L6 - Drug Action in the CNS - Epilepsy

Question 1

What is epilepsy?

Answer 1

Unprovoked seizures – hyper excitability of the CNS

- High frequency discharge by a group of neurones

Question 2

What is the focus?

Answer 2

Where seizure activity begins – high level of action potential firing

Question 3

What are the 4 main types of epilepsy?

Answer 3

Partial – limited spread of action potentials
- Not all electrodes show abnormal activity on ECG
Generalised – spread of action potentials across both hemispheres
- Mediated by Ca channels
Complex – always include a loss of consciousness
Simple – no loss of consciousness

Question 4

How is epilepsy diagnosed?

Answer 4

Diagnoses with EEG

Question 5

What do epilepsy symptoms depend on?

Answer 5

Depend on what part of the brain is affected

Question 6

What are the symptoms if the seizures reach the hypothalamus?

Answer 6

Autonomic discharge

Loose control of bladder, sweating

Question 7

What are the symptoms if the seizures reach the motor cortex?

Answer 7

Convulsions – contraction of muscle

Question 8

What are the symptoms if the seizures reach the reticular formation?

Answer 8

Loose consciousness

Question 9

What can uncontrolled seizures lead to?

Answer 9

Can lead to death of neurones – neuronal degeneration

Question 10

What are seizures precipitated by?

Answer 10

Altered blood glucose of pH
Stress
Fatigue
Flashing lights or loud noise

Question 11

What mutations have been shown to cause epilepsy?

Answer 11

Mutations in voltage gated sodium channels - familial epilepsy
Mutations also identified in K channels and nicotinic receptors

Question 12

What is the target for anti-epileptic drugs?

Answer 12

GABAa receptors

Increase inhibitory neurotransmission - increase GABAA mediated neurotransmission

Question 13

Drugs that increase GABA neurotransmission act at one of which 3 sites?

Answer 13

GABAa receptor increasing its activity – benzodiazepines
GABAa uptake inhibitors
Inhibitors of GABA metabolism – act on the enzymes that metabolise it
Last two will affect all GABA neurotransmission - less selective

Question 14

What are the 3 classes of anti-epileptic drugs that increase GABA transmission?

Answer 14

Benzodiazepines
Uptake inhibitors
Metabolic inhibitors

Question 15

What are two examples of benzodiazepines?

Answer 15

Diazepam

Barbiturates -  phenobarbitone and primidone

Question 16

What are the problems with diazepam?

Answer 16

Used in vivo for status epilepticus
Sedation
Tolerance
Withdrawal

Question 17

What are the problems with Barbiturates?

Answer 17

Low therapeutic index
Sedation
Complex pharmacokinetics

Question 18

What is an example of an uptake inhibitor?

Answer 18

Tiagabine

Question 19

What are two examples of metabolic inhibitors?

Answer 19

Vigabatrin

Valporate

Question 20

What are the problems with vigabatrin?

Answer 20

Depression

Question 21

What are the problems with valproate?

Answer 21

High protein binding (not just enzymes involved in GABA breakdown)
Rarely hepatotoxic
Teratogenic

Question 22

How is GABA created?

Answer 22

Created as a side product of the Krebs cycle
GAD – glutamic acid decarboxylate
- Only neurones that use GABA as their neurotransmitter have this enzyme
- Will increase expression of GAD therefore increasing production of GABA

Question 23

What is GABA broken down by?

Answer 23

GABA transaminase – inhibited by vigabatrin – suicide inhibitor
- Need to synthesise new enzyme to replace it
- GABA levels in brain build up
Succinate semialdehyde

Question 24

What are the epigenetic modifications of genes at the level of chromatin?

Answer 24

DNA acetylation by histone acetyl transferases leads to gene expression
DNA methylation by DNA methylases leads to gene silencing
Histone deacetylases remove histone acetyl groups

Question 25

What is the role of sodium valproate?

Answer 25

Valproic acid and histone deacetylase inhibitors allow histone acetylation and gene activation Chronic antiepileptic effects of valproate due to histone deacetylases-mediated regulation of the GABA synthetic enzyme - glutamate decarboxylase

Question 26

How do antiepileptic drugs function

Answer 26

Block excitatory transmission at focus and limit spread of epileptic activity Use-dependent Na+ channel inhibitors Only binds to channels that are active - targets rapidly firing neurones - Stop the seizure developing at the focus Binds to the inactive state of the channel prolonging it - less channels available to open

Question 27

What is the aim of antiepileptic drugs?

Answer 27

Decrease excitatory neurotransmission in brain areas involved Stop high frequency discharge occurring or limit its spread Limit action potential generation and propagation in neurons firing abnormally

Question 28

What are the targets of antiepileptic drugs?

Answer 28

Na channels blockers stop action potentials Decrease in release of glutamate - limiting spread - Important they only act on neurons behaving abnormally - use dependent blockers

Question 29

What are the problems with antiepileptic drugs?

Answer 29

Na channels found in all nerves and muscle - drugs currently available do not show much selectivity so many side effects

Question 30

Summary of the use of Na channel blockers to treat epilepsy?

Answer 30

Stabilize inactivated state of the channel They show use dependence – target most active neurones They are not sedative

Question 31

What are examples of 3 Na channel blockers?

Answer 31

Phenytoin carbamazepine Lamotrigine

Question 32

Phenyotin summary

Answer 32

Problems - complex pharmacokinetics, vertigo, ataxia, headaches, rashes Useful for – partial epilepsy, grand mal Not useful for – absence seizures, petite mal

Question 33

Carbamazepine summary

Answer 33

Problems - microsomal enzyme induction, shouldn’t be combined with other drugs Other drugs impact on the concentration of the anti-convulsant Not useful for – absence seizures

Question 34

Lamotrigine summary

Answer 34

Problems - nausea, dizziness, ataxia, rashes

Question 35

What are Ca channel blockers used to treat?

Answer 35

T-type Ca channels used for absence seizures

Question 36

What are two examples of Ca channel blockers?

Answer 36

Ethosuximide | GABApentin

Question 37

Ethosuximide summary

Answer 37

Not lipid soluble and no protein binding | Long half life

Question 38

Gabapentin summary

Answer 38

Controls the trafficking of voltage gated Ca channels to the membrane More broad in its action

Question 39

What is a new drug target for the treatment of epilepsy?

Answer 39

Levetiracetam - Completely new target – not ion channel or receptor - Targets SV2A protein found on synaptic vesicles - Impacts glutamate signalling - Amount of glutamate stores in vesicles - Interferes with fusion of vesicles with plasma membrane