Chlordiazepoxide half-life

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). 

It was conclusively shown that deoxychlordiazepoxide (393) had none of the phototoxic properties of the parent drug, at least in the rat [225]. Chlordiazepoxide, demethylchlordiazepoxide, demoxepam and diazepam-4-oxide were all phototoxic to a bacterial cell preparation. There was a close relationship between the phototoxicities of the A-oxides and the toxicity in the dark of their oxaziridines. The reduced forms of the four compounds were not phototoxic [ 228 ]. Kinetic studies demonstrated that the oxaziridine (390) covalently bonds to plasma proteins. The half-life of the oxaziridine in the presence of high concentrations of protein was about 30 min. It therefore has time not only to bind to biomolecules in the skin surface, but also to attack internal organs. This was put forward as the explanation of previously observed kidney and liver damage in the rat [229]. 

B. Chlordiazepoxide, through its metabolites, has a relatively long biological half-life. It will prevent many of the severe symptoms of acute alcohol withdrawal. Buspirone is not a sedative and will not suppress alcohol withdrawal. The other agents have sedative properties and could potentially suppress alcohol withdrawal but each has a much shorter biological half-life than chlordiazepoxide. 

The clinical duration of action of benzodiazepines does not correlate witii die elimination half-life. Intramuscular lorazepam is well absorbed. We do not recommend intramuscular chlordiazepoxide or diazepam. Source. Adapted from Teboul and Chouinard 1990. 

Fate Most benzodiazepines, including chlordiazepoxide and diazepam, are metabolized by the hepatic microsomal metabolizing system (see p. 14) to compounds that are also active. For these benzodiazepines, the apparent half-life of the drug represents the combined actions of the parent drug and its metabolites. The benzodiazepines are excreted in urine as glucuronides or oxidized metabolites. 

Half-life. Plasma half-life, chlordiazepoxide 5 to 30 hours (mean 15), demoxepam 14 to 95 hours (mean 40) desmethyldiazepam about 40 to 100 hours, but there is considerable intersubject variation—see under Nordazepam. 

Chlordiazepoxide (2) is completely absorbed upon oral administration and reaches peak plasma concentrations in 1-2 h (90). As a highly lipophilic molecule it is 94% bound to plasma proteins (91) and readily penetrates the brain, with CSF levels paralleling unbound plasma levels (92). Chlordiazepoxide has a mean half-life of 15 h. It is metabolized first by oxidative removal of the N-2 methyl group (to give N-desmethylchlordiazepoxide), followed by hydrolysis to the lactam (demox-epam), and reduction of the N-5 oxide to give desmethyldiazepam. All of these metabolites are pharmacologicallyactive. 

Oxazepam, which is available only in oral preparations, is metabolized rapidly, and hence has a relatively shorter disposition half-life of 5 to 14 hours. Oxazepam is absorbed less rapidly than diazepam after oral administration, limiting its usefulness in the treatment of insomnia. As with diazepam, when alcohol is taken at the same time, the rate of oxazepam absorption is slowed, but food does not affect either the rate or extent of absorption. In healthy subjects, oxazepam is relatively highly protein bound (about 90 to 95%), like other benzodiazepines. Unlike chlordiazepoxide and diazepam, the biotransformation of... 

These inhibit oxidative metabolism and at the same time enhance glucuronidation. Consequently, the half-lives of benzodiazepines such as alprazolam, chlordiazepoxide, diazepam, and triazolam were found to be increased, and the half-life of Iorazepam, and to a lesser extent that of oxazepam, can be significantly reduced. 

Figure 1-3. Serum concentration-time curve after administration of chlordiazepoxide as an intravenous bolus. The experimental data are plotted on a semilogarithmic scale as filled circles. This drug follows first-order kinetics and appears to occupy two compartments. The initial curvilinear portion of the data represents the distribution phase, with drug equilibrating between the blood compartment and the tissue compartment. The linear portion of the curve represents drug elimination. The elimination half-life (f gj) can be extracted graphically as shown by measuring the time between any two plasma concentration points that differ by twofold. (See Chapter 3 for additional details.) (Modified and reproduced, with permission, from Greenblatt DJ, Koch-Weser J. Drug therapy Clinical pharmacokinetics. N Engl J Med 1975 293 702.)...

Chlordiazepoxide is well absorbed after oral administration, and peak blood concentration usually is reached in approximately 4 hours. Intramuscular absorption of chlordiazepoxide, however, is slower and erratic. The half-life of chlordiazepoxide Is variable but usually quite long (6-30 hours). The initial N-demethylation product, N-desmethylchloridiazepoxide, undergoes deamination to form the demoxepam (Fig. 22.18), which is extensively metabolized, and less than 1 % of a dose of chlordiazepoxide is excreted as demoxepam. Demoxepam can undergo four different metabolic fates. Removal of the N-oxide moiety yields the active metabolite, N-desmethyIdiazepam (desoxydemoxepam). This product is a metabolite of both chlordiazepoxide and diazepam and can be hydroxylated to yield oxazepam, another active metabolite that is rapidly glucuronidated... 

Diazepam is rapidly and completely absorbed after oral administration. Maximum peak blood concentration occurs in 2 hours, and elimination is slow, with a half-life of approximately 20 to 50 hours. As with chlordiazepoxide, the major metabolic product of diazepam is N-desmethyIdiazepam, which is pharmacologically active and undergoes even slower metabolism than its parent compound. Repeated administration of diazepam or chlordiazepoxide leads to accumulation of N-desmethyIdiazepam, which can be detected in the blood for more than 1 week after discontinuation of the drug. Hydroxylation of N-desmethyIdiazepam at the 3-position gives the active metabolite oxazepam (Fig. 22.18). 

Oxazepam is an active metabolite of both chlordiazepoxide and diazepam and is marketed separately, as a shortacting anxiolytic agent. Oxazepam is rapidly inactivated to glucuronidated metabolites that are excreted in the urine (Fig. 22.18). The half-life of oxazepam is approximately 4 to 8 hours, and cumulative effects with chronic therapy are much less than with long-acting benzodiazepines, such as chlordiazepoxide and diazepam. Lorazepam is the 2 -chloro derivative of oxazepam and has a similarly short half-life (2-6 hours) and pharmacological activity. 

Flurazepam is administered orally as the dihydrochloride salt. It is rapidly N-dealkylated to give the 2 -fluoro derivative of N-desmethyIdiazepam, and it subsequently follows the same metabolic pathways as chlordiazepoxide and diazepam (Fig. 22.18). The half-life of flurazepam is fairly long ( 7 hours) consequently, it has the same potential as chlordiazepoxide and diazepam to produce cumulative clinical effects and side effects (e.g., excessive sedation) and residual pharmacological activity, even after discontinuation. Chlorazepate is yet another benzodiazepine that is rapidly metabolized (3-decarboxylation) to N-desmethyIdiazepam and so shares similar clinical and pharmacokinetic properties to chlordiazepoxide and diazepam. 

A controlled study found that the mean half-life of intravenous chlordiazepoxide 600 micrograms/kg was virtually doubled (11.6 hours eom-... 

Metabolism of benzodiazepine derivatives - Biological half-life studies of chlordiazepoxide in man showed desmethylchlordlazepoxlde (29a) and demoxepam (29b) to be major metabolites. In dogs, metabolism of 29b involves two oxidative pathways. One leads to two phenolic products ... 

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