Methyldopa

Methyldopa is an older centrally acting antihypertensive with a long safety record in pregnancy. It remains widely used in East Africa for hypertension in pregnancy because it is cheap and available. Its main problems are sedation, depression, hepatotoxicity and haemolytic anaemia.

Classification. Centrally acting alpha 2 agonist prodrug; false neurotransmitter.

Mechanism. Converted in the brain to alpha methylnoradrenaline, which stimulates central alpha 2 receptors, reducing sympathetic outflow and peripheral resistance. Heart rate and cardiac output change little.

Pharmacodynamics. Onset 4 to 6 hours after an oral dose; peak 6 to 8 hours; duration 12 to 24 hours. Renal blood flow is maintained. Fluid retention can follow long use.

Pharmacokinetics. Oral bioavailability about 50% and variable. Half life 1.5 to 2 hours (longer in kidney failure). Metabolised in the liver and excreted by the kidney; crosses the placenta.

Hypertension in pregnancy, adult.

• Start 250 mg orally two or three times daily.

• Increase by 250 mg every 2 days to the lowest dose that controls pressure.

• Usual range 500 mg to 2 g daily in 2 to 4 divided doses.

• Maximum 3 g daily.

• Stop within 2 days after delivery because of the risk of postnatal depression, and switch to another drug if pressure remains raised.

• Labetalol or nifedipine are alternatives where available. It acts too slowly to treat severe hypertension, which needs an intravenous or immediate release agent.

Hypertension, non-pregnant adult (rarely first line). Same dose range; start 250 mg two or three times daily. Used when other classes are contraindicated or unavailable.

Children, hypertension. 10 mg/kg daily in 2 to 4 divided doses, increased as needed to a maximum 65 mg/kg daily or 3 g daily, whichever is less.

Duration. Long term in chronic hypertension; short term in pregnancy until after delivery.

Contraindications. Active liver disease (acute hepatitis, active cirrhosis); previous methyldopa associated liver damage or Coombs positive haemolytic anaemia; depression; phaeochromocytoma; porphyria; concurrent monoamine oxidase inhibitors.

Warnings. Sedation and depression, particularly in the first weeks. Positive direct antiglobulin (Coombs) test in 10 to 20%, haemolytic anaemia in under 1%, which can complicate blood cross matching. Hepatitis, fever and eosinophilia in the first 6 to 12 weeks. Lupus like syndrome, orthostatic hypotension and peripheral oedema.

Adverse effects. Drowsiness, dry mouth, dizziness, headache, nasal congestion, depression, sexual dysfunction, nightmares, bradycardia, fluid retention, hepatic enzyme rise.

Interactions. Iron salts reduce absorption; separate by at least 2 hours. Lithium: toxicity possible. Monoamine oxidase inhibitors: hypertensive crisis. Sympathomimetics and tricyclic antidepressants oppose its effect. Other antihypertensives and anaesthetics add hypotension.

Special groups.

• Pregnancy: first line choice in many settings; extensive experience without foetal harm.

• Breastfeeding: small amounts in milk; compatible.

• Older adults: start 125 mg; sedation and hypotension.

• Kidney impairment: eGFR under 50 mL/min: lengthen interval to every 8 to 12 hours; under 10 mL/min: every 12 to 24 hours; removed by dialysis.

• Liver impairment: avoid in active liver disease.

Formulations. Tablets 125 mg, 250 mg and 500 mg.

Administration. Oral, with or without food, with a larger dose at bedtime to limit daytime sedation. Pressure falls steadily; avoid very early dose escalation.

Baseline. Blood pressure, liver function, full blood count, haemoglobin, direct Coombs test if blood transfusion may be needed, depression screen.

Monitoring. Blood pressure at each visit; liver function every 3 months for the first year and if fever or jaundice appears; full blood count and Coombs test at 6 and 12 months, and if anaemia develops; mood, sedation and fluid retention.

Stopping. Stop and do not restart if hepatitis, haemolytic anaemia or drug fever develops. Taper over 1 to 2 weeks in non-pregnant patients.

Common prescribing errors. Using it for a hypertensive emergency; continuing after delivery for weeks; forgetting that a positive Coombs test is a drug effect; combining with iron without a spacing instruction.