Anti-convulsants

Question 1

Define Epilepsy

Answer 1

A neurological condition causing frequent seizures

Seizures
‘sudden changes in behaviour caused by electrical hypersynchronisation of the neuronal networks in the cerebral cortex’

Question 2

How can epilepsy be diagnosed?

Answer 2

EEG
&
MRI

Question 3

2 types seizures?

Answer 3

(1) General seizures

(2) Partial/focal seizures

Question 4

Explain General Seizures

Answer 4

Begins simultaneously in BOTH hemispheres of brain

Seizure types & Symptoms:

(a) Tonic-clonic seizures
• loss of consciousness –> muscle stiffening –> jerking/twitching –> deep sleep –> wake up

(b) Absence seizures
• brief staring episodes w. behavioural arrest

(c) Tonic/atonic seizures
• sudden muscle stiffening/sudden loss of muscle control

(d) Myoclonic seizures
• sudden, brief muscle contractions

(e) Status epilepticus
• >5min of continous seizure

Cause: could be possible genetic link/disorder

Question 5

Explain Partial/Focal Seizure

Answer 5

Begins within a particular area of the brain & may spread OUT

Seizure types & Symptom:

(a) Simple
• retained awareness/consciousness

(b) Complex
• impaired awareness/consciousness

Cause: may be a result of an injury OR insult

Question 6

Briefly explain regular brain activity and what happens during seizure activity

Answer 6

Regular activity:

There are distinctive wave patterns associated with each level of consciousness:
 	Gamma 
  • aware – hyperactive
 	Beta 
  • aware – thinking
 	Alpha 
  • aware – relaxed
 	Theta 
  • drowsy – meditation
 	Delta 
  • deep sleep

Seizure activity:

The wave patterns are irregular or asynchronous due to neuronal OVER-activity.

Question 7

Broadly explain the 2 ways anti-convulsants work

Answer 7

(1) Glutamate INHIBITION

(2) GABA ENHANCEMENT

Question 8

Explain what occurs in the Glutamatergic Synapse in regards to neurotransmission

Answer 8

1. VGSC opens –> membrane depolarisation
2. VGKC opens –> membrane repolarisation
3. VGCC-mediated Ca2+ influx –> glutamate vesicle exocytosis
   (a) SV2A (Synaptic Vesicle Associated) protein allows vesicle attachment to the presynaptic membrane
4. Glutamate binds to post-synaptic receptors
   • e.g. NMDA, AMPA, Kainate receptors

Question 9

Potential areas of target in Glutamate-mediated Neurotranmission

Answer 9

(1) VGSC Blockers
• antagonists

(2) VGKC Enhancers
• hyperpolarises the cell

(3) VGCC Blockers
• prevents exocytosis of glutamate vesicles

(4) Glutamate Exocytosis & Receptor Modifiers

Question 10

State and explain the drugs associated with (1)

Answer 10

(1) VGSC Blockers

 Carbamazine – VGSC antagonist:

Treats:
• partial seizures
• tonic-clonic seizures

Pharmacodynamics:
• STABILISES inactive state of VGSC –> reduce neuronal activity

Pharmacokinetics:
• Induces hepatic enzyme
• T1/2 = 16-30 hours.
• Dangerous in people with HLA-B*1502 alleles

 Lamotrigine– VGSC antagonist:

Treats:
• tonic-clonic seizures
• absence seizures

Pharmacodynamics:
• inactivates VGSC –> reduces glutamate neuronal activity

Pharmacokinetics:
• Onset = <1hour
• T1/2 = 24-34 hours

(note difference in pharmacodynamics between the 2)

Question 11

State and explain the drugs associated with (3)

Answer 11

(3) VGCC Blockers
– prevents exocytosis of glutamate vesicles:

 Ethosuximide:

Treats:
• absence seizures

Pharmacodynamics:
• T-type Ca2+-channel antagonist –> reduces activity in relay thalamic neurones

Pharmacokinetics:
• T1/2 = 50 hours (LONG)

Question 12

State and explain the drugs associated with (4)

Answer 12

(4) Glutamate Exocytosis & Receptor Modifiers

 Levetiracetam:

Treats:
• myoclonic seizures

Pharmacodynamics:
• SV2A inhibitor (of vesicle exocytosis)
• binds to this synaptic vesicle associated protein –> preventing glutamate release

Pharmacokinetics:
• Onset = 1 hour (FAST),
• T1/2 = 10 hours (SHORT)

 Topiramate – :

Treats:
• myoclonic seizures (most types of epilepsy)

Pharmacodynamics:
• Kainate-R GluK5 subunit inhibitor
• NMDA inhibitor
• Also affects VGSCs and GABA receptors – dirty drug

Pharmacokinetics:
• Onset = 1 hour (FAST),
• T1/2 = 20 hours (LONG)

Question 13

Overall pharmacology of Glutamatergic Synpase drugs?

Answer 13

(1) VGSC antagonist:
• e.g Carbamazepine

(2) VGCC antagonist:
• Ethosuximide (T-type antagonist)

(3) SV2A inhibitor:
• Levetiracetam

(4) Glutamate receptor antagonist:
• Topiramate

Question 14

Explain neurotransmission at GABAergic synapses

Answer 14

1. GABA is released tonically (basally) and/or via neuronal stimulation
2. GABA activates post-synaptic inhibitory GABAA receptors
3. GABAa receptors are Cl—channels –> lead to membrane hyperpolarisation
   4a. GABA is taken up by GAT (GABA Transporter)
   4b. GABA is metabolised by GABA-T (GABA Transaminase).

Question 15

Potential areas of target in GABAergic-mediated Neurotranmission

Answer 15

(1) GABAaR Blockers

(2) GABA Metabolism Inhibitors

Question 16

State and explain the drugs associated with (1)

Answer 16

(1) GABAaR Blockers

 Diazepam:

Treats:
• Status epilepticus

Pharmacodynamics:
• GABA receptor PAM –> increases GABA-mediated inhibition
• as it is a BDZ, binds to the BDZ-receptor protein of GABAa-R

Pharmacokinetics:
• Rectal gel - FAST onset (within 15mins)
• T1/2 = 2hours

Question 17

State and explain the drugs associated with (2)

Answer 17

(2) GABA Metabolism Inhibitors

 Sodium Valproate – :

Treats:
• ALL FORMS of epilepsy

Pharmacodynamics:
• GABA-T inhibitor –> increases GABA-mediated inhibition

Pharmacokinetics:
• Onset = 1 hour (FAST)
• T1/2 = 12 hours (meh).

Question 18

Which drug for which Type of Seizure?

Answer 18

Tonic-clonic seizures:
• Carbamazepine
• Lamotrigine
• Valproate

Absence seizures:
• Ethosuximide
• Lamotrigine
• Valproate

Tonic/atonic seizures:
• Valproate

Myoclonic seizures:
• Levetiracetam
• Valproate
• Topiramate

Status epilepticus:
• Diazepam

Simple partial/ Complex partial:
 • Carbamazepine
 • Lamotrigine
 • Levetiracetam
 • Valproate