What are the different types of antihistamines (anti-histamine medications)?

Antihistamine Medications: Complete Classification

Antihistamines are divided into two main generations—first-generation and second-generation H1 antihistamines—plus H2 antihistamines that target different receptors, with second-generation agents strongly preferred for allergic conditions due to superior safety profiles. 1

First-Generation H1 Antihistamines

These older agents cross the blood-brain barrier extensively, causing significant sedation and anticholinergic effects that limit their utility in modern practice. 1

Specific agents include:

• Diphenhydramine - causes marked sedation and performance impairment 1
• Hydroxyzine - associated with drowsiness and impaired driving performance that worsens with cellular phone use 1
• Clemastine - produces sedative effects in many patients 1
• Chlorpheniramine - causes sedation and anticholinergic effects 2
• Brompheniramine - has anticholinergic (drying) and sedative effects 3, 2

Critical safety concerns: First-generation antihistamines impair performance even when patients deny feeling drowsy, increase fatal automobile accident risk by 1.5-fold, cause occupational accidents, impair learning in children, and should be avoided in children under 6 years and older adults. 1, 4

Second-Generation H1 Antihistamines

These agents have minimal blood-brain barrier penetration, providing effective symptom relief with dramatically reduced sedation and anticholinergic effects. 1

Non-sedating agents (at recommended doses):

• Fexofenadine - maintains non-sedating properties even at higher than FDA-approved doses, making it truly non-sedating 4, 5
• Loratadine - non-sedating at recommended doses but may cause sedation if exceeded 4
• Desloratadine - non-sedating at recommended doses but may cause sedation at higher doses 4
• Bilastine - considered truly non-sedating, similar to fexofenadine 5

Minimally sedating agents:

• Cetirizine - may cause mild drowsiness in 13.7% of patients (versus 6.3% placebo), has rapid onset of action and is available generically 1, 4
• Levocetirizine - the active enantiomer of cetirizine with similar efficacy profile 4

Key advantages: Second-generation antihistamines have longer duration of action, similar onset to first-generation agents (30 minutes), but peak plasma concentrations occur at 60-120 minutes with maximal tissue effect requiring an additional 60-90 minutes. 1

Intranasal Antihistamines

Azelastine - may cause sedation at recommended doses, offers rapid onset and increased effectiveness over oral antihistamines for nasal congestion, but has poor taste and higher cost. 1, 4

H2 Antihistamines

These target H2 receptors primarily in the gastrointestinal tract with limited vascular smooth muscle distribution. 1

Clinical role: H2 antihistamines are sometimes used concurrently with H1 antihistamines for anaphylaxis, though rigorous supporting evidence is lacking and they play only a minor role in allergic pathophysiology. 1

Clinical Selection Algorithm

For allergic rhinitis: Choose second-generation agents as first-line therapy, with fexofenadine offering the best balance of effectiveness and complete non-sedation across all doses. 4, 6

For patients requiring maximum potency: Cetirizine is the most potent antihistamine available and can be dose-titrated for severe symptoms unresponsive to other agents. 6

For older adults or those at high impairment risk: Fexofenadine is particularly advantageous due to its truly non-sedating properties. 4

For anaphylaxis: Antihistamines serve only as adjunctive therapy after epinephrine administration—they relieve cutaneous symptoms (pruritus, flushing, urticaria) but do not treat cardiovascular or respiratory symptoms and should never replace or delay epinephrine. 1

Critical Pitfalls to Avoid

Never use first-generation antihistamines as first-line therapy for allergic rhinitis given their significant sedation, performance impairment, and anticholinergic effects. 1, 4

Do not assume all second-generation antihistamines have identical sedation profiles—important differences exist, particularly between fexofenadine/loratadine/desloratadine versus cetirizine. 4

Avoid combining first-generation antihistamines at bedtime with second-generation agents in the morning—first-generation agents dosed at bedtime still cause significant daytime drowsiness and performance impairment due to prolonged plasma half-lives. 1

Be cautious with standard doses of loratadine or desloratadine in low body mass patients who may experience sedation due to higher relative dosing. 4