Benzodiazepine drug-drug interactions commonly occurring in clinical practice

Abstract

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.

Ethanol inhibits in-vitro metabolism of nifedipine, triazolam and testosterone in human liver microsomes

“…Given the results of our study and the dose-dependent CYP3A induction by ethanol (Feierman et al 2003), the net effects of ethanol on CYP3A are likely to be complicated and may depend on the extent, as well as the duration, of ethanol consumption (Sellers et al 1978). However, in acute alcohol consumption/intoxication, inhibitory effects may contribute significantly to clinically important interactions (Abernethy et al 1984;Hollister 1990).…”

“…while Phase II metabolism is unaffected (Abernethy et al 1984;Hollister 1990). Given the results of our study and the dose-dependent CYP3A induction by ethanol (Feierman et al 2003), the net effects of ethanol on CYP3A are likely to be complicated and may depend on the extent, as well as the duration, of ethanol consumption (Sellers et al 1978).…”

Interactions of benzodiazepines on psychomotor skills.

“…It is natural that well-known inhibitors of hepatic drug metabolism (cimetidine etc.) retard the elimination of those BZ derivatives which undergo hydroxylation whereas the conjugation of that hydroxyl group is not sensitive towards metabolic inhibitors (Abernethy et al, 1984). That type of interaction can prove important when BZ derivatives with strong and brief action (midazolam, triazolam) are used, expecting their effects to disappear as usual.…”

“…The drug-drug interactions of various BZs with many clinically important drugs have been in the interest of clinicians although the effects have been other than on psychomotor performance (Abernethy et al, 1984). It is natural that well-known inhibitors of hepatic drug metabolism (cimetidine etc.)…”

“…The processes subject to alterations comprise absorption, binding to plasma proteins, and elimination. Members of the BZ family are metabolized to varying extents, and an inhibition of their metabolism may result in elevated drug levels in tissues (Abernethy et al, 1984 . One might expect that their combined action is even synergistic, but such a supra-additive effect has been documented only occasionally if ever.…”