Antiepileptic Farmacology SURE

7/30/2019 Antiepileptic Farmacology SURE

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Antiepileptic DrugPharmacology

SURYADI


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Drug Therapy

Seizures result when there is an imbalancebetween inhibitory and excitatoryneurotransmission

Numerous attempts at monotherapy should bemade before proceeding to polytherapy


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Excitation

Inhibition

GABA

glutamate,

aspartate

Abnormal Excitation


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Reduce excitation

Increase inhibition

Excitation Inhibition

Restoring Balance


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Goals of Therapy

Seizure free

No/minimal adverse effects

Therapy optimized based on comorbidconditions and their treatment

AED monotherapy preferred

Improved quality of life

Early, aggressive treatment


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Properties of an Ideal Antiepileptic Drug

Effective for seizure type / seizure syndromeWide therapeutic indexNo organ toxicity

No teratogenicityNo drug-drug interactionsLong half-lifeNo protein bindingWater solubleNo active metabolites


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Chronic Toxicity of AEDs

Nervous systemSkinLiver

BloodImmune systemEndocrine systemBoneConnective tissue

Pregnancy


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AED Selection: Seizure Type

Partial onset seizures

Phenytoin

Valproate

Gabapentin

Primidone

Topiramate

Levetiracetam

Zonisamide

Carbamazepine

Lamotrigine

Phenobarbital

Felbamate

Tiagabine

Oxcarbazepine


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Mechanisms of Action of AEDs

Sodium channel blockade

Calcium channel blockade

Glutamate antagonism

GABA potentiation

Carbonic anhydrase inhibition

White HS. Epilepsia. 1999;40(suppl 5):S2-S10.


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Proposed Mechanisms of Action of AEDs

AED

Sodiumchannel

blockade

Calciumchannel

blockadeGlutamate

antagonismGABA

potentiation

Carbonicanhydraseinhibition

1ST

GENERATIONEthosuximidePhenytoinCarbamazepine

DiazepamPhenobarbitalValproate

2ND GENERATION

XX

X

X

X X [HI]XXX

FelbamateGabapentinLamotrigine

X

X

XXX

X XX

LevetiracetamTopiramateTiagabineZonisamide

X

X

X

X

UNKNOWNX X

XX

X

X


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AED Selection: Seizure Types (cont)

Generalized seizures

Absence: Valproate, Ethosuximide,Lamotrigine, Zonisamide

Myoclonic: Valproate, Clonazepam,Zonisamide, Topiramate,Felbamate

Tonic-clonic: Valproate, Topiramate,Lamotrigine, Zonisamide,

Felbamate


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AED Indications (First generation AEDs)

Physicians Desk Reference . 54th ed. Montvale, NJ: Medical Economics Co; 2000.

Diazepam, (Valium)Clonazepam, (Klonopin)

Both drugs are often used for treatment of StatusEpilepticus; may also be used for uncomplicatedabsence; efficacy compromised by development oftolerance.

Generalized tonic-clonic seizures; partialseizures with or without 2nd generalization

Phenobarbital(Luminal)

IndicationAED


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AED Indications (Second generation AEDs)


Topiramate(Topamax)

Lamotrigine(Lamictal)

Gabapentin

(Neurontin)

Partial-onset seizures in adults and children aged2 years; primary generalized tonic-clonic seizuresin adults and children aged 2 years

Partial seizures in adults (adjunctive therapy);Lennox-Gastaut Syndrome

Partial seizures in adults and children aged

12 years (adjunctive therapy)

Partial seizures with and without generalization;Lennox-Gastaut Syndrome (not indicated asfirst-line therapy)

Felbamate(Felbatol)

IndicationAED


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AED Indications (Second generation AEDs)


Zonisamide

(Zonegran)

Oxcarbazepine(Trileptal)

Levetiracetam(Keppra)

Adjunctive Therapy: partial-onset seizures in adults

Monotherapy: partial-onset seizures with andwithout secondary generalized seizures in adults

Adjunctive Therapy: partial-onset seizures inchildren aged 4 to 6 years

Partial-onset seizures in adults (adjunctive therapy)

Partial-onset seizures in adults and childrenaged 12 years (adjunctive therapy)

Tiagabine(Gabitril)

AED Indication


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Optimizing Clinical Outcome

Select AED based on spectrum of efficacy indifferent seizure types

Titrate based on response, tolerance, and plasmalevels (if appropriate)

Try a different single AED as monotherapy beforeusing combination therapy

Watch for AED-induced seizure aggravation


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First Generation AED Tolerability

Non-dose r elated AE.

Physicians Desk Reference , 53rd ed. Montvale, NJ: Medical Economics Co; 2000.

Carbamazepine Double vision, blurring of vision, vertigo, cognitiveimpairment, lethargy, behavioral changes,dyskinesias, cardiac conduction disturbances

diarrhea, fluid retentio n

Nystagmus, cognitive impairment, incoordination,dyskinesias, seizure exacerbation;

hirsut ism, coarsening of facial features, worsening of

acne, gingival h yperplasia, osteopenia, neuropathy,

folate def ic iency anemia

Phenytoin

Adverse EventAED

GI upset, liver enzyme elevations, tremor,hyperammonemia, initial somnolence, behavioral

changes

weight g ain, nausea, hair loss and changes in texture

Valproate


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AED Tolerability:Most Common Adverse Events in Adul ts

Non-dose r elated AE.


Phenobarbital Sedation, mental dullness, cognitive impairment,hyperactivity, ataxia, changes in sleep pattern

lethargy, decrease in attent ion span, osteopenia

Anorexia, nausea, fatigue, headache

blo od -dysc rasia, SLE-l ike reaction, hepatit is

Ethosuximide

Adverse EventAED

Lethargy, depression, tremor, headacheBenzodiazepines


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Novel AED Tolerability:Most Common Adverse Events in Adul ts

AEs commo n in both chi ldren and adults.


Oxcarbazepine Dizziness,headache,diplopia, ataxia,weakness,hyponatremia

Zonisamide Somnolence,headache, dizziness, ataxia, renal calculi

Levetiracetam Dizziness,somnolence,irr i tabi l i ty

Tiagabine Dizziness, asthenia, nervousness, tremor, diarrhea,decreased muscle tone

Topiramate Somnolence, weight loss,dizziness, ataxia, speech

disorders, psychomotor slowing,renal calculi

Gabapentin Somnolence, dizziness,ataxia, fatigue, nystagmus

Lamotrigine Dizziness,ataxia, somnolence, headache, diplopia,rash

Anorexia, vomi t ing, insomnia,nausea,headache,weight loss

Felbamate

Adverse EventAED


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AED Safety: Id ios yncrat ic Tox ic i ty

ToxicityAED

None IdentifiedBenzodiazepines

Allergic deratitis, Stevens-Johnson Syndrome,serum sickness reaction, granulocytesuppression

Phenobarbital

None identifiedEthosuximide

Reye-like syndrome, fetal drug effects,hepatic failure, pancreatitis, coma or stupor

Valproate

Granulocyte suppression, allergic dermatitis,

Stevens-Johnson syndrome, aplastic anemia,hepatic and kidney failure

Carbamazepine

Allergic dermatitis, fetal drug effects, hepaticfailure, serum sickness reaction, SLE-likereaction, hyperglycemia, aplastic anemia,granulocyte suppression

Phenytoin



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Epilepsy Summary

Base treatment on seizure type/epilepsy syndrome

Balance efficacy vs side effects

Choose drugs to best treat comorbidity

Begin monotherapy with first-line drug; use best alternative

if unsuccessful

Successful long-term treatment requires patient complianceand appropriate clinical monitoring

Observe special considerations in patient populations

Children Women

Elderly

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Antiepileptic Farmacology SURE