Dementia Pharmacology

3 major post-mortem findings in Alzheimer’s patients

1. Neuritic plaques

1. Neurofibrillary tangles

2. Loss of neurons, synapses (cholinergic, serotonergic, dopaminergic, noradrenergic)

What are neuritic plaques?

Extracellular precipitates of insoluble beta-amyloid protein

What are neurofibrillary tangles?

Hyperphosphorylated tau protein

What is the amyloid paradox?

• animal models with lots of beta amyloid plaques have mild phenotypes

• postmortem studies show that healthy people have high levels of beta amyloid plaques and some Alzheimer’s patients have minimal plaques

• amyloid beta oligomers have more toxicity to neurone than insoluble plaques

• amyloid should always precede tau, but that is not always the case

Cholinergic hypothesis of Alzheimer’s disease

• depletion of acetylcholine (esp. at later stages)

• decline in choline acetyltransferase (ChAT) activity

• loss of cholinergic neurons (late, esp. in forebrain)

• loss of muscarinic type 2 receptors

• loss of nicotinic receptors in hippocampus and cortex

• decreased acetylcholinesterase activity

What 3 gene mutations are strongly associated with familial AD development?

• APP (amyloid precursor protein)

• PSEN1 (presenilin 1)

• PSEN2 (presenilin 2)

What is the general cause for sporadic AD (SAD)?

Failure of homeostasis resulting in failure of self-reinforcing feedback loops

e.g., neuroinflammation damages cells, damaged cells produce beta-amyloid, beta-amyloid increases neuroinflammation

3 parts of the cholinesterase active site

• Choline subsite (Chol)

• Catalytic subsite (Cat)

• Acyl subsite (Ac)

What are the 3 cholinesterase inhibitors?

1. Donepezil

2. Galantamine

3. Rivastigmine

Which cholinesterase inhibitor is the only pseudo-irreversible drug?

Rivastigmine (bond takes much longer to break than the other 2)

Differences in efficacy between the cholinesterase inhibitors

All considered to have similar efficacy

Which cholinesterase inhibitor is a competitive inhibitor?

Galantamine

Which cholinesterase inhibitor is not selective for the brain (i.e., has peripheral effects)?

Galantamine

Cholinesterase inhibitor toxicity

• vivid dreams / nightmares / insomnia

  • Due to increased central cholinergic signalling

• Diarrhea

• Incontinence

• Decreased heart rate

Galantamine metabolism

CYP 2D6 and 3A4

Donepezil metabolism

CYP 2D6, 3A4, 1A2

Drug interactions with cholinesterase inhibitors

• sedatives and hypnotics (worsen confusion, memory impairment, increased falls)

• antidepressants (TCAs - sedation, anticholinergic)

• antipsychotics (sedation, cognitive impairment, drops in BP, anticholinergic)

• 1st gen antihistamines (anticholinergic)

Memantine MOA

NMDA antagonist with affinity for 5-HT3 receptor and nicotinic receptors

Why does Memantine help treat AD?

• Beta-amyloid plaques may enhance glutamate release (so weak antagonism allows for some neurotransmission while inhibiting excess that could result in excitotoxicity and further damage)

• Improves cognition and global functionaing

Memantine’s place in therapy

Often combined with donepezil or other cholinesterase inhibitor

Memantine toxicity

• confusion

• dizziness

• drowsiness

• headache

• insomnia

• agitation

• hallucination

Which medications have limited evidence as antioxidants for AD?

• vitamin E

• Selegiline

Which Mabs are FDA approved for AD?

• Lecanemab

• Donanemab

(designed to clear beta-amyloid plaques)