ANTIEPILEPTIC DRUGS

Dr. RAGHU PRASADA M SMBBS,MDASSISTANT PROFESSOR DEPT. OF PHARMACOLOGYSSIMS & RC.

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Definition

Epilepsies are the group of disorders of CNS characterized by paroxysmal cerebral dysrythmia, manifesting as brief episodes of loss of conciousness with or without characteristic body movements(convulsions), sensory or psychiatric phenomena.

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Classification of epilepsies

1. GTCS-generalised tonic clonic seizures-Major, grandmal Commonest Time -1-2 min Sequence –Aura Cry unconciousness tonic

spasms Clonic jerking prolonged sleepprolonged sleep depression of CNS function

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Absence seizures-minor, petitmal

Common in children Time -30 sec Momentary loss of conciousness Patient apparently freezes and stares

in one direction 3hz-spikes discharge- voltage

regulated Ca+ channels

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Atonic seizures (akinetic seizures)

Unconciousness with relaxation of all muscles due to excessive inhibitory discharges

Myoclonic seizures Infantive spasms- intermittent

muscle spasm and progressive mental deterioration

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Partial seizures

Simple partial seizures Time 30sec Localised sensory disturbancesComplex partial seizures-temporal lobe

epilepsybizzare confused behaviour Todds paralysis, jacksonian seizures- simple partial or

complex partial

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Aetiology

Genetic Brain lesions Infections Metabolic discharges Sudden withdrawal Television

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Main categories of therapeutics:

1. Inhibition of voltage-gated Na+ channels to slow neuron firing.

2. Enhancement of the inhibitory effects of the neurotransmitter GABA.

3. Inhibition of calcium channels.

4. Hyper –excitability of neurons, hypersyncrony of neurons

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Classification

Mechanism of drugs used in grandmal seizuresInhibition of use-dependent Na channelsPhenytoinCarbamazepineValproateLacosamideLamotrigine

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Drugs used in grandmal seizures

Enhancement of GABA ergic actionPhenobarbital and BenzodiazepinesVigabatrinTiagabine Valproic acidBlockade of NMDA or AMPA receptorsFelbamate, PhenobarbitalTopiramate Lamotrigine, Valproate

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Drugs used in grandmal seizures

Blockade of voltage gated N-type Ca+ channels Lamotrigine and Gabapentin

Selective binding to synaptic vesicular protein (SV2A)Levetiracetam By blocking the effect of neurotropic factorsLacosamide

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Mechanisms of drugs used in petit mal (absence seizures)

Inhibition of T type Ca channels Ethosuximide Valproic acid

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Na+ Channel Inhibitors

blocks voltage-gated sodium channels by selectively binding to the channel in the inactive state and slowing its rate of recoveryFinally glutamate release is inhibited

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Phenytoin or Diphenylhydantoin Limited water solubility – not given i.m. Slow, incomplete and variable absorption. Extensive binding to plasma protein. Metabolized by hepatic ER by hydroxylation. Chance

for drug interactions. Therapeutic plasma concentration: 10-20 µg/ml Shift from first to zero order elimination within

therapeutic concentration range.

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Phenytoin – Toxicity and Adverse Events

Acute Toxicity

High i.v. rate: cardiac arrhythmias ± hypotension; CNS depression.

Acute oral overdose: cerebellar and vestibular symptoms and signs:

nystagmus, ataxia, diplopia vertigo.

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Chronic Toxicity Folate Deficiency - megaloblastic anemia Hypoprothrombinemia and hemorrhage in

newborns Hypersenstivity Reactions – could be severe.

SLE, fatal hepatic necrosis, Stevens-Johnson syndrome.

Pseudolymphoma syndrome Teratogenic Drug Interactions: decrease (cimetidine,

isoniazid) or increase (phenobarbital, other AED’s) rate of metabolism; competition for protein binding sites.

Phenytoin – Toxicity

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Fosphenytoin

A Prodrug. Given i.v. or i.m. and rapidly converted to phenytoin in the body.

Avoids local complications associated with phenytoin: vein irritation, tissue damage, pain and burning at site, muscle necrosis with i.m. injection, need for large fluid volumes.

Otherwise similar toxicities to phenytoin.

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Na Channel Blockers

CARBAMAZEPINE: structurally related to TCAs-GTCS, trigeminal neuralgiaManic depressive psychosismay have adrenergic mechanism as wellAlso for trigeminal neuralgia Serious hematological toxicity: aplastic anemia,

aplastic anemia Antidiuretic effect increase ADHTeratogenicityD/I-enzyme inducerOXCARBAMAZEPINE:Mild enzyme inducer

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Na+ Channel Inhibitors: Zonisamide

is a sulfonamide derivative that has a broad spectrum of actionPartial, generalised tonic clonic and myoclonic seizures, lennox-gastaut syndrome

Other Mechanism of Action: ▪ Inhibits T-type Ca2+ currents.▪ Binds to GABA receptors.▪ Facilitates dopaminergic and serotonergic

neurotransmission.S/E-drowsiness, amnesia, kidney stones

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Na+ Channel Inhibitors- Lamotrigine

Other Mechanism of Action: May inhibit synaptic release of glutamate.

Indications: Adjunct therapy-Simple & complex partial seizuresGeneralized seizures of Lennox-Gastaut SyndromeMonotherapy: Simple & complex partial seizuresBipolar disorderS/E-dizziness, diplopia, enzyme inducers

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Felbamate

Wide spectrum antiepileptic Unpredictable toxicity Blocks voltage gated Na channels Blockade of NMDA receptorsUSES Drug refractory epilepsies- lennox-gastaut syndrome Atonic seizures, atypical seizures, partial seizures GTCSS/E- Aplastic anaemia, hepatotoxicity

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Levetiracetam

Piracetam derivative Binds selectively to SV2A protein of synaptic vesicles

in glutamatergic and GABAergic neurons. Partial seizuresS/E-Asthenia, DizzinessLACOSAMIDE-Acts by inhibiting voltage gated Na channelsCRMP-2(Collapsin Response Mediator Protein) Brain

Derived Neurotropic FactorepileptogenesisBioavailability -100%

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Enhancers of GABA Transmission- Phenobarbital The only barbiturate with selective anticonvulsant

effect. MOA-Bind at allosteric site on GABA receptor and

↑ duration of opening of Cl channel. ↓ Ca-dependent release of neurotransmitters at

high doses. Use dependent Na+ channels blockade AMPA receptors-inhibit glutamate Febrile seizures, simple partial P/K-Plasma t1/2- 100hrs Dose 60-180mg orally HS

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Enhancers of GABA Transmission

Toxic effects: Inducer of microsomal enzymes – drug interactions. sedation (early; tolerance develops) Gingival hyperplasia, hirsuitism Nystagmus & ataxia at higher dose; Osteomalacia, folate deficiency and vit. K deficiency. In children: paradoxical irritability, hyperactivity and

behavioral changes. Deoxybarbiturates: primidone: active but also

converted to phenobarbital. Some serious additional ADR’s: leukopenia, SLE-like.

C/I-Petitmal And Prophyrias

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Sedative - hypnotic- anxiolytic drugs. Bind to another site on GABA receptor. Other

mechanisms may contribute. ↑ frequency of opening of Cl channel.

Clonazepam and clorazepate for long term treatment of complex partial seizures.

Diazepam and lorazepam: for control of status epilepticus. Disadvantage: short acting.

Toxicities: chronic: lethargy drowsiness.in status epilepticus: iv administration

respiratory and cardiovascular depression. Phenytoin and PB also used.

Enhancers of GABA Transmission:Benzodiazepines

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Vigabatrin: Irreversible inhibitor of GABA transaminase.

Simple and complex partial seizures Drug refractory epilepsy and infantile spasm Potential to cause psychiatric disorders (depression

and psychosis). Weight gain Vigabatrin can cause irreversible visual field defects

Tiagabine: decreases GABA uptake by neuronal, extraneuronal tissues and increases the GABA content of brain

Enhancers of GABA Transmission

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Gabapentin and pregabalin

Developed as GABA analogues readily cross BBB Mechanism: Increases release of GABA Inhibit N type Ca channelsinhibit synaptic release of

glutamate Absorption of gabapentin from intestine depends on the

carrier system Resistant partial seizures, GTCS Chronic nerve injury α2δ subunits of L-type Ca channels, in

peripheral nerves, get upregulated resulting in various types of neuropathiesgabapentin binds to α2δ subunits

Post-herpetic neuralgia, trigeminal neuralgia, multiple sclerosis

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Valproic Acid

Effective in multiple seizure types. Blocks Na and Ca channels. Inhibits GABA transaminase. Increases GABA synthesis. Decrease in the glutamate Antiepileptic use- absence seizures GTCS, myoclonic seizures DOC- lennox gastaut syndrome Infantile spasms Non-epileptic use-manic depressive psychosis, Migraine, cluster headache, cushings syndrome, Tardive dyskinesia, trigeminal neuralgia

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Valproic Acid

Toxicity: most serious: fulminant hepatitis. More common if antiepileptic polytherapy in children < 2 years old.

Tremors, thrombocytopenia, hair loss Drug interactions: inhibits Phenobarbital and

phenytoin metabolism.

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Blockade of NMDA and AMPA receptors

TOPIRAMATE multiple mechanisms of action (Na channel, GABA

enhancement like BZD, antagonist at AMPA subtype of glutamate receptors (not NMDA).

GTCS, partial and absence seizures Lennox-gastaut syndrome S/E- urolithiasiscarbonic anhydrase inhibition

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ZONISAMIDE

Broad spectrum anticovulsant Blockade of use dependant Na channels Inhibition of t-type of Ca channels Negligible protein binding and renal excretion GTCS, myoclonic seizures Infantile spasms Lennox- gastaut syndrome S/E-drowsiness, amnesia, kidney stones

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Inhibitors of Calcium ChannelsEthosuximide

Drug of choice for Absence. Blocks Ca++ currents (T-currents) in the thalamus.

Pure petitmal drug Preferred in pregnancy GI complaints most common CNS effects: drowsiness lethargy Has dopamine antagonist activity ( In seizure control)

but causes Parkinsonian like symptoms. Potentially fatal bone marrow toxicity and skin

reactions THANK YOU