Antiepileptic Drugs

Muhammad Asaduzzaman, PhD

Professor
School of Pharmacy
 Epilepsy
• Globally, epilepsy is the third most common neurologic
disorder after cerebrovascular and Alzheimer’s disease.
• Epilepsy is not a single entity but an assortment of different
seizure types and syndromes originating from several
mechanisms that have in common the sudden, excessive, and
synchronous discharge of cerebral neurons.
• Epilepsy is a heterogeneous symptom complex—a chronic
disorder characterized by recurrent seizures.
 Definition
• Epilepsy is a common condition that affects the brain
and causes frequent seizures.

• Seizures: bursts of electrical activity in the brain that

temporarily affect how it works. They can cause a
wide range of symptoms.

• Epilepsy can start at any age, but usually starts either

in childhood or in people over 60. It's often lifelong,
but can sometimes get slowly better over time.
 Symptoms of epilepsy
Possible symptoms include:
• uncontrollable jerking and shaking – called a "fit"
• losing awareness and staring blankly into space
becoming stiff
• strange sensations – such as a "rising" feeling in the
tummy, unusual smells or tastes, and a tingling
feeling in your arms or legs collapsing
• sometimes you might pass out and not remember
what happened.
 Aetiology of epilepsy
• Epilepsy can be due to an underlying genetic, structural,
or metabolic cause or an unknown etiology.

• Focal areas that are functionally abnormal may be

triggered into activity by changes in physiologic factors,
such as an alteration in blood gases, pH, electrolytes,
and blood glucose and changes in environmental factors,
such as sleep deprivation, alcohol intake, and stress. A
number of causes, such as illicit drug use, tumor, head
injury, hypoglycemia, meningeal infection, and the rapid
withdrawal of alcohol from an alcoholic, can precipitate
seizures.
 Epilepsy and Pregnancy
• Most women with epilepsy will have a healthy
pregnancy and go on to have a healthy baby. But
there is a slightly higher risk of having a baby with
a birth defect or developmental problem
Mechanism of Seizure Generation
Deregulation of balance occurs in two ways:
1. Excitation (too much)
• Ionic‐inward Na+, Ca++ current
• Neurotransmitters : glutamate, aspartate

2. Inhibition (too little)

• Ionic‐inward CI‐, outward K+ currents
• Neurotransmitter: GABA
Classification of Epilepsy
Partial (lobe/ hemisphere), no loss of
consciousness, fear, strange smell,
can remember something
happened, jerking

Loss of consciousness, may not

remember
 Focal Epilepsy
A. Focal or Partial
Focal seizures involve only a portion of the
brain, typically part of one lobe of one
hemisphere. The symptoms of each seizure type
depend on:
• the site of neuronal discharge
• the extent to which the electrical activity
spreads to other neurons in the brain.
 Focal epilepsy
Simple partial:
i. caused by a group of hyperactive neurons exhibiting
abnormal electrical activity
ii. confined to a single locus in the brain.
iii. The electrical discharge does not spread, and the
patient does not lose consciousness or awareness.
Complex partial:
i. These seizures exhibit complex sensory hallucinations
and mental distortion.
ii. Motor dysfunction may involve chewing movements,
diarrhea, and/or urination. Consciousness is altered.
 Generalized epilepsy
B. Generalized
• Generalized seizures may begin locally
• progress to include abnormal electrical
discharges throughout both hemispheres of
the brain.
• may be convulsive or nonconvulsive
• patient usually has an immediate loss of
consciousness.
Classification of Epilepsy
 Generalized epilepsy
Clonic:
• These seizures consist of short episodes of muscle contractions
• closely resemble myoclonic seizures.
• Consciousness is more impaired with clonic seizures as compared to
myoclonic.

Tonic:
• These seizures involve increased tone in the extension muscles
• generally less than 60 seconds long.

Atonic:
• These seizures are also known as drop attacks
• characterized by a sudden loss of muscle tone.
 Generalized epilepsy
Tonic–clonic:
• result in loss of consciousness
• followed by tonic (continuous contraction) and clonic (rapid
contraction and relaxation) phases.
Absence:
• brief, abrupt, and self limiting loss of consciousness.
• occurs in patients at 3 to 5 years of age and lasts until
puberty or beyond.
Myoclonic:
• consist of short episodes of muscle contractions that may
recur for several minutes.
• generally occur after wakening and exhibit as brief jerks of
the limbs.
Special conditions associated to
seizures and epilepsy
 Status Epilepticus
• A seizure that lasts longer than 5 minutes, or having
more than 1 seizure within a 5 minute period,
without returning to a normal level of consciousness
between episodes is called status epilepticus.

• This is a medical emergency that may lead to

permanent brain damage or death.
 Lennox–Gastaut Syndrome
• a rare and severe form of epilepsy that typically becomes
apparent during infancy or early childhood (typically
between 3-5 years)

• Affected children experience several different types of

recurrent seizures most commonly atonic, tonic and
atypical absence seizures.

• It has been associated with several gene mutations,

perinatal injuries, congenital infections, brain
tumors/malformations, and genetic disorders such as
tuberous sclerosis
• Children with Lennox-Gastaut syndrome may also
develop cognitive dysfunction, delays in reaching
developmental milestones and behavioral problems

• Associated with slow spike waves on EEG

• Associated with high morbidity and mortality

• Can be difficult to treat because it is resistant

(refractory) to many kinds of anti-seizure
medications.
 Diagnosis of Epilepsy
• Brain imaging
1. MRI
2. CT scan
-- Both look for abnormalities and tumor
• EEG: look for abnormalities in electrical
discharge
• Because epilepsy varies so diagnosis requires
test and examination of clinical history.
 Treatment
Treatments include:

• medicines called anti-epileptic drugs (AEDs)

• surgery to remove a small part of the brain that's causing

the seizures

• a procedure to put a small electrical device inside the

body that can help control seizures

• a special diet (ketogenic diet) that can help control

seizures
 Mechanism of Action of Antiepileptic
Drugs
• An imbalance between excitation and inhibition has been a
longstanding proposed mechanism regarding epilepsy.
• This imbalance is related to increased extracellular glutamate in the
brain and/or reduction in GABA concentrations, leading to
excitotoxicity, seizures, and cell death.

• Established antiepileptic drugs (AEDs) decrease membrane

excitability by interacting with neurotransmitter receptors or ion
channels.
• Drugs reduce seizures through mechanisms such as blocking
voltage-gated channels (Na+ or Ca2+), enhancing inhibitory γ-
aminobutyric acid (GABA)ergic impulses and interfering with
excitatory glutamate transmission.
Mechanism of Action of Antiepileptic
Drugs
Three main mechanisms –
• Enhancement of GABA action
• Inhibition of sodium channel function
• Inhibition of calcium channel function

Other mechanisms include:

• Inhibition of glutamate release and
• Block of glutamate receptors (eg. NMDA, AMPA
receptors)- clinical studies still ongoing
 Mechanism of Action of Antiepileptic
Drugs
• Some antiseizure medications appear to have multiple targets
within the central nervous system (CNS), whereas the mechanism
of action for some agents is poorly defined.

• Antiseizure medications suppress seizures but do not “cure” or

“prevent” epilepsy.
 Drugs for Epilepsy

DRUG SELECTION

➢Choice of drug treatment is based on

• the classification of the seizures,
• patient-specific variables (for example, age, comorbid medical
conditions, lifestyle, and personal preference), and
characteristics of the drug.
Anti-epilepsy Medication
 Enhancement of GABA Action
• GABA-A receptors are the major inhibitory transmitter
receptors in the brain.
• GABA binding to the GABA-A receptor, causes an influx of
chloride ions into the cells, causing the membrane potential
to become highly negative which results in neuronal
hyperpolarization and inhibition of neuronal signaling.
 Enhancement of GABA Action
• Several antiepileptic drugs (e.g. phenobarbital and
benzodiazepines) enhance the activation of GABA-A
receptors, thus facilitating the GABA-mediated opening of
chloride channels.

• phenobarbital is also thought to have similar pharmacological

activity as phenytoin, but it is seldom used now because it
causes sedation.

• Newer drugs also enhance GABA activity by preventing

reuptake of the neurotransmitter.
 Benzodiazepines
➢Benzodiazepines bind and activate GABA inhibitory receptors to
reduce firing rate of neurons.
➢Most benzodiazepines are reserved for emergency or acute seizure
treatment due to tolerance.
➢However, clonazepam and clobazam may be prescribed as adjunctive
therapy for particular types of seizures. Diazepam is also available for
rectal administration to avoid or interrupt prolonged generalized
tonic–clonic seizures or clusters when oral administration is not
possible.
 Inhibition of Sodium Channel
Function
• Many antiepileptic drugs (e.g. carbamazepine, phenytoin and
newer drugs like lamotrigine affect membrane excitability by
an action on voltage-dependent sodium channels which carry
the inward membrane current necessary for the generation of
an action potential.

• In other words, they block the excitation of cells that are firing
repetitively, and the higher the frequency of firing, the greater
the block produced.
 Phenytoin
Phenytoin blocks voltage-gated sodium channels by
• selectively binding to the channel in the inactive state and slowing its
rate of recovery.
• It is effective for treatment of focal and generalized tonic– clonic
seizures and in the treatment of status epilepticus.
• Phenytoin induces drugs metabolized by the CYP2C and CYP3A
families and the UGT enzyme system (Uridine Diphosphate-
Glucuronosyltransferases).
• Phenytoin exhibits saturable enzyme metabolism resulting in
nonlinear pharmacokinetic properties (small increases in the daily
dose can produce large increases in plasma concentration) resulting in
drug-induced toxicity.
 Phenytoin
• Depression of the CNS occurs particularly in the cerebellum and
vestibular system, causing nystagmus and ataxia.
• The elderly are highly susceptible to this effect. Gingival
hyperplasia may cause the gums to grow over the teeth.
• Long-term use may lead to development of peripheral
neuropathies and osteoporosis.
• Although phenytoin is advantageous due to its low cost, the
actual cost of therapy may be much higher, considering the
potential for serious toxicity and adverse effects.
 Carbamazepine
• Carbamazepine is chemically related to the tricyclic antidepressant
Drugs. Its actions resemble those of phenytoin, although it appears to
be particularly effective in treating certain partial seizures.
• Carbamazepine is a powerful inducer of hepatic enzymes, and thus
accelerates the metabolism of many other drugs, such as phenytoin,
oral contraceptives, warfarin and corticosteroids, as well as of itself.
• Carbamazepine produces a variety of unwanted effects ranging from
drowsiness, dizziness and ataxia to more severe mental and motor
disturbances. It can also cause water and a variety of gastrointestinal
and cardiovascular side effects. The incidence and severity of these
effects is relatively low, however, compared with other drugs.
 Inhibition of Calcium Channels
• Drugs that are used to treat absence seizures (e.g.
ethosuximide and valproate) share the ability to block T-type
low-voltage-activated calcium channels.

• This leads to a decrease in burst firing of thalamocortical

neurons, which stabilizes the nerve activity in the brain and
prevents seizures.

• T-type channel activity is important in determining the

rhythmic discharge of thalamic neurons associated with
absence seizures.
 Sodium Valproate
Valproate is a simple monocarboxylic acid usually administered as the
sodium salt.

• It inhibits most kinds of experimentally induced convulsions and is

effective in many kinds of epilepsy, being particularly useful in certain
types of infantile epilepsy, where its low toxicity and lack of sedative
action are important, and in adolescents who exhibit both tonic–clonic
or myoclonic seizures as well as absence seizures, because valproate
(unlike most antiepileptic drugs) is effective against each.
• If possible, valproate should be avoided in pregnant women as it can
have a detrimental effect on cognitive abilities in children.

Valproate works by several mechanisms:

• Like ethosuximide, it can inhibit T-type calcium channels
• It inhibits sodium channels, but less so than phenytoin
• It inhibits GABA transaminase and has shown the ability to reduce
glutamate action.
NEWER ANTIEPILEPTIC DRUGS
Newer drugs with similar mechanisms of action to
older drugs or novel mechanisms of action may offer
advantages in terms of efficacy in drug-resistant
epilepsies, better pharmacokinetic profile, improved
tolerability, lower potential for interaction with other
drugs and fewer adverse effects.
Newer AEDs: mechanism of action
• Vigabatrin:
Irreversibly inhibits GABA transaminase, an enzyme that is
responsible for the inactivation/degradation GABA in astrocytes
and GABAergic nerve terminals.

• Tiagabine:
An inhibitor of the ‘neuronal’ GABA transporter GAT1 that is
expressed on GABAergic nerve terminals, and, to a lesser extent,
on neighboring astrocytes, thus inhibiting the removal of GABA
from the synapse. It elevates the extracellular GABA
concentration, thus prolonging GABA-mediated synaptic
responses in the brain.
• Topiramate:
Blocks voltage-dependent sodium channels at high
firing frequencies
Increases frequency at which GABA opens CI channels
(different site from benzodiazepines)
Antagonizes glutamate actions at receptor subtype
• Gabapentin:

Gabapentin, is designed as a simple analogue of GABA. However,

it does not act at GABA receptors.

By binding to P/Q-type calcium channels both gabapentin and

pregabalin (a related analogue) reduce the calcium entry into the
nerve terminals.

This leads to decreased Ca+ influx in presynaptic vesicles and

reduces the release of various neurotransmitters.

It is approved as adjunct therapy for focal seizures and treatment

of postherpetic neuralgia.
Many other newer antiepileptic drugs were developed, although
their mechanism of action at the cellular level is not fully
understood.
• Levetiracetam is believed to interfere with neurotransmitter
release by binding to synaptic vesicle protein 2A (SV2A),
which is involved in synaptic vesicle docking and fusion.

• Brivaracetam, a related antiepileptic agent, also binds to

SV2A with 10-fold higher affinity.

They bind to SV2A protein to prevent the release of glutamate

and other excitatory neurotransmitters from the presynaptic
neuron.
Antagonism at ionotropic excitatory amino acid receptors
has been a major focus in the search for new antiepileptic
drugs.

They would inhibit the activation of the excitatory receptors

such as AMPA by glutamate to prevent neuronal excitation.

Despite showing efficacy in animal models, by and large

however, they did not prove useful in the clinic, because
there were too many side effects, such as loss of motor
coordination.

However, perampanel, a non-competitive AMPA-receptor

antagonist, has been approved as an add on treatment for
partial seizures.
• Lamotrigine
Along with blocking the sodium channels, it may also
inhibit the release of the excitatory neurotransmitter,
glutamate.
It is a broad spectrum antiepileptic with significant
efficacy against absence seizures. It is commonly used
as an add-on therapy.

Pregnancy can significantly alter the pharmacokinetics

of lamotrigine. As pregnancy progresses, women can
require increased dosages to maintain blood
concentrations and seizure control.
• Felbamate
It occasionally causes severe reactions resulting in
aplastic anaemia or hepatitis. For this reason, its
recommended use is limited to intractable epilepsy
(e.g. in children with Lennox–Gastaut syndrome, a type
of epilepsy with multiple types of seizures) that is
unresponsive to other drugs.
Mechanisms of AEDs (anticonvulsants)
 Basic principles for initiating Antiepileptic
therapy

• Select a single AED

• Start the AED at a fraction of the initial target dose
(exceptions are phenytoin and phenobarbital).
• Inform patient of potential risks of treatment.
• Evaluate the patient after the initial target dose has been
achieved. Make a small dosage reduction if dose-related
adverse effects are problematic. Slowly increase the dose if
seizures have recurred.
• In general, seizures can be controlled with one medication in
approximately 75% of patients. Patients may require more
than one medication in order to optimize seizure control, and
some patients may never obtain total seizure control.
 Basic principles for initiating Antiepileptic
therapy

• Add a second AED if the maximum tolerated dose of the first

AED has failed to achieve satisfactory seizure control.
• Gradually withdraw the first AED after the maintenance dose
of the second drug has been achieved.
• Polytherapy is usually reserved for patients who have failed
monotherapy with 2-3 drugs. In some cases, patients may
have fewer side effects with relatively low doses of two
concomitant AEDs.
 Adverse Effects of AEDs and
Management
Dose-related effects
• Dizziness, sedation, fatigue, ataxia, cognitive and psychiatric
symptoms and nausea.
• Dose reduction
• Slow release instead of immediate release
Idiosyncratic reactions
• Skin rash (phenytoin, carbamazepine and lamotrigine)
Long-term effects
• increased risk of low bone density and fracture
• Vitamin-D supplement
 Common Side-effects
• drowsiness
• a lack of energy
• agitation
• headaches
• uncontrollable shaking (tremor)
• hair loss or unwanted hair growth
• swollen gums
 Uncommon side-effects

• rashes – GP or specialist should be contacted

immediately. It may occur due to serious
reaction to your medicine.
• symptoms similar to being drunk, such
as unsteadiness, poor concentration and
vomiting. This could mean drug dose is too
high.
 Important
Please go through the case studies in Lipincott
and Katzung's pharmacology books