1.4 - Pharmacology of epilepsy (core drugs)

Question 1

What are the four types of anticonvulsants?

Answer 1

• lamotrigine
• sodium valproate
• diazepam
• levetiracetam

Question 2

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 the common side effects of lamotrigine?

Answer 4

• rash
• drowsiness

Question 5

What are the less common but serious side effects of lamotrigine?

Answer 5

• Steven-Johnson’s syndrome
• suicidal thoughts

Question 6

What is some extra information about lamotrigine?

Answer 6

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

Question 7

How can combined oral contraceptive (COC) pill affect lamotrigine?

Answer 7

• 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

Question 8

Why does taking OCP and lamotrigine cause increased seizures during 2nd and 3rd week of 4wk contraceptive cycle, and more drowsy during 4th week?

Answer 8

• 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

Question 9

What is the primary mechanism of action of sodium valproate?

Answer 9

• 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

Question 10

What is the drug target of sodium valproate?

Answer 10

GABA transaminase

Question 11

What are the common side effects of sodium valproate?

Answer 11

• stomach pain and diarrhoea
• drowsiness
• weight gain
• hair loss

Question 12

What are some serious side effects of sodium valproate?

Answer 12

• hepatotoxicity
• teratogenicity (avoid in pregnancy as it can affect embryonic development –> neural tube defects, decreased IQ, autism - after in utero exposure)
• pancreatitis

Question 13

What is some extra information about sodium valproate?

Answer 13

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

Question 14

What is the primary mechanism of action of diazepam?

Answer 14

• increases Cl- influx in response to GABA binding at the GABA A receptor
• increased Cl- influx associated with hyperpolarisation of excitatory neurones

Question 15

What is the drug target of diazepam?

Answer 15

Benzodiazepine site on GABA A receptor

Question 16

What are some common side effects of diazepam?

Answer 16

• drowsiness
• respiratory depression (if IV or at high dose)

Question 17

What are some uncommon but serious side effects of diazepam?

Answer 17

• haemolytic anaemia
• jaundice

Question 18

Why isn’t diazepam used long term?

Answer 18

• not used long term for suppression of seizures is due to development of tolerance
• addictive drug - addiction-prone individuals likely to become dependent

Question 19

What is the primary mechanism of action of levetiracetam?

Answer 19

• inhibition of synaptic vesicle protein SV2A
• prevents vesicle exocytosis
• reduces glutamate secretion and therefore glutamate excitotoxicity

Question 20

What is the drug target of levetiracetam?

Answer 20

Synaptic vesicle protein SV2A

Question 21

What are some common side effects of levetiracetam?

Answer 21

• dizziness
• somnolence (drowsiness)
• fatigue
• headache

Question 22

What is an advantage of using levetiracetam?

Answer 22

This drug’s metabolism has no effect on cytochrome P450 enzyme system so is favourable in terms of no drug-drug interactions

Question 23

What are some important points to remember about anticonvulsants?

Answer 23

• 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)

Question 24

What are some different types of epileptic seizures? (2 + 4)

Answer 24

• 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

Question 25

What on EEG can show increased risk of seizure recurrence?

Answer 25

Interictal epileptiform discharge (IED)

Question 26

What is something important you need to do if a patient has epilepsy?

Answer 26

Must document advice to contact DVLA that they cannot drive

Question 27

What is first-line treatment for focal seizures?

Answer 27

• carbamazepine or lamotrigine
• child-bearing potential: carbamazepine or levetiracetam

Question 28

What is first-line treatment for absence seizures?

Answer 28

• ethosuximide or sodium valproate
• child-bearing potential: ethosuximide only

Question 29

What is first-line treatment for generalised tonic-clonic seizures?

Answer 29

• sodium valproate
• child-bearing potential: lamotrigine (or carbamazepine)

Question 30

What is first-line treatment for myoclonic seizures?

Answer 30

• sodium valproate
• child-bearing potential: levetiracetam (or carbamazepine)

Question 31

What is first-line treatment for tonic/atonic seizures?

Answer 31

• sodium valproate
• child-bearing potential: sodium valproate (pregnancy prevention programme)