ALDOMET

Methyldopa, or α-methyldopa, is a centrally acting sympatholytic agent and an antihypertensive agent.

It is an analog of

DOPA (3,4‐hydroxyphenylanine), and it is a prodrug, meaning that the drug requires biotransformation to an active metabolite for therapeutic effects.

Methyldopa works by binding to alpha(α)-2 adrenergic receptors as an agonist, leading to the inhibition of adrenergic neuronal outflow and reduction of vasoconstrictor adrenergic signals.

Methyldopa exists in two isomers

D-α-methyldopa and L-α-methyldopa, which is the active form.

First introduced in as an antihypertensive agent, methyldopa was considered to be useful in certain patient populations, such as pregnant women and patients with renal insufficiency.

Since then, methyldopa was largely replaced by newer, better-tolerated antihypertensive agents; 4 however, it is still used as monotherapy 11 or in combination with hydrochlorothiazide.

Methyldopa is also available as intravenous injection, which is used to manage hypertension when oral therapy is unfeasible and to treat hypertensive crisis.

Methyldopa is indicated for the management of hypertension as monotherapy 11 or in combination with hydrochlorothiazide.

Methyldopa injection is used to manage hypertensive crises.

Antihypertensive effects of methyldopa are mostly mediated by its pharmacologically active metabolite, alpha-methylnorepinephrine, which works as an agonist at central inhibitory alpha-adrenergic receptors.

Stimulation of alpha-adrenergic receptors leads to decreased peripheral sympathetic tone and reduced arterial pressure.

Methyldopa causes a net reduction in the tissue concentration of serotonin, dopamine, norepinephrine, and epinephrine.

Overall, methyldopa lowers both standing blood pressure and especially supine blood pressure, with infrequent symptomatic postural hypotension.

Methyldopa also reduces plasma renin activity but has negligible effects on glomerular filtration rate, renal blood flow, or filtration fraction.

It also has no direct effect on cardiac function but in some patients, a slowed heart rate may occur.

Following oral administration, blood-pressure-lowering effects are observed within 12-24 hours in most patients, and a maximum reduction in blood pressure occurs in 4-6 hours.

Blood pressure returns to pre-treatment levels within 24-48 hours following drug discontinuation.

Following intravenous administration, the blood-pressure-lowering effects of methyldopa last for about 10-16 hours.

Methyldopa is incompletely absorbed from the gastrointestinal tract following oral administration.

In healthy individuals, the inactive D-isomer is less readily absorbed than the active L-isomer.

The mean bioavailability of methyldopa is 25%, ranging from eight to 62%.

Following oral administration, about 50% of the dose is absorbed and T max is about three to six hours. 6, 4.

The apparent volume of distribution ranges between 0.19 and 0.32 L/kg and the total volume of distribution ranges from 0.41-0.72 L/kg. Since methyldopa is lipid-soluble 4, it crosses the placental barrier, appears in cord blood, and appears in breast milk.

Two isomers of methyldopa undergo different metabolic pathways.

L-α-methyldopa is biotransformed to its pharmacologically active metabolite, alpha-methylnorepinephrine.

Methyldopa is extensively metabolized in the liver to form the main circulating metabolite in the plasma, alpha (α)-methyldopa mono-O-sulfate.

Its other metabolites also include 3-O-methyl-α-methyldopa; 3,4-dihydroxyphenylacetone; α-methyldopamine; and 3-O-methyl-α-methyldopamine.

These metabolites are further conjugated in the liver to form sulfate conjugates.

After intravenous administration, the most prominent metabolites are alpha-methyldopamine and the glucuronide of dihydroxyphenylacetone, along with other uncharacterized metabolites.

D-α-methyldopa, which is the inactive isomer of methyldopa, is also metabolized to 3-O-methyl-α-methyldopa and 3,4-dihydroxyphenylacetone to a minimal extent; however, there are no amines (α-methyldopamine and 3-O-methyl-α-methyldopamine) formed.

Hover over products below to view reaction partners Methyldopa 3-O-methyl-alpha-methyldopa 3-O-methyl-alpha-methyldopa sulfate Alpha-methyldopamine Alpha-methylnorepinephrine Alpha-methylepinephrine 3-O-methyl-alpha-methyldopamine Alpha-methyldopa-mono-O-sulfate 3,4-Dihydroxyphenylacetone 3,4-Dihydroxyphenylacetone glucuronide.

Approximately 70% of absorbed methyldopa is excreted in the urine as unchanged parent drug (24%) and α-methyldopa mono-O-sulfate (64%), 6, 11 with variability.3-O-methyl-α-methyldopa accounted for about 4% of urinary excretion products.

Other metabolites like 3,4-dihydroxyphenylacetone, α-methyldopamine, and 3-O-methyl-α-methyldopamine are also excreted in urine.

Unabsorbed drug is excreted in feces as the unchanged parent compound.

After oral doses, excretion is essentially complete in 36 hours.

Due to attenuated excretion in patients with renal failure, accumulation of the drug and its metabolites may occur, 4 possibly leading to more profound and prolonged hypotensive effects in these patients.

The plasma half-life of methyldopa is 105 minutes.

Following intravenous injection, the plasma half-life of methyldopa ranges from 90-127 minutes.

The renal clearance is about 130 mL/min in normal subjects and is decreased in patients with renal insufficiency.

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The lowest published toxic dose via oral route is 44 gm/kg/3Y (intermittent) in a female.

LD is 5000 mg/kg in rats and 5300 mg/kg in mice.

LD is 300 mg/kg in rats and 150 mg/kg in mice.

Acute overdosage is characterized by acute hypotension and other presentations attributed to the brain and gastrointestinal dysfunction, such as excessive sedation, weakness, bradycardia, dizziness, light-headedness, constipation, distention, flatus, diarrhea, nausea, and vomiting.

Symptomatic and supportive measures should be initiated in the event of methyldopa overdose.

Overdosage following recent oral ingestion can be managed by gastric lavage or emesis, as well as infusions to limit further drug absorption.

Cardiac rate and output, blood volume, electrolyte balance, paralytic ileus, urinary function and cerebral activity should be closely monitored.

The use of sympathomimetic drugs such as levarterenol, epinephrine, and metaraminol bitartrate, or dialysis may be considered.

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 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 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 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 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.

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.

The usual starting dosage of methyldopa tablets is 250 mg two to three times a day in the first 48 hours.

The daily dosage then may be increased or decreased, preferably at intervals of not less than 2 days, until an adequate response is achieved.

To minimize the sedation, start dosage increases in the evening.

By adjustment of dosage, morning hypotension may be prevented without sacrificing control of afternoon blood pressure.

When methyldopa tablets are given to patients on other antihypertensives, the dose of these agents may need to be adjusted to effect a smooth transition.

When methyldopa tablets are given with anti-hypertensives other than thiazides, the initial dosage of methyldopa tablets should be limited to 500 mg daily in divided doses; when methyldopa tablets are added to a thiazide, the dosage of thiazide need not be changed.

The usual daily dosage of methyldopa tablets is 500 mg to 2 g in two to four doses.

Although occasional patients have responded to higher doses, the maximum recommended daily dosage is 3 g.

Once an effective dosage range is attained, a smooth blood pressure response occurs in most patients in to 24 hours.

Since methyldopa has a relatively short duration of action, withdrawal is followed by return of hypertension usually within 48 hours.

This is not complicated by an overshoot of blood pressure.

Occasionally tolerance may occur, usually between the second and third month of therapy.

Adding a diuretic or increasing the dosage of methyldopa frequently will restore effective control of blood pressure.

A thiazide may be added at any time during methyldopa therapy and is recommended if therapy has not been started with a thiazide or if effective control of blood pressure cannot be maintained on 2 g of methyldopa daily.

Methyldopa is largely excreted by the kidney and patients with impaired renal function may respond to smaller doses.

Syncope in older patients may be related to an increased sensitivity and advanced arteriosclerotic vascular disease.

This may be avoided by lower doses.

Initial dosage is based on 10 mg/kg of body weight daily in two to four doses.

The daily dosage then is increased or decreased until an adequate response is achieved.

The maximum dosage is 65 mg/kg or 3 g daily, whichever is less.

Tablets, USP are supplied as film-coated tablets containing either 250 mg or 500 mg of Methyldopa, USP.

The 250 mg tablet is a beige, film-coated, round, biconvex, beveled-edge tablet debossed with “RA04” on one side of the tablet and plain on the other side.

They are available as follows

NDC 64980-571-01 bottles of 100 tablets The 500 mg tablet is a beige, film-coated, capsule-shaped, biconvex, beveled-edge tablet debossed with “RA05” on one side of the tablet and plain on the other side.

NDC 64980-572-01 bottles of 100 tablets Store at 20° to 25°C (68° to 77°F).

Protect from light.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. † The brands listed are trademarks of their respective owners.

Manufactured for

Brunswick, NJ 08816 Issued: 08/2024 200722 PIR57250-01.

Reproduction studies performed with methyldopa at oral doses up to 1000 mg/kg in mice, 200 mg/kg in rabbits and 100 mg/kg in rats revealed no evidence of harm to the fetus.

These doses are 16.6 times, 3.3 times and 1.7 times, respectively, the maximum daily human dose when compared on the basis of body weight; 1.4 times, 1.1 times and 0.2 times, respectively, when compared on the basis of body surface area; calculations assume a patient weight of 50 kg. There are, however, no adequate and well-controlled studies in pregnant women in the first trimester of pregnancy.

Because animal reproduction studies are not always predictive of human response, methyldopa should be used during pregnancy only if clearly needed.

Published reports of the use of methyldopa during all trimesters indicate that if this drug is used during pregnancy the possibility of fetal harm appears remote.

In five studies, three of which were controlled, involving 332 pregnant hypertensive women, treatment with methyldopa was associated with an improved fetal outcome.

The majority of these women were in the third trimester when methyldopa therapy was begun.

In one study, women who had begun methyldopa treatment between weeks and 20 of pregnancy gave birth to infants whose average head circumference was reduced by a small amount (34.2 ± 1.7 cm vs. 34.6 ± 1.3 cm [mean ± 1 S.D).

Long-term follow-up of 195 (97.5%) of the children born to methyldopa-treated pregnant women (including those who began treatment between weeks and 20) failed to uncover any significant adverse effect on the children.

At 4 years of age, the developmental delay commonly seen in children born to hypertensive mothers was less evident in those whose mothers were treated with methyldopa during pregnancy than those whose mothers were untreated.

The children of the treated group scored consistently higher than the children of the untreated group on five major indices of intellectual and motor development.

At age and one-half, developmental scores and intelligence indices showed no significant differences in children of treated or untreated hypertensive women.

Methyldopa appears in breast milk.

Therefore, caution should be exercised when methyldopa is given to a nursing woman.

There are no well-controlled clinical trials in pediatric patients.

Information on dosing in pediatric patients is supported by evidence from published literature regarding the treatment of hypertension in pediatric patients. See DOSAGE AND ADMINISTRATION..

Of the total number of subjects in clinical studies of methyldopa, 223 patients were 65 years of age and over, while 33 patients were 75 years of age and over.

No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. See DOSAGE AND ADMINISTRATION. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function.