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dr. Woro Rukmi Pratiwi, M.Kes., SpPD.

Departement of Pharmacology and Therapy Faculty of medicine, Universitas Gadjah Mada

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 prediabetes *>200 mg/dl signals diabetes

A.K.A.: Glycated Hemoglobin tests A1C

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.

Insulin drug evolution


Stage 1 Insulin was extracted from the glands of cows and pigs. (1920s)

Stage 2 Convert pig insulin into human insulin by removing the one amino acid that distinguishes them and replacing it with the human version.

Stage 3 Insert the human insulin gene into E. coli and culture the recombinant E.coli to produce insulin (trade name = Humulin). Yeast is also used to produce insulin. (1987).

Recombinant DNA technology has also made it possible to manufacture slightly-modified forms of human insulin that work faster (Humalog and NovoLog) or slower (Lantus) than regular human insulin.

Types of insulin

Regular insulins Insulin analogs Pre-mixed insulin

Short peptide mimics

Regular insulins:

Human insulin: Humulin (from E.coli), Novalin (from yeast) NPH - neutral protamine Hagedorn (NPH), protamine mixed. Lente insulin / Ultralente insullinzinc added

Types of insulin

Regular insulins Insulin analogs Pre-mixed insulin

Short peptide mimics

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)

Amino Acid Substitutons


Achai n Position
Source/ Type Human Aspart Lispro Glulisin e Glargine A21 Asn Asn Asn Asn Gly Lys B3 Asn

B- chain Position

B28 Pro Aspartic acid Lys Pro Pro

B29 Lys Lys Pro Glu Lys

B30 Thr Thr Thr Thr Thr

B31 And B32

rapid-acting

Arg

Detemir

Lys

Myristic acid

long-acting

6 Classes :

Sulfonylureas Biguanides Sulfonylureas and biguanide combination drugs Thiazolidinediones Alpha-glycosidase inhibitors Meglitinides

Sulfonylureas interact with receptors on pancreatic b-cells to block ATP-sensitive potassium channels This, in turn, leads to opening of calcium channels Which leads to the production of insulin

1st generation

bind to protein

(1)Orinase

(tolbutamide) (3)Tolinase (tolazamide) (6)Diabinese (chlorpropamide)


may become dislodged delayed activity

Rel. Potency

2nd generation
(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

Sulfonylureas interact with receptors on pancreatic b-cells to block ATP-sensitive potassium channels This, in turn, leads to opening of calcium channels Which leads to the production of insulin

R R R N R N
H H +

Metformin

H N H N N N N

N R N

- Glucophage, Fortamet, H Riomet

N R

HCl

- mechanism improves insulin sensitivity by increasing peripheral glucose uptake and utilization. - Zhou et al (2001) showed that metformin stimulates the hepatic enzyme AMP-activated protein kinase - 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. Metformin is a widely used monotherapy, and also used in combination with the sulfonylureas in treatment of type 2 diabetes

*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).

Glyburide & Metformine HCl

NH

&

O S

NH O O
H N H N N H + N H H

&
O O NH

HCl

Cl 1-[[ p-[ 2-( 5-chloro-o-anisamido) ethyl] phenyl] sulfonyl]-3-cyclohexylurea

Pioglitazone

O S NH

O 5-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzyl}-thiazolidine-2,4-dione

- 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 thereby regulates the transcription of many genes involved in glucose and fatty acid metabolism. - Marketed in USA in August of 1999

AGIs - acarbose

- miglitol

O H O N

H 1-(2-Hydroxy-ethyl)-2-hydroxymethylpiperidine-3,4,5-triol

Meglitinides
O

- repaglinide

N NH

O O

OH

2-Ethoxy-4-{[3-methyl-1-(2-piperidin-1-yl-phenyl)-butylcarbamoyl]-methyl}-benzoic acid

NH

- nateglinide

O O OH 2-[(4-Isopropyl-cyclohexanecarbonyl)-amino]-3-phenyl-propionic acid

6 Classes :

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 digest
starches

Meglitinides stimulate cells (dependant upon glucose conc.)

LIVER PANCREAS GLUCOSE PRODUCTION Metformin Thiazolidinediones

ADIPOSE TISSUE

MUSCLE

INTESTINE

INSULIN SECRETION Sulfonylureas: Glyburide, Gliclazide, Glimepiride Non-SU Secretagogues: Repaglinide, Nateglinide

PERIPHERAL GLUCOSE UPTAKE Thiazolidinediones Metformin

GLUCOSE ABSORPTION Alpha-glucosidase inhibitors


Adapted from Sonnenberg, Kotchen Curr Opin Nephrol Hypertens 1998; 7:551-5.