Drugs for Diabetes Mellitus Chapter 57 Drugs for Diabetes Mellitus 1

Diabetes Mellitus: Overview of the Disease and Its Treatment Greek word for “fountain” Latin word for “honey” Disorder of carbohydrate metabolism Deficiency of insulin Resistance to action of insulin Sustained hyperglycemia, polyuria, polydipsia, ketonuria, and weight loss 2

Types of Diabetes Mellitus Type 1 diabetes 5%–10% of all cases Also called insulin-dependent diabetes mellitus (IDDM) or juvenile-onset diabetes mellitus Primary defect is destruction of pancreatic beta cells 3

Types of Diabetes Mellitus Type 2 diabetes Most prevalent form of diabetes Approximately 22 million Americans have it Also called non–insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes mellitus Insulin resistance and impaired insulin secretion 4

Complications of Diabetes Short-term Hyperglycemia and hypoglycemia Long-term Macrovascular damage Heart disease Hypertension Stroke Hyperglycemia Altered lipid metabolism 5

Complications of Diabetes Long-term (cont’d) Microvascular damage Retinopathy Nephropathy Neuropathy Gastroparesis Amputation secondary to infection 6

Diabetes and Pregnancy Before insulin: many babies born to severely diabetic women died Factors during pregnancy Placenta produces hormones that antagonize the actions of insulin Production of cortisol increases threefold Glucose can pass freely from the maternal to the fetal circulation (fetal hyperinsulinemia) 7

Diabetes and Pregnancy Proper glucose levels needed in pregnant patient and in fetus to prevent teratogenic effects Fetal death frequently occurs near term Earlier delivery is desirable Gestational diabetes 8

Diagnosis of Diabetes Excessive plasma glucose is diagnostic of diabetes Patient must be tested on two separate days, and both tests must be positive Three tests Fasting plasma glucose (FPG) Casual plasma glucose Oral glucose tolerance test (OGTT) Hemoglobin A1c, oral glucose tolerance test 9

Prediabetes Impaired fasting plasma glucose between 100 and 125 mg/dL Impaired glucose tolerance test Increased risk for developing type 2 diabetes May reduce risk with diet changes and exercise and possibly with certain oral antidiabetic drugs Many people who meet criteria for “prediabetes” never develop diabetes, even if they do not take precautions against diabetes 10

Overview of Diabetes Treatment Primary goal is to prevent long-term complications Tight control of blood glucose level is important Also important to control blood pressure and blood lipids 11

Type 1 Diabetes Requires comprehensive plan Integrated program of diet, self-monitoring of blood glucose, exercise, and insulin replacement Dietary measures Total number of carbohydrates, not the type of carbohydrates, is most important Glycemic index 12

Type 2 Diabetes Similar to type 1, requires comprehensive plan Should be screened and treated for: Hypertension, nephropathy, retinopathy, neuropathy, dyslipidemias Glycemic control with: Modified diet and exercise Drug therapy 13

Monitoring Treatment Self-monitoring of blood glucose (SMBG) Hemoglobin A1c 14

Insulin: Physiology Biosynthesis Secretion Metabolic actions Metabolic consequences of insulin deficiency 15

Seven Types of Insulin Short duration: rapid acting Insulin lispro (Humalog) Insulin aspart (NovoLog) Insulin glulisine (Apidra) Short duration: slower acting Regular insulin (Humulin R, Novolin R) Intermediate duration Neutral protamine Hagedorn (NPH) insulin Insulin detemir (Levemir) Long duration Insulin glargine 16

Insulin Concentration Mixing insulins 100 units/mL (U-100) NPH with short-acting insulins Short-acting insulin drawn first 17

Administration Subcutaneous injection Subcutaneous infusion Syringe and needle Pen injectors Jet injectors Subcutaneous infusion Portable insulin pumps Implantable insulin pumps (experimental) Intravenous infusion 18

Storage Unopened vials should be stored under refrigeration until needed Should not be frozen Can be used until expiration date if kept in refrigerator After opening, can be kept up to 1 month without significant loss of activity Keep out of direct sunlight and extreme heat 19

Storage Mixtures of insulin in vials are stable for 1 month at room temperature and for 3 months under refrigeration Mixtures in pre-filled syringes should be stored in refrigerator for at least 1 week and should be stored vertically with needle pointing up 20

Insulin: Therapeutic Use Indications Principal: diabetes mellitus Required by all type 1 and some type 2 patients IV insulin for DKA Hyperkalemia: can promote uptake of potassium Aids in the diagnosis of GH deficiency 21

Insulin Therapy of Diabetes Dosage Dosing schedules Conventional therapy Intensive conventional therapy Continuous subQ infusion Achieving tight glucose control 22

Complications of Insulin Treatment Hypoglycemia Lipohypertrophy Allergic reactions Hypokalemia Drug interactions Hypoglycemic agents Hyperglycemic agents Beta-adrenergic blocking agents 23

Oral Hypoglycemics Biguanides Sulfonylureas Metformin (Glucophage) Sulfonylureas Thiazolidinediones (glitazones) Rosiglitazone (Avandia) Pioglitazone (Actos) Meglitinides (Glinides) Repaglinide (Prandin) Nateglinide (Starlix) 24

Oral Hypoglycemics Alpha-glucosidase inhibitors Gliptins Acarbose (Precose) Miglitol (Glyset) Gliptins Combination products 25

Combination Products Metformin/Glyburide Metformin/Glipizide Metformin/Saxagliptin Metformin/Pioglitazone Metformin/Repaglinide Metformin/Sitagliptin Pioglitazone/Glimepiride Rosiglitazone/Glimepiride Rosiglitazone/Metformin Sitagliptin/Simvastatin 26

Injected Drugs (Other than Insulin) Exenatide Adjunctive therapy to improve glycemic control in patients with type 2 diabetes Adverse effects Hypoglycemia Gastrointestinal effects Liraglutide Pramlintide 27

Acute Complications of Poor Glycemic Control Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmotic nonketotic syndrome (HHNS): Both conditions are hyperglycemic crises Hyperglycemia is more severe in HHNS No ketoacidosis in HHNS 28

Diabetic Ketoacidosis Severe manifestation of insulin deficiency Symptoms evolve quickly in a period of hours or days Most common complication in pediatric patients and leading cause of death Characteristics Hyperglycemia Ketoacids Hemoconcentration Acidosis Coma 29

Diabetic Ketoacidosis Altered glucose metabolism Hyperglycemia Water loss Hemoconcentration Altered fat metabolism Production of ketoacids 30

Diabetic Ketoacidosis Treatment Insulin replacement Bicarbonate for acidosis Water and sodium replacement Potassium replacement Normalization of glucose levels 31

HHNS Large amount of glucose excreted in urine Dehydration and loss of blood volume Increases the blood concentrations of electrolytes and nonelectrolytes (particularly glucose); also increases hematocrit Blood “thickens” and becomes sluggish 32

HHNS Little or no change in ketoacid levels Little or no change in blood pH No sweet or acetone-like smell to urine or breath HHNS occurs most frequently with type 2 diabetes mellitus with acute infection, acute illness, or some other stress 33

HHNS Can evolve slowly Metabolic changes begin a month or two before signs and symptoms become apparent If untreated, HHNS can lead to coma, seizures, and death Management Correct hyperglycemia and dehydration with IV insulin, fluids, and electrolytes 34

Glucagon for Insulin Overdose Preferred treatment is IV glucose Immediately raises blood glucose level Glucagon can be used if IV glucose is not available Delayed elevation of blood glucose Will not work in starvation Promotes glycogen breakdown and the malnourished have little glycogen left 35