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Analysis of onset mechanism of drug-induced TdP in LQT3 patient

Introduction: TdP occurred in LQT3 patient after switching perospirone (PER) to blonanserin (BLO) for her nocturnal delirium. PER blocked α 1 -adrenoceptors with pA 2 of 2.0 ng/mL. While BLO may also have such potential, 1 μg/mL of it can inhibit hERG K + channel by 82%. We studied onset mechanism of TdP. Methods: PER hydrochloride (n=4) and BLO (n=4) of 0.01, 0.1 and 1 mg/kg, i.v., were administered to the halothane-anesthetized dogs. Results: The low dose of PER decreased total peripheral vascular resistance (TPR), but increased heart rate (HR) and cardiac output (CO), and facilitated AV conduction. The middle dose decreased mean blood pressure (MBP) and prolonged repolarization period besides those observed after the low dose. Although the high dose decreased MBP and TPR, it did not increase HR or CO. It tended to delay AV conduction, and significantly prolonged repolarization period. BLO dose-dependently decreased TPR, but increased HR, CO and cardiac contractility without affecting electrophysiological variables. Conclusion: Lack of the reflex-mediated increase of sympathetic tone after the high dose of PER may suggest its Ca 2+ channel inhibition suppressing TdP. BLO-induced increase of Ca 2+ current might have induced TdP in the LQT3 patient.