Anesthesia—As shown in Figure 22–1, high doses of certain sedative-hypnotics depress the CNS to the point known as stage III of general anesthesia (see Chapter 25). However, the suitability of a particular agent as an adjunct in anesthesia depends mainly on the physicochemical properties that determine its rapidity of onset and duration of effect. Among the barbiturates, thiopental and methohexital are very lipid-soluble, penetrating brain tissue rapidly following intravenous administration, a characteristic favoring their use for the induction of anesthesia. Rapid tissue redistribution (not rapid elimination) accounts for the short duration of action of these drugs, a feature useful in recovery from anesthesia.
Benzodiazepines—including diazepam, lorazepam, and midazolam—are used intravenously in anesthesia (see Chapter 25), often in combination with other agents. Not surprisingly, benzodiazepines given in large doses as adjuncts to general anesthetics may contribute to a persistent postanesthetic respiratory depression. This is probably related to their relatively long half-lives and the formation of active metabolites. However, such depressant actions of the benzodiazepines are usually reversible with flumazenil.
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Anticonvulsant effects—Most sedative-hypnotics are capable of inhibiting the development and spread of epileptiform electrical activity in the CNS. Some selectivity exists in that some members of the group can exert anticonvulsant effects without marked CNS depression (although psychomotor function may be impaired). Several benzodiazepines—including clonazepam, nitrazepam, lorazepam, and diazepam—are sufficiently selective to be clinically useful in the management of seizures (see Chapter 24). Of the barbiturates, phenobarbital and metharbital (converted to phenobarbital in the body) are effective in the treatment of generalized tonic-clonic seizures, though not the drugs of first choice. However, zolpidem, zaleplon, and eszopiclone lack anticonvulsant activity, presumably because of their more selective binding than that of benzodiazepines to GABAA receptor isoforms.
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Muscle relaxation—Certain drugs in the sedative-hypnotic class, particularly members of the carbamate (eg, meprobamate) and benzodiazepine groups, exert inhibitory effects on polysynaptic reflexes and internuncial transmission and at high doses may also depress transmission at the skeletal neuromuscular junction. Somewhat selective actions of this type that lead to muscle relaxation can be readily demonstrated in animals and have led to claims of usefulness for relaxing contracted voluntary muscle in muscle spasm (see Clinical Pharmacology of Sedative-Hypnotics). Muscle relaxation is not a characteristic action of zolpidem, zaleplon, and eszopiclone.
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At hypnotic doses in healthy patients, the effects of sedative-hypnotics on respiration are comparable to changes during natural sleep. However, even at therapeutic doses, sedative-hypnotics can produce significant respiratory depression in patients with pulmonary disease. Effects on respiration are dose-related, and depression of the medullary respiratory center is the usual cause of death due to overdose of sedative-hypnotics.