Pyrimethamine

Pyrimethamine is a synthetic antiparasitic medication that acts as a dihydrofolate reductase inhibitor. It is used primarily as part of combination therapies for malaria and toxoplasmosis, and has historically been employed in other parasitic infections. In malaria, it is usually combined with a sulfonamide such as sulfadoxine (forming Fansidar) to enhance efficacy and limit resistance. For toxoplasmosis, it is given with sulfadiazine and leucovorin (folinic acid) to mitigate hematologic toxicity.

Mechanism of action: Pyrimethamine inhibits the parasite’s dihydrofolate reductase, blocking the conversion of dihydrofolate to tetrahydrofolate. This disrupts thymidylate and purine synthesis, impairing DNA replication and parasite growth. The drug has marked selectivity for the parasite enzyme but can affect human folate pathways, which underpins some adverse effects.

Clinical use and regimens: In malaria, pyrimethamine is used in chloroquine-resistant Plasmodium falciparum infections and in preventive regimens in areas where resistance patterns permit. In toxoplasmosis, it is part of a combination regimen with sulfadiazine and leucovorin, used for treatment of acute infection and for prophylaxis in immunocompromised individuals. Because of dose-limiting bone marrow toxicity, leucovorin rescue is commonly employed in toxoplasmosis regimens. Pyrimethamine has become less favored for Pneumocystis jirovecii pneumonia where trimethoprim-sulfamethoxazole is preferred.

Adverse effects and precautions: The drug can cause bone marrow suppression leading to megaloblastic anemia, leukopenia, and thrombocytopenia, as well as folate deficiency, rash, and hypersensitivity. It is teratogenic and should be used in pregnancy only when clearly indicated with appropriate folinic acid rescue. Monitoring of blood counts and folate status is recommended during therapy.

Resistance and pharmacokinetics: Resistance can arise from mutations in the parasite dihydrofolate reductase gene. Pyrimethamine is orally active, with hepatic metabolism and renal excretion; it crosses the placenta.