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


The pharmacokinetics of a compound can influence its onset and duration of effect and, in certain instances, its side-effect profile. Furthermore, a compound's dose-response relationship can be closely associated with its unique pharmacokinetic profile. These concepts are of particular relevance to antihypertensive drugs. The primary pharmacokinetic parameters, which influence the selection of an antihypertensive agent, include absorption/bioavailability, volume of distribution, compound half-life (plasma and tissue-based components), and mode of elimination (hepatic and/or renal).

As previously noted, the absorption rate of a compound generally determines its onset of action. For example, buccally administered nifedipine is rapid-acting because of its quick absorption. Another example of absorption rate dictating onset of response is captopril. Among the ACE inhibitors, it is the most rapidly absorbed and consequently effects blood pressure change the most quickly. The extent of compound absorption is an additional key determinant of drug effect. Complete or relatively complete absorption is a useful compound feature -- in part because anticipated day-to-day variation in drug absorption influences the body's total amount of drug exposure. Absorptive variability is of most relevance when low-end therapeutic doses are given.

The VD of a compound is a relative consideration in how an antihypertensive compound reduces blood pressure. Compounds with a more extensive VD are -- at least in theory -- characterized by greater penetration into deep tissue compartments, from which other compounds (with a small VD) might be excluded. Finally, the half-life of a compound approximates, in a relatively crude fashion, the duration of its effect. For many antihypertensive compounds, the half-life at the main site of action would more reliably predict duration of effect if such were measurable. Unfortunately, the inability to sample at such locations limits the understanding of the concentration-effect relationship for most drugs. An example of this is the compound clonidine, whose primary locus of action is within the central nervous system. Finally, in the instance of the AT1-RAs, the issue of receptor affinity must be considered if AT1-RAs are to be compared. In that respect, certain of the AT1-RAs, such as irbesartan, candesartan, and telmisartan, are quite proficient.