Thioamides (or rarely thionamides) are major drugs for treatment of thyrotoxicosis and hyperthyroidism. Some alternative antithyroid drugs are iodide, glucocorticoids and anion inhibitors (perchlorate (ClO4–), pertechnetate (TcO4–), and thiocyanate (SCN–).
Indications
In general, antithyroid drugs are used in two ways: as the primary treatment for hyperthyroidism or as preparative therapy before radiotherapy or surgery. Antithyroid drugs are most often used as the primary treatment for persons with Graves' disease, in whom "remission," which is usually defined as remaining biochemically euthyroid for one year after cessation of drug treatment, is possible. In contrast, antithyroid drugs are not generally considered to be primary therapy for patients with toxic multinodular goiters and solitary autonomous nodules, because spontaneous remissions rarely occur. Antithyroid drugs are also the preferred primary treatment in pregnant patients and in most children and adolescents. The decision to use antithyroid drugs as primary treatment must be weighed against the risks and benefits of the more definitive therapy that radioiodine and surgery provide. For example, antithyroid drugs might be preferable in patients with severe Graves' eye disease, in whom radioiodine therapy has been associated with worsening ophthalmopathy.
Is radioiodine more likely than antithyroid drugs to worsen ophthalmopathy in patients with Graves disease?
Relationship Between Graves' Ophthalmopathy and Type of Treatment of Graves' Hyperthyroidism
Classification
Thioamides are relatively simple molecules which contain a sulfhydryl group and a thiourea moiety within a heterocyclic structure. Most common thionamides are the
Amongst them, the most used agents are propylthiouracil and methimazole. Methimazole is used in most of Europe and Asia while propylthiouracil and methimazole are the antithyroid drugs used in the United States.
These agents are actively concentrated by the thyroid gland against a concentration gradient. Their primary effect is to inhibit thyroid hormone synthesis by interfering with thyroid peroxidase–mediated iodination of tyrosine residues in thyroglobulin, an important step in the synthesis of thyroxine (T4) and triiodothyronine (T3).
Pharmacokinetics
Propylthiouracil is rapidly absorbed from the gastrointestinal tract, reaching peak serum levels after 1 hour. The bioavailability of 50–80% may be due to incomplete absorption or a large first-pass effect in the liver. The volume of distribution approximates total body water with accumulation in the thyroid gland. Most of an ingested dose of propylthiouracil is excreted by the kidney as the inactive glucuronide within 24 hours.
In contrast, methimazole is completely absorbed but at variable rates. It is readily accumulated by the thyroid gland and has a volume of distribution similar to that of propylthiouracil. Excretion is slower than with propylthiouracil; 65–70% of a dose is recovered in the urine in 48 hours.
The short plasma half-life of these agents (1.5 hours for propylthiouracil and 6 hours for methimazole) has little influence on the duration of the antithyroid action or the dosing interval because both agents are accumulated by the thyroid gland. For propylthiouracil, giving the drug every 6–8 hours is reasonable since a single 100 mg dose can inhibit iodine organification by 60% for 7 hours. Since a single 30 mg dose of methimazole exerts an antithyroid effect for longer than 24 hours, a single daily dose is effective in the management of mild to moderate hyperthyroidism.
The two drugs differ in their binding to serum proteins. Methimazole is essentially free in serum, whereas 80 to 90 percent of propylthiouracil is bound to albumin.
Molecular Mechanism
The thioamides act by multiple mechanisms. The major action is to prevent hormone synthesis by inhibiting the thyroid peroxidase-catalyzed reactions and blocking iodine organification. In addition, they block coupling of the iodotyrosines. They do not block uptake of iodide by the gland. Propylthiouracil and (to a much lesser extent) methimazole inhibit the peripheral deiodination of T4 and T3 (Figure 38–1). Since the synthesis rather than the release of hormones is affected, the onset of these agents is slow, often requiring 3–4 weeks before stores of T4 are depleted.
Mechanism of action of Methimazole
These medications possess other noteworthy effects. Antithyroid drugs may have clinically important immunosuppressive effects. In patients taking antithyroid drugs, serum concentrations of antithyrotropin-receptor antibodies decrease with time.
Antithyroid Drugs Inhibit Thyroid Hormone Receptor-Mediated Transcription
In addition can also be found reduced leves of other important molecules, including intracellular adhesion molecules and soluble interleukin-2 and interleukin-6 receptors. Furthermore these drugs may induce apoptosis of intrathyroidal lymphocytes, as well as decrease HLA class II expression. Finally it is also frequent seeing an increased number of circulating suppressor T cells and a decreased number of helper T cells, natural killer cells, and activated intrathyroidal T cells during antithyroid-drug therapy.
Side effects
Antithyroid drugs are associated with a variety of minor side effects, as well as potentially life-threatening or even lethal complications. Side effects of methimazole are dose-related, whereas those of propylthiouracil are less clearly related to dose. This may favor use of low-dose methimazole rather than propylthiouracil in the average patient with hyperthyroidism.
Adverse reactions to the thioamides occur in 3–12% of treated patients. Most reactions occur early, especially nausea and gastrointestinal distress. An altered sense of taste or smell may occur with methimazole. The most common adverse effect is a maculopapular pruritic rash (4–6%), at times accompanied by systemic signs such as fever.
The development of arthralgias, while classified as a "minor" reaction, should prompt drug discontinuation, since this symptom may be a harbinger of a severe transient migratory polyarthritis known as "the antithyroid arthritis syndrome".
Other rare adverse effects are lymphadenopathy, hypoprothrombinemia and exfoliative dermatitis, polyserositis.
Both thioamides cross the placental barrier and are concentrated by the fetal thyroid, so that caution must be employed when using these drugs in pregnancy. Because of the risk of fetal hypothyroidism, both thioamides are classified as pregnancy category D (evidence of human fetal risk based on adverse reaction data from investigational or marketing experience). Of the two, propylthiouracil is preferable in pregnancy because it is more strongly protein-bound and, therefore, crosses the placenta less readily. In addition, methimazole has been, albeit rarely, associated with congenital malformations. Both thioamides are secreted in low concentrations in breast milk but are considered safe for the nursing infant.
Toxicity
Agranulocytosis is the most feared side effect of antithyroid-drug therapy. agranulocytosis (an absolute granulocyte count of less than 500 per cubic millimeter) occurred in 0.37 percent of patients receiving propylthiouracil and in 0.35 percent receiving methimazole. Agranulocytosis must be distinguished from the transient, mild granulocytopenia (a granulocyte count of less than 1500 per cubic millimeter) that occasionally occurs in patients with Graves' disease, in some patients of African descent, and occasionally in patients treated with antithyroid drugs. A baseline differential white-cell count should be obtained before initiation of therapy.
Most cases of agranulocytosis occur within the first 90 days of treatment, but this complication can occur even a year or more after starting therapy. It is important to note that agranulocytosis can develop after a prior uneventful course of drug therapy, a finding that is important since renewed exposure to the drug frequently occurs when patients have a relapse and undergo a second course of antithyroid therapy.
Agranulocytosis is thought to be autoimmune-mediated, and antigranulocyte antibodies are shown by immunofluorescence and cytotoxicityassays.
Agranulocytosis induced by propylthiouracil: evidence of a drug dependent antibody reacting with granulocytes, monocytes and haematopoietic progenitor cells
All patients should be instructed to discontinue the antithyroid drug and contact a physician immediately if fever or sore throat develops. A white-cell count and differential count should be obtained immediately and the drug discontinued if the granulocyte count is less than 1000 per cubic millimeter, with close monitoring of the granulocyte count if it is more than 1000 per cubic millimeter but less than 1500 per cubic millimeter.
Hepatotoxicity is another major side effect of antithyroid drugs. Estimates regarding the frequency of this condition are imprecise, but it probably ranges from 0.1 percent to 0.2 percent. The recognition of propylthiouracil-related hepatotoxicity may be difficult, since in up to 30 percent of patients with normal baseline aminotransferase levels who are treated with propylthiouracil, transient acute increases in those levels develop, ranging from 1.1 to 6 times the upper limit of normal — levels that resolve while therapy is continued. Also, asymptomatic elevations in serum aminotransferase levels occur frequently in untreated patients with hyperthyroidism and are not predictive of further increases after the institution of propylthiouracil therapy.
Propylthiouracil-induced hepatotoxicity
Vasculitis is the third major toxic reaction seen with antithyroid-drug treatment, more commonly found in connection with propylthiouracil than with methimazole. Serologic evidence consistent with lupus erythematosus develops in some patients, fulfilling the criteria for drug-induced lupus. Antineutrophil cytoplasmic antibody–positive vasculitis has also been reported, especially in Asian patients treated with propylthiouracil. Most patients have perinuclear antineutrophil cytoplasmic antibodies, with a majority of them having antimyeloperoxidase antineutrophil cytoplasmic antibodies. It has been hypothesized that antithyroid drugs, especially propylthiouracil, can react with myeloperoxidase to form reactive intermediates that promote autoimmune inflammation.
Inhibition of oxidation activity of myeloperoxidase (MPO) by propylthiouracil (PTU) and anti-MPO antibodies from patients with PTU-induced vasculitis
