TREATMENT OF EPILEPSY

Dr.M.Purna chandra kala.MD,

Professor,Dept.of Pharmacology,

DCMS,Hyd

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

8.Phenytrizine Lamotrigine

9.Cyclic GABA analogue Gabapentin

10.Newer drugs Vigabatrin,

Topiramate,

Tiagabin,

Zonisamide,

Levetiracetam

AEDsOld

Primidone Phenobarbitone Fosphenytoin Phenytoin Clobazam Clonazepam Ethosuximid Valproate Carbamazepine

New Lamotrigine Oxcarbazepine Topiramate Gabapentin Felbamate Vigabatrin Levatiracetam Zonisamide Tiagabin

Mechanism of action of AEDsInhibition 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

Efficacy of AEDsAll 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

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

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

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

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

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 syndromevigabatrin

felbamate, lamotrigine, valproate

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

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

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.

Drug interactionsEnzyme inductors

carbamazepine, phenytoinphenobarbital, 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

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 epilepsyrespond well to AED treatment.

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

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

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

Epilepsy and breast feeding

Breast feeding is not contraindicated with women on AEDs.

Sleep deprivation can provoke seizures.

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

THANK YOU