Treatment of Treatment of Parkinson’s DiseaseParkinson’s Disease

Thomas L. Davis, M.D.Thomas L. Davis, M.D.

Associate Professor of Associate Professor of NeurologyNeurology

Vanderbilt School of MedicineVanderbilt School of Medicine

Treatment of PDTreatment of PDQuestion DiagnosisQuestion Diagnosis

Four cardinal features PDFour cardinal features PD (parkinsonism = 2/4 features(parkinsonism = 2/4 features Rest tremorRest tremor BradykinesiaBradykinesia RigidityRigidity Loss of postural reflexesLoss of postural reflexes

Drug Induced ParkinsonismDrug Induced Parkinsonism – – treatment is to stop the offending agent treatment is to stop the offending agent

Treatment of PDTreatment of PDNeuroprotectionNeuroprotection

No proven treatments – this is the No proven treatments – this is the subject of a large NIH trial – potential subject of a large NIH trial – potential agents under study include:agents under study include:

MinocyclineMinocyclineCreatineCreatineCoQCoQ1010

GPi- 1485GPi- 1485

Treatment Of PDTreatment Of PDGeneral StrategyGeneral Strategy

Continuous dopaminergic stimulation – Continuous dopaminergic stimulation – may avoid long term motor fluctuationsmay avoid long term motor fluctuations Small frequent dosesSmall frequent doses Longer acting agents (dopamine agonists, Longer acting agents (dopamine agonists,

sustained release prep of L-DOPA)sustained release prep of L-DOPA) Delay metabolism of L-DOPA or dopamine Delay metabolism of L-DOPA or dopamine

(COMT inhibitors, MAO inhibitors) (COMT inhibitors, MAO inhibitors)

Treatment of PDTreatment of PDL-DOPAL-DOPA

Mainstay of therapy – single most Mainstay of therapy – single most effect agenteffect agent

Increases lifespan in PD pts.Increases lifespan in PD pts. Many pharmacokinetic challengesMany pharmacokinetic challenges Now used more sparing than in the Now used more sparing than in the

past to minimize motor fluctuations.past to minimize motor fluctuations.

Treatment of PD Treatment of PD Dopamine agonistDopamine agonist

Longer duration than L-DOPALonger duration than L-DOPA Less effective than L-DOPALess effective than L-DOPA Less tolerated then L-DOPALess tolerated then L-DOPA Frequently used early in disease and Frequently used early in disease and

as an adjunct to L-DOPAas an adjunct to L-DOPA

Treatment of PDTreatment of PDCOMT InhibitionCOMT Inhibition

Blocks conversion of L-DOPA to Blocks conversion of L-DOPA to inactive 3-O-methyldopa in the gutinactive 3-O-methyldopa in the gut

Prolongs the duration of effect of L-Prolongs the duration of effect of L-DOPADOPA

Increases AUC of L-DOPA without Increases AUC of L-DOPA without effecting Teffecting Tmaxmax

Treatment of PDTreatment of PDOther AgentsOther Agents

Selegiline / Rasagiline – specific Selegiline / Rasagiline – specific MAO-B inhibitor – prolongs the MAO-B inhibitor – prolongs the duration of L-DOPA by blocking the duration of L-DOPA by blocking the metabolism of dopaminemetabolism of dopamine

Amantadine – many minor actions Amantadine – many minor actions including glutamate antagonist – including glutamate antagonist – has mild antiparkinsonian effect has mild antiparkinsonian effect and may block dyskinesiaand may block dyskinesia

It is legal to prescribe a non- It is legal to prescribe a non- approved medication for your approved medication for your patients ?patients ?

1.1. TrueTrue

2.2. FalseFalse

Treatment of PDTreatment of PDNon motor symptomsNon motor symptoms

Cognitive difficulty Cognitive difficulty DepressionDepression ConstipationConstipation Sexual dysfunctionSexual dysfunction Sleep disordersSleep disorders

Treatment of PDTreatment of PDDrug AE’sDrug AE’s

Nausea – carbidopa / domperidoneNausea – carbidopa / domperidone Nightmares / Hallucinations – Nightmares / Hallucinations –

atypical neuroleptic – use with atypical neuroleptic – use with caution caution

Orthostatic hypotension – water, Orthostatic hypotension – water, salt, salt,

Impulse control disorder - atypical Impulse control disorder - atypical neuroleptic neuroleptic

Treatment of PDTreatment of PDDeep Brain StimulationDeep Brain Stimulation

Use to treat PD complicated by Use to treat PD complicated by severe motor fluctuations not severe motor fluctuations not responsive to medications. responsive to medications.

In general, it does not improve sx In general, it does not improve sx that L-DOPA does not.that L-DOPA does not.

New Therapies for New Therapies for Parkinson’s DiseaseParkinson’s Disease

Apomorphine – rapidly acting, brief Apomorphine – rapidly acting, brief duration SQ dopamine agonist for duration SQ dopamine agonist for unpredictable off periods.unpredictable off periods.

Rapidly dissolvable L-DOPARapidly dissolvable L-DOPA Transdermal dopamine agonistTransdermal dopamine agonist