Antiepileptics

- INTRODUCTION

- CLASSIFICATION OF SEIZURE

- ETIOLOGY

- PATHOPHYSIOLOGY

- ANTI-EPILEPTIC DRUGS

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.

GENERALISED SEIZURES

- involve cerebral hemisphere diffusely• GTCS-main seizure type , 10% of all persons with

epilepsy,lasts 1-2 min.• Usual seq.-auracryunconsciousnesstonic 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 SEIZUREshock like momentary contracture of group of muscle

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

SEIZUREunconscious with aura purposeless movements,emotional changes lasting 1-2 min

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

YOUNG ADULTS (18–35 YEARS) -Trauma -Alcohol withdrawal -drug use -Brain tumor -IdiopathicOLDER 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

Barbiturates• PhenobarbitoneIon Channel Inhibitors• Carbamazepine• Oxcarbamazepine• Phenytoin • EthosuximideBenzodiazepines• Diazepam• Clonazepam

Gabapentin

Pregabalin

Lamotrigine

Tiagabine

TopiramateFelbamate ZonisamideLacosamideRufinamide Vigabatrin Levetiracetam

Mechanism of Action

Anti epileptic drugs act primarily by blocking the initiation or spread of seizure.

Decrease propagation of action potentials

Na+, Ca++ influx (delay depolarization / prolong repolarization)

Cl- influx (hyperpolarize membrane) glutamate release

Exert antiepileptic effect without CNS depression

Mechanism of actionTherapeutic dose – prolonged

inactivation of voltage sensitive sodium channels

Higher concentration – Reduction in calcium influx Facilitate GABA Inhibit Glutamate – decrease intracellular

sodium ion

Absorption is slow per orallyHigh plasma protein binding(90%)

[widely distributed]Metabolised in liver by

CYP2C9,2C19First → 0 order kinetic(high dose)t half 12-24 hrs at therapeutic level

Gum hypertrophy Hirsutism, acne, coarsening of facial featuresMegaloblastic anaemiaOsteomalaciaFetal 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

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

Ist efficacious antiseizure Mechanism of actionEnhancement of GABAA receptor

mediated synaptic inhibition

Pharmacokinetics Slow oral absorption 40-60% plasma protein bound 25% renal excretion

Sedation (most frequent)Nystagmus,ataxia(excessive dosage)Irratability,confusion in childrenMegaloblastic anemiaosteomalacia

UsesGTCSPartial seizuresStatus epilepticusDose: 60 mg 1-3 times a day

Chemically related to imipramine

Mechanism of action

Like phenytoin –slow rate of recovery of Na channels from inactivation at therapeutic conc.

PHARMACOKINETICSAbsorption is slow and variable Metabolized in liver to 10 -11

epoxycarbamazepine(active form)

Initial t½ (20 – 40 hours)

Later (10 – 20 hours)Therapeutic conc. 6-12μg/dl

Sedation, dizziness, vertigo and ataxia,blurred vision,GIT upsetRashes, photodermatitis, hepatitisWater retention and hyponatremia – old ageAplastic 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

Effective in GTCS and SPS

Trigeminal and other neuralgias

MDP and acute mania

Dose : 200-400 mg TDS

Children- 15-30 mg /kg /d

10 mono hydroxy derivative of carbamazepineAdvantage –weak enzyme induction Conc of VALPROATE ,PHENYTOIN not

decreased

USESIn partial seizures

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

GIT –nausea,vomiting,anorexiaHeadache Drowsiness,dizziness,agitationInability to concentrate Bone marrow

depression(pancytopenia,thrombocytopenia)

IndicationAbsence seizure

Dose: 20-30 mg /kg/d

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

Anorexia, vomiting, drowsiness, ataxia,

tremor

Alopecia

Weight gain

Fulminant hepatitis below 3 years age(inc.

hepatic tranaminases)

Neural tube defect – pregnancy

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

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 epilepticusTetanusEclampsia

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

Action like carbamazepineBroad 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

Absorbed well and metabolized in liver

Drug Interaction

- Phenytoin carbamazepine or phenobarbitone decrease t½

- Valproate increase plasma level - Lamotrigine decreases valproate plasma

level

ADR

Sleepiness, dizziness, ataxia, diplopia

and vomiting ,Rash – severe reaction -

MECHANISM OF ACTION enhances GABA release

PHARMACOKINETICSAbsorption well, excretion unchanged in

urine

ADRSedation, dizziness, unsteadiness

INDICATION Simple partial seizureRefractory partial seizuresComplex partial seizure Dose: 300 mg OD , increase up to 300- 600 mg TDS

as required

MECHANISM OF ACTIONinhibit gaba transporter GAT-

1reduces gaba uptake in neuronsPharmacokineticsRapid oral absorptionExtremely plasma protein boundLiver metabolism by CYP3A

indicationAdd on therapy of partial seizures

ADRSedation, abdominal pain

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

Mechanism of actionInhibit t type Ca channelsProlong inactivation of Na channel

pharmacokineticsComplete oral absorption40% binding to plasma protein85% urine excretion

Phenytoin,phenobarbitone,carbamazepine-decreases its level

ADRSomnolecenceAtaxia,anorexia,nervousnessRenal Calculi USESPartial Seizure(adjunctive)Dose25-100 mg BD

Partial Seizure(adjunctive In >17yrs) MECHANISM OF ACTIONInactivation of Na channel

RUFINAMIDEAdjunctive treatment of lennox gastaut

syndrome MECHANISM OF ACTIONSlow inactivation of Na channels

Refractory partial seizureInfantile spasm MECHANISM OF ACTION

Irreversible GABA tranaminase inhibitorincrease GABA

LEVETIRACETAMRefractory partial seizures Mechanism of action is not knownFree of drug interactions Few side effectsGood tolerability , now increasingly used in CPS, GTCSDOSE: 0.5 mg BD

seizure type first line drugs second line drugs

Simple partial seizure Carbamazepine phenytoin valproate

Gabapentin lacosamide tiagabine rufinamide topiramatezonisamide

Complex partial seizure carbamazepine phenytoin valproate

Gabapentin lacosamide tiagabine rufinamide topiramatezonisamide

Partial with generalised tonic clonic seizure

carbamazepine phenytoin valproate phenobarbital

Gabapentin lacosamide tiagabine rufinamide topiramatezonisamide

Seizure type First line drugs second line drugs

Absence seizure Valproateethosuximide

LamotrigineTopiramate

Myoclonic seizure ValproateClonazepam

LevetiracetamLamotrigine

Tonic clonic seizure

carbamazepine phenytoin valproate phenobarbital

Lamotrigine Topiramate