Alzheimers Treatment

Question 0

Pathophysiology of AD

Answer 0

Senile plaques - accumulations of B-amyloid
Neurofibrillary tangles - tau proteins

NFT and plaques most often seen in hippocampus and associative regions of the cortex

Atrophy of cortical and sub cortical neurons
Atrophy of basalis of meynert which provides cholinergic innervation of entire cerebral cortex

Question 1

Alzheimer’s disease

Answer 1

Loss of neurons and synapses
Gross atrophy
Short term memory lost initially with long term preserved till late
Death from complications from immobility

Question 2

Cholinergic hypothesis

Answer 2

Cholinergic deficiency is associated with AD symptoms
Anti muscarinic agents

Choline acetyltransferase (ChAT) less active

Problem: drugs to correct Ach deficiencies are not curative
Most drugs for AD target this hypothesis
Aimed at inhibiting AChE and BuChE

Question 3

B-amyloid hypothesis

Answer 3

AB deposits the primary causative agent
AB deposits from aberrant cleavage of amyloid B precursor (APP) ->produces annular pores or holes

A. Down’s syndrome with APP on chromosome 21, nearly all have AD symptoms by 40

Problem: amyloid plaques levels do not correlate with neuron loss
:

Question 4

Tau hypothesis

Answer 4

Micro tubule stabilization protein tau is abnormally hyperphosphorylated -> degradation of neuronal cytoskeleton -> neuronal death

Question 5

Tacrine

Answer 5

AChE inhibitor
Non-competitive
Slows degradation of Ach and increases its amounts in the synapse

Side effects:
GI cramps, nausea, vomiting, diarrhea
Increased serum transaminases (liver toxins)

No longer used

Question 6

Donepezil

Answer 6

Reversible inhibitor of AChE in CNS
Bioavailability near 100%, not influenced by food or time of administration
Half life 70hrs
Increased risk of stomach ulcers

Question 7

Galantamine

Answer 7

Reversible, competitive inhibitor of AChE
Alkaloid from European daffodil
Prevents ACh breakdown
Ally steric modification of nicotinic receptors = greater release of Ach
Clearance 20% less in females

Question 8

AChE inhibitors

Answer 8

Tacrine
Donepezil
Rivastigmine
Galantamine

Question 9

Rivastigmine

Answer 9

Pseudo irreversible inhibitor of AChE, binds at esteratic sites
Food delays absorption and reduces effect
NSAIDs increase risk of stomach ulcers
Hydrolysis to the decarbsmylated metabolite

Question 10

Memantine

Answer 10

Non AChE inhibitors

Binds to NMDA receptor operated cation channels and blocks calcium