First-Generation Antihistamines: Examples and Characteristics
First-generation antihistamines include diphenhydramine, hydroxyzine, chlorpheniramine, brompheniramine, clemastine, and cyproheptadine. 1
Commonly Used First-Generation Agents
Most Frequently Prescribed
- Diphenhydramine (Benadryl): Available in 25 mg and 50 mg tablets, dosed at 25-50 mg four times daily in adults, with a half-life of 2.6-4.3 hours and a 50% sedation rate 1
- Chlorpheniramine (Chlor-Trimeton): Available in 4 mg, 8 mg, and 12 mg formulations, dosed at 4 mg four times daily, with a half-life of 12-24 hours and approximately 45% sedation rate 1
- Hydroxyzine (Atarax): Dosed in adults with a half-life of approximately 20 hours and an 80% sedation rate 1
Additional First-Generation Options
- Brompheniramine (Dimetapp): Available as 12 mg tablets and 1 mg/5 mL liquid, dosed 1-2 times twice daily, with a half-life of 24.9 hours 1, 2
- Clemastine (Tavist): Available in 1.34 mg and 2.68 mg tablets, dosed twice to three times daily, with a half-life of 21.3 hours and a 14% sedation rate 1
- Cyproheptadine (Periactin): Available as 4 mg tablets and 2 mg/5 mL liquid, dosed at 4 mg three times daily, with a half-life of 16 hours 1
Critical Safety Considerations
Why These Agents Are Generally Not Recommended
Second-generation antihistamines are strongly preferred over first-generation agents for treating allergic conditions due to their superior safety profile. 1, 3
- Drivers taking first-generation antihistamines are 1.5 times more likely to be responsible for fatal automobile accidents compared to non-users 1, 3
- Performance impairment occurs even without subjective awareness of drowsiness, affecting work productivity and increasing occupational accidents 1
- Impaired learning and decreased school performance occur in children taking these medications 1, 3
- Bedtime-only dosing does not eliminate daytime sedation due to prolonged plasma half-lives and persistent end-organ effects 1
Anticholinergic Effects
- Dry mouth and eyes, constipation, urinary retention, and increased risk of narrow-angle glaucoma occur with all first-generation agents 1
- Older adults are at particularly high risk for cognitive impairment, falls, fractures, and subdural hematomas 1, 3
- Cognitive decline is especially concerning in elderly populations with repeated use 1
Drug Interactions
- Concomitant use with alcohol, sedatives, hypnotics, or antidepressants significantly enhances performance impairment 1
- Cellular phone use while taking hydroxyzine further worsens driving performance 1
Special Clinical Applications
Despite their limitations, first-generation antihistamines have specific roles:
- Cyproheptadine has dual H1-blocking and antiserotonergic activity, making it useful for diarrhea and nausea in mast cell activation syndrome 1
- The anticholinergic properties may provide better control of rhinorrhea compared to second-generation agents in select patients 1
- Ketotifen, though sedating, is used for dermatologic, gastrointestinal, and neuropsychiatric symptoms when compounded 1
Patient Counseling Requirements
Before prescribing any first-generation antihistamine, physicians must ensure patients understand both the potential for adverse effects and the availability of safer second-generation alternatives. 1