DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Side effects of hypnotic agents may limit their usefulness
for insomnia management. The use of hypnotics for long-term
insomnia is problematic for many reasons. Long-term hypnotic use
leads to a decrease in effectiveness and may produce rebound
insomnia on discontinuance. Almost all hypnotics change sleep
architecture. The barbiturates reduce REM sleep; the benzodiazepines
reduce slow-wave non-REM sleep and, to a lesser extent,
REM sleep. While the significance of these findings is not clear,
there is an emerging consensus that slow-wave sleep is particularly
important for physical restorative processes. REM sleep may aid in
the consolidation of learning. The blockade of slow-wave sleep by
benzodiazepines may partly account for their diminishing effectiveness
over the long term, and it also may explain their effectiveness
in blocking sleep terrors, a disorder of arousal from slow-wave
sleep.
Long-acting benzodiazepines can cause next-day confusion,
with a concomitant increase in falls, whereas shorter-acting agents
can produce rebound next-day anxiety. Paradoxically, the acute
amnestic effects of benzodiazepines may be responsible for the
patient’s subsequent report of restful sleep. Triazolam has been
postulated to induce cognitive changes that blur the subjective distinction
between waking and sleeping (Mendelson, 1993).
Anterograde amnesia may be more common with triazolam. While
the performance-disruptive effects of alcohol and diphenhydramine
are reduced after napping, those of triazolam are not
(Roehrs et al., 1993).
Benzodiazepines may worsen sleep apnea. Some hypersomnia
patients do not feel refreshed after a night’s sleep and so may
ask for sleeping pills to improve the quality of their sleep. The consensus
is that hypnotics should not be given to patients with sleep
apnea, especially of the obstructive type, because these agents
decrease upper airway muscle tone while also decreasing the arousal
response to hypoxia (Robinson and Zwillich, 1989). These individuals
benefit from all-night sleep studies to guide treatment.
Insomnia in Older Patients. The elderly, like the very young, tend to
sleep in a polyphasic (multiple sleep episodes per day) pattern rather
than the monophasic pattern characteristic of younger adults. They
may have single or multiple daytime naps in addition to nighttime
sleep. This pattern makes assessment of adequate sleep time difficult.
Anyone who naps regularly will have shortened nighttime sleep
without evidence of impaired daytime wakefulness, regardless of
age. This pattern is exemplified in “siesta” cultures and probably is
adaptive.
Changes in the pharmacokinetic profiles of hypnotic agents
occur in the elderly because of reduced body water, reduced renal
function, and increased body fat, leading to a longer t 1/2
for benzodiazepines.
A dose that produces pleasant sleep and adequate daytime
wakefulness during week 1 of administration may produce
daytime confusion and amnesia by week 3 as the level continues to
rise, particularly with long-acting hypnotics. For example, the benzodiazepine
diazepam is highly lipid soluble and is excreted by the
kidney. Because of the increase in body fat and the decrease in renal
excretion that typically occur from age 20-80, the t 1/2
of the drug
may increase 4-fold over this span.
Elderly people who are living full lives with relatively unimpaired
daytime wakefulness may complain of insomnia because they
are not sleeping as long as they did when they were younger.
Injudicious use of hypnotics in these individuals can produce daytime
cognitive impairment and so impair overall quality of life.
Once an older patient has been taking benzodiazepines for an
extended period, whether for daytime anxiety or for nighttime sedation,
terminating the drug can be a long, involved process. Since
attempts at drug withdrawal may not be successful, it may be necessary
to leave the patient on the medication, with adequate attention
to daytime side effects.
Management of Patients After Long-Term Treatment
with Hypnotic Agents. Patients who have been taking
hypnotics for many months or even years pose a special
problem (Fleming, 1993). If a benzodiazepine has been
used regularly for >2 weeks, it should be tapered rather
than discontinued abruptly. In some patients on hypnotics
with a short t 1/2
, it is easier to switch first to a hypnotic
with a long t 1/2
and then to taper. The onset of withdrawal
symptoms from medications with a long t 1/2
may be
delayed. Consequently, the patient should be warned
about the symptoms associated with withdrawal effects.
Prescribing Guidelines for the Management of
Insomnia. Hypnotics that act at GABA A
receptors,
including the benzodiazepine hypnotics and the newer
agents zolpidem, zopiclone, and zaleplon, are preferred
to barbiturates because they have a greater therapeutic
index, are less toxic in overdose, have smaller effects on
sleep architecture, and have less abuse potential.
Compounds with a shorter t 1/2
are favored in patients
with sleep-onset insomnia but without significant daytime
anxiety who need to function at full effectiveness
during the day. These compounds also are appropriate
for the elderly because of a decreased risk of falls and
respiratory depression. However, the patient and physician
should be aware that early-morning awakening,
rebound daytime anxiety, and amnestic episodes also
may occur. These undesirable side effects are more
common at higher doses of the benzodiazepines.
Benzodiazepines with longer t 1/2
are favored for
patients who have significant daytime anxiety and who
may be able to tolerate next-day sedation but would be
impaired further by rebound daytime anxiety. These
benzodiazepines also are appropriate for patients
receiving treatment for major depressive episodes
because the short-acting agents can worsen earlymorning
awakening. However, longer-acting benzodiazepines
can be associated with next-day cognitive
impairment or delayed daytime cognitive impairment
(after 2-4 weeks of treatment) as a result of drug accumulation
with repeated administration.
Older agents such as barbiturates, chloral hydrate, and
meprobamate should be avoided for the management of insomnia.
They have high abuse potential and are dangerous in overdose.
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CHAPTER 17
HYPNOTICS AND SEDATIVES