Epilepsy and Anti epileptic drugs. Cellular mechanism of epilepsy. Classification of epileptic drugs. Pharmacological action of epilepsy. Treatment of epilepsy.

1. Prepared by A. Gowtham Sashtha 1st M.Pharm
Department of pharmacology
K.M College of pharmacy, Madurai – 625107.
Epilepsy &
Anti-epileptic drugs
Epilepsy
Anti-epileptic drugs

2. Definition of seizure epilepsy
Seizure ?
✧ A seizure is a proximal event characterised by abnormal (or)
excessive hypersynchronous discharge of brain neurone activities.
Epilepsy ?
✧ Epilepsy can be define as the chronic conditions of seizure
disorder or group of disorder characterized by seizures that
usually recure unpredictably in the absence of a provoking factors.

3. Classification of seizure
1) Partial seizures
2) Generalized Seizures
3) Unclassified seizure
4) Status epilepticus

4. Types of seizure epilepsy

5. I)Partial seizures (common 80% of patients)
1) Simple Partial Seizure
location : Cortical origin
Do not cause loss of consciousness.
Symptoms :
Motor-convulsive jerking, chewing motions, lip smacking.
Sensory-Paresthesias,
Autonamic-Sweating, flushing, pupil dilation.
Behaviour-Hallucination,dysphasia

6. 2)Complex partial seizure
location : Temporal lobe area.
Symptoms :
Impairment of consciousness
Confused behaviour
Emotional changes
Olfactory hallucination.
3)Secondary generalized seizure
This seizure occurs evolves in to generalized tonic
clonic seizures with loss of consciousness.

7. II) Generalized seizure
location : Affecting whole brain.
3types
1) Idiopathic epilepsies
➜Age related
➜Genetic related
2) Symptomatic epilepsies
➜Disorder of CNS
3) Cryptogenic epilepsies
➜Disorder of a hidden course
➜Age related

8. 1)Absence Seizure :
✧(minor epilepsy): prevalent in children, lasts about
1/2 min.
Symptoms :
✧Momentary loss of consciousness,
✧patient apparently freeze and stares in one
direction, and litte jerking.
✧EEG shows characteristic 3 cycles per secnd spike
and wave pattern.

9. 2)Myoclonic seizures
✧ Shock-like momentary contraction of muscles of a
limb or the whole body. Tonic-clonic seizures (Major
epilepsy commonest, lasts 1–2 min
Symptoms :
✧ cry—unconsciousness
✧tonic spasm of all body muscles
✧clonic jerking followed by prolonged sleep and
depression of all CNS functions.

10. 3)Atonic seizures (Akinetic epilepsy):
Symptoms :
Unconsciousness with relaxation of all muscles due to excessive
inhibitory discharges. Patient may fall.
Tonic phase :
✧Become rigid falls to the ground.
✧Respiration are interrupted.
✧last about 1 mins.
Clonic phase :
✧Rapid muscle jerking.
✧Muscle flaccidity.
✧Tongue biting,High salivation.

11. III) Unclassified seizure
✧This seizure may be unclassified due to inadequate
information to allow it to be placed in the focal, generalized
or unknown onset categories.
This includes some neonatal
seizures.
Neonatal seizure :
✧A seizure is caused by sudden, abnormal and
excessive electrical activity in the brain.this seizure
produced in baby younger than 4 weeks old.

12. IV) Status epilepticus
✧A seizure that lasts longer than 5 minutes,
✧This types of seizure occurs repeatedly with no
recovery of the consciousness.

13. Causes
✧High fever ,Drug use , Alcohol withdrawal.
✧Metabolic disturbances.
✧Head trauma.
✧Brain tumours ,some infections ,Stroke
✧Complication diabetes and pregnancy

14. Pathophysiology

16. Cellular mechanisms of seizure generation
✧Excitation (too much)
➜ionic---inward Na⁺ , Ca⁺ ⁺
➜Neurotransmitter---glutamate,aspartate.
✧Inhibition (too little)
➜Inward---Cl⁻, Outward K⁺
➜Neurotransmitter---GABA,Glycine

17. Classification of Anti-epileptic drugs
1. Barbiturate
Phenobarbitone
2. Deoxybarbiturate
Primidone
3. Hydantoin
Phenytoin
Fosphenytoin
4. Iminostilbene
Carbamazepine
Oxcarbazepine
5. Succinimide
Ethosuximide
6. Aliphatic carboxylic acid
Valproic acid.
Divalproex
(sodium valproate)
7. Phenyltriazine
Lamotrigine

18. 8. Benzodiazepines
Clonazepam
Diazepam
Lorazepam
Clobazam
9. Cyclic GABA analogues
Pregabalin
Gabapentin
10. Newer drugs
Zonisamide
Topiramate
Levetiracetam
Vigabatrin
Tiagabine
Lacosamide

19. Mechanism
of
action

20. ☞Pharmacological action
☞Adverse Drug Reaction
☞Use
☞Dose

21. Pharmacological action
1)Barbiturate
Phenobarbitone :
→Phenobarbitone was the cheapest and less toxic and first
efficacious anti-epilepti drug.
→Enhancement of GABAA receptor mediated synaptic inhibition
appears to be most important mechanism.also act as anti-glutamate
activity (Ca⁺ ⁺ reduction) Its produced CNS depression action.
ADR :
→Long term administration—behavioral abnormalities,
learning and memory, hyperactivity in children, mental confusion in older
people,Rashes, megaloblastic anaemia and osteo- malacia (similar to that
with phenytoin)

22. USE :
→This drug is used to Generalized tonic-clonic (GTC), simple
partial (SP) and complex partial (CP) seizures.It is not effective in
absence seizures.
Dose of 60 mg 1–3 times a day in adults; in children (3–5 mg/kg/
day)
Status epilepticus: Phenobarbitone sod. may be injected i.m. or
i.v. but response is slow to develop

23. 2)Deoxybarbiturate
Primidone :
→A deoxybarbiturate, converted by liver to phenobarbitone and
phenylethyl malonamide (PEMA). primidone is less potent activity.similar
mechanism of action of Phenobarbitone.
ADR :
→similar to phenobarbitone.
In addition,anaemia,leukopenia,psychotic reaction and lymph node enlargement
occur rarely.
USE :
→It is infrequently used now in GTCS and partial epilepsy
Dose : 250–500 mg, children 10–20 mg/kg/day.

24. 3)Hydantoin
Phenytoin (Diphenylhydantoin)
✧It is a major Anti-epileptic drug.It dose not produce CNS
depression.some sedation occurs at therapeutic doses.
Mechanism of action :
✧It prolonging the inactivated state of voltage sensitive neuronal Na+
channel.
✧As a result high frequency discharges are inhibited with little effect
on normal low frequency discharges which allow Na+ channel to recover
even when their inactivation is prolonged.
✧while other effects like reduction in Ca2+ influx, inhibition of
glutmate and facilitation of GABA responses have been demonstrated.

25. ADR :
1) In therapeutic levels
✧Hirsutism, Hypersensitivity reactions are rashes,
lymphadenopathy,neutropenia.
✧Megaloblastic anaemia : decrease folate absorption and it's
increase excretion.
✧Osteomalacia : Metabolic activation Vit D / calcium
absorption.
✧Hyperglycemia.
✧Used during pregnancy, phenytoin can produce foetal
hydantoin syndrome

26. 2)In plasma levels
✧Ataxia,vertigo, drowsiness,behavioral changes,mental confusions,
hallucination, rigidity.
✧In taking the during with meals - Epigastric pain, nausea vomiting.
✧i.v - local vascular injury - damaged blood vessels / vein and
thrombosis,Cardiac arrhythmias.
USE :
1. Generalized tonic-clonic, simple and complex partial seizures. It is
ineffective in absence seizures.
2. Status epilepticus: occasionally used by slow i.v. injection
(Fosphenytoin replaced it)
Dose: 100 mg - 400 mg/day adult ; Children 5–8 mg/kg/day.

27. Fosphenytoin :
✧This is water soluble prodrug.
✧it Difficulties in i.v. administration of phenytoin,which it has
replaced for use in status epilepticus. In the body, it is rapidly
converted to phenytoin.
✧While phenytoin cannot be injected in a drip of glucose
solution (because it gets precipitated),fosphenytoin can be injected
with both salin and glucose.
ADR : Same as phenytoin
Dose : 50 mg/ml in 2 ml, 10 ml inj. (Fosolin)

28. 4)Iminostilbene
Carbamazepine :
✧Chemically related to imipramine.
✧Now it is a first line antiepileptic drug
✧Its pharmacological actions resemble phenytoin.
✧It also has antidiuretic action, probably by enhancing ADH action on
renal tubules
ADR :
✧Neurotoxicity—sedation, dizziness,vertigo, diplopia and ataxia
✧Vomiting, diarrhoea,coma, cardiovascular collapse,rashes, aplastic
anaemia,hyponatremia.
USE : The most commonly used drug for GTCS and SPS.
Dose : Dose: 200–400 mg ; Children 15–30 mg/kg/day.

29. 5)Succinimide:
Ethosuximide :
✧Ethosuximide selectively suppresses T current without affectingother types
of Ca2+ or Na+ currents. It also doe not potentiate GABA at therapeutic
concentions. This correlates well with its selectve action in absence seizure.
ADR :
✧Gastrointestinal intolerance, tiredness, mood changes, agitation,headache,
drowsiness and inability to concentrate.
Hypersensitivity reactions like rashes,No liver or kidney damage.
USE :
The only indication for ethosuximide is absence seizures.

30. 6)Aliphatic Carboxylic acid:
Valproic acid :
✧Valproate produces little sedation or other central effects.
Likewise, itis effective in partial seizures and GTCS as well as absence
seizures.
✧A phenytoin-like frequency-dependent prolongation of Na+
channel inactivation.
✧Weak attenuation of Ca2+ mediated.(ethosuximide like).
✧Augmentation of release of inhibitory transmitter of GABA

31. ADR :
✧Anorexia, vomiting, loose motions and heart burn are common but
mild. Drowsiness, ataxia and tremor are dose-related side effects.
✧Alopecia, curling of hair, weight gain and increased bleeding tendency
have been observed Rashes and thrombocytopenia.
USE :
✧Valproic acid is the drug of choice for absence seizures
✧Used during pregnancy, it has produced spina bifida.
Divalproex (Semisodium valproate)
✧It is the co-ordination compound of valproic acid with
sodium valproate. Oral absorption is slow.
✧Same MOA of valproic acid.

32. 7)Benzodiazipines (clonazepam,clobazam,diazepam,lorazepam)
✧Benzodiazepines potentiate GABA induced Cl– influx to produce
sedation and the same mechanism has been held responsible for the
anticonvulsant property.
ADR:
✧Over sedation, dullness,lack of concentration, irritability, ataxia.
✧Salivation and increased respiratory secretion.

33. USE :
➝Clonazepam : primarily used in absence seizure also used as
adjuvant in myoclonic sezure
➝Clobazem : Used in partial,GTCS, absence atonic seizure.
➝Diazepam and lorazepam : it is a first line drug for emergency
control of convulsions, e.g. status epilepticus, tetanus, eclampsia,
convulsant drug poisoning,

34. 8)phenyltriazine
Lamotrigine
✧It is new anti-convulsion drug.It act as Prolongation of Na+ channel
inactivation.
✧Also preventing release of excitatory neurotransmitters, mainly
glutamate and aspartate.
ADR :
✧Sleepiness,dizziness,diplopia,ataxia,vomiting.
USE :
✧partial seizure,GTCS,absence, myoclonic seizure have been successfuly
treated.

35. 9) Cyclic GABA analogue
Gabapentin :
✧It is postulated that decreased entry of Ca2+ into the presynaptic
neurone through these channels could reduce glutamate release,
lowering neuronal excitability.
ADR :
Mild sedation, tiredness, dizzines.
USE :
Secondary partial seizure, Complex partial seizure.

36. 10)Newer drugs
Topiramate :
It appears to act by multiple mechanisms, viz phenytoin like
→prolongation of Na+ channel inactivation,
→GABA potentiation by a postsynaptic effect,
→antagonism of certain glutamate receptors
→ neuronal hyperpolarization through certain K+ channels
→Recently, topiramate has been approved for
prophylaxis of migraine; may be used when β blocker.
Zonisamide : Selective prolongation of Na+ channel inactivation.

37. levetirecetam : (keppra)
✧MAO is Not exactly know
✧Binds to the synaptic vesicle protein 2A (SV2A) in the brain also
regulate the neurotransmitter release.
✧inhibits the release of calcium from intracellular stores.
✧This can likely modify pre synaptic release of glutmate and GABA
ADR :
Drowsiness, fatigue, dizziness, ataxia.
USE :
Partial seizure , Tonic clonic seizure
myoclonic seizure.

38. Thiagabin :
Selective GAT- 1 blocking agent.
ADR :
Mild sedation, nervousness,asthenia, amnesia, abdominal pain.
USE :
partial seizure.

39. Vigabatrin :
✧It is an inhibitor of GABA-transaminase, the enzyme which
degrades GABA.
✧Anticonvulsant action may be due to increase in synaptic
GABA concentration
Lacosamide :
✧It acts by enhancing Na+ channel inactivation.
✧Lacosamide is metabolized by CYP2C19 and excreted in urine.
USE : partial seizure.

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