How does Benadryl (diphenhydramine) cause sodium channel blockade, particularly in patients with pre-existing heart conditions?

Mechanism of Diphenhydramine-Induced Sodium Channel Blockade

Diphenhydramine causes sodium channel blockade by directly inhibiting fast voltage-gated cardiac sodium channels, similar to class Ia and Ic antiarrhythmic drugs, which slows phase 0 depolarization of the cardiac action potential and leads to QRS prolongation, wide-complex tachycardia, and potentially life-threatening ventricular arrhythmias. 1

Direct Sodium Channel Inhibition

• Diphenhydramine acts as a direct antagonist of fast sodium channels in cardiac myocytes, blocking the rapid influx of sodium ions during phase 0 of the cardiac action potential 2, 3
• This blockade slows intraventricular conduction velocity, manifesting as QRS prolongation on ECG (typically >120 ms in toxicity) 1, 4, 5
• At higher concentrations, diphenhydramine also inhibits repolarizing potassium channels, which further prolongs the action potential duration and causes QT interval prolongation 2, 3

Dose-Dependent Cardiotoxicity

• Sodium channel blockade becomes clinically evident at toxic doses, with a critical threshold around 1.0 g (1000 mg) 2
• Therapeutic serum concentrations range from 9-120 ng/mL, but toxicity manifests at concentrations >1000 ng/mL with severe sodium channel effects 5
• The mechanism is concentration-dependent: at lower doses, antihistaminic and anticholinergic effects predominate, while sodium channel blockade emerges as the dominant life-threatening toxicity at higher exposures 3, 4

Electrocardiographic Manifestations

The sodium channel blockade produces characteristic ECG findings that mirror tricyclic antidepressant toxicity:

• QRS prolongation (>120-130 ms) due to slowed phase 0 depolarization 1, 4, 5
• Terminal rightward axis deviation with a positive R wave in lead aVR, indicating severe sodium channel blockade 1, 4
• Wide-complex tachycardia that can progress to ventricular dysrhythmias 1, 6, 5
• QT/QTc prolongation (up to 638/759 ms reported) from combined sodium and potassium channel effects 3, 6

Clinical Implications in Cardiac Patients

Patients with pre-existing heart conditions face amplified risk because:

• Baseline conduction abnormalities (bundle branch blocks, prior MI) are exacerbated by additional sodium channel blockade, increasing the risk of complete heart block or ventricular arrhythmias 1
• Pre-existing structural heart disease reduces cardiac reserve, making patients more susceptible to diphenhydramine-induced hypotension and cardiogenic shock 1
• The combination of anticholinergic-induced tachycardia (which increases myocardial oxygen demand) and sodium channel blockade creates a particularly dangerous scenario in patients with coronary artery disease 1, 5

Protective Paradox of Tachycardia

• Interestingly, the anticholinergic-induced tachycardia from diphenhydramine may provide some protection against torsades de pointes, as bradycardia typically facilitates this arrhythmia 3
• This creates a management dilemma: avoiding iatrogenic bradycardia is prudent in acute diphenhydramine toxicity, even though tachycardia worsens other aspects of toxicity 3

Treatment Implications

The sodium channel blockade mechanism directly informs treatment:

• Hypertonic sodium bicarbonate (1000 mEq/L in adults) is the primary antidote, working by increasing extracellular sodium concentration to overcome channel blockade and inducing alkalemia to reduce drug binding 1, 4, 5
• Sodium bicarbonate has been shown to narrow QRS duration and terminate wide-complex tachycardia in documented pediatric and adult cases 4, 5
• Intravenous lipid emulsion therapy may be considered for refractory cases, as it actively shuttles lipophilic diphenhydramine away from cardiac tissue 1, 6
• Physostigmine is contraindicated when sodium channel blockade is present (QRS >100 ms), as it can precipitate asystole or worsen conduction delays 5

Common Pitfalls

• Underestimating over-the-counter availability: Diphenhydramine's easy accessibility leads clinicians to overlook its potential for severe cardiotoxicity, particularly in intentional overdoses where patients may ingest 10-20 grams 6, 5
• Misattributing ECG changes: The combination of QRS prolongation and terminal R wave in aVR can mimic tricyclic antidepressant toxicity or Brugada pattern, requiring careful history-taking 1, 4
• Delaying sodium bicarbonate: Waiting for laboratory confirmation before treating obvious sodium channel blockade (QRS >120 ms with appropriate clinical context) can allow progression to ventricular arrhythmias 4, 5