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CELLULAR REGULATION: GLUCOSE METABOLISM Diabetes & Antidiabetic Medications TWO TYPES OF DIABETES Diabetes Insipidus: A disorder of the pituitary gland that involved antidiuretic hormone (ADH) Diabetes Mellitus: A disorder of insulin production and/or glucose utilization. DIABETES MELLITUS Est. 23.6 million people are diagnosed with diabetes but 5.7 million are unaware they have the disease. Prevalence in the US: Approximately 5-10% of the population have Type I DM Complications from diabetes are the 3rd leading cause of death in the US Rates in African Americans, Native Americans and those of Hispanic ethnicity (in adults age 45-65) are 2-3x higher than in Caucasians. History: 1500’s writings mention “honeyed urine” Insulin was developed by Eli Lilly in 1921 GLUCOSE Glucose is the simplest form of carbohydrate (“sugar”) All of our cells require glucose as an energy source Glucose must be consumed through food sources Excess glucose is converted and stored in the body as adipose tissue (“fat”) and as glycogen in the liver and in the skeletal muscles Inadequate food intake leads to: Glycogen stores are broken down first by the liver Gluconeogenesis, or the body’s production of glucose from non-carbohydrate sources such as fat (ketones) and muscle tissue occurs second Diabetes mellitus is fundamentally a disease of cellular starvation for glucose. PHYSIOLOGY OF CELLULAR GLUCOSE: THE HOMEOSTASIS BLOOD SUGAR Pancreatic cells Islets of Langerhans Beta cells produce insulin Alpha Delta F cells (used in digestion) OF ROLE OF HORMONES AND BLOOD GLUCOSE HOMEOSTASIS Glucose Counter-regulatory Hormones • These increase glucose levels in the body: • Cortisol – chronic stress (Cortisone) • Epinephrine – sympathetic nervous system • Human Growth hormone • Glucagon – produced by the pancreas and stimulates the liver to make glucose REGULATION OF BLOOD GLUCOSE… Food is eaten PATHOPHYSIOLOGY AND ETIOLOGY Diabetes mellitus is a serious chronic disease that affects people of all ages and ethnic groups Types: Type I Type 2 Gestational (pregnancy) Other Drug induced (e.g., Prednisone); Medical condition (e.g., hyperthyroidism, pancreatitis, pancreatic cancer) Usually resolves when underlying condition is corrected ETIOLOGY OF DIABETES Theories link cause of DM to combination of these factors Genetic Autoimmune Viral Environmental – obesogenic lifestyles (Type II) Regardless of its cause, diabetes is primarily a disorder of glucose metabolism related to absent or insufficient insulin supply and/or cell membrane resistance to available insulin. TYPE I DIABETES MELLITUS Most often occurs in people younger than 40 years of age Occurs more frequently in younger children End result of long-standing process Theorized to be autoimmune Progressive destruction of pancreatic -cells by body’s own T cells Antibodies cause a reduction of 80% to 90% in normal -cell function before manifestations occur. TYPE I DIABETES MELLITUS (CONT’D) Will require exogenous insulin Clinical manifestations: Polyuria & polydipsia Polyphagia Weakness and fatigue Diabetic ketoacidosis (DKA) Occurs in absence of exogenous insulin Life-threatening condition Results in metabolic acidosis PATHOPHYSIOLOGY OF DIABETIC KETOACIDOSIS TYPE II DIABETES MELLITUS Pre-diabetes is a precursor to diabetes FBS 100-140 Characterized by insulin resistance at the cell level and eventually reduced insulin production Affects adults and children Genetic predisposition + Environment Contributes to Metabolic Syndrome: Diabetes Abdominal obesity Hypertension – high total cholesterol, low LDL High triglycerides, atherosclerotic changes CLINICAL MANIFESTATIONS OF TYPE II DIABETES Nonspecific symptoms May have classic symptoms of Type 1 Common symptoms: Fatigue Recurrent infections Recurrent vaginal yeast infection Prolonged wound healing Visual changes Copyright © 2011, 2007 by Mosby, Inc., an affiliate of Elsevier Inc. GESTATIONAL DIABETES Occurs only during pregnancy Related to increased levels of natural progesterone, cortisol and human placental lactogen. Associated with higher birth weight babies (more glucose in mother = more nutrients for infant) Also associated with later onset of Type II diabetes in the woman First screen: urine tests positive for glucose at each office visit. Second screen: Glucose Tolerance Test (GTT) A fasting glucose is drawn then high carbohydrate solution is ingested. Blood is drawn every 30-60” for 3 hours. CRITERIA FOR DIABETES DIAGNOSIS Consistent fasting plasma glucose of 126 mg/dL Hemoglobin A1C level = or > 6.5% Clinical symptoms of diabetes and hyperglycemia May include a chemical, or “fruity” breath due to ketones Urine positive for: Albumin, Protein (muscle breakdown due to gluconeogenesis) Ketones (due to fat breakdown) Glucose (due to excess glucose in the serum) HEMOGLOBIN A1C TEST Hemoglobin A1c: Normal is <6.5 A measure of glucose bonded to hemoglobin molecules Used to estimate fluctuating blood sugar levels over time Turnover of Hgb is about every 3-months Better test for looking at overall glycemic control SERUM GLUCOSE LEVELS TREATMENT GOAL IS TO NORMALIZE BLOOD GLUCOSE LEVELS Diet Exercise Medications Insulin Oral antidiabetics Self-care Chronic infections Glucose is a rich environment for bacteria Slow wound healing Poor circulation due to capillary fragility Dependent ulcers Gangrene and amputations Renal disease & renal failure Visual retinopathy leading to blindness COMPLICATIONS OF POORLY MANAGED DIABETES Cataracts Peripheral neuropathies Atherosclerosis (“hardening of the arteries”) Cerebrovascular disease Ischemic heart disease DIABETIC RETINOPATHY & CATARACT Cataract FOOT ULCERS IN DIABETIC PATIENTS DRUGS AFFECTING BLOOD GLUCOSE LEVELS ANTIDIABETIC DRUGS Used to control or manage diabetes (not cure) Two groups: Insulin Replaces the body’s own missing insulin Other antidiabetic agents Sulfonylureas: Stimulate beta cells to release more insulin Non-sulfonylureas: Promote glucose transportation into the cells & inhibit glucagon production Incretin modifiers/mimetics: Increase action of incretin hormones to release more insulin and decrease glucagon hormones. INSULIN Synthetic insulin (exogenous) acts in the same manner as endogenously (human) insulin. Sources of exogenous insulin historically included pork and beef pancreas, but now only recombinant DNA technology or genetic engineering is used to create human-like insulin. Human-sourced insulin is considered the standard therapy. INSULIN Insulin promotes the uptake of glucose, amino acids, and fatty acids converting them into substances that are stored in body cells. Insulins are injected subcutaneously (subQ, or SQ). The abdomen absorbs most consistently. Orally will break down and not be absorbed. Insulin syringes are marked as 100 units per 1 mL. Insulin is always ordered in “units” (0.1 mL) TYPES OF INSULIN Rapid-acting Must be given within 5 minutes of eating Humalog (insulin lispro) NovaLog (insulin aspart) Short-acting Onset 30”-1 hr, Peak 2-4 hrs., Duration 6-8 hrs. Can be given 30” before meals Only Regular Insulin can be given IV (all others SQ only) *Regular Insulin Intermediate-acting Onset 1-2 hrs. Peak 6-12 hrs. Duration 18-24 hrs. Lente, NPH and Humulin N TYPES OF INSULIN (CONT’D) Long-acting Available in prefilled, 3-mL cartridges “OptiPen One” insulin pen devices or via traditional injections Levemir (insulin detmir) Duration 12-24 hrs. *Lantus (insulin glargine) Duration 24 hrs. Given once a day, usually at HS Combination – commercial mixes. Example: Humulin 70/30 (70% NPH and 30% Regular) Available in vials or prefilled syringe “pens” Prototypes: Regular Insulin and Insulin Glargine (Lantus) INSULIN THERAPY REGULAR INSULIN: CORE DRUG KNOWLEDGE Pharmacotherapeutics All types of diabetes mellitus Pharmacokinetics Administered: SC or IV Pharmacodynamics Injected insulin mimics the effect of endogenous insulin REGULAR INSULIN: CORE DRUG KNOWLEDGE (CONT.) Contraindications and precautions Hypoglycemia Side effects and/or Adverse effects Hypoglycemia and lipoatrophy Patient and family education Discuss how to administer insulin properly. Discuss storage of insulin. Discuss side effects of therapy. Ongoing assessment and evaluation Evaluate ability to administer insulin. Monitor fasting blood glucose daily and hemoglobin A1C levels every few months. STORAGE OF INSULIN Refrigerate unopened vials until needed Once opened: Room temperature for 1 month; or Refrigerator for 3 months Less tissue irritation if at room temperature Roll the vials to mix contents before withdrawing (roll the Pens before injecting) Pre-filled syringes should be stored in the refrigerator and used within 1-2 weeks SLIDING SCALE INSULIN COVERAGE Insulin may be given in varying doses dependent on the patients glucose levels Glucose testing is performed several times a day, and insulin dose is given based on those test results Example: ADVERSE REACTIONS TO INSULIN Hypoglycemic reaction (Insulin shock) Nervousness, trembling, lack of coordination Cold and clammy skin Headache, dizziness Slurred speech Mental confusion, agitation, combativeness Seizures (Coma and Death may occur) Hypoglycemia symptoms are treated by administering glucose in any form - preferably oral ADVERSE REACTIONS TO INSULIN Hypokalemia (↓ K) – palpitations, arrhythmias Somogyi Effect Hypoglycemia between 2:00-4:00 am Dawn Phenomenon Hyperglycemia on wakening. Sxs are a headache on waking, night sweats, and nightmares INSULIN PUMPS Implantable Surgically implanted into the abdomen Delivers basal insulin and boluses of insulin with meals either intraperitoneal or IV Portable Continuous subQ insulin infusion (CSII) Battery operated device outside of the body that stores Regular insulin with wires that enter the body placed subQ in the location that the patient prefers About the size of a cell phone Delivers basal and bolus insulin Doses are programmed by the patient – pushes a button to deliver the insulin EXAMPLES OF INSULIN PUMPS QUESTION Which of the following SC site provides the most rapid absorption of insulin therapy? A. Arm B. Abdomen C. Buttocks D. Thigh QUESTION Which of the following SC site provides the most rapid absorption of insulin therapy? A. Arm B. Abdomen C. Buttocks D. Thigh B. Abdomen Rationale: The most rapid absorption occurs when administration is into the abdominal SC layer (as much as 50% faster than other routes). The next most rapid is into the arm, followed by the thigh, and finally the buttocks. ORAL HYPOGLYCEMICS - SULFONYLUREAS Sulfonylureas Stimulate the beta cells to secrete insulin plus increase tissue response to insulin and decrease glucose production by the liver Only for Type II Diabetes Chemically related to sulfonamides but no antibacterial properties Prototype Drug: Glipizide (Glucotrol, Glucotrol XL) GLIPIZIDE: CORE DRUG KNOWLEDGE Pharmacotherapeutics Adjunctive treatment to lower blood glucose levels in diabetes mellitus Type 2 Pharmacokinetics Administered: oral. Metabolism: liver. Excreted: urine and feces. Onset: 2 hours. Protein bound. Pharmacodynamics Hypoglycemic action results from the stimulation of pancreatic beta cells causing them to release more insulin. GLIPIZIDE: CORE DRUG KNOWLEDGE (CONT.) Contraindications and precautions Hypersensitivity, Sulfa allergy Side effects Anorexia, nausea, vomiting, heartburn, and a metallic taste in the mouth Adverse effects Hypoglycemia Drug interactions Drug interactions are possible because these drugs are metabolized by the CYP3A3/4 system. GLIPIZIDE: CORE DRUG KNOWLEDGE (CONT.) Patient and family education Administer before breakfast or the first main meal of the day. Teach about diabetes management. Diet Exercise Conditions that can increase blood glucose Teach patients and families the signs and symptoms of hypoglycemia. QUESTION The mechanism of action of glyburide is the decreased production of insulin by the liver, which results in decreased blood glucose levels. A. True B. False QUESTION The mechanism of action of glyburide is the decreased production of insulin by the liver, which results in decreased blood glucose levels. B. False Rationale: The mechanism of action of glyburide is stimulation of the beta cells in the pancreas. Hypoglycemic action of glyburide results from the stimulation of pancreatic beta cells. ORAL HYPOGLYCEMICS Nonsulfonylureas Prototype: Metformin (Glucophage) Decreases liver production of glucose from stored glycogen Decreases the absorption of glucose from the small intestine Increases insulin sensitivity and uptake at the cells Does not cause hypoglycemia May be combined with other antidiabetic medications METFORMIN: CORE DRUG KNOWLEDGE Pharmacotherapeutics Lower blood glucose in type 2 diabetes Pharmacokinetics Administered: oral. Metabolism: liver. Excreted: kidneys. Pharmacodynamics Decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake. METFORMIN: CORE DRUG KNOWLEDGE (CONT.) Contraindications and precautions Hepatic disease Side effects Anorexia, nausea and vomiting, weight loss, abdominal discomfort, dyspepsia, flatulence, diarrhea, and a metallic taste sensation Diarrhea is the biggest problem! Adverse effects No significant adverse effects. Will not cause hypoglycemia Drug interactions May react with contrast media used for radiographic procedures METFORMIN: PLANNING AND INTERVENTIONS Maximizing therapeutic effects Administer metformin twice a day with the morning and evening meal. Adherence with the recommended diabetic diet and daily exercise help in the control of type 2 diabetes. Minimizing adverse effects Taking the drug at mealtimes and using gradual dosage increments minimize side effects. QUESTION Metformin is contraindicated in which patients? A. Type 2 diabetics with open skin lesion B. Type 2 diabetics with chronic obstructive pulmonary disease C. Type 2 diabetics with coronary artery disease D. Type 2 diabetics with cirrhosis QUESTION Metformin is contraindicated in which patients? A. Type 2 diabetics with open skin lesion B. Type 2 diabetics with chronic obstructive pulmonary disease C. Type 2 diabetics with coronary artery disease D. Type 2 diabetics with cirrhosis D. Type 2 diabetics with cirrhosis Rationale: Metformin is contraindicated in patients with chronic liver disease. ORAL HYPOGLYCEMICS Incretin Modifiers Incretin is a hormone that stimulates insulin secretion in response to meals. Drugs act to slow the inactivation of incretin hormones, increase insulin secretion, and suppress glucagon secretion to reduce glucose production Used in combination with diet & exercise in Type II diabetes Prototype: Sitagliptin (Januvia) ORAL HYPOGLYCEMICS Incretin Mimetics Act to improve beta cell responsiveness, enhance insulin secretion, suppress glucagon secretion, slow gastric emptying and reduce food intake promoting weight loss. Not a substitute for insulin – not used for Type I DM Also approved as a weight loss drug Prototype: Liraglutide (Victoza) LIRAGLUTIDE: CORE DRUG KNOWLEDGE Pharmacotherapeutics Type II diabetes Weight loss Administration Given once daily Given subcutaneously using pre-filled pen syringe Side effects Nausea, bloating, delayed gastric emptying, decreased appetite Adverse effects Possible thyroid tumors, including cancer HYPERGLYCEMIC DRUG USED TO RAISE BLOOD SUGAR IN AN EMERGENCY Prototype: Glucagon Hormone secreted by alpha cells in the pancreas Stimulates glycogenolysis (breakdown of glucose) Available for subQ, IM and IV use Indicated to treat insulin-induced hypoglycemia in the patient who is semiconscious or unconscious Glucose levels increases in 5-20 minutes after dosing GLUCAGON: CORE DRUG KNOWLEDGE Pharmacotherapeutics Hypoglycemia Pharmacokinetics T½: 3 to 10 minutes Pharmacodynamics Increases blood glucose levels by stimulating glycogenolysis in the peripheral tissues GLUCAGON: CORE DRUG KNOWLEDGE (CONT.) Contraindications and precautions Hypersensitivity Adverse effects Hypotension, respiratory distress, nausea and vomiting Drug interactions Oral anticoagulants Minimizing adverse effects Administer supplemental carbohydrates as soon as possible once consciousness has been achieved. CASE STUDY Maria is a 67-yo, retired woman who states that she has nocturia 3-7x each night and increased hunger and thirst for the past 2 weeks. She is distressed that she may need additional medications to control her blood sugar. Her past medical history includes type 2 diabetes mellitus (diagnosed 15 years ago) which has been dietcontrolled, hypertension and hyperlipidemia. Data obtained from the nursing assessment include the following: Weight: 215 pounds Height: 5 feet, 4 inches Vital Signs: 152/82 – 88 – 16 T-98.2 F Labs: Glucose: 361 mg/dL (fasting); HgbA1C: 13.2 Cholesterol 315, Triglycerides 218 CASE STUDY The patient’s current medication therapy includes the following: Glucophage (Metformin) 1000 mg PO bid 1. What is the mechanism of action of metformin? 2. What are the common side effects of metformin? 3. Identify one other medication that she might be prescribed, its mechanism of action and its common side effects. 4. What core patient-specific variables are important to consider in doing patient education?