Pharmacology of antidiabetic drugs

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1. Pharmacology of A ntidiabetic drugs Lecture by Dr. T.S. M ohamed Saleem M.Pharm ., Ph.D Assistant Professor & Head, Department of Pharmacology Annamacharya College of Pharmacy, Rajampet 21-04-2017 Dr. T.S. Mohamed Saleem 1

2. I ntroduction The endocrine pancreas - 1 million islets of Langerhans Four hormone-producing cells are present I nsulin - the storage and anabolic hormone of the body; Islet amyloid polypeptide (IAPP, or amylin ) - modulates appetite , gastric emptying, and glucagon and insulin secretion; Glucagon - hyperglycemic factor that mobilizes glycogen stores; Somatostatin - a universal inhibitor of secretory cells; gastrin , which stimulates gastric acid secretion; and pancreatic peptide 21-04-2017 Dr. T.S. Mohamed Saleem 2

3. Diabetes mellitus An elevated blood glucose associated with absent or inadequate pancreatic insulin secretion, With or without concurrent impairment of insulin action Classified into four categories: type 1, insulin-dependent diabetes; type 2 , non–insulin-dependent diabetes; type 3, other; MODY type 4, gestational diabetes mellitus 21-04-2017 Dr. T.S. Mohamed Saleem 3

4. Type 1 Diabetes Mellitus The hallmark of type 1 diabetes is selective beta cell (B cell) destruction and severe or absolute insulin deficiency. Type 1 diabetes is further subdivided into immune and idiopathic causes. The immune form is the most common form of type 1 diabetes . Susceptibility appears to involve a multifactorial genetic linkage, but only 10–15% of patients have a positive family history. 21-04-2017 Dr. T.S. Mohamed Saleem 4

5. Type 1 For persons with type 1 diabetes, insulin replacement therapy is necessary to sustain life . Interruption of the insulin replacement therapy can be life-threatening and can result in diabetic ketoacidosis or death. Diabetic ketoacidosis is caused by insufficient or absent insulin and results from excess release of fatty acids and subsequent formation of toxic levels of ketoacids . 21-04-2017 Dr. T.S. Mohamed Saleem 5

6. Type 2 Diabetes Mellitus Tissue resistance to the action of insulin combined with a relative deficiency in insulin secretion . I nsulin is produced by the beta cells in these patients, it is inadequate to overcome the resistance, and the blood glucose rises. The impaired insulin action also affects fat metabolism, resulting in increased free fatty acid flux and triglyceride levels and reciprocally low levels of high-density lipoprotein (HDL). 21-04-2017 Dr. T.S. Mohamed Saleem 6

7. Type II Individuals with type 2 diabetes may not require insulin to survive , but 30% or more will benefit from insulin therapy to control blood glucose. It is likely that 10–20% of individuals in whom type 2 diabetes was initially diagnosed actually have both type 1 and type 2 or a slowly progressing type 1 called latent autoimmune diabetes of adults (LADA), and they ultimately require full insulin replacement . Dehydration in individuals with untreated or poorly controlled type 2 diabetes can lead to a life-threatening condition called nonketotic hyperosmolar coma . 21-04-2017 Dr. T.S. Mohamed Saleem 7

8. Type 3 Diabetes mellitus The type 3 designation refers to multiple other specific causes of an elevated blood glucose: Pancreatectomy , Pancreatitis , Nonpancreatic diseases , Drug therapy, etc. MODY 21-04-2017 Dr. T.S. Mohamed Saleem 8

9. Type 4 Diabetes Mellitus Gestational diabetes (GDM) is defined as any abnormality in glucose levels noted for the first time during pregnancy. Gestational diabetes is diagnosed in approximately 7% of all pregnancies in the USA. During pregnancy, the placenta and placental hormones create an insulin resistance that is most pronounced in the last trimester . Risk assessment for diabetes is suggested starting at the first prenatal visit. High-risk women should be screened immediately. Screening may be deferred in lower-risk women until the 24th to 28th week of gestation. 21-04-2017 Dr. T.S. Mohamed Saleem 9

10. INSULIN Insulin is a small protein with a molecular weight in humans of 5808 . It contains 51 amino acids arranged in two chains (A and B ) linked by disulfide bridges Proinsulin , a long single-chain protein molecule , is processed within the Golgi apparatus of beta cells and packaged into granules, where it is hydrolyzed into insulin and a residual connecting segment called C-peptide by removal of four amino acids 21-04-2017 Dr. T.S. Mohamed Saleem 10

11. Insulin is shown as the shaded (orange color ) peptide chains, A and B. Differences in the A and B chains and amino acid modifications for the rapid-acting insulin analogs ( aspart , lispro , and glulisine ) and long-acting insulin analogs ( glargine and detemir ) are discussed in the text. 21-04-2017 11 Dr. T.S. Mohamed Saleem Structure of human proinsulin (C-peptide plus A and B chains) and insulin

12. Insulin and C-peptide are secreted in equimolar amounts in response to all insulin secretagogues Granules within the beta cells store the insulin in the form of crystals consisting of two atoms of zinc and six molecules of insulin. The entire human pancreas contains up to 8 mg of insulin, representing approximately 200 biologic units . 21-04-2017 Dr. T.S. Mohamed Saleem 12

13. Insulin Secretion Insulin is released at a low basal rate and at a much higher stimulated rate in response to a variety of stimuli , especially glucose. Other stimulants such as other sugars ( eg , mannose), amino acids (especially gluconeogenic amino acids , eg , leucine , arginine), hormones such as glucagon-like polypeptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide ( GIP), glucagon, cholecystokinin, high concentrations of fatty acids, and β-adrenergic sympathetic activity are recognized. 21-04-2017 Dr. T.S. Mohamed Saleem 13

14. Stimulatory drugs are sulfonylureas, meglitinide and nateglinide , isoproterenol , and acetylcholine . Inhibitory signals are hormones including insulin itself and leptin , α-adrenergic sympathetic activity , chronically elevated glucose, and low concentrations of fatty acids. Inhibitory drugs include diazoxide , phenytoin, vinblastine , and colchicine. 21-04-2017 Dr. T.S. Mohamed Saleem 14

15. figure Secretion of Insulin 21-04-2017 15 Dr. T.S. Mohamed Saleem

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17. Insulin Degradation The liver and kidney are the two main organs that remove insulin from the circulation. Liver normally clears - 60 % of the insulin Kidney removing 35–40 % Subcutaneous insulin injections, this ratio is reversed Liver normally clears - 60% of the insulin Kidney removing 35–40% The half-life of circulating insulin is 3–5 minutes . Basal insulin values of 5–15 μU /mL (30–90 pmol /L) are found in normal humans, with a peak rise to 60–90 μU /mL (360–540 pmol /L) during meals. 21-04-2017 Dr. T.S. Mohamed Saleem 17

18. The Insulin Receptor Identified in the primary target tissues, ie , liver, muscle, and adipose tissue H igh specificity and affinity in the picomolar range I ncrease in glucose uptake; increased glycogen synthase activity increased glycogen formation; multiple effects on protein synthesis, lipolysis, and lipogenesis ; activation of transcription factors that enhance DNA synthesis and cell growth and division 21-04-2017 Dr. T.S. Mohamed Saleem 18 Translocation of glucose transporter (GLUT 4)

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20. Insulin Preparations Rapidacting , with very fast onset and short duration; Short-acting , with rapid onset of action; C lear solutions at neutral pH and contain small amounts of zinc to improve their stability and shelf life. Intermediate-acting ; turbid suspension at neutral pH with protamine in phosphate buffer ( neutral protamine Hagedorn [NPH ] insulin) Long-acting, with slow onset of action Insulin glargine and insulin detemir are clear, soluble long-acting insulins 21-04-2017 Dr. T.S. Mohamed Saleem 20

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22. Rapid-acting and short-acting insulin preparations Modification of the amino acid sequence of regular insulin produces analogs that are rapid-acting insulins . Insulin lispro - lysine and proline at positions 28 and 29 in the B chain are reversed. Peak levels - 30 to 90 minutes, as compared with 50 to 120 minutes for regular insulin . Mimic the prandial ( mealtime) release of insulin and to control postprandial glucose . Administered in the 15 minutes proceeding a meal or within 15 to 20 minutes after starting a meal 21-04-2017 Dr. T.S. Mohamed Saleem 22

23. Intermediate-acting insulin Neutral protamine Hagedorn ( NPH ) insulin - addition of zinc and protamine to regular insulin . insulin isophane less soluble , resulting in delayed absorption and a longer duration of action 21-04-2017 Dr. T.S. Mohamed Saleem 23

24. Long-acting insulin Lower isoelectric point leading to formation of a precipitate at the injection site slower onset and a flat, prolonged hypoglycemic effect with no peak Insulin detemir has a fatty acid side chain that enhances association to albumin 21-04-2017 Dr. T.S. Mohamed Saleem 24

25. Pharmacokinetics and fate Human insulin is produced by recombinant DNA technology Modification of the amino acid sequence of human insulin produces insulins with different pharmacokinetic properties . Insulin preparations vary primarily in their onset and duration of activity . Dose , injection site, blood supply, temperature, and physical activity can also affect the onset and duration of various insulin preparations. Because insulin is a polypeptide generally administered by subcutaneous injection. Continuous subcutaneous insulin infusion (also called the insulin pump) is another method of insulin delivery. 21-04-2017 Dr. T.S. Mohamed Saleem 25

26. Adverse reactions to insulin Hypoglycemia Weight gain, Local injection site reactions Lipodystrophy Diabetics with renal insufficiency may require a decrease in insulin dose. 21-04-2017 Dr. T.S. Mohamed Saleem 26

27. ORAL ANTIDIABETIC AGENTS 21-04-2017 Dr. T.S. Mohamed Saleem 27

28. Drug classification Insulin secretagogues sulfonylureas , meglitinides , D-phenylalanine derivatives biguanides , thiazolidinediones , α- glucosidase inhibitors, incretin -based therapies, an amylin analog, a bile acidbinding sequestrant 21-04-2017 Dr. T.S. Mohamed Saleem 28

29. SULFONYLUREAS 21-04-2017 Dr. T.S. Mohamed Saleem 29

30. Mechanism of action Increase insulin release from the pancreas A reduction of serum glucagon levels Closure of potassium channels in extrapancreatic tissue 21-04-2017 Dr. T.S. Mohamed Saleem 30

31. Insulin Release from Pancreatic Beta Cells Sulfonylureas bind to a 140-kDa high-affinity sulfonylurea receptor inhibits the efflux of potassium ions depolarization . opens a voltage-gated calcium channel calcium influx the release of preformed insulin. 21-04-2017 Dr. T.S. Mohamed Saleem 31

32. Pharmacokinetics and fate Given orally Bind to serum proteins, Metabolized by the liver Excreted in the urine and feces The duration of action ranges from 12 to 24 hours 21-04-2017 Dr. T.S. Mohamed Saleem 32

33. Tolbutamide Well absorbed but rapidly metabolized in the liver . Its duration of effect is relatively short, with an elimination half-life of 4–5 hours Dicumarol , phenylbutazone , some sulfonamides that inhibit the metabolism of tolbutamide . 21-04-2017 Dr. T.S. Mohamed Saleem 33

34. Chlorpropamide half-life of 32 hours Slowly metabolized in the liver 20–30 % is excreted unchanged in the urine . contraindicated in patients with hepatic or renal insufficiency. Dosages higher than 500 mg daily increase the risk of jaundice. The average maintenance dosage is 250 mg daily, ADR Prolonged hypoglycemic reactions hyperemic flush after alcohol ingestion Dilutional hyponatremia . Hematologic toxicity (transient leukopenia , thrombocytopenia ) occurs in less than 1% of patients. 21-04-2017 Dr. T.S. Mohamed Saleem 34

35. Tolazamide shorter duration of action. more slowly absorbed. Its half-life is about 7 hours. Metabolized to several compounds that retain hypoglycemic effects. If more than 500 mg/d are required the dose should be divided and given twice daily. 21-04-2017 Dr. T.S. Mohamed Saleem 35

36. Glyburide Metabolized in the liver into products Very low hypoglycemic activity. starting dosage is 2.5 mg/d or less, maintenance dosage is 5–10 mg/d ADR hypoglycemia Flushing slightly enhances free water clearance contraindicated in the presence of hepatic impairment and in patients with renal insufficiency. 21-04-2017 Dr. T.S. Mohamed Saleem 36

37. Glipizide Shortest half-life (2–4 hours) ingested 30 minutes before breakfast starting dosage is 5 mg/d, with up to 15 mg/d 90 % of glipizide is metabolized 10 % is excreted unchanged in the urine Contraindicated in patients with significant hepatic or renal impairment, who would be at high risk for hypoglycemia. 21-04-2017 Dr. T.S. Mohamed Saleem 37

38. Glimepiride approved for once-daily use as monotherapy or in combination with insulin. 1 mg has been shown to be effective, and the recommended maximal daily dose is 8 mg. Long duration of effect with a half-life of 5 hours, Completely metabolized by the liver to metabolites with weak or no activity. 21-04-2017 Dr. T.S. Mohamed Saleem 38

39. Other insulin secretagogues 21-04-2017 Dr. T.S. Mohamed Saleem 39

40. Repaglinide T he first member of the meglitinide group Mechanism of action is similar to sulfonylureas Two binding sites in common with the sulfonylureas and one unique binding site. 21-04-2017 Dr. T.S. Mohamed Saleem 40

41. Pharmacokinetics V ery fast onset of action Peak effect within 1 h Duration of action is 4–7 hours Metabolism by CYP3A4 Indicated for use in controlling postprandial glucose excursions . Doses of 0.25–4 mg (maximum 16 mg/d); Hypoglycemia is a risk C/I in renal and hepatic impairment. 21-04-2017 Dr. T.S. Mohamed Saleem 41

42. Nateglinide a D-phenylalanine derivative Stimulates very rapid and transient release of insulin from beta cells through closure of the ATP-sensitive K + channel . Partially restores initial insulin release in response to an intravenous glucose tolerance test Special role in the treatment of individuals with isolated postprandial hyperglycemia , but it has minimal effect on overnight or fasting glucose levels. 21-04-2017 Dr. T.S. Mohamed Saleem 42

43. Pharmacokinetics Ingested just before meals. It is absorbed within 20 minutes with a time to peak concentration of less than 1 hour Metabolized in the liver by CYP2C9 and CYP3A4 with a half-life of about 1 hour. The overall duration of action is about 4 hours. nateglinide has the advantage of being safe in those with very reduced renal function. 21-04-2017 Dr. T.S. Mohamed Saleem 43

44. BIGUANIDES Metformin Insulin sensitizer . It increases glucose uptake and use by target tissues , decreasing insulin resistance. 21-04-2017 Dr. T.S. Mohamed Saleem 44

45. Mechanism of action Metformin Activate AMP activated protein kinase (AMPA-PK) Reduce hepatic glucose production Lower blood glucose level 21-04-2017 Dr. T.S. Mohamed Saleem 45

46. Actions impairment of renal gluconeogenesis, slowing of glucose absorption from the gastrointestinal tract, increased glucose to lactate conversion by enterocytes, direct stimulation of glycolysis in tissues, increased glucose removal from blood, Reduction of plasma glucagon levels. 21-04-2017 Dr. T.S. Mohamed Saleem 46

47. ADME Orally well absorbed Half-life of 1.5–3 hours Excreted by the kidneys Impair the hepatic metabolism of lactic acid. Increase the risk of lactic acidosis The dosage of metformin is from 500 mg to a maximum of 2.55 g daily, with the lowest effective dose being recommended. 21-04-2017 Dr. T.S. Mohamed Saleem 47

48. ADR Gastrointestinal (20%) anorexia , nausea, vomiting, abdominal discomfort, and diarrhea which occur in up to 20% of patients . Vitamin B12 deficiency Renal failure – lactic acidosis 21-04-2017 Dr. T.S. Mohamed Saleem 48

49. THIAZOLIDINEDIONES Pioglitazone and rosiglitazone Decrease insulin resistance. Ligands of peroxisome proliferator-activated receptor gamma ( PPAR-f), Found in muscle, fat , and liver. Modulate the expression of the genes involved in lipid and glucose metabolism, insulin signal transduction, adipocyte and other tissue differentiation. 21-04-2017 Dr. T.S. Mohamed Saleem 49

50. Mechanism of actions Thiazolidinediones Activates peroxisome proliferator–activated receptor- γ ( PPAR γ ) Regulates the transcription of several insulin responsive genes increased insulin sensitivity 21-04-2017 Dr. T.S. Mohamed Saleem 50

51. ADME Pioglitazone Well absorbed orally Absorption is decreased with concomitant use of bile acid sequestrants . Metabolized by CYP2C8 and CYP3A4 starting dose is 15–30 mg/d, and the maximum is 45 mg/d. 21-04-2017 Dr. T.S. Mohamed Saleem 51

52. ADME Rosiglitazone rapidly absorbed and highly protein-bound. It is metabolized predominantly by CYP2C8 and to a lesser extent by CYP2C9. It is administered once or twice daily; 2–8 mg is the usual total dose. 21-04-2017 Dr. T.S. Mohamed Saleem 52

53. ADR Liver toxicity Weight gain osteopenia and increased fracture risk increase the risk of bladder cancer 21-04-2017 Dr. T.S. Mohamed Saleem 53

54. α- Glucosidase inhibitors Acarbose miglitol 21-04-2017 Dr. T.S. Mohamed Saleem 54

55. Mechanism of action 21-04-2017 Dr. T.S. Mohamed Saleem 55

56. ADME Acarbose is poorly absorbed. It is metabolized primarily by intestinal bacteria, Excreted into the urine. Miglitol is very well absorbed No systemic effects. It is excreted unchanged by the kidney. 21-04-2017 Dr. T.S. Mohamed Saleem 56

57. ADR Flatulence , diarrhea, Abdominal cramping 21-04-2017 Dr. T.S. Mohamed Saleem 57

58. Amylin analogue Pramlintide Synthetic amylin anlaogue Injectable hypoglycemic agents Approved for preprandial use in type I and II diabetes 21-04-2017 Dr. T.S. Mohamed Saleem 58

59. Actions Suppress the release of glucagon Delay gastric emptying central nervous system mediated anorectic effects 21-04-2017 Dr. T.S. Mohamed Saleem 59

60. Pharmacokinetics Rapid absorption after S.C injection Most preferable site is abdomen and thigh Arm administration is less reliable Reach peak plasma concentration with in 20 min Duration of action up to 120 min Metabolized and excreted via kidney route Even in less creatinine clearance no change in bioavailability efficacy 21-04-2017 Dr. T.S. Mohamed Saleem 60

61. Dose and administration Inject just before meal Type I - 15-60 mcg S.C Typer II – 60-120 mcg S.C Meal time insulin administration should be reduced 50% because of hypoglycemic risk 21-04-2017 Dr. T.S. Mohamed Saleem 61

62. ADR Hypoglycemia Gastrointestinal symptoms Nausea , Vomiting Anorexia 21-04-2017 Dr. T.S. Mohamed Saleem 62

63. GLUCAGON-LIKE POLYPEPTIDE-1 (GLP-1) RECEPTOR AGONISTS Exenatide Liraglutide 21-04-2017 Dr. T.S. Mohamed Saleem 63

64. Action Restore GLP-1 activity Potentiate glucose mediate insulin secretion Suppress postprandial glucagon release Slow gastric emptying Central mediated loss of appitite 21-04-2017 Dr. T.S. Mohamed Saleem 64

65. Exenatide A derivative of the exendin-4 peptide in Gila monster venom First incretin therapy available in market 53% homology with native GLP-1 , Glycine substitution to reduce degradation by dipeptidyl peptidase-4 (DPP-4 ) Recommended for suboptimal glycemic control 21-04-2017 Dr. T.S. Mohamed Saleem 65

66. Exenatide cont ….. Availabe injection formulation Equal absorption from arm, abdomen and thigh Reach peak conc with in 2 h Duration of action is 10 h Dose adjustment is required in case of CrCl less than 30 mL/min 21-04-2017 Dr. T.S. Mohamed Saleem 66

67. ADR Nausea Vomiting Diarrohoea Necrotizing and hemorrhogic pancreatitis 21-04-2017 Dr. T.S. Mohamed Saleem 67

68. Liraglutide Long-acting synthetic GLP-1 analog with 97 % homology to native GLP-1 Peak levels are obtained in 8–12 hours Elimination half-life is about 13 hours Prolonged half-life that permits once-daily dosing. 21-04-2017 Dr. T.S. Mohamed Saleem 68

69. Action Liraglutide interacts with the GLP-1 receptor Increase insulin release Decrease glucagon 21-04-2017 Dr. T.S. Mohamed Saleem 69

70. ADR Headache Nausea Diarrhea A ntibody formation Urticaria Pancreatitis Risk of endocrine cancer (FDA black box warning) 21-04-2017 Dr. T.S. Mohamed Saleem 70

71. DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS Sitagliptin Saxagliptin L inagliptin 21-04-2017 Dr. T.S. Mohamed Saleem 71

72. Mechanism of action Incretin hormones Dipeptidyl peptidase – 1 degradation 21-04-2017 Dr. T.S. Mohamed Saleem 72 Sitagliptin Sexagliptin Linagliptin Increase circulating levels of native GLP-1 Glucose-dependent insulinotropic polypeptide (GIP), I ncreasing glucose-mediated insulin secretion Decreasing glucagon levels. Inhibition of enzyme

73. Sitagliptin Orally well absorbed Bioavailability 85% Reach PPC with in 1-4 h Half life is 12 h Oral dose is 100 mg Metabolized via CYP3A4 Excreted via urine by tubular secretion 21-04-2017 Dr. T.S. Mohamed Saleem 73

74. ADR Nasopharyngitis U pper respiratory infections Headaches Hypoglycemia Post marketing report Acute pancreatitis Hypersensitivity reactions 21-04-2017 Dr. T.S. Mohamed Saleem 74

75. Sexagliptin Orally well absorbed Dose is 2.5 to 5 mg daily Less protein binding Reach peak plasma conc within 2 h Undergo metabilosm by CYP3A4/5 to form active molecule Peak plasma conc of metabolite is 4 h Both are excreted via urine 21-04-2017 Dr. T.S. Mohamed Saleem 75

76. ADR I ncreased rate of infections Upper respiratory tract and urinary tract Headaches, peripheral edema hypoglycemia H ypersensitivity reactions urticaria , facial edema 21-04-2017 Dr. T.S. Mohamed Saleem 76

77. Any questions 21-04-2017 Dr. T.S. Mohamed Saleem 77 ?