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. Sedation is a side effect of many drugs that are not considered general CNS depressants (e.g., antihistamines and antipsychotic agents). Although these and other agents can intensify the effects of CNS depressants, they usually produce their desired therapeutic effects at concentrations lower than those causing substantial CNS depression. For example, benzodiazepine sedative-hypnotics do not produce generalized CNS depression. Although coma may occur at very high doses, neither surgical anesthesia nor fatal intoxication is produced by benzodiazepines unless other drugs with CNS-depressant actions are concomitantly administered; an important exception is midazolam, which has been associated with decreased tidal volume and respiratory rate. Moreover, specific antagonists of benzodiazepines exist, such as flumazenil, which is used to treat cases of benzodiazepine overdose. 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 benzodiazepine receptor agonists (the “Z compounds”) have largely displaced older agents for the treatment of insomnia and anxiety.
The CNS depressants discussed in this chapter include benzodiazepines, the Z compounds, barbiturates, as well as several sedative-hypnotic agents of diverse chemical structure. The sedative-hypnotic drugs that do not specifically target the benzodiazepine receptor belong to a group of older, less-safe, sedative-hypnotic drugs that depress the CNS in a dose-dependent fashion, progressively producing a spectrum of responses from mild sedation to coma and death. These older sedative-hypnotic compounds share these properties with a large number of chemicals, including general anesthetics (see Chapter 21) and alcohols, most notably ethanol (see Chapter 23). The newer sedative-hypnotic agents, such as benzodiazepines and Z drugs, are safer in this regard.
Humans have long sought sleep unburdened by worry and, to this end, have consumed many potions. In the mid-19th century, bromide was introduced specifically as a sedative-hypnotic. Chloral hydrate, paraldehyde, urethane, and sulfonal were used before the introduction of barbiturates (barbital, 1903; phenobarbital, 1912), of which about 50 were distributed commercially. Barbiturates were so dominant that fewer than a dozen other sedative-hypnotics were marketed successfully before 1960.
The partial separation of sedative-hypnotic-anesthetic properties from anticonvulsant properties characteristic of phenobarbital led to searches for agents with more selective effects on CNS functions. As a result, relatively nonsedating anticonvulsants, notably phenytoin and trimethadione, were developed in the late 1930s and early 1940s (Chapter 17). The advent of chlorpromazine and meprobamate in the early 1950s, with their taming effects in animals, and the development of increasingly sophisticated methods for evaluating the behavioral effects of drugs, set the stage in the 1950s for the synthesis of chlordiazepoxide, the introduction of which into clinical medicine in 1961 ushered ...