What medications can cause Long QT Syndrome (LQTS)?

Medications That Cause Long QT Syndrome

Numerous medications across multiple drug classes can cause acquired Long QT Syndrome (LQTS), with antiarrhythmic drugs carrying the highest risk (1-10% incidence), followed by various non-cardiac medications including antibiotics, antipsychotics, antiemetics, and methadone. 1

High-Risk Medications (>1% Incidence)

The following antiarrhythmic drugs require hospitalization for monitoring during initiation due to frequent QT prolongation 1:

• Disopyramide 1
• Dofetilide 1
• Ibutilide 1
• Procainamide 1
• Quinidine 1
• Sotalol 1
• Ajmaline 1

These medications cause QT prolongation in 1-10% of patients and carry the highest risk for torsades de pointes (TdP) among all drug classes 1.

Moderate-Risk Cardiovascular Medications

Amiodarone paradoxically has a surprisingly low incidence of TdP despite causing QT prolongation, and may even be effective in patients with previous drug-induced TdP 1. Other cardiovascular drugs include:

• Bepridil (calcium channel blocker, associated with polymorphic ventricular arrhythmias) 1
• Arsenic trioxide 1

Antibiotic-Related LQTS

Macrolides (Highest Antibiotic Risk)

Macrolides carry the greatest overall risk for QT prolongation and TdP among commonly used antibiotics 2:

• Erythromycin - directly blocks IKr (HERG) potassium channels, causing excessive repolarization lengthening and multiple cases of TdP and sudden cardiac death 1, 2
• Clarithromycin - malignant arrhythmia risk of approximately 3 per million prescriptions; FDA label warns of QT prolongation, TdP, and fatalities 2, 3
• Azithromycin - causes dose-dependent QT prolongation with FDA warnings about TdP risk 2
• Spiramycin - associated with acquired LQTS including cardiac arrest in newborns 1

Fluoroquinolones

• Sparfloxacin - significant risk with malignant arrhythmia rate of 14.5 per million prescriptions 1, 2
• Levofloxacin - FDA warns to avoid in patients with known QT prolongation, uncorrected hypokalemia, or those receiving Class IA/III antiarrhythmics 2
• Moxifloxacin - very low incidence (1:100,000 to 1:1,000 exposures) 1
• Ciprofloxacin - lowest risk among fluoroquinolones (approximately 1 per million) 2

Other Anti-Infectives

• Pentamidine 1
• Halofantrine 1
• Trimethoprim-sulfamethoxazole - sulfamethoxazole component blocks potassium channels; genetic polymorphisms significantly increase susceptibility 2

Gastrointestinal Medications

• Cisapride - withdrawn from most markets due to TdP risk when combined with CYP3A4 inhibitors 1, 3
• Domperidone 1
• Droperidol 1
• Ondansetron 4, 5
• Prochlorperazine 5

Antipsychotic Medications

Typical Antipsychotics

• Thioridazine - causes 25-30ms QT prolongation with dose-dependent increased risk of sudden death; multiple TdP cases reported 1, 6
• Haloperidol - causes 7ms QT prolongation; similar relative risk of sudden cardiac death as thioridazine; TdP cases reported 1, 6
• Chlorpromazine 1
• Pimozide - FDA contraindication when combined with clarithromycin due to fatal cardiac arrhythmias 1, 3
• Mesoridazine 1
• Droperidol 1

Atypical Antipsychotics

• Quetiapine - causes 6ms QT prolongation; FDA label warns to avoid combination with other QT-prolonging drugs and in patients with cardiac arrhythmias, hypokalemia, or hypomagnesemia 7, 6, 8
• Ziprasidone - significant QT prolongation; TdP cases reported 7, 6, 8
• Olanzapine - causes 2ms QT prolongation; TdP cases reported 6, 9, 8
• Risperidone - lower doses had higher relative risk than haloperidol for cardiac arrest and ventricular arrhythmia 6
• Sertindole - significant QTc prolongation; not FDA approved due to cardiac risk 6
• Iloperidone - among highest risk for QT prolongation 8

Aripiprazole and lurasidone appear to have minimal risk for QT prolongation (0ms prolongation) 6, 8.

Antidepressants

Tricyclic Antidepressants (TCAs)

TCAs prolong QT and increase risk of cardiac arrest (OR=1.69); TdP cases reported with multiple agents 10, 5, 6:

• Amitriptyline 6
• Imipramine 6
• Doxepin 6

Selective Serotonin Reuptake Inhibitors (SSRIs)

• Citalopram - FDA warnings about QT prolongation 10, 6
• Fluoxetine - depresses IKr current in dose-dependent manner 6
• Paroxetine 9
• Fluvoxamine 9

SSRIs have been associated with QTc prolongation but no cases of TdP have been reported; no increased risk of sudden death identified in large epidemiological studies 6.

Other Antidepressants

• Trazodone 6, 9

Opioid Dependence Agents

Methadone - causes pronounced QT prolongation with several reported cases of TdP; high-profile example of non-antiarrhythmic drug causing TdP 1, 10, 7

Antihistamines

Withdrawn Due to Cardiac Risk

• Terfenadine - potent HERG channel blocker (nanomolar affinity); withdrawn from most markets due to TdP risk, particularly when combined with CYP3A4 inhibitors like ketoconazole or erythromycin 1, 11
• Astemizole - potent cardiac K+ channel blocker; withdrawn due to TdP risk 1, 11

Contraindicated in Cardiac Disease

• Mizolastine - contraindicated in clinically significant cardiac disease and prolonged QT interval 11

Safe Antihistamines (No QT Prolongation)

Fexofenadine, cetirizine, loratadine, desloratadine, levocetirizine, and acrivastine do not block cardiac K+ channels and are not associated with QT prolongation 11.

Major Risk Factors for Drug-Induced TdP

The following risk factors often coexist and substantially increase TdP risk 1:

• Female gender 1, 10
• Hypokalemia 1, 10
• Hypomagnesemia 1, 10
• Bradycardia 1, 10
• Recent conversion from atrial fibrillation 1, 10
• Congestive heart failure 1, 10
• Digitalis therapy 1
• High drug concentrations (exception: quinidine), often due to drug interactions 1
• Rapid intravenous drug administration 1
• Baseline QT prolongation 1
• Left ventricular hypertrophy 1
• Subclinical congenital LQTS (occurs in 1 in 2,500 individuals) 1
• Certain DNA polymorphisms (frequencies up to 15% in some populations) 1
• Concomitant use of 2 or more QT-prolonging drugs 1, 9
• Combination of QT-prolonging drug with its metabolic inhibitor 1
• Age over 65 years 6
• Structural heart disease 10

Critical Management Principles

In patients with drug-induced LQTS, removal of the offending agent is indicated (Class I recommendation, Level of Evidence A) 1.

Acute Treatment

• Intravenous magnesium can suppress episodes of TdP without necessarily shortening QT, even when serum magnesium is normal 1
• Temporary pacing is highly effective in managing recurrent TdP after potassium repletion and magnesium supplementation 1
• Potassium repletion to maintain serum potassium >4 mM/L 1

Critical Pitfall

Amiodarone, while often used to suppress ventricular tachycardia, is potentially harmful in the setting of LQTS and TdP 5. In patients with polymorphic VT without significant cardiovascular disease history, drug-induced LQTS should be high in the differential diagnosis 5.

High-Risk Drug Combinations

The following combinations significantly elevate diLQTS risk and require heightened monitoring 9:

• Olanzapine & fluvoxamine 9
• Olanzapine & trazodone 9
• Quetiapine & paroxetine 9
• Sulpiride & fluvoxamine 9
• Sulpiride & trazodone 9
• Bepridil & clarithromycin (categorized as "avoid combination") 9
• Chlorpromazine & haloperidol 9

Monitoring Recommendations

QT intervals uncorrected for rate are generally >500 msec in drug-induced TdP; prominent U waves are common, and marked QTU prolongation may only be evident on post-pause beats 1.

For patients requiring QT-prolonging medications 2:

• Obtain detailed cardiac history
• Review complete medication list for drug interactions
• Check baseline electrolytes (potassium, magnesium)
• Perform baseline ECG to measure QTc interval
• Follow-up ECG monitoring as clinically indicated

An up-to-date list of QT-prolonging drugs is maintained at www.torsades.org and www.qtdrugs.org 1.