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CHAPTER 22 Sedative-Hypnotic Drugs 389

Benzodiazepines—including diazepam, lorazepam, and Tolerance: Psychological &
midazolam—are used intravenously in anesthesia (see Chapter 25), Physiologic Dependence
often in combination with other agents. Not surprisingly, benzodi-
azepines given in large doses as adjuncts to general anesthetics may Tolerance—decreased responsiveness to a drug following repeated
contribute to a persistent postanesthetic respiratory depression. This exposure—is a common feature of sedative-hypnotic use. It may
is probably related to their relatively long half-lives and the forma- result in the need for an increase in the dose required to maintain
tion of active metabolites. However, such depressant actions of the symptomatic improvement or to promote sleep. It is important to
benzodiazepines are usually reversible with flumazenil. recognize that partial cross-tolerance occurs between the sedative-
hypnotics described here and also with ethanol (see Chapter 23)—a
4. Anticonvulsant effects—Most sedative-hypnotics are capa- feature of some clinical importance, as explained below. The mecha-
ble of inhibiting the development and spread of epileptiform nisms responsible for tolerance to sedative-hypnotics are not well
electrical activity in the CNS. Some selectivity exists in that some understood. An increase in the rate of drug metabolism (metabolic
members of the group can exert anticonvulsant effects with- tolerance) may be partly responsible in the case of chronic admin-
out marked CNS depression (although psychomotor function istration of barbiturates, but changes in responsiveness of the CNS
may be impaired). Several benzodiazepines—including clonaz- (pharmacodynamic tolerance) are of greater importance for most
epam, nitrazepam, lorazepam, and diazepam—are sufficiently sedative-hypnotics. In the case of benzodiazepines, the development
selective to be clinically useful in the management of seizures (see of tolerance in animals has been associated with down-regulation
Chapter 24). Of the barbiturates, phenobarbital and metharbital of brain benzodiazepine receptors. Tolerance has been reported
(converted to phenobarbital in the body) are effective in the treat- to occur with the extended use of zolpidem. Minimal tolerance was
ment of generalized tonic-clonic seizures, though not the drugs observed with the use of zaleplon over a 5-week period and eszopi-
of first choice. However, zolpidem, zaleplon, and eszopiclone clone over a 6-month period.
lack anticonvulsant activity, presumably because of their more The perceived relief of anxiety, euphoria, disinhibition, and
selective binding than that of benzodiazepines to GABA receptor promotion of sleep have led to the compulsive misuse of virtually
A
isoforms. all sedative-hypnotics by vulnerable individuals. (See Chapter 32
for a detailed discussion.) For this reason, most sedative-hyp-
5. Muscle relaxation—Certain drugs in the sedative-hypnotic notic drugs are classified as Schedule III or Schedule IV drugs for
class, particularly members of the carbamate (eg, meprobamate) prescribing purposes. The consequences of abuse of these agents
and benzodiazepine groups, exert inhibitory effects on polysyn- can be defined in both psychological and physiologic terms. The
aptic reflexes and internuncial transmission and at high doses psychological component may initially parallel simple neurotic
may also depress transmission at the skeletal neuromuscular junc- behavior patterns difficult to differentiate from those of the
tion. Somewhat selective actions of this type that lead to muscle inveterate coffee drinker or cigarette smoker. When the pattern
relaxation can be readily demonstrated in animals and have led to of sedative-hypnotic use becomes compulsive, more serious
claims of usefulness for relaxing contracted voluntary muscle in complications develop, including physiologic dependence and
muscle spasm (see Clinical Pharmacology of Sedative-Hypnotics). tolerance.
Muscle relaxation is not a characteristic action of zolpidem, Physiologic dependence can be described as an altered
zaleplon, and eszopiclone. physiologic state that requires continuous drug administra-
tion to prevent an abstinence or withdrawal syndrome. In the
6. Effects on respiration and cardiovascular function— case of sedative-hypnotics, this syndrome is characterized by
At hypnotic doses in healthy patients, the effects of sedative- states of increased anxiety, insomnia, and CNS excitability
hypnotics on respiration are comparable to changes during natural that may progress to convulsions. Most sedative-hypnotics—
sleep. However, even at therapeutic doses, sedative-hypnotics can including benzodiazepines—are capable of causing physiologic
produce significant respiratory depression in patients with pulmo- dependence when used on a long-term basis. However, the
nary disease. Effects on respiration are dose-related, and depres- severity of withdrawal symptoms differs among individual
sion of the medullary respiratory center is the usual cause of death drugs and depends also on the magnitude of the dose used
due to overdose of sedative-hypnotics. immediately before cessation of use. When higher doses of
At doses up to those causing hypnosis, no significant effects sedative-hypnotics are used, abrupt withdrawal leads to more
on the cardiovascular system are observed in healthy patients. serious withdrawal signs. Differences in the severity of with-
However, in hypovolemic states, heart failure, and other diseases drawal symptoms resulting from individual sedative-hypnotics
that impair cardiovascular function, normal doses of sedative- relate in part to half-life, since drugs with long half-lives are
hypnotics may cause cardiovascular depression, probably as a eliminated slowly enough to accomplish gradual withdrawal
result of actions on the medullary vasomotor centers. At toxic with few physical symptoms. The use of drugs with very short
doses, myocardial contractility and vascular tone may both be half-lives for hypnotic effects may lead to signs of withdrawal
depressed by central and peripheral effects, possibly via facilita- even between doses. For example, triazolam, a benzodiazepine
tion of the actions of adenosine, leading to circulatory collapse. with a half-life of about 4 hours, has been reported to cause
Respiratory and cardiovascular effects are more marked when daytime anxiety when used to treat sleep disorders. The abrupt
sedative-hypnotics are given intravenously. cessation of zolpidem, zaleplon, or eszopiclone may also result