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

Receptor Occupancy

Receptor affinity is just one of several factors that influence the action of an AT1-RA. An AT1-RA is recognized as demonstrating insurmountable or noncompetitive blockade if increasingly higher concentrations of angiotensin-II are unable to overcome receptor blockade. The terms surmountable, competitive, insurmountable, and noncompetitive are often used in an inconsistent fashion.[6,7] Eprosartan functions as a competitive antagonist; agonists and antagonists individually compete for receptor binding. Surmountable antagonism implies that antagonist blockade can eventually be overcome if high enough angiotensin-II concentrations are present in the system being studied. Losartan demonstrates surmountable antagonism. Noncompetitive, irreversible antagonism involves the loss of receptor numbers by a process of chemical modification. Insurmountable antagonists are bound to their receptors in a semi-irreversible fashion. An insurmountable antagonist releases from its receptor slowly. Valsartan, candesartan, irbesartan, telmisartan, and the active metabolite of losartan (E-3174) demonstrate this form of antagonism.[8,9,10] To date, the specific mode of receptor occupancy has not been clearly linked with the blood pressure response to an AT1-RA.