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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)
Physicians Desk Reference . 54th ed. Montvale, NJ: Medical Economics Co; 2000.
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)
Physicians Desk Reference . 54th ed. Montvale, NJ: Medical Economics Co; 2000.
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.
Physicians Desk Reference , 53rd ed. Montvale, NJ: Medical Economics Co; 2000.
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.
Physicians Desk Reference , 53rd ed. Montvale, NJ: Medical Economics Co; 2000.
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
Physicians Desk Reference , 53rd ed. Montvale, NJ: Medical Economics Co; 2000.
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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