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.

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Pathophysiological Conditions Enhancing Convulsions

Ú Low PO2 Ú High pHÚ Increased Intracranial PressureÚ Low Ca++Ú Low Glucose Ú OverhydrationÚ Fatigue Ú Emotional State

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Causes of ConvulsionsÚPoisonsÚTraumaÚ InfectionÚ Space Occupying LesionsÚFeverÚDrugs ÚEpilepsies

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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

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Classification of EpilepsiesPetit Mal or Minor Epilepsy or Absence States:

Psychomotor Epilepsy:Ú Automatic movementsÚ Clouded dreamy feeling Ú Aggressiveness

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Classification of Epilepsies

ÚStatus Epilepticus ÚParietal Lobe EpilepsyÚInfantile MyospasmÚetc.......

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Provocative Procedures

ÚPentylene tetrazole "Metrazole"

ÚHyperventilation

ÚPhotic stimulation - Flicker Fusion

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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.

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Barbiturates

ÚPhenobarbital ÚMephobarbitalÚMethabarbitalÚPrimidone

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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.

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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

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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.

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PhenytoinÚPharmacokinetics:

– Slow absorption– 90% bound– Metabolized:

Zero order in high doses used in epilepsy, so, no SSL achieved.

– Interactions:Protein binding.Enzyme induction.

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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

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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.

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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.

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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.

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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.

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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

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Valproic Acid (1969)ÚPetit mal and myoclonic epilepsyÚMixed seizures.ÚBipolar disorder and migraine prophylaxis.

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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.

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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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