Chapter A25: Flumazenil

INTRODUCTION

Flumazenil is a competitive benzodiazepine receptor antagonist. Its role in patients with an unknown overdose is limited because seizures and dysrhythmias may develop when the effects of a benzodiazepine are reversed if the patient has taken a mixed overdose of a benzodiazepine and a proconvulsant. 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 (IV) benzodiazepines.²⁴ 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 benzodiazepines must be reversed during or 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 ethanol intoxication. In patients with hepatic encephalopathy, further study is necessary before it can be recommended.⁴ Case reports raise the possibility of a role for flumazenil in patients with paradoxical reactions to therapeutic doses of benzodiazepines.^78,86 Flumazenil is neither rational nor effective in patients who overdose with baclofen.¹⁵ Flumazenil is effective for overdoses of zolpidem and zaleplon, nonbenzodiazepines that interact with ω₁ receptors, a subclass of central benzodiazepine receptors.^50,62,65,79

HISTORY

The initial work of Haefely and Hunkeler^42,82 on chlordiazepoxide synthesis led to an attempt to develop benzodiazepine derivatives that would act as antagonists.³⁷ This endeavor was initially unsuccessful but led to the promising γ-aminobutyric acid (GABA) hypothesis as the benzodiazepine mechanism of action. Radioligand binding identified specific high-affinity benzodiazepine binding sites and others isolated a product produced by a Streptomyces species that had the basic 1,4-benzodiazepine structure. Synthetic derivatives of this molecule led to the creation of 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 agonist activity. An inability to enter the central nervous system (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 efficacy of diazepam led to the discovery of a benzodiazepine antagonist. Further modifications led to the synthesis of flumazenil.^23,68

PHARMACOLOGY

Mechanism of Action

The benzodiazepine receptor modulates the effect of GABA on the GABA_A 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–hypnotic, amnestic, and muscle relaxant effects.³⁸ Flumazenil is a water-soluble benzodiazepine analog with a molecular weight of 303 Da. It acts as ...