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Chemotherapy of Malaria

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Classification of Antimalarial Drugs

By Chemical Class

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Mechanisms of Action

1. Quinolines (Chloroquine, Quinine, Mefloquine)

• Act primarily on asexual erythrocytic stages
• Inhibit hemozoin (malaria pigment) formation — toxic heme accumulates and kills the parasite
• Chloroquine concentrates in the parasite's digestive vacuole, inhibiting heme polymerization
• Mefloquine forms a complex with heme that is directly toxic to the parasite; it has relatively poor affinity for DNA and does not significantly inhibit nucleic acid/protein synthesis (Harrison's, p. 6367)

2. Artemisinins

• React with intraparasitic heme iron to generate free radicals
• Alkylate and damage parasitic proteins
• Rapid action; act on rings, trophozoites, and gametocytes
• Short half-life — must be combined with a longer-acting partner drug (ACT)

3. Antifolates

• Pyrimethamine inhibits dihydrofolate reductase (DHFR) → blocks folate synthesis → inhibits DNA/RNA synthesis
• Proguanil (biguanide) is converted to cycloguanil, also a DHFR inhibitor
• Sulfonamides/sulfones inhibit dihydropteroate synthase (DHPS) → synergistic combination (e.g., SP = Fansidar)

4. 8-Aminoquinolines (Primaquine, Tafenoquine)

• Only drugs active against hepatic hypnozoites (P. vivax, P. ovale) — radical cure
• Also active against gametocytes (block transmission)
• Mechanism: oxidative stress through quinone metabolites

5. Atovaquone

• Inhibits mitochondrial electron transport (cytochrome bc1 complex) → collapses mitochondrial membrane potential
• Always combined with proguanil (Malarone) to prevent resistance

6. Doxycycline/Tetracycline

• Inhibit parasite protein synthesis (apicoplast ribosomes)
• Slow-acting; used in combination or for prophylaxis

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Drug Profiles

Chloroquine

• Drug of choice for chloroquine-sensitive P. vivax, P. ovale, P. malariae, P. knowlesi
• No longer effective for P. falciparum in most endemic regions
• Dose: 25 mg base/kg over 3 days (10 + 10 + 5 mg/kg)
• Adverse effects: nausea, pruritus (especially in Africans), retinopathy (long-term use), QTc prolongation

Quinine / Quinidine

• Used for severe malaria (IV quinidine in the US; IV artesunate preferred globally)
• Active against asexual erythrocytic stages only
• Cinchonism: tinnitus, high-tone hearing loss, nausea, dysphoria
• Must be combined with doxycycline/tetracycline/clindamycin for full course

Mefloquine

• Used for prophylaxis and treatment of chloroquine-resistant malaria
• Effective in most of the world; resistance documented in parts of Africa and Southeast Asia (Harrison's, p. 6367)
• Cross-resistance with halofantrine and, in limited areas, quinine
• Adverse effects: neuropsychiatric effects (anxiety, nightmares, psychosis), GI disturbance, QTc prolongation
• Acts on asexual erythrocytic stages only

Artemisinin-based Combination Therapies (ACTs) — First-line for P. falciparum

• WHO recommends ACTs as first-line treatment for uncomplicated P. falciparum malaria
• Artemisinin clears parasites rapidly; partner drug eliminates residual parasites

Primaquine / Tafenoquine

• Mandatory for radical cure of P. vivax and P. ovale to eliminate liver hypnozoites
• Contraindicated in G6PD deficiency (risk of hemolytic anemia — screen before use)
• Tafenoquine: single-dose alternative to 14-day primaquine

Atovaquone-Proguanil (Malarone)

• Effective for prophylaxis and treatment of uncomplicated falciparum malaria
• Excellent tolerability; taken with food (fat increases absorption)
• Resistance emerges rapidly if used as monotherapy

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Treatment Protocols

Uncomplicated P. falciparum Malaria

1. First-line: ACT (e.g., Artemether-Lumefantrine × 3 days)
2. Alternatives: Atovaquone-Proguanil, Quinine + Doxycycline

Severe P. falciparum Malaria

• IV Artesunate is the drug of choice worldwide (Harrison's, p. 6442)
• If unavailable: IV Quinine + Doxycycline/Clindamycin
• Patients unable to take oral drugs should receive parenteral therapy immediately
• If resistance status is uncertain, treat as resistant

P. vivax / P. ovale Malaria

1. Blood-stage: Chloroquine (if sensitive) OR ACT
2. Radical cure (hypnozoites): Primaquine × 14 days (after G6PD screening)
3. Chloroquine-resistant P. vivax (PNG, Indonesia, parts of South America): use ACT

P. malariae / P. knowlesi

• Chloroquine (sensitive; no hypnozoite stage → no primaquine needed for malariae)
• P. knowlesi: treat as falciparum given risk of rapid severe disease

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Chemoprophylaxis

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Drug Resistance

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Special Situations

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Summary

• ACTs are the cornerstone of P. falciparum treatment globally
• IV Artesunate is the standard of care for severe malaria
• Primaquine/Tafenoquine are essential for radical cure of relapsing malarias
• Prophylaxis choice depends on destination, resistance patterns, and patient factors
• Resistance surveillance is critical, especially for artemisinin-based regimens