Losartan

Losartan

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Systematic (IUPAC) name
(2-butyl-4-chloro-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazol-5-yl)methanol
Clinical data
Pregnancy category	AU: D US: D (Evidence of risk)
Routes of administration	Oral
Legal status
Legal status	℞ (Prescription only)
Pharmacokinetic data
Bioavailability	25–35%
Metabolism	Hepatic (CYP2C9, CYP3A4)
Biological half-life	1.5–2 hours
Excretion	Renal 13–25%, biliary 50–60%
Identifiers
CAS Number	114798-26-4
ATC code	C09CA01 (WHO)
PubChem	CID 3961
IUPHAR/BPS	590
DrugBank	APRD00052
Chemical data
Formula	C22H23ClN6O
Molar mass	422.91[[]]
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Losartan (rINN) (pronounced /loʊˈsɑrtən/) is an angiotensin II receptor antagonist drug used mainly to treat high blood pressure (hypertension). Losartan was the first angiotensin II receptor antagonist to be marketed. It is currently marketed by Merck & Co. under the trade name Cozaar. As of 2010 Losartan is now available in generic form.

Clinical use

Main article: Angiotensin II receptor antagonist

As with all angiotensin II type 1 receptor (AT₁) antagonists, losartan is indicated for the treatment of hypertension. Losartan 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, losartan may be used first-line in patients with increased cardiovascular risk. The LIFE study demonstrated that losartan 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.

Combination with diuretic

Losartan is available in a combination formulation with a low dose thiazide diuretic to achieve an additive antihypertensive effect.

The losartan/hydrochlorothiazide combination preparation is marketed by Merck under the trade name Hyzaar and by Xeno Pharmaceuticals under the name Anzaplus. In the Philippines, it is manufactured by the local company Chira Pharmaceuticals and sold as 2Zaris. Merck, Sharp & Dohme market it as Ocsaar Plus in Israel.

In 2010, the patent for the combination expired, and Teva promptly filed and received approval to sell the generic losartan, with and without hydrochlorothiazide, in the United States.

Pharmacokinetics

Losartan is well absorbed following oral administration and undergoes significant first-pass 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 Losartan. This metabolite is 10-40 times more potent in blocking AT1 receptors than the original Losartan. Its bioavailability is about 32%.

Research

Losartan 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. Effects on TGF-β expression may also account for its potential efficacy in Marfan syndrome and Duchenne muscular dystrophy (DMD) – losartan has been shown to prevent aortic aneurysm and certain pulmonary complications in a mouse model of the disease.

Losartan 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 losartan to "block" - reverse neoplastic changes - caused by this gene.

Mechanism of action & pharmacological actions

Losartan is a selective, competitive Angiotensin II receptor type 1 (AT₁) receptor antagonist, reducing the end organ responses to angiotensin II. Losartan 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 losartan. Reduction in blood pressure occurs independently of the status of the renin-angiotensin system. As a result of losartan dosing, plasma renin activity increases due to removal of the angiotensin II feedback.

Other uses

Losartan is an uricosuric. Because losartan can cause hyperkalemia, potassium supplements or salt substitutes containing potassium should not be used without consulting the prescribing physician.

Losartan is being researched as a possible drug for marked slowing of aortic enlargement in Marfan and related syndromes.

Synthesis

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Carini, D. J.; Duncia, J. V.; Wong, P. C. B; 1992, U.S. Patent 5,138,069.

See also

• Angiotensin Receptor Blockers: Drug discovery and development
• Losartan potassium

de:Losartan uk:Лозартан