You are on page 1of 17

ANTIPARKINSON

Sumber Bacaan :
Mycek, M.J., Harvey, R.A., dan Champe, P.C., 2001, Farmakologi Ulasan
Bergambar, ed. 2, Terjemahan Azwar Agoes, Widya Medika, Jakarta, 81
88
Ganiswarna, S., (ed.), 1995, Farmakologi dan Terapi, ed. 4, Bagian
Farmakologi, Fakultas Kedokteran, Universitas Indonesia, Jakarta, 175
188
Hardman, J.G. & Limbird, L.E. (ed.), 1996, Goodman and Gilman's The
Pharmacological Basis of Therapeutics, 9th ed., McGraw-Hill, Health
Professions Division, Section III, Chapter 22
Neurodegenerative diseases
Treatments for the
neurodegenerative
disorders are symptomatic
Parkinson's disease The most effective
Alzheimer's disease symptomatic therapies are
Huntington's disease those for Parkinson's
amyotrophic lateral disease;
sclerosis (ALS) The treatments available
for Alzheimer's disease,
Huntington's disease, and
ALS are less satisfactory
Parkinsonism
Firstly described by James Parkinson in 1817 as paralysis
agitans. Described later as idiopathic PD.
A clinical syndrome comprising 4 cardinal features:
bradykinesia (slowness and poverty of movement),
muscular rigidity,
resting tremor (which usually abates during voluntary
movement),
impairment of postural balance leading to disturbances of gait
and falling.
Etiologi

Penyebab pasti belum jelas


Ditemukan toksin yang timbulkan
sindroma bila memapari primata secara
eksperimental
Berhubungan dgn penurunan aktivitas
inhibitor saraf dopaminergik dalam
substansia nigra dan korpus striatum
(neostriatum) pada sistem ganglia
basalis otak yang berfungsi mengatur
gerakan
Diagram of the basal ganglia (normal) The basal ganglia in Parkinson's disease
The neostriatum (STR) is the principal input structure of the basal The primary defect is destruction of the dopaminergic
ganglia and receives excitatory, glutamatergic input from many neurons of the SNpc. The striatal neurons which form the
areas of cerebral cortex. Outflow from the STR proceeds along direct pathway from the STR to the SNpr and MGP
two routes. The direct pathway, from the STR to the substantia express primarily the excitatory D1 dopamine receptor,
nigra pars reticulata (SNpr) and medial globus pallidus (MGP), while the striatal neurons which project to the LGP and
uses the inhibitory transmitter GABA. The indirect pathway, from form the indirect pathway express the inhibitory D2
the STR through the lateral globus pallidus (LGP) and the dopamine receptor. Thus, loss of the dopaminergic input
subthalamic nucleus (STN) to the SNpr and MGP consists of two to the striatum has a differential effect on the two outflow
inhibitory, GABAergic links and one excitatory, glutamatergic pathways; the direct pathway to the SNpr and MGP is
projection. The substantia nigra pars compacta (SNpc) provides less active, while the activity in the indirect pathway is
dopaminergic innervation to the striatal neurons giving rise to both increased. The net effect is that neurons in the SNpr and
the direct and indirect pathways, and regulates the relative activity MGP become more active. This leads to increased
of these two paths. The SNpr and MGP are the output structures inhibition of the VA/VL thalamus and reduced excitatory
of the basal ganglia, and provide feedback to the cerebral cortex input to the cortex. Thin line, normal pathway activity;
through the ventroanterior and ventrolateral nuclei of the thalamus thick line, increased pathway activity in PD; dashed line,
(VA/VL) reduced pathway activity in PD
Mekanisme parkinsonisme

SUBSTANSI NIGRA :
Sbg smbr neuron dopaminergik, berakhir dlm striatum
Satu neuron dopaminergik menimbulkan ribuan kontak sinaptik dlm striatum,
shg memodulasi sebagian besar aktivitas sel
Prinsip pengobatan
Parkinsonisme
Dopaminergic terminal

Dopamine (DA) is synthesized within neuronal


terminals from the precursor tyrosine by the
sequential actions of the enzymes tyrosine
hydroxylase, producing the intermediary L-
dihydroxyphenylalanine (DOPA), and aromatic
L-amino acid decarboxylase. In the terminal,
dopamine is transported into storage vesicles
by a transporter protein (T) associated with the
vesicular membrane. Release, triggered by
depolarization and entry of Ca2+, allows
dopamine to act on postsynaptic dopamine
receptors (DAR); The actions of dopamine are
terminated by the sequential actions of the
enzymes catechol-O-methyl-transferase
(COMT) and monoamine oxidase (MAO), or by
reuptake of dopamine into the terminal.
Obat parkinsonisme

Bersifat simptomatik Dopamin (DA)


Hanya membebaskan EKSOGEN tdk dpt
dari gejala lewati sawar darah-otak
Tidak mengadakan L-DOPA lewat sawar
regenerasi neuron darah otak, diubah
Levodopa (L-DOPA) jadi DA
sebagai obat pilihan
L-DOPA

Prekursor metabolik DA
Kembalikan kadar DA dalam substansia
nigra ke striatum
Efek simptomatik selama obat ada dalam
tubuh
Dosis besar timbulkan efek samping
perifer : mual, muntah, aritmia jantung,
hipotensi
L-DOPA

Cepat diabsorbsi secara aktif dari usus halus


Sangat bergantung pada kecepatan
pengosongan lambung
Relatif sedikit yang capai sirkulasi karena :
Cepat degradasi dalam lambung
Dirusak oleh flora usus
Mekanisme absorbsi lambat di duodenum
distal
L-DOPA
Tanpa makanan, cepat diabsorbsi
Waktu paruh sangat singkat
Konsentrasi plasma berubah cepat
Respon motorik turun naik (fenomena on-off)
Pasien tiba-tiba kehilangan morbiditas normal

Diet kaya protein ganggu transpor ke SSP


AA BM tinggi (LEU dan ILE) ganggu
absorbsi di usus dan di sawar otak
Metabolism of levodopa (L-DOPA)

AD, aldehyde dehydrogenase;


COMT, catechol-O-methyl
transferase;
DbH, dopamine b-hydroxylase;
AAD, aromatic L-amino acid
decarboxylase;
MAO, monoamine oxidase.
Karbidopa

Perkuat kerja L-DOPA pada SSP


Inhibitor dekarboksilase perifer, sehingga
L-DOPA tidak berubah jadi DA di perifer
Kurangi metabolisme L-DOPA di sal cerna
dan perifer
Mengurangi kebutuhan dosis L-DOPA,
sehingga mengurangi efek samping
Efek samping
Efek perifer
Stimulasi pusat muntah, anoreksia, nausea, muntah
Takikardia
Midriasis
Ludah dan urin coklat = pigmen melanin hasil oksidasi
katekolamin

Efek sentral
Halusinasi visual dan pendengaran
Depresi, ansietas
Interaksi

Piridoksin
Tingkatkan degradasi L-DOPA di perifer,
efek turun
Inhibitor MAO
Tingkatkan pelepasan NE
Hipertensi meningkat
Obat lain

Agonis dopamin : bromokriptin dan derivat


Antikolinergik : triheksifenidil, antihistamin
Dopamino-antikolinergik : amantadin, TCA
Inhibitor MAO-B : selegilin