Candesartan Cilexetil

Abstract

Candesartan cilexetil is completely converted to the nonpeptide angiotensin II receptor blocker candesartan during absorption from the gastrointestinal tract. Candesartan selectively blocks and dissociates slowly from the angiotensin II subtype 1 (AT₁) receptor which mediates most of the known activities of angiotensin II. When administered once daily, oral candesartan cilexetil 8 to 32mg dose-dependently and effectively reduces blood pressure in patients with mild to moderate essential hypertension. In comparative studies, candesartan cilexetil 8 mg/day was as effective as usual therapeutic dosages of enalapril, losartan potassium, hydrochlorothiazide and amlodipine. One study showed candesartan cilexetil 16 mg/day to be more effective than losartan potassium 50 mg/day. Furthermore, the combination of candesartan cilexetil with either hydrochlorothiazide or amlodipine resulted in additive antihypertensive effects. Preliminary evidence suggests that the blood pressure-lowering effects of candesartan cilexetil are associated with the prevention or improvement of end-organ damage in patients with hypertension. However, this requires further confirmation in clinical studies. Candesartan cilexetil improves insulin sensitivity in patients with hypertension and does not affect glucose homeostasis or the serum lipid profile in those with coexisting type 2 (non-insulin-dependent) diabetes mellitus. Candesartan cilexetil is well tolerated in patients with hypertension. Pooled data indicate that the tolerability profile of the drug is not significantly different from that of placebo, with headache being the most commonly reported event. Adverse events are not dose related and are mostly mild to moderate in severity. Candesartan cilexetil is better tolerated than enalapril, primarily because of a reduced incidence of cough, and was not associated with the hypokalaemia or hyperuricaemia seen with hydrochlorothiazide in a study in patients aged ≥75 years. The drug has an adverse events profile similar to that of losartan potassium in patients with mild to moderate hypertension. Conclusions: Once daily candesartan cilexetil is effective and well tolerated when used once daily (as monotherapy or in combination with other antihypertensive agents) in patients with mild, moderate or severe hypertension. Initially, however, the drug is likely to be used as an alternative to other agents in patients not responding to or intolerant of their current drug therapy. Candesartan cilexetil is completely converted to the active compound candesartan during absorption from the gastrointestinal tract. Candesartan is a nonpeptide angiotensin II receptor blocker which binds selectively to and dissociates slowly from the angiotensin II receptor subtype 1 (AT₁), thereby inhibiting the activity of angiotensin II at this receptor. The drug has no activity at the AT2 receptor subtype. Consistent with angiotensin II receptor inhibition, single oral doses of candesartan cilexetil 1 to 8mg increased plasma renin activity and plasma angiotensin II levels in healthy volunteers and patients with hypertension. Both variables increased significantly within 4 hours of administration compared with placebo. In addition, single and multiple oral administration of the drug dose-dependently inhibited the pressor response to exogenous angiotensin II; ≈50% inhibition was observed 24 hours after an 8mg dose. Results from animal studies suggest that candesartan cilexetil is effective in the prevention and regression of left ventricular (LV) hypertrophy. A preliminary clinical study indicated that the drug caused LV hypertrophy regression in patients with hypertension. Candesartan cilexetil appears to preserve or improve renal function in patients with hypertension and to reduce urinary albumin excretion in those with coexisting type 2 (non-insulin-dependent) diabetes mellitus and microalbuminuria. Preclinical evidence suggests that candesartan cilexetil may have a cardioprotective effect after myocardial infarction. The effects of candesartan cilexetil on stroke have not been clearly established, although the drug maintained cerebral blood flow despite reducing systemic blood pressure in 1 study. In stroke-prone spontaneously hypertensive rats, administration of oral candesartan cilexetil from 22 to 32 weeks of age reduced the incidence of stroke compared with untreated controls. Candesartan cilexetil appears to improve insulin sensitivity in patients with essential hypertension and has no effects on glucose homeostasis or the serum lipid profile in patients with essential hypertension or coexisting type 2 diabetes mellitus. After tablet administration, candesartan cilexetil is rapidly and completely hydrolysed to the active compound candesartan during absorption in the gastrointestinal tract. Peak plasma candesartan concentrations (C_max) are reached ≈3 to 5 hours (t_max) after tablet administration and increase dose dependently. No drug accumulation occurs with repeated dosing of candesartan cilexetil. The bioavailability of an oral solution of candesartan is ≈42% and is not affected by food. Volume of distribution is estimated to be 0.13 L/kg after intravenous administration; >99% of candesartan is plasma protein bound. Candesartan is mainly eliminated unchanged although a small amount is metabolised by the isoenzyme cytochrome P450 (CYP)2C9 in human liver microsomes to the inactive metabolite CV 15959. The oral clearance of candesartan in 185 patients with hypertension who received candesartan cilexetil 2 to 16 mg/day for 28 days was calculated to be 14.07 L/h. The terminal elimination half-life (t½β) ranged from ≈9 to 13 hours and was independent of dose. After oral administration, approximately 33% of the dose is recovered in urine and 68% in faeces as either candesartan or CV 15959. Over 90% of a dose is excreted within 72 hours of administration...