Benzodiazepines

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Chlordiazepoxide Hydrochloride, United States Pharmacopeia (USP). Chlordiazepoxide hydrochloride, 7-chloro-2-(methylamino)-5-phenyl-3h-1,4-benzodiazepine 4-oxide monohydrochloride (Librium), is well absorbed after oral administration. Peak plasma levels are reached in 2 to 4 hours. The half-life of chlordiazepoxide is 6 to 30 hours. n-demethylation and hydrolysis of the condensed amidino group are rapid and extensive, producing demox-epam as a major metabolite. Demoxepam can undergo four different metabolic fates. It is converted principally to its active metabolite nordazepam, which is also a major active metabolite of diazepam, clorazepate, and prazepam. Nordazepam, in turn, is converted principally to active ox-azepam (marketed separately), which conjugated to the excreted glucuronide. Because of the long half-life of parent drug and its active metabolites, this drug is long acting and self-tapering. As with diazepam (vide infra), repeated administration of chlordiazepoxide can result in accumulation of parent drug and its active metabolites, and thus cause excessive sedation.

Diazepam, USP. Diazepam, 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2h-1,4-benzodiazepine-2-one (Valium), is prototypical and was the first member of the benzodi-azepine-2-one group to be introduced. It is very lipophilic and is thus rapidly and completely absorbed after oral administration. Maximum peak blood concentration occurs in 2 hours and elimination is slow, with a half-life of about ~46 hours. As with chlordiazepoxide, diazepam is metabolized by n-demethylation to active nordazepam, which is 3-hydroxylated to active oxazepam (vide infra) and then metabolized according to the general scheme (Fig. 12.2). Like chlordiazepoxide, repeated administration of diazepam leads to accumulation of an active nordazepam,

which can be detected in the blood for more than 1 week after discontinuation of the drug. This drug is a long acting for the same reason. Diazepam is metabolized to nordazepam by CYP2C19 and CYP3A4. Cimetidine, by inhibiting CYP3A4, decreases the metabolism and clearance of diazepam. Thus, drugs that affect the activity of CYP2C19 or CYP3A4 may alter diazepam kinetics. Because diazepam clearance is decreased in the elderly and in patients with hepatic insufficiency, a dosage reduction may be warranted. It is widely used for several anxiety states and has an additional wide range of uses (e.g., as an anticonvulsant, a premedication in anesthesiology, and in various spastic disorders).

Prazepam, USP. Prazepam, 7-chloro-1-(cyclopropyl-methyl)-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one (Verstran), has a long overall half-life. Extensive N-dealkyla-tion occurs to yield active nordazepam. 3-Hydroxylation of both prazepam and nordazepam occurs.

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