How do antihistamines exhibit their therapeutic effect?

Mechanism of Action of Antihistamines

Antihistamines primarily exhibit their therapeutic effect by acting as inverse agonists at histamine receptors, competitively blocking histamine from binding to its receptors, particularly H1 receptors, which prevents histamine-mediated allergic and inflammatory responses. 1

Primary Mechanism of Action

• Antihistamines compete with histamine for binding sites on histamine receptors, preventing histamine-receptor interaction, making them more effective at preventing rather than reversing histaminic actions 1
• They function as inverse agonists at histamine receptors, particularly at H1 receptors, which are present on nerve endings, smooth muscles, and glandular cells 2
• This competitive antagonism blocks histamine's effects on target tissues, reducing allergic symptoms such as pruritus, flushing, and urticaria 3

Types of Histamine Receptors Affected

• There are four known histamine receptors (H1, H2, H3, and H4) located throughout the body, but H1 receptors are the most clinically relevant for allergic responses 3
• Most antihistamines used for allergic conditions primarily target H1 receptors 3
• H2 receptors are mostly found within the gastrointestinal tract with limited distribution in vascular smooth muscle cells and play a minor role in allergic pathophysiology 3

Clinical Effects Based on Receptor Blockade

• H1 receptor blockade effectively treats cutaneous symptoms including pruritus, flushing, and urticaria 3
• Antihistamines are less effective at treating cardiovascular and respiratory symptoms such as hypotension or bronchospasm when used acutely 3
• When given orally, antihistamines begin working within 30 minutes, but peak plasma concentrations aren't reached until 60-120 minutes, with maximal tissue effects taking an additional 60-90 minutes 3

Differences Between First and Second Generation Antihistamines

• First-generation antihistamines (e.g., diphenhydramine, hydroxyzine) penetrate the blood-brain barrier and have additional anticholinergic, sedative, local anesthetic, and anti-serotonergic effects 2, 3
• Second-generation antihistamines (e.g., cetirizine, loratadine) preferentially block peripheral H1 receptors without significantly crossing the blood-brain barrier, resulting in fewer CNS side effects 4, 5
• The primary difference between first and second-generation antihistamines is central nervous system penetration, which explains the greater sedation with first-generation agents 3

Additional Mechanisms Beyond H1 Receptor Blockade

• Some antihistamines have additional anti-inflammatory properties beyond simple H1 receptor antagonism 2
• Certain antihistamines can inhibit IgE-mediated histamine and leukotriene release from mast cells and basophils 2
• Some agents reduce eosinophilic infiltration at sites of antigen challenge 2
• Newer research shows that certain antihistamines can suppress upregulation of histidine decarboxylase (HDC) gene expression, the enzyme responsible for histamine synthesis, providing an additional mechanism for symptom control 6

Clinical Applications Based on Mechanism

• Antihistamines are most effective when used prophylactically rather than after symptoms develop, due to their mechanism of preventing histamine-receptor binding 1
• They are indicated for allergic conditions including allergic rhinitis and urticaria 7, 4
• First-generation antihistamines may be more effective for certain symptoms due to their additional anticholinergic and CNS effects, but come with more side effects 3

Important Clinical Considerations

• The potency of antihistamines in suppressing allergic symptoms doesn't always correlate directly with their H1 receptor binding affinity, suggesting additional mechanisms contribute to their therapeutic effects 6
• When treating anaphylaxis, antihistamines should never be used as first-line treatment in place of epinephrine, as they cannot reverse the life-threatening cardiovascular and respiratory effects of severe allergic reactions 3
• For optimal therapeutic effect, antihistamines should be taken regularly rather than as needed during periods of allergen exposure 1