Plethora of PD Meds Marian L. Dale, MD Assistant Professor, Neurology Medical University of South Carolina

Thank you! For welcoming me to Charleston and introducing me to your active support group A little about me Oregonlive.com 12 years in NBA, including Portland Trail Blazers – dx at age of 36 in 2008 Exercises programs for young diagonosed

Disclosures No financial interest Provider practice preferences vary Colors may vary The “right” med for PD patients is an individual decision: pro/con discussion between patient and physician Plenty of non-medication ways to treat PD: exercise!!!

Plan of Attack 1. The “big two” symptomatic meds 2. Possibly neuroprotective meds 3. Add-ons for wearing off with levodopa 4. Treatment for dyskinesia 5. Meds for tremor & dystonia 6. Other forms of levodopa and rescue meds 7. Other symptomatic treatments

Overview 1: The “Big 2” For Symptoms Levodopa: carbidopa-levodopa (sinemet) Dopamine agonists: mirapex (pramipexole) & requip (ropinirole) For symptomatic therapy

What’s The Difference In How They Work? Carbidopa-levodopa replaces the missing dopamine in the brain Dopamine agonists attach to the dopamine receptors in the brain and mimic dopamine Made in substantia nigra and VTA ventral tegmental area> up to striatum (caudate, putamen) to frontal cortex, nucleus accumbens, hippocampus

Pros & Cons of Levodopa “tried and true” efficacy for bradykinesia inexpensive less waiting time to build up to required dose dyskinesia (“wiggles”) over time timing: better to separate from high protein meals Amino acid, big mac attack

Pros and Cons of Dopamine Agonists less risk of dyskinesia (though still possible, especially when adding to levodopa) generic, but insurance may still prefer one over the other obsessive-compulsive behaviors, impulsivity ankle swelling “sleep attacks” requires patience with titration may not treat bradykinesia adequately Apomorphine injectable rescue DA

Side Effects of Both Levodopa and Dopamine Agonists? nausea lightheadedness Hallucinations more about these later….

How We Generally Put It All Together Prefer to start dopamine agonist (DA) on a younger patient (because they have more years ahead of them to develop dyskinesia), assuming no risk factors for OCD/impulsivity Prefer to bypass DA for an older patient, especially if bradykinesia is significant Older have more issues tolerating the dopamine agonists

More About Levodopa: “What’s the Carbidopa About?” carbidopa-levodopa 25/100 = sinemet= “without emesis” Top 3 levodopa questions, blocks dopa decarboxylase DDC enzyme slideshare.net

“Does Levodopa Stop Working Over Time?” Due to natural progression of PD, patients require more levodopa over time… >more dyskinesia and complications But even advanced PD patients have more symptoms if levodopa is missed Not good literature on negative feedback mechanisms; “will my body stop making levodopa if I take it in pill form?” My advice is to take it when bradykinesia is limiting exercise efforts Short answer: no

“What’s A High Dose Of Sinemet?” 25/100 or 25/250 : add up all the second parts Starting dose generally 25/100, 1 tab 3x daily= 300 mg daily High dose ~1500 mg levodopa total daily Needed and tolerated amount varies from person to person May have nausea when starting, watch for lightheadedness and hallucinations when increasing About 30 minutes before or 1.5 hours after a high protein meal

Plan Of Attack 1. The “big two” symptomatic meds 2. Possibly neuroprotective meds 3. Add-ons for wearing off with levodopa 4. Treatment for dyskinesia 5. Meds for tremor & dystonia 6. Other forms of levodopa and rescue meds 7. Other symptomatic treatments

Overview 2: Possibly Neuroprotective Meds- MAO-B Inhibitors Azilect (rasagiline) and selegiline Work on the back end to prevent dopamine breakdown May slow down PD progression Some patients also notice a mild symptomatic benefit Some ask why would I take a medication if I can’t tell that it is improving my symptoms? Thought to work in striatal glia (support cells) bc absent from nigrostriatal nerve terminals

Rasagiline vs Selegiline and Why Do We Say “May Slow Down Progression rasagiline (azilect) selegiline once daily dosing study data stronger for neuroprotection, but cautious interpretation* 2x daily dosing (am and midday) usually cheaper TEMPO delayed start, one group got it right away, one group had it delayed, progressed more slowly in immediate group; ADAGIO 1 mg group did better (UPDRS wise) than 2 mg group also a delayed start study (both may cause dry mouth, nausea, but generally well tolerated) *TEMPO study & ADAGIO study

What About Red Wine or Antidepressants With MAO-B Inhibitors?

Plan Of Attack 1. The “big two” symptomatic meds 2. Possibly neuroprotective meds 3. Add-ons for wearing off with levodopa 4. Treatment for dyskinesia 5. Meds for tremor & dystonia 6. Other forms of levodopa and rescue meds 7. Other symptomatic treatments

Overview 3: Add-ons For Levodopa Wearing Off COMT-inhibitors: entacapone (COMTAN) 100 or 200mg tabs with every IR levodopa administration side effects: discolored urine, levodopa-like: nausea, dry mouth, dyskinesia Bridging medication also may need to make levodopa more frequently throughout the day

Plan Of Attack 1. The “big two” symptomatic meds 2. Possibly neuroprotective meds 3. Add-ons for wearing off with levodopa 4. Treatment for dyskinesia 5. Meds for tremor & dystonia 6. Other forms of levodopa and rescue meds 7. Other symptomatic treatments

Overview 4: Treatment Of Dyskinesia (Wiggles) amantadine 1, 2 or less commonly 3x a day medication usually 100mg 2x daily rare side effect: livedo reticularis also some symptomatic benefit in older patients: confusion, can also be activating: restlessness, difficulty sleeping> can take morning and midday Mechanism of action: works on multiple receptors

Plan Of Attack 1. The “big two” symptomatic meds 2. Possibly neuroprotective meds 3. Add-ons for wearing off with levodopa 4. Treatment for dyskinesia 5. Meds for tremor & dystonia 6. Other forms of levodopa and rescue meds 7. Other symptomatic treatments

Overview 5: Meds For Tremor And Dystonia anticholinergics: artane (trihexiphenidyl), parsitan (ethopropazine) these work on a different neurotransmitter chemical (acetylcholine, not dopamine) caution: may worsen walking, balance and thinking in the long run Only helps tremor and dystonia (though levodopa timed right also helps dystonia) https://www.canadadrugs.com/products/parsitan

Plan Of Attack 1. The “big two” symptomatic meds 2. Possibly neuroprotective meds 3. Add-ons for wearing off with levodopa 4. Treatment for dyskinesia 5. Meds for tremor & dystonia 6. Other forms of levodopa and rescue meds 7. Other symptomatic treatments

Overview 6: Other Forms of Levodopa carbidopa-levodopa ER/SA/long acting: I prefer to use at night; “erratic release” parcopa: orally disintegrating tab; discoloration of saliva stalevo: carbidopa-levodopa + entacapone (Stalevo 100= 25 carbidopa + 100 levodopa + 200 entacapone) “Football pills” On tongue- ODT- orally disintegrating tablet Should not crush stalevo or long acting SA carbidopa-levodopa

Overview 6: Other Forms of Levodopa Duopa Jan 2015: pump to small intestine Rytary Jan 2015: short and long-acting carbidopa-levodopa together, 95/145/195/245mg levodopa CVT-301: inhaled levodopa: in phase 3 studies (Hinson PI) FDA approval dates Rytary is a lot of capsules /dose but supposedly less doses; can be difficult to adjust to; shouldn’t be crushed Duodopa in Europe since 2004 Phase 3: effectiveness, side effects- etc placebo controlled – if passes, released: past IV is post marketing surveillance

Overview 6: Rescue Meds-an Injectable Dopamine Agonist apomorphine designed as a rescue injection for off periods same side effects of dopamine agonists in general test doses must be given with nurse supervision, primarily to monitor blood pressure changes Subcutaneous injection, needs to be titrated up, initial test dose 2 mg, monitor BP and often anti-nausea medication when starting

Plan Of Attack 1. The “big two” symptomatic meds 2. Possibly neuroprotective meds 3. Add-ons for wearing off with levodopa 4. Treatment for dyskinesia 5. Meds for tremor & dystonia 6. Other forms of levodopa and rescue meds 7. Other symptomatic treatments Won’t spend as long on these since I think Dr. Cooper went over PD non-motor symptoms last month

Overview 7: Hallucinations donepezil/Aricept (Alzheimer’s medication conserves acetylcholine): for low heart rate seroquel: EKG first clozapine: atypical antipsychotic, WBC frequently new: pimavanserin “Nuplazid”: EKG Anecdotally dyskinesias with pimavanserin and in someone with duopa pump actually WORSE hallucinations (%5) confusion (6%), nausea 7%, leg swelling 7% QTc prolongation/interval/cardiac meds Enroll in program/weekly at first Check EKG with nuplazid not required but I would still check risk for QTc prolongation : mech action, inverse agonist and antagonist for 5HT2A (specific type of serotonin receptor), supposedly doesn’t work on/have affinity for dopamine receptors

Overview 7: Low BP (Orthostatic Hypotension) For lightheadedness, especially when getting up fludrocortisone (florinef): watch for low potassium, avoid in heart failure midodrine: sleep with head of bed at 45◦, avoid at bedtime newer: droxidopa (similar, but works on norepinephrine system specifically) also increase salt in diet, compression stockings, calf pumping exercises, get up more deliberately Florinef not good for heart failure conditions, promotes resorption of sodium Midodrine alpha agonist, risk supine hypertension, avoid if kidney disease Droxidopa (Northera) works more on epinephrine system

Overview 7: Nausea With Levodopa can take it with bread/carbohydrates (avoid simultaneous protein) take extra carbidopa with each dose (Lodosyn) some try zofran initially domperidone from Canada (more dopamine specific) avoid phenergan, reglan (metaclopromide)!!! May make PD symptoms worse

And On That Note…