What medications can prolong the QT interval, especially in older adults or individuals with pre-existing heart conditions?

Medications That Prolong the QT Interval

Major Drug Classes That Prolong QT Interval

The most clinically significant QT-prolonging medications include antiarrhythmics (Class IA and III), macrolide antibiotics, fluoroquinolones, antipsychotics, and certain antiemetics, with the highest risk occurring when multiple agents are combined or in patients with additional risk factors. 1

Antiarrhythmic Medications

• Class IA antiarrhythmics (quinidine, procainamide, disopyramide) directly prolong the QT interval and carry significant risk of torsades de pointes, with quinidine specifically causing more than three times the mortality compared to placebo in atrial fibrillation trials 2, 3
• Class III antiarrhythmics (sotalol, dofetilide, ibutilide, amiodarone) all prolong QT, though amiodarone causes marked QT prolongation but has relatively lower risk of torsades de pointes due to uniform repolarization delay across all myocardial layers 1, 3
• Dofetilide requires hospitalization during initiation due to significant QT prolongation risk 4

Antimicrobial Agents

• Macrolide antibiotics (azithromycin, clarithromycin, erythromycin) prolong QT both directly and by inhibiting cytochrome P450 metabolism of other proarrhythmic drugs, with 85 deaths per 1 million courses in high-risk patients 1, 5
• Fluoroquinolones (moxifloxacin, levofloxacin, ciprofloxacin) carry QT prolongation risk, particularly when combined with other QT-prolonging agents 1, 6
• Antifungals (ketoconazole, voriconazole, itraconazole, fluconazole) prolong QT through CYP3A4 inhibition and direct effects 4, 6
• Antimalarials (chloroquine, hydroxychloroquine) can significantly prolong QT, especially when combined with azithromycin 1, 6
• Bedaquiline (antitubercular) requires monthly ECG monitoring due to QT prolongation risk 1

Psychotropic Medications

• Typical antipsychotics: Thioridazine causes 25-30 ms prolongation, intravenous haloperidol causes 7 ms prolongation (dramatically higher risk than oral/IM routes), and pimozide causes 13 ms prolongation 1, 6
• Atypical antipsychotics also carry QT risk, though generally lower than typical agents 1
• Tricyclic antidepressants (amitriptyline) cause more QT prolongation than SSRIs, with mean increase of 24 ms versus -1 ms with SSRIs 6
• Citalopram and escitalopram can prolong QT in patients with pre-existing cardiovascular disease 6
• Methadone is high-risk, with nearly 1 million Americans using it; requires pretreatment ECG, follow-up within 30 days, and annual monitoring 6

Antiemetics

• 5-HT3 receptor antagonists (ondansetron, granisetron, dolasetron) carry FDA warnings for QT prolongation, with ondansetron causing mean QTc increases of 19.5 ms at 32 mg IV doses 7, 4
• Metoclopramide can prolong QT and should be used with extreme caution only, particularly when combined with other QT-prolonging medications 7, 4
• Domperidone prolongs QTc and should be avoided 7, 6
• Droperidol carries FDA black box warning for QT prolongation, torsades de pointes, and sudden death 7

Other Medications

• Calcium channel blockers (verapamil, diltiazem) prolong PR interval through AV nodal blockade and when combined with QTc-prolonging drugs create additive risk 6, 3
• Pentamidine (for Pneumocystis pneumonia) can prolong QT interval 6

Critical Risk Factors for Torsades de Pointes

Patients with any of the following factors should not receive QT-prolonging medications without careful consideration and counseling:

Non-Modifiable Risk Factors

• Female sex is a major risk factor for drug-induced torsades de pointes 1, 6
• Age >65-80 years significantly increases vulnerability to QT prolongation 1, 6
• Personal or family history of QT prolongation, congenital long QT syndrome, or sudden unexplained death 1
• Structural heart disease: acute coronary syndrome, heart failure (ejection fraction <40%), hypertrophic cardiomyopathy, left ventricular hypertrophy 1, 6
• Bradycardia (heart rate <45 beats/min) or conduction abnormalities 1, 6
• Recent cardiac events: cardiac arrest within 24 hours, syncope/seizure within 24 hours, stroke or head trauma within 7 days 1
• Genetic polymorphisms can increase susceptibility to drug-induced QT prolongation 6

Modifiable Risk Factors

• Electrolyte disturbances are critical: hypokalemia (potassium <3.4-4.5 mmol/L), hypomagnesemia (magnesium <1.7 mg/dL), hypocalcemia (calcium <4.65 mg/dL) 1, 6
• Concomitant use of multiple QT-prolonging drugs creates additive risk and should be avoided 1, 6
• Drug interactions that increase levels of QT-prolonging medications through CYP3A4 inhibition (azole antifungals, macrolides, protease inhibitors) 1, 6, 5
• Renal or hepatic dysfunction slows elimination of quinidine and other QT-prolonging drugs, leading to toxicity if dosage not reduced 2

Pre-Treatment Requirements

Before initiating any QT-prolonging medication, the following must be completed:

• Obtain baseline ECG to measure QTc interval in all patients 1, 4
• Screen for cardiac history: heart disease, previous low serum potassium, slow pulse rate, family history of sudden death, or known prolonged QT interval 1
• Review complete medication list for other QT-prolonging agents and drug interactions that may increase levels through CYP3A4 inhibition 1, 6
• Check electrolytes (potassium, magnesium, calcium) and correct abnormalities before initiating therapy, maintaining potassium >4.0-4.5 mEq/L and normalizing magnesium 1, 7
• Assess renal and hepatic function for medications eliminated by these routes 4, 2

QTc Interval Thresholds and Actions

Use the following algorithm for QTc management:

Green Light (Low Risk)

• QTc <460 ms (prepubertal males/females), <470 ms (postpubertal males), or <480 ms (postpubertal females): Proceed with QT-prolonging therapy as indicated 1
• Quick check: If QT interval is less than one-half the preceding RR interval, the calculated QTc will always be <460 ms 1

Yellow Light (Moderate Risk)

• QTc 460-500 ms: Document increased risk, correct electrolyte abnormalities (K+ >4, Mg2+ >2), discontinue/avoid other QT-prolonging medications, place on telemetry 1

Red Light (High Risk)

• QTc ≥500 ms or increase ≥60 ms from baseline: Treatment with the particular drug should be ceased or dose reduced immediately 1, 4
• This threshold represents only 1% of patients but carries highest risk of torsades de pointes 1

Monitoring Protocol During Treatment

Follow this structured monitoring approach:

• One month after initiating therapy: Perform second ECG to exclude development of prolonged QTc interval 1
• For high-risk medications (methadone, bedaquiline): Follow-up ECG within 30 days, then monthly for first 3 months 1, 6
• With any new QT-prolonging drug added or dose increase: Repeat ECG assessment 1
• Ongoing monitoring: Check electrolytes regularly, particularly potassium and magnesium 4, 6
• Continuous ECG monitoring until QTc returns to baseline after discontinuing offending drug 4

Special Considerations for High-Risk Populations

Elderly Patients (≥65 Years)

• Treatment should be done with extreme caution as elderly patients are more susceptible to drug-associated effects on the QT interval 1
• Elderly patients with calcium channel blockers metabolized by CYP3A4 are at particular risk for acute kidney injury when combined with clarithromycin 5

Patients with Structural Heart Disease

• Referral to cardiologist should be considered in cases of structural heart disease, QT prolongation, or cardiac symptoms 1
• The risk of active antiarrhythmic therapy is probably greatest in patients with structural heart disease 2

ICU Patients

• Critically ill patients are particularly prone to QTc prolongation due to exposure to multiple QT-prolonging drugs and prevalent risk factors (electrolyte abnormalities, organ dysfunction) 3
• Intravenous administration carries higher risk than oral dosing due to greater cardiac drug exposure and rapid infusion rates 6

Management of QT Prolongation

If QT prolongation develops during treatment:

1. Discontinue the offending drug immediately if QTc >500 ms or increases >60 ms from baseline 1, 4
2. Correct electrolyte abnormalities: Maintain potassium >4.5 mEq/L, normalize magnesium and calcium 1
3. Avoid combinations of multiple QT-prolonging drugs 1, 4
4. Consider alternative medications with lower risk of QT prolongation 4
5. For torsades de pointes: Administer 2g intravenous magnesium as initial drug of choice, regardless of serum magnesium level; temporary pacing is highly effective for recurrent episodes 7
6. For sustained ventricular arrhythmias with hemodynamic instability: Non-synchronized defibrillation 7

Common Pitfalls to Avoid

• Do not assume all QT prolongation leads to torsades de pointes - the risk varies significantly by medication, with amiodarone causing significant QT prolongation but relatively lower risk of torsades 6
• Do not overlook non-cardiac medications - many drugs not primarily prescribed for cardiac conditions can cause significant QT prolongation 6
• Do not ignore drug interactions - CYP3A4 inhibitors can dramatically increase levels of QT-prolonging drugs, with ketoconazole plus amiodarone being contraindicated 1, 6, 5
• Do not use Bazett's formula at high heart rates - it overcorrects at heart rates >80 bpm; use Fridericia's formula instead 1
• Do not forget that QT prolongation risk is dose-dependent for most medications 6
• Do not overlook that nausea, vomiting, and diarrhea lead to loss of potassium and magnesium that further prolongs QT interval, making patients with hyperemesis particularly vulnerable 7