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Mechanisms of Action of Antiepileptic Drugs CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Seizure 1995; 4:267-272 Mechanisms of action of antiepileptic drugs JOHN A. DAVIES Department of Pharmacology and Therapeutics, University of Wales College of Medicine, Heath Park, Cardiff, UK Depending on their mechanism of action, anticonvulsant drugs in clinical use may be divided into three groups: those drugs which facilitate ~-aminobutryic acid (GABA)ergic neurotransmission; those which block neuronal ion channels; and those whose mechanism of action is unresolved. The compounds acting on GABAer- gic systems may be further subdivided into those which modulate transmission through chloride channels, e.g. the barbiturates and the benzodiazepines; those compounds, in particular vigabatrin, which reduce the degra- dation of GABA by blocking GABA transaminase; and those which inhibit the re-uptake of GABA into the presynaptic terminal. The other group of compounds whose mechanism of action is known are those which block neuronal ion channels. Blockage of voltage-operated sodium channels by lamotrigine, phenytoin or carbamazepine leads to decreased electrical activity and, probably, a subsequent reduction in glutamate release. Conversely, ethosuxi- mide, blocks voltage-operated calcium channels, especially those which mediate calcium currents in thalamic neurones. Of those drugs in which the mechanism of action is unknown, sodium valproate is the prime example. An antagonistic action at the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor might also be a possibility, which could be the case with some of the newer compounds currently undergoing evaluation. Key words: epilepsy; anticonvulsants; mechanisms of action. INTRODUCTION transmitter in both long axonal tracts and, In spite of a considerable research effort, the perhaps more importantly in relation to epi- neurochemical irregularities underlying epi- lepsy, is the transmitter of many interneurones. lepsy are still not clearly understood. Un- The function of these cells is to regulate the controlled electrical activity in the central electrical activity in relatively small areas of nervous system may occur, either through a neuropile and consequently the output of that reduction in inhibitory neurotransmission or, area. For example, the vast majority of inter- conversely, through an increase in excitatory neurones in the cerebral cortex are GABAergic transmission. Changes in ionic conductances and play an important part in controlling gluta- through neuronal membranes may underlie mate-mediated excitatory activity within the these abnormalities. cortex, as well as excitatory output from the The major groupings of antiepileptic drugs cortex. There are two subtypes of GABA recep- can be defined as: tors, designated GABAA and GABAB. GABAA receptors (which are bicuculline-sensitive) are 1. those which facilitate ~/-aminobutyric acid located predominantly on postsynaptic mem- (GABA) transmission by various mechan- branes and are involved in fast neurotrans- isms; mission; it is the interaction with these 2. those which block voltage-gated ion channels receptors that accounts for the action of both the and thus reduce excitatory transmission; benzodiazepines and the barbiturates. 3. those whose mechanism of action is still open The GABAA receptor is part of the trans- to debate. mitter-gated channel which consists of five membrane-spanning subunits that form the DRUGS ACTING ON GABAERGIC pore through which chloride ions enter the MECHANISMS postsynaptic neurone following GABAA recep- GABA is the major inhibitory transmitter tor occupation. Each of the five subunits in throughout the neuroaxis and functions as the turn consists of four distinct transmembrane- 1059-1311/95/040267+06 $12.00/0 (~) 1995 British Epilepsy Association 268 J.A. Davies spanning domains. These subunits, which form to facilitate GABAergic transmission is that the ionophore, have been designated ~, ~, ~, 8 which inhibits the re-uptake of GABA. The and p, and each, with the exception of 8, have prototypic compound in this group was nipe- multiple isoforms. As a result of amino acid cotic acid which was shown to be an effective sequencing, there are six ~ subunits (al-a6), re-uptake inhibitor in vitro. However, when four 13 subunits (~1-~4), three ~ subunits (~- given in vivo it did not cross the blood-brain ~3), a single ~ subunit, as well as two p sub- barrier. Currently undergoing clinical trials, a units (pl-p2), with the latter appearing to be derivative of nipecotic acid, tiagabine, has localized in the retina (see Enna for a review) 1. been shown to block the re-uptake of GABA5 The presence of these many isoforms, and and to be active in vivo. consequently of different pentameric combi- GABAB receptors, which are bicuculline nations of subunits, raises the possibility of insensitive, are found both pre- and post- many different types of GABAA receptors with synaptically and are linked to guanosine tri- varying physiological characteristics. At phosphate (GTP) binding proteins. Depending present it is known, following co-expression of on the cellular location of these receptors, acti- the various subunits in Xenopus oocytes, that vation can lead to various physiological effects. and 13 subunits must be combined with a ~2 or GABAB receptors (autoreceptors) located on ~3 in order to obtain a normal response to presynaptic GABAergic terminals are involved benzodiazepines, while substitution with a in the regulation of GABA release 6. Stimu- subunit removes any sensitivity. lation of these receptors leads to a decrease in The action of the benzodiazepines is described GABA release, either through the opening of as allosteric modulation, because these drugs potassium channels or by inhibiting calcium have no intrinsic activity at the GABAA recep- entry into the terminal. Either (or both) mech- tor, both drug and transmitter having to be anisms would lead to a reduction in exocytosis. present simultaneously in order to facilitate Antagonists at GABAB autoreceptors would neurotransmission. The resulting effect is an have potential anticonvulsant activity. increased frequency of opening of chloride chan- nels. In the case of phenobarbitone there is a prolongation in the open time of the channel. DRUGS ACTING ON VOLTAGE-OPERATED The resulting influx of chloride leads to hyper- ION CHANNELS polarization of the postsynaptic neurone and consequently a decrease in neuronal firing rate. Voltage-operated sodium and calcium ion It must also be pointed out that a 2,3-benzo- channels in neuronal membranes are modified diazepine molecule (GYKI 52466), which has by antiepileptic drugs in current clinical anticonvulsant properties, has been shown to usage. An inhibitory action at either, or both, non-competitively block the AMPA (L-alpha- of these channels has a marked effect of amino-3-hydroxy-5-methyl-4-isoxazole-propri- neuronal activity. onic acid)/kainate subtype of glutamate recep- The anticonvulsant action of phenytoin is tor2; phenobarbitone has also been reported to considered to be via a membrane-potential- be an antagonist at this receptor3. dependent blockade of sodium channels. The mechanism of action of vigabatrin is However, such a general reduction in sodium- also through a modification of GABAergic mediated transmission in a tetrodotoxin transmission. Following the release of GABA (TTX)-like manner is difficult to reconcile with from a presynaptic terminal, some 70-80% of a selective action of the drug on seizures. the transmitter is taken back into the neurone Phenytoin is far more effective in reducing by a specific sodium/chloride voltage- sodium currents during high-frequency repeti- dependent re-uptake system. However, some of tive stimulation (neuronal conditions which the released GABA is metabolized to succinic are present during a seizure) than during semialdehyde by GABA-transaminase and this normal brain activity which occurs at lower also occurs to a small proportion of the GABA frequencies7. The diversity of voltage-operated which is taken up into the terminal. Viga- potassium and calcium channels has been batrin, by blocking GABA-transaminase4, in- recognized for a number of years. However, it creases both synaptic and terminal GABA is only recently that different voltage-operated levels, thus leading to a potentiation of sodium channels have been described (see GABAergic-induced inhibition. Mandel for a review)s. These channels have A further group of drugs with the potential been shown to have varying pharmacological Mechanisms of action of anUepileptic drugs 269 and functional characteristics. Perhaps the ium efflux. Either of these mechanisms could most important functional difference in these account for its antiepileptic action. However, channels is their inactivation kinetics in that two recent papers have shown that carbamaze- some which are sensitive to TTX are slowly pine blocks the N-methyl-D-aspartate (NMDA) inactivating and these may thus play a vital subtype of glutamate receptor in cultured role in sustained firing, as seen during a seiz- spinal cord neurones 16 and in cortical wedges ure. A specific action of phenytoin on a subtype prepared from genetically epilepsy-prone DBA/ of sodium channel could account for its phar- 2 mice 17. In this latter study, concentrations of macological action. 0,5--10ftM carbamazepine reduced NMDA- Phenytoin has also been shown to affect evoked depolarizations but concentrations extacellular Ca 2+ concentration by blocking above 50pM
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