What are the currently used 1st generation antihistaminics (first generation antihistamines) and their indications?

Currently Used First-Generation Antihistamines and Their Indications

First-generation antihistamines remain available for treating allergic rhinitis, urticaria, and rhinorrhea, but their use should be limited due to significant safety concerns including sedation, cognitive impairment, and increased accident risk—second-generation agents are safer alternatives for most indications. 1, 2

Available First-Generation Agents

The following first-generation antihistamines are currently used in clinical practice:

Diphenhydramine (Benadryl)

• Dosing: 25-50 mg four times daily in adults (available as 25 mg and 50 mg tablets, 12.5 mg/mL liquid) 1, 2
• Half-life: 2.6-4.3 hours 1, 2
• Sedation rate: 50% 1, 2
• Age restriction: ≥2 years 1

Chlorpheniramine (Chlor-Trimeton)

• Dosing: 4 mg four times daily (available as 4 mg, 8 mg, 12 mg tablets and 2 mg/5 mL liquid) 1, 2
• Half-life: 12-24 hours 1, 2
• Sedation rate: 45% 1, 2
• Age restriction: ≥2 years 1

Hydroxyzine (Atarax)

• Dosing: 25 mg four times daily (available as 10,25,50,100 mg tablets and 10 mg/5 mL liquid) 1, 2
• Half-life: ~20 hours 1, 2
• Sedation rate: 80% 1, 2
• Age restriction: All ages 1

Brompheniramine (Dimetapp)

• Dosing: 12 mg once or twice daily (available as 12 mg tablets and 1 mg/5 mL liquid) 1
• Half-life: ~24.9 hours 1
• Age restriction: ≥2 years 1

Clemastine (Tavist)

• Dosing: 1.34 mg twice to three times daily (available as 1.34 mg and 2.68 mg tablets, 0.67 mg/5 mL liquid) 1, 2
• Half-life: 21.3 hours 1, 2
• Sedation rate: 14% 1, 2
• Age restriction: ≥6 years 1

Cyproheptadine (Periactin)

• Dosing: 4 mg three times daily (available as 4 mg tablets and 2 mg/5 mL liquid) 1, 2
• Half-life: 16 hours 1, 2
• Age restriction: ≥2 years 1

Promethazine (Phenergan)

• Dosing: Variable based on indication (available as 12.5,25,50 mg tablets) 1
• Sedation rate: 60-73% 1
• Age restriction: ≥2 years 1
• Special warning: Contraindicated in children <2 years due to respiratory depression risk 3

Clinical Indications

Primary Indications

• Allergic rhinitis (seasonal and perennial): All first-generation agents are effective but less preferred than second-generation alternatives 1, 4
• Urticaria (acute and chronic): Effective for symptom relief 5, 4
• Rhinorrhea control: The anticholinergic properties may provide superior control of rhinorrhea compared to second-generation agents, particularly in nonallergic rhinitis syndromes 1
• Vasomotor rhinitis: Effective for this specific form of nonallergic rhinitis 1
• Gustatory rhinitis: Special role in preventing rhinorrhea 1

Special Applications

• Cyproheptadine: Dual H1-blocking and antiserotonergic activity makes it useful for diarrhea and nausea in mast cell activation syndrome 2
• Adjunct to narcotic analgesics during labor: Promethazine may be used, though limited data suggest minimal effect on labor duration 3

Critical Safety Concerns That Limit Use

Central Nervous System Effects

• Driving impairment: Patients taking first-generation antihistamines are 1.5 times more likely to be responsible for fatal automobile accidents compared to non-users 2
• Performance impairment occurs without subjective awareness of drowsiness, affecting work productivity and increasing occupational accidents 1, 2
• Impaired learning and decreased school performance in children 1, 2
• Bedtime-only dosing does NOT eliminate daytime sedation due to prolonged plasma half-lives and persistent end-organ effects 1, 2

Anticholinergic Effects

• Dry mouth and eyes, constipation, urinary retention, and increased risk of narrow-angle glaucoma occur with all first-generation agents 1, 2
• Older adults are at particularly high risk for cognitive impairment, falls, fractures, and subdural hematomas 2
• Patients with prostatic hypertrophy, elevated intraocular pressure, or pre-existing cognitive impairment are at highest risk 1

Drug Interactions

• Concomitant use with alcohol, sedatives, hypnotics, narcotics, or antidepressants significantly enhances performance impairment 1, 2, 3
• Promethazine specifically requires dose reduction of barbiturates by at least one-half and narcotics by one-quarter to one-half when used concomitantly 3

Clinical Decision-Making Algorithm

When first-generation antihistamines might be considered:

• Rhinorrhea is the predominant symptom unresponsive to second-generation agents 1
• Cyproheptadine specifically for mast cell activation syndrome symptoms 2
• Cost is a significant barrier (first-generation agents cost ~$0.37 per dose vs. $0.52-2.39 for newer agents) 6

Absolute contraindications:

• Children <2 years of age (all first-generation agents) 1, 3
• Patients who drive or operate machinery 2
• Elderly patients with cognitive impairment or fall risk 2
• Concurrent use of CNS depressants unless doses are appropriately reduced 3

Preferred alternative: Second-generation antihistamines (cetirizine, fexofenadine, loratadine, desloratadine) provide similar efficacy with significantly less sedation and no cognitive impairment 6, 7, 8, 4

Essential Patient Counseling

Before prescribing any first-generation antihistamine, ensure patients understand:

• The potential for sedation and cognitive impairment even without feeling drowsy 2
• The availability of safer second-generation alternatives 2
• Absolute prohibition of driving, operating machinery, or supervising children during treatment 2, 3
• Avoidance of alcohol and other CNS depressants 3
• Increased risk in elderly patients for confusion, falls, and cognitive decline 2, 3