ORAL HYPOGLYCEMIC AGENTS

The Slides which gives an Clear knowledge about Diabetes mellitus and Oral drugs which is used for treatment of diabetes.

1. ORAL HYPOGLYCEMIC AGENTS PRESENTED BY PRADEEPAN RAMASAMY, M.PHARM 2 ND SEMESTER, DEPARTMENT OF PHARMACOLOGY, COP SRIPMS.

2. INTRODUCTION DIABETES MELLITUS A chronic metabolic disorder results in hyperglycemia Involves Insufficient insulin secretion Reduced responsiveness to insulin Major symptoms include Polyphagia Polyuria Polydipsia

3. GLUCOSE HOMEOSTASIS

4. TYPES OF DIABETES MELLITUS

5. TYPE 1 DIABETES MELLITUS Failure of pancreas to produce sufficient insulin. Insulin dependent diabetes mellitus / Juvenile diabetes. Loss of β cells of Islets of Langerhans T-cell mediated autoimmune attack/Idiopathic Loss of β cells Insulin deficiency

6. TYPE 2 DIABETES MELLITUS Failure of cells to respond to insulin properly Non insulin dependent diabetes mellitus / Maturity onset diabetes Excessive body weight Lack of physical exercise Poor diet Stress REASONS

7. GESTATIONAL DIABETES Elevated glucose intolerance during pregnancy. Involves a combination of inadequate insulin secretion and responsiveness of cells. Observed in second or last trimester of pregnancy. Improves or disappears after delivery.

8. MAJOR COMPLICATIONS OF DIABETES MELLITUS MICROVASCULAR MICROVASCULAR EYE Retinopathy Cataract glaucoma KINDEY Nephropathy Peripheral neuropathy BRAIN Increased risk of stroke Transient ischemic Attack Cognitive impairment HEART Myocardial infarction Atherosclerosis Hypertension EXTREMITIES Gangrene foot Slow wound healing

9. ORAL HYPOGLYCEMIC AGENTS

10. Tolbutamide Tolazamide Chlorpropamide Glibenclamide Glipizide Gliclazide Glimepiride Repaglinide Nateglinide Exenatide Liraglutide Albiglutide D ulaglutide S emaglutide Sitagliptin Vildagliptin Saxagliptin Alogliptin Linagliptin FIRST GENERATION SECOND GENERATION CLASSIFICATION

11. Pioglitazone Rosiglitazone Metformin Phenformin Acarbose Miglitol Voglibose Dapagliflozin Remogliflozin Canagliflozin S ergliflozin

12. Pramlintide Bromocriptine Colesevelam

13. MECHANISM OF ACTION S ULFONYLUREAS K ATP channel blockers Enhances the insulin secretion Second generation drugs are more potent than that of first generation.

14. G iven orally which binds to plasma proteins(90-99%). M etabolised in liver. E xcreted by kidney. Tolbutamide - short duration of action (6-12 hrs) . glipizide & glyburide - intermediate acting. glimepiride & gliclazide - last about 24 hours. Glibenclamide - 150 times more potent than tolbutamide. PHARMACOKINETICS

15. Type 1 diabetes Pregnancy Lactation Hepatic or renal insufficiency W eight gain due to fluid retention and oedema. Hyperinsulinemia and hypoglycemia. Hepatic or renal insufficiency - risk of hypoglycemia. CONTRAINDICATIONS ADVERSE EFFECTS

16. MEGLITINIDE / D-PHENYLALANINE ANALOGUES K ATP channel blockers Q uick and short lasting insulinemic action. D esigned to normalise meal time glucose excursions. It cannot provide stable blood glucose control

17. Hypoglycemia : i ncidence lower than sulfonylureas. Hypoglycemia is a major risk if meal is delayed. Repaglinide - causes hypoglycemia with lipid lowering drugs . caution in patients with hepatic and renal insufficiency. PHARMACOKINETICS ADVERSE EFFECTS

18. AMPK ACTIVATORS (BIGUANIDES) METFORMIN well absorbed orally half-life - 3hours. excreted unchanged via urine.

19. Nausea, vomiting and diarrhoea Gastro intestinal disturbances Lactic acidosis Long term use affects vitamin B 12 absorption. Renal failure Hepatic insufficiency Hypoxic pulmonary disease Heart failure ADVERSE EFFECTS CONTRAINDICATIONS

20. PPAR γ ACTIVATORS Thiazolidinediones PPAR γ- group of nuclear hormone receptors R egulation of genes related to glucose and lipid metabolism MECHANISM OF ACTION

21. ADVERSE EFFECTS congestive heart failure B one fracture Macular oedema Fluid retention & oedema Weight gain

22. GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR AGONISTS GIP & GLP-1 -Incretins released from the gut Secreted by the lower intestine Stimulates βcells of pancreas to secrete insulin MECHANISM OF ACTION Suppresses glucagon secretion Decreases beta cell apoptosis Delays gastric emptying Suppresses appetite OTHER ACTIONS

23. EXENATIDE Exendin-4, is a naturally occurring 39–amino acid reptilian peptide. P otent GLP-1 receptor agonist . It is not metabolised by DPP-4. Synthetic exendin-4 -monotherapy and as adjunctive therapy. Extended-release SC injection once a week Gila Monster

24. PHARMACOKINETICS Long-acting synthetic agents. Exenatide - SC inj. (typically before meals). R apidly absorbed Peak concentrations - 2 hours Half-life - 2–3 h ours Clearance of drugs primarily by kidneys. Albiglutide has a half-life of 5–7 days. Semaglutide - oral drug

25. ADVERSE EFFECTS

26. DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS DPP-4 enzyme - a serine protease Spre ad widely throughout the body DPP-4 inhibitors - increases AUC of GLP-1 & GIP

27. These drugs are well absorbed in GIT The 80% of drugs were excreted unchanged in the urine. Half-life - about 8 to 14 hours. Upper respiratory tract infection Nasopharyngitis Headache ADVERSE EFFECTS PHARMACOKINETICS

28. ALPHA GLUCOSIDASE INHIBITORS MECHANISM OF ACTION

29. P oorly absorbed Metabolised by intestinal bacteria E xcreted via urine. PHARMACOKINETICS ADVERSE EFFECTS V ery well absorbed but has no systemic effects. E xcreted unchanged via urine Acarbose Miglitol CONTRAINDICATIONS Flatulence Diarrhoea A bdominal cramping Inflammatory bowel disease Colonic ulceration Intestinal obstruction

30. AMYLIN ANALOGUE MECHANISM OF ACTION Islet amyloid polypeptide(AMYLIN) 37–amino acid peptide produced in the pancreatic β cell PRAMINITIDE - A synthetic form of amylin

31. Subcutaneously injected prior to meals. Extensively bound to plasma proteins t ½ - 50 minutes. Metabolism and clearance are primarily by the kidney. Differences in p H , same syringe as insulin should not be used N ausea and vomiting. H ypoglycemia in addition with insulin Gastroparesis D isorders with motility. ADVERSE EFFECTS CONTRAINDICATIONS PHARMACOKINETICS

32. SGLT-2 INHIBITOR MECHANISM OF ACTION

33. Urinary tract infections Genital infections Electrolyte imbalance Increased urinary frequency. G ood oral bioavailability (60%–80%). Peak levels 1–2 h after ingestion. 90% bound to circulating proteins Half-life of about 12 hours Metabolised in liver and excreted renally PHARMACOKINETICS ADVERSE EFFECTS

34. Interruption of enterohepatic circulation of bile Decrease in FXR activation Indirectly related to TGR5 (or) GP-BAR-1 Increased secretion of GLP-1 incretins BILE ACID SEQUESTRANT RESIN – COLESEVELAM

35. Powder for oral solution and as tablets Absorbed in intestinal tract in trace amounts Distribution is limited to the git Constipation Dyspepsia Abdominal pain Nausea Intestinal obstruction PHARMACOKINETICS ADVERSE EFFECTS

36. D2 RECEPTOR AGONISTS - BROMOCRIPTINE Nausea & v omiting Headache Fatigue Dizziness Orthostatic hypotension Bromocriptine D 2 receptors Dopamine activity Insulin resistance Hepatic glucose production Triglycerides Free fatty acids ADVERSE EFFECTS

37. COMPARING DIFFERENT CLASSES OF ORAL HYPOGLYCEMIC AGENTS

38. Biguanides DPP- 4 inhibitors α- Glucosidase inhibitors sulfonylureas Non sulfonylureas ↓ Hepatic glucose production Prolong endogenous GLP-1 action ↓ GI glucose absorption ↑ Insulin secretion ↑ Insulin secretion SGLT2 inhibitor Thiazolidinediones GLP-1R agonist Amylin agonists ↑ Renal glucose excretion ↓ Insulin resistance, ↑ glucose utilization ↑ Insulin, ↓ glucagon, slow gastric emptying, satiety Slow gastric emptying, ↓ glucagon MECHANISM OF ACTION

39. Biguanides DPP- 4 inhibitors α- Glucosidase inhibitors sulfonylureas Non sulfonylureas Weight neutral, do not cause hypoglycemia, inexpensive Do not cause hypoglycemia ↓ Postprandial glycemia Inexpensive Rapid onset of action, lower postprandial glucose SGLT2 inhibitor Thiazolidinediones GLP-1R agonist Amylin agonists Mild weight loss & BP reduction; do not cause hypoglycemia; CV benefit Lower insulin requirements Weight loss, CV benefit Reduce postprandial glycemia; weight loss SPECIFIC ADVANTAGES

40. Biguanides DPP- 4 inhibitors α- Glucosidase inhibitors sulfonylureas Non sulfonylureas Diarrhoea, nausea, lactic acidosis Expensive GI flatulence, liver function tests Hypoglycemia, weight gain Hypoglycemia, precautions for elderly and renal impairment SGLT2 inhibitor Thiazolidinediones GLP-1R agonist Amylin agonists ↑ Rate of lower urinary tract and genital mycotic infections; hypotension; rarely DKA ↑ Rate of lower urinary tract and genital mycotic infections; hypotension; rarely DKA Injection, nausea, ↑ risk of hypoglycemia with insulin secretagogues Injection, nausea, ↑ risk of hypoglycemia with insulin SPECIFIC DISADVANTAGES

41. Biguanides DPP- 4 inhibitors α- Glucosidase inhibitors sulfonylureas Non sulfonylureas Diarrhoea, nausea, lactic acidosis ↓ Dose with renal disease Renal/liver disease Renal/liver disease Renal/liver disease SGLT2 inhibitor Thiazolidinediones GLP-1R agonist Amylin agonists Renal disease CHF, liver disease Renal disease, agents that also slow GI motility, pancreatitis Agents that also slow GI motility CONTRAINDICATIONS

42. CONCLUSION

43. BIBLIOGRAPHY Powers AC, Alessio DD. Endocrine Pancreas and Pharmacotherapy of Diabetes Mellitus and Hypoglycemia. ln: Brunton LL, Chabner BA, Knollmann BC. Goodman &Gilman’s The Pharmacological Basis of Therapeutics, 13 th ed. New York: McGraw-Hill; 2011. Tripathi KD. Essentials of Medical Pharmacology. 8 th ed. New Delhi: Jaypee Brothers Medical Publishers; 2019. Rang HP, Dale MM, Ritter JM, Moore PK. Pharmacology: 5 th ed. Edinburgh: Churchill Livingstone; 2003. Sharma HL, Sharma KK. Principles of Pharmacology. 3 rd ed. New Delhi: Paras publishers; 2017.