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Antithyroid drugs (thionamides)
The main action of thionamides (methimazole, carbimazole, and propylthiouracil) is to inhibit the organification of iodide and coupling of iodotyrosines, thus blocking the synthesis of thyroid hormones[2-4]. Since carbimazole is almost completely converted to methimazole (MMI) in the body, their effects are comparable. Propylthiouracil (PTU) has the additional effect of inhibiting the conversion of T4 to T3 in peripheral tissues. Despite this property of PTU, in most patients MMI therapy results in a more rapid normalization of serum T4 and T3. This may be due to the greater intrinsic potency of MMI and to its longer duration of action. The main pharmacological features of antithyroid drugs are summarized in Table 3. Table 3: Pharmacological features of thionamides.
Both MMI and PTU are extremely effective in controlling hyperthyroidism; therefore, in most instances the choice between the two drugs is largely a matter of personal preference and local availability. Since these compounds do not inhibit iodide transport or block the release of stored thyroid hormones, control of hyperthyroidism is not immediate and in most cases requires 2 to 6 weeks. Factors that determine the speed of restoration of euthyroidism include disease activity, initial levels of circulating thyroid hormones, and intrathyroidal hormone stores. Serious side effects (Table 4) are not common with antithyroid
drugs, being observed in approximately 3 of every 1000 patients[2-4]. Agranulocytosis
(granulocyte count < 500 per cubic ml), the most feared problem, may
be observed with both MMI and PTU, but a low dose of MMI is safer than
a high dose of either drug. The elderly may be more susceptible to this
side effect; however, agranulocytosis can occur in any age group. Agranulocytosis
may develop suddenly and usually occurs within the first 3-4 months after
starting therapy. Agranulocytosis typically presents with fever and evidence
of infection; therefore, all patients taking antithyroid drugs should be
instructed to report these symptoms immediately if they occur. In addition
to prompt discontinuation of the antithyroid drug, treatment of agranulocytosis
involves the administration of broad-spectrum antibiotics and growth factors
to stimulate recovery of bone marrow. Patients usually recover within 2
to 3 weeks, but a few deaths have been reported from this complication.
Hepatitis, vasculitis, and lupus-like syndromes are rare complications,
but make the discontinuation of antithyroid drugs mandatory. Minor side
effects are much more frequent, occurring in 1 to 5 % of patients. Among
them, pruritus, rash and, less commonly, urticaria are the most prominent
manifestations. These side effects may resolve spontaneously despite continued
therapy, but in general call for substitution of one thionamide for the
other, although cross-sensitivity to these drugs may occur.
Minor (1-5%)
Beta-adrenergic antagonist drugs These drugs are an integral part of the management of hyperthyroidism[2-4]. Blockade of beta-adrenergic receptors rapidly ameliorates some manifestations of thyrotoxicosis, such as tremor, palpitation, and anxiety. Beta-adrenergic antagonists do not affect thyroid hormone synthesis and release, therefore should not be used alone except for short periods before and/or after radioiodine therapy, or in patients with self-limited forms of thyrotoxicosis. Since the introduction of propranolol, a number of new agents became available with a longer duration (atenolol, metoprolol, and nadolol), or with greater cardioselectivity (atenolol, metoprolol, bisoprolol). In practice, any of these drugs is effective, and the choice largely depends on the personal experience of the physician. The usual contraindications of beta-adrenergic antagonists, such as asthma, should be considered. Despite the initial concern, propranolol or other beta-adrenergic antagonists are widely used in thyrotoxic heart disease, in view of the notion that tachycardia and tachyarrhytmias are the most prominent factors involved in this condition. Iodide Inorganic iodide given in pharmacological doses (as Lugol's solution or as saturated solution of potassium iodide, SSKI) decreases its own transport into the thyroid, inhibits iodide organification (the Wolff-Chaikoff effect), and rapidly blocks the release of T4 and T3 from the gland[2]. However, after a few days or weeks, its antithyroid action is lost, and thyrotoxicosis recurs or may worsen. The usual dose of Lugol's solution is 3-5 drops three times a day, and that of SSKI is 1 drop three times daily. Short-term iodide therapy is used to prepare patients for surgery, usually in combination with a thionamide drug. Iodide is also used in the management of severe thyrotoxicosis (thyroid storm), because of its ability to inhibit thyroid hormone release acutely. Oral cholecystographic agents (iopanoic acid and sodium ipodate) have a dual action: they produce a fall in the serum concentration of thyroid hormones, which results from the block of thyroid hormone secretion due to the inorganic iodide released from the drug, and inhibit the peripheral conversion of T4 to T3[2]. Although early reports suggested that these iodinated compounds in doses of 0.5 to 1.0 gram (g) daily could be successfully used as a primary therapy of hyperthyroidism, they proved to be of limited value because of the escape of thyroid hormone synthesis from the effect of iodide. On the other hand because of their rapid effect on serum T3 concentrations, oral cholecystographic agents may be given in conjunction with thionamides for a more rapid normalization of thyroid status. Perchlorate Perchlorate interferes with accumulation of iodide by the thyroid[2,3]. In conjunction with thionamides it has successfully been used in the treatment of amiodarone-induced hyperthyroidism. Gastric irritation and toxic reactions (aplastic anemia) limit the long-term use of perchlorate in the management of hyperthyroidism. Glucocorticoids Glucocorticoids in high doses inhibit the peripheral conversion of T4 to T3[3]. In Graves' hyperthyroidism, glucocorticoids appear to decrease T4 secretion by the thyroid, but the efficiency and duration of this effect is unknown. In severe hyperthyroidism, short-term glucocorticoid administration may be used as a general supportive treatment. The immunosuppressive effect of glucocorticoids in high doses is commonly exploited in the treatment of ophthalmopathy and dermopathy of Graves' disease, but not in the management of uncomplicated Graves' hyperthyroidism. |
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