L1 Epilepsy

Question 1

Definition of epileptic seizures

Answer 1

Episodic high frequency discharges by a localised group of neurons in the brain

Question 2

Symptoms of motor cortex seizure

Answer 2

Convulsions

Question 3

Symptoms of seizure affecting hypothalamus

Answer 3

Peripheral autonomic effects

Question 4

Symptoms of seizure in reticular formation

Answer 4

Loss of consciousness

Question 5

Drug treatment is effective in what percentage of epileptic patients?

Answer 5

~70%

Question 6

Epilepsy incidence

Answer 6

~0.5% of the general pop (1:200)

Question 7

Cause of primary epilepsy

Answer 7

Idiopathic

Question 8

Cause of secondary epilepsy

Answer 8

Result of brain damage, or a tumour acting on a particular brain region

Question 9

Forms of epilepsy

Answer 9

1. Partial seizures (focal): simple or complex
2. Generalised seizures: absence or tonic-clonic

Question 10

Difference between partial and generalised seizures

Answer 10

Partial seizures - discharge localised to one brain region and hemisphere
Generalised seizures - discharge involves both hemispheres and reticular system (consciousness affected)

Question 11

What percentage of patients with partial seizures can sometimes experience a secondary generalised seizure?

Answer 11

~30%

Question 12

Absence (petit mal) seizures are most common in __ and are characterised by __

Answer 12

children
staring spells

Question 13

How is neurotransmission altered in epilepsy?

Answer 13

• increased excitatory neurotransmission
• decreased inhibitory neurotransmission
• repeated discharge (excitotoxicity)

Question 14

Animal models of epilepsy

Answer 14

• Chemical: ICV Kainate injections (glutamate agonist)
• Physical: Kindling - repeated low intensity brain stimulation (electrodes)

Question 15

Main aims of AEDs

Answer 15

• Reduce electrical excitability of excitatory neurons (glutamate)
• Increased inhibitory (GABA) neurotransmission

Question 16

Main mechanisms of AEDs

Answer 16

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

Question 17

List Na⁺ channel blockers used to treat epilepsy

Answer 17

• Carbamazepine
• Oxcarbazepine
• Phenytoin
• Lamotrigine
• Zonisamide

Question 18

Na⁺ channel blocker stabilises the receptor in its __ state

Answer 18

inactivated

Question 19

Na⁺ channel blockers mainly affect neurons with __ frequency discharge

Answer 19

high

Question 20

What is the most widely-used AED?

Answer 20

Carbamazepine

Question 21

CBZ metabolism

Answer 21

• Epoxidation to CBZ-10,11-epoxide, hydrolysis to CBZ-10,11-trans-dihydrodiol
• Strong inducer of CYP450 enzymes
• Autoinducer of its own metabolism

Question 22

CBZ increases metabolism of…

Answer 22

phenytoin, warfarin, oral contraceptives

Question 23

CBZ half-life

Answer 23

30h for single dose, decreased to 15h on repeated dosing

Question 24

CBZ side effects

Answer 24

• Neurological: drowsiness, dizziness, ataxia, cognitive & motor disturbances
• Hypersensitivity reactions (skin, liver)

Question 25

Pro-drug analogue of CBZ

Answer 25

Oxcarbazepine

Question 26

Advantage of oxcarbazepine over CBZ

Answer 26

- Less P450 induction, therefore less drug interactions - Does not interact with warfarin, cimetidine, erythromycin

Question 27

Why have CBZ and oxcarbazepine been used for neuropathic pain and schizophrenia?

Answer 27

because they also act as GABA receptor agonists

Question 28

First-line treatment for partial and secondary generalised seizures

Answer 28

Phenytoin

Question 29

Phenytoin MOA

Answer 29

Na⁺ and Ca²⁺ channel inhibitor

Question 30

Combination of phenytoin and __ is not recommended due to toxicity risk

Answer 30

valproate

Question 31

Phenytoin is highly bound to __

Answer 31

plasma albumin (80-90%)

Question 32

Why are drug interactions common with phenytoin?

Answer 32

because it's metabolised by and induces CYP450 enzyme activity, which increases metabolism of CBZ, phenobarbital and valproate

Question 33

Phenytoin side effects

Answer 33

- Plasma conc. >100µM: vertigo, ataxia, headache - Plasma conc. >150µM: confusion, intellectual deterioration - Hypersensitivity reactions (skin, liver) - Gum hyperplasia - Vit D def - Teratogenesis

Question 34

Safer pro-drug of phenytoin

Answer 34

Fosphenytoin

Question 35

Sodium-blocking AED that also inhibits presynaptic depolarisation of glutamatergic neurons

Answer 35

Lamotrigine

Question 36

Lamotrigine is usually combined with __

Answer 36

valproate

Question 37

Why is Lamotrigine preferred in the elderly?

Answer 37

Low CNS toxicity

Question 38

Can Lamotrigine be used in pregnancy?

Answer 38

Yes

Question 39

Zonisamide MOA

Answer 39

- Inhibits both Na⁺ and Ca²⁺ channels - Neuroprotective by free radical scavenging - Metabolised by CYP450, then glucuronidation

Question 40

Half-life of Zonisamide

Answer 40

60h, less when combined with phenytoin, CBZ or valproate (well-tolerated, not prone to serious DDIs)

Question 41

Low threshold __ Ca²⁺ channels implicated in periodic discharges of partial seizures

Answer 41

T-type

Question 42

T-type Ca²⁺ channel blocker used to control absence seizures

Answer 42

Ethosuximide

Question 43

What is gabapentin?

Answer 43

Pre-synaptic L-type Ca²⁺ channel inhibitor that binds α₂𝛿 subunit of Ca²⁺ channels in cerebral neocortex, hippocampus & SC to decrease release of glutamate and increase GABA levels (by stimulating GAD)

Question 44

More potent pro-drug of gabapentin

Answer 44

Pregabalin

Question 45

Valproate MOA

Answer 45

Increases GABA by stimulating glutamate decarboxylase and inhibiting GABA deaminase. Also weak block of Na⁺ and Ca²⁺ channels

Question 46

Side effects of valproate

Answer 46

Hepatotoxicity, teratogenesis

Question 47

How does vigabatrin increase GABA in the brain?

Answer 47

by irreversibly inhibiting GABA deaminase

Question 48

What is tiagabine?

Answer 48

Lipophilic GABA analogue that irreversibly inhibits GAT-1 in neurons & glia to prevent GABA re-uptake, prolonging GABA effect at inhibitory synapses

Question 49

Pharmacological agents that increase GABAa receptor response to reduce seizure duration

Answer 49

- Phenobarbital - Benzodiazepines e.g. diazepam, lorazepam, clonazepam

Question 50

What happens if you overdose on phenobarbital?

Answer 50

Severe respiratory and circulatory depression, coma

Question 51

When are benzodiazepines used?

Answer 51

in emergency (status epilepticus) - IV admin, fast-acting

Question 52

Felbamate MOA

Answer 52

NMDA glutamate receptor antagonist. Also weakly blocks Na⁺ and Ca²⁺ channels

Question 53

Topiramate MOA

Answer 53

AMPA glutamate receptor antagonist. Also blocks Na⁺ channels, raises GABA levels, and weakly blocks carbonic anhydrase

Question 54

__ channel blockers better in partial seizures

Answer 54

Na⁺

Question 55

__ channel blockers better in generalised seizures

Answer 55

Ca²⁺

Question 56

Carbonic anhydrase inhibitor that increases carbonic acid levels to increase seizure threshold

Answer 56

Acetazolamide

Question 57

Progesterone is __-convulsant

Answer 57

anti (increases GABAa conductance, reduces glutamatergic excitation)

Question 58

Oestrogen is __-convulsant

Answer 58

pro (reduces GABAa conductance)

Question 59

What is Dravet syndrome?

Answer 59

Severe myoclonic epilepsy of infancy (SMEI)

Question 60

What is cannabidiol?

Answer 60

- CBD: non-psychoactive component of cannabis plant - Oil extracted from a plant high in CBD & low in THC - Can help in MS, Dravet syndrome, chemo-induced nausea or loss-of-appetite