TRC: Centrally acting antihypertensives

Centrally acting antihypertensives

α2-adrenergic receptors and I1-imidazoline receptors in the medulla/pons are the main site of action of centrally acting antihypertensives. Stimulation of these receptors results in decrease of peripheral sympathetic activity and thus in decreased blood pressure and heart frequency.

Methyldopa is a prodrug, which is ultimately converted into the active metabolite, α-methylnorepinephrine. α-methylnorepinephrine is released from neurosecretory vesicles in adrenergic neurons in the brain instead of norepinephrine in order to inhibit neuronal outflow from the brainstem. Hence, actually it mimics the autoinhibitory action of norepinephrine.

Methyldopa probably also acts as an α2-receptor agonist to attenuate output of vasoconstrictor adrenergic signals to the peripheral sympathetic nervous system. It reduces vascular resistance, without much effect on the cardiac output. Hypotension is not a common side effect, because methyldopa does not completely block baroreceptor-mediated vasoconstriction.

The main adverse effect is sedation with decreased reaction and concentration due to inhibition of brain centres involved in alertness and wakefulness (α2-receptors). Dry mouth (xerostomia) is another common side effect. Infrequently, methyldopa can also cause serious hepatotoxicity and haemolytic anaemia. Methyldopa is used to treat hypertension in pregnant women and in combination with a diuretic.

Clonidine, guanfacine, and moxonidine also stimulate α2-receptors in the brain, which results in a reduced sympathetic outflow. They also decrease cardiac output and peripheral resistance. Sedation and xerostomia occur in 50% of the cases. Bradycardia and dry mucous tissues are the main adverse effects. These drugs are used to treat hypertension in combination with diuretics, as well as pheochromocytoma. Clonidine may be associated with rapid rebound of blood pressure when treatment is stopped abruptly.