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Pharmacology - Drug Treatment of Demention


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definition of dementia
decline in memory and intellect that causes decreased functioning in ADLs

impaired memory
impaired language use
loss of ingrained motor routines
imparied abstract thought
impaired planning
major personality changes
disregard for social stds
Etiology of dementia
can be caused by lots of diseases

80-90% are from AD or vascular dementia

other common causes:
brain trauma
brain tumor
exogenous toxins
metabolic disorders
neurodegenerative disease
Epidemiology of dementia
unusual in people under 65 yo
3% in >75yo
30-50% in >85 yo
Notes on Alzheimers Disease
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
Notes on AD (2)
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)
Notes on AD (3)
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
Notes on AD (4)
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
Mixed dementia
AD and vascular dementia

vascular dementia
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
drug treatment of AD
presynaptic cholinergic terminals die --> less ACh release
drug treatment of AD- basis
death of pre-synaptic cholinergic terminals
Treatments for AD
ACh precursors
muscarinic autoreceptor antagonists
Nicotinic autoreceptor agonist
postsynaptic receptor agonists
AChE inhibitors
Treatments for AD:
ACh Precursors
***not effective ***

lecithin - metabolized to choline
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)
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
Treatments for AD:
postsynaptic receptor agonist (muscarinic and nicotinic)
stimulates post-synaptic terminals

replaces the dying presynaptic cells

still want M1, M3 specificity
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
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
Treatments for AD:
AChE inhibitors - efficacy
30-50% with mild-moderate AD get "modest but useful" improvement

improved: cognitions, ADL

AChE Inhibitors:

Rarely used

doesn't cross BBB well, so lots of SEs

liver damage possible
AChE inhibitors:

most widely used

no liver damage, less PNS SE's
AChE inhibitors:

similar to donepezil
AChE inhibitors:

acts as AChE-I, but also increases cholinergic activation of Nicotinic receptors

doesn't lead to therapeutic advantage
Drug treatments for AD:
Glutamate NMDA receptor antagonists

memantine mech of action
antagonist of glutamate = down excitotoxicity

uncompetitive NMDA channel blocker
- frequency dependent
- channels that don't open often = don't get blocked -->down SEs
Memantine SE's
none noteworthy

No ketamine-like effects
memantine efficacy
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
B-amyloid production
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
B-amyloid facts
monomers/oligomers = soluble
fibrils = insoluble

Formerly fibrils thought to be toxic
Now dimers/oligomers may be the most toxic
Inhibition of B-amyloid formation
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
Anti-Amyloid/Anti-Tau Treatment options
Down B-amyloid formation
Up B-amyloid destruction/removal
Prevent aggregation of B-amyloid into dimers, or more
Prevent abnormal tau formation
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
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
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
Anti-Amyloid/Anti-Tau Treatment options:
Prevent abnormal Tau formation
increase phosphorylase
decrease kinase

down B-amyloid also should down tau
Misc Agents:
Trophic factors

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
Misc Agents:
thought that cell death is due to free radicals

EX: VitE, deprenyl (selegyline, ELDEPRYL, gingko biloba)
Misc Agents:
Vit E
may be effective at preventing and treating AD
Misc agents:
seems to be effect TRT but not prevention

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