Downloaded 20 times
Uploaded byKarun Kumar
Drugs for Type 2 DM 6.6.23.pptx
The document outlines drug therapies for type 2 diabetes mellitus (DM), detailing diagnostic criteria and various classes of oral antidiabetic medications. It emphasizes the use of metformin as the first-line treatment due to its non-hypoglycaemic effects, weight loss benefits, and potential to prevent diabetes complications. Other drug classes discussed include sulfonylureas, meglitinides, DPP-4 inhibitors, GLP-1 receptor agonists, and others, highlighting their mechanisms of action, benefits, and side effects.
More Related Content
Similar to Drugs for Type 2 DM 6.6.23.pptx
More from Karun Kumar
Drugs for Type 2 DM 6.6.23.pptx
- 1. Drugs for Type2 DM Dr. Karun Kumar Assistant Professor Dept. of Pharmacology
- 2. Criteria for diagnosisof 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 drugtherapy in type 2 DM 1. Improve insulin availability 1. Exogenous insulin 2. Sulfonylureas 3. Meglitinide/phenylalanine analogues 4. Dipeptidyl peptidase-4 inhibitors (DPP-4Is) 2. Overcome insulin resistance 1. Biguanides (Metformin) 2. Thiazolidinediones (Pioglitazone) 3. α glucosidase inhibitors (Acarbose)
- 5.
- 7. Oral antidiabetic drugs • Thesedrugs lower blood glucose levels and are effective orally
- 8. Sulfonylureas (KATP 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 ↑ Ca2+ influx exocytotic release of insulin
- 10. • After fewmonths 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.
- 11. Interactions • Drugs thatenhance SU action (may precipitate hypoglycaemia) are— 1. Displace from protein binding Phenylbutazone, sulfinpyrazone, salicylates, sulfonamides 2. Inhibit metabolism/excretion Cimetidine, Ketoconazole, sulfonamides, warfarin, chloramphenicol, acute alcohol intake 3. Synergise with or prolong pharmacodynamic action: Salicylates, propranolol (cardioselective β1 blockers are less liable), sympatholytic antihypertensives, lithium, theophylline, alcohol
- 12. • Drugs thatdecrease SU action (vitiate diabetes control) are— 1. Induce metabolism Phenobarbitone, phenytoin, rifampicin, chronic alcoholism. 2. Opposite action/suppress insulin release Corticosteroids, thiazides, furosemide, oral contraceptives.
- 13. Adverse effects 1. 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 Weight gain, nausea, vomiting, flatulence, diarrhoea or constipation, headache and paresthesias are generally mild and infrequent 3. Hypersensitivity Rashes, photosensitivity, purpura, transient leukopenia, rarely agranulocytosis
- 14. Meglitinide analogues • Theseare KATP 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.
- 15. • Lower riskof 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
- 16. Nateglinide • Stimulates the1st 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
- 17. 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 Ca2+ channels ↓ Release of insulin from granules
- 18. Dipeptidyl peptidase-4 (DPP-4) inhibitors •DPP-4 Expressed 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
- 19. • 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.
- 20. • Widely usedto 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 Mild nausea, loose stools, headache, etc.
- 21. Glucagon-like peptide-1 (GLP-1) receptoragonists • 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 Important 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
- 22. • GLP-1 inducesinsulin 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
- 25. Biguanide (AMPK activator) •Metformin It is a ‘normoglycaemic’ • Mechanism of action Activation of AMP dependent protein kinase (AMPK) 1. Suppresses hepatic gluconeogenesis and glucose output from liver (major action) 2. Enhances insulin-mediated glucose uptake and disposal in skeletal muscle and fat. 3. Interferes with mitochondrial respiratory chain and promotes peripheral glucose utilization through anaerobic glycolysis
- 26.
- 27. • 1st choicedrug for T2DM (M-O-S-T) • Advantages of metformin are: 1. Non hypoglycaemic 2. Weight loss promoting 3. Has potential to prevent macrovascular as well as microvascular complications of diabetes 4. 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
- 28. Thiazolidinedione (PPARγ 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.
- 29. • Hepatic gluconeogenesisis suppressed and lipogenesis in adipose tissue contributes to the insulin sensitizing action • Well tolerated; A/E Plasma 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.
- 30. Interactions 1. Failure oforal contraception may occur during Pioglitazone therapy. 2. Ketoconazole inhibits and rifampin induces metabolism of Pioglitazone.
- 31. 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
- 33. • Acarbose isa 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
- 34. 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 Induces 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
- 35. • Glycosuria canpredispose to urinary and genital infections, electrolyte imbalance • Long-term safety yet to be established • Employed to supplement SU/Met./other antidiabetic drugs
- 37. Adverse effects observedwith oral hypoglycemic agents
- 38. Oral hypoglycaemics indiabetes mellitus • Only in type 2 DM not controlled by diet and exercise • Most effective in patients with— 1. Age above 40 years at onset of disease 2. Obesity at the time of presentation 3. Duration of disease < 5 years when starting treatment 4. Fasting blood sugar < 200 mg/dl 5. Insulin requirement < 40 U/day 6. No ketoacidosis or a history of it, or any other complication
- 39. • Current recommendationis 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
Editor's Notes
- #3 DCCT, Diabetes Control and Complications Trial; FPG, fasting plasma glucose; OGTT, oral glucose tolerance test; WHO, World Health Organization; 2-h PG, 2-h plasma glucose. *In the absence of unequivocal hyperglycemia, diagnosis requirestwo abnormal test results from the same sample or in two separate test samples.
- #4 DCCT, Diabetes Control and Complications Trial; FPG, fasting plasma glucose; OGTT, oral glucose tolerance test; WHO, World Health Organization; 2-h PG, 2-h plasma glucose. *In the absence of unequivocal hyperglycemia, diagnosis requires two abnormal test results from the same sample or in two separate test samples. leaving no doubt
- #10 Mechanism of action of insulin secretagogues The sulfonylureas (SU) and meglitinide analogues (Megli) block the sulfonylurea receptor (SUR1) which constitutes a subunit of the inwardly rectifying ATP-sensitive K+ channel (KATP) in the membrane of pancreatic b cells. The inward flow of K+ ions is thereby restricted, intracellular K+ concentration falls and the membrane is partially depolarized augmenting Ca2+ channel opening as well as release of Ca2+ from intracellular stores. The Ca2+ ions promote fusion of insulin containing intracellular granules with the plasma membrane and exocytotic release of insulin. Incretins such as glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP) act upon their own G-protein coupled receptors on the b cell membrane to activate adenylyl cyclase and generate cAMP, which also promotes exocytosis of insulin. Exenatide (Exe) and liraglutide (Lira) are GLP1 receptor agonists—produce the same response as GLP1. The incretins GLP1 and GIP are rapidly inactivated by the capillary endothelial enzyme dipeptidyl peptidase-4 (DPP-4). Their action is enhanced by DPP-4 inhibitors sitagliptin (sita) and vildagliptin (vilda). The DPP-4 inhibitors thus markedly accentuate the insulin response to ingested glucose/meal and attenuate post-prandial glycaemia.
- #13 spoil or impair the quality or efficiency of.
- #25 Mechanism of action of insulin secretagogues The sulfonylureas (SU) and meglitinide analogues (Megli) block the sulfonylurea receptor (SUR1) which constitutes a subunit of the inwardly rectifying ATP-sensitive K+ channel (KATP) in the membrane of pancreatic b cells. The inward flow of K+ ions is thereby restricted, intracellular K+ concentration falls and the membrane is partially depolarized augmenting Ca2+ channel opening as well as release of Ca2+ from intracellular stores. The Ca2+ ions promote fusion of insulin containing intracellular granules with the plasma membrane and exocytotic release of insulin. Incretins such as glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP) act upon their own G-protein coupled receptors on the b cell membrane to activate adenylyl cyclase and generate cAMP, which also promotes exocytosis of insulin. Exenatide (Exe) and liraglutide (Lira) are GLP1 receptor agonists—produce the same response as GLP1. The incretins GLP1 and GIP are rapidly inactivated by the capillary endothelial enzyme dipeptidyl peptidase-4 (DPP-4). Their action is enhanced by DPP-4 inhibitors sitagliptin (sita) and vildagliptin (vilda). The DPP-4 inhibitors thus markedly accentuate the insulin response to ingested glucose/meal and attenuate post-prandial glycaemia.
- #28 Metformin pref. in Obese pts.; Sulfonylureas pref. in thin pts.
- #35 Glycosuria is a term that defines the presence of reducing sugars in the urine, such as glucose, galactose, lactose, fructose, etc. Glucosuria connotes the presence of glucose in the urine and is the most frequent type of glycosuria
- #37 MOA of SGLT-2 inh.
- #41 Met—Metformin; SU—Sulfonylurea; Megli—Meglitinide/d-phenylalanine analogue; DPP-4i—Dipeptidyl peptidase-4 inhibitor; α Gli—α Glucosidase inhibitor; Pio—Pioglitazone; GLP-1 Ago—GLP-1 receptor agonist.