Proarrhythmic and Torsadogenic Effects of Potassium Channel Blockers in Patients

Abstract

Summary The most common arrhythmia requiring drug therapy is atrial fibrillation, which affects 2–5 million Americans and continues to be a major cause of morbidity and increased mortality. Despite recent advances in catheter-based and surgical therapies, antiarrhythmic drugs continue to be the mainstay of therapy for most patients with symptomatic AF. However, many antiarrhythmics block the rapid component of the cardiac delayed rectifier potassium current (IKr) as a major mechanism of action, and marked QT prolongation and pause-dependent polymorphic ventricular tachycardia (torsades de pointes) are major class toxicities. Although this arrhythmia is usually seen in patients with one of the congenital long QT syndromes, torsades de pointes has also been observed with certain antibiotics, antipsychotics, antihistamines and chemotherapeutic agents and is a leading cause of post-market drug withdrawal and relabeling. Clinical risk factors associated with drug-induced long QT syndrome include female gender, bradycardia, electrolyte disturbances, recent conversion from atrial fibrillation to sinus rhythm, variations in drug distribution and sub-clinical long QT syndrome. A unifying concept of reduced repolarization reserve has been proposed to explain the variable risk of torsades de pointes. In this monograph, we provide a historical perspective on drug-induced long QT syndrome, briefly discuss the underlying mechanisms, and detail recent advances in torsadogenic risk factors and the complex interplay between individual patient-related clinical risk characteristics and the development of torsades de pointes with potassium-channel blocking drugs.

A new paradigm for predicting risk of Torsades de Pointes during drug development: Commentary on: “Improved prediction of drug‐induced Torsades de Pointes through simulations of dynamics and machine learning algorithms”

“…DiLQTS places a patient at risk of developing Torsades de Pointes (TdP), a malignant polymorphic ventricular tachycardia associated with arrhythmic sudden cardiac death (SCD). In addition to diLQTS, other clinical risk factors for TdP include female gender, bradycardia, electrolyte disturbances, recent conversion to normal (sinus) rhythm, and congenital LQTS …”

Torsade de pointes associated with chloroquine, hydroxychloroquine, and azithromycin: a retrospective analysis of individual case safety reports from VigiBase

“…In our study, most cases reporting TdP were in females and co-prescribing with drugs that can prolong the QT was common. Consistently, the effects of drugs in the QT interval have been described to be greater in women [ 36 ] and have been considered a risk factor for HCQ-induced TdP [ 37 , 38 ]. Moreover, concomitant medication known to prolong the QT may have a synergistic effect in QT prolongation risk.…”

Preoperative Management of Cardiovascular Medications: A Society for Perioperative Assessment and Quality Improvement (SPAQI) Consensus Statement

“…Class III antiarrhythmic agents are both antiarrhythmogenic and proarrhythmogenic because of their potential to increase the corrected QT (QTc) interval and torsades de pointes. 79 This risk is magnified in patients with long QTc syndrome, and the use of other QTc-prolonging drugs should be avoided. Amiodarone can cause bradycardia and AV block because of its class IV effects.…”