neurodegeneration Flashcards
Alzheimer's medication: summarise and compare the mechanisms of action of drugs used to treat Alzheimer's disease
2 current classes of drugs used to treat Alzheimer’s disease (don’t relate to pathophysiology)
anticholinesterases, CNS NMDA receptor blocker
3 anticholinesterases which are used to treat Alzheimer’s disease, and what severity of Alzheimer’s disease they treat
donepezil (first line; mild-to-moderate and severe Alzheimer’s), rivastigmine (mild-to-moderate Alzheimer’s), galantamine (mild-to-moderate Alzheimer’s)
donepezil mechanism of action and plasma half-life
reversible AChE inhibitor; long plasma half-life
rivastigmine mechanism of action and plasma half-life
pseudo-reversible AChE and BChE inhibitor (typically found in liver also, so not good as causes side effects); reformulated as transdermal patch (make it more specific to AChE); 8 hour half-life
galantamine mechanisms of action and plasma half-life
reversible AChE inhibitor and a7 nAChR agonist; 7-8 hour half-life
effect of increasing CNS ACh in Alzheimer’s disease
enhances or reverses some symptoms in Alzheimer’s disease (good immediate effect but only lasts for <2 years)
example of NMDA receptor blocker used to treat Alzheimer’s disease
memantine
memantine mechanism of action and plasma half-life
use-dependent (most effective when excess glutamate activity e.g. in Alzheimer’s) non-competitive NMDA receptor blocker with low channel affinity (only for moderate-severe Alzheimer’s disease); long plasma half-life
3 treatment failures for Alzheimer’s disease
y-secretase inhibitors, B-amyloid immunotherapy (mainly target B-amyloid plaques), Tau inhibitors
2 examples of y-secretase inhibitors
tarenflurbil (similar to aspirin - inflammation hypothesis), semagacestat
tarenflurbil mechanism of action
binds to amyloid precursor protein (APP) molecule to prevent cleavage by y-secretase
semagacestat mechanism of action
small molecule y-secretase inhibitor (inhibited notch protein and increased chance of skin cancer)
2 examples of B-amyloid humanised monoclonal antibodies (passive) which failed clinical trials
bapineuzumab, solanezumab (both target fibrils of entire plaque); aducanumab (targets B-amyloid monomers as well as fibrils of entire plaque)
what do B-amyloid vaccines (active) in development target
B-secretase enzyme
example of tau inhibitor in phase III clinical trials
methylene blue (used for treatment of methaemoglobinaemia)
what is the effect of why many of these treatments don’t work
question whether B-amyloid hypothesis is what is causing Alzheimer’s disease
