Anxiolytics sleep

Benzodiazepines are used as daytime anxiolytics, sleep inducers, anesthetics, anticonvulsants (also known as antiseizure agents), and muscle relaxants they will be discussed in depth in Chapters 20 and 22. Examination of the basic pharmacodynamic properties of the benzodiazepines (defined as receptor-specific binding activity) show that the clinically useful benzodiazepines exhibit comparable sedative activity at therapeutically comparable doses (Fig. 19.1) (13). The use of a specific benzodiazepine as a hypnotic is based primarily on... 

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. 

Benzodiazepines and other anxiolytics. Although benzodiazepines are widely used in the treatment of acute alcohol withdrawal, most nonmedical personnel involved in the treatment of alcoholism are opposed to the use of medications that can induce any variety of dependence to treat the anxiety, depression, and sleep disturbances that can persist for months following withdrawal. Researchers have debated the pros and cons of the use of benzodiazepines for the management of anxiety or insomnia in alcoholic patients and other substance abuse patients during the postwithdrawal period (Ciraulo and Nace 2000 Posternak and Mueller 2001). 

Neuropeptide S (NPS) is a recently discovered bioactive peptide that has emerged as a new signaling molecule in the complex circuitry that modulates sleep-wakefulness and anxiety-like behavior. The peptide precursor is expressed most prominently in a novel nucleus located in the perilocus coeruleus, a brain structure with well-defined functions in arousal, stress, and anxiety. NPS was also found to induce anxiolytic-like behavior in a battery of four different tests of innate responses to stress. Infusion of NPS potently increases wakefulness and suppresses non-REM (NREM) and REM sleep (Xu et al, 2004). NPS binds to a G-protein-coupled receptor, the NPS receptor, with nanomolar affinity activation of the receptor mobilizes intracellular calcium. The NPS receptor is expressed throughout the brain, particularly in regions relevant to the modulation of sleep and waking, in the tuberomammillary region, lateral hypothalamus, and medial thalamic nuclei. 

Zolpidem, chemically unrelated to benzodiazepines or barbiturates, acts selectively at the y-aminobutyric acidA (GABAA)-receptor and has minimal anxiolytic and no muscle relaxant or anticonvulsant effects. It is comparable in effectiveness to benzodiazepine hypnotics, and it has little effect on sleep stages. Its duration is approximately 6 to 8 hours, and it is metabolized to inactive metabolites. Common side effects are drowsiness, amnesia, dizziness, headache, and GI complaints. Rebound effects when discontinued and tolerance with prolonged use are minimal, but theoretical concerns about abuse exist. It appears to have minimal effects on next-day psychomotor performance. The usual dose is 10 mg (5 mg in the elderly or those with liver impairment), which can be increased up to 20 mg nightly. Cases of psychotic reactions and sleep-eating have been reported. 

Benzodiazines bind to GABAa receptors, and they have sedative, anxiolytic, muscle relaxant, and anticonvulsant properties. They increase stage 2 sleep and decrease REM and delta sleep. 

Herbai sedatives and anxioiytics are a diverse group of plant drugs that commonly act as depressants of the central nervous system (CNS) (table 6.1). Pharmaceutical CNS depressants are used as anxiolytics, anti-epiieptics, sedatives, sleep-inducers (sedatives or hypnotics), general anesthetics, and recreationai drugs (e.g., ethanol) (table 6.2). CNS... 

Depending on their blood levels, both benzodiazepines and barbiturates produce calming and sedative effects, the former group also being anxiolytic. At higher dosage, both groups promote the onset of sleep or induce it (C). 

The range of elimination half-lives for different benzodiazepines or their active metabolites is represented by the shaded areas (B). Substances with a short half-life that are not converted to active metabolites can be used for induction or maintenance of sleep (light blue area in B). Substances with a long half-life are preferable for long-term anxiolytic treatment (light green area)... 

Diazepam exhibits anxiolytic, sedative, soporific, central myorelaxant, and anticonvulsant action. It suppresses feelings of fear, worry, and stress. It is nsed for nervons stress, excitement, anxiety, sleep distnrbance, neurovegetative disorders, psychonenrosis, obsessive neurosis, hysterical or hypochondriac reactions, and phobias. The most freqnently used synonyms are sednxen, relaninm, valium, sibazon, apaurin, and many others. 

Related hypnotics that also act at benzodiazepine receptors are the newer agents zolpidem, a imida-zopyridine, zaleplon a pyrazolopyrimidine and the cyclopyrrolone zopiclone. Zopiclone might have a role for the treatment of benzodiazepine addiction. In patients in whom zopiclone was substituted for a benzodiazepine for 1 month and then itself abmptly terminated, improved sleep was reported during the zopiclone treatment, and withdrawal effects were absent on discontinuation of zopiclone. A series of non-sedating anxiolytic drugs derived from the same structural families as the above mentioned nonbenzodiazepines, have been developed, such as alpi-dem and pagoclone. 

The longstanding use in some countries of hydroxyzine, a centrally-acting Hi-histamine receptor antagonist, is supported by positive findings in controlled trials in GAD (Ferreri and Hantouche 1998 Lader and Scotto 1998). Hydroxyzine promotes sleep and its anxiolytic effects have an early onset. Although it causes sedation, tolerance to this effect often occurs and effects on psychomotor performance are smaller than with benzodiazepines (de Brabander and Deberdt 1990). It is well-tolerated and withdrawal effects have not been reported. Although the evidence for its efficacy is not large, hydroxyzine provides an option for some patients with GAD for whom standard treatments are unsuitable. 

In usual sedative doses, zolpidem preserves deep sleep (stages 3 and 4) and has only minor and inconsistent effects on REM sleep. Compared with the benzodiazepines, zolpidem has relatively weak anxiolytic, anticonvulsant, and skeletal muscle relaxant properties at therapeutic doses. Zolpidem has a rapid onset and a relatively short duration of action. It is well absorbed after oral administration, with approximately 70% bioavail-abUity. It undergoes hydroxylation and oxidation to inactive metabohtes in the fiver. Its elimination half-life is approximately 2.5 hours, which is usually sufficient to provide for a normal 8 hours of sleep without daytime grogginess. 

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. 

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