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Parkinson’s
A Review and
Practical Guide to a
Common and
Complex Disease
Financial Disclosure
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loans.
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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 nonmovement related symptoms.
Epidemiology
Second most common neurodegenerative 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.
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
Signs & Symptoms
Motor Symptoms
Cardinal Manifestations
-
Tremor
Bradykinesia
Rigidity
Non-Motor Symptoms
Neuropsychiatric
Autonomic Dysfunction
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”
Non-Motor Symptoms
Neuropsychiatric
Cognitive dysfunction and
dementia
Psychosis and hallucinations
Depression, anxiety, and apathy
Sleep disturbances
Fatigue
Non-Motor Symptoms
Neuropsychiatric
Autonomic dysfunction
Olfactory dysfunction
Pain and sensory disturbances
Dermatologic findings
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
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
Typical Physiology
Pathophysiology
DA Metabolism
DA is a Hatch of Sea Turtles
Peripheral LDOPA/DA Metabolism
AADC
COMT
Central LDOPA/DA Metabolism
COMT
MAO-B
DA Metabolism
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)
Targets of Available Drug Therapy
Periphery:
- AADC – Carbidopa
- COMT – Etacapone, Tolcapone
Central:
- COMT – Tolcapone
- MAO-B – Selegeline, Rasagiline
Targets of Drug Therapy
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
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
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
Drugs to Reduce Metabolism of LDOPA
•
AADC antagonist
(Carbidopa)
•
COMT inhibitor
(Entacapone; Tolcapone)
•
MAO-B inhibitor
(Selegeline, rasagiline)
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
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
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
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)
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
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, livedo reticularis
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
Common Dosing Strategies
DA agonists:
•Pramipexole: start at 0.125mg TID
and increase to 0.75 mg TID over 46 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
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
Treatment Related Sequelae:
Wearing Off
Wearing off = return to unmedicated 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)
Treatment Related Sequelae:
Dyskinesias
Dyskinesias = involuntary
move-ments of the head, neck,
torso, and limbs
• “shakes, wiggles, extramovements”
Treatment:
• Reduce dose of DA drugs
(includes metabolism inhibitors)
• Add amantadine
• Deep brain stimulation (STN
Treatment Overview
Drug sequence in naïve, early
onset patient:
•
•
•
•
DA agonists
MAO-B inhibitor
Anticholinergic (optional)
Carbidopa/Levodopa
- Add Entacapone
• Amantadine
Two Case
Studies
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
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
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