A client who had a subtotal thyroidectomy asks how hyperthyroidism may develop

Antithyroid drugs (eg, methimazole and propylthiouracil) have been used for hyperthyroidism since their introduction in the 1940s. These medications are employed for long-term control of hyperthyroidism in children, adolescents, and pregnant women. In adult men and nonpregnant women, they are used to control hyperthyroidism before definitive therapy with radioactive iodine.

Antithyroid medications inhibit the formation and coupling of iodotyrosines in thyroglobulin. Because these processes are necessary for thyroid hormone synthesis, this inhibition induces a gradual reduction in thyroid hormone levels over 2-8 weeks or longer. A second action of propylthiouracil (but not methimazole) is inhibition of conversion of thyroxine (T4) to triiodothyronine (T3). T3 is more biologically active than T4; thus, a quick reduction in T3 levels is associated with a clinically significant improvement in thyrotoxic symptoms.

The antithyroid drug dose should be titrated every 4 weeks until thyroid functions normalize. Some patients with Graves disease go into a remission after treatment for 12-18 months, and the drug can be discontinued. Notably, half of the patients who go into remission experience a recurrence of hyperthyroidism within the following year. Nodular forms of hyperthyroidism (ie, toxic multinodular goiter [28] and toxic adenoma) are permanent conditions and will not go into remission.

Methimazole is more potent than propylthiouracil and has a longer duration of action. In addition, methimazole is taken once daily, whereas propylthiouracil is taken 2-3 times daily; consequently, patient compliance is often better with methimazole than with propylthiouracil.

Methimazole is not recommended for use in the first trimester of pregnancy, because it has been associated (albeit rarely) with cloacal and scalp (cutis aplasia) abnormalities when given during early gestation. [4, 29] Generally, if a nonpregnant woman who is receiving methimazole desires pregnancy, she should be switched to propylthiouracil before conception. After 12 weeks of gestation, she can be switched back to methimazole, with frequent monitoring.

Propylthiouracil remains the drug of choice in uncommon situations of life-threatening severe thyrotoxicosis (ie, thyroid storm) because of the additional benefit of inhibition of T4-to-T3 conversion. In this setting, propylthiouracil should be administered every 6-8 hours. The reduction in T3, which is 20-100 times more potent than T4, theoretically helps reduce the thyrotoxic symptoms more quickly than methimazole would. Once thyroid levels have decreased to nearly normal values, the patient can be switched to methimazole therapy.

Except in thyroid storm, propylthiouracil is considered a second-line drug therapy. It is reserved for use in patients who are allergic to or intolerant of methimazole and in women who are in the first trimester of pregnancy or planning pregnancy.

The most common adverse effects of antithyroid drugs are allergic reactions manifesting as fever, rash, urticaria, and arthralgia, which occur in 1-5% of patients, usually within the first few weeks of treatment. Serious adverse effects include agranulocytosis, aplastic anemia, hepatitis, polyarthritis, and a lupuslike vasculitis. All of these adverse effects, except agranulocytosis, occur more frequently with propylthiouracil: agranulocytosis occurs in 0.2-0.5% of patients overall and is no more common with one drug than with the other.

Patients with agranulocytosis usually present with fever and pharyngitis. After the drug is stopped, granulocyte counts usually start to rise within several days but may not normalize for 10-14 days. Granulocyte colony-stimulating factor (G-CSF) appears to accelerate recovery in patients with a bone marrow aspiration showing a granulocyte-to-erythrocyte ratio of 1:2 or greater than 0.5.

In 2010, the US Food and Drug Administration (FDA) added a boxed warning, the strongest warning issued by the FDA, to the prescribing information for propylthiouracil. The warning emphasized the risk for severe liver injury and acute liver failure, some cases of which have been fatal. [30] Severe liver injury has rarely been reported with methimazole (5 cases, 3 of which resulted in death).

The FDA recommends the following measures for patients receiving propylthiouracil (for more information, see the FDA Safety Alert) [30] :

• Closely monitor patients for signs and symptoms of liver injury, especially during the first 6 months after initiation of therapy

• For suspected liver injury, promptly discontinue propylthiouracil, evaluate the patient for evidence of liver injury, and provide supportive care

• Counsel patients to contact their health care provider promptly for the following signs or symptoms: fatigue, weakness, vague abdominal pain, loss of appetite, itching, easy bruising, or yellowing of the eyes or skin

In severe thyrotoxicosis from Graves disease or subacute thyroiditis, iodine or iodinated contrast agents have been administered to block the conversion of T4 to T3 and the release of thyroid hormone from the gland. This therapy is reserved for severe thyrotoxicosis because its use prevents definitive therapy for Graves thyrotoxicosis with radioactive iodine for many weeks.

A saturated solution of potassium iodide (SSKI) can be administered at a dosage of 10 drops twice daily, with a consequent rapid reduction in T3 levels. Iopanoic acid/ipodate at a dosage of 1 g/day is also effective; it has not been available in the United States for several years but is available in some areas of Europe.

These drugs must not be administered to patients with toxic multinodular goiter or toxic adenomas. The autonomous nature of these conditions can lead to worsening of the thyrotoxicosis in the presence of pharmacologic levels of iodide, a substrate in thyroid hormone synthesis. This phenomenon typically presents in patients living in iodine deficient areas who relocate to an iodine sufficient geographical area or upon ingestion of iodine (Jod-Basedow syndrome).

Another drug that might be considered in management of severe thyrotoxicosis would be cholestyramine, a bile salt sequestrant. It decreases thyroid hormone levels by depleting the pool by enhancing clearance from enterohepatic circulation. Doses up to 12 grams in 3 divided daily dose have been used for 4 weeks.

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