Thionamides

Thionamides are the primary drugs used to decrease thyroid hormone production. They do not inhibit secretion of stored thyroid hormone, and therefore, when they are used alone, their clinical effects are not appar ent 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 thyroid 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 effect. As the drug is concentrated in thyroid follicular cells, the expression of thyroid antigen and the release of prostaglandins and cytokines are decreased. Subsequently, 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 unclear.

Thionamide drugs are well absorbed from the gastrointestinal tract. Although they have short plasma half-lives (propylthiouracil 1.5 hours; methimazole 6 hours), they accumulate in the thyroid gland, and a single 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 restore 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 prescribed. 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 developing 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.

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