Agents to Control Blood Glucose Levels PDF

Chapter 38 Agents to Control Blood Glucose Levels Copyright Copyright © 2012 © 2017 Wolters Wolters Kluwer Kluwer...

Chapter 38 Agents to Control Blood Glucose Levels Copyright Copyright © 2012 © 2017 Wolters Wolters Kluwer Kluwer Health All | Lippincott Rights Reserved Williams & Wilkins Glucose Regulation #1  Pancreas o Endocrine gland  Produces hormones in the islets of Langerhans  Glucagon  Insulin  Somatostatin o Exocrine gland  Releases sodium bicarbonate and pancreatic enzymes directly into the common bile duct to be released into the small intestine Copyright © 2023 Wolters Kluwer All Rights Reserved Glucose Regulation #2  Insulin o Produced by beta cells of the islets of Langerhans o Released into circulation when levels of glucose around these cells rise o Reacts with specific insulin receptor sites to stimulate transport of glucose into cells to be used for energy o Stimulates liver to be able to uptake, store, use glucose o Released after meals  Circulates and affects metabolism  Causes blood glucose levels to fall Copyright © 2023 Wolters Kluwer All Rights Reserved Glucose Regulation #3 Glucagon o Released from alpha cells in islets of Langerhans in response to low blood glucose level o Causes immediate mobilization of glycogen  Raises blood glucose levels o Stimulates liver to convert protein into glucose Copyright © 2023 Wolters Kluwer All Rights Reserved Glucose Regulation #4  Adipocytes secrete adiponectin, which increases insulin sensitivity, decreases release of glucose from liver, and protects blood vessels from inflammation.  Endocannabinoid receptors seem to be part of signaling system to keep the body in a state of energy gain to prepare for stressful situations.  SNS decreases insulin release, increases release of stored glucose, and increases fat breakdown.  Corticosteroids decrease insulin sensitivity, increase glucose release, and decrease protein building.  Growth hormone decreases insulin sensitivity, increases FFAs, increases protein building. Copyright © 2023 Wolters Kluwer All Rights Reserved Loss of Blood Glucose Control Hyperglycemia: Increased blood sugar Glycosuria: Sugar is spilled into the urine Polyuria: Increased urination Polyphagia: Increased hunger Polydipsia: Increased thirst Lipolysis: Fat breakdown Ketosis: Metabolism shifts to use of fat for energy Acidosis: Liver cannot remove all of the waste products Copyright © 2023 Wolters Kluwer All Rights Reserved Diabetes Mellitus Characterized by complex disturbances in metabolism Affects carbohydrate, protein, and fat metabolism Clinical signs o Hyperglycemia (fasting blood sugar level greater than 126 mg/dL) o Glycosuria (presence of sugar in the urine) Over the long-term results in vascular damage Copyright © 2023 Wolters Kluwer All Rights Reserved Disorders Associated With Diabetes Atherosclerosis Retinopathy Neuropathies Nephropathy Infections Foot ulcers Copyright © 2023 Wolters Kluwer All Rights Reserved Classifications of Diabetes Mellitus #1 Type 1 o Caused by autoimmune destruction of beta cells of the pancreas o Patients need insulin replacement Type 2 o Progressive loss of beta cell release of insulin o Decreased insulin sensitivity in peripheral cells (insulin resistance) Copyright © 2023 Wolters Kluwer All Rights Reserved Classifications of Diabetes Mellitus #2 Diabetes due to other causes o Hyperglycemia due to secondary causes o Examples: medication-induced diabetes Gestational diabetes o Diagnosed in second or third trimester of pregnancy Copyright © 2023 Wolters Kluwer All Rights Reserved Clinical Signs and Symptoms of Hyperglycemia Fatigue Lethargy Irritation Glycosuria Polyphagia Polydipsia Frequent infections Poor wound healing Copyright © 2023 Wolters Kluwer All Rights Reserved Signs of Impending Dangerous Complications of Hyperglycemia Fruity breath Dehydration Slow, deep respirations Loss of orientation and coma Copyright © 2023 Wolters Kluwer All Rights Reserved Hypoglycemia Blood glucose 70 mg/dL or lower Initial response is parasympathetic stimulation o Increased GI activity to aid digestion and absorption SNS then responds with “fight-or-flight” reaction o Breakdown of fat and glycogen to release glucose o Pancreas releases glucagon to increase glucose and somatostatin Copyright © 2023 Wolters Kluwer All Rights Reserved Use of Antidiabetic Agents Across the Lifespan Copyright © 2023 Wolters Kluwer All Rights Reserved Question #1 Which is a clinical manifestation of hyperglycemia? A. Edema B. Lack of thirst C. Frequent infections D. Hyperexcitability Copyright © 2023 Wolters Kluwer All Rights Reserved Answer to Question #1 C. Frequent infections Rationale: Hyperglycemia , or high blood sugar, results when there is an increase in glucose in the blood. Clinical signs and symptoms include fatigue, lethargy, irritation, glycosuria, polyphagia, polydipsia, frequent infections, and poor wound healing. Copyright © 2023 Wolters Kluwer All Rights Reserved Sites of Action of Drugs Used to Treat Diabetes Copyright © 2023 Wolters Kluwer All Rights Reserved Insulin #1 Therapeutic actions o Promotes the storage of the body’s fuels o Facilitates the transport of various metabolites and ions across cell membranes o Simulates the synthesis of glycogen from glucose, of fats from lipids, of proteins from amino acids o Reacts with specific receptor sites on the cells Copyright © 2023 Wolters Kluwer All Rights Reserved Insulin #2  Indications o Treatment of type 1 diabetes mellitus o Treatment of type 2 diabetes mellitus in adults who have no response to diet, exercise, and other agents  Pharmacokinetics o Various preparations available: short- and long-term coverage o Processed within the body like endogenous insulin o Peak, onset, and duration vary based on preparation Copyright © 2023 Wolters Kluwer All Rights Reserved Insulin #3  Contraindications o None in general o Inhaled insulin: people with asthma, COPD, lung cancer or history of lung cancer  Cautions o Pregnancy and lactation  Adverse effects o Hypoglycemia o Local reactions at injection sites o Decreased blood potassium levels Copyright © 2023 Wolters Kluwer All Rights Reserved Insulin #4 Drug–drug interactions o Any drug that decreases glucose levels o Beta-blockers o Thiazide diuretics or glucocorticoids o Possible interactions with various herbal therapies Copyright © 2023 Wolters Kluwer All Rights Reserved Prototype Insulin Copyright © 2023 Wolters Kluwer All Rights Reserved Sulfonylureas #1 Stimulate functioning beta cells in pancreatic islets to release insulin May improve insulin binding to insulin receptors and increase number of insulin receptors Increase effect of antidiuretic hormone on renal cells Effective only in patients with functioning beta cells May lose effectiveness over time Second-generation sulfonylureas have several advantages over first-generation drugs Copyright © 2023 Wolters Kluwer All Rights Reserved Sulfonylureas #2 Therapeutic actions o Stimulate insulin release from the beta cells in the pancreas o They improve binding of insulin to insulin receptors Indications o Adjunct to diet and exercise to lower blood glucose levels in type 2 diabetes o Off-label use: Adjunct to insulin and metformin to improve glucose control Copyright © 2023 Wolters Kluwer All Rights Reserved Sulfonylureas #3  Pharmacokinetics o Rapidly absorbed from the GI tract; undergo hepatic metabolism o Excreted in the urine o Glyburide also excreted via bile o Peak and duration vary with each drug  Contraindications o Allergy o Diabetic complications o Type 1 diabetes o Pregnancy Copyright © 2023 Wolters Kluwer All Rights Reserved Sulfonylureas #4 Adverse effects o Hypoglycemia o GI distress o Allergic skin reactions Drug–drug interactions o Beta-blockers o Alcohol o Many herbal therapies Copyright © 2023 Wolters Kluwer All Rights Reserved Prototype Sulfonylurea Copyright © 2023 Wolters Kluwer All Rights Reserved Question #2 Please answer the following statement as true or false. Second-generation sulfonylureas have several advantages over first-generation sulfonylureas including the fact that they interact with more protein-bound drugs. Copyright © 2023 Wolters Kluwer All Rights Reserved Answer to Question #2 False Rationale: Second-generation sulfonylureas have several advantages over the first-generation drugs, including the following: o They do not interact with as many protein-bound drugs as the first-generation drugs do. o They have a longer duration of action, making it possible to take them only once or twice a day, thus increasing adherence. Copyright © 2023 Wolters Kluwer All Rights Reserved Alpha-Glucosidase Inhibitors #1 Therapeutic actions o Inhibit alpha-glucosidase, which breaks down glucose for absorption o Delay absorption of glucose o Assist in lowering HbA1c levels Indications o Used in combination with other agents for people whose glucose levels cannot be controlled with a single agent or with diet and exercise alone Copyright © 2023 Wolters Kluwer All Rights Reserved Alpha-Glucosidase Inhibitors #2  Pharmacokinetics o Absorbed orally at variable amounts o Acarbose metabolized in GI tract; miglitol excreted without being metabolized o Excreted by kidneys  Contraindications o Known hypersensitivity o DKA o GI disorders o Acarbose: cirrhosis Copyright © 2023 Wolters Kluwer All Rights Reserved Alpha-Glucosidase Inhibitors #3 Cautions o Renal impairment Adverse effects o GI effects o Anemia Drug–drug interactions o Other glucose-lowering agents o Medications that increase blood glucose Copyright © 2023 Wolters Kluwer All Rights Reserved Alpha-Glucosidase Inhibitor Prototype Copyright © 2023 Wolters Kluwer All Rights Reserved Biguanide #1 Therapeutic actions o Decreases production and increases uptake of glucose o Lowers both basal and postprandial blood glucose levels o Decreases hepatic glucose production o Improves insulin sensitivity of peripheral cells Indications o First-line standard of care for people with type 2 diabetes Copyright © 2023 Wolters Kluwer All Rights Reserved Biguanide #2 Pharmacokinetics o Absorbed orally o Not metabolized; excreted primarily in urine o Absorption and elimination times vary based on type of formulation Contraindications o Known hypersensitivity reactions o Metabolic acidosis o Severe renal impairment Copyright © 2023 Wolters Kluwer All Rights Reserved Biguanide #3 Cautions o Hepatic impairment o Excessive alcohol intake o Patients not eating/drinking due to surgery o Patients undergoing radiologic studies with contrast o Age 65 years or older o Hypoxic state Copyright © 2023 Wolters Kluwer All Rights Reserved Biguanide #4  Adverse effects o Boxed warning: lactic acidosis o GI side effects o Dizziness, headache, upper respiratory infection, taste disturbance  Drug–drug interactions o Alcohol use o Carbonic anhydrase o Iodine-containing contrast media o Check drug interactions before administration Copyright © 2023 Wolters Kluwer All Rights Reserved Biguanide Prototype Copyright © 2023 Wolters Kluwer All Rights Reserved DPP-4 Inhibitors #1 Therapeutic actions o Slow inactivation of incretin hormones o Increase insulin release o Lower glucagon secretion Indications o Adjunct to diet and exercise to lower blood glucose levels in patients with type 2 diabetes Copyright © 2023 Wolters Kluwer All Rights Reserved DPP-4 Inhibitors #2  Pharmacokinetics o Rapidly absorbed o Peak effects in 1 to 5 hours o Metabolism can vary o Excretion primarily via kidneys  Contraindications o DKA or type 1 diabetes o History of severe hypersensitivity reactions  Cautions o Renal impairment Copyright © 2023 Wolters Kluwer All Rights Reserved DPP-4 Inhibitors #3 Adverse effects o Most people do not report adverse effects o Rare: pancreatitis, heart failure, severe arthralgia, hypersensitivity reactions, exfoliative skin conditions Drug–drug interactions o Other medications that lower blood glucose o May be other drug interactions based on individual drug’s metabolism Copyright © 2023 Wolters Kluwer All Rights Reserved DPP-4 Inhibitor Prototype Copyright © 2023 Wolters Kluwer All Rights Reserved Meglitinides #1 Therapeutic actions o Similar to sulfonylureas Indications o Adjunct to diet and exercise in treatment of type 2 diabetes Pharmacokinetics o Rapidly absorbed o Extensively metabolized by liver o Quickly eliminated by kidneys Copyright © 2023 Wolters Kluwer All Rights Reserved Meglitinides #2 Contraindications o Type 1 diabetes or DKA o Known hypersensitivity Cautions o No studies regarding pregnancy o Patients should not breast or chestfeed Adverse effects o Upper respiratory infection, headache, arthralgia, nausea, diarrhea, hypoglycemia Copyright © 2023 Wolters Kluwer All Rights Reserved Meglitinides #3 Drug–drug interactions o Multiple; check for potential interactions. o Gemfibrozil should not be administered with repaglinide. Copyright © 2023 Wolters Kluwer All Rights Reserved Meglitinide Prototype Copyright © 2023 Wolters Kluwer All Rights Reserved SGLT-2 Inhibitors #1  Therapeutic actions o Block cotransporter system so glucose is not reabsorbed but lost in urine  Indications o Adjunct to diet and exercise in treatment of type 2 diabetes o Ongoing research on risk/benefit for type 1 diabetes  Pharmacokinetics o Absorbed from GI tract o Metabolized in liver; excreted via kidneys and feces Copyright © 2023 Wolters Kluwer All Rights Reserved SGLT-2 Inhibitors #2 Contraindications o DKA or type 1 diabetes o Severe renal impairment o Second or third trimester of pregnancy Cautions o Patients should not breast or chestfeed Copyright © 2023 Wolters Kluwer All Rights Reserved SGLT-2 Inhibitors #3 Adverse effects o Dehydration and hypotension o UTIs and genital fungal infections o DKA o Canagliflozin: loss of bone density and bone fractures o Lower limb amputation Drug–drug interactions o Medications that enhance metabolism of SGLT-2 inhibitors Copyright © 2023 Wolters Kluwer All Rights Reserved SGLT-2 Inhibitor Prototype Copyright © 2023 Wolters Kluwer All Rights Reserved Thiazolidinediones #1  Therapeutic actions o Decrease insulin resistance in peripheral cells and liver o Increase responsiveness to insulin  Indications o Adjunct to diet and exercise to lower blood glucose in type 2 diabetes  Pharmacokinetics o Absorbed orally o Metabolized by liver; excreted via kidneys and feces Copyright © 2023 Wolters Kluwer All Rights Reserved Thiazolidinediones #2  Contraindications o Moderate or severe heart failure  Cautions o Monitor for any changes in liver function  Adverse effects o Upper respiratory infections, headache, muscle pains o Increased total cholesterol o Rare: hepatic injury o Rapid weight gain and edema due to fluid retention Copyright © 2023 Wolters Kluwer All Rights Reserved Thiazolidinediones #3 Drug–drug interactions o Insulin o CYP2C8 inhibitors Copyright © 2023 Wolters Kluwer All Rights Reserved Thiazolidinedione Prototype Copyright © 2023 Wolters Kluwer All Rights Reserved Human Amylin #1  Therapeutic actions o Slows gastric emptying o Suppresses glucagon secretion from the liver o Regulates food intake by modulating appetite  Indications o Patients with both type 1 and type 2 diabetes who are also treated with insulin  Pharmacokinetics o Rapid onset of action; peaks in 20 min o Should be injected before each major meal Copyright © 2023 Wolters Kluwer All Rights Reserved Human Amylin #2 Contraindications o Hypersensitivity o Gastroparesis Cautions o When starting, insulin dosing should be decreased Adverse effects o Nausea, vomiting, anorexia, headache, injection site reactions o Severe hypoglycemia Copyright © 2023 Wolters Kluwer All Rights Reserved Human Amylin #3 Drug–drug interactions o Pramlintide and insulin or other antidiabetic medications o Absorption of oral medications may be inhibited o Gastric-slowing medications (e.g., opioids) Copyright © 2023 Wolters Kluwer All Rights Reserved Human Amylin Prototype Copyright © 2023 Wolters Kluwer All Rights Reserved GLP-1 Agonists #1 Therapeutic actions o Increase insulin release o Decrease glucagon release o Slow GI emptying Indications o Adjunct to diet and exercise for people with type 2 diabetes o Some also are used to reduce risk of major CV events in people with type 2 diabetes and CV disease Copyright © 2023 Wolters Kluwer All Rights Reserved GLP-1 Agonists #2 Pharmacokinetics o Most are administered via subcutaneous injection o Metabolism and excretion vary Contraindications o Liraglutide and semaglutide: boxed warnings for risk of thyroid C-cell tumors in animals o Type 1 diabetes or DKA o Pregnancy and breast or chestfeeding Copyright © 2023 Wolters Kluwer All Rights Reserved GLP-1 Agonists #3 Adverse effects o Pancreatitis o GI effects Drug–drug interactions o Oral medications: effects may be slowed o Other antidiabetic agents Copyright © 2023 Wolters Kluwer All Rights Reserved GLP-1 Agonist Prototype Copyright © 2023 Wolters Kluwer All Rights Reserved Glucose-Elevating Agents #1 Therapeutic actions o Increase the blood glucose levels by decreasing insulin release and accelerating the breakdown of glycogen in the liver to release glucose Indications o Treatment of hypoglycemia Pharmacokinetics o Rapidly absorbed and widely distributed throughout the body o Excreted in the urine Copyright © 2023 Wolters Kluwer All Rights Reserved Glucose-Elevating Agents #2 Contraindications o Diazoxide: Known allergies to sulfonamides or thiazides; pregnancy o Glucagon: No adequate studies on pregnancy Cautions o Lactation o Hepatic dysfunction or CV disease Copyright © 2023 Wolters Kluwer All Rights Reserved Glucose-Elevating Agents #3 Adverse effects o Glucagon and dasiglucagon: GI upset, nausea, vomiting o Diazoxide: vascular effects Drug–drug interactions o Diazoxide: thiazide diuretics o Glucagon and dasiglucagon: oral anticoagulants Copyright © 2023 Wolters Kluwer All Rights Reserved Glucose-Elevating Agent Prototype Copyright © 2023 Wolters Kluwer All Rights Reserved Question #3 Which of the following is a primary action of glucose- elevating agents? A. Accelerate the breakdown of glycogen B. Increase insulin release C. Improve binding to insulin receptors D. Decrease use of incretins Copyright © 2023 Wolters Kluwer All Rights Reserved Answer to Question #3 A. Accelerate the breakdown of glycogen Rationale: These agents increase the blood glucose level by decreasing insulin release and accelerating the breakdown of glycogen in the liver to release glucose. Copyright © 2023 Wolters Kluwer All Rights Reserved