Diazepam metabolic pathways

Cimetidine. Since cimetidine may inhibit certain metabolic pathways, an increased action of concurrently administered drugs that are metabolized via these pathways should be anticipated. For example, cimetidine may inhibit the metabolism of diazepam and certain other benzodiazepines, and the sedative effect of these agents may be enhanced as a result of the interaction. Particular caution is necessary in older patients who may exhibit an increased sensitivity to the depressant... 

The mephenytoin metabolic pathway is utilized by commonly used drugs, such as mephobarbital, hexobarbital, diazepam, imipramine and omepra-zol, but only 3-5% of Caucasians and 8% of Blacks are poor metabolizers of mephenytoin, compared to 15-20% of Chinese and Japanese populations (Kupfer et al., 1988). This enzyme s activity is inhibited by floconazole and fluoxetine and induced by drugs such as barbiturates and nicotine (smoking). 

Propylene glycol is used as solvents in many formulations (e.g., oral, topical, and parenteral routes) for poorly soluble compounds such as phenobarbital, phenytoin, diazepam, and multivitamin concentrates. Because of the limited metabolic pathways in children younger than four years, number of adverse events has been described (laxative effects per os, contact dermatitis) but mainly serious systemic CNS depression. Seven of... 

Studies by Klotz et al. (1975,1976a,b) suggest that biliary excretion of diazepam is unimportant in man, but there is some evidence (see above) for species differences (Klotz etal., 1975,1976a van der Kleijn et al., 1971). Urinary excretion of diazepam is mainly in the form of sulphate and glu-curonide conjugates (Mandelli et al., 1978). The main metabolic pathway is demethylation and hydroxylation to metabolites with CNS depressant activity in animals and man. These metabolites are desmethyldiazepam and oxazepam. 

Cimetidine inhibits the liver enzymes associated with oxidative metabolism. Hence, the serum levels of most benzodiazepines affected by this metabolic pathway (aiprazoiam, diazepam, cbiordiazepoxide, fiurazepam, nitrazepam, and triazoiam) were found to be increased when cimetidine was co-administered. Benzodiazepines metabolized by glucuronide conjugation (iorazepam, oxazepam, and temazepam) are not affected by cimetidine. Ranitidine probably has no significant interaction with most benzodiazepines. 

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. 

Disulfiram inhibits the initial metabolism (A-demethylation and oxidation) of both chlordiazepoxide and diazepam by the liver so that an alternative but slower metabolic pathway is used. This results in the accumulation of these benzodiazepines in the body. In contrast, the metabolism (glucuronidation) of oxazepam and lorazepam is minimally affected by disulfiram so that their clearance from the body remains largely unaffected. The possible interaction between disulfiram and temazepam is not understood, as temazepam is also mainly eliminated in the urine as the inactive glucuronide metabolite, and so its metabolism would not be expected to be affected by disulfiram. 

Metabolic pathways, drug clearance and elimination (Diazepam)... 

The BZs are all metabolized in the liver via the hepatic cytochrome P450 (CYP) enzymes through one or both of the following pathways phase I oxidation and dealkylation, and/or phase II conjugation to glucuron-ides, sulfates, and acetylated compounds. Diazepam, chlordiazepoxide, and flurazepam all undergo both phase 1 and phase 11 metabolism. Lorazepam, lorme-tazepam, oxazepam, and temazepam are all metabolized by phase 11 alone and are better tolerated by patients with liver impairment. 

TCAs ANXIOLYTICS AND HYPNOTICS - BZDs Possible t plasma concentrations of diazepam Inhibition of CYP2C19-mediated metabolism of diazepam. The clinical significance of this depends upon whether diazepam s alternative pathways of metabolism are also inhibited by co-administered drugs Watch for excessive sedation with diazepam... 

Diazepam readily crosses the placenta, particnlarly in the later stages of pregnancy and dnring labor its pathways of metabolism are altered in the ferns and newborn, and this prolongs the elimination of both diazepam and desmethyl-diazepam. Diazepam mnst therefore be nsed jndicionsly in patients who are pregnant and in labor. Diazepam and des-methyldiazepam appear in breast milk and in the plasma of breast-fed infants (see also Fignre 50). 

Metabolic breakdown of several benzodiazepine compounds commonly prescribed in the body leads to the production of several intermediate metabolites which have anxiolytic properties. Oxazepam occupies the position of a final common pathway in the metabolic breakdown process, further chemical changes producing inactive compounds. The failure of oxazepam to prevent diazepam withdrawal symptoms when it has been described as producing such symptoms on its own account (39 ) suggests another unresolved complexity in benzodiazepine dependence. 

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