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Insulin & Oh Gs(10 13) Insulin & Oh Gs(10 13) Presentation Transcript

  • DR.UMA KADAM M.B.B.S. MD ASSOCIATE PROFESSOR PHARMACOLOGY SKNMC DR.UMA K.
  • 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.
  • 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.
  • 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.
  • Pancreas
    • Endocrine
    • Exocrine
    • Islands of Langerhans secretes 3 hormones:
      • Glucagon (alpha cells)
      • Insulin (beta cells)
      • Delta cells - somatostatin
    DR.UMA K.
  • 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.
  • DR.UMA K.
  • 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.
  • 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.
  • 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.
  • 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.
  • DR.UMA K. proinsulin
  • 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.
  • 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.
  • Normal Insulin Production
    • Pancreas releases insulin into the bloodstream
    • Blood carries it to all cells in the body
    DR.UMA K.
  • 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
  • Normal Insulin Profiles Mealtime insulin Background insulin Blood sugar Daily Requirements Breakfast Lunch Evening Meal
  • Physiological Insulin Levels DR.UMA K. Breakfast Lunch Dinner Insulin Levels
  • 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.
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  • DR.UMA K.  subunit  subunit
  • DR.UMA K. insulin  
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  • Type 2 Diabetes Etiology
    • There is abnormally high level of glucose
    • Pancreas does produce insulin
    • Body resists the insulin’s effects
    DR.UMA K.
  • 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.
  • DR.UMA K. NORMAL GLUCOSE UPTAKE INSULIN RESISTANCE
  • Insulin is like the key that cannot get fit into the lock (cells)!!!! DR.UMA K.
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  • Insulin Resistance: Causes and Associated Conditions Medications Aging INSULIN RESISTANCE Atherosclerosis Genetics Obesity and inactivity Rare disorders PCOS Dyslipidemia Hypertension Type 2 diabetes
  • DR.UMA K.
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  • Type 2 Diabetes Signs and Symptoms
    • Hyperglycemia
    • Polyuria
    • Polydipsia
    • Blurred vision
    • Fatigue
    • Paresthesias
    • Skin infections
    DR.UMA K.
  • Type 2 Diabetes
    • 80% are obese
    • 10% non-obese
    • 10% unstable: may look more like a Type 1 Diabetic
    DR.UMA K.
  • 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.
  • 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.
  • Insulin Treatment
    • Insulin preparations
      • Onset of action
      • Duration of action
      • Degree of purity
      • Source
    DR.UMA K.
  • 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.
  • DR.UMA K. (semilente)
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  • 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.
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  • Short-Acting Insulin
    • Soluble
    • Clear
    • Onset 30 minutes
    • Peak 1 - 3 hours
    • Duration up to 8 hours
  • 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
  • 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
  • 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.
  • 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)
  • DR.UMA K.
  • 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
  • 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.
  • DR.UMA K. Twice daily injections e.g. Humulin M3 Breakfast Lunch Dinner Insulin Levels Soluble insulin Long/intermediately acting insulin
  • DR.UMA K. 3-4 daily injections - more physiological profile Breakfast Lunch Dinner Insulin Levels
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  • 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)
  • Insulin Delivery
    • Insulin devices (pens)
      • Durable (replace insulin cartridge)
      • Disposable (no need to replace cartridge)
    • Insulin vials and syringes
    DR.UMA K.
  • 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.
  • Who is a good candidate for an Insulin Pump? DR.UMA K.
  • 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
  • Adverse effects of insulin: DR.UMA K.
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  • 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.
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  • 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.
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  • DR.UMA K. /Miglitol Antihyperglycemic
  • 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.
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  • 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.
  • 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.
  • Checking Blood Glucose
    • CBGs
    • AccuChecks
    • Glucometer
    • Glucoscan
    DR.UMA K.
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  • 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
  • Values for HbA 1c
    • Non-diabetic <6 %
    • Diabetic with good control <7 %
    • Diabetic out of control >8 %
    DR.UMA K.
  • 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.
  • 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
  • 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.
  • Effects of ILLNESS on Blood Glucose
    • Fever
    • Flu
    • Infections
    • N & V
    • Surgery
    • Sunburn
    DR.UMA K.
  • Being sick usually makes blood sugar HIGH!
    • Stress increases Blood Glucose
    • Never OMIT normally ordered insulin!!!
    DR.UMA K.
  • Interventions for ILLNESS
    • Check Blood Glucose q4 hr >240? Check for ketones!!!
    • Ketones: call MD!!!!
    • Sick Day Guidelines…
    DR.UMA K.
  • Treatment of diabetes DR.UMA K.
  • DR.UMA K. Diabetic Ketoacidosis/ ketotic coma Hyperosmolar/ Nonketotic coma Type-1(IDDM) Type-2 (NIDDM)
    • 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
    • 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.
    • 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.
  • 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.
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  • 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.
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  • 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
  • THE END!!!!