Neurocognitive Dx (MC) - Block 2

Question 1

Can we cure AD?

Answer 1

No cure, but we can slow the progression of sx

Question 2

What is natural lingand of Acetylcholinesterase Inhibitors?

Answer 2

Acetylcholine

Question 3

MOS of Acetylcholinesterase Inhibitors?

Answer 3

1. Indirect-acting cholinomimetics
2. Cholinergic neuronal degeneration may cause memory/cognitive defects -> increase Ach activity

Question 4

How Can we Target AChE?

Answer 4

1. Compounds that bind with greater affinity than acetylcholine but are not a substrate for the enzyme (not metabolized)
2. Compounds that are substrates for the enzyme and form an acylated enzyme that is more stable than the normal acetylated enzyme which can still be hydrolyzed and regenerated eventually
   * Carbamates
   * Reversible NOT irreversible
   * Enzyme is inactive when acetylated/acylated
   * Hence, enzyme will be inactivated for a longer time period

Question 5

Describe the binding site of Ach?

Answer 5

1. H-bods
2. Cation

Question 6

Describe the Ach metabolism from Acetylcholinesterase?

Answer 6

Question 7

Donepizil

Brand, MOA

Answer 7

Aricept
MOA: AChEI, Not a carbamate so doesn’t form acylated enzyme

Question 8

Donezepil

Selectivity

Answer 8

Selective for CNS AChE

Question 9

Rivastigmine

MOA

Answer 9

MOA:
1. AChEI: Acylates enzyme via Carbamate
2. Inhibits both plasma cholinesterase and acetylcholinesterase
3. Preferentially inhibits G1 isoform of AChE – higher in brains of AD patients

Question 10

What AChEI is given as a transdermal patch?

Answer 10

Rivastigmine

Question 11

Galantamine

MOA

Answer 11

MOA: Competitive AChE inhibitor
* Not a carbamate so doesn’t form acylated enzyme

Question 12

Why is donepezil have high F?

Answer 12

Very lipophilic

Question 13

What makes galantamine different than other AchEI?

Answer 13

Allosterically binds to nAChRs (nicotinic acetylcholinergic receptors)
* Dual cholinergic action

Question 14

What are the benefits of AChEI?

Answer 14

1. 6-12 month delay in progression of sx
   * Begin tx as early as possible (delaying may see a loss in benefit)

Question 15

ADR of AChEI?

Answer 15

AchE is widespread throughout the body
1. N/V
2. D
3. SZ
4. CNS (HA, DZ, Insomnia)
5. Bradycardia

Question 16

DDI of AChEI?

Answer 16

Donepezil/galantamine:Metabolized by CYP2D6 and 3A4 – Caution with inhibitors
Donepezil/rivastigmine/galantamine: NSAIDs -> GI bleed
Donepezil/rivastigmine: Beta blockers
Rivastigimine: Quinidine

Question 17

Memantine

Brand, MOA

Answer 17

Namenda
MOA: Excitotoxic activation of glutamate transmission through NMDA (N-methyl-D-aspartate) receptors -> contributes to pathophys of AD
* Noncompetitive, use-dependent block that binds to NMDA receptors

Question 18

Memantine

PK

Answer 18

Lipophilic “cage-like” ring structure -> BBB and metaboism resistance

Question 19

Memantine

ADR

Answer 19

Better tolerated: Dz, constipation, confusion, HA, HTN

Question 20

Aducanumab

MOA, Indication

Answer 20

MOA: Beta-amyloid targeting antibody
INdication: No meaningful clinical benefit

Question 21

Lecanemab

MOA, ADR

Answer 21

MOA: beta-amyloid targeting antibody
ADR: potential for brain bleeding/seizures (amyloid-related imaging abnormalities (ARIA))
* potential for brain bleeding/seizures (amyloid-related imaging abnormalities (ARIA))
* infusion-related reactions

Question 22

Lecanemab

Efficacy

Answer 22

**Phase II study **- decreased brain plaques over 18 months
Phase III: showed reduction in cognitive decline

Question 23

What are you AChEI?

Answer 23

1. Donepezil (Aricept)
2. Rivastigmine
3. Galantamine

Question 24

What are you beta amyloid targeting antibodies?

Answer 24

1. Aducanumab
2. Lecanemab