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  1. 1. TREATMENT OF EPILEPSY Dr.M.Purna chandra kala.MD, Professor,Dept.of Pharmacology, DCMS,Hyd
  2. 2.  CLASSIFICATION 1.Barbiturate Phenobarbitone 2.Deoxybarbiturate Primidone 3.Hydantoin Phenytoin,Fosphenytoin 4.Iminostibene Carbamazepine, Oxacarbazepine 5.Succinimide Ethosuximide 6.Aliphatic carboxylic acid Valproic acid(sodium valproate) 7.Benzodiazepines Clonazepam,Diazepam,Lorazepam,Clobazam
  3. 3. 8.Phenytrizine Lamotrigine 9.Cyclic GABA analogue Gabapentin 10.Newer drugs Vigabatrin, Topiramate, Tiagabin, Zonisamide, Levetiracetam
  4. 4. AEDs Old  Primidone  Phenobarbitone  Fosphenytoin  Phenytoin  Clobazam  Clonazepam  Ethosuximid  Valproate  Carbamazepine New  Lamotrigine  Oxcarbazepine  Topiramate  Gabapentin  Felbamate  Vigabatrin  Levatiracetam  Zonisamide  Tiagabin
  5. 5. Mechanism of action of AEDs Inhibition of voltage gated Na, Ca channels Na: phenytoin, carbamazepine, oxcarbazepine, lamotrigine, topiramate, felbamate, zonisamide Ca: ethosuximid, valproate? lamotrigine, topiramate, zonisamide Potentiaton of GABA mediated inhibition phenobarbital, benzodiazepins, vigabatrin, tiagabine, topiramate, valproate, gabapentin, felbamate Decrease of glutamate mediated excitation felbamate, topiramate
  6. 6. Efficacy of AEDs All seizure types: absence, myoclonic, generalised tonic- clonic seizures, partial seizures valproate, lamotrigine, topiramate clobazam, clonazepam phenobarbital, primidon felbamate levatiracetam, zonisamide Partial seizures, generalised tonic-clonic seizures carbamazepine, oxcarbazepine gabapentin, vigabatrin, tiagabine phenytoin Absence ethosuximid
  7. 7. Pharmacology of AEDs I. Hepatic metabolism valproate, carbamazepine, oxcarbazepine, lamotrigine, topiramate, clobazam, clonazepam, phenobarbital, primidon, phenytoin, ethosuximid, felbamate, tiagabin No metabolism gabapentin, vigabatrin (topiramate, levatiracetam) Hepatic enzyme induction carbamazepine, phenytoin, phenobarbital, primidon (oxcarbazepine) Hepatic enzyme inhibition valproate, felbamate
  8. 8. Pharmacology of AEDs II. Phenytoin 7-20 days Phenobarbital 10-30 Primidon 2-5 Valproate 2-5 Carbamazepine 3-5 Ethosuximid 7-12 Clobazam 4-5 Lamotrigine 3-10 Topiramate 3-6 Gabapentin 2-5 Vigabatrin 2-5 Steady state Binding to plasma proteins Pronounced (>90%) binding phenytoin valproate Moderate (30-80%) binding carbamazepine clobazam lamotrigine No or minimal (<20%) binding gabapentin vigabatrin topiramate ethosuximid
  9. 9. Side effects of AEDs  Allergy  Central nervous system side effects (dose dependent)  drowsiness, headache  dizziness, dysequilibrium  cognitive dysfunction (memory)  Idiosynchratic reactions / chronic side effects  bone marrow suppression  hepatic failure  rash  weight gain, weight loss  tremor  polycystic ovary syndrome  visual field defect
  10. 10. Selection of AEDs  Selection of AED is based on:  Seizure type / epilepsy syndrome  Other: side effects, pharmacology, drug interactions, comorbidities  As there are no major differences among first-line AEDs, safety and tolerability must be of paramount consideration in choosing AED.  Matching drugs to patients (holistic approach):  Side effects  Work  Sleep  Mood  Well being
  11. 11. Selection of AEDs Idiopathic generalised epilepsies valproate, topiramate, lamotrigine, levatiracetam Localisation related epilepsies (eg. temporale lobe epilepsy) carbamazepine, oxcarbazepine, valproate, lamotrigine, topiramate, gabapentin, levatiracetam Symptomatic generalised epilepsies West-syndrome Lennox-Gastaut syndrome vigabatrin felbamate, lamotrigine, valproate
  12. 12. Therapeutic principles  Aim: maximal seizure control, minimal side effects  Monotherapy  Usually gradual introduction of AED  Assessment of AED effect (seizure frequency)  After AED has reached steady state  Depends on the average time interval of seizures before treatment
  13. 13. Possible causes of AED inefficacy  Inadequate dose → dose escalation  Lack of compliance → measure blood AED levels  False diagnosis: the patient doesn’t have epilepsy  ‘Pseudoseizures’ → precise description of seizure, EEG / video monitoring  Inadequate selection of AED  True inefficacy of AED → AED switch  Other AED on monotherapy  AED combination
  14. 14. AED combinations  Rules of AED combination:  Establish optimal dose of baseline AED  Avoid combining similar modes of action  Add drug with multiple mechanisms  Titrate new drug slowly  Be prepared to reduce dose of original drug  Replace either drug if response is poor  Some effective combinations:  valproate-lamotrigine  valproate-carbamazepine/oxcarbazepine  valproate-topiramate  etc.
  15. 15. Drug interactions Enzyme inductors carbamazepine, phenytoin phenobarbital, primidon Increase of metabolism / decrease of efficacy valproate, lamotrigine, topiramate, carbamazepine oral contraception oral anticoagulation Enzyme inhibitors valproate Decrease of metabolism / increase in efficacy - toxicity lamotrigine, carbamazepine, phenytoin Does not cause interaction lamotrigine, gabapentin, topiramate, vigabatrin, tiagabin  
  16. 16. Therapeutic success- remission rates Partial epilepsies First AED in monotherapy: 43% Second AED in monotherapy: 7% Other monotherapies: 2% AED combination: 5% Total in remission: 57% Juvenile myoclonic epilepsy First AED (valproate) in monotherapy: 85% Altogether 65-70% of patients with epilepsy respond well to AED treatment.
  17. 17. Discontinuation of AED  After 3-5 seizure free years  A decision of both the doctor and patient  AED should be very slowly tapered, lasting weeks- months.  Discontinuation of AED is not recommended:  Earlier unsuccessful AED withdrawal  Earlier refractoriness to treatment  Known brain lesion  Juvenile myoclonic epilepsy
  18. 18. Epilepsy and pregnancy  Teratogenic risk  In normal population: 2-3%  In women on AEDs: 4-9%  Teratogenic risk is increased  High AED dose  Fluctuating plasma levels  Polytherapy  Occurrence of spina bifida in the family  Folic acid deficiency
  19. 19. Epilepsy and pregnancy: what to do?  Before conception:  Attain the best possible seizure control with the lowest possible AED dose, preferably in monotherapy  Folic acid profilaction 4 mg/day  During pregnancy:  During first trimester supplement folic acid 4 mg/nap  Change medication only if seizure control worsens  Screening of fetal malformations (ultrasound on week 16 and 20, AFP)  In case of enzyme inductor AEDs, give vitamin K in the third trimester
  20. 20. Epilepsy and breast feeding  Breast feeding is not contraindicated with women on AEDs.  Sleep deprivation can provoke seizures.
  21. 21. Epilepsy and driving  Driving is prohibited for one year after a seizure with loss of consciousness  Driving is permitted:  2-3 years of seizure free interval with patients on AEDs  2-3 years of seizure free interval after withdrawal of AEDs
  22. 22. THANK YOU