Unit-I A Antidiabetic drugs saeed w.pptx

Pharmacy

1. UNIT I A). Diabetes, and antidiabetic drugs SAEED ULLAH Bsn

2. Objectives By the completion of this section the learners will be able to: Discuss the role of Insulin in metabolic process. Discuss different types of anti-diabetic agents with their mode of action, side effects and care. List the principles of therapy for all anti-diabetic agents. State reasons for combinations of insulin and oral hypoglycemic agents. Calculate drug dosage accurately.

3. Diabetes Mellitus Diabetes mellitus is a chronic metabolic disorder characterized by a high blood glucose concentration (hyperglycemia). Diabetes develops when the level of blood sugar increases due to insufficient or ineffective insulin . Fasting plasma glucose of 126 mg/ dL (7.0 mmol/L) or more, documented on more than one occasion. What is metabolic disorder? Metabolic disorder occurs when the metabolism process fails and causes the body to have either too much or too little of the essential substances needed to stay healthy. Disease in the liver, pancreas, endocrine glands or other organs involved in metabolism lead to metabolic disorder.

4. Types Type 1 diabetes: In type 1 there is selective beta cell (B cell) destruction and severe or absolute insulin deficiency Type 2 diabetes: it is characterized by tissue resistance to the action of insulin combined with a relative deficiency in insulin secretion

5. New risk factors for obesity and diabetes: Environmental chemicals

6. Glucose transporters

7. Classification of Anti diabetic drugs Parenteral 1. Insulin 2. Glucagon-like Polypeptide-1 (GLP-1) Receptor agonists Exenatide Liraglutide Oral antidiabetic drugs A. Sulfonylurea's Tolbutamide Chlorpropamide Tolazamide Glimepiride Glipizide B. M iglitinides /Glinides Repaglinide Nateglinide C. Biguanides Metformin D . Thiazolidinediones Rosiglitazone Pioglitazone E . α- Glucosidase inhibitors Acarbose Miglitol F . Dipeptidyl peptidase-4 inhibitors (DPP-4) Sitagliptin Saxagliptin Linagliptin G . Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors Canagliflozin Ipragliflozin Dapagliflozin

8. Classification Enhance Insulin secretion (sectertogagus) Sulfonylureas First generation: Tolbutamide Second generation: Glibenclamide, Glipizide , Meglitinide analogues Repaglinide, Nateglinide Gluc a g o n- li k e pe p ti d e - 1 (GL P- 1) r ece p t or a g o n i s ts ( Injec t able drugs) Exenatide, Liraglutide Dipeptidyl peptidase-4 (DPP-4) inhibitors Sitagliptin, Vildagliptin.

9. Classification Overcome Insulin resistance (insulin sensitizer) 1. Biguanide Metformin 2. Thiazolidinediones (PPAR  activator) Pioglitazone

10. Miscellaneous antidiabetic drugs α- Glucosidase inhibitors Acarbose, Miglitol, Voglibose Sodium-glucose cotransport-2 (SGLT-2) Inhibitor : Dapagliflozin

11. Insulin Insulin is a peptide hormone produced by beta cells of the pancreatic islets. It is a protein containing 51 amino acids. Insulin Secretion: Insulin is released from pancreatic beta cells in response to a variety of stimuli, especially glucose and incretin hormones. Basal insulin values of 30–90 pmol/L) are found in normal humans.

12. Insulin Secretion Insulin is released from pancreatic beta cells in response to Glucose, Certain peptide hormones (incretin) such as glucagon-like polypeptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide ( GIP.

13. Cell Organization in Pancreas Exocrine acinar cells surround a small duct Endocrine cells secrete near a capillary

14. Cell Types in the Pancreatic Islets Alpha cells (20%) produce glucagon Beta cells (70%) produce insulin Delta cells (5%) produce somatostatin Daily pancreatic production of insulin in the adult individual is approximately 50 units ( 0.7–1.3 mg) .

15. Insulin discovery Insulin was discovered in 1921 by Banting and Best who demonstrated the hypoglycemic action of an extract of pancreas.

16. Release of insulin from beta cells Glucose enters the β-cells through the glucose transporters,  GLUT2. Glucose goes into glycolysis and the Krebs cycle, where multiple, high-energy ATP molecules are produced. An increased intracellular ATP closes the ATP-sensitive potassium channel preventing potassium ions (K + ) from leaving the cell. As a result, the inside of the cell becomes less negative(depolarization) Upon depolarisation, voltage-gated calcium ion (Ca 2+ ) channels open, which allows calcium ions to move into the cell. Then, increased amounts of calcium ions in the cells causes the release of stored insulin from secretory vesicles.

17. How Insulin act ? After insulin enter the circulation, it diffuses into tissues, where it is bound by receptors. The insulin receptor consists an α subunit, which is entirely extracellular having a recognition site, and a β subunit that cross the membrane contains a tyrosine kinase. The binding of an insulin molecule to the α subunits activates the receptor by phosphorylation followed by several reactions occurring within the cell representing insulin’s second message and exert multiple effects on glucose regulating organs.

18. Mechanism of insulin

19. Effect on liver Inhibits glycogenolysis Inhibits Gluconeogenesis Promotes glycogen synthesis Increases triglyceride synthesis (lipogenesis) Effect on muscle Promotes protein synthesis. Increased glycogen synthesis Increases glucose transport and glycogen synthesis. Effect on adipose tissue Lipogenesis as promotes the storage of fat Increases g lucose uptake

20. Various insulin preparations for details please read Lippincott self study Rapid-acting insulin preparations (lispro, aspart) Short-acting insulin preparations (humulin R) Intermediate-acting insulin (Humulin N) Long-acting insulin preparations (lantus, levemir) Insulin combinations (premixed ) eg. Humulin 30/70

21. Adverse reactions to insulin Hypoglycemia Weight gain

22. Reactions to insulin Hypoglycemia can occur following unintentional injection of large dose, by missing a meal after injection or by performing vigorous exercise. Hypoglycemia symptoms are palpitation, tremor, dizziness , headache, behavioral changes, fatigue. Treatment : Glucose must be given orally or i.v. (for severe cases)—reverses the symptoms rapidly.

23. Glucagon-like Polypeptide-1 (GLP-1) Receptor agonists Incretin mimetics Incretins are hormones produced by intestines in response to food. Orally administered glucose stimulate greater release of insulin than the same amount of glucose delivered by injection. Some signal is produced from the gastrointestinal tract (or “gut”) that increases insulin release whenever food is consumed. These signals are incretins   (peptide hormones) Incretins increase insulin secretion and decrease glucagon Furthermore , people with Type 2 diabetes have diminished insulin release in response to meals.

24. Examples: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 is made in the small intestine and colon GIP is made by cells in the upper small intestine

25. Dipeptidyl peptidase-IV (DPP-IV ) is an enzyme which cause the degradation of GLP-1 leading to termination of action. What is Dipeptidyl peptidase-IV (DPP-IV) ?

26. What is incretin effect? Incretin effect is defined as the increased stimulation of insulin secretion after oral ingestion of glucose as compared with intravenous administration of glucose. Incretin hormones are responsible for 60% to 70% of postprandial insulin secretion. Patients with type 2 diabetes exhibit loss of incretin effect. 

27. Incretin mimetics are agents that act like incretin hormones. Examples; Glucagon-like Polypeptide-1 or (GLP-1) Receptor agonists Exenatide Liraglutide Incretin mimetics

28. The incretin mimetics are agonists of GLP-1 receptors. Insulin secretion Slow gastric emptying time Reduce food intake Decrease postprandial glucagon secretion Promote β-cell proliferation Mechanism of action

29. Exenatide Exenatide approved in 2005) is a peptide GLP-1 receptor agonist that was originally isolated from lizard venom (exendin). Liraglutide is more effective than exenatide because it is more stable: it is resistant to degradation by DPP-4. Moreover, anti- exentide antibodies  formation led to decrease efficacy exenatide. Pharmacokinetics and fate: Being polypeptides, exenatide and liraglutide must be administered subcutaneously. Liraglutide is highly protein bound and has a long half-life, allowing for once-daily dosing without regard to meals.

30. Nausea Vomiting Constipation Pancreatitis decreased gastric motility weight loss Adverse effects

31. Oral Anti-diabetic Drugs

32. GLP-1 and GIP are the known substrates of DPP4, it is important for drugs to selectively inhibit this enzyme in order to prolong the action of incretins. Drugs: Sitagliptin Vildagliptin Alogliptin Linagliptin The first agent of the class sitagliptin  was approved by the FDA in 2006 Dipeptidyl peptidase 4 inhibitors (DPP-4)

33. Mechanism of action DPP-4 Inhibitors DPP-4 inhibitors inhibit the enzyme DPP-4, prolonging the activity of incretin hormones, increases insulin release in response to meals. Pharmacokinetics: The DPP-4 inhibitors are well absorbed after oral administration. Food does not affect the extent of absorption. Alogliptin and sitagliptin are mostly excreted unchanged in the urine. All DPP-4 inhibitors except linagliptin require dosage adjustments in renal dysfunction.

34. Adverse effects Most common adverse effects are Nasopharyngitis and Headache . Although infrequent, pancreatitis has occurred with use of all DPP-4 inhibitors.

35. Sulfonylureas Sulfonylureas are also know as insulin secretagogues, because they promote insulin release from the β cells of the pancreas. Sulfonylureas were among the first oral medicines available for the treatment of Type 2diabetes. They were discovered by accident in France by a researcher who was working on drugs for typhoid fever. Animals that were given sulfonylureas displayed unusual behaviors and were found to have hypoglycemia (low blood glucose). It was quickly recognized that these drugs could be used for the treatment of diabetes. Since sulfonylureas work by stimulating the pancreas to release insulin, they are only useful in people with Type 2 diabetes whose beta cells still produce insulin.

36. Mechanism of action of sulfonylureas These drugs exert their hypoglycemic effects by stimulating insulin secretion from the pancreatic beta-cell.

37. Sulfonylureas mechanism of action Sulfonylureas bind sulfonylurea receptor present on ATP-sensitive potassium channel inhibiting the efflux of potassium ions causing depolarization. Depolarization opens a voltage-gated calcium channel and results in calcium influx and the release of preformed insulin. Voltage-gated ion channel: any ion channel that opens and closes in response to changes in electrical potential across the cell membrane.

38. Adverse effects of sulfonylureas Weight gain Hypoglycemia They should be used with caution in hepatic or renal insufficiency as accumulation of sulfonylurea's may cause hypoglycemia.

39. Meglitinides / Glinides This class of agents includes repaglinide and nateglinide . Glinides are also considered insulin secretagogues. Mechanism of action: Like the sulfonylureas, the glinides stimulate insulin secretion. They bind to β cell, closing ATP-sensitive K+ channels, and initiating a series of reactions that results in the release of insulin. In contrast to the sulfonylureas, the glinides have a rapid onset and a short duration of action. They are particularly effective in the early release of insulin that occurs after a meal and are categorized as postprandial glucose regulators. Glinides should not be used in combination with sulfonylureas due to overlapping mechanisms of action. This would increase the risk of serious hypoglycemia.

40. Meglitinides / Glinides Pharmacokinetics and fate: Glinides should be taken prior to a meal and are well absorbed after oral administration. Both glinides are metabolized to inactive products by cytochrome P450 3A4 in the liver and are excreted through the bile. Adverse effects: Although glinides can cause hypoglycemia and weight gain, the incidence is lower than that with sulfonylureas. These agents should be used with caution in patients with hepatic impairment.

41. Biguanides Metformin, the only biguanide, is classified as an insulin sensitizer. It increases glucose uptake and use by target tissues, thereby decreasing insulin resistance.

42. Biguanides Mechanism of action: The main mechanism of action of metformin is reduction of hepatic gluconeogenesis. Metformin also slows intestinal absorption of sugars and improves insulin sensitivity by increasing peripheral glucose uptake and utilization . Weight loss may occur because metformin causes loss of appetite. The American Diabetic Association recommends metformin as the initial drug of choice for type 2 diabetes. Metformin may be used alone or in combination with other oral agents or insulin.

43. Biguanides Unwanted effects : D ose-related gastrointestinal disturbances Lactic acidosis is a rare but potentially fatal toxic effect Long-term use may interfere with absorption of vitamin B 12 Contra indications: metformin should not be given to patients with Renal failure Hepatic disease Hypoxic pulmonary disease Heart failure or s hock

44. Thiazolidinedione's The thiazolidinediones (TZDs) are also insulin sensitizers. The two members of this class are pioglitazone and rosiglitazone . Although insulin is required for their action , the TZDs do not promote its release from the β cells, so hyperinsulinemia is not a risk.

45. Cont.. Mechanism of action: The TZDs lower insulin resistance by acting as agonists for the peroxisome proliferator–activated receptor-γ (PPARγ ), a nuclear hormone receptor. Activation of PPARγ regulates the transcription of several genes with products that are important in insulin signaling , resulting in increased insulin sensitivity in adipose tissue, liver, and skeletal muscle.

46. Cont.. Unwanted effects TZDs : Weight gain fluid retention, Headache Fatigue Gastrointestinal disturbances.

47. α-Glucosidase inhibitors Acarbose and miglitol are oral agents used for the treatment of type 2 diabetes . Mechanism of action: Located in the intestinal brush border, α- glucosidase enzymes break down carbohydrates into glucose and other simple sugars that can be absorbed. Acarbose and miglitol reversibly inhibit α- glucosidase enzymes. When taken at the start of a meal, these drugs delay the digestion of carbohydrates, resulting in lower postprandial glucose levels.

48. Cont… Unwanted effects : Flatulence Loose stools or diarrhea Abdominal pain Bloating

49. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of diabetic medications indicated only for the treatment of type 2 diabetes. Canagliflozin Dapagliflozin Mechanism of action : by inhibiting SGLT2, canagliflozin , dapagliflozin decrease reabsorption of glucose, increase urinary glucose excretion, and lower blood glucose . Sodium–glucose cotransporter 2 inhibitors

50. Adverse effects Genital mycotic infections (candidiasis) Urinary tract infections Osmotic diuresis Increase urinary frequency Hypotension Gliflozins can increase the diuretic effect of thiazides, loop diuretics and related diuretics and therefore increase the risk of dehydration and hypotension

51. Principles of treatment with antihyperglycemic agents Metformin is the preferred initial oral antihyperglycemic agent [A ]. If metformin is contraindicated or intolerable as the initial treatment, then another class of antihyperglycemic agent can be used, depending on the clinical situation [E ]. If monotherapy fails to achieve the glycemic goal, then combination therapy using a second agent with a different mechanism of action should be initiated [A]. Dual combination therapy can be used as the initial management strategy, depending on the patient [B].

52. Principles of treatment with antihyperglycemic agents Although the maximal dosage of a single oral agent may be prescribed, early initiation of combination therapy is suitable after considering the glucose-lowering efficacy and side-effects of the drug [B]. When selecting a class of antihyperglycemic agents for combination therapy, the glucose-lowering efficacy, risk of hypoglycemia, body weight gain, and cardiovascular benefits associated with the drugs are preferentially considered [E]. The different mechanisms of action, drug interactions, and patient preferences for combination therapy with more than two classes of antihyperglycemic agents should be considered [C].

53. References Lippincott Illustrated Reviews: Pharmacology Sixth Edition