Flumazenil (also known as
flumazepil, code name
Ro 15-1788, trade names
Anexate,
Lanexat,
Mazicon,
Romazicon) is a
benzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
antagonistA 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...
.
It was introduced in 1987 by
Hoffmann-La RocheF. 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.
Flumazenil is of benefit in patients who become excessively drowsy after benzodiazepines are used for either
diagnosticIn medicine, diagnosis is a label given for a medical condition or disease identified by its signs, symptoms, and from the results of various diagnostic procedures...
or therapeutic procedures.
It has been used as an
antidoteAn 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.
Flumazenil (also known as
flumazepil, code name
Ro 15-1788, trade names
Anexate,
Lanexat,
Mazicon,
Romazicon) is a
benzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
antagonistA 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...
.
It was introduced in 1987 by
Hoffmann-La RocheF. 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.
Uses
Flumazenil is of benefit in patients who become excessively drowsy after benzodiazepines are used for either
diagnosticIn medicine, diagnosis is a label given for a medical condition or disease identified by its signs, symptoms, and from the results of various diagnostic procedures...
or therapeutic procedures.
It has been used as an
antidoteAn 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
GABAAThe GABA
A 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 GABA
A receptor selectively conducts Cl- through its pore,...
receptorIn biochemistry, a receptor is a protein molecule, embedded in either the plasma membrane or cytoplasm of a cell, to which a mobile signaling molecule may attach...
. There are many complications that must be taken into consideration when used in the
acute careAcute care is necessary treatment of a disease for only a short period of time in which a patient is treated for a brief but severe episode of illness...
setting.
It has been found to be effective in overdoses of non-benzodiazepine sleep enhancers, namely
zolpidemZolpidem 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 that potentiates gamma-aminobutyric acid , an inhibitory neurotransmitter, by binding to gamma-aminobutyric acid receptors at the...
and
zaleplonZaleplon 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...
.
It has also been used in
hepatic encephalopathyHepatic encephalopathy is a potentially-reversible neuropsychiatric abnormality in the setting of liver failure, whether chronic or acute...
, 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) have longer
half-livesHalf-life is the period of time, for a substance undergoing decay, to decrease by half. The name originally was used to describe a characteristic of unstable atoms , but may apply to any quantity which follows a set-rate decay....
than flumazenil. Therefore, repeat doses of flumazenil may be required to prevent recurrent
symptomA 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
seizureAn epileptic seizure is a transient symptom of excessive or synchronous neuronal activity in the brain. It can manifest as an alteration in mental state, tonic or clonic movements, convulsions, and various other psychic symptoms...
, upon administration of flumazenil.
It is not recommended for routine use in those with a decreased
level of consciousnessLevel of consciousness is a measurement of a person's arousability and responsiveness to stimuli from the environment. A mildly depressed level of consciousness may be classed as lethargy; someone in this state can be aroused with little difficulty. People who are obtunded have a more depressed...
.
PET radioligand
Radiolabeled with the radioactive isotope
carbon-11Carbon-11 or
11C is a radioactive isotope of carbon. It decays 100% by positron emission to Boron-11. It has a half-life of 20.38 min....
flumazenil may be used as a
radioligandA radioligand is a radioactive biochemical substance that is used for diagnosis or for research-oriented study of the receptor systems of the body....
in
neuroimagingNeuroimaging includes the use of various techniques to either directly or indirectly image the structure, function/pharmacology of the brain...
with
positron emission tomographyPositron emission tomography is a nuclear medicine imaging technique which 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 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
sedationSedation is a medical procedure involving the administration of sedative drugs, generally to facilitate a medical procedure with local anaesthesia.- Uses :...
, 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 as shown in the following data from a study in normal volunteers.
Other