Flumazenil

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

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]

Availability

Flumazenil is sold under a wide variety of brand names worldwide like Anexate, Lanexat, Mazicon, Romazicon.

External links

References

Anvisa. RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial Diário Oficial da União, 31 March 2023, retrieved 16 August 2023^
Selective antagonists of benzodiazepines Nature, April 1981^
Pharmacology of flumazenil Acta Anaesthesiologica Scandinavica. Supplementum, 1 January 1995^

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]