| Indication |
For use in the treatment of hypertension. |
| Pharmacodynamics |
Methyldopa is an aromatic-amino-acid decarboxylase inhibitor in animals and in man. 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 filtration 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. |
| Mechanism of action |
Although the mechanism of action has yet to be conclusively
demonstrated, the resultant hypotensive effect is most likely due to the
drug's action on the CNS. Methyldopa is converted into the metabolite,
alpha-methylnorepinephrine, in the CNS, where it stimulates the central
inhibitory alpha-adrenergic receptors, leading to a reduction in
sympathetic tone, total peripheral resistance, and blood pressure.
Reduction in plasma renin activity, as well as the inhibition of both
central and peripheral norepinephrine and serotonine production may also
contribute to the drug's antihypertensive effect, although this is not a
major mechanism of action. This is done through the inhibition of the
decarboxylation of dihydroxyphenylalanine (dopa)—the precursor of
norepinephrine—and of 5-hydroxytryptophan (5-HTP)—the precursor of
serotonin—in the CNS and in most peripheral tissues. |
| Absorption |
Absorption from the gastrointestinal tract is variable but averages approximately 50%. |
| Volume of distribution |
Not Available |
| Protein binding |
Low (less than 20%). |
| Metabolism |
Hepatic, extensively metabolized. The known urinary metabolites
are: a-methyldopa mono-0-sulfate; 3-0-methyl-a-methyldopa;
3,4-dihydroxyphenylacetone; a-methyldopamine;
3-0-methyl-a-methyldopamine and their conjugates. |
| Route of elimination |
Methyldopa is extensively metabolized. The known urinary
metabolites are: α-methyldopa mono-O-sulfate; 3-0-methyl-α-methyldopa;
3,4-dihydroxyphenylacetone; α-methyldopamine;
3-0-methyl-α-methyldopamine and their conjugates. Approximately 70
percent of the drug which is absorbed is excreted in the urine as
methyldopa and its mono-O-sulfate conjugate. Methyldopa crosses the
placental barrier, appears in cord blood, and appears in breast milk. |
| Half life |
The plasma half-life of methyldopa is 105 minutes. |
| Clearance |
- Renal cl=130 mL/min [healthy]
|
| Toxicity |
The oral LD50 of methyldopa is greater than 1.5 g/kg in
both the mouse and the rat. Symptoms of overdose include bloating,
constipation, diarrhea, dizziness, extreme drowsiness, gas,
light-headedness, nausea, severely low blood pressure, slow heartbeat,
vomiting, and weakness. |
