CENTRALLY ACTING SYMPATHOPLEGIC DRUGS
Centrally acting sympathoplegic drugs were once widely used in the treatment of hypertension. With the exception of clonidine, these drugs are rarely used today.
These agents reduce sympathetic outflow from vasomotor centers in the brainstem but allow these centers to retain or even increase their sensitivity to baroreceptor control. Accordingly, the antihy-pertensive and toxic actions of these drugs are generally less depen-dent on posture than are the effects of drugs that act directly on peripheral sympathetic neurons.Methyldopa (L-α-methyl-3,4-dihydroxyphenylalanine) is ananalog of L-dopa and is converted to α-methyldopamine and α-methylnorepinephrine; this pathway directly parallels the synthesisof norepinephrine from dopa illustrated in Figure 6–5. Alpha-methylnorepinephrine is stored in adrenergic nerve vesicles, where it stoichiometrically replaces norepinephrine, and is released by nerve stimulation to interact with postsynaptic adrenoceptors. However, this replacement of norepinephrine by a false transmitter in periph-eral neurons is not responsible for methyldopa’s antihypertensive effect, because the α-methylnorepinephrine released is an effective agonist at the α adrenoceptors that mediate peripheral sympathetic constriction of arterioles and venules. In fact, methyldopa’s antihy-pertensive action appears to be due to stimulation of centralα adre-noceptors by α-methylnorepinephrine or α-methyldopamine.
The antihypertensive action of clonidine, a 2-imidazoline derivative, was discovered in the course of testing the drug for use as a nasal decongestant.
After intravenous injection, clonidine produces a brief rise in blood pressure followed by more prolonged hypotension. The pressor response is due to direct stimulation of α adrenoceptors in arterioles. The drug is classified as a partial agonist at α receptors because it also inhibits pressor effects of other α agonists.
Considerable evidence indicates that the hypotensive effect of clonidine is exerted at α adrenoceptors in the medulla of the brain. In animals, the hypotensive effect of clonidine is prevented by central administration of αantagonists. Clonidine reduces sympathetic and increases parasympathetic tone, resulting in blood pressure lowering and bradycardia. The reduction in pres-sure is accompanied by a decrease in circulating catecholamine levels. These observations suggest that clonidine sensitizes brain-stem vasomotor centers to inhibition by baroreflexes.
Thus, studies of clonidine and methyldopa suggest that nor-mal regulation of blood pressure involves central adrenergic neurons that modulate baroreceptor reflexes. Clonidine and α-methylnorepinephrine bind more tightly to α2 than to α1 adreno-ceptors. As noted, α2 receptors are located on presynaptic adrenergic neurons as well as some postsynaptic sites. It is possible that clonidine and α-methylnorepinephrine act in the brain to reduce norepinephrine release onto relevant receptor sites. Alternatively, these drugs may act on postsynaptic α2 adre-noceptors to inhibit activity of appropriate neurons. Finally, cloni-dine also binds to a nonadrenoceptor site, the imidazolinereceptor, which may also mediate antihypertensive effects.
Methyldopa and clonidine produce slightly different hemody-namic effects: clonidine lowers heart rate and cardiac output more than does methyldopa. This difference suggests that these two drugs do not have identical sites of action. They may act primarily on different populations of neurons in the vasomotor centers of the brainstem.
Guanabenz and guanfacine are centrally active antihyperten-sive drugs that share the central α-adrenoceptor–stimulating effects of clonidine. They do not appear to offer any advantages over clonidine and are rarely used.