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Initial Treatment of Idiopathic Parkinson’s Disease

Initial Treatment of Idiopathic Parkinson’s Disease. Sandra Derghazarian August 2013. Treatment in PD. Complex because of Motor and non-motor features Disease is progressive Both early and late side effects. Goals of treatment in PD. Prevention of disease progression

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Initial Treatment of Idiopathic Parkinson’s Disease

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  1. Initial Treatment of Idiopathic Parkinson’s Disease Sandra Derghazarian August 2013

  2. Treatment in PD • Complex because of • Motor and non-motor features • Disease is progressive • Both early and late side effects

  3. Goals of treatment in PD • Prevention of disease progression • Symptomatic treatment of motor symptoms • Management of motor complications • Wearing off/motor fluctuations • Dyskinesias • Symptomatic treatment of non-motor symptoms

  4. Prevention of progression

  5. Prevention of disease progression • “Neuroprotectionis an unmet need in Parkinson’s disease and no drug can be recommended yet for this purpose in practice.”

  6. Canadian PD Guidelines 2012 • Following should not be used for neuroprotection • Vitamin E • Following should only be used as neuroprotection in context of clinical trials • Coenzyme Q10 • Dopamine agonists • MAO B inhibitors • Insufficient evidence to make recommendations for: • Amantadine • Thalamotomy • No evidence on L-dopa for neuroprotection Canadian PD Practice Guidelines

  7. Initial treatment of MOTOR SYMPTOMS

  8. Motor symptoms • Symptoms that are being targeted by medications • Tremor • Rigidity • Bradykinesia • Gait/postural instability

  9. What to take into account? • Know that no single medication is recommended for initial treatment • Remember goals • Reduce motor symptoms • Improve QOL • Avoid side effects Canadian PD Practice Guidelines

  10. What to take into account? • Consider following factors • Symptom severity • Ability/desire to continue to work • Patient preference • May have fears that meds will cause deterioration • There is NO evidence to suggest this • In fact, L-Dopa may spare dopaminergic neurons Canadian PD Practice Guidelines

  11. What are the options? “It is not possible to identify a universal first-choice drug for early PD.” Canadian PD Practice Guidelines

  12. Levodopa • Remains the most effective for motor symptoms • Converted into dopamine • Always combined with either • Carbidopa (Sinemet) or • Benserazide (Prolopa) • They prevent peripheral decarboxylation avoid peripheral side effects of dopamine

  13. Levodopa • L-dopa/carbidopa formulations • Regular (Sinemet R) • Usually use tablets of 100/25 • L-dopa = 100mg, Carbidopa = 25mg • Can break tablets if necessary • Sustained–release (Sinemet CR) • 100/25 or 200/50 • Not used in early treatment • 25-30% less bioavailable than Sinemet R • Remember to adjust dose!

  14. Levodopa • How to start? • No guidelines • Usually 1 tab (100/25) potid • Should see considerable improvement • Beware of undertreating • If no effect  likely not idiopathic PD

  15. Levodopa Side-Effects • Early side effects – most common • Peripheral • Nausea, orthostatic hypotension • If severe –> Domperidone 10 mg tab • Central • Somnolence, confusion, hallucinations • Punting – repetitivepurposelessbehavior • Dopamine dysregulation syndrome – “addiction” to dopamine • Latesideeffects • Motor complications

  16. Motor complications • What are motor fluctuations/off time? • Periods of alteration of symptom control • On/off time – initially predictable, later unpredictable • What are dyskinesias? • Drug-induced involuntary movements that include chorea and dystonia • Risk factors for development • Younger age at onset of PD, severity, higher L-dopa dose and longer disease duration

  17. Levodopa • Try to keep dose at lowest effective possible to help avoid motor complication • No evidence that sustained-release form reduces motor complications • No evidence that entocapone delays motor complications Canadian PD Practice Guidelines

  18. Levodopa - Recommendations • May be used as a symptomatic treatment for early PD • Dose should be kept as low as possible to maintain good function, in order to reduce development of motor complications • Modified-release levodopa should not be used to delay onset of motor complications in early PD Canadian PD Practice Guidelines

  19. What are the options? “It is not possible to identify a universal first-choice drug for early PD.” Canadian PD Practice Guidelines

  20. Dopamine Agonists • Stimulate dopamine receptors directly • Do not need to be converted • 2nd most potent for control of motor symptoms after L-dopa • Can be used with success in early PD • Titrate slowly to effective dose • Less risk of fluctuations but higher risk of side-effects Canadian PD Practice Guidelines

  21. Dopamine Agonists • Ergot agonists • Bromocriptine (only one available in Canada) • Non-ergot agonists • Pramipexole (Mirapex) • Ropinirole (Requip) • [Rotigotine (patch, Neupro)] Canadian PD Practice Guidelines

  22. Ergot Dopamine Agonists • Bromocriptine • Risk of pleuropulmonary and cardiac valve fibrosis • ESR, renal function, cardiac echo and CXR before starting and q-yearly • Risk of erythromelalgia • Because of complications and need for monitoring, rarelyused • If possible, switch to a non-ergot DA-agonist Canadian PD Practice Guidelines

  23. Non-Ergot Agonists • Principle of start low, go slow • Pramipexole (Mirapex) • Titrate to 0.5mg potid over 3 weeks • E.g. 0.125 tid x 1 wk, 0.25 tid x 1 week, then 0.5 tid • Maintenance dose: 0.5 – 1.5 mg potid • Ropinirole (Requip) • Titrate to 2-3 mg potid over 6-9 weeks • Start at 0.25 tid, 0.5 tid, 0.75 tid, 1 tid, 1.25 tid etc

  24. Non-Ergot Agonists • Clinical effect • Moderate • Of long duration (don’t notice wearing off) • Side effects • Nausea • Can treat with domperidone • Somnolence (“sleep attacks”) • Hallucinations • Behavioral changes • Peripheral edema

  25. Behavioral Complications • Behavioral changes with DA-agonists– overall 13% • Gambling (50%) • Hypersexuality (40%) • Excessive spending (10%) • Management • ASK about symptoms – patients will not offer • Reduce dose or discontinue

  26. DA-Agonists Recommendations • Dopamine agonists may be used as a symptomatic treatment in early PD • Titrated to a clinically efficacious dose • If side effects prevent this  use another agonist or drug from another class • If use an ergot-derived dopamine agonist • Minimum of RFTs, ESR, and chest X-ray before starting treatment, and annually thereafter. • Given monitoring required with ergot-DA agonists, non-ergot agonist preferred Canadian PD Practice Guidelines

  27. What are the options? “It is not possible to identify a universal first-choice drug for early PD.” Canadian PD Practice Guidelines

  28. Monoamine Oxidase (MAO) • Group of enzymes involved in monoamine metabolism • Dopamine, serotonin, norepinephrine • Two enzyme subtypes • A and B • In basal ganglia  80% is MAO-B • MAOI and the “cheese reaction” • Hypertensive crisis if eat foods rich in tyramine • Does not happen with selective MAO-B inhibitors

  29. MAO-B Inhibitors • Selective MAO-B inhibitors • Selegiline • Rasagiline • Selegiline • Start at 5mg daily • Increase to 5mg bid (maximum dose) • Rasagiline • Start at 0.5mg daily • Increase to 1mg daily (maximum dose)

  30. MAO-B Inhibitors • Clinical effects • Moderate but definite • Long duration • No evidence of neuroprotection • Side effects • Nausea • Confusion • Headache

  31. MAO-B Inhibitors - Recommendations • May be used as a treatment for people with early PD Canadian PD Practice Guidelines

  32. What are the options? “It is not possible to identify a universal first-choice drug for early PD.” Canadian PD Practice Guidelines

  33. Amantadine • Used in PD for over 40 years • AntiparkinsonianMoA not fully known • Partial NMDA receptor antagonist • Partial dopamine agonist

  34. Amantadine - Use • Dose • 100 mg po daily to qid • Clinical effect • Modest for motor symptoms • Side effects • Livedoreticularis, leg edema, • Same side effect profile as dopamine agonists • Generally well-tolerated

  35. Amantadine - Recommendations • May be used as treatment in early PD but should not be drug of first choice Canadian PD Practice Guidelines

  36. What are the options? “It is not possible to identify a universal first-choice drug for early PD.” Canadian PD Practice Guidelines

  37. Anticholinergics • Mechanism of Action in PD • Not clearly known • Degeneration of DA-ergicnigrostriatal neurons  imbalance between striatal dopamine and Ach • Anticholinergics help counteract the imbalance • Use in PD • Typically for tremor-predominant young patients • Options • Benztropine, Ethopropazine, Procyclidine, Trihexyphenidyl

  38. Anticholinergics • Main ones (start low, go slow): • Trihexyphenidyl (Artane) • Start 0.5-1mg bid, increase to 2mg tid • Benztropine (Cogentin) • Start 0.5-1 mg bid, increase to 2mg bid • Side effects • Confusion, hallucinations, blurry vision, increased intraocular pressure, dry mouth, urinary retention, constipation

  39. Anticholinergics • May be used in symptomatic treatment • Typically in young patients with early PD and severe tremor • Should not be drug of first choice due to limited efficacy and side-effect profile Canadian PD Practice Guidelines

  40. A few words on Motor complications – Late effect

  41. Motor Symptoms Later in PD • Levodopa remains the most effective • Over years, duration of benefit decreases • Patients feel “wearing off” before next dose • Eventually  unpredictable on/off, freezing • Also, start to develop dyskinesias • As per recommendations, it is not possible to identify a universal first-choice adjuvant therapy for late PD Canadian PD Practice Guidelines

  42. What are the options? Canadian PD Practice Guidelines

  43. COMT Inhibitors • Entocapone • Blocks key enzyme responsible for breaking down levodopa before it reaches the brain • (Tolcapone • Not used due to hepatotoxicity ) • Improves duration of response to levodopa • Hence its usefulness in wearing off • Adds 1-2 hours of on-time/day

  44. Entocapone (Comtan) • How to start • 1 tab of 200 mg with each dose of L-dopa • Will increase peak levodopa • often recommend 30% reduction in levodopa • practically difficult - often cannot • Side effects • Same as increasing Sinemet • Increased dyskinesias possible • Stalevo (L-dopa, carbidopa, entocapone) • 50 Ldopa/12.5 carbidopa/200 mg entacapone • Advantage is convenience

  45. Motor Complications - Recommendations • To reduce off time • Entocapone and rasagiline should be offered • Pramipexole and ropinirole should be considered • Sustained-release L-dopa may be used but should not be first choice • To reduce dyskinesias • Amantadine may be considered Canadian PD Practice Guidelines

  46. Two Words on Surgery • DBS of the STN may be considered to • Improve motor function • Reduce dyskinesias • Reduce medication usage • Candidates for bilateral GPi stimulation • Motor complications refractory to med mgmnt • Healthy, no significant comorbidity • L-dopa responsive • No psychiatric problems Canadian PD Practice Guidelines

  47. Two Words on Surgery • No evidence to state whether GPi or STN is preferred target of DBS • DBS of thalamus may be considered • Patients with predominantly severe disabling tremor • STN DBS cannot be performed Canadian PD Practice Guidelines

  48. Non-motor symptomsNote: I didn’t update these based on the canadian guidelines. All from AAN 2006 guidelines.

  49. Non-motor symptoms • “Non-motor symptoms dominate the clinical picture of advanced Parkinson’s disease and contribute to severe disability, impaired quality of life, and shortened life expectancy”

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