Candesartan

By William T. Elliott, MD and James Chan, PharmD, PhD

Astra merck has received approval from the FDA to market candesartan (Atacand), the fourth angiotensin II receptor blocker (ARB) now on the market following losartan, valsartan, and irbesartan. Candesartan has been available for use in several European countries since 1997. The drug is a potent and selective antagonist of the angiotensin II receptor subtype 1 (AT1). It appears the AT1 receptors mediate most of the known effects on angiotensin II. Candesartan is formulated as an inactive prodrug (candesartan cilexetil) to improve oral bioavailability. It is almost completely converted to the active candesartan during gastrointestinal absorption.1

Indications

Candesartan is indicated for the treatment of hypertension as monotherapy or in combination with other antihypertensive agents.

Dosing Information

Candesartan is supplied in 4 mg, 8 mg, 16 mg, and 32 mg strength tablets. The recommended starting dose is 16 mg once daily when used as monotherapy. Total daily dose ranges from 8 mg to 32 mg daily. Candesartan can be administered once or twice daily, although there does not appear to be any advantage for twice daily dosing. Once daily dosing has been shown to maintain blood pressure reduction throughout a 24-hour period with a trough to peak ratio more than 80%.2,5 Candesartan may be administered regardless of food, and no initial dosage adjustment is necessary for elderly patients or for patients with mildly impaired renal or hepatic function.2

If response is inadequate, the addition of hydrochlorothiazide (12.5 mg) may be considered. A response rate of 85% has been reported with a combination of candesartan 16 mg/HCTZ 12.5 mg in patients with mild-to-moderate (stage 1, 2) hypertension.6

Potential Advantages

Candesartan is not metabolized by the cytochrome P450 system; therefore, interactions with drugs that are metabolized by or are inhibitors or inducers of these isoenzymes are not expected.2 Candesartan has been reported to have strong affinity for the AT1 receptor. In an in vivo and ex vivo study, candesartan was found to have a higher affinity and/or a slower off-rate from the site of action than losartan.3

Even though these two angiotensin II receptor antagonists have similar pharmacokinetics, candesartan (16 mg) was reported to be more effective than losartan (50 mg) in reducing trough-sitting blood pressure (mean difference of 3.7 mmHg) when both drugs were administered once daily.4

Potential Disadvantages

As with other drugs that affect the renin angiotensin-system, candesartan is somewhat less effective in black patients, as this group of patients tend to have low renin levels.2 Candesartan should not be used during the second and third trimester of pregnancy.2 The long-term effects of candesartan and other ARBs on mortality or morbidity remain to be established.

Comments

Candesartan is the fourth angiotensin receptor blocker to be introduced since 1995. Drugs in this class are generally well tolerated with a side-effect profile not significantly different than placebo, including adverse metabolic effects (e.g., glucose or lipid levels). The efficacy of ARBs are similar to angiotensin-converting enzyme inhibitors (ACEIs), but they are not associated with cough. The lack of cough associated with angiotensin II receptor antagonist appears to be related to its lack of effect on the bradykinin metabolism. The enzyme that converts angiotensin I to angiotensin II is identical to the kinase enzyme that metabolizes bradykinin. Thus, ARBs provide more specific inhibition of angiotensin II as well as more complete inhibition, since angiotensin II can be produced by non-renin related pathways.

Candesartan provides a trough blood pressure reduction of 8-12/4-8 mmHg, with dosing of 8-32 mg compared to placebo. The effect is generally seen within two weeks, and full effects should be seen in four weeks.2 It is not clear whether candesartan offers any significant advantage over the newer agents, such as valsartan or irbesartan, as results from comparative trials are currently not available. All of these agents offer once daily dosing, are well tolerated, and generally have low potential for drug interactions.

Clinical Implications

The recent National Health and Nutritional Examination Survey (NHANES III, phase 2) indicated that the control of hypertension among Americans is woefully inadequate. Only 27% of hypertensives surveyed had their blood pressure controlled, (< 140/90 mmHg).7 This figure actually represented a decline of 1.6% from the previous survey. The control of blood pressure remains a public health priority. A recent study suggests that more aggressive reduction in blood pressure (< 85 mmHg, along with 75 mg of aspirin daily) may be more beneficial in terms of cardiovascular events.8

Diuretics and beta-blockers remain drugs of first choice for uncomplicated hypertension because of their proven efficacy in lowering cardiovascular morbidity and mortality. For patients with certain coexisting conditions, there may be indications for other drug options. For example, ACE inhibitors are the treatment of choice for diabetics with proteinuria.7 Due to lack of long-term efficacy data, ARBs, such as candesartan, are recommended for patients in whom an ACE inhibitor is indicated but cough becomes problematic.

The cost of candesartan is similar to other ARBs. The wholesale cost for 8 mg or 16 mg is about $1.10 per tablet and the 32 mg is about $1.55 per tablet.

References

1. van Lier JJ, et al. J Hum Hypertens 1997;11(Suppl 2): S27-S28.

2. Atacand Product Information. Astra Pharmaceuticals. June 1998.

3. Belz GG, et al. J Hum Hypertens 1997;11(Suppl 2): S45-S47.

4. Andersson OK, et al. J Hum Hypertens 1997;11(Suppl 2):S63-S64.

5. Sever P. J Hum Hypertens 1997;11(Suppl 2):S91-S95.

6. Philipp T, et al. J Hum Hypertens 1997;11(Suppl 2): S67-S68.

7. The Joint National Committee: JNC-VI. Arch Intern Med 1997;157:2413-2445.

8. The HOT Study Group. Lancet 1998;751:1755-1762.