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INSULIN DAN ANTI DIABETIK ORAL Dr. dr. NURDIANA, M.Kes LAB. FARMAKOLOGI FK UNIBRAW MALANG.

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Presentasi berjudul: "INSULIN DAN ANTI DIABETIK ORAL Dr. dr. NURDIANA, M.Kes LAB. FARMAKOLOGI FK UNIBRAW MALANG."— Transcript presentasi:

1 INSULIN DAN ANTI DIABETIK ORAL Dr. dr. NURDIANA, M.Kes LAB. FARMAKOLOGI FK UNIBRAW MALANG

2 PANKREAS 1 juta pulau langerhans memproduksi hormon (lihat tabel) SEL B PANKREAS SINTESIS oleh DNA ATAU RNA INSULIN BM : 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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4 STRUKTUR PROINSULIN MANUSIA

5 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

6 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 PUMP INSULIN  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 T’BERUBAH  GINJAL

7 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)

8 Insulin hati otot Jar.lemak

9 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)

10 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

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12 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 % 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  U/ml (  mol/L), pada saat makan.

13 TERAPI INSULIN DIABETES TIPE 1  INSULIN DEPENDENT GROUP DIABETES TIPE 2  TDK 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 DPT  BRAIN DAMAGE KOMPLIKASI TERAPI INSULIN A.HIPOGLIKEMI  PENYEBAB : TERLAMBAT MAKAN AKTIVITAS FISIK TDK SESUAI DOSIS INSULIN > UTK KEPERLUAN MENDADAK

14 ORANG TUA DG DM  MENDPT “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  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

15 2. Immune insulin resistance : a. Tx insulin : low titer IgG anti insulin antibodies b. a+ terapi insulin kurang murni +jar kurang sensitif insulin  IgG 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

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17 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 +

18 OAD (oral anti diabetic) OBATDoA (jam) SULFONILUREA -Chlorpropamid -Tolbutamid -Glimepirid -Glipizid -Gliburid MIGLITINID -Repaglinid S/d BIGUANID -Metformin10-12 THIAZOLIDINNEDION -Pioglitazone -Rosiglitazone >24  -GLUCOSIDASE INHIBITOR -Acarbose3-4

19 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 tua  hipoglikemia 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 (<4jam). tdk perlu titrasi dosis, insiden hipoglikemi rendah

20 Sulphonylureas 1 st generation : chlorpropamid 2 nd generation : gliclazide, glipizide gliburid, glibenklamid 3 nd generation : glimepiride Others : Meglitinide : Repaglinide  utk DM tipe 2 yg alergi sulfonylurea Nateglinide  Stimulate beta cells to release insulin (assumes there is residual beta cell activity) Side effects: hypoglycaemia, weight gain, GI disturbances, headache

21 EFEK SAMPING Sulfonilurea -nausea, vomiting -jaundice -agranulositosis, anemia aplastik -teratogenik -toksik : Hipoglikemi

22 DeFronzo RA. Diabetes. 1988;37: Lebovitz HE. In Joslin's Diabetes Mellitus. 1994: Blood glucose Insulin resistance 1Intestine: glucose absorption 2Muscle and adipose tissue: glucose uptake 4Liver: hepatic glucose output 3Pancreas: insulin secretion Sulfonylureas insulin secretion  Insulin resistance Sulfonylureas: Mechanism of Action

23 Insulin resistance Blood glucose Insulin resistance 1Intestine: glucose absorption 3Pancreas: insulin secretion Meglitinides  Insulin secretion 4Liver: hepatic glucose output 2Muscle and adipose tissue: glucose uptake Wolffenbuttel BHR. Eur J Clin Pharmacol. 1993;45: C Meglitinides: Mechanism of Action

24 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

25 DeFronzo RA et al. J Clin Endocrinol Metab. 1991;73: Insulin resistance Blood glucose Insulin resistance 1Intestine: glucose absorption 3Pancreas: insulin secretion 4 Liver: hepatic glucose output Metformin HGO 2 Muscle and adipose tissue: glucose uptake Metformin glucose utilization Metformin: Mechanism of Action

26 Metformin cont’d Side effects Nausea, vomiting, diarrhoea, abdominal discomfort

27 1 Intestine: glucose absorption Acarbose glucose absorption secondary to digestion of carbohydrate Insulin resistance 4Liver: hepatic glucose output Amatruda JM. In: Diabetes Mellitus Blood glucose Insulin resistance 3 Pancreas: insulin secretion 2Muscle and adipose tissue: glucose uptake  -Glucosidase Inhibitors :Mechanism of Action

28 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

29 Acarbose cont’d Side effects: –GI intolerance –flatulence, diarrhoea, abdominal distension & pain

30 Whitcomb RW et al. In: Diabetes Mellitus Cavaghan MK et al. J Clin Invest. 1997;100: Ehrmann DA et al. J Clin Endocrinol Metab. 1997;82: 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  -cell function

31 The PPAR Family (Peroxisome proliferator-activated receptor) Ligand Effect on: Receptor FibratesThiazolidinedionesFatty acids Carbohydrate metabolism Lipoprotein expression Lipid synthesis Peroxisome proliferation PPAR-  PPAR-  PPAR-  Saltiel AR, Olefsky JM. Diabetes. 1996;45:

32 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

33 Thiazolidinediones cont’d Pioglitazone, rosiglitazone Adjunct with either metformin or SU

34 Thiazolidinediones ? Alternative to insulin Side effects: oedema, weight gain, GI disturbances, headache, dizziness

35 Sites of Action by Therapeutic Options Adapted from Sonnenberg and Kotchen Curr Opin Nephrol Hypertens 1998;7(5): INCREASE GLUCOSE ABSORPTION MUSCLE PANCREAS ADIPOSE TISSUE LIVER INTESTINE HYPERGLYCEMIA DECREASED PERIPHERAL GLUCOSE UPTAKE INCREASED GLUCOSE PRODUCTION DECREASED INSULIN SECRETION Therapy: Thiazolidinediones (Biguanides) Therapy: Sulfonylureas Meglitinides Insulin Therapy: Biguanides Thiazolidinediones Therapy: Alpha-glucosidase inhibitors

36 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

37 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

38 Stepwise management of type 2 diabetes Insulin ± oral agents Oral combination Oral monotherapy Diet & exercise

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