Effect of sedative drugs upon receptor binding in vivo.

Osamu Inoue, Kaoru Kobayashi and Tetsuya Suhara: Effect of Sedastive Drugs upon Receptor Binding In Vivo. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1992, 16(6): 783–789.

1. 1. Acute treatment with pentobarbital (PB), ethanol and flunitrazepam significantly decreased ³H-SCH 23390 binding in mouse striatum in a dose dependent manner. In contrast, no significant alterations in ³H-SCH 23390 binding in the cerebral cortex have been observed in mice treated with these sedative and hypnotic drugs.

2. 2. Flumazenil (Ro15-1788) reversed the effect of flunitrazepam suggesting the reduction in dopamine D₁ receptor binding in the striatum was mediated via GABA-Bz-Cl channel complex.

3. 3. Using kinetic analysis, it was found that such changes in dopamine D₁ receptor binding in vivo were mainly due to changes in rates of ligand-receptor binding in vivo.

4. 4. Other non-site-specific drugs such as propanol and buthanol also decreased ³H-SCH 23390 binding in vivo, depending on their lipophilicities. These results indicated that micro-environmental factors surrouwding receptors, including cellmembranes seem to have important roles in receptor binding in vivo.

5. 5. Both PB and flunitrazepam decreased muscarinic acetylcholine receptor binding in mouse cortex, striatum, hippocampus and other regions. Together with the fact that PB also altered ³H-Ro15-1788 binding in vivo, this suggested global changes in micro-environmental factors may occur due to these sedative drugs. In vivo qauntitative analysis of neuroreceptors with positron emission tomography (PET) seems to have some potencies to reveal the neurochemical base of benzodiazepine dependence.

The use of flumazenil (Anexate, Ro 15-1788) in the management of drug overdose

This is a report of a large selfadministered overdose of temazepam and meprobamate. The administration of flumazenil (Ro 15-1788) led to the partial antagonism of the depressant action of the drugs which was sufficient to avoid the need for invasive respiratory and cardiovascular support.     

Effects of the benzodiazepine antagonist flumazenil on postoperative performance following total intravenous anaesthesia with midazolam and alfentanil

Postoperative performance following total intravenous anaesthesia (TIVA) using midazolam and alfentanil was studied with and without the administration of a single dose of a benzodiazepine antagonist, flumazenil (Ro 15-1788). Performance was compared with a reference group anaesthetized with thiopentone, alfentanil and nitrous oxide. All patients were assessed by use of a rating scale which took into account the degree of sedation, amnesia, comprehension and cooperation as well as temporal and spatial orientation. There was a slow recovery following TIVA with somnolence and amnesia lasting several hours. Administration of flumazenil 1.0 mg i.v. at extubation caused a significant reduction of sedation (P less than 0.001) during the first postoperative hour, with patients fully awake or only lightly sedated, but was later followed by resedation. The patients of the reference group were moderately sedated during the observation period. Five and six hours postoperatively there was no difference between the groups. Amnesia was more profound in the groups that received midazolam; the effect of the antagonist could only be seen for 15 min after its administration. Comprehension and cooperation, as well as orientation, were equally good in the antagonist and in the reference group during the immediate postoperative period, whereas in the TIVA group a gradual improvement over the first hours was seen. In the antagonist group there was no increase in the number of analgesic requirements, no anxiety attacks or other adverse effects. It is concluded that flumazenil offers an improvement in postoperative performance following TIVA induced by midazolam and alfentanil, but the effects are of short duration.     

Speed of reversal of midazolam-induced respiratory depression by flumazenil - a study in patients undergoing upper G.I. endoscopy

Intravenous midazolam was given to 17 patients coming to upper G.I. endoscopy. All patients had an ear oximeter and calibrated induction plethysmograph attached to record oxygen saturation and minute volume continuously. Midazolam induced significant depression of respiration. Following removal of the endoscope, a new base line was obtained before giving intravenous flumazenil in an attempt to reverse the sedative and ventilatory effects of midazolam. When 0.5 mg of flumazenil was given over 20 s, followed by 0.1 mg every minute, up to a total of 1.0 mg, all patients were apparently awake in under 2 min. Although the flumazenil had clearly reversed the sedative effects of midazolam, the ventilatory effects were largely uninfluenced. The implications are discussed.     

Flumazenil and midazolam in anaesthesia

Flumazenil, the first benzodiazepine antagonist, is currently used widely as an emergency drug, and has also been utilized in planned procedures, to time arousal intra- or post-operatively. It is known that flumazenil, used at the end of a procedure, causes instant recovery by reversing the residual effects of, for example, midazolam. An agonist-antagonist concept, midazolam-flumazenil, where benzodiazepine sedation or anaesthesia is terminated at will, is, therefore, finding increasing application. In neuroanaesthesia, for example, it facilitates immediate recovery, cardiovascular stabilization and the use of midazolam as an alternative to thiopentone and inhalational agents, and in ear, nose and throat endoscopies, it permits more rapid turnover of patients and is a good choice for haemodynamic stability in patients with a high cardiovascular risk factor. There continues to be debate over the term used to describe the level of sedation remaining after the effects of the antagonist have worn off. 'Resedation' is often used incorrectly to describe what is in reality residual sedation. Given the correct use of midazolam or the exploitation of synergism using opioids, flumazenil will cause arousal, while maintaining the benefit of opioid analgesia. Such a technique may eliminate the need for formal recovery facilities in many ambulatory patients, thereby reducing dependence on trolleys, beds and nurses. This has major implications for health economics, particularly in relation to endoscopy clinics and when co-induction of anaesthesia is employed.     

Does the PCPA induced anticonflict effect involve activation of the GABAA/benzodiazepine chloride ionophore receptor complex?

Summary The effects of the benzodiazepine (BDZ) receptor antagonist flumazenil (Ro 15-1788) and the GABA_A receptor antagonist bicucuiline on the anticonflict effect observed after depletion of brain serotonin (5-HT), were examined in a modified Vogel's punished drinking conflict model. Pretreatment with para-chlorophenylalanine (PCPA; 300 mg/kg/day for three days, last injection –24 h) markedly decreased brain 5-HT levels and produced clearcut anticonflict effects. The anticonflict effect, but not the biochemical effect, of PCPA pretreatment was completely counteracted by both flumazenil (10 mg/ kg, –30 min) and bicuculline (2.0 mg/kg, –10 min), in doses not altering the behavior per se. The findings suggest a behavioral interaction between 5-HT systems and the GABA_A/BDZ chloride ionophore receptor complex, possibly involving a direct neuronal interaction, neuromodulation or hormonal alterations.     

Flumazenil for the Reversal of Refractory Benzodiazepine-Induced Shock

Abstract

Benzodiazepines are known to cause central nervous system and centrally mediated cardiovascular depression. The benzodiazepine antagonist flumazenil has been shown to antagonize benzodiazepine-induced central nervous system depression. We report a case in which cardiovascular depression secondary to benzodiazepine use was reversed by this agent.