What is the difference between 1st (first) generation antihistamines and 2nd (second) generation antihistamines in terms of their sedative effects and clinical use?

Differences Between First and Second Generation Antihistamines

Second-generation antihistamines are strongly preferred over first-generation antihistamines due to their superior safety profile, minimal sedation, and lack of anticholinergic effects, with fexofenadine, loratadine, and desloratadine being truly non-sedating options. 1, 2

Central Nervous System Effects and Sedation

First-Generation Antihistamines

• First-generation antihistamines readily cross the blood-brain barrier due to their high lipophilicity, causing significant sedation in 10-25% of users and performance impairment that can occur without subjective awareness of drowsiness. 1, 3
• These agents cause daytime drowsiness, decreased alertness, and impaired performance in school and driving even when taken only at bedtime, due to prolonged plasma half-lives and persistent end-organ effects. 1
• The use of first-generation antihistamines has been directly associated with increased automobile accidents and occupational injuries. 1
• Performance deficits include impaired divided attention, working memory, vigilance, and processing speed. 4

Second-Generation Antihistamines

• Second-generation antihistamines are large, lipophobic molecules with charged side chains that do not significantly cross the blood-brain barrier, resulting in minimal to no sedation. 5, 6, 3
• Fexofenadine maintains complete non-sedating properties even at doses exceeding FDA recommendations, making it the gold standard when sedation must be absolutely avoided. 1, 2, 5
• Loratadine and desloratadine do not cause sedation at recommended doses but may cause sedation at higher-than-recommended doses. 1, 2
• Cetirizine and intranasal azelastine may cause mild sedation at recommended doses (13.7% vs 6.3% placebo for cetirizine). 1, 2

Anticholinergic Effects

First-Generation Antihistamines

• First-generation antihistamines produce significant anticholinergic effects including dry mouth and eyes, constipation, urinary retention, and increased risk of narrow-angle glaucoma. 1
• These anticholinergic properties may explain better control of rhinorrhea compared to second-generation agents, but the risks outweigh this benefit. 1

Second-Generation Antihistamines

• Second-generation antihistamines have minimal to no anticholinergic effects, making them safer for long-term use. 1, 6
• When anticholinergic effects are specifically needed for rhinorrhea, topical ipratropium bromide nasal spray is preferred over systemic first-generation antihistamines. 1

Special Population Considerations

Older Adults

• Older adults are at significantly increased risk for falls, fractures, subdural hematomas, and cognitive impairment from first-generation antihistamines and should avoid them entirely. 1, 2
• Pre-existing conditions such as benign prostatic hypertrophy, elevated intraocular pressure, and cognitive impairment place older adults at even higher risk from anticholinergic effects. 1
• Second-generation antihistamines, particularly fexofenadine, are strongly preferred in this population. 2

Pediatric Patients

• Second-generation antihistamines have been shown to be well-tolerated with good safety profiles in young children. 2, 7
• First-generation antihistamines should be avoided in children under 6 years due to safety concerns. 2
• Many antihistamines are prescribed off-label in children younger than 2 years, where safety data are most lacking. 7

Patients with Low Body Mass

• Standard doses of loratadine or desloratadine may cause sedation in patients with low body mass due to higher relative mg/kg dosing. 1, 2

Receptor Selectivity and Pharmacology

• First-generation antihistamines have poor H1-receptor selectivity and antagonize multiple receptors including muscarinic, alpha-adrenergic, and serotonergic receptors, contributing to their adverse effect profile. 8, 3
• Second-generation antihistamines are highly selective for peripheral H1-receptors with minimal effects on other receptor systems. 6, 8
• Fexofenadine, as documented in FDA labeling, displays no anticholinergic or alpha1-adrenergic blocking effects and does not cross the blood-brain barrier in animal studies. 5

Clinical Implications and Common Pitfalls

• The AM/PM dosing strategy (combining a second-generation agent in the morning with a first-generation agent at bedtime) is not recommended, as first-generation antihistamines dosed at bedtime still cause significant daytime impairment. 1
• Performance impairment from first-generation antihistamines is enhanced by concomitant use of alcohol and other CNS-active substances. 1
• Patients may not subjectively perceive drowsiness despite objective performance impairment, creating a dangerous situation for activities requiring vigilance. 1, 2
• Among second-generation agents, no single agent has been conclusively found to achieve superior overall response rates for allergic rhinitis symptoms. 1