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Chemotherapy of Malaria

Overview

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Classification of Antimalarial Drugs

By Stage of Action

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Major Drug Classes

1. Quinoline Derivatives

Chloroquine

• Mechanism: Concentrates in parasite food vacuole; inhibits heme polymerization → toxic heme accumulates → parasite death.
• Use: Drug of choice for chloroquine-sensitive P. vivax, P. malariae, P. ovale. Largely ineffective for P. falciparum due to widespread resistance.
• Resistance: Mediated by mutations in pfcrt (chloroquine resistance transporter gene).
• Toxicity: Pruritus (especially in Africans), retinopathy with chronic use, QT prolongation.

Quinine / Quinidine

• Mechanism: Similar to chloroquine (heme polymerization inhibition); also intercalates DNA.
• Use: Severe/complicated P. falciparum malaria (IV quinine or quinidine); oral quinine with doxycycline or clindamycin for uncomplicated disease when ACT unavailable.
• Toxicity: Cinchonism (tinnitus, high-tone deafness, nausea, dysphoria), hypoglycemia, QT prolongation, "blackwater fever" (massive hemolysis).

Mefloquine

• Mechanism: Blood schizonticide; exact mechanism unclear (may affect membrane function).
• Use: Chemoprophylaxis and treatment of chloroquine-resistant malaria.
• Toxicity: Neuropsychiatric effects (vivid dreams, anxiety, psychosis), contraindicated in psychiatric illness and epilepsy.

Primaquine

• Mechanism: Oxidative stress on parasite mitochondria; only drug effective against hepatic hypnozoites.
• Use: Radical cure of P. vivax and P. ovale (to prevent relapses); gametocytocidal in P. falciparum.
• Toxicity: Hemolytic anemia in G6PD-deficient patients — G6PD testing is mandatory before use. Methemoglobinemia.

Tafenoquine

• Mechanism: Similar to primaquine (8-aminoquinoline); long half-life allows single-dose radical cure.
• Use: Radical cure of P. vivax (single dose).
• Toxicity: Same as primaquine; G6PD testing mandatory.

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2. Artemisinin Compounds (Sesquiterpene Lactones)

• Mechanism: Iron-catalyzed activation of endoperoxide bridge → free radicals → alkylation of parasite proteins and membrane damage.
• Pharmacokinetics: Rapid onset, short half-life (~1–2 hours) — hence always combined with a long-acting partner drug.
• Use: First-line for all P. falciparum malaria (as ACT); IV artesunate is preferred over IV quinine for severe malaria (superior efficacy, lower toxicity).
• Resistance: Partial artemisinin resistance (kelch13 mutations) is emerging in Southeast Asia and now reported in Africa — major public health concern.
• Toxicity: Generally well tolerated; rare hemolytic anemia post-IV artesunate (delayed, immune-mediated).

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3. Antifolate Combinations

Sulfadoxine-Pyrimethamine (SP, Fansidar)

• Mechanism: Sequential blockade of folate synthesis — pyrimethamine inhibits dihydrofolate reductase (DHFR); sulfadoxine inhibits dihydropteroate synthase (DHPS).
• Use: Intermittent preventive treatment in pregnancy (IPTp) and infancy (IPTi); ACT partner drug in some regions.
• Resistance: Widespread due to point mutations in pfdhfr and pfdhps.

Proguanil (with atovaquone)

• Mechanism: Metabolized to cycloguanil (DHFR inhibitor); with atovaquone synergistically collapses mitochondrial membrane potential.

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4. Atovaquone-Proguanil (Malarone)

• Mechanism: Atovaquone inhibits the mitochondrial cytochrome bc1 complex (electron transport); proguanil acts synergistically.
• Use: Chemoprophylaxis (preferred for travelers); treatment of uncomplicated P. falciparum.
• Advantages: Causal prophylactic (kills pre-erythrocytic stage), short post-exposure period needed.
• Toxicity: GI side effects; expensive; resistance develops rapidly if used as monotherapy.

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5. Antibiotics with Antimalarial Activity

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Treatment Regimens

Uncomplicated P. falciparum Malaria

• Artemether-lumefantrine (AL) — 6-dose regimen over 3 days
• Artesunate-amodiaquine
• Artesunate-mefloquine (SE Asia)
• Dihydroartemisinin-piperaquine
• Artesunate-pyronaridine

According to Harrison's (p. 6443), the choice of ACT partner drug depends on likely sensitivity of the infecting parasites; artemisinin combinations are sometimes unavailable in temperate countries.

Uncomplicated P. vivax / P. ovale / P. malariae

• Chloroquine (where sensitive) + Primaquine (for radical cure in P. vivax / P. ovale)
• ACT where chloroquine resistance exists (P. vivax resistance reported in Papua/Indonesia)

Severe/Complicated Malaria (P. falciparum)

• IV artesunate — drug of choice (superior to IV quinine)
• IV quinine + doxycycline/clindamycin — if artesunate unavailable
• Transition to oral ACT once patient can tolerate oral medications
• Supportive care: IV fluids, antipyretics, blood transfusion, renal replacement therapy as needed

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Chemoprophylaxis for Travelers

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Drug Resistance

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Special Populations

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Summary Table: Key Antimalarial Drugs

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