What is the primary mechanism by which diphenhydramine (Benadryl) causes dizziness?

Mechanism of Diphenhydramine-Induced Dizziness

Diphenhydramine causes dizziness primarily through its antagonism of H1 histamine receptors in the central nervous system, particularly in the vestibular nuclei and brain regions controlling balance and coordination. 1

Primary Mechanism: H1 Receptor Antagonism in the CNS

Diphenhydramine is a first-generation H1-receptor antagonist with significant central nervous system penetration. Its mechanism of action related to dizziness involves:

1. Central H1 Receptor Blockade:

   • Diphenhydramine readily crosses the blood-brain barrier and blocks H1 receptors in the brain 1
   • This central action affects vestibular nuclei and areas controlling balance 1
   • Unlike second-generation antihistamines, diphenhydramine has poor receptor selectivity and affects multiple CNS pathways 2

2. Anticholinergic Effects:

   • Diphenhydramine has significant anticholinergic properties that contribute to dizziness 1
   • These effects can cause inner ear disturbances and disrupt balance mechanisms

Secondary Contributing Mechanisms

Several other pharmacological properties of diphenhydramine contribute to its dizziness-inducing effects:

• NMDA Receptor Antagonism:

  • Diphenhydramine inhibits NMDA-mediated membrane currents at clinically relevant concentrations (half-maximal inhibition around 25 μM) 3
  • This occurs through a noncompetitive open channel blocking mechanism
  • NMDA receptor antagonism contributes to sedation and potentially affects balance

• Sedative Properties:

  • The drug's sedative effects impair coordination and alertness 4
  • FDA labeling warns about "marked drowsiness" which contributes to dizziness 4
  • Sedation is a direct result of central H1 receptor blockade and other CNS effects

• Hypotensive Effects:

  • Diphenhydramine can cause hypotension, which may manifest as dizziness 1
  • This effect is particularly notable with intravenous administration

Clinical Implications

The dizziness caused by diphenhydramine has important clinical implications:

• Safety Concerns:

  • Patients should be warned about operating machinery or driving 4
  • Alcohol and other CNS depressants potentiate these effects 4

• Medication Selection:

  • Second-generation antihistamines (cetirizine, fexofenadine, loratadine) cause significantly less dizziness due to reduced CNS penetration 2, 5
  • These newer agents represent a therapeutic advance with fewer CNS adverse effects 2

• Individual Variation:

  • Some patients may experience paradoxical excitation rather than sedation, particularly CYP2D6 ultrarapid metabolizers (approximately 1-2% of the US population) 6
  • This genetic variation affects how diphenhydramine is metabolized

Clinical Pearls and Pitfalls

• Common Pitfall: Using diphenhydramine for its sedative effects without considering the risk of dizziness and falls, especially in elderly patients

• Caution: Diphenhydramine should be avoided in patients with:

  • History of falls or balance problems
  • Glaucoma (due to anticholinergic effects)
  • Prostatic hypertrophy (may cause urinary retention) 4
  • Concurrent use of other sedatives or tranquilizers 4

• Alternative Considerations: For allergic conditions requiring antihistamines, second-generation agents provide similar efficacy with significantly less dizziness and sedation 5

The central H1 receptor antagonism remains the primary mechanism through which diphenhydramine causes dizziness, with its anticholinergic properties and NMDA receptor antagonism serving as important secondary mechanisms.