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Benadryl is Primarily an antihistamine, although it possesses some anticholinergic and (maybe) some dopaminergic activity. So if a patient is on compazine or promethazine these drugs will block dopamine at the receptor, causing EPS. Diphenhydramine will then block acetylcholine and this will bring balance to the dopamine and acetylcholine system in the substantia nigra - reducing or eliminating the EPS.

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