Diabetes

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Diabetes

  1. 1. PHARMACOTHERAPY OF DIABETES MELLITUS Aaditya Udupa
  2. 2. <ul><li>Physiological factors regulating blood sugar : </li></ul><ul><ul><li>Glycolysis </li></ul></ul><ul><ul><li>Dietary Intake Glycogen synthesis </li></ul></ul><ul><ul><li>Glycogenolysis Lipogenesis </li></ul></ul><ul><ul><li>Gluconeogenesis Glycoprotein synthesis Excretion [abnormal] </li></ul></ul><ul><ul><li>Insulin : Reduces BSL </li></ul></ul><ul><ul><li>Epinephrine, Glucagon, Growth hormone, Glucocorticoids: Raise BSL </li></ul></ul>BLOOD GLUCOSE Dr. Aaditya
  3. 3. <ul><li>Physiology of Insulin secretion : </li></ul><ul><ul><ul><li>Increased BSL, FFA, amino acids, Incretins [gastrin, VIP, GLP, GIP] </li></ul></ul></ul><ul><ul><ul><li>Glucagon, vagal stimulation ………………… </li></ul></ul></ul><ul><ul><ul><li>Increase insulin secretion </li></ul></ul></ul><ul><ul><ul><li>Somatostatin,  2 adrenergic stimulation, hypokalemia…………………... </li></ul></ul></ul><ul><ul><ul><li> Decrease insulin secretion </li></ul></ul></ul>Dr. Aaditya
  4. 4. <ul><li>Metabolic effects of Insulin : </li></ul><ul><ul><ul><li>Carbohydrate: </li></ul></ul></ul><ul><ul><ul><ul><li>Increase glucose uptake by Skeletal Muscle, adipose tissue, liver </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Increase glycogenesis </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Decrease glycogenolysis </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Decrease gluconeogenesis </li></ul></ul></ul></ul><ul><ul><ul><li>Lipid: </li></ul></ul></ul><ul><ul><ul><ul><li>Stimulates endothelial lipoprotein lipase </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Inhibits hormone sensitive lipase in adipose tissue </li></ul></ul></ul></ul><ul><ul><ul><ul><li>……… .. Decrease plasma TG and increase adipose tissue fat [ LIPOGENIC ] </li></ul></ul></ul></ul><ul><ul><ul><li>Protein: </li></ul></ul></ul><ul><ul><ul><ul><li>Increase amino acid uptake by cells </li></ul></ul></ul></ul><ul><ul><ul><ul><li>………… Protein synthesis [ less breakdown ] </li></ul></ul></ul></ul>Dr. Aaditya
  5. 5. <ul><li>Lack of Insulin: </li></ul><ul><ul><ul><li>Lipids: </li></ul></ul></ul><ul><ul><ul><ul><li>Adipose tissue: </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Activation of Hor. sensitive Lipase  Increase in FFA and glycerol </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Inhibition of Endothelial lipase </li></ul></ul></ul></ul>LIVER TG synthesis Acetyl Co A Fatty liver Ketone bodies Gluconeogenesis Cholesterol synthesis Metabolised Dr. Aaditya Hypertriglyceridemia
  6. 6. <ul><li>Carbohydrates: </li></ul><ul><ul><ul><li>Increased glycogenolysis or gluconeogenesis  </li></ul></ul></ul><ul><ul><ul><li> ……………………… .HYPERGLYCEMIA </li></ul></ul></ul><ul><li>Proteins: </li></ul><ul><ul><ul><li>Increased protein breakdown  .. Increased gluconeogenesis </li></ul></ul></ul><ul><ul><ul><li> .. Negative nitrogen balance </li></ul></ul></ul><ul><ul><ul><li>Diabetes mellitus </li></ul></ul></ul><ul><ul><ul><li>Metabolic disorder characterized by hyperglycemia, glycosuria, hyperlipidemia, negative nitrogen balance leading to acute/chronic complications </li></ul></ul></ul>Dr. Aaditya
  7. 7. <ul><li>Consequences of metabolic derangements: </li></ul><ul><ul><li>Dyslipidemia  Atherosclerosis  CAD </li></ul></ul><ul><ul><li>Hyperglycemia  </li></ul></ul><ul><ul><ul><li>Glycosylation of proteins  AGE products  </li></ul></ul></ul><ul><ul><ul><ul><li>thickening of basement membranes and vascular matrix  Microvascular complications </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Activation of macrophages  Cellular proliferative and </li></ul></ul></ul></ul><ul><ul><ul><ul><li>degradative changes </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Aldose reductase </li></ul></ul></ul></ul><ul><ul><ul><li>Glucose Sorbitol  Osmotic injury to tissues </li></ul></ul></ul><ul><ul><ul><li>Glucose competes with myoinositol for transport into neural cells Neuropathy </li></ul></ul></ul><ul><ul><li>Ketoacidosis </li></ul></ul><ul><ul><li>Reduced cellular immunity </li></ul></ul>Dr. Aaditya
  8. 8. <ul><li>TYPES OF DIABETES MELLITUS: </li></ul><ul><li>Type I </li></ul><ul><li>Type II </li></ul><ul><li>Secondary </li></ul><ul><li>Gestational </li></ul><ul><li>CLINICAL FEATURES OF DIABETES MELLITUS: </li></ul><ul><ul><li>Polyuria, polydipsia, polyphagia </li></ul></ul><ul><ul><li>Delayed wound healing, sepsis </li></ul></ul><ul><ul><li>Acute complications---- Ketoacidosis </li></ul></ul><ul><ul><li>Long term complications ----- Retinopathy, neuropathy, nephropathy, Cardiovascular events </li></ul></ul>Dr. Aaditya
  9. 9. <ul><li>Modalities of treatment of Diabetes mellitus: </li></ul><ul><ul><li>Insulin [ Replacement therapy ] </li></ul></ul><ul><ul><li>Oral anti-diabetic agents: </li></ul></ul><ul><ul><ul><ul><li>Insulin releasing agents </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Insulin sensitizing agents </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Those which reduce carbohydrate absorption </li></ul></ul></ul></ul><ul><ul><li>Newer agents </li></ul></ul>Dr. Aaditya
  10. 10. <ul><li>Classification of insulin preparations: </li></ul><ul><li>A] On the basis of source: </li></ul><ul><li>Bovine pancreas </li></ul><ul><li>Porcine pancreas </li></ul><ul><li>recombinant Human insulin [ E. coli or yeast ] </li></ul><ul><li>B] On the basis of purity: </li></ul><ul><li>Conventional : Bovine- Porcine </li></ul><ul><li>Newer-Purer insulin- </li></ul><ul><li> Single peak insulin [ Actrapid, Lentard] </li></ul><ul><li> Monocomponent insulin [ Actrapid MC, Monotard MC] </li></ul><ul><li> Enzymatically modified porcine insulin </li></ul><ul><li> Recombinant Human insulin </li></ul><ul><li>Advantages of newer insulins: </li></ul><ul><ul><ul><ul><li>Purer--- less lipoatrophy, Stable, Neutral …………….. </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Less antigenic– Less allergy, resistance </li></ul></ul></ul></ul>Dr. Aaditya
  11. 11. <ul><li>C] On the basis of onset and duration of action: </li></ul>Dr. Aaditya PREP. pH Protein Onset [hrs] Peak [hrs] Dura [hrs] Remarks Regular 3.2 - 0.5 -1 2-4 6-8 <ul><li>Can be given I.V. </li></ul><ul><li>Mixed with Isophane </li></ul>Semilente 7.2 - 1 8 12-14 I.M or S.C
  12. 12. <ul><li>C] On the basis of onset and duration of action: </li></ul>Dr. Aaditya PREP. pH Protein Onset [hrs] Peak [hrs] Dura [hrs] Remarks Regular 3.2 - 0.5 -1 2-4 6-8 <ul><li>Can be given I.V. </li></ul><ul><li>Mixed with Isophane </li></ul>Semilente 7.2 - 1 8 12-14 I.M or S.C Isophane [NPH] 7.2 Protamine 1-2 6-12 18-24 I.M or S.C Lente 7.2 - 1-2 6-12 18-24 I.M or S.C
  13. 13. <ul><li>C] On the basis of onset and duration of action: </li></ul>Dr. Aaditya PREP. pH Protein Onset [hrs] Peak [hrs] Dura [hrs] Remarks Regular 3.2 - 0.5 -1 2-4 6-8 <ul><li>Can be given I.V. </li></ul><ul><li>Mixed with Isophane </li></ul>Semilente 7.2 - 1 8 12-14 I.M or S.C Isophane [NPH] 7.2 Protamine 1-2 6-12 18-24 I.M or S.C Lente 7.2 - 1-2 6-12 18-24 I.M or S.C PZI 7.2 Protamine 4-6 14-18 24-36 Not used now-a-days Ultralente 7.2 4-6 14-18 24-36 I.M or S.C
  14. 14. <ul><li>Newer insulin analogues: </li></ul><ul><li>Ultra rapid acting insulins: </li></ul><ul><li>Insulin lispro </li></ul><ul><li>Insulin aspart </li></ul><ul><li>Insulin glulysine </li></ul><ul><li>Peakless insulin : </li></ul><ul><li>Insulin glargine </li></ul><ul><li>Myristoylated insulin </li></ul><ul><li>Insulin detemir </li></ul>Dr. Aaditya
  15. 15. Dr. Aaditya LIMITATION PRECAUTION/ TREATMENT HYPOGLYCEMIA <ul><li>Explain the symptoms of hypoglycemia to patient </li></ul><ul><li>Ask pt. to avoid unaccustomed exercise or fasting </li></ul><ul><li>Ask pt. to carry with him glucose/ sweets/ biscuits </li></ul><ul><li>Ask the patient to carry identification and treatment card with him </li></ul><ul><li>Ask patient to avoid non-selective beta-blockers </li></ul><ul><li>Prefer insulin glargine—[peakless] </li></ul><ul><li>IV glucose [50ml of 50%], Glucagon </li></ul>INSULIN RESISTANCE <ul><li>Increase dose </li></ul><ul><li>Add oral agents </li></ul><ul><li>Use purer, newer insulins </li></ul><ul><li>Try glucocorticoids </li></ul>INSULIN ALLERGY <ul><li>Use purer, newer insulins </li></ul>
  16. 16. Dr. Aaditya LIMITATION PRECAUTION/ TREATMENT INSULIN LIPODYSTROPHY <ul><li>Frequent changing of site of injection </li></ul><ul><li>Inject newer insulin at margins of lipoatrophic site </li></ul>INSULIN EDEMA/ PRESBYOPIA/ NEUROPATHY Requires frequent injections Jet injections, Inhaled insulin, Insulin pumps Does not mimic physiologic pattern [high hepatic] Investigational- Rectal route, Intraperitoneal injection, liposomal preparations for oral use Plasma insulin level does not exactly match the BSL Microprocessor containing devices- artificial pancreas--- Used mainly for research purpose 30 min lag period  rigid planning of meal timings Use insulin lispro/ aspart/ glulysine
  17. 17. <ul><li>Indications for insulin: </li></ul><ul><li>IDDM </li></ul><ul><li>NIDDM if </li></ul><ul><ul><li>Cannot be controlled by diet and oral hypoglycemics </li></ul></ul><ul><ul><li>Oral anti diabetic not tolerated </li></ul></ul><ul><ul><li>Underweight, Age <40yrs, Long standing hyperglycemia </li></ul></ul><ul><ul><li>Acute complication [ Diabetic ketoacidosis ] </li></ul></ul><ul><ul><li>Surgery, infection </li></ul></ul><ul><ul><li>Pregnancy </li></ul></ul><ul><li>Along with glucose to treat hyperkalemia </li></ul><ul><li>Along with glucose and potassium to treat hypokalemia </li></ul><ul><li>Diagnosis of Growth hormone deficiency </li></ul>Dr. Aaditya
  18. 18. <ul><li>Indications of newer insulin </li></ul><ul><li>Insulin allergy </li></ul><ul><li>Insulin resistance </li></ul><ul><li>Insulin lipodystrophy </li></ul><ul><li>Treatment of newly diagnosed gestational diabetes </li></ul><ul><li>Short term use e.g. perioperative period, diabetic ketoacidosis </li></ul>Dr. Aaditya
  19. 19. <ul><li>Modalities of treatment of Diabetes mellitus: </li></ul><ul><ul><li>Insulin [ Replacement therapy ] </li></ul></ul><ul><ul><li>Oral anti-diabetic agents: </li></ul></ul><ul><ul><ul><ul><li>Insulin releasing agents </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Insulin sensitizing agents </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Those which reduce carbohydrate absorption </li></ul></ul></ul></ul><ul><ul><li>Newer agents </li></ul></ul>Dr. Aaditya
  20. 20. Dr. Aaditya <ul><li>Most antigenic insulin </li></ul><ul><li>Suitable for diabetic ketoacidosis </li></ul><ul><li>Longest acting insulin </li></ul><ul><li>4. Contains 30% rapid acting insulin </li></ul><ul><li>Human Isophane Insulin </li></ul><ul><li>Bovine PZI </li></ul><ul><li>Porcine regular crystalline insulin </li></ul><ul><li>D. Lente insulin </li></ul>
  21. 21. Dr. Aaditya 1 . The rapid acting insulin analogue formed by replacing proline of B28 with aspartic acid. 2. The rapid acting insulin analogue formed by replacing lysine at B29 with glutamine and lysine replaces aspargine at B23. 3. The rapid acting insulin analogue that is formed by exchanging the positions of amino acids at B28 and B29. 4 The insulin analogue whose pharmacokinetic pecularity depends on the acidic pH of the preparation and gives a prolonged action on s/c injection . <ul><li>Glargine Insulin </li></ul><ul><li>Human insulin </li></ul><ul><li>Gluslysine Insulin </li></ul><ul><li>Lispro Insulin </li></ul><ul><li>Aspart Insulin </li></ul><ul><li>F. Insulin Detemer </li></ul>
  22. 22. Dr. Aaditya SULFONYLUREAS BIGUANIDES <ul><li>Binds to SU receptors on pancreatic  -cell </li></ul><ul><li> Closure of ATP sensitive K+ channel </li></ul><ul><li>Depolarization  opening of VS Calcium Channels </li></ul><ul><li>Increased I/C calcium </li></ul><ul><li>INSULIN release </li></ul><ul><li>Suppresses gluconeogenesis [minor] </li></ul><ul><li>Secondary action is sensitization of tissues to insulin action and </li></ul><ul><li>Inhibits gluconeogenesis in liver </li></ul><ul><li>Enhances insulin mediated glucose uptake by the peripheral tissues </li></ul><ul><li>Reduces absorption of glucose from GIT </li></ul><ul><li>Interferes with aerobic glycolysis  promotes anaerobic glycolysis  increased glucose utilization </li></ul>
  23. 23. Dr. Aaditya SULFONYLUREAS BIGUANIDES HYPOGLYCEMIC ANTIHYPERGLYCEMIC Weight gain Anorexia and Weight loss Requires atleast 30% functioning pancreas Requires presence of insulin for its action Hypoglycemia; Skin rash; Antabuse reaction & cholestatic jaundice [Chlorpropamide] Lactic acidosis GI upset B 12 and folate defeciency
  24. 24. <ul><li>SULFONYLUREAS : </li></ul><ul><ul><li>First generation : Chlorpropamide, Tolbutamide </li></ul></ul><ul><ul><li>Second generation : Glyburide, Glypizide, Glimepiride, Glyclazide </li></ul></ul><ul><li>Limitations: </li></ul><ul><ul><ul><li>Require functioning pancreas [at least 30%] </li></ul></ul></ul><ul><ul><ul><li>May cause hypoglycemic episodes [less with gymepiride] </li></ul></ul></ul><ul><ul><ul><li>Cause weight gain [less with glyclazide] </li></ul></ul></ul><ul><ul><ul><li>Potential for drug interactions- </li></ul></ul></ul><ul><ul><ul><ul><li>Protein binding/ Enzyme inducers and inhibitors </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Hypo/hyperglycemic agents </li></ul></ul></ul></ul>Dr. Aaditya
  25. 25. <ul><li>BIGUANIDES: [ Phenformin] ; Metformin </li></ul><ul><li>Limitations: </li></ul><ul><ul><ul><li>Less effect on BSL when used alone </li></ul></ul></ul><ul><ul><ul><li>May cause lactic acidosis [ rarely] </li></ul></ul></ul><ul><ul><ul><li>Phenformin > Metformin; </li></ul></ul></ul><ul><ul><ul><li>Especially in alcoholics, liver/ kidney/ CVS/ RS derangements </li></ul></ul></ul><ul><ul><ul><li>Nausea, metallic taste, Gastrointestinal upset, </li></ul></ul></ul><ul><ul><ul><li>Decrease Vitamin B12 and folate absorption </li></ul></ul></ul><ul><ul><ul><li>Advantages : Cause weight loss [suitable for obese NIDDM cases] </li></ul></ul></ul><ul><ul><ul><li> Useful in treatment of PCOS </li></ul></ul></ul>Dr. Aaditya
  26. 26. <ul><li>Repaglinide: </li></ul><ul><ul><ul><li>Benzoic acid derivitive [meglitinide] </li></ul></ul></ul><ul><li>Nateglinide: </li></ul><ul><ul><ul><li>D-phenylalanine derivative </li></ul></ul></ul><ul><ul><ul><li>Acts within 10-20min </li></ul></ul></ul><ul><ul><ul><li>Insulin secretogogue — like sulfonylureas but act fast and for short duration </li></ul></ul></ul><ul><ul><ul><li>Use cautiously in hepatic dysfunction </li></ul></ul></ul><ul><ul><ul><li>Adverse effects: </li></ul></ul></ul><ul><ul><ul><li> Hypoglycemia — [least with nateglinide] </li></ul></ul></ul><ul><ul><ul><li>USE : </li></ul></ul></ul><ul><ul><ul><li>Type 2 diabetes mellitus for controlling </li></ul></ul></ul><ul><ul><ul><li> post-prandial hyperglycemia </li></ul></ul></ul>Dr. Aaditya
  27. 27. <ul><li>THIAZOLIDINEDIONES: [Troglitazone]; Pioglitazone; Rosiglitazone </li></ul><ul><li>Selective agonists of the PPAR-  receptor </li></ul><ul><li>They activate genes that regulate fatty acid and carbohydrate metabolism in the peripheral tissue [primary site is adipose tissue] </li></ul><ul><ul><li>Reduces efflux of fatty acids </li></ul></ul><ul><ul><li>Secretion of adiponectin [increased insulin sensitivity] </li></ul></ul><ul><li>Increased expression of genes involved in Insulin signal transduction </li></ul><ul><li>Increased differentiation and maturation of adipocytes </li></ul>Dr. Aaditya
  28. 28. <ul><li>LIMITATIONS : </li></ul><ul><ul><li>Clinical benefits are not observed until 6-12 weeks </li></ul></ul><ul><ul><li>Adverse effect: ? Hepatotixicity, anemia, edema [volume expansion]  may ppt. or cause heart failure, Weight gain </li></ul></ul><ul><li>CLINICAL UTILITY : </li></ul><ul><ul><ul><li>Type 2 diabetes mellitus [Insulin sensitizer] </li></ul></ul></ul><ul><ul><ul><li>HIV associated lipodystrophy </li></ul></ul></ul><ul><ul><ul><li>Non-alcoholic hepatosteatosis </li></ul></ul></ul><ul><li>Usually added to other drugs </li></ul>Dr. Aaditya
  29. 29. <ul><li>AGENTS THAT INHIBIT ABSORPTION OF GLUCOSE: </li></ul><ul><li> -GLUCOSIDASE INHIBITORS: Acarbose, Miglitol </li></ul><ul><ul><li>Inhibit the  -glucosidase in the intestinal brush border Inhibit break down of poly/disaccharides to monosaccharide's reduced absorption of carbohydrates other than monosaccharide's </li></ul></ul><ul><li>Adverse effect: Gastro-intestinal upset, </li></ul><ul><li> Rarely hypoglycemia [ Treat with oral glucose not sugar/ starch ] </li></ul><ul><li>Use: Mainly to reduce post-prandial hyperglycemia </li></ul><ul><li>GUAR GUM: Dietary fibre that inhibits absorption of carbohydrates and fats by adsorptive property </li></ul>Dr. Aaditya
  30. 30. <ul><li>Indications for oral antidiabetics: </li></ul><ul><ul><li>NIDDM not controlled by diet and exercise alone </li></ul></ul><ul><ul><li>Maturity onset diabetes > 40yrs age, duration <5yrs </li></ul></ul><ul><ul><li>BSL < 300mg% </li></ul></ul><ul><ul><li>Use Repaglinide or Nateginide for post-prandial hyperglycemia </li></ul></ul><ul><ul><li>In obese individuals prefer Metformin or Glyclazide </li></ul></ul><ul><ul><li>a </li></ul></ul><ul><ul><li>One drug combine drugs from each class if inadequate response Add TZDs Switch over to insulin </li></ul></ul>Dr. Aaditya
  31. 31. <ul><li>NEW DRUGS: </li></ul><ul><li>Acting via GLP 1 mechanism </li></ul><ul><li>Increase meal stimulated insulin release, Decrease glucagon release and may slow gastric emptying </li></ul><ul><li>Exenetide: GLP1 analog [s/c] </li></ul><ul><li>Liraglutide: GLP 1 agonist </li></ul><ul><li>Sitagliptine: DPP IV inhibitor [prevents degradation of endogenous GLP 1] </li></ul><ul><li>Pramlintide : Synthetic amylin that reduces glucagon secretion and delays gastric emptying [s/c]. </li></ul><ul><li>Useful in type 1 and type 2 DM </li></ul>Dr. Aaditya
  32. 32. <ul><li>PHARMACOTHERAPY OF DIABETIC KETOACIDOSIS : </li></ul><ul><li>INSULIN LACK + PRECIPITATING FACTORS </li></ul><ul><li>HYPERGLYCEMIA KETONE BODIES </li></ul><ul><li> hyperventilation vomiting ketonuria, </li></ul><ul><li>osmotic diuresis loss of water/ DEHYDRATION electrolytes </li></ul><ul><li>ELECTROLYTE IMBALANCE </li></ul><ul><li>[Reduced Na+, K+] ACIDOSIS </li></ul>Dr. Aaditya
  33. 33. <ul><li>Insulin 0.1 U/kg/hr in NS as CLDII </li></ul><ul><li>When BSL reaches 250mg% </li></ul><ul><li>reduce the dose of insulin to half; </li></ul><ul><li>add 50gm glucose per Litre; </li></ul><ul><li>add K (phosphate) [20mEq/hr] </li></ul><ul><li>IV fluids: 1.5L in first hour; 1L/Hr for next 3-4 hours; ½ L/hr later </li></ul><ul><li>If Se. Na+ >15omEq/L--- Administer 0.45% saline </li></ul><ul><li>If acidosis persists : NaHCO 3 in saline infusion </li></ul><ul><li>Treat the precipitating factor </li></ul><ul><li>Give antibiotics </li></ul><ul><li>When oral intake starts switch over to s.c. insulin [ continue insulin infusion for 30 minutes after s.c. injection ] </li></ul>Dr. Aaditya

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