Anticonvulsants for Pharmacology and Therapeutics

Question 1

What is an epileptic seizure?

Answer 1

• Sudden changes in behaviour caused by electrical hypersynchronisiation of neuronal networks in the cerebral cortex (i.e multiple, simultaneous, synchronised neuronal firing in cerebral cortex causing behavioural change)

Question 2

What is epilepsy?

Answer 2

A tendency to recurrent, unprovoked seizures

Question 3

How are epileptic seizures diagnosed?

Answer 3

• EEG
• MRI

Question 4

When are the two peaks in incidence of epilepsy and what are they usually caused by?

Answer 4

• Young adults – where genetic predispositions begin to manifest
• Later years – when patients start getting brain injuries e.g. stroke

Question 5

What are the two main types of epilepsy?

Answer 5

1. Partial/Focal – the excess discharge is localised to one area of the brain
2. Generalised – the synchronised discharge affects all brain areas

Question 6

List and describe the 5 types of general seizure in epilepsy

Answer 6

1. Tonic-clonic seizure
   * Loss of consciousness → muscle stiffening → jerking/twitching → deep sleep → wakes up
2. Absence seizure
   * Brief staring episodes with behavioural arrest
3. Tonic / Atonic seizures
   * Sudden muscle stiffening/sudden loss of muscle control
4. Myoclonic seizures
   * Sudden, brief muscle contractions
5. Status Epilepticus
   * > 5 min of continuous seizure activity

Question 7

List and describe briefly the 2 types of partial / focal seizure in epilepsy

Answer 7

1. Simple - retained awareness/consciousness
2. Complex - impaired awareness/consciousness

Question 8

What is a key characteristic of absence seizures?

Answer 8

• 3 Hz brain activity

Question 9

Are the folllowing NTs excitatory or inhibitory, and thus describe how they are manipulated in epilepsy treatment?

1) Glutamate
2) GABA

Answer 9

1)

• Glutamate is excitatory - therefore Glutamergic transmission must be inhibited for epilepsy treatment

2)

• GABA is inhibitory - therefore we must enhance GABAergic transmission for epilepsy treatment

Question 10

Outline the step-wise process of glutaminergic synapse transmission, including the post-synaptic receptors it acts upon

Answer 10

1. Voltage-gated Na+ channel (VGSC) opens → membrane depolarisation
2. Voltage-gated K+ channel (VGKC) opens → membrane repolarisation
3. Ca2+ influx through voltage-gated calcium channels (VGCCs) → vesicle exocytosis
4. Synaptic vesicle associated (SV2A) protein allows vesicle attachment to presynaptic membrane
5. Glutamate activates excitatory post-synaptic receptors (e.g. NMDA, AMPA & kainate receptors)

Question 11

What are the 3 main types of ligand-ion channels that glutamate activates

Answer 11

1. NMDA-R
2. Kainate-R
3. AMPA

Question 12

State some drugs that induce carbamazepine metabolism

Answer 12

• Phenytoin
• Phenobarbital

Question 13

1) Describe the different states that voltage-gated Na⁺ channels exist in and thus how a certain Na⁺ channel blockers works - also name this blocker
2) When is the use of these indicated?

Answer 13

1)

• Na⁺ channels are either in their closed, open, or inactive states
• Carbamazepines stabilises inactive state of Na⁺ channel → reducing neuronal activity

2)

• Tonic-clonic seizures
• Partial seizures

Question 14

1) What are the two most severe forms of allergic reaction to Carbemazepine?
2) What polymorphism confers increased risk of getting these severe allergic reactions?

Answer 14

1)

1. Stevens-Johnsons Syndrome
2. Toxic Epidermal Necrosis (TEN)

2)

• HLA-B*1502

Question 15

1) What does Carbamazepine do?
2) When is it indicated?
3) Pharmacokinetics - slow or fast onset and duration of action?

Answer 15

1)

• Carbamazepine is a sodium channel blocker - it maintains the sodium channels in their inactive state

2)

• Tonic-clonic seizures
• Partial seizures

3)

• Fast onset
• Long duration of action

Question 16

How do sodium channel blocker drugs work to target epilepsy in its treatment?

Answer 16

• Use-dependency blockade meaning that it only blocks the nerve conduction when the neurones are firing excessively (i.e. during a seizure) and so the drugs inhibit seizures without affecting normal cognitive function

Question 17

1) What does Lamotrigmine do?
2) Describe pharmacokinetics
3) When is it indicated?

Answer 17

1)

• Inactivates Na⁺ channels → reducing glutamate neuronal activity

2)

• Fast onset
• Long duration of action

3)

• Tonic-clonic seizures
• Myoclonic seizures

Question 18

1) What class of drugs does Ethosuximide belong to and describe its mode of action?
2) Describe pharmacokinetics
3) When is it indicated?

Answer 18

1)

• Voltage gated calcium channel blockers
• T-type (type found in neurones) Ca2+ channel antagonist → reduces activity in relay thalamic neurones
• This prevents the promotion of synaptic vesicles binding the presynaptic membrane and ultimately preventing exocytosis

2)

• Long half-life

3)

• Indicated in treatment of absence seizures

Question 19

1) What does Leveteracetam do?
2) Describe pharmacokinetics
3) When is it indicated?

Answer 19

1)

• Binds to synaptic vesicle associated protein (SV2A) → preventing glutamate containing synaptic vesicles binding presynaptic CSM → thereby preventing exocytosis of glutamate to prevent glutamate transmission

2)

• Fast onset

3)

• Myoclonic seizures

Question 20

1) What does Topiramate do?
2) Describe pharmacokinetics
3) When is it indicated?

Answer 20

1)

• Inhibits NMDA & kainate receptors
• Thereby prevents the excitation by glutamate (which acts on these receptors to excite post-synaptic neurone)
• Also affects VGSCs & GABA receptors (not important - can ignore)

2)

• Fast onset of action

3)

• Myoclonic seizures

Question 21

Summarise again the process of glumatergic transmission and then the 4 different types of pharmacological actions to inhibit this in order to treat epilepsy - giving the name of the drug for each of these

Answer 21

Neurotransmission

1. VGSC → depolarisation → VGKC → repolarisation
2. Ca2+ influx through VGCCs → vesicle exocytosis
3. SVA2 allows vesicle attachment to membrane
4. Glutamate activates excitatory post-synaptic receptor

Pharmacology

1. VGSC antagonist: e.g Carbamazepine
2. VGCC antagonist: Ethosuximide (T-type antagonist);
3. SV2A inhibitor: Levetiracetam
4. Glutamate receptor antagonist: Topiramate

Question 22

In the metabolism of GABA, what is GABA taken up by and what is it metabolised by?

Answer 22

• Glutamate is taken up by GAT (glutamate transporter) into glial cells
• Here it is metabolised by GABA transaminase (GABA-T) into succinic semialdehyde
• And succinic semialdehyde dehydrogenase (SSDH) finally converts it into succinic acid

Question 23

1) What does diazepam do - mode of action?
2) Describe pharmacokinetics
3) When is it indicated?

Answer 23

1)

• Positive allosteric modulator that facilitates GABA -GABA-receptor interaction - thereby promoting GABA’s inhibitory effect

2)

• Fast onset
• Short duration of action

3)

• Status epilepticus

Question 24

1) What does Sodium valproate do?
2) Describe pharmacokinetics
3) When is it indicated?

Answer 24

1)

• Inhibits GABA-transaminase and succinic semialdehyde dehydrogenase (both enzymes that metabolise GABA and its metabolite) → therefore increases synaptic [GABA] → therefore increases GABA mediated inhibitory signals

2)

• Fast onset
• Short half-life

3)

• Indicated for ALL forms of epilepsy

Question 25

Complete the table matching the type of seizure with the medication used

Answer 25