Antiepileptics Flashcards
How do anti-epileptics work in general?
- Decrease membrane excitability by altering Na+ and Ca2+ conductance during action potentials
- Enhance effects of inhibitory neurotransmitters
Which anti-epileptic drugs are first line for newly diagnosed partial and generalised tonic clonic seizures?
- Phenytoin
- Carbamazepine
- Valproate
What is the MOA of phenytoin?
Blocks voltage-dependent Na+ channels
What types of seizures is phenytoin suitable for?
All except absence seizures
Why does phenytoin require TDM?
Phenytoin exhibits non-linear dose-concentration relationship due to
- narrow therapeutic range (40-100uM)
- saturation kinetics
What types of seizures is carbamazepine suitable for?
All except absence seizures
What is the MOA of carbamazepine?
Blocks voltage-dependent Na+ channels
What are the special pharmacokinetic attributes of carbamazepine?
→ CYP450 inducer
→ T1/2 shortens w repeated doses – hepatic enzyme autoinduction (induces enzymes metabolising it)
What is the allele that predisposes patients taking carbamazepine to develop SJS?
HLA B*1502
What is the MOA of sodium valproate?
Blocks voltage-dependent Na+ and Ca2+ channels
What types of seizures is sodium valproate suitable for?
All
What is the special pharmacokinetic attribute of sodium valproate?
binds strongly to plasma proteins, to the extent of displacing all other anti-epileptics
What are the dose-related adverse effects and anti-epileptics in general?
drowsiness, confusion, nystagmus, ataxia, slurred speech, nausea, unusual behaviour, mental changes, coma
What are the non-dose-related adverse effects and anti-epileptics in general?
hirsutism, acne, gingival hyperplasia, folate deficiency, Osteomalacia, hypersensitivity reactions (incl SJS)
What is the MOA of the benzodiazepines?
Enhances binding of GABA to receptor coupled to Cl- channel, resulting in greater entry of Cl- ions to lead to hyperpolarization of cell
What type of benzodiazepine is diazepam?
Long-acting (1-3 days duration of action)
What are the possible unwanted effects of benzodiazepines?
Acute Toxicity/Overdose (esp w alcohol)
Side Effects
→ Drowsiness, confusion, amnesia
→ Impaired muscle coordination
Tolerance and Dependence
What is the antidote for benzodiazepine toxicity?
Flumazenil (benzodiazepine antagonist)
What is the MOA of barbituates?
Also potentiate GABA-mediated Cl- currents, but at a site distinct from benzodiazepines
(ie flumazenil will not work here)
What are barbituates used for?
Used as anti-epileptic for paediatric/neonatal pts (IV loading dose then IV or PO maintenance dose)
What is the MOA of levetiracetam?
Unclear - apparently binds to synaptic vesicle protein 2A to protect against seizures
What is levetiracetam used for?
- 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
What are the pharmacokinetic attributes of levetiracetam?
→ Highly soluble and permeable
→ Linear PK w low intra and inter subject variability
→ Either IV or PO
What are the common side effects of levetiracetam?
headache, vertigo, cough, depression, insomnia
What are the rare (and serious) side effects of levetiracetam?
Agranulocytosis, suicide, delirium, dyskinesia
What is the MOA of lamotrigine?
- Blocks voltage-gated sodium channels
- Inhibits release of glutamate
- Impedes sustained repetitive neuronal depolarization
What are the indications for lamotrigine?
- Adjunctive Tx or monoTx of partial seizures and generalised seizures, incl tonic-clonic
- MonoTx of typical absence seizure
What are the PK attributes of lamotrigine?
→ 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
What are the common side effects of lamotrigine?
headache, irritability/aggression, tiredness
What are the rare (and serious) side effects of lamotrigine?
agranulocytosis, hallucination, movement disorders (worsens PD), SJS/TEN, hepatic failure
What is the MOA of topiramate?
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
What are the indications for topiramate?
- 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
What are the pharmacokinetic attributes of topiramate?
→ Linear PK
→ PO
→ Long T1/2
→ Predominantly renal clearance, not a potent inducer of drug metabolizing enzymes
What are the common side effects of topiramate?
depression, somnolence, fatigue, nausea, weight change
What are the rare (and serious) side effects of topiramate?
neutropenia, mania, tremor, transient blindness, SJS/TEN, hepatic failure
When are antiepileptic drug levels tested?
- Assessment of compliance to drug Tx for refractory epilepsy
- Assessment of Sx due to possible antiepileptic drug toxicity
- Titration of phenytoin dose
What are the chronic adverse effects of carbamazepine?
peripheral neuropathy, osteomalacia, suicidal ideation
What is the chronic adverse effect of phenobarbital?
osteomalacia
What are the chronic adverse effects of phenytoin?
gingival hyperplasia, hirsutism, peripheral neuropathy at high doses, osteomalacia
What are the chronic adverse effects of valproate?
Alopecia, reversible weight gain, suicidal ideation
What is the TDM reference range for phenytoin?
10-20mg/L
What is the TDM reference range for valproate?
50-100mg/L
What is the TDM reference range of carbamazepine?
4-12 mg/L
What is the TDM reference range of phenobarbital?
15-40mg/L
