Medication Summary
Patients require hormone replacement and other medications following total thyroidectomy and bilateral adrenalectomy or when they have postoperative hypoparathyroidism. Patients who develop postoperative hypoparathyroidism need supplemental calcium and/or vitamin D.
The corticosteroid hydrocortisone 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 beta-blocker can be considered, espcially if patients develop tachycardia or if tighter blood pressure control is needed. 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 or bisphosphonates (such as pamidronate or zoledronic acid) or denosumab. These patients may need parathyroidectomy if surgical indications are met 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.
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.
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.
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.
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.
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.
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.
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
Intra-venous 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 for treatment of osteoporosis. 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.
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.
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.
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.
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.
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.
Zoledronate (Reclast, Zometa)
Zoledronate inhibits bone resorption. It inhibits osteoclastic activity and induces osteoclastic apoptosis.
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.
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.
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.
Hydrocortisone
Hydrocortisone is the drug of choice for patients with adrenocortical insufficiency. It is used in replacement doses for postsurgical adrenalectomy.
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.
Rank Ligand Inhibitor
Denosumab
Densosumab is a humanzed monoclonal antibody which inhibits osteocalstic activity by binding to the rank ligand receptor and results in lowering of serum calcium when used sub-cutaneously. It is also used to treat osteoporosis where it is given every 6 months. For hypercalcemia, the dose used is typically higher than that used for treatment of osteoporisis.
Tables
Risk Level |
RET codon Mutation |
Possible Diagnoses |
Prophylactic Thyroidectomy Recommendations |
Follow-up |
Highest Risk (HST) |
M918T+All MEN2B |
MEN2B |
Within the first year of life or the first months of life based upon specialist and parental discussions. The ability to identify and preserve or transplant parathyroid glands determines level VI dissection. |
Physical exam, neck US, serum Ctn, and serum CEA every 6 mos first year, then annually; begin screening for pheochromocytoma at age 11 yr |
High Risk (H) |
C634, A883F |
MEN2A |
At or before age 5 yr, to be determined on the basis of serum Ctn |
Physical exam, neck US, serum Ctn, and serum CEA every 6 mos first year, then annually. Begin screening for pheochromocytoma at age 11. |
Moderate Risk (MOD) |
All other mutations |
MEN2A |
When serum Ctn becomes elevated or in childhood to avoid lengthy evaluation period. |
Evaluate every 6 months for 1 year. Annual follow-ups thereafter if serum Ctn is normal or undetectable. Begin screening for pheochromocytoma at age 16 yr |
