Brands, Medical Use, Clinical Data
- Antihypertensive Agents
- Antiarrhythmic Agents
- Angiotensin II Receptor Antagonists
Brands / Synonyms
Cozaar; DUP 89; Hyzaar; Lacidipine; Lortaan
For the treatment of hypertension.
Losartan is the first of a class of antihypertensive agents called angiotensin II (AG II) receptor antagonists. It is, along with its longer acting active metabolite (E-3174), a specific and selective AT1 receptor antagonist. Losartan blocks 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).
Mechanism of Action
Losartan and its longer acting active metabolite (E-3174) interfere with the binding of angiotensin II to the angiotensin II AT1-receptor by, themselves, binding reversibly to the receptors in vascular smooth muscle and the adrenal gland. As angiotensin II is a vasoconstrictor, which also stimulates the synthesis and release of aldosterone, blockage of its effects results in decreases in systemic vascular resistance. Neither Losartan or its metabolite inhibit the angiotensin converting enzyme, other hormone receptors, or ion channels.
Well absorbed, the systemic bioavailability of losartan is approximately 33%
Hypotension and tachycardia; Bradycardia could occur from parasympathetic (vagal) stimulation, LD50= 1000 mg/kg (orally in rat)
Biotrnasformation / Drug Metabolism
Hepatic. Oxidation of the 5-hydroxymethyl group on the imidazole ring results in the active metabolite of losartan.
COZAAR is contraindicated in patients who are hypersensitive to any component of this product.
No significant drug-drug pharmacokinetic interactions have been found in interaction studies with
hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital. Rifampin, an inducer of drug metabolism,
decreased the concentrations of losartan and its active metabolite. In humans, two inhibitors of P450 3A4 have been
studied. Ketoconazole did not affect the conversion of losartan to the active metabolite after intravenous
administration of losartan, and erythromycin had no clinically significant effect after oral administration.
Fluconazole, an inhibitor of P450 2C9, decreased active metabolite concentration and increased losartan
concentration. The pharmacodynamic consequences of concomitant use of losartan and inhibitors of P450 2C9 have not
been examined. Subjects who do not metabolize losartan to active metabolite have been shown to have a specific, rare
defect in cytochrome P450 2C9. These data suggest that the conversion of losartan to its active metabolite is
mediated primarily by P450 2C9 and not P450 3A4.
As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing
diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing
potassium may lead to increases in serum potassium.
As with other antihypertensive agents, the antihypertensive effect of losartan may be blunted by the
non-steroidal anti-inflammatory drug indomethacin.