Antidotes

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The risks of non-specific antagonists (physostigmine, doxapram, aminophylline) outweigh the toxicity of benzodiazepines. Naloxone has proved to be inactive.

Flumazenil is an antagonist of the benzodiazepine receptors with a high affinity for these sites. It has no significant intrinsic effects, and rapidly antagonizes the properties of both agonists and inverse agonists.

Flumazenil rapidly reverses central nervous system and respiratory depression. Arousal usually occurs 30 to 60 s after intravenous administration and may last for 1 to 2 h. The rate of gradual relapse of sedation depends on the substances involved and their metabolites. Slow injection is recommended because of the frequent side-effects associated with sudden arousal, including anxiety, palpitations, nausea, and vomiting. Measures to prevent aspiration (lateral position, suction equipment) must be taken. The usual dose consists of 0.1 to 0.2 mg/min every 30 s until sufficient alertness and adequate respiration and reflexes are obtained; full recovery should not be the goal. Continuous infusion of 0.5 to 2 mg/h may be needed to maintain the effect ( Lheure.u.x.,et...a./ 1991) since flumazenil has a much shorter half-life

(about 1 h) than most agonists.

Flumazenil can be used as a diagnostic tool (iSp.r.e.n.g.e.r.,e.t..a/ 1994). However, it must be administered with caution in patients with history of chronic benzodiazepine abuse because of the risk of acute withdrawal syndrome associated with agitation, delirium, and seizures. Flumazenil should not be used in patients who are also intoxicated with proconvulsant or arrhythmogenic compounds (antidepressants, theophylline, antiarrhythmics, chloral hydrate, halogenated hydrocarbons, etc.) because of the risk of unmasking the toxic effects of these substances when the protective effects of benzodiazepines are antagonized. It should not be used in patients who present ventricular arrhythmias or an enlarged QRS complex (>100 msec) because simultaneous intoxication with cardiotoxic drugs may be suspected. Administration of flumazenil is contraindicated in patients with epilepsy, particularly if they are on long-term treatment with benzodiazepines ( Lheureux et a/. 1991)

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