Drugs used for Diabetes Mellitus BY Dr. Haitham Alwali Pharm B.Sc., Ph. D. (Pharmacology)

1. Drugs used for Diabetes Mellitus BY Dr. Haitham AlwaliPharm B.Sc., Ph. D. (Pharmacology)

2. Pancreatic Islet Cells and Their Secretory Products. • A cell (alpha) -Secret glucagon, which appose many action of insulin by ↑ blood glucose through activation of hepatic glycogenolysis and gluconeogenesis • B cell (beta) 1-amylin which modulates appetite, gastric emptying, and glucagon and insulin secretion 2- insulin, the storage and anabolic hormone of the body • D cell (delta) - Somatostatin a universal inhibitor of secretory cells • F cell (PP cell) -Pancreatic polypeptide (PP) a small protein that facilitates digestive processes

3. Diabetes mellitus Is a chronic metabolic disorder characterised by a high blood glucose concentration- (fasting plasma glucose > 7.0 mmol/l, or plasma glucose > 11.1 mmol/l 2 hours after a meal)-caused by insulin deficiency, often combined with insulin resistance.

4. Types of diabetes mellitus: • Type 1: Insulin-dependent diabetes mellitus (IDDM) • Destruction of pancreatic beta cells • Is the result of an autoimmune process • Type 2: Non-insulin dependent diabetes mellitus (NIDDM) • Results from a combination of insulin resistance and altered insulin secretion • Gestational diabetes • Glucose intolerance during pregnancy

5. Hyperglycemia occurs because of uncontrolled hepatic glucose output and reduced uptake of glucose by skeletal muscle with reduced glycogen synthesis. • When the renal threshold for glucose reabsorption is exceeded, glucose spills over into the urine -glycosuria and causes an osmotic diuresis - polyuria, which in turn, results in dehydration, thirst and increased drinking – polydipsia.

6. ▲INSULIN►Chemistry • Insulin is a small protein. It contains 51 amino acids arranged in two chains (A and B) linked by disulfide bridges. • Proinsulin, a long single-chain protein molecule is hydrolyzed into insulin and a residual connecting segment called C-peptide by removal of four amino acids • Although proinsulin may have some mild hypoglycemic action, C-peptide has no known physiologic function.

7. Insulin synthesis

8. ►Insulin Secretion • Insulin is released from pancreatic B cells in response to a variety of stimuli, especially glucose. • Hyperglycemia results in increased intracellular ATP levels, which close the ATP-dependent potassium channels. • Decreased outward potassium efflux results in depolarization of the B cell and opening of voltage-gated calcium channels. • The resulting increased intracellular calcium triggers secretion of the hormone.

10. Pharmacokinetics • Insulin is destroyed inthe GIT, and must be given parenterally (s.c., i.v., i.m.). Pulmonary absorption occurs and inhalation of an aerosol is a new route of administration. • Once absorbed, insulin has an elimination half-life of approximately 10 min, it is inactivated enzymatically in the liver and kidney

11. Mechanism of action • Insulin acts via receptors that are transmembrane glycoproteins. • Each receptors has two insulin binding sites. Receptor occupancy results in: • 1. Activation of insulin-dependent glucose transport processes in adipose tissue and muscle. • 2. Inhibition of adenylyl cyclase-dependent processes (lipolysis,proteolysis, glycogenolysis).

12. 4. Intracellular accumulation of potassium and phosphate (which are linked to glucose transport in some tissue). • 5. Increased cellular amino acid uptake, DNA and RNA synthesis. • 6. Increased oxidative phosphorylation.

13. Effects of insulin Insulin on its targets • Insulin promotes the storage of fat as well as glucose (both sources of energy) within specialised target cells and influences cell growth and metabolic functions of a wide variety of tissues.

14. 1-Effects on Liver: • Insulin increase the storage of glucose as glycogen in the liver, and this involve the fallowing: 1-insertion of additional GLUT2 glucose transport molecules in cell plasma membrane. 2-increase synthesis of the enzyme pyruvate kinase, phosphofructokinase, and glucokinase. 3-suppression of several other enzymes. -Insulin also decreases the catabolism of protein. • ↓Gluconeogenesis, ↓Glycogenolysis, ↑Glycolysis, ↑Glycogenesis, ↑Lipogenesis, ↓Lipolysis↓Protein breakdown

15. ↓Gluconeogenesis:decrease formation of glucose • ↓Glycogenolysis:decrease degredation of glycogen to glucose • ↑Glycolysis:increase convesion of glucose to ATP • ↑Glycogenesis:increase formation of glycogen from glucose • ↑Lipogenesis:increase lipid formation • ↓Lipolysis:decrease oxidation of FFA(FFA is one of precursors of glucose • ↓Protein breakdown:decrease AA release(AA is one of precursors of glucose)

16. 2-Effects on skeletal muscle: • -Insulin stimulate glycogen and protein synthesis. • -Glucose transport into muscle cells is facilitated by insertion of GLUT4 transporter into cell plasma membranes. • ↑Glucose uptake, ↑Glycolysis, ↑Glycogenesis, ↑Amino acid uptake,↑Protein synthesis

17. 3-Effects on adipose tissues: • -Insulin facilitate TG storage by activating plasma lipoprotein lipase, increasing glucose transport into cells via GLUT4 transporters, and reducing intracellular lipolysis. • ↑Glucose uptake, ↑Glycerol synthesis, ↑Synthesis of triglycerides, ↑Fatty acid synthesis, ↓Lipolysis

18. ►Sources of Insulin: -Human insulin has largely replaced that isolated from beef or pork pancreas for therapeutic uses. -Human insulin is produced by recombinant DNA technology using special strain of E.coli or yeast. ►Insulin preparations: • 1-Rapid-acting • 2-Short-acting • 3-Intermediate-acting • 4-Long-acting

19. 1-Rapid-acting: -It involve 3 injected insulin analogs (insulin lispro, insulin aspart, and insulin glulisine) and the inhaled form of insulin. -They have rapid onset of action and early peak of activity that permit control of postprandial glucose levels. -The rapid acting insulins are injected immediately before a meal and they are preferred insulins for continuous s.c infusion devices. -They also can be used for emergency treatment of uncomplicated diabetic ketoacidosis

20. 2-Short – acting: • Regular insulin is used I.V in emergency or used s.c in ordinary maintenance regimens, alone or mixed with intermediate or long acting prerperations. • Given 1 hr before meal.

21. 3-Intermediate – acting: • -Neutral protamine Hagedorn insulin (NPH insulin) is a combination of regular insulin and protamine (a highly basic protein also used to reverse the action of unfractionated heparin) -It exhibit delayed onset and peak of action. -NPH insulin is often combined with regular and rapid-acting insulins. -Lente insulin:This is an amorphous ppt of insulin with zinc combined with 70% of ultralente insulin, it is not suitable for I.V administration

22. 4-Long – acting: • Insulin glargine and insulin determir are modified form of human insulin that provide a peakless basal insulin level lasting more than 2o hr, which helps control basal glucose levels without producing hypoglycemia. • Ultralente insulin : a suspension of zinc crystals in acetate buffer, this produce large particles that are slow to dissolve resulting in a slow onset of action and long lasting hypoglycemic effects.

23. Rapid (Lispro,Glulisine, Aspart) Short (Regular) Intermediate (NPH) Long (Detemir,Glargine) Insulin Time Action Curves 140 120 100 80 Insulin Effect 60 40 20 0 0 2 4 6 8 10 12 14 16 18 20 Hours adapted from R. Bergenstal, IDC

24. 5-Insulin delivery systems: • The standard mode of insulin therapy is s.c injection with disposable needles and syringes. • Portable pen-sized injections are used to facilitate s.c injection. • Continuous s.c insulin infusion devices avoid the need for multiple daily injections and provide flexibility in the scheduling of patients daily activity. • Programmable pump deliver a constant 24-hr basal rate, made to accommodate change in insulin requirement. • An inhaled formulation of insulin can be used to cover mealtime insulin requirement.

25. Fig. Portable pen injectors permitted

26. Insulin Clinical uses of insulin: 1-Patients with DM1 require long-term maintenance treatment with insulin. 2-An intermediate-acting preparation is often combined with a short-acting preparations taken before meals 3-Soluble insulin is used (i.v.) in emergency treatment of hyperglycemic diabetic emergencies (ketoacidosis) 4-Many patients with DM2 ultimately require insulin treatement 5-Short-term treatment of patients with DM2 or impaired glucose tolerance during intercurrent events (operations, infections,myocardial infarction) 6-Emergency treatment of hyperkalemia: insulin is given withglucose to lower extracellular K+ via redistribution into cells

27. ►Adverse effects of insulin: 1-Hypoglycemia: is the most common complication resulting from excessive insulin effect. • Long term diabetics often do not produce adequate amounts of counter-regulatory hormones(glucagon,epinephrine, cortisol, and GH), which normally provide an effective defense against hypoglycemia. • Treatment of hypoglycemia include: administration of glucose (suger or candy by mouth, glucose by vein) or glucagon I.M .

29. 2-Insulin-induced Immunological complications: • The most common form is the formation of Abs to insulin or to non-insulin protein content which result in: • Resistance to the action of insulin • Allergic reactions. -The current use of highly purified human insulin decrease the chance of immunological reactions.

30. 3.Hypokalemia: may occur in the acidosis patients who use a lot of insulin and glucose, it can lead to the patient death with abnormal heart beat. 4-weight gain: • Due to increased caloric storage of glucose by insulin, and some is due to renal sodium retention resulting in fluid retention and edema. These effects can synergize with oral agents that are often coadministered with insulin, particularly thiazolidinediones.

31. -Pramlintide: • -Injectable synthetic analogue of amylin(hormone that produced by pancreatic B cells). • -It suppresses glucagon release, slow gastric emptying, and works in CNS to reduce appetite. • - After s.c injection, it is rapidly absorbed and has shorter duration of action. • -It is used in combinationwith insulin to control postprandial glucose level. • -The major side effects is hypoglycemiaand GIT disturbances.

32. 1. Drugs that sensitize the body to insulin and/or control hepatic glucose production 2. Drugs that stimulate the pancreas to make more insulin( Insulin secretagogues) 3. Drugs that slow the absorption of starches 4-Incretin Therapy Biguanides Thiazolidinediones Sulfonylureas Meglitinides Alpha-glucosidase inhibitors Exenatide Sitaglaptin Major classes of oral antidiabetic drugs

33. 1. Drugs that sensitize the body to insulin and/or control hepatic glucose production ▲Biguanides(metformin) ▲Thiazolidinediones(pioglitazone and rosiglitazone)

34. Biguanides(Metformin) • Metformin is now considered a first-line drug for the treatment of type II DM. ►Mechanism of Action (1) Direct stimulation of glycolysis in tissues, with increased glucose removal from blood. (2) Reduced hepatic and renal gluconeogenesis. (3) Slowing of glucose absorption from the GIT, with increasedglucose to lactate conversion by enterocytes. (4) Reduction of plasma glucagon levels.

35. Metabolism & Excretion: • Metformin has a half-life of 1.5–3 hours, is not bound toplasma proteins, is not metabolized, and is excreted by the kidneys as the active compound. • As a consequence of metformin's blockade of gluconeogenesis, the drug may impair the hepatic metabolism of lactic acid. In patients with renal insufficiency, biguanides accumulate and thereby increase the risk of lactic acidosis.

36. Clinical Use: • Because metformin is an insulin-sparing agent and does not increase weight or provoke hypoglycemia, it offers obvious advantages over insulin or sulfonylureas in treating hyperglycemia due to ineffective insulin action, ie, insulin resistance syndrome • Metformin therapy decreases the risk of macrovascular as well as microvascular disease (approved to ↓LDL &VLDL , ↑HDL)

37. Biguanides are also indicated for use in combination with insulin secretagogues or thiazolidinediones in type 2 diabetics in whom oral monotherapy is inadequate. • Metformin is useful in the prevention of type 2 diabetes; the metformin is efficacious in preventing the new onset of type 2 diabetes in middle-aged, obese individuals with impaired glucose tolerance and fasting hyperglycemia.

38. Unwanted effects of metformin  1-The commonest unwanted effects of metformin are dose-related gastrointestinal disturbances (e.g. anorexia, diarrhoea, nausea). 2-Lactic acidosis is a rare but potentially fatal toxic effect.(Dose –dependant) 3-Metformin is contraindicated in pregnancy. 4- Long-term use may interfere with absorption of vitamin B12

39. Thiazolidinediones (Tzds): -Mechanism of action: • Thiazolidinediones (Tzds) act to decrease insulin resistance by activating peroxisome proliferator-activated receptor-gamma (PPAR-γ ) . • Their primary action is the nuclear regulation of genes involved in glucose and lipid metabolism and adipocyte differentiation.

40. Mechanism of Action: These agents act through the activation of peroxisome proliferator-activated receptor-γ (PPAR-γ). Ligands for PPAR-γ regulate adipocyte production, secretion of fatty acids and glucose metabolism. Agents binding to PPAR-γ result in increased insulin sensitivity is adipocytes, hepatocytes and skeletal muscle. Hyperglycemia, hypertriglyceridemia and elevated HbA1c are all improved. HDL levels are also elevated. Accumulation of subcutaneous fat occurs with these agents.

41. *Effects of Thiazolidinediones: • In persons with diabetes, a major site of Tzd action is adipose tissue, where the drug promotes glucose uptake and utilization and modulates synthesis of lipid hormones or cytokines and other proteins involved in energy regulation. • Tzds also regulate adipocyte apoptosis and differentiation.

42. Two thiazolidinediones are currently available: pioglitazone and rosiglitazone • The triglyceride lowering effect of pioglitazone is more significant than that observed with rosiglitazone. • Drug interactions with rosiglitazone is much less than with pioglitazone • Tzds are considered "euglycemics" and are efficacious in about 70% of new users.

43. Because their mechanism of action involves gene regulation, the Tzds have a slow onset and offset of activity over weeks or even months. • Long-term therapy is associated with a drop in triglyceride levels and a slight rise in HDL and low-density lipoprotein (LDL) cholesterol values.

44. Adverse effects:  • An adverse effect common to both Tzds is fluid retention, which presents as a mild anemia and peripheral edema especially when used in combination with insulin or insulin secretagogues.  • Combination therapy with sulfonylureas and insulin can lead to hypoglycemia and may require dosage adjustment

45. Many users have a dose-related weight gain (average 1–3 kg), which may be fluid-related. • These agents should not be used during pregnancy, in the presence of significant liver disease, or if there is a concurrent diagnosis of heart failure.

46. Rosiglitazone=(Avandia):

47. Drugs that stimulate the pancreas to make more insulin( Insulin secretagogues) ▲ Sulfonylureas ►First-Generation Sulfonylureas (Tolbutamide , Chlorpropamide) ►Second-Generation Sulfonylureas (Glyburide,Glibenclamide,Glimepiride,Glipizide ▲ Meglitinides (repaglinide and nateglinide)

48. INSULIN SECRETAGOGUES: A-SULFONYLUREAS ►Mechanism of Action 1-The major action of sulfonylureas is to increase insulin release from the ß-cell of pancreas by blocking the ATP-sensetive channels resulting in depolarization and ca influx and the release of preformed insulin . 2-Reduction of serum glucagon levels 3-Increasing of insulin binding to target tissues.

49. ►First-Generation Sulfonylureas ▲Tolbutamide • Is well absorbed but rapidly metabolized in the liver. • Because of its short half-life, it is the safest sulfonylurea for elderly diabetics. ▲ Chlorpropamide • Has a half-life of 32 hours and is slowly metabolized in the liver to products that retain some biologic activity; • It is contraindicated in patients with hepatic or renal insufficiency.

50. ►Second-Generation Sulfonylureas • The second-generation sulfonylureas are more frequently prescribed than the first-generation agents because they have fewer adverse effects and drug interactions. ▲ Glyburide • Is metabolized in the liver into products with very low hypoglycemic activity. • Given as a single morning dose. • Glyburide has few adverse effects other than its potential for causing hypoglycemia