Efecto antagonista del flumazenil sobre el isoflurano en la emersión de la anestesia general / Antagonist effect of flumazenil on isofluran in reversion of general anesthesia

INTRODUCTION AND OBJECTIVES: Isoflurane, an inhalational general anesthetic widely used in medical practice, belonging to the group of volatile liquids together with desflurane and sevoflurane, with various properties including sedation, hypnosis and anesthesia of patients undergoing treatment. surgical acts. Volatile inhalational anesthetics (halogenated) as mechanism of action, has the property of increasing inhibitory synaptic transmission at postsynaptic level by potentiating ion channels regulated by ligand activated by alpha-aminobutyric acid (GABA). Flumazenil is a benzodiazepine antagonist belonging to the group of imidazobenzodiazepine. It is currently known that there is no specific drug capable of antagonizing the effects of halogenates that allow the rapid and complete recovery of general anesthesia, for this reason this work focuses its efforts on demonstrating whether flumazenil has the ability to reverse the actions of the patient. isoflurane and allow an early restoration of the level of consciousness. MATERIAL AND METHODS: The study to be performed is a clinical type of longitudinal, prospective, unicentric and double blind. The sample will be formed by patients who are going to be subjected to a balanced general anesthesia. The sample will be divided into 2 large groups: group C (control) and group F (Flumazenil). At the end of the surgery, the mixture will be administered according to the selected group in a random manner (Flumazenil 0.25 mg or 0.9% solution in a 20 cc syringe) and the time of extubation, recovery time of the level of consciousness, time of discharge UCPA and hemodynamic state (FC, TAM and SO2). RESULTS: The flumazenil group showed a significantly shorter time from injection to extubation than the placebo group (p = 0.007). Differences in terms of shorter times needed to achieve Aldrete of 9 points in the flumazenil group (P = 0.04) were observed as were shorter anesthetic arousal times represented by a Ramsey 2. Heart rate, mean arterial pressure and saturation they had similar values between the 2 groups. CONCLUSION: The study showed that a single dose of 0.25 mg of flumazenil administered at the end of the surgical act, just after completing all surgical stimulation was beneficial (P = 0.007) in the context of extubation times and shorter anesthetic arousal times.

INTRODUCCIÓN Y OBJETIVOS: El isoflurano un anestésico general inhalatorio usado ampliamente en la práctica médica, perteneciente al grupo de los líquidos volátiles junto con el desflurano y sevoflurano, con variadas propiedades entre las que se encuentran la sedación, hipnosis y anestesia de los pacientes sometidos a actos quirúrgicos. Los anestésicos inhalatorios volátiles (halogenados) como mecanismo de acción, tiene la propiedad de aumentar la transmisión sináptica inhibidora a nivel postsináptico potenciando los canales iónicos regulados por ligando activados por ácido alfa-aminobutírico (GABA). El flumazenil es un antagonista benzodiazepínico perteneciente al grupo de los imidazobenzodiazepina. Se conoce actualmente que no existe un fármaco específico capaz de antagonizar los efectos de los halogenados que permitan la recuperación rápida y completa de la anestesia general, por tal motivo este trabajo centra sus esfuerzos en demostrar si el flumazenil tiene la capacidad para revertir las acciones del isoflurane y permitir un restablecimiento temprano del nivel de conciencia. MATERIALES Y MÉTODOS: El estudio a realizar es de tipo clínico de corte longitudinal, prospectivo, unicéntrico y doble ciego. La muestra se conformará por pacientes que vayan a ser sometidos a anestesia general balanceada. Se procederá a dividir la muestra en 2 grandes grupos: grupo C (control) y grupo F (flumazenil). Al final de la cirugía se administrará la mezcla según grupo seleccionado de manera al azar (flumazenil 0,25 mg o solución 0,9% en una jeringa de 20 cc) y se valorará el tiempo de extubación, tiempo de recuperación del nivel de conciencia, tiempo de alta de la UCPA y estado hemodinámico (FC, TAM y SO2). RESULTADOS: El grupo de flumazenil presentó un tiempo desde la inyección hasta la extubación significativamente más bajo que el grupo placebo (p = 0,007). Se observaron diferencias en términos de tiempos más bajos necesario para alcanzar Aldrete de 9 puntos en el grupo flumazenil (P = 0,04) al igual que tiempos de despertar anestésico más cortos representados por un Ramsey 2. La frecuencia cardíaca, presión arterial media y la saturación tuvieron valores similares entre los 2 grupos. CONCLUSIÓN: El estudio demostró que una única dosis de 0,25 mg de flumazenil administrado al final del acto quirúrgico, justo después de culminar toda estimulación quirúrgica fue beneficiosa (P = 0,007) en el contexto de tiempos de extubación y tiempos de despertar anestésico más cortos.

Effect of (+)-dehydrofukinone on GABAA receptors and stress response in fish model

(+)-Dehydrofukinone (DHF) is a major component of the essential oil of Nectandra grandiflora (Lauraceae), and exerts a depressant effect on the central nervous system of fish. However, the neuronal mechanism underlying DHF action remains unknown. This study aimed to investigate the action of DHF on GABAA receptors using a silver catfish (Rhamdia quelen) model. Additionally, we investigated the effect of DHF exposure on stress-induced cortisol modulation. Chemical identification was performed using gas chromatography-mass spectrometry and purity was evaluated using gas chromatography with a flame ionization detector. To an aquarium, we applied between 2.5 and 50 mg/L DHF diluted in ethanol, in combination with 42.7 mg/L diazepam. DHF within the range of 10-20 mg/L acted collaboratively in combination with diazepam, but the sedative action of DHF was reversed by 3 mg/L flumazenil. Additionally, fish exposed for 24 h to 2.5-20 mg/L DHF showed no side effects and there was sustained sedation during the first 12 h of drug exposure with 10-20 mg/L DHF. DHF pretreatment did not increase plasma cortisol levels in fish subjected to a stress protocol. Moreover, the stress-induced cortisol peak was absent following pretreatment with 20 mg/L DHF. DHF proved to be a relatively safe sedative or anesthetic, which interacts with GABAergic and cortisol pathways in fish.

Participation of the GABAergic system in the anesthetic effect of Lippia alba (Mill.) N.E. Brown essential oil

The objective of this study was to identify the possible involvement of the GABAergic system in the anesthetic effect of Lippia alba essential oil (EO). We propose a new animal model using silver catfish (Rhamdia quelen) exposed to an anesthetic bath to study the mechanism of action of EO. To observe the induction and potentiation of the anesthetic effect of EO, juvenile silver catfish (9.30 ± 1.85 g; 10.15 ± 0.95 cm; N = 6) were exposed to various concentrations of L. alba EO in the presence or absence of diazepam [an agonist of high-affinity binding sites for benzodiazepinic (BDZ) sites coupled to the GABA A receptor complex]. In another experiment, fish (N = 6) were initially anesthetized with the EO and then transferred to an anesthetic-free aquarium containing flumazenil (a selective antagonist of binding sites for BDZ coupled to the GABA A receptor complex) or water to assess recovery time from the anesthesia. In this case, flumazenil was used to observe the involvement of the GABA-BDZ receptor in the EO mechanism of action. The results showed that diazepam potentiates the anesthetic effect of EO at all concentrations tested. Fish exposed to diazepam and EO showed faster recovery from anesthesia when flumazenil was added to the recovery bath (12.0 ± 0.3 and 7.2 ± 0.7, respectively) than those exposed to water (9.2 ± 0.2 and 3.5 ± 0.3, respectively). In conclusion, the results demonstrated the involvement of the GABAergic system in the anesthetic effect of L. alba EO on silver catfish.

Effect of withdrawal of diazepam or morphine treatment on gastric motility (charcoal meal test) in mice: possible role of different central and peripheral receptors.

Increased gastrointestinal motility in mice as one of the withdrawal symptoms of commonly abused drugs like diazepam or morphine and its possible mechanism of action was studied. Male Laka mice (20-25 g) were made addict to either diazepam (20 mg/kg, ip for 7 days) or morphine (10 mg/kg, sc for 9 days). Withdrawal symptoms were noted 24 hr after the last injection of diazepam or morphine. The animals were injected with Ro 15-1788 (flumazenil) (1 mg/kg, ip) or naloxone (2 mg/kg, ip) in the respective group to precipitate the withdrawal symptoms. Gastrointestinal motility was assessed by charcoal-meal test. Animals developed tolerance to acute sedative effect of diazepam, and similarly to the acute nociceptive action of morphine. On abrupt cessation of these drugs after chronic treatment the animals showed hyperlocomotion and hyperreactivity in diazepam withdrawal group and hyperalgesia on hot plate in morphine withdrawal groups, respectively. Increase in gastrointestinal motility was observed in all the drug withdrawal groups. Treatment with respective antagonists, Ro 15-1788 (flumazenil) and naloxone precipitated the withdrawal symptoms. The results suggest the involvement of both central and peripheral receptors of benzodiazepines and opioid (mu) receptors in the withdrawal symptoms of the benzodiazepines and morphine, respectively.

Flumazenil como antagonista del midazolam en pacientes sometidas a legrado uterino por aborto incompleto / Flumazenil as antagonist of midazolam in D&C incomplete abortion

Se investigó el efecto antagónico del flumazenil en relación al uso de midazolam como inductor. Se estudiaron 20 pacientes a las cuales se les practicó LUI mediante anestesia general endovenosa. Clasificadas ASA I-II, edad promedio 27.1 ñ 3.4. La inducción fue con midazolam 300 µg/kg IV; al término del procedimiento se administró flumazenil 200 µg IV y dosis subsecuentes de 100 µg según el grado de sedación, la dosis promedio fue 330 µg. La dosis promedio de midamizolam fue 22.7 ñ 4.2 mg. El 15 por ciento de las pacientes respondió con 200 µg, 50 por ciento con 300 µg, 25 por ciento mejoró con 400 µg y sólo 10 por ciento requirió 500 µg. No encontramos diferencia significativa en los parámetros respiratorios y hemodinámicos básales y los registrados a los 15, 30 y 60 minutos de seguimiento. La acción clínica del flumazenil se observó a los 5 minutos posteriores a su administración. Concluimos que el flumazenil resulta efectivo para antagonizar el efecto sedante del midazolam cuando se ha utilizado como inductor en procedimientos de corta duración

Reversäo pelo flumazenil do efeito cardiodepressor induzido pelo diazepam / Reversal by flumazenil of the cardiodepressant effect induced by diazepam

Foram estudados em sete ratos de raça wistar os efeitos do antagonista dos receptores GR (centrais). Flumazenil (8-fluoro-1,6-dihidro-5-metil-5-fenil-2h-1,4-benzodiazepina-3-carboxilato de etila) nas concentrações de dez mcg/ml, na depressÒo miocßrdica induzida pelo Diazepam (7-cloro-1,3-dihidro-1-metil-5-fenil-2h-1,4-benzodiazepin-1-ona) em doses de 100 mcg/ml em coraçöes isolados de ratos. Nestes experimentos foi utilizado o mÚtodo de LANGENDORFF e tÚcnica de GOTTLIEB e MAGNUS, modificada por PITCHON, utilizando como perfusato a soluçÒo de Krebs-Henseleit. Podemos constatar que nesta experimentaçÒo, o Flumazenil foi capaz de antagonizar os efeitos cardioinibidores do Diazepam. Estas açöes nos levam a sugerir a presença de receptores Gabarelacionados nos coraçöes isolados estudados.

Antídotos de uso reciente

Los antídotos son sustancias cuya función es contrarrestar el efecto farmacológico y tóxico de otras sustancias, teniendo en cuenta la importancia de las medidas generales en el manejo del intoxicado (baño general, emesis, lavado gástrico, carbón activado, catárticos). Cada día aparecen sustancias nuevas con dichas características. En el presente artículo se pretende dar información breve y detallada sobre las propiedades farmacológicas, indicaciones, dosificación, efectos secundarios y contraindicaciones de algunos de uso general (carbón activado, soluciones electrolíticas con polietilenglycol) y principalmente de algunos específicos de uso reciente: flumazenil, fragmentos Fab-antidigoxina, glucagón, naloxona, clonidina, N-acetil-cisteína, azul de metileno, nitrito y tiosulfato de sodio, ácido-2-3-dimercaptosuccínico, penicilina benzatínica, glicopirrolato y S-adenosil-metionina.

Antagonismo del midazolam con flumazenil en pacientes ambulatorios / Flumazenil antagonism of midazolam in ambulatory patients

El objetivo fue comprobar la efectividad de flumazenil para la reversion de los efectos de midazolam, mejorar las condiciones psicomotosas del paciente ambulatorio y disminuir el tiempo de estancia hospitalario. Se estudiaron 60 pacientes divididos en 3 grupos de 20 cada uno, siendo 18 del sexo femenino y 42 del sexo masculino. El grupo I solamente recibió anestésico tópico a base de lidocaina spray. El grupo II recibió midazolam + flumazenil y el grupo III recibió únicamente midazolam. A los 3 grupos se les aplicó la Prueba Gestaltica visomotora de Bender. La primera prueba antes de administrar medicamento; de segunda prueba a los 30 min de administrar medicamento y la tercera prueba a los 45 min de la última dosis. Los cambios que se encontraron en las pruebas psicométricas después de las endoscopías gástricas en los grupos II y III nos indican que hubo disminución de la función psicomatora y percepción, sin embargo se mantuvo la estabilidad cardiovascular y respiratoria. El fulmazenil revierte los efectos del midazolam en una forma inmediata por lo que es favorable para pacientes externos que requieren de una pronta recuperación tanto hemodinámica como psicomotora, y así disminuir el tiempo de estancia hospitalaria

Propofol versus midazolam antagonized by flumazenil after completion of surgery in day case surgery

In this study, speed of recovery was evaluated by using sedation scores in 45 male patients ASA I or II presented for diagnostic cystoscopy under general anesthesia. Induction of anesthesia was started in groups I and II [15 patients each] with mean [SD] doses of [0.17 + 0.06 mg/kg] or [0.17 + 0.04 mg/kg] midazolam, respectively, group II received i.v. flumazenil [0.54 + 0.17 mg/kg] after completion of surgery. Group III [15 patients] received propofol [1.60 + 0.23 mg/kg]. Anesthesia was maintained with isoflurane in 33% oxygen and nitrous oxide in all patients. Flumazenil showed tendency to improve tests of recovery after midazolam anesthesia, but faster recovery was significant in propofol group. Recovery after propofol anesthesia was associated with better psycomotor test results and less impairment of mental state as judged by sedation and amnesia scores

The use of flumazenil in reversing the midazolam and diazepam sedation in outpatients undergoing gastroscopy.

A prospective double blind randomized study was conducted to assess the efficacy and safety of flumazenil in patients for upper gastrointestinal endoscopy, sedated with midazolam or diazepam. Flumazenil significantly reduced the degree of sedation in both treatment groups without significant intergroup differences. There was no evidence of rebound sedation during the observation period of 4 hours. Anterograde amnesia was effectively antagonized in both groups. Flumazenil was a well tolerated safe and effective benzodiazepine antagonist. The combination of benzodiazepine with flumazenil makes it possible to reduce the recovery period and may be useful in outpatients undergoing endoscopy.

Memory modulation by brain benzodiazepines

1. Recent evidence indicates that post-training memory processes are down-regulated by benzodiazepine/GABA-A systems inthe amygdala, septum and hippocampus. Havituation and avoidance learning are accompanied by a decrease of benzodiazepine-like immunoreactivity in the three structures, explainable by a release of benzodiazepines. Immediate post-training microinjection of the benzodiazepine antagonist flumazenil into the hippocampus enhances retention of habituation. The post-training administration of glumazenil into any of the three structures enhances relation of avoidance learning. 2. The mode of operation of these systems was studied in detail in the amygdala using avoidance paradigms. The release of endogenous benzodiazepines during and particularly after training enhances sensitivity of local GABA-A receptors to muscimol, activation of the GABA-A receptors opens chloride channels that can be selectively blocked by picrotoxin and by Ro-4864. Training enhances, and fluazenil reduces, sensitivity of the amygdala to the amnestic effect of locally injected muscimol by a factor of 100. Post-training intra-amygdala administration of picrotoxin or Ro5-4864 enhances retention. 3. These findings suggest that the endogenous benzoidiazepine/GABA-A mechanisms that down-regulate memory int he amygdala, septum and hippocampus are activated in response to the anxiety and/or stress associated with each task. Memory lability which occurs in the psot-training period and characterizes consolidation would thus be a consequence of the brain's response to anxiety or stress

O uso do antagonista benzodiazepínico (flumazenil) para reversäo da sedaçäo por midazolam em endoscopia digestiva / The use of benzodiazepine antagonist (flumazenil) to revert midazolan sedation in digestive endoscopy

Sessenta e dois pacientes submetidos a endoscopia digestiva diagnóstica foram sedados com miazolam por via endovenosa e divididos em dois grupos após o término da endoscopia: 32 pacientes receberam o antagonista benzodiazepínico, flumazenil (grupo F); 30 pacientes (grupo M) permaneceram em repouso para recuperaçäo da sedaçäo, servindo como grupo controle. O flumazenil reverteu o efeito sedativo do midazolam após cinco minutos de sua administraçäo em 89,3% dos pacientes. O tempo médio de recuperaçäo completa foi de 97 min no grupo M e de 44 min no grupo F, com significância estatística. Näo foram observadas alteraçöes das funçöes vitais com o uso de midazolan e flumazenil, tendo sido bem tolerados em ambos os grupos. A amnésia anterógrada desencadeada pelo midazolam näo foi revertida pelo flumazenil. O midazolam é um agente eficaz na sedaçäo de procedimentos endoscópicos digestivos. O antagonista benzodiazepínico, flumazenil, reverteu o efeito sedativo do midazolam, sendo droga indispensável para uso eventual e/ou emergencial

Effect of post-training injections of flumazenil into the amygdala, hippocampus and septum on retention of habituation and of inhibitory avoidance in rats

Adult rats were submitted to two different behavioral tasks using the same apparantus: the habituation of exploration of the apparatus considered as a novel environment as measured by the decrease in number of reaings and of ambulation between training and testing, and step-down inhibitory avoidance as measured by the increase in the latency to step down from a start platform into an electrified grid between the training and the test session.The training-test interval for both tasks was 20 h.The immediate post-training injection of the benzodiazepine receptor antagonist flumazenil (10 nmol) bilateral into the hippocampus enhanced retention of the two tasks.Application of the same drug, at the same dose to the septum or amygdala had no effect on habituation but enhanced retention of the avoidance task. The data are consistent with previous findings showing that both tasks are accompanied by the release of benzodiazepine like immunoreactivity in the three structures and that this release is greater after the avoidance task. The present findings suggest a differential regional involvement of endogenous benzodiazepine-mediated mechanisms in memory modulation, according to the task undertaken

Anxiolytic effect of midazolam microinjected into the dorsal periaqueductal grey area of rats

In order to investigate the role of the dorsal periaqueductal grey (DPAG) area in the anxiolytic effect of benzodiazepines male Wistar rats (N=10), weighing 200-250 g at the time of surgery, were microinjected into this structure with midazolam (80 nmol) and submitted to the elevated plus-maze, an ethologically based model of anxiety. Midazolam significantly increased the percentage of open arm entries from 32.4 ñ 4.6 (control) to 49.5 ñ 3.0 and of time spent in the open arms from 21.0 ñ 4.5 (control) to 35.6 ñ4.8 without affecting the total number of entries into either open or enclosed arms. This effect typifies an anxiolytic effect in the test and was antagonized by the benzodiazepine receptor antagonist flumazenil (80 nmol) microinjection. Microinjection of flumazenil alone had no effect. These results provide additional evidence for the participation of the DPAG in the physiopathology of anxiety and suggest that it that it may be a site for the anxiolytic effect of systemically injected benzodiazepines

Effect of pre-training flumazenil administration on the acquisition of three diferent tasks in rats

The central benzodiazepine receptor antagonist, flumazenil (5.0 mg/kg), given ip 30 min prior to training, enhanced retention test performance of step-down inhibitory avoidance in rats. A lower dose (2.0 mg/kg) given pre-training, or post -training was ineffective. The effect of flumazenil seems to result from an influence on acquisition, in spite of the fact that the drug did not alter training session performance. Pre-training flumazenil (5.0 mg/kg) also facilitated retention test performance of habituation to a buzzer, but not of habituation to an open field. The effect of flumazenil is not atributable to a general influence on inhibitory learning for the following reasons: 1) it enhanced acquisition of two different tasks in which behavioral inhibition plays entirely different roles; 2) it enhanced acquisition of one form of habituation but not of another; 3) data from the literature indicate that flumazenil aso enhances acquisition of active avoidance. In the present experiments, the two tasks that were sensitive to the drug were more stressful or "anxiogenic" than the open field task. There is evidence from the literature that stress activates endogenous benzodiazepine-medicated mechanisms in the brain. The effect of flumazenil suggests that acquisition in stressful or anxiogenic circunstances may be normally down-regulated by such mechanisms