PYRIMETHAMINE
Clinical safety rating
avoidPositive evidence of fetus risks but benefits may outweigh risks in some cases
Pyrimethamine inhibits dihydrofolate reductase (DHFR) in the parasite, blocking the conversion of dihydrofolate to tetrahydrofolate, thereby inhibiting nucleic acid synthesis.
| Metabolism | Primarily hepatic, via involvement of CYP450 enzymes (not definitively characterized). Partially metabolized by CYP2C8 and CYP3A4. |
| Excretion | Primarily renal (approximately 30% unchanged and 20-30% as metabolites); additional biliary/fecal elimination (20-30% as metabolites). Total urinary excretion of parent drug and metabolites accounts for 60-80% of dose. |
| Half-life | Terminal elimination half-life is approximately 96 hours (range 80-123 hours) in adults with normal renal function; prolonged in renal impairment (up to 200 hours). This long half-life supports weekly dosing regimens. |
| Protein binding | Approximately 87% bound to plasma proteins, primarily albumin. |
| Volume of Distribution | Apparent volume of distribution is 2.3 L/kg (range 1.7-3.0 L/kg), indicating extensive tissue distribution (e.g., kidneys, liver, spleen). |
| Bioavailability | Oral: Well absorbed with absolute bioavailability of 95-100%. |
| Onset of Action | Oral: Onset of antimalarial effect is within 1-2 hours; for toxoplasmosis, clinical response may take 24-48 hours. |
| Duration of Action | Oral: Antimalarial prophylaxis persists for 1 week after a single dose due to long half-life; for toxoplasmosis, treatment duration is typically 4-6 weeks based on clinical response. |
| Molecular Weight | 248.71 |
For toxoplasmosis: 200 mg orally once, then 50-75 mg orally once daily for 4-6 weeks, plus sulfadiazine and folinic acid. For malaria prophylaxis: 25 mg orally once weekly.
| Dosage form | TABLET |
| Renal impairment | CrCl <50 mL/min: not recommended; CrCl 50-90 mL/min: no adjustment needed. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce dose by 50%; Child-Pugh C: contraindicated. |
| Pediatric use | For toxoplasmosis: 1 mg/kg/day orally divided twice daily (max 25 mg/day) for 2 days, then 1 mg/kg/day once daily (max 25 mg/day) followed by 0.5 mg/kg/day (max 25 mg/day) for 4-6 weeks; plus sulfadiazine and folinic acid. For malaria prophylaxis: <1 year: 6.25 mg once weekly; 1-3 years: 12.5 mg once weekly; 4-8 years: 25 mg once weekly; >8 years: 50 mg once weekly. |
| Geriatric use | Start at lowest adult dose; monitor for folate deficiency and renal function; consider dose adjustment based on renal function. |
| 1st trimester | Risk of teratogenicity (folate antagonist); avoid unless benefit outweighs risk. Use with folinic acid supplementation. |
| 2nd trimester | May be used with caution; monitor for folate deficiency. Supplement with folinic acid. |
| 3rd trimester | May cause neonatal hemolysis if given near term; avoid in G6PD deficiency. Supplement with folinic acid. |
Clinical note
Other drugs that cause folate deficiency can have additive effects Can cause megaloblastic anemia and blood dyscrasias.
| Placental transfer | Crosses placenta readily; fetal levels similar to maternal. |
| Breastfeeding | Enters breast milk in small amounts; avoid in nursing infants with G6PD deficiency or folate deficiency. Monitor infant for rash, hemolysis, or megaloblastosis. |
| Lactation Rating | L3 (Moderately Safe) |
| Teratogenic Risk | Pyrimethamine is a folic acid antagonist and is teratogenic in animals (cleft palate, hydrocephalus). Human data limited but may cause neural tube defects, cardiovascular anomalies, and oral clefts if used in first trimester. Risk may be mitigated by concurrent folinic acid supplementation (not folic acid). Avoid in first trimester unless essential for life-threatening toxoplasmosis. Second and third trimester: risk lower but evidence of potential effects on fetal hematopoiesis (megaloblastic anemia) and growth restriction. All trimesters: monitor fetal growth and amniotic fluid index. |
| Fetal Monitoring | Maternal: CBC with differential and platelet count weekly (risk of megaloblastic anemia and neutropenia); serum folate and vitamin B12 levels; renal and hepatic function tests. Fetal: Ultrasound for structural anomalies (especially if used in first trimester); serial growth scans for intrauterine growth restriction (IUGR). Neonatal: CBC at birth for cytopenias; assess for hemolysis if G6PD screen positive. |
| Fertility Effects | No direct human studies on fertility. Animal studies suggest reversible suppression of spermatogenesis at high doses. Folate antagonism may theoretically impair ovulation and implantation; concurrent folinic acid is recommended to mitigate. No evidence of permanent infertility. |
■ FDA Black Box Warning
Pyrimethamine may cause bone marrow suppression, including pancytopenia, especially with prolonged use or high doses. Concomitant use with sulfonamides may increase risk of severe adverse reactions.
| Common Effects | toxoplasmosis |
| Serious Effects |
Hypersensitivity to pyrimethamineMegaloblastic anemia due to folate deficiencyBlood dyscrasiasSevere hepatic impairment
| Precautions | Bone marrow suppression (monitor CBC), folic acid supplementation recommended to prevent hematologic toxicity; hepatotoxicity; hypersensitivity reactions; renal impairment; pregnancy (may cause fetal harm); lactation. |
| Food/Dietary | No specific dietary restrictions, but pyrimethamine should be taken with food to minimize gastrointestinal irritation. Avoid alcohol due to potential hepatotoxicity. Folate-rich foods (e.g., leafy greens, beans) do not significantly affect efficacy but ensure adequate folate intake unless contraindicated. |
| Clinical Pearls | Pyrimethamine is a dihydrofolate reductase inhibitor used primarily for toxoplasmosis and malaria. For toxoplasmosis, it is combined with sulfadiazine and folinic acid (leucovorin) to prevent myelosuppression. Monitor complete blood counts regularly due to risk of dose-dependent bone marrow suppression. Renal dose adjustment is necessary; avoid in severe hepatic impairment. Note that pyrimethamine has a long half-life (4-6 days) allowing weekly dosing for malaria chemoprophylaxis. Use with caution in patients with folate deficiency or seizure disorders. |
| Patient Advice | Take pyrimethamine exactly as prescribed; do not miss doses. · You will likely need to take folinic acid (leucovorin) to prevent side effects on your blood cells. · Report any signs of infection (fever, sore throat), easy bruising, or unusual bleeding immediately. · Avoid alcohol as it may increase the risk of liver side effects. · Use effective contraception during treatment and for at least 4 weeks after stopping, as pyrimethamine can harm a fetus. · Do not drive or operate heavy machinery until you know how pyrimethamine affects you; dizziness may occur. · Take the medication with food to reduce gastrointestinal upset. |
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