antiseizure drugs
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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.
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