Flumazenil, also known as flumazepil,[2] is a selective GABAA receptor antagonist[3] administered via injection, or intranasally. Therapeutically, it acts as both an antagonist and antidote to benzodiazepines (particularly in cases of overdose), through competitive inhibition.
It was first characterized in 1981,[4] and was first marketed in 1987 by Hoffmann-La Roche under the trade name Anexate. However, it did not receive FDA approval until December 1991. The developer lost its exclusive patent rights in 2008 and generic formulations are available. Intravenous flumazenil is primarily used to treat benzodiazepine overdoses and to help reverse anesthesia. Administration of flumazenil by sublingual lozenge and topical cream has also been tested.[5][6]
Medical uses
Flumazenil benefits people who become excessively drowsy after use of benzodiazepines for either diagnostic or therapeutic procedures.[7]
Flumazenil has been used as an antidote in the treatment of benzodiazepine overdoses.[7] It reverses the effects of benzodiazepines by competitive inhibition at the benzodiazepine (BZ) recognition site on the GABA/benzodiazepine receptor complex.[7]
Flumazenil has been effectively used to treat overdoses of non-benzodiazepine hypnotics, such as zolpidem, zaleplon and zopiclone (also known as the "Z-drugs").[8]
It may also be effective in reducing excessive daytime sleepiness while improving vigilance in primary hypersomnias, such as idiopathic hypersomnia.[5]
Flumazenil has also been used in hepatic encephalopathy. It may have beneficial short‐term effects in people with cirrhosis, but there is no evidence for long-term benefits.[9]
The onset of action is rapid, and effects are usually seen within one to two minutes. The peak effect is seen at six to ten minutes. The recommended dose for adults is 200 μg every 1–2 minutes until the effect is seen, up to a maximum of 3 mg per hour. It is available as a clear, colourless solution for intravenous injection, containing 500 μg in 5 mL. Additional doses may be needed within 20 to 30 minutes if evidence of oversedation reappears.[10]
It is not recommended for routine use in those with a decreased level of consciousness.[11]
In terms of drug enforcement initiatives, diversion control programs and required post-marketing surveillance of adverse events, orders for flumazenil may trigger a prescription audit to the search for benzodiazepine misuse and for clinically significant adverse reactions related to their use.[12]
PET radioligand
Radiolabeled with the radioactive isotope carbon-11, flumazenil may be used as a radioligand in neuroimaging with positron emission tomography to visualize the distribution of GABAA receptors in the human brain.[13]
Treatment for benzodiazepine dependence & tolerance
Epileptic patients who have become tolerant to the anti-seizure effects of the benzodiazepine clonazepam became seizure-free for several days after treatment with 1.5 mg of flumazenil.[14] Similarly, patients who were dependent on high doses of benzodiazepines (median dosage 333 mg diazepam-equivalent) were able to be stabilised on a low dose of clonazepam after 7–8 days of treatment with flumazenil.[15]
Flumazenil has been tested against placebo in benzodiazepine-dependent subjects. Results showed that typical benzodiazepine withdrawal effects were reversed with few to no symptoms.[16] Flumazenil was also shown to produce significantly fewer withdrawal symptoms than saline in a randomized, placebo-controlled study with benzodiazepine-dependent subjects. Additionally, relapse rates were much lower during subsequent follow-up.[17]
In vitro studies of tissue cultured cell lines have shown that chronic treatment with flumazenil enhanced the benzodiazepine binding site where such receptors have become more numerous and uncoupling/down-regulation of GABAA has been reversed.[18][19][20] After long-term exposure to benzodiazepines, GABAA receptors become down-regulated and uncoupled. Growth of new receptors and recoupling after prolonged flumazenil exposure has also been observed. It is thought this may be due to increased synthesis of receptor proteins.[21]
Flumazenil was found to be more effective than placebo in reducing feelings of hostility and aggression in patients who had been free of benzodiazepines for 4–266 weeks.[22] This may suggest a role for flumazenil in treating protracted benzodiazepine withdrawal symptoms.
Low-dose, slow subcutaneous flumazenil administration is a safe procedure for patients withdrawing from long-term, high-dose benzodiazepine dependency.[23] It has a low risk of seizures even amongst those who have experienced convulsions when previously attempting benzodiazepine withdrawal.[24]
In Italy, the gold standard for treatment of high-dose benzodiazepine dependency is 8–10 days of low-dose, slowly infused flumazenil.[25] One addiction treatment centre in Italy has used flumazenil to treat over 300 patients who were dependent on high doses of benzodiazepines (up to 70 times higher than conventionally prescribed) with physicians being among the clinic's most common patients.[26]
Pharmacology
Flumazenil, an imidazobenzodiazepine derivative, antagonizes the actions of benzodiazepines on the central nervous system. Flumazenil competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex.[27] It also exhibits weak partial agonism of GABAA receptor complexes that contain α6-type monomers; the clinical relevance of this is unknown.[28]
Flumazenil does not antagonize all of the central nervous system effects of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (including ethanol, barbiturates, and most anesthetics) and does not reverse the effects of opioids. It will however antagonize the action of non-benzodiazepine z-drugs, such as zolpidem and zopiclone, because they act via the benzodiazepine site of the GABA receptor[29] - it has been used to successfully treat z-drug overdose.[29][30][31]
Pharmacodynamics
Intravenous flumazenil has been shown to antagonize sedation, impairment of recall, psychomotor impairment and ventilatory depression produced by benzodiazepines in healthy human volunteers.
The duration and degree of reversal of sedative benzodiazepine effects are related to the dose and plasma concentrations of flumazenil.
Availability
Flumazenil is sold under a wide variety of brand names worldwide like Anexate, Lanexat, Mazicon, Romazicon.
External links
References
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- Selective antagonists of benzodiazepines Nature, April 1981^
- Pharmacology of flumazenil Acta Anaesthesiologica Scandinavica. Supplementum, 1 January 1995^
- Flumazenil: a benzodiazepine antagonist BMJ, October 1988^
- Modulation of vigilance in the primary hypersomnias by endogenous enhancement of GABAA receptors Science Translational Medicine, November 2012^
- {{ClinicalTrialsGov|NCT01183312|Flumazenil for the Treatment of Primary Hypersomnia}}^
- Goldfrank's toxicologic emergencies McGraw-Hill Medical Publ. Division, 2002^
- Goldfrank's toxicologic emergencies McGraw-Hill, Medical Pub. Division, 2006^
- Flumazenil versus placebo or no intervention for people with cirrhosis and hepatic encephalopathy The Cochrane Database of Systematic Reviews, August 2017^
- Goodman & Gilman's: The Pharmacological Basis of Therapeutics McGraw Hill, 2023^
- Principles of critical care McGraw-Hill Professional, 2005^
- Midazolam-related drug interactions: detection of risk situations to the patient safety in a brazilian teaching hospital Journal of Patient Safety, June 2009^
- Grey and white matter flumazenil binding in neocortical epilepsy with normal MRI. A PET study of 44 patients Brain, June 2003^
- Feasibility of reversing benzodiazepine tolerance with flumazenil Lancet, January 1991^
- High dose benzodiazepine dependence: description of 29 patients treated with flumazenil infusion and stabilised with clonazepam Psychiatry Research, August 2012^
- Intravenous flumazenil following prolonged exposure to lormetazepam in humans: lack of precipitated withdrawal International Clinical Psychopharmacology, June 1996^
- Intravenous flumazenil versus oxazepam tapering in the treatment of benzodiazepine withdrawal: a randomized, placebo-controlled study Addiction Biology, October 2002^
- Chronic treatment with flumazenil enhances binding sites for convulsants at recombinant alpha(1)beta(2)gamma(2S) GABA(A) receptors Biomedicine & Pharmacotherapy, August 2005^
- Enhancement of benzodiazepine binding sites following chronic treatment with flumazenil European Journal of Pharmacology, January 2005^
- Chronic exposure of cells expressing recombinant GABAA receptors to benzodiazepine antagonist flumazenil enhances the maximum number of benzodiazepine binding sites Life Sciences, December 2004^
- The role of transcriptional and translational mechanisms in flumazenil-induced up-regulation of recombinant GABA(A) receptors Neuroscience Research, July 2008^
- Reduction of aggression during benzodiazepine withdrawal: effects of flumazenil Pharmacology, Biochemistry, and Behavior, August 2010^
- Slow subcutaneous infusion of flumazenil for the treatment of long-term, high-dose benzodiazepine users: a review of 214 cases Journal of Psychopharmacology, October 2016^
- Low risk of seizures with slow flumazenil infusion and routine anticonvulsant prophylaxis for high-dose benzodiazepine dependence Journal of Psychopharmacology, October 2017^
- Agonist substitution for high-dose benzodiazepine-dependent patients: let us not forget the importance of flumazenil Addiction, April 2011^
- What is stopping us from using flumazenil? Addiction, July 2012^
- Benzodiazepine dependence and its treatment with low dose flumazenil British Journal of Clinical Pharmacology, February 2014^
- Cloning of cDNAs encoding the human gamma-aminobutyric acid type A receptor alpha 6 subunit and characterization of the pharmacology of alpha 6-containing receptors Molecular Pharmacology, February 1996^
- The clinical and forensic toxicology of Z-drugs Journal of Medical Toxicology, June 2013^
- Pediatric zolpidem ingestion demonstrating zero-order kinetics treated with flumazenil Pediatric Emergency Care, November 2013^
- Zolpidem intoxication mimicking narcotic overdose: response to flumazenil Human & Experimental Toxicology, March 1990^