Transcript ANTISEIZURE DRUGS

ANTISEIZURE DRUGS
Zenaida N. Maglaya,MD,FPSECP
Department of Pharmacology
SEIZURE
 Is
a finite episodes of brain
dysfunction resulting from
abnormal discharge of cerebral
neurons.
 PRIMARY SEIZURES
 SECONDARY
SEIZURES
CLASSIFICATION OF SEIZURE TYPES
PARTIAL SEIZURES
Simple partial seizures
Complex partial seizures
Partial seizures secondarily
generalized
CLASSIFICATION OF SEIZURE TYPES
GENERALIZED SEIZURES
 Generalized tonic-clonic (grand mal) Sz
 Absence (petit mal) seizures
 Tonic/ Atonic Seizures
 Clonic & myoclonic seizures
 Infantile Spasms
 Febrile Seizures
 Status Epilepticus
PRIMARY DRUGS
CARBAMAZEPINE
 PHENYTOIN
 VALPROIC ACID
 PHENOBARBITAL
 PRIMIDONE
 DIAZEPAM /LORAZEPAM
 CLONAZEPAM
 ETHOSUXIMIDE

ADJUNCTIVE DRUGS
FELBAMATE
LAMOTRIGINE
TOPIRAMATE
LEVETIRACETAM
GABAPENTIN
TIAGABINE
VIGABATRIN
ZONISAMIDE
ANTISEIZURES CLASSIFICATION
I. TONIC-CLONIC & PARTIAL SEIZURES
 Carbamazepine. Phenytoin, valproic acid
II.ABSENCE SEIZURES
 Ethosuximide, valproic acid, clonazepam
III MYOCLONIC SEIZURES
 Valproic acid, clonazepam
IV. ADJUNCT/NEWER ANTICONVULSANTS
MECHANISM OF ACTION
 Inhibition
of sodium channels function:
 Inhibition
of calcium channel function:
phenytoin, carbamazepine,
lamotrigine
ethosuximde
 Enhancement
of GABA action:
benzodiazepines,phenobarbital
gabapentin,vigabatrin, tiagabine
 Multiple
& Complex Mechanism:
Valproic Acid
PHENYTOIN
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BLOCK SODIUM CHANNELS
USE: partial seizures; generalized tonic-clonic
seizures, Antiarrhymic drug0
Oral, IV
highly bound to plasma proteins
T ½ 12 -36 hrs
Metabolized, dose dependent elimination
Fosphophytoin, mephenytoin, ethotoin.
phenacemide
Phenytoin Adverse Effects
 nystagmus, diplopia, ataxia,
sedation, gingival hyperplasia &
hirsutism, coarsening of facial
features, mild peripheral
neuropathy, megaloblastic anemia
fever, skin rash, fetal hydantoin
syndrome
PHENYTOIN DRUG INTERACTIONS
Sulfonamides, valproate &
phenylbutazone: displace
phenytoin from binding sites
2. Cimetidine, disulfiram, doxycycline,
isoniazid, phenylbutazone, sulfas,
warfarin, chloramphenicol: inhibits
phenytoin metabolism
1.
PHENYTOIN DRUG INTERACTIONS
3.Barbiturates & carbamazepine,
pyridoxine, theophylline: enhance
phenytoin metabolism
4.PHENYTOIN decreases serum levels
of: carbamazepine, chloramphenicol,
corticosteroids, haloperidol,
quinidine, theophylline, oral
contraceptives, warfarin
CARBAMAZEPINE
BLOCK SODIUM CHANNELS
 DOC for partial seizures
 Generalized tonic-clonic seizures
 Trigeminal neuralgia
 Mania:bipolar disorders
 Orally absorbed with slow distribution
 Completely metabolized
 CAUSE: diplopia & ataxia, idiosyncratic blood
dyscrasias, aplastic anemia &
agranulocytosis, leukopenia
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CARBAMAZEPINE DRUG INTERACTIONS
1. Increase carbamazepine levels via metabolism:
cimetidine, erythromycin, isoniazid
2. Decrease carbamazepine levels via increase
metabolism: phenytoin, valproic acid
3. Carbamazepine decreases drug levels :warfarin,
oral contraceptives, doxycycline, phenytoin,
haloperidol
4. Carbamazepine increases drug levels :
cimetidine, isoniazid
5. Lithium induces carbamazepine toxicity.
PHENOBARBITAL
Enhancement of inhibitory process
 Dimimution of excitatory transmission
 USE: partial seizures, generalized tonicclonic seizures
 May cause: CNS depression
 Tolerance & dependence
CI in porphyria disorders
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PHENOBARBITAL DRUG INTERACTIONS
Increase phenobarbital levels via
metabolism; acute ethanol ingestion,
chloramphenicol, valproic acid
 Decrease phenobarbital levels via increase
metabolism, chronic alcohol ingestion,
pyridoxine, rifampin
 Barbiturates decrease serum levels:
tricyclics, warfarin, beta blockers, oral
contraceptives, digitoxin, doxycycline,
metronidazole, theophyllline
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PRIMIDONE
 Metabolized
to:
 PHENOBARBITAL
 PHENYLETHYLMALONAMIDE(PEMA)
 Mechanism of action similar to
phenytoin
 May cause sedation, ataxia, vertigo,
GIT upset, megaloblastic anemia
 CI: porphyria, hypersensitivity
VIGABATRIN
Inhibits GABA transaminase
 Partial seizures & ‘WEST syndrome
 In patients unresponsive to conventional
drugs
 Rapid absorption
 T ½ 6 -8 hrs
 CAUSES: drowsiness, behavioral & mood
changes, weight gain, visual field defect
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LAMOTRIGINE
Inhibits sodium channels
 Partial seizures
 Absense seizures
 Completely absorbed
 T ½ of 24 hours
 Broad therapeutic profile
 CAUSES: hypersensitivity rxns, diplopia,
ataxia, headache, dizziness, life
threatening skin disorders, hematotoxicity
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FELBAMATE
MOA is unknown
 For partial seizures
 Broad therapeutic profile
 For intractable cases
 T ½ is 20 hrs
 CAUSES: severe hypersensitivity rxs
aplastic anemia, hepatotoxicity
 Increase plasma phenytoin & valproic acid
 Decrease carbamazepine levels
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GABAPENTIN
MOA: alters GABA metabolism, its
nonsynaptic release or its reuptake by
GABA transporters
 Also binds to the α2δ subunit of voltage
sensitive calcium channels
 FOR PARTIAL & GENERALIZED SEIZURES
 SATURABLE ABSORPTION
CAUSE: somnolence, dizziness, ataxia,
headache & tremor
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TOPIRAMATE
 Complex
action: GABA effect, blocks
voltage dependent sodium channels
 Similar to phenytoin with lower side
effects & simpler pharmacokinetics
 Risk of teratogenesis
 Sedation, mental dulling, renal
stones, weight loss
TIAGABINE
 Nicotinic
acid derivative
 GABA uptake inhibitor in both
neurons & glia
 Partial seizures
 Dizziness, tremor, difficulty in
concentration, psychosis
ETHOSUXIMIDE
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DOC for absense seizures
Effect on calcium channels( reduce low threshold
(T type) currents
Inhibits NA/K/ ATPase, depresses the cerebral
metabolic rate & inhibits GABA aminotransferase
Absorption is complete
Completely metabolized
CAUSES; gastric distress, lethargy & headache
DI: valproic acid inhibits its metabolixm
VALPROIC ACID
 On
partial seizures sodium channel
effects
 Increased levels of GABA inhibits
GABA transaminase & succinic
semialdehyde dehydrogenase
 Sodium channel blockade
VALPROIC ACID
 CLINICAL
USES:
1. ABSENCE SEIZURES
2. MYOCLONIC SEIZURES
3. GENERALIZED TONIC-CLONIC TYPE
OF SEIZURES
4. ATONIC ATTACKS
5. PARTIAL SEIZURES
6. MIGRAINE PROPHYLAXIS
7. BIPOLAR DISORDER
 Well
VALPROIC ACID
absorbed; ppc within 2 hrs
 Bioavailability > 80%
 T ½ is 9 -18 hrs
 CAUSES: nausea, vomiting, pain &
heart burn, sedation uncommon, fine
tremors, weight gain, increase in
appetite & hair loss, hepatotoxicity,
thrombocytopenia,
 SPINA BIFIDA
VALPROIC DRUG INTERACTIONS
 Decrease
valproic acid levels from
increase metabolism with
carbamazepine
 Increase valproic acid levels with
antacid (increase absorption)
 salicylates (displacements from
binding sites)
 When used with clonazepam may
precipitate absence status
BENZODIAZEPINES
 Diazepam,
lorazepam, clonazepam,
clorazepate, Nitrazepam, clobazam
 Well absorbed, widely distributed
 Extensively metabolized with many
active metabolites
 May cause sedation, tolerance
 DIAZEPAM: DOC for status epilepticus
STATUS EPILPETICUS
 DIAZEPAM
 LORAZEPAM
 PHENYTOIN
 PHENOBARBITAL
EFFECTIVE PLASMA LEVELS
DRUG
Effective
Level(ug/m
Carbamzepine
4 - 12
TOXIC LEVEL
(ug/mL)
>8
Phenytoin
10 - 20
>20
Phenobarbital
10 - 40
> 40
Ethosuximide
50 -100
Valproic Acid
50 - 100
> 100
> 100
And we know that all things work
together for good to those who love
God, to those who who are called
according to His purpose.
ROMANS 8: 28