ANTISEIZURE DRUGSANTISEIZURE DRUGS

Zenaida N. Maglaya,MD,FPSECPZenaida N. Maglaya,MD,FPSECP

Department of PharmacologyDepartment of Pharmacology

SEIZURESEIZUREFinite episodes of brain Finite episodes of brain

dysfunction resulting from dysfunction resulting from abnormal discharge of cerebral abnormal discharge of cerebral neurons.neurons.

EPILEPSY: disorderEPILEPSY: disorderPRIMARY SEIZURES: idiopathicPRIMARY SEIZURES: idiopathicSECONDARY SEIZURES: primary SECONDARY SEIZURES: primary

problemproblem

CLASSIFICATION OF EPILEPTIC CLASSIFICATION OF EPILEPTIC SEIZURESSEIZURES

I. PARTIAL SEIZURESI. PARTIAL SEIZURESSimple partial seizuresSimple partial seizuresComplex partial seizuresComplex partial seizuresPartial w/ secondarily Partial w/ secondarily

generalized tonic clonicgeneralized tonic clonic

seizuresseizures

II. GENERALIZED SEIZURESII. GENERALIZED SEIZURES

Generalized tonic-clonic (grand Generalized tonic-clonic (grand mal seizures)mal seizures)

Absence (petit mal) seizuresAbsence (petit mal) seizuresMyoclonic seizuresMyoclonic seizures

Febrile SeizuresFebrile SeizuresStatus EpilepticusStatus Epilepticus

PRIMARY DRUGSPRIMARY DRUGSCARBAMAZEPINECARBAMAZEPINEPHENYTOINPHENYTOINVALPROIC ACIDVALPROIC ACIDPHENOBARBITALPHENOBARBITALPRIMIDONEPRIMIDONEDIAZEPAM /LORAZEPAM DIAZEPAM /LORAZEPAM

CLONAZEPAMCLONAZEPAMETHOSUXIMIDEETHOSUXIMIDE

ADJUNCTIVE DRUGSADJUNCTIVE DRUGS

FELBAMATE GABAPENTIN FELBAMATE GABAPENTIN

LAMOTRIGINELAMOTRIGINE TIAGABINE TIAGABINE

TOPIRAMATE VIGABATRIN TOPIRAMATE VIGABATRIN

LEVETIRACETAM ZONISAMIDELEVETIRACETAM ZONISAMIDE

ANTISEIZURES CLASSIFICATIONANTISEIZURES CLASSIFICATION

I. I. TONIC-CLONIC SEIZURESTONIC-CLONIC SEIZURESCarbamazepine. valproic acid, Carbamazepine. valproic acid,

Phenytoin, Primidone, Phenytoin, Primidone, PhenobarbitalPhenobarbital

Recent: Lamotrigine, TopiramateRecent: Lamotrigine, Topiramate

II.ABSENCE SEIZURESII.ABSENCE SEIZURES

Ethosuximide, valproic acid, Ethosuximide, valproic acid, clonazepam clonazepam Recent: LamotrigineRecent: Lamotrigine

III III MYOCLONIC SEIZURESMYOCLONIC SEIZURESValproic acid, clonazepamValproic acid, clonazepamRecent: Lamotrigine /topiramateRecent: Lamotrigine /topiramate

PARTIAL SEIZURESPARTIAL SEIZURESSIMPLE/PARTIAL: SIMPLE/PARTIAL: CARBAMAZEPINE, CARBAMAZEPINE,

VALPROATEVALPROATEPHENYTOIN,PHENYTOIN,Recent : gabapentin, Recent : gabapentin,

tiagabine tiagabine lamotrigine,levetiracetam lamotrigine,levetiracetam topiramate, zonisamidetopiramate, zonisamide

PARTIAL W/ 2PARTIAL W/ 200 GENERALIZED GENERALIZED TONIC-CLONIC SEIZURESTONIC-CLONIC SEIZURES

CARBAMAZEPINE, CARBAMAZEPINE, VALPROATEVALPROATE PHENOBARBITALPHENOBARBITALPHENYTOIN PHENYTOIN Recent : gabapentin, Recent : gabapentin, tiagabinetiagabine

lamotrigine,levetiracetam, lamotrigine,levetiracetam, topiramate, zonisamidetopiramate, zonisamide

MECHANISM OF ACTIONMECHANISM OF ACTIONInhibition of sodium Inhibition of sodium channels functionchannels function: :

phenytoin phenytoin VALPROATEVALPROATE

CarbamazepineCarbamazepine lamotriginelamotrigineTopiramateTopiramatezonisamidezonisamide

Mechanism of ActionMechanism of Action

Inhibition of calcium Inhibition of calcium channel function:channel function:

ethosuximdeethosuximdeVALPROATEVALPROATE

MECHANISM OF ACTIONMECHANISM OF ACTION

Enhancement of GABA Enhancement of GABA actionaction: :

benzodiazepines,phenobbenzodiazepines,phenobarbital arbital gabapentin,vigabatrin, gabapentin,vigabatrin, tiagabinetiagabine

VALPROATEVALPROATE

PHENYTOINPHENYTOINBLOCK SODIUM CHANNELSBLOCK SODIUM CHANNELSModify pattern of maximal Modify pattern of maximal

electroshock seizures but not electroshock seizures but not inhibit clonic seizures by inhibit clonic seizures by pentylenetetrazolepentylenetetrazole

USE:USE: partial seizures;partial seizures; generalized tonic-clonic seizuresgeneralized tonic-clonic seizures

PHENYTOINPHENYTOIN

Oral, IV Oral, IV highly bound to plasma highly bound to plasma

proteinsproteinsT ½ 12 -36 hrsT ½ 12 -36 hrsMetabolized, dose dependent Metabolized, dose dependent

eliminationeliminationFosphophytoinFosphophytoin

Phenytoin Adverse EffectsPhenytoin Adverse Effects nystagmus, diplopia, ataxia, nystagmus, diplopia, ataxia,

sedation, gingival hyperplasia sedation, gingival hyperplasia & hirsutism, coarsening of & hirsutism, coarsening of facial features, mild peripheral facial features, mild peripheral neuropathy, megaloblastic neuropathy, megaloblastic anemia fever, skin rashanemia fever, skin rash

fetal hydantoin syndromefetal hydantoin syndrome

PHENYTOIN DRUG PHENYTOIN DRUG INTERACTIONSINTERACTIONS

1.1. Sulfonamides, valproate & Sulfonamides, valproate & phenylbutazone: phenylbutazone: displacedisplace phenytoin from binding sitesphenytoin from binding sites

2. Cimetidine, disulfiram, 2. Cimetidine, disulfiram, doxycycline, isoniazid, doxycycline, isoniazid, phenylbutazone, sulfas, phenylbutazone, sulfas, warfarin, chloramphenicol: warfarin, chloramphenicol: iinhibitsnhibits phenytoin metabolism phenytoin metabolism

PHENYTOIN DRUG PHENYTOIN DRUG INTERACTIONSINTERACTIONS

3.Barbiturates & carbamazepine, 3.Barbiturates & carbamazepine, pyridoxine, theophylline: pyridoxine, theophylline: enhanceenhance phenytoin metabolism phenytoin metabolism

4.PHENYTOIN 4.PHENYTOIN decreasesdecreases serum serum levels of: carbamazepine, levels of: carbamazepine, chloramphenicol,corticosteroidchloramphenicol,corticosteroids, haloperidol, quinidine, s, haloperidol, quinidine, theophylline, oral theophylline, oral contraceptivescontraceptives

warfarinwarfarin

CARBAMAZEPINECARBAMAZEPINE(IMINOSTILBENES)(IMINOSTILBENES)

BLOCK SODIUM CHANNELSBLOCK SODIUM CHANNELSDOC for partial seizuresDOC for partial seizuresGeneralized tonic-clonic seizuresGeneralized tonic-clonic seizuresTrigeminal neuralgiaTrigeminal neuralgiaMania:bipolar disordersMania:bipolar disordersOrally absorbed with slow Orally absorbed with slow

distributiondistributionCompletely metabolizedCompletely metabolized

CARBAMAZEPINECARBAMAZEPINEAdverse EFfectsAdverse EFfects

diplopia & ataxiadiplopia & ataxia

idiosyncratic blood idiosyncratic blood dyscrasias,dyscrasias,

aplastic anemia aplastic anemia

agranulocytosisagranulocytosis

leukopenialeukopenia

CARBAMAZEPINE DRUG CARBAMAZEPINE DRUG INTERACTIONSINTERACTIONS

1. 1. IIncrease carbamazepine levels carbamazepine levels via metabolism: cimetidine, via metabolism: cimetidine, erythromycin, isoniaziderythromycin, isoniazid

2. 2. DecreaseDecrease carbamazepine levels carbamazepine levels via increase metabolism: via increase metabolism: phenytoin, valproic acidphenytoin, valproic acid

3. Carbamazepine 3. Carbamazepine decreasesdecreases drug drug levels :warfarin, oral levels :warfarin, oral contraceptives, doxycycline, contraceptives, doxycycline, phenytoin, haloperidolphenytoin, haloperidol

CARBAMAZEPINE Drug CARBAMAZEPINE Drug InteractionsInteractions

4. Carbamazepine 4. Carbamazepine increasesincreases drug levels : cimetidine, drug levels : cimetidine, isoniazidisoniazid

5. Lithium 5. Lithium inducesinduces carbamazepine toxicity.carbamazepine toxicity.

PHENOBARBITALPHENOBARBITAL Inhibits tonic hind limb extension Inhibits tonic hind limb extension

in the maximal electroshock in the maximal electroshock model, clonic seizures evoked by model, clonic seizures evoked by pentylenetrazol, and kindled pentylenetrazol, and kindled seizuresseizures

Enhancement of inhibitory processEnhancement of inhibitory processDimimution of excitatory Dimimution of excitatory

transmissiontransmissionUSE: USE: partial & generalized tonic-clonic partial & generalized tonic-clonic

seizuresseizures

PHENOBARBITAL DRUG PHENOBARBITAL DRUG INTERACTIONSINTERACTIONS

Increase phenobarbital levels via phenobarbital levels via metabolism; acute ethanol ingestion, metabolism; acute ethanol ingestion, chloramphenicol, valproic acidchloramphenicol, valproic acid

DecreaseDecrease phenobarbital levels via phenobarbital levels via increase metabolism, chronic alcohol increase metabolism, chronic alcohol ingestion, pyridoxine, rifampiningestion, pyridoxine, rifampin

Barbiturates Barbiturates decreasedecrease serum levels: serum levels: tricyclics, warfarin, beta blockers, oral tricyclics, warfarin, beta blockers, oral contraceptives, digitoxin, doxycycline, contraceptives, digitoxin, doxycycline, metronidazole, theophylllinemetronidazole, theophyllline

PRIMIDONEPRIMIDONEMetabolized to:Metabolized to:PHENOBARBITALPHENOBARBITALPHENYLETHYLMALONAMIDE(PEMA)PHENYLETHYLMALONAMIDE(PEMA)Mechanism of action similar to Mechanism of action similar to

phenytoinphenytoinMay cause sedation, ataxia, vertigo, May cause sedation, ataxia, vertigo,

GIT upset, megaloblastic anemiaGIT upset, megaloblastic anemiaCI: porphyria, hypersensitivityCI: porphyria, hypersensitivity

VIGABATRINVIGABATRIN

Inhibits GABA transaminaseInhibits GABA transaminasePartial seizures & ‘WEST syndromePartial seizures & ‘WEST syndromeIn patients unresponsive to In patients unresponsive to

conventional drugsconventional drugsRapid absorptionRapid absorptionT ½ 6 -8 hrsT ½ 6 -8 hrsCAUSES: drowsiness, behavioral & CAUSES: drowsiness, behavioral &

mood changes, weight gain, visual mood changes, weight gain, visual field defectfield defect

LAMOTRIGINELAMOTRIGINE

Inhibits sodium channelsInhibits sodium channelsPartial seizuresPartial seizuresAbsense seizuresAbsense seizuresCompletely absorbedCompletely absorbedT ½ of 24 hoursT ½ of 24 hoursBroad therapeutic profileBroad therapeutic profileCAUSES: hypersensitivity rxns, CAUSES: hypersensitivity rxns,

diplopia, ataxia, headache, diplopia, ataxia, headache, dizziness, life threatening skin dizziness, life threatening skin disorders, hematotoxicitydisorders, hematotoxicity

FELBAMATEFELBAMATEMOA : blocks glumate NMDA MOA : blocks glumate NMDA

receptorsreceptorsFor partial seizuresFor partial seizuresBroad therapeutic profileBroad therapeutic profileFor intractable casesFor intractable casesT ½ is 20 hrsT ½ is 20 hrsCAUSES: severe hypersensitivity CAUSES: severe hypersensitivity

rxs aplastic anemia, hepatotoxicity rxs aplastic anemia, hepatotoxicity ↑↑

↑↑↑↑ plasma phenytoin & valproic acidplasma phenytoin & valproic acid ↓↓ ↓↓ carbamazepine levelscarbamazepine levels

GABAPENTINGABAPENTIN

MOA: alters GABA metabolism, its MOA: alters GABA metabolism, its nonsynaptic release or its nonsynaptic release or its reuptake by GABA transportersreuptake by GABA transporters

Also binds to the Also binds to the αα22δδ subunit of subunit of voltage sensitive calcium voltage sensitive calcium channelschannels

FOR PARTIAL & GENERALIZED FOR PARTIAL & GENERALIZED SEIZURE SEIZURE

CAUSE: somnolence, dizziness, CAUSE: somnolence, dizziness, ataxia, headache & tremorataxia, headache & tremor

TOPIRAMATETOPIRAMATE

Complex action: GABA effect, blocks Complex action: GABA effect, blocks voltage dependent sodium channelsvoltage dependent sodium channels

Blocks glutamate receptorsBlocks glutamate receptorsSimilar to phenytoin with lower side Similar to phenytoin with lower side

effects & simpler pharmacokineticseffects & simpler pharmacokineticsRisk of teratogenesisRisk of teratogenesisSedation, mental dulling, renal Sedation, mental dulling, renal

stones, weight lossstones, weight loss

TIAGABINETIAGABINENicotinic acid derivativeNicotinic acid derivativeGABA uptake inhibitor in both GABA uptake inhibitor in both

neurons & glianeurons & gliaPartial seizuresPartial seizuresDizziness, tremor, difficulty in Dizziness, tremor, difficulty in

concentration, psychosisconcentration, psychosis

LEVETIRACETAM LEVETIRACETAM

A pyrolidineA pyrolidine Inhibits partial & secondarily Inhibits partial & secondarily

generalized tonic- clonic seizuresgeneralized tonic- clonic seizures MOA: unknownMOA: unknown Add on to drugs used for partial Add on to drugs used for partial

seizuresseizures AE: somnolence, asthenia and AE: somnolence, asthenia and

dizzinessdizziness

ZONISAMIDEZONISAMIDEInhibits the t-type CaInhibits the t-type Ca2+2+ currents currentsNaNa++ channels block channels blockFor partial & secondarily gen For partial & secondarily gen

tonic clonic Stonic clonic ST1/2: 63 hrsT1/2: 63 hrsAE: somnolence, fatigue, AE: somnolence, fatigue,

nervousness, anorexia, ataxianervousness, anorexia, ataxiaPhenytoin, pheno, carba Phenytoin, pheno, carba ↓↓ its conc its concLamotrigine Lamotrigine ↑↑ it it

ETHOSUXIMIDEETHOSUXIMIDEDOC for absense seizuresDOC for absense seizures↓↓ calcium channels (T type) calcium channels (T type)

currentscurrentsInhibits NA/K/ ATPase, depresses Inhibits NA/K/ ATPase, depresses

the cerebral metabolic rate & the cerebral metabolic rate & inhibits GABA aminotransferaseinhibits GABA aminotransferase

Absorption is completeAbsorption is completeCompletely metabolizedCompletely metabolized

ETHOSUXIMIDEETHOSUXIMIDE(Succinimides)(Succinimides)

ADVERSE EFFECTSADVERSE EFFECTSgastric distressgastric distresslethargy lethargy headacheheadacheDI: valproic acid inhibits its DI: valproic acid inhibits its

metabolixmmetabolixm

VALPROIC ACIDVALPROIC ACIDOn partial seizures sodium On partial seizures sodium

channel effectschannel effectsIncreased levels of GABA inhibits Increased levels of GABA inhibits

GABA transaminase & succinic GABA transaminase & succinic semialdehyde dehydrogenasesemialdehyde dehydrogenase

Sodium channel blockadeSodium channel blockade

VALPROIC ACIDVALPROIC ACIDCLINICAL USES:CLINICAL USES:1. ABSENCE SEIZURES1. ABSENCE SEIZURES2. MYOCLONIC SEIZURES2. MYOCLONIC SEIZURES3. GENERALIZED TONIC-CLONIC 3. GENERALIZED TONIC-CLONIC

TYPE OF SEIZURESTYPE OF SEIZURES4. ATONIC ATTACKS4. ATONIC ATTACKS5. PARTIAL SEIZURES5. PARTIAL SEIZURES6. MIGRAINE PROPHYLAXIS6. MIGRAINE PROPHYLAXIS7. BIPOLAR DISORDER7. BIPOLAR DISORDER

VALPROIC ACIDVALPROIC ACIDWell absorbed; ppc within 2 hrsWell absorbed; ppc within 2 hrsBioavailability > 80%Bioavailability > 80%T ½ is 9 -18 hrsT ½ is 9 -18 hrsCAUSES: nausea, vomiting, pain & CAUSES: nausea, vomiting, pain &

heart burn, sedation uncommon, heart burn, sedation uncommon, fine tremors, weight gain, fine tremors, weight gain, increase in appetite & hair loss, increase in appetite & hair loss, hepatotoxicity, thrombocytopenia,hepatotoxicity, thrombocytopenia,

SPINA BIFIDASPINA BIFIDA

VALPROIC DRUG INTERACTIONSVALPROIC DRUG INTERACTIONSDecreaseDecrease valproic acid levels valproic acid levels

from increase metabolism with from increase metabolism with carbamazepinecarbamazepine

IncreaseIncrease valproic acid levels with valproic acid levels with antacid (increase absorption) antacid (increase absorption)

salicylates (displacements from salicylates (displacements from binding sites)binding sites)

When used with clonazepam may When used with clonazepam may precipitate absence statusprecipitate absence status

BENZODIAZEPINESBENZODIAZEPINESDiazepam, lorazepam, Diazepam, lorazepam,

clonazepam, clorazepate, clonazepam, clorazepate, Nitrazepam, clobazamNitrazepam, clobazam

Well absorbed, widely distributedWell absorbed, widely distributedExtensively metabolized with Extensively metabolized with

many active metabolitesmany active metabolitesMay cause sedation, toleranceMay cause sedation, toleranceDIAZEPAM: DOC for status DIAZEPAM: DOC for status

epilepticusepilepticus

STATUS EPILPETICUSSTATUS EPILPETICUS

DIAZEPAMDIAZEPAMLORAZEPAMLORAZEPAMPHENYTOINPHENYTOINPHENOBARBITALPHENOBARBITAL

EFFECTIVE PLASMA LEVELSEFFECTIVE PLASMA LEVELSDRUGDRUG Effective Effective

Level(ug/mLevel(ug/mTOXIC LEVEL TOXIC LEVEL

(ug/mL)(ug/mL)

CarbamzepineCarbamzepine 4 - 124 - 12 > 8> 8

PhenytoinPhenytoin 10 - 2010 - 20 >20>20

PhenobarbitalPhenobarbital 10 - 4010 - 40 > 40> 40

EthosuximideEthosuximide 50 -10050 -100 > 100> 100

Valproic AcidValproic Acid 50 - 10050 - 100 > 100> 100

THERAPEUTIC PRINCIPLESTHERAPEUTIC PRINCIPLES11. . When to initiateWhen to initiate2. Choice of a drug2. Choice of a drug MonotherapyMonotherapy Combined therapy: adverse Combined therapy: adverse

effects effects drug interactiondrug interaction3. Measurement of plasma drug 3. Measurement of plasma drug

concnconcn ComplianceCompliance toxicitytoxicity

THERAPEUTIC PRINCIPLESTHERAPEUTIC PRINCIPLES

4. 4. Duration of TherapyDuration of Therapy at least 2 yearsat least 2 years taper over several monthstaper over several months5. Infantile Spasms with 5. Infantile Spasms with

hypsarrhythmiahypsarrhythmia Corticotropin/glucocorticoidsCorticotropin/glucocorticoids6. Lennox-Gastauf Syndrome: cognitive 6. Lennox-Gastauf Syndrome: cognitive

impairment, multiple types of impairment, multiple types of seizuresseizures

+ lamotrigine+ lamotrigine7. PREGNANCY7. PREGNANCY teratogenecityteratogenecity

And we know that all things And we know that all things work together for good to work together for good to

those who love God, to those who love God, to those who who are called those who who are called according to His purpose.according to His purpose.

ROMANS 8: 28ROMANS 8: 28