Angiotensin II-Receptor Blockers: Clinical Relevance and Therapeutic Role

Jo E. Rodgers and J. Herbert Patterson


Am J Health Syst Pharm. 2001;58(8) 

In This Article

Pharmacokinetic Differences

The potential benefit of angiotensin II-receptor antagonism is not limited to well-tolerated blood pressure control. Angiotensin II has complex effects on the heart and kidneys. Blocking the effects of angiotensin II via receptor antagonism and the consequent correction of hypertension may result in cardiovascular and renal protection, much as with ACE inhibitors. Thus, the potential advantages of angiotensin II-receptor antagonism have spurred the development of many ARBs. Losartan, introduced in 1995, was the first ARB indicated for use in the treatment of hypertension. Six ARBs are currently available in the United States for hypertension: losartan, valsartan, irbesartan, candesartan, eprosartan, and telmisartan (Table 1).

All ARBs share certain features because of their common mechanism of action. Most important among these are selectivity for the angiotensin type 1 receptor and a lack of agonist activity at this receptor site. All the agents are orally administered; bioavailability is afforded to these agents by their nonpeptide chemical structure.

Although ARBs have some structural and pharmacokinetic differences, the class is more remarkable for its consistent clinical effects. The pharmacokinetic properties of ARBs are listed in Table 2. No definitive data are available indicating that these pharmacologic differences are clinically relevant.

ARBs include nonpeptide imidazole derivatives with biphenyltetrazole structures, except for eprosartan, a novel nonbiphenyl, nontetrazole molecule. (The poor bioavailability of eprosartan may be partly attributable to this structural difference.) Losartan and its primary metabolite (E3174) actively antagonize angiotensin type 1 receptors. Valsartan, irbesartan, eprosartan, and telmisartan are active compounds without any active metabolites. Candesartan cilexetil is a prodrug. The initial form of the drug (clinically active or requiring metabolic activation) is unrelated to efficacy, except in a few patients who may not efficiently biotransform a prodrug into the active moiety.

The mechanism of action of an ARB is based on selective binding to angiotensin type 1 receptors. In competitive antagonism, also known as surmountable antagonism, the blockade by the antagonist can be overcome by increasing concentrations of angiotensin II. In noncompetitive, irreversible antagonism, also known as insurmountable antagonism, the decrease in the maximum response cannot be overcome by increasing concentrations of angiotensin II.[17] Although losartan, the active parent molecule, binds to the angiotensin type 1 receptor competitively, E3174 binds noncompetitively or irreversibly; therefore, the blockade of the pressor effect of angiotensin II is more closely correlated with the plasma concentration of E3174 than with that of the parent molecule.[7] All the ARBs used to treat hypertension, except eprosartan, bind noncompetitively to angiotensin type 1 receptors and therefore have relatively long terminal half-lives. Eprosartan and losartan bind competitively, which contributes to a somewhat shorter duration of action. Twice-daily administration of eprosartan and losartan may therefore be required to achieve smooth 24-hour blood pressure control.

A few pharmacologic differences distinguish some of the ARBs. Clinically significant interactions of losartan with rifampin and fluconazole have been found. Rifampin induces the metabolism of losartan and its active metabolite, while fluconazole decreases the metabolism of losartan to E3174.[7] These interactions are believed to be related to cytochrome P-450 isoenzymes 3A4 and 2C9. No significant drug interactions involving valsartan, irbesartan, or candesartan have been reported. There is a potential interaction between telmisartan and digoxin, manifested as an increase in peak and trough plasma digoxin concentrations.[10] The mechanism of this interaction is not clearly understood; however, it is believed to be related to an increase in digoxin bioavailability.[a]

Finally, losartan is the only ARB that has been shown to reduce serum uric acid levels.[18,19] In patients pretreated with thiazide diuretics, losartan significantly inhibited the diuretic-induced increase in plasma uric acid levels.[20] In cyclosporine-treated heart transplant patients, losartan also lessened cyclosporine-induced hyperuricemia.[21] Although evidence suggests that elevated serum uric acid is associated with cardiovascular disease,[22,23] the clinical significance of reducing serum uric acid levels must be further investigated. While the benefit of the uricosuric effect of losartan remains unclear, preliminary data suggest no detrimental effect. During 21 days of losartan treatment of hypertensive patients with thiazide-induced hyperuricemia, Shahinfar et al.[24] observed an increase in uric acid excretion without an increase in dihydrogen urate, the primary risk factor for acute urate nephropathy.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: