Indications
Methyldopa is primarily indicated for the management of hypertension and can be used effectively as monotherapy or in combination with hydrochlorothiazide. Additionally, methyldopa injection is utilized to address hypertensive crises, providing a versatile option in the treatment of elevated blood pressure levels.
Pharmacodynamics
The antihypertensive effects of methyldopa are largely attributed to its active metabolite, alpha-methylnorepinephrine, which functions as an agonist at central inhibitory alpha-adrenergic receptors. This stimulation results in decreased peripheral sympathetic tone and a subsequent reduction in arterial pressure. Methyldopa lowers the concentration of neurotransmitters like serotonin, dopamine, norepinephrine, and epinephrine in tissues. It effectively reduces both standing and supine blood pressure while minimizing incidences of symptomatic postural hypotension. Additionally, methyldopa decreases plasma renin activity without significantly affecting the glomerular filtration rate, renal blood flow, or filtration fraction. While the drug does not directly influence cardiac function, some patients may experience a slowed heart rate.
Absorption
When administered orally, methyldopa is incompletely absorbed from the gastrointestinal tract, with its bioavailability averaging around 25%, though it can range from 8% to 62%. The absorption of the active L-isomer is more efficient compared to the inactive D-isomer. Upon oral intake, approximately 50% of the dose is absorbed, reaching peak plasma concentration (Tmax) within three to six hours.
Metabolism
Methyldopa undergoes extensive metabolism, with its isomers following different pathways. The L-α-methyldopa is converted into the active metabolite alpha-methylnorepinephrine, whereas the primary circulating metabolite in plasma is alpha-methyldopa mono-O-sulfate. Other metabolites include 3-O-methyl-α-methyldopa, 3,4-dihydroxyphenylacetone, and α-methyldopamine, which are further conjugated in the liver to form sulfate conjugates. After intravenous administration, predominant metabolites include alpha-methyldopamine and the glucuronide of dihydroxyphenylacetone, along with several uncharacterized metabolites. The inactive D-α-methyldopa is minimally metabolized to 3-O-methyl-α-methyldopa and 3,4-dihydroxyphenylacetone, without the formation of amines such as α-methyldopamine.
Mechanism of Action
Methyldopa's mechanism of action is not entirely understood, but its primary function involves interaction with alpha-adrenergic receptors and, to a lesser degree, the aromatic L-amino acid decarboxylase enzyme. The regulation of sympathetic outflow is facilitated by alpha-2 adrenergic receptors and imidazoline receptors situated on adrenergic neurons in the rostral ventrolateral medulla. Methyldopa undergoes metabolism to form α-methylnorepinephrine, through dopamine beta-hydroxylase activity, and subsequently α-methylepinephrine via phenylethanolamine-N-methyltransferase activity. These active metabolites act as agonists at presynaptic alpha-2 adrenergic receptors located in the brainstem, thereby mediating methyldopa's therapeutic effects. By stimulating these receptors, the adrenergic neuronal outflow is inhibited, leading to a decreased release of norepinephrine within the brainstem. This process diminishes the transmission of vasoconstrictor signals to the peripheral sympathetic nervous system, ultimately resulting in lowered blood pressure. Additionally, the L-isomer of alpha-methyldopa contributes to blood pressure reduction by inhibiting aromatic L-amino acid decarboxylase, also known as DOPA decarboxylase, which is crucial for dopamine and serotonin synthesis. The inhibition of this enzyme leads to a minor depletion of biogenic amines such as norepinephrine, although this pathway plays a relatively minimal role in the blood-pressure-lowering effect of methyldopa.
