Chlordiazepoxide dosage

Table 7.2 Comparison of Diazepam and Chlordiazepoxide Dosage Form Analysis Using SFC and HPLC...

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. 

According to Sternbach s account of the discovery of chlordiazepoxide, chance was also at work in the laboratories of Hoffmann-1 a Roche, although in a different way of the series of substances that Stembach had synthesized, why should it have been chlordiazepoxide, of all others, that had been left behind untested in the chemist s laboratory Rather than stressing this chance occurrence, the well-conducted clinical trial of the experimental preparation should be emphasized instead. This study was not restricted to a single indication or dosage range, but was extended in the face of initial unfavorable results into those indications within which the then standard preparation meprobamate achieved its best results (Cohen, 1970). 

Benzodiazepines undergo extensive and complex metabolism. They are excreted mainly in the urine, largely in the form of several metabolites. Biotransformation processes include mainly hydroxylation and A-dealkylation reactions, whereas the end-products include both free and conjugated compounds (116). Chlordiazepoxide, for example, is metabolized to oxazepam and other metabolites and, depending on its dosage, urine may contain significant concentrations of oxazepam (117). 

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. 

D. J. White, J. T. Stewart, and I. L. Honigberg, Quantitative analysis of chlordiazepoxide hydrochloride and related compounds in drug substance and tablet dosage forms by HPTLC and scanning densitometry, JP C, 4 330 (1991). 

Direct spectrophotometric analysis of chlordi-azepoxide has not been found to be applicable if significant quantities of the known hydrolytic contaminants are present. For material not containing the interfering species the reported maxima at 245-6 nm and 311-12 nm in acidified 3A alcohol may be used for quantitative measurements. The a values at these maxima are 110.9 and 34.2 respectively. The Technicon Autoanalyzer system for dosage form assays of chlordiazepoxide is based on the direct spectrophotometric assay. 

As with chlordiazepoxide, the dosage of diazepam should be lower in the elderly (initial dose, about half the usual), not only because of the pharmacokinetic differences but also because accumulation of the parent drug and active metabolites is more likely to lead to confusion and muscle weakness in the elderly. Furthermore, the elderly seem to be more sensitive to the depressant effects of diazepam than are younger patients. 

The FDA (USP DI Volume III) defines the term as Drug products are considered pharmaceutical equivalents if they contain the same active ingredient(s), are of the same dosage form, route of administration and are identical in strength or concentration (e.g., chlordiazepoxide hydrochloride,... 

There seems to be only one report (with temazepam) of a olinieally signif-ieant interaction between disiifiram and the benzodiazepines, and this report is unconfirmed, as the patient did not take temazepam alone. The other reports only describe potential interactions that have been identified by single-dose studies. These do not necessarily reliably predict what will happen in practice. However, it seems possible that some patients will experience increased drowsiness, possibly because of this interaction, and because drowsiness is a very common adverse effect of disulfiram. Reduce the dosage of the benzodiazepine if necessary. Benzodiazepines that are metabolised by similar pathways to diazepam and chlordiazepoxide, may possibly interact in the same way (e.g. bromazepam, clonazepam, clorazepate, prazepam, ketazolam, clobazam, flurazepam, nitrazepam, medazepam) but this needs confirmation. Alprazolam, oxazepam and lo-razepam appear to be non-interacting alternatives. 

The documentation of these interactions is limited but what has been reported is consistent with the way rifampicin interacts with many other drugs. The clinical importance of some of these interactions between the benzodiazepines and related drugs and rifampicin has not yet been assessed but what is known suggests that the dosage of diazepam and nitrazepam may need to be increased if rifampicin is given. Be alert for a reduction in the effects of other similarly metabolised benzodiazepines (e.g. chlordiazepoxide, flurazepam). 

Po and Irwin (1979) used TLC to separate numerous tricyclic neuroleptic tranquilizers. Samples were dissolved in ethyl acetate, and the mobile phase consisted of mixtures of different n-alcohols with water. Circular development in a Camag U chamber was used, and spots were detected by fluorescence quenching. The /Jp values of some of the better known drugs developed in methanol-water (90 10) were amitriptyline, 0.17 clopenthixol, 0.40 doxepin, 0.42 nortriptyline, 0.37 and promazine, 0.14. Shirke et al. (1994) determined amitriptyline and chlordiazepoxide in combined dosage forms using ethyl acetate-methanol-dieth-ylamine (9.5 0.5 0.05) mobile phase and scanning at 245 nm. 

Shirke, P. P., Patel, M. K., Tamhane, V. A., Tirodkar, V. B., and Sethi, P. D. (1994). Determination of amitriptyline hydrochloride and chlordiazepoxide in combined dosage forms by high performance thin layer chromatography. East Pharm. 37 179-180. 

A case is described when, after a 36-week gestation, female monozygotic twins were delivered. Tlie clinical course of both infants was uncomplicated for the first 3 weeks of life. On the 21st day both infants were noted to be irritable with coarse tremors. Blood taken at this time did not show any trace of chlordiazepoxide. Twin A was swaddled in a quiet environment and Twin B was given pheno-barbital 8 mg/kg/day. Despite a temporary improvement, irritability and tremor persisted and on day 26 both twins were given intramuscular diazepam 0.5 mg every 12 hours. Within 48 hours a marked improvement had occurred and after a further 5 days the dosage of diazepam was tapered and stopped after 9 days. Tlie further clinical course of both infants remained uneventful. 

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