Drugs for Type 2 DM 6.6.23.pptx

Hello friends. In this PPT I am talking about drugs used in the treatment of type 2 diabetes mellitus. If you like it, please do let me know in the comments section. A single word of appreciation from you will encourage me to make more of such videos. Thanks. Enjoy and welcome to the beautiful world of pharmacology where pharmacology comes to life. This video is intended for MBBS, BDS, paramedical and any person who wishes to have a basic understanding of the subject in the simplest way.

1. Drugs for Type 2 DM Dr. Karun Kumar Assistant Professor Dept. of Pharmacology

2. Criteria for diagnosis of DM (ADA, 2023) FPG ≥ 126 mg/ dL (7.0 mmol /L). Fasting is defined as no caloric intake for at least 8 h* OR 2-h PG ≥ 200 mg/ dL (11.1 mmol /L) during OGTT. The test should be performed as described by WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water* OR

3. A1C ≥ 6.5% (48 mmol / mol ). The test should be performed in a laboratory using a method that is NGSP certified and standardized to the DCCT assay* OR In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥ 200 mg/ dL (11.1 mmol /L)

4. Approaches to drug therapy in type 2 DM Improve insulin availability Exogenous insulin Sulfonylureas Meglitinide /phenylalanine analogues Dipeptidyl peptidase-4 inhibitors (DPP-4Is) Overcome insulin resistance Biguanides (Metformin) Thiazolidinediones (Pioglitazone) α glucosidase inhibitors ( Acarbose )

5. Classification

6. Oral antidiabetic drugs These drugs lower blood glucose levels and are effective orally

7. Sulfonylureas (K ATP Channel blockers) Lowering of blood glucose level in normal subjects and in type 2 diabetics, but not in type 1 diabetics Sulfonylureas provoke a brisk release of insulin from pancreas by acting on sulfonylurea receptors (SUR1) on β cells  cause depolarization by ↓ conductance of ATP sensitive K + channels  ↑ Ca 2+ influx  exocytotic release of insulin

8. After few months of administration, the insulinaemic action of SUs declines, probably due to down regulation of sulfonylurea receptors (SUR1) on β cells, but improvement in glucose tolerance is maintained In this phase, they sensitize the target tissues (especially liver) to the action of insulin. This is due to increase in number of insulin receptors and/or a postreceptor action—improving translation of receptor activation.

9. Interactions Drugs that enhance SU action (may precipitate hypoglycaemia) are— Displace from protein binding  Phenylbutazone , sulfinpyrazone , salicylates, sulfonamides Inhibit metabolism/excretion  Cimetidine, Ketoconazole, sulfonamides , warfarin, chloramphenicol, acute alcohol intake Synergise with or prolong pharmacodynamic action: Salicylates, propranolol ( cardioselective β1 blockers are less liable), sympatholytic antihypertensives , lithium, theophylline, alcohol

10. Drugs that decrease SU action (vitiate diabetes control) are— Induce metabolism  Phenobarbitone , phenytoin, rifampicin, chronic alcoholism. Opposite action/suppress insulin release  Corticosteroids, thiazides, furosemide, oral contraceptives.

11. Adverse effects Hypoglycemia  It is the commonest problem, may occasionally be severe and rarely fatal Treatment is to give glucose, may be for a few days because hypoglycemia may recur 2. Nonspecific side effects  W eight gain, nausea, vomiting, flatulence, diarrhoea or constipation, headache and paresthesias are generally mild and infrequent 3. Hypersensitivity  Rashes, photosensitivity, purpura, transient leukopenia, rarely agranulocytosis

12. Meglitinide analogues These are K ATP channel blockers with a quick and short lasting insulinemic action Repaglinide  Acts in an analogous manner by binding to SUR → closure of ATP dependent K+ channels → depolarisation → insulin release It induces fast onset short-lasting insulin release. It is administered before each major meal to control postprandial hyperglycemia; the dose should be omitted if a meal is missed.

13. Lower risk of serious hypoglycaemia . Side effects are mild headache, dyspepsia, arthralgia and weight gain. Repaglinide is indicated only in selected type 2 diabetics who suffer pronounced post prandial hyperglycaemia , or to supplement metformin/long-acting insulin. It should be avoided in liver disease

14. Nateglinide Stimulates the 1st phase insulin secretion; faster onset and shorter lasting hypoglycaemia than repaglinide . There is little effect on fasting blood glucose level. Episodes of hypoglycaemia are less frequent than with SUs. Side effects are dizziness, nausea, flu like symptoms and joint pain. It is used in type 2 DM to control postprandial rise in blood glucose

15. MOA of SU & MG SU & MG inhibit ATP sensitive K + channels ↓ K + cannot go out resulting in more + ve charge in β-cell ↓ Depolarization starts ↓ Opening of Ca 2+ channels ↓ Release of insulin from granules

16. Dipeptidyl peptidase-4 (DPP-4) inhibitors DPP-4  E xpressed on capillary endothelial cells; rapidly degrades the incretins glucagon-like peptide-1 (GLP-1) & glucose-dependent insulinotropic polypeptide (GIP) which are peptides released from gut in response to ingested glucose DPP 4 inh . limit the postprandial glycemia by releasing insulin from β cells & inhibiting glucagon release from α cells Also suppress appetite & retard gastric emptying

17. Sitagliptin , Vildagliptin , Saxagliptin , Teneligliptin potentiate GLP-1 and GIP by preventing their degradation Limit postprandial hyperglycaemia & lower fasting (basal) blood glucose level in type 2 diabetics, without producing hypoglycaemia in overdose or when a meal is missed.

18. Widely used to supplement Metformin ± other hypoglycaemics in diabetics not adequately controlled by the other drugs Monotherapy advised only when Metformin cannot be used Well tolerated & neither ↑, nor ↓ body weight S/E  M ild nausea, loose stools, headache, etc.

19. Glucagon-like peptide-1 (GLP-1) receptor agonists Taken orally, glucose & other nutrients generate chemical signals called incretins from the gut which act on pancreatic β cells to trigger anticipatory release of insulin GLP-1  I mportant incretin; induces insulin release, inhibits glucagon release from α cells, slows gastric emptying and suppresses appetite by activating specific GLP-1 receptors, which are cell surface GPCRs expressed on β and α cells

20. GLP-1 induces insulin release only at high glucose conc. Incretin system appears to promote β cell health as well Exenatide & Liraglutide have been found clinically effective in type 2 DM Exenatide injected s.c. BD is being used as add on therapy in pts. not adequately controlled by OHA

21. Biguanide (AMPK activator) Metformin  It is a ‘ normoglycaemic ’ Mechanism of action  A ctivation of AMP dependent protein kinase (AMPK) Suppresses hepatic gluconeogenesis and glucose output from liver (major action) Enhances insulin-mediated glucose uptake and disposal in skeletal muscle and fat. Interferes with mitochondrial respiratory chain and promotes peripheral glucose utilization through anaerobic glycolysis

22. MOA of Metformin

23. 1 st choice drug for T2DM (M-O-S-T) Advantages of metformin are: Non hypoglycaemic Weight loss promoting Has potential to prevent macrovascular as well as microvascular complications of diabetes Can prevent new onset type 2 DM in obese, middle aged subjects with impaired glucose tolerance Side effects  Abdominal pain, anorexia, bloating, nausea, metallic taste, mild diarrhoea and tiredness

24. Thiazolidinedione (PPAR γ agonist) Selective agonists for the nuclear peroxisome proliferator activated receptor γ ( PPARγ ) expressed mainly in fat cells which enhances the transcription of several insulin responsive genes Pioglitazone  Reverses insulin resistance by enhancing GLUT4 expression and translocation to the cell membrane so that entry of glucose into muscle and fat is improved.

25. Hepatic gluconeogenesis is suppressed and lipogenesis in adipose tissue contributes to the insulin sensitizing action Well tolerated; A/E  P lasma volume expansion, edema, weight gain, headache, myalgia and mild anaemia ; CHF may be precipitated or worsened. Monotherapy with glitazones is not associated with hypoglycaemic episodes Indicated in type 2 DM, but not in type 1 DM Used to supplement SU/Met. and in insulin resist.

26. Interactions Failure of oral contraception may occur during Pioglitazone therapy. Ketoconazole inhibits and rifampin induces metabolism of Pioglitazone.

27. α Glucosidase inhibitors Acarbose  It is a complex oligosaccharide which reversibly inhibits α- glucosidases , the final enzymes for the digestion of carbohydrates in the brush border of small intestine mucosa It slows down and decreases digestion and absorption of polysaccharides (starch, etc.) and sucrose  postprandial glycaemia is reduced without significant increase in insulin levels

28. Acarbose is a mild antihyperglycaemic and not a hypoglycaemic ; may be used as an adjuvant to diet (with or without metformin/SU) in obese diabetics. S/E  Flatulence, abdominal discomfort and loose stools Miglitol and Voglibose are other α glucosidase inhibitors with similar properties, use and side effects

29. Sodium-glucose co-transport-2 (SGLT-2) inhibitor All the glucose filtered at the glomerulus is reabsorbed in the proximal tubules, primarily by SGLT-2 Canagliflozin & Dapagliflozin  I nduces glycosuria & lowers blood glucose in type 2 DM, causes weight loss, approved for T/t of T2DM After single daily dose it produces round-the-clock glucosuria and lowers blood glucose levels

30. Glycosuria can predispose to urinary and genital infections, electrolyte imbalance Long-term safety yet to be established Employed to supplement SU/Met./other antidiabetic drugs

31. Adverse effects observed with oral hypoglycemic agents

32. Oral hypoglycaemics in diabetes mellitus Only in type 2 DM not controlled by diet and exercise Most effective in patients with— Age above 40 years at onset of disease Obesity at the time of presentation Duration of disease < 5 years when starting treatment Fasting blood sugar < 200 mg/dl Insulin requirement < 40 U/day No ketoacidosis or a history of it, or any other complication

33. Current recommendation is to institute metformin therapy right at the diagnosis of type 2 DM, along with dietary and other lifestyle measures, without waiting to see if the latter alone are sufficient Metformin may delay progression of diabetic severity by favorably affecting β cell health and retarding β cell failure It is especially valuable for obese patients; may also aid weight reduction It also has the potential to reduce the risk of myocardial infarction and stroke