Medications That Cause QT Interval Prolongation
High-Risk Antiarrhythmic Medications
Class IA and Class III antiarrhythmics represent the highest-risk medications for QT prolongation and should be used with extreme caution, requiring continuous ECG monitoring. 1
- Class IA antiarrhythmics (quinidine, procainamide, disopyramide) directly prolong the QT interval through their mechanism of action and carry significant risk of torsades de pointes 1
- Class III antiarrhythmics (sotalol, dofetilide, ibutilide) are specifically designed to prolong repolarization and have high torsades risk 1
- Amiodarone causes marked QT prolongation (often >40 ms) but paradoxically has relatively lower torsades risk due to uniform repolarization delay across all myocardial layers 1, 2
- Amiodarone should be avoided in combination with other QT-prolonging drugs, as this combination is explicitly contraindicated 1
Antipsychotic Medications
First-generation antipsychotics carry substantially higher QT prolongation risk than second-generation agents, with thioridazine causing the most severe prolongation (25-30 ms). 1
First-Generation Antipsychotics (Higher Risk):
- Thioridazine: 25-30 ms prolongation, highest risk among antipsychotics 1
- Intravenous haloperidol: 7 ms prolongation, dramatically higher risk than oral or IM routes 1, 3
- Chlorpromazine: significant prolongation with dose-dependent risk 1, 4
- Pimozide: 13 ms prolongation 1
Second-Generation Antipsychotics (Lower Risk):
- Quetiapine: moderate risk with approximately 6 ms prolongation 5, 3
- Olanzapine, risperidone: minimal QT prolongation (4 ms for risperidone) 4, 6
- Aripiprazole: minimal to no QT prolongation risk 7
- Ziprasidone and iloperidone: highest risk among second-generation agents 7
Antimicrobial Agents
Antibiotics:
- Macrolides: clarithromycin, erythromycin, azithromycin (dose-dependent prolongation with FDA warnings for azithromycin) 1
- Fluoroquinolones: moxifloxacin > levofloxacin > ciprofloxacin in order of risk 1, 8
- Trimethoprim-sulfamethoxazole: causes prolongation through potassium channel blockade 1
Antifungals:
- Azole antifungals: ketoconazole and other imidazole antimycotics prolong QT 1
- Ketoconazole combined with amiodarone is contraindicated due to severe overdose risk 1
Antimalarials:
- Chloroquine, hydroxychloroquine, halofantrine: all cause QT prolongation 1
Other Anti-infectives:
- Pentamidine: used for Pneumocystis pneumonia, causes QT prolongation 1
Antidepressants
Tricyclic antidepressants cause significantly more QT prolongation than SSRIs, particularly in overdose situations (mean increase 24 ms vs -1 ms). 1
- Citalopram and escitalopram: can prolong QT, especially in patients with pre-existing cardiovascular disease 1
- Sertraline (sertralina): lower risk than tricyclics but still capable of QT prolongation 5
- Venlafaxine, mirtazapine: listed as QT-prolonging agents 5
- Combination therapy: antipsychotic plus antidepressant causes significantly more QT prolongation (24 ± 21 ms) than antipsychotic monotherapy (-1 ± 30 ms) 9
Antiemetic Medications
5-HT3 receptor antagonists carry FDA warnings for QT prolongation and should be avoided in patients with baseline QT prolongation. 10
- Ondansetron: causes mean QTc increase of 19.5 ms at 32 mg IV doses 10
- Dolasetron, granisetron: known to prolong QT interval 1, 10
- Metoclopramide: can prolong QT but appears to have lower risk than high-risk medications 10, 5
- Domperidone: prolongs QTc and should be avoided 10, 5
- Droperidol: carries FDA black box warning for QT prolongation, torsades de pointes, and sudden death 10
- Prochlorperazine: contraindicated with other QT-prolonging medications 10
Other High-Risk Medications
- Methadone: high-risk medication with nearly 1 million Americans using it; requires pretreatment ECG, follow-up ECG within 30 days, and annual monitoring 1
- Cisapride: withdrawn from US market due to QT prolongation 1
- Antihistamines: diphenhydramine, hydroxyzine, loratadine can cause QT prolongation 1
- Respiratory medications: albuterol, terbutaline, phenylephrine can prolong QT 1
- Anticancer agents: arsenic trioxide, tyrosine kinase inhibitors 5
Critical Risk Factors for Torsades de Pointes
Female sex, age >65 years, baseline QTc >500 ms, hypokalemia (K+ <4.5 mEq/L), and hypomagnesemia are the most important modifiable and non-modifiable risk factors. 1
- Female gender: major risk factor for drug-induced torsades 1, 10
- Advanced age: particularly >65 years 1
- Electrolyte abnormalities: potassium <4.5 mEq/L and low magnesium must be corrected before initiating QT-prolonging medications 1, 10
- Bradycardia or conduction abnormalities: significantly increase risk 1, 10
- Pre-existing cardiovascular disease: heart failure, left ventricular hypertrophy, structural heart disease 1, 10
- Baseline QT prolongation: QTc >500 ms or congenital long QT syndrome 1
- Recent conversion from atrial fibrillation: increases torsades risk 1
- Concomitant use of multiple QT-prolonging drugs: creates additive risk 1, 10
- Drug interactions: CYP3A4 inhibitors (azole antifungals, macrolides, protease inhibitors) dramatically increase levels of QT-prolonging medications 1
- Genetic polymorphisms: increase susceptibility to drug-induced QT prolongation 1
Monitoring and Management Algorithm
Baseline Assessment:
- Obtain baseline ECG to measure QTc interval in all patients before initiating QT-prolonging medications 1, 10
- Check electrolytes (potassium, magnesium, calcium) and correct abnormalities before starting therapy 1, 10
- Review complete medication list for drug interactions, particularly CYP3A4 inhibitors 1
- Obtain detailed cardiac history including family history of sudden cardiac death 1
During Treatment:
- Follow-up ECG within 30 days for high-risk medications (e.g., methadone) or after dose titration 1
- Repeat ECG 7 days after starting therapy and after any dose change 1, 5
- Monitor electrolytes regularly, maintaining potassium >4.5 mEq/L 1, 10
Critical Thresholds:
- QTc >500 ms or increase >60 ms from baseline: warrants immediate attention and medication adjustment 1, 10
- Discontinue medication if QTc exceeds 500 ms during treatment 1, 5
Management of Torsades de Pointes:
- Immediate removal of the offending agent 1
- Intravenous magnesium 2g as initial drug of choice, regardless of serum magnesium level 1, 10, 5
- Temporary pacing (rates 90-110 bpm) is highly effective for recurrent torsades 5
- Isoproterenol IV titrated to heart rate >90 bpm when temporary pacemaker not immediately available 5
- Non-synchronized defibrillation may be indicated for sustained episodes 5
Critical Pitfalls and Caveats
- Not all QT prolongation leads to torsades de pointes—risk varies significantly by medication 1
- Amiodarone paradox: causes significant QT prolongation but has relatively lower torsades risk compared to other antiarrhythmics 1
- Route of administration matters: IV haloperidol has dramatically higher torsades risk than oral or IM administration 1
- Dose-dependent risk: QT prolongation risk is dose-dependent for most medications 1
- Drug interactions significantly amplify risk: CYP3A4 inhibitors can dramatically increase antiarrhythmic levels 1
- Many non-cardiac medications cause QT prolongation—always consider the complete medication profile 1
- Hyperemesis and diarrhea cause potassium and magnesium loss, further prolonging QTc in patients requiring antiemetics 10
- Combination therapy risk: antipsychotic plus antidepressant causes significantly more QT prolongation than monotherapy 9
Special Populations
ICU Patients:
- Particularly vulnerable due to multiple QT-prolonging drug exposures and prevalent risk factors (electrolyte abnormalities, cardiovascular disease) 11
- Require continuous ECG monitoring when receiving high-risk medications 11
Elderly Patients:
- More susceptible to drug-associated QT effects 8
- Precaution required when using ciprofloxacin or other fluoroquinolones with concomitant QT-prolonging drugs 8