Benadryl - Drug Monograph

Introduction

Benadryl (diphenhydramine hydrochloride) is a first-generation ethanolamine-class antihistamine with additional anticholinergic, antiemetic, and sedative properties. Originally approved by the FDA in 1946, it remains one of the most widely recognized and utilized over-the-counter medications for allergic conditions and sleep disturbances.

Mechanism of Action

Diphenhydramine competitively inhibits histamine at H₁ receptors, preventing histamine-mediated allergic responses including vasodilation, increased vascular permeability, and smooth muscle contraction. Its sedative effects result from crossing the blood-brain barrier and antagonizing central H₁ receptors. The drug also exhibits significant anticholinergic activity through muscarinic receptor blockade, contributing to both therapeutic and adverse effects.

Indications

FDA-approved indications:

• Perennial and seasonal allergic rhinitis
• Allergic conjunctivitis
• Mild, uncomplicated allergic skin manifestations (urticaria, angioedema)
• Amelioration of allergic reactions to blood or plasma
• Anaphylaxis adjunct therapy
• Motion sickness prevention and treatment
• Parkinsonian syndrome (including drug-induced extrapyramidal symptoms)
• Nighttime sleep aid

Off-label uses:

• Acute dystonic reactions
• Insomnia (short-term management)
• Pruritus of various etiologies

Dosage and Administration

• Allergic conditions: 25-50 mg every 4-6 hours (max 300 mg/day)
• Motion sickness: 25-50 mg 30 minutes before travel, then every 4-6 hours
• Sleep aid: 50 mg 30 minutes before bedtime
• Extrapyramidal symptoms: 25-50 mg 1-3 times daily

• Initial dose: 25 mg every 6-8 hours
• Maximum: 150 mg/day (increased sensitivity to anticholinergic effects)

• CrCl <30 mL/min: Avoid or reduce frequency to every 12 hours

• Use with caution; consider dose reduction

• Oral tablets: Swallow whole with water
• Chewable tablets: Chew thoroughly before swallowing
• Liquid formulations: Use measuring device provided
• IM/IV administration: Reserved for hospital settings under medical supervision

Pharmacokinetics

Contraindications

• Hypersensitivity to diphenhydramine or other ethanolamine antihistamines
• Neonates and premature infants
• Acute asthma attacks
• Narrow-angle glaucoma
• Bladder neck obstruction
• Peptic ulcer disease with concomitant anticholinergic therapy
• Prostatic hypertrophy with urinary retention
• Monoamine oxidase inhibitor use (concurrent or within 14 days)

Warnings and Precautions

• CNS depression: May impair mental/physical abilities required for hazardous tasks
• Paradoxical excitation: May occur in children and elderly patients
• Anticholinergic effects: Use caution in patients with cardiovascular disease, hypertension, hyperthyroidism
• Respiratory depression: Avoid in patients with lower respiratory diseases
• Elderly patients: Increased risk of falls, confusion, anticholinergic toxicity
• Pregnancy Category B: Use only if clearly needed
• Lactation: Secreted in breast milk; may cause irritability in infants

Drug Interactions

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

• Warfarin: Possible altered anticoagulant effect
• Cholinergic agents: Reduced efficacy

Adverse Effects

• Sedation/drowsiness
• Dry mouth/nose/throat
• Dizziness
• Coordination impairment

• Headache
• Nausea/vomiting
• Constipation
• Blurred vision
• Tachycardia

• Anaphylaxis
• QT prolongation
• Seizures
• Severe hypotension
• Acute glaucoma
• Urinary retention
• Blood dyscrasias

Monitoring Parameters

• Efficacy: Symptom relief for allergic conditions
• Safety: Mental status changes, anticholinergic effects
• Cardiovascular: Heart rate, blood pressure (especially in elderly)
• Renal/hepatic function: In patients with impairment
• Fall risk assessment in elderly patients
• Signs of paradoxical excitation in children

Patient Education

• Take exactly as directed; do not exceed recommended dosage
• Avoid alcohol and other CNS depressants
• Be aware of potential drowsiness; avoid driving or operating machinery
• Use caution when rising from sitting/lying position
• Chewable tablets contain phenylalanine (important for PKU patients)
• Liquid formulations may contain alcohol
• Report any serious side effects immediately
• Not recommended for children under 2 years without medical advice
• Use as sleep aid should be short-term (<2 weeks)
• Store at room temperature away from moisture

References

1. Simons FER. Advances in H₁-antihistamines. N Engl J Med. 2004;351(21):2203-2217. 2. FDA Drug Label: Diphenhydramine Hydrochloride. DailyMed. 2023. 3. Church MK, Maurer M. H₁-antihistamines and allergic inflammation. Clin Exp Allergy. 2010;40(2):153-164. 4. Tashiro M, et al. Central effects of fexofenadine and diphenhydramine measured by positron emission tomography. J Allergy Clin Immunol. 2006;117(4):846-852. 5. Agrawal A, et al. Diphenhydramine overdose with intracerebral hemorrhage. J Emerg Med. 2013;44(6):e391-e393. 6. American Academy of Allergy, Asthma & Immunology. Guidelines for the diagnosis and management of food allergy. J Allergy Clin Immunol. 2010;126(6 Suppl):S1-S58. 7. Lexicomp Online. Diphenhydramine monograph. Wolters Kluwer Clinical Drug Information. 2023.