INSULIN DAN OBAT

HIPOGLIKEMIK ORAL

DIABETES MELLITUS
syndromes characterized by
hyperglycemia; altered metabolism of
lipids,carbohydrates, and proteins; and
an increased risk of complications from
vascular disease
The American Diabetes Association (ADA)
symptoms of DM (e.g., polyuria,
polydipsia, and unexplained weight loss)
a random plasma glucose concentration
of greater than 200 mg/dl (11.1 mM)

DM
a fasting plasma glucose concentration of
greater than 126 ml/dl (7 mM)
a plasma glucose concentration of greater
than 200 mg/dl (11 mM) 2 hours after the
ingestion of an oral glucose load
Classification
Type 1 diabetes mellitus = IDDM
Type 2 diabetes mellitus = NIDDM
Type 3 diabetes mellitus
Type 4 diabetes mellitus

Risk factor

Family history of diabetes

Obesity
Habitual physical inactivity
Race/ethnicity
Previously identified IFG or IGT
History of GDM or delivery of baby >4 kg
Hypertension
HDL cholesterol level <35 mg/dL (0.90 mmol/L)
and/or a triglyceride level >250 mg/dL (2.82
mmol/L)
Polycystic ovary syndrome

INSULIN
Insulin contains 51 amino acids
two chains (A and B) linked by disulfide
bridges
precursor : preproinsulin proinsulin
The islet of Langerhans is composed of four
types of cells
in the (B) cell: insulin
in the (A) cell: glucagon
in the (D) cell: somatostatin
in the PP or F cell: pancreatic polypeptide

Insulin production and

regulation of secretion

Preproinsulin proinsulin : in rough

endoplasmic reticulum
Proinsulin insulin : in golgi complex
Insulin stored in granules
Insulin secretion mainly depends on blood
glucose level
The islets of Langerhans are richly innervated
by both adrenergic and cholinergic nerves
Intracellular Ca2+ acts as the insulin
secretagogue

Distribution and degradation of

insulin
Under fasting conditions
40 g (1 unit) of insulin per hour into the
portal vein to achieve a concentration of
insulin in portal blood of 2 to 4 ng/ml (50 to
100 units/ml)
0.5 ng/ml (12 units/ml) or about 0.1 nM in
the peripheral circulation
After ingestion of a meal, there is a rapid
rise in the concentration of insulin in portal
blood, followed by a parallel but smaller rise
in the peripheral circulation

Distand degrade

The half-life of insulin in plasma is about 5

to 6 minutes
Degradation of insulin occurs primarily in
liver, kidney, and muscle
The complex of insulin and its receptor is
internalized into small vesicles termed
endosomes, where degradation is initiated
The primary insulin-degrading enzyme is a
thiol metalloproteinase

Classification of insulin

type

Appe
ar.

Add.
Prot.

Zn
Buffer
content

Onset

Peak

Durati
on

Rapid
Regular

Clear

0.01
0.04

None

0.50.7

1.54

58

Lispro

Clear

0.02

Phosph
at

0.25

0.51.5

25

Aspart

Clear

0.0196

Phosph
at

0.25

0.60.8

35

Glulisin
e

Clear

None

0.51.5

12.5

Interme
diate
NPH

Cloud
y

Lente

Protami
ne

0.016
0.04

Phosph
at

12

612

1824

Cloud
y

0.20.25

Acetate 12

612

1824

Cloud

0.20.25

Acetate 46

1618

2036

Slow
Ultra

Insulin absorption
Insulin usually is injected into the
subcutaneous tissues of the abdomen,
buttock, anterior thigh, or dorsal arm
Affecting factors:
subcutaneous blood flow
Posture
volume or concentration of injected
insulin
CSII ???

Adverse reaction

Hypoglycemia
Insulin allergy and resistance
Lipoathrophy and lipohipertrophy
Insulin edema

Drug interaction
Drugs with Hypoglycemic Effects e.g
B Adrenergic receptor antagonists
Salicylates
Ethanol
Angiotensin-converting enzyme
inhibitors
Theophylline
Calsium

interact
Drugs with
Hyperglycemic
Effects
Epinephrine
Glucocorticoids
Diuretics
Atypical
antipsychotics
HIV-1 protease
inhibitors
A Adrenergic receptor
agonists

Ca2+-channel
blockers
Phenytoin
H2-receptor blockers
Morphine
Heparin
Marijuana
Nicotine*

Oral hypoglycemic agent

classification
INSULIN SECRETAGOGUE
Sulfonylurea
Meglitinide
Nateglinide
BIGUANIDE
THIAZOLIDINEDIONE
GLUCOSIDASE INHIBITOR

Sulfonylurea

Mechanism of action

stimulating insulin release from

pancreatic cells
(may) reduce hepatic clearance of the
hormone
Stimulate release of somatostatin, and
they may suppress the secretion of
glucagon slightly.

Absorption, fate, and

excretion

food and hyperglycemia can reduce the

absorption of sulfonylureas
short half-lives
largely (90% to 99%) bound to protein
metabolized by the liver
metabolites are excreted in the urine
Adverse effect: hypoglycemia
CI: type 1 DM, pregnancy, lactation, and
for significant hepatic or renal
insufficiency

Dosing: (given 30 minutes before eating)

glyburide is 2.5 to 5 mg, and daily doses
of more than 20 mg are not recommended
glipizide 5 mg given once daily. The
maximal recommended daily dose is 40
mg( daily doses of more than 15 mg
should be divided)
gliclazide is 40 to 80 mg/day, and the
maximal daily dose is 320 mg
Glimepiride : as low as 0.5 mg once per
day. The daily maximal effective is 8 mg

Meglitinide
Repaglinide
derivative of benzoic acid
stimulates insulin release by closing ATPdependent potassium channels
absorbed rapidly from the GI tract
half-life of the drug is about 1 hour
multiple preprandial use
Dose : 0,5-2 mg
CI: hepatic insufficiency

Nateglinide

derived from D-phenylalanine

stimulates insulin secretion by blocking
ATP-sensitive potassium channels
Fewer hypoglycemic events
CI: hepatic insufficiency
dose of 120mg, 1 to 10 minutes before a
meal

biguanide
Metformin
antihyperglycemic, not hypoglycemic
reduces glucose levels primarily by decreasing
hepatic glucose production and by increasing
insulin action in muscle and fat
absorbed mainly from the small intestine
does not bind to plasma proteins
half-life of about 2 hours
The maximum recommended daily dose in the
United States is 2.5 g given in two or three
doses with meals

CI : renal impairment, hepatic disease, a

past history of lactic acidosis (of any
cause), cardiac failure requiring
pharmacological therapy, or chronic
hypoxic lung disease
AE (acute): diarrhea, abdominal
discomfort, nausea,metallic taste, and
anorexia
AE (chronic) : decreased absorption of
vitamin B12 and folate

thiazolidinediones
(troglitazone), rosiglitazone, and pioglitazone
selective agonists for nuclear peroxisome
proliferatoractivated receptor- (PPAR )
activates insulin-responsive genes that regulate
carbohydrate and lipid metabolism
increasing insulin sensitivity in peripheral tissue
but also may lower glucose production by the
liver
increase glucose transport into muscle and
adipose tissue by enhancing the synthesis and
translocation of specific forms of the glucose
transporters

taken once a day

absorbed within about 2 hours
Dosing:
pioglitazone 1545mg oncedaily
rosiglitazone 28 mg once daily
CI: hepatic insufficiency
AE: hepatotoxic, anemia, weight gain,
edema, and plasma volume expansion

Glucosidase inhibitor
Acarbose
reduce intestinal absorption of starch,
dextrin, and disaccharides
AE: malabsorption, flatulence, diarrhea,
and abdominal bloating
Dosing: 25 mg at the start of a meal for
4 to 8 weeks, followed by increases at 4to 8-week intervals to a maximum of 75
mg before each meal

Therapeutic uses
Dosing Principle of Sulfonylureas
Small divided doses before meals better
than large single morning dose
(hypoglycemic risk>)
Obtain day curve for 2-3 days (with or
without OAD).
Follow up closely once weekly
Start with one OAD and monitor bl gl by day
curve (observe which value is exceeded)
If far from goal (>8.0%), add another OAD
(preferred:metformin, repaglinide, acarbose,
or pioglitazone when not contra-indicated)

Darmansjah, 1994
Dosing schedule of second generation
sulfonylureas should be revised:
Some sulfonylureas (especially glibenclamide)
have been given in single daily doses to
prolong action, increase ease, and
compliance

They are prone to cause hypoglycemia;

divided doses (bid or tid) is better