Can Benadryl (diphenhydramine) prolong the QT interval?

Does Benadryl Prolong the QT Interval?

Yes, diphenhydramine (Benadryl) can prolong the QT interval, particularly at higher doses or in the presence of specific risk factors, and should be used with caution in patients with cardiac disease or those taking other QT-prolonging medications. 1

Mechanism and Evidence

Diphenhydramine inhibits fast sodium channels and, at higher concentrations, blocks repolarizing potassium channels, leading to prolongation of the action potential and QT interval. 2 This effect is dose-dependent, with toxicity becoming clinically significant at doses exceeding 1.0 g. 2

Clinical data confirm QT prolongation with diphenhydramine:

• In overdose cases (typically >500 mg), mean QTc was significantly prolonged to 453 ± 43 ms compared to 416 ± 35 ms in controls (p <0.001). 3
• Despite QT prolongation, torsades de pointes appears rare even in overdose situations, with no cases reported in a series of 126 overdose patients. 3
• Diphenhydramine is one of the most frequently prescribed QT-prolonging medications in emergency departments, accounting for 46.1% of cases involving such drugs. 4

Risk Factors Requiring Heightened Vigilance

The following patients are at increased risk for clinically significant QT prolongation with diphenhydramine: 1

• Concurrent use of other QT-prolonging medications (particularly common with famotidine, another over-the-counter drug) 4
• Pre-existing cardiac conditions, especially those with baseline QT prolongation 1
• Electrolyte abnormalities (hypokalemia, hypomagnesemia) 1
• Advanced age 1
• Renal failure (impairs drug clearance and increases risk) 5, 2
• Female gender 4

Monitoring Recommendations

For patients with risk factors requiring diphenhydramine: 1

• Obtain baseline ECG assessment before initiating therapy 1
• Monitor QTc in the same lead over time if following for drug-induced QT prolongation 1
• Discontinue diphenhydramine immediately if QTc exceeds 500 ms or increases >60 ms from baseline 1
• Correct electrolyte abnormalities, particularly potassium and magnesium, before and during treatment 1

Clinical Management Algorithm

When considering diphenhydramine use:

1. Screen for risk factors: cardiac disease, baseline QT prolongation, concurrent QT-prolonging drugs, electrolyte abnormalities, renal failure, advanced age 1

2. If risk factors present: Obtain baseline ECG and electrolytes 1

3. Consider alternatives: Second-generation antihistamines like cetirizine and loratadine carry minimal QT prolongation risk and should be preferred in high-risk patients 5

4. If diphenhydramine necessary despite risks: Use lowest effective dose, correct electrolytes, monitor ECG, and avoid combining with other QT-prolonging medications 1

5. Special populations: Avoid diphenhydramine in renal failure patients when possible; if used, reduce dose and monitor closely 5, 2

Critical Pitfalls to Avoid

• Over-the-counter availability creates false sense of safety: Diphenhydramine is frequently combined with other QT-prolonging medications (like famotidine) without recognition of cumulative risk 4
• Dialysis patients are particularly vulnerable: End-stage renal disease patients commonly experience pruritus and receive diphenhydramine, but impaired clearance significantly increases QT prolongation risk 2
• ECG screening remains inadequate: Only 20.9% of patients receiving multiple QT-prolonging drugs receive ECG monitoring in emergency departments 4

Comparative Context

While diphenhydramine does prolong QT interval, its risk appears lower than high-risk medications like antiarrhythmics (quinidine, sotalol, dofetilide with 1-10% TdP incidence), methadone, thioridazine, and haloperidol. 6 However, this does not eliminate the need for appropriate risk assessment and monitoring in vulnerable populations. 1