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Thursday, May 19, 2011

Non-benzodiazepine hypnotics

Non-benzodiazepine hypnotics
These drugs comprise the barbiturates, alcohols and a new class of cyclopyrrolone hypnotics. Because of the severity of their side effects and their dependence potential, the barbiturates should not be used to treat insomnia. The alcohol type of hypnotics include the chloral derivatives, of which chloral hydrate and chlormethiazole are still occasionally used in the elderly, and ethchlorvynol. Chloral hydrate is metabolized to another active sedative hypnotic trichlorethanol. These drugs all have a similar effect on the sleep profile. They are short half-life drugs (about 4–6 hours) that decrease the sleep latency and number of awakenings; slow-wave sleep is slightly depressed while the overall REM sleep time is largely unaffected, although the distribution of REM sleep may be disturbed. Chloral hydrate and its active metabolite have an unpleasant taste and cause epigastric distress and nausea. Undesirable effects of these drugs include lightheadedness, ataxia and nightmares, particularly in the elderly. Allergic skin reactions to chloral hydrate have been reported. Chronic use of these drugs can lead to tolerance and occasionally physical dependence. Like the barbiturates, overdosage can lead to respiratory and cardiovascular depression. Therapeutic use of these drugs has largely been superseded by the benzodiazepines.
Any new hypnotic should induce and maintain natural sleep without producing residual sedative effects during the day; it should not cause dependence or interact adversely with other sedatives, including alcohol. The ideal hypnotic should not cause respiratory depression or precipitate cardiovascular collapse when taken in overdose. So far no drug fulfils all these criteria. Several new anxiolytic and sedative drugs act at the benzodiazepine receptor site, or one of the subsets that comprise this receptor site even though the chemical structure of these molecules differs substantially from the benzodiazepines. One of the first of these compounds to be developed was the cyclopyrrolone zopiclone. A structurally somewhat similar moleculezolpidem, an imidazopyridine, has also been marketed recently as has the beta-carboline abercarnil. Of the newer benzodiazepines, the tetracyclic 2,4 benzodiazepine bretazenil has also been introduced as a short-acting sedative–hypnotic.

The therapeutic profile and adverse effects of the non-benzodiazepine sedative–hypnotics Zopiclone was the first of the new sedative–hypnotics to be launched in the late 1970s and has been shown to be equi-effective with the standard sedative–hypnotic benzodiazepines such as flurazepam and temazepam.
There is evidence that zopiclone may cause less ‘‘hang-over’’ effects than the conventional benzodiazepines but some studies have shown that this drug does produce performance decrement when this is tested shortly after treatment. A similar profile has been reported for zolpidem while abercarnilhas been reported to cause a performance decrement for the first few days of treatment that then largely disappears. Bretazenil has been shown to cause dose-related disruptions in psychomotor performance, but these effects are not as prominent as occurs following an equivalent dose of diazepam or alprazolam. A somewhat unusual side effect has been described by patients taking zopiclone – a bitter, unpleasant taste and a dry mouth. The cause of these effects is presently unknown. Regarding abuse liability, to date there have been only few studies in which newer sedative–hypnotics have been investigated. Nevertheless there is some evidence that those with a history of sedative abuse preferred high doses of triazolam and zopiclone to placebo. There is some evidence that bretazenil has a lower abuse potential than the benzodiazepines. Abuse liability of these novel sedative hypnotics has also been evaluated in primates. Abercarnil causes a lower incidence of withdrawal effects than conventional benzodiazepines. This may be due to the differences in the intrinsic efficacy rather than the bioavailability of these drugs for the brain. However, zopiclone and bretazenil did lower the seizure threshold to electroshock-induced seizures in mice whereas the seizure threshold was unaffected by zolpidem, tracozalate and C1 218,872. In baboons zolpidem may cause physiological dependence; similar studies in monkeys show that mild withdrawal effects occur after the abrupt withdrawal of zopiclone, whereas withdrawal from diazepam caused severe symptoms. It may be concluded that sedative–hypnotic drugs with a limited efficacy such as bretazenil and zolpidem are also limited in their ability to cause physiological dependence.
In human studies, there is some evidence that withdrawal signs such as nervousness, anxiety and vertigo occur following sub-chronic administration of zopiclone but the frequency and intensity of the withdrawal effects are greater after conventional 1, 4-benzodiazepines. No rebound effects have been seen in patients with insomnia who received zolpidem daily for 7–180 days. By contrast, after 3 weeks of abercarnil treatment of patients with generalized anxiety disorder possible signs of withdrawal resulted, the incidence of these withdrawal effects being related to doses of abercarnil administered. From the published clinical studies, it would appear that the partial agonists bretazenil and abercarnil are less likely to cause physiological dependence, have lower reinforcing effects and a lower incidence of subjective effects associated with abuse liability than the conventional 1, 4-benzodiazepine sedative–hypnotics. It is presently unclear whether the full agonists for the GABA-A receptor, zolpidem and zopiclone, offer a real advance in the treatment of insomnia although their adverse effect profiles and abuse liability may be lower than that of the conventional benzodiazepines.

Drugs used to treat insominia

Drugs used to treat insominia
1. Benzodiazepine receptor agonists
Benzodiazepines (triazolam, temazepam, midazolam, lorazepam, estazolam). Non-benzodiazepines (imidazopyridines, e.g. zolpidem; pyrazopyrimidines, e.g. zaleplon; cyclopyrolones, e.g. zopiclone).
2. Pharmacological effects
Benzodiazepines – shorter latency to sleep, longer duration of sleep, decreased REM sleep, increased slow-wave sleep. Zopiclone – similar to benzodiazepines. Zaleplon and zolpidem – stated to have little adverse effect on sleep profile. There is evidence that the therapeutic efficacy is maintained even after several months of treatment.
3. Main side effects
Long half-life benzodiazepines cause day-time sedation. Dose-related anterograde amnesia. Impaired reaction time and vigilance. In elderly, cognitive impairment; falls causing fractures. Rebound insomnia can occur after withdrawal of short half-life drugs. Recurrence of original symptoms can occur when drug is stopped. Withdrawal effects on abrupt discontinuation of drug. These include:
dizziness, confusion and dysphoria.
Because of the frequency of side effects, benzodiazepine ligands are only recommended for the short-term (4 weeks) treatment of insomnia.
4. Other treatments include:
Sedative antidepressants (venlafaxine, trazodone, nefazodone, TCAs, mianserin, mirtazepine). Antihistamines (diphenhydramine, doxylamine). Melatonin (may shorten sleep latency but little effect on sleep time). Valerian extract (evidence of efficacy in double-blind studies). It should be noted that all these alternative treatments for insomnia also have side effects, some of which (e.g. TCAs) are potentially more serious than those occurring with the benzodiazepine group.

Use of hypnotics

Use of hypnotics
Despite the fact that man spends approximately one-third of his life asleep, the purpose of sleep still remains a mystery. The clinical importance of sleep is reflected in the frequency and severity of complaints about insomnia, a condition that signifies unsatisfactory or insufficient sleep. Problems may involve difficulty in getting to sleep, disturbing dreams, early wakening, and day-time drowsiness due to poor sleep at night. In most cases, these symptoms are fairly transient and may be associated with a specific or identifiable event such as a family or work situation, a temporary financial problem, etc. Should the sleep disturbance persist for longer than 3 weeks, specific treatment may be indicated. The Association of Sleep Disorders Centres has classified sleep disorders into two broad classes – disorders of initiating and maintaining sleep (DIMS) and disorders of excessive somnolence (DOES); these definitions have now been appended to the DSM–IV. The hypnogram of a patient with an underlying psychiatric illness may be characterized by a delay in sleep onset, the presence of residual muscular activity causing frequent awakenings, fragmented sleep, reduced REM and slow-wave sleep, and day-time drowsiness. Such disorders are generally not associated with a recent or transient event and the cause cannot usually be identified. Often such changes in the sleep architecture are associated with major psychiatric disorders such as depression, mania, psychosis or severe anxiety states.
For the purpose of considering the prescribing of hypnotics, insomnia may be classified into three major types:
1. Transient insomnia. This occurs in normal sleepers who experience an acute stress or stressful situation lasting for a few days, for example, air travel to a different time zone or hospitalization.
2. Short-term insomnia. This is usually associated with situational stress caused, for example, by bereavement or which may be related to conflict at work or in the family.
3. Long-term insomnia. Studies suggest that insomnia in up to 50% of patients in this category is related to an underlying psychiatric illness.
Of the remainder of the patients in this category, chronic alcohol or drug abuse may be the cause of the sleep disruption. Whenever the use of hypnotics is considered appropriate, it is universally agreed that patients should be given the smallest effective dose for the shortest period of time necessary. This recommendation applies particularly to elderly patients. For transient and short-term insomnia there is no clear consensus, although in practice the use of a medium or short half-life hypnotic for a few days is sometimes recommended when sleep disturbance is associated with shift work or ‘‘jet-lag’’. For chronic insomnia, careful investigation of the underlying cause of the condition is essential before hypnotics are routinely prescribed. Should the insomnia be associated with a psychiatric condition or drug abuse, specific treatment of the core illness will often obviate the need for hypnotics.
For all practical purposes, the benzodiazepines are the group of drugs most widely used to treat insomnia. These may be divided into three classes based on their pharmacokinetic characteristics:
1. Short half-life drugs, such as triazolam, midazolam and brotizolam, with elimination half-lives of about 6 hours.
2. Intermediate half-life drugs, such as temazepam, lormetazepam and loprazolam, with half-lives of 6–12 hours.
3. Long half-life drugs, such as nitrazepam, flurazepam and flunitrazepam, with half-lives over 12 hours.
The elimination half-lives of a number of commonly used hypnotics. It should be noted that many of the drugs in current use have active metabolites which considerably prolong the duration of their pharmacological effect. This is particularly true for the elderly patient in whom the half-life of the hypnotic is prolonged due to decreased metabolism and renal clearance; such individuals are also more sensitive to the sedative effects of any psychotropic medication. In general, the efficacy of hypnotics for short-term use is well established and there is a close relationship between their pharmacokinetic and pharmacodynamic profiles. The most widely used hypnotic in the UK, for example, is temazepam, which is relatively slowly absorbed and therefore has only a marginal effect on the sleep latency but facilitates sleep duration.The short elimination half-lives of drugs such as brotizolam ensure that residual sedative effects do not occur during the day. In contrast, fast elimination hypnotics such as midazolam and triazolam, which are effective in treating sleep onset insomnia, often give rise to rebound insomnia on withdrawal. It should be emphasized that the abrupt withdrawal of hypnotics, particularly when they have been given for several weeks or longer, is generally accompanied by REM rebound which results in an increased frequency of dreams and nightmares and can precipitate disturbed sleep and anxiety. Slow reduction in the night-time dose of the hypnotic over several days may reduce the risk of such a rebound. Regarding the efficacy of hypnotics when used long-term, there is evidence that sleep latency shows more tolerance than sleep time. Furthermore, it is generally accepted that each hypnotic has a minimal effective dose and that increasing this does little to improve the duration of sleep but is more likely to increase the side effects.

Sleep and the EEG

Sleep and the EEG
In general, the sleep cycle is synchronized via the SCN. All sensory stimuli activate the ascending reticular activating system, thereby causing cortical arousal and preventing the cortex reverting to its basic slow-wave oscillating rhythm. The excitatory, arousing mechanisms are complemented by inhibitory inputs from the hypothalamus. At least four different types of neurotransmitters are involved in regulating the EEG pattern in the sleep–wake cycle. Thus acetylcholine causes a desynchronization of the cortical EEG while REM sleep is induced by cholinomimetic drugs (such as arecoline and physostigmine) but blocked by atropine.
The central histamine 1 receptors are active in the posterior hypothalamus during the waking phase but inactive during the slow-wave sleep and REM stages of the sleep–wake cycle. Antagonists of the H1 histamine receptors cause sedation. There is evidence that the histaminergic tract that passes from the posterior hypothalamus to the cortex via the thalamus is inhibited by a GABAergic pathway. It is now known that H3 receptors act as autoreceptors on histaminergic neurons and that agonists of H3 receptors augment slowwave sleep. In addition, histamine can increase cortical arousal by enhancing excitatory cholinergic neurons from the basal forebrain and also inhibits the hypothalamic pre-optic area which normally promotes sleep. With respect to the control of the circadian rhythm, histamine has both excitatory (H1) and inhibitory (H2) effects on the SCN. Thus in addition to acetylcholine, noradrenaline and 5-HT, histamine would also appear to play a crucial role in regulating the sleep pattern. Noradrenaline – the EEG is aroused by stimulants such as the amphetamines and methylphenidate whereas drugs such as reserpine which deplete brain noradrenaline have the opposite effect. Similar effects to the stimulants may be obtained by the electrical stimulation of the locus coeruleus which has been shown to decrease in activity during the REM sleep phase of the sleep cycle. The precise role that noradrenaline plays in sleep is uncertain. While it may be involved in sleep induction, noradrenaline also has many other physiological functions including control of the heart rate, blood pressure, autonomic activity, etc. which play a role in the entraining process.
Dopamine – low doses of the dopamine agonist apomorphine increase slow-wave sleep and, like other dopaminometics, cause somnolence in patients with Parkinson’s disease. Conversely, dopamine autoreceptor antagonists, which enhance dopamine release, reduce both REM and non-REM sleep. Stimulants such as cocaine cause arousal by activating D2 postsynaptic receptors, effects which are blocked by most neuroleptics. Serotonin – the reduction in the release of 5-HT in the brain (for example, by blocking 5-HT synthesis with parachlorophenyl alanine) induces sleep while the electrical stimulation of the raphe´ nuclei causes excitation. It would appear that the activity of the raphe´ nuclei is decreased in slow-wave sleep. However, the role of specific 5-HT receptors in mediating the effects of 5-HT is unclear. This is due to the relative lack of specificity of the drugs available but also due to the fact that 5-HT modulates the activity of other neurotransmitter systems involved in the regulation of sleep. For example, 5-HT1A receptor agonists increase the frequency of slow-wave sleep which may be due to its inhibitory effect on the release of acetylcholine from the nucleus basalis. It would appear however that the serotonergic system is active during the waking phase but reduced during the sleep phase of the sleep–wake cycle.
In animals, two main types of sleep pattern may be identified termed nonrapid eye movement sleep (non-REM or slow-wave sleep) and rapid eye movement sleep (REM sleep). Normal sleep is composed of several REM and non-REM cycles. Non-REM sleep is divided into light sleep (stages 1 and 2) and slow-wave or delta sleep (stages 3 and 4). Stage 1 sleep is characterized by alpha rhythm on the EEG and forms the transition between wakefulness and sleep; it occupies approximately 5% of the time. Muscle tone is relatively weak and while a certain amount of mental activity persists, concentration and imagination fluctuate. As the sleep deepens, hypnagogic hallucinations may occur. Stage 2 sleep represents over 50% of the total sleeping time and is marked by characteristic sleep spindles and K complexes in the EEG; delta waves are also present occasionally. Muscle tone is weak and there are no eye movements. Stages 3 and 4, slow-wave sleep, occupy approximately 20% of the sleep time. The EEG is characterized by more than 50% of the sleep pattern being in the form of delta waves. This stage of sleep is the recuperative phase which is associated with growth hormone secretion and tissue repair; the secretion of prolactin is not associated with any specific phase of sleep. Dreaming may occur but tends to be of brief duration and of a rational nature. Nocturnal terrors and sleep walking are associated with stage 4 sleep.
REM sleep occupies approximately 20% of the sleep time in the normal adult, up to 30% in the young child and less than 20% in the aged or mentally handicapped. The cortical EEG activity resembles that of wakefulness, but is accompanied by muscular weakness; 4Hz ‘‘sawtooth’’ waves herald the onset of REM sleep. The precise physiological function of REM sleep is unknown but it is associated with dreaming sleep, the dreams being long, emotional and animated. The physiological changes accompanying REM sleep include hypertension, tachycardia alternating with bradycardia, pelvic congestion in the female and penile tumescence in the male. Cortisol secretion appears to peak during the latter part of the sleep cycle when REM sleep is most pronounced. This type of sleep is also characterized by bursts of eye movement and small sporadic muscular twitches of the face and extremities. The typical sleep pattern of the young adult is composed of four to six cycles of non-REM sleep alternating with REM sleep at approximately 90 minute intervals. The subject first goes into non-REM sleep and then gradually descends from stage 1 through to stage 4 sleep, the frequency of the waves becoming slower and their amplitude greater. The depth of sleep then briefly (for a few minutes) returns to stage 2, after which the first episode of REM sleep appears. Bodily movements often occur at this stage. This may be illustrated by means of a hypnogram.
It should be noted that stages 3 and 4 are more pronounced during the early part of the sleep period, whereas REM sleep tends to increase during the sleep cycle. The actual period of sleep is to some extent genetically determined, some individuals requiring at least 8 hours while others need only 4 hours to function normally. The sleep pattern becomes more fragile with advancing age, so that in the elderly the number of nocturnal awakenings increases and REM sleep becomes more evenly distributed throughout the night. The sleep architecture may be modified by disease and by certain drugs. In the healthy individual, the duration of the first phase of REM sleep is usually 3 minutes. In patients with depression or narcoplexy, the time of onset of the first REM phase is shorter than usual, while those with anxiety disorders have a delayed time of onset of the first REM phase. The duration of the first REM phase is also increased in depressed patients. All hypnotics in current clinical use alter the sleep architecture by reducing the quantity and quality of the REM sleep phase in particular. Thus a single dose of a hypnotic benzodiazepine suppresses REM during the period in which it is present, but for up to the two following nights the amount of REM sleep is generally increased (so-called REM rebound). When the hypnotic is given for a prolonged period, the REM sleep gradually returns to normal, but abrupt withdrawal can lead to prolonged rebound in REM sleep, which is often associated with intense and unpleasant dreams and anxiety on wakening. Most hypnotics also affect the quality of the non-REM sleep, particularly the slow-wave sleep pattern.
Thus stage 3 and stage 4 sleep are suppressed and remain so during the period of drug administration. following drug withdrawal, the slow-wave sleep gradually returns to normal, but this may take up to 15 days. However, no rebound effect appears to occur in slow-wave sleep. All hypnotics in current use also decrease stage 1 of non-REM sleep and prolong stage 2 sleep; this may be the reason why the nocturnal awakenings decrease, so that the individual feels that the quality of sleep under the influence of the hypnotic has improved! The effect of a hypnotic on the quality of the REM and slow-wave sleep is shown diagrammatically. Disturbance in the sleep pattern commonly occurs in the alcoholic. The sleep pattern in this type of patient is characterized by frequent awakenings and decreased REM and slow-wave sleep. Concomitantly, stages 1 and 2 are increased but shallower than usual. After withdrawal from alcohol, the patient experiences insomnia and REM rebound occurs. The sleep profile of the alcoholic often remains abnormal for 1–2 years following withdrawal. Most antidepressants decrease the quantity of REM sleep in the depressed patient, although it is difficult to say whether this is a reflection of the action of the drugs or due to the underlying pathology. Abrupt withdrawal of antidepressants, particularly the monoamine oxidase inhibitors, is often associated with REM rebound.

Physiology of sleep

Physiology of sleep
Although there is no evidence for a specific sleep ‘‘centre’’ in the brain, it is generally accepted that the level of consciousness is located in the diffuse network of nerve cells that comprise the reticular formation. This region consists of tegmental parts of the medulla, pons and midbrain. Lesions of the reticular formation result in somnolence or coma, sensory stimuli failing to arouse the animal. Such observations led to the conclusion that the brain stem reticular activity system maintains alertness and wakefulness, while lack of sensory stimulation results in sleep. Arousal from sleep by sensory stimuli is attributed to collateral pathways that link the main sensory pathways to the reticular formation. Undoubtedly this is a gross simplification of the anatomical substrate for sleep and wakefulness. There is evidence, for example, that animals may recover consciousness following lesions of the reticular formation and that the forebrain is not completely dependent on inputs from the reticular formation to maintain consciousness. Nevertheless, it is generally accepted that the reticular formation plays an important, if not a key role, in sleep and wakefulness.
Physiological basis of sleep – circadian rhythmicity It is a well-known fact that the circadian rhythm is entrained for diurnal cues to approximately 24 hours. However, a non-entrained rhythm, which operates in the absence of external cues, lasts between 25 and 27 hours. Thus the human sleep–wake cycle normally shows a 24-hour rhythm but not all physiological processes (for example, body temperature) follow the sleep–wake cycle. It is now known that circadian rhythms are controlled by clock genes which are found in species as wide apart as insects and mammals. It would appear that the clock genes are activated by light falling on the retina. The activated retina neurons then stimulate the retinohypothalamic tract which projects to the suprachiasmatic nucleus and thence to the anterior pituitary.
This pathway is responsible for coupling the circadian rhythm with the light cycle. The lateral geniculate nucleus (LGN) activates the suprachiasmatic nucleus (SCN) in the case of the non-light-based stimuli such as motor activity. The raphe´ nuclei also impact on the SCN. Thus several pathways appear to be involved in the entraining process.

Drug Treatment of Insomnia

Drug Treatment of Insomnia
Apart from the benzodiazepines, the sedative hypnotics are a group of drugs that depress the brain in a relatively non-selective manner. This results in a progressive change from drowsiness (sedation), sleep (hypnosis) to loss of consciousness, surgical anaesthesia, coma and finally cardiovascular and respiratory collapse and death. The central nervous system (CNS)depressant drugs include general anaesthetics, barbiturates and alcohols, including ethanol. Before the advent of the benzodiazepines, barbiturates in low doses were widely used as anxiolytics. A sedative drug is one that decreases CNS activity, moderates excitement and generally calms then individual, whereas a hypnotic produces drowsiness and facilitates the onset and maintenance of sleep from which the individual may be easily aroused. Historically the first sedative hypnotics to be introduced were the bromides in the mid 19th century, shortly followed by chloral hydrate, araldehyde and urethane. It was not until the early years of this century
that the first barbiturate, sodium barbitone, was developed and this was shortly followed by over 50 analogues, all with essentially similar pharmacological properties. The major breakthrough in the development of selective, relatively non-toxic sedative hypnotics followed the introduction of chlordiazepoxide in 1961. Most of the benzodiazepines in current use have been selected for their high anxiolytic potency relative to their central depressant effects. Because of their considerable safety, the benzodiazepines have now largely replaced the barbiturates and the alcohols, such as chloral hydrate and trichloroethanol, as the drugs of choice in the treatment of insomnia. The hypnotics are some of the most widely used drugs, over 15 million prescriptions being given for this group of drugs in Britain in 1985; the number of prescriptions for hypnotics has remained fairly constant over the last decade despite the reduction in anxiolytic prescriptions by about 50% over this same period. This situation is hard to reconcile with the fact that all benzodiazepines in current use have hypnotic properties if given in slightly higher therapeutic doses. This implies that what determines their use as anxiolytics, for day-time administration, or hypnotics, for night-time use, is largely a question of dose and marketing. As discussed in considerable detail elsewhere (see p. 213), there is a metabolic interrelationship between the commonly used 1,4-benzodiazepines and their mode of action is similar. It is of interest that the hypnotic benzodiazepines have received little media attention, in contrast to the anxiolytics of the same class, regarding their possible dependence-forming effects.