Parkinsons Disease

Question 1

What is Parkinson’s disease?

Answer 1

Idiopathic, degenerative, CNS disorder with 4 characteristic features

1. Slowness and poverty of movement
2. Muscular rigidity
3. Resting tremor
4. Postural instability

Question 2

Explain the goal of managing PD

Answer 2

Not replace dopamine or cure

But to manage symptoms and maintain function & autonomy

Question 3

How is a diagnosis for PD made?

Answer 3

Based on clinical signs, physical examination, history.
2 of the 3 cardinal signs must be present:
- Tremor (resting tremor)
- Rigidity (“ratchet” like stiffness)
- Akinesia/bradykinesia

Question 4

Features of idiopathic PD at initial presentation

Answer 4

• Asymmetric
• Positive response to levodopa or apomorphine
• Postural instability (&falls) - not present
• Less rapid progression (rapid = H&Y 3 in 3 years)
• Autonomic dysfunction - not present
• Neuroimaging - may not be able to see anything on neuroimaging
• Impaired olfaction?

Question 5

Pathology of PD

Answer 5

Loss of dopaminergic neurons in the substantia nigra
about 80% loss → clinical symptoms

• Age-related
• Environmental toxin/insults
• Genetics

Question 6

What is used to measure PD? What does it measure?

Answer 6

Hoen and Yahr staging of PD
1-5
(1 is mildest symptoms, 5 is most severe symptoms)
Assesses mobility (not nonmotor symptoms)

Question 7

How many % of neurons need to be lost before seeing symptoms?

Answer 7

80%

Question 8

Which agents are used in early/young onset PD?

Answer 8

Dopamine agonists used in preference to levodopa due to longer elimination half life or duration of action, and prevent the development of dyskinesia

Question 9

Features of early/young onset PD

Answer 9

Slower disease progression 
Features 
- Less cognitive decline
- Earlier motor complications
- Dystonia is common initial presentation vs falls and freezing in late onset

Question 10

Which agent can be used to prevent nerves from degenerating, i.e. neuroprotective agent?

Answer 10

No treatment for PD has ever been shown to be “neuroprotective”

Question 11

Are non-pharmacologic treatments important in the management of PD? What are some examples?

Answer 11

Yes. helps patients cope with symptoms.

• PT - stretching, transfers, posture walking
• OT - mobility aids, home and workplace safety
• Speech and swallowing
• Surgery

Question 12

Pharmacological management of PD

Answer 12

Increase central dopamine, dopaminergic transmission

• Levodopa + DCI
• Dopamine agonists
• MAO B inhibitors
• COMT inhibitors

Correct imbalance in other pathways

• Anticholinergics
• NMDA antagonists

Question 13

MOA of PD pharmacologicals

Answer 13

Increase central dopamine
Increase dopaminergic transmission
Correct imbalance in other pathways

Question 14

What symptoms are levodopa most effective and less effective in treating?

Answer 14

More effective in bradykinesia and rigidity

Less effective for speech, postural reflex and gait disturbancs

Question 15

Why do we need to administer levodopa with DCI?

Answer 15

Dopamine cannot cross the BBB

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

Question 16

How to increase bioavailability of levodopa?

Answer 16

Add benserazide or carbidopa

Question 17

How is absorption of levodopa affected by high fat or high protein meals? Implication?

Answer 17

Levodopa is absorbed by an active saturable carrier system for large neutral amino acids

If patients are required to be on high protein meals, need to seperate the administration of both by at least 2 hours.

Question 18

What are the targets in reducing peripheral conversion of levodopa and dopamine? Examples of each?

Answer 18

Decarboxylase (carbidopa, benserazide)
COMT (entacapone)
MAO-B (selegiline)

Question 19

Do DCIs cross the BBB?

Answer 19

No, they do not

Question 20

Adverse effects of levodopa

Answer 20

• Nausea and Vomiting
• Orthostatic hypotension
• Drowsiness, sudden sleep onset
• Hallucinations, psychosis
• Dyskinesias (usual onset: 3-5 years of initiating treatment with levodopa)

Question 21

Motor complications with levodopa

Answer 21

“on-off phenomenon”
“wearing off”
Dyskinesias

Question 22

What is the “on off phenomenon”?

Answer 22

ON = response to levodopa
OFF = no response to levodopa
Mechanism unclear

Question 23

What is the “wearing off” phenomenon?

Answer 23

Effect of levodopa wanes before the end of the dosing interval
Shortened “ON” time
Associated with disease progression

Question 24

How to manage “wearing off”

Answer 24

Modify times of administration

Replace with modified-release preparations at the appropriate time

Question 25

What is dyskinesia? When does it occur and how to manage?

Answer 25

Involuntary, uncontrollable twitching and jerking
Peak dose
Management: add amantadine, replace specific doses with modified release levodopa

Question 26

What are the changes in levodopa response associated with progression of PD?

Answer 26

In early PD: long duration of motor response, low incidence of dyskinesia
Moderate PD: shorter duration of motor response, increased incidence of dyskinesia
Advanced PD: short duration motor response, “ON”-time consistently associated with dyskinesia

Question 27

What is the advantage of sustained release Levodopa?

Answer 27

Releases levodopa/DCI over a longer period which mitigates the wearing off effect

Question 28

Why do dose adjustments have to be made with SR levodopa and how are they made?

Answer 28

Lower bioavailability with SR.
IR to SR: generally increase dose needed
SR to IR: generally decrease dose needed

Question 29

Does dosing frequency change when SR formulations of levodopa are used?

Answer 29

No, frequency remains the same even in sustained release formulations