Drug Treatment of Epilepsy

Question 1

What are epileptic seizures?

Answer 1

Episodic high frequency discharges by a localised group of neurons in the brain
- They are not constantly occurring
- There are factors which decreases seizure threshold including stress and sleep deprivation

Question 2

How do drugs in relation to epilepsy work?

Answer 2

to prevent excessive neurotransmission - whether that be increase excitation or increase inhibiton

Question 3

Main Excitatory “ON” switch in the brain

Answer 3

Glutamate

Question 4

Main Inhibitory “OFF” switch in the brain

Answer 4

GABA

Question 5

Symptoms of Epilepsy depend on…

Answer 5

The area of the brain affected
- Motor Cortex → Convulsions
- Hypothalamus → Peripheral autonomic effects
- Reticular formation (Upper brainstem) → loss of consciousness

Question 6

Why is determining the correct dosage of anti-epileptics essential?

Answer 6

Over medication can result in sedative effects including memory loss

Question 7

The primary cause of epilepsy

Answer 7

Idiopathic

Question 8

What is secondary epilepsy?

Answer 8

a result of brain damage which generally leads to seizures

Question 9

What are partial seizures?

Answer 9

Also known as Local or Focal

Discharge is localised to one brain region and hemisphere

Can be Simple or Complex

Question 10

Complex local seizure

Answer 10

Consciousness is affected (often the Temporal lobe)

Question 11

What are generalised seizures?

Answer 11

Discharge involves both hemispheres and reticular systems - consciousness is affected

Can be differentiated to Absence Seizures or Tonic-Clonic

Question 12

Absence Seizure

Answer 12

Also known as Petit Mal..
Most common in children: staring

Question 13

Tonic-Clonic Seizures

Answer 13

Also known as Grand Mal
Tonic phase - muscle spasm, respiration stops, bowel/bladder discharge
Clonic phase - release

Physical signs - violent jerking, unable to stand

Question 14

Main aims of antiepileptics

Answer 14

to reduce electrical excitability of excitatory neurons (i.e., glutamate) or to increase inhibitory neurotransmission (i.e., GABA)

Question 15

4 Main Mechanisms of Antiepileptic Drugs

Answer 15

1. Use-dependent Na+ channel block
2. Ca2+ channel inhibition
3. Increase GABA-mediated neural inhibition
4. Inhibit glutaminergic

Question 16

Other approved antiepileptic strategies

Answer 16

Carbonic anhydrase inhibitors
CBD (i.e., think of Dravett’s)
Ketogenic diet

Question 17

Example of drug which blocks use-dependent Na+ channel

Answer 17

Phenytoin, Carbamazepine, Lamotrigine, Valproate

Question 18

Example of drug which inhibits Ca2+ channel

Answer 18

Ethosuximide, Gabapentin, (Phenytoin & Valproate as well)

Question 19

Drugs which inhibit glutaminergic transmission

Answer 19

NMDA/AMPA/mGluR antagonists

Question 20

Drugs to enhance GABA activation

Answer 20

Phenobarbital, Benzodiazepeines

Question 21

Drugs which inhibit GABA deaminase

Answer 21

Valproate, Vigabatrin

Question 22

Inhibit GABA reuptake

Answer 22

Tigabine

Question 23

Na+ channel blockers stabilise these channels when..

Answer 23

in its inactivate state (i.e., when it is use-dependent!)

Question 24

The most widely used AED?

Answer 24

Carbamazepine (CBZ)
→ strong inducer of P450 enzymes
→ increases metabolism of phenytoin, warfarin, OCP etc..

Question 25

Prodrug analog of CBZ

Answer 25

Oxcarbazepine - metabolised in the liver to CBZ

• used as a monotherapy in children, but in adjunct therapy in adults with partial therapy

Less drug interactions as it is less potent on P450

Question 26

What is generally first line treatment of partial and secondary generalised seizures?

Answer 26

Phenytoin

Question 27

How is Ca2+ channel inhibition useful in treatment of epilepsy?

Answer 27

Ca2+ activates proteases responsible for vesicle fusion

Question 28

Which Ca2+ Channels are implicated in periodic discharge observed in partial seizures?

Answer 28

Low threshold T channels

Question 29

MOA of Ethosuximide

Answer 29

inhibits T type Ca2+ channels (pre & postsynaptic)
Also inhibits Na+/K+ ATPase and GABA deaminase

Question 30

MOA of gabapentin

Answer 30

NOTHING TO DO WITH GABA

Presynaptic L type Ca2+ channel inhibitor
Decreases release of glutamate and other associated modulators, therefore increasing GABA levels

Question 31

MOA of Valproate

Answer 31

Increases GABA in the brain

Simulates glutamate decarboxylase, inhibits GABA deaminase and weakly blocks Na+ and Ca2+ channels

Question 32

MOA of Vigabatrin

Answer 32

irreversibly blocks GABA deaminase, therefore increasing GABA in the brain

• Side effects: Depression and psychotic disturbances