Methyldopa

METHYLDOPA- methyldopa tablet
Mylan Institutional Inc.

Methyldopa is an antihypertensive and is the L-isomer of alpha-methyldopa. It is levo-3-(3,4-dihydroxyphenyl)-2-methylalanine sesquihydrate. Methyldopa is supplied as tablets for oral administration, containing 250 mg and 500 mg of methyldopa. The amount of methyldopa is calculated on the anhydrous basis. Its molecular formula is C 10 H 13 NO 4 •1 1/2 H 2 O, with a molecular weight of 238.24, and its structural formula is:

Methyldopa Structural Formula

Methyldopa is a white to yellowish white, odorless fine powder and is sparingly soluble in water.

The tablets contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, sodium lauryl sulfate, titanium dioxide, triacetin, FD&C yellow No. 6 aluminum lake and FD&C blue No. 2 aluminum lake.

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 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. It usually produces highly effective lowering of the supine pressure with infrequent symptomatic postural hypotension. Exercise hypotension and diurnal blood pressure variations rarely occur.

Pharmacokinetics 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 to 48 hours.

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% 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.

INDICATIONS AND USAGE

Hypertension.

CONTRAINDICATIONS

Methyldopa is contraindicated in patients:

  • with active hepatic disease, such as acute hepatitis and active cirrhosis.
  • with liver disorders previously associated with methyldopa therapy (see WARNINGS).
  • with hypersensitivity to any component of this product.
  • on therapy with monoamine oxidase (MAO) inhibitors.

WARNINGS

It is important to recognize that a positive Coombs test, hemolytic anemia, and liver disorders may occur with methyldopa therapy.The rare occurrences of hemolytic anemia or liver disorders could lead to potentially fatal complications unless properly recognized and managed. Read this section carefully to understand these reactions.

With prolonged methyldopa therapy, 10% to 20% of patients develop a positive direct Coombs test which usually occurs between 6 and 12 months of methyldopa therapy. Lowest incidence is at daily dosage of 1 g or less. This on rare occasions may be associated with hemolytic anemia, which could lead to potentially fatal complications. One cannot predict which patients with a positive direct Coombs test may develop hemolytic anemia.

Prior existence or development of a positive direct Coombs test is not in itself a contraindication to use of methyldopa. If a positive Coombs test develops during methyldopa therapy, the physician should determine whether hemolytic anemia exists and whether the positive Coombs test may be a problem. For example, in addition to a positive direct Coombs test there is less often a positive indirect Coombs test which may interfere with cross matching of blood.

Before treatment is started, it is desirable to do a blood count (hematocrit, hemoglobin, or red cell count) for a baseline or to establish whether there is anemia. Periodic blood counts should be done during therapy to detect hemolytic anemia. It may be useful to do a direct Coombs test before therapy and at 6 and 12 months after the start of therapy.

If Coombs-positive hemolytic anemia occurs, the cause may be methyldopa and the drug should be discontinued. Usually the anemia remits promptly. If not, corticosteroids may be given and other causes of anemia should be considered. If the hemolytic anemia is related to methyldopa, the drug should not be reinstituted.

When methyldopa causes Coombs positivity alone or with hemolytic anemia, the red cell is usually coated with gamma globulin of the lgG (gamma G) class only. The positive Coombs test may not revert to normal until weeks to months after methyldopa is stopped.

Should the need for transfusion arise in a patient receiving methyldopa, both a direct and an indirect Coombs test should be performed. In the absence of hemolytic anemia, usually only the direct Coombs test will be positive. A positive direct Coombs test alone will not interfere with typing or cross matching. If the indirect Coombs test is also positive, problems may arise in the major cross match and the assistance of a hematologist or transfusion expert will be needed.

Occasionally, fever has occurred within the first 3 weeks of methyldopa therapy, associated in some cases with eosinophilia or abnormalities in one or more liver function tests, such as serum alkaline phosphatase, serum transaminases (SGOT, SGPT), bilirubin, and prothrombin time. Jaundice, with or without fever, may occur with onset usually within the first 2 to 3 months of therapy. In some patients the findings are consistent with those of cholestasis. In others the findings are consistent with hepatitis and hepatocellular injury.

Rarely, fatal hepatic necrosis has been reported after use of methyldopa. These hepatic changes may represent hypersensitivity reactions. Periodic determinations of hepatic function should be done particularly during the first 6 to 12 weeks of therapy or whenever an unexplained fever occurs. If fever, abnormalities in liver function tests, or jaundice appear, stop therapy with methyldopa. If caused by methyldopa, the temperature and abnormalities in liver function characteristically have reverted to normal when the drug was discontinued. Methyldopa should not be reinstituted in such patients.

Rarely, a reversible reduction of the white blood cell count with a primary effect on the granulocytes has been seen. The granulocyte count returned promptly to normal on discontinuance of the drug. Rare cases of granulocytopenia have been reported. In each instance, upon stopping the drug, the white cell count returned to normal. Reversible thrombocytopenia has occurred rarely.

PRECAUTIONS

General

Methyldopa should be used with caution in patients with a history of previous liver disease or dysfunction (see WARNINGS).

Some patients taking methyldopa experience clinical edema or weight gain which may be controlled by use of a diuretic. Methyldopa should not be continued if edema progresses or signs of heart failure appear.

Hypertension has recurred occasionally after dialysis in patients given methyldopa because the drug is removed by this procedure.

Rarely, involuntary choreoathetotic movements have been observed during therapy with methyldopa in patients with severe bilateral cerebrovascular disease. Should these movements occur, stop therapy.

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