The Effects of a Benzodiazepine Antagonist Ro 15–1788 in the Presence of Stable Concentrations of Midazolam

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.

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“…In the study of Lauven et al (1985) a mean steady-state concentration of midazolam of 0.6 mg! L was obtained by infusion in 7 volunteers.…”

Section: Antagonism Of the Actions Of Benzodiazepinesmentioning

confidence: 99%

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

Klotz

Kanto

1988

Clinical Pharmacokinetics

122

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“…Flumazenil is a 1,4-imidazobenzodiazepine derivate and was developed as a specific antagonist for therapeutic doses or overdoses of benzodiazepines in humans. Diazepam and midazolam-induced sedation, respiratory depression, and muscle relaxation in humans can be reversed by flumazenil (Lauven et al, 1985;Klein and Kilde, 1989;Gross et al, 1991). Flumazenil also has been used in veterinary anesthesia: dogs (Hess, 1991), cats (Lin et al, 1993), river otters (Lutra canadensis) (Spelman, 1997), and guanacos (Lama guanicoe) (Karesh et al, 1998).…”

mentioning

confidence: 99%

Partial Antagonism of Tiletamine-Zolazepam Anesthesia in Cheetah

Walzer¹,

Huber²

2002

Journal of Wildlife Diseases

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This study evaluated partial antagonism of tiletamine-zolazepam (TZ) anesthesia in cheetahs (Acinonyx jubatus) and differences between two benzodiazepine antagonists, flumazenil and sarmazenil, in this species. Four cheetahs were anesthetized three times at an interval of 14 days with an average intramuscular dose of 4.2 mg/kg TZ. In trials 2 and 3 flumazenil at 0.031 mg/kg and sarmazenil at 0.1 mg/kg, respectively, were applied intramuscularly 30 min after initial TZ injection. There was a highly significant difference between the duration of TZ anesthesia with and without antagonist. Use of the antagonists significantly shortened duration and recovery and eliminated excitatory behavior during the recovery phase. No significant differences could be determined between the two antagonists. We recommend the use of sarmazenil and flumazenil to antagonize TZ anesthesia in cheetahs.

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“…In clinical situations, the equilibrium function (EF ) test, an established method to judge the recovery from anesthetics, 4^6 is easier to apply and more objective compared with other tests. Flumazenil, a specific antagonist of benzodiazepines, 7 acts by the competitive inhibition of binding these drugs to the central gamma-aminobutyric acid (GABA )^benzodiazepine receptor complex, and reverses the sedative effects of benzodiazepines 8,9 ; however, because of its relatively short b-elimination half-life compared with other benzodiazepines, 10 resedation should be considered after treatment with flumazenil.…”

Section: ^3mentioning

confidence: 99%

Effect of Flumazenil on Disturbance of Equilibrium Function Induced by Midazolam

Miyagawa

Miyawaki

Higuchi

et al. 2008

Anesthesia Progress

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Benzodiazepines in intravenous sedation are useful, owing to their outstanding amnesic effect when used for oral surgery as well as dental treatments on patients with intellectual disability or dental phobia. However, compared with propofol, the effect of benzodiazepine lasts longer and may impede discharge, especially when it is administered orally because of fear of injections. Although flumazenil antagonizes the effects of benzodiazepine quickly, its effect on the equilibrium function ( EF) has never been tested. Since EF is more objective than other tests, the purpose of this study is to assess the sedation level and EF using a computerized static posturographic platform. The collection of control values was followed by the injection of 0.075 mg/kg of midazolam. Thirty minutes later, 0.5 mg or 1.0 mg of flumazenil was administered, and the sedation level and EF were measured until 150 minutes after flumazenil administration. Flumazenil antagonized sedation, and there was no apparent resedation; however, it failed to antagonize the disturbance in EF. This finding may be due to differences in the difficulty of assessing the sedation level and performing the EF test, and a greater amount of flumazenil may effectively antagonize the disturbance in EF.

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The Effects of a Benzodiazepine Antagonist Ro 15–1788 in the Presence of Stable Concentrations of Midazolam

Cited by 91 publications

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

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

Partial Antagonism of Tiletamine-Zolazepam Anesthesia in Cheetah

Effect of Flumazenil on Disturbance of Equilibrium Function Induced by Midazolam

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