Diphenhydramine - Drug Monograph

Introduction

Diphenhydramine is a first-generation ethanolamine-class antihistamine that has been widely used in clinical practice since its approval in 1946. It possesses antihistaminic, anticholinergic, antiemetic, and sedative properties, making it one of the most versatile over-the-counter medications available. While primarily recognized for its role in allergic conditions, diphenhydramine has multiple therapeutic applications across various clinical settings.

Mechanism of Action

Diphenhydramine exerts its primary therapeutic effects through competitive antagonism of histamine at H₁ receptors. This action prevents histamine-mediated allergic responses including vasodilation, increased vascular permeability, and smooth muscle contraction. Additionally, diphenhydramine demonstrates significant anticholinergic activity through muscarinic receptor blockade, contributing to both its therapeutic effects (anti-motion sickness) and adverse effects (dry mouth, urinary retention). Its central nervous system penetration and histamine receptor blockade in the tuberomammillary nucleus are responsible for its sedative properties.

Indications

• FDA-approved indications:

- Allergic rhinitis and allergic conjunctivitis - Mild allergic skin reactions (urticaria, angioedema) - Motion sickness prevention and treatment - Nighttime sleep aid (insomnia) - Antitussive effects (in combination products) - Parkinsonian symptoms (including drug-induced extrapyramidal symptoms)

• Off-label uses:

- Acute dystonic reactions - Nausea and vomiting in pregnancy (limited use) - Adjunctive treatment in anaphylaxis (after epinephrine)

Dosage and Administration

• Allergic conditions: 25-50 mg every 4-6 hours (max 300 mg/day)
• Sleep aid: 50 mg 30 minutes before bedtime
• Motion sickness: 25-50 mg 30-60 minutes before travel

• 25 mg every 6 hours (max 150 mg/day) due to increased sensitivity

• 2-6 years: 6.25 mg every 4-6 hours (max 37.5 mg/24h)
• 6-12 years: 12.5-25 mg every 4-6 hours (max 150 mg/24h)
• ≥12 years: Adult dosing

• CrCl <30 mL/min: Avoid or reduce dose by 50%

• Use with caution; consider dose reduction

• Oral (tablets, capsules, liquid)
• Intravenous (IV)
• Intramuscular (IM)
• Topical (cream, gel, spray)

Pharmacokinetics

Contraindications

• Hypersensitivity to diphenhydramine or similar compounds
• Neonates and premature infants
• Acute asthma attacks
• Narrow-angle glaucoma
• Bladder neck obstruction
• Peptic ulcer disease with pyloroduodenal obstruction
• Concurrent MAOI therapy

Warnings and Precautions

• CNS depression: May impair mental/physical abilities required for hazardous tasks
• Anticholinergic effects: Use cautiously in patients with:

- Prostatic hypertrophy - Cardiovascular disease - Hyperthyroidism - Increased intraocular pressure

• Paradoxical excitation: May occur in pediatric patients and elderly
• Tolerance: May develop with prolonged use
• Withdrawal: Abrupt discontinuation after prolonged use may cause insomnia

Drug Interactions

• CNS depressants (alcohol, benzodiazepines, opioids): Additive sedation
• MAOIs: Increased anticholinergic effects
• Anticholinergic agents (TCAs, antipsychotics): Enhanced adverse effects
• CYP2D6 inhibitors (fluoxetine, paroxetine): Increased diphenhydramine levels

• Warfarin: Possible increased INR
• Metoprolol: Reduced metabolism of metoprolol

Adverse Effects

• Somnolence/drowsiness
• Dry mouth/nose/throat
• Dizziness
• Headache
• Gastrointestinal upset

• Urinary retention
• Blurred vision
• Tachycardia
• Hypotension
• Thickening of bronchial secretions

• Anaphylaxis
• Blood dyscrasias
• Seizures
• Extrapyramidal symptoms
• Photosensitivity

Monitoring Parameters

• Efficacy: Relief of allergic symptoms, sleep quality, motion sickness prevention
• Safety:

- Mental status changes - Anticholinergic effects (dry mouth, urinary retention) - Cardiovascular status (heart rate, blood pressure) - Signs of paradoxical excitation (especially in children)

• Long-term use: Periodic assessment of continued need and potential tolerance

Patient Education

• Take exactly as directed; do not exceed recommended dosage
• Avoid alcohol and other CNS depressants during therapy
• Be aware of potential drowsiness; avoid driving or operating machinery
• Report any unusual side effects (palpitations, difficulty urinating, vision changes)
• Use sugar-free formulations if diabetic
• Do not use for more than 2 weeks for sleep without medical supervision
• Keep out of reach of children (safety risk with ingestion)

• Pregnancy: Use only if clearly needed (Category B)
• Breastfeeding: Small amounts excreted in milk; use cautiously
• Elderly: Increased risk of falls and confusion

References

1. Simons FER, Simons KJ. H1 antihistamines: current status and future directions. World Allergy Organ J. 2008;1(9):145-155. 2. Church MK, Maurer M, Simons FER, et al. Risk of first-generation H1-antihistamines: a GA²LEN position paper. Allergy. 2010;65(4):459-466. 3. FDA Drug Approval Package: Benadryl. U.S. Food and Drug Administration. 4. McEvoy GK, ed. AHFS Drug Information. Bethesda, MD: American Society of Health-System Pharmacists; 2023. 5. Patel T, Kurdi MS. A comparative study between oral midazolam and oral diphenhydramine: which is more effective for premedication in children? J Anaesthesiol Clin Pharmacol. 2015;31(2):213-216. 6. Schroeckenstein DC, Bush RK, Chervinsky P, Busse WW. Effectiveness and safety of fexofenadine, a new nonsedating H1-receptor antagonist, in the treatment of fall allergies. Allergy Asthma Proc. 1998;19(3):135-141.