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Pharmacologic Treatment of
Parkinson’s Disease
Part 3 of 7
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Parkinson’s Disease Slide Library Version 2.0 - All Contents Copyright © WE MOVE 2001
Treatment Options
• Preventive treatment
– No definitive treatment available
• Symptomatic treatment
– Pharmacological
– Surgical
• Non-motor management
• Restorative—experimental only
– Transplantation
– Neurotrophic factors
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Drug Classes in PD
• Dopaminergic agents
– Levodopa
– Dopamine agonists
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COMT inhibitors
MAO-B inhibitors
Anticholinergics
Amantadine
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Sites of Action of PD Drugs
Substantia Nigra
selegiline
Amantadine*
levodopa
GABA
DA
BBB
carbidopa
benserazide
tolcapone
entacapone
Dopamine agonists
bromocriptine
pergolide
pramipexole
ropinirole
ACh
Striatum
baclofen
trihexiphenidyl
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Anticholinergics
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Dopaminergic depletioncholinergic overactivity
Initially used in the 1950s
Effective mainly for tremor and rigidity
Common agents (Start low, go slow):
– Trihexyphenidyl: 2-15 mg/day
– Benztropine: 1-8 mg/day
– Ethopropazine: 10-200 mg/day
• Side effects:
– Dry mouth, sedation, delirium, confusion, hallucinations,
constipation, urinary retention
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Amantadine
• Antiviral agent; PD benefit found accidentally
• Tremor, bradykinesia, rigidity & dyskinesias
• Exact mechanism unknown; possibly:
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enhancing release of stored dopamine
inhibiting presynaptic reuptake of catecholamines
dopamine receptor agonism
NMDA receptor blockade
• Side effects —autonomic, psychiatric
• 200-300 mg/day
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Selegiline
• Irreversible MAO-B inhibitor
• Clinically active by inhibiting dopamine metabolism in
brain
• May be neuroprotective
• Dosage: 5 mg at breakfast and lunch
• Side effects: insomnia, hallucinations, nausea (rarely), OH
• Potential interactions with tricyclics and SSRI
antidepressants
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Evidence for Neuroprotection
• DATATOP study (NEJM 1989, 1993)
– 800 de novo patients took selegiline or vitamin E or
both
• Results:
– Selegiline delayed need for levodopa by 9 months
– Reduced likelihood of needing levodopa by 50%
– No effect from vitamin E
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DATATOP Follow-Up
• DATATOP: 3 year follow-up studies (Ann
Neurol 1996)
– subjects requiring levodopa (n=352)
• selegiline made no difference with regard to disease
severity, wearing-off or dyskinesias
– subjects not requiring levodopa (n=162)
• No difference in parkinsonian disability between the
two groups
• 8 year follow-up (Ann Neurol 1998)
– No increase in mortality
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Levodopa
• Most effective drug for parkinsonian symptoms
• First developed in the late 1960s; rapidly became the drug of
choice for PD
• Large neutral amino acid; requires active transport across the
gut-blood and blood-brain barriers
• Rapid peripheral decarboxylation to dopamine without a
decarboxylase inhibitor (DCIs: carbidopa, benserazide)
• Side effects: nausea, postural hypotension, dyskinesias, motor
fluctuations
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Diagram of LD Metabolism
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Is Levodopa Toxic?
• Early patients develop motor fluctuations, but may be a
function of neuronal cell loss
• Increased life expectancy with LD introduction
• LD-naive advanced PD patients develop fluctuations
almost immediately with LD induction
• No LD neuronal dropout in laboratory animals
• Recent data suggest possible neuroprotection
• Some believe continuous infusion may be safer than
pulsatile therapy
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Levodopa-Induced Dyskinesias
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Manifestation of excessive dopaminergic stimulation
Typically late effect, and with higher doses
Narrowing of therapeutic window
Rare in LD-naive patients on DA monotherapy
Most common is “peak dose” dyskinesia
– disappears with dose reduction
• Choreiform, ballistic and dystonic movements
• Most patients prefer some dyskinesias over the alternative
of akinesia and rigidity
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Levodopa/Carbidopa Formulations
Immediate Release
Onset
Duration
20-40 min
2-4 hr
30-60 min
3-6 hr
10-20 min
0.5-1 hr
10/100, 25/100, 25/250
Controlled Release
25/100, 50/200
“Liquid levodopa”
(dissolved tablets)
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COMT Inhibitors
• Newest class of antiparkinsonian drugs: tolcapone, entacapone
• MOA similar to dopa decarboxylase inhibitors
• Potentiate LD: prevent peripheral degradation by inhibiting
catechol O-methyl transferase
• Reduces LD dose necessary for a given clinical effect
• Helpful for both early and fluctuating Parkinson’s disease
• May be particularly useful for patients with “brittle” PD, who
fluctuate between off and on states frequently throughout the
day
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Tolcapone
®
(Tasmar )
• First COMT inhibitor licensed in the U.S.
• 100 mg TID or 200 mg TID
• Reduced LD dosage by 12%, improved motor fluctuations by 14% in
non-fluctuating pts
• Reduced LD dosage by 30%, and on time increased from 1.7 to 2.9
hrs/day in fluctuating pts
• Side effects: Diarrhea, OH, dyskinesias, confusion
• Acute fulminant hepatic necrosis
– 3/60,000+
– FDA warning prevents use unless alternative therapy unsuccessful
– liver monitoring every 2 weeks for a year and less frequently thereafter
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Entacapone
• Dosage: 200 mg w/each levodopa dose
• Parkinson’s Study Group 1997: Increased on time
by 5%, more in pts w/least on time
• Rinne et al., 1998: Increased on time by ~10%;
decreased levodopa
• Diarrhea, dopaminergic SEs
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Dopamine Agonists: Distinguishing Features
• Directly stimulate dopamine receptors
• No metabolic conversion; bypasses nigrostriatal neurons
• No absorption delay from competition with dietary amino
acids
• Longer half-life than levodopa
• Monotherapy or adjunct therapy
• May delay or reduce motor fluctuations & dyskinesias
associated with levodopa
• May be neuroprotective
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Dopamine Receptor Subtypes
• D1, D2 subcortical
• D3, D4, D5 cortical
• Differentiated biochemically & pharmacologically
into two families:
– D1 family: D1, D5
– D2 family: D2, D3, D4
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DAs: Receptor Effects
D1
D2
D3
D4
D5
Ergot
Bromocriptine
Cabergoline
Lisuride
Pergolide
0
+
+
++
+++
++
+++
++
?
?
++++
+
?
?
+
+
?
?
+
Non-Ergot
Pramipexole
Ropinirole
0
0
++
++
++++ ++
++++ +
?
0
Neurology 1998; 50(suppl 3)
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DA Pharmacokinetics and Dosage
T1/2
Dosage (monotherapy)
Bromocriptine (Parlodel) 6 hr
7.5-30 mg/day
Cabergoline
65+ hr
2-5 mg/day
Lisuride
2-4 hr
1-5 mg/day
Pergolide (Permax)
12-27 hr
1.5-12 mg/day
Pramipexole (Mirapex)
8 hr
1-4.5 mg/day
Ropinirole (Requip)
4 hr
3-24 mg/day
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DAs: Therapeutic Responses and Patient Outcomes
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DAs: Common Adverse Effects
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Nausea, vomiting
Dizziness, postural hypotension
Headache
Dizziness
Drowsiness & somnolence
Dyskinesias
Confusion, hallucinations, paranoia
Erythromelalgia; pulmonary & retroperitoneal fibrosis;
pleural effusion & pleural thickening; Raynaud’s
phenomena. May be more common with ergotoline DAs
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Apomorphine
• D1/D2 agonist
• Parenteral delivery (s.c., i.v., sublingual, intranasal, rectal)
• Rapid “off” period rescue
– 2-5 mg s.c.; pen injection systems
• Treatment of unpredictable, frequent motor fluctuations
– continuous s.c. infusion via mini-pump
• SE: nausea, vomiting, hypotension
– trimethobenzamide 250 mg t.i.d.
– domperidone 20 mg t.i.d.; not available in U.S.
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Faculty for the WE MOVE
Parkinson’s Disease Teaching Slide Set
Mark Stacy, MD
Barrow Neurological
Institute
Phoenix, Arizona, USA
Richard B. Dewey, Jr., MD
University of Texas
Southwestern Medical
Center
Dallas, Texas, USA
Charles H. Adler, MD, PhD
Mayo Clinic Scottsdale
Scottsdale, Arizona, USA
William G. Ondo, MD
Lisa M. Shulman, MD
Baylor College of Medicine Health Policy Fellow
Houston, Texas, USA
U.S. House of
Representatives
Washington, DC, USA
Rajesh Pahwa, MD
University of Kansas
Celia Stewart, PhD
Medical Center
Mount Sinai Medical
Kansas City, Kansas, USA Center
New York, New York, USA
Kathleen Albany, PT, MPH
WE MOVE
New York, New York,
USA
Ali H. Rajput, MD
Royal University Hospital
Saskatoon, Saskatchewan,
Canada
Reviewed by the Education Committee of the Movement Disorder Society
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