1. Parkinson’s Disease Medications
Teresa Mangin, MD
UW Department of Neurology
Movement Disorders

2. “Every art should become science, and every science should become art
-Friedrich von Schlegel

3. A Patient Walks into the Neurologist’s Office. . .

4. 59 year-old woman Right hand tremor Smaller handwriting Softer voice
Dream enactment behavior
Gradually progressive over the last 6 months.
Concerned that she may have PD.
School principal - not functionally impaired at work but feeling somewhat self conscious.
Mild but definite signs of parkinsonism on exam.

5. Early Parkinson’s Disease
Clinical Diagnosis

6. Choice of Therapy Should be Individualized
Manifestations of the disease
Patient preferences
Age
Other medical conditions and medications
Functional goals
Level of physical activity

7. How Do PD Medications Work?

9. Drug Class Generic Name Brand Name Levodopa carbidopa-levodopa
Sinemet, Parcopa, Rytary, Duopa
Dopamine Agonist
Pramipexole
Ropinirole
Rotigotine
Apomorphine
Mirapex
Requip
Neupro (patch)
Apokyn
MAO-B Inhibitor
Selegiline
rasagiline
Eldepryl, Deprenyl, Zelapar
Azilect
COMT Inhibitor
Entacapone
Tolcapone
Comtan, Stalevo
Tasmar
Anticholinergic
Benztropine
Trihexyphenidyl
Cogentin
Artane
Amantadine
Symmetrel

10. Option #1 No Medication
Encourage exercise, adequate sleep, stress minimization. Close follow up. Medication is symptomatic treatment and no medication has thus far been proven to slow disease progression.

11. Option #2 Go Right to the Gold Standard
Levodopa (Sinemet)
Levodopa is the most effective medication and most direct way of augmenting dopamine levels in the brain.
It does not stop working sooner if you start it earlier.
There are some potential complications of levodopa use that tend to develop in ½ of patients by 5 years on tx.
Is it toxic to dopamine nerve cells? Conventional wisdom says no.

12. Option #3 Levodopa-Sparing
MAO-B Inhibitor
Dopamine Agonist
Amantadine
Anticholinergic
MAO-B inhibitor (selegiline or rasagiline). Advantages of less frequent dosing and good tolerability. Disadvantages of potential drug interactions and lack of potency.
DA - slow titration, many potential side effects vs good efficacy for many patients, once daily formulations
Amantadine or an anticholinergic - potential cognitive side effects, etc

13. The patient decides to postpone medication for tremor.
She starts melatonin for sleep symptoms.

14. Follow-up Appointment 1 Month Later...

15. Time to Process the Diagnosis is Important
Dream enactment behavior resolved with melatonin
Some anxiety about the future
More self-conscious about tremor
Walking and arm-swing improved with exercise
Wants to start treatment
Concerns about levodopa
Ready to start a medication for PD, but wants to be sure it won’t impact cognition or cause sleepiness

16. Early Treatment is Favored in PD
Opportunity to forestall clinical progression
Maintenance or improvement of function
Prevention of secondary complications
Lack of evidence for long term toxicity
Difficulty titrating meds in crisis mode
Restoration of normal dopa- minergic tone is hypothesised to reset the basal ganglia function towards normal, and to support or reverse the compensa- tory systems, including those that are deleterious.1 The results of several large double blind randomised placebo con- trolled studies support this hypothesis. DATATOP, TEMPO and ELLDOPA used different dopaminergic agents in patients with early PD and showed that those patients who began active treatment as opposed to placebo were better off, even when that treatment was stopped (ELLDOPA) or when placebo was subse- quently switched to active drug (TEMPO). This evidence has swung the pendulum towards earlier treatment for PD, and physicians may bear this in mind when considering treatment initiation for an individual patient.
The onset of motor symptoms in PD significantly affects a patient’s health status.1,2 This effect on health status is even more pronounced when patients are untreated.3
In an 18-month observational study in the UK, patients left untreated after diagnosis showed a significant decline in a PD self-reported health status measurement compared with those who received treatment in the early phase.3
Initial treatment consisted of LD in 51% of patients, dopamine agonists in 43%, and other (ie, selegiline, trihexyphenidyl, and amantadine) in 6%.3

17. Untreated Parkinson's Patients Experience a Significant Decline
*Initial treatment included levodopa, LD (51% of patients), dopamine agonists (43%), and other (6%). Horizontal line within box=median value; box edges=lower and upper quartiles; whiskers display range.
Untreated Parkinson's Patients Experience a Significant Decline
in Self-Reported Health Status Over 18 Months

18. Option #2 Go Right to the Gold Standard
Levodopa (Sinemet)
Levodopa is the most effective medication and most direct way of augmenting dopamine levels in the brain.
It does not stop working sooner if you start it earlier.
There are some potential complications of levodopa use that tend to develop in ½ of patients by 5 years on tx.
Is it toxic to dopamine nerve cells? Conventional wisdom says no.

19. Of patients 40-59 at onset will develop dyskinesia by 5 years.
50%
Of patients at onset will develop dyskinesia by 5 years.

20. Option #3 Levodopa-Sparing
MAO-B Inhibitor
Dopamine Agonist
Amantadine
Anticholinergic
MAO-B inhibitor (selegiline or rasagiline). Advantages of less frequent dosing and good tolerability. Disadvantages of potential drug interactions and lack of potency.
DA - slow titration, many potential side effects vs good efficacy for many patients, once daily formulations
Amantadine or an anticholinergic - potential cognitive side effects, etc

21. MAO-B Inhibitors Boost Dopamine
Selegiline (Eldepryl, Deprenyl, Zelapar)
Rasagiline (Azilect)
Prevent recycling of dopamine in the synapse
Prolong the action of levodopa

22. Dopamine Agonists Mimic Dopamine Effects
Ropinirole (Requip)
Pramipexole (Mirapex)
Rotigotine (Neupro)
May delay onset of dyskinesia
Longer acting than levodopa
Problematic side effects

23. Amantadine Can Be Used First-Line
Multiple pharmacologic properties
Promotes release of dopamine
Inhibits dopamine reuptake
Effects on glutamate, acetylcholine
Useful for tremor
Can help with fatigue

24. Anticholinergic Medications Can Help Tremor
Used mainly for tremor
Trihexyphenidyl (Artane), benztropine (Cogentin)
Dose limiting side effects
Avoided in the elderly

25. Leaves with Prescription for Rasagiline

26. Follow-up 9 months Later...
More Bothersome Symptoms

27. Treatment Should Match Functional Goals
Tremor more obvious and bothersome
Difficulty knitting, writing, typing, buttoning shirts
Wants to continue working
Prefers to postpone levodopa

28. Dopamine Agonists Mimic Dopamine Effects
Ropinirole (Requip)
Pramipexole (Mirapex)
Rotigotine (Neupro)
May delay onset of dyskinesia
Longer acting than levodopa
Problematic side effects

29. Patient has recently been hospitalized
3 years later. . .
Patient has recently been hospitalized
Hospitalization can be a risky time - getting meds on schedule, being exposed to meds that make PD worse, higher risk of delirium, etc

30. PD-related Complications in the Hospital
Disruption of normal med schedule
Side effects from commonly used medications
Increased risk of post-operative delirium

31. Some Medications Should be Avoided in PD
Anti-nausea medications and antipsychotics have dopamine-blocking properties.
Narcotics less likely to be tolerated in PD patients.

32. Periodic Medication Review is Important
Patient is now ~4 years post diagnosis, age 63
Treated with MAO-B and dopamine agonist so far
Recovering from hospitalization with complications
Noticing ankle swelling, daytime sleepiness
Family reveals some behavioral changes
ICDs with dopamine agonist

33. “Change is the only constant.” Heraclitus

34. PD Symptoms Evolve Over Time
Tremor in both sides, worse on the right
More difficulty with fine motor tasks in both hands
Toe and foot cramps during the night and morning
Stiffness of muscles on exam
Goal of weaning off dopamine agonist, due to side effects
ICDs with dopamine agonists

35. Levodopa Remains the Gold Standard
Always given with carbidopa
Converted to dopamine in the brain
Most effective medication for motor symptoms of PD
Does not produce tolerance
Several dosage forms

37. Wearing Off and Dyskinesia
Fast Forward 4 Years...
Wearing Off and Dyskinesia

38. Mid-stage PD Presents Unique Challenges
Patient now 67, 8 years post-diagnosis
Good function during “on” time
Taking levodopa every 4 hours, lasting about hours
Some doses take a long time to kick in
Dyskinesia moderately embarrassing
Still taking rasagiline

39. There are Many Strategies for Wearing Off
Add a COMT inhibitor or MAO-B inhibitor
Add a dopamine agonist
Increasing dose of levodopa
Dose levodopa more frequently
Continuous levodopa infusion (Duopa)

40. Option #1 MAO-B Inhibitor
Our patient already on rasagiline

41. Option #2 COMT Inhibitor
Give along with levodopa doses

42. Option #3 Dopamine Agonist
Contraindicated in our patient due to ICD

43. Option #3 Levodopa Adjustments
Different dosing strategy or formulation

44. Approach is Informed by Past Treatment
Our patient is already on an MAO-B inhibitor (rasagiline).
Dopamine agonists should be avoided due to ICD.
We can still try a COMT inhibitor or a different formulation of levodopa.

45. COMT Inhibitors Can Smooth Out Fluctuations
Only given in conjunction with carb/levo
Entacapone (Comtan or Stalevo) works peripherally
Tolcapone (Tasmar) works peripherally and centrally
More potent
Requires liver function monitoring
Diarrhea, dark discoloration

46. Rytary is a Longer Acting Carbidopa-Levodopa
Capsule with timed release
Intended to last >4-5 hours
Decreased frequency of dosing
Requires an overall increased dose
Helpful for some patients

47. Duopa Allows Continuous Coverage
Tube delivers levodopa to small intestine at steady rate
Requires wearing an external cartridge
Allows even dosing over 16 hours
Can reduce off time by 2 hours

48. Dyskinesia May Prompt Med Adjustments
Redistribution of PD Meds
Reduction of doses of PD Meds
Addition of amantadine

50. Amantadine Has a Niche for Dyskinesia
Multiple pharmacologic properties
Promotes release of dopamine
Inhibits dopamine reuptake
Effects on glutamate, acetylcholine
Can reduce dyskinesia by 25-45%
Benefit may be temporary

51. Cognitive Symptoms and Visual Hallucinations
Fast Forward 10 years. . .
Cognitive Symptoms and Visual Hallucinations

52. Visual Hallucinations Can Progress
Patient now age 77, 18 years after diagnosis
Frequent well-formed visual hallucinations
Insight retained
Non-threatening
More trouble with complex cognitive tasks
Patient accompanied by spouse and daughter, who are distressed by the visual hallucinations
Cognitive- dysexecutive, IADL impairment

53. Of PD patients experience at least mild hallucinations
66%
Of PD patients experience at least mild hallucinations

54. Cognitive Symptoms = Medication Revision
Streamline PD meds in a specific order
Consider adding a cholinesterase inhibitor
Consider adding quetiapine (Seroquel) or clozapine (Clozaril)
Pimavanserin (Nuplazid)
Pimavanserin serotonin 5HT2A inverse agonist

55. More Frequent Dosing
Add Dopamine Agonist
Add MAO-B or COMT
Streamline Medications
Reduce Doses
Consider Antipsychotic
Monotherapy
More Potent Medication
Increase Doses
Rational Polypharmacy
Reduce Doses
Redistribute Dopaminergics
Consider Amantadine
Early PD
Mild Symptoms
More Symptoms
Cognitive Sx, Hallucinations
Wearing Off
Dyskinesia

56. Financial Assistance for Prescription Costs
Patient Access Network (PAN) Foundation
1 (866)
Up to $16,500 in prescription cost coverage per year for eligible patients

57. Closing Thoughts
Medications play an important part in living well with PD
PD meds help restore brain chemistry
Side effects often influence treatment options
Voice any concerns to your provider
Treatment regimens will change over time

58. “It is not the strongest of the species that survives
“It is not the strongest of the species that survives. It is the one that is most adaptable to change.”
Charles Darwin