Exam 3 - Rochet/Campbell (Parkinsons/Alzheimer's) Flashcards
1
Q
Parkinson’s Disease (PD):
it is progressive (reversible or irreversible) disease resulting in neurological deficit in the ________ system
A
Irreversible;
deficit in extrapyramidal
2
Q
Parkinson’s Disease Symptoms?
A
Resting tremor Rigidty Bradykinesia Impaired balance/coordination Mask-like appearance speech difficulties, cognitive deficits
3
Q
Parkinson’s Disease (PD) is characterized by a loss of _________ in the _______
A
dopamine neurons; in substantia nigra
4
Q
what is a lewy body?
A
there are dense spherical protein deposits in the brain
surviving neurons in the brains of PD pt have them
5
Q
where are lewy bodyies found in PD pt?
A
in the substantia nigra and other parts like cortex
6
Q
Lewy bodies are enriched with what things?
A
fibrillar forms of protein alpha-synuclein
7
Q
what are the Braak stages?
A
way to stage Parkinsons;
based on “alpha-synuclein neuropathology”
8
Q
how many braak stages are there
A
6
9
Q
Stage 1 of Braak – means neuropathology starts in ______
A
lower brainstem
10
Q
List Stages 1 - 6 of Braak Stages
A
1 - lower brainstem (starts here and ascends!) 2 - Raphe 3 - Substania Nigra 4 - Mesocortex/Thalamus 5 - Neocortex/Prefrontal Cortex 6 - Entire Neocortex
11
Q
Environmental poisons that are linked to increased PD risk happen because they do what?
A
they inhibit mitochondrial function and/or trigger oxidative stress
12
Q
what are examples of environmental poisons that are linked to Parkinson’s Disease (PD)
A
- Pesticides
- Herbicides
- Metals (manganese)
- MPTP (a heroin contaminant, complex I inhibitor)
13
Q
Basal ganglia is made up of the ________ and ______
A
striatum and globus pallidus
14
Q
The striatum is made of ______ and _____
A
caudate nucleus; putamen
15
Q
the globus pallidus is broken into what?
A
GPi and GPe
Globus pallidus internal and globus pallidus external
16
Q
Dopamine Neurons and Pathways:
Indirect pathway involves D1 or D2 receptors?
A
D2
17
Q
Dopamine Neurons and Pathways:
Direct pathway involves D1 or D2 receptors?
A
D1
18
Q
Dopamine Neurons and Pathways:
D1 receptor works through direct or indirect pathway?
A
direct
19
Q
Dopamine Neurons and Pathways:
D2 receptor works through direct or indirect pathway?
A
indirect
20
Q
what is an antimuscarinic that be used as adjunct therapy in PD
A
benzotropine
21
Q
why are antimuscarinics used as adjunct therapy in parkinsons?
A
when dopamine decreases — the cholinergic pathway ramps up (aka chill out that pathway by using anticholinergics)
22
Q
what is the “gold standard” for PD therapy
A
L-DOPA
23
Q
why cant we give dopamine directly?
A
dopamine has a + charge and cant enter CNS;
L-DOPA = no charge = CAN enter CNS!
24
Q
what can be added to L-DOPA as a regimen to decrease the dose of L-DOPA needed
A
add carbidopa
25
why does giving carpidopa lead to a lesser dose of L-DOPA being needed
Carbidopa inhibits DCC (aka L-DOPA does not turn to Dopamine)
26
L-DOPA ---(what enzyme?)--> Dopamine
DCC (DOPA decarboxylase)
27
T or F: Carbidopa can cross the blood brain barrier
FALSE!
| it can NOT cross BBB -- aka cannot inhibit DCC in the SN
28
what is definition of dyskinesias
exaggerated/aberrant motor effects
29
L-DOPA Therapy:
| __________ are seen immediately after dosage of L-DOPA
Dyskinesias
30
to prevent dyskinesias and the on/off effect it is best ot give L-DOPA in a ______ manner
continuous manner!!
| pulsatile is crap
31
L-DOPA Therapy:
a key limitation is associated with _________; this becomes a bigger issue when the patients get older/the disease progresses
prodrug conversion
| as disease progresses --- pts become less responsive to L-DOPA because they cant convert it to dopamine as easily
32
Dopamine Agonist or Inhibitor of Dopamine Metabolism?
| Apomorphine
DA receptor agonist
33
Dopamine Agonist or Inhibitor of Dopamine Metabolism?
| Ergoline drug class
Dopamine receptor agonist
34
Dopamine Agonist or Inhibitor of Dopamine Metabolism?
| Bromocriptine
DA receptor agonist (it is an ergoline)
35
Dopamine Agonist or Inhibitor of Dopamine Metabolism?
| Pergolide
DA receptor Agonist (it is an ergoline)
36
What drugs are ergolines
Bromocriptine
Pergolide
Cabergoline
37
Dopamine Agonist or Inhibitor of Dopamine Metabolism?
| Non-Ergoline Drug Class
DA receptor agonist
38
Dopamine Agonist or Inhibitor of Dopamine Metabolism?
| Ropinirole
DA receptor agonist - it is an NON-ergoline
39
Dopamine Agonist or Inhibitor of Dopamine Metabolism?
| Rotigotine
DA receptor agonist - it is an NON-ergoline
40
Dopamine Agonist or Inhibitor of Dopamine Metabolism?
| Pramipexole
DA receptor agonist - it is an NON-ergoline
41
Dopamine Agonist or Inhibitor of Dopamine Metabolism?
| MAO-B inhibitors
inhibit metabolism
42
Dopamine Agonist or Inhibitor of Dopamine Metabolism?
| Selegiline
inhibit metabolism (MAO-B inhibitors)
43
Dopamine Agonist or Inhibitor of Dopamine Metabolism?
| Rasagiline
inhibit metabolism (MAO-B inhibitor)
44
Dopamine Agonist or Inhibitor of Dopamine Metabolism?
| Safinamide
inhibit metabolism (MAO-B inhibitor)
45
what drugs are MAO-B inhibitors
Selegiline
Rasagiline
Safinamide
46
Dopamine Agonist or Inhibitor of Dopamine Metabolism?
| Entacapone
inhibit metabolism (COMT inhibitors)
47
Dopamine Agonist or Inhibitor of Dopamine Metabolism?
| Tolcapone
inhibit metabolism (COMT inhibitors)
48
what drugs are COMT Inhibitors?
Entacapone
| Tolcapone
49
Dopamine Agonist or Inhibitor of Dopamine Metabolism?
| COPT inhibitors
inhibit metabolism
50
Which dopamine agonist(s) is a mixed D1/D2 agonist
Apomorphine
51
"extra" effect of Apomorphine
has potent emetic effect (makes people vomit)
52
which dopamine agonist(s) are D2 agonists
(Ergolines!!)
bromocriptine
and
pergolide
53
which dopamine agonist is no longer used due to heart valve damage
pergolide
54
T or F: Bromocriptine is not very effective on its own and is used as only adjunct
truuuuuuue
55
which drug agonist(s) are D2/D3 agonists
(the Non-ergonlines)
Ropinirole
Pramipexole
Rotigotine
56
Ergolines are ________ agonists
Non-Ergolines are ______ agonists
(D 1,2,3??)
Ergoline: D2
| Non-Ergoline: D2/D3
57
what drugs are propargylamines
Selegiline
and
Rasagiline
58
what is MAO-B's normal mechanism of action?
turns DA --> DOPAL
59
T or F: Entacapone will increase potency of L-DOPA
FALSE!! it increases duration of action NOT potency!!
60
Entacapone and Tolcapone are both COMT inhibitors:
| which one decreases L-DOPA in periphery and which one decreases L-DOPA metabolism in the CNS?
in periphery: Entacapone
in CNS: Tolcapone*
(Tolcapone does work in periphery too....)
61
Pharmacologic Therapy for Parkinsons:
| 1st Line?
Rule out Drug induced PD
Dopamine Agonist
Dopamine Precursor
62
Pharmacologic Therapy for Parkinsons:
| 2nd line?
MAO-B inhibitor
| Amantadine
63
Types of LD Motor Fluctuations
- wearing off
- freezing
- delayed onset
- pear dose dyskinesia
64
definition of peak dose dyskinesia
involuntary body movement cause by high DA levels
65
definition of "freezing"
inability to move due to fluctuating DA levels
66
side effects of levodopa/carbidopa
- N/V
- LD motor fluctuations
- hallucinations
67
what is ICD and examples of it?
ICD: impulse control disorder
| shopping/gambling/inappropriate sexual behaviors
68
benefits of dopamine agonists (compared to LD/CD)?
no motor fluctuations
| long acting formulations
69
ADEs of Dopamine Agonists
- N/V
- Sudden onset sleep
- hallucinations
- ICD (impulse control disorder)
- Edema
70
ADEs of COMT Inhibitors
N/V
Brown/Orange Urine Discoloration
Hepatoxicity
71
ADEs of MAO-B inhibitors
N/V
HA
Insomnia
Hypotnesion/Hypertension
72
ADEs of Anticholinergics
Confusion/Dementia!!
Blurred vision, Urinary Retention, Dry mouth, Constipation
73
```
Alzheimers Neuropathology:
Have ______ plaques
________ tangles
and
_______ loss
```
Amyloid plaques
Neurofibriallary tangles
Synapse loss
74
Alzheimers: AB Peptide
AB peptide is released from _____ by activity of ____ and _____
released from APP (amyloid precursor protein)
by activity of beta-secretase and gamma-secretase
75
Alzheimers:
Amlyoid plaques are found ____cellularly
and
Neurofibrillary tangles are found ____cellularly
Amyloid: EXTRAcellular
neurofibrillary: INTRAcell
76
Alzheimers:
Amlyoid plaques are made up of ______
and
Neurofibrillary tangles are made up of _______
Amyloid: AB peptide (amyloid beta)
Neurofibriallary: Hyperphosphorylated tau
77
There was a debate if AB or tau was the key pathogenic molecule in Alzheimers - which one is it and what evidence is there to support this claim?
AB!
Evidence:
- mutations in APP (the AB precursor) is linked to early onset AD
- Downs Syndrome (Trisomy 21) == extra copy of APP gene and they have AD like symptoms around 40 y.o
- Presenlilin Proteins involved are also linked to AD
78
AB peptide is around how many amino acids long
40 or 42
79
which AB amino acid length tends to make fibrils more than the other? (AB42 or AB40)
AB42 makes fibrils more
80
AB peptide is hydrophobic or hydrophillic
phobic!! therefore tend to aggregates easily
81
Alzheimers:
| what gene affects the components of the y-secretase complex
presenilin-1 or 2
| PSEN1 or PSEN2
82
Alzheimers:
| Mutations in the PSEN1 or PSEN2 gene leads to what?
alters y-secretase complex which causes MORE AB or more AB42
83
Alzheimers:
| AB peptide is released from _____ by the activity of _____ and ______
released FROM APP (amyloid precursor protein)
by b-secretase and y-secretase
84
Alzheimers:
| Cleavage of APP by ________ leads to a non-toxic/non-amyloidogenic fragment being released
a-secretase
85
Alzheimers:
| how is AB aggregation and neurofibrillary tangles thought to be related?
AB peptide oligomers tend to activate kinases - those kinases hyperphosphorylate tau --- and lead to neurofibrillary tangles
86
Alzheimers:
| Why are neurofibrillary tangles problematic?
disruption of cytoskeleton
| disruption of axonal trafficking
87
Alzheimers:
| when tau is not hyperphosphorylated --- what is its normal ufnction
stabilize microtubules
88
Alzheimers:
| what enzyme can degrade AB
Neprilysin
89
Alzheimers:
| when AB aggregation occurs - do microglial cells get activated or down regulated
activated!
| they try to clean up the mess (aka the amyloid clusters)
90
Alzheimers:
| when microglia cells are activated --- how do they respond
they release pro-inflammatory cytokines (causes NEUROINFLAMMATION)
they release reactive oxygen and nitrogen species (causes OXIDATIVE STRESS)
91
Alzheimers:
| Risk is increased when LDL levels are _____ and HDL levels are _____
if LDL is high and HDL is low
92
what two disease states may increase risk for alzhemiers
Vascular disease
and
Diabetes
93
what gene related to cholesterol has an affect AB deposition
ApoE
94
Alzheimers:
| what are the different isoforms of ApoE
ApoE2, ApoE3, ApoE4
95
which ApoE isoform has an increased risk of AD
ApoE4
96
Alzheimers:
| what drugs are cholinesterase inhibitors
Donepezil
Rivastigamine
Galantamine
97
why are cholinesterase inhibitors a beneficial therapy option for Alzheimers?
the inhibitor increases the amount of Ach -- which is good because AD causes a degeneration of cholinergic nerve terminals
98
Alzheimers:
| what drugs are anti-glutamatergic?
Memantine (NMDA antagonist)
99
ADEs of Cholinesterase inhibitors
```
SLUD
(salivation
lacriamation
urination
defication)
```
You become a leaky mess
100
Key Concepts of Dementia Therapy?
Target dose is what is whatever highest dose can be tolerated
Many ADEs- early recognition is better
AVOID Sudden stopping of therapy
Withdrawal of therapy should be considered with progressed symptoms
management of behavioral sxs of dementia poorly responsive to drug (?)
101
Parkinson's - Managing LD Motor Fluctuations
| If medicine is wearing off - what do you do?
- increase CD/LD dose or frequency
- Add DA agonist, MAOI, COMTI
- XR CD/LD
102
Parkinson's - Managing LD Motor Fluctuations
| If patient is freezing - what do you do?
- increase CD/LD dose or frequency
| - Add DA agonist, MAOI, COMTI
103
Parkinson's - Managing LD Motor Fluctuations
| If delayed onset - what do you do?
- take CD/LD on empty stomach
- ODT CD/LD
- Avoid CR/XR or CD/LD
104
Parkinson's - Managing LD Motor Fluctuations
| If peak dose dyskinesias - what do you do?
- Add amantadine
| - decrease CD/LD dose
105
Parkinson's - Treating Non-Motor Symptoms:
| If Anxiety or Depression... how to treat?
AVOID BZDs
CAUTION: TCAs
CBT (cognitive behavioral therapy), SSRIs, and SNRIs are good options
106
Parkinson's - Treating Non-Motor Symptoms:
| If Dementia... how to treat?
Cholinesterase inhibitors!
| AVOID: Anticholinergics, BZDs, antihistamine, and sedatives
107
Parkinson's - Treating Non-Motor Symptoms:
| If psychosis... how to treat?
Reduce PD medication Doses
Pimvanserin
Clozapine/Quetiapine (are options)
AVOID: haloperidol, olanzapine, paliperidone, risperidone
108
Parkinson's - Treating Non-Motor Symptoms:
| if Constipation... how to treat?
increase fluid and fiber intake
stool softeners/laxatives
any meds causing this?
109
Parkinson's - Treating Non-Motor Symptoms:
| If insomnia...how to treat?
AVOID: BZDs
| Can use melatonin, and non-BZD sedatives (zolpidem, ezopiclone,zaleplon, and zopiclone)
110
Parkinson's - Treating Non-Motor Symptoms:
| if orthostatic hypotension...how to treat?
Midodrine
Non-pharm counseling...
medical equipment to stabilize patient
