High Blood Pressure / Hypertension

Angiotensin II receptor antagonists

By Cardiologist on July 7th, 2011

Pharmacology and mechanism of action

As described above, Angiotensin-converting enzyme inhibitors are useful antihypertensive drugs whose major mechanism of action involves inhibiting the synthesis of angiotensin II. In view of this extensive experience, it is not surprising that angiotensin II receptor antagonists are efficacious in lowering blood pressure in patients with hypertension. Losartan, a nonapeptide angiotensin II receptor antagonist, was the first drug in this class available for treating hypertension. Other examples include valsartan, eprosartan, candesartan, and irbesartan (see Table Angiotensin II Receptor Antagonists).

Angiotensin receptors are coupled to G proteins that contribute to the activation of smooth muscle contraction and growth. They share many signal transduction pathways with α₁-adrenergic receptors. Two angiotensin receptors are now known, namely, AT₁ and AT₂ receptors. AT₁ receptors are involved in the mechanism by which angiotensin II stimulates smooth muscle contraction in blood vessels and aldosterone secretion from the adrenal cortex. In response to blockade of these receptors, plasma concentrations of renin and angiotensin II rise. The possible clinical significance of these adaptations is not known. The available angiotensin II receptor antagonists are selective for AT₁ receptors.

Losartan is well absorbed after oral administration, and it undergoes extensive first-pass metabolism by the cytochrome P450 system. A very potent active metabolite is produced that is responsible for most of losartin’s pharmacologic effects. Although the parent compound has a short half-life (about 2 hours), the main active metabolite has a half-life of about 6–9 hours. Unlike losartan, valsartan is not a pro-drug and is not dependent on cytochrome P450 metabolism for activation. Valsartan has a longer half-life and duration of action. Candesartan exhibits noncompetitive antagonism at AT₁ receptors, and its very high affinity for these receptors appears to contribute to its long duration of action. The therapeutic relevance of these differences is currently uncertain.

Clinical use and adverse effects of angiotensin II receptor antagonists

Losartan is efficacious in the treatment of hypertension. Its capacity to lower blood pressure as monotherapy is similar to that of many other antihypertensive drugs. How closely the efficacy of angiotensin II receptor antagonists compares with Angiotensin-converting enzyme inhibitors will be better known with greater clinical experience. The maximal antihypertensive effects may require 4–6 weeks at a given dose, a time course found for many antihypertensive drugs. Controlled trials have demonstrated that adding a thiazide diuretic to established therapy has added benefit. Indeed, the actions of angiotensin receptor antagonists can be conceptually linked with those of the better known Angiotensin-converting enzyme inhibitors.

The adverse effects of Angiotensin-converting enzyme inhibitors due to decreased activation of angiotensin receptors should be expected in patients receiving an angiotensin II receptor antagonist. Specifically, this applies to the adverse effects described above in the Angiotensin-converting enzyme inhibitor section for renal function and potassium retention. This also includes the advisory that these drugs not be used in pregnant women because of the importance of the renin–angiotensin system in fetal development, especially in the second and third trimesters. Cough induced by Angiotensin-converting enzyme inhibitors is not thought to involve changes in angiotensin II’s effects; as expected, cough appears rarely with angiotensin II receptor antagonists. The incidence of angioedema likely will also be less than with Angiotensin-converting enzyme inhibitors. However, the experience with the receptor antagonists is so far relatively limited. In addition, the possible consequences, if any, of chronic, marked activation of the renin–angiotensin II system with these drugs remains to be determined.

Recommendations

The first marketed angiotensin II receptor antagonist became available in the United States as recently as 1995. As a consequence, the long-term effects of these drugs are not yet known, for neither reduction of risk of clinically important endpoints such as stroke nor potential long-term adverse effects.

PRINCIPLES

It is an obvious truism that long-term consequences of new drugs are generally not known when they are introduced; the physician and patient should balance this uncertainty with the apparent potential advantages of using a new drug.

Angiotensin II receptor antagonists are effective in lowering the blood pressure of hypertensives and are useful in combination with diuretics. The drugs may be useful in those patients who have unacceptable Angiotensin-converting enzyme inhibitor-induced cough. However, to what extent they may share the benefits of Angiotensin-converting enzyme inhibitors in hypertensive patients with congestive heart failure or type I diabetes is not yet known. The results of a study designed to compare the safety and efficacy of losartan with captopril in older patients with congestive heart failure had an unanticipated beneficial impact on overall mortality in the losartan group. A follow-up study (ELITE 2, an adequately powered multicentered clinical trial) is currently under way to determine whether this was a chance finding or a superior benefit of losartan compared with Angiotensin-converting enzyme inhibitors in patients with congestive heart failure.

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