pharmacotherapy

2. Seizure or epilepsy?
• Seizure: Abnormal discharge at high frequency from neuron in
cerebral cortex
 Genetic
 CNS lesion
 Drugs
 Metabolic disorder
 Infection
• Recurrent seizure = Epilepsy

3. GABA Glutamate
Normal
GABA
Glutamate
Epilepsy
Neurotransmitter in Epilepsy

4. Pathophysiology
Initiated in thalamus: T type Ca channel
Propogated by Na channels
Initiated in cortex
Propogated by Na channel
No role of T type calcium channel

5. Aim of treatment
1. Reduce ability of neuron to fire action potential
2. Inhibit spread:
Increase GABA(inhibitory) transmission
Decrease glutamate(excitatory) transmission

6. Mechanism of action of drugs

7. Mechanism of action of drugs

8. Drugs targeting channels
Voltage gated sodium channel Phenytoin, Fos-phenytoin,
Carbamazepine, Oxcarbamazepine,
Lamotrigine,
Lancosamide, Zonisamide, Rufinamide
Voltage gated calcium channel Ethosuximide
Voltage gated potassium channel Retigabine

9. GABA enhancers
GABA-A Receptor Benzodiazipines
Phenobarbital
GAT 1 Transporter Tiagabine
GABA transaminase inhibitor Vigabatrine
Glutamate receptor
AMPA receptor Perampanel
NMDA receptor Felbamate

10. Synaptic release mechanism
SV2A Levetricetam
⍺2𝛿 Gabapentin, Pergabalin
Mixed or unknown action:
Valproate
Topiramate

11. Phenytoin & Fosphenytoin
• MOA: Blocks Nav channel
• Uses: Partial seizure, GTCS
• Pharmacokinetics:
• Slow oral absorption(80-90%)
• Difference in bioavaliability with brand
• Not given IV/IM(precipitate in muscle – pain, thrombophlebitis, slow IV)
• 90% protein bound
• Inducer of CYP3A4, Glucoronyl transferase
• Eliminated in urine, saliva
• Half life 24 hour

12. Phenytoin & Fosphenytoin
• Dose: start with 300mg/day
Increased by 25-30mg
• Plasma concentration monitoring required(10-20 µg/ml safe)
10-20 µg/ml: first order kinetics
>20 µg/ml: zero order kinetics

13. Phenytoin & Fosphenytoin
Side effects:
• Gum hypertrophy: due to overgrowth of gingival collagen fibres
• Hirsutism
• Hypersensitivity
• Megaloblastic anaemia decreases folate absorption
• Osteomalacia: interferes with metabolic activation of vit D and with
calcium absorption/metabolism
• Hyper- glycaemia: inhibit insulin release
• Foetal hydantoin syndrome

14. Fetal hydantoin syndrome

15. Phenobarbital
MOA: Increase duration of GABA Chloride channel
Block AMPA
Pharmacokinetics:
• Slow, complete oral absorption
• Metabolized in liver
• Half life- 100hrs(protein binding)
• Enzyme inducer:CYP2A, CYP2B, CYP2C, CYP3A, Glucoronyl transferase
Dose: 60-180mg/day
Side effects: Enzyme inducer side effects
Teratogenicity increase with phenytoin

16. Carbamazpine & Oxcarbamazepine
• Blocks voltage gated sodium channel
• Uses: Partial seizure, Generalized tonic clonic
• Contraindicated in absence seizure
• Dose: 100-200mg BD or TDS carbamazepine
300mg BD or TDS oxcarbamazepine
• Therapeutic level: 4-8µg/ml
• Pharmacokinetics: slow absorption, excreted in urine

17. • Carbamazepine is enzyme inducer(oxcarbamazepine is not)
Induces CYP3A4, glucoronyl transferase
• Metabolized by CYP3A4
• Adverse effects:
Carbamzepine : Drowsiness, Headache, Vertigo, Allergic reactions,
ADH secretion, Teratogenic
Oxcarbamazepine : Less hypersensitivity, Less side effects
Carbamazpine & Oxcarbamazepine

18. Finger nail hypoplasia

19. Ethosuximide
Absence seizure
• MOA: Blocks T type calcium channel
• Dose: 20-30mg/kg/day
• Therapeutic level:60-100µg/ml
• Pharmacokinetics: Absorbed orally
Metabolized in liver, excreted through kidney
• Adverse effects: GI Side effects, Headache, Lethargy, Dizziness
Less teratogenic

20. Valproic acid
• MOA: Bocks voltage gated sodium channel
Increase GABA activity
Decrease Glutamate activity
Blocks T type calcium channel
•Gradual withdrawal- precipitate seizure
•Dose: 300mg BD increased to 500mg- 1g BD
•Therapeutic level: 50-100µg/ml
•Pharmacokinetics: 90-95% protein bound
Food delays absorption
Enzyme inhibitor(inhibit metabolism of phenobarbital and self)

21. Valproic acid
Uses: Absence seizure, Atonic, Myoclonic, GTCS, Partial seizure
Adverse effect: Weight gain, Increase appetite
GIT side effects
Tremors
Reversible alopecia
Hepatitis, Pancreatitis
PCOS
Teratogenicity: Neural tube defects, spina bifida

22. Benzodiazepines
• MOA: Enhance frequency of GABA mediated chloride channel opening
• High dose: Block sodium channel
Lorazepam: First choice in status epilepticus(4mg IV @ 2mg/min)
Diazepam: Febrile seizure to prevent recurrence
10-30mg slow IV in status epilepticus
Local anesthesia induced seizure
• Drawback: Sedative
Tolerance

23. Vigabatrin
• MOA: Irreversible inhibitor of GABA transaminase
• Uses: Simple and complex partial seizure, generalized seizure,
infantile spasm
• Dose: 2g/day orally
• Adverse effect: Behavioral change
Sedation, amnesia
Weight gain
Irreversible field defect(retinal atrophy)

24. Tiagabine
• MOA: Inhibits GABA uptake
• Uses: Partial seizure
• Dose: 20-60mg/day
• Adverse effects: Dizziness, sedation
Fatigue
Tremor
Confusion

25. Gabapentine & Pregabaline
MOA: GABA analogue
Increase synthesis and release of GABA
Blocks calcium channel
Decrease glutamate release
GABAB agonist
Pharmacokinetics: Carrier mediated absorption(safe in high dose)
Minimum interaction
Excreted unchanged in urine

26. Dose:
Gabapentin:200-300mg TDS
Pergabaline:200-600mg TDS
Adverse effect:
Dizziness
Fatigue
Weight gain
Ataxia
Gabapentine & Pergabaline

27. Topiramate
MOA: Blocks sodium channel
GABAA receptor
Blocks AMPA receptor
Dose: 300-600mg/day
Uses: Generalized tonic clonic seizure, Partial seizure
Adverse effects: Sedation, Somnolence
Amnesia
Urolithiasis(inhibit carbonic anhydrase)
Teratogenic(hypospadias)

28. Zonisamide
MOA: Blocks sodium channel
Inhibit T type calcium channel
Uses: Partial seizure, GTC Seizure, Myoclonic seizure, Infantile spasm
Pharmacokinetics: Good bioavailability
Negligible protein binding
Dose: 100- 600mg/day
Adverse effects: Drowsiness, Amnesia
Rash
Kidney stone

29. Lamotrigine
MOA: Block voltage gated sodium channel
N type calcium channel
Inhibit release of glutamate
Uses: Partial seizure, GTC seizure, Atonic seizure, Absence seizure, Myoclonic
seizure
Dose:Start with 50mg/day, increase upto100-300mg/day
Adverse effects: Dizziness, ataxia, diplopia, rash
Interactions: Enzyme inducers (phenytoin) decrease half-life of lamotrigine

30. Felbamate
MOA: Blocks voltage gated sodium channel
Blocks NMDA receptor with NR2B subunit
Uses: Atonic seizure partial seizure, GTC seizure, atypical absence seizure
Dose: 2000-4000mg/day
Adverse effects: Nausea
Dizziness
Insomnia
Aplastic anemia
Hepatotoxicity

31. Lacosamide
• MOA: Blocks voltage gated sodium channel
• Binds CRMP-2(Collapsin response mediator protein)
• Uses: Partial seizure
• Dose: 50mg BD oral
• Increased 50mg BD every week till 200mg BD
• 100% Oral bioavailability
• Adverse effects: Well tolerated
Headache, Nausea, Dizziness

32. Treatment
• Underlying cause: Electrolyte imbalance
Drugs
CNS Lesion
• Avoidance of precipitating factors
• Antiepileptics:
Choice of drugs:
1. Generalized seizure: Carbamazepine, Phenobarbital, Phenytoin, Valproate
2. Partial seizure: Carbamazepine, Phenytoin, Valproate
3. Absence seizure: Valproate, Ethosuximide
4. Myoclonic seizure: Valproate, Clonazepam

33. When to start
• Recurrent seizure of unknown etiology
• Known etiology but cant be reversed
• Goal: Monotherapy
• First episode: If abnormal neurological examination
Abnormal EEG
Family history
Status epilepticus

34. Initiation and monitoring
• Response unpredictable
• Optimum dose: trail and error
• Start with lowest dose
• Increase to achieve steady state
• Do serum antiepileptic level
• Seizure frequency and side effects key determinants

35. • Switch: Seizure on maximum tolerated dose
• Add second drug with the first one
• Withdraw first gradually
Initiation and monitoring

36. When to discontinue
• Remain seizure free on medication for 1- 5yrs
• Single seizure type
• Normal neurological examination
• Normal EEG
Reduce dose in 3 months and withdraw
May re-occur

37. Refractory seizure
• Require combination of drugs
• Surgical treatment(temporal lobectomy)

38. Status epilepticus
• Continuous seizure 15 to 20 mins with impaired consciousness in
interictal period
• Emergency
• Irreversible neuronal damage

40. Seizure and pregnancy
• No antiepileptic is safe
• Avoid valproate
• Do not change drug
• Give folic acid 1-4 mg/day (antifolate)
• Oral vitamin K in last 2 weeks of pregnancy(enzyme inducing drugs,
cause deficiency of vitamin k dependent clotting factors)
• Infant: IV Vitamin K 1mg at birth