Flumazenil

Summary

Synopsis

Flumazenil, a 1,4-imidazobenzodiazepine, is a specific benzodiazepine antagonist which is indicated for use when the effect of a benzodiazepine must be quickly attenuated or terminated. Following intravenous administration, the onset of clinically apparent benzodiazepine antagonism usually occurs within 1 to 5 minutes. Although flumazenil has a short elimination half-life of about 1 hour, a single intravenous dose of up to 1mg is usually sufficient to attain and maintain for about 2 hours the desired level of consciousness after general anaesthesia or conscious to moderate sedation indued by benzodiazepines. After intoxication with high doses of benzodiazepines the initial single dose of flumazenil will require supplementing with repeated low intravenous doses or an infusion (0.1 mg/h) to maintain a state of wakefulness. Flumazenil is well tolerated, and since it reliably attenuates or reverses the central effects of benzodiazepines and is specific for these drugs, it facilitates diagnosis by eliminating benzodiazepine intoxication in patients in whom the cause of unconsciousness is unknown. While results of some studies suggested that flumazanil may have intrinsic benzodiazepine partial agonist or inverse agonist activity, this is unlikely to be clinically important with usual doses.

Thus, flumazenil is a very promising, effective, short acting benzodiazepine antagonist which is well tolerated by most patients. Undoubtedly, its full clinical potential has yet to be realised.

Pharmacodynamic Studies

Flumazenil is a benzodiazepine antagonist which inhibits the central effects of benzodiazepine agonists by competing with these drugs for the benzodiazepine receptor. In a variety of tests in mice, rats and cats, flumazenil 0.3 to 30 mg/kg intravenously, 0.5–10 mg/kg intraperitoneally, a total dose of 30 to 100mg orally and of 2.5µg by the intracerebroventricular route, has been shown to antagonise the central effects of benzodiazepine agonists (e.g. diazepam, triazolam, midazolam) and inverse agonists [e.g. dimethoxy-ethyl-carbomethoxy-β-carboline (DMCM)].

The inhibitory effect of flumazenil is specific for central benzodiazepine receptors. Following injection of ¹¹C-flumazenil the pattern of distribution of radioactivity in human brain, as evidenced by the use of positron emission tomography, closely corresponded to the previously known distribution of benzodiazepine receptors in individual brain areas. These findings support the suggestion that in man, as in animals, flumazenil antagonises the central pharmacological effects of the benzodiazepines by interacting with these drugs at the central benzodiazepine receptor binding sites. The absence of change in plasma concentrations of diazepam or midazolam following administration of flumazenil at dosages that reversed the central effects of these benzodiazepines, indicated that flumazenil does not antagonise the actions of these drugs by altering their bioavailability. Numerous studies in healthy subjects have demonstrated that flumazenil 100 to 200mg orally or 2.5 to 20mg intravenously, antagonised the pharmacological effects (such as sedation, impaired cognitive and motor function, and anaesthesia) of diazepam, meclonazepam, flunitrazepam and midazolam when the benzodiazepine agonist and flumazenil were administered concomitantly or separately at various intervals.

While initial studies in animals failed to reveal any intrinsic pharmacological activity of flumazenil, subsequent studies in animals and in humans demonstrated both partial agonist and partial inverse agonist activity, albeit generally slight. In animals, partial agonist effects have been observed usually with high doses of flumazenil (30 to 50 mg/kg), while inverse agonist-like activity has been evident most often at lower doses. This latter activity has often been observed only under particular test and environmental conditions.

In humans however, evidence for intrinsic effects of flumazenil is less clear. Some reports of subjective mood changes have been interpreted as flumazenil-induced anxiety, but this is not convincing. In a detailed analysis of the effects of different doses of flumazenil in healthy subjects, it was reported that flumazenil 100mg orally produced benzodiazepine-like effects, and that the effects which were more pronounced at the lower dose of 30mg were unlike those of the benzodiazepines. In a small group of epileptic patients, flumazenil 2.5mg intravenously or 50mg orally, exhibited anticonvulsant activity in the EEG. Nevertheless, the intrinsic effects in humans are generally weak and seem unlikely to detract from its clinical use as a specific benzodiazepine antagonist.

Pharmacokinetic Properties

After oral administration of a single 200mg dose of flumazenil to healthy subjects a mean peak plasma concentration of 255 µg/L (range 143 to 439) was attained 41 minutes (mean) after ingestion. Similar plasma concentrations were attained 5 minutes after intravenous bolus administration of a single 20mg dose. Following oral administration flumazenil undergoes considerable first-pass metabolism in the liver, resulting in about 16% of the ingested dose reaching the systemic circulation in unchanged form.

In healthy subjects, positron tomography has indicated that distribution of radioactivity in the brain following injection of 11C-flumazenil corresponds closely to previously known distribution of benzodiazepine receptors. Average volume of distribution was about 1.1 L/kg following intravenous administration of flumazenil and was very similar after either 20 or 40mg doses.

Flumazenil is extensively metabolised in the liver, with only 0.12% (mean) excreted unchanged in the urine over a 12-hour period after intravenous injection. To date, 3 metabolites have been identified (N-desmethylflumazenil, N-desmethylflumazenil ‘acid’ and flumazenil ‘acid’). In healthy subjects total plasma clearance of flumazenil following single intravenous doses has been reported to range from 691 to 1198 ml/min (41 to 72 L/h) and elimination half-life was generally less than 1 hour.

Therapeutic Trials

The efficacy of flumazenil in reversing the central effects of benzodiazepines has been demonstrated in numerous, usually small, groups of patients. Much of the preliminary clinical experience has been during the recovery period following surgery in patients anaesthetised with midazolam or flunitrazepam, or sedated with midazolam for minor surgery or diagnostic procedures. Following general anaesthesia, flumazenil administered intravenously in individually titrated dosages of up to 1mg was clearly superior to placebo in reversing benzodiazepine-induced sedation, as assessed by sedation rating scores. Differences between treatment groups were significant 1 to 5 minutes after flumazenil or placebo administration, and remained so for 30 to 75 minutes. Mean duration of amnesia was also significantly shorter after flumazenil compared with placebo, although in some studies this difference was of doubtful clinical significance.

In patients sedated with midazolam or diazepam to a level where they were alseep but rousable on command, flumazenil at dosages of up to 1mg intravenously resulted in rapid recovery and shortening of amnesia. As expected, the clinical relevance of results with flumazenil in patients sedated with the short acting drug midazolam was less apparent than in patients sedated with the longer acting diazepam. In some instances the duration of a significant difference in alertness between flumazenil and placebo was only about 15 minutes in patients sedated with midazolam. In contrast, in subjects given diazepam, significant differences between flumazenil and placebo, as rated by sedation scales, persisted up to 120 minutes after flumazenil administration.

Intravenously administered flumazenil has been successfully used to reverse the central effects of high doses of benzodiazepines in small groups of patients who intentionally ingested overdoses, and in those in whom therapeutically administered benzodiazepines resulted in intoxication. In such patients flumazenil was usually administered at a dose of 0.2 to 0.5 mg/min until patients were fully awake or a total dose of several milligrams had been given. A return to consciousness generally occurred within 5 minutes in patients who were unconscious as a result of pure benzodiazepine overdose or intoxication. In patients in whom unconsciousness was due to ingestion of unknown drugs, administration of flumazenil facilitated diagnosis by eliminating the effects of any benzodiazepines ingested. The duration of effect of the initially effective dose of flumazenil generally varied from 1 to 2 hours to 3 to 5 hours, although in some patients, sedation did not reappear after its reversal by flumazenil.

Side Effects

Usual therapeutic doses of flumazenil have been very well tolerated by most patients. Only nausea and/or vomiting occurred in more than 1% of patients who received flumazenil for the reversal of benzodiazepine-induced sedation or general anaesthesia. In double-blind trials in anaesthesiology, side effects were observed in 21% of patients receiving flumazenil and 10% given placebo. However, the higher incidence of nausea and vomiting experienced by anaesthetised patients compared with other groups treated with flumazenil suggests that such effects may have been due in part to ancillary drug therapy or to the surgical procedure. In patients treated for benzodiazepine intoxication, the most frequent event was agitation (6.5%), followed by discomfort (unspecified), tearfulness, anxiety and a sensation of coldness. These usually mild effects have generally not been regarded as benzodiazepine withdrawal symptoms. Careful analysis of reported side effects indicated possible withdrawal effects precipitated by flumazenil have occurred in fewer than 1% of patients.

Dosage and Administration

The dosage of flumazenil should be titrated individually to obtain the desired level of consciousness. Generally, doses of 0.3 to 0.6mg administered intravenously have been adequate to reduce the degree of sedation to the required extent in patients sedated or anaesthetised with benzodiazepines for carrying out surgery, while doses of 0.5 to 1mg are usually sufficient to completely abolish the effect of a therapeutic dose of a benzodiazepine in other settings. In patients who are unconscious due to ingestion of an overdose of drugs that have not been positively identified, failure to respond to intravenous doses of 5mg flumazenil may indicate the involvement of intoxicants other than benzodiazepines or the presence of functional or organic disorders.