L6 - Drug Action in the CNS - Epilepsy Flashcards
What is epilepsy?
Unprovoked seizures – hyper excitability of the CNS
- High frequency discharge by a group of neurones
What is the focus?
Where seizure activity begins – high level of action potential firing
What are the 4 main types of epilepsy?
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
How is epilepsy diagnosed?
Diagnoses with EEG
What do epilepsy symptoms depend on?
Depend on what part of the brain is affected
What are the symptoms if the seizures reach the hypothalamus?
Autonomic discharge
Loose control of bladder, sweating
What are the symptoms if the seizures reach the motor cortex?
Convulsions – contraction of muscle
What are the symptoms if the seizures reach the reticular formation?
Loose consciousness
What can uncontrolled seizures lead to?
Can lead to death of neurones – neuronal degeneration
What are seizures precipitated by?
Altered blood glucose of pH
Stress
Fatigue
Flashing lights or loud noise
What mutations have been shown to cause epilepsy?
Mutations in voltage gated sodium channels - familial epilepsy
Mutations also identified in K channels and nicotinic receptors
What is the target for anti-epileptic drugs?
GABAa receptors
Increase inhibitory neurotransmission - increase GABAA mediated neurotransmission
Drugs that increase GABA neurotransmission act at one of which 3 sites?
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
What are the 3 classes of anti-epileptic drugs that increase GABA transmission?
Benzodiazepines
Uptake inhibitors
Metabolic inhibitors
What are two examples of benzodiazepines?
Diazepam
Barbiturates - phenobarbitone and primidone
What are the problems with diazepam?
Used in vivo for status epilepticus
Sedation
Tolerance
Withdrawal
What are the problems with Barbiturates?
Low therapeutic index
Sedation
Complex pharmacokinetics
What is an example of an uptake inhibitor?
Tiagabine
What are two examples of metabolic inhibitors?
Vigabatrin
Valporate
What are the problems with vigabatrin?
Depression
What are the problems with valproate?
High protein binding (not just enzymes involved in GABA breakdown)
Rarely hepatotoxic
Teratogenic
How is GABA created?
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
What is GABA broken down by?
GABA transaminase – inhibited by vigabatrin – suicide inhibitor
- Need to synthesise new enzyme to replace it
- GABA levels in brain build up
Succinate semialdehyde
What are the epigenetic modifications of genes at the level of chromatin?
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
What is the role of sodium valproate?
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
How do antiepileptic drugs function
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
What is the aim of antiepileptic drugs?
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
What are the targets of antiepileptic drugs?
Na channels blockers stop action potentials
Decrease in release of glutamate - limiting spread
- Important they only act on neurons behaving abnormally - use dependent blockers
What are the problems with antiepileptic drugs?
Na channels found in all nerves and muscle - drugs currently available do not show much selectivity so many side effects
Summary of the use of Na channel blockers to treat epilepsy?
Stabilize inactivated state of the channel
They show use dependence – target most active neurones
They are not sedative
What are examples of 3 Na channel blockers?
Phenytoin
carbamazepine
Lamotrigine
Phenyotin summary
Problems - complex pharmacokinetics, vertigo, ataxia, headaches, rashes
Useful for – partial epilepsy, grand mal
Not useful for – absence seizures, petite mal
Carbamazepine summary
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
Lamotrigine summary
Problems - nausea, dizziness, ataxia, rashes
What are Ca channel blockers used to treat?
T-type Ca channels used for absence seizures
What are two examples of Ca channel blockers?
Ethosuximide
GABApentin
Ethosuximide summary
Not lipid soluble and no protein binding
Long half life
Gabapentin summary
Controls the trafficking of voltage gated Ca channels to the membrane
More broad in its action
What is a new drug target for the treatment of epilepsy?
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
