Mechanisms of Action of Antiepileptic Drugs

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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 degradation 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, ethosuximide, 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 epilepsy, 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 channels. 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 potentiated the depolarizations. the potassium-stimulated uptake of Ca 2+ into This inhibitory action of carbamazepine on brain slices9. During a seizure l°, or even before NMDA receptors could contribute to its anti- the initiation of a seizure 1~, the extracellular convulsant action (see later). concentration of potassium increases mark- The final drug in this group of antagonists at edly, resulting in depolarization of the voltage-operated ion channels is ethosuximide. neurones in that region. This depolarization It is well documented that ethosuximide leads to a decrease in extracellular calcium reduces low-threshold calcium currents (T- concentration as voltage-operated calcium current) in thalamic preparations at thera- channels open and calcium goes down its con- peutic concentrations18. Thalamocortical centration gradient into the neurone. The in- neurones have been shown to have a spon- creased interneuronal calcium concentration taneous oscillatory activity of low frequency would then lead to exocytosis and enhanced (approximately 3 Hz) and these pacemaker os- excitatory neurotransmission; phenytoin, by cillations involve T-currents. These oscillatory blocking the entry of calcium, would reduce currents are considered to play an important this excitation. However, an action of pheny- role in the generation of 3Hz spike-wave toin on sodium channels could also account for rhythms characteristic of absence epilepsy. these changes in the extracellular concen- The action of ethosuximide in reducing these trations of calcium and potassium. T-currents probably explains its therapeutic Lamotrigine ~2 and carbamazepine 13 have action. Recent evidence on the role of GABAB both been shown to have similar actions to receptors in the thalamus have shown that ac- phenytoin in that they are able to decrease sus- tivation of these receptors produces hyper- tained repetitive high-frequency stimulation of polarization which promotes T-currents and neuronal preparations. This action of both enhances seizure frequency in animal models, compounds may again be explained by an while GABAB receptor antagonists decreased effect on voltage-operated sodium channels. the incidence of seizures ~9. These results might Lamotrigine has also been shown to decrease explain why absence seizures are aggravated the release of veratridine-stimulated gluta- by those drugs which facilitate GABAergic mate from rat cortical slices, but was without neurotransmission. effect on potassium-stimulated release 14. These results with lamotrigine again point to an action on voltage-operated sodium channels DRUGS WHOSE MECHANISM OF ACTION IS in that veratridine opens these channels. The UNRESOLVED reduction in the release of the major excitatory neurotransmitter in the central nervous Although sodium valproate has been in clinical system might account for the anticonvulsant use for the treatment of a wide spectrum of action of lamotrigine, but it does appear con- seizure types for many years, its mechanism of tradictory in that TTX also blocks veratridine- action is still not fully understood. Early work induced glutamate release ~5, but obviously has suggested that valproate increased GABA no anticonvulsant properties. levels presynaptically rather than acting Carbamazepine, as well as being an anticon- through a facilitatory action on postsynaptic vulsant, is used in bipolar illness and in the receptor mechanisms. The elevation of GABA treatment of trigeminal neuralgia. As stated concentrations could be accounted for by val- above, this drug also blocks sustained repeti- proate inhibiting the enzymes involved in tive firing through an inhibitory action on GABA degradation (GABA transaminase and sodium channels 13 and also facilitates potass- succinic semialdehyde); however, concen- 270 J.A. Davies trations needed for such an action are much pentin has also been shown to bind to a novel higher than those achieved clinically2° and high-affinity site in the central nervous system valproate is far less effective in this respect and to be displaced by the anticonvulsant 3- than is vigabatrin. Valproate has also been isobutyl GABA. There is evidence that this site shown to increase GABA synthesis through may be linked to the transporter for large stimulation of glutamic acid decarboxylase. neutral L-amino acids such as L-methionine, L- Valproate also decreases the effect of high- leucine and L-isoleucine. These amino acids frequency repetitive firing of sodum-dependent also potently displace gabapentin from its action potentials in a use- and voltage- binding site 25. The significance of this finding dependent manner. Howver, 2-en-valproate, a and its possible relationship to an anticonvul- metabolite of valproate, which has equivalent sant action is unknown. In addition, recent anticonvulsant properties to the parent com- work has shown that gabapentin does not have pound in some animal models of epilsepy, has any effect on sodium or calcium voltage- no effect on high-frequency repetitive firing of dependent channels or on GABA, glycine or sodium-dependent action potentials 23. This glutamate (both NMDA and non-NMDA) latter observation raises doubts about the receptors26. blockage of the sodium channel hypothesis. NMDA receptors play an important role in Another possible mechanism of action, es- the mechanisms underlying epilepsy. The pecially as valproate is effective in absence NMDA receptor-operated complex consists of seizures, is an inhibition of low-threshold T- an ion channel that allows an influx of calcium currents, as is the case with ethosuximide. and to a lesser extent sodium and an efflux of However, Coulter et al is found no effect on this potassium..As well as the channel, there are a current in thalamic neurones, whereas Kelly et number of binding sites on this complex where a121 reported that valproate reduced T-current antagonism could have potential anticonvul- in nodose ganglion neurones. Sodium val- sant properties. proate has also been shown to activate a pot- Felbamate has been shown to have anticon- assium conductance in rat hippocampal slices vulsant properties against NMDA-induced and such an action would lead to an efflux of convulsions in mice and also to inhibit binding potassium and subsequent hyperpolariz- of [3H] 5,7 dichloro:kynurenic acid at the gly- ation 22. It is probable that the reason why cine site on the NMDA receptor27. The glycine valproate has such a wide spectrum of anticon- site positively modulates NMDA receptor acti- vulsant activity is due to a combination of vation and antagonists at this site show anti- mechanisms of action, its effect on GABAergic convulsant properties. Such an action could systems being augmented by possible sodium account for the anticonvulsant effects of felba- and T-current channel blockade (see Loscher mate. for a recent review23). Another compound undergoing clinical trials Gabapentin, which has recently been intro- is remacemide whose activity probably resides duced, has been shown to be effective in partial in its desglycine metabolite. Remacemide is ef- and generalized epilepsy. It was originally syn- fective in inhibiting the effects of maximal thesized as a lipophilic analogue of GABA electroshock in rats and NMDA-induced seiz- which would cross the blood-brain barrier. ures in mice. In binding studies 2s the parent However, gabapentin does not possess high af- compound was reported not to bind to gluta- finity for either GABAA or GABAB receptors. mate, GABAA, adenosine A1, benzodiazepine Initial studies suggested an antagonistic effect or NMDA receptors (at either the glycine or ion at the glycine modulatory site on the NMDA channel sites). However, further work showed receptor complex (see below) in that D-serine that the desglycinated metabolite displaced (an agonist at this site) reversed the anticon- MK801 binding from rat synaptosomal mem- vulsant action of gabapentin on tonic seizures branes. An antagonistic action of remacemide in mice. However, binding studies demon- desglycine at a site(s) on the NMDA receptor- strated that gabapentin did not displace [3H] operated channel is probable. glycine or [3H]MK801 binding to brain mem- In conclusion, the mechanism of action of the branes. 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