Oral hypoglycemic agent

Manish yadav .M Pharm First year
Pharmacology . Under -guidence of
Professor Dr. Govind Singh .
M.D.University Rohtak
Department Pharmaceutical science

1. Maharshi Dayanand University, Rohtak Department of Pharmaceutical Sciences Topic - Oral Hypoglycemic Drugs Submitted To : Dr. Govind Singh Submitted By : Manish Yadav Associate professor(P’Cology) Roll no : 4101 M. Pharm ( Pharmacology) Second Semester

2. Oral Hypoglycemic Drugs Definition : Oral antihyperglycemic agents lower glucose levels in the blood . They are commonly used in the treatment of diabetes mellitus.

3. Objectives : By the end of the lecture , you should know: ● Classify different categories of antidiabetic drugs. ● Identify mechanism of action , pharmacokinetics and pharmacodynamics of each class of antidiabetic drugs. ● Identify the clinical uses of antidiabetic drugs ● Know the side effects , of each class of antidiabetic drugs.

4. Types of diabetes mellitus Type II VS Type I Due to obesity & genetic factors . Due to autoimmune or viral - 80-90% occurrence diseases (the only treatment for insulin -Over age 35 dependent diabetes is insulin injections) ssss

5. Patients with Type II diabetes have two physiological defects : 1. Abnormal insulin secretion. ( partial production of insulin) 2. Resistance to insulin action in target tissues associated with decreased number of insulin receptors.

6. Treatment of Type II Diabetes Stage 1 Stage 4. Stage 2 Stage 3 . Proper dietary management. Increase physical activity. Caloric restriction and weight loss are IMP in obese diabetic patients. Oral antidiabetic drugs.

7. Stage 1. Proper dietary management

8. 2.Increase physical activity

9. Stage 3. Caloric restriction and weight loss are IMP in obese diabetic patients

10. Stage 4: Oral antidiabetic drugs

11. General trick to manage Type 2 diabetes is managed through a stepwise approach Step1 . Starting with diet and exercise than . Step 2 . followed by oral hypoglycemic drugs. Step 3 . Then combination therapy if the patient is not responding to monotherapy of oral hypoglycemics. Step 4 . And finally in advanced severe cases insulin injections are used. Step 5 . They increase the p roductio n of insulin. Step6 . They increase the sensitivity of peripheral tissues to insulin .

12. Oral hypoglycemic drugs ( Antidiabetic drugs ) 1: Insulin secretagogues 2 . Insulin sensitizers : 1. Sulfonylurea drugs. 1. Biguanides 2. Meglitinides 2. Thiazolidinedione 3 . Agents that reduce 4 Agents that reduce glucose renal reabsorption carbohydrate absorption (Increase glucose excretion): 1. Alpha glucosidase inhibitor 1. Sodium/glucose cotransporter 2 (SGLT2) inhibitors :

13. 1.Insulin secretagogues Definition : ● Are drugs which increase the amount of insulin secreted by the pancreas ★ Their action depends upon functioning pancreatic β-cells . ● It includes: a. Sulfonylureas b. Meglitinides

14. ( 1-1) sulfonylureas Class First generation (-amide) Second generation (-ride/ zide ) Drug -Acetohexamide - Tolbutamide - Glyburide (glibenclamide) - Gliclazide - Glimepiride - Glipizide -Chlorpropamide Long acting Short acting Long acting (-ride) Short acting (- zide ) P.K ● Orally -- well absorbed. ★ All are highly bound to -- plasma proteins . ● Excreted in- - urine . ★ Cross placenta , stimulate fetal β- cells to release insulin → fetal hypoglycemia at birth. ● Reach peak concentration after- - 2-4 hr ● Duration of action is variable ● Metabolized in- - liver

15. Uses ● Treatment of Type II diabetes-- monotherapy or in combination with other antidiabetic drugs . ADR 1. Hyperinsulinemia & Hypoglycemia: ○ More common in long acting sulfonylureas ; particularly (glyburide, and glimepiride) ○ More in old age , hepatic or renal diseases. 2. Weight gain due to increase in appetite unless the diabetic diet and exercise program are followed. NOTE: 1. All hypoglycemic drugs are C.I during pregnancy , even if the patient was diagnosed with type 2 diabetes. 2. The only treatments that is allowed during pregnancy is insulin .

16. MOA: Step1 : Sulfonylureas Step2 : Bind to specific receptor on Beta cell of islets of pancreas Step 3: Blockade of ATP dependent K+ channels Step4 : Opening of voltage-dependent Ca+ channels Step 5: By depolarization and influx of calcium ions into Beta cell Step 6 ↑Intracellular calcium in the beta cell Step 7: By Degranulation and increased release of stored insulin from Beta cell Step 8: ↑Insulin release in blood

17. .

18. ( 1-2) Meglitinides Drug -- Repaglinide P.K ● Orally, well absorbed . ★ Very fast onset of action, peak 1 h. ● Short duration of action (4 h ). ● Metabolized in liver and excreted in bile. ★ Taken just before each meal (3 times/day ) ○ The dose should be skipped if the meal is missed 1 Uses ● Type II diabetes as a monotherapy or in combination with other oral hypoglycemic drugs ADR ● Less incidence than sulfonylureas 2 ○ Hypoglycemia . ○ Weight gain

19. MOA : Meglitinides ,Meglitinides (glinides) are based on the sulfonylurea moiety of glibenclamide (called meglitinide). They bind to the SUR1 receptor on the β-cell , although with lower affinity than sulfonylureas, and stimulate insulin release in the same way . Note : 1 Sulfonylurea monotherap y is associated with higher risk for all-cause mortality, major hypoglycemic episodes, and cardiovascular events compared with metformin 2. Meglitinides are secretagogues like sulfonylureas, although not structurally related

20. .Note: Sulfonylureas and meglitinides Sulfonylureas and meglitinides directly stimulate release of insulin from pancreatic beta cells and thereby lower blood glucose concentrations . Because they work by stimulating insulin secretion, they are useful only in patients with some beta cell function

21. 2- Insulin sensitizers Definition: Drugs that increase the sensitivity of peripheral target organs to insulin 1. Biguanides 2. Thiazolidinediones E.g. Metformin E .g Pioglitazone

22. 1.Biguanides -- Drug -- Metformin P.K ● Orally ● Not bound to serum protein, . t 1⁄2: 3 hours. ● Not metabolized , excreted unchanged in urine Advantages ★ No risk of hypoglycemia2 ● No weight gain ● Inexpensive

23. Uses ★ In patients with type 2 diabetes who are obese because it promotes modest weight reduction (first-line therapy ). ● Type 2 diabetes as monotherapy or in combination with other antidiabetics. ADR ● GIT disturbances: ○ Metallic taste in the mouth, nausea , vomiting , diarrhea ○ Metformin should be taken with meals and should be started at a low dose to avoid intestinal side effects then increase gradually. ★ Lactic acidosis 5 (very rare): ● In long term use: Interference with vitamin B12 absorption8

24. MOA : Metformin 1 . Decreases the liver's production of glucose via activation of AMP-activated protein kinase (AMPK) Adenosine Monophosphate-Activated Protein Kinase 2. Other possible mechanism may contribute to its effects, and include: inhibiting the breakdown of fatty acids used to produce glucose at very high doses it may increase the removal of glucose from muscle, the liver, and other body tissues where it is stored.

25. MOA: Metformin

26. ( 2- 2) Thiazolidinediones Drug -- Pioglitazone & Rosiglitazone (-glitazone) P.K ● Orally (once daily dose). ● Highly bound to plasma albumins (99%) ● Slow onset of activity ● Half life 3-4 h 2 ● Metabolized in the liver ● Excreted in bile and urine Uses ● Type II diabetes with insulin resistance . ● Used either alone or in combination with sulfonylurea, biguanides or insulin . ★ No risk of hypoglycemia when used alone ADR ● Hepatotoxicity (monitor liver function tests for 1st year of therapy). ★ Fluid retention (Edema ) ★ Congestive heart failure3 ● Mild weight gain ● Failur e of estrogen-containing oral contraceptives

27. MOA: Thiazolidinediones : They increase sensitivity of peripheral tissue to insulin Step 1: Pioglitazone ( drug ) Step 2: Bind to nuclear PPAR-y Step 3: . Activate peroxisome proliferator-activated receptor-Gamma (PPAR-Gamma. Step 4: Activate insulin – responsive gene that regulate carbohydrate and lipid metabolism Step 5: ● Increase sensitivity of target tissues ( peripheral tissue ) to insulin. Step 6: ● Increase glucose uptake or transport into muscle cell and adipose tissue .utilization in muscle and adipose tissue .inhibit hepatic gluconeogenesis .

28. Class- 3. α- Glucosidase inhibitors Drug -- Acarbose , Miglitol P.K ● No hypoglycemia if used alone ● Given orally, not absorbed so taken just before meals . Uses ★ Are effective alone in the earliest stages of impaired glucose tolerance ● Are not recommended alone as therapy for moderate to severe hyperglycemia ○ Most useful in combination with other oral hypoglycemic drugs or with insulin . ADR ● GIT: Flatulence, b loating , diarrhea , abdominal pain .

29. MOA: . α- Glucosidase inhibitors Acarbose Reversible inhibitors of intestinal α -glucosidases in intestinal brush border cells that are responsible for carbohydrate digestion. ● Decrease carbohydrate digestion and glucose absorption in small intestine (lower postprandial glucose level).

30. Class 4. Sodium-glucose transporter 2 inhibitors Drug ---- Canagliflozin, Dapagliflozin, Empagliflozin (-gliflozin) Uses ● Used with diet and exercise to control high blood sugar in patients with type 2 diabetes. ● To reduce risk of major adverse cardiovascular events1 in adults with type 2 diabetes and established cardiovascular disease. ADR ★ Urinary tract infections . ★ Yeast infections2 (vagina or penis ) ● Increased urination and dry mouth . ● Thirst ● Itching (vagina or penis) ● Fatigue

31. MOA: Sodium-glucose transporter 2 inhibitors Canagliflozin Inhibits SGLT2 in the kidneys inhibits glucose and Na reabsorption this allows excess glucose to be excreted in the urine → this will reduce blood sugar levels.

32. Summary

33. Reference Blau JE, Taylor SI (2018): Adverse effects of SGLT2 inhibitors on bone health. Nature Reviews Nephrology. 14:473-474. Chang H-Y et al (2018): Association Between Sodium-Glucose Cotransporter 2 Inhibitors and Lower Extremity Amputation Among Patients With Type 2 Diabetes. JAMA Intern Med. 178(9):1190-1198. doi:10.1001/jamainternmed.2018.3034 Das L et al (2018): Unmasking and aggravation of polycythemia vera by canagliflozin. Case Report. Diabetic Medicine. 35(11): 1613-1616. Kuriyama C et al (2014): Analysis of the Effect of Canagliflozin on Renal Glucose Reabsorption and Progression of Hyperglycemia in Zucker Diabetic Fatty Rats. J Pharmacol Exp Ther 351:423-431. McCulloch DK (2014): Management of persistent hyperglycemia in type 2 diabetes mellitus. In: UpToDate, Basow , DS (Ed), Waltham, MA. Cited 6/16/14. Neal B et al (2017): Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R): A randomized, placebo-controlled trial. Diabetes Obes Metab .