Treatment of Parkinson's Disease Laura Mayans, MD
Family Medicine Spring Symposium April 10, 2015
TreatmentofParkinson’sDisease • Objectives: 1. Discusstreatmentoptionsforthemotor symptomsofParkinson’sDisease. 2. Describedifferenttreatmentstrategiesthatcan differbasedonageatpresentation. 3. RelatethebestͲevidencetreatmentoptionsfor thenonͲmotorsymptomsofParkinson’s. 4. Outlinedrugsininvestigationfortreatmentof Parkinson’sdisease.
Parkinson’sDisease: TreatmentofMotorandNonͲmotor Symptoms LauraMayans,MD AssistantProfessor DepartmentofFamilyandCommunityMedicine April10th,2015
Background
Treatment:motorsymptoms
• 2nd mostcommonneurodegenerativedisorder • Lossofdopaminergicneurons • Definedby 1. 2. 3. 4.
Carbidopa/Levodopa MonoamineOxidaseͲBInhibitors(MAOͲB) DopamineAgonists CatecholOͲmethyltranferase Inhibitors (COMT) • Anticholinergics • Latediseaseagents • • • •
Bradykinesia(slowness) Rigidity(stiffness) Tremor(restingtremor) posturalinstability(impairedbalance)
• Symptomsoftenasymmetric,progressive • ManyassociatednonͲmotorsymptoms
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Treatment of Parkinson's Disease Laura Mayans, MD
Family Medicine Spring Symposium April 10, 2015
Treatment:motorsymptoms
Treatment:motorsymptoms
• Mainstay:Carbidopa/Levodopa
• Carbidopa/Levodopa
– Mechanism:
– Dosing:
• Levodopaconvertedtodopaminebyneurons
• IR:10/100,25/100,25/250(3Ͳ4timesdaily) • CR:25/100,50/200 (twicedaily) • ODT:(Parcopa™)bioequivalenttoIRformulations
– Theseneuronsaredegenerating– resultsinљresponse/љ predictabilityovertime
• Carbidopablocksperipheralmetabolismoflevodopa
– DosingConsiderations: • Startat½tabdailyandјby½tabeveryweek – lessensnausea
Treatment:motorsymptoms
Treatment:motorsymptoms
• Carbidopa/Levodopa
• MAOͲBInhibitors
– ShortͲtermAdverseEffects:
– Mechanism:
• Nausea/vomiting,drowsiness,dizziness,hypotension
• јhalfͲlifeofdopaminebyblockingitsbreakdown
– LongͲtermAdverseEffects:
– Agents:
• Motorfluctuations
• Selegiline
– “wearingoff”– nolongerlastsbetweendoses
– 5mgtwicedaily
• Dyskinesias
• Rasagiline (Azilect™)
– Choreiform movementsoccurringat“peakdose”
– 0.5– 1.0mgoncedaily
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Treatment of Parkinson's Disease Laura Mayans, MD
Family Medicine Spring Symposium April 10, 2015
Treatment:motorsymptoms
Treatment:motorsymptoms • DopamineAgonists
• MAOͲBInhibitors
– Mechanism:
– Use:
• Directlystimulatedopaminereceptors
• monotherapyearly
– Agents:
– CandelayinitiationofCarbidopa/Levodopa
• Ergots:Bromocriptine,Pergolide • Nonergots:
• adjunct(treatmotorfluctuations) – When“offͲtime”becomesimpairing » Canincreasedyskinesias
– Pramipexole (Mirapex™) » IR:0.125mgTID,Ɵtratedј(max=0.5mgTID) » ER:0.375daily,Ɵtratedј(max=4.5mg/day) – Ropinirole (Requip™) » IR:0.25mgTID,titratedto1mgTID(usualdose) » ER:2mgdaily,Ɵtratedј(max=24mg/daily)
– AdverseEffects: • Potentiatethedopaminergicsideeffects • RiskofSerotoninSyndrome
Treatment:motorsymptoms
Treatment:motorsymptoms • COMTInhibitors
• DopamineAgonists
– Mechanism:
– Use:
• Blocksmetabolismoflevodopa(toaninactive compound),јplasmaandbrainlevels
• Monotherapyearly – Candelayinitiationofcarbidopa/levodopa
– Agents:
• Adjunctlate
• Entacapone
– Decreasemotorfluctuations
– 200mgwitheachdoseofcarbidopa/levodopa – Stalevo™iscarbidopa/levodopa/entacapone
– AdverseEffects: • Sleepiness,hallucinations,peripheraledema, • Impulsecontroldisorders:
• Tolcapone – 100Ͳ200mgTID – BlackBoxWarning
– Hypersexuality,pathologicalgambling
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Treatment of Parkinson's Disease Laura Mayans, MD
Family Medicine Spring Symposium April 10, 2015
Treatment:motorsymptoms
Treatment:motorsymptoms • Anticholinergics
• COMTInhibitors
– Uses:
– Uses:
• Reducetremor
• AdjuncttherapytoљmotorŇuctuaƟons/oīƟme
– Agents:
– AdverseEffects:
• Trihexyphenidyl,Benztropine,Diphenhydramine • Lowdoses,1Ͳ3timesdaily
• Diarrhea,orangediscolorationofthebodilyfluids • Potentiationofdopaminergicsideeffects • Tolcapone – hepaticfailure
– AdverseEffects: • Constipation,urinarydysfunction,blurryvision,dry mouth,cognitivedysfunction,hallucinations, tachycardia • Usuallyusedinpatientsunder60yrsofageand withoutanyexistingcognitivedysfunction
– Greatlylimitsuse(mostseverepatientsonly)
Treatment:motorsymptoms
Treatment:motorsymptoms
• OptionsinLateDisease:
• OptionsinLateDisease:
– Amantadine
– Apomorphine
100mgtwicetofourtimesdaily Exactmechanismunknown Reducespeakdosedyskinesias Weanslowly,d/cassociatedwithpronounced worseningofPDsymptoms • Sideeffectssimilartodopamineagonists,including hallucinations • • • •
• • • • •
– livedo reticularis
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Nonergot dopamineagonistgivenbysubͲqinjection Rescuemedicationforacute,severehypomobility Onsetofaction10Ͳ15minutes,lastsabout60Ͳ120min Pronouncednausea,givenwithantiemetic Dosemustbecarefullydeterminedinofficebytrained physicians.
Treatment of Parkinson's Disease Laura Mayans, MD
Family Medicine Spring Symposium April 10, 2015
Treatment:motorsymptoms
Treatment:motorsymptoms
• OptionsinLateDisease:
• AlternativeTherapies
– DeepBrainStimulation
– Thereisnogoodevidencetosupporttheuseof anyherbalmedicationsorsupplements – Thereisnoknowndrugthatprovides neuroprotectionor slowsprogression – Thereissufficientevidencetorecommend AGAINSTVitaminE
• Approvedformedicallyrefractorysymptoms • Doesnotcureoralterprogression • ImprovesLEVODOPAͲRESPONSIVEsymptoms – Tremor,motorfluctuations,dyskinesias
• Patientcharacteristics – Younger,withoutdementia,depression,orpsychosis
• StudieshaveshownitdoesNOTslowdisease progression
TreatmentConsiderations
TreatmentConsiderations
• Initiation
• Levodopaeventuallyproducesmotor fluctuationsanddyskinesias
– AANrecommendsstartingtherapywhenpatients developfunctionaldisability – Carbidopa/Levodopa,DopamineAgonists,and MAOͲBInhibitorsareallappropriatefirstline, monotherapyagents
– Initially: • NeuronsconvertLevodopatodopamine • Neuronscanstorethedopamineandreleaseitmore smoothly/appropriately
– Late: • Moreneuronsdegenerate – Convertingandstoringcapacityisdecreased,variable,and unpredictable
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Treatment of Parkinson's Disease Laura Mayans, MD
Family Medicine Spring Symposium April 10, 2015
TreatmentConsiderations
TreatmentConsiderations
• DopamineAgonistsandMAOͲBInhibitors
• Inearlydisease/mildimpairment
– LesseffectivethenCarbidopa/Levodopaat treatingbradykinesia,rigidity,imbalance – Lessincidenceofmotorfluctuationsand dyskinesias
– ConsiderinitiatingadopamineagonistorMAOͲB inhibitor,particularlyinyoungerpatients(