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Chapter: Basic & Clinical Pharmacology : Antiprotozoal Drugs

Inhibitors of Folate Synthesis - Malaria

Inhibitors of enzymes involved in folate metabolism are used, generally in combination regimens, in the treatment and prevention of malaria.


Inhibitors of enzymes involved in folate metabolism are used, generally in combination regimens, in the treatment and prevention of malaria.

Chemistry & Pharmacokinetics

Pyrimethamine is a 2,4-diaminopyrimidine related to trimetho-prim . Proguanil is a biguanide derivative (Figure 52–2). Both drugs are slowly but adequately absorbed from the gastrointestinal tract. Pyrimethamine reaches peak plasma lev-els 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; only its triazine metabolite, cycloguanil, is active. Fansidar, a fixed combination of the sulfon-amide 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.

Antimalarial Action & Resistance

Pyrimethamine and proguanil act slowly against erythrocytic forms of susceptible strains of all four human malaria species. Proguanil also has some activity against hepatic forms. Neither drug is adequately gametocidal or effective against the persistent liver stages of P vivax or P ovale. Sulfonamides and sulfones are weakly active against erythrocytic schizonts but not against liver stages or gametocytes. They are not used alone as antimalarials but are effective in combination with other agents.

The mechanism of action of pyrimethamine and proguanil involves selective inhibition of plasmodial dihydrofolate reductase, a key enzyme in the pathway for synthesis of folate. Sulfonamides and sulfones inhibit another enzyme in the folate pathway, dihy-dropteroate synthase. As described and shown in Figure 46–2, combinations of inhibitors of these two enzymes provide synergistic activity.

Resistance to folate antagonists and sulfonamides is common in many areas for P falciparum and less common for P vivax. Resistance is due primarily to mutations in dihydrofolate reductase and dihydropteroate synthase, with increasing numbers of muta-tions leading to increasing levels of resistance. At present, resis-tance seriously limits the efficacy of sulfadoxine-pyrimethamine (Fansidar) 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 against malaria. Because different mutations may mediate resistance to different agents, cross-resistance is not uniformly seen.

Clinical Uses

A. Chemoprophylaxis

Chemoprophylaxis with single folate antagonists is no longer rec-ommended because of frequent resistance, but a number of agents are used in combination regimens. The combination of chloroquine (500 mg weekly) and proguanil (200 mg daily) was previously widely used, but with increasing resistance to both agents it is no longer recommended. Fansidar and Maloprim (the latter is a com-bination of pyrimethamine and the sulfone dapsone) are both effective against sensitive parasites with weekly dosing, but they are no longer recommended because of resistance and toxicity. Considering protection of populations in endemic regions, trimethoprim-sulfamethoxazole, an antifolate combination that is more active against bacteria than malaria parasites, is increas-ingly used as a daily prophylactic therapy for HIV-infected patients in developing countries. Although it is administered primarily to prevent typical HIV opportunistic and bacterial infections, this regimen offers partial preventive efficacy against malaria in Africa.

B. 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, typically with Fansidar, which benefits from simple dosing and prolonged activ-ity. Considering the two highest risk groups for severe malaria in Africa, this strategy is best validated in pregnant women and is increasingly studied in young children. Typical schedules include single doses of Fansidar during the second and third trimesters of pregnancy and monthly doses whenever children present for scheduled immunizations or, in areas with seasonal malaria, monthly doses during the transmission season. However, optimal preventive dosing schedules have not been established.

C. Treatment of Chloroquine-Resistant Falciparum Malaria

Fansidar is commonly used to treat uncomplicated falciparum malaria and until recently it was a first-line therapy for this indica-tion in some tropical countries. Advantages of Fansidar are ease of administration (a single oral dose) and low cost. However, rates of resistance are increasing, and Fansidar is no longer a recom-mended therapy. In particular, Fansidar should not be used for severe malaria, since it is slower-acting than other available agents. Fansidar is also not reliably effective in vivax malaria, and its use-fulness against P ovale and P malariae has not been adequately studied. A new antifolate-sulfone combination, chlorproguanil-dapsone (Lapdap), was until recently available in some African countries for the treatment of uncomplicated falciparum malaria, and the combination of chlorproguanil-dapsone and artesunate (Dacart) was under development. However, this project was dis-continued in 2008 as a result of concerns about hematologic tox-icity in those with G6PD deficiency, and chlorproguanil-dapsone will no longer be marketed.

D. Toxoplasmosis

Pyrimethamine, in combination with sulfadiazine, is first-line therapy in the treatment of toxoplasmosis, including acute infec-tion, congenital infection, and disease in immunocompromised patients. For immunocompromised patients, high-dose therapy is required followed by chronic suppressive therapy. Folinic acid is included to limit myelosuppression. Toxicity from the combina-tion is usually due primarily to sulfadiazine. The replacement of sulfadiazine with clindamycin provides an effective alternative regimen.

E. Pneumocystosis

P jiroveci is the cause of human pneumocystosis and is now recog-nized to be a fungus, but this organism is discussed because it responds to antiprotozoal drugs, not antifungals. (The related species P carinii is now recognized to be the cause of ani-mal infections.) First-line therapy of pneumocystosis is trimetho-prim plus sulfamethoxazole. Standard treatment includes high-dose intravenous or oral therapy (15 mg trimethoprim and 75 mg sulfamethoxazole per day in three or four divided doses) for 21 days. High-dose therapy entails signifi-cant toxicity, especially in patients with AIDS. Important toxici-ties include nausea, vomiting, fever, rash, leukopenia, hyponatremia, elevated hepatic enzymes, azotemia, anemia, and thrombocytope-nia. Less common effects include severe skin reactions, mental status changes, pancreatitis, and hypocalcemia. Trimethoprim-sulfamethoxazole is also the standard chemoprophylactic drug for the prevention of P jiroveci infection in immunocompromised individuals. Dosing is one double-strength tablet daily or three times per week. The chemoprophylactic dosing schedule is much better tolerated than high-dose therapy in immunocompromised patients, but rash, fever, leukopenia, or hepatitis may necessitate changing to another drug.

Adverse Effects & Cautions

Most patients tolerate pyrimethamine and proguanil well. Gastrointestinal symptoms, skin rashes, and itching are rare. Mouth ulcers and alopecia have been described with proguanil. Fansidar is no longer recommended for chemoprophylaxis because of uncommon but severe cutaneous reactions, including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Severe reactions appear to be much less common with single-dose or intermittent therapy, and use of the drug has been justified by the risks associated with falciparum malaria.

Rare adverse effects with a single dose of Fansidar are those associated with other sulfonamides, including hematologic, gas-trointestinal, central nervous system, dermatologic, and renal toxicity. Maloprim is no longer recommended for chemoprophy-laxis because of unacceptably high rates of agranulocytosis. Folate antagonists should be used cautiously in the presence of renal or hepatic dysfunction. Although pyrimethamine is teratogenic in animals, Fansidar has been safely used in pregnancy for therapy and as an intermittent chemoprophylactic regimen to improve pregnancy outcomes. Proguanil is considered safe in pregnancy. Folate supplements should be routinely administered during preg-nancy, but in women receiving Fansidar preventive therapy, high-dose folate supplementation (eg, 5 mg daily) should probably be avoided because it may limit preventive efficacy. The standard recommended dosage of 0.4–0.6 mg daily is less likely to affect Fansidar’s protective efficacy.

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