Lifezar Mechanism of Action

Angiotensin II Receptor Blocker.
Pharmacology: Pharmacodynamics: 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 angiotensin II subtype 1 (AT₁) receptor found in many tissues such as vascular smooth muscles, adrenal gland, kidneys, and the heart. A second angiotensin II receptor has been identified as the AT₂ receptor subtype 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 that for the AT₂ receptor. In vitro binding studies indicate that losartan is a reversible, competitive inhibitor of the AT₁ receptor. The active metabolite is 10 to 40 times more potent by weight than losartan and appears to be a reversible, non-competitive inhibitor of the AT₁ receptor.
Losartan does not bind to or block other hormone receptors or ion channels important in cardiovascular regulation. Furthermore, losartan does not inhibit ACE (kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin). Angiotensin II receptor antagonism results in dose-related increases in plasma renin levels, angiotensin I and angiotensin II levels, and a decrease in plasma aldosterone concentration.
Pharmacokinetics: Losartan is well absorbed after oral administration. It undergoes presystemic metabolism, forming an active metabolite (E-3174) and other inactive metabolites. Systemic bioavailability of losartan tablets is about 33%. Mean peak concentrations of losartan and its active metabolite are reached in 1 hour and in 3 to 4 hours, respectively. There is no clinically significant effect on the plasma concentration profile of losartan when the drug is administered with a meal.
Both losartan and its metabolite are highly bound (≥99%) to plasma proteins, primarily albumin. Losartan's volume of distribution is 34 L.
Plasma concentrations of the active metabolite are higher than those of losartan at all doses, C_max and AUC for E-3174 are about 2 and 5 to 8 times greater than the corresponding values for losartan itself.
After oral administration, plasma concentrations of losartan and its active metabolite decline polyexponentially with terminal half-lives of about 2 hours (1.5 to 2.5 hours) and 6 to 9 hours, respectively. As anticipated from their short half-lives, neither losartan nor its active metabolite accumulates significantly in plasma during once-daily dosing with 100 mg.
The plasma clearance of losartan and its active metabolite is approximately 600 mL/min and 50 mL/min, respectively. Losartan is extensively metabolized in the liver. Approximately 35% of an oral losartan dose is excreted in urine as unchanged compound and metabolites. Only 4% of the dose is eliminated unchanged via the kidneys. Renal clearance of losartan and its active metabolite is about 74 mL/min and 26 mL/min, respectively. Losartan and its metabolites are also eliminated by biliary excretion, with 58% of an oral dose recovered in the feces.