Pharmacology
When given in the absence of a benzodiazepine receptor agonist,
flumazenil has little discernible CNS effect. Although intrinsic (agonist and inverse
agonist) effects have been ascribed to flumazenil,[417]
they are clinically unimportant. It has been postulated that in low doses a stimulating
effect can be seen and in high doses a central depressant effect becomes more likely.
[375]
When given to volunteers and patients in
clinically
relevant doses, flumazenil has no effect on the EEG or cerebral metabolism.[424]
[426]
[427]
In
animals,
flumazenil has no anticonvulsant properties and in fact reverses the anticonvulsant
properties of benzodiazepines in local anesthetic-induced seizures.[428]
When administered to patients who have benzodiazepine-induced CNS depression, flumazenil
produces rapid and dependable reversal of unconsciousness, respiratory depression,
sedation, amnesia, and psychomotor dysfunction.[374]
[422]
[429]
Flumazenil
can be given before, during, or after the agonist to block or reverse the CNS effects
of the agonist. The usual clinical need is to reverse the effects of agonists given
before flumazenil. Flumazenil has successfully reversed the effects of midazolam,
diazepam, lorazepam, and flunitrazepam. Its onset is rapid, with peak effect occurring
in 1 to 3 minutes,[374]
which coincides with the
detection of 11
C-flumazenil in human brain.[430]
Flumazenil reverses the agonist by replacing it at the benzodiazepine receptor,
and its onset and duration are governed by the law of mass action (see Equation 1).
A predicted therapeutic plasma level for flumazenil is 20 ng/mL[423]
;
however, because the relative binding characteristics of agonist and antagonist in
part dictate benzodiazepine receptor occupation by the residual agonist, different
doses and plasma levels of flumazenil are required to reverse the effects of particular
agonists.
The duration of action of flumazenil is determined by its dose,
the dose of the agonist, and the specific agonist that is being reversed. The duration
is dictated by the factors given in Equation 1. Studies have shown that during a
constant infusion of agonist, the duration of flumazenil action is dependent on the
dose, but 45 to 90 minutes of antagonism can be expected after an intravenous dose
of 3.0 mg or 2 to 3 hours after a dose of 0.8 mg/kg.[34]
[431]
This setting is artificial because in clinical
practice, flumazenil is given after the administration of agonist has been discontinued.
Flumazenil is devoid of the respiratory and cardiovascular depressant
effects of benzodiazepine receptor agonists. A relatively large dose of flumazenil
(0.1 mg/kg) administered to volunteers did not produce significant respiratory depression.
[432]
However, when flumazenil is given in the
presence
of agonists, significant respiratory effects occur because it reverses the respiratory
depression caused by the agonists (e.g., when given to volunteers made apneic with
midazolam).[433]
The reversal of midazolam-induced
(0.13 mg/kg) respiratory depression with flumazenil (1.0 mg/kg) lasts between 3 and
30 minutes.[388]
Other agonists and other doses
would have different durations of antagonism of respiratory depression. If the respiratory
depression is related to opioid administration, flumazenil will not reverse it.[434]
Incremental doses, up to 3 mg intravenously, in patients with ischemic heart disease
had no significant effect on cardiovascular variables.[433]
Administration of flumazenil to patients given agonists is remarkably free of cardiovascular
effects,[374]
[435]
unlike the experience of opioid reversal with naloxone. Of particular interest is
the effect of benzodiazepine receptor agonist reversal with flumazenil on plasma
catecholamines because this effect on catecholamines is the suspected mechanism of
the hyperdynamic response in opioid reversal. Although flumazenil does reverse sedation,
it is not associated with significantly higher catecholamine levels than are found
in patients receiving saline,[435]
but the rise
in catecholamines that accompanies arousal is more rapid after flumazenil.[436]
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