Oral Hypoglycemic Agents and You

1. Oral Hypoglycemic Agents and You John Kashani DO St. Josephs Medical Center New Jersey Poison Center

2. Objectives • Outline Insulin physiology, glucose regulation and hypoglycemia • Discuss type 2 diabetes and medications used in it’s treatment • Outline the management and disposition of patients exposed to these agents

3. Physiologic effects of insulin • Effects will vary depending on the tissue involved • Facilitates the entry of glucose into muscle, adipocytes and various other tissues • Stimulates the production of glycogen in the liver

4. Physiologic effects of insulin • Activates hexokinase • Inhibits glucose-6-phosphatase • Activates phosphofructokinase and glycogen synthase • Promotes the synthesis of fatty acids • Inhibits the breakdown of fat in adipose tissue

5. Physiologic effects of insulin • Inhibits intracellular lipase • Stimulates the uptake of amino acids • Increases the permeability of cells to potassium, magnesium and phosphate ions

6. Glucagon • Maintains blood glucose levels between meals and fasting periods • Initiates glycogenolysis • Increase the transport of amino acids in the liver – gluconeogenesis • Activates adipose cell lipase – makes fatty acids available for energy

7. Cathecholamines • Norepinephrine and epinephrine • Maintain blood glucose levels during periods of stress • Increase lipase activity – increases the mobilization of fatty acids • inhibits insulin release • Promotes glycogenolysis

8. Growth Hormone • Increases protein synthesis • Mobilizes fatty acids • Antagonizes the effects of insulin • Decreases the cellular uptake of glucose • Initial plasma glucose-lowering effect

9. Glucocorticoids • Critical to survival during periods of fasting and starvation • Stimulate gluconeogensis • Decrease tissue use of glucose • Initial plasma glucose-lowering effect similar to growth hormone

10. Glucose Regulation • Glucose maintained between 70-140 mg/dL by several mechanisms • Above this range, pancreatic beta cells secrete insulin • Below this range, the major acute defense is glucagon release

12. Type 2 Diabetes • Heterogeneous condition describing hyperglycemia and relative insulin deficiency • High, normal or low insulin levels • No HLA markers or antibodies • Usually middle aged and overweight • Symptoms tend to be more gradual than type 1

13. Oral Hypoglycemic Agents • An increasing number of medications available for the treatment of type 2 diabetes mellitus • Vary in mechanism of action, adverse effects and toxicity • There is little experience with toxicity and overdose with some of the newer agents

14. Common Scenarios • Accidental ingestion in a child • Took too much by accident • Intentional overdose • Diabetic vs. non-diabetic

15. Type 2 Agents • Hypoglycemic agents • Sulfonylureas • Benzoic acid derivatives • Antihyperglycemic agents • Biguanides • -glucosidase inhibitors • Thiazolidinedione derivatives

16. Sulfonylureas • Stimulate the beta cells of the pancreas to produce insulin • Bind to the sulfonylurea receptor on the pancreatic beta cell • Ineffective in type I diabetics who lack the capacity to produce insulin • Lower the blood glucose in type 2 diabetic patients • Lower the blood glucose in non-diabetic patients

17. Sulfonylurea Mechanism sulfonylurea Ca KATP Sulfonylurea receptor I K+ I I I Pancreatic  cell insulin

18. Sulfonylureas • Decrease hepatic insulin clearance • Increase serum insulin concentrations • Reduce hepatic glucose production • Increase peripheral insulin sensitivity

19. Sulfonylureas • Highly protein bound • Metabolized in the liver • Renal excretion • Large Vd (10-15 L/kg)

20. 1st Generation Sulfonylureas • Acetohexamide • Chlorpropamide • Tolazamide • Tolbutamide

21. 1st Generation • Reduce hepatic clearance of insulin • Produce active hepatic metabolites • Long half life and duration of action • Dependent on urinary excretion to maintain euglycemia

22. Half-life may be >24 hours with up to 60 hours duration of action Can cause hyponatremia (SIADH) Disulfuram reaction Cholestatic jaundice Agranulocytosis, thrombocytopenia, anemia Elimination enhanced by urinary alkalinization Chlorpropamide

23. 2nd Generation Sulfonylureas • Glimeperide • Glipizide • Glyburide • 100x more potent than first generation • Improved safety profile

24. 2nd Generation • Half lives approach 24 hours • Associated with substantial fecal excretion of the parent drug • More lipid soluble than first generation

25. Sulfonylureas

26. Sulfonylureas • Chlorpropamide, Glyburide, and Glipizide are the most likely to cause prolonged hypoglycemia • Duration of action prolonged in presence of renal and hepatic disease

27. Pediatric Ingestion • 5 year retrospective review (Clin Tox 34(3)1996) • 93 cases, 25 patients (27%) developed hypoglycemia • 79% onset within 4 hours • Remainder up to 16 hours

28. Biguanides • Active component of Galega officinalis, the French lilac • Lower the blood glucose in diabetic patients • Does not lower blood glucose in normal patients • Improves insulin sensitivity

29. Galega officinalis

30. Everything Spectatularis

31. Biguanides • Phenformin • Withdrawn from the US market in 1976 • 1/4000 patients develop lactic acidosis • Metformin (Glucophage) • Introduced in the US in 1995

32. Metformin • Inhibits gluconeogenesis and reduces hepatic glucose output • Reduces fasting plasma glucose • Increases glycogen formation • Causes increase in glucose uptake and utilization in peripheral tissues • Reduction of serum insulin concentrations • Inhibits lipolysis

33. Orally absorbed within six hours Peak serum levels 2-3 hours Minimally bound to plasma proteins Not metabolized by the liver Half life 4 - 8.7 hours Excreted by the kidney Metformin

34. Metformin • Lactic acidosis • 1/40000-80000 patients • Majority have renal insufficiency • Has been found in association with levels above 5 ug/ml • Generally assumed to be type B

35. Mechanism of Lactic Acidosis • Inhibit gluconeogenesis - accumulation of pyruvate • Fat catabolism - oxidation of fatty acids - depletes NAD+ - increases NADH • Increased ratio inhibits pyruvate dehydrogenase and the entry of pyruvate into the Kreb’s cycle

36. Mechanism of Lactic Acidosis • Fatty acid oxidation increases acetyl CoA/CoA ratio - further decreases entry of pyruvate into the Kreb’s cycle • With pyruvate dehydrogenase inhibited and gluconeogenesis blocked, the accumulated pyruvate is metabolized to lactate

37. -glucosidase Inhibitors • Acarbose • Miglitol • Do not cause hypoglycemia but may potentiate the action of the sulfonylureas

38. Acarbose • Results in competitive inhibition of the -glucosidase on the brush border of the small bowel • Reduces intestinal starch and disaccharide absorption • Delayed carbohydrate absorption and redistribution throughout the intestines yields a decreased, constant insulin production due to lowered postprandial glucose concentrations

39. Acarbose • Only 1-2% is absorbed by the gut • Does not cause hypoglycemia • Toxicity: • Abdominal discomfort • Mild GI effects • Flatulence, abdominal bloating • Hepatic toxicity has been reported

40. Thiazolidinediones • Troglitazone (Rezulin) • Withdrawn from the market in the US in 2000 due to cases of fatal liver toxicity • Rosiglitazone (Avandia) • Pioglitazone (Actos)

41. Thiazolidinediones • Increase insulin sensitivity • Decrease hepatic glucose output • Mechanism: • Bind to nuclear peroxisome proliferator-activated receptors involved in transcription of insulin-responsive genes and in regulation of adipocyte differentiation and lipid metabolism

42. Thiazolidinediones • Rapidly absorbed • Highly (>99%) protein bound • Metabolized by CYP3A4 • Loss of contraceptive effect reported with ethinyl estradiol/norethindrone • Half-life 16 - 34 hours • 2 reports of hepatotoxicity with rosiglitazone

43. Benzoic Acid Derivatives • Repaglinide • Limited experience with this agent • Binds to the KATP channel on the beta cell at a different receptor from the sulfonylureas • Extrapancreatic effect leading to increased insulin sensitivity postulated

44. Repaglinide • Rapidly absorbed • Metabolized by the 3A4 • Short half-life (1 hr) • Excreted primarily in the bile • Highly protein bound (>98%) • Hypoglycemia is expected in overdose, no cases reported to date

45. Repaglinide • Severe hypoglycemia from clarithromycin-repaglinide drug interaction • Khamaisi M, Leitersdorf E • Pharmacotherapy. 2008 May;28(5):682-4

46. Repaglinide • Serious hypoglycemia associated with misuse of repaglinide • Flood TM • Endocr Pract. 1999 May-Jun;5(3):137-8

47. Repaglinide • Hypoglycemia probably due to accidental intake of repaglinide • Lee IT, Sheu WH, Lin SY • Chang Gung Med J. 2002 Nov;25(11):783-6

48. Management • Patient asymptomatic with normal glucose, but agent known to produce hypoglycemia • Activated charcoal • Prophylactic glucose not recommended • Observe 8 hours, if hypoglycemia develops admit

49. Management • Patient already hypoglycemic: IV dextrose • Adult initially 1g/kg of D50W • Children .5 to 1 g/kg D25W • Neonates .5 to 1 g/kg D10W

50. IV Glucose • D10 maintenance infusion • Rate of infusion adjusted to keep the patient euglycemic • Central venous line when D20 is required • As the patient begins to eat and glucose rises, taper the infusion • Switch to D5W