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)
