Antiepileptics

About antiepileptics, their pathophysiology, mechanism of action, adr and uses.

2. - INTRODUCTION
- CLASSIFICATION OF SEIZURE
- ETIOLOGY
- PATHOPHYSIOLOGY
- ANTI-EPILEPTIC DRUGS

3. Seizure: Is a paroxysmal event due to
abnormal , excessive and hypersynchronous
discharges from an aggregate of central nervous
system neurons.
Epilepsy : It is clinical phenomenon in which a
person has recurrent seizures due to a chronic
underlying process.

4. GENERALISED SEIZURES
- involve cerebral hemisphere diffusely
• GTCS-main seizure type , 10% of all persons with
epilepsy,lasts 1-2 min.
•Usual seq.-auracryunconsciousnesstonic spasm of
body
• ABSENCE SEIZURES-prevalent in children, last 1-2 min.
•Momentary loss of consciousness,no muscular
component,EEG spike and wave pattern of 3 cycles per sec.
•ATONIC SEIZURE-unconsciousness with relaxation of all
muscles due to excessive inhibitory discharges
•MYOCLONIC SEIZURE shock like momentary
contracture of group of muscle

5. PARTIAL SEIZURE
Discrete region of cerebral cortex is involved
SIMPLE PARTIAL usually lasts 1-2 min
Confined to group of muscles depending upon area
of cortex involved.
COMPLEX PARTIAL SEIZURE unconscious
with aura purposeless movements,emotional
changes lasting 1-2 min

6. Neonates
•Perinatal hypoxia and ischemia
Intracranial hemorrhage and trauma
Acute CNS infection
Metabolic disturbances (hypoglycemia, hypocalcemia, hypomagnesemia,
pyridoxine deficiency)
Developmental disorders
INFANTS AND CHILDREN
Febrile seizures
Genetic disorders (metabolic, degenerative, primary epilepsy syndromes)
CNS infection
Developmental disorders
Trauma

7. YOUNG ADULTS (18–35 YEARS)
-Trauma
-Alcohol withdrawal
-drug use
-Brain tumor
-Idiopathic
OLDER ADULTS (>35 YEARS)
-Cerebrovascular disease
-Brain tumor
-Alcohol withdrawal
-Metabolic disorders (uremia, hepatic failure,
electrolyte abnormalities, hypoglycemia)
-Alzheimer's disease and other degenerative CNS
diseases
-Idiopathic

9. Barbiturates
•Phenobarbitone
Ion Channel Inhibitors
•Carbamazepine
•Oxcarbamazepine
•Phenytoin
•Ethosuximide
Benzodiazepines
•Diazepam
•Clonazepam

10. Gabapentin
Pregabalin
Lamotrigine
Tiagabine
Topiramate
Felbamate
Zonisamide
Lacosamide
Rufinamide
Vigabatrin
Levetiracetam

11. Mechanism of Action
Anti epileptic drugs act primarily by
blocking the initiation or spread of
seizure.
Decrease propagation of action potentials
ß Na
+
, Ca
++
influx (delay depolarization
/ prolong repolarization)
Ý Cl
-
influx (hyperpolarize
membrane)
ß glutamate release

12. Exert antiepileptic effect without CNS
depression
Mechanism of action
Therapeutic dose – prolonged inactivation of
voltage sensitive sodium channels
Higher concentration –
Reduction in calcium influx
Facilitate GABA
Inhibit Glutamate – decrease intracellular sodium
ion

13. Absorption is slow per orally
High plasma protein binding(90%)[widely
distributed]
Metabolised in liver by CYP2C9,2C19
First 0 order kinetic(high dose)
→
t half 12-24 hrs at therapeutic level

14. Gum hypertrophy
Hirsutism, acne, coarsening of facial features
Megaloblastic anaemia
Osteomalacia
Fetal hydantoin syndrome
At higher concentration:
Ataxia, vertigo, nystagmus
Alteration in behavior, mental confusion & hallucination
Epigastric pain, nausea & vomiting
Mod elevation of hepatic transaminases
Hyperglycemia and glycosuria

15. Phenytoin - OCP, theophylline
↓
Phenytoin inhibits warfarin metabolism
Phenobarbitone competitively inhibits phenytoin metabolism, by
enzyme induction both enhances each others degradation.
Carbamazepine & phenytoin metabolism of each other
↑

GTCS
Simple partial seizures
Complex partial seizures
Status epilepticus
Dose : 100 mg BD
Indications

16. Ist efficacious antiseizure
Mechanism of action
Enhancement of GABAA receptor mediated
synaptic inhibition
Pharmacokinetics
Slow oral absorption
40-60% plasma protein bound
25% renal excretion

17. Sedation (most frequent)
Nystagmus,ataxia(excessive dosage)
Irratability,confusion in children
Megaloblastic anemia
osteomalacia
Uses
GTCS
Partial seizures
Status epilepticus
Dose: 60 mg 1-3 times a day

18. Chemically related to imipramine
Mechanism of action
Like phenytoin –slow rate of recovery of Na channels from
inactivation at therapeutic conc.
PHARMACOKINETICS
Absorption is slow and variable
Metabolized in liver to 10 -11 epoxycarbamazepine(active form)
Initial t
½
(20 – 40 hours)
Later (10 – 20 hours)
Therapeutic conc. 6-12μg/dl

19. Sedation, dizziness, vertigo and ataxia,blurred vision,
GIT upset
Rashes, photodermatitis, hepatitis
Water retention and hyponatremia – old age
Aplastic anaemia,eosinophilia,lymphadenopathy
Drug interaction
Phenytoin, valproate and phenobarbitone - carbamazepine
↓
conc.by CYP3A4 induction
 Fluoxetine and isoniazid and eryhromycin - carbamazepine
↑
Carbamazepine lowers
valproate,lamotrigine,tiagabine,topiramate

20. Effective in GTCS and SPS
Trigeminal and other neuralgias
MDP and acute mania
Dose : 200-400 mg TDS
Children- 15-30 mg /kg /d

21. 10 mono hydroxy derivative of carbamazepine
Advantage –weak enzyme induction
Conc of VALPROATE ,PHENYTOIN not decreased
USES
In partial seizures

22. Primary agent for absence seizure
MECHANISM OF ACTION
Selectively suppressed T type Ca currents without
effecting other types of calcium and sodium currents
PHARMACOKINETICS
Absorption complete(slow),peak plasma-3hrs
Half life-40-50hrs
Metabolism – liver, Excretion – kidney

23. GIT –nausea,vomiting,anorexia
Headache
Drowsiness,dizziness,agitation
Inability to concentrate
Bone marrow
depression(pancytopenia,thrombocytopenia)
Indication
Absence seizure
Dose: 20-30 mg /kg/d

24. Broad spectrum anti seizure drug
MECHANISM OF ACTION
-Prolongation of sodium channel inactivation
-Suppression of calcium mediated T currents
-Increase in GABA release by inhibiting GABA
transaminases
PHARMACOKINETICS
well absorbed orally, high plasma protein bindings
Metabolism – liver ,
Excretion – kidney

25. Anorexia, vomiting, drowsiness, ataxia, tremor
Alopecia
Weight gain
Fulminant hepatitis below 3 years age(inc. hepatic
tranaminases)
Neural tube defect – pregnancy

26. Drug of choice
Absence seizure
Myoclonic and atonic seizure
Alternate Drugs
mania, GTCS, SPS and CPS
Dose:
Start with 200 mg TDS max dose 800 mg TDS
Children- 15-30 mg/kg/d

27. Benzodiazepines potentiate GABA induced Cl
influx .
Not used for long term due to prominent sedation
and rapid development of tolerance.
 It is first line drug for:
Emergency control of convulsions
Status epilepticus
Tetanus
Eclampsia
Dose : 0.2-0.5 mg/kg slow iv injection followed by small
repeated doses max 100 mg /d
ADR: Thrombophlebitis of injected vein, marked fall in BP,
respiratory depression

28. Action like carbamazepine
Broad spectrum
Mechanism of action
-Prolongation of sodium channel inactivation
-May directly block sodium channels – stabilized
presynaptic membrane and prevent glutamate and
aspartate release
-Indications:
-Add on therapy in refractory cases of GTCS and partial
seizures
-Dose: 50mg/d initially , increase upto 300 mg/d

29. Absorbed well and metabolized in liver
Drug Interaction
-Phenytoin carbamazepine or phenobarbitone
decrease t
½
-Valproate increase plasma level
-Lamotrigine decreases valproate plasma level
ADR


Sleepiness, dizziness, ataxia, diplopia and
vomiting ,Rash – severe reaction
-

30. MECHANISM OF ACTION
enhances GABA release
PHARMACOKINETICS
Absorption well, excretion unchanged in urine
ADR
Sedation, dizziness, unsteadiness
INDICATION
 Simple partial seizure
Refractory partial seizures
Complex partial seizure
Dose: 300 mg OD , increase up to 300- 600 mg TDS as
required

31. MECHANISM OF ACTION
inhibit gaba transporter GAT-1reduces gaba
uptake in neurons
Pharmacokinetics
Rapid oral absorption
Extremely plasma protein bound
Liver metabolism by CYP3A
indication
Add on therapy of partial seizures
ADR
Sedation, abdominal pain

32. Mechanism of action
-Prolongation of sodium channel inactivation
-Post synaptic GABA potentiation
-Glutamate receptor antagonist
-Pharmacokinetics
-Rapid oral absoprtion
-10-20% plasma protein binding
-Excreted in urine
Indications
-SPS, CPS and GTCS
-ADR
-Sedation, ataxia, psychiatric symptoms and renal
stones

33. Mechanism of action
Inhibit t type Ca channels
Prolong inactivation of Na channel
pharmacokinetics
Complete oral absorption
40% binding to plasma protein
85% urine excretion

34. Phenytoin,phenobarbitone,carbamazepine-
decreases its level
ADR
Somnolecence
Ataxia,anorexia,nervousness
Renal Calculi
USES
Partial Seizure(adjunctive)
Dose
25-100 mg BD

35. Partial Seizure(adjunctive In >17yrs)
MECHANISM OF ACTION
Inactivation of Na channel
RUFINAMIDE
Adjunctive treatment of lennox gastaut syndrome
MECHANISM OF ACTION
Slow inactivation of Na channels

36. Refractory partial seizure
Infantile spasm
MECHANISM OF ACTION
Irreversible GABA tranaminase inhibitorincrease GABA
LEVETIRACETAM
Refractory partial seizures
Mechanism of action is not known
Free of drug interactions
Few side effects
Good tolerability , now increasingly used in CPS, GTCS
DOSE: 0.5 mg BD

37. seizure type
first line drugs

second line drugs
Simple partial seizure Carbamazepine
phenytoin
valproate
Gabapentin
lacosamide
tiagabine
rufinamide
topiramate
zonisamide
Complex partial seizure carbamazepine
phenytoin
valproate
Gabapentin
lacosamide
tiagabine
rufinamide
topiramate
zonisamide
Partial with generalised tonic clonic
seizure
carbamazepine
phenytoin
valproate
phenobarbital
Gabapentin
lacosamide
tiagabine
rufinamide
topiramate
zonisamide

38. Seizure type First line drugs second line drugs
Absence seizure Valproate
ethosuximide
Lamotrigine
Topiramate
Myoclonic seizure Valproate
Clonazepam
Levetiracetam
Lamotrigine
Tonic clonic seizure
carbamazepine
phenytoin
valproate
phenobarbital
Lamotrigine
Topiramate