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