A22: Antidotes in Depth

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. 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.²¹ 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 ethanol intoxication. Flumazenil may be considered for patients with hepatic encephalopathy although 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.⁷¹ Flumazenil was not effective in overdose of baclofen in which a benzodiazepine receptor is not involved.¹⁵ Flumazenil is effective for overdoses of zolpidem and zaleplon, nonbenzodiazepines that interact with ω₁ receptors, a subclass of central benzodiazepine receptors.^43,53,56

HISTORY

The initial work of Haefely and Hunkeler⁶⁷ on chlordiazepoxide synthesis led to an attempt to develop benzodiazepine derivatives that would act as antagonists.³³ This endeavor was initially unsuccessful but led to the promising γ-aminobutyric acid (GABA) hypothesis as the benzodiazepine mechanism of action. In 1977 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 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 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 potency led to the discovery of a benzodiazepine antagonist. Further modifications led to the synthesis of flumazenil (Ro 15-1788).^20,57

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. Flumazenil is a water-soluble benzodiazepine analog with a molecular weight of 303 Da. It is a competitive antagonist at the benzodiazepine receptor, with ...