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39 Cards in this Set
- Front
- Back
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definition of dementia
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decline in memory and intellect that causes decreased functioning in ADLs
traditional: impaired memory impaired language use loss of ingrained motor routines imparied abstract thought impaired planning major personality changes disregard for social stds delusions |
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Etiology of dementia
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can be caused by lots of diseases
80-90% are from AD or vascular dementia other common causes: brain trauma brain tumor infection exogenous toxins metabolic disorders neurodegenerative disease anoxia |
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Epidemiology of dementia
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unusual in people under 65 yo
3% in >75yo 30-50% in >85 yo |
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Notes on Alzheimers Disease
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begins subtly, gradual deterioration
decreases life expectancy (4.2 yr for men, 5.7 for women) death generally from prolonged immobility -->infection, accident, aspiration women more susceptible 2% are autosomal dominant |
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Notes on AD (2)
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neuritic plaques, neurofibrillary tangles
loss of neurons (10%) - some areas unaffected, but memory, higher intellect, and emotional control areas are biggest losers (neocortex, hippocampus, entorhinal cortex, amygdala, basal forebrain - nucleus of Meynert) |
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Notes on AD (3)
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degeneration of cholinergic projection going from basal forebrain to hippocampus, cerebral cortex, and amygdala
- thought to cause memory deficit and other cognitive/emotional probs -basis of current approach to drug therapy Also affects NE, 5HT, glutamate, GABA, dopamine, somatostatin, substance P, NPY |
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Notes on AD (4)
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Neuron death thought to be due to amyloid beta protein
multiple forms of amyloid, but all are neurotoxic Normal Tau = stabilizes microtubular system HyperPo4'd Tau dissociates from microtubulues thought that beta amyloid cause hyperPO4'd tau |
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Mixed dementia
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AD and vascular dementia
multiplicative |
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vascular dementia
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causes:
ischemic brain lesions ischemic-hypoxic brain lesions Rarely caused by cerebral atherosclerosis progressive loss of tissue due to small/medium infarctions over years sometimes similar to AD, but others are stepwise after each stroke often memory is not affected much in VD --> differentiate from AD |
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drug treatment of AD
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presynaptic cholinergic terminals die --> less ACh release
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drug treatment of AD- basis
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death of pre-synaptic cholinergic terminals
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Treatments for AD
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ACh precursors
muscarinic autoreceptor antagonists Nicotinic autoreceptor agonist postsynaptic receptor agonists AChE inhibitors |
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Treatments for AD:
ACh Precursors |
***not effective ***
choline lecithin - metabolized to choline |
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Treatments for AD:
Muscarinic autoreceptor antagonists |
*** seems to be effective***
block autoreceptors = up NT Need to be M2, M4 specific (can't block M1, M3) |
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Treatments for AD:
Nicotinic autoreceptor agonists |
*** effective ***
nicotinic autoreceptors increase NT release Also may stimulate post-synaptic heteroreceptors Don't smoke though, not worth it |
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Treatments for AD:
postsynaptic receptor agonist (muscarinic and nicotinic) |
stimulates post-synaptic terminals
replaces the dying presynaptic cells still want M1, M3 specificity |
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Treatments for AD:
AChE inhibitors - mceh of action |
Mech(s) of action:
-down AChE means up time for ACh -still need some ACh -inhibition of BChE doesn't add efficacy - theoretically could target CNS isoform over PNS isoform, but none exist yet |
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Treatments for AD:
AChE inhibitors - ADEs |
N&V, diarrhea, GI cramping, anorexia, wt. loss (due to others)
all from PNS activity tolerated well after induction period |
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Treatments for AD:
AChE inhibitors - efficacy |
30-50% with mild-moderate AD get "modest but useful" improvement
improved: cognitions, ADL ***NOT A MAJOR VALUE*** |
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AChE Inhibitors:
tetrahydroaminoacridine |
TACRINE
Rarely used doesn't cross BBB well, so lots of SEs liver damage possible |
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AChE inhibitors:
donepezil |
ARACEPT
most widely used no liver damage, less PNS SE's |
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AChE inhibitors:
rivastigmine |
EXELON
similar to donepezil |
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AChE inhibitors:
galantamine |
REMINYL
acts as AChE-I, but also increases cholinergic activation of Nicotinic receptors doesn't lead to therapeutic advantage |
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Drug treatments for AD:
memantine |
Glutamate NMDA receptor antagonists
NAMENDA |
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memantine mech of action
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antagonist of glutamate = down excitotoxicity
uncompetitive NMDA channel blocker - frequency dependent - channels that don't open often = don't get blocked -->down SEs |
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Memantine SE's
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none noteworthy
No ketamine-like effects |
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memantine efficacy
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are used with AChE-I, but no data supports this
indicated only for moderate-severe - only TRT for severe AD Effects are less than those for AChE-I's |
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B-amyloid production
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Amyloid precursor protein (APP)
General pathway: Alpha or Beta cuts APP, then gamma cuts the nub off the cell wall --> B-amyloid or p3 production alpha-pathway = no B-amyloid production, p3 instead Beta-pathway = creates B-amyloid |
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B-amyloid facts
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monomers/oligomers = soluble
fibrils = insoluble Formerly fibrils thought to be toxic Now dimers/oligomers may be the most toxic |
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Inhibition of B-amyloid formation
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1. up alpha-secretase activity - flurbiprofen (FLURIZAN)
2. down beta/gamma secretase - easy to make B-secretase, but it has potential toxic SEs -Hard to block gamma-secretase, but very hard to synthesize |
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Anti-Amyloid/Anti-Tau Treatment options
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Down B-amyloid formation
Up B-amyloid destruction/removal Prevent aggregation of B-amyloid into dimers, or more Prevent abnormal tau formation |
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Anti-Amyloid/Anti-Tau Treatment options:
imporve B-amyloid destruction |
Immunization against B-amyloid
Active Immunization -causes efflux of B-amyloid out of CNS --> encephalitis - try to make a smaller protein passive immunization Inject mouse Ab's = expected to produce fewer SEs |
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Anti-Amyloid/Anti-Tau Treatment options:
Enhance metaboism |
don't know what enzyme degrades it, but try to up them when you figure it out
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Anti-Amyloid/Anti-Tau Treatment options:
prevent aggregation of B-amyloid into dimer/oligomers/fibrils |
find compounds that bind to the mono/oligomers
tramiprosate - ALZHEMED |
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Anti-Amyloid/Anti-Tau Treatment options:
Prevent abnormal Tau formation |
increase phosphorylase
decrease kinase down B-amyloid also should down tau |
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Misc Agents:
Trophic factors |
neurotrophins
chemicals from glial cells to prompt growth Can't cross BBB, so need direct IJ into brain EX: nerve growth factor, brain derived neurotropic factor more work is needed to figure out a better way |
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Misc Agents:
antioxidants |
thought that cell death is due to free radicals
EX: VitE, deprenyl (selegyline, ELDEPRYL, gingko biloba) |
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Misc Agents:
Vit E |
may be effective at preventing and treating AD
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Misc agents:
deprenyl |
seems to be effect TRT but not prevention
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