pp a-2 parkinson

8/2/2019 Pp a-2 Parkinson

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SISTEM PIRAMIDAL


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PARKINSON


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DEFENISI

Suatu kelainan fungsi otak yang disebabkan

oleh proses degeneratif progresif sehubungan

dengan proses menua di sel-sel substansia

nigrapars compacta, ditandai dengan tremor

waktu istirahat, kekakuan otot dan sendi

(rigidity), kelambanan gerak dan bicara

(bradikinesia), dan instability posisi tegak(postural instability).


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KLASIFIKASI

Primer atau idiopatik Tidak diketahui penyebabnya.

Ada peran toksin, faktor genetis.

Sekunder atau akuisita Timbul setelah terpajan suatu penyakit.

Efek samping dari obat.

Sindrom parkinson plus Gejala parkinson timbul bersama gejala neurologi lain.

Kelainan degeneratif diturunkan (heredodegeneratif

disorders) Gejala parkinsonism menyertai penyakit-penyakit yang

diduga berhubungan dengan penyakit neurologi lain yangfaktor keturunan memegan peran sebagai etiologi, sepertipenyakit Alzheimer, Wilson disease, dan lain-lain.


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ETIOLOGISampai saat ini belum diketahui dengan

pasti penyebab kematian sel-sel SNc.

FAKTOR RISIKO

Genetik Lingkungan

Usia

Ras Cedera kraniosrebral

Stres emosional


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MANIFESTASI KLINIS

Resting tremor, bradikinesia, rigidity &

postural instability scr umum merupakan

tanda tanda pokok dari PD & merupakan

suatu disfungsi motorik.

Gejala motorik sekunder

Gejala non motorik


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Stadium V

- Stadium kakeksia

- hanya bisa berbaring/ berjalan walaupundibantu

- bicara x jelas, wajah x berekspresi, mata

jarang berkedip

- memerlukan perawatan tetap


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Patofisiologi Bradikinesia


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Bradikinesia pada Parkinson

SNpc (substansia nigra pars compacta) sedikit keluarkan Dopamin receptor D1 (direct) tidak ubah Dopamin menjadiGABA di MGP (Medial Globus Pallidus), jadi hanya Glutamat yang masuk ke MGP. Reseptor D2 (indirect) yangmengirim dopamin ke LGP (Lateral Globus Paliidus) jg tdk adekuat. Maka STN (Subthalamic Nuclei) yg punyaGlutamat sendiri merubahnya menjadi GABA di MGP utk menyeimbangkan kerja dgn glutamat dr korteks di MGP.

GABA yg HANYA dr STN tadi dikirim ke thalamus dgn jlh sedikit kortexbradikinesia (krn tdk adekuat).

Cortexstriatum

SNpc

SNpr MGP

LGP STN

VL

Thalamus

Glutamat

D1

D2

GABA

Glutamat

GABA


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PENATALAKSANAAN


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How to treat deficit of dopamine?

Levodopa (L-DOPA) the first-line drug

Levodopa dopamine

Dopamine does not penetrate the blood-brain barrier.

DOPA conversion to dopamine in the periphery, which would

cause troublesome adverse effects

is largely prevented by the decarboxylase inhibitor.Since the inhibitor does not penetrate the blood-brain barrier,

decarboxylation occurs rapidly within the brain (95% of the

levodopa dose).

Dopa decarboxylase

(1) dopamine precursors (replacement of dopamine)


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Levodopa (L-DOPA)

Pharmacokinetics:

Absorbed by the small intestine by an activetransport system

Decarboxylation occurs in peripheral tissues(gut wall, liver and kidney

decrease amount available for distribution 1% of anoral dose

Extracerebral dopamine amounts causing unwantedeffects (benserazide)

Short half-life


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Levodopa (L-DOPA)

Adverse effects (type A)dyskinesia - involuntary writhing movements develop in the majority

of patients within 2 years of starting levodopa therapy :

affect the face and limbs

are dose-dependent (disappear if the dose is reduced)

on-off effect rapid fluctuation in clinial state where hypokinesia and rigiditysuddenly worsen (for anything from a few minutes to a few hours) and then

improve again (probably the fluctuations reflect the changing plasma

levodopa concentration)

Others:

nausea and anorexia, hypotension,

by increase dopamine activity in the brain----schizophrenia-like syndrome with

delusions and hallucinations

confusion, disorientation, insomnia (in 20% of patients)


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a. increase in dopamine release-b. blockade of amine neuronal reuptake

potent agonists at dopamine D2 receptors in theCNS :

= bromocriptine derived from the ergot alkaloids

lisuride and pergolide

= amantadine :- increases dopamine release,

- activates D2 receptors

- less active, more tolerated

Dopamine receptors agonists


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Dopamine Agonists -

Possible Advantages

Do not generate free radicals

May decrease dopamine turnover

Delay need for levodopa

Decreased risk of dyskinesias

Possible neuroprotection Longer half lives


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Rationale for Dopamine

Agonists

Direct stimulation of dopamine receptors

No need for presynaptic conversion

No competition at the gut or BBB

Selective receptor activation possible

Alternate routes of administration


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MIRAPEX (pramipexole dihydrochloride) Product Monograph Boehringer Ingelheim (Canada) Ltd. 1998

Pramipexole: Pharmacokinetics

Absorption Rapidly absorbed: peak concentration

between 1 - 3 hours Absolute bioavailability >90%

Can be administered without regard to mealsDistribution Protein binding


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Dopamine receptor agonists

Adverse effects:

Use gradual dose titration

Nausea+ Vomitting (particularly Apomorphine)

Dyskinesia

Hallucinations and confusion

Peripheral vasospasm (Raynaunds)

Respiratory depression (Apomorphine


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MAO-B blockade

Selegilinea selective inhibitor for MAO-B, which prediminates

in dopamine containing regions in the CNS

MAO-B inhibition:

protects dopamine from intraneuronaldegradation

lacks the adverse peripheral effects of non-selective MAO inhibitors used to treat depression

does not provoke the cheese reactionCombination of levodopa + selegilin is more effective

in relieving symptoms and prolonging life


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Anticholinergics

reduce the relative overactivity of theneurotransmitter acetylcholine to balance the

diminished dopamine activity.

This class of drugs is most effective in the

control of tremor, and they are used as

adjuncts to levodopa.

Side effects associated with anticholinergic

drugs include dry mouth, blurred vision,

constipation, and urinary retention


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How to treat excitatory function of cholinergic

and glutaminergic neurons?

MUSCARINIC ACETYLCHOLINE RECEPTOR ANTAGONISTS

Atropineaction is more limited (than that of levodopa):

tremor is more diminished than rigidity or hypokinesia

Adverse effects (type A- troublesome peripheralaction):

dry mouth, constipation, impaired vision, urinaryretention

Benzatropinehas less peripheral effect in relation to their central effect than

does atropine


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COMT (catechol-O-methyl transferase)Inhibitors

These new class of Parkinson's medications augment

levodopa therapy by inhibiting the COMT enzyme,

which metabolizes levodopa before it reaches the

brain.

Inhibiting COMT increases the amount of levodopa

that enters the brain.

These drugs are only effective when used withlevodopa

- Entacapone (Comtan)- Tolcapone (Tasmar)


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COMT-I

MoA: inhibits the breakdown of levodopa

Pharmacokinetics: variability of absorption,

extensive first-pass metabolism, short half-

life

Adverse effects: dyskinesias, hallucinations;

N, V, Dia and abdominal pain

New combination

Levodopa/carbidopa/entacapone (Stalevo)

as 1 tablet (50, 100, 150mg


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Amantadine (Symmetrel)

Originally an antiviral drug, now used as conjunctivetherapy for dyskinesis effects produced by Levodopa

MoA:

stimulates/promotes the release of dopamine stored in thesynaptic terminals

Reduces reuptake of released dopamine by pre-synaptic neuron

Pharmacokinetics:

Well absorbed, long half-life, excreted unchanged by the kidney

Adverse effects:

Not many

Ankle oedema, postural hypotension, nervousness, insomnia,hallucinations (high dose)


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Antimuscarinic/Anticholinergic Drugs:

Trihexyphenidyl (Artane); Benztropine (Cogentin);

Orphanadrine (Disipal); Procycline (Arpicolin)

Less common drugs but they affect Ach based

interactions MoA: blocking cholingeric (ACh) receptors to

restore balance

Pharmacokinetics: fairly well absorbed, extensive

hepatic metabolism, intermediate to long half-lifes

Adverse effects: dry mouth and confusion


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Komplikasi


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-depresi

- tidak bisa tidur

- sulit mengunyah dan menelan

-sulit BAK

-konstipasi

-disfungsi seksual


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Diagnosa Banding


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Essential tremor (ET)

Progressive supranuclear palsy (PSP)

Multiple system atrophy (MSA)

Corticobasal degeneration (CBD)

Diffuse Lewy body dementia (LBD)

Alzheimer's disease

Drug-induced parkinsonism

Vascular parkinsonism


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Prognosis


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Tingkat keparahan gejala penyakit Parkinson sangatbervariasi dari individu ke individu dan tidak mungkinuntuk memprediksi seberapa cepat gangguantersebut akan maju. PenyakitParkinson sendiri bukanlah penyakit fatal, danharapan hidup rata-rata adalah samadengan orang tanpa penyakit. Komplikasisekunder, seperti pneumonia, jatuh cedera yangberhubungan, dan tersedak bisa mengakibatkan

kematian. Ada banyak pilihan pengobatan yang dapatmengurangi beberapa gejala dandapat memperpanjang kualitas hidup seorangindividu dengan penyakit Parkinson.

pp a-2 parkinson

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