Treatment: motor symptoms. Background. Parkinson s Disease: Treatment of Motor and Non motor Symptoms. Objectives:

Treatment of Parkinson's Disease Laura Mayans, MD Family Medicine Spring Symposium April 10, 2015 TreatmentofParkinson’sDisease • Objectives: 1. ...
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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(

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