Sedation and antihistamines: a review of inter-drug differences using proportional impairment ratios

Abstract

The use of antihistamines (AHs) has until recently been associated with a number of undesirable side effects, the most troublesome of which is sedation. There are two aspects to sedation. The first, an objectively determined measure based on the results of psychometric tests from controlled trials, and the second, the subject's response to the administration of a drug. Since AHs are largely used in ambulant patients, a complete evaluation of sedation should be performed through standardised objective and subjective tests, shown to be sensitive to the central effects of AHs. An extensive review of the literature identified 76 studies of H1 receptor antagonists in healthy volunteers, in which assessment of sedation was the primary objective. Results from studies published in peer‐reviewed journals which employed a placebo condition as well as a positive internal control using a crossover design were analysed to determine the extent to which a particular antihistamine produced impairments on a battery of psychometric tests. The impairment index for each antihistamine was calculated and subsequently compared with the impairment index obtained for all other AHs. The calculation of this proportional impairment ratio enabled the sedative potential of an individual antihistamine to be identified relative to all other AHs and thus allowed the ranking of AHs with respect to their ability to cause impairments of cognitive and psychomotor function. Findings from this review clearly demonstrate that there are distinct classes of AHs with respect to their ability to impair cognitive function and psychomotor performance. Copyright © 2000 John Wiley & Sons, Ltd.

Effects of sedative and nonsedative antihistamines on prefrontal activity during verbal fluency task in young children: a near-infrared spectroscopy (NIRS) study

“…It is well known that some antihistamines such as d-chlorpheniramine and ketotifen exert undesirable side effects including sedation (Yanai and Tashiro 2007), while other antihistamines such as fexofenadine and epinastine can avoid such side effects. There is considerable evidence showing differential sedation effects of antihistamines in adult behavioral performance (Shamsi and Hindmarch 2000;Tashiro et al 2005;Turner et al 2006;Theunissen et al 2006a, c), H 1 receptor occupancy rate (Tashiro et al , 2006Mochizuki et al 2004), and neural correlates of cognitive performance (Mochizuki et al 2002;Theunissen et al 2006b;Tsujii et al 2007). Yet, it remains unknown whether these findings can be extended to behavioral and neural response in young children.…”

A double-blind, placebo- and positive-internal-controlled (alprazolam) investigation of the cognitive and psychomotor profile of pregabalin in healthy volunteers

“…This test battery has been shown to be sensitive to an extensive range of psychotropic substances having very different mechanisms of activity. These include benzodiazepines (Hindmarch et al 1990), anaesthetics (Moss et al 1987) anti-dementia agents (Fairweather et al 1993a), hypnotics (Hindmarch et al 1990), neuroleptics (Hindmarch and Tiplady 1994), antidepressants (Ridout and Hindmarch 2001), antihistamines (Shamsi and Hindmarch 2000), cognitive enhancers (Rigney et al 1999), nicotine (Parkin et al 1998), alcohol (Ridout et al 2003a), and caffeine . While the precise mechanism of pregabalin's pharmacological activity at the neuronal level continues to be elucidated, the use of a validated and sensitive objective test battery assessing a wide range of cognitive and psychomotor skills, together with a selfrating scale (Line Analogue Rating Scales, LARS), allows the pharmacodynamic properties of pregabalin 450 mg/day to be determined.…”

H1 Antihistamines: Current Status and Future Directions

“…Blood-brain barrier penetration is related to their lipophilicity, relatively low molecular weights, and lack of substrate recognition by the P-glycoprotein efflux pump expressed on the luminal surfaces of nonfenestrated endothelial cells in the CNS vasculature. Central nervous system penetration is also documented in randomized controlled studies involving electroencephalographic monitoring, sleep latency measurements, and standardized performance tests ranging from simple reaction time tests to complex sensorimotor tasks, for example, computer-monitored driving [2-4,10,42,43]. …”

“…The second-generation H 1 antihistamines therefore have a low likelihood of causing CNS effects, although some of them, such as cetirizine and loratadine, potentially cause sedation when manufacturers' recommended doses are exceeded. Fexofenadine, in off-label doses up to and including 360 mg daily, is the least sedating of these medications and is therefore considered to be the H 1 antihistamine of choice for airline pilots and people in other safety-critica[2-4,10,42,43]…”