Antiepileptic Drugs

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Anti-epileptic Drugs

• Classification of Seizures
• Partial simple or complex
• Generalized absence, tonic, clonic,
  tonic-clonic, myoclonic, febrile
• Animal Models of Seizures
• Chemical-induced pentylenetetrazole, kainic
  acid,
• Maximal electrochock
• Kindling

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Pathophysiology of Seizures

• The Interictal Spike (paroxysmal depolarization
  shift)
• Increased excitability
• Membrane depolarization, potassium buildup
• Increased excitatory (EAA, glutamate) input
• Decreased inhibitory (GABA) input

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Evidence for the Pathophysiology of Seizures

• Increased EAA
• Increased Excitatory Amino Acid Transmission
• Increased sensitivity to EAA
• Progressive increase in glutamate release during
  kindling
• Increased glutamate and aspartate at start of
  seizure
• Upregulation of NMDA receptors in kindled rats

• Decreased GABA
• Decreased binding of GABA and benzodiazepines
• Decreased Cl- currents in response to GABA
• Decreased glutamate decarboxylase activity
  (synthesizes GABA)
• Interfere with GABA causes seizures

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Strategies in Treatment

• Stabilize membrane and prevent depolarization by
  action on ion channels
• Increase GABAergic transmission
• Decrease EAA transmission

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Classification of Anticonvulsants
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Classification of Anticonvulsants

• Classical
• Phenytoin
• Phenobarbital
• Primidone
• Carbamazepine
• Ethosuximide
• Valproic Acid
• Trimethadione

• Newer
• Lamotrigine
• Felbamate
• Topiramate
• Gabapentin
• Tiagabine
• Vigabatrin
• Oxycarbazepine
• Levetiracetam
• Fosphenytoin
• Others

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R1
X
R2
R3
Phenytoin
Ethosuximide
Trimethadione
Valproic Acid
Phenobarbital
Carbamazepine
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Phenytoin or Diphenylhydantoin

• Limited water solubility not given i.m.
• Slow, incomplete and variable absorption.
• Extensive binding to plasma protein.
• Metabolized by hepatic ER by hydroxylation.
  Chance for drug interactions.
• Therapeutic plasma concentration 10-20 µg/ml
• Shift from first to zero order elimination within
  therapeutic concentration range.

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Relationship between Phenytoin Daily Dose and
Plasma Concentration In 5 Patients
Plasma Concentration (mg/L)
Dose (mg/day)
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Phenytoin Toxicity and Adverse Events

• Acute Toxicity
• High i.v. rate cardiac arrhythmias
  hypotension CNS depression.
• Acute oral overdose cerebellar and vestibular
  symptoms and signs
• nystagmus, ataxia, diplopia vertigo.

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Phenytoin Toxicity

• Chronic Toxicity
• Dose related vestibular/cerebellar effects
• Behavioral changes
• Gingival Hyperplasia
• GI Disturbances
• Sexual-Endocrine Effects
• Osteomalacia
• Hirsutism
• Hyperglycemia

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Phenytoin Toxicity and Adverse Events

• Chronic Toxicity
• Folate Deficiency - megaloblastic anemia
• Hypoprothrombinemia and hemorrhage in newborns
• Hypersenstivity Reactions could be severe. SLE,
  fatal hepatic necrosis, Stevens-Johnson syndrome.
• Pseudolymphoma syndrome
• Teratogenic
• Drug Interactions decrease (cimetidine,
  isoniazid) or increase (phenobarbital, other
  AEDs) rate of metabolism competition for
  protein binding sites.

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Fosphenytoin

• A Prodrug. Given i.v. or i.m. and rapidly
  converted to phenytoin in the body.
• Avoids local complications associated with
  phenytoin vein irritation, tissue damage, pain
  and burning at site, muscle necrosis with i.m.
  injection, need for large fluid volumes.
• Otherwise similar toxicities to phenytoin.

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Other Na Channel Blockers

• Carbamazepine may have adrenergic mechanism as
  well. Serious hematological toxicity aplastic
  anemia. Antidiuretic effect (anti ADH).
• Also for trigeminal neuralgia
• Lamotrigine possible other mechanisms.
  Effective in Absence seizures and has
  antidepressant effects in bipolar depression. No
  chronic associated effects.

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Inhibitors of Calcium ChannelsEthosuximide

• Drug of choice for Absence. Blocks Ca currents
  (T-currents) in the thalamus.
• Not effective in other seizure types
• GI complaints most common
• CNS effects drowsiness lethargy).
• Has dopamine antagonist activity (? In seizure
  control) but causes Parkinsonian like symptoms.
• Potentially fatal bone marrow toxicity and skin
  reactions (both rare)

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Enhancers of GABA Transmission

• Phenobarbital
• The only barbiturate with selective
  anticonvulsant effect.
• Bind at allosteric site on GABA receptor and ?
  duration of opening of Cl channel.
• ? Ca-dependent release of neurotransmitters at
  high doses.
• Inducer of microsomal enzymes drug
  interactions.
• Toxic effects sedation (early tolerance
  develops) nystagmus ataxia at higher dose
  osteomalacia, folate deficiency and vit. K
  deficiency.
• In children paradoxical irritability,
  hyperactivity and behavioral changes.
• Deoxybarbiturates primidone active but also
  converted to phenobarbital. Some serious
  additional ADRs leukopenia, SLE-like.

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Enhancers of GABA Transmission

• Benzodiazepines
• Sedative - hypnotic- anxiolytic drugs.
• Bind to another site on GABA receptor. Other
  mechanisms may contribute. ? frequency of
  opening of Cl channel.
• Clonazepam and clorazepate for long term
  treatment of some epilepsies.
• Diazepam and lorazepam for control of status
  epilepticus. Disadvantage short acting.
• Toxicities chronic lethargy drowsiness.
• in status epilepticus iv administration
  respiratory and cardiovascular depression.
  Phenytoin and PB also used.

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GABA-A Receptor Binding Sites
Cl-
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Enhancers of GABA Transmission

• Gabapentin Developed as GABA analogue.
  Mechanism Increases release of GABA by unknown
  mechanism.
• Vigabatrin Irreversible inhibitor of GABA
  transaminase. Potential to cause psychiatric
  disorders (depression and psychosis).
• Tiagabine decreases GABA uptake by neuronal and
  extraneuronal tissues.

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GABA
Vigabatrin
Gabapentin
Tiagabine
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Modulators of GABA Transmission
GBP
TPM
GABA-T
VGB
BZD
TGB
TGB
GABA-T
VGB
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Valproic Acid

• Effective in multiple seizure types.
• Blocks Na and Ca channels. Inhibits GABA
  transaminase. Increases GABA synthesis.
• Toxicity most serious fulminant hepatitis.
  More common if antiepileptic polytherapy in
  children lt 2 years old. (?) Toxic metabolites
  involved.
• Drug interactions inhibits phenobarbital and
  phenytoin metabolism.

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Other Drugs

• Topiramate multiple mechanisms of action (Na
  channel, GABA enhancement like BZD, antagonist at
  AMPA subtype of glutamate receptors (not NMDA).
• Felbamate multiple mechanisms Na channel
  block modulates glutamate transmission interacts
  with glycine site. Serious hematological and
  hepatic toxicities.

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Treatment of Epilepsy

• Start with a single agent. Raise to maximum
  tolerated dose before shifting to another.
• If therapy fails may use combination of drugs.
• Frequent physician visits early on and
  therapeutic drug monitoring.
• Importance of compliance.
• Aim and duration of therapy.

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