Post on 20-Jul-2015
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GANGGUAN GERAKBERLATAR BELAKANG GANGGUAN SARAF
ETIOLOGI
PATOLOGI
TOPIS LESI
GAMBARAN KLINIS
DIAGNOSIS NEUROLOGIS:
Dx/ KLINIS - TOPIS – ETIOLOGIS
sangat ditunjang oleh penguasaan pengetahuan anatomi
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GANGGUAN GERAK
GANGGUAN SARAF
• STROKE
• PENYAKIT PARKINSON
•
Gangguan Gerak Hipokinetis(kelumpuhan = paresis/paralisis plegi)
• Gangguan Gerak Hiperkinetis
(gangguan gerak abnormal - involunter)
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Gangguan gerak abnormal - involunter
berlatar belakang gangguan saraf
Penyakit Parkinson - tokoh-tokoh terkenal penyandangnya
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Diagnosa Neurologis:
- Diagnosa Klinis Gambaran Klinik yang muncul
Simptom, Sign, Sindrom- Topis Dimana letak lesi
- Etiologi Penyebabnya
Problem Klinis:
- Tingkat individu: Manifestasi Klinis Sistem apa yang
terkena
Organ
Jaringan
sel
Biomolekuler- Tingkatan Sistem/ subsistem
- Tingkatan Organ
- Tingkatan Sel dengan sub selnya
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Gangguan Gerak - Gangguan Gerak Hipokinetis(kelumpuhan = paresis/paralisis plegi)- Gangguan Gerak Hiperkinetis(gangguan gerak abnormal - involunter)
Gangguan Saraf - STROKE- PENYAKIT PARKINSON
Gangguan gerak abnormal - involunterberlatar belakang gangguan saraf Penyakit
Parkinson dan Stroke
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SUBSTRAT ANATOMIdari sistem saraf yang berkaitan dengan gerak tubuh
KOMPONEN FUNGSI MOTORIK
Sistem piramidal (UPPER MOTONEURON )dan
Saraf tepi (LOWER MOTONEURON )
Sistem ekstrapiramidal
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SUBSTRAT ANATOMI
KOMPONEN FUNGSI MOTORIK:
• sistem piramidal *melanjut sebagai serabut-serabut
saraf tepi **
gerakan “jitu” dan“tangkas”
... jari-jari lentik
gadis kecil memetik bunga …
(* upper motoneuron …...... penyilangan
dan ** lower motoneuron)
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MANIFESTASI KLINIS
• GANGGUANSISTEM PIRAMIDALIS – JARAS KORTIKOBULBARIS:
saraf-saraf kranial
• strabismus (kero)• asimetri otot-otot wajah• nasolalia (bindeng)• gangguan menelan• disartri (pelo)
– JARAS KORTIKOSPINALIS
(upper motoneuron) kelumpuhan spastik (ciri-ciri?)• hemiparesis (lumpuh separuh badan) akibat stroke:
GARENG ?
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MANIFESTASI KLINIS
• GANGGUAN SARAF TEPI (lower
motoneuron)
kelumpuhan flaksid (ciri-ciri?)
- poliomyelitis anterior acuta
- Bell’s palsy …………….....
- neuropati perifer:
sindrom Guillan Barre dll.
Bell Palsy Gangguan saraf VII perifer (LMN) otot dahi, wajah,mata lumpuh
Gangguan n.VII central dahi masih bisa berkerut
Gangguan Supranuklear PusatInfranuklear Tepi
Polio Kerusakan badan sel motorik Cornu anterior medulla spinalis tapikerusakan yang kenanya adalah LMN menifestasi gangguan saraf tepi.Ciri: Flacid, Uniparesis, monoparesis, (tungkai saja)
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SUBSTRAT ANATOMI
KOMPONEN FUNGSI MOTORIK:
• Sistem ekstrapiramidal memelihara tonus otot,
“menyiapkan” gerak“jitu” &“tangkas”
dan
• serebelum
(otak kecil) integrasi impuls sensibel dan motorik
Sistem Piramidal lintasan spesifik Sistem Extrapiramidal:
- Kumpulan badan sel dengan sirkuit memberikan impuls masalkeseluruh otot tanpa disadari untuk pelihara tonus otot gerakan jitu dan tangkas
- Melibatkan cerebellum
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SUBSTRAT ANATOMI
SISTEM EKSTRAPIRAMIDAL:
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SISTEM EKSTRAPIRAMIDAL
SUBSTRAT ANATOMI(telah diuraikan di depan)
FUNGSI
Meletakkan landasan gerak “jitu” dan“tangkas”
Penyampaian impuls difus dan masal keseluruh otot tubuh untuk menjaga
tonus otot sebelum, selama dansesudah aktifitas sistem piramidalberlangsung
Kelola inhibisi gejala kelepasan (release phenomenon)
hiper / hipokinetis
Inhibisi – Eksitasi Proses yang kontinyuInhibisi yang berlebihan terjadi eksitasi.Eksitasi yang berlebihan terjadi inhibisi
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MANIFESTASI KLINIS• GANGGUAN SISTEM EKSTRAPIRAMIDAL
(BURISRAWA atau DURSASANA ? BATARA NARADA ?)
(GERAK INVOLUNTER)
TREMOR
HEMIBALISMUS KHOREA
ATETOSIS
DISTONIA
MIOKLONIA TIK
ATAKSIA
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PERANAN SEREBELUM (otak kecil)
INTEGRASI FUNGSI SENSORIMOTOR
GANGGUAN KOORDINASI
MEKANISME REFLEKS‘LENGKUNG REFLEKS’
RESEPTOR – AFEREN – PUSAT – EFEREN – EFEKTOR
REFLEKS PADA INDIVIDU DEWASA:GERAK OTOT SKELETAL YANG BANGKITSEBAGAI JAWABAN ATAS SUATU RANGSANGAN
• REFLEKS FISIOLOGIS• REFLEKS PATOLOGIS
- Ataxia Kecenderungan untuk jatuh pada 1 sisi ~ lesi.Tergantung topisnya : Nistagmus, Trunk ataxia, Lumataxia
- Tremor Intensional Tremor yang muncul waktu akan memulaigerakan. Bedakan dengan Tremor pada Parkinson ( Tremor atrest/waktu istirahat)
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Refleks pada individu dewasa:Gerak otot skeletal yang bangkit Sebagai jawaban atassuatu rangsangan
Refleks fisiologis:- Reflek Monosinaptic Reflek yang serabut
afferen dan eferennya pake saraf yang sama.
Ex: Refleks Patela, Reflek TendoReflek patela Monosinaptic dan Polisinaptic(karena adanya relaksasi otot antagonisnya)
- Refleks Polisinaptic Ex: Refleks cornea
Refleks patologis Tidak bisa deskripsikan dengan
baik arcusnya dimana. Ex: Refleks Balbinski
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PARKINSON’S DISEASE
PATHOPHYSIOLOGYDIAGNOSIS
THERAPY
Amin Husni
Bagian Anatomi-Neurologi FK UNDIP
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DEFINITION
AND CLASSIFICATION
• PARKINSONISM
•
PARKINSON’S DISEASE
IDIOPATHIC
SECONDARY PARKINSONISM
PARKINSON-PLUS SYNDROME
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ETIOLOGY
IDIOPATHIC
RISK FACTORS(MULTIFACTORIAL)
• AGING
• RACE
• GENETIC
• ENVIRONMENT
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PATOPHYSIOLOGY
BASAL GANGLIAEXTRAPYRAMIDAL SYSTEM
DOPAMINERGIC VS CHOLINERGIC
DIRECT PATHWAY
VS
INDIRECT PATHWAYParkinson dissease kerusakan pada substansia nigra pars compacta yang didalamnyaterdapat sel yang mensekresi dopamin karena rusak maka kadar dopamin <<
Substansia nigra Inhibisi Globus palidus kurang Galak
Kolinergik ↑ Hipokinesia ( Sindroma Parkinson)
Dopamin ↑, Kolinergik ↓ Hiperkinesia
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THE PATOPHYSIOLOGY OF PARKINSON’S DISEASE
1. IMBALANCE BETWEEN THE DOPAMINERGIC AND
CHOLINERGIC NEURONS
Korpus striatum selain menerima persarafandopaminergik yang datang dari substansia nigra, jugadisarafi oleh saraf kolinergik dengan asetilkolin ( AKA )
sebagai neurotransmiternya, pengaruh dari striatumterhadap fungsi motorik korteks ditentukan olehkegiatan kedua saraf tersebut.
Bila mana kegiatan dopaminergik meningkat dan atau
kegiatan kolinergik menurun maka pengaruhdopaminergik akan dominan shg timbullah gejalahiperkinesia, sebaliknya jika kegiatan dopaminergikmenurun dan atau kolinergik meningkat maka pengaruhkolinergik akan dominan shg timbullah gejala hipokinesia
( sindroma parkinson )
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THE PATOPHYSIOLOGY OF PARKINSON’S DISEASE
2. IMBALANCE BETWEEN THE DIRECT AND INDIRECT
PATHWAYS
Baik jalur langsung maupun tidak langsung keduanyaakan bermuara ke GPi / SNr dan selanjutnya dari siniakan mengeluarkan output menuju talamus dan korteks,bila masukan dari keduanya seimbang maka output -
nyapun akan seimbang pula sehingga tidak timbulkelainan gerakan motorik.
Akan tetapi manakala terjadi hiperaktif jalur langsungatau hipoaktif jalur tak langsung maka output dari GPi
dan SNr ke arah talamo korteks akan menurun makaakan terjadi gerakan hiperkinesia.
Sebaliknya jika terjadi hipoaktifitas jalur langsung danhiperaktifitas jalur tak langsung maka keluaran dari Gpidan SNr akan meningkat maka terjadi gerakan
hipokinesia / sindroma parkinson.
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B R A I N
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B R A I N
Ganglia basalis
Acetylcholin Normal
Dopamin
Acetylcholin PD
Perokside Radical HTissue
damage
Anticholinergic
(Trihexylphenidyl)
MAO MAO I ( selegiline )
D2
Dopamin
Receptor
Dopamin Agonist
Ergot
(bromocryptin) Non Ergot
(pramipexole)
Levodopa
Levodopa
Dopamin
Decarboxylase
Decarboxylase Inhibitor
(Benzeraside)
(carbidopa)
3 OMD
COMT
COMT Inhibitor
(entacapone)
BLOOD BRAIN BARIER
PHERIFER
Decarboxylase
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• Neurotransmiter:
Produksi Transport (mikrotubuler) Penyimpanan (Vesicle) Pelepasan (pembukaan vesikle) Synaptic clef ditangkapreseptor neuron binding, dihancurkan, atau ditangkap kembali(autoreseptor)
• Produksi dopamin ↓: - Dopamin yang diberikan dari luar tidak bisa menembus sawar
darah otak yang diberikan Rivodopa (prekursor dopamin)
Agonis Dopamin membuat seolah-olah dopamin meningkat
bisa ditangkap- penghancuran dopamin oleh : Enzim monoamin Inhibitor,
COMT inhibitor, radikal bebas
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DIAGNOSIS
CLINICAL DIAGNOSISBASED ON THE CLINICAL FEATURES
GENERAL AND SPECIFIC
T . R . A . P .• CLINICALLY
• KOLLER
• GELB• ETC.
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DIAGNOSTIC APPROACH
• CLINICALLY POSSIBLETHE PRESENCE OF ANY ONE OF THE SALIENT FEATURES: TREMOR(RESTING); RIGIDITY; BRADYKINESIA; IMPAIRMENT OF POSTURALREFLEXES
• CLINICALLY PROBABLECOMBINATION OF ANY TWO CARDINAL FEATURES (INCLUDINGIMPAIRED POSTURAL REFLEXES); ALTERNATIVELY, ANY ONE OFTHE FIRST THREE IF ASYMMETRICAL
• CLINICALLY DEFINITEANY COMBINATION OF THREE OF THE FOUR FEATURES;ALTERNATIVELY, ANY TWO WITH ONE OF FIRST THREEDISPLAYING ASYMMETRY
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MODIFIED HOEHN AND YAHR
STAGING
• STAGE 0 = NO SIGNS OF DISEASE
• STAGE 1 = UNILATERAL DISEASE
• STAGE 1.5 = UNILATERAL PLUS AXIAL
INVOLVEMENT
• STAGE 2 = BILATERAL DISEASE,
WITHOUT IMPAIRMENT OF BALANCE
• STAGE 2.5 = MILD BILATERAL DISEASE,
WITH RECOVERY ON PULL TEST
•
STAGE 3 = MILD-TO-MODERATE BILATERAL DISEASE;SOME POSTURAL INSTABILITY;
PHYSICALLY INDEPENDENT
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MAJOR CONSEPTUAL
ON PHARMACOLOGIC / SURGICALTREATMENT
»SYMPTOMATIC
»PROTECTIVE
»RESTORATIVE
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• TO IMPROVE SIGNS AND SYMPTOMS
OF THE DISEASE
• TO INTERFERE WITH THE
PATHOPHYSIOLOGIC MECHANISMEOF THE DISEASE
•
TO PROVIDE NEW NEURONS ORTO STIMULATE GROWTH AND
FUNCTION OF REMAINING CELLS
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GOAL OF THERAPY: TO REVERSE
THE FUNCTIONAL DISABILITY
• ABOLITION OF ALL SYMPTOMS AND SIGNS
IS NOT CURRENTLY POSSIBLE EVEN WITHHIGH DOSES OF MEDICATION
• TREATMENT IS INDIVIDUALIZED
• PATIENT AND PHYSICIAN PLAYS A MAJOR
ROLE IN THERAPEUTIC DECISIONS
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LEVODOPAPRECURSOR OF DOPAMINE
• REPLACEMENT OF DEPLETED
TRANSMITTER
• COMPLICATION OF CHRONIC
THERAPYTHE “ON-OFF” REACTION, DYSKINESIAS,
AND VISUAL HALLUCINATIONS
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ADDITIONAL AND DISTINCTLY
DIFFERENT PHARMACOLOGIC
ADVANCES
• CARBIDOPA
• CONTROLLED RELEASECARBIDOPA/LEVODOPA
• DOPAMINE AGONIST
•
INHIBITOR OF CATECHOL-O- METHYLTRANSFERASE (COMT)
• MONOAMINE OXIDASE TYPE B (MAO-B)
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• CARBIDOPA
(INHIBITOR OF DOPA DECARBOXYLASE)
COMBINED WITH LEVODOPA, REDUCESPERIPHERAL DECARBOXYLATION OFLEVODOPA TO DOPAMINE
• CONTROLLED RELEASE
TO PROLONGE LEVODOPA’S 90-MINUTESHALF-LIFE
• DOPAMINE AGONIST
USED AS PHARMACOLOGICALLY SUBSTITUTES
FOR CARBIDOPA/LEVODOPA IN EARLY DISEASETO PROVIDE SUPPLEMENTATION IN LATERSTAGES
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• INHIBITORS OF CATECHOL-O-METHYL
TRANSFERASE (COMT)
INCREASE THE AMMOUNT OF LEVODOPACROSSING THE BLOOD BRAIN BARRIER
• MONOAMINE OXIDASE TYPE B (MAO-B)
INHIBITORS
TO SLOW DOPAMINE’S METABOLIC
BREAKDOWN
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THERAPEUTIC ALGORITHM
FOR MANAGEMENTOF PARKINSON’S DISEASE
(SEE TEXT)
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• INITIAL DECISION :WHETHER ANY PHARMACOTHERAPY IS
NEEDED
• NO CONCLUSIVE EVIDENCETHAT TREATMENT IS HELPFUL BEFORE
SYMPTOMS START TO AFFECT THEPATIENT’S LIFE
EARLY STAGE : MAY BE BETTER LEFTUNTREATED IF IT DOES NOT LIMIT MOTORFUNCTION
• DECISION IS MADE ON THE BASIS OF HOWSYMPTOMS ARE AFFECTING INDIVIDUALPATIENTS
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CHOICE:INTRODUCE LEVODOPA
OR ANOTHER ANTIPARKINSONIAN AGENT
• DEVELOPMENT OF COMPLICATIONASSOCIATED WITH LONG-TERM USE OFLEVODOPA
• OTHER ANTIPARKINSONIAN DRUGS SHOULD BE CONSIDERED FIRST TO DELAYTHE INTRODUCTION OF LEVODOPA
• LEVODOPA IS APPROPRIATE IF THE
PATIENT’S SYMPTOMS ARE STARTING TOINTERFERE WITH HIS OR HER ACTIVITIES
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PATIENTS WITH MILD SYMPTOMS
MAY BE TREATED IN OTHER WAYS
CHOICES INCLUDE :
INTRODUCING SELEGILINE FOR
ITS POSSIBLENEUROPROTECTIVE BENEFIT
INITIATING TREATMENT WITH
ANTICHOLINERGIC DRUG,AMANTADINE,
OR A DOPAMINE AGONIST AGENT
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SELEGILINE (L-DEPRENYL) AS AN ADJUNCT TO CARBIDOPA/LEVODOPA
FOR PATIENTS WHO EXHIBIT DETERIORATION IN
RESPONSE TO LEVODOPA
•
SHOWN TO PROLONG THE SYMPTOMATICBENEFIT OF LEVODOPA
• IMPROVEMENT OF MOTOR SCORES AFTER THE INITIATION OFTHE DRUG AND DETERIORATION OF SCORES ON ITS WITHDRAWL
•
MAY HAVE SOME NEUROPROTECTIVEEFFECT• STATISTICALLY REDUCED DISABILITY COMPARED TO PLACEBO
WAS FOUND EVEN AMONG DEPRENYL PATIENTS WHO INITIALLYHAD NO IMPROVEMENT IN MOTOR SCORES
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SELEGILINE MONOTHERAPY
• SELEGILINE’S NEUROPROTECTIVE EFFECTS
• LEVODOPA TREATMENT TOXICITY WILL BE REDUCED BY
SELEGILINE INHIBITION OF MAO-B OXIDATION OF
DOPAMINE
• APPROPRIATE CANDIDATES FOR SELEGILINE
MONOTHERAPY:
- EARLY-STAGE PATIENTS
WITHOUT DISABLING SYMPTOMS
- YOUNG PATIENTS (< 65 YEARS OF AGE)
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ANTICHOLINERGICS
• TO BE EFFECTIVE FOR THE SYMPTOMS OF
TREMOR, ALTHOUGH RIGIDITY AND
BRADYKINESIA ARE NOT MUCH ALTERED
• SHOULD BE USED WITH CAUTION IF AT ALL
IN THE ELDERLY SINCE THEY HAVE A POOR
THERAPEUTIC INDEX AND HIGH TOXICITY
• NUMBER OF SIDE EFFECTS
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AMANTADINEFOR PATIENTS WHOSE EARLY SYMPTOMS DO NOT RESPOND
TO ANTICHOLINERGICS
• AN ANTI VIRAL AGENTPRECISE MECHANISM OF ACTION REMAINS TO BEDEFINED
RELEASES DOPAMINE FROM PERIPHERAL NEURAL STOAGE SITES;
SIMILAR ACTION ON THE RESIDUAL, INTACT DOPAMINERGIC
TERMINALS IN THE STRIATUM OF PARKINSONIAN PATIENTS
• REPORTED ACTIONS :
- RELEASE OF DOPAMINE FROM CENTRAL NEURON
- DELAY OF DOPAMINE UPTAKE BY NEURAL CELLS
- BLOCKADE F NMDA RECEPTORS- ANTICHOLINERGIC EFFECTS
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DOPAMINE AGONISTS
• LONG HALF-LIFE
ASSOCIATED WITH LESS RISK OFDEVELOPING DYSKINESIA
• USE OF THESE COMPOUNDSPRIOR THE LEVODOPA INITIATION IN EARLYDISEASE TO AVOID OR DELAY THEPRODUCTION OF DYSKINESIA, ESPECIALLY
IN PATIENTS WHO ARE YOUNG
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DEVELOPMENT OF DYSKINESIA
• DEPEND ON DISEASE SEVERITY AND THE
HALF-LIFE OF THE DOPAMINERGIC AGENT
• ENOUGH DOPAMINE TERMINALS TO
REGULATE DOPAMINE RELEASE AND
PROVIDE POSTSYNAPTIC DOPAMINE
RECEPTOR WITH RELATIVELY PHYSIOLOGIC
DOPAMINE STIMULATION
• MORE ADVANCED DISEASE:
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NOT ENOUGH DOPAMINE TERMINALS TO
REGULATE DOPAMINE RELEASE
FLUCTUATION IN STRIATAL LEVODOPA
THE RESULTING EXPOSURE OF STRIATAL RECEPTORSTO ALTERNATING HIGH AND LOW CONCENTRATIONSOF DOPAMINE ----
INDUCE THE POSTSYNAPTIC CHANGES THAT LEAD TO
THE DEVELOPMENT OF DYSKINESIA & MOTORCOMPLICATIONS
INITIAL MONOTHERAPY: USEFUL IN YOUNGERPATIENTS
WHO ARE MORE PRONE TO THE EARLY DEVELOPMENTOF LEVODOPA-RELATED CLINICAL FLUCTUATIONS
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INHIBITORS OFCATECHOL-O-METHYLTRANSFERASE
ADDITION OF CARBIDOPA TO LEVODOPAINCREASES THE AMMOUNT OF DRUGAVAILABLE TO CROSS THE BLOOD-BRAIN
BARRIER LEVODOPA IS METABOLIZED IN THE GUT
AND LIVER BY COMT
COMT INHIBITORY AGENTS PREVENT THE
BREAKDOWN ; PROLONGING THE HALF-LIFE OF LEVODOPA, INCREASING ITS
TRANSPORT INTO THE BRAIN TO RISE
DOPAMINE LEVELS
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COMT inhibitionLevodopa plus DDCI Levodopa plus DDCI plus COMT inhibitor
BBB = blood brain barrierDDC = DOPA-decarboxylaseDDC = DOPA-decarboxylase inhibitorCOMT = Catechol-O-methyl transferase3-OMD = 3-O-methyldopa
Peripheral CentralPeripheralCentral
Dopamine
Levodopa
3-OMD
COMT
BBB
DDC
3-OMD
Levodopa
Dopamine
COMT
DDC
Dopamine
Levodopa
3-OMD
COMT
BBB
DDC
3-OMD
Levodopa
Dopamine
COMT
DDC
Kaakkola S, et al. General properties and clinical possibilities of new selective inhibition of cathecol-O-methyl transferase. Gen. Pharmacol 1994a; 25: 813 - 824.
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• Pengobatan dengan Levodopa tunda sedini mungkin komplikasi motorik.
Levodopa Toksik pemberian jangka panjang akan merusak
reseptor secara struktural dan fungsional• Penyakit dengan stage ringan jangan pake levodopa tapi pake
Agonis Dopamin
• Pasien Muda pake Agonis Dopamin
• Levodopa Pasien tua dengan stage berat
• Komplikasi muncul pada tahun kelima
• Antikolinergik muncul tremor