Pyrimethamine antimalarial actions

MECHANISMS OF ANTIMALARIAL ACTION AND RESISTANCE The 2,4-diaminopyrimidines inhibit dihydrofolate reductase of plasmodia at concentrations far lower than those required to inhibit the mammalian enzymes. The dihydrofolate reductase in malaria resides on the same polypeptide chain as thymidylate synthase and is not upregulated in the face of inhibition, which contributes to the selective toxicity of the antifolates. Synergism between pyrimethamine and the sulfonamides or sulfones has been attributed to inhibition of two steps in an essential metabolic pathway. 

Different antimalarials selectively kill the parasite s different developmental forms. The mechanism of action is known for some of them pyrimethamine and dapsone inhibit dihydrofolate reductase (p. 273), as does chlorguanide (proguanil) via its active metabolite. The sulfonamide sulfadoxine inhibits synthesis of dihydrofolic acid (p. 272). Chlo-roquine and quinine accumulate within the acidic vacuoles of blood schizonts and inhibit polymerization of heme, the latter substance being toxic for the schizonts. 

Potentiation of antimalarial effects are obtained by conhinatlons of driigs with varied mechanisms of action. The antimalarial effects of certain sulfones and svilfonamides apparently involve blockage of incorporation of jg-aminobenzoic acid (PABA) in the formation of folic acid in the parasite. Pyrimethamine acts at a different point in the same metabolic pathway. 30 dds may be competitive with PABA in the Zwitterion form.3I-... 

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