ANTI EPILEPTIC DRUGS

DR. KAUSHIK MUKHOPADHYAY

DEPT. OF PHARMACOLOGY, ESI-PGIMSR

SEIZURE VS EPILEPSY

• Seizure is a paroxysmal event due to abnormal excessive or synchronous neuronal activity in the brain.

• Epilepsy describes a condition in which a person has recurrent seizures due to a chronic, underlying process.

this definition implies that a person with a single seizure, or recurrent seizures due to correctable or avoidable circumstances, does not necessarily have epilepsy.

ACTION POTENTIAL

Seizu

reFocal

Seizure

Without Dyscognitive Symptoms

With Dyscognitive Symptoms

GeneralizedSeizure

Absence

Typical

Atypical

Generalized Tonic Clonic Seizure

Tonic

Clonic

Atonic

Myoclonic

Focal, Generalizedor Unclear

(Epileptic spasms)

GENERATION OF SEIZURES

Absence Seizure

GTCSTonic phase:

Sustained powerful muscle contraction (involving all body musculature) which arrests ventilation

Clonic phase:Alternating contraction and relaxation, causing a reciprocating movement which could be bilaterally symmetrical

MECHANISMS OF ANTISEIZURE DRUGS:

• Modification of ion conductance Prolongation of Na+ channel inactivation Inhibition of `T` type Ca++ current

• Increase inhibitory (GABAergic) transmission – Cl- Channel.

• Glutamate receptor antagonism (NMDA, AMPA, or kainic acid)

SODIUM CHANNEL – 3 STATES

• PHENYTOIN• CARBAMAZEPINE• VALPROATE• TOPIRAMATE• LAMOTRIGINE• LACOSAMIDE

GABA MEDIATED

• BARBITURATE• BZD• VALPROATE• TIAGABINE• VIGABATRINE

T-TYPE CA2+ CHANNELS @ THALAMUS

PHENYTOIN(DILANTIN/EPSOLIN/EPTOIN)

Pharmacological actions:• Not CNS depressant• Abolish tonic phase of GTC seizure• Prevents spread of seizure activity• Tonic-clonic epilepsy is suppressed but no change in

EEG and aura..• In CVS – depresses ventricular automaticity,

accelerates AV conduction

PHENYTOIN – CONTD.Mechanism of action:• Prevents repetitive detonation of normal brain cells

during `depolarization shift`• Prolonging the inactivation of voltage gated Na+ channel• At concentrations 5- to 10-fold higher - reduction of

spontaneous activity and enhancement of responses to GABA

Pharmacokinetics• Slow oral absorption, 80-90% bound to plasma protein• Metabolized in liver by hydroxylation and glucoronide

conjugation• Elimination varies with dose – first order to zero order• T1/2 life is 12 to 24 hrs • Monitoring of plasma concentration

PHENYTOIN – CONTD.Adverse effects:• Hirsutism, coarsening of facial features • Gum hypertrophy and Gingival hyperplasia.• Hypersensitivity – rashes, lymphadenopathy• Megaloblastic anaemia• Osteomalacia• Hyperglycaemia• Cognitive impairment• Fetal Hydantoin Syndrome

Toxicity

• Ataxia, Vertigo, Confusion, Disorientation • i.v – local vascular injury, arrhythmia

PHENYTOIN – CONTD.

DDI:• CBZ & Phenytoin – induce each other’s metabolism• Valproate, Cimetidine, Isoniazid – inhibits metabolism• Acidic drug displaces from protein binding sites

Fosphenytoin

• Aqueous soluble prodrug

CARBAMAZEPINE (TEGRETOL/TEGRITAL)

• Chemically related to imipramine• Trigeminal neuralgia• Lithium like action – mood stabilizer• Resembles phenytoin in pharmacological actions• MOA:

• Stabilizes Na+ channel (Voltage gated) in inactivated state – less excitability

• Potentiation of GABA receptor

CARBAMAZEPINE – CONTD.

• Pharmacokinetics:• Poorly water soluble and

oral absorption is low• 75% bound to plasma

protein• Metabolized in liver• Substrate and inducer of

CYP3A4• Half life – 20 to 40hrs.

Decreases afterwards due to induction

• Adverse effects:• Autoinduction of metabolism• Hypersensitivity – rash,

photosensitivity, hepatitis, • granulocyte suppression and

aplastic anemia• ADH action enhancement –

hyponatremia and water retention

• Teratogenicity• Exacerbates absence seizures

CARBAMAZEPINE – CONTD.

• Uses:• Complex partial seizure• GTCS and SPS • Trigeminal and related neuralgias• Manic depressive illness and acute mania

• Available as tabs (100mg 200, 400 etc.) and syr.

Oxcarbamazepine

VALPROIC ACID(ENCORATE/VALPARIN)

• Broad spectrum anticonvulsant• Effective in partial, GTCS and absence seizures

• Mechanism:• Na+ channel inactivation• Ca++ mediated `T` current attenuation• Inhibition of GABA transaminase

• Pharmacokinetics:

well absorbed orally, 90% bound to plasma protein and completely metabolized in liver and excreted in urine t1/2 is 10-15 hrs.

VALPROIC ACID – CONTD.

• Adverse effects:• Elevated liver enzymes• Abdominal pain and

heartburn• Tremor, hair loss,

weight gain• hepatotoxicity• In Girls – polycystic

ovarian disease and menstrual irregularities

• Teratogenicity: spina bifida

• Drug Interactions:• Valproate and

carbamazepine induce each others metabolism

• Inhibits phenobarbitone metabolism and increases its plasma level

• Displaces phenytoin from protein binding sites and thereby decreases its metabolism – phenytoin toxicity

ETHOSUXIMIDE

• Drug of choice for absence seizures• Not plasma protein or fat binding• Mechanism of action involves reducing low threshold Ca2+

channel current (T-type channel) in thalamus

At high concentrations:• Inhibits Na+/K+ ATPase• Depresses cerebral metabolic rate

BZD

• Diazepam:• Commonly used as anticonvulsant in a variety of convulsions

• But, not used for long term – sedation effect

• Mechanism of anticonvulsant is mediated by same mechanism of sedation: Cl- channel

• Used in emergency control of convulsion – status epilepticus, tetanus, febrile convulsion etc.

• Status epilepticus – Diazepam, Lorazepam may be used as alternative

• Usually given 0.2 to 0.5 mg/kg body weight IV followed by repeated doses if required – maximum dose 100 mg/day

• Rectal diazepam

PHENOBARBITONE• First effective organic antiseizure agent• Mechanism:

• GABAA receptor mediated like other Barbiturates• Pharmacokinetics:

• Slowly absorbed and long t1/2 (80 – 120 hrs)• Metabolized in liver and excreted unchanged in kidney

• Uses:• Many consider them the drugs of choice for

seizures only in infants• GTC

• Dose:• 60 mg 1-3 times a day• Child: 3-6 mg/kg/day

PHENOBARBITONE – CONTD.

• Adverse effects:• Sedation• Behavioural abnormalities• Hyperactivity in children• Rashes, megaloblastic anaemia and osteomalacia

• Primidone:• Deoxybarbiturate• Converted to Phenobarbitone and PEMA Short half life

6-14 hrs

NEWER ANTIEPILEPTICS

1. Lamotrigine2. Topiramate3. Levetiracetam4. Tiagabine5. Vigabatrine6. Gabapentin7. Lacosamide

LAMOTRIGINE

• Phenyltriazine derivative, newer agent• CBZ like, Broad spectrum activity

• Mechanisms:• Delays recovery from inactivation of Na+ channels prolong Na+ channel

inactivation• Glutamate and aspartate inhibition: By directly blocking Na+ channels -

stabilizes pre synaptic membrane and prevent release by excitatory neurons

• Uses: Partial (simple and complex) and secondarily generalized, absence seizure, myoclonic seizure in youngs• Mood Stabilizer

• ADR: Rash

TOPIRAMATE

• Broad spectrum antiseizure drug• Pharmacological effects and MOA:

• Carbonic anhydrase inhibitor• Multiple actions – Na+ channel, K+ channel, AMPA-kainate subtypes of

glutamate• Pharmacokinetics:

• Rapidly absorbed orally, 10-20% bound to plasma protein, excreted unchanged in urine

• Metabolized by hydroxylation, glucoronidation and hydrolysis• Reduction in estradiol level

• Uses: GTCS, SP and CPS as supplement drug in refractory cases

GABAPENTIN

• GABA derivative and can cross BBB• MOA - Enhances GABA release, but not agonist of GABAA

Binds a protein in cortical membrane – similar to L type of voltage sensitive Ca++ channel, but do not alter Ca++ currents

• Pharmacokinetics:• Absorbed orally• Not metabolized in humans• Not bound to plasma proteins and excreted unchanged in urine

• ADR:• Sedation, dizziness

Thank You