What are the common drugs that cause torsades de pointes?

Common Drugs That Cause Torsades de Pointes

The highest-risk medications for torsades de pointes are Class IA antiarrhythmics (quinidine, procainamide, disopyramide) and Class III agents (sotalol, dofetilide, ibutilide), with incidence rates of 1-10%, followed by macrolide antibiotics (especially IV erythromycin), fluoroquinolones (particularly moxifloxacin), and certain antipsychotics (thioridazine, IV haloperidol, pimozide). 1, 2

Antiarrhythmic Medications (Highest Risk)

Class IA Agents

• Quinidine, procainamide, and disopyramide carry a 1-10% incidence of torsades de pointes and represent the most dangerous antiarrhythmic category. 1, 2

Class III Agents

• Sotalol, dofetilide, and ibutilide similarly carry a 1-10% torsades risk. 1, 2, 3
• Amiodarone causes marked QT prolongation (often >60 ms) but paradoxically has a relatively lower torsades risk due to uniform repolarization delay across all myocardial layers. 1

Anti-Infective Agents

Macrolide Antibiotics

• Erythromycin (especially IV formulation) carries the highest risk among macrolides. 1
• Clarithromycin poses significant risk, particularly when combined with CYP3A4 inhibitors. 1, 4
• Azithromycin causes dose-dependent QT prolongation with specific FDA warnings. 1

Fluoroquinolones (Ranked by Risk)

• Moxifloxacin > levofloxacin > ciprofloxacin in descending order of QT prolongation risk. 1
• Moxifloxacin requires careful monitoring, especially in patients with hypokalemia. 1

Antifungals

• Ketoconazole and other azole antifungals significantly prolong QTc and are contraindicated when combined with amiodarone. 1

Antiprotozoals

• Pentamidine significantly prolongs QT interval. 1, 2

Antimalarials

• Chloroquine, hydroxychloroquine, halofantrine, mefloquine, and quinine all cause QT prolongation. 1, 2

Antipsychotic Medications

High-Risk Agents

• Thioridazine causes 25-30 ms QT prolongation and carries an FDA black-box warning. 1
• Haloperidol (IV route) causes 7 ms prolongation but has dramatically higher torsades risk via IV compared to oral or IM administration. 1
• Pimozide causes 13 ms QT prolongation. 1, 2

Moderate-Risk Agents

• Chlorpromazine, ziprasidone, quetiapine, and clozapine produce smaller QTc increases (approximately 5-10 ms). 1, 2

Antidepressants

• Tricyclic antidepressants (especially amitriptyline) cause greater QT prolongation than SSRIs, with mean increases of 24 ms versus -1 ms for SSRIs, particularly dangerous in overdose. 1
• Citalopram and escitalopram can prolong QT in patients with pre-existing cardiovascular disease. 1

Gastrointestinal Agents

Antiemetics (All with FDA Warnings)

• Ondansetron, dolasetron, granisetron (5-HT3 antagonists) carry FDA warnings for QT prolongation. 1, 2
• Droperidol poses significant risk. 1, 2

Prokinetic Agents

• Domperidone prolongs QTc and should be avoided entirely in at-risk patients. 1, 2
• Metoclopramide prolongs QT interval and requires extreme caution. 1
• Cisapride (withdrawn from US market) causes QT prolongation. 1

Opioid Medications

• Methadone is a high-risk medication, with nearly 1 million Americans using it; guidelines mandate pretreatment ECG, follow-up ECG within 30 days, and annual monitoring. 1, 2

Critical Risk Amplifiers

Patient-Specific Factors

• Female sex increases torsades risk approximately 3-fold compared to males. 1, 2, 3
• Age >65 years is an independent predictor of QT-related arrhythmia. 1, 2
• Baseline QTc >500 ms is an absolute contraindication for adding QT-prolonging agents. 1, 2

Electrolyte Abnormalities (Exponential Risk Amplification)

• Hypokalemia (K+ <4.5 mEq/L) dramatically increases torsades risk; maintain potassium at 4.5-5.0 mEq/L. 1, 2
• Hypomagnesemia potentiates QT prolongation even when serum levels appear normal. 1, 2
• Hypocalcemia further amplifies risk. 1

Cardiac Conditions

• Bradycardia or heart block creates "short-long-short" sequences that trigger torsades. 1, 2
• Congestive heart failure, left ventricular hypertrophy, or structural heart disease dramatically raise risk. 1, 2
• Recent conversion from atrial fibrillation increases susceptibility. 1, 2

Drug Interactions (Highest Risk Combinations)

• CYP3A4 inhibitors (azole antifungals, macrolides, protease inhibitors) combined with amiodarone or quinidine are contraindicated due to severe overdose risk. 1, 4
• Ketoconazole + amiodarone is explicitly contraindicated. 1
• Concomitant use of multiple QT-prolonging drugs creates additive risk exponentially. 1, 2

Route-of-Administration Considerations

• Intravenous administration markedly raises torsades risk compared to oral or IM routes, especially for haloperidol and erythromycin. 1
• Rapid IV infusion further escalates danger. 1

Critical Action Thresholds

• QTc ≥500 ms: Discontinue all QT-prolonging medications immediately (Class I recommendation). 1, 2
• QTc increase >60 ms from baseline: Stop offending agents regardless of absolute QTc value. 1, 2
• QTc 450-499 ms: Heightened monitoring and consider medication adjustment. 1

Common Pitfalls

• Not all QT prolongation leads to torsades; risk varies significantly by medication—amiodarone causes marked QT prolongation but has relatively lower torsades risk. 1
• Many non-cardiac medications (antibiotics, antiemetics, antipsychotics) cause QT prolongation, often overlooked in medication reviews. 1
• Drug interactions via CYP3A4 inhibition can dramatically increase plasma levels of QT-prolonging agents, exponentially raising torsades risk. 1, 4
• IV haloperidol has dramatically higher torsades risk than oral or IM formulations—avoid IV route when possible. 1
• Genetic polymorphisms can increase individual susceptibility even without clinical congenital long QT syndrome. 1, 2