What is the role of methyldopa (antihypertensive) in treating hypertension (htn)?

Methyldopa for Hypertension

Primary Role: Pregnancy-Specific Antihypertensive

Methyldopa is primarily indicated for hypertension during pregnancy, where it serves as a first-line agent with established long-term safety data, but has been largely replaced by other antihypertensive classes for non-pregnant populations due to inferior side effect profiles. 1, 2

Clinical Use in Pregnancy

First-Line Status

• Methyldopa remains a first-line option for chronic and gestational hypertension in pregnancy, supported by extensive long-term follow-up studies demonstrating safety for both mother and infant 1, 2
• It is the only antihypertensive with comprehensive long-term pediatric outcome data 2
• For non-severe hypertension in pregnancy (BP 140-149/90-95 mmHg), oral methyldopa is among the drugs of choice alongside labetalol and calcium antagonists 1

Dosing and Administration

• Typical dosing ranges from 250-1000 mg daily, with adjustments often required as pregnancy progresses 2
• Maximum blood pressure reduction occurs 4-6 hours after oral administration, with smooth control achieved within 12-24 hours once effective dosing is established 3

Evolving Preferences

• In high-income countries, nifedipine and labetalol are increasingly preferred over methyldopa as first-line agents due to superior efficacy in preventing preeclampsia and more favorable side effect profiles 2
• Labetalol provides more balanced blood pressure control through combined alpha-1 and non-selective beta-blocking properties 2

Use in Hypertensive Emergencies During Pregnancy

• For severe hypertension or preeclampsia requiring urgent treatment, oral methyldopa is indicated alongside IV labetalol and oral nifedipine 1, 4
• IV hydralazine is no longer first-line due to excess perinatal adverse effects 1, 4

Critical Contraindication

• Methyldopa should NOT be used postpartum due to increased risk of postpartum depression 2

Mechanism and Hemodynamic Effects

• Methyldopa is metabolized to alpha-methylnorepinephrine, which lowers blood pressure by stimulating central inhibitory alpha-adrenergic receptors 3
• It maintains cardiac output without cardiac acceleration and typically does not reduce glomerular filtration rate or renal blood flow 3
• Some evidence suggests methyldopa may improve renal function in hypertensive pregnancy by stimulating nitric oxide synthesis 5

Blood Pressure Lowering Efficacy

• In non-pregnant populations, methyldopa at doses of 500-2250 mg daily reduces systolic/diastolic BP by approximately 13/8 mmHg compared to placebo 6
• In pregnancy, methyldopa significantly reduces mean arterial pressure during second and third trimesters and may prolong gestational age by approximately 10 days 7
• It effectively reduces the frequency of severe hypertension occurring antepartum and during labor 8

Adverse Effects Profile

Common Side Effects

• Approximately 14-17% of patients experience adverse reactions requiring drug discontinuation, most commonly lack of energy and dizziness 8, 9
• Hypotension is the most frequent adverse effect, occurring more often in younger patients, those with renal impairment, lighter-weight individuals, and those receiving higher doses 9

Serious Adverse Effects

• Life-threatening reactions occur in approximately 6% of reactors, primarily hypotension associated with cardiac or cerebral ischemia 9
• Therapy should be initiated cautiously in younger, non-obese patients and those with elevated blood urea nitrogen 9

Pharmacokinetics

• Plasma half-life is 105 minutes with essentially complete excretion in 36 hours 3
• Approximately 70% of absorbed drug is excreted in urine as methyldopa and its mono-O-sulfate conjugate 3
• Methyldopa crosses the placental barrier and appears in breast milk 3

Role in Modern Practice

Non-Pregnant Populations

• Methyldopa has been largely replaced by other antihypertensive classes (ACE inhibitors, ARBs, calcium channel blockers, thiazide diuretics) that offer better tolerability and equivalent or superior cardiovascular outcomes 6
• Its continued use in developing countries is primarily cost-driven 6
• No evidence exists demonstrating methyldopa's effect on mortality or cardiovascular morbidity outcomes 6

Pregnancy Populations

• Remains relevant as a safe, established option with long-term safety data 1, 2
• ACE inhibitors and ARBs are absolutely contraindicated in pregnancy due to fetal developmental abnormalities and toxicity 1, 2, 4

Clinical Pitfalls to Avoid

• Do not use methyldopa postpartum 2
• Avoid in patients with renal impairment without dose adjustment, as renal clearance is diminished 3, 9
• Do not assume methyldopa improves clinical outcomes beyond blood pressure control—evidence for mortality/morbidity benefit is lacking 6
• Monitor closely for hypotension, particularly in high-risk subgroups 9