Antimalarial drugs: QT prolongation and cardiac arrhythmias.
Most available antimalarial drugs induce cardiac side effects. These side effects include various mild heart rate changes (amodiaquine) to excessive prolongation of the QT interval (halofantrine) which may lead to lethal arrhythmias such as Torsade de Pointes (TdP). The cellular mechanism of such events during antimalarial therapy is principally related to ion channel inhibition (e.g., human ether-a-go-go related gene channel) which may slow the repolarisation process and create a good substrate for arrhythmia (when dispersion of repolarisation is present). However, other antimalarial drugs do not show as potent cardiac side effects, like co-arthemeter and sulfadoxine-pyrimethamine. Considering that TdP are favoured by a complex combination of electrophysiological changes, a predictive cardiosafety strategy for new antimalarial drugs should comprise assays with an increasing level of information from ion channel level, cellular and organ level, to the whole organism. In this review, the actual knowledge on underlying mechanisms of QT prolongation and TdP is described, followed by the cardiac safety profiles of present antimalarial drugs.
Traebert
Martin
M
Exploratory Development, Safety Profiling and Assessment, Novartis Pharma AG, MUT-2881.204, CH-4002 Basel, Switzerland. Martin.Traebert@pharma.novartis.com
Dumotier
Berengere
B
D000655:Amodiaquine / Q000009:adverse effects* / Q000627:therapeutic use; D017277:Drug Approval; D004594:Electrophysiology; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D008288:Malaria / Q000188:drug therapy; D010616:Phenanthrenes / Q000009:adverse effects* / Q000627:therapeutic use; D018570:Risk Assessment; D012307:Risk Factors; D016171:Torsades de Pointes / Q000139:chemically induced*
D010616:Phenanthrenes; D000655:Amodiaquine; C023768:halofantrine