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Pharmacology > Anticonvulsants > Flashcards

Anticonvulsants Flashcards

1
Q

What is epilepsy?

A
  • Epilepsy is a neurological condition causing frequent seizures
  • Seizures are “sudden changes in behaviour caused by electrical hypersynchronization of neuronal networks in the cerebral cortex” (over-excitation due to too much glutamatergic activity)
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2
Q

What is the main excitatory NT within the CNS?

A

Glutamate -> over-activity causes hyper-excitability

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3
Q

What is the prevalence and incidence of epilepsy?

A
  • Prevalence between 2-7% of the population – relatively common neurological condition
  • Incidence is increasing, and has been over the last 30-40 years
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4
Q

How is epilepsy diagnosed?

A

Brain activity can be measured using:

  • Electroencephalography (EEG)
  • Magnetic resonance imaging (MRI)

In an epileptic seizure, the waveforms seen on an EEG have a much higher frequency. The EEG is a useful tool for diagnosing different types of epilepsy, and can be used with sensitivity and specificity.

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5
Q

What are the different types of seizures seen in epilepsy?

A

Generalised seizures

  • tonic clonic seizures
  • absence seizures
  • tonic atonic seizures
  • myoclonic seizures
  • status epilepticus

Partial/focal seizures

  • simple
  • complex
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6
Q

What are the different types of generalised seizures and their symptoms?

A
  1. Tonic-clonic seizures: Loss of consciousness -> muscle stiffening -> jerking/twitching -> deep sleep -> wakes up – this is the most commonest manifestation of epilepsy
  2. Absence seizures: Brief staring episodes with behavioural arrest
  3. Tonic/atonic seizures: Sudden muscle stiffening (tonic)/sudden loss of muscle control (atonic)
  4. Myoclonic seizures: Sudden, brief muscle contractions – we see lots of muscle movement
  5. Status epilepticus: Over 5 minutes of continuous seizure activity – less common, most dangerous
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7
Q

What are the different types of partial/focal seizures and their symptoms?

A
  1. Simple: Retained awareness/consciousness
  2. Complex: Impaired awareness/consciousness

A partial seizure can progress into a generalised seizure. The symptoms are dependent on where it occurs.

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8
Q

What happens in a glutamatergic synapse?

A
  1. The action potential arrives at the pre-synaptic terminal
  2. Voltage-gated Na+ channel (VGSC) opens à membrane depolarisation
  3. Voltage-gated K+ channel (VGKC) opens -> membrane repolarisation
  4. Ca2+ influx through VGCCs -> vesicle exocytosis
  5. Synaptic vesicle associated (SV2A) protein allows vesicle (containing glutamate) attachment to the presynaptic membrane (docking protein)
  6. Glutamate is released into the synapse
  7. Glutamate activates excitatory post-synaptic receptors (e.g. NMDA, AMPA & kainate receptors)
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9
Q

Give an example of a voltage gated sodium channel blocker

A

carbamazepine

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10
Q

How does carbamazepine work?

A

The VGSCs open, and then enter an inactive state. Carbamazepine stabilises the inactive state of the Na+ channel -> more likely to remain in an inactive state -> reduced neuronal activity

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11
Q

What are the indications for carbamazepine use?

SE?

A
  • Tonic-clonic seizures and partial seizures.
  • Because it is an enzyme inducer of the cytochrome P450 pathways, it reduces the activity of a number of other drugs
  • Potential severe skin side effects (SJS & TEN) are seen in individuals with HLA-B*1502 allele
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12
Q

How long does carbamazepine take to work and what is its half life?

A
  • Fast onset of activity (within 1 hour)

- Long half life: 16-30 hours

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13
Q

How does lamotrigine work?

A
  • Directly inactivates Na+ channels -> reduces glutamate neuronal activity
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14
Q

What is the time for lamotrigine onset, and its half life and what is it more selective for?

A

It has a fast onset of activity (within 1 hour)

  • A long half-life (24-34 hours)
  • It is more selective for glutamatergic neurones
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15
Q

What are the indications for lamotrigine?

A

Tonic-clonic seizures and absence seizures

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16
Q

Voltage gated calcium channels - L type and T type

A
  • The VGCCs are a large group of ion channels
  • L-type VGCCs are the ones that are found on the blood vessels and the heart – they are targeted by calcium channel blockers (used for treatment of hypertension)
  • These channels are different to the channels found within the CNS (T-type VGCCs).
17
Q

What is ethosuximide?

A

A T type calcium channel antagonist

18
Q

How does ethosuximide work?

A

T-type Ca2+ channel antagonist -> reduces activity in relay thalamic neurones (prevents the propagation of the AP -> decreased neurotransmission)

19
Q

What is the half life of ethosuximide?

A

It has a long half-life (50 hours)

20
Q

What are the indications for ethosuximide?

A

Only useful for absence seizures

21
Q

What does levetiracetam do?

A

Levetiracetam binds to synaptic vesicle associated protein (SV2A) -> prevents and reduces glutamate exocytosis

22
Q

What is the speed of onset of levetiracetam and what is the half life of it?

A
  • Fast-onset (1 hour)

- Short half-life (10 hours

23
Q

What are the indications for levetiracetam?

A

myoclonic siezures

24
Q

What does topiramate do?

A

Topiramate inhibits NMDA & kainate receptors and also affects VGSCs & GABA receptors. It affects a few receptors

25
Q

What is the speed of onset of topiramate and its half life?

A
  • Fast-onset (1 hour)

- Long half-life (20 hours)

26
Q

What are the indications for topiramate?

A

myoclonic seizures

27
Q

What happens at the glutamatergic synpase?

A
  1. VGSC -> depolarisation, VGKC -> repolarisation
  2. Ca2+ influx through VGCCs -> vesicle exocytosis
  3. SVA2 allows vesicle attachment to membrane
  4. Glutamate activates excitatory post-synaptic receptor
28
Q

What do carpamazepine, ethosuximide, levetiracetam and topiramate do?

A
  1. VGSC antagonist: e.g. Carbamazepine
  2. VGCC antagonist: Ethosuximide (T-type antagonist)
  3. SV2A inhibitor: Levetiracetam
  4. Glutamate receptor antagonist: Topiramate
29
Q

……….

A

We want to reduce glutamate activity in epilepsy. There is a balance that exists in the brain – usually we have lots of GABAergic activity that it stopping glutamate activity. The other way of reducing neuronal activity is to increase GABA transmission.

30
Q

What happens at the gabaergic synpase?

A

You do not necessarily need excitation at the pre-synaptic terminal for GABA to be released – it is released often by itself. This is why GABA is the most active NT.

  1. GABA can be released tonically
  2. It can also be released following neuronal stimulation
  3. GABA activates inhibitory post-synaptic GABAA receptors
  4. GABAA receptors are chloride (Cl-) channels
  5. This leads to membrane hyperpolarisation
  6. GABA is taken up by the GAT transporter
  7. GABA is then metabolised by GABA transaminase (GABA-T)
  8. GABA is broken down back into glutamat
31
Q

What does diazepam do?

A

Diazepam is a positive allosteric modulator of GABA-A receptors – it doesn’t activate the channel alone, but it increases the activity of the GABA that binds to the channel. It increases GABA activity, but doesn’t increase the amount of GABA in the synapse.

GABA receptor, PAM -> increases GABA-mediated inhibition

32
Q

Describe the pharmacokinetics of diazepam?

A

Rectal gel – It has a fast-onset (within 15 min), but a short half-life (2 hours). In status epilepticus, we may not be able to access the veins – this is why the rectal gel is useful

33
Q

What are the indications of diazepam?

A

Status epilepticus

34
Q

What does sodium valproate do?

A

Inhibits GABA transaminase enzyme -> increases GABA-mediated inhibition

It has dual MOA: by inhibiting GABA-T, it is increasing the amount of GABA, and also reducing the amount of glutamate being formed

Vigabatrin has a similar MOA.

35
Q

Describe the pharmacokinetics of sodium valproate

A

Fast onset (1 hour), and a half-life of 12 hours

36
Q

What are the indications for sodium valproate?

A

Indicated for all forms of epilepsy (apart from status epilepticus)

37
Q

………..

A
  1. Inhibition of VGSCs (e.g. Carbamazepine, lamotrigine) – Tonic-clonic, partial
  2. Inhibition of VGCCs (e.g. Ethosuximide) – Absence
  3. Inhibit vesicular release (e.g. Levetiracetam) – Myoclonic
  4. Inhibit glutamate receptors (e.g. Topiramate) – Myoclonic
  5. Enhance GABA channel activity (e.g. Diazepam) – status epilepticus
  6. Inhibit GABA metabolism (e.g. Valproate) – all types

Pharmacology (26 decks)

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