Angiotensin II-Receptor Antagonists: An Overview

Raquel Dina and Mahtab Jafari


Am J Health Syst Pharm. 2000;57(13) 

In This Article

Losartan Potassium

Losartan potassium (Cozaar, Merck) was the first orally bioavailable, long-acting, nonpeptide AT-II type 1-receptor antagonist to be used in humans.[10,13] It has been extensively studied in both animals and human volunteers.[13] Its effectiveness as an antihypertensive agent has been established. [13,14]

Peak plasma concentrations of losartan are achieved within one hour of oral administration. Losartan has a half-life of 1.5-2.5 hours ( Table 1 ).[15,16] It is rapidly absorbed from the gastrointestinal tract, independent of food intake. Losartan undergoes first-pass hepatic metabolism via cytochrome P-450 (CYP) isoenzymes 2C9 and 3A4 to its active carboxylic acid metabolite, EXP-3174, which reaches peak plasma concentration in two to four hours and has a half-life of six to nine hours.[15,16] Despite the biotransformation of losartan by CYP isoenzymes, no pharmacokinetic or pharmacodynamic interactions with warfarin or digoxin have been reported. The consequences of using losartan with potent CYP2C9 inhibitors have not been examined. In vitro studies have shown that oxidation of losartan to EXP-3174 is markedly inhibited by ketoconazole, a potent inhibitor of CYP3A4; however, the clinical consequences, if any, of this interaction have yet to be determined. [17]

Several clinical trials have demonstrated the relative tolerability of losartan.[8,14,18,19,20] The most frequent adverse reaction, as observed in a clinical trial of 2900 patients assessing the safety and tolerability of losartan, 20 was dizziness, reported by 4.1% of patients taking losartan versus 1.3% of placebo recipients. Other adverse events (headache, upper-respiratory- tract infections, diarrhea, fatigue, and cough) occurred with similar frequencies in the losartan and placebo groups and thus were not considered drug related.

Unlike other AT-II-receptor blockers, losartan has a uricosuric effect after single or multiple doses in salt-depleted or salt-loaded normotensive patients, 21 sodium-repleted patients with essential hypertension,[22] and hypertensive patients with intrinsic renal disease.[23] The hypouricemic and uricosuric properties have been linked to the parent compound but not to its metabolite.[24] It is postulated that a decrease in serum uric acid levels could potentially be advantageous, but uricosuria may enhance the development of uric acid nephropathy. [21] However, uric acid nephropathy has not been reported thus far.

Once-daily administration of losartan is possible because the drug's effects are extended by the EXP-3174 metabolite, which is 40 times more potent than losartan 13 and has been found to produce consistent reductions in blood pressure over a 24- hour period.[18] The usual starting dosage of losartan potassium is 50 mg once daily. The dosage can be increased to a maximum of 100 mg daily. Doses exceeding 100 mg have not been found to produce any additional decrease in systolic or diastolic blood pressure.[18] In patients who have hepatic impairment or who may be volume depleted, such as those taking large doses of a diuretic, the starting dosage should be reduced to 25 mg once daily to minimize the occurrence of symptomatic hypotension.

Losartan potassium is marketed as a single-ingredient product and in combination with hydrochlorothiazide (Hyzaar, Merck; losartan potassium 50 mg plus hydrochlorothiazide 12.2 mg and losartan potassium 100 mg plus hydrochlorothiazide 25 mg). Use of the combination product may be appropriate if losartan monotherapy has failed to control blood pressure. The maximum antihypertensive effect is usually apparent within three weeks. The combination product is not recommended for patients with hepatic impairment because losartan is usually initiated in this group of patients at a dosage of 25 mg once daily. The combination product should also be avoided in patients with renal impairment (creatinine clearance [CL cr ], <30 mL/min).


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