The widespread use of benzodiazepines as anxiolytics and anticonvulsants has been accompanied by an increase in the incidence of self-induced toxicity with these agents. Alone or as coingestants, benzodiazepines have been estimated to be involved in 30 to 60 percent of admissions for intoxication.1
Benzodiazepines produce anxiolysis, sedation, hypnosis and centrally mediated muscle relaxation; individual sensitivity for these effects varies greatly1,2 While the abuse of benzodiazepines alone rarely results in fatalities,3 the emergency treatment of the patient with an altered level of consciousness due to substance abuse often necessitates hospitalization and invasive procedures (e.g., intubation, lavage). In the search for more selective benzodiazepine compounds, flumazenil (RO 15-1788) proved instead to be the first specific benzodiazepine receptor antagonist.
Isolated in 1981, flumazenil is an imidazobenzodiazepine capable of blocking the centrally mediated effects of benzodiazepines at the receptor level.4 Its utility may parallel that of naloxone in opiate toxicity; however, controversy over its use in the emergency department persists.5
A specific benzodiazepine receptor in the CNS has been identified with highest densities located in the cerebral cortex, limbic structures and cerebellum. Benzodiazepines are believed to potentiate gamma amino butyric acid (GABA) neuronal inhibition. The GABA/benzodiazepine receptor complex is composed of a separate benzodiazepine receptor, a GABA receptor and a chloride channel.
Effects of stimulation of the GABA receptor produces increased conductance of chloride ions intracellularly via the chloride channel thereby shunting electrical currents that would otherwise depolarize the membrane. When the benzodiazepine receptor is stimulated, the sensitivity of the GABA receptor complex for GABA is increased and prolonged. The inhibitory effect of the GABA/benzodiazepine complex on neuronal discharge produces sedation, anticonvulsant activity, anxiolysis and striated muscle relaxation.6,7,8,9
Flumazenil is a competitive benzodiazepine receptor antagonist. An imidazobenzodiazepine derivative, flumazenil antagonizes the actions of benzodiazepines on the CNS. It competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex.6,7 The drug appears to act at CNS but not peripheral benzodiazepine receptor binding sites. Flumazenil is the purest antagonist synthesized and has limited agonist or inverse agonist activity.6
The onset of reversal to benzodiazepine mediated effects is usually evident after one to two minutes post intravenous administration. Eighty percent response will be reached within three minutes. Peak effects occur at six to ten minutes post administration. The duration and degree of reversal are related to the plasma concentration of the benzodiazepine as well as the dose of flumazenil.7,10
After IV administration, flumazenil plasma concentrations follow a two compartment model with an initial distribution half-life of seven to 15 minutes and a terminal half-life of 41 to 79 minutes.
Peak concentrations are proportional to dose, with an initial volume of distribution of 0.5 L./kg. After tissue uptake, the volume of distribution ranges from 0.77 to 1.60 L./kg. Protein binding is 50 percent with no preferential partitioning into red blood cells.
Clearance occurs primarily by hepatic metabolism and is dependent on hepatic blood flow. Total clearance ranges from 0.7 to 1.3 L./kg. per hour in healthy volunteers. One percent of the drug is excreted unchanged in the urine.10
Oral doses are rapidly and completely absorbed, with peak levels reached after 29 to 90 minutes; however, bioavailability is low due to a hepatic first-pass effect.6 The pharmacokinetics are not significantly affected by gender, age, renal failure or hemodialysis beginning one hour after drug administration. Clearance is decreased with hepatic impairment. This results in prolongation of half-life from 0.8 hours in healthy subjects to 1.3 hours in patients with moderate hepatic impairment and 2.4 hours in severely impaired patients.
The pharmacologic profile of flumazenil is unaltered in the presence of benzodiazepine agonists and the kinetics profiles of those benzodiazepines are unaltered by flumazenil.7,10
Death has occurred in patients who received flumazenil. The majority of deaths occurred in patients with serious underlying disease or in patients who had ingested large amounts of non-benzodiazepine drugs as part of the overdose.
Seizures can occur in patients who have used benzodiazepines for the treatment of seizure disorders, in patients who are physically dependent on benzodiazepines or in patients who have ingested drugs (e.g., cyclic antidepressants, cocaine, lithium, methylxanthines, isoniazid, propoxyphene, monoamine oxidase inhibitors, bupropion HCl and cyclosporine) that place them at risk for the development of seizures.5
Adverse effects most frequently associated with flumazenil alone were limited to dizziness, injection site pain, increased sweating, headache and abnormal or blurred vision.
Studies indicate that no significant pharmacologic effects occurred even in oral doses of 600 mg. or intravenous doses of 100 mg.11,12 Flumazenil has a therapeutic index of 3212 or greater than 3000 times the required clinical dose for benzodiazepine reversal.1 The efficacy of flumazenil has been demonstrated in clinical trials including:
O'Sullivan et al.13 — a randomized, double blinded, placebo-controlled trial of 60 patients (aged 18-65) admitted to a health care facility with altered mental status. Verification of the type of ingestion was based on serum, urine and gastric analysis. All patients received charcoal and mannitol. Flumazenil was administered over five minutes to a maximum dose of 1 mg. The subjects were monitored for improvements in their level of consciousness using a modified Glasgow Coma Scale (GCS) over a 24 hour period.
O'Sullivan reported a significant increase in the GCS scores (in relation to their baseline) for the subgroups receiving flumazenil with confirmed benzodiazepine overdoses and mixed overdoses with benzodiazepines. The most common adverse reactions were anxiety and distress. Mild withdrawal reactions were noted in three patients, however none required pharmacologic interventions.
Hojer et al.14 — a randomized, double blinded, placebo-controlled trial of 105 patients admitted with suspected drug overdosage. Verification of the ingested substances and initial assessment of the patients proceeded along a standardized evaluation. Flumazenil was administered over three minutes and reassessment of the subjects performed. In the group receiving flumazenil, Hojer documented increases in the level of consciousness that resulted in a more accurate history and eliminated the need for several standard interventions (e.g., intubation). Moreover in polydrug ingestions unresponsive to flumazenil no seizure activity or arrhythmias occurred.
Additionally trials of patients with conscious sedation or undergoing general anesthesia in which benzodiazepines were used as an adjunct demonstrated very effective reversal of sedation.10
Scattered cases reports suggest a role for flumazenil in the reversal of ethanol intoxication15,16,17 and in carbamazepine poisoning.17,18 Scientific investigation has yet to confirm or disprove the value of flumazenil in these situations.
Flumazenil may be considered for the reversal of benzodiazepine sedation in cases where general anesthesia has been induced and/or maintained with benzodiazepines; where sedation has been produced by benzodiazepines for diagnostic and therapeutic procedures; in therapeutic misadventures and for the management of benzodiazepine overdose in patients who are not at risk for seizures. (See Contraindications below.)10
Flumazenil is contraindicated in patients who are showing signs of serious cyclic antidepressant overdose; in patients who have ingested drugs (e.g., cyclic antidepressants, cocaine, lithium, methylxanthines, isoniazid, propoxyphene, monoamine oxidase inhibitors, bupropion HCl and cyclosporine) that place them at risk for the development of seizures; in patients who are physically addicted to benzodiazepines which puts them at risk for withdrawal seizures; in patients with a known hypersensitivity to flumazenil or benzodiazepines and in patients who have been given a benzodiazepine for the control of a potentially life-threatening condition (e.g., control of intracranial pressure or status epilepticus).5,10
Flumazenil is a benzodiazepine antagonist with clinical utility in the reversal of sedation and CNS depression due to benzodiazepines. Flumazenil must be used with caution in patients who have been on benzodiazepines for long-term sedation, anticonvulsant therapy, or in overdose cases where cyclic antidepressants or other seizurogenic drugs were ingested. Since flumazenil has been associated with the occurrence of serious adverse effects (e.g., seizures) in high-risk groups, it should not be routinely administered with dextrose, oxygen, naloxone and thiamine to the unconscious patient.
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