Parkinson disease Rx
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Transcript of Parkinson disease Rx
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Parkinsons diseaseTherapeutic 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
Parkinsons disease?
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Modality of treatment
Symptoms base treatment Phamacologic VS Non-phamacologic
MotorVS Non-motor symptom
Neuro-protective treatment Reversing pathology Prevention
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Signs and Symptoms of PDSigns and Symptoms of PD
Tremor at rest "Pill rolling"
Rigidity(stiffness) "lead pipe" or like a "cogwheel"
Akinesia (inability to move) orBradykinesia (slowmovement) mask-like face, micrographia, freezing, impaired swallowing
Postural instability with gait problems
Motor symptoms (TRAP)Motor symptoms (TRAP)
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Non-Motor Symptoms
Psychological depression , psychosis, anxiety, apathy, memory problems
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 PDPathophysiology of PD
and dopamineand dopaminemetabolismmetabolism
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Neurotransmitters of the Basal Ganglia
Inhibitory
Dopamine
Norepinephrine
Epinephrine
GABA
Excitatory
Acetylcholine
Serotonin
Histamine
Glutamate
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Symptoms of PD
Dopamine Ach
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Enhance dopaminergic
transmission
Dopamine Ach
Drug manipulatingneurotransmitter
Symptomatic Treatment
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Tyrosine
L-Dopa
Dopamine
DA
Tyrosine
DA
Reuptake
Degradation
COMT
DA Receptors
Release
BindingDegradation
AmantidineStimulates release of DA
Inhibits reuptake
MAO-B
DA AgonistsBind to DA receptors
SelegelineInhibits MAO-B
LevodopaIncreases L-Dopa levels
Acetylcholine InhibitorsBlock action of ACh in striatum
COMT InhibitorBlock degradation of D
and L-Dopa
Sites of
action of
common
therapies
for
Parkinsons
disease
Parkinsons disease
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Enhance Dopaminergic transmissionEnhance Dopaminergic transmission
DA precursor Administer DA agonists
Ergolides
Non- ergolides
Direct or indirect potentiate dopaminergictransmission 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)
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Enhance DA releaseEnhance DA release
Amantadine Methylphetamine
Dextroamphetamine Pemoline Nicotine
Electroconvulsive
therapy
Block DA reuptakeBlock DA reuptake
Amantadine Tricyclics
Bupropion Mazidol
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Inhibit DA catabolismInhibit DA catabolism
(degradation)(degradation)
COMT inhibition
(Tolcapone, Entacapone) MAO-B inhibitors
Depreny (seligiline)
Administer DA agonistAdminister DA agonist
Bromocryptine Pergolide
Lisuride
Apomorphine 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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0Stage
1
2
0
3
1- 4
3- 4
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The Natural History of Response to Levodopa inThe Natural History of Response to Levodopa in
Patients With Parkinson's DiseasePatients With Parkinson's Disease
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When to started?
Patient to patientPatient to patient
Job to jobJob to job
Interfering with activitiesInterfering with activities
of daily livingof daily living
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Early-anti-PD therapy
L-dopa
VS
Dopamine agonist
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Levodopa
BenefitBenefit
Marked improvement in themajor motor signs andsymptoms
Virtually all PD patientsresponse
May improve mortality rate
DisadvantageDisadvantage
Cause side effect Dyskinesia and dystonia
Motor fluctuation
Parkinsonian psychosis
Do not treat all feature of PD Do not stop disease progression Theoretically: oxidative
metabolites may accelerateddisease progression
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Young patientYoung patient
risks VS benefits: L-dopa VS dopamine agonist drugs discuss
age < 65, or age > 65 with no other co-morbidity are started ondopamine agonist as initial monotherapydopamine agonist as initial monotherapy
ElderlyElderly
long-term complications of L-dopa therapy minimal: shortlive
short-term side-effects of dopamine agonists high: comorbid
L-dopa as the first-lineL-dopa as the first-line
D i i tD i i t
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Dopamine agonistDopamine agonist
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Dopamine agonist
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Dopamine agonist
Drug Formulation,mg Starting dose,mg
Target dosemg/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, 0.25,0.5, 1.0, 1.5
0.125 twicedaily
3.0-4.5
ropinirole 0.25, 0.5, 1.0,2.0, 5.0
0.25 twice daily 6-24
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Dopamine agonist
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Levodopa
Levodopa + DDI
Madopar (levodopa+benserazide)
Sinemet (levodopa+carbidopa)
Madopar HBS
Sinemet CR
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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 ofthese 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 612 weeks on this dose.
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L-dopa side effect
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COMT: early or late
AdvantagesAdvantages
No titration: easy toadminister
Decrease off time,increase on time
Enhanced motorresponses in motorfluctuation patient
Reduce risk of motorcomplication if used fromonset of levodopa
therapy
DisadvantageDisadvantage
Dopaminergic side effect,esp dyskinesia
Discoloration of urine
Tolcapone (peripheral+central COMT
Entacapone (peripheral COMT)
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Anticholinergic drugs
Advantage
Someantiparkinsonian
efficacy
Peripheral actingagent may be useful
to treating sialorrhea
DisadvantageDisadvantage
Relatively ineffective forthe more disabling
feature of PD
Cognitive side effect Troublesome
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
As the disease progress
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As the disease progress,
the Therapeutic window narrowsymptoms and side effects occur as the levodopa therapeutic window diminishes
Dyskinesia thres
Efficacy thres
Smooth, extend response
Absent or infrequent dyskinesia Diminished duration Increased incidence ofdykinesia
Short, unpredictableresponse
on time is associaredwith dyskinesia
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ENDENDThank U
Proposed Mechanisms of
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Overactive
Microglial Cell
Dopamine-
Producing Cell
Overactive
Glutamate-
Producing Cel
Glu
[Ca2+ ]
NO
NO
NO
Superoxide FreeRadicals
Superoxide Fe
Unknown substance
releases iron from
storage molecules
More FreeRadicals
Fe + Dopamine
Mitochondrial
complex I
inhibited
Loss of
mitochondrial
funcion
Free radicals
cause cell
damage
Cell Death
Mutation inmitochondrial gene
Unknown toxin acts on
mitochondrial protein
Dopaminergic Neuron Death i
Parkinsons Disease
Parkinsons disease