Obat Insulin Dan Oad

7/27/2019 Obat Insulin Dan Oad

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INSULIN DAN ANTI DIABETIK ORAL

Dr. dr. NURDIANA, M.Kes

LAB. FARMAKOLOGI

FK UNIBRAW MALANG


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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


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STRUKTUR PROINSULIN MANUSIA


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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 agarkadar gula darah segera kembali normal


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FARMAKODINAMIK INSULIN

INSULINAGONIS

INSULINSIRKULASI 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 ANTIBODI

METAB : LIVER, OTOT DAN GINJAL

EKSKRESI : METABOLIT, FRAKSI KECIL YG TBERUBAH GINJAL


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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

disim an stora e


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Insulin

hati

otot

Jar.lemak


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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)


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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. Longacting, slow

onset of action

tabel


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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, sebaliknyaCirculating 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.


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TERAPI INSULIN

DIABETES TIPE 1 INSULIN DEPENDENT GROUP

DIABETES TIPE 2TDK BTH INSULIN UTKSURVIVAL, TP

UTKOPTIMAL 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


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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


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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 INJEKSISudah 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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Type 2 diabetes: the role of insulin resistance

and -cell failureInsulin resistance

Hyperinsulinaemia

Increasing insulin

resistance

Type 2 diabetes

Impaired glucose tolerance

Adapted from: Reaven GM. Diabetes 1988;37:15951607 and Beck-Nielsen H, Groop LC. J Clin Invest1994;94:17141721

-cell failure+


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OAD (oral anti diabetic)

OBAT DoA (jam)SULFONILUREA -Chlorpropamid

-Tolbutamid

-Glimepirid

-Glipizid-Gliburid

MIGLITINID -Repaglinid

S/d 60

6-12

12-24

10-2410-24

1-3

BIGUANID -Metformin 10-12THIAZOLIDINNEDION -Pioglitazone

-Rosiglitazone

15-24

>24

-GLUCOSIDASE INHIBITOR-Acarbose 3-4


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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 tuahipoglikemia

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 (


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Sulphonylureas

1st generation : chlorpropamid

2nd generation : gliclazide, glipizide gliburid,glibenklamid

3nd generation : glimepiride

Others : Meglitinide : Repaglinide utk DM tipe 2 ygalergi sulfonylurea

Nateglinide

Stimulate beta cells to release insulin (assumes there isresidual beta cell activity)

Side effects: hypoglycaemia, weight gain, GIdisturbances, headache


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EFEK SAMPING

Sulfonilurea-nausea, vomiting-jaundice-agranulositosis, anemia aplastik-teratogenik

-toksik : Hipoglikemi


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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: hepatic

glucose output

3 Pancreas: insulin secretion

Sulfonylureas

insulin secretion

Insulin

resistance

Sulfonylureas: Mechanism of Action


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Insulin

resistance

Blood glucose

Insulin resistance

1 Intestine: glucose absorption


Meglitinides Insulin 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


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Biguanides

Metformin

Drug of choice in obese patients only

Monotherapy or adjunct

Decreases gluconeogenesis

Increases peripheral uptake of glucose in tocells

Basal & post prandial glucose levels Weight neutral

Increased insulin sensitivity

Beneficial effect on plasma lipid profile


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

Insulin

resistance

Blood glucose

Insulin resistance

1 Intestine: glucose absorption


4 Liver: hepatic

glucose output

Metformin HGO

2 Muscle and adipose tissue:

glucose uptake

Metformin glucose utilization

Metformin: Mechanism of Action


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Metformincontd

Side effects

Nausea, vomiting, diarrhoea, abdominaldiscomfort


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1 Intestine: glucose absorptionAcarbose glucose absorption secondary

to digestion of carbohydrate

Insulin

resistance

4 Liver: hepatic

glucose output

Amatruda JM. In: Diabetes Mellitus. 1996.

Blood glucose

Insulin resistance


2 Muscle and adipose

tissue: glucose uptake

-Glucosidase Inhibitors :Mechanism of Action


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Alpha glucosidase inhibitors

Acarbose

monotherapy or adjunct

Inhibits intestinal enzyme, specific activity onsucrase, delaying digestion of starch andsucrose into absorbable monosaccharides such

as glucose Safe

Weight neutral


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Acarbosecontd

Side effects:

GI intoleranceflatulence, diarrhoea, abdominal distension

& pain


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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 -cellfunction


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The PPAR Family

(Peroxisome proliferator-activated receptor)

Ligand

Effect on:

Receptor

Fibrates Thiazolidinediones Fatty acids

Carbohydrate

metabolism

Lipoprotein

expression

Lipid

synthesis

Peroxisome

proliferation

PPAR- PPAR-g PPAR-d

Saltiel AR, Olefsky JM. Diabetes. 1996;45:1661-1669.


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Thiazolidinediones

Counteract insulin resistance

Bind to PPAR-gamma (receptor), forming a

complex promoting transcription of genessensitive to insulin.

Receptors are present in skeletal muscle,

adipose tissue &liver, thereby promotinguptake of fatty acids &glucose at these sites


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Thiazolidinedionescontd

Pioglitazone, rosiglitazone

Adjunct with either metformin or SU


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Thiazolidinediones

? Alternative to insulin

Side effects:

oedema, weight gain, GI disturbances,

headache, dizziness


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Sites of Action by Therapeutic Options

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

INCREASEGLUCOSE

ABSORPTION

MUSCLE

PANCREAS

ADIPOSETISSUE

LIVER

INTESTINE

HYPERGLYCEMIA DECREASEDPERIPHERAL

GLUCOSE

UPTAKE

INCREASED

GLUCOSEPRODUCTION

DECREASED

INSULIN

SECRETION

Therapy:

Thiazolidinediones

(Biguanides)

Therapy:

Sulfonylureas

Meglitinides

Insulin

Therapy:

Biguanides

Thiazolidinediones

Therapy:

Alpha-glucosidase

inhibitors


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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


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TAHAPAN TERAPI DIABETES MELITUS

Diagnosis

Health education

Diet, exercise, weight control

Oral agent monotherapySU, metformin, meglitinide, thiazolidinedione, acarbose

Oral agent combination therapy (2 different classes)

Insulin + oral agent

Insulin


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Stepwise management of type 2 diabetes

Insulin oral agents

Oral combination

Oral monotherapy

Diet & exercise


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Obat Insulin Dan Oad

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