Parkinson disease Rx

8/14/2019 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


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


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

Parkinson disease Rx

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