Parkinson ’ s A Review and Practical Guide to a Common and Complex Disease.
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Transcript of Parkinson ’ s A Review and Practical Guide to a Common and Complex Disease.
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Parkinson’s
A Review and Practical Guide to a Common and Complex
Disease
A Review and Practical Guide to a Common and Complex
Disease
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Financial Disclosure
• Still paying off school loans.
• No one has offeredto help.
• If you work in industry and would like a shill, call me!
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• 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.
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EpidemiologySecond 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.
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EtiologyIdiopathic
>80% loss of DA neurons in the substantia nigra pars compacta
Multifactoral etiology-Genetic (α-synuclein)-Environment (pesticide exposure)
IatrogenicAntipsychotics: DA-receptor antagonists
Antiemetics: prochlorperazine, metoclopramide
Others: lithium, VPA, amiodarone
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Signs & SymptomsMotor Symptoms
Cardinal Manifestations
-Tremor-Bradykinesia-Rigidity
Non-Motor SymptomsNeuropsychiatricAutonomic Dysfunction
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Motor SymptomsCardinal 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”
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Non-Motor SymptomsNeuropsychiatric
Cognitive dysfunction and dementia
Psychosis and hallucinations
Depression, anxiety, and apathy
Sleep disturbances
Fatigue
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Non-Motor SymptomsNeuropsychiatric
Autonomic dysfunction
Olfactory dysfunction
Pain and sensory disturbances
Dermatologic findings
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Non-Motor SymptomsCognitive 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
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Non-Motor SymptomsPsychosis and Hallucinations
All PD meds can cause psychotic symptoms•DA agonists produce more
than levodopa
Delusions are often paranoid in nature
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Typical Physiology
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Pathophysiology
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DA Metabolism
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DA is a Hatch of Sea Turtles
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Peripheral LDOPA/DA Metabolism
AADC COMT
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Central LDOPA/DA Metabolism
COMT MAO-B
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DA Metabolism
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Drugs Used to Treat PD
• Dopamine replacement✓ Levodopa (LDOPA)
• Dopamine receptor agonists (D2)✓ Pramipexole✓ Ropinirole✓ Bromocriptine
• Anticholinergics✓ Trihexylphenidyl✓ Benztropine
Drugs which reduce the metabolism of Dopamine✓AADC inhibitor (Carbidopa)✓COMT inhibitor (Entacapone, Tolcapone)✓MAOI-B inhibitor (Selegiline, Rasagiline)
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Targets of Available Drug Therapy
Periphery: - AADC – Carbidopa - COMT – Etacapone, TolcaponeCentral: - COMT – Tolcapone - MAO-B – Selegeline, Rasagiline
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Targets of Drug Therapy
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DA Replacement Therapy
LevodopaMost effective agent
Short t1/2
Competes with dietary AA for absorption
Almost always administered with AADC/COMT inhibitor
Effectiveness decreases with prolonged use
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DA Replacement Therapy
Levodopa - side effectsHigh doses cause dyskinesias
Hallucination/delusions
Peripheral conversion to DA causes:
N/V/D
Orthostatic hypotension
Taper dose when discontinuing to avoid neuroleptic malignant syndrome
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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
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Drugs to Reduce Metabolism of LDOPA
• AADC antagonist (Carbidopa)
• COMT inhibitor (Entacapone; Tolcapone)
• MAO-B inhibitor (Selegeline, rasagiline)
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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
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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
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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
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Modulators of DA Metabolism Available Products
Carbidopa
•25mg available as a single agentEntacapone (Comtan)
•200mg as a single agentSelegeline
•ODT: 1.25mg
•Oral: 5mg
•Patch: 6mg; 9mg; 12mg/24 hoursRasagiline (Azilect)
•0.5mg up to 2mg (1mg most common and effective)
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DA AgonistsD-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
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AmantadineAmantadine (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, livedo reticularis
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AnticholinergicsTrihexyphenidyl (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
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Common Dosing StrategiesDA 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
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Common Dosing StrategiesMAO-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
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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)
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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)
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Treatment Overview
Drug sequence in naïve, early onset patient:
•DA agonists
•MAO-B inhibitor
•Anticholinergic (optional)
•Carbidopa/Levodopa
- Add Entacapone
•Amantadine
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Two Case Studies
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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
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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
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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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