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Pharmacology > Anticonvulsants > Flashcards

Anticonvulsants Flashcards

1
Q

what is epilepsy?

A
  • disorder involving the hyperexcitability of the CNS
  • unprovoked seizures - characterised according to the location of abnormal activity and how the activity spreads throughout the brain
  • high frequency discharge of neurons
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2
Q

what are the causes and triggers of epilepsy?

A

causes: head injury, tumours, infections
- can be genetic - mutations in ion channels involved in AP generation, Na+ channels, K+ channels, GABAa receptors

triggers: flashing lights, low/high blood glucose and pH, fatigue, noise, stress

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3
Q

what are the symptoms of epilepsy?

A

depend on brain areas affected:
- motor cortex -> convulsions
- hypothalamus -> autonomic discharge
- reticular formation -> loss of consciousness

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4
Q

how is epilepsy diagnosed?

A

with EEG recordings of discharge

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5
Q

what mutations can cause familial epilepsy?

A
  • GOF mutation in Na+ channels responsible for depolarisation causes hyperexcitability of neurons
  • LOF mutation in K+ channels can cause epilepsy
  • LOF mutations in GABAa receptors
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6
Q

what types of seizures can be seen in epilepsy?

A
  1. partial - spread of seizure is limited to a certain part of the brain
  2. generalised - seizure in both hemispheres of the brain
    - simple seizures = no loss of consciousness
    - complex seizures = always includes loss of consciousness
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7
Q

what abnormal firing patterns are seen in partial seizures on an EEG?

A
  • discharge begins locally and remains localised
  • symptoms: involuntary muscle contraction, abnormal sensory experience, autonomic discharge, effects on mood/behaviour
  • confined to one hemisphere attributed to local lesion
  • incidence increases with age
  • not all electrodes show activity as it is limited to one hemisphere
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8
Q

what abnormal firing patterns are seen in generalised seizures on an EEG?

A
  • whole brain involved
  • immediate loss of consciousness if seizure spreads to reticular formation
  • tonic-clonic seizures: rhythmic contraction and relaxation, loss of consciousness
  • absence seizures: oscillatory behaviour in neuronal firing (common in children) - brief loss and return of consciousness, but do stare into space
  • every electrode has unsynchronised activity displayed
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9
Q

what is the aim of antiepileptic drugs?

A

to inhibit abnormal neuronal discharge
- doesnt cure the underlying cause

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10
Q

what are the animal models of epilepsy?

A
  1. chemical models: penicillin crystals, PTZ, kainate
    - these can be used to trigger acute seizures as they inhibit GABAa
    - repeated kainic acid injections cause excitotoxicity and local damage of inhibitory neurons results in spontaneous seizures
  2. kindling model - repeated low-level electrical stimulation
    - localised hypersensitivity and adaptive changes in networks
    - production of animal which shows spontaneous seizures
  3. genetically modified animals carrying epileptic mutations
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11
Q

what are the 3 methods in which antiepileptic drugs can work?

A
  1. increase activity of inhibitory synapses
  2. decrease activity of excitatory synapses
  3. block Ca2+ channels at excitatory synapses
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12
Q

how do antiepileptic/anticonvulsant drugs target inhibitory synapses?

A
  • they can counterbalance hyperexcitability of CNS by increasing GABA-mediated inhibitory neurotransmission
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13
Q

How do antiepileptic drug increase GABA-mediated inhibitory neurotransmission?

A
  1. increasing the activity of GABAa receptor by PAMs e.g. BZs
    - very selective
  2. GABA uptake inhibitors - blocking uptake of GABA means it stays in cleft for longer and stimulates postsynaptic GABAa receptors for longer
  3. GABA metabolism inhibitors - prevent breakdown of GABA so GABA can build up and have more activation of inhibitory receptors

2 and 3 are less selective

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14
Q

what antiepiletpic drugs increase GABA-mediated inhibitory neurotransmission?

A
  1. benzodiazepines e.g. clonazepam, clobazepam, diazepam
    - used intraveously during epileptic seizure
    - problems: sedation, tolerance, withdrawal
  2. barbiturates e.g. phenobarbitone, primidone
    - problems: low therapeutic index, sedation, complex pharmacokinetics
  3. uptake inhibitors e.g. tiagabine
  4. metabolic inhibitors
    - vigabatrim - can cause depression
    - valproate - works against both generalised and epileptic seizures. problems: high protein binding, complex pharmacokinetics
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15
Q

how is GABA made and hydrolysed?

A
  • synthesised by precursor glutamate (biproduct of Krebs cycle)
  • in GABAergic neurons is glutamic acid decarboxylase (GAD) enzyme which converts glutamate into GABA
  • GABA is broken down by GABA transaminase and then succinate semialdehyde dehydroxylase

valproate or vigabatrin inhibit break down of GABA

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16
Q

what is valproate? how does it increase action of GABA?

A
  • valproate favours open DNA and increased transcription of GAD to synthesise more GABA
  • valproate inhibits histone-deacetylases (HDACs), which would normally reduce the production of GAD by deacetylation of DNA, so that histone acetylation occurs for further gene activation and more GAD transcribed

antiepileptic effects of valproate are due to the inhibition of HDAC-mediated regulation of GAD

17
Q

how do antiepileptic drugs target excitatory synapses?

A
  • they decrease excitatory neurotransmission, mediated by glutamate
  • they stop high frequency discharge occuring at all, or limiting its spread
  • limits AP firing and propagation in neurons which fire abnormally
  • decreases secretion or glutamate or decreases receptiveness of receptors to glutamate
18
Q

what antiepileptic drugs decrease glutamate-mediated excitatory transmission?

A

use-dependent Na+ channel blockers:
- prevent AP firing by decreasing the release of glutamate from the synapse
- act on neurons which are only discharging at high frequency
- therefore need to use use-dependent Na+ channel blockers

problems: Na+ channels are found in all nerves and muscle, so its hard to be selective and therefore there are side effects

19
Q

what are the 3 functional states of voltage-gated channels?

A
  1. resting: closed state that occurs during normal resting potential
  2. activated: open state favoured by brief depolarisation
  3. inactivated: blocked state resulting from a trapdoor-like occlusion of the open channel by an intracellular appendage of the channel protein
20
Q

how do use-dependent Na+ channel blockers work?

A
  • they maintain the inactivated state of the voltage-gated Na+ channel so the channel cannot return to resting state
  • the inactivated channels now take more time to revert to resting state, so it takes longer to fire another AP
  • maintains refractory period of the neuron to limit AP firing
21
Q

why do use-dependent antiepileptic drugs target hyperexcitable neurons?

A
  • as they have the most active Na+ channels
  • they show a selective affinity for the inactivated state after an AP has fired
  • in the presence of the drug, the proportion of channels in the inactivated state is increased, prolonging the refractory period and reducing AP firing
  • this type of block is called use-dependent as the binding of these drugs increases as a function of rate of AP discharge, which governs the rate in which the channel is inactivated
  • therefore the drugs reduce the no. channels that can become activated
22
Q

what are some Na+ channel inhibitors used to treat epilepsy?

A
  1. phenytoin: anticonvulsant without sedative effects
    - problems: complex pharmacokinetics, limited solubility, absorption from oral administration is slow (3-12hrs), headaches, ataxia
  2. carbamazepine: most commmon
    - problems: cant be combined with other drugs, slow absorption (4-24hrs), limited water solubility
  3. lamotrigine: used in combination with other drugs for partial seizures
    - completely absorbed without complex pharmacokinetics
    - problems: nausea, dizziness, ataxia, rashes, enzymes reduce half-life
23
Q

how do T-type Ca2+ channel blockers treat epilepsy?

A

T-type Ca2+ channels cause oscillatory behaviour in absence seizures

Ethosuximide is a T-channel blocker which prevents the oscillatory discharge of APs
- not lipid soluble and no protein binding, but does have long half-life

valproate can also be used

24
Q

what is pregabalin (gabapentin)? what is its role in treating epilepsy?

A

acts on the alpha2-delta subunit on calcium channels:
- calcium channels are important for trafficking of other channels to the synaptic membrane
- pregabalin restricts their trafficking so that there are less Ca2+ channels at the membrane to reduce excitatory neurotransmission
- also used in pain management

25
Q

what is levetiracetam and how does it work in treating epilepsy?

A

acts at level of synaptic transmission by limiting glutamate transmission
- binds to protein on synaptic vesicles and controls the levels of glutamate inside the vesicles
- reduces amount of glutamate released from synapse

Pharmacology (10 decks)

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