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422 Chapter 16 Epilepsy
enhances GABA function may be particularly
advantageous, for example carbamazepine together with
vigabatrin. Importantly, however, these mechanistic
strategies are unlikely to dominate in an area as complex
as epilepsy.
Side eects Potential side eects inuence the choice of
initial drug. For example, adolescents may be particularly
troubled by possible side eects of phenytoin: gum
hypertrophy, hirsutism (unwanted hair growth, particularly
problematic for females), and acne. e common
unwanted eects of AEDs are drowsiness (which can limit
ability to drive), visual problems such as nystagmus (a
disorder of eye movement), slurring of speech, and poor
control of limb movement. ese eects are reduced by
careful and slow titration of dose, with the aim of achieving
seizure control with the lowest possible dose.
Some AEDs, including carbamazepine, oxcarbazepine,
lamotrigine, and phenytoin, are associated with the rare
(~1:5000) but potentially fatal antiepileptic
hypersensitivity syndrome, which usually develops within
2 months of starting treatment. It is characterized by
severe skin reactions, fever, liver dysfunction, and renal
and pulmonary abnormalities, progressing to multiorgan failure and death in approximately 10% of patients.
e drug should be withdrawn immediately if symptoms
occur, and the patient should not be re-exposed.
Importantly, cross-reactivity can occur between some
AEDs.
It is also now recognized that certain AEDs present a
small risk of increased suicidal thoughts and behaviour,
and patients should be monitored and counselled with
this in mind. In addition, as discussed in Box 16.3, some
AEDs have proepileptic eects that must be considered.
Antiepileptic drugs and pregnancy All AEDs present
problems in pregnancy, and many have been shown to
have teratogenic eects in animal studies. e enzyme
dihydrofolate reductase is commonly inhibited, and
compensatory folic acid supplements should be taken
during pregnancy to reduce the risk of neural tube defects
in the developing baby. A reference guide should be
consulted, with the aim of achieving an acceptable degree
of seizure control while minimizing risks (considering the
signicant risk that uncontrolled epilepsy has on the
unborn child). Some aspects of this are developed in
Workbook 13.
Antiepileptic therapy is usually long-term. Where a
patient remains seizure free for over 2–3 years, gradual
withdrawal can be considered. For many patients,
however, lifelong drug therapy is needed.
Key references and suggested reading
Chaplin S, Hart Y. Lacosamide: new adjunctive treatment for
partial seizures. Prescriber 2009; 20(10): 16–20.
Epilepsy in Adults: Quick Reference Guide. National Institute
for Health and Care Excellence Clinical Guideline CG20,
2003. http://www.nice.org.uk/nicemedia/pdf/
CG020adultsquickrefguide.pdf.
Manning J-PA, Richards DA, Bowery NG. Pharmacology of
absence epilepsy. Trends Pharmacol Sci 2003; 24(8): 428–33.
Packham B. How to improve compliance with antiepileptic
drugs. Prescriber 2009; 20: 12–20.
Silver N, Cockerel C. Status epilepticus: features and
appropriate management. Prescriber 2009; 20(6): 17–28.
SUMMARY OF DRUGS USED FOR EPILEPSY
16.5 Strategy and side effects in the drug treatment of epilepsy 423
Therapeutic
Class
First-generation
antiepileptic drugs
Drugs Mechanism of action Common clinical uses Comments Common adverse drug
reactions
Sodium valproate 1) Inhibits GABA-metabolizing
Carbamazepine
Phenytoin
Fosphenytoin
(pro-drug of
phenytoin)
Benzodiazepines:
Clonazepam
Clobazam
Diazepam
Midazolam
Ethosuximide
Phenobarbital
Primidone (pro-drug
of phenobarbital)
enzymes
2) Decreases glutamate influence
on NMDA receptors
3) Blocks T-type Ca2+ channels
4) Use-dependent Na+ channel
blocker
1) Use-dependent Na+ channel
blocker
2) Enhances GABA function
3) Blocks L-type Ca2+ channels
Use-dependent Na+ channel
blocker
1) Increase affinity of GABAA
receptor for GABA
2) Increase Cl– current through
GABAA receptor resulting in
hyperpolarization and reducing
neuronal excitability
Selectively blocks T-type Ca2+
channels
Mimic action of GABA on the
GABAA receptor complex
Primary generalized seizures
Migraine prophylaxis
Mood stabilizer—an alternative
to lithium for bipolar disorder
Epilepsy—generalized tonic–
clonic and partial seizures
Trigeminal neuralgia
(neuropathic pain)
Mood stabilizer for treatment
of bipolar disorder
Epilepsy (all types of seizures
apart from absence seizures)
Status epilepticus
Trigeminal neuralgia
Epilepsy
Diazepam, clonazepam, and
midazolam used in status
epilepticus
Clonazepam used for all forms
of epilepsy
Anxiety
Epilepsy (particularly absence
seizures)
Epilepsy (all forms except
absence seizures)
Fewer drug–drug interactions than other
antiepileptic drugs
Not effective against absence and
myoclonic seizures
Strong inducer of hepatic CYP enzymes
leading to drug interactions
Not effective for absence seizures
Non-linear pharmacokinetics
Plasma concentrations can be
unpredictable
High degree of binding to albumin
Induces hepatic CYP enzymes leading to
drug interactions
Usually reserved for second-line use in
epilepsy
Short-term use due to tolerance
Dependence potential
Long plasma half-life (>60 h)
Similar clinical uses to phenytoin but
rarely used because of strong sedative
properties
Strong inducer of hepatic CYP enzymes
leading to drug interactions
Nausea
Vomiting
Weight gain
Tremor (dose-related)
Drowsiness
Liver toxicity
Teratogenic effect
Drowsiness
Blurred vision
Diplopia (double vision)
Headache
Rash
Water retention
Dry mouth
GI disturbances
Thrombocytopenia
Liver dysfunction
Drowsiness
Nausea
Vomiting
Gingival hypertrophy
Acne
Hirsutism
Fetal malformation
Drowsiness
Confusion
Ataxia
Muscle weakness
Anorexia
Nausea
Vomiting
Epigastric pain
Mood changes
Sedation
In overdose: coma, respiratory
depression, and circulatory failure
In addition for primidone:
Nausea
Visual disturbances
424 Chapter 16 Epilepsy
Therapeutic
Class
Second-generation
antiepileptic drugs
Drugs Mechanism of action Common clinical uses Comments Common adverse drug
reactions
Lamotrigine
Topiramate
Gabapentin
Pregabalin
Vigabatrin Irreversibly inhibits GABA
Tiagabine Inhibits neuronal and glial uptake
Oxcarbazepine
Use-dependent Na+ channel
blocker
1) Use-dependent Na+ channel
blocker
2) Enhances GABAA receptor
function
3) Inhibits glutamate function at
the AMPA receptor
4) Blocks L-type Ca2+ channels
Interact with voltage-sensitive
Ca2+ channels
transaminase
of GABA, prolonging presence of
GABA in the synapse
Use-dependent Na+ channel
blocker
Epilepsy (particularly partial
seizures)
Mood stabilizer for treatment
of bipolar disorder
Epilepsy (partial and
generalized tonic–clonic
seizures)
Migraine prophylaxis
Mood stabilizer for treatment
of bipolar disorder
Epilepsy
(particularly partial seizures)
Neuropathic pain
Migraine prophylaxis
(gabapentin)
Anxiety (pregabalin)
Epilepsy (partial seizures) Reserved for last resort
Epilepsy (add-on therapy for
partial seizures)
Epilepsy
(particularly partial seizures)
Mood stabilizer for treatment
of bipolar disorder
Broader therapeutic area than firstgeneration Na+ channel blockers
Can be used for absence seizures
Recently introduced drug GI disturbances
Avoid abrupt withdrawal
Pregabalin is a more potent analogue of
gabapentin
Few interactions compared with other
AEDs
Long-term therapy leads to serious
visual problems in about a third of
patients
Avoid in acute porphyria Diarrhoea
Derivative of carbamazepine Hypersensitivity syndrome
Rash
Hypersensitivity reactions (mainly
skin; can be serious, particularly
in children)
Nausea
Dizziness
Fatigue
Headache
Dizziness
Depression
Sedation
Dizziness
Ataxia
GI disturbances
Weight gain
Tremor
Hypertension
Dry mouth
Memory impairment
Irritability
Blurred vision
Peripheral visual field defect
Fatigue
Sedation
Memory impairment
Dizziness
Tiredness
Confusion
GI disturbances
Acne
Alopecia (hair loss)
Fatigue
Headache
Agitation
Confusion
Blurred vision
WORKBOOK 13
Epilepsy
Ambreen, a patient with a first tonic–clonic seizure at age 23
Ambreen: a simplified case history
It happened when they were strolling along the half-deserted beach. Ambreen and Pavitar had
beenhavinganotherlazyday,snorkellingandbirdwatchingonthebeachonNorthStradbroke
Island, off the coast of Brisbane. They had first met in his pharmacy on the island 2 years ago.
She also was a pharmacist, having trained in England, now working in Brisbane.
Ambreen stopped unexpectedly and Pavitar noticed that she looked strange—stiff and upright.
With her neck and arms straightened, she made a strange sound, like a large exhalation, and
then suddenly fell to the ground, writhing with a shaking movement of her entire body,
especially her legs, which were moving very oddly. Pavitar stared down at her, startled and
afraid.
Foramomenthefeltparalysed.Thenhisclinicalpharmacytrainingkickedinandherealized
shewashavingatonic–clonicepilepticseizure.Hekneltbesideher,turnedherpartlyonher
side, and firmly placed his hand under her chin, applying firm upward pressure to keep her
airwaysopen.Hewasstartledtorealizethatshewasnotbreathingproperly.Holdingoneofher
hands still he saw that her fingers had a bluish tinge. Within a few minutes her breathing
became more orderly, and she lay still. He phoned the island’s ambulance and they were taken
straight to the dock, and on to the mainland. By now Ambreen was conscious again but
confused, holding her head and complaining of pains. The long ambulance ride to the hospital
in Brisbane was a nightmare—Ambreen had two more fits, with only minutes between. With a
shiver of alarm the term ‘status epilepticus’ crept into Pavitar’s mind.
A table of clinical clerking abbreviations is given on page xviii.
CLINICAL CLERKING FOR AMBREEN
Age: 23 years
PC: Convulsive episodes
HPC: Three years ago she started having episodes that she now describes as staring, but which she
thought at the time was daydreaming. No further episodes since.
PMH: Two febrile convulsions as a child. Episodes of absence. Otherwise healthy.
426 Chapter 16 Epilepsy
Ambreen has been completely healthy apart from contracting the usual childhood illnesses.
During two such viral infections her temperature got so high that she had convulsions. Although
most children who suffer from febrile convulsions do not become epileptic, a small number do.
Her staring episodes could have been due to absence epilepsy.
DH: Microgynon® (oral contraceptive)
The only medication Ambreen currently takes is oral contraception.
Becauseshehadhadtwofurtherseizuresclosetogetherwhileintheambulance,Ambreenwas
treatedwithadiazepamsuppository.
Diazepam is a benzodiazepine used for treating status epilepticus (seizures persisting for 30 minutes
or more), or when two discrete seizures are not separated by complete recovery of consciousness, as
was the case with Ambreen. Diazepam may also be given intravenously for this indication.
SH: Recent pharmacy graduate, lives alone
O/E: Normal
Unlike most illnesses, epilepsy is episodic. Patients may appear perfectly normal between seizures,
and so may show no signs of illness at routine medical examinations.
Biochemistry:
1) Urea and electrolytes (Us & Es) = normal
2) Full blood count (FBC) = normal
3) Toxicology and alcohol screen = normal
4) Glucose levels = normal
The above tests are all normal, ruling out the following possible causes of seizures: infection,
hypoglycaemia, or intoxication.
Investigations:
1) Electroencephalography (EEG)
2) Magnetoencephalography (MEG)
EEG is the most common examination for diagnosing suspected epilepsy. It detects electrical
activity in the brain and is used to reveal abnormalities. EEG can, however, be unreliable in
diagnosing epilepsy, with at least 50% of sufferers showing no abnormalities. Conversely, 20% of
unaffected people exhibit minor EEG abnormalities, and 1–3% show distinctly epileptic discharges.
Similarly, a small number of people without symptoms of epilepsy show photosensitive reactions (i.e.
seizure induced by flashing lights) on their EEG traces.
Where EEG detects abnormal electrical activity in brain region(s) affected by seizures, this method
only gives a rough localization of the epileptic focus. This can be more precisely identified using
magnetoencephalography (MEG), a recently developed scanning method based on the magnetic
fields generated by neuronal activity.
WORKBOOK 13 Epilepsy 427
3) Magnetic resonance imaging (MRI)
MRI uses magnetic fields and radio waves to generate a three-dimensional picture of the inside of
the body. MRI can be useful in determining the cause of epilepsy by detecting possible structural
abnormalities (e.g. tumour or scar tissue) in the brain.
Ambreen’sMRIscansrevealnostructuralabnormalitiesthatcouldexplainherseizures;thisis
common with epilepsy.
It is often difficult to confidently diagnose epilepsy. For example, up to 10% of teenagers who have
experienced a syncopal-type attack (i.e. ‘fainting’ due to a temporary decrease in blood flow to the
brain) are misdiagnosed with epilepsy. Need for accurate diagnosis is paramount, particularly as
treatment can have life-changing implications (e.g. for driving) and often needs to be continued for
years. Brain imaging is therefore now commonly used to aid diagnosis. An independent witness to
the attacks is often the best diagnostic tool.
InAmbreen’scase,Pavitarandtheparamedicswitnessedherseizures,andprovidedinvaluable
accounts.
Whileinhospital,Ambreensufferstwomoreseizuresaccompaniedbyincontinence.
Diagnosis: Epilepsy: generalized tonic–clonic seizures with possible absence seizures.
Plan: Commence sodium valproate
The aim of pharmacological treatment is to control seizures without affecting normal function or
inducing side effects. To minimize adverse effects, treatment should be initiated with a single drug
at the lowest possible dose, thereby optimizing its use.
Established (i.e. ‘first-generation’) antiepileptic drugs should be used first line.
The choice of drug will depend on several factors, including:
• seizuretype
• personalsituationofthepatient(e.g.concurrentdrugs,pregnancy,etc.)
Sodium valproate is effective for treating epilepsy in which both generalized tonic–clonic seizures
and absence seizures occur.
1) What is epilepsy? Describe what occurs in neurons during a seizure.
2) List three possible causes of epilepsy.
3) What possible changes in neuronal excitability can occur in epilepsy?
4) List the major seizure categories, including two seizure types from each.
5) What is the main aim of treatment in epilepsy?
6) Describe the nature of the duration of treatment for epilepsy.
7) List the three primary mechanisms of action of antiepileptic drugs.
8) When is diazepam commonly used in the treatment of epilepsy?
428 Chapter 16 Epilepsy
9) What are the proposed mechanisms of action of sodium valproate?
10) Describe one mechanism of action by which sodium valproate can reduce seizures without affecting
normal neurophysiological function.
11) Explain why it is important that women of childbearing age are counselled when prescribed sodium
valproate.
Ambreen stays in hospital for two weeks and during this time she suffers two more episodes.
Afterherdrugdoseisdoubled,sheremainsseizurefreeandisdischarged.
Meanwhile Ambreen’s parents have arrived from England to look after her. Pavitar must return
to his business. When he gets back to the island he studies the latest reports on the drug
treatmentofepilepsy,andrealizesthatalthoughsomenewdrugshavebeenintroducedsince
he qualified, the fundamental approach to epilepsy treatment has not changed.
UnfortunatelyAmbreenstartshavingmoreseizuresathome.Shevisitsherneurologisttwice,
and despite further increasing the dose of sodium valproate, up to its maximum, she still has at
leastoneseizureaweek.Shehasapparentlynotsufferedfromsideeffectsoftheantiepileptic
drug. Her doctor decides to admit her to hospital.
Whilesheisinhospitalthepatternsofherseizureswillbeobservedbeforeanyfurther
changes to her medication are made. On the second day in hospital, Ambreen develops
encephalopathy (brain dysfunction often caused by metabolic abnormalities). An urgent
investigation into her plasma levels of sodium valproate is carried out, and it is found to be
extremely elevated.
Note that plasma levels of sodium valproate are not an index of drug efficacy, but can be useful for
indicating toxicity.
The neurologist is confused because despite the elevated level of drug, Ambreen is still
having fits and yet is free from side effects at home. He convinces Ambreen to be truthful
about her compliance. She admits that she has not been taking her medication due to
unpleasant side effects, including severe nausea and drowsiness. Unaware of this, her
doctor had kept increasing the dose. In hospital she took the medication under the
supervision of a nurse, and exposure to such a high dose of sodium valproate has led to the
toxic effects.
12) What are the side effects of sodium valproate?
Followingfurtherinvestigation,theneurologistrealizesthatbecauseAmbreenisapharmacist
she had not been properly counselled by the prescribing pharmacist about her medication
during her previous admission. Ambreen has not been in a fit state to think clearly about her
own condition, and in fact has never felt confident about her understanding of antiepileptic
drugs.
WORKBOOK 13 Epilepsy 429
It is vital that a patient with epilepsy agrees with treatment goals. The expected outcomes of
treatment and potential side effects and management should be discussed with the patient. Patients
should be involved during decision-making as this will lead to better adherence and clinical
management.
The patient needs to understand the following:
• theaimsandimplicationsoftreatment
• theimportanceofregularmedication.
Without this understanding treatment may well fail.
The pharmacist has an important role in the management of epilepsy by:
• ensuringthatthebestdrugchoiceismade
• applyingpharmacokineticknowledgetomonitordrugeffects,includingadverseeffectsanddrug
interactions
• preparingmedication(e.g.intravenousdiazepam)
• monitoringpatienthealth
• makingdischargearrangements(e.g.dosetitrationplans)
• counsellingpatientsabouttheneedtocomplywithmedicines.
The neurologist decides that, because of the side effects Ambreen is suffering, sodium
valproate should be changed to another drug. The ideal replacement would be another
antiepilepticeffectivefortreatingbothgeneralizedtonic–clonicandabsenceseizures.
Otherwise, sodium valproate may have to be replaced with two drugs.
13) Which other drugs are effective for treating tonic–clonic seizures?
14) Of these drugs, would any also be beneficial in treating absence seizures?
The neurologist discusses the options with Ambreen. He talks to her about phenytoin, an older
drugthatisveryeffectiveformostformsofseizuresapartfromabsence-typeseizures.
15) What are the mechanisms of action of phenytoin?
The neurologist tells Ambreen that, despite its being effective, there are reasons why he is
reluctant for her to use phenytoin. These include certain side effects that could be distressing
to a young woman.
16) What are the side effects of phenytoin?
17) Which of these could lead to non-compliance in a young woman?
430 Chapter 16 Epilepsy
He also tells her that she will have to go to her doctor regularly for her blood level of phenytoin
to be checked.
After careful consideration the neurologist and Ambreen together decide against phenytoin.
Theynextdiscusscarbamazepine.
18) What are the similarities in the mechanisms of action of phenytoin and carbamazepine?
ThedoctortellsAmbreenthatheroralcontraceptivepillswouldbeaffectedbycarbamazepine
(itinducestheliverenzymesthatmetabolizeoestrogenand/orprogesterone).
Theydecideagainstcarbamazepine.Theneurologistproposesanewerantiepilepticdrug,
lamotrigine,whichhasasimilarmodeofactiontophenytoinandcarbamazepine.
Lamotrigine also has certain advantages, particularly in women of childbearing age.
1) It does not interact with oral contraceptives.
2) It can be used in pregnancy.
3) Itisalsoeffectiveinthetreatmentofabsenceseizures.
The Medicines and Healthcare Products Regulatory Agency (MHRA) of the UK recently (2015) issued
a strong warning that sodium valproate is associated with a dose-dependent risk of abnormal
pregnancy outcome. Based on recent studies, the risk of congenital malformation with sodium
valproate is now approximately 10%, with an additional high risk (30–40%) of developmental delays.
As a result, the Committee on Safety of Medicines (CSM) has advised that women of childbearing
age should not be prescribed sodium valproate without specialist neurological advice. In addition,
other AEDs including lamotrigine and carbamazepine have been associated with teratogenic effects
(i.e. birth defects).
Despite this, lamotrigine may be considered as a first-line drug for use in women of childbearing age
with generalized epilepsy, although the lowest possible therapeutic dose should be used during
pregnancy. Lamotrigine decreases the enzyme dihydrofolic acid reductase, reducing folic acid levels.
Supplements of folic acid are therefore advised, particularly in pregnancy or in women trying to
conceive.
As an alternative approach in some countries, for example Australia, there is no ‘drug of choice’ in
pregnancy, and all but sodium valporate are considered.
Lamotrigine is commenced at a very low dose, as sodium valproate inhibits its metabolism
and could therefore increase the risk of side effects. Once an appropriate dose is reached,
sodiumvalproateisslowlywithdrawn.Thewithdrawalprocesstypicallytakes2–3months,but
because of the severity of the side effects Ambreen has suffered, the rate of withdrawal is
accelerated.
When switching antiepileptic drugs, withdrawal is carried out incrementally in order to avoid
withdrawal seizures.
WORKBOOK 13 Epilepsy 431
The neurologist and pharmacist monitor Ambreen very carefully for signs of side effects which
could lead to non-compliance.
19) How would you counsel a patient starting lamotrigine for the first time?
20) How would you switch from one antiepileptic drug to another?
In general, the following should be monitored with all anticonvulsants.
•Clinicalefcacy:seizurecontrolshouldbemonitored.
•Adversedrugreactions:slowinitiationoftenreducestherisk.
•Therapeuticdrugmonitoring(TDM):measuringplasmadruglevelsandtheirpharmacokinetic
interpretation is integral to the management of patients on carbamazepine and phenytoin (it is less
of an issue with other antiepileptic drugs).
TDM should be carried out:
•attheonsetoftherapy
•ifseizurecontrolispoororsuddenchangesoccur
•tomonitordrug–druginteractions,oriftoxicityissuspected
•ifpoorornon-complianceissuspected
•whenchangingantiepilepticdrug.
Stabilized patients only require monitoring once or twice annually. Patients for whom any of the
above apply will need monitoring more regularly.
Afterthreefurtherseizure-freeweeksinhospital,Ambreenisdischargedonlamotrigine.
Before her discharge, she asks what other drugs are available should this fail. The neurologist
tells her that there are several newer antiepileptic drugs available as second-line or adjunctive
therapy if treatment with lamotrigine is unsuccessful.
Examples of such drugs include tiagabine, topiramate, vigabatrin, and gabapentin. There are also older
drugs that could be used, such as clonazepam, although problems with side effects are more common.
21) What are the mechanisms of action of topiramate?
22) Would topiramate be a suitable choice for Ambreen if required? If so, why?
23) List three antiepileptic drugs that act by enhancing GABA transmission in different ways, and
describe their mechanisms of action in detail.
SixmonthslaterAmbreenreturnstotheclinic.Shehasbeenseizurefreeexceptforone
episode of absence, but this did worry her. The neurologist tells her that there is one drug that
couldbeaddedtolamotrigine,whichwouldcontrolabsenceseizuresmoreeffectively,butit
carriestheriskofpotentiatingtonic–clonicseizures.Inviewofthis,andthefactthatitwasjust
asingleepisodeofabsence,theneurologistwouldprefertowaitanother6months.Theyagree
thatifAmbreenhasanymoreabsenceseizurestheywilldiscussaddingthisdrug.