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Losartan
Systematic (IUPAC) name
(2-butyl-4-chloro-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1 H-imidazol-5-yl)methanol
Identifiers
CAS number 114798-26-4
ATC code C09CA01
PubChem 3961
DrugBank APRD00052
Chemical data
Formula C 22H23ClN6O 
Mol. mass 422.91
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 25–35%
Metabolism Hepatic (CYP2C9, CYP3A4)
Half life 1.5–2 hours
Excretion Renal 13–25%, biliary 50–60%
Therapeutic considerations
Pregnancy cat. D(AU) D(US)
Legal status Prescription only
Routes Oral
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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.

Contents

Clinical use

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).[1]

Although angiotensin I 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.[2]

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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. A Philippine-based drug company, Chira Pharmaceuticals, markets the combination formulation under the trade name "2Zaris" in the country. Merck, Sharp & Dohme market it as Ocsaar Plus in Israel.

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 long-acting (6 to 8 hr), noncompetitive antagonist at the AT1 receptor and contribute 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.[3] 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.[4]

Losartan is being studied for use in the treatment 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. [5][6]

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.

References

  1. ^ Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
  2. ^ 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 (March 2002). "Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol". Lancet 359 (9311): 995–1003. doi:10.1016/S0140-6736(02)08089-3. PMID 11937178.  
  3. ^ 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
  4. ^ 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
  5. ^ University of Michigan Health System (06-07-2009). "Breast Cancer Gene Can Be Blocked By Blood Pressure Drug" (in Eng). ScienceDaily. http://www.sciencedaily.com/releases/2009/06/090601182651.htm. Retrieved 06-08-2009.  
  6. ^ 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

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