Pharmacokinetics

Flumazenil is a short-lived compound. Table 10-1 includes a summary of its pharmacokinetics, which has been described in a variety of clinical settings.^{[422] [423] [424]} Of particular note is that when compared with benzodiazepine receptor agonists, flumazenil has the highest clearance and shortest elimination half-life. The plasma half-life of flumazenil is about 1 hour—it is the shortest lived of all benzodiazepines used in anesthetic practice. This short half-life means that the potential exists for the antagonist to be cleared, with sufficient concentrations of agonist left at the receptor site to cause resedation. ^[419] To maintain a constant therapeutic blood level over a prolonged period, either repeated administration or a continuous infusion is required. An infusion rate of 30 to 60 µg/min (0.5 to 1 µg/kg/min) has been used for this purpose.^[425] The rapid blood clearance of flumazenil approaches hepatic blood flow, a finding indicating that liver clearance is partially dependent on hepatic blood flow. When compared with other benzodiazepines, flumazenil has a relatively high proportion of unbound drug; its protein binding is low, with the free fraction ranging from 54% to 64%. ^[423] This property of flumazenil could contribute to its rapid onset and greater clearance, but this hypothesis is unproven.