Drug-Induced QT Prolongation
Drug-induced QT prolongation increases the risk of torsades de pointes, a potentially fatal arrhythmia. Hundreds of drugs affect the QT interval.
## Overview
QT prolongation represents delayed ventricular repolarization on the electrocardiogram. When the corrected QT interval (QTc) exceeds 500 ms, or increases by more than 60 ms from baseline, the risk of torsades de pointes (TdP) — a polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation — rises significantly. Drug-induced QT prolongation is the most common cause of drug withdrawal from the market.
## Mechanism: The hERG Channel
The human ether-a-go-go-related gene (hERG) encodes the alpha subunit of the IKr potassium channel, which conducts the rapid delayed rectifier current essential for cardiac repolarization. The hERG channel has an unusually large inner vestibule that accommodates structurally diverse drug molecules, explaining why so many different drug classes cause QT prolongation. Channel blockade delays phase 3 repolarization, prolonging the action potential duration and the QT interval.
## High-Risk Drug Classes
**Antiarrhythmics**: Class IA (quinidine, procainamide, disopyramide) and Class III (sotalol, dofetilide, amiodarone) directly target cardiac ion channels. Amiodarone prolongs QT but paradoxically has low TdP risk due to multi-channel blockade.
**Antibiotics**: Macrolides (erythromycin, azithromycin, clarithromycin) and fluoroquinolones (moxifloxacin > levofloxacin > ciprofloxacin). Azithromycin's QT risk gained attention from a 2012 NEJM study showing increased cardiovascular death.
**Antipsychotics**: Thioridazine (withdrawn), haloperidol (IV), ziprasidone, and pimozide. Risk is dose-dependent and increased by rapid IV administration.
**Antifungals**: Ketoconazole and fluconazole, partly through CYP3A4 inhibition increasing levels of co-administered QT-prolonging drugs.
**Antiemetics**: Ondansetron (dose-dependent), droperidol (black box warning), domperidone.
**Methadone**: Significant QT risk, especially at doses above 100 mg/day. Baseline ECG recommended.
## Risk Factors for TdP
Patient factors: female sex (longer baseline QTc), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, heart failure, hepatic impairment (reduced drug clearance), congenital long QT syndrome.
Drug factors: high dose, rapid IV administration, CYP inhibitor co-administration (increasing drug levels), and combination of multiple QT-prolonging agents.
## Monitoring and Prevention
Baseline ECG before initiating known QT-prolonging drugs is recommended. Electrolytes (potassium, magnesium) should be corrected before and maintained during therapy. CredibleMeds (crediblemeds.org) maintains a regularly updated risk classification of QT-prolonging drugs. Avoid combining two or more QT-prolonging agents when possible.
## Key Takeaways
- hERG potassium channel blockade is the dominant mechanism of drug-induced QT prolongation
- QTc >500 ms or increase >60 ms from baseline signals high TdP risk
- Hypokalemia, female sex, and drug combinations amplify risk
- CredibleMeds.org is the authoritative resource for QT drug risk classification
- Baseline ECG and electrolyte correction are the cornerstones of prevention