A large number of compounds interfere either directly or indirectly with the synthesis, release, or action of thyroid hormones (Table 56-2). Inhibitors are classified into four categories: (1) antithyroid drugs, which interfere directly with the synthesis of thyroid hormones; (2) ionic inhibitors, which block the iodide transport mechanism; (3) high concentrations of iodine itself, which decrease release of thyroid hormones and may also decrease hormone synthesis; and (4) radioactive iodine, which damages the gland with ionizing radiation. Adjuvant therapy with drugs that have no specific effects on thyroid hormone synthesis is useful in controlling the peripheral manifestations of thyrotoxicosis, including inhibitors of the peripheral deiodination of T4 to T3, 3 adrenergic receptor antagonists, and Ca2+ channel blockers.
Examples of Inhibitors
Active transport of iodide
Complex anions: Perchlorate, fluoborate, pertechnetate, thiocyanate Thionamides: propylthiouracil, methimazole,
Carbimazole Thiocyanate; iodide Aniline derivatives; sulfonamides Thionamides; sulfonamides Lithium salts; iodide Nitrotyrosines
Thiouracil derivatives; amiodarone
Oral cholecystographic agents
Inducers of hepatic drug-metabolizing enzymes:
phenobarbital, rifampin, carbamazepine, phenytoin Thyroxine analogs; amiodarone Cholestyramine
Iodination of thyroglobulin
Coupling reaction Hormone release Iodotyrosine deiodination Peripheral iodothyronine deiodination Hormone excretion/
inactivation Hormone action Binding in gut
The antithyroid drugs that have greatest clinical utility are the thioureylenes, which belong to the family of thionamides (Figure 56-6).
MECHANISM OF ACTION Antithyroid drugs inhibit the formation of thyroid hormones by interfering with the incorporation of iodine into tyrosyl residues of thyroglobulin; they also inhibit the coupling of these iodotyrosyl residues to form iodothyronines. The inhibition of hormone synthesis eventually results in depletion of stores of iodinated thyroglobulin as the protein is hydrolyzed and the hormones are released into the circulation. Clinical effects only become apparent when the preformed hormone is reduced and the concentrations of circulating thyroid hormones begin to decline.
In addition to blocking hormone synthesis, propylthiouracil also inhibits the peripheral deiodi-nation of T4 to T3; this added effect provides a rationale for the choice of propylthiouracil over methimazole in the treatment of severe hyperthyroid states such as thyroid storm.
ABSORPTION, METABOLISM, AND EXCRETION The antithyroid drugs used in the U.S. are propylthiouracil (6-n-propylthiouracil) and methimazole (1-methyl-2-mercaptoimidazole; tapazole). In Europe, carbimazole (neo-mercazole), a carbethoxy derivative that is converted to methimazole, also is used. Some pharmacological properties of propylthiouracil and methimazole are shown in Table 56-3. Because of its shorter t1/2, propylthiouracil must be dosed more frequently than methimazole. In severe hyperthyroid states, even a 500-mg dose of propylthiouracil must be dosed every 6-8 hours to yield complete thyroid inhibition, while doses of 20-40 mg of methimazole may be given once-daily. The drugs are concentrated in the thyroid and drugs and metabolites largely are excreted in the urine. propylthiouracil and methimazole cross the placenta equally and also can be found in milk. Their use in pregnancy is discussed below.
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