Basic pharmacology of alpha-adrenoceptor antagonists and hybrid drugs

Selective alpha 1-adrenoceptor antagonists, which can be used as antihypertensives, cause dilation of both resistance and capacitance vessels, as a result of alpha 1-adrenoceptor blockade at postsynaptic sites. Reflex tachycardia is weak or absent, owing to the following mechanisms: (1) The absence of presynaptic alpha 2-receptor blockade, thus preventing the accelerated release of noradrenaline from the nerve endings; and (2) the blockade of central alpha 1-adrenoceptors, causing a blunting of the reflex tachycardia via the baroreceptor mechanism. Prazosin and its successor drugs doxazosin, trimazosin and terazosin are the prototypes of selective alpha 1-adrenoceptor antagonists. Urapidil, labetalol and ketanserin are well-known examples of hybrid drugs, which possess additional pharmacological activities besides their alpha 1-adrenoceptor antagonistic potency. Labetalol is predominantly a (beta 1 + beta 2)-blocker with much weaker alpha 1-adrenoceptor antagonistic activity. The compound contains four stereoisomers with different pharmacodynamic properties and as such is not a true hybrid drug. Ketanserin is a selective 5-hydroxytryptamine (5HT2)-receptor antagonist, with modest alpha 1-adrenoceptor activity. Urapidil, a selective alpha 1-adrenoceptor antagonist, simultaneously displays central hypotensive activity which, unlike that of clonidine and related drugs, is not mediated by alpha 2-adrenoceptors. Urapidil is also a weak beta 1-blocker. It consists of one single molecule without stereoisomers and is therefore a true hybrid drug, combining two or more activities in the same molecule. Urapidil's obvious central hypotensive activity, which is caused by an unusual, so far unknown mechanism, is an interesting feature, which may contribute to the absence of reflex tachycardia.