Anticonvulsants

Question 1

<p>What is epilepsy?</p>

Answer 1

<p>Epilepsy is a neurological condition causing frequent seizures.</p>

Question 2

<p>What is a seizure?</p>

Answer 2

<p>Over-excitation due to too much glutamatergic activity</p>

Question 3

<p>What is the prevalence and incidence of epilepsy?</p>

Answer 3

<p>Prevalence between 2-7% of the population – relatively common neurological condition. Incidence is increasing, and has been over the last 30-40 years.</p>

Question 4

<p>How can epilepsy be diagnosed?</p>

Answer 4

<p>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.</p>

Question 5

<p>What are the different types of seizures?</p>

Answer 5

<p>Tonic-clonic
Absence seizures
Tonic/atonic
Myoclonic seizure
Status epilepticus</p>

Question 6

<p>What are the features of tonic-clonic seizures?</p>

Answer 6

<p>Loss of consciousness which leads to muscle stiffening, jerking/twitching and deep sleep before they wake up – THIS IS THE MOST COMMON MANIFESTATION OF EPILEPSY.
</p>

Question 7

<p>What are the features of absence seizures?</p>

Answer 7

<p>Brief staring episodes with behavioural arrest.

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Question 8

<p>What are the features of tonic/atonic seizures?</p>

Answer 8

<p>Sudden muscle stiffening (tonic)/sudden loss of muscle control (atonic).
</p>

Question 9

<p>What are the features of myoclonic seizures?</p>

Answer 9

<p>Sudden, brief muscle contractions – we see lots of muscle movement.
</p>

Question 10

<p>What are the features of status epilepticus seizures?</p>

Answer 10

<p>Over 5 minutes of continuous seizure activity – THIS IS LESS COMMON BUT IS THE MOST DANGEROUS.</p>

Question 11

<p>What are the two main categories of seizures?</p>

Answer 11

<p>Partial and generalised

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Question 12

<p>What are the types of partial seizure?</p>

Answer 12

<p>Simple: Retained awareness/consciousness.
Complex: Impaired awareness/consciousness.

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

Question 13

<p>Describe transmission through a glutamatergic synapse</p>

Answer 13

<p>The action potential arrives at the presynaptic terminal.
Voltage-gated Na+ channel (VGSC) opens which leads to membrane depolarisation. Voltage-gated K+ channel (VGKC) opens leading to membrane repolarisation.
Ca2+ influx through VGCCs which results in vesicle exocytosis. Synaptic vesicle associated (SV2A) protein allows vesicle (containing glutamate) attachment to the presynaptic membrane (docking protein).
Glutamate is released into the synapse. Glutamate activates excitatory postsynaptic receptors (e.g. NMDA, AMPA and kainate receptors).
</p>

Question 14

<p>Name 2 VGSC blockers</p>

Answer 14

<p>Carbamazepine (tonic-clonic seizures and partial seizures)
Lamotrigine (tonic-clonic seizures and absence seizures)</p>

Question 15

<p>How does carbamazepine work?</p>

Answer 15

<p>Carbamazepine stabilises the inactive state of the Na+ channel so it is more likely to remain in an inactive state which leads to reduced neuronal activity.</p>

Question 16

<p>What are some things to bear in mind when using carbamazepine?</p>

Answer 16

<p>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 and TEN) are seen in individuals with HLA-B*1502 allele.
</p>

Question 17

<p>How does lamotrigine work?</p>

Answer 17

<p>Lamotrigine directly inactivates Na+ channels which reduces glutamate neuronal activity. It has a fast onset of activity (within 1 hour), and a long half-life (24-34 hours). It is more selective for glutamatergic neurones.
</p>

Question 18

<p>What is a VGCC?</p>

Answer 18

<p>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).
</p>

Question 19

<p>Name a VGCC blocker</p>

Answer 19

<p>Ethosuximide (absence seizures)</p>

Question 20

<p>Describe how ethosuximide works</p>

Answer 20

<p>T-type Ca2+ channel antagonist which leads to reduces activity in relay thalamic neurones (prevents the propagation of the AP, leading to decreased neurotransmission).
It has a long half-life (50 hours).

</p>

Question 21

<p>Name two drugs that affect glutamate exocytosis and receptors</p>

Answer 21

<p>Levetiracetam (Myoclonic seizures)

| Topiramate (Myoclonic seizures)</p>

Question 22

How does levetiracetam work?

Answer 22

Levetiracetam binds to synaptic vesicle associated protein (SV2A) which prevents and reduces glutamate exocytosis.

Question 23

How does topiramate work?

Answer 23

Topiramate inhibits NMDA and kainate receptors and also affects VGSCs and GABA receptors. It affects a few receptors (so a bit of a ‘dirty drug’)

Question 24

Describe neurotransmission of a GABAergic synapse.

Answer 24

You do not necessarily need excitation at the presynaptic terminal for GABA to be released – it is released often by itself. This is why GABA is the most active NT.
GABA can be released tonically. It can also be released following neuronal stimulation. GABA activates inhibitory postsynaptic GABA-A receptors.
GABA-A receptors are chloride (Cl-) channels. This leads to membrane hyperpolarisation.
GABA is taken up by the GAT transporter. GABA is then metabolised by GABA transaminase (GABA-T). GABA is broken down back into glutamate.

Question 25

Name 2 drugs that act on a GABAergic synapse

Answer 25

Diazepam (status epilepticus)
Sodium Valproate (everything apart from status epilepticus)

Question 26

What are the pharmacodynamics and pharmacokinetics of diazepam?

Answer 26

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.

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.

Question 27

Describe how sodium valproate works

Answer 27

Inhibits GABA transaminase enzyme and thus increases GABA-mediated inhibition. It has dual mechanism of action; by inhibiting GABA-T, it is increasing the amount of GABA, and also reducing the amount of glutamate being formed.

NOTE: Vigabatrin has a similar MOA.