Sleep Sedative-hypnotics

This large category of depressants comprises alcohol "sleeping pills/ and certain tranquilizers. In low doses these drugs promote relaxation and restfulness (sedation), especially in the daytime. Larger doses, especially at night, induce sleep (the word hypnosis comes from the name of the Greek god of sleep). "Sedative-hypnotic" refers to this double action. 

The clinical effects of sedative-hypnotics include sedation and sleep. Sedative-hypnotic drugs depress the function of the CNS and in a dose-dependent fashion produce drowsiness (sedation). Several sedative-hypnotic drugs, especially the older ones, produce sedation, sleep, unconsciousness, surgical anesthesia, coma, and ultimately may cause fatal depression of respiration and cardiovascular regulation. 

Barbituric acid is the parent of a group of compounds known as barbiturates The bar biturates are classified as sedative-hypnotic agents meaning that they decrease the responsiveness of the central nervous system and promote sleep Thousands of deriva lives of the parent ring system of barbituric acid have been tested for sedative-hypnotic activity the most useful are the 5 5 disubstituted derivatives... 

Melatonin [73-31-4] C 2H N202 (31) has marked effects on circadian rhythm (11). Novel ligands for melatonin receptors such as (32) (12), C2yH2gN202, have affinities in the range of 10 Af, and have potential use as therapeutic agents in the treatment of the sleep disorders associated with jet lag. Such agents may also be usehil in the treatment of seasonal affective disorder (SAD), the depression associated with the winter months. Histamine (see Histamine and histamine antagonists), adenosine (see Nucleic acids), and neuropeptides such as corticotropin-like intermediate lobe peptide (CLIP) and vasoactive intestinal polypeptide (VIP) have also been reported to have sedative—hypnotic activities (7). 

Pharmacological Profiles of Anxiolytics and Sedative—Hypnotics. Historically, chemotherapy of anxiety and sleep disorders rehed on a wide variety of natural products such as opiates, alcohol, cannabis, and kawa pyrones. Use of various bromides and chloral derivatives ia these medical iadications enjoyed considerable popularity early ia the twentieth century. Upon the discovery of barbiturates, numerous synthetic compounds rapidly became available for the treatment of anxiety and insomnia. As of this writing barbiturates are ia use primarily as iajectable general anesthetics (qv) and as antiepileptics. These agents have been largely replaced as treatment for anxiety and sleep disorders. 

Glassification of Substance-Related Disorders. The DSM-IV classification system (1) divides substance-related disorders into two categories (/) substance use disorders, ie, abuse and dependence and (2) substance-induced disorders, intoxication, withdrawal, delirium, persisting dementia, persisting amnestic disorder, psychotic disorder, mood disorder, anxiety disorder, sexual dysfunction, and sleep disorder. The different classes of substances addressed herein are alcohol, amphetamines, caffeine, caimabis, cocaine, hallucinogens, inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics, polysubstance, and others. On the basis of their significant socioeconomic impact, alcohol, nicotine, cocaine, and opioids have been selected for discussion herein. 

Other apphcations of sodium bromide iaclude use ia the photographic iadustry both to make light-sensitive silver bromide [7785-23-1] emulsions and to lower the solubiUty of silver bromides during the developing process use as a wood (qv) preservative in conjunction with hydrogen peroxide (14) as a cocatalyst along with cobalt acetate [917-69-1] for the partial oxidation of alkyl side chains on polystyrene polymers (15) and as a sedative, hypnotic, and anticonvulsant. The FDA has, however, indicated that sodium bromide is ineffective as an over-the-counter sleeping aid for which it has been utilized (16). 

Since there was some evidence that these compounds owe their action to interference with the action of histamine, this class has earned the soubriquet "antihistamines." This class of drugs is further characterized by a spectrum of side effects which occur to a greater or lesser degree in various members. These include antispasmodic action, sedative action, analgesia, and antiemetic effects. The side effects of some of these agents are sufficiently pronounced so that the compounds are prescribed for that effect proper. Antihistamines, for example, are used as the sedative-hypnotic component in some over-the-counter sleeping pills. 

Sedative-hypnotic. A drug that decreases responsiveness of the central nervous system to the point of promoting sleep. 

Sporadic use (e.g., for the induction of sleep after a psychostimulant binge) does not require specific detoxification. Sustained use can be treated as described in the previous sections on detoxification from therapeutic or high dosages but with added caution. In mixed opioid and benzodiazepine abuse, the patient should be stabilized with methadone (some clinicians use other oral preparations of opioids) and a benzodiazepine. Buprenorphine should not be administered with benzodiazepines, because a pharmacodynamic interaction is possible (Ibrahim et al. 2000 Kilicarslan and Sellers 2000) and fatalities have been reported with the combination (Reynaud et al. 1998). Sedative-hypnotic withdrawal is the more medically serious procedure, and we usually... 

Restless-legs syndrome treatment involves suppression of abnormal sensations and leg movements and consolidation of sleep. Dopaminergic and sedative-hypnotic medications are prescribed commonly. 

Sedative-hypnotic A CNS depressant used to reduce anxiety (sedation) and promote sleep (hypnotic). 

Transient and short-term insomnia should be treated with good sleep hygiene and careful use of sedative-hypnotics if necessary. 

Sodium oxybate (yhydroxybutyrate a potent sedative-hypnotic) improves excessive daytime sleepiness and decreases episodes of sleep paralysis, cataplexy, and hypnagogic hallucinations. It is taken at bedtime and repeated 2.5 to 4 hours later. Side effects include nausea, somnolence, confusion, dizziness, and incontinence. 

Cannabis use does not appear to induce a "hangover" syndrome like that produced with alcohol or sedative-hypnotics in terms of sleep effects, mood, psychomotor skills, or cognitive function (Chait 1990). 

Dating back to the 1800s, some of the earliest snccessfnl psychiatric medications were those nsed to promote sleep. Sleep-promoting medications, called sedative-hypnotics, have remained an important component of onr pharmacological armamentarium. Over the past 100-plus years, as we have learned more abont both pharmacology and sleep physiology, a series of refinements have improved the safety and effectiveness of sleep medications. 

Like the barbiturates, the benzodiazepines make it easier to fall asleep and to stay asleep through the night. However, they also suppress REM sleep, which can lead to REM rebound when they are discontinued. Tolerance to their sleep-promoting effects often develops after chronic use. Some long-acting benzodiazepines, such as flurazepam (Dalmane), are associated with pronounced hangover effects in the morning and are therefore problematic as sedative-hypnotics. Others, with a short-to-intermediate dnration of action, are more desirable as hypnotics. 

Antihistamines. After alcohol, antihistamines are the most commonly self-administered sleep medications. Foremost among these is diphenhydramine (Benadryl), which is also available as a component in a variety of over-the-counter nighttime medications including Tylenol PM and Excedrin PM. Prescription antihistamines like hydroxyzine (Vistaril, Atarax) are also occasionally used to treat insomnia. Finally, it is the antihistamine effect of some antidepressants and anti-psychotics that contribute to their utility as sedative-hypnotics. 

Dopamine-Boosting Medications. Levodopa/carbidopa (Sinemet), bromocriptine (Parlodel), pramipexole (Mirapex), and ropinirole (Requip) increase dopamine nenrotransmission in the brain by one or another mechanism. These medications do not reliably induce sleep, and in some patients are activating. They are certainly not true sedative-hypnotics. They are most often used by neurologists to treat Parkinson s disease. 

Patients suspected of having sleep apnea should undergo a sleep study. If sleep apnea is diagnosed, these patients should be treated with weight reduction, a continuous positive airway pressure (CPAP) machine, and, in extreme cases, surgery. Sleep apnea patients in general should not be prescribed sedative-hypnotics. 

Nevertheless, sedative-hypnotic agents often play a useful role in treatment. In particular, by providing a successful night s sleep, these medications can break the cycle of anxious anticipation and dread that afflicts the insomnia sufferer during the night. We generally prefer using zolpidem or zaleplon as a first-line treatment for early-to-middle insomnia. Late insomnia often responds well to trazodone or eszopiclone, and trazodone often is a first choice in the presence of substance abuse for all insomnias. 

Whichever sedative-hypnotic agent is selected, the following guidelines can help ensure a safe and effective treatment. Use the minimal therapeutic dose at first to decrease possible hangover effects. Consider using the medication on an as-needed basis if the insomnia is intermittent, and after 2-4 weeks attempt a trial off medication to see if it is still required. Many individuals with chronic insomnia will relapse after a 14-28 day trial of treatment, but this time frame also affords an opportunity to implement sleep hygiene improvements. 

The sedative-hypnotic action of chloral hydrate should be explained by the formation of trichloroethanol, which is synthesized as a result of its reduction in tissues. Despite the fact that the precise mechanism of action of chloral hydrate is not known, it evidently acts analogous to ethanol on the CNS by inCTeasing membrane permeability, which leads to sedation or sleep. Chloral hydrate can be used for insomnia as an alternative to benzodiazepines. Synonyms for this drug are aquachloral, chloradorm, chloratol, noctec, and others. 

Quazepam (Doral) [C IV] [Sedative/Hypnotic/ Benzodiazepine] Uses Insomnia Action Benzodiazepine Dose 7.5-15 mg PO hs PRN i in elderly hqjatic failure Caution [X, /-] NA glaucoma Contra PRG, sleep apnea Disp Tabs SE Sedation, hangovCT, somnolence, resp depression Interactions T Effects W/ azole antifungals, cimetidine, digoxin, disulfiram, INH, levodopa, macrolides, neuroleptics, phenytoin, quinolones, SSRIs, verapamil, grapefruit juice, EtOH effects W/carbamazepine, rifampin, rifabutin, tobacco EMS Use caution w/ other benzodiazepines, antihistamines, opioids and verapamil, can T CNS depression concurrent EtOH and grapefruit juice use T CNS depression OD May cause profound CNS depression, confusion, bradycardia, hypotension, and altered reflexes flumazenil can be used as antidote activated charcoal may be effective... 

Insomnia includes a wide variety of sleep disturbances, such as difficulty in falling asleep, early or frequent awakenings, and remaining unrefreshed after sleep. Use of sedative-hypnotic drugs is one approach to the therapy of insomnia. Other measures include advice to avoid stimulants before retiring, maintenance of a proper diet, initiation of an exercise program, and avoidance of stressful or anxiety-provoking situations. 

A significant advantage of the benzodiazepines over other central nervous system depressants (e.g., the barbiturates) is that they possess a much greater separation between the dose that produces sleep and the dose that produces death. This increased margin of safety has been one of the major reasons benzodiazepines have largely replaced the barbiturates and other types of sedative-hypnotics in the treatment of anxiety and insomnia. In addition, benzodiazepine aclministration is associated with few side effects. 

All of the benzodiazepines will produce sedative-hypnotic effects of sufficient magnitude to induce sleep, provided that the dose is high enough. However, the aim in the treatment of sleep disorders is to induce sleep that is as close as possible to natural sleep so that the patient falls asleep quickly, sleeps through the night, and has sleep of sufficient quality to awake refreshed. 

Extensive sleep studies have been conducted with a variety of sedative-hypnotic drugs, and all of these drugs appear to alter the normal distribution of rapid eye movement (REM) and non-REM sleep. Most of the older sedative-hypnotic agents markedly depress REM sleep. In contrast, when the benzodiazepines are used in appropriate doses, they depress REM sleep to a much smaller extent. As with treatment of anxiety, the choice... 

Several Hi histamine antagonists (e.g., diphenhydramine, promethazine, and hydroxyzine) have been used as sedative-hypnotics, since they produce some degree of sedation. While this sedation is usually considered a side effect of their antihistaminic activity, in some cases the sedation is sufficient to allow the drugs to be used in the treatment of anxiety and sleep disturbances. For these drugs, the anxiolytic properties are thought to be a direct consequence of their ability to produce sedation. 

The principal disadvantages of barbiturates as hypnotics include the development of physical dependence, a relatively low therapeutic index (and the potential of poisoning, as in suicide), suppression of REM sleep, and possible hangover effects. As mentioned above, benzodiazepines (e.g., flurazepam or brotizolam) are hypnotics as effective as barbiturates and are much safer in terms of their therapeutic index, addiction potential, and REM sleep-deprivation effects. Thus benzodiazepines have displaced barbiturates as sedative hypnotics. 

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