Many agents can depress the function of the central nervous system and produce calming or drowsiness (sedation). 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.
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. For example, they cannot induce surgical anesthesia in the absence of other agents. 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.
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 (Chapter 19) and aliphatic alcohols, most notably ethanol (Chapter 23). Only two landmarks on the continuum of CNS depression produced by increasing concentrations of these agents can be defined with a reasonable degree of precision: surgical anesthesia, a state in which painful stimuli elicit no behavioral or autonomic response (Chapter 19), and death, resulting from sufficient depression of medullary neurons to disrupt coordination of cardiovascular function and respiration. The "end points" at lower concentrations of CNS depressants are defined with less precision—in terms of deficits in cognitive function (including attention to environmental stimuli) or motor skills (e.g., ataxia) or of the intensity of sensory stimuli needed to elicit some reflex or behavioral response. Other important indices of decreased CNS activity, such as analgesia and seizure suppression, do not necessarily fall along this continuum; they may not be present at sub-anesthetic concentrations of a CNS depressant drug (e.g., a barbiturate), or they may be achieved with minimal sedation or other evidence of CNS depression (e.g., with low doses of opioids, phenytoin, or ethosuximide).
Since antiquity, alcoholic beverages and potions containing laudanum and various herbals have been used to induce sleep. In the middle of the nineteenth century, bromide was the first agent to be introduced specifically as a sedative-hypnotic. Chloral hydrate, paraldehyde, urethane, and sulfonal came into use before the introduction of barbital in 1903 and phenobarbital in 1912. Their success spawned the synthesis and testing of >2500 barbiturates, of which ~50 were distributed commercially. The barbiturates were so dominant that less than a dozen other sedative-hypnotics were marketed successfully before 1960.
The partial separation of sedative-hypnotic-anesthetic from anticonvulsant properties embodied in phenobarbital led to searches for agents with more selective effects on CNS functions. As a result, relatively non-sedating anticonvulsants, notably phenytoin and trimethadione, were developed in the late 1930s and early 1940s (Chapter 21). 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 by Sternbach and the discovery of its unique pattern of actions by Randall. The introduction of chlordiazepoxide into clinical medicine in 1961 ushered in the era of benzodiazepines. Most of the benzodiazepines that have reached the marketplace were selected for high anxiolytic potency in relation to their depression of CNS function. However, all benzodiazepines possess sedative-hypnotic properties to varying degrees; these properties are exploited extensively clinically, especially to facilitate sleep. Mainly because of their remarkably low capacity to produce fatal CNS depression, the benzodiazepines have displaced the barbiturates as sedative-hypnotic agents.
All benzodiazepines in clinical use have the capacity to promote the binding of the major inhibitory neurotransmitter γ-aminobutyric acid (GABA) to the GABAA subtype of GABA receptors, which exist as multi-subunit, ligand-gated chloride channels, thereby enhancing the GABA-induced ionic currents through these channels (see Figure 14–11). Pharmacological data suggest heterogeneity among sites of binding and action of benzodiazepines; biochemical and molecular biological investigations reveal the numerous varieties of subunits that make up the GABA-gated chloride channels expressed in different neurons. Since receptor subunit composition appears to govern the interaction of various allosteric modulators with these channels, there has been a surge in efforts to find agents displaying different combinations of benzodiazepine-like properties that may reflect selective actions on one or more subtypes of GABA receptors. These efforts led to the development of zolpidem (AMBIEN), an imidazopyridine, the pyrazolopyrimidines zaleplon (SONATA) and the cyclopyrrolones zopiclone and eszopiclone (LUNESTA); these so-called "Z compounds" all apparently exert sedative-hypnotic effects by interacting with a subset of benzodiazepine binding sites.
Although the benzodiazepines exert qualitatively similar clinical effects, important quantitative differences in their pharmacodynamic spectra and pharmacokinetic properties have led to varying patterns of therapeutic application. ...