Drug class: Central alpha-Agonists


Methyldopa (Systemic) is also contained as an ingredient in the following combinations:
Methyldopa and Hydrochlorothiazide

Medically reviewed by Drugs.com on Apr 10, 2024. Written by ASHP.

Introduction

Hypotensive agent; centrally acting α₂-adrenergic agonist.

Uses for Methyldopa

Hypertension

Used alone or in combination with other classes of antihypertensive agents in the management of hypertension.

Not considered a preferred agent for initial management of hypertension according to current guidelines for the management of hypertension in adults, but may be used as add-on therapy if BP not adequately controlled with the recommended antihypertensive drug classes (i.e., ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, thiazide diuretics).

Generally reserved as a last-line treatment option because of the drug's ability to cause substantial adverse CNS effects, especially in geriatric patients.

May be more effective when used with a diuretic.

Use of a diuretic may prevent tolerance to methyldopa and permit reduction of methyldopa dosage.

Also has been used with other hypotensive agents, permitting a reduction in the dosage of each drug and, in some patients, minimizing adverse effects while maintaining BP control.

Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).

A 2017 ACC/AHA multidisciplinary hypertension guideline classifies BP in adults into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension. (See Table 1.)

Source: Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-115.

Individuals with SBP and DBP in 2 different categories (e.g., elevated SBP and normal DBP) should be designated as being in the higher BP category (i.e., elevated BP).

The goal of hypertension management and prevention is to achieve and maintain optimal control of BP. However, the BP thresholds used to define hypertension, the optimum BP threshold at which to initiate antihypertensive drug therapy, and the ideal target BP values remain controversial.

The 2017 ACC/AHA hypertension guideline generally recommends a target BP goal (i.e., BP to achieve with drug therapy and/or nonpharmacologic intervention) of <130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk. In addition, an SBP goal of <130 mm Hg generally is recommended for noninstitutionalized ambulatory patients ≥65 years of age with an average SBP of ≥130 mm Hg. These BP goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of SBP.

Other hypertension guidelines generally have based target BP goals on age and comorbidities. Guidelines such as those issued by the JNC 8 expert panel generally have targeted a BP goal of <140/90 mm Hg regardless of cardiovascular risk, and have used higher BP thresholds and target BPs in elderly patients compared with those recommended by the 2017 ACC/AHA hypertension guideline.

Some clinicians continue to support previous target BPs recommended by JNC 8 due to concerns about the lack of generalizability of data from some clinical trials (e.g., SPRINT study) used to support the 2017 ACC/AHA hypertension guideline and potential harms (e.g., adverse drug effects, costs of therapy) versus benefits of BP lowering in patients at lower risk of cardiovascular disease.

Consider potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs when deciding a patient's BP treatment goal.

For decisions regarding when to initiate drug therapy (BP threshold), the 2017 ACC/AHA hypertension guideline incorporates underlying cardiovascular risk factors. ASCVD risk assessment is recommended by ACC/AHA for all adults with hypertension.

ACC/AHA currently recommend initiation of antihypertensive drug therapy in addition to lifestyle/behavioral modifications at an SBP ≥140 mm Hg or DBP ≥90 mm Hg in adults who have no history of cardiovascular disease (i.e., primary prevention) and a low ASCVD risk (10-year risk <10%).

For secondary prevention in adults with known cardiovascular disease or for primary prevention in those at higher risk for ASCVD (10-year risk ≥10%), ACC/AHA recommend initiation of antihypertensive drug therapy at an average SBP ≥130 mm Hg or an average DBP ≥80 mm Hg.

Adults with hypertension and diabetes mellitus, chronic kidney disease (CKD), or age ≥65 years are assumed to be at high risk for cardiovascular disease; ACC/AHA state that such patients should have antihypertensive drug therapy initiated at a BP ≥130/80 mm Hg. Individualize drug therapy in patients with hypertension and underlying cardiovascular or other risk factors.

In stage 1 hypertension, experts state that it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target BP. Consider initiation of antihypertensive therapy with 2 first-line agents from different pharmacologic classes in patients with stage 2 hypertension and average BP >20/10 mm Hg above BP goal.

Recommended by ACOG and other experts as an appropriate drug of choice in pregnant women who require antihypertensive therapy.

Hypertensive Crises

Has been used IV for the management of hypertensive crises. Because of the slow onset of action, other agents (e.g., labetalol, esmolol, fenoldopam, nicardipine, sodium nitroprusside) are preferred.

Methyldopa Dosage and Administration

General

BP Monitoring and Treatment Goals

• Monitor BP regularly (i.e., monthly) during therapy and adjust dosage of the antihypertensive drug until BP controlled.

• If unacceptable adverse effects occur, discontinue drug and initiate another antihypertensive agent from a different pharmacologic class.

• If adequate BP response not achieved with a single antihypertensive agent, either increase dosage of single drug or add a second drug with demonstrated benefit and preferably a complementary mechanism of action (e.g., ACE inhibitor, angiotensin II receptor antagonist, calcium-channel blocker, thiazide diuretic). Many patients will require at least 2 drugs from different pharmacologic classes to achieve BP goal; if goal BP still not achieved with 2 antihypertensive agents, add a third drug.

Administration

Administer methyldopa orally and methyldopate hydrochloride by IV infusion.

Usually administer orally; may be administered IV if parenteral administration is required.

IM or sub-Q administration not recommended because of unpredictable absorption.

Oral Administration

Minimize adverse effects (e.g., drowsiness) by initiating dosage increases in the evening.

IV Administration

For solution and drug compatibility information, see Compatibility under Stability.

Dilution

Dilute methyldopate hydrochloride injection in 5% dextrose in water injection.

Add the required dose of the drug to 100 mL of 5% dextrose in water injection. Alternatively, dilute the required dose in 5% dextrose in water injection to provide a solution containing 100 mg/10 mL.

Rate of Administration

Administer slowly by IV infusion over 30–60 minutes.

Dosage

Available as methyldopa or methyldopate hydrochloride; dosage expressed in terms of methyldopa or methyldopate hydrochloride, respectively.

Pediatric Patients

Hypertension

Monotherapy

Oral

Initially, 10 mg/kg daily given in 2–4 divided doses.

Adjust dosage until an adequate response is achieved. Maximum dosage is 65 mg/kg daily, or 3 g daily, whichever is less.

IV

Usual dosage: 20–40 mg/kg per 24 hours administered in equally divided doses at 6-hour intervals.

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

When BP is controlled, should substitute oral therapy at the same dosage.

Adults

Hypertension

Monotherapy

Oral

Initially, 250 mg 2 or 3 times daily for 2 days. Increase or decrease dosage every 2 days until an adequate response is achieved.

For maintenance therapy, manufacturers recommend 0.5–2 g daily given in 2–4 divided doses.

Some experts state usual dosage range of 0.25–1 g daily in 2 divided doses; if needed, add another antihypertensive agent to the regimen rather than increasing maximum dosage to >1 g daily (poor patient tolerance).

IV

Usual dosage: 250–500 mg every 6 hours as required. Maximum dosage is 1 g every 6 hours.

Combination Therapy

Oral

Fixed combination with a thiazide diuretic is not recommended for initial combination therapy; adjust initial and subsequent dosages by administering each drug separately. Consider fixed combination if the optimum maintenance dosage corresponds to the ratio in a commercial combination preparation.

Methyldopa in fixed combination with hydrochlorothiazide: Initially, 250 mg of methyldopa and 15 mg of hydrochlorothiazide given 2–3 times daily, or 250 mg of methyldopa and 25 mg of hydrochlorothiazide given twice daily. Alternatively, 500 mg of methyldopa and either 30 or 50 mg of hydrochlorothiazide once daily.

If tolerance occurs, add separate dosages of methyldopa or replace the fixed combination with each drug separately until the new effective dosage is reestablished by titration.

Combination with hypotensive drugs other than thiazide diuretics: Initially, maximum recommended dosage is 500 mg daily in divided doses. Adjust dosage of other hypotensive drugs if necessary.

Prescribing Limits

Pediatric Patients

Hypertension

Oral

Maximum 65 mg/kg daily, or 3 g daily, whichever is less.

IV

Maximum 65 mg/kg daily, or 3 g daily, whichever is less.

Adults

Hypertension

Oral

Maximum 3 g daily as maintenance therapy recommended by manufacturers. Some experts recommend maximum 1 g daily because of poor patient tolerance.

Combination therapy with hypotensive drugs other than thiazide diuretics: Initially, maximum 500 mg daily in divided doses.

IV

Maximum 1 g every 6 hours.

Special Populations

Renal Impairment

Consider dosage reduction.

Geriatric Patients

Consider dosage reduction to avoid syncope. (See Geriatric Use under Cautions.)

Cautions for Methyldopa

Contraindications

• Active hepatic disease (e.g., acute hepatitis, active cirrhosis). (See Hepatic Effects under Cautions.)

• Liver disorders with previous methyldopa therapy.

• Direct Coombs’ positive hemolytic anemia with previous methyldopa therapy.

• Concomitant therapy with MAO inhibitors or ferrous sulfate or gluconate. (See Specific Drugs and Laboratory Tests under Interactions.)

• Pheochromocytoma.

• Known hypersensitivity to methyldopa or any ingredient in formulations, including sulfites (with IV injection).

Warnings/Precautions

Warnings

Hematologic Effects

Positive direct antiglobulin (Coombs’) test results reported, usually after 6–12 months of therapy; rarely associated with potentially fatal hemolytic anemia. After discontinuance of the drug, positive Coombs’ test reverses within weeks to months.

At treatment initiation, perform a hemoglobin, hematocrit, or a red blood cell count. Periodic blood counts recommended during therapy to detect hemolytic anemia.

May be useful to obtain a direct Coombs’ test before treatment initiation and after 6 and 12 months of therapy. If a positive Coombs’ test occurs, perform appropriate laboratory studies to determine if hemolytic anemia is present. If there is evidence of hemolytic anemia, discontinue the drug; do not reinstitute therapy if anemia is related to methyldopa.

Hemolytic anemia usually resolves promptly; if not, corticosteroids may be given and other causes of anemia should be considered and investigated.

If a blood transfusion is required, perform a direct and indirect Coombs’ test prior to transfusion. A positive direct Coombs’ test alone will not interfere with typing or crossmatching. If both the indirect and direct Coombs’ tests are positive, problems with major crossmatching may occur, and the assistance of an expert may be required.

Reversible leukopenia (primarily granulocytopenia) and immune thrombocytopenia reported rarely.

Hepatic Effects

Possible abnormal liver function test results (e.g., increased serum concentrations of alkaline phosphatase, aminotransferases, and bilirubin and abnormal PT).

Rarely, reversible jaundice, with or without fever, reported, usually within the first 2–3 months of therapy. These effects may be associated with cholestasis, hepatitis, hepatocellular injury, or cirrhosis. Potentially fatal hepatic necrosis reported rarely.

Hepatic dysfunction may represent hypersensitivity reactions. (See Sensitivity Reactions under Cautions.)

Assess hepatic function periodically, especially during the first 6–12 weeks of therapy or whenever unexplained fever occurs. If unexplained fever, abnormal liver function test results, or jaundice occurs, discontinue methyldopa. If methyldopa is the causative agent, temperature and liver function generally return to normal within a few months after methyldopa is discontinued; do not reinstitute therapy in such patients.

Use with caution in patients with a history of previous liver disease or dysfunction. Use contraindicated in patients with active hepatic disease. (See Contraindications under Cautions.)

Sensitivity Reactions

Eosinophilia, myocarditis, pericarditis, vasculitis, and lupus-like syndrome reported.

Fever may be associated with eosinophilia or hepatic dysfunction and may represent hypersensitivity reactions. (See Hepatic Effects under Cautions.)

Positive Coombs’ test and hemolytic anemia may represent hypersensitivity reactions. (See Hematologic Effects under Cautions.)

IV formulation contain sulfites, which can cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes. Such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.

General Precautions

Nervous System Effects

Involuntary choreoathetotic movements reported rarely in patients with severe bilateral cerebrovascular disease. If such symptoms occur, discontinue therapy.

Cardiovascular Effects

Sodium retention resulting in edema and weight gain reported; usually controlled by concomitant administration of a thiazide diuretic. Discontinue therapy if edema progresses or leads to CHF.

Possible paradoxical pressor response following IV administration.

Rebound hypertension has occurred rarely following abrupt withdrawal of oral methyldopa or following dialysis.

Neonatal Morbidity

In neonates born to women treated with methyldopa, SBP may be decreased during the first 2–3 days after delivery; tremors also have been reported.

Specific Populations

Pregnancy

Category C (IV injection); Category B (tablets).

Lactation

Distributed into milk. Caution if used in nursing women; monitor nursing infant (particularly if preterm) for potential systemic effects of the drug (e.g., decreased respiration, BP, or alertness).

Pediatric Use

No well-controlled studies in pediatric patients; dosage recommendations based on published literature.

Safety and efficacy of preparations containing methyldopa in fixed combination with hydrochlorothiazide not established.

Geriatric Use

Possibility exists of greater sensitivity to the drug in some geriatric individuals.

Possible syncope; may be related to an increased sensitivity to the drug and advanced arteriosclerotic vascular disease. (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use with caution in patients with a history of previous liver disease or dysfunction.

Renal Impairment

Generally considered to be safe for use; however, reduced dosage may be required.

Common Adverse Effects

Drowsiness or sedation.

Drug Interactions

Specific Drugs and Laboratory Tests

Methyldopa Pharmacokinetics

Absorption

Bioavailability

Generally about 50% of an oral dose is absorbed with peak plasma concentrations usually attained in approximately 3–6 hours.

Onset

Following oral administration, maximum decrease in BP occurs in 4–6 hours.

Following IV administration, BP begins to decrease in 4–6 hours.

Duration

Following discontinuance of oral therapy, BP returns to pretreatment levels within 24–48 hours.

Following IV administration, hypotensive effect lasts for 10–16 hours and hypertension recurs within 48 hours.

Distribution

Extent

Crosses the blood-brain barrier.

Methyldopa crosses the placenta in humans and is distributed into milk.

Plasma Protein Binding

Weakly bound to plasma proteins.

Elimination

Metabolism

Metabolized in the brain to α-methylnorepinephrine, the pharmacologically active metabolite. Other active metabolites include α-methylepinephrine and α-methyldopamine.

Extensively metabolized, probably in the GI tract and the liver, to sulfate conjugates.

Elimination Route

49% of an IV dose is excreted in the urine (via glomerular filtration) as the parent drug and the sulfate conjugate.

70% of an oral dose is excreted in the urine as parent drug and metabolites.

Unabsorbed methyldopa is excreted in the feces unchanged.

Half-life

Plasma half-life is 105 or 90–127 minutes for methyldopa or methyldopate, respectively.

Special Populations

In patients with renal impairment, renal clearance is decreased.

Removed by hemodialysis and peritoneal dialysis.

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at 15–30°C. Protect methyldopa in fixed combination with hydrochlorothiazide from moisture and freezing.

Parenteral

Solution for Injection

15–30°C.

Compatibility

Parenteral

Solution CompatibilityHID

Drug Compatibility

Actions

• Central effects: Appears to stimulate α₂-adrenergic receptors in the CNS (mainly in the medulla oblongata), causing inhibition of sympathetic vasomotor centers. Contributes predominantly to hypotensive effects.

• Central effects result in reduced peripheral sympathetic nervous system activity, total peripheral resistance, and BP.

• Reduces BP in both supine and standing patients.

• Produces little change in cardiac output and heart rate.

• Stimulates peripheral α₂-adrenergic receptors leading to a decrease in the release of norepinephrine and a reduction in sympathetic tone.

• Inhibits 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. Not a major mechanism of action.

• Renal and metabolic effects: Usually does not reduce renal blood flow or GFR.

• Causes sodium and water retention and increased plasma volume.

• Reduces plasma renin activity (PRA).

• Increases serum prolactin concentrations.

Advice to Patients

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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