Snyder S H, Snowman A M
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Ann Allergy. 1987 Dec;59(6 Pt 2):4-8.
First-generation H1-antagonist antihistamines such as hydroxyzine have a significant ability to cross the blood-brain barrier and cause sedation, which limits their usefulness in the treatment of allergic disorders. Cetirizine, a carboxylated metabolite of hydroxyzine, possesses the parent compound's antihistaminic activity but does not cause sedation. This lack of CNS effects may be due to cetirizine's greater selectivity or potency at H1 receptors in the brain, compared with its effects at the receptors involved in sedation, or it may result from the agent's relative exclusion from the CNS compartment. We compared cetirizine's activity at central H1 sites with the activity of hydroxyzine and terfenadine. We also compared the abilities of cetirizine and three other antihistamines to cross the blood-brain barrier. We found the drugs' potency at H1 receptors in the CNS to be similar to their activities in other tissues. However, their selectivity varied widely. Cetirizine, in fact, failed to bind at any of the receptors investigated except H1 sites, even at concentrations as high as 10 micron. Both hydroxyzine and D-chlorpheniramine crossed the blood-brain barrier in significant amounts. Terfenadine did so to a much lesser extent, and cetirizine passed into the CNS only half as readily as terfenadine. We suggest that cetirizine's reduced incidence of sedative side effects may stem partly from its selectivity for H1 receptors over sites involved in sedation, and partly from its relative exclusion from the CNS.
第一代H1受体拮抗剂类抗组胺药，如羟嗪，具有显著的穿越血脑屏障并引起镇静的能力，这限制了它们在治疗过敏性疾病中的效用。西替利嗪是羟嗪的一种羧化代谢产物，具有母体化合物的抗组胺活性，但不会引起镇静。缺乏中枢神经系统效应可能是由于西替利嗪在大脑中对H1受体的选择性更高或效力更强，相比于其对参与镇静的受体的作用，或者可能是由于该药物相对难以进入中枢神经系统。我们比较了西替利嗪在中枢H1位点的活性与羟嗪和特非那定的活性。我们还比较了西替利嗪和其他三种抗组胺药穿越血脑屏障的能力。我们发现这些药物在中枢神经系统H1受体上的效力与其在其他组织中的活性相似。然而，它们的选择性差异很大。事实上，西替利嗪除了在H1位点外，在任何所研究的受体上都未能结合，即使在浓度高达10微米时也是如此。羟嗪和右旋氯苯那敏都能大量穿越血脑屏障。特非那定穿越血脑屏障的程度要小得多，而西替利嗪进入中枢神经系统的难易程度仅为特非那定的一半。我们认为，西替利嗪镇静副作用发生率较低可能部分源于其对H1受体相对于参与镇静的位点的选择性，部分源于其相对难以进入中枢神经系统。
