Antihistamine
Diphenhydramine (Benadryl)
Also called Benadryl
Indications
- Allergic reactions such as urticaria, pruritus and angioedema, including transfusion and acetylcysteine reactions
- Anaphylaxis, as an adjunct after epinephrine for skin symptoms
- Acute dystonic reactions (off-label) and parkinsonism when oral drugs cannot be used
- Premedication after a prior allergic-like reaction to a drug or contrast, with a corticosteroid (off-label)
- Motion sickness
Dosing
| Where | Dose |
|---|---|
| Other common pushes | Diphenhydramine: 25–50 mg IV |
Mechanism of action
Diphenhydramine is a first-generation H1 antihistamine and inverse agonist: it stabilizes the inactive state of the Gq-coupled H1 receptor, cutting histamine-driven and baseline phospholipase C–IP₃ signaling. This blocks histamine's vasodilation, capillary leak and itch, and because it crosses the blood–brain barrier it blocks the central H1 receptors that sustain wakefulness, causing sedation. It is also a muscarinic antagonist (drying, delirium, antidystonic effect), and in overdose it blocks fast cardiac sodium channels (wide QRS) and hERG potassium channels (long QT).
Pharmacology
- CNS: sedation and psychomotor slowing; antiemetic and anti-vertigo; relieves dystonia; paradoxical excitation in children; delirium in older adults; seizures in overdose
- Allergic: blunts urticaria, itch, flushing and vascular leak, but does not reverse airway edema, bronchospasm or shock
- Cardiovascular: tachycardia; hypotension, more likely in older adults (label); in overdose, wide QRS, long QT and ventricular dysrhythmias
- Anticholinergic: dry mouth, urinary retention, slowed gut, mydriasis and anhidrosis with heat retention
- Other: local anesthetic and cough-suppressing effects; inhibits CYP2D6
Pharmacokinetics
| Onset | Minutes IV; oral peak at 2–3 h |
|---|---|
| Duration | About 4–6 h; longer in older adults |
| Half-life | 4–9 h in young adults; about 13.5 h in older adults and 5.4 h in children (Simons 1990) |
| Distribution | Vd 3.3–6.8 L/kg; crosses the blood–brain barrier and placenta and enters breast milk |
| Protein binding | High, about 80–99% (estimates vary) |
| Metabolism | Liver, mainly CYP2D6 (also 1A2, 2C9, 2C19): N-demethylation, then oxidation to diphenylmethoxyacetic acid; extensive first pass |
| Elimination | Urine, almost all as metabolites; about 1% unchanged |
| Bioavailability | Oral 40–60% |
Chemistry
- Ethanolamine-class H1 antihistamine: 2-(diphenylmethoxy)-N,N-dimethylethanamine, a benzhydryl ether with a tertiary amine
- Achiral: the central carbon carries two identical phenyl rings
- Weak base, pKa about 9.0: about 97% ionized at pH 7.4, yet the lipophilic un-ionized fraction (log P 3.3) enters the brain readily
- Injection: 50 mg/mL hydrochloride, pH 4.0–6.5; push IV no faster than 25 mg/min; maximum 400 mg/day (label)
Adverse effects and cautions
In the one-pagers
- Toxidromes and AntidotesToxidromes at a glance: Anticholinergic (diphenhydramine, jimsonweed): High HR, temp: Dilated; hot, dry, red: Delirium, urinary retention, quiet bowel
- CEN Adult Medical Pearls: Neuro, GI and Respiratory Look-alikesConfusion that a drug explains: Older adult confused after a nighttime sleep aid: Swap it for hydroxyzine or another antihistamine: First-generation antihistamines (diphenhydramine, doxylamine, hydroxyzine, meclizine, promethazine) are all Beers drugs: highly anticholinergic, cleared slowly with age
- Mental Health: Meds and CommunicationAntipsychotics and Benzodiazepines: Acute dystonia: Hours to days: IM/IV benztropine or diphenhydramine; airway
- Sedation, Pain and Delirium ScalesSleep promotion and early mobility: Melatonin per the 2025 update; avoid new hypnotics and diphenhydramine.
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Sources
- FDA label: diphenhydramine injection (2018)
- Simons 1990 (kinetics by age)
- Hamelin 2000 (CYP2D6 interaction)
- PubChem: diphenhydramine
For education and exam preparation only. Follow your institution’s protocols. Typical adult values for study. Follow the order, the label and your institution's protocols.