CNS VI: Antiseizure Drugs Flashcards
List five causes of seizure
- Head trauma
- Stroke
- Fever
- Alcohol withdrawal
- Channelopathies
Describe the three phases of tonic-clonic seizures
Tonic: Lots of brain activity, writhing movement.
Clonic: less brain activity, clenching and unclenching of muscles
Coma
Opening ____ channels can be a treatment to seizures
Potassium
True or false. Seizures can be due to too much excitation AND too little inhibition
True
What are the three main mechanisms of antiepileptic drugs?
Suppress the formation or spread of abnormal electrical discharges by:
- Blocking Na/Ca ion channels
- Diminishing action of excitatory glutamatergic transmission (block NMDA or AMPA receptors)
- Augment the action of GABAergic neurotransmission
What are the three main classes of anti-seizure drugs?
- Phenytoin, carbamazepine and Valproic acid: Na channel blockers (the gold standard for seizures)
- Gabapentin and pregabalin (Increase GABA, ALSO block voltage dependent calcium channels)
- Levetiracetam (block docking of excitatory NT with presynaptic terminal)
Others block NMDA and AMPA/Kainate receptors
How do Na channel blockers treat seizures? (gold standard)
eg. phenytoin, carbamazepine, valproic acid
- Increase refractory period
- Most effect on neurons firing repetitively and less effect on normal neurotransmission when drugs preferentially bind to the inactivated state of the Na channel
Dirty drugs, but very effective.
Describe phenytoin
- Na channel blocker
- Used for tonic-clonic and partial seizures
- Binds to inactivated Na Channels
- Inhibits release of NT and hormones by effecting Ca channels
- Decreases release of glutamate and increases release of GABA
Difficulties
- Big variability in first pass (hard to titrate)
- First order kinetics at moderate doses (depends on drug concentration), zero order at high doses (doesn’t depend on concentration, buildup and saturation can lead to toxicity)
- Drug interactions
What is carbamazepine?
A anti-seizure drug
- Related to tricyclics
- Reduces high frequency neural firing by blocking Na channels
- Tonic-clonic and partial seizures
Describe calcium channel blockers for seizures
What do these work in conjunction with to prevent absence seizures
Ethosuximide or valproic acid reduce rhythmic cortical discharge from the thalamus by blocking T-type (LVA) Ca channels in thalamic neurons (good for absence seizures)
A benzodiazepine called clonazepam can block hyperpolarization of GABAergic interneurons and allow them to inhibit excitatory neurons in the thalamus.
What is valproic acid?
A broad spectrum anticonvulsant
- Blocks Na channels
- Inhibits Ca influx through T-type calcium channels
- Inhibits metabolism of some substrates metabolized by CYP3A4 (kind of dirty)
- Has some serious potential side effects, including liver toxicity and pacreatitis
What are pregabalin and gabapentin?
- Increase neuronal GABA
- Increase in glutamic acid decarboxylase!
- Decrease in neuronal calcium currents by binding of alpha 2 delta subunit of the voltage gated calcium channel (N-type, low voltage)
What are:
- L and N type calcium channels?
- T type calcium channels?
- L and N type calcium channels: need extra depolarization (high voltage)
- T type calcium channels: lower voltage activated
What are topiramate and falbamate and how do they work to treat seizures?
Topiramate
- Blocks Na channels at high firing frequencies
- Antagonizes AMPA//kainate
Felbamate
- Blocks Na channels at high firing frequencies
- Modulates NMDA receptor
What are two methods of increasing GABA in the synapse?
- Inhibit GABA transaminase
- Inhibit GAP1 glial transporter
