Parkinson’s disease

Therapeutic strategies

Surat Tanprawate, MD
Division of Neurology
University of Chiang Mai
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 Scope

• Modality of treatment
• Pathophysiology of PD and dopamine
metabolism
• Drugs
• Are there guidelines for the treatment of
Parkinson’s disease?

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 Modality of treatment

• Symptoms base treatment

 Phamacologic VS Non-phamacologic
 Motor VS Non-motor symptom
• Neuro-protective treatment
• Reversing pathology
• Prevention

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 Signs and Symptoms of PD
Motor symptoms (TRAP)
• Tremor at rest
 "Pill rolling"
• Rigidity (stiffness)
 "lead pipe" or like a "cogwheel"
• Akinesia (inability to move) or Bradykinesia (
slow movement)
 mask-like face, micrographia, freezing, impaired
swallowing
• Postural instability with gait problems
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 Non-Motor Symptoms
• Psychological
 depression , psychosis, anxiety, apathy, memory problem
s
• Sleep
 RLS, REM behavior disorder
• Autonomic Dysfunction
 constipation, drooling, decreased BP, temp regulation
• Others
 fatigue, speech, swallowing, seborrhea, pain, weight loss)
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Pathophysiology of PD
and dopamine
metabolism

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Neurotransmitters of the Basal Ganglia

Inhibitory Excitatory

Dopamine Acetylcholine
Norepinephrine Serotonin
Epinephrine Histamine
GABA Glutamate

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 Symptoms of PD

Dopamine Ach

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 Symptomatic Treatment
Enhance dopaminergic
transmission Drug manipulating
neurotransmitter

Dopamine Ach

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10
 Tyrosine
Sites of
action of Tyrosine
common Levodopa
L-Dopa Increases L-Dopa levels
therapies
for
Dopamine
Parkinson’s
disease MAO-B Selegeline
Inhibits MAO-B
DA
DA Degradation
Release
Amantidine
Stimulates release of DA Reuptake
Inhibits reuptake
Degradation COMT Inhibitors
DA Agonists Binding Block degradation of DA
Bind to DA receptors and L-Dopa
COMT
DA Receptors

Acetylcholine Inhibitors
Block action of ACh in striatum 11
Parkinson’s disease
 Enhance Dopaminergic transmission

• DA precursor
• Administer DA agonists
 Ergolides
 Non- ergolides
• Direct or indirect potentiate dopaminergic
transmission
 Enhance DA release
 Block DA reuptake
 Inhibit DA catabolism (degradation)

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 Increase DA synthesis

• Stimulate tyrosine hydroxylase

(tetrahydrobiopterin)
• DA precursors (tyrosine, levodopa)
• Modify levodopa phamacokinetic
 Dietary modification (minimize AA intake, asminister
antacids)
 Block peripheral dopa decarboxylase (carbidopa,
benserazide)
 Slow-release levodopa (sinemet CR, Madopa HBS) 13
Enhance DA release Block DA reuptake
• Amantadine • Amantadine
• Methylphetamine • Tricyclics
• Dextroamphetamine • Bupropion
• Pemoline • Mazidol
• Nicotine
• Electroconvulsive
therapy

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Inhibit DA catabolism Administer DA agonist
(degradation) • Bromocryptine
• COMT inhibition • Pergolide
(Tolcapone, Entacapone) • Lisuride
• MAO-B inhibitors • Apomorphine
Depreny (seligiline)
• Pramipexole
• Ropinirole
• Cabergolide
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 Drug manipulating other
neurotransmitter
• Anti-cholinergic drugs
 Trihexyphenidyl(Artane)
 Benztropine(Cogentin)
 Biperidine(Akineton)
 Orphenadrine(Disipal)
 Procyclidine(Kemadrine)

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 How to management?

• When to started?
• Drug choice?
• Disease progression, management and
complication of treatment

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Stage
0
0 1- 4

3 3- 4

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The Natural History of Response to Levodopa in
Patients With Parkinson's Disease

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 When to started?

Interfering with activities

of daily living

Patient to patient
Job to job

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21
Early-anti-PD therapy

L-dopa

VS

Dopamine agonist

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 Levodopa
Benefit Disadvantage
• Marked improvement in the • Cause side effect
 Dyskinesia and dystonia
major motor signs and
symptoms  Motor fluctuation
 Parkinsonian psychosis
• Virtually all PD patients
• Do not treat all feature of PD
response
• Do not stop disease progression
• May improve mortality rate • Theoretically: oxidative
metabolites may accelerated
disease progression

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 Dopamine agonist
Benefit
• Anti parkinson effect when
use as mono Rx or
adjunctiove Rx
• Reduced risk for
developing L-dopa related
motor complication
• Do not generate oxidative
metabolite
• Levodopa sparing effect
• Potential neuropotential
effect
Disadvantage
• Neuropsychiatric side
effect
• Agonist specific side
effect
• Sedative side effect
• Do not treat all feature of
PD
• Do not stop disease
progression

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Elderly
•long-term complications of L-dopa therapy minimal: short
live
•short-term side-effects of dopamine agonists high: comorbid
L-dopa as the first-line
Young patient
• risks VS benefits: L-dopa VS dopamine agonist drugs discuss
• age < 65, or age > 65 with no other co-morbidity are started on
dopamine agonist as initial monotherapy

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Dopamine agonist

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Dopamine agonist

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 Dopamine agonist

Drug Formulation, Starting dose, Target dose

mg mg mg/d
Bromocriptine 2.5, 5.0 1.25 daily 15-30

Pergolide 0.05, 0.25, 1.0 0.05 daily 1.5-30

Pramipexole 0.125, 0.25, 0.125 twice 3.0-4.5

0.5, 1.0, 1.5 daily
ropinirole 0.25, 0.5, 1.0, 0.25 twice 6-24
2.0, 5.0 daily
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Dopamine agonist

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 Levodopa

Madopar (levodopa+benserazide)
Sinemet (levodopa+carbidopa)
Levodopa + DDI
Madopar HBS
Sinemet CR 30
Doses of the preparations of Sinemet
and Madopar

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 How should L-dopa be started?
• Gradually introduced
 L-dopa 100 mg/day is the traditional starting dose
 Madopar 62.5 twice daily, or Sinemet 62.5 twice daily.
(Both of these tablet formulations contain 50 mg of L-
dopa.)
• The daily dose of L-dopa should be increased by
 100 mg after 1 week
 same amount after 2 weeks
• If tolerated, further increases should be reviewed
after 6–12 weeks on this dose.
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L-dopa side effect

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 COMT: early or late
Advantages Disadvantage
• No titration: easy to • Dopaminergic side effect,
administer esp dyskinesia
• Decrease off time, • Discoloration of urine
increase on time
• Enhanced motor
responses in motor
fluctuation patient
• Reduce risk of motor Tolcapone (peripheral+central COMT)
complication if used from
onset of levodopa
therapy Entacapone (peripheral COMT)

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 Anticholinergic drugs
Advantage Disadvantage
• Some • Relatively ineffective for
antiparkinsonian the more disabling
efficacy feature of PD
• Peripheral acting • Cognitive side effect
agent may be useful • Troublesome
to treating sialorrhea muscarinic side effect

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 MAO-B inhibitor (selegiline)

• Enhance the L-dopa effect

• May be neuroprotective property
• Start 5 mg twist daily

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 As the disease progress,
the Therapeutic window narrow
symptoms and side effects occur as the levodopa therapeutic window diminishes

Dyskinesia threshold

Efficacy threshold

• Smooth, extend
• Diminished duration • Short, unpredictable
response response
• Absent or infrequent • Increased incidence • ‘on’ time is associared
dyskinesia of dykinesia with dyskinesia

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END
Thank U

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 Proposed Mechanisms of
Dopaminergic Neuron Death in
Parkinson’s Disease
Overactive
Unknown substance
Microglial Cell Superoxide Free releases iron from
NO Radicals storage molecules

Superoxide  Overactive
Mitochondrial NO  Fe 
Glutamate-
“complex I”
inhibited
Producing Cell
Fe + Dopamine
Mutation in More Free
mitochondrial gene Radicals NO  Glu
Free radicals [Ca2+] 
Unknown toxin acts on
mitochondrial protein cause cell
Loss of damage Dopamine-
mitochondrial Producing Cell
funcion
Cell Death

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Parkinson’s disease