Hormonal Methimazole

Hyperthyroidism (thyrotoxicosis), defined as excessive thyroid activity, causes a state of thyroid hormone excess (thyrotoxicosis) characterized by an increased metabolic rate, increase in body temperature, sweating, tachycardia, tremor, nervousness, increased appetite and loss of weight. Common causes of hyperthyroidism are toxic multinodular goiter, toxic adenoma or diffuse toxic goitre ( Graves disease). Antithyroid diugs (methimazol, carbimazole, propylthiouracil) block thyroid hormone production and are hence suitable for the treatment of hyperthyroidism. 

Some neonates born to mothers with Graves disease will be hyperthyroid at delivery. Antithyroid drug therapy (propylthiouracil 5-10 mg/kg per day or methimazole 0.5-1 mg/kg per day) may be required for up to 12 weeks. One drop per day of SSKI may be used in the first few days to rapidly reduce thyroid hormone synthesis and release. 

Drugs used for hyperthyroidism can be classified as drugs that suppress thyroid hormone synthesis in the anterior lobe of the hypophysis, and they consist of diiodotyrosine and iodine, as well as drugs that suppress thyroid hormone synthesis in thyroid glands (propylthiouracil, methylthiouracil, methimazole, and carbimazole). 

The available agents with antithyroid activity are the thioamides propylthiouracil, carbimazole and methimazole also known as thiamazole. Their thio-carbamide group is indispensable for antithyroid activity. The mechanism of action is complex. The most important action is the prevention of hormone synthesis by an inhibition of the thyroid peroxidase-catalyzed reactions involved in iodine organification. These agents also block the coupling of the iodoty-rosines. 

PTU possesses special benefit it inhibits peripheral deiodination, thereby blocking the conversion of thyroxine to the active hormone tri-iodothyronine. PTU is rapidly absorbed from the gut, reaching peak blood levels within one hour, and is excreted in urine as the inactive glucuronide within 24 hours. In contrast methimazole which is absorbed at variable rates, is excreted slower (only 65-70% within 48 hours in urine). The short plasma half-life of... 

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 Dl, which deiodinates T4 to Tj. Because of this additional action, propylthiouracil is often used to provide a rapid alleviation of severe thyrotoxicosis. 

Levothyroxine is taken orally or intravenously and is normally prescribed to treat hypothyroidism or to suppress the release of thyroid hormone so as to manage cancerous thyroid nodules (i.e., thyroid cancer) and growth of goiters. Other less frequently prescribed thyroid and parathyroid drugs include methimazole (Tapazole), various iodides, lithioronine (Triostat), and liotrix (Thyrolar). 

The function of the target molecule may be critical or mncritical. Thus, if the target molecule is an enzyme, this could be involved in a crucial metabolic pathway, such as mitochondrial oxidative phosphorylation. In this case, an adverse interaction with the ultimate toxicant is likely to lead to cell dysfunction and possibly death (e.g., as with cyanide or salicylate). Chemicals such as methimazole and resorcinol, which are activated to free radical intermediates by thyroperoxidase, cause destruction of the enzyme. This then disturbs thyroid hormone synthesis and thyroid function with pathological consequences such as thyroid tumors. 

Lithium blocks the release of iodine and thyroid hormones from the thyroid and has been used to treat hyperthyroidism, as an adjunct to radioiodine therapy (602-605) and in metastatic thyroid carcinoma (606). However, it can also cause hyperthyroidism. Lithium enhanced the efficacy of radioiodine in 23 patients (607), but was ineffective in a larger comparison of lithium (n = 175) or radioiodine alone (n = 175) (608). In 24 patients with Graves disease, lithium attenuated or prevented increases in thyroid hormone concentration after methimazole withdrawal and radioiodine treatment (602,609). 

Thiourea derivatives are known for their anti-thyroid effects due to inhibition of thyroid peroxidase [1], Two thiourea compounds especially, have found wide application in the treatment of patients with hyperthyroidism, i.e., PTU and 2-mer-capto-l-methylimidazole (methimazole). It was soon recognized, however, that while methimazole only blocks thyroid hormone synthesis PTU has an additional effect on thyroid hormone metabolism [13]. These clinical findings have been confirmed in vitro showing that PTU, but not methimazole, is a potent inhibitor of the type I deiodinase [5-8]. Structure-activity studies of thiourea analogues [44,45] have... 

The imidazoles methimazole [60-56-0] (MMI) (12) and Carbimazole [22232-54-8] (13) act by inhibiting intrathyroidal hormone synthesis, whereas the thiouracils (10) [51-52-5] and (11) [56-04-2] also inhibit the peripheral deiodination of T4 to T3. Thus, the latter are preferred in the treatment of thyroid storm (thyrotoxic crisis) where a quick drop in circulating T3 is desired (2,9). In general, the imidazoles are 10 times as active as the thiouracils. 

Q8 The drug treatment of thyrotoxicosis involves using antithyroid drugs car-bimazole (which is converted to the active compound methimazole) and propylthiouracil inhibit the synthesis of thyroid hormone. Propylthiouracil also inhibits peripheral conversion of T4 to T3. Many of the symptoms of hyperthyroidism can also be alleviated by fl-adrenoceptor antagonists. Iodine... 

B Of the thioamides PTU is less likely to cross the placenta compared with methimazole and is the pr erred agent in pregnancy. PTU is also preferred over methimazole because it deaeases the peripheral conversion of Tt to Tj, whereas methimazole does so minimally. Both thioamides are used before surgery to decrease thyroid hormone stores and prevent intraoperative complications. PTU is routinely used during thyroid storm and not myxedema coma. 

The steps in thyroid hormone synthesis and the antithyroid agents effects upon them are summarized in Table VII-2-2. The clinical uses and their potential complications are presented in greater detail for the thioamides (propylthiouracil and methimazole) and iodine. 

FIGURE 66 Methimazole inhibits the synthesis of thyroid hormone by interfering with the incorporation of iodine into tyrosine and the formation of iodothyronine. 

Methimazole is an antithyroid agent that inhibits synthesis of thyroid hormones. It is indicated in long-term therapy of hyperthyroidism and amelioration of hyperthyroidism in preparation for subtotal thyroidectomy or radioactive iodine therapy. 

Methimazole (15 to 60 mg p.o. daily until patients are euthyroid) is indicated in the treatment of hyperthyroidism. Propylthiouracil, carbimazole, and methimazole, thyroid hormone antagonists, exert their effects by inhibiting iodide organification, and by inhibiting the formation of diiodo-thyronine (DIT) (see Figure 66). 

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