## Mechanism of Action **Key Point:** Pyrimethamine is a selective inhibitor of *Plasmodium* dihydrofolate reductase (DHFR), blocking the conversion of dihydrofolate to tetrahydrofolate, which is essential for nucleotide synthesis and parasite DNA replication. ## Antimalarial Classification by MOA | Drug Class | Mechanism | Examples | |---|---|---| | Folate antagonists | Inhibit DHFR | Pyrimethamine, Proguanil | | Artemisinin derivatives | Endoperoxide bridge cleavage | Artemisinin, Artemether | | Quinolines | Heme polymerization inhibition | Chloroquine, Quinine | | Atovaquone-proguanil | Dual: DHFR + ubiquinone pathway | Atovaquone-proguanil | ## Clinical Use **High-Yield:** Pyrimethamine is used primarily in combination with sulfadiazine for *Plasmodium falciparum* and *P. vivax* malaria, and is also the drug of choice for toxoplasmosis prophylaxis in HIV patients. **Clinical Pearl:** Pyrimethamine causes reversible bone marrow suppression; folinic acid (leucovorin) is given concurrently to mitigate hematologic toxicity without reducing antimalarial efficacy. ## Resistance Point mutations in the DHFR gene lead to pyrimethamine resistance, particularly in *P. falciparum*-endemic regions. This is why it is rarely used as monotherapy in modern practice.
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