METHYLDOPATE HCL

Clinical safety rating: safe

Lithium may cause increased lithium toxicity Can cause hemolytic anemia and positive Coombs test.

How it works

Methyldopate hydrochloride is a prodrug that is metabolized to alpha-methylnorepinephrine, which acts as a central alpha-2 adrenergic receptor agonist, reducing sympathetic outflow from the CNS and decreasing peripheral vascular resistance, thereby lowering blood pressure.

What the body does with it

Metabolism	Hepatic metabolism via conjugation and sulfation; active metabolite alpha-methylnorepinephrine formed by decarboxylation and beta-hydroxylation; also metabolized by catechol-O-methyltransferase (COMT).
Excretion	Renal: 70% unchanged drug and metabolites (sulfate conjugates, O-methylated derivatives). Biliary/fecal: 30% (enterolepatic circulation present).
Half-life	Terminal half-life: 1.5–2 hours (alpha phase); prolonged in renal impairment (up to 6–8 hours in severe CKD).
Protein binding	90–95% bound to albumin (primarily to alpha-2-globulin).
Volume of Distribution	0.2–0.4 L/kg (low distribution, primarily intravascular; higher in hypertension due to expanded plasma volume).
Bioavailability	Oral: 25–60% (first-pass effect; mean ~50%). IV: 100%.
Onset of Action	Oral: 3–6 hours (max effect at 6–12 hours). IV: 2–4 hours.
Duration of Action	Oral: 12–24 hours (single dose); steady-state in 2–3 days. IV: 6–12 hours.

Classification & Brands

Dosing & administration

250 mg orally every 8 to 12 hours, titrated up to a maximum of 3 g/day in divided doses. Intravenous dose: 250-500 mg every 6-8 hours, infused over 30-60 minutes.

Dosage form	Injectable
Renal impairment	GFR 10-50 mL/min: administer every 12-24 hours. GFR <10 mL/min: administer every 24-48 hours. Methyldopa is dialyzable; supplement after dialysis.
Liver impairment	Child-Pugh Class A: no adjustment required. Child-Pugh Class B or C: contraindicated due to risk of hepatic toxicity and encephalopathy.
Pediatric use	Oral: 10 mg/kg/day in 2-4 divided doses, titrated up to 65 mg/kg/day or 3 g/day maximum. IV: 5-10 mg/kg/dose every 6-8 hours, up to 65 mg/kg/day.
Geriatric use	Initiate at 250 mg daily or every other day; titrate slowly. Monitor for hypotension, syncope, and CNS depression. Avoid in patients with cerebrovascular disease or postural hypotension.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Lithium may cause increased lithium toxicity Can cause hemolytic anemia and positive Coombs test.

FDA category	Human
Breastfeeding	Methyldopa is excreted into human breast milk in low concentrations; M/P ratio approximately 0.2-0.5. Considered compatible with breastfeeding, but monitor infant for hypotension and sedation.
Teratogenic Risk	First trimester: Limited data, but methyldopa is considered low risk. Second and third trimesters: No evidence of teratogenicity; chronic use associated with decreased placental perfusion and fetal growth restriction in high doses.

Warnings & precautions

■ FDA Black Box Warning

None.

Side Effect Profile

Common Effects	Sedation
Serious Effects

Absolute Contraindications

["Hypersensitivity to methyldopa or methyldopate","Active hepatic disease (e.g., acute hepatitis, active cirrhosis)","History of previous methyldopa-associated liver disorders","Concomitant use with MAO inhibitors","Pheochromocytoma"]

Clinical Precautions

Precautions

["Sedation (common, usually transient)","Positive direct Coombs test (may occur, rarely hemolytic anemia)","Liver toxicity (hepatitis, hepatic necrosis; monitor liver function)","Paradoxical pressor response with IV administration","Involuntary choreoathetotic movements (may occur, especially in patients with cerebrovascular disease)","May impair mental alertness and motor skills","Requires dosage adjustment in renal impairment"]

Clinical Tips & Counseling

Drug interactions

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METHYLDOPATE HCL

Clinical safety rating: safe

Lithium may cause increased lithium toxicity Can cause hemolytic anemia and positive Coombs test.

How it works

What the body does with it

Metabolism	Hepatic metabolism via conjugation and sulfation; active metabolite alpha-methylnorepinephrine formed by decarboxylation and beta-hydroxylation; also metabolized by catechol-O-methyltransferase (COMT).
Excretion	Renal: 70% unchanged drug and metabolites (sulfate conjugates, O-methylated derivatives). Biliary/fecal: 30% (enterolepatic circulation present).
Half-life	Terminal half-life: 1.5–2 hours (alpha phase); prolonged in renal impairment (up to 6–8 hours in severe CKD).
Protein binding	90–95% bound to albumin (primarily to alpha-2-globulin).
Volume of Distribution	0.2–0.4 L/kg (low distribution, primarily intravascular; higher in hypertension due to expanded plasma volume).
Bioavailability	Oral: 25–60% (first-pass effect; mean ~50%). IV: 100%.
Onset of Action	Oral: 3–6 hours (max effect at 6–12 hours). IV: 2–4 hours.
Duration of Action	Oral: 12–24 hours (single dose); steady-state in 2–3 days. IV: 6–12 hours.

Classification & Brands

Dosing & administration

250 mg orally every 8 to 12 hours, titrated up to a maximum of 3 g/day in divided doses. Intravenous dose: 250-500 mg every 6-8 hours, infused over 30-60 minutes.

Dosage form	Injectable
Renal impairment	GFR 10-50 mL/min: administer every 12-24 hours. GFR <10 mL/min: administer every 24-48 hours. Methyldopa is dialyzable; supplement after dialysis.
Liver impairment	Child-Pugh Class A: no adjustment required. Child-Pugh Class B or C: contraindicated due to risk of hepatic toxicity and encephalopathy.
Pediatric use	Oral: 10 mg/kg/day in 2-4 divided doses, titrated up to 65 mg/kg/day or 3 g/day maximum. IV: 5-10 mg/kg/dose every 6-8 hours, up to 65 mg/kg/day.
Geriatric use	Initiate at 250 mg daily or every other day; titrate slowly. Monitor for hypotension, syncope, and CNS depression. Avoid in patients with cerebrovascular disease or postural hypotension.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Lithium may cause increased lithium toxicity Can cause hemolytic anemia and positive Coombs test.

FDA category	Human
Breastfeeding	Methyldopa is excreted into human breast milk in low concentrations; M/P ratio approximately 0.2-0.5. Considered compatible with breastfeeding, but monitor infant for hypotension and sedation.
Teratogenic Risk	First trimester: Limited data, but methyldopa is considered low risk. Second and third trimesters: No evidence of teratogenicity; chronic use associated with decreased placental perfusion and fetal growth restriction in high doses.

Warnings & precautions

■ FDA Black Box Warning

None.

Side Effect Profile

Common Effects	Sedation
Serious Effects