Amodiaquine-associated adverse effects after inadvertent overdose and after a standard therapeutic dose

Abstract

SUMMARYA case of an acute dystonic reaction in a child presumptively treated for malaria with amodiaquine, and a case of persistent asymptomatic bradycardia in another child with mild pulmonary stenosis treated with a standard dose of amodiaquine for parasitologically confirmed uncomplicated malaria, is reported. Both subjects were homozygous for the wild type allele of cytochrome P450 2C8, the main enzyme responsible for amodiaquine metabolism. In both subjects, plasma concentrations of N-desethylamodiaquine and N-bisdesethylamodiaquine, the main metabolites of amodiaquine, were normal. No other drugs were detectable in the plasma of these two subjects after further toxicological screening. These observations, which suggest altered metabolism in the subject with an acute dystonic reaction, support the assertion that amodiaquine-associated dystonia is an idiosyncratic reaction. However, the occurrence of bradycardia after a standard dose of amodiaquine, which coincided with the time of expected peak concentrations of the active metabolite of amodiaquine, suggests a direct drug effect. These less reported adverse effects are likely to increase in parallel with the increased use of amodiaquine as a partner drug for combination therapy of malaria in Ghana. Further studies aimed at elucidating the mechanisms underlying these effects are, therefore, required.

Drug Induced Pure White Cell Aplasia: A Case Report and Review of Literature

“…The literature search revealed two postulated mechanisms by which amodiaquine can cause agranulocytosis:the first being dose dependent inhibitory effect on myeloid precursors [14] and second, an immune phenomenon attributed to anti IgG anti-neutrophil antibodies detected in the sera of the patients that were treated with amodiaquine and later developed agranulocytosis [15]. What really led to this extreme degree of agranulocytosis in our patient remains highly speculative.…”

The cardiovascular effects of amodiaquine and structurally related antimalarials: An individual patient data meta-analysis

“…In keeping with our findings, 16 (64%) of 20 patients had sinus bradycardia after amodiaquine monotherapy at total doses of 30 to 35 mg/kg over 3 days in the only cardiac safety study of amodiaquine in adults with uncomplicated malaria [ 19 ], which was conducted in Cameroon. In the few studies [ 19 , 20 ] of amodiaquine with electrocardiographic monitoring not included in this meta-analysis and in case reports [ 51 , 52 ], sinus bradycardia after amodiaquine has been recorded almost exclusively (24/25) in patients ≥12 years around the time of expected maximum drug concentration of amodiaquine and desethylamodiaquine. This bradycardia can be symptomatic with easy fatiguability [ 51 ] and dizziness when accompanied by hypotension [ 52 ].…”

Induction of Amodiaquine Metabolism by Rifampicin Following Concurrent Administration in Healthy Volunteers

“…Although ADQ is not known to have a narrow therapeutic window, the significant elevation of the Cmax may explain some of the observed adverse reactions, such as agranulocytosis and hepatitis. 27 Drug toxicities must be acceptable and cause less harm than the malaria itself, in order to encourage compliance and reduce mortality. 28 The AUC 0-α after single dose of ADQ alone was 572.53 ± 121.9644 ng/L*h, while the value of 196.42 ± 77.39 ng/L*h (66% decrease in exposure to ADQ) was obtained when it was coadministered with RIF.…”