Interactions with Benzodiazepines or Z-Drugs, and Other Drugs

Drug-drug interactions often amplify the effects and side effects of the medications involved and may introduce new and unexpected reactions. These are far too many to enumerate here, and the reader is referred to the FDA-approved prescribing information of the individual agents. It is important, however, to outline a few of the major interactions of concern.

It is no surprise that other sedating substances accelerate the sedating and cognitive / psychomotor impairing effects of benzodiazepines and Z-drugs. Because it is so commonly used, it is generally understood that alcohol amplifies these negative outcomes. Respiratory depression-related overdose death is rare for benzodiazepines taken alone, but is not infrequent when combined with alcohol and/or opioids. Benzodiazepines are detected in at least one-half of opioid-related deaths. Many such pharmacodynamic effects of drug interactions are subserved by the various agents through actions of each at the GABA_A receptor. Of notable importance here are the fluroquinolones which may block the GABA_A receptor and result in acute benzodiazepine withdrawal symptoms. Please see the section on Sensitization to Fluoroquinolones for a description of how this occurs.

In addition to additive or synergistic pharmacodynamic effects, the pharmacokinetics of drugs also relate to adverse reactions. Interactions can affect absorption, protein binding, metabolism, and elimination which, in turn, affect the amounts of benzodiazepines and Z-drugs available to exert their effects – good or bad – after they are taken. Drugs are metabolized through Phase I (P450 oxidation) and / or Phase II (glucuronidation, sulfation) and are unique to each individual chemical moiety. Pharmacogenetics determine if metabolism proceeds normally or at an increased or decreased level, rate that can be affected by other substances. To date, however, genetic testing has limited clinical utility.

Among medications commonly prescribed, interactions have been noted with anti-fungals, macrolide / fluroquinolone antibiotics, antiretrovirals, oral contraceptinves, anti-convulsants, calcium channel blockers, cimetidine, omeprazole, rifampin, barbiturates, phenothiazines, antihistaminics, psychotropics, opioids and other CNS depressants. Too much to review here, the reader is referred to the FDA-approved labels of these medications and the evidence-based literature for details.