Doxar Mechanism of Action

Pharmacology: Pharmacodynamics and Pharmacokinetics: Losartan potassium is a long-acting antihypertensive, nonpeptide angiotensin II type I-receptor (AT1 receptor) antagonist. Losartan reduces risk of stroke and cardiovascular death due to myocardial infarction and heart failure in hypertensive patients with left ventricular hypertrophy. Losartan provides renal protection for type 2 diabetic patients with proteinuria. Losartan is used in the management of hypertension, particularly in patients who develop cough with ACE inhibitors.
Renin, secreted within the kidney, catalyzes the formation of angiotensin I from angiotensinogen. Angiotensin converting enzyme (ACE) then converts angiotensin I to angiotensin II, the effector molecule of the renin-angiotensin system, and a major determinant of the pathophysiology of hypertension. Angiotensin II binds to the AT1 receptor found in many tissues (e.g. vascular smooth muscle, adrenal gland, kidneys, and the heart) and elicits several important biological actions, including vasoconstriction and the release of aldosterone, which results in increased blood pressure. Angiotensin II contributes to the development of nephropathy through several mechanisms, including constriction of the glomerular arteries leading to increased microcirculatory pressure and abnormal albumin secretion. In addition to its hemodynamic effects, angiotensin II can cause glomerular damage.
Losartan is a potent, orally active compound that binds selectively to the AT1 receptor. The maximum hypotensive effect is achieved in about 3 to 6 weeks after starting treatment. It does not bind to or block other hormone receptors or ion channels important in cardiovascular regulation. Furthermore, losartan does not inhibit ACE, the enzyme that degrades bradykinin. Consequently, effects not directly related to blocking the AT1 receptor, such as the potentiation of bradykinin-mediated effects (e.g. cough) or the generation of edema are not associated with losartan. Angiotensin II may be synthesized through other pathways, so ACE-inhibitors may not be able to completely block angiotensin II effects. Losartan and its potent metabolite are able to completely inhibit the physiologic effects of angiotensin II, reducing blood pressure and retarding the development of nephropathy.
Following oral administration, losartan is readily absorbed from the gastrointestinal tract. Food has minimal effect on its absorption. About 14% of an orally administered dose of losartan is converted to the active metabolite that is responsible for most of the angiotensin II receptor antagonism caused by losartan. Losartan undergoes substantial first-pass hepatic metabolism via cytochrome P-450 (CYP) isoenzymes to an active 5-carboxylic acid metabolite designated EXP-3174. This active metabolite has more potent pharmacological activity than losartan and some inactive metabolites. Losartan has a peak plasma concentration of about one hour while the metabolite E-3174 reaches peak plasma concentration in three to four hours. Plasma half-lives of losartan and EXP-3174 are 2.5 and 6 to 9 hours respectively. Both losartan and its active metabolite are highly bound to plasma proteins, primarily albumin. About 35% of the oral dose of losartan is excreted in the urine and about 60% in the feces. About six percent is excreted in urine as the active metabolite. Biliary excretion also contributes to the elimination of losartan and its metabolites.