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British Journal of Anaesthesia, 2003, Vol. 90, No. 2 199-211
© 2003 The Board of Management and Trustees of the British Journal of Anaesthesia

Laboratory Investigations

Differential interaction of anaesthetics and antiepileptic drugs with neuronal Na+ channels, Ca2+ channels, and GABAA receptors

R. Lingamaneni and H. C. Hemmings Jr*

Departments of Anesthesiology and Pharmacology, Box 50, LC-203A, Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10021, USA

Corresponding author. E-mail: hchemmi@med.cornell.edu

Background. Current theories favour multiple agent-specific neuronal actions for both general anaesthetics and antiepileptic drugs, but the pharmacological properties that distinguish them are poorly understood. We compared the interactions of representative agents from each class on their putative targets using well-characterized radioligand binding assays.

Methods. Synaptosomes or membranes prepared from rat cerebral cortex were used to analyse drug effects on [35S]t-butyl bicyclophosphorothionate ([35S]TBPS) binding to the picrotoxinin site of GABAA receptors, [3H]batrachotoxinin A 20-{alpha} benzoate ([3H]BTX-B) binding to site 2 of voltage-gated Na+ channels, (+)-[methyl-3H]isopropyl 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarboxyl-2,6-dimethyl-3-pyridinecarboxylate ([3H]PN200-110; isradipine) binding to L-type Ca2+ channels, and [cyclohexyl-2,3-3H](N)glibenclamide ([3H]GB) binding to KATP channels.

Results. I.V. anaesthetics other than ketamine preferentially inhibited [35S]TBPS binding (etomidate {approx} alphaxalone > propofol > thiopental > pentobarbital). Volatile anaesthetics inhibited both [35S]TBPS and [3H]BTX-B binding with comparable potencies (halothane {approx} isoflurane {approx} enflurane). Antiepileptic drugs preferentially antagonized either [35S]TBPS (diazepam > phenobarbital) or [3H]BTX-B (phenytoin > carbamazepine) binding. Local anaesthetics (lidocaine, tertracaine) selectively antagonized [3H]BTX-B binding. None of the drugs tested were potent antagonists of [3H]PN200-110 or [3H]GB binding.

Conclusions. Comparative radioligand binding assays identified distinct classes of general anaesthetic and antiepileptic drugs based on their relative specificities for a defined target set. I.V. anaesthetics interacted preferentially with GABAA receptors, while volatile anaesthetics were essentially equipotent at Na+ channels and GABAA receptors. Antiepileptic drugs could be classified by preferential actions at either Na+ channels or GABAA receptors. Anaesthetics and antiepileptic drugs have agent-specific effects on radioligand binding. Both general anaesthetics and antiepileptic drugs interact with Na+ channels and GABAA receptors at therapeutic concentrations, in most cases with little selectivity.

Br J Anaesth 2003; 90: 199–211


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