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ISSN: 2167-0277
Journal of Sleep Disorders & Therapy
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Comparative Action of Sedative Hypnotics on Neurophysiology of Sleep

Ashish Kumar U1 and Princy Louis Palatty2*
13rd Year MBBS Student, Father Muller Medical College, Kankanady, Mangalore, Karnataka, India
2Department of Pharmacology, Father Muller Medical College, Kankanady, Mangalore, Karnataka, India
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 Disord 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.

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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 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 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.
Electrophysiology of sleep
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.
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. Ï´ 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 Ï´ waves. Stage two shows Ï´ waves with interspersed spindles. While the stage 3 of NREM sleep shows Ï´,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 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.
Action of benzodiazepines on electro physiology of sleep
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.
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].
Barbiturates
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.
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 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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