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.

KEYWORDS: AEDs n anticonvulsant drugs n antiepileptic drugs n epilepsy Aaron M Cook1

n mechanism of action n seizures & Meriem K
Bensalem-Owen†
The therapeutic armamentarium for the treat- patients with refractory seizures. The aim of this 1
UK 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–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

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: 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
channel blocker is phenytoin, which blocks their inhibitory chloride channels is another com-
voltage-­g ated 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

 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. 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 ketamine 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-
neuro­t ransmitters 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
Membrane potential (mV)

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
agonists
„„ SV2a vesicle inhibition
Levetiracetam is the first of several agents able to -70
inhibit the synaptic vesicle protein 2a (SV2a) [6] . K-channel
-90 openers
SV2a appears to be integral to the process of
-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
if they ultimately garner US FDA approval [7] . Figure 1. Effects of antiepileptic drugs on the neuronal action potential.

future science group www.futuremedicine.com 309

Review Cook & Bensalem-Owen

„„ Sodium channel blockade is the only drug specifically indicated for use
(fast inactivation) in severe myoclonic epilepsy 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 neurotransmitters 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 Perampanel, 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
status epilepticus [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 enzyme 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
Tiagabine 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 hydantoin hypersensitivity
steroids (e.g., ganaxolone) also augment GABA syndrome, which presents as a Stevens–Johnson
inhibition by binding a steroid receptor on the Syndrome-like rash, 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.

310 Therapy (2011) 8(3) future science group

 Mechanisms of action of antiepileptic drugs Review
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 plasma protein binding
this is the development of the more water soluble (primarily albumin) is also often a factor that
prodrug, fosphenytoin. 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 bioavailability
Several of these, including exogenous drug that exhibit low interpatient variability and that
metabolism, 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 cholesterol 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 warfarin, 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 amitriptyline, lamot- tissue are promising alternatives under develop-
rigine and nifedipine) 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 pharmacokinetics 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

future science group www.futuremedicine.com 311

Review Cook & Bensalem-Owen

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, valnoctamide 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 epileptogenesis 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 ion channel 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 epilepsies. 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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n Reviews how advances in the physiology of
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ion channels and information on the
gated sodium currents in epileptic disorders.
genetics of idiopathic epilepsies can be n The authors determined predictors and
CNS Drugs 23(7), 555–568 (2009).
applied to the search for improved relative incidence of common AED-related
19 Kellinghaus CS, Besselmann M: Intravenous antiepileptic drugs (AEDs). rash in a large population of patients.
lacosamide as successful treatment for
29 Johannessen SI, Landmark CJ: Antiepileptic 39 Zaccara G, Franciotta D, Perucca E:
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control: Discovery and development of n AEDs are a group of drugs that are highly n Describes idiosyncratic reactions of common
topiramate, a structurally unique antiepileptic susceptible to drug interactions. This article AEDs, their frequency of occurrence, the
drug. Curr. Topics Med. Chem. 9, 1049–1062 reviews clinically relevant interactions of risk factors involved, and preventative as
(2009). AEDs with other drugs. well as management strategies.
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