K :

I NI
KL O M
I O N
K :
OG
L AF O T
I N I
KO R K L O M
MA YA
I O N
FA TEM LOG
R -S
O T
O A F
SI MAK
S
A R
R S Y
FA EM-
IS T
S
SULANTO SALEH-DANU R., dr., SpFK
Bagian Farmakologi & Terapi
Fakultas Kedokteran UDM

.
 NERVOUS SYSTEM

CENTRAL N.S. PERIPHERAL N.S.

AUTONOMIC N.S. SOMATIC N.S.

PARASYMPAT
SYMPATHETIC
HETIC
SYSTEM
SYSTEM
SUSUNAN SYARAF SUSUNAN SYARAF PERAN / FUNGSI
PUSAT (SSP /CNS) TEPI / PERIPHERAL

SERABUT :

CEREBRUM NN CRANIALIS: AFFERENT

CEREBELLUM I XII EFFERENT :
MOTORIC

AUTONOMIC
MEDULA-
SPINALIS NN SPINALIS SOMATIC

3
SISTEM SUSUNAN
SYARAF

CEREBRUM
SUSUNAN SYARAF PUSAT CEREBELLUM
MEDULA SPINALIS

SIMPATIS
SISTEM SYARAF OTONOM PARASIMPATIS

SUSUNAN SYARAF TEPI SERABUT SYARAF

CRANIALIS I XII
SERABUT SYARAF
SPINALIS
MENUNJANG FUNGSI GANGLION PARA -
SUSUNAN SYARAF: SPINALIS
Vaskularisasi; Darah (Nutrisi);
Mineral, dll 4
 OBAT-OBAT MENINGKATKAN
aktifitas neurotransmitter dengan
cara :
1. OBAT-OBAT: RESEPTOR AGONISTS;
2. OBAT-OBAT YANG MENSTIMULASI
PELEPASAN NEUROTRANSMITTER,
3. OBAT-OBAT YANG MENGHAMBAT
METABOLISME / DEGRADASI
NEUROTRANSMITTER.

ARTI KLINIS BERKAITAN DENGAN

PENGGUNAAN OBAT-OBAT.

OBAT-OBAT MENEKAN
aktifitas neurotransmitter dengan
cara:

1. MEMBLOK SYARAF PRESYNAPTIC

2. ANTAGONIST RESEPTORS
3. GANGLION BLOCKERS

5
 BEBERAPA NEURO-TRANSMITTER
SUSUNAN SYARAF PUSAT TEPI &
AUTONOMIC NERVOUS SYSTEM (ANS)
1. Actylcholin (Ach)
2. Adenosine triphosphat (ATP)*
3. Calcitonin gene-related peptide (CGRP)
4. Cholecystokinin (CCK)*
5. Dopamine*
6. Enkephalin & related opioid peptides
7. Galanin
8. GABA (gama-aminobutyric acid)*
9. Gastrin-releasing peptide (GRP)
10.Neuropeptide Y (NPY)
11.Nitric Oxide (NO)*
12.Norepinephrine (NE)
13.Serotonin (5-HT)* *) = COTRAMMITTERS
14.Substance P (related tachykinins)
15.Vasoactive intestinal peptide (VIP)*
6
Susunan Syaraf - OTONOM
Syaraf SIMPATIS / ADRENERGIK :
sifat catabolic ( memakan energi )
(fight and flight system)
jantung HR meningkat;
dilatasi bronchus;
sekresi kelenjar turun/berkurang
Syaraf PARASIMPATHIS / CHOLINERGIK :
bersifat menghemat energi
- jantung HR turun
- stimulasi GIT
7
 PRESYNAPTIC POSTSYNAPTIC
PARASYMPATHETIC :
Ach Cardiac
Ach Smooth muscle
MEDULA [ [
N M Glands cell
Gastrointestinal

SYMPATHETIC :
Ach Ach Sweat glands
[ [
N M SYMPATHETIC :
GANGLION Cardiac
Ach NE Smooth muscle
[ [
1. N alpha; beta Glands cell 2.
Nerve terminals
Ach D SYMPATHETIC :
[ [
N D1 Renal Vascular
Smooth muscle
SPINAL
Adren
CORD medula
Ach Epi SOMATIC :
[ [
N NE Skeletal muscle

Voluntary motor nerve Ach

[
N

1.SIMPATIK : SEGMENT THORACOLUMBAL

2.PARASIMPATIK : SEGMENT CRANIOSACRAL
6
 BAGAN SERABUT SYARAF TEPI/
SYARAF OTONOM PERIPHERAL FIBERS
presynaptic neurons
postsynaptic neurons
SYMPHATETIC
(thoracolumbar) Noradrenaline (adrenergic)

ACh (nicotinic)
PARASYMPHATETIC ACh (muscarinic)
(craniosacral) Effector
(cells,
tissues,
organs)
ACh (nicotinic)

SOMATIC MOTOR

neurotransmitter &
receptors ACh (nicotinic)
9
 TIPE TIPE RESEPTOR SUSUNAN SYARAF OTONOM (1)

NAMA RESEPTOR : TYPICAL LOCATION :

CHOLINOCEPTORS :

Muscarinic M 1 Neuron CNS; Sympathetic postganglionic

neurons; beberapa berada di presynptic
Muscarinic M 2 Myocardium; otot polos; beberapa di pre-
synaptic; Neuron CNS.
Muscarinic M 3 Kelenjar exocrine; pembuluh darah (otot po-
los dan endothelium); Neuron CNS.
Muscarinic M 4 Neuron CNS dan mungkin di vagal nerve
ending.
Muscarinic M 5 Endothekium vasakuler; terutama pemb uluh
darah CNS ; Neuron CNS.

Nicotinic NN Neuron postganglionic ; beberapa pada

terminal cholinergic presynaptic .
Nicotinic NM Otot skelet ; neuromuscular endplates.
 TIPE TIPE RESEPTOR SUSUNAN SYARAF OTONOM (2)

NAMA RESEPTOR : TYPICAL LOCATION :

ADRENOCEPTORs:

Alpha 1 Postsynaptic sel efektor; terutama di otot

polos.
Alpha 2 Presynaptic terminal syaraf adrenergik;
trombocyt/platelets; lipocytes; otot polos.
Beta 1 Posttsynaptis sel efektor (jantung, lipocytes,
otak); terminal presynaptic adrenergic &
cholinergic; juxtaglomerular apparatus
pada apparatus tubulus renalis; epithelium
ciliary body.
Beta 2 Postsynaptic sel efektor; terutama otot
polos dan otot jantung.
Beta 3 Postsynaptic sel efektor, terutama lipocytes
dan jantung.
 TIPE TIPE RESEPTOR SUSUNAN SYARAF OTONOM (3)

NAMA RESEPTOR : TYPICAL LOCATION :

DOPAMINE RECEPTORs :

D 1 (DA 1), D 5 Otak; jaringan efektor, terutama otot polos

yang terletak di vasa renal.
D 2 (DA 2) Otak; jaringan efektor terutama otot polos;
terminal syaraf presynaptic.
D3 Otak.
D4 Otak ; sistem kardiovaskuler.
Susunan Syaraf - OTONOM

GLANDs
JANTUNG

VASKULER
MATA
URO-
G.I.T. GENIT
Tract AL
UTERUS
 SISTEM SYARAF OTONOM
AUTONOMIC NERVOUS SYSTEM
( ANS )

SISTEM SIMPATIS SISTEM PARASIMPATIS

AGONIST
AGONIST ANTAGONIST cholinergic

lfa- AGONIST ANTAGONIST

lfa- BLOCKER anticholinergic
Beta-AGONIST

Non selective Beta-BLOCKER MUSCARINIC

- AGONIST
NICOTINIC

14
 SISTEM SIMPATIS
AGONIST ANTAGONIS
T
lfa- Beta- lfa- Beta-
AGONIST AGONIST BLOCKER BLOCKER
Non-selective :Non-selective ; Non- Non-selective :
- nor-adrenaline. -isoprenaline -propranolol
selective :
lfa-1 agonist : Beta-1 agonist : - -pindolol
-dobutamine phenoxybenzamin -timolol
-phenylephrine
-methoxamine Beta-2 agonist : e
Alfa-1 Alfa-Beta
-metaraminol -phentolamine
-salbutamol
-mephenteramine blocker :
-ergotamine blocker:
-terbutaline
-oxymetazoline -salmeterol -prazosin -labetalol
-xylometazoline -formoterol -terazosin -carvedilol
-perbuterol -doxazosin -medroxalol
Alfa-2 agonist :
-alfuzosin
-clonidine -tamsulosin Beta-1 blocker:
Non Alfa-2
selective - -atenolol
blocker: -metoprolol
AGONIST
-adrenaline -yohimbin -esmolol
-dopamine
-ephedrine
-amphetamine
15
Phenylalanin
e
BIOSINTESA
Hydroxylase CATECHOLAMINE
Tyrosine

Tyrosine hydroxylase

DOPA RESEPTOR :
DOPA decarboxylase

Dopamine 1
DA -hydroxylase 2
Noradrenali
ne 1
N-methyl transferase 2
Adrenaline 3
16
 SYNTHESIS -STORAGE- RELEASE & METABOLISME
of NOREPINEPHRINE (NE)
Terminal
syaraf

store in
Tyrosine vesicle 1vasokonstriksi
2vasodilatasi
NE
-reseptor RESPONSE
NE
Tyrosine DOPA NE Uptake- 2
NE
-reseptor RESPONSE
DA NE
NE
Metabolites COMT 1
MAO NE Uptake-1 2
Metabolites 3
Presynaptic
membrane Postsynaptic
note: membrane
DA = dopamine
NE = nor-epinephrine
COMT = Catechol-O-methyl Transferase
MAO = monoamine oxidase
(Padmaja U., 2011) 17
KLASSIFIKASI
OBAT-OBAT ADRENERGIK

I. CHEMICAL CLASSIFICATION :
I . 1. CATECHOLAMINES : nor-epinephrine (adrenaline);
epinephrine (adrenaline); dopamine.
synthetic : isoprenaline; dobutamine; dopexamine;
dipiverine .

I . 2. NON-CATECHOLAMINES : ephedrine; amphetamine

18
II. DEPENDING ON THE MODE OF ACTION :
II. 1. DIRECTLY ACTING (by interacting with adrenergic receptor)
nor-adrenaline; adrenaline; dopamine; isoprenaline;
phenylephrine; salbutamol; xylometazoline; methoxamine.

II. 2. INDIRECTLY ACTING (by releasing NA from nerve terminals)

tyramine ; amphetamine

II. 3. MIXED ACTION AMINE (both direct & indirect action) :

ephedrine; pseudoephedrine; phenylpropanolamine (PPA)

II. 4. CATECHOLAMINE REUPTAKE INHIBITORS :

atomoxetine; reboxetine; duloxetine; sibutramine

19
III.THERAPEUTIC / CLINICAL CLASSIFICATION :
III.1. VASOPRESSORS: noradrenaline; dopamine; phenylephrine;
methoxamine; mephentermine;metaraminol.

III. 2. CARDIAC STIMULANTS : adrenaline; dopamine; dopexamine;

dobutamine; fenoldopam; isoprenaline;
ephedrine.

III. 3. CNS STIMULANTS : amphetamine; dexamphetamine; ephedrine..

III. 4. BRONCHODILATORS : adrenaline; isoprenaline; salbutamol;

terbutaline; salmeterol; perbuterol; fenoterol;
formoterol.

III. 5. NASAL DECONGESTANTS : ephedrine; pseudoephedrine; PPA;

phenylephrine; oxymetazoline; xylomethazoline;
naphazoline.

III. 6. APPETITE SUPPRESSANTS ( ANORECTICS) : fenfluramine;

dexfenfluramine; sibutramine.

III. 7. URINE RELAXANTS : salbutamol; terbutaline; isosuxprine; ritodrine.

20
Serabut syaraf SYMPHATIS.

Neurotransmitter yang berperan :

kelompok CATECHOLAMINE
( norepinehrine / noradrenaline &
epinephrine / adrenaline ),
pada neuron postsynaptic dan akan terikat pada
reseptor adrenergic 1,2 ,1, atau 2 .

Pada stress kelenjar ADRENALIN sekresikan

epinephrine atau adrenaline dalam sirkulasi darah dan
berakibat menstimulasi (agonist) semua serabut symphatis,
kecuali kelenjar keringat

21
 Beberapa contoh
OBAT-OBATAN SYARAF OTONOM
SYMPHATIS / ADRENERGIK

A. SIMPATOMIMETIK LANGSUNG (direct symphatomimetic)

CATECHOLAMINES :
- epinephrine/adrenaline
- norepinephrine/noradrenaline
- isoproterenol
- dobutamine B. SIMPATOMIMETIK INDIREK dan MIXED :
- dopamine Obat-obat yang INDIRECT :
amphetamine
NONCATECHOLAMINES : methamphetamine
- phenylephrine
- metaproterenol MIXED SYMPHATOMIMETIC :
- methoxamine ephedrine
- albuterol hydroxyamphetramine
- terbutaline mephenteramine
- bitoterol metaraminol
phenylpropanolamine
22
C. ADRENERGIC BLOCKER :
Yang bekerja pada secara SENTRAL :
- clonidine
- guanabenz
- guanefacine
- alpha-methyl-DOPA

Yang bekerja pada syaraf peripheral

(Perpheral Presynaptic Anti-
Adrenergic): D. ADRENERGIC ANTAGONIST:
- guanethidine - phenoxybenzamine ( alpha 1 & 2)
- bretyllium - phentolamine ( alpha 1 & 2)
- reserpine - prazosine ( selective alpha 1)
- terazosine ( selective alpha 1)
- labetalol ( alpha 1; beta 1 & 2 )
- propranolol ( beta 1 & 2 )
- nadolol ( beta 1 & 2 )
- timolol ( beta 1 & 2 )
- pindolol ( beta 1 & 2, intrinsic
symphatomimetic activity)
- metoprolol ( beta 1 specific )
- atenolol ( beta 1 specific )
- acebutolol ( beta 1 specific ) 23
 LOKASI RESEPTOR ADRENERGIK
dan EFEK bila DIPACU (1)

Reseptor ALPHA-1 : Reseptor ALPHA-2 :

ARTERIOLES & VENA Terminal CNS POSTSYNAPTIC:

vasokonstriksi alur simpatis dari otak turun
KELENJAR : Terminal CNS PRESYNAPTIC:
sekresi turun pelepasan norepinephrine turun
MATA: sel BETA P.Langerhans di PANCREAS
kontraksi otot radial sekresi turun
GASTROINTESTINAL :
motilitas turun Reseptor ALPHA yang belum diidentifikasi :

KANDUNG KEMIH otot sphincter kontraksi:

retensi urine
UTERUS (Kehamilan)
kontraksi
PENIS :
ejaculasi
24
 (2)

Reseptor BETA 1 :
Reseptor BETA 2 :
JANTUNG :
- heart reat naik TRACHEA dan BRONCHIOLES :
- contractility naik - relaksasi
- alir konduksi naikUTERUS (HAMIL ataupun TIDAK):
- otomatisasi naik - relaksasi
GINJAL: ARTERIOLES(kecuali : pada kulit dan otak)
- sekresi renin dan VENA :
meningkat - vasodilatasi

Reseptor BETA belum teridentifikasi :

MATA :
relaksasi m. ciliaris (efek minimal)
KANDUNG KEMIH:
relaksasi m detrussor (efek minimal)
25
 SIMPATHOMIMETICS :

LANGSUNG (DIRECT) : - catecholamines

- non-catecholamines

TIDAK LANGSUNG (INDERCT) dan MIXED :

INDIRECT : amphetamine & deriva

MIXED : ephedrine
metaraminol
phenyl propanolamine
( ppa )
hydroxyamphetamine
mephenteramine

26
 SIMPATHOMIMETICS (1)
LANGSUNG (DIRECT) : (receptor alpha & beta)

CATECHOLAMINES : - adrenaline (epinephrine) receptor >

- norepinehrine receptor > 1 > 2
- isoproterenol receptor
- dobutamine receptor 1 > 2 =
- dopamine receptor Dopamine &
receptor 1

NON-CATEHOLAMINES : - phenylephrine receptor (terutama)

- methoxamine sda
- metaproterenol receptor 2 (terutama)
- albuterol sda
- bitolterol sda
- terbutaline sda
- ritodrine sda
- isoetharine sda

27
 SIMPATHOMIMETICS (2)

TIDAK LANGSUNG (INDERCT) dan MIXED

INDIRECT : amphetamine receptor 1 (alpha-1) ;
(karena release nor-epinehrine).
methamphetamine sda

MIXED : ephedrine receptor 1 (alpha-1)

hydroxyamphetamine sda
mephenteramine sda
metaraminol receptor 1 (alpha-1)
phenyl-propanolamine sda

28
 LOKASI & STIMULASI PADA
RECEPTOR ADRENERGIK (1)

RECEPTOR (alpha).
-1- alpha 1 : -2 - alpha 2 : ? - alpha ? :

Arteriole & vena : SSP (terminal postsinaptik) m. sphinter v.urinaria

vasokonstriksi symphathetic outflow otak kontraksi retensi
urine.
Glandula : SSP (terminal presinaptik)
sekresi norephinehrine release Uterus (kehamilan)
kontraksi
Mata : sel kelenjar pankreas :
kontraksi otot radial sekressi Penis :
ejaculation
GIT (intestinum) :
motilitas

29
 LOKASI & STIMULASI PADA
RECEPTOR ADRENERGIK (2)
RECEPTOR (beta)
1 receptor beta 1. 2 receptor beta 2. ? receptor beta ?

Jantung : Trachea & bronchioles : Mata :

heart rate (SA node) relaksasi / relaksasi m.ciliaris
kontraktilitas bronchodilator (efek minimal)
conduction velocity
automaticity Uterus : Vesica urinaria :
relaksasi relaksasi m.detrussor)
Ginjal : (efek minimal)
sekresi renin Arteriole (kecuali dikulit &
SSP) dan vena :
dilatasi

30
 SISTEM PARASIMPATIS
PARASYMPHATIC / CHOLINERGIC

NEUROTRANSMITTER : acetylcholine
RECEPTORS : Muscarinic type 1 (M1) di lambung, ganglion, CNS
M2 jantung (S-A node), atria, A-V node, paru-paru,
lambung,
kandung kemih, dan penis
M3 kelenjar-kelenjar, otot polos, mata
M4 & M5 SSP
Nicotinic otot skelet, ganglion, CNS (Central Nervus
Sysytem)
Metabolisme :
acetylcholinesterase asam
asetat
acetylcholine
eg1.: Carbamyl ester inhibition
choline
2. Competitive acetylcholinesterase
3. Organophosphorus inhibitor
ACETYLCHOLINESTERASE INHIBITOR (AChI)
31
Serabut syaraf PARASYMPHATIS

ACh (Acetylcholine) ditransmisikan serabut syaraf PARASYMPHATIS

pada setiap end organ (jantung, paru, usus, dll) dan
terikat pada reseptor MUSCARINIC.

Peran lain dari ACh : 1. neurotransmitter pada semua serabut PRESYNAPTIC,

atau ganglionic transmission diotak maupun medula spinalis,
ke reseptor nicotinic (NG) pada neuron POSTSYNAPTIC.

Obat-obat yang memblok ganglionic transmission akan

memblok syaraf symphatis maupun parasymphatis.

2. neuromuscular transmission, pelepasan ACh pada

serabut syaraf somatic kontraksi otot seran lintang. Disini
ACh terikat pada reseptor nicotinic pada otot (reseptor Nm)

3. central neurotransmission, ACh juga merupakan

neurotransmitter di otak terutama melalui reseptor muscarinic.

32
 BIOSINTESA & RESEPTOR
Terminal SISTEM PARASIMPATIS
syaraf

reseptor
Muscarinic : M1
Ach M2
M3
Ach M4
Ach M5
Ach Ach
Acetyl CoA + cholin .
Ach Reseptor
Ach Ach cholinergic
AXON Ach
Ac Ach
h NM
Ach
Ach cholinesterase reseptor
Ach
Nicotinic :
cholin + as.asetat
store in NN
vesicle

Presynaptic
membrane
Postsynaptic
(Padmaja U., 2011) membrane 33
 SISTEM PARASIMPATIS
ANTAGONIST
anticholinergic
AGONIST
cholinergic MUSCARINIC NICOTINIC

-acetylcholine Non-selective :
-methacholine
-atropin
-carbachol NM :
-scopolamine
-betanechol -tubocurarine
M1 Blocker :
-pilocarpine
- pirenzepine
-muscarine
- telenzepine NN:
-hexamethonium
Other derivates:
Anticholinesterases: -homatropine
-physostigmine -eucatropine
-neostigmine -cyclopentolate
-edrophonium -propanthaline
-organophosphates -ipratropium
-glycopyrrolate
34
KLASIFIKASI CHOLINERGIK :
I. DIRECT ACTION :
1. Esters of cholin : Acetylcholine;
Metacholine;
Carbachol;
Betanechol.
2. Cholinomimetic alkaloids :
Pilocarpine
Muscarine, Arecinsulin
Nicotine

II. INDIRECT ACTION : (acetylcholinesterase inhibitors)

1. Reversible : neostigmin; physoastigmine;
pyridostigmine; ambenonium;
edrophonium; galantamine.
2. Irreversible :
A. Organophosphorus coumpound : Echothiophate; Malathion;
Parathion; Sumithion; Dyflos; Diazinon (TIK 20);
TOXIC NERVE GASes : Sarin; Tabun.
B. Carbamate insecticides :
Carbamyl (SEVIN); Propoxure (BAYGON);
( Padmaja U., 2011) Aldicarb (TEMIK)
35
 PARASYMPHATIS / CHOLINERGIC
AGONIST CHOLINERGIK /
PARASYPMPHATOMIMETIC/
CHOLINOMIMETICS :

1. AGONIST CHOLINERGIC LANGSUNG:

- acetylcholine

DERIVAT CHOLIN :
- carbachol
- methacholine 2. INHIBITOR ENZ. ACETYLCHOLINESTERASE :
- bethanechol - physostigmin carbamyl
- demecarium organophosphorus
ALKALOID : - echothiophate organophosphorus
- pilocarpin - diisopropyl-fluorophosphate organophosphorus
- muscarine - neostigmine (prostigmine) carbamyl
- nicotine - edrophonium competitive (pada anionic)
- ambenorium carbamyl
- pyridostigmin carbamyl
- parathion organophosphorus
- malathion organophosphorus
36
 ANTAGONISTS CHOLINERGIC :

1. ANTAGONIST MUSCARINIC
2. GANGLION BLOCKERS
3. NEUROMUSCULAR BLOCKER
2. GANGLION BLOCKERS :
1. ANTAGONISTS MUSCARINIC. - hexamethonium
ALKALOID : - mecamylamine
-atropine - trimethephan
-scopolamine
SINTETIK tertiary & quarternary 3. NEUROMUSCULAR BLOCKERS.
compunds : NONDEPOLARIZING BLOCK :
- dicyclomine - vecuronium
- oxybutinin - atracurium
- trihexyphenidyl - pancuronium
- benztropine - d-tubocurarine
- propantheline (probanthene) - mivacurium
BENZODIAZEPINE: - pipecuronium
- pirenzepine (gastrozepine) - gallamine and decamethonium
DEPOLARIZING BLOCK:
- succinylcholine 37
 EFEK LANGSUNG DARI SERABUT PARASIMPATHIS
PADA BEBERAPA ORGAN (1).

ORGAN AKSI RESEPTOR

MATA :
Otot radial IRIS -- --
Otot sirkuler IRIS konytaksi M1
Otot ciliaris kontraksi M1
JANTUNG :
Nodus SA (SinoAtrial) menurun M2
Pacemaker Ektopik -- --
Kontraktilitas menurun (atrium) M2
VASKULER :
Kulit; pemb. Splanchnicus -- --
Otot skelet -- --
Endothel vasa : jantung; sintesa dan melepas M3; M5
otak dan viscera EDRF (Endothelium-
Derived Relaxing Factor)
BRONCHUS :
Oto polos bronchiolar kontraksi M3
 EFEK LANGSUNG DARI SERABUT PARASIMPATHIS
PADA BEBERAPA ORGAN (2).

ORGAN AKSI RESEPTOR

SAL. GASTROINTESTINAL :
Otot polos :
dinding GIT kontraksi M3
Sphincters relaksasi M3
sekresi kelenjar meningkat M3

OTOT POLOS SAL. UROGENITAL :

Dinding V.urinaria kontraksi M3
Sphincters relaxasi M3
Uterus (pada kehamilan) kontraksi M3
Penis, vesicula seminalis ereksi M

KULIT:
Otot polos pilomotor -- --
Sweat glands -- --
(eccrine ; Apocrine)
 EFEK LANGSUNG DARI SERABUT PARASIMPATHIS
PADA BEBERAPA ORGAN (3).

ORGAN AKSI RESEPTOR

FUNGSI METABOLIK :
Hepar -- --
Jaringan Lemak --
Ginjal -- --
 i a n
Sek
dan m w. w
l a i ku
m u a
s s a la
Wa