indication

For use in the treatment of hypertension.

pharmacology

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.

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.

biotransformation

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.

absorption

Absorption from the gastrointestinal tract is variable but averages approximately 50%.

half life

The plasma half-life of methyldopa is 105 minutes.

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.

drug interactions

Carteolol: Possible hypertensive crisis

Dobutamine: Increased arterial pressure

Dopamine: Increased arterial pressure

Entacapone: Entacapone may increase the effect and toxicity of the sympathomimetic, methyldopa.

Ephedra: Increased arterial pressure

Ephedrine: Increased arterial pressure

Epinephrine: Increased arterial pressure

Fenoterol: Increased arterial pressure

Haloperidol: Methyldopa increases haloperidol effect or risk of psychosis

Iron: Iron decreases the absorption of dopa derivatives

Iron Dextran: Iron decreases the absorption of dopa derivatives

Isoproterenol: Increased arterial pressure

Levodopa: Methyldopa increases the effect and toxicity of levodopa

Lithium: Methyldopa may increase the adverse effects of lithium without affecting lithium serum levels. Monitor for signs and symptoms of lithium toxicity during concomitant therapy.

Mephentermine: Increased arterial pressure

Metaraminol: Increased arterial pressure

Methoxamine: Increased arterial pressure

Nadolol: Possible hypertensive crisis

Norepinephrine: Increased arterial pressure

Orciprenaline: Increased arterial pressure

Oxprenolol: Possible hypertensive crisis

Penbutolol: Possible hypertensive crisis

Phenylephrine: Increased arterial pressure

Phenylpropanolamine: Increased arterial pressure

Pindolol: Possible hypertensive crisis

Pirbuterol: Increased arterial pressure

Procaterol: Increased arterial pressure

Propranolol: Possible hypertensive crisis

Pseudoephedrine: Increased arterial pressure

Salbutamol: Increased arterial pressure

Sotalol: Possible hypertensive crisis

Terbutaline: Increased arterial pressure

Timolol: Possible hypertensive crisis

Tranylcypromine: The MAO inhibitor, Tranylcypromine, may increase the adverse effects of Methyldopa. Concomitant therapy is contraindicated.