APDA Symposium: The What and Why of Parkinson’s Medications – Webinar Notes

APDA Symposium: The What and Why of Parkinson’s Medications – Webinar Notes

On November 19-20 the Upper Midwest Chapter of the APDA hosted a Parkinson’s Symposium.  On the second day, movement disorders specialist Dr. Lynn Struck spoke about the What and Why of Parkinson’s Medications.  She gave a quick summary of every medication related to treatment of Parkinson’s symptoms, including the mechanism of operation, what it is best used for, side effects, and dosages.  If you have ever been confused about why you are taking one thing and another person with PD is taking something different, watch this webinar!

Her talk can be seen here. Day 2 video, timestamp 2:45.

This webinar is posted to the Stanford Parkinson’s Community Outreach Program’s webpage on Medications, along with other podcasts, webinars, online articles, and printable information about Parkinson’s medications and medication management.

And now, on to my notes…

– Denise

Upper Midwest APDA, Parkinson’s Symposium, November 19-20

The What and Why of Parkinson’s Medications

Speaker:  Lynn Struck, MD

Parkinson’s Disease 101
Anatomy of PD
Brain Regions Affected by Parkinson’s Disease

  • Basal Gangia – doesn’t get enough dopamine from an area of the brain stem called the
  • Substantia Nigra
    • Lack of dopamine causes tremors, rigidity, bradykinesia (slowness), and balance difficulties, the classic symptoms of PD

[Slide showing the lack of pigmentation in the substantia nigra, which is normally visible in the presence of dopamine]

Etiology of PD

  • The vast majority of people have idiopathic PD, meaning there is no known cause
  • Genetics is the cause in 10-15% of people (multiple genetic variants)
  • Environmental (risk factors include pesticides, organic solvents, well water, living in rural areas)
    • Dr. Struck lives in Iowa, where the incidence of PD is higher than in other parts of the US
  • Genes + environment + age-related factors the most likely cause in many people

PD: Motor Signs (cartoon drawing showing these symptoms) – not all people with PD have all of these symptoms

  • Blank facial expression
  • Forward tilt to posture
  • Slow, monotonous, occasionally slurred speech
  • Reduced arm swing
  • Rigidity and resting tremor of extremities and head
  • Short, shuffling gait

PD: Epidemiology

  • 1 million individuals affected in the US
  • Annual incidence of 60,000
  • Prevalence increasing as population ages – because baby boomers are over age 60, and people are living longer
    • Age 60-70 – Men 406/100,000, Women 298/100,000
    • Over age 80 – Men 4280/100,000, Women 2069/100,000
  • Mean age of onset is 62.4 years
  • Lifetime risk of PD – Men 2%, Women 1.3%
  • 85% of patients are over age 65

Medical Management of PD: General Guidelines

  • Each patient is assessed and treated individually – what’s right for one person are not right for another
    • Consider daily activities (especially if still employed with dependents), underlying medical issues
  • Initiate symptomatic treatment when patient begins to experience functional disability
    • Initial symptom(s) that become disabling may be different from person to person
  • Treat the most bothersome symptoms 
    • It is impossible to eliminate all PD symptoms, so the goal is to minimize the most disabling or annoying
  • Levodopa-sparing strategies should be considered to limit long-term motor complications, especially in younger people
    • Minimize dopamine-replacement therapies as long as possible in younger people
    • This is not as important in older people.  The difference will be explained later in this talk.

Pharmacological Options in PD – just a list

  • Dopaminergic agents
    • Dopamine agonists
    • Carbidopa / levodopa
    • MAO-B inhibitors
    • Anticholinergic agents
  • Antiviral agents (Amantadine, Gocovri)
  • COMT-inhibitors
  • Adenosine A2A receptor antagonists

Advantages of Carbidopa / Levodopa – Sinemet, Sinemet CR (controlled release), Rytary, and Parcopa

  • Most efficacious symptomatic PD medication
  • Virtually all PD patients respond – if someone does not experience symptom relief, the diagnosis of PD should be in question
  • Symptomatic improvement with preserved capacity to maintain activities of daily living (ADLs) and employment
  • May decrease mortality

Disadvantages of Levodopa Treatment in PD

  • Patients may develop motor complications (more details later in this talk)
  • Neuropsychiatric problems (especially in the presence of underlying dementia) – confusion, psychosis
  • Does not treat all features of PD such as 
    • freezing
    • postural instability (balance difficulties)
    • autonomic dysfunction (abnormal sweating, swallowing, blood pressure control)
    • speech abnormalities
    • dementia (about 30% of people with PD have dementia)
  • Does not stop disease progression

Levodopa: Motor Complications

  • Motor fluctuations – medication wears off before the next dose, sometimes medication does not work at all.  When medication is working is an ‘on’ period, when medication is not working is an ‘off’ period.  On-off times can be unpredictable.
    • Up to 50% of patients experience this after 5 years of treatment
    • 70% or more of patients experience after 15 years of treatment
    • Younger people are more likely to experience motor fluctuations than older-onset patients
  • Dyskinesias – involuntary movements related to levodopa 
    • Three types – choreoathetoid, dystonic, and diphasic
  • 3 biggest risk factors: duration / dose of levodopa, disease duration, younger-onset PD (under age 60)

The following are newer medication that Dr. Struck gets asked about the most:
Timed-Release Carbidopa / Levodopa (Rytary)

  • Medication held in microspheres that are engineered to break down at different rates
  • Contains immediate and sustained release levodopa (ratio of carbidopa to levodopa is 1:4)
  • Has been shown to improve “on” time with less troublesome dyskinesias and reduce “off” time by two-fold

COMT (Cathechol-O-Methy-Transferase) – Inhibitors

  • Entacapone (Comtan) – more prescribed due to potential liver function issues with tolocapone
  • Tolocapone (Tasmar) – liver function monitoring is required with tolcapone because of the potential for hepatotoxicity
  • Reducing the Peripheral Metabolism of Levodopa
    • As levodopa is broken down, 2 enzymes are produced:
      • COMT
      • DDC – the carbidopa part of levodopa

COMT Inhibitors: Rationale – COMT Inhibitors prevent the breakdown of levodopa

  • Prolongs levodopa action by inhibiting enzyme COMT, involved in levodopa metabolism 
  • Extend duration of levodopa effect
  • Indicated as adjunct to carbidopa / levodopa for patients experiencing “wearing off”
  • No role as monotherapy (used alone); used only in combination with levodopa

Carbidopa / Levodopa / Entacapone (Stalevo) – available as a generic

  • Indication: Patients with end-of-dosing wearing off
  • Strengths available: CLE 12.5/50/200 ; 25/75/200 ; 25/100/200 ; 31.25/125/200 ; 37.5/150/200 ; 50/200/200
  • Max Dose: 1200 mg/day (CLE 150 * 8)
  • Safety: Safety and tolerability consistent with separate entacapone and carbidopa / levodopa formulation

Dopamine Agonists

  • First Generation
    • Bromocriptine (Parlodel) – no longer prescribed due to unacceptable side-effects and exorbitant cost)
  • Second Generation (more details later in this talk)
    • Ropinirole (Requip)
    • Pramipexole (Mirapex)
    • Rotigotine (Neupro)
    • Apomorphine hydrochloride (Apokyn / Kynmobi)

Advantages of Dopamine Agonist Treatment in PD

  • Directly stimulates dopamine receptors (not dopamine, but makes the brain think its dopamine)
  • Dietary amino acids (proteins) do not interfere with dopamine absorption & transport across the blood-brain barrier
    • Levodopa is an amino acid and proteins are made from amino acids
    • If you eat a high protein meal near the time you take levodopa, the medication competes for absorption with proteins
    • You may not absorb as much levodopa as you need, making symptom relief minimal until your next levodopa dose
  • Longer duration of action than immediate release of levodopa and the controlled variance of levodopa (discussed above) 
  • No metabolic conversion ; bypass degenerating nigrostriatal neurons
    • The nigrostriatal nerve cells are dying
    • Because of that, the effectiveness of levodopa to be broken down into dopamine is impaired.
    • This drug class does not require that conversion
  • Reduce incidence of levodopa-related motor complications (wearing off, random “off” times, dyskinesias)

Disadvantages of Dopamine Agonist Treatment in PD

  • Not as effective as carbidopa / levodopa.  Can be used early in the disease or as an addition to carbidopa / levodopa.
    • At some point everyone must take carbidopa / levodopa
  • Specific side-effects 
    • Sedation – people have been known to fall asleep while driving, without any warning 
    • Compulsive / obsessive tendencies
    • Orthostatic hypotension – blood pressure drop when changing position (laying to sitting/standing, or sitting to standing)
      • more likely to happen taking these medications than when taking carbidopa / levodopa
    • Increased likelihood of confusion
  • Does not completely prevent development of levodopa-related motor complications (dyskinesias)
  • Does not treat all features of PD (freezing, postural instability, autonomic dysfunction, dementia), same as carbidopa / levodopa

Monoamine Oxidase Type B (MAO-B) Inhibitor

  • Selegiline – not often used.  
  • If this class of drug is an option in your care, discuss the pros and cons of these 3 with your doctor:
    • Rasagiline mesylate (Azilect)
    • Sydis selegiline (Zelapar)
    • Salfinamide (Xadago)
  • Monoamine oxidase type B is an enzyme that naturally breaks down dopamine in your brain
  • Monoamine oxidase B inhibitors inhibit dopamine metabolism in the brain – therefore, more dopamine is available in the brain for longer

Amantadine (Gocovri, Symmetrel)

  • Antiviral agent discovered by chance to have antiparkinson activity
  • May be useful in early PD, especially for bradykinesia and/or tremor
  • This is the only medication some people can tolerate
  • Useful as an adjunct to levodopa when levodopa does not provide adequate symptom relief or smoothing out on/off times
  • May decrease dyskinesias
  • Side-effects:  leg edema, livedo reticularis (skin mottling, usually in the legs, mostly cosmetic), hallucinations can be significant, confusion
  • Dosage: 200-300 mg/day

Gocovri (amantadine extended-release capsules)

  • Extended-release formulation of amantadine taken once daily at bedtime
  • Provides a slow, steady release of medication during sleep, providing plasma drug levels of the drug during the daytime approximately twice that of immediate release amantadine
  • Effective with wearing off of carbidopa / levodopa
  • Reduced dyskinesias by 37-46%
  • Most common side-effects (there are many others your physician should talk with you about)
    • Hallucinations (8%)
    • Orthostatic hypotension
    • Livedo reticularis

Duopa (carbidopa / levodopa enteral suspension)

  • Continuous delivery of levodopa to the jejunum (small bowel) via a PEG-J tube and an external programmable pump
  • Reduced “off” time by 4hrs vs. 2.1 hrs for placebo
  • Similar improvement in “on” time without troublesome dyskinesias
  • Majority of side-effects occurred in the immediate postop period (infection, bleeding, etc.)
  • Can cause vitamin B6 deficiency
  • Withdrawal can occur if treatment is suddenly stopped (i.e. there is a pump failure or j-tube migration)

Anticholinergics – trihexyphenidyl (Artane); enztropine (Cogentin)

  • Dopamine depletion leads to overactivity of cholinergic neurotransmitters.  
    • Anticholinergics try to put the cholinergic neurotransmitters back into better balance
  • Effective mainly for tremor, even dramatically
  • Common agents (start low, go slowly) because side-effects can be significant
    • Trihexyphenidyl: 2-15 mg/day
    • Benztropine: 10-200 mg/day
  • Limited by significant side-effects: dry mouth, significant confusion, constipation, visual blurring, significant urinary retention

Nourianz (istradefylline) – brand new, released early 2020, expensive and some insurance may not cover

  • Adenosine A2A receptor antagonist
  • Thought to reduce overactivity of the striatopallidal pathway involved in Parkinson’s
  • Indicated as adjunctive treatment to levodopa in patients experiencing “off” episodes
  • Studies reveal an additional increase in “on” time without troublesome dyskinesia and a decrease in “off” time
  • Doses: 20-40 mg/day (very long 1/2 life, so only once daily)
  • Most common side-effects (>/=5%)
    • Dyskinesia – due to amplification of levodopa effects
    • Hallucinations / Psychotic behavior – due to amplification of levodopa effects
    • Impulse control / Compulsive behaviors
    • Dizziness – orthostatic hypotension (OH) blood pressure issues when changing posture
    • Insomnia

Inbrija (levodopa inhalation powder) – new drug

  • Approved for treating “off” periods of PD in patients being treated with carbidopa / levodopa
  • Unique in that absorption occurs rapidly in the lung rather than in the gastrointestinal tract
  • Rapid delivery allows management of “off” episodes – rescue medication
    • Takes as little as 10 minutes to be effective
    • Short-acting, about 60 minutes in most people
    • Significantly greater proportion of patients taking Inbrija 84mg (58%) vs. placebo (36%) returned to an “on” state and sustained “on” through 60 minutes
  • Dose: 84 mg; up to 5 times daily
    • If a person is using it that often throughout the day, your PD meds probably need to be increased
  • Most common side-effects:
    • Cough (15% vs. 2% in placebo group)
    • Nausea (5% vs. 3%)
    • Upper respiratory complaints (6% vs. 3%)
    • Discolored sputum (%5 vs. 0%)
  • Not recommended in patients with asthma, COPD, or other chronic lung diseases

Kynmobi (apomorphine HCI) sublingual film – new medication

  • Sublingual film used to treat short term (acute) intermittent “off” episodes – rescue medicatioin
  • Clinical improvement in 15 minutes & persists 90 minutes
  • Indicated for:
    • Morning “off”
    • Wearing “off” and delayed “on”
      • Example: need to get to work on time but medications haven’t kicked in, yet
      • Out golfing and feel your medications wearing off.  You don’t want to be stuck out there!
    • Unpredictable / Unexpected “off”
      • This is more common in advanced PD
  • High incidence of nausea / vomiting – therefore often initially started with an antiemetic (anti-nausea) medication
  • With initiation of medication, blood pressure and pulse require monitoring
  • Common side-effects:
    • Drowsiness
    • Dizziness (due to low blood pressure)
    • Nausea / vomiting (often just the first few weeks)
    • Oral mucosa irritation
    • Obsessive-compulsive behaviors (because it is a dopamine agonist)
  • Dose: must be titrated
    • If you start with too high a dose it will cause a blood pressure drop.  Start with a low dose and take blood pressure.  Increase dose and take blood pressure repeatedly until the right dose for you is found.

Northera (Droxidopa) – newer, more expensive 

  • Newer drug used to treat orthostatic hypotension (OH) caused by primary autonomic failure, including PD
    • There are older, cheaper, medications used to treat OH
    • If those don’t work, try Northera.  If your insurance won’t cover, they may with a letter from your doctor that you have tried all other medication options.
  • Improved standing systolic blood pressure
  • Common side-effects:
    • Headache
    • Dizziness
    • Nausea
    • Hypertension – too high blood pressure

Nuplazid (pimavanserin) – multiple other medications may be tried first

  • Used to treat delusions / hallucinations associated with PD psychosis in elderly patients
  • Does not impact motor function in PD, with other antipsychotics can amplify PD symptoms
  • Most common side-effects: 
    • Peripheral edema (swelling in the feet)
    • Nausea
    • Confusion
    • Constipation
    • Gait difficulties
  • Risk of QT prolongation and serious arrhythmia and heart rate – If your doctor is considering that you should take this medication and you have a heart condition; your cardiologist should be involved in the decision as to whether it is safe for you to take.

Future Goals: Unmet Needs in PDThere are many drugs in the pipeline that instill a lot of hope in Dr. Struck.  Unfortunately, research has been slowed due to COVID-19.

  • Long-acting catechol-O-methyl transferase inhibitors
  • Subcutaneous levodopa infusions, like an insulin pump with a needle under your skin
  • Subcutaneous apomorphone, continuous infusion
  • Many medications that provide true disease modification and halt/slow progression of neurodegeneration

Questions and Answers

Q.  There was a question about medication costs.
A.  Wisconsin, Iowa, and Minnesota chapters of the APDA offer a patient aid program so anyone with PD can apply once yearly for patient aid funding that can go toward medication, respite care, transportation, adaptive wear, etc.

Q.  Do you know if insurance covers Rytary?
A.  If you have commercial insurance or Tricare, yes.  But it is more difficult to get Medicare to cover it, depending on the rider you have for your supplemental.

Q.  I feel like I take a ton if pills.  Is there anything I can do to minimize that?
A.  If you have underlying conditions, like high blood pressure, diabetes, and Parkinson’s, you should sit with your doctor to see if anything can be done.  If that is not satisfactory, ask to meet with a pharmacologist or meet with your pharmacist.

Q.  You mentioned that after 5 years the efficiency of carbidopa / levodopa reduces.  What would be the next step to try?
A.  The effectiveness continues, but the disease progresses.  You may have to increase the dosage or dosage frequency.  You may have to add an additional medication.  If your symptoms are still not controlled, ask your doctor if deep brain stimulation (DBS) would help your particular symptoms.

Q.  Does the amount of drugs needed change after DBS?
A.  Immediately following DBS, medications don’t change.  It isn’t until we turn on the DBS generator it is at a very low setting, which increases over time.  So, it is a gradual process of adjusting the DBS and reducing medications.  Most people are able to reduce medications by 30-40%.

Q.  Are you aware of any new drugs in the pipeline?
A.  There is a new COMT inhibitor and there’s a new apomorphine with a pump and levodopa in a pump, similar to an insulin pump.

Q.  I’ve heard terazosin (Hytrin) may slow the progression of PD.  Do you know anything about that?
A.  Terazosin (Hytrin) is an old drug.  There is very early, small research in a phase II trial being done in Iowa.  Unfortunately, covid interrupted that research.

Q.  Are you aware of any gene therapy in the pipeline?
A.  There are several, including genetic transfer treatments, but everything is on hold due to covid.
People are putting messages in the chat with thanks for giving hope with medications in the pipeline

Q.  Are there vitamins or supplements I should be taking for PD?
A.  Coenzyme Q10 has shown benefit, anywhere between 600-800 mg/day.  Vitamin D supplements, especially for those in northern hemispheres.

Q.  Are you aware of any good research articles regarding supplements?
A.  No.  I go by medical training.  APDA may have something posted or be able to give you a link to something for the general public.

Q.  I took Azilect for many years but stopped so I could take Zoloft.
A.  Research has shown that it is safe to take these medications together in low doses as long as blood pressure is monitored.

Q.  What’s the best way to stay on top of medication changes and trials?
A.  The APDA, Parkinson’s Trials, The American Academy of Neurology, and the NIH.

Q.  What age is too old for DBS?
A.  The health of the individual is the biggest issue.  If you are 79 with no health issues who exercises and has no cognitive issues I would proceed with surgery.  If you are a 65-year-old with diabetes, heart disease, and other issues I would not proceed.  Personally, over age 80 the risk-benefit starts to slip.

Q.  How do I get my spouses doctor to talk to them about when it’s time to stop driving?
A.  Most doctors will do screening if they see you are not doing well from a cognitive perspective.  I ask the patient if they’ve had any accidents and I ask care partners if they are afraid to drive with the person with PD.  I take a look at response time of their feet.  If you are concerned, you can leave a note with the nurse or email the doctor asking the doctor to bring up the issue at your husband’s next appointment.  There are driver training programs for seniors he can try to either improve skills or receive a professional evaluation of driving ability.  That way, it isn’t the family who is removing his ability to drive.