CLINICAL PHARMACOLOGY
Methyldopa is an aromatic-amino-acid decarboxylase inhibitor
in animals and in man. Although the mechanism of action
has yet to be conclusively demonstrated, the antihypertensive
effect of methyldopa probably is due to its metabolism
to alpha-methylnorepinephrine, which then lowers arterial
pressure by stimulation of central inhibitory alpha-adrenergic
receptors, false neurotransmission, and/or reduction of
plasma renin activity. Methyldopa has been shown to cause
a net reduction in the tissue concentration of serotonin,
dopamine, norepinephrine, and epinephrine.
Only methyldopa, the L-isomer of alpha-methyldopa, has
the ability to inhibit dopa decarboxylase and to deplete
animal tissues of norepinephrine. In man, the antihypertensive
activity appears to be due solely to the L-isomer. About
twice the dose of the racemate (DL-alpha-methyldopa) is
required for equal antihypertensive effect.
Methyldopa has no direct effect on cardiac function and
usually does not reduce glomerular fiftration rate, renal
blood flow, or filtration fraction. Cardiac output usually
is maintained without cardiac acceleration. In some patients
the heart rate is slowed.
Normal or elevated plasma renin activity may decrease
in the course of methyldopa therapy. Methyldopa reduces
both supine and standing blood pressure. Methyldopa usually
produces highly effective lowering of the supine pressure
with infrequent symptomatic postural hypotension. Exercise
hypotension and diurnal blood pressure variations rarely
occur.
Pharmacoklnetlcs and Metabolism
The maximum decrease in blood pressure occurs four to
six hours after oral dosage. Once an effective dosage
level is attained, a smooth blood pressure response occurs
in most patients in 12 to 24 hours.After withdrawal, blood
pressure usually returns to pretreatment levels within
24-48 hours.
Methyldopa is extensivefy metabolized. The known urinary
metabolites are: a-methyldopa mono- O-sulfate;3-0-methyl-a-methyldopa;3.4,-dihydroxyphenylacetone;
a-methyldopamine;3-0- methyl-a-methyldopamine and their
conjugates.
Approximately 70% of the drug which is absorbed is excreted
in the urine as methyldopa and its mono-O-sulfate conjugate.
The renal clearance is about 130 mL/min . in normal subjects
and is diminished in renal insufficiency. The plasma half-life
of methyldopa is 105 minutes. After oral doses, excretion
is essentially complete in 36 hours.
Methyldopa crosses the placental barrier, appears in
cord blood, and appears in breast milk.
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