Pharmacology of flumazenil

Abstract

Flumazenil, an imidazobenzodiazpine, is the first benzodiazepine antagonist available for clinical use. It is a specific competitive antagonist at benzodiazepine receptors, which are associated with receptors for gammaaminobutyric acid, the most important inhibitory neurotransmitter in the central nervous system. Administered orally, it has a low bioavailability and the preferred route is intravenous. Its usual clinical role is to reverse the effects of benzodiazepine sedation; however, administered before, or with, other benzodiazepines, it modifies their effects, the extent of such modification depending on the dose, duration of effect and relative receptor affinity of the agonist. Flumazenil also reverses adverse physiological effects of benzodiazepines. Its indications include reversal of benzodiazepine‐induced sedation, termination of benzodiazepine‐induced anaesthesia, return of spontaneous respiration and consciousness in intensive care patients and the treatment of paradoxical reactions to benzodiazepines. Other potential indications include its use in hepatic encephalopathy, alcohol intoxication and coma; however, these claims still require substantiation. Following sedation reversed with flumazenil, minimal residual effects of the agonist can sometimes be detected using psychomotor tests and are due to the relatively short half‐life of flumazenil, but are of no clinical consequence. There is concern that flumazenil could precipitate an acute withdrawal syndrome following long‐term benzodiazepine administration; however, the available evidence suggests otherwise and that it could be useful in the treatment of benzodiazepine tolerance. The existence of flumazenil is important, with implications for future research and the development of minimally invasive therapy and day‐case surgery. With increasing pressures on non‐anaesthetically trained practitioners to perform sedation, flumazenil has important implications for safety.

A comparison of chlordiazepoxide, bretazenil, L838,417 and zolpidem in a validated mouse Vogel conflict test

“…Moreover, Gonzalez and File 1997 found that flumazenil was unable to antagonise the anxiolytic effect of midazolam infused into the dorsal raphe nucleus in rats on the elevated plus-maze. Clearly, there are various potential explanations, not the least of the low affinity of flumazenil for the benzodiazepine site and its short half-life in combination with a very high potency ligand such as BRZ (Whitwam and Amrein 1995;Sieghart 1995) In addition, unlike CDP, BRZ has appreciable affinity and efficacy at α 4 containing GABA A receptors, at which flumazenil has a positive modulatory effect (Wafford et al 1996;Benke et al 1997), and this may account for the flumazenilinsensitive anti-conflict effect of BRZ.…”

Investigation of the anticonvulsive effect of acute immobilization stress in anxious Balb/cByJ mice using GABAA-related mechanistic probes

“…To confirm that the effects of progesterone occur through its conversion to allopregnanolone, this compound was combined with progesterone in the finasteride-treated animals. Likewise, to ascertain that the clonazepam activity is mainly attributable to the direct interaction with the benzodiazepine site at the GABA A receptor, clonazepam was administered with flumazenil, a central-type benzodiazepine receptors antagonist (Whitwam and Amrein 1995). Etifoxine, progesterone, and clonazepam were administered at higher doses than those used previously to compare the antagonist potencies of finasteride and picrotoxin or flumazenil.…”

Flumazenil-induced Ballism

“…Other potential indications include hepatic encephalopathy, and other forms of coma (1). Flumazenil is a relative safe drug, with rare central nevous system (CNS) side effects, such as seizure, agitation and anxiety (2)(3)(4).…”