What is the receptor action of antihistamines, specifically in relation to histamine (H1) receptors?

Receptor Action of Antihistamines

Antihistamines primarily act as inverse agonists at histamine receptors, binding to H1 receptors to inhibit histamine-induced inflammation and block the effects of histamine on target tissues. 1

Mechanism of Action

• H1 Receptor Antagonism:

  • Antihistamines competitively bind to H1 receptors, preventing histamine from activating these receptors
  • They function as inverse agonists rather than simple antagonists, stabilizing the receptor in an inactive conformation 1
  • This action blocks both neural and vascular H1 receptors, reducing symptoms such as nasal itching, sneezing, and rhinorrhea 2

• Receptor Distribution and Effects:

  • H1 receptors are widely distributed throughout the body, particularly in:
    • Nasal trigeminal nerve fibers (mediating itch and sneezing)
    • Nasal endothelial cells (affecting plasma extravasation and edema)
    • Smooth muscle cells (affecting contraction)
  • Activation of H1 receptors on nasal trigeminal nerve fibers transmits nasal itch and triggers sneezing 3
  • H1 receptor activation on endothelial cells causes contraction, leading to plasma extravasation and edema formation 3

• Additional Receptor Types:

  • There are four histamine receptor types in the body (H1, H2, H3, and H4) 4
  • H2 receptors are primarily found in the gastrointestinal tract with limited distribution in vascular smooth muscle cells 4
  • H3 receptors modulate neurogenic inflammation
  • H4 receptors affect immune cell functions 3

First vs. Second Generation Antihistamines

• First-Generation Antihistamines:

  • Have significant anticholinergic effects and CNS penetration
  • Examples include diphenhydramine 5 and chlorpheniramine
  • More effective in suppressing URI-induced cough than second-generation antihistamines due to:
    1. Greater anticholinergic activity
    2. Central penetration affecting H1 histaminergic and/or M1 muscarinic receptors in the CNS 4
  • Associated with sedation and cognitive decline, particularly in elderly patients 4

• Second-Generation Antihistamines:

  • Higher specificity and affinity for peripheral H1 receptors
  • Examples include loratadine 6, cetirizine, and fexofenadine
  • Less sedating due to reduced CNS penetration 7
  • Longer duration of action but similar onset of action compared to first-generation agents 4
  • Often used at 2-4 times FDA-approved doses in conditions like mast cell activation syndrome 4

Pharmacokinetics and Clinical Effects

• Onset and Duration:

  • Oral antihistamines are rapidly absorbed but may take 30-60 minutes for onset of action
  • Peak plasma concentrations occur at 60-120 minutes
  • Additional 60-90 minutes may be needed for diffusion into extravascular tissues for maximal effect 4
  • Second-generation antihistamines typically provide 24-hour symptom relief, allowing once-daily dosing 3

• Clinical Effects:

  • Most effective for symptoms like itching, sneezing, and rhinorrhea
  • Less effective for nasal congestion/blockage (both H1 and H2 antihistamines have weak effects) 8
  • Reduce proinflammatory effects mediated by H1 receptors
  • Improve physical and mental performance by reducing allergy-related activity impairment 3

Important Clinical Considerations

• Limitations in Acute Reactions:

  • Antihistamines are poorly effective in treating cardiovascular and respiratory symptoms such as hypotension or bronchospasm when used acutely as monotherapy 4
  • Not appropriate as first-line treatment for anaphylaxis due to slower onset compared to epinephrine 4

• Safety Considerations:

  • First-generation antihistamines should be avoided in elderly patients due to increased risk of falls, cognitive impairment, and anticholinergic effects 9
  • Second-generation antihistamines are generally safe with minimal adverse effects 3
  • No evidence of tachyphylaxis, tolerance, or rebound with modern antihistamines 3

• Combination Therapy:

  • Combined H1 and H2 antihistamine therapy may be beneficial for controlling histamine-related symptoms in certain conditions 9
  • H1 antihistamines are often used alongside other medications such as intranasal corticosteroids for allergic rhinitis 2

Understanding the receptor action of antihistamines is crucial for appropriate clinical use and maximizing therapeutic benefits while minimizing adverse effects.