US Pharm. 2013;38(1):35-39.
ABSTRACT: Epilepsy is a disorder comprising a
collection of seizures that differ in cause, symptoms, severity, and
treatment. Seizures are assigned to one of two major categories: partial
or generalized. Epilepsy cases can involve more than one type of
seizure. Epilepsy may be classified into etiologic types and then
further defined by presenting features. Drug therapy is based on type of
seizure, age, gender, comorbidities, adverse-effect potential, drug
interactions, and cost. Once treatment is initiated, about 60% of
patients achieve adequate seizure control with monotherapy. Monitoring
of serum concentrations is beneficial when suspecting toxicity,
assessing medication adherence, or making dose adjustments. Pharmacists
can improve patient outcomes through dose recommendations, drug
interaction surveillance, adherence counseling, and adverse-effect
Commonly referred to as seizure disorder, epilepsy is a disorder comprising a collection of seizures that differ in regard to cause, symptoms, severity, and treatment.1
Approximately 2 million people in the United States have epilepsy, and
it is estimated that about 140,000 people develop the disorder every
year.2 Despite advances in technology and treatment, epilepsy
still remains a huge economic burden, with an estimated health care
cost of $2.7 billion per year.3
Seizures occur when there is a disturbance in the balance of excitation and inhibition in the central nervous system (CNS).4
Many different mechanisms can cause neuronal hyperexcitability and lead
to the development of seizures. These factors include changes in ion
channel conduction, membrane receptor response, messenger systems, and
gene transcription. Imbalances between excitatory (glutamate) and
inhibitory (gamma-aminobutyric-acid, or GABA) neurotransmitters, as well
as excessive acetylcholine, norepinephrine, and serotonin levels, may
also precipitate seizures.1
Excitatory and inhibitory currents are primarily mediated
by different channels including voltage- and ligand-gated channels.
Voltage-gated channels include sodium and calcium channels. Ligand-gated
channels include GABA and glutamate channels. Most of the pharmacologic
agents used in treating epilepsy target these different channels.1
Seizures represent the clinical manifestations or symptoms
of disturbed electrical activity, while epilepsy is a disorder of
recurrent seizures. A patient is considered to have epilepsy when he or
she has had two or more unprovoked seizures.1 Patients with
an isolated seizure or seizures secondary to a reversible cause (e.g.,
hypoglycemia, alcohol withdrawal, high fever) are not considered to have
Seizures are classified according to the classification scheme proposed by the International League Against Epilepsy (ILAE).5
It is recommended that seizures be assigned to one of two major
categories: partial seizures or generalized seizures. Partial seizures
are further classified into simple partial seizures (patient has no loss
of consciousness) or complex partial seizures (patient has loss of
The classification of epilepsies is more complex. Since
epilepsy cases can involve more than one seizure type, specific
classification of epilepsies is less meaningful. Rather, the newly
recommended approach is to refer to epilepsies in regard to
etiology—genetic, structural/metabolic, or unknown. The epilepsy can
then be further characterized based on different presenting features
(e.g., age of onset, EEG findings, neurologic examination).6
Seizures involve abnormal electrical activity that can
produce changes in consciousness, motor and sensory activity, and
behavior. The symptoms that occur can vary significantly from patient to
patient and generally depend on the type of seizure or epilepsy.
Generally, partial seizures originate in one hemisphere and can involve
disturbances in motor function, sensory perception, autonomic function,
and behavior. Sensory symptoms include paresthesias, abnormal tastes or
smells, flashing lights, and hearing changes. Patients can report
different autonomic symptoms, like sweating, epigastric sensation, or
piloerection. Some patients can experience psychic symptoms including
dysphasia, fear, and hallucinations. Automatisms, or repetitive
movements, can be described in some patients and often present as
chewing, swallowing, or sucking. A number of patients can experience an
aura or warning symptoms minutes to hours before a seizure. Aura
symptoms can differ significantly; examples include irritability,
nausea, headache, and fear. Loss of consciousness and memory loss may
also occur with partial seizures. Partial seizures may not terminate and
can evolve into secondary generalized seizures.5,7
Generalized seizures involve both hemispheres and typically include bilateral motor symptoms and loss of consciousness.5
The many different types of generalized seizures (absence, myoclonic,
tonic, clonic, tonic-clonic, atonic) will vary in motor symptom
Antiepileptic drug (AED) therapy may or may not be
indicated after a patient experiences a first seizure. AED therapy is
generally reserved for patients diagnosed with recurrent, unprovoked
seizures or epilepsy and is typically not indicated in patients who have
experienced an isolated seizure or seizures secondary to a reversible
With the many different types of seizures and epilepsy
syndromes, there really is no specific agent that is considered the drug
of choice. Rather, specific AEDs are generally more effective and
useful for certain types of seizures or epilepsy syndromes compared to
others. A number of studies have compared agents for different types of
seizures. The VA Cooperative Study compared carbamazepine,
phenobarbital, phenytoin, and primidone in the treatment of partial and
secondarily generalized tonic-clonic seizures.8 Based on the
results, carbamazepine and phenytoin had the greatest treatment success.
However, this study was conducted in the early 1980s and does not
consider the use of newer AEDs. More recent studies have compared newer
AEDs as initial monotherapy and have shown little difference in
efficacy, but these studies are limited in duration (<1 year) and do
not evaluate long-term efficacy.9-11
One of the latest studies, the Standard and New Antiepileptic Drugs (SANAD) trial, followed patients for 3 years.12 Results
demonstrated that for partial seizures, lamotrigine and oxcarbazepine
had the longest time to treatment failure in comparison to
carbamazepine, topiramate, and gabapentin. For time to 12-month
remission, lamotrigine and carbamazepine were significantly better
versus oxcarbazepine, topiramate, and gabapentin.12 For
generalized seizures, valproate and lamotrigine had the longest time to
treatment failure, while valproate and topiramate had the shortest time
to 12-month remission.13
The ILAE guidelines summarize evidence for efficacy of
initial monotherapy for the treatment of newly diagnosed or untreated
epilepsy.14 The American Academy of Neurology has issued
guidelines assessing the efficacy, tolerability, and safety of newer
AEDs in the treatment of newly diagnosed epilepsies.15
Although these guidelines make general recommendations on which AEDs
should be considered for use based on efficacy or safety, they do not
make specific recommendations on which AED is the clear drug of choice.14,15
With limited data and lack of specific recommendations from
evidence-based guidelines, drug therapy is individualized, and selection
of the most appropriate AED is based on a number of important
considerations including seizure or epilepsy type, age, gender,
comorbidities, potential adverse effects, drug interactions, and cost.14 Once treatment is initiated, approximately 60% of patients achieve adequate seizure control with monotherapy.16
Seizure Type: Each AED is generally
effective for certain types of seizures and can be classified as either
broad or narrow spectrum. Broad-spectrum agents are effective for many
different types of seizures. Narrow-spectrum agents are effective for
only specific types of seizures. Determining seizure and epilepsy type
is important in selecting the most appropriate agent (TABLE 1 lists specific agents and dosing).17
Adverse Effects: Since treatment of
epilepsy is long-term and medication adherence is crucial for treatment
success, drug tolerability is a major issue. AEDs can cause various
adverse effects, and this is an important factor to consider when
selecting therapy. Although most AEDs can cause common CNS side effects
(dizziness and drowsiness), some agents are more tolerable compared to
others. Impaired cognition is one major concern for many patients and
family members. In general, newer agents like gabapentin and
levetiracetam appear to have the least effects on cognition and may be
Patients with renal dysfunction should have dosage
adjustment performed for topiramate, oxcarbazepine, levetiracetam,
pregabalin, and lacosamide to avoid accumulation of the drug or its
A number of agents can affect the liver. Carbamazepine,
phenytoin, and valproic acid can cause elevations in liver enzymes and
thus should be avoided in patients with liver disease. Although these
agents have also been known to cause hepatotoxicity, more severe liver
problems are rare.19
AEDs may also cause different dermatologic reactions.
Phenytoin can cause skin rash. Rare, fatal skin reactions like
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have
been reported with most agents, but appear to be more common with
carbamazepine, valproic acid, phenytoin, phenobarbital, and lamotrigine.20,21
Suicidal behavior or ideation has been reported in
numerous studies evaluating the use of AEDs for epilepsy and psychiatric
conditions. Due to the potential risk, a black box warning has been
added to the labeling of all AEDs, and distribution of medication guides
is required. It is generally recommended to monitor patients on AEDs
for any new or worsening thoughts of suicidal behavior.22
Childbearing Plans: Because of
significant concerns for teratogenicity, AED selection is also affected
by a woman’s childbearing plans. Possible birth defects include
intrauterine growth retardation, major malformations, and postnatal
developmental delay. Since there is no consensus on the safest agent
during pregnancy, the most effective agent is generally used at the
lowest effective dose. However, because studies do demonstrate a greater
risk for birth defects with valproic acid, it is commonly avoided.23
Women on oral contraceptives should be educated about the potential
interaction between enzyme-inducing oral contraceptives and AEDs. When
necessary, alternative contraception should be recommended.23
Drug Interactions: Many AEDs are
metabolized through the CYP450 system in the liver and can be either
enzyme inducers or enzyme inhibitors. Phenytoin, phenobarbital,
carbamazepine, and primidone are well-known enzyme inducers, while
valproic acid is the only major enzyme inhibitor. Enzyme inducers can
enhance the metabolism of warfarin, oral contraceptives, antibiotics,
and antidepressants resulting, in decreased serum concentrations and
effects. Valproic acid can decrease the metabolism of warfarin, statins,
and tricyclic antidepressants, resulting in increased serum
concentrations and effects (TABLE 2).24 Carbamazepine
is metabolized through CYP3A4 and can interact with CYP3A4 inhibitors,
resulting in increased carbamazepine levels (e.g., erythromycin,
diltiazem, cimetidine). Combination AED therapy is sometimes necessary,
but drug interactions between AEDs are possible too. Since these agents
can cause drug interactions with other medications and concomitant AEDs,
it is important to screen for potential drug interactions prior to drug
Therapeutic Drug Monitoring
Therapeutic drug monitoring for AEDs is commonly used to
help guide and assist clinicians with optimal dosing in patients.
Monitoring serum concentrations can allow clinicians to achieve seizure
control while minimizing adverse effects. Established drug levels for
various AEDs should be primarily viewed as reference ranges and not
therapeutic levels (see TABLE 1 for agents with established
reference ranges). A serum concentration that falls below the reference
range is unlikely to result in a therapeutic response, while a serum
concentration that falls above the reference range is likely to result
in toxicity. Yet it is important to recognize that because of individual
variation and patient response, many patients can still achieve
adequate seizure control at concentrations outside established reference
ranges or develop toxicity at concentrations that fall within reference
ranges. Thus, reference ranges serve merely as a guide, and each
patient will have an individualized therapeutic level. Monitoring serum
concentrations is most beneficial when suspecting toxicity, assessing
medication adherence, or assisting with dosing in patients with altered
Epilepsy and the Pharmacist’s Role
Epilepsy is a chronic disorder that continues to be a huge
economic burden. Although newer AEDs aim to increase treatment success
and decrease the risk for adverse effects, there is still a strong need
for improving patient outcomes. Pharmacists can play a significant role
in optimizing therapy for patients with epilepsy. Patient counseling on
the potential adverse effects of AEDs is important. Patients and family
members should be educated on expected CNS and cognitive side effects,
potential skin reactions, and the risk for suicidal behavior. Patient
education should also address the importance of medication adherence.
Patient medication profiles should be reviewed for possible drug
interactions, and dosage adjustments or alternative agents should be
recommended if necessary. Additionally, pharmacists can advise
clinicians on appropriate therapeutic drug monitoring.
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