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INSULIN<br />Dr.Nagula Praveen<br />
Insulin is not a cure for diabetes; it is a treatment. It enables the diabetic to burn sufficient carbohydrates, so that p...
Laughter is the best medicine - unless you're diabetic, then insulin comes pretty high on the list. Jasper Carrott <br />
Introduction<br />Is  a protein<br />Synthesised from the beta cells of islets of langerhans.<br />Deficiency causes DIABE...
History<br />1869---Paul Langerhans–two distinct group of cells in pancreas –acinar cells ,islets.<br />1889---Minkowski--...
Best and Banting<br />
BANTING AND BEST<br />
Leonard thompson<br />
V.SHESHAIH<br />
Secretion of insulin<br />Β cells of islets of langerhans in the pancreas—secrete 110 AA chain ,single chain—PREPROINSULIN...
Structure of insulin<br />51 amino acids<br />5808 daltons<br />2 peptide chains A and B<br />One intrasubunit and two int...
Equimolar amounts of C peptide,insulin are released into the circulation.<br />C peptide has no biological function.<br />...
Structure of insulin<br />Conserved  portions of insulin—3 disulfide bonds<br />Both ends of A chain<br />C terminal resid...
INSULIN STRUCTURE<br />
Genetics of insulin<br />Single insulin gene –chromosome 11<br />Close to IGF-1<br />Single protein product in most specie...
Existence of insulin<br />Isolated chains of insulin are inactive.<br />In acid solution –dimers<br />At neutral Ph—exist ...
Pharmacology of insulin <br />Introduction of insulin of human insulin,proinsulin gene into organisms—e.coli,yeast-recombi...
NN= SaccharomycesCerevisiae<br />Eli lilly= non-disease producing strain of E.Coli<br />Sanofi= non-disease producing stra...
Insulin receptor<br />Insulin binds to N and C terminal of  subunit of the receptor.<br />cysteine rich region in alpha s...
hexamer<br />
After injection<br />
Regulation of insulin secretion<br />Prinicipal stimulus  for insulin secretion is the glucose.<br />Sugar is more effecti...
Insulin secretion is BIPHASIC.<br />First phase—peak at 1-2 min,short lived.<br />Second phase-delayed onset,long duration...
Rate of secretion  in fasting—1U of insulin /hr into portal vein<br />Conc of insulin 2-4 ng/ml.50-10031U/ml-portal vein<...
degradation<br />Liver,kidney,muscle<br />50% insulin that reaches liver is destroyed.<br />It is filtered by glomeruli-re...
Functions of insulin<br />Globally—<br />Control of cellular intake of certain substance-glucose in muscle,adipose tissue....
Cellular level<br />Increased glycogen synthesis.<br />Increased fatty acid synthesis.<br />Increased esterification of fa...
Types of insulin<br />20types of insulin products available in four basic forms,each with a different time of onset and du...
Types of insulin<br />Five different types<br />Some are clear in appearance .,some are cloudy<br />RAPID ONSET-FAST ACTIN...
Insulin sliding scale<br />Not recommended for subcutaneous  injection <br />50U -50 ml NS <br />Every one hour until the ...
Somoygi phenomenon<br />Somogyi effect is a rebounding high blood sugar that is a response to low blood sugar.<br />It is ...
Dawns phenomenon<br />Early morning hyperglycemia without nocturnal hypoglycemia.<br />It is due to counter regulatory hor...
Increasing requirements<br />Infection,stress,puberty,pregnancy,acromegaly,cushings syndrome.<br />Lipohypertrophy at the ...
Decreaesing requirements<br />Impending renal failure<br />Honeymoon phase in type 1<br />Hypothyroidism<br />Addisons dis...
In renal disease<br />Half of the sliding scale of insulin dose to be given<br />As insulinase enzyme does not function<br...
Indications for insulin therapy<br />Type 1 diabetes<br />Women with diabetes who become pregnant or are breastfeeding<br ...
Side effects of insulin use<br />Hypoglycemia<br />Weight gain<br />Locally-allergy<br />                  infection<br />...
Insulin devices<br />Insulin syringes<br />Delivery pens<br />Insulin pumps<br />Insulin syringes—10ml insulin vials<br />...
Insulin pumps-reservoir of insulin-infusion set<br />      worn outside the body—abdomen<br />      Only short or rapid ac...
Mode of administration<br />Subcutaneous<br />Intravenous<br />Inhaled<br />Intramuscular<br />
Subcutaneous injection<br />
Sites <br />Rotation of injection site to prevent lipohypertrophy.<br />Within one area.<br />Abdomen has fastest rate of ...
Sites of injection<br />
syringes<br />1ml most common<br />26-31 guage needle<br />30 or 31 bend in single use<br />No sharing of needles<br />Reu...
Insulin syringe and vial<br />
Timing of insulin<br />30 min prior to meals <br />Not to exceed  30 min in case of rapidly acting insulins<br />Intermedi...
Insulin injection<br />Cloudy insulin gently rolled in between<br />Pen needs to be rotated upside down for at least ten t...
Alternative routes—failed<br />Jet injectors—deliver high pressure stream of insulin.<br />Useful in lipoatrophy.<br />Tra...
Intranasal<br />Bioavailability is 8-15%<br />Nasal irritation is common<br />High rates of treatment failure.<br />Gelifi...
Thank you<br />
Types of insulin<br />
Types of insulin and action<br />
Regular insulin<br />Clear  solution at neutral pH<br />0.4% zinc added-hexamers<br />Phenol or cresol-prevent growth of m...
indications<br />In case of type1 DM ,type 2 DM –DKA,HONK,Pregnancy,patients being taken up for surgery,acute illness.<br ...
NPH or isophane insulin<br />At hagedorn university in 1940.<br />Protamine added in 1:6 ratio to regular insulin<br />Pho...
Lente insulin<br />Zinc in amounts 10 times to NPH<br />Acetate as buffer<br />Insoluble zinc insulin complexes<br />Semil...
Premixed formulations<br />30:70<br />50:50<br />25:75<br />Regular and NPH insulin<br />
Rapidly acting insulins—insulin analogues<br />Analogous to keep insulin in monomeric form<br />Only change in aminoacid s...
Aspart<br />
Aspart<br /> by Novo Nordisk as Novolog or Novorapid<br />B28 ---proline is substituted by aspartic acid residue.<br />Inc...
   NovoRapid (Insulin Aspart )<br />Pro<br />Phe<br />Gly<br />Arg<br />Phe<br />Asp<br />Tyr<br />Glu<br />B20<br />Thr<b...
Lispro<br />
Lispro<br />Marketed by Eli Lilly—HUMALOG<br />First insulin analogue.<br />Penultimate lysine and proline residues on the...
Glulisine<br />
Glulisine<br />Marketed by sanofiaventis. APIDRA<br />Asparagine is replaced by lysine at B3<br />Lysine replaced by gluta...
Long  acting insulin analogues<br />Steady basal insulin levels<br />Glargine –isoelectric at 7.4<br />Clear and soluble a...
Glargine<br />
Glargine<br />Marketed by sanofiaventis—Lantus<br />Resembles basal insulin secretion of non diabetic  pancreatic beta cel...
Glargine<br />In 2009 there was conflicting and confusing data  regarding the link of glargine insulin and cancer developi...
Detemir<br />
C14 fatty acid chain<br />(Myristic acid)<br />Phe<br />Gly<br />Phe<br />Arg<br />Glu<br />Tyr<br />Thr<br />Gly<br />Pro...
Detemir<br />Marketed by Novo Nordisk –LEVEMIR<br />Fatty acid myristic acid is  bound to lysine aminoacid at B29.<br />qu...
levemir<br />Albumin binding: Makes Levemir therapy with a smooth and peakless profile throughout the day  <br />
Time-action profile<br />Up to 24 hours <br />Predictability<br />lower within-patient variability than NPH and glargine<b...
Premixed analogue<br />Protamine insulin +rapidly acting analogues.<br />
Strength of insulin<br />40 U /ml –most widely used<br />WHO—all insulin across the globe to be U 100.<br />Storage<br />R...
Mixing insulins<br />glargine is not mixed with any other insulin.<br />
Problems with syringes / vials<br />Cumbersome procedure<br />Difficult to transport and carry around<br />Inaccuracy in w...
Advantages with Devices<br />Simplicity - Simple to operate and inject<br />Accuracy - A new superior standard in dose acc...
Device vs. Syringe<br />
Prefilled pen<br />Contain a built-in, single-use insulin cartridge <br />Loading<br />Require no loading by patient<br />...
FlexPen®<br />Easy to use<br /><ul><li>dialling dose; accurate / reliable
good control during injection
‘can hear clicks’
minimal pressure required
can be administered with one hand</li></ul>Easy to read (white font on black)<br /><ul><li>numbers clearly visible
safer because mistakes less likely</li></ul>Convenient; pre-filled / no re-loading<br /><ul><li>easy to attach needles
easy to teach</li></ul>Portable and discreet<br /><ul><li>comes in carry case</li></li></ul><li>
FlexPen®<br />FlexPen® is a unique dial-a-dose insulin pen. You can dial doses from 1 to 60 units inincrements of 1 unit<b...
<ul><li>Single unit increment
Easy dial back
Large & easy to ready display
Max single dose-60 U
Virtually painless 31G needle </li></ul>FlexPen- Easy to use and teach<br />
Design Characteristic of FlexPen<br />The FlexPen is a disposable, prefilled insulin delivery device— there is no insulin ...
FlexPen Prefilled syringes are available with three insulin analog preparations: Levemir, NovoRapid, and NovoMix 30.<br />...
<ul><li>LevemirFlexPen = identified by green push button
NovoMix 30 FlexPen = identified by Blue push button
NovoRapidFlexPen = identified by orange push button</li></li></ul><li>Durable pen<br />Patient has to insert an insulin ca...
NOVO NORDISK<br />
Insulin dose calculation<br />Calculate total daily insulin TDI<br />0.5 *WEIGHT (KG) or   sum of current doses<br />Ex—60...
Insulin dosage<br />DKA<br />Bolus dose—IV 0.1U/kg<br />IM-0.3U/kg<br />Then 0.1U/kg/hr<br />Mild episodes of DKA—short ac...
Pre prandial insulin dose<br />INSULIN /CARBOHYDRATE ratio<br />1-1.5 U/10 gm of carbohydrate<br />Supplemental or correct...
Twice daily regimens<br />Long acting insulinNPH.regular insulin –morning,bed time.<br />2/3 of insulin in the morning<br ...
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Insulin22

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ALL ABOUT INSULIN FROM HISTORY TO PRESENT TRENDS OF USE...

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  1. 1. INSULIN<br />Dr.Nagula Praveen<br />
  2. 2. Insulin is not a cure for diabetes; it is a treatment. It enables the diabetic to burn sufficient carbohydrates, so that proteins and fats may be added to the diet in sufficient quantities to provide energy for the economic burdens of life. <br /> — Sir Frederick Grant Banting'Diabetes and Insulin', Nobel Lecture, 15 September 1925. In Nobel Lectures: Physiology or Medicine, 1922-1941 (1965), 68. <br />
  3. 3. Laughter is the best medicine - unless you're diabetic, then insulin comes pretty high on the list. Jasper Carrott <br />
  4. 4. Introduction<br />Is a protein<br />Synthesised from the beta cells of islets of langerhans.<br />Deficiency causes DIABETES MELLITUS.<br />Gene located on chromosome 11.<br />Name 'insulin'by J de meyer .-1907.<br />Insulin –first hormone for which radioimmunoassay was developed.<br />Name ''insulin'' is derived from word insula—meaning island---a latin word.<br />Connaught initial name<br />Novo nordisk –since 1923<br />
  5. 5. History<br />1869---Paul Langerhans–two distinct group of cells in pancreas –acinar cells ,islets.<br />1889---Minkowski---pancreactomized dogs—diabetes mellitus.<br />1921—Frederick Grant Banting–insulin secreted was destroyed by proteolytic digestion<br />Charles .H.Best, a fourth year medical student –ligated the pancreatic ducts<br />Leonard Thompson, a 14 yr old was the first person to receive insulin .---11 JAN 1922<br />J.M.Collip-who purified epinephrine,purified insulin also.<br />Purified and crystallized –Abev<br />Aminoacid sequence by Sanger—1960<br />Complete synthesis of protein-1963<br />3 dimensional structure—Hodgkins-1971<br />NOBEL PRIZE in medicine or physiology-1923-Banting and Best,Mcleod and Collip<br />
  6. 6.
  7. 7. Best and Banting<br />
  8. 8.
  9. 9. BANTING AND BEST<br />
  10. 10. Leonard thompson<br />
  11. 11. V.SHESHAIH<br />
  12. 12. Secretion of insulin<br />Β cells of islets of langerhans in the pancreas—secrete 110 AA chain ,single chain—PREPROINSULIN.<br />Rough endoplasmic reticulum---24 AAterminal( NH2)of preproinsulin is cleaved off—PROINSULIN<br />During formation of PROINSULIN,the molecule folds,disulfide bonds are formed<br />Converted to INSULIN-golgi complex.<br />During conversion –4 basic AA are removed,remaining connector or C peptide removed byproteolysis.<br />Insulin formed is stored in vesicles.<br />Bound to zinc atoms.<br />Exist in hexamer form.<br />
  13. 13. Structure of insulin<br />51 amino acids<br />5808 daltons<br />2 peptide chains A and B<br />One intrasubunit and two intersubunit disulphide bonds<br />A-21 AA,B-30 AA<br />Slight difference in structure in species<br />Porcine-one AA<br />Bovine—3 AA<br />C peptide differs in all.<br />
  14. 14. Equimolar amounts of C peptide,insulin are released into the circulation.<br />C peptide has no biological function.<br />It is useful index of insulin secretion.<br />Proinsulin-insulin by 2 Ca endopeptidases<br />PC2 lysine arginine—C-A<br />PC3 argininearginine –C-B<br />
  15. 15. Structure of insulin<br />Conserved portions of insulin—3 disulfide bonds<br />Both ends of A chain<br />C terminal residues of B chain<br />
  16. 16.
  17. 17.
  18. 18. INSULIN STRUCTURE<br />
  19. 19. Genetics of insulin<br />Single insulin gene –chromosome 11<br />Close to IGF-1<br />Single protein product in most species<br />2 genes encode—rat,mice---two molecules differ from each other by 2 AA residuesin B chain.<br />Several  helical regions in both A and B chains.<br />Proinsulin –INS gene<br />
  20. 20. Existence of insulin<br />Isolated chains of insulin are inactive.<br />In acid solution –dimers<br />At neutral Ph—exist as hexamers and with Zn.<br />Insulin in solution exists as monomer,dimer,hexamer<br />Intermediate,long acting insulins have hexamers are common <br />2 molecules of zn are incorporated in hexamer .<br />Zn plays a role in crystallization.<br />Monomer is active.<br />
  21. 21. Pharmacology of insulin <br />Introduction of insulin of human insulin,proinsulin gene into organisms—e.coli,yeast-recombinant DNA technology.<br />Insulin ppt at ph—5.4—soluble at 2-3<br />1 U of insulin -38.5 ug of substance<br />40 U and 100 U –40u/ml,100u/ml<br />10 U for infants<br />T1/2—40 min<br />
  22. 22. NN= SaccharomycesCerevisiae<br />Eli lilly= non-disease producing strain of E.Coli<br />Sanofi= non-disease producing strain of E.Coli<br />
  23. 23. Insulin receptor<br />Insulin binds to N and C terminal of  subunit of the receptor.<br />cysteine rich region in alpha subunit.<br />Affinity towards receptor-effect on glucose metabolism.<br />Insulin is a member of IGF s.<br />IGF1,IGF2 –are similar to proinsulin ,concerned with growth,Cpeptides are not removed.<br />IGF1 –somatomedin,growth promoting actions of insulin.<br />Proinsulin has 2% metabolic potency of insulin,50% as potent for mitogenesis---atherosclerosis<br />
  24. 24.
  25. 25. hexamer<br />
  26. 26.
  27. 27.
  28. 28. After injection<br />
  29. 29. Regulation of insulin secretion<br />Prinicipal stimulus for insulin secretion is the glucose.<br />Sugar is more effective in provoking insulin secretion when taken orally than when taken IV –inc vagal activity.<br />Stimulants—various nutrients-glucose,AA,FA,ketones.<br /> GI hormones<br /> pancreatic hormones<br /> autonomic neuro transmitters<br />2 adrenergic receptor—inhibits insulin receptor.<br />Β2 adrenergic receptor,vagal—release.<br />Hypoxia,hypothermia,surgery,severe burns—suppress insulin secretion.<br />2 antagonists—increases insulin<br />B2 antagonists—decreases insulin<br />HORMONES—GLP-1,GIP-inc insulin<br />Similarly gastrin,secretin,cholecystokinin,VIP,GRP,enteroglucagon<br />
  30. 30. Insulin secretion is BIPHASIC.<br />First phase—peak at 1-2 min,short lived.<br />Second phase-delayed onset,long duration.<br />Depends on intracellular calcium<br />Intracelular Ca—increased by phospholipase C by Ach,cholecystokinin<br />Inc c AMP-b adenylcyclase---GLUCAGON.<br />Insulin circulates in blood as monomer.<br />Distributed in ECF..<br />Aminoacid which causes secretion of insulin –arginine.<br />Glucokinase acts as glucose sensor.<br />Glucose conc <90mg/dl—no insulin release<br />
  31. 31. Rate of secretion in fasting—1U of insulin /hr into portal vein<br />Conc of insulin 2-4 ng/ml.50-10031U/ml-portal vein<br />Peripheral circulation—0.5ng/ml,12U/ml.<br />Goal of insulin therapy is to mimic this pattern –diificult to achieve with SC injection.<br />T1/2-insulin 5-6 min in normal subjects<br />Increased in diabetes <br />Proinsulin -17 min <br />C peptide -30 min serves as a marker of insulin secretion<br />
  32. 32. degradation<br />Liver,kidney,muscle<br />50% insulin that reaches liver is destroyed.<br />It is filtered by glomeruli-reabsorbed by tubules –degrade it<br />Renal function impairement appears to affect the rate of disappearance of circulating insulin to a greater extent than hepatic disease<br />Degraded in endosomes of liver.<br />Thiolmetalloproteinases in liver,muscle,kidney,brain<br />insulinase<br />
  33. 33. Functions of insulin<br />Globally—<br />Control of cellular intake of certain substance-glucose in muscle,adipose tissue.<br />Increase of DNA replication and protein synthesis<br />Modification of activity of numerous enzymes.<br />
  34. 34. Cellular level<br />Increased glycogen synthesis.<br />Increased fatty acid synthesis.<br />Increased esterification of fatty acids<br />Decreased proteolysis<br />Decreased lipolysis<br />Decreased gluconeogenesis<br />Decreased autophagy<br />Increased aminoacid uptake<br />Increased potassium uptake<br />Relaxes arterial muscle tone,increases blood flow-micro arteries<br />Increases HCL secretion in stomach.<br />
  35. 35. Types of insulin<br />20types of insulin products available in four basic forms,each with a different time of onset and duration of action.<br />Which to choose is individulaised<br />Choosing insulin depends on<br />Onset-how soon it starts working<br />peak time-when it works the hardest<br />Duration-how long it lasts in the body.<br />Obesity affects the work of insulin in the body.extra fat tissue –more resistant to insulin.<br />
  36. 36. Types of insulin<br />Five different types<br />Some are clear in appearance .,some are cloudy<br />RAPID ONSET-FAST ACTING INSULIN-novo rapid (insulin Aspart)<br />humalog (Lispro) <br /> SHORT ACTING INSULIN—actrapid,Humulin,hypurin neutral(bovine)<br />INTERMEDIATE ACTING INSULIN-cloudy—protamine or zinc added<br />Protamine—protaphane,humulinNPH.hypurinisophane<br />MIXED INSULIN—RAPID/INTERMEDIATE—novomix 30,humalog mix 25,mixtard 30/70,mixtard 20/80<br />30/70—30% is short acting,70% long acting<br />LONG ACTING INSULIN-lantus-(glargine).levemir(detemir)<br />
  37. 37.
  38. 38. Insulin sliding scale<br />Not recommended for subcutaneous injection <br />50U -50 ml NS <br />Every one hour until the blood glucose level stabilises<br />Rate of infusion adjusted as per blood sugar.<br /><120mg/dl-no insulin<br />120-200---2U/hr<br />200-300—3U/hr<br />300-500---5U/hr<br />>500---7U/hr<br /> -JAPI october 2007<br />
  39. 39. Somoygi phenomenon<br />Somogyi effect is a rebounding high blood sugar that is a response to low blood sugar.<br />It is due to counteracting hormones release –glucagon,adrenaline,cortisol<br />Frequent monitoring of blood glucose<br />Night dose to be low compared to morning dose.<br />
  40. 40. Dawns phenomenon<br />Early morning hyperglycemia without nocturnal hypoglycemia.<br />It is due to counter regulatory hormones<br />No need of insulin dose change.<br />
  41. 41. Increasing requirements<br />Infection,stress,puberty,pregnancy,acromegaly,cushings syndrome.<br />Lipohypertrophy at the site of injection<br />Malignancies<br />Compliance of the patient<br />
  42. 42. Decreaesing requirements<br />Impending renal failure<br />Honeymoon phase in type 1<br />Hypothyroidism<br />Addisons disease<br />Hypopituitarism<br />Remission of diabetes<br />
  43. 43. In renal disease<br />Half of the sliding scale of insulin dose to be given<br />As insulinase enzyme does not function<br />The duration of insulin action increases.<br />
  44. 44. Indications for insulin therapy<br />Type 1 diabetes<br />Women with diabetes who become pregnant or are breastfeeding<br />Transiently in type 2 diabetes in special situations- renal & hepatic disease, pancreatitis, HHS, during surgery, infections etc. <br />In type 2 diabetes, inadequately controlled on OADs<br />
  45. 45. Side effects of insulin use<br />Hypoglycemia<br />Weight gain<br />Locally-allergy<br /> infection<br /> abscess<br />anaphylaxis<br />
  46. 46. Insulin devices<br />Insulin syringes<br />Delivery pens<br />Insulin pumps<br />Insulin syringes—10ml insulin vials<br /> 30 unit—0.3 ml,50 unit-0.5 ml,100 unit-1ml<br />Needles -8mm to 13mm<br /> Use each syringe only once.<br />Insulin pen-insulin catridge-3ml-300units fits into the device<br /> Disposable, reusable<br /> Durable pens are—Novopen3,Novopen demi,Innovo and HumaPen<br /> Pre filed disposable devices –innolet,flexpen and Novolet.<br />
  47. 47. Insulin pumps-reservoir of insulin-infusion set<br /> worn outside the body—abdomen<br /> Only short or rapid acting insulin are used—mimics physiological pattern<br />Inhaled insulin<br />
  48. 48. Mode of administration<br />Subcutaneous<br />Intravenous<br />Inhaled<br />Intramuscular<br />
  49. 49. Subcutaneous injection<br />
  50. 50. Sites <br />Rotation of injection site to prevent lipohypertrophy.<br />Within one area.<br />Abdomen has fastest rate of absorption<br />Exercise increases<br />lipohypertrophydecreasees<br />Rate of absorption after IM is faster.<br />
  51. 51. Sites of injection<br />
  52. 52. syringes<br />1ml most common<br />26-31 guage needle<br />30 or 31 bend in single use<br />No sharing of needles<br />Reuse is widely practiced<br />Infection---poor hygeine,concurrent illness<br />
  53. 53. Insulin syringe and vial<br />
  54. 54.
  55. 55. Timing of insulin<br />30 min prior to meals <br />Not to exceed 30 min in case of rapidly acting insulins<br />Intermediate acting insulin –bed time.<br />
  56. 56. Insulin injection<br />Cloudy insulin gently rolled in between<br />Pen needs to be rotated upside down for at least ten times before using<br />Air of volume equal to dose of insulin should be injected in vial.<br />No use of alcohol may destroy silicon coating.<br />90 angle—thin 45  <br />Routine aspiration not needed<br />Embedded for 5 sec after complete depression--pens<br />
  57. 57.
  58. 58. Alternative routes—failed<br />Jet injectors—deliver high pressure stream of insulin.<br />Useful in lipoatrophy.<br />Transdermal<br />Iontophoresis<br />Low frequency ultra sound<br />Transferomes—phosphatidylcholine vesicles<br />50% SC efficiency<br />
  59. 59. Intranasal<br />Bioavailability is 8-15%<br />Nasal irritation is common<br />High rates of treatment failure.<br />Gelified nasal insulin <br />Oral<br />Enteric—limited bioavailability<br />Too large,hydrophilic<br />Only 0.5% reaches circulation<br />Buccal—aerosol solution<br /><ul><li>Pulmonary—large surface area—premeal delivery</li></ul>Lung cancer risk<br />
  60. 60.
  61. 61. Thank you<br />
  62. 62. Types of insulin<br />
  63. 63. Types of insulin and action<br />
  64. 64.
  65. 65. Regular insulin<br />Clear solution at neutral pH<br />0.4% zinc added-hexamers<br />Phenol or cresol-prevent growth of microorganisms<br />Onset of action within 15-30 min after SC<br /> max activity-120 -150 min<br />Action -6-8 hrs<br />Insulin to be given 30-40 min prior to meals<br />
  66. 66. indications<br />In case of type1 DM ,type 2 DM –DKA,HONK,Pregnancy,patients being taken up for surgery,acute illness.<br />Controls post prandial blood glucose levels when used with long acting insulins.<br />
  67. 67. NPH or isophane insulin<br />At hagedorn university in 1940.<br />Protamine added in 1:6 ratio to regular insulin<br />Phosphate buffer for neutral ph<br />Zinc ,cresol.<br />Peak of action at 5-7 hrs<br />Action lasts for 12-15 hrs.<br />Bed time to control FBS.<br />Cloudy.<br />
  68. 68. Lente insulin<br />Zinc in amounts 10 times to NPH<br />Acetate as buffer<br />Insoluble zinc insulin complexes<br />Semilente---amorphous,biphasic absorption<br />Ultralente—long acting crystalline suspension<br />Can’t be mixed with regular insulin. <br />
  69. 69. Premixed formulations<br />30:70<br />50:50<br />25:75<br />Regular and NPH insulin<br />
  70. 70. Rapidly acting insulins—insulin analogues<br />Analogous to keep insulin in monomeric form<br />Only change in aminoacid sequence at a particular point.<br />Action starts within 15 min after SC injection.<br />Peaks at 60-90 min<br />Over by 4 hrs<br />Post prandial excursions curtailed<br />No delayed hypoglycemia.<br />
  71. 71. Aspart<br />
  72. 72. Aspart<br /> by Novo Nordisk as Novolog or Novorapid<br />B28 ---proline is substituted by aspartic acid residue.<br />Increased charge repulsion—no hexamers<br />Components-<br />zinc-metal ion19.6g/ml<br />buffer-disodium hydrogen phosphate dihydrate1.25 mg/ml<br />Preservative-- m cresol 1.72mg/ml Phenol 1.50mg/ml<br />Isotoncity agent –glycerin and Nacl<br /> ph 7.2-7.6<br />
  73. 73. NovoRapid (Insulin Aspart )<br />Pro<br />Phe<br />Gly<br />Arg<br />Phe<br />Asp<br />Tyr<br />Glu<br />B20<br />Thr<br />Gly<br />Asp<br />Cys<br />Lys<br />B28<br />B30<br />Thr<br />Val<br />Asn<br />Cys<br />A21<br />Tyr<br />Leu<br />A1<br />Gly<br />Asn<br />Tyr<br />Ile<br />Glu<br />Leu<br />Val<br />Leu<br />Ala<br />Glu<br />Gln<br />Glu<br />Gln<br />Tyr<br />Val<br />Leu<br />Cys<br />Ser<br />Cys<br />Leu<br />Ile<br />Ser<br />Thr<br />Cys<br />His<br />Ser<br />Gly<br />Cys<br />Leu<br />B1<br />His<br />Gln<br />Asn<br />Val<br />Phe<br />
  74. 74. Lispro<br />
  75. 75. Lispro<br />Marketed by Eli Lilly—HUMALOG<br />First insulin analogue.<br />Penultimate lysine and proline residues on the Cterminal end of B chain are reversed---no change in receptor binding.<br />No formation of hexamers<br />Post prandial excursions are controlled.<br />
  76. 76. Glulisine<br />
  77. 77. Glulisine<br />Marketed by sanofiaventis. APIDRA<br />Asparagine is replaced by lysine at B3<br />Lysine replaced by glutamic acid at B29<br />3B-lysine-29B-glutamic acid-human insulin<br />
  78. 78.
  79. 79. Long acting insulin analogues<br />Steady basal insulin levels<br />Glargine –isoelectric at 7.4<br />Clear and soluble at acidic ph<br />Ppt after SC injection<br />Action >24 hrs<br />Detemir—fatty acid chain attached to it.<br />
  80. 80. Glargine<br />
  81. 81. Glargine<br />Marketed by sanofiaventis—Lantus<br />Resembles basal insulin secretion of non diabetic pancreatic beta cells.<br />Controls fast blood glucose.<br />Glycine for asparagine at A21 and two arginine added to carboxy terminal of B chain.<br />Formulated at acid pH—4.0<br />Hexamers at pH-7.4<br />Can be injected with I port<br />
  82. 82. Glargine<br />In 2009 there was conflicting and confusing data regarding the link of glargine insulin and cancer developing risk.<br />ADA –the avaailable data does not provide a cause for concern and that changes to the prescribing advice are therefore not necessary.<br />
  83. 83. Detemir<br />
  84. 84. C14 fatty acid chain<br />(Myristic acid)<br />Phe<br />Gly<br />Phe<br />Arg<br />Glu<br />Tyr<br />Thr<br />Gly<br />Pro<br />Cys<br />Lys<br />Val<br />Thr<br />Lys<br />Cys<br />Asn<br />A21<br />B29<br />Leu<br />Tyr<br />Gly<br />A1<br />Asn<br />Tyr<br />Ile<br />Glu<br />Leu<br />Val<br />Leu<br />Ala<br />Glu<br />Glu<br />Gln<br />Gln<br />Tyr<br />Val<br />Cys<br />Leu<br />Leu<br />Cys<br />Ser<br />Ser<br />Thr<br />Cys<br />Ile<br />His<br />Ser<br />Gly<br />Cys<br />Leu<br />Gln<br />His<br />Asn<br />Val<br />Phe<br />B1<br />Design of Insulin Detemir - 1<br />LysB29(N-tetradecanoyl)des(threonine)human insulin<br />Des-threonine myristic(mir) acid<br />
  85. 85. Detemir<br />Marketed by Novo Nordisk –LEVEMIR<br />Fatty acid myristic acid is bound to lysine aminoacid at B29.<br />quickly absorbed—binds to Albumin—complex<br />Better control of blood glucose levels<br />Appreciable decrease in HbA1c levels--<br />
  86. 86. levemir<br />Albumin binding: Makes Levemir therapy with a smooth and peakless profile throughout the day <br />
  87. 87. Time-action profile<br />Up to 24 hours <br />Predictability<br />lower within-patient variability than NPH and glargine<br />Glycaemic control<br />Better glycaemic control <br />Hypoglycaemia<br />Lesser hypoglycaemia compared with NPH & glargine<br />Weight<br />No undesirable weight gain shown in all studies<br />
  88. 88. Premixed analogue<br />Protamine insulin +rapidly acting analogues.<br />
  89. 89. Strength of insulin<br />40 U /ml –most widely used<br />WHO—all insulin across the globe to be U 100.<br />Storage<br />Refrigerated<br /><2 and >30 C<br />Excess agitation avoided<br />Used for > 1 month –may lose potency.<br />Away from sunlight.<br />
  90. 90. Mixing insulins<br />glargine is not mixed with any other insulin.<br />
  91. 91. Problems with syringes / vials<br />Cumbersome procedure<br />Difficult to transport and carry around<br />Inaccuracy in withdrawing the correct amount of insulin<br />Difficulty in mixing insulin<br />Insulin wastage<br />Stigma of injections and hence suggestion of ill-health<br />Needle passes a rubber membrane and losses sharpness-more pain <br />
  92. 92. Advantages with Devices<br />Simplicity - Simple to operate and inject<br />Accuracy - A new superior standard in dose accuracy<br />Reliability - High quality materials and finish<br />Discreeteness - Non-medical, non-syringe design<br />All-in-one - Pen + insulin cartridge + needles<br />Portability - Small & compact, robust carrying case - with space for extra needles and cartridge<br />
  93. 93. Device vs. Syringe<br />
  94. 94. Prefilled pen<br />Contain a built-in, single-use insulin cartridge <br />Loading<br />Require no loading by patient<br />Ease of use<br />Portable, durable, & lightweight delivery systems <br />patients who have difficulty handling the <br /> cartridges in reusable pens<br />persons with busy schedules<br />short - term therapy = GDM, Post-Surgery<br />Ease of disposal<br />are made of non-polluting plastic <br />it breaks down into naturally occurring substances when burned industrially<br />it can be safely landfilled<br />
  95. 95. FlexPen®<br />Easy to use<br /><ul><li>dialling dose; accurate / reliable
  96. 96. good control during injection
  97. 97. ‘can hear clicks’
  98. 98. minimal pressure required
  99. 99. can be administered with one hand</li></ul>Easy to read (white font on black)<br /><ul><li>numbers clearly visible
  100. 100. safer because mistakes less likely</li></ul>Convenient; pre-filled / no re-loading<br /><ul><li>easy to attach needles
  101. 101. easy to teach</li></ul>Portable and discreet<br /><ul><li>comes in carry case</li></li></ul><li>
  102. 102. FlexPen®<br />FlexPen® is a unique dial-a-dose insulin pen. You can dial doses from 1 to 60 units inincrements of 1 unit<br />
  103. 103. <ul><li>Single unit increment
  104. 104. Easy dial back
  105. 105. Large & easy to ready display
  106. 106. Max single dose-60 U
  107. 107. Virtually painless 31G needle </li></ul>FlexPen- Easy to use and teach<br />
  108. 108. Design Characteristic of FlexPen<br />The FlexPen is a disposable, prefilled insulin delivery device— there is no insulin cartridge to change. <br />The FlexPen is simply thrown away when the last of the insulin has been used, or at the end of the in-use time. <br />
  109. 109. FlexPen Prefilled syringes are available with three insulin analog preparations: Levemir, NovoRapid, and NovoMix 30.<br />Each FlexPen is named for the insulin it contains and is color branded for easy identification.<br />
  110. 110. <ul><li>LevemirFlexPen = identified by green push button
  111. 111. NovoMix 30 FlexPen = identified by Blue push button
  112. 112. NovoRapidFlexPen = identified by orange push button</li></li></ul><li>Durable pen<br />Patient has to insert an insulin cartridge into pen's delivery chamber <br />Flexibility<br />Allows greater flexibility for some patients<br />Changing types of insulin without needing to buy another pen if prescription changes<br />Ease of use<br />Durable and easy to use<br />Designed for longer duration of use.<br />With individual use - risk of infection is minimized<br />
  113. 113. NOVO NORDISK<br />
  114. 114.
  115. 115. Insulin dose calculation<br />Calculate total daily insulin TDI<br />0.5 *WEIGHT (KG) or sum of current doses<br />Ex—60 kg---30U.<br />Total meal time insulin—lispro,aspart,regular<br />60% 0f TDI<br />18U-----three divided doses—breakfast,lunch.dinner<br />Total basal insulin—NPH,glargine,ultrlente<br />40% of TDI<br />12U---bed time insulin<br />
  116. 116. Insulin dosage<br />DKA<br />Bolus dose—IV 0.1U/kg<br />IM-0.3U/kg<br />Then 0.1U/kg/hr<br />Mild episodes of DKA—short acting insulin analogues<br />IV regular insulin to be used in infusion until acidosis resolves <br />0.05-0.1U/kg/hr.<br />
  117. 117. Pre prandial insulin dose<br />INSULIN /CARBOHYDRATE ratio<br />1-1.5 U/10 gm of carbohydrate<br />Supplemental or correcting insulin—1Uof insulin for every 50mg/dl of glucose over the preprandial glucose target.<br />Ex<br />A 60kg male has FBG 0f 250 mg/dl,desired is 100mg/dl,the insulin dose is 60*(250-100)/1500<br />60(150/1500-----60*150/1500----6U<br />
  118. 118. Twice daily regimens<br />Long acting insulinNPH.regular insulin –morning,bed time.<br />2/3 of insulin in the morning<br />1/3 of insulin at bed time<br />To prevent nocturnal hypoglycemia.<br />FBG-prior evening long acting insulin<br />Pre lunch glucose—morning short acting insulin<br />Pre supper glucose-morning long acting insulin’<br />Bed time—pre supper short acting insulin.<br />Not an optimal regimen for 1 DM<br />
  119. 119.
  120. 120.
  121. 121. Continuous subcutaneous insulin infusion CSII<br />Very effective insulin regimen for type 1 DM<br />To the basal infusion,,a pre prandial insulin bolus is delivered by the device based on instructions from the patient—who uses an individualized algorithm incorporating the preprandial plasma glucose and anticipated carbohydrate intake.<br />Sophisticated device<br />Advantages:<br /> programmed dose<br /> basal infusion rates altered during exercise<br /> different doses of insulin can be matched based on meals<br />reqiures education of the patient and frequent interactions<br />Disadvantages---infection,hyperglycemia,DKA<br />Short acting insulin analogues are used.<br />SBMG<br />
  122. 122.
  123. 123.
  124. 124.
  125. 125. EXUBERA<br />
  126. 126. SEP 2006-OCT 2007<br />Powdered form of recombinant human insulin<br />Effective but no better than short acting insulin.<br />Discontinued because of poor sales.<br />Marketed by pfizer.<br />1mg-3U<br />Increment is not linear<br />1mg given subsequently is more insulin than 3 mg given once.<br />3mg—8U<br />May be associated with lung cancer<br /> not Cost effective<br />Mannkind --AFREZZA<br />
  127. 127. Drug interactions<br />Enhances blood glucose lowering effect---OAD,ACEI,disopyramide,fibrates,fluoxetine,MAOI,pentoxyfilline,propoxyphene,salicylates,sulphonamides.<br />Reduces blood glucose lowering effect—corticosteroids,danazol,diazoxide,diuretics,glucagon,isoniazid,etrogens,phenothiazine,somatropin,salbutamol.<br />
  128. 128. Thank you<br />sagittarian<br />
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