Oral Hypoglycemic agents.pptx presentations

ppt

1. Medicinal chemistry ii (Phar 3112) Oral hypoglycemic agents Abdu Tuha ( B- Pharm , MSc in Medicinal Chemistry) 1

2. Oral hypoglycemic agents Some forms of diabetes mellitus( type II) that do not respond to diet management or weight loss and exercise can be treated with oral hypoglycemic agents. The success of oral hypoglycemic drug therapy is usually based on a restoration of normal blood glucose levels . 2

3. Currently, 6 + classes of oral antidiabetic drugs (OADs) are available: Biguanides (e.g., Metformin ), Sulfonylureas (e.g., Glimepiride ), Meglitinides (e.g., Repaglinide ), Thiazolidinediones (e.g., Pioglitazone ), Dipeptidyl peptidase IV inhibitors (e.g., Sitagliptin ), and α - glucosidase inhibitors  3

4. Sulfonylureas Sulfonylureas are the most widely prescribed drugs in the treatment of type II diabetes mellitus. The initial sulfonylureas were introduced nearly 50 years ago and were derivatives of the antibacterial sulfonamides. Although their structural similarities to the sulfonamide antibacterial agents are readily apparent, the sulfonylureas possess no antibacterial activity. 4

5. Mechanism of Action The primary mechanism of action of the sulfonylureas is direct stimulation of insulin release from the pancreatic β -cells . At higher doses, these drugs also decrease hepatic glucose production The second-generation sulfonylureas may possess additional extrapancreatic effects that increase insulin sensitivity 5

6. The sulfonylureas are ineffective for the management of type I and severe type II diabetes mellitus, since the number of viable β -cells in these forms of diabetes is small. Severely obese diabetics often respond poorly to the sulfonylureas , possibly because of the insulin resistance that often accompanies obesity . 6

7. Sub classified as 1 st generation 2 nd generation 7

8. a. 1 st generation The first-generation sulfonylureas are not frequently used in the modern management of diabetes mellitus because of their relatively low specificity of action delay in time of onset occasional long duration of action, and a variety of side effects They also tend to have more adverse drug interactions than the second-generation sulfonylureas 8

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10. SAR These are urea derivatives with an aryl sulfonyl group in the 1 position and an aliphatic group in the 3 position Small alkyl substituents such as methyl or ethyl are not active In 1 st generation, the aromatic substituent is relatively simple (e.g. methyl, amino, acetyl, chloro , bromo , methylthio , CF 3 ) however, 2 nd generation analogues have a larger p-( β - arylcarboxyamidoethyl ) group that leads to higher potency. 10

11. The R’ confers lipophilic property to the molecule Aryl substituents at this position gives toxic compounds 11

12. b. 2 nd generation The second-generation sulfonylureas display A higher specificity and affinity for the sulfonylurea receptor More predictable pharmacokinetics in terms of time of onset and duration of action Fewer side effects . 12

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14. 2) Bigaunides 14

15. Metformin , a biguanide that acts directly against insulin resistance , is regarded as an insulin sensitizing drug and is considered to be a cornerstone in the treatment of T2DM This class of agents are capable of reducing sugar absorption from the gastrointestinal tract. They also decrease gluconeogenesis while increasing glucose uptake by muscle and fat cells 15

16. 3) α lpha -Glucosidase Inhibitors The α - glucosidase inhibitors primarily act to decrease postprandial hyperglycemia by slowing the rate at which carbohydrates are absorbed from the gastrointestinal tract. Work by preventing digestion of carbohydrates Alpha glucosidase inhibitors are saccharides w/h act as competitive inhibitors of enzymes needed to digest carbohydrates Oligosaccharides →glucose by alpha glucosidase Inhibition of this enzyme reduces the rate of digestion of carbohydrates 16

17. i . Acarbose is a complex oligosaccharide it delays CHO metabolism by inhibiting  -D- Glucosidase ii. voglibose is orally active inhibitor of  -D- Glucosidase much more potent and with fewer side effects than Acarbose 17

18. 18 Acarbose Voglibose

19. 4) Thiazolidinediones Thiazolidinediones (sometimes termed glitazones ) are a novel class of drugs that were initially identified for their insulin-sensitizing properties . The thiazolidinediones are insulin-sensitizing drugs that improve whole-body insulin sensitivity through gene regulation They all act to decrease insulin resistance and enhance insulin action in target tissues. Thiazolidinediones activate the nuclear peroxisome proliferator –activated receptor (PPAR) γ and modulate the expression of insulin-sensitive genes 19

20. These agents increase glucose uptake via glucose transporter-4 in skeletal muscle and reduce rates of gluconeogenesis in the liver The patient who would benefit the most from a thiazolidinedione is a type II diabetic with a substantial amount of insulin resistance 20

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22. 5. Glinides Meglitinides such as repaglinide and nateglinide are prandial insulin releasers that stimulate rapid insulin secretion.  Repaglinide ( NovoNorm ®, Prandin ®, GlucoNorm ®) is the first clinically available insulin secretagog that specifically enhances early-phase prandial insulin response by increasing the sensitivity of β- cells to elevated glucose levels, producing a greater insulin release under hyperglycemic conditions.   Repaglinide increases insulin release from β-cells only in the presence of glucose , whereas glibenclamide stimulates insulin secretion in the absence of glucose 22

23. MOA   Repaglinide binds to the sulfonylurea receptor-1 in the β- cell membrane at a site distinct from the SU binding site. Binding at sulfonylurea receptor-1 closes ATP-dependent K + channels, leading to β- cell depolarization and opening of calcium channels. The resulting increased calcium influx induces insulin secretion. 23

24. 24 Repaglinide Nateglinide

25. 6. Dipeptidyl Peptidase-IV Inhibitors Dipeptidyl peptidase-IV (DPP-IV) inhibitors suppress the degradation of a variety of bioactive peptides, including glucagon-like peptide-1(GLP-1) , leading to an enhancement of their action. GLP-1 is a potent antihyperglycemic hormone, inducing the β-cells of the pancreas to release the hormone insulin in response to rising glucose , while suppressing glucagon secretion. 25

26. DPP-IV inhibitors are orally administered drugs with a significant effect on glucose tolerance. Sitagliptin was approved by the FDA in 2006 as an adjunct to diet and exercise in patients with T2DM. 26 Sitagliptin Saxagliptin Linagliptin