Parkinson
Gender differences in Parkinson’s disease
•
Lower incidence and higher age at onset in women:
because the development of symptomatic PD may be
delayed by higher physiological striatal dopamine
levels, possibly due to the activity of oestrogens
(Charlotte
et al
., 2006).
•
The mechanisms whereby oestrogen may be
neuroprotective may include activation of the
mitogen activated protein kinase pathway,18
modulation of Bcl-x(L) expression,19 and/or synergy
with the free radical scavenger
(Wooten
et al
., 2004).
Putative factors reported with increased risk for PD
• Demographic factors * age – elderly * gender – men * race – white • Genetic factors * family history of PD or essential tremor * onset of PD before 50 years of age in twin study* families with a number of kindreds with PD &
parkinsonism
• Infection agents or disease * HIV,Japanese B
encephalitis, coxackie B, influenza A, herpessimplek measles, mump, diphteria
•
Environmental exposures * rural living, farmingactivities, well-water drinking neurotoxin(MPTP), pesticide exp- insectiside, herbicide, fungicide, rodenticide
• Life experience
* head injury, emotional stres, personality (shyness &
depressed mood) • Dietary factor
* animal fat consumption, metal expos-lead, Mn, Hg, iron, copper &amalgam • Occupational factor
* teacher, oil/gas field
Putative factors reported with
reduced risk for PD
•
Antioxidant: β caroten, vit A, vit C, Vit E (α-tocopherol)
•
Dietary factors: niacin-containing food, coffe, tea
•
Life experience: cigarette smoking, alkohol drinking
ETIOPATOGENESIS
•
Teori penuaan yang cepat
• Kadar glutathion peroxydase & katalase menurun
• Monoamine oxydase menurun & melanin berakumulasi
•
Teori toksin
• MPTP memblokir reseptor2 dopamine
• Merusak neuron2 dopamine
•
Teori genetik
• Pola herediter yang dominan termasuk defek genetik yang menyebabkan kerusakan di subtantia nigra
• Mutasi alpha synuclein ( merupakan katalisator)
•
Teori peroksidasi oleh radikal bebas
• Proses oksidasi meningkat dan mempercepat proses kematian sel neuron dopamin
Mempercepat kematian sel2
KLASIFIKASI PARKINSONISM
–
Parkinsonism Idiopatik / Primer
= Penyakit Parkinson
–
Parkinsonism Sekunder
Drug Induced, Infeksi, Trauma,
Tumor/paraneuplastik, Vaskuler, Toksin,
Metabolic, Hidrosefalus.
–
Parkinsonism Plus
Alzheimer’s Disease, Multiple System Atrophy
–
Heredodegenerative Disease
Huntington’s Disease, Familial
Olivopontocerebellar
•
TREMOR
•
RIGIDITY
•
AKINESIA
•
POSTURAL INSTABILITY
Symptom & sign (TRAP)
Tremor
•
Resting tremor, postural tremor
•
Kasar, 3-7 getaran / detik
Rigidity
•
Cogwheel phenomenon
Akinesia
•
Slow to walking atau bradikinetic
(Bradikinesia)
•
Mask face, Hipofonia, Drooling,
mikrografia
•
Langkah pendek dan diseret
Postural Instability
•
Imbalance, Prone to Fall
•
In late stage of Parkinson’s
Disease
•
STAGING ( SKALA HOEHN AND YAHR )
• STADIUM I
– UNILATERAL
– EKSPRESI WAJAH BERKURANG
– TREMOR , FLEKSI , DAN AYUNAN BERKURANG PADA LENGAN
• STADIUM II
– BILATERAL
– POSTUR BUNGKUK KEDEPAN
– GAYA JALAN LAMBAT DENGAN LANGKAH KECIL
– SUKAR BERBALIK BADAN
• STADIUM III
– GANGGUAN GAYA JALAN MENONJOL
– INSTABILITAS POSTURAL , TETAPI JARANG JATUH
• STADIUM IV
– DISABILITAS JELAS
– BERJALAN TERBATAS TANPA BANTUAN
– LEBIH CENDERUNG JATUH
• STADIUM V
– HANYA BISA BERBARING ATAU DUDUK DI KURSI RODA
– BICARA TIDAK JELAS , WAJAH TANPA EKSPRESI , JARANG BERKEDIP
Stages of Parkinson’s Disease
► Mild symptoms, no disability
► Non-pharmacological approaches
► Moderate symptoms with some disability
► Multiple treatments available including l-dopa
► Progression of symptoms
► Levodopa required +/- other meds
Early Moderate Advanced
► Disease progresses
► Non-motor complications may
outweigh motor disturbances
Adjunctive Drug Therapy for Advanced PD Report of the Quality Standards Subcommittee of the
A G E FUNCTIONAL DISABILITY / SEVERITY OF SYMPTOMS C O M O R B I D I T I E S COGNITIVE FUNCTIONAL TREATMENT PLAN
MANAGEMENT
Early or Moderate Stage Management of PD
► Level A – MAO-B inhibitors – selegiline, rasagiline
► Level A – Dopamine agonists – pramipexole, ropinirole, rotigotine
– caution in elderly, cognitive impairment, young males (?)
► Level A - Carbidopa/levodopa – immediate release
► Level B - Carbidopa/levodopa – controlled release
Recommended
Years 1-5 (possibly more?)
Questionable ► Co-enzyme Q10
► Amantadine
Therapeutic Agents
Adjunctive Drug Therapy for Advanced PD
Miyasaki, JM, et al., Neurology 2002;58:11–17 O. Suchowersky, et al., Neurology 2006; 66: 976-982
Advanced Management of PD
Treating Motor Fluctuations
► Level A – entacapone, rasagiline
► Level B – pramipexole, ropinirole, tolcapone - caution hepatotoxicity
► Level C – apomorphine, cabergoline, and selegiline
► Level C (surgical) – STN deep brain stimulation
► Level C (dyskinesias) - amantadine
► Disregarded – bromocriptine, sustained release carbidopa/levodopa
Evidence
Years 1-3 and following
Adjunctive Drug Therapy for Advanced PD Pahwa, R., et al., Neurology 2006;66:983–995
Korteks frontal
D 1 D 2 D 2
Globus palidus eksterna
Nukleus subtalamikus Globus palidus
interna Talamus
Mechanism of Dopamin Agonist
Jalur direct Jalur indirect
Glutamatergik(eksitatorik) GABA-ergik (inhibitorik)
Dopamin Agonis dopamin Striatum
Kondisi pada penyakit parkinson Pemberian agonis dopamin
Goals of Current Therapeutic Strategies
DA GABA ACh
Striatum
Substantia Nigra
Levodopa Amantadine Selegiline Zydis selegiline Rasagiline Dopamine agonists Apomorphine Bromocriptine Pergolide Pramipexole Ropinirole Rotigotine Baclofen Anticholinergics BBB Carbidopa Benserazide Tolcapone Entacapone MAO-B Stalevo® (carbidopa/levodopa/entacapone) Parcopa®Sites of Action of PD Drugs
Levodopa
Enzim dopa dekarboksilase
Dopamin
+ Penghambat
dopa dekarboksilase Karbidopa
Benserazid
Levodopa Levodopa Dopamin
Enzim dopa dekarboksilase
Stimulation of direct (reseptor dopamin striatum D1) Inhibition of indirect (reseptor dopamin striatum D2)
Mechanism of Levodopa
Perifer Sentral
SIMPTOMATIC TREATMENT
Increase of Dopaminergic
•
L-dopa + Dopa dekarboksilase Inhibitor
•
Slow released L-dopa
•
Release of Dopamin (Amantadin, Nikotin)
•
Dopamin Agonist (Pramipexole, Bromokriptin)
•
Degradation of Dopamin (Comt inhibitor:
Entacapone, MAOB inhibitor: Selegilin)
Simptomatic Treatment
•
If drugs treatment failure
•
Palidotomi, Talamotomi
•
Deep brain stimulation
Indications and possible side-effects of
dopamine agonists
combination L-dopa+++
+
+
Ropinirole
+++
+
+
+
Pramipexole
+
+
+
Pergolide
NS
+
+
+
+
Bromocriptine
Sleep attack Ergot side effects Late Early Mono- therapyAgent
Possible SEs
Indication
ergot side effects (coronary vasoconstriction, Raynaud’s phenomenon, retroperitoneal fibrosis, pleural pulmonary fibrosis); NS = non significant
Initiating therapy and titration doses of
dopamine agonists
Increase by 0.25 mg/dose/week, up to 3 mg/day; then increase by 0.5
mg/dose/week
Followed by 0.25 mg tid for one week, then 0.5 mg tid for
one week and then increase by 0.5 mg/week
50 mg/week until 4 tablets then 50 mg/2 weeks Increase by 0.125 mg/week
Increase by 1.25 mg/week Suggested titration schedule
3 – 24 4 – 18 0.25 mg tds
Ropinirole
1.5 – 4.5 3 – 7 0.125 mg tdsPramipexole
150 – 250 3 – 7 50 mg odPiribedil
0.75 – 4.5 3 – 33 0.25 mg qdsPergolide
7.7 – 45 3 - 33 1.25 mg qdsBromocriptine
dose range (mg/day) Titration (weeks) dose for the1st week
Agent
Qds = quarter die sumendus (four times daily); tds = ter die sumendus (three times daily); od = omni die (once daily)
Obat yang digunakan dna
mekanismenya
Meningkatkan kadar dopamin endogen – L-Dopa : prekursor Dopa
– Carbidopa, Benserazid : menghambat metabolisme perifer oleh dopa dekarboksilase
– Entacapon, tolcapon : menghambat degradasi Dopa oleh Ometiltransferase – Selegilin : menghambat degradasi Dopa oleh MAO B
– Amantadin : meningkatkan sintesis dan pelepasan dopamin, menghambat re-uptake Mengaktifkan reseptor dopamin dengan agonis
– Bromokriptin, lisurid : agonis D2
– Pramipeksol, ropinirol : agonis D2 dan D3 – Pergolid, apomorfin : agonis D1 dan D2
Menekan aktivitas kolinergik dgn obat-obat antikolinergik – Benztropin, triheksifenidil
Biointesis dan Degradasi Ketokolamin
MAO : Monoamin oksidase
Evidence Based Medicine Parkinson
What is the role of selegiline in the treatment of early PD?
Selegiline has mild symptomatic benefit (class II). There is no convincing clinical evidence for neuroprotective benefit with selegiline (class II). There is no convincing evidence for increased mortality with selegiline whether it is given in combination with levodopa or as monotherapy (class II).
Recommendations for patients with PD who require symptomatic treatment. Initial symptomatic treatment of patients with PD with selegiline in order to confer mild, symptomatic benefit prior to the institution of dopaminergic therapy may be considered (level A, class II evidence). There is insufficient evidence to recommend the use of selegiline to confer neuroprotection in patients with PD (level U).
When symptomatic therapy is required does levodopa or a
dopamine agonist offer best control of motor symptoms?
Conclusions: Levodopa, cabergoline, ropinirole, and pramipexole
are effective in ameliorating motor and ADL (activities of daily
living) disability in patients with PD who require dopaminergic
therapy.
Levodopa is more effective than cabergoline, ropinirole, and
pramipexole in treating the motor and ADL features of PD.
When symptomatic therapy is required, does levodopa or a dopamine agonist offer the most favorable long-term complication profile?
Conclusions : Cabergoline, ropinirole, and pramipexole treatment of PD patients requiring dopaminergic therapy results in fewer motor complications than levodopa treatment after 2.5 years of follow-up.
Cabergoline, ropinirole, and pramipexole treatment of PD patients requiring dopaminergic therapy is associated with more frequent adverse events including hallucinations, somnolence, and edema than levodopa therapy.
Recommendations:In patients with PD who require the initiation of dopaminergic treatment, either levodopa or a dopamine agonist may be used. The choice depends on the relative impact of improving motor disability (better with levodopa) compared with the lessening of motor complications (better with dopamine agonists) for each individual patient with PD (level A, class I and class II evidence).
Sustained-release versus immediate release levodopa: When initiating levodopa therapy, which formulation should be used—immediaterelease or sustained-release levodopa?
Conclusions : When initiating therapy with levodopa, there is no difference in the rate of motor complications between immediaterelease levodopa and sustained-release levodopa.
Recommendations. For patients with PD in whom levodopa treatment is being instituted, either an immediate-release or sustained-release preparation may be considered (level B, class II evidence)
