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Insulin & Oh Gs(10 13)

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    • 1. DR.UMA KADAM M.B.B.S. MD ASSOCIATE PROFESSOR PHARMACOLOGY SKNMC DR.UMA K.
    • 2. Insulin and Oral Hypoglycemics
      • OBJECTIVES:
      • 1. Understand the process of insulin synthesis and secretion
      • 2. Understand the physiology of circulating insulin, C-peptide and proinsulin.
      • 3. Identify factors influencing insulin secretion.
      • 4. Describe the metabolic effects of insulin and the major metabolic aberrations of insulin resistance.
      • 5. Identify therapeutic problems encountered in insulin therapy.
      DR.UMA K.
    • 3. Insulin and Oral Hypoglycemics
      • OBJECTIVES:
      • 6.Explain the limitations of oral Hypoglycemics in management
      • 7. Explain the differences among commercially available insulin preparations.
      • 8. Understand the different mechanisms of action between the commonly used oral hypoglycemic agents.
      DR.UMA K.
    • 4. Prototype Drugs:
      • Insulin and analogs:
      • Insulin (Humulin)
      • LisPro (Humalog)
      • Glargine (Lantus)
      • Insulin aspart (NovoLog)
      • Inhaled Insulin (Exubera)
      • Somatostatin analogs:
      • Octreotide (Sandostatin)
      • Hyperglycemic Agent
      • Diazoxide (Proglycem)
      • Oral Hypoglycemic Agents:
      • Sulfonylureas: Glipizide
      • Tolbutamide
      • Meglitinides: Repaglinide
      • Biguanides: Metformin
      • Thiazolidinediones
      • Rosiglitazone, Pioglitazone
      • Synthetic Incretin: Exenatide
      • Alphaglucosidase inhibitors: Acarbose, Miglitol
      • Others : Gaurgum
      DR.UMA K.
    • 5. Pancreas
      • Endocrine
      • Exocrine
      • Islands of Langerhans secretes 3 hormones:
        • Glucagon (alpha cells)
        • Insulin (beta cells)
        • Delta cells - somatostatin
      DR.UMA K.
    • 6. INSULIN: Polypeptide hormone secreted by the pancreatic Islets of Langerhans essential for the metabolism of carbohydrates and is used in the treatment and control of diabetes mellitus DR.UMA K.
    • 7. DR.UMA K.
    • 8. Insulin Biosynthesis and Secretion
      • 1. Insulin gene is on chromosome 11
      • 2. Synthesized by β cells of the Islets of
      • Langerhans of the endocrine pancreas as a 12,000 Dalton precursor (preproinsulin) which is processed to final secreted products (proinsulin, insulin, C-peptide).
      • 3. Synthesis is regulated at the transcriptional and translational levels.
      DR.UMA K.
    • 9. Three Biosynthetic Products:
      • A. Proinsulin
      • - Released in small amounts (3-4%)
      • except in pathologic states*
      • - Constitutes 10-50% of circulating immunoreactive insulin content
      • - Reduced biological action ~ 2% activity of insulin
      • - Prolonged circulation time - T1/2 = 17 min.
      • * Insulinoma, familial hyperproinsulinemia
      • - Diagnostic = 80%
      DR.UMA K.
    • 10. B. C-peptide
      • - Connecting peptide (joins A and B chains)
      • - Removed from proinsulin by proteases within secretory granules
      • - Released in equimolar amounts with insulin
      • - Not removed from the circulation by the liver - thus found in higher concentrations than insulin (4:1)
      • - Clinically important marker of insulin secretion
      • DIAGNOSTIC
      DR.UMA K.
    • 11. C. Insulin
      • Released from the beta cell in a rapid first phase and
      • slower second phase
      • - Represents release of insulin stored in granules and
      • newly synthesized insulin, respectively.
      • - Significant amount is removed during first pass
      • through the liver, therefore hepatic insulin levels exceed
      • peripheral level.
      • - T1/2 = 5-6 min
      DR.UMA K.
    • 12. DR.UMA K. proinsulin
    • 13. Insulin needs
      • Normal daily pancreatic output 30-40U/day
      • Diabetics usually need 30-50U/day (best to start lower and build up)
      • Need continuous background level of insulin with larger amounts at the time of meals and snacks
      DR.UMA K.
    • 14. Endogenous Insulin
      • Protein Hormone
      • Secreted Beta Cells-Pancreas
      • 1-2 Units per hour
      • 4-6 Units per meal
        • 1 units x 24hrs +
        • 4 units x 3 meals
          • Total 36 Units per day
      DR.UMA K.
    • 15. Normal Insulin Production
      • Pancreas releases insulin into the bloodstream
      • Blood carries it to all cells in the body
      DR.UMA K.
    • 16. Normal Insulin Profiles After a meal Just to function normally Basic Requirements What happens when you eat and a background level of insulin and extra insulin is needed the blood sugar rises the body needs a constant level of sugar in the blood
    • 17. Normal Insulin Profiles Mealtime insulin Background insulin Blood sugar Daily Requirements Breakfast Lunch Evening Meal
    • 18. Physiological Insulin Levels DR.UMA K. Breakfast Lunch Dinner Insulin Levels
    • 19. Factors Affecting Insulin Secretion
      • A. Stimulatory Factors:
      • Metabolic components
      • glucose* / amino acids / fatty acids / ketones
      • Hormonal components - cAMP - Ca2+
      • Growth Hormone / ACTH / Glucagon
      • Cholinergic and β2-adrenergic stimulation (Propranolol )
      • Intestinal nutrients via gastrin, secretin, enteroglucagon, CCK, Glucagon Like Peptide (GLP)-1
      • - Oral vs. iv glucose yields a larger response
      • B. Inhibitory Factors :
      • Decrease cAMP Levels
      • Insulin / epinephrine / adrenergic stimulation / serotonin
      DR.UMA K.
    • 20. DR.UMA K.
    • 21. DR.UMA K.
    • 22. DR.UMA K.
    • 23. DR.UMA K.
    • 24. DR.UMA K.  subunit  subunit
    • 25. DR.UMA K. insulin  
    • 26. DR.UMA K.
    • 27. DR.UMA K.
    • 28. DR.UMA K.
    • 29. DR.UMA K.
    • 30. DR.UMA K.
    • 31. DR.UMA K.
    • 32. DR.UMA K.
    • 33. DR.UMA K.
    • 34. DR.UMA K.
    • 35. DR.UMA K.
    • 36. Type 2 Diabetes Etiology
      • There is abnormally high level of glucose
      • Pancreas does produce insulin
      • Body resists the insulin’s effects
      DR.UMA K.
    • 37. As a result, the glucose circulating cannot enter the cells, so that the glucose cannot be used for energy!!!!!! Therefore, there is INSULIN RESISTANCE!!! DR.UMA K.
    • 38. DR.UMA K. NORMAL GLUCOSE UPTAKE INSULIN RESISTANCE
    • 39. Insulin is like the key that cannot get fit into the lock (cells)!!!! DR.UMA K.
    • 40. DR.UMA K.
    • 41. DR.UMA K.
    • 42. Insulin Resistance: Causes and Associated Conditions Medications Aging INSULIN RESISTANCE Atherosclerosis Genetics Obesity and inactivity Rare disorders PCOS Dyslipidemia Hypertension Type 2 diabetes
    • 43. DR.UMA K.
    • 44. DR.UMA K.
    • 45. DR.UMA K.
    • 46. Type 2 Diabetes Signs and Symptoms
      • Hyperglycemia
      • Polyuria
      • Polydipsia
      • Blurred vision
      • Fatigue
      • Paresthesias
      • Skin infections
      DR.UMA K.
    • 47. Type 2 Diabetes
      • 80% are obese
      • 10% non-obese
      • 10% unstable: may look more like a Type 1 Diabetic
      DR.UMA K.
    • 48. Summary
      • Diabetes mellitus is a complicated spectrum of conditions
      • Each patient requires tailored therapy depending on:
        • Pathology of diabetes
        • Lifestyle
        • Special circumstances/ill health
      DR.UMA K.
    • 49. Summary 2
      • Drugs that lower blood sugar form only part of the treatment of diabetes
      • Attention must be paid to many other aspects including:
        • lifestyle
        • diet/alcohol consumption
        • cardiovascular risk factors
        • foot care
      DR.UMA K.
    • 50. Insulin Treatment
      • Insulin preparations
        • Onset of action
        • Duration of action
        • Degree of purity
        • Source
      DR.UMA K.
    • 51. Insulin Preparations
      • Short Acting
        • Regular- Humulin R
        • ALWAYS USED FOR SLIDING SCALE COVERAGE!!!!!!
        • Semilente
      • Intermediate Acting
        • NPH-Humulin N
      • Mixtures
        • 70/30= 70 Units NPH & 30 Units Regular
      • Long Acting
        • Lantus
      DR.UMA K.
    • 52. DR.UMA K. (semilente)
    • 53. DR.UMA K.
    • 54. DR.UMA K.
    • 55. Flexible insulin
      • Insulin Lispro
      • Change in 2 amino acids from physiological insulin
      • Molecules dissociate and are absorbed from injection sites more quickly
      • can be given immediately before eating rather than 30 minutes before food
      • Injection devices
      • Insulin pen devices
      DR.UMA K.
    • 56. DR.UMA K.
    • 57. Short-Acting Insulin
      • Soluble
      • Clear
      • Onset 30 minutes
      • Peak 1 - 3 hours
      • Duration up to 8 hours
    • 58. Intermediate Acting Insulin
      • Crystals in suspension (need re-suspending)
      • Cloudy
      • NPH or Isophane (NPH = Neutral Protamine Hagedorn)
      • Onset 1 1 / 2 hours
      • Peak 4 - 12 hours
      • Duration up to 24 hours
    • 59. Pre-mixed Insulin
      • Pre-mixed combinations of short and intermediate acting Insulins (biphasic)
      • Cloudy (needs re-suspending)
      • 5 different combinations (10, 20, 30, 40, 50)
        • e.g. 30/70 Mixture = 30% fast acting
        • + 70% intermediate acting
      • Onset 30 minutes
      • Peak 2 - 8 hours
      • Duration up to 24 hours
    • 60. Long-Acting Insulin Glargine (Lantus)
      • Synthetic Human Insulin
        • Do not mix with any other insulin
        • Long Acting Up to 24 hours
        • NO PEAK
        • Given at BEDTIME
      DR.UMA K.
    • 61. DR.UMA K. Lispro Lente Insulin Regular Insulin NPH Insulin Ultralente Insulin 70/30 (human isophane sus./NPH& human insulin-DNA origin) 50/50 (human isophane sus.& human insulin-DNA origin)
    • 62. DR.UMA K.
    • 63. Species of Insulin
      • Human - Genetically engineered using either yeast (pyr) or e.coli (prb)
      • Animal
        • Beef - Increased incidence of allergic problems
        • Pork - Less antigenic than beef (Kurtz et al. 1980)
          • - Available as purified insulin
    • 64. Insulin regimes
      • Soluble insulin at the time of meals
      • Intermediate or long acting insulin to provide background cover
      • Minimise number of injections
      • Questions
      • How do soluble, intermediate and long acting insulin differ?
      DR.UMA K.
    • 65. DR.UMA K. Twice daily injections e.g. Humulin M3 Breakfast Lunch Dinner Insulin Levels Soluble insulin Long/intermediately acting insulin
    • 66. DR.UMA K. 3-4 daily injections - more physiological profile Breakfast Lunch Dinner Insulin Levels
    • 67. DR.UMA K.
    • 68. DR.UMA K.
    • 69. Storage of Insulin
      • Before use Store in fridge
      • In-use vials Store in fridge (3 months)
      • Out of fridge at max 25 C
      • (4-6 weeks)
      • In-use pens Out of fridge at max 25 C (4 weeks)
    • 70. Insulin Delivery
      • Insulin devices (pens)
        • Durable (replace insulin cartridge)
        • Disposable (no need to replace cartridge)
      • Insulin vials and syringes
      DR.UMA K.
    • 71. Insulin Devices
      • Advantages
      • Improved dose accuracy
      • More convenient
        • Easy to use
        • Portable
        • Quick and discreet
      • May improve client self-management/compliance
      • Preferred by patients
      • Disadvantages
      • Cannot mix insulin in a free-mixing regimen
      DR.UMA K.
    • 72. Who is a good candidate for an Insulin Pump? DR.UMA K.
    • 73. Insulin Pumps
      • Continuous subcutaneous insulin infusion (CSII)
      • Battery operated
      • Programmable computer
      • Basal insulin throughout day
      • Bolus insulin before meals
      • Needles/catheters changed
      • every 2-3 days
    • 74. Adverse effects of insulin: DR.UMA K.
    • 75. DR.UMA K.
    • 76. DR.UMA K.
    • 77. DR.UMA K.
    • 78. DR.UMA K.
    • 79. Drug interactions and diabetes
      • Increase risk of hypoglycaemia
        • beta blockers, alcohol, sulphonamides, monoamine oxidase inhibitors
      • Decrease awareness of hypoglycaemia
        • beta blockers
      • Raise blood glucose
        • corticosteroids, oral contraceptive, thiazides, loop diuretics, diazoxide
      DR.UMA K.
    • 80. DR.UMA K.
    • 81. DR.UMA K.
    • 82. DR.UMA K.
    • 83. DR.UMA K.
    • 84. DR.UMA K.
    • 85. DR.UMA K.
    • 86. DR.UMA K.
    • 87. DR.UMA K.
    • 88. DR.UMA K.
    • 89. DR.UMA K.
    • 90. Nateglinide:
      • Nonsulfonylurea principally stimulates first phase insulin release resulting in rapid onset & short duration of hypoglycemic action than repaglitanide
      • Ingested 10-30 minutes before meal, limits pp hyperglycemia in NIDDM patients.
      • Does not produce late phase hypoglycemia & little effect on fasting BSL
      • EPISODES OF HYPOGLYCEMIA ARE LESS FREQUENT COMPARED TO SULFONYLUREAS
      DR.UMA K.
    • 91. DR.UMA K.
    • 92. DR.UMA K.
    • 93. DR.UMA K. /Miglitol Antihyperglycemic
    • 94. OTHER ANTIHYPERGLYCEMICS:
      • GAURGUM:
      • Dietary fiber obtained from Indian cluster beans (Gaur)
      • Forms viscous gel after coming with contact with water
      • If mixed with food or taken before meal it slows gastric emptying & GI transit time hence decrease carbohydrate absorption; prevents pp hyperglycemia
      • Used as an adjuvant with sulphonylureas; it lowers dose of it.
      • GI discomfort, flatulence, diarrhea are common ADRs
      DR.UMA K.
    • 95. DR.UMA K.
    • 96. DR.UMA K.
    • 97. DR.UMA K.
    • 98. DR.UMA K.
    • 99. Nursing Assessment for All Diabetic Clients
      • What time will the insulin/oral agent act?
      • What carbohydrates are available?
      • Observe for Therapeutic Effects
      • What are the Adverse Effects?
      DR.UMA K.
    • 100. Lab Assessment for All Diabetic Clients
      • Blood tests
      • 1. Fasting Blood Glucose
      • Test (Cavenaugh pg. 105)
      • 2. Blood Glucose
      • Monitor Systems
      • 2. Oral Glucose
      • Tolerance Test
      • 3. Glycosylated Hemoglobin
      • Assays
      • 4. Glycosylated Serum Proteins and Albumin
      DR.UMA K.
    • 101. Checking Blood Glucose
      • CBGs
      • AccuChecks
      • Glucometer
      • Glucoscan
      DR.UMA K.
    • 102. DR.UMA K.
    • 103. Hemoglobin A 1c
      • A blood test that shows glucose levels for the past 3 months
      • No preparation needed i.e. fasting, etc.
      DR.UMA K. Hb A1c
    • 104. Values for HbA 1c
      • Non-diabetic <6 %
      • Diabetic with good control <7 %
      • Diabetic out of control >8 %
      DR.UMA K.
    • 105. ADA Treatment Goals
      • Hgb A1C maintained at 7% or below
      • Premeal blood glucose level 70 to 110mg/dl
      • Blood glucose at bedtime 100-140mg/dl
      DR.UMA K.
    • 106. HbA 1c Predicts CHD in Type 2 CHD mortality Incidence (%) in 3.5 years All CHD events Incidence (%) in 3.5 years HbA 1c HbA 1c Low <6% Middle 6-7.9% High >7.9% Low <6% Middle 6-7.9% High >7.9% 0 5 10 15 20 25 0 5 10 15 20 25
    • 107. Effects of EXERCISE on Blood Glucose
      • By increasing the uptake of glucose by body muscles, exercise does what to Blood Glucose?
        • Lowers it by
        • increasing the
        • number of insulin
        • receptors!!!!
      DR.UMA K.
    • 108. Effects of ILLNESS on Blood Glucose
      • Fever
      • Flu
      • Infections
      • N & V
      • Surgery
      • Sunburn
      DR.UMA K.
    • 109. Being sick usually makes blood sugar HIGH!
      • Stress increases Blood Glucose
      • Never OMIT normally ordered insulin!!!
      DR.UMA K.
    • 110. Interventions for ILLNESS
      • Check Blood Glucose q4 hr >240? Check for ketones!!!
      • Ketones: call MD!!!!
      • Sick Day Guidelines…
      DR.UMA K.
    • 111. Treatment of diabetes DR.UMA K.
    • 112. DR.UMA K. Diabetic Ketoacidosis/ ketotic coma Hyperosmolar/ Nonketotic coma Type-1(IDDM) Type-2 (NIDDM)
    • 113.
      • More frequent in IDDM; infrequent in NIDDM
      • Common precipitating cause is infection; others are pancreatitis, trauma, stroke, stress & inadequate insulin doses
      • A medical emergency treatment as follows…..
      • Regular insulin to correct metabolic abn0rmalities, bolus dose of 0.1 – 0.2 U/kg iv followed by 0.1U/kg/hr infusion; rate can be doubled if no significant fall in BSL in 2 hrs.*
      • After 4-6 hrs when BSL becomes 300mg/dl rate of infusion can be made 2-3 U/hr & maintained till patient become conscious.(later insulin can be given sc)
      • Massive therapy with 1U/kg iv + 1U/kg sc followed by 1U/kg sc every 2 hrs is the must
      Treatment for Diabetic Ketoacidosis DR.UMA K. Osmotic diuresis Hyperglycemia Glycosuria Hyperventilation Impairment of consciousness Hypotension Shock Tachycardia Vomitting Dehydration
    • 114.
      • Correct fluid volume and electrolyte deficit
        • 1 liter of isotonic saline (NS)over 1 hour followed by gradual reduction to 0.5L/4hr
        • 1 liter of hypotonic saline (1/2NS)over 6 to 8 hrs once BP/PR/Renal perfusion become normal
        • When BSL becomes 300mg/dl 1/2NS + 5%D:
        • Since BSL falls before ketones are fully cleared from circulation
        • Glucose required to restore exhausted hepatic glycogen stores
        • Once ketosis subsides K + driven intracellularly may cause dangerous hypokalemia to overcome this KCL 10-20mEq /hr should be added into infusion after 4 hrs.
      Treatment for Diabetic Ketoacidosis DR.UMA K.
    • 115.
      • 50 mEq sodium bicarbonate added into infusion fluid for correcting acidosis
      • 5-10 m mol /hr of sod. / pot. Phosphate infusion
      • Antibiotics
      Treatment for Diabetic Ketoacidosis DR.UMA K.
    • 116. Hyperosmolar (Nonketotic /hyperglycemic) coma
      • More common in elderly with type-2 (NIDDM)
      • Precipitating factors same as DKA
      • Uncontrolled glycosuria produce diuresis resulting in dehydration & haemoconcentration over several days
      • Finally urine output is reduced & glucose gets accumulated in blood: >800mg/dl leading to coma & death (despite intensive therapy mortality rate is high)
      • Treatment line remain same except:
      • Rapid fluid replacement
      • Inj. Heparin to avoid thrombosis
      • Alkali not needed
      DR.UMA K.
    • 117. DR.UMA K.
    • 118. DR.UMA K.
    • 119. Management of Hypoglycemia
      • Hypoglycemic protocol
        • Mild hypoglycemia (BG < 60 and symptomatic)
        • - 10 to 15g of carbohydrate
        • - Recheck BG in 15minutes
        • Moderate (BG < 40 and symptomatic)
        • -15 to 30g of rapidly absorbed CHO
        • Severe (BG < 20 and unable to swallow)
        • - 1mg of glucagon IM/SQ or amp of D50 IVP
      DR.UMA K.
    • 120. DR.UMA K.
    • 121. DR.UMA K.
    • 122. DR.UMA K.
    • 123. DR.UMA K.
    • 124. DR.UMA K.
    • 125. DR.UMA K.
    • 126. DR.UMA K. Complex internalised Drugs used to treat diabetes mellitus Gut Food Absorption Glucose Insulin Pancreas Insulin stored in  -islet cells Liver
      • Reduced gluconeogenesis
      • Glycogenesis
      • Reduced lipolysis
      Receptor (tyrosine kinase) Muscle/fat cell Stimulates glucose uptake Adipose cell Insulin receptor Peroxisome proliferator-activated receptor Insulin Sulfonyl- ureas Metformin Acarbose Glitazones
    • 127. THE END!!!!