ANTISEIZURE DRUGS

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ANTISEIZURE DRUGS

• Zenaida N. Maglaya,MD,FPSECP
• Department of Pharmacology

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SEIZURE

• Is a finite episodes of brain dysfunction
  resulting from abnormal discharge of cerebral
  neurons.
• PRIMARY SEIZURES
• SECONDARY SEIZURES

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CLASSIFICATION OF SEIZURE TYPES

• PARTIAL SEIZURES
• Simple partial seizures
• Complex partial seizures
• Partial seizures secondarily generalized

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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

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PRIMARY DRUGS

• CARBAMAZEPINE
• PHENYTOIN
• VALPROIC ACID
• PHENOBARBITAL
• PRIMIDONE
• DIAZEPAM /LORAZEPAM
• CLONAZEPAM
• ETHOSUXIMIDE

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ADJUNCTIVE DRUGS

• FELBAMATE GABAPENTIN
• LAMOTRIGINE TIAGABINE
• TOPIRAMATE VIGABATRIN
• LEVETIRACETAM ZONISAMIDE

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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

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MECHANISM OF ACTION

• Inhibition of sodium channels function
  phenytoin, carbamazepine, lamotrigine
• Inhibition of calcium channel function
  ethosuximde
• Enhancement of GABA action benzodiazepines,phenob
  arbital gabapentin,vigabatrin, tiagabine
• Multiple Complex Mechanism Valproic Acid

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PHENYTOIN

• 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

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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

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PHENYTOIN DRUG INTERACTIONS

1. Sulfonamides, valproate phenylbutazone
   displace phenytoin from binding sites
2. Cimetidine, disulfiram, doxycycline, isoniazid,
   phenylbutazone, sulfas, warfarin,
   chloramphenicol inhibits phenytoin metabolism

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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

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CARBAMAZEPINE

• BLOCK SODIUM CHANNELS
• DOC for partial seizures
• Generalized tonic-clonic seizures
• Trigeminal neuralgia
• Maniabipolar 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.

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PHENOBARBITAL

• Enhancement of inhibitory process
• Dimimution of excitatory transmission
• USE partial seizures, generalized tonic-clonic
  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

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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 a2d 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

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TIAGABINE

• Nicotinic acid derivative
• GABA uptake inhibitor in both neurons glia
• Partial seizures
• Dizziness, tremor, difficulty in concentration,
  psychosis

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ETHOSUXIMIDE

• 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

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VALPROIC ACID

• On partial seizures sodium channel effects
• Increased levels of GABA inhibits GABA
  transaminase succinic semialdehyde
  dehydrogenase
• Sodium channel blockade

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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

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VALPROIC ACID

• Well absorbed ppc within 2 hrs
• Bioavailability gt 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

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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

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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

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STATUS EPILPETICUS

• DIAZEPAM
• LORAZEPAM
• PHENYTOIN
• PHENOBARBITAL

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EFFECTIVE PLASMA LEVELS
DRUG Effective Level(ug/m TOXIC LEVEL (ug/mL)
Carbamzepine 4 - 12 gt 8
Phenytoin 10 - 20 gt20
Phenobarbital 10 - 40 gt 40
Ethosuximide 50 -100 gt 100
Valproic Acid 50 - 100 gt 100

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Thank You!!!

• 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