Arbloc Mechanism of Action

Pharmacology: Losartan Potassium is an angiotensin II receptor (type AT₁) antagonist. 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. Its effects are vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal re-absorption of sodium. 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 in many tissues (e.g. vascular smooth muscle, adrenal gland). There is also an AT₂ receptor in many tissues but it is not known to be associated with cardiovascular homeostasis. Both Losartan and its principal active metabolite have much greater affinity (about 1,000 fold) for the AT₁ than for the AT₂ receptor and do not exhibit any agonist activity.
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 the weight than Losartan and appears to be a reversible, non-competitive inhibitor of the AT₁ receptor.
Losartan do not inhibit ACE (kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin) nor do they bind to or block other hormone receptor or ion channels known to be important in cardiovascular regulation. It inhibits the pressor effect of angiotensin II (as well as angiotensin I) infusions. Removal of the negative feedback of angiotensin II causes 2- to 3-fold rise in plasma renin activity and a consequent rise in angiotensin II plasma concentration in hypertensive patients. The resulting increased plasma renin activity and angiotensin II circulating levels are insufficient to alter the effects of Losartan and its principal active metabolite on blood pressure. There was a small uricosuric effects with Losartan leading to a minimal decrease in serum uric acid (mean decrease less than 0.4 mg/dL) during chronic oral administration.
Pharmacokinetics: Losartan Potassium is readily absorbed from the gastrointestinal tract following oral administration, with an oral bioavailability of about 33%. It undergoes first-pass metabolism to form an active carboxylic acid metabolite, which has a greater pharmacological activity than Losartan Potassium, and some inactive metabolites. Metabolism is primarily by cytochrome P450 isoenzymes CYP2C9 and CYP3A4. Peak plasma concentrations of Losartan Potassium and its active metabolite occur about 1 hour and 3 to 4 hours, respectively, after an oral dose. Both Losartan Potassium and its active metabolite are more than 98% bound to plasma proteins. Losartan Potassium is excreted in the urine and in the feces via bile as unchanged drug and metabolites. Following oral dosing about 35% of the dose is excreted in the urine and about 60% in the feces. The terminal elimination half-lives of Losartan Potassium and its metabolite are about 1.5 to 2.5 hours and 3 to 9 hours, respectively.