(3.10) Pharmacology of anticonvulsant drugs & drugs used to tx focal, generalized tonic-clonic seizures Flashcards
What is the general MOA of anticonvulsant drugs?
Stabilize and reduce neuronal excitability (reduce E/I balance)
What are the 4 specific MOAs of anticonvulsant drugs?
- Decrease Na influx, prolong inactivation of Na channels
- Reduce of Ca influx (critical for absence seizures)
- Enhance GABA-mediated neuronal inhibition
- Antagonism of excitatory transmitters
What are the presynaptic targets at the excitatory (glutamatergic) synapse?
Na and Ca channels
What are the post-synaptic targets at the excitatory (glutamatergic) synapse?
NMDA and AMPA receptors
What are the presynaptic targets at the inhibitory (GABAergic) synapse?
- GABA transporter (GAT-1)
- GABA transaminase (GABA-T)
What are the post-synaptic targets at the inhibitory (GABAergic) synapse?
- GABAa receptors
- GABAb receptors
What do a number of anti-seizure drugs have in common regarding structure?
- Common heterocyclic ring structure
X group: - N hydantoin derivatives
- C-N barbiturates
- C succinimides
What drug class is phenytoin?
Hydantoin
What is the MOA of phenytoin?
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)
What other drug in the hydantoin class has a similar MOA?
Fosphenytoin (Cerebyx): injectable phosphate PRODRUG
What is phenytoin elimination kinetics dependent on?
Dose
Phenytoin elimination kinetics is dose dependent. What does this lead to?
Non linear PK
What can phenytoin be displaced by?
Phenytoin can be displaced from plasma proteins by other drugs (e.g. Valproate), leading to an increase in its plasma conc
What does phenytoin induce?
Phenytoin induces liver cytochrome P450, thereby increasing the rate of metabolism of other drugs
What are the SEs/toxicities of phenytoin?
- Arrhythmia
- Visual issues
- Ataxia
- GI sxs
- Gingival hyperplasia, hirsutism (growth of facial hair)
- Hypersensitivity rxns (skin rash)
What drug class is carbamazepine (Tegretol) and oxcarbazepine (Trileptal)?
Iminostilbenes
What is the MOA of iminostilbenes?
Binds and stabilizes the inactivated state of Na channels
What are the toxicities of iminostilbenes?
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
What is the MOA of lacosamide (Vimpat)?
Enhances inactivation of voltage-gated Na channels
What are the toxicities of lacosamide (vimpat)?
Dermatological rxns, cardiac risks (PR interval prolongation), visual disturbances
What drugs are in the barbiturates class?
Phenobarbital (Luminal) and Primidone (Mysoline)
When is phenobarbital the drug of choice?
In infants up to 2 months of age
What is the MOA of phenobarbital?
Binds to an allosteric regulatory site on the GABAa receptor, increases duration of Cl channel opening events (and thus enhances GABA inhibitory signaling)
What are DIs of phenobarbital?
Induces liver cytochrome P450 enzymes
What are the toxicities of phenobarbital?
Sedation, physical dependence (potential of abuse)
What drugs are in the benzodiazepines class?
Diazepam (Valium) and clonazepam (klonopin)
When is diazepam esp useful?
Esp useful for tonic clonic status epilepticus; often administered as a rectal gel for acute control of seizure activity
What is the MOA of diazepam?
Binds to an allosteric regulatory site on the GABAa receptor, increases frequency of Cl channel opening events (and thus enhances GABA inhibitory signaling)
What are toxicities of diazepam?
Sedation, physical dependence (tolerance); therefore, not useful for chronic tx
What is clonazepam useful for?
Useful for acute tx of epilepsy and absence seizures
What is the MOA of gabapentin?
- Increases GABA release
- Decreases presynaptic Ca influx, thereby reducing glutamate release
What are toxicities of gabapentin?
Sedation, ataxia
What is the MOA of vigabatrin (sabrile)?
Irreversible inhibitor of GABA transaminase (GABA-T), the enzyme responsible for degrading GABA
What are toxicities of vigabatrin (sabrile)?
Sedation, depression, visual field defects
What is the MOA of tiagabine (gabatril)?
Inhibits GABA transporter (GAT-1)
What are toxicities of tiagabine (gabatril)?
Sedation, ataxia
What is the MOA of felbamate (felbatol)?
NMDA receptor antagonist
What is the toxicity of felbamate (felbatol)?
Severe hepatitis (which is why it’s a 3rd line drug)
What is the MOA of topiramate (topamax)?
AMPA and kainate receptor antagonist
What are toxicities of topiramate (topamax)?
Confusion, cognitive dysfunction, sedation, vision loss
