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)
