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Dopamine Release onto Striatal Neurons Pic
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Treatment Strategies
- Symptomatic: improves symptoms
- Neuroprotective: slows nerve cell loss
- Restorative: restores cell function or increases the number of cells
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Restorative Thereapies-Under study- probably not on exam
- Intraputamenal GDNF: demonstrated improvement in 6 weeks, double blind trial results were disappointing
- CERE-120: Intrastriatal neurturin (NTN) therapy funded by ceregene phase II planned
These are surgical interventions
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Neuroprotection for PD-Under study- probably not on exam
- Coenzyme Q 10: provacative data using 1200mg/day (about $200/month)
- Selegiling (Eldepryl): not neuroprotective in over 800 patients in DATATOP Trial
- Vitamin E: DATATOP study, not neuroprotective
- Creatinine: Further study merited
- Isradipine (Dynacirc): Ca+ channel blocker, (calcium channels present in dopamine cells), shown to affect disease progression Mike Lee does work with transgenic mice models for parkinsons in the football stadium
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Symptomatic Research Therapies-Under study- probably not on exam
- Adenosin A2a antagonists: provide a dopaminergic effect. e.g.. istradefylline
- Dopamine agonists: SLV-208 or once daily ropinirole
- AMPA blockers: E2000
- Gene Thereapies: shown some benifit but maybe placebo
Under study- probably not on exam
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What are the current symptomatic medication options?
- Levodopa/carbidopa (Sinemet): Gold Standard sinemet is latin for without vomiting
- Anticholinergics: trihexyphenidyl (Artane) and beztropine (cogentin)
- Amantadine (symmetrel):
- Selegiline (Eldepryl):
- Rasagiline (Azilect):
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What are the two classes of Dopamine Agonists?
Ergots and Non-ergots
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Dopamine Agonists - Ergots
Bromocriptine (Parlodel): may cause fibrosis
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Dopamine Agonist- Non-ergots
- Pramipexole (Mirapex):
- Ropinirole (Requip):
- Apomorphine (Apokyn):
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COMT Inhibitors
- entacapone (comtan):
- tolcapone (Tasmar):
- entacapone/carbidopa/levodopa (Stalevo):
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How do the medications work? -Memorize this pic
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Levodopa/Carbidopa (Sinemet): Dose, S/Es, Notes
- Most effective treatment for all features
- Controversial as to when to begin and the most appropriate dose.
- Doses: 10/100, 25/100, 25/250
- S/Es: nausea, light-headedness, dyskinesias, hallucinations, sleep attacks
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Sinemet CR
- Doses: 25/100 and 50/200
- Half life longer
- improves motor fluctuations
- slower absorption
- good for dosing at night
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COMT Inhibitors
- COMT metabolizes L-dopa primarily in the GI tract
- Peripheral COMT blockade improves CNS L-dopa levels
- Central COMT inhibition is of unclear benefit
Stalevo: carbidopa + l-dopa + entacapone
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COMT Inhibitors-Mechanism, S/Es, indication, dosing
- Mechanism: more l-dopa gets into the brain
- S/Es: the increase l-dopa may result in side-effects such as dykinesias
- Clinical indication: to improve motor fluctuations in chronic PD
- Dosing: l-dopa dose reduction is often required after starting COMT inhib.
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Tolcapone:
- Rarely used.
- More effective than entacapone but rarely used.
- Liver failure.
- Must carefully monitor.
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Stalevo
- Doses: 50, 100, 150mg
- Doses reflect mgs of levodopa combined with 200 mg entacapone and varying amounts of carbidopa
- comptan and sinemet together
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Entacapone (comtan): MOA, S/Es, Cost, dose
- MOA: peripheral blockade of COMT
- S/Es: diarrhea, increased dyskinesias
- Cost: $166/month
- Dose: 200 mg entacapone with each l-dopa dose
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Dopamine Agonists MOA
Simulate the action of dopamine
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Dopamine Agonist Half-lives
- Levodopa: 1 hour
- Bromocriptine: 3-8 hours
- Ropinirols: 4-6 hours
- Pramipexole: 8-12 hours
- Cabergoline: 65-72 hours (for breast feeding mothers)
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Dopamine Agonists Side Effects
- Orthostatic hypotension:
- hallucinations: are more frequent with agonists than levodopa
- somnolence:
- sleep attacks: (resulting in Motor Vehicle Accidentss)
- nausea:
- increase dyskinesias:
- compulsive behaviors:
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Are MOAb inhibitors neuroprotective or symptomatic?
symptomatic
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MAOb Inhibitors
- Selegiline: alleviate Sxs by MAO-B blockade, SSRI and TCA interaction
- Rasagiline: made by same company that makes the generic seleginline
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Anticholinergics: MOA, Indications, S/Es
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Anticholinergic Meds
- Trihesyphenidyl (Artane):
- Cogentin (benztropine):
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Amantadine (Symmetrel):
 - Not conclusive if this works!
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Motilium (domperidone)
- Indication: management of nausea associated with levodopa
- Mech: Peripheral dopamine antagonist
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Lodosyn (carbidopa)
Indication: nausea for when more carbidopa is needed
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Whats the most effective drug for parkinsons disease? (key question)
Carbidopa/levodopa
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What drug causes compulsive gambling?
Dopamine Agonists
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What causes splotcy legs?
Amantadine
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What drug interactions should you be careful for with selegiline?
- 1. SSRIs and TCAs: serotonin syndrome
- 2. Meperidine (demorol):
- 3. Tyramine containing foods: hypertensive crisis
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