Background

Type 2 multiple endocrine neoplasia (MEN 2) is a rare familial cancer syndrome caused by mutations in the RET proto-oncogene. Sipple first described an association between thyroid cancer and pheochromocytoma (benign tumor of the adrenal medulla) in 1961. The thyroid cancer found with pheochromocytoma was discovered in 1965 to be a medullary carcinoma characterized by stromal amyloid. In 1968, this familial constellation of pathology in conjunction with parathyroid hyperplasia was recognized as MEN 2. (See Pathophysiology and Etiology.) Although patients with mucosal neuromas were identified at this time, the distinction between MEN 2A and MEN 2B was not made until 1975. The differences between these variations of the disease are as follows (see Presentation and Workup): Phenotype - MEN 2A patients do not have the phenotypic abnormalities of mucosal neuromas and marfanoid habitus found in MEN 2B patients Medullary thyroid carcinoma - MEN 2A patients have a less virulent form of medullary thyroid carcinoma than do MEN 2B patients Parathyroid hyperplasia - MEN 2A patients may have parathyroid hyperplasia, which is exceedingly rare in MEN 2B patients A third subtype of MEN 2 is familial medullary thyroid carcinoma only (FMTC only).

Epidemiology
The overall frequency of MEN 2 in the United States is 1 case per 30,000-50,000 persons in the United States. In decreasing order of frequency, MEN occurs as follows: MEN 2A, FMTC only, and MEN 2B. In MEN 2A patients, 50% of those with RET gene mutations develop the disease by age 50 years, and 70% develop the disease by age 70 years. Medullary thyroid carcinoma has been detected shortly after birth in MEN 2B. (See Workup and Treatment.)

Patient education
Adhering to a surveillance program lessens disease complications. Order genetic counseling for the patient so that gene testing and reproductive options can be discussed. For patient education information, see Thyroid Problems. (See Treatment.)

Pathophysiology
As previously stated, MEN 2 is a rare familial cancer syndrome caused by mutations in the RET protooncogene. Inherited as an autosomal dominant disorder, MEN 2 has 3 distinct subtypes, including MEN 2A, MEN 2B, and FMTC only. The subtypes are defined by the combination of tissues affected. Developmental abnormalities may also be present. By age 70 years, the penetrance rate is 70%. Genetic testing and clinical surveillance beginning in childhood provide the opportunity to treat the devastating and sometimes fatal complications of this disorder.[1] The RET proto-oncogene is 80 kilobases (kb) long and encodes a putative tyrosine kinase receptor. Its endogenous ligand may be glial cell linederived neurotrophic factor (GDNF), which appears to play a critical role in the normal function of pathways involved in enteric nervous system neurogenesis and renal organogenesis. Data suggest that an overrepresentation of mutant RET as an undefined second hit event may trigger tumorigenesis. However, alterations in other genes may contribute to this overrepresentation of RET or may influence MEN 2-related tumor development through completely different mechanisms and pathways. Glandular hyperplasia begins with an increase of C cells located in the thyroid gland follicles and can progress to malignancy.

Medullary thyroid carcinoma

Virtually all patients with MEN 2A develop medullary thyroid carcinoma. This is often the first expressed abnormality and usually occurs in the second or third decade of life. The medullary thyroid carcinoma in patients with MEN 2A is typically bilateral and multicentric, in contrast to sporadic medullary thyroid carcinoma, which is unilateral.

Pheochromocytoma
Pheochromocytomas are present in approximately half of MEN 2A patients. They are bilateral in 60-80% of patients, compared with 10% of patients with sporadic pheochromocytomas. Pheochromocytomas tend to be diagnosed at the same time as medullary thyroid carcinoma or several years later (with both occurring primarily in the second or third decade). The pheochromocytomas of MEN 2A patients are nearly all benign. Even so, these lesions can cause a life-threatening hypertensive episode or arrhythmia.

Parathyroid hyperplasia
Parathyroid hyperplasias are present in nearly half of patients with MEN 2A but are less common than pheochromocytomas. In many patients, such hyperplasias can be clinically silent. However, as in other cases of hyperparathyroidism, symptoms can often be elucidated following comprehensive questioning.

Etiology
Mutations in RET, a transmembrane proto-oncogene, have been localized to 10q11.2 and are responsible for MEN 2. Although its function is still unknown, the protein produced by RET is critical during embryonic development of the enteric nervous system and kidneys. RET consists of 3 domains, including a cysteine-rich extracellular receptor domain, a hydrophobic transmembrane domain, and an intracellular tyrosine kinase catalytic domain. Point mutations associated with MEN 2A and the FMTC-only subtype were identified in exons 10 and 11. Evidence of genotype/phenotype correlation exists. Almost all individuals with MEN 2B have an identical mutation in codon 918 of exon 16. Inheritance is autosomal dominant, with variable penetrance and expressivity. Substantiation of the genotype-phenotype correlation of inherited medullary thyroid carcinoma may lead to the development of an individual approach to risk management in childhood genotype carriers, and research into potential modifying factors should take place. Early total thyroidectomy remains effective in preventing the development of medullary thyroid carcinoma in the long-term.[2]

Prognosis
Early treatment of medullary thyroid carcinoma can prevent death, and careful monitoring for pheochromocytomas can decrease the chance of hypertensive episodes. MEN 2A, MEN 2B, and the FMTC-only subtype elicit overlapping and distinct abnormalities. The characteristic tumor of MEN 2 medullary thyroid carcinoma is present in all subtypes. Pheochromocytomas appear in MEN 2A and MEN 2B patients. Primary hyperparathyroidism frequently develops in patients with MEN 2A but rarely in those with MEN 2B. Gastrointestinal, skeletal, and dermatologic abnormalities occur only in patients with MEN 2B.

Medullary thyroid carcinoma

The prognosis of medullary thyroid carcinoma is associated with the disease stage at the time of diagnosis. Because the penetrance of medullary thyroid carcinoma is nearly 100%, perform prophylactic thyroidectomy in infancy for patients with high-risk RET mutations or by age 5 years in children with an identifiable RETmutation.[3, 4] For patients who are at risk but who have not had genetic screening, perform annual biochemical screening. The 5- and 10-year survival rates in patients with medullary thyroid carcinoma and MEN 2A are approximately 90% and 75%, respectively.

Pheochromocytoma
These benign tumors of the adrenal medulla occur in 50% of patients with MEN 2 by the time they are in their late 30s; however, prevalence varies in different families. Pheochromocytomas develop in more than 50% of patients with MEN 2B and can appear during early childhood. The earliest possible detection of these tumors can prevent a hypertensive crisis. Adrenalectomy should be considered when patients have biochemical confirmation and an adrenal mass or enlargement on imaging. A bilateral adrenalectomy is reserved for bilateral adrenal masses. Subtotal adrenalectomy remains controversial.[5, 6]

Hyperparathyroidism
Extremely uncommon in MEN 2B patients, parathyroid hyperplasia affects 20-30% of MEN 2A patients. Patients may present with hypercalcemia and other vague symptoms.

History
The most important questions to ask relate to a family history of multiple endocrine neoplasms. Patients may present with symptoms related to medullary thyroid carcinoma, hyperparathyroidism, or pheochromocytoma. However, clinical presentation is associated with the patient's age. A young patient with an identified RET proto-oncogene mutation will probably be asymptomatic. These patients generally have thyroid C-cell hyperplasia without progression to medullary carcinoma. Virtually all index patients have medullary thyroid carcinoma at the time of diagnosis, although their clinical presentation may be consistent with pheochromocytoma or hyperparathyroidism. Symptoms in type 2 multiple endocrine neoplasia (MEN 2) can include hypertension, episodic sweating, diarrhea, pruritic skin lesions, or compressive symptoms from a neck mass. Patients with hypercalcemia may present with constipation, polyuria, polydipsia, memory problems, depression, nephrolithiasis, glucose intolerance, gastroesophageal reflux, and fatigue, or they may have no symptoms. They may also lose bone density.

Hypertension
If pheochromocytomas develop, an increase in blood pressure and heart rate may be the only signs. These increases can be chronic or episodic. Some patients have episodes of sweating and headaches.

Diarrhea
If a patient has medullary thyroid carcinoma, he or she may have a history of diarrhea from extensive disease. This may be related to elevated prostaglandin or calcitonin levels.

Chronic constipation
This constant finding in MEN 2B patients results from hyperplasia of the intrinsic autonomic ganglia in the intestinal wall. Infants may fail to thrive.

Pruritic skin lesions

Cutaneous lichen amyloidosis in MEN 2A patients manifests as multiple pruritic, hyperpigmented, lichenoid papules in the scapular area of the back.[7] These lesions are associated with the deposition of altered cytokeratins rather than of calcitoninlike peptides.

Physical Examination
The physical signs of MEN 2 are extremely variable and often subtle. A neck mass or a dominant thyroid nodule is discovered; anterior neck lymph nodes are nontender, arise insidiously with progressive enlargement, and may signify regional metastasis. Blood pressure and heart rate may be elevated if a pheochromocytoma is present.

The marfanoid habitus of high-arched palate, pectus excavatum, bilateral pes cavus, and scoliosis are observed in MEN 2B patients. Neuromas on the eyelids, conjunctiva, nasal and laryngeal mucosa, tongue, and lips are frequent findings. Patients also have prominent, hypertrophied lips leading to a characteristic facies. Localized pruritus appears over the upper back in MEN 2B patients.

iagnostic Considerations
Hereditary pheochromocytomas may occur with the following conditions: Von Hippel-Lindau syndrome Von Recklinghausen disease (neurofibromatosis) Sturge-Weber syndrome Tuberous sclerosis Hereditary hyperparathyroidism may occur with the following conditions: Type 1 multiple endocrine neoplasia (MEN 1) Familial hyperparathyroidism Familial hypocalciuric hypercalcemia

Approach Considerations
Perform genetic screening for RET mutations in all index patients. If a mutation is identified, also screen family members who are at risk. For individuals identified with a mutation or for persons who are at risk, biochemical screening consists of ascertainment of baseline calcitonin levels and of serum calcium and parathyroid hormone (PTH) levels, along with urine collection for catecholamines and metanephrine concentrations. (However, a plasma metanephrine level can be used for screening.) If a patient's calcitonin level is within reference ranges, a pentagastrin and/or Ca ++stimulation test may be used as a guide to assess the necessity of a central compartment or modified neck dissection. Patients who have been diagnosed with medullary thyroid carcinoma require serial calcitonin (+/provocative testing) and carcinoembryonic antigen (CEA) testing to assess for persistent or recurrent disease.

Fine-needle aspiration
Avoid the removal of cells from thyroid masses for cytology in patients with type 2 multiple endocrine neoplasia (MEN 2) who have had their diagnosis previously confirmed by either genetic analysis or elevated calcitonin levels. These patients have an established diagnosis, and a biopsy increases the possibility of tumor spread. A fine-needle aspiration biopsy is primarily used in an index patient who presents with a thyroid nodule when the clinician considers the presence of medullary thyroid carcinoma to be unlikely.

Screening for Cancer and Hyperparathyroidism

Screening for medullary thyroid carcinoma is done with the pentagastrin stimulation test, with serum calcitonin measured at baseline and at 2, 5, and 10 minutes. False-positive and false-negative results have been reported. Urinary catecholamines and metanephrines screen for pheochromocytomas. (If these are elevated, imaging studies of the adrenals are recommended.) Serum calcium level and PTH levels screen for hyperparathyroidism. An inappropriately elevated PTH level in relation to the serum calcium is consistent with primary hyperparathyroidism. If the 24-hour urine calcium level is low, the presence of familial hypocalciuric hypercalcemic syndrome should be considered.

Imaging Studies

Perform computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the adrenals. A metaiodobenzylguanidine (MIBG) scan is useful for localizing pheochromocytomas. [8, 9, 10] If calcitonin levels are elevated at either baseline or with provocative testing, evaluate the chest and abdomen for metastatic disease. Available modalities include CT scanning, MRI, octreotide scanning, and, in some instances, laparoscopy. Radionuclide scanning may reveal the extent of metastasis. OctreoScan provides a whole-body examination and is used to examine the spread of medullary thyroid carcinoma. The somatostatin analogue octreotide, which is used for the treatment of hormone-related symptoms, is labeled with the isotope indium-111 (111 In) and injected intravenously. The next day, the patient is examined with a gamma camera, which can detect the accumulation of radioactivity.

Histologic Findings
The tumor in medullary thyroid carcinoma is well demarcated, firm, and grayish white. Polygonal cells are uniform, with finely granular eosinophilic cytoplasm with central nuclei. Amyloid formed from calcitonin molecules is often found. Other findings include the following: C-cell hyperplasia - Frequently found; is a precursor in the malignant transformation to medullary thyroid carcinoma. Pheochromocytomas - Benign tumors, often bilateral and multifocal, that arise from diffuse hyperplasia of the adrenal medulla Parathyroid hyperplasia - In this, overgrowth is the most common finding, although adenomatous changes occur in a small percentage of cases

Staging
TNM classification is used for postoperative staging. (T = the size of the primary lesion, N = the presence or absence of regional lymph node metastatic involvement, and M = the presence or absence of distant metastatic lesions.) Primary lesions are designated as follows: T1 - Tumor 2cm or less in greatest dimension, limited to the thyroid T2 - Tumor greater than 2 cm but less than or equal to 4 cm; limited to the thyroid T3 - Tumor greater than 4 cm; limited to the thyroid T4a - Tumor of any size that extends extrathyroidally and invades subcutaneous soft tissues T4b - Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels Regional lymph node metastatic involvement is designated as follows: N0 - No evidence of lymph node metastases N1 - Regional lymph node metastasis N1a - Metastasis to level VI (central compartment) cervical lymph node(s) N1b - Metastasis to unilateral or bilateral cervical nodes or to superior mediastinal lymph node(s) Occurrence of distant metastatic lesions is designated as follows: M0 No evidence of distant metastases exists M1 Distant metastatic lesions exist Postoperative staging is as follows: Stage 1 - T1,N0,M0 Stage II - T2,N0,M0 Stage III (T3,N0,M0), (T1,N1a,M0), (T2,N1a,M0), (T3,N1a,M0) Stage IVA - (T4a,N0,M0), (T4a,N1a,M0), (T1,N1b,M0), (T2,N1b,M0), (T3,N1b,M0), (T4a,N1b,M0) Stage IVB - T4b, any N, M0 Stage IVC - Any T, any N, and M1

Approach Considerations

Type 2A multiple endocrine neoplasia (MEN 2A) is treated with surgery. Preoperative medical treatment may consist of prostaglandin inhibitors to alleviate diarrhea that may be associated with medullary thyroid cancer. Evaluation for pheochromocytomas is important because these should be removed before other surgical interventions. This evaluation can be performed beforeparathyroidectomy or thyroidectomy under a single general anesthetic if the patient is stable.

Pheochromocytoma
Preoperatively, prepare patients with pheochromocytomas by treating them with an alpha-blocker or a tyrosine hydroxylase inhibitor, such as metyrosine, for 1-2 weeks, after which administration of a betablocker can be considered. Reports of successful management using a calcium channel blocker rather than an alpha blocker have been noted. Many practitioners routinely treat patients with a beta-blocker, while others selectively treat patients based on blood pressure control and tachycardia.

Hypercalcemia
Patients presenting with severe hypercalcemia should first be hydrated, after which they should be treated with furosemide. If they remain severely hypercalcemic, consider treatment with calcitonin, glucocorticoids, or bisphosphonates (such as pamidronate). While bisphosphonates are most commonly used, cinacalcet, a calcimimetic, can also be effective at reducing serum calcium levels. These patients need urgent parathyroidectomy when calcium levels have been lowered, ideally below 14 mg/dL. Patients who are not surgical candidates may also benefit from cinacalcet.

Thyroid supplementation
Thyroid hormone supplementation is necessary following total thyroidectomy in carriers of RET mutations or following a diagnosis of medullary thyroid carcinoma.

Transfer
Transfer patients for surgical intervention if necessary.

Deterrence/prevention
Start annual 24-hour urine collections for catecholamine concentrations to detect pheochromocytoma at the earliest age possible. Begin annual testing of serum calcium and PTH levels at age 10 years.

Outpatient care
Monitor patients for recurrence of medullary thyroid carcinoma with calcitonin, CEA, and +/- provocative calcitonin testing. Perform annual screening for hyperparathyroidism with serum calcium and PTH levels in MEN 2A patients. Obtain urinary catecholamine levels on an annual basis to assess for pheochromocytoma. Carefully monitor medication dosage and adverse effects.

Consultations
Consultations with the following specialists may be necessary: Geneticists Endocrinologists Oncologists

Medullary Thyroid Carcinoma Surgery

The advent of genetic analysis has negated the need for pentagastrin stimulation testing to identify patients with hereditary medullary thyroid carcinoma. Carefully screen patients without a family history for pheochromocytoma and hyperparathyroidism because almost 19% of sporadic cases of medullary thyroid carcinoma are index MEN 2A cases.

Calcitonin and CEA determinations remain useful serologic tests to identify recurrent disease. With nearly 100% penetrance of medullary thyroid carcinoma in MEN 2A patients, surgical intervention is recommended in all patients who are identified to carry the MEN2A gene. With genetic analysis available, these patients are often found to have an earlier stage of disease, with many patients having only parafollicular C-cell hyperplasia. Total thyroidectomy has been recommended for patients as young as 3 years for MEN 2A if they contain the genetic mutation. In patients with the RET genetic mutation for MEN 2B, total thyroidectomy is recommended in infancy because medullary thyroid carcinoma behaves more aggressively in these patients. In contrast to patients who have sporadic cases of medullary thyroid carcinoma with solitary tumors, patients with MEN 2A have bilateral and multifocal disease.

Surgical strategies
The extent of surgery is controversial. Total thyroidectomy with central neck dissection is recommended for all patients with proven or probable medullary thyroid carcinoma. The need for either a unilateral or a bilateral modified neck dissection is controversial. The inclusion of a modified neck dissection has been recommended for patients with palpable jugular chain lymphadenopathy. Some surgeons advocate a routine modified neck dissection. Others sample the jugular chain at operation with frozen section, proceeding with dissection only with histologic evidence of metastatic disease. Children often do not require a node dissection, because their disease is at the hyperplasia stage and has not reached metastatic potential. Moreover, patients undergoing prophylactic thyroidectomy do not require lymphadenectomy. Patients who have late-stage medullary thyroid cancer with symptomatic or progressive disease who are not surgical candidates may benefit from treatment with vandetanib, a tyrosine-kinase inhibitor that inhibits vascular endothelial growth factor and epidermal growth factor.

Persistent or recurrent calcitonin elevation

The treatment of persistent or recurrent elevations of calcitonin with random testing or following pentagastrin stimulation has been a clinical dilemma. Some investigators have found calcitonin levels to remain stable for approximately 5 years and have recommended surgical excision only for clinically apparent disease. Others have found that 66% of patients with node-positive disease died secondary to medullary thyroid carcinoma and advocate a more aggressive approach to follow-up care and surgery.

Parathyroid Disease Surgery

Hyperparathyroidism is the least common manifestation of MEN 2A. It usually manifests in patients older than 30 years. Histologically, the parathyroid glands in MEN 2A patients consist of a chief-cell hyperplasia; this hyperplasia is asymmetrical in terms of parathyroid size. To reduce the risk of postoperative hypocalcemia, remove only grossly abnormal parathyroid glands. If all parathyroid glands are enlarged, a subtotal parathyroidectomy is advocated, leaving an approximately 60mg remnant. Perform a cervical thymectomy because of the increased risk of supernumerary parathyroid glands.[11] Persistent or recurrent hyperparathyroidism is unusual and less likely to occur in MEN 2A patients than in MEN 1 patients.

Pheochromocytoma Surgery
Screen all MEN 2A patients for pheochromocytomas. This screening should consist of a 24-hour urine collection for catecholamines and metanephrine. Localization studies are not necessary unless biochemical evidence is consistent with pheochromocytoma.

While all MEN 2A patients may have bilateral adrenal medullary hyperplasia, the tumors may or may not be present bilaterally at the time of initial operation. In this situation, a unilateral adrenalectomy avoids the risk of Addisonian crisis and improves the quality of life by not requiring replacement therapy. Some investigators have advocated bilateral adrenalectomy in all patients owing to the risk of malignancy (rare) and the operative complications from subsequent surgeries. The advent of laparoscopic adrenalectomy has substantially decreased the morbidity of adrenalectomy. A subtotal adrenalectomy can be performed to preserve adrenal cortical function, but the risk for recurrence may be increased. Remember that one fourth of patients with apparently sporadic pheochromocytoma may be carriers of mutations characteristic of syndromes associated with pheochromocytomas.

Long-Term Monitoring
Patients should be monitored on a lifelong basis for evidence of recurrent disease. After an initial followup visit, patients may be evaluated at 6 months, then yearly if they are asymptomatic. During these evaluations, patients should undergo physical examination, 24-hour urine catecholamine, metanephrine and vanillylmandelic acid, CEA level, calcitonin, and serum calcium testing. If recurrent hypercalcemia is suggested, consider patients for repeat cervical exploration. If pheochromocytoma is suggested, evaluate patients for surgical resection. This tumor is likely in the remaining contralateral adrenal, although workup should include a CT scan and an MIBG scan to evaluate for recurrence at the resected area or at an extra-adrenal site. Recurrences in the resected area are more common if a subtotal adrenalectomy had been performed initially. The management of calcitonin/CEA elevations has been controversial. Resect any palpable cervical disease. Some practitioners have advocated routine cervical ultrasonography with exploration for any evidence of recurrence. Many patients remain asymptomatic with elevated calcitonin levels for 20 years or longer.

Medication Summary
Patients require hormone replacement following total thyroidectomy and bilateral adrenalectomy or when they have postoperative hypoparathyroidism. In addition, patients who develop postoperative hypoparathyroidism need supplemental calcium and/or vitamin D. The corticosteroid cortisone and the mineralocorticoid fludrocortisone acetate can be used in combination in patients suffering from adrenocortical insufficiency. Preoperatively, prepare patients with pheochromocytomas by treating them with an alpha-blocker or a tyrosine hydroxylase inhibitor, such as metyrosine, for 1-2 weeks, after which administration of a betablocker can be considered. Many practitioners routinely treat patients with a beta-blocker, while others selectively treat patients based on blood pressure control and tachycardia. Patients presenting with severe hypercalcemia should first be hydrated, after which they should be treated with furosemide. If they remain severely hypercalcemic, consider treatment with calcitonin, glucocorticoids, or bisphosphonates (such as pamidronate). These patients need urgent parathyroidectomy when calcium levels have been lowered, ideally below 14 mg/dL.

Alpha-Adrenergic Receptor Blockers

Class Summary
At low doses, alpha-adrenergic receptor blockers may be used as monotherapy in the treatment of hypertension. At higher doses, they may cause sodium and fluid to accumulate. As a result, concurrent diuretic therapy may be required to maintain the hypotensive effects of alpha-receptor blockers.
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Phenoxybenzamine hydrochloride (Dibenzyline)

This is a long-acting adrenergic alpha-receptor blocker that can produce and maintain a chemical sympathectomy. Phenoxybenzamine hydrochloride lowers supine and upright blood pressure. It does not affect the parasympathetic nervous system.
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Doxazosin mesylate (Cardura, Cardura XL)

Doxazosin mesylate is a quinazoline compound that is a selective alpha1-adrenergic antagonist. It inhibits postsynaptic alpha-adrenergic receptors, resulting in the vasodilation of veins and arterioles and a decrease in total peripheral resistance and blood pressure.
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Phentolamine mesylate (Oraverse)

This is a nonselective alpha-adrenergic blocking agent. Its drug action is transient and alpha-adrenergic blockade incomplete. Phentolamine mesylate is often used immediately prior to or during adrenalectomy to prevent or control paroxysmal hypertension resulting from anesthesia, stress, or operative manipulation of the tumor. It is an alpha1- and alpha2-adrenergic blocking agent that blocks circulating epinephrine and norepinephrine action, reducing hypertension that results from catecholamine effects on alpha receptors.

Tyrosine Kinase Inhibitors

Class Summary
These agents are used to inhibit catecholamine synthesis in pheochromocytoma.
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Metyrosine (Demser)
Metyrosine inhibits tyrosine hydroxylase, the rate-limiting step in catecholamine synthesis. In patients with pheochromocytoma, administration of metyrosine reduces catecholamine biosynthesis by 35-80%, as measured by urinary catecholamine levels. It is indicated in patients with malignant pheochromocytoma or in cases of pheochromocytoma in which surgery is contraindicated. It can be useful in patients who are refractory to phenoxybenzamine therapy, or it can be administered as an adjunct to phenoxybenzamine therapy.

Beta-Adrenergic Receptor Blocking Agents

Class Summary
These agents compete with beta-adrenergic agonists for available beta-receptor sites.
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Propranolol hydrochloride (Inderal LA, InnoPran XL)

This is a nonselective beta-adrenergic receptor blocker. After primary treatment with an alpha-receptor blocker, propranolol hydrochloride may be used as adjunctive therapy if control of tachycardia becomes necessary before or during surgery. It may be used to treat excessive beta-receptor stimulation in patients with inoperable metastatic pheochromocytoma. The drug has membrane-stabilizing activity and decreases the automaticity of contractions. Propranolol hydrochloride is not suitable for the emergency treatment of hypertension; do not administer it intravenously in hypertensive emergencies.
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Atenolol (Tenormin)
Atenolol selectively blocks beta1 receptors, with little or no affect on beta2 types.

Diuretics, Loop
Class Summary
Diuretics induce calciuresis. In patients with severe hypercalcemia, the individual typically is volume depleted, which means that volume should be replaced with saline prior to institution of diuretic therapy.
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Furosemide (Lasix)
Furosemide inhibits the resorption of sodium and chloride in the loop of Henle and the proximal and distal tubules of the kidney. Its onset of action is rapid after an intravenous dose.

Calcium Metabolism Modifiers

Class Summary
Bisphosphonates may be used if the patient remains severely hypercalcemic following the diuretic therapy. These agents are analogues of inorganic pyrophosphate and act by binding to hydroxyapatite in bone matrix, thereby inhibiting the dissolution of crystals. They prevent osteoclast attachment to the bone matrix and osteoclast recruitment and viability. For maximum gut absorption, all oral bisphosphonates should be taken at least 2 hours before or after meals. The newer bisphosphonates are not completely free of the risk of causing a mineralization defect, but their safe therapeutic window is much wider. They clearly are more potent than etidronate in reducing disease activity and normalizing alkaline phosphatase levels. Calcitonin analogues may also be used if the patient remains severely hypercalcemic following the diuretic therapy. These agents directly inhibit osteoclastic bone resorption and have a significant analgesic effect on bone. Human calcitonin is no longer available. Salmon calcitonin is more likely than human calcitonin to cause resistant antibodies. As many as 26% of patients treated with salmon calcitonin demonstrated loss of biochemical responsiveness after initial improvement. High titers of salmon calcitonin antibodies produce resistance. All patients resistant to salmon calcitonin responded to human calcitonin.
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Pamidronate (Aredia)
The main action of pamidronate is to inhibit the resorption of bone. The mechanism by which this inhibition occurs is not fully known. The drug is adsorbed onto calcium pyrophosphate crystals and may block the dissolution of these crystals, also known as hydroxyapatite, which are an important mineral component of bone. There is also evidence that pamidronate directly inhibits osteoclasts.
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Alendronate (Fosamax)
Alendronate is a potent third-generation bisphosphonate that principally acts by inhibiting osteoclastic bone resorption. It is recommended for treatment of Paget disease. Retreatment may be considered after 6-month posttreatment evaluation in patients whose serum alkaline phosphatase level did not normalize.
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Risedronate (Actonel, Atelvia)

Risedronate is a potent aminobisphosphonate that principally acts by inhibiting osteoclastic bone resorption. It is recommended for the treatment of Paget disease.
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Etidronate (Didronel)

Etidronate was the first bisphosphonate to be studied in humans and approved in the United States (1978) for the treatment of Paget disease. It is the least potent of currently available bisphosphonate drugs.
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Tiludronate (Skelid)
Tiludronate is a sulfur-containing bisphosphonate of intermediate potency between etidronate and newer nitrogen-containing bisphosphonates. No food, indomethacin, or calcium should be ingested within 2 hours before and 2 hours after. A 3-month posttreatment evaluation follows.
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Zoledronate (Reclast, Zometa)

Zoledronate inhibits bone resorption. It inhibits osteoclastic activity and induces osteoclastic apoptosis.
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Salmon calcitonin (Miacalcin, Fortical)

This agent may be used if the patient remains severely hypercalcemic following the diuretic therapy. This agent is a peptide hormone that binds to calcitonin receptors on osteoclasts and rapidly inhibits bone resorption. Osteoclasts do not induce cytotoxic effects in bone cells. Salmon calcitonin induces reductions in urinary hydroxyproline and serum alkaline phosphatase levels. Serum alkaline phosphatase begins to decline 4 weeks after initiation of treatment. Levels of urinary hydroxyproline may decrease quickly, indicating inhibition of bone resorption. These laboratory markers slowly increase back to pretreatment levels if treatment is stopped. If no response is noted by 3 months, treatment should be discontinued. Restoration of more normal bone can be seen radiographically, especially after long-term calcitonin treatment. Bone biopsy samples also reflect reduced disease activity because decreased bone cells, marrow fibrosis, and woven bone are present. Reduction in bone pain, cardiac output, and skin temperature over lower limb bones can be observed. Improvement of neurologic deficits and stabilization of hearing have been noted. Reduction of hemorrhage from orthopedic procedures has been demonstrated with preoperative calcitonin treatment. However, salmon calcitonin only partially suppresses disease while treatment continues.

Thyroid Hormones
Class Summary
These agents are used for supplemental therapy in hypothyroidism.
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Levothyroxine sodium (Synthroid, Levoxyl, Levothroid, Tirosint)

The goal of therapy for primary hypothyroidism is to achieve and maintain a clinical and biochemical euthyroid state. In active form, thyroid hormones influence growth and maturation of tissues. These hormones are involved in normal growth, metabolism, and development.

Vitamins, Fat-Soluble
Class Summary
Vitamin D supplements may increase serum calcium levels by improving calcium absorption.
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Calcitriol (Rocaltrol, Vectical, Calcijex)

Calcitriol may be required in the management of hypocalcemia and its clinical manifestations in patients with postsurgical hypoparathyroidism. This supplement is important in maintaining calcium balance and in the regulation of PTH. Patients are advised to have a dietary intake of calcium of, at minimum, 1000mg daily.

Corticosteroids
Class Summary
Corticosteroids cause profound and varied metabolic effects. These agents modify the body's immune response to diverse stimuli.
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Cortisone
Cortisone is the drug of choice for patients with adrenocortical insufficiency. It is used in replacement doses for postsurgical adrenalectomy.
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Fludrocortisone acetate (Florinef)

Mineralocorticoids provide a partial replacement therapy for primary and secondary adrenocortical insufficiency. The combination of fludrocortisone acetate tablets with a glucocorticoid, such as hydrocortisone or cortisone, provides substitution therapy approximating normal adrenal activity, with minimal risk of unwanted effects.