Module 8 Notes PDF

Module 8: Endocrine Unit A: Diabetic Medications Diabetes There are two main forms of diabetes. Despite both forms having similar signs and symptoms, the etiology, prevalence, treatments, and outcomes differ. Type 1 diabetes mellitus. The primary cause of type 1 diabetes is a result of autoimmune-i...

Module 8: Endocrine Unit A: Diabetic Medications Diabetes There are two main forms of diabetes. Despite both forms having similar signs and symptoms, the etiology, prevalence, treatments, and outcomes differ. Type 1 diabetes mellitus. The primary cause of type 1 diabetes is a result of autoimmune-induced pancreatic beta cell destruction. The cells responsible for insulin synthesis, the pancreatic beta cells, eventually die off, resulting in zero insulin production. Type 1 diabetes mellitus usually occurs in people younger than 30, with a prevalence of about 5%. Patients with Type 1 diabetes present with involuntary weight loss, polyuria, polydipsia, and polyphagia. However, the presentation can also be when the patient suffers from diabetic ketoacidosis. These patients present with dehydration, abdominal pain, vomiting, and a decreased level of consciousness. The treatment for type 1 diabetes is life-long insulin therapy. Typically, basal insulin and boluses of short-acting insulin are given to provide coverage for mealtimes and snacks in patients with Type 1 diabetes. Type 2 diabetes mellitus. Type 2 diabetes is considered to have a genetic predisposition plus a strong environmental component. This can be called the "genetics loads the gun, but the environment pulls the trigger" phenomenon. Patient education on the benefits of consuming a healthy diet, regular exercise, and managing stress early on is critical. With type 2 diabetes, there is reduced tissue sensitivity to insulin, resulting in high blood sugar levels, also known as hyperglycemia. The body attempts to maintain a balance, so the high circulating glucose levels keep telling the pancreas to produce more insulin. For many years, the body can continue this cycle of producing and thus cranking out more insulin in response to the body's high glucose levels. But, after many years of high glucose levels and worsening insulin resistance, the pancreatic beta cells become impaired and die off, as the body's demands just cannot keep up. Medications Insulin Insulin therapy is required to treat Type 1 diabetes and is used in the later stages of type 2 diabetes. Insulin is a protein, and proteins are digested in the stomach. Therefore, insulin is not bioavailable when given orally; it must be given by injection or intravenously (IV). Insulin is administered as a subcutaneous (SC) injection or as an intravenous infusion. Consistency and rotation of sites are recommended. The site selection is based on the different rates of insulin absorption. The most common area for injection is in the abdomen, followed by the outer back of the arms, the outer thighs, and the buttocks. Insulin can be given via a pump, pen, or inhalation. When adjusting insulin in type 1 diabetes, be very careful. Remember, in type 1 diabetes, these patients produce no endogenous insulin and are very sensitive to any insulin dosing adjustments. Here is a list of the most commonly used types of insulin preparations based on the duration of action. However, newer products are on the horizon. Rapid Acting Insulin. It is used for the immediate treatment of blood glucose levels, is often used in insulin pumps, and is administered in association with meals. Two examples of rapid- acting insulin are lispro (Humalog) and aspart (NovoLog). Short-Acting Insulin Two examples of short-acting insulin are Regular (Humulin R, Novolin R). Intermediate-Acting Insulin Examples of NPH are Humulin N, Novolin N. Long-acting (basal) Glargine (Lantus) and detemir (Levemir) are examples of long-acting insulin. Insulin glargine (Lantus) should NOT be mixed with other insulins in the same syringe. It can be given twice daily if glucose levels are difficult to control. It has a long duration of action of ~ 24 hours. Long-acting (basal) Premixed Insulin Combinations Examples are Novolog Mix 70/30, Humalog Mix 75/25, Humalog Mix 50/50, Humulin 70/30, and Novolin 70/30. Basal-Bolus Insulin via Insulin Pump: Patients with type 1 diabetes commonly use the insulin pump. In type 2 diabetes, those patients who have not responded to multiple-dose insulin injections may also benefit from the insulin pump. Insulin is delivered via a steady, measured, and continuous dose (the "basal" insulin) paired with a surge ("bolus") dose to cover mealtimes. However, only one insulin type is used for basal and mealtime coverage in the insulin pump (e.g., Lispro). The advantages of the pump are that it more accurately mimics the release of insulin by the body, eliminates the need for multiple injections, delivers with greater accuracy, improves HgA1c levels, and results in fewer blood glucose swings up and down. It also allows the patient to exercise without eating many carbohydrates beforehand (I wonder if this is where the phrase "carbohydrate loading" originated)? The disadvantage of the pump is that it contains insulin, it can cause weight gain. If the catheter comes out, it can lead to diabetic ketoacidosis (DKA). The pump is quite expensive, and it requires insurance approval. Insulin Inhaler: The insulin inhaler delivers a powdered form of insulin via an inhaler into the lungs, where it is absorbed. In general, inhaled insulins are more rapidly absorbed than subcutaneously injected insulins; they have a faster peak serum concentration and faster metabolism. Inhaled insulin has a Black Box Warning: Acute bronchospasm has been observed in patients with asthma and COPD using inhaled insulin. Use is contraindicated in chronic lung diseases such as asthma and COPD patients. Before initiating inhaled insulin, perform a detailed medical history, physical examination, and spirometry to identify potential lung disease in all patients. Complications of insulin. The greatest risk is hypoglycemia. However, insulin can also lead to hypokalemia and lipohypertrophy. Lipohypertrophy is an abnormal accumulation (mass) of fat under the skin, and it commonly occurs in those with diabetes because of repeated injections. Other Diabetic Medications The risk of an additive effect of hypoglycemia is a risk when combined with other antihyperglycemic agents. The doses should be adjusted to lessen this risk. Hyperglycemic agents These are considered drugs such as thiazides, glucocorticosteroids, and sympathomimetics (e.g., epinephrine, albuterol, pseudoephedrine) because they essentially raise blood glucose levels- -hence why combinations of insulin with any of these agents may require a dose increase of the insulin. Beta-adrenergic blockers Beta-adrenergic blockers are a class of drugs that can delay drug awareness and the response to hypoglycemia by masking the stimulation of the sympathetic nervous system that hypoglycemia causes. Therefore, tachycardia, palpitations, and shaking may not be as prominent or even occur; this can be quite troublesome for someone with diabetes. Agents to Manage Type 2 Diabetes 1. The sulfonylureas and the meglitinides stimulate the pancreas to release insulin. 2. The biguanides and sulfonylureas enhance insulin receptor sensitivity. 3. Biguanides inhibit the liver's glucose production (gluconeogenesis) and liver breakdown of glycogen into glucose (glycolysis). 4. The alpha-glucosidase inhibitors inhibit the enzyme alpha-glucosidase, which causes a decrease in the intestinal secretion of glucose. 5. The thiazolidinediones increase sensitivity to insulin in the skeletal muscle. 6. The gliptins or dipeptidyl peptidase 4 (DPP-4 ) inhibitors increase insulin release, reduce glucagon release, and decrease hepatic glucose production. A brief overview of the basic order of medications *FYI!!! Metformin is generally the drug of choice for initial monotherapy. If metformin alone does not achieve the desired A1C goal, comorbidities or cost may determine the choice of a second drug. Typically, we use an SGLT2 inhibitor or GLP-1 receptor agonist for patients with cardiovascular disease or chronic kidney disease; an SGLT2 inhibitor for patients with heart failure, or a sulfonylurea if the cost is an issue. If maximum doses of two drugs are insufficient to achieve glycemic control, insulin or another drug can be added. Biguanides-metformin (Glucophage) Metformin (Glucophage), if not contraindicated and if tolerated, is the preferred initial pharmacologic agent for treating type 2 diabetes. Metformin works through several pathways, and it lowers blood glucose levels by inhibiting glucose production by the liver, reducing its absorption in the gut, and sensitizing insulin receptors in target tissues (skeletal muscles and fat), which increases glucose uptake regardless of insulin levels. In contrast to sulfonylureas, metformin does not actively drive down glucose levels, so hypoglycemia is not a concern. It also does not lead to weight gain, like the sulfonylureas typically do, but instead may lead to weight loss. Typically, metformin lowers fasting blood glucose concentrations by approximately 20% (similar to sulfonylurea). It also lowers serum triglycerides, free fatty acid concentrations, and low- density lipoprotein levels--all while raising the high-density lipoprotein levels. Metformin reduces microvascular complications and lessens the risk of cardiovascular events. It has recently been shown that metformin alters the gut microbiome (this could be why patients have so many gastrointestinal side effects). Whether this is ultimately positive or negative remains to be seen. The disadvantages include that metformin can increase the risk for lactic acidosis; it can cause significant gastrointestinal side effects (e.g., diarrhea), and a decrease in vitamin B12 and folic acid levels. Performing a periodic measurement of vitamin B12 levels should be considered, especially in those with anemia or peripheral neuropathy. The advantages of a biguanide, metformin, are that it does not cause weight gain, doesn't lead to hypoglycemia, and is a great add-on agent. Pharmacokinetics. Take it with meals. Remember to start at a low dose to avoid intestinal side effects (e.g., diarrhea). The dose can be increased slowly to a maximum of 2550 mg/day (850 mg TID). Black Box Warning: Lactic acidosis is a rare problem seen with metformin. However, it may be fatal in up to 50% of cases. What is lactic acid? It is a waste product. If a patient is scheduled for a radiological procedure requiring IV contrast (which is also a stress on the kidney), have the patient hold metformin for 48 hours after the procedure. The rationale for this recommendation is to avoid the potential for high plasma metformin concentrations if the patient develops contrast-induced acute renal failure. When taking metformin, avoid alcohol. Alcohol combined with metformin can also increase the risk of lactic acidosis. Side Effects of Metformin. The most common side effects are gastrointestinal, but these typically subside over time (~ 3 months). Other side effects include a metallic taste in the mouth, abdominal discomfort, and nausea. Monitoring. Check the renal function (eGFR) before therapy initiation and at least annually (more often in patients at risk of developing renal impairment). Contraindicated. Do not use in those with severe renal disease (eGFR 9%. Thiazolidinediones Thiazolidinediones “insulin sensitizers”: glitazones: pioglitazone (Actos) and rosiglitazone (Avandia). Thiazolidinediones reverse insulin resistance by acting on muscle, fat, and to a lesser extent, the liver. They increase glucose utilization and diminish its production. Thiazolidinediones redistribute fat from the visceral compartment to the subcutaneous compartment, which helps lessen the insulin resistance in diabetes. Black Box Warning: May cause or exacerbate heart failure. There have been reports of severe liver injury in small numbers of patients receiving Rezulin (which has been removed from the market). Most cases of liver damage occurred early in treatment with the drug and were reversible when it was stopped (although some deaths occurred). The newer agents (Actos and Avandia) have a much lower incidence of this side effect. Meglitinides: Repaglinide (Prandin) The meglitinides stimulate insulin release from beta cells (they promote insulin secretion). These medications are taken with meals and benefit patients with erratic meal schedules, for those with normal fasting plasma glucose (FPG) readings but high postprandial blood glucose levels. The meglitinides have a rapid onset and short half-life, so the risk of hypoglycemia is less than some of the other hypoglycemic agents. If used, they're the third line and used in combination with metformin. Side effects are bloating, abdominal cramps, diarrhea, and flatulence. Alpha-glucosidase Inhibitors: acarbose (Precose) & miglitol (Glyset) The alpha-glucosidase inhibitors delay carbohydrate digestion and absorption. However, whenever a drug interferes with absorption, gastrointestinal effects usually ensue. It is because of these gastrointestinal effects that alpha-glucosidase inhibitors are used sparingly. They inhibit the upper gastrointestinal enzymes that convert dietary starch and other complex carbohydrates into simple sugars, which can then be absorbed. The result is to slow the absorption of glucose after meals. The advantage of these drugs is that they work in the gut, so there is little risk of hypoglycemia. Since they only affect postprandial blood glucose levels, they are to be taken with the first bite of each main meal up to three times a day. This drug class will be better tolerated if the client also decreases sugar intake. Side effects include flatulence and diarrhea, although it's usually mild and does not necessitate discontinuation. Sodium/glucose cotransporter 2 (SGLT2) inhibitors "gliflozins." This is the newest diabetes drug. This class works by preventing kidneys from re-absorbing glucose and increasing the urinary excretion of glucose. This class protects the heart and preserves the kidneys in those with type 2 diabetes. The FDA recently approved the drug Canagliflozin (an SGLT2 inhibitor) to improve glycemic control in patients with type 2 diabetes. This drug was also approved to reduce the risk of major adverse CV events in adults with type 2 diabetes and established CV disease. In the newest recommendations, SGLT2 inhibitors are now used for patients with atherosclerotic cardiovascular heart disease risk factors, established heart failure, and/or diabetic kidney disease. This class is associated with an increased risk of lower limb amputation and diabetic ketoacidosis (a serious diabetes complication). Of note, this drug's Black Box Warning: warning of causing limb amputation was found to be no longer warranted by the FDA, it is now only an associated risk. In the video above it states otherwise, please note that is no longer a BBW. However, patients taking canagliflozin should still be educated and monitored for new pain, tenderness, sores, ulcers, and infections in the legs and feet, as it is still a potential concern. Non-Insulin Injectable Hypoglycemic Agents There are two non-insulin injectable hypoglycemic classes of drugs for managing Type 2 DM: GLP-1 agonists (incretin mimetics) and Amylin analogs. GLP-1 agonists/Incretin Mimetics Exenatide (Byetta) & liraglutide (Victoza). These classes mimic hormones that help regulate blood glucose by stimulating GLP-a receptors, stimulating insulin release. They also inhibit postprandial glucagon release and slow gastric emptying. Side Effects: Nausea, hypoglycemia, and possible weight loss. Black Box Warning: The GLP-1 agonists may increase the risk of thyroid tumors, as seen in animal studies. Pregnancy and Lactation: Pregestational Diabetes The preconception period is ideal for establishing euglycemia, preferably several months before conception. When blood glucose levels are controlled several months before conception, the fetus will be exposed to fewer risks, including major congenital anomalies and miscarriages. Treatment includes diet, exercise, and medication regimens when necessary. Depending on each individual situation plans for conception, and contraceptive status, the provider must consider medications known to be safe in pregnancy. For those clients who already suffer from diabetes, medication adjustments during pregnancy are often required due to the propensity for hypoglycemia in pregnancy and the damaging effects of both hyper and hypoglycemia. Gestational Diabetes (GDM) In any given group, the prevalence of GDM is directly correlated with type 2 diabetes. Globally, gestational diabetes is rising for the same reasons type 2 diabetes is rising: poor diet, a sedentary lifestyle, and increased overweight and obesity. Gestational diabetes--as with type 2 diabetes in the general population--is a form of "carbohydrate intolerance" that may occur under two physiologic circumstances: either the client was an undiagnosed diabetic before pregnancy and is diagnosed for the first time during prenatal care, or becomes diabetic for the first time during pregnancy and is thus diagnosed during prenatal care. Significant fetal risks are associated with GDM. Pregnancy's normal physiologic and hormonal changes cause insulin resistance and reduced insulin effectiveness. When these hormonal changes are in balance, and the woman is not diabetic, this physiologic change inherently protects the fetus and ensures adequate caloric deposition to the fetoplacental unit. But for those clients who are diabetic, these changes cause higher than normal amounts of glucose to be transported from the maternal system to the placental and fetal systems, resulting in hyperglycemia. Euglycemia significantly reduces these risks; therefore, prevention when possible and strict control is critical. GDM is associated with an increased risk of adverse perinatal outcomes, including large for gestational age (LGA), macrosomia (usually defined as birthweight > 4 kg or > 4.5 kg), induction of labor, congenital heart disease (CHD), and cesarean section. There is also growing evidence that GDM is associated with an increased risk of long-term ill-health outcomes in the mother (type 2 diabetes and cardiovascular disease) and offspring (obesity and associated cardiometabolic risk). GDM and Medication Those who follow a diabetic diet and maintain regular exercise often avoid the need for medications. Nutritional and exercise counseling, dietary modifications, an appropriate exercise regimen, and glucose monitoring are the first step in GDM management. Medications are needed if diet and exercise don't adequately control glucose levels. This is when you will be consulting, co-managing, or referring. Two pharmacologic drug classes are available for safe use in pregnancy: Parenteral insulin and the oral antidiabetic medication metformin (Glucophage). Insulin is considered the gold standard due to its long-term safety profile and inability to cross the placenta. According to the American College of Obstetricians and Gynecologists (ACOG), oral antidiabetic medications should be considered only if the pregnant client declines insulin or if the provider determines that safety issues with insulin administration outweigh its benefits. Metformin, a biguanide, is the best choice if an oral agent is necessary. For additional information on managing GDM, look for the most recent ACOG updates on managing GDM in pregnancy. Subcutaneous Insulin Insulin requires collaboration with or referral to an obstetrician or maternal-fetal medicine specialist (MFM). Oral Medications Metformin a biguanide (Glucophage). Growing evidence shows that metformin is likely safe and effective during pregnancy and is a category B. Some data suggest that metformin may be the optimal oral antihyperglycemic for overweight or obese women, and it is not associated with fetal hyperinsulinemia and maternal hypoglycemia. The first-generation sulfonylureas are contraindicated during pregnancy due to fetal hyperinsulinemia, as they readily cross the placenta. Severe hypoglycemia lasting 4 to 10 days has been noted in infants born to mothers taking a sulfonylurea at delivery. Typically, the sulfonylureas are not used during pregnancy. But if they are used, the sulfonylureas should be discontinued at least two weeks before the expected delivery date. Lactation In general, successful breastfeeding is undeterred in patients with diabetes. As in pregnancy, euglycemia is essential. Glycemic control supports the hormonal processes of lactation, and normal blood glucose enables the maternal prolactin release necessary for lactation. Normal insulin levels are also needed for successful lactation. Insulin NPH and regular human insulin are considered safe with breastfeeding. Exogenous insulin is excreted into breast milk, including newer biosynthetic insulins (e.g., aspart, glargine glulisine, lispro). Insulin is a normal component of breast milk. There are no reported adverse reactions, and newborn exposure to insulin in breast milk may help prevent type 1 diabetes in these infants. Aspart, detemir, glargine, glulisine, lispro: While they are probably safe, caution is advised for using the newer biosynthetic insulins with breastfeeding due to limited studies. Be sure to keep up to date as the information becomes available. Unit B: Thyroid Disorders, Testosterone Deficiency, Erectile Dysfunction, and Benign Prostatic Hyperplasia The Thyroid Gland The thyroid hormones regulate “just about everything,” essential for the body to function normally. The body functions best when they are in their correct balance. The thyroid produces a hormone called triiodothyronine (T3) and a hormone called thyroxine (T4). These hormones regulate your body’s temperature, metabolism, and heart rate. Most of the T3 in your body binds to protein. Think about how each body part is affected (e.g., eyes, intestines, brain function, etc.) and whether it is sped up or slowed down. The disorders, the medications, and the adverse effects will begin to make more sense. Hyperthyroidism There are two forms of hyperthyroidism, Grave’s Disease, and Toxic Nodular Goiter. In Grave's disease, thyroid dysfunction is caused by thyroid-stimulating antibodies directed against receptors on the surface of the thyroid cell. Normally, the thyroid gets its production orders from the thyroid-stimulating hormone (TSH) released by the pituitary gland. But in Graves' disease, a malfunction in the body's immune system releases abnormal antibodies that mimic TSH. Spurred by these false signals to produce, the thyroid hormone factories work overtime and exceed their normal quota. Exactly why the immune system begins to produce these aberrant antibodies is unclear. Heredity may have some part, but most likely, it is thought to be triggered by genetics and environmental factors. Graves disease is the most common cause of hyperthyroidism. Please advise your patients not to smoke, which can worsen the eye symptoms. In a Toxic Nodular Goiter, thyroid dysfunction is due to TSH-secreting tumors. Toxic nodular goiter is a condition that can occur when a hyper-functioning nodule develops within a long-standing goiter. This results in hyperthyroidism without the ophthalmologic effects seen in Grave's disease. Hyperthyroidism results in a hypermetabolic state. The symptoms may include tremors, tachycardia, tachypnea, heat intolerance, exophthalmos, and pretibial edema. Antithyroid Treatment Treatment aims to normalize thyroid hormone production, minimize symptoms, and decrease complications. Treatment may also be initiated to achieve a euthyroid state before surgery. Antithyroid treatment includes surgical ablation of thyroid tissue, radioactive dye, or antithyroid medications to destroy the overactive thyroid tissue. The beta-adrenergic blocker propranolol (Inderal) may be prescribed to treat the symptoms of tachycardia, tremor, and anxiety until the euthyroid state is achieved. Hypothyroidism The most common cause of hypothyroidism is Hashimoto's thyroiditis. "Thyroiditis" is an inflammation of the thyroid gland. Hashimoto's thyroiditis is an autoimmune disorder. With Hashimoto’s, your body produces antibodies that attack and destroy the thyroid gland. A viral infection may also cause thyroiditis. Other causes may include radiation to the neck, radioactive iodine treatment, certain medicines to treat heart problems, psychiatric conditions, and cancer, which can sometimes affect thyroid hormone production. Thyroid surgery thyroid, if all is removed. If only part of the thyroid is removed, the remaining gland may still be able to produce enough hormone for the body's needs. Low-iodine diets can cause thyroid dysfunction, as the body needs iodine to function. The reason isn’t clear, but sometimes, thyroid inflammation occurs after pregnancy. This is called postpartum thyroiditis. Pregnant patients with this condition usually have a severe increase in thyroid hormone levels followed by a sharp drop in thyroid hormone production. Most with postpartum thyroiditis will regain their normal thyroid function. Disorders of the pituitary gland and the hypothalamus can also negatively impact the thyroid gland. A hypometabolic state characterizes hypothyroidism. The resulting symptoms include lethargy and fatigue, weight gain, skin changes, cold sensitivity, constipation, hyperlipidemia, and bradycardia. Medications that can induce thyroid dysfunction. Lithium, amiodarone, and interferon can cause thyroid dysfunction. Treatment goals. The goal is to replace the missing thyroid hormone. Normalizing the thyroid-stimulating hormone levels is important. Thyroid replacement therapy is now synthetic. At one time, desiccated thyroid was used, but it has been almost entirely replaced by synthetic thyroid preparation such as levothyroxine (Synthroid), which is only T4. Levothyroxine (Synthroid) Levothyroxine (T4) is converted to T3 in the body, and therefore it can produce nearly normal levels of both T3 & T4, making T3 supplementation unnecessary in most patients. It is highly protein-bound--97%. The anticipated initial dose for an adult is 75-125 mcg levothyroxine (or about 1.6 mcg/kg/dl of ideal body weight), but this can vary on the source you reference. Based on clinical response and serum TSH, adjust the initial dose by 12 to 25 mcg/day every 4 to 8 weeks. For the elderly, the dosage is 75% or less than that of the adult dose, so start low and go slow. Monitor for the onset of cardiac symptoms (e.g., angina) and decrease the dose if needed. Some sources say in cardiac disease, to start as low as 12.5 mcg/day, especially if the patient is frail. This drug has 5-6 drug half-lives, so a recommended testing interval post-adjustment change is 6-8 weeks. Once TSH is stabilized, check it at six and then 12-month intervals. Levothyroxine is very specific and how it is best absorbed. Patient education is essential. Common Drugs/Supplements that Reduce Absorption. Drugs that can reduce the absorption and, therefore, the effectiveness of the proton pump inhibitors, calcium and iron supplements, and aluminum-containing antacids. Warfarin (Coumadin). Levothyroxine accelerates the degradation of Vitamin K-dependent clotting factors. As a result, the effects of warfarin are increased/enhanced. If thyroid replacement is started when the patient takes warfarin, the warfarin may need to be reduced. Levothyroxine may increase the requirements of insulin and digoxin. Symptoms of over-replacement. To help you conceptualize, think too much about thyroid replacement or think of the symptoms of hyperthyroidism. Heart palpitations or a faster heart rate (even at rest), trouble falling asleep, feeling jittery, sweaty, anxious, diarrhea, loose stools, weight loss, and even bone loss. What about replacing it with triiodothyronine (T3) and thyroxine (T4)? As we have learned that despite hypothyroidism and its symptomology being due to both low T3 and T4 levels, we prescribe, for the most part, only thyroxine (T4). Sometimes, despite therapeutic doses of levothyroxine, patients will remain symptomatic. This is when T3, in addition to T4, might be beneficial. However, these patients should typically be seen by a specialist or a provider with thyroid expertise in this area. This is because triiodothyronine (T3) has a very short lifespan, so it needs to be taken several times a day. Due to these required multiple daily doses, T3 levels fluctuate in the body. When T3 levels are high, symptoms of hyperthyroidism often occur. When taking T3, avoiding "T3 spikes" is impossible, which can lead to unpleasant hyperthyroid symptoms, particularly anxiety, and tachycardia. Black Box Warning: Thyroid hormones, including levothyroxine, either alone or with other therapeutic agents, should not be used to treat obesity or weight loss. In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction. Larger doses may produce serious or life-threatening toxicity manifestations, particularly when associated with sympathomimetic amines, such as those used for anorexic effects. Thyroid Disorders in Pregnancy and Lactation Thyroid hormones are crucial for the normal development of the baby’s brain and nervous system. During the first trimester, the fetus depends on the mom’s supply of thyroid hormone. At around 12 weeks, the fetus’s thyroid starts to work independently, but it doesn’t make enough thyroid hormone until 18 to 20 weeks of pregnancy. Two pregnancy-related hormones, human chorionic gonadotropin (hCG) and estrogen, cause higher measured thyroid hormone levels. The thyroid enlarges slightly in healthy women during pregnancy but is usually insufficient to feel during a physical exam. Thyroid problems can be hard to diagnose in pregnancy due to higher levels of thyroid hormones and other symptoms that occur in both pregnancy and thyroid disorders. Some symptoms of hyperthyroidism or hypothyroidism are easier to spot. Untreated hypothyroidism during pregnancy can lead to preeclampsia, anemia, miscarriage, LBW, and CHF. An untreated hyperthyroidism during pregnancy can lead to a miscarriage, premature birth, LBW, low birth weight, preeclampsia, thyroid storm, and CHF. Hypothyroidism. The fetus completely relies on the parent for thyroid hormone until after the first trimester. Insufficiency can lead to profound fetal effects, such as compromised fetal brain development. levothyroxine (Synthroid) - synthetic T4 - is category A and considered a first-line treatment for hypothyroidism in pregnancy. If a client is already taking thyroid replacement, note that dosage requirements significantly increase in pregnancy and that regular monitoring of serum TSH is necessary. Levothyroxine is also considered safe for breastfeeding. Hyperthyroidism. Note FDA pregnancy risk categories for propylthiouracil (PTU), and methimazole are both category "D". Nonetheless, endocrinologists will prescribe propylthiouracil due to the client and the fetal risks associated with untreated hyperthyroidism. Propylthiouracil is preferred since it is highly protein-bound, resulting in less drug transfer to the placenta and fetus. Both propylthiouracil and methimazole are considered compatible with breastfeeding, with propylthiouracil being safer. Screening. If a patient develops postpartum depression, consider checking a TSH. Check a TSH as well for signs and symptoms of thyroid dysfunction. About 5% of women develop a thyroid disorder postpartum. Testosterone Deficiency Testosterone deficiency is considered primary if it is testicular in origin and secondary from hypothalamus-pituitary dysfunction. It is estimated that 14 million men >45 years of age who visit a primary care provider may have testosterone deficiency. Due to the aging population and the number of "baby boomers" moving into the ranks of senior citizens, there is an increased focus on maintaining health. The increase in testosterone is marketed to the public that with an increase in testosterone, there is improved sexual function, mood, and muscle mass. Whether men need testosterone replacement with advances in age is not clear. Clinicians should use a total testosterone level below 300 ng/dL as a reasonable cut-off in support of the diagnosis of low testosterone. The diagnosis of low testosterone should be made only after two total testosterone measurements are taken on separate occasions, with both conducted in an early morning fashion. The clinical diagnosis of testosterone deficiency is only made when patients have low total testosterone levels combined with symptoms and signs. As a man ages, his body's testosterone gradually declines. This decline starts after age 30 and continues throughout life. Some causes of low testosterone levels are due to injury, infection, or loss of the testicles, chemotherapy or radiation treatment for cancer, genetic abnormalities, especially hormones used to treat prostate cancer, and corticosteroid drugs. Because these symptoms are non-specific, the diagnosis must be based on signs and symptoms, plus a low testosterone level. Clinicians should consider measuring total testosterone in patients with a history of unexplained anemia, bone density loss, diabetes, exposure to chemotherapy, exposure to testicular radiation, HIV/AIDS, chronic narcotic use, male infertility, pituitary dysfunction, and chronic corticosteroid use, even in the absence of symptoms or signs associated with testosterone deficiency. Men with testosterone deficiency interested in fertility should have a reproductive health evaluation before treatment. Testosterone Before offering testosterone therapy, clinicians should measure hemoglobin and hematocrit and inform patients regarding the increased risk of polycythemia. Prostate-specific antigens should be measured in men over 40 before testosterone therapy to exclude a prostate cancer diagnosis. Before initiating treatment, clinicians should counsel patients that, at this time, it cannot be stated definitively whether testosterone therapy increases or decreases the risk of cardiovascular events (e.g., myocardial infarction and stroke). However, treatment for those men with lower-than-normal testosterone levels may improve sexual, physical, and psychological health and increase energy. Often providers have been reluctant to prescribe testosterone due to concerns about an increased risk of prostate cancer, but there is inadequate evidence to quantify the risk-benefit ratio of testosterone therapy. Comorbidities of testosterone deficiency include metabolic syndrome, diabetes, cardiovascular disease, hypertension, chronic obstructive pulmonary disease, and autoimmune diseases. Black Box Warning: Secondary exposure causing virilization has been reported in children who were secondarily exposed to topical testosterone gel and solution. Children should avoid contact with unwashed or unclothed application sites in men using topical testosterone. Testosterone can cause blood pressure increases that can increase the risk of major adverse cardiovascular events and serious pulmonary micro embolism reactions. Risks/Benefits of Therapy. The treatment goal is to increase patients' quality of life with symptomatic testosterone deficiency. Patients may have an increased libido, an enhanced mood, and improved bone and muscle mass. There are few well-controlled studies on the impact of testosterone replacement in aging. A positive benefit for diabetics is that blood sugar may be lowered. Adverse effects. Worsening sleep apnea, gynecomastia, acne, and accelerated male patterned baldness are some of the adverse effects of testosterone. Erythrocytosis, prostate carcinoma, metastatic prostate cancer progression, acne, oily skin, decreased spermatogenesis and fertility, and an increased risk of cardiovascular events in men can also occur. Contraindications: Prostate and breast cancer are absolute contraindications. Warnings/Precautions: Long-term use (> 10 years) of parenteral testosterone for male hypogonadism may increase the risk of breast cancer. Testosterone may alter serum lipid profiles, so use caution with a history of myocardial infarction within the last three months or in those with coronary artery disease. Testosterone therapy should not be used in patients with a history of cardiovascular disease. It may increase the risk of gynecomastia, benign prostatic hyperplasia (BPH), prostate cancer, and venous thromboembolic events, including deep vein thrombosis (DVT) and pulmonary embolisms. Testosterone levels should be measured every 6-12 months while on testosterone therapy. Erectile Dysfunction Erectile dysfunction is the persistent inability to maintain and sustain an erection sufficient for sexual intercourse. Occasional erectile dysfunction is ok. Many men experience it during times of stress. Frequent occurrences, however, can be a sign of health problems that may require treatment. It can also be a sign of emotional or relationship difficulties that may need to be addressed by a professional. It is often a combination of emotional and physical difficulties, so please consider both and address both concerns. Although several methods exist to treat erectile dysfunction, the most commonly utilized treatment is pharmacological. Erectile dysfunction is a risk marker for underlying cardiovascular disease and other health conditions that may warrant evaluation and treatment. In men with erectile dysfunction, morning serum total testosterone levels should be measured to rule out low testosterone levels. Conditions that can lead to erectile dysfunction. Many conditions can lead to erectile dysfunction, including cardiovascular disease, high blood pressure, obesity, low testosterone or other hormone imbalances, increased age, stress, anxiety, or depression, to name a few. The penis becomes erect after sexual stimulation due to the release of nitric oxide. This results in the dilation of the blood vessels in the corpus cavernosum. The dilation is due to the accumulation of the cyclic guanosine monophosphate(cGMP); the enzyme that breaks down cGMP is PDE5. Phosphodiesterase type 5 inhibitors The PD5 inhibitors may be used for benign prostatic hyperplasia and erectile dysfunction. In erectile dysfunction, these cause smooth muscle relaxation and inflow of blood to the corpus cavernosum. In benign prostatic hypertrophy, this class causes a reduction in the smooth muscle, endothelial cell proliferation, decreased nerve activity, and an increase in smooth muscle relaxation and tissue perfusion of the prostate and bladder. Possible adverse effects: Headache, dyspepsia, flushing, gastritis, priapism, myalgias, abnormal vision, and elevated LFTs. Metabolism: Phosphodiesterase type 5 inhibitors are metabolized through the CYP450 systems (CYP 3A4), so caution is used when taking other drugs metabolized through this same pathway (grapefruit juice). Potential D2D interactions: These drugs may potentiate the hypotensive effects of nitrates, alpha-blockers, and other antihypertensives. Plasma levels are increased by CYP3A4 inhibitors such as ketoconazole, itraconazole, erythromycin, grapefruit juice, and protease inhibitors. Levels are decreased by rifampin (an inducer of CYP3A4). Contraindications: Concurrent use of nitrates. Precaution: Cardiovascular disease. Patient Education. Take 1 hour before sexual intercourse and no more than once daily. None of the PDE 5 inhibitors are affected by alcohol ingestion, although alcohol ingestion is associated with erectile dysfunction. Hig Additional Points. Men with erectile dysfunction and testosterone deficiency (TD) considering treatment with phosphodiesterase type 5 inhibitors should be informed that they may be more effective if combined with testosterone therapy (if the testosterone levels are low). There are other more invasive therapies, too, requiring urology involvement. Choosing which PDE-5 inhibitor to use. The choice of medication depends on the frequency of intercourse (occasional use or regular therapy, 3-4 times weekly) and the patient's experience with the medications. There are more invasive therapies, but this would involve specialty care. Benign Prostatic Hyperplasia An enlarged prostate gland or benign prostatic hypertrophy is common as men age. An enlarged prostate gland can cause uncomfortable urinary symptoms, such as blocking urine flow out of the bladder. It can also cause bladder, urinary tract, or kidney problems. Several effective prostate gland enlargement treatments include medications, minimally invasive therapies and procedures, and surgery. The severity of symptoms in people with prostate gland enlargement varies, but symptoms tend to worsen gradually over time. Common signs and symptoms may include the frequent or urgent need to urinate, increased frequency of urination at night (nocturia), difficulty starting urination, weak urine stream or a stream that stops and starts, and dribbling at the end of urination, and the inability to completely empty the bladder. The size of your prostate doesn't necessarily determine the severity of your symptoms. Some men with only slightly enlarged prostates may have significant symptoms, while others with very enlarged prostates may only have minor urinary symptoms. In some men, symptoms eventually stabilize and might even improve over time. Medications Alpha-1 Blockers Alpha-blockers can be used to treat benign prostatic hyperplasia. These medications relax the bladder, neck muscles, and muscle fibers in the prostate, making urination easier. Alpha- blockers, which include tamsulosin (Flomax), usually work quickly in men with relatively small prostates. Alpha-blockers for benign prostatic hyperplasia work by blocking the alpha-1a receptor in the prostate and the bladder. Alpha-blockers relax the muscles of the bladder, neck, and prostate and allow easier urine flow. Alpha-blockers are very effective in treating benign prostatic hyperplasia; roughly 50 percent of men see an improvement in symptoms within the first 48 hours to one week after therapy initiation. However, patients may only retain symptom relief for up to 4 years, and alpha-blockers do not shrink the prostate or slow the progression. Adverse effects that may occur with alpha-blockers include hypotension, fatigue, prolonged erection, atrial fibrillation, 5-Alpha-Reductase Inhibitors 5-alpha-reductase inhibitors are another class of drugs used to treat an enlarged prostate (benign prostatic hyperplasia). 5-alpha-reductase inhibitors block dihydrotestosterone to shrink the prostate and increase urine flow. 5-alpha-reductase inhibitors can take three to six months, which may be a drawback for many patients. In a small percentage (4%) of patients, 5- alpha-reductase inhibitors can also lead to impotence. Adverse effects that may occur with 5-alpha-reductase inhibitors include allergic reactions, breast or high-grade prostate cancer, decreased sexual drive, abnormal ejaculation, impotence, gynecomastia (male breast enlargement), and dizziness or lightheadedness. PDE-5 Inhibitors: See above Unit C: Osteoporosis Osteoporosis Osteoporosis, which most commonly occurs in the hip, spine, and wrist, puts persons at increased risk of fragility and fractures. Fragility fractures and low bone mineral density (BMD), as determined by dual-energy x-ray absorptiometry (DEXA), aid in diagnosis. Pharmacologic treatment options, most of which are targeted at preventing bone resorption, include bisphosphonates, peptide hormones, calcium, vitamin D, and estrogen and selective estrogen receptor modulators (for postmenopausal women). Bisphosphonates have been shown to reduce vertebral, nonvertebral, and hip fractures and should be offered to women with osteoporosis to help decrease their risk of experiencing a hip or vertebral fracture. This recommendation is supported by high-quality evidence of effectiveness in postmenopausal women. Calcium and vitamin D can be added as dietary supplements, but their effectiveness in preventing fractures is unknown. Primary osteoporosis is caused by age-related bone loss; secondary osteoporosis is medication- or disease-induced. Secondary causes can include taking chronic steroids, androgen deficiency, hypogonadism, anorexia nervosa or bulimia, celiac disease, hyperthyroidism, and ankylosing spondylitis, to name a few. Pharmacologic treatment with bisphosphonates is for five years. Although evidence is insufficient to determine the appropriate duration of pharmacologic treatment, most studies indicate that the benefit lasts up to five years. Continuing treatment after five years may benefit some patients and be suitable after weighing the risks and benefits of ongoing treatment. However, it is often recommended to take a drug holiday, as staying on therapy for greater than five years may increase the risk of atypical fractures. Because current evidence does not indicate the benefit of monitoring bone density during the five years of pharmacologic treatment, it does not need to be performed during this time frame. Treating women 65 years and older with osteopenia at high risk of fracture should consider patient preference, fracture risk, benefits, harms, and costs. In addition, more evidence is needed about the use of medications in persons with osteopenia. Bisphosphonates should be offered to men with osteoporosis to decrease their risk of vertebral fracture. Preventive strategies are essential and include a diet high in calcium, regular bone-strengthening exercise, calcium (1200-1500mg daily) and vitamin D (800-1000 IU daily) supplementation as needed, and reduction in modifiable risk factors such as smoking, alcohol intake of more than two drinks/day, high caffeine intake, low calcium & vitamin D intake, and physical inactivity. The most common medications are antiresorptive drugs that decrease the bone-destroying activity of the osteoclasts and include: bisphosphonates, hormone therapy (HT), selective estrogen receptor modulators (SERMs), and rank ligand inhibitors. Parathyroid hormone is also an antiresorptive agent, but its mechanism of action (MOA) is the activation of osteoblasts. The goal of pharmacologic therapy is to prevent fractures that are associated with high morbidity and mortality. Medications Bisphosphonates In postmenopausal patients at high risk of fractures, initial treatment with bisphosphonates (alendronate, risedronate, & zoledronic acid) is recommended to reduce fracture risk. Bisphosphonates are structural analogs of pyrophosphate, a normal bone constituent. These drugs undergo incorporation into the bone, and then they inhibit bone resorption by inhibiting the activity of the osteoclasts. Pharmacologic treatment should continue for five years. However, after five years, patients stop taking the bisphosphonate due to the risk of atypical fractures. The positive benefits, however, typically last longer. Bisphosphonates increase bone mass density at the spine and hip and reduce fracture risk. Candidates must be screened for low serum calcium and adequate kidney function before initiation--low serum calcium or an inadequate glomerular filtration rate are contraindications to their use. Clients must also take calcium and vitamin D with bisphosphonates for maximum effectiveness. Side effects. Possible damage to the upper gastrointestinal tract, specifically the throat, and esophagus. The oral formulation may swell in the esophagus if not taken with a full glass of water in an upright position causing esophageal irritation. Patients should remain upright for 30 to 60 minutes after dosing. Educated the patient to inform the dentist that they are on this medication. Rare but severe side effects may include atypical femur fractures, esophageal cancer, and jaw osteonecrosis due to reduced blood supply to the jaw. Contraindications. If a patient cannot sit upright, suffers from esophageal motility disorders, or has poor renal function, do not give oral bisphosphonates. Monoclonal antibody/RANKL inhibitor-Denosumab (Prolia) This is a receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitor. By binding to the transmembrane or soluble protein RANKL, this drug inhibits osteoclasts' formation, function, and survival, resulting in decreased bone resorption and increased bone mass and strength. It also prevents RANKL from activating the RANK receptor on the surface of osteoclast-like giant cells. So, it lessens the process of bone breakdown. It is given via injection every six months. Risk factors are serious infections of the abdomen, urinary tract, and ear; dermatological reactions (dermatitis); back and musculoskeletal pain; atypical femur fractures; and hypocalcemia. Parathyroid Hormone Analogs-Teriparatide (Forteo) The parathyroid hormone analog is the only medication on the market that promotes bone formation for men and women. The pharmacologic activity is similar to the physiologic activity of parathyroid hormone and includes stimulating osteoblast function, increasing gastrointestinal calcium absorption, and increasing renal tubular calcium reabsorption. This class increases the skeletal mass and bone strength. The analogs are approved for 48 months, after which the safety is unknown. Due to its high-risk side-effect profile, it is reserved for extreme cases for those patients with a high risk for fractures. Selective estrogen receptor modulators (SERMS) raloxifene (Evista) Depending on the site, these agents bind to estrogen receptors and create an agonist or antagonist effect. Although the exact mechanism of action is unknown, these agents reduce osteoclast activity (so the breakdown of bone) and lower breast cancer risk (reduces risk). They ultimately cause a reduction of bone resorption and an increase in bone mineral density (BMD). It may be considered an alternative treatment option to reduce the risk of vertebral fractures in patients for whom bisphosphonates and denosumab are unsuitable or in patients with a high risk of fracture and a high risk of invasive breast cancer. That being said, these agents carry the risk of deep vein thrombosis. This class can be used after menopause for osteoporosis, but they are not to treat menopausal symptoms. Although high-quality evidence indicates that raloxifene reduces vertebral fractures in women with osteoporosis, it is not associated with a statistically significant reduction in the risk of nonvertebral or hip fractures and is associated with major harm (e.g., thromboembolism). The adverse effects can include hot flashes, weight gain, flu-like symptoms, arthralgias, and infections. There is a Black Box Warning for thromboembolic events. The selective estrogen receptor modulators are contraindicated in patients with a history of venous thromboembolic disorders or at risk for thromboembolism (e.g., active malignancy). The risk is highest during the first four months of treatment. In summary, the selective estrogen response modulators may be less effective than bisphosphonates and teriparatide and may increase the risk for venous thromboembolism. Hormone Replacement Therapy (HRT) Hormone therapy with estrogen or estrogen/progestogen must be made on a case-by-case decision after reviewing the patients' risks and benefits. While HRT may be associated with a reduction in fractures in postmenopausal patients, it is associated with several risks, including some major ones (e.g., cerebrovascular accidents, venous thromboembolism, breast cancer, and cholestasis), which may outweigh the possible benefits of its use. However, that being said, HRT may be used for the prevention and treatment of osteoporosis in postmenopausal patients with the goal of inhibiting bone resorption and reducing the risk of osteoporotic fractures. The mechanism of action of HRT is that it prevents bone loss in postmenopausal patients by inhibiting osteoclast-driven bone resorption and reducing the rate of bone remodeling. HRT is contraindicated in those with a history of venous thromboembolism per FDA and United States product package labeling. There is a Black Box Warning for HRT: Endometrial cancer, cardiovascular disease, breast cancer, and dementia because of these risks. Estrogens with or without progestins should be prescribed at the lowest effective dose and for the shortest duration, consistent with treatment goals. Unit D: Rheumatoid Arthritis, Corticosteroids, and Disease-Modifying Anti-rheumatic Drugs Rheumatoid Arthritis Rheumatoid arthritis is a chronic, autoimmune, inflammatory disorder affecting more than just your joints. In some people, the condition can damage various body systems, including the skin, eyes, lungs, heart, and blood vessels. Rheumatoid arthritis occurs when your immune system mistakenly attacks your body's tissues. This wear-and-tear damage of osteoarthritis and rheumatoid arthritis affects the lining of your joints, causing a painful swelling that can eventually result in bone erosion and joint deformity. The inflammation associated with rheumatoid arthritis can also damage other parts of the body. While new types of medications have improved treatment options dramatically, severe rheumatoid arthritis can still cause physical disabilities. Signs and symptoms of rheumatoid arthritis may include tender, warm, and swollen joints, joint stiffness that is usually worse in the mornings and after inactivity, fatigue, fever, and loss of appetite. Early rheumatoid arthritis tends to affect the smaller joints first. As the disease progresses, symptoms often spread to the wrists, knees, ankles, elbows, hips, and shoulders. In most cases, symptoms occur in the same joints on both sides. About 40 percent of people with rheumatoid arthritis also experience signs and symptoms that don't involve the joints. Rheumatoid arthritis may affect many non-joint structures, including skin, eyes, lungs, kidneys, etc. A rheumatologist usually initiates the medication, and then the nurse practitioner follows the patient for routine care. Knowing the potential side effects is important to monitor patient tolerance and safety during this process. Non-pharmacotherapy. Warm baths, massage, and application of heat to affected joints. A balance of rest and movement is highly recommended. Medications This autoimmune disease can be halted, and patients may experience a protracted remission if proper drug therapy is initiated early in the disease. However, this remission typically is not full, and this chronic disease marches on. Treatments are meant to lessen pain, inflammation, and joint stiffness, minimize systemic symptoms, and delay disease progression. Clinical remission should be the primary treatment target, but low disease activity may be appropriate for patients with long-standing diseases or comorbidities. Classes of antiarthritic drugs: Nonsteroidal anti-inflammatory drugs (NSAIDs), Glucocorticoids, and Disease-modifying antirheumatic drugs (DMARDs), Nonsteroidal anti-inflammatory drugs (NSAIDs) These are the “relievers.” NSAIDs can provide rapid symptom relief. Essentially they are safer than glucocorticoids and DMARDs. NSAIDs are used for their anti-inflammatory role as well as their analgesic effects. They exert these effects by inhibiting cyclooxygenase (COX). There are two main classes of NSAIDs; first-generation NSAIDs inhibit COX-1 and COX-2, and the 2nd generation NSAIDs target COX-2 only. COX-1 inhibition leads to many of this class's adverse effects (in particular, COX-1 inhibition causes adverse gastrointestinal effects). Inhibition of COX-2, on the other hand, leads to this class's anti-inflammatory and analgesic effects. 1st generation NSAIDs include aspirin, diclofenac, Ibuprofen, Naproxen, and Meloxicam (to name a few). The 2nd generation NSAID is celecoxib (Celebrex), which inhibits COX-2. The selection of which NSAID to use is based on the cost, safety, and efficacy (some might work better than others for certain patients). Black Box Warning for NSAIDs: NSAIDs may cause an increased risk of serious cardiovascular events, MI, and stroke, which can be fatal. This risk may be increased in patients with cardiovascular disease or risk factors for cardiovascular disease. NSAIDs can also cause an increased risk of serious GI adverse events, especially in the elderly, including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. Corticosteroids These are powerful anti-inflammatory agents and can relieve those painful rheumatoid symptoms. Glucocorticoids may also help prevent disease progression. These should be reserved for more widespread symptoms, flares, and when starting a DMARD, as the DMARDs are not used for acute flares. In terms of using corticosteroids long-term, this should be only if other drugs fail. The long-term risks associated are plentiful. Corticosteroids are named for their effects on glucose metabolism, yet they affect virtually every cell in the body. They impact glucose metabolism, production, and utilization. They also influence lipid metabolism and the fluid and electrolyte balance. Steroids impact the body's immunological, bone, gastrointestinal, neuropsychological, and developmental processes. Corticosteroids are most commonly used to suppress immune function in conditions such as asthma, allergic reactions, severe pain, rheumatoid arthritis, inflammatory bowel disease, unresponsive to first-line therapy, relapsing multiple sclerosis, and many others. Corticosteroids are also associated with many adverse effects. The prescriber should carefully consider the associated risks. Some notable side effects include altered metabolism (which may lead to hyperglycemia with short-term use, protein wasting, and increased lipid deposition), altered immune response (this may be one of the medication goals, yet this effect will also mask signs of infection), impaired bone health (will cause calcium to leach out of the bones and could increase the risk for osteoporosis), skin changes (may thin skin with topical use daily), neurological impacts (cranial nerve palsy, mood instability), cardiac (may increase hypertension due to fluid retention associated with its impact on excretion of potassium and retention of sodium and water), ocular (glaucoma and cataracts), and it may also cause tremor, hunger, agitation, and aggression. The chronic use of corticosteroids may include hypothalamic pituitary adrenal axis suppression, Cushing's syndrome, osteoporosis, immunosuppression, and skin changes, including atrophy, striae, telangiectasia, and acne. Pregnancy and Lactation and Steroids (FYI) Preterm labor: Corticosteroids such as betamethasone (most commonly) and dexamethasone are recommended for women between 24 and 36 6/7 weeks gestation who are at risk for preterm delivery within a week. A single intramuscular course (which includes more than one dose) is given to help fetal organs mature and decrease the incidence and severity of neonatal respiratory distress syndrome. Topical corticosteroids may be used in pregnancy if safer alternative treatments have failed. One of our basic pharmacology prescribing rules comes into play with steroid use and pregnancy: use the lowest dose for the shortest time. Avoid use beyond two weeks due to systemic absorption. There are times when an oral corticosteroid (prednisolone, category C) is needed for severe PUPPS (Puritic, urticaria, papules, and plaques of pregnancy). Most often, it is only needed for a limited period of time. This medication should be tapered over several days if utilized longer than one week; otherwise, no tapering is necessary. Low doses of systemic steroids for short periods of time are considered safe with breastfeeding, and topical low-dose steroids are safe. Consultation is advised if high or prolonged doses of either route are necessary. Except in extreme situations, the benefits of continuing to breastfeed will likely outweigh the medication-associated risks. Prednisone is considered compatible with breastfeeding. High-potency topical steroids should be avoided on or near the nipple, face, or genital area in the majority of cases. Patient Education To help minimize side effects, carefully monitor patients and use at lowest potency at the lowest effective dose required to manage the underlying condition. Patients should be informed about the adverse effects of systemic corticosteroid use and implement lifestyle modification strategies that may help reduce the risk of these events. Take steroids with a full glass of water after food at the same time daily and keep doses to 20 mg or less at a time. Patients may need to dose more than twice daily to avoid stomach upset. Tapering This allows the adrenal glands to resume their normal function. Prednisone 40 mg for five days, a dosing regimen often used for acute asthma exacerbations, can be discontinued without a taper. No taper is required if the dosing regimen is less than 40 mg for five days. For longer therapy, reduce the dose by 2.5 to 5.0 mg decrements every 3–7 days until the dosage is at 2.5 mg for three days; at this point, the patient can discontinue. A rheumatologist usually initiates the medication, and the advanced practitioner follows the patient for routine care. Knowing the potential side effects is important to monitor patient tolerance and safety during this process. Think Twice Before Prescribing a Steroid Burst *hot off the press. As most of you are becoming increasingly aware, the long-term use of oral corticosteroids is associated with numerous adverse events across multiple organ systems. The risks are numerous and significant. However, even short bursts of steroids can be detrimental to the body. Short bursts, defined as courses of steroids lasting fewer than two weeks, are often used in the primary care setting. However, these “bursts” are not as safe as once thought. Even when used for under two weeks, steroids increase the risk of gastrointestinal bleeding, sepsis, and heart failure. These risks are the greatest during the first month after treatment, but for the three months following steroid use, monitor patients closely for these conditions and provide the proper patient education. Disease-Modifying Antirheumatic Drugs (DMARDs) These include methotrexate, infliximab, leflunomide, and hydroxychloroquine. These drugs exert their effects by causing immunosuppression before starting a DMARD screen for Hepatitis B, Hepatitis C, and latent TB. Be sure to give all age-appropriate immunizations. Live vaccines are contraindicated once therapy has started. Methotrexate (Rheumatrex) This is a folic acid antagonist. It affects leukocyte suppression, which decreases inflammation caused by by-products of cell degradation. It also inhibits cellular replication. It is highly effective, achieving 70-75% symptom improvement within 3 to 8 weeks. It is the fastest-acting DMARD. However, it is contraindicated during pregnancy, breastfeeding, and in those clients with leukopenia. Additionally, it can be used to treat severe psoriasis, a form of leukemia, and polyarticular juvenile arthritis. Do not drink alcohol while on this drug. Methotrexate cannot be combined with certain antibiotics as it can cause hepatotoxicity. There is a Black Box Warning: It can cause bone marrow suppression, renal impairment, hepatotoxicity, secondary malignancy, dermatologic toxicity, secondary infections, severe toxic reactions, and embryo-fetal toxicity. Adverse effects are leukopenia, thrombocytopenia, oral ulcers, and hepatic and pulmonary toxicity. Methotrexate can interact with other drugs metabolized by the liver, especially alcohol. It reduces the response to vaccines, and live vaccines are contraindicated. Therefore, vaccinate before starting therapy as necessary. Infliximab (Remicade): Infliximab (Remicade): is another DMARD. As you likely remember from the GI module, DMARDs can treat many ailments; but come with many adherent risks. Infliximab carries a Black Box Warning: serious infections and malignancy. There is also a concern about tuberculosis (both active infection and reactivation of latent tubercular infection). As mentioned above, infliximab can treat various autoimmune disorders, including ankylosing spondylitis, Crohn’s disease, ulcerative colitis, psoriatic arthritis, and rheumatoid arthritis. When used for rheumatoid arthritis, it is typically paired with methotrexate. The mechanism of action of infliximab is that it acts as a monoclonal antibody that binds to human tumor necrosis factor-alpha (TNFα), essentially lessening the body’s attack on itself. Leflunomide (Arava) Leflunomide (Arava): This is a powerful immunosuppressant for rheumatoid arthritis. It is effective, yet it is more hazardous and expensive than methotrexate. Leflunomide suppresses the immune response and possibly inflammation. Black Box Warning: Embryo-fetal toxicity and Hepatotoxicity. Leflunomide can negatively interfere with the metabolism of other NSAIDs leading to toxicity. Hydroxychloroquine (Plaquenil) Hydroxychloroquine (Plaquenil): This is a drug with antimalarial actions. It is often combined with methotrexate, but how it works in rheumatoid arthritis is not fully understood. It takes 3-6 months to work fully. It can treat lupus, Sjogren’s, and other autoimmune disorders. Retinal damage leading to blindness is rare, but it happens due to drug toxicity (higher doses equal higher risks of eye damage). Hydroxychloroquine prolongs the QT interval. Biologic DMARDs- Tumor Necrosis Factor Inhibitors These drugs inhibit tumor necrosis factor (TNF), an important immune mediator of joint injury. There are 5 TNF inhibitors, each with the same risks of serious infections, severe allergic reactions, heart and liver failure, and cancer. These are typically reserved for patients with high disease activity or poor prognostic features. TNF-inhibitor Black Box Warnings: Increased risk of serious infections and malignancies. Unit E: Treatment of Obesity Obesity Obesity is a chronic condition characterized by an excess of body fat. It is most often defined by the body mass index (BMI), a mathematical formula highly correlated with body fat. BMI is weight in kilograms divided by height in meters squared (kg per m2). Worldwide, adults with a BMI of 25 to 30 kg per m2 are categorized as overweight, and those with a BMI greater than 30 kg per m2 are categorized as obese. Obesity results from long-term mismatches in energy balance, in which daily energy intake exceeds daily energy expenditure. Many factors, including metabolic rate, appetite, diet, and physical activity, modulate energy balance. Although genetic traits influence these factors, the increase in obesity prevalence in the past few decades cannot be explained by changes in the human gene pool, and it is more often attributed to environmental changes that promote excessive food intake and discourage physical activity. Less commonly, obesity may be induced by drugs (e.g., high-dose glucocorticoids, antipsychotics, antidepressants, oral hypoglycemics, antiepileptics) or be secondary to various neuroendocrine disorders, such as Cushing syndrome and polycystic ovary syndrome. Obesity is a risk factor for several chronic diseases, including hypertension, dyslipidemia, diabetes, cardiovascular disease, sleep apnea, osteoarthritis, depression, social isolation, and some cancers. The relationship between increasing body weight and mortality is curvilinear, in which mortality is highest in adults with very low body weights (BMI less than 18.5 kg per m2) and in adults with the highest body weights (BMI greater than 35 kg per m2). Obese adults have more annual hospital admissions, outpatient visits, higher prescription drug costs, and worse health-related quality of life than those with normal weight. Obesity is stigmatized in much of the modern world, although it was seen as a symbol of wealth and fertility at other times in history and still is in some parts of the world. The National Institutes of Health issued guidelines for obesity treatment, which indicate that all obese adults (BMI greater than 30 kg per m2) and all adults with a BMI of at least 27 kg per m2 and obesity-associated chronic diseases are candidates for drug treatment. Morbidly obese adults (BMI greater than 40 kg per m2) and all adults with a BMI of at least 35 kg per m2 and obesity-associated chronic diseases are candidates for bariatric surgery. Caloric restriction and increased physical activity are the mainstays of health promotion counseling and are considered the first-line treatment for patients that are overweight or obese. Bariatric surgery and pharmacotherapy are adjuncts to diet, exercise, and behavioral modification. Dietary changes are crucial, as are increased physical activity and behavior changes. Try writing an exercise prescription, but be specific and design joint goals. Frequent visits are associated with the greatest chance of success, so see patients at least 16 times per year. Approach patients with empathy. Often obesity is a difficult subject for both you and your clients, and it requires effective communication strategies free from bias. Medications The role of medication is to augment or amplify the effects of behavioral changes. The goal is to lead to a reduction in caloric consumption. Medications do not work on their own. Consider drug therapy for patients with a BMI > 30 or BMI >27 with one or more comorbidities (e.g., diabetes). Naltrexone/bupropion extended-release (Contrave) Naltrexone, an opioid antagonist, and bupropion, an aminoketone antidepressant (with weak inhibitory effects on neuronal reuptake of dopamine and norepinephrine), act to regulate food intake by increasing the firing rate of the hypothalamic pro-opiomelanocortin neurons (appetite regulatory center) and the mesolimbic dopamine circuit (rewards system). The exact mechanism is not fully understood. Effects may result from the action on brain areas that regulate food intake and the reward system. Ultimately, it combines the effects of the dopamine and norepinephrine-reuptake inhibitor (bupropion) with an opioid antagonist (naltrexone). It is used for weight management. There are many contraindications. Black box warnings include suicidal thinking. This drug can cause acute opioid withdrawal and elevate the heart rate and blood pressure. It can cause neuropsychiatric effects, hepatotoxicity, seizures, and hypoglycemia in diabetics from weight loss. Adverse effects include headaches, sleep disorders, and gastrointestinal distress. This drug will decrease the efficacy of opioids. Lipase Inhibitor-Orlistat (available OTC-Alli and by Rx-Xenical) A reversible inhibitor of gastric and pancreatic lipases, thus inhibiting the absorption of dietary fats by 30%. Used for weight loss and to reduce risk for weight gain after weight loss. Adverse effects include rectal leakage, flatulence, and frequent bowel movements (the GI symptoms often lessen over time). URIs and pedal edema may also occur. This drug is contraindicated in pregnancy, chronic malabsorption syndrome, and cholestasis. Increased risk for cholelithiasis, hepatoxicity, and increased urinary oxalate levels may lead to kidney stones. Orlistat may decrease the absorption of fat-soluble vitamins. Take Orlistat within 1 hour of a fatty meal (omit it if consuming a low-fat meal). **Serotnin Receptor Agonsit: Lorcaserin (Belviq)** This medication was removed from the US market in 2020. Though this is briefly mentioned in the recorded lecture above, we will not discuss this drug further in this course. Anorexiant, Anticonvulsant, Sympathomimetic-Phentermine/topiramate-ER (Qsymia) Phentermine reduces appetite through its secondary central nervous system effects, including hypothalamus stimulation to release norepinephrine. It acts similarly to amphetamines. It is thought that topiramate works by suppressing the appetite and enhancing satiety. It is used for weight management, a reduced-calorie diet, and increased physical activity. Adverse effects include increased heart rate, which can cause insomnia, paresthesia, constipation, and poor memory. This drug is contraindicated in hyperthyroidism, glaucoma, or with MAO inhibitors. It is also contraindicated in pregnancy and those adverse effects with cardiac disease. It has been associated with acute myopia and secondary angle-closure glaucoma in adults and children; typically, it might occur within one month of initiation but may occur at any time. It, too, is a controlled substance. GLP-1 Receptor Agonist- Liraglutide (Saxenda, Victoza) Liraglutide is a long-acting analog of human glucagon-like peptide-1 (GLP-1) (an incretin hormone). It slows gastric emptying, decreases food intake, and increases beta-cell growth and replication. It, too, is used for chronic weight management to improve glycemic control in Type 2 DM and reduce the risk of cardiovascular events in those at risk. Adverse effects include an increased heart rate, headaches, hypoglycemia, and gastrointestinal distress. Do not use it during pregnancy or breastfeeding. Antibody formation of anti-liraglutide antibodies can occur. A Black Box Warning about the risk of medullary thyroid cancer is seen in animal studies. This appears to be dose and duration dependent. Clinical Pearls Weight-loss drugs suppress appetite. Leptin and Ghrelin are the main satiety hormones. Serotonin is a neurotransmitter that plays a significant role in regulating mood, emotions, and appetite, which can indirectly influence feelings of satiety. Stimulant-type drugs (e.g., Phentermine, Diethylpropion) can lead to insomnia, increased blood pressure, fast heart rate, restlessness, drug dependence, and withdrawal symptoms. Stimulants are only approved short-term (for up to 12 weeks). Orlistat (Alli/Xenical) is a drug that interferes with fat absorption. This can lead to oily stools, flatulence, and bowel incontinence. If a patient is on Orlistat, they are at risk for fat-soluble vitamin deficiencies. Patients should be encouraged to supplement with vitamins. Take Orlistat within an hour of a fatty meal. Do not take with malabsorption syndrome. Weight loss drugs that affect neurotransmitters, such as lorcaserin and bupropion/naltrexone, can be linked with causing headaches, nausea, vomiting, confusion, dry mouth, and dizziness. Surgery. The most effective means of significant and sustained weight loss for obese patients is bariatric surgery. Gastric bypass patients typically lose 30% of their weight, while gastric banding patients lose approximately 20% of their weight. A meta-analysis of studies related to bariatric surgery demonstrated that effective weight loss was achieved in morbidly obese patients through surgery. Patients who undergo gastric bypass surgery will have altered absorption of oral medications. Reduced surface area for absorption (drug solubility is altered). Tablets require dissolution and disintegration, which may impact absorption.  Reduced hydrochloric acid & reduced intestinal enzymes result in altered medication absorption. To account for these changes, prescribe alternate formulations such as liquid, injectable, transdermal, rectal, vaginal, and intranasal. If a tablet is the only formulation for the medication, avoid extended-release and sustained-release formulations. Patient education should include that calcium absorption is reduced, rapid weight loss after surgery can lead to gallstones, lifelong B-12 supplementation is recommended, and vitamins A, D, E, and K should be given (fat-soluble vitamins). Oral medications are not well absorbed (oral contraceptive pills are ineffective; therefore, please educate patients on this risk). Pediatrics (FYI) Screening Guidelines. The United States Preventative Screening and Preventative Task Force (USPSTF) recommends that clinicians screen for obesity in children and adolescents six years and older and offer or refer them to comprehensive, intensive behavioral interventions to promote improvements in weight status. Obesity is a huge health concern, and it can start early. Primary treatment is diet, exercise, and behavioral modification. As with adults, medication is to augment dietary changes, increase physical activity, and behavioral modifications. Preventing pediatric obesity by promoting a healthy diet, activity, and environment should be a primary goal. Unfortunately, achieving effective, long-lasting results with lifestyle modification once obesity occurs is much more difficult. Despite some behavioral and pharmacotherapy studies reporting modest success, additional research is needed. The drugs approved by the FDA for obesity in the pediatric population should be administered only with a concomitant lifestyle modification program of the highest intensity and only by clinicians who are experienced in using anti-obesity agents and aware of their adverse effects. Those medications approved for the pediatric population require the same education and pose the same concerns (if not heightened) as they do with adults. Bariatric surgery is reserved for severe cases of pediatric obesity and only for experts in the field. Medications. Orlistat (Xenical) is approved for children aged 12 and over. Remember that patients must be given a vitamin with fat-soluble vitamins (D, E, A, K). Phentermine is approved for adolescents aged 16 and older. Diethylpropion is approved for adolescents 16 and older. Remember, this drug is a stimulant and is potentially addictive. Pregnancy and Obesity Obesity is rising in developed countries, making pregravid overweight one of the most common high-risk obstetric situations. Although the designs and populations of published studies vary widely, authors agree that pregravid overweight increases maternal and fetal morbidity. Even moderate overweight is a risk factor for gestational diabetes and hypertensive disorders of pregnancy, and the risk is higher in subjects with overt obesity. Weight loss drugs are not recommended during pregnancy. The best treatment for obesity during pregnancy is dietary control, exercise, and behavioral modification. Ultimate control of obesity occurs before conception. Obese patients who lose even small amounts of weight before conception have a greater chance of improved pregnancy outcomes.