Flumazenil

Also known as

Anexate, flumazenilo, flumazenilum, flumazepil, lanexat, romazicon

Classification

CNS antagoniser

Overview

Flumazenil reverses the effects of benzodiazepine sedatives such as Valium, Versed, Xanax, Tranxene, and others. Benzodiazepines are sometimes used as sedatives before surgery or other medical procedures.

Flumazenil is used to reverse benzodiazepine sedation to help you wake up after your medical procedure. Flumazenil is also used to treat benzodiazepine overdose in adults .

Fumazenil is an imidazobenzodiazepine derivative and a potent benzodiazepine receptor antagonist that competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex, thereby reversing the effects of benzodiazepine on the central nervous system .

Medical usage

For the complete or partial reversal of the sedative effects of benzodiazepines in cases where general anesthesia has been induced and/or maintained with benzodiazepines, and where sedation has been produced with benzodiazepines for diagnostic and therapeutic procedures. Also for the management of benzodiazepine overdose as an adjunct for appropriate supportive and symptomatic measures .

Flumazenil is indicated for the complete or partial reversal of the central sedative effects of benzodiazepines. It may therefore be used in anaesthesia and in intensive care .

What does it look like?

Clear colourless solution for intravenous injection .

Dosage

Therapeutic

Intravenous

Benzodiazepine Sedation Reversal

• Initial - 0.2 mg IV over 15 seconds,
• Titrate - 0.2 mg each minute to 1 mg total .

Overdose Reversal

• Initial - 0.2 mg IV over 30 seconds,
• Titrate - 0.3 - 0.5 mg q30 seconds to 3 mg total .

Repeat dosing protocol

• Repeat Dose - 0.005 mg/kg q1 - 2 minutes,
• Maximum cumulative dose - 1 mg,
• May repeat regimen every 20 minutes .

How long do its effects last?

Onset of effects

• intravenous - 1 - 2 minutes .

Peak

• intravenous - 6 - 10 minutes .

Pharmacology

Pharmacodynamics

Flumazenil antagonizes the CNS effects produced by benzodiazepines, but does not antagonise the central nervous system effects of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (including ethanol, barbiturates, or general anaesthetics) and does not reverse the effects of opioids .

Metabolism

Hepatic. Flumazenil is completely (99%) metabolised. The major metabolites of flumazenil identified in urine are the de-ethylated free acid and its glucuronide conjugate .

Half-life

Initial distribution half-life is 4 to 11 minutes and the terminal half-life is 40 to 80 minutes. Prolongation of the half-life to 1.3 hours in patients with moderate hepatic impairment and 2.4 hours in severely impaired patients .

Elimination

Flumazenil is completely (99%) metabolised. Elimination of radiolabeled drug is essentially complete within 72 hours, with 90% to 95% of the radioactivity appearing in urine and 5% to 10% in the faeces .

Lethal dosage

LD50 in rats 1.8903 mol/kg .

Mechanism of action

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 man .

Precautions

• Avoid in patients with chronic use (risks of severe withdrawal including Seizures),
  • Most toxicology guidelines do not recommend Flumazenil in Overdose,
  • Potential harms appear to outweigh benefits in most cases,
  • See also 'Adverse Events Associated with Flumazenil Treatment' .
• May cause acute withdrawal if physically dependent.
• Do not give routinely to comatose patients,
  • Only use if identity of drug is known, and certain that the patient has not used chronically.
• Reverses Seizure protection of Benzodiazepines,
  • Increases risk of drugs that lower Seizure threshold (Cocaine, Tricyclic Antidepressants) .

Effects

Serious side-effects

Call your doctor at once if you have any of these serious side-effects -

• seizures (convulsions),
• weak or shallow breathing,
• continued drowsiness for longer than 2 hours after receiving flumazenil,
• confusion,
• fear,
• panic attack,
• fast or uneven heart rate .

Less serious

• tremors,
• warmth, redness, or tingly feeling under your skin,
• dizziness,
• sweating or shivering,
• headache,
• blurred vision,
• tinnitus .

History

Flumazenil was synthesised at Hoffmann La Roche Laboratories during the search for a benzodiazepine with a very short duration of action. Animal testing of the new compound revealed no benzodiazepine-like activity despite radio-labeling studies that demonstrated binding to benzodiazepine receptors in the brain. In 1981, flumazenil was identified as the first specific benzodiazepine antagonist .

Flumazenil has been available since 1987 in Europe and was introduced into Canada and the USA in the early 1990's .

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