Flumazenil in Benzodiazepine Antagonism

Abstract

In anaesthesia and in the intensive care unit, benzodiazepines have proven safe and effective agents for the induction and maintenance of sedation for a variety of therapeutic goals. However, in these contexts, or in benzodiazepine overdose, it is often desirable to be able to terminate or interrupt sedation without waiting for the effect of the benzodiazepine to become dissipated by normal metabolism and excretion. Flumazenil, a 1,4-imidazobenzodiazepine, is a highly effective, specific benzodiazepine antagonist which is indicated for use when the effect of a benzodiazepine must be attenuated or terminated at short notice. It acts by displacing other benzodiazepines from the receptor site by competitive inhibition. The onset of effect after intravenous administration occurs within 1 to 3 minutes. The optimal dosage is determined for each patient by a dose titration procedure and lies in the range 0.2 to 1.0mg in anaesthesiology, and 0.1 to 2.0mg in intensive care use. Despite its short elimination half-life of around 1 hour, after general anaesthesia or conscious to moderate sedation for short procedures, a single dose of flumazenil is usually sufficient to attain and maintain the desired level of consciousness. After intoxication with high benzodiazepine doses, the duration of effect of a single dose of flumazenil is not expected to exceed 1 hour. In such cases, the period of wakefulness can be prolonged as necessary by repeated low intravenous doses of flumazenil or by infusion (0.1 mg/hour). Flumazenil is well tolerated both systemically and locally. The only adverse events seen with greater frequency after flumazenil compared with placebo were nausea and/or vomiting after general anaesthesia, although the incidence of actual vomiting was not significantly different between the 2 groups. Since these effects were virtually absent in studies of intensive care patients and after sedation for short procedures, and were not seen in tolerability studies in healthy volunteers receiving intravenous bolus doses of up to 100mg, there may be a link between these symptoms and the other agents used in general anaesthesia, some of which have well-known emetic properties. Thus, flumazenil provides a safe and effective means of attenuating or reversing the CNS-depressant effects of benzodiazepines whenever indicated, e.g. following benzodiazepine-induced general anaesthesia, conscious sedation, or after benzodiazepine overdose, either alone or in combination with other agents.(ABSTRACT TRUNCATED AT 400 WORDS)

Benzodiazepine receptor antagonist (flumazenil) does not affect sleep-related breathing disorders

“…The dose of flumazenil used in the present study was derived from existing results of pharmacological and toxicological studies of the drug [17,34]. Several authors have reported that patients with pure benzodiazepines overdose require <1 mg flumazenil to fully reverse benzodiazepine-induced coma [35,36].…”

Novel Drugs for the Management of Hepatic Encephalopathy: Still a Long Journey to Travel

“…Flumazenil is well known as a benzodiazepine antagonist with the potential to bind with gamma-aminobutyric acid receptors. 73 Few studies have reported the GABA-A upregulation and augmented tone of GABAergic tone in patients with HE. 74,75 Upregulation of GABAergic neurons performs a vital role in the alteration of J o u r n a l P r e -p r o o f 9 neurocognitive outcomes in patients with HE.…”

Hepatic Encephalopathy: Current and Emerging Treatment Modalities

“…Flumazenil is a competitive antagonist of benzodiazepines binding to gamma aminobutyric acid (GABA)-A receptor. 69 Because GABAergic neurons up-regulation has been suggested to be involved in pathogenesis of HE, flumazenil can be used as a potential treatment for HE. 70 In a meta-analysis including 12 trials with 842 patients, flumazenil had a beneficial effect on HE (RR, 0.75; 95% CI, 0.71-0.80), with no significant difference in serious adverse events as compared with placebo.…”