Angiotensin II-Receptor Antagonists: An Overview

Raquel Dina and Mahtab Jafari


Am J Health Syst Pharm. 2000;57(13) 

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Candesartan Cilexetil

Candesartan cilexetil (Atacand, Astra Merck), another long-acting nonpeptide antagonist of AT-II type 1 receptors, is a prodrug that is hydrolyzed to its active metabolite candesartan during gastrointestinal absorption.[48] The half-life of candesartan is about nine hours, and it is 98% protein bound. About 60% of a dose is eliminated through the urine and 40% through the bile. Cande-sartan cilexetil and candesartan are not metabolized by CYP isoenzymes.

Candesartan cilexetil lowers blood pressure in a dose-dependent manner (at doses of up to 32 mg).[49,50,51] The 16- and 32-mg daily doses seem to be more effective than lower doses (4 and 8 mg/day) in lowering blood pressure; mean reductions in blood pressure were 10.7 and 12.6 mm Hg for candesartan cilexetil 16 and 32 mg, respectively, and 9.9 and 10.5 mm Hg for 4- and 8-mg doses.[49] After administration of 4-32 mg, peak plasma candesartan levels are achieved within three to four hours. Dosages of 4-16 mg/day have no effect on plasma aldosterone concentrations; however, a decrease in the plasma aldosterone concentration is seen when 32 mg/day is administered.

There have been no reports of clinically important interactions between candesartan and other agents commonly used by patients with hypertension (hydrochlorothiazide, warfarin, digoxin, nifedipine, glyburide, or the major components of oral contraceptives, levonorgestrel and ethinyl estradiol).[52] Interactions with drugs that inhibit or are metabolized by CYP isoenzymes would not be expected.

A randomized, double-blind, placebo- controlled, parallel-group study in patients with mild hypertension and type 2 diabetes mellitus showed that, after 12 weeks of therapy with candesartan cilexetil 8-16 mg once daily, systolic and diastolic blood pressure decreased by a mean of 7.1 and 6.3 mm Hg, respectively, and that greater than 69% of the patients had their blood pressure controlled. [53] Candesartan cilexetil had no effect on the lipid profiles or glucose homeostasis of diabetic patients. Mean hemoglobin A 1c levels were 7.1% at baseline and at 12 weeks in patients receiving candesartan cilexetil and 7.2% at baseline and 7.1% at 12 weeks in patients receiving placebo. Lipid profiles showed no significant changes between baseline and week 12, nor were there any differences between the candesartan and placebo groups.

Candesartan cilexetil is well tolerated, with no relationship seen between dosage or time of administration and occurrence of adverse events.[49,54,55,56] Headache (7%), upper-respiratory- tract infection (7%), pain (8%), and dizziness (4%) were among the most commonly reported adverse events, and these events generally resolved without discontinuation of therapy. Rates of adverse events were similar to those for placebo. [49,55]

The dosage of candesartan cilexetil must be individualized. When administered as monotherapy to patients who are not volume depleted, the usual staring dosage is 16 mg once daily with or without food. Dosages greater than 32 mg once daily have not been extensively studied and do not seem to be more effective than 32 mg/day for reducing blood pressure. An antihypertensive effect should be apparent in two weeks, with maximum reduction in blood pressure occurring within four to six weeks. If blood pressure is not controlled with candesartan cilexetil (8- 16 mg/day) alone, a diuretic such as hydrochlorothiazide (12.5 mg/day) or another antihypertensive agent may be added.[57,58] No reduction in the starting dosage is necessary in patients who have mild renal or hepatic impairment or in the elderly.


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