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Initial Treatment of Idiopathic Parkinson’s Disease

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Presentation on theme: "Initial Treatment of Idiopathic Parkinson’s Disease"— Presentation transcript:

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
“Neuroprotection is 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 Guidelines 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! L-dopa/bensazeride (Prolopa) Less used 50/12.5,100/25, 200/50

14 Levodopa How to start? Should see considerable improvement
No guidelines Usually 1 tab (100/25) po tid 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 – repetitive purposeless behavior Dopamine dysregulation syndrome – “addiction” to dopamine Late side effects Motor complications DDS typically involves male patients with early onset PD who take increasing quantities of dopaminergic drugs despite increasingly severe drug-induced dyskinesia [79,80]. DDS can be associated with a cyclical mood disorder characterized by hypomania or manic psychosis. Tolerance (or frank dysphoria) to the mood elevating effects of dopaminergic therapy develops, and a withdrawal state occurs with dose reduction or withdrawal. Impulse control disorders including hypersexuality and pathologic gambling may accompany DDS

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 Non-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, rarely used 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 po tid over 3 weeks E.g tid x 1 wk, 0.25 tid x 1 week, then 0.5 tid Maintenance dose: 0.5 – 1.5 mg po tid Ropinirole (Requip) Titrate to 2-3 mg po tid 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 Side effects 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
Start at 5mg daily Increase to 5mg bid (maximum dose) Start at 0.5mg daily Increase to 1mg daily (maximum dose) Note: almost no MAO activity in neurons of the SN

30 MAO-B Inhibitors Clinical effects Side 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
Antiparkinsonian MoA not fully known Partial NMDA receptor antagonist Partial dopamine agonist

34 Amantadine - Use Dose Clinical effect Side effects
100 mg po daily to qid Clinical effect Modest for motor symptoms Side effects Livedo reticularis, 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 Use in PD Options
Not clearly known Degeneration of DA-ergic nigrostriatal 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 ounteracting the imbalance between striatal dopamine and acetylcholine activities caused by the degeneration of dopaminergic nigrostriatal neurons in Parkinson´s disease

38 Anticholinergics Main ones (start low, go slow): Side effects
Trihexyphenidyl (Artane) Start 0.5-1mg bid, increase to 2mg tid Benztropine (Cogentin) Start 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 (Tolcapone
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


45 Entocapone (Comtan) How to start Will increase peak levodopa
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

46 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

47 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

48 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

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

50 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”

51 Pathophysiology Non-dopaminergic-cell dysfunction thought to play a major part in the development of the non-motor symptoms However, neuroanatomy and neurochemistry of non-motor symptoms are unknown


53 Non-motor symptoms Neuropsychiatric symptoms Sleep disorders
Depression, apathy, anxiety, hallucinations, dementia, impulsive behavior (usu drug-induced) Sleep disorders Restless legs and period limb movements, REM-sleep behavior disorder, excessive daytime somnolence Autonomic symptoms Bladder (urgency, nocturia, frequency), sweating, orthostatic hypotension, sexual dysfunction GI symptoms (overlap with dysautonomia) Dribbling saliva, constipation, dysphagia, ageusia, Sensory symptoms Olfactory disturbance, pain, paresthesias

54 Management Depression Anxiety Psychosis Orthostatic hypotension
Dementia Sexual dysfunction Sleep dysfunction

55 Management - Depression
Can affect from 10-45% of patients Likely has a biological contribution May be a result of impaired 5HT transmission What is best pharmacological treatment? (AAN 2006) The highest level of evidence is for amitriptyline Although it may be considered, it is not necessarily the first choice for treatment of depression associated with PD. Insufficient evidence to make recommendations regarding other treatments for depression SSRIs and SNRIs are used but little published data in PD amitriptyline, nortriptyline, citalopram, fluoxetine, sertraline, pergolide, pramipexole, and nefazodone

56 Management – Anxiety and Apathy
Anxiety disorder common Often coexists with depression Panic attacks, phobias, GAD, related to motor fluctuations AAN practice parameters regarding treatment Insufficient evidence to make any recommendations

57 Management - Psychosis
What is the best treatment for patients with PD and psychosis? Clozapine should be considered Remember: associated with agranulocytosis that may be fatal. The absolute neutrophil count must be monitored. Quetiapine may be considered Olanzapine should not be routinely considered No proven efficacy and may worsen motor function Note that not FDA approved because of increased risk of death in pts with dementia Side effects are worsening of motor function, weight gain, insulin resistance and diabetes

58 Management - Dementia What are the most accurate screening tools in PD? MMSE and CAMCog (Cambridge cognitive assessment) MMSE as sensitive but not as specific What is the most effective treatment for dementia in PD? Rivastigmine probably effective in improving cognitive function. Modest effect and may exacerbate tremor Donepezil is probably effective in improving cognitive function. Modest effect. Donepezil – non-competitive ACHesterase inhibitor (Aricept) One study – measured at 20 weeks, MMSE, improved by 2 points Galantamine – ACHesterase inhibitor, centrally acting, competitive and reversible. (Reminyl) Rivastigmine – competitive inhibitor of ACHesterase (Exelon)

59 Management – Orthostatic Hypotension
Defined as a 20mmHg drop in systolic BP or a 10mmHg drop in diastolic BP Challenge in PD DA-ergic agents often worsen OH Reducing dose usually insufficient to treat What treatments are effective? (AAN 2006) Insufficient data to recommend to any particular treatment Symptoms variable – can be disabling Lightheadedness, syncope, fatigue, cognitive slowing, neck tightness, headache, unsteadiness

60 Management – Orthostatic Hypotension
Compression stockings Increasing water intake Fludrocortisone Dose: 0.1 – 0.3mg daily + high Na intake Supine hypertension, peripheral edema Midodrine Peripheral alpha1 receptor agonist Dose: 2.5 to 5mg tid Others: domperidone, pyridostigmine, indomethacin Domperidone – peripheral DA antagonist therefore blocks peripheral effects of DA

61 Management – Sexual Dysfunction
Common in both men and women Multifactorial Motor dysfunction, medication side effects, mood disorders, and dysautonomia Dysautonomia  erectile dysfunction One study looked at sildenafil in ED 12 patients with PD, BP > 90/50 Sildenafil at 50mg significantly improved ED

62 Management – Sexual Dysfunction
AAN Practice Parameter Sildenafil possibly efficacious Need to ensure that other treatable causes of ED/sexual dysfctn have also been addressed Note: hypersexuality can be seen in PD associated with DA-ergic agents

63 Management – Sleep Dysfunction
Range of sleep dysfunction REM sleep behavior disorder (RBD) Excessive daytime somnolence (EDS) Insomnia Restless legs syndrome and periodic limb movement

64 Management – RBD A type of parasomnia characterized by patients acting out dramatic or violent dreams during the REM sleep stage. What treatments are effective in PD? Insufficient data What treatments are available for RBD? Clonazepam to 1mg po qhs Melatonin

65 Management - EDS May be 2ary to disease process or medication side effect Dopaminergic agents can cause mild to severe somnolence Falling asleep at wheel of car Agonists > L-dopa FDA warnings for pramipexole and ropinirole Patients should be advised to d/c DA agonists if marked increase in sleepiness

66 Management - EDS What treatments are available?
Modafinil improves SUBJECTIVE feeling of sleepiness but doesn’t change OBJECTIVE measurements of somnolence Dose: 200mg daily in am

67 Management - Insomnia Etiology is multifactorial
Mood disturbances, persistent tremor, nighttime PD symptoms, nocturia, and reversal of sleep patterns Practice parameter: Insufficient data Available treatments Bedtime L-dopa – may improve nocturnal PD sx Melatonin – Improves perception Sedating antidepressants (trazodone) Mild sedatives – zopiclone, zolpidem Over-the-counter sleeping aids – beware of side effects (anticholinergic effect)

68 Management - RLS Occurs in up to 20% of patients
No evidence on how to treat of RLS in PD May use ropinirole and pramipexole FDA approved treatment in primary RLS

69 Summary L-dopa Dopamine agonists Entocapone
Most effective, early and late PD Associated with motor complications Dopamine agonists Second most effective, early PD 2nd line for motor complications, late PD Entocapone First-line adjunct for wearing off May increase dyskinesias

70 Summary MAOB Inhibitors Anticholinergics Amantadine
Monotherapy, early PD Rasagiline to reduce off time Anticholinergics Young patients with predominant tremor Not for motor complications Amantadine Monotherapy, early PD (not first choice) May use to reduce dyskinesias

71 Summary Depression Psychosis Dementia Orthostatic hypotension
Consider amitryptilline Psychosis Clozapine > quetiapine Dementia Rivastigmine and donepezil Orthostatic hypotension Non-pharm; fludro, midodrine, domperidone

72 Summary RBD EDS RLS Clonazepam Warn patients! Remove offending agent
Pramipexole and ropinirole

73 Thank you

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