1. Parkinson’s Disease: How Pharmacists Can Make a Difference Marsha K. Millonig, MBA, RPh President & CEO Catalyst Enterprises, LCC

2. Disclosure Information Parkinson’s Disease Marsha K. Millonig I have no financial relationship to disclose. AND I may discuss off-label/investigational use in my presentation.

3. Objectives Identify the visual and clinical testing tools used to diagnose PD Identify the classes of medications used to treat PD Understand the pros and cons of each class of medications and when to use these medications Understand how concomitant disease states and medications that could lead to further exacerbation of PD symptoms and how to avoid these situations Understand ways that pharmacists can assist PD patients, their caregivers, and physicians to properly manage their condition

4. What is Parkinson’s Disease? Chronic, progressive condition Motor symptom disorders Dysfunction/degeneration of dopaminergic neurons Domaminergic neurons in the substantia nigra control proper coordination and muscle group movement

5. Pathophysiology Lewy body structures also Inclusions of α- synuclein Disrupts normal neuronal function Lewy body: Dense Core with Halo

6. Pathophysiology Cell death due to dopaminergic neuron degeneration may be occurring up to 6 years before symptoms appear When symptoms appear, about 70% to 80% of the neurons have been lost Autonomic, cognitive, other non-motor symptoms usually appear before the motor symptoms

7. Autonomic Dysfunctions Constipation Dry mouth Urinary retention/incontinence Erectile dysfunction/decreased libido Orthostatic hypertension Drooling Heat/cold intolerance

8. Cognitive Impairments Apathy Anxiety –Occurs in 20% to 40% patients Depression –Occurs in 40% of patients Psychosis

9. Other Non-Motor Symptoms Unilateral aches and pains Fatigue Restlessness Paresthesias Sensation of internal tremor Continue as the disease progresses

10. Causes… Drawing by Jack Chen, Western University, Adapted from: McNaught K St P et al. Ann Neurol. 2003; Olanow CW, Tatton WG. Annu Rev Neurosci. 1999; Steece-Collier K et al. Proc Natl Acad Sci USA. 2002; Vila, Przedborski. Nat Rev Neurosci. 2003. UCH-L1 = ubiquitin hydrolase L1 Pathogenic Cascade Failure of UPS Protein aggregation Mitochondrial dysfunction Oxidative stress Excitotoxicity Neuroinflammation Spreading Apoptosis (cell death) Aging Environment Pesticides Agricultural toxins Other (?) Genes PARK 1-10  -synuclein Nurr-1 Parkin UCH-L1 UPS = ubiquitin proteosome system

11. May be Some Protective Factors Alcoholism OR = 0.41 (0.19-0.89) Coffee OR = 0.35 (0.16-0.78) Smoking OR = 0.69 (0.45-1.08) Ascherio et al. Am J Epidemiol 2004 Tanner et al. Neurology 2002 Ragonese et al. Neuroepidemiology 2003 Quik M. Trends Neurosci 2004 Wirdefeldt et al. Ann Neurol 2005 From Chen/Fagan 2005.

12. Scope of the Problem 1 million Americans 2nd most common neurodegenerative disease Average age of onset: 60 years 5%-10% cases in people under 50 years Slightly more men than women Lifetime risk: 1 in 45 Progression: 10-20 years or more

13. Cost of the Problem $6 billion Direct and indirect costs Treatment Psycho-social care

14. Does anyone have a family or friend with PD?

15. Impact Reduced quality of life Worse than CHF, CVA, back pain, OA, DM, CHD Trouble with daily routines May trigger frustration, anger, stress Higher susceptibility to anxiety and depression Personal, family, societal costs

16. Impact Increased medical expenses (physician visits and emergency care) Caregiver burden Risk of early nursing home placement

17. Diagnosis No definitive imaging techniques or biomarkers Diagnosis relies on physical and neurological exam Most common criteria: UK PD Society Brain Bank

18. From: Chen/Fagan 2005 adapted from Gelb DJ, Oliver E, Gilman S. Arch Neurol 1999; 56:33-39. Bradykinesia Rigidity Resting Tremor Postural Instability Classic Cardinal Symptom Tetrad

19. Diagnosis Drug history—some drugs can cause side effects mistaken with early PD –Dopamine Receptor Blockers –Conventional & Atypical Antipsychotics ( except clozapine) –Metoclopramide –Antiemetics (droperidol, prochlorperazine, promethazine) –Pimozide (Orap), amoxapine

20. Diagnosis Bradykinesia plus: –Rest tremor or rigidity Unilateral onset Insidious onset Absence of early falls, dementia Good response to dopamine Unmistakable in advanced disease Difficult to differentiate in early disease

21. Scans CT or MRIs Assess damage to s. nigra in later stages of PD Rule out tumors, strokes, other disorders: –Supranuclear Palsy –Shy-Dager Syndrome –Wilson’s Disease

22. Self-Assessment Question One A definitive diagnosis of PD includes which of the following: A. A complete physical and neurological assessment B. A blood test C. MRI and CT scans D. All of the above E. A and C only

23. Self-Assessment Question One A definitive diagnosis of PD includes which of the following: A. A complete physical and neurological assessment B. A blood test C. MRI and CT scans D. All of the above E. A and C only

24. Things to look for… –Gait disturbances –Lack of manual dexterity –Reduced arm swing –Postural instability –Rigidity –Tremor

25. Additional Motor/Non-Motor Features of Parkinson’s From: Chen et. al. JMCP 15:3:S1-21

26. PD Classification Uses a 5-stage classification system Called Hoehn and Yahr after creators UPDRS is another system –Unified PD Rating Scale that measures mental functioning on a scale from 0 to 199 (total disability) –Used most in clinical trials

27. Hoehn & Yahr Staging Stage 1:Unilateral disease Stage 2:Mild bilateral disease; good balance Stage 3:Mild/moderate bilateral; some postural instability; still independent Stage 4:Severe disability; Unable to function independently Stage 5:Wheel chair bound Hoehn MM, Yahr MD. Neurology 1967;17:427-442

28. Self-Assessment Question Two What is the most common means used to determine the stage of a person’s PD? A. Unified Parkinson Disease Rating Scale (UPDRS) B. Parkinson’s staging scale C. Hoehn and Yahr system D. DSM-IV

29. Self-Assessment Question Two What is the most common means used to determine the stage of a person’s PD? A. Unified Parkinson Disease Rating Scale (UPDRS) B. Parkinson’s staging scale C. Hoehn and Yahr system D. DSM-IV

30. Treatment Guidelines American Academy of Neurology www.aan.org 2006 Neurology 2006;66:7:983-995 http://neurology.jwatch.org/cgi/content /full/2006/801/1http://neurology.jwatch.org/cgi/content /full/2006/801/1

31. Recommendations From: Chen et. al. JMCP 15:3:S1-21

32. Quality Indicators for PD From: Chen et. al. JMCP 15:3:S1-21

33. Treatment Options Dopamine precursor Dopamine agonists Preservation of dopamine in brain –COMT inhibitors –MAO-B inhibitors Regulation of muscle movement –Anticholinergics

34. Therapeutic Agents From: Chen et. al. JMCP 15:3:S1-21

35. Anticholinergics/Precursors Benztropine (Cogentin) Trihexyphenidyl (Apo-Trihex) Procyclidine (DSC in US) Carbidopa/Levadopa (Sinemet CR)

36. COMT Inhibitors Entacapone (Comtan) Tolcapone (Tasmar)

37. MAO-B Inhibitors Rasagiline (Azilect) Selegiline (Eldepryl, Emsam, Zelapar)

38. Dopamine Receptor Agonists Apomorphine (Apokyn) Bromocriptine (Parlodel) Pramipexole (Mirapex) Ropinirole (Requip) Rotigotine (Neupro, recalled in 4/2008)

39. NMDA Receptor Inhibitor Amantadine (Symmetrel)

40. DA GABA ACh Striatum Substantia Nigra Levodopa Amantadine Selegiline Rasagiline Dopamine agonists: apomorphine bromocriptine pergolide pramipexole ropinirole Trihexiphenidyl Benztropine BBB dopamine levodopa 3-OMD DDCCOMT Carbidopa Entacapone Tolcapone From Chen/Fagan 2005. Adapted from www.wemove.org Symptomatic Treatment

41. Therapy: What is the Chief Complaint? Predominant SymptomClinical Options No functional impairment Neuroprotection (?) Mild symptoms Amantadine, MAO-B inhibitor Mild-moderate sxs Dopamine agonist, levodopa Discrete symptoms Tremor—antimuscarinic Dyskinesias – amantadine Motor fluctuations Entacapone, apomorphine Surgery