ATI receptor antagonists

Angiotensin II receptor antagonists selectively block the type 1 A-II receptor (ATj receptor). They inhibit the RAS independently from the source of A-II and block any effects of ATI resulting from com pensatory stimulation of renin, such as reflex activation of the sympathetic nervous system. Hence, they do not cause tachycardia or an increase in cardiac contractility and are used in the treatment of hypertension. However, they are ineffective in primary hyperaldos-teronism. Their antihypertensive effect is similar to that of ACE inhibitors and they may be useful in the management of cardiac failure, as they reduce afterload and increase cardiac output. AT¡ antagonists have no effect on bradykinin metabolism or prostaglandin synthesis, so they do not produce the cough or rash associated with ACE inhibitors. They are generally well tolerated and produce few adverse effects, although angio-oedema has been reported. However, plasma concentrations of renin, A-I and A-II increase, and aldosterone concentrations decrease during long-term therapy; hyperkalaemia may occur if potassium-sparing diuretics are also administered.

The prototype ATj antagonist was saralasin, a peptide analogue of A-II, which is rapidly inactivated in the gut and therefore used only for experimental or diagnostic purposes. All clinically available ATj-receptor antagonists are non-peptide imidazole compounds. The active compounds bind specifically and non-competitively to the ATi receptor without agonist activity. They are highly protein-bound, with a prolonged duration of action exceeding their plasma half-life, and a maximum antihypertensive effect 2-4 weeks after starting therapy. Their antihypertensive effect is enhanced when combined with a thiazide diuretic; combination formulations are available. In common with ACE inhibitors, they are contraindicated in pregnancy and are likely to have an adverse effect in patients with renal artery stenosis or those taking NSAIDs. The pharmacological properties of some ATi-receptor antagonists are shown in Table 7.11.

There are few data describing the effects of ATj-receptor antagonists in the perioperative period, but caution would be appropriate when large fluid or blood losses are expected.

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