Methyldopa (l-α-methyl-3,4-dihydroxyphenylalanine) is an analog of l-dopa and is converted to α-methyldopamine and α-methylnorepinephrine; this pathway directly parallels the synthesis of norepinephrine from dopa illustrated in Figure 6–5. Alphamethylnorepinephrine 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 peripheral 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 anti-hypertensive action appears to be due to stimulation of central α adrenoceptors 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 α antagonists. Clonidine reduces sympathetic and increases parasympathetic tone, resulting in blood pressure lowering and bradycardia. The reduction in pressure 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 normal regulation of blood pressure involves central adrenergic neurons that modulate baroreceptor reflexes. Clonidine and α-methylnorepinephrine bind more tightly to α2 than to α1 adrenoceptors. As noted in Chapter 6, 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 adrenoceptors to inhibit activity of appropriate neurons. Finally, clonidine also binds to a nonadrenoceptor site, the imidazoline receptor, which may also mediate antihypertensive effects.
Methyldopa and clonidine produce slightly different hemodynamic 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 brain stem.
Guanabenz and guanfacine are centrally active antihypertensive 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.
chiefly by reducing peripheral vascular resistance, with a variable reduction in heart rate and cardiac output.
Most cardiovascular reflexes remain intact after administration of methyldopa, and blood pressure reduction is not markedly dependent on posture. Postural (orthostatic) hypotension sometimes occurs, particularly in volume-depleted patients. One potential advantage of methyldopa is that it causes reduction in renal vascular resistance.