Antiepileptic Drugs

Dr. M.T.Madhushika
Lecturer
Department of Pharmacology
Faculty of Medicine
"This teaching material has been developed for Medical Undergraduates of Faculty of Medicine,
University of Ruhuna, Sri Lanka to be used as online teaching material in the Learning Management
System of the University during the COVID-19 pandemic.”
2021.06.01 1
 Objectives
• At the end of the lecture students will be able to
 Recall the pathophysiology of different types of epilepsy
 Classify antiepileptic drugs according to their mode of action with
examples
 Describe pharmacodynamics of antiepileptic drugs
 Classify the antiepileptic drugs according to clinical use with
examples
 Describe the pharmacokinetics of antiepileptic drugs
 List the clinical uses of the above drugs
 State the important adverse effects and precautions of commonly
used antiepileptic drugs
 Describe the pharmacological management of status epilepticus
2021.06.01 2
 Pathophysiology of Epilepsy

• Seizure – A clinical symptom or sign caused

by abnormal electrical activity in the brain

• Epilepsy – The clinical syndrome of

recurrent seizures – implies a pathological
state that predisposes to further future
seizures

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 Causes of epilepsy
 Genetic – e.g. - sodium channel
mutations
 Early developmental – cerebral palsy

Acquired –
 Alcohol
 Stroke
 Traumatic head injury
 Brain tumors
 Infection
2021.06.01 4
 Pathophysiology of Epilepsy

• Seizures are caused by paroxysmal

discharges from groups of neurons in
the brain, which arise as a result of
excessive excitation or loss of
inhibition.
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 Types of seizures

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Focal seizures can propagate very quickly to become a secondary6
2021.06.01 7
Antiepileptic drugs – Mechanism of action

Inhibit
epileptogenic Without interfering
significantly with
neuronal physiological neural
discharges & their activity
propagation

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Antiepileptic drugs – Mechanisms of
action

1. Decrease electrical excitability

2. Decrease synaptic vesicle release

3. Enhancement of gamma- aminobutyric acid

(GABA) transmission

4. Inhibition of excitatory neurotransmitters

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 1. Decrease electrical excitability
1)-Inhibit voltage dependent sodium channels
-reduce cell membrane permeability to ions
• Phenytoin, Carbamazepine, Lamotrigine,
Lacosamide

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Carbamazepine
MOA –
• Block voltage dependent sodium channel
• Reduce membrane excitability

• Pharmacokinetics -
• Metabolized to an epoxide (which also has
antiepileptic activity)

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 Carbamazepine - Pharmacokinetics
 Induce hepatic enzymes-Reduce effective plasma
level of other drugs, metabolized by liver
• Eg – glucocorticoids, contraceptive pill,
theophylline, warfarin, phenytoin
• Autoinduction  t1/2 falls from 35h to 20h over
the first few weeks of therapy
• Metabolism -inhibited by valproate
• Dose -100-200 mg tablets are available
- 15-25 mg/kg bd or qid doses
- Can go up to 1200 mg/day

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Carbamazepine - Uses
 Focal seizures (with/ without secondary
generalization)
 Primary generalized tonic-clonic seizures
Not recommended for myoclonic epilepsy,
absence seizures which can be worsened
 Trigeminal neuralgia (1st line)
 Prophylaxis of bipolar
Disorder (unresponsive to Li)

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 Carbamazepine – Adverse Effects
• Depress electrical excitability  Cerebellar &
brainstem dysfunction
-Eg: Dizziness, diplopia, ataxia, nausea, reversible
blurring of vision, drowsiness
• Depression of cardiac AV node conduction
• Hepatic induction  enhanced metabolism of
folic acid  folic acid deficiency
vitamin D  osteomalacia
• Rash, Stevens Johnson syndrome
• GI symptoms, headache, blood disorders (e.g. –
leucopenia), SIADH, liver & thyroid dysfunction
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Oxcarbazepine
• Analogue to carbamazepine
• t 1/2 of the drug is 2 h(metabolite- t ½ -11 h)
• No epoxide –Lower frequency of unwanted effects
• Uses – Monotherapy/ add-on therapy for focal seizures

Eslicarbazepine
• Similar to carbamazepine
• Hydroxyl derivative of oxcarbazepine
• Uses - Focal epilepsy with/ without secondary
generalization

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Phenytoin
MOA –
• Block voltage-dependent sodium channels
• Membrane stabilization
• Discourage the spread of seizure discharges

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 Phenytoin - Pharmacokinetics
• Oral phenytoin – well absorbed
• Achieve therapeutic range concentrations within 24hrs
• A potent inducer of hepatic enzymes - (that
metabolise drugs – carbamazepine, warfarin, vitamin D,
folate, phenytoin itself)
• Drugs that inhibit phenytoin metabolism – sodium
valproate, isoniazid, certain NSAIDS
• Hydroxylated extensively in the liver
• 1st order kinetics  zero order kinetics
• Dose increments of equal size - disproportional rise in
steady-state plasma concentration
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 Phenytoin - Uses
 Emergency control of seizures, status epilepticus
 To prevent focal seizures with/ without secondary
generalization
• Generally not used first line -due to adverse effects
profile (& narrow therapeutic range) – not favoured for
long term therapy
 May worsen primary generalized seizures -absence,
myoclonic
 Other –trigeminal neuralgia, myotonic dystrophy,
Cardiac arrhythmia 2021.06.01 20
Phenytoin – Adverse Effects
• Narrow therapeutic range
 CNS – Cognitive impairment, cerebellar ataxia,
dyskinesias, tremor, peripheral neuropathy
 Cutaneous - Rashes, coarsening of facial features,
hirsutism, lupus like syndrome, gum hyperplasia,
Dupuytren’s contracture
 Haematological – Macrocytic anemia,
IgA hypergammaglobulinaemia, lymphadenopathy,
pseudolymphoma
 Osteomalacia
 IV Phenytoin – Cardiac depression, distal ischaemia
(purple glove syndrome), drug extravasation  severe
local ulceration
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Phenytoin – Adverse Effects
• Overdose  cerebellar symptoms & signs, coma,
apnoea, seizures

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Fosphenytoin
• A prodrug of phenytoin
• Easier & safer to administer
• Conversion to phenytoin in the blood is
rapid

• Uses –alternative to phenytoin in status

epilepticus

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 Lamotrigine
MOA –
 Stabilize presynaptic neuronal membranes by blocking
voltage dependent sodium & calcium channels
 Reduce the release of excitatory neurotransmitters
(glutamate, aspartate)
• PK – t 1/2 – 24 h . No IV forms
Uses –
 A favoured 1st line drug for focal & generalized epilepsy-
Effective, well tolerated
 Bipolar disorder – mood stabilizer
 Doses – 50mg/ 100 mg/ 200mg
 Usual maintenance dose – 2021.06.01
500mg/day 24
Lamotrigine – Adverse Effects
Few cognitive or sedating effects relative to other
AED
 Insomnia,Headache
 Rash, rarely, Stevens-Johnson syndrome, Toxic
Epidermal Necrolysis – start with a low dose
and increase slowly
 Carbamazepine, phenytoin and barbiturates
accelerate the metabolic breakdown of
lamotrigine
 Valproate inhibits- breakdown of lamotrigine
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 Lacosamide
• MOA – Selectively facilitates a ‘slow-inactivating’
component of the voltage-gated sodium channel
• Targets a neuronal protein called ‘collapsin-response
mediator protein 2’ [CRMP2]-involved in neuronal
differentiation, axonal outgrowth and gene expression
• Oral/IV/Syrup
• Uses - refractory focal epilepsy
• Adverse effects –
• Common antiepileptic unwanted effects such as sedation
or cognitive impairment are less
• dizziness, nausea, headache and prolongation of the PR
interval on the ECG 2021.06.01 26
Lacosamide

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 1. Decrease electrical excitability

2) Potassium channel opener - Retigabine

• Retigabine- enhancement of voltage-gated

K+ currents
• hyperpolarizes the neuronal resting
membrane potential
• leading to an inhibition of spontaneous or
synoptically-triggered neuronal activity

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 2. Decrease synaptic vesicle release
A) Calcium channel blockers
Gabapentin, Pregabalin, Ethosuximide
 Calcium channel activation is required for synaptic
vesicle release
 CCB  Reduce calcium entry into nerve terminals
 Reduce release of neurotransmitters 
Decrease synaptic transmission
 Especially during periods of high burst activity
 Calcium channel blockade may also reduce excitoxicity – a
pathological process by which repetitive neuronal
depolarization leads to calcium entry into neurons, with
resultant cell death
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Gabapentin
 MOA – Analogue of GABA
Main action – Inhibit voltage gated calcium channels
(Interaction with α2γ subunit)
Facilitate GABAergic transmission
PK – Sufficiently lipid soluble to cross the BBB
• Excreted unchanged, do not affect hepatic metabolism
Uses – Focal seizures, secondary generalized epilepsy
• Neuropathic pain, anxiety- Doses 300- 1800 mg
Adverse effects – Somnolence, unsteadiness, dizziness,
fatigue
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Pregabalin
MOA - Act similarly to gabapentin

Use –
• In place of gabapentin when it has been
ineffective for refractory focal seizures
• Neuropathic pain
• Anxiolytic properties
• Doses- 75mg-600mg

AE – Confusion, dizziness, weight gain

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Ethosuximide
• MOA – Blocks low voltage gated T-type
calcium channels
• T type - active in primary generalized epilepsies

• Main use – Absence seizures / Myoclonic seizure

in children
• Doses -250mg- 1.5g

• Adverse effects – gastric upset, CNS effects,

allergic reactions – eosinophilia, lupus
erythematous
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 2. Decrease synaptic vesicle release

B) Inhibit Synaptic vesicle protein 2A (SV2A)

• Reduce synaptic vesicle recycling
• Levetiracetam

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Levetiracetam
MOA – Inhibit synaptic vesicle protein 2A (SV2A)
• Reduce synaptic vesicle recycling
• High therapeutic index

Uses – Focal & generalized seizures – became popular as

1st line
• Relatively well tolerated- no drug interavtions
• Doses -250 mg-1000 mg
• Oral-tab, liquid /IV
• Adverse effects- weakness, dizziness and drowsiness
• Relatively specific - emotional liability, behavioral
disturbance and psychosis
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3. Enhancement of GABA transmission
• Benzodiazepines, Phenobarbital, Sodium
valproate, Vigabatrin, Tiagabine

GABA – principal inhibitory neurotransmitter -CNS

• Enhance GABA transmission (GABAA receptor)

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Sodium Valproate
MOA –
 Enhance GABA transmission-
Inhibiting GABA transaminase increasing GABA
levels hence neuronal inhibition
 Inhibit Sodium channels
 Inhibit T-type calcium channels
PK-
• Metabolized extensively in the liver
• Non specific metabolic inhibitor
• Inhibit its own metabolism, Lamotrigine, phenytoin,
carbamazepine 2021.06.01 36
Sodium Valproate - Pharmacokinetics

Sodium Valproate – Uses

• Generalized & focal seizures
• Including absence seizures, myoclonic
epilepsy
• Migraine prevention
• Mania – mood stabilizer

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Sodium Valproate – Adverse Effects
• Weight gain, impaired glucose tolerance
• Polycystic ovarian syndrome
• Teratogenicity
• Loss of hair
• Nausea, dyspepsia  enteric coated formulation
• Rise in liver enzymes, rarely – liver failure 
monitor LFT
• Pancreatitis
• Coagulation disorder, thrombocytopenia,
inhibition of platelet aggregation
• Hyperammonaemia  acute confusion
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 Barbiturates – Phenobarbital
E.g. - Phenobarbital, Primidone (prodrug)
MOA – Increased activation of GABAA receptors by binding to
GABA-A receptor and facilitating cl- channel opening
PK – Enzyme induction (doses 15mg-120mg)
Uses – Status epilepticus
Adjunct for long term control of refractory focal seizures

Adverse effects
High – sedation
• Overdose  Cardiac, respiratory arrest
• Dependency/ addiction
• Interactions (enzyme induction
2021.06.01 ) 39
Benzodiazepines

 Diazepam
 Midazolam
 Lorazepam
 Clonazepam
 Clobazam

• MOA – Increased activation of GABAA receptors

• Facilitate GABA mediated opening of Cl-
channels  Reduce cell excitability
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Benzodiazepines cont.
Lorazepam, Diazepam, Midazolam –
• Uses – 1st line – rapid control of acute seizures
• Overdose  Respiratory depression, hypotension,
sedation
• Not recommended for long term prophylaxis – due
to AE
• Adverse effects – sedation, tolerance, addiction

Clonazepam – Adjunct in myoclonic epilepsy –

muscle relaxant/Status Epilepticus
Clobazam – establishing rapid seizure control, Drug
resistant focal seizures
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Vigabatrin
MOA - Structurally related to GABA
• Irreversibly inhibit GABA-transaminase  Increase
GABA level
PK – Not metabolized, Does not induce hepatic enzymes
Uses - Only for refractory epilepsy - Focal & secondarily
generalized seizures, infantile spasms- monotherapy
•Worsens for absence & myoclonic seizures
Adverse effects – Visual field constriction – 40% 
insidious irreversible ,tunnel vision
•Patients need 6 monthly visual field monitoring
•Confusion, psychosis, weight gain
•Doses 250 mg-3000mg/day 2021.06.01 42
 Tiagabine
MOA –
• Inhibit GABA uptake by GAT1 transporter from
the synapse
• Increase level of GABA in the synapse

Uses – Focal seizures

Anxiety disorders
• Doses 4—8mg

AE– Sedation, dizziness, lightheadedness

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2021.06.01 44
4. Inhibition of excitatory neurotransmitters

• Topiramate, Felbamate, perampanel

• Glutamate inhibition
• Block glutamate receptors (AMPA, NMDA)
• Stop neuronal excitation – in the short term
• Stop excitotoxicity & cell death in the long
term

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Topiramate
MOA -
• Block glutamate receptors – AMPA receptors
• Block voltage gated sodium channels, calcium channels
• Enhance GABA activity
• Weakly inhibit carbonic anhydrase  reduce central
nervous excitability

PK – t1/2 – 21 h  once daily dosing

• Excreted in urine – unchanged drug
• Doses 25mg-200mg
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Topiramate
Uses –
• Focal seizures
• Generalized tonic clonic seizures
• Migraine prevention

Adverse effects –
• Weight loss
• Cognitive impairment
• Acute myopia, Raised intraocular pressure
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Felbamate
MOA – NMDA receptor blocker  Inhibit
glutamate

Uses – For severe epilepsy (refractory

focal seizures)

Adverse effects – Aplastic anemia, liver

damage

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 Zonisamide
• Zonisamide is a sulphonamide analogue - acts as a
carbonic anhydrase inhibitor
• It also blocks both sodium and T-type calcium
channels
• Its sodium channel– blocking effect increases latency
for neuronal recovery following inactivation
AE
• Cognitive impairment
Uses
• An adjunct for refractory partial epilepsy
• Migraine 2021.06.01 49
Site of actions of AED

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 Antiepileptic Drugs - Classification
Classical Newer
Phenytoin Lamotrigine
Phenobarbital Felbamate
Carbamazepine Topiramate
Valproate (Valproic Acid) Gabapentin
Ethosuximide Tiagabine
Benzodiazepines Vigabatrin
Primidone Oxycarbazepine
Levetiracetam
Fosphenytoin
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Magnesium Sulphate
• Drug of choice in eclampsia
• Prevention of seizures in pre-eclampsia
• Produces anticonvulsant effects by

• Decreasing amount of acetylcholine released

at end-plate by motor nerve impulse
• 4g IV –loading dose+ 1g/hour IV Infusion

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 Summary of AED
Epilepsy type 1st line AED 2nd line AED
Generalized Epilepsy
Generalized tonic Sodium valproate Carbamazepine
clonic Lamotrigine Oxcarbazepine
Levetiracetam Phenytoin
Topiramate Phenobarbital
Clobazam
Clonazepam
Myoclonic Sodium valproate Clobazam
Levetiracetam Lamotrigine
Topiramate
Clonazepam
Absence Ethosuximide Clonazepam
Sodium valproate Clobazam
Lamotrigine
Tonic, atonic Sodium valproate Lamotrigine
Clonazepam
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Summary of AED
Epilepsy type 1st line AED 2nd line AED

Focal Epilepsy

Focal Carbamazepine Clobazam

With or without Oxcarbazepine Phenytoin
secondary Sodium valproate Topiramate
generalization Levetiracetam Gabapentin
Lamotrigine Pregabalin
Zonisamide
Lacosamide
Tiagabine

2021.06.01 54
Management of Status Epilepticus
Status Epilepticus
• Continuous or rapid sequential seizure activity
for 30 minutes or more
• A medical emergency

"This teaching material has been developed for Medical Undergraduates of Faculty of Medicine,
University of Ruhuna, Sri Lanka to be used as online teaching material in the Learning Management
System of the University during the COVID-19 pandemic.”
2021.06.01 55
Pharmacological management of Status
Epilepticus (SE)

• Airway, O2, IV fluids, CBS

↓
• IV Lorazepam/ IV Diazepam/ IV Clonazepam
↓
• IV Phenytoin/ IV Phenobarbital
↓
• IV Thiopental/ Propofol/ Midazolam + Intensive
care
2021.06.01 56
Treatment of SE

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Antiepileptic drug therapy – Principles
1) When to initiate AED?
• After 2 or more distinct seizure episodes
( with more than a few weeks apart between
the episodes)
• Anticonvulsants are not generally prescribed
following a single seizure
(or even a single cluster of seizures - over a
few days)
• Exceptions+

2021.06.01 58
2) 1st line therapy
 Monotherapy – single drug
 Generally restricted to one of only a few drugs
that have a good track record & relatively safe &
well tolerated
 Majority – 70% of seizure patients – can remain
on monotherapy for adequate control

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3) Choice of drug
 In certain cases the spectrum of seizure efficacy is
limited
 Certain seizure types can be worsened by ill-
chosen drugs
o carbamazepine is an effective first-line therapy
for partial seizures -worsen primary generalised,
absence or myoclonic seizures
o More modern anticonvulsants are in general
effective over a much broader range of seizure
types
o Eg – sodium valproate, lamotrigine, levetiracetam
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4) How is AED therapy initiated?
 Started at their lowest dose
 Small increments made every 1–2 weeks
 The lowest dose within the generally
recognized maintenance dose range that
achieves a reasonable degree of seizure
control should be established
5) Maintenance
 Keep to a particular proprietary brand
 Different brands of the same generic agent
may exhibit varying pharmacokinetics
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6) How are monotherapy drugs changed?
 Recheck diagnosis
 Monotherapy with a second drug
 The change to the 2nd drug should be cautious
 Slowly withdraw the first drug only when the
new regimen has been established
7) Decision for polytherapy
 If a trial of 3 or so consecutive AED does not
control a patient’s epilepsy can consider dual
therapy
 Usually drugs with different mechanisms of
action are combined
2021.06.01 62
8) Can drugs be withdrawn suddenly?
 Effective therapy must never be stopped
suddenly
- a well-recognized trigger for SE

 If rapid withdrawal is required (toxicity e.g.

due to a severe rash, significant liver
dysfunction)  a new drug ought to be
started simultaneously

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9) How are antiepileptic drugs withdrawn?
• If patients have remained seizure-free for more
than a few years (2-3 years), it is reasonable to
consider withdrawal of antiepileptic drug
therapy
• Withdraw the antiepileptic drug over a period
of 6 months
• If a seizure occurs during this time, full therapy
must recommence until the patient has been
free from seizures for several years
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 Epilepsy & Pregnancy
• High risk of teratogenicity – sodium valproate,
phenytoin, phenobarbital
• Folic acid 5 mg per day should be given for several
months in advance

• Safer antiepileptics - Lamotrigine

Levetiracetam
Ethosuximide
Carbamazepine
Oxcarbazepine

2021.06.01 65
Epilepsy & breastfeeding

• Antiepileptic drugs pass into breast milk

• Phenobarbital, primidone, ethosuximide
– in significant quantities
• Pheytoin, sodium valproate – less
• Risk - sedation, poor suckling
• Benefit vs risk

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Antiepileptic drugs & OCP

 Enzyme inducing AED can cause

contraceptive failure (Carbamazepine,
Oxcarbazepine, Pheytoin, Barbiturates,
Topiramate) 
 Alternative / Use OCP with oestrogen
content above 50µg + ‘tri-cycling’

2021.06.01 67
 References
• Clinical pharmacology- Bennett and Brown
• Pharmacology- Rang & Dale’s

"This teaching material has been developed for Medical Undergraduates of

Faculty of Medicine, University of Ruhuna, Sri Lanka to be used as online
teaching material in the Learning Management System of the University
during the COVID-19 pandemic.”2021.06.01 68