Sleep disorders, sedative-hypnotics

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. 

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. 

Sedatives and hypnotics as a group, and BZDs in particular, are frequently implicated in drug-related hospital admissions in the elderly ( 333, 334). This group is at particular risk for abrupt drug discontinuation when hospitalized, with resulting withdrawal symptoms that may be unrecognized as such and attributed to other health problems (313, 335, 336 and 337). BZD hypnotics should not be routinely prescribed in the hospital unless the patient has a demonstrated sleep disorder ( 338). Even then, reassurance that restless sleep is normal in such a situation may obviate the need for a hypnotic ( 330). 

Assignment of a drug to the sedative-hypnotic class indicates that it is able to cause sedation (with concomitant relief of anxiety) or to encourage sleep. Because there is considerable chemical variation within the group, this drug classification is based on clinical uses rather than on similarities in chemical structure. Anxiety states and sleep disorders are common problems, and sedative-hypnotics are widely prescribed drugs worldwide. 

Several drugs with novel chemical structures have been introduced more recently for use in sleep disorders. Zolpidem, an imidazopyridine, zaleplon, a pyrazolopyrimidine, and eszopiclone, a cyclopyrrolone (Figure 22-4), although structurally unrelated to benzodiazepines, share a similar mechanism of action, as described below. Eszopiclone is the (S) enantiomer of zopiclone, a hypnotic drug that has been available outside the United States since 1989. Ramelteon, a melatonin receptor agonist, is a new hypnotic drug (see Ramelteon). Buspirone is a slow-onset anxiolytic agent whose actions are quite different from those of conventional sedative-hypnotics (see Buspirone). 

When these issues are taken into consideration, there is still a high frequency of primary insomnia, as well as secondary insomnia the primary cause of which cannot be satisfactorily treated. Many patients also have both a psychiatric disorder and a primary insomnia. Still others have a psychiatric disorder requiring a sleep-disrupting antidepressant. Here we will discuss the use of sedative-hypnotics for these patients. 

RBD is characterized by a relative absence of the atonia characteristic of REM sleep. This lack of atonia permits the physical acting out of dream mentation, particularly dreams involving confrontation, aggression and violence. RBD is seen most frequently in older men. RBD occurs in both acute and chronic forms. Acute RBD can occur during withdrawal from alcohol or sedative-hypnotics. RBD has also been induced by the tricyclics, SSRIs and venlafaxine. The chronic form of RBD may occur as part of an identifiable underlying neurological disorder, but typically is idiopathic. RBD may also be an initial manifestation of parkinsonism. RBD is very responsive to clonazepam, although this use has not been FDA approved. 

Flunitrazepam is a tranquilizer developed in the 1960s by Hoffmann-LaRoche, Inc., and first marketed under the trade name Rohypnol in Switzerland in 1975. It is a member of a class of drugs called the benzodiazepines, which includes drugs such as Librium , Xanax , and Valium. This family of sedative-hypnotic drugs is used to treat anxiety, convulsions, muscle tension, and sleep disorders. Rohypnol is a very powerful sedative that can last up to 12 hours, with some residual effects lasting as long as 24 hours. Rohypnol is 10 times more potent than the most commonly known benzodiazepine, Valium (Figure 2.1). 

Methyprylon is a sedative-hypnotic agent that has been used in the treatment of anxiety, nervousness, and sleep disorders (insomnia). The drug was withdrawn from the US market in 1988. It was a commonly abused sedative-hypnotic agent. 

Valerian is promoted in the United States primarily as a sedative-hypnotic for treatment of insomnia, and as an anxiolytic for restlessness and sleeping disorders associated with anxiety (4,7). 

The following are a number of selected websites that pertain to sleep disorders and/or sedative-hypnotics. 

The use of sedative-hypnotics for sleep (hypnotic) should be short term or there is a chance that the patient could become dependent on the medication or develop a tolerance. Patients who take high doses of sedative-hypnotics over long periods must gradually discontinue the medication rather than abruptly stopping the dmg which can cause withdrawal symptoms. Sedative-h5 notics should not be administered to patients who have severe respiratory disorders or who are pregnant. 

Drugs that act as agonists at this receptor are used mostly but not exclusively in sleep and anxiety disorders. Benzodiazepines (see later) have hypnotic, sedative, anxiolytic, anticonvulsant and (central) muscle relaxant actions. They form a significant but not the only part of available pharmacological treatments, as the following account will illustrate. 

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