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Anticonvulsant or Antiepileptic Drugs
Munir Gharaibeh, MD, PhD, MHPESchool of Medicine, The University of Jordan
March, 2018
Anticonvulsant or Antiepileptic Drugs
Seizure: an abnormal electrical activity, not necessarily to result in a convulsion. Convulsion (Fit): the attack itself.Epilepsy: a disease characterized by recurrent attacks of convulsions.
Neuronal Mechanisms involved in SeizuresÚSuppression of Inhibition---------Onset ÚPost-tetanic Potentiation-------Spread and
Maintenance ÚReinstitution of Inhibition---Termination ÚPattern related to anatomical site of the
focus.
March 18 3Munir Gharaibeh, MD, PhD, MHPE
Pathophysiological Conditions Enhancing Convulsions
Ú Low PO2 Ú High pHÚ Increased Intracranial PressureÚ Low Ca++Ú Low Glucose Ú OverhydrationÚ Fatigue Ú Emotional State
March 18 4Munir Gharaibeh, MD, PhD, MHPE
Causes of ConvulsionsÚPoisonsÚTraumaÚ InfectionÚ Space Occupying LesionsÚFeverÚDrugs ÚEpilepsies
March 18 5Munir Gharaibeh, MD, PhD, MHPE
Classification of EpilepsiesÚGrand Mal or Major Epilepsy or Tonic-
Clonic Epilepsy: Ú Aura Ú Cry-Loss of consciousnessÚ Tonic Phase: Rigid violent muscle contraction
with limbs fixed.
Ú Clonic Phase: Repetitive muscle jerksÚ Post-ictal depression and incotinence
March 18 6Munir Gharaibeh, MD, PhD, MHPE
Classification of EpilepsiesPetit Mal or Minor Epilepsy or Absence States:
Psychomotor Epilepsy:Ú Automatic movementsÚ Clouded dreamy feeling Ú Aggressiveness
March 18 7Munir Gharaibeh, MD, PhD, MHPE
Classification of Epilepsies
ÚStatus Epilepticus ÚParietal Lobe EpilepsyÚInfantile MyospasmÚetc.......
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Provocative Procedures
ÚPentylene tetrazole "Metrazole"
ÚHyperventilation
ÚPhotic stimulation - Flicker Fusion
March 18 11Munir Gharaibeh, MD, PhD, MHPE
Principles of Epilepsy Treatment Ú Seizures are self-limiting.ÚOne drug at a time( Monotherapy):
Lower incidence of adverse reactions.Avoidance of drug interactions.Improved patient compliance.Lower medication cost.
Ú Start with a small dose.ÚMonitor serum level.
March 18 12Munir Gharaibeh, MD, PhD, MHPE
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Barbiturates
ÚPhenobarbital ÚMephobarbitalÚMethabarbitalÚPrimidone
March 18 15Munir Gharaibeh, MD, PhD, MHPE
BarbituratesÚOldest but still used.ÚRelatively safe, but sedating.ÚEffective in Grand mal and partial seizures.ÚMight worsen patients with other types.ÚBind to GABA receptor, to prolong opening of Cl-
channels.ÚAlso, at high doses, block Na+ and Ca++ channels (L
and N type). Ú Also block Glutamate receptors.
March 18 16Munir Gharaibeh, MD, PhD, MHPE
Barbiturates
Adverse Effects:Ú SedationÚ AllergiesÚ AnemiaÚ Drug Interactions Ú Enzyme Induction ----- Withdrawal!!Ú Additive to CNS depressants.
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Phenytoin(1938)
ÚGeneralized tonic - clonic seizures ÚPartial seizures with complex symptomatology ÚAntipsychoticÚAntiarrhythmicÚMany othersÚRevolutionary
March 18 18Munir Gharaibeh, MD, PhD, MHPE
PhenytoinMechanism of Action:Acts on several physiologic systems.Major action is sodium channel blockade, arising from
preferential binding to and prolongation of the inactivated state of the Na + channel.
Also, inhibits Ca++ influx, membrane potential, as well as, the concentrations of amino acids, NE, ACh, and GABA .
Blocks sustained high-frequency repetitive firing of action potentials.
March 18 19Munir Gharaibeh, MD, PhD, MHPE
PhenytoinÚPharmacokinetics:
– Slow absorption– 90% bound– Metabolized:
Zero order in high doses used in epilepsy, so, no SSL achieved.
– Interactions:Protein binding.Enzyme induction.
March 18 20Munir Gharaibeh, MD, PhD, MHPE
PhenytoinAdverse Effects:
Ú Skin rashes, feverÚ Blood: megaloblastic anemia, agranulocytosis,
lymphadenopathy. Ú Gingival hyperplasia (50%)Ú HirsutismÚ "Hydantoin Facies"Ú Peripheral neuropathyÚ Cerebellar degeneration Ú Teratogenic ------- Folate Deficiency
March 18 21Munir Gharaibeh, MD, PhD, MHPE
PhenytoinOverdose:Ú Nystagmus,Ú Ataxia,Ú Vertigo,Ú Diplopia Ú Loss of consciousness.
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CarbamazepineÚPartial seizuresÚGeneralized tonic - clonicÚNot for petit mal Ú Initially marketed for Trigeminal Neuralgia. Ú Bipolar mood disorders, it is a tricyclic compound. Ú Peripheral NeuropathyÚ Migraine ------------ etc
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Carbamazepine
Mechanism of Action:Like phenytoin, blocks Na+ channels.
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Carbamazepine
ÚSlow and erratic absorptionÚT½ 12-60 hr.ÚInduces liver enzymes = Autoinduction.ÚInteractions.ÚBlood monitoring is necessary.
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CarbamazepineAdverse Effects:Vertigo , Ataxia , Diplopia appear early.ÚDrowsiness , nausea , headache, dizziness.ÚTolerance develops to the above effects.ÚSkin rashes , fever , hepatosplenomegaly ,
lymphadenopathy. ÚBlood dyscrasias: leukopenia, aplastic anemia,
and agranulocytosis.
March 18 27Munir Gharaibeh, MD, PhD, MHPE
Oxacarbazepine.
ÚLess capacity to induce enzymes.ÚT½ 1-2hr.ÚMay be safer.
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VigabatrinÚGABA-Transaminase irreversible inhibitor,
which breaks down GABA in the brain.ÚRenal elimination.ÚPartial seizures ____ Not for absence or
myoclonicÚWell tolerated: drowsiness, dizziness, weight
gain, visual field defects.
March 18 29Munir Gharaibeh, MD, PhD, MHPE
Lamotrigine
ÚPartial and generalized seizures.ÚInhibits Na+ and Ca++ channels, also decreases
release of glutamate.ÚCompletely absorbed.ÚGlucoronidated, so will not induce or inhibit
enzymes.ÚSide Effects:
Similar to carbamazepine.Skin rashesCerebellovestibular symptoms.
March 18 30Munir Gharaibeh, MD, PhD, MHPE
Gabapentin and Pregabalin
ÚPartial SeizuresÚGABA analogs, but work indirectly to increase
GABA levels in the brain.ÚGood PK Properties.ÚEffective when combined with others. ÚSafe: somnolence, dizziness, ataxia.
March 18 31Munir Gharaibeh, MD, PhD, MHPE
Benzodiazepines
ÚGABA mechanism, and,ÚNa+ channel inhibition in doses used in
status epilepticus.
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Benzodiazepines
ÚDiazepam ----------- Status epilepticus ÚLorazepam ---------- Longer actingÚClonazepam --------- Petit mal, but causes
sedation and droolingÚNitrazepam -------- Infantile Spasms
March 18 33Munir Gharaibeh, MD, PhD, MHPE
Valproic Acid (1969)ÚPetit mal and myoclonic epilepsyÚMixed seizures.ÚBipolar disorder and migraine prophylaxis.
March 18 34Munir Gharaibeh, MD, PhD, MHPE
Valproic AcidÚIncreases GABA levels by enhancing synthesis
and inhibiting transaminase.ÚAlso, blocks NMDA receptors, Na+ channels and
T-Ca++ channels.Ú90% bound to plasma proteins.
March 18 35Munir Gharaibeh, MD, PhD, MHPE
Valproic Acid
Toxicity:ÚHepatotoxic ÚNeural tube defectsÚ Thrombocytopenia. ÚAlopeciaÚGI.ÚInhibits metabolism of many drugs.
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Ethosuximide (1960s)
ÚPetit mal, still first choice. ÚBlocks transient Ca++ CurrentsÚSafe.
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AcetazolamideÚHelpful in all types of seizures.ÚUsed as an adjunct to others in refractory
seizures.ÚWorks by decreasing intracellular pH .ÚTolerance develops.ÚSpecial role for seizures at the time of menses.
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March 18 39Munir Gharaibeh, MD, PhD, MHPE