Clinical Pharmacology of the Angiotensin Receptor Antagonists

Domenic A. Sica, MD, Division of Clinical Pharmacology and Hypertension, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA.

In This Article

Route of Elimination

It is well recognized that the systemic clearance of a compound is dependent on the integrity of both renal and hepatic function. If renal and/or hepatic dysfunction exists in a patient, repeated dosing with an antihypertensive compound will inevitably lead to drug accumulation and the need to adjust the dose in order to lessen concentration-related side effects. The process of drug accumulation of an antihypertensive compound is most evident when angiotensin-converting enzyme (ACE) inhibitors, which are mainly eliminated by the kidney, are chronically given to patients with renal insufficiency.[3] In these patients, significant drug accumulation occurs with repeated dosing, except in the case of the ACE inhibitors fosinopril and trandolapril. Both of these compounds undergo at least 50% hepatic clearance, which limits their systemic accumulation in the renal failure patient.[35]

The AT1-RAs have only recently been studied in terms of their renal and/or hepatic handling (Table II). Most of these drugs undergo a significant degree of hepatic elimination, with the exception of candesartan and the metabolite of losartan, which are 40% and 50% hepatically cleared, respectively.[36,37] Irbesartan and telmisartan undergo the greatest degree of hepatic elimination among the AT1-RAs, with <5% of their systemic clearance via the kidneys.[21,38] Valsartan and eprosartan both undergo about 30% renal clearance.[39,40,41] On the surface, the mode of elimination for an AT1-RA may seem a trivial issue. In reality, it proves to be an important variable in the renally compromised patient and may, in fact, dictate some change in therapy. In those who develop acute renal failure when given a renally cleared ACE inhibitor or AT1-RA, the duration of any renal failure episode is linked to the kidney's inability to eliminate the compound.[42] Although this has not been formally studied, compounds that are extensively hepatically cleared should cause fewer renal problems.

To date, very few studies have been conducted assessing the BP-lowering effect of AT1-RAs in patients with decreased renal function.[43,44,45,46] In studies so far completed, the BP-lowering effect of these compounds is clearly maintained in the renal failure patient and, in certain instances, may be significant. Additional experience is needed with the AT1-RAs before definitive statements can be made concerning their efficacy in this population, and whether relevant drug accumulation occurs with the AT1-RAs that undergo at least 50% renal clearance, as is the case with the E-3174 metabolite of losartan and candesartan.