Snowman A M, Snyder S H
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2105.
J Allergy Clin Immunol. 1990 Dec;86(6 Pt 2):1025-8. doi: 10.1016/s0091-6749(05)80248-9.
First-generation H1-antagonist antihistamines, such as hydroxyzine, have the 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 causes less sedation. We compared the activity of cetirizine at central H1 sites with that of hydroxyzine and terfenadine. We also compared the ability of cetirizine and three antihistamines to cross the blood-brain barrier. In each case we found that the drug's potency at H1 receptors in the central nervous system was similar to its activity in displacing H1 receptors in the lung. However, the selectivity for H1 receptors varied widely from drug to drug. Cetirizine did not bind at any of the receptors investigated, except H1 sites, even at concentrations as high as 10 mumol/L. Hydroxyzine and dexchlorpheniramine and, to a lesser extent, terfenadine crossed the blood-brain barrier in significant amounts. Cetirizine passed into the central nervous system only half as readily as terfenadine. These findings suggest that cetirizine's low incidence of sedative effects is most likely caused by its diminished potential to cross the blood-brain barrier and also may be partly the result of its greater selectivity for H1 receptors, compared with its effect at other receptors that may be involved in sedation.
第一代H1拮抗剂类抗组胺药，如羟嗪，能够穿过血脑屏障并引起镇静作用，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，但引起的镇静作用较小。我们比较了西替利嗪在中枢H1位点与羟嗪和特非那定的活性。我们还比较了西替利嗪和三种抗组胺药穿过血脑屏障的能力。在每种情况下，我们发现该药物在中枢神经系统中H1受体的效力与其在肺中置换H1受体的活性相似。然而，对H1受体的选择性因药物而异。西替利嗪在高达10 μmol/L的浓度下，除了H1位点外，在任何所研究的受体上均未结合。羟嗪和右氯苯那敏，以及在较小程度上特非那定，大量穿过血脑屏障。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。这些发现表明，西替利嗪镇静作用发生率低很可能是由于其穿过血脑屏障的潜力降低，并且也可能部分是由于与可能参与镇静作用的其他受体相比，它对H1受体具有更高的选择性。
