Methadone Blockade of Inward Rectifier Potassium Current Promotes Both Early and Delayed Repolarization Arrhythmias: Mechanistic Insights From Computational Modeling

BACKGROUND: Methadone blocks several ionic currents with different half-maximal inhibitory concentrations, including the rapid component of the delayed and inward (I_K1) rectifier potassium current, the L-type calcium current, and the late sodium current. Despite the well-known proarrhythmic effect of methadone, the underlying mechanisms remain less well understood. METHODS: Computer simulations were used to explore the proarrhythmic effects of methadone by investigating how its blocking effects on ionic currents act alone or together in arrhythmogenesis. RESULTS: The major findings are (1) blocking I_K1 potentiates QT prolongation-related arrhythmogenesis by enhancing a tissue-scale dynamical instability for the spontaneous genesis of ectopic excitations; blocking I_K1 and the rapid component of the delayed rectifier potassium current together results in a synergistic effect, greatly increasing the arrhythmia propensity, much larger than that of blocking either one alone; (2) blocking I_K1 in combination with lowering L-type calcium current potentiates phase 2 reentry caused by spike-and-dome action potential morphology, an arrhythmia mechanism of early repolarization or Brugada syndrome, whereas blocking the rapid component of the delayed rectifier potassium current exhibits little effect for this mechanism of arrhythmias; and (3) hypoxia, often comorbid in methadone populations, can potentiate QT prolongation-related arrhythmias at high sympathetic activity and phase 2 reentry at low sympathetic activity, mainly via its effect on the L-type calcium current. CONCLUSIONS: Methadone promotes both early and delayed repolarization arrhythmias. Early repolarization may be responsible for methadone-related deaths occurring mainly during sleep and occurring more often in men. Blocking I_K1 can work synergistically with other channel blockers to disproportionately increase arrhythmia propensity, greatly increasing methadone’s risk when it is combined with other proarrhythmic drugs or under disease conditions.