parkinson Flashcards
what are 5 movement disorders
tremor chorea athetosis dystonia tics
what is tremor
rhythmic oscillation around a joint
what is postural tremor
tremor while trying tp maintain posture
when is tremor associated with parkinsons (2 things)
rigidity and impairment of voluntery movement
what is intentional tremor
when you have a tremor when you want to move
which tremor is associated with essential (familial tremor)
postural tremor
what can intentional tremors be associated with (3 things)
lesions of brainstem (cerebellum), alcohol, drug toxicity
what does chorea mean (1 word)
dance
what types of movement characterize chorea
irregular, unpredictable movements
what does chorea do to voluntary activity
impair
which muscles are most affected by chorea
proximal muscles
what are some of the movements called in chorea and why
ballistic movements - more violent because they arise from proximal movements (like move whole arm instead of just hand)
is chorea hereditary
sometimes
what can cause chorea (3)
hereditary
general medical disorders
drug therapies
what is athetosis
slow writing movements (like twisting squirming controtions)
what is dystonia
sustained movement with abnormal posture
what causes athetosis (3)
perinatal (right before and after birth) damage, CNS lesions, drug treatments
what causes dystonia (3)
perinatal damage (right before and after birth), CNS lesions, drug treatments
what are Tics
sudden coordinated abnormal movements
what is tourettes syndrome
multiple chronic tics
what kind of drugs can induce parkinsons-like syndroms (2)
dopamine antagosnists or drugs that destroy DA releasing neurons
where do the Dopaminergic cells come from
substantia nigra compcta
where do the DA releasing cells project to (which neurons and where)
GABAergic cells in the striatum
what does DA do to GABAergic cells in striatum
inhibit
what does ACh do to GABAergic cells in striatum
excite
what causes parkinsons disease (which neurons are effected, what does this cause)
loss of DA releasing cells, less inhibition on GABA cells, so excess GABA release
what disease is characterized by a loss of nigral DA cells
parkinsons
what causes huntingtons disease (which neurons are effected, what does this cause)
Loss of cholinergic input, GABA cells die off, less GABA inhibition (so you get violent movements)
what disease is characterized by a loss of cholinergic input onto GABA cells in striatum
huntingtons
what disease is characterized by a loss GABA cells in striatum
huntingtons
what is another name for parkinsonism
paralysis agitans
what 4 things characterize parkinsons
- rigidity
- bradykinesia (slow movement)
- tremor
- postural instability
what usually causes parkinsons
unknown (idiopathic)
what may cause early onset parkinsons
genetics
is parkinsons progressive
yes
what is the frequency of the resting tremor
4-6Hz
what is the word for movements when the hands arent extended
“pill rolling”
what is the parkinsons gait +where flexion (3 places)
stooped posture, flexion at knees, hips and neck
what kind of steps do people with parkinsons take+ what is it like when they turn
small shuffling steps, emphasized when turning
is it difficult to initiate or change movements with parkinsons
yes
can you cure parkinsons
no
can you stop parkinsons progression
no
what % of neuron loss do you start getting parkinsons symptoms
80%
what is the primary therapy for Parkinson’s
enhance DA levels in striatum
what are 2 ways to enhance DA levels in the striatum (which drugs/ kind of drugs)
levodopa and dopamine agonists
what is secondary therapy for Parkinson’s
enhance DOPA entry into and persistance in brain
which drug helps enhance DOPA entry into brain + persistence in brain
carbidopa
what G protein for D1
Gs
what G protein for D2
Gi
what does D1 do to adenylyl cyclase
induce
where are D1 neurons located (2)
- on DA neurons in nigra
- presynaptic terminals of cortical projections to striatum (glu receptive neurons)
what do D2 to adenylyl cyclaes activity
inhibit
where are D2 neurons located
- postsynaptic on striatal GABA cells
- presynaptic on basal ganglia inputs to nigra
which effects of dopamine (agonism/anta) on which receptors can induce Parkinson’s symptoms (D1 D2)
D2 antagonists of dopamine
which DA receptor action of dopamine are antiparkinsonian
D2
do you need D1 or D2 action to do antiparkinsons therapy
mostly D2 but some D1 is needed
does dopamine pass the BBB
no
why are D2 actions of dopamine antiParkinson’s
because D2 activation on striatal GABA cells inhibits extra GABA release (less GABA release so less of the Parkinson’s stiffness)
why does D2 antagonism induce Parkinson’s like symptoms
because D2 agonism helps reduce GABA release. D2 antagonism is similar to the death fo DA releasing neurons
what is Levodopa’s relation to DA
it is a metabolic precursor to DA synthesis (AMD bypasses the rate-limiting synthesis step)
what step of DA synthesis does levodopa bypass
the rate-limiting step
does levodopa penetrate the BBB (how much)
yes at 1-10%
where is levodopa transformed into DA
in the brain and periphery
why is levodopa allowed to enter the brain
because it looks like an amino acid
where is levodopa absorbed
in the small intestine
how easily is levadopa absorbed
fast and easy
why dont you want to take levodopa with food
because the amino acids from food with compete with levodopa with transporter
how does levodopa get absorbed into the blood
absorbed in the small intestine via amino acid transporters
when do plasma concentrations of levodopa peak in the blood (how long, time)
1-2 hours
what is the plasma 1/2 life of levodopa
1-3 hours (considerable variability)
what are the metabolites of levodopa (2)
- homovanillic acid HVA
- DOPAC (dihydroxyphenylacetic acid)
what % of unmetabolized levodopa enters the brain
1-3%
what is the therapeutic goal of levodopa use
increase levodopa into the CNS
what kind of drug is coadministered with levodopa
periphreal DOPA decarboxylase inhibitor
why would you want to administer a periphreal DOPA decarboxylase inhibitor with levodopa
to help prevent its breakdown outside the brain so more can come in
what is Carbidopa’s relation to the dopamine pathway
it is structurally similar to DOPA
what is the mechanism of action of carbidopa
inhibits DOPA-decarboxylase
what are the intermediates between tyrosine and dopamine
just DOPA (L-DOPA)
what turns L-DOPA into dopamine
dopa decarboxylase
how is carbidopa given in treatment
ratio of 1:10 or 1:4 with levodopa
what does carbidopa permit with levodopa
up to 10% of levodopa to enter the brain (increases levodopa entering into brain)
what is sinemet
carbidopa + levodopa
what is the ratio of carbidopa and levodopa in sinemet
initial treatment and final
25 carbidopa:100 levodopa
increases to
25 carbidopa:250 levodopa
(efficacity of levodopa decreases with treatment)
how does the effect of levodopa change with treatment
it decreases inefficacy
what drugs do you often add to sinemet in advanced stages
add dopaminergics
what are some gastrointestinal effects of levodopa (3)
nausea vomit weight loss
what causes vomiting with levodopa
DA action at the vomiting center
where is the vomiting centre
in CNS but outside BBB
why is there more vomiting centre activation with levodopa
because levodopa increases DA which activates the vomiting center
what are 3 ways to help prevent the GI issues of levodopa
- smaller more frequent doses
- using carbidopa too
- antacids
do antiemetic phenothiazines help with GI issues with levodopa
no
what are cardiovascular effects of levodopa
tachycardia, arrhythmia, postural hypotension
what causes the adverse cardio effects of levodopa
increase catecholamine formation in periphery
what can help counteract the cardio effects of levodopa and how
carbidopa because it reduces the circulating dopamine
what % of people get dyskinesias with levodopa
80%
why does dyskinesia vary with levodopa use
because its dose-related with individual responses
what can help the dyskinesias with levodopa
- improvement with levodopa alone
- drug holidays
- surgery (reduce doses of levodopa needed)
what are the adverse behavioural effects of levodopa (6)
depression, anxiety, agitation, confusion, delusions, mood changes
are there more of lessBEHAVIOURAL effects with just levodopa or levodopa and a DDC inhibitor (carbidopa)
worse with both drugs than just levodopa
what are some drugs that can help with the behavioural effects of levodopa
some antipsychotics
what 2 things cause/effect the fluctuation of response of levodopa
- increasing frequency with treatment
- some related to timing of doses (wearing-off, end-of dose akinesa)
what is the on-off phenomenon
periods of akinesia alternate with mobility and dyskenesia (sudden, sometimes unpredictable changes in a PD patient’s symptoms, varying between mobility (usually with dyskinesia) and immobility)
what is the mechanism of the on-off phenomenon
its unknown
what are 2 ways to help reduce on-off phenomenon
reduce protein intake (DA is a tyrosine derivative)
controlled release sinemet or COMT inhibitors
is on-off phenomenon related to dose timing
no
what are drug holidays and the point of them
taking breaks to help reduce adverse effects
are drug holidays good for on-off phenomenon
it can help for some people
what happens with abrupt cessation of levodopa
severe akinesia
what happens if you do drug holiday then start again with a low dose
there will be fewer averse effects than before
how long do the benefits of drug holidays last
not long
what 3 benefits of using DA agonists
- they dont have potentially toxic metabolites
- they do not compete with other substances for transporters
- they are receptor selective
how do you use dopamine agonists in treatment
with adjuct to levodopa/carbidopa, or to gradually replace to levodopa
what are 2 examples of dopamine agonists
bromocriptine and pergolide
which receptor does bromocriptine bind
agonist at D2
which receptor does pergolide bind
mixed D1 and D2 agonist
is pergolide or bromocriptine better
pergolide
what do bromocriptine and pergolide do to the required dose of levodopa
lower
what are the adverse effects of bromocriptine and pergolide
similar to levodopa but less sever (but mental symptoms are worse)
which dopamine agonists are the ergot derivatives
bromocriptine and pergolide (older ones)
which dopamine agonists are the older drugs
bromocriptine and pergolide
which dopamine agonists are the newer drugs
pramipexole and ropinirole
why are bromocriptine and pergolide able to stick around longer
because they are not shaped like a.a. unlike levodopa
how are pramipexole and ropinirole used in parkinsons therapy
they can be prescribed alone
how are bromocriptine and pergolide used in therapy
often given with levodopa
which DA receptors does pramipexole bind
D3 (D2 class) agonist
which DA receptors does ropinirole bind
pure D2 agonist
what are the adverse effects like for pramipexole and ropinirole
similar to levodopa
what are 2 benefits of using pramipexole
effective in advances parkinsons
possible neuroprotective effect
what does MAO B metabolize
dopamine
what is selegiline do
blocks MAO B
when is selegiline used in treatment and how
with levodopa when its effects start declining
what are some contraindications for selegiline
patients that use TCAs or SSRIs
what does COMT do
metabolizes levodopa
what happens to COMT levels with more DDC inhibition
increase levels
which drug may also have antioxidant antiapoptotic effects in animals
selegiline (dont worry if dont know)
what are 2 examples of COMT inhibitors
tolcapone and entacapone
where does tolcapone act
centrally and peripheral (hepatotoxic)
where does entacapone act
only peripherally
what are some side effects of tolcapone and entacapone +1 really bad one
similar to levodopa, diarrhea, orange urine, orthostatic hypotension
tolcapone is hepatotoxic
which of tolcapone and entacapone is hepatotoxic
tolcapone
how does tolcapone and entacapone reduce the amount of levodopa needed
(COMT inhibitors)
increases its half life
increases levels of 3OMD which competes for transporters taking levodopa into blood (?idk)
what is amantadine
antiviral
how does amantadine work
blocks NMDA receptor on cholinergic neurons, may increase release brain dopamine
what are some bad things about using amantadine in parkinsons
it has lots of adverse effects
when are using anticholinergics the best for parkinsons
when the tremor is the main symptoms
when are using anticholinergics not great for parkinsons
if its rigidity or bradykineasia
why can anticholinergics be good for parkinsons
because a lack of DA release means overbalance of cholinergic excitation in the basal ganglia
