Pharmacology of Epilepsy - Core Drugs & Case Study

Question 1

What are the 4 core drug (class) used in the treatment of epilepsy?

Answer 1

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

Question 2

In 2020 - lamotrigine was the 94th most commonly prescribed drug in West London area.

What is the primary mechanism of action of 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 of Lamotrigine?

Answer 3

Voltage gated Na+ channels

Question 4

What are some of the potential side effects of taking Lamotrigine?

Answer 4

Common:

• Rash
• Drowsiness

Less common but serious:

• Steven-Johnson’s syndrome
• Suicidal thoughts

Question 5

What is one of the keys to reducing the frequency and severity of allergic skin reactions when prescribing lamotrigine to treat epilepsy?

Answer 5

Introducing lamotrigine gradually

Question 6

What is the benefit of introducing lamotrigine gradually when treating epilepsy?

Answer 6

It’s one of the keys to reducing the frequency and severity of allergic skin reactions

Question 7

In 2020 - sodium valproate was the 78th most commonly prescribed drug in West London

What is the primary mechanism of action of sodium valproate?

Answer 7

Inhibition of GABA transaminase

Prevents breakdown of GABA

Increases GABA concentrations directly in synapse presynaptically

Also indirectly prolongs GABA in the synapse due to the fact that extraneuronal metabolism of GABA is slowed which also slows GABA removal from the synapse

Question 8

What is the function of GABA?

Answer 8

Reduces neuronal excitability by inhibiting nerve transmission

= Primary inhibitory neurotransmitter for CNS

Question 9

What is the drug target for sodium valproate?

Answer 9

GABA transaminase

Question 10

What are the potential side effects of taking sodium valproate?

Answer 10

Many side effects inc.

Common:

• Stomach pain
• Diarrhoea
• Drowsiness
• Weight gain
• Hair loss

Serious:

• Hepatotoxicity
• Teratogenicity
• Pancreatitis

Question 11

Sodium valproate is a broad CYP enzyme inhibitor. How might this affect co-administered drugs?

Answer 11

It increases serum concentration of many co-administered drugs

Question 12

In 2020 - Diazepam was 61st most commonly prescribed drug in West London

What is the primary mechanism of action of Diazepam?

Answer 12

Increases chloride ion influx in response to GABA binding at the GABA-A receptor

Increased Cl- influx associated with hyperpolarisation of excitatory neurones

Question 13

What is the drug site and target for Diazepam?

Answer 13

Benzodiazepine site on the GABA-A receptor

Question 14

What are some potential side effects of taking diazepam?

Answer 14

Common:

• Drowsiness
• Respiratory depression (if i.v. or at high dose)

Uncommon but serious:

• Haemolytic anaemia
• Jaundice

Question 15

What is a common side effect that one might consider when taking diazepam at a high dose or through an I.V.?

Answer 15

Respiratory depression

Question 16

What is the main reason for diazepam not being used for long term suppression of seizures?

Answer 16

The development of tolerance

Question 17

Diazepam is a Schedule 4 controlled drug. What is the significance of this?

Answer 17

Addiction prone individuals more likely to become dependent on diazepam

Question 18

In 2020 - Levetiracetam was the 74th most commonly prescribed drug in West London area.

What is the primary mechanism of action of Levetiracetam?

Answer 18

Inhibition of the synaptic vesicle protein SV2A

This prevents vesicle exocytosis

Leads to a reduction in glutamate secretion which reduces glutamate excitotoxicity

Question 19

What is the drug target of Levetiracetam?

Answer 19

Synaptic vesicle protein SV2A

Question 20

What are some potential side effects of taking Levetiracetam?

Answer 20

Common:

• Dizziness
• Somnolence
• Fatigue
• Headache

Question 21

Levetiracetam is favourable in terms of no drug-drug interactions.

Why is this?

Answer 21

Its metabolism has no effect on the cytochrome P450 enzyme system

Question 22

The metabolism of levetiracetam has no effect on the cytochrome P450 enzyme.

What is the significance of this?

Answer 22

It’s favourable in terms of no drug-drug interactions

Question 23

What does the treatment of epilepsy depend on?

Answer 23

The type of seizure

The individual patient

Question 24

How might you classify epilepsy seizures?

Answer 24

• Absence
• Focal
• Generalised tonic-clonic
• Myoclonic
• Tonic or atonic

Question 25

What might an EEG show in a patient who has generalised tonic-clonic seizures (in Epilepsy)?

Answer 25

Interictal epileptiform discharge (IED)

Question 26

An EEG shows interictal epileptiform discharge (IED). What is the significance of this?

Answer 26

Increased risk of seizure reoccurence

Question 27

A patient experiences seizures with the following characteristics/symptoms: - Loses consciousness - Stiffening of body - Jerking movements - Last few mins, 30 mins afterwards before recovery What type of seizures is this patient having?

Answer 27

Generalised tonic-clonic seizures

Question 28

A patient experiences jerking/twitching movements after waking up. What type of seizures is this characteristic of?

Answer 28

Myoclonic

Question 29

A patient is found to have generalised tonic clonic seizures. Their EEG shows interictal epileptiform discharge (IED). What is the therapeutic objective for this patient?

Answer 29

The main goals of anti-epileptic drug (AED) therapy would be - To eliminate seizures or reduce their frequency as much as possible - To avoid adverse effects associated with long-term treatments - To improve quality of life + how they're coping with seizures; help them maintain normal lifestyle and continue social + vocational activities - To prevent premature death

Question 30

A patient is found to have seizures and epilepsy. What MUST you document? ***HINT - DVLA***

Answer 30

Must document advice to contact DVLA that they cannot drive

Question 31

A woman of child-bearing age is diagnosed with seizures and epilepsy. Should you prescribe sodium valproate? Give a reason for your answer.

Answer 31

No, unless on pregnancy prevention programme Because SV can affect foetal development following in utero exposure and can cause many things, inc. - Neural tube defects - Decreased IQ - Autism (Serious, though uncommon, side effect of SV = teratogenicity)

Question 32

The combined oral contraceptive pill appears to have an impact on lamotrigine blood levels - co-administration leads to a reduced level of lamotrigine in the blood. Lamotrigine does not appear to have an impact on blood ethinyl estradiol levels. What are we worried about in this case?

Answer 32

Drug-drug interaction There is no contraceptive failure but we would be worried about a reduction in seizure control which could lead to an increase in seizure frequency/severity

Question 33

The combined oral contraceptive pill appears to have an impact on lamotrigine blood levels - co-administration leads to a reduced level of lamotrigine in the blood. Lamotrigine does not appear to have an impact on blood ethinyl estradiol levels. What might explain this?

Answer 33

COC may reduce lamotrigine absorption so less gets into the blood in the first place COC may enhance lamotrigine metabolism and so more is cleared from the blood COC may enhance lamotrigine excretion and thus enhance clearance from the blood

Question 34

The combined oral contraceptive pill appears to have an impact on lamotrigine blood levels - co-administration leads to a reduced level of lamotrigine in the blood. Lamotrigine does not appear to have an impact on blood ethinyl estradiol levels. What might explain this?

Answer 34

COC may reduce lamotrigine absorption so less gets into the blood in the first place COC may enhance lamotrigine metabolism and so more is cleared from the blood COC may enhance lamotrigine excretion and this enhance clearance from the blood

Question 35

A patient is taking lamotrigine for their epilepsy. A year later, their seizures are well controlled but they want to go on the COC pill. The combined oral contraceptive pill appears to have an impact on lamotrigine blood levels - co-administration leads to a reduced level of lamotrigine in the blood. Lamotrigine does not appear to have an impact on blood ethinyl estradiol levels. What prescription change should be made?

Answer 35

Either 1. Increase dose of lamotrigine (COC can reduce lamotrigine by 50%) 2. Change contraception

Question 36

A patient is on lamotrigine for their epilepsy treatment. They have recently started the oral contraceptive pill which is known to impact lamotrigine levels in the blood. 3 months on, the patient has since noticed that she has been having more seizures during the 2nd and 3rd week of the 4 week contraceptive cycle. Her GP increased the dose of lamotrigine 2 fold to combat this. The patient has found that this has reduced the seizure frequency but she has felt particularly drowsy during the 4th week of the contraceptive cycle. What do you think is going on? What would be the preferred method to combat this?

Answer 36

COC taken over 4 weeks First 3 weeks - active drug The 4th week of the COC cycle - given a placebo pill - No COC affecting liver enzymes - Liver enzymes normalise - Lamotrigine levels increase (due to higher dose given to combat effect of pill on lamotrigine) System is over-suppressed - Starts to feel drowsy In reality, change AED or change contraception

Question 37

Sodium valproate and levetiracetam can be used in the treatment of generalised tonic clonic seizures. Compare the mechanism of action of these 2 drugs.

Answer 37

1. Target SV - GABA Transaminase L - synaptic vesicle protein SV2A 2. Location SV - Inhibitory presynaptic terminal L - Excitatory presynaptic terminal 3. Effect SV - increase GABA availability L - reduces glutamate transmission

Question 38

A patient on lamotrigine for epileptic seizures stopped taking it after feeling very drowsy leading up to an important set of exams. During this period, the patient had a continuous convulsive seizure that lasted over 6 mins. Her boyfriend took her to the hospital for treatment. Whilst being assessed in hospital, the patient has another seizure. Using BMJ Best Practice: (https://bestpractice.bmj.com/topics/ en-gb/3000127/treatment-algorithm) Which drug would you administer first?

Answer 38

1o - 4mg Lorazepam - Single dose - Repeat after 10 - 20 mins if required 2o - 10mg Diazepam - Single dose - " " OR Midazelam - 10mg buccally; repeat after if req. IV - Faster delivery - In hospital, so can do this - Patient is also convulsing

Question 39

How are the hormones mentioned below thought to influence seizures? - Oestrogen - Progesterone

Answer 39

Oestrogen - Generally though of as seizure promoting Progesterone - Generally thought of as seizure inhibiting