Page 402 - Basic _ Clinical Pharmacology ( PDFDrive )

388 SECTION V Drugs That Act in the Central Nervous System

behavior may be more related to behavioral disinhibitory effects of
The Versatility of the Chloride Channel sedative-hypnotics, including euphoria, impaired judgment, and
GABA Receptor Complex loss of self-control, which can occur at dosages in the range of those
used for management of anxiety. The benzodiazepines also exert
The GABA A -chloride channel macromolecular complex is one dose-dependent anterograde amnestic effects (inability to remember
of the most versatile drug-responsive machines in the body. In events occurring during the drug’s duration of action).
addition to the benzodiazepines, barbiturates, and the newer
hypnotics (eg, zolpidem), many other drugs with central ner- 2. Hypnosis—By definition, all of the sedative-hypnotics induce
vous system effects can modify the function of this important sleep if high enough doses are given. The effects of sedative-
ionotropic receptor. These include alcohol and certain intra- hypnotics on the stages of sleep depend on several factors, including
venous anesthetics (etomidate, propofol) in addition to thio- the specific drug, the dose, and the frequency of its administration.
pental. For example, etomidate and propofol (see Chapter 25) The general effects of benzodiazepines and older sedative-hypnotics
appear to act selectively at GABA A receptors that contain α2 on patterns of normal sleep are as follows: (1) the latency of sleep
and α3 subunits, the latter suggested to be the most impor- onset is decreased (time to fall asleep); (2) the duration of stage 2
tant with respect to the hypnotic and muscle-relaxing actions NREM (non-rapid eye movement) sleep is increased; (3) the dura-
of these anesthetic agents. The anesthetic steroid alphaxalone tion of REM (rapid eye movement) sleep is decreased; and (4) the
is thought to interact with GABA A receptors, and they may duration of stage 4 NREM slow-wave sleep is decreased. The newer
also be targets for some of the actions of volatile anesthetics hypnotics all decrease the latency to persistent sleep. Zolpidem
(eg, halothane). Most of these agents facilitate or mimic the decreases REM sleep but has minimal effect on slow-wave sleep.
action of GABA. However, it has not been shown that all these Zaleplon decreases the latency of sleep onset with little effect on
drugs act exclusively by this mechanism. Other drugs used total sleep time, NREM, or REM sleep. Eszopiclone increases total
in the management of seizure disorders indirectly influence sleep time, mainly via increases in stage 2 NREM sleep, and at low
the activity of the GABA A -chloride channel macromolecular doses has little effect on sleep patterns. At the highest recommended
complex by inhibiting GABA metabolism (eg, vigabatrin) or the dose, eszopiclone decreases REM sleep. Suvorexant decreases time
reuptake of the transmitter (eg, tiagabine). Central nervous sys- to persistent sleep and increases total sleep time.
tem excitatory agents that act on the chloride channel include More rapid onset of sleep and prolongation of stage 2 are
picrotoxin and bicuculline. These convulsant drugs block the presumably clinically useful effects. However, the significance of
channel directly (picrotoxin) or interfere with GABA binding older sedative-hypnotic drug effects on REM and slow-wave sleep
(bicuculline). is not clear. Deliberate interruption of REM sleep causes anxiety
and irritability followed by a rebound increase in REM sleep at
the end of the experiment. A similar pattern of “REM rebound”
can be detected following abrupt cessation of drug treatment with
GABA-receptor function (see Chapter 1). Their interaction with older sedative-hypnotics, especially when drugs with short dura-
BZ sites on the GABA receptor can produce anxiety and seizures, tions of action (eg, triazolam) are used at high doses. With respect
A
an action that has been demonstrated for several compounds, to zolpidem and the other newer hypnotics, there is little evidence
especially the β-carbolines, eg, n-butyl-β-carboline-3-carboxylate of REM rebound when these drugs are discontinued after use of
(β-CCB). In addition to their direct actions, these molecules can recommended doses. However, rebound insomnia occurs with
block the effects of benzodiazepines. both zolpidem and zaleplon if used at higher doses. Despite pos-
The physiologic significance of endogenous modulators of the sible reductions in slow-wave sleep, there are no reports of dis-
functions of GABA in the CNS remains unclear. To date, it has not turbances in the secretion of pituitary or adrenal hormones when
been established that the putative endogenous ligands of BZ bind- either barbiturates or benzodiazepines are used as hypnotics. The
ing sites play a role in the control of states of anxiety, sleep patterns, use of sedative-hypnotics for more than 1–2 weeks leads to some
or any other characteristic behavioral expression of CNS function. tolerance to their effects on sleep patterns.

D. Organ Level Effects 3. Anesthesia—As shown in Figure 22–1, high doses of certain
1. Sedation—Benzodiazepines, barbiturates, and most older sedative-hypnotics depress the CNS to the point known as stage
sedative-hypnotic drugs exert calming effects with concomitant III of general anesthesia (see Chapter 25). However, the suitability
reduction of anxiety at relatively low doses. In most cases, however, of a particular agent as an adjunct in anesthesia depends mainly
the anxiolytic actions of sedative-hypnotics are accompanied by on the physicochemical properties that determine its rapidity of
some depressant effects on psychomotor and cognitive functions. onset and duration of effect. Among the barbiturates, thiopental
In experimental animal models, benzodiazepines and older sedative- and methohexital are very lipid-soluble, penetrating brain tissue
hypnotic drugs are able to disinhibit punishment-suppressed rapidly following intravenous administration, a characteristic
behavior. This disinhibition has been equated with antianxiety favoring their use for the induction of anesthesia. Rapid tissue
effects of sedative-hypnotics, and it is not a characteristic of all redistribution (not rapid elimination) accounts for the short dura-
drugs that have sedative effects, eg, the tricyclic antidepressants and tion of action of these drugs, a feature useful in recovery from
antihistamines. However, the disinhibition of previously suppressed anesthesia.