L15-L16 Parkinson's Disease Flashcards
Differentiate the various types of Parkinson’s diseases.
1) Idiopathic PD (iPD)
2) Parkinson’s plus (simply variations of PD):
- Multiple system atrophy (aka Shy-Drager syndrome)
- Progressive supranuclear palsy
- Corticobasal degeneration
- Lewy body disease
3) Parkinsonism / Parkinsonian syndrome
- Drug-induced / Toxin-induced
- Vascular
Briefly describe what iPD is.
Idiopathic Parkinson’s Disease:
- Progressive, degenerative CNS disorder w/ 4 characteristic features:
1) Slowness & poverty of movement (i.e. bradykinesia)
2) Muscular rigidity
3) Rest tremors
4) Postural instability (late-stage) - NOT a PNS disorder despite affecting motor functions!
iPD is an idiopathic, progressive degenerative PNS disorder with is typically presented with at least two of the three cardinal symptoms of bradykinesia, rest tremors & muscular rigidity. True or false?
False!
iPD is a CNS disorder, NOT a PNS disorder, despite affecting motor functions.
How is iPD diagnosed in patients?
Based on clinical signs, physical examination & PMHx to exclude DDx of PD:
2 out of 3 cardinal signs must be present:
1) Tremors:
- Resting tremor (disappears w/ movement), increases w/ stress
2) Rigidity:
- “ratchet”-like stiffness (cogwheel rigidity); also leadpipe rigidity
3) Akinesia / Bradykinesia
- Subjective sense of weakness
- Loss of dexterity
- Difficulty using kitchen tools
- Loss of facial expression
- Reduced blinking
- Difficulty getting out of bed/chair
- Difficulty turning while walking
Describe the features in the initial presentation of a patient with iPD.
Asymmetric
Positive response to levodopa or apomorphine
Postural instability & falls usually not present
- If present, useful for DDx of other reasons outside of iPD
Less rapid progression
- Rapid = Hoehn & Yahr (H&Y) 3 in 3 years
- Autonomic dysfunction not present
- Neuroimaging to detect other causes that may be causing parkinsonism
- Impaired olfaction?
What morbidities are often associated with iPD as it progresses?
1) Inability to perform basic activities of daily living (ADLs) (or to perform them safely)
- Mobility (walking, using stairs)
- Feeding self
- Grooming, personal hygiene
- Toileting
- Showering/bathing
- Continence for both bowel & bladder
2) Dysphagia -> Pneumonia
- Epiglottis is NOT working properly, resulting in sialorrhea & choking, due to difficulty swallowing saliva
3) Falls due to poor coordination
Briefly explain the pathology of iPD.
Loss of dopaminergic neurons in the substantia nigra
- About 80% loss results in clinical symptoms
Reasons for loss of dopaminergic neurons:
- Age-related losses
- Environmental toxin & insults via MPTP-MPP+ (intrinsic formulation contaminants), pesticides & herbicides
- Genetic abnormalities, leading to increased predisposition to toxins & insults
What are some non-motor symptoms presented in patients with iPD?
1) Cognitive impairment:
- Dementia
2) Psychiatric symptoms:
- Depression
- Psychosis
3) REM sleep behaviour disorders
4) Autonomic dysfunction:
- Constipation
- Decreased GI motility
- Orthostatic hypotension
- Sialorrhea
5) Fatigue
What are some clinical instruments used to measure the progression of iPD?
1) Hoehn & Yahr (H&Y) Staging
- Assess mobility
- If on treatment, H&Y should be assessed when the person is in the “ON” AND “OFF” state (i.e. on medication and when not taking medication)
2) Unified Parkinson’s Disease Rating Scale (UPDRS)
(a) Mentation, behaviour, mood
- E.g. intellectual impairment, depression
(b) Activities of Daily Living (ADLs)
- E.g. speech, salivation, swallowing, dressing, hygiene, walking
(c) Motor examination
- E.g. facial expression, tremor at rest, gait
(d) Complications of Therapy
- E.g. dyskinesia, clinical fluctuations
3) Movement Disorder Society - Parkinson’s Disease Rating Scale (MDS-PDRS)
- Non-motor experiences of daily living
- Motor experiences of daily living
- Motor examination
- Motor complications
- Modified version of UPDRS
Describe what the onset and disease progression of iPD is like.
20 years prodrome:
- Hyposmia
- Constipation
- Bladder disorder
10 years prodrome:
- Sleep disorder
- Obesity
- Depression
Onset:
- Unilateral rest tremors
- Rigidity
- Akinesia
10 years progression:
- Poor balance
- Bilateral disease
20 years progression:
- Falls, dependency, cognitive decline
- Chair/bed bound, dementia
Describe each stage of the Hoehn & Yahr (H&Y) Staging.
Increasing disability; decreasing indepedence:
1) Symptoms on ONE SIDE of the body ONLY
2) BILATERAL symptoms; NO balance impairment
3) Impaired postural reflexes; physically independent
4) Severe disability, yet still able to walk/stand unassisted
5) Wheelchair-bound or bedridden
Differentiate the progression & treatment plans for patients with young-onset iPD and the typical geriatric patients with iPD.
1) Young-onset PD has a slower disease progression.
2) Feature differences:
- Slower cognitive decline in young-onset pt
- Earlier motor complications in young-onset pt
- Dystonia is the common initial presentation in young-onset pt vs. falls & freezing in late-onset pt.
3) Dopamine agonists are used in preference over levodopa in young-onset pt to reduce motor complications from chronic levodopa Tx
Describe the algorithm used in the identification, diagnosis & prognosis of PD.
1) Identification:
- Presence of 2/3 classical symptoms: Tremors at rest, Rigidity, Akathisia/Bradykinesia
2) Diagnosis
- Refer to specialist & consider the possibility of atypical parkinsonism.
- DDx: early falls, poor response to levodopa, symmetry at onset, rapid progression, lack of tremor, prominent dysautonomia
- Diagnosis is via EXCLUSION of DDx since NO confirmatory tests are available
3) Prognosis
- Predictors of more benign course: Early/young onset, rest tremors
- Predictors of more rapid course: Older onset and rigidity/hypokinesia, postural instability/freezing gait, dementia, associated comorbidities, male gender, poor levodopa response
The use of levodopa in the treatment of Parkinson’s disease (PD) has been shown to be neuroprotective, as it allows for dopamine replacement & thus has the ability to cure PD. True or false?
FALSE
NO Tx for PD has ever been shown to be neuroprotective!!
Therapeutic goals of Tx of PD are:
1) Manage symptoms
2) Maintain function & autonomy
Pharmacological & non-pharmacological treatments are equally important treatment modalities used in the Tx of iPD. True or false?
True
List all available non-pharmacological options to manage the symptoms of iPD progression.
1) Physiotherapy
- Stretching, transfers, posture, walking
2) Occupational therapy
- Mobility aids, home & workplace safety
3) Speech & swallowing therapy
- Pt are usually soft-spoken as a result of dysphagia.
4) Surgery
What pharmacological agents can be used in the symptomatic Tx of iPD?
EITHER
1) Dopaminergic MOA to increase central dopamine & thus dopaminergic transmission
- Levodopa + dopa-decarboxylase inhibitors (DCI) (e.g. benserazide & carbidopa)
- Dopamine agonists (e.g. bromocriptine, cabergoline, pergolide [ergot derivatives], ropinirole, pramipexole, rotigotine (transdermal) & apomorphine (SC) [non-ergot derivatives])
- MAO-B inhibitors (e.g. selegiline, rasagiline)
- COMT inhibitors (e.g. tolcapone & entacapone)
OR
2) Correct imbalance in other pathways
- Anticholinergics (e.g. benztropine & trihexyphenidyl)
- NMDA antagonists (e.g. amantadine)
Describe the algorithm used in deciding the treatment options for pt with iPD.
Upon confirmation of iPD:
1) If NO functional impairment, monitor for disease progression & manage w/ non-pharmacological options
2) If functional impairment present, consider:
- Typical: Immediate-release carbidopa/levodopa
- Young-onset: Dopamine agonist
- Increase dose to max tolerated dose if progression continues
3) If motor complications develop, fractionate carbidopa/levodopa Tx into 5x/day AND consider adding a dopamine agonist, MAO-B inhibitor OR COMT inhibitor.
4) If severe motor fluctuations occur, consider referral for apomorphine Tx.
5) If severe dyskinesia, REDUCE carbidopa/levodopa!
- Change from controlled-release preparation to immediate-release if applicable!!
- Consider changing to amantadine.
6) if no improvement after Steps 4 or 5, refer for possible functional neurosurgery.
Levodopa is most effective in the symptomatic treatment of iPD, especially bradykinesia, rigidity and rest tremors. True or false?
False!!
Levodopa is NOT effective for symptomatic Tx of rest tremors!!
What is the clinical advantage of using levodopa for symptomatic Tx of iPD?
Most effective for symptomatic Tx for bradykinesia & rigidity.
- NOT for rest tremors!!
- Less effective for speech, postural reflex & gait disturbances
Explain why dopamine cannot be used as the symptomatic treatment for iPD.
Does NOT cross the BBB!
Moreover, levodopa (prodrug) is readily converted into active dopamine, BEFORE crossing BBB!
- Catalysed by dopa-decarboxylases, MAO or COMT
- Thus, co-formulation with a dopa-decarboxylase inhibitor is required to block the peripheral conversion of levodopa into active dopamine by dopa-decarboxylases.
- F = 33% w/o DCI; 75% w/ DCI
What are some administration considerations when taking levodopa orally? Why so?
Absorption of levodopa is via saturable active transport of large neutral amino acids (i.e. tryptophan)
- Thus, absorption decreases with high fat or high protein meals due to saturable active transport.
Administration considerations
- Take with high protein load in the evening: Subtherapeutic dose less impactful
- Should NOT change to low protein meals or avoid proteins: Pt need strength to participate in PT & OT
- However, it may be hard to space dosing & meals out when dosing freq. can be up to 5x/day
- 5x/day food intake for pt. on NGT will have clinical problems.
How much levodopa per day will saturation of dopa-decarboxylase be achieved via PO administration?
75-100mg required to saturate dopa decarboxylase.
List all available formulations of levodopa in SG.
DCI : Levodopa
1: 4 - Sinemet, Madopar (i.e. 25/100mcg)
1: 10 - Sinemet (i.e. 25/250mcg)
What are some adverse effects of levodopa?
N/V
Orthostatic hypotension
Drowsiness, sudden sleep onset
Hallucinations, psychosis
Dyskinesia
- NOT a feature of iPD, BUT a key adverse effect of levodopa
- Usual onset w/in 3-5 years of initiating levodopa
Explain what the motor complications of levodopa are, and how they are managed, if any.
1) “On-off” phenomenon:
- On = response to levodopa
- Off = no response to levodopa
- Unpredictable & NOT related to dose/dosing interval
- MOA is unclear & thus difficult to control w/ meds
2) Wearing off:
- Effect of levodopa wanes before the end of dosing interval i.e. shortened “On” interval
- Associated w/ disease progression
- Management includes modifying dosing freq. and/or replace w/ modified-release preparations at appropriate dosing intervals
3) Dyskinesia
- Involuntary, uncontrollable twitching & jerking
- Manifest as peak-dose dyskinesia i.e. happened at peak PDC or
- Dystonia: sudden cramping of muscles; can be painful & associated w/ peak dose
- Management includes adding amandatine (NMDA antagonist) or replace specific doses w/ modified-release levodopa
Explain why there is a need to change the dose, dosing frequency and dosage formulation as iPD progresses.
Due to changes in pre- and post-synaptic receptor responses
- i.e. higher response threshold & lower dyskinesia threshold as PD progresses
- Resulting in increasing dose or dosing freq. to achieve higher peak to cross response threshold, BUT hitting dyskinesia threshold easier
1) Levodopa in early PD:
- Long duration of motor response
- Low incidence of dyskinesia
2) Levodopa in moderate PD:
- Shorter duration of motor response
- Increased incidence of dyskinesia
3) Levodopa in advanced PD:
- Short duration of motor response
- “ON”-time consistently associated w/ dyskinesia
Explain the difference in the formulations of sustained-release preparations of levodopa and in conventional sustained-release formulations of other pharmaceutical drugs.
1) Sustained-release formulations of levodopa/DCI are designed to release levodopa/DCI over a longer period of about 4-6h vs immediate-release formulations
- BUT significantly shorter as compared to conventional sustained-release formulations!!
- Thus, unlike conventional controlled-release formulations, levodopa CR may be given MORE THAN ONCE A DAY to sustain the effect of levodopa (i.e. possibly 3-4x/day)!
2) Sustained-release formulations of levodopa/DCI has LOWER bioavailability compared to immediate-release levodopa formulation
- BUT minimal differences in F in sustained-release formulations of conventional drugs as compared to their immediate-release formulations counterparts!!
Explain how the conversion between immediate-release formulations and controlled-release formulations of levodopa is done.
Due to lower F in controlled-release formulation:
- IR -> CR: Generally increase dose by 25-50%
- CR -> IR: Generally decrease dose since F for IR»_space; F for CR
