What medications or medication interactions can cause an increased PR interval and an increased QTc (corrected QT) interval?

Medications and Drug Interactions Causing Increased PR and QTc Intervals

While numerous medications prolong the QTc interval through potassium channel blockade, medications that simultaneously increase both PR and QTc intervals are primarily limited to specific antiarrhythmics and calcium channel blockers that affect multiple cardiac ion channels.

Medications That Prolong Both PR and QTc Intervals

Class IA and III Antiarrhythmics

• Amiodarone is the prototypical drug causing both PR and QTc prolongation, blocking sodium channels (PR prolongation), potassium channels (QTc prolongation), and calcium channels, though it paradoxically has lower torsades de pointes risk despite marked QTc prolongation 1, 2
• Quinidine prolongs both intervals through sodium channel blockade (PR) and potassium channel blockade (QTc), with significant risk of torsades de pointes, particularly in patients with bradycardia, hypokalemia, or preexisting long QT syndrome 3, 4
• Sotalol (Class III) primarily prolongs QTc but can affect AV nodal conduction at higher doses 2, 4
• Procainamide and disopyramide (Class IA) prolong QTc significantly and may affect PR interval through sodium channel effects 2, 4

Calcium Channel Blockers

• Verapamil and diltiazem prolong the PR interval through AV nodal blockade and when combined with QTc-prolonging drugs create additive risk, though they don't significantly prolong QTc as monotherapy 5, 6

Critical Drug Interactions Causing Combined PR/QTc Prolongation

CYP3A4 Inhibitors with Antiarrhythmics

• The highest-risk interactions involve CYP3A4 inhibitors (azole antifungals, macrolides, protease inhibitors) combined with amiodarone or quinidine, dramatically increasing antiarrhythmic levels and both PR/QTc effects 5, 1, 7
• Ketoconazole with amiodarone is contraindicated due to severe risk of overdose and combined conduction abnormalities 5, 1
• Clarithromycin or erythromycin with amiodarone increases amiodarone levels by 50-84%, potentiating both PR and QTc prolongation 8, 1, 9
• Protease inhibitors increase amiodarone concentrations significantly through CYP3A4 inhibition 5, 1

Multiple QTc-Prolonging Agents

• Combining amiodarone with other QTc-prolonging drugs (antipsychotics, macrolides, fluoroquinolones) is explicitly contraindicated due to additive repolarization effects, though PR prolongation remains primarily from amiodarone 5, 10, 2

Medications Causing Isolated QTc Prolongation (Without PR Effects)

High-Risk QTc-Prolonging Drugs

• Antipsychotics: Thioridazine (25-30 ms), haloperidol IV (7 ms), chlorpromazine, pimozide, quetiapine 10, 2
• Macrolide antibiotics: Erythromycin and clarithromycin carry highest risk (3 per million prescriptions for malignant arrhythmia); azithromycin has dose-dependent effects 8, 9
• Fluoroquinolones: Sparfloxacin (14.5 per million), moxifloxacin, levofloxacin; ciprofloxacin has lowest risk (1 per million) 8
• Antiemetics: Ondansetron, domperidone, metoclopramide, dolasetron 10, 2
• Antidepressants: Citalopram, escitalopram, tricyclics (amitriptyline causes 24 ms prolongation) 2, 11
• Methadone: High-risk requiring pretreatment ECG, 30-day follow-up, and annual monitoring 2
• Trimethoprim-sulfamethoxazole: Causes QTc prolongation through potassium channel blockade, with genetic polymorphisms increasing susceptibility 8

Critical Risk Factors for Torsades de Pointes

Patient-Specific Factors

• Female sex, age >65 years, and baseline QTc >500 ms are the strongest predictors of drug-induced torsades 2, 7
• Electrolyte abnormalities: Potassium <4.5 mEq/L, hypomagnesemia, hypocalcemia must be corrected before initiating any QTc-prolonging medication 2, 7
• Bradycardia, recent atrial fibrillation conversion, congestive heart failure, structural heart disease 2, 7
• Congenital long QT syndrome or family history 2, 3

Drug-Related Factors

• Intravenous administration carries dramatically higher risk than oral (particularly haloperidol IV vs oral/IM) 2
• Concomitant use of ≥2 QTc-prolonging drugs 10, 2
• Drug interactions increasing levels through CYP3A4 inhibition 1, 7
• Renal/hepatic dysfunction reducing drug elimination 3, 7

Monitoring Algorithm

Baseline Assessment (Before Initiating Therapy)

• Obtain baseline ECG measuring QTc in all patients; contraindicate if QTc >450 ms (men) or >470 ms (women) 10, 2
• Check electrolytes (potassium, magnesium, calcium) and correct abnormalities 10, 2
• Review complete medication list for interactions 7
• Assess cardiac history, structural disease, and genetic predisposition 8

During Treatment

• Repeat ECG 7 days after starting therapy and after any dose change 10
• Discontinue immediately if QTc >500 ms or increases >60 ms from baseline 10, 2
• Monitor electrolytes, especially with diuretic use 7
• For methadone: ECG within 30 days and annually 2

Management of Torsades de Pointes

• Administer magnesium sulfate 1-2 g IV immediately, regardless of serum magnesium level 10, 7
• Discontinue all offending agents 10, 7
• Correct all electrolyte abnormalities 10
• Non-synchronized defibrillation for hemodynamic instability 10
• Overdrive pacing (90-110 bpm) or isoproterenol IV if pacemaker unavailable 10

Common Pitfalls

• Amiodarone causes marked QTc prolongation but rarely causes torsades due to uniform repolarization across myocardial layers; do not withhold in life-threatening arrhythmias despite QTc prolongation 2, 1
• Never use amiodarone to treat polymorphic VT if drug-induced long QT is suspected—this worsens the underlying problem 11
• Grapefruit juice increases amiodarone levels by 50% and must be avoided 1
• Genetic polymorphisms can cause silent predisposition to drug-induced QTc prolongation, particularly with trimethoprim-sulfamethoxazole 8
• Many non-cardiac medications (antibiotics, antiemetics, antidepressants) cause significant QTc prolongation in everyday practice 6, 9