Benzodiazepines enzyme inducers

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 authors of one study suggest that antiepileptics with fewer enzyme-inducing properties than phenytoin should he used as prophylaxis if busulfan is given for bone marrow transplant pretreatment. One UK manufacturer recommends prophylaxis with a benzodiazepine rather than phenytoin if high-dose busulfan is given. Clobazam , (p.619), has been suggested as a possible alternative to phenytoin. ... 

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. 

The probable reason for the reduction in sedative effects with these drugs is that some of the components of tobacco smoke are enzyme inducers, which increase the rate at which the liver metabolises these benzodiazepines, thereby reducing their effects. The inference to be drawn is that smokers may possibly need larger doses than non-smokers to achieve the same therapeutic effects. Smoking also possibly reduces the drowsiness that the benzodiazepines and non-benzodiazepine hypnotics, such as zolpidem, can cause. However, one study suggested that caffeine intake, and others suggest age, may affect the response to benzodiazepines, so the picture is not altogether clear. Whether any of these interactions has much clinical relevance awaits assessment. 

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 such as barbiturates and carbamazepine induce certain enzymes and will then trigger faster breakdown of some concomitantly used antipsycho-tics and antidepressants. In contrast, paroxetine, fluoxetine and fluvox-amine, acting by different mechanisms, inhibit the breakdown of other concomitantly administered drugs such as benzodiazepines, antidepressants, antiepileptics and neuroleptics (Table 5.1). 

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. 

The barbiturates were formerly the mainstay of treatment used to sedate the patient or to induce and maintain sleep. Today, they have been largely replaced by the benzodiazepines, mainly because barbiturates induce tolerance, drug-metabolizing enzymes, physical dependence, and very severe withdrawal symptoms. Foremost is their ability to cause coma in toxic doses. Certain barbiturates, such as the very short-acting thiopental, are still used to induce anesthesia (see p. 115). 

Enzyme induction can be problematic with co-administration of benzodiazepines and rifampicin or certain anticonvulsants (phenobarbital, phenytoin, carbamaze-pine). However, despite enzyme stimulation, the net effect of adding these anticonvulsants can be augmentation of benzodiazepine-induced sedation. 

Benzodiazepines produce fewer drug interactions because they do not induce hepatic microsomal enzymes. 

Alternative atypical antipsychotics (for psychosis) or combination therapies Carbamazepine or oxcarbazepine induce liver enzymes and may affect the metabolism and blood levels of concomitant medications lithium, antipsychotics, and benzodiazepines increase the risk of adverse effects and cognitive impairment... 

G Kominami, et al. Combined high performance liquid chromatography and enzyme immunoassay for active metabolites of a sleep inducer (rilmazafone), a ring opened derivative of benzodiazepines, in human plasma. I Chromatogr-Bio 417 216, 1987. 

Other adverse effects Barbiturates and carbamates (but not benzodiazepines, buspirone, zolpidem, or zaleplon) induce the formation of the liver microsomal enzymes that metabolize dmgs. This enzyme induction may lead to multiple drug interactions. Barbiturates may also precipitate acute intermittent porphyria in susceptible patients. Chloral hydrate may displace coumarins from plasma protein binding sites and increase anticoagulant effects. 

Pharmacokinetics PO/PR/IM/IV. Well absorbed orally. Give IM only if patient cant take orally. Give IV slowly because of fall in blood pressure. Barbiturates vary markedly in lipid solubility and plasma protein binding (Table 3.86). Barbiturates induce P450 enzymes in the liver which T metabolism of phenytoin, digitoxin, coumadin and others. Pharmacokinetics Primary difference between various benzodiazepine agonists are their pharmacokinetic properties (Table 3.8C). 

The inconsistency of these reports is not understood. Benzodiazepine-induced changes in the metabolism of phenytoin as well as alterations in the apparent volume of distribution have been suggested as possible mechanisms. Enzyme induction by phenytoin may possibly account... 

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