Metabolism temazepam

Disulfiram inhibits CYP enzymes 1A2, 2C9, and 3A4 many benzodiazepines are metabolized via these pathways lorazepam, temazepam, and oxazepam are NOT metabolized via the CYP4S0 system and are reasonable alternatives. 

With the exception of temazepam, which is eliminated by conjugation, all benzodiazepine hypnotics are metabolized by microsomal oxidation followed by glucuronide conjugation. 

The benzodiazepines that have been most commonly marketed as sedative-hypnotics include temazepam (Restoril), estazolam (ProSom), flurazepam (Dalmane), quazepam (Doral), and triazolam (Halcion). Of these five, temazepam is the most easily metabolized and eliminated. Therefore, temazepam is preferred for elderly and medically ill patients to minimize the risk of drug accumulation. 

Does not include agents metabolized by glucuronidation (lorazepam, oxazepam, temazepam). 

Other drugs are metabolised by Phase II synthetic reactions, catalysed typically by non-microsomal enzymes. Processes include acetylation, sulphation, glycine conjugation and methylation. Phase II reactions may be affected less frequently by ageing. Thus according to some studies, the elimination of isoniazid, rifampicin (rifampin), paracetamol (acetaminophen), valproic acid, salicylate, indomethacin, lorazepam, oxazepam, and temazepam is not altered with age. However, other studies have demonstrated a reduction in metabolism of lorazepam, paracetamol (acetaminophen), ketoprofen, naproxen, morphine, free valproic acid, and salicylate, indicating that the effect of age on conjugation reactions is variable. 

Most benzodiazepines undergo oxidative metabolism in the liver that may be enhanced by enzyme inducers (e.g. carbamazepine, phenytoin) or slowed by inhibitors (sodium valproate, fluoxetine, fluvoxamine). Oxazepam, lorazepam and temazepam are directly conjugated and are not subject to these interactions. 

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. 

Knowing the structure of a particular BZ drug can help predict the metabolic pathway for that drug. For example, oxazepam, lorazepam, and temazepam are all 3-OH BZs and are directly conjugated (Chouinard et ah, 1999). Temazepam is partly demethylated to oxazepam, but otherwise these drugs have no active metabolites (Bellantuono et ah, 1980). 

Most sedative drugs, including narcotics and alcohol, potentiate the sedative effects of benzodiazepines. In addition, medications that inhibit hepatic cytochrome P450 (CYP) 3A3/4 increase blood levels and hence side effects of clonazepam, alprazolam, midazolam, and triazolam. Lorazepam, oxazepam, and temazepam are not dependent on hepatic enzymes for metabolism. Therefore, they are not affected by hepatic disease or the inhibition of hepatic enzymes. 

Benzodiazepines [P] Decreased metabolism of alprazolam, chlordiazepoxide, diazepam, halazepam, prazepam, and clorazepate but not oxazepam, lorazepam, or temazepam. 

Some other benzodiazepines are metabolized by glucuronic acid conjugation. Of these, the clearance of temazepam was increased when oral contraceptives were administered concomitantly, but the clearance of loraze-pam and oxazepam was not (335). Again, it is unlikely that these are interactions of clinical importance. 

Benzodiazepine and azapirone derivatives are widely used drugs in this class, and most are metabolized extensively by enzymes of the CYP3A family, except oxazepam, lorazepam, and temazepam, which are mostly glucuronidated (52). Again, several studies have shown that inducers and inhibitors of CYP3A can markedly alter plasma concentrations of many of these drugs, but in only a few cases have toxic effects, such as deep unconsciousness, been reported (19,52,53). Nonetheless, patients on these drugs should probably be monitored carefully, particularly the elderly, who may suffer severe physical injury as a result of falls from impairment of psychomotor function. 

Cimetidine can impair benzodiazepine metabolism and lead to adverse effects (SEDA-18, 43). In contrast, a few benzodiazepines are metabolized exclusively by glucuro-nide conjugation (lorazepam, oxazepam, temazepam), and are therefore unaffected by concomitant therapy with cimetidine and other oxidation inhibitors (123). 

FLUOXETINE, FLUVOXAMINE, PAROXETINE BZDs - ALPRAZOLAM, DIAZEPAM, MIDAZOLAM t in plasma concentrations of these BZDs. Likely t sedation and interference with psychomotor activity Alprazolam, diazepam and midazolam are subject to metabolism by CYP3A4. Fluvoxamine, fluoxetine and possibly paroxetine are inhibitors of CYP3A4 sertraline is a weak inhibitor. SSRIs are relatively weak compared with ketoconazole, which is possibly 100 times more potent as an inhibitor Warn patients about risks associated with activities that require alertness. Consider use of alternatives such as oxazepam, lorazepam and temazepam, which are metabolized by glucuronidation >- For signs and symptoms of CNS depression, see Clinical Features of Some Adverse Drug Interactions, Central nervous system depression... 

BZDs, NOT LORAZEPAM, OXAZEPAM, TEMAZEPAM RIFAMPICIN 1 BZD levels Induction of CYP3A4-mediated metabolism Watch for poor response to these BZDs consider increasing the dose, e.g. diazepam or nitrazepam 2-3-fold... 

ALPRAZOLAM, DIAZEPAM, MIDAZOLAM-ORAL GRAPEFRUIT JUICE Possibly t efficacy and t adverse effects, e.g. sedation, CNS depression Possibly t bioavailability, 1 presystemic metabolism. Constituents of grapefruit juice irreversibly inhibit intestinal CYP3A4. Transport via P-gp and MRP-2 efflux pumps is also inhibited Avoid concomitant use. Be particularly vigilant in elderly patients or those with impaired liver function. Consider alternative, e.g. temazepam... 

The benzodiazepines, one of the most widely prescribed groups of drugs, undergo extensive metabolism by routes already described for the barbiturates, namely 7V-dealkylation and hydroxylation. However, unlike the barbiturates, metabolic conversion yields derivatives which have similar pharmacological activities and potencies to those of the parent compounds. For example, the three major metabolites of diazepam are desmethyl-diazepam (nordazepam), 3 -hydroxydiazepam (temazepam), and desmethyl-3-hydroxydiazepam... 

The metabolism of lorazepam (e.g., Ativan), oxazepam (e.g., Serax), and temazepam (e.g., Restoril) are not likely to be affected, and one of these agents may be preferred when a benzodiazepine is indicated in a patient being treated with cimetidine. The experience with ranitidine (e.g., Zantac), famotidine (Pepcid), and nizatidine (Axid) suggests that these agents are not likely to inhibit hepatic enzyme systems, and these other histamine H2-receptor antagonists are less likely than cimetidine to interact with other drugs that are metabolized via these pathways. 

Oral contraceptives alter the metabolism of some benzodiazepines that undergo oxidation (alprazolam, chlordiazepoxide, diazepam) or nitroreduction (nitrazepam) (166). For these drugs, oral contraceptives inhibit enzyme activity and reduce clearance. There is nevertheless no evidence that this interaction is of clinical importance. It should be noted that for other benzodiazepines that undergo oxidative metabolism, such as bromazepam or clotiazepam, no change has ever been found in oral contraceptive users. Some other benzodiazepines, such as lorazepam, oxazepam, and temazepam, are metabolized by glucuronic acid conjugation. The clearance of temazepam was increased when oral contraceptives were coadministered, but the clearances of lorazepam and oxazepam were not (167). Again, it is unlikely that this is an interaction of clinical importance. 

The main differences between the different drugs are their pharmacodynamics especially half-life and metabolism (see figme 16-A). Those with a longer half-life tend to build up in the system—even if taken only once a day. Most are metabolized by the liver and therefore can build up in the system when the liver is impaired, as with alcoholic liver disease. The three least dependent on the liver are lorazepam, temazepam, and oxazepam. The ones with a very short half-life... 

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