Toxicology Agents

Description: Flumazenil is a parenteral benzodiazepine antagonist. It is an imidazobenzodiazepine derivative and was the first benzodiazepine antagonist to undergo clinical trial. Flumazenil is used to treat benzodiazepine overdose and to reverse benzodiazepine sedation during anesthesia. Flumazenil will also antagonize the sedative actions of zolpidem and eszopiclone. Flumazenil is administered only by rapid IV injection because it is highly irritating, and care should be taken to avoid extravasation. It does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants. Flumazenil was approved by the FDA in December 1991.

Mechanism of Action: Flumazenil has a high affinity for the GABA/benzodiazepine-receptor complex, the specific binding site of benzodiazepines. This site is where inhibition occurs. Flumazenil competes with benzodiazepines for binding. Because binding is competitive and flumazenil has a much shorter duration of action than do most benzodiazepines, it is possible for the effects of flumazenil to dissipate sooner than the effects of the benzodiazepine.

While flumazenil reverses benzodiazepine-induced sedation, it has no proven effectiveness in the treatment of hypoventilation induced by benzodiazepines. Any beneficial effects on ventilatory response from flumazenil use can be outlived by the effects of the benzodiazepines. Prompt detection of hypoventilation with suitable ventilatory support is essential, especially in reversal of acute benzodiazepine overdosage. Abrupt awakening following flumazenil administration may be associated with dysphoria, agitation, and possibly increased adverse effects. If administered to patients who have received a benzodiazepine chronically, abrupt interruption of benzodiazepine agonism by flumazenil can induce benzodiazepine withdrawal including seizures. Flumazenil does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants.

Pharmacokinetics: Flumazenil is administered intravenously because if given orally, it undergoes extensive first-pass metabolism. The drug rapidly enters the brain with an onset of action of 1—2 minutes. Peak concentrations are proportional to dosage and occur 1—3 minutes after the administration of flumazenil. Protein binding is approximately 50% and decreases in patients with hepatic impairment. Hepatic metabolism is responsible for clearance of the drug. Decreased hepatic blood flow or severe hepatic dysfunction radically alters clearance of flumazenil. The initial half-life is 7—15 minutes, with a 20—30 minute half-life in the brain. The terminal half-life is 41—79 minutes. Severe hepatic dysfunction reduces clearance to about 25% of normal and prolongs the half-life. Half-life can increase from roughly 1 hour in patients with normal hepatic function up to 2.4 hours in patients with severe hepatic dysfunction. Food in the GI tract increases the rate of clearance by about 50%, probably because of increased hepatic blood flow associated with digestion. Excretion is about 90—95% renal, mainly as metabolites, with 5—10% appearing in the feces, and excretion is essentially complete within 72 hours.

Drug Information Provided by
Gold Standard, Inc. � 2007