Pharmacology of Epilepsy

Question 1

What are the 4 most common main drug classes prescribed for epilepsy / convulsions?

Answer 1

1. Lamotrigine
2. Sodium valproate
3. Diazepam
4. Levetiracetam

Question 2

What is the primary mechanism of action for Lamotrigine?

Answer 2

Blocks voltage gated Na+ channels preventing Na+ influx

Prevents depolarisation of glutamatergic neurones and reduces glutamate excitotoxicity

Question 3

What is the drug target site for Lamotrigine?

Answer 3

Voltage gated Na+ channels

Question 4

What are the main side effects for Lamotrigine?

Answer 4

Side effects:

Common: Rash, drowsiness

Less common but serious:

Steven-Johnson’s syndrome, suicidal thoughts

Question 5

What is some extra information about Lamotrigine?

Answer 5

Introducing lamotrigine gradually is one of the keys to reducing the frequency and severity of allergic skin reactions

Question 6

What is the primary mechanism of action for Sodium valproate?

Answer 6

Inhibition of GABA transaminase prevents the breakdown of GABA
This increases GABA concentrations directly in the synapse presynaptically and also indirectly prolongs GABA in the synapse due to the fact that extraneuronal metanolism of GABA is slowed which also slows GABA removal from the synapse

Question 7

What is the drug target site for Sodium valproate?

Answer 7

GABA transaminase

Question 8

What are the main side effects for Sodium valproate?

Answer 8

Side effects (MANY):

Common: Stomach pain and diarrhoea, drowsiness, weight gain, hair loss

Serious:

hepatotoxicity, teratogenicity, pancreatitis

Question 9

What is some extra information about Sodium valproate?

Answer 9

Broad CYP enzyme inhibitor - increases serum concentration of many co-administered drugs



Question 10

What is the primary mechanism of action for Diazepam?

Answer 10

Increases choride ion influx in response to GABA binding at the GABA A receptor. Increased chloride ion influx associated with hyperpolarisation of excitatory neurones

Question 11

What is the drug target site for Diazepam?

Answer 11

Benzodiazepine site on the GABA A receptor

Question 12

What are the main side effects for Diazepam?

Answer 12

Side effects:

Common: Drowsiness, respiratory depression (if i.v. or at high dose)

Uncommon but serious:

Haemolytic anaemia, jaundice

Question 13

What is some extra information about Diazepam?

Answer 13

Main reason that diazepam is not used for long term suppression of seizures is due to the development of tolerance

Diazepam is a Schedule 4 controlled drug - addiction prone individuals more likely to become dependent on diazepam

Question 14

What is the primary mechanism of action for Levetiracetam?

Answer 14

Inhibition of the synaptic vesicle protein SV2A. It inhibits this protein and prevents vesicle exocytosis. A reduction in glutamate secretion is reduces glutamate excitotoxicity

Question 15

What is the drug target site for Levetiracetam?

Answer 15

Synaptic vesicle protein SV2A

Question 16

What are the main side effects for Levetiracetam?

Answer 16

Common:

dizziness, somnolence, fatigue and headache

Question 17

What is some extra information about Levetiracetam?

Answer 17

The metabolism of levetiracetam has no effect on the cytochrome P450 enzyme system so it is favorable in terms of no drug–drug interactions

Question 18

What are the first three steps for pharmacology?

Answer 18

Identify the patient’s problem
Specify the therapeutic objective
Select a drug

Question 19

Essie = 21F referred to first seizure/urgent assessment neurology clinic from A&E after a single episode of collapse with jerking.

Was sitting and chatting on the sofa, and the next thing she remembers is feeling disorientated on the floor. Stressed lately, not much sleep. Essie’s boyfriend confirms Essie lost consciousness and started convulsing before she ‘came around’ a minute later. Essie makes strange quick jerk of her arms when she wakes up in the morning. 18 months ago – one minute she was putting her gym clothes on and next she was on the floor feeling confused.

A full physical examination is performed and Essie is sent for an EEG.

In A&E – Urea, electrolytes , calcium and glucose: All normal

General and neurological examinations were normal

What is the patient’s problem?

Answer 19

Epilepsy

Tonic clonic seizures
Myoclonic seizures

Question 20

What are the types of seizures?

Answer 20

Absence
Focal
Generalised tonic-clonic
Myoclonic
Tonic or atonic

Question 21

What are the stages of tonic-clonic seizures?

Answer 21

Tonic stage: lose of consciousness, stiffening of the body

Clonic stage: Jerk

Question 22

What did the EEG show?

Answer 22

Interictal epileptiform discharge - risk of seizure recurrence

Question 23

What is the therapeutic objective for the patient?

Answer 23

Reduce severity of seizures
Reduce frequency of seizures
Prevent long term effects
Identify triggers (stress, lack of sleep etc.)
Educate patient
Friends and family should be educated on management of seizures

Question 24

What are the main goals of anti-epileptic drug treatment?

Answer 24

Eliminate seizures or reduce frequency
Evade the adverse effects associated with long term treatment

Aid patients in maintaining or restoring their usual psychical and vocational activities and in maintaining a normal lifestyle

Question 25

What drugs could be give to treat tonic-clonic seizures in women of child bearing age?

Answer 25

Lamotrigine or Carbemazepine

Question 26

What is the mechanism of action of Lamotrigine?

Answer 26

Blocks voltage gated Na+ channels preventing Na+ influx Prevents depolarisation of glutamatergic neurones and reduces glutamate excitotoxicity

Question 27

Why is sodium valproate not given to women of child bearing age?

Answer 27

Can cross placental barrier and cause physical birth defects or developmental uses e.g. Neural tube defects Decreased IQ

Question 28

Why might the OCP affect Lamotrigine concentration?

Answer 28

OCP may impact lamotrigine absorption so less gets into the blooding the first place OCP may enhance metabolism so more is cleared from the blood OCP may enhance excretion of Lamotrigine

Question 29

She begins taking the OCP, why might she be feeling more drowsy during the fourth week of her cycle?

Answer 29

During the fourth week of contraceptive cycle you stop taking the OCP Therefore the concentration of the anti-epileptic while be twice as high in the fourth week as there is nothing reducing its concentration. Increasing the side effects of Lamotrigine one of which is drowsiness

Question 30

What are the side effects of Lamotrigine?

Answer 30

``` Dizziness Diarrhoea Loss of balance Abnormal eye movements Trouble speaking Drowsiness ```

Question 31

What is the mechanism of action levetiracetam?

Answer 31

Inhibition of the synaptic vesicle protein SV2A It inhibits this protein and prevents vesicle exocytosis A reduction in glutamate secretion is reduces glutamate excitotoxicity

Question 32

What is the mechanism of action of Sodium Valproate?

Answer 32

Inhibition of GABA transaminase prevents the breakdown of GABA This increases GABA concentrations directly in the synapse presynaptically and also indirectly prolongs GABA in the synapse due to the fact that extraneuronal metanolism of GABA is slowed which also slows GABA removal from the synapse

Question 33

What adjuvant therapy would you offer the patient? How would administration differ in community or in hospital?

Answer 33

Benzodiazepines e.g. IV lorazepam But continue usual therapy In community take drug orally due to absence of trained staff to administer IV or rectally

Question 34

Essie - individuaalised treatment:

Answer 34

Oestrogens are generally thought of as seizure promoting and progesterone has been shown to be seizure inhibiting. Many women have an increased frequency of seizures during a particular phase of the ovulatory cycle e.g. day 10-13 (periovulatory estrogen peak) If lamotrigine is effective and well tolerated by Essie, then the simplest solution will be to change her oral contraceptive to a long-term progesterone implant such as Implanon/Nexplanon If Essie were to get pregnant later in life there is a chance her seizure frequency could increase. Lamotrigine dose may be reduced due to fears of harming the unborn child. In addition, pregnancy may lead to changes in liver metabolism. As a result, lamotrigine levels may decrease and be associated with increased seizures. Essie would need to have serum lamotrigine checked at the beginning of pregnancy and during the second and third trimester. Dose could then be adjusted as described.