Anti Diabetes Mellitus

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

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Anti Diabetes Mellitus