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Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
Pharmacotherapy of diabetes mellitus
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Pharmacotherapy of diabetes mellitus

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Treatment of diabetes mellitus with description of drugs

Treatment of diabetes mellitus with description of drugs

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  • Viz eyes , kidneys, nerves, heart and blood vessels. In nut shell diabetes can be defined as metabolic as well as vascular disorder.
  • Diagnosis of DM based on urine sugar is unreliable, when fasting plasma glucose is or random blood sugar is . On more than one ocassion
  • Marked increase in peripheral insulin resistance at receptor or post receptor level and increased hepatic glucose output GESTATIONAL DIABETES MELLITUS: FASTING > 126, PP > 140
  • Term origins from inselgerman word for islet/island.1869: Paul langerhans noticed clumps of cells scattered throughout the bulk of pancreas named them islets of langerhans
  • In spring of 1921 a canadian scientist Banting, asked JJR Macleod, professor of physiology to allow him to work in his lab , initially he was sckeptical but later on agreed alloweed him to use lab during summer vacation, supplied him with 2 10 dogs and 2 assistants but banting required only one assistant so flip of coin between charles best a medical student and clarknobel, best won it . So clark not only lost the flip but also the nobel
  • Biosynthesis of insulin takes place in two intermediate stages , preproinsulin and pro insulin. Synthesis of pre proinsulin takes place in endoplasmic reticulum which is cleaved by protease activity to proinsulin, Pre pro insulin is a single chain polypeptide containing 86 aminoacidsPre pro insulin -> proinsulin +  insulin + c peptide The resultant pro insulin is packaged in vesicles and transported to golgii apparatus. The cleavage of pro insulin occurs in golgii apparatus to insulin and c peptide by enzymes trypsin and carboxy peptidase B like activity. After removal of c peptide insulin co precipitates with zinc as microcrystals within secretory granules. Conversion of proinsulin to insulin takes 30 to 120 min , pre pro insulin to proinsulin 10 -20 min The yielding insulin has low solubilty and co-precipitates with zinc to form microcrystals within the secretory granule , insulin is associated into diamers and presence of zinc can associate into hexamers . Zinc hexamers are then packed together to form a crystal lattice2 atoms of zinc can complex with 6 atoms of insulin, human pancreas can contain upto 8 mg of insulin = 220 units 1mg = 28 U insulin
  • Structure of insulin was fully worked out by sanger in 1956 Insulin is a 2 chain polypeptide having 51 aminoacids and 6000 molecular weight There are minor differences between human pork & beef insulin , pork insulin differs from human insulin in 1 amino acid only , beef insulin differs in 3 amino acids at 8, 10, 30 positionsHuman TIT , PORK TIA, BEEF AVA. C peptide: facilitates the correct folding of A & B chains of insulin and also maintains the alignment of the disulfide bridge in the insulin molecule before its removal , insulin is extracted in liver where as C peptide is not therefore plasma level of c peptide is good indicator of insulin secretion, it also has some biological actions , ameliorates autonomic neuropathy, stimulates glucose transport in muscles, induces vascular smooth muscle dilation.
  • Recombinant insulin synthesized by using E coli was first isolated by hebertboyer in year 1977
  • OTHER STIMULANTS FOR INSULIN RELEASE INCLUDE AMINO ACIDS MAINLY ARGININE AND LEUCINE, FATTY ACIDS.
  • Or by its potency of inducing hypoglycemic convulsions
  • Islets richly supplied by sympathetic & vagal nerves PRIMARY CENTRAL SITE OF REGULATION OF INSULIN SECRETION IS HYPOTHALAMUS Ventrolaterl nuclei stimulate insulin releaseVentromedial nuclei – opposite effect
  • Glucagon evokes release of insulin as well as somatostatinInsulin inhibits glucagon secretion Somatostatin inhibits the release of both insulin and glucagon
  • The over all actions of insulin are to favour storage of fuel: glucose, fats & proteins through effects on liver, muscles and adipose tissue It also influences cell growth, and metabolic function of various tissues Excess secretion of insulin leads to hypoglycemia and deficient secretion leads to hyperglycemia
  • Depending on type of action Liver, adipose tissue & muscle
  • Increased storage of fuel ↑ Transport of glucose inside the cell except in tissues where glucose is the only source of energy like brain, RBC, WBC, MEDULLARY CELLS OF KIDNEY
  • INSULIN
  • Degraded in GIT if given orally Monomeric form insulin is easily difffusible and biologically active
  • Other proteins like proinsulin, other polypeptides, pancreatic proteins
  • Conventional insulin preparations derived from pork and beef pancreas, Prompt insulin Zn suspension(Semilente)Regular insulin has to be injected 2-3 times a day, so it has been modified by zinc or protamine to yield slow absorption and longer action. The protamine zinc insulin and lenteinsulins are no longer available commercialyNPH insulin does not contain either excess of zinc or protamine hence it can be mixed with regular insulin in any proportion immediately before use.
  • Conventional or standard preparations of insulin contain 1 % or more of other proteins (proinsulin, other polypeptides) which are potentially antigenic. In the 1970s the improved purification techniques were applied which resulted in availability of highly purified and practically non antigenic preparations Immunogenecity of pork MC insulin equivalent to human insulins where as single peak preparations still have significant immunogenecityThese preparations are more costly but have greater stabilty, less allergic reactions, less insulin resistance & lipodystrophy.
  • It is unwise to transfer stabilized patient from one species of insulin to other without any good reason, though it is desirable to employ human highly purified insulin in all diabetics, in developing countries conventional insulin preparations are still used due to economic reasons
  • The presently available insulins tend to form hexamers when stored. After SC administration this self associated hexamers dissociate into diamers and then monomers. The monomeric form is the active form of insulin. This sequence of events takes around 30 to 40 min resulting in slow rise & fall in insulin concentration compared to insulin secreted by the beta cells in response to eating. This results in high postprandial hyperglycemia and susceptibility to hypoglycemia particularly before next meal. Further in between the meals and at night the beta cells secrete insulin at a constant rateto maintain basal conc with a flat profile. The conventional isophane and lente preparations are not able to maintain constant basal conc of insulin. Hence presently available soluble insulin or intermediate acting insulin are not able to match the natural insulin profile that occurs post prandially and in post absorptive period. This has prompted the development of designer insulins which will have physiological action profile like normal insulin
  • First recommended DNA analogue approved by FDA in 1996Developed with the aim of improving glycemic control at meal times. This modification did not alter receptor binding, but blocked the formation of insulin dimer and hexamer. Thisallowed larger amount of active monomeric insulin to beavailable for postprandial or after meal, injections.USING REGIMEN OF 2-3 DAILY MEAL TIME INSULIN LISPRO INJECTIONS, A SLIGHLTLY GREATER REDUCTION IN HbA1c compared to regular insulin has been reported. Fewer episodes of hypoglycemia occurred
  • It remains soluble at ph 4 of formulation but precipitates at neutral ph encountered on SC injection , a depot is created from which monomeric insulin dissociates slowly to enter circulation.Onset is delayed but relatively low levels of insulin are maintained for upto 24 hrs, smooth peakless effect obtained, thus it is suitable for once daily injection to provide background insulin action
  • Local reactions: swelling, erythema, stinging , lipodystrophy and lipoatrophy not seen with newer preparations Allergy: infrequent due to contaminating proteins : urticaria, angioedema, anaphylaxis are the manifestations Edema: some patients develop short lived dependent edema due to sodium retention
  • Acute intake of Alcohol Precipitates hypoglycemia by depleting hepatic glycogenSalicylates, lithium, theophylline, may accenuate hypoglycemia By enhancing insulin secretion and increasing peripheral glucose utilization.
  • Many type II diabetics can be treated with exercise and controlled diet only
  • 0.4 to 0.8 U /Kg
  • Along with OHA –( SU / Metformin )
  • DKA is a complication of Type I DM very rare in NIDDM, The common precipitating factors are infection, trauma, stress, etc. Clinical features are anorexia, nausea, vomiting, polyuria, abdominal pain, hypotension, tachycardia, hyperventilation, altered consciousness or coma in untreated cases
  • ↑ Acetyl coA (substrate for ketone production)
  • Treatment of precipitating cause: infection, trauma, acute stress General measures: gastric aspiration, catheterization of urinary bladder, antibiotic cover
  • , hence IV infusion of isotonic saline should be started first after blood sample has been collected If serum sodium more than 150 mEq/L hypotonic saline is indicated When BSL reaches 250 mg% fluid should be changed to 5 % dextrose with concurrent insulin administration In order to avoid hypoglycemia, it takes time for acidosis to get corrected than blood glucose Care should be taken
  • With this regimen the plasma glucose level should fall at rate of 50 mg/hr it usually comes down to half the initial value in 6 to 8 hrs, if at the end of 2-3 hrs plasma glucose doesn’t show any predictable fall the doses od insulin infusion doubled 12 U/hr
  • In initial stage of treatment potassium not administered as in presence of acidosis there will be high potassium it begins to fall with tretment of DKA There is no definite guideline when to start potassium it can be started when urine output is good, potassium levels should be evaluated every 2 hrs or as necessary, tall T waves in ecg so ecg monitoring, ringer lactate and fructose should be avoided in DKA
  • Phosphates Serum phosphate changes similar to potassium May cause muscle weakness & lethargy Non availability of ideal preparationReplacement not very essential unless < 1 mEq/LSometimes potassium phosphate may be administered in place of KCL In absence of facilities to measure ph hurried respiration > 36 /min is clinical pointer to administer bicarboateWITH RESUMPTION OF ORAL FLUID MILK REPLINISHES THE PHOSPHATES RAPIDLY
  • Hormone sensitive lipase is concerned with mobilization of fatty acids Cvp Monitoring is necessary in this syndrome There is high mortality rate in HONK
  • Acute: develops rapidly & is of short duration , infection, trauma, emotional stress, corticosteroids , ketoacidosisChronic: generally seen in patients treated for years with conventional insulin preparations, antibodies to homologus contaminating proteins are formed which also bind insulin. Common in type II Development of such insulin resistance is an indicator to switch over to newer preparations
  • Long term effect with lungs unclear Cannot use if smoker, start smoking, or if you quit smoking less than 6 months ago Adaptation of dose unclear in smokers, asthma, pneumonia & COPD Inhalation devices clumsy bulky, fragile and/or weighty Larger dose necessary compared to SC insulin Difficult to achieve with pts on large doses of insulinNasal insulin was not successful because of variable absorption withdrawn from the US marketOral insulin preparation are under trial
  • Hepatic degradation of insulin is slowed Extrapancreatic actions: sensitize the target
  • I. SU binds to specific binding sites (SUR-1) on the pancreatic β-cell plasma membrane that are coupled to ATP – dependent K+ channelsII. Closure of ATP – dependent K+ channels & inhibition of efflux of K+III. Depolarization of the plasma membrane & opening up of L-type voltage dependent Ca2+ channelsIV. Influx of Ca2+ into the cytosolV. Stimulation of extrusion of both mature & immature insulin granules
  • DIRA – Duodenal Insulin Releasing Agent – a gut factor2 polar active metabolites
  • 2. Renal failure:serum creatinine: > 2 mgs% (Avoid Glibenclamide, chlorpropamide), > 3 mgs% (Avoid all SU)
  • The pharmacokinetics, the PPHG and overall glycaemic control make repaglinide suitable for administration preprandiallyMetabolised by liver Eliminated via the biliary routeWith the opportunity for flexible meal arrangements, including skipped meals, Without the risk of hypoglycaemia allow for flexible meal schedules
  • Little or no hypoglycemia in non diabetics even in diabetics the episodes of hypoglycemia to due to metformin are rare, they do not stimulate pancreatic beta cells
  • Do not cause insulin release but presence of some insulin is essential for their action Suppress hepatic gluconeogenesis & glucose output from liver : major action
  • Reduces FPG by 16 %Reduces PPG by 25 %Reduces all cause mortality by 36 %Action in Fasting & Prandial state.Better action in milder disease.No Hypoglycemias.
  • PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA RECEPTORS Reverse insulin resistance by stimulating GLUT 4 EXPRESSion and translocation and entry of glucoseThe first thiazolidinedione, ciglitazone, was synthesized in 1982(1). It was soon thereafter discovered that ciglitazone reduced insulin resistance in obese and diabetic animals. Because of their effects on insulin resistance, thiozolidinediones have been developed as pharmacological agents for the management of type 2 diabetes, although they were initially synthesized as potential lipid-reducing agents. Since their discovery, three thiozolidinediones have been introduced to the market in the U.S. : troglitazone (Rezulin), rosiglitazone (Avandia), and pioglitazone (Actos). In March 2000, troglitazone was withdrawn from the market because of liver toxicity. Reset glucose fatty acid cycle by reduction in circulating free fatty acids and by transcription of several genes that are imp for otimal insulin sensitivity as well as glucose and fat metabolism
  • [Note: Whether the adipogenic effects can be separated from those of increased insulin sensitivity is the subject of much research, particularly because of the role of obesity in this disease.] Pioglitazone and rosiglitazone can be used as monotherapy or in combination with other hypoglycemics or with insulin. The dose of insulin required for adequate glucose control in these circumstances may have to be lowered. The glitazones are recommended as a second-line alternative for patients who fail or have contraindications to metformin therapy.
  • FAILURE OF ORAL CONTRACEPTION CAN OCCUR WITH PIOGLITAZONE THERAPY, KETOCONAZOLE INHIBITS METABOLISM OF PIOGLITAZONE Duration of effect lasts more than 24 hours
  • Suppresses & Prevents TNF alfa
  • Thus slows down digestion and absorption of polysaccharides In diabetics also reduces cardiovascular events, Acarbose is not hypoglycemic drug, may be used as adjuvant to diet in type II DM with or without sulfonylurea in obese diabetics Can be used as monotherapy in early type ii diabetes, and with sulfonylureas in obese type II diabetes.
  • Flatulence, diarrhoea, abdominal pain: due to fermentation of undigested carbohydrates in lower GIT
  • Glucagon like peptide I is a hormone released from intestinal L cells in response to orally ingested nutrients. The GLP I hormone is an incretin hormone which has got potent antihyperglycemic action by amplifying nutrient insulin secretion, it is advantageous as this hormone will not produce hypoglycemia when administered, GLP-I is administered subcutaneously is susceptible for enzymatic degradation by dipeptidyl peptidase IV(DPP-IV) , this has prompted the researchers to develop GLP-I analogs which are resistant to DPP-IV degrdationIs released from L cells in ileum and colon– Stimulates insulin response From β cells in a glucose dependent manner– Inhibits gastric emptying– Reduces food intake and body weight– Inhibits glucagon secretion from α cells in a glucose- dependent manner– Effect on β-cell turnover in preclinical models
  • Current indication as an additional drug with metformin or SU in type II diabetics who have inadequate response to oral hypoglycemics
  • Prevents degradation of endogenous GLP-I potentiating there action Undergoing trial as an add on drug for treatment of type II DM with SU/Metformin
  • Amylin: a polypeptide produced by pancreatic beta cells which reduces glucagon secretion from alpha cells and delays gastric emptying Duration of action is 2-3 hours, has been marketed as an adjuvant to insulin, SU, Metformin, for control of meal time glycemia in both type I and type II diabetics.
  • Lean impaired renal function Secretagogues (short acting SU)--No control TZD or GLP Over weight with impaired hepatic function give secretagogue if suboptimal control Suboptimal controlBasalInsulin
  • Transcript

    • 1. Pharmacotherapy of Diabetes Mellitus <br />Dr Naser Ashraf Tadvi<br />Associate Professor <br />Kamineni Institute of Medical Sciences <br />Narketpally, Nalgonda <br />
    • 2. Diabetes<br />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<br />Diabetes causes long term damage, dysfunction & failure of various organs <br />
    • 3. Diagnosis of diabetes <br />Fasting Plasma Glucose ≥ 126 mg / dl<br />Symptoms of DM and a random blood glucose level of ≥ 200 mg/dl<br />Oral glucose tolerance test<br />2 hr after 75 gm glucose load ≥ 200 mg / dl<br />
    • 4. Classification of DiabetesProposed by ADA - 1997.<br />Type I: <br />Absolute Insulin Deficiency due to islet cell destruction <br />Either immune mediated or idiopathic <br />Type II: <br />Relative insulin deficiency due to impaired -cell function <br />Marked ↑ peripheral insulin resistance<br />Type III: Other Specific types<br />Type IV:Gestational Diabetes<br />
    • 5. Other specific types<br />A) Genetic defects of Beta cell function<br />B) Genetic defects in Insulin action<br />C) Diseases of the Exocrine Pancreas<br />D) Secondary to Endocrinopathies<br />E) Drugs / Chemical induced <br />F) Infections<br />G) Uncommon form of Immune Mediated Diabetes.<br />H) Other Genetic Syndromes associated with Diabetes<br />MODY Syndromes<br />Lipo atrophic Diabetes<br />FCPD<br />Pancreatitis<br />Trauma<br />Neoplasia<br />Cystic Fibrosis<br />Hemochromatosis<br />Acromegaly<br />Cushings Syndrome<br />Pheochromocytoma<br />Hyperthyroidism<br />Steroids<br />Thiazides<br />Diazoxide<br />Beta Blockers<br />Thyroid Hormones<br />Congenital Rubella<br />CMV<br />Anti insulin Receptor Antibodies<br />Down’s Syndrome<br />Turners<br />Klinefelters<br />
    • 6.
    • 7. Type 2 Diabetes <br />
    • 8. β cells : insulin 65-70 %<br />cells : glucagon 25 %<br />δcells : somatostatin10 % <br />PP (or F cells): pancreatic polypeptide 2 % <br />
    • 9. Physiology of Human Insulin<br />Beta cell statistics<br /><ul><li>Only 2% of the pancreas weight is endocrine. 98 % Exocrine
    • 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
    • 15. 1 unit Insulin 8-10 gm. Glucose</li></li></ul><li>Insulin <br />
    • 16. Discovery of insulin <br />
    • 17. The Miracle of Insulin<br /> Patient leonardthomson.,, February 15, 1923<br />December 15 1922<br />
    • 18. Biosynthesis of insulin <br />Preproinsulin<br />Proinsulin<br />Insulin<br />
    • 19. Structure of insulin <br />21 amino acids <br />30 AA<br />
    • 20. Difference between human, pork, beef insulin <br />
    • 21.  Cell at rest <br />
    • 22. Secretion of insulin <br />> 70 mg/ml<br />GLUT 2<br />
    • 23. Bioassay of insulin <br />1 IU reduces the BSL to 45 mg/dl in fasting rabbits <br />1 mg insulin = 28 IU<br />Can also be measured by radioimmunoassay or enzyme immunoassay <br />
    • 24. Regulation of insulin secretion<br /><ul><li>Direct stimulation
    • 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
    • 30. Sympathetic NS inhibits insulin release through 2 receptor activation </li></li></ul><li>
    • 31. Actions of insulin <br />Intermediary actions <br />Rapid actions <br />Long term<br />Sec / min <br />Few hours <br />> 24 hrs <br /><ul><li>↑ multiplication
    • 32. ↑ differentiation of cells
    • 33. Imp role in intrauterine & extrauterine growth </li></ul>Through DNA<br />e.g<br /><ul><li> ↑ GLUT synthesis
    • 34. Synthesis of enzymes for AA metabolism </li></ul>E.g Metabolic actions <br />
    • 35. Actions of insulin <br />Metabolic: <br /> carbohydrate, lipid , protein, electrolyte<br />Vascular <br />Anti-inflammatory <br />Fibrinolytic<br />Growth <br />Steroidogenesis<br />
    • 36. Carbohydrate metabolism <br />Over all action of insulin is to ↓ glucose level in blood <br />↑ Transport of glucose inside the cell<br />↑ Peripheral utilization of glucose <br />↑ Glycogen synthesis<br />↓ Glycogenolysis<br />↓ Neoglucogenesis<br />
    • 37. Lipid metabolism<br />↓ Lipolysis<br />↑ Lipogenesis<br />↑ Glycerogenesis<br />↓ Ketogenesis<br />↑ Clearance of VLDL & chylomicrons from blood through enzyme Vascular Endothelial Lipoprotein Lipase<br />
    • 38. Protein metabolism <br />Protein synthesis <br />↑ entry of amino acids in cells <br />Electrolyte metabolism <br /><ul><li>↑ transport of K+, Ca++, inorganic phosphates </li></li></ul><li>Other actions <br />Vascular actions: <br />Vasodilation ? Activation of endothelial NO production <br />Anti-inflammatory action<br />Especially in vasculature <br />Decreased fibrinolysis<br />Growth<br />Steroidogenesis<br />
    • 39. <ul><li>Glucose transporters –
    • 40. GLUT 1 </li></ul> Non insulin mediated glucose uptake<br /><ul><li>GLUT 3
    • 41. GLUT 2 – Beta cell – Glucose sensors
    • 42. GLUT 4 – Insulin mediated glucose uptake in </li></ul> muscle & Adipose tissue <br />
    • 43. Mechanism of action of insulin <br />
    • 44. Insulin molecule<br />INS<br />Insulin Mediated Glucose Transport<br />Insulin<br />Receptor<br />Complex<br />a subunit<br />a<br />a<br />Tyrosine Kinase Activation<br />b<br />b<br />b subunit<br />Metabolised<br />Stored as Glycogen<br />Glucose<br />b<br />b<br />INS<br />a<br />a<br />G<br />Storage vesicle<br />containing<br />GLUT 4<br />
    • 45. Fate of insulin <br />Distributed only extracellularly<br />Must be given parenterally<br />Addition of zinc or protein decreases its absorption & prolongs the DOA <br />Insulin released from pancreas is in monomeric form<br />Half life of insulin = 5 -9 minutes <br />
    • 46. Different types of insulin preparations <br />Conventional preparations of insulin <br />Produced from beef or pork pancreas <br />1 % of other proteins<br />Potentially antigenic <br />Highly purified insulin preparations <br />Gel filtration reduces proinsulin (50-200PPM) <br />Human insulins<br />Newer insulin analogs <br />
    • 47. Conventional insulin preparations <br />
    • 48. Highly purified insulin preparations <br />Single peak insulins<br />Purified by gel filtration contain 50 to 200 PPM proinsulin<br />Actrapid: purified pork regular insulin <br />Monotard: purified pork lente<br />Mixtard: purified pork regular(30%) + isophane(70%)<br />Mono component insulins<br />After gel filtration purified by ion exchange chromatography contain 20 PPM proinsulin<br />Actrapid MC, Monotard MC <br />
    • 49. Human insulins<br />Human (Actrapid, monotard, insulatard, mixtard)<br />Obtained by recombinant DNA technology <br />Advantages<br />More water soluble as well as hydrophobic <br />More rapid SC absorption , earlier & more defined peak <br />Less allergy <br />Disadvantages <br />Costly <br />Slightly shorter DOA <br />
    • 50. Indications of human insulins<br />Insulin resistance <br />Allergy to conventional preparations <br />Injection site lipodystrophy<br />During pregnancy <br />Short term use of insulin<br />
    • 51. Newer Insulin analogs <br />
    • 52. Insulin Lispro<br />Produced by Inversing proline at B28 with lysine at B29. <br />Forms weak hexamers , dissociate rapidly <br />Needs to be injected immediately before, during or even after meals <br />Better control of meal time glycemia & lower incidence of PP hypoglycemia <br />
    • 53. Insulin aspart:<br />Proline at B28 replaced by aspartic acid <br />Change reduces tendency for self aggregation <br />Insulin glulisine<br /> lysine replaces aspargine at B3 & glutamic acid replaces lysine at position B29<br />
    • 54.
    • 55.
    • 56. Insulin glargine<br />Prepared by adding 1 glycine at A21 together with 2 arginine residues at end of B chain <br />Improved Stability<br />Much better bioavailabilty <br />Smooth peakless effect is obtained <br />Fasting & interdigestive BGL effectively lowered irrespective of time of day <br />Lower hypoglycemic episodes<br />Cannot be mixed with other insulins<br />
    • 57. Insulin detemir<br />Soluble long acting basal insulin analog with flat action profile and prolonged duration <br />Threonine in B30 ommited & C14 fatty acid chain attached to amino acid B29 <br />Prolonged action<br />Strong self association <br />Albumin binding<br />Fatty acid side chain<br />
    • 58. Aspart, glulisine, lispro 4–5 hours<br />Regular 6–8 hours<br />NPH 12–16 hours<br />Detemir ~14 hours<br />Ultralente 18–20 hours<br />Glargine ~24 hours<br />2<br />5<br />3<br />4<br />6<br />7<br />8<br />9<br />12<br />13<br />14<br />15<br />16<br />17<br />18<br />19<br />20<br />21<br />22<br />23<br />24<br />0<br />1<br />10<br />11<br />Action Profiles of Insulins<br />Plasma<br />insulin<br />levels<br />Hrs<br /> Danne T et al. Diabetes Care. 2003;26:3087-3092<br />
    • 59. Insulin analogs score over conventional insulins<br /><ul><li>Less nocturnal hypoglycemia
    • 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
    • 67. Improved predictability, tolerability, and flexibility </li></li></ul><li>Adverse effects of insulin <br />Hypoglycemia <br />Local reactions <br />Lipodystrophy<br />Lipoatrophy<br />Allergy <br />Obesity<br />Insulin induced edema <br />
    • 68. Drug interactions of insulin <br />Non selective beta blockers <br />Thiazides,furosemide, corticosteroids, OCP , nifedipine↑ BSL<br />Alcohol Precipitates hypoglycemia <br />Salicylates, lithium, theophylline, may accenuate hypoglycemia <br />
    • 69. Uses of insulin <br />Diabetes mellitus <br />Must for type I diabetics <br />Can be used in type II diabetics <br />Diabetic ketoacidosis<br />Hyperosmolar non ketotic hyperglycemic coma <br />
    • 70. Indications of insulin in type II DM<br />Primary or secondary failure of oral hypoglycemics<br />Pregnancy<br />Perioperative period <br />CKD<br />Steroid therapy<br />LADA<br />Fasting > 300 mgms HbA1c > 10<br />Unintentional wt loss with or with out ketosis<br />Type 2 with DKA ( severe beta cell dysfunction)<br />
    • 71. Recommended sites for S/C Insulin injections<br />
    • 72. Initial Insulin dosage in T1DM <br /><ul><li>0.5 U/kg/day with negative to moderate ketones
    • 73. 0.7 U/kg/day with large ketones</li></li></ul><li>Clinical case<br /><ul><li>14 yrs old, Chitra
    • 74. 3Ps & weight loss – 10 days duration
    • 75. RBS 418 mg %
    • 76. 36 kg wt
    • 77. No marked dehydration
    • 78. T1DM- No ketoacidosis
    • 79. Proceed?</li></li></ul><li>Insulin dose for this child<br /><ul><li>(0.5 U/kg/day with negative to moderate ketones)
    • 80. 36 kg wt
    • 81. No ketoacidosis
    • 82. 36 X 0.5 = 18 U/day</li></li></ul><li>18 U/day as“Four-shot-per-day”<br /><ul><li>Basal-Bolus therapy
    • 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)</li></ul>3U Prebreakfast<br /> 3U Prelunch<br /> 3U Predinner<br />
    • 86. 18 U/day as“Five-shot-per-day”<br /><ul><li>Basal-Bolus therapy
    • 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)</li></ul>3U Prebreakfast<br /> 3U Prelunch<br /> 3U Predinner<br />
    • 90. 18 U/day as “Two-shot-per-day”<br />Split mixed regimen <br /><ul><li>2/3 prebreakfast (12 U)
    • 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</li></ul> “8 N/4 R - 0 - 3N/3R” <br />
    • 94. 18 U/day as “Three-shot-per-day”<br /><ul><li>2/3 prebreakfast (12 U)
    • 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
    • 98. 3 U NPH at bedtime</li></li></ul><li>How to initiate insulin treatment in type 2<br /><ul><li>Start with 0.2 units / kg (or)
    • 99. Body weight divided by 5 (or)
    • 100. Dose = FBS-50 (or) 10
    • 101. Average fasting blood sugar divided by 18</li></li></ul><li>Continuous I.V. insulin infusion<br /><ul><li>Admit the patient
    • 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
    • 107. 80% (30 U/day) used as outpatient therapy </li></li></ul><li>Pathogenesis of DKA <br />Insulin deficiency Absolute / relative <br />+<br />Counter hormone excess<br />↓ Anabolism <br />↑ catabolism<br />↑ Glycogenolysis↑ Glycolysis ↑Gluconeogenesis<br />↓Peripheral utilization of Glucose<br />Hyperglycemia<br />Dehydration<br />↓ Fluid intake<br />Heavy Glucosuria (osmotic diuresis)<br />Loss of water & electrolytes<br />Hyperosmolarity<br />
    • 108. Pathogenesis of DKA (How ketoacidosis occurs) <br />Hyperketonemia<br />↑ Lipolysis<br />↑ FFA to liver<br />↓ Alkali reserve<br />↑ Acetyl coA<br />Acidosis <br />↑ AcetoacetylcoA<br />-Hydroxy butrate<br />Acetoacetate<br />Acetone <br />
    • 109. Treatment of DKA <br />Fluid therapy <br />Rapid acting regular insulin <br />Potassium <br />Bicarbonate <br />Phosphate <br />Antibiotics <br />Treatment of precipitating cause<br />General measures<br />
    • 110. Fluid therapy <br />Adequate tissue perfusion is necessary insulin action <br />Normal saline is fluid of choice for initial rehydration <br />1 litre in first hour <br />Next 1 L in next 2 hours <br />2 litres in next 4 hours <br />2 litres in next 8 hours <br />i.e 4 to 6 litres in 24 hours <br />When BSL reaches 300 mg% fluid should be changed to 5 % dextrose with concurrent insulin <br />
    • 111. Insulin in DKA <br />Regular/ short acting insulin IV treatment of choice <br />Loading dose = 0.1-0.2 U/kg IV bolus <br />Then 0.1 U /kg/hr IV by continuous infusion<br />Rate doubled if no significant fall in BSL in 2 hr<br />2-3 U/hr after BSL reaches 300mg%<br />If patient becomes fully conscious encouraged to take oral food & SC insulin started <br />
    • 112. Potassium replacement <br />In initial stage of treatment potassium not administered because in DKA it remains normal or ↑<br />In presence of insulin infusion Sr potassium ↓ hence 10 mEq/L potassium can be added with 3rd bottle of normal saline <br />Sr K+ < 3.3 mEq/L : 20 -30 mEq/hr <br />
    • 113. Bicarbonates & phosphates <br />Bicarbonates <br />If blood pH > 7.1 no need of sodium bicarbonate <br />In presence of severe acidosis 50 mEq of sodium bicarbonate added to IV fluid <br />Phosphates <br />Non availability of ideal preparation<br />Replacement not very essential unless < 1 mEq/L<br />potassium phosphate 5-10 m mol/hr <br />
    • 114. Hyperosmolar Non Ketotic Coma <br />Usually occurs in type II <br />Dehydration with severe hyperglycemia without ketoacidosis, because insulin inhibits hormone sensitive lipase <br />The general principle of T/t is same as for DKA except that pt needs more faster fluid replacement <br />Half NS preferred 2 Lit in 2 Hrs followed by 1 Lit in next 2 hrs<br />Low dose heparin to prevent vascular thrombosis & intravascular coagulation <br />
    • 115. Insulin resistance <br />State in which normal amount of insulin produces subnormal amount of insulin response <br />↓ insulin receptors <br />↓ affinity for receptors <br />May be acute or chronic <br />Requirement of > 200 Units of insulin per day in absence of stress <br />Common in type II diabetics & obese <br />
    • 116. Newer insulin delivery devices <br />Prefilled insulin syringes <br />Pen devices <br />Jet injectors <br />Inhaled insulin <br />Insulin pumps <br />External artificial pancreas <br />Insulin complexed with liposomes: intraperitoneal, rectal, oral <br />
    • 117. 40 units/ml<br /> 100 units/ml<br /> Tuberculin syringe <br />
    • 118.
    • 119. PEN INJECTORS<br /><ul><li>Easy to carry
    • 120. Easier to accurately measure dose
    • 121. more expensive than vials</li></ul>JETINJECTORS<br /><ul><li>Needleless system.
    • 122. Uses high pressure air to force a tiny</li></ul> stream of insulin through the skin<br />
    • 123. Insulin Pump<br /> Pro<br /><ul><li>Simplified insulin dosing
    • 124. Precise delivery
    • 125. Greater impact in those with highest starting A1c
    • 126. Slightly less insulin use per day</li></ul> Con<br /><ul><li>More DKA
    • 127. More severe hypoglycemia</li></li></ul><li> Inhaled Insulin (Exubera) <br /><ul><li>Advantages
    • 128. Improved pt convenience
    • 129. Faster onset of action compared to Regular SC insulin
    • 130. No needles risk of infection
    • 131. Potential earlier onset of insulin therapy in Type 2 DM</li></li></ul><li>Oral antidiabetic drugs <br />Sulfonylureas:<br />Meglitinides: <br />Biguanides :<br />Thiazolidinediones:<br />-glucosidase inhibitors:<br />
    • 132. Sulfonylureas<br />I Generation<br />Tolbutamide<br />Chlorpropamide<br />II Generation<br />Glipizide<br />Gliclazide<br />Glibenclamide (Glyburide) <br />Glimepiride<br />
    • 133. Mechanism of action <br />Release of insulin by acting on SUR1 receptors <br />Primarily augment phase 2 of insulin secretion<br />Presence of at least 30% functional -cells essential for their action.<br />Minor action: ↓ glucagon secretion <br />Extra pancreatic action: ↑sensitivity of peripheral tissue to insulin by ↑insulin receptors <br />
    • 134.
    • 135. Pharmacokinetics <br />Well absorbed orally <br />Highly bound to plasma proteins > 90% <br />Have low volume of distribution <br />Cross placenta C/I in pregnancy <br />Metabolized in liver<br />Excreted in urine <br />
    • 136. Daily dose & Duration of action <br />
    • 137. Individual Sulfonylurea <br />
    • 138. GLIMEPIRIDE<br />Lesser risk of hypoglycemia<br />Insulin sparing effect (Significant extra pancreatic effects)<br />Relatively safe in elderly and mild renal failure<br />Antiplatelet and antifibrinolytic activity<br />Little or no weight gain<br />FDA approved combination therapy with insulin<br />Safe and effective for use in the pediatric population<br />↑Levels of plasma adiponectin & ↓ TNF α<br />Stimulates GLUT4 expression<br />
    • 139. Why Glibenclamide is more potent and longer acting than other SU<br />1. May accumulate within  cells and directly stimulate exocytosis of insulin granules<br />2. Greater/longer binding to SUR-1 receptors<br />3. Slower absorption and distribution<br />4. Inhibition of hepatic insulinase<br />5. Suppressionof several counter-regulatory hormones<br />6. More suppression of HGO<br />7. May stimulate insulin synthesis<br />
    • 140. Adverse effects <br />Hypoglycemia:<br />GI disturbances: Nausea, vomiting, metallic taste, diarrhoea & flatulence <br />Weight gain <br />Hypersensitivity <br />Not safe in pregnancy <br />Chlorpropamide:<br />cholestatic jaundice, dilutionalhyponatremia, antabuse reaction<br />
    • 141. Contraindications <br />Allergy to SU<br />Renal failure:<br />3. Significant hepatic dysfunction<br />4. Severe infections, stress, trauma, major surgery, CVA, AMI<br />5. Pregnancy (except Glibenclamide)<br />6. T1DM<br />
    • 142. Drug interactions <br />Drugs that ↑ SU action <br />Salicylates, sulfonamides <br />Cimetidine , warfarin, sulfonamides <br />Propranolol<br />Drugs that ↓ SU action <br />Phenytoin, phenobarbitone , rifampicin<br />Corticosteroids, thiazides, furosemide, OCP <br />
    • 143. Selection of SU<br />
    • 144. SU + other antihyperglycemic agents<br /><ul><li> SU + Metformin (best)
    • 145. SU + Glitazones (best)
    • 146. SU + AGI (better)
    • 147. SU + 2 or more drugs (good)
    • 148. SU + Insulin (good)
    • 149. SU + Meglitinides (bad)
    • 150. SU + SU (worst) </li></li></ul><li>Meglitinide analogs <br />Quick & short acting insulin releasers <br />MOA: same as Sulfonylureas but act through different receptor SUR2 <br />Mainly used to control Post prandial hyperglycemia <br />Less hypoglycemia <br />
    • 151. Repaglinide<br />Well tolerated in elderly patients in renal impairment<br />Adverse effects: <br />Mild headache, dyspepsia, arthralgia, headache <br />Indicated in type II DM <br />Dose : start 0.5mg with meals can ↑ 16mg/day<br />
    • 152. Nateglinide<br />Stimulates first phase of insulin secretion <br />More rapid acting & shorter duration than repaglinide<br />Mainly used in post prandial hyperglycemia without producing late phase hypoglycemia <br />Little effect on fasting BSL <br />Adverse effects: diziness, nausea, flu like symptoms <br />Dose: 60 to 180 mg TDS with meals <br />
    • 153. Biguanides<br />Metformin & phenformin<br />Little or no hypoglycemia<br />Also improves the lipid profile in type II diabetic patients <br />Metformin dose = 0.5 to 2.5 g/day in 2-3 divided doses <br />
    • 154. Mechanism of action <br />Suppress hepatic & renal gluconeogenesis<br />↑ uptake & utilization of glucose by skeletal muscles which reduces insulin resistance <br />Inhibit alimentary absorption of glucose<br />Interfere with mitochondrial respiratory chain & promote peripheral glucose utilization by enhancing anaerobic glycolysis<br />
    • 155. Pharmacokinetics <br />Taken orally , well absorbed through GI tract <br />Not metabolized at all <br />Excreted unchanged in urine <br />
    • 156. METFORMIN - INDICATIONS<br /><ul><li>Obese Type 2 Diabetes.
    • 157. Secondary Sulfonylurea Failure state.
    • 158. To reduce Insulin requirements.
    • 159. Can be combined with Sulfonylureas, Glitazones, Insulin.</li></li></ul><li>Adverse effects <br />Anorexia, nausea, vomiting, diarrhoea<br />Metallic taste <br />Loss of weight <br />Skin rashes <br />Lactic acidosis: rare <br />Vitamin B12 deficiency: due to malabsorption<br />Usually does not cause hypoglycemia even in large doses <br />
    • 160. Contraindications of metformin<br />Renal failure – <br />( Sr. Crt > 1.5 / Crt. Clearance < 40 <br />Advanced Liver Disease.<br />Alcohol abusers.<br />Cardiac Disease.<br />Pregnancy.<br />
    • 161. Thiazolidinediones (Glitazones) <br />Rosiglitazone & pioglitazone <br />Selective agonists of PPAR<br />Bind to nuclear PPAR<br />Activate insulin responsive genes - regulate carbohydrate & lipid metabolism <br />Sensitize the peripheral tissues to insulin <br />↓blood glucose by <br />Inhibit hepatic gluconeogenesis<br />Promote lipogenesis<br />↑ Glucose transport into muscle & adipose tissue <br />
    • 162. Thiazolidinediones<br />Hyperglycemia, hyperinsulinemia, and elevated HbA1c levels are improved. <br />Pioglitazone has no effect on LDL levels, ↓ triglyceride & ↑ HDL <br />Rosiglitazone has inconsistent effect on lipid profile it ↑ HDL & LDL levels<br /> The TZDs lead to a favorable redistribution of fat from visceral to subcutaneous tissues. <br />
    • 163. Pharmacokinetics <br />Both Rosiglitazone & pioglitazone are completely absorbed from GIT <br />Highly bound to plasma proteins (>95%) <br />Rosiglitazone metabolized by CYP2C8, Pioglitazone metabolized by CYP2C8 & CYP3A4<br />Drug interactions less with rosiglitazone<br />Metabolites of rosiglitazone are excreted in urine and those of pioglitazone in bile <br />
    • 164. Pioglitazone: <br />15 to 45 mg once daily orally <br />Rosiglitazone: <br />4 to 8 mg once daily orally<br />Pt who benefit most are type II DM with substantial amount of insulin resistance<br />Also used in PCOD <br />Monotherapy – Hypoglycemia rare <br />Add-on Therapy – readjust dosage.<br />Takes one month to act<br />
    • 165. Adverse effects <br />Weight gain: due to fluid retention & edema <br />↑ Extracellular fluid volume <br />Worsening of CHF <br />↑ Deposition of subcutaneous fat <br />Mild anemia: due to hemodilution<br />Hepatotoxicity : rare <br />Rosiglitazone: ↑risk of fractures especially in elderly women <br />
    • 166. Contraindications <br />Liver disease <br />Congestive heart failure <br />Pregnancy <br />Lactating mother <br />Children <br />
    • 167. Alpha glucosidase inhibitors<br />Acarbose<br />Miglitol<br />Voglibose<br />
    • 168. Pancreatic amylase<br />Oligosaccharides/ Disaccharides<br />Maltose, Isomaltose, Sucrose<br /> glucosidase enzymes (in the lining of cells of intestinal villi)<br />Monosaccharides<br />(Glucose, fructose)<br />Absorbed in lower part of intestine<br />Mechanism of action<br />Dietary Carbohydrates (Starch)<br />Glucosidase inhibitors<br />X<br />104<br />
    • 169. Acarbose<br />Complex oligosaccharide <br />Inhibits -glucosidase as well as -amylase <br />Reduces postprandial hyperglycemia without increasing insulin levels<br />Regular use reduces weight <br />In prediabetics reduces occurrence of type II DM, hypertension & cardiac disease<br />Dose: 50 to 100 mg TDS <br />Given just before food or along with food <br />
    • 170. Adverse effects <br />Flatulence, diarrhoea, abdominal pain<br />Do not cause hypoglycemia by themselves but may cause if used with Sulfonylureas<br />If hypoglycemia occurs should not be treated with routine sugar (sucrose),<br />Glucose should be used <br />Contraindicated in inflammatory bowel disease & intestinal obstruction <br />
    • 171. Voglibose<br /><ul><li>Advantages over Acarbose and Miglitol
    • 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 mg</li></ul>107<br />
    • 177. Newer drugs for Type II DM<br />GLP-1 Analogues<br />Exenatide<br />Liraglutide<br />DPP-IV Inhibitors<br />Sitagliptin<br />Vildagliptin<br />Alogliptin<br /><ul><li>Amylin analog:
    • 178. Pramlintide</li></li></ul><li>Exenatide<br />Synthetic GLP I analogue resistant to DDP IV <br />↑ Post prandial insulin release<br />Supresses glucagon release <br />Supresses appetite and slows gastric emptying<br /> injected SC twice daily 1 hour before meals acts for 6 to 10 hours <br />Nausea is important side effect <br />
    • 179. Sitagliptin<br />Orally active inhibitor of DPP-4 <br />Prevents degradation of endogenous GLP-I<br />Dose: 100mg a da<br />Mainly used in post prandial hyperglycemia <br />No action on weight and lipids <br />Costly <br />
    • 180. Pramlintide<br />Synthetic amylin analog<br />Improves overall glycaemic control,↓ PPG<br />Reduces BW : anorectic action <br />Well tolerated <br />Given SC before meals <br />SE: GI disturbances/Less hypoglycemia when used alone<br />Can be used in type I DM <br />
    • 181. Principles of treatment of Type 2 DM<br />Grade Diabetes Mellitus as mild, moderate or severe <br />NB: FBG (150 -200 ---mild ) HbA1c < 8 <br /> ( 200-250 --- Moderate) HbA1c 8 - 9<br /> ( more than 250 severe) HbA1c 9 - 10<br />For severe DM start on insulin if there is wt loss & ketosis<br />For mild & moderate DM use metformin if obese & sulfonylureas if not obese <br />
    • 182. Principles of treatment of Type 2 DM<br /><ul><li>Classify obese non obese
    • 183. Assess Liver function is normal or abnormal
    • 184. Assess the kidney function </li></li></ul><li>
    • 185. If diabetes not controlled<br /> <br /> Look for SU failure <br /> <br />     Occult infection – TB – UTI<br /> <br />     Drug history and compliance<br /> <br />    Food history – hypoglycaemia<br /> and compliance <br /> <br />
    • 186.  <br />cardiac problem – avoid glitazones<br /> if in failure avoid metformin<br /> <br />Renal problem – avoid metformin<br /> <br />
    • 187. Liver problem – avoid glitazone<br /> and metformin<br /> <br />In general <br />patients with complication <br />Short acting SU or insulin<br /> <br />
    • 188. Be ware of other drugs<br /> <br />        - Diuretics <br />         - Corticosteroid <br />         - Other hormones <br />         - ACE inhibitors <br />

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