Parkinson's Flashcards
usual time of diagnosis of parkinson’s
55-65
when patients are symptomatic, they’ve already lost how many dopamine neurons in the brain?
70-80%
dopamine
What is it
Where is it
an inhibitory NT in the extra pyramidal system
what is the excitatory NT in the EPS?
acetylcholine
when dopaminergic activity decreases,
cholinergic activity dominates - resulting in motor disturbances
which area in the EPS is most affected by Parkinson’s?
the dopamine neurons in the substantial nigra (the lewy bodies)
extrapyramidal system responsible for (3)
movement,
dampens erratic motions,
maintains muscle tone and posture.
the dopamine cell bodies are located in ______ and project to _________
the midbrain in the substantial nigra. they project to the dorsal striatum.
dopamine pathways in the brain (3)
nigrostriatal
mesolimbic and mesocortical
tuberoinfundibular
dopamine signaling and cholinergic signaling in a normal brain
there is a balance between them which results in controlled movement
in the Parkinson’s brain
the neurons that supply dopamine to the striatum degenerate leading to unopposed cholinergic signaling. results in disturbed movement.
direct and indirect pathway originate from
distinct populations of gaba neurons in the striatum
direct pathway activation does what?
promotes movement
indirect pathway activation
inhibits movement
dopamine receptor subtypes
d1 and d2
d1 receptors are expressed on
on gaba neurons in the striatum that form the DIRECT pathway
d2 receptors are expressed
expressed exclusively on gaba neurons in the striatum that form the INDIRECT pathway
dopamine receptor agonists used to treat Parkinson’s disease are all
selective D2 receptor agonists
why are dopamine receptor agonists used?
analogous to replacing dopamine on direct pathway, dampening indirect pathway activity.
drug related Parkinsonism may be seen with
antipsychotics
anti emetics
metoclopramide
(all dopamine receptor antagonists)
MPTP
neurotoxin which destroys dopamine nerve terminals
rotenone and paraquat
pesticides which resemble MPTP. used to be commonly used in agriculture and farming.
TRAP signs and symptoms of Parkinson’s disease
motor
T - tremor (“pill rolling”)
R - rigidity
A - akinesia or bradykinesia
P - postural instability and abnormal gait
SOAP signs and symptoms of parkinson’s
non motor
S - sleep disturbance
O - other/misc
A - autonomic (urinary, sweating)
P - psychologic
new parkinson’s drug for parkinson’s psychosis. controversial because it hasn’t been properly vetted and patients have noted worsening symptoms.
Pimavanzserin
therapeutic goals of pharmacotherapy for parkinson’s
improve ability to carry out ADLs and to improve the non motor symptoms associated with the disease
classes of Parkinson’s disease treatments (5)
inhibitors of MAO B dopamine receptor agonists amantadine anticholinergics dopamine augmentation/precursor (levidopa)
drugs that are used to enhance levidopa (2)
inhibitor of dopa decarboxylase (carbidopa)
inhibitor of COMT (metabolizes levodopa)
major goal of therapy
increase dopamine activity in the brain
gold standard for parkinson’s
levodopa/carbodopa
levopdopa is
the precursor to dopamine in the brain
MAO B inhibitors do what
stop dopamine breakdown
specific symptoms of parkinson’s can mainly be treated with
anti cholinergics
mild symptoms of Parkinson’s can be treated with what drug class?
MAO-B inhibitors
2 examples of MAO-B inhibitors
selegiline
rasagiline
for more severe Parkinson’s symptoms, what medication combos may be used? (2)
levodopa and carbidopa
levodopa and dopamine receptor agonist
which is a stronger drug, levodopa or carbidopa?
levodopa
levodopa compared to dopamine recept agonists
levodopa is more effective but long term use carries a higher risk for dyskinesias
what medication should be tried first in mod-severe parkinson’s
dopamine receptor agonists for as long as possible before changing to levodopa
why is it recommended to wait as long as possible before starting levodopa?
long term use carries higher risk for dyskinesias
once the dopamine receptor agonists are no longer effective for symptom management, what med should be introduced?
levodopa.
“off” time defined
periods of the day when levodopa is not working well, causing a worsening of symptoms/bradykinesia/akinesia
“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.
“on” times
periods off sufficient control of symptoms with levodopa
as Parkinson’s disease progresses, what happens with “off” times
they become longer and longer
MAO-B inhibitor stands for
monoamine oxidase B inhibitor
COMT inhibitor stands for
catechol-O-methyltransferase inhibitors
if symptoms are severe and unrelieved with medications, what may need to be considered
surgery like DBS
what is MAO-B’s role in the brain?
metabolism/inactivation of dopamine
what is the MoA of MAO-B inhibitors?
inhibit MAO-B, thus increasing dopamine levels in the striatum.
How are MAO-Bs like rasagiline or seligiline used? (2)
alone for milder Parkinson’s
or
in combo with levodopa to reduce off times
downside of MAO-B inhibitors
efficacy declines within 12-24 months
side effect unique to selegiline
insomnia due to its metabolites
active metabolites of selegiline which cause insomnia in patients
amphetamine
d-amphetamine
patient education for selegiline
take med before noon bc of insomnia risk
anti muscarinic/anti cholinergic drugs for parkinson’s
for mild symptoms in younger patients
indications for anticholinergics in parkinson’s
mild disease
younger patients (<60)
decrease tremor
which anticholinergics may you see in parkinson’s? (2)
benztropine
trihexyphenidyl
anticholinergics vs dopamine agonists
less effective but better tolerated in younger patients
use of amantadine as mono therapy in parkinson’s
tremor if mild
amantadine can also be used in combo with
levodopa/carbidopa
amantadine may be used as an alternative to
anticholinergics in older patients with mild symptoms
dosing of amantadine
dose adjust for renal sufficiency
efficacy of amantadine
diminished after a few months, requiring drug holiday
drug holiday for amantadine
efficacy can be restored after 1-2 week drug holiday and reintroduction.
first line drugs for parkinson’s
dopamine agonists
dopamine agonist MoA
directly activate D2 receptors in the brain
which is more efficacious, D2 agonist or levodopa?
levodopa
levodopa is the precursor to
dopamine
levodopa to dopamine
levodopa is converted to dopamine in the dopamine terminals via enzymatic conversion
in order for levodopa to work, you need to have
dopamine terminals in the striatum
loss of dopamine terminals in parkinson’s means what for levodopa?
it becomes less effective
unlike levodopa, dopamine agonists
do not rely on enzymatic conversion to be active
levodopa and dietary proteins
dietary proteins compete with levodopa for active transporters to cross the BBB
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.
dopamine agonists have a ____ incidence of response failure as compared to levodopa
lower
which drug is less likely to cause dyskinesias, dopamine agonist or levodopa?
dopamine agonist
two types of dopamine receptor agonists
derivatives of ergot
non-ergot derivatives
adverse effect unique to pramipexole and not other D2 agonists
sleep attacks
why do d2 agonists cause impulse control disorders?
because dopamine signaling is increased in the frontal cortex. you lose inhibitory control over impulsive behaviors.
d2 agonists and MAO b inhibitors may be
neuro protective when started early
Ropinirole mono therapy
for mild symptoms
ropinirole for more advanced symptomatology will be
given with levodopa/carbidopa
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
pramipexole elimination
entirely by kidneys
ropinirole elimination
hepatic metabolism
what may be a determining factor between pramipexole and ropinirol?
renal and liver function
when is rotigotine appropriate?
in early stage disease
rotigotine route and rationale
transdermal patch
PO goes through significant first pass effect
how often is rotigotine patch changed
q24 hours
how often can rotigotine be titrated?
weekly
adverse effects of rotigotine?
and which is more prominent of rotigotine among the d2 agonists?
sleep disorders dizziness headache hallucinations dyskinesia nausea/vomiting*
route of apomorphine
SC injection
drug interactions of apomorphine: ondansetron
severe hypotension
drug interactions of apomorphine: anti htn
cancels the anti htn effect
ekg abnormalities with apomorphine
causes tachycardia and cardiac dysrhythmias. be careful when given with drugs which prolong QTC
severe adverse effect of apomorphine and intervention
severe nausea.
start anti emetic 3 days prior, but not a 5HT3 antagonist like ondansetron
apomorphine sexual side effects
enhanced erections and arousal/promiscuity
cornerstone of PD treatment since the 1960s
levodopa
if a patient with parkinson’s is given levodopa and does not respond
they do not have Parkinson’s disease
pt education for levodopa regarding clinical effect
- full therapeutic response will not be seen for several months
- beneficial effects will diminish over time
levodopa therapeutic window
narrows over time as disease progresses
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
most troubling adverse effect of levodopa
drug induced dyskinesias
all patients with PD, at some point, will require
levodopa
levodopa is always combined with
carbidopa
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
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
drug used for prolonging levodopa’s half life
entacapone
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.
entacapone is
a COMT inhibitor
MoA levodopa
reduces symptoms by increasing dopamine synthesis in the striatum
how does levodopa enter the brain
via an active transport system across the BBB
once levodopa is in the brain
it enters dopamine nerve terminals in the striatum, where it will be synthesized into dopamine
levodopa has no direct effects on its own, instead
it is converted to dopamine, its active form.
levodopa helps to restore a proper balance between
dopamine and acetylcholine.
active transporter for levodopa
L-amino acid transporter
L-amino acid performs active transport for levodopa across the ____ and ____
GI mucosa
BBB
what competes with levodopa for the L-amino acid transporter?
dietary protein
when to take levodopa
1-2 hours before a meal
why can’t we just give patients dopamine?
- half life is too short
- can cause cardiac dysrhythmias
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
carbidopa on its own
has no therapeutic effect
does carbidopa cross the BBB?
No.
carbidopa allows you to give ____ the dose of levodopa if it were given alone
1/5th
why is carbidopa so important?
it allows you to use the lowest dose possible for as long as possible, delaying the development of dyskinesias.
adverse effects of levodopa/carbidopa
N/V dyskinesias dystonia postural hypotension psychosis hallucination vivid dreams insomnia somnolence
trade off with levodopa/carbidopa
tremor may actually worsen but bradykinesia and rigidity will respond.
effectiveness of levodopa/carbidopa over time
will decrease. dose will need to be increased.
levodopa/carbidopa is contraindicated with what condition
narrow angle glaucoma
what drugs do levodopa/carbidopa interact with?
anticholinergics
MAO-A inhibitors
levodopa/carbidopa interact with anticholinergics because
anticholinergics delay gastric emptying, decreasing the absorption of levodopa/carbidopa
levodopa/carbidopa and MAO-A inhibitors
HTN crisis
inhaled levodopa
rescue med during off episodes
new development
onset of action of inhaled levodopa
~10 min
adverse effects of inhaled levodopa
cough
URI
nausea
discolored saliva
MAOIs and inhaled levodopa
MAOIs need to be stopped ~2 weeks prior
COMT inhibitors MoA
selective and reversible inhibitors of catechol-O-methyl transferase
catechol I methyl transferase is an
enzyme capable of metabolizing peripheral levodopa
COMT inhibitors and levodopa
prolong half life and duration of action of levodopa by decreasing peripheral levodopa metabolism.
when catechol-O-methyl transferase (COMT) metabolizes levodopa, its metabolite can
compete with levodopa for the active transporter
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
COMT inhibitors, like entacapone, combined with levodopa
increases the duration of the on phase as well as reduces the wearing off phenomenon.
example of COMT inhibitor
entacapone
entacapone is used
to reduce the wearing off phenomenon of levodopa
adverse effects of entacapone
dyskinesias nausea diarrhea hallucination orthostatic hypotension urine discoloration
