Treatment of Parkinson’s Disease Thomas L. Davis, M.D. Associate Professor of Neurology Vanderbilt School of Medicine

Treatment of PD Question Diagnosis Four cardinal features PD (parkinsonism = 2/4 features Four cardinal features PD (parkinsonism = 2/4 features Rest tremor Rest tremor Bradykinesia Bradykinesia Rigidity Rigidity Loss of postural reflexes Loss of postural reflexes Drug Induced Parkinsonism – treatment is to stop the offending agent Drug Induced Parkinsonism – treatment is to stop the offending agent

Treatment of PD Neuroprotection No proven treatments – this is the subject of a large NIH trial – potential agents under study include: No proven treatments – this is the subject of a large NIH trial – potential agents under study include: Minocycline Minocycline Creatine Creatine CoQ 10 CoQ 10 GPi GPi- 1485

Treatment Of PD General Strategy Continuous dopaminergic stimulation – may avoid long term motor fluctuations Continuous dopaminergic stimulation – may avoid long term motor fluctuations Small frequent doses Small frequent doses Longer acting agents (dopamine agonists, sustained release prep of L-DOPA) Longer acting agents (dopamine agonists, sustained release prep of L-DOPA) Delay metabolism of L-DOPA or dopamine (COMT inhibitors, MAO inhibitors) Delay metabolism of L-DOPA or dopamine (COMT inhibitors, MAO inhibitors)

Treatment of PD L-DOPA Mainstay of therapy – single most effect agent Mainstay of therapy – single most effect agent Increases lifespan in PD pts. Increases lifespan in PD pts. Many pharmacokinetic challenges Many pharmacokinetic challenges Now used more sparing than in the past to minimize motor fluctuations. Now used more sparing than in the past to minimize motor fluctuations.

Treatment of PD Dopamine agonist Longer duration than L-DOPA Longer duration than L-DOPA Less effective than L-DOPA Less effective than L-DOPA Less tolerated then L-DOPA Less tolerated then L-DOPA Frequently used early in disease and as an adjunct to L-DOPA Frequently used early in disease and as an adjunct to L-DOPA

Treatment of PD COMT Inhibition Blocks conversion of L-DOPA to inactive 3-O-methyldopa in the gut Blocks conversion of L-DOPA to inactive 3-O-methyldopa in the gut Prolongs the duration of effect of L- DOPA Prolongs the duration of effect of L- DOPA Increases AUC of L-DOPA without effecting T max Increases AUC of L-DOPA without effecting T max

Treatment of PD Other Agents Selegiline / Rasagiline – specific MAO-B inhibitor – prolongs the duration of L-DOPA by blocking the metabolism of dopamine Selegiline / Rasagiline – specific MAO-B inhibitor – prolongs the duration of L-DOPA by blocking the metabolism of dopamine Amantadine – many minor actions including glutamate antagonist – has mild antiparkinsonian effect and may block dyskinesia Amantadine – many minor actions including glutamate antagonist – has mild antiparkinsonian effect and may block dyskinesia

It is legal to prescribe a non- approved medication for your patients ? 1. True 2. False

Treatment of PD Non motor symptoms Cognitive difficulty Cognitive difficulty Depression Depression Constipation Constipation Sexual dysfunction Sexual dysfunction Sleep disorders Sleep disorders

Treatment of PD Drug AE’s Nausea – carbidopa / domperidone Nausea – carbidopa / domperidone Nightmares / Hallucinations – atypical neuroleptic – use with caution Nightmares / Hallucinations – atypical neuroleptic – use with caution Orthostatic hypotension – water, salt, Orthostatic hypotension – water, salt, Impulse control disorder - atypical neuroleptic Impulse control disorder - atypical neuroleptic

Treatment of PD Deep Brain Stimulation Use to treat PD complicated by severe motor fluctuations not responsive to medications. Use to treat PD complicated by severe motor fluctuations not responsive to medications. In general, it does not improve sx that L-DOPA does not. In general, it does not improve sx that L-DOPA does not.

New Therapies for Parkinson’s Disease Apomorphine – rapidly acting, brief duration SQ dopamine agonist for unpredictable off periods. Apomorphine – rapidly acting, brief duration SQ dopamine agonist for unpredictable off periods. Rapidly dissolvable L-DOPA Rapidly dissolvable L-DOPA Transdermal dopamine agonist Transdermal dopamine agonist