Hypnotics

Soporifics, Hypnotics
During sleep, the brain generates a patterned
rhythmic activity that can be
monitored by means of the electroencephalogram
(EEG). Internal sleep cycles
recur 4 to 5 times per night, each
cycle being interrupted by a Rapid Eye
Movement (REM) sleep phase . The
REM stage is characterized by EEG activity
similar to that seen in the waking
state, rapid eye movements, vivid
dreams, and occasional twitches of individual
muscle groups against a background
of generalized atonia of skeletal
musculature. Normally, the REM stage is
entered only after a preceding non-REM
cycle. Frequent interruption of sleep
will, therefore, decrease the REM portion.
Shortening of REM sleep (normally
approx. 25% of total sleep duration) results
in increased irritability and restlessness
during the daytime. With undisturbed
night rest, REM deficits are
compensated by increased REM sleep
on subsequent nights .
Hypnotics fall into different categories,
including the benzodiazepines
(e.g., triazolam, temazepam, clotiazepam,
nitrazepam), barbiturates (e.g.,
hexobarbital, pentobarbital), chloral hydrate,
and H1-antihistamines with sedative
activity (p. 114). Benzodiazepines
act at specific receptors (p. 226). The
site and mechanism of action of barbiturates,
antihistamines, and chloral hydrate
are incompletely understood.
All hypnotics shorten the time
spent in the REM stages . With repeated
ingestion of a hypnotic on several
successive days, the proportion of
time spent in REM vs. non-REM sleep
returns to normal despite continued
drug intake. Withdrawal of the hypnotic
drug results in REM rebound, which tapers
off only over many days . Since
REM stages are associated with vivid
dreaming, sleep with excessively long
REM episodes is experienced as unrefreshing.
Thus, the attempt to discontinue
use of hypnotics may result in the
impression that refreshing sleep calls
for a hypnotic, probably promoting
hypnotic drug dependence.
Depending on their blood levels,
both benzodiazepines and barbiturates
produce calming and sedative effects,
the former group also being anxiolytic.
At higher dosage, both groups promote
the onset of sleep or induce it .
Unlike barbiturates, benzodiazepine
derivatives administered orally
lack a general anesthetic action; cerebral
activity is not globally inhibited
(respiratory paralysis is virtually impossible)
and autonomic functions, such as
blood pressure, heart rate, or body temperature,
are unimpaired. Thus, benzodiazepines
possess a therapeutic margin
considerably wider than that of barbiturates.
Zolpidem (an imidazopyridine)
and zopiclone (a cyclopyrrolone) are
hypnotics that, despite their different
chemical structure, possess agonist activity
at the benzodiazepine receptor.
Due to their narrower margin of
safety (risk of misuse for suicide) and
their potential to produce physical dependence,
barbiturates are no longer or
only rarely used as hypnotics. Dependence
on them has all the characteristics
of an addiction.
Because of rapidly developing tolerance,
choral hydrate is suitable only
for short-term use.
Antihistamines are popular as
nonprescription (over-the-counter)
sleep remedies (e.g., diphenhydramine,
doxylamine), in which case their
sedative side effect is used as the principal
effect.
Sleep–Wake Cycle and Hypnotics
The physiological mechanisms regulating
the sleep-wake rhythm are not completely
known. There is evidence that
histaminergic, cholinergic, glutamatergic,
and adrenergic neurons are more
active during waking than during the
NREM sleep stage. Via their ascending
thalamopetal projections, these neurons
excite thalamocortical pathways
and inhibit GABA-ergic neurons. During
sleep, input from the brain stem decreases,
giving rise to diminished thalamocortical
activity and disinhibition
of the GABA neurons. The shift in
balance between excitatory (red) and
inhibitory (green) neuron groups
underlies a circadian change in sleep
propensity, causing it to remain low in
the morning, to increase towards early
afternoon (midday siesta), then to decline
again, and finally to reach its peak
before midnight (B1).
Treatment of sleep disturbances.
Pharmacotherapeutic measures are indicated
only when causal therapy has
failed. Causes of insomnia include emotional
problems (grief, anxiety, “stress”),
physical complaints (cough, pain), or
the ingestion of stimulant substances
(caffeine-containing beverages, sympathomimetics,
theophylline, or certain
antidepressants). As illustrated for emotional
stress (B2), these factors cause an
imbalance in favor of excitatory influences.
As a result, the interval between
going to bed and falling asleep becomes
longer, total sleep duration decreases,
and sleep may be interrupted by several
waking periods.
Depending on the type of insomnia,
benzodiazepine with short or
intermediate duration of action are indicated,
e.g., triazolam and brotizolam
(t1/2 ~ 4–6 h); lormetazepam or temazepam
(t1/2 ~ 10–15 h). These drugs shorten
the latency of falling asleep, lengthen
total sleep duration, and reduce the frequency
of nocturnal awakenings. They
act by augmenting inhibitory activity.
Even with the longer-acting benzodiazepines,
the patient awakes after about
6–8 h of sleep, because in the morning
excitatory activity exceeds the sum of
physiological and pharmacological inhibition
(B3). The drug effect may, however,
become unmasked at daytime when
other sedating substances (e.g., ethanol)
are ingested and the patient shows an
unusually pronounced response due to
a synergistic interaction (impaired ability
to concentrate or react).
As the margin between excitatory
and inhibitory activity decreases with
age, there is an increasing tendency towards
shortened daytime sleep periods
and more frequent interruption of nocturnal
sleep .
Use of a hypnotic drug should not
be extended beyond 4 wk, because tolerance
may develop. The risk of a rebound
decrease in sleep propensity after
drug withdrawal may be avoided by
tapering off the dose over 2 to 3 wk.
With any hypnotic, the risk of suicidal
overdosage cannot be ignored.
Since benzodiazepine intoxication may
become life-threatening only when
other central nervous depressants (ethanol)
are taken simultaneously and can,
moreover, be treated with specific benzodiazepine
antagonists, the benzodiazepines
should be given preference
as sleep remedies over the all but obsolete
barbiturates.