Block 6 - AED drugs and anesthetics Flashcards by Kate Ball

What is the MOA of gabapentin/pregabalin?

Block the alpha-2-delta subunit of P/Q-type calcium channels on the presynaptic membrane

this blocks the influx of calcium and prevents glutamate release

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What is the MOA of phenytoin?

What other drugs have the same MOA?

blocks voltage gated sodium channels on the presynaptic membrane, preventing depolarization.

Carbamazepine
Oxcarbazepine
Fosphenytoin

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What is the MOA of levetiracetam?

blocks the exocytosis machinery involved in glutamate release (SV2A inhibitor)

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What is the MOA of felbamate?

NMDA receptor blocker

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What is the MOA of perampanel?

AMPA receptor blocker

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What is the MOA of retigabine?

Enhances the effects of Girk channels (KCNQ potassium channels), thereby hyperpolarizing the membrane on both the pre-synaptic and post-synaptic cell membranes

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class 1b anti-rhythmic agents can be used to treat…

partial seizures: sequester aberrant focal point neurons (carbamazepine and phenytoin)
tonic-clonic (general) seizures: both used
status epilepticus: phenytoin IV used at relatively large doses to sequester the AP propagations, particularly when GABA failure occurs from loss of chloride gradient

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What are the side effects of class 1b anti-rhythmic agents?

nausea, headache, interactions with CYP

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Give an example of a broad-spectrum cation channel blocker and explain how it works.

What is it typically used for?

What major risk is associated with it?

Lamictal (lamotrigine)

Blocks sodium channels, but not in the same manner as class 1b. It also blocks some calcium channels.

Tonic-clonic seizures (and others to a lesser extent)

Stevens-Johnson syndrome is a risk

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Other than seizures, what can sodium channel blocker AEDs be used for?

Bipolar disorder

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What are KCNQ enhancers used for? What is the major side effect?

Give an example of a KCNQ enhancer

Partial seizures

Retinal deformity and loss of visual acuity

Retigabine (ezogabine)

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Where do voltage gated calcium channel regulatory subunit blockers bind?

On the alpha-2-delta-2 subunit, even though the site of action is the alpha-2-delta-1 subunit

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Describe the mechanism of action of neurontin and lyrica. What are they used to treat?

They bind at the alpha-2-delta-2 subunit of axonal calcium channels on glutamate neurons and block the alpha-2-delta-1 subunit (no calcium influx)

they’re used to treat partial seizures, but they’re not first line

they can also be used for pain treatment

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Where does keppra (levetiracetam) bind?

How does it work (MOA)?

Selectively binds to SV2A (a synaptic vesicle integral membrane protein)

It blocks glutamate release

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Keppra is used to treat…

What are its side effects?

Partial seizures

Tonic/Clonic seizures

Status epilepticus

Side effect - sleepiness

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Give an example of a drug that works as an AMPA channel blocker. What kind of antagonist is it?

Perampanel

Noncompetitive antagonist

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Felbamate is what kind of drug?

Why is it rarely used?

NMDA channel blocker and GABA enhancer

It destroys the liver or blood cells

Identify the drug described below:

MOA unknown (could be from actions on potassium or non-GABA chloride ion channels)
used for absence, generalized tonic-clonic, and partial seizures
known teratogen
causes dizziness, diarrhea, and many other side effects

Depakote (VPA, Valproate)

What is topamax (topiramate) used to treat?

Side effects include…

Mainly used for partial seizures, but can be used in all

May also be used for alcohol dependency rehab, weight loss, and migraines

Side effects include suicide risk

What can stimulation of the vagus nerve do?

Can blunt tonic-clonic seizure occurrences, but the reason why is not yet known

Explain how ethosuximide works.

It is a T-type calcium channel blocker of thalamic neurons
- it is a first-line treatment for absence seizures because blocking the T-type channels works to prevent the brain from going into “sleep-like mode” due to thalamic stimulation

How do benzodiazepines and barbiturates (like phenobarbital) work?

They are GABA-A receptor agonists that work to increase the effect of chloride ion influx
- this hyperpolarizes the post-synaptic membrane and prevents action potentials

Describe the MOA of tiagabine.

Tiagabine prevents GABA re-uptake/degradation by blocking the GAT-1 channel.

What is GABA-T? How can you block it and why would you want to?

GABA-T is GABA-transaminase that breaks down GABA

You can block it with vigabatrin (drug) (it is an irreversible inhibitor)

This would increase the amount of GABA available, allowing for more to bind to the post-synaptic cell for the prevention of seizures (APs)

Explain the MOA of benzodiazepines, BNZ antagonists, and Z-drugs.

All of them compete for the BNZ binding site on GABA-A. Benzodiazepines are positive allosteric modulators and bind between alpha (1-3 and 5) and gamma subunits Z drugs only bind on the alpha-1 sub-unit, which is associated with sedation, amnesia, and ataxia; thus, these are not used for anxiety or epilepsy (just sleep) BNZ-antagonists only block drugs from the site (both BNZ drugs and Z-drugs); they have no other effects. they're given IV for BNZ overdoses.

What suffix is associated with benzodiazepines (BNZ drugs)?

---zapam (or zolam)

Give 1-2 examples of: - Benzodiazepines - Z drugs

BNZ: - Alprazolam (xanax) - Diazepam (valium) - Lorazepam (ativan) Z drugs: - Zolpidem (ambien) - Zalepon

Which drug class will (at high doses) work as a direct GABA-A agonist?

Barbiturates

How do barbiturates work at low doses?

At low doses, they work as positive allosteric modulators of GABA-A - this increases the druation of GABA-A channel opening

Compare and contrast the effect of low doses of barbiturates with the effect of BNZ drugs.

Both work as positive allosteric modulators of GABA-A channels, but: - at low doses, barbiturates work to keep the channel open longer (increased duration) - BNZ drugs increase GABA-A's affinity for GABA (making it more likely to bind)

What is a risk associated with high levels of barbiturates?

Can lead to fatal overdoses, especially with ethanol

True or false: barbiturates can act as antagonists to glutamate-AMPA receptors

True - which may be involved in their use as AEDs and for general anesthesia

Give examples of barbiturates.

Phenobarbital Belladonna Amobarbital things that have bital as the suffix (butalbital)

What are the different effects that general anesthetics may have on ion channels?

1 - most activate or enhance GABA-A channels 2 - many inhalational GAs also activate inhibitory K+ 2-pore channels (K2P) 3 - some GAs and dissociative anesthetics block AMPA/NMDA channels

What types of seizures can barbiturates be used for? Why are BNZs used very often for chronic AEDs?

they are used for partial and tonic-clonic seizures | BNZs aren't very effective and they produce confusion/addiction. also, Z drugs are not effective and GA is too strong

List some characteristics of drugs that have the suffix ____flurane & halothane

- very lipophilic - fast acting but not very potent - act on K2P channels and GABA-A channels - lowers blood pressure - toxic effect of malignate hyperthermia (all muscles go into tetany)

A hyperactive amygdala results in...

anxiety

While both BNZs and buspirone can be used as anxiolytics, they have different MOAs. Compare them.

BNZs can have a calming effect by inhibiting the amgydala and associated areas but it's by GABA-A positive allosteric stimulation. Buspirone (and other similar drugs) are 5HT1A agonists. 5HT1A is a GPCR coupled with Gi, so activation of the receptor decreases amygdala activity. **Also, 5HT1A agonists lower anxiety without marked sedation, hypnotic, or euphoric effects.

Why is buspirone not effective in treatment of panic disorders?

Buspirone is an agonist/partial agonist of the 5HT1A receptor, however, it has slow-onset as an anxiolytic agent. Effects take 3-4 weeks, so it's not effective for acute anxiety treatment, just for GAD.

Why might a beta blocker help with anxiety/panic attacks?

Norepinephrine excites the amygdala, so blocking it could have some anxiolytic effects

Describe the MOA of propofol.

activates/enhances GABA-A channels | - is most widely used as an injectable GA

What makes ketamine unique as far as GAs go?

- NMDA antagonist that is a "dissociative" anesthetic - INCREASES breathing, HR, and BP - does not have the small window of other IV GA's but still has opioid effects - at lower doses, can be used to treat depression, PTSD, and pain