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 Binding and Half-Life

The half-life of a compound is a pure pharmacokinetic term, and does not always correlate exactly with the duration of effect of a compound. This has typically been the case with antihypertensive compounds, including both ACE inhibitors and the AT1-RAs. The discrepancy between the pharmacokinetic and pharmacodynamic half-life of a compound derives from the fact that the predominant site of drug action is in locations other than the plasma compartment. Because of the inability to sample at these extravascular sites of action of many drugs, the more meaningful tissue-based half-life cannot be determined. This is particularly the case for the AT1-RAs, since AT1 receptors are to be found in multiple locations outside the vascular compartment, and blocking AT1 receptors at these alternative locations may, in an as yet undefined way, influence the manner in which BP is reduced.

Despite this reservation, the pharmacokinetic half-life of an AT1-RA roughly approximates its duration of effect. Several of the AT1-RAs, such as candesartan, telmisartan, and irbesartan, are once-daily compounds in pharmacokinetic terms. For example, irbesartan has a half-life of 11-15 hours and, like candesartan and telmisartan, clearly behaves as a once-daily compound.[47] The true impact of pharmacologic half-life for these compounds is probably in relation to the fact that drug remains available in suitable amounts for a longer period of time as new AT1 receptors are formed. This phenomenon becomes obvious if the pressor response to angiotensin-II is evaluated.