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ANTIEPILEPTIC DRUGS Department of Pharmacology NEIGRIHMS, Shillong

Antiepileptic drugs (new) - drdhriti

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Page 1: Antiepileptic  drugs (new) - drdhriti

ANTIEPILEPTIC DRUGS

Department of Pharmacology NEIGRIHMS, Shillong

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HISTORY OF EPILEPSY

In 400 B.C., the early physician Hippocrates suggested that epilepsy was a disorder of the brain

Famous Persons Afflicted: ALEXANDER THE GREAT JULIUS CAESAR NAPOLEON LEWIS CARROLL

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WHAT ARE EPILEPSIES?

Definition: These are Group of disorders of the CNS characterized by paroxysmal cerebral dysrhythmia, manifesting as brief episodes (seizure) of loss of consciousness, with or without characteristic body movements (convulsions), sensory or psychiatric phenomena

What is a seizure? A seizure is a transient alteration of behaviour due to the

disordered, synchronous, and rhythmic firing of populations of brain neurons. Seizure can be non-epileptic and can be evoked in normal brain

A seizure is a paroxysmal behavioral spell generally caused by an excessive disorderly discharge of cortical nerve cells

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EPILEPSIES – CLINICALLY

• Epilepsy is a syndrome of two or more unprovoked or recurrent seizures on more than one occasion

• Epileptic seizures range from clinically undetectable (electrographic seizure) to convulsions

• Not to be confused: Remember its Not only falling down and unconsciousness of patients: Alteration in mental state, tonic or clonic movements, convulsions, and various other psychic symptoms

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CLASSIFICATION OF EPILEPTIC SEIZURES Generalized:

1. Generalized tonic-clonic seizure2. Absence seizure3. Tonic seizures4. Atonic Seizure5. Myoclonic seizure6. Infantile spasm

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TYPES OF SEIZURES – CONTD.

Partial (focal) Seizures: 80% of Adult epilepsies

Simple Partial Seizures Complex Partial Seizures Simple partial or complex partial secondarily

generalized

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GENERALIZED SEIZURES

1. Generalized tonic-clonic GTCS/major epilepsy/grand mal Commonest of all Lasts for 1-2 minutes Aura-cry-unconsciousness-tonic phase-clonic phase Usually occurs in both the hemispheres Manifestations are determined by cortical site of seizure

occurrence 2 phases: tonic phase followed by clonic phase Tonic 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

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EEG CHANGES IN GTCS

Tonic: Rythmic high frequency, high voltage discharges with cortical neurons undergoing sustained depolarization, with protracted trains of action potentials

Clonic: Characterized by groups of spikes on the EEG and periodic neuronal depolarizations with clusters of action potentials

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GENERALIZED SEIZURES – CONTD.

Absence seizure: Also called minor epilepsy/petit mal Usually in Children and lasts for 1-2 minutes Typical generalized spike-and-wave type

discharges at 3 per second (3 Hz) Momentary loss of consciousness (not

convulsion), patient stares at one direction No motor (muscular component) No convulsions Minor muscular twitching restricted to eyelids

(eyelid flutter) and face No loss of postural control.

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GENERALIZED SEIZURES – CONTD.

Atonic Seizures: Unconsciousness with relaxation of all muscles Patient falls down Loss of postural tone, with sagging of the head or falling

Myoclonic Seizures: Isolated clonic jerks associated with brief bursts of multiple

spikes in the EEG Momentary contractions of muscles of limbs or whole body No loss of postural control

Infantile spasm: An epileptic syndrome Characterized by brief recurrent myoclonic jerks (muscle

spasm) of the body with sudden flexion or extension of the body and limbs

Progressive mental deterioration

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PARTIAL (FOCAL) SEIZURES

Simple partial seizure (Jacksonian)

Lasts for 20 – 60 seconds Motor, sensory, vegetative or

psychic symptomatology Typically consciousness is

preserved Confined to a group of

muscles or localized sensory disturbances depending on area of cortex involved

For example – if motor cortex of the left thumb then jerking movement of left thumb, and if it is sensory cortex then paresthesia of left thumb.

No alteration of consciousness

EEG: Excessive synchronized discharge by a small group of neurons. Contralateral discharge

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SCHEME OF SEIZURE SPREADSimple (Focal) Partial

Seizures

Contralateral spread

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PARTIAL (FOCAL) SEIZURES – CONTD. Complex partial seizure (temporal

lobe/psychomotor epilepsy)

Focus is located in temporal lobe Confused behaviour and purposeless movements and

emotional changes lasting for 30 seconds to 2 minutes An aura often present Automatisms (repetitive coordinated movements)

perioral and hand automatisms Wide variety of clinical manifestations and Consciousness is

impaired

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COMPLEX PARTIAL SEIZURE – CONTD.

….Deja vu …

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PARTIAL (FOCAL) SEIZURES – CONTD. Secondarily generalized (Jacksonian):

Partial seizures initially Followed by generalized tonic-clonic

seizure

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SCHEME OF SEIZURE SPREAD

Complex Partial Seizures

Complex Secondarily Generalized Partial Seizures

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PARTIAL (FOCAL) SEIZURES – CONTD.

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STATUS EPILEPTICUS

Continuous seizure activity for more than 30 minutes, or 2 or more seizures without recovery of consciousness

Its an Emergency Condition: Recurrent tonic-clonic convulsions without recovery in between

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EXPERIMENTAL MODELS

1. Maximal electroshock seizures (MES): tonic phase abolished by drugs effective in GTCS and also Partial seizures

2. PTZ clonic seizures (Pentylenetetrazole): Can be prevented by drugs effective in absence seizure (Petit mal)

3. Kindled seizures: bursts of weak electrical impulses – tonic-clonic seizure

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WHY EPILEPSY OCCURS?

Children: Birth traumas, infections – meningitis and congenital abnormalities

Middle age: Alcohol, infections, head injury and Drugs like cocaine, low blood sugar, low oxygeen, low blood Na+ and low Ca+ etc.

Elderly: Stroke, tumors etc. Congenital:

Hippocampus DYSGENESIS (FAILURE OF CORTEX TO GROW PROPERLY)\

VASCULAR MALFORMATIONS AT LEAST EIGHT SINGLE LOCUS GENETIC DEFECTS ARE

ASSOCIATED WITH EPILEPSY – motor cortex, somatosensory cortex, visual cortex, auditory cortex, temporal lobe cortex and olfactory.

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CLASSIFICATION OF ANTIEPILEPTIC DRUGS Hydantoins: phenytoin, phosphenytoin Barbiturates: phenobarbitone Iminostilbenes: carbamazepine,

oxcarbazepine Succinimides: ethosuximide Aliphatic carboxylic acid: Valproic acid,

divalproex Benzodiazepines: clonazepam, diazepam,

lorazepam New compounds: gabapentin,

lamotrigine, tiagabine, topiramate, vigabatrin, zonisamide, felbamate

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MECHANISMS OF SEIZURE & ANTISEIZURE DRUGS:

Most common ones: 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)

Genetic mechanism

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The Sodium Channel:

A. Resting State

B. Arrival of Action Potential causes depolarization and channel opens allowing sodium to flow in.

C. Refractory State, Inactivation – reduce the rate of recovery.

Na+

Na+

Na+

Sustain channel in this

conformation

Anticonvulsant mechanism – contd.

m gate

h gate

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THE SODIUM CHANNEL – CONTD.

Drugs acting via this channel: Phenytoin, Sodium Valproate,

Carbamezepine, Lamotrigine, Topiramide and Zonisamide

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ANTICONVULSANT MECHANISM – CONTD.T type Ca++ current inhibition: Thalamic neurons exhibit prominent T

current which is a low threshold Ca++ current

T type current is responsible for 3 Hz spike-and-wave

Throughout the thalamus `T` current has large amplitudes – thalamocortical oscillations

Bursts of action potential is by action of T current

In absence seizure Drugs – ethosuximide, valproate and

trimethadione

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ANTICONVULSANT MECHANISM – CONTD.

The GABA mediated CL- channel opening

Drugs: barbiturates, benzodiazepines, vigabatrin, gabapentin and valproate

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PHENOBARBITONE

First effective organic antiseizure agent Mechanism:

Mechanism of CNS depression like other barbiturates, but less effect on Ca++ channel and glutamate release – less hypnotic effect

GABAA receptor mediated like other Barbiturates Continued use – sedation effect lost but not anticonvulsant

action Raises seizure threshold and limits spread Suppresses kindled seizures

Pharmacokinetics: Slowly absorbed and long t1/2 (80 – 120 hrs) Metabolized in liver and excreted unchanged in kidney Single dose after 3 wks. – steady state

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PHENOBARBITONE – CONTD.(GARDENAL/LUMINAL)

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

Uses: Many consider them

the drugs of choice for seizures only in infants

GTC SP and CPS

Dose: 60 mg 1-3 times a

day Child: 3-6

mg/kg/day Available as tabs –

30/60mg, syr. and inj.

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PHENYTOIN(DILANTIN/EPSOLIN/EPTOIN)

Pharmacological actions: Not CNS depressant But muscular rigidity and excitement at

toxic doses Abolish tonic phase of GTC seizure No effect on clonic phase 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

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PHENYTOIN – CONTD.

Mechanism of action:

Prevents repetitive detonation of normal brain cells during `depolarization shift`

Prolonging the inactivation of voltage sensitive Na+ channel

No high frequency discharges

Na+ channel recovers No interference with

kindling – only on high frequency firing

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 Cannot metabolize by

liver if plasma conc. Is above 10 mcg/ml

Monitoring of plasma concentration

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PHENYTOIN – CONTD.

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

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PHENYTOIN SODIUM – CONTD.

Phenytoin Toxicities

Fetal Hydantoin Syndrome

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PHENYTOIN SODIUM – CONTD.

Uses: It is the first line antiepileptic for GTCS, no effect in

absence seizure Status epilepticus Trigeminal neuralgia

– 2nd to Carbamazepine

Available as caps/tabs/inj

25 to 100 mg caps and tabs

Drug Interactions: Phenytoin and

carbamazepine increases each others metabolism

Induces microsomal enzyme – steroids, digitoxin etc

Phenytoin metabolism inhibition – by warfarin, isoniazide etc.

Sucralfate – decreases phenytoin ebsorption

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CARBAMAZEPINE (TEGRETOL/TEGRITAL) Chemically related to imipramine Trigeminal neuralgia Lithium like action – mood stabilizer Resembles phenytoin in pharmacological actions Unlike phenytoin – inhibits kindling, modifies

electroshock seizures and raises threshold to PTZ and electroshock

MOA: Stabilizes Na+ channel (Voltage gated) in

inactivated state – less excitability Potentiation of GABA receptor

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CARBAMAZEPINE – CONTD.

Pharmacokinetics: Poorly water soluble and

oral absorption is low 75% bound to plasma

protein Metabolized in liver:

active 10-11 epoxy carbamazepine

Substrate and inducer of CYP3A4

Half life – 20 to 40hrs. Decreases afterwards due to induction

Adverse effects: Autoinduction of

metabolism Nausea, vomiting,

diarrhoea and visual disturbances

Hypersensitivity – rash, photosensitivity, hepatitis, granulocyte suppression and aplastic anemia

ADH action enhancement – hyponatremia and water retention

Teratogenicity Exacerbates absence

seizures

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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

Interactions: Enzyme inducer –

reduce efficacy of OCPs and others

Metabolism is induced by – phenobarbitone, phenytoin, valproate

Inhibits its metabolism – isoniazide and erythromycin

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ETHOSUXIMIDE

Drug of choice for absence seizures Does not modify maximal electroshock seizure or

inhibit kindling High efficacy and safety Not plasma protein or fat binding Mechanism of action involves reducing low threshold

Ca2+ channel current (T-type channel) in thalamusAt high concentrations: Inhibits Na+/K+ ATPase Depresses cerebral metabolic rate Potentiates GABA

Phensuximide = less effective Methsuximide = more toxic

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ETHOSUXIMIDE – CONTD.

Toxicity: Gastric distress, including, pain, nausea and

vomiting Lethargy and fatigue Headache Hiccups Euphoria Skin rashes

Doses: 20-30mg/kg/day Available as syr./caps.

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VALPROIC ACID(ENCORATE/VALPARIN)

Broad spectrum anticonvulsant Effects on chronic experimental seizure and kindling Potent blocker of PTZ seizure 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.

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VALPROIC ACID – CONTD.

Adverse effects: Elevated liver enzymes

including own – rise in serum transaminase

Nausea and vomiting Abdominal pain and

heartburn Tremor, hair loss, weight

gain Idiosyncratic

hepatotoxicity In Girls – polycystic

ovarian disease and menstrual irregularities

Negative interactions with other antiepileptics

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

Available as tabs. (200/300/500, syr. and inj.)

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GABAPENTIN

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

Originally designed to be centrally active GABA agonist – rapid transfer across BBB

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

Pharmacological Effects: Inhibits hindlimb extension in ME seizure Inhibits clonic seizures induced by PTZ Efficacy is equal to valproic acid but different from

carbamazepine and phenytoin

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GABAPENTIN – CONTD.

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

urine Half life is 4 to 6 hrs. No known drug interaction

Uses: Partial seizures with or without secondary generalization in

addition to other drugs 900-1800mg/day is equivalent to 300 mg/day of

carbamazepine if used alone Usual starting dose is 300mg/day

Adverse effects: somnolence, dizziness, ataxia etc.

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LAMOTRIGINE

Phenyltriazine derivative, newer agent Carbamazepine like action profile and modify MES seizures Originally, as antifolate agent 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

Inhibition of Ca++ in neurons Actions: Broad spectrum activity – action in areas other than Na+

channels, suppresses tonic hind limb extension in ME seizure, no action on PTZ seizures,

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

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LAMOTRIGINE – CONTD.

Pharmacokinetics: Completely absorbed from GIT and metabolized

by glucoronidation Plasma half-life – 15 to 30 hrs Phenobarbitone, carbamazepine and phenytoin –

reduces half life Valproate – increases plasma concentration but its

concentration reduces Together with Carbamazepine – increase in 10,11-

epoxide and toxicity Uses: Monotherapy and add on therapy in simple

partial and secondarily generalized seizures. Daily dose – 100 to 300 mg

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TOPIRAMATE

Sulfamate substituted monosaccharide Pharmacological effects and MOA:

Broad spectrum antiseizure drug Carbonic anhydrase inhibitor Antiseizure activity against PTZ, ME seizure and partial and

secondarily generalized tonic-clonic kindling Multiple actions – Na+ channel, K+ channel, GABAA, 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

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BENZODIAZEPINES

Mainly used agents – Clonazepam, Diazepam, Lorazepam and Clobazam

Common Antiseizure properties: Prevents PTZ induced seizures prominently and

modifies electroshock seizure pattern Clonazepam has potent effect on PTZ

induced seizures but almost nil action on ME seiures

Suppress the spread of kindled seizures and generalized convulsions

Do not abolish abnormal discharges at site of stimulation

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DIAZEPAM

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. 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

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BENZODIAZEPINES – CONTD.

Adverse effects: Long term use of Clonazepam – drowsiness and lethargy –

tolerance to antiseizure effects Muscular incoordination and ataxia Hypotonia, dysarthria and dizzziness Behavoiural abnormalities in children – aggression,

hyperactivity, irritability and difficulty in concentration Increased bronchial and salivary secretions Exacerbation of seizures

Therapeutic uses: Clonazepam in absence seizure and myoclonic seizure in

children (1 to 6 months) Dose initial – 1.5mg/day, children – 0.01 to 0.03mg/kg/day Status epilepticus – Diazepam, Lorazepam may be used as

alternative

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TREATMENT OF EPILEPSIES

1. Aim of the treatment: Control and prevent all seizure activity (seizure - freedom and

improvement in quality of life!) To search the cause of epilepsy Attempts to remove the causes Symptomatic treatment with antiepileptic drugs To consider status epilepticus as medical emergency and treat

efficiently and promptly2. Initiation of treatment:

Initiate therapy even if it is isolated tonic-clonic seizure with family history of seizure, abnormal neurological examination, abnormal EEG and an abnormal MRI

Treat with monotherapy, Substitute another drug if fails Combination therapy – only when all monotherapy fail Therapeutic monitoring of drugs – dose adjustments

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3. CHOICE OF DRUGS: ACCORDING TO THE SEIZURE TYPES

Seizure types 1st choice 2nd choice

Generalized tonic-clonic or simple partial seizure

Carbamazepine, Phenytoin and Valproic acid

Phenobarbitone and Valproate

Absence seizure Valproate Ethosuximide

Complex partial seizure with or without generalization

Phenytoin, Carbamazepine and Valproate

GabapentinLamotrigine

Myoclonic Valproate LamotrigineTopiramate

Status epilepticus DiazepamLorazepam

Phenytoin IVPhosphenytoin IV

Febrile convulsions Diazepam rectal 0.5mg/kg

-

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TREATMENT OF EPILEPSIES – CONTD.

4. Withdrawal of drugs: Gradual withdrawal Prolong therapy – life long/3yrs after last seizure Withdrawal – childhood epilepsy, absence of family history,

primarily generalized tonic-clonic seizure and normal EEG

5. Seizure diary6. Antiepileptics and pregnancy

Drugs should not be stopped if conceive – status epilepticus

Fits during pregnancy – birth defects, mental retardation etc.

Folic acid and vit.K supplementation

7. Care during attacks: tonic-clonic seizures8. Surgical removal

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GENERALIZED ONSET SEIZURES – DRUG THERAPY

Tonic-clonic, myoclonic, and absence seizures: 1st line drug is usually valproate

Generalized seizures: Phenytoin and carbamazepine are

effective on tonic-clonic seizures but not other types of seizures

Absence seizures: Valproate and ethosuximide are equally

effective in children, but only valproate protects against the tonic-clonic seizures that sometimes develop

Risk of hepatoxicity with valproate—should not be used in children under 2

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PARTIAL SEIZURES - TREATMENT

Without generalization Phenytoin and carbamazepine may be

slightly more effective With secondary generalization

First-line drugs are carbamazepine and phenytoin (equally effective)

Valproate, phenobarbital, and primidone are also usually effective

Phenytoin and carbamazepine can be used together (but both are enzyme inducers)

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PARTIAL SEIZURES – CONTD.

Adjunctive (add-on) therapy: newer drugs gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, and zonisamide

Phenytoin and carbamazepine failure: Lamotrigine, oxcarbazepine, felbamate approved for monotherapy

Refractory partial seizures: Topiramate can be effective

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STATUS EPILEPTICUS

Goal of therapy: Rapid termination of seizure activity – more difficult to

control – permanent brain damage Prompt treatment with effective Drugs Attention to hypoventilation and hypotension Treatment is IV only

Diazepam 10mg IV bolus injection (2mg/min) Fractional dose at every 10 min. or titrated dose by slow

infusion Lorazepam: 0.1mg/kg

Followed by Phenobarbitone IM/IV (100-200mg)/min or Phenytoin slow IV in saline (25-50mg/min)

Resistant cases (refractory): IV anaesthetics (Propofol or thiopentone)

General supportive measures

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IMPORTANT TO STUDY

Mechanism of action and Adverse effects/Uses of Phenytoin/Valproate/Carbamazepine/ETHSX

Short Notes: Gabapentine, Lamotrigine, Topiramate

Clinical: Pharmacotherapy of Status Epilepticus Pharmacotherapy of GTCS

Reasoning Questions: Valproic acid in absence seizure Phenytoin is not used in absence seizure Benzodiazepines as anticonvulsant

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HAVE A NICE DAY !

Thanks