Flumazenil (Ro 15-1788) and physostigmine

Abstract

The pharmacologic effects of benzodiazepines may be counteracted either by functional antagonists like physostigmine acting via cholinergic mechanisms or by competitive antagonists like flumazenil (Ro 15-1788) acting via GABAergic mechanisms (GABA = Gamma-AminoButyric Acid). The lipophilic choline esterase inhibitor physostigmine adjusts a relatively or absolutely decreased concentration of acetylcholine at central cholinergic synaptic sites. As the neuronal network is very complex, many lipophilic compounds may cause a central anticholinergic syndrome even if they primarily do not affect cholinergic but, like benzodiazepines, GABAergic synaptic sites. Prolonged and/or adverse effects of such drugs may therefore be treated with 1–2 mg physostigmine at a maximal rate of 1 mg/min. The onset of physostigmine action can be expected within 2–20 min. Furthermore, the benzodiazepine action can very effectively be counteracted by the specific antagonist flumazenil. It could be demonstrated in volunteer and clinical studies that the hypnotic effect of benzodiazepines could be antagonized within 1–2 min. However, the minimal duration of action proved to be about 2 h as could be demonstrated by clinical observations, EEG-studies and psychometric tests. In clinical practice, a flumazenil dose of 0.3–0.8 mg proved to be the optimal dose range. The indication to treat unwanted central effects of benzodiazepines either with flumazenil or with physostigmine after anaesthesia should be restricted to cases of distinctly prolonged sedation after adequate dosage or adverse side effects. In intensive care, special indications for flumazenil and/or physostigmine may result after high benzodiazepine dosage or to differentiate a coma of undefined origin if centrally acting drugs including benzodiazepines are involved.