Flumazenil, also known as flumazepil, is a selective GABA_A

receptor antagonist A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of rec ...

administered via injection, otic insertion, or intranasally. Therapeutically, it acts as both an antagonist and antidote to benzodiazepines (particularly in cases of overdose), through

competitive inhibition Competitive inhibition is interruption of a chemistry, chemical pathway owing to one chemical substance inhibiting the effect of another by competing with it for molecular binding, binding or chemical bond, bonding. Any metabolism, metabolic or c ...

. It was first characterized in 1981, and was first marketed in 1987 by

Hoffmann-La Roche F. Hoffmann-La Roche AG, commonly known as Roche (), is a Swiss multinational holding healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on ...

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 Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

flumazenil is primarily used to treat benzodiazepine overdoses and to help reverse anesthesia. Administration of flumazenil by

sublingual Sublingual (List of abbreviations used in medical prescriptions, abbreviated SL), from the Latin for "under the tongue", refers to the pharmacological route of administration by which substances diffuse into the blood through Tissue (biology), t ...

lozenge and topical cream has also been tested.

Medical uses

Flumazenil benefits people who become excessively drowsy after use of

benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...

s for either

diagnostic Diagnosis (: diagnoses) is the identification of the nature and cause of a certain phenomenon. Diagnosis is used in a lot of different academic discipline, disciplines, with variations in the use of logic, analytics, and experience, to determine " ...

therapeutic A therapy or medical treatment is the attempted remediation of a health problem, usually following a medical diagnosis. Both words, ''treatment'' and ''therapy'', are often abbreviated tx, Tx, or Tx. As a rule, each therapy has indications an ...

procedures. Flumazenil has been used as an

antidote An antidote is a substance that can counteract a form of poisoning. The term ultimately derives from the Greek term φάρμακον ἀντίδοτον ''(pharmakon antidoton)'', "(medicine) given as a remedy". An older term in English which is ...

in the treatment of benzodiazepine overdoses. It reverses the effects of benzodiazepines by

at the benzodiazepine (BZ) recognition site on the

GABA GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...

/benzodiazepine receptor complex. Flumazenil has been effectively used to treat overdoses of non-benzodiazepine hypnotics, such as

zolpidem Zolpidem, sold under the brand name Ambien among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and after beh ...

zaleplon Zaleplon, sold under the brand name Sonata among others, is a sedative and hypnotic which is used to treat insomnia. It is a nonbenzodiazepine or Z-drug of the pyrazolopyrimidine class. It was developed by King Pharmaceuticals and approved fo ...

and

zopiclone Zopiclone, sold under the brand name Imovane among others, is a nonbenzodiazepine, specifically a cyclopyrrolone, used to treat difficulty sleeping. Zopiclone is molecularly distinct from benzodiazepine drugs and is classed as a cyclopyrrolone ...

(also known as the "Z-drugs"). It may also be effective in reducing excessive daytime sleepiness while improving

vigilance Vigilance may refer to: * Alertness * Vigilance, a creature ability in the ''Magic: The Gathering'' collectible card game * ''Vigilance'' (album), by Threat Signal * Vigilance (behavioural ecology), the watchfulness of prey for nearby predator ...

in primary hypersomnias, such as

idiopathic hypersomnia Idiopathic hypersomnia (IH) is a neurological disorder which is characterized primarily by excessive sleep and excessive daytime sleepiness (EDS). Idiopathic hypersomnia was first described by Bedrich Roth in 1976, and it can be divided into t ...

. Flumazenil has also been used in

hepatic encephalopathy Hepatic encephalopathy (HE) is an altered level of consciousness as a result of liver failure. Its onset may be gradual or sudden. Other symptoms may include movement problems, changes in mood, or changes in personality. In the advanced stag ...

. It may have beneficial short‐term effects in people with

cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, chronic liver failure or chronic hepatic failure and end-stage liver disease, is a chronic condition of the liver in which the normal functioning tissue, or parenchyma, is replaced ...

, but there is no evidence for long-term benefits. 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 Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...

, containing 500 μg in 5 mL. Additional doses may be needed within 20 to 30 minutes if evidence of oversedation reappears. It is not recommended for routine use in those with a decreased

level of consciousness An altered level of consciousness is any measure of arousal other than normal. Level of consciousness (LOC) is a measurement of a person's arousability and responsiveness to stimuli from the environment. A mildly depressed level of consciousn ...

. 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.

PET radioligand

Radiolabeled with the radioactive isotope

carbon-11 Carbon (6C) has 14 known isotopes, from to as well as , of which only and are stable nuclide, stable. The longest-lived radionuclide, radioisotope is , with a half-life of years. This is also the only carbon radioisotope found in nature, as ...

, flumazenil may be used as a

radioligand A radioligand is a microscopic particle which consists of a Radiopharmaceutical, therapeutic radioactive isotope and the cell-targeting compound - the ligand. The ligand is the target binding site, it may be on the surface of the targeted cancer c ...

neuroimaging Neuroimaging is the use of quantitative (computational) techniques to study the neuroanatomy, structure and function of the central nervous system, developed as an objective way of scientifically studying the healthy human brain in a non-invasive ...

with

positron emission tomography Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, r ...

to visualize the distribution of GABA_A receptors in the human brain.

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. 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. Flumazenil has been tested against placebo in benzodiazepine-dependent subjects. Results showed that typical benzodiazepine withdrawal effects were reversed with few to no symptoms. 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.

In vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

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 GABA_A has been reversed. After long-term exposure to benzodiazepines, GABA_A 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. 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. 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. It has a low risk of seizures even amongst those who have experienced convulsions when previously attempting benzodiazepine withdrawal. In Italy, the gold standard for treatment of high-dose benzodiazepine dependency is 8–10 days of low-dose, slowly infused flumazenil. 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.

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. It also exhibits weak partial agonism of GABA_A receptor complexes that contain α₆-type monomers; the clinical relevance of this is unknown. 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-drug Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive, depressant, sedative, hypnotic, anxiolytic drugs that are benzodiazepine-like in uses, such as f ...

s, such as

and

, because they act via the

benzodiazepine site The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Accurate regulation of GABAergic tra ...

of the GABA receptor - it has been used to successfully treat z-drug overdose.

Pharmacodynamics

Intravenous flumazenil has been shown to antagonize

sedation Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ether, ...

, impairment of recall, psychomotor impairment and ventilatory depression produced by benzodiazepines in healthy human volunteers. The duration and degree of reversal of

sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or Psychomotor agitation, excitement. They are central nervous system (CNS) Depressant, depressants and interact with brain activity, causing its decelera ...

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.

References

External links

* {{Authority control Antidotes Anxiogenics Carboxylate esters Chemical substances for emergency medicine Convulsants Fluoroarenes GABAA receptor negative allosteric modulators Drugs developed by Hoffmann-La Roche Imidazobenzodiazepines Lactams Wakefulness-promoting agents