What are antihistamines?

Antihistamines: Mechanism and Clinical Applications

Antihistamines are medications that block histamine's effects on target tissues by competitively antagonizing histamine receptors, particularly H1 receptors, which are present on nerve endings, smooth muscles, and glandular cells. 1

Mechanism of Action

• Antihistamines work by preventing histamine-receptor interaction through competition with histamine for histamine receptors, making them more effective at preventing rather than reversing histaminic actions 2
• There are four known histamine receptors (H1, H2, H3, and H4), but H1 receptors are most clinically relevant for allergic responses 1
• H1 receptor blockade effectively treats cutaneous symptoms including pruritus, flushing, and urticaria, with effects beginning within 30 minutes but peak tissue effects taking up to 3 hours 1
• Antihistamines are less effective at treating cardiovascular and respiratory symptoms such as hypotension or bronchospasm when used acutely 1

Types of Antihistamines

First-Generation Antihistamines

• First-generation antihistamines (e.g., diphenhydramine, hydroxyzine, clemastine) cross the blood-brain barrier and cause significant sedation and performance impairment 3
• These agents have significant anticholinergic effects including dryness of mouth and eyes, constipation, urinary retention, and risk for narrow angle glaucoma 3
• First-generation antihistamines have been associated with impaired learning and school performance in children, as well as driving impairment in adults 3
• Drivers responsible for fatal automobile accidents were 1.5 times more likely to be taking first-generation antihistamines than drivers killed but not responsible for accidents 3
• Paradoxical CNS stimulation may occur with first-generation antihistamines, particularly in children 3

Second-Generation Antihistamines

• Second-generation antihistamines (e.g., loratadine, cetirizine) are minimally sedating as they do not readily cross the blood-brain barrier 4
• These agents selectively bind to peripheral histamine H1 receptors with fewer effects on other neuronal or hormonal systems 5
• Second-generation antihistamines are generally preferred over first-generation antihistamines for the treatment of allergic rhinitis due to their improved safety profile 3
• Among second-generation antihistamines, cetirizine may cause noticeable sedation in about 10% of patients 5

Clinical Applications

• Antihistamines are effective in reducing rhinorrhea, sneezing, and itching associated with allergic rhinitis but have limited effect on nasal congestion 3
• They are beneficial for symptoms of allergic conjunctivitis, which often accompany allergic rhinitis 3
• Antihistamines have a limited role in treating nonallergic rhinitis syndromes 3
• For allergic conditions, continuous treatment is more effective than intermittent use, primarily due to unavoidable, ongoing allergen exposure 3
• Antihistamines are first-line treatments for allergic diseases such as atopic dermatitis, pollinosis, food allergies, and urticaria 4

Important Clinical Considerations

• When treating anaphylaxis, antihistamines should never be used as first-line treatment in place of epinephrine, as they cannot reverse life-threatening cardiovascular and respiratory effects 1
• For food allergies, antihistamines should be prescribed alongside epinephrine autoinjectors, with antihistamines used for mild symptoms and epinephrine for severe symptoms 3
• Older adults are more sensitive to psychomotor impairment from first-generation antihistamines and are at increased risk for complications such as falls 3
• The AM/PM dosing regimen (combining a second-generation agent in the morning with a first-generation agent in the evening) is not recommended due to potential daytime drowsiness and performance impairment 3
• Non-brain-penetrating antihistamines (a subset of second-generation antihistamines) are considered first-line drugs for allergic diseases due to minimal adverse reactions 4

Combination Therapy

• Oral antihistamines may be used in combination with leukotriene receptor antagonists (LTRAs) for allergic rhinitis, which can have an additive effect, though this approach is generally less efficacious than intranasal corticosteroids 3
• Oral decongestants combined with antihistamines help reduce nasal congestion in both allergic and nonallergic rhinitis 3
• Antihistamines can be effective in decreasing local reactions during immunotherapy, particularly during cluster and rush protocols 3