Benzodiazepines chlordiazepoxide

Sternbach, LH, Randall, LO and Gustafson, SR (1964) 1,4-Benzodiazepines (chlordiazepoxide and related compounds). In Medicinal Chemistry, Volume 1, Psychopharmacological Agents (Ed. Gordon, M), Academic Press, New York London, pp. 137-224. 

The first benzodiazepine, chlordiazepoxide, was initially synthesized in 1947 and first sold commercially in i960 as Librium (because it produced an emotional equilibrium). Shortly thereafter, diazepam was sold as Valium (Latin for be strong and well ) and quickly became the most prescribed anti-anxiety drug in the western world. Both of these drugs are converted into other psychoactive agents within the brain and body. Some of these metabolites were isolated from the urine of people taking Valium and Librium and were discovered to be quite... 

Cornelissen PJG, Beijersbergen van Henegouwen GMJ, Gerritsma KW. Photochemical decomposition of 1,4-benzodiazepines. Chlordiazepoxide. Int J Pharm 1979 3 205-220. 

Cornellissen PJ, Beijersbergen van Henegouwen G, Gerritsma KW. Photochemical decomposition of 1,4-benzodiazepines. Chlordiazepoxide. Int J Pharm 1979 3 205-220. Vargas F, Rivas C, Canudas N. Formation of a perbenzoic acid derivative in the photodegradation of fenofibrate phototoxicity studies on etrythrocytes. J Pharm Sci 1993 87(6) 590-591. 

Clinically important, potentially hazardous interactions with alprazolam, benzodiazepines, chlordiazepoxide, clonazepam, clorazepate, diazepam, dihydroergotamine, ergot, flurazepam, lorazepam, methysergide, midazolam, oral contraceptives, oxazepam, quazepam, temazepam, triazolam... 

A few cases have been reported of slight and insignificant delays in the absorption of benzodiazepines (chlordiazepoxide and diazepam) and possibly more significant delays in absorption with clorazepate (activated by acid conditions). 

Benzodiazepines Chlordiazepoxide, diazepam, temazepam Alprazolam, clonazepam Flurazepam, lorazepam, nitrazepam, oxazepam, triazolam... 

A novel crystal form II of the benzodiazepine chlordiazepoxide was reported [49] the standard form I and the new one II are similar with respect to the cell volume or crystal symmetry. Both structures consist of a pair of hydrogen-bonded dimers in the asymmetric unit. The major difference is the crystal packing of the dimers in the form II the dimers are displaced with respect to each other. Both forms were characterized by solid-state C NMR and the obtained spectra were different. The splitting of the methyl group signal was observed in II. Notable differences were also found for aromatic and olefinic carbons. The differing chemical environments in the two crystal structures can explain these effects. 

Benzodiazepines, therapeutically used as tranquillizers, hypnotics, anticonvulsants, and centrally acting muscle relaxants, rank among the most frequently prescribed drugs. In 1960, the first benzodiazepine, chlordiazepoxide, was introduced. To date, more than 50 benzodiazepines have been marketed in over 100 different preparations. They appear mainly as capsules and tablets, however, some are marketed in other forms such injectable solutions or powders. Benzodiazepines were introduced to replace barbiturates and methaqualone as tranquillizers, hypnotics, anticonvulsants, and muscle relaxants. Currently there are 33 benzodiazepines on the control list all of which appear as tablets or capsules, though some also appear as vials or powders for preparation of injection (Figure 7). 

The benzodiazepines currently available for clinical use vary substantially in pharmacokinetics, acute euphoriant effects, and frequency of reported dependence. It is likely, therefore, than not all benzodiazepines have the same potential for abuse. Diazepam, lorazepam, and alprazolam may have greater abuse potential than chlordiazepoxide and clorazepate (Wolf et al. 1990). Similarly, oxazepam has been reported to produce low levels of abuse (Eliding 1978). Jaffe et al. (1983) found that in recently detoxified alcoholic patients, halazepam produces minimal euphoria even at a supratherapeutic dosage. The development of partial agonist and mixed agonist/antagonist compounds at the benzodiazepine receptor complex may offer an advantage over approved benzodiazepines for use in alcoholic patients. 

Medical use of benzodiazepines has been declining. Prescribing trends show an overall decline in the number of all benzodiazepine prescriptions written, with a market shift to increased prescribing of short elimination half-life agents (lorazepam, alprazolam), compared with long-elimination half-life agents (diazepam, chlordiazepoxide) (Ciraulo et al. 2004). In 2001, alprazolam was the most widely prescribed benzodiazepine (Ciraulo et al. 2004), and it also was the most widely prescribed psychiatric medication in that year for mood and anxiety disorders (Stahl 2002). 

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

Figure 19.4 The activity spectrum of the benzodiazepines. Motor impairment and CNS depression increases with drug dose. (Based on data for chlordiazepoxide (Sternbach, Randall and Gustafson 1964))...

Benzodiazepines (including alprazolam, chlordiazepoxide, diazepam, flurazepam, halzepam, prazepam, triazolam)... 

Benzodiazepines are the evidence-based treatment of choice for uncomplicated alcohol withdrawal.17 Barbiturates are not recommended because of their low therapeutic index due to respiratory depression. Some of the anticonvulsants have also been used to treat uncomplicated withdrawal (particularly car-bamazepine and sodium valproate). Although anticonvulsants provide an alternative to benzodiazepines, they are not as well studied and are less commonly used. The most commonly employed benzodiazepines are chlordiazepoxide, diazepam, lorazepam, and oxazepam. They differ in three major ways (1) their pharmacokinetic properties, (2) the available routes for their administration, and (3) the rapidity of their onset of action due to the rate of gastrointestinal absorption and rate of crossing the blood-brain barrier. 

Oxazepam is available in oral form only, so it is useful only for uncomplicated withdrawal. Other benzodiazepines are available in injectable form and will be further described below. Diazepam and lorazepam are more lipophilic than chlordiazepoxide and oxazepam, resulting in quicker gastrointestinal absorption and passage across the blood-brain barrier, which makes them valuable in an inpatient setting, especially to treat or prevent seizures. However, their faster onset of action maybe associated with feeling high, which can be a disadvantage of their use. 

Diazepam and its nordiazepam, oxazepam, and temazepam metabolites are well retained by the MIP, while they are much less retained on NIP, also exhibiting large RSD. Other benzodiazepines of similar structures (Figure 1.50) were well retained on the MIP, showing that this template can be used for the general class of benzodiazepines. Two benzodiazepines studied, chlordiazepoxide and flunitrazepam, were poorly retained, indicating poor fit of these structures into the templated MIP. 

Some of the benzodiazepine group of tranquillizers and hypnotics, for example, chlordiazepoxide and nitrazepam, have been shown to be phototoxic [221],... 

Chlordiazepoxide is the pioneer member of the 1,4-benzodiazepines to be employed clinically as an antianxiety agent in humans. A number of methods based on extraction processes are available for the assay of this drug, namely spectrofluorometry, polarography and electron-capture GC-technique but RIA measures it directly in the blood without involving extraction and possesses very low sensitivity. 

Specificity of Antibody binding of Chlordiazepoxide A good number of benzodiazepines are tested for their ability to complete with labelled chlordiazepoxide for the respective antibody binding site. The various competitors are adequately tested at a concentration of 200 ng i.e.., 10-times the concentration of chlordiazepoxide required to produce a 50% inhibition of binding as shown in Table 32.2. 

Hydrolytic cleavage of a seven-membered ring occurs in the metabolism of chlordiazepoxide (5.82, Fig. 5.22,a) and other benzodiazepines (see also Sect. 11.9). The lactam ring opened metabolite 5.83 was detected in humans and dogs and is believed to be generated by hydrolysis of the intermediate lactam [181][182], However, the diazepine ring can be split by other mech-... 

Benzodiazepines. Like the barbiturates, benzodiazepines bind to the GABA receptor and are therefore cross-tolerant with alcohol. As a result, they also make suitable replacement medications for alcohol and are widely used for alcohol detoxification. Theoretically, any benzodiazepine can be used to treat alcohol withdrawal. However, short-acting benzodiazepines such as alprazolam (Xanax) are often avoided because breakthrough withdrawal may occur between doses. Intermediate to long-acting benzodiazepines including chlordiazepoxide (Librium), diazepam (Valium), oxazepam (Serax), lorazepam (Ativan), and clonazepam (Klonopin) are more commonly utilized. 

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. 

In essence, all of the older benzodiazepines that are structurally related to chlordiazepoxide and diazepam are termed 1,4-benzodiazepines. The chemical structure of some commonly used benzodiazepines is shown in Figure 9.2. They enhance the actions of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the brain. As a consequence, they affect the activities of the cerebellum (concerned with balance and coordination), the limbic areas of the brain and the cerebral cortex (thought and decision making, fine movement control). 

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