How do antihistamines work in patients with allergic reactions?

How Antihistamines Work in Allergic Reactions

Antihistamines work by competitively blocking histamine from binding to H1 receptors on nerve endings, smooth muscles, and glandular cells, thereby preventing—not reversing—the allergic cascade that causes symptoms like itching, sneezing, rhinorrhea, and urticaria. 1

Primary Mechanism of Action

Antihistamines function as competitive antagonists and inverse agonists at H1 receptors, stabilizing these receptors in an inactive state and preventing histamine from triggering allergic symptoms. 1, 2 This mechanism explains why antihistamines are most effective when used prophylactically or early in the allergic response, rather than after symptoms are fully established. 2

Receptor Specificity

• H1 receptors are the primary target for antihistamines used in allergic conditions, located on nerve endings, smooth muscle cells, and glandular tissue throughout the body. 1
• Four histamine receptor subtypes exist (H1, H2, H3, H4), but H1 receptors mediate the majority of allergic symptoms including pruritus, flushing, urticaria, rhinorrhea, and sneezing. 1
• H2 receptors are predominantly gastrointestinal and play minimal roles in typical allergic reactions. 1

Clinical Effects and Timing

Antihistamines begin working within 30 minutes of administration, but peak plasma concentrations aren't reached until 60-120 minutes, with maximal tissue effects requiring an additional 60-90 minutes. 1, 3 This delayed onset has important clinical implications:

• Continuous daily dosing is more effective than intermittent use for seasonal or perennial allergic rhinitis, primarily due to unavoidable ongoing allergen exposure. 4
• Protection wanes significantly 12-24 hours after the last dose, which explains rebound symptoms when doses are missed. 3

Symptom-Specific Efficacy

Antihistamines are highly effective for:

• Rhinorrhea, sneezing, and nasal/ocular itching associated with allergic rhinitis 4
• Cutaneous symptoms including pruritus, flushing, and urticaria 1
• Allergic conjunctivitis symptoms that often accompany allergic rhinitis 4

Antihistamines have limited efficacy for:

• Nasal congestion (little objective effect) 4
• Cardiovascular symptoms like hypotension during acute reactions 1
• Bronchospasm and respiratory compromise in severe reactions 1

First-Generation vs. Second-Generation Agents

The critical difference between generations is central nervous system penetration, with first-generation agents causing significant sedation, performance impairment, and anticholinergic effects. 4, 1

Second-Generation Antihistamines Are Preferred

Second-generation antihistamines (loratadine, desloratadine, cetirizine, fexofenadine) should be used preferentially because they:

• Have high specificity and affinity for peripheral H1 receptors with minimal CNS penetration 5, 6
• Produce less or no sedation and performance impairment 4, 5
• Avoid anticholinergic effects like dry mouth and urinary retention 4

First-Generation Agents Should Be Avoided

First-generation antihistamines (diphenhydramine, chlorpheniramine, brompheniramine) cause:

• Significant sedation and performance impairment that patients may not subjectively perceive 4, 5
• Prolonged daytime impairment even when dosed at bedtime 3
• Worsened sleep architecture 5

Critical Clinical Limitations

Antihistamines Are NOT First-Line for Anaphylaxis

Antihistamines should never replace epinephrine as first-line treatment for anaphylaxis, as they cannot reverse life-threatening cardiovascular and respiratory effects of severe allergic reactions. 1 They serve only as adjunctive therapy after epinephrine administration.

Limited Role in Asthma

Antihistamines are not recommended as first-line treatment for asthma, though they may provide modest benefit for upper respiratory symptoms in patients with concomitant allergic rhinitis and asthma. 4 Inhaled corticosteroids and long-acting bronchodilators remain the preferred asthma treatments. 4

Practical Prescribing Considerations

For allergic rhinitis management:

• Use second-generation antihistamines as first-line for mild-to-moderate symptoms 4
• Consider continuous daily dosing rather than as-needed use for optimal symptom control 4
• Combine with oral decongestants if nasal congestion is prominent 4
• Escalate to intranasal corticosteroids for more severe symptoms or inadequate response 4

Common pitfall: Antihistamines taken before immunotherapy injections may mask minor reactions that would otherwise alert physicians to impending systemic reactions, though premedication has been shown to reduce severe systemic reaction frequency in some protocols. 4