Download - 7 - Insulin Dan Oad
INSULIN DAN ANTI DIABETIK ORAL
Dr. dr. NURDIANA, M.Kes
LAB. FARMAKOLOGI
FK UNIBRAW MALANG
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
STRUKTUR PROINSULIN MANUSIA
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 agar kadar gula darah segera kembali normal
FARMAKODINAMIK INSULIN
INSULIN AGONIS
INSULIN SIRKULASI 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 ANTIBODIMETAB : LIVER, OTOT DAN GINJALEKSKRESI : METABOLIT, FRAKSI KECIL YG T’BERUBAH GINJAL
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
disimpan (storage)
Insulin
hati
otot
Jar.lemak
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)
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. Long – acting, slow onset of action
tabel
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, sebaliknya
Circulating 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.
TERAPI INSULINDIABETES TIPE 1 INSULIN DEPENDENT GROUPDIABETES TIPE 2TDK BTH INSULIN UTK SURVIVAL, TP
UTK OPTIMAL 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
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
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 INJEKSI
Sudah berkurang karena insulin babi dan manusia yang murni, pH netral.
Sekarang terjadi hipertropi lemak s.c bl disuntik berulang ditempat yg sama
liposuction
Type 2 diabetes: the role of insulin resistance and -cell failure
Insulin resistance
Hyperinsulinaemia
Increasing insulin resistance
Type 2 diabetes
Impaired glucose tolerance
Adapted from: Reaven GM. Diabetes 1988;37:1595–1607 and Beck-Nielsen H, Groop LC. J Clin Invest 1994;94:1714–1721
-cell failure+
OAD (oral anti diabetic)
OBAT DoA (jam)
SULFONILUREA -Chlorpropamid -Tolbutamid -Glimepirid -Glipizid -Gliburid
MIGLITINID -Repaglinid
S/d 606-1212-2410-2410-24
1-3
BIGUANID -Metformin 10-12
THIAZOLIDINNEDION -Pioglitazone -Rosiglitazone
15-24>24
-GLUCOSIDASE INHIBITOR -Acarbose 3-4
Sulphonylureas
• 1st generation : chlorpropamid• 2nd generation : gliclazide, glipizide, glibenklamid• 3nd generation : glimepiride• Others : Repaglinide Nateglinide
• Stimulate beta cells to release insulin (assumes there is residual beta cell activity)
• Side effects: hypoglycaemia, weight gain, GI disturbances, headache
EFEK SAMPINGSulfonilurea -nausea, vomiting -jaundice -agranulositosis, anemia aplastik -teratogenik -toksik : Hipoglikemi
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: hepaticglucose output
3 Pancreas: insulin secretionSulfonylureas
insulin secretion
Insulinresistance
Sulfonylureas: Mechanism of Action
Insulinresistance
Blood glucose
Insulin resistance
1 Intestine: glucose absorption
3 Pancreas: insulin secretionMeglitinidesInsulin 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
Biguanides
• Metformin• Drug of choice in obese patients only• Monotherapy or adjunct• Decreases gluconeogenesis• Increases peripheral uptake of glucose in to
cells Basal & post prandial glucose levels• Weight neutral• Increased insulin sensitivity• Beneficial effect on plasma lipid profile
DeFronzo RA et al. J Clin Endocrinol Metab. 1991;73:1294-1301.
Insulinresistance
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 uptakeMetformin glucose utilization
Metformin: Mechanism of Action
Metformin cont’d
• Side effects• Nausea, vomiting, diarrhoea, abdominal
discomfort
1 Intestine: glucose absorptionAcarbose glucose absorption secondaryto digestion of carbohydrate
Insulinresistance
4 Liver: hepaticglucose 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
Alpha glucosidase inhibitors
• Acarbose • monotherapy or adjunct
• Inhibits intestinal enzyme, specific activity on sucrase, delaying digestion of starch and sucrose into absorbable monosaccharides such as glucose
• Safe• Weight neutral
Acarbose cont’d
• Side effects: – GI intolerance– flatulence, diarrhoea, abdominal distension
& pain
Whitcomb RW et al. In: Diabetes Mellitus. 1996.Cavaghan MK et al. J Clin Invest. 1997;100:530-537.
Ehrmann DA et al. J Clin Endocrinol Metab. 1997;82:2108-2116.
Blood glucose
Intestine: glucose absorption
Pancreas: insulin secretion
Muscle and adipose tissue: Thiazolidinediones insulin resistance
glucose uptake
Liver: hepaticglucose outputThiazolidinediones HGO
Thiazolidinediones: Mechanism of Action
Improve -cellfunction
The PPAR Family(Peroxisome proliferator-activated receptor)
Ligand
Effect on:
Receptor
Fibrates Thiazolidinediones Fatty acids
Carbohydratemetabolism
Lipoproteinexpression
Lipidsynthesis
Peroxisomeproliferation
PPAR- PPAR- PPAR-
Saltiel AR, Olefsky JM. Diabetes. 1996;45:1661-1669.
Thiazolidinediones
• Counteract insulin resistance
• Bind to PPAR-gamma (receptor), forming a complex promoting transcription of genes sensitive to insulin.
• Receptors are present in skeletal muscle, adipose tissue &liver, thereby promoting uptake of fatty acids &glucose at these sites
Thiazolidinediones cont’d
• Pioglitazone, rosiglitazone• Adjunct with either metformin or SU
Thiazolidinediones
• ? Alternative to insulin
• Side effects:
• oedema, weight gain, GI disturbances, headache, dizziness
Sites of Action by Therapeutic Options
Adapted from Sonnenberg and Kotchen Curr Opin Nephrol Hypertens 1998;7(5):551-555.
INCREASEGLUCOSE
ABSORPTION
MUSCLE
PANCREAS
ADIPOSE TISSUE
LIVER
INTESTINE
HYPERGLYCEMIA DECREASED PERIPHERAL
GLUCOSE UPTAKE
INCREASED GLUCOSE
PRODUCTION
DECREASED INSULIN
SECRETION
Therapy:Thiazolidinedion
es(Biguanides)
Therapy:SulfonylureasMeglitinides
Insulin
Therapy:Biguanides
Thiazolidinediones
Therapy:Alpha-glucosidase
inhibitors
EFEK SAMPINGSulfonilurea -nausea, vomiting -jaundice -agranulositosis, anemia aplastik -teratogenik -toksik : HipoglikemiBiguanid : -asidosis laktat -nausea, diare -menghambat absorpsi vit.B12Thiazolidindione -jarang hipoglikemi -udema, anemia ringanGlukosidase inhibitor: -flatulen, diare, nyeri abdomen
TAHAPAN TERAPI DIABETES MELITUS
Diagnosis
Health education
Diet, exercise, weight control
Oral agent monotherapy
SU, metformin, meglitinide, thiazolidinedione, acarbose
Oral agent combination therapy (2 different classes)
Insulin + oral agent
Insulin
Stepwise management of type 2 diabetes
Insulin ± oral agents
Oral combination
Oral monotherapy
Diet & exercise