24 Questions
What is the mechanism of action of iminostilbenes on NaV channels?
Preventing transition to the resting state of NaV channels
What is the consequence of alkylation at the urea group of the dibenzazepine core in iminostilbenes?
Dramatic loss of anticonvulsant activity
What is the significance of carbamazepine (CBZ) in the context of AEDs?
It is the gold standard for comparing new AEDs
What is the effect of higher doses of older iminostilbenes like CBZ and OXC on selectivity for hyperfunctioning neurons?
Loss of selectivity
What is the functional moiety of iminostilbenes?
Dibenzazepine core
What is the significance of the ethylene group in iminostilbenes?
It can be metabolically oxidized without loss of activity
What is the effect of iminostilbenes on NaV channels?
They stabilize the inactive state of NaV channels
What is the therapeutic significance of carbamazepine (CBZ)?
It was initially designed as an antidepressant and antipsychotic
What is a potential contribution of lamotrigine's inhibition of dihydrofolate reductase to its adverse effect profile?
Unique adverse effect profile
What is a characteristic of lacosamide compared to older NaV channel blockers?
Improved safety profile
What is the mechanism of action of lamotrigine, carbamazepine, and phenytoin?
Inhibition of presynaptic fast NaV channels
What is the class of voltage-gated calcium channel modulators that are structural analogues of GABAA?
Gabapentinoids
What is the year in which lacosamide was approved by the FDA as an adjuvant for partial-onset seizures in adults?
2008
What is the therapeutic use of lamotrigine, carbamazepine, and phenytoin?
Treatment of partial-onset seizures
What is the chemical structure similarity between lamotrigine and phenytoin?
Similarity in the chemical space of the two aromatic rings
What is the characteristic of lamotrigine that contributes to its unique adverse effect profile?
Inhibition of dihydrofolate reductase
What is the mechanism of action of gabapentinoids in reducing excessive hyperactivity associated with seizures?
By attenuating the release of glutamate
What is the pharmacophore for gabapentinoids?
A weakly acidic carboxylic acid or bioisostere, cyclic or acyclic hydrocarbons, and a weakly basic primary amine
What is gabapentin approved to treat?
Partial seizures and neuralgia
What is pregabalin approved to treat?
Generalized anxiety disorder, diabetic peripheral neuropathy, and partial-onset seizures
What is the structural relationship between gabapentinoids and older classes of CaV blockers?
Gabapentinoids are structurally related to the succinimides and oxazolidinediones
What is the common feature of gabapentin and pregabalin?
Both contain a GABA amino acid core
What is the mechanism of action of gabapentinoids in reducing excessive hyperactivity associated with seizures, not related to?
Modulating CaV channel gating
What is the functional effect of gabapentinoids on CaV channel gating?
Decrease the release of glutamate
Study Notes
Voltage-Gated Sodium Channel Modulators
- Lamotrigine (Lamictal) is an inhibitor of presynaptic fast NaV channels and dihydrofolate reductase.
- Lamotrigine's mechanism of action is similar to that of carbamazepine (CBZ) and phenytoin.
- The two aromatic rings of lamotrigine occupy a similar chemical space as the two aromatic rings of CBZ.
Miscellaneous
- Lacosamide (Vimpat) is a third-generation AED approved by the FDA in 2008 as an adjuvant for partial-onset seizures in adults.
- Lacosamide has an improved safety profile over older NaV channel blockers, with minimal drug-drug interactions (DDIs) or induction of metabolic enzymes.
Voltage-Gated Calcium Channel Blockers
Gabapentinoids
- Gabapentinoids are structural analogues of GABA that modulate CaV channel gating, causing a net reduction in glutamate release.
- Gabapentinoids reduce excessive hyperactivity associated with seizures by attenuating the release of the excitatory neurotransmitter glutamate.
- The pharmacophore for gabapentinoids consists of a weakly acidic carboxylic acid or bioisostere, cyclic or acyclic hydrocarbons attached to the 3-position, and a weakly basic primary amine.
Gabapentinoids
- Gabapentin (Neurontin) was FDA approved in 1993 as adjunctive treatment of partial seizures and is also approved to treat neuralgia.
- Pregabalin (Lyrica) was approved in 2005 as adjunctive treatment of partial-onset seizures, and is also approved to treat neuropathic pain, generalized anxiety disorder, and diabetic peripheral neuropathy.
Succinimides and Oxazolidinediones
- Succinimides and oxazolidinediones are older classes of CaV blockers that are structurally related to the ureides.
Learn about lamotrigine, a medication that works similarly to CBZ and phenytoin, inhibiting presynaptic fast NaV channels and dihydrofolate reductase.
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