Benzodiazepine effects

The duration and degree of reversal of benzodiazepine effects are related to the dose and plasma concentrations of flumazenil. The onset of reversal is usually evident within 1 to 2 minutes after the injection is completed. Within 3 minutes, 80% response will be reached, with the peak effect occurring at 6 to 10 minutes. Pharmacokinetics After IV administration, flumazenil has an initial distribution half-life of 7 to 15 minutes and a terminal half-life of 41 to 79 minutes. Peak concentrations of flumazenil are proportional to dose, with an apparent initial volume of distribution of 0.5 L/kg. After redistribution the apparent volume of distribution ranges from 0.77 to 1.6 L/kg. Protein binding is approximately 50%. 

Seizure risk The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk populations. 

Hypoventilation Monitor patients who have received flumazenil for the reversal of benzodiazepine effects (after conscious sedation or general anesthesia) for resedation, respiratory depression or other residual benzodiazepine effects for an appropriate period (120 minutes or less) based on the dose and duration of effect of the benzodiazepine employed, because flumazenil has not been established as an effective treatment for hypoventilation due to benzodiazepine administration. Flumazenil may not fully reverse postoperative airway problems or ventilatory insufficiency induced by benzodiazepines. In addition, even if flumazenil is initially effective, such problems may recur because the effects of flumazenil wear off before the effects of many benzodiazepines. 

Mixed drug overdosage Particular caution is necessary when using flumazenil in cases of mixed drug overdosage toxic effects of other drugs taken in overdose (especially cyclic antidepressants) may emerge with reversal of the benzodiazepine effect by flumazenil. 

The pharmacological relevance of GABAa receptor subtypes for the spectrum of benzodiazepine effects was recently identified based on a genetic approach (Rudolph et al. 1999, 2001 Low et al. 2000 McKernan et al. 2000 ... 

Monitor for seizures, sedation, respiratory depression, or other residual benzodiazepine effects for an appropriate period (up to 120 min) based on dose and duration of effect of the benzodiazepine employed pharmacokinetics of benzodiazepines are not altered in the presence of flumazenil... 

The other brain region involved in benzodiazepine effects on anxiety is the central gray region. Benzodiazepines injected into the central gray have been shown to reduce anxiety in the elevated plus maze. 

Benzodiazepines are highly effective anxiolytics and sedatives. They also have muscle relaxant, amnestic, and anticonvulsant properties. Benzodiazepines effectively treat both acute and chronic generalized anxiety and panic disorder. The high-potency benzodiazepines alprazolam and clonazepam have received more attention as antipanic agents, but double-blind studies also have confirmed the efficacy of diazepam and lorazepam in the treatment of panic disorder. Although only a few benzodiazepines are specifically approved by the... 

Knnsman, G.W., Manno, J.E., Manno, B.R., Kunsman, C.M., Przekop, M.A. The use of microcomputer-based psychomotor tests for the evaluation of benzodiazepine effects on human performance a review with emphasis on temazepam. Br. J. Clin. Pharmacol. 34, 289-301, 1992. 

Bickel, W.K., Hughes, J.R., and Higgins, S.T., Human behavioral pharmacology of benzodiazepines effects on repeated acquisition and performance of response chains, Drug Dev. Res., 20, 53, 1990. 

If benzodiazepine is given to a drug-naive patient, there is an acute benzodiazepine effect, and the channel opens a lot. 

Recreational drug users note the same effects. Several comment on similarities between olanzapine and quetiapine and the benzodiazepine drugs, such as diazepam (Valium), because of the intense sedation. However none report the euphoria that characterises benzodiazepine effects. One correspondent reported protracted insomnia after stopping olanzapine, comparing it to benzodiazepine withdrawal (Sixseal.com 2007). 

Flumazenil is used as a benzodiazepine antagonist in the treatment of poisoning or the reversal of benzodiazepine effects in anesthesia 1,2) or in neonates (3). Guidelines for its use have been summarized (4). The problems in its use are those of dose adjustment, the risks of panic anxiety, seizures, or other signs of excessively rapid benzodiazepine withdrawal, and pharmacokinetic problems due to the short half-life of flumazenil (about 1 hour) compared with the longer half-lives of most benzodiazepines (5). Its use is also commonly associated with vomiting and headache, and rarely with psychosis or sudden cardiac death (SEDA-17,... 

Patients who receive flumazenil to reverse benzodiazepine effects should be monitored for up to 2 hours for resedation, respiratory depression, or other lingering benzodiazepine effects... 

Overdose. Benzodiazepines are remarkably safe in acute overdose and the therapeutic dose x 10 induces sleep from which the subject is easily aroused. It is said that there is no reliably recorded case of death from a benzodiazepine taken alone by a person in good physical (particularly respiratory) health, which is a remarkable tribute to their safety (high therapeutic index) even if the statement is not absolutely true, death must be extremely rare. But deaths have occurred in combination with alcohol (which combination is quite usual in those seeking to end their own lives) and from complications of prolonged unconsciousness. Flumazenil selectively reverses benzodiazepine effects and is useful in diagnosis and in treatment (see below). 

The benzodiazepine antagonist flumazenil is available for the complete reversal of benzodiazepine effects however, because of the mild degree of effects, the relative safety of benzodiazepines and the potential to produce excitability, the reversal of benzodiazepines is rarely indicated. Flumazenil is contraindicated in head trauma because it may elevate intracranial pressure (ICP). 

Among the reasons for increased safety is a benzodiazepine receptor that, when stimulated, produces effects opposite to those of the benzodiazepines—effectively turning the drug into an inverse agonist. Because of the relative lack of sensitivity of these receptors, they are stimulated... 

B. Rapid reversal of benzodiazepine effect in patients with benzodiazepine addiction or high tolerance may result in an acute withdrawal state, including hyperexcitability, tachycardia, and seizures (rarely reported). 

A large scale placebo-controlled study in a total of 120 healthy young medical students used psychomotor tests to measure the effect of benzodiazepines with and without grapefiuit juice. Subjects were given midazolam 10 mg or triazolam 250 micrograms with 300 mL of grapefruit juice. Only a minor increase in the benzodiazepine effects occurred with grapefruit juice, and these effects were of little or no practical importance. ... 

The doeumentation is somewhat sparse and there is a need for more study over the range of benzodiazepines and related drugs, but the overall pie-ture is that these interactions are established. The extent to which these xanthines aetually reduce the anxiolytic effects of the benzodiazepines remains uncertain (it needs assessment) but be alert for redueed benzodiazepine effects if both are used. Caffeine in tea or eoffee appears to reduee the sedative effeets of triazolam and zopielone. This would appear to be a disadvantage at night, but may possibly be useful the next morning. 

The Flumazenil in Intravenous Conscious Sedation with Midazolam Multicenter Study Group II. Reversal of central benzodiazepine effects by intravenous flumazenil after conscious sedation with midazolam and opioids a multicenter clinical study. Clin Ther 1992 14(6) 878-94. 

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