EPILEPSY- By VINAY KUMAR. KUTAGULLA

1. Epilepsy
Presented as a part of M.Pharmacy 1st sem curriculum
By
Vinay kumar kutagulla
submitted to
Mr. A. Sudheer, M.pharm.,(Ph.D)
Associate Professor
Department of Pharmacology
Raghavendra Institute of Pharmaceutical Education and Research
(RIPER)- Autonomous,
Ananthapuramu , Andhra Pradesh -515721 1

2. HISTORICAL BACKGROUND
Epilepsy derived from a Greek term: Epilambanei -to posses, to take hold of,
to grab or to seize.
Vedic period of 4500-1500BC : Ancient Indian Medicine refined and
developed the basic concept of epilepsy
Charaka Samhita- The Ayurvedic literature 400 BC: Describe epilepsy as
‘Apasmara’means loss of consciousness.
Hippocrates 400 BC: ‘This is not a sacred disease rather disorder of brain’ .
He described some physical treatment of epilepsy and stated it is an incurable
chronic illness.
Ibn Sina 370 AH: Describe epilepsy as a brain disease.
2

3. Europe and USA 1857: Bromide was used as first anti-epileptic drugs.
1873 H. Jackson: Neurologist of Londondescribed relationship of
electrochemical discharge of brain and seizure.
1920 H. Berger: German Psychiatrist developed EEG to measure brainwaves
and its application in the field of epilepsy.
3

4. EPILEPSY
Epilepsy is 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.
Can cause
◦ Loss of consciousness
◦ Abnormal movements
◦ Atypical or odd behavior
◦ Distorted perceptions
4

5. EPILEPSY
The site of origin of the abnormal neuronal firing determines the symptoms that
are produced
 If the motor cortex is involved, the patient may experience abnormal
movements or a generalized convulsion
 Seizures originating in the parietal or occipital lobe may include visual,
auditory, and olfactory hallucinations
5

6. CONVULSIONS
 Involuntary violent spasm of large muscles of face, neck, arms, and legs
 Not synonymous with seizure
 In most cases epilepsy has no identifiable cause(Idiopathic epilepsy)
 Symptomatic epilepsy (secondary to another cause)
 Activity in focal areas that are functionally
 abnormal may be triggered by:
o Changes in physiologic factors such as blood gases, pH, electrolytes, and
blood glucose
o Changes in environmental factors such as sleep deprivation alcohol intake
and stress
6

7. Idiopathic epilepsy (primary)
 When no specific anatomic cause for the seizure, such as trauma or neoplasm,
is present
 Can result from inherited abnormality in the CNS.
Patients are treated chronically with anti-seizure drugs or vagal nerve
stimulation.
7

8. Symptomatic epilepsy
 Can be caused by illicit drug use, tumor, head injury, hypoglycemia,
meningeal infection, and the rapid withdrawal of alcohol in alcoholics.
 When two or more seizures occur, the patient may be diagnosed with
symptomatic (secondary) epilepsy.
 The primary cause of the seizure should be corrected if possible
8

9. TYPES OF SEIZURES
Types Description
1.Partial Seizures
(seizures begin locally)
A. Simple (without impairment of
consciousness)
1. with motor symptoms.
2. with special sensory or soma to
sensory symptoms.
3. with psychic symptoms
B. Complex (with impairment of
consciousness)
1. Simple partial onset followed by
impairment of consciousness with
or without automatisms.
2. Impaired consciousness at onset
– with or without automatisms.
C. Secondarily Generalized (partial
onset evolving to generalized tonic
clonic seizures)
II. Generalized seizures
(bilaterally symmetrical
and without local onset)
III. Unclassified Seizures
IV. Status epileptics 9

10. PARTIAL SEIZURES
 Involve only a portion of the brain, typically part of one lobe of one
hemisphere.
 Symptoms depend on the site of neuronal discharge and on the extent to
which the electrical activity spreads to other neurons.
 May occur at any age.
 Consciousness is usually preserved.
 Partial seizures may progress to become generalized tonic-clonic seizures
Include.
1. Simple partial seizures
2. Complex partial seizures
10

11. PARTIAL SEIZURES
1.Simple partial seizures:
 Caused by a group of hyperactive neurons confined to a single locus in the
brain.
 The patient does not lose consciousness.
 Abnormal activity of a single limb or muscle group controlled by the region
of the brain experiencing the disturbance.
 The patient may also show sensory distortions.
 May occur at any age.
11

12. PARTIAL SEIZURES
2. Complex partial seizures:
 Complex sensory hallucinations and mental distortion.
 Motor dysfunction may involve chewing movements, diarrhea, and/or
urination.
 Consciousness is altered.
12

13. GENERALIZED SEIZURES
 Include abnormal electrical discharges throughout both brain hemispheres
 May be convulsive or nonconvulsive Patient usually has an immediate loss
of consciousness
1. Tonic-clonic seizures
2. Absence seizures
3. Myoclonic seizures
4. Febrile seizures
5. Status epilepticus
13

14. GENERALIZED SEIZURES
1. Tonic-clonic seizures:
Result in loss of consciousness, followed by tonic and clonic phases
May be followed by a period of confusion and
exhaustion due to the depletion of glucose and energy
2. Absence seizures:
Involve a brief, abrupt, and self-limiting loss of consciousness
Onset: 3-5 years of age and lasts until puberty or beyond
The patient stares and exhibits rapid eye-blinking for 3-5 seconds
14

15. GENERALIZED SEIZURES
3. Myoclonic seizures:
 Short episodes of muscle contractions that may recur for several minutes
 Occur at any age but usually begin around puberty or early adulthood
4. Febrile seizures:
 Young children may develop seizures with illness accompanied by high fever
 Consist of generalized tonic-clonic convulsions and do not necessarily lead to
a diagnosis of epilepsy
5. Status epilepticus:
 Life-threatening and requires emergency treatment
Two or more seizures occur without recovery of full consciousness between them
15

16. PATHOPHYSIOLOGY OF EPILEPSY
 In normal brain inhibitory circuits limits synchronous discharge. GABA
is particularly play this role.
 When GABA receptors blocked Rhythmic and repetitive
hypersynchronus discharge of neurons seizures
 Excitatory NT Ach , Aspartate and Glutamate also involved to develop
seizures
 Intracellular recording shows burst of rapid action potential firing with
reduction of transmembrane potential.
 inhibitory system + excitation genesis of seizures
 Abnormalities in Ion Channel (Na+, K+, Ca-) may cause seizures.
(Prolongation of depolarization state)
16

17.  Repeated subthreshhold of a neuron
generates an action potentials seizures
 It has been suggested that chronic epileptic
discharges may lead to secondary epileptogenesis.
 Short, uncomplicated seizures cause no permanent/
progressive neorological dysfunctions in human brain
 BUT uncontrolled generalized tonic-clonic seizures
or status epilepticus is associated with high
neurological morbidity and permanent brain damage
( due to hypo perfusion, hypoxia, acidosis and other metabolic disturbance). 17

18. CAUSES OF EPILEPSY
In 28% cases cause can be determined. Rests (72%) are Idiopathic.
Determined causes:
Inherited genetic
Acquired : trauma, Neuro surgery, Inflammatory, Metabolic,
Infections, Tumor, Toxic disorders, drugs, etc.
Congenital: inborn error of metabolism.
Withdrawal of drugs Alcohol, Benzodiazepine,
Barbiturates, Other Anti- Epileptics
18

19. DRUG THAT INDUCE SEIZURES
Antibiotics: Penicillin, INH, Cycloserin, Ciprofloxacin, Metronidazole.
Anti Diabetic: Insulin ,Phenformin.
Hormonal: Prednisolone, OCP, Oxytocin
Cardiac: Lidocaine, Procaine, Disopiramide
Anesthetics: Methohexital, Ketamin, Halothane,Propofol
Antimalarial: Chroloquine, Mefloquine, Proguanil.
Anti Spastic: Baclofen
Stimulant: Aminophylline, Doxapram, Theophyline.
Radiographic contrast: Meglumine derivatives, Metrizamide.
19

20. Antidepressant: TCA- (Amitriptaline, Imipramine, Clomipramine), Dosulepin,
Buproprion. Venlafaxine, Duloxitine,Reboxetine
Antipsychotics: Chlorpromazine, Zotepine, Loxapine,Depot Anti
psychotics,Clozapine
Mood Stabilizer: Lithium
Psycho stimulant: Amphetamine
Safe Psychiatric medication in Epilepsy
Antidepressant: Moclobemide, SSRI (with cautious)
Antipsychotics: Haloperidol, Trifluphenazine, Sulpiride
20

21. DIAGNOSIS OF EPILEPSY
 Thorough History taking :
From patients
From reliable valid informants
From observer (who observed seizures)
 Physical Examination:
Specially neurological system
Higher Psychic function
 Laboratory Investigation:
S. Electrolytes, S. Prolactin, Blood sugar, CBC, TFT,
LFT, RFT, CSF study
 Imaging:
EEG, Video EEG telemetry, CT Scan of Brain, MRI of
Brain, MRS, PET, SPECT.
 Polysomnography 21

22. DIFFERNTIAL DIAGONIS
Condition mimicking Seizures:
• Pseudoseizure
• Syncope
• Some sleep disorders
• Hypoperfusion in brain
• Cardiac Arrhythmia
• Emotional Outburst
• Dissociative fugue
• Drop Attacks
• Migraine
• Hypoglycaemia
22

23. MANAGEMENT OF EPILEPSY
 Medical treatment:
 Immediate care of seizures
 Move persons away from danger
 Recovery position (semi prone)
 Ensure clear airway
 Do not insert anything into mouth Urgent medical attention- (patent airway, O2 ,
anticonvulsant, investigate cause)
 Should not be left alone after recovery
 Consider about regular AED
 Surgical treatment:
 Indicated when seizures shown to be intractable to medical treatment.
 Removal of epileptic focus (eg:mesial temporal sclerosis)
 Anterior Temporal Lobectomy
 Corpus callostomy
 Subpial transection
 Vagus Nerve stimulation 23

24. GUIDELINES FOR ANTICONVULSANT DRUGS
 Start with one first line drugs
 Start with low dose: Gradually increase to effective dose or until side effects.
 Check compliance
 If first drug fails due to side effects or continue seizures, start second line
drugs whilst gradually withdrawing first.
 Try Three AED singly before using combinations
 Beware about drug interactions
 Do not use more than two drugs in combination at any one time
 If above fails consider occult structural or metabolic lesion and whether
seizures are truly epileptic.
24

25. MECHANISM OF ACTION OF ANTIEPILEPTIC
DRUGS
 Blocking voltage gated channels (Na+ or Ca2+) Enhancing inhibitory
GABA impulses Interfering with excitatory glutamate transmission
 Some antiepileptic drugs appear to have multiple targets in CNS
 Antiepilepsy drugs suppress seizures but do not “cure” or “prevent”
epilepsy
25

26. DRUG CHOICE OF EPILEPSY
Choice of drug treatment is based on:
 Classification of the seizures
 Patient-specific variables (age, comorbid medical conditions)
 Characteristics of the drug (cost, toxicity and drug interactions)
26

27. CLASSIFICATION OF DRUGS USED IN THE
THERAPY OF EPILEPSIES
Seizure type Conventional
anti-seizure drug
Recently developed
anti-seizure drug
Partial seizures
Simple partial
Carbamazepine
Phenytoin
Phenobarbital
Primidone
Valproate
Gabapentin
Lamotrigine
(ii) Complex partial Carbamazepine
Phenobarbital
Phenytoin
Primidone
Valproate
Gabapentin
Lamotrigine
(iii) Partial with
secondly generalized
tonic clonic seizure
Carbamazepine
Phenobarbital
Phenytoin
Primidone
Valproate
Gabapentin
Lamotrigine
27

28. II. Generalized seizure
(I) Absence Seizures Clonazepam
Ethosuximide
Valproate
(ii) Myoclonic Seizure Valproate
(iii) Tonic-clonic Seizure Carbamazepine
Phenobarbital
Phenytoin
Primidone
Valproate
28

29. Chemical Class Examples of antiepileptic drug
Barbiturates Phenobarbitone, Mephobarbitone,
Primidone
Hydantoins Phonations, Mephenytoin
Iminostilbene Carbamazepine
Oxazolidinedione Trimethadione (Troxidone)
Succinimide Ethosuximide
Aliphatic Carboxylic acid Valproic acid (Sodium valproate)
Benzodiazepines Clonazepam, Diazepam
Acetyl urea Phenacemide
Newer drugs Progabide, Vigabatrin, Gabapentin
Lamotrigine, Felbamate, Topiramate,
Tiagabine
Miscellaneous Acetazolamide, Dexamphetamine
29

30. Benzodiazepines
Most are reserved for emergency or acute seizures
Bind to GABA inhibitory receptors to reduce firing rate
Clonazepam, clobazam, diazepam and lorazepam are used as adjunctive therapy for
myoclonic,
partial and generalized tonic-clonic seizures
Diazepam is available for rectal administration
Phenobarbital
Enhances the inhibitory effects of GABA-mediated neurons
Phenobarbital in epilepsy should be used primarily in the treatment of status epilepticus
Primidone
Metabolized to phenobarbital
Adverse effects: Agranulocytosis
30

31. Tiagabine
 Blocks GABA uptake into presynaptic neurons, permitting more GABA to be
available for receptor binding, and enhancing inhibitory activity
 Effective in partial onset epilepsy > 95% protein bound
 Adverse effects: fatigue, dizziness, GI upset
Vigabatrin
 Irreversible inhibitor of GABA transaminase
 Adverse effects:
 Visual field loss
31

32. Carbamazepine
Blocks sodium channels inhibiting generation of repetitive action potentials in
the epileptic focus and preventing their spread
Effective for partial seizures and generalized tonic-clonic
seizures
Also used for trigeminal neuralgia and bipolar disorder
Absorbed slowly and erratically following oral administration and may vary
from generic to generic
Metabolized by CYP3A4
Inducer of CYP1A2, CYP2C, CYP3A enzymes
Not well tolerated by the elderly
Adverse effects:
◦ Hyponatremia may be noted in some patients, especially elderly
◦ Rash
Should not be prescribed for patients with absence seizures because it may
increase seizures
32

33. Phenytoin and fosphenytoin
Phenytoin blocks voltage-gated sodium channels
Phenytoin is effective for treatment of partial seizures and
generalized tonic-clonic seizures and status epilepticus
Phenytoin is 90% bound to plasma albumin
Phenytoin exhibits saturable enzyme metabolism at low concentration
(zero-order pharmacokinetics)
Small increases in a daily dose can produce large increases in the plasma
concentration resulting in drug induced toxicity
Side effects:
◦ Gingival hyperplasia (the gums growing over the teeth )
◦ Nystagmus
◦ Ataxia
◦ Peripheral neuropathies
33

34. Oxcarbazepine
A prodrug that is rapidly reduced to the 10- monohydroxy (MHD) metabolite
responsible for its anticonvulsant activity
MHD blocks sodium channels, preventing the spread of the abnormal
discharge
Approved for use in adults and children with partial onset seizures
Levetiracetam
Approved for adjunct therapy of partial seizures, myoclonic seizures, and
primary generalized tonicclonic seizures in adults and children
The exact mechanism of anticonvulsant action is unknown
Side effects: dizziness, sleep disturbances, headache,
and weakness
34

35. Ethosuximide
Reduces propagation of abnormal electrical activity in the brain by inhibiting
calcium channels
Effective in treating only primary generalized absence seizures
Pregabalin
Binds to voltage-gated calcium channels in the CNS, inhibiting excitatory
neurotransmitter release
Effective for partial onset seizures, neuropathic pain associated with diabetic
peripheral neuropathy, and fibromyalgia
Side effects: Drowsiness, blurred vision, weight gain, and peripheral edema.
35

36. Felbamate
Broad spectrum anticonvulsant
Proposed mechanisms
1) Blocking voltage-dependent sodium channels
2) Competing with the glycine-coagonist binding site on the N-methyl-D-
aspartate (NMDA) glutamate receptor
3) Blocking calcium channels
4) Potentiating the action of GABA
Reserved for use in refractory epilepsies because of the risk of aplastic anemia
and hepatic failure
36

37. Gabapentin
GABA analog
Does not act at GABA receptors
Mechanism of action is not known
Approved as adjunct therapy for partial seizures
Lamotrigine
Blocks sodium channels and calcium channels
Effective in a wide variety of seizures including partial
seizures and generalized seizures
Approved for use in bipolar disorder
Half life is decreased by enzyme inducing drugs like carbamazepine and phenytoin and
increased by greater than 50% with the addition of valproate
Rapid titration to high serum concentrations of lamotrigine can cause a rash, which may
progress to a serious life threatening reaction
37

38. Topiramate
Broad spectrum anti-seizure activity
MOA
◦ Blocks voltage-dependent Na channels
◦ Increases the frequency of chloride channel opening by binding to the GABA
receptor
◦ Reduces high-voltage Ca currents
◦ May act at glutamate (NMDA) sites
Effective and approved for partial and primary generalized
epilepsy
Also approved for treatment of migraine
It inhibits CYP2C19 and is induced by phenytoin and carbamazepine
Coadministration of topiramate reduces ethinyl estradiol
◦ Women taking the drug should be counseled to use additional methods of birth
control
Adverse effects: somnolence, weight loss and paresthesias
38

39. Valproic acid and divalproex
Valproic acid is available as a free acid
Divalproex sodium is a combination of sodium valproate and valproic acid
that is converted to valproate when it reaches the GIT
◦ Improved GI tolerance of valproic acid
All forms are equivalent in efficacy
Mechanisms of action:
◦ Sodium channel blockade
◦ Blockade of GABA transaminase
Broad spectrum of activity against seizures
Effective for partial and primary generalized epilepsies
>90% bound to albumin
Adverse effects:
◦ Rare hepatic toxicity
◦ Teratogenic; cognitive and behavioral abnormalities and neural
tube defects 39

40. ADVERSE EFFECTS OF ANTI-SEIZURE DRUGS
40

41. SIDE EFFECTS
41

42. WITHDRAWAL OF ADE
 After complete control of seizures for 2-4 years, withdrawal of Anti
Epileptic drugs may be considered. But in case of special professional
group (car driver, machine man etc) withdraw the AED after keen
follow-up.
 AED should be tapered during the stopping of medications. Slow
reduction by increments over at least 6 months.
 If the patient is taking two AEDs one drug should be slowly withdrawn
before the second is tapered 42

43. PROGNOSIS
 Generalized seizures are more readily controlled than partial seizures.
 Childhood onset epilepsy (particularly classical absence seizures) carries the
best prognosis for successful drug withdrawal.
 The presence of a structural lesion makes complete control of epilepsy less
likely.
Epilepsy outcome: After 20 years
50% seizure-free, without drugs, for last 5 years
20% seizure-free, continue to take medication, for last 5 years
30% seizures continue in spite of adequate dose of AEDs.
Refractory epilepsy: When seizure control is not achieved with the first two
appropriate and well tolerated AED schedules taken as mono therapy or in
combination.
43

44. FAMOUS PERSONS WITH EPILEPSY
 Aristotle
 Socrates
 Julius Caesar
 Fyodor Dostoyevsky
 Lord Byron
 Vincent Van Gogh
 Alfred Nobel
 Vlaldimir Illyich Lenin
 Naepoleon Bonaparte
 Tony Greig
44

45. 45