Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, NC 27710, USA.
Sleep Med Rev. 2013 Aug;17(4):263-72. doi: 10.1016/j.smrv.2012.08.001. Epub 2013 Jan 26.
The pharmacologic management of insomnia has long been dominated by agents that facilitate gamma amino butyric acid inhibition. These agents have served as the clinical model for understanding the pharmacodynamic effects of insomnia agents according to which sleep effects parallel plasma drug levels (pharmacokinetic effects). Agents with other mechanisms also exist for treating insomnia; however, their effects are less well understood. Many of these diminish the activity in one or more of the key wake-promoting systems. This review focuses on one such mechanism, blockade of the wake promoting effects of histamine via H1 receptor antagonism. Although drugs with H1 antagonist effects have long been available, this review was prompted by new studies of a selective H1 antagonist, which provide the first indication of the effects that are specifically associated with H1 antagonism. The findings do not conform to our long-standing model of insomnia agents in that factors other than drug blood level are needed to explain the clinical effects. We suggest a model for understanding these unique effects based on a review of the basic neurobiology of the histamine system. In addition to drug blood level, clinical effects reflect circadian variation in activity in the histamine system and other parallel wake promoting systems as well as factors such as pain and stress. We hypothesize that significant sleep enhancing effects are likely when the histamine system is relatively active and the activity in other parallel wake promoting systems is relatively minimal. Although the focus of this review is on the novel properties of H1 antagonism, the principles that emerge from this analysis are most likely relevant to all agents that selectively block wake promoting systems, and as such, this review provides a new paradigm for understanding the effects of insomnia medications.
长期以来，失眠的药物治疗一直以促进γ-氨基丁酸抑制的药物为主。这些药物一直是根据失眠药物的药效动力学效应来理解临床模型的，根据该模型，睡眠效应与血浆药物水平（药代动力学效应）平行。也存在用于治疗失眠的其他机制的药物；然而，它们的作用不太为人理解。许多这些药物都能降低一个或多个关键觉醒促进系统的活性。这篇综述重点介绍了一种这样的机制，即通过 H1 受体拮抗作用阻断组胺对觉醒的促进作用。尽管具有 H1 拮抗作用的药物早已存在，但这篇综述是由一项新的选择性 H1 拮抗剂研究引发的，该研究首次提供了与 H1 拮抗作用特异性相关的作用的迹象。这些发现不符合我们长期以来的失眠药物模型，因为除了药物血药水平外，还需要其他因素来解释临床效果。我们根据组胺系统的基本神经生物学综述，提出了一种理解这些独特作用的模型。除了药物血药水平外，临床效果还反映了组胺系统和其他平行觉醒促进系统的昼夜变化，以及疼痛和压力等因素。我们假设，当组胺系统相对活跃且其他平行觉醒促进系统的活性相对较小时，睡眠增强作用很可能显著。虽然这篇综述的重点是 H1 拮抗作用的新特性，但从这种分析中得出的原则很可能与选择性阻断觉醒促进系统的所有药物都相关，因此，这篇综述为理解失眠药物的作用提供了一个新的范例。
