anticonvulsant drugs edward d. french, ph.d. department of pharmacology university of arizona...

ANTICONVULSANT DRUGSANTICONVULSANT DRUGSEdward D. French, Ph.D.

Department of Pharmacology

University of Arizona

College of Medicine

SIMPLISTIC VIEW OF SIMPLISTIC VIEW OF SEIZURESSEIZURES

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 General Principles of AEDs Sites of ActionSites 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 ASodium Channels As ASite of Action for Some Site of Action for Some

AEDsAEDs

• 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:Increasing Neuronal Inhibition:The GABA ConnectionThe 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 ReceptorsGABA 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 IonophoreGABA-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 ConnectionThe 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.

THE IDEAL ANTIEPILEPTIC DRUGTHE 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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