Epilepsy Pharmacology

Discuss drugs used in treatment of epilepsy and indicate the main

molecular target of each - Also GABA-A receptor function
What is epilepsy?
• Group of neurological disorders characterized by recurrent seizures
• Seizures come about due to episodic high-frequency discharge of impulses of groups of neurons
in CNS
• Different types:
• Generalized
• Convulsive
• Tonic – rigidity
• Clonic – jerks
• Non-convulsive
• Petit mal
• Absence seizures
• Loss of awareness
• Partial
• Focal seizures (one brain area)
• Can spread to cause secondary seizures
• Status epilepticus
• Long persistent seizure (>5mins)
• Can be fatal (no ventilation)
Pathophysiology
• Single/multiple mutations in channels which control neuronal activity
• SCN1A and GABA
• Can be caused by physical onslaught
• Post-stroke
• Head injury
• Brian tumor
• Often idiopathic
Cause of Epilepsy
• Epileptogenesis
• Disruption in the balance of excitatory and inhibitory signals
• Glutamate receptor agonists or GABA receptor antagonists/blockers
can be used to trigger seizures
• Loss of GABAergic neurons in cortex
• Paroxysmal depolarising shift
• Maintained change in resting membrane potential and threshold
• Resembling prolonged glutamate release
 GABA-A receptors

• Expressed post and extra synaptically

• Large extracellular N-terminus, 4
transmembrane domains of which TM2
lines the pore
• The loop (intracellular) between TM3 and
TM4 is the site of modulation for this
receptor
• Permeable to chloride ions (resulting in
hyperpolarisation)
• GABA binds at alpha/beta interface (2
binding sites normally)
GABA Pharmacology
• Lorazepam and Diazepam – used to treat status epilepticus
• Lead to tolerance, dependence and sedation (unsustainable)
• Tiagabine
• Inhibits GABA uptake (GAT1)
• Increases extracellular concentration of GABA
• Add-on for partial seizures
• Vigabatrin
• Irreversibly inhibits GABA transaminase (GAT)
• Increase GABA concentration and release
• Irreversibly therefore long lasting effect
• Use in absence seizures and patients refractory to other treatment
Sodium Channel Blockers
• Lamotrigine
• Use dependent blocker
• May also block glutamate release
• Carbamazepine
• Use dependent blocker
• Used in absence seizures
• Bad side effects: Ataxia, hypersensitivity reaction
• Metabolised by CYP450 so drug-drug interactions
• Lacosamide
• Enhances slow inactivation
• In partial seizures
• Phenytoin
• Use dependent
• Odd side effects: gum hyperplasia, excessive hair growth and
ataxia
Calcium channel modulators
• Used for Absence seizures
• Oscillations by 3Hz in EEG- Thalamocortical circuit
1. Activation of T type calcium channels in thalamocortical neurons
2. These neurons stimulate cortex and reticular thalamic nucleus-
activate in bursts
3. GABA from the reticular thalamic nucleus inhibits the
thalamocortical neurons which promotes the re-priming of T-type
calcium channels
4. This activates thalamocortical neurons again
• Ethosuximide
• Absence seizure treatment only
• May cause mood changes
• Gabapentin
• Binds alpha2-delta1 accessory subunit
• Decreases Cav channel membrane expression
• Also effective in partial seizures
• Sodium valproate
• Inhibits Nav channels and GABA transaminase
• Use in generalised and partial seizures
• May cause curling or thinning of the hair
Miscellaneous
• Zonisamide
• Blocks Nav, Cav and may enhance GABA-A
• Add-on therapy in generalized seizures
• Topiramate
• Blocks Cav, Nav, AMPA receptor and enhances GABA-A
• Used for partial/generalised seizures
• Retigabine
• Kcnq2 channel opener
• Whites of eyes turned blue
• No longer used
• Levetiracetam
• SV2A binds (synaptic vesicle protein)
• Affects synaptic vesicle docking – less transmitter released
• Used for partial/generalised seizures
Teratogenic risk
• All antiepileptic drugs have teratogenic risk
• Teratogens are drugs, chemicals, or even infections that
can cause abnormal foetal development
• Valproate for example can’t be prescribed to fertile
women without contraception ads it carries such
severe risks of birth defects and long-term effects on
cognitive development

• Some antiepileptic drugs which induce hepatic

CYP3A4 enzymes may be increasing oral
contraceptive metabolism and hence promote
vitamin K deficiency in the newborn