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Antihistamines: Are Newer Drugs Always a Better Choice?

  • Authors: Authors: Bruce Bender, PhD; Henry Milgrom, MD
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Target Audience and Goal Statement

This activity is intended for physicians working in the primary care arena.

The goal of this activity is to review the most recent data related to the side effects of first-generation antihistamines and to identify the optimal uses for this category of medications.

Upon completion of this activity, participants will be able to:

  1. Review the mechanisms of action of first-generation antihistamines and the indications for use.
  2. Describe recent literature related to the side effects associated with first-generation antihistamines and discuss these findings in comparison with the side effects of second-generation antihistamines.
  3. Describe the recommended approach to using first-generation antihistamines.

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Antihistamines: Are Newer Drugs Always a Better Choice?


Sedation Levels Associated With First- and Second-Generation Antihistamines

Since histamine itself can induce arousal and alertness, an excess of antihistamine can produce sleepiness, if the drug crosses the blood-brain barrier. By interacting with midbrain H1-receptors, antihistamines can produce sleepiness and impair psychomotor and cognitive function.[3]

During the last 2 decades, pharmaceutical companies have developed new antihistamines in an attempt to provide the efficacy of earlier compounds but without the sedating properties. These newer medications were synthesized to be less lipophilic in order not to cross the blood-brain barrier and therefore not gain access to H1-receptors in the brain; however, they would still have access to peripheral H1-receptors, allowing targeting of symptoms.[3,10]

In general, studies of the new generation of drugs show a weaker sedative effect when compared with the first-generation drugs.[2-5] However, the second-generation drugs, often called nonsedating antihistamines, can also induce sedation.[2,5,15,16] As noted by Shamsi and Hindmarch,[2] "...most [antihistamines] possess some sedative properties at some point in the dose ranges investigated." Many antihistamines have a "dose window" in which they are nonsedating, but administration at higher doses has a negative impact on cognitive and psychomotor ability. For example, the second-generation drugs loratadine and cetirizine induce negligible sedation at their prescribed clinical dose of 10 mg, yet higher doses have resulted in impairment.[2,10]

In a meta-analysis of 18 studies carefully selected from a MEDLINE database, Bender and colleagues[5] examined the sedating and performance-impairing effects of diphenhydramine relative to placebo and second-generation antihistamines. The findings were mixed, with no clear, consistent advantage seen for second-generation compounds. All of the studies analyzed focused on atopic disease and included control subjects. They were written in English, were randomized and blinded, objectively examined alertness and psychomotor performance, and reported means and variances.

When compared with either placebo or second-generation antihistamines (including acrivastine, astemizole, cetirizine, fexofenadine, loratadine, or terfenadine), data showed that diphenhydramine impaired performance. However, results varied; diphenhydramine showed only a modest sedating effect on average; in some instances, performance testing of the diphenhydramine group showed a stronger performance than demonstrated by the control or second-generation antihistamine control groups.

Diphenhydramine is one of the most commonly used verum control drugs in antihistamine clinical studies.[17] Given the large volume of data concerning diphenhydramine use, one would expect that if diphenhydramine produces a consistent, measurable, sedating effect, this would be readily revealed by an examination of 18 randomized, well-controlled studies that included objective measurements and a modicum of statistical analysis. Instead, the researchers conducting this analysis found only a modest sedative effect from diphenhydramine. This was despite the prevalence of 50-mg dosing in 15 of the 18 studies when a 25-mg dose might have been adequate to relieve symptoms.

In the analysis by Bender and colleagues, none of the second-generation antihistamines produced performances that were consistently superior to the performance of either placebo or diphenhydramine.[5,18] In addition, although diphenhydramine showed larger sedative effects overall, second-generation drugs also were sedating, albeit to a lesser extent than diphenhydramine. Thus, although second-generation antihistamines represent an advance in antihistamine development, they can also cause sedation. Furthermore, for the treatment of allergic rhinitis, some level of sedative effect may be tolerable, given the fact that the condition itself induces fatigue and pain.[9]

A third generation of antihistamines is emerging, composed of the nonsedating metabolites fexofenadine and desloratadine. In one analysis, fexofenadine received a performance impairment ratio of 0.00 compared with 0.92 for cetirizine and 1.94 for loratadine.[3] The sedation effects related to desloratadine have been less thoroughly investigated than those of fexofenadine, although early findings suggest that this antihistamine also may be relatively free of sedative effects.