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Ashish Kumar and Palatty, J Sleep Disorders Ther 2013, 2:7
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Sleep Disorders & Therapy
Review Article
Open Access
Comparative Action of Sedative Hypnotics on Neurophysiology of Sleep
Ashish Kumar U1 and Princy Louis Palatty2*
1
2
3rd Year MBBS Student, Father Muller Medical College, Kankanady, Mangalore, Karnataka, India
Department of Pharmacology, Father Muller Medical College, Kankanady, Mangalore, Karnataka, India
Abstract
In spite of tremendous advances in medical science, sleep has not been understood completely. The causes
for many of parasomnias are still not evident. Even then these parasomnias are treated with different drugs, one of
the major groups among them being sedative hypnotics. The use of sedative hypnotics are always associated with
adverse effect, and there is many a times loss of the normal sleep architecture. This causes problems both during
drug intake and with the withdrawal of drugs. Hence the need for today is the use of sedative hypnotics with minimum
alteration in sleep architecture. The changes in the sleep architecture with the administration of sedative hypnotics
can be recorded with the changes in the normal sleep EEG pattern. In this review effort has been made in elaborating
the various sleep EEG pattern changes, resulting with the use of different groups of sedative hypnotic drugs with a
brief note on their respective mechanism of action and pharmacological properties.
Keywords: Sedative hypnotics; Neurophysiology of sleep; EEG
pattern; Benzodiazepines
Introduction
Sleep is regarded physiologically as absence of alertness and
wakefulness. The biological clock/ circadian rhythm or the central
pace maker which is located at the supra chiasmatic nuclei in the
hypothalamus regulates diurnal variation of physiological functions
of the body. The wand that regulates this variation is melatonin (the
hormone from pineal gland).
Sleep is defined as a reversible period of oblivion with minimum
alertness and is essential to mankind (also animals). Alternatively sleep
has also been defined as a state of consciousness that is different from
alert wakefulness by a loss of critical reactivity to event stimuli in the
environment. Scientists now agree that sleep is not passive or inactivity
rather it involves the active reorganisation of the brain. Despite a great
amount of research is done on sleep there remain grey areas in this
field.
Method
This review explores the actions of various sedatives hypnotics
on the neurophysiology of sleep. A PubMed literature search
was conducted exploring the mechanism of action of various
sedative hypnotics presently available and the correlation with the
neurophysiology of sleep. The present review compiled all data to
bring fourth relevant aspects for the improved understanding of sleep
physiology. Most of the articles reviewed were repetitive and only the
significant gleaned and presented in this review. A unique paper of old
[1967] titled “neurophysiology of the states of sleep” by Michel Jouvet
was a stimulating introspection of the knowledge of sleep then, but
prophetic in its conjecture. The study type was explorative description.
Areas of Interest
Neuro physiology of sleep
The normal sleep pattern consists of six to eight cycles of sleep that
transcends from light sleep to deep sleep. Sleep is characterised into
two types, Non Rapid Eye Movement (NREM) sleep and rapid eye
movement sleep (REM) sleep.
NREM sleep; there is sequential transition of sleep from stage
one to four in NREM sleep. One NREM sleep last approximately 20
J Sleep Disorders Ther
ISSN: 2167-0277 JSDT, an open access journal
minutes. It is characterised by dominant parasympathetic activity with
reduced metabolic rate, heart rate, cardiac output, peripheral vascular
resistance etc. NREM sleep is of a peaceful nature, and EEG shows
basically alpha rhythm with sleep spindles. Muscle tone diminishes
progressively. There is no movement of eye ball in NREM sleep.
In stage four NREM sleep there is more preponderance of ischemic
cerebro vascular stroke. Growth hormone secretion occurs in stage
three and four of NERM sleep [1]. The American academy of sleep
medicine alternatively classifies NREM sleep into three stages-N1, N2,
N3. N3 includes stage 3 and stage 4 of the conventional classification
also called the slow wave sleep.
REM sleeps; REM sleep last approximately 30 minutes but
progressively increases in the latter sleep cycles. In an uninterrupted
normal sleep the person awakens from REM sleep in the morning.
REM sleep is characterised by sympathetic activity. In REM sleep all
the voluntary muscles except extra ocular muscles are found flaccid. As
75% of the dreams occur during REM sleep, it is usually associated with
corresponding rise in heart rate, muscle, respiratory rate etc. The EEG
in the REM sleep resembles that in awake person i.e. beta rhythm. The
brain shows increased oxygen consumption. Obstructive sleep apnoea
there is extreme hypotonia of the muscles of the moderate respiratory
passages. Hypertensive hypoxic cardio vascular events occur during
REM sleep due to the secretions of catecholamines. REM sleep does
not affect growth hormone secretion. REM sleep constitutes 25% of the
total sleeping time.
A normal man spend one third of his life in sleep. Adequate sleep
is necessity of healthy life. Insomnia indicates lack of sleep which may
*Corresponding author: Princy Louis Palatty, Professor, Department of
Pharmacology, Father Muller Medical College, Kankanady, Mangalore, Karnataka,
India, Tel: +91 98451 04505, 0824-22380000; Fax: 0824-2436661; E-mail:
[email protected]
Received June 20, 2013; Accepted October 22, 2013; Published October 26,
2013
Citation: Ashish Kumar U, Palatty PL (2013) Comparative Action of Sedative
Hypnotics on Neurophysiology of Sleep. J Sleep Disorders Ther 2: 150.
doi:10.4172/2167-0277.1000150
Copyright: © 2013 Ashish Kumar U, et al. This is an open-access article
distributed under the terms of the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided
the original author and source are credited.
Volume 2 • Issue 7• 1000150
Citation: Ashish Kumar U, Palatty PL (2013) Comparative Action of Sedative Hypnotics on Neurophysiology of Sleep. J Sleep Disorders Ther 2: 150.
doi:10.4172/2167-0277.1000150
Page 2 of 4
be due to variability in initiation or maintenance of sleep. Parasomnias
are a group of sleep disorders that are associated with sleep such as
sleepwalking, bruxism, night terrors, sleep paralysis, enuresis etc.
Lack of sleep leads to poor concentration, motor in coordination,
attention deficit, irritability, restlessness, raised blood pressure and
heart rate etc.
Benzodiazepines
Alprazolaam,brotizolam,chlordiazepoxide,
clobazam,clonazepam,clorazepate,
diazepam, estazolam, flumazenil, lorazepam,
oxazepam, triazolam
Z compounds
(benzodiazepine receptor
agonist)
Zolpidem, zopiclone, zaleplon, eszopiclone
Electrophysiology of sleep
Barbiturates
Phenobarbitone, mephobarbitone
Newer agents
Melatonin agonists, orexin antagonists
Sleep is classified into stages based on the electroencephalogram
(EEG) readings, electro ocular gram reading (EOG) and electromyogram
(EMG) readings-i.e. into NREM sleep and REM sleep.
Miscellaneous
The EEG wave patterns has been divided into 4 types
1.
α wave; high amplitude, 8- 14 cycles per second
2.
β wave; low amplitude, 15-35 cycles per second
3.
ϴ wave; low amplitude, 4-7 cycles per second
4.
δ wave; high amplitude, 0-5 -3 cycles per second
In stage 1 of NREM sleep alpha waves are predominant being
interspersed with ϴ waves. Stage two shows ϴ waves with interspersed
spindles. While the stage 3 of NREM sleep shows ϴ,δ waves, stage 4
shows predominance of δ activity.
The electrical activity of the sleeping brain has a recurrent evolution
preceding from two opposite modes- the slow wave sleep and the
activated sleep also called the paradoxical sleep.
The EEG aspect of Slow Wave Sleep (SWS) consist of 11 to 16
cycles/ sec of high amplitude spindles that are often synchronous with
the cortex and present at the level of the frontal and reticular formation
and associative areas. The spindles are usually followed by 1 to 4 cycles/
sec high voltage slow waves, also recorded at the sub cortical level.
On the other hand the EEG recording of a paradoxical sleep
shows tonic activity characterised by a neo cortical diencephalic and
mesencephalic low voltage fast activity (20-30 cycles/ sec), being
similar to the cortical desynchronization that usually follows arousal
or attention states. However, the EEG recording during a paradoxical
sleep is differentiated from that due to arousal or attention states by the
presence of some electrical local cortical and subcortical activity [2-4].
The continuous presence of theta rhythm during paradoxical sleep is
characteristic [5-12].
Site of Action of Sedative Hypnotics
Sedative produces calming and drowsiness. It decreases activity
and moderates excitement. Hypnotics are a drug that induce sleep and
maintains sleep just like natural sleep. Sedative hypnotics are a group of
drugs that are widely used in clinical care. Sedation on the other hand,
is the very common adverse effect of most drugs especially those that
have generalised CNS depressant action. Examples, antihistaminic,
anti psychotics, alcohol.
Sedative hypnotics are used widely in clinical care as in, the
treatment of insomnia, sedatives, anxiolytics, muscle relaxants etc.
The need of the day is the use sedative hypnotics that do not or
causes least alteration in the normal sleep architecture. There is an
increasing emphasis on quality of sleep along with the quantity of sleep
which was the main emphasis before (Table 1).
Sedative hypnotic drugs cause grades of CNS depression i.e.
drowsiness (sedation), sleep (hypnotic), unconsciousness, coma, fatal
J Sleep Disorders Ther
ISSN: 2167-0277 JSDT, an open access journal
paraldehyde, chloral hydrate, meprobromate
Table 1: Classification of sedative hypnotics.
respiratory depression, death. The index of CNS depressant activity is
noted from cognitive deficit and attention to environmental stimuli.
GABAa Receptor
There are three types of GABA receptors- GABAa and GABAb and
GABAc. The most important among the three is the GABAa receptor
which is a ligand gated chloride channel. The GABAa receptor has
three subunits-alpha, beta and gamma. GABAa receptor could be
either pentameric or tetrameric protein in which the subunits assemble
around a central pore. The GABAa receptor has separate binding sites
for GABA, benzodiazepine, and barbiturates. There are six subgroups
of alpha subunit and three each of beta and gamma, indicating the
presence of large group of GABAa receptor types.
Benzodioazepines
Chlordiazepoxide and diazepam were the first benzodiazepines
to be introduced in 1960, replacing the order barbiturate group of
sedative hypnotics.
The basic structure of benzodiazepines consists of benzene ring
fused to seven member diazepine ring. All effects of benzodiazepines
are based on their action on the specific receptors present in the CNS,
which includes effects like sedation, hypnosis, anterograde amnesia,
decreased anxiety, muscle relaxation and anticonvulsant activity. Most
of the benzodiazepines are absorbed completely on oral administration
and are highly protein bound in the plasma. Even with excessive
doses of BZD usages surgical anaesthesia cannot be achieved, unless
other drugs are added. The benzodiazepines receptors agonists have
least potecyl of respiratory depression and are the preferred sedative
hypnotics today. Benzodiazepines are use full in the treatment of
insomnia, by decreasing the time needed to enter stage 1 of NREM
sleep, decrease awakefullness. Benzodiazepines are safer as compared
to barbiturates due to lesser depression of respiration, heart and blood
pressure and also due to the presence of a effective antidote flemazenil,
in cases of toxicity. On long term use of benzodiazepines, there is
usually development of tolerance. Cross tolerance is also known to
occur with alcohol.
Mechanism of action
Benzodiazepines act by interacting with the inhibitory
neurotransmitter receptor activated directly by GABA. There are
predominately two types of GABA receptors-GABAa and GABAb.
Benzodiazepines act by binding to the ionotropic GABA a receptors
and have not action on the GABA b receptors. The binding site
of benzodiazepines are distinct from that of GABA binding.
Benzodiazepines do not act on the GABA a receptor directly but they
potentiate the action of GABA on GABA a receptors. Benzodiazepines
increase the chloride current in response to GABA activation by
increasing the frequency of chloride channel opening.
Volume 2 • Issue 7• 1000150
Citation: Ashish Kumar U, Palatty PL (2013) Comparative Action of Sedative Hypnotics on Neurophysiology of Sleep. J Sleep Disorders Ther 2: 150.
doi:10.4172/2167-0277.1000150
Page 3 of 4
Action of benzodiazepines on electro physiology of sleep
Barbiturates
Benzodiazepines decreases the time spent in stage 1 NREM sleep,
while the time spent in stage 3 and stage 4 of NREM sleep is decreased
considerably. However the time taken from the onset of spindle sleep
to REM sleep is increased because of increase in the time spent in the
stage 2 of NREM sleep, that being the major fraction of NREM stage
of sleep. Benzodiazepines increase NREM sleep [13]. While REM
sleep period is decreased by most of the benzodiazepines, although
the number of cycles of REM sleep is increased. With chronic use
of benzodiazepine the affect on various stages of sleep declines, and
if such a chronic use is discontinued there can be rebound of the
pattern of drug induced changes of sleep parameter. The withdrawal
symptoms may also include agitations, depression, abdominal pain,
Insomnia, seizures. Dependence to benzodiazepines can be prevented
and controlled through dose tapering, medication switching and/ or
medication augmentation.
One among the pioneers groups of sedative hypnotics, Barbiturates
have been replaced now by the much safer benzodiazepines. Barbiturates
consists of 2,4,6- trioxohexahydropyrimidine and alkyl or aryl groups
at the position 5, which confers the molecule the central sedative
hypnotic property. On oral administration the absorption is almost
complete and is distributed widely. Before excretion by the kidney
almost all barbiturates undergo complete metabolism or conjugation
in the liver. Barbiturate cause respiratory depression which is lethal
at high doses, compared to the benzodiazepines which have minimal
effect on respiration, heart rate and blood pressure.
Benzodiazepines cause anterograde amnesia, and hence can cause
illusion of anaesthesia in pre anaesthetic doses.
The changes in the neurophysiology of sleep with the administration
of drugs belonging to the benzodiazepine group remains minimal with
only mild changes relating to the potency of the individual drugs.
Known as the ‘benzodiazepine signature’, there is usually a 10-15 Hz
increase and lower-frequency (<10 Hz) suppression relative to the
preceding drug-free night [14]. In a study aimed at observing the effects
of haloxazolam, flunitrazepam, and triazolam, on the EEG pattern of
subjects, showed that the three drugs induced EEG changes of similar
pattern. It was observed that higher frequency (including the sigma and
beta bands) activity increased and lower frequency activity reduced
with the administration of drugs [15]. Triazolam (0.25 mg) induces
changes in the EEG spectra which are typical for benzodiazepine
receptor agonists characterised by EEG power density in non-REM
sleep reduced in the frequency range of 1.25-10.0 Hz and enhanced in
the range of sleep spindles (12.25-13.0 Hz) [16].
Z Compounds
These compounds though not structurally related to benzodiazepines
act by binding to and activating the benzodiazepine receptor site in
the GABA a receptors. Drugs in this class include zolpicone, zolpidem,
zaleplon etc. Z drugs are now replacing benzodiazepines. They are
specific sedative hypnotics and hence lack anticonvulsant, ant anxiety,
muscle relaxant properties. They cause minimum hangover when
compared to the benzodiazepines.
Action of Benzodiazepine Receptor Agonist on Electro
Physiology of Sleep
Unlike benzodiazepines these drugs have little effect on the
stages of sleep. Zolpidem and zaleplon suppress REM sleep to a lesser
extent as compared to the benzodiazepines, and hence are considered
superior [13]. Zolpidem and zaleplon don’t show rebound insomnia
on abrupt discontinuation [17]. On administration of zolpidem in
mince the change in EEG pattern is found to be distinct from that see
due to benzodiazepines, and this affect is due to the action of zolpidem
on alpha 1 GABAa receptor [18]. The EEG profile of heath volunteers
administered with zolpidem was characterised by a decrease of alpha
activity and an increase in delta and beta activity. The effect on beta
activity was marked within the first hour and then disappeared [19].
The drug also reduced REM sleep but did not significantly affect other
sleep stages and subjective sleep parameter [20].
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Mechanism of action
Barbiturates act by binding to the barbiturate receptor in the
GABA a receptor, distinct from that of GABA and benzodiazepine
receptors and enhancing the inhibitory neurotransmission. In contrast
to benzodiazepines, barbiturates cause increased duration of chloride
channel opening. They also have a direct stimulatory effect on GABA
receptors by acting as a GABA agonist and causing inhibitory action
directly.
Action of barbiturates on electro physiology of sleep
Barbiturates also alter the sleep stages in manner almost similar to
the benzodiazepines. Rapid eye movement (REM) sleep during barbital
treatment was reduced to half the time as compared to that seen in drug
free subjects [21].
A quantitative analysis of beta-rhythms can differentiate the effects
of barbiturates and benzodiazepine drugs on the EEG [22].
Newer and Miscellaneous Group of Sedative Hypnotics
Chloral hydrate, paraldehyde, triclophos etc are included in the
miscellaneous group of sedative hypnotics which are only of historical
importance today. Chloral hydrate banned today in many countries
for it addiction potency is capable of inducing sleep and modifying the
sleep EEG, improving organization of sleep spindles and generalized
paroxysms [23]. However there is a lack of sufficient data to describe
the EEG changes in sleep due to paraldehyde and others.
Melatonin agonists the newer sedative hypnotic is structurally
similar to melatonin- the hormone secreted from the pineal gland, the
biological clock. The secretions from the pineal gland play an important
role in synchronizing the sleep- wake cycle with the circadian rhythm.
The melatonin agonists have hence played an important role in the
treatment of jet lag. Melatonin agonists have little effect on sleep
latency and duration of sleep. The effect on the electrophysiology of
sleep is also minimal. Although melatonin agonists are unlikely to
have the adverse effect of conventional sedative hypnotic, its long term
safety is not clear.
Receptor antagonists of the neurotransmitter orexin are another
group of newer sedative hypnotics, called orexin antagonists. Orexin
regulates arousal, appetite, wakefulness [24]. This newer group of
drugs has been found useful in the treatment of sleep pathology such
as insomnia [25,26]. In a study which involved intracerebro ventricular
orexin A administration, differently affected fronto-occipital EEG
waves in the different frequent bands. The power of the Delta and alpha
waves decreased while that of theta and beta waves increased.
Potential Drug Targets
The sedative hypnotic effect of the present day drugs are not optimal
Volume 2 • Issue 7• 1000150
Citation: Ashish Kumar U, Palatty PL (2013) Comparative Action of Sedative Hypnotics on Neurophysiology of Sleep. J Sleep Disorders Ther 2: 150.
doi:10.4172/2167-0277.1000150
Page 4 of 4
and beset with adverse reaction and change in sleep architecture. The
quest for new drugs and probable target is on. The elusive endogenous
benzodiazepine could be a potential target.
Conclusion
Sedative hypnotic are one among the most commonly used drugs
in clinical practice such as for the treatment of insomnia, as anti
convalescents etc. They are associated with a large number of side effect
and hence there is a need for understanding their action on various
systems thoroughly, one of them being the changes the induce in
electrical activity of the brain during sleep.
The neuro physiology of sleep leaves a lot of lacunae that impedes
the understanding of sleep. The drug group availed are not optimal in
the treatment of sleep disorders. The lookout for potential targets and
molecules still continues. Optimizing the presently available sedative
hypnotics concurrent with functional imaging and somnographic
techniques would be the order of the day.
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Citation: Ashish Kumar U, Palatty PL (2013) Comparative Action of Sedative
Hypnotics on Neurophysiology of Sleep. J Sleep Disorders Ther 2: 150.
doi:10.4172/2167-0277.1000150
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ISSN: 2167-0277 JSDT, an open access journal
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