Life Cycle Drug Targets
Causal Prophylactics
Kill Hepatic Schizonts
- Atovaquone-proguanil
- Doxycycline
- Stop 7 days after leaving endemic area
- Prevent blood-stage infection entirely
Antirelapse (Hypnozoites)
8-Aminoquinolines Only
- Primaquine / Tafenoquine
- Only drugs active against hypnozoites
- Required for radical cure of P. vivax and P. ovale
- Glucose-6-phosphate dehydrogenase test mandatory before use
Suppressive Prophylactics
Chloroquine, mefloquine: kill blood-stage only — continue 4 weeks after leaving endemic area (liver stage matures into blood during this window).
Drug Mechanisms
4-Aminoquinolines
Chloroquine
- Blocks heme polymerization in digestive vacuole
- Free heme accumulates → lethal to parasite
- Resistance: pfcrt K76T exports drug from vacuole
Endoperoxides
Artemisinins
- Fe²+ cleaves endoperoxide bridge → free radicals
- Multi-target protein and lipid alkylation
- Active against all blood stages including rings
- Short half-life → always combined with partner drug
Mitochondrial Inhibitor
Atovaquone-Proguanil
- Atovaquone: blocks cytochrome bc1 (complex III)
- Proguanil: inhibits dihydrofolate reductase (as cycloguanil)
- Causal prophylactic: stop 7 days after return
Prophylaxis Selection
| Agent |
Type |
Stop After Return |
Key Contraindication |
| Chloroquine |
Suppressive |
4 weeks |
Resistant areas (most of world) |
| Atovaquone-proguanil |
Causal |
7 days |
Severe renal impairment |
| Doxycycline |
Causal |
4 weeks |
Pregnancy; age under 8 years |
| Mefloquine |
Suppressive |
4 weeks |
Psychiatric history; seizures |
| Primaquine |
Causal |
7 days |
Glucose-6-phosphate dehydrogenase deficiency |
Key Toxicities
Chloroquine / Hydroxychloroquine
Retinopathy
- Accumulates in retinal pigment epithelium
- Bull's-eye maculopathy pattern
- Dose-dependent; largely irreversible
- Risk with long-term use (rheumatologic indications)
8-Aminoquinolines
Hemolytic Anemia
- Oxidative metabolites overwhelm G6PD-deficient red blood cells
- Heinz body formation → hemolysis
- Test glucose-6-phosphate dehydrogenase before prescribing
- Tafenoquine: quantitative test required (not qualitative)
Mefloquine — Neuropsychiatric Toxicity
Vivid dreams, anxiety, dizziness → psychosis, seizures. FDA black box warning. Contraindicated with psychiatric history or seizure disorder. Start 2–3 weeks before departure to detect intolerance before remote travel.
Corrected QT Prolongation
Quinoline class (quinine, quinidine, mefloquine, lumefantrine, piperaquine): block cardiac rapid delayed rectifier potassium channel. Risk amplified by hypokalemia and hypomagnesemia. Highest risk: quinine IV and quinidine IV.
Resistance Mechanisms
Chloroquine Resistance
pfcrt K76T Mutation
- Mutant transporter exports chloroquine from digestive vacuole
- Prevents lethal heme accumulation
- Prevalent: virtually all sub-Saharan Africa, SE Asia, S. America
- Sensitive areas: Central America (west of Panama Canal), Haiti
Artemisinin Partial Resistance
pfkelch13 C580Y Mutation
- Ring-stage parasites reduce metabolic activity during drug peak
- Survive artemisinin exposure; resume development when levels fall
- Delayed parasite clearance (clearance half-life >5 hours)
- Partner drug resistance + K13 = artemisinin-based combination therapy failure