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Mechanisms of action of antiepileptic

Epilepsy affects up to 1% of the general population and causes substantial disability. The management of in patients with relies heavily on antiepileptic drugs (AEDs). , , and valproic have been the primary medications used to treat epilepsy for several decades. Since 1993 several AEDs have been approved by the US FDA for use in epilepsy. The choice of the AED is based primarily on the type, spectrum of clinical activity, side effect profile and patient characteristics such as age, comorbidities and concurrent medical treatments. Those AEDs with broad- spectrum activity are often found to exert an action at more than one molecular target. This article will review the proposed mechanisms of action of marketed AEDs in the US and discuss the future of AEDs in development.

1 KEYWORDS: AEDs n drugs n antiepileptic drugs n epilepsy Aaron M Cook n n seizures & Meriem K Bensalem-Owen† The therapeutic armamentarium for the treat- patients with refractory seizures. The aim of this 1UK HealthCare, 800 Rose St. H-109, ment of seizures has broadened significantly article is to discuss the past, present and future of Lexington, KY 40536-0293, USA †Author for correspondence: over the past decade [1]. Many of the newer AED pharmacology and mechanisms of action. College of Medicine, Department of anti­epileptic drugs (AEDs) have clinical advan- Neurology, University of Kentucky, 800 Rose Street, Room L-455, tages over older, so-called ‘first-generation’ First-generation AEDs Lexington, KY 40536, USA AEDs in that they are more predictable in their Broadly, the mechanisms of action of AEDs can Tel.: +1 859 323 0229 Fax: +1 859 323 5943 dose–response profile and typically are associ- be categorized by their effects on the neuronal [email protected] ated with less –drug interactions. In addi- or their post-synaptic inhibi- tion, many of the newer AEDs also have unique tion of neuronal impulse generation. Inhibition mechanisms of action compared with previously of the neuronal action potential is typically available agents. First-generation AEDs are pro- focused on the activation of voltage-gated chan- posed to have a couple of primary mechanisms nels involved in the electrical propagation of of action. channel blockade and GABA the seizure. Sodium channels are integral to the potentiation both result in a reduction of neu- action potential and neuronal depolarization. ronal discharge. More recent AEDs that have The fulfilled action potential typically results in been approved have provided more of a variety the release of a , which further in drug targets, such as specific GABA subunits propagates the signal at a neuronal synapse or and inhibition. Currently, there results in a terminal effect on the brain or other are several viable agents in the AED pipeline that leading to extracranial organs. expand the spectrum of effective mechanisms of action even further (Table 1). „„ blockade Such a variety of pharmacologic targets for the (fast inactivation) treatment of seizures is desirable for several rea- Inhibition of sodium channels is the most com- sons. First, more specific targeting of receptors mon mechanism of action of the early first-gen- implicated in seizure propagation may lead to eration AEDs (Figure 1). During the neuronal less adverse effects (both neurologic and other­ action potential, sodium concentrations spike wise). Second, currently available AEDs are upwards once the depolarization threshold is not often broadly active in numerous models of reached. The large extracellular sodium con- seizure. By increasing the variety of pharmaco- centration, as well as negative electrical gradi- logic targets, less common and more treatment ent inside the cell, creates a significant influx refractory seizure disorders may gain viable treat- of sodium when the voltage-gated sodium ment options. Finally, utilizing a combination channels are opened. Agents such as first-gen- of AEDs with multiple mechanisms of action eration AEDs phenytoin, carbamazepine and may allow for synergistic activity, particularly for , as well as second generation AEDs

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Table 1. Summary of antiepileptic drugs’ proposed mechanisms of action. Mechanism of action Effect on neuronal First-generation AEDs Second/third-generation AEDs under transmission AEDs development Sodium channel blockade Slowed recovery from Phenytoin (fast inactivation) inactivated state Carbamazepine Valproate blockade Post-synaptic (T-type) Topiramate inhibitory action Valproate Zonisamide (T-type) Lamotrigine GABA agonism/potentiation Inhibitory activity Felbamate by permitting Topiramate hyperpolarization Valproate NMDA receptor blockade Decreased excitatory Felbamate synaptic activity AMPA receptor blockade Decreased excitatory Topiramate synaptic activity SV2a vesicle inhibition Decreased excitatory synaptic activity Sodium channel blockade Recovery of neurons from (slow inactivation) prolonged depolarization blockade Oxcarbazepine Topiramate Potassium channel activation Retigabine

For more information about drug–drug interactions and adverse effects with individual agents, readers may refer to the prescribing information for the individual agents or several recent reviews [37–40]. AED: Anti­epileptic drug; NMDA: N-methyl-d-aspartate; SV2a: Synaptic vesicle protein 2a.

oxcarbazepine and lamotrigine, work in this „„GABA potentiation manner. The principle example of a sodium Potentiation or agonism of GABA receptors and is phenytoin, which blocks their inhibitory chloride channels is another com- voltage-­gated sodium channels in the motor mon mechanism of action for first-generation cortex and seems to block repetitive firing of AEDs, particularly benzodiazepines. Rather than neurons, but has little impact on neurons with modifying the influx of cations, GABA agonists a low rate of firing [2,3]. Therefore, there is a push the to hyperpolarization by open- greater effect of phenytoin on neurons with ing chloride channels. Barbiturates also activate more pronounced depolarization or more GABA receptors by binding to a different site frequent firing. than benzodiazepines. Valproic acid promotes the Phenytoin reduces inward sodium movement formation and inhibits the endogenous degrada- by binding to inactivated voltage-gated channels tion of GABA, although the clinical impact of after depolarization and modifying their sodium this mechanism of action is ill-defined [2].

permeability. This results in an increase in the Benzodiazepines bind to GABA A receptors inactivation (or refractory) period of frequently between the a and g subunits, primarily a-1 firing neurons. Phenytoin also appears to dimin- and g-2 [5]. This extracellular binding opens the ish the amplitude of the action potential and and permits chloride influx slows neuronal conduction, both likely related due to the extracellular concentration gradi- to sodium channel inhibition [3]. Interestingly, ent. Various a subunits are present in human it appears as though lamotrigine, carbamazepine neurons, most of which exhibit similar benzodi- and phenytoin all bind to the same receptor on azepine binding. Subsequent hyperpolarization the extracellular aspect of the voltage-gated decreases the membrane potential of neurons, sodium channel, suggesting that each of the making generation of an action potential more drugs may compete with the other for occupancy unlikely and abrogating the depolarized state of of available receptors [4]. activated neurons.

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Barbiturates binding to GABA A recep- In particular, brivaracetam may have added tors differs from benzodiazepines in that the activity, as it also inhibits fast inactivation of binding site is in the membrane portion of the voltage-gated sodium channels [8,9]. receptor [5]. This induces a conformational change in the chloride channel that permits „„NMDA receptor blockade influx. Barbiturates also appear to potenti- N-methyl-d-aspartate (NMDA) receptor ate GABA (and ) activity by antagonists act on membrane-associated post- enhancing the inhibitory response to endog- synaptic calcium channels [10]. The NMDA enous GABA [2]. Barbiturates vary subtly in receptor interacts with the excitatory neuro- their structure, which confers a spectrum of transmitter, glutamate, and allows calcium effects (i.e., and thio- influx into the neuron. This represents one of pental being very sedating, phenobarbital being the major mechanisms for neurotoxicity during minimally sedating). , stroke and status epi- lepticus. Several agents can inhibit the action „„Calcium-channel blockade of glutamate on the NMDA receptor, includ- Blockade of calcium channels also confers some ing topiramate and zonisamide [11]. Other older antiepileptic activity. Calcium channels are evi- agents, such as felbamate and phenobarbital, dent in presynaptic neurons and are involved may have some modicum of inhibition at the in neuronal depolarization. Ethosuximide is a NMDA receptor, although it does not appear unique agent used for absence seizures, which that this is the principal mechanism of action appears to inhibit low threshold calcium chan- of these AEDs. The anesthetic also nels in thalamic neurons [2]. Valproate appears inhibits NMDA receptors, which likely imparts to have similar activity at these T-channels, the efficacy of ketamine in late, refractory status which also makes this agent helpful for absence epilepticus [12]. seizures. Some evidence suggests that pheny- toin may have some activity in inhibiting cal- „„Potassium channel potentiation cium channel activation presynaptically. Other In addition to increasing the level of newly agents such as felbamate, which antagonizes synthesized GABA, retigabine’s antiepileptic glutamate–NMDA receptors, and barbiturates, properties are largely due to its ability to acti- which attenuate the response to excitatory vate and prolong the opening of neuronal potas- neuro­transmitters such as glutamate, inhibit sium KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) calcium influx postsynaptically. channels [13,14].

New generation of AEDs The current and future generations of AEDs will 50 include a variety of new pharmacologic targets, more specific binding of previously targeted mechanisms of action and molecules similar to currently available AEDs that exhibit dramati- cally decreased rates of toxicity. Drug develop- 0 ment efforts are also aimed at providing AEDs Na-channel that are more tolerable and less associated with blockers complex drug–drug interactions. GABA -50 „„SV2a vesicle inhibition agonists Membrane potential (mV) Levetiracetam is the first of several agents able to -70 inhibit the synaptic vesicle protein 2a (SV2a) [6]. K-channel -90 SV2a appears to be integral to the process of openers -100 neurotransmitter exocytosis into the synap- 0 1 2 3 4 5 tic cleft. Inhibition of this protein appears to Time (ms) Voltage-gated Na channels result in a broad-spectrum attenuation of exci- tatory activity. Brivaracetam and seletracetam are more potent inhibitors of this presynaptic K channels protein and may provide an even broader spec- trum of antiepileptic activity over levetiracetam Figure 1. Effects of antiepileptic drugs on the neuronal action potential. if they ultimately garner US FDA approval [7].

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„„Sodium channel blockade is the only drug specifically indicated for use (fast inactivation) in severe of infancy (also Rufinamide showed broad-spectrum anticon- known as Dravet syndrome) [23,24]. vulsant properties. The principal mechanism of action of rufinamide is considered to be sup- „„Calcium channel blockade pression of neuronal hyperexcitability by pro- Gabapentin was initially synthesized to mimic longation of the inactive state of voltage-gated the chemical structure of GABA, but it is not sodium channels. Rufinamide was found to believed to act on the same brain receptors. be effective in the treatment of patients with Gabapentin was shown to bind to the α2d sub- Lennox–Gastaut syndrome [15,16]. unit of the voltage-dependent calcium channel in the CNS [25]. „„Sodium channel blockade Like gabapentin, pregabalin binds to the α2d (slow inactivation) subunit of the voltage-dependent calcium chan- Slow inactivation of voltage-dependent sodium nel in the CNS. Pregabalin decreases the release channels appears to be a separate and novel of such as glutamate (excita- mechanism of inhibiting sodium influx in tory neurotransmitter), noradrenaline and sub- depolarizing neurons. Lacosamide is the first stance P. Pregabalin increases neuronal GABA AED available that promotes slow inactivation levels by producing a dose-dependent increase in of sodium channels. Whereas fast inactivation glutamic acid decarboxylase (GAD). GAD con- of sodium channels with older AEDs, such as verts glutamate into the inhibitory GABA [26]. phenytoin and carbamazepine, tends to have effects on frequently firing neurons, slow inac- „„AMPA receptor blockade tivation occurs in neurons, which are repetitively , currently in Phase III development discharged and have prolonged depolarization. for epilepsy, has shown in preclinical studies to Slow inactivation probably involves a structural inhibit AMPA-induced increases in intracellular alteration to the sodium channel that develops calcium concentration [27]. Agents that inhibit over a more prolonged period of time than fast- or decrease the AMPA receptor activity have the inactivation [17]. At this point, the clinical role potential to reduce excessive excitatory responses of lacosamide seems to be a viable option for and confer neuroprotection [28]. patients with refractory partial epilepsy and in [18,19]. General characteristics of future AEDs „„GABA potentiation The future of AED development will likely Augmentation of GABAminergic inhibition of incorporate many of our currently available neurons can also be achieved by new methods drug entities, while also building upon new sci- aside from enhancing the endogenous activity ence and discovery in drug delivery. Many of of GABA (as previously discussed). Vigabatrin, the older AEDs are limited by severe adverse a structural analog of GABA, inhibits GABA- effects, cumbersome drug–drug interactions transaminase, which is the responsi- and a narrow therapeutic index. Felbamate is a ble for degrading GABA in the synaptic cleft, unique example of a newer AED with severe tox- thereby increasing GABA concentrations [11]. icity and adverse event problems. Severe aplastic also increases GABA concentrations, anemia and hepatic failure have both occurred but, unlike vigabatrin, does so by decreas- with felbamate. It seems as though the reactions ing glial and neuronal uptake of GABA [11]. are idiosyncratic with little indication of predic- Topiramate, among its numerous mechanisms tive factors for developing one of these devastat- of antiepileptic activity, also appears to enhance ing side effects. Phenytoin is another example GABA activity [20]. Retigabine, currently under of an AED with characteristic adverse effects. review for approval by the FDA, also likely Some adverse effects are drug entity-specific, increases GABA synthesis [21]. Neuroactive such as the risk of hypersensitivity (e.g., ) also augment GABA syndrome, which presents as a Stevens–Johnson inhibition by binding a receptor on the Syndrome-like , usually after 1–2 weeks of GABA complex, increasing the permeability of use. Other effects are related to the intravenous the chloride channel [22]. Stiripentol appears to formulation, such as purple-glove syndrome, enhance central GABA transmission by increas- which causes digital thrombosis and ischemia,

ing the duration of opening of GABA A recep- likely due to the dramatically elevated pH of the tor channels in hippocampal slices. Stiripentol phenytoin solution for injection.

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Newer AEDs that are available now or are require a wide range of doses among differ- likely to be available in the future are less associ- ent patients, depending on their body size and ated with severe reactions. A classic example of composition. Extensive this is the development of the more water soluble (primarily albumin) is also often a factor that , . This improved method can affect the total concentration of some of the of delivering phenytoin intramuscularly or intra- older AEDs, such as valproic acid and pheny- venously has mitigated the formulation-related toin. In addition, it is becoming more apparent adverse effects to some extent, although the drug that some older AEDs may be subject to phar- entity-specific adverse effects remain. macogenetic variations in metabolic capacity, Drug–drug interactions with older AEDs are which may also affect the dose requirements of frequent and commonly alter concomitantly certain individuals. One of the focuses of the administered medications. The cytochrome development of new AEDs appears to be the p450 (CYP450) system participates prominently development of pharmaceutical preparations in a host of endogenous metabolic pathways [29]. that yield consistent, predictable Several of these, including exogenous drug that exhibit low interpatient variability and that , vitamin D and bone metabolism, are not subject to genetic polymorphisms that gonadal steroid metabolism and the metabolism may impact the disposition and elimination of of and other markers of vascular risk, these medications. have been shown to be affected by the induc- Antiepileptic drug therapy may also be ing AEDs. Hepatic induction by barbiturates, impacted by other advances aside from new carbamazepine and phenytoin can decrease the agents. In models of drug-resistant epilepsy, it serum concentrations of other hepatically metab- appears that drug efflux pumps may be respon- olized medications, typically by induction of the sible for pumping out AEDs, thereby making CYP450 enzyme system. Patients with compli- the tissue concentrations of pharmacotherapy cated medication regimens for other disease lower than would be expected by the corre- states, such as HIV, are particularly affected by sponding serum concentrations. Modulation these drug–drug interactions [30]. Other medi- of drug efflux transporters has the potential to cations, such as , cyclosporine, vorico- reverse treatment failure in patients with drug- nazole and many other hepatically metabolized resistant epilepsy by preserving AED concen- AEDs such as felbamate and carbamazepine, may trations in astrocytes and neurons [34]. Unique have lower serum concentrations after enzyme drug-­delivery strategies are already in use, such induction. Inhibition of hepatic metabolism is as osmotic pump tablets for extended-release also evident with some AEDs such as valproic preparations. However, novel strategies that acid. These agents can increase some concomi- maximize the delivery of the AED into the target tant medications (such as , lamot- tissue are promising alternatives under develop- rigine and ) to potentially toxic con- ment. Nanoparticles appear to aid in the solu- centrations [31]. The classic complex drug–drug bility of hydrophobic AEDs, as well as increase interaction between AEDs is phenytoin and the blood–brain barrier penetration of medica- valproic acid, where phenytoin induces valproic tions. Liposomal formulations are amphiphilic acid metabolism. Simultaneously, valproic acid carriers, which can be used to deliver AEDs in inhibits phenytoin metabolism and increases the carefully selected locations based on temperature fraction of unbound drug due to another type of or pH. Liposomes can also facilitate the delivery drug–drug interaction mechanism, displacement of drug substances directly into the intracellu- of plasma protein binding. Newer AEDs, such lar environment. Intranasal and rectal formula- as lacosamide, pregabalin and levetiracetam, do tions for immediate delivery when the oral and not induce or inhibit hepatic CYP450 enzyme intravenous routes are acutely unavailable are function, therefore making these drugs much also already available, but being refined to opti- less likely to impact the biotransformation of mize drug delivery and to expand the number of concomitant medications [32,33]. medications available by these alternative routes. The of older AEDs tend Readers are referred to a recent excellent review to exhibit marked inter-individual variability. on new drug-delivery options [35]. Routine therapeutic drug monitoring is nec- essary for many of the older AEDs, such as Conclusion & future perspective phenobarbital, carbamazepine, valproic acid As reviewed in this article, the current AEDs and phenytoin. Dosing is often based on body under development in Phase III trials include weight and fluctuations in bioavailability may brivaracetam, ganaxolone, retigabine and

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perampanel. A total of seven additional AEDs in There are no randomized controlled trials development appear promising. These include: indicating that antiepileptic drugs should be 2-deoxy-glucose, huperizine A, ICA-105665, chosen according to the mechanism of action NAX-5055, T-2007, and YK3089. and undertaking such trials might be useful. The reader can find a more in-depth review on Beyond seizures, the side effects of cer- new AEDs in different stages of development tain AEDs represent a burden to patients and in the progress report on new AEDs by Bialer the development of rational drug designs of et al. [36]. blockers for specific subunits of the excita- The currently available anticonvulsant agents tory amino acid receptors may provide ther- suppress the symptoms of epilepsy but are not apeutic activity without the side effects of truly antiepileptic drugs. A rational approach to nonspecific blockers. prevent epilepsy would be to use drugs to target Efforts in order to understand the relation- abnormal brain mechanisms that are activated ship between target and effect should continue during the latent period of fol- to provide important information about the lowing an acquired brain injury such as trauma neuropathology of the epileptic network and or stroke. to facilitate the development of novel therapies There is a growing list of a number of muta- for the prevention of epileptogenesis and the tions in genes that have been impli- treatment of medically refractory epilepsy. cated in various human epilepsy syndromes. As we are thinking about new drugs for preventing Financial & competing interests disclosure the development of epilepsy or for the treatment MK Bensalem-Owen has received grants for sponsored of seizures, we need to be thinking about what research as principal or subinvestigator from UCB, Glaxo- other targets are involved in the control of seizures Smith-Kline, Ovation, Orhto-McNeil Janssen, and and develop new therapies that would be specific Marinus pharmaceuticals. The authors have no other rel- to a channelopathy or epileptic syndrome. evant affiliations or financial involvement with any organi- A better understanding and knowledge of the zation or entity with a financial interest in or financial molecular mechanisms underlying some specific conflict with the subject matter or materials discussed in the epileptic syndromes may prove more successful manuscript apart from those disclosed. than mass screening techniques using animal No writing assistance was utilized in the production of models for some of the . this manuscript.

Executive summary ƒƒ There are a number of multiple molecular targets for various antiepileptic drugs. They primarily include GABA receptors, glutamate receptors and voltage-gated ion channels. The end result of this is to stabilize neuronal function, reduce neuronal synchronization and reduce neurotransmitter and neuropeptide release. Several antiepileptic drugs of the first, second or third generation exert an action at more than one molecular target. Future perspective ƒƒ Efforts should be made to develop new drugs with antiepileptic properties that would prevent epileptogenesis and the emergence of seizures in certain situations, such as brain injury, or that alter the underlying mechanisms of a particular epilepsy or prevent its progression. ƒƒ New therapies that would be specific to an epileptic syndrome should be developed as new mutations in ion channels implicated in certain epileptic syndromes have been discovered. ƒƒ In order to minimize side effects from antiepileptic drugs, drugs acting as blockers for specific subunits of the excitatory amino acid receptors should be designed.

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