Pharmacology Of Flumazenil

Indication	For the complete or partial reversal of the sedative effects of benzodiazepines in cases where general anesthesia has been induced and/or maintained with benzodiazepines, and where sedation has been produced with benzodiazepines for diagnostic and therapeutic procedures. Also for the management of benzodiazepine overdose as an adjunct for appropriate supportive and symptomatic measures.
Pharmacodynamics	Flumazenil antagonizes the CNS effects produced by benzodiazepines, but does not antagonize the central nervous system effects of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (including ethanol, barbiturates, or general anesthetics) and does not reverse the effects of opioids.
Mechanism of action	Flumazenil, an imidazobenzodiazepine derivative, antagonizes the actions of benzodiazepines on the central nervous system. Flumazenil competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex. Flumazenil is a weak partial agonist in some animal models of activity, but has little or no agonist activity in man.
Absorption	Not Available
Volume of distribution	0.9 to 1.1 L/kg
Protein binding	Protein binding is approximately 50%, mostly (66%) to albumin. Protein binding is reduced in patients with hepatic cirrhosis.
Metabolism	Hepatic. Flumazenil is completely (99%) metabolized. The major metabolites of flumazenil identified in urine are the de-ethylated free acid and its glucuronide conjugate.
Route of elimination	Flumazenil is completely (99%) metabolized. Elimination of radiolabeled drug is essentially complete within 72 hours, with 90% to 95% of the radioactivity appearing in urine and 5% to 10% in the feces.
Half life	Initial distribution half-life is 4 to 11 minutes and the terminal half-life is 40 to 80 minutes. Prolongation of the half-life to 1.3 hours in patients with moderate hepatic impairment and 2.4 hours in severely impaired patients. Compared to adults, the elimination half-life in pediatric patients was more variable, averaging 40 minutes (range: 20 to 75 minutes).
Clearance	1 L/hr/kg [healthy volunteers receiving a 5-minute infusion of a total of 1 mg]
Toxicity	In clinical studies, most adverse reactions to flumazenil were an extension of the pharmacologic effects of the drug in reversing benzodiazepine effects.