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Losartan


Losartan
Systematic (IUPAC) name
(1-((2'-(2H-tetrazol-5-yl)biphenyl-4-yl)methyl)- 2-butyl-4-chloro-1H-imidazol-5-yl)methanol
Identifiers
CAS number	114798-26-4
ATC code	C09CA01
PubChem	3961
DrugBank	APRD00052
Chemical data
Formula	C₂₂H₂₃ClN₆O
Mol. mass	422.91
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 (USA, Australia)
Legal status	℞ Prescription only
Routes	Oral

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.

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1 Clinical use
- 1.1 Combination with diuretic
2 Pharmacokinetics
3 Research
4 Mechanism of action & pharmacological actions
5 References
6 See also

Clinical use

As with all angiotensin II receptor 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 II receptor antagonists are not usually considered first-line, because of the proven effectivity 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]

Combination with diuretic

Losartan is available in a combination formulation with a low dose thiazide diuretic, invariably hydrochlorothiazide, to counteract the increase in renin and to achieve an additive antihypertensive effect. The losartan/hydrochlorothiazide combination preparation is marketed by Merck under the trade name Hyzaar.

Pharmacokinetics

Absorption

Losartan is well absorbed following oral administration.

Metabolism

Losartan 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. It is 10-40 times more potent in blocking AT1 receptors than Losartan.

Bioavailability

Losartan's bioavailability is about 32%.

Half life

Losartan's half life is very short: i.e only 2 hrs.

Excretion

Following oral administration, 6 % of Losartan is excreted unchanged in the urine.

Doses

Initial dose; 50mg/day
Usual dose: 25-100 mg/day

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]

Mechanism of action & pharmacological actions

Losartan is a selective, competitive 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.

References

^ Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
^ Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359(9311):995-1003. PMID 11937178
^ 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
^ 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