to its metabolites.
Elimination: Total plasma clearance of Losartan and the active metabolite is about 600 mL/min and 50 mL/min, respectively, with renal clearance of about 75 mL/min and 25 mL/min, respectively. The terminal half-life of Losartan Is about 2 hours and of the metabolite is about 6-9 hours. After single doses of Losartan administered orally, about 4% of the dose is excreted unchanged in the urine and about 6% is excreted in urine as active metabolite. 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 60% in the feces. Following an intravenous dose of 14C-labeled Losartan, about 45% of radioactivity is recovered in the urine and 50% in the feces. Neither Losartan nor its metabolite accumulates in plasma upon repeated once-daily dosing.