Cytochrome benzodiazepine metabolism

Some selective serotonin re-uptake inhibitors are powerful inhibitors of cytochrome P450 enzymes and the metabolism of e.g. tricyclic antidepressants can be inhibited resulting in serious toxicity. Additive sedation can be expected when given in combination with CNS depressants such as benzodiazepines but also with alcohol. Selective serotonin re-uptake inhibitors should not be used in combination with monoamine oxidase inhibitors as fatal reactions have been reported. 

All SSRIs (e.g., Feonard et ah, 1997) and in particular fluoxetine, Fluvosamine and paroxetine are metabolized by hepatic cytochrome P450 enzymes. Therefore, it is important to be aware of the possibility that the therapeutic or toxic effects of other medications metabolized by the cytochrome P450 isoenzyme system can be increased. Substantial inhibition of these isoenzymes converts a normal metabolizer into a slow metabolizer with regard to this specific pathway. Inhibition of the hepatic oxidative isoenzymes has been associated with a reduction, to a varying extent, in the clearance of many therapeutic agents, including the TCAs, several neuroleptics, antiarrhythmics, theophy-lene, terfenadine, benzodiazepines, carbamazepine, and warfarin (for a complete list, see Nemeroff et ak, 1996). 

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. 

Since benzodiazepines are metabolized by the cytochrome P450 family of isozymes,1 potential inhibitors of these may produce significant increases in blood concentrations of benzodiazepines. An example of this inhibition is the drug midazolam, administered as a presurgical anesthetic. Lam et al.11 reported a mean increase in the area under the curve of midazolam by ketoconazole (772%) and nefazodone (444%) in a group of 40 healthy human subjects administered 200 mg ketoconazole per day and 400 mg nefazodone per day. The authors concluded that caution should be exercised when use of midazolam is warranted with potent CYP3A4 inhibitors.11... 

The risk of development of tolerance and dependence with extended use of zolpidem appears to be less than with the use of hypnotic benzodiazepines. Zolpidem is rapidly metabolized to inactive metabolites by the liver via oxidation and hydroxylation. The elimination half-life of the drug is 1.5-3.5 hours, with clearance decreased in elderly patients. Dosage reductions are recommended in patients with hepatic dysfunction, in elderly patients, and in patients taking cimetidine. Rifampin, an inducer of hepatic cytochrome P450, decreases the half-life of zolpidem. 

Only phenobarbital strongly induces the synthesis of the hepatic cytochrome P-450 drug metabolizing system. Phenobarbital is contraindicated in the treatment of acute intermittent porphyria. Buspirone lacks the anticonvulsant and muscle-relaxant properties of the benzodiazepines and causes only minimal sedation, v ... 

Biotransformation of benzodiazepines occurs in the liver, where the drugs vmdergo phase I metabolism by the cytochrome P450 enzyme complex. Other drugs that may compete with benzodiazepines for liver microsomal enz)mies and result in decreased metabolism of benzodiazepines are erythromycin, ketoconazole, verapamil and... 

I Drug-Drug Interactions. Carbamazepine induces the hepatic cytochrome P450 isoenzymes (1A2, 3A4, 2C9/10, and 2D6), which increases the metabolism of many medications, such as anticonvulsants (i.e., lamotrigine, topiramate, and valproate), antidepressants (i.e., tricyclics and bupropion), antipsychotics (i.e., clozapine, haloperi-dol, fluphenazine, olanzapine, and thiothixene), benzodiazepines, oral contraceptives, and protease inhibitors. " Women who receive carbamazepine require higher dosages of oral contraceptives or alternative contraceptive methods." ... 

With the exception of temazepam, which is eliminated by conjugation, all benzodiazepine hypnotics are metabolized by hepatic microsomal oxidation and then undergo glucuronide conjugation. Oxidation may be inhibited in patients with impaired liver function, advanced age, or concurrent use of drugs that inhibit oxidation. Drugs that inhibit the cytochrome P450 3A4 enzyme (e.g., erythromycin, nefazodone, fluvoxamine, and ketoconazole) reduce the clearance of triazolam and increase its plasma concentrations."... 

Most benzodiazepines are metabolized by liver cytochromes P450. 

The elimination of most benzodiazepines involves their metabolism by liver enz5Tnes, including cytochrome P450 isozymes. In a patient with liver dysfunction, lorazepam, which is metabolized extrahepatically, is less hkely to cause excessive CNS depression. Benzodiazepines are not eliminated via the kidneys or lungs. Flumazenil is used to reverse excessive CNS depression caused by benzodiazepines. The answer is (C). 

Benzodiazepines such as lorazepam, oxazepam and temazepam, which are mainly conjugated without prior phase I metabolism, are unlikely to be involved in interactions with inhibitors or inducers of cytochrome P450. Benzodiazepines themselves do not significantly induce cytochrome P450 isoenzymes, so interactions involving enhanced metabolism of other drugs are not usual. 

Alprazolam, midazolam and triazolam are metabolised by the cytochrome P450 isoenzyme CYP3A4, which is inhibited, to varying degrees, by the protease inhibitors. Benzodiazepine levels and effects are therefore increased by saquinavir and ritonavir. Zolpidem metabolism depends on several isoenzymes so inhibition of CYP3A4 alone may not produce clinically significant changes in its clearance. 

Rifampicin is a potent liver enzyme inducer, which increases the metabolism of several benzodiazepines and the non-benzodiazepine hypnotics, zaiepion, zoipidem and zopiclone, thereby decreasing their levels. The metabolism of midazolam by the cytochrome P450 isoenzyme CYP3A4 in both liver and gut is affected. The enzyme inducing effects of rifampicin seem to predominate if isoniazid (an enzyme inhibitor) is also present. Temazepam undergoes glucuronidation and is therefore unaffected by rifampicin. 

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