Conclusions on the position of urapidil

Abstract

rapid& a derivative of uracil, combines 2 and possiU bly more pharmacologic activities in its molecule. Because this molecule is not composed of any stereoisomers but consists of 1 single chemical entity, urapidil is an example of a true hybrid drug. Urapidil is an a-adrenoceptor antagonist with a certain selectivity for q adrenoceptors, which is less pronounced than that of prazosin, the prototype of selective (~1 blockers. The qadrenoceptor antagonistic activity of urapidil, which can be readily demonstrated in various animal models, in human volunteers and in hypertensive patients, is probably the most important background of its vasodilator and antihypertensive potency. Urapidil is a weak ,&-adrenoceptor antagonist with intrinsic sympathomimetic activity, but Badrenoceptor blockade does not play any role when urapidil is applied as a therapeutic dose in humans. Peripheral activities other than a-adrenoceptor blockade do not contribute to urapidil’s antihypertensive effect, but an additional central hypotensive mechanism can be readily demonstrated in animal models. Although central hypotensive activity is very difficult to demonstrate in humans, there is circumstantial evidence that suggests that such a mechanism may play an additional role when urapidil is applied in humans. This central mechanism in animals is obviously different from that of the classic centrally acting antihypertensive agents clonidine and (Ymethyl-dihydroxyphenylalanine, which act through the stimulation of central (~2 adrenoceptors, whereas such receptors are not involved in urapidil’s central hypotensive activity. In contrast, most (but not all) animal pharmacologic studies suggest that urapidil is a selective agonist at the level of the S-HTIA receptors in the Bi or Bs regions of the ventral medulla, thus inhibiting the serotonergic neurons that are excitatory to the preganglionic sympathetic neurons in the intermediolateral cell column of the spinal cord. This mechanism is currently assumed to be the basis of the drug’s central hypotensive activity.