Drugs for Diabetes Mellitus FFG2414 PDF

FFG2414 Pharmacology II Chapter 5 Drugs for Diabetes Mellitus Learning outcome After completing this lesson, the students should be able to:  Describe the pancreatic hormones and functions  Describe the types of diabetes mellitus  Describe pharmacology of drugs for diabetes mellitus...

FFG2414 Pharmacology II Chapter 5 Drugs for Diabetes Mellitus Learning outcome After completing this lesson, the students should be able to:  Describe the pancreatic hormones and functions  Describe the types of diabetes mellitus  Describe pharmacology of drugs for diabetes mellitus Structure of the lesson  Pancreas and pancreatic hormones  The regulation of blood glucose concentrations  Diabetic Mellitus  Drugs for Diabetic Mellitus  Hyperglycemic drugs Pancreas and pancreatic hormones  The hormones secreted by the endocrine pancreas are produced in clusters of cells called islets of Langerhans.  These islets contain four types of cells: α (or alpha), β (or beta), δ (or delta) and F cells.  The δ cells produce glucagon, and the β cells secrete insulin.  These two major hormones of the endocrine pancreas are primarily concerned with regulation of glucose metabolism and blood glucose concentration.  Insulin promotes the uptake, utilization, and storage of glucose and thereby lowers the plasma glucose concentration, whereas glucagon increases the hepatic glucose output and blood glucose concentration. 1 3 June 2024  FFG2414 Pharmacology II  If insulin secretion or insulin sensitivity is not sufficient to maintain normal blood glucose concentrations, diabetes mellitus (DM) results.  The δ cells are the source of somatostatin, and the F cells produce pancreatic peptide, a peptide that appears to facilitate digestive processes. The regulation of blood glucose concentrations  The beta cells of a healthy person release a small amount of insulin into the blood stream throughout the day and night called basal insulin release.  Blood glucose rises to a peak usually within 30 minutes of starting a meal. When a healthy person begins to eat a meal, stored insulin is released immediately.  The insulin should be sufficient to meet the amount of glucose from the meal.  Usually within 1 to 2 hours after the meal, the blood glucose level should return to normal as a result of insulin secretion.  As the blood glucose concentration increases, glucose binds to its receptors on the plasma membrane of beta cells, causing the release of insulin.  Insulin binds to plasma membrane receptors on skeletal and heart muscle and adipose tissue, open the carrier protein, allowing glucose into the cell.  As the glucose enters the cell, there are fewer glucose molecules in the bloodstream, decreasing of blood glucose concentration. 2 3 June 2024  FFG2414 Pharmacology II  Glucagon is produce by α cells of the pancrease in response to decreased blood glucose concentration.  It activates glycogenolysis and gluconeogenesis and thereby increases hepatic glucose production. 3 3 June 2024  FFG2414 Pharmacology II Diabetes Mellitus  Diabetes mellitus, which is a disorder of glucose homeostasis characterized by the elevation of both basal and postprandial blood glucose concentration.  The disease is classified into four categories: i. Type I Diabetes - Type I diabetes mellitus usually has its onset before the patient reaches 30 years of age, with a median onset of 12 years of age. - It is believed to be an autoimmune disease that is triggered by a viral infection or other environmental factor. - This destroys the beta cells, the production of insulin decreases, the hyperglycaemia ensues. - Because patients with Type I DM require exogenous insulin for survival, this type of disease is also called insulin-dependent diabetes mellitus (IDDM). 4 3 June 2024  FFG2414 Pharmacology II ii. Type II Diabetes Mellitus - Type II diabetes mellitus usually has its onset after the patient reaches 30 years of age. - Most patients with type II DM have normal or elevated concentrations of insulin and do not require exogenous insulin for survival. - Type II DM is also called non-insulin-dependent diabetes mellitus (NIDDM). - These patients can effectively be treated with oral anti-diabetic medications in combination with dietary modifications and exercise. - Obesity is a common risk factor for this type of diabetes. - It can also be due to insulin resistance. - This occurs because the circulating endogenous insulin is inadequate for tissue sensitivity or due to deficiency of pancreatic β cell’s response to glucose. 5 3 June 2024  FFG2414 Pharmacology II iii. Type III Diabetes Mellitus  This refers to diabetes which the elevated blood glucose is caused by pancreatitis, pancreatectomy, drug therapy and so on. iv. Type IV Diabetes Mellitus  This refers to gestational diabetes which is defined as any abnormality in glucose levels noted for the first time during pregnancy.  Type I and Type II are the two major forms of diabetes mellitus, with the latter accounting for about 85% of cases of DM. 6 3 June 2024  FFG2414 Pharmacology II 7 3 June 2024  FFG2414 Pharmacology II Drugs for Diabetes Mellitus  The therapy of DM is directed at regulating the blood glucose level through diet control, exercise, and drug administration. In both forms of diabetes, patients’ diets are adjusted to limit the intake of carbohydrates.  Drugs used in the treatment of DM are divided into two groups: (a) parenteral administration and (b) oral antidiabetic drugs.  The parenteral drugs for DM include: (i) insulins  Insulin binds to the insulin receptors on the plasma membrane and to regulate the blood glucose and metabolism.  These receptors are located in the adipose tissues, liver and skeletal muscles.  The nerves, red blood cells, kidney and the lens of the eye DO NOT require insulin for glucose transport.  There are four types of injected insulins: - Rapid-acting, with very fast onset, short duration - Short-acting, with rapid onset of action - Intermediate-acting, and - Long acting, with slow onset of action 8 3 June 2024  FFG2414 Pharmacology II  Rapid-acting and short-acting insulins are dispensed as clear solutions at neutral pH and contain small amount of zinc to improve stability and shelf life.  Intermediate-acting NPH insulins are dispensed as a turbid suspension at neutral pH with protamine in phosphate buffer.  Insulin glargine and insulin detemir are clear, soluble long-acting insulins.  Combining short-acting and long-acting insulins helps to manage blood glucose levels effectively throughout the day. Short-acting insulin covers the spikes in blood glucose after meals, while long-acting insulin provides a steady baseline level of insulin to control blood glucose between meals and overnight. (ii) Amylin analog  Amylin is the hormone co-secreted by the pancreas beta cells with insulin.  Amylin secretion results from insulin’s response to food intake and blood glucose concentration.  Amylin slows gastric emptying and suppresses glucagon secretion.  This reduces the postprandial glucose absorption load and output from the liver by glucagon. 9 3 June 2024  FFG2414 Pharmacology II  Pramlintide is an amylin analog. It is given as an adjunct treatment with insulin or oral antidiabetic drugs. (iii) incretin mimetics  Incretins are peptide hormones secreted from the duodenum.  Incretins stimulate insulin secretion, inhibit glucagon secretion and delays stomach emptying time so absorption is distributed over longer time.  This avoids hyperglycemic peaks.  Exenatide is an incretin mimetic which activates the incretin receptor (GLP-1 agonist), produces the same effect as incretin.  The oral anti-diabetic drugs are further classified into: (i) Secretagogues  These drugs cause the release of insulin. Therefore they have no value in the treatment of type 1 DM because there is no insulin produced by the beta cells. (e.g. glibenclamide) (ii) Alpha-glucosidase inhibitors  These drugs inhibit α-glucosidase so that glucose absorption is delayed, the blood glucose level after meals does not immediately peak.  e.g. acarbose (iii) Biguanides  These drugs lower postprandial blood glucose levels by decreasing liver glucose production and intestinal glucose absorption.  e.g. metformin (iv) Thiazolidinediones  These drugs are also called insulin sensitizers  They do not stimulate insulin secretion  They enhance peripheral cell response to insulin, allowing glucose to be utilized more efficiently  They decrease insulin resistance and increase insulin sensitivity of fat, skeletal muscle, and liver cells,  e.g. rosiglitazone, pioglitazone (v) Dipeptidyl peptidase-4 (DDP4) inhibitors  The gut hormone incretin, GLP-1 causes the release of insulin from the beta cells. 10 3 June 2024  FFG2414 Pharmacology II  But it is rapidly metabolized by dipeptidyl peptidase-4 (DDP-4).  These drugs inhibit DPP-4 in the intestine so GLP-1 has more time to stimulate insulin secretion and decrease glucogon secreation.  e.g. sitagliptin, saxagliptin. Hyperglycemic drugs  Patient with diabetes mellitus continue to produce glucagon.  Glucagon is available in a formulation for subcutaneous injection that is used to counteract hypoglycemic reactions in patients with DM. References  Rang H.P., Dale MM, Ritter JM, Moore PK, (2003).Pharmacology (5th ed.). Churchill Livingstone  Tripathi KD, Essentials of Medical Pharmacology, 2004 ( 5th ed. ) Jaypee.  Kaye M., Favaro, A. (2005). Introduction to Pharmacology (10th ed.).  WB Saunders. Holland LN, Adams MP. Core concepts in Pharmacology. 2003, Prentice Hall. 11 3 June 2024  FFG2414 Pharmacology II Tutorial A. Multiple Choice Questions 1 Insulin is produced in the __________. A pancreas B hypothalamus C anterior pituitary gland D adrenal gland 2 Type __________ diabetes is also known as Insulin Dependent Diabetes Mellitus (IDDM) A I B II C α D β 3 __________ is a common risk factor for diabetes. A High dietary salt B Vegetarianism C Obesity D Underweight 4 __________ inhibit the conversion of complex carbohydrates to monosacharrides in the intestine. A Alpha-glucosidase inhibitors B Insulin secretogogues C Glucocorticoids D Mineralocorticoids 5 __________ is used to treat severe hypoglycemia. A Insulin B Insulin secretogogue C Glucagon D Glycogen 6 Insulin is produced by _________ cells in the islets of Langerhans. A alpha B beta C delta 12 3 June 2024  FFG2414 Pharmacology II D omega 7 Insulin is usually used in __________. A Type I diabetes B Type II diabetes C gestational diabetes D diabetes insipidus 8 Non-insulin Dependent Diabetes Mellitus is due to __________. A deficiency of pancreatic cell’s response to glucose B influence of hormones during pregnancy C autoimmune response D allergic reactions 9 Islets of Langerhans contains __________. I alpha cells II beta cells III delta cells IV gamma cells A I, II, III B I, II, IV C I, III, IV D II, III, IV 10 __________ diabetes is believed to be an autoimmune disease. A Type I B Type II C Type IV D Gestational 11 Insulin receptors are located on the plasma membrane of __________. A nerves B skeletal muscles C red blood cells D kidneys 12 Select the oral anti-diabetic agent. 13 3 June 2024  FFG2414 Pharmacology II A Aspirin B Insulin C Metformin D Captopril 13 __________ increase tissue sensitivity to insulin. A Thiazolidinediones B Biguanides C Glucocorticoids D Mineralocorticoids 14 Sulfonylureas such as glibenclamide and glypizide __________. A inhibit the conversion of complex carbohydrates to monosaccharides B stimulate insulin release C prevents the gastrointestinal intake of cholesterol and phytosterols D prevents absorption of dietary cholesterol 15 __________ cells of the pancreas produce glucagon. A Alpha (A) B Beta (B) C Delta (D) D F 16 Insulin receptors are predominantly found in the following, EXCEPT __________. A bones B adipose tissues C liver D skeletal muscles 17 __________ stimulate insulin release. A Glycogen B Insulin secretogogues C Biguanides D Alpha-glucosidase inhibitors 18 What is the side-effect of insulin? A diabetic ulcer B neuropathy 14 3 June 2024  FFG2414 Pharmacology II C hyperglycemia D lipodystrophy 19 Non-insulin Dependent Diabetes Mellitus usually occurs in __________. A adults B infants C children D pregnancies 20 The following do not require insulin for glucose transport, EXCEPT __________. A the nerves B the red blood cells C the kidneys D the skeletal muscles 21 __________ inhibit conversion of complex carbohydrates to monosaccharides in the intestine. A Insulin secretogogues B Biguanides C Thiazolidinediones D Alpha-glucosidase inhibitors 22 Select the INCORRECT description about diabetes mellitus. A It can be insulin dependent or insulin independent B Pancreatic beta cells do not response to glucose well C It is due to over-production of insulin in the body D It can be treated by insulin and oral anti-diabetic agents 23 Based on the two statements below, select the CORRECT choice of answers: 1) Type 1 diabetes is non-insulin dependent. 2) Type 1 diabetes occurs in juveniles. A Statement 1) is TRUE, and statement 2) is FALSE B Statement 1) is FALSE, and statement 2) is TRUE C Both statements 1) and 2) are TRUE D Both statements 1) and 2) are FALSE 24 Which of the following antidiabetic drugs is an inhibitor of alpha glucosidase? 15 3 June 2024  FFG2414 Pharmacology II A Glibenclamide B Metformin C Acarbose D Sitagliptin 25 Based on the two statements below, select the correct choice of answers: 1) Insulin activates tyrosine kinase receptors in the skeletal muscles. 2) The nerves and kidneys do NOT require insulin for glucose transport. A Statement 1) is TRUE, and statement 2) is FALSE B Statement 1) is FALSE, and statement 2) is TRUE C Both statements 1) and 2) are TRUE D Both statements 1) and 2) are FALSE 26 Which of the following antidiabetic drugs increases tissue sensitivity to insulin? A Tolbutamide B Rosiglitazone C Acarbose D Sitagliptin 27 Which of the following antidiabetic drugs is an inhibitor of alpha glucosidase? A Glibenclamide B Metformin C Acarbose D Sitagliptin 28 __________ is used in Type I Diabetes Mellitus. A Insulin B Metformin C Acarbose D Rosiglitazone 29 Glucagon __________. A is used in hyperglycemia B increases the release of insulin from the pancreas C reduces the production of glucose in the liver D increase blood glucose levels in the blood 30 Select the WRONG description for diabetes mellitus. 16 3 June 2024  FFG2414 Pharmacology II A Obesity is a common risk factor for Type II diabetes B Type I diabetes has an onset of 30 years of age C Beta cells are destroyed in Type II diabetes D Abnormality in glucose levels may happen during pregnancy B. Short Essay Questions 1 List 4 types of cells in islets of Langerhans. 2 ____ secretes insulin. 3 Illustrate regulation of glucose in the body with a diagram. 4 Where are the insulin receptors located? 5 List 2 main types of diabetes mellitus. Which one is insulin dependent? Which one is not? 6 Which type of diabetes is an autoimmune disease? 7 What are the main causes of Type II Diabetes? 8 Give FOUR (4) types of insulin. 9 Give FIVE (5) types of oral anti-diabetic drugs and their examples. 10 Define hypoglycemia and name its treatment. 11 Diagram below shows the pancreas. Answer the following questions by referring to Diagram a) Name the hormone released by the islets of Langerhans after having a meal. b) What will happen when hormone in (a) is released? c) Define diabetes mellitus. d) There are two main types of diabetes mellitus. Why is Type I diabetes also called Insulin-Dependent Diabetes Mellitus (IDDM)? 17 3 June 2024  FFG2414 Pharmacology II e) Why is Type II Diabetes Mellitus called Non-Insulin Dependent Diabetes Melllitus (NIDDM)? f) Name THREE (3) oral anti-diabetic medications used in the treatment of Type II diabetes mellitus. g) Name the hormone released by the islets of Langerhans when blood glucose level is low or hypoglycemia. h) What does hormone in (g) do to increase the blood glucose level? 18 3 June 2024