Drug therapy of Alzheimer's

Question 1

List pathological features in the neurochemistry of Alzheimer’s

Answer 1

• Disproportionate decrease in ACh and nicotinic receptors
• B amyloid deposits form plaques
• AChE has a role in accelerating formation of amyloid fibrils by forming stable complexes with AB
• ApoE4 allele binds to AB, making it insoluble and promoting plaque formation
• ER associated binding protein enhances neurotoxic effects of AB
• Elevated homocysteine levels
• Chronic glutamatergic activity
• Hyperphosphorylation of Tau protein

Question 2

Describe the two major strategies to improve outcomes in Alzheimer’s

Answer 2

1. Increase ACh by blocking ACh metabolism

2. Decrease NMDA mediated glutamatergic signaling

Question 3

Describe the mechanism of action of donepezil

Answer 3

Reversible AChE inhibitor, greater affinity for CNS AChE vs plasma BuChE

Question 4

List adverse reactions with donepezil

Answer 4

Generally well tolerated/ few peripheral effects
CNS: headache, drowsiness, dizziness, anorexia, vivid dreams
GI: NVD

Question 5

List three medications for which GI bleed is an absolute contraindication

Answer 5

Donepezil
Rivastigmine
Galantamine

Question 6

List two contraindications that are specific to galantamine (do not apply to rivastigmine, donepezil)

Answer 6

Renal failure, severe hepatic disease

Question 7

List precautions that are shared betweeen galantamine, rivastigmine, and donepezil

Answer 7

Bradycardia, succinylcholine, COPD, ashtma, bladder obstruction

Question 8

Describe the mechanism of action of rivastigmine

Answer 8

Pseudo-irreversible inhibitor of AChE (carbamoylates the enzyme but is eventually hydrolyzed off, dissociates slowly)
10x greater inhibition of CNS AChE than BuChE in periphery

Question 9

Describe the adverse side effects seen with rivastigmine

Answer 9

CNS: dizziness, headache, drowsiness, tremor
GI: NVD, anorexia, pain, constipation

Question 10

Describe the mechanism of action of galantamine

Answer 10

Reversible competitive inhibitor 53x selective for AChE over BuChE, also a positive allosteric modulator of nicotinic receptors

Question 11

Describe the mechanism of action of memantine

Answer 11

Noncompetitive low-affinity antagonist at NMDA glutamate receptor, blocks intracellular calcium accumulation and helps to prevent further nerve damage

Question 12

Describe the side effects of memantine

Answer 12

Same as placebo

Question 13

Describe the precautions for memantine

Answer 13

Dose adjustment for renal failure

Question 14

Memantine is unique in that it is approved for use in:

Answer 14

More advanced stages of Alzheimer’s

Question 15

THC is a potential therapeutic agent for AD because there is evidence that it’s mechanism of action includes:

Answer 15

competitive inhibitor of AChE and inhibits b-amyloid aggregation