Pharmacology of Epilepsy - Core Drugs & Case Study Flashcards
What are the 4 core drug (class) used in the treatment of epilepsy?
- Lamotrigine
- Sodium valproate
- Diazepam
- Levetiracetam
In 2020 - lamotrigine was the 94th most commonly prescribed drug in West London area.
What is the primary mechanism of action of lamotrigine?
Blocks voltage gated Na+ channels preventing Na+ influx
Prevents depolarisation of glutamatergic neurones and reduces glutamate excitotoxicity
What is the drug target of Lamotrigine?
Voltage gated Na+ channels
What are some of the potential side effects of taking Lamotrigine?
Common:
- Rash
- Drowsiness
Less common but serious:
- Steven-Johnson’s syndrome
- Suicidal thoughts
What is one of the keys to reducing the frequency and severity of allergic skin reactions when prescribing lamotrigine to treat epilepsy?
Introducing lamotrigine gradually
What is the benefit of introducing lamotrigine gradually when treating epilepsy?
It’s one of the keys to reducing the frequency and severity of allergic skin reactions
In 2020 - sodium valproate was the 78th most commonly prescribed drug in West London
What is the primary mechanism of action of sodium valproate?
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
What is the function of GABA?
Reduces neuronal excitability by inhibiting nerve transmission
= Primary inhibitory neurotransmitter for CNS
What is the drug target for sodium valproate?
GABA transaminase
What are the potential side effects of taking sodium valproate?
Many side effects inc.
Common:
- Stomach pain
- Diarrhoea
- Drowsiness
- Weight gain
- Hair loss
Serious:
- Hepatotoxicity
- Teratogenicity
- Pancreatitis
Sodium valproate is a broad CYP enzyme inhibitor. How might this affect co-administered drugs?
It increases serum concentration of many co-administered drugs
In 2020 - Diazepam was 61st most commonly prescribed drug in West London
What is the primary mechanism of action of Diazepam?
Increases chloride ion influx in response to GABA binding at the GABA-A receptor
Increased Cl- influx associated with hyperpolarisation of excitatory neurones
What is the drug site and target for Diazepam?
Benzodiazepine site on the GABA-A receptor
What are some potential side effects of taking diazepam?
Common:
- Drowsiness
- Respiratory depression (if i.v. or at high dose)
Uncommon but serious:
- Haemolytic anaemia
- Jaundice
What is a common side effect that one might consider when taking diazepam at a high dose or through an I.V.?
Respiratory depression
What is the main reason for diazepam not being used for long term suppression of seizures?
The development of tolerance
Diazepam is a Schedule 4 controlled drug. What is the significance of this?
Addiction prone individuals more likely to become dependent on diazepam
In 2020 - Levetiracetam was the 74th most commonly prescribed drug in West London area.
What is the primary mechanism of action of Levetiracetam?
Inhibition of the synaptic vesicle protein SV2A
This prevents vesicle exocytosis
Leads to a reduction in glutamate secretion which reduces glutamate excitotoxicity
What is the drug target of Levetiracetam?
Synaptic vesicle protein SV2A
What are some potential side effects of taking Levetiracetam?
Common:
- Dizziness
- Somnolence
- Fatigue
- Headache
Levetiracetam is favourable in terms of no drug-drug interactions.
Why is this?
Its metabolism has no effect on the cytochrome P450 enzyme system
The metabolism of levetiracetam has no effect on the cytochrome P450 enzyme.
What is the significance of this?
It’s favourable in terms of no drug-drug interactions
What does the treatment of epilepsy depend on?
The type of seizure
The individual patient
How might you classify epilepsy seizures?
- Absence
- Focal
- Generalised tonic-clonic
- Myoclonic
- Tonic or atonic
What might an EEG show in a patient who has generalised tonic-clonic seizures (in Epilepsy)?
Interictal epileptiform discharge (IED)
An EEG shows interictal epileptiform discharge (IED).
What is the significance of this?
Increased risk of seizure reoccurence
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?
Generalised tonic-clonic seizures
A patient experiences jerking/twitching movements after waking up.
What type of seizures is this characteristic of?
Myoclonic
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?
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
A patient is found to have seizures and epilepsy.
What MUST you document?
HINT - DVLA
Must document advice to contact DVLA that they cannot drive
A woman of child-bearing age is diagnosed with seizures and epilepsy.
Should you prescribe sodium valproate? Give a reason for your answer.
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)
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?
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
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?
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
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?
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
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?
Either
- Increase dose of lamotrigine (COC can reduce lamotrigine by 50%)
- Change contraception
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?
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
Sodium valproate and levetiracetam can be used in the treatment of generalised tonic clonic seizures.
Compare the mechanism of action of these 2 drugs.
- Target
SV - GABA Transaminase
L - synaptic vesicle protein SV2A
- Location
SV - Inhibitory presynaptic terminal
L - Excitatory presynaptic terminal
- Effect
SV - increase GABA availability
L - reduces glutamate transmission
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?
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
How are the hormones mentioned below thought to influence seizures?
- Oestrogen
- Progesterone
Oestrogen
- Generally though of as seizure promoting
Progesterone
- Generally thought of as seizure inhibiting
