Dr. M a h a t m a SpPD SMF Penyakit Dalam F.K. UMS SURAKARTA EAGLE FLIES ALONE, MHT

Dr. M a h a t m a SpPD SMF Penyakit Dalam F.K. UMS SURAKARTA

EAGLE FLIES ALONE, MHT

-Cardiology -Pulmonology -Nephrology -Hematology -Gastrohepatoenterology -Endocrinology -Rheumatology -Infectious Diseases -Geriatri -Immunology -Psikosomatis

Topik  LATAR BELAKANG  TINJAUAN ANATOMIS FISIOLOGIS

 DEFINISI  PATOFISIOLOGI  DIAGNOSA

 PENATALAKSANAAN  KOMPLIKASI

Topik  LATAR BELAKANG

DM Prevalence

INDONESIA 2000  5.6 million people with DM 2030  21.3 million people with DM

The 4th of world largest prevalence !! (International Diabetes Federation)

 Diabetes Mellitus ( DM ) :  WHO (1993) : prevalensi DM 6%, >100 jt. 2003 : 177jt, 2025 : 300jt.  Indonesia 1998 : 3,5 juta, 8,5 juta (tahun 2020)  Pre-diabetes ??  Faktor yg berperan dlm  jml DM : usia >40 tahun yg , kemakmuran, pola hidup serba berkecukupan,  penyakit infeksi, angka harapan hidup 

 Nefropati Diabetika (ND) :  Prevalensi 20-30%  17 kali >> Non-DM  Di AS > 50.000/ thn (GGT, ESRD)  ND tertinggi

 Biaya dialisis  : - Pencegahan komplikasi DM - Menghambat progresivitas ND

Absolut

Topik  TINJAUAN ANATOMIS FISIOLOGIS

Normal

1/3 Bag

Otot

1/3 Bag

Hepar

1/3 Bag

Jar. lain

Seimbang

Tidak tergantung insulin

Intake glukosa oral

DM

Hepatic glucose uptake lambat

Hiperglikemi Postprandial

Overview of Carbohydrate metabolism

INS INS

INS

INS INS

INS

INS INS

GLUT 4 (Glucose transporters 4) and insulin action

Synthesis

Adapted from Shepherd PR et al. Glucose transporters and insulin action. NEJM, July 22, 1999

Topik  DEFINISI

Diabetes Mellitus • • • • •

Kelainan bersifat kronik Gangguan metabolisme KH-L-P Komplikasi Makro & Mikro Vaskuler Berkaitan dengan faktor genetik Gejala Utama Intoleransi Glukosa

Masuknya glukosa usus  darah

Berpindahnya glukosa darah  jaringan tubuh

Seimbang ( normal )  Insulin  Glukagon  Hormon lain

sel  Insulin  sel  Glukagon 

Bahan Toksik

Kurang Protein

 Hiperglikemi  Tidak Ketosis

Faktor 2  Fungsi Endo. Pank ( DM )  Genetik  Virus & Bakteri  Bahan Toksik  Nutrisi

Topik 

PATOFISIOLOGI

Glucosa Toxicity

Disfungsi Beta Cell dan Resistensi Insulin B Cell Disfunction

Signaling Defect

Loss Of Insulin

Insulin Resistance

Post Prandial Glucosa

Fasting Glucosa

HIPERGLYCAEMIA

Genetik Lingkungan

IFG Dislipidemi

Hipertensi

Resistensi Insulin

CHD Mikroalbuminuria

Gg.Fibrinolitik

Inflamasi Obesitas sentral

Stages of type 2 Diabetes in relationship to 100 -cell function

Beta cell function (%)

75

50

IGT

Postprandial Hyperglycemia

25

Type 2 Diabetes Phase 1

Type 2 Diabetes Phase 3

Type 2 Diabetes Phase 2

0 - 12 - 10

-6

-2

0

2

Years from diagnosis hypoX-jsk-7-99

6

10

14

Problem Insulin Resistance :

• Reseptor:  Kuantitias / fungsi

• ―Post-receptor‖ (paling sering): Translokasi GLUT 4  Sintesis GLUT 4

ADA. Consensus Development on Insulin Resistance. 1997

Why Does the -cell Fail? Hyperinsulinemia to compensate for insulin resistance1,2

Glucotoxicity2

Lipotoxicity3

Amyloid deposit

Chronic hyperglycemia

Pancreas

High circulating free fatty acids

Lipolysis

HGP Uptake

SlametS

-cell IR Dysfunction

TNF 

Hyperglycemia AGE formation

Glucose auto oxidation

Sorbitol pathway  Antioxidants

 Oxidative Sress Lipid peroxidation  Leukocyte adhesion  Foam cell formation  TNF a

Endothelial dysfunction  NO  Endothelin  Prostacyclin  TXA2

Hypercoagulability Fibrinolysis  Coagulability  Platelet reactivity

Vascular complications

Retinopathy SlametS

Nephropathy

Neuropathy

Topik  DIAGNOSA

Criteria for the Diagnosis of Pre-DM (IGT & IFG) and DM Normal

Pre - Diabetes

Diabetes Mellitus

(mg/dl)

(mg/dl)

(mg/dl)

IGT FPG < 110 2-h PG < 140

IFG

FPG 2h-PG 140-199 110-125 New IFG*:

100-125

T2DM FPG > 126 2-h PG > 200 CPG > 200 with Classical Symptoms

A Dx of Diabetes must be confirmed on a subsequent day by any one of the 3 Methods. Fasting means : No Calorie intake for at least 8 hours *IGT by OGTT; *IFG by FPG Glucose Load : 75g Anhydrous Glucose in Water

Topik  PENATALAKSANAAN

Criteria for Diabetes Control Good

Fair

Poor

Fasting blood glucose (mg/dl)

80-109

110-125

≥126

2hpp blood glucose (mg/dl

80-144

145-179

≥180

A1C (%)

<6.5

6.5-8

>8

Total- cholesterol (mg/dl)

<200

200-239

≥240

LDL-cholesterol (mg/dl)

<100

100-129

>130

HDL-cholesterol (mg/dl)

>45

Triglyceride (mg/dl)

<150

150-199

≥200

Body mass index (kg/m2)

18.5-22.9

23-25

>25

Blood pressure (mmHg)

<130/80

130-140/80-90

>140/90

Perkeni, 2009

Treatment : stepwise approach Blood Glucose Control +

+ 3 2 1

+

4

5

Proposed New Treatment Paradigm for Type 2 Diabetes ( 1999 ) 2002 Medical Nutrition Therapy, Exercise , Education and SMBG

HbA1c 7 - 8%

HbA1c < 7 %

COMBO (OHO + OHO)

Consider oral monotherapy

Target not Met

INSULIN

Add insulin sensitizer or secretagoque

Target not Met

+ INSULIN (Continue 1 OAD)

Full Insulin therapy With Or without Oral agent(s) SlametS

HbA1c >8%

Add insulin sensitizer And secretagoque

Target not Met

+ OAD Start Insulin Or Add Third oral agent

Treatment Algorithm for Type 2 daibetes in Adults 2004 EASD FPG (<130 mg/dl)

Goals :

SMBG (<120mg/dl )

HbA1c (< 7%)

Goals not met after 1 mo

Goals met

Follow up q 3-6 mo

Start monotherapy OHA

Insulin

Adequate

Not Adequate after 3 mo

Continue q 3-6 mo

Consider : Other OHA therapy Or insulin/analog + OHA Adequate

Continue q 3-6 mo

SlametS Henry EASD 2004 Robert

or Early dual OHA

Not Adequate after 3 mo

Add glargine or NPH at bedtime Switch to split dose insulin Basal + prandial insulin (Glargine + glulisine) Refer to specialist

Penyuluhan Kesehatan Penderita

Dokter Kerjasama

Pihak lain Terpadu Rinci Sistematis Praktis

Menuntun Penderita  Memahami penyakitnya  Menerima keadaan dirinya  Menyongsong masa depan (Rasional)

DIET  Disesuaikan dgn Pola diit  Diberikan tiap jam Kalori berdasar BBR / IMT

Latihan Fisik (Olah Raga) Olah Raga

Dampak Positif Sesuai kondisi • Fisik • Metabolik

Dampak Negatif    

Ketosis Hipoglikemi Komplikasi kronik  Trauma sendi

 Sensitifitas Insulin - Reseptor   Perbaikan profil lipid  Perbaikan kondisi kardiovaskuler

Olah Raga  Meningkatkan afinitas insulin - reseptor  Sesuai kemampuan fisik  Teratur

Insulin IDDM ( tipe 1 ) MRDM ( DMM ) NIDDM ( tipe 2 ) + Komplikasi akut & berat + sedang butuh insulin • Lama bekerja Preparat insulin • Derajat kemurnian

Bagan 2. Algoritma Pengelolaan DM T2 pd diabetisi dg BB lebih dan Tidak Gemuk

Bagan 2a. Algoritma Pengelolaan DM tipe 2 yang belum mendapat terapi HbA1C

Terapi

GD rata (mg/dl)

• Metformin • TZD • AGI

6 -7

135 - 170

Monoterapi:

7-8

170 - 205

Terapi Kombinasi: • Metiglinid • AGI • Metformin • TZD • SU

8 -9

205 - 240

Terapi Kombinasi: • Metformin • TZD • SU • Glargine

9 - 10

240 - 275

Terapi Kombinasi: • Metformin • TZD • SU • Glargine

> 10

> 275

Terapi Insulin

KONSENSUS PERKENI 2006

Hipoglikemik Oral  Sulfonilurea

 Memacu sel   Menghambat sel    afinitas Insulin-Reseptor

 Biguanid

 Menghambat Glucose release  Menghambat Glucose utilization

  - Glucosidase Inhibitor

 Menghambat absorbsi Glucosa di usus  Short acting  Intermediate  Long acting

Insulin Target Tissues

Thiazolidinediones (TZDs)

TZDs

Increase Glucose Uptake

Biguanides

TZDs

Decrease Hepatic Glucose Production

Decrease Lipolysis

Sulfonylureas and Nonsulfonylurea Secretagogues

?

Liver

Increase Insulin Secretion

Adipose Tissue Increased Lipolysis

Increased Glucose Production

Skeletal Muscle Decreased Glucose Uptake

Lipotoxicity

Increased Free Fatty Acids

Pancreatic Beta Cells Lipotoxicity

DEFECTIVE INSULIN SECRETION

INSULIN RESISTANCE

Glucotoxicity

-Glucosidase Inhibitors Delay Intestinal Carbohydrate Absorption

Small Intestine Carbohydrate Absorption

Decreased Insulin Secretion

HYPERGLYCEMIA (type 2 diabetes)

Choice of agents in current use Glipizide Gliclazide Glimepiride Glibenclamide

TZDs

Sulphonylureas

Metformin

Acarbose Miglitol Voglibose

-glucosidase inhibitors

Meglitinides Rosiglitazone Pioglitazone

Repaglinide Nateglinide

Sites/Mechanisms of Action hypoglycemic Agents

Decreased digestion of complex sugars Alpha-glucosidase inhibitors Sulfonylureas Meglitinides Normoglycemia Biguanides Thiazolidinediones Decrease in hepatic glucose production

Increased insulin secretion Thiazolidinediones Biguanides

Increase in glucose uptake

Generasi 1  Generasi 2  Generasi 3

SULFONILUREA Paling banyak digunakan

• Makin efektif • Efek samping > kecil

dalam praktek

!

DOSIS 

• Normoglikemi Komplikasi • Hiperinsulinemi  vaskuler

Glimepiride (Generasi 3)

Hipoglikemi • Potensi ekstra pankreas > efektif • Kerja cepat & bertahan lama • Dosis kecil Efek samping minimal

Memacu sekresi insulin

NIDDM NON OBESE TIDAK KURUS • Potensi Sel   • Masih mampu dipacu

SULFONILUREA

Meningkatkan Afinitas Reseptor-Insulin

 Dasar Pemikiran Terapi Sulfonilurea

 Bilamana Terapi dimulai

 Bagaimana cara Pemberian obat

 Memacu sekresi insulin  Memperbaiki Glucose Clearance  Memperbaiki profil lipid  BB Normal  Glukosa darah puasa 140 mg/dl  Diit, OR biguanid  gagal  Belum butuh Insulin

 Mulai dosis kecil tunggal  dosis terbagi/berulang  Ditelan 30 mnt AC

Hepatic Insulin Clearance

Reseptor Insulin Hepatosit

• Glikogenolisis • Glukoneogenesis

Insulin > lama dalam plasma Glycogen Synthase

(+)

Glikogenesis

(-)

(-)

Hepatic Glucoce Production

Hiperglikemi Puasa

SULFONILUREA (-)

(+)

INSULIN Pyruvate dehydrogenase

Metabolik oksidatif Glukosa intrasel

(+)

(+)

Muscle Glucose uptake

Hiperglikemi Post Prandial

Metabolik

Pengendalian Kadar glukosa darah

SULFONILUREA

Vaskuler

Mencegah angiopati  membersihkan radikal bebas  Memperbaiki fungsi trombosit  Memacu fibrinolisis

SEL BETA Pore-forming Sub unit

SULFONILUREA

Reseptor

Drug binding Sub unit K-ATP channel Tertutup

Voltage-dependent Calcium channels Terbuka

Eksositosis Granula insulin

Abssorbsi ( Usus )

Metabolisme ( Hepar )

Ekskresi ( Ginjal )

Potensi Obat

Gangguan Faal

 Hepar  Ginjal

> Mudah terjadi Hipoglikemi

Farmakokinetik dari Bermacam-macam Sulfonilurea Waktu Paruh ( Jam )

Jangka Waktu Kerja ( Jam )

Dosis/ hari ( mg )

ACETOHEXAMIDE

0.8 - 2.4

12 - 18

250 - 1500

2

-

CHLORPROPAMIDE

24 - 48

24 - 72

100 - 500

1

-

GLICLAZIDE

6 - 15

10 - 15

40 - 320

1-2

-

GLIPIZIDE

1-5

14 - 16

2.5 - 20

1-2

-

GLIBURIDE

2-4

20 - 24

2.5 - 20

1-2

-

TOLBUTAMIDE

3 - 28

6 - 10

500 - 3000

2-3

-

TOLAZAMIDE

4-7

16 - 24

100 - 1000

1-2

-

Obat

Tablet/ Metabolit hari Aktif

(Generasi ketiga terbaru) • Diabsorbsi sempurna (1 jam) • Kadar maksimal dalam plasma (2 - 3 jam) • Waktu paruh eliminasi (9.2  3.6 jam) • Jangka waktu kerja (2 jam) • Metabolit

60% - urine 40% - feses  Efek extra pankreas >

• Efek samping hipoglikemik <  Insulino Tropik <  Metabolit > aktif

Pengaruh Sampingan • Hipoglikemi

• Nausea

• Alergi kulit

• Icterus

• Trombositopeni

• Gangguan faal hepar

• Agranulositosis

• Flushing

• Anemia hemolitik

• Retensi cairan

• Dispepsia

 Glucose

(—) Hepatic Glucose production

(+) (=)

 Insulin sensitivity

 Insulin sensitivity

FFA ?

 Muscle glucose uptake

METFORMIN Visceral Adipose tissue ?

Model showing the potential contribution of the related loss of visceral adipose tissue to the beneficial effects of metformin on the features of the metabolic syndrome FFA : free fatty acids

Metformin Improved

Reduced

Insulin sensitivity Fibrinolysis Nutritive capillary flow Haemorrheology Postischaemic flow

Hypertriglyceridaemia AGE formation Cross-linked fibrin Neovascularisation Oxidative stress

Reduced cardiovascular risk AGE : advanced glycation end-products

Vascular benefits of metformin

Effects of metformin on non-conventional factors (Grant PJ, 2003).

Risk marker

Effect

PlAI-1 Factor VII Fibrinogen

Marker reduction Reduction Equivocal , some studies report reduction, others no effect Reduces A and B subunit Alters structure / function Reduction Reduction platelet growth factor 4 and thromboglobulin, stabilises platelet and antioxidant effect Metformin increases hemodynamic responses to Larginine. Lowers levels of asymptomatic dimethylarginine, improves post ischemic blood flow and improves blood flow in both sekeletal muscle and adipose tissue

Factor XIII Fibrin C-reactive protein Platelets

Blood flow

Reciprocal effect of increased activity of the Randle cycle and treatment with metformin on glucose / lipid metabolism in T2DM (Del Prato 1995) Item

Increased Randle Metformin cycle activity Treatment

Lipid oxidation Glucose tolerance Glucose disposal Glucose oxidation Insulin sensitivity Hepatic glucose production

↑ ↓ ↓ ↓ ↓ ↑

↓ ↑ ↑ ↑ ↑ ↓

Alpha Glucosidase Inhibitors (AGIs) • Ingested with meals • Delay the digestion of complex carbohydrate • Competitive inhibition of alpha glucosidase in the intestine • Blunts postprandial glucose spikes • Gastrointestinal side effects

The use of acarbose 1. 2. 3. 4. 5. 6.

It has direct effect on postprandial glucose Does not cause hypoglycemia when given alone Does not cause weight gain Side effects are trivial It can be used as first - line drug therapy It can be used as an adjunct to existing and conventional therapy 7. Modulates peaks and delays glucose absorption 8. Hypothesized that AGI administration to IGT cases may delay or prevent T2DM and CVD risks

Insulin

Glucose

Insulin receptor

Synthesis GLUT 4 PPARg

mRNA

RXR

PPRE

transcription

promoter

Coding reg

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.

Resistensi Insulin Glucose

Insulin

receptor

X

PPARg +RXR

X Synthesis GLUT 4 mRNA

PPRE

promoter

transcription

Coding reg

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.

Pioglitazone reduced Insulin resistance Insulin

Glucose

Insulin receptor

PPARg +RXR Synthesis GLUT 4

mRNA Pio

PPRE

transcription

promoter

Coding reg

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.

Pancreatic β cell of db/db mice

Normal Islet

Degenerated

6th weeks treatment

Pioglitazone

Nateglinide Ishida, Metabolism 2004

Pancreatic β cell of db/db mice

Normal Islet

Degenerated

6th weeks treatment

Pioglitazone

Nateglinide Ishida, Metabolism 2004

Comparison of therapies for T2DM when used as monotherapy (Nathan 2003) Diet

Sulfonyl urea

Bigua nide

Glucosidase Inhibitor

Thiazoli dinedione

Insulin

Metabolic effects Improves resistance Improves secretion Overnight HGP Postprandial excursion HbA1c Lowers FFA Weight gain Hypoglycemia Allergic phenomena

+ + + + + + -

+ ++ + ++ ++ + + + +

++ + ++ + ++ + +

+ + + ++ + + + -

+++ + + + + + + +

++ + + ++ +++ ++ ++ ++ +

Other side effects Anabuse effect Hyponatremia Lactic acidosis Gastrointestinal Hepatic dusfunction

-

+* +* -

+ + -

_ _ _ ++ -

+#

-

* common with 2nd generation sulfonylureas (glipizide, gliburide), most common chlorpropamide # severe idiosyncratic failure in 1/35.000 – 1/50000 patients treated with troglitazons (others less)

• Kegagalan Primer

• Kegagalan Sekunder

Terapi Kombinasi • Biguanide ? • Insulin ?

Kesalahan Indikasi

• Penderita

• • • •

Diit tidak benar OR Kurang Stress Penyakit lain yang menghambat Pengobatan

• Metabolik

• Resitensi insulin • Defisiensi insulin

• Terapi

• • • •

Dosis kurang Resistensi obat Hambatan absorbsi Obat-obat penyerta

Combination / co-administration and combined-drugs : Available combined-drugs Avandamet (Metformin – Rosiglitazone) Metaglib (Metformin - Glipizide) Glucovance (Metformin - Glibenclamide) Amaryl-M (Metformin – Glimepiride) Actoplusmet (Metformin - Pioglitazone)

Topik KOMPLIKASI

Overview

KOMPLIKASI DIABETES MELLITUS • Akut : - Hipoglikemia - Koma Asidosis Diabetika - Hiperosmoler Non Ketotik - Koma Laktat Asidosis

• Kronik : - Mikroangiopati : - Nefropati D M - Retinopati DM - Kardiomiopati DM - Neuropati DM - Makroangiopati : - PJK - CVA - Ulkus/ ganggren - Neuropati DM - Rentan Infeksi : - TB Pulmo, dll.

COMPLICATIONS OF DIABETES

KOMPLIKASI AKUT DM

LIFE THREATENING METABOLIC DISORDERS (KEGAWATAN)

HIPERGLIKEMI

HIPOGLIKEMI

• Edema cerebri • Kerusakan SSP KETOASIDOSIS

• • • • •

LAKTOASIDOSIS

Kontraktilitas miokard  Cardiac output  Tensi  Perfusi ke organ2  Respons vaskuler thd katekolamin 

• Syok hipovolemi

HIPEROSMOLER

• Syok hipovolemi • Trombo-emboli

Koma Diabetikum Kesadaran   Koma  Hipoglikemi  Hiperglikemi  Ketoasidosis

 Honk  Laktoasidosis

Koma Ketoasidosis Insulin  Glukagon  • Hiperglikemi • Ketosis • Asidosis

KETOASIDOSIS • Infeksi akut

• Gangguan metabolisme KH, L, P

• Penghentian Insulin / dosis kurang • New onset DM



• Gangguan keseimbangan cairan, elekt, asam-basa

30% kasus dapat tampil Dalam kondisi hiperosmoler

• • • • • •

Hiperglikemi berat Ketonemi Asidosis metab Dehidrasi s/d syok nafas kussmaul kesadaran  s/d koma



Poliuri, Polidipsi Nausea, Vomitus



Kulit & Mukosa kering



Nafas kuszmaul



Dehidrasi  syok



Lemah, Depresi, Kejang



Kesadaran   koma



Diagnosis laborat      

Hiperglikemi berat Glukosuri berat Ketonuri berat pH darah  PO O2  Tekanan osmose plasma 

Tujuan terapi Ketoasidosis

 Menurunkan glukosa darah  Membersihkan serum & urine dari ketoacids

 Koreksi gangguan keseimbangan cairan & elektrolits  Menghilangkan faktor presipitasi

INSULIN

• • • •

NaCL isotonik Kalium Bikarbonat Fosfat

DEHIDRASI

Sudah dapat makan Seperti biasa

REHIDRASI Koreksi

Sliding Scale @ 4 jam s.c • > 300 mg/dl  20 u • 251 – 300 mg/dl  15 u • 201 – 250 mg/dl  10 u

• 150 – 200 mg/dl  5 u • < 150 mg/dl



-

• Short acting 3x / hari 30 menit sebelum porsi makan utama • Intermediate acting malam hari 15 – 20 unit

50% i.v 0.3 – 0.4 unit/KgBB 50% s.c • s.c Tergantung sarana

• Continous infusion

 Banyak diminati dalam praktek  efek terapi cepat  komplikasi minimal • Hipoglikemi • Hipokalemi • 0.1 u/kgBB/jam — me  insulin plasma — memenuhi (100 – 200 µ u/mL) kapasitas maksimal reseptor insulin • Glukosa  (< 50-100 mg/dl)  dosis  (2x) • Dosis  s/d 100 u/jam  + kortikosteroid (menekan resist. Insulin) • Glukosa  (250 mg/dl)  dosis  50% + dextrose

• mencegah hipoglikemi • menekan ketoasidosis

 KALIUM

• Indikasi K+ < 5.5 mEq/L • KCL ( 2/3 ) • Preparat • KPO4 ( 1/3 )

 BIKARBONAT

• Indikasi • pH < 7 (darah arteri) • HCO3 < 5.0 mEq/L • K+ > 6.5 mEq/L • Hipotensi respon ( - ) thd pemb. cairan • Payah jantung kiri • Depresi pernafasan

 ANTIBIOTIKA

• Indikasi infeksi akut

HIPEROSMOLER Perbedaan dng Ketoasidosis

 Hiperglikemi > berat  Peningkatan osmolalitas > tinggi  Ketoasidosis (-)  Tromboemboli

Mengapa Berbeda

?

 Insulin  (tdk adekwat mengatasi hiperglikemi)  Counter regulatory hormones  (tdk setinggi pada ketoasidosis)  Osmolalitas   menekan lipolisis ( sumber elemen keton bodies )

Data Laboratorium klinik LABORATORIUM

KAD

HONK

Glukosa plasma (mg/dl)

> 250

> 600

pH

< 7.3

> 7.3

HCO3 serum (mEq/L)

< 15

> 20

Keton urine

 3+

 1+

Keton serum

(+) pengenceran 1:2

(-) pada pengenceran 1:2

Osmolalitas serum (mOsm/Kg)

Bervariasi

 330

Natrium serum (mEq/L)

130 – 140

145 – 155

Kalium serum (mEq/L)

5–6

4–5

18 - 25

20 - 40

BUN (mg/dl)

Panduan klinik praktis untuk membedakan KAD & HONK Dengan pengertian sekitar 30% penderita KAD dapat Tampil dalam kondisi HONK

LAKTOASIDOSIS PERBEDAAN DENGAN KETOASIDOSIS & HIPEROSMOLER

 Hipoksia jaringan  Hipovolemia  Disfungsi miokard

 Syok sepsis  Gangguan fungsi hepar  laktic hepatic clearance 

 Biguanid  laktat   DM lansia

 DIAGNOSIS

 Faktor presipitasi +

 Laktat > 5 meq/L  PH < 7.0

 TERAPI

 Koreksi perfusi jaringan  Terapi thd faktor pencetus  Continous infusion bikarbonat s/d pH  ( mencapai 7.2 ) & bikarbonat  (mencapai 12 meq/L)  Hemodialisis

 Dichloronacetate  memacu piruvat dehidrogenase  inotropik +

Koma Hipoglikemi Insulin  Koma Diet 

OHO 

 lapar  Lemah

 Berdebar  Pusing

 Gemetar  Keringat dingin

 Gelisah  Kesadaran 

Reaksi tubuh yang normal akibat keadaan hipoglikemi : Aktivasi saraf otonom : Berdebar, lapar, gemetar, keringat dingin, nausea

Neuro-glycopenia : Mengantuk, perilaku aneh, sukar konsentrasi inkoordinasi, sulit bicara. Akibat berat : hemiparesis, konvulsi, chore-atetosis ataxia, dekortikasi.

Otak dalam keadaan normal : butuh 50% produksi glukosa basal ( 1 mg/kg/menit ) Kerusakan otak tergantung dari lama, berat, cepat Bila Hipoglikemia akan merusak

korteks serebri hipokampus batang otak /spinal bebas. Bila Hipoksia menyebabkan

neuropati sensorimotor perifer

4.6 mmol/l inhibition of endogenous insulin secretion 3.8 mmol/l counter-regulatory hormone release: glucagon adrenalin 3.2-2.8 mmol/l onset of symptom autonomic neuroglycope n 3.0-2.4 mmol/l neurophysiological dysfunction. -evoked responses 2.8 mmol/l cognitive dysfunct: inability perform complex tasks 2.0 mmol/l –onset of EEG changes <1.5 mmol/l severe neuroglycopenia: reduced consciousness level,convulsions, coma.

 Hipoglikemi Murni ( True Hypoglycemia )  Reaksi Hipoglikemi ( Hypoglycemic Reaction )  Hipoglikemi Reaktif ( Reactive Hypoglycemia )  Koma Hipoglikemi ( Hypoglycemic Coma ) Terapi : 

  

Ekstra diet Minum bergula Glukosa 40% I.V Glukosa 10% infus

< 60 mg%  Cepat 3-5 jam pp

< 30 mg%

Penanganan hipoglikemia Glukosa :

• kalori reaksi cepat , oral/parenteral •Glukagon 1 mg i.m •adrenalin ( bukan CS ) • Infus D5 diberikan selama 1 – 2 hari •Belum sadar ?? •Pikirkan penyebab lain

Diabetes and Vascular Complications Diabetes

Macroangiopathy

Microangiopathy

Coronary artery disease Peripheral vascular disease Stroke

Nephropathy Retinopathy Neuropathy

Glukosa

Mortalitas Kardiovaskuler

Post Prandial Korelasi

 Hiperglikemi  Hipertrigliseridemi

 Disfungsi endotel  Aterogenesis

PJK

• Kebutaan  30% DM (Retinopati) • Komplikasi P. Darah perifer

MORBIDITAS & MORTALITAS

 40 x non-DM Amputasi tungkai  10% DM • Kematian 2-5 x non-DM • Penyakit Jantung • Gagal Ginjal Kronik • Penyakit Serebro Vaskular • Life Expectacy  (5 - 10 th)

Mikroangiopati

Penebalan MB Basalis P. Darah Kapiler

Perubahan Viskositas darah & fungsi trombosit

Gangguan Hemodinamic

Gangguan hemodinamik

• GFR  ekskresi protein • Retina • aliran darah  • Tekanan i.v  • dilatasi • Ekstremitas • Aliran darah  • Transportasi prot. Plasma trans. Kapiler 

Critical Vaskular Beds

Penyempitan kapiler

• Retina • Glomeruli • Vasa nervorum

Produksi Prostasiklin  Produksi Aktivator Fibrinolisis 

Produksi Thromboxane A2 

• Viskositas • Mikrotrombus • Penyempitan vaskuler Deformabilitas eritrosit

Hambatan aliran darah

tissue factor S

S S

PAI-1 i i

i

i

i

Permeabel Hiperinsulin

S = selectin i = imunoglobulin( VCAM dll)

INTIMA

SS

MONOSIT LDL

DM tissue factor S LDL kecil

S S

PAI-1 i i

i

i

i

LDL ox

SEL BUSA

Radikal Bebas. AGEs

INTIMA

MEDIA

Makrofag

SEL OTOT POLOS

SS

MONOSIT LDL

LUMEN

Glukose

fibrinolisis agregasi tr.

DM tissue factor S LDL kecil

S S

i i

i

i

i

PAI-1 PLAQUE PLAQUE

LDL ox

Hiperinsulin

SEL BUSA

Radikal Bebas. AGEs

INTIMA

Migrasi

Makrofag

Sitokin+ f. pertumbuhan MEDIA

SEL OTOT POLOS

Proliferasi

SS

Pro-oxidant effects of glucose leading to increased CV risks Glucose

AGEs

Glycolysis

Autoxidation

Glycation

Reactive intermediates Mitochondrial resp. chain

Sorbitol Pathway

GSH reduction Reactive intermediates NAD(P)H Oxidase

Generation of reactive oxygen species ROS

RAGE

Ca signalling

?

Protein kinase C

Vascular disease

NFkB

Perjalanan penyakit pd nefropati diabetik Perubahan fungsi • • • •

GFR  Albuminuria reversible Ginjal membesar Hyperfiltration

0

2

Incipiens Nephropathy • Hiperfiltrasi • Mikroalbuminuria • Hipertensi

5

Awal DM

Waktu (tahun)

• Penebalan membrana basalis • Ekspansi mesangium • Hyperperfusion

creat mg/dl 0,8

20

 ACE Inhibitor

Perubahan struktur

 GFR ml/mnt 150  Serum

15

25

ESRD

Overt nephropathy  Makroalbuminuri/ gross protein  Kreatinin  120

60

< 10

1

> 2,0

>5

(dikutip dari Harrison Ed 16 : Adapted RA defronzo 1998 )

DIABETIC RETINOPATHY

ERECTILE DYSFUNCTION

Kita lahir & besar bersama. Tapi mengapa kamu mati duluan ?

Patofisiology

Mekanisme Rentan Infeksi Pada DM • Keadaan Nutrisi intra sel berkurang (malnutrisi, dehidrasi) • Insufisiensi Vaskular ( makro dan mikroangiopati ) • Neuropati • Fungsi Leukosit Berkurang -

Penurunan kemampuan Intracelluler Killing PMN, MN Defisiensi Komplemen Berkurangnya jumlah T- helper Disfungsi Makrofag

Patofisiology

Mekanisme Rentan Infeksi TB Pada DM • Fungsi Leukosit Berkurang Penurunan Intracelluler Killing PMN, MN Defisiensi Komplemen

Berkurangnya jumlah T- helper Disfungsi Makrofag

Disfungsi Makrofag

Penurunan kemampuan Intracelluler Killing PMN, MN Kemotaksis Perlekatan

Fagositosis H2O2, spesies oksigen aktif

Intracellular Killing

Eksositosis

THE CONCEPTS OF INSULIN

• Insulin ditemukan pada tahun 1921 • Marjorie (anjing) adalah pasien pertama yang menerima ekstrak pankreas • 1922 Eli Lilly memproduksi insulin secara massal • Insulin hewan digunakan sampai tahun 1983

Insulin secretion in normal individu  An amount of insulin will be secreted by human pancreas about 49-50 units insulin / day  Two phases of insulin secretion :  Basal insulin secretion : fasting 10 microU/ml post prandial 100 microU/ml peak at 30 – 40 minutes without eksogen stimuli  Stimulated insulin secretion with eksogen stimuli burst insulin release decreased with gradually

Kronologik Kerja Insulin

Detik

Insulin terikat pada reseptor Otofosfolirasi reseptor Aktifasi protein kinase reseptor

Menit

Aktifasi transport glukosa Aktifasi transport ion Inhibisi glukoneogenesis Stimulasi glikogenesis Insulin-induced receptor internalisation

Jam

Sintesis protein Sintesis lipid Maximal insulin-induced down regulation Pertumbuhan sel

Insulin DM Tipe - 1

Insulin DM Tipe – 2 Komplikasi Akut

Insulin DM Tipe – 2 Pengendalian Glukosa darah

 Perkembangan Ilmu  Perkembangan Teknologi Farmasi  Pengalaman Praktek

INSULIN Short acting Intermediate acting Long acting Rapid acting Extended acting

Konvensional

Human Mono - Component  Insulin konvensional  Transpeptidasi  Purifikasi  Biosintesis • E. Coli • Saccharomyces

Twenty four hours profiles of blood insulin and glucose concentration in normal Human

Insulin (U/mL)

75 –

Breakfast

Lunch

Supper

INSULIN

50 – 25 –

Basal insulin

0–

Glucose (mg/dL)

150 –

GLUCOSE

100 – Basal glucose

50 – 0– 7 8

9 10 11 12 1 a.m

2

3

Time of day

4

5 6 7

8

9

p.m

Twenty four hours profiles of blood insulin and glucose concentration in normal Human

IDEAL

( Program Insulin )

Menjelang Makan Pagi

Menjelang Makan Siang

Menjelang Makan Malam

Short – Acting

Short – Acting

Short – Acting

Menekan Hiperglikemi Post Prandial

Menjelang Tidur Malam Extended – Action

Mengendalikan Glukosa darah Basal Menekan Hepatic Glucose Production

Insulin (U/mL)

75 –

Breakfast

Lunch

Supper

INSULIN

50 – 25 –

Basal insulin

0–

Glucose (mg/dL)

150 –

GLUCOSE

100 – Basal glucose

50 – 0– 7 8

9 10 11 12 1 a.m

2

3

Time of day

4

5 6 7

8

9

p.m

Twenty four hours profiles of blood insulin and glucose concentration in normal Human

60 ng/ml

Individu normal Insulin plasma

FAS E 1 3-5 mnt

FAS E- 2 waktu

50-60 menit

Penderita DM tipe-2 Insulin

(Tumpul)

Lebih tinggi dan lama

FAS E-1

FAS E-2

plasma Comparative profiles Secretion of bloodWaktu insulin Normally and (Delayed Insulin D secretion) M

The various processes determining the absorption of insulin, its distribution in the circulation Insulin preparation (human/bovine insulin)

Administration

Factors: site, depth, temperature, preparation, exercise

Absorption

Dissolution Dissociation Diffusion

Tissue depot

Degradation

Circulating Insulin Distribution

B cell

Antibody-bound  Free insulin Renal excretion (1%)

Diet

Target cells

• Liver 60-80% • Kidney 10-20% • Muscle % fat

Exercise Counterregulation Action

Degradation

10-20%

Biological effects

Elimination

Metabolic benefit of insulin therapy (Edelman 1995)

1. Reduce fasting and postprandial glucose levels 2. Suppresses HGP hepatic glucose production 3. Stimulates peripheral glucose utilization 4. Increase glucose oxidation/storage in muscles 5. Improves lipoprotein composition 6. Reduces AGEP advanced glycosylation end products 7. Reduces glucose toxicity 8. Improves endogenous insulin secretion ability 1-4 maintain normoglycemia 5-6 prevent complications 7-8 preserving β-cell function

Profiles of injectable insulin

No human insulin can mimick physiological insulin response to meals

No human insulin can mimick physiological insulin response to meals

Scheme of putative process Zn-insulin hexamer complex dissociates into smaller units ( ADA )

Molar concentration Dissociation Diffusion

10-3

Hexamers

10-4

Zn2+

10-5

Dimers

?

Capillary membrane

Bloodstream

10-8

Monomers

• 1983: Human Insulin Menggunakan bakteri untuk menghasilkan insulin manusia (rekombinan DNA)

• Insulin terbaru : - analog insulin : Humalog & Humalog Mix25 - insulin nasal



PERTANYAAN YANG HARUS DI JAWAB

APAKAH BENAR BAHWA PEND. DM ( INSULIN REQUIRING ) MEMBUTUHKAN PREPARAT BARU LONG – ACTING INSULIN

Jawaban Rasional  Preparat Konvensional • Intermediate – Acting : - NPH - Lente • Long – Acting : Ultra Lente  Insulin Glargine  Homeostasis Glukosa Inter Prandial & Nokturnal

Peak-Action Profile  Insulin Fisiologik

Peakless Extended-Action Profile = Insulin Fisiologik

LONG-ACTING BASAL INSULIN ANALOGUE  Konsep baru dalam pengobatan DM tipe–1 & DM tipe–2  Subkutan malam menjelang tidur



NATIVE HUMAN INSULIN

Modifikasi

Struktur biokimiawi  Potensi pengendalian glukosa = NPH  Efek Hipoglikemi 

 Delayed Onset  Constant  Peakless

24 jam

EFEKTIF & AMAN

 US FOOD & DRUG ADMINISTRATION ( APRIL 2000 )  EUROPEAN AGENCY FOR THE EVALUATION OF MEDICINAL PRODUCTS ( JUNI 2000 )

Harapan Dunia Medik Human Insulin

Preparat insulin Memenuhi kebutuhan insulin basal Recombinant DNA

( 21A – Gly – 30 BA – L – Arg – Human Insulin )

 DELAYED ONSET  CONSTANT  PEAKLESS



Sekresi Insulin Basal pada non-diabetes kondisi Post-Absorbtive

12 –

A

11 – Regular human insulin

10 – 9– Insulin Lispro (Humalog)

8– 7– 6– 5– 4–

Meal + SC Insulin injection

3–

-60

-30

0

30

60

90

120

150 180 210

240

Time (min) Blood glucose exursions of ten T1DM patients after consumption of a meal rich in rapidly-absorbable carbohydrates [pizza, sugar-sweetened cola, tiramisu (total caloric content was 1016 kcal)]. After subcutaneous injection of 15.4  3.5 U at time zero, the meal was eaten within 20 min. On one of two study days, insulin Lispro (open circles) was injected : on the other day regular human insulin (solid circles) was injected. Blood Glucose was kept constant at 6.7 mmol/L-1 in the 3 hours prior to the meal by means of glucose clamp. Free plasma insulin concentrations.(Heinemann 1996 – De Felippis 2003 )

11.0 Meal

190

Plasma glucose, mmol/L

9.0

Lispro or Hum-R

170

150

8.0

7.0

130

6.0

110 Hum-R

5.0

4.0

Plasma glucose, mg/dL

— Hum-R (- 5 min) — Hum-R (-30 min) — Lispro (humalog) — 6 nondiabetics

10.0

90

12.30 0

70 60

120

180

240

300

360

420

Time, min Postprandial blood glucose after subcutaneous Lispro (Eli Lilly, Indianapolis, IN) administration at mealtime versus human insulin (Hum-R) given either at mealtime or 30 min prior to the meal in patients with insulindependent diabetes mellitus of short duration & residual -cell function, N = 6 patients with insulin-dependent Diabetes mean  SEM (Bolli 1999)

FARMAKOKINETIK & FARMAKODINAMIK

 PROLONGED ABSORBTION  FLAT METABOLIC PROFILE

ONSET OF ACTION

DURATION OF ACTION

 Glargine 1,3 jam  NPH 0,7 jam

 Glargine 22 jam  NPH 14 jam

VARIASI KECEPATAN ABSORBSI

INTER INDIVIDUAL

= CSII

GLARGINE

<

Ultra Lente

MULAI

PUNCAK

AKHIR

NPH

50 menit

3 – 6 jam

14 jam

GLARGINE

90 menit

—

24 jam

SHORT – ACTING Menjelang makan Pagi – Siang – Malam

Glukosa darah Post Prandial & Inter Prandial

Terkendali

GLARGINE Menjelang tidur malam

Hipoglikemi

Tidak Terjadi

Early Insulinisation for Type 2 Diabetes Management

Diabetes Management (Region) 6.17%

4.00%

3.48% 9.93%

Diet only Insulin only OHA only OHA + Insulin Others

76.42%

Early Insulinisation DCCT & UKPDS : 1. Reducing hyperglycaemia reduces incident risk & progression of diabetic complications 2. Target HbA1C 6.5% to 7%

UKPDS Data – Lowered 1% HbA1C leads to reduction of : • • • •

21% diabetes-related mortality 14% MI 37% microvascular complications 43% PVD

Early Insulinisation Challenge of Type 2 DM Control Type 2 DM – a progressive disease • • • • •

Progressive decline of –cell function Late diagnosis – average 12 years Loss of initial BG control within few years Exogenous Insulin becomes necessary Often, Insulin therapy need intensified

Early Insulinisation When Insulin Becomes Necessary ? UKPDS Study Data • 50% of Type 2 patients need long-term insulin after 6 years • Lowest -cell function at diagnosis  greatest risk of OAD failure

Marre M. Int J Obesity (2002) ; 26 (Suppl 3) : S25-S30

Initiating Insulin in Type 2 DM Target • Improve BG control – target : HbA1C < 6.5% • Fasting sugar of < 108 mg/dL • PP sugars of < 144 mg/dL

Insulins :

Types and Examples

Bolus Insulins • Rapid-acting • Short-acting

Humalog Regular (Humulin R)

Basal Insulins • Intermediate-acting • Long-acting

NPH, Lente (Humulin N) Ultralente, Lantus

Pre-Mixed Insulins • NPH/Regular Based • NPL/Lispro Based • NPA/Aspart Based

30/70 (Humulin) Humalog Mix 25 Novolog Mix 30

Penyimpanan Insulin  Dalam lemari es 20 - 80 hingga kadaluarsa  Pada suhu ruang (30 derajat Celcius), insulin stabil selama 30 hari  Hindari suhu yang ekstrim (terlalu panas atau terlalu dingin)

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