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🦟 ANTIMALARIAL DRUGS - Complete Study Notes

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1. LIFE CYCLE & DRUG TARGETS

Key point: Exo-erythrocytic stage is absent in P. falciparum - so no relapses occur with falciparum malaria.

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2. CLASSIFICATION BY USE

A. Primary Tissue Schizonticides (Causal Prophylaxis)

• Primaquine, Proguanil

B. Erythrocytic Schizonticides

• M - Mefloquine
• A - Atovaquone
• C - Chloroquine (+ amodiaquine + piperaquine)
• H - Halofantrine (+ lumefantrine)
• A - Artemisinins
• R - Res-Q (Quinine)

• Proguanil, Pyrimethamine, Sulfonamides, Tetracyclines

C. Exo-Erythrocytic Schizonticides (Radical Cure)

• Primaquine (only drug)

D. Gametocides (Prevent Transmission)

• Chloroquine, Quinine, Pyrimethamine, Primaquine, Artemisinins
• Primaquine kills gametes of all species of Plasmodium

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3. INDIVIDUAL DRUGS

🔵 CHLOROQUINE

• MOA: Concentrates in food vacuole of parasite → prevents heme polymerization to hemozoin → heme accumulates and is toxic to parasite
• Largest volume of distribution (>1300 L)
• DOC for: Non-falciparum malaria, CQ-sensitive P. falciparum, malaria in pregnancy
• Erythrocytic schizonticide only - no effect on exo-erythrocytic stage
• Other uses (mnemonic: RED LIP Mahatma Gandhi):
  • Rheumatoid arthritis, Extraintestinal amoebiasis, Discoid lupus, Lepra reaction, Infectious mononucleosis, Photogenic reactions, Malaria, Giardiasis
• ADRs: Skin rashes, peripheral neuropathy, T-wave changes, auditory impairment, toxic psychosis
• Serious: Prolonged use → retinal damage (Bull's eye maculopathy) → blindness; precipitates porphyria

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🔵 QUININE

• MOA: Similar to chloroquine (not fully clear)
• Major use: P. falciparum resistant to chloroquine (DOC)
• Combined with doxycycline or clindamycin to limit toxicity/resistance
• NOT used for chemoprophylaxis (delays resistance emergence)
• 70% protein-bound (especially α1-acid glycoprotein)
• Quinidine (d-isomer) used IV for severe P. falciparum
• ADRs:
  • Hypoglycemia (palpitations, sweating, tachycardia) → give IV quinine in 5% dextrose (NOT normal saline)
  • Cinchonism (toxic doses): GI distress, vertigo, blurred vision, headache, tinnitus
  • Cardiac conduction abnormalities, hemolysis in G6PD deficiency

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🔵 MEFLOQUINE

• Used for chloroquine-resistant P. falciparum
• Good for treatment AND prophylaxis
• Can cause cardiac conduction abnormalities, psychosis, seizures
• Contraindicated: prolongs QT interval
• Effective as single dose treatment

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🔵 PRIMAQUINE

• MOA: Forms redox compounds acting as cellular antioxidants
• Tissue (pre + exo-erythrocytic) schizonticide
• Kills gametes of all Plasmodium species (unlike chloroquine/quinine)
• Always used with blood schizonticides
• Radical cure of P. vivax (given for 14 days to kill hypnozoites)
• For P. falciparum: single dose to kill gametes
• Contraindications: Pregnancy, G6PD deficiency (causes hemolysis + methemoglobinemia), P. falciparum (no exo-erythrocytic stage)
• Tafenoquine - new oral drug similar to primaquine; approved as single oral dose for radical cure of P. vivax malaria

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🔵 ANTIFOLATE DRUGS

• Pyrimethamine + Proguanil (prodrug) → inhibit DHFRase
• Act through sequential blockade with sulfadoxine
• Slow-acting blood schizonticides
• Active against chloroquine-resistant P. falciparum
• Proguanil + atovaquone = treatment + chemoprophylaxis of CQ-resistant malaria

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🔵 ATOVAQUONE

• Rapidly acting blood schizonticide
• Collapses parasite's membrane potential
• Also used for Pneumocystis jirovecii pneumonia and Toxoplasma gondii

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🔵 ARTEMISININ DERIVATIVES

• From Chinese herb Artemisia annua
• Artemisinins are prodrugs → activated to dihydroartemisinin
• Generate highly active free radicals that damage parasite membranes
• Fastest acting drugs against malaria
• Artesunate: very short half-life, can be given IV; used for multidrug-resistant and cerebral malaria
• NOT for chemoprophylaxis
• Rarely cause QT prolongation

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🔵 HALOFANTRINE & LUMEFANTRINE

• Halofantrine: erratic oral bioavailability; potentially serious cardiotoxicity (especially with mefloquine)
• Reserved only for chemoprophylaxis
• Lumefantrine: new drug similar to halofantrine; always used with artemether

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4. NATIONAL TREATMENT GUIDELINES (NBVDCP)

Uncomplicated Malaria

Severe/Complicated Malaria (P. falciparum)

• Artesunate IV/IM (minimum 48 hours) → followed by oral ACT
• (All trimesters of pregnancy: same regimen)

Preferred ACT (India):

• North-Eastern states: Artemether + Lumefantrine
• Rest of India: Artesunate + Sulfadoxine/Pyrimethamine

⚠️ Important footnotes:

• Primaquine is contraindicated in pregnancy, infants, G6PD deficiency
• For P. vivax: Primaquine given 14 days (to kill hypnozoites)
• For P. falciparum: Primaquine given as single dose (to kill gametes only)

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5. WHO RECOMMENDED ACTs

1. Artemether-Lumefantrine
2. Artesunate-Mefloquine
3. Dihydroartemisinin-Piperaquine
4. Artesunate-Amodiaquine
5. Artesunate-Sulfadoxine-Pyrimethamine

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6. CHEMOPROPHYLAXIS

• Doxycycline: contraindicated in pregnancy and children < 8 years
• Mefloquine: contraindicated in patients with convulsions/neuropsychiatric conditions

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7. QUICK REVISION TABLE - Primaquine Special Points

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