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This activity provides healthcare professionals with an in-depth review of diphenhydramine, a first-generation antihistamine commonly prescribed to manage allergic disorders, insomnia, pruritus, urticaria, vertigo, motion sickness, and dystonias. Clinical applications, mechanism of action, adverse effects, contraindications, and off-label uses receive focused attention, ensuring healthcare professionals understand the broad range of conditions where diphenhydramine may play a role. Pharmacokinetics, administration strategies, and clinically significant drug interactions are reviewed to support safe and effective prescribing practices. This activity also addresses diphenhydramine’s toxicity profile, highlighting risks associated with inappropriate dosing, drug interactions, and patient-specific factors. Evidence-based strategies for optimizing therapeutic benefits while minimizing adverse outcomes are discussed in detail. Healthcare professionals gain essential information to adjust dosing regimens, recognize contraindications, and make informed treatment decisions. By enhancing understanding of diphenhydramine’s clinical utility and safety considerations, this activity supports improved patient care and safer prescribing practices across various care settings. Objectives: Evaluate the mechanisms of action of diphenhydramine. Identify the FDA-approved indications and off-label uses of diphenhydramine. Assess the possible adverse events associated with diphenhydramine administration. Implement effective collaboration and communication among interprofessional team members to improve the efficacy of diphenhydramine pharmacotherapy and the outcomes for patients who might benefit from it. Access free multiple choice questions on this topic.

Signs and Symptoms of Overdose Diphenhydramine overdose can cause significant toxicity and result in various sequelae, including agitation, cardiac arrhythmias, rhabdomyolysis and the classic anticholinergic toxidrome.[39][40][41][42][41][39] Signs and symptoms of a diphenhydramine overdose are listed below. Delirium Agitation Confusion Restlessness Hallucinations Ataxia Tremor Seizure Dry sweat glands and mucous membranes Flushed skin Elevated body temperature Mydriasis and blurry vision Urinary retention Tachycardia Rhabdomyolysis Management of Overdose Treatment of a diphenhydramine overdose may involve the following: Activated charcoal: may be attempted if the patient presents within 1 hour of ingesting oral diphenhydramine Benzodiazepines: typically administered for agitation and seizures Phenobarbital and propofol may be preferred; avoid phenytoin and fosphenytoin, as they further block sodium channels Sodium bicarbonate: prolongs the QRS interval and is typically administered to overcome sodium channel blockade Adult dose: 2 mEq/kg (typically 2 to 3 ampules of bicarbonate) via continuous infusion. Mix 3 ampules of sodium bicarbonate in 1L D5W, and run this infusion at 250 mL/hr. Magnesium sulfate: should be administered intravenously for a prolonged QT interval Vasopressors: administered to treat hypotension Physostigmine: acetylcholinesterase inhibitor that binds reversibly to inhibit acetylcholinesterase in the central and peripheral nervous system, which in turn allows acetylcholine to bind to muscarinic receptors to overcome the anticholinergic block. Physostigmine should be administered while in contact with a medical toxicologist or poison control specialist. Dose: 0.5 to 2 mg over 5 min (IV) The onset of action typically occurs within 20 minutes Atropine should be ready at the bedside, and patients should be monitored for bradycardia Further studies are needed to investigate the potential treatment of diphenhydramine toxicity using sodium bicarbonate and intravenous lipid emulsion therapy.[43] Severe diphenhydramine toxicity can cause cardiac adverse effects due to sodium channel blockade. Lipid emulsion therapy may serve as an alternative treatment, as the lipids bind to diphenhydramine, potentially reversing its blockage of sodium channels.[44]

Diphenhydramine is now available over the counter, but that does not mean that interprofessional healthcare team members should not pay close attention when patients report self-administering it. Clinicians must educate the patient on the safe use of this agent. While the drug is relatively safe, it should not be combined with alcohol, other sedatives, and hypnotics. The patient should be shown how to read the product labeling and advised not to take more than the recommended dose. Parents should also be educated on the safe storage of this agent to prevent accidental ingestion by children.[31] Immunologists can provide valuable insight into refractory anaphylaxis. Emergency medicine physicians need to be prepared to handle potential overdose or severe reactions. Toxicologists offer expertise in managing toxic exposures and adverse effects related to diphenhydramine. Collaboration among interprofessional teams and exchanging information can enhance patient outcomes and mitigate adverse events related to diphenhydramine therapy.