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

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

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

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.

Early Parkinson’s Disease Clinical Diagnosis

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

How Do PD Medications Work?

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

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.

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.

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

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

Follow-up Appointment 1 Month Later...

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

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

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

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.

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

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

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

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

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

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

Leaves with Prescription for Rasagiline

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

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

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

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

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

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.

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

“Change is the only constant.” Heraclitus

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

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

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

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 3-3.5 hours Some doses take a long time to kick in Dyskinesia moderately embarrassing Still taking rasagiline

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)

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

Option #2 COMT Inhibitor Give along with levodopa doses

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

Option #3 Levodopa Adjustments Different dosing strategy or formulation

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.

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

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

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

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

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

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

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

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

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

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

Financial Assistance for Prescription Costs Patient Access Network (PAN) Foundation 1 (866) 316-7263 www.panfoundation.org Up to $16,500 in prescription cost coverage per year for eligible patients

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

“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