Parkinson's Flashcards
1
Q
usual time of diagnosis of parkinson’s
A
55-65
2
Q
when patients are symptomatic, they’ve already lost how many dopamine neurons in the brain?
A
70-80%
3
Q
dopamine
What is it
Where is it
A
an inhibitory NT in the extra pyramidal system
4
Q
what is the excitatory NT in the EPS?
A
acetylcholine
5
Q
when dopaminergic activity decreases,
A
cholinergic activity dominates - resulting in motor disturbances
6
Q
which area in the EPS is most affected by Parkinson’s?
A
the dopamine neurons in the substantial nigra (the lewy bodies)
7
Q
extrapyramidal system responsible for (3)
A
movement,
dampens erratic motions,
maintains muscle tone and posture.
8
Q
the dopamine cell bodies are located in ______ and project to _________
A
the midbrain in the substantial nigra. they project to the dorsal striatum.
9
Q
dopamine pathways in the brain (3)
A
nigrostriatal
mesolimbic and mesocortical
tuberoinfundibular
10
Q
dopamine signaling and cholinergic signaling in a normal brain
A
there is a balance between them which results in controlled movement
11
Q
in the Parkinson’s brain
A
the neurons that supply dopamine to the striatum degenerate leading to unopposed cholinergic signaling. results in disturbed movement.
12
Q
direct and indirect pathway originate from
A
distinct populations of gaba neurons in the striatum
13
Q
direct pathway activation does what?
A
promotes movement
14
Q
indirect pathway activation
A
inhibits movement
15
Q
dopamine receptor subtypes
A
d1 and d2
16
Q
d1 receptors are expressed on
A
on gaba neurons in the striatum that form the DIRECT pathway
17
Q
d2 receptors are expressed
A
expressed exclusively on gaba neurons in the striatum that form the INDIRECT pathway
18
Q
dopamine receptor agonists used to treat Parkinson’s disease are all
A
selective D2 receptor agonists
19
Q
why are dopamine receptor agonists used?
A
analogous to replacing dopamine on direct pathway, dampening indirect pathway activity.
20
Q
drug related Parkinsonism may be seen with
A
antipsychotics
anti emetics
metoclopramide
(all dopamine receptor antagonists)
21
Q
MPTP
A
neurotoxin which destroys dopamine nerve terminals
22
Q
rotenone and paraquat
A
pesticides which resemble MPTP. used to be commonly used in agriculture and farming.
23
Q
TRAP signs and symptoms of Parkinson’s disease
motor
A
T - tremor (“pill rolling”)
R - rigidity
A - akinesia or bradykinesia
P - postural instability and abnormal gait
24
Q
SOAP signs and symptoms of parkinson’s
non motor
A
S - sleep disturbance
O - other/misc
A - autonomic (urinary, sweating)
P - psychologic
25
new parkinson's drug for parkinson's psychosis. controversial because it hasn't been properly vetted and patients have noted worsening symptoms.
Pimavanzserin
26
therapeutic goals of pharmacotherapy for parkinson's
improve ability to carry out ADLs and to improve the non motor symptoms associated with the disease
27
classes of Parkinson's disease treatments (5)
```
inhibitors of MAO B
dopamine receptor agonists
amantadine
anticholinergics
dopamine augmentation/precursor (levidopa)
```
28
drugs that are used to enhance levidopa (2)
inhibitor of dopa decarboxylase (carbidopa)
| inhibitor of COMT (metabolizes levodopa)
29
major goal of therapy
increase dopamine activity in the brain
30
gold standard for parkinson's
levodopa/carbodopa
31
levopdopa is
the precursor to dopamine in the brain
32
MAO B inhibitors do what
stop dopamine breakdown
33
specific symptoms of parkinson's can mainly be treated with
anti cholinergics
34
mild symptoms of Parkinson's can be treated with what drug class?
MAO-B inhibitors
35
2 examples of MAO-B inhibitors
selegiline
| rasagiline
36
for more severe Parkinson's symptoms, what medication combos may be used? (2)
levodopa and carbidopa
| levodopa and dopamine receptor agonist
37
which is a stronger drug, levodopa or carbidopa?
levodopa
38
levodopa compared to dopamine recept agonists
levodopa is more effective but long term use carries a higher risk for dyskinesias
39
what medication should be tried first in mod-severe parkinson's
dopamine receptor agonists for as long as possible before changing to levodopa
40
why is it recommended to wait as long as possible before starting levodopa?
long term use carries higher risk for dyskinesias
41
once the dopamine receptor agonists are no longer effective for symptom management, what med should be introduced?
levodopa.
42
"off" time defined
periods of the day when levodopa is not working well, causing a worsening of symptoms/bradykinesia/akinesia
43
"off" time
| explained
unexplainable. it is not related to falling concentrations of the drug. it is a phenomenon where for certain parts of the day, the drug is not effective.
44
"on" times
periods off sufficient control of symptoms with levodopa
45
as Parkinson's disease progresses, what happens with "off" times
they become longer and longer
46
MAO-B inhibitor stands for
monoamine oxidase B inhibitor
47
COMT inhibitor stands for
catechol-O-methyltransferase inhibitors
48
if symptoms are severe and unrelieved with medications, what may need to be considered
surgery like DBS
49
what is MAO-B's role in the brain?
metabolism/inactivation of dopamine
50
what is the MoA of MAO-B inhibitors?
inhibit MAO-B, thus increasing dopamine levels in the striatum.
51
How are MAO-Bs like rasagiline or seligiline used? (2)
alone for milder Parkinson's
or
in combo with levodopa to reduce off times
52
downside of MAO-B inhibitors
efficacy declines within 12-24 months
53
side effect unique to selegiline
insomnia due to its metabolites
54
active metabolites of selegiline which cause insomnia in patients
amphetamine
| d-amphetamine
55
patient education for selegiline
take med before noon bc of insomnia risk
56
anti muscarinic/anti cholinergic drugs for parkinson's
for mild symptoms in younger patients
57
indications for anticholinergics in parkinson's
mild disease
younger patients (<60)
decrease tremor
58
which anticholinergics may you see in parkinson's? (2)
benztropine
| trihexyphenidyl
59
anticholinergics vs dopamine agonists
less effective but better tolerated in younger patients
60
use of amantadine as mono therapy in parkinson's
tremor if mild
61
amantadine can also be used in combo with
levodopa/carbidopa
62
amantadine may be used as an alternative to
anticholinergics in older patients with mild symptoms
63
dosing of amantadine
dose adjust for renal sufficiency
64
efficacy of amantadine
diminished after a few months, requiring drug holiday
65
drug holiday for amantadine
efficacy can be restored after 1-2 week drug holiday and reintroduction.
66
first line drugs for parkinson's
dopamine agonists
67
dopamine agonist MoA
directly activate D2 receptors in the brain
68
which is more efficacious, D2 agonist or levodopa?
levodopa
69
levodopa is the precursor to
dopamine
70
levodopa to dopamine
levodopa is converted to dopamine in the dopamine terminals via enzymatic conversion
71
in order for levodopa to work, you need to have
dopamine terminals in the striatum
72
loss of dopamine terminals in parkinson's means what for levodopa?
it becomes less effective
73
unlike levodopa, dopamine agonists
do not rely on enzymatic conversion to be active
74
levodopa and dietary proteins
dietary proteins compete with levodopa for active transporters to cross the BBB
75
if you eat a protein rich meal and take levodopa at the same time,
reduced of absorption of levodopa through GI lumen and decreased availability of transporter to pump levodopa to brain.
76
dopamine agonists have a ____ incidence of response failure as compared to levodopa
lower
77
which drug is less likely to cause dyskinesias, dopamine agonist or levodopa?
dopamine agonist
78
two types of dopamine receptor agonists
derivatives of ergot
| non-ergot derivatives
79
adverse effect unique to pramipexole and not other D2 agonists
sleep attacks
80
why do d2 agonists cause impulse control disorders?
because dopamine signaling is increased in the frontal cortex. you lose inhibitory control over impulsive behaviors.
81
d2 agonists and MAO b inhibitors may be
neuro protective when started early
82
Ropinirole mono therapy
for mild symptoms
83
ropinirole for more advanced symptomatology will be
given with levodopa/carbidopa
84
for a more active patient who may still be working, which med would be better between pramipexole and ropinirole?
ropinirole because there is less risk for sleep effects
85
pramipexole elimination
entirely by kidneys
86
ropinirole elimination
hepatic metabolism
87
what may be a determining factor between pramipexole and ropinirol?
renal and liver function
88
when is rotigotine appropriate?
in early stage disease
89
rotigotine route and rationale
transdermal patch
| PO goes through significant first pass effect
90
how often is rotigotine patch changed
q24 hours
91
how often can rotigotine be titrated?
weekly
92
adverse effects of rotigotine?
| and which is more prominent of rotigotine among the d2 agonists?
```
sleep disorders
dizziness
headache
hallucinations
dyskinesia
nausea/vomiting*
```
93
route of apomorphine
SC injection
94
drug interactions of apomorphine: ondansetron
severe hypotension
95
drug interactions of apomorphine: anti htn
cancels the anti htn effect
96
ekg abnormalities with apomorphine
causes tachycardia and cardiac dysrhythmias. be careful when given with drugs which prolong QTC
97
severe adverse effect of apomorphine and intervention
severe nausea.
| start anti emetic 3 days prior, but not a 5HT3 antagonist like ondansetron
98
apomorphine sexual side effects
enhanced erections and arousal/promiscuity
99
cornerstone of PD treatment since the 1960s
levodopa
100
if a patient with parkinson's is given levodopa and does not respond
they do not have Parkinson's disease
101
pt education for levodopa regarding clinical effect
- full therapeutic response will not be seen for several months
- beneficial effects will diminish over time
102
levodopa therapeutic window
narrows over time as disease progresses
103
how long is levodopa typically beneficial for? and then what?
2-5 years
| pre treatment state may return in 5-8 years from initiation of treatment
104
most troubling adverse effect of levodopa
drug induced dyskinesias
105
all patients with PD, at some point, will require
levodopa
106
levodopa is always combined with
carbidopa
107
acute loss of effect of levodopa
drug wears off near the end of the dosing interval, indicating the drug level has declined to subtherapeutic level
108
how to minimize wearing off of levodopa
- shorten the dose interval
- give a drug that prolongs levodopa's half life
- give direct acting dopamine agonist
109
drug used for prolonging levodopa's half life
entacapone
110
wearing off vs off time
wearing off occurs when levodopa's therapeutic levels have fallen to subtherapeutic, for instance at the end of the dosing interval.
off times are an unexplainable phenomenon where levodopa stops working for a few minutes to up to 2 hours. this is not related to plasma levels.
111
entacapone is
a COMT inhibitor
112
MoA levodopa
reduces symptoms by increasing dopamine synthesis in the striatum
113
how does levodopa enter the brain
via an active transport system across the BBB
114
once levodopa is in the brain
it enters dopamine nerve terminals in the striatum, where it will be synthesized into dopamine
115
levodopa has no direct effects on its own, instead
it is converted to dopamine, its active form.
116
levodopa helps to restore a proper balance between
dopamine and acetylcholine.
117
active transporter for levodopa
L-amino acid transporter
118
L-amino acid performs active transport for levodopa across the ____ and ____
GI mucosa
| BBB
119
what competes with levodopa for the L-amino acid transporter?
dietary protein
120
when to take levodopa
1-2 hours before a meal
121
why can't we just give patients dopamine?
- half life is too short
| - can cause cardiac dysrhythmias
122
why are levodopa and carbidopa always given together
carbidopa enhances the half life and bioavailability of levidopa by binding to and inhibiting dopa-d-carboxylase in the peripheral tissues, the enzyme that metabolizes levidopa
123
carbidopa on its own
has no therapeutic effect
124
does carbidopa cross the BBB?
No.
125
carbidopa allows you to give ____ the dose of levodopa if it were given alone
1/5th
126
why is carbidopa so important?
it allows you to use the lowest dose possible for as long as possible, delaying the development of dyskinesias.
127
adverse effects of levodopa/carbidopa
```
N/V
dyskinesias
dystonia
postural hypotension
psychosis
hallucination
vivid dreams
insomnia
somnolence
```
128
trade off with levodopa/carbidopa
tremor may actually worsen but bradykinesia and rigidity will respond.
129
effectiveness of levodopa/carbidopa over time
will decrease. dose will need to be increased.
130
levodopa/carbidopa is contraindicated with what condition
narrow angle glaucoma
131
what drugs do levodopa/carbidopa interact with?
anticholinergics
| MAO-A inhibitors
132
levodopa/carbidopa interact with anticholinergics because
anticholinergics delay gastric emptying, decreasing the absorption of levodopa/carbidopa
133
levodopa/carbidopa and MAO-A inhibitors
HTN crisis
134
inhaled levodopa
rescue med during off episodes
| new development
135
onset of action of inhaled levodopa
~10 min
136
adverse effects of inhaled levodopa
cough
URI
nausea
discolored saliva
137
MAOIs and inhaled levodopa
MAOIs need to be stopped ~2 weeks prior
138
COMT inhibitors MoA
selective and reversible inhibitors of catechol-O-methyl transferase
139
catechol I methyl transferase is an
enzyme capable of metabolizing peripheral levodopa
140
COMT inhibitors and levodopa
prolong half life and duration of action of levodopa by decreasing peripheral levodopa metabolism.
141
when catechol-O-methyl transferase (COMT) metabolizes levodopa, its metabolite can
compete with levodopa for the active transporter
142
inhibiting COMT not only prolongs half life and duration of action of levodopa, but it also
reduces competition for the active transporter, getting levodopa into the brain faster
143
COMT inhibitors, like entacapone, combined with levodopa
increases the duration of the on phase as well as reduces the wearing off phenomenon.
144
example of COMT inhibitor
entacapone
145
entacapone is used
to reduce the wearing off phenomenon of levodopa
146
adverse effects of entacapone
```
dyskinesias
nausea
diarrhea
hallucination
orthostatic hypotension
urine discoloration
```
