What is the difference between first and second generation antihistamines?

Differences Between First and Second Generation Antihistamines

Second-generation antihistamines are strongly preferred over first-generation antihistamines due to significantly less sedation, minimal performance impairment, and fewer anticholinergic effects, while maintaining similar efficacy for allergic symptoms. 1

Key Differences

First-Generation Antihistamines

• Sedation and Performance Impairment:

  • High sedation rates (diphenhydramine 50%, hydroxyzine 80%, promethazine 60-73%) 2
  • Cause significant performance impairment even without subjective awareness of drowsiness 1
  • Associated with impaired learning, decreased school/work performance, and increased risk of accidents 1
  • Drivers taking first-generation antihistamines are 1.5 times more likely to be responsible for fatal accidents 1

• Anticholinergic Effects:

  • Cause dry mouth and eyes, constipation, urinary retention 1
  • Increase risk of narrow-angle glaucoma 1
  • Particularly problematic in elderly patients 1, 2

• Pharmacokinetics:

  • Long half-lives and active metabolites 1
  • Effects persist longer than plasma levels of parent compound 1

• Examples: Diphenhydramine (Benadryl), hydroxyzine (Atarax), clemastine, chlorpheniramine, brompheniramine 1, 3

Second-Generation Antihistamines

• Sedation and Performance:

  • Minimal or no sedation at recommended doses 1
  • Significantly less performance impairment 4, 5
  • Sedation rates vary: fexofenadine (1.3%), desloratadine (2.1%), loratadine (8%) 2

• Anticholinergic Effects:

  • Minimal to none 1

• Blood-Brain Barrier Penetration:

  • Limited penetration of blood-brain barrier 6
  • Primarily act on peripheral H1 receptors 6, 7

• Cardiac Safety:

  • Generally excellent cardiovascular safety profiles 5
  • Earlier second-generation agents (terfenadine, astemizole) had cardiac concerns and were withdrawn 6

• Examples: Fexofenadine (Allegra), loratadine (Claritin), desloratadine (Clarinex), cetirizine (Zyrtec) 1, 5

Important Distinctions Among Second-Generation Antihistamines

• Non-sedating at recommended doses: Fexofenadine, loratadine, desloratadine 1
• May cause sedation at recommended doses: Cetirizine, intranasal azelastine 1
• May cause sedation at higher than recommended doses: Loratadine, desloratadine 1
• No sedation even at higher doses: Fexofenadine 1, 5

Clinical Implications

• Elderly patients: Second-generation antihistamines are strongly preferred due to increased sensitivity to sedation, cognitive effects, and fall risk in older adults 1, 2

• Driving and occupational safety: First-generation antihistamines significantly impair driving ability and increase occupational accidents 1, 4

• AM/PM dosing regimens: Not recommended to use first-generation antihistamines at night and second-generation in morning, as sedation can persist into the next day 1

• Efficacy: Both generations have similar efficacy for allergic symptoms, though second-generation options may have varying onset of action 4, 3

• Cost considerations: Second-generation antihistamines cost slightly more than first-generation options, but the safety benefits generally outweigh this difference 4

Common Pitfalls to Avoid

1. Underestimating sedation: Performance impairment can occur with first-generation antihistamines even when patients deny feeling drowsy 1

2. Combining with other CNS depressants: Effects of first-generation antihistamines are enhanced when combined with alcohol, sedatives, or antidepressants 1

3. Inappropriate use in elderly: First-generation antihistamines pose particular risks in older adults due to increased sensitivity to sedation and anticholinergic effects 1, 2

4. Assuming all second-generation antihistamines are identical: There are important differences in sedation potential among second-generation options 1

5. Overlooking intranasal options: Intranasal antihistamines can be effective first-line treatments for allergic rhinitis, though they may cause some sedation due to systemic absorption 1