Flumazenil is a benzodiazepine

Benzodiazepine

A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...

 antagonist

Receptor antagonist

A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...

 available for injection only, and the only benzodiazepine receptor antagonist on the market today.

It was first introduced in 1987 by Hoffmann-La Roche

Hoffmann-La Roche

F. Hoffmann-La Roche Ltd. is a Swiss global health-care company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX Swiss Exchange....

 under the trade name Anexate, but only approved by the FDA on December 20, 1991. Some years ago an oral preparation was under development , though it had low bio-availability and was thus abandoned. There is hope that oral flumazenil or other benzodiazepine antagonists such as B-carbolines will be developed in the future.

Uses

Flumazenil is of benefit in patients who become excessively drowsy after benzodiazepines are used for either diagnostic

Medical diagnosis

Medical diagnosis refers both to the process of attempting to determine or identify a possible disease or disorder , and to the opinion reached by this process...

 or therapeutic procedures.

It has been used as an antidote

Antidote

An antidote is a substance which can counteract a form of poisoning. The term ultimately derives from the Greek αντιδιδοναι antididonai, "given against"....

 in the treatment of benzodiazepine overdoses. It reverses the effects of benzodiazepines by competitive inhibition at the benzodiazepine binding site on the GABA_A

GABA A receptor

The GABAA receptor is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid , the major inhibitory neurotransmitter in the central nervous system. Upon activation, the GABAA receptor selectively conducts Cl- through its pore, resulting in...

 receptor

Receptor (biochemistry)

In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...

. There are many complications that must be taken into consideration when used in the acute care

Acute care

Acute care is a branch of secondary health care where a patient receives active but short-term treatment for a severe injury or episode of illness, an urgent medical condition, or during recovery from surgery...

 setting.

It has been found to be effective in overdoses of non-benzodiazepine sleep enhancers, namely zolpidem

Zolpidem

Zolpidem is a prescription medication used for the short-term treatment of insomnia, as well as some brain disorders. It is a short-acting nonbenzodiazepine hypnotic of the imidazopyridine class that potentiates gamma-aminobutyric acid , an inhibitory neurotransmitter, by binding to GABAA...

 and zaleplon

Zaleplon

Zaleplon is a sedative/hypnotic, mainly used for insomnia. It is a nonbenzodiazepine hypnotic from the pyrazolopyrimidine class. In terms of adverse effects zaleplon appears to offer little improvement compared to both benzodiazepines and other non-benzodiazepine Z-drugs.Sonata is manufactured by...

.

There is some evidence that flumazenil is effective for protracted benzodiazepine withdrawal (or benzodiazepine post-withdrawal syndrome) with promising results , though larger studies with more regular dosing intervals are needed to confirm this. There have also been some studies investigating the drugs effect in reducing benzodiazapine tolerance , with promising results. In binding to the benzodiazepine receptor, flumazenil may reset the receptors sensitivity, restoring the receptor to its pre-drug affinity.

It has also been used in hepatic encephalopathy

Hepatic encephalopathy

Hepatic encephalopathy is the occurrence of confusion, altered level of consciousness and coma as a result of liver failure. In the advanced stages it is called hepatic coma or coma hepaticum...

, though results have been mixed.

The onset of action is rapid and usually effects are 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, 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.

Many benzodiazepines (including midazolam

Midazolam

Midazolam is a short-acting drug in the benzodiazepine class developed by Hoffmann-La Roche in the 1970s. The drug is used for treatment of acute seizures, moderate to severe insomnia, and for inducing sedation and amnesia before medical procedures. It possesses profoundly potent anxiolytic,...

) have longer half-lives

Half-life

Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...

 than flumazenil. Therefore, repeat doses of flumazenil may be required to prevent recurrent symptom

Symptom

A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...

s of overdosage once the initial dose of flumazenil wears off. It is hepatically metabolised to inactive compounds which are excreted in the urine. Subjects who are physically dependent on benzodiazepines may suffer benzodiazepine withdrawal symptoms, including seizure

Seizure

An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...

, upon administration of flumazenil.

It is not recommended for routine use in those with a decreased level of consciousness.

PET radioligand

Radiolabeled with the radioactive isotope carbon-11 flumazenil may be used as a radioligand

Radioligand

A radioligand is a radioactive biochemical substance that is used for diagnosis or for research-oriented study of the receptor systems of the body....

 in neuroimaging

Neuroimaging

Neuroimaging includes the use of various techniques to either directly or indirectly image the structure, function/pharmacology of the brain...

 with positron emission tomography

Positron emission tomography

Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...

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

Clinical 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. Flumazenil is a weak partial agonist in some animal models of activity, but has little or no agonist activity in humans.

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, or general anesthetics) and does not reverse the effects of opioids.

In animals pretreated with high doses of benzodiazepines over several weeks, Flumazenil injection elicited symptoms of benzodiazepine withdrawal, including seizures. A similar effect was seen in adult human subjects.

Pharmacodynamics

Intravenous Flumazenil has been shown to antagonize sedation

Sedation

Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure...

, 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.

Chemistry

Gerecke, M.; Hunkeler, W.; Kyburz, E.; Mohler, H.; Pieri, L.; Pole, P.; 1982, .

Other

• Romazicon product information, Roche USA