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Methyldopa and Methyldopate Hydrochloride

Pronunciation

Pronunciation: METH-il-DOE-pa and METH-il-DOE-pate HYE-droe-KLOR-ide
Class: Antiadrenergic agent, centrally acting

Trade Names

Methyldopa
- Tablets 250 mg
- Tablets 500 mg

Methyldopate Hydrochloride
- Injection, solution 50 mg/mL

Apo-Methyldopa (Canada)

Pharmacology

Causes central alpha-adrenergic stimulation, which inhibits sympathetic cardioaccelerator and vasoconstrictor centers; reduces plasma renin activity; reduces standing and supine BP.

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Pharmacokinetics

Absorption

Absorption following oral administration is variable and incompletely absorbed. Mean bioavailability is approximately 50%.

Distribution

Crosses the blood-brain and placental barriers, appears in cord blood and breast milk, and is approximately 8% protein bound.

Metabolism

Extensively metabolized to multiple metabolites. Approximately 17% appears in plasma as free methyldopa.

Elimination

Approximately 70% (oral) and approximately 49% (IV) is excreted in urine as methyldopa and its mono-O-sulfate conjugate; excretion is complete in 36 h after oral dose. The half-life is 1.8 h (oral) and 1.5 to 2.1 h (IV), and the renal Cl is approximately 130 mL/min (oral) and 156 mL/min (IV).

Onset

Onset is 4 to 6 h.

Peak

Time to peak effect is 12 to 24 h (oral).

Duration

Duration is 24 to 48 h (oral) and 10 to 16 h (IV).

Special Populations

Renal Function Impairment

Methyldopa is largely excreted by the kidneys. Patients with renal impairment may respond to smaller doses.

Indications and Usage

Treatment of hypertension.

Unlabeled Uses

Hypertension in pregnancy.

Contraindications

Active hepatic disease or previous hepatic disease associated with methyldopa therapy; coadministration with MAOIs; hypersensitivity to any component of the product.

Dosage and Administration

Adults

PO 250 mg 2 to 3 times daily in the first 48 h initially, then 500 mg to 2 g/day (max, 3 g/day) in 2 to 4 divided doses. Adjust doses at intervals of not less than 2 days until adequate response is achieved. To minimize sedation, increase dosage in the evening.

IV 250 to 500 mg every 6 h as needed (max, 1 g every 6 h).

Children

PO 10 mg/kg/day in 2 to 4 doses (max, 65 mg/kg/day or 3 g/day, whichever is less).

IV 20 to 40 mg/kg/day in divided doses every 6 h (max, 65 mg/kg/day or 3 g/day, whichever is less).

General Advice

  • Oral
  • When given with antihypertensives other than thiazides, limit the initial dosage of methyldopa to 500 mg/day in divided doses. The dosage of the concomitant antihypertensive may need to be adjusted. When added to a thiazide, the dosage of thiazide does not need to be changed.
  • Parenteral
  • Add the desired dose of methyldopate to 100 mL of dextrose 5% injection. Alternatively, the desired dose may be given in dextrose 5% in water in a concentration of 100 mg per 10 mL.
  • Do not administer if particulate matter or cloudiness is noted.
  • Administer methyldopate by slow IV infusion over 30 to 60 min.

Storage/Stability

Store between 68° and 77°F.

Drug Interactions

Anesthetics

May require reduced doses of anesthetics. Hypotension during anesthesia can be controlled by vasopressors because adrenergic receptors remain sensitive.

Antihypertensives

When methyldopa is used with other hypotensive agents, the hypotensive effect may be potentiated. Closely monitor the patient to detect adverse reactions or manifestations of idiosyncratic reactions.

Beta-blockers, nonselective (eg, propranolol)

May cause paradoxical hypertension (rare). Closely monitor for acute increases in BP. If an acute increase occurs, discontinuation of the beta-blocker and treatment with an alpha-adrenergic blocking agent (eg, phentolamine) may be needed.

Ferrous sulfate or gluconate

May decrease oral methyldopa absorption. Coadministration is not recommended.

Haloperidol

May result in dementia or sedation. If adverse mental symptoms occur, discontinue one or both drugs.

Levodopa

BP-lowering effects of methyldopa may be potentiated. Central effects of levodopa in Parkinson disease may be potentiated. Monitor BP and for signs of toxicity. If either occurs, adjust the dose of either drug as needed.

Lithium

May precipitate lithium toxicity. Closely monitor the patient for signs and symptoms of lithium toxicity and adjust the lithium dose as needed.

MAOIs (eg, phenelzine)

May lead to excessive sympathetic stimulation. Coadministration is contraindicated.

Phenothiazines

Serious elevations in BP may occur. Closely monitor BP. If hypertension occurs, discontinue one or both drugs.

Sympathomimetics (eg, norepinephrine)

May potentiate pressor effects of sympathomimetics and lead to hypertension. Monitor BP. If hypertension occurs, discontinuation of the sympathomimetic agent or treatment with an alpha-adrenergic blocking agent (eg, phentolamine) may be needed.

Tizanidine

Additive hypotensive effects may occur. If coadministration cannot be avoided, closely monitor BP and adjust treatment as needed.

Laboratory Test Interactions

May interfere with tests for urinary uric acid, serum creatinine, and AST; may give falsely high levels of urinary catecholamines.

Adverse Reactions

Cardiovascular

Aggravation of angina pectoris, bradycardia, CHF, edema, orthostatic hypotension, paradoxical pressor response with IV use, prolonged carotid sinus hyperactivity, prolonged carotid sinus hypersensitivity.

CNS

Asthenia or weakness, Bell palsy, decreased mental acuity, depression, dizziness, headache, involuntary choreoathetotic movements, light-headedness, nightmares, paresthesias, parkinsonism, reversible mild psychoses, sedation, symptoms of cerebrovascular insufficiency.

Dermatologic

Rash, TEN.

EENT

Nasal stuffiness, sore or “black” tongue.

GI

Colitis, constipation, diarrhea, distention, dry mouth, flatus, nausea, pancreatitis, sialadentis, vomiting.

Genitourinary

Amenorrhea, decreased libido, impotence, rise in BUN.

Hematologic

Bone marrow depression; granulocytopenia; hemolytic anemia; leukopenia; positive Coombs test; positive tests for anti-nuclear antibody, lupus erythematosus cells, and rheumatoid factor; thrombocytopenia.

Hepatic

Liver disorders, including abnormal LFTs, hepatitis, and jaundice.

Hypersensitivity

Drug-related fever, eosinophilia, lupus-like syndrome, myocarditis, pericarditis, vasculitis.

Metabolic

Breast enlargement, gynecomastia, hyperprolactinemia, lactation.

Musculoskeletal

Arthralgia with or without joint swelling, myalgia.

Precautions

Monitor

Perform a blood cell count (hematocrit, hemoglobin, or RBC) before treatment is started for a baseline or to establish whether there is anemia. Perform periodic blood cell counts to detect hemolytic anemia. A direct Coombs test may be useful before therapy and at 6 and 12 mo later. Perform periodic determinations of hepatic function, particularly during the first 6 to 12 wk of therapy or when an unexplained fever occurs.


Pregnancy

Category B (methyldopa); Category C (methyldopate).

Lactation

Excreted in breast milk.

Children

Individualize dosage.

Elderly

Syncope in older patients may be related to an increased sensitivity and advanced arteriosclerotic vascular disease. May be avoided by lower doses.

Renal Function

Use with caution in patients with renal impairment. Hypertension has recurred occasionally after dialysis in patients taking methyldopa because the drug is removed by this procedure.

Hepatic Function

Use with caution in patients with previous liver disease or dysfunction.

Blood transfusions

Perform a direct and indirect Coombs test. A positive direct Coombs test alone will not interfere with typing or crossmatching. If the indirect Coombs test is also positive, problems may arise in the major crossmatch and assistance from a hematologist or transfusion expert will be needed.

Discontinuation of therapy

Because methyldopa has a short duration of action, withdrawal is followed by return of hypertension, usually within 48 h. This is not complicated by overshoot of BP.

Edema/Weight gain

May occur in some patients and can be controlled by use of a diuretic. Discontinue if edema progresses or if signs of heart failure appear.

Hematologic effects

Reversible reduction of the WBC with a primary effect on granulocytes has occurred rarely.

Involuntary choreoathetotic movements

Have been observed in patients with severe bilateral cerebrovascular disease. Discontinue therapy if these movements occur.

IV use

Paradoxical pressor response has been reported.

Liver disorders

Jaundice, with or without fever, may occur. Fever has occurred within the first 3 wk of therapy, associated in some cases with eosinophilia or abnormalities in 1 or more LFTs, such as serum alkaline phosphatase, ALT, AST, bilirubin, and PT. Fatal hepatic necrosis has been reported rarely. If symptoms or tests indicate liver effects, the drug may need to be discontinued.

Positive Coombs test/hemolytic anemia

May occur; monitor patient closely because of potentially fatal complications.

Sulfite sensitivity

Use caution in sulfite-sensitive patients; some parenteral preparations contain sodium bisulfite.

Tolerance

May occur occasionally, usually between the second and third month of therapy. Adding a diuretic or increasing the dosage of methyldopa will frequently restore effective control of BP.

Overdosage

Symptoms

Acute hypotension, bradycardia, constipation, diarrhea, distention, dizziness, flatus, light-headedness, nausea, sedation, vomiting, weakness.

Patient Information

  • Encourage patient's compliance with health care provider recommendations of weight reduction, sodium and alcohol restriction, cessation of smoking, regular exercise, stress reduction, and other methods of BP control.
  • Teach patient or family proper technique for BP monitoring at home.
  • Prepare schedule for return visits to health care provider for additional monitoring of BP and hepatic function. Emphasize the importance of return visits.
  • Caution patient not to stop taking drug abruptly.
  • Warn patient that dizziness may occur and that hot baths or showers may aggravate dizziness.
  • Inform patient that nausea, vomiting, or diarrhea may cause an increase in hypotensive effect because of dehydration. If this occurs, the patient should contact health care provider for dosage adjustment.
  • Instruct patient to report the following symptoms to health care provider: fever, flu-like symptoms, jaundice, muscle aches.
  • Advise patient to take sips of water frequently, suck on ice chips or sugarless hard candy, or chew sugarless gum if dry mouth occurs. Dry mouth usually does not continue for more than 2 wk; if it does, patient should contact health care provider.
  • Caution patient to avoid sudden position changes to avoid orthostatic hypotension.
  • Instruct patient to avoid intake of alcoholic beverages.
  • Advise patient that drug may cause drowsiness, especially during first days of therapy or when dose is increased, and to use care while driving or performing other activities requiring mental alertness.

Copyright © 2009 Wolters Kluwer Health.

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