Chlordiazepoxide pharmacokinetics

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. 

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. 

There appear to be gender differences in the pharmacokinetics of selective benzodiazepines such as chlordiazepoxide and diazepam. As would be predicted from studies evaluating the effect of OCs on various P450 enzymes, the levels of hydroxylated and demethylated benzodiazepines are increased in OC users, and the levels of conjugated benzodiazepines are decreased in OC users. Importantly, however, the pharmacokinetic effect may not always predict the impairment on psychomotor and cognitive tasks seen in women who are concurrently given OCs and benzodiazepines. 

The pulse polarographic determination of chlordiazepoxide and its metabolites in plasma has also been described [191]. Chlordiazepoxide and its metabolites are extracted from serum buffered to pH 9.0 followed by a TLC separation, elution, and final quantitation in 0.5 M H2S04. The detection limit of the assay of 0.05-0.1 ng of each compound per milliliter of serum using a 2-mL sample is sufficiently useful for pharmacokinetic studies. 

Following daily oral administration of 10 mg three times a day to 8 subjects, mean steady-state plasma concentrations were chlordiazepoxide 0.5 to 1.0 pg/ml (mean 0.8), desmethylchlordiazepoxide 0.3 to 0.8 pg/ml (mean0.5),demoxepam0.24to0.44 pg/ml(mean0.36)(H. G. Boxenbaum et al., J. Pharmacokinet. Biopharm., 1977, 5, 25-39). 

Pharmacokinetics. Benzodiazepines are effective after administration by mouth but enter the circulation at very different rates that are reflected in the speed of onset of action, e.g. alprazolam is rapid, oxazepam is slow (Table 19.8). The liver metabolises them, usually to inactive metabolites but some compoimds produce active metabolites, some with long t) which greatly extends drug action, e.g. chlordiazepoxide, clorazepate and diazepam all form desmethyldiazepam (t/ 80 h). 

A pharmacokinetic model for the disposition of chlordiazepoxide HC1 in the dog has been presented in terms of a six-compartment open system16. The excellent agreement between the simulated and experimental data reflects the reliability of the assumption of first-order kinetics for all processes. The model provides a basis for the elucidation and quantitation of chlordiazepoxide and its pharmacologically active biotransformation products, the N-desmethyl metabolite and the lactam. The pathways in man17-19 have been shown to be similar to those in the dog to the extent to which they are described in the model. 

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. 

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.)...

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. 

After taking disulfiram 500 mg daily for 14 to 16 days, the plasma clearance of single doses of chlordiazepoxide and diazepam were reduced by 54% and 41%, respectively, and Ihe half-lives were increased by 84% and 37%, respectively. The plasma levels of chlordiazepoxide were approximately doubled. Oxazepam was also given following disulfiram treat-menl bul changes in oxazepam pharmacokinetics were minimal. There was no difference in Ihe interaction belween alcoholic subjects (without hepatic cirrhosis) and healthy subjects. ... 

Similar but less marked effects were found in other studies in women taking oral contraceptives given chlordiazepoxide, diazepam, alprazolam and to an even lesser extent with triazolam and nitrazepam. No clinically significant pharmacokinetic changes were seen with bromazepam, clotiazepam, midazolam (given orally intramuscularly or intravenously ) or zolpidem."... 

The pharmacokinetics of alprazolam, chlordiazepoxide and lorazepam are not affected by influenza vaccination. 

The pharmacokinetics of single doses of oral alprazolam 1 mg, or intravenous lorazepam 2 mg remained unaffected in healthy subjects when the benzodiazepines were given 7 and 21 days after 0.5 mL of an intramuscular trivalent influenza vaccine. Similarly, in another study, neither lorazepam nor chlordiazepoxide metabolism was altered when they were given 1 and 7 days after a trivalent influenza vaccine. There would seem to be no reason for avoiding the concurrent use of these drugs. 

Some studies have suggested that smoking does not affect the pharmacokinetics of diazepam, chlordiazepoxide, clorazepate, lorazepam, ... 

Several of the most-used benzodiazepine tranquillizers seem to act as the metabolic product, nordazepam (3.47), which has the full therapeutic action of the starting materials, and acts faster. Thus diazepam (12.95) ( Valium ) loses 1-Me, chlordiazepoxide ( Librium ) loses 4-0 and hydrolyses 2-MeNH- to=0, whereas clorazepate ( Tranxene ) loses 4-CO2, and in each case nordazepam is the product. While the latter is available for prescribing, clinical experience with the pro-drugs is greater moreover they have very different pharmacokinetics, diazepam being absorbed quickly and chlordiazepoxide slowly from the gastrointestinal tract. See further Section 12.7 Garattini, Mussini and Randall (1973), Nicholson a/. (1976), and Hollister (1978). 

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