INSULIN DAN ANTI DIABETIK ORAL

Dr. dr. NURDIANA, M.KesLAB. FARMAKOLOGIFK UNIBRAW MALANG

PANKREAS 1 juta pulau langerhans memproduksi hormon (lihat tabel) SEL B PANKREAS SINTESIS oleh DNA ATAU RNAINSULIN BM : 5808 2 RANTAI : RANTAI A RANTAI B lihat gambar RANTAI DISULFIDAPROINSULIN RANTAI TUNGGAL, PANJANGDIPROSES 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 luarMuch higher stimulated rate : ada stimuli dari luar terutama glukosa stimuli lain mannose, asam amino : leucine,arginin, rangs vagus

EFEK FISIOLOGI INSULIN MENURUNKAN KADAR GULA DARAHInteraksi glukosa-insulin neg feed back mengatur agar kadar gula darah segera kembali normal

FARMAKODINAMIK INSULININSULIN 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 TBERUBAH 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 bergarisMeningkatkan 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 :Glkogenolisis/glukoneogenesisPenggunaan glukosa oleh sel periferJumlah reseptor insulin pada selKadar antibodi insulinHormon yg mempengaruhi metab. Glukosa : insulin, glucagon, cortison, epinefrin dan GH Insulin, vit C, chromium me metab glukosa. Exercise me penggn glukosa

KONDISI PATOLOGISGgn sekresi insulin : meningkat : reactive hypoglycemia, insulinoma menurun : defisiensi insulin DMDM bisa disebabkan antibodi yg menghalangi kerja insulin atau kurangnya reseptor insulin, kemampuan jar menggunakan glukosa (obesitas)

Sifat preparat insulinA. Tipe dan lama kerjaUltra short acting, very rapid onset, short durationShort acting, rapid onset of actionIntermediate-actingLong acting, slow onset of action

tabel

Degradasi insulin- dilakukan oleh hati dan ginjal, membersihkan insulin dari sirkulasiCara hidrolisis ikatan disulfid antara rantai A dan B melalui kerja insulinase (glutathione insulin transhidrogenase) proteolysisInsulin endogen hati : 60 % ginjal 35-40 %Insulin eksogen, sebaliknyaCirculating insulin half life 3-5

Pengukuran insulin RIA picomolar, berdasarkan reaksi dg antibodibisa 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 DMDM TIPE 1 COMPREHENSIVE SELF-MANAGEMENT TRAINING, DIMULAI SESUDAH PUBERTAS UMUR 7 TH , TDK BOLEH KONTROL KETAT, KARENA HIPOGLIKEMI DPTBRAIN DAMAGE

KOMPLIKASI TERAPI INSULINHIPOGLIKEMI 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

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 failureInsulin resistanceHyperinsulinaemiaIncreasing insulin resistance Type 2 diabetesImpaired glucose toleranceAdapted from: Reaven GM. Diabetes 1988;37:15951607 and Beck-Nielsen H, Groop LC. J Clin Invest 1994;94:17141721-cell failure+

OAD (oral anti diabetic)

OBATDoA (jam)SULFONILUREA -Chlorpropamid -Tolbutamid -Glimepirid -Glipizid -GliburidMIGLITINID -RepaglinidS/d 606-1212-2410-2410-24

1-3BIGUANID -Metformin10-12THIAZOLIDINNEDION -Pioglitazone -Rosiglitazone15-24>24-GLUCOSIDASE INHIBITOR -Acarbose 3-4

INSULIN SECRETAGOGUES

1. SULFONYLUREA : GENERASI 1 : CHLORPROPAMIDE, TOLBUTAMIDE, TOLAZAMIDEGENERASI 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 (

Sulphonylureas1st generation : chlorpropamid2nd generation : gliclazide, glipizide gliburid, glibenklamid 3nd generation : glimepirideOthers : Meglitinide : Repaglinide utk DM tipe 2 yg alergi sulfonylurea NateglinideStimulate 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. 1994:508-529Blood glucoseInsulin resistance1Intestine: glucose absorption2Muscle and adipose tissue: glucose uptake4Liver: hepatic glucose outputPancreas: insulin secretion Sulfonylureas insulin secretion

Insulin resistanceSulfonylureas: Mechanism of Action

Insulin resistanceBlood glucoseInsulin resistance1Intestine: glucose absorption3Pancreas: insulin secretionMeglitinides Insulin secretion4Liver: hepatic glucose output2Muscle and adipose tissue: glucose uptakeWolffenbuttel BHR. Eur J Clin Pharmacol. 1993;45:113-116.CMeglitinides: Mechanism of Action

Biguanides

MetforminDrug of choice in obese patients onlyMonotherapy or adjunctDecreases gluconeogenesisIncreases peripheral uptake of glucose in to cells Basal & post prandial glucose levelsWeight neutralIncreased insulin sensitivityBeneficial effect on plasma lipid profile

DeFronzo RA et al. J Clin Endocrinol Metab. 1991;73:1294-1301.Insulin resistanceBlood glucoseInsulin resistance1Intestine: glucose absorption3Pancreas: insulin secretion4 Liver: hepatic glucose output Metformin HGO

2 Muscle and adipose tissue: glucose uptake Metformin glucose utilization

Metformin: Mechanism of Action

Metformin contd

Side effectsNausea, vomiting, diarrhoea, abdominal discomfort

1 Intestine: glucose absorption Acarbose glucose absorption secondary to digestion of carbohydrate

Insulin resistance4Liver: hepatic glucose outputAmatruda JM. In: Diabetes Mellitus. 1996.Blood glucoseInsulin resistance3 Pancreas: insulin secretion2Muscle and adipose tissue: glucose uptakea-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 glucoseSafeWeight neutral

Acarbose contd

Side effects: GI intoleranceflatulence, 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 glucoseIntestine: glucose absorptionPancreas: insulin secretion Muscle and adipose tissue: Thiazolidinediones insulin resistance glucose uptake Liver: hepaticglucose outputThiazolidinediones HGOThiazolidinediones: Mechanism of ActionImprove b-cellfunction

The PPAR Family(Peroxisome proliferator-activated receptor) LigandEffect on:ReceptorFibratesThiazolidinedionesFatty acidsCarbohydrate metabolismLipoprotein expressionLipid synthesisPeroxisome proliferationPPAR-aPPAR-gPPAR-dSaltiel AR, Olefsky JM. Diabetes. 1996;45:1661-1669.

Thiazolidinediones

Counteract insulin resistanceBind 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 contd

Pioglitazone, rosiglitazoneAdjunct with either metformin or SU

Thiazolidinediones? Alternative to insulin

Side effects: oedema, weight gain, GI disturbances, headache, dizziness

Sites of Action by Therapeutic OptionsAdapted from Sonnenberg and Kotchen Curr Opin Nephrol Hypertens 1998;7(5):551-555.INCREASEGLUCOSEABSORPTIONMUSCLEPANCREASADIPOSE TISSUELIVERINTESTINEHYPERGLYCEMIADECREASED PERIPHERAL GLUCOSE UPTAKEINCREASED GLUCOSE PRODUCTIONDECREASED INSULIN SECRETIONTherapy:Thiazolidinediones(Biguanides)Therapy:SulfonylureasMeglitinidesInsulinTherapy:BiguanidesThiazolidinedionesTherapy: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 MELITUSDiagnosisHealth educationDiet, exercise, weight control Oral agent monotherapySU, metformin, meglitinide, thiazolidinedione, acarboseOral agent combination therapy (2 different classes)Insulin + oral agentInsulin

Stepwise management of type 2 diabetes Insulin oral agentsOral combinationOral monotherapyDiet & exercise

*It is not clear whether it is insulin resistance or -cell failure that is the primary defect in Type 2 diabetes it is likely to be a combination of both.

The onset of insulin resistance results in compensatory hyperinsulinaemia. With increasing insulin resistance, the -cells fail to compensate fully for the increased insulin resistance and a state of impaired glucose tolerance arises. As -cell function deteriorates further, glucose tolerance continues to fall resulting in overt Type 2 diabetes. Eventually, when the -cells fail completely, a state of hypoinsulinaemia arises and the individual will require therapy with insulin.

Reaven GM. Diabetes 1988;37:15951607Beck-Nielsen H, Groop LC. J Clin Invest 1994;94:17141721

*Slide V/13Biguanides work principally at the liver, decreasing hepatic glucose output.155 Metformin, the only biguanide available, is particularly useful in obese patients as it does not produce weight gain and may facilitate weight reduction. Side effects, particularly those affecting the gastrointestinal system, are not uncommon, however, and care is necessary to avoid lactic acidosis, the most dangerous side effect. The UKPDS provides evidence of its benefit as single therapy, with equivocal results in combination with a sulfonylurea.107 Sulfonylureas reduce blood glucose concentrations by stimulating insulin secretion through their effect on ATP-sensitive potassium channels in the beta cell.155 Their use is associated with weight gain, their long-term safety as regards macrovascular disease has been in doubt since publication of the UGDP study;137 however, this was not confirmed in the UKPDS.50 Alpha-glucosidase inhibitors decrease glucose absorption by inhibiting the breakdown of disaccharides to monosaccharides. They reduce postprandial glycemia and HbA1c levels.156 Poor tolerability due to mild to moderate gastrointestinal side effects limits their use.The thiazolidinediones are a new class whose first member is troglitazone.157 These agonists for peroxisome proliferator-activated receptor (PPAR) gamma improve insulin sensitivity in muscle and adipose tissue.155 The class is effective alone and particularly in combination with sulfonylureas or metformin. Use of troglitazone requires careful monitoring because of idiosyncratic hepatic toxicity.157Type 2 diabetics often need insulin eventually,158 but it can be associated with weight gain. Combining insulin with metformin or troglitazone is useful.

*Type 2 diabetes is traditionally treated in a stepwise manner. Initial therapy is usually diet and increased exercise. However, lifestyle measures generally fail to control glycaemia and, therefore, pharmacological treatment is instigated. Initial therapy is with a single oral drug although monotherapy often fails over a period of time and a combination of two or more oral therapies is used. Subsequently, failure of all oral combination therapy may occur when -cell failure has progressed to such a degree that additional, exogenous insulin is required.