Parkinson’s Disease

1. Parkinson’s Disease Review of Pathophysiology, Diagnosis, & Current Therapy

2. Historical Perspective • Dr. James Parkinson (1755-1828) • 1817 • “involuntary tremulous motion” • “pass from a walking to a running pace” • “shaking palsy” • London home

3. Epidemiology • Average incidence is 20 per 100,000 in North America • 1 Million affected in the United States • 50,000 new cases per year • Cost estimated to exceed $5.6 Billion annually

4. Epidemiology • Average age of onset 62.5 • Men and women affected equally • Genetic Link • African-Americans and Asians less likely than Caucasians to develop Parkinson’s • Caffeine and smoking shows some protective effects

5. Case Example • JJ is a 66 y/o Caucasian man who underwent surgical management for spinal stenosis and was admitted for rehabilitation. JJ has a past history of Parkinson’s, hypertension, coronary artery disease, GERD, and depression. Upon admission appropriate measures were taken for pain management and aforementioned medical conditions. JJ’s surgical management and rehabilitation was complicated by advanced Parkinson’s. During his stay advances were made in his strength, endurance, and ADL’s. JJ was discharged and will receive assistive care from his wife. Overall, the care for JJ was appropriate and followed standard of care practices.

6. Medication Profile • Carbidopa/Levodopa (Sinemet) 25/100/po-6times daily-(Parkinson's) • Lansoprazole (Prevacid) 30mg/po-ACBR-(GERD) • Baclofen (Lioresal) 10mg/po-qhs-(Parkinson's Dystonia) • Quinine sulfate (Quinidine) 260mg/po-qhs-(Muscle Cramps) • Quetiapine (Seroquel) 25mg/po-qhs-(Hallucinations) • Ropinirole (Requip) 1mg/po-1mg5Xdaily&2mgq6am-(Parkinson's) • Docusate Sodium (Colace) 100mg/po-bid-(Constipation) • Metoprolol (Lopressor) 50mg/po-qd-(Hypertension) • Calcium Carbonate (Tums) 500mg/po-1000mgbid-(Calcium supplement) • Oxaprozin (Daypro) 600mg/po-qd-(Osteoarthritis) • Propoxyphen/APAP (Darvocet N-100) 100mg/650mg/po-1q4hprn-(Pain Management) • Bethanechol (Urecholine) 10mg/po-20mgprn-(Urinary Retention) • Docusate Sod-Casanthranol (Pericolace) 100mg/30mg/po-qdprn-(Constipation) • Bisacodyl Supp (Ducolax) 10mg/pr-qodprn-(Constipation)

7. Pathogenesis • Four Theories • Oxidative damage • Impaired protection • Environmental toxins • MPTP-Methyl-phenyl tetrahydropyridine • Genetic predisposition • Mutations in the gene for the protein alpha-synuclein located on chromosome 4 • Accelerated aging

8. Pathophysiology • Imbalance of dopamine and acetylcholine • Loss of 80 to 90% of dopaminergic production in the substantia nigra • Lewy Bodies

9. Diagnostic Features • Four Cardinal Signs • T remor • R igidity • A kinesian and bradykinesia • P ostural instability

10. Characteristic Problems • Micrographia-small handwriting • Hypomimia-decreased facial animation • Hypophonia-soft speech • Dysarthria-unclear pronunciation • Dyspnea-labored breathing • Festination-Shuffling gait

14. Diagnosis • Bradykinesia must be present with at least two of the following: limb muscle rigidity, resting tremor (abolished with movement), or postural instability. • Need to eliminate secondary causes; • Postencephalitic • Drug-Induced • Toxic • Stroke • Trauma • Neoplasm • Other neurodegenerative conditions • Wilson’s disease • Alzheimer’s • Lewy Body dementia

15. Hoehn and Yahr Staging of Severity of Parkinson’s Disease

16. Schwab & England Activities of Daily Living Scale

17. Pharmacotherapy • Levodopa • Dopamine agonists • COMT inhibitors • Amantadine • Anticholinergics • Selegiline

19. Levodopa • L-Dopa (Larodopa by Roche) • Introduced in the late 1960s • “Gold Standard” • Crosses the blood-brain barrier • Adverse effects such as nausea, vomiting, postural hypotension, involuntary movements, restlessness, and cardiac arrhythmias

21. Levodopa • Today L-dopa/carbidopa (Sinemet) used almost exclusively • Initial dose of 25/100mg ½ QD for 7 days, increase by ½ tab daily for 7 days until up to 1 tablet TID. Extended release dosed as 25/100mg QD and titrated up to TID over a months time. Maximum dose of L-dopa is 800mg/day. • Adverse effects minimized with carbidopa • “End-of-dose wearing-off effect” • “On-off effect”

23. Dopamine Agonists“Synthetic Dopamine” • Bromocriptine Mesylate (Parlodel) • Pergolide Mesylate (Permax) • Pramipexol (Mirapex) • Ropinirole HCL (Requip)

24. Dopamine Agonists • Monotherapy or combination • Are particulary usefull for: • Prolonging the effective treatment period in patients with deteriorating response. • Delaying the onset of L-dopa therapy. Particularly in younger patients. • Treating patients who cannot tolerate high doses of L-dopa. • Associated with more side effects than L-dopa • Potential adverse effects include somnolence, dyskinesias, nausea, vomiting, orthostatic hypotension, nightmares, hallucinations, confusion, dizziness

25. Ergot Agonist Dosing • Bromocriptine (Parlodel) • Initial 1.25mg QD-BID • Titrate 1.25mg to 2.5mg/d every week • Average dose <30mg/day. Some patients may require up to 120mg/day • Pergolide (Permax) • 13 times more potent than bromocriptine • Initial 0.05mg/d for 2 days, increasing by 0.1 to 0.15mg/d every 3 days over a 12 day period • May increase by 0.25mg every 3 days until symptoms are eliminated or adverse effects occur • Mean dose 3mg/d

26. Nonergot Agonist Dosing • Pramipexole (Mirapex) • Monotherapy or Adjunct • Initial dose of 0.125 mg TID and increased every 5 to 7 days as tolerated up to 3 to 4.5mg/d • Higher doses are not more effective than 1.5mg/d and are associated with more side effects • Mean 27% reduction of L-Dopa • Decrease dose with renal function impairment • Drugs that are secreted by the cationic transport system may decrease the clearance of pramipexole by 20%. These include cimetidine, diltiazem, quinidine, quinine, ranitidine, triamterene, and verapamil.

27. Nonergot Agonist Dosing • Ropinirole (Requip) • Monotherpy or Adjunct • Initial dose of 0.25mg TID and increased by 0.25mg TID on a weekly basis. After the fourth week doses may be increased by 1.5mg/d up to 9mg/d. Further adjustment may be obtained by 3mg/d increases up to 24mg/day • Mean 19% reduction of L-dopa • Drugs that inhibit or induce CYP1A2 will affect the clearance of ropinirole. Inhibitors such as cimetidine, ciprofloxacin, clarithromycin, diltiazem, enoxacin, erythromycin, fluvoxamine, mexiletine, norfloxain, omeprazole, ritonavir, and troleandomycin. Inducers such as carbamazepine, phenobarbital, phenytoin, and rifampin. • If therapy is stopped, discontinue over seven days

28. COMT Inhibitors • Entacapone (Comtan) • Tolcapone (Tasmar)

29. COMT Inhibitor Dosing • Entacapone (Comtan) • Adjunct therapy • Initial dose of 200mg with each dose of levodopa up to 8 times daily • Decrease of L-dopa may be necessary • Exacerbation of L-dopa side effects , diarrhea, urine discoloration, abdominal pain

30. COMT Inhibitor Dosing • Tolcapone (Tasmar) • Adjunct therapy • Initial 100mg TID up to 200mg TID • More potent and longer acting than entacapone • Decrease L-dopa by 25 to 50% • Exacerbation of L-dopa side effects, diarrhea, urine discoloration, liver toxicity. • Monitor LFTs every 2 weeks for 1 year, every 4 weeks for 6 months, then every 8 weeks

31. Amantadine • Amantadine HCL (Symmetrel) • Inhibits dopamine recapture • Blocks acetylcholine and glutamate receptors • Dose 100mg BID to TID • Caution in renal failure patients • Currently used to reduce choreic movements • Narrow therapeutic range • Unpleasant side effects such as nausea, dizziness, confusion, hallucinations, nightmares, dry mouth peripheral edema, and livedo reticularis

32. Anticholinergics • Trihexyphenidyl HCL (Artane) • Benztropine Mesylate (Cogentin) • Monotherapy or adjunct • Predopaminergic therapy • Long touted as most effective for reducing tremor • Use Limited by side effects especially in the elderly.

33. Anticholinergics • Trihexyphenidyl HCL (Artane) • Initial dose of 1mg and increase by 2 mg every 3 to 5 days until 6 to 10 mg/day. Usually given TID with meals or QID with meals and at bedtime. • Possible adverse effects include dry mouth, blurred vision, somnolence, hallucinations, memory impairment, confusion, urinary retention, and constipation. • Benztropine Mesylate (Cogentin) • Initial dose of 0.5 to 1 mg at bedtime. Increase by 0.5mg every 5 to 6 days up to a total daily dosage of 6mg. • Possible adverse effects include dry mouth, blurred vision, somnolence, hallucinations, memory impairment, confusion, urinary retention, and constipation.

34. Selegiline • Selegiline HCL(Eldepryl)

35. Selegiline • Selegiline HCL (Eldepryl) • Monotherapy or adjunct • MOA-inhibits monoamine oxidase-B (MAO-B) • Inhibition of MAO-A does not occur • Dosage of 5 mg BID with breakfast and lunch • When used as monotherapy delays the need of L-dopa by an average of nine months. • Possible adverse effects include nausea, dizziness, abdominal pain, confusion, and exacerbation of L-dopa side effects • Controversial theory of decreased rate of neuronal death due to a reduction of free radicals.

36. Surgical Options • Pallidotomy and Pallidal Stimulation • Thalamotomy and Thalamic Stimulation • Introduced in 1950 • Pallidotomy improves tremor, rigidity, and bradykinesia • Thalamotomy relieves tremor, rigidity, but not bradykinesia • Neurosurgical treatment came to a end with the introduction of L-dopa in late 1960s • Resurgence of neurosurgical intervention with the failure of pharmacological treatments after 10 to 15 years of disease progression • Two methods: Ablation and deep brain stimulation

37. Grafting • Suprarenal to brain transplantation • Fetal tissue transplantation • Cell culture transplantation

38. Under Investigation • Implantable pumps • Implantable capsules containing dopamine-producing cells • New medications to target one of the five individual brain receptors for dopamine • Continued genetic research

39. References • Cosgrove, G. Rees, Eskandar, Emad N., Shinobu, Leslie A. “Surgical Treatment of Parkinson Disease.” JAMA December 26, 2001;286:3056-3059. • Dipiro, Joseph T., ed. Pharmacotherapy Fourth Edition. Stamford, Connecticut: Appleton & Lange, 1999. • “Early Parkinson’s Disease: Dopamine Agonists Have Increasingly Important Role in Symptom Management.” Drug Ther Perspect 2001;17(17):5-9. • Faulkner, Thomas P. “Parkinson’s Disease.” 7 December 1999. http://www.onu.edu/user/FS/tfaulkner/parkinso.html 23 May 2002. • Hermanowiez, Neal. “Management of Parkinson’s Disease.” Postgraduate Medicine 2001;110(6):15-28 • Korczyn, Amos D. “Hallucinations in Parkinson’s Disease.” Lancet 2001;358(9287):1031-1032. • Lindvall, Olle. “Stem Cell Transplantation.” Lancet 2001;358(Supplement);s47. • Nicholl, David. “Parkinson’s Disease.” 22 April, 1998. http://medweb.bham.ac.uk/http/depts/clin_neuro/teaching/tutorials/parkinsons/parkinsons1... 27 May, 2002. • Ninds. “Parkinson’s Disease-Hope Through Research.” http://accessible.ninds.nih.gov/health_and_medical /pubs/parkinson_disease_htr.htm • Referenced on 5/27/02. • Stephenson, Joan. “Exposure to Home Pesticides Linked to Parkinson Disease.” JAMA June 21, 2000;283(23):3055-3058.