A 28-year-old woman from Mumbai is diagnosed with uncomplicated P. falciparum malaria. She is started on artemether (intramuscular) 120 mg on day 1, followed by 80 mg daily for 4 days, then switched to oral artemisinin-based combination therapy (ABCT) with artesunate + amodiaquine for 3 days. On day 8 of treatment, she develops sudden-onset dizziness, vertigo, and nystagmus. Audiometry shows bilateral sensorineural hearing loss. Which antimalarial is most likely responsible for this adverse effect?

Explanation

## Clinical Presentation The patient develops bilateral sensorineural hearing loss and vestibular symptoms (dizziness, vertigo, nystagmus) on day 8 of antimalarial therapy, after receiving intramuscular artemether 120 mg on day 1 followed by 80 mg daily for 4 days (total 5 days of IM artemether). ## Why Artemether Is Responsible **Key Point:** Artemether is a highly lipophilic artemisinin derivative administered intramuscularly. Its lipophilicity allows it to cross the blood-brain barrier and accumulate in lipid-rich neural tissues, including the vestibulocochlear apparatus of the inner ear. Prolonged or high-dose parenteral artemether has been associated with neurotoxicity, including sensorineural hearing loss and vestibular dysfunction, as documented in animal studies and clinical case reports (KD Tripathi, Essentials of Medical Pharmacology, 8th ed.). **High-Yield:** Artemether neurotoxicity features: - Occurs with parenteral (IM) administration more than oral routes due to higher systemic exposure - Lipophilic metabolites (dihydroartemisinin) accumulate in the inner ear and brainstem - Manifests as vestibulocochlear dysfunction: vertigo, nystagmus, bilateral SNHL - More likely with prolonged high-dose parenteral regimens (as in this case: 5 days IM) - Oral artemisinin derivatives at standard doses carry minimal ototoxic risk **Clinical Pearl:** The timeline is critical — symptoms appear on day 8, after 5 days of IM artemether (days 1–5). Amodiaquine was only started on day 6 (oral ABCT for 3 days), making cumulative amodiaquine toxicity implausible in such a short exposure window. The IM route and lipophilic nature of artemether make it the most likely culprit. ## Comparison of Antimalarial Neurotoxicity/Ototoxicity | Drug | Ototoxicity Risk | Mechanism | Route Dependence | |------|------------------|-----------|-----------------| | Artemether (IM) | **Moderate–High** | Lipophilic; accumulates in inner ear/brainstem | Higher risk with parenteral use | | Quinine | **High** | 4-aminoquinoline; cinchonism | Dose-dependent | | Chloroquine | **Moderate** | 4-aminoquinoline; chronic use | Cumulative | | Amodiaquine | **Low–Rare** | 4-aminoquinoline; rarely reported | Requires prolonged exposure | | Artesunate (oral) | **Minimal** | Hydrophilic; poor CNS penetration | Negligible at therapeutic doses | **Why the other options are wrong:** - **Option A (Amodiaquine):** Only 3 days of exposure — insufficient for cumulative 4-aminoquinoline ototoxicity; amodiaquine ototoxicity is rare and underreported in standard Indian pharmacology texts (KD Tripathi). - **Option B (Artesunate):** Oral artesunate is hydrophilic with minimal CNS/inner ear penetration; not a recognized cause of ototoxicity at therapeutic doses. - **Option C (Synergistic combination effect):** No established pharmacological basis for synergistic vestibulocochlear toxicity between artemisinin derivatives and amodiaquine. **Mnemonic:** **LANA** = **L**ipophilic **A**rtemether → **N**eurotoxicity → **A**ccumulation in inner ear (with parenteral use). *Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed., Chapter on Antimalarials; WHO Guidelines for Treatment of Malaria, 3rd ed.*