Antidiabetic Drugs
Objectives
When you reach the end of this chapter, you will be able to do the following:
1 Discuss the normal functions of the pancreas.
3 Differentiate gestational diabetes from type 1 and type 2 diabetes mellitus.
5 Identify the various drugs used to manage type 1 and type 2 diabetes mellitus.
8 Compare the signs and symptoms of hypoglycemia and hyperglycemia and their related treatments.
Drug Profiles
Key Terms
Diabetes mellitus A complex disorder of carbohydrate, fat, and protein metabolism resulting from the lack of insulin secretion by the beta cells of the pancreas or from defects of the insulin receptors; it is commonly referred to simply as diabetes. There are two major types of diabetes: type 1 and type 2. (p. 512)
Diabetic ketoacidosis (DKA) A severe metabolic complication of uncontrolled diabetes that, if untreated, leads to diabetic coma and death. (p. 513)
Gestational diabetes Diabetes that develops during pregnancy. It may resolve after pregnancy but may also be a precursor of type 2 diabetes in later life. (p. 515)
Glucagon A hormone produced by the alpha cells in the islets of Langerhans that stimulates the conversion of glycogen to glucose in the liver. (p. 511)
Glucose One of the simple sugars that serves as a major source of energy. It is found in foods (e.g., fruits, refined sweets) and also is the final breakdown product of complex carbohydrate metabolism in the body; it is commonly referred to as dextrose. (p. 511)
Glycogen A polysaccharide that is the major carbohydrate stored in animal cells. (p. 511)
Glycogenolysis The breakdown of glycogen to glucose. (p. 511)
Hemoglobin A1C (A1C) Hemoglobin molecules to which glucose molecules are bound; blood levels of hemoglobin A1C are used as a diagnostic measure of average daily blood glucose levels in the monitoring and diagnosing of diabetes; it is also called glycosylated hemoglobin and most commonly referred to as A1C. (p. 515)
Hyperglycemia A fasting blood glucose level of 126 mg/dL or higher or a nonfasting blood glucose level of 200 mg/dL or higher. (p. 512)
Hyperosmolar nonketotic syndrome (HNKS) A metabolic complication of uncontrolled type 2 diabetes, similar in severity to diabetic ketoacidosis but without ketosis and acidosis. (p. 514)
Hypoglycemia A blood glucose level of less than 50 mg/dL, or above 50 mg/dL with signs and symptoms of hypoglycemia. (p. 525)
Impaired fasting glucose level A fasting glucose level of at least 100 mg/dL but lower than 126 mg/dL; it defines a prediabetic state that is sometimes called prediabetes. (p. 515)
Insulin A naturally occurring hormone secreted by the beta cells of the islets of Langerhans in the pancreas in response to increased levels of glucose in the blood. (p. 511)
Ketones Organic chemical compounds produced through the oxidation of secondary alcohols (e.g., fat molecules), including dietary carbohydrates. (p. 512)
Polydipsia Chronic excessive intake of water; it is a common symptom of uncontrolled diabetes. (p. 512)
Polyphagia Excessive eating; it is a common symptom of uncontrolled diabetes. (p. 512)
Polyuria Increased frequency or volume of urinary output; it is a common symptom of diabetes. (p. 512)
Type 1 diabetes mellitus Diabetes mellitus that is a genetically determined autoimmune disorder characterized by a complete or nearly complete lack of insulin production; it most commonly arises in children or adolescents. (p. 513)
Type 2 diabetes mellitus A type of diabetes mellitus that most commonly presents in adults and is becoming more common in children and adolescents due to inactivity and weight gain. The disease may be controlled by lifestyle modifications, oral drug therapy, and/or insulin, but patients are not necessarily dependent on insulin therapy. (p. 514)
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Anatomy, Physiology, and Pathophysiology Overview
Pancreas
The pancreas is a large, elongated organ that is located behind the stomach. It is both an exocrine gland (secreting digestive enzymes through the pancreatic duct) and an endocrine gland (secreting hormones directly into the bloodstream and not through a duct). The endocrine functions of the pancreas are the focus of this chapter. Two main hormones that are produced by the pancreas are insulin and glucagon. Both hormones play an important role in the regulation of glucose homeostasis, specifically the use, mobilization, and storage of glucose by the body. Glucose is one of the primary sources of energy for the cells of the body. It is also the simplest form of carbohydrate (sugar) found in the body and is often referred to as dextrose. There is a normal amount of glucose that circulates in the blood to meet requirements for quick energy. When the quantity of glucose in the blood is sufficient, the excess is stored as glycogen in the liver and, to a lesser extent, in skeletal muscle tissue, where it remains until the body needs it. Glucose is also stored in adipose tissue as triglyceride body fat. When more circulating glucose is needed, glycogen—primarily that stored in the liver—is converted back to glucose through a process called glycogenolysis. The hormone responsible for initiating this process is glucagon. Glucagon has only minimal effects on muscle glycogen and adipose tissue triglyceride stores.
Glucagon is a protein hormone consisting of a single chain of amino acids (polypeptide chain). Its molecules are about half the size of those of insulin. Glucagon is released from the alpha cells of the islets of Langerhans in the pancreas. Insulin is secreted from the beta cells of these same islets. Insulin is a protein hormone composed of two amino acid chains (acidic A chain and basic B chain) joined by a disulfide linkage. There is a continuous homeostatic balance in the body between the actions of insulin and those of glucagon. This natural balance serves to maintain optimal blood glucose levels, which normally range between 70 and 100 mg/dL. Because of the critical role of the pancreas in producing and maintaining these two hormones, the drastic measures of pancreatic or islet cell transplant are sometimes undertaken to treat type 1 diabetes that has not been successfully controlled by other means. Another common treatment is continuous insulin administration via a mechanized insulin pump, which may be used to treat type 1 or type 2 diabetes.
Insulin serves several important metabolic functions in the body. It stimulates carbohydrate metabolism in skeletal and cardiac muscle and in adipose tissue by facilitating the transport of glucose into these cells. In the liver, insulin facilitates the phosphorylation of glucose to glucose-6-phosphate, which is then converted to glycogen for storage. By causing glucose to be stored in the liver as glycogen, insulin keeps the kidney free of glucose. Without insulin, blood glucose levels rise; when the kidneys are unable to reabsorb this excess glucose, they excrete large amounts of glucose (a critical body nutrient and energy source), ketones, and other solutes into the urine. This loss of nutrient energy sources eventually leads to polyphagia, weight loss, and malnutrition. The presence of these solutes in the distal renal tubules and collecting ducts also draws large volumes of water into the urine through osmotic diuresis, which leads to polyuria, dehydration, and polydipsia.
Insulin also has a direct effect on fat metabolism. It stimulates lipogenesis and inhibits lipolysis and the release of fatty acids from adipose cells. In addition, insulin stimulates protein synthesis and promotes the intracellular shift of potassium and magnesium into the cells, thereby temporarily decreasing elevated blood concentrations of these electrolytes. Other substances such as cortisol, epinephrine, and growth hormone work synergistically with glucagon to counter the effects of insulin and cause increases in the blood glucose level.
Pathophysiology of Diabetes Mellitus
Hyperglycemia is a state involving excessive concentrations of glucose in the blood and results when the normal counterbalancing actions of glucagon and insulin fail to maintain normal glucose homeostasis (i.e., serum levels of 70 to 100 mg/dL). Complications in protein and fat metabolism (dyslipidemia; see Chapter 27) are also involved. The current key diagnostic criterion for diabetes mellitus is hyperglycemia with a fasting plasma glucose level of higher than 126 mg/dL or a hemoglobin A1C (A1C) level greater than or equal to 6.5%. Diagnostic indicators are described in more detail in Box 32-1. It is important to note that the diagnostic definition of diabetes established by the American Diabetes Association (ADA) differs from that issued by the American College of Endocrinology. This text uses the ADA as a reference.
Diabetes mellitus, more commonly referred to simply as diabetes, is primarily a disorder of carbohydrate metabolism that involves either a deficiency of insulin, a resistance of tissue (e.g., muscle, liver) to insulin, or both. Whatever the cause of the diabetes, the result is hyperglycemia. Uncontrolled hyperglycemia correlates strongly with serious long-term macrovascular and microvascular complications. Macrovascular complications are usually secondary to large vessel damage caused by deposition of atherosclerotic plaque. This compromises both central and peripheral circulation. In contrast, microvascular complications are secondary to damage to the capillary vessels, which impairs peripheral circulation and damages eyes and kidneys. In addition, both autonomic and somatic nerve damage occur, caused primarily by the metabolic changes themselves and to a lesser degree by the compromised circulation. Table 32-1 lists the common long-term complications of diabetes.
TABLE 32-1
MAJOR LONG-TERM CONSEQUENCES OF TYPE 1 AND TYPE 2 DIABETES
| PATHOLOGY | POSSIBLE CONSEQUENCES |
| Macrovascular (Atherosclerotic Plaque) | |
| Coronary arteries | Myocardial infarction |
| Cerebral arteries | Stroke |
| Peripheral vessels | Peripheral vascular disease (e.g., neuropathies [see below], foot ulcers, possible amputations) |
| Microvascular (Capillary Damage) | |
| Retinopathy (retinal damage) | Partial or complete blindness |
| Neuropathy (autonomic and somatic nerve damage, due to both metabolic alterations and compromised circulation) | Autonomic nerve damage: Example: diabetic gastroparesis, bladder dysfunction, unawareness of hypoglycemia, sexual dysfunction Somatic nerve damage: Example: diabetic foot ulcer and/or leg or foot amputation (resulting from undetected injuries due to loss of sensation and also from compromised circulation) |
| Nephropathy (kidney damage) | Proteinuria (microalbuminuria), chronic renal failure (may require dialysis or kidney transplantation) |
Data from American Diabetes Association: Executive summary: standards of medical care in diabetes, Diabetes Care 35(Suppl 1): S4-S10, 2012.
Diabetes mellitus has been recognized since 1550 BC, when Egyptians wrote of a malady they called honeyed urine. The first step toward identifying the cause of diabetes mellitus occurred in 1788 when Thomas Cawley, an English physician, voiced his suspicion that the source of the illness lay in the pancreas. However, it took over a century to prove this conjecture correct, and it took even longer to discover the active substance, insulin, that is secreted from the pancreas. Not until the early 1920s was insulin finally isolated. Its discovery is now considered one of the greatest triumphs of twentieth-century medicine, and its use in the treatment of diabetes mellitus has proved to be life saving for millions of people affected by the disease.
Diabetes mellitus actually is not a single disease, but a group of progressive diseases. For this reason, it is often regarded as a syndrome rather than a disease. In some cases, diabetes is caused by a relative or absolute lack of insulin that is believed to result from the destruction of beta cells in the pancreas. As a result, insulin cannot be produced. However, hyperglycemia can also be caused by defects in insulin receptors that result in insulin resistance. The proteins that serve as insulin receptors are attached to the surface of cells in the liver, muscle, and adipose tissue. These receptor proteins are stimulated by insulin molecules to move glucose from blood to cells. When insulin receptors become defective, they no longer respond normally to insulin molecules. Although serum insulin and glucose levels are both elevated, they do not respond and transport glucose into the cell where it is needed. The result is that glucose molecules remain in the blood, rather than being used in the cell or stored in the tissues.
Two major types of diabetes mellitus are currently recognized and designated by the ADA: type 1 and type 2. Type 1 diabetes was previously called insulin-dependent diabetes mellitus (IDDM) or juvenile-onset diabetes. Type 2 diabetes was previously called non–insulin-dependent diabetes mellitus (NIDDM) or adult-onset diabetes. The numeric designations for both conditions were adopted by the ADA as the preferred terms in 1995. The previous designations were abandoned for several reasons. One reason is that many patients with type 2 diabetes do eventually become dependent on insulin therapy for control of their illness. A second reason is that the current epidemic of both child and adult obesity in the United States is increasing the incidence of type 2 diabetes in children, adolescents, and young adults. Obesity is one of the major risk factors for the development of type 2 diabetes. Nonwhite ethnic groups, including African Americans, Asian Americans, Hispanic Americans, and Native Americans, are all at higher risk for the disease than are whites.
The usual differences between type 1 and type 2 diabetes mellitus are listed in Table 32-2. Interestingly, approximately 10% of patients with type 2 diabetes have circulating antibodies that suggest an autoimmune origin for the disease. This condition is known as latent autoimmune diabetes in adults (LADA) and is basically a more slowly progressing form of type 1 diabetes.
TABLE 32-2
CHARACTERISTICS OF TYPE 1 AND TYPE 2 DIABETES
| CHARACTERISTIC | TYPE 1 | TYPE 2 |
| Etiology | Autoimmune destruction of beta cells in the pancreas | Multifactorial genetic defects; strong association with obesity and insulin resistance resulting from a reduction in the number or activity of insulin receptors |
| Incidence | 10% of cases | 90% of cases |
| Onset | Juvenile onset, usually younger than 20 yr | Previously maturity onset, age older than 40 yr; now increasingly seen in younger adults and even adolescents—attributed to obesity epidemic |
| Endogenous insulin | Little or none | Normal or high levels in early disease; reduced later in disease |
| Insulin receptors | Normal | Decreased or defective |
| Body weight | Usually nonobese | Obese (80% of cases) |
| Treatment | Insulin | Weight loss, diet and exercise, and oral hypoglycemics; only about one third of all patients need insulin. Earlier use of insulin is associated with improved outcomes. |
The most common signs and symptoms of diabetes are elevated blood glucose level (fasting glucose level higher than 126 mg/dL) and polyuria, polydipsia, polyphagia, glucosuria, weight loss, blurred vision, and fatigue.
Type 1 Diabetes Mellitus
Type 1 diabetes mellitus is characterized by a lack of insulin production or by the production of defective insulin, which results in acute hyperglycemia. Affected patients require exogenous insulin to lower the blood glucose level and prevent diabetic complications. It is believed that a genetically determined autoimmune reaction gradually destroys the insulin-producing beta cells of the pancreatic islets of Langerhans (Figure 32-1). The preclinical phase of beta cell destruction may be prolonged, possibly lasting several years. At some critical point, a rapid transition from preclinical to clinical type 1 diabetes occurs. This transition is believed to be triggered by a specific event such as an acute illness or major emotional stress. An unidentified viral infection is also strongly suspected as an environmental trigger. Those stressors trigger the release of the counter-regulatory hormones cortisol and epinephrine. These hormones then mobilize glucagon to release glucose from the storage sites in the liver. This further increases the already rising levels of glucose in the blood secondary to islet cell damage. At some point during this critical cascade of events, an autoimmune reaction may be initiated that destroys the insulin-producing beta cells of the pancreatic islets of Langerhans. The result is essentially a complete lack of endogenous insulin production by the pancreas, which necessitates long-term insulin replacement therapy. Fortunately, type 1 diabetes accounts for fewer than 10% of all diabetes cases. Uncontrolled type 1 diabetes is often referred to as brittle diabetes, and these patients have large fluctuations in their blood glucose levels.
Acute Diabetic Complications: Diabetic Ketoacidosis and Hyperosmolar Nonketotic Syndrome
When blood glucose levels are high but no insulin is present to allow glucose to be used for energy production, the body may break down fatty acids for fuel, producing ketones as a metabolic by-product. If this occurs to a sufficient degree, diabetic ketoacidosis (DKA) may result. DKA is a complex multisystem complication of uncontrolled diabetes. Without treatment, DKA will lead to coma and death. DKA is characterized by extreme hyperglycemia, the presence of ketones in the serum, acidosis, dehydration, and electrolyte imbalances. Approximately 25% to 30% of patients with newly diagnosed type 1 diabetes mellitus present with DKA. Another complication of comparable severity that is also triggered by extreme hyperglycemia is hyperosmolar nonketotic syndrome (HNKS). The most common precipitator of DKA and HNKS is some type of physical or emotional stress. It was formerly believed that DKA occurred only in type 1 diabetes and HNKS occurred only in type 2 diabetes. However, it is now recognized that both disorders can occur with diabetes of either type, and this overlap is increasingly common with the rapidly decreasing age of patients with type 2 diabetes.
Table 32-3 describes the subtle differences between DKA and HNKS. Treatment for either complication involves fluid and electrolyte replacement as well as intravenous insulin therapy (more common for DKA).
TABLE 32-3
COMPARISON OF FEATURES OF DIABETIC KETOACIDOSIS AND HYPEROSMOLAR NONKETOTIC SYNDROME
| CONDITION | ||
| FEATURE | DIABETIC KETOACIDOSIS | HYPEROSMOLAR NONKETOTIC SYNDROME |
| Age of patient | Younger than 40 yr | Older than 40 yr |
| Duration of symptoms | Less than 2 days | More than 5 days |
| Serum glucose level | Lower than 800 mg/dL | Higher than 800 mg/dL |
| Serum Na level | Normal or low | Normal or high |
| Serum HCO3 level | Low | Normal |
| Ketone bodies | At least 4+ | Less than 2+ |
| pH | Low | Normal |
| Serum osmolality | Less than 350 mOsm/kg | Greater than 350 mOsm/kg |
| Prognosis | 3% to 10% mortality | 10% to 20% mortality or more |
| Subsequent course | Insulin therapy required in all cases | Insulin therapy not required in many cases after initial treatment |
Adapted from Harmel AP, Mathur R: Davidson’s diabetes mellitus: diagnosis and treatment, ed 5, Philadelphia, 2004, Saunders.
Type 2 Diabetes Mellitus
Type 2 diabetes mellitus is by far the most common form of diabetes, accounting for at least 90% of all cases of diabetes mellitus and affecting over 23 million people in the United States. Because this form of diabetes does not always require insulin therapy, there are many common and dangerous misconceptions regarding type 2 diabetes mellitus: that it is a mild diabetes; that it is easy to treat; and that tight metabolic control is unnecessary because these patients, who are mostly older adults, will die before diabetic complications develop. The clinical realities of this disease demonstrate otherwise.
Type 2 diabetes mellitus is caused by both insulin resistance and insulin deficiency, but there is no absolute lack of insulin as in type 1 diabetes. One of the normal roles of insulin is to facilitate the uptake of circulating glucose molecules into tissues to be used as energy. In type 2 diabetes, all of the main target tissues of insulin (i.e., muscle, liver, and adipose tissue) are hyporesponsive (resistant) to the effects of the hormone. Not only is the absolute number of insulin receptors in these tissues reduced, but their individual sensitivity and responsiveness to insulin is decreased as well. Therefore, it is possible for a patient with type 2 diabetes mellitus to have normal or even elevated levels of insulin yet still have high blood glucose levels. These processes also result in impaired postprandial (after a meal) glucose metabolism, which is another problematic feature of type 2 diabetes that contributes to the hazardous hyperglycemic state.
In addition to the reduction in the number and sensitivity of insulin receptors in type 2 diabetes, there is often reduced insulin secretion by the pancreas. This insulin deficiency results from a loss of the normal responsiveness of the beta cells in the pancreas to elevated blood glucose levels. When the beta cells do not recognize glucose, they do not secrete insulin, and the normal insulin-facilitated transport of glucose into cells of muscle, liver, and adipose tissue does not occur.
Type 2 diabetes is a multifaceted disorder. Although loss of blood glucose control is its primary hallmark, several other significant conditions are strongly associated with the disease. These include obesity, coronary heart disease, dyslipidemia, hypertension, microalbuminuria (spilling of protein into the urine), and an increased risk for thrombotic (blood clotting) events. For patients with type 2 diabetes, the ADA recommends the use of aspirin for prevention of coronary artery (heart) disease and antihyperlipidemic drug therapy (see Chapter 27), when indicated, in addition to any necessary antidiabetic drug therapy. These comorbidities are strongly associated with the development of type 2 diabetes and are collectively referred to as metabolic syndrome (also known as insulin-resistance syndrome and syndrome X). Roughly 80% of patients with diabetes are obese at the time of initial diagnosis. Obesity serves only to worsen the insulin resistance, because adipose tissue is often the site of a large proportion of the body’s defective insulin receptors. The goal for patients with diabetes is a blood pressure less than 130/80 mm Hg and a low-density lipid (LDL) less than 100 mg/dL.
Gestational Diabetes
Gestational diabetes is a type of hyperglycemia that develops during pregnancy. Relatively uncommon, it occurs in about 2% to 10% of pregnancies. Many patients are well controlled with diet, but the use of insulin may be necessary to decrease the risk of birth defects, hypoglycemia in the newborn, and high birth weight. In most cases, gestational diabetes subsides after delivery. However, as many as 30% of patients who experience gestational diabetes are estimated to develop type 2 diabetes within 10 to 15 years.
All pregnant women need to have blood glucose screenings at regular prenatal visits. Women who develop gestational diabetes need to be screened for lingering diabetes 6 to 8 weeks postpartum and be advised of their increased risk for recurrent diabetes and of the importance of regular medical checkups and weight control. Women who are known to be diabetic before pregnancy should have detailed prepregnancy counseling and prenatal care from a prescriber who is experienced in managing pregnancies in diabetic women. Specific drug therapy issues pertaining to gestational diabetes are discussed further in the section on insulins.
Prevention and Screening
Both macrovascular and microvascular problems are now recognized to occur at fasting plasma glucose (FPG) levels as low as 126 mg/dL. Fasting is defined loosely as an 8-hour or an overnight fast (no food from midnight until after the blood sample is taken in the morning). Impaired fasting glucose level is defined as an FPG level higher than or equal to 100 mg/dL but less than 126 mg/dL. This condition often proves to be a precursor to diabetes and is therefore referred to as prediabetes. The 2012 ADA guidelines renamed prediabetes as “categories of increased risk for diabetes” and define it as impaired fasting glucose and hemoglobin A1C of 5.7% to 6.4%. Another recognized prediabetic condition is impaired glucose tolerance, which is identified using an oral glucose challenge test (see Box 32-1). The ADA, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Centers for Disease Control and Prevention recommend that all adults 45 years of age and older be screened for elevated FPG levels every 3 years. Several preventive measures are also recommended. Reducing alcohol consumption is helpful, because alcohol is broken down in the body to simple carbohydrates, which leads to increases in blood glucose levels. Regular exercise, in addition to having beneficial effects on weight and high blood pressure, also lowers blood glucose levels by increasing insulin receptor sensitivity.
Nonpharmacologic Treatment Interventions
Patients diagnosed with type 1 diabetes always require insulin therapy. For patients with new-onset type 2 diabetes, lifestyle changes should be initiated as a first step in treatment. Weight loss not only lowers the blood glucose and lipid levels of these patients, but it also reduces another common comorbidity, hypertension. Other recommended lifestyle changes include improved dietary habits (e.g., consumption of a diet higher in protein and lower in fat and carbohydrates), smoking cessation, reduced alcohol consumption, and regular physical exercise. Cigarette smoking doubles the risk of cardiovascular disease in diabetic patients, largely because of its effects on peripheral vascular circulation and respiratory function. In fact, smoking cessation would probably save far more lives than antihypertensive, antilipemic, and antidiabetic drug treatment combined!
Glycemic Goal of Treatment
The glycemic goal recommended by the ADA for diabetic patients is a hemoglobin A1C (A1C) level of less than 7%. The A1C test measures the percentage of hemoglobin A that is irreversibly glycosylated. A1C is an indicator of glycemic control in a patient over the preceding 2 to 3 months (the average lifespan of a red blood cell) and is not affected by recent fluctuations in blood glucose levels. The ADA recommended a fasting blood glucose goal for diabetic patients of 70 to 130 mg/dL.
Pharmacology Overview
The major classes of drugs used to treat diabetes mellitus are the insulins and the oral antidiabetic drugs. Several new classes of injectable drugs with unique mechanisms of action have been developed that may be used in addition to insulins or oral antidiabetic drugs to treat resistant diabetes. All of these drugs are referred to as antidiabetic drugs, and they are aimed at producing a normoglycemic or euglycemic (normal blood glucose) state.
INSULINS
Insulin is required in patients with type 1 diabetes. Patients with type 2 diabetes are not generally prescribed insulin until other measures (i.e., lifestyle changes and oral drug therapy) no longer provide adequate glycemic control. Currently insulin is synthesized in laboratories using recombinant deoxyribonucleic acid (DNA) technology and is referred to as human insulin. Insulin was originally isolated from cattle or pigs, but bovine (cow) and porcine (pig) insulins are associated with a higher incidence of allergic reactions and insulin resistance than human insulin and are no longer available in the U.S. market. Recombinant insulin is produced by bacteria or yeast that have been altered to contain the genetic information necessary for them to reproduce an insulin that is like human insulin. The pharmacokinetic properties of insulin (onset of action, peak effect, and duration of action) can be altered by making various minor modifications to either the insulin molecule itself or the drug formulation (final product). This practice has led to the development of many different insulin preparations, including several combination insulin products that contain more than one type of insulin in the same solution. Chemical manipulation of insulin activity in this way helps to meet the individual meal-related metabolic demands of patients with diabetes. Further modifications can be accomplished by mixing compatible insulin preparations in the syringe before administration. The latest syringe compatibility data for currently available insulin products are given in Table 32-4. Thoroughly educate patients regarding how, when, and whether they can (or cannot) mix different types of insulin. Some combinations are chemically incompatible and can result in an undesirable alteration of glycemic effects.
TABLE 32-4
INSULIN MIXING COMPATIBILITIES
| TYPE OF INSULIN | COMPATIBLE WITH |
| Regular insulin (Humulin R, Novolin R) | All insulins except glargine, and glulisine |
| Insulin glulisine (Apidra) | NPH only |
| Insulin lispro (Humalog), insulin aspart (NovoLog) | Regular, NPH insulins |
| Insulin detemir (Levemir) | Must be given alone |
| Insulin glargine (Lantus) | Must be given alone due to low pH of diluent |
| NPH 70% and regular insulin 30% (Humulin 70/30, Novolin 70/30) |  Premixed; do not mix with other insulins |
| NPH 50% and regular insulin 50% (Humulin 50/50) | |
| Insulin aspart protamine suspension 75% and insulin aspart 25% (NovoLog Mix 75/25) | |
| Insulin lispro protamine suspension 75% and insulin lispro 25% (Humalog Mix 75/25) |
Mechanism of Action and Drug Effects
Exogenous insulin functions as a substitute for the endogenous hormone. It serves to replace the insulin that is either not made or is made defectively in a diabetic patient. The drug effects of exogenously administered insulin involve many body systems. They are the same as those of normal endogenous insulin. That is, exogenous insulin restores the patient’s ability to metabolize carbohydrates, fats, and proteins; to store glucose in the liver; and to convert glycogen to fat stores. Unfortunately, exogenous insulin does not reverse defects in insulin receptor sensitivity. Insulin pumps are a very attractive way to administer insulin to patients. The insulin pump provides an alternative to multiple daily subcutaneous injections and allows patients to match their insulin intake to their lifestyle. When an insulin pump is used, insulin is administered constantly over a 24-hour period, and the patient is then allowed to give bolus injections based on the amount of food ingested. Insulin pumps are described further in the Nursing Process section.
Indications
All insulin preparations can be used to treat both type 1 and type 2 diabetes, but each patient requires careful customization of the dosing regimen for optimal glycemic control. Additional therapeutic approaches such as lifestyle modifications (e.g., dietary and exercise habits) are also indicated and, for type 2 diabetes, oral drug therapy as well.
Contraindications
Contraindications to the use of all insulin products include known drug allergy to the specific product. Insulin is never to be administered to an already hypoglycemic patient. Blood glucose must always be tested prior to administration.
Adverse Effects
Hypoglycemia resulting from excessive insulin dosing can result in brain damage, shock, and possible death. This is the most immediate and serious adverse effect of insulin. Other adverse effects of insulin therapy include weight gain, lipodystrophy at the site of repeated injections, and in rare cases allergic reactions. Because weight gain is a common and often undesirable adverse effect, insulin therapy is usually delayed in type 2 patients until other agents and lifestyle changes have failed to bring the blood glucose to target levels.
Interactions
Drug interactions that can occur with the insulins are significant; they are listed in Table 32-5.
DOSAGES
Selected Human-Based Insulin Products
| DRUG (PREGNANCY CATEGORY) | PHARMACOLOGIC CLASS | USUAL DOSAGE RANGE | INDICATIONS |
| Rapid Acting |  Diabetes mellitus type 1 and type 2 | ||
| insulin lispro (Humalog) (B) | Human recombinant rapid-acting insulin analogue | Subcut: 0.5-1 unit/kg/day; doses are highly individualized to desired glycemic control; rapid-acting insulins are best given 15 min before a meal May be given per sliding scale or as basal/bolus; may also be given via continuous subcutaneous infusion pump | |
| Short Acting | |||
| ♦ regular insulin (Humulin R, Novolin R) (B) | Human recombinant short-acting insulin | Subcut: Same dosage as insulin lispro; subcut doses of regular insulin are best given 30 min before a meal Regular insulin may also be given per sliding scale or basal/bolus and is the insulin usually given IV as a continuous infusion | |
| Long Acting | |||
| insulin glargine (Lantus) (C) | Human recombinant long-acting insulin analogue | Subcut only: Same dosage as others but is approved only for once- or twice-daily dosage (basal dosing) |
TABLE 32-5
SELECTED DRUG INTERACTIONS WITH ANTIDIABETIC DRUGS
| DRUG | INTERACTING DRUG | MECHANISM | RESULT |
| insulin | Corticosteroids, niacin, diuretics, sympathomimetic drugs, thyroid drugs | Antagonizes insulin effect | Increased blood glucose levels |
| Alcohol, anabolic steroids, sulfa antibiotics, clofibrate, MAOIs, salicylates | Increases the hypoglycemic effects of insulin | Decreased blood glucose levels | |
| Nonselective beta blockers | Masks the tachycardia from hypoglycemia | Risk of not noticing hypoglycemic symptoms | |
| Hypoglycemic drugs | Additive effects | Additive hypoglycemia | |
| metformin | Cimetidine | Inhibits metabolism | Increased metformin effects |
| Diuretics, steroids | Additive effects | Additive hypoglycemia | |
| Contrast media | Decreases excretion | Lactic acidosis | |
| glipizide | Alcohol, antacids, cimetidine, clofibrate, fluconazole, NSAIDs, sulfonamide antibiotics, garlic, ginger, ginseng | Enhanced effects | Increased hypoglycemia |
| Carbamazepine, phenobarbital, phenytoin, rifampin | Increases metabolism | Decreased effectiveness |
MAOI, Monoamine oxidase inhibitor; NSAID, nonsteroidal antiinflammatory drug
Dosages
For dosage information on the various insulin products, see the table above. The concentration of insulin is expressed as the number of units of insulin per milliliter. For example, U-100 insulin has 100 units in 1 milliliter. Insulin is usually given by subcutaneous injection or via a subcutaneous infusion pump. In emergency situations requiring prompt insulin action, regular insulin can be given intravenously.
Insulin Use in Special Populations
Two special patient populations for whom careful attention is required during insulin therapy are pediatric patients and pregnant women. Insulin dosages for both are calculated by weight as they are for the general adult population. The usual dosage range is 0.5 to 1 units/kg/day as a total daily dose. Be aware that there are a few important differences regarding the use of some insulin products in pediatric populations. The rapid-acting insulin lispro is approved for use in children older than 3 years of age. However, the combination lispro product Humalog 75/25, which contains 75% insulin lispro protamine (an intermediate-acting insulin) and 25% insulin lispro (a rapid-acting insulin), is not currently approved for use in children younger than 18 years of age. Children need age-appropriate education and supervision by health care professionals and parents, which includes a safe and gradual transfer of responsibility for self-management of their illness, as appropriate.
Pregnant women also require special care with regard to diabetes management. Although most of these mothers will return to a normal glycemic state after pregnancy, they are at risk of developing diabetes again in later life. All currently available oral and injectable antidiabetic drugs are classified as pregnancy category B or C drugs. Oral medications are generally not recommended for pregnant patients because of a lack of firm safety data. For this reason, insulin therapy is the only currently recommended drug therapy for pregnant women with diabetes. Roughly 15% of women who develop gestational diabetes require insulin therapy during pregnancy. Insulin does not normally cross the placenta. Effective glycemic control during pregnancy is essential because infants born to women with gestational diabetes have a twofold to threefold greater risk of congenital anomalies. In addition, the incidence of stillbirth is directly related to the degree of maternal hyperglycemia. Weight reduction is generally not advised for these women, because it can jeopardize fetal nutritional status. Women with gestational diabetes tend to have babies that weigh more, and these children may have low blood sugar postnatally. Insulin is excreted into human milk. It is currently unknown whether insulin glargine is excreted in breast milk, and thus it is to be avoided in breastfeeding women. It is very important that insulin therapy and diet be well controlled for a nursing mother, because inadequate or excessive glycemic control may reduce milk production.
Drug Profiles
There are currently four major classes of insulin, as determined by their pharmacokinetic properties: rapid acting, short acting, intermediate acting, and long acting. The duration of action ranges from several hours to over 24 hours depending on the insulin class (Figure 32-2). The insulin dosage regimen for all diabetic patients is highly individualized and may consist of one or more classes of insulin administered at either fixed dosages or variable dosages in response to self-measurements of blood glucose level or the number of grams of carbohydrate consumed. With the use of insulins, clarity, color, and appearance are important to understand for patient safety and for the prevention of adverse effects and complications. Several insulins are clear, colorless solutions. These include regular insulin, insulin lispro (Humalog), and insulin glargine (Lantus). Other insulins, such as NPH insulin (insulin isophane), are white opaque (cloudy) solutions. This issue is discussed further in the Implementation section under Nursing Process.
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