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Losartar Losartar Systematic (IUPAC) name (2-butyl-4-chloro-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazol-5-yl)methanol Chemical data Formula Mol. mass C22H23ClN6O 422.91 Pharmacokinetic data Bioavailability Metabolism Half-life Excretion 25–35% Hepatic (CYP2C9, CYP3A4) 1.5–2 hours Renal 13–25%, biliary 50–60% Therapeutic considerations Pregnancy cat. Legal status Routes D(AU) D(US) ℞ Prescription only Oral Losartar is an angiotensin II receptor antagonist drug used mainly to treat high blood pressure (hypertension). Losartar was the first angiotensin II receptor antagonist to be marketed. Clinical use As with all angiotensin II type 1 receptor (AT1) antagonists, Losartar is indicated for the treatment of hypertension. Losartar may also delay progression of diabetic nephropathy and is also indicated for the reduction of renal disease progression in patients with type 2 diabetes, hypertension and microalbuminuria (>30 mg/24 hours) or proteinuria (>900 mg/24 hours). Although angiotensin II receptor antagonists are not usually considered first-line, because of the proven efficacy and lower costs of thiazide diuretics and beta blockers, Losartar may be used first-line in patients with increased cardiovascular risk. The LIFE study demonstrated that Losartar was significantly superior to atenolol in the primary prevention of adverse cardiovascular events (myocardial infarction or stroke), with a significant reduction in cardiovascular morbidity and mortality for a comparable reduction in blood pressure Dosage Range Combination with diuretic Losartar is available in a combination formulation with a low dose thiazide diuretic to achieve an additive antihypertensive effect. Pharmacokinetics Losartar is well absorbed following oral administration and undergoes significant firstpass metabolism to produce 5-carboxylic acid metabolite, designated as EXP3174. This metabolite is a long-acting (6 to 8 hr), noncompetitive antagonist at the AT1 receptor and contributes to the pharmacological effects of Losartar. This metabolite is 10-40 times more potent in blocking AT1 receptors than the original Losartar. Its bioavailability is about 32%. Research Losartar has been found to downregulate the expression of transforming growth factor beta (TGF-β) types I and II receptors in the kidney of diabetic rats, which may partially account for its nephroprotective effects.[4] Effects on TGF-β expression may also account for its potential efficacy in Marfan syndrome and Duchenne muscular dystrophy (DMD) – Losartar has been shown to prevent aortic aneurysm and certain pulmonary complications in a mouse model of the disease Losartar is being studied for use in the treatment of the 20% of breast cancer tumors positive for AGTR1. The University of Michigan Comprehensive Cancer Center has announced the result of an animal study which found Losartar to "block" - reverse neoplastic changes - caused by this gene. Mechanism of action & pharmacological actions Losartar is a selective, competitive Angiotensin II receptor type 1 (AT1) receptor antagonist, reducing the end organ responses to angiotensin II. Losartar administration results in a decrease in total peripheral resistance (afterload) and cardiac venous return (preload) All of the physiological effects of angiotensin II, including stimulation of release of aldosterone, are antagonized in the presence of Losartar. Reduction in blood pressure occurs independently of the status of the renin-angiotensin system. As a result of Losartar dosing, plasma renin activity increases due to removal of the angiotensin II feedback. Other uses Losartar is an uricosuric. Because Losartar can cause hyperkalemia, potassium supplements or salt substitutes containing potassium should not be used without consulting the prescribing physician. Losartar is being researched as a possible drug for marked slowing of aortic enlargement in Marfan and related syndromes.