Anti-convulsion drugs

Question 1

Why do convulsions occur?

Answer 1

Imbalance between inhibitory and excitatory signals in the CNS.
Too much excitatory signalling.
Two options for drugs- increase inhibition or decrease excitation.

Question 2

Main symptoms of epilepsy

Answer 2

Unprovoked seizures.

Hyperexcitibility of a group of neurons

Question 3

How are the different classes of epilepsy named?

Answer 3

By the type of seizure experienced- not by the underlying cause of the seizure

Question 4

Where does the seizure begin?

Answer 4

Focus- neurons fire too many APs

Question 5

Partial seizure

Answer 5

Only one hemisphere

Question 6

Generalised seizure

Answer 6

Spreads to both hemispheres

Question 7

Simple seizure

Answer 7

No loss of conciousness

Question 8

Complex seizure

Answer 8

Always a loss of consciousness

Question 9

Causes?

Answer 9

Head injury 
Stroke 
Infection 
Tumours 
Genetic factors such as mutations in ion channels

Question 10

Where are the mutations

Answer 10

Nav channels
NAChR
K+ channels

Question 11

What will you see if the seizure spreads to the hypothalamus?

Answer 11

Loss of control of autonomic processes such as-
Sweating
Salivating
Bladder/bowel control

Question 12

What will you see if the seizure spreads to the reticular formation?

Answer 12

Loss of consciousness- complex

Question 13

Triggers?

Answer 13

Flashing lights C
Certain sounds 
Alterations in blood pH or glucose 
Stress 
Fatigue

Question 14

How do you diagnose epilepsy

Answer 14

EEG- electroencephalogram
Electrodes in each side of the brain
Look at focus and if there is spread- if spread then the electrodes on both sides of the brain will be activated (generalised)

Question 15

What happens if there is a rapid onset of activity

Answer 15

Whole body convulsions
Loss of consciousness
Muscle contraction
Patient goes rigid and falls to the floor

Question 16

What is another side effect of epilepsy

Answer 16

Neurotoxicity- if the neurons are being overexcited- they will become damaged which will lead them to dying and thus there is neurodegeneraion

Question 17

Absence Seizures

Answer 17

Person is absent for a few seconds 
No loss of consciousness
No convulsions 
Oscillatory pattern in the EEG- very intermittent and short 
Mediated by Cav channels

Question 18

Treatment- increasing inhibition

Answer 18

Target GABAa receptors- use benzodiazepines to enhance GABA effects and thus inhibition
Also prevent the metabolism of GABA in the cleft- if is around more so it will initiate more APs.

Question 19

What do paramedics administer in an uncontrolled seizure?

Answer 19

Intravenous benzodiazepines to switch off the electrical activity of that part of the brain

Question 20

What drugs can be used to treat epilepsy?

Answer 20

Benzodiazepines- used for status epilepticus (uncontrolled). Can lead to sedation, tolerance, withdrawal symptoms.
Uptake inhibitors- tiagabine
Metabolic inhibitors- valprolate inhibits breakdown of GABA by inhibiting GABA transaminase. However it also binds glutamate and NDMA receptors. It also targets chromatin remodelling proteins- can promote the transcription of GABA as well as inhibiting its breakdown

Question 21

How is GABA produced

Answer 21

Side product of the Krebs cycle.
Produced from glutamate by glutamic acid decarboylase. Only neurons which produce GABA have this enzyme which makes it easy to stain for GABAergic neurons.

Question 22

Why is valprolate called a suicide inhibitor?

Answer 22

It is used as an anti-convulsant- when the drug binds to GABA transaminase. it completely inhibits the breakdown of GABA.

Question 23

How is excitatory signalling inhibited?

Answer 23

Nav blockers- Use dependent Na+ channels inhibitors. This inhibits the release of glutamate which is an excitatory NT. 
This class of drug only binds to activated Na+ channels- they can only interact with open state channels because of their configuration/structure. 
By doing this- prolong the inactivated state and thus less channels can open. The neuron has to be firing a lot of APs to have a lot of activated channels- drugs therefore preferentially target highly active neurons.

Question 24

Why Na+ blockers in instead of benzodiazepines?

Answer 24

Side effects of benzodiazepines mean that there is increased incidence of sedative effects and patients can become tolerant/dependent. Epilepsy is a lifelong disease which means that these types of drugs are unsuitable.

Question 25

What is use dependence?

Answer 25

This is a property of Na+ channel blockers- they select for active channels and therefore neurons which are firing APs frequently.
The inactivated state of the channel ony occurs after the firing of APs.
Drugs will only bind to this conformation- only bind to channels which have previously been activated.

Question 26

What are the 3 types of Na+ channel blockers.

Answer 26

Phenytoin- non-sedative and anti-convulsant. Very complex pharmacokinetics- can cause vertigo, ataxia, headaches, rashes. Can be useful for grand mal and partial epilepsy- not useful for absent seizures.
Carbamazepine- most widely used. Problems include microsomal enzyme induction- it also cannot be used together with other drugs.
Lamotrigine- problems include nausea, dizziness, ataxia and rashes

Question 27

Do Na+ blockers cure or control epilepsy? What dies this mean?

Answer 27

Control- they only alleviate the symptoms. This means that any factor which will affect the concentration in the body increase chance the seizure- have to be wary of taking other drugs- could affect metabolism.

Question 28

Drugs for absent seizures

Answer 28

Ca2+ channel blockers-
T-type Ca channels are used for absent seizures.
Not involved in other processes such as muscle contraction and NT release- means that drugs will not affect these processes.
Ethosuximide and GABApentin (prevents trafficking of the channel to the membrane).

Question 29

New drug targets for epilepsy?

Answer 29

Levetiracetam- doesn’t target the receptor- thought to act via glutamate signalling- either affects the amount of glutamate in vesicles and thus excitatory signalling or interferes with docking and fusion of the vesicle with the membrane.