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• 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
Pathophysiology of Seizures
• The Interictal Spike (paroxysmal
depolarization shift)
• Increased excitability
– Membrane depolarization, potassium buildup
– Increased excitatory (EAA, glutamate) input
– Decreased inhibitory (GABA) input
Evidence for the
Pathophysiology of Seizures
Increased EAA Decreased GABA
• Increased Excitatory • Decreased binding of
Amino Acid Transmission GABA and
• Increased sensitivity to benzodiazepines
EAA • Decreased Cl- currents in
• Progressive increase in response to GABA
glutamate release during
kindling • Decreased glutamate
• Increased glutamate and
decarboxylase activity
aspartate at start of seizure (synthesizes GABA)
• Upregulation of NMDA • Interfere with GABA
receptors in kindled rats causes seizures
Strategies in Treatment
• Stabilize membrane and prevent
depolarization by action on ion
channels
R2 X
R3
Dose (mg/day)
Phenytoin – Toxicity and
Adverse Events
Acute Toxicity
Cl-
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.
GABA Vigabatrin
Tiagabine Gabapentin
Modulators of GABA Transmission
GBP
TPM
GABA-T
VGB
BZD
TGB
GABA-T
VGB
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 <
2 years old. (?) Toxic metabolites involved.
• Drug interactions: inhibits phenobarbital and
phenytoin metabolism.
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.
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.