Wk6/7 - epilepsy pharmacology

What are the three most common mechanisms of anti-epileptic drugs?

Enhance GABA transmission, inhibit Na⁺ channels, inhibit Ca²⁺ channels

How were most anti-epileptic drugs discovered?

Serendipitously or empirically – not designed

What do benzodiazepines do in epilepsy?

Potentiate GABA at GABA_A receptors via modulatory site – examples: clobazam, lorazepam

What do barbiturates do in epilepsy?

Potentiate GABA at GABA_A receptors via channel modulatory site – example: phenobarbital

What was gabapentin designed to be?

A GABA_A agonist – but it is NOT; it works on P/Q-type Ca²⁺ channels

How does vigabatrin work?

Inhibits GABA transaminase (GABA-T) → increases GABA available for release

How does valproate affect GABA?

Increases amount of GABA in the brain (exact mechanism unclear) – also has other mechanisms

How does tiagabine work?

Inhibits GABA uptake via GAT1 transporter → GABA stays in synapse longer

What does GAT1 stand for?

GABA transporter 1

How do Na⁺ channel blockers work in epilepsy?

Block voltage-gated Na⁺ channels → stop action potentials → prevent spread of seizure activity

What is "use-dependency" of Na⁺ channel blockers?

They act preferentially on cells that are repetitively firing (during seizures)

What state of Na⁺ channels do these drugs block?

The inactivated state – slows recovery from inactivation

Name 6 drugs that block Na⁺ channels.

Phenytoin, carbamazepine, lamotrigine, valproate, rufinamide, lacosamide

What type of Ca²⁺ channel is targeted for absence seizures?

T-type voltage-gated Ca²⁺ channels

What drug is first-line for absence seizures?

Ethosuximide (T-type Ca²⁺ channel blocker)

What other drugs block T-type Ca²⁺ channels?

Valproate, clonazepam

What does gabapentin actually target?

P/Q-type Ca²⁺ channels (not GABA_A)

What is levetiracetam's mechanism?

Binds to SV2A (synaptic vesicle protein 2A) – modulates neurotransmitter release

What is perampanel?

An AMPA receptor antagonist – one of the newest anti-epileptic drugs

What are the mechanisms of topiramate?

Multiple: blocks Na⁺ channels, blocks Ca²⁺ channels, enhances GABA, blocks AMPA receptors

Have NMDA receptor antagonists been effective for epilepsy?

No – they have not proved effective

What drug both enhances GABA and blocks Na⁺ channels and glutamate receptors?

Phenobarbital

Which anti-epileptic drug is a GABA-T inhibitor?

Vigabatrin

Which anti-epileptic drug is a GAT1 inhibitor?

Tiagabine

Which anti-epileptic drug was designed as a GABA agonist but works on Ca²⁺ channels?

Gabapentin