A Mechanism for the Increased Sensitivity to Benzodiazepines in Hepatocellular Failure: Evidence from an Animal Model
Fowler, Jeffrey M.
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Patients with severely impaired hepatocellular function are known to exhibit increased sensitivity to the neuroinhibitory actions of hypnotic drugs, such as benzodiazepines. This study was designed to determine whether changes in end-organ responsiveness could contribute to this phenomenon. Recently, a binding site for benzodiazepines has been demonstrated on postsynaptic receptors for the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Furthermore, benzodiazepines have been shown to interact synergistically with GABA in mediation of neuroinhibition. Since it has been shown that the density of postsynaptic receptors for GABA is increased in the brains of rabbits when acute hepatic failure occurs,. it seemed possible that altered numbers of benzodiazepine binding sites might occur in this syndrome. Therefore, acute hepatic failure was induced in rabbits of a highly inbred strain by intravenous injection of galactosamine HC1. Control rabbits and rabbits in hepatic coma were sacrificed by cervical dislocation. A membrane fraction enriched in synaptic areas was prepared from whole brain homogenates and repeatedly washed. The specific binding of tritiated flunitrazepam to membranes was determined over a large concentration ran6e using standard techniques. Scatchard plots of binding data were linear for both control and hepatic coma rabbits, indicating a single class of binding sites. Affinity was unaltered in hepatic coma (control: 2.50 +- .3l2; hepatic coma: 2.62 +- .230 liters/mole +-SEM) but the density of the binding sites was increased (control: 4.63 +- .485; hepatic coma: 7.32 +- .532 pmoles/mg membrane protein SEM: p<: .001). Together with previous findings, the results of this study would suggest that 1) the benzodiazepine binding site and GABA receptor may be regulated as a single operational unit and 2) the increased sensitivity of the brain to benzodiazepines in hepatocellular failure may be mediated by an increased density of benzodiazepine receptors permitting increased drug effect.