- Insulin is used to treat diabetes by replicating the body's natural insulin secretion. Various insulin preparations have different onset and duration of action. Oral antidiabetic drugs include sulfonylureas, meglitinides, biguanides, thiazolidinediones, DPP-4 inhibitors, GLP-1 analogs, and alpha-glucosidase inhibitors which lower blood glucose through different mechanisms such as stimulating insulin secretion or increasing insulin sensitivity. Choice of treatment depends on the type of diabetes, severity of hyperglycemia, and individual patient factors. All drugs have potential adverse effects like hypoglycemia that require monitoring.

1. Drugs forDiabetesMellitusInternal Medicine2010

2. Islets of Langerhanscells – glucagon

3. cells – insulin

4. cells – SomatostatinPP cells – pancreatic polypeptide

5. Drugs used in Diabetes MellitusInsulinper oremRapid Short-ActingInsulin SecretagogueBiguanidesIntermediate ActingInsulin SynthesizerSlow, long acting Glucosidase inhibitor

6. Insulinduplicate normal physiologic secretion of insulintype 2 DMuse during times of illness or stress to maintain glycemic controlpatients who are unable to maintain adequate controlexact time course of each insulin will depend on each particular preparation and site of injection

7. Effects of InsulinLiverIncreases storage of glucose as glycogen in liverDecrease protein catabolismMuscleStimulates glycogen synthesis and protein synthesisAdipose TissueFacilitates triglyceride storage by: activating plasma lipoprotein lipaseIncreasing glucose transport into cells via GLUT 4 transportersReducing intracellular lipolysis

8. Normal Plasma Glucose and Insulin Profile

9. Human Insulin1982: "recombinant DNA" into lab-cultivated bacteria or yeastvery short half life insulin preparations are formulated to release insulin slowly into circulationrecombinant human insulin has replaced animal-derived insulin, such as pork and beef insulininsulin analogsstructure differs slightly from human insulin to change onset and peak of action

10. Insulin and Insulin Analogs

11. Short and Rapid-Acting Insulinact as mealtime insulinadminister before meals to mimic physiologic increases of insulin which occurs after mealsASPART, GLULISINE, LISPROmore rapid onset of action and shorter duration of action than regular insulinpremeal control before the next meal may be difficult due to short duration of action if used alone

12. Crystalline zinc (Regular) Insulinas a mealtime insulin, its use may be limited because onset is not so rapid to meet the quick, unpredictable increase in postprandial blood glucoseconsidered basal insulincan be given IV or SQgiven 30 to 45 minutes ac

13. Intermediate and Long-Acting Insulinsgiven SQ onlyintend to mimic normal physiologic basal insulin secretionusually given 1-2 times/dayLENTEIntermediate-Acting InsulineULTRALENTE, DETEMIR, GLARGINEBasal/ Long-Acting Insulins

14. Combinationsshort- and long-acting combinations are available commercially or may be combined in a single syringe by the patient30% R/ 70% NPH50/5020/80

19. Different Insulin Regimen2 daily injectionsMultiple Daily Insulin InjectionContinuous Subcutaneous Insulin InfusionAdverse ReactionsHypersensitivity reactionsHypoglycemiaLipoatrophy or lipohyperthrophy

20. Oral Antidiabetic AgentssensitizersBiguanides: MetforminTZDs (PPAR): Pioglitazone, Rivoglitazone, RosiglitazoneDual PPAR agonist: Muraglitazar

21. Oral Antidiabetic AgentssecretagoguesK+ ATPsulfonylureas1st gen: Gliclazide2nd gen: Glibenclamide, Glipizide3rd gen: Glimepiridemeglitinides: nateglinide, repaglinideGLP-1 analogs: exenatideDPP-4 inhibitors: saxagliptin, sitaglipitin

22. Oral Antidiabetic Agentsα –glucosidase inhibitorsacarbose, voglibose, miglitolamylinpramlintideSLGT2 inhibitorsdapaglifozineothersbenfluorex, tolrestat

24. SulfonylureasMechanism of ActionStimulate insulin release from pancreatic β cellsDecrease hepatic clearance of insulinPrimarily act by binding to the SUR subunit of the ATP-sensitive potassium (KATP) channel and inducing channel closure

25. SulfonylureasAbsorption, Fate, and Excretionabsorbed from gitdecreased absorption with food and hyperglycemia90 to 99% protein bound in plasmametabolize in livermetabolites excreted in kidney2nd gen half lifeshort (3 to 5h)long duration of action (12 to 24h)

26. Sulfonylureas1st GENERATIONChlorpropamide/ Tolazamide/ Tolbutamide: once daily dosing, administer with breakfast2nd GENERATIONGlibenclamide/ Gliclazide/ Glimepiride: once daily, administer with breakfastGlipizide: 15-30 min before breakfast

27. SulfonylureasAdverse Reactions: hypoglycemia, allergic reactions. GI upsetuse with caution in patients with hepatic or renal failureshould not be used in DKA, major surgery, severe infections. stress or trauma, sulfa allergydisulfiram reaction may occur with chlorpropamide and alcohol

29. MeglitinidesREPAGLINIDEinitial dose: 0.5 mg PO prior to meals; max: 16mg/dayMOA: derivative of benzoic acid; stimulate insulin release by closing ATP-dependent K channels in pancreatic β cellsabsorbed rapidly from GIT; peak blood levels within 1 hourMetabolize90% in liver10% in kidney

30. MeglitinidesNATEGLINIDE120mg PO 1-30min prior to main mealsMOA: from D-phenylalanine; stimulate insulin release by closing ATP-dependent K channels in pancreatic β cellsReduce postprandial hypoglycemiaMetabolize:84% IN LIVER16% IN KIDNEY

31. BiguanidesMETFORMINabsorbed mainly in small intestinestable but does not bind with proteinexcreted unchanged in urinehalf life – 2 hoursMOA:decrease hepatic glucose production -  gluconeogenesisincrease insulin action in muscle and fat

32. BiguanidesMETFORMINCONTRAINDICATIONS: renal impairment, hepatic disease, past history of lactic acidosis, cardiac failure, chronic hypoxic lung diseaseWithheld for 48 hours after giving contrast media – to insure N kidneyADVERSE REACTIONS: lactic acidosis, diarrhea, GI discomfort, nausea, metallic taste, anorexiauptitrate slowly

33. Thiazolidinediones (TZDs)selective agonist for nuclear peroxisomeproliferator-activated receptor-gamma (PPAR)requires insulin insulin resistance in peripheral tissue

34. Thiazolidinediones (TZDs)ROSIGLITAZONE AND PIOGLITAZONEOD doseAbsorbed within 2 hoursMax effect observed in 6 to 12 weeksMetabolized in LiverCytochrome P450 enzymesMonitor liver enzymes regularlyMay be given to patients with renal insufficiencyAE: anemia, weight gain, edemaC/I: Heart Failure

35.  Glucosidase Inhibitor GI absorption of starch, dextrin, disaccharide by inhibiting the action of intestinal brush border ( glucosidase)slow carbohydrate absorption

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