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Flumazenil is a competitive benzodiazepine receptor antagonist. Its role in patients with unknown overdose is limited because seizures and dysrhythmias may develop when the effects of a benzodiazepine are reversed in a mixed overdose. Flumazenil also has the potential to induce benzodiazepine withdrawal symptoms, including seizures in patients who are benzodiazepine dependent. Flumazenil does not reliably reverse the respiratory depression induced by intravenous benzodiazepines.57 Flumazenil is the ideal antidote for the relatively few patients who are both naïve to benzodiazepines and who overdose solely on a benzodiazepine as well as benzodiazepine-naïve patients whose benzodiazepine component must be reversed after procedural sedation. Because the duration of effect of flumazenil is shorter than that of most benzodiazepines, repeat doses may be necessary and vigilance is warranted. Flumazenil has no role in the management of ethanolintoxication but may be considered for patients with hepatic encephalopathy. However, further study is needed before its routine use can be recommended.4 Case reports raise the possibility of a role for flumazenil in patients with paradoxical reactions to therapeutic doses of benzodiazepines.75 Flumazenil is not expected to be effective in sedating overdoses such as baclofen in which a benzodiazepine receptor is not involved.14 Flumazenil is effective for overdoses of zolpidem and zaleplon, nonbenzodiazepines that interact with ω1 receptors, a subclass of central benzodiazepine receptors.41,51,54

Haefely and Hunkeler's initial work on chlordiazepoxide synthesis69 led to an attempt to develop benzodiazepine derivatives that would act as antagonists.32 This endeavor was initially unsuccessful but led to the promising γ-aminobutyric acid (GABA) hypothesis of benzodiazepine mechanism of action. In 1977, the then-new technique of radioligand binding identified specific high-affinity benzodiazepine binding sites. Other investigators simultaneously isolated a product produced by a Streptomyces species that had the basic 1,4-benzodiazepine structure. Synthetic compounds subsequently were derived from this molecule to act as potential tranquilizers. Further research attempted to produce benzodiazepines with potent anxiolytic and anticonvulsant activity and diminished sedative and muscle-relaxing properties. Testing revealed these derivatives had high in vitro binding affinities but lacked in vivo activity. An inability to enter the CNS was considered an explanation for the discordance. During an experiment that attempted to demonstrate CNS penetration of these derivatives, diazepam given to incapacitate the animals had a surprisingly weak effect. This lack of potency led to the discovery of a benzodiazepine antagonist. Further modifications led to the synthesis of flumazenil (Ro 15-1788).20,55

The benzodiazepine receptor modulates the effect of GABA on the GABAA receptor by increasing the frequency of Cl− channel opening, leading to hyperpolarization. Agonists such as diazepam stimulate the benzodiazepine receptor to produce anxiolytic, anticonvulsant, sedative, amnestic, and muscle relaxant effects at low doses, and hypnosis at high doses.33Flumazenil is a water-soluble benzodiazepine analog with a molecular weight of 303 Daltons. It is a competitive antagonist at the benzodiazepine receptor, with very weak agonist properties both in animal models ...

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