Anticonvulsant therapy

Question 1

What is kindling?

Answer 1

concept where repetitive subconvulsive stimuli can eventually induce convulsions, or even unprovoked seizures, via a “learning” process

Question 2

What are some general mechanisms of epileptogenesis?

Answer 2

cellular: increased excitability, decreased inhibitory input, or changes in ion channels
Local/regional networks: alterned synaptic anatomy and physiology; bursing neurons entrain other neurons in a network that leads to regionalized spread and generalization (kindling)

Question 3

What underlies primary generalized epilepsy?

Answer 3

excitatory thalamo-cortical activity usually has negative feedback from GABA-ergic neurons (specifically, nRT or thalamic reticular nucleus cells). The GABA-ergic neurons “know” when to fire based on when the glutaminergic neurons are firing b/c the glutaminergic neurons (and their targets!) all feedback onto the GABA neurons. columns of excitatory/inhibitory pairs are synchronized with each other. firing of these columns is the cause of spike-waves in epilepsy.

Question 4

Why doesn’t hypersynchrony occur all the time?

Answer 4

adjacent nRT neurons inhibit each other. Thus, these circuits’ firing is usually slightly de-synchronized. If inhibitory connections between nRT (GABA-ergic neurons) are lost, then the brain is primed for synchronice firing and epilepsy

Question 5

Typical Na channel blocking drugs. Typical action.

Answer 5

phenytoin, carbamazepine (and oxcarbazepine), lamotrigine (these 3 are the prototypes); topiramte, zonisamide (have additional activities)
Also maybe valproate?
Most act by stabilizing the inactivated state of the Na channel to limit sustained repetitive firing

Question 6

What are the 2 new Na channel binding drugs and how do they work?

Answer 6

rufinamide and lacosamide. stabilize Na channels- lead to slow inactivation.

Question 7

What kinds of drugs enhance GABA-A mediated inhibition?

Answer 7

barbiturates, benzodiazepines, tiagabine

topiramate- weak effect, vigabatrin, gabapentin?

Question 8

How do gabapentin, vigabatrin, and tiagabine work?

Answer 8

increase effects of GABA-A mediated inhibition by increasing GABA release or decreasing GABA reuptake

Question 9

How does vigabatrin work?

Answer 9

increase effects of GABA-A mediated inhibition by decreasing the breakdown of GABA-A receptors

Question 10

What drugs block glutamate receptors?

Answer 10

felbamate and topiramate

Question 11

What is felbamate? How does it work and what should I know about its use?

Answer 11

acts at NMDA receptors to block glutamate activation
Can also block glycine
But, felbamate can cause aplastic anemia and lead to patient death in ways that are UNPREDICABLE and thus UNPREVENTABLE. Very difficult consent involved with this drug. Use only as last line before brain surgery.

Question 12

What does topiramate do?

Answer 12

Na, AMPA (glutamate channel), and GABA-A channel effects

Question 13

What drugs block Ca channels and how do they work?

Answer 13

Ethosuximide, valproate, and zonisamide, gabapentin
block T-type Ca channels (that open after hyperpolarization) to interrupt oscillatory thalamo-cortical activation. Especially good for childhood absence seizures.

Question 14

What drugs enhance K channels?

Answer 14

enhance K channels, since these channels repolarize the cell

Ezogabine/retigavine (Potiga)

Question 15

Side effects of ezogabine/retigavine?

Answer 15

blue skin

retinopathy

Question 16

What does primidone do and how does it work?

Answer 16

Primidone reduces sustained repetitive firing. But, its metabolites (phenobarbital and PEMA) enhance GABA action

Question 17

How does zonisamide work?

Answer 17

action on Na and Ca channels

Question 18

How does valproate work?

Answer 18

action on Na, Ca channels; maybe GABA?

Question 19

Benzodiazepines vs. barbiturates

Answer 19

benzos: increase GABA-A receptor affinity for GABA
barbiturates: increase duration of channel opening following GABA binding

Question 20

What is a key limitation of gabapentin?

Answer 20

absorption is a challenge; you are limited by l-amino acid transporters. careful about food. Also, the more gabapentin you give, the smaller the proportion of it that is absorbed

Question 21

What drugs are strong protein binders? Moderate?

Answer 21

pheytoin, valproate (strong)

moderate are carbamazepine and lamotrigine

Question 22

What is the most important drug-drug interation with seizure meds?

Answer 22

valproate increases the risk of LAMOTRIGINE-INDUCED STEVENS JOHNSONS RASH and DEATH

Question 23

Main metabolism of anti-seizure drugs? What are inducers?

Answer 23

mostly CYP450. UDP glucuronyl transferase also important.
Carbamazepine, barbiturates, phenytoin and topiramate.
Carbamazepine + OCPs = PROBLEM- increased OCP degradation can lead to ACCIDENTAL PREGNANCY

Question 24

What are causes of non-linear kinetics for seizure drugs?

Answer 24

gabapentin: absorption differences
valproate: distribution diffs
phenytoin: metabolism diffs

Question 25

What should I know about seizures and menstruation?

Answer 25

catemenial seizures: associated with menstruation. Estrogen is pro-seizure; progesterone is anti-seizure. We see seizures most during menstruation (high estrogen/progesterone ratio) and during months without ovulation (low progesterone)

Question 26

What should I know about seizure and pregnancy?

Answer 26

valproate increases birth defects 7 fold as well as persistant lower IQ levels for the child
lamotrigine and carbamazepine are relatively safe

Question 27

What drugs are most dangerous for bone health?

Answer 27

phenytoin, primidone, and phenobarbital.