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Chapter 42. Sedative-Hypnotics

Seiji Nishino, M.D., Ph.D.; Kazuo Mishima, M.D., Ph.D.; Emmanuel Mignot, M.D., Ph.D.; William C. Dement, M.D., Ph.D.
DOI: 10.1176/appi.books.9781585623860.421159

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In this chapter, we examine some of the pharmacological properties of benzodiazepines, barbiturates, and other sedative-hypnotic compounds. Sedative drugs moderate excitement, decrease activity, and induce calmness, whereas hypnotic drugs produce drowsiness and facilitate the onset and maintenance of a state that resembles normal sleep in its electroencephalographic characteristics. Although these agents are central nervous system (CNS) depressants, they usually produce therapeutic effects at doses that are far lower than those that cause coma and generalized depression of the CNS.

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FIGURE 42–1. Chemical structures of some commonly used benzodiazepines.

FIGURE 42–2. The GABAA–benzodiazepine receptor complex.(A) Schematic model of the mammalian -aminobutyric acid type A (GABAA) receptor embedded in the cell membrane, representatively possessing the , , and subunits (2:2:1). The binding of two molecules of GABA to the action site composed of and subunits causes the opening of the chloride channel pore, and the chloride ions diffuse into the cell. Each subunit comprises four transmembrane domains (TM1–TM4). The ion channel pore consists of TM2 of five subunits with a rosette formation. (B) Structure of the 1 subunit, with amino acid sequence, indicating amino acid residues implicated in GABA and benzodiazepine binding domains.Source. Modified from Ueno et al. 2001.

FIGURE 42–3. Three nonbenzodiazepine hypnotics—zolpidem (an imidazopyridine), zopiclone (a cyclopyrrolone), and zaleplon (a pyrazolopyrimidine)—have been shown to be useful sedative-hypnotics with benzodiazepine-like profiles.

FIGURE 42–4. Properties of the various types of benzodiazepine receptor ligands.GABA = -aminobutyric acid.

FIGURE 42–5. Metabolic pathways for the principal 1,4-benzodiazepines.Solid and broken arrows denote major and minor pathways, respectively; commercially available drugs are underscored. Flurazepam, flunitrazepam, nitrazepam, and triazolam have separate metabolic pathways.

FIGURE 42–6. Duration of action of hypnotics and hangover and rebound insomnia.Hypnotics with long half-lives may impair daytime performance the day after drug administration, whereas short-acting compounds may induce rebound insomnia on discontinuation.

FIGURE 42–7. Structure–activity relations among barbiturates.
Table Reference Number
TABLE 42–1. Comparative properties of benzodiazepines and barbiturates on sleep parameters
Table Reference Number
TABLE 42–2. Pharmacokinetic properties of the most commonly used (in the United States) hypnotic compounds acting on the benzodiazepine receptors
Table Reference Number
TABLE 42–3. Nosological classification of insomnia (International Classification of Sleep Disorders diagnostic criteria)

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Which of the following benzodiazepines has a particularly short half-life and the shortest half-life among the agents shown?
2.
Benzodiazepines affect sleep architecture in which of the following ways?
3.
Which of the following nonbenzodiazepines has the longest half-life and may be especially useful for patients who have early morning awakening?
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