Metabolism benzodiazepines

Drugs and other substances demonstrated to be CYP3A inhibitors on the basis of clinical studies involving benzodiazepines metabolized similarly to alprazolam or on the basis of in vitro studies with alprazolam or other benzodiazepines (caution is recommended during coadministration with alprazolam) Available data from clinical... 

Benzodiazepines + cimetidine, disulfiram —> inhibition of benzodiazepine metabolism causing increased sedation. 

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). 

Omeprazole can impair benzodiazepine metabolism and lead to adverse effects (SEDA-18, 43). 

Diltiazem caused a 43% mean increase in the half-life of midazolam in 30 patients who underwent coronary artery bypass grafting (57). Similar effects were observed with alfentanil. The proposed mechanism was diltiazem-induced inhibition of benzodiazepine metabolism by CYP3A. Patients taking diltiazem had delayed early postoperative recovery as a result. 

Omeprazole, like cimetidine, can impair benzodiazepine metabolism and lead to adverse effects (SEDA-18, 43). Other drugs, including antibiotics (erythromycin, chloramphenicol, isoniazid), antifungal drugs (ketoconazole, itraconazole, and analogues), some SSRIs (fluoxetine, paroxetine), other antidepressants (nefazodone), protease inhibitors (saquinavir), opioids (fentanyl), calcium channel blockers (diltiazem, verapamil), and disulfiram also compete for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone (SEDA-22,39) (SEDA-22,41). 

Clonazepam, U5P. Clonazepam S-(2-chlorophenyl)-3-dihydro-7-nitro-2//-1,4-benzodiazpin-2-one (iCIonopin). partially selective at benzodiazepine allosteric binding sites on GABAa receptors, is useful in ab.sence seizures and in myoclonic seizures. Tolerance to the anticonvulsant effect often develops, a common problem with the benzodiazepines. Metabolism involves hydroxylation of the 3 position, followed by glucuronidation and nitro group reduction, followed by acetylation. 

In general the first, and most rapid, step in 1,4-benzodiazepine metabolism (Fig. 9.2) is the oxidative removal of the N-1 alkyl substituent, if present (82). Benzodiazepines with a methyl group at N-1 are the most stable and the rate of dealkylation increases with the size of the N-1 alkyl group. For example, the dealkylation half-life for diazepam is 20-30 h, but for prazepam, which bears a cyclopropyl-methyl group at N-1, this half-life is approximately 1 h (82). Substituents elsewhere in the molecule have little impact on the rate of deal-... 

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. 

Benzodiazepines do not induce their own metabolism, and thete is no evidence for the development of pharmacokinetic toletance (Gteenblatt and Shader 1986). The behavioral tolerance seen with chronic dosing is explicable entirely on the basis of pharmacodynamic tolerance (as described earlier in the overview of neuropharmacology). 

Kilicarslan T, Sellers EM Lack of interaction of buprenorphine with flunitrazepam metabolism. Am J Psychiatry 137 1164-1166, 2000 King SA, Strain JJ Benzodiazepines and chronic pain. Pain 41 3-4, 1990a King SA, Strain JJ Benzodiazepine use by chronic pain patients. Clin J Pain 6 143-147, 1990b... 

Petursson H, Lader MH Benzodiazepine dependence. BrJ Addict 76 133—143,1981a Petursson H, Lader MH Withdrawal from long-term benzodiazepine treatment. Br Med J (Clin Res Ed) 283 643—643, 1981b Pichard L, Gillet G, Bonfils C, et al Oxidative metabolism of zolpidem by human liver... 

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. 

Benzodiazepines (alprazolam) COCs may inhibit oxidative metabolism Increase side effects of benzodiazepines... 

The structures of the drugs used as a small test set for the model are listed in Table 17.1. Loperamide and asimadoline are P-gp substrates terfenadine and ebastine are compounds that are rapidly metabolized alprazolam, dobazam, di-and mono-hydroxy-L66858 [11] are benzodiazepines testosterone and corticosterone are hormones and cefadroxyl, cefaclor, cephalotin and cefmetazole are cephalosporins [12]. Finally, peptides 1 to 10 are peptidomimetic drugs [13]. 

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