Clinical and Hemodynamic Effects of a Specific Benzodiazepine Antagonist (Ro 15–1788) After Open Heart Surgery

Louis, Martine A.; Forster, A.; Suter, Peter M.; Gemperle, M.

doi:10.1097/00000542-198409001-00061

Cited by 34 publications

(8 citation statements)

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“…There are some short reports on the use of flumazenil in anaesthesiology (Alon et al 1985;Forster et al 1983;Jensen et al 1985;Louis et al 1984;Martinez-Aquirre & Navarro 1982). In many of these earlier studies quite a high dose of flumazenil was used (up to lOmg or more intravenously).…”

Section: Use In Anaesthesiologymentioning

confidence: 99%

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

Klotz

Kanto

1988

Clinical Pharmacokinetics

122

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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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Section: Use In Anaesthesiologymentioning

confidence: 99%

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

Klotz

Kanto

1988

Clinical Pharmacokinetics

122

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“…(11.0 (10.7-12.2)) (11.2 (9.7-11.6)) (11.9 (10.5-12.4)) @Pa) (5.5 (5.2-6.0)) (5.7 (5.3-6.1)) (5.6 (5.36.0)) (5.4 (5.1-5.7)) (5.4 (5.2-5.1)) (5.6 (5.3-5.7)) its pronounced antagonistic properties, flumazenil may exhibit some intrinsic activity, as suggested in certain animal behavioural tests (6, 7 ) . However, experimental evidence for intrinsic actions in humans has been conflicting (8-lo), although anxiety reactions have been described following reversal of midazolam sedation (25). In that study, the supposed inverse agonistic effect might be related to a rapid injection of a high dose of flumazenil (0.1 mg/kg).…”

Section: Discussionmentioning

confidence: 93%

The Effect of the Benzodiazepine Antagonist Flumazenil on Regional Cerebral Blood Flow in Human Volunteers

Wollf

Friberg

et al. 1991

Survey of Anesthesiology

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The influence of the benzodiazepine antagonist flumazenil on regional cerebral blood flow (rCBF) was investigated in ten healthy, alert volunteers. The design was a randomized, placebo-controlled, double-blind, cross-over study. rCBF was measured by 133-Xe inhalation and single photon emission computerized tomography, SPECT, immediately before, and 5 and 35 min after intravenous injection of flumazenil 1.0 mg or placebo. In addition, mean arterial blood pressure and Paco, were measured. There were no significant differences in the mean arterial blood pressures or Paco,. rCBF were analysed for changes in various regions of interest (RoI). No alterations were found either in the global CBF or in rCBF in RoI after flumazenil injection. The results showed that a clinically active dose of flumazenil did not directly affect the cerebral circulation in the normal brain and indicated absence of significant intrinsic activity of the drug.

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“…In one double-blind study in patients recovering from open heart surgery (Louis et al 1984), 10 of 10 patients in the flumazenil group and none of the 10 in the placebo group awoke within 5 minutes of administration of the trial medication (p < 0.001).…”

Section: Reversal Of Long Term Benzodiazepine Sedationmentioning

confidence: 98%

“…Cardiovascular parameters remained stable even in patients at greater risk, such as those with cardiac or valvular disease undergoing cardiac catheterisation, cardioversion or intracardiac catheter ablation (Geller et al 1986a,b), in high-risk surgical patients (Urdinovic 1986), and in patients recovering from open heart surgery (Louis et al 1984) or other types of cardiovascular surgery (Klausen et al 1986b). …”

Section: Other Measures Of Safety and Safety In High-risk Patientsmentioning

confidence: 99%

Flumazenil in Benzodiazepine Antagonism

et al. 1987

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In anaesthesia and in the intensive care unit, benzodiazepines have proven safe and effective agents for the induction and maintenance of sedation for a variety of therapeutic goals. However, in these contexts, or in benzodiazepine overdose, it is often desirable to be able to terminate or interrupt sedation without waiting for the effect of the benzodiazepine to become dissipated by normal metabolism and excretion. Flumazenil, a 1,4-imidazobenzodiazepine, is a highly effective, specific benzodiazepine antagonist which is indicated for use when the effect of a benzodiazepine must be attenuated or terminated at short notice. It acts by displacing other benzodiazepines from the receptor site by competitive inhibition. The onset of effect after intravenous administration occurs within 1 to 3 minutes. The optimal dosage is determined for each patient by a dose titration procedure and lies in the range 0.2 to 1.0mg in anaesthesiology, and 0.1 to 2.0mg in intensive care use. Despite its short elimination half-life of around 1 hour, after general anaesthesia or conscious to moderate sedation for short procedures, a single dose of flumazenil is usually sufficient to attain and maintain the desired level of consciousness. After intoxication with high benzodiazepine doses, the duration of effect of a single dose of flumazenil is not expected to exceed 1 hour. In such cases, the period of wakefulness can be prolonged as necessary by repeated low intravenous doses of flumazenil or by infusion (0.1 mg/hour). Flumazenil is well tolerated both systemically and locally. The only adverse events seen with greater frequency after flumazenil compared with placebo were nausea and/or vomiting after general anaesthesia, although the incidence of actual vomiting was not significantly different between the 2 groups. Since these effects were virtually absent in studies of intensive care patients and after sedation for short procedures, and were not seen in tolerability studies in healthy volunteers receiving intravenous bolus doses of up to 100mg, there may be a link between these symptoms and the other agents used in general anaesthesia, some of which have well-known emetic properties. Thus, flumazenil provides a safe and effective means of attenuating or reversing the CNS-depressant effects of benzodiazepines whenever indicated, e.g. following benzodiazepine-induced general anaesthesia, conscious sedation, or after benzodiazepine overdose, either alone or in combination with other agents.(ABSTRACT TRUNCATED AT 400 WORDS)

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Clinical and Hemodynamic Effects of a Specific Benzodiazepine Antagonist (Ro 15–1788) After Open Heart Surgery

Cited by 34 publications

References 0 publications

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

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

The Effect of the Benzodiazepine Antagonist Flumazenil on Regional Cerebral Blood Flow in Human Volunteers

Flumazenil in Benzodiazepine Antagonism

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