12 - Parkinson's Flashcards
1
Q
What are the cardinal motor features of Parkinson’s?
A
- Bradykinesia
- Tremor at rest
- Rigidity
- Postural instability
- Diagnosis = 1 + 2 or 3; 4 comes later
* Slow, progressive, degenerative CNS disorder
- Often presents asymmetrically
2
Q
Describe the “tremor at rest” of Parkinson’s
A
- 70% of px
- Rhythmic, asymmetric
- Hands (pill rolling), feet, lip, jaw (not usually head or neck)
- May disappear w/ voluntary movement & sleep
3
Q
Describe the rigidity of Parkinson’s
A
- 90% of px
- Lead pipe, cogwheel
- Neck, trunk, limbs
- Resistance to passive movement of limbs/ joints
4
Q
Describe the bradykinesia of Parkinson’s
A
- 70% of px
- Slowness of all movements including walking
- Difficulty initiating movement
5
Q
Describe the postural instability of Parkinson’s
A
- Often later presentation
- Shuffling gait
- Narrow base, festination
- Freezing and falls
6
Q
4 dopaminergic pathways in the brain
A
- Mesolimbic – high DA = positive sx of schizophrenia
- Mesocortical – low DA = negative sx of schizophrenia
- Tuberinfundibular – low DA = hyperprolactinemia
- Substantia nigra – extrapyramidal system; low DA = parkinson’s; high DA = dyskinesia
7
Q
Substantia nigra
A
- Nigrostriatal pathway achieves smooth movement when acetylcholine (the “no go” or inhibitory NT) & dopamine (the “go” or excitatory NT) are in balance
- When dopamine is blocked, acetylcholine > dopamine => movement becomes jerky & stiff b/c there is a relative excess of “no go” NT
8
Q
Which drugs cause drug-induced parkinsonism and how?
A
- Typical antipsychotics (ex: haloperidol) block all 4 pathways
- Atypical antipsychotics selectively block dopamine in the mesolimbic pathway (less frequent EPS)
- GI agents (prochlorperazine, promethazine, metoclopramide)
9
Q
What are the types and sx of drug-induced EPS
A
- Dystonia = sustained contraction (onset = hours to days)
- Akathisia = restlessness (onset = hours to days)
- Pseudo-parkinsonism = bradykinesia, cogwheel-like tone/ rigidity, tremor (onset < 30 days of starting medications)
- Tardive dyskinesia = irregular/ twisting movements (ex: cheek puffing, facial grimacing, lip smacking); onset months to years, often irreversible
10
Q
Which drugs cause drug-induced Parkinson-like motor sx
A
- Antipsychotics (FGA > SGA; risperidone > olanzapine > quetiapine/ clozapine)
- Anti-emetics (metoclopramide, prochlorperazine)
- Older antihypertensives (methyldopa)
- SSRI (serotonin may inhibit dopamine activity)
- Valproic acid (GABA – bradykinesia, tremors)
- Resting tremors –> lithium, valproic acid, SSRIs, TCAs, amiodarone, EtOH
11
Q
Drug-induced Parkinson-like motor sx – onset and resolution
A
- Onset w/in weeks of starting drug
- May take 2-6 months for sx to resolve after d/c
12
Q
Risk factor for drug-induced parkinsonism
A
- Older age
- Female
- High doses of offending drug
- Hx of movement disorder
13
Q
Drug-induced neuroleptic malignant syndrome (NMS)
A
- Life-threatening
- Thought to be a result of sudden decrease in dopaminergic transmission
- Antipsychotics (dopamine blocker) & sudden withdrawal of dopamine enhancers (ex: levodopa) has resulted in NMS
- Sx:
- FARM (fever, autonomic instability (unstable HR, BP, sweating, drooling), rigidity, mental status changes
- Delirium, severe immobility
- Leukocytosis, rhabdomyolysis, high sCr
14
Q
Parkinson’s disease
A
- Loss of pigmented cells in substantia nigra
- Sx appear when 60-80% of these neurons have been lost
15
Q
Main goal of Parkinson’s disease, what does each drug do to achieve this?
A
- *Enhance/increase dopamine or block acetylcholine
- Dopamine precursor – L-dopa converts to dopamine
- Dopamine agonist – activates dopamine receptors
- NMDA receptor antagonist – increases dopamine release
- COMT or MAO-B inhibitor – decreases dopamine metabolism
- Anticholinergics – block acetylcholine in striatum
16
Q
Goals of therapy
A
- *Improve motor & non-motor sx to maintain best possible QOL
- Preserve ability to perform activities of daily living
- Minimize adverse effects and tx complications
- Improve non-motor features (ex: cognitive impairment, depression, fatigue, sleep disorders)
17
Q
When should Parkinson’s tx be initiated? How long is it continued?
A
- Early, mild sx causing no disability (clumsiness of hands, fatigue, sensory discomfort) don’t warrant therapy
- When disability interferes w/ px social, emotional, or work life, therapy is warranted
- Duration of therapy is usually lifelong (w/ monitoring)
18
Q
Pharmacotherapy options for Parkinson’s
A
- Anticholinergic (block acetylcholine, relative increase in DA)
- Amantadine (NMDA antagonist increases DA release)
- MAO-B inhibitor (reduce DA breakdown)
- COMT inhibitor (reduce levodopa breakdown)
- Dopamine agonist (directly stimulates DA receptors)
- Levodopa (converted to DA by dopa decarboxylase)
19
Q
Anticholinergics for Parkinson’s – agents, MOA, SE
A
- Benztropine, trihexyphenidyl, procyclidine, ethopropazine
- Block acetylcholine in the striatum
- SE = blurred vision, confusion, constipation, dry mouth, cognitive impairment, urinary retention
- Need to taper over 1 week when stopping to prevent Parkinson’s exacerbation (even if no perceived benefit was realized)
20
Q
When should anticholinergics be used for Parkinson’s?
A
- Can be used alone or in combination
- Tremor is predominant
- Drooling
- Drug-induced EPS
- Modest antiparkinson effect – not as effective for more disabling features of PD
- SE limit use (younger may tolerate)
21
Q
Amantadine for Parkinson’s – MOA, role, SE
A
- Inhibits NMDA receptors and increases dopamine release from presynaptic terminals
- Role:
- Modest antiparkinson effect
- Used early to help w/ tremor
- Used later to reduce L-dopa dyskinesia (antiglutamate)
- Better tolerated in young px
- SE = CNS (confusion, insomnia), anticholinergic (dry mouth), GI upset, hypotension, tachyphylaxis (pt initially has good response but then all of a sudden stops working)
- Abrupt withdrawal can worsen PD/ cause NMS
22
Q
Livedo reticularis
A
- Cosmetic, not life threatening
- Not dose-dependent
- Reversible diffuse purplish-red mottling of the skin
- Affects upper or lower extremities +/- low extremity edema
23
Q
Drugs that prevent DA breakdown
A
- COMT inhibitors prevent breakdown of levodopa
- MAO-B inhibitors prevent breakdown of dopamine into active metabolites
24
Q
Monoamine oxidase B inhibitors – dosing, role, SE, drug interaction
A
- Selegiline, rasagiline
- Selegiline taken AM or at lunch to decrease insomnia; tyramine intake shouldn’t be a concern at typical doses
- Rasagiline – high fat meals decrease levels; theoretical tyramine hypertensive crisis (but no diet restrictions)
- Selective & irreversible MAO-B inhibitor in the brain – interferes w/ DA breakdown
- Role
- Mild-moderate symptomatic benefit
- Early Parkinson’s disease monotherapy
- Add-on to levodopa (1h extended “on” time)
- Lab models suggest neuroprotection, but no definitive evidence in px
- Selegiline SE = insomnia, hallucinations, confusion, orthostatic hypotension
- Rasagiline SE = minimal GI, neuropsychiatric
- Drug interaction w/ serotonergic agents (ex: meperidine contraindicated, some antidepressants used w/ caution)
25
Q
Catechol-O-methyl transferase inhibitors – MOA, role, SE
A
- Entacapone (produced as single or w/ levodopa & carbidopa – triple product expensive & not used often)
- Reversible peripheral COMT inhibitor
- Reduces GI metabolism of levodopa
- Prolongs levodopa t1/2 & increase bioavailability
- No effect w/o levodopa
- May provide up to 1-2 h of extended “on” time for px w/ “wearing off” of levodopa
- Typically used later on as add-on
- SE = N/V, abdominal pain, brown-orange urine/ sweat discolouration, delayed onset diarrhea, hypotension, NMS
26
Q
Dopamine agonists – MOA, SE
A
- Directly stimulates dopamine receptors (mimics real dopamine)
- Moderate clinical effect (not as potent as levodopa)
- Less motor complications but more side effects than levodopa
- May be preferred over levodopa in younger px (who can tolerate SE) to delay levodopa dyskinesias
- Reduce frequency of “off” periods & may allow levodopa dose reductions
- SE = nausea, cognitive impairment (esp > 70 y/o), lower extremity edema; serious = impulsivity, sleep attacks; erythromelalgia/ cardiac valve fibrosis (ergot derived); can increase frequency & severity of levodopa-induced dyskinesia
- Abrupt withdrawal/ significant dose reduction => risk of NMS & not resolved w/ other PD drugs (need to resume previous dopamine agonist)
27
Q
Titration of dopamine agonists
A
- Must be titrate slowly & up to therapeutic dose; otherwise will just cause SE w/o much clinical benefit
- Pramipexole –> initiate at low dose & increase slowly over 4-6 weeks; usual dose = 0.5 – 1.5 mg TID w/ meals
28
Q
Types of dopamine agonists
A
- Ergot-derived agonist (bromocriptine) –> not 1st line b/c cardiac valve disease
- Non-ergot agonist (pramipexole, ropinirole, rotigotine) –> used alone in mild PD or adjunct to levodopa in px w/ motor fluctuations
29
Q
Rotigotine
A
- Steady release of drug from patch, but not proven to achieve better control of Parkinson’s sx
- Use based on pt preference
30
Q
Levodopa – MOA, role, SE
A
- Most effective therapy for Parkinson’s disease
- Virtually all px respond
- Improves disability, prolongs capacity to maintain employment and ADL
- Reduced mortality rate
- Superior motor benefit but associated w/ dyskinesias
- May not be appropriate to delay solely based on concern for dyskinesia
- Levodopa (L-dopa) –> dopamine
- Combined w/ dopamine decarboxylase inhibitors (carbidopa or benserazide)
- Allows more L-dopa to cross BBB (increases t1/2)
- Prevents conversion to dopamine in periphery
- Minimizes acute peripheral SE (nausea, hypotension)
- MOA –> levodopa in periphery converted to dopamine by L-aromatic amino acid decarboxylase which causes SE (N/V, low BP); levodopa cross BBB to CNS & is then converted to dopamine which causes movement (SE = headache, vivid dreams, insomnia)
- SE = nausea (ensure 75-200 mg carbidopa is being used; take w/ low protein food); hypotension (ensure adequate water/ salt intake, consider domperidone); hallucination, nightmares, motor fluctuations
31
Q
Benefit of regular release levocarb
A
- Better absorption if taken before meals
- Can be taken w/ meals if nausea (protein rich foods decrease absorption)
32
Q
When to use controlled release LevoCarb?
A
- No evidence that CR is better than regular release
- Should not be used as initial therapy b/c:
- Less well absorbed
- Less noticeable response since reaches CNS more slowly
- Makes evaluating & monitoring initial response more difficult
- Generally ineffective for “wearing off” effect in most middle of night/ very early AM sx
- Likely adds about 90 min to duration of effect
- CR 70% bioavailable compared to regular release
- Delayed onset may require supplemental regular release LevoCarb for optimal control in the mornings
33
Q
Duodopa Gel
A
- Levodopa/carbidopa in a 100 mL cassette
- Intraduodenal infusion
- Indicated for severe, debilitating motor fluctuation and hyper-/dyskinesia despite optimized tx w/ available meds
34
Q
Motor fluctuations in Parkinson’s
A
- PD is progressive
1. End-of-dose “wearing off” / “on-off”
2. “Delayed-on” and “no-on” response
3. “Freezing”
4. Peak-dose (“on” period) dyskinesias
5. Early morning “off-period” dystonia
35
Q
End-of-dose “wearing off” / “on-off” – onset and management
A
- Onset 5-6 months (often 1-5 years) after starting levodopa
- Progressive loss of neuronal dopamine storage & short levodopa t1/2
- Waning effect of levodopa w/in 4 h of last dose
Management: - Smaller & more frequent levodopa dosing (take next dose 30-60 mins earlier) –> watch for dyskinesia
- Consider adding dopamine agonist, COMT inhibitor (entacapone), or MAO-B inhibitor (rasagiline) –> watch for dyskinesia (abnormal movement as a result of too much dopamine)
- Reduce protein in diet
36
Q
“Delayed-on” and “no-on” response
A
- Delayed gastric emptying or decreased absorption in the duodenum
- Management –> chew/crush tablet & drink full glass of water
37
Q
“Freezing”
A
- Sudden or episodic inhibition of lower-leg motor function
- Feet suddenly feel stuck to the floor
- Anxiety/ perceived obstacles encountered
- Fall risk**
- Physical therapy, assistive walking devices, sensory cues
- Changes to drug regimen may not be helpful
38
Q
Peak-dose (“on”) dyskinesias
A
- Too much dopamine
- Involuntary repetitive, rapid/jerky movements – usually neck, trunk, and lower/upper extremities
- Management:
- Add amantadine (antidyskinesia effect)
- Decrease levodopa & add dopamine agonist –> watch for worsening of Parkinson’s sx
- Decrease or d/c COMT inhibitor/ MAO-B inhibitor –> watch for worsening of Parkinson’s sx
39
Q
“Off-period” dystonia
A
- Sustained muscle contractions – normally in distal lower extremities (ex: clenching of toes, turning of foot)
- Early morning hours (waning drug levels)
- Improve w/ first levodopa dose of the day
- Management:
- Chew regular release LevoCarb tablets and take w/ carbonated drink to increase absorption
- Controlled-release LevoCarb (esp at bedtime)
40
Q
Principles of pharmacotherapy for Parkinson’s
A
- Initial drug choice must be individualized based on sx severity and other comorbidities
- Treat px w/ each drug (increasing doses weekly) until desired effect is seen, the maximum dose is achieved, or adverse effects become intolerable **start low, go slow
- If partial response (w/ acceptable level of SE) has been seen w/ the initial drug, continue this drug and add the next drug in the sequence
- As disease progresses, often w/in 6 months to 1 year of starting therapy, pharmacologic response to levodopa will deteriorate
- When adding adjuvant therapy to levodopa/ carbidopa, reduce the dose of levodopa
- No role for drug holidays as any benefit is usually short-lived and risks include immobility, aspiration/ pneumonia, severe depression
- Therapy shouldn’t be d/c abruptly (parkinsonian crisis & neuroleptic malignant syndrome have been reported)
41
Q
Initial pharmacologic management for Parkinson’s
A
- Only initiate therapy if functional impairment
- If < 60 y/o w/ tolerable sx –> dopamine agonists, MAO-B inhibitors, levodopa
- If pt has unacceptable SE or lack of efficacy –> use levodopa
- If 60 years & older, or severe impairment –> levodopa
42
Q
Levodopa-associated motor complications
A
- Predominant end-of-dose “wearing off” w/ mild/no dyskinesia –> increase levodopa frequency, add entacapone, add dopamine agonist, add MAO-B inhibitor, or change to slow release levodopa
- Predominant end-of-dose “wearing off” w/ moderate dyskinesia –> increase smaller dose levodopa frequency, add amantadine, or decrease levodopa & add dopamine agonist
- Predominant dyskinesia w/ mild/no “wearing off” –> decrease levodopa, add amantadine, d/c anticholinergic, or d/c MAO-B or COMT inhibitor
43
Q
Monitoring for Parkinson’s
A
- Efficacy for parkinsonian sx – weekly during titration period, then q3months once pt has been stabilized
- Safety
- CNS psychosis –> monitor confusion, agitation, hallucinations, depression
- Abnormal involuntary movements (AIMs) –> sx are dose-related (minimized w/ dose reduction); must titrate dose to minimize AIMs
- CV –> orthostatic hypotension (especially when initiating therapy, usually decreases w/ continued therapy)
- GI –> N/V (especially w/ initiating therapy; usually decreases w/ continued therapy); take w/ food/milk
- Convenience –> swallowing/ motor fluctuation management
44
Q
Pt counselling for Parkinson’s
A
- Medication administration times –> IR carbidopa/ L-dopa is absorbed best on an empty stomach but commonly taken w/ food to minimize nausea
- Ensure pt and/or caregivers understand the prescribed medication regimen
- Inquire specifically about dose-by-dose effects of medication
- Inquire about concerns that caregivers may have about the pt
- Monitor for non-adherence
- Monitor for presence of drugs that can exacerbate idiopathic Parkinson’s disease motor features and anticholinergic agents causing cognitive impairment
45
Q
Non-drug interventions for Parkinson’s
A
- Pt/family education and support
- Physical therapy (improve gait)
- Speech therapy (improve volume)
- Occupational therapy (for mobility, safety, driving skills, maintain social/ family/ work roles)
- Nutrition counselling
- Sleep hygiene
