Paradoxical Reactions to Benzodiazepines in Intravenous Sedation: DISCUSSION

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15 Dec 2009


The management of paradoxical reaction should be done in a systematic manner. The procedure is stopped. Calm reassurance of the patient is initiated. If the patient is disinhibited, aggressive, and agitated, a diagnosis of paradoxical reaction should be considered. Administration of oxygen should be continued to avoid hypoxia. Flumazenil should be given as soon as possible. The initial dose of flumazenil is 0.1-0.2 mg administered intravenously. The effect is titrated using the same dose 1 minute apart. A maximum dose of 1 mg every 20 minutes is recommended. The onset of flumazenil’s effect is seen at 1-3 minutes, and its peak effect occurs at 6 minutes. Flumazenil should be used cautiously if the patient has a history of seizures controlled with benzodiazepines. Monitoring the patient postoperatively is essential because resedation might occur and paradoxical reaction might reappear, although this has not been reported.

Paradoxical reactions have been described for many drugs that interact with the GABA receptors. Diverse classes of sedatives and general anesthetic agents including barbiturates, volatile anesthetics, and etomidate are believed to mediate their effect, to some extent, through GABA-A receptors. discount drugs canda

There are different theories concerning the mecha nism of paradoxical reactions. Van der Bijl and Roe-lofse suggested that the reactions may involve central cholinergic effect. Their theory was supported by the reversal of paradoxical reactions with physostigmine in the 1980s; physostigmine was recommended as an antidote for paradoxical rage and as a reversal agent for benzodiazepines in the late 1970s. It is suggested that physostigmine is very effective when central anticholinergic symptoms of coma, delirium, hallucinations, and disorientation are present. Physostigmine only partially reverses the paradoxical reaction and is no longer recommended as a first-line agent for disinhibition reactions considering the associated risk of bradycardia, nausea, and vomiting.

In 1983, Biggio and Costa described a new class of ligands. The beta-carboline derivatives decrease GABA-ergic transmission and display the opposite effects anticipated. Activation of benzodiazepine receptors may induce a spectrum of responses ranging from sedation to hyperactivity.

Serotonergic mechanisms may play a role in the paradoxical reactions. The disinhibition displayed in a paradoxical reaction can be attributed to a serotonin imbalance, which can produce aggression and rage.

Tallman and Gallager proposed that multiple allelic forms of benzodiazepine receptors exist with variable affinities for their agonists. The description of a paradoxical reaction in a pair of monozygotic twins supports this hypothesis.
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Figure 1. Different subunits and their actions

Figure 1. Different subunits and their actions once stimulated by gamma-aminobutyric acid or benzodiazepines. Mutation of an alpha subunit in rat experiment showed desensitization of this particular receptor to diazepam but not to gamma-aminobutyric acid.

Benson et al have studied the pharmacology of recombinant GABA receptors in rats and have altered the genes to make some GABA receptors insensitive to diazepam. The mutation consisted of a substitution of a histidine with an arginine in the 101st position of the alpha-1 subunit of the receptor (Figure 1). The receptor responded normally to GABA but was unaffected by diazepam. This study suggests that the configuration of the different types of subunits and their combination can alter the pharmacodynamics of the benzodiazepine. A single mutation in one of the GABA receptor subunits had a profound effect on the response to diazepam. The classical benzodiazepines such as diazepam interact with all benzodiazepine-sensitive GABA-A receptor subtypes (alpha-1, alpha-2, alpha-3, and alpha-5) with similar affinities. Currently, there are 18 known members of the mammalian GABA-A receptor family. It is proven that at least 1 alpha, 1 beta, and 1 gamma subunit are required to reconstruct a GABA-A receptor with pharmacological properties similar to a native mammalian receptor. A classical representation of a GABA receptor is depicted in Figure 2. The alpha subunit captures the most interest because it is the primary binding site for a benzodiazepine molecule, and this particular subunit appears to determine the pharmacodynamics and biologic response. Different alpha subunits combined with a pair of beta-gamma subunits exhibit a broad spectrum of pharmacology. Receptors with alpha-2 subunits will confer anxioiysis, whereas alpha-1 subunits will provide sedation, anticonvulsion, and anterograde amnesic properties. There are 6 known alpha subunits. It is difficult to explain the distinct amnesic aspect, which is part of the paradoxical reaction. *antibiotics online pharmacy

Figure 2. Classic representation

Figure 2. Classic representation of a gamma-aminobutyric acid receptor and its subunits. Gamma-aminobutyric acid binds to the alpha subunits and facilitates the entry of chloride in the ion channel to hyperpolarize the membrane and prevent depolarization.

Overall, the pharmacodynamics of benzodiazepines are modulated through different factors. Lipophilicity, metabolic stability, receptor affinity, density, heterogen-icity, occupancy, reserves, regulation, imbalance in stimulation of different receptors in different areas of the brain, and receptor pathology are all factors that we need to take into account when studying adverse effects of any medication. Research might find an answer through molecular biotechnology and alteration of receptor configuration. *prescription drugs online canada

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