Parkinson

A Dive into the Different Parkinson’s Drug Classes – Webinar notes Stanford PD Community Blog

In late April, the Parkinson and Movement Disorder (PMD) Alliance hosted a webinar on the different drug classes for Parkinson’s disease (PD) medication. The speaker was movement disorder specialist Dr. Yasser Torres-Yaghi.

There are multiple medications available to help improve the quality of life of individuals with PD.  The five major drug classes that Dr. Torres-Yaghi focused on are dopamine agents (such as levodopa), COMT inhibitors, MAO-B inhibitors, anticholinergics, and amantadine. 

According to the speaker, polypharmacy, using a combination of medications that treat different systems and symptoms, is a common approach. It may help with some of the motor complications as well as minimize the side effects associated with high doses of one medication.  The goal of medications are to provide symptomatic relief, reduce functional disability, reduce or delay long-term complications of drug therapy, and slow disease progression “neuroprotection.” 

For more information on medications used in PD, please see this Stanford Parkinson’s Community Outreach webpage: 

PD Medications

The session recording can be found on the PMD Alliance’s YouTube channel here.

See below for notes on the April 22nd webinar.

Regards, 

– Joëlle Kuehn


“A Dive into the Different Parkinson’s Drug Classes” – Webinar notes

Speaker: Yasser Torres-Yaghi, MD, movement disorder specialist, Director of the Parkinsonism and Dementia Clinic, MedStar Georgetown University Hospital, Washington, DC

Webinar Host: PMD Alliance

Webinar Date:  April 22, 2021 

Summary by Joëlle Kuehn, Stanford Parkinson’s Community Outreach

Goal – management of PD:

  • Provide symptomatic relief
  • Reduce functional disability – improve functional capabilities
    • Exercise, mood, staying alert
    • Mitigate motor fluctuations
  • Reduce or delay long-term complications of drug therapy
    • Motor fluctuations
    • Dyskinesia
  • Slow disease progression “neuroprotection”

Clinical decision-making in:

  • Disease severity
    • Degree of functional impairment
    • Impact on quality of life
  • Age of patient
    • Comorbidities
    • Risk of acute drug intolerance
    • Risk of long-term complications

Treatment options:

  • Preventative treatment
    • No definitive treatment available
  • Symptomatic treatment
    • Pharmacological (with medications)
    • Surgical (non-pharmacological)
  • Non-motor symptoms management
  • Restorative
    • Is experimental only
    • Transplantation
    • Neurotrophic factors

Major drug classes in PD:

  • Dopaminergic agents
    • Levodopa
    • Dopamine agonists
  • COMT inhibitors
  • MAO-B (monoamine oxidase – B) inhibitors
  • Anticholinergics
  • Amantadine

Can be best to use a “cocktail” of different medications that work on different symptoms

Anticholinergics:

  • Dopaminergic depletion causes cholinergic overactivity
  • Initially used in the 1950’s
  • Effective mainly for tremor and rigidity
  • Common agents (start low, and increase doses slowly)
    • Trihexyphenidyl (Artane): 2 – 15 mg/day
    • Benztropine: 1 – 8 mg/day
    • Ethopropazine: 10 – 200 mg/day
  • Side effects:
    • Dry mouth, sedation, delirium, confusion, hallucinations, constipation, urinary retention
    • Isn’t always an option for many of our patients, not everyone is a good candidate for this
    • If someone is already struggling with constipation, urinary retention, this medication may not be for them.  We have to consider PD symptoms, and other conditions they may have

Amantadine:

  • Antiviral agent; PD benefit found accidentally
  • Helps with: tremor, bradykinesia, rigidity, dyskinesias
  • Exact mechanism unknown; however it is possibly:
    • Enhancing release of stored dopamine
    • Inhibiting presynaptic reuptake of catecholamines
    • Dopamine receptor agonism
    • NMDA receptor blockade (can help reduce dyskinesia)
  • Side effects – autonomic (lower extremity swelling, low blood pressure), psychiatric (confusion)
  • 200-300 mg/day.  Difference between medication that causes side effects and medication that provides benefit can be the dose
  • Long acting formulation: Gocovri 

Carbidopa/Levodopa (Sinemet):

  • Gold standard for PD
  • Most effective drug for parkinsonism symptoms 
  • First developed in late 1960’s; rapidly became the drug of choice for PD
  • Large neutral amino acid; requires active transport across the gut-blood and blood-brain barriers
  • Rapid peripheral decarboxylation to dopamine without a decarboxylase inhibitor (DCI’s: carbidopa, benserazide)
  • Side effects: nausea, postural hypotension (blood pressure changes when going from sitting to standing), dyskinesias, motor fluctuations
  • Different formulations: immediate release, controlled release, inhaled levodopa – changes onset (how long it takes to work) and duration (how long it works)
  • One capsule can have both immediate and controlled release

MAO-B (monoamine oxidase – B) inhibitors:

  • Selegiline:
    • Irreversible MAO-B (monoamine oxidase – B) inhibitor
    • Clinically activate by inhibiting dopamine metabolism in brain
    • Dosage: 5 mg at breakfast and lunch
    • Side effects: insomnia, hallucinations, nausea (rarely), orthostatic hypotension
    • Potential interactions with tricyclics and SSRI antidepressants (cheese reaction)
  • Rasagiline:
    • Also a MAO-B inhibitor
    • Can potentially delay the need for Levodopa
    • Could have cognitive benefits
  • Safinamide:
    • Reversible MAO-B inhibitor
    • Once daily

COMT inhibitors:

  • Entacapone
  • MOA similar to dopa decarboxylase inhibitors
  • Potentiate levodopa: prevent peripheral degradation by inhibiting catechol O-methyltransferase
  • Reduces levodopa dose necessary for a given clinical effect
  • Helpful for both early and fluctuating PD
  • May be particularly useful for patients with “brittle” PD, who fluctuate between off and on states frequently throughout the day
  • There is a new formulation: Opicapone

Dopamine agonists: 

  • Directly stimulate dopamine receptors
  • No metabolic conversion; bypasses nigrostriatal neurons
  • No absorption delay from competition with dietary amino acids
  • Longer half-life than levodopa
  • Monotherapy or adjunct therapy
  • May delay or reduce motor fluctuations & dyskinesias associated with levodopa
  • May be neuroprotective
  • Common adverse effects:
    • Nausea, vomiting, dizziness, postural hypotension, headache, drowsiness & somnolence, dyskinesias confusion, hallucinations, paranoia 
    • Erythromelalgia, pulmonary & retroperitoneal fibrosis, pleural effusion and pleural thickening; Raynaud’s phenomenon are more common with ergotoline DA’s
  • Can be a patch

There are also some on-demand therapies:

  • Apokyn Subcutaneous: 
    • Injections with a pen, or infusion via a mini-pump
    • Side effects: nausea, vomiting, hypotension
  • Sublingual Apomorphine.  Strip placed under tongue

Deep Brain Stimulation (DBS):

  • High frequency, pulsatile, bipolar electrical stimulation
  • Stereotactically placed into target nucleus
  • Can be activated and deactivated with an external magnet
  • Exact physiology unknown, but higher frequencies mimic cellular ablation, not stimulation
  • Subthalamic DBS:
    • Open label trials
    • Increased “on” time
    • Reduced dyskinesias
    • Reduced medication requirements

Question & Answer:

Question: What dosage of amantadine is required to achieve a therapeutic effect?

Answer: It’s hard to know for each person, but you can give amantadine in varying doses, and you can work your way up to higher doses. There are also different doses, some are one a day, some are multiple times a day.

Question: Can you talk about pimavanserin?

Answer: It can help with psychosis. Having psychosis can prevent from taking other medications, because those medications’ side effects already have hallucinations and delusions. It’s a 5HT2A inverse agonist. It doesn’t block dopamine receptors to avoid psychosis. 

Question: Can you talk about impulse disorders as a side effect?

Answer: Our goal is to titrate to efficacy, start low and find a dose that works. We don’t want to hit the side effect dose, we want to stay away from that. We modify based on the side effect and can bring down the dose. We may not be able to reach a therapeutic dose that fixes it, but we could be on a half dose without any side effects.

Question: Is it true that dyskinesia is a result of taking Sinemet, and that once you develop dyskinesias you can never get rid of them?

Answer: As the medicine kicks in and wears off, you may have dyskinesias. If you do start hitting the threshold of dyskinesias we may add another medicine to bridge the gap, or you may use an extended release function. If you are at that part of the disease it may be hard to get off the medication so the dyskinesias may stay. There are possible surgical alternatives like DBS or infusion pumps. 

Question: How do you manage extreme nausea as a side effect of Sinemet?

Answer: Trimethobenzamide is an anti-nausea medication we use in the US but they stopped making it and the other medications aren’t good for people with PD. We recommend adequate hydration, exercising, crackers, ensuring there’s no gastrointestinal problems, and eating healthy.

Question: Why are there some medications that people with PD can’t take?

Answer: Some medications such as antipsychotics block dopamine receptors, and some are unsafe and shouldn’t be used. Pain medication could worsen constipation and cause confusion. It’s really important to know your medication list and advocate for yourself or have someone to advocate on your behalf so that everyone knows what medication you are on, and which ones you should not be taking. 

Question: Is there an increased risk of melanoma with Neupro (dopamine agonist patch)?

Answer: It will always be on there as a possible side effect, so we may recommend seeing a dermatologist, because all PD patients are at an increased risk of all skin conditions (including melanoma).

Question: What is a good rule of thumb for when a person should consider starting medications if they don’t start right off the bat?

Answer: This is a personal decision. We can start to delay possible symptoms (using MAO-B inhibitors). There might be a treatment option and use for a medication early on. 

Question: What is the maximum dose of Sinemet?

Answer: It’s all personalized, and can also depend on what other medicines they are on, what they can tolerate and what side effects they have.

Question: Where are we in research in terms of a cure? 

Answer: So much has changed. In the present, we have a lot of treatment options. We are looking at disease modifying therapies, and they are in trials currently. We want to modify the disease to make people as asymptomatic as possible. 


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