Clinical Lecture: Epilepsy

Question 1

What is a seizure?

Answer 1

Abnormally excessive and Hypersynchronous activity of neurones located predominantly in the cerebral cortex.

Question 2

What are the 2 scenarios in which a seizure can occur?

Answer 2

This can occur due to:

- Too much excitation - enhances sodium and calcium inward currents or from increased release of excitory neurotransmitters into the synaptic cleft such as glutamate, aspartate 
- Too little inhibition due to insufficient negatively charged negative ions such as inwards chloride and outward potassium or insufficient inhibitory GABA neurotransmitter.

Question 3

How do interneurones allow the electrical impulsed to be tightly focused?

Answer 3

When the brain is working normally very small numbers of cells are activate at a given time. The activity is kept tightly focused as it flows it is generally not allowed to flow out. This is done by inhibitory interneurons such as somatostatin type, neurogliaform cells, parvalbumin and VIP type. They allow activity to spread in one direction but not sideward.

Question 4

What is the most common anti-epileptic drug?

Answer 4

Valporic acid - Valporate

Question 5

What is the main inhibitor neurotransmitter in the brain?

Answer 5

GABA

It is found in 30% of all synapses in the brain and acts via 2 types of GASA receptors - GABAa (ligand gates chloride channel receptors) and GABAb which are G-protein coupled receptors. It is the GABAa receptor that are most relevant in terms of seizures and epilepsy.

Question 6

What drugs can we use to enhance GABAergic transmission?

Answer 6

• Enhance the action using benzodiazepines or barbiturates

- Vigabatrin and Tiagabine - can inhibit the reuptake of GABA and its transmission

Question 7

What is Status Epilepticus?

Answer 7

This is a life-threatening condition in which the brain is in a state of persistent seizure. It meets one of the following requirements:

- More than 30- minutes continuous seizure activity OR 
- Two or more sequential seizures spanning this period without full recovery between seizures 

Status epilepticus is a medical emergency because the longer a seizure lasts, the less likely it is to stop on its own. SE confers greater risk for future unprovoked seizures. Treated with Diazepam I.V. and GABAa receptor agonist.

Question 8

What type of drugs is Diazepam?

Answer 8

Benzodiazepines.

Other examples include:

- Clonazepam - effective in generalised tonic-clonic, absence and partial seizures 
- Clorazepate - effective against partial seizures. Used in conjunction with other
- Diazepam (Valium) and lorazepam - effective against status epilepticus when given I.V

Question 9

What are the effects of Benzodiazepines?

Answer 9

• Muscle relaxant
• Anxiolytic
• Sedative
• Hynotic (initiate or prolongs sleep)
• Anticonvulsant
• Amnesic

Question 10

What is the mechanism of acton of Benzodiazepines?

Answer 10

• Increasing the affinity of GABA for its receptor - increasing chloride current, suppressing seizure focus by raising the action potential threshold and strengthens surround inhibition (prevents spread)
  • Main unwanted effect is sedation
  • Significant problem of tolerance and dependence - avoid long term use
  • Can lead to respiratory depression if used I.V

Question 11

Give examples of anti-epileptic drugs that inhibit sodium channels.

Answer 11

• Phenytoin
  
  • Carbamazepine and oxcarbazepine
  • Lamotrigine

Question 12

What is the mechanism of action of Phenytoin?

Answer 12

During an action potential voltage gated channels exit in three channels - closed, open and inactivated. Sodium channels do not recover from the inactivated state until the membrane has repolarised. Phenytoin bend to the inactivated state and slows down its recovery.

	Phenytoin in only binds to sodium channels that have opened. The block is therefore known as "use dependent." Only rapid firing neurones are blocked so it does not interfere with normally firing neurones. The more channels that are opened. The more that will be in the inactivated state, and so available to be accessed by Phenytoin.

Question 13

What is the difference between tonic and phasic blockage of sodium channels?

Answer 13

When there are long intervals between the impulses, the level of inhibition of each stimulus is the same - this is known as tonic blockage.

When the intervals between impulses is short, the level of inhibition increases with each impulses - this is known as phasic blockage.

Question 14

What are the pharmacokinetics of Phenytoin?

Answer 14

• Taken orally - well absorbed
  - Highly protein bound (particularly albumin) - 80-90% have the same bindings sites of many other drugs such as valproate
  - If taken together this produces more free Phenytoin
  - This tends to increase hepatic clearance of the drug so effects can be unpredictable
  - Metabolism is saturable - it can get to the point liver metabolise it further
  - The consequence of this is that the half life of (around 20hours) increases as the dose increases

Question 15

What are the unwanted effects of Phenytoin?

Answer 15

Mild effects at 100 micro moles/L - include vertigo, ataxia, headache and nystagmus
Severe effects start to show at 150 micromoles/L
- Confusion, intellectual deterioration - acute and reversible
- Hyperplasia of the gums, hirsutism, gradual
- Megaloblastic anaemia - folate metabolism
- Hypersensitivity and rashes (common)
- Hepatitis
Foetal malformations - cleft palate (foetal hydantoin syndrome)

Question 16

What is the mechanism of Valproate?

Answer 16

It is not structurally related to other classes of anti-epileptics. It is unusual as it is effective in both tonic-clonic and absence seizure. It can also be usefulness in bipolar depressive disorders. It can be taken orally and is well absorbed.

It has more than one mechanism:

- Inhibits sodium channels but weaker than phenytoin 
- Decreases GABA turnover - inhibition of succinic semialdehyde dehydrogenase and thereby indirectly inhibition GABA transaminase. It may lead to increased synaptic GABA levels. 
- It blocks neurotransmitter release by blocking T-type calcium channels
- Valproate is a HDAC inhibitor - histone deacetylase 

Due to the mixed actions, it is affective to so many seizure types.