What is a seizure?
- high frequency of bursts of APs (influx of Ca and activation of Na channels or a decrease in inhibitory interneurons) or hypersynchronization
what are the 3 main MOAs for for anticonvulsants?
- blockade of voltage-gated Na channels (AP generation) - used for partial and secondarily generalized tonic-clonic seizures
- enhancement of principal inhibitory neurotransmitter in the CNS (GABA) - used for partial and secondarily generalized tonic-clonic seizures
- inhibition of voltage-activated T-type Ca channels - used for absence seizures
What are the Na channel blockers
Carbamazepine Phenytoin Topiramate Lamotrigine Valproate Zonisamide
Where do the anti-seizure drugs act in the GABA pathway?
- benzos and barbiturates - act on post-synaptic side
2. Valproate works at pre-synaptic side by inhibiting GABA metabolism and increasing quantum yield release of GABA
What is the net effect of the Ca channel blockers
to reduce activity of pacemaker currents that underlies the thalamic rhythm in spikes and waves
What is a major ADE for anti-convulsants?
Suicidal ideation (1-24 weeks after starting drug) - educate patients, minimally effective drug levels should be used to manage epilepsy
How should we treat epilepsy?
Monotherapy, switch if it doesn’t work, then consider polypharamcy
- adverse effects vary from minimal impairment to death from aplastic anemia or hepatic failure
MOA of carbamazepine, Lacosamide, lamotrigine, phenytoin
block Na channels
MOA of clonazepam
GABA allosteric agonist – shift dose reponse curve for GABA to left.
MOA of ethosuximide
block T-type Ca channel
MOA of felbamate
inhibit NMDA, activate GABA
MOA of Gabapentin and Pregabalin
inhibit alpha 2 delta1 subunit of Ca channel
MOA of oxcarbazepine
inhibit Na channel, possibly increase K channel and decrease Ca channel
MOA of topiramate
inhibit Na channels, activate K current, activate GABA, decrease glutamate activity
MOA of Valproate
activate GABA, inhibit Na chanel
MOA of Zonisamide
inhibit N and T-type Ca channel
ADMA summary of anti-convulsants
- oral
- limited protein binding -except phenytoin and valproate
- hepatic metabolism w/ urinary elimination
- CYP interactions
- long half lives
- slow release products facilitate adherence - fewer doses/day
Which anti-convulsants don’t have hepatic metabolism
- gabapentin
- Pregabalin
- minor topiramate
Which anti-convulsants is eliminated in stool
phenytoin
Which anti-convulsants have no CYP interaction?
Gabapentin, Levetiracetam, pregabalin, topiramate
Which anti-convulsants have CYP activity that does it’s own hepatic metabolism?
- this leads to a drug decrease due to increased rate of hepatic metabolism
Carbamazepine, phenytoin
Which anti-convulsants need routine drug levels?
Carbamazepine, ethosuximide, gabapentin, phenytoin, valproate
What is a concern w/ topiramate and zonisamide?
they are weak carbonic anhydrase inhibitors –> leads to renal bicarb loss –> metabolic acidosis and may promote stone formation by reducing urinary citrate excretion and increasing urinary pH
What is abrupt discontinuation a problem w/ anti-convulsants?
can precipitate status epilepticus, increase the frequency of seizures and lead to various neurologic issues
