Which has less activity for QT (QT interval) prolongation, diphenhydramine or hydroxyzine?

Diphenhydramine Has Less QT Prolongation Activity Than Hydroxyzine

Diphenhydramine should be preferred over hydroxyzine when QT prolongation is a concern, as hydroxyzine is explicitly recognized in current guidelines as a QT-prolonging antihistamine with documented cases of torsade de pointes, while diphenhydramine has minimal and dose-dependent cardiac risk. 1

Guideline-Based Risk Stratification

Hydroxyzine: Established QT Risk

• The American Academy of Pediatrics explicitly lists hydroxyzine as a QT-prolonging antihistamine alongside loratadine in pediatric guidelines, indicating formal recognition of its cardiac risk. 1
• The British Journal of Dermatology guidelines recommend considering alternative antihistamines (fexofenadine, desloratadine) specifically in patients with multiple risk factors when hydroxyzine would otherwise be used. 1
• Hydroxyzine demonstrates concentration-dependent inhibition of multiple human cardiac ion channels, including hERG potassium channels, which directly prolongs ventricular repolarization. 2
• Pharmacovigilance data identified 59 reports of QT prolongation and/or torsade de pointes linked to hydroxyzine use between 1955-2016. 2
• Even small doses (12.5 mg) of hydroxyzine have caused torsade de pointes, particularly in patients with bradycardia or complete atrioventricular block. 3

Diphenhydramine: Minimal and Dose-Dependent Risk

• Diphenhydramine is notably absent from guideline lists of QT-prolonging medications that require routine cardiac monitoring. 4
• QT prolongation with diphenhydramine is rare, dose-dependent, and primarily occurs with toxicity above the critical dose limit of 1.0 g—well above therapeutic dosing. 5
• The mechanism involves inhibition of fast sodium channels and, only at higher concentrations, repolarizing potassium channels. 5
• Published cases of diphenhydramine-associated QT prolongation are extremely limited and typically involve overdose, renal failure, or multiple confounding factors. 5, 6

Required Monitoring for Hydroxyzine (Not Diphenhydramine)

Baseline Assessment

• Obtain baseline ECG before initiating hydroxyzine therapy in any patient with cardiovascular risk factors. 1
• Correct electrolyte abnormalities (potassium <4.5 mEq/L, hypomagnesemia) before starting hydroxyzine. 1

Ongoing Monitoring

• Monitor QTc at baseline and after dose adjustments, with particular attention to QTc >500 ms or increases >60 ms from baseline. 1
• If QTc reaches >500 ms or increases >60 ms from baseline, hydroxyzine should be ceased or dose reduced. 4

High-Risk Populations Requiring Extra Caution with Hydroxyzine

• Patients with cardiovascular disorders plus concomitant treatment with drugs known to induce arrhythmia represent the greatest combined risk factor. 2
• Elderly patients require particular caution with hydroxyzine. 4
• Patients with bradycardia are at especially high risk, as demonstrated by torsade de pointes occurring with just 12.5 mg in a patient with complete AV block. 3

Clinical Decision Algorithm

For patients requiring antihistamine therapy:

1. If any cardiovascular risk factors present (structural heart disease, QT prolongation, bradycardia, electrolyte abnormalities, concomitant QT-prolonging drugs):

   • Choose diphenhydramine over hydroxyzine
   • Or select alternative antihistamines (fexofenadine, desloratadine) 1

2. If hydroxyzine must be used despite risk factors:

   • Obtain baseline ECG 1
   • Correct all electrolytes 1
   • Monitor QTc after dose changes 1
   • Avoid concomitant QT-prolonging medications 4

3. If diphenhydramine is used:

   • Standard monitoring sufficient in most cases 4
   • Avoid doses approaching 1.0 g 5
   • Exercise caution in renal failure 6

Critical Pitfall to Avoid

Do not assume all first-generation antihistamines carry equal cardiac risk. While hydroxyzine requires formal cardiac risk assessment and ECG monitoring per current guidelines 1, diphenhydramine does not carry the same level of documented risk and is not included in lists requiring routine cardiac surveillance. 4 The comparative animal study directly demonstrated that hydroxyzine prolonged QT interval at therapeutic doses (1-10 mg/kg), while cyproheptadine (another antihistamine) had minimal effect on ventricular repolarization. 7 This confirms meaningful differences exist between antihistamines in their cardiac effects.