Clinical pharmacology of flumazenil.

(1) Flumazenil is a highly specific benzodiazepine (BZ) antagonist. It exerts its effect by competitive interaction at the BZ receptor site. (ii) Flumazenil antagonizes all central BZ effects irrespective of its contiguity to the BZ administration. (iii) The pharmacological effect of flumazenil depends upon the number of BZ receptors that can be occupied by flumazenil according to the mass-action law. Receptor occupancy is determined by the affinity of the BZ for the receptor and the free BZ concentration near the receptor. (iv) The minimal effective dose of flumazenil is 0.2 mg. After extreme BZ overdose 1 mg may be needed. (v) The optimal dosing strategy starts with an initial dose of flumazenil 0.2 mg i.v. The administration of further low doses of 0.1 mg at 1-min intervals allows the interruption of the injection of flumazenil exactly at the stage of vigilance that is most convenient for the patient. (vi) The duration of effect depends upon the type and dose of the administered BZ, the dose of flumazenil, and the time interval between flumazenil and the BZ administration. (vii) The therapeutic or safety index is above 3000, which means that a 3000 times overdose is still tolerated.