Pyrimethamine is a 2,4-diaminopyrimidine related to trimethoprim (see Chapter 46). Proguanil is a biguanide derivative (Figure 52–2). Both drugs are slowly but adequately absorbed from the gastrointestinal tract. Pyrimethamine reaches peak plasma levels 2–6 hours after an oral dose, is bound to plasma proteins, and has an elimination half-life of about 3.5 days. Proguanil reaches peak plasma levels about 5 hours after an oral dose and has an elimination half-life of about 16 hours. Therefore, proguanil must be administered daily for chemoprophylaxis, whereas pyrimethamine can be given once a week. Pyrimethamine is extensively metabolized before excretion. Proguanil is a prodrug; its triazine metabolite, cycloguanil, is active. Fansidar, a fixed combination of the sulfonamide sulfadoxine (500 mg per tablet) and pyrimethamine (25 mg per tablet), is well absorbed. Its components display peak plasma levels within 2–8 hours and are excreted mainly by the kidneys. The average half-life of sulfadoxine is about 170 hours.
Pyrimethamine and proguanil act slowly against erythrocytic forms of susceptible strains of all four human malaria species. Proguanil also has activity against hepatic forms. Neither drug is adequately gametocidal or effective against hypnozoites of P vivax or P ovale. Sulfonamides and sulfones are weakly active against erythrocytic schizonts but not against liver stages or gametocytes.
Pyrimethamine and proguanil inhibit plasmodial dihydrofolate reductase, a key enzyme in the pathway for synthesis of folate. Sulfonamides and sulfones inhibit another enzyme in the folate pathway, dihydropteroate synthase. As described in Chapter 46, inhibitors of these two enzymes provide synergistic activity when used together (see Figure 46–2).
Resistance of P falciparum to folate antagonists and sulfonamides is common in many areas. Resistance is due primarily to mutations in dihydrofolate reductase and dihydropteroate synthase, with increasing numbers of mutations leading to increasing levels of resistance. Resistance seriously limits the efficacy of sulfadoxine-pyrimethamine for the treatment of malaria in most areas, but in Africa most parasites exhibit an intermediate level of resistance, such that antifolates may continue to offer some preventive efficacy.
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Chemoprophylaxis—Chemoprophylaxis with single folate antagonists is no longer recommended because of frequent resistance and toxicity. However, the antifolate combination trimethoprim-sulfamethoxazole is commonly used as a daily prophylactic therapy for HIV-infected patients in developing countries, and this regimen offers partial preventive efficacy against malaria in Africa.
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Intermittent preventive therapy—A new strategy for malaria control is intermittent preventive therapy, in which high-risk patients receive intermittent treatment for malaria, regardless of their infection status. This practice is most accepted in pregnancy, with the use of two or more doses of sulfadoxinepyrimethamine after the first trimester now standard policy in Africa, although efficacy is limited. In children intermittent preventive therapy has not been widely accepted, but the WHO now recommends seasonal malaria chemoprevention with amodiaquine plus sulfadoxine-pyrimethamine in the Sahel subregion of Africa, where malaria is highly seasonal and resistance to antifolates is relatively uncommon. In most other areas drug resistance seriously limits the preventive efficacy of antifolates.
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