SLEEP DISORDERS: HYPNOTICS and CNS STIMULANTS
Insomnia and narcoleptic syndrome are the major sleep disorders. Insomnia is by far the most
common of the two and is one of the major complaints in medicine. Although about 40% of the
people complain of insomnia only 4% seek treatment with a female:male ration of 2:1.
A. Insomnia
Insomnia is no one state. It merely reflects dissatisfaction with quality of sleep which
could have several causes and diverse manifestations, e.g., inability to fall asleep,
multiple awakenings and early awakenings.
Insomnia may be primary with no underlying cause or secondarily caused by
environmental factors (noise), psychiatric illness, alcohol or drugs, sleep apnea, medical
illness (pain), physical discomfort (nasal congestion, cough), periodic limb movement
disorder.
The duration of insomnia may be transient (reactive insomnia lasting less than three
days), short term (due to ongoing stress of illness, grief, or job, lasting up to 3 weeks),
and long term (no external cause and lasts for more than 3 weeks). It should be
ascertained whether insomnia is initial (difficulty in falling asleep), middle or does it
manifest in early awakening with inability to return to sleep.
The major controversies in the management of insomnia are (1) whether to use
nonpharmacological means (reduction in intake of caffeine or other stimulants, change in
sleep habits, pain relief, proper diet, exercise) or pharmacological means (sleep-inducing
drugs), (2) whether to use short acting or longer acting sleep-inducing drugs.
Insomnia is pharmacologically treated with hypnotics - drugs that promote sleep.
Characteristics of an Ideal or desirable hypnotic drug
• low sleep latency (rapid onset of sleep)
• normal sleep pattern
• sufficient duration of sleep
• no “hangover” (drowsiness, mental and motor depression, anxiety, dysphoria)
• no daytime carryover of sleepiness
• no drug interactions
• ideal for chronic use i.e., absence of physical dependence or chances of rebound
insomnia on abrupt discontinuation of drug
However, most of these criteria are not met by any of the hypnotics. For example,
hypnotic-induced sleep is not similar to normal sleep (see below). In hypnotic-induced
sleep, short wave sleep (stages 3 and 4 of NREM sleep) is shortened, EEG sleep
spindles appear, REM sleep is suppressed and total sleep time is prolonged; after 3-4
weeks of use the amount and intensity of REM sleep increases to levels greater than
before the hypnotic use. In addition, they
• produce physical dependence
• elicit synergism between the effects of hypnotics and ethanol and other CNS
depressants
• impair judgment and fine motor skills
Sleep Disorders: Hypnotics and CNS stimulants
Dr. Bhatnagar, 4/27/05
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Hypnotic drugs
1. OTC sleep aids
diphenhydramine, doxylamine
2. older hypnotics (bromides and barbiturates)
3. benzodiazepines
triazolam
flurazepam
quazepam
temazepam
estazolam
4. nonbenzodiazepines
chloral hydrate
zopiclone
zolpidem
zaleplon
Normal sleep
Wake-sleep rhythm is the result of a balanced alteration of activity in the wake-sleep
systems because endogenous circadian rhythms are linked to environmental cues
particularly light and darkness. Besides, sleep is coupled to restorative cellular
processes. Sleep deprivation, amongst other thing impairs mental performance.
Based on the electroencephalogram, the electromyogram and the electroculogram, two
categories of sleep can be distinguished.
1. Non-rapid eye movement (NREM) sleep (70-75% of total sleep)
2. Rapid eye movement (REM) sleep. NREM and REM sleep cycle every 90
minutes - the REM latency period or the time between onset of sleep and first
part of REM. This cycle is repeated 4-5 times all through the night.
EEG correlates for waking and sleep states (See figure)
Relaxed state rhythmic synchronized pattern of 8-12 Hz frequency
(alpha rhythm) (alpha rhythm) and moderate amplitude (20-30 µv).
Aroused state desynchronized pattern of higher frequency (beta
(beta rhythm) rhythm; 13-30 Hz) and lower amplitude (5-10 µv).
Drowsiness to deep sleep progressively increased synchrony (1-4 Hz
in 4 stages collectively frequency) and amplitude (30-150 µv). Also called
known as NREM sleep slow wave sleep.
(delta rhythm)
Rapid eye movement EEG pattern similar to a beta rhythm but sleep state
(REM) sleep even deeper than the slow wave sleep in terms of
the arousal of the individual. REM sleep is
characterized by the beta rhythm, phasic eye
movements, and tonic suppression of skeletal
muscle tone. Most dreaming occurs during REM
sleep.
Sleep Disorders: Hypnotics and CNS stimulants
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NREM sleep can be divided into four stages (See Figure)
Stage 1 5% of total sleep; lightest stage of sleep
Stage 2 50% of total sleep; EEG “sleep spindle like”
Stage 3 12% of total sleep; EEG high voltage, slow-wave synchronous
activity
Stage 4 13% of total sleep; EEG high voltage, slow-wave synchronous
Major components of the central control of sleep
• Reticular formation. The reticular formation is a complex network of neurons in the
medulla and pons and extends into the thalamus. The ascending and descending
reticular formation are involved in the regulation of skeletal muscle tone as well as in
sensory, psychological and alerting activity of the cerebral cortex. Drugs that act on the
reticular formation may affect behavior and the levels of consciousness.
• Serotonin containing raphe nuclei inhibit the cortical alerting activity of reticular formation
and are involved in both REM and NREM phases of sleep. Destruction of serotonin rich
neurons of raphe nuclei or marked inhibition of their activity produce insomnia. The
results of both human and animal studies suggest that antagonism of 5-HT2C and 5-HT2A
receptors increase slow wave sleep. Therefore, 5-HT receptor subtypes may have
interacting or opposite roles in regulating sleep.
• Norepinephrine neurons in locus coeruleus are crucial in regulating REM sleep
• Acetylcholine containing neurons in the pons have a central role in the manifestation of
REM sleep. Carbachol-induced activation of muscarinic receptors of the reticular
formation of pons promotes REM sleep.
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• Melatonin secreted by the pineal gland influences the sleep-wake pattern. The pineal
gland is under the control of hypothalamus which in turn is connected to the reticular
formation. Melatonin reestablishes normal sleep – wake cycle in persons suffering from
jetlag or changing shifts of work.
Hypnotic drugs
• decrease the latency of sleep onset
• increase the duration of stage 2 NREM sleep
• decrease the duration of REM sleep
• decrease the duration of stages 3 and 4 NREM sleep
The decrease in latency of sleep onset and increase in stage 2 NREM sleep are clinically
desirable effects. The significance of effects on REM sleep and slow wave sleep (stages
3 and 4 NREM) remain unclear.
Pharmacology of hypnotic agents
1. Older hypnotics
Older hypnotic agents such as inorganic bromide, chloral hydrate and
barbiturates although effective and inexpensive have few recommended
indications today. These will not be discussed, as they are no longer drugs of
choice for the treatment of insomnia or anxiety because of serious side effects
and liability for misuse and abuse.
2. Benzodiazepines
Triazolam (Halcion)
Triazolam is the most widely prescribed hypnotic in the world. It has been used
in overcoming jet lag (daytime sleepiness and nighttime insomnia), sleep
problems due to shift changes (e.g., by airline pilots, truck drivers, nuclear power
plant personnel) - problems which would otherwise lead to accidents, social,
economic, health and diplomatic problems.
Triazolam is a potent, highly lipid soluble and is rapidly absorbed and taken up
by the brain. It has fast onset and short duration of action and when
appropriately used, is safe. Its elimination half life is about 3 hours. When taken
at bedtime it is cleared by breakfast.
Adverse effects and problems
• early morning insomnia
• daytime anxiety
• rebound insomnia
(All three adverse effects above may reinforce drug taking behavior and produce
drug dependence)
• Some reports of criminal behavior exist, however, it is not clear whether the
criminal behavior is due to underlying psychiatric disorder of social deviants, due
to multidrug use, or due to idiosyncratic hypersensitivity to benzodiazepines.
• Amnesia occurs at higher rate with triazolam than with other benzodiazepines.
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• Chronic use is counter productive because of short elimination half life. After two
weeks of continuous use, withdrawal of triazolam produces rebound insomnia;
sleep markedly worsens; effectiveness of triazolam is reduced. This rebound
phenomenon is not seen with long acting benzodiazepines such as flurazepam
and diazepam.
Flurazepam and Quazepam
These have elimination half-life of greater than 40 hours. They don’t produce
early morning awakening nor do they produce rebound effects when withdrawn.
In fact, they are useful in insomnia of early awakening type.
3. Nonbenzodiazapines
Chloral hydrate is used only in elderly.
Zolpidem, zopiclone and zaleplon bind to benzodiazepine receptors, have a
greater therapeutic index than benzodiazepines, are less toxic in overdose; have
less effect on sleep pattern; are less likely to be abused. The incidence of
withdrawal or rebound insomnia after chronic use and daytime sedation or
amnesia is low. However, they should not be used for long term (no more than 4
weeks).
Choice of a hypnotic agent.
The following factors influence the choice of an appropriate drug.
• Onset and duration of action required
• Period of treatment
• Personality and age
• Presence of pain
• Nature of insomnia: if insomnia is initial i.e., difficulty in getting to sleep, than
short acting hypnotics are preferred; if insomnia represents early awakening and
difficulty in returning to sleep, then long acting hypnotics are preferred.
Special Consideration:
• Drugs that are rapidly eliminated produce more worsening of sleep manifested
as rebound insomnia, or early morning insomnia than those with long half-life.
The worsening of sleep may be a reflection of development of tolerance and
physical dependence.
• Prescribe these drugs for intermittent use.
• Reduce dose in stepwise fashion rather than abrupt discontinuation.
• Should not be prescribed if drug abuse or multidrug reaction are possibilities.
• Establish the nature and cause of insomnia, and emotional stability of patient.
• Benzodiazepines must be avoided for the treatment of chronic insomnia and for
the use greater than 3 weeks; drug holidays must be interspersed between drug
usage.
• Intermediate acting drugs (half life is about 15 hours) are better for elderly
patients and those in nursing homes because they show less cumulative build up
and reduced chances of psychomotor impairment, vertigo, incontinence, anxiety,
irritability, hallucinations and manic behavior are reduced.
Sleep Disorders: Hypnotics and CNS stimulants
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B. CNS Stimulants for Narcolepsy
Narcolepsy is a rare sleep disorder that is characterized by unavoidable excessive
daytime sleeping and cataplexy. CNS stimulants are used in the treatment for
narcolepsy.
1. Psychomotor or sympathomimetic agents
a. Amphetamines (amphetamine, amphetamines (amphetamine,
dexamphetamine and methamphetamine) stimulate many brain regions
which include the striatum and the reticular activating system.
There are two isomers of amphetamine -- dextro-isomer
(dexamphetamine; Dexedrine) and levo-isomer (Levamphetamine).
Dextro-isomer has more potent CNS effects.
Mechanism of action
(a) release of catecholamines by displacement from
presynaptic neurons
(b) inhibition of neuronal amine reuptake
(c) agonistic action at serotonin and dopamine receptors
(d) inhibition of monoamine oxidase at high doses
(e) forms "false neurotransmitters"
Amphetamines and their derivatives are used for the therapy of narcolepsy,
hyperkinetic children and combating fatigue in crisis. It has been used as an
anorexic agent but rapid tolerance develops to the anorexic effects.
Acutely, amphetamine may produce anxiety, insomnia, dysphoria, and
sympathomimetic effects (increase in heart rate and blood pressure). When
used on a long-term basis delusions occur. In high doses freak psychosis,
seizures and cardiac irregularities occur.
b. Methylphenidate
This compound has been used in hyperkinetic states (attention deficit-
hyperactivity disorder (ADHD) and in therapy of narcolepsy and is
pharmacologically similar to amphetamines. It may cause nightime
insomnia, tolerance and dependence. (Atomoxetine, a selective
norepinephrine uptake inhibitor, has recently been introduced for ADHD)
c. Modafinil
It increases alertness and is useful in narcolepsy. Has fewer
cardiovascular adverse effects and less abuse potential as compared to
amphetamines. It is an agonist of α1B-adrenergic receptors in the CNS.
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