Antiepileptics

Question 1

How do anti-epileptics work in general?

Answer 1

• Decrease membrane excitability by altering Na+ and Ca2+ conductance during action potentials
• Enhance effects of inhibitory neurotransmitters

Question 2

Which anti-epileptic drugs are first line for newly diagnosed partial and generalised tonic clonic seizures?

Answer 2

• Phenytoin
• Carbamazepine
• Valproate

Question 3

What is the MOA of phenytoin?

Answer 3

Blocks voltage-dependent Na+ channels

Question 4

What types of seizures is phenytoin suitable for?

Answer 4

All except absence seizures

Question 5

Why does phenytoin require TDM?

Answer 5

Phenytoin exhibits non-linear dose-concentration relationship due to
- narrow therapeutic range (40-100uM)
- saturation kinetics

Question 6

What types of seizures is carbamazepine suitable for?

Answer 6

All except absence seizures

Question 7

What is the MOA of carbamazepine?

Answer 7

Blocks voltage-dependent Na+ channels

Question 8

What are the special pharmacokinetic attributes of carbamazepine?

Answer 8

→ CYP450 inducer
→ T1/2 shortens w repeated doses – hepatic enzyme autoinduction (induces enzymes metabolising it)

Question 9

What is the allele that predisposes patients taking carbamazepine to develop SJS?

Answer 9

HLA B*1502

Question 10

What is the MOA of sodium valproate?

Answer 10

Blocks voltage-dependent Na+ and Ca2+ channels

Question 11

What types of seizures is sodium valproate suitable for?

Answer 11

All

Question 12

What is the special pharmacokinetic attribute of sodium valproate?

Answer 12

binds strongly to plasma proteins, to the extent of displacing all other anti-epileptics

Question 13

What are the dose-related adverse effects and anti-epileptics in general?

Answer 13

drowsiness, confusion, nystagmus, ataxia, slurred speech, nausea, unusual behaviour, mental changes, coma

Question 14

What are the non-dose-related adverse effects and anti-epileptics in general?

Answer 14

hirsutism, acne, gingival hyperplasia, folate deficiency, Osteomalacia, hypersensitivity reactions (incl SJS)

Question 15

What is the MOA of the benzodiazepines?

Answer 15

Enhances binding of GABA to receptor coupled to Cl- channel, resulting in greater entry of Cl- ions to lead to hyperpolarization of cell

Question 16

What type of benzodiazepine is diazepam?

Answer 16

Long-acting (1-3 days duration of action)

Question 17

What are the possible unwanted effects of benzodiazepines?

Answer 17

Acute Toxicity/Overdose (esp w alcohol)

Side Effects
→ Drowsiness, confusion, amnesia
→ Impaired muscle coordination

Tolerance and Dependence

Question 18

What is the antidote for benzodiazepine toxicity?

Answer 18

Flumazenil (benzodiazepine antagonist)

Question 19

What is the MOA of barbituates?

Answer 19

Also potentiate GABA-mediated Cl- currents, but at a site distinct from benzodiazepines
(ie flumazenil will not work here)

Question 20

What are barbituates used for?

Answer 20

Used as anti-epileptic for paediatric/neonatal pts (IV loading dose then IV or PO maintenance dose)

Question 21

What is the MOA of levetiracetam?

Answer 21

Unclear - apparently binds to synaptic vesicle protein 2A to protect against seizures

Question 22

What is levetiracetam used for?

Answer 22

• Adjunct for partial onset seizures, myoclonic and primary generalized tonic-clonic seizure
• Can be used as monotherapy for partial onset seizures in newly diagnosed epilepsy

Question 23

What are the pharmacokinetic attributes of levetiracetam?

Answer 23

→ Highly soluble and permeable
→ Linear PK w low intra and inter subject variability
→ Either IV or PO

Question 24

What are the common side effects of levetiracetam?

Answer 24

headache, vertigo, cough, depression, insomnia

Question 25

What are the rare (and serious) side effects of levetiracetam?

Answer 25

Agranulocytosis, suicide, delirium, dyskinesia

Question 26

What is the MOA of lamotrigine?

Answer 26

- Blocks voltage-gated sodium channels - Inhibits release of glutamate - Impedes sustained repetitive neuronal depolarization

Question 27

What are the indications for lamotrigine?

Answer 27

- Adjunctive Tx or monoTx of partial seizures and generalised seizures, incl tonic-clonic - MonoTx of typical absence seizure

Question 28

What are the PK attributes of lamotrigine?

Answer 28

→ Linear PK → PO → T1/2 is generally shorter in children → T1/2 is significantly reduced by coadministration w carbamazepine and phenytoin, increased by coadministration w valproate

Question 29

What are the common side effects of lamotrigine?

Answer 29

headache, irritability/aggression, tiredness

Question 30

What are the rare (and serious) side effects of lamotrigine?

Answer 30

agranulocytosis, hallucination, movement disorders (worsens PD), SJS/TEN, hepatic failure

Question 31

What is the MOA of topiramate?

Answer 31

Unclear, but seems to increase GABA activation of GABA-A receptors, enhance GABA induction of Cl- flux but does not inc channel opening time. May act on benzodiazepine-insensitive subtype of GABA-A receptors

Question 32

What are the indications for topiramate?

Answer 32

- Indicated for monotherapy of partial seizures and generalised seizure, tonic clonic seizures - Adjunctive Tx for Lennox-Gastaut syndrome (severe childhood epilepsy) - Prophylaxis of migraine headaches in adults

Question 33

What are the pharmacokinetic attributes of topiramate?

Answer 33

→ Linear PK → PO → Long T1/2 → Predominantly renal clearance, not a potent inducer of drug metabolizing enzymes

Question 34

What are the common side effects of topiramate?

Answer 34

depression, somnolence, fatigue, nausea, weight change

Question 35

What are the rare (and serious) side effects of topiramate?

Answer 35

neutropenia, mania, tremor, transient blindness, SJS/TEN, hepatic failure

Question 36

When are antiepileptic drug levels tested?

Answer 36

- Assessment of compliance to drug Tx for refractory epilepsy - Assessment of Sx due to possible antiepileptic drug toxicity - Titration of phenytoin dose

Question 37

What are the chronic adverse effects of carbamazepine?

Answer 37

peripheral neuropathy, osteomalacia, suicidal ideation

Question 38

What is the chronic adverse effect of phenobarbital?

Answer 38

osteomalacia

Question 39

What are the chronic adverse effects of phenytoin?

Answer 39

gingival hyperplasia, hirsutism, peripheral neuropathy at high doses, osteomalacia

Question 40

What are the chronic adverse effects of valproate?

Answer 40

Alopecia, reversible weight gain, suicidal ideation

Question 41

What is the TDM reference range for phenytoin?

Answer 41

10-20mg/L

Question 42

What is the TDM reference range for valproate?

Answer 42

50-100mg/L

Question 43

What is the TDM reference range of carbamazepine?

Answer 43

4-12 mg/L

Question 44

What is the TDM reference range of phenobarbital?

Answer 44

15-40mg/L