Epilepsy

Question 1

Sodium Channels

Answer 1

• Phenytoin
• Carbamazepine

 Bind to the inner pore of the sodium channel in its inactivated state (immediately after depolarization).
(!) Zero order kinetics seen in phenytoin.

 Leads to an increased refractory period (delay in time taken to return to resting state)
(!) Carbamazepine: liver enzyme induction.

NOT USED IN ABSENCE SEIZURES

• Sodium valproate

 All types of seizures (not to be used in pregnancy).

Question 2

T-type Calcium Channels

Answer 2

• Ethosuximide (used in absence seizures)
• Zonasamide

Work on T-type calcium channels which require less depolarization to be activated.

Question 3

L-type calcium channels

Answer 3

• Carbamazepine
• Phenytoin
• Topiramate (also increases GABA transmission and inhibits glutamate and works on sodium channels)

Work on L-type calcium channels: allow post-depolarization calcium influx and are slowly inactivated. Inhibiting these channels causes inhibition of calcium influx post-depolarization.

Question 4

N and P/Q-type channels

Answer 4

• Lamotrigine (inhibition of glutamate release as well as target in sodium channels (inner pore binding)
• Topiramate
• Levetiracetam (also SV2A binding)
• Pregabalin - alpha-2-delta subunit of N-type

Act on N and P/Q-type channels expressed presynaptically (boutons) and mediate calcium entry for neurotransmitter release.

Question 5

Neurotransmitter release

Answer 5

• Levetiracetam

Binds to synaptic vesicle protein SV2A as well as inhibiting presynaptic calcium channels REDUCING NEUROTRANSMITTER RELEASE

Question 6

GABAa Receptor

Answer 6

Benzodiazepines (e.g. Clonazepam, lorazepam, diazepam)

 Expressed post-synaptically, lead to fast inhibitory transmission (hyperpolarization) through influx of Cl- (higher extracellularly than intracellularly).
 Stops propagation of electrical activity in cerebral cortex.
 Acts as a positive modulator by increasing frequency of receptor opening

Barbiturates (e.g. Phenobarbitone)

 Acts as a positive modulated by prolonged receptor opening and therefore more hyperpolarization.
 At high concentration: directly activates the channels which causes an anaesthetic effect.
 Liver enzyme induction.

Question 7

GABA Modulation

Answer 7

Vigabatrin (Affects GABA synthesis)
• Inhibits GABA Transaminase leads to an increase in GABA levels (increased GABA desensitises GABA autoreceptors, reducing inhibitory feedback on release).

Tiagabine (Affects GABA uptake)
• Inhibits GAT-1 (transporter involved in removing GABA from the synaptic cleft).

Question 8

Glutamate Receptors

Answer 8

Perampanel (recent drug) - Antagonist of AMPA receptors

Felbamate - Antagonist of NMDA receptors

Question 9

Prescription guidelines for anti-epileptics

Answer 9

• Focal seizures with or without secondary
generalisation (carbamazepine,
lamotrigine, sodium valproate)

• Tonic-clonic seizures (carbamazepine,
lamotrigine, sodium valproate)

• Absence seizures (ethosuximide, sodium
valproate)

• Myoclonic seizures (sodium valproate,
clonazepam, levetiracetam)