Losartan is an angiotensin II receptor antagonist with antihypertensive activity due mainly to selective blockade of AT1 receptors and the consequent reduced pressor effect of angiotensin II.
Losartan is readily absorbed from the gastrointestinal tract after oral doses, but undergoes substantial first-pass metabolism resulting in a systemic bioavailability of about 33%. It is metabolised to an active carboxylic acid metabolite E-3174 (EXP-3174), which has greater pharmacological activity than losartan; some inactive metabolites are also formed. Metabolism is primarily by cytochrome P450 isoenzymes CYP2C9 and CYP3A4. Peak plasma concentrations of losartan and E-3174 occur about 1 hour and 3 to 4 hours, respectively, after an oral dose. Both Losartan and E-3174 are more than 98% bound to plasma proteins. Losartan is excreted in the urine, and in the faeces via bile, as unchanged drug and metabolites. About 4% of an oral dose is excreted unchanged in urine and about 6% is excreted in urine as the active metabolite. The terminal elimination half-lives of losartan and E-3174 are about 1.5 to 2.5 hours and 3 to 9 hours, respectively.
It is used in the management of hypertension particularly in patients who develop cough with ACE inhibitors and to reduce the risk of stroke in patient with left ventricular hypertrophy, and in the treatment of diabetic nephropathy. It has also been tried in heart failure and in myocardial infarction.
DOSAGE AND ADMINISTRATION:
Losartan is given by mouth as the potassium salt. The maximum hypotensive effect is achieved in about 3 to 6 weeks after initiating treatment.
In hypertension the usual dose is 50mg once daily. The dose may be increased, if necessary, to 100mg daily as a single dose or in two divided doses. An initial dose of 25mg once daily should be given to patients with intravascular fluid depletion, and is recommended in the elderly over 75 years of age. Similar reductions may be appropriate in patients with hepatic or renal impairment. Children aged 6 years or over with hypertension may be given an initial dose of 700 micrograms/kg once daily, with a maximum of 50mg, adjusted according to response.
In diabetic nephropathy Losartan is given in an initial dose of 50mg once daily, increased to 100 mg once daily depending on the blood pressure.