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Chapter: Modern Pharmacology with Clinical Applications: Thyroid and Antithyroid Drugs

Drugs Used in the Treatment of Hyperthyroidism

Treatment of hyperthyroidism is directed at reducing the excessive synthesis and secretion of thyroid hor-mones.



Treatment of hyperthyroidism is directed at reducing the excessive synthesis and secretion of thyroid hor-mones. This may be accomplished by inhibiting thy-roidal synthesis and secretion with antithyroid drugs, by reducing the amount of functional thyroid tissue, or by both. Unfortunately, only a small proportion of patients treated with antithyroid drugs obtain long-term remis-sion of their hyperthyroidism. Ablative therapy is often necessary. Since many of the signs and symptoms of hy-perthyroidism reflect increased cellular sensitivity to adrenergic stimulation, a β-adrenergic antagonist is of-ten used adjunctively. Propranolol (Inderal), the most widely used β-adrenoceptor blocker, is effective in ame-liorating many of the manifestations of thyrotoxicosis. It may reduce thyrotoxicosis-induced tachycardia, palpita-tions, tremor, sweating, heat intolerance, and anxiety, which are largely mediated through the adrenergic nervous system. Propranolol may also impair the con-version of T4 to T3. The use of propranolol is contraindi-cated in thyrotoxic patients with asthma or chronic obstructive pulmonary disease because it impairs bron-chodilation. It is also contraindicated in patients with heart block and those with congestive heart failure, un-less severe tachycardia is a contributory factor.




Thionamides are the primary drugs used to decrease thyroid hormone production. They do not inhibit secre-tion of stored thyroid hormone, and therefore, when they are used alone, their clinical effects are not apparent until the preexisting intrathyroidal store of thyroid hormone is depleted. This may take several weeks. Propylthiouracil and methylthiouracil (methimazole; Tapazole) are the most commonly used preparations in the United States.


Thionamide drugs interfere with peroxidase-catalyzed reactions. In the thyroid gland, they inhibit the activity of the enzyme TPO, which is required for the intrathyroidal oxidation of I- , the incorporation of I- into Tg, and the coupling of iodotyrosyl residues to form thyroid hormones. Thus, these drugs inhibit thy-roid hormone synthesis and with time, also secretion. Propylthiouracil, but not methimazole, also inhibits D1, which deiodinates T4 to T3. Because of this additional action, propylthiouracil is often used to provide a rapid alleviation of severe thyrotoxicosis.


In patients with autoimmune thyroid disease, thion-amide drugs may also exert an immunosuppressive ef-fect. As the drug is concentrated in thyroid follicular cells, the expression of thyroid antigen and the release of prostaglandins and cytokines are decreased. Subse-quently, the autoimmune response is impaired. Thion-amides also inhibit the generation of oxygen radicals in T cells, B cells, and particularly the antigen-presenting cells within the thyroid gland. Thus, thionamides may cause a decline in thyroid autoantibody titers, although the clinical importance of immunosuppression is un-clear.


Thionamide drugs are well absorbed from the gas-trointestinal tract. Although they have short plasma half-lives (propylthiouracil 1.5 hours; methimazole 6 hours), they accumulate in the thyroid gland, and a sin-gle daily dose may exert effects for greater than 24 hours. Thionamides undergo hepatic conjugation to form glucuronides and are excreted in the bile and urine. Nevertheless, few glucuronide conjugates are found in the feces because they are absorbed from the gastrointestinal tract.


The thionamide drugs are used in the management of hyperthyroidism and thyrotoxic crisis and in the preparation of patients for surgical subtotal thyroidec-tomy. Although the use of thionamides alone may re-store euthyroidism, it is difficult to adjust the dosage in some patients. This has led to the development of block-and-replace regimens in which a full blocking dose of thionamide plus a levothyroxine supplement is pre-scribed. Although thionamides may be used to treat hy-perthyroidism during pregnancy, they should be given in minimally effective doses to avoid inducing infantile hypothyroidism and thyroid enlargement in the devel-oping fetus.


If given in excessive amounts over a long period, thionamides may cause hypothyroidism and enlargement of the thyroid gland. The most serious adverse effects are granulocytopenia and agranulocytosis, which occur in about 0.5% of patients and usually within 3 months of starting therapy. The most frequently observed adverse

effect is rash. Arthralgia, myalgia, cholestatic jaundice, lymphadenopathy, drug fever, psychosis, and a lupuslike syndrome have also been reported.


Iodine and Iodine-Containing Agents



The effects of iodide on the thyroid gland are complex. When administered in pharmacological amounts, potas-sium iodide (KI) causes a transient inhibition of the up-take and incorporation of I- into Tg (Wolff-Chaikoff ef-fect). In addition, high doses of KI also inhibit the secretion of thyroid hormone and thyroid blood flow. These effects make KI an ideal agent for treating severe thyrotoxicosis or thyroid crisis when a rapid decrease in plasma T4 and T3 is desirable. As the thyroid gland es-capes from Wolff-Chaikoff effect, I- accumulates within the gland and hormone synthesis resumes. With contin-ued treatment with KI alone, the inhibition of thyroid secretion may also diminish. Hypersecretion of thyroid hormone and thyrotoxicosis may return at the previous or a more severe intensity. For this reason, iodide alone is not used for the management of hyperthyroidism. Nevertheless, KI has long been used in combination with propylthiouracil in the management of thyrotoxic crisis to rapidly inhibit thyroid hormone secretion. Iodide plus a thionamide has also been used in the im-mediate preoperative preparation of patients about to undergo total or subtotal surgical thyroidectomy.


The ability of KI to block the thyroidal uptake of I- and its incorporation into Tg would prove useful in the event of an accident at a nuclear power plant. In such an event, large quantities of radionuclides, including iso-topes of radioiodine, could be released into the atmos-phere. Administration of KI (Thyro-Block) to inhibit the uptake and incorporation of radioiodine would be the most effective means of limiting the potential dam-age to the thyroid gland.


Adverse reactions to iodine can be divided into in-trathyroidal and extrathyroidal reactions. Among the intrathyroidal reactions is iodine-induced thyrotoxico-sis (Jod-Basedow’s phenomenon), which may occur in patients with nontoxic nodular goiter given low doses ( 25 mg/day) of potassium or sodium iodide. At higher doses (50–500 mg/day), iodide goiter or hypothyroidism or both may develop, but this usually requires long ex-posure. Extrathyroidal adverse reactions to iodine are relatively rare and generally not serious. These include rash, which may be acneiform; drug fever; sialadenitis (inflammation of the salivary glands); conjunctivitis and rhinitis; vasculitis; and a leukemoid eosinophilic granu-locytosis.



Oral Cholecystographic Agents


The iodine-containing oral cholecystographic contrast agents (OCAs) include sodium ipodate (Oragrafin), iopanoic acid (Telepaque), tyropanoic acid (Bilopaque), and iocetamic acid (Cholebrine). They all inhibit D1 and D2. These actions make OCAs useful as adjunctive therapy with other antithyroid drugs by promoting a rapid fall in the plasma T3 concentration of the seriously thyrotoxic patient.


In addition, the metabolism of OCAs results in the release of large amounts of I- into the circulation. As described for KI, I- released from OCAs may have ef-fects at the thyroid gland and if used alone to treat hy-perthyroidism, OCAs carry the same potential to in-duce increased secretion of thyroid hormone and exacerbation of thyrotoxicosis. When an OCA is used in the treatment of hyperthyroidism, large doses of an-tithyroid agents are usually administered concomi-tantly. However, the combination of OCAs and antithy-roid drugs may cause resistance to the antithyroid drugs with time, presumably because of the elevation in in-trathyroidal I- content. Thus, it is recommended that the use of OCAs be reserved for short-term treatment of patients with severe thyrotoxicosis and significant co-morbidity (e.g., myocardial infarction, sepsis, stroke) for rapid control of plasma T3 concentrations.


When the OCAs are used for these purposes, they are administered at much lower doses than when used for cholecystography. At the higher doses, the major ad-verse effects of these compounds are acute renal failure, thrombocytopenia, and athrombocytosis; possible mi-nor adverse reactions include diarrhea, nausea, vomit-ing, and dysuria.




Millicurie amounts of 131I ( Iodotope I-131) are used for thyroid ablation in the management of hyperthy-roidism. 131I is taken up and trapped in the same manner as I- . The ablative effect is exerted primarily through - particle emissions, which destroy thyroid tissue. The ma-jor disadvantage associated with this therapy is the de-velopment of hypothyroidism after thyroid ablation. Microcurie amounts of radioiodine also are used for the diagnostic evaluation of thyroid function.


Potassium Perchlorate


The perchlorate ion of potassium perchlorate, KClO4, is a competitive inhibitor of thyroidal I- transport via the Sodium Iodide Symporter (NIS). This drug can cause fa-tal aplastic anemia and gastric ulcers and is now rarely used. If administered with careful supervision, in limited low doses and for only brief periods, serious toxic effects can be avoided. The compound is especially effective in treating iodine-induced hyperthyroidism, which may oc-cur, for example, in patients treated with the antiar-rhythmic compound amiodarone. Perchlorate ion can also be used in a diagnostic test of I- incorporation into Tg, the so-called perchlorate discharge test.

Lithium Carbonate


Lithium inhibits thyroidal incorporation of I- into Tg, as well as the secretion of thyroid hormones, but it does not inhibit the activity of the NA+ –I symporter or the accumulation of I- within the thyroid. Lithium offers no particular advantage over drugs of the thionamide class but may be employed for temporary control of thyro-toxicosis in patients who are allergic to both thion-amides and iodide.


Drug Interactions


As the plasma levels of T4 and T3 fall after the adminis-tration of antithyroid drugs, the catabolism of vitamin K–dependent clotting factors decreases, thus reducing the effectiveness of coumarin anticoagulants. During concomitant therapy, the dosage of the anticoagulant may have to be increased. Conversely, the use of an-tithyroid therapy in patients with diabetes mellitus may decrease the patient’s requirement for insulin or oral hy-poglycemic agents. Similarly, patients receiving cardiac glycosides, such as digitoxin, may require a smaller dose.


Lithium carbonate, administered for affective and bipolar disorders, may enhance the effects of antithy-roid drugs. Potassium iodide, used as an expectorant, is a major ingredient in many cough medications. Iodide derived from this source may enhance the effects of an-tithyroid drugs and lead to iodine-induced hypothy-roidism. Iodine in topical antiseptics and radiological contrast agents may act in a similar manner.

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