Sedative-hypnotics agents

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... 

Taper off antipsychotics, benzodiazepines or sedative-hypnotic agents if possible... 

Glutarimides may be regarded as oxidized piperidines, and many drugs containing this moiety are sedatives and anticonvulsants. A spiro derivative, alonimid (105) is such a sedative-hypnotic agent. It can be prepared by K t-butoxide catalyzed biscyano-ethylation of phenylacetonitrile, leading to 101. Alkaline hydrolysis produces tricarboxylic acid 102 which is smoothly Converted to the glutaric acid anhydride (103) with acetic anhydride. Friedel-Crafts... 

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 following general discussion of the barbiturates refers to their use as sedative-hypnotic agents and as anticonvulsants. 

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... 

Chloral hydrate (Noctec, Somnos) was developed in the late 1800s and is still used as a sedative-hypnotic agent. It is a hydrated aldehyde with a disagreeable smell and taste that is rapidly reduced in vivo to trichloroethanol, which is considered to be the active metabohte. It produces a high incidence of gastric irritation and allergic responses, occasionally causes cardiac arrhythmias, and is unreliable in patients with liver damage. 

The utility of barbituric acid derivatives as sedative-hypnotic agents is discussed in more detail later in this chapter. Studies on the chemical simplification of these pyrimidinetrione derivatives led to the discovery that pyridinediones, or glutarimides,... 

The barbimrate sedative-hypnotic agents arguably constitute the oldest class of medicinal agents whose synthesis was not prompted by some biologically active natural product. The first compound in this series, barbital (67-3) (R = = Et), has... 

Treatment With Antianxiety and Sedative-Hypnotic Agents... 

Finally, long-term insomnia is not only persistent but disabling. Studies suggest that almost all of these patients have either an associated psychiatric disorder, an associated drug use, abuse, or withdrawal problem, or an associated medical disorder. As mentioned above, treatment of these associated disorders may be sufficient to treat the insomnia as well. However, if the underlying disorder is not treatable or if there is a requirement to relieve the symptom of insomnia before the underlying condition can be relieved, it may be necessary to treat the insomnia symptomatically with a sedative-hypnotic agent. 

The newer sedative-hypnotics that are not benzodiazepines are rapidly becoming the first-line treatment for insomnia. These agents not only have pharmacodynamic advantages over benzodiazepines in terms of their mechanism of action, but perhaps more importantly, pharmacokinetic advantages as well. Three nonbenzodiazepine sedative-hypnotic agents that are now available are zaleplon (a pyrazolopyrimidine), zopiclone (a cyclopyrrolone not available in the United States), and zolpidem (an imidazopyridine) (Figs. 8—28-8—30 Table 8—4). 

The nonbenzodiazepine sedative-hypnotics zaleplon, zolpidem, and zopiclone are replacing benzodiazepine sedative-hypnotics as first-line treatments for insomnia. Some antidepressants, such as sedating tricyclic antidepressants and trazodone, are also used as sedative-hypnotic agents for the treatment of insomnia. 

Although they have been used for over 30 years, benzodiazepines are still widely prescribed in the treatment of anxiety disorders and other medical conditions. These drugs are classified as sedative-hypnotic agents, which depress or slow down the body. In the past 15 years, the development of the newer selective serotonin reuptake inhibitors (SSRIs) for the treatment of depression and anxiety have pushed benzodiazepines aside as the first treatment choice because the SSRIs as a class of drugs have not yet been found to be addictive. 

The researchers Joseph von Mering and Emil Fischer, a student of von Baeyer, developed the first barbiturate drug to be marketed. Fischer produced 5.5-diethylbarbituric acid, a hypnotic (medication to help patients sleep) and sedative (medication to relax people with constant nervousness and anxiety). This sedative/hypnotic drug was known by the trade names Barbital, Veronal, and Dorminal. Barbital proved to be a more effective sedative/hypnotic agent and replaced the class of drugs, sedative bromides, which were used at the time.14... 

Barbiturates are still used as sedative/hypnotic agents (see Chapter 3), but they have been largely replaced by benzodiazepines for treatment of anxiety and insomnia (difficulty sleeping). Barbiturates are still used occasionally, but benzodiazepines have proven to be much safer and have less risk of accidental overdose. 

I could not locate any reliable recent estimates for the number of patients taking BZs. More than a decade ago, it was estimated that 15% of American adults used these or similar sedative/hypnotic agents during any given year, usually through a physician s prescription (Gold et al., 1995). Almost 2% of the population was using BZs more or less chronically (DuPont, 1986). In 1993, Xanax topped the list for frequency of use, followed by Klonopin. 

People who use BZs to calm their anxiety will frequently use alcohol and other sedatives interchangeably for the same purpose, either in combination or at different times. As they switch from drug to drug, they tend to find little or no difference in the antianxiety effect. This confirms that BZs have no specificity for anxiety in comparison to other sedative/ hypnotic agents. 

The effects of the BZs on the electroencephalogram (EEG) resemble those of other sedative/hypnotic agents, including decreased alpha activity and increased low-voltage fast activity, especially beta activity (Rail, 1990). Their effects on sleep are also similar to those of other CNS depressants and provide a window into the dysfunctions they produce (Rail, 1990). 

Alprazolam, 269, a popular sedative/hypnotic agent and benzodiazepine receptor agonist, has been labelled257 with 11C in metabolically stable position in reaction of the amidrazone, 7-chloro-5-phenyl-3//-l,4-benzodiazepine-2-yl hydrazone, 270, with 1-[ Cjacetyl chloride followed by pyrolysis of the resulting 1-acetylhydrazone 271. Compound 269 has been obtained in 43-65% yield during 40-55 min at specific activity 0.93-2.18 Ci /miol-1, and used for metabolism and tissue distribution studies257 (equation 107). 

The introduction of chlordiazepoxide (Librium) into clinical medicine in 1961 ushered in the era of benzodiazepines. Most of the benzodiazepines that have reached the marketplace were selected for their effectiveness as antianxiety agents, not for their ability to depress CNS function. However, all benzodiazepines possess sedative-hypnotic properties to varying degrees these properties are extensively exploited clinically, especially to facilitate sleep and ease anxiety. Mainly because of their remarkably low capacity to lead to fatal suppression of key CNS functions, the benzodiazepines have displaced barbiturates as sedative-hypnotic agents. 

Weitzel KW, Wickman JM, Augustin SG, Strom JG. Zaleplon a pyrazolopyrimidine sedative-hypnotic agent for the treatment of insomnia. Clin Ther 2000 22 1254-67. 

One of the most popular sedative hypnotic agents in psychopharmacology... 

Keywords Acetylcholine Autonomic nervous system Cyclosporine Epinephrine General anesthetics Immunostimu-lating agents Immunosuppressive agents Mycophenolate mofetil Opioid drugs Sedative-hypnotic agents... 

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