Pharmacotherapy

of the epilepsies
• Dr.U.P.Rathnakar. MD. DIH. PGDHM
www.pharmacologyfordummies.blogspot.com
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 Pharmacotherapy of the epilepsies
• Seizure: Transient alteration of
behaviour Due to Disordered synchronous
rhythmic discharges of Brain neurons
• Epilepsy: Disorder of brain function
characterized by periodic, unpredictable
occurrence of seizures
• Seizures “ Non-epileptic”- Evoked in normal
brain by electroshock or chemical
convulsants
• Seizures “ Epileptic”- When occuring
without provocation*
 Importance
• 1% of the world's population has epilepsy
• Second most common neurologic disorder
after stroke
• Standard therapy permits control of
seizures in 80% of these patients,
• Millions (500,000 people in the USA
alone) have uncontrolled epilepsy

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 Epileptic seizures
• Partial seizures-begin focally in a cortical
site, [Simple or Complex]
• Generalized seizures- involve both
hemispheres widely from the outset.
• Behavioral manifestations of a seizure
• Determined by the functions of the cortical
site at which the seizure arises.
 Why Seizures?
Inhibition Excitation
Too little inhibition Excess of excitation
• Inhibitory • Excitatory NT
neurotransmitters • Glutamate
• GABA • Sodium or Ca Channels
• GABA receptors
• Chloride channels • EPSP
• IPSP

• Inactivate NA and CA
• Increase GABA activity channels
• Modulate receptors • Modulate Glutamate
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Inhibition and excitation
Mechanism of seizures
 What triggers a seizure?
1. Reduction of inhibitory synaptic activity
or
2. Enhancement of excitatory synaptic
activity
Two amino acids- inhibitory and
excitatory neurotransmitters,

1. γ-aminobutyric acid (GABA)

principal inhibitory
2. Glutamate being principal
excitatory
Studies showed-
Antagonists of the GABAA receptors
or
Agonists of glutamate receptors (NMDA, AMPA)

trigger seizures in experimental animals.

Pharmacological modulation of synaptic

function can affect the propensity for seizures.
Individual neurons undergo depolarization and fire
action potentials at HIGH FREQUENCIES.
This pattern of RAPID FIRING is characteristic of a
seizure but is uncommon during normal neuronal
activity

Selective inhibition of this rapid firing would

be expected to reduce seizures with minimal
unwanted effects.

How to achieve this?

 Selective inhibition of this rapid firing would be expected to reduce
seizures with minimal unwanted effects.

How to achieve this?

•Reducing the ability of Na+ channels to recover from
inactivation,
•Prolongs the refractory period
•Another action potential cannot be evoked.
Reducing the rate of recovery of Na+ channels from
inactivation would limit the ability of a neuron to fire at
high frequencies.

Eg. Carbamazepine, lamotrigine, phenytoin,

topiramate, valproic acid, and zonisamide
 Actions of Phenytoin on Na+ Channels

Na+

A. Resting State
B. Arrival of Action
Potential causes
depolarization and Na+
channel opens
allowing sodium to B. Active
flow in.
Na+
n nel
C. Refractory State, i n cha
ta s
Sus in thi tion C. Inactive
Inactivation f orma
con
Action of drugs on rapid firing

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 The principal postsynaptic receptor of
synaptically released
GABA is the GABAA receptor

Activation of the GABA-A receptor

inhibits the postsynaptic cell by increasing Cl– inflow into the cell and
hyperpolarizing the neuron
Benzodiazepines and Barbiturates
Enhance GABAA receptor–mediated hyperpolarization through actions on
the GABAA receptor -Effective anti-seizure action

At higher concentrations, also inhibit high-frequency firing

A second mechanism of enhancing GABA-mediated synaptic inhibition is

Inhibition of the GABA transporter GAT-1 - reduces uptake of GABA and
thereby increasing synaptic concn of GABA
 VG Na CH
Phenytoin
Carb.
Lamo.
Lacosamide

SV2A VG Ca CH
Levetiracetam Ethox
Lamo.
Valpro

K CH
Retigabine
AMPA Rec
NMDA Pheno
Felbamate Lamotrigine

Molecular targets for antiseizure drugs at the excitatory,

glutamatergic synapse.
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 GABA-transaminase
vigabatrin

GABA transporters
GAT-1,
Tiagabine);

GABAA
Benzodiazepines);

Molecular targets for antiseizure drugs at the inhibitory,

GABAergic synapse
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 Classification -

• Guides clinical assessment and management,

and selection of antiseizure drugs
• More than 40 distinct epileptic syndromes
• The partial epilepsies -60% of all epilepsies-lesion
in some part of the cortex (e.g., tumor,
developmental malformation, damage, trauma or
stroke), may also be genetic.
• The generalized epilepsies -40% of all epilepsies
and usually are genetic.
• Myoclonic, tonic-clonic, and often absence
seizures.
 Classification of Epileptic Seizures
I. Partial (focal) Seizures
A. Simple Partial Seizures
B. Complex Partial Seizures
C. SPS, CPS→Generalized

II. Generalized Seizures

A. Generalized Tonic-Clonic Seizures
B. Absence Seizures
C. Tonic Seizures
D. Atonic Seizures
E. Clonic Seizures
F. Myoclonic Seizures
G. Infantile Spasms
 Classification of epileptic seizures
Seizure type Features
 Partial
1. Simple partial Conciousness ++
[SPS] 20-60Sec.

Motor or sensory
2. Complex Conciousness impaired, 30-120
partial[CPS] Sec, Purposeless movements
3. Partial Loss of conciousness
secondarily SPS, CPS-evolves generalized
generalized-
1-2 Mts.
tonic-clonic
 Classification of epileptic seizures contd…..

Seizure type Features

Generalized

•Absence Abrupt loss of conciousness

[Petitmal] Staring, cessation of activities
30-60 sec
Myoclonic Brief[A Second], shock like
contraction of muscles
A part or general,
Tonic-clonic General tonic-clonic
Not preceded by partial
 Anti-epileptic drugs
Gapapentine & Pregabalin
1. Carbamazapine
Lamotrigine
2. Phenytoin Levetiracetam
3. Valproate Tiagabine

4. Phenobarbitone Topiramate

Zonisamide
5. Primidone
Felbamate
6. Ethosuximide Lacosamide

7. BENZODIAZEPINES Acetazolamide

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 Clinical classification of anti-seizure drugs
Seizure type Conventional New drugs

Simple 1. Carbamazapine Gapapentine

Partial Seizure 2. Phenytoin Lamotrigine

3. Valproate Levetiracetam

Tiagabine

Topiramate

Zonisamide

Complex Partial ‘ Same as above’ ‘Same as above’

Seizure

1. Partial…. Carbamazapine ‘Same as above’

generalized Phenobarbitone
Phenytoin
Primidone
Valproate
 Clinical classification of anti-seizure drugs
Seizure type Conventional New drugs
Absence  Ethosuximide Lamotrigine

 Valproate

Myoclonic  Valproate Lamotrigine

Topiramate

 Carbamazapine
Tonic-clonic  Phenobarbitone Lamotrigine

 Phenytoin Topiramate

 Primidone
 Valproate
 Clinical classification of anti-seizure drugs

Seizure Drugs Second choice

Febrile Diazepam rectal

Status Diazepam i.v. Fosphenytoin i.v.

epilepticus Lorazepam i.v. Pheno i.v.

Movie!
 MOA of antiseizure drugs
• Enhance Na or Ca channel inactivation
→ Reduce excitation→Reduce EPSP

Carbamazapine Lamotrigine Valproate

Phenytoin Valproate Ethosuximide
TopiramateZonisamide Trimethadione
 MOA of antiseizure drugs

• Enhance GABA transmission [Cl channells]

→ Promote inhibition → Promote IPSP
GABA
Vigabatrine ↓ GABA-T
Succinic semialdehyde
GABA ↓ Dehydrogenase
Valproate Metabolites
Tiagabine

GAT-1
GABA
BZD

Barbiturates

GABA
BINDING SITES
 Excitatory
Inhibition

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 Phenytoin[Diphenylhydantoin]

• Earlier drugs –sedatives with

antiseizure properties
• Phenytoin is not a sedative
• Prompted researchers look for
selective antiseizure drugs-not
gen.CNS depressants*
 Ph.Properties-Phenytoin
• Antiseizure activity without
gen.CNS dep.
• MOA:
 Slows rate of recovery of
inactivated Na channels- limits
the repetitive firing of action
potentials
Toxic concn.-Ca channels and Cl
channels. Toxic effect than Th.effect*
 Phenytoin-PK

• Highly protein bound-90%

• Non-linear elimination kinetics
• First order→upto 10 ug →Zero order
• Half life- 6h →60h
• Small adjustment in dosage →Plasma
concn.disproportanately↑
• Metabolism-CYP-saturable
• Other substrates inhibit Phenytoin metabo.
• Phenytoin may also inhibit others-Warfarin*
 Phenytoin-PK

• Enzyme inducer of →CYP3A4 → OCP

→Unplanned pregnancy.
Importance-Phenytoin is Terratogenic

• Low water solubility →Fosphenytoin

→Prodrug →i.v.use*
 Phenytoin-Toxicity
[Route of administration, the duration of exposure, and the dosage]

• Acute
• Fosphenytoin –i.v. cardiac arrhythmias,
with or without hypotension, and/or CNS
depression.[Elderly]
• i.v rate-150mg/mt
• Acute oral overdosage signs -cerebellum
and vestibular system;
• High doses -associated with cerebellar
atrophy.
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 Phenytoin-Toxicity
[Route of administration, the duration of exposure, and the dosage]
• Chronic treatment -dose-related
• Cerebellarvestibular effects, behavioral changes,
increased seizures
• Gastrointestinal (GI) symptoms, gingival
hyperplasia,
• Osteomalacia, and megaloblastic anemia.
• Hirsutism is an annoying untoward effect in young
females.
• Hypersensitivity, hematological reactions, SLE etc.
• Usually, can be diminished by proper adjustment of
dosage. www.manipal.edu
 Phenytoin-Toxicity
Gingival hyperplasia-20% on chronic
therapy
• Due to altered collagen metabolism
• Toothless portion not affected
• Good oral hygiene minimizes
Megaloblastic anemia-FA absorption &
excretion
Osteomalacia-↓Ca absorption,↓Response
of tissues to Vit D
Hyperglycemia- ↓Insulin
Gum Hyperplasia-Phenytoin toxicity
 Phenytoin-Toxicity Contd…

Terratogenicity-Hydantoin syndrome
Increased metabolism of Vit K- affects Ca
metabolism. Osteomalacia does not
respond to Vit D.

 TDM-Plasma concn:
 10μg →Good seizure control
 20 μg →Toxic affects appear*
 Drug Interactions-Phenytoin

• Pheno & Phenytoin: Both induce enzymes→

metabolism of each other →Result
unpredictable
• CBMZP & Phenytoin →Induce each others
metabolism
• Valproate →Displaces phenytoin → Also
decreases metabolism! →Phenytoin toxicity
• Chloromphenicol, Cimetidine etc. inhibit
Phenytoin metabolism
• Phenytoin inhibits Warfarin metabolism
• OCP and Phenytoin*
 Phenytoin-Uses
• SPS, CPS, Tonic-Clonic seizures
• Not in absence
• Status epilepticus
• Trigeminal neuralgia(DOC-CRBMZP)
• 100 mg bd-TDM
• Cardiac arrhythmia.
• *[MEPHENYTOIN, ETHOTOIN,]
 Choice of product
• Patients treated with the same drug from a
single manufacturer.
• Before switching products-care should be
taken to select a therapeutically equivalent
product
• Patients should be monitored for loss of
seizure control or onset of new toxicities.

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 Phenobarbitone
• Tonic-clonic, SPS, CPS
• MOA_ GABA
• Advantages-Low cost, low toxicity,
Effective
• Behavioral disturb. In children
• Sedation
• 60mg. 1-3 times a day
• No tolerance to antiepileptic[Unlike Diazepam]
 Primidone: Prodrug. Converted Pheno and
PhenylEthylMelanamine in liver[both active]. Uses same as Pheno. *
 Carbamazepine
• Iminostilben
• MOA:
Slows rate of recovery of inactivated Na
channels →Prevents repetitive firing of AP.
• Ph.effects:
Similar to phenytoin
Effective in MDP [Phenytoin is not-
MOA??]
Anti-diuretic effect*
 Carbamazepine-PK

• Absorbed slowly-erratically
• Metabolized in liver[CYP3A4]
• 10-11 epoxy product is active
• Enz. inducer-CYP2C, CYP3A,
UGT,→OCP *
 Carbamazepine-Toxicity
• Neuro: Drowisiness, Ataxia, Diplopia,
Blurred vision →Gradual increase in
dosage →Tolerance
• Hematological: Agranulocytosis, Aplastic
anemia, Leukopenia, Neutropenia.
• Hypersensitivity: Dermatitis,
Eosinophelia, Lymphadenopathy,
Splenomegaly
• Water retention*
 Carbamazepine-DI
• Enzyme inducer→OCP, Lamotrgine,
Haloperidol
• Pheno., Phenytoin →Increase
metabolism
• Enz. Inhibitors →Inhibit CRBMZP
metabolism*
 Carbamazepine-Uses

• CPS, GTC, SPS

• Neuralgias- Not an analgesic,
blocks afferent impulse.
• MDP
• 200-400mg TID. SR tablets*
 Oxycarbazepine
• Prodrug→10-monohydroxy
derivative
• Less of an enzyme inducer
• Less potent than Carbamazepine*
 Absence Seizures (Petite Mal)

• Brief and abrupt loss of

consciousness, vacant stare.
• Typical 2.5 – 3.5 Hz, 3/sec, high
voltage, spike-and-wave discharge.
 Generalized Absence Seizures

EEG: Bilaterally synchronous, high voltage 3-per-second spike-and-wave

discharge pattern.
 Scheme of Seizure Spread

Thalamocortial
relays are believed
to act on a
hyperexcitable
cortex

A low threshold Ca2+ current

Oscillatory responses in thalamic neurons
 Ethosuximide
• Reduces Ca flow in ‘T’ type Ca channels
• Reduces 3Hz spikes[EEG] from thalamus
neurones
• Effective in absence seizures only
[ No action on Na and GABA]
• ADE- GI, Behavioral effects[Anxiety,
inability to concentrate]
• 250-300mg./day. →Increase 25 every
week*
 Valproic acid
– Discovery-Serendipitously
• Carboxylic acid
• MOA-Multiple
Na channels
Ca channels
Increases synthesis, Decreases
degradation of GABA
 Valproic acid-toxicity

• GIT
• Alopecia
• Neurological:- Ataxia, blurred vision
• Fulminant hepatitis- Children below
2y, with other antiepileptics
• Fetus-Spina bifida, neural tube
defects*
 Valproic acid-DI & uses

• DI:
 Inhibits metabolism of Phenytoin & Pheno
 Inhibits UGT-Lamotrigine, Lorezepam
 Displaces & Inhibits metabolism of
Phenytoin
 Valproic + Clonezepam→’Absence’ status
• Uses-Broad spectrum
 15mg/kg →60mg.kg. *
 Valproic acid-DI
• 75% protein bound→Phenytoin

• Enzyme inhibitor of CYP[Phenytoin] & UGTs

[Lamotrigene] [It is metabolized by UGTs and
oxidation]

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 Valproic acid-Uses
• Absence, myoclonic, partial,and tonic-
clonic seizures.

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 Benzodiazepines
• Clonazepam →Absence & Myoclonic
• Diazepam & Lorazepam →Status
• Clobazam, Clorazepate + Other drugs → Partial
seizures
 Diazepam:
 Not used in long term[Sedation, tolerance]
 Control of convulsions[Epilepsy & others]
 0,2-0.5mg/kg slow i.v. →100mg/day
 ADE-Fall of BP, Resp.dep.,
 Rectally in children-Febrile
 Lorazepam: 0.1mg/kg-i.v.-Long duration of action*
 Other [new] Anti epileptics
Gabapentine-
Increses GABA release
Used in Partial seizures
Vigabatrine
Inhibits GABA transaminase
Used as adjuant
Tiagabine
Inhibits GABA Tpt-GAT 1
ADD on in Partial seizures*
 Lamotrigine

• Developed as anti-folate agent

• Anti-convulsant action-not related to
anti-folate
• MOA-Na channels
• Moa as broad spectrum not understood
Others: Levetiracetam, Topiramate,
Felbamate, Zonisamide, Acetazolamide*
 Principle of management

• Attend causative factor- Tumor

• Educate-Disease, Duration,
Toxicity, Compliance
• Avoid-Alcohol,Sleep deprivation,
stress
• Anticipate natural
variation-’Catamenial’
• Justify drug therapy*
 Guidelines to drug therapy
• Start with single, well tried safe drug
• According to type of seizure
• Age, sex-Hirsutism, terratogenicity,
hepatitis
• Single drug → Failure →SUBSTITUTE with
second[difft.MOA] →withdrawal of First
gradual
• Three drug hardly useful
• Dosage increased at particular time*
 Dosage and administration

• Once or twice daily

• Small dose → increased two weekly
→ To Minimum effective dose →
further increase depends on
occurrence of seizures

• TDM: Important for Phenytoin*

 Drug withdrawal
• Seizure free for 2 years
Factors decide recurrence:
• Type of epilepsy
• Early remission better outlook
• Single drug or multiple drug for remission
• Underlying lesion
• Associated neurological deficit
20% relapse early- 20% Relapse in 5 years
Withdrawn over 6 months
Recurrence→Another 2 years of tt. *
 Spl.Situations
• Status epilepticus:Lorazepam, Diazepam
→ Pheno 100-200mg, i.m/i.v.
→Fosphenytoin25/50mg/Mt i.v. infusion,
max.1000mg. → i.v.Midazolam, Propofol,
Thiopentone, Curarization, G.A
• Care of unconscious
 Febrile: Rectal diazepam during fever in
high risk children*
Pharmacotherapy of status epilepticus in adults
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 Spl. situations
1. Pregnancy:
• OCP failure
• Terratogenic
• Folate supplementation 0.4 mg/day
• Trial of drug free interval in women who
want to be pregnant
• Monotherapy if possible
• Vit K in last month
• Carbamazepine safest*
• 50% of seizures are eliminated by
medication,
• 30% of seizures are reduced in intensity
and frequency by medication,
• 20% of seizures are resistant to
medication.
SUMMARY: ANTISEIZURE DRUGS
[REF: KATZUNG, 11TH ED

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SUMMARY: ANTISEIZURE DRUGS
[REF: KATZUNG, 11TH ED

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SUMMARY: ANTISEIZURE DRUGS
[REF: KATZUNG, 11TH ED

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