α2-adrenergic receptors and imidazoline1-receptors in the medulla/pons are the main site of action of central 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 eventually converted into α-methylnorepinephrine, the active metabolite. 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. So, actually it mimics the autoinhibitory action of norepinephrine.
Verdana, Arial; font-size: medium; background-color: #e4eaff;">Methyldopa probably also acts as 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 effects are sedation with decreased reaction and concentration, due to the inhibition of brain centres involved in alertness and wakefulness (α2-receptors). Dry mouth is another common side effect. Methyldopa can also cause serious, but rare hepatotoxicity and hemolytic anemia. Methyldopa is regarded by many as a drug of choice for managing hypertension during pregnancy, mainly because of its long established safety profile.
Check the cardiology section for more information on central acting antihypertensives.
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Extra info: By occupying the presynaptic α2-receptors, α-methylnorepinephrine strengthens the inhibition of norepinephrine (NE) secretion in the synapse. To compensate for this decrease of NE, the α2-receptors are down-regulated to prevent more inhibition by α-methylnorepinephrine. Consequently, when one stops methyldopa therapy, there is no inhibition of NE secretion and a rebound hypertension occurs. Methyldopa’s absorption is around 50% when given orally.