Diphenhydramine

Indications

• FDA-approved for allergic rhinitis, urticaria, allergic reactions, motion sickness, and as an over-the-counter nighttime sleep aid.
• The parenteral form is approved for amelioration of allergic reactions and for active treatment of motion sickness and parkinsonism.
• In psychiatry the central use is acute antipsychotic-induced dystonia, where 25-50 mg IM or IV relieves spasm within minutes.
• Also used off-label for antipsychotic-induced akathisia and parkinsonism, though propranolol, benztropine or amantadine usually serve better.
• As a hypnotic, tolerance to the sedative effect develops within days and there is no evidence supporting sustained use for insomnia.
• The AGS Beers Criteria list it as potentially inappropriate in adults 65 and older, so chronic use in that group should be avoided.

Mechanism of action

• Ethanolamine H1 inverse agonist that readily crosses the blood-brain barrier, and central H1 blockade produces its characteristic sedation.
• Potent muscarinic antagonism restores the striatal dopamine-acetylcholine balance, which is why it reverses acute dystonic reactions.
• Weak alpha-1 adrenergic blockade contributes to orthostatic hypotension, particularly after intravenous administration in older patients.
• Sodium channel blockade gives local anesthetic properties and, in overdose, produces QRS widening, arrhythmia and seizures.
• It also inhibits CYP2D6 at ordinary doses, so it acts as a perpetrator of drug interactions as well as a victim of them.

Pharmacokinetics

• Oral bioavailability is only about 40-60% because of first-pass metabolism, with peak concentrations roughly 2 h after a dose.
• Elimination half-life is 4-9 h in young adults but extends toward 13.5 h in older adults, which explains next-day impairment.
• Extensively metabolized by CYP2D6 with minor contributions from CYP1A2, CYP2C9 and CYP2C19, and metabolites are excreted renally.
• Protein binding is high at roughly 98%, and the drug crosses both the placenta and into breast milk.
• Hepatic impairment and advanced age prolong clearance substantially, so both dose and dosing interval need adjustment.

Dosing

• Acute dystonia: 50 mg IV or deep IM, repeated once after 20-30 min if needed, then 25-50 mg orally every 6 h for 24-72 h to prevent rebound.
• Allergic indications in adults: 25-50 mg orally every 4-6 h, with a maximum of 300 mg in 24 h from over-the-counter products.
• Parenteral dosing is 10-50 mg by deep intramuscular or slow intravenous route, up to 100 mg per dose, not exceeding 400 mg daily.
• Sleep aid dosing is 50 mg at bedtime and should be limited to a few nights; do not renew it as a standing hypnotic.
• Pediatric dosing is 5 mg/kg/day divided every 6 h to a maximum of 300 mg/day; it is contraindicated in neonates and premature infants.
• Reduce the dose and lengthen the interval in older adults and hepatic impairment, and avoid it entirely in narrow-angle glaucoma.

Adverse effects

• Sedation and psychomotor slowing are near-universal, and driving impairment after a single dose can match a legal blood alcohol level.
• Anticholinergic effects include dry mouth, blurred vision, constipation, urinary retention, tachycardia and impaired sweating.
• Delirium and acute cognitive impairment are common in older adults, which is the basis for the Beers Criteria recommendation.
• Paradoxical excitation, irritability and even hallucinations occur in children and occasionally in cognitively impaired elders.
• Cumulative anticholinergic exposure has been associated with increased dementia incidence in large observational cohorts.
• Overdose causes an anticholinergic toxidrome with seizures, wide-complex arrhythmia and rhabdomyolysis; it is also misused for hallucinations.

Monitoring

• Track total anticholinergic burden across the medication list rather than judging diphenhydramine in isolation.
• In older adults check cognition, gait and falls after any dose, and ask specifically about confusion overnight.
• For dystonia confirm resolution within 20-30 min and watch for recurrence over the following 24-72 h.
• Ask about urinary hesitancy and constipation in men with prostatic hypertrophy and check intraocular pressure concerns in glaucoma.
• Reassess the indication at every visit; any use beyond a few days for sleep should prompt a switch to a better-supported treatment.

Interactions

• Additive sedation with alcohol, benzodiazepines, opioids, gabapentinoids and sedating antipsychotics, with real respiratory risk in combination.
• Additive anticholinergic effects with benztropine, tricyclics, oxybutynin, clozapine, olanzapine and quetiapine can precipitate delirium.
• As a CYP2D6 inhibitor it raises concentrations of metoprolol, risperidone, aripiprazole and venlafaxine and blunts tamoxifen activation.
• It pharmacologically opposes donepezil, rivastigmine and galantamine, so it should not be given to patients on cholinesterase inhibitors.
• MAO inhibitors intensify and prolong the anticholinergic effects, and the combination should generally be avoided.

Special populations

• Pregnancy: one of the better-studied antihistamines with reassuring human data, and it is commonly used for nausea and allergy.
• Lactation: small amounts appear in milk and may sedate the infant or reduce milk supply, so occasional rather than regular use is advised.
• Pediatric: contraindicated in neonates and premature infants, and it should never be used to sedate a child for convenience.
• Geriatric: the Beers Criteria advise avoiding it entirely; a single dose to break dystonia is defensible, chronic dosing is not.
• Hepatic or renal impairment prolongs the half-life and calls for lower doses and longer intervals between them.

Clinical pearls

• 50 mg IV or IM breaks acute dystonia in minutes; continue orally 2-3 days to prevent rebound.
• Beers Criteria: avoid ongoing use over 65, where delirium, falls and retention follow quickly.
• Hypnotic tolerance develops within days, so it is never a durable treatment for insomnia.