Flumazenil nervous system

Both zolpidem and zaleplon appear to be nonfatal in overdose. However, overdoses in combination with other central nervous system (CNS) depressant agents pose a greater risk. Recommended treatment consists of general symptomatic and supportive measures, including gastric lavage. Use of flumazenil may be helpful. 

The benzodiazepine antagonist flumazenil is sometimes used to accelerate recovery from excessive sedative actions of intravenous benzodiazepines, but reversal of respiratory depression by flumazenil is less predictable. Its short duration of action (< 90 minutes) may necessitate multiple doses to prevent recurrence of central nervous system depressant effects of longer-acting benzodiazepines. 

There was a variety of significant nervous system adverse effects in six of 104 patients who underwent transesophageal echocardiography, including aggression, euphoria, depression, and intense hiccups (42). These effects occurred despite careful titration and relatively low doses of intravenous midazolam (mean 4.8 mg), and were generally reversible with intravenous flumazenil 0.25-0.5 mg. 

This suggests that flumazenil may be an effective therapeutic option if carisoprodol intoxication results in nervous system depression. However, carisoprodol overdose can also produce myoclonic movements or agitation (4), in which case it is questionable if flumazenil should be used. 

Benzodiazepines are involved in many intentional overdoses. While these overdoses are rarely fatal when a benzodiazepine is the sole ingestant, they often complicate overdoses with other central nervous system depressants (e.g., ethanol and sedatives) due to their synergistic activity. Flumazenil finds its greatest utility in the reversal of benzodiazepine-induced sedation from minor surgical procedures. The initial flumazenil dose is 0.2 mg and should be administered intravenously over 30 s. If no response occurs after an additional 30 s, a second dose is recommended. Additional incremental doses of 0.5 mg may be administered at 1 min intervals until the desired response is noted or until a total of 3 mg has been administered. Flumazenil should not be administered... 

The GABA-receptor complex, the primary inhibitory neural network within the central nervous system, is associated with HE. This receptor complex is composed of a GABA-binding site, and a benzodiazepine receptor site, which mediate chloride conductance. Based on evidence of an increase in benzodiazepine receptor ligands in patients with hepatic encephalopathy, flumazenil has been evaluated in uncontrolled studies and has demonstrated significant clinical improvement, with one case report documenting long-term benefit. In these reports, discontinuation of flumazenil resulted in prompt clinical deterioration. 

I. Pharmacology. Flumazenil (Romazicon) is a highly selective competitive inhibitor of central nervous system benzodiazepine receptors. It has no demonstrable benzodiazepine agonist activity and no significant toxicity even in high closes. It has no effect on alcohol or opioid receptors, and it does not reverse alcohol intoxication. Flumazenil is most effective parenterally (high first-pass effect with oral administration). After intravenous administration, the onset of benzodiazepine reversal occurs within 1-2 minutes, peaks at 6-10 minutes, and lasts for... 

Nervous system Seizures have been attributed to flumazenil [104, 105, 106, 107, 108, 109, 110, 111 ], including status epilepticus [112, 113 ], which can be fatal. However, it has been suggested that seizures are not a toxic effect of flumazenil, but are in many cases instead due to unmasking of the anticonvulsant effect of the benzodiazepine or to a severe benzodiazepine-withdrawal syndrome furthermore, in some cases they may be due to other drugs taken at the same time, such as tricyclic antidepressants [1143]. Thus, it has been recommended that flumazenil should not be given to patients who have used benzodiazepines for seizure disorders or to patients who have taken other drugs that increase the risk of seizures (e.g. bupropion, ciclosporin, cocaine, cyclic antidepressants, isoniazid, lithium, methylxanthines, monoamine oxidase inhibitors, and propoxyphene). 

Saissy JM, Vitris M, Demaziere J, Seek M, Marcoux L, Gaye M. Flumazenil counteracts intrathecal baclofen-induced central nervous system depression in tetanus. Anesthesiology 1992 76(6) 1051-3. 

The Flumazenil in Intravenous Conscious Sedation with Midazolam Multicenter Study Group I. Reversal of central nervous system effects by flumazenil after intravenous conscious sedation with midazolam report of a multicenter clinical study. Clin Ther 1992 14(6) 861-77. 

---