Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic class: ANTIDOTES, ATC Code: V03AB25

Flumazenil, imidazo-benzodiazepine, is a benzodiazepine and related substances (zolpiden, zopiclone) antagonist: it specifically blocks by competitive inhibition the effects exerted on the central nervous system of substances that act on benzodiazepine receptors.
In animal experimentation, the effects produced by the substances that do not have an affinity for benzodiazepine receptors (for example, barbiturates, ethanol, meprobamate, GABA-mimetic substances and adenosine receptor agonists) were not modified by flumazenil; however, the effects exerted by non-benzodiazepine agonists of benzodiazepine receptors, such as cyclopyrrolones (for example zopiclone) and triazolopyrradazines were blocked.

The hypnotic and sedative effects of benzodiazepines are rapidly neutralised by flumazenil injected intravenously (1 to 2 minutes, for equimolar doses) and could reappear progressively within hours depending on the half life of the products and the existing ratio between the agonist and antagonist doses administered. Flumazenil is well tolerated, even at high doses and especially on a haemodynamic level.

Flumazenil can exert a low intrinsic agonist activity, for example anticonvulsive.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

Distribution
Flumazenil is a weak lipophilic base, with a plasma protein binding ratio of approximately 50%.
Albumin accounts for two thirds of the plasma proteins to which it binds.

Flumazenil is widely distributed in the extravascular space.

Plasma flumazenil concentrations decrease with a half-life of 4 to 11 minutes during the distribution phase.

Its mean distribution volume at the plateau concentration (Ves=0.95 l/kg) is close to that of benzodiazepines with a similar structure.

Metabolism

Flumazenil is largely metabolised by the liver. The main metabolite identified in plasma (as the free form) and in urine (as the conjugated form) is carboxylic acid.

This metabolite turned out to be inactive.

Elimination
Flumazenil metabolites are almost entirely (99%) eliminated by urinary route.

Less than 1% of the flumazenil dose injected is excreted as the unchanged form in urine, suggesting a complete metabolic degradation in the body.
Elimination is fast, as shown by the short elimination half-life of 40 to 80 minutes. The total plasma clearance of flumazenil is 0.8 to 1 l/h/kg and could be attributed to hepatic clearance.

The basic pharmacokinetics parameters of flumazenil were not modified during simultaneous administration of flumazenil with benzodiazepines, midozolam, flunitrazepam or lormetazepam.

Special clinical situations

The elimination half life of flumazenil in patients with hepatic failure is longer and the total clearance is smaller than in healthy subjects.

The flumazenil pharmacokinetics are not significantly affected by sex, age, chronic renal failure or in patients undergoing haemodialysis.
In children over 1 year, the elimination half-life is shorter and more variable than in adults. It is of 40 minutes on average and generally ranges between 20 and 75 minutes. The clearance and distribution volume with respect to body weight are within limits equivalent to those observed in adults.

There are no pharmacokinetic data on infants under 1 year.