Diphenhydramine (Benadryl) | Medication Reference

Bedside Snapshot

Core Use: Classic first-generation H1 blocker used as adjunct in allergic reactions/anaphylaxis (after epinephrine), for histamine-mediated pruritus/urticaria, and for treatment of acute dystonic reactions
Onset/Duration: IV ~5–15 minutes; IM ~20–30 minutes; PO ~30–60 minutes. Duration of antihistamine effect ~4–8 hours, with sedation often lasting longer
Typical Dosing: Adults: 25–50 mg IV or IM q4–6h as needed; PO 25–50 mg q4–6h (max 300 mg/day)
Key Limitation: In anaphylaxis, diphenhydramine is adjunctive only—treats cutaneous symptoms but does NOT reverse airway edema, shock, or bronchospasm. Never delay or replace epinephrine
Key Dangers: Sedation, significant anticholinergic effects (dry mouth, urinary retention, constipation), confusion/delirium (especially elderly), QT prolongation in overdose

Brand & Generic Names

Generic Name: Diphenhydramine hydrochloride
Brand Names: Benadryl, various generics

Medication Class

First-generation H1 antihistamine; anticholinergic; sedative

Pharmacology

Mechanism of Action:

Competitively blocks H1 histamine receptors, reducing the effects of histamine on capillary permeability, vasodilation, and sensory nerve endings associated with pruritus and urticaria
Readily crosses the blood–brain barrier and acts as an antagonist at central H1 receptors, producing significant sedation
Has substantial anticholinergic (antimuscarinic) activity, contributing to drying of secretions and adverse effects such as dry mouth, urinary retention, constipation, and tachycardia
Also exhibits some sodium channel–blocking properties and other membrane-stabilizing actions at high doses, contributing to cardiotoxicity and seizures in overdose

Pharmacokinetics:

Onset: IV ~5–15 minutes; IM ~20–30 minutes; PO ~30–60 minutes
Peak Effect: ~1–3 hours after PO dosing; earlier with IV
Duration: 4–8 hours for antihistamine effect; sedative and anticholinergic effects may persist longer
Distribution: Widely distributed, including CNS; high protein binding (~78%)
Metabolism: Primarily hepatic via CYP2D6 and other pathways to inactive metabolites
Elimination: Excreted primarily in urine as metabolites; terminal half-life in adults ~4–9 hours, prolonged in elderly and in hepatic/renal impairment

Indications

Adjunct treatment of acute allergic reactions and anaphylaxis (after epinephrine) to relieve pruritus, urticaria, and other histamine-mediated cutaneous symptoms
Symptomatic treatment of pruritus and urticaria from various causes when parenteral or rapid therapy is needed
Prevention and treatment of acute dystonic reactions or extrapyramidal symptoms from antipsychotics or antiemetics (usually IV/IM)
Adjunctive therapy for motion sickness and nausea in some protocols (more commonly oral/IM outside ICU)
Sedation/insomnia: generally avoided in ICU/older adults due to delirium/anticholinergic risk; not preferred as a primary sedative

Dosing & Administration

Available Forms:

IV/IM solution: commonly 50 mg/mL in 1 mL vials/ampules. Must be diluted for slow IV injection to reduce local irritation
Oral capsules/tablets: 25 mg, 50 mg; various OTC liquid formulations (e.g., 12.5 mg/5 mL)
Topical formulations (creams, gels) exist but are not typically used in ED/ICU practice

Dosing – Diphenhydramine (Adult):

Indication	Dose & Route	Frequency	Notes
Allergic reaction / urticaria (parenteral)	25–50 mg IV or IM	Every 4–6 hours as needed	Give IV slowly (over at least 2–5 minutes) to minimize local irritation and hypotension
Adjunct in anaphylaxis (after epinephrine)	25–50 mg IV or IM	Once, may repeat q4–6h for symptoms	Treats cutaneous symptoms only; does not replace epinephrine
Acute dystonic reaction (e.g., from antipsychotics)	25–50 mg IV or IM	Single dose; may repeat once in 15–30 min if needed	Often followed by PO diphenhydramine for 24–48h to prevent recurrence
Oral dosing for allergy/pruritus	25–50 mg PO	Every 4–6 hours as needed	Do not exceed 300 mg/day in adults
Geriatric or frail patients	12.5–25 mg IV/IM/PO	Every 6–8 hours as needed	High risk of delirium and falls; avoid if possible
Maximum adult dosing	300 mg/day PO or parenteral (total across all routes); lower limits in elderly or organ dysfunction

Contraindications

Absolute Contraindications:

Known hypersensitivity to diphenhydramine or other ethanolamine antihistamines
Newborn or premature infants (relative/labeling contraindication)
Breastfeeding without risk–benefit assessment (may cause infant sedation/irritability)

Major Precautions:

Older adults: high risk of anticholinergic toxicity, delirium, falls—on Beers Criteria as a potentially inappropriate medication
Angle-closure glaucoma, urinary retention/BPH, severe constipation or GI obstruction: anticholinergic effects can worsen these conditions
Cardiovascular disease or concomitant QT-prolonging drugs: in overdose or high doses, can widen QRS and prolong QT, predisposing to arrhythmias
Hepatic or renal impairment: reduced clearance and prolonged half-life; use lower doses and extended intervals
Concomitant CNS depressants (opioids, benzos, alcohol, sedative-hypnotics): additive sedation and respiratory depression

Critical Warning: In anaphylaxis, give epinephrine first and don't let diphenhydramine slow you down—it is for comfort (skin) symptoms, not for airway or shock. High risk of delirium in elderly patients (Beers Criteria).

Adverse Effects

Common:

Sedation, drowsiness, impaired coordination
Dry mouth, blurred vision, constipation, urinary retention (anticholinergic)
Dizziness, confusion (especially in older adults)
Local pain or irritation with IV/IM injection

Serious:

Delirium, hallucinations, paradoxical agitation (especially in pediatrics/elderly)
Seizures and severe anticholinergic toxicity in overdose (hyperthermia, mydriasis, flushed skin, absent bowel sounds)
Cardiac arrhythmias due to sodium channel blockade and QT prolongation at toxic doses
Significant hypotension with rapid IV injection (rare with appropriate dosing)

Special Populations

Geriatric Patients:

Use reduced doses (12.5–25 mg) due to high risk of delirium, falls, and anticholinergic toxicity
Listed on Beers Criteria as potentially inappropriate medication in older adults
Avoid if possible; consider alternative antihistamines with less CNS penetration

Hepatic Impairment:

Reduced clearance; use lower doses and extended intervals
Monitor for prolonged sedation and anticholinergic effects

Renal Impairment:

Prolonged half-life; reduce dose and extend dosing interval
Monitor for accumulation with repeated dosing

Pregnancy & Lactation:

Generally considered safe in pregnancy when used for short-term treatment of allergic reactions
May cause sedation or irritability in breastfed infants
Use lowest effective dose

Pediatric Considerations:

Paradoxical agitation can occur in children
Not recommended in newborns or premature infants
Use weight-based dosing per pediatric protocols

Monitoring

Clinical Monitoring:

Mental status and level of sedation, especially in older adults and when combining with other sedatives or opioids
Vital signs (HR, BP, RR) during IV administration and in hemodynamically unstable patients
Urinary output and signs of urinary retention in patients with BPH or neurogenic bladder
In recurrent or severe allergic reactions, monitor for progression to anaphylaxis despite symptomatic improvement

Laboratory Monitoring:

ECG monitoring in overdose, high-dose use, or when combined with other QT-prolonging or sodium-channel–blocking medications

Clinical Pearls

Anaphylaxis Priority: In anaphylaxis, give epinephrine first and don't let diphenhydramine slow you down—it is for comfort (skin) symptoms, not for airway or shock.

Dystonic Reactions: For acute dystonic reactions, IV/IM diphenhydramine often produces rapid relief; follow it with a short oral course (e.g., 25–50 mg PO q6h for 1–2 days) to prevent recurrence.

Avoid as Sleep Aid: If you're reaching for diphenhydramine purely as a sleep aid in the ICU, reconsider—risk of delirium and anticholinergic burden is high; use more targeted agents instead.

Dosing in Elderly: Be cautious giving full 50 mg IV doses in older adults or patients with borderline BP or delirium risk; 12.5–25 mg often works well and is safer.

OTC Products: Educate staff that OTC "PM" products nearly all contain diphenhydramine or similar first-generation antihistamines and can significantly add to a patient's anticholinergic load.

References

1. Lexicomp. (2025). Diphenhydramine: Drug information. Wolters Kluwer.
2. American Academy of Allergy, Asthma & Immunology. (2020). Anaphylaxis: Clinical guidance.
3. American Geriatrics Society Beers Criteria Update Expert Panel. (2019). American Geriatrics Society 2019 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. Journal of the American Geriatrics Society, 67(4), 674–694.
4. Drugs.com. (2024). Diphenhydramine dosage guide. https://www.drugs.com/dosage/diphenhydramine.html
5. LITFL. (2023). Antihistamine toxicity. https://litfl.com/antihistamine-toxicity/