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 Pancreatic  cell Sulfonylurea receptor sulfonylurea K ATP Ca I I I I insulin K+

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. Chlorpropamide 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

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 AgentOnset (h)Peak (h)Duration (h) Acetohexamide2412-24 Chlorpropamide1524-72 Glimepride2.524 Glipizide0.51< 24 Glyburide0.5424 Tolazamide1518 Tolbutamide166-12

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. Metformin 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

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 K ATP 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 D 50 W –Children.5 to 1 g/kg D 25 W –Neonates.5 to 1 g/kg D 10 W

50. IV Glucose D 10 maintenance infusion Rate of infusion adjusted to keep the patient euglycemic Central venous line when D 20 is required As the patient begins to eat and glucose rises, taper the infusion Switch to D 5 W

51. Octreotide Semisynthetic long-acting analog of somatostatin IV half life of 72 minutes Inhibits the secretion of insulin, glucagon, growth hormone, gastrin and other hormones

52. Octreotide 50 - 100  g subcutaneously every 8 -12 hours Has been shown to reduce the glucose infusion requirements to maintain euglycemia following sulfonylurea overdose Most frequent side effect is mild steatorrhea

53. Diazoxide A vasodilator Effective for refractory hypoglycemia Directly inhibits insulin secretion by opening K ATP channels Increases hepatic glucose production Decreases cellular glucose utilization Slow IV infusion (300 mg IV over 30 minutes every 4 hours)

54. Glucagon Recruits hepatic glycogen stores and induces gluconeogenesis Partially dependent on the adequacy of glycogen stores Reserve for temporizing treatment in patients in whom IV access cannot be rapidly established

55. Dialysis Not effective for most oral hypoglycemic agents because of their high protein binding May be needed for severe lactic acidosis from biguanides –Corrects metabolic acidosis –Removes lactate, ketones, and metformin

56. Other Management Points Treat lactic acidosis early and intensively –Sodium bicarbonate for pH < 7.1 Urinary alkalinization effective only for chlorpropamide –A pH of 7-8 can reduce the half-life from 49 to 13 hours –Check Potassium frequently

57. Who Needs Admission? Hypoglycemia in the setting of an oral Sulfonylurea Pediatric exposures (potential) to a sulfonylurea Hypoglycemic Repaglinide exposures

58. Salient Points Don’t F%$# with hypoglycemia Chlorpropamide excretion may be increased by urinary alkanilization 1st generation oral Suffonylurease are sulfonamide based GI upset is expected with  -glucosidase Inhibitors Hepatic toxicity may occur with Thiazolidinediones