title: Anaesthetic potency of diazepam is resistant to cholinergic overstimulation.
abstract: Patients suffering from organophosphorus intoxication are compromised by generalised seizures and respiratory insufficiency, either being potentially lethal. In these patients induction of general anaesthesia to allow artificial ventilation is an important therapeutic option. Previously, it has been demonstrated that cholinergic overstimulation impaired network depressing effects of etomidate and sevoflurane. In this study we tested the impact of cholinergic overstimulation on inhibitory effects of diazepam in organotypic slice cultures of cerebrocortical neurons. Effects of clinically relevant concentrations of diazepam on spontaneous action potential activity were assessed by extracellular action potential recordings under basal cholinergic tone as well as in the presence of acetylcholine (1 μM). Diazepam at anaesthetic concentrations (25-500 μM) impeded spontaneous network activity in a concentration dependent manner (EC₅₀ 80.5±8.0 μM). In the presence of 1 μM acetylcholine the potency of diazepam was not significantly altered (EC₅₀ 83.6±8.4 μM). The results demonstrate that the potency of diazepam to depress neocortical network-excitability is not significantly impaired by cholinergic overstimulation. Diazepam thereby differs from other anaesthetics like etomidate or sevoflurane whose potencies and efficacies were severely attenuated. Hence diazepam might be preferable for induction and maintenance of general anaesthesia in patients suffering from nerve agent intoxication.
authors.affiliation: Department of Anaesthesiology, Experimental Anaesthesiology Section, Eberhard-Karls-University, Schaffhausenstrasse 113, 72072 Tuebingen, Germany.
authors.forename: Berthold
authors.initials: B
authors.lastname: Drexler
authors.forename: Stefan
authors.initials: S
authors.lastname: Zinser
authors.forename: Thomas
authors.initials: T
authors.lastname: Seeger
authors.forename: Horst
authors.initials: H
authors.lastname: Thiermann
authors.forename: Bernd
authors.initials: B
authors.lastname: Antkowiak
authors.forename: Christian
authors.initials: C
authors.lastname: Grasshoff
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D000200:Action Potentials / Q000187:drug effects; D018681:Anesthetics, General / Q000494:pharmacology*; D000818:Animals; D018679:Cholinergic Agonists / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D051379:Mice; D019579:Neocortex / Q000187:drug effects*; D009415:Nerve Net / Q000187:drug effects; D009924:Organ Culture Techniques
chemical_list: D018681:Anesthetics, General; D018679:Cholinergic Agonists; D000109:Acetylcholine; D003975:Diazepam