12. Anti-epileptic drugs Flashcards
What is the 1st line therapy for: partial seizures, generalised seizures and seizures in pregnant women?
- Partial seizures = CARBAMAZEPINE
- Generalised seizures = SODIUM VALPROATE
- Pregnant women = LAMOTRIGINE
Describe the MOA of carbamazepine.
Is a Na+ channel blocker: binds to VGSC in inactivated state during membrane depolarisation… prolongs inactivation state… decreased neuronal AP firing rate.
Self-regulating as detaches from binding site once membrane potential back to normal.
Why is carbamazepine not effective against absence seizures?
Absence seizures generated by Ca2+ channel dysfunction.
Why is drug monitoring required in carbamazepine use?
Strong CYP450 inducer so affects own Phase I metabolism with repeated use. T1/2 = 30hrs initially but then lowers to 15hrs - need to adjust dose.
Does carbamazepine cause any ADRs?
Commonly causes CNS ADRs: dizziness, drowsiness, ataxia, motor disturbance, numbness, tingling
Can also cause:
- GI disturbance, vomiting
- BP variations
- rashes
- hyponatraemia
Rare: severe BM depression (neutropenia)
What are the possible DDIs of carbamazepine?
- CYP450 inducer so increases clearance of other drugs e.g. warfarin, OCP, systemic corticosteroids, phenytoin, benzodiazepines…
- Anti-depressants (SSRIs, MAOIs and TCAs) interfere with CBZ action at neuronal level… decreased efficiency
Describe the MOA of sodium valproate?
Several effects:
- weak inhibition of GABA inactivation enzymes… increase [GABA]
- weak stimulation of GABA synthesising enzymes… increase [GABA]
- VGSC blocker and weak Ca2+ channel blocker
Does sodium valproate cause any ADRs?
Generally less severe than with other AEDs.
- CNS: sedation, ataxia, tremor
- Weight gain
- Hepatic function: increased transaminases in 40% - can rarely cause hepatic failure
What are the possible DDIs of sodium valproate?
- Can be used as adjunct therapy with other AEDs (effective in all seizure types)
- Anti-depressants (SSRIs, MAOIs, TCAs) inhibit SV action
- Anti-psychotics antagonise SV by lowering convulsive threshold
- Aspirin - competitive plasma binding increases SV conc. (90% SV plasma bound)
What is the MOA of lamotrigine?
- Na+ channel blocker… prolongs VGSC inactivation state
- Ca2+ channel blocker?
- decreased glutamate release?
Does lamotrigine cause ADRs?
Less marked CNS ADRs (diziness, ataxia, somnolence)
Can still cause some mild (10%) and serious (0.5%) skin rashes.
ADRs increased in paeds.
Why must epileptic women who want to have children be careful?
All AEDs increase risk of congenital malformations (8% vs 2% normally).
Sodium valproate most teratogenic - sodium valproate syndrome: neural tube defects, face and digit hypoplasia.
Use folate supplement - reduces risk of NTDs, and vitK in last trimester - reduces AED-associated vitK deficiency in newborn
Name 3 examples of benzodiazepines and their indicated use.
- CLONAZEPAM - absence seizure short term use
2. LORAZEPAM and MIDAZOLAM - status epilepticus
Describe the MOA of benzodiazepines.
Bind to GABAa R… increase Cl- influx on GABA binding… lowers negative membrane potential so increase AP generation threshold… post-synaptic inhibition.
Binding of GABA or BZD enhance each other’s binding - act as +ve allosteric effectors.
Do benzodiazepines have any ADRs?
Many ADRs that limit use:
- sedation, confusion
- impaired co-ordination
- aggression
- resp. and CNS depression
- tolerance and dependence with chronic use
- abrupt withdrawal = seizure trigger
