Drug-induced QT interval prolongation: mechanisms and clinical management

Abstract

The prolonged QT interval is both widely seen and associated with the potentially deadly rhythm, Torsades de Pointes (TdP). While it can occur spontaneously in the congenital form, there is a wide array of drugs that have been implicated in the prolongation of the QT interval. Some of these drugs have either been restricted or withdrawn from the market due to the increased incidence of fatal polymorphic ventricular tachycardia. The list of drugs that cause QT prolongation continues to grow, and an updated list of specific drugs that prolong the QT interval can be found at www.qtdrugs.org. This review focuses on the mechanism of drug-induced QT prolongation, risk factors for TdP, culprit drugs, prevention and monitoring of prolonged drug-induced QT prolongation and treatment strategies.

Keywords: QT interval; Torsades de Pointes; drugs.

Conflict of interest statement

Conflict of interest statement: The authors declare no conflict of interest in preparing this article.

Figures

Figure 1.

Five phases of cardiac depolarization and repolarization. Phase 0: Large inward current of sodium ions (INa). Phase 1: Inactivation of INa and the transient efflux of potassium ions (It0). Phase 2: Plateau phase with influx of calcium ions through L-type calcium channels (ICa) and outward repolarizing potassium currents (IK). Phase 3: Efflux of potassium (IKr, IKu, IKs). Phase 4: Inward rectifier potassium current (IK1) maintaining resting potential. ICa, calcium current; IK, potassium current; IK1, inwardly rectifying potassium current; INa, depolarizing sodium current; It0, transient outward potassium current; IKr, rapidly activating delayed rectifier potassium current; IKs, slowly activating delayed rectifier potassium current. (Reproduced with permission from Titier et al. [2005].)

Figure 2.

(a) A single hERG subunit containing six α-helical transmembrane domains, S1–S6. (b) Structure of a KcsA K+ channel crystallized in the closed state. Only two of the four subunits are shown. White spheres are K+ ions located within the selectivity filter. The Gly (red) and Tyr (yellow) residues of the selectivity filter are also indicated. (c) Structure of the pore domain of a Kv1.2 K+ channel crystallized in the open state. Only two of the four subunits are shown. (d) Crystal structure of a single Kv1.2 α-subunit7 viewed from the side. Color coding of the helical domains is the same as in panel (a). Grey spheres represent K+ ions. (e) Side view and (f) view from the cytoplasmic side of the membrane of the crystal structure of the complete, tetrameric Kv1.2 channel. (Reproduced with permission from Sanguinetti and Tristani-Firouzi [2006].)

Figure 3.

QT interval nomogram for determining ‘at risk’ QT–HR pairs from a single 12-lead ECG. Use: The QT interval should be measured manually on a 12-lead ECG from the beginning of the Q wave until to the end of the T wave in multiple leads (i.e. six leads including limb and chest leads and median QT calculated). The QT interval is plotted on the nomogram against the heart rate recorded on the ECG. If the point is above the line then the QT–HR is regarded as ‘at risk’. (Reproduced with permission from Chan et al. [2007].)

Figure 4.

Ventricular premature contractions (VPCs) occurring in a patient with heart block and prolonged QT. The timing of the second VPC (arrow) is such that it occurs on the T-wave of a preceding T-wave, instigating an episode of Torsades de Pointes (TdP).