Treatment of diabetes mellitus with description of drugs

1. Pharmacotherapy of Diabetes Mellitus Dr Naser Ashraf Tadvi Associate Professor Kamineni Institute of Medical Sciences Narketpally, Nalgonda

2. Diabetes Diabetes is a group of metabolic disorders characterized by chronic hyperglycemiaassociated with disturbances of carbohydrate, fat and protein metabolism due to absolute or relative deficiency in insulin secretion and/or action Diabetes causes long term damage, dysfunction & failure of various organs

3. Diagnosis of diabetes Fasting Plasma Glucose ≥ 126 mg / dl Symptoms of DM and a random blood glucose level of ≥ 200 mg/dl Oral glucose tolerance test 2 hr after 75 gm glucose load ≥ 200 mg / dl

4. Classification of DiabetesProposed by ADA - 1997. Type I: Absolute Insulin Deficiency due to islet cell destruction Either immune mediated or idiopathic Type II: Relative insulin deficiency due to impaired -cell function Marked ↑ peripheral insulin resistance Type III: Other Specific types Type IV:Gestational Diabetes

5. Other specific types A) Genetic defects of Beta cell function B) Genetic defects in Insulin action C) Diseases of the Exocrine Pancreas D) Secondary to Endocrinopathies E) Drugs / Chemical induced F) Infections G) Uncommon form of Immune Mediated Diabetes. H) Other Genetic Syndromes associated with Diabetes MODY Syndromes Lipo atrophic Diabetes FCPD Pancreatitis Trauma Neoplasia Cystic Fibrosis Hemochromatosis Acromegaly Cushings Syndrome Pheochromocytoma Hyperthyroidism Steroids Thiazides Diazoxide Beta Blockers Thyroid Hormones Congenital Rubella CMV Anti insulin Receptor Antibodies Down’s Syndrome Turners Klinefelters

7. Type 2 Diabetes

8. β cells : insulin 65-70 % cells : glucagon 25 % δcells : somatostatin10 % PP (or F cells): pancreatic polypeptide 2 %

10. Total number of Islets…. 1 lakh

11. Number of cell / Islet 1-2 thousand

12. Beta cells / Islet 65-70 %

13. Total Insulin storage 200 units

14. Daily insulin release 40 -50 units

16. Discovery of insulin

17. The Miracle of Insulin Patient leonardthomson.,, February 15, 1923 December 15 1922

18. Biosynthesis of insulin Preproinsulin Proinsulin Insulin

19. Structure of insulin 21 amino acids 30 AA

20. Difference between human, pork, beef insulin

21.  Cell at rest

22. Secretion of insulin > 70 mg/ml GLUT 2

23. Bioassay of insulin 1 IU reduces the BSL to 45 mg/dl in fasting rabbits 1 mg insulin = 28 IU Can also be measured by radioimmunoassay or enzyme immunoassay

25. Plasma glucose or Amino Acids , ketones

26. Hormonal regulation

27. Gastrointestinal hormones (GIP, CCK) directly stimulate β cells

28. Neural regulation

29. Parasympathetic stimulates insulin release through IP3/ DAG

32. ↑ differentiation of cells

34. Synthesis of enzymes for AA metabolism E.g Metabolic actions

35. Actions of insulin Metabolic: carbohydrate, lipid , protein, electrolyte Vascular Anti-inflammatory Fibrinolytic Growth Steroidogenesis

36. Carbohydrate metabolism Over all action of insulin is to ↓ glucose level in blood ↑ Transport of glucose inside the cell ↑ Peripheral utilization of glucose ↑ Glycogen synthesis ↓ Glycogenolysis ↓ Neoglucogenesis

37. Lipid metabolism ↓ Lipolysis ↑ Lipogenesis ↑ Glycerogenesis ↓ Ketogenesis ↑ Clearance of VLDL & chylomicrons from blood through enzyme Vascular Endothelial Lipoprotein Lipase

41. GLUT 2 – Beta cell – Glucose sensors

42. GLUT 4 – Insulin mediated glucose uptake in muscle & Adipose tissue

43. Mechanism of action of insulin

44. Insulin molecule INS Insulin Mediated Glucose Transport Insulin Receptor Complex a subunit a a Tyrosine Kinase Activation b b b subunit Metabolised Stored as Glycogen Glucose b b INS a a G Storage vesicle containing GLUT 4

45. Fate of insulin Distributed only extracellularly Must be given parenterally Addition of zinc or protein decreases its absorption & prolongs the DOA Insulin released from pancreas is in monomeric form Half life of insulin = 5 -9 minutes

46. Different types of insulin preparations Conventional preparations of insulin Produced from beef or pork pancreas 1 % of other proteins Potentially antigenic Highly purified insulin preparations Gel filtration reduces proinsulin (50-200PPM) Human insulins Newer insulin analogs

47. Conventional insulin preparations

48. Highly purified insulin preparations Single peak insulins Purified by gel filtration contain 50 to 200 PPM proinsulin Actrapid: purified pork regular insulin Monotard: purified pork lente Mixtard: purified pork regular(30%) + isophane(70%) Mono component insulins After gel filtration purified by ion exchange chromatography contain 20 PPM proinsulin Actrapid MC, Monotard MC

49. Human insulins Human (Actrapid, monotard, insulatard, mixtard) Obtained by recombinant DNA technology Advantages More water soluble as well as hydrophobic More rapid SC absorption , earlier & more defined peak Less allergy Disadvantages Costly Slightly shorter DOA

50. Indications of human insulins Insulin resistance Allergy to conventional preparations Injection site lipodystrophy During pregnancy Short term use of insulin

51. Newer Insulin analogs

52. Insulin Lispro Produced by Inversing proline at B28 with lysine at B29. Forms weak hexamers , dissociate rapidly Needs to be injected immediately before, during or even after meals Better control of meal time glycemia & lower incidence of PP hypoglycemia

53. Insulin aspart: Proline at B28 replaced by aspartic acid Change reduces tendency for self aggregation Insulin glulisine lysine replaces aspargine at B3 & glutamic acid replaces lysine at position B29

56. Insulin glargine Prepared by adding 1 glycine at A21 together with 2 arginine residues at end of B chain Improved Stability Much better bioavailabilty Smooth peakless effect is obtained Fasting & interdigestive BGL effectively lowered irrespective of time of day Lower hypoglycemic episodes Cannot be mixed with other insulins

57. Insulin detemir Soluble long acting basal insulin analog with flat action profile and prolonged duration Threonine in B30 ommited & C14 fatty acid chain attached to amino acid B29 Prolonged action Strong self association Albumin binding Fatty acid side chain

58. Aspart, glulisine, lispro 4–5 hours Regular 6–8 hours NPH 12–16 hours Detemir ~14 hours Ultralente 18–20 hours Glargine ~24 hours 2 5 3 4 6 7 8 9 12 13 14 15 16 17 18 19 20 21 22 23 24 0 1 10 11 Action Profiles of Insulins Plasma insulin levels Hrs Danne T et al. Diabetes Care. 2003;26:3087-3092

60. Less weight gain

61. Better efficacy (?)

62. More physiological action profiles

63. Less premeal lag time (0-15 mts)

64. Lispro & Glulisine even after meals

65. Better PP glucose control

66. Less intra-patient/inter-patient variability

68. Drug interactions of insulin Non selective beta blockers Thiazides,furosemide, corticosteroids, OCP , nifedipine↑ BSL Alcohol Precipitates hypoglycemia Salicylates, lithium, theophylline, may accenuate hypoglycemia

69. Uses of insulin Diabetes mellitus Must for type I diabetics Can be used in type II diabetics Diabetic ketoacidosis Hyperosmolar non ketotic hyperglycemic coma

70. Indications of insulin in type II DM Primary or secondary failure of oral hypoglycemics Pregnancy Perioperative period CKD Steroid therapy LADA Fasting > 300 mgms HbA1c > 10 Unintentional wt loss with or with out ketosis Type 2 with DKA ( severe beta cell dysfunction)

71. Recommended sites for S/C Insulin injections

74. 3Ps & weight loss – 10 days duration

75. RBS 418 mg %

76. 36 kg wt

77. No marked dehydration

78. T1DM- No ketoacidosis

80. 36 kg wt

81. No ketoacidosis

83. Ideal for better control & flexible lifestyle

84. 50% Basal dose= 9 U at bedtime (NPH,G,D)

85. 50% Bolus dose = 9 U premeals (R,A,L,Glu)3U Prebreakfast 3U Prelunch 3U Predinner

87. Ideal for better control & flexible lifestyle but “too many shots”

88. 50% Basal dose= 9 U divided as 5 U prebreakfast + 4 U at bedtime (G or D)

89. 50% Bolus dose = 9 U premeals (R,A,L,Glu)3U Prebreakfast 3U Prelunch 3U Predinner

91. 1/3 predinner (6 U)

92. Prebreakfast:8 U NPH + 4 U Regular (A,L,G)

93. Predinner:3 U NPH + 3 U Regular “8 N/4 R - 0 - 3N/3R”

95. 8 U NPH + 4 U Regular (A,L,Glu)

96. 1/3 peridinner (6 U)

97. 3 U Regular ( or A,L,Glu) Predinner

99. Body weight divided by 5 (or)

100. Dose = FBS-50 (or) 10

102. Insulin I.V.drip

103. Achieve & maintain euglycemia

104. Calculate the insulin required for 12-24 hrs

105. 80% of that used as O.P. therapy

106. Ex., 40 U to maintain euglycemia for 24 hrs

108. Pathogenesis of DKA (How ketoacidosis occurs) Hyperketonemia ↑ Lipolysis ↑ FFA to liver ↓ Alkali reserve ↑ Acetyl coA Acidosis ↑ AcetoacetylcoA -Hydroxy butrate Acetoacetate Acetone

109. Treatment of DKA Fluid therapy Rapid acting regular insulin Potassium Bicarbonate Phosphate Antibiotics Treatment of precipitating cause General measures

110. Fluid therapy Adequate tissue perfusion is necessary insulin action Normal saline is fluid of choice for initial rehydration 1 litre in first hour Next 1 L in next 2 hours 2 litres in next 4 hours 2 litres in next 8 hours i.e 4 to 6 litres in 24 hours When BSL reaches 300 mg% fluid should be changed to 5 % dextrose with concurrent insulin

111. Insulin in DKA Regular/ short acting insulin IV treatment of choice Loading dose = 0.1-0.2 U/kg IV bolus Then 0.1 U /kg/hr IV by continuous infusion Rate doubled if no significant fall in BSL in 2 hr 2-3 U/hr after BSL reaches 300mg% If patient becomes fully conscious encouraged to take oral food & SC insulin started

112. Potassium replacement In initial stage of treatment potassium not administered because in DKA it remains normal or ↑ In presence of insulin infusion Sr potassium ↓ hence 10 mEq/L potassium can be added with 3rd bottle of normal saline Sr K+ < 3.3 mEq/L : 20 -30 mEq/hr

113. Bicarbonates & phosphates Bicarbonates If blood pH > 7.1 no need of sodium bicarbonate In presence of severe acidosis 50 mEq of sodium bicarbonate added to IV fluid Phosphates Non availability of ideal preparation Replacement not very essential unless < 1 mEq/L potassium phosphate 5-10 m mol/hr

114. Hyperosmolar Non Ketotic Coma Usually occurs in type II Dehydration with severe hyperglycemia without ketoacidosis, because insulin inhibits hormone sensitive lipase The general principle of T/t is same as for DKA except that pt needs more faster fluid replacement Half NS preferred 2 Lit in 2 Hrs followed by 1 Lit in next 2 hrs Low dose heparin to prevent vascular thrombosis & intravascular coagulation

115. Insulin resistance State in which normal amount of insulin produces subnormal amount of insulin response ↓ insulin receptors ↓ affinity for receptors May be acute or chronic Requirement of > 200 Units of insulin per day in absence of stress Common in type II diabetics & obese

116. Newer insulin delivery devices Prefilled insulin syringes Pen devices Jet injectors Inhaled insulin Insulin pumps External artificial pancreas Insulin complexed with liposomes: intraperitoneal, rectal, oral

117. 40 units/ml 100 units/ml Tuberculin syringe

120. Easier to accurately measure dose

122. Uses high pressure air to force a tiny stream of insulin through the skin

124. Precise delivery

125. Greater impact in those with highest starting A1c

128. Improved pt convenience

129. Faster onset of action compared to Regular SC insulin

130. No needles risk of infection

132. Sulfonylureas I Generation Tolbutamide Chlorpropamide II Generation Glipizide Gliclazide Glibenclamide (Glyburide) Glimepiride

133. Mechanism of action Release of insulin by acting on SUR1 receptors Primarily augment phase 2 of insulin secretion Presence of at least 30% functional -cells essential for their action. Minor action: ↓ glucagon secretion Extra pancreatic action: ↑sensitivity of peripheral tissue to insulin by ↑insulin receptors

135. Pharmacokinetics Well absorbed orally Highly bound to plasma proteins > 90% Have low volume of distribution Cross placenta C/I in pregnancy Metabolized in liver Excreted in urine

136. Daily dose & Duration of action

137. Individual Sulfonylurea

138. GLIMEPIRIDE Lesser risk of hypoglycemia Insulin sparing effect (Significant extra pancreatic effects) Relatively safe in elderly and mild renal failure Antiplatelet and antifibrinolytic activity Little or no weight gain FDA approved combination therapy with insulin Safe and effective for use in the pediatric population ↑Levels of plasma adiponectin & ↓ TNF α Stimulates GLUT4 expression

139. Why Glibenclamide is more potent and longer acting than other SU 1. May accumulate within  cells and directly stimulate exocytosis of insulin granules 2. Greater/longer binding to SUR-1 receptors 3. Slower absorption and distribution 4. Inhibition of hepatic insulinase 5. Suppressionof several counter-regulatory hormones 6. More suppression of HGO 7. May stimulate insulin synthesis

140. Adverse effects Hypoglycemia: GI disturbances: Nausea, vomiting, metallic taste, diarrhoea & flatulence Weight gain Hypersensitivity Not safe in pregnancy Chlorpropamide: cholestatic jaundice, dilutionalhyponatremia, antabuse reaction

141. Contraindications Allergy to SU Renal failure: 3. Significant hepatic dysfunction 4. Severe infections, stress, trauma, major surgery, CVA, AMI 5. Pregnancy (except Glibenclamide) 6. T1DM

142. Drug interactions Drugs that ↑ SU action Salicylates, sulfonamides Cimetidine , warfarin, sulfonamides Propranolol Drugs that ↓ SU action Phenytoin, phenobarbitone , rifampicin Corticosteroids, thiazides, furosemide, OCP

143. Selection of SU

145. SU + Glitazones (best)

146. SU + AGI (better)

147. SU + 2 or more drugs (good)

148. SU + Insulin (good)

149. SU + Meglitinides (bad)

151. Repaglinide Well tolerated in elderly patients in renal impairment Adverse effects: Mild headache, dyspepsia, arthralgia, headache Indicated in type II DM Dose : start 0.5mg with meals can ↑ 16mg/day

152. Nateglinide Stimulates first phase of insulin secretion More rapid acting & shorter duration than repaglinide Mainly used in post prandial hyperglycemia without producing late phase hypoglycemia Little effect on fasting BSL Adverse effects: diziness, nausea, flu like symptoms Dose: 60 to 180 mg TDS with meals

153. Biguanides Metformin & phenformin Little or no hypoglycemia Also improves the lipid profile in type II diabetic patients Metformin dose = 0.5 to 2.5 g/day in 2-3 divided doses

154. Mechanism of action Suppress hepatic & renal gluconeogenesis ↑ uptake & utilization of glucose by skeletal muscles which reduces insulin resistance Inhibit alimentary absorption of glucose Interfere with mitochondrial respiratory chain & promote peripheral glucose utilization by enhancing anaerobic glycolysis

155. Pharmacokinetics Taken orally , well absorbed through GI tract Not metabolized at all Excreted unchanged in urine

157. Secondary Sulfonylurea Failure state.

158. To reduce Insulin requirements.

160. Contraindications of metformin Renal failure – ( Sr. Crt > 1.5 / Crt. Clearance < 40 Advanced Liver Disease. Alcohol abusers. Cardiac Disease. Pregnancy.

161. Thiazolidinediones (Glitazones) Rosiglitazone & pioglitazone Selective agonists of PPAR Bind to nuclear PPAR Activate insulin responsive genes - regulate carbohydrate & lipid metabolism Sensitize the peripheral tissues to insulin ↓blood glucose by Inhibit hepatic gluconeogenesis Promote lipogenesis ↑ Glucose transport into muscle & adipose tissue

162. Thiazolidinediones Hyperglycemia, hyperinsulinemia, and elevated HbA1c levels are improved. Pioglitazone has no effect on LDL levels, ↓ triglyceride & ↑ HDL Rosiglitazone has inconsistent effect on lipid profile it ↑ HDL & LDL levels The TZDs lead to a favorable redistribution of fat from visceral to subcutaneous tissues.

163. Pharmacokinetics Both Rosiglitazone & pioglitazone are completely absorbed from GIT Highly bound to plasma proteins (>95%) Rosiglitazone metabolized by CYP2C8, Pioglitazone metabolized by CYP2C8 & CYP3A4 Drug interactions less with rosiglitazone Metabolites of rosiglitazone are excreted in urine and those of pioglitazone in bile

164. Pioglitazone: 15 to 45 mg once daily orally Rosiglitazone: 4 to 8 mg once daily orally Pt who benefit most are type II DM with substantial amount of insulin resistance Also used in PCOD Monotherapy – Hypoglycemia rare Add-on Therapy – readjust dosage. Takes one month to act

165. Adverse effects Weight gain: due to fluid retention & edema ↑ Extracellular fluid volume Worsening of CHF ↑ Deposition of subcutaneous fat Mild anemia: due to hemodilution Hepatotoxicity : rare Rosiglitazone: ↑risk of fractures especially in elderly women

166. Contraindications Liver disease Congestive heart failure Pregnancy Lactating mother Children

167. Alpha glucosidase inhibitors Acarbose Miglitol Voglibose

168. Pancreatic amylase Oligosaccharides/ Disaccharides Maltose, Isomaltose, Sucrose  glucosidase enzymes (in the lining of cells of intestinal villi) Monosaccharides (Glucose, fructose) Absorbed in lower part of intestine Mechanism of action Dietary Carbohydrates (Starch) Glucosidase inhibitors X 104

169. Acarbose Complex oligosaccharide Inhibits -glucosidase as well as -amylase Reduces postprandial hyperglycemia without increasing insulin levels Regular use reduces weight In prediabetics reduces occurrence of type II DM, hypertension & cardiac disease Dose: 50 to 100 mg TDS Given just before food or along with food

170. Adverse effects Flatulence, diarrhoea, abdominal pain Do not cause hypoglycemia by themselves but may cause if used with Sulfonylureas If hypoglycemia occurs should not be treated with routine sugar (sucrose), Glucose should be used Contraindicated in inflammatory bowel disease & intestinal obstruction

172. 20-30 times more potent then acarbose

173. Does not affect digoxin bioavailability unlike acarbose

174. No dosage adjustment required in renal impairment patients unlike miglitol

175. Superior tolerability

176. Dose: 0.2 to 5 mg107

179. Sitagliptin Orally active inhibitor of DPP-4 Prevents degradation of endogenous GLP-I Dose: 100mg a da Mainly used in post prandial hyperglycemia No action on weight and lipids Costly

180. Pramlintide Synthetic amylin analog Improves overall glycaemic control,↓ PPG Reduces BW : anorectic action Well tolerated Given SC before meals SE: GI disturbances/Less hypoglycemia when used alone Can be used in type I DM

181. Principles of treatment of Type 2 DM Grade Diabetes Mellitus as mild, moderate or severe NB: FBG (150 -200 ---mild ) HbA1c < 8 ( 200-250 --- Moderate) HbA1c 8 - 9 ( more than 250 severe) HbA1c 9 - 10 For severe DM start on insulin if there is wt loss & ketosis For mild & moderate DM use metformin if obese & sulfonylureas if not obese

183. Assess Liver function is normal or abnormal

185. If diabetes not controlled Look for SU failure Occult infection – TB – UTI Drug history and compliance Food history – hypoglycaemia and compliance

186. cardiac problem – avoid glitazones if in failure avoid metformin Renal problem – avoid metformin

187. Liver problem – avoid glitazone and metformin In general patients with complication Short acting SU or insulin

188. Be ware of other drugs - Diuretics - Corticosteroid - Other hormones - ACE inhibitors