OBAT ANTIDIABET
LAB FARMAKOLOGI FK UBUMI KALSUM
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DefinisiApakah Diabetes itu ??
DEFINISI :
Kumpulan gejala penyakit yang timbul pada seseorang yang disebabkan oleh peningkatan kadar gula darah akibat penurunan sekresi insulin yang disebabkan oleh kerusakan sel beta pancreas dan resistensi insulin ( PERKENI)
– Apabila hormon insulin yang dihasilkan oleh sel beta pankreas tidak mencukupi untuk merubah glukose menjadi energi, maka glukose akan tetap dalam darah dan kadarnya akan meningkat
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Diabetes DiagnosisCategory FPG (mg/dL) 2h 75g OGTT A1C
Normal <100 <140 <5.7
Prediabetes 100-125 140-199 5.7-6.4
Diabetes >126 >200 >6.5
Fasting Plasma Glucose (FPG)
Oral Glucose Tolerance Test (OGTT )
Diabetes Care 34:Supplement 1, 2011Diabetes Care 34:Supplement 1, 2011https://www.aace.com/publications/guidelines 2011 2011
Klasifikasi Diabetes Mellitus Berdasarkan Etiologinya American Diabetes Association ( ADA, 2003)
1. Diabetes Mellitus Tipe 1:Destruksi sel β umumnya menjurus ke arah defisiensi insulin absolut, melalui proses imunologik (Otoimunologik) dan Idiopatik
2.Diabetes Mellitus Tipe 2Bervariasi, mulai yang predominan resistensi insulin disertai defisiensi insulin relatif sampai yang predominan gangguan sekresi insulin bersama resistensi insulin
3. Diabetes Mellitus GestasionalDiabetes mellitus yang muncul pada masa kehamilan, disebabkan oleh hormon yang disekresikan plasenta yang akan menghambat kerja insulin, umumnya bersifatsementara, tetapi merupakan faktor risiko untuk DM Tipe 2
4. Diabetes Mellitus Tipe Lain-Defek genetik fungsi sel β-Penyakit pankreas-Autoimun
5. Gangguan Toleransi GlukosaA. IFG (Impaired Fasting Glucose) = GPT (Glukosa Puasa Terganggu)B. IGT (Impaired Glucose Tolerance) = TGT (Toleransi Glukosa terganggu)
DRUGS FOR THE TREATMENT OF DRUGS FOR THE TREATMENT OF DIABETES MELLITUSDIABETES MELLITUS
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Generasi 2
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DIABETES MELLITUS TIPE 1 : - Jarang / populasinya sedikit (5-10 % dari penderita
diabetes mellitus)
- Gangguan produksi insulin pada DM Tipe 1 umumnya terjadi karena kerusakan sel-sel β pulau Langerhans yang disebabkan oleh reaksi otoimun, virus, dsb
- Destruksi otoimun dari sel-sel β pulau Langerhans kelenjar langsung mengakibatkan defisiensi sekresi insulin.
DIABETES MELLITUS TIPE 2
- sangat umum terjadi
- populasinya 90 – 95 % penderita Diabetes Mellitus
- Etiologinya belum terungkap dengan jelas, kebanyakan karena pola hidup, faktor genetik dan pengaruh lingkungan.
- sel-sel sasaran insulin gagal atau tak mampu merespon insulin secara normal. Keadaan ini lazim disebut sebagai “Resistensi Insulin”.
Diabetes gestasional
Diabetes pada kehamilan- Diabetes / intoleransi glukosa yang terjadi pada masa
kehamilan- Umumnya timbul pada atau setelah trimester ke 2- Sekitar 4-5 % wanita hamil menderita DM- Berlansung sementara dan dapat pulih setelah
kehamilan
Akibat DM gestasional•Malformasi kongenital•Berat badan bayi berlebih•Resiko mortalitas perinatal
Perbedaan dm TIPE 1 DAN DM TIPE 2
Mula muncul Umumnya masa kanakkanakdan remaja,walaupun ada juga padamasa dewasa < 40 tahun
Pada usia tua, umumnya> 40 tahun
Keadaan klinis saatdiagnosis
Berat Ringan
Kadar insulin darah
Rendah, tak ada Cukup tinggi, normal
Berat badan Biasanya kurus Gemuk atau normal
Pengelolaan yangdisarankan
Terapi insulin, diet,olahraga
hipoglikemik oralDiet, olahraga,
PatofisiologiFungsi insulin :
Berikatan dengan reseptor pada sel / jaringan untuk membuka jalan bagi masuknya glukosa darah ke dalam sel untuk dirubah menjadi tenaga.
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Characteristic Type 1 ( 10% ) Type 2
Onset (Age) Usually < 30 Usually > 40
Type of onset Abrupt Gradual
Nutritional status Usually thin Usually obese
Diet Mandatory with insulin Mandatory with or without drug
Hypoglycemic drugs Should not be used Clinically indicated
Clinical symptoms Polydipsia, polyphagia, polyurea, Wt loss
Often asymptomatic
Ketosis Frequent Usually absent
Endogenous insulin Absent Present, but relatively ineffective
Related lipid abnormalities
Hypercholesterolemia frequent, all lipid fractions elevated in ketosis
Cholesterol & triglycerides often elevated; carbohydrate- induced hypertriglyceridemia common
Insulin therapy Required Required in only 20 - 30% of patients
• Glucose homeostasis
Figure 26.8
Insulin
Beta cellsof pancreas stimulatedto release insulin into
the blood
Bodycells
take up moreglucose
Blood glucose leveldeclines to a set point;
stimulus for insulinrelease diminishes
Liver takesup glucose
and stores it asglycogen
High bloodglucose level
STIMULUS:Rising blood glucoselevel (e.g., after eating
a carbohydrate-richmeal) Homeostasis: Normal blood glucose level
(about 90 mg/100 mL) STIMULUS:Declining blood
glucose level(e.g., after
skipping a meal)
Alphacells of
pancreas stimulatedto release glucagon
into the blood
Glucagon
Liverbreaks down
glycogen and releases glucose
to the blood
Blood glucose levelrises to set point;
stimulus for glucagonrelease diminishes
ATP/ADP binding sites
K+ K+ K+ K+ K+ K+ K+ K+
K+ K+ K+
Phosphorylation
site
Ca2+ channel opened
Ca2+ /Calmodulin-dependent kinase
GLUT2
Insulin containing secretory granules
ß-cell plasma membr
ane
Glucose
Gluc-6P
ATP
K+ channel clodsed
Ca2+Ca2+ Ca2+
Protein Kinase C
Protein phosphorelation
Exocytosis
Glucose
Glucokinase
+ + +
– – –
GLUCOSE REGULATION ON INSULIN SECRETION
INSULIN
INSULIN
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Mechanism of Insulin Action• Insulin binds to specific high
affinity membrane receptors with tyrosine kinase activity
• Phosphorylation cascade results in translocation of Glut-4 (and some Glut-1) transport proteins into the plasma membrane.
• It induces the transcription of several genes resulting in increased glucose catabolism and inhibits the transcription of genes involved in gluconeogenesis.
• Insulin promotes the uptake of K+into cells.
Insulin: Actions• Increases glucose uptake in to cells• Increases glycolysis• Increases glycogen synthesis• Reduces glycogen breakdown• Reduces gluconeogenesis
• Reduces lipolysis• Increases fatty acid synthesis• Increases cholesterol & LDL synthesis
• Increases amino acid transport• Increases protein synthesis• Reduces protein breakdown• K+ uptake into cell
INSULIN DEFICIENCY – DIABETES MELLITUS
GLUCOSE UPTAKE
HYPERGLYCEMIA
GLYCOSURIA
DEHYDRATION,
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AA
mobilization
PLASMA AA
LIPOLYSIS
PLASMA FFA
KETOSIS
ACIDOSIS
GlucoseGlucose
The biphasic insulin response
Adapted from Howell SL. Chapter 9. In: Pickup JC, Williams G (Eds). Textbook of Diabetes. Oxford. Blackwell Scientific Publications 1991: 72–83.
Insulin preparations
Short acting onset 30 mins Humulin Speak 2-4 hours Actrapidduration 8 hours
Intermediate onset 1-2 hours Insulatard(zinc) peak 4-12 hours Humulin I
duration 16-24 hoursLong acting onset 1-2 hours Human Ultratard(protamine) peak 4-12 hours Humulin Zn
duration 20-35 hoursAnalogue onset 0-15mins Humalog(designer) peak 1-2 hours Novorapid
duration 4-6 hours
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
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Insulin Administration
Pharmacology for Technicians by Ballington, Lauglin. EMC Paradigm 2006, Fig. 14.9
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SIDE EFFECTS OF INSULIN THERAPY
1. Severe Hypoglycemia (< 50 mg/dl )– Life threatening
Overdose of insulin
Excessive (unusual) physical exercise
2. Local or systemic allergic reactions (rare)
3. Lipodystrophy at injection sites
4. Insulin resistance
4. Hypokalemia
ORAL ANTI-DIABETIC DRUGS
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Oral Anti-Diabetic Drugs
All taken orally in the form of tablets.
Patients with type II diabetes have two physiological defects:
1. Abnormal insulin secretion
2. Resistance to insulin action in target tissues associated with decreased number of insulin receptors
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GlucoseGlucose
LiverLiver
Peripheral TissuesPeripheral Tissues(Muscle)(Muscle)
PancreasPancreas
Receptor +Receptor +post receptor post receptor
defectdefect
Increased Increased glucoseglucose
productionproduction
Impaired insulinImpaired insulinsecretionsecretion
InsulinInsulinresistanceresistance
P.P.3030
Causes of Hyperglycemia in Type 2 Diabetes
©©1997 PPS1997 PPS
Type 2 diabetes: the role of insulin resistance and -cell failure
Insulin resistanceInsulin resistance
HyperinsulinaemiaHyperinsulinaemia
Increasing insulin Increasing insulin resistance resistance
Type 2 diabetesType 2 diabetes
Impaired glucose toleranceImpaired glucose tolerance
Adapted from: Reaven GM. Adapted from: Reaven GM. Diabetes Diabetes 1988;37:1595–1607 and Beck-Nielsen H, Groop LC.1988;37:1595–1607 and Beck-Nielsen H, Groop LC. J Clin Invest J Clin Invest 1994;94:1714–1721 1994;94:1714–1721
-cell failure-cell failure++
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Oral Antidiabetic Drugs
● Classification
Sulfonylureas
Meglitinides
Biguanides
α-glucosidase inhibitors
Thiazolidinediones
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Tolbutamid short-acting
Acetohexamide
intermediate-acting
Tolazamide intermediate-
acting
Chlorpropamide
long- acting
Absorption Well Well Slow Well
Metabolism Yes Yes Yes Yes
Metabolites Inactive* Active +++ ** Active ++ ** Inactive **
Half-life 4 - 5 hrs 6 – 8 hrs 7 hrs 24 – 40 hrs
Duration of action
Short
(6 – 8 hrs)
Intermediate
(12 – 20 hrs)
Intermediate
(12 – 18 hrs)
Long
( 20 – 60 hrs)
Excretion Urine Urine Urine Urine
FIRST GENERATION SULPHONYLUREA COMPOUNDS
* Good for Px with renal impairment Good for Px with renal impairment
** Px with renal impairment can expect long t1/2
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Glipizide
Short- acting
Glibenclamide
(Glyburide)
Long-acting
Glimepiride
Long-acting
Absorption Well Well Well
Metabolism Yes Yes Yes
Metabolites Inactive Inactive Inactive
Half-life 3 – 4 hrs Less than 3 hrs 5 - 9 hrs
Duration of action
10 – 16 hrs 12 – 24 hrs 12 – 24 hrs
Excretion Urine Urine Urine
SECOND GENERATION SULPHONYLUREA COMPOUNDS
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MECHANISM OF ACTION OF SULPHONYLUREAS
1) Release of insulin from β-cells
2) Reduction of serum glucagon concentration
3) Potentiation of insulin action on target tissues
DeFronzo RA. DeFronzo RA. Diabetes. Diabetes. 1988;37:667-687.1988;37:667-687.Lebovitz HE. In Lebovitz HE. In Joslin's Diabetes MellitusJoslin's Diabetes Mellitus. 1994:508-529. 1994:508-529
Blood glucoseBlood glucose
Insulin resistanceInsulin resistance
1. 1. Intestine: glucose absorptionIntestine: glucose absorption 2. 2. Muscle and adipose tissue:Muscle and adipose tissue:glucose uptakeglucose uptake
44 . Liver: hepatic. Liver: hepaticglucose outputglucose output
3. Pancreas: insulin secretion3. Pancreas: insulin secretionSulfonylureas insulin Sulfonylureas insulin
secretionsecretion
InsulinInsulinresistanceresistance
Sulfonylureas: Mechanism of Action
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SIDE EFFECTS OF SULPHONYLUREAS
1) Nausea, vomiting, abdominal pain, diarrhea
2) Hypoglycaemia
3) Dilutional hyponatraemia & water intoxication (Chlorpropamide)
4) Disulfiram-like reaction with alcohol (Chlorpropamide)
5) Weight gain
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SIDE EFFECTS OF SULPHONYLUREAS (contd.)
6) Blood dyscrasias
(not common; less than 1% of patients)
- Agranulocytosis
- Haemolytic anaemia
- Thrombocytopenia
7) Cholestatic obstructive jaundice (uncommon)
8) Dermatitis (Mild)
9) Muscle weakness, headache, vertigo (not common)
10) Increased cardio-vascular mortality with
longterm use ??
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CONTRAINDICATIONS OF SULPHONYLUREAS
1) Type 1 DM ( insulin dependent)
2) Parenchymal disease of the liver or kidney
3) Pregnancy, lactation
4) Major stress
5) DM 2 + complication
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DRUGS THAT AUGMENT THE HYPOGLYCEMIC ACTION OF SULPHONYLUREAS
WARFARIN
SULFONAMIDES
SALICYLATES
PHENYLBUTAZONE
PROPRANOLOL
ALCOHOL
CHLORAMPHENICOL
FLUCONAZOLE
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DRUGS THAT ANTAGONIZE THE HYPOGLYCEMIC ACTION OF SULPHONYLUREAS
DIURETICS (THIAZIDE, FUROSEMIDE) DIAZOXIDE
CORTICOSTEROIDS
ORAL CONTRACEPTIVES
PHENYTOIN, PHENOBARB., RIFAMPIN
ALCOHOL ( chronic px )
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MEGLITINIDES
e.g. Repaglinide, Nateglinide
PHARMACOKINETICS
Taken orally
Rapidly absorbed ( Peak approx. 1hr )
Metabolized by liver
t1/2 = 1 hr
Duration of action 4-5 hr
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MEGLITINIDES (Contd.)
MECHANISM OF ACTION
Bind to the same KATP Channel
as do Sulfonylureas,
to cause insulin release from β-cells.
InsulinInsulinresistanceresistance
Blood glucoseBlood glucose
Insulin resistanceInsulin resistance
1. 1. Intestine: glucose absorptionIntestine: glucose absorption
3.3. Pancreas: insulin secretionPancreas: insulin secretion
MeglitinidesMeglitinidesInsulin secretionInsulin secretion
4.4. Liver: hepatic Liver: hepatic glucose outputglucose output
2.2. Muscle and adipose tissue:Muscle and adipose tissue:glucose uptakeglucose uptake
Wolffenbuttel BHR. Wolffenbuttel BHR. Eur J Clin PharmacolEur J Clin Pharmacol. 1993;45:113-116.. 1993;45:113-116.
CC
Meglitinides: Mechanism of Action
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MEGLITINIDES (Contd.)
CLINICAL USE
Approved as monotherapy and in combination with metformin in type 2 diabetes
Taken before each meal, 3 times / day
Does not offer any advantage over sulfonylureas;
Advantage: Px allergic to sulfur or sulfonylurea
SIDE EFFECTS:
Hypoglycemia
Weight gain ( less than SUs )
Caution in px with renal & hepatic impairement.
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BIGUANIDES e.g. Metformin
PHARMACOKINETICS
Given orally
Not bind to plasma proteins
Not metabolized
Excreted unchanged in urine
t 1/2 2 hr
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BIGUANIDES (Contd.)
MECHANISM OF ACTION
1. Increase peripheral glucose utilization
2. Inhibits gluconeogenesis
3. Impaired absorption of glucose from the gut
DeFronzo RA et al.DeFronzo RA et al. J Clin Endocrinol Metab. J Clin Endocrinol Metab. 1991;73:1294-1301.1991;73:1294-1301.
InsulinInsulinresistanceresistance
Blood glucoseBlood glucose
Insulin resistanceInsulin resistance
1.1. Intestine: glucose absorptionIntestine: glucose absorption
3. 3. Pancreas: insulin secretionPancreas: insulin secretion
4. Liver: hepatic4. Liver: hepatic
glucose outputglucose output
Metformin HGOMetformin HGO
2. Muscle and adipose tissue:2. Muscle and adipose tissue:glucose uptakeglucose uptake
Metformin glucose utilizationMetformin glucose utilization
Metformin: Mechanism of Action
Advantages of Metformin over SulfonylureaDoes not cause hypoglycemia ( why ? )Does not result in wt gain ( why ? )
( Ideal for obese px )
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1. Metallic taste in the mouth2. Gastrointestinal (anorexia, nausea, vomiting,
diarrhea, abdominal discomfort) 3. Vitamin B 12 deficiency (prolonged use)4. Lactic acidosis ( rare – 01/ 30,000-exclusive in
renal & hepatic failure)
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BIGUANIDES (Contd.)
SIDE EFFECTS1. Metallic taste in the mouth2. Gastrointestinal (anorexia, nausea, vomiting,
diarrhea, abdominal discomfort) 3. Vitamin B 12 deficiency (prolonged use)4. Lactic acidosis ( rare – 01/ 30,000-exclusive in
renal & hepatic failure)
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1. Hepatic impairment2. Renal impairment3. Alcoholism4. Heart failure
INDICATIONS
1. Obese patients with type II diabetes2. Alone or in combination with sulfonylureas
BIGUANIDES (Contd.) CONTRAINDICATIONS
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α-GLUCOSIDASE INHIBITORS
e.g. Acarbose
PHARMACOKINETICS
Given orally
Not absorbed from intestine except small amount
t1/2 3 - 7 hr
Excreted with stool
α-Glucosidase InhibitorsThis enzyme hydrolyses
oligosaccharides to monosaccharides which are then absorbed. Acarbose also inhibits pancreatic amylase. The normal post-prandial glucose rise is blunted, glucose levels rise modestly and remain slightly elevated for a prolonged period, less of an insulin response is required and hypoglycemia is avoided; use with other agents may result in hypoglycemia. Sucrase is also inhibited by these drugs.
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MECHANISM OF ACTION
Inhibits intestinal alpha-glucosidases and delays carbohydrate absorption, reducing postprandial increase in blood glucose
α-GLUCOSIDASE INHIBITORS(Contd.)
1. Intestine: glucose absorption1. Intestine: glucose absorptionAcarbose glucose absorption secondaryAcarbose glucose absorption secondary
to digestion of carbohydrateto digestion of carbohydrate
InsulinInsulinresistanceresistance
4. 4. Liver: hepaticLiver: hepaticglucose outputglucose output
Amatruda JM. In: Amatruda JM. In: Diabetes MellitusDiabetes Mellitus. 1996.. 1996.
Blood glucoseBlood glucose
Insulin resistanceInsulin resistance
3 .Pancreas: insulin secretion3 .Pancreas: insulin secretion
2. 2. Muscle and adipose Muscle and adipose tissue: glucose uptaketissue: glucose uptake
-Glucosidase Inhibitors :Mechanism of Action
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SIDE EFFECTSFlatulenceLoose stool or diarrheaAbdominal painAlone does not cause hypoglycemia
α-GLUCOSIDASE INHIBITORS(Contd.)
INDICATIONSPatients with Type II inadequately controlled by diet with or without other agents( SU, Metformin) Can be combined with insulin
may be helpful in obese Type II patients (similar to metformin)
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INDICATIONS
Patients with Type II inadequately controlled by diet with or without other agents( SU, Metformin) Can be combined with insulin may be helpful in obese Type II patients (similar to metformin)
α-GLUCOSIDASE INHIBITORS(Contd.)
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THIAZOLIDINEDIONE DERIVATIVES
New class of oral antidiabetics insulin
sensitizer e.g.: Rosiglitazone, Pioglitazone
PHARMACOKINETICS- 99% absorbed- Metabolized by liver- 99% of drug binds to plasma proteins- Half-life 3 – 4 h- Eliminated via the urine 64% and feces 23%
Whitcomb RW et al. In: Whitcomb RW et al. In: Diabetes Mellitus. Diabetes Mellitus. 1996.1996.Cavaghan MK et al. Cavaghan MK et al. J Clin InvestJ Clin Invest. 1997;100:530-537.. 1997;100:530-537.
Ehrmann DA et al. Ehrmann DA et al. J Clin Endocrinol MetabJ Clin Endocrinol Metab. 1997;82:2108-2116.. 1997;82:2108-2116.
Blood glucoseBlood glucose
Intestine: glucose absorptionIntestine: glucose absorption
Pancreas: insulin secretionPancreas: insulin secretion
Muscle and adipose tissue:Muscle and adipose tissue:
ThiazolidinedionesThiazolidinediones
insulin resistanceinsulin resistance
glucose uptakeglucose uptake
Liver: hepaticLiver: hepatic
glucose outputglucose output
ThiazolidinedionesThiazolidinediones
HGOHGO
Thiazolidinediones: Mechanism of Action
Improve Improve -cell-cell
functionfunction
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MECHANISM OF ACTION
- Increase target tissue sensitivity to insulin by: reducing hepatic glucose output & increase
glucose uptake & oxidation in muscles & adipose tissues.
They do not cause hypoglycemia (similar to metformin and acarbose ) .
THIAZOLIDINEDIONE DERIVATIVES (Contd.)
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ADVERSE EFFECTS
- Mild to moderate edema
- Weight gain
- Headache
- Myalgia
- Hepatotoxicity ?
THIAZOLIDINEDIONE DERIVATIVES(Contd.)
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INDICATIONS
Type II diabetes alone or in combination with
metformin or sulfonylurea or insulin in patients resistant to insulin treatment.
THIAZOLIDINEDIONE DERIVATIVES(Contd.)
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
Insulin Sensitizers
Two classes of oral hypoglycemics work by improving insulin target cell response; the biguanides and thiazolidinediones.
Biguanides:• Metformin is classified as an insulin sensitizer, it increases
glucose uptake and utilization by target tissues. It requires the presence of insulin to be effective but does not promote insulin secretion. The risk of hypoglycemia is greatly reduced.
Thiazolidinediones• These agents are insulin sensitizers, they do not promote
insulin secretion from β-cells but insulin is necessary for them to be effective. Pioglitazone and rosigglitazone are the two agents of this group.
Insulin SensitizersThiazolidinediones
(Glitazones)• These agents are
insulin sensitizers, they do not promote insulin secretion from β-cells but insulin is necessary for them to be effective. Pioglitazone and rosigglitazone are the two agents of this group.
Sites of Action by Therapeutic Options
Adapted from Sonnenberg and Kotchen Adapted from Sonnenberg and Kotchen Curr Opin Nephrol HypertensCurr Opin Nephrol Hypertens 1998;7(5):551-555. 1998;7(5):551-555.
INCREASEINCREASE
GLUCOSEGLUCOSE
ABSORPTIOABSORPTIONN MUSCLEMUSCLE
PANCREASPANCREAS
ADIPOSE ADIPOSE TISSUETISSUE
LIVELIVERR
INTESTINEINTESTINE
HYPERGLYCEMIAHYPERGLYCEMIA DECREASEDDECREASED PERIPHERAL PERIPHERAL
GLUCOSE GLUCOSE UPTAKEUPTAKE
IINCREASEDNCREASED GLUCOSE GLUCOSE
PRODUCTIONPRODUCTION
DECREASED DECREASED INSULIN INSULIN
SECRETIONSECRETION
Therapy:Therapy:
ThiazolidinedionThiazolidinedioneses
(Biguanides)(Biguanides)
Therapy:Therapy:
SulfonylureasSulfonylureas
MeglitinidesMeglitinides
InsulinInsulin
Therapy:Therapy:
BiguanidesBiguanides
ThiazolidinedionThiazolidinedioneses
Therapy:Therapy:
Alpha-glucosidaseAlpha-glucosidase
inhibitorsinhibitors
Stepwise management of type 2 diabetes
Insulin ± oral agentsInsulin ± oral agents
Oral combinationOral combination
Oral monotherapyOral monotherapy
Diet & exerciseDiet & exercise
STEP WISE MANAGEMENT OF DIABETES MELITUS
DiagnosisDiagnosis
Health educationHealth education
Diet, exercise, weight Diet, exercise, weight control control
Oral agent monotherapyOral agent monotherapy
SU, metformin, meglitinide, thiazolidinedione, SU, metformin, meglitinide, thiazolidinedione, acarboseacarbose
Oral agent combination therapy (2 different Oral agent combination therapy (2 different classes)classes)
Insulin + oral Insulin + oral agentagent
InsulinInsulin
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