anti parkinson
DESCRIPTION
farmakologi obat anti parkinsonTRANSCRIPT
![Page 1: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/1.jpg)
OBAT OBAT ANTI PARKINSONDr.A.Basori,MS
![Page 2: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/2.jpg)
PARKINSONISMGangguan neurologi yang menyebabkan disfungsi basal ganglia dan struktur terkait
Symptoms :- Resting tremor - Muscular Rigidity - Akinesia, Bradykinesia, Abnormalities of posture and
gait - Instabilitas posture mudah jatuh, kehilangan
keseimbangan- Disfungsi autonomic constipation, drooling,
dysphagia, blurred vision, hypotension, impotence- Cognitive/affective depression, dementia, night time
awakenings, hallucinations- Lain lain : immobility, underactivity, facial immobility,
reduced blinking, difficulty in visual focusing, micrographia, difficulty arising from a chair & beginning to walk. Autonomic dysfunction, Dimentia,Depression.
![Page 3: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/3.jpg)
Parkinson Disease (PD) Penyakit degenerative dari basal ganglia yang
ditandai a.l,tremor at rest, muscle rigidity , hypokinesia, coreoathetosis,dementia. Akhirnya menjadi neurodegenerasi secara umum
Ethiology :
Idiopahic-70% (mutasi a-synuclein dan parkin) Viral encephalitis, stroke, cerebral
arteriosclerosis, carbon monoxide poisoning & chronic manganese intoxication,pesticides, herbicides, Industrial chemicals (mengandung senyawa yang menghambat complex I di mitochondria), head trauma,excitotoxicity, oxidative stress dan
apoptosis. Drugs addicts pengguna heroin (terkontaminasi oleh MPTP). MPTP kerusakan neuron dopaminergic di
nigrostriatal parkinson syndrome (irreversible)
![Page 4: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/4.jpg)
![Page 5: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/5.jpg)
![Page 6: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/6.jpg)
FRONTAL SECTION OF BRAINSherwood, 2001 p 145
![Page 7: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/7.jpg)
![Page 8: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/8.jpg)
Gambaran patologi umum :1. Kematian / degenerasi sel-2 penghasil dopamine di Nigrostriatum menurunnya
kadar Dopamine overaktivasi dari indirect pathway
2. Menurunnya sistem dopaminergic peningkatan efek eksitatori dari neuron cholinergic pada neuron striatal GABA-ergic.
Neuron Dopaminergic pasca sinaps pada neuron
GABA-ergic adalah D2 Parkinson = keseimbangan dopaminergic dan cholinergic 3. Adanya Lewy bodies – inklusi eosinophilic sangat kecil didalam neurons dari SNc
Akibat :- Degenerasi dari nigrostriatal pathway- Menurunnya eksitasi thalamic dari motor cortex
![Page 9: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/9.jpg)
![Page 10: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/10.jpg)
DRUG INDUCED PARKINSONISM
Iatrogenic- induced by antipsychotic drugs. Butyrophenone dan Phenothiazine
antagonist reseptor D2 Reserpine dosis tinggi deplesi Dopamine MPTP Parkinson disease
![Page 11: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/11.jpg)
![Page 12: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/12.jpg)
Normal subjects
ACh Dopamine
Parkinson’s diseaseDopamineACh
![Page 13: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/13.jpg)
![Page 14: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/14.jpg)
Jalur Dopaminergic Di SSP Mesolimbic : VTA (mid brain) limbic system (n.
accumbens,amygdala,hippocampus) : emotion, rewards, mood. Aktifitas DA meningkat positive symptom
Mesocortical: VTA prefrontal cortex : motivation,planning,attention,social behaviour.
Aktifitas DA turun negative symptom
Nigrostriatal : s.nigra (mid brain) corpus striatum (extrapyramidal tract):pengendalian motorik.
Aktifitas DA turun Extra Pyramidal Syndrome
Tuberoinfundibular : Hypothalamus Hypophyse Aktifitas DA menghambat sekresi Prolactin
Area prostrema : Chemotrigger Zone (CTZ) Aktifitas DA naik Emesis
![Page 15: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/15.jpg)
![Page 16: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/16.jpg)
![Page 17: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/17.jpg)
Monoamine Oxidase (MAO)
![Page 18: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/18.jpg)
![Page 19: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/19.jpg)
MAO-A MAO-B Selectively Inhibited by Clorgyline Selegilene
Moclobemide (RIMA)
Substrates Serotonin (5-HT) PhenylethylamineEpinephrine Benzylamine
Methylhistamine
Non-SelectiveTyramineOctopamineDopamine (DA)Norepinephrine (NE)Tryptamine
![Page 20: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/20.jpg)
Extrapyramidal tractExtrapyramidal tract
Corpus striatum
Substantia nigra
ACh
Dopamine GABA
- +
-
Pathway via
thalamus
Cortex
Spinal cord
Output menuju muscle
![Page 21: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/21.jpg)
Parkinson’s DiseaseParkinson’s DiseaseCorpus striatum
Substantia nigra
ACh
Dopamine GABA
- +
-
Pathway via
thalamusCortex
Spinal cord
Parkinson’s disease
![Page 22: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/22.jpg)
PENGOBATAN PARKINSON• Meningkatkan aktifitas Dopaminergic meningkatkan sintesa dan pelepasan Dopamine menghambat metabolisme Dopamine aktifasi reseptor Dopamine• Mengurangi aktifitas Cholinergic mengeblok reseptor Muscarinic cholinergic
Surgery (Posterior Pallidectomy) ?
Transplantation ?
![Page 23: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/23.jpg)
PengobatanPengobatan
Levodopa
Amantidine
Bromocriptine
Deprenyl
ACh
Dopamine
![Page 24: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/24.jpg)
Anticholinergic drugsAnticholinergic drugs
ACh Dopamine
PengobatanTrihexyphenidyl (Artane®)Diphenhydramine (Benadryl®)Benztropine (Cogentin®) Procyclidine (Kemadrin®) Ethopropazine (Parsidol®)
![Page 25: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/25.jpg)
DOPAMINE
• NT utama yg mengatur pergerakan subconscious dari skeletal muscles
• Terutama banyak didaerah terminal pathway dari neuronal cell bodies di SNc menuju striatum
• Pada umumnya menghambat fungsi striatal neurons & striatal outputs
• Bila produksi dopamine menurun terjadi gangguan movement, balance dan gait
![Page 26: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/26.jpg)
D-2
Serotonin-Dopamine InteractionsSerotonin-Dopamine Interactions
Prefrontal CortexPrefrontal Cortex
LimbicLimbicSystemSystem
GABA/AChGABA/ACh
StriatumStriatum
Ventral Tegmental AreaVentral Tegmental Area(A10)(A10)
Substantia NigraSubstantia Nigra(A9)(A9)
DorsalDorsalRapheRaphe
MedianMedianRapheRaphe
5-HT5-HT2A2A antagonists antagonists
mencegah dopamine mencegah dopamine dari blokade dan dari blokade dan mencegah EPSmencegah EPS
Blockade DBlockade D22 receptors receptors
oleh Typical AP oleh Typical AP menyebabkan EPSmenyebabkan EPS
Motor OutputsMotor Outputs
Dopamine (DA)Dopamine (DA)
Serotonin (5-HT)Serotonin (5-HT)
5-HT2
5-HT25-HT2
D2
D25-HT2
![Page 27: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/27.jpg)
L-DOPA (Levodopa) + Carbidopa (Sinemet®)
L-Dopa + Benserazide (Madopar)
DA (D2) Receptor Agonists
Bromocriptine mesylate,Lysuride, Pergolide, Apomorphine
Cholinergic Antagonists
Benztropine, Benzhexol,Biperidene, Orphenadrine,
Trihexyphenidyl, Procyclidin
Amantadine
Selegilline (= Deprenyl)
COMT Inhibitors (Tolcapone)
Obat obat Anti Parkinson
![Page 28: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/28.jpg)
![Page 29: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/29.jpg)
![Page 30: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/30.jpg)
Levodopa
• Farmakodinamik Merupakan suatu pro-drug Mengalami transport menuju otak oleh Dopa decarboxylase diubah menjadi Dopamine Pemakaian dikombinasi dgn Carbidopa (inhibitor dopa decarboxylase perifer) Pemakaian sendiri dosis besar efek samping• Farmakokinetik Absorpsi p.o sangat baik Pemberian dengan makanan protein tinggi kompetisi dengan AA pada transport menuju otak (melalui BBB)
![Page 31: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/31.jpg)
Levodopa• Efek Farmakologi Menghilangkan simtom parkinson (mis, bradycardia) Efeknya berfluktuasi Efeknya menurun seiring dengan waktu• Efek Samping Bersifat dose dependent• Efek samping : anorexia, emesis, postural hypotension, tachycardia, asystole, arrhytmia (jarang), Dyskinesia, halusinasi, gelisah, kebingungan, cemas, delusi, depresi• Interaksi Obat Levodopa + MAO inhibitor non selective dopamine perifer meningkat hypertensive crisis Levodopa + Pyridoxine meningkatkan kerusakan
levodopa diperifer efikasi menurun Levodopa + Antipsikosos efikasi menurun• On – Off Phenomenon Perubahan yang sangat cepat dari respon klinik T ½ sangat pendek kdr plasma cepaat menurun imobilitas mendadak, tremor, dan kramp
![Page 32: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/32.jpg)
Carbidopa Suatu Dopamine decarboxylase inhibitor Tidak menembus BBB Kombinasi dgn Levodopa meningkatkan kdr
dopamine di otak Pemakaian Carbidopa menurunkan dosis Levodopa
4 x Efikasi pengobatan menurun seiring dgn progesifitas penyakit
![Page 33: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/33.jpg)
Bromocriptine• Farmakodinamik
Merupakan alkaloid ergot
Merupakan agonist terhadap reseptor D-2
• Efek Samping / Toksik
GIT : anorexia, nauseaa, vomiting
Kardiovaskuler : postural hypotennsion, cardiac arrhytmia,
Dyskinesia
Perilaku : bingung, halusinasi, delusi, delirium
Efek lainnya : pulmonary infiltrate, erythrolmelalgia
Kontraindikasi : penderita psikosis
• Guna Klinik :
+ Levodopa menurunkan efek toksik dari Levodopa
+ Levodopa meningkatkan efektifitas Levodopa
Digunakan pada penderita yang tdk mentolerir levodopa
Digunakan pada penderita yang refrakter thd Levodopa
Obat pilihan pada hyperprolactinemia
![Page 34: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/34.jpg)
Pergolide (Permax®) Mirip dengan Bromocriptine. Direct-acting ( agonist reseptor D-1 dan D-2) Digunakan kombinasi dengan levodopa. Efek samping mirip dengan levodopa dan bromocriptine (kebingungan, halusinasi, orthostatic hypotension, infeksi saluraan saluran kencing)
Ropinirole (Requip®) Merupakan D2 receptor agonist. Efek samping : Light headedness, fainting yang disertai bradycardia, ( 12% pada penderita PD awal dan 3% fase lanjut) nausea, drowsiness, dystonias, hallucinations. Ciprofloxacin menghambat ekskresi ropinirole meningkatkan kadar dalam darah
![Page 35: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/35.jpg)
Pramipexole (Mirapex®) Direct-acting DA receptor agonist Terutama sangat selektif thd D3/D4 DA receptors. Mempunyai efek neuroprotective. Diberikan bersama dengabn Sinemet. Orthostatic hypotension, nausea, drowsiness
Apomorphine Dicoba secara subcutaneous dalam kombinasi dengan pemberian oral levodopa untuk mencegah fluktuasi response dari Levodopa Pemberian domperidone mencegah efek emetic.
![Page 36: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/36.jpg)
Amantadine• Farmakodinamik
Meningkatkan sintesa Dopamine
Meningaktakn pelepasan Dopamine
Menghambat re-uptake Dopamine• Efek Farmakologi
Menghilangkan simtom bradykinesia, rigidity, tremor
Efektif hanya beberapa minggu
Efektifitas meningkat bila dikombinasi dgn Levodopa
Mempunyai efek anti viral (untuk pengobatann influenza) • Toksisitas :
Efek perilaku: gelisah, agitasi, insomnia, bingung,
halusinasi, acute toxic psychosis
reaksi dermatologi : skin rash
Efek lainnya : gangguan GIT, retensi urin, postural
hypotension, edema perifer ( biasamya hilang jika diberi
diuretik
![Page 37: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/37.jpg)
Selegilene (Deprenyl)
1. Hanya menghambat MAO-B ( tidak menyebabkan “cheese” effect /hypertensive crisis bila mengkonsumsi makanan yang mengandung tyramine)
2. Inhibisi MAO akan melindungi DA di striatum
3. Menghambat pembentukan H2O2 (hasil monoamine catabolism) may mencegah lipid peroxidation dan neurotoxicity
4. Meningkatkan activitas dari superoxide dismutase (SOD) catalase
5. Mengalami metabolisme menjadi amphetamine dan methamphetamine insomnia, halllucination
6. Inhibitor lemah dari catecholamine re-uptake
7. Meningkatkan konsentrasi phenylethylamine (PEA) (stimulant)
8. Digunakan kombinasi dengan Levodopa
9. Memperlambat progesifitas dari PD
![Page 38: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/38.jpg)
Anticholinergic Drugs Merupakan Central muscarinic receptor antagonists Mengurangi cholinergic output dari striatum Mensetimbangkan sistem keseimbangan dopaminergic & cholinergic di striatum. Beberapa (benztropine, trihexyphenidyl) mempunyai efek menghambat presynaptic dopamine reuptake meningkatkan dopaminergic transmission Dipakai sebagai pengobatan tunggat atau kombinasi dengan levodopa atau amantadine. Menghilangkan tremor, rigidity dan bradykinesia Kurang efektif jika dibandingkan thd levodopa. Penggunaan dibatasi oleh efek samping Penggunaan jangka panjang kurang efektif. Efektif mencegah gangguan extrapyramidal symptoms akibat obat obat antipsychotic .
![Page 39: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/39.jpg)
Efek Samping / Toksik a. Peripheral anticholinergic: dry mouth, mydriasis, cycloplegia, tachycardia, constipation, urinary retention b. Central anticholinergic: gangguan memory, insomnia, restlessness, delirium, paranoid reaction, hallucinations c. Beberapa mempunyai efek efek antihistaminic (mis, diphenhydramine) drowsiness dan dizziness.
Specific Anticholinergic Agents
Trihexyphenidyl (Artane®) Benztropine (Cogentin®) Biperiden (Akineton®) Procyclidine (Kemadrin®) Diphenhydramine (Benadryl® Ethopropazine (Parsidol®)
![Page 40: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/40.jpg)
Tolcapone (Tasmar®) - COMT Inhibitor: Menghambat catechol-O-methyl transferase (COMT). Enzyme COMT juga memecah L-DOPA Inhibisi COMT akan meningkatkan kadar L-Dopa dan keberadaannya di sirkulasi otak meningkatkan efektifitas L-Dopa memperpanjang "on" period dan memperpendek "off" time. Efek samping Umum : nausea, drowsiness, insomnia, dizziness, confusion, urine discoloration, dyskinesia Hati hati: Tolcapone dapat mempengaruhi liver enzymes fungsi liver harus di skrining dahulu Drug Interactions: hati hati kombnasi dgn obat obat yang metabolisme utamanya di liver (mis, warfarin).
![Page 41: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/41.jpg)
Tolcapone Cont’d,Talcapone also reduces the amount of Sinemet required to reduce tremors.
.
![Page 42: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/42.jpg)
Selegiline Cont’dThe usual recommended dose of 5 mg twice a day has minimal adverse effects.
![Page 43: Anti Parkinson](https://reader033.vdocuments.net/reader033/viewer/2022061510/5695d4921a28ab9b02a1ef07/html5/thumbnails/43.jpg)
DRUG LIST
Levodopa (L-Dopa) Dopamine Agonists:carbidopa® apomorphinelevodopa/carbidopa (Sinemet®) bromocriptine (Parlodel®)Amantadine (Symmetryl®) pergolide (Permax®)
ropinirole (Requip®)Anticholinergic Agents: pramipexole (Mirapex®)trihexyphenidyl (Artane®)diphenhydramine (Benadryl®) MAO-B Inhibitors:biperiden (Akineton®) selegiline (Eldepryl®)benztropine (Cogentin®) procyclidine (Kemadrin®) Others:ethopropazine (Parsidol®) haloperidol (Haldol®)
pimozideCOMT Inhibitor: clonidineTolcapone (Tasmar®) MPTP
MPP+