Clinical Features and Management of Poisoning due to Antimalarial Drugs

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Abstract
The toxicities of antimalarial drugs vary because of the differences in the chemical structures of these compounds. Quinine, the oldest antimalarial, has been used for 300 years. Of the 200 to 300 compounds synthesised since the first synthetic antimalarial, primaquine in 1926, 15 to 20 are currently used for malaria treatment, most of which are quinoline derivatives. Quinoline derivatives, particularly quinine and chloroquine, are highly toxic in overdose. The toxic effects are related to their quinidine-like actions on the heart and include circulatory arrest, cardiogenic shock, conduction disturbances and ventricular arrhythmias. Additional clinical features are obnubilation, coma, convulsions, respiratory depression. Blindness is a frequent complication in quinine overdose. Hypokalaemia is consistently present, although apparently self-correcting, in severe chloroquine poisoning and is a good index of severity. Recent toxicokinetic studies of quinine and chloroquine showed good correlations between dose ingested, serum concentrations and clinical features, and confirmed the inefficacy of haemodialysis, haemoperfusion and peritoneal dialysis for enhancing drug removal. The other quinoline derivatives appear to be less toxic. Amodiaquine may induce side effects such as gastrointestinal symptoms, agranulocytosis and hepatitis. The main feature of primaquine overdose is methaemoglobinaemia. No cases of mefloquine and piperaquine overdose have been reported. Overdose with quinacrine, an acridine derivative, may result in nausea, vomiting, confusion, convulsion and acute psychosis. The dehydrofolate reductase inhibitors used in malaria treatment are sulfadoxine, dapsone, proguanil (chloroguanide), trimethoprim and pyrimethamine. Most of these drugs are given in combination. Proguanil is one of the safest antimalarials. Convulsion, coma and blindness have been reported in pyrimethamine overdose. Sulfadoxine can induce Lyell and Stevens-Johnson syndromes. The main feature of dapsone poisoning is severe methaemoglobinaemia which is related to dapsone and to its metabolites. Recent toxicokinetic studies confirmed the efficacy of oral activated charcoal, haemodialysis and haemoperfusion in enhancing removal of dapsone and its metabolites. No overdose has been reported with artemesinine, a new antimalarial tested in the People’s Republic of China. The general management of antimalarial overdose include gastric lavage and symptomatic treatment. Chloroquine and quinine overdose require early monitoring of vital signs, ECG, blood pressure and intensive supportive treatment of cardiovascular disturbances: adrenaline (epinephrine) for circulatory arrest, isoprenaline (isoproterenol) for shock and conduction disturbances, DC countershock for ventricular tachycardia or fibrillation and sometimes pacemaker stimulation for later ventricular arrhythmia. Correction of hypokalaemia should be done very cautiously when cardiac depression has been rectified. Experimental and clinical data have shown that diazepam may reverse chloroquine cardiotoxicity. After ingestion of a large dose or when cardiotoxic symptoms are present, diazepam should be given systematically as a loading dose of 1 mg/kg followed by a continuous infusion. Dapsone-induced methaemoglobinaemia requires méthylene blue administration and repeated oral doses of activated charcoal. Haemodialysis may be indicated if methaemoglobinaemia recurs. Chloroquine overdose remains the most severe and frequent cause of antimalarial drug poisonings. Its prognosis and high mortality should be improved by adequate supportive treatment and by the systematic and early treatment with diazepam.