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Parkinson ’ s

Parkinson ’ s. A Review and Practical Guide to a Common and Complex Disease. Financial Disclosure. Still paying off school loans. No one has offered to help. If you work in industry and would like a shill, call me!.

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Parkinson ’ s

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  1. Parkinson’s • A Review and Practical Guide to a Common and Complex Disease

  2. Financial Disclosure • Still paying off school loans. • No one has offeredto help. • If you work in industry and would like a shill, call me!

  3. A neurodegenerative disease characterized by a loss of dopaminergic neurons in the substantia nigra (pc) leading to a clinical syndrome which manifests in movement and non-movement related symptoms.

  4. Epidemiology • Second most common neuro-degenerative disease. • Affects 1-1.5 million people in U.S. • Prevalence 1% of all people over 60yo, 4% of those over 80yo. • Lifetime risk: 1 in 40. • In U.S., number affected expected to double by 2030.

  5. Etiology Idiopathic • >80% loss of DA neurons in the substantia nigra pars compacta • Multifactoral etiology • Genetic (α-synuclein) • Environment (pesticide exposure) Iatrogenic • Antipsychotics: DA-receptor antagonists • Antiemetics: prochlorperazine, metoclopramide • Others: lithium, VPA, amiodarone

  6. Signs & Symptoms Motor Symptoms • Cardinal Manifestations • Tremor • Bradykinesia • Rigidity Non-Motor Symptoms • Neuropsychiatric • Autonomic Dysfunction

  7. Motor Symptoms Cardinal Manifestations • Tremor – “pill-rolling” characteristically a rest tremor. • Worse at rest and lessens with purposeful action • Bradykinesia – generalized slowness of movement • Major cause of disability • Rigidity – increased resistance to passive movement around a joint • Can be “cogwheel” or “lead pipe”

  8. Non-Motor Symptoms Neuropsychiatric • Cognitive dysfunction and dementia • Psychosis and hallucinations • Depression, anxiety, and apathy • Sleep disturbances • Fatigue

  9. Non-Motor Symptoms Neuropsychiatric • Autonomic dysfunction • Olfactory dysfunction • Pain and sensory disturbances • Dermatologic findings

  10. Non-Motor Symptoms Cognitive dysfunction and dementia • Independent predictor of mortality Parkinson Disease Dementia (PDD) • Psychomotor retardation, memory loss, altered personality • Deficits in executive function seen early in disease • PDD occurs late in the course of PD and is often confused with Lewy body dementia

  11. Non-Motor Symptoms Psychosis and Hallucinations • All PD meds can cause psychotic symptoms • DA agonists produce more than levodopa • Delusions are often paranoid in nature

  12. Typical Physiology

  13. Pathophysiology

  14. DA Metabolism

  15. DA is a Hatch of Sea Turtles

  16. Peripheral LDOPA/DA Metabolism • AADC COMT

  17. Central LDOPA/DA Metabolism • COMT MAO-B

  18. DA Metabolism

  19. Drugs Used to Treat PD • Drugs which reduce the metabolism of Dopamine • AADC inhibitor (Carbidopa) • COMT inhibitor (Entacapone, Tolcapone) • MAOI-B inhibitor (Selegiline, Rasagiline) • Dopamine replacement • Levodopa (LDOPA) • Dopamine receptor agonists (D2) • Pramipexole • Ropinirole • Bromocriptine • Anticholinergics • Trihexylphenidyl • Benztropine

  20. Targets of Available Drug Therapy • Periphery: • - AADC – Carbidopa • - COMT – Etacapone, Tolcapone • Central: • - COMT – Tolcapone • - MAO-B – Selegeline, Rasagiline

  21. Targets of Drug Therapy

  22. DA Replacement Therapy Levodopa • Most effective agent • Short t1/2 • Competes with dietary AA for absorption • Almost always administered with AADC/COMT inhibitor • Effectiveness decreases with prolonged use

  23. DA Replacement Therapy Levodopa - side effects • High doses cause dyskinesias • Hallucination/delusions • Peripheral conversion to DA causes: • N/V/D • Orthostatic hypotension • Taper dose when discontinuing to avoid neuroleptic malignant syndrome

  24. Carbidopa/Levodopa Products • Immediate release (Sinemet) • 10/100; 25/100; 25/250 • Sustained release (Sinemet CR) • 12.5/50; 25/100; 50/200 • Combo with entacapone (Stalevo) • 50; 75; 100; 125; 150; 200 • Number is the LDOPA component • 50 contains 12.5mg carbidopa, 75 contains 18.5mg carbidopa, all others have 25mg and all contain 200mg of entacapone

  25. Drugs to Reduce Metabolism of LDOPA • AADC antagonist (Carbidopa) • COMT inhibitor (Entacapone; Tolcapone) • MAO-B inhibitor (Selegeline, rasagiline)

  26. Drugs to Reduce Metabolism of LDOPA • COMT inhibitors (entacapone; tolcapone) • Primary activity is blocking peripheral COMT • Entacapone given with every dose of LDOPA • Not used as monotherapy • If used early, may shorten time to developing treatment related dyskinesias • Side effects similar to LDOPA

  27. Drugs to Reduce Metabolism of LDOPA • AADC antagonist (Carbidopa) • Blocks dopa decarboxylase in the periphery only • Reduces premature transformation of LDOPA to DA • Reduces SE from excessive DA in the periphery • Effective dose is at least 75mg per day

  28. Drugs to Reduce Metabolism of LDOPA • MAO-B inhibitors (selegiline, rasagiline, rotigitine) • Selegiline metabolized to amphetamines • ODT and patch reduce these metabolites • Only rasagiline approved as monotherapy • No tyramine reactions reported • Generally well tolerated • May delay clinical progression

  29. Modulators of DA Metabolism Available Products • Carbidopa • 25mg available as a single agent • Entacapone (Comtan) • 200mg as a single agent • Selegeline • ODT: 1.25mg • Oral: 5mg • Patch: 6mg; 9mg; 12mg/24 hours • Rasagiline (Azilect) • 0.5mg up to 2mg (1mg most common and effective)

  30. DA Agonists • D-2 Receptor agonists (ropinirole; pramipexole) • Longer duration of action than LDOPA (8-24hrs) • LDOPA “sparing” agents • Particularly effective for on/off syndrome • Both are available as IR and XR formulations • Often prescribed in early onset PD to postpone LDOPA • SE’s: hallucinations, N, fatigue/somnilence • Bromocriptine rarely used due to SE’s

  31. Amantadine • Amantadine (Symmetrel) • NMDA antagonist, increased DA release and decreased reuptake, some anticholinergic effects • Mildly effective • May be used to counter treatment related dyskinesias • SE: anticholinergic, insomnia, confusion, livedoreticularis

  32. Anticholinergics • Trihexyphenidyl (Artane); benzotropine (Cogentin) • Block over-activity of cholinergic neurons in striatum resulting from DA loss. • Modest benefit (mostly for tremor) • SE profile (Anticholinergic) prevents use in older patients

  33. Common Dosing Strategies • DA agonists: • Pramipexole: start at 0.125mg TID and increase to 0.75 mg TID over 4-6 weeks • Ropinerole: start at 0.25mg TID and increase to 3-4 mg TID over 6 weeks • DA replacement: IR or SR • Begin with 25/100 BID or TID and increase slowly to 50/200 BID, TID, or QID • Entacapone most often given with each dose if it is being used

  34. Common Dosing Strategies • MAO-B inhibitors • Selegiline: • ODT: begin with 1.25 mg qd and increase to 2.5mg (max dose) after 6 weeks • Oral tab/cap: 5mg QAM and increase to max of 5mg QAM and 5mg Qnoon • Rasagiline: • Begin with 0.5mg qd and increase to 1mg (max 2mg) • 1mg preferred and shown more efficacious than 2mg

  35. Treatment Related Sequelae:Wearing Off • Wearing off = return to unmedi-cated state • Intra-daily fluctuations (early morning, end-of-dose, random) • Treatment: • Increased frequency and/or dose of LDOPA • DA agonist, entacapone, rasagiline • Deep brain stimulation (STN)

  36. Treatment Related Sequelae:Dyskinesias • Dyskinesias = involuntary move-ments of the head, neck, torso, and limbs • “shakes, wiggles, extra-movements” • Treatment: • Reduce dose of DA drugs (includes metabolism inhibitors) • Add amantadine • Deep brain stimulation (STN and/or Gpi)

  37. Treatment Overview • Drug sequence in naïve, early onset patient: • DA agonists • MAO-B inhibitor • Anticholinergic (optional) • Carbidopa/Levodopa • Add Entacapone • Amantadine

  38. Two Case Studies

  39. Study #1 • KD 49 yom with PD since 1996 s/p DBS (R) in 2005 now with worsening sx’s including: difficulty walking, rigidity, shuffling/falling, freezing episodes and tremors. Also c/o dyskinesias and dystonias in the non-stim side. • Refractory to further medications and dependent on current regimen. Admitted for DBS of (L) side. • Current regimen as documented in Impact and note: • Stalevo 125 TID-WA • Carbidopa/levodopa (Sinemet) 25/100 TID-WA

  40. Study #2 • DB 54yom s/p DBS, refractory to meds with significant worsening of movement requiring sgy. Has long hx of intolerance and resistance to meds. • Home regimen as entered in Impact: • Ropinerole 15mg qd • Entacapone 200mg 5 times daily • Sinemet CR 50/200 nightly • Sinemet 25/100 2 tabs QID • Pt actually took: • Ropinerole 3mg 5 times a day at 0600, 1000, 1400, 1800, and 2200. • Entacapone 200mg 5 times a day at those times (lucky) • Sinemet IR 25/100 2 tabs QID at 0600, 1000, 1400, 1800 • Sinemet CR 50/200 at 2200

  41. Practical Issues Polypharmacy • Many patients have multiple comorbidities • Average PD patient on 5-7 drugs • Complex regimens necessitate pharmacist vigilance Dosing schedule • Very precise dosing times with multiple formulations of DA agents • Many will want to take personal supply

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