Review Mechanisms of action of antiepileptic drugs Epilepsy affects up to 1% of the general population and causes substantial disability. The management of seizures in patients with epilepsy relies heavily on antiepileptic drugs (AEDs). Phenobarbital, phenytoin, carbamazepine and valproic acid 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 seizure 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 anticonvulsant drugs antiepileptic drugs epilepsy Aaron M Cook mechanism of action 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 anti epileptic 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–drug interactions. In addi- action potential 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. Sodium 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 neurotransmitter, which further in drug targets, such as specific GABA subunits propagates the signal at a neuronal synapse or and synaptic vesicle inhibition. Currently, there results in a terminal effect on the brain or other are several viable agents in the AED pipeline that neurons leading to extracranial organs. expand the spectrum of effective mechanisms of action even further (Table 1). Sodium channel 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 valproate, as well as second generation AEDs 10.2217/THY.11.19 © 2011 Future Medicine Ltd Therapy (2011) 8(3), 307–313 ISSN 1475-0708 307 Review Cook & Bensalem-Owen Mechanisms of action of antiepileptic drugs Review 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 Topiramate (fast inactivation) inactivated state Carbamazepine Zonisamide Valproate Oxcarbazepine Lamotrigine Felbamate Rufinamide Calcium channel blockade Post-synaptic Ethosuximide (T-type) Topiramate inhibitory action Valproate Zonisamide (T-type) Gabapentin Lamotrigine Pregabalin GABA agonism/potentiation Inhibitory activity Benzodiazepines Felbamate Retigabine by permitting Barbiturates Topiramate Neurosteroids hyperpolarization Valproate Vigabatrin Stiripentol NMDA receptor blockade Decreased excitatory Felbamate synaptic activity AMPA receptor blockade Decreased excitatory Topiramate synaptic activity SV2a vesicle inhibition Decreased excitatory Levetiracetam Seletracetam synaptic activity Brivaracetam Sodium channel blockade Recovery of neurons from Lacosamide (slow inactivation) prolonged depolarization Potassium channel 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: Anti epileptic 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 channel blocker 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 neuron 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 chloride channel 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. 308 Therapy (2011) 8(3) future science group Review Cook & Bensalem-Owen Mechanisms of action of antiepileptic drugs Review 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 benzodiazepine) 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 sedative effects (i.e., pentobarbital and thio- influx into the neuron. This represents one of pental being very sedating, phenobarbital being the major mechanisms for neurotoxicity during minimally sedating). traumatic brain injury, 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.