pyrimethaminesulfadiazine

Pyrimethamine is a synthetic antiprotozoal medication used mainly in the treatment and prevention of malaria and in the management of toxoplasmosis. It acts as a selective inhibitor of the parasite enzyme dihydrofolate reductase (DHFR), blocking the conversion of dihydrofolate to tetrahydrofolate and thereby inhibiting thymidine and purine synthesis required for DNA replication. Because folate synthesis is essential to many parasites, its action is often combined with a sulfonamide that blocks a separate step in the folate pathway, increasing anti-parasitic effectiveness and delaying resistance.

Medical uses include malaria treatment and prophylaxis, typically in combination with sulfadoxine (forming sulfadoxine-pyrimethamine, known as SP). This fixed-dose therapy has been used in areas with chloroquine resistance, though rising resistance has limited its effectiveness in some regions. Pyrimethamine is also employed, in combination with sulfadiazine and leucovorin (folinic acid), for toxoplasmosis, including toxoplasmic encephalitis and ocular toxoplasmosis, with leucovorin given to reduce bone marrow toxicity.

Pharmacology and pharmacokinetics vary by formulation but generally involve oral administration with hepatic metabolism and renal excretion. The drug can cause bone marrow suppression, megaloblastic anemia, leukopenia, and gastrointestinal upset, with risk increased by folate deficiency or concurrent methotrexate use. Leucovorin rescue mitigates hematologic toxicity in toxoplasmosis regimens. Resistance often involves mutations in parasite DHFR, reducing drug affinity and diminishing efficacy. Pyrimethamine is typically not used as monotherapy due to resistance and toxicity concerns.