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ANTICONVULSANT DRUGS
Edward D. French, Ph.D.
Department of Pharmacology
University of Arizona
College of Medicine
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.
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.
Sodium Channels As A
Site 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)
Increasing Neuronal Inhibition:
The 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
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.
GABA-A Receptor Ionophore
• Benzodiazepines bind to a BZD binding site on the subunit of the GABA-ionophore.
• BZD’s 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.
The Glutamate Connection
• Glutamate receptors:
– AMPA, Kainate & NMDA receptor subtypes: ionchannel complexes
– Metabotropic: second messenger coupled
• NMDA ionophore--voltage/use dependent, modulated by
glycine (non-strychnine), polyamines, & phencyclidine.
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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