Pharmacokinetic and pharmacodynamic studies with two α‐adrenoceptor antagonists, doxazosin and prazosin in the rabbit

1 The cardiovascular effects of doxazosin, a quinazoline derivative related to prasozin were investigated and compared to prazosin in the rabbit. 2 Radioligand binding studies using rabbit cerebral membranes showed that both doxazosin and prazosin were roughly equipotent at displacing [ 3 H]‐prazosin from specific binding sites. However, the lower pA 2 value for doxazosin at α 1 ‐adrenoceptors in isolated thoracic aorta preparations suggests a lower potency compared to prazosin. 3 The dose‐related pressor effects of intravenous phenylephrine were used to assess vascular α 1 ‐adrenoceptor antagonism in vivo. There was a close agreement between α 1 ‐adrenoceptor antagonist potency and maximum hypotensive effects with both doxazosin and prazosin. The α 1 ‐adrenoceptor antagonist effects of doxazosin were more prolonged than those of prazosin. 4 Studies using either radioligand binding or pressor responses to B‐HT 920 showed that doxazosin did not show any significant affinity for the α 2 ‐adrenoceptor. Similarly, no direct vasodilator effects were observed either in animals administered angiotensin II or in isolated thoracic aorta spiral strip preparations contracted with potassium. 5 Doxazosin has a longer terminal elimination half‐life than prazosin. The pharmacokinetics of doxazosin were linear over the dose range examined. 6 Following pharmacological ‘autonomic blockade’ and treatment with prazosin, doxazosin did not cause any further fall in blood pressure. 7 These observations suggest that doxazosin, like prazosin, appears to exert its hypotensive action through α 1 ‐adrenoceptor antagonism. The prolonged fall in blood pressure and well sustained α 1 ‐adrenoceptor antagonism after doxazosin raise the possibility of an active metabolite which also has α 1 ‐adrenoceptor blocking properties.