Farmakodinamik Obat

Diabetes Melitus

Nur Asma S Somadayo

Abdurahman Ridho
The pancreatic exocrine function involves the acinar cells secreting
digestive enzymes that are transported into the small intestine by the
pancreatic duct. Its endocrine function involves the secretion of insulin
(produced by beta cells) and glucagon (produced by alpha cells) within
the pancreatic islets. These two hormones regulate the rate of glucose
metabolism in the body. T
https://www.drawittoknowit.com/term/physiology/endocrine-pancreas
Bertram Katzung, Susan Masters, Anthony Trevor-Basic and Clinical Pharmacology, 11th Edition (LANGE Basic
Science) -McGraw-Hill Medical (2009) p 728
 DiabetesMellitus :
Diabetes mellitus (DM) is a group of metabolic disorders characterized by
hyperglycemia and abnormalities in carbohydrate, fat, and protein metab- olism. It
results from defects in insulin secretion, insulin sensitivity, or both.

 20.8 million in US ( 7% of population)

 estimated 14.6 million diagnosed (only 2/3)
 Consists of 3 types:
1) Type 1 diabetes
2) Type 2 diabetes
3) Gestational diabetes

Barbara Wells, Joseph DiPiro, Terry Schwinghammer, Cecily DiPiro-

Pharmacotherapy Handbook-McGraw-Hill Medical (2008)
Irl B. H., (2001) Clin. Diabetes 19, 146-7
Diagnosis of Diabetes Mellitus

 Hba1C ≥6,5%* or ≥7,0%**

 Fasting Plasma Glucose (8 jam) ≥126 mg/dL (7,0 mmol/L)
 2 hours plasma glucose ≥200 mg/dL (11,1 mmol/L) or more during an oral
glucose tolerance test (OGTT) using a glucose load containing the equivalent
of 75 g anhydrous glucose dissolved in water
 Randome plasma glucoe ≥200 mg/dL (11.1 mmol/L) or more with classic
symptoms of hyperglycemia
*American Association of Clinical Endocrinologists
**American Diabetes Association
Glukose metabolism
Insulin-mediated glucose transport signaling
pathway
Insulin

IR
a a
b b

P
IRS
PI3K

Glut4 Akt
P
cont
Insulin-mediated glucose transport signaling
pathway
Glucose Uptake Assay
Insulin

IR
glucose a a
b b

P
IRS
PI3K

Akt
P
insulin sulfonylurea

biguanida tiazolidindione

Alfa GLP-1
Agonist and
glukosidase DPP 4
inhibitor Inhibitor
INSULIN
Insulin is a small protein consisting of an A
A chain chain of 21 amino acids linked by two disulfide
(S—S) bridges to a B chain of 30 amino acids.

Beta cells have channels in their plasma

membrane that serve as glucose
detectors. Beta cells secrete insulin in
response to a rising level of circulating
glucose.
B chain
Glukose metabolism
Insulin-mediated glucose transport signaling
pathway
Insulin

IR
a a
b b

P
IRS
PI3K

Glut4 Akt
P
cont
Insulin-mediated glucose transport signaling
pathway
Glucose Uptake Assay
Insulin

IR
glucose a a
b b

P
IRS
PI3K

Akt
P
 Amino Acid Substitutons
A- B- chain Position
chai
n
Position
Source/ A21 B3 B28 B29 B30 B31
Type And
B32
Human Asn Asn Pro Lys Thr
Aspart Asn Aspartic Lys Thr
acid
Lispro Asn Lys Pro Thr
Glulisin Asn Lys Pro Glu Thr rapid-acting
e
Glargine Gly Pro Lys Thr Arg
Detemir Lys Myristic
acid long-acting
Bertram Katzung, Susan Masters, Anthony Trevor-Basic and Clinical Pharmacology, 11th Edition (LANGE
Sulfonylureas : stimulate β cells to produce more insulin

 1st generation
2-(p-aminobenzenesulfonamido)-5-isopropyl -thiadiazole
(1)Orinase (tolbutamide)

bind to protein
 (IPTD) was used in treatment of typhoid fever in 1940’s 
hypoglycemia
Currently > 12,000
 (3)Tolinase (tolazamide)
 (6)Diabinese (chlorpropamide)
 may become dislodged  delayed activity
¨ 2nd generation
Rel. Potency

– (75)Glucotrol (glipizide)
– (150)Glucotrol XL (ex. rel. glipizide)
– (150)Micronase, Diabeta (glyburide)
– (250)Glynase (micronized glyburide)

¨ 3rd generation
– (350)Amaryl (glimepiride)
*Hydroxylation of the aromatic ring appears to be the most favored metabolic pathway
*Hydroxylated derivatives have much lower hypoglycemic activity
Mechanism action of sulfonilurea

 Katzung,Bertram G. . 2009. Farmakologi Dasar dan Klinik Edisi 11EGC : Jakarta.

Lang, Veronica and Light, Peter E. . 2010. The Moleculer Mechanisms and Pharmacotherapy of ATP-Sensitive Potassium Channel Gen Mutations Underlying Neonatal Diabetes.
Pharmacogenomics and Personalized Medicine.Dove Medical Press Ltd. 3. 145-161
 Biguanides : improves insulin’s ability to
move glucose into cells (esp. muscle)
 Mechanisms of Action A full explanation of the
mechanism of action of the bigua- nides remains
elusive, but their primary effect is to reduce he-
patic glucose production through activation of the
enzyme AMP-activated protein kinase (AMPK).
Possible minor mechanisms of action include
impairment of renal gluconeo- genesis, slowing of
glucose absorption from the gastrointesti- nal tract,
with increased glucose to lactate conversion by
enterocytes, direct stimulation of glycolysis in
tissues, in- creased glucose removal from blood, and
reduction of plasma glucagon levels. The biguanide
blood glucose-lowering action does not depend on
functioning pancreatic beta cells. Patients with type
2 diabetes have considerably less fasting hyperglyce-
mia as well as lower postprandial hyperglycemia
after bigu- anides; however, hypoglycemia during
biguanide therapy is essentially unknown. These
agents are therefore more appro- priately termed
“euglycemic” agents.
Bertram Katzung, Susan Masters, Anthony Trevor-Basic and Clinical Pharmacology,
11th Edition (LANGE Basic Science) -McGraw-Hill Medical (2009)
Graham Rena & Ewan R. & Kei Sakamoto, 2013. Molecular mechanism of action of metformin: old or new
insights
Thiazolidindiones (Pioglitazone,
Rosiglotazone)
 They are ligans of peroxisome proliferator-activated receptor gamma
(PPAR-f), part of the steroid and thyroid superfamily of nuclear receptors.
They enhance insulin sensitivity in muscle, liver, and fat tissues. When given
for 6 months at maximal doses, thiazolidindione reduce A1C by ~1.5% and FPG
by 60 to 70 mg/dL (3.3–3.9 mmol/L).
 Fluid retention may occur, and peripheral edema is reported in 4% to 5% of
patients. When used with insulin, incidence of edema is ~15%. Weight gain of
1.5 to 4 kg is common.
 Thiazolidindione have also been associated with liver injury, increased
fractures, and a slightly increased risk of bladder cancer.
Mechanism of Action of
Thiazolidinediones
GLP-1 Agonist (Exenatide, liraglutide))

 GLP-1 Agonist enhances insulin secretion and reduces hepatic glucose

production. It also increases satiety, slows gastric emptying, and promotes
weight loss. It significantly decreases postprandial glucose but has only a
modest effect on FPG. Average A1C reduction is ~0.9% with twice-daily
exenatide.
 The most common adverse effects are nausea (44%), vomiting, and diarrhea.
Injection site reactions (nodules, erythema) may occur with extended-release
product. All of the GLP-1 receptor agonists may increase the risk of
pancreatitis
DPP-4 Inhibitor (Sitagliptin, Saxagliptin)

 DPP-4 inhibitors partially reduce the inappropriately elevated glucagon

postprandially and stimulate glucose-dependent insulin secretion. Average
A1C reduction 0.7% to 1% at maximum dose.
 Common adverse effects include nasopharyngitis, upper respiratory
infections, and headaches. Hypoglycemia can occur when the drug is
combined with insulin secretagogues or insulin. There have been
postmarketing reports of acute pancreatitis (fatal and nonfatal) and severe
allergic and hypersensitivity reactions.
Mechanism of Action of GLP-1 Agonist
and DPP 4 Inhibitor
Mechanism of Action of Alfa Glucosidase
Inhibitor
 The antihyperglycemic action of acarbose results from a competitive,
reversible inhibition of pancreatic alpha-amylase and membrane-bound
intestinal alpha-glucoside hydrolase enzymes. Pancreatic alpha-amylase
hydrolyzes complex starches to oligosaccharides in the lumen of the small
intestine, while the membrane-bound intestinal alpha-glucosidases hydrolyze
oligosaccharides, trisaccharides, and disaccharides to glucose and other
monosaccharides in the brush border of the small intestine. In diabetic
patients, this enzyme inhibition results in a delayed glucose absorption and a
lowering of postprandial hyperglycemia.
 The most common side effects are flatulence, bloating, abdominal
discomfort, and diarrhea, which can be minimized by slow dosage titration.
 If hypoglycemia occurs when used in combination with a hypoglycemic agent
(sulfonylurea or insulin), oral or parenteral glucose (dextrose) products or
glucagon must be given because the drug will inhibit breakdown and
absorption of more complex sugar molecules (eg, sucrose).
Daftar pustaka

  Graham Rena & Ewan R. & Kei Sakamoto, 2013. Molecular mechanism of
action of metformin: old or new insights
 https://www.drawittoknowit.com/term/physiology/endocrine-pancreas
diakses tanggal 14 november 2018
 Katzung,Bertram G. . 2009. Farmakologi Dasar dan Klinik Edisi 11EGC :
Jakarta.
 Lang, Veronica and Light, Peter E. . 2010. The Moleculer Mechanisms and
Pharmacotherapy of ATP-Sensitive Potassium Channel Gen Mutations
Underlying Neonatal Diabetes. Pharmacogenomics and Personalized
Medicine.Dove Medical Press Ltd. 3. 145-161