Anti-seizure Drugs

Question 1

Two main categories of seizures

Answer 1

Partial (focus seizures)

Generalized

Question 2

2 types of generalized seizures

Answer 2

They affect the entire brain!

1. Tonic-clonic (grand mal)
2. Absence (petit mal) - looks like slow wave sleep

Question 3

2 general mechanisms of seizures

Answer 3

Excitation (too much) - ionic inward Na/Ca currents, or glutamate
Inhibition (too little) - ionic inward Cl, outward K, GABA

Question 4

3 mechanisms of antiepileptic drugs

Answer 4

Suppress the formation or spread of abnormal electrical discharges by:

1. Blocking ion channels (Na, Ca)
2. Enhance the action of GABAergic neurotransmission
3. Diminish the action of excitatory glutaminergic transmission (block NMDA or AMPA receptors)

Question 5

Mechanism of drugs that block Na channels

Answer 5

Channels open when neuron is activated - causes depolarization
The Na channel is inactivated by closure of the inactivation gate
The inactivation gate must be opened before the next AP can occur
Drugs that block these channels prolong the inactivation state of the channel and increase the refractory period of the neuron (ones that bind the inactivate state have the most effect)

Question 6

3 examples of Na channel blockers

Answer 6

Phenytoin
Carbamazepine
Valproic Acid

Question 7

Phenytoin (what is it used to treat and how does it work)

Answer 7

Used to treat tonic-clonic and partial seizures
Reduces sustained high frequency neuronal firing by binding to inactivated Na channels
Also effects Ca channels and inhibits the release of NTs and hormones
Can decrease the release of glutamate and increase release of GABA

Question 8

Phenytoin PK/PD

Answer 8

Variable bioavailability due to differences in first pass mechanism
Elimination kinetics shift from first order to zero order at moderate-high doses (from little change in plasma concentration to massive change)
There are drug drug interactions

Question 9

Cabamazepine

what are they structurally similar to, how do they work, what do they treat

Answer 9

Structurally related to tricyclic ADs
Reduces high frequency neuronal firing
Treats tonic-clonic and partial seizures
Blocks Na channels

Question 10

Drugs that block Ca channels

Answer 10

Blockage of T-Type Ca channels in thalamic neurons blocks the rhythmic cortical discharge observed in absence seizures

Question 11

Mechanism of Barbiturates on GABAa receptors

Answer 11

Bind to receptors at allosteric site
Prolong GAGA mediated chloride channel openings
Low concentrations: potentiate GABA that is there
High concentrations: direct agonist actions
Some blockage of VDSCs

Question 12

Mechanism of BZs on GABAa receptors (and 2 examples of drugs)

Answer 12

Allosteric modulators of GABAa receptors
Increase frequency of GABA mediated Cl channel openings
1. Clonazepam - used to treat absence and myotonic seizures
2. Diazepam - used for status epileticus (recurrent tonic clonic seizures)

Question 13

Enzyme that terminates the action of GABA

Answer 13

GABA transaminase

Question 14

Depolarization shift

Answer 14

Prolongation of AP in postsynaptic nerve

Question 15

Synchronization

Answer 15

Causes the depolarization of other neighbouring neurons too

Question 16

Topiramate

Answer 16

Blocks voltage dependent Na channels firing at high frequencies
Antagonizes glutamate action at AMPA/KA receptors

Question 17

Felbamate

Answer 17

Blocks voltage dependent Na channels at high firing frequencies
Modulates NMDA receptor (no depolarization shift)

Question 18

NMDA channels

Answer 18

Need a strong depolarization via AMPA receptor in order to remove the Mg block and then get depolarization
Causes synaptic memory - get depolarized again and it is very fast

Question 19

Toxicity of anti-seizure drugs

Answer 19

Overdose toxicity (most are CNS depressants so can get respiratory depression at high doses - also additive effects with other CNS depressants)
Teratogenicity (valproic acid associated neural tube defects, carbamazepine assocaited craniofacial abnormalities/spina bifida, phenytoin associated fetal hydrantoin syndrome)