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When does Parkinson's usually set in?
45-70 years of age
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What are the causes of Parkinson's?
- genetic link
- toxins, oxidative stress
- environmental factors (pesticides, rural living, well water)
- medications (antipshychotics, antiemetics)
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What behaviors have an inverse relationship to PD?
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Why doesn't glutathione protect against Parkinson's?
We don't produce enough of it
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What are the effects of PD on the cortex?
decreased direct pathway stimulation = decreased facilitation of movement
increased indirect pathway stimulation = increased inhibition of movement
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When symptoms occur how much damage is already done to the DA neurons?
70-80% loss of neurons
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2 of what symptoms present in a patient are probable for Parkinson's diagnosis?
- bradykinesia
- resting tremor (usually unilateral)
- rigidity
- postural imbalance
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What are the motor symptoms of PD?
- fenestrating gait
- dysphagia
- difficulty rising from sitting
- hypophonia
- diminished arm swing
- hypomimia
- micrographia
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What are the autonomic and sensory symptoms of PD?
- sialorrhea
- sexual dysfunction
- constipation
- incontinence
- diaphoresis
- olfactory disturbances
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What are the mental status changes of PD?
- anxiety
- apathy
- slow thought process
- depression
- confusion
- hallucinations
- dementia
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What is not always present at PD diagnosis?
tremor
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What is often found on an autopsy of a person with PD?
Lewy bodies
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What are the comorbidities of PD?
- dementia ~ 40%
- psychosis ~ 25%
- mild psychotic symptoms ~ 50%
- depression ~ 40%
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What are the goals of PD therapy?
- improve QOL
- minimize/improve symptoms
- minimize side effects of medication
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What are the nonpharmacological treatments for PD?
- exercise (tango is best)
- deep brain stimulation (implanted stimulator)
- implantation of DA secreting tissue in the brain
- glial-derived neurotrophic factor (GDNF)
- occupational therapy
- speech therapy
- support
- diet
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What causes PD?
decreased DA
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How do we treat PD?
- Replace DA
- L-Dopa
- Mimic DA (stimulate the receptors)
- pramipexole
- ropinirole
- bromocriptine
- apomorphine
- pergolide
- Stop the breakdown of DA
- selegiline (MAO-B in brain)
- rasagiline (MAO-B in brain)
- tolcapone (COMT in brain and periphery)
- entacapone (stops breakdown of L-Dopa by COMT in periphery)
- carbidopa (stops breakdown of L-Dopa by Dopa Decarboxylase in periphery)
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What causes depletion of DA?
free radicals
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What factors increase risk of motor disturbances in PD?
- age
- duration of disease
- dose of medication
- severity of disease
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What drug is used in PD as a precursor to DA that can cross the BBB?
levodopa (L-Dopa)
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What is used to increase the amount of L-Dopa that crosses the BBB?
Carbidopa - inhibits the breakdown of L-Dopa in the periphery by Dopa Decarboxylase
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What is the half-life of L-Dopa?
1-3 hrs (duration may exceed half-life during early treatment because the neurons can still absorb and use it)
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What are the advantages of L-Dopa?
It works fast (peak in 1-2 hrs)
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What are the disadvantages of L-Dopa?
- short half-life
- waning effect results in "off" periods (motor fluctuations) = even shorter half-life
- may be converted in periphery = increased SE and decreased levels in brain
- dyskinesias
- pharmacokinetic variability
- NAUSEA if broken down in periphery
- competes with proteins for absorption in the gut and for transport across BBB
- absorption affected by GI conditions
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How can you combat the waning effect of L-Dopa?
- increase dosing frequency
- add entacapone
- add risagiline
- add a DA agonist (apomorphine - only helps for 100 min)
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What are the SE of L-Dopa?
- nausea (tolerance develops; use antacids)
- dyskinesias (as soon as 6 mo; reversible)
- hallucinations
- confusion
- orthostatic hypotension
- no use in pts with psychosis
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How do you combat delayed "on" or "no on" with L-Dopa?
- use oral disintegrating tablets
- separate from protein
- give apomorphine
- drug holiday
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How do you combat "freezing" with L-Dopa?
- physical therapy
- increase dose
- add a DA agonist or MAO-B inhibitor
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How do you combat dyskinesias with L-Dopa?
- decrease dose
- give amantadine
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What DI does L-Dopa have?
- MAO-A inhibitors
- pyridoxine (vitamin B6)
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What are the CI of L-Dopa?
- angle-closure glaucoma
- psychosis
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Why not start L-Dopa in everyone right away?
- motor complications
- waning effects
- other classes of drugs are effective
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What type of drug are selegiline and rasagiline?
MAO-B inhibitors
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What is the MOA of selegiline and rasagiline?
irreversible inhibition of MAO-B
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What are the advantages of selegiline and rasagiline?
- May use as monotherapy in early PD (delays need for L-Dopa)
- modest improvements in motor function
- evidence that rasagiline delays functional decline
- oral disintegrating tablet available
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What are the disadvantages of selegiline and rasagiline?
- side effects from active metabolites....methamphetamine, amphetamine (selegiline only)
- may augment motor and cognitive side effects of L-dopa therapy
- interactions with tyramine containing foods (cheddar, tap beer, salami, wine, soy)
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What else can selegiline and rasagiline be used for besides PD?
major depressive disorder
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What are the SE of selegiline and rasagiline?
- anxiety
- insomnia
- hallucinations
- worsens existing psychosis and dyskinesia SE of L-Dopa (selegiline)
- orthostatic hypotension
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What are the DI of selegiline and rasagiline?
- may increase risk of serotonin syndrome
- pseudoephedrine and pheynylephrine cause HTN
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What are the CI of selegiline and rasagiline?
- TCAs
- meperidine
- dextromethorphan, methadone, propoxyphene, tramadol - with the ODT
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Do selegiline and rasagiline modify the disease in PD?
Yes, the slowed breakdown of DA may result in less free radicals
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When should selegiline and rasagiline be administered?
- before meals
- last dose should be early in day due to SE
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What are the COMT inhibitors used in PD?
tolcapone and entacapone
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What is the MOA of tolcapone and entacapone?
prevent peripheral conversion of L-Dopa by COMT
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What are the advantages of tolcapone and entacapone?
- reduce off time
- combination available with carbidopa/levodopa (entacapone)
- extend duration of activity for L-Dopa
- first line adjunct for motor fluctuations (entacapone)
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What are the disadvantages of tolcapone and entacapone?
- cannot be used as monotherapy
- administered up to 8 times daily (entacapone)
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What are the SE of tolcapone and entacapone?
- hepatotoxicity (tolcapone)
- delayed onset diarrhea (tolcapone)
- brownish-orange colored urine (tolcapone)
- nausea
- orthostatic hypotension
- dyskinesias
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How are tolcapone and entacapone administered for PD?
- co-adminster with carbidopa/levodopa
- do not stop abruptly
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What are the advantages to using DA agonists in PD?
- fewer motor fluctuations; reduced risk
- well tolerated in younger patients
- longer DOA than L-Dopa
- do not rely on neuronal functional capacity
- monotherapy in mild disease
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What are the disadvantages of DA agonists in PD?
- frequent dosing
- worsening of L-Dopa induced dyskinesias
- class SE (nausea, neurologic, postural hypotension, compulsive behaviors, hallucinations)
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What are the advantages of pramipexole and ropinirole in PD?
- can titrate faster than ergot derivatives
- safer than ergot derivatives
- well tolerated in younger patients
- duration of action longer than L-Dopa
- potentially less generation of free radicals (d/t less catabolism of DA)
- may be used as initial therapy (monotherapy in mild PD)
- do not rely on neuronal function
- may be taken with food to decrease nausea SE
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What are the disadvantages of pramipexole and ropinirole in PD?
- tid administration
- worsening of dyskinesias
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What are the SE of pramipexole and ropinirole?
- somnolence
- nausea
- hallucinations
- dyskinesias
- orthostatic hypotension
- constipation
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What are the DI of pramipexole and ropinirole?
minimal
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Do pramipexole and ropinirole modify the disease in PD?
potentially (decreased free radicals)
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How are pramipexole and ropinirole administered for PD?
with or without food (may help with nausea)
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What are the advantages of apomorphine in PD?
rapidly triggers "on" response
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What are the disadvantages of apomorphine in PD?
- adminstered SQ
- severe nausea; premedicate with trimethobenzamide
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What are the SE of apomorphine?
- nausea/vomiting
- postural hypotension (test dose)
- somnolence
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What are the CI for apomorphine?
concomittant administration with 5-HT3 agents (ondansetron, dolasetron, granisetron, palonosetron)
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What is the duration of action of apomorphine?
100 min
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Why are anticholinergics used in PD?
because decreased levels of DA results in extra ACh (causes EPS - tremor, rigidity; drooling
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What are the disadvantages to anticholinergics?
(trihexylphenidyl and benztropine)
- minimal improvement of bradykinesia
- elderly are more susceptible to SE of anticholinergics
- no more effective than DA agents
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What are the side effects of anticholinergics?
(tryhexyphenidyl and benztropine)
- mad as a hatter
- hot as a hen
- red as a beet
- dry as a bone
- blind as a bat
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What is the MOA of trihexyphenidyl and benztropine in PD?
inhibition of PNS
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What are the DI of trihexyphenidyl and benztropine?
may increase levels and/or effect of potassium
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What are the CI of trihexyphenidyl and benztropine?
- narrow angle glaucoma
- use with caution in males with BPH
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What PD drugs are CI in glaucoma?
- L-Dopa
- trihexyphenidyl
- benztropine
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Why is amantadine used in PD?
it supresses L-Dopa induced dyskinesias
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What is the MOA of amantadine in PD?
unknown
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What are the disadvantages of amantadine?
benefit is short lived
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What are the SE of amantadine?
- confusion
- dizziness
- dry mouth
- nausea
- orthostatic hypotension
- edema
- livedo reticularis
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What are the DI of amantadine?
may increase levels and/or effect of potassium
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What are the risks for PD psychosis?
- disease duration and severity
- medication use - dose and duration DO NOT MATTER
- depression
- cognitive impairment
- age
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When removing PD agents to improve PD psychosis, in what order do you do so?
- anticholinergics
- MAO-B inhibitors
- amantadine
- DA agonists
- COMT inhibitors
- L-Dopa/carbidopa
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What drugs are used for PD psychosis?
- clozapine
- risperidone
- olanzapine
- quetiapine - DOC!!!!
- ziprasidone
- aripiprazole
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What should be the initial treatment for PD?
- selegiline
- L-Dopa
- DA agonist
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What should you consider when choosing a PD agent?
- delay initiation of L-Dopa if possible
- MAO-B inhibitors for most patients
- DA-agonists for younger patients
- amantadine for dyskinesias
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What drugs should be used as adjuntive tx for "wearing off" in PD?
- COMT inhibitors
- MAOB inhibitors
- DA agonists
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