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47 Cards in this Set
- Front
- Back
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How many cases of Parkinson's are due to spontaneous genetic mutations
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10%, probably another gene inheritance giving susceptibility
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Parkinson's onset time
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Usually 55-60 y/o
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Genetic mutation causing Parkinson's, Classic Pathologic Finding
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Alpha Synuclein A to G leading to an alanine being changed to a threonine
Unsure of fxn but classic pathologic finding Builds up in Lewy bodies microscopically in dopaminergic neurons Thought Lewy bodies was the toxic thing, BUT now thought that they buy time for neuron to survive. worse if smaller particles of alpha synucleun floating around |
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Braak Staging Hypothesis for Parkinson's
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First parts of brain with Lewy bodies are in medulla and olfactory bulb. As disease progresses the bodies progress in brainstem up until affecting the substantia nigra
Substantia nigra is actually affected AFTER pathology spreads from elsewhere Toxic substance that starts dominoes might start in nose or gut via CN X (lewy bodies in myeneteric plexus) since affects medulla and olfactory bulb first. |
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Mechanism of neurodegeneration in Parkinson's
FIND OUT WHAT NEED TO KNOW |
Genetic factors (Alpha-synuclein, Parkin, UCH-L1, LRRK2, dardarin, others) cause altered protein conformation, and have ubiquitin proteosome dysfunction leading to protein aggregates
Environmental Factors: (PINK1, DJ1, LRKK2, dardarin) mutations cause mitochondrial problems. oxidative stress, pesticides, toxins can REDUCED COMPLEX I and higher ROS leading to toxic injury apoptosis or inflammation excitotoxicity Both lead to NIGRAL CELL DEATH MUTATIONS RELATED TO CLEARING ABNORMAL PROTEINS OR MITO FXN. MPTP toxin, Combination of apoptotic excitotoxicity leads to cell death. As proteins are collecting may or may not be good. Could buy time |
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Free Radical Generation in Levodopa metabolism, effects
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Normally converted to dopamine via Aromatic L amino acid decarboxylase
Dopamine converted to to DHPA, ammonia and hydrogen peroxide via MAO (normal breakdown in synaptic terminal) Glutathionine peroxidase converts hydrogen peroxidase to GSSG and water to clear BUT H2O2 sometimes converted to free radical OH via Fe2+ to Fe3+ if it builds up Effects: Reduced mitochondrial function, less glutathionine (to breakdown dopamine), higher Ca2+ which activates degradative enzymes leading to exitotoxicity and cell death Deficiency of glutathione in Parkinsonian brain |
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Deficiency of what in Parkinson's brain leads to ROS formation
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Glutathionine
Without H2O2 in Fenton reaction (w/ iron) can be converted to two HO that can destroy membrane, mitochondrial fxn, Ca2+ increase leads to degredation |
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Parkinson's TRAP presentation
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Tremor - usually UNIL, early sign, disapears or improves with PURPOSEFUL action
Rigidity Akinesia Postural instability |
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Parkinson's Postural Stages
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1) UNIL - blank facies on side, affected arm in semiflexed position with tremor, lean to unaffected side
2) BIL - slow shuffling, decreased leg excursion 3) Pronounced gait problems, moderate generalized disability, tendency tto fall 4) Significant disability, limited ambulation with assistance 5) complete invalidism, confined to bed or chair, cant stand or walk even if assisted |
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Non-motor parkinson's symptoms
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episodic sweating
Central horner's syndrome Seborrhea Salivary drooling due to dysphagia (cricothyroid) Prolonged stomach emptying time, bowel hypmotility leading to constipation Othrostatic hypotension Bladder dysfunction (hard to initiate) Thermal paresthesia |
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FluoroDopa Use
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Can look at brain to see Parkinson's distribution
Will have HIGH localization to striatum in normal. Less in presymptomatic and FAR less in symptomatic state Can be used to diagnose presymptomatically if have + FHx |
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DAT-SCAN
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Measures progressive loss of striatal dopamine transporter in Parkinson's
Can be used to dx presymptomatically if have + FHx |
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Gross Parkinson's findings
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Loss of substantia nigra and Locus coeruleus (Norepi in dopamine pathway so affected)
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DDx of Parkinsons and distinguishing features
Essential Tremor Progressive supranuclear palsy Multiple system atrophy Corticobasal degeneration Diffuse Lewy Body dementia Alzheimers Drug induced parkinsonism Vascular parkinsonism |
Essential tremor - will ONLY have one tremor and doesn't respond to drugs, symmetric
Progressive supranuclear palsy - supranuclear gaze palsy, CAN"T MOVE EYES, WIDE EYED STARE vs hunched poker face of parkinsons, gait instability with falls, upright posture, staring facies, dysphagia, cognitive dysfunction, IMAGING distinguishes Multiple system atrophy - ANS disturbance, ORTHOSTASIS, cerebellar signs, NO TREMOR, dysphagia, gait problems Corticobasal degeneration - APRAXIA (loss of motor memory), limp apraxia, sensory abnormalities, alien limb, unilateral tremor, early dementia Diffuse Lewy Body dementia - early dementia, psychosis, agitation Alzheimers - just dementia Drug-induced parkinsonism - EXPOSURE TO DOPAMINE BLOCKER, LACK OF REST TREMOR, symmetric Vascular parkinsonism - HISTORY OF HTN, DM, use imaging to see LACUNES For all of these Levodopa WILL NOT help, whereas if have idopathic Parkinson's will get better. |
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MRI sign in Parkinson's Brainstem
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Penguin or Hummingibrd sign
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How to test for Corticobasal degeneration
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DDx in Parkinson, do Apraxia test. Will be positive in CBGD
Ask them to do peace sign or OK sign. They may say cannot do and they will not be able to do it |
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Distinguishing Parkinson's from OPCA
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MRI, see tons of cerebellar degeneration
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Motor features of Parkinson's
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Rest tremor
Bradykinesia Rigidity Gait imbalance Masked facies |
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Non-motor features of Parkinson's
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Autonomic dysfunction (orthostatic hypotension, constipation, urinary symptoms, sexual dysfunction), cognitive impairment, sleep disorders, depression/anxiety
Meds are better at treating motor problems |
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Dopamine receptor classes and structure, location
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G-coupled ligand receptors
D1-like (D1 and D5) - Coupled to Gas, stimulate adenylate cyclase to UP cAMP which activate PKA D2-like (D2, D3, D4) - Coupled to Gai, inhibit adenylate cyclase, decrease cAMP levels to inhibit PKA MOST are postsynaptic, Short form of D2 is PREsynaptic Autoreceptor that serves as feedback on dopamine synthesis, storage and release |
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Short form of D2 receptor role
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PREsynaptic autoreceptor that serves as feedback on dopamine synthesis, storage and release
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Predominant striatum Dopamine receptors
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D1 and D2 (3,4,5 are in other CNS locations)
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Levodopan MOA, ASE, adjuvant, considerations
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Dopamine precursor, crosses BBB (UNLIKE DOPAMINE) via large neutral amino acid transporter, metabolized by AADC peripherally so less reaches brain.
ASE: nausea and hypotension due to peripheral metabolism by AADC. Also sedation, psychosis (hallucination, delusion), dyskinesias, impulsive control disorders Adjuvant: AADC inhibitors (carbidopa, benserazoide) - lower dose needed and less ASE, JUST BLOCKS PERIPHEAL AADC to prevent ASE, therapeutic effect is preserved Considerations: NEED PROTEIN RICH MEALS |
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Most effective med for parkinson's disease
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Levodopa with AADC inhibitors and a protein rich meal
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Levodopa mech for wearing off
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Plasma half life is very short even when given with carbidopa.
In early disease it is stored in presynaptic terminals so THERAPEUTIC HALF LIFE is longer, but as it progresses more cells die so duration is closer to that of the short plasma half life |
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Dyskinesias mechanism in Levodopa
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Usually in treated pts, seem a little overactive which is abnormal. As drug wears off this calms down.
Unclear but could be due to pulsatile dopamine receptor stimulation, receptor hypersensitivity in D1 leading to dyskinesis, alterations in signaling targets, dopamine release from serotonergic neurons or alterations in glutamate receptor signaling |
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COMT inhibitors, MOA, Indications, ASE
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ENTACAPON - peripheral (terminal L-dopa) COMT only (MOST USED)
TOLCAPON - central COMT (cleft) and peripheral COMT. MOA: Peripheral effect: block COMT breakdown of Ldopa to 3OMD (terminal) or Central effect: block COMT breakdown of dopamine to 3MT (synaptic cleft) Indications - used to increase on-time in fluctuating patients ASE: Dopaminergic - worsens dyskinesias, nausea/vomiting Diarrhea Urine discoloration LIVER TOX WITH TOLCAPONE |
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3-OMD effect
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competes with L-dopa for intestinal absorption (reduces) and transport across BBB (reduces) but does not activate dopamine receptors
COMT generates it |
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Which drug causes liver toxicity
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TOCAPONE (COMT inhibitor)
use Entacapone |
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MAO inhibitors, MOA, Indications
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Rasagiline, Selegiline
MOA: inhibit MAO-B breakdown of dopamine to DOPAC in cleft Selegiline - irreversible inhibitor of MAO-B, metabolized to amphetamine and metaphetamine (may be stimulant to some which can help since fatigue is an issue) Rasagiline - irreversible inhibitor of MAO-B, may be neuroprotective Indications - helps treat motor fluctuations ASE: hallucinations, dopaminergic if used with l-dopa, insomnia (selegiline), HTN crisis or serotonin syndrome if used with SSRIs or tyramine containing substances |
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Parkinson's treatment that can cause HTN crisis or serotonin syndrome
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MAO-B inhibitors Selegiline or Rasagiline
especially if used in combo with SSRIs or tyramine containing substances (cheese, red wine, etc.) |
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Dopamine receptor agonists, MOA, Indications
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Pramipexole, Ropinirole, Rotigotine
MOA: Activate Dopamine receptors in the cleft, agonists for D2 (pramipexole, ropinirole) OR D3>D2>D1 agonist (Rotigotine) Indications: EARLY and ADVANCED Parkinsons, delay onset of motor complicatoins, less likely to cause dyskinesias ASE: nausea, vomiting, hypotension, bradycardia, hallucinations, sleep, impulse |
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Rotigotine
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Patch formulation that is a D3>D2>D1 agonist used to treat Parkinsons
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Other dopamine receptor agonists
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Apomorphine - mixed D1 and D2 (just want 2) - used for severe freeezing ONLY
Ergot agonists - not used due to possible heart valve dysfunction |
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Indications
a) L-dopa b) COMT inhibitor c) MAO inhibitor d) Dopamine R agonists |
a) Best one
b) Increase on-time in fluctuating patients c) Treat motor fluctuations d) early and advanced PD, delay onset of motor complications, history of dyskinesias side effect |
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L-dopa, dopamine agonists and MAO inhibitors effect on oxidative stress and dopamine
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L-dopa - may promote neuronal toxicity but probably safe, more dopamine drives MAO pathway and more H202. Could kill neurons
Dopamine agonists - may be protective by reducing dopamine release b/c activate receptors without needed dopamine release. Hit D2 autoreceptors to lower dopamine made and less H2O2 MAO inhibitors - may be protective (Rasagiline NOT selegiline), stop conversion of dopamine to DOPAC and H2O2 |
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Anticholinergic drugs MOA, use, ASE
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Trihexyphenidyl, Benztropine
MOA: inhibits cholinergic muscarinic receptors (overactive in PD) Use: treat tremors and stiffness. Often for psychiatric patients taking dopamine antagonists NOT USED B?C OF ASE ASE: confusion, hallucinations, urine retention, constipation, blurred vision, dry mouth, tachycardia |
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Amantadine MOA, use, ASE
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MOA: unknown, promotes dopamine release, inhibits uptake, may activate receptor, blocks glutamate receptors and may be anticholingergic
Use: reduce dyskinesias ASE: well tolerated, may get ankle edema or livedo reticularis |
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Meds to use Early PD, Late PD
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Early PD
DA agonists if under 70 to delay dyskinesias development (levodopa long term use), L-dopa in elderly (less ASE, better, not worried about dyskinesias later) Rasagiline to slow progression Artane in tremor predominant Advanced PD As previous doesn't work, add MAO or COMT inhibitors. Amantadine if dyskinesia |
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ANS dysfunction symptom treatment
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Orthostatic hypotension - conservative, decrease HTN meds, meds. Florinef, Midodrine, Octreotide (if BP down with meals), Desmopressin (retain urine)
Drooling - atropine drops, botox, anticholinergics Urinary symptoms - anticholinergics, desmopressin, catheter Constipation - fluids and high fiber diet, stool softeners , polyethylene glycol, laxitives, prokinetic agents |
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Sleep disorders associated with parkinson's, how to treat
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Majority have them
Apnea, restless leg, daytime sleepiness, nocturnal immobility Treat: sleep study to find cause, CPAP for apnea, melatonin or klonopin if REM problem, cut agonists if daytime sleepiness, Dopamine meds at night with nocturnal immobility |
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Treating cognitive dysfunction in parkinson's
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Hallucinations - treat contributing illness, reduce meds acting on brain, acetylcholinesterase inhibitors
Dementia - cholinesterase inhibitors |
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Surgical treatment, ideal candidate, risks
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Deep Brain stimulation of globus pallidus interna, subthalamic nucleus or Vim nucleus of thalamus
Ideal candidate: initial good motor response to treatment, development of complications from treatment, no cognitive or psychiatric issues Improves bradykinesia, rigidity, tremor, dyskinesia BUT NOT GAIT DISTURBANCE, can reduce meds Risks: stroke, hemorrhage (RARE), BIL can cause dysarthria and dysphagia, Mood and cognitive side effects |
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Surgical treatment associated with mood and cognitive side effects
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STN DBS
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MPTP toxin
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Gets into astrocyte and MAO-B converts to a MPDP and MPP which goes to domaine cells and acts as a toxin to destroy Mitochondria and lead to apoptosis and cell death
Causes parkinson like symptoms |
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Main biochemical loss in Parkinsons
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Loss of SnC leads to less inhibition of the indirect path (D2) and less activation of the direct (D1) path
GPi is more active, inhibits VL more so less movement |
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Why can't dopamine be used to treat PD
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doesnt' cross BBB, lots of ASE
Use Levodopa instead |
