1st Generation Antihistamines

Summary

First generation antihistamines are a class of drugs that include Chlorpheniramine and Diphenhydramine. These drugs work by blocking histamine receptors, muscarinic receptors, and alpha-1 adrenergic receptors. Blocking H1 histamine receptors can reduce histamine-mediated vasodilation and vascular permeability, helping to treat allergy symptoms. Blocking muscarinic receptors can help to treat vestibular nausea, or motion sickness.  However, due to their multiple mechanisms, first generation antihistamines also cause a variety of side effects. As antimuscarinic drugs, these drugs can cause anticholinergic symptoms like dry mouth, constipation, confusion, and hallucinations.  Blockade of alpha-1 receptors can lead to orthostatic hypotension, characterized by lightheadedness and dizziness. Finally, blockade of histamine receptors can lead to sedation or drowsiness by blocking inhibiting centers in the brain.

Key Points

• First-Generation Antihistamines
  • Drug Names
    • Diphenhydramine
    • Chlorpheniramine
    • Promethazine
    • Hydroxyzine
    • Dimenhydrinate
    • Doxylamine
    • Meclizine
  • Mechanism
    • Blocks H1 histamine receptors
      • Reversible antagonism of H1 receptors blocks histamine signaling at blood vessels
      • Reduces vasodilation and vascular permeability, especially in airways and at the skin
      • Inhibits wakefulness and arousal centers in CNS
  • Clinical Use
    • Allergy
      • Reduced vasodilation and vascular permeability helps reduce nasal mucus production and airway reactivity
    • Motion sickness (vestibular nausea)
      • Due to antimuscarinic activity at M1 receptors (see adverse effects below), which regulate vestibular function
    • Insomnia / sleep aid
      • Due to inhibition of H1-mediated wakefulness and arousal centers in CNS
  • Adverse Effects
    • Sedation
      • First-generation antihistamines are lipophilic and cross the blood brain barrier
      • Antagonism of H1 receptors in the CNS can inhibit wakefulness and arousal centers to lead to sedation
      • Contrast vs. Second-Generation Antihistamines which do not have these sedative effects
    • Antimuscarinic
      • Strong anticholinergic effects can cause confusion, hallucinations, dry mouth, and constipation
      • Elderly are at especially high risk of altered mental status and should avoid first-generation antihistamines (see: Beers Criteria)
    • Anti-α1 activity
      • May cause orthostatic hypotension due to inhibition of alpha-1 adrenergic receptors at blood vessels