INSULIN DAN ANTI DIABETIK ORAL

Dr. dr. NURDIANA, M.Kes

LAB. FARMAKOLOGI
FK UNIBRAW MALANG

PANKREAS SEL B PANKREAS

INSULIN

1 juta pulau langerhans memproduksi hormon (lihat tabel) SINTESIS oleh DNA ATAU RNA
BM : 5808 2 RANTAI : RANTAI A RANTAI B RANTAI DISULFIDA lihat gambar

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 kadar gula darah segera kembali normal

mengatur agar

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 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 bergaris Meningkatkan sintesis lemak di di jar lemak glukoneogenesis , glikogenolisis pertumbh peningkatan sintesis protein dan as. nukleat oksidasi lemak utk enersi
insulin

ketosis
proses anabolik produksi enersi

glukosa

disimpan (storage)

Insulin

hati

otot
Jar.lemak

Fluktuasi kadar glukosa dalam serum dipengaruhi faktor-faktor :

1. 2. 3. 4. 5. 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 metab glukosa. Exercise me penggn glukosa

Insulin, vit C, chromium me

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 Short acting, rapid onset of action Intermediate-acting

2. 3.

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 INSULIN DIABETES TIPE 1 INSULIN DEPENDENT GROUP DIABETES 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

+ -cell failure

Impaired glucose tolerance

Type 2 diabetes

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

OAD (oral anti diabetic)

OBAT
SULFONILUREA -Chlorpropamid -Tolbutamid -Glimepirid -Glipizid -Gliburid -Repaglinid -Metformin

DoA (jam)
S/d 60 6-12 12-24 10-24 10-24 1-3

MIGLITINID BIGUANID

10-12 15-24 >24 3-4

THIAZOLIDINNEDION -Pioglitazone -Rosiglitazone -GLUCOSIDASE INHIBITOR -Acarbose

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

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

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

Sulfonylureas: Mechanism of Action

1 Intestine: glucose absorption 2 Muscle and adipose tissue: glucose uptake
Insulin resistance

Blood glucose

4 Liver: hepatic glucose output

Insulin resistance 3 Pancreas: insulin secretion Sulfonylureas insulin secretion

DeFronzo RA. Diabetes. 1988;37:667-687. Lebovitz HE. In Joslin's Diabetes Mellitus. 1994:508-529

Meglitinides: Mechanism of Action

1 Intestine: glucose absorption

2 Muscle and adipose tissue: glucose uptake

Insulin resistance

Blood glucose 4 Liver: hepatic glucose output

Insulin resistance 3 Pancreas: insulin secretion Meglitinides Insulin secretion

Wolffenbuttel BHR. Eur J Clin Pharmacol. 1993;45:113-116.

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

Metformin: Mechanism of Action

1 Intestine: glucose absorption 2 Muscle and adipose tissue: glucose uptake Metformin glucose utilization
Insulin resistance

Blood glucose 4 Liver: hepatic glucose output Metformin HGO

Insulin resistance 3 Pancreas: insulin secretion

DeFronzo RA et al. J Clin Endocrinol Metab. 1991;73:1294-1301.

Metformin contd
Side effects Nausea, vomiting, diarrhoea, abdominal discomfort

-Glucosidase Inhibitors :Mechanism of Action

1 Intestine: glucose absorption Acarbose glucose absorption secondary to digestion of carbohydrate 2 Muscle and adipose tissue: glucose uptake
Insulin resistance

Blood glucose

4 Liver: hepatic glucose output

Insulin resistance 3 Pancreas: insulin secretion

Amatruda JM. In: Diabetes Mellitus. 1996.

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 contd
Side effects: GI intolerance flatulence, diarrhoea, abdominal distension & pain

Thiazolidinediones: Mechanism of Action

Muscle and adipose tissue: Thiazolidinediones Intestine: glucose absorption insulin resistance glucose uptake

Liver: hepatic glucose output Thiazolidinediones HGO

Blood glucose

Improve -cell function

Pancreas: insulin secretion

The PPAR Family (Peroxisome proliferator-activated receptor)

Ligand
Fibrates Thiazolidinediones Fatty acids

Receptor

PPAR-

PPAR-g

PPAR-d

Effect on: Lipoprotein Peroxisome expression proliferation

Lipid synthesis

Carbohydrate metabolism

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 contd
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

PANCREAS LIVER

Therapy: Biguanides Thiazolidinediones

INCREASED GLUCOSE PRODUCTION

DECREASED INSULIN SECRETION

Therapy: Sulfonylureas Meglitinides Insulin

HYPERGLYCEMIA
INTESTINE

DECREASED PERIPHERAL GLUCOSE UPTAKE ADIPOSE TISSUE

Therapy: Alpha-glucosidase inhibitors

INCREASE GLUCOSE ABSORPTION MUSCLE

Therapy: Thiazolidinediones (Biguanides)

Adapted from Sonnenberg and Kotchen Curr Opin Nephrol Hypertens 1998;7(5):551-555.

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

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