DM Drugs

made simple

1. Drugs for Diabetes Mellitus Internal Medicine 2010

2. Islets of Langerhans c ells – glucagon c ells – insulin c ells – Somatostatin PP cells – pancreatic polypeptide

3. Drugs used in Diabetes Mellitus Insulin p er orem Rapid Short-Acting Intermediate Acting Slow, long acting Insulin Secretagogue Biguanides Insulin Synthesizer  Glucosidase inhibitor

4. Insulin duplicate normal physiologic secretion of insulin type 2 DM use during times of illness or stress to maintain glycemic control patients who are unable to maintain adequate control exact time course of each insulin will depend on each particular preparation and site of injection

5. Effects of Insulin Liver Increases storage of glucose as glycogen in liver Decrease protein catabolism Muscle Stimulates glycogen synthesis and protein synthesis Adipose Tissue Facilitates triglyceride storage by: activating plasma lipoprotein lipase Increasing glucose transport into cells via GLUT 4 transporters Reducing intracellular lipolysis

6. Normal Plasma Glucose and Insulin Profile

7. Human Insulin 1982 : "recombinant DNA" into lab-cultivated bacteria or yeast v ery short half life i nsulin preparations are formulated to release insulin slowly into circulation recombinant human insulin has replaced animal-derived insulin, such as pork and beef insulin insulin analogs structure differs slightly from human insulin to change onset and peak of action

8. Insulin and Insulin Analogs Insulin Onset of action (minutes) Time to peak concentration (minutes) Maximum duration of action (hours) Regular insulin 30-60 90-120 5-12 Insulin lispro ( Humalog ) 10-15 30-60 3-4 Insulin aspart 10-15 40-50 3-5 Insulin glulisine 10-15 55 3-5 NPH insulin 60-120 240-480 10-20 Insulin glargine 60-120 None 24 Insulin detemir 60-120 None 20

9. Short and Rapid-Acting Insulin act as mealtime insulin administer before meals to mimic physiologic increases of insulin which occurs after meals ASPART, GLULISINE, LISPRO more rapid onset of action and shorter duration of action than regular insulin premeal control before the next meal may be difficult due to short duration of action if used alone

10. Crystalline zinc ( Regular ) Insulin as a mealtime insulin, its use may be limited because onset is not so rapid to meet the quick, unpredictable increase in postprandial blood glucose considered basal insulin can be given IV or SQ given 30 to 45 minutes ac

11. Intermediate and Long-Acting Insulins given SQ only intend to mimic normal physiologic basal insulin secretion usually given 1-2 times/day LENTE Intermediate-Acting Insuline ULTRALENTE, DETEMIR, GLARGINE Basal/ Long-Acting Insulins

12. Combinations short- and long-acting combinations are available commercially or may be combined in a single syringe by the patient 30% R/ 70% NPH 50/50 20/80

13. Different Insulin Regimen 2 daily injections Multiple Daily Insulin Injection Continuous Subcutaneous Insulin Infusion Adverse Reactions Hypersensitivity reactions Hypoglycemia Lipoatrophy or lipohyperthrophy

14. Oral Antidiabetic Agents sensitizers Biguanides : Metformin TZDs (PPAR): Pioglitazone , Rivoglitazone , Rosiglitazone Dual PPAR agonist: Muraglitazar

15. Oral Antidiabetic Agents secretagogues K+ ATP sulfonylureas 1 st gen: Gliclazide 2 nd gen: Glibenclamide , Glipizide 3 rd gen: Glimepiride meglitinides : nateglinide , repaglinide GLP-1 analogs: exenatide DPP-4 inhibitors: saxagliptin , sitaglipitin

16. Oral Antidiabetic Agents α – glucosidase inhibitors acarbose , voglibose , miglitol amylin pramlintide SLGT2 inhibitors dapaglifozine others benfluorex , tolrestat

17. Sulfonylureas Mechanism of Action Stimulate insulin release from pancreatic β cells Decrease hepatic clearance of insulin Primarily act by binding to the SUR subunit of the ATP-sensitive potassium (K ATP ) channel and inducing channel closure

18. Sulfonylureas Absorption, Fate, and Excretion absorbed from git decreased absorption with food and hyperglycemia 90 to 99% protein bound in plasma metabolize in liver metabolites excreted in kidney 2 nd gen half life short (3 to 5h) long duration of action (12 to 24h)

19. Sulfonylureas 1 st GENERATION Chlorpropamide / Tolazamide / Tolbutamide : once daily dosing, administer with breakfast 2 nd GENERATION Glibenclamide / Gliclazide / Glimepiride : once daily, administer with breakfast Glipizide : 15-30 min before breakfast

20. Sulfonylureas Adverse Reactions: hypoglycemia, allergic reactions. GI upset use with caution in patients with hepatic or renal failure should not be used in DKA, major surgery, severe infections. stress or trauma, sulfa allergy disulfiram reaction may occur with chlorpropamide and alcohol

21. Generic Name Daily Dose Duration of Action Clearance Glimepiride 1 – 8 mg 24H H, R Glipizide 2.5 – 40 mg 12-18H H Glipizide (ER) 5 – 10 mg 24H H Glyburide 1.25 – 20 mg 12-24H H, R Glyburide (Micronized) 0.75 – 12 mg 12-24H H, R Repaglinide 0.5 – 16 mg 2-6H H

22. Meglitinides REPAGLINIDE initial dose: 0.5 mg PO prior to meals; max: 16mg/day MOA: derivative of benzoic acid; stimulate insulin release by closing ATP-dependent K channels in pancreatic β cells absorbed rapidly from GIT; peak blood levels within 1 hour Metabolize 90% in liver 10% in kidney

23. Meglitinides NATEGLINIDE 120mg PO 1-30min prior to main meals MOA: from D-phenylalanine; stimulate insulin release by closing ATP-dependent K channels in pancreatic β cells Reduce postprandial hypoglycemia Metabolize: 84% IN LIVER 16% IN KIDNEY

24. Biguanides METFORMIN absorbed mainly in small intestine stable but does not bind with protein excreted unchanged in urine half life – 2 hours MOA: decrease hepatic glucose production -  gluconeogenesis increase insulin action in muscle and fat

25. Biguanides METFORMIN CONTRAINDICATIONS: renal impairment, hepatic disease, past history of lactic acidosis, cardiac failure, chronic hypoxic lung disease Withheld for 48 hours after giving contrast media – to insure N kidney ADVERSE REACTIONS: lactic acidosis, diarrhea, GI discomfort, nausea, metallic taste, anorexia uptitrate slowly

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

27. Thiazolidinediones (TZDs) ROSIGLITAZONE AND PIOGLITAZONE OD dose Absorbed within 2 hours Max effect observed in 6 to 12 weeks Metabolized in Liver Cytochrome P450 enzymes Monitor liver enzymes regularly May be given to patients with renal insufficiency AE: anemia, weight gain, edema C/I: Heart Failure

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

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