At1 Angiotensin Ii Receptor Antagonists

Nonpeptide antagonists of the ATj angiotensin II receptor approved for the treatment of hypertension include losartan (cozaar), candesartan (atacand), irbesartan (avapro), valsartan (diovan), telmisartan (micardis), and eprosartan (teveten). By antagonizing the effects of AnglI, these agents relax smooth muscle and thereby promote vasodilation, increase renal salt and water excretion, reduce plasma volume, and decrease cellular hypertrophy (see Chapter 30).

Distinct subtypes of AnglI receptors are designated as ATj and AT2. The ATj receptor subtype is located predominantly in vascular and myocardial tissue and also in brain, kidney, and adrenal glomerulosa cells, which secrete aldosterone (see Chapter 30). Because the ATj receptor mediates feedback inhibition of renin release, renin and AnglI concentrations are increased during ATJ receptor antagonism. The clinical consequences of increased AngII effects on an uninhibited AT2 receptor are unknown; emerging data suggest that the AT2 receptor may elicit antigrowth and antiproliferative responses.

ADVERSE EFFECTS AND PRECAUTIONS Adverse effects of ACE inhibitors that result from inhibiting AngII-related functions also occur with ATJ receptor antagonists, including hypotension, hyperkalemia, and reduced renal function (especially associated with renal artery stenosis). Hypotension most often occurs in patients in whom the blood pressure is highly dependent on AnglI, including those with volume depletion (e.g., with diuretics), renovascular hypertension, cardiac failure, and cirrhosis; in such patients initiation of treatment with low doses and attention to volume status is essential. Hyperkalemia may occur in conjunction with other factors, such as renal insufficiency, ingestion of excess K+, and the use of drugs that promote K+ retention. Cough is much less frequent with AngII receptor antagonists, and angioedema occurs very rarely. ATj receptor antagonists also should not be administered during pregnancy and should be discontinued as soon as pregnancy is detected.

THERAPEUTIC USES When given in adequate doses, the ATj receptor antagonists appear to be as effective as ACE inhibitors in the treatment of hypertension. As with ACE inhibitors, these drugs may be less effective in African Americans and patients with low-renin hypertension. The full effect of ATJ receptor antagonists on blood pressure typically is not observed until ~4 weeks after initiation of therapy. If blood pressure is not controlled by an ATj receptor antagonist alone, a low dose of a thiazide or other diuretic may be added. In patients with mild-to-severe hypertension, the addition of an ATj receptor antagonist to a thiazide can produce significant additional reductions in blood pressure in patients who demonstrated an insufficient response to the first agent alone. A smaller initial dosage is preferred for patients who have already received diuretics and therefore have intravascular volume depletion, and for other patients whose blood pressure is highly dependent on AngII. Given their different mechanisms, there is no assurance that the effects of ACE inhibitors and antagonists of the ATj receptor will be equivalent in preventing target organ damage in patients with hypertension.

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