Dr. Sasan Zaeri (PharmD, PhD) Department of Pharmacology, BPUMS

 The most common metabolic disease  Chronic hyperglycemia Biochemical criteria Normal PrediabeticDiabetic FBS < 100 mg/dL mg/dL>126 mg/dL 2-h GTT <140 mg/dL mg/dL>200 mg/dL Hb A 1 C <5.6% %>6.5% 2

DM type I  An autoimmune disease  Onset during childhood  Destruction of β-cells  Treatment with insulin DM type II  A progressive disorder  Onset in adulthood  Insulin resistance + progressive destruction of β-cells  Early stages controlled with noninsulin antidiabetic drugs  Later stages often require addition of insulin to drug regimen 3

InsulinsBiguanides α -Glucosidase inhibitors SulfonylureasThiazolidinediones 5

 A small peptide hormone produced in the pancreas  Synthesis as prohormone proinsulin (86 aa)  Cleavage to insulin (51 aa) & C-peptide  Proinsulin & C-peptide have no physiologic actions 6

 Liver:  ↑ Storage of glucose as glycogen  ↓ Protein catabolism  Skeletal muscle:  ↑ Glucose transport into muscle cells  ↑ Glycogen synthesis and protein synthesis  Adipose tissue:  ↑ Glucose transport into fat cells  ↑ TG storage  ↓ Intracellular lipolysis 7

DM I DM II DM emergencies Diabetic pregnant women 8

Different capacity to lower blood glucose. ◦ Rapid acting ◦ Short acting ◦ Intermediate acting ◦ Long acting 9

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Lispro, aspart, glulisine Onset: <15 min Duration: 3-4 h rapid onsets and early peaks of activity 11

Lispro, aspart, glulisine Indications: ◦ control of postprandial glucose (immediately before a meal ) ◦ emergency treatment of uncomplicated diabetic ketoacidosis 12

Regular Onset: h Duration: 4-6 h 13

Regular Indications: ◦ emergencies of hyperglycemia (IV) ◦ ordinary maintenance regimens (SC) alone or mixed with intermediate preparations 14

Lente, Neutral Protamine Hagedorn (NPH) Onset: 1-4 h Duration : h 15

NPH insulin: exhibits a delayed onset and peak of action NPH insulin is often combined with regular and rapid-acting insulins 16

Glargine, Detemir, Ultralente Gradual release pattern from injection site Onset: 4 h Duration: h 17

Glargine, Detemir, Ultralente Effects: provide a peakless basal insulin level lasting more than 20 h Indication: control basal glucose levels without producing hypoglycemia 18

Hypoglycemia Insulin induced immunologic complication Injection pain Weight Gain 19

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Insulin secretagogues (sulfonylureas) Biguanide (metformin) Thiazolidinediones (pioglitazone) α-glucosidase inhibitors (acarbose) Most commonly for TM II treatment 21

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Insulin secretagogues MOA: ◦ Blockade of ATP-dependent K + channels (K ATP ) in β-cells of pancreas→membrane depolarization → ↑release of insulin Effects: ◦ ↑ Basal and postprandial insulin secretion ◦ No effect in patients with non-functional pancreatic β cells 24

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1st generation:  Tolbutamide, Chlorpropamide 2nd generation:  Glibenclamide (Glyburide), Glipizide, Glimepiride ◦ More potent ◦ Used more commonly than the older agents 26

Indication: DM II Dosing: Once or twice daily Side effects: ◦ Hypoglycemia ◦ Weight gain 27

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Metformin MOA: ◦ ↓hepatic glucose release ◦ ↓ gluconeogenesis ◦ Enhance peripheral glucose uptake & utilization ◦ ↑peripheral tissue sensitivity to insulin Effects: Enhancement of insulin action, decrease weight Depends upon:Presence of insulin Metformin is a euglycemic agent Slower action 29

Indications: ◦ DM II Dosing: Two to three times daily Side effects: Nausea ↓appetite & weight loss ◦ Lactic acidosis ◦ diarrhea 30

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MOA: ◦ Carbohydrate analogs → α-glucosidase inhibition within the intestine → ↓glucose liberation → ↓intestinal glucose absorption → ↓(mild) blood glucose Acarbose & Miglitol 32

Effects: ◦ Delays carbohydrate absorption ◦ ↓Postprandial hyperglycemia ◦ No effect on fasting blood sugar and insulin release 33

DM II Prevent DM II in prediabetics Must be taken just before a meal Can be combined with other oral hypoglycemic agents Dosing: Three times daily (with each meal) 34

Flatulence  Diarrhea  Abdominal pain 35

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 Pioglitazone, Rosiglitazone 37

 MOA:  stimulation of nuclear receptors important for insulin action  peroxisome proliferator-activated receptor-gamma nuclear receptor (PPAR-γ receptor)  ↑target tissue sensitivity to insulin  skeletal muscle and adipose tissues  Effects:  ↑glucose uptake in muscle and adipose tissue  ↓both fasting and postprandial hyperglycemia  Inhibition of hepatic gluconeogenesis (↓hepatic glucose output)  Change in lipid metabolism and the distribution of body fat  Shift of TG from non-adipose tissues to adipose tissue (↓serum TG) 38

Indications: ◦ DM II ◦ ↓ risk of DM II in high-risk patients Dosing: Once daily Side effects: ◦ Fluid retention  presents as mild anemia and edema ◦ ↑ risk of MI (Rosiglitazone) 39

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