Diphenhydramine

Mechanism of action

◎Histamine H1 receptorDiphenhydramine

ⓘ The figure shows doxepin, a tricyclic first-generation H1 blocker, in the human H1 receptor; diphenhydramine binds the same site.

Diphenhydramine is an ethanolamine H1 inverse agonist that crosses the blood–brain barrier easily. Blocking central H1 receptors causes sedation; blocking muscarinic receptors gives anticholinergic effects that are useful against motion sickness and drug-induced parkinsonism or dystonia, but cause dry mouth, urinary retention and confusion. It also blocks sodium channels, which gives local anaesthetic action and explains the wide-QRS arrhythmias of overdose.

1. Diphenhydramine enters the brain easily
2. It blocks central and peripheral H1 receptors: sedation, less allergy
3. It also blocks muscarinic receptors: dry mouth, less nausea
4. In overdose, sodium-channel block widens the QRS

Indications

• Allergy and cold symptoms: sneezing, runny nose, itchy eyes Allergic rhinitis →
• Anaphylaxis, as an add-on to epinephrine once the acute symptoms are controlled Anaphylaxis →
• Motion sickness
• Drug-induced parkinsonism and acute dystonia (injection)
• Short-term insomnia in adults (not to make children sleep) Insomnia disorder →

Adverse effects

Common

• Drowsiness and slowed reactions
• Dry mouth, blurred vision and constipation
• Urinary retention, especially with an enlarged prostate
• Dizziness and poor coordination

Contraindications

• Newborns and premature infants
• Breastfeeding (injection label)
• Use as a local anaesthetic (risk of local necrosis)
• Caution in angle-closure glaucoma, prostate enlargement or bladder outlet obstruction
• Older adults: avoided where possible because of confusion, falls and urinary retention

Key interactions

Alcohol, benzodiazepines, opioids and other CNS depressants

Additive sedation and slowed breathing

Other anticholinergic drugs (tricyclic antidepressants, oxybutynin, antipsychotics)

Additive dry mouth, urinary retention, constipation and confusion

MAO inhibitors

Prolong and intensify the anticholinergic effects

What is monitored

• Level of sedation and breathing, especially with other depressants
• Urine output and bowel habit
• Confusion and fall risk in older adults

Administration and safety

• Oral, intravenous (slowly) or deep intramuscular; never as a local anaesthetic injection
• It is in many night-time cold and sleep products: check labels to avoid double dosing
• Not used to make a child sleep

Pregnancy and breastfeeding

Diphenhydramine has long pregnancy use; it is avoided near delivery and in breastfeeding because newborns are very sensitive to antihistamines.

Nursing care

• Check breathing and sedation after injection; raise bed rails and assist walking
• Watch for urinary retention and constipation, especially in older men
• In anaphylaxis, make sure epinephrine has been given first
• Teach not to drive or operate machinery until the effect is known, and to avoid alcohol

Pharmacokinetics

Absorption

Well absorbed by mouth; also given intravenously or intramuscularly

Distribution

Widely distributed, including the brain

Metabolism

Liver, with first-pass metabolism

Elimination

As metabolites in the urine

Onset and duration

Sedation and relief within an hour by mouth, faster by injection

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Connections

← Back to the class: H1 antihistamines

Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: DailyMed - DIPHENHYDRAMINE HYDROCHLORIDE injection (DailyMed (U.S. National Library of Medicine), 2026); Diphenhydramine: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2026); ATCDDD - ATC/DDD Index (WHO Collaborating Centre for Drug Statistics Methodology, 2026).

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Representative model, for educational purposes only.