Additive Proarrhythmic Effect of Combined Treatment with QT-Prolonging Agents

Abstract

Drug combinations may elevate the risk of proarrhythmia. The aim of the present study was to investigate whether combinations of non-cardiovascular agents induce an additive increase in the proarrhythmic risk. In 12 female rabbit hearts, a drug combination of cotrimoxazole (300 µM), ondansetron (5 µM) and domperidone (1 µM) was infused after obtaining baseline data. In another 13 hearts, a combination of cotrimoxazole (300 µM), ondansetron (5 µM) and erythromycin (300 µM) was infused. Monophasic action potentials and ECG displayed a significant QT prolongation in all groups. This was accompanied by a significant increase in action potential duration. Of note, addition of each drug resulted in a further increase in the QT interval. Furthermore, a significant elevation of spatial dispersion of repolarization was observed. Lowering of potassium concentration in bradycardic AV-blocked hearts provoked early afterdepolarizations and torsade de pointes (TDP) in both study groups. Under baseline conditions, no episodes of TDP recorded. After administration of the first agent, TDP occurred in 5 of 12 hearts (37 episodes) and 5 of 13 hearts (26 episodes), respectively. After additional infusion of the second drug, TDP were recorded in 7 of 12 hearts (55 episodes) and 8 of 13 hearts (111 episodes). After additional infusion of the third drug, TDP occurred in 11 of 12 hearts (118 episodes) and 9 of 13 hearts (88 episodes). Combined treatment with several non-cardiovascular QT-prolonging agents resulted in a remarkable occurrence of proarrhythmia. An additive and significant prolongation of cardiac repolarization combined with an increased spatial dispersion of repolarization represents the underlying electrophysiological mechanism.

Prescription Medication Use Among Children and Adolescents in the United States

“…More than threequarters of potential major DDIs we identified involved prescription medications used acutely (eg, macrolide antibiotics, antiemetics, and albuterol), and nearly half of these interacting combinations also involved an antidepressant. The potential for QT prolongation is especially noteworthy given that it is often asymptomatic and unpredictable yet can develop quickly into a serious arrhythmia or sudden cardiac death, 23,24 a serious yet underreported problem in children and adolescents. 25,26 Instability in insurance coverage for children and fragmentation of health care (eg, use of retail clinics and emergency departments for episodic care) may increase the risk that a physician prescribing medication for an acute illness is unaware of a child's chronic medication regimen.…”

Drug-Associated QTc Prolongation in Geriatric Hospitalized Patients: A Cross-Sectional Study in Internal Medicine

“…In line with previously published papers showing an increased risk of LQTS with the use of QT interval-prolonging drug combinations compared with single drugs, we observed that QTc interval correlated with the number of QT interval-prolonging agents at Pearson correlation. In animal studies, the simultaneous administration of two potassium channel blockers markedly potentiated the increase of the QTc interval [26,27]. Moreover, most clinical studies have highlighted an enhanced TdP risk in patients prescribed multiple QT interval-prolonging drugs.…”

Potential Multidrug Interactions in Elderly Ambulatory Patients

“…Age-related changes in pharmacokinetics in the elderly make them especially sensitive to these interactions [23]. Increasing the levels of substrate drugs which are involved in a pharmacodynamic pMDIs to prolong the QT will further amplify the risk of torsades de pointes given the additive effect on the QT interval for each drug [24]. The high prevalence of involvement of psychotropic drugs is particularly worrisome given the known association between psychotropic medication and an increased risk of death [25][26][27][28][29][30][31][32].…”