EUH Hunt Conference: What are the mechanisms and risks of drug-induced QT prolongation?

The Bottom Line: Risk of severe and fatal ventricular arrhythmias, presenting as Torsade de Pointes (TdP), is increased in congenital and acquired forms of long QT syndromes (LQTS). Drug-induced inhibition of K+ currents, IKs, IKr, IK1, and/or Ito, delay repolarization, prolong QT, and increase the risk of TdP. Drug-induced interferences with IKr is the most common cause of acquired LQTS/TdP (Cubeddux 2016).

References: Cubeddu LX. Drug-induced inhibition and trafficking disruption of ion channels: Pathogenesis of QT abnormalities and drug-induced fatal arrhythmias. Current Cardiology Review, 2016; 12(2):141-154.

Ramakrishma H, O’Hare M, Mookadam F, Gutsche JT, et al. Sudden cardiac death and disorders of the QT interval: Anesthetic implications and focus on perioperative management. Journal of Cardiothoracic and Vascular Anesthesia, Dec 2015; 29(6):1723-1733.

Summary: The depolarization-repolarization cycle at the membrane level is the key determinant of QT prolongation. It is well known that blocking channels in the rapid phase of repolarization lays the foundation for arrhythmogenesis by prolonging repolarization or depolarization. Propagation of this cascade also is seen in drug-induced ventricular arrhythmias, such as TdP, in which the initial result of increased duration of the action potential or repolarization leads to a net reduction in the outflow of intracellular potassium (Ramakrishma et al, 2015).

The overall treatment goals in LQTS therapy are to prevent sudden cardiac death and serious ventricular arrhythmias, such as TdP. Established data indicate that the estimated mortality in symptomatic LQTS (untreated) exceeds 20% in the first year after diagnosis and approaches 50% within a decade. With effective therapy, this 10-year mortality can be reduced to 3% to 4%.

Cubeddu (2016) provides “8 practical aspects” to guide practitioners in prescribing drugs with known risk of severe arrhythmias and sudden death: past medical history, medication history, family history, risk factors, baseline ECG, serum electrolytes, treatment plan and follow-up plan, and genetic testing. See article for complete descriptions and explanations.

Additional resource: For updated information about drugs associated with increased risk of TdP, Cubeddu suggests www.crediblemeds.org.

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