1. www.wemove.org Parkinson’s Disease Slide Library Version 2.0 - All Contents Copyright © WE MOVE 2001 Pharmacologic Treatment of Parkinson’s Disease Part 3 of 7

2. Treatment Options Preventive treatment –No definitive treatment available Symptomatic treatment –Pharmacological –Surgical Non-motor management Restorative—experimental only –Transplantation –Neurotrophic factors www.wemove.org

3. Drug Classes in PD Dopaminergic agents –Levodopa –Dopamine agonists COMT inhibitors MAO-B inhibitors Anticholinergics Amantadine www.wemove.org

4. DA GABA ACh Striatum Substantia Nigra levodopa Amantadine* selegiline Dopamine agonists bromocriptine pergolide pramipexole ropinirole baclofen trihexiphenidyl BBB carbidopa benserazide tolcapone entacapone Sites of Action of PD Drugs www.wemove.org

5. Anticholinergics Dopaminergic depletion  cholinergic overactivity Initially used in the 1950s Effective mainly for tremor and rigidity Common agents (Start low, go slow): –Trihexyphenidyl: 2-15 mg/day –Benztropine: 1-8 mg/day –Ethopropazine: 10-200 mg/day Side effects: –Dry mouth, sedation, delirium, confusion, hallucinations, constipation, urinary retention www.wemove.org

6. Amantadine Antiviral agent; PD benefit found accidentally Tremor, bradykinesia, rigidity & dyskinesias Exact mechanism unknown; possibly: –enhancing release of stored dopamine –inhibiting presynaptic reuptake of catecholamines –dopamine receptor agonism –NMDA receptor blockade Side effects —autonomic, psychiatric 200-300 mg/day www.wemove.org

7. Selegiline Irreversible MAO-B inhibitor Clinically active by inhibiting dopamine metabolism in brain May be neuroprotective Dosage: 5 mg at breakfast and lunch Side effects: insomnia, hallucinations, nausea (rarely), OH Potential interactions with tricyclics and SSRI antidepressants www.wemove.org

8. Evidence for Neuroprotection DATATOP study (NEJM 1989, 1993) –800 de novo patients took selegiline or vitamin E or both Results: –Selegiline delayed need for levodopa by 9 months –Reduced likelihood of needing levodopa by 50% –No effect from vitamin E www.wemove.org

9. DATATOP Follow-Up DATATOP: 3 year follow-up studies (Ann Neurol 1996) –subjects requiring levodopa (n=352) selegiline made no difference with regard to disease severity, wearing-off or dyskinesias –subjects not requiring levodopa (n=162) No difference in parkinsonian disability between the two groups 8 year follow-up (Ann Neurol 1998) –No increase in mortality www.wemove.org

10. Levodopa Most effective drug for parkinsonian symptoms First developed in the late 1960s; rapidly became the drug of choice for PD Large neutral amino acid; requires active transport across the gut-blood and blood-brain barriers Rapid peripheral decarboxylation to dopamine without a decarboxylase inhibitor (DCIs: carbidopa, benserazide) Side effects: nausea, postural hypotension, dyskinesias, motor fluctuations www.wemove.org

11. Diagram of LD Metabolism www.wemove.org

12. Is Levodopa Toxic? Early patients develop motor fluctuations, but may be a function of neuronal cell loss Increased life expectancy with LD introduction LD-naive advanced PD patients develop fluctuations almost immediately with LD induction No LD neuronal dropout in laboratory animals Recent data suggest possible neuroprotection Some believe continuous infusion may be safer than pulsatile therapy www.wemove.org

13. Levodopa-Induced Dyskinesias Manifestation of excessive dopaminergic stimulation Typically late effect, and with higher doses Narrowing of therapeutic window Rare in LD-naive patients on DA monotherapy Most common is “peak dose” dyskinesia –disappears with dose reduction Choreiform, ballistic and dystonic movements Most patients prefer some dyskinesias over the alternative of akinesia and rigidity www.wemove.org

14. Levodopa/Carbidopa Formulations OnsetDuration Immediate Release 20-40 min2-4 hr 10/100, 25/100, 25/250 Controlled Release 30-60 min3-6 hr 25/100, 50/200 “Liquid levodopa” 10-20 min 0.5-1 hr (dissolved tablets) www.wemove.org

15. COMT Inhibitors Newest class of antiparkinsonian drugs: tolcapone, entacapone MOA similar to dopa decarboxylase inhibitors Potentiate LD: prevent peripheral degradation by inhibiting catechol O-methyl transferase Reduces LD dose necessary for a given clinical effect Helpful for both early and fluctuating Parkinson’s disease May be particularly useful for patients with “brittle” PD, who fluctuate between off and on states frequently throughout the day www.wemove.org

16. Tolcapone (Tasmar ® ) First COMT inhibitor licensed in the U.S. 100 mg TID or 200 mg TID Reduced LD dosage by 12%, improved motor fluctuations by 14% in non-fluctuating pts Reduced LD dosage by 30%, and on time increased from 1.7 to 2.9 hrs/day in fluctuating pts Side effects: Diarrhea, OH, dyskinesias, confusion Acute fulminant hepatic necrosis –3/60,000+ –FDA warning prevents use unless alternative therapy unsuccessful –liver monitoring every 2 weeks for a year and less frequently thereafter www.wemove.org

17. Entacapone Dosage: 200 mg w/each levodopa dose Parkinson’s Study Group 1997: Increased on time by 5%, more in pts w/least on time Rinne et al., 1998: Increased on time by ~10%; decreased levodopa Diarrhea, dopaminergic SEs www.wemove.org

18. Dopamine Agonists: Distinguishing Features Directly stimulate dopamine receptors No metabolic conversion; bypasses nigrostriatal neurons No absorption delay from competition with dietary amino acids Longer half-life than levodopa Monotherapy or adjunct therapy May delay or reduce motor fluctuations & dyskinesias associated with levodopa May be neuroprotective www.wemove.org

19. Dopamine Receptor Subtypes D1, D2 subcortical D3, D4, D5 cortical Differentiated biochemically & pharmacologically into two families: –D1 family: D1, D5 –D2 family: D2, D3, D4 www.wemove.org

20. DAs: Receptor Effects D1D2D3D4D5 Ergot Bromocriptine-++++++ Cabergoline0+++??? Lisuride+++??? Pergolide++++++++++ Non-Ergot Pramipexole0++++++++? Ropinirole0+++++++0 Neurology 1998; 50(suppl 3) www.wemove.org

21. DA Pharmacokinetics and Dosage T1/2 Dosage (monotherapy) Bromocriptine (Parlodel)6 hr 7.5-30 mg/day Cabergoline65+ hr2-5 mg/day Lisuride2-4 hr1-5 mg/day Pergolide (Permax)12-27 hr 1.5-12 mg/day Pramipexole (Mirapex) 8 hr1-4.5 mg/day Ropinirole (Requip) 4 hr3-24 mg/day www.wemove.org

22. DAs: Therapeutic Responses and Patient Outcomes www.wemove.org

23. DAs: Common Adverse Effects Nausea, vomiting Dizziness, postural hypotension Headache Dizziness Drowsiness & somnolence Dyskinesias Confusion, hallucinations, paranoia Erythromelalgia; pulmonary & retroperitoneal fibrosis; pleural effusion & pleural thickening; Raynaud’s phenomena. May be more common with ergotoline DAs www.wemove.org

24. Apomorphine D1/D2 agonist Parenteral delivery (s.c., i.v., sublingual, intranasal, rectal) Rapid “off” period rescue –2-5 mg s.c.; pen injection systems Treatment of unpredictable, frequent motor fluctuations –continuous s.c. infusion via mini-pump SE: nausea, vomiting, hypotension –trimethobenzamide 250 mg t.i.d. –domperidone 20 mg t.i.d.; not available in U.S. www.wemove.org

25. Faculty for the WE MOVE Parkinson’s Disease Teaching Slide Set Mark Stacy, MD Barrow Neurological Institute Phoenix, Arizona, USA Charles H. Adler, MD, PhD Mayo Clinic Scottsdale Scottsdale, Arizona, USA Kathleen Albany, PT, MPH WE MOVE New York, USA Richard B. Dewey, Jr., MD University of Texas Southwestern Medical Center Dallas, Texas, USA William G. Ondo, MD Baylor College of Medicine Houston, Texas, USA Rajesh Pahwa, MD University of Kansas Medical Center Kansas City, Kansas, USA Ali H. Rajput, MD Royal University Hospital Saskatoon, Saskatchewan, Canada Lisa M. Shulman, MD Health Policy Fellow U.S. House of Representatives Washington, DC, USA Celia Stewart, PhD Mount Sinai Medical Center New York, New York, USA Reviewed by the Education Committee of the Movement Disorder Society www.wemove.org