Diphenhydramine and Liver Toxicity
Diphenhydramine (Benadryl) does not typically cause liver toxicity at therapeutic doses, but there have been rare documented cases of hepatotoxicity with excessive doses, particularly in overdose situations.
Evidence on Diphenhydramine and Liver Effects
Normal Use and Safety Profile
Diphenhydramine is a first-generation antihistamine with anticholinergic and sedative properties that has been widely used for allergic symptoms and as a sedative adjunct 1. At therapeutic doses (25-50 mg), diphenhydramine is not known to cause significant liver injury.
The most common adverse effects of diphenhydramine include:
- Hypotension
- Dizziness
- Blurred vision
- Dry mouth
- Epigastric discomfort
- Urinary retention
- Wheezing 1
Liver-Related Considerations
Evidence of Liver Toxicity
A case report from 2017 documented the only known case of diphenhydramine-induced acute liver injury in the absence of concomitant medications. This involved a patient taking excessive doses (up to 400 mg nightly) for insomnia, resulting in markedly elevated liver enzymes (AST >20,000 IU/L, ALT >5,000 IU/L) 2.
In patients with pre-existing liver disease, diphenhydramine's half-life may be prolonged (15.2 ± 1.5 hours vs. 9.3 ± 0.9 hours in healthy individuals), correlating with severity of liver disease 3. However, this study found that a single intravenous dose provided safe and effective sedation in patients with cirrhosis.
Dose-Dependent Toxicity
Diphenhydramine shows clear dose-dependent toxicity, with:
- Mild symptoms occurring at lower doses
- Moderate symptoms occurring above 300 mg
- Severe symptoms (delirium/psychosis, seizures, coma) occurring above 1000 mg 4
However, hepatotoxicity is not specifically mentioned as a common feature of overdose in these studies.
Clinical Implications
Risk Assessment
- Therapeutic doses (25-50 mg) are unlikely to cause liver injury in most patients
- Patients with pre-existing liver disease may experience prolonged drug effects but not necessarily increased hepatotoxicity
- Excessive doses (>400 mg) may potentially cause liver injury in rare cases
Monitoring Recommendations
- For patients on standard therapeutic doses, routine liver function monitoring is not necessary
- For patients with pre-existing liver disease, consider monitoring diphenhydramine effects due to prolonged half-life
- For suspected overdose (>300 mg), monitor for systemic toxicity including potential liver effects
Conclusion
While diphenhydramine is generally considered safe for the liver at therapeutic doses, healthcare providers should be aware of the potential for hepatotoxicity with excessive doses. The single documented case of severe liver injury occurred with chronic high-dose use (400 mg daily) 2. For patients requiring antihistamine therapy, second-generation antihistamines may offer a more favorable side effect profile with similar efficacy 5.