ANTICONVULSANT DRUGS

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ANTICONVULSANT DRUGS Edward D. French,
Ph.D. Department of Pharmacology University of
Arizona College of Medicine
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SIMPLISTIC VIEW OF SEIZURES
All that separates a normal brain from an
epileptic seizure is the control of
excitation. The normal neuronal network is kept
in balance between fast, inherently dangerous,
excitatory events and inhibitory suppression of
those events.
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General Principles of AEDs Sites of Action

• Decrease Na channel-mediated excessive
  depolarization that propagates excitability
  within and without a brain region.
• Increase neuronal inhibition.
• Reduce neuronal excitation evoked by an
  excitatory amino acid.
• Reduce activity of T-type (low-threshold) calcium
  channels.

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Sodium Channels As ASite of Action for Some AEDs

• Action potentials from increased sodium
  conductance open-inactivated-closed-open
• with seizure activity sustained depolarization
• AEDs that act on sodium channels show
• voltage dependence (membrane potential more
  positive)
• use dependence (frequency of action potentials
  increased)

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Increasing Neuronal InhibitionThe GABA
Connection

• Increasing GABA-mediated chloride conductance,
  resulting in an increase inside the neuron of a
  negatively charged ion.
• Increasing GABA synthesis and release
• Attenuating GABA uptake and metabolism
• Result greater hyperpolarization of neuronal
  membrane potential

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GABA Receptors

• GABA receptors--?, ?, ? subunit assemblies
• GABA-A and GABA-B receptors
• GABA-A chloride ionophore
• GABA-B G-protein coupled potassium channel how
  would potassium efflux affect excitability?
• Receptor composition may differ in different
  brain regions.
• GABA-A receptor has binding sites for GABA,
  barbiturates, benzodiazepines, neurosteroids,
  ethanol and picrotoxin.

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GABA-A Receptor Ionophore

• Benzodiazepines bind to a BZD binding site on the
  ?-subunit of the GABA-ionophore.
• BZDs increase the frequency of GABA-mediated
  channel openings, but not mean open time.
• Barbiturates affect GABA-A receptors irrespective
  of subunit composition.
• BARBS increase channel mean open times but not
  open frequency.

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The Glutamate Connection

• Glutamate receptors
• AMPA, Kainate NMDA receptor subtypes
  ion-channel complexes
• Metabotropic second messenger coupled
• NMDA ionophore--voltage/use dependent, modulated
  by glycine (non-strychnine), polyamines,
  phencyclidine.

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THE IDEAL ANTIEPILEPTIC DRUG

• Known mechanism of action
• Fully effective in monotherapy in a variety of
  seizure types without tolerance
• No serious side effects
• No dose-related neurotoxicity within the
  therapeutic range
• High therapeutic index
• Non-teratogenic
• No long-term adverse tissue effects or cognitive
  impairment
• Favorable/predictable pharmacokinetics without
  drug interactions
• Low cost

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