Can Diphenhydramine Cause Important Drug Interactions?

Astemizole and terfenadine were the prototypic nonsedating antihistamines, but they have the potential to cause cardiac arrhythmias by interfering with cardiac potassium channels and prolonging the QT interval. The risk is heightened because the levels of these drugs increase in the presence of inhibitors of cytochrome P450 3A4 (CYP3A4). Recently, diphenhydramine (DPH) (Benadryl and others), the prototypic H₁-receptor antagonist, has been found to inhibit CYP2D6 in vitro. DPH can also prolong the QT interval.

Investigators in Quebec conducted an in vivo study of the potential interaction between DPH and the beta-blocker metoprolol (Lopressor and others), which is metabolized by CYP2D6. Of the 16 subjects who received a standard 100-mg dose o…