Alzheimers and Parkinsons Flashcards
(41 cards)
alzheimer disease
dementia
-not related to a distinct cause
causes problems: -memory, language, judgment/thinking -personality -perceptin
alzheimer patho
- decrease in brain size from neuronal death
- protein aggregation:
- -neurofibrillary tangles: hyperphosephorylated tau (clumps together)
- -amyloid plaque: amyloid beta
- deficits in cholinergic signaling
- -hippocampus (memory and learning)
- -frontal cortex (executive function)
alzheimer decrease in 5 things
choline acetyltransferase activity ACh amount AChsterase? choline transport Nicotinin ACh receptor expression
Alzheimer drug classes
cholinesterase inhibitors
NMDA receptor antagonist
Cholinesterase inhibitors MOA
preven action of AChsterase thereby increasing ACh [ ] in synapse
Cholinesterase inhibitors ex
Donepezil (Aricept)
Rivastigmine (Exelon)
Galantamine (Razadyne
Cholinesterase inhibitors: indication, route, side effects
mild to moderate AD, slight improvement in cognitive function, does not halt disease
-Oral 1-2/day
SE: N/D, dizziness, HA, bronchoconstriction
NMDA receptor antagonist MOA
signal to noise hypothesis/reduced excitotoxicity
2 different mechanisms:
1.Blocking “leaky” channels to help reduce calcium induced excitotoxicity
2.Blocking“leaky” channels helps reduce background noise, making signals relatively stronger
**Mg not blocking channel so too much Ca rushes in causing damage to neurons–chronic neruodegeneration
*these drugs act as Mg, block NMDA
NMDA receptor antagonist ex
Memantine (Namenda)
NMDA receptor antagonist indication, side effects
moderate to sever AD, very modest benefits
SE:Dizziness, Headache,
Fatigue, Sedation,
Hypertension, Rash,
Diarrhea, Weight Gain, Urinary Frequency, Anemia
AD future tx? Protein aggregates, 2 pathways
Amyloid plaques–amyloid beta AB
APP: amyloid precursor protein
Non-amyloidogenic pathway
-APP protein gets cleaved by a-secratase followed by gamma-secretase: NO AB formed
Amyloidogenic pathway
-APP protein gets cleaved by b-secretase followed by gamma-secretase: AB40/42 aggregates—forms plaques
effects of AB plaques
unclear
most likely the soluble AB derivates cause cognitive effects, rather than the plaques themselves
Genetic consideration
early onset AD–genetic factor
many mutations associated with AD increase amount of AB
ApoE genotype
- encodes for a protein that facilitates the clearance of AB
- significant risk factor…ones that are bad at facilitating the clearance of AB resulting in the build up
- ApoE2: lower risk
- ApoE3: normal risk
- ApoE4: increased risk
- –one copy: 3 fold increase risk
- –2 copies: 12-15 fold increase risk
Tau Protein
in microtubules in normal neurons
- hyperphosphorylated in AD–no longer support microtubules
- proteins become tangled and form neurofibrillary tangles
- correlates with neuronal death–neuron starts loosing shape
Potential new drug targets
AB -block synthesis -promotes clearance -block plaque formation Tau -block aggregation
Parkinsons disease, definition, characterized
a mvmt diaorder-occuring (mostly) in elderly -no obvious cause -some genetic risk factors Characterized by -Dyskinesia: difficulty of mvmt -difficulty starting mvmt -difficulty stopping mvmt one started -muscle rigidity -tremor at rest -cognitive impairments, depression
Basal ganglia
striatum
Globus Pallidus
Subthalamic nuclei
Substantia nigra
Basal ganglia function
start purposeful mvmt, suppresses unwanted mvmt
Normal: Dopamine (DA) and ACh are balanced–results in controlled mvmt
Parkinsons: decreased DA in striatum, creating a imbalance btwn DA and ACh -70% lose of DA neurons from substantial nigra to striatum BEFORE systems appear
Pharm strategies (PD)
goal to increased DA
- Dopaminergic agent: increase amt of DA in striatum, increase delivery or decrease degradation
- mimics effects of DA (dopamine agonists)
- Alternative: ACH agents
- -prevent Cholinergic inhibition of DA release
Levodopa: dopamine precursor
- Levodopa is converted to Dopamine, providing dopamine to the striatum
- This happens in periphery AND brain
- *Dosing problem……
- Levodopa can be degraded by decarboxylases and also by catecholamine O-methyl transferase (COMT), but dopamine does not cross the blood-brain barrier
- Despite large doses of Levodopa, only a small amount of will reach the brain.
- Large amounts of dopamine cause problems in the periphery.
Solution to Levodopa dosing problem
- Dose Levodopa with:
- Carbidopa (peripheral decarboxylase inhibitor)
- entacapone (COMT inhibitor)
- means the same amount of Levodopa can reach the brain with a smaller dose.
- *Entacapone is added when effectiveness of Levodopa/Carbidopa wanes.
Levodopa side effects
-Involuntary movements (Dyskinesias)
-‘on-off’ effect: fluctuations between hypokinesia and improvements
-Acute (disappear after a few weeks)
Nausea
Anorexia
Hypotension
Psychosis: schizophrenia like symptoms with excess dopamine
Levodopa drug interactions
In patients taking Non-selective MAO Inhibitors: an overload of dopamine and norepinephrine can occur.
-May cause peripheral side effects.
