What medications can cause QT prolongation?

Medications That Cause QT Prolongation

Multiple drug classes cause QT prolongation, with antiarrhythmics, antipsychotics, and certain antibiotics posing the highest risk—thioridazine (25-30 ms), ziprasidone (5-22 ms), and intravenous haloperidol (7 ms) are among the most dangerous, while aripiprazole (0 ms) and olanzapine (2 ms) are preferred safer alternatives when antipsychotic therapy is needed. 1

High-Risk Cardiovascular Medications

Antiarrhythmic Agents

• Class IA antiarrhythmics (quinidine, procainamide, disopyramide) significantly prolong QT interval and require careful monitoring 2, 3
• Class III antiarrhythmics (sotalol, dofetilide, ibutilide) cause substantial QT prolongation 2, 3
• Amiodarone causes marked QT prolongation but paradoxically has a relatively lower risk of torsades de pointes compared to other antiarrhythmics due to uniform repolarization delay across all myocardial layers 1, 3

Antipsychotic Medications (Ranked by Risk)

Highest Risk Antipsychotics

• Thioridazine: 25-30 ms mean QTc prolongation with FDA black box warning—avoid if possible 1, 3
• Pimozide: 13 ms mean QTc prolongation 1
• Ziprasidone: 5-22 ms mean QTc prolongation—avoid if possible 1

Moderate Risk Antipsychotics

• Intravenous haloperidol: 7 ms mean QTc prolongation with dramatically higher risk than oral or IM routes; associated with 46% increased risk of ventricular arrhythmia/sudden cardiac death (adjusted OR 1.46,95% CI 1.17-1.83) 1, 3
• Clozapine: 8-10 ms mean QTc prolongation 1
• Quetiapine: 6 ms mean QTc prolongation; FDA label warns to avoid combination with other QT-prolonging drugs 1, 4

Lower Risk Antipsychotics (Preferred Options)

• Aripiprazole: 0 ms mean QTc prolongation—first-line choice when QTc prolongation is a concern 1
• Brexpiprazole: No clinically significant QTc prolongation—first-line choice 1
• Olanzapine: 2 ms mean QTc prolongation—second-line option 1
• Risperidone: 0-5 ms mean QTc prolongation—third-line option 1

Anti-Infective Agents

Antibiotics

• Macrolides: Erythromycin, clarithromycin, and azithromycin directly block cardiac potassium channels (IKr) and inhibit cytochrome P450 metabolism of other QT-prolonging drugs 2, 3
• Fluoroquinolones: Sparfloxacin (14.5 per million risk), moxifloxacin, levofloxacin (1 per million risk), and ciprofloxacin (1 per million risk) 2, 3
• Trimethoprim-sulfamethoxazole: The sulfamethoxazole moiety causes QT prolongation and torsades de pointes 2

Antifungals

• Ketoconazole and imidazole antimycotics: Directly block cardiac K+ channels and inhibit cytochrome P450 metabolism of other drugs 2, 3

Antimalarials

• Chloroquine, hydroxychloroquine, halofantrine: Cause QT prolongation with high risk in children; halofantrine associated with sudden cardiac arrest 2, 3
• Quinidine: Used in larger doses for chloroquine-resistant malaria 2

Antivirals

• Pentamidine: Used for Pneumocystis carinii pneumonia; multiple reports of polymorphic ventricular arrhythmias including 80 deaths leading to market withdrawal 2, 3

Antidepressants

• Tricyclic antidepressants (amitriptyline, desipramine, nortriptyline): Cause more QT prolongation than SSRIs, particularly in overdose (mean increase 24 ms vs -1 ms with SSRIs); increase cardiac arrest risk (OR 1.69) 1, 3
• Citalopram and escitalopram: FDA warnings for QT prolongation, especially in patients with pre-existing cardiovascular disease 1, 3

Other High-Risk Medications

• Methadone: Causes pronounced QT prolongation; nearly 1 million Americans use it for narcotic dependence or chronic pain; requires pretreatment ECG, follow-up ECG within 30 days, and annual monitoring 1, 3
• Antiemetics: Ondansetron, dolasetron, domperidone, droperidol 3
• Cisapride: Withdrawn from U.S. market after at least 341 reports of arrhythmias including 80 deaths 2, 3

Critical Risk Factors for Torsades de Pointes

Patient-specific factors that dramatically increase risk:

• Female sex and age >65 years 2, 1, 3
• Baseline QTc >500 ms or congenital long QT syndrome 2, 1, 3
• Hypokalemia (especially <4.5 mEq/L) or hypomagnesemia 2, 1, 3
• Bradycardia or recent conversion from atrial fibrillation 2, 3
• Congestive heart failure, left ventricular hypertrophy, or pre-existing cardiovascular disease 2, 1, 3
• Concomitant use of multiple QT-prolonging drugs or drug interactions that increase levels 2, 3
• Genetic polymorphisms encoding potassium channels more sensitive to drug blockade 2, 3

Monitoring and Management Algorithm

Baseline Assessment

• Obtain ECG before initiating any QT-prolonging medication 2, 1, 3
• Measure electrolytes (potassium, magnesium) and correct abnormalities before starting therapy 1, 3
• Screen for risk factors listed above 2

Follow-Up Monitoring

• Repeat ECG 7 days after initiation and after any dose changes 1
• For methadone specifically: Follow-up ECG within 30 days and annual monitoring 3
• Monitor electrolytes regularly, particularly potassium levels 1, 3

Action Thresholds

• QTc >500 ms or increase >60 ms from baseline: Consider immediate medication adjustment or discontinuation 2, 1, 3
• Discontinue offending agent in patients with drug-induced LQTS 3
• Administer intravenous magnesium sulfate to suppress torsades de pointes episodes even when serum magnesium is normal 3
• Temporary cardiac pacing is highly effective for recurrent torsades de pointes after electrolyte repletion 1

Common Pitfalls and Caveats

• Route of administration matters critically: IV haloperidol carries dramatically higher torsades risk than oral or IM administration 1, 3
• Drug interactions amplify risk: Macrolides and imidazole antifungals inhibit cytochrome P450, increasing plasma levels of other QT-prolonging drugs like terfenadine 2, 3
• Not all QT prolongation leads to torsades de pointes: Risk varies substantially by medication—amiodarone causes significant QT prolongation but rarely causes torsades 3
• Dose-dependent effects: QT prolongation risk increases with higher doses for most medications 3
• Grapefruit juice can inhibit metabolism of certain QT-prolonging drugs like terfenadine 2
• Women are at higher risk of QTc prolongation and torsades de pointes with antipsychotics 1