Insulin & Oral Hypoglycemic Agents.

In this PPTs you will get in depth information about insulin and the first class of oral hypoglycemic agents , Sulfonylurea.
useful for GPAT and Third Year B.Pharm students.

1. Presented by;- Mr. Tejas Mahendra Bhatia. Third Year (Fifth Semester) B.Pharmacy, Appasaheb Birnale College of Pharmacy, Sangli. Insulin & Oral Hypoglycemic Agents. Pharmacology-2

2. CONTENTS:- Introduction to Diabetes Mellitus. INSULIN. Oral Hypoglycemic Agents.

3. Introduction Diabetes Mellitus is a group of metabolic diseases in which a person has high blood sugar levels, either because, The pancreas do not produce enough INSULIN. Cells do not respond to INSULIN produced. The high blood sugar level produces classical symptoms:- POLYURIA POLYDIPSIA POLYPHAGIA.

4. Diagnosis for DM:- DM is diagnosed by :- Fasting blood glucose if exceeds 6.1-7.0 mmol.(126mg/dl). Postprandial glucose if exceeds 200mg/dl. HBA1C (glycosylated hemoglobin) exceeds 6.5gm%.

5. Types of DM:- Type 1 DM . It results from the body’s failure to produce insulin, and requires the person to inject insulin or insulin pump. Is due to BETA CELLS destruction in pancreas. Is LESS COMMON. Is known as IDDM or JUVENILE diabetes. Treatment by INSULIN only.

6. TYPE 2 DM:- Results from INSULIN RESISTANCE, a condition in which cells fail to use insulin properly. Sometimes combined with an ABSOLUTE INSULIN DEFICIENCY. Moderate destruction in beta cells. MORE COMMON. Is known as NIDDM or Adult-Onset Diabetes. Treatment by orally active drugs or injection.

7. Difference Between TYPE 1 & TYPE 2 DM:- Image Courtesy; ANA E-Learning

8. OVER 90% CASES OF DIABETES are of TYPE 2 DM. Causes may be:- Abnormality in Gluco Receptor of beta cells so they respond at higher glucose levels. Reduced sensitivity of peripheral tissue to insulin receptors. Excess RELEASE of HYPERGLYCEMIC HORMONES (glucagon). Gestational Diabetes refers to onset of glucose intolerance in women during pregnancy. It excludes women who were diabetic before pregnancy.

9. Pancreas:- The pancreas is an organ located in the abdomen,  The pancreas has two main functions: an exocrine function that helps in digestion and an endocrine function that regulates blood sugar.

10. Pancreas at a glance:- ALPHA CELLS:- Hormone:- GLUCAGON. Function:- Stimulates the conversion of stored glycogen (stored in liver) to glucose. Stimulates GLYCOGENOLYSIS. Disorder:- Hypo secretion causes hypoglycemia. BETA CELLS:- Hormones:- INSULIN. Function:- Controls blood sugar level by signaling the liver, muscle and fat cells to take in glucose from blood and stimulates GLYCOGENESIS. Disorder:- Hypo secretion causes DM.

11. DELTA CELLS:- Hormone:- SOMATOSTATIN. Function:- Suppresses release of INSULIN & GLUCAGON. F CELLS:- Hormone:- Pancreatic Polypeptide. Function:- Inhibit the release of digestive secretions of the pancreas.

12. The external secretions of PANCREAS is digestive in function, and ENDOCRINE functions are performed by ISLETS OF LANGERHANS. Islets of Langerhans:-Small, highly vascularized masses of cells scattered throughout pancreas, forming only 1-3 % of entire organ. Contains 4 types of secretary cells, viz ALPHA, BETA, DELTA, F CELLS. Insulin secreting Beta cells are the most numerous (70-80%) Alpha cells-20% Delta cells:- 4% F cells:- Less than 2%.

13. INSULIN:- Discovered by BANTING & BEST . There are 51 AMINO ACID in an insulin molecule. (ACTIVE FORM ONLY). TWO CHAIN POLYPEPTIDES. Chain A:- has 21 Amino Acids. Chain B:- has 30 Amino Acids. BOTH CHAINS ARE CONNTECTED BY DISULPHIDE BRIDGES . (P.Y GPAT).

14. Isolated in 1921, used in treatment of DM in 1922. Polypeptide with MW of about 6000. A chain is ACIDIC & B chain is BASIC. Disulphide bridges are essential for biological activity. Immediate precursor of insulin, PROINSULIN is within the pancreatic beta cells in which A & B chains are joined by connecting peptide (C-Peptide) COMPOSED OF 31 AA . The pig(porcine) insulin closely resembles human insulin which may accounts for it’s low antigenicity.

15. Insulin is soluble in water, but undergoes molecular aggregatation at extremes of pH 3.2 and 10). Such aggregations are also encouraged by presence of Zinc which brings about crystallization of insulin. Isoelectric point:- 5.3 Insoluble between pH 4 & 7. It can combine with proteins like globin and protamine, whereby its activity is retained and duration of action is prolonged. Recently human insulin has been successfully produced through E.COLI by rDNA technology or by chemical modification of pork insulin to replace AA that is different from human insulin.

16. Glucose is the main stimulus for release of insulin from BETA CELLS OF PANCREAS. Glucose stimulates GLUT-2 and inhibits ATP sensitive Potassium channels: factors that are responsible for depolarization of beta cells and release of insulin. ALPHA 2 receptor stimulation inhibits insulin secretion. Beta 2 Agonist and vagal stimulation enhances insulin release. Somatostatin inhibits whereas glucagon stimulates the release insulin. Adrenergic system regulates insulin release via ALPHA 2 (decreases) and BETA 2 (increases) receptors.

17. Insulin is synthesized from BETA CELLS of pancreatic islets, from a precursor preproinsulin.(110 AA) The connection or C PEPTIDE (35 AA) is split off by proteolysis in GOLGI APPARATUS . Both insulin and C peptide are stored in granules within the cells , C peptide is secreted in cells. Half life of insulin:- 4-6 minutes.

18. Actions of Insulin:- CARBOHYDRATE METABOLISM (By stimulating entry of glucose into cells by increasing synthesis of glucose transporter 4 (GLUT-4) FAT METABOLISM PROTEIN METABOLISM (Anabolic Effect).

19. MODE OF ACTION_INSULIN:- Attachment of insulin molecule to a specific insulin receptor on cell surface. Insulin lowers cAMP in some tissues by inhibiting adenylate cyclase enzyme It also stimulates cyclic nucleotide phosphodiesterase (enzyme destroying cAMP)

20. Lowering cAMP contents of cells. Due to less cAMP in cells glycogen breakdown decreases and glycogen synthesis increases . Facilitates potassium transport in cells.

21. ORAL HYPOGLYCAEMIC AGENTS:-

22. ORAL HYPOGLYCAEMIC AGENTS:- These are agents used in the treatment of type 2 DM. These are classified into several groups based on MOA or structures as follows:- 1) ENHANCED INSULIN SECRETION:- ( Acts as potassium channel blockers causing depolarization of beta cells) Sulphonylurea :- First generation: Chlorpropamide , Tolbutamide . Second Generation:- Glipizide , Glibenclamide .(More potent) Meglitinides /Phenylalanine Analogues:- Nateglinide Repaglinide .

23. 2) OVERCOME INSULIN RESISTANCE:- A) Biguanides ( AMPk Activator):- Metformin Phenformin . B) Thiazolidinediones :- Troglitazone Pioglitazone Rosiglitazone 3) Retard Carbohydrates Absorption:- Alpha Glucosidase inhibitors:- Acarbose Voglibose Miglitol

24. 4) Miscellaneous Drugs:- A) Glucagon like peptide (GLP-1) agonist:- Exenatide Liraglutide . B) Dipeptidyl peptidase-4(DPP-4) inhibitors:- Sitagliptin Vildagliptin Saxagliptin C) Sodium Glucose Co-transporter-2 inhibitors:- Dapagliflozin Canagliflozin D) Amylin analogue:- Pramlintide .

25. Sulfonylurea:- First Generation:- Tolbutamide . Chlorpropamide . Second Generation;- (4G’s ) Glibenclamide Glipizide Glicazide Glimepiride

26. SULFONYLUREA:- Chemically related to sulphonamides , but with no antibacterial action. MODE OF ACTION:- Inhibits ATP sensitive Potassium channels and causes DEPOLARIZATION of beta cells. This results in release of insulin. Effective only if 30% or more of beta cells in the pancreas are functional. Effective in TYPE-2 DM only.

27. Second Generation are more potent than first generation drugs. All causes HYPOGLYCEMIA (maximum with chlorpropamide ). Chlorpropamide can cause dilution hyponatremia (ADH like action), Cholestic jaundice, and dilsulfiram like action. Gliclazide has additional ant platelets activity. Contraindicated in liver and kidney failure due to risk of hypoglycemia. Tolbutamide is safest and is DOC in renal diseases due to it’s shorter duration of action and is contraindicated in pregnancy and lactation. Tolbutamide : Shortest Acting Sulfonylurea. T-Half:- 6-8 hours. Chlorpropamide is longest acting with T-Half of 30-36 hours.

28. Glycburide ( Glibenclamide ) has maximum insulinotropic potency whereas tolbutamide has least. MECHANISM OF ACTION:- Drugs acts on the sulfonylurea receptor on pancreatic beta cell membrane. Inhibits ATP sensitive Potassium channels. Causes depolarization of beta cells. Enhance Calcium reflux. Resulting in INSULIN SECRETION.

29. MOA FOR SU:-

30. INTERACTION WITH OTHER DRUGS:- A) Drugs that enhance SU action: Displace from protein binding:- Phenylbutazone Sulfinpyrazone Inhibit Metabolism:- Sulfonamide. Warfarin . Acute alcohol intake (Also synergizes by causing hypoglycemia). Synergizes or prolongs pharmacological action: Salicyclates , Propranolol , Sympatholytic Antihypertensive.

31. Drugs that decrease SU action:- Induce Metabolism;- Phenobarbitone Phenytoin . Chronic Alccoholism . Opposite Action/Suppress Insulin Release:- Corticosteroid Thiazide Furosemide Oral Contraceptive.

32. SIDE EFFECTS:- Severe Hypoglycaemia . Weight gain. Allergic skin reactions (rashes). (GPAT P.Y) Bone Marrow Depression. Dilsulfiram like reactions. (CHLORPROPAMIDE) Chlolestatic jaundice. Teratogenic -Not safe during pregnancy.