Do benzodiazepine ligands contribute to hepatic encephalopathy?

1. Levels of BZ receptor ligands are elevated in the brain of animal models of FHF and humans with FHF. Some of these ligands have agonist properties and some are known 1, 4-BZs which bind to the DS receptor. Much of the BZ receptor ligand activity in HE is unidentified and it is possible that some may bind to receptor subtypes other than the DS receptor. 2. Average levels of BZ receptor ligands in the brain in HE do not appear to be sufficient to augment GABAergic tone to a degree that would result in severe encephalopathy (i.e. coma). However, these ligands have a heterogeneous distribution in the brain and their neuroinhibitory effects may be potentiated by increased availability of GABA at GABAA receptors. Furthermore, that these ligands may contribute to HE is suggested by anecdotal reports of ameliorations of HE being induced in a majority of patients by the BZ receptor antagonist flumazenil. 3. The response of HE to flumazenil in humans is usually incomplete and in animal models may be modest. Potential explanations for these findings include pharmacokinetics, BZ receptor subtype specificity and higher levels of BZ receptor ligands in the brain in humans with HE than in animal models. 4. Certain BZ receptor ligands e.g. Ro 15-3505 and Ro 15-4513, that are structurally related to flumazenil, are more efficacious at ameliorating HE than flumazenil in animal models. These findings may be more dependent on differences in BZ receptor subtype specificity than differences in intrinsic activity. The properties of an ideal BZ receptor ligand for administration to a patient with HE would appear to be: (i) antagonist action at BZ receptors, (ii) no intrinsic activity apparent after a conventional pharmacologic dose, (iii) high specificity and affinity for BZ receptors, (iv) slow metabolism, and (v) absence of toxic effects. Promising ligands, such as Ro 15-3505, with weak partial inverse agonist actions and hence analeptic potential, require careful evaluation of their therapeutic index before clinical application. 5. BZ receptor ligands may be useful in the management of HE. Specifically, they may be given IV: (i) to reverse effects of exogenous BZs; (ii) to aid in the differential diagnosis of encephalopathy; (iii) to provide prognostic information; and (iv) to optimize brain function. They may also be given orally with the objective of reducing dietary protein intolerance in patients with chronic liver disease.