Ketoconazole Benzodiazepines

Drugs that may be affected by proton pump inhibitors include azole antifungal agents (eg, itraconazole, ketoconazole), benzodiazepines, cilostazol, clarithromycin, digoxin, phenytoin, salicylates, sulfonylureas, and warfarin. Drugs that may affect proton pump inhibitors include sucralfate and clarithromycin. 

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. 

Drugs that may affect benzodiazepines include alcohol, antacids, barbiturates, cimetidine, disulfiram, fluoxetine, isoniazid, ketoconazole, metoprolol, oral contraceptives, narcotics, probenecid, propoxyphene, propranolol, ranitidine, rifampin, scopolamine, theophylline, and valproic acid. 

Rifampin is known to induce the hepatic microsomal enzymes that metabolize various drugs such as acetaminophen, oral anticoagulants, barbiturates, benzodiazepines, beta blockers, chloramphenicol, clofibrate, oral contraceptives, corticosteroids, cyclosporine, disopyramide, estrogens, hydantoins, mexiletine, quinidine, sulfones, sulfonylureas, theophyllines, tocainide, verapamil, digoxin, enalapril, morphine, nifedipine, ondansetron, progestins, protease inhibitors, buspirone, delavirdine, doxycycline, fluoroquinolones, losartan, macrolides, sulfonylureas, tacrolimus, thyroid hormones, TCAs, zolpidem, zidovudine, and ketoconazole. The therapeutic effects of these drugs may be decreased. 

Drugs that may be affected by atazanavir include the following antiarrhythmics, atenolol, benzodiazepines, calcium channel blockers, cisapride, clarithromycin, ergot derivatives, HMG-CoA reductase inhibitors, immunosuppressants, indinavir, irinotecan, itraconazole, ketoconazole, oral contraceptives, PDE5 inhibitors, pimozide, rifabutin, saquinavir, tenofovir, tricyclic antidepressants, voriconazole, warfarin. 

St. John s wort, rifamycins, and ritonavir. Drugs that may be affected by efavirenz include phenytoin, phenobarbital, carbamazepine, itraconazole, ketoconazole, methadone, ritonavir, amprenavir, benzodiazepines, clarithromycin, ethinyl estradiol, indinavir, nelfinavir, saquinavir, and warfarin. 

Flurazepam (Dalmane) [C-IV] [Sedative/Hypnotic/ Benzodiazepine] Uses Insomnia Action Benzodiazepine Dose Adults Beds >15 y. 15-30 mg PO qhs PRN X in elderly Caution [X, /-] Elderly, low albumin, hepatic impair Contra NAG PRG Disp Caps SE Hangover d/t accumulation of metabolites, apnea, anaphylaxis, angioedema, amnesia Interactions T CNS depression W/ antidepressants, antihistamines, opioids, EtOH T effects OF digoxin, phenytoin T effects W/ cimetidine, disulfiram, fluoxetine, iso-niazid, ketoconazole, metoprolol, OCPs, propranolol, SSRIs, valproic acid. 

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... 

Cyt 3A3/4 metabolizes clozapine, sertindole, quetiapine common substrates -tricyclic antidepressants, nefazodone, sertraline, carbamazepine, ethosuximide, terfenadine, benzodiazepines, diltiazem, nifedipine, verapamil, erythromycin, cyclosporine, lidocaine, quinidine, cisapride, paracetamol. Common inhibitors -nefazodone, fluvoxamine, fluoxetine, ketoconazole. 

Fahey JM, Pritchard GA, von Moltke LL, et al. The effects of ketoconazole on triazolam pharmacokinetics, pharmacodynamics and benzodiazepine receptor binding in mice. J Pharmacol Exp Ther 1998 285 271-276. 

Antifungal imidazoles (ketoconazole, itraconazole, and analogues) compete for hepatic oxidative pathways that metabolize most benzodiazepines, as well as zolpidem, zopiclone, and buspirone (SEDA-22, 39, 41-43). 

Ketoconazole increases plasma concentrations of the Z drugs and increases their sedative effects (20) this occurs to a lesser extent than the similar effect on benzodiazepines that are exclusively metabolized by CYP3A4. 

Potential interactions of zolpidem with three commonly prescribed azole derivatives (ketoconazole, itraconazole, and fluconazole) have been evaluated in a controlled clinical study. Co-administration of zolpidem with ketoconazole impaired zolpidem clearance and enhanced its benzodiazepine-like agonist pharmacodynamic effects. Itraconazole and fluconazole had a small effect on zolpidem kinetics and dynamics. The findings were consistent with in vitro studies of differentially impaired zolpidem metabolism by azole derivatives (45). 

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). 

Zolpidem is metabolized by CYP3A. Ketoconazole 200 mg bd impaired the clearance of zolpidem 5 mg and enhanced its benzodiazepine-like pharmacodynamic effects. In contrast, itraconazole 100 mg bd and fluconazole 100 mg bd had small effects on zolpidem kinetics and dynamics (59). 

E Itraconazole. Imatinib is primarily metabolized by the CYP3A4 hepatic enzyme system. Drugs that may inhibit this enzyme (such as ketoconazole, itraconazole, erythromycin, clarithromycin, etc.) may impair clearance of imatinib and result in increased toxicity. Imatinib itself is also a fairly potent inhibitor of the CYP3A4 enzyme and may result in toxicity due to other drugs that are substrates for this enzyme (such as simvastatin, warfarin, benzodiazepines, etc.). The other medications iisted are uniikeiy to affect the function of 0 P3A4 or interact adversely with imatinib. 

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... 

Benzodiazepines alprazolam, clonazepam, diazepam, midazolam, triazolam, zolpidem Calcium channel blockers diltiazem, nifedipine, nimodipine, verapamil Steroids androgens, estrogens, cortisol Others erythromycin, terfenadine, cyclosporine, dapsone, ketoconazole, lovastatin, lidocaine, alfentanil, amiodarone, astemizole, codeine, sildenafil... 

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