1. School of Pharmacy, University of Nizwa
Anti-diabetic drugs
Course Coordinator
Jamaluddin Shaikh, Ph.D.
School of Pharmacy, University of Nizwa
Lecture 17
April 22, 2013

2. Diabetes Mellitus
Diabetes is a heterogeneous group of syndromes characterized by an elevation of blood glucose caused by a relative or absolute deficiency of insulin
Four clinical classifications of diabetes:
Type 1 diabetes (formerly insulin-dependent diabetes mellitus),
Type 2 diabetes (formerly noninsulin dependent diabetes mellitus)
Gestational diabetes
Diabetes due to other causes (e.g., genetic defects or medication induced)

3. Comparison

4. Type 1 Diabetes Mellitus
It is common in puberty or early adulthood
The disease is characterized by an absolute deficiency of insulin caused by massive β-cell necrosis
Loss of β-cell function is usually ascribed to autoimmune-mediated processes. As a result, the pancreas fails to respond to glucose, and the Type 1 diabetic shows classic symptoms of insulin deficiency
Type 1 diabetics require exogenous insulin
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body

5. Type 1 Diabetes: Cause
In the post absorptive period of a normal individual, basal levels of circulating insulin are maintained through constant β-cell secretion
A burst of insulin secretion occurs within 2 minutes after ingesting a meal, in response to transient increases in the levels of circulating glucose and amino acids. This lasts for up to 15 minutes, and, is followed by the postprandial secretion of insulin
However, having virtually no functional β cells, the Type 1 diabetic can neither maintain a basal secretion level of insulin nor respond to variations in circulating fuels
Postprandial literally means "after a meal

6. Type 1 Diabetes: Treatment
A Type 1 diabetic must rely on exogenous (injected) insulin to control hyperglycemia
The goal in administering insulin to Type 1 diabetics is to maintain blood glucose concentrations as close to normal as possible and to avoid wide swings in glucose levels that may contribute to long-term complications
Use of home blood glucose monitors facilitates frequent self-monitoring and treatment with insulin injections
Continuous subcutaneous insulin infusion also called the insulin pump is another method of insulin delivery

7. Type 2 Diabetes Most diabetics are Type 2
Influenced by genetic factors, aging, obesity, and peripheral insulin resistance rather than by autoimmune processes or viruses

8. Type 2 Diabetes: Cause
In Type 2 diabetes, the pancreas retains some β-cell function, but variable insulin secretion is insufficient to maintain glucose homeostasis
The β-cell mass may become gradually reduced in Type 2 diabetes
In contrast to patients with Type 1, those with Type 2 diabetes are often obese

9. Type 2 Diabetes: Treatment
The goal in treating Type 2 diabetes is to maintain blood glucose concentrations within normal limits and to prevent the development of long-term complications
Weight reduction, exercise, and dietary modification decrease insulin resistance and correct the hyperglycemia of Type 2 diabetes in some patients
However, most patients are dependent on pharmacologic intervention with oral hypoglycemic agents
As the disease progresses, β-cell function declines, and insulin therapy is often required to achieve satisfactory serum glucose levels

10. Insulin
Insulin is a polypeptide hormone consisting of two peptide chains that are connected by disulfide bonds
It is synthesized as a precursor (pro-insulin) that undergoes proteolytic cleavage to form insulin and C peptide, both of which are secreted by the β cells of the pancreas

11. Insulin Secretion
Insulin secretion is most commonly triggered by high blood glucose, which is taken up by the glucose transporter into the β cells of the pancreas
Products of glucose metabolism enter the mitochondrial respiratory chain and generate ATP
The rise in ATP levels causes a block of K+ channels, leading to membrane depolarization and an influx of Ca2+, which results in insulin exocytosis

12. Model of glucose-induced
insulin secretion
Ca2+ K
Insulin
ATP
Glucose

13. Model of glucose-induced
insulin secretion
Ca2+ K
Insulin
ATP
Glucose

14. Model of glucose-induced
insulin secretion
Ca2+ K
Insulin
ATP
Glucose

15. Model of glucose-induced
insulin secretion
Ca2+ K
Insulin
ATP
Glucose

16. Source of Insulin
Human insulin is produced by recombinant DNA technology using special strains of E. coli or yeast that have been genetically altered to contain the gene for human insulin
Modifications of amino acid sequence of human insulin have produced insulins with different pharmacokinetic properties
Insulins lispro, aspart, and glulisine have a faster onset and shorter duration of action than regular insulin. On the other hand, glargine and detemir are long-acting insulins and show prolonged, flat levels of the hormone following injection

17. Insulin Administration
As insulin is a polypeptide, it is degraded in GI tract if taken orally. Generally administered by s.c. injection
Continuous s.c. insulin infusion has become popular, because it does not require multiple daily injections
Insulin preparations vary primarily in their times of onset of activity and in their durations of activity. This is due to differences in the amino acid sequences of the polypeptides
Dose, site of injection, blood supply, temperature, and physical activity can affect the duration of action of the various preparations
Inactivated by insulin-degrading enzyme (also called insulin protease), which is found mainly in the liver and kidney

18. Insulin Preparations and Treatment
It is important that any change in insulin treatment be made cautiously by the clinician, with strict attention paid to the dose
Types of insulin:
Rapid-acting and short-acting insulin preparation
Intermediate-acting insulin preparation
Long-acting insulin preparation

19. Rapid-acting and Short-acting Insulin Preparations
Four insulin preparations fall into this category: regular insulin, insulin lispro, insulin aspart, and insulin glulisine
Regular insulin is a short-acting
Regular insulin is usually given s.c., and it rapidly lowers blood glucose

20. Rapid-acting and Short-acting Insulin Preparations
Peak levels of insulin lispro are seen at 30 to 90 min after injection, as compared with 50 to 120 min for regular insulin
Insulin aspart and insulin glulisine have pharmacokinetic and pharmacodynamic properties similar to those of insulin lispro. Like regular insulin, they are administered subcutaneously
Insulin lispro is usually administered 15 minutes prior to a meal or immediately following a meal, whereas glulisine can be taken either 15 minutes before a meal or within 20 minutes after starting a meal. Insulin aspart must be administered just prior to the meal

21. Intermediate-acting Insulin Preparations
Neutral protamine Hagedorn (NPH) insulin is a suspension of crystalline zinc insulin combined at neutral pH with a positively charged polypeptide, protamine
Duration of action is intermediate. This is due to delayed absorption of the insulin because of its conjugation with protamine, forming a less-soluble complex
NPH insulin should only be given subcutaneously and is useful in treating all forms of diabetes except diabetic ketoacidosis or emergency hyperglycemia
Used for basal control and is usually given along with rapid- or short-acting insulin for mealtime control
Diabetic ketoacidosis is a problem that occurs in people with diabetes. It occurs when the body cannot use sugar (glucose) as a fuel source because there is no insulin or not enough insulin

22. Long-acting Insulin Preparations
Types of long-acting insulin:
Insulin glargine:
It is slower in onset than NPH insulin and has a flat, prolonged hypoglycemic effect
Like the other insulins, it must be given subcutaneously
Insulin detemir:
Insulin detemir has a fatty-acid side chain. The addition of the fatty-acid side chain enhances association to albumin. Slow dissociation from albumin results in long-acting properties similar to those of insulin glargine

23. Adverse reaction to Insulin
The symptoms of hypoglycemia are the most serious and common adverse reactions to an overdose of insulin
Long-term diabetics often do not produce adequate amounts of the counter-regulatory hormones (glucagon, epinephrine, cortisol, and growth hormone), which normally provide an effective defense against hypoglycemia
Other adverse reactions include weight gain, allergic reactions, lipodystrophy, and local injection site reactions
Lipodystrophy is a medical condition characterized by abnormal or degenerative conditions of the body's adipose tissue. ("Lipo" is Greek for "fat" and "dystrophy" is Greek for "abnormal or degenerative condition".)

24. Oral Agents Four different types of oral agents are used :
Insulin secretagogues
Insulin sensitizers
α-Glucosidase inhibitors
Dipeptidyl peptidase-IV inhibitors

25. Insulin Secretagogues
These agents are useful in the treatment of patients who have Type 2 diabetes but who cannot be managed by diet alone.
The patient most likely to respond well to oral hypoglycemic agents is one who develops diabetes after age 40 and has had diabetes less than 5 years
Patients with long-standing disease may require a combination of hypoglycemic drugs with or without insulin to control their hyperglycemia

26. Types of Insulin Secretagogues
Two types of secretagogues are used:
Sulfonylureas
Meglitinide analogs

27. Sulfonylureas
These agents are classified as insulin secretagogues, because they promote insulin release from the β cells of the pancreas
The primary drugs used today are tolbutamide and the second-generation derivatives, glyburide, glipizide, and glimepiride
A secretagogue is a substance that causes another substance to be secreted

28. Sulfonylureas: Mechanisms of Action
Three different mechanisms of action available:
1) stimulation of insulin release from the β cells of the pancreas by blocking the ATP-sensitive K+ channels
2) reduction in hepatic glucose production
3) increase in peripheral insulin sensitivity

29. Sulfonylureas: PharmacokineticsX
Sulfonylureas: Pharmacokinetics
Oral administration
Metabolized by the liver
Excreted by the liver or kidney
Tolbutamide has the shortest duration of action (6 to12 hours), whereas the second-generation agents (glyburide, glipizide, and glimepiride) last about 24 hours

30. Sulfonylureas: Adverse Effects
Weight gain, hyperinsulinemia, and hypoglycemia
Should be used with caution in patients with hepatic or renal insufficiency, because delayed excretion of the drug resulting in its accumulation may cause hypoglycemia

31. Meglitinide Analogs: Mechanism of Action
Like the sulfonylureas, their action is dependent on functioning pancreatic β cells. They bind to a distinct site on the sulfonylurea receptor of ATP-sensitive potassium channels, thereby initiating a series of reactions culminating in the release of insulin
Effective in the early release of insulin that occurs after a meal and, thus, are categorized as postprandial glucose regulators. Combined therapy with metformin or the glitazones has been shown to be better than monotherapy with either agent in improving glycemic control
Meglitinides should not be used in combination with sulfonylureas due to overlapping mechanisms of action

32. Meglitinide Analogs: PharmacokineticsX
Meglitinide Analogs: Pharmacokinetics
Well absorbed orally after being taken 1 to 30 minutes before meals
Both meglitinides are metabolized to inactive products by CYP3A4 in the liver
Excreted through the bile

33. Meglitinide Analogs: Adverse EffectsX
Meglitinide Analogs: Adverse Effects
Although these drugs can cause hypoglycemia, the incidence of this adverse effect appears to be lower than that with the sulfonylureas
Repaglinide has been reported to cause severe hypoglycemia in patients who are also taking the lipid-lowering drug gemfibrozil
These agents must be used with caution in patients with hepatic impairment

34. Oral Agents Four different types of oral agents are used :
Insulin secretagogues
Insulin sensitizers
α-Glucosidase inhibitors
Dipeptidyl peptidase-IV inhibitors

35. Insulin Sensitizers
These agents lower blood sugar by improving target-cell response to insulin without increasing pancreatic insulin secretion

36. Types of Insulin Sensitizers
Two classes of oral agents available:
Biguanides
Thiazolidinediones

37. Biguanides
Metformin, the only currently available biguanide, is classed as an insulin sensitizer; that is, it increases glucose uptake and utilization by target tissues, thereby decreasing insulin resistance

38. Biguanides: Mechanism of Action
Mechanism of action of metformin is reduction of hepatic glucose output, largely by inhibiting hepatic gluconeogenesis
Metformin also slows intestinal absorption of sugars and improves peripheral glucose uptake and utilization
A very important property of this drug is its ability to modestly reduce hyperlipidemia
Metformin may be used alone or in combination with one of the other agents, as well as with insulin
Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids

39. Biguanides: PharmacokineticsX
Biguanides: Pharmacokinetics
Metformin is well absorbed orally
Not bound to serum proteins
Not metabolized
Excretion is via the urine

40. Biguanides: Adverse Effects
Metformin is contraindicated in diabetics with renal and/or hepatic disease, acute myocardial infarction, severe infection, or diabetic ketoacidosis
It should be used with caution in patients greater than 80 years of age or in those with a history of congestive heart failure or alcohol abuse
Long-term use may interfere with vitamin B12 absorption
acute myocardial infarction results from the interruption of blood supply to a part of the heart, causing heart cells to die
Diabetic ketoacidosis is a problem that occurs in people with diabetes. It occurs when the body cannot use sugar (glucose) as a fuel source because there is no insulin or not enough insulin. Fat is used for fuel instead.

41. Thiazolidinediones
Another group of agents that are insulin sensitizers are the thiazolidinediones (TZDs) or, more familiarly the glitazones
Although insulin is required for their action, these drugs do not promote its release from the pancreatic β cells; thus, hyperinsulinemia does not result
Troglitazone was the first of these to be approved for the treatment of Type 2 diabetic, but was withdrawn after a number of deaths due to hepatotoxicity were reported
Presently, two members of this class are available, pioglitazone and rosiglitazone

42. Thiazolidinediones: Mechanism of ActionX
Thiazolidinediones: Mechanism of Action
They are known to target the a nuclear hormone receptor, peroxisome proliferator activated receptor-γ (PPARγ)
Ligands for PPARγ regulate adipocyte production and secretion of fatty acids as well as glucose metabolism, resulting in increased insulin sensitivity in adipose tissue, liver, and skeletal muscle
Pioglitazone and rosiglitazone can be used as monotherapy or in combination with other hypoglycemics or with insulin
The glitazones are recommended as a second-line alternative for patients who fail or have contraindications to metformin therapy

43. Thiazolidinediones: PharmacokineticsX
Thiazolidinediones: Pharmacokinetics
Absorbed very well after oral administration
Bound to serum albumin
Metabolised by different cytochrome P450 isozymes
Pioglitazone and its metabolites excreted in the bile and eliminated in the feces
The metabolites of rosiglitazone are primarily excreted in the urine

44. Thiazolidinediones: Adverse Effects
Very few cases of liver toxicity have been reported
Weight increase can occur, possibly through the ability of TZDs to increase subcutaneous fat or due to fluid retention
Glitazones have been associated with osteopenia and increased fracture risk
Other adverse effects include headache and anemia
Osteopenia is a condition where bone mineral density is lower than normal

45. α-Glucosidase Inhibitors
Acarbose and miglitol are orally active drugs used for the treatment of patients with Type 2 diabetes

46. α-Glucosidase Inhibitors: Mechanism of Action
They act by delaying the digestion of carbohydrates, thereby resulting in lower postprandial glucose levels
Both drugs exert their effects by reversibly inhibiting membrane-bound α-glucosidase in the intestinal brush border. This enzyme is responsible for the hydrolysis of oligosaccharides to glucose and other sugars
Unlike the other oral hypoglycemic agents, these drugs do not stimulate insulin release, nor do they increase insulin action in target tissues
When used in combination with the sulfonylureas or with insulin, hypoglycemia may develop

47. α-Glucosidase Inhibitors: PharmacokineticsX
α-Glucosidase Inhibitors: Pharmacokinetics
Acarbose is poorly absorbed. It is metabolized primarily by intestinal bacteria, and some of the metabolites are absorbed and excreted into the urine
Miglitol is very well absorbed but has no systemic effects. It is excreted unchanged by the kidney

48. α-Glucosidase Inhibitors: Adverse EffectsX
α-Glucosidase Inhibitors: Adverse Effects
Major side effects are diarrhea, and abdominal cramping
Patients with inflammatory bowel disease, colonic ulceration, or intestinal obstruction should not use these drugs

49. Dipeptidyl Peptidase-IV Inhibitors
Sitagliptin is an orally active dipeptidyl peptidase-IV (DPP-IV) inhibitor used for the treatment of patients with Type 2 diabetes

50. Dipeptidyl Peptidase-IV Inhibitors: Mechanism of ActionX
Dipeptidyl Peptidase-IV Inhibitors: Mechanism of Action
Sitagliptin inhibits the enzyme DPP-IV, which is responsible for the inactivation of incretin hormones, such as glucagon-like peptide-1 (GLP-1)
Prolonging the activity of incretin hormones results in increased insulin release in response to meals and a reduction in inappropriate secretion of glucagon

51. Dipeptidyl Peptidase-IV Inhibitors: PharmacokineticsX
Dipeptidyl Peptidase-IV Inhibitors: Pharmacokinetics
Sitagliptin is well absorbed after oral administration. Food does not affect the extent of absorption
The majority of sitagliptin is excreted unchanged in the urine

52. Dipeptidyl Peptidase-IV Inhibitors: Adverse EffectsX
Dipeptidyl Peptidase-IV Inhibitors: Adverse Effects
Common adverse effects being nasopharyngitis and headache

53. Summary (Oral Drugs)