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

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

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

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  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 : 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

  3. STRUKTUR PROINSULIN MANUSIA

  4. 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

  5. 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

  6. 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)

  7. Insulin hati otot Jar.lemak

  8. Fluktuasi kadar glukosa dalam serum dipengaruhi faktor-faktor : • Glkogenolisis/glukoneogenesis • Penggunaan glukosa oleh sel perifer • Jumlah reseptor insulin pada sel • Kadar antibodi insulin • 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)

  9. Sifat preparat insulin • A. Tipe dan lama kerja • Ultra short acting, very rapid onset, short duration • Short acting, rapid onset of action • Intermediate-acting • Long – acting, slow onset of action • tabel

  10. 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.

  11. 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 • HIPOGLIKEMI  PENYEBAB : TERLAMBAT MAKAN • AKTIVITAS FISIK TDK SESUAI • DOSIS INSULIN > UTK KEPERLUAN • MENDADAK

  12. 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  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

  13. 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 • 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

  14. Type 2 diabetes: the role of insulin resistance and -cell failure Insulin resistance Hyperinsulinaemia Increasing insulin resistance -cell failure + Impaired glucose tolerance Type 2 diabetes Adapted from: Reaven GM. Diabetes 1988;37:1595–1607 and Beck-Nielsen H, Groop LC. J Clin Invest 1994;94:1714–1721

  15. OAD (oral anti diabetic)

  16. 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

  17. Sulphonylureas • 1st generation : chlorpropamid • 2nd generation : gliclazide, glipizide gliburid, glibenklamid • 3nd 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

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

  19. Sulfonylureas: Mechanism of Action 1 Intestine: glucose absorption 2 Muscle and adipose tissue:glucose uptake Insulin resistance Blood glucose 4 Liver: hepaticglucose output Insulinresistance • Pancreas: insulin secretionSulfonylureas • insulin secretion DeFronzo RA. Diabetes. 1988;37:667-687. Lebovitz HE. In Joslin's Diabetes Mellitus. 1994:508-529

  20. C Meglitinides: Mechanism of Action 2 Muscle and adipose tissue:glucose uptake 1 Intestine: glucose absorption Insulin resistance Blood glucose 4 Liver: hepatic glucose output Insulinresistance 3 Pancreas: insulin secretion Meglitinides Insulin secretion Wolffenbuttel BHR. Eur J Clin Pharmacol. 1993;45:113-116.

  21. 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

  22. Metformin: Mechanism of Action 2 Muscle and adipose tissue:glucose uptakeMetformin glucose utilization 1 Intestine: glucose absorption Insulin resistance Blood glucose 4 Liver: hepatic glucose output Metformin HGO Insulinresistance 3 Pancreas: insulin secretion DeFronzo RA et al. J Clin Endocrinol Metab. 1991;73:1294-1301.

  23. Metformin cont’d • Side effects • Nausea, vomiting, diarrhoea, abdominal discomfort

  24. a-Glucosidase Inhibitors :Mechanism of Action 1 Intestine: glucose absorptionAcarbose glucose absorption secondaryto digestion of carbohydrate 2 Muscle and adipose tissue: glucose uptake Insulin resistance Blood glucose 4 Liver: hepaticglucose output Insulinresistance 3 Pancreas: insulin secretion Amatruda JM. In: Diabetes Mellitus. 1996.

  25. 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

  26. Acarbose cont’d • Side effects: • GI intolerance • flatulence, diarrhoea, abdominal distension & pain

  27. Thiazolidinediones: Mechanism of Action Muscle and adipose tissue: Thiazolidinediones insulin resistance glucose uptake Intestine: glucose absorption Liver: hepatic glucose output Thiazolidinediones HGO Blood glucose Pancreas: insulin secretion Improve b-cell function 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.

  28. The PPAR Family(Peroxisome proliferator-activated receptor) Fibrates Thiazolidinediones Fatty acids Ligand PPAR-a PPAR-g PPAR-d Receptor Effect on: Lipoproteinexpression Peroxisomeproliferation Lipidsynthesis Carbohydratemetabolism Saltiel AR, Olefsky JM. Diabetes. 1996;45:1661-1669.

  29. 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

  30. Thiazolidinedionescont’d • Pioglitazone, rosiglitazone • Adjunct with either metformin or SU

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

  32. Sites of Action by Therapeutic Options PANCREAS LIVER Therapy: Biguanides Thiazolidinediones Therapy: Sulfonylureas Meglitinides Insulin DECREASED INSULIN SECRETION INCREASED GLUCOSE PRODUCTION HYPERGLYCEMIA DECREASED PERIPHERAL GLUCOSE UPTAKE INTESTINE ADIPOSE TISSUE INCREASE GLUCOSE ABSORPTION Therapy: Alpha-glucosidase inhibitors Therapy: Thiazolidinediones (Biguanides) MUSCLE Adapted from Sonnenberg and Kotchen Curr Opin Nephrol Hypertens 1998;7(5):551-555.

  33. 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

  34. 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

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

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