OBAT ANTIDIABET

LAB FARMAKOLOGI FK UB
UMI KALSUM

Definisi
Apakah
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

Diabetes Diagnosis
Category

FPG (mg/dL)

2h 75g OGTT

A1C

Normal

<100

<140

<5.7

140-199

5.7-6.4

>200

>6.5

Prediabetes 100-125
Diabetes

>126

Fasting Plasma Glucose (FPG)

Oral Glucose Tolerance Test (OGTT )

Diabetes Care 34:Supplement 1, 2011

https://www.aace.com/publications/guidelines 20

Klasifikasi Diabetes Mellitus Berdasarkan Etiologinya

American Diabetes Association ( ADA, 2003)
1.

2.

3.

Diabetes Mellitus Tipe 1:

Destruksi sel umumnya menjurus ke arah defisiensi insulin
absolut, melalui proses imunologik (Otoimunologik) dan
Idiopatik
Diabetes Mellitus Tipe 2
Bervariasi, mulai yang predominan resistensi insulin disertai
defisiensi insulin relatif sampai yang predominan gangguan
sekresi insulin bersama resistensi insulin
Diabetes Mellitus Gestasional
Diabetes mellitus yang muncul pada masa kehamilan,
disebabkan oleh hormon yang disekresikan plasenta yang
akan menghambat kerja insulin, umumnya bersifat
sementara, tetapi merupakan faktor risiko untuk DM Tipe 2

4.

Diabetes Mellitus Tipe Lain

-Defek genetik fungsi sel
-Penyakit pankreas
-Autoimun

5.

Gangguan Toleransi Glukosa

A. IFG (Impaired Fasting Glucose) = GPT (Glukosa Puasa
Terganggu)
B. IGT (Impaired Glucose Tolerance) = TGT (Toleransi
Glukosa terganggu)

DRUGS FOR THE TREATMENT OF

DIABETES MELLITUS

Generasi 2

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 pulau Langerhans yang
disebabkan oleh reaksi otoimun, virus, dsb
- Destruksi otoimun dari sel-sel 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
kanakkanak
dan remaja,
walaupun ada juga pada
masa dewasa < 40 tahun

Pada usia tua,

umumnya
> 40 tahun

Keadaan klinis
saat
diagnosis

Berat

Ringan

Kadar insulin
darah

Rendah, tak ada

Cukup tinggi, normal

Berat badan

Biasanya kurus

Gemuk atau normal

Pengelolaan yang
disarankan

Terapi insulin, diet,

olahraga

hipoglikemik oral
Diet, olahraga,

Patofisiologi
Fungsi insulin :
Berikatan dengan reseptor pada sel /
jaringan untuk membuka jalan bagi
masuknya glukosa darah ke dalam sel untuk
dirubah menjadi tenaga.

Characteristic

Type 1 ( 10% )

Type 2

Onset (Age)

Usually < 30

Usually > 40

Type of onset

Abrupt

Gradual

Nutritional status

Usually thin

Usually obese

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; carbohydrateinduced hypertriglyceridemia
common

Insulin therapy

Required

Required in only 20 - 30% of

patients

Hypoglycemic drugs

Should not be used

Clinically indicated

Diet

Mandatory with insulin

Mandatory with or without

drug
15

 Glucose homeostasis
Insulin

Beta cells
of pancreas stimulated
to release insulin into
the blood
High blood
glucose level
STIMULUS:
Rising blood glucose
level (e.g., after eating
a carbohydrate-rich
meal)

Body
cells
take up more
glucose

Liver takes
up glucose
and stores it as
glycogen

Homeostasis: Normal blood glucose level

(about 90 mg/100 mL)

Blood glucose level

rises to set point;
stimulus for glucagon
release diminishes

Figure 26.8

Blood glucose level

declines to a set point;
stimulus for insulin
release diminishes

Liver
breaks down
glycogen and
releases glucose
to the blood

STIMULUS:
Declining blood
glucose level
(e.g., after
skipping a meal)

Alpha
cells of
pancreas stimulated
to release glucagon
into the blood
Glucagon

GLUCOSE REGULATION ON INSULIN SECRETION

K+ channel
clodsed

Glucose

Ca2+ channel
opened

+++
GLUT2

Phosphorylation

Glucose

site
ATP

Glucokinase

ATP/ADP

binding sites

Ca2+Ca2+
Ca2+

Gluc-6P
K+ K+
K+ K+ K+
K+ K+ K+
K+ K+ K+
Insulin containing
secretory granules

Exocytosis

Protein Kinase C
Ca2+ /Calmodulindependent kinase
Protein
phosphorelation

-cell
plasma
membr
ane

INSULIN

18

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

AA

LIPOLYSIS

mobilization
PLASMA FFA

HYPERGLYCEMIA
PLASMA AA
GLYCOSURIA

Glucose

KETOSIS
21

The biphasic insulin response

Adapted from Howell SL. Chapter 9. In: Pickup JC, Williams G (Eds). Textbook of Diabetes. Oxford.
Blackwell Scientific Publications 1991: 7283.

Insulin preparations
Short acting onset 30 mins Humulin S
peak 2-4 hours Actrapid
duration 8 hours
Intermediate onset 1-2 hours
Insulatard
(zinc) peak 4-12 hours
Humulin I duration 16-24 hours
Long acting onset 1-2 hours
Human Ultratard
(protamine) peak 4-12 hours
Humulin Zn
duration 20-35 hours
Analogue
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
24

25

Insulin Administration

Pharmacology for Technicians by Ballington, Lauglin. EMC Paradigm 2006, Fig. 14.9

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

27

ORAL ANTI-DIABETIC DRUGS

28

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
29

Causes of Hyperglycemia in
Type 2 Diabetes
Peripheral Tissues
(Muscle)

Receptor +
post receptor
defect

Glucose
Liver
Increased
glucose
production

P.30
1997 PPS

Pancreas
Impaired insulin
secretion

Insulin
resistance

Type 2 diabetes: the role of insulin resistance

and -cell failure
Insulin resistance
Hyperinsulinaemia
Increasing insulin
resistance

+ -cell failure

Impaired glucose tolerance

Type 2 diabetes

Adapted from: Reaven GM. Diabetes 1988;37:15951607 and Beck-Nielsen H, Groop LC. J Clin Invest 1994;94:1714172

Oral Antidiabetic Drugs

Classification
Sulfonylureas
Meglitinides
Biguanides
-glucosidase inhibitors
Thiazolidinediones

32

FIRST GENERATION SULPHONYLUREA COMPOUNDS

Tolbutamid
short-acting

Acetohexamide
intermediateacting

Tolazamide
intermediateacting

Well

Well

Slow

Well

Metabolism Yes

Yes

Yes

Yes

Metabolites Inactive*

Active +++ **

Active ++ **

Inactive **

Half-life

6 8 hrs

7 hrs

24 40 hrs

Duration of Short
action
(6 8 hrs)

Intermediate
(12 20 hrs)

Intermediate
(12 18 hrs)

Long
( 20 60 hrs)

Excretion

Urine

Urine

Urine

Absorption

4 - 5 hrs

Urine

Chlorpropamide
long- acting

* Good for Px with renal impairment

** Px with renal impairment can expect long t1/2

33

SECOND GENERATION SULPHONYLUREA

COMPOUNDS
Glipizide
Shortacting

Glibenclamide Glimepiride
(Glyburide)
Long-acting
Long-acting

Absorption
Metabolism
Metabolites
Half-life
Duration of
action

Well
Yes
Inactive
3 4 hrs
10 16 hrs

Well
Yes
Inactive
Less than 3 hrs
12 24 hrs

Well
Yes
Inactive
5 - 9 hrs
12 24 hrs

Excretion

Urine

Urine

Urine

34

MECHANISM OF ACTION OF
SULPHONYLUREAS

1) Release of insulin from -cells

2) Reduction of serum glucagon concentration
3) Potentiation of insulin action on target tissues

35

1.

Sulfonylureas: Mechanism of Action

2.

Intestine: glucose absorption

Muscle and adipose tissue:

glucose uptake

Insulin resistance

Blood glucose
4 . Liver: hepatic
glucose output

Insulin
resistance
3. Pancreas: insulin secretion
Sulfonylureas insulin
secretion
DeFronzo RA. Diabetes. 1988;37:667-687.
Lebovitz HE. In Joslin's Diabetes Mellitus. 1994:508-529

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

37

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 ??
38

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
39

DRUGS THAT AUGMENT THE HYPOGLYCEMIC

ACTION OF SULPHONYLUREAS
WARFARIN
SULFONAMIDES
SALICYLATES
PHENYLBUTAZONE
PROPRANOLOL
ALCOHOL
CHLORAMPHENICOL
FLUCONAZOLE
40

DRUGS THAT ANTAGONIZE THE HYPOGLYCEMIC

ACTION OF SULPHONYLUREAS

DIURETICS (THIAZIDE, FUROSEMIDE)

DIAZOXIDE

CORTICOSTEROIDS
ORAL CONTRACEPTIVES
PHENYTOIN, PHENOBARB., RIFAMPIN
ALCOHOL ( chronic px )
41

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
42

MEGLITINIDES (Contd.)
MECHANISM OF ACTION
Bind to the same KATP Channel
as do Sulfonylureas,
to cause insulin release from -cells.

43

Meglitinides: Mechanism of Action

Intestine: glucose absorption

2. Muscle and adipose tissue:

glucose uptake
Insulin resistance

Blood glucose
4. Liver: hepatic
glucose output

Insulin
resistance
3. Pancreas: insulin secretion
Meglitinides Insulin secretion
Wolffenbuttel BHR. Eur J Clin Pharmacol. 1993;45:113-116.

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.

45

BIGUANIDES
e.g. Metformin
PHARMACOKINETICS
Given orally
Not bind to plasma proteins
Not metabolized
Excreted unchanged in urine
t 1/2 2 hr
46

BIGUANIDES (Contd.)
MECHANISM OF ACTION
1. Increase peripheral glucose utilization
2. Inhibits gluconeogenesis
3. Impaired absorption of glucose from the
gut
47

Metformin: Mechanism of Action

2. Muscle and adipose tissue:
glucose uptake
Metformin glucose utilization

1. Intestine: glucose absorption

Insulin resistance

Blood glucose

4. Liver: hepatic
glucose output
Metformin HGO

Insulin
resistance
3.

Pancreas: insulin secretion

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

Advantages of Metformin over Sulfonylurea

Does not cause hypoglycemia ( why ? )
Does not result in wt gain ( why ? )
( Ideal for obese px )
1. Metallic taste in the mouth
2. 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)
49

BIGUANIDES (Contd.)
SIDE EFFECTS
1. Metallic taste in the mouth
2. 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)

50

BIGUANIDES (Contd.)
CONTRAINDICATIONS

1. Hepatic impairment
2. Renal impairment
3. Alcoholism
4. Heart failure
INDICATIONS
1. Obese patients with type II diabetes
2. Alone or in combination with sulfonylureas
51

-GLUCOSIDASE INHIBITORS
e.g. Acarbose
PHARMACOKINETICS
Given orally
Not absorbed from intestine except small amount
t1/2 3 - 7 hr
Excreted with stool
52

-Glucosidase Inhibitors
This enzyme hydrolyses
oligosaccharides to
monosaccharides which are
then absorbed. Acarbose
also inhibits pancreatic
amylase. The normal postprandial 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.

-GLUCOSIDASE INHIBITORS
(Contd.)
MECHANISM OF ACTION
Inhibits intestinal alpha-glucosidases and
delays carbohydrate absorption, reducing
postprandial increase in blood glucose

54

-Glucosidase Inhibitors :Mechanism of Action

1. Intestine: glucose absorption
Acarbose glucose absorption secondary
to digestion of carbohydrate
2.

Muscle and adipose

tissue: glucose uptake

Insulin resistance

Blood glucose

4.

Liver: hepatic
glucose output

Insulin
resistance
3 .Pancreas: insulin secretion
Amatruda JM. In: Diabetes Mellitus. 1996.

-GLUCOSIDASE INHIBITORS
(Contd.)
INDICATIONS
Patients with Type II inadequately controlled by
diet with or without other agents( SU, Metformin)
Can be combined with insulin

SIDE EFFECTS
Flatulence
Loose stool or diarrhea
Abdominal pain
Alone does not cause hypoglycemia
may be helpful in obese Type II patients
(similar to metformin)

56

-GLUCOSIDASE INHIBITORS
(Contd.)
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)

57

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%
58

Thiazolidinediones: Mechanism of Action

Muscle and adipose tissue:

Intestine: glucose absorption

Thiazolidinediones
insulin resistance
glucose uptake

Liver: hepatic

Blood glucose

glucose output
Thiazolidinediones
HGO

Improve -cell

Pancreas: insulin secretion

Whitcomb RW et al. In: Diabetes Mellitus. 1996.

Cavaghan MK et al. J Clin Invest. 1997;100:530-537.
Ehrmann DA et al. J Clin Endocrinol Metab. 1997;82:2108-2116.

function

THIAZOLIDINEDIONE
DERIVATIVES (Contd.)
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 ) .
60

THIAZOLIDINEDIONE DERIVATIVES
(Contd.)
ADVERSE EFFECTS
- Mild to moderate edema
- Weight gain
- Headache
- Myalgia
- Hepatotoxicity ?
61

THIAZOLIDINEDIONE DERIVATIVES
(Contd.)
INDICATIONS
Type II diabetes alone or in combination with
metformin or sulfonylurea or insulin in
patients resistant to insulin treatment.

62

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 -cells but insulin is necessary for them
to be effective. Pioglitazone and rosigglitazone are the two
agents of this group.

Insulin Sensitizers
Thiazolidinediones
(Glitazones)
These agents are
insulin sensitizers, they
do not promote insulin
secretion from -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

Therapy:

PANCREAS

LIVE
R

Biguanides

DECREASED
INSULIN
SECRETION

Thiazolidinedion
INCREASED
es
GLUCOSE

Sulfonylureas
Meglitinides

PRODUCTION

HYPERGLYCEMIA

DECREASED
Insulin
PERIPHERAL
GLUCOSE
UPTAKE

INTESTINE

Therapy:

Alpha-glucosidase
inhibitors

Therapy:

ADIPOSE
TISSUE

INCREASE
GLUCOSE

ABSORPTIO
N

MUSCLE

Therapy:
Thiazolidinedion
es

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

Stepwise management of type 2 diabetes

Insulin oral agents

Oral combination
Oral monotherapy
Diet & exercise

STEP WISE MANAGEMENT OF DIABETES MELITUS

Diagnosis
Health education
Diet, exercise, weight control
Oral agent monotherapy
SU, metformin, meglitinide, thiazolidinedione, acarbose
Oral agent combination therapy (2 different classes)
Insulin + oral agent
Insulin

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