OBAT ANTIDIABETIK
Fathiyah Safithri
Laboratorium Farmakologi FK-UMM
2009
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Diabetes Mellitus:
Diabetes Mellitus
Type 2 Diabetes
Type 1 Diabetes
sel beta rusak
Produksi insulin & pe
(autoimmun disease),
kerja insulin (resistansi
sekresi insulin (-)
insulin = kadar serum
terdeteksi sblm 30th
insulin N / , tp tdk bisa
Tx : insulin (insulin
bekerja maksimal
dependen)
terdeteksi stl 40th
Kx utama : Diabetic
sering dihubungkan dg
ketoacidosis (karena obesitas.
overproduksi ketoacids)
lama2 gagal sel beta,
sekresi insulin <<
Tx : OAD
US develop
gestational
diabetes
Gestational Diabetes
Preprandial
glucose
(average)
Normal (mg/dL)
Goal (mg/dL)
Suggested
< 100
80 120
< 80 or >140
100 - 140
<100 or >160
<7
>8
(whole blood)
Action
Bedtime
glucose
(whole blood)
HbA1c (%)
< 6*
< 110
(average)
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Komplikasi DM
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PANKREAS
- glukagon glikogenolisis
- insulin
SEL OTOT
- insulin uptake glukosa ke sel otot
- kerja fisik kontraksi otot glukosa lbh byk msk ke dlm sel
(tanpa bantuan insulin)
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glukoneogenesis
ADENOHIPOFISE
growth hormon (GH)
hormon yg mempunyai efek berlawanan dg insulin
me gula darah
LEMAK
WX2
Slide 8
WX2
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Bekerja
di sel produksi
lemak enzim
Menghambat
tertentu.
amino acids
uptake
glucose
uptake
protein
synthesis
glycogen
synthesis
synthesis
enzyme
production
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fat
glycogen
breaking
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Sekresi Insulin
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FAKTOR-FAKTOR YG MEMPENGARUHI
SEKRESI INSULIN
GLUT-2
M2
+ -
Glucose metabolism
- (glucokinase)
+
+ -
ACh
ATP
+X
K+
IP3
ASKC
Ca
ATP
VDCC
2
NE
X
insulin
granule
Ca2+
++
somatostatin
ER
Ca2+
cAMP?
release
2
NE
Senyawa lain :
- amino acids (Lys, Leu), FFA, ketones
- hormon sal. Cerna : sekretin, GIP, gastrin, CCK
(kolesistokinin), VIP, enteroglucagon
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Tujuan Terapi DM
Mengontrol hiperglikemi dan ketoasidosis
serta menghindari hipoglikemi
hiperglikemi dapat menyebabkan berbagai
komplikasi
Hipoglikemi dapat menyebabkan koma dan
kerusakan sel otak.
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Pendekatan Terapi DM
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PRINSIP PENATALAKSANAAN DM
Pengaturan diet
Latihan jasmani
Farmakoterapi
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FARMAKOTERAPI
DIABETES MELLITUS
Insulin
- Pasien Diabetes Tipe 1, tidak ada
produksi insulin.
- Pasien diabetes Type 2, produksi insulin
tdk mencukupi.
Obat Antidiabetik Oral
- Gol. Sulfonilurea, Biguanid, Glitazone,dll
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TERAPI INSULIN
K1
Slide 24
K1
Kedokteran, 11/24/2006
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hipoglikemi
Gangguan oral
fungsi ginjal atau hati yang berat.
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Farmakokinetik Insulin
Pemberian per-oral tidak effektif
diberikan secara parenteral :
- sc atau im
- iv pd keadaan emmergency atau
selama operasi
T plasma <9 menit
Inaktivasi oleh hepar dan ginjal
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Klasifikasi Insulin
1. Insulin kerja singkat :
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Insulin resistance
Mengaktifkan antibodi, abnormal glucocorticoids, jaringan
menjadi tdk responsif akibat kelebihan insulin
TANDA HIPOGLIKEMI
Tergantung cepat / tidaknya penurunan
kadar glukosa dlm plasma
Cepat :
keringat dingin, takikardi, tremor, mual,
lapar
Lambat :
sakit kepala, blurred vision, bingung,
inkoheren speech, kejang, koma
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Oral Antidiabetics
Ada 5 kelompok :
A. Sulfonylureas
B. Meglitinide
C. Biguanid
E.
Alpha-glucosidase inhibitor
D. Glitazone
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Mekanisme kerja
Oral Antidiabetics (OAD)
Me absorbsi glukosa : acarbose, biguanid
Me
sekresi
:
sulfonilurea
1stinsulin
, 2nd ,3rd(secretagogues)
, meglitinide
Me produksi glukosa hepar : biguanid
sulfonilurea
Me uptake
di perifer
:
2nd,glukosa
3rd , biguanid,
thiazolidindion
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Sulfonylurea
1st generation
tolbutamide ( Rastinon, Orinase)
tolazamide (Tolinase )
chlorpropamide (Diabinese)
Rel. Potency
2nd generation
Gliclazid
Glipizide (Minidiab, Glucotrol)
Glyburide / Glibenclamid (Daonil, Glulo, Prodiabet)
Gliklasid (Diamicron, Glidiabet, Zumadiac)
3rd generation
Glimepiride (Amaryl )
*Hydroxylation of the aromatic ring appears to be the most favored metabolic pathway
*Hydroxylated derivatives have much lower hypoglycemic activity
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Insulin resistance
Blood glucose
4 Liver: hepatic
glucose output
3
DeFronzo RA. Diabetes. 1988;37:667-687.
Lebovitz HE. In Joslin's Diabetes Mellitus. 1994:508-529
Insulin
resistance
SULFONILUREA
Mekanisme Kerja :
Menstimuli release insulin endogen dari sel beta
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+ 400
0.5-2
1
500
6 - 10
3
30
80
24
5-10
16 - 24
1
1.25-5
24
3
1- 4
24
2.4
Repaglinide
Relative Risk
1-2
Tolbutamide
Gliclazide
1 - 2(2)
Glipizide
2(1)
3 - 4(3)
Glimepiride
5(1)
Penggunaan Sulfonilurea
p
lg baik utk pasien Usia > 40 th, menderita DM < 10th,
jk memakai insulin < 40 unit
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Interaksi Obat
Obat yg dpt meresiko hipoglikemi :
insulin, alkohol (meglukoneogenesis), fenformin,
sulfonamid, salisilat dosis besar (mesekresi insulin),
fenilbutazon, oksifenbutazon, probenezid, dikumarol,
kloramfenikol, MAO inhibitor, guanetidin, anabolik
steroid, fenfluramin, dan klofibrat
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Meglitinides
mis. Repaglinid (Novonorm) , Nateglinid
(Starlix)
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Insulin resistance
Blood glucose
4 Liver: hepatic
glucose output
Insulin
BIGUANID
Mis. Metformin,
Mekanisme kerja :
Farmakokinetik :
- Peroral aktif
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Insulin resistance
Blood glucose
4 Liver: hepatic
glucose output
Metformin HGO
Insulin
resistance
Actions of Metformin
HG output
Circulating
insulin
Body weight
B.P.
progression of IGT
to type 2 diabetes
Hyperglycemia
LDL & TG
PAI-1
Insulin
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Improve
ovulatory
function
Kontraindikasi
Glitazones (thiazolidinediones)
Mis. Troglitazone, Rosiglitazone,
Pioglitazone (Actos)
Bekerja dg cara me resistensi insulin mell
regulasi gen yg terlibat dlm metab glukosa
& lemak serta diferensiasi sel lemak
Mek. Kerja : berikatan dg peroxisome
Troglitazone
merupakan glitazone
pertama utk
proliferator-activated
receptor-(PPAR)
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Liver: hepatic
Muscle
and adipose tissue:
glucose
output
Thiazolidinediones
HGO
Improve -cell
function
Thiazolidinediones
insulin resistance
glucose uptake
Blood glucose
glitazones akan :
me gluconeogenesis, glucose output, dan produksi
TG di hepar
me glucose uptake dan penggunaannya di otot
skeletal
me glucose uptake dan me fatty acid output di
jaringan lemak.
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TZD
adiponectin
FFA
Resistin
TNF
insulin resistance
TZD
PPAR agonist
In the liver
In adipose tissue
esp. visceral fat
Cortisol
Cortisol
Visceral obesity
resistance
Hepatic
steatosis
Hepatic insulin
TG
HDL production
small dense LDL
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angiotensin
Aldosterone
Farmakokinetik Glitazone
Pioglitazones: diberikan per oral dg atau tanpa
makanan
kdr dlm plasma mencapai puncak stl 3 jam
t1/2 : 3-7 j; metabolit aktif shg t1/2= 16-24 j
metabolisme di hepar oleh CYP2C8 dan CYP3A4
Rosiglitazone
dg baik,
atau tanpa
Eksresi lewatdiabsorbsi
feces (2/3) dan
urine dg
(1/3)
makanan
kdr dlm plasma mencapai puncak stl 1 jam
t1/2 : 3-4 j; metabolit aktif, t1/2 :103-158 j
Metabolisme oleh CYP2C8
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Alpha--glucosidases inhibitors
mis. Acarbose dan Miglitol
Diberikan peroral
Bekerja di usus dg cara memperlambat dan
memperpanjang masa absorbsi glukosa di GI
Sedikit menurunkan glukosa darah
Pd monoterapi, tdk menyebabkan hipoglikemi
competitive
inhibitors diberikan sebelum
makan
ES : gangguan GIT; hepatotoksik (jarang)
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Blood glucose
4 Liver: hepatic
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6 Classes :
Sulfonylureas stimulate cells
Biguanides improves insulins ability to move glucose
Sulfonylureas and biguanide combination
drugs BOTH
Thiazolidinediones cells more sensitive to insulin
Alpha-glycosidase inhibitors Block enzymes that help
digest starches
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Biguanides
Thiazolidinediones
DECREASED
INSULIN
SECRETION
INCREASED
PANCREAS
GLUCOSE
LIVER
PRODUCTION
Therapy:
INTESTINE
Therapy:
Alpha-glucosidase
inhibitors
Therapy:
Sulfonylureas
Meglitinides
Insulin
DECREASED
PERIPHERAL
GLUCOSE
HYPERGLYCEMIA
UPTAKE
ADIPOSE
TISSUE
INCREASE
GLUCOSE
ABSORPTION
MUSCLE
Therapy:
Thiazolidinediones
(Biguanides)
Adapted from Sonnenberg and Kotchen Curr Opin Nephrol Hypertens 1998;7(5):551-555.
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Kombinasi OAD
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The End
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