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7/27/2019 Obat Insulin Dan Oad
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INSULIN DAN ANTI DIABETIK ORAL
Dr. dr. NURDIANA, M.Kes
LAB. FARMAKOLOGI
FK UNIBRAW MALANG
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PANKREAS 1 juta pulau langerhans
memproduksi hormon (lihat tabel)
SEL B PANKREAS SINTESIS oleh DNA ATAU RNA
INSULIN BM : 5808
2 RANTAI : RANTAI A
RANTAI B lihat gambar
RANTAI DISULFIDA
PROINSULIN RANTAI TUNGGAL, PANJANG
DIPROSES DALAM GOLGI APPARATUS MENJADI INSULIN (HIDROLISA),SEGMEN SISANYA C-PEPTIDA
INSULIN DISEKRESI SETARA DENGAN STIMULAN/ SECRETAGOGUES
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STRUKTUR PROINSULIN MANUSIA
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SEKRESI INSULIN
Insulin dilepas dari sel B pankreas :Low basal rate : tanpa stimuli dari luar
Much higher stimulated rate : ada stimuli dari luar terutama glukosa
stimuli lain mannose, asam amino :
leucine,arginin, rangs vagus
EFEK FISIOLOGI INSULIN MENURUNKAN KADAR GULA
DARAH
Interaksi glukosa-insulin neg feed back mengatur agarkadar gula darah segera kembali normal
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FARMAKODINAMIK INSULIN
INSULINAGONIS
INSULINSIRKULASI BERIKATAN DENGAN RESEPTOR PADA MEMBRAN SEL, MENGHASILKAN RESPON BIOLOGIS YANG SESUAI SIFAT KOMPLEKS IKATAN.
TARGET TISSUE TERUTAMA : HATI, OTOT, JARINGAN LEMAK
INSULIN BERIKATAN DG RESEPTOR DG SPESIFISITAS DAN AFINITAS TINGGI
(picomolar).
FARMAKOKINETIK INSULIN
INSULIN TIDAK DIBERIKAN PERORAL KARENA DIRUSAK OLEH PEPTIDASE DI
G.I.T. , SEHINGGA DIBERIKAN SC, IM, IV, NASAL SPRAY DAN IMPLANTABLE
PUMPINSULIN ABSORBSI DARAH CAIRAN EKSTRASEL DISTRB
HALF LIFE : ORG SEHAT, CEPAT, DL BEBERAPA MENIT
DM, LBH LBT, KARENA BERIKATAN DG ANTIBODI
METAB : LIVER, OTOT DAN GINJAL
EKSKRESI : METABOLIT, FRAKSI KECIL YG TBERUBAH GINJAL
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Efek fisiologis Insulin metab. glukosa
transport aktif glukosa utk masuk ke dl sel
* meningkatkan penggunaan glukosa oleh jar. tbh
* meningkatkan glikogenesis di otot dan hati
* oksidasi KH utk enersi di otot bergaris
Meningkatkan sintesis lemak di di jar lemak
glukoneogenesis , glikogenolisis
peningkatan sintesis protein dan as. nukleat pertumbh
oksidasi lemak utk enersi ketosis
insulin proses anabolik
glukosa produksi enersi
disim an stora e
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Insulin
hati
otot
Jar.lemak
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Fluktuasi kadar glukosa dalam serum dipengaruhi faktor-faktor :
1. Glkogenolisis/glukoneogenesis
2. Penggunaan glukosa oleh sel perifer
3. Jumlah reseptor insulin pada sel
4. Kadar antibodi insulin
5. Hormon yg mempengaruhi metab. Glukosa : insulin, glucagon, cortison,
epinefrin dan GH
Insulin, vit C, chromium me metab glukosa. Exercise me penggn glukosa
KONDISI PATOLOGIS
Ggn sekresi insulin : meningkat : reactive hypoglycemia, insulinoma
menurun : defisiensi insulin DM
DM bisa disebabkan antibodi yg menghalangi kerja insulin atau kurangnya
reseptor insulin, kemampuan jar menggunakan glukosa (obesitas)
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Sifat preparat insulin
A. Tipe dan lama kerja
1. Ultra short acting,very rapid onset,
short duration
2. Short acting, rapid
onset of action
3. Intermediate-acting
4. Longacting, slow
onset of action
tabel
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Degradasi insulin
- dilakukan oleh hati dan ginjal, membersihkan insulin dari sirkulasi
-Cara hidrolisis ikatan disulfid antara rantai A dan B melalui kerja insulinase(glutathione insulin transhidrogenase) proteolysis
Insulin endogen hati : 60 %
ginjal 35-40 %
Insulin eksogen, sebaliknyaCirculating insulin half life 3-5
Pengukuran insulin
RIA picomolar, berdasarkan reaksi dg antibodi
bisa mengukur insulin sapi, babi dan manusia
basal insulin value, 5 15 U/ml (30-90 mol/L)pada manusia, kadar puncak
60-90 U/ml (360-540 mol/L), pada saat makan.
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TERAPI INSULIN
DIABETES TIPE 1 INSULIN DEPENDENT GROUP
DIABETES TIPE 2TDK BTH INSULIN UTKSURVIVAL, TP
UTKOPTIMAL HEALTH
GLYCEMIC CONTROL PADA DM
DM TIPE 1 COMPREHENSIVE SELF-MANAGEMENT TRAINING,
DIMULAI SESUDAH PUBERTAS
UMUR 7 TH , TDK BOLEH KONTROL KETAT, KARENA
HIPOGLIKEMI DPTBRAIN DAMAGE
KOMPLIKASI TERAPI INSULIN
A. HIPOGLIKEMI PENYEBAB : TERLAMBAT MAKAN
AKTIVITAS FISIK TDK SESUAI
DOSIS INSULIN > UTK KEPERLUAN
MENDADAK
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ORANG TUA DG DMMENDPT LONG ACTING INSULIN
-AUTONOMIC WARNING : SIMP : Takikardi, palpitasi,sweating, tremor
SIGNAL P.SIMP : Nausea, lapar
-KEGGL FS CNS : Mental confusion, bizzare behaviour, coma
TERAPI HIPOGLIKEMIA
Berikan glukosa * mild hipoglycemia, sadar, dpt menelan : makanan manis
* more severe, stupor 20-50 ml gluc 50 % i.v
glucagon 1 mg s.c atau i.m.
B. IMMUNOPATHOLOGY OF INSULIN THERAPY
Insulin antibodi IgA, IgD, IgE, IgG dan IgM
2 gangguan immunitas pd DM dg terapi insulin :
1 Alergi insulin : urtikaria , syok anafilaktik,nodul ditempat suntikan
makin murni insulin, alergi
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2. Immune insulin resistance :
a. Tx insulin : low titer IgG anti insulin antibodies
b. a+ terapi insulin kurang murni +jar kurang sensitif insulinIgG
antiinsulin antibodies
kebutuhan insulin > 200 U/hari
C. LIPODISTROPI PADA TEMPAT INJEKSISudah berkurang karena insulin babi dan manusia yang murni, pH netral.
Sekarang terjadi hipertropi lemak s.c bl disuntik berulang ditempat yg sama
liposuction
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Type 2 diabetes: the role of insulin resistance
and -cell failureInsulin resistance
Hyperinsulinaemia
Increasing insulin
resistance
Type 2 diabetes
Impaired glucose tolerance
Adapted from: Reaven GM. Diabetes 1988;37:15951607 and Beck-Nielsen H, Groop LC. J Clin Invest1994;94:17141721
-cell failure+
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OAD (oral anti diabetic)
OBAT DoA (jam)SULFONILUREA -Chlorpropamid
-Tolbutamid
-Glimepirid
-Glipizid-Gliburid
MIGLITINID -Repaglinid
S/d 60
6-12
12-24
10-2410-24
1-3
BIGUANID -Metformin 10-12THIAZOLIDINNEDION -Pioglitazone
-Rosiglitazone
15-24
>24
-GLUCOSIDASE INHIBITOR-Acarbose 3-4
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INSULIN SECRETAGOGUES
1. SULFONYLUREA :
GENERASI 1 : CHLORPROPAMIDE, TOLBUTAMIDE,
TOLAZAMIDE
GENERASI 2 : GLYBURIDE, GLIPIZIDE, GLIMEPIRIDE
kelebihan generasi 2 : efek samping dan interaksi obat lbh sedikit
hati-hati pada pasien dg penderita peny.jantung dan orang tuahipoglikemia
2. MEGLITINIDE : REPAGLINIDE
onset of action cepat, peak conc.1 jam, duration of act 5-8 jam
kontrol gula darah postprandial
3. D-PHENYLALANINE DERIVATIVE : NATEGLINIDE
digunakan sebelum makan, masa kerja pendek (
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Sulphonylureas
1st generation : chlorpropamid
2nd generation : gliclazide, glipizide gliburid,glibenklamid
3nd generation : glimepiride
Others : Meglitinide : Repaglinide utk DM tipe 2 ygalergi sulfonylurea
Nateglinide
Stimulate beta cells to release insulin (assumes there isresidual beta cell activity)
Side effects: hypoglycaemia, weight gain, GIdisturbances, headache
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EFEK SAMPING
Sulfonilurea-nausea, vomiting-jaundice-agranulositosis, anemia aplastik-teratogenik
-toksik : Hipoglikemi
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DeFronzo RA. Diabetes. 1988;37:667-687.Lebovitz HE. In Joslin's Diabetes Mellitus. 1994:508-529
Blood glucose
Insulin resistance
1 Intestine: glucose absorption 2 Muscle and adipose tissue:glucose uptake
4 Liver: hepatic
glucose output
3 Pancreas: insulin secretion
Sulfonylureas
insulin secretion
Insulin
resistance
Sulfonylureas: Mechanism of Action
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Insulin
resistance
Blood glucose
Insulin resistance
1 Intestine: glucose absorption
3 Pancreas: insulin secretion
Meglitinides Insulin secretion
4 Liver: hepatic
glucose output
2 Muscle and adipose tissue:
glucose uptake
Wolffenbuttel BHR. Eur J Clin Pharmacol. 1993;45:113-116.
C
Meglitinides: Mechanism of Action
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Biguanides
Metformin
Drug of choice in obese patients only
Monotherapy or adjunct
Decreases gluconeogenesis
Increases peripheral uptake of glucose in tocells
Basal & post prandial glucose levels Weight neutral
Increased insulin sensitivity
Beneficial effect on plasma lipid profile
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DeFronzo RA et al. J Clin Endocrinol Metab. 1991;73:1294-1301.
Insulin
resistance
Blood glucose
Insulin resistance
1 Intestine: glucose absorption
3 Pancreas: insulin secretion
4 Liver: hepatic
glucose output
Metformin HGO
2 Muscle and adipose tissue:
glucose uptake
Metformin glucose utilization
Metformin: Mechanism of Action
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Metformincontd
Side effects
Nausea, vomiting, diarrhoea, abdominaldiscomfort
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1 Intestine: glucose absorptionAcarbose glucose absorption secondary
to digestion of carbohydrate
Insulin
resistance
4 Liver: hepatic
glucose output
Amatruda JM. In: Diabetes Mellitus. 1996.
Blood glucose
Insulin resistance
3 Pancreas: insulin secretion
2 Muscle and adipose
tissue: glucose uptake
-Glucosidase Inhibitors :Mechanism of Action
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Alpha glucosidase inhibitors
Acarbose
monotherapy or adjunct
Inhibits intestinal enzyme, specific activity onsucrase, delaying digestion of starch andsucrose into absorbable monosaccharides such
as glucose Safe
Weight neutral
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Acarbosecontd
Side effects:
GI intoleranceflatulence, diarrhoea, abdominal distension
& pain
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Blood glucose
Intestine: glucose absorption
Pancreas: insulin secretion
Muscle and adipose tissue:Thiazolidinediones
insulin resistance
glucose uptake
Liver: hepatic
glucose output
Thiazolidinediones
HGO
Thiazolidinediones: Mechanism of Action
Improve -cellfunction
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The PPAR Family
(Peroxisome proliferator-activated receptor)
Ligand
Effect on:
Receptor
Fibrates Thiazolidinediones Fatty acids
Carbohydrate
metabolism
Lipoprotein
expression
Lipid
synthesis
Peroxisome
proliferation
PPAR- PPAR-g PPAR-d
Saltiel AR, Olefsky JM. Diabetes. 1996;45:1661-1669.
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Thiazolidinediones
Counteract insulin resistance
Bind to PPAR-gamma (receptor), forming a
complex promoting transcription of genessensitive to insulin.
Receptors are present in skeletal muscle,
adipose tissue &liver, thereby promotinguptake of fatty acids &glucose at these sites
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Thiazolidinedionescontd
Pioglitazone, rosiglitazone
Adjunct with either metformin or SU
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Thiazolidinediones
? Alternative to insulin
Side effects:
oedema, weight gain, GI disturbances,
headache, dizziness
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Sites of Action by Therapeutic Options
Adapted from Sonnenberg and Kotchen Curr Opin Nephrol Hypertens 1998;7(5):551-555.
INCREASEGLUCOSE
ABSORPTION
MUSCLE
PANCREAS
ADIPOSETISSUE
LIVER
INTESTINE
HYPERGLYCEMIA DECREASEDPERIPHERAL
GLUCOSE
UPTAKE
INCREASED
GLUCOSEPRODUCTION
DECREASED
INSULIN
SECRETION
Therapy:
Thiazolidinediones
(Biguanides)
Therapy:
Sulfonylureas
Meglitinides
Insulin
Therapy:
Biguanides
Thiazolidinediones
Therapy:
Alpha-glucosidase
inhibitors
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EFEK SAMPING
Sulfonilurea-nausea, vomiting-jaundice-agranulositosis, anemia aplastik-teratogenik-toksik : Hipoglikemi
Biguanid : -asidosis laktat-nausea, diare-menghambat absorpsi vit.B12
Thiazolidindione
-jarang hipoglikemi-udema, anemia ringan
Glukosidase inhibitor:-flatulen, diare, nyeri abdomen
TAHAPAN TERAPI DIABETES MELITUS
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TAHAPAN TERAPI DIABETES MELITUS
Diagnosis
Health education
Diet, exercise, weight control
Oral agent monotherapySU, metformin, meglitinide, thiazolidinedione, acarbose
Oral agent combination therapy (2 different classes)
Insulin + oral agent
Insulin
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Stepwise management of type 2 diabetes
Insulin oral agents
Oral combination
Oral monotherapy
Diet & exercise
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