Anxiolytics chlordiazepoxide

Benzodiazepines such as chlordiazepoxide (Librium) and diazepam (Valium) were discovered in the early 1960s and found to have clinically important anxiolytic. 

Although the chemical structure of the benzodiazepines was first described by Sternbach in the 1930s, the clinical efficacy of these anxiolytics was only fully realized following a clinical trial of chlordiazepoxide by Harris in the USA in 1960. 

Chlordiazepoxide (Librium, Mitran, libritabs) [C-IV] [Anxiolytic, Sedative/Hypnotic/Benzodiazepine] Uses Anx-... 

The benzodiazepines constitute the most commonly used group of anxiolytics and sedative-hypnotics. Since the first member of this group, chlordiazepoxide, was introduced, many congeners have been marketed. Most of these drugs possess anxiolytic, sedative-hypnotic, and anticonvulsant properties. Thus, the clinical indications for specific benzodiazepines are not absolute, and their uses overlaps considerably. 

The CNS depressants include barbiturates, nonbarbiturate sedatives, and the benzodiazepines. As the medical use of barbiturates decreased, primarily because of their high addiction liability and the danger of acute lethality, the use of the benzodiazepine anxiolytics increased. The most commonly abused barbiturates are secobarbital, pentobarbital, and amobarbital. Pheno-barbital is not generally abused, because of its slow onset of action. The most commonly abused anxiolytics include diazepam, chlordiazepoxide, midazolam, lo-razepam, and flurazepam. These drugs are readily attainable from illicit sources. 

During the early twentieth century the barbiturates were used in children and adolescents for their sedative and hypnotic effects however, their safety profile and propensity to cause physical dependence led scientists in search of safer anxiolytics. The development of animal models of behavioral disorders facilitated the formulation of drugs with more specific central nervous system (CNS) effects. In 1959, chlordiazepoxide (Librium) was the first benzodiazepine (BZ) to receive a patent. It entered the market in 1960, followed by diazepam (Valium) in 1963. Today, over 35 BZs have been formulated and over 10 are available in the United States (Ballenger, 1995 Hobbs et ah, 1996). 

This difference m body temperature is called stress-induced hyperthermia (SIH) and is thought to reflect an anticipatory type of anxiety. Following pretreatment of all mice hvmg m the same cage with an anxiolytic compound (chlordiazepoxide m the example given m Fig. 10), the body temperature of the... 

Figure 4.10 Anxiolytic effect of chlordiazepoxide (CDZ) r the slress-nduced...

File, Si. The use of social interaction as a method for detecting anxiolytic activity of chlordiazepoxide-like drugs. J. NeuroscL Methods 2 219—238, 1980. 

OFFICIAL NAMES Minor tranquilizers (sedative-hyp-notics/anxiolytics)/Benzodiazepines Alprazolam (Xanax) chlordiazepoxide (Librium, Novopoxide) clonazepam (Klonopin) clorazepate (Azene, Tranxene) diazepam (Valium) estazolam (ProSom) flunitrazepam (Rohypnol/illegal in the United States) flurazepam (Dalmane) halazepam (Paxipam) lorazepam (Ativan) midazolam (Versed) oxazepam (Serax) prazepam (Centrax) quazepam (Doral) temazepam (Restoril) triazolam (Halcion)... 

Most of the minor tranquilizers in the BZD exhibit similar clinical effects they differ primarily in their duration of action and in the dosage required to achieve the same effect. The BZDs are classified as short- (triazolam [Halcion]), intermediate- (alprazolam [Xanax] and lorazepam [Ativan]), and long-acting (chlordiazepoxide [Librium] and diazepam [Valium]). Of the various BZDs available in the United States in 2002, those primarily prescribed as anxiolytics and hypnotics include the intermediate- and long-acting variety. 

The coat state assessment is a fast and simple qualitative method of assessing mouse depression-like states through observation of the condition of an animal s fur. In rodents, coat state tends to decline with increased depression, similar to depressed patients who frequently exhibit poor hygiene (29-31). Antidepressants have been shown to improve the coat condition of mice while reducing depression-like symptoms (29-31). For example, the reduction of corticotropin-releasing factor (CRF) has been associated with improved coat state (and is implicated in depression) (32). Of importance here, antidepressants (e.g., imipramine) and anxiolytics (e.g., chlordiazepoxide) have been shown to interact with corticotropin-releasing factor (33) (see Note 7). 

Historically the first sedative hypnotics to be introduced were the bromides in the mid 19th century, shortly followed by chloral hydrate, paraldehyde and urethane. It was not until the early years of this century that the first barbiturate, sodium barbitone, was developed and this was shortly followed by over 50 analogues, all with essentially similar pharmacological properties. The major breakthrough in the development of selective, relatively non-toxic sedative hypnotics followed the introduction of chlordiazepoxide in 1961. Most of the benzodiazepines in current use have been selected for their high anxiolytic potency relative to their central depressant effects. Because of their considerable safety, the benzodiazepines have now largely replaced the barbiturates and the alcohols, such as chloral hydrate and trichloroethanol, as the drugs of choice in the treatment of insomnia. 

According to the chemical structure, the anxiolytic agents used in allopathic medicine may be divided into three classes carbamate of propanodiol and related compounds, BZDs and several others compounds. The most effective are the BDZs Chlordiazepoxide, Fig. (3), which was commercialized in 1960 as a therapeutic innovation for the treatment of anxiety. As from the identification of its property, dozens of new BDZs derivates were commercialized, including diazepam. Fig. (3), one of the medicines most prescribed worldwide. 

The best-known and most-used anxiolytics are the benzodiazepines, of which those in use include alprazolam, bromazepam, chlordiazepoxide, clobazam, clonazepam, diazepam, flunitrazepam, halazepam, loprazolam, lorazepam, medazepam, midazolam, oxazepam, quazepam, temazepam and triazolam. The benzodiazepines work by acting as benzodiazepine binding-SITE AGONISTS at a site of the GABA receptors. 

Benzodiazepines. After the first phase of the launch of heterocyclic sedative-hypnotics, as exemplified by glutethimide and methyprylone, most significant milestones were reached by Roche. In 1960, Roche launched Librium (chlordiazepoxide)and in 1963, Valium (diazepam). These two compounds were the first two 1,4-benzodiazepine class compounds launched in the world. Subsequently a number of companies launched several other 1,4-benzodiazepines for a number of indications (sedative-hypnotic, anxiolytic, anticonvulsant, and muscle relaxant). 

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