Alzheimer's

Question 1

Cholinergic Hypothesis

Answer 1

• ACh important neurotransmitter in brain regions involved in memory
• Loss of ACh in Alzheimer’s correlates with impairment of memory
• Brain memory: hippocampus, cerebral cortex, amygdala
• Treatment approach: enhancement of cholinergic fx may stabilize or improve cognitive fx and may affect behavior and daily functioning
• Cholinergic deficiency contributes to cognitive decline in Alzheimer’s Dz (AD) (may contribute to behavioral sx: psychosis-agitation, apathy-indifference, disinhibition, aberrant motor behavior)
• Cholinergic therapy may partially improve behavioral sx of AD (does not interrupt the dz process)
• Blocking AChE makes more ACh available

Question 2

Cholinesterase Inhibitors (ChEI)
- First Line AD/dementia with lewy bodies

Answer 2

• Reversible inhibition of cholinesterase (prevents ACh hydrolysis)
• Efficacy in mild/moderate AD
• Limited info on long term/late stage dz
• Generally safe and well tolerated

Question 3

Donepezil (Aricept)

• First line AD/dementia with lewy bodies
• Improves cognition and global function

Answer 3

• MOA: ChEI
• Improves cognition and global function
• ADR: N/V/D, muscle cramps, insomnia
• Higher doses w/ cholinergic ADR
• P450 metabolized: CYP3A4 and CYP2D6

Question 4

Rivastigmine (Exelon)

• First line AD/dementia with lewy bodies
• Improves cognition and global funcion

Answer 4

• MOA: ChEI
• ADR: N/V/D, HA, dizziness, significant wt loss, dyspepsia
• Fewer ADR when taken with food
• Metabolism totally independent P450— NOT P450

Question 5

Galantamine (Razadyne)

• First line AD/dementia with lewy bodies
• Improves major aspects of AD for 12 months (cognition, behavior, function)

Answer 5

• DUAL MOA: Competitive inhibition of AChE; Allosteric modulation of presynaptic and postsynaptic nicotinic receptors
• ADR: N/V, agitation, sleep disturbances, wt loss
• May increase release of ACh, may have neuroprotective effect
• DRUG INTERACTIONS: minimal (no effect on digoxin or warfarin); used with caution in heart block or sick sinus syndrome

Question 6

NMDA Receptor Antagonist

Answer 6

Memantine (Namenda)

- Other NMDA antagonist: Dextromethorphan, Ketamine, Amantadine

Question 7

Memantine (Namenda)

- moderate/severe AD (monotherapy/ with AChEI)

Answer 7

• MOA: uncompetitive NMDA receptor antagonist (increase glutamate release in CNS produces excitotoxic reactions and cell death)
• USE: moderate/severe AD (monotherapy/ with AChEI)
• ADR: agitation, D, insomnia; Neurocognitive (dizziness, HA, hallucinations)
• Slower decline in overall function and in loss of activities of daily living (no significant effect on cognition)
• Evaluate for ADR after 2-4 weeks
• Evaluate for effectiveness q6months