Domepa Mechanism of Action

Pharmacology: Methyldopa is a hypotensive agent that is structurally related to the catecholamine and their precursors. Although the mechanism of action has to be continually demonstrated, the antihypertensive effect of methyldopa probably is due to its metabolism in the central nervous system to alpha-methyl-norepinephrine which is thought to stimulate adrenergic alpha receptors resulting in a reduction in sympathetic tone and a fall in blood pressure. Therefore, methyldopa is considered as sympatholytic agent with central action.
Reduction in plasma renin activity may also contribute to the antihypertensive effect of methyldopa. Methyldopa inhibits decarboxylation of dihydroxyphenylalanine (dopa) (precursor of norepinephrine) and of 5-hydroxytryptophan (precursor of serotonin) in the central nervous system and in most peripheral tissues. Although the major hypotensive effect is not attributed to decarboxylase inhibition, some contribution by peripheral mechanism cannot be ruled out. Methyldopa has been proven to decrease tissue concentrations of serotonin, dopamine, norepinephrine and epinephrine.
Methyldopa lowers the blood pressure both in standing and when lying down. Methyldopa has no direct effect on kidney and heart function. Heart minute volume is usually maintained, without any increase of pulse beat-frequency. In some cases one may see that the pulse heart rate decreases. Glomerular filtration, kidney blood flow or filtration fraction is usually not affected. This means that effective blood pressure control can be maintained also in patients with decreased kidney function. Symptoms of postural hypotension, hypotension during and variation in blood pressure during the period are very rarely seen problems.
Methyldopa can be used in combination with other blood pressure lowering drugs, especially with thiazide diuretics and including combination of thiazide plus amiloride. Methyldopa can also be combined with beta receptor blocking drugs.
Pharmacokinetics: Since the key to the effect of methyldopa is through its metabolism to alpha-methyl-norepinephrine, the plasma concentration of methyldopa itself has limited relevance predicted effect.
The absorption of methyldopa is incomplete. Average bioavailability only reaches 25% of given dose and the variation between individuals is very large. Maximum plasma concentration is reached within 2-4 hours after an oral dose. The antihypertensive effect is maximal in 4-6 hours after a single oral dose. Plasma half-life is 1-2 hours in patients with normal kidney function and increases when kidney function decreases. Volume of distribution is 0.6 liter/kg.
Approximately 70% of given dose is excreted in the urine, where of 60% as free methyldopa and the rest as conjugated metabolites.