Pharmacokinetics and Clinical Use of Flumazenil (Ro 15-1788)

Abstract

Flumazenil (Ro 15-1788) is a specific benzodiazepine antagonist which can prevent or abolish selectively at the receptor level all centrally mediated effects of benzodiazepines. Following oral administration flumazenil is rapidly absorbed (peak concentrations are achieved after 20 to 90 minutes), but bioavailability is low (16%) due to significant presystemic elimination. As less than 0.2% of an intravenous dose was recovered as unchanged drug in the urine, extensive metabolism must occur and so far 3 metabolites of flumazenil (N-demethylated and/or hydrolysed products) have been identified. For the clinical value of flumazenil a rapid onset of action is mandatory, which is facilitated by its fast uptake and regional brain distribution as verified by positron emission tomography. The limited duration of benzodiazepine-antagonistic action of flumazenil (2 to 3 hours) is due to its rapid hepatic elimination. This can be characterised either by the short half-life (0.7 to 1.3 hours) or better by the high plasma or blood clearance of 520 to 1300 ml/min (31 to 78 L/h). The low plasma protein binding of flumazenil (about 40%) will not limit its wide distribution (apparent distribution volume 0.6 to 1.6 L/kg) or its partly flow-dependent hepatic elimination. Whereas in first trials flumazenil appeared to be without its own pharmacological effects, there is now increasing evidence that flumazenil is not devoid of intrinsic actions. Dependent on the dose, the basal clinical conditions and experimental tests, flumazenil has both weak agonist-like and inverse agonist-like properties which might be explained by a modulation of GABA-ergic activity. In several clinical studies intravenous doses down to 0.2mg of flumazenil initiated a rapid and reliable reversal of benzodiazepine-induced sedation, hypnosis or coma. Small incremental intravenous doses of 0.1 to 0.2mg of flumazenil are useful in benzodiazepine intoxications, in differential diagnosis of coma, excessive postoperative sedation and possibly in reversing paradoxical reactions of benzodiazepines. Because flumazenil is short acting, careful clinical observation is crucial. To maintain its antagonistic action repeated administrations will be necessary. At present, the therapeutic indications are restricted to some special situations. However, flumazenil is an interesting agent, which might contribute also to a better understanding and future development of more specific benzodiazepines, hopefully without the potential for dependence seen with existing compounds.

Possible interaction of fluoroquinolones with the benzodiazepine‐GABAA‐ receptor complex.

“…We therefore further investigated the interaction of ciprofloxacin, norfloxacin and ofloxacin with the benzodiazepine (BZD)-GABAAreceptor complex in a radio-receptor assay (RRA) either the short-acting BZD-agonist midazolam (Allonen et al, 1981) or the specific BZDantagonist flumazenil (Klotz & Kanto, 1988 Subjects/Study design After obtaining written informed consent, 12 drug-free healthy volunteers (three females, nine males) between 23 and 47 years old participated in the study, which was approved by the Ethics committee of our hospital. Inclusion criteria were normal values in the haematological, physical and clinical safety checkups and a stable alpha-rhythm with an alpha proportion > 40%, evaluated in an EEG pre-screening.…”

Plasma concentrations of flumazenil following intranasal administration in children

“…The first four patients received the entire dose of flumazenil in one nostril and, given the large volumes, it is conceivable that some, if not most, of the flumazenil was absorbed via the gastrointestinal tract. This would result in first pass hepatic metabolism with reduced bioavailability, as reported by Klotz et al .,4 where oral flumazenil has a bioavail -ability of only 16%. Indeed, the pharmacokinetic analysis of the final six patients yielded a peak plasma concentration that was 50% greater than that of the whole study group.…”

“…Klotz et al . 4 concluded that plasma concentrations of 10 to 20 ng·mL -1 may effectively reverse BZD induced CNS depression. In another study, the mean plasma concentration of flumazenil required to reverse midazolam, as measured by the ability of the patient to identify him-or herself verbally after midazolam anesthesia, was 29.9 ng·mL -1 .…”

“…After induction, 40 µg·kg -1 flumazenil Anexate®, Roche, 0.1 mg·mL -1 (0.4 mL·kg -1 )) were administered via a syringe as drops, prior to nasal intubation. Venous plasma samples were drawn prior to administration of flumazenil (t=0), and then at 2, 4,6,8,10,15, 20, 30, 40, 60, and 120 min thereafter. The plasma samples were immediately processed by the onsite laboratory and then stored at -70°C, before batch analysis via high performance liquid chromatography assay.…”

“…2 Oral BZD sedation is often used in pediatric patients, particularly toddlers, without concurrent intravenous access and, if adverse reactions such as excessive sedation, agitation and restlessness occur, antagonism may be required. 3 However, flumazenil, a competitive BZD antagonist that reverses the central nervous system effects of all BZD, 4 is only available as a parenteral preparation, and in those patients without intravenous access that require BZD antagonism, an alternative emergency route of flumazenil administration may be useful. Intranasally administered flumazenil may be such an alternative route, but has not been studied in children.…”