Sedative-hypnotic drugs benzodiazepines

For testing sedative hypnotic drugs of the triazolam type the preparation was undertaken of 8-chloro-6-(o-chlorophenyl)-4ff-.y-triazolo[4,3-a][l,4]benzodiazepin-1 -valeric acid methyl ester as an intermediate, with subsequent cyclization and amida-... 

Buspirone is as effective as the benzodiazepines in the treatment of general anxiety. However, the full anxiolytic effect of buspirone takes several weeks to develop, whereas the anxiolytic effect of the benzodiazepines is maximal after a few days of therapy. In therapeutic doses, buspirone has little or no sedative effect and lacks the muscle relaxant and anticonvulsant properties of the benzodiazepines. In addition, buspirone does not potentiate the central nervous system depression caused by sedative-hypnotic drugs or by alcohol, and it does not prevent the symptoms associated with benzodiazepine withdrawal. 

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... 

Withdrawal from long-term high-dose use of alcohol or sedative-hypnotic drugs can be life threatening if physical dependence is present. Benzodiazepines, such as chlordiazepoxide Librium) and diazepam Valium), are sometimes used to lessen the intensity of the withdrawal symptoms when alcohol or sedative-hypnotic drug use is discontinued. Benzodiazepines are also employed to help relieve the anxiety and other behavioral symptoms that may occur during rehabilitation. 

Buspirone causes less psychomotor impairment than benzodiazepines and does not affect driving skills. The drug does not potentiate effects of conventional sedative-hypnotic drugs, ethanol, or tricyclic antidepressants, and elderly patients do not appear to be more sensitive to its actions. Nonspecific chest pain, tachycardia, palpitations, dizziness, nervousness, tinnitus, gastrointestinal distress, and paresthesias and a dose-dependent pupillary constriction may occur. Blood pressure may be significantly elevated in patients receiving MAO inhibitors. 

Benzodiazepines, barbiturates, and most older sedative-hypnotic drugs exert calming effects with concomitant reduction of anxiety at relatively low doses. In most cases, however, the anxiolytic actions of sedative-hypnotics are accompanied by some depressant effects on psychomotor and cognitive functions. In experimental animal models, benzodiazepines and older sedative-hypnotic drugs are able to disinhibit punishment-suppressed behavior. This disinhibition has been equated with antianxiety effects of sedative-hypnotics, and it is not a characteristic of all drugs that have sedative effects, eg, the... 

Blocks actions of benzodiazepines and zolpidem but not other sedative-hypnotic drugs... 

Overdosage with ethanol and sedative-hypnotic drugs (eg, benzodiazepines, barbiturates, 7-hydroxybutyrate [GHB], carisoprodol [Soma] see Chapters 22 and 23) occurs frequently because of their common availability and use. 

Several drugs with novel chemical structures have been introduced recently. Buspirone is an anxiolytic agent that has actions different from those of conventional sedative-hypnotic drugs. Zolpidem and zaleplon, while structurally unrelated to benzodiazepines, share a similar mechanism of action. 

The extensive clinical use of triazolam has led to reports of serious central nervous system effects including behavioral disinhibition, delirium, aggression, and violence. While behavioral disinhibition may occur with sedative-hypnotic drugs, it does not appear to be more prevalent with triazolam than with other benzodiazepines. Disinhibitory reactions during benzodiazepine treatment are more clearly associated with the use of very high doses and the pretreatment level of patient hostility. 

Diazepam, lorazepam, and midazolam are used in anesthetic procedures. The primary indication is for premedication because of their sedative and amnestic properties. (The basic pharmacology of benzodiazepines is discussed in Chapter 22 Sedative-Hypnotic Drugs.) Diazepam and lorazepam are not water-soluble, and their intravenous use necessitates nonaqueous vehicles, which may cause local irritation. Midazolam formulations are water-soluble and thus produce less irritation, but the drug becomes lipid-soluble at physiologic pH and readily crosses the blood-brain barrier. 

Finally, very rapid onset benzodiazepines have been widely reported as a means of "date rape," by using a small tasteless dose of the drug to make the victim incapable of protecting herself (or himself). This produces intoxication but not dependence. The drug most commonly used in this situation has been flunitrazepam (Rohypnol, "roofies," not available in the USA) and more recently GHB. The amnesia-producing effects of the benzodiazepines (see Chapter 22 Sedative-Hypnotic Drugs) make the victim unable to describe the events after she or he has recovered. 

Benzodiazepines such as lorazepam or diazepam are used prior to the initiation of chemotherapy to reduce anticipatory vomiting or vomiting caused by anxiety. The pharmacology of these agents is presented in Chapter 22 Sedative-Hypnotic Drugs. 

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). 

Sedation should be avoided and therapy should be oral if possible regimens should be planned to avoid breakthrough pain. Antidepressants can often be useful. Sedative-hypnotic drugs, e.g. benzodiazepines, may be needed for anxiety but may induce depression. 

Sedative-hypnotic drugs and anxiolytic drugs are CNS depressants that are used medically to reduce anxiety and/or induce sleep. They may also be used as anticonvulsants. Phenobarbital, for example, is often the maintenance drug of choice for seizure-prone individuals. In general, the sedative-hypnotic family of drugs includes alcohol, barbiturates, benzodiazepines, and such barbiturate-like drugs as chloral hydrate, glutethi-mide, meprobamate, and methaqualone. 

As noted, the barbiturates once were used extensively as sedative-hypnotic drugs, but except for certain specialized uses they now have been replaced by the safer benzodiazepines. Short-acting barbiturates still are used to produce anesthesia. Other current uses include emergency treatment of convulsions and prevention of seizures in persons with certain types of epilepsy (Perrine, 1996). 

Triazolam, USP. Triazolam. 8-chloro-6-(o-chlorophc-nyl)-l-methyl-4Ay-j-triaz.olol4.3-a f l,4 benzxxliazcpinc (Hal-cion). has all of the characteristic benzodiazepine pharmacological actions. It is marketed as a sedative-hypnotic drug said to impair little, if any. daytime function. It is rapidly metabolized to the I-methyl alcohol, which is then conjugated and excreted. 

For details of the chemistry and SARs of the benzodiazepines. see the discussion of anxiolytic-.sedative-hypnotic drugs. Among the present clinically useful drugs, the structural features associated with anticonvulsant activity arc identical with those as.sociatcd with anxiolytic-scda-tive-hypnutic activity. - Animal models predict that benzodiazepines are modestly effective against generalized tonic-clonic and partial seizures and very highly active... 

The benzodiazepines are primarily administered for their sedative-hypnotic effects. Benzodiazepines are commonly used as anxiolytics, muscle relaxants, anticonvulsants, and to treat alcohol withdrawal, insomnia, and agitation. They are administered pre-operatively for their anterograde amnesia effects and are combined frequently with other medications for conscious sedation before procedures. They are also utilized as drugs of abuse. 

S.2.2.2 Barbiturates. A major event in the field was the launching of barbital (6,5-dieth-ylbarbituric acid) in 1903 and phenobarbital (5-ethyl-5-phenylbarbituricacid)in 1912. The barbiturates dominated the field for nearly 50 years, until the launch of Librium (chlordiaz-epoxide) in 1960, the first of the benzodiazepine class drugs. Benzodiazepines completely overtook the barbiturates and had become The dominant class of sedative hypnotic drugs until the launch of retrocyclic sedative-hypnotics. 

---