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8/12/2019 Treatment of Epilepsy in View of Newer Antiepileptic
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PRESENTED BY
Dr DHARMENDERGUPTAPG II YR
DEPT . OF PHARMACOLOGY
SRMSIMS
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8/12/2019 Treatment of Epilepsy in View of Newer Antiepileptic
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• The epilepsies are common & frequently devastating
disorder
• Approx 1% of world’s population has epilepsy
• Epilepsy is a heterogeneous symptom complex- a chronic
disorder characterized by recurrent seizures
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• Seizures are finite episodes of brain
dysfunction resulting from abnormal discharge
of cerebral neurons
• Seizures- transient alteration of behavior d/tdisordered, synchronized & rhythmic firing of
population of brain neurons
• The causes of epilepsy ranges from infection
to neoplasm & head injury
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• Congenital defects, head injuries, trauma, hypoxia
• Infection e.g. meningitis, brain abscess, viral encephalitis
• Concussion, depressed skull, fractures.
• Brain tumors (including tuberculoma), vascular occlusion.
• Drug withdrawal, e.g. CNS depressants .
• Fever in children (febrile convulsion).
• Hypoglycemia
• PKU
• Photo epilepsy
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Fatigue,
Stress,
Poor nutrition,
Alcohol
Sleep deprivation.
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Primary
Types of
s
(focal)
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A drug which decreases the frequencyand/or severity of seizures in people with
epilepsy
Treats the symptom of seizures, not theunderlying epileptic condition
Goal—maximize quality of life by minimizing
seizures and adverse drug effects
P-Slide 7April 12, 2014
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DrugsSeizure disorder
Carbamazepine orValproate or
Phenytoin or
Phenobarbital
Tonic-clonic(Grand mal)Drug of Choice
Topiramte
Lamotrigine (as adjunct or alone) Gabapentin (as adjunct)
Alternatives:
Carbamazepine or Topiramte or
Phenytoin or
Valproate
Partial (simple or complex)
Drug of choice
Phenobarbital
Lamotringine (as adjunct or alone)
Gabapentin (as adjunct )
Alternatives:
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April 12, 2014 9
Valproate or EthosuximideAbsence ( petit mal)
Drug of cho ice
Clonazepam,LamotrigineAlternat ives:
ValproateMyoclonic, Aton ic
Drug of cho ice
ClonazepamAlternat ives:
Diazepam, i.v.
or Phenytoin, i.v. or Valproate
Status Epi lept icus
Drug of cho ice
Phenobarbital, i.vAlternat ives:
Diazepam, rectal*
Diazepam ,i.v
Valproate
Febrile Seizures
* Preferred
8/12/2019 Treatment of Epilepsy in View of Newer Antiepileptic
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• Up to 80% of pts can expect partial or completecontrol of seizures with appropriate treatment.
• Antiepileptic drugs suppress but do not cure
seizures
• Antiepileptics are indicated when there is two or
more seizures occurred in short interval (6m -1 y)
• An initial therapeutic aim is to use only one drug
(monotherapy)April 12, 2014 10
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• Advantage of Mono-therapy:
• Fewer side effects, decreased drug-drug interactions,
better compliance, lower costs
• Addition of a second drug is likely to result in
significant improvement in only approx. 10 % of
patients.
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when a total daily dose is increased, sufficient time(about 5 t 1l2) should be allowed for the serumdrug level to reach a new steady-state level.
• The drugs are usually administered orally
• The monitoring of plasma drug levels is very
useful
• Precipitating or aggravating factors can affectseizure control by drugs
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• The sudden withdrawal of drugs should be
avoided
withdrawal may be considered after seizure- free
period of 2-3 or more years
• Relapse rate when antiepileptics are withdrawn is
20 -40 %
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• Normal neurological examination
• Normal IQ
• Normal EEG prior to withdrawal
• Seizure- free for 2-5 yrs or longer
• NO juvenile myoclonic epilepsy
• withdrawal may be encouraged after careful assessment of the
individual patient.April 12, 2014 14
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1. Vigabatrin 1989
2. Gabapentin , 1993
3. Felbamate 1993
4. Lamotrigine 19945. Topiramate 1996
6. Tiagabine 1997
7. Levetiracetam 1999
8. Zonisamide 2000
9. Lacosamide -2008
10. Rufinamide
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• NEWER AGENTS DIFFER FROM OLDER
DRUGS BY
Relatively lack of drug-drug interaction
(simple pharmacokinetic profile) Improvedtolerability
HOWEVER THEY ARE
Costly with limited clinical experience
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Pharmacological effects:Drug of choice for infantilespasms
• Not bound to proteins ,Not metabolized andexcreted unchanged in urine
• Plasma t1/2 4-7 hrsMechanism of action :
Inhibits GABA metabolising enzyme & increase GABAcontent in the brain( similar to valproate).
Side effects:
Visual field defects, psychosis and depression (limitsits use).
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• Structural analogue of GABA .May increase the activity of
GABA or inhibits its re-uptake.
Pharmacokinetics:
Not bound to proteins
Not metabolized and excreted unchanged in urine
• Does not induce or inhibit hepatic enzymes (similar to
lamotrigine)
• Plasma t ½ 5-7 hours
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• Side effects:
• Somnolence, dizziness, ataxia, fatigue and nystagmus.
• Uses:
• As an adjunct with other antiepileptics
• Considered to be first line drug in diabetic neuropathy,
post herpetic neuralgia
• Can also be used for prophylaxis of migraine
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• Wider spectrum of antiepileptic activity
• Has not been popular due to its unpredictable toxicity
• Blocks voltage –gated Na+ channels
• useful in drug refractory epilepsies such as Lennox-
Gastaut syndrome.
• Other indications –
atonic seziures , atypical absenceseziures , partial seziures and GTCS
• s/e – insomnia ,nausea , dizziness, ataxia
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• Mechanism of Action:
Inhibits excitatory amino acid release (glutamate & aspartate )
by blockade of Na channels.
• Uses:
• As add-on therapy or as monotherapy in refractory cases of
partial seizures and GTCS
• Side effects:
• Skin rash, somnolence, blurred vision, diplopia, ataxia,
headache, aggression, influenza – like syndrome
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Resembles phenytoin in its pharmacological effects
Well absorbed from GIT
Metabolized primarily by glucuronidation
Does not induce or inhibit C. P-450 isozymes ( its
metabolism is inhibited by valproate )
Plasma t 1/2 approx. 24 hrs.
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• Well absorbed orally ( 80 % )
• Food has no effect on absorption
• Has no effect on microsomal enzymes
• 9-17 % protein bound ( minimal )
• Mostly excreted unchanged in urine
• Plasma t1l2 18-24 hrs
• Mechanism of Action:
• Blocks sodium channels (membrane stabilization) and also
potentiates the inhibitory effect of GABA.
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Side effects:
• Psychological or cognitive dysfunction
• Weight loss
• Sedation
• Dizziness
• Fatigue
• Urolithiasis
• Paresthesias (abnormal sensation )
• Teratogenecity (in animal but not in human)
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• Adjunctive therapy in partial and generalized tonic-clonic seizures
• Bioavailability > 90 %
• Highly protein bound ( 96% )
• Metabolized in the liver
• Plasma t ½ 4 -7 hrs
• Mode of action:
• inhibits GABA uptake and increases its level
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• Side effects:
• Asthenia
• Sedation
• Dizziness
• Mild memory impairment
• Abdominal pain
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• Mechanism –
uncertain
• Binds to proteins of synaptic vesicles in
glutamatergic and GABAergic neurons
• used specifically for treating partial seziures .
• Dose -500mg ,bd
• s/e – somnolence ,asthenia , dizziness
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Pharmacokinetics:• Well absorbed from GIT (100 %)
• Protein binding 40%
• Extensively metabolized in the liver
• No effect on liver enzymes• Plasma t ½ 50 -68 hrs
Clinical Uses:Add-on therapy for partial seizures
Side Effects:Drowsiness, ataxia , headache, loss of appetite,nausea&
vomiting, Somnolence .
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• Acts by inhibiting sodium channels
• Dose – 50 mg BD orally increasing 100 mg every
week till 300mg BD
• s/e headache , nausea , dizziness ,
• Has 100% oral bioavailability
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• Triazole derivative
• Enhances slow activation of voltage gated Na+
channels
• Limits sustained repetitive firing
• Used as adjunctive treatment of seziures associated
with Lennox – Gastaut syndrome in children of 4
years and older and in adults as well.
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• General features: • It is essential to have an accurate and
comprehensive diagnosis.
• Must treat underlying causes e.g. hypoglycemia ,infection and tumor
• Diagnosis: Adequate description of symptoms both
from patient and eye witness.
• EEG( supportive)
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• EEG should not be an indication for confirming
epilepsy nor to stop treatment for seizure free
patients.
• 20% of pts admitted after positive recording with EEG
did not have the disorder (Betts,1983 )
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1. Improper diagnosis of the type of seizures
2. Incorrrect choice of drug
3. Inadequate or excessive dosage
4. Poor compliance
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–Seizure very harmful for pregnant women.
– Monotherapy usually better than drugscombination.
– Folic acid is recommended to be given for every
pregnant women with epilepsy – Phenytoin, sodium valproate are absolutely
contraindicated and oxcarbamazepine is betterthan carbamazepine.
– Experience with new anticonvulsants still notreliable to say that are better than old ones.
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• Vagus nerve stimulation
• Approved by FDA
• Treatment of partial complex seizures with / out
secondary generalization• Visceral afferents from left vagus stimulate the
solitary nucleus which induces neuronal changes
• Safe with tolerable side effects – transienthoarseness of voice with coughing and painduring stimulation
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April 12 2014 37