Graves Disease Medication
- Author: Sai-Ching Jim Yeung, MD, PhD, FACP; Chief Editor: Romesh Khardori, MD, PhD, FACP more...
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.
Thioamides function as antithyroid agents mainly by inhibiting iodide organification and coupling processes, thereby preventing synthesis of thyroid hormones. Half-life of T4 is 7 d in persons who are euthyroid and somewhat shorter in patients who are thyrotoxic. This accounts for a several-week delay in onset of clinical improvement in most patients. Agents have been reported to alter intrathyroidal immunoregulatory mechanisms. Only oral preparations are available, but they have been used as retention enemas in patients in whom oral intake is not possible or is contraindicated.
Although these agents fall under pregnancy category D, they have been used safely in many pregnant patients. Retrospective study indicates rate of major congenital malformations with PTU (3%) or methimazole (2.7%) was not significantly different from normal background rate (2-5%). Duration of treatment ranged from 0-23 wk, with doses ranging from 100-600 mg/d of PTU or 10-60 mg/d of methimazole.
Concentrations of methimazole are higher in breast milk; therefore, PTU is preferred in this patient population.
Risk of agranulocytosis is similar (0.2-0.5%) in members of this class. In general, PTU is associated with transaminase elevation in susceptible individuals, while methimazole may cause a cholestatic effect.
The US Food and Drug Administration (FDA) added a boxed warning, the strongest warning issued by the FDA, to the prescribing information for PTU. The boxed warning emphasizes the risk for severe liver injury and acute liver failure, some of which have been fatal. The boxed warning also states that PTU should be reserved for use in patients who cannot tolerate other treatments, such as methimazole, radioactive iodine, or surgery.
Medically treated Graves disease has a significant risk of relapse (23% within 6 months of discontinuation of antithyroid medication and 42% within 5 years). The presence of goiter is associated with an increased risk of relapse after medical therapy.
The decision to include a boxed warning was based on the FDA's review of postmarketing safety reports and on meetings held with the American Thyroid Association, the National Institute of Child Health and Human Development, and the pediatric endocrine clinical community.
The FDA has identified 32 cases (22 adult and 10 pediatric) of serious liver injury associated with PTU. Of the adults, 12 deaths and 5 liver transplants occurred, and among the pediatric patients, 1 death and 6 liver transplants occurred. PTU is indicated for hyperthyroidism due to Graves disease. These reports suggest an increased risk for liver toxicity with PTU compared with methimazole. Serious liver injury has been identified with methimazole in 5 cases (3 resulting in death).
PTU is considered to be a second-line drug therapy, except in patients who are allergic to or intolerant of methimazole, or in women who are in the first trimester of pregnancy. Rare cases of embryopathy, including aplasia cutis, have been reported with methimazole during pregnancy. The FDA recommends the following criteria be considered for prescribing PTU (for more information, see the FDA Safety Alert):
- Reserve PTU use during first trimester of pregnancy, or in patients who are allergic to or intolerant of methimazole.
- Closely monitor PTU therapy for signs and symptoms of liver injury, especially during the first 6 months after initiation of therapy.
- For suspected liver injury, promptly discontinue PTU therapy, evaluate the patient for evidence of liver injury, and provide supportive care.
- PTU should not be used in pediatric patients unless the patient is allergic to or intolerant of methimazole and no other treatment options are available.
- Counsel patients to promptly contact their health care provider for the following signs or symptoms: fatigue, weakness, vague abdominal pain, loss of appetite, itching, easy bruising, or yellowing of the eyes or skin.
Derivative of thiourea that inhibits organification of iodine by thyroid gland. Blocks oxidation of iodine in thyroid gland, thereby inhibiting thyroid hormone synthesis; inhibits T4-to-T3 conversion by blocking type I deiodinase (advantage over other agents). Usual course/duration of therapy is 1-2 y; sustained remission more likely after 1-2 y vs 3-6 mo of therapy.
Inhibits thyroid hormone by blocking oxidation of iodine in thyroid gland; however, not known to inhibit peripheral conversion of thyroid hormone. Considerable debate surrounds optimal dosage/duration.
Both cardioselective and noncardioselective types are important adjuncts in treating hyperthyroidism. Beta-blockade provides rapid relief of hyperadrenergic symptoms and signs of thyrotoxicosis (eg, palpitations, tremors, anxiety, heat intolerance, various eyelid signs) before any decrease in thyroid hormone levels demonstrated. Also useful in preventing episodes of hypokalemic periodic paralysis in susceptible individuals. DOC for thyroiditis, which is self-limiting. High-dose propranolol can inhibit peripheral T4-to-T3 conversion. Also useful in preparing thyrotoxic patients for surgery.
DOC in treating cardiac arrhythmias resulting from hyperthyroidism. Controls cardiac and psychomotor manifestations within minutes.
Drug completely absorbed from GI tract; because of extensive first-pass metabolism in liver, systemic bioavailability affected by hepatic blood flow, intrinsic clearance in liver, and genetic and age differences in individuals.
Dosage prediction for IV from prior PO difficult; therefore, careful titration of IV dose necessary.
Selectively blocks beta1 receptors with little or no effect on beta2 types. Useful in treating cardiac arrhythmias resulting from hyperthyroidism.
Have long been used to treat thyrotoxicosis and are still important adjunctive therapy for hyperthyroidism in modern medicine. In pharmacologic concentrations (100-times normal plasma level), decrease activity of thyroid gland. Action involves decreasing thyroidal iodide uptake, decreasing iodide oxidation and organification, and blocking release of thyroid hormones (Wolff-Chaikoff effect).
Oral contrast agents ipodate or iopanoic acid also shown to be potent inhibitors of T4-to-T3 conversion, making them ideal for severe or decompensated thyrotoxicosis. Generally administered after thioamide is started. Also used as preoperative preparation for thyroid surgery for Graves disease.
In combination with thioamides and/or propranolol, iodines are used routinely before thyroidectomy. Iodines are given for 2-3 weeks before surgery and decrease vascularity of hyperthyroid gland. Making patient euthyroid before surgery prevents intraoperative and postoperative complications.
Inhibits thyroid hormone secretion.
Contains 5% iodine and 10% potassium iodide. Contains 8 mg of iodide per drop. May be mixed with juice or water for intake.
Blocks release of thyroid hormones.
Iopanoic acid (Telepaque)
Oral contrast agent for rapid and significant inhibition of peripheral T4-to-T3 conversion. Inorganic iodide released also blocks release of thyroid hormones.
Bile acid sequestrants
Based on the observation that a small portion of L-thyroxine is usually reabsorbed in the bowel and recycled in the enterohepatic circulation, exchange resins have been used to bind thyroid hormones in the GI tract. Enterohepatic circulation of thyroxine is increased in cases of hyperthyroidism.
Can be used to lower serum thyroid hormone levels. This cholesterol-lowering resin has been used as adjunctive therapy in management of hyperthyroid Graves disease. Proved to be effective and well-tolerated adjunctive therapy, leading to a more rapid reduction of thyroid hormone levels.
Act in a manner similar to iodine but is not routinely used because of transient effect and risk of potentially serious adverse effects. Now primarily used as a backup agent when other first-line agents are contraindicated because of hypersensitivity or toxicity.
Patients intolerant to iodine can be treated with lithium, which also impairs thyroid hormone release. Can be used in patients who cannot take PTU or MMI. Use of iodine alone is debatable.
Amiodarone, an iodinated benzofuran, is an important antiarrhythmic medication that also alters thyroid hormone metabolism. High iodine content of this molecule (37.5%) is responsible for hypothyroidism. On the other hand, amiodarone can lead to hyperthyroidism through 2 complex mechanisms. Type I amiodarone-induced thyrotoxicosis is due to increased thyroid hormone synthesis and release in patients with multinodular goiter or Graves disease, while type II amiodarone-induced thyrotoxicosis is a destructive thyroiditis with release of preformed thyroid hormone.
Case report described successful normalization of thyroid hormone level in a patient with Graves disease who had fulminant PTU-induced hepatitis. However, experience and information in treatment of Graves disease is scant.
Graves disease is an autoimmune disease. Although glucocorticoids have been shown to decrease T4-to-T3 conversion and decrease thyroid hormones by yet undiscovered mechanisms, the adverse effect profile of long-term glucocorticoid therapy makes it unattractive for long-term management of Graves hyperthyroidism. However, glucocorticoids may have a role in rapidly lowering thyroid hormone levels in the clinical setting of thyroid storm. With regard to Graves ophthalmopathy, current evidence indicates that glucocorticoids represent the only class of drug therapy that, either alone or combined with other therapies, has an unequivocal role in management.
Has been customarily used in management of Graves ophthalmopathy. Other oral glucocorticoids at equipotent doses may also be effective.
Has been customarily used for high-dose pulse steroid therapy in management of Graves ophthalmopathy. Other glucocorticoids at equipotent doses may also be effective. Intravenous high dose glucocorticoid therapy may be more effective and better tolerated than oral steroid therapy in the management of Graves ophthalmopathy (Aktaran, 2007).
In healthy persons, induces decrease in serum T3 levels without a change in serum T4 levels, suggesting an effect of dexamethasone on peripheral T3-to-T4 conversion.
In patients with Graves hyperthyroidism, induces rapid fall in serum thyroid hormone levels. Changes are too rapid to be explained by a steroid-induced fall in the level of a circulating IgG thyroid stimulator (TSI). Mechanism for this observation is unclear.
Selective beta1-adrenergic receptor blocker that decreases automaticity of contractions. Useful in treating cardiac arrhythmias resulting from hyperthyroidism. During IV administration, carefully monitor BP, heart rate, and ECG.
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