Benzodiazepines metabolism/excretion

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. 

Zopiclone is widely used as a sedative-hypnotic. It is metabolized to an inactive N-desmethylated derivative and an active N-oxide compound, both of which contain chiral centres. S-Zopiclone has a 50-fold higher affinity for the benzodiazepine receptor site than the R-enantiomer. This could be therapeutically important, particularly if the formation and the urinary excretion of the active metabolite benefits the S-isomer, which appears to be the case. As the half-life of the R-enantiomer is longer than that of the S-form, it would seem advantageous to use the R-isomer in order to avoid the possibility of daytime sedation and hangover effects which commonly occur with long-acting benzodiazepine receptor agonists. 

The distribution of the benzodiazepines from blood to tissues and back again is a dynamic process with considerable influence on the onset and duration of the therapeutic effects produced by these compounds. Those having greater lipid solubility tend to enter the central nervous system more rapidly and thus tend to produce their effects more quickly. Several of the benzodiazepines have therapeutic effects that are much shorter in duration than would be predicted based on their rates of metabolism and excretion redistribution away from the central nervous system is of primary importance in terminating their therapeutic effects. 

Duration and degree of benzodiazepine reversal depend on dosage and plasma concentration. Protein binding 50%. Metabolized by the liver excreted in urine. 

As mentioned above, oxidative reactions will be rate-limiting in most instances. However, some medications are simply metabolized through conjugation. For example, benzodiazepines such as lorazepam are conjugated and excreted. The rate of conjugative reactions may be increased by OCs accelerating the elimination of these compounds because this reaction is rate-limiting [Yonkers and Hamilton 1995 Stoehr et al. 1984). 

At equipotent doses, all benzodiazepines have similar effects. The choice of benzodiazepine is generally based on half-life, rapidity of onset, metabolism, and potency. In patients with moderate to severe hepatic dysfunction, it may be useful to avoid benzodiazepines. All benzodiazepines are metabolized at various levels by the liver, which leads to an increased risk of sedation and confusion in hepatic failure. If it is necessary to prescribe this class of medication, lorazepam and oxazepam are reasonable choices because they are predominantly eliminated by renal excretion. 

Benzodiazepines are lipid soluble and are found in breast milk. They are metabolized in the liver and excreted as glucuro-nide metabolites at different rates. For example, the half-life of triazolam is 2 to 5 hours, while that of diazepam varies between... 

First-pass metabolism (first-pass effect) The passage of the drug from the portal circulation into hepatocytes and conversion there into metabolites. These metabolites may have a pharmacological profile different from that of the parent drug. They are typically then excreted by the hepatocytes into the biliary system and pass back into the small bowel where enterohepatic recirculation may occur (e.g., benzodiazepines, bupropion, nefazodone, neuroleptics, tricyclic antidepressants). 

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). 

Hepatic metabolism accounts for the clearance of all benzodiazepines. The patterns and rates of metabolism depend on the individual drugs. Most benzodiazepines undergo microsomal oxidation (phase I reactions), including TV-dealkylation and aliphatic hydroxylation. The metabolites are subsequently conjugated (phase II reactions) to form glucuronides that are excreted in the urine. However, many phase I metabolites of benzodiazepines are pharmacologically active, with long half-lives. 

The benzodiazepine alkaloids are thoroughly excreted into the medium, thus keeping the cellular content of the hyphal cells very low. The alkaloid content cannot be substantially increased, even after artificial breakdown of membrane barriers. Permeabilization of hyphal cell membranes by lowering the ATP content (see above) is reversible by adding ATP or by allowing ATP net synthesis after removal of the metabolic inhibitors. Even if cyclopenin is present during such a permeabilization—reimpermeabilization cycle, the resealed cells do not... 

Triazolam, USP. Triazolam. 8-chloro-6-(o-chlorophc-nyl)-l-methyl-4Ay-j-triaz.olol4.3-a f l,4 benzxxliazcpinc (Hal-cion). has all of the characteristic benzodiazepine pharmacological actions. It is marketed as a sedative-hypnotic drug said to impair little, if any. daytime function. It is rapidly metabolized to the I-methyl alcohol, which is then conjugated and excreted. 

Oxazepam (6) is formed during the metabolism of many other benzodiazepines, but its own metabolic profile is relatively simple. Like lorazepam, the major metabolic pathway is glucuronidation at the 3-hydroxy group followed by urinary excretion. Up to 80% of the dose is recovered from the urine as the glucuronide. The mean half-life of oxazepam is approximately 9 h (98). 

As with most benzodiazepines, lorazepam is highly bound to plasma proteins (over 85 percent). The serum half-life of lorazepam is approximately 12 to 15 hours. The drug undergoes hepatic metabolism and is rapidly conjugated to an inactive glucuronide. Excretion of the metabolite is primarily renal, with a small percentage excreted through the bile. 

This inhibits the hepatic glucuronidation metabolism and the renal excretion of many drugs, including benzodiazepines. As a result, elimination half-lives of agents such as Iorazepam have been reported to increase (up to 2-fold). 

Metabolism and excretion Sedative-hypnotics are metabolized prior to elimination from the body, mainly by hepatic enzymes. Metabolic rates and pathways vary among different dmgs. Many benzodiazepines are converted initially to active metabolites with... 

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