Drug Interactions with Benzodiazepines: Epidemiologic Correlates with Other CNS Depressants and In Vitro Correlates with Inhibitors and Inducers of Cytochrome P450 3A4

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Abstract

The benzodiazepines are a class of a relatively large number of drugs that share a common chemical structure and have anxiolytic to sedative action on the central nervous system (CNS). They are chemically diverse, but share a classic structure that consists of a benzene fused to a seven-membered diazepine ring. Benzodiazepines are noted to have both pharmacodynamic and pharmacokinetic drug interactions. The former can be most devastating, and usually arise from co-exposure to another CNS depressant (e.g., ethanol, opioids, barbiturates, anesthe­tics). These have been associated with enhanced impairment and mortality, usually from respiratory depression. Pharmacodynamic interactions occur with all benzodiazepines and are not related to their structure. Pharmacokinetic interactions, on the other hand are highly structure dependent, as most arise from either inhibition or induction of the cytochrome P450s involved in the metabolism of the benzodiazepine. Numerous examples of pharmacokinetic interactions that alter the pharmacokinetics of the benzodiazepine have been reported and these are herein described for an assortment of drug. These interactions may have sufficient changes to significantly reduce efficacy (induction of metabolism), but toxicity from inhibition of metabolism was rarely seen at the therapeutic doses used in clinical studies. These consequences, however, could be magnified in the overuser. Numerous drug interactions between benzodiazepines and other drugs do occur; those with other CNS depressants are of greatest concern.