Parkinson's Flashcards
What is the most important risk factor for Parkinson’s?
Age
Other risk factors include positive family history, male gender, environmental exposure (i.e. herbicide, pesticide, well water etc.), race, life experiences (i.e. trauma, emotional stress etc.)
Inverse correlation in smoking and caffeine intake
Why is age the most important risk factor in PD?
Dopamine pathways are most affected by age
Normally a 10% loss of both dopamine and dopamine receptors per decade (but in PD it is an accelerated loss with threshold for onset at 80% loss)
What are the clinical symptoms versus the primary diagnostic criteria for PD?
Symptoms: resting tremor, bradykinesia, cogwheel rigidity, postural instability
Diagnostic features (TRABP): Tremor, Rigidity, Akinesia, Bradykinesia, Postural instability
What are the Hoehn and Yahr Stages of Severity? (0-5)
0: No clinical signs evident
1: unilateral signs
2: bilateral signs without postural abnormalities
3: bilateral signs with mild postural imbalance or history of poor balance/falls (still independent pt)
4: bilateral signs with postural instability (assistance required)
5: severe, fully developed end stage disease (bedridden)
How is PD diagnosed? What makes it challenging?
Hard to get definitive neurodiagnostic tests, mostly diagnosed through exclusion and only for sure post-mortem
Can do a drug challenge: if patient symptoms improve with levodopa or apomorphine then supports PD diagnosis
How might Parkinsonism be drug-induced?
Medications with an MOA involving reducing dopamine or blocking dopamine receptors can result in Parkinson symptoms or pseudoparkinsons i.e. anti-psychotics like phenothiazines and haloperidol
How are the dopamine and acetylcholine system related?
In non-diseased state there is a balance between INHIBITORY dopaminergic and EXCITATORY cholinergic systems
In PD: loss of dopamine neurons in basal ganglia of substantia nigra results in loss of ability to control posture and initiate movment (dopamine is inhibitory in this pathway)…
Primary loss in dopamine leads to secondary increase in acetylcholine in basal ganglia (Ach is excitatory in this pathway)
So can try to block cholinergic effects in order to rebalance the decrease in dopaminergic effects
How was MPTP in the early 1980’s related to PD?
MPTP was added to heroin, MPTP is converted into MPP+ that is a toxin selective for dopaminergic neurons of substantia nigra = “frozen addicts” (induced Parkinsonism from permanent damage)
Especially if onset is before 50 years old, what are the possible genes involved?
PARK1 = autosomal dominant, fast progression, Lewy-body Parkinsonism PARK2 = autosomal recessive juvenile parkinsonism PARK3 = 40% develop in 5th decade PARK4 = develop between 30-60 years old PARK5 = toxic protein aggregation (ubiqutin Carboxy-Terminal Hydroxylase)
How does damage to the substantia nigra correlate to PD symptom development?
50%+ of neurons lost before onset of symptoms
Lewy bodies can appear in asymptomatic individuals but incidental Lewy body disease may indicate pre-symptomatic PD
Can use PET/SPECT imaging since preclinical disease is rarely identified by clinical assessment
What are the general mechanisms for PD treatment?
Increase endogenous dopamine (by inhibiting metabolism by dopa decarboxylase, COMT, or MAO B) Use dopamine agonists (D1, D2, D3 or partial agonists) Adenosine A2a (involved in dopamine release regulation in the brain) Anticholinergics (since Ach and dopamine systems are correlated)
Does timing matter in providing drug therapy for PD?
Yes
Includes short-term relief for symptom control for ADL, and long-term management
Timing is based on patient functional ability and evolves as the disease progresses
Treatment should be titrated over time to maximize therapeutic response
What is the ultimate goal of PD pharmacotherapy?
Slow or halt progression by replenishing dopamine (no cure though)
Also decreasing Ach may help with symptomatic tremor and rigidity (anticholinergics)
LEVODOPA/Carbidopa (Sinemet)… this flash card specifically is talking about the levodopa component of Sinemet
This is the GOLD STANDARD for PD treatment (also is the most commonly prescribed remedy)
Mechanism: immediate precursor to dopamine and can cross the BBB, is taken up by dopaminergic presynaptic neurons in striatum, and converted to dopamine via aromatic L-amino acid decarboxylase
ADR: usually due to peripheral effects of dopamine (i.e. N/V, anorexia from stimulation of emetic center, tachycardia, arrythmias), CNS effects i.e. hallucinations, depression, DYSKINESIA etc.
Drug Interactions: vitamin B6/pyridoxine increases peripheral breakdown of Levodopa, MAOIs in combination can lead to HTN crisis from increased catecholamine production, antipsychotic meds are anti-dopamine
Why is Levodopa (L-Dopa) given with Carbidopa?
Since some of the Levodopa is converted peripherally into dopamine, results in side effects
Needs Carbidopa as an enzyme inhibitor to minimize the 95% of the Levodopa would be metabolized in the periphery (without it, less than 5% reaches brain)
Take on empty stomach to increase absorption and transport across BBB (since has short half-life)
What is “wearing off” (or “end-of-dose wearing off”)?
Benefits of Levodopa get shorter over time with symptoms returning between doses, may mean disease is worsening
*Tolerance to Levodopa/Carbidopa usually develops after 3-5 years of therapy
How can “wearing-off” be addressed?
Increase Levodopa dose or number of doses
Add a dopamine agonist or increase its dose
Use a COMT inhibitor (to decrease dopamine breakdown)
What is Carbidopa mechanism of action and ADR?
Inhibits aromatic L-amino acid decarboxylase by binding to the pyridoxal binding site of the enzyme
Blocks enzyme in periphery but not CNS, which makes Levodopa more bioavailable for the CNS specifically
Reduces amount of Levodopa needed by 75% and reduces N/V and bad effects on the heart (75mg of Carbidopa needed to prevent peripheral ADRs)
ADR: increases incidence/severity of behavioral ADR from L-Dopa, increases dyskinesias from L-Dopa
What do direct dopamine agonists do for PD and name the examples?
Direct stimulation of dopamine receptors (and can be used alone or with Carbidopa/Levodopa)
i.e.
Pergolide (full D2 partial D1; FDA withdrawn due to heart valve damage)
Cabergoine (D2 not FDA indicated for PD)
Bromocriptine (full D2; high 1st pass metabolism and protein binding with 3hr half-life)
Pramipexole (D2; renal excretion with 8-12hr half-life)
Ropinirole (D3>D2>4; CYP1A2 metabolism with 6hr half-life)
Apopmorphine (D4>D2, D3, D5>D1)
What are the advantages of using dopamine agonists for PD as opposed to Levodopa/Carbidopa?
May beneficial as monotherapy in early PD (FDA indicated for Pramipexole and Ropinerole)
Less risk of motor complications and dyskinesias, increased symptom management, increased “time-on”, decreased need of Levodopa/Carbidopa
Potential neuroprotection (antioxidant properties… interacts with presynaptic dopamine receptors to decrease autooxidation/free radicals, decreased Levodopa requrements and toxic Levodopa metabolites)
What are ADRs of dopamine agonists?
Similar to those of Levodopa
ADR often a limiting factor i.e. sedating effects, hypotension, hallucination/psychosis, possible dyskinesia, N/V, leg edema
Narcolepsy reported with Pramipexole and Ropinirole
Since may stimulate mesolimbic dopamine pathway/reward, there is potential for increased compulsive behavior i.e. gambling (treat by reducing DA agonist or switching to different DA agonist)
Name a dopamine agonist that can be used transdermally
Rotigotine (Neupro)
Has high affinity for all dopamine receptor subtypes (D1/D2/D3)… but also means has potential for a lot of side effects peripherally due to affinity
Given once daily, can be monotherapy in early disease but is adjunctive therapy in advanced disease (useful for patients who can’t swallow)
Gives more continuous dopaminergic stimulation, good to lessen motor fluctuation and dyskinesias associated with PUSLATILE DA treatment long-term
ADR: site reaction, nausea, somnolence (serious if LOC while driving as shown in studies)
*possible to lower/maintain Levodopa doses theoretically when using a patch as supplement?
Give examples of MAO-B inhibitors that can be used to treat PD
Selegiline
Rasagiline
Emsam
Selegiline (Deprenyl, Eldepryl)
Mechanism: IRREVERSIBLE MAO-B inhibitor, blocking dopamine breakdown can extend L-Dopa actions up to 1hr or the time before L-Dopa is needed by 9 months
Indications: for patients with intact cognition and with “wearing off”
ADR: insomnia, jitteriness, HTN, worsened preexisting symptoms like hallucination/delusion
If used with SSRI then rarely may get serotonin syndrome (SSRI used to treat depression, commonly found in people with PD)
*Inconclusive evidence that it slows PD progression
