Parkinson Disease PDF October 29-31, 2024

Parkinson Disease Cheryl Sadowski October 29-31, 2024 1 Parkinson Disease A chronic, progressive neurologic disorder characterized by tremor, bradyk...

Parkinson Disease Cheryl Sadowski October 29-31, 2024 1 Parkinson Disease A chronic, progressive neurologic disorder characterized by tremor, bradykinesia, rigidity, and postural instability. What does this mean to patients? How does this inform the relationship you will have with these patients? https://time.com/3110842/robin-williams-the-heart-of-comedy/ 2 History 1817 – Essay on the Shaking Palsy 1884 - apomorphine 1961 - L-Dopa 1969 - dopa decarboxylase inhibitors 1973 - CR formulation 1982 – pergolide 1977 – MPTP 1994 - COMT – inhibitors 2002 – DBS 3  normal Pathophysiology A. Dopaminergic pathways of the basal ganglia– thalamocortical circuit. Activation of D1 and D2 receptors results in depolarization and hyperpolarization, respectively, of postsynaptic neurons. (Red dots and lines represent excitatory input; black dots and lines represent inhibitory input) B. In Parkinson disease, degeneration of presynaptic nigrostriatal neurons results in inhibition of the impactof thalamocortical circuit and reduced signaling to the degeneration motor cortex. (Dashed lines represent reduction of neurotransmitter activity; GPe, globus pallidus externa; GPi, globus pallidus interna; SNc, substantia nigra pars compacta; SNr, substantia nigra pars reticulata; STN, subthalamic nucleus.) Citation: Chapter 78 Parkinson Disease, DiPiro JT, Yee GC, Haines ST, Nolin TD, Ellingrod VL, Posey L. DiPiro’s Pharmacotherapy: A Pathophysiologic Approach, 12th Edition; 2023. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=3097&sectionid=265902106 Copyright © 2024 McGraw-Hill Education. All rights reserved Dopamine Receptors Different DA tracts throughout the brain D1, D5 - dyskinesias D2, D3, D4 - improvement in movement Role Influences arousal, motivation, reward, emotion, cognition, memory, motor control, regulation of prolactin release 5  Etiology Current hypothesis: Genetic Factors + Toxin exposure environmental exposure Parkin gene + Exogenous (e.g. well water, farming) Alpha-synuclein + Endogenous (e.g. free radicals, infection, iron) Emerging research: Gut microbiome, inflammation IBS https://www.allaroundthehouse.ca/home- 6 inspection-blog/ontarios-water-well-regulations Risks - Environmental Veterans Affairs comparison of camps Volatile organic compound (VOC) (e.g. trichloroethylene) exposure vs camp without VOC exposure Camp Lejeune risk of PD OR = 1.70 (95%CI 1.39-2.07) Goldman SM, et al. JAMA Neurol 2023  6 Honolulu Heart Study, JAMA 2000 5 4 Hazard Ratio P < 0.001 for trend Risk Factors 3 2 1 0 0 oz 4-8 oz 12-16 oz 20-24 oz >28 Ounces of coffee/day Increased risk Nurses' Health Study Age 50 Rural residence, farming, pesticides PD Inc/100,000 Pers- 40 Frequent consumption of dairy 3glassesper day 30 years 20 Ever Never 10 Protective factors 0 45-49 50-54 55-59 60-64 65-69 70-74 Age Cigarette smoking Health Professionals Follow-up Study Black Coffee, tea, caffeine (dose of 3-5mg/kg) 200 Others studied – possibly protective PD Inc/100,000 pers- 150 Dietary (e.g. vitamin D) years 100 ever Hormonal (e.g. sex hormones) 50 never Vascular (e.g. homocysteine, hypertension) 0 Medications (e.g. NSAIDs, statins) 45-49 50-54 55-59 60-64 65-69 70-74 75+ 8 Age Ann Neurol 2001 Risk Factors - Summary evidence weight highlights howmuch Ascherio et al. Lancet Neurol 2016  Secondary Parkinsonism Drug induced causes Dopamine blockers Eps Fairdivedyskinesia antipsychotics metoclopramide reserved forpt w chemoinduced orseverepostsurgNIV Health Canada warning (July 2011) – TD found mostly in older women after 12 weeks of use paakkthonism 20 Dopamine depletors methyldopa reserpine Case reports Calcium channel blockers Antiepileptics (e.g. phenytoin, valproate, levetiracetam) Antidepressants (e.g. lithium, MAOIs, SSRIs) Chemotherapy (e.g. cystosine, cyclophosphamide, vincristine, adriamycin, doxorubicin, paclitaxel, prednisone) Immunosuppressants (e.g. cyclosporine, tacrolimus) 10 https://www.ti.ubc.ca/2022/11/29/139-how-well-do-you-know-your-dopamine-antagonists/ Secondary Parkinsonism Medical causes Normal pressure hydrocephalus (NPH) Infarction Infection (e.g. neurosyphylis) Trauma Any lesion or neoplasm to the substantia nigra 11  Classification Based on cause Idiopathic vs secondary unknowncause Age of onset Young vs old canaffectapproach totx howaggressive Rate or progression Rapid vs slow Proposed subtypes Armstrong MJ, JAMA 2020 12  Epidemiology Incidence = 14-20 cases/100 000 160/100,000 if age 65y and older Based on standardized annual incidence rates in high-income countries Prevalence = 300 cases/100 000 May be as high as 572/ 100 000 if age 45y and older Race equal if in same community Up to 10% are early onset (before age 40) Approximately 10% of LTCF residents longtermcarefacility Lifetime risk at age 40y morecommon 2% for men, 1.3% for women in men Differences in sex take into account competing risks (e.g. death from CV disease, cancer) Ascherio, et al. Lancet Neurol 2016 Deliz JR, et al. Current Neurology and Neuroscience Reports 2024 13 Hallmark Features Resting tremor Bradykinesia Rigidity Postural instability 14  Motor symptoms Micrographia Masked face Decreased blink rate Shuffling gait Festinating gait Associated Microphonia Autonomic impairment Characteristic Constipation Sweating Problems Postural hypotension Dysphagia not required fordiagnosis Mental status Depression Cognitive impairment Dementia 15 Question Canadian CPG for PD start with which of the following? A. Diagnosis B. Clinical presentation C. Epidemiology D. Definitions E. Communication  Canadian Guidelines https://www.cmaj.ca/content/191/36/E989 17 Guidelines - Communication David Grimes et al. CMAJ 2019;191:E989-E1004 Guidelines Most guidelines begin with Assessment and Diagnosis Note that these guidelines begin with communication Rationale for this: Based on the presentation of PD it can be difficult to communicate E.g. masked face, microphonia Patients with neurologic disease can be stigmatized, infantilized, or ignored The disease progresses and we must maintain communication as the disease changes, therapies are modified, complications arise, etc The patient will have a team – family, friends, caregivers – others who are impacted need communication as well All healthcare professionals should be engaged with care and this requires communication across the health system and with the patient  Canadian Guidelines https://www.cmaj.ca/content/191/36/E989 20 Guidelines – Diagnosis, Progression Diagnosis C8: diagnosed with MDS Clinical Diagnostic Criteria Progression C19: Vit E, CoQ10 not neuroprotective C20: Dopaminergic tx are not neuroprotective David Grimes et al. CMAJ 2019;191:E989-E1004 Diagnosis Diagnositc modalities Misdiagnosis common *Clinical presentation No biological markers Neuroimaging LD challenge Olfaction (ancillary) 22 https://www.imperial.ac.uk/medicine/multiple-sclerosis-and-parkinsons-tissue-bank/ Diagnostic Criteria (MDS, Canadian) Must have: Parkinsonism (essential criterion) Bradykinesia + at least 1 of tremor or rigidity At least 2 supportive criteria E.g. olfactory loss, dramatic response to dopaminergic therapy, progressive Must not have: Exclusion criteria E.g. Restricted to lower limbs, treatment with dopamine blocker at onset No red flags E.g. rapid progression, absence of non-motor features at 5y Postuma RB, et al, Mov Disord 2015 Pharmacotherapy text (11th ed) Table 76.1 23 Question The prognosis for a patient diagnosed in midlife (usual diagnosis age 55-65y) with PD is: a) 1-2y b) 5 years c) 10 years d) 15 years e) 20 years Question Most patients with PD will die from which of the following? a) Bradykinesia b) Tremor c) Rigidity d) Postural instability e) None of the above  Canadian Guidelines Important to consider a palliative approach as part of the continuum of disease First PD Guideline that includes a discussion of MAiD 26  Canadian Guidelines https://www.cmaj.ca/content/191/36/E989 27 Guidelines – Motor Symptoms Note 3 tables Recommendations C23 – C66 David Grimes et al. CMAJ 2019;191:E989-E1004 Guidelines – Motor Symptoms General Considerations C23-29 Pharmacologic therapy in early PD C30-C41 Pharmacologic therapy in later PD C42-48 Surgery C49-55 Rehabilitation C56-C66 29 Staging Staging useful for assessment Used in clinical trial Decide if pt is early or late Know if the stage is later, severe, early, etc 30 Goals of Therapy Right now there is no evidence to Neuroprotection protect neurons that remain or prevent the loss of lost neurons Evidence is lacking Relieve symptoms Maximize independence and function Prevent injury Prevent long-term drug complications Overall focus on HRQL 31  Guidelines – Diagnosis, Progression Note that neuroprotection does not have evidence Do NOT use vitamin E Pharmacotherapy should NOT be used for neuroprotection David Grimes et al. CMAJ 2019;191:E989-E1004  Outcomes “For neurologists Parkinsonism is all in the brain; for people with Parkinsonism it is mostly below the neck.” Mary Baker President, European Federation of neurological Associations, 2001 33 Dr. Prem Pillay Question How would you measure efficacy of a therapy in a PD study?  Time to change in management Imaging techniques Time to start Levodopa Amount of ↑ or ↓ in Levodopa dose Outcomes Time to clinical event First dopaminergic of complication Lenesia Time to motor fluctuations Caregiver burden Importance Changes in clinical HRQL (PD specific scales instruments) Economics 35  Unified Parkinson Disease Rating Scale (UPDRS) know what fromtools scoremeans Section Completed by Examples Non-motor aspects of Clinician Cognition, Depression, Psychosis, Anxiety experiences of daily living (Part A) Non-motor aspects of Patient Sleep, Pain, Constipation, Fatigue experiences of daily living (Part B) Motor aspects of Patient Speech, Drooling, Eating, Getting out of bed experiences of daily living Motor Exam Clinician Speech, facial expression, rigidity, postural stability Hoehn and Yahr Stage included Motor complications Patient/Clinician Dyskinesia, motor fluctuations, dystonia https://www.movementdisorders.org/MDS/MDS-Rating-Scales/MDS-Unified-Parkinsons-Disease-Rating-Scale-MDS-UPDRS.htm QoL Measures (Parkinson’s Impact Scale) Domain Content (examples) Self + How positive you feel about yourself (optimism, self-worth) Self - How negative you feel about yourself (stress, anxiety, depression) Family relationships Spouse, children, immediate family Community relationships Neighbours, friends, co-workers, providing services (e.g. doctor, store clerks) Work Job, running of your home, ability to support yourself and family Leisure Ability to continue enjoyable activities (hobbies, sports, volunteering) Travel Reach your destination (work, social) Safety Do what you want without injuring yourself or others (driving, kitchen) Financial security Support your family, yourself Sexuality Maintain a satisfactory sexual relationship Calne S, et al. Parkinsonism & Related Disorders 1996  Starting therapy early in disease ◦AAN AAN Guidelines  Approach to Treatment Focus of this guideline is on tremor and chronological age Other guidelines now prioritize patient function General approach to the management of early to advanced Parkinson disease. *Age is not the sole determinant for drug choice. Other factors such as cognitive function and overall tolerability of drug (especially in the elderly) should be considered. Dipin  Approach to Treatment ◦CPS is Simpler and more aligned with what we do in practice emphasis on final impairmen “Clinical equipoise surrounds medication choices for patients with early Parkinson's disease.” - RMA de Bie, et al. Lancet 2020 CPS Considerations for Functional Impairment toiletingfeeding ADL vs IADL T.in giiE aooutnoucanaeiesare Dominant vs. non-dominant hand Employment mg iiiT.ititie ars us it atisretired Bradykinesia vs tremor ifseverestarttx Treatment philosophy 41  Rehabilitation PT OT Non- SLP speech communication w lessmaskedface Pharmacologic Treatment Technology Computer-based VR AI 42  Guidelines - Rehabilitation ©2019 by Canadian Medical Association Pharmacologic – General Considerations 44 Pharmacologic - Early 45 Pharmacologic - Late 46 Case MF, 61yo M Dx: idiopathic PD Presentation: feeling slow, generalized muscle stiffness in the morning; became bothersome 4-5 months ago; mild tremor dominant hand; generalized slowing most bothersome Function: scores for ADL are normal, patient reports for IADL he has stopped driving; Parkinson Impact Scale shows minimal impact. Social Hx: Works as a manager for Canada Post Hobby – outdoor photography He is able to mobilize to most outdoor locations. Married to wife for past 18 years; previously divorced 2 children from 1st marriage, children do not live in Edmonton Lives in a 2-storey home, bedroom on 2nd floor Medical Hx: Hypertension, Osteoarthritis Medication Hx: HCTZ 12.5 mg daily, Acetaminophen ER 650 mg TID Vaccination Hx: Flu shot annually, COVID (5 doses)  Approach to Treatment “Clinical equipoise surrounds medication choices for patients with early Parkinson's disease.” - RMA de Bie, et al. Lancet 2020 Approach – AAN Guidance Levodopa is the mainstay MAO-I leasteffectivebut okfor pts w earlyon in disease nocottageminemetabolite statisfin Selegiline Rasagiline Safinamide Brand name Eldepryl Azilect Onstryv Mechanism of action Irreversible Reversible Inhibits MAO-B Selective for MAO-B Indication Initial monotherapy Adjunct to LD Adjunct to LD PK Extensive first pass Negligible first pass metabolism T1/2 = 3 h T1/2 = 20-26h takes daysfor T1/2 = 1.6 h Active metabolites No amphetamine metabolites Metabolism: CYP a minor role aging Hydrolysis, fom (amphetamine) Metabolism via CYP450 T1/2 = 20.5 h 1A2 Metabolism via CYP450 2B6, 1A2 Intx MAO-I Standard Warning: Antidepressants that increase serotonin levels TCA, SSRI, Venlafaxine, St. John’s Wort Dextromethorphan Analgesics (methadone, meperidine, tramadol) Sympathomimetic agents (ephedrine) Pseudoephedrine Precautions Standard MAO-I warning: Wait 14 days after discontinuation to initiate an antidepressant Wait 14 days after discontinuation to undergo surgery Dosing Initial = 5 mg daily Monotherapy = 1 mg daily Initially = 50 mg daily Titrate to 5 mg BID (AM, If on LD = 0.5 mg daily Titrate to 100 mg daily after 2 noon)5amstunch weeks Side effects Jitteriness Headache Dyskinesia Insomnia Arthralgia Headache Anxiety Dyspepsia Nausea 50 MAOB-I Dosing Well tolerated at low dose Early in the day (note: selegiline amphetamine metabolite) Standard MAO-I warnings and precautions Vs tailored warnings Selection of agent Often depends on benefits/coverage Generally avoid amphetamine metabolites in older adults Antidepressant effects Some evidence of improved mood slightlyimproved Does not substitute for an antidepressant if indicated Neuroprotective DATATOP studies initially promising (early 1990’s) Not reproduced not did effects continue 51 Case MF, 61yo M Dx: idiopathic PD Presentation: feeling slow, generalized muscle stiffness in the morning; became bothersome 4-5 months ago; mild tremor dominant hand; generalized slowing most bothersome Function: scores for ADL are normal, patient reports for IADL he has stopped driving; Parkinson Impact Scale shows minimal impact. Social Hx: Works as a manager for Canada Post Hobby – outdoor photography He is able to mobilize to most outdoor locations. Married to wife for past 18 years; previously divorced 2 children from 1st marriage, children do not live in Edmonton Lives in a 2-storey home, bedroom on 2nd floor Medical Hx: Hypertension, Osteoarthritis Medication Hx: HCTZ 12.5 mg daily, Acetaminophen ER 650 mg TID Vaccination Hx: Flu shot annually, COVID (5 doses) Case – update 3y later MF, 64yo M Dx: idiopathic PD Presentation: saw neurologist at MD clinic after having 2 falls Fell, hit head on 2nd fall – transferred to ER, CT scan (head) was negative for bleed Ipogressive Staging: H&Y stage 2 disease Slowness, tremor – both slightly improved with his Rx rasagiline Questions: What would you ask about his function? Eeteftaking Any questions about his rasagiline? What approach would you like to take now? Dopamine Agonists or levodopa Directly stimulate dopamine receptor Used in early disease to minimize use of LD Used in late disease as adjunct to LD 54 DA Older Agents Newer Agents Less receptor specificity Receptor specific (D2-4) Low cost High cost High ADR Lower ADR Adjunct Adjunct or monotherapy Selective agents mainstay of therapy 55  not tested on dose every single one requires titration Dopamine Agonists knowstainting thighed ftp.EEEtudied Bromocriptine Pramipexole Ropinirole Cabergoline Rotigotine Apomorphine needsspecia Brand name Parlodel Mirapex Requip Dostinex Neupro Movapo accessinCana Kynmobi Type Ergot Non-ergot Non-ergot Ergot Non-ergot Non-ergot Receptor D2 D3>D2>D4 D3>D2>D4 D2>D1 D2, D3 Mixed D1, D2 agonist α, β, 5-HT, GABA 5-HT 5-HT, α 5-HT non-selective for D1, D2, D3, D4, D5 Indication Adjunct to LD Adjunct to LD Adjunct to LD Adjunct to LD Adjunct to LD Adjunct to LD for off Early mono-tx Early mono-tx Early mono-tx Early Mono-tx episodes Metabolism CYP 3A4 Renal CYP 1A2 Hydrolysis Conjugation, Demethylation, dealkylation glucuronidation, P450 sulfation Intx (PK) Macrolides Cimetidine, EtOH Ciprofloxacin macrolides Renally eliminated meds Intx (PD) Antihypertensive agents Sedatives Dopamine antagonists metocloramide Starting dose 1.25 mg bid 0.125 mg tid 0.25 mg tid 0.25 mg qd 2 mg/24h 2 mg SQ TID (PRN off episodes) Max dose 30 mg tid 1.5 mg tid 8 mg tid 5 mg qd 8 mg/24h 6 mg SQ TID 56 Dosing Titrate slowly – q1-2 weeks Decrease dose of LD up to 25% ifaddedto aptalready on levodopa Newer formulations – ER for some products in other countries(e.g. pramipexole in US for early PD) Patches (some shortages) 57 Adverse Effects GI: N/V (25-30%) that's whystartlow aslow Cardiac: orthostasis (approx 50% - advanced disease) in BP Psychiatric: Double that of LD (4-5% vs 8-9%) Hallucinations (10-20%) be dopamine Neuro: syncope (12%) – associated with increase in dosage be BP excessive daytime sleepiness insomnia hardtopredict dyskinesias addiction disorders 58 Debates with DA Agonists Not neuroprotective Duration of benefit Usually clinically significant for 1 year thenhavetostartmaking adjustments e g dose or LD Cost vs LD More expensive than LD Response to different agents Variety of products, formulations Mood effects Increased dopamine can elevate mood 59 Case – update 1y later MF, 65yo M Dx: idiopathic PD Presentation: Seen by neurologist in MD clinic trial of rotigotine with some benefit but with titrating dose has severe GI complaints, hallucinations Staging: H&Y stage 2.5 Rx: Rotigotine patch started 1mg/d; increased gradually to 6mg/d Questions: Should he continue rotigotine? Should he switch to another DA? What approach would you like to take now?  knowdosing Levodopa Gold Standard L-form used Dosing Start 100/25 TID Max 1500 mg LD/day Usually dose ceiling 800 mg LD/day 955 Minimum dose of carbidopa = 75 mg/day 00 Sin emet sin no emeriningl Titration every few weeks 61  Sinemet: (LD/carbidopa) Be able to select for exam IR: 100/10, 100/25, 250/25 CR: 200/50 CR, 100/25 CR Prolopa: (LD/benserazide) IR: 50/12.5, 100/25, 200/50 used in Europe Product Stalevo (all IR products): Selection LD/carbidopa/entacapone 50/12.5/200 75/18.75/200 100/25/200 125/31.25/200 150/37.5/200 Duodopa: LD/carbidopa intestinal gel (by NG or PEG) 1 mL = 20 mg LD/5 mg carbidopa 62 Sinemet Formulations not interchangeable EEtaEd Property Immediate Release (IR) Controlled Release (CR) Onset onemptystomachlightcars 30 min. 2h Duration 2h 4-6 h Bioavailability 95% 70% Dosing interval 3 times/day (early ds) 3-4 times/day >4 times/day (late ds) Cost/month $$ $$$ Pro Rapid, immediate effect Control late stage complications Can be crushed, chewed Lower peaks Lower cost Can be split (scored) Con Multiple doses/day Expensive Dependence on “burst” Higher dose required Peak related dyskinesias Not chewed or crushed More fluctuations in symptoms Does not provide “burst” Video: Off meds, On meds – LD 63 Video: Off meds, On meds Question Which dose of LD do you recommend to start? a) Sinemet 100/10 daily b) Sinemet 100/25 daily c) Sinemet 100/25 TID d) Sinemet CR 100/25 TID e) Stalevo 50/12.5/200 usuallydoesnt start w conti Question When starting LD how should the DA be managed? Easier to titrate back up after reducing a) Abrupt discontinuation dose than giving too much dopaminergic agents and causing syncope, hallucinations, nausea, etc b) Gradual taper c) Keep the same dose d) Reduce the dose e) Switch to cabergoline (longest t1/2) then taper AAN Guideline Dopamine Metabolism Levodopa DA + CO2 DA + O2 + H2O 3,4 DHPA + NH3 + H2O2 H2O2 + Fe+2 OH + OH- + Fe+3 67  PD changes as disease progresses Early on pt have good Levodopa Pharmacodynamics storage capacity ◦IR products able to store dopamin produced ◦Good effect, lasts over hours As disease progresses ◦Less storage, drug lasts for less time.. need more frequent dosing ◦Receptors become desensitized..happ ens about ve years after starting levodopa Advanced ◦Almost like need continuous infusion ◦Early TID and as progresses, QID and can go up to 8x/day Question As the disease progresses and LD is given more frequently, how would you supply this to the patient if using calendar packaging?  Delays the breakdown of levodopa so LD lasts longer Given with levodopa but available by itself COMT Inhibitors COMT present in: bowel (conversion before absorption) liver (first pass) brain erythrocytes Tolcapone - emergency release Entacapone peripheral enzyme inhibitor dosed with each LD dose (max 8/day) Average reduction in LD = 25% 70  chatecol o methyl transferase COMT Inhibitors Suggest early use with LD to decrease oxidative stress by lowering LD dose Side effects – excessive LD Drug interactions Antidepressants medication metabolized by COMT Dobutamine, epinephrine, methyldopa, isoproterenol 71  COMT-I Adverse effects exaggeration of LDeffects be LDretained Neuro: confusion (10.5%), hallucinations (8%) GI nausea (28%), diarrhea (13%), hepatotoxicity (tolcapone) Cardiac orthostasis (13%) Intx: catecholamine reuptake inhibitors (antidepressants) methyldopa isoproterenol dobutamine epinephrine (increase risk of arrhythmias) 72 Question We can advise the patient to address which of the following dietary interactions? LD comti a) Avoid protein b) Reduce protein Depends how much protein But the best answer is to consult with a c) Shift protein to a different time of day dietician Take with little carbs if have nausea but d) Do not take LD with protein not protein We dont want pt to cut protein out of e) None of the above the diet.. just avoid taking protein with LD  Protein competes with LD ◦Light meal ok, light snack, light carbs Proteins will delay or reduce absorption Interactions Drug – Food Protein in diet Drug – Drug Additive AE (e.g. nausea) Dopamine blocking agents Anticholinergics (e.g. gastric emptying) Iron NOT B vitamins Drug - Disease 74  Guidelines - Rehabilitation ©2019 by Canadian Medical Association Adverse Effects GI N/V less compared to dopamineagonists 150less monitor carbidopa, entacapone dose use peripheral motility agent Domperidone 10 mg po ac Neurologic Dyskinesia, hallucinations, confusion Cardiac hypotension 76 Debates with Levodopa Debate with Levodopa higher scores – delayed start indicating more severe disease LD showed no disease modifying effect There is no reason to delay higher scores treatment We dont want to delay treatment Prob ok to give LD earlier so patient is indicating a more functional lower disease- related quality of life Verschuur CVM, et al. NEJM 2019 78  Debate - LD vs DA Half will have stopped Dopamine agonists Figure 2 PD-MED Trial Proportion of patients stopping treatment with allocated drug class 79 The Lancet 2014;384(9949):1196 - 1205  DA have higher AE in every area and is more likely to be stopped vs LD LD vs DA DA over long term has less movement problems but about half of pt discontinue the drug anyway Tolerance LD better tolerated Dopamine agonists have higher rates of side effects. Edema OR = 3.68 (CI95 = 2.62 – 5.18) Somnolence OR = 1.49 (CI95 1.12 – 2.00) Dizziness OR = 1.45 (CI95 1.09 – 1.92) Hallucinations OR = 1.69 (CI95 1.13 – 2.52) Nausea OR = 1.32 (CI95 1.05 – 1.66) Patients more likely to stop dopamine agonist versus LD OR = 2.49 (CI95 2.08 – 2.98) Efficacy LD better at symptomatic control, treating the hallmark symptoms Dopamine agonists have fewer motor complications. Dyskinesia OR = 0.51 (CI95 0.43 – 0.59) Dystonia OR = 0.64 (CI95 0.51-0.81) Motor fluctuations OR = 0.75 (CI95 0.63 – 0.90) Stowe R, et al. Dopamine agonist therapy in early Parkinson’s 80 Disease. Cochrane Database 2008 LD vs DA Cochrane Review (29 studies, N=5247) DA more side effects, discontinuations Fewer motor complications Bottom Line: fewer long term complications, but less efficacious LD more effective for hallmark features Bottom Line: LD better tolerated, better efficacy, but higher motor complications laterindisease 81 LD vs DA 3-7 year enrollment N=1620 LD vs DA vs MOA-I Outcomes Generally similar Patient mobility scores and quality of life higher with LD Greater incidence of dyskinesias in LD group PD-MED Collaborative Group, Lancet Neurol 2014 82 Dopaminergic Therapy - Safety Question When dispensing a new DA how should you counsel the patient for safety? a) Apply auxiliary label for “Do not operate heavy machinery” b) Ask what the doctor recommended c) Review the cognitive side effects with the patient d) Review the potential drug interactions with the patient e) Advise and document that the patient was instructed to avoid driving for at least 1 month  Main reason why patients are told to stop driving Adverse Effects - EDS usuallyhappens in passive situation e.glisteningto Excessive Daytime Sleepiness (EDS) present in 51% of sample EDS present in 50% of drivers Recommendations Health professionals must recognize daytime sleepiness Use a scale including relevant questions Consider underlying sleep disorders Use medications at the lowest effective dose Inform patients of the dangers of driving Reduce the dose in patients who experience sedation; stop driving temporarily 85  EDS - Epworth Sleep Scale “How likely are you to doze off or fall asleep in the following situations, in contrast to feeling just tired?” Examples: Sitting and reading Watching TV Sitting, inactive in a public place 86 Case – update 2y later MF, 67yo M Dx: idiopathic PD Presentation: Seen by neurologist in MD clinic Seen in f/u visit to address new onset gambling and significant loss of finances Staging: H&Y stage 3 Rx: Stalevo Ropinirole Question: What does gambling have to do with our pharmacy practice? Impulse Control Disorders (ICD) “A failure to resist impulses despite severe personal, familial, or vocational losses.” A number of different behaviours E.g. gambling, shopping, binge eating 89 1 Mechanism Dopamine increases in the striatum; rate of dopamine increase Reinforces compulsions, habits Debove I, et al. Journal of the Movement Disorder Society 2024 88 ICD Due to DA alone, or total dopaminergic load? 3 aspects: DA that bind to D3 receptors in the mesolimbic pathways are the main risks 1. Failure to resist the impulse or temptation (impulsivity) Affect approximately 20% of PD patients over 2. Repetitive execution with a lack their lifetime of self control (compulsivity) 14-35% in PD patients 3. Negative consequences for the individual or their environment Example – Pathological gambling (functional impact) Prevalence - General popl’n = 0.4 -1.0% Patients with PD = 3% Patients on DA = 6% Debove I, et al. Journal of the Movement Disorder Society 2024 89 ICD Risks Young onset PD Personality Male Unmarried Hx – family, substance use, psychiatric Use of a DA 90  ICD Management Ask the patient Alternate tx Less aggressive DA use, slower titration Monitor total dopaminergic load Non-pharmacologic – DBS may be considered 91 Question When should you use an anticholinergic therapy for a PD patient? a) Early in the disease as mono-therapy when pts dontwanna start dopaminergic t b) At any point in the disease as adjunct therapy c) Late in the disease as adjunct therapy d) Whenever the patient is experiencing dopaminergic SE e) Never Anticholinergics Does not treat problem of decreased dopamine Useful in tremor or dystonia in younger patients Very poorly tolerated by older adults, cognitively impaired Dosing: Benztropine: 0.5 mg po qd Procyclidine: 2.5 mg po tid Trihexyphenidyl: 1 mg po qd Safety GI: constipation, dry mouth GU: urinary retention Neuro: confusion, dizziness, sedation Ophtho: blurred vision 93  Amantadine Traditionally used for influenza advanced PD MOA in PD unknown Use: Young patients, early therapy Research supports use if dyskinesias (late disease) Side effects: GI: Nausea, anorexia, dry mouth, constipation Neuro: Dizziness, insomnia anticholinergic Derm: Livedo reticularis Cardiac: orthostasis Interactions: additive effects with anticholinergics Monitor renal function 94 Question If a patient with diagnosed PD asked you about recommendations for herbal supplements what would you recommend? a) Avoid all herbal supplements b) If he wants to he can try, but they don’t have evidence c) They could interact with his dopaminergic therapy so avoid them d) They could have dietary interactions with his levodopa e) None of the above Natural Health Products Frequently used in patients with chronic or progressive diseases Overall weak evidence with small pilot studies for short duration Some guidelines specifically recommend avoiding vitamin E and CoQ10 due to evidence showing no neuroprotection Canadian guidelines recommend talking to a healthcare professional before starting a NHP Some products (e.g. ashwaganda) actually contain L-dopa Kim SW, Alzheimer's and Parkinson's Disease Int 2023 96 Case – update MF, 67yo M Dx: idiopathic PD Presentation: Seen by neurologist in MD clinic Experiencing dyskinesia at peak dose LD Staging: H&Y stage 3 Rx: Stalevo Ropinirole Question: How can we manage LD as it becomes a narrow therapeutic index drug?  Motor Complications 50% of patients at 5y have motor complications Wearing off phenomenon - LD effect not lasting it.ie o On-off phenomenon - Changes in absorption, intx e.s.us iitii tn akathesia Dyskinesias - Sensitization of receptors Dystonias - Acute lack of dopamine 98  Mimics how the brain releases dopamine Levodopa 2.0 Foslevodopa/foscarbidopa solution Brand: Vyalev Continuous SQ infusion (24h) using infusion pump Maximum 6000mg foslevodopa (25 mL)/ 24h Replaces LD and COMT-I Levodopa/carbidopa intestinal gel Brand: Duodopa Percutaneous endoscopic gastrostomy-jejunostromy (PEG-J) Can be administered through NJ tube Continuous intestinal infusion 1 cassette lasts 16h  Video: Michael J Fox Motor Complications Complication Onset Treatment options Wearing off Delayed (years) Add dopamine agonist phenomenon Add COMT-I (End of dose Shorten LD interval phenomenon) Use CR LD preparation Redistribute protein On-off phenomenon Delayed Adjust time of LD dose Redistribute protein Add COMT-I Dyskinesias Early or delayed Smaller, more frequent LD doses COMT-I or DA with LD reduction Consider IR LD vs CR Add amantadine Dystonias Early or delayed CR LD given at hs Add dopamine agonist or COMT-I Add anticholinergic Add baclofen or BTX inj 100 Case – update MF, 69yo M Dx: idiopathic PD Presentation: Seen by neurologist in MD clinic Experiencing dyskinesia frequently throughout the day Patient is experiencing cognitive impairment, low mood, and has irregular sleep patterns Staging: H&Y stage 4 Rx: Stalevo Ropinirole Amantadine Question: How can we manage these psychiatric complications?  Canadian Guidelines https://www.cmaj.ca/content/191/36/E989 102  Psychiatric Complications Complication Pharmacologic Management Depression Consider MAO-I Consider dopamine agonist 1st line - SSRI – monitor movement disorders 1st line alternative – SNRI, bupropion 2nd line - TCA – monitor anticholinergic effects Sleep (REM) Melatonin tendedonCR products Clonazepam 3rd line – Rivastigmine Sleep (insomnia) Zopiclone, donepezil, melatonin Dementia 1st line - Rivastigmine 2nd line – Donepezil, Galantamine Behavioural 1st line - atypical antipsychotics (e.g. quetiapine) disturbances 2nd line - low-dose clozapine (↑ efficacy, evidence vs risk agranulocytosis) Delirium Remove in sequence: 1.Anticholinergics 2.Amantadine 3.Selegiline 4.Dopamine agonists 5.LD 103 Case – update MF, 69yo M Dx: idiopathic PD Presentation: Patient diagnosed with Parkinson Disease Dementia Patient experiencing drooling and constipation Staging: H&Y stage 4 Rx: Stalevo Ropinirole Amantadine Plan: Placement in LTC Question: How can we manage these autonomic complications?  Autonomic Complications Complication Management Orthostasis, heart-rate Orthostasis variability, arrhythmias, Minimize dose of antihypertensives sudden cardiac death Minimize dose of PD meds Pressure stockings Pressors (e.g. midodrine, fludrocortisone) as necessary Investigational – droxidopa Arrhythmias Work-up and monitoring Decreased GI motility Avoid anticholinergics “Hypersalivation”: Optimize dysphagia Atropine eye gtts given SL TID Ipratropium spray BTX injection Dysphagia: domperidone Constipation: aggressive management with fiber/fluids, softeners, stimulants, PEG Urinary dysfunction Bethanechol for retention Management of urgency Temperature dysregulation Monitor wearing off effect of medications Treat hyperhydrosis with environmental modification Sexual dysfunction Treatment of erectile dysfunction 105 Sensory Complications Pain Urge sensations (e.g. RLS, stereotypies) Paraesthesia Olfactory disturbances 106 Complications 107  Monitoring Improvement: Time Drug Dose Food Response SE improvement in symptoms 7:00 increased function 7:30 decreased ‘off’ time, increased ‘on’ 8:00 time LD dose Toxicity: Neuro, GI, Cardiac 108  Surgical Intervention Deep brain stimulation >20 RCT, up to 3-year follow-up Benefits: improved on-time better QoL reduced dyskinesias lower drug doses (LD, DA) possible improvement on mood (some studies) Challenges: Not complete resolution of symptoms Complications: depression, behaviours, cognitive impairment Other forms of surgery Thalamotomy Video: Medial pallidotomy On/Off with Fetal transplantation DBS 109 Questions? 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