Methyldopa (aldomet) is a centrally acting antihypertensive agent that exerts its antihypertensive action via an active metabolite. Methyldopa's significant adverse effects currently limit its use in the U.S. to treatment of hypertension in pregnancy, where it has a record for safety. Methyldopa (a-methyl-3,4-dihydroxy-l-phenylalanine), an analog of 3,4-dihydroxyphenylalanine (DOPA), is metabolized by the l-aromatic amino acid decarboxylase in adrenergic neurons to a-methyldopamine, which then is converted to a-methyl-NE. a-Methylnorepinephrine is stored in the secretory vesicles of adrenergic neurons, substituting for NE. Thus, when adrenergic neurons discharge neurotransmitter, a-methyl-NE is released instead of NE. Because a-methyl-NE is as potent a vasoconstrictor as NE, its substitution for NE in peripheral adrenergic neurosecretory vesicles does not alter the vasoconstrictor response to peripheral adrenergic neurotransmission. Rather, a-methylnorepinephrine acts in the CNS to inhibit adrenergic neuronal outflow from the brainstem. Methylnorepinephrine probably acts as an agonist at presynaptic a2 adrenergic receptors in the brainstem, attenuating NE release and thereby reducing the output of vasoconstrictor adrenergic signals to the peripheral sympathetic nervous system.
PHARMACOLOGICAL EFFECTS In younger patients with uncomplicated essential hypertension, methyldopa reduces vascular resistance without much change in cardiac output or heart rate. In older patients, cardiac output may be decreased as a result of decreased heart rate and stroke volume secondary to relaxation of veins and reduced preload. The fall in arterial pressure is maximal 6-8 hours after an oral or intravenous dose. Although the decrease in supine blood pressure is less than that in the upright position, symptomatic orthostatic hypotension is less common with methyldopa than with drugs that act exclusively on peripheral adrenergic neurons or autonomic ganglia; this is because methyldopa attenuates but does not completely block baroreceptor-mediated vasoconstriction. It therefore is well tolerated during surgical anesthesia. Any severe hypotension is reversible with volume expansion. Renal blood flow is maintained and renal function is unchanged during treatment with methyldopa.
Plasma concentrations of NE fall in association with reduction in arterial pressure, reflecting decreased sympathetic tone. Renin secretion also is reduced, but this is not necessary for methyl-dopa's hypotensive effects. Salt and water often are gradually retained with prolonged use, blunting the antihypertensive effect. This effect, termed "pseudo-tolerance," can be overcome with concurrent use of a diuretic.
ABSORPTION, METABOLISM, AND EXCRETION When administered orally, methyl-dopa is absorbed by an active amino acid transporter. Peak plasma concentrations occur after 2-3 hours. The drug is eliminated with a t1/2 of ~2 hours (prolonged to 4-6 hours in patients with renal failure). Methyldopa transport into the CNS apparently is an active process. Methyldopa is excreted in the urine primarily as the sulfate conjugate (50-70%) and as the parent drug (25%). The remainder is excreted as other metabolites, including methyldopamine, methylnorepinephrine, and O-methylated products of these catecholamines.
In spite of its rapid absorption and short t1/2, the peak effect of methyldopa is delayed for 6-8 hours, even after intravenous administration, and the duration of action of a single dose is usually ~24 hours; this permits once- or twice-daily dosing. The discrepancy between the effects and the measured concentrations of the drug in plasma is likely related to the time required for transport into the CNS, conversion to the active metabolite, storage of a-methyl-NE and its subsequent release in the vicinity of relevant a2 receptors in the CNS.
ADVERSE EFFECTS AND PRECAUTIONS In addition to lowering blood pressure, the active metabolite of methyldopa acts on a2 adrenergic receptors in the brainstem to inhibit the centers that are responsible for wakefulness and alertness, producing sedation that is largely transient. Decreased mental acuity and lassitude may persist in some patients, and depression occurs occasionally. Medullary centers that control salivation are inhibited by a adrenergic receptors, and methyldopa may produce dry mouth. Other side effects related to pharmacological effects in the CNS include decreased libido, parkinsonian signs, and hyperprolactinemia that may become sufficiently pronounced to cause galactorrhea. In individuals who have sinoatrial node dysfunction, methyldopa may precipitate severe bradycardia and sinus arrest, including that which occurs with carotid sinus hypersensitivity.
Methyldopa also produces adverse effects that are unrelated to its pharmacological action. Hepa-totoxicity, sometimes associated with fever, is an uncommon but potentially serious toxic effect. Prompt diagnosis of hepatotoxicity requires a low threshold for considering the drug as a cause for hepatitis-like symptoms (e.g., nausea, anorexia) and screening for hepatotoxicity (e.g., with determination of hepatic transaminases) after 3 weeks and again 3 months after initiation of treatment. The incidence of methyldopa-induced hepatitis is unknown, but ~5% of patients will have transient increases in hepatic transaminases in plasma. Hepatic dysfunction usually is reversible with prompt drug discontinuation but will recur if methyldopa is given again; a few cases of fatal hepatic necrosis have been reported. It is advisable to avoid the use of methyldopa in patients with hepatic disease.
Methyldopa can cause hemolytic anemia. At least 20% of patients who receive methyldopa for a year develop a positive Coombs test due to autoantibodies directed against the Rh antigen on erythrocytes. This does not necessitate drug discontinuation; 1—5% of these patients will develop a hemolytic anemia that mandates prompt drug discontinuation. The Coombs test may remain positive for as long as a year after discontinuation of methyldopa, but the hemolytic anemia usually resolves within a matter of weeks. Severe hemolysis may be attenuated by treatment with glu-cocorticoids. Rarer adverse effects include leukopenia, thrombocytopenia, red cell aplasia, lupus erythematosus—like syndrome, lichenoid and granulomatous skin eruptions, myocarditis, retroperitoneal fibrosis, pancreatitis, diarrhea, and malabsorption.
THERAPEUTIC USES Methyldopa is a preferred drug for treatment of hypertension during pregnancy based on its effectiveness and safety for both mother and fetus. The usual initial dose of methyldopa is 250 mg twice daily, and there is little additional effect with doses >2 g/day. Administration of a single daily dose of methyldopa at bedtime minimizes sedative effects, but administration twice daily is required for some patients.
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Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...