Diazepam, inhibition

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... 

Whole-body autoradiography of mice was employed as the technique to study the distribution of diazepam, chlordiazepoxide, and their metabolites. The former con und was more highly localized in body fat thetn the latter however, the rate of penetration of chlordiazepoxide into the brain was slower than that of diazepam. The major metabolite of diazepam was the N-demethylated compound. vitro, in preparations of rat or mouse liver microsomes, the major metabolites of diazepam were N-methyloxazepam or N-demethyldiazepam, respectively. Diazepam inhibited the conversion by mouse liver microsomes of N-methyloxazepam to oxazepam. Prazepam, the cyclopropyl derivative of the N-methyl group of diazepam, was metabolized by the dog in a manner similar to that for dicusepam the major urinairy metabolite was oxazepam glucuronide. ... 

Unfortunately, the pharmacology of chloride channels is poorly developed. Specific and highly useful inhibitors or modulators (e.g. strychnine, picrotoxin, diazepams) are only available for ligand-gated chloride channels (but these are covered in a different chapter). There are several chloride channel inhibitors such as the stilbene-disulfonates DIDS and SITS, 9-antracene-carboxylic acid (9-AC), arylaminobenzoates such as DPC and NPPB, niflumic acids and derivates, sulfony-lureas, and zinc and cadmium. All of these inhibitors, however, are not veiy specific. Several of these inhibitors (e.g. DIDS) inhibit many chloride channels only partially even at millimolar concentrations and have effects on other types of transport proteins. 

As Shown in table 2, a comparative dose of 10 n units of PCP-like activity inhibited 3H-PCP binding in rat brain membranes, but did not inhibit binding of 3 H - d i hydromorphi ne, 3H - D - a 1 a2 - D -1 eu5-enkephalin, 3H-ethylketocyclazocine, 3H-diazepam, or -neurotensin. These results indicate that the active material is specific and selective from PCP receptors, as binding to the mu, delta, and kappa opioid receptors was unaffected, as was binding to benzodiazepine and neurotensin receptors. 

While generally not of major concern, omeprazole may inhibit the metabolism of warfarin, diazepam, and phenytoin lansoprazole may decrease theophylline concentrations. Drug interactions with omeprazole are of particular concern in patients who are considered slow metabolizers, as are approximately 3% of the Caucasian population. Unfortunately, it is unclear which patients have the polymorphic gene variation that makes them slow metabolizers.17 The metabolism of esomeprazole may also be altered in patients with this polymorphic gene variation. Patients on potentially interacting drugs should be monitored for development of drug-related problems. 

Compounds 227 and 232 were tested in vitro for inhibition of [3H]-diazepam-specific binding to benzodiazepine receptors in membranes from synaptosomes of rat brain and in vivo for their effects on conditioned behavior in rats (89FES29). 

From table 32.2 it is evident that the highest cross-reaction is 5% with N-desmethylchlordiazepoxide while demoxepam, N-desmethyldiazepam, diazepam and clonazepam displayed less than 1% inhibition. However, the RIA method appears to be reliable over a range of 2-100 ng per tube of chlordiazepoxide and, therefore, the sensitivity limit stands at 20 ng ml 1 using a 1.0 ml sample of plasma. 

GABAA benzodiazepine j8-carbolines act as inverse agonists of the GABAA benzodiazepine receptor (Mehta and Ticku 1989). Whereas benzodiazepines such as diazepam stimulate Cl- influx, j8-carbolines inhibit it. Harmine, harmaline, harmane, and harmalol inhibit flunitrazepam binding in the micromolar range (half-maximal inhibition between 28 and 130 pM) (Mousah et al. 1986). Endogenous j8-carbolines, such as harmane, have also been found in the human brain, but their endogenous functions are uncertain (Tse et al. 

Hypersensitivity to benzodiazepines psychoses acute narrow-angle glaucoma patients with clinical or biochemical evidence of significant liver disease intra-arterial use (lorazepam injection) children younger than 6 months of age, lactation (diazepam) coadministration with ketoconazole and itraconazole caused by inhibition of cytochrome P450 3A. 

The importance of these enzymes for drug interactions is that enzyme inducers and inhibitors may preferentially affect certain isoforms and consequently may only affect the metabolism of selected drugs. For example, ketoconazole has the potential to inhibit the metabolism of drugs metabolised to a great extent by the sub-family 3A (e.g. midazolam) but not of those metabolised by sub-family 1A (e.g. theophylline), 2C (e.g. diazepam), or 2D (e.g. metaprolol). In contrast, although fluconazole is a weaker inhibitor of the sub-family 3A than ketoconazole, it also inhibits the sub-family 2C, and so the interactions of fluconazole differ from those of ketoconazole. 

Management of methanol and ethylene glycol poisoning is similar. Symptomatic support of respiration and circulation is augmented by correction of metabolic acidosis with intravenous bicarbonate infusion, and control of seizures with diazepam. Ethanol inhibits the metabolism of methanol and ethylene glycol to the toxic metabolites, and can give time for further treatment. The goal is to maintain blood ethanol concentrations between 100 and 150 mg per decilitre, sufficient to saturate alcohol... 

Benzodiazepines also possess muscle relaxant activity. Their pharmacology is discussed in Chapter 30. Diazepam Valium) has been used for control of flexor and extensor spasms, spinal spasticity, and multiple sclerosis. The muscle relaxant effect of the benzodiazepines may be mediated by an action on the primary afferents in the spinal cord, resulting in an increased level of presynaptic inhibition of muscle tone. Polysynaptic reflexes are inhibited. The most troublesome side effect is drowsiness, which is dose dependent. Tolerance to both the therapeutic effects and the side effects develops. 

A. Diazepam is metabolized in the liver by CYP3A4 and CYP2C19 efavirenz inhibits both of these isozymes and is likely to increase plasma levels of diazepam. Diazepam is almost completely converted to inactive metabolites therefore, renal elimination is not much of a concern. Lamivudine may produce fatigue as a side effect but does not potentiate the depressant activity of diazepam. Zidovudine does not induce cytochrome P450 activity, and diazepam does not have to be converted to an active form for sedative activity. 

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