QT Prolongation with Hydroxyzine and Diphenhydramine
Both hydroxyzine and diphenhydramine can prolong the QT interval, with hydroxyzine carrying a more established and clinically significant risk that warrants specific contraindications and monitoring, while diphenhydramine's QT prolongation is primarily seen in overdose situations but can occur at therapeutic doses in high-risk patients. 1, 2, 3
Hydroxyzine: Established QT Prolongation Risk
FDA-Mandated Warnings and Contraindications
Hydroxyzine is contraindicated in patients with pre-existing QT prolongation and carries an FDA black box-level warning regarding QT prolongation and torsades de pointes (TdP). 2
Post-marketing surveillance has documented 59 cases of QT prolongation and/or TdP associated with hydroxyzine use between 1955 and 2016, though the majority occurred in patients with additional risk factors such as cardiovascular disease, electrolyte abnormalities, or concomitant arrhythmogenic drugs. 4
Hydroxyzine is explicitly listed in pediatric guidelines as a QT-prolonging antihistamine alongside loratadine. 1
Mechanism and Clinical Evidence
Hydroxyzine demonstrates concentration-dependent inhibition of human cardiac hERG potassium channels, the primary mechanism underlying drug-induced QT prolongation. 4
The drug is classified as having "conditional risk of TdP" rather than absolute risk, meaning danger increases substantially when combined with other risk factors. 4
High-Risk Scenarios Requiring Avoidance
Hydroxyzine should not be used in patients with:
- Congenital long QT syndrome or family history of long QT syndrome 2
- Recent myocardial infarction 2
- Uncompensated heart failure 2
- Bradyarrhythmias 2
- Concomitant use of Class IA antiarrhythmics (quinidine, procainamide) or Class III antiarrhythmics (amiodarone, sotalol) 2
- Concurrent use of other QT-prolonging medications including certain antipsychotics (ziprasidone, clozapine, quetiapine), antidepressants (citalopram, fluoxetine), or macrolide antibiotics (azithromycin, erythromycin) 2
Diphenhydramine: Dose-Dependent QT Risk
Clinical Evidence and Risk Profile
Diphenhydramine causes QT prolongation primarily in overdose situations (typically >500 mg), though it can occur at therapeutic doses in vulnerable patients. 3, 5
In a study of 126 diphenhydramine overdose patients, mean QTc was significantly prolonged (453 ± 43 ms vs 416 ± 35 ms in controls, p<0.001), but notably, no cases of torsades de pointes occurred. 3
The protective effect against TdP in diphenhydramine overdose appears related to concurrent tachycardia (mean heart rate 103 ± 25 bpm), which shortens the vulnerable period for arrhythmia initiation. 3, 6
Recent Toxicology Data
A 2022 poison center study found diphenhydramine had a statistically significant association with QTc >500 ms, placing it alongside medications officially listed as "Known Risk of TdP" despite not being in that category. 5
Among 760 exposures to QT-prolonging substances, diphenhydramine was associated with prolonged QTc, though life-threatening dysrhythmias remained rare (0.8% incidence of VT/VF overall). 5
Mechanism
Diphenhydramine inhibits fast sodium channels and, at higher concentrations, repolarizing potassium channels, leading to action potential prolongation and QT interval extension. 7, 6
Toxicity is dose-dependent with a critical threshold of approximately 1.0 g. 7
Comparative Risk Assessment
Hydroxyzine carries greater clinical concern than diphenhydramine for several reasons:
Regulatory status: Hydroxyzine has FDA contraindications for QT prolongation, while diphenhydramine does not. 2
Therapeutic dose risk: Hydroxyzine can cause QT prolongation at therapeutic doses in high-risk patients, whereas diphenhydramine primarily causes problems in overdose. 4, 3
Guideline recognition: Hydroxyzine is explicitly listed in multiple clinical guidelines as a QT-prolonging antihistamine requiring monitoring. 1
Clinical Management Recommendations
For Hydroxyzine
Obtain baseline ECG before initiating therapy in any patient with cardiovascular risk factors. 8
Monitor QTc at baseline and after dose adjustments, with particular attention to QTc >500 ms or increases >60 ms from baseline. 8
Correct electrolyte abnormalities (potassium <4.5 mEq/L, hypomagnesemia) before starting therapy. 8
Consider alternative antihistamines (fexofenadine, desloratadine) in patients with multiple risk factors. 1
For Diphenhydramine
Exercise caution in patients with:
- End-stage renal disease (reduced clearance increases risk) 7
- Pre-existing cardiovascular disease 5
- Concomitant use of other QT-prolonging medications 5
Avoid treating diphenhydramine overdose-related tachycardia aggressively, as the elevated heart rate may provide protection against TdP. 6
Common Pitfalls
Assuming all first-generation antihistamines carry equal cardiac risk: Hydroxyzine has substantially more documented QT risk than other first-generation agents. 4
Failing to recognize additive effects: Both medications can potentiate QT prolongation when combined with other at-risk drugs, even if each individual agent might be tolerated alone. 2, 5
Overlooking diphenhydramine in cardiac risk assessments: Despite not being officially categorized as high-risk, recent data demonstrates significant QT prolongation potential. 5
Neglecting elderly patients: Hydroxyzine requires dose reduction and careful monitoring in geriatric populations due to decreased renal function and increased sensitivity. 2