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Sunday, July 27, 2025

Diphenhydramine


Diphenhydramine is a first-generation antihistamine with sedative, anticholinergic, antiemetic, and antipruritic properties. It is primarily used for allergic conditions, nausea, insomnia, cough suppression, and motion sickness. As a H1 receptor antagonist, it competitively blocks histamine activity at peripheral and central H1 receptors. Unlike second-generation antihistamines, diphenhydramine readily crosses the blood-brain barrier, leading to significant CNS depressant effects such as drowsiness.

Pharmacological Classification

  • Therapeutic class: Antihistamine

  • Pharmacologic class: First-generation H1 receptor antagonist

  • ATC code: R06AA02

  • Legal status: OTC (oral, topical); Rx-only (injectable or high-dose forms in some countries)

Brand Names and Formulations

  • Benadryl (US, UK – varies by formulation)

  • Nytol, Sominex, Unisom SleepGels (marketed for insomnia)

  • Allernix, Diphen, Banophen, Sleepinal, ZzzQuil

  • Formulations:

    • Oral tablets/capsules (12.5 mg, 25 mg, 50 mg)

    • Oral solution/syrup

    • Injectable (50 mg/mL for anaphylaxis or sedation)

    • Topical creams/gels/sprays (for itch relief)

Mechanism of Action

Diphenhydramine works through multiple receptor pathways:

1. Histamine H1 Receptor Antagonism

  • Competes with histamine for H1-receptor sites on effector cells in the GI tract, blood vessels, and respiratory tract

  • Reduces allergic symptoms: sneezing, rhinorrhea, hives, and pruritus

2. CNS Depression

  • Crosses the blood-brain barrier → binds central H1 receptors

  • Produces drowsiness, sedation, and antianxiety effects

3. Anticholinergic Activity

  • Inhibits muscarinic acetylcholine receptors

  • Reduces motion sickness, nausea, and excessive salivation

  • Can cause dry mouth, blurred vision, urinary retention

4. Sodium Channel Blockade (in overdose)

  • Membrane-stabilizing effect → may contribute to seizures or arrhythmias at toxic doses

Indications

Approved Uses

  • Allergic rhinitis, urticaria, anaphylaxis (adjunct)

  • Cough (nonproductive)

  • Insomnia (short-term)

  • Motion sickness prevention and treatment

  • Parkinsonism-related extrapyramidal symptoms

  • Nausea/vomiting

  • Itching or insect bites (topical use)

Off-label / less common uses

  • Migraine prophylaxis (adjuvant)

  • Dystonia induced by antipsychotics

  • Anxiety or acute agitation (especially parenteral use in hospitals)

Dosage and Administration

Adults

  • Allergic reactions: 25–50 mg orally every 4–6 hours (max 300 mg/day)

  • Insomnia: 50 mg orally at bedtime

  • Motion sickness: 25–50 mg taken 30 minutes before travel, then every 4–6 hours as needed

  • Cough suppressant: 25 mg every 4 hours (not to exceed 150 mg/day)

  • Injectable (for anaphylaxis or dystonia): 10–50 mg IM/IV every 4–6 hours

Children

  • 2–6 years: 6.25 mg every 4–6 hours (max 25 mg/day)

  • 6–12 years: 12.5–25 mg every 4–6 hours (max 150 mg/day)

  • Not recommended under 2 years (risk of respiratory depression)

Contraindications

  • Hypersensitivity to diphenhydramine or excipients

  • Newborns or premature infants

  • Breastfeeding women (risk of sedation and decreased milk supply)

  • Use with other CNS depressants without supervision

  • Topical and oral use simultaneously (to avoid overdose)

Warnings and Precautions

  • CNS depression: Caution when driving or operating machinery

  • Elderly: Higher sensitivity to anticholinergic effects – increased risk of confusion, falls, or delirium

  • Asthma or COPD: Risk of thickened bronchial secretions

  • Narrow-angle glaucoma, urinary retention, prostatic hypertrophy: May worsen symptoms due to antimuscarinic effects

  • QT prolongation: Risk increases in overdose or with other QT-prolonging agents

Adverse Effects

Common (1–10%)

  • Drowsiness, sedation

  • Dry mouth, dry eyes, urinary retention

  • Dizziness, confusion

  • Constipation

  • Thickened bronchial secretions

Uncommon/Rare (<1%)

  • Paradoxical excitation (especially in children and elderly)

  • Palpitations, tachycardia

  • Blurred vision

  • Seizures (overdose or high-dose IV use)

  • Hallucinations, delirium in toxic doses

  • Photosensitivity or rash (with topical forms)

Drug Interactions

Additive CNS Depression

  • Alcohol

  • Benzodiazepines, opioids, barbiturates

  • Other sedating antihistamines or muscle relaxants

Potentiation of Anticholinergic Effects

  • Tricyclic antidepressants (e.g., amitriptyline)

  • Antipsychotics (e.g., chlorpromazine)

  • Antiparkinsonian agents (e.g., benztropine)

QT Prolongation Risk

  • When combined with antiarrhythmics, macrolides, or fluoroquinolones

Use in Pregnancy and Lactation

Pregnancy

  • Generally considered safe (Category B, US FDA)

  • Widely used during pregnancy for nausea or allergies

  • Should be avoided in late pregnancy if possible (risk of neonatal sedation)

Lactation

  • Excreted in breast milk

  • May cause infant sedation, irritability, or poor feeding

  • May reduce milk supply (due to anticholinergic effects)

Use in Special Populations

  • Elderly: Avoid if possible; listed in Beers Criteria due to anticholinergic and sedative effects

  • Pediatrics: Risk of paradoxical excitation, overdose (never use under 2 years without supervision)

  • Hepatic impairment: Use with caution; primarily metabolized in liver

  • Renal impairment: No adjustment needed, but monitor for CNS effects

Comparative Insights (No Tables)

Diphenhydramine vs. Cetirizine

  • Diphenhydramine causes more sedation, anticholinergic effects

  • Cetirizine is a second-generation antihistamine with less drowsiness

  • Diphenhydramine may be better in acute allergic reactions but not for daily use

Diphenhydramine vs. Doxylamine

  • Both are first-generation antihistamines

  • Doxylamine is longer-acting and more sedating → often used for sleep induction

  • Diphenhydramine is more versatile (IV use, antiemetic, antitussive)

Diphenhydramine vs. Promethazine

  • Promethazine is also a first-generation antihistamine with stronger antiemetic properties

  • Promethazine carries higher risk of respiratory depression in children

  • Diphenhydramine is safer OTC, but promethazine is preferred for nausea in clinical settings

Overdose and Toxicity

Symptoms

  • Extreme drowsiness, progressing to coma

  • Seizures

  • Anticholinergic toxidrome: dry mouth, flushed skin, dilated pupils, hallucinations

  • Cardiac arrhythmias due to sodium channel blockade

  • Rhabdomyolysis, hyperthermia

Management

  • Supportive care: airway protection, IV fluids

  • Activated charcoal (if early presentation)

  • Benzodiazepines for seizures

  • Sodium bicarbonate for wide QRS arrhythmias

  • Avoid physostigmine unless severe CNS symptoms and no cardiac involvement

Patient Counseling Points

  • May cause drowsiness – avoid driving or alcohol

  • Avoid in children under 2 years unless instructed

  • For motion sickness, take 30–60 minutes before travel

  • Do not combine with other sedatives or sleep aids

  • Report signs of urinary retention, confusion, or palpitations

  • Topical diphenhydramine: do not use on large areas or broken skin

  • If using for insomnia, do not use for more than 2 weeks

Regulatory and Clinical Guidelines

  • UK MHRA and US FDA warn against OTC use in children under 2 years

  • Beers Criteria: Avoid diphenhydramine in older adults due to anticholinergic burden

  • ACOG and AAP support short-term use in pregnancy if necessary

  • NICE does not recommend sedating antihistamines for long-term allergic rhinitis




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