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7/31/2019 Anti Diabetes Mellitus
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dr. Woro Rukmi Pratiwi, M.Kes., SpPD.
Departement of Pharmacology and TherapyFaculty of medicine, Universitas Gadjah Mada
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Fasting Plasma Glucose Test
(FPG) - (cheap, fast)
*fasting B.G.L. 100-125 mg/dl
signals pre-diabetes
*>126 mg/dl signals diabetes
Oral Glucose Tolerance Test
(OGTT)
*tested for 2 hrs after
glucose-rich drink
*140-199 mg/dl signals pre-
diabetes
*>200 mg/dl signals diabetes
80 to 90 mg per 100 ml, is the normal fasting blood glucose
concentration in humans and most mammals which is
associated with very low levels of insulin secretion.
A.K.A.: Glycated Hemoglobin tests
A1C
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Stage 1 Insulin was extracted from the glands ofcows and pigs. (1920s)
Stage 2 Convert pig insulin into human insulin byremoving the one amino acid that distinguishes themand replacing it with the human version.
Insulin drug evolution
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Stage 3 Insert the humaninsulin gene into E. coli andculture the recombinantE.coli to produce insulin(trade name = Humulin).Yeas t i s a l so used to
produce insulin. (1987).
Recombinant DNA technology has also made it possible tomanufacture slightly-modified forms of human insulin that
work faster (Humalog and NovoLog) or slower
(Lantus) than regular human insulin.
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Types of insulin
Regular insulins
Insulin analogs
Pre-mixed insulin
Short peptide mimics
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Regular insulins:
Human insulin: Humulin(from E.coli),
Novalin(from yeast)
NPH - neutral protamine Hagedorn (NPH),protamine mixed.
Lenteinsulin / Ultralenteinsullin-
zincadded
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Types of insulin
Regular insulins
Insulin analogs
Pre-mixed insulin
Short peptide mimics
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Insulin Analogs:
Fatty Acid Acylated insulins
Insulin Lispro (Humalog) (1996)
Insulin Aspart (NovoLog) (2000)
Insulin Glargine (Lantus) (2002)
Insulin Detemir (Levemir) (Jun.,2005)
Insulin Glulisine (Apidra) (Jan., 2006)
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Amino Acid Substitutons
A-chain
Position
B- chain Position
Source/Type
A21 B3 B28 B29 B30 B31AndB32
Human Asn Asn Pro Lys Thr
Aspart AsnAspartic
acid Lys Thr
Lispro Asn Lys Pro Thr
Glulisin
e
Asn Lys Pro Glu Thr
Glargine Gly Pro Lys Thr Arg
Detemir Lys Myristicacid
rapid-acting
long-acting
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Sulfonylureas interact with receptors onpancreatic b-cells to block ATP-sensitivepotassium channels
This, in turn, leads to opening of calciumchannels
Which leads to the production of insulin
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1st generation (1)Orinase (tolbutamide)
(3)Tolinase (tolazamide)
(6)Diabinese (chlorpropamide)
2nd generation
(75)Glucotrol (glipizide)
(150)Glucotrol XL (ex. rel. glipizide)
(150)Micronase, Diabeta (glyburide) (250)Glynase (micronized glyburide)
3rd generation
(350)Amaryl (glimepiride)
Rel.Potency
bindtoprotein
may become dislodged delayed activity
*Hydroxylation of the aromatic ring appears to be the most favored metabolic pathway*H drox lated derivatives have much lower h o l cemic activit
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Sulfonylureas interact with receptors onpancreatic b-cells to block ATP-sensitivepotassium channels
This, in turn, leads to opening of calciumchannels
Which leads to the production of insulin
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Metformin- Glucophage, Fortamet,
Riomet
*only anti-diabetic drug that has been proven to reduce the complications of diabetes, as evidenced in a large study of overweight patients with
diabetes (UKPDS 1998).
- Metformin was first described in the scientific literature in 1957 (Unger et al).
- It was first marketed in France in 1979 but did not receive FDA approval for Type
2 diabetes until 1994.
NN
NN
N
R
R R
R
RR
R
N N
N
N
N
H
H
H
H H
+ HCl
- mechanism improves insulin sensitivity by increasing peripheral glucoseuptake and utilization.
- Zhou et al (2001) showed that metformin stimulates the hepatic enzyme
AMP-activated protein kinase
Metformin is a widely used monotherapy, and also used in combination with
the sulfonylureas in treatment of type 2 diabetes
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Glyburide & Metformine HCl
NH
O
NH
SO
O
O
O
NH
Cl
1-[[ p-[ 2-( 5-chloro-o-anisamido) ethyl] phenyl] sulfonyl]-3-cyclohexylurea
N N
N
N
N
H
H
H
H H
+ HCl
&
&
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Pioglitazone
- binds to and activates the gamma isoform of the peroxisome proliferator-activated receptor (PPAR).
- PPAR is a member of the steroid hormone nuclear receptor superfamily, and is found in adipose tissue,
cardiac and skeletal muscle, liver and placenta
- upon activation of this nuclear receptor by a ligand such as a TZD,
PPARligand complex binds to a specific region of DNA and therebyregulates the transcription of many genes involved in glucose and fatty
acid metabolism.
S
NH
O
O
ON
5-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-thiazolidine-2,4-dione
- Marketed in USA in August of 1999
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AGIs
- acarbose
- miglitolN
OO
O
O
O
H
H H
H H
1-(2-Hydroxy-ethyl)-2-hydroxymethyl-piperidine-3,4,5-triol
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Meglitinides
- repaglinide
- nateglinide
O
OHO
NH
N
O
2-Ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid
O
OH
NH
O
2-[(4-Isopropyl-cyclohexanecarbonyl)-amino]-3-phenyl-propionic acid
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Sulfonylureas stimulate cells
Biguanides improves insulins ability to move glucose
Sulfonylureas and biguanide combination drugs BOTH
Thiazolidinediones cells more sensitive to insulin
Alpha-glycosidase inhibitors Block enzymes that help digeststarches
Meglitinides stimulate cells(dependant upon glucose conc.)
6 Classes :
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GLUCOSE
ABSORPTION
GLUCOSEPRODUCTION
Metformin
Thiazolidinediones
MUSCLE
PERIPHERAL
GLUCOSE UPTAKE
Thiazolidinediones
Metformin
PANCREAS
INSULIN SECRETION
Sulfonylureas: Glyburide, Gliclazide, Glimepiride
Non-SU Secretagogues: Repaglinide, Nateglinide
ADIPOSE
TISSUELIVER
Alpha-glucosidase inhibitors
INTESTINE
Adapted from Sonnenberg, Kotchen Curr Opin Nephrol Hypertens 1998; 7:551-5.
http://localhost/var/www/apps/conversion/current/tmp/scratch14282/FARMAKO%20SINDROMA%20METABOLIK.pptx