View source for Losartan

{{drugbox | verifiedrevid = 310804391
|
|width=200
|image=Losartan structure.svg
|IUPAC_name = (2-butyl-4-chloro-1-{[2'-(1''H''-tetrazol-5-yl)biphenyl-4-yl]methyl}-1''H''-imidazol-5-yl)methanol
|CASNo_Ref = {{cascite}}
| CAS_number = 114798-26-4
| ATC_prefix = C09
| ATC_suffix = CA01
| PubChem = 3961
| IUPHAR_ligand = 590
| DrugBank = APRD00052
| C=22 | H=23 | Cl=1 | N=6 | O=1
|molecular_weight = 422.91
| smiles = CCCCc1nc(Cl)c(CO)n1Cc1ccc(cc1)c1ccccc1c1n[nH]nn1
|bioavailability = 25–35%
|metabolism = [[Hepatic]] ([[CYP2C9]], [[CYP3A4]])
|elimination_half-life = 1.5–2 hours
|excretion = [[Renal]] 13–25%, [[biliary]] 50–60%
|pregnancy_AU = D
|pregnancy_US = D
|legal_status = Rx-only
|routes_of_administration = Oral
}}
'''Losartan''' ([[International Nonproprietary Name|rINN]]) ({{pronEng|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==
{{dablink|Main article: [[Angiotensin II receptor antagonist]]}}

As with all angiotensin II type 1 receptor (AT<sub>1</sub>) 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&nbsp;mg/24 hours) or [[proteinuria]] (>900&nbsp;mg/24 hours).<ref name="AMH2006">Rossi S, editor. [[Australian Medicines Handbook]] 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3</ref> 

Although angiotensin II receptor antagonists are not usually considered [[First-line treatment|first-line]], because of the proven efficacy and lower costs of [[thiazide diuretic]]s 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 [[death|mortality]] for a comparable reduction in blood pressure.<ref name="pmid11937178">{{cite journal
| author = Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H
| title = Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol
| journal = Lancet
| volume = 359
| issue = 9311
| pages = 995–1003
| year = 2002
| month = March
| pmid = 11937178
| doi = 10.1016/S0140-6736(02)08089-3
| url = 
| issn = 
}}</ref>

===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. <ref>http://www.marketwatch.com/story/teva-announces-final-approval-of-generic-hyzaarr-and-cozaarr-2010-04-07</ref>

==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.<ref>Guo ZX, Qiu MC. [Losartan downregulates the expression of transforming growth factor beta type I and type II receptors in kidney of diabetic rat] Zhonghua Nei Ke Za Zhi 2003;42(6):403-8. PMID 12895325</ref> 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.<ref>Habashi JP, Judge DP, Holm TM, Cohn RD, Loeys BL, Cooper TK, et al. Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome, and preserves muscle tissue architecture in DMD mouse models. Science 2006;312(5770):117-21. PMID 16601194</ref>

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.<ref>{{cite news| last = University of Michigan Health System| first = | coauthors = | title = Breast Cancer Gene Can Be Blocked By Blood Pressure Drug| work = | place =| pages = | language = Eng| publisher = ScienceDaily| date = 2009-06-07
  | url = http://www.sciencedaily.com/releases/2009/06/090601182651.htm| accessdate = 06-08-2009}}</ref><ref>Rhodes DR, Ateeq B, Cao Q, Tomlins SA, Mehra R, Laxman B, Kalyana-Sundaram S, Lonigro RJ, Helgeson BE, Bhojani MS, Rehemtulla A, Kleer CG, Hayes DF,Lucas PC, Varambally S, Chinnaiyan AM. AGTR1 overexpression defines a subset of breast cancer and confers sensitivity to losartan, an AGTR1 antagonist. PNAS 2009; www.pnas.org/cgi/doi/10.1073/pnas.0900351106</ref>

==Mechanism of action & pharmacological actions==
Losartan is a selective, competitive [[Angiotensin II receptor type 1]] (AT<sub>1</sub>) 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==
[[File:Losartan syn.png|500px]]

Carini, D. J.; Duncia, J. V.; Wong, P. C. B; 1992, {{US Patent|5,138,069}}.

==References==
{{Reflist}}

==See also==
*[[Angiotensin Receptor Blockers: Drug discovery and development]]
* [[Losartan potassium]]

{{Merck&Co}}
{{Angiotensin II receptor antagonists}}

[[Category:Angiotensin II receptor antagonists]]
[[Category:Tetrazoles]]
[[Category:Imidazoles]]
[[Category:Organochlorides]]
[[Category:Alcohols]]

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