Pharmacology of the endocrine

pancreas

Dr. H. Zulkarnain Rangkuti, Msi

Dr. Sake Juli Martina, SpFK
Pharmacology and Therapeutic Department, School of Medicine
Universitas Sumatera Utara

Introduction
Charles Best, a 4th medical student in Canada,
had a girl-friend with high glucose blood
level. Together with his mentor, surgeon Frederick
Banting, isolated a pancreatic extract from dogs
that could reduce blood glucose in diabetic dogs.
In 1923, Banting was awarded Nobel Price in
Medicine, and he shared his award with Best

Apollonius (250 SM, Memphis) :

Diabetes = untuk menggunakan atau mengeringkan

(harfiah) = siphon atau mengalirkan volume urin besar

Mellitus = bahasa latin dari madu = sweet ada glukosa dalam
urin

Diabetes Mellitus

a group of diseases characterized by high levels of blood glucose

resulting from defects in insulin production, insulin action, or both

Physiologic and Pharmacologic Regulation of Glucose Homeostasis

GIT
Dietary complex carbohydrates
-glucosidase
inhibitors

cell
Glucosidases
Blood

Other tissues

Glucose
Metabolism
Muscle
cell

Glucose
(from GIT
& liver)

Adipose cell
glucose

Triglyceride

Glycogen

Metabolism

Insulin
secretion

ATP
Sulfonylureas,
meglitinides

Insulin

Liver cell
Glucose
Glucose

PPAR
Thiazolidinediones

Glucose

Diazoxide

To tissues

To tissues
Insulin

Insulin

Glucose

Endogenous insulin
(from cell) or
Exogenous insulin

Glycogen

Glucagon

Gluconeogenesis

Biguanides

Dietary complex CH are broken down to simple sugars in the GIT by the action of glucosidases; simple sugar then absorbed by GI epithelial cells
and transported into the bloodstream. Glucose in the blood is taken up by all metabolically active tissues in the body. In pancreatic cells, glucose
metabolism levels of cytosolic ATP, which stimulates insulin secretion. Insulin then acts on plasma membrane insulin receptors in target tissues
(muscle, adipose, liver) to glucose uptake and storage as glycogen or TG. Glucose is also taken up by other cells and tissues to fuel metab. In
muscle cells, ins. Promotes glucose storage as glycogen. In adipose cells, ins. Promotes glucose conversion to TG. Peroxisme proliferatoractivated recr (PPAR) also promotes the conversion of glucose to TG in adipose cells. In liver cells, insulin promotes glucose storage as
glycogen. Glucagon promotes both the conversion of glycogen back to glucose and gluconeogenesis; glucose generated from glycogen or by
gluconeogenesis is transported out of the liver cell into the bloodstream. Pharmacologic interventions that blood gluc. Levels include : inhibiting
intestinal -glucosidase; administering exogenous ins; using sulfonylurea or meglitinides to augment secretion of insulin by cells; and using
5
biguanides or thiazolidinediones to enhance the action of insulin in liver or adipose cells, respectively. Diazoxide inhibits insulin scretion from
pancreatic cells.

INSULIN

Mekanisme intrasel sekresi insulin oleh cells

1) Glukosa masuk ke cells dengan

bantuan glucose transporters
(GLUT2).
2) Di dalam cells glukosa difosforilasi
glucose-6 phosphate yang
dimetabolisme menghasilkan ATP
(glycolysis, mitochondria).
3) rasio ATP/ADP ratio tertutupnya
ATP sensitive K+ channels,membrane
depolarization dan membuka voltagedependent Ca2+ channels.
4) Ca2+intrasellular exositosis dari
insulinsecretory granules.

Penatalaksanaan
Diet : medical nutrition therapy
Aktivitas Fisik/OR
Farmakoterapi
Kontrol BB
Self-monitoring of blood glucose (SMBG)
Patient self-management education

KEBERHASILAN MANAJEMEN
ASPEK METABOLIK DARI DM

Farmakoterapi
Insulin Replacement Therapy
1. Insulin dependent group (type 1) :
- virtually no insulin secretion
- depends on administration of exogenous insulin
2. Type 2 :
- most type 2 diabetics do not require exogenous insulin
for survival, but many need exogenous supplementation
of their endogenous secretion to achieve optimum health
- 20% taking insulin
8

Characteristics of Available Insulin Preparations

4 principal types of insulins :

1. Rapid acting :
- very fast onset & short duration
- duration of action : 3-5 hours
2. Short acting: rapid onset of action :
- onset of action : within 30 minutes
- duration of action : 5-8 hours
3. Intermediate acting
4. Long acting : slow onset of action
9

Characteristics of Available Insulin Preparations

10

11

Neutral Protamine Hagedorn/isophane

Insulin Delivery Systems

R, lispro
2. Continuous Subcutaneous Insulin Infusion
Devices (CSII, Insulin Pumps)

1. Portable Pen Injectors

R, lispro,NPH, pre-mixed NPH 70%/R

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3. Inhaled insulin

13

Lokasi penyuntikan insulin yang

dianjurkan
Perut : absorpsi cepat
Lengan : absorpsi sedang
Paha : absorpsi lambat
Gluteus : absorpsi lambat
Contoh peta penyuntikan insulin selama 1 tahun
pada penderita DM tipe 1

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Complications of Insulin Therapy

1. Hypoglycemia
- Delay in taking a meal

causes

- Inadequate carbohydrate consumed

- Physical over exertion
- Dose of insulin too large for immediate needs
- Autonomic hyperactivity :

signs

Sympathetic : tachycardia, palpitations, sweating, tremulousness

Parasympathetic : nausea, hunger

- Convulsions
- Coma

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Complications of Insulin Therapy

1. Hypoglycemia
- Mild hypoglycemia : conscious and able to swallow :

treatment

Orange juice
Glucose gel
Any sugar containing beverage/food
- Severe hypoglycemia : unconsciousness/stupor :
20-50 ml of 50% glucose solution (IV infusion over 2-3 minutes)
1 mg glucagon : IM/SC
small amounts of honey or syrup : buccal pouch
Contraindication : oral feeding

16

Complications of Insulin Therapy

- Insulin allergy :

2. Immunopathology of Insulin Therapy

Rare condition

treatment

Urticaria
Anaphylaxis
Highly purified and human insulins : insulin allergy
- Immune insulin resistance :
A low titer of circulating IgG anti-insulin antibodies that neutralize
the action of insulin to a negligable extent develops in most insulintreated patients.
Rarely, the titer of insulin antibodies will lead to insulin resistance
and may be associated with other systemic autoimmune processes
such as lupus erythematosus

17

Complications of Insulin Therapy

3. Lipodystrophy at injection sites
- Atrophy
- Hyperthrophy

Corrected by :
- avoidance of that spesific injection
- liposuction
18

Oral Antidiabetic Agents

Major Classes of Medications
1. Drugs that stimulate
the pancreas to make
more insulin (Insulin
secretagogues)
2. Drugs that sensitize
the body to insulin
and/or control
hepatic glucose
production (Insulin
sensitizers)
3. Drugs that slow the
absorption of
starches

Sulfonylureas
Meglitinides

Thiazolidinediones
Biguanides

Alpha-glucosidase
inhibitors
19

Physiologic and Pharmacologic Regulation of Glucose Homeostasis

GIT
Dietary complex carbohydrates
-glucosidase
inhibitors

cell
Glucosidases
Blood

Other tissues

Glucose
Metabolism
Muscle
cell

Glucose
(from GIT
& liver)

Adipose cell
glucose

Triglyceride

Glycogen

Metabolism

Insulin
secretion

ATP
Sulfonylureas,
meglitinides

Insulin

Liver cell
Glucose
Glucose

PPAR
Thiazolidinediones

Glucose

Diazoxide

To tissues

To tissues
Insulin

Insulin

Glucose

Endogenous insulin
(from cell) or
Exogenous insulin

Glycogen

Glucagon

Gluconeogenesis

Biguanides

Dietary complex CH are broken down to simple sugars in the GIT by the action of glucosidases; simple sugar then absorbed by GI epithelial cells
and transported into the bloodstream. Glucose in the blood is taken up by all metabolically active tissues in the body. In pancreatic cells, glucose
metabolism levels of cytosolic ATP, which stimulates insulin secretion. Insulin then acts on plasma membrane insulin receptors in target tissues
(muscle, adipose, liver) to glucose uptake and storage as glycogen or TG. Glucose is also taken up by other cells and tissues to fuel metab. In
muscle cells, ins. Promotes glucose storage as glycogen. In adipose cells, ins. Promotes glucose conversion to TG. Peroxisme proliferatoractivated recr (PPAR) also promotes the conversion of glucose to TG in adipose cells. In liver cells, insulin promotes glucose storage as
glycogen. Glucagon promotes both the conversion of glycogen back to glucose and gluconeogenesis; glucose generated from glycogen or by
gluconeogenesis is transported out of the liver cell into the bloodstream. Pharmacologic interventions that blood gluc. Levels include : inhibiting
intestinal -glucosidase; administering exogenous ins; using sulfonylurea or meglitinides to augment secretion of insulin by cells; and using
20
biguanides or thiazolidinediones to enhance the action of insulin in liver or adipose cells, respectively. Diazoxide inhibits insulin scretion from
pancreatic cells.

Oral Antidiabetic Agents

Insulin secretagogues : sulfonylureas
Hati-hati pada alergi sulfa

Mechanism of Action :
- To increase the insulin release from pancreatic cells
- Reduction of serum glucagon concentrations
- Potassium channel closure in extrapancreatic
tissues

21

Sulfonylureas

Rel. Potency

b
i
n
d
t
o
p
r
o
t
e
i
n

1st generation
- tolbutamide
- tolazamide
- chlorpropamide

may become dislodged delayed activity

2nd generation
Glipizide
glyburide

- glimepiride

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Oral Antidiabetic Agents

Insulin secretagogues : sulfonylureas
1st generation

1. Tolbutamide :
- well absorbed but rapidly metabolized in the liver
- duration of effect : short
- t1/2 : 4-5 hours
- safest for elderly diabetics
- dicumarol, phenylbutazone, some sulfonamide
inhibit the metabolism tolbutamide
hypoglycemia
23

Oral Antidiabetic Agents

Insulin secretagogues : sulfonylureas
1st generation

2. Tolazamide :
- more slowly absorbed than the other sulfonylurea
- t1/2 : 7 hours
- metabolized to several compounds that retain hypoglycemia
- dosages > 500 mg daily ~ divided twice daily

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Oral Antidiabetic Agents

Insulin secretagogues : sulfonylureas
1st generation

3. Chlorpropamide :
- slowly metabolized
- t1/2 : 32 hours
- 20-30% excreted unchanged in the urine
- drug int. : dicumarol, phenylbutazone, some sulfonamide
- contraindicated : hepatic /renal insufficiency, elderly patients
- dosages > 500 mg daily increase the risk of jaundice
- side effects : hypoglicemia, hyperemic flush, hematologic
toxicity ( transient leukopenia, thrombocytopenia)
~ 1%
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Oral Antidiabetic Agents

Insulin secretagogues : sulfonylureas
2 nd generation

fewer side effects

fewer drug interaction

1. Glyburide /glybenclamide :

- metabolized in the liver into products with very low hypoglycemic

activity
- usual starting dosage : 2,5 mg/d or less
- average maintenance dosage : 5-10 mg/d single morning dose
- maintenace dosages higher than 20 mg/d are not recommended
- adverse effects : hypoglycemia, flushing
- contraindication : hepatic impairment, renal insufficiency
26

Oral Antidiabetic Agents

Insulin secretagogues : sulfonylureas
2 nd generation
2. Glipizide (Glucotrol )

- shortest half life : 2-4 hours

- 30 minutes before breakfast
- 90% metabolized in the liver to inactive products
- 10% excreted unchanged in the urine
-starting dosage : 5 mg/d up to 15 mg/d as a single dose
max. 40 mg/d
- lower hypoglycemia compared long acting glyburide
- contraindicated : hepatic impairment, renal insufficiency
27

Oral Antidiabetic Agents

Insulin secretagogues : sulfonylureas
3. Glimepiride
- t1/2 : 5 hours
- long duration of effect
- once daily use as monotherapy or in combination
with insulin ~ compliance
- lowets dose of anysulfonylurea compound : 1 mg
single daily dose, maximal 8 mg.
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Oral Antidiabetic Agents

Insulin secretagogues : meglitinides
Meglitinides stimulate insulin secretion (rapidly and for a
short duration) in the presence of glucose.
quick-on, quick-off (awal kerja cepat, masa kerja
pendek) kontrol postprandial yang lebih baik dan
menurunkan insiden hipoglikemia postprandial.
Efficacy
Decreases peak postprandial glucose
Decreases plasma glucose 60-70 mg/dl (3.3-3.9 mmol/L)

Other Effects
Hypoglycemia (although may be less than with sulfonylureas if patient has
a variable eating schedule)
Weight gain

Ex: repaglinide (Prandin), nateglinide (Starlix)

can be taken safely by people with impaired kidney function or sulfa allergies.
29

Oral Antidiabetic Agents

Insulin secretagogues : D- phenylalanine derivative
Nateglinide
the latest insulin secretagogue to become clinically available
stimulate release of insulin very rapidly and transiently from
B cells through closure of the ATP-sensitivie K+ channel
ingested just prior to meal
absorbed within 20 minutes after oral administration
t1/2 1,5 hours
metabolized by CYP2C9 and CYP3A4
hypoglycemia : lowest
safe in : very reduced renal function

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Oral Antidiabetic Agents

Insulin secretagogues

31

Oral Antidiabetic Agents

Biguanides------ Metformin
Mechanisms of Action
1. Direct stimulation of glycolisis in tissues
2. Reduced hepatic & renal gluconeogenesis
3. Slowing of glucose absorption from GIT
4. Reduction of plasma glucagon levels
Metabolism & Excretion
Metformin :
t1/2 : 1,5-3 hours
Is not bound to plasma protein
Is not metabolized
Is excreted by the kidney as the active compound

32

Oral Antidiabetic Agents

Biguanides------ Metformin
Clinical Use
Insulin resistance syndrome
Dosage : 500 mg to max 2,55 gr daily
Toxicities
anorexia, nausea, vomiting, abdominal discomfort, diarrhea
lactic acidosis
Contraindication
renal disease, alcoholism, hepatic disease, conditions
predisposing to tissue anoxia (eg. Chronic cardiopulmonary
dysfunction)

33

Oral Antidiabetic Agents

Thiazolidinediones
Pioglitazone (Actos), rosiglitazone (Avandia),
[troglitazone (Rezulin) - (muncul 1997, ditarik tahun
2000 karena dicurigai menyebabkan idiosinkratik
hepatoselular)
Decrease : insulin resistance

34

Oral Antidiabetic Agents

Alpha Glucosidase Inhibitors
Alpha-glucosidase inhibitors block the enzymes that digest starches in
the small intestine slowing the rise in B.G.L.
Efficacy
Decrease peak postprandial glucose 40-50 mg/dl (2.2-2.8 mmol/L)
Decrease fasting plasma glucose 20-30 mg/dl (1.4-1.7 mmol/L)
Other Effects
Flatulence or abdominal discomfort
No specific effect on lipids or blood pressure
No weight gain
Contraindicated in patients with inflammatory bowel disease or
cirrhosis
Examples:

acarbose (Glucobay),
miglitol (Glyset) absorpsi oral yang lebih baik daripada acarbose
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Pathophysiology of Type 2 Diabetes

One last observation

In 1930 La Barre described a greater effect of oral rather
parenteral glucose in increasing insulin secretion.
In 1986 Nauck demonstrated that a glucose infusion
graded to achieve plasma glucose levels identical o
those achieved with oral glucose led to a insulin
response that was only one quarter as great.
J Clin Endocrinol Metab. 1986;63:492-498.

Incretin hormones were discovered during researchers

trials to find out interpretation to this phenomenon which
has been called the incretin effect.
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What are incretins?

Hormones produced by the gastrointestinal
tract in response to incoming nutrients, and
have important actions that contribute to
glucose homeostasis.
Two hormones:
- Gastric inhibitory polypeptide (GIP)
- Glucagon-like peptide-1 (GLP-1)
37

Physiological effects of incretins

prandial insulin secretion
glucagon secretion
Acid secretion and GI motility (
gastric emptying
satiety and food intake
? cell protection
? Cardiovascular effects
38

Incretins and glycaemic control

Ingestion
of food

Glucose dependent

Insulin

from beta cells

(GLP-1 and GIP)

GI tract

Release of
incretin gut
hormones
Active
GLP-1 and GIP

DPP-4
enzyme rapidly
degrades
incretins

Pancreas

Insulin
increases
peripheral
glucose
uptake

Beta cells
Alpha cells

Glucagon

from alpha cells

(GLP-1)
Glucose
dependent

Blood
glucose
control
Increased insulin
and decreased
glucagon
reduce
hepatic
glucose output

39
Adapted from 7. Drucker DJ. Cell Metab. 2006;3:153165. 8. Miller S, St Onge EL. Ann Pharmacother 2006;40:1336-1343.

What are incretins?

Gastric Inhibitory Polypeptide

(GIP)
Secreted by the K cells of the proximal
gut.
However, type 2 diabetes patients are
resistant to its action (high blood level),
making it a less attractive therapeutic
target.
40

What are incretins?

Glucagon-like peptide-1 (GLP-1)

a 30-amino acid peptide secreted in
response to the oral ingestion of nutrients
by L cells, primarily in the ileum and colon.
There are GLP-1 receptors in islet cells
and in the central nervous system, among
other places.
GLP-1 is metabolized by the enzyme
dipeptidyl peptidase-IV (DPP-IV) .
41

Actions of GLP-1
It enhances glucose-dependent insulin
secretion.
Inhibits glucagon secretion and
therefore hepatic glucose production
Slows gastric emptying
Increases satiety resulting in less food
intake.
Appears to stimulate insulin gene
transcription and insulin synthesis.
42

Actions of GLP-1

The Problem
Unfortunately, GLP-1 is rapidly broken down
by the DPP-IV enzyme (very short half-life in
plasma - requires continuous IV infusion)
The solution:
1. Incretin mimeticGLP-1 agonist
2. Dipeptidyl peptidase-IV (DPP-IV)
antagonist will inhibit the breakdown
of GLP-1
43

1. Incretin mimetics : Exenatide

The first incretin-related therapy available for
patients with type 2 diabetes.
Naturally occurring peptide from the saliva of the
Gila Monster.
Has an approximate 50% amino acid homology
with GLP-1.
Binds to GLP-1 receptors and behaves as GLP-1.

44

1. Incretin mimetics : Exenatide

Resistant to DPP-IV inactivation.
Following injection, it is measurably
present in plasma for up to 10 hours.
Suitable for twice a day administration by
subcutaneous injection.
Regul Pept. 2004;117:77-88.
Am J Health Syst Pharm. 2005;62:173-181.

45

46

Incretin mimetics : Recent Advances

Liraglutide:
- Another GLP-1 analog with longer half-life
- similar to exenatide with once-daily
injection. Diabetes Care. 2007;30:1608-1610
Long acting exenatide:
- Highly effective with once weekly injection.
Diabetes Care. 2007;30:1487-1493
47

2. Dipeptidyl Peptidase-IV Antagonists

The concept is to allow the endogenous GLP-1 to
remain in circulation for a longer period.
DPP-IV inhibitors are oral, rather than injectable.
Weight neutral.
Associated with a low incidence of hypoglycemia
or gastrointestinal side effects. Diabetes Care.
2004;27:2874-2880.

Preliminary long-term studies suggest a durable

effect on glycemia and improvement in some
parameters of beta-cell function. (www.glucagon.com).
48

2. Dipeptidyl Peptidase-IV Antagonists:

Sitagliptin and Vildagliptin
Sitagliptin and vildagliptin are the first agents in
this class to have received FDA approval.
Incidence of adverse reactions was reported to
be very low in a pooled safety data from 5141
patients. ADA meeting, Chicago, June 2007.
They are indicated as monotherapy and in
combination with metformin, thiazolidinediones
and insulin.
They look to be at least weight neutral.

49

Mode of action of sitagliptin

Ingestion
of food

Glucose dependent

Insulin

from beta cells

(GLP-1 and GIP)

GI tract

Release of
incretin gut
hormones
Active
GLP-1 and GIP

Sitagliptin is a
DPP-4 inhibitor
and inhibits the
breakdown of
incretins and
thereby increases
active incretin
levels

DPP-4
enzyme
rapidly
degrad
es
incretins

DPP-4= dipeptidyl peptidase 4 inhibitor

Pancreas

Insulin
increases
peripheral
glucose
uptake

Beta cells
Alpha cells

Glucagon

from alpha cells

(GLP-1)
Glucose
dependent

Adapted from 8. Miller S, St Onge EL. Ann Pharmacother 2006;40:1336-1343.

Blood
glucose
control
Increased insulin
and decreased
glucagon
reduce
hepatic
glucose output

50

 Insulin resistance and relative insulin

secretory defect are key elements of
the pathogenesis of type 2 diabetes.
GLP-1 deficiency is another key
component in diabetic pathophysiology
contributing to:
- insulin secretory deficit.
- excess of plasma glucagon.
- postprandial hyperglycemia.
51

ISLET AMYLOID POLYPEPTIDE

(IAPP, AMYLIN)
37-amino-acid peptide
derived from amyliod deposits in pancreas material from patients
with longstanding type 2 diabetes or insulinomas
inhibit the action of insulin to promote muscle uptake of glucose
pramlintide (analog IAPP) : adjunct to insulin therapy in type 1
diabetic patients with recurrent episodes of severe insulin-induced
hypoglycemia. still in clinical trial

52

GLUCAGON
Pharmacologic Effects
metabolic effects : glucagon recr liver cells-Gs protein-linked
increase I adenyly cyclase activity-cAMP> ~ catabolism of stored
glycogen and increases gluconeogenesis and ketogenesis
release of insulin from normal pancreatic B cells, cathecolamines
from pheochromocytoma, calcitonin from medullary carcinoma cells
smooth muscle : profound relaxation of intestine
cardiac effects : inotropic (+)ve and chronothropic (+)ve

53

GLUCAGON
Clinical Use
severe hypoglicemia
endocrine diagnosis
beta-blocker poisoning
radiology of the bowel
Adverse Reactions
transient nausea and occasional vomiting

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KEBANGGAAN INDONESIA UNTUK DUNIA

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