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Physiology and Pharmacology of Cells > L6 - Drug Action in the CNS - Epilepsy > Flashcards

L6 - Drug Action in the CNS - Epilepsy Flashcards

1
Q

What is epilepsy?

A

Unprovoked seizures – hyper excitability of the CNS

- High frequency discharge by a group of neurones

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2
Q

What is the focus?

A

Where seizure activity begins – high level of action potential firing

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3
Q

What are the 4 main types of epilepsy?

A

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

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4
Q

How is epilepsy diagnosed?

A

Diagnoses with EEG

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5
Q

What do epilepsy symptoms depend on?

A

Depend on what part of the brain is affected

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6
Q

What are the symptoms if the seizures reach the hypothalamus?

A

Autonomic discharge

Loose control of bladder, sweating

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7
Q

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

A

Convulsions – contraction of muscle

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8
Q

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

A

Loose consciousness

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9
Q

What can uncontrolled seizures lead to?

A

Can lead to death of neurones – neuronal degeneration

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10
Q

What are seizures precipitated by?

A

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

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11
Q

What mutations have been shown to cause epilepsy?

A

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

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12
Q

What is the target for anti-epileptic drugs?

A

GABAa receptors

Increase inhibitory neurotransmission - increase GABAA mediated neurotransmission

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13
Q

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

A

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

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14
Q

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

A

Benzodiazepines
Uptake inhibitors
Metabolic inhibitors

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15
Q

What are two examples of benzodiazepines?

A

Diazepam

Barbiturates -  phenobarbitone and primidone

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16
Q

What are the problems with diazepam?

A

Used in vivo for status epilepticus
Sedation
Tolerance
Withdrawal

17
Q

What are the problems with Barbiturates?

A

Low therapeutic index
Sedation
Complex pharmacokinetics

18
Q

What is an example of an uptake inhibitor?

A

Tiagabine

19
Q

What are two examples of metabolic inhibitors?

A

Vigabatrin

Valporate

20
Q

What are the problems with vigabatrin?

A

Depression

21
Q

What are the problems with valproate?

A

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

22
Q

How is GABA created?

A

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

23
Q

What is GABA broken down by?

A

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

24
Q

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

A

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

25
Q

What is the role of sodium valproate?

A

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

26
Q

How do antiepileptic drugs function

A

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

27
Q

What is the aim of antiepileptic drugs?

A

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

28
Q

What are the targets of antiepileptic drugs?

A

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

29
Q

What are the problems with antiepileptic drugs?

A

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

30
Q

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

A

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

31
Q

What are examples of 3 Na channel blockers?

A

Phenytoin
carbamazepine
Lamotrigine

32
Q

Phenyotin summary

A

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

33
Q

Carbamazepine summary

A

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

34
Q

Lamotrigine summary

A

Problems - nausea, dizziness, ataxia, rashes

35
Q

What are Ca channel blockers used to treat?

A

T-type Ca channels used for absence seizures

36
Q

What are two examples of Ca channel blockers?

A

Ethosuximide

GABApentin

37
Q

Ethosuximide summary

A

Not lipid soluble and no protein binding

Long half life

38
Q

Gabapentin summary

A

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

39
Q

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

A

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

Physiology and Pharmacology of Cells (13 decks)

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