What are the classifications and features of antihistaminics?

Antihistaminics Classification and Features

Antihistamines are primarily classified into first-generation and second-generation categories, with second-generation antihistamines being strongly preferred due to their significantly better safety profile and similar efficacy for allergic symptoms. 1, 2

Classification of Antihistamines

First-Generation Antihistamines

• Examples: Diphenhydramine (Benadryl), Chlorpheniramine (Chlor-Trimeton), Hydroxyzine (Atarax), Clemastine (Tavist), Cyproheptadine (Periactin), Promethazine (Phenergan)
• Key characteristics:
  • High lipophilicity - readily cross blood-brain barrier 1
  • Significant sedation (50-80% of patients) 1, 2
  • Anticholinergic effects (dry mouth, constipation, urinary retention) 1
  • Performance impairment even without subjective awareness of sedation 1
  • Prolonged plasma half-life and active metabolites 1

Second-Generation Antihistamines

• Examples: Cetirizine (Zyrtec), Loratadine (Claritin), Fexofenadine (Allegra), Desloratadine (Clarinex), Levocetirizine (Xyzal), Azelastine (Astelin nasal)
• Key characteristics:
  • Low lipophilicity - minimal penetration of blood-brain barrier 1, 3
  • Minimal sedation (typically 1-8% vs 50-80% with first-generation) 1, 2
  • Fewer anticholinergic effects 1
  • Similar efficacy for allergic symptoms 2
  • Some (e.g., terfenadine, astemizole) have been withdrawn due to cardiac risks 4

Clinical Features and Safety Considerations

Sedation and Performance Impairment

• First-generation antihistamines:

  • Associated with 1.5× higher risk of fatal automobile accidents 1
  • Impair learning, school performance, and work productivity 1, 5
  • Effects cannot be eliminated by bedtime-only dosing due to prolonged half-life 1
  • Sedation rates: Diphenhydramine (50%), Hydroxyzine (80%), Promethazine (60-73%) 2

• Second-generation antihistamines:

  • Minimal sedation: Fexofenadine (1.3%), Desloratadine (2.1%), Loratadine (8%) 2
  • Significantly less impact on cognitive function and performance 5

Anticholinergic Effects

• First-generation antihistamines have significant anticholinergic effects:
  • Dry mouth and eyes
  • Constipation
  • Urinary retention (especially in men with prostatic hypertrophy)
  • Risk of narrow-angle glaucoma exacerbation 1
  • Better control of rhinorrhea due to anticholinergic properties 1

Special Populations

• Elderly patients: Should strictly avoid first-generation antihistamines due to increased sensitivity to sedation, cognitive effects, and fall risk 2
• Children: First-generation antihistamines may cause paradoxical excitation; many antihistamines are used off-label in children under 2 years 6
• Patients with comorbidities: Increased risk with prostatic hypertrophy, elevated intraocular pressure, cognitive impairment 1

Drug Interactions

• Concomitant use of CNS-active substances (alcohol, sedatives) enhances performance impairment 1, 2
• Some second-generation antihistamines (particularly older ones like terfenadine) can cause QT interval prolongation when combined with CYP450 inhibitors 4

Clinical Applications

Route of Administration

• Oral: Most antihistamines are available in oral formulations
• Intranasal: Azelastine, olopatadine available as nasal sprays
• Combination therapy: For mixed rhinitis, combination of intranasal antihistamine with intranasal corticosteroid may provide additive benefit 1

Dosage Forms

• Various formulations available including tablets, liquids, and sprays with age-specific dosing 1

Clinical Recommendation

When prescribing antihistamines, second-generation agents should be selected over first-generation options due to their superior safety profile, minimal sedation, and similar efficacy 1, 2. First-generation antihistamines should be avoided when possible, especially in elderly patients, those who drive or operate machinery, and children due to significant risks of sedation, performance impairment, and anticholinergic effects 1, 2, 5.