1.4 - Pharmacology of epilepsy (core drugs) Flashcards
What are the four types of anticonvulsants?
- lamotrigine
- sodium valproate
- diazepam
- levetiracetam
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 the common side effects of lamotrigine?
- rash
- drowsiness
What are the less common but serious side effects of lamotrigine?
- Steven-Johnson’s syndrome
- suicidal thoughts
What is some extra information about lamotrigine?
Introducing lamotrigine gradually is one of the keys to reducing the frequency and severity of allergic skin reactions
How can combined oral contraceptive (COC) pill affect lamotrigine?
- COC appears to have an impact on lamotrigine blood levels - coadministration leads to a reduced level of lamotrigine in the blood
- COC may reduce lamotrigine absorption/enhance metabolism/enhance excretion
- lamotrigine does not appear to have an impact on blood ethinyl oestradiol levels
- key point: drug-drug interaction, reduced seizure control, no contraceptive failure
Extra: COC has oestrogen (ethinyl oestradiol) and can induce uridine diphosphate glucuronic acid leading to lamotrigine clearance
Why does taking OCP and lamotrigine cause increased seizures during 2nd and 3rd week of 4wk contraceptive cycle, and more drowsy during 4th week?
- COC taken over 4 weeks
- first 3 weeks: active drug
- 4th week: nothing / ‘dummy’
- therefore 4th week, no COC affecting liver enzymes = liver enzymes normalise
- lamotrigine levels increase
What is the primary mechanism of action of sodium valproate?
- inhibition of GABA transaminase prevents breakdown of GABA
- increases [GABA] directly in synapse presynaptically
- also indirectly prolongs GABA in synapse since extraneuronal GABA metabolism is slowed = also slows GABA removal from synapse
What is the drug target of sodium valproate?
GABA transaminase
What are the common side effects of sodium valproate?
- stomach pain and diarrhoea
- drowsiness
- weight gain
- hair loss
What are some serious side effects of sodium valproate?
- hepatotoxicity
- teratogenicity (avoid in pregnancy as it can affect embryonic development –> neural tube defects, decreased IQ, autism - after in utero exposure)
- pancreatitis
What is some extra information about sodium valproate?
Broad CYP enzyme inhibitor - increases serum concentration of many co-administered drugs
What is the primary mechanism of action of diazepam?
- increases Cl- influx in response to GABA binding at the GABA A receptor
- increased Cl- influx associated with hyperpolarisation of excitatory neurones
What is the drug target of diazepam?
Benzodiazepine site on GABA A receptor
What are some common side effects of diazepam?
- drowsiness
- respiratory depression (if IV or at high dose)
What are some uncommon but serious side effects of diazepam?
- haemolytic anaemia
- jaundice
Why isn’t diazepam used long term?
- not used long term for suppression of seizures is due to development of tolerance
- addictive drug - addiction-prone individuals likely to become dependent
What is the primary mechanism of action of levetiracetam?
- inhibition of synaptic vesicle protein SV2A
- prevents vesicle exocytosis
- reduces glutamate secretion and therefore glutamate excitotoxicity
What is the drug target of levetiracetam?
Synaptic vesicle protein SV2A
What are some common side effects of levetiracetam?
- dizziness
- somnolence (drowsiness)
- fatigue
- headache
What is an advantage of using levetiracetam?
This drug’s metabolism has no effect on cytochrome P450 enzyme system so is favourable in terms of no drug-drug interactions
What are some important points to remember about anticonvulsants?
- drug-drug interactions are common
- frequently involve drug-induced changes in liver metabolism
- antiepileptic drugs commonly interfere with metabolism of other drugs (including combined oral contraceptive)
What are some different types of epileptic seizures? (2 + 4)
- focal - affect just one side of brain
- generalised - affect both sides of the brain from the start
- absence: briefly pause for 10s then carry on
- generalised tonic-clonic: patients lose consciousness and then limbs stiffen (tonic) and start jerking (clonic), confusion often follows
- myoclonic: sudden jerk of limb/trunk/face
- tonic or atonic: sudden loss of muscle tone, causing the patient to fall, whilst retaining consciousness
What on EEG can show increased risk of seizure recurrence?
Interictal epileptiform discharge (IED)
What is something important you need to do if a patient has epilepsy?
Must document advice to contact DVLA that they cannot drive
What is first-line treatment for focal seizures?
- carbamazepine or lamotrigine
- child-bearing potential: carbamazepine or levetiracetam
What is first-line treatment for absence seizures?
- ethosuximide or sodium valproate
- child-bearing potential: ethosuximide only
What is first-line treatment for generalised tonic-clonic seizures?
- sodium valproate
- child-bearing potential: lamotrigine (or carbamazepine)
What is first-line treatment for myoclonic seizures?
- sodium valproate
- child-bearing potential: levetiracetam (or carbamazepine)
What is first-line treatment for tonic/atonic seizures?
- sodium valproate
- child-bearing potential: sodium valproate (pregnancy prevention programme)
