Epilepsy is a disorder characterized by recurrent seizures that involve abnormal neuronal activity in the brain. It is caused by an imbalance between excitatory and inhibitory neurotransmitters like glutamate and GABA. Anti-seizure drugs work by enhancing GABA activity, blocking sodium and calcium channels, or modulating glutamate activity. Treatment depends on the type of seizures, which can be focal, generalized tonic-clonic, absence or myoclonic. Adverse effects include skin rashes, weight changes, fatigue and cognitive issues. Novel approaches include targeted drug delivery and electrical brain stimulation to prevent seizures.

1. Epilepsy
03/10/2018
Presented by Aaqib Naseer
M,pharm [1st semester]
Department Of Pharmacology, SPER , Jamia Hamdard
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2. Contents :
• Introduction
• Pathophysiology
• Clinical approach
• Drugs used
• Novel approach in treatment
• references
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3. Epilepsy (def.) :
 The term epilepsy refers to a disorder of brain function characterized by the periodic and unpredictable
occurrence of seizures.
 The term seizure refers to a transient alteration of behavior due to the disordered, synchronous, and
rhythmic firing of populations of brain neurons.
 Seizures arise from cortical, thalamocortical, limbic, or even brainstem circuits. The behavioral
manifestations of a seizure are determined by the functions normally served by the brain region at
which the seizure arises. For example, a seizure involving motor cortex is associated with clonic jerking
of the body part controlled by this region of cortex
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4.  Seizures involve the abnormal or rapid neuronal activity of the brain. (Abnormal
single occurrence at a time neuronal phenomenon)
 Epilepsy : is defined as two or more unprovoked seizures). (Disorder)
 Convulsions occur when a person's body shakes rapidly and uncontrollably. A
convulsion is a medical condition where body muscles contract and relax rapidly and
repeatedly, resulting in an uncontrolled shaking of the body. (Body phenomenon)
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Difference between Seizure ,Epilepsy & Convulsions :

5. Diagnosis :
Epilepsy can often be confirmed with an
electroencephalogram (EEG)
An EEG can aid in locating the focus of the epileptic
seizure
With the help of EEG it has been demonstrated
that the epilepsies
are disorders of neuronal excitability
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Epilepsy is reflected on EEG as a sharp wave or
spike. Normal EEG Epileptic EEG

6. Pathopysiology :
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• There Is imbalance between excitatory & inhibitory neurotransmitters in brain leading to abnormal
hypersynchronous hyperexcitibility of neurons . Transitory imbalances between the main neurotransmitters,
glutamate (excitatory) and γ-aminobutyric-acid (GABA) (inhibitory), and neuromodulators(e.g., acetylcholine,
norepinephrine, and serotonin) might play a role in precipitating seizures in susceptible patients.
• Other mechanisms that might contribute to synchronous hyperexcitability include :
(1) Alterations in the distribution , number, type and biophysical properties of ion channels in the neuronal
membranes
(2) Biochemical modifications of receptors
(3) Modulation of second messaging systems and gene expression
(4) Changes in extracellular ion concentrations
(5) Alterations in neurotransmitter uptake and metabolism in glial cells; and
(6) Modifications in the ratio and function of inhibitory circuits. In addition local neurotransmitter imbalances
could be a potential mechanism for focal epileptogenesis .

7.  Glutamate is the major excitatory neurotransmitter and GABA the
major inhibitory neurotransmitter. Potentiation of glutamate has
been shown to promote seizure activity, while the use of glutamate
antagonists reduces seizure activity.
 The major ionotropic glutamate receptors include AMPA, kainite
and NMDA receptors and all are permeable to Na+, K+ & Ca++
and it is this mechanism that is responsible for excitotoxicity
following excessive neuronal activation.
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8. Classification of epilepsies :
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• The nomenclature developed by the International League Against Epilepsy is
considered the standard way to classify seizures and epilepsy syndromes.
• Seizures have been classified into two broad groups: focal
and generalized.
A. Focal/Partial seizures :
Focal seizures involve only a portion of the brain, typically part of
one lobe of one hemisphere.
1. Simple partial : Here the electrical discharge
does not spread, and the patient does not lose consciousness or
awareness. The patient often exhibits abnormal activity of a single
limb or muscle group that is controlled by the region of the brain
experiencing the disturbance. The patient may also show sensory
distortions. This activity may spread.

9. 2. Complex partial: These seizures exhibit complex sensory
Hallucinations and mental distortion. Motor dysfunction may involve
chewing movements, diarrhea, and/or urination. Consciousness
is altered. Simple partial seizure activity may spread to become
complex and then spread to a secondarily generalized convulsion.
Complex partial seizures may occur at any age.
B. Generalized seizures :
Generalized seizures may begin locally and then progress to include
abnormal electrical discharges throughout both hemispheres of
the brain. Primary generalized seizures usually has an immediate loss of
consciousness.
1. Tonic–clonic: These seizures result in loss of consciousness,
followed by tonic (continuous contraction) and clonic (rapid contraction
and relaxation) phases. The seizure may be followed by a
period of confusion and exhaustion due to the depletion of glucose
and energy stores.
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10. 2. Absence: These seizures involve a brief, abrupt, and self-limiting
loss of consciousness. The onset generally occurs
in patients at 3 to 5 years of age and lasts until puberty or
beyond. The patient stares and exhibits rapid eye-blinking,
which lasts for 3 to 5 seconds.
3. Myoclonic: These seizures consist of short episodes of muscle
contractions that may recur for several minutes. They generally
occur after wakening and exhibit as brief jerks of the limbs.
Myoclonic seizures occur at any age but usually begin around
puberty or early adulthood.
4. Clonic: These seizures consist of short episodes of muscle
contractions that may closely resemble myoclonic seizures.
Consciousness is more impaired with clonic seizures as compared
to myoclonic.
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11. 5. Tonic: These seizures involve increased tone in the extension
muscles and are generally less than 60 seconds long.
6. Atonic: These seizures are also known as drop attacks and are
characterized by a sudden loss of muscle tone.
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12. Clinical approach:
The mechanisms of action of anti seizure drugs fall into three major categories. :-
1) One is to limit the sustained,repetitive firing of hyperexcited neurons, an effect mediated by
promoting the inactivated state of voltage-activated Na+ channels.
2) A second mechanism appears to involve enhanced γ-aminobutyric acid (GABA)–mediated synaptic
inhibition,an effect mediated either by a presynaptic or postsynaptic Action.
3) Drugs effective against absence seizure, a lesscommon form of epileptic seizure, limit activation of a
particular voltage-activated Ca2+ channel known as the T current.
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13. 13
Major Mechanisms of Anti convulsant action
(Image Copyright : Essentials of Medical Pharmacology by K.D Tripathi)

14. Mechanism of action :
Drug Mechanism
1) Phenytoin Prolong inactivated Na+ channels
2) Valproate GABA activity , Prolong inactivated NA+ channels, Block T Ca2+
channels
3) Lamotrigine Glutamate activity , Prolong inactivated NA+ channels
4) Gabapentin GABA activity
5) Ethosuximide Block T Ca2+ channels
6) Topiramate GABA activity Glutamate activity
7) Phenobarbitone GABA activity
8) Benzodiazepines GABA activity
9) Felbamate Glutamate activity
10) Zonisamide Prolong inactivated NA+ channels, Block T Ca2+ channels
11) Tiagabine GABA activity
12) Retigabine K+ channel opener
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15.  Under trial drugs :
 Retigabine is an activator of neuronal KCNQ (Kv7) potassium channels that underlie
the M current which controls membrane excitability.
 Lacosamide may enhance sodium channel inactivation, but unlike other antiepileptic
drugs it appears to affect slow rather than rapid inactivation processes.
 Ganaxolone, structurally resembling endogenous neurosteroids is a positive allosteric
modulator of GABAA receptors containing δ subunits .
 Tonabersat is a neuronal gap junction inhibitor.
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16. Type of Epilepsy & associated
treatment :
Conventional anti
seizure drug
• Carbamazepine,
• phenytoin,
• Valproate
Recently developed drugsPartial seizures
1) Simple partial
• Gabapentin,
• lamotrigine,
• levetiracetam,
• tiagabine,
• topiramate,
• zonisamide
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17. 17
2) Complex partial
Conventional drugs :
• Carbamazepine,
• phenytoin,
• valproate
Recent drugs :
• Gabapentin,
• lamotrigine,
• levetiracetam,
• tiagabine,
• topiramate,
• zonisamide

18. Absence seizure
Tonic seizure
• Ethosuximide ,
• Valproate
Valproate
Lamotrigine
• Lamotrigine,
• topiramate
Conventional
drugs
Recent drugsGenerlized
seizures 18

19. • Tonic-clonic seizure • Carbamazepine,
• phenobarbital,
• phenytoin,
• primidone,
• valproate
19• Lamotrigine,
• topiramate

20. Adverse effects :
Classical Drugs :
1. Phenytoin :
Hirsuitism,osteomalacia,teratogenicity,anaemia,atax
ia,arrhythmias
2. Carbamazepine : ataxia , vertigo,diplopia
3. Valproic acid : Pancreatitis , Hyperammonemia ,
neural tube defects in neonates
4. Ethosuximide & Trimethadione : photophobia
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21. 21
Newer Drugs :
1. Vigabatrin : visual defects due to retinal atrophy,dizziness,joint
Pain , cold
2. Lamotrigine : steven jhonson syndrome(severe skin reaction)
3. Gabapentin : neuralgia ataxia, dizziness, drowsiness, fatigue, fever,
nystagmus (dancing eyes), sedated state
4. Ganaxolone : Seizures during menstruation,
somnolence (sleepiness), dizziness, and fatigue
5. Topiramate : weight loss, tiredness,
drowsiness, dizziness, nervousness,
numbness ,coordination problems, diarrhea , weight loss.

22. Novel approach:
1) Targeted Drug Approach For Less sedative Effect :
Yang and colleagues used optical stimuli to rapidly convert an inactive prodrug already circulating in the
tissue back into an active form. They had previously used a caged gamma-aminobutyric acid (GABA) analog,
which is inactive in its parent form, but then releases active GABA when exposed to ultraviolet (UV) light.
2) Stopping Seizures With a Pacemaker for the Brain :
Just as a pacemaker controls heart rhythms, this implantable device for the brain detects abnormal activity and
corrects it . This innovative device is called a neurostimulator
VNS Therapy (also called vagus nerve stimulation) has been approved by the U.S. Food and Drug Administration
(FDA) as an add-on therapy for adults and children 4 years and older. It is approved to treat focal or partial
seizures that do not respond to seizure medications. This is called drug-resistant epilepsy or refractory
epilepsy. Vagus nerve stimulation prevents seizures by sending regular, mild pulses of electrical energy to the
brain via the vagus nerve.
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23. References :
 Goodman Gillman's The Pharmacological Basis of Pharmacotherapeutics 11th
edition/PHARMACOTHERAPY OF THE EPILEPSIES/ /chapter 19/James O McNamara/page501
 Pharmacotherapy A pathophysiologic approach 7th edition/Chapter 58/Epilepsy/SUSAN J.
ROGERS AND JOSE E. CAVAZOS//Joseph t dipiro , Robert l talbert , Gary v cee , Gary r
matzke ,Barbara G Wells ,L. Michael posey
 Review of Pharmacology by Sparsh Gupta & Gobind Rai Garg /chapter 8 – central nervous
system/ Page 277
 https://www.hopkinsmedicine.org/neurology_neurosurgery/centers_clinics/epilepsy/seizures/i
ndex.html
 https://www.aesnet.org/sites/default/files/file_attach/epcu-13-2-
95%20Basic%20Commentary%20Wong.pdf
 https://en.wikipedia.org/wiki/Epilepsy#Epilepsy
 https://stanfordhealthcare.org/stanford-health-now/2017/imagine/stopping-seizures-with-
brain-pacemaker.html
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24.  Lippincott’s illustrated reviews pharmacology 6th edition . Karen Whalen,
Richard Finkel, Thomas A. Panavelil, Drugs for Epilepsy Jeannine M.
Conway and Angela K. Birnbaum ,chapter 12 page 159
 RANG AND DALE’S Pharmacology 7th edition . H P M M Dale ,J M Ritter
, R J G Henderson . Section 4 , chapter 44 , Antiepileptic Drugs page
540
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