Treatment of Epilepsy in View of Newer Antiepileptic

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

April 12, 2014 1



• 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



• 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)

April 12, 2014 6



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



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:

April 12, 20148



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



• 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



• 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



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

April 12, 2014 18



• 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

April 12, 2014 21



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.

April 12, 2014 22



• 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.

April 12, 2014 23





Side effects:

• Psychological or cognitive dysfunction

• Weight loss

• Sedation

• Dizziness

• Fatigue

• Urolithiasis

• Paresthesias (abnormal sensation )

• Teratogenecity (in animal but not in human)

April 12, 2014 25



• 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

April 12, 2014 26



• Side effects:

• Asthenia

• Sedation

• Dizziness

• Mild memory impairment

• Abdominal pain

April 12, 2014 27



• 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

April 12, 2014 28



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 .

April 12, 2014 29



• 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

April 12, 2014 30



• 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)

April 12, 2014 32



• 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 )

April 12, 2014 33



1. Improper diagnosis of the type of seizures

2. Incorrrect choice of drug

3. Inadequate or excessive dosage

4. Poor compliance

April 12, 2014 34



–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.

April 12, 2014 35



• 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

April 12, 2014 36



April 12 2014 37

Documents

Treatment of Epilepsy in View of Newer Antiepileptic