(3.10) Pharmacology of anticonvulsant drugs & drugs used to tx focal, generalized tonic-clonic seizures

Question 1

What is the general MOA of anticonvulsant drugs?

Answer 1

Stabilize and reduce neuronal excitability (reduce E/I balance)

Question 2

What are the 4 specific MOAs of anticonvulsant drugs?

Answer 2

1. Decrease Na influx, prolong inactivation of Na channels
2. Reduce of Ca influx (critical for absence seizures)
3. Enhance GABA-mediated neuronal inhibition
4. Antagonism of excitatory transmitters

Question 3

What are the presynaptic targets at the excitatory (glutamatergic) synapse?

Answer 3

Na and Ca channels

Question 4

What are the post-synaptic targets at the excitatory (glutamatergic) synapse?

Answer 4

NMDA and AMPA receptors

Question 5

What are the presynaptic targets at the inhibitory (GABAergic) synapse?

Answer 5

• GABA transporter (GAT-1)
• GABA transaminase (GABA-T)

Question 6

What are the post-synaptic targets at the inhibitory (GABAergic) synapse?

Answer 6

• GABAa receptors
• GABAb receptors

Question 7

What do a number of anti-seizure drugs have in common regarding structure?

Answer 7

• Common heterocyclic ring structure
  X group:
• N hydantoin derivatives
• C-N barbiturates
• C succinimides

Question 8

What drug class is phenytoin?

Answer 8

Hydantoin

Question 9

What is the MOA of phenytoin?

Answer 9

Binds and stabilizes the inactivated state of Na channels (not isoform selective thus can target Na channels in brain as well as other parts of body)

Question 10

What other drug in the hydantoin class has a similar MOA?

Answer 10

Fosphenytoin (Cerebyx): injectable phosphate PRODRUG

Question 11

What is phenytoin elimination kinetics dependent on?

Answer 11

Dose

Question 12

Phenytoin elimination kinetics is dose dependent. What does this lead to?

Answer 12

Non linear PK

Question 13

What can phenytoin be displaced by?

Answer 13

Phenytoin can be displaced from plasma proteins by other drugs (e.g. Valproate), leading to an increase in its plasma conc

Question 14

What does phenytoin induce?

Answer 14

Phenytoin induces liver cytochrome P450, thereby increasing the rate of metabolism of other drugs

Question 15

What are the SEs/toxicities of phenytoin?

Answer 15

• Arrhythmia
• Visual issues
• Ataxia
• GI sxs
• Gingival hyperplasia, hirsutism (growth of facial hair)
• Hypersensitivity rxns (skin rash)

Question 16

What drug class is carbamazepine (Tegretol) and oxcarbazepine (Trileptal)?

Answer 16

Iminostilbenes

Question 17

What is the MOA of iminostilbenes?

Answer 17

Binds and stabilizes the inactivated state of Na channels

Question 18

What are the toxicities of iminostilbenes?

Answer 18

Blurred vision, ataxia, GI disturbances, sedation at high doses, serious skin rash (Stevens-Johnson syndrome/toxic epidermal necrolysis), drug rxn w eosinophilia and systemic sxs (DRESS) hypersensitivity rxn

Question 19

What is the MOA of lacosamide (Vimpat)?

Answer 19

Enhances inactivation of voltage-gated Na channels

Question 20

What are the toxicities of lacosamide (vimpat)?

Answer 20

Dermatological rxns, cardiac risks (PR interval prolongation), visual disturbances

Question 21

What drugs are in the barbiturates class?

Answer 21

Phenobarbital (Luminal) and Primidone (Mysoline)

Question 22

When is phenobarbital the drug of choice?

Answer 22

In infants up to 2 months of age

Question 23

What is the MOA of phenobarbital?

Answer 23

Binds to an allosteric regulatory site on the GABAa receptor, increases duration of Cl channel opening events (and thus enhances GABA inhibitory signaling)

Question 24

What are DIs of phenobarbital?

Answer 24

Induces liver cytochrome P450 enzymes

Question 25

What are the toxicities of phenobarbital?

Answer 25

Sedation, physical dependence (potential of abuse)

Question 26

What drugs are in the benzodiazepines class?

Answer 26

Diazepam (Valium) and clonazepam (klonopin)

Question 27

When is diazepam esp useful?

Answer 27

Esp useful for tonic clonic status epilepticus; often administered as a rectal gel for acute control of seizure activity

Question 28

What is the MOA of diazepam?

Answer 28

Binds to an allosteric regulatory site on the GABAa receptor, increases frequency of Cl channel opening events (and thus enhances GABA inhibitory signaling)

Question 29

What are toxicities of diazepam?

Answer 29

Sedation, physical dependence (tolerance); therefore, not useful for chronic tx

Question 30

What is clonazepam useful for?

Answer 30

Useful for acute tx of epilepsy and absence seizures

Question 31

What is the MOA of gabapentin?

Answer 31

• Increases GABA release
• Decreases presynaptic Ca influx, thereby reducing glutamate release

Question 32

What are toxicities of gabapentin?

Answer 32

Sedation, ataxia

Question 33

What is the MOA of vigabatrin (sabrile)?

Answer 33

Irreversible inhibitor of GABA transaminase (GABA-T), the enzyme responsible for degrading GABA

Question 34

What are toxicities of vigabatrin (sabrile)?

Answer 34

Sedation, depression, visual field defects

Question 35

What is the MOA of tiagabine (gabatril)?

Answer 35

Inhibits GABA transporter (GAT-1)

Question 36

What are toxicities of tiagabine (gabatril)?

Answer 36

Sedation, ataxia

Question 37

What is the MOA of felbamate (felbatol)?

Answer 37

NMDA receptor antagonist

Question 38

What is the toxicity of felbamate (felbatol)?

Answer 38

Severe hepatitis (which is why it’s a 3rd line drug)

Question 39

What is the MOA of topiramate (topamax)?

Answer 39

AMPA and kainate receptor antagonist

Question 40

What are toxicities of topiramate (topamax)?

Answer 40

Confusion, cognitive dysfunction, sedation, vision loss