- 2 of the 3 cardinal signs must be present - Tremor: resting tremor (disappears with movement), increases with stress - Rigidity: “ratchet”- like stiffness (cogwheel rigidity); also lead pipe rigidity - 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.

Parkinson's Disease Flashcards by Jocelyn Chan

What are the different types of PD

Idiopathic PD (most often)
Parkinson’s plus (less data on what agents work eg. levodopa):
Multiple system atrophy (aka Shy-Drager syndrome)
Progressive supranuclear palsy
Corticobasal degeneration
Lewy body disease
Parkinsonism (manifestation of the syndrome? Different MOA from idiopathic PD)
Drug-induced, toxin-induced
Vascular

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What are the 4 characteristic features of PD

Tremor - resting tremor (not doing anything)
Rigidity - muscular rigidity (cogwheel hypertonic? Increase contraction)
Akinesia - slowness & poverty of movement
Postural instability (gait)

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How to diagnose PD?

2 of the 3 cardinal signs must be present
Tremor: resting tremor (disappears with movement), increases with stress
Rigidity: “ratchet”- like stiffness (cogwheel rigidity); also lead pipe rigidity
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.

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What features appear at initial presentation of idiopathic PD

Asymmetric
Positive response to levodopa or apomorphine
Postural Instability (& falls)- not present at diagnosis
Less rapid progression (rapid= H&Y 3 in 3 years)
Autonomic dysfunction– not present
Neuroimaging- ??
Impaired olfaction (?)
Honeymoon period of 1st 3 yrs whr even w diagnosis, dont need/minimal pharmacological intervention, pt still can lead normal life.

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What happens to pt as PD progresses

Unable to perform basic ADLs (or to perform them safely):
Mobility (walking, using stairs) - increase falls
Feeding self
Grooming, personal hygiene
Toileting
Showering/bathing
Continence (bowel and bladder)
Choking (swallowing problems)
Pneumonia
Falls

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What is the greatest burden of PD

Costs

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What are the features of early/young onset PD <40y/o

Slower disease progression
Features:
< Cognitive decline
Earlier motor complications
Dystonia is common initial presentation vs falls & freezing in late-onset
Dopamine agonists used in preference to levodopa

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What is goals of tx for PD

No cure
Manage symtpoms
Maintain function and autonomy
No treatment for PD has ever been shown to be “neuroprotective”

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What are the classes of drugs for PD Tx

Increase central dopamine, dopaminergic transmission:
- Levodopa + DCI
- Dopamine agonists
- MAO B inhibitors
- COMT inhibitors

Correct imbalance in other pathways
- Anticholinergics
- NMDA antagonists

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What is nonpharm tx for PD

PT (help them move):
- Stretching, transfers, posture
- Walking (draw a line or shine a light then they walk towards it to “unfreeze” them)

OT:
- Mobility aids, home &
- Workplace safety
- Speech & swallowing (how big can they swallow? Can crush?)
- Surgery

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Which drug is most effective for treating PD smx

Levodopa

Esp bradykinesia & rigidity
Less effective for speech, postural reflex & gait disturbances

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Can dopamine be used as a treatment? Why?

No, it does not cross the blood-brain- barrier

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SE of levodopa

N/V (take with meals), orthostatic hypotn, drowsiness, sudden sleep onset, hallucinations, psychosis, dsykinesias

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How does levodopa work?

Peripheral conversion of levodopa to dopamine: Is catalysed by DOPA decarboxylase, MAO, COMT

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Why are DCI (benserazide, carbidopa) added to levodopa?

Increased bioavailability, prevents break down on levodopa outside of BBB

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What type of meals affect absorption of levodopa

Absorption ↓ with high fat or high protein meals.

Counselling: space apart from heavy meal.

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Does DCI cross BBB?

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What is dose of levodopa

75-100mg daily

DCI : levodopa
either 1:4 or 1:10

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What is the “On-off” phenomenon?

ON = response to levodopa (helps gain mobility -> so less adherence issues),
OFF = no response to levodopa
Unpredictable, not related to dose/dosing interval (cant tweak dosing regimen)
“throwing a light switch”
Mechanism unclear
Difficult to control with meds

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What is the “wearing off” complication and how to manage it

Effect of levodopa wanes before the end of the dosing interval
Shortened “ON” time
Associated with disease progression
Management:
Modify times of administration, and/or
Replace with modified-release preparations at the appropriate time

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What is dyskinesias motor complications and how to manage?

Can be unpredictable like “on-off” even if you flatten the peak dose so add amantadine
Involuntary, uncontrollable
Twitching, jerking
Peak dose dyskinesia
Dystonia
Management : add amantadine; replace specific doses with modified-release levodopa

How to dose adjustment when switching btw immediate release and controlled release forms?

IR to CR : generally ↑ dose needed (~25%,-50%)
CR to IR : generally ↓ dose needed

Sustained released forms are useful for __

↓ stiffness upon waking

Examples of sustained released forms

Sinemet SR
Madopar HBS

What DDI with levodopa?

Pyridoxine: - Cofactor for dopa decarboxylase - Generally not a problem if levodopa is administered with a DCI but do be aware of the possibility of interactions with High dose B6 for haematological problems or in high potency vit B complex tabs Iron: Affects absorption of levodopa -> space out administration Protein: Affects absorption of levodopa -> space out administration Dopamine antagonists: - Metoclopramide, prochlorperazine (N&V) - Antiemetic of choice in PD = domperidone (for GI motility) - 1st gen antipsychotics - if possible, avoid unless thr is indication then R vs B, which is more pressing issue to tackle - Risperidone

Examples of dopamine agonists

Cabergoline Ropinirole Pramipexole

Peripheral SE of dopamine agonists

N&V Orthostatic hypotension Leg edema

Central SE of dopamine agonists

- Hallucinations (usually visual > auditory) - Somnolence, day-time sleepiness (similar to levo due to similar MOA) - Compulsive behaviours: Gambling, shopping, eating, hypersexuality Act on reward system Caregivers need to watch out! Then stop drug

CV SE of dopamine agonists

Fibrosis: - Pulmonary, pericardiac, retro-peritoneal - May be partially reversible upon withdrawal - Lower risk with non-ergot agents Valvular heart disease: Incidence appears to be greater with ergot-derived agents (∴not used often now)

Dopamine agonists vs levodopa place in therapy?

- < motor complications than levodopa but… - > hallucinations, sleep disturbances, leg oedema, orthostatic hypotension - No clinically significant differences in efficacy between agents - Frequently preferred over levodopa in younger patients: to maximise treatment options and delay the onset of levodopa- induced motor complications (unless rly bothered by tx)

Dopamine agonists place in therapy?

- Monotherapy In Young-onset PD - Adjunct to levodopa in moderate/severePD - Management Of Motor Complications Caused By Levodopa -> can give lower dose - Neuroprotection, disease modification??

Which PD drug is available as transdermal patch?

Rotigotine

Examples of MAO-B inhibitors for PD

Selegiline, rasagiline

What is MAO-Bi place in therapy?

Effective as monotherapy in early stages

Dose of selegiline

5mg OM to BD (second dose in afternoon)

Dose of rasagiline

0.5 to 2mg once daily

DDI with MAOBi

- SSRIs, SNRIs, TCAs: Wash out periods recommended - Pethidine, tramadol, - Linezolid - Dextromethorphan - Dopamine - Sympathomimetics : nasal decongest eg. pseudoephedrine, phenylephrine - Another MAOi

Food interactions with MAOBi

tyramine, cheeses, meat, soy sauce

Among levodopa, dopamine agonists and MAOBi, which has more improvements in motor smx and more motor complications?

Levodopa

Example of Catechol-O-Methyl Transferase Inhibitors (COMT-i)

Entacapone

DDI with entacapone

- Iron, calcium, - Avoid concurrent nonselective MAOi (but safe with MAO- Bi, caution with selective MAO-Ai) - any catecholamine drug - Enhance anticoagulant effect of warfarin

SE of entacapone

Diarrhoea, urine discolouration (orange), dyskinesia upon initiation, orthostatic hypotn, N/V

Which drug must Entacapone be taken with

Levodopa

Anticholinergics place in therapy

Limited use, primarily used to control temors

Example of anticholinergic used in PD

Benzhexol

NMDA antagonists place in therapy

Adjunctive, manage levodopa-induced dyskinesia

SE of NMDA antagonist

Nausea, light headedness, insomnia, confusion, hallucinations, livedo reticularis

What complementary medicines have shown some effect for PD

Co-enzyme Q10 Creatine Vit E Gluthathione Riboflavin Lipoic acid Acetyl carnitine Curcumin

How to differentiate drug induced parkinsonism vs PD

Smx tend to occur bilaterally in DIP Withdrawal of the drug usually leads to improvement in 80% of smx in 8wks

Examples of drugs that can induce parkinsonism

High risk: Typical antipsychotics Atypical antipsychotics a-methyldopa Cinnarizine Intermediate risk: Valproate, phenytoin, levetiracetam Prochlorperazine, metoclopramide Diltiazem, verapamil Lithium