Overview of the Endocrine System and Agents

Hypopituitarism

Hypopituitarism, or a deficiency in pituitary hormones, is rare. Common causes are pituitary surgery or radiation therapy for pituitary tumors or a tumor that blocks blood flow to the pituitary gland. When blood flow to the pituitary gland is decreased, hormones from the hypothalamus cannot reach the pituitary to stimulate the production and release of pituitary hormones. Other causes of hypopituitarism include genetic disorders, head injuries, and other diseases affecting the blood flow to the pituitary gland and hypothalamus.³

Signs and symptoms of hypopituitarism are those seen with deficiencies of the target glands. For example, the patient will display signs and symptoms of thyroid hormone deficiency (hypothyroidism) since the thyroid is not stimulated to produce thyroid hormone due to the lack of TSH from the pituitary.^2,3 However, patients may have an excess of prolactin because of the disruption of inhibition from the hypothalamus.²

Treatment of hypopituitarism depends on the cause of the pituitary deficiency. For causes that cannot be treated, replacement of either the pituitary hormone or the target hormone is essential. Patients are most often treated with glucocorticoids, such as prednisone or hydrocortisone (for ACTH deficiency), thyroid hormones (for TSH deficiency), and sex hormones (for LH and FSH deficiency).^2,3 GH and vasopressin replacement may also be required.³ Hormone replacement for hypopituitarism will often be lifelong, and patients will require monitoring for the various hormones.²

Excessive Growth Hormone (Acromegaly)

Acromegaly is caused by excessive GH production, usually from a tumor in the anterior pituitary. Sometimes, a tumor located outside the pituitary can secrete GH, also resulting in acromegaly. Overproduction of GHRH by the hypothalamus can cause overproduction of GH, which will also lead to acromegaly.^2,3

Patients with acromegaly have overgrowth of soft tissues. They may have large hands and fingers, large feet, an enlarged tongue, and coarse facial features. Many patients will have heart disease and high blood pressure. Osteoarthritis and joint problems are common in patients with acromegaly. These patients may also have type 2 diabetes mellitus, sleep apnea, or respiratory disorders.^2,3 Diagnosis of acromegaly is made based on the blood levels of certain chemicals and markers, as well as glucose tolerance tests (see Chapter 10, Diabetes Mellitus).²

Treatment of acromegaly depends on the cause for the excessive GH. If acromegaly is caused by a tumor outside the pituitary, then removal of the tumor will usually cure the acromegaly. If the patient has a pituitary tumor that cannot be removed with surgery, the patient can be treated with radiation therapy or pharmacological therapy. Pharmacologic therapies include dopamine agonists, somatostatin analogs, and GH receptor antagonists.^2,3

Bromocriptine and cabergoline are the dopamine agonists used to treat acromegaly.^2,3 Bromocriptine will decrease GH levels within 1–2 hours after an oral dose, and the GH levels will remain low for 4–5 hours.² Most patients will see a benefit within 4–8 weeks of bromocriptine therapy.^2,4 The initial dose is 1.25 or 2.5 mg daily.⁴ The dose may be increased in 1.25 or 2.5 mg increments every 3–7 days as needed to suppress GH levels. The maximum dose is 100 mg daily, although most patients with acromegaly can be controlled with doses of 20–30 mg daily.^2,4 For acromegaly, the daily bromocriptine dose should be divided into three or four doses.²

Cabergoline is a long-acting dopamine agonist that is dosed twice a week and is used off-label to treat acromegaly.^2,4 Cabergoline is usually begun with a dose of 0.25 mg twice weekly and may be increased as needed.⁴ Cabergoline doses for acromegaly are much higher than those used for hyperprolactinemia (up to 0.5 mg/day).³

Dopamine agonists often cause nausea, constipation, and headache. Other common side effects include orthostatic hypotension (a decrease in blood pressure upon standing), dry mouth, drowsiness, and vomiting. Cold-sensitive digital vasospasm (constriction of the blood vessels in the fingers as a response to cold temperatures) may occur with high doses of bromocriptine.^2,4 Administration with food is recommended to decrease the likelihood of gastrointestinal side effects.²

Somatostatin is naturally produced by the body and has many functions, including inhibition of the secretion of GH, insulin, and TSH. Because somatostatin has a short half-life and must be given by continuous intravenous (IV) infusion, somatostatin analogs have been developed that have a longer duration of action and more specific activity.⁵ Somatostatin analogs used to treat acromegaly are octreotide, lanreotide, and pasireotide.^2,3

Octreotide is a somatostatin analog often prescribed to prevent the secretion of GH by the pituitary gland. Octreotide is an injection available in two different formulations: a subcutaneous (SUBQ) solution used as initial treatment and a depot suspension used for maintenance therapy. The SUBQ solution is injected 3 times daily, and the dose is adjusted as needed to maintain the appropriate GH and insulin-like growth factor-1 (IGF-1) levels in the body.^2,4 The target GH blood level is <1 ng/mL.^2,4,6 The target IGF-1 level is based on the age-normalized IGF-1 level.⁶ Once a patient is on a stable dose of SUBQ octreotide for at least 2 weeks, the drug can be switched to the depot formulation. The depot suspension is injected intramuscularly every 4 weeks.⁴

The initial dose of octreotide depot injection is 20 mg every 4 weeks. After 3 months, the dose can be adjusted based on response. The maximum dose of octreotide depot injections is 40 mg every 4 weeks, and doses greater than 40 mg are not recommended for acromegaly. Patients receiving octreotide injections commonly develop diarrhea, nausea, and dyspnea (breathing difficulties). Octreotide injections may also cause injection-site pain, dizziness, fatigue, malaise, gallbladder problems, joint pain, and hyperglycemia (high glucose levels). Octreotide may alter heart rate and the conduction of the electrical signal through the heart muscle. Because of this, octreotide may slow the heart rate and enhance the effect of other medications that affect the conduction in the heart.^2,4

Lanreotide is another somatostatin analog indicated for the treatment of acromegaly. Lanreotide is an SUBQ depot injection that is given every 4 weeks. The initial dose is 90 mg every 4 weeks. After the first 3 months, the dose is adjusted based on GH and IGF-1 levels.^2,4 The lanreotide dose is decreased to 60 mg every 4 weeks if the GH and IGF-1 levels are normal and the patient’s symptoms are controlled.⁴ Patients receiving lanreotide injections have reported constipation, diarrhea, nausea, abdominal pain, and injection-site reactions. Lanreotide may decrease the heart rate, cause gallstones, and alter blood glucose levels.^2,4

Pasireotide is the third somatostatin analog. It is available as a long-acting release (LAR) intramuscular formulation for treatment of acromegaly and as a short-acting SUBQ formulation used only as treatment for Cushing’s disease.^2,9,10 Pasireotide LAR intramuscular injection should be initiated at 40 mg every 4 weeks. After 3 months, the dose is titrated based on GH and IGF-1 levels.² Hyperglycemia is more common with pasireotide LAR than with octreotide or lanreotide, and patients may require treatment for diabetes. Other adverse effects include diarrhea, headache, decreased heart rate, and gallstones.^2,9

Somatostatin analogs may decrease the secretion of TSH by the pituitary gland. This will decrease the production of thyroid hormones and may lead to hypothyroidism. Thyroid function should be monitored regularly in patients receiving octreotide, lanreotide, or pasireotide.⁴

Pegvisomant is a GH receptor antagonist used to lower IGF-1 levels without affecting GH secretion. It is administered daily as an SUBQ injection.² A loading dose of 40 mg is given under physician supervision then followed by a daily dose of 10 mg. The dose may be adjusted by 5 mg every 4–6 weeks based on IGF-1 levels. Pegvisomant treatment may not be appropriate for patients with elevated liver enzymes at baseline. If liver enzymes become elevated during treatment, the medication may have to be discontinued.^2,4 Common adverse effects are injection-site reactions, nausea, diarrhea, and flu-like symptoms.² Growth hormone deficiency (GHD) symptoms may occur, even in patients with elevated GH concentrations.⁴

Growth Hormone Deficiency

GHD usually occurs with hypopituitarism, and patients may have signs of other pituitary hormone deficiencies. GHD without hypopituitarism is usually due to a genetic defect. Regardless of the cause, patients with GHD are often short or have delayed growth.^2,12 They may be obese, with excessive fat deposits around the abdomen. Adults may have more bone fractures due to weaker bones. High cholesterol and insulin resistance are also common in adults with GHD.^3,12

GHD is treated with hormone replacement. Somatropin is a GH produced using recombinant DNA technology; it is identical to that secreted by the human pituitary gland.^2,5 Somatropin is usually administered daily as an SUBQ injection, although some products can be given intramuscularly. In children, therapy is usually continued until the desired height is reached or until after the pubertal growth spurt.² In adults, GH replacement decreases body fat, increases lean body mass, and improves cholesterol levels.³ Recombinant GH is also used to treat children with short stature not related to GHD.²

In children, adverse effects from GH are uncommon, although injection-site reactions and joint pain have been reported. Some patients experience headache, blurred vision, nausea, and vomiting. This usually resolves when the somatropin is discontinued.² Hyperglycemia and diabetes mellitus can occur in both adults and children; patients already being treated for diabetes may need therapy adjustments.^3,13 Because GH can stimulate the growth and recurrence of tumors, patients with a malignant tumor or history of recurrent tumors should not be treated with GH.⁵ (See Medication Table 8-1; Medication Tables are located at the end of the chapter).

Hypothyroidism

Hypothyroidism is a condition in which the body is not producing enough thyroid hormone. In the United States, the most common cause of hypothyroidism is a condition called Hashimoto’s thyroiditis, an autoimmune disorder, which causes the body to produce antibodies that destroy the thyroid gland.^2,3,14 Other causes may be radioactive iodine therapy, surgical removal of the thyroid gland, side effects of medications such as amiodarone or lithium, pregnancy, and iodine deficiency (more common in underdeveloped countries). Clinical features of hypothyroidism are due to the body’s decreased metabolic state and include weight gain, fatigue, cold intolerance, dry skin, brittle hair, constipation, and depression.^2,14

Diagnosis of thyroid disorders can be done through blood tests called thyroid function tests, which measure the amounts of TSH, free T4, and T3 circulating in the bloodstream.^2,3,14 The level of TSH in the body is the best indicator of how the thyroid gland is working. In hypothyroidism, TSH is elevated and the amounts of free T4 and T3 are low, because the pituitary gland detects low T3 and T4 and releases more TSH in an attempt to stimulate more thyroid hormone production.^3,14

Treatment of hypothyroidism is through thyroid replacement therapy. The treatment of choice is levothyroxine, T4, a synthetic hormone that replenishes the body’s low thyroid hormone levels.¹⁵ Just as the body’s endogenous thyroid hormones work, levothyroxine is converted into the more active hormone, T3, in the liver and other body tissues. Levothyroxine is available in oral and IV formulations. The oral formulation has an onset of action of 3–5 days and has a slow elimination half-life (6–7 days), which makes the levels of medication more constant and predictable in a patient. Oral doses are started at 12.5–50 mcg and may be titrated up every 4–6 weeks to maintain normal TSH levels. The medication should be taken on an empty stomach, at least 30 minutes before eating.^2,4,15

Liothyronine, T3, has a rapid onset of action (2–3 hours) and is more rapidly cleared from the body than levothyroxine (elimination half-life 2.5 days). This can make the levels of medication in the body fluctuate. Because the body converts T4 to T3, there is no clear benefit of liothyronine over levothyroxine. Liothyronine is available in oral and IV formulations. Oral doses are initiated at 25 mcg/day and are titrated by 12.5–25 mcg/day. A typical maintenance dose is 25–75 mcg/day.⁴

Liotrix, a combination of synthetic T4 and T3, is less commonly prescribed due to cost and difficulty of monitoring. The dose is typically initiated at 25 mcg daily and titrated up to a maintenance dose of 60–120 mcg/day. Thyroid USP, also known as desiccated thyroid, is a natural hormone derived from the thyroid of beef and pork. Natural thyroid hormone products are less commonly prescribed because the potency and amount of drug absorbed by the patient can vary.^2,4

The dose of thyroid replacement therapy is typically based on factors such as patient age, weight, and other disease states. Although symptoms may improve after 2–3 weeks, steady-state TSH concentrations are not achieved for 6–8 weeks. Once steady state is reached, TSH levels are assessed to determine how the patient is responding to the medication and if the dosage is appropriate.² Once the patient is maintained on an appropriate replacement dose, TSH levels are typically measured annually. Adverse effects are unusual if the patient is receiving the correct dosage of medication. If patients are receiving too much medication they may experience symptoms of hyperthyroidism. Thyroid replacement hormones can interact with other medications, including warfarin, digoxin, rifampin, and carbamazepine.⁴ Patients who are also taking antacids, cholestyramine, orlistat, sucralfate, or iron must separate the time of administration of thyroid replacement by at least 4 hours.⁴ Thyroid replacement medications may be safely used during pregnancy. Hypothyroidism caused by pregnancy or medications may resolve after delivery or when the medications are discontinued.⁴ Autoimmune hypothyroidism, caused by Hashimoto’s thyroiditis, is permanent and patients are treated lifelong with hormone therapy.^2,3

Myxedema coma is a rare consequence of severe hypothyroidism, which leads to hypothermia and decreased mental status, which may progress to coma. Myxedema coma has a high mortality rate and is considered a medical emergency. Treatment of myxedema coma is with IV levothyroxine or liothyronine. The medications may be used together or individually.²

Hyperthyroidism

Hyperthyroidism is a condition in which the body produces too much thyroid hormone. The most common cause of hyperthyroidism is Grave’s disease, a genetic autoimmune disorder in which the body produces antibodies that attack the thyroid gland and causes the thyroid gland to make too much thyroid hormone. Hyperthyroidism can also be caused by tumors, nodules, or too much medication for treatment of hypothyroidism.^2,3,14

Clinical features of hyperthyroidism are due to the body’s increased metabolic state and include heat intolerance, weight loss, increased sweating, heart palpitations, increased pulse and systolic pressure, nervousness, irritability, emotional liability, and insomnia. Thyroid function tests of patients with hyperthyroidism will show decreased TSH and increased T4 and T3 because the thyroid gland is overproducing T4 and T3, which in turn inhibits the production of TSH.^2,3,14

Hyperthyroidism can be treated with radioactive iodine, antithyroid medications, or surgery if a nodule is causing the problem. Radioactive iodine is taken orally and works by damaging the thyroid cells. Radioactive iodine is a cure of hyperthyroidism but may lead to hypothyroidism. There are two antithyroid medications that are approved by the Food and Drug Administration (FDA) for the treatment of hyperthyroidism: propylthiouracil and methimazole.² These medications work by blocking the body’s productions of thyroid hormones. Patients often require high initial doses and notice improvement in 4–8 weeks. Dose changes may be made on a monthly basis. Methimazole is initiated at 15–30 mg/day in three divided doses and gradually reduced to a maintenance dose of 5–15 mg/day given in three divided doses. Prophylthiouracil is initiated at 300 mg daily in three divided doses and decreased to a maintenance dose of 50–300 mg/day in three divided doses. Occasionally patients may require 600–900 mg daily.⁴

Propylthiouracil can interact with other medications, including warfarin and lithium. Methimazole may interact with medications that cause bone marrow suppression. Patients are usually treated with antithyroid medications for 1–2 years and 40% to 50% are cured.¹⁴ If patients are cured by medications they still need to continue to be monitored because hyperthyroidism may recur. The medications are usually tolerated well. Adverse effects of the medications include rash, joint aches, and fever.⁴ (See Medication Table 8-2.)

Hypoparathyroidism

Individuals who lack available or functioning PTH have a disorder known as hypoparathyroidism. This disorder may be hereditary, often occurring with no known cause (idiopathic), or it may be the result of surgical procedures that damage the parathyroid glands, autoimmune disorders, radiation-induced damage (from cancer treatments), and severe, chronically low magnesium. If the parathyroid glands functioned normally, PTH would be secreted in response to low calcium levels causing decreased calcium clearance in the kidneys and an increased rate of bone breakdown, leading to a flow of calcium into the blood. Because PTH is absent in hypoparathyroidism, the body’s response to low calcium levels does not occur and other physiologic systems are affected. Symptoms of hypoparathyroidism include burning and tingling of the extremities, seizures, anxiety, calcium deposits in vital organs, tremors, ataxia, nystagmus, vertigo, apathy, depression, irritability, delirium, and psychosis. These symptoms are associated with abnormally low blood levels of calcium and magnesium and high phosphate levels, which often disappear once these electrolyte abnormalities are corrected. Individuals are diagnosed with hypoparathyroidism if they present with low calcium and magnesium levels, high phosphate levels, and little to no PTH present. Past medical and family history, kidney function, and the potential for vitamin D deficiency are also taken into account.^3,19

The primary treatment for hypoparathyroidism is long-term calcium and vitamin D replacement to correct and maintain calcium levels slightly below the normal.^2,3,19 Treatment with oral calcium supplements includes the use of calcium carbonate and calcium citrate. Typical dosing is 500–1,000 mg elemental calcium 3 times daily with meals. Calcium supplements will be discussed in more detail in Chapter 14.

Vitamin D therapy is used to correct vitamin D deficiency. Available therapies include ergocalciferol—vitamin D₂, calcifediol—vitamin D₃, calcitriol, and dihydrotachysterol. The vitamin D analogs paricalcitol and doxercalciferol will be discussed later in this section.

Calcitriol, the active metabolite of vitamin D, is a widely used alternative to fat-soluble formulations of vitamin D. Calcitriol has a rapid onset of action, rapid turnover, and is not fat soluble. The initial dose is 0.25 mcg daily, with maintenance dosages ranging from 0.5–2 mcg oral or IV per day. Doses may be increased every 2–4 weeks.

Treatment with oral calcium and vitamin D, however, does not reverse the decrease in calcium reabsorption from the urinary tract that is typical of hypoparathyroidism. While taking calcium and vitamin D replacements, patients are at risk of developing kidney stones. Thiazide diuretics (discussed in Chapter 13) can be used to reduce urinary calcium levels and lower the risk of kidney stones.

Pseudohypoparathyroidism (PHP) is a collection of disorders resulting from genetic mutations. Patients exhibit symptoms of hypoparathyroidism but have normal kidney function and normal levels of vitamin D. PTH levels are also elevated, but patients don’t respond due to resistance to the hormone.^3,17,18

As in the treatment of hypoparathyroidism, calcium and vitamin D supplementation is also the mainstay for treatment of PHP. The goals of treatment are to bring calcium and PTH levels back to normal and to avoid high calcium levels in the urine (hypercalciuria). A total daily dose of 1–3 grams elemental calcium is recommended to normalize and maintain calcium levels. Calcitriol is the vitamin D supplement of choice because individuals with PHP often require less vitamin D supplementation than individuals with hypoparathyroidism. Additionally, calcitriol is not fat soluble. The effective dose of calcitriol ranges from 0.25 mcg twice daily to 0.5 mcg 4 times daily.

Hyperparathyroidism

Overactive parathyroid glands are the cause of hyperparathyroidism. This condition is classified as primary, secondary, or tertiary depending on the cause of parathyroid hyperactivity and the presence of hyper- or hypocalcemia.³

Primary hyperparathyroidism (PHPT) is a response to one or more enlarged glands causing overproduction of PTH resulting in hypercalcemia. Women are three times more likely than men to develop PHPT, and the condition is more common after menopause, with an estimated prevalence of 1%.^16,20 PHPT is typically the result of growth or a tumor and is independent of other organs. Overgrowth of the gland(s) is considered irreversible. Other potential causes of PHPT include external neck irradiation, genetic mutations, and lithium therapy.^3,16,20

Unlike primary hyperparathyroidism, secondary hyperparathyroidism (SHPT) occurs in response to long-term states of hypocalcemia and is associated with resistance to PTH. The result, however, is similar with enlarged glands and overproduction of PTH. Most notably SHPT occurs in the presence of chronic kidney disease and decreased renal function, but it is also frequently due to other causes of bone softening (eg, deficiency of vitamin D action and pseudohypoparathyroidism).^2,16 Unlike PHPT, overgrowth of the gland(s) can be reversed if the underlying condition is corrected. In the early stages of chronic renal failure, PTH secretion is consistently elevated in order to correct calcium and phosphate levels. As kidney function worsens, less phosphorus is eliminated leading to high phosphate levels and plummeting calcium levels. Another complication of worsening kidney function is severe vitamin D deficiency because there is less conversion of vitamin D to its active metabolite. Because PTH is produced continuously, resistance to the effects of calcium and vitamin D therapy develops because fewer vitamin D and calcium-sensing receptors are available. Over time renal osteodystrophy (bone disease) develops.²

When patients with secondary hyperparathyroidism are no longer responsive to medical treatment, a chronic state of hypercalcemia develops due to constant overproduction of PTH. The term tertiary hyperparathyroidism (THPT) originated to describe these patients exhibiting severe manifestations of secondary hyperparathyroidism despite aggressive medical efforts to correct the condition.³ The treatment of choice for PHPT and THPT in symptomatic patients is surgery to remove one or more of the affected parathyroid glands. Surgical management is also recommended for asymptomatic PHPT patients who are less than 50 years old; are not able to participate in adequate medical follow-up; have serum calcium more than 1 mg/dL (0.25 mmol/L); have a T-score less than or equal to −2.5 at the lumbar spine, total hip, femoral neck, or distal one-third radius; have significant bone mineral density decrease; and/or have creatinine clearance <60 mL/min.²¹

Because SHPT is considered reversible if electrolyte imbalances are corrected, SHPT can be managed with medication instead of surgery. The goals for managing SHPT include the management of PTH, phosphate, and calcium balances, while minimizing aluminum exposure. These activities are important in slowing or preventing the progression of SHPT, renal osteodystrophy, and calcifications in the cardiovascular system or soft tissues. Phosphate-binding medications, calcium supplements, vitamin D, and calcimimetics are all therapies utilized to meet these goals.^2,3,16

Phosphate-binding agents are medications that work in the gastrointestinal tract, combining dietary phosphates with other molecules to form insoluble salts. This prevents the phosphate from being absorbed into the bloodstream; instead, it is excreted in the feces, resulting in an overall lowering of circulating phosphates.

Available phosphate-binding agents include calcium-, lanthanum-, aluminum-, and magnesium-containing compounds, sevelamer hydrochloride, and sevelamer carbonate. Newer agents include sucroferric oxyhydroxide and ferric citrate.²² Sevelamer HCl is a nonabsorbable hydrogel phosphate-binding agent that does not contain aluminum, calcium, or magnesium. The dose is determined based on the patient’s current serum phosphate level and is adjusted as needed. Doses typically range from 800–1,600 mg 3 times daily. Common side effects include nausea and vomiting, indigestion, flatulence, and diarrhea. It also has the potential to cause a drop or increase in blood pressure. Sevelamer carbonate is an agent similar to sevelamer hydrochloride but contains a carbonate buffer instead. The carbonate component was added to maintain bicarbonate levels and reduce gastrointestinal (GI) side effects. Dosing strategies and side effects are the same as for sevelamer HCl and may affect the bioavailability of antiarrhythmic and anticonvulsant medications. The sevelamer agents should be given at least 1 hour before or 3 hours after antiarrhythmic or anticonvulsant drugs to reduce the potential for drug interactions.

Lanthanum carbonate is a phosphate-binding agent that complexes with phosphates in meals and prevents their absorption. The initial dose is 1,500 mg daily, administered in divided doses. The dose may be titrated up every 2–3 weeks to a maximum recommended dose of 3,000 mg per day. Common side effects include diarrhea, nausea, and vomiting.

Aluminum carbonate and aluminum hydroxide are used if phosphorus levels are particularly high. Aluminum salts are considered third-line agents in the treatment of higher-than-normal phosphate levels, known as hyperphosphatemia, and may be prescribed alone or in combination with calcium-containing binding agents or sevelamer for patients who do not respond to one agent alone. Long-term use can lead to aluminum toxicity and could result in the development of the bone disease osteomalacia, anemia, joint disease, and encephalopathy. Dosing ranges from 300–600 mg 3 times daily with meals, depending on the agent used. Typical side effects include constipation, nausea and vomiting, and a chalky taste.

Antacids containing magnesium carbonate or magnesium hydroxide can also be used as phosphate binders, which may decrease the need for calcium-based phosphate-binding agents; however, use of these agents may be limited because of magnesium accumulation and resulting toxicity. The typical dose is given 3 times daily and ranges from 70 mg (magnesium carbonate) to 300–400 mg (magnesium hydroxide). Common side effects include diarrhea, GI distress, and elevated magnesium and potassium levels.

Calcium supplements, such as calcium carbonate and calcium acetate, are considered first-line therapy in the treatment of hyperphosphatemia associated with low calcium levels. Calcium supplements are especially useful in the early stages of chronic kidney disease (CKD) to treat and prevent the hypocalcemia that leads to an overproduction of PTH. Calcium acetate is more potent and binds twice as much phosphorus in comparison to calcium carbonate when given in similar doses. Because of the higher binding capacity for phosphorus there is less calcium absorption in the GI tract. Doses of calcium agents range from 500–667 mg per meal, or 168–200 mg elemental calcium per meal, depending on which calcium agent is used. Individuals taking a calcium supplement should take no more than 1,500 mg daily, with a 2,000-mg daily limit that includes all sources of calcium.

Sucroferric oxyhydroxide and ferric citrate are oral iron-based phosphate binders indicated for patients on dialysis with CKD and hyperphosphatemia.²² The iron in these agents binds strongly to phosphorus and the resulting iron-phosphorus compound is not soluble and therefore precipitates out. Sucroferric oxyhydroxide binds to phosphate ions in the GI tract by ligand exchange between hydroxyl groups or water in the dietary phosphate and sucroferric oxyhydroxide. Tablets of sucroferric oxyhydroxide are chewable and are available in a strength of 2,500 mg, which is equivalent to 500 mg of iron. It is recommended to take one tablet prior to each meal 3 times daily. Titration up or down in increments of 500 mg of iron per day (2,500 mg sucroferric oxyhydroxide) may occur after the first week to achieve recommended serum phosphorus levels <5.5 mg/dL. Ferric citrate creates the precipitate ferric phosphate when it binds to dietary phosphate in the GI tract. Ferric citrate comes in a 1-g chewable tablet, which is equivalent to 210 mg of ferric iron. The recommended starting dose of ferric citrate is 2 tablets (420 mg ferric iron) taken with meals orally 3 times daily. The dose may be increased weekly by 1 to 2 tablets to a maximum of 12 tablets daily (2,520 mg ferric iron) to achieve serum phosphorus levels <5.5 mg/dL. Common side effects of iron-based phosphate binders include nausea, vomiting, diarrhea or constipation, and discolored stool. Ferric citrate has the potential to increase aluminum absorption, so it is important to watch for aluminum toxicity.²²

Because sucroferric oxyhydroxide and ferric citrate are iron based, potential drug interactions may occur. Therefore, it is important to review the timing of medication administration. Ferric citrate has the potential to reduce the absorption of medications that bind to polyvalent cations. Examples include levothyroxine, quinolone antibiotics (eg, ciprofloxacin), some antivirals (eg, dolutegravir), and levodopa preparations. Sucroferric oxyhydroxide may reduce absorption of levothyroxine, cephalexin, tetracyclines, and aspirin.

Vitamin D therapy is often necessary because patients with CKD cannot convert vitamin D to its active form in the kidneys; therefore, the active form of vitamin D, calcitriol, is used in the treatment of SHPT in addition to the vitamin D analogs paricalcitol and doxercalciferol. Oral formulations may be used in earlier stages, but IV treatment is given to those who are on dialysis. For patients who are not on dialysis, oral calcitriol is initiated at a dose of 0.25 mcg daily. For dialysis patients who require the IV formulation, the dose is initiated at 0.5 mcg 3 times weekly at dialysis (about every other day). Doses are adjusted based on PTH levels and may be increased every 2–4 weeks. Potential side effects include edema, nausea and vomiting, itching, dizziness, and headache.

Paricalcitol is a synthetic analog of vitamin D₂. If PTH levels are very low, paricalcitol may be administered orally in doses of 1 mcg daily or 2 mcg 3 times a week given every other day. For patients whose PTH level is nearer the normal range, paricalcitol may be given orally as 2 mcg daily or 4 mcg 3 times per week given every other day. The IV form of paricalcitol is given at dialysis (before, during, or after) with an initial dose of 2.8–7 mcg. Dose increases may be done every 2–4 weeks. Common side effects of paricalcitol include nausea, diarrhea, skin rash, and edema.

Doxercalciferol is also a synthetic analog of vitamin D₂ and is available in oral and IV dosage forms. For patients not yet on dialysis, doxercalciferol may be given in doses of 1 mcg by mouth daily with the dose adjustments based on PTH levels. For those patients who are on dialysis, doxercalciferol may be given at the time of dialysis. Common side effects of doxercalciferol include nausea and vomiting, dizziness, itching, headache, general malaise, cough, dyspnea, and edema.

Potential drug interactions are important to consider when vitamin D therapy is prescribed. Bile acid sequestrants (eg, cholestyramine) and drugs affecting lipid absorption (eg, orlistat) can decrease the oral absorption of calcitriol, paricalcitol, and doxercalciferol. Paricalcitol and doxercalciferol have also shown interactions with drugs such as ketoconazole that inhibit certain liver enzymes. This inhibition can lead to dangerously elevated levels of vitamin D analogues and other medications.

Cinacalcet is a calcimimetic agent approved to treat patients with SHPT on dialysis. Cinacalcet is not a source of calcium, but it binds to calcium-sensing receptors on parathyroid cells and mimics the action of extracellular ionized calcium. The result is an increase in sensitivity of the calcium receptors to extracellular calcium levels, which reduces the release of PTH and decreases blood calcium levels. For patients on dialysis, the starting dose is 30 mg orally once daily and may be titrated up every 2–4 weeks to a maximum dose of 180 mg daily. Side effects most often reported with cinacalcet use include nausea and vomiting, hypocalcemia, cramping, myalgias, tetany, and convulsions. Because cinacalcet is processed in the liver and is a potent inhibitor of at least one liver enzyme, drug interactions may be an issue. If cinacalcet is added to a regimen including drugs metabolized by the liver, dose adjustments may be required. Concentrations of cinacalcet may also be significantly increased if given with some liver enzyme inhibitors such as erythromycin and ketoconazole.

For patients taking cinacalcet, serum calcium levels must be monitored. If a patient’s serum calcium rises above the normal range or PTH decreases, cinacalcet use should be discontinued or avoided.

Cinacalcet is also effective in treating the hypercalcemia associated with parathyroid carcinoma, a type of cancer. Dosing of cinacalcet in this situation is different compared to SHPT. The initial dose is 30 mg orally twice daily, with titration every 2–4 weeks in sequential doses of 60 mg twice daily, 90 mg twice daily, to 90 mg 3–4 times daily, up to a maximum of 360 mg per day. At these doses, nausea and vomiting are the most common side effects and may require a reduction in the dose or even discontinuing cinacalcet. (See Medication Table 8-3.)