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2. Insulin
Mekanisme kerja Obat Hipoglikemik O
Sulphonylurea Insulin
secretion
Incretin Glucagon and insulin
Biguanides Glucose
Thiazolidinediones production
-glucosidase
- Slow carbohydrate
inhibitors digestion
Metformin is not
metabolized, but
excreted intact in 2-5 h
Mekanisme kerja Metformin
Pancreas
Impaired
Insulin secretion
Liver – + Muscle
Metformin
Multiple Action Mechanisms of
Metformin
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
asidosis laktat
GLUT-2 Sulfonylurea/non
Glucokinase
Glucokinase sulfonylurea
Glucose
Glucose
Glucose G-6-P
G-6-P
Metabolism
Metabolism
Signal
Signal (S)
(S) ATP
ATP
ADP K
K++
ADP ATP
ATP
Secretory
Secretory Depolarization
Granules
Granules Ca
Ca++
++
Ca++
Insulin Secretion
Sulfonilurea
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
Mechanism:
Closes ATP-sensitive potassium channels
on ß-cells.
Binds to a site distinctly separate from the
sulphonylureas.
Meglitinide Analogs
Bind to ß cells via SU receptor
Rapid absorption, metabolism & clearance, T1/2 < 1 h
After www.bentham.org/sample-issues/cmc9-1/kecskemeti/fig8.gif
Nateglinide/Repaglinide
K
K++
140
140
kDa
kDa
65
65
kDa
kDa
Sulphonylurea Receptor
K
KATP channel
ATP channel
K
K++
Quicker attachment
Earlier Detachment
Insulin Levels in
Nateglinide/Repaglinide
Repaglinide
Traditional
Sulphonylurea
Advantages of
Nateglinide/Repaglinide
Flexibility in mealtime dosing
No significant increase in bodyweight
Can be utillised in mild to moderate
renal failure
Nateglinide: approved in hepatic failure
Dosage: Repaglinide:
0.5mg/1mg/2mg/4mg per dose per
meal
Nateglinide: 60mg/120mg per dose per
meal
Lower incidence of hypoglycemia
◦ elderly patients in whom hypoglycaemia is a concern
Useful
◦ Patients with irregular Situations
meal patterns
140
140 -- cell
cell
Glimepiride kDa
kDa membrane
membrane
65
65
Sulphonylurea kDa
kDa
Receptor
K
KATP channel
ATP channel
K
K++
GLUT-4
So What ??
mg/tablet 500 80 5 5 1
Kontra indikasi
• DM tipe 1
• Kehamilan
• Menyusui
Glucobay®
-glucosidases are
enzymes in the gut that
breakdown complex
carbohydrates –
This reduces and delays
the postprandial rise in
Oligosaccharides blood glucose levels
from starch
Acarbose acts non-systemically to delay
carbohydrate absorption
Upper small
Carbohydrate intestine
absorption
Carbohydrates
Lower small
Carbohydrate
intestine absorption
Alpha glucosidase inhibitors
Memperlambat pemecahan sukrosa dan starch dengan demikian
memperlambat absorpsi.
Efek samping:
normale
absorption
Time
Rosiglitazone
Pioglitazone
Menurunkan haemoglobin
Slides current until 2008
Insulin Glucose
transloca
tion
Insulin
receptor
Synthesis GLUT 4
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
t ion
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
DPP-4
Intestinal enzyme
GIP and GLP-1
release
GIP (1-42)
GIP (1–42) Rapid degradation
GLP-1 (7-36)
GLP-1 (7–36) (minutes)
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: 581–593. Ahrén B. Curr Enzyme Inhib. 2005; 1: 65–73.
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
Pertahankan metformin
<7%
Factors to Consider when Choosing an
Anti Hyperglycemic agents
• Safety profile
• Tolerability
• Expense
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
liver disease Mild Neutral Mild Neutral Neutral Moderate Neutral Neutral Neutral Neutral
(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
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
Insulin :
▪ hormon utama yang mengontrol metaolisme
▪ effek : menurunkan kadar gula darah (BG)
▪ insulin ( insulin resistance) DM
konsekuensi
STRUKTUR KIMIA:
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
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Profile of Insulin Glargine vs NPH
NPH
Glargine
87
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
- 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.
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Efek samping
A. Hipoglikemia ….!!!!
• Menunda jadwal makan
• Aktivitas berlebihan dari biasanya
• Kurang asupan karbohidrat
Oral tablets
Inhaled aerosol
Intranasal, Transdermal
Ultrasound pulses
95
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