Losartan: a selective angiotensin II type 1 (AT1) receptor antagonist for the treatment of heart failure

Losartan (COZAAR) is the prototype of a new class of potent and selective angiotensin II (AII) type 1 (AT(1)) receptor antagonists with the largest published preclinical and clinical data base. Since all of the AII antagonists are selective for the AT(1) receptor, these drugs should exhibit similar cardiovascular effects. However, since the pharmacokinetic/pharmacodynamic profiles of these agents and their degree of affinity for the AT(1) receptor differ, it is likely that differences in clinical profiles between these drugs exist and will require investigation. Losartan (parent compound), has moderate affinity for the AT(1) receptor (competitive inhibition). Losartan is well-absorbed orally as an active drug and is rapidly converted via oxidation in the human liver to a more potent metabolite (designated E3174) with an affinity 20- to 30-times greater for the AT(1) receptor (non-competitive inhibition). E3174 has a half-life of 6 - 9 h; elimination is via renal and hepatic routes. Antihypertensive and, in heart failure patients, haemodynamic activity is observed over a 24 h period with once daily dosing. Over 6 million patients have been treated for hypertension with continued excellent tolerability. Clinical experience in heart failure is growing, and recent data suggest an improved survival with losartan versus captopril, a drug from the angiotensin-converting-enzyme inhibitor class with proven benefit in this population. The current comprehensive losartan clinical end-point programme (4 large scale morbidity/mortality trials) should provide evidence regarding the efficacy of direct blockade of the AT(1) receptor with losartan compared to standard therapy: 1) The Losartan Heart Failure Survival Study - ELITE II, 2) The Losartan Post-Myocardial Infarction Survival Study - OPTIMAAL, 3) The Losartan Hypertension Survival Study - LIFE and 4) The Losartan Renal Protection Study - RENAAL.