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

Overview and Introduction

Selective blockade of the angiotensin (AT1) receptor is a novel means by which the renin-angiotensin axis can be interrupted. Several compounds capable of blocking the AT1 receptor are now marketed in the United States. Each of these compounds has a unique set of pharmacologic characteristics that ultimately influence the manner in which blood pressure is reduced. Often, the pharmacologic characteristics of an AT1 receptor antagonist have been emphasized to support a superiority argument. Unfortunately, it has proven difficult to equate a specific pharmacologic feature -- beyond that of duration of receptor binding -- with a particular pattern of blood pressure reduction. Most angiotensin receptor antagonists are indicated for once-daily dosing but may occasionally lose efficacy at the end of the dosing interval, thereby necessitating twice-daily dosing. The issue of frequency of dosing is complex, in that sensitivity to a medication may dictate the need for multiple daily dosing to the same extent as a drug that has a shorter plasma or tissue half-life.

Selective angiotensin receptor antagonists (AT1-RAs) are a relatively new class of drugs employed in the treatment of hypertension. These agents work selectively at the AT1 receptor subtype, the receptor that mediates all of the known physiologic effects of angiotensin-II that are relevant to cardiovascular and cardiorenal homeostasis.[1] Each AT1-RA has a unique pharmacologic profile.[2,3] The pharmacologic differentiation of the various compound AT1-RAs is a topic of growing relevance, in that individual drugs in this drug class may differ in their ability to reduce blood pressure (BP).[4,5] Since the release of the first AT1-RA, losartan (Cozaar®), in 1995, five other compounds have been developed and are now marketed in the U.S. These compounds are candesartan (Atacand®), eprosartan (Tevetan®), irbesartan (Avapro®), telmisartan (Mycardis®), and valsartan (Diovan®). In addition, three different fixed-dose combination products are currently available: losartan/hydrochlorothiazide 50/125 and 100/25 mg (Hyzaar®); irbesartan/hydrochlorothiazide 150/125 and 300/125 mg (Avalide®); and valsartan/hydrochlorothiazide 80/125 and 160/125 mg (Diovan-HCTZ®). Other fixed-dose combination products with the AT1-RAs candesartan and telmisartan plus hydrochlorothiazide will soon be released. Currently available information does not suggest that any specific pharmacologic differences exist for these agents if they are administered alone or together with hydrochlorothiazide in a fixed-dose combination product.