Drugs for Malaria

Malaria is one of the most common diseases worldwide and a leading cause of death. Plasmodium species that infect humans (P falciparum, P malariae, P ovale, P vivax) undergo a primary developmental stage in the liver and then parasitize erythrocytes. P falciparum and P malariae have only 1 cycle of liver cell invasion. The other species have a dormant hepatic stage responsible for recurrent infections and relapses. Primary tissue schizonticides (eg, primaquine) kill schizonts in the liver, whereas blood schizonticides (eg, chloroquine, quinine) kill these parasitic forms only in the erythrocyte. Sporonticides (proguanil, pyrimethamine) prevent sporogony and multiplication in the mosquito.

Drugs used for the treatment of malaria are shown in Table 52-1.

TABLE 52-1 Drugs used in the treatment of malaria.

Drug Uses Adverse Effects Chloroquine Prophylaxis and treatment in areas without resistant P falciparum; treatment of P vivax and P ovale malaria GI distress, rash, headache; auditory dysfunction and retinal dysfunction (high dose) Mefloquine Prophylaxis and treatment in areas with resistant P falciparum GI distress, rash, headache; cardiac conduction defects and neurologic symptoms (high dose) Quininea

Treatment of multidrug-resistant malaria Cinchonism, hemolysis in G6PD deficiency, blackwater fever Primaquine Eradication of liver stages of P vivax and P ovale GI distress, methemoglobinemia, hemolysis in G6PD deficiency Antifolates Prophylaxis and treatment of multidrug-resistant P falciparum malaria GI distress, renal dysfunction, hemolysis, folate deficiency Atovaquone-proguanil (Malarone) Prophylaxis and treatment of multidrug-resistant P falciparum malaria GI distress, headache, rash hemolysis, folate deficiency Artesunate, Artemether Treatment of multidrug-resistant malaria GI distress

aIn most cases quinine is used together with doxycycline or clindamycin, or an antifolate. Quinidine gluconate (IV) is used in severe infections or for patients unable to take oral quinine.

Chloroquine

Classification and Pharmacokinetics

Chloroquine is a 4-aminoquinoline derivative. The drug is rapidly absorbed when given orally, is widely distributed to tissues, and has an extremely large volume of distribution. Antacids may decrease oral absorption of the drug. Chloroquine is excreted largely unchanged in the urine.

Mechanism of Action

Chloroquine accumulates in the food vacuole of plasmodia and prevents polymerization of the hemoglobin breakdown product heme into hemozoin. Intracellular accumulation of heme is toxic to the parasite. Decreased intracellular accumulation via increased activity of membrane “pumps” is a mechanism of resistance to chloroquine and other antimalarial drugs. Resistance in P falciparum can also result from decreased intravacuolar accumulation of chloroquine via a transporter encoded by the pfcrt (P falciparum chloroquine-resistance transporter) gene.

Clinical Use

Chloroquine is the drug of choice for acute attacks of nonfalciparum and sensitive falciparum malaria and for chemoprophylaxis, except in regions where P falciparumis resistant. The drug is solely a blood schizonticide. Chloroquine and hydroxychloroquine are also used in autoimmune disorders, including rheumatoid arthritis.

Toxicity

At low doses, chloroquine causes gastrointestinal irritation, skin rash, and headaches. High doses may cause severe skin lesions, peripheral neuropathies, myocardial depression, retinal damage, auditory impairment, and toxic psychosis. Chloroquine may also precipitate porphyria attacks.

Quinine

Classification and Pharmacokinetics

Quinine is rapidly absorbed orally and is metabolized before renal excretion. Intravenous administration of quinine is possible in severe infections.

Mechanism of Action

Quinine complexes with double-stranded DNA to prevent strand separation, resulting in block of DNA replication and transcription to RNA. Quinine is solely a blood schizonticide.

Clinical Use

The main use of quinine is in P falciparum infections resistant to chloroquine in patients who can tolerate oral treatment. Quinine is commonly used with doxycycline or clindamycin to shorten the duration of therapy and limit toxicity. Quinidine, the dextrorotatory stereoisomer of quinine, is used intravenously in the treatment of severe or complicated falciparum malaria. To delay emergence of resistance, quinine should not be used routinely for prophylaxis.

Toxicity

Quinine commonly causes cinchonism, symptoms of which include gastrointestinal distress, headache, vertigo, blurred vision, and tinnitus. Severe overdose results in disturbances in cardiac conduction that resemble quinidine toxicity. Hematotoxic effects occur, including hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient patients. Blackwater fever (intravascular hemolysis) is a rare and sometimes fatal complication in quinine-sensitized persons. Quinine is contraindicated in pregnancy.

Mefloquine

Classification and Pharmacokinetics

Mefloquine is a synthetic 4-quinoline derivative. Because of local irritation, mefloquine can only be given orally, although it is subject to variable absorption. Its mechanism of action is not known.

Clinical Use

Mefloquine is a first-line drug (taken weekly) given for prophylaxis in all geographical areas with chloroquine resistance and an alternative drug to quinine in acute attacks and uncomplicated infections resulting from P falciparum. Resistance to mefloquine has emerged in regions of Southeast Asia.

Toxicity

Common adverse effects include gastrointestinal distress, skin rash, headache, and dizziness. At high doses, mefloquine has caused cardiac conduction defects, psychiatric disorders, neurologic symptoms, and seizures.

Primaquine

Classification and Pharmacokinetics

Primaquine is a synthetic 8-aminoquinoline. Absorption is complete after oral administration and is followed by extensive metabolism.

Mechanism of Action

Primaquine forms quinoline-quinone metabolites, which are electron-transferring redox compounds that act as cellular oxidants. The drug is a tissue schizonticide and also limits malaria transmission by acting as a gametocide.

Clinical Use

Primaquine eradicates liver stages of P vivax and P ovale and should be used in conjunction with a blood schizonticide. Although not active alone in acute attacks of vivax and ovale malaria, a 14-d course of primaquine is standard after treatment with chloroquine, and the drug is also an alternative (daily) for primary prevention.

Toxicity

Primaquine is usually well tolerated but may cause gastrointestinal distress, pruritus, headaches, and methemoglobinemia. More serious toxicity involves hemolysis in G6PD-deficient patients. Primaquine is contraindicated in pregnancy.

Antifolate Drugs

Classification and Pharmacokinetics

The antifolate group includes pyrimethamine, proguanil, sulfadoxine, and dapsone. All these drugs are absorbed orally and are excreted in the urine, partly in unchanged form. Proguanil has a shorter half-life (12-16 h) than other drugs in this subclass (half-life >100 h).

Mechanisms of Action

Sulfonamides act as antimetabolites of PABA and block folic acid synthesis in certain protozoans by inhibiting dihydropteroate synthase. Proguanil (chloroguanide) is bioactivated to cycloguanil. Pyrimethamine and cycloguanil are selective inhibitors of protozoan dihydrofolate reductases. The combination of pyrimethamine with sulfadoxine has synergistic antimalarial effects through the sequential blockade of 2 steps in folic acid synthesis.

Clinical Use

The antifols are blood schizonticides that act mainly against P falciparum.

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