CPTP 3.21 Neuropharmacology 6 Antiepileptics

Question 1

Define epilepsy

Answer 1

Occasional, sudden, excessive local discharges of grey matter

Question 2

What is a convulsion?

Answer 2

A ‘fit’: muscular contractions during a seizure

Question 3

What is a seizure?

Answer 3

A period of synchronous discharge of neurones

Question 4

What are anticonvulsants?

Answer 4

Drugs active against seizures

Question 5

What are the potential causes of epilepsy?

Answer 5

• Trauma, tumour or infection of the brain
  
  • Drug withdrawal
  • High fever
  • Metabolic imbalances
  • Heavy metal toxicity

Can also be idiopathic

Question 6

What are the types of epilepsy?

Answer 6

Partial Seizures - where the epileptic focus is localised
• Jacksonian
• Temporal lobe epilepsy
• Psychomotor

Generalised
• Petit mal (absence)
• Grande mal (tonic-clonic)

Question 7

How is brain electrical activity monitored?

What is normal and abnormal when using this?

Answer 7

EEG

Brain activity can be unsynchronised or synchronised when the activity of groups of neurones is summated. Unsynchronised is normal. (IMG 11 shows an example using six neurones). Synchronising suggests it is being caused by some underlying pathology

Question 8

What do the symptoms of epilepsy depend on? Give examples

Answer 8

The location of the epileptic focus

Temporal lobe
• Hallucinations

Motor cortex
• Bizarre movements

Question 9

Define a partial siezure

Answer 9

Synchronous activity with a localised epileptic focus (starting site)

Question 10

Why is temporal lobe epilepsy associated with hallucinations?

Answer 10

It contains auditory and visual processing areas which are overstimulated during synchronous activity

Question 11

Describe petit mal seizures

What causes them?

Answer 11

• Generalised seizures
  
  • Synchronous discharge at all electrode sites at 3Hz
  • Short duration and random
  • ‘Absence’ (a brief loss and return of consciousness)
  • NO MOTOR SYMPTOMS
  • No post ictal coma

Dysfunction in thalamocortical circuits

Question 12

What are grand mal seizures also known as?

Answer 12

Tonic-clonic seizures

Question 13

Describe grand mal seizures, including where they start

Name the type of epilepsy characterised by a similar type of seizure but prolonged and continuous

Answer 13

• No focus at onset
• Involves synchronous discharge at all electrode sites
• Random with a LONG duration
• Post ictal coma occurs
• Two phases:
> ‘tonic’ (classic arched back away from floor)
> ‘clonic’ (looks like decerebrate posturing but with bent legs) (IMG 12)

Status epilepticus (prolonged tonic-clonic seizure)

Question 14

What can precipitate and complicate status epilepticus?

Answer 14

Precipitated by:
• Fever and sweating
• Hypertension

Complicated by:
• Hypoxia

Question 15

How are status epilepticus seizures stopped?

Answer 15

Induced coma

Question 16

What are the main excitatory and inhibitory neurotransmitters in the brain?

Answer 16

Excitatory: Glutamate
Inhibitory: GABA

Question 17

which receptors and channels contribute to epileptic activity?

Answer 17

• NMDA
  
  • AMPA
  • Subthreshold Na+ channels
  • Voltage-gated Ca2+ channels

Question 18

What terminates epileptic activity?

Answer 18

• Glutamate depletion
  
  • Glutamate receptor desensitisation

Hyper-polarisation:
• Na+ channel inactivation
• K+ channel activation

Question 19

How do anticonvulsants work?

Answer 19

They target mediators of neuronal excitability (channels and receptors)
• Increasing GABA transmission
> Positively modulate receptors
> GABA reuptake inhibition
> GABA transaminase inhibition
• Block sodium channels
• Block calcium channels

Question 20

Name the formulary anticonvulsants

Answer 20

• Diazepam (benzodiazepines)
  
  • Sodium Valproate
  • Phenytoin
  • Carbamazepine
  • Barbiturates

Question 21

What can barbiturates and benzodiazepines also be used to treat?

Answer 21

Used as anxiolytics and hypnotics (lowers activity)

Question 22

Describe GABAergic neurotransmission

Answer 22

GABA neurones are found all over the brain, in the form of short interneurones which make up 20% of neurones and are involved in 30% of synapses

Question 23

Describe the GABA receptors receptor types

Answer 23

GABA-A
• Ligand gated ion channel

GABA-B
• G-protein linked receptor

Question 24

Recall how barbiturates and benzodiazepines work

Answer 24

Enhances GABAergic neurotransmission:

Barbiturates
• Inhibits Na+ channels thus preventing action potentials. Also a GABA-A agonist.

Benzodiazepines
• Allosteric modulators of GABA-A receptor
• IMG 12

Question 25

Recall why barbiturates have a small therapeutic window.

Answer 25

They activate GABA-A receptors without the need for endogenous GABA. Also targets Na+ channels

Question 26

Describe the effect of benzodiazepine agonists on: • Maximum effect of GABA • Minimum effect of GABA • EC50 of GABA

Answer 26

IMG 12 | No change in minimum or maximum effect, but lowers EC50 of GABA on receptor

Question 27

Describe GABA synthesis

Answer 27

* Glutamine is taken up * This is converted into glutamate * Glutamic acid decarboxylase converts this into GABA

Question 28

How is GABA broken down?

Answer 28

It is broken down by GABA transaminase into succinic semialdehyde

Question 29

What potential do voltage-gated sodium channels open at?

Answer 29

-55mV (threshold)

Question 30

What states do sodium channels exist in?

Answer 30

* Open * Inactivated * Resting

Question 31

What can cause an epileptic focus to become overactive?

Answer 31

Paroxysmal depolarising shift: • A rapid depolarising of the membrane which provokes repetitive firing • This is caused by the premature transition of the receptor from the resting state, ready to be activated again by the cell potential which hasn't had enough time to restore to normal yet • IMG 14 - rapid depolarisation, then rapid action potentials within this depolarised state

Question 32

How can you identify a paroxysmal depolarising shift in an EEG to identify an epileptic focus?

Answer 32

IMG 15 | • Spike followed by a slow wave

Question 33

What are the three brain 'states' which can be seen on an EEG?

Answer 33

IMG 16 • Normal - no pattern seen as all potentials balance out • Interictal - occassional spikes and slow waves caused by paroxysmal depolarising shifts • Ictal - seizure state whereby epileptic focus initiates long periods of activity and depolarisation

Question 34

What is the rationale of using voltage gated sodium channel inhibitors to selectively treat epilepsy?

Answer 34

Blocks repetitive firing in a use-dependent and voltage-dependent manner so that they only act on the pathological region of the brain which is rapidly firing (i.e. the epileptic focus) It does this by binding to resting receptors, preventing their premature transition back to open/closed state

Question 35

Which anticonvulsants target sodium channels?

Answer 35

* Phenytoin * Carbamazepine * Sodium Valproate * Lamotrigine

Question 36

What is each of the following treated by: 1) Generalised tonic clonic 2) Partial epilepsy 3) Status epilepticus

Answer 36

1) Carbamazepine, phenytoin, sodium valproate, lamotrigine 2) As in generalised tonic clonic 3) Diazepam, lorazepam, phenytoin

Question 37

Why are benzodiazepines or barbiturates used for Status epilepticus?

Answer 37

Status epilepticus does not end, and must be treated by using these hypnotics to pharmacologically induce a coma

Question 38

Which anticonvulsant drugs induce metabolism of other medications including themselves? What other pharmacological property of these properties is of note?

Answer 38

* Phenytoin * Carbemazepine These have a narrow therapeutic window

Question 39

What non-drug treatments are available for epilepsy?

Answer 39

* Surgery * Vagus nerve stimulation * Deep brain stimulation