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INTRODUCTION

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The CNS depressants discussed in this chapter include benzodiazepines, other benzodiazepine receptor agonists (the "Z compounds"), barbiturates, and sedative-hypnotic agents of diverse chemical structure. Older sedative-hypnotic drugs depress the CNS in a dose-dependent fashion, progressively producing a spectrum of responses from mild sedation to coma and death. A sedative drug decreases activity, moderates excitement, and calms the recipient, whereas a hypnotic drug produces drowsiness and facilitates the onset and maintenance of a state of sleep that resembles natural sleep in its electroencephalographic characteristics and from which the recipient can be aroused easily.

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Sedation is a side effect of many drugs that are not general CNS depressants (e.g., antihistamines and antipsychotic agents). Although such agents can intensify the effects of CNS depressants, they usually produce more specific therapeutic effects at concentrations far lower than those causing substantial CNS depression. The benzodiazepine sedative-hypnotics resemble such agents; although coma may occur at very high doses, neither surgical anesthesia nor fatal intoxication is produced by benzodiazepines in the absence of other drugs with CNS-depressant actions; an important exception is midazolam, which has been associated with decreased tidal volume and respiratory rate. Moreover, specific antagonists of benzodiazepines exist. This constellation of properties sets the benzodiazepine receptor agonists apart from other sedative-hypnotic drugs and imparts a measure of safety such that benzodiazepines and the newer Z compounds have largely displaced older agents for the treatment of insomnia and anxiety.

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The sedative-hypnotic drugs that do not specifically target the benzodiazepine receptor belong to a group of agents that depress the CNS in a dose-dependent fashion, progressively producing calming or drowsiness (sedation), sleep (pharmacological hypnosis), unconsciousness, coma, surgical anesthesia, and fatal depression of respiration and cardiovascular regulation. They share these properties with a large number of chemicals, including general anesthetics (see Chapter 19) and alcohols, most notably ethanol (see Chapter 23).

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BENZODIAZEPINES

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All benzodiazepines in clinical use promote the binding of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) to the GABAA receptor, a multi-subunit, ligand-gated chloride channel. GABA binding induces the Cl current through these channels (see Figure 14-6).

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Pharmacological data suggest heterogeneity among sites of binding and action of benzodiazepines; different subunit combinations comprise the GABA-gated chloride channels expressed in different neurons. Receptor subunit composition appears to govern the interaction of various allosteric modulators with these channels, giving hope to efforts to find agents displaying different combinations of benzodiazepine-like properties that reflect selective actions on 1 or more subtypes of GABAA receptors. A number of distinct mechanisms of action are thought to contribute to the sedative-hypnotic, muscle-relaxant, anxiolytic, and anticonvulsant effects of the benzodiazepines, and specific subunits of the GABAA receptor are responsible for specific pharmacological properties of benzodiazepines. While only the benzodiazepines used primarily for hypnosis are discussed in detail, this chapter describes the general properties of the group and important differences among individual agents ...

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