Peran Anti Diabetik Oral da

pada Managemen Diabete

Penatalaksanaan Diabetes
 Terapi obat-obatan
1. Obat Hipoglikemik Oral (OHO)
Insulin sensitisizer : biguanid ( metformin ),
thiazolidinedione (pioglitazone)
Insulin secretagogue :
Sulfonylurea :glibenclamide, glimepiride
Non-sulfonylurea : nateglinide and repaglinide
Glucosidase inhibitor ( acarbose )
Incretin dan DPP-4 inhibitor
2. Insulin
Mekanisme kerja Obat Hipoglikemik O

Agents Site of action MOA

Sulphonylurea Insulin
secretion
Incretin Glucagon and insulin

Biguanides Glucose
Thiazolidinediones production

-glucosidase
- Slow carbohydrate
inhibitors digestion

Thiazolidinediones Peripheral insulin

(biguanides) sensitivity

DeFronzo. Ann Intern Med 1999;131:281-30

 1. Metformin (biguanid)

Derivat guanidin, dari Gallega officinalis

Menurunkan produksi glukosa di hati
Menurunkan kadar glukosa darah puasa
Mempunyai efek terhadap sensitivitas otot terhadap insulin

Slides current until 2008

 Therapeutic Actions of Metformin:
correcting the pathophysiology of type 2 diabetes

Pancreas

Impaired
Insulin secretion

produksi glukosa Decreased

meningkat glucose
Hyperglycaemia uptake

Liver + Muscle

Metformin
 Multiple Action Mechanisms of Metformin

Metformin Insulin Glucose

Plasma membrane
surface charge

Plasma membrane
fluidity, plasticity
of receptors &
transporters
Insulin-stimulated
receptor phosphorylation
& kinase activity
Glucose transporter
translocation and activation
Enzymatic effects on Glucose
metabolic pathways metabolism
and storage
 Efek pada RESITENSI INSULIN

SEBELUM metformin
insulin

glukosa
glucose
glucose
transporter
transporter

SESUDAH
metformin
 Metformin:
multiple mechanisms for CVD protection
Metformin addresses CV risk by a range of mechanisms

Improved Reduced
Insulin sensitivity Hypertriglyceridaemia
Glycaemia AGE formation
Fibrinolysis Intravascular thrombus
Microcirculation Oxidative stress
Endothelial function Atherogenesis
Obesity management Dyslipidaemia

Reduced cardiovascular risk

 Metformin
Dosis awal: 500 mg OD dosis dinaikkan , 1-2 minggu
Dosis maksimal 2.250 mg/ reached within 2-3 months,
medication should b2 atau 3 kali
Jika target terapi belum tercapai, tambahkan obat
dari kelas lain
Target harus tercapai dalam 6 bulan
 Biguanides
Kontra indikasi
Gagal ginjal
Ggn fungsi hati
Gagal jantung
Gangguan GITyang berat
Keuntungan
Tidak menyebabkan hipoglikemia jika diberikan sebagai obat tunggal
Tidak meningkatkan berat badan, bahkan berperan terhadap
menurunkan berat badan.
Efek samping:
GIT ( mual, abdominal discomfort diarrhea dan kemungkinan konstipasi)
asidosis laktat

Slides current until 2008

 Increasing or adding
Jika target terapi belum tercapai dalam 2-3 bulan,
harus ditambahkan obat dari kelas lain
Target harus tercapai dalam 6 bulan
Insulin harus ditambahkan jika mungkin untuk
mencapai target terapi.
Golongan Generik Merk mg/tab Dosis Dosis Lama Frek.
Harian Awal Kerja / hari

Biguanid Metformin Glucophage 500-850 250-3000 - 6-8 1-3

Diabex
Glumin
Mechanism of Glucose-Mediated Insulin Secretion

GLUT-2 Sulfonylurea/non
Glucokinase
Glucokinase sulfonylurea
Glucose
Glucose
Glucose G-6-P
G-6-P
Metabolism
Metabolism
Signal
Signal (S)
(S) ATP
ATP K
ADP K++
ATP
ADP ATP

Secretory
Secretory Depolarization
Granules
Granules Ca
Ca++
++

Ca++

Insulin Secretion
 Sulphonylureas

Meningkatkan sekresi insulin

Ada banyak jenis

Efek samping
Hipoglikemia
Stimulasi nafsu makan dan meningkatkan berat badan
Mual, rasa penuh di perut, dan rasa terbakar di ulu hati
Kadang kadang timbul rash
pembengkakan

Slides current until 2008

 Class Generic Brand mg/tab Daily dose Initial Duration Frequency
dose of action /day
Sulfonyl Glibenclamide Daonil 2.5 , 5 2.5 15 2.5 12-24 1-2
urea Euglucon
Glipizide Minidiab 5, 10 5-20 5 10-16 1-2
Glucotrol XL
Gliclazide Diamicron 80 80-240 80 10-20 1-2
Gliquidone Glurenorm 30 30-120 30 - 1-3
Glimepiride Amaryl 1, 2, 3, 4 0.5

Non- Nateglinide Starlix 60, 120 tid with 60 6-8 With meal
sulfonyl meal
urea Repaglinide Novonorm 1, 2, 3, 4 tid with 1 6-8 With meal
meal
 Pharmacological Comparison of Sulfonylureas
Gliben- Glime-
Tolbutamide Gliclazide Glipizide clamide piride

Relative potency 1 30 50 - 100 150 - 400 400-1000

mg/tablet 500 80 5 5 1

Plasma peak (h) 3 4 1 3 2.4

Duration of 6 - 10 10 -20 10 -16 12 -24 24

action (h)

Gerich N. Engl. J. Med 321 (18) 1231-45,1989

HMR Amaryl Monograph
 Sulphonylureas

Kontra indikasi
DM tipe 1
Kehamilan
Menyusui

Sulphonylureas - hati-hati pada ggn fs hati dan ginjal

Meglitinides ggn. Fungsi hati berat

Slides current until 2008

 Sulfonil urea
Ingat !!
Hipoglikemia
Ada yang dapat diberikan satu kali sehari, sehingga lebih
mudah diingat untuk minum obat
Generasi I, spt, chlorpropamide dapat terakumulasi dan
menyebabkan hipoglikemia .
 Alpha glucosidase
inhibitors(Acabose)
Acarbose is a pseudo-
oligosaccharide that
reversibly
inhibits -glucosidases
-glucosidases are enzymes
Glucobay
in the gut that breakdown
complex carbohydrates
This reduces and delays the
postprandial rise in blood
glucose levels
Oligosaccharides
from starch
 Acarbose acts non-systemically to delay
carbohydrate absorption

Without With acarbose

Acarbose
Stomach

Upper small
Carbohydrate intestine
absorption

Carbohydrates

Lower small
Carbohydrate
intestine absorption
Alpha glucosidase inhibitors

Memperlambat pemecahan sukrosa dan starch dengan

demikian memperlambat absorpsi.
Memperlambat kenaikan glukosa post-prandial

Efek samping:
Flatulence, abdominal discomfort , diarrhoea
Sebagai dosis tunggal, tidak menyebabkan hipoglikemia
Hipoglikemia dapat terjadi jika ditambahkan dengan
golongan insulin sekretagogue(e.g. a sulphonylurea)

Slides current until 2008

 Prinsip mekanisme kerja acarbose

Glucose absorption is slower

and stretched over a longer
time period Resorption of glucose in the small intestine

normale
absorption

Less glucose per time unit under acarbose

will reach the blood stream (same integral)

Time

Less insulin is needed

Should protect the -cell

Golongan Generik Merk mg/tab Dosis Dosis Lama Frek.
Harian Awal Kerja / hari

Gluk. Acarbose Glucobay 50 - 100 150 50 - 1-3

- Inhibitor
 4. Thiazolidinedion
Troglitazone
Rosiglitazone
Pioglitazone

Spesifik pada Reseptor PPAR gama

 Thiazolidinediones

Meningkatkan sensitivitas terhadap insulin di otot, jaringan

lemak dan hati.
Mengurangi sekresi glukosa dari hati
Mengubah distribusi lemak melalui penurunan lemak visceral
dan meningkatkan lemak perifer.
efek samping
Peningkatan berat badan, retensi air
ISPA dan sakit kepala
Menurunkan haemoglobin

Slides current until 2008

 Insulin Glucose
transloca
tion
Insulin
receptor

Synthesis GLUT 4

PPAR RXR mRNA

PPRE transcription
promoter Coding reg

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

receptor X

PPAR +RXR
X Synthesis GLUT 4
mRNA

PPRE transcription
promoter Coding reg

Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2 nd Ed.
Pioglitazone reduced Insulin resistance
Insulin Glucose
transloca
tion
Insulin
receptor

PPAR +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, 2 nd Ed.
 Thiazolidinediones
Kontra indikasi
Penyakit hati, gagal ginjal dan riwayat penyakit jantung
tidak dikontra indikasikan pada gagal ginjal.
Keuntungan
Menurunkan kadar kolester olLDL- dan meningkatkan kadar
kolesterol HDL

Slides current until 2008

Hormon Incretin
Efek Incretin : GLP-1 dan GIP
 DPP-4 Inhibition
Prevent DPP-1v destruction by DPP-4 enzym
Increases Levels GLP-1 and GIP

Meal DPP-4 inhibitor

DPP-4
Intestinal enzyme
GIP and GLP-1
release

GIP (1-42)
GIP (142) Rapid degradation
GLP-1 (7-36)
GLP-1 (736) (minutes)

GIP and GLP-1

actions
Adapted from Deacon CF et al Diabetes 1995;44:11261131; Kieffer TJ et al Endocrinology 1995;136:35853596; Ahrn B Curr
Diab Rep 2003;3:365372; Deacon CF et al J Clin Endocrinol Metab 1995;80:952957; Weber AE J Med Chem 2004;47:4135
35
4141.
 Blocking DPP-4 Can Improve Incretin Activity and
Correct the Insulin:Glucagon Ratio in T2DM
Insulin
T2DM
Incretin
Further
response Hyperglycemia
impaired islet
diminished function

Glucagon

DPP-4 inhibitor
Insulin

Incretin
Improved islet Improved
activity
function glycemic control
prolonged

Glucagon
DPP-4=dipeptidyl peptidase-4; T2DM=type 2 diabetes mellitus
Adapted from Unger RH. Metabolism. 1974; 23: 581593. Ahrn B. Curr Enzyme Inhib. 2005; 1: 6573.
 DPP-4 inhibitor
Sitagliptin (Januvia)
Vildagliptin ( Galvus)
Saxagliptin (Onglyza)
 Clinical implication
Characteristic Sitagliptin Vildagliptin Saxagliptin
MK-0431 LAF237 BMS-477118
Therapeutic dose 100 2x50 5
(mg/day)
Half life Long Short Short (but active
metabolite)
Administration Once daily Twice daily Once daily
Active metabolite No No Yes (BMS-510849)
Fraction bound to Intermediate Low Very low
protein (%)
Renal excretion Predominant Intermediate Predominant
Dose reduction Yes (25-50 mg) No Yes (2.5 mg)
with renal
impairment
 Which the alternative therapy?
HbA1C Advantages Disadvantages
Metformin 1-2 No hypoglycemia,no weigh gain GI symptomps
Broad benefit CI renal insufisiency
SU 1.5 Rapidly effective Weight gain and
inexpensive hypoglycaemia

TZD 0.51.4 No hypoglycaemia, some fluid retention, heart failure,

benefits on lipids and inflamtion weight gain, expensive
Insulin 1.53+ Most effective, no maximum Hypoglycaemia, weight gain,
doze, improved lipid profile need for SMBG
AGI 0.50.8 No hypoglycaemia, weight GI side-effects, expensive
neutral
GLP-1 0.51.0 No hypoglycaemia, weight loss GI side-effects, expensive,
analogue injected
DPP-4 inhibitor, 0.50.8 Weight neutral Long-term safety not established,
expensive

Meglitinide 1.01.5 Fewer hypos than sulfonylurea TID dosing, expensive

Pramlintide 0.51.0 Weight loss Three injections daily, frequent GI side
effects, long-term safety notestablished,
expensive

Nathan, et al. Diabetes Care 2009;32: 193-203

 Jika OHO TIDAK Efektif
analisa diet dan olah raga
pertimbangkan pemberian insulin long-akting
pada malam hari
pertahankan metformin
pertimbangkan mengurangi atau
menghentikan sulphonylurea di pagi hari

Slides current until 2008

 Algoritme Perkeni (2011)

<7%
Factors to Consider when Choosing an Anti Hyperglycemic
agents

Effectiveness in lowering glucose

Extraglycemic effects that may reduce long-
term complications
Safety profile
Tolerability
Expense
Effect on body weight

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

 prinsip terapi kombinasi

Dua atau lebih OHO yang mempunyai mekanisme kerja

yang berbeda
Jika pemberian obat kombinasi menghindari dosis
maksimal
Efek samping lebih sedikit dibandingkan mono terapi

Slides current until 2008

 Target Pengendalian Diabetes (Perkeni
2006)
Baik Sedang Buruk

Gula darah puasa ( mg/dl) 80-109 110-125 126

Gula darah 2 jam (mg/dl) 80-144 145-179 180

A1c (%) <6,5 6,5-8 >8

Kolesterol total (mg/dl) <200 200-239 240

Kolesterol LDL ( mg/dl) <100 100-129 130
Kolesterol HDL (mg/dl) >45
Trigliserida( mg/dl) <150 150-199 200
>25
IMT ( kg/m2) 18,5-22,9 23-25

Tekanan darah (mmHg) <130/80 130-140/80-90 >140/90

 Indikasi Terapi Insulin
Temporal : Permanen :

Kadar gula terlalu tinggi gagal jantung yang tidak taha

Hamil obat minum
Penyakit akut dg GD tinggi Gagal kombinasi ADO
Penggunaan obat yang Efek samping obat ADO
meningkatkan GD DM tipe 1
Sekitar operasi Gangguan fungsi hati berat
Gagal ginjal
Selama perawatan di rumah
sakit
Serangan jantung atau strok
Humalog, Novorapid, Apidra

Actrapid, Humulin R

Humulin N, Insulatard

Lantus
Levemir
 The Basal-Bolus Insulin Concept

Endogenous Insulin
Bolus Insulin
Insulin Effect

Basal Insulin

B L D HS
Time of Administration
B, breakfast; L, lunch; D, dinner; HS, bedtime.
Adapted from:
1. Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.
2. Bolli GB et al. Diabetologia. 1999;42:1151-1167.
 The BENEFITS AND RISKS OF MEDICATIONS (Endocr Pract. 2009;15)
(No.6)
MEDICATIONS*

GLP-3 Sulfonyl
Metformin DPP4 Agonist urea Glinide** Thiazolidinedione Colesevelam Alpha- Insulin Pramlintide
(MET) inhibitor (Increatin (SU) TZD) glucosidase
mimetic) Inhibitor (AGI)

BENEFITS

Postprandial Mild Moderate Moderate to Moderate Moderate Mild Mild Moderate Moderate Moderate to
Glucose (PPG)- marked to marked marked
lowering

Fasting glucose Moderate Mild Mild Moderate Mild Moderate Mild Neutral Moderate Mild
(FPG) lowering to marked

Nonalcoholic fatty Mild Neutral Mild Neutral Neutral Moderate Neutral Neutral Neutral Neutral
liver disease
(NAFLD)

RISKS

Hypoglycemia Neutral Neutral Neutral Moderate Mild Neutral Neutral Neutral Moderate Neutral
To severe

Gastrointestinal Moderate Neutral Moderate Neutral Neutral Neutral Moderate Moderate Neutral Moderate
symptoms

Risk of use with Severe Moderate Moderate Moderate Neutral Mild Neutral Neutral Moderate Unknown
renal insufficiency

Contraindicated in
liver failure or Severe Neutral Neutral Moderate Moderate Moderate Neutral Neutral Neutral Neutral
predisposition to
lactic acidosis

Heart failure/ Use with Mild/Moderate Neutral

Edema caution in Neutral Neutral Neutral Neutral Contraindicated Neutral Neutral Uniess with Neutral
CHF In class 3,4 CHF TZD

Weight gain Benefit Neutral Benefit Mild Mild Moderate Neutral Neutral Mild to Benefit
Moderate

Fractures Neutral Neutral Neutral Neutral Neutral Moderate Neutral Neutral Neutral Neutral

Drug-Drug Neutral Neutral Neutral Moderate Moderate Neutral Neutral Neutral Neutral Neutral
interaction

Glycemic Control Algorithm,

Type of Insulin Preparation & Action
PENDAHULUAN:

Insulin :
hormon utama yang mengontrol metaolisme
effek : menurunkan kadar gula darah (BG)
insulin ( insulin resistance) DM

konsekuensi
STRUKTUR KIMIA:

Fig . Insulin molecule

SINTESIS & SEKRESI INSULIN
Sintesis & sekresi
Faktor-faktor yang mempengaruhi sekresi insulin
Fig . 2-phases release of insulin
Efek insuli pada saat puasa dan makan
Mekanisme kerja insulin

Fig. Insulin Signaling Pathway

 Farmakokinetik Insulin

GIT : dirusak sc, iv

paru: inhalasi insulin
Eliminasi : hati & ginjal
gagal ginjal dosis diturunkan
masalah : fluktuasi insulin plasma
fluktuasi gula darah
 Sediaan insulin
Prinsip:
1. Kerja cepat : (lispro dan aspart)
Onset of action dan duration of action sangat cepat
Onset of action : 5-15 menit (lispro); 10-12 menit(aspart)
Puncak : 1 jam
Duration of action : 3-5 jam
menyerupai sekresi insulin endogen secara fisiologis pada saat
makan
Pemberian :SC, CSII
Dapat dicampur dengan NPH, lente, atau ultralente dalam satu
siring tanpa mempengaruhi absorpsi
Diberikan segera sebelum makan (5 menit sebelum makan)
 Sediaan insulin
2. Kerja pendek: (regular insulin)
Onset of action cepat
Onset of action : 30 menit (lispro)
Puncak : 2 dan 3 jam
Duration of action : 5-8 jam
Hexamer mula kerja dan lama kerjanya lebih
lama
Pemberian : dapat diberikan iv (ketoasidosis, setelah
operasi atau infeksi akut)
Diberikan 30 menit sebelum makan
 Sediaan insulin
3. Kerja sedang : (lente,NPH)insulin
Lente insulin:
Campuran 30% semilente (onset of action cepat) +
70% ultralente insulin (onset and duration of action
panjang)
NPH
onset of action lambat
Terdiri dari kombinasi protamin dan insulin
Setiap molekul protamin mengandung 6 molekul
insulin
Setelah pemberian SC, enzim proteolitik jaringan
mendegradasi protamin insulin dapat diabsorpsi

 Sediaan insulin
4. Kerja panjang:
ultra lente
Glargin insulin
Onset of action: 1-1,5 jam
Duration of action: 11-24 jam atau lebih
Biasanya diberikan 1 kali sehari tapi, kadang-kadang 2 kali
sehari.
Tidak dapat dicampur dengan insulin lain dalam satu siring
Pola absorpsi tergantung tempat injeksi
Cara pemberian insulin
Lokasi/tempat
injeksi
Tabel. Beberapa sediaan insuli yang dipakai di AS
Fig.
Fig. Extent
Extent and
and DOA
DOA of
of various
various insulin
insulin
Glargine

72
Profile of Insulin Glargine vs NPH
NPH
Glargine

73
 Indikasi Insuli n

DM tipe 1
diabetic ketoacidosis, nonketotic coma
DM tipe 2 yang tidak terkontrol hanya dengan diit / OHO
penggunaan jangka pendek : operasi, infeksi, AMI
gestational diabetes
EMG treatment of hyperkalemia
insulin + glucose extra cellular K+ (redistribution into the cell)
Preparasi insulin

1.
1. Portable
Portable pen
pen injections
injections

2.
2. Continuous
Continuous Subcutaneous
Subcutaneous Insulin
Insulin Infusion
Infusion Devices
Devices
(CSII,
(CSII, INSULIN
INSULIN PUMPS)
PUMPS)

3.
3. Inhaled
Inhaled Insulin
Insulin
 - Replaceable cartridge of 100 U
- Portable, comfortable
- No need of syringe & bottle

1. PORTABLE PEN INJECTORS

 - The most physiologic method of insulin replacement
Individual basal & bolus insulin BG self monitoring result

2. CONTINUOUS SUBCUTANEOUS INSULIN INFUSION DEVICES

(CSII, INSULIN PUMPS)
 3. INHALED INSULIN

- Aerosol insulin
- Small particle alveolar wall circulation
- Rapid onset & short DOA
[ to correct High BG / cover meal time
BUT not to provide basal insulin coverage ]
 Insulin Degradation
Hydrolysis of the disulfide linkage between
A&B chains.
60% liver, 40% kidney(endogenous insulin)
60% kidney,40% liver (exogenous insulin)
Half-Life 5-7min (endogenous insulin)
Delayed-release form( injected one)
Usual places for injection: upper arm, front&
side parts of the thighs& the abdomen.
Not to inject in the same place ( rotate)
Should be stored in refrigerator& warm up to
room temp before use.
Must be used within 30 days.
79
Efek samping
A. Hipoglikemia .!!!!
Menunda jadwal makan
Aktivitas berlebihan dari biasanya
Kurang asupan karbohidrat

B. Insulin allergy & resistance

- insulin allergy (type-1 hy-sensitivity rx) very rare
- immune insulin resistance (IgG anti-insulin Ab)

C. Lipodystrophy pada tempat suntikan

- atrophy / hypertrophy subcutaneous fatty tissue
 Methods of Adminisration
Insulin Syringes
Pre-filled insulin pens
External insulin pump
Under Clinical Trials
Oral tablets
Inhaled aerosol
Intranasal, Transdermal
Insulin Jet injectors
Ultrasound pulses

81
82