Benzodiazepine drug-drug interactions commonly occurring in clinical practice

Pharmacokinetic drug-drug interactions which involve currently available benzodiazepines may be classified into two major categories: interactions which affect benzodiazepine rate of absorption, and interactions which affect clearance and, therefore, elimination half-life. Ethanol is the prototype for absorptive interactions. Concurrent ethanol use and oral ingestion of benzodiazepine derivatives uniformly slows the rate but does not change the extent of benzodiazepine absorption. Interactions which affect benzodiazepine clearance affect only those derivatives which are oxidatively metabolized or cleared as a function of hepatic blood flow (high first-pass clearance). Conjugated benzodiazepines are not implicated in such interactions. Rifampin and chronic ethanol use induce benzodiazepine oxidation, while cimetidine, oral contraceptives, ethanol (acute ingestion), disulfiram, isoniazid, and propranolol inhibit benzodiazepine oxidation. In addition, ethanol, cimetidine and isoniazid decrease first-pass hepatic extraction of triazolam, enhancing its systemic availability and decreasing oral clearance. The pharmacokinetic consequence of induction of benzodiazepine oxidation is higher clearance and decreased steady-state concentrations during chronic dosing. Conversely, inhibition of benzodiazepine oxidation decreases clearance and increases steady-state benzodiazepine concentrations during chronic dosing. Because a correlation of benzodiazepine plasma concentration and pharmacological effect is not established, the pharmacodynamic consequences of these interactions are not currently well characterized.