methyldopa
Central alpha-2 agonist· Brands: Aldomet, Apo-Methyldopa, Dopamin, Medopa, MethyldopPO
Mechanism of action
Methyldopa is a prodrug that is converted in the brain to alpha-methylnorepinephrine, which acts as an agonist at central alpha-2 adrenergic receptors. This reduces sympathetic outflow from the central nervous system, leading to decreased peripheral vascular resistance and a reduction in blood pressure. The effect is primarily central, with minimal direct action on peripheral receptors.
Pharmacokinetics
Methyldopa is incompletely and variably absorbed after oral administration, with bioavailability around 25%. It is actively transported into the brain and other tissues. Metabolism occurs mainly in the liver, with conjugation to sulfate and glucuronide. The parent drug and metabolites are excreted in urine. The half-life is about 2 hours, but the antihypertensive effect lasts longer, typically 12 to 24 hours.
Indications & dosing
Hypertension
Start at 250 mg twice daily, increase as needed.
- adult · PO: 250–500 mg twice daily · Start at 250 mg twice daily, increase as needed.
Hypertension in pregnancy
Preferred agent for hypertension in pregnancy.
- adult · PO: 250–500 mg twice daily · Preferred agent for hypertension in pregnancy.
Hypertension (pediatric)
Maximum 65 mg/kg/day or 3 g/day.
- pediatric · PO: 10–65 mg/kg/day in 2-3 divided doses · Maximum 65 mg/kg/day or 3 g/day.
Contraindications & precautions
- Active hepatic disease or liver cirrhosis · Methyldopa is metabolized in the liver, and hepatic injury can occur.
- History of methyldopa-induced liver damage · Recurrence of liver injury is possible.
- Concurrent use of monoamine oxidase inhibitors (MAOIs) · Risk of hypertensive crisis.
- Depression · Methyldopa may exacerbate or precipitate depression.
- Pheochromocytoma · Could interfere with catecholamine metabolism; use with caution.
- Monitor liver function tests and blood cell counts periodically during therapy.
- Perform a direct Coombs test before and during prolonged treatment.
- Use with caution in patients with a history of depression.
- Avoid abrupt withdrawal of methyldopa; taper the dose when discontinuing.
- Dose adjustment may be required in renal impairment; monitor blood pressure.
Adverse effects
- Sedation
- Dry mouth
- Orthostatic hypotension
- Positive direct Coombs test
- Haemolytic anaemiaserious
- Hepatitis or liver necrosisserious
- Drug-induced lupus erythematosusserious
- Bradycardiaserious
Renal & hepatic adjustment
- eGFR 0–30: Reduce dose and monitor blood pressure. Consider increasing dosing interval.
- Hepatic impairment (mild): Use with caution; monitor liver function.
- Hepatic impairment (moderate): Reduce dose and monitor liver function.
- Hepatic impairment (severe): Avoid in active hepatic disease or methyldopa-induced hepatic injury. (avoid)
Monitoring, pregnancy & toxicity
- Blood pressure · Regularly during dose titration and maintenance
- Heart rate · Monitor for bradycardia
- Liver function tests · Before initiation and periodically during therapy
- Full blood count · May be needed to detect haemolytic anaemia
- Direct Coombs test · Before treatment and at intervals; positive test may indicate haemolysis
- Pregnancy: Safe for use during pregnancy; commonly used as first-line treatment for hypertension in pregnancy.
- Toxicity: Sedation and hypotension are the main features of overdose. · Supportive care; monitor blood pressure and heart rate. Administer IV fluids and vasopressors if needed. Provide respiratory support if necessary.
- Toxicity: Hepatotoxicity may occur with long-term therapy or overdose. · Discontinue the drug; monitor liver function and provide supportive care.
Clinical notes
Methyldopa is used for hypertension, particularly in pregnancy because of its long safety record. It is often a third-line agent or used when other drugs are contraindicated. Common adverse effects include sedation, dizziness, dry mouth, and orthostatic hypotension. It can cause positive Coombs test, haemolytic anaemia, and hepatotoxicity. Because of central effects, it may interfere with mental alertness. Monitor liver function and blood counts periodically. Doses are usually started low and titrated up.
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BNF; local formulary