Hyperthyroidism is a common endocrine disease. Although thionamide antithyroid drugs are the cornerstone of hyperthyroidism treatment, some patients cannot tolerate this drug class because of its serious side effects including agranulocytosis, hepatotoxicity, and vasculitis. Therefore, nonthionamide antithyroid drugs (NTADs) still have an important role in controlling hyperthyroidism in clinical practice. Furthermore, some situations such as thyroid storm or preoperative preparation require a rapid decrease in thyroid hormone by combination treatment with multiple classes of antithyroid drugs. NTADs include iodine-containing compounds, lithium carbonate, perchlorate, glucocorticoid, and cholestyramine. In this narrative review, we summarize the mechanisms of action, indications, dosages, and side effects of currently used NTADs for the treatment of hyperthyroidism. In addition, we also describe the state-of-the-art in future drugs under development including rituximab, small-molecule ligands (SMLs), and monoclonal antibodies with a thyroid-stimulating hormone receptor (TSHR) antagonist effect.
Graves’ disease (GD) is the most common cause of hyperthyroidism in clinical practice [
In this narrative review, we provide data about the mechanisms of action, indications, dosages, and side effects of NTADs that are currently used including iodine-containing compounds, lithium carbonate, perchlorate, glucocorticoids, and cholestyramine. Furthermore, we provide an up-to-date review of studies that have investigated drugs acting on the pathogenesis of GD including rituximab and treatment targeting the thyroid-stimulating hormone receptor (TSHR) as well as the future prospects for new therapies for GD that have not been mentioned together in previous reviews.
In this section, we describe currently available NTADs including their mechanisms of action, indications, and side effects. For quick reference, we have also summarized indications and dosing data in Table
Nonthionamide antithyroid drug dosage.
(1) Iodine-containing compounds (oral route) | ||
Iodide 200–2000 mg/d | [ | |
Iodine-containing compound (in patients with gastrointestinal problem) | ||
SSKI 0.4 ml via sublingual every 8 h | [ | |
SSKI 5–10 drops via rectal every 6–8 h | [ | |
(2) Glucocorticoids | ||
(Thyroid storm) | Hydrocortisone 300 mg intravenous load then 100 mg every 8 h | [ |
Dexamethasone 2 mg intravenously every 6 h | [ | |
(Preoperative) | Hydrocortisone 100 mg orally or intravenously every 8 h | [ |
Dexamethasone 2 mg orally or intravenously every 6 h | [ | |
(1) Iodine-containing compound (mild Graves’ disease) | ||
KI 50 mg/d | [ | |
(2) Cholestyramine (an adjuvant drug with a thionamide antithyroid drug) | ||
Cholestyramine 4 g orally every 6–12 h | [ | |
(3) Lithium carbonate | ||
Lithium 300 to 450 mg orally every 8 h | [ | |
Age over 60 y: lithium 500 to 750 mg/d | ||
Age over 80 y: lithium should not exceed 450 mg/d | ||
(1) Potassium perchlorate | ||
Potassium perchlorate 1 g/d (or lower) divided into 2–4 times/d | [ | |
(2) Lithium carbonate | ||
Lithium 300 to 450 mg orally every 8 h | [ | |
Age over 60 y: lithium 500 to 750 mg/d | ||
Age over 80 y: lithium should not exceed 450 mg/d |
SSKI: saturated solution of 5% potassium iodide.
Mechanism of nonthionamide antithyroid drugs. Iodine-containing compounds mainly inhibit thyroid hormone release and transiently inhibit organification. Lithium also inhibits thyroid hormone release and may inhibit thyroid hormone synthesis. Perchlorate inhibits active iodide uptake by competitively binding with NIS. Glucocorticoid inhibits peripheral T4 to T3 conversion and may inhibit thyroid hormone secretion. MAbs act at the ectodomain of the TSH receptor while SMLs act at the transmembrane domain of the TSH receptor. MAbs: monoclonal antibodies; NIS: sodium iodide symporter; SMLs: small-molecule ligands; Tg: thyroglobulin; TSHR: thyroid-stimulating hormone receptor.
Iodine was used to treat hyperthyroidism before the discovery of thionamide antithyroid drugs. The iodine-containing compounds used in the treatment of hyperthyroidism are potassium iodide (KI) in the form of KI tablets, a saturated solution of potassium iodide (SSKI), and Lugol’s solution. SSKI is prepared by adding KI crystals to water until the saturation point of KI is reached. Lugol’s solution is an aqueous solution of elemental iodine and KI [
The major actions of iodide on thyroid function are inhibition of thyroid hormone release from the thyroid gland and a transient decrease in thyroid hormone synthesis (the acute Wolff-Chaikoff effect) [
Previous studies have shown the putative mechanism of iodide’s inhibition of thyroid hormone release from the thyroid gland. An
Iodide causes a transient decrease in thyroid hormone synthesis. This mechanism is known as the Wolff-Chaikoff effect. It is an autoregulatory mechanism of the thyroid gland to handle excess iodine intake and prevent excessive thyroid hormone formation. In 1948, Wolff and Chaikoff showed that receiving a large amount of iodide stopped the organification of the thyroid cells in rats [
“Escape” from the acute Wolff-Chaikoff effect protects patients from hypothyroid state even though their high iodide status is continuous. If high iodide status is continuous, iodine transportation into the thyroid cell decreases because of the decreases in sodium iodide symporter (NIS) mRNA, NIS protein [
The principles of preparation for emergency surgery are similar to thyroid storm treatment. These include rapid reduction of thyroid hormone level and control of hyperthyroidism symptoms with a combination drug regimen. Therefore, iodine-containing compounds at the same dose as thyroid storm treatment should be used in preoperative management and stopped immediately after surgery [
Some hyperthyroidism patients cannot receive iodine orally due to gastrointestinal problems. Alfadhli and Gianoukakis [
In an observational study of GD with thionamide-associated side effects, 44 patients received KI 13–100 mg per day initially, and the doses were adjusted depending upon the biochemical responses. Sixty-six percent (29 of 44) of patients achieved normal thyroid function at a median of 35 days (range 8–329), and 38.6% of patients (17 of 44) were in remission after a median of 7.4 years (range 1.9–23) after KI therapy. After 32–609 days of treatment, 25% of patients (11 of 44) escaped from iodine responses [
A previous retrospective study showed the benefit of KI as an adjunctive therapy of radioactive iodine (RAI) treatment. KI (around 250 mg/day) was administered at one week after RAI therapy and helped to shorten the duration of hyperthyroidism. However, patients taking KI more often developed transient hypothyroidism [
Iodine has a few mild side effects such as rash, drug fever, sialoadenitis, conjunctivitis, mucositis, vasculitis, and leukemoid eosinophilic granulocytosis [
There are two lithium carbonate preparations, namely, immediate-release and sustained-release. The immediate-release and sustained-release preparations reach a peak plasma concentration at about 1-2 hours and 4-5 hours after administration, respectively. The elimination half-life of lithium is about 18–36 hours, and it is mostly excreted by the kidneys. Lithium clearance is considered to decrease with aging and renal impairment [
Lithium is concentrated by the thyroid gland at a level 3 to 4 times of that in the plasma, probably by active transport [
It has been proposed that the thyroid gland may escape from the inhibitory effect of lithium. Nevertheless, data about this are sparse because most studies only used lithium for short durations. In 1974, lithium was used as monotherapy for 6 months in 11 patients with GD who relapsed from conventional therapy, and none of those patients escaped from the lithium effect [
Lithium has been proposed as an adjunct to radioactive iodine (RAI) for the treatment of hyperthyroidism because lithium inhibits the release of iodine from the thyroid gland [
Serum lithium should be monitored at 1 week after starting treatment as well as after dose adjustment and weekly until reaching the therapeutic level. The serum lithium concentrate should be maintained in the range of 1 mEq/L [
Symptoms of chronic intoxication can be classified to mild, moderate, and severe toxicity. The symptoms of mild toxicity (lithium level 1.5–2 mEq/L) include nausea, vomiting, diarrhea, hand tremor, and drowsiness while the symptoms of moderate toxicity (level 2–2.5 mEq/L) include myoclonic twitches, nystagmus, dysarthria, ataxia, and confusion. Severe toxic symptoms (level > 2.5 mEq/L) are renal impairment, impaired consciousness, seizure, coma, and death. Precipitating factors of chronic lithium toxicity might be an increase in the dose of the lithium regimen, a decline in renal function decline, or receival of some medications such as thiazides, nonsteroidal anti-inflammatory drugs, and angiotensin-converting enzyme inhibitors. These medications increase renal reabsorption of lithium, causing increased serum lithium concentration. However, toxic symptoms may occur even in the therapeutic range of lithium [
Perchlorate is the dissociated anion of perchlorate salts. It is rapidly absorbed from the gastrointestinal tract after oral administration. Perchlorate reaches peak plasma concentration at 3 hours and has a half-life of approximately 6–8 hours. It is excreted by the kidney in an unchanged form [
Perchlorate inhibits iodide uptake in the thyroid gland by competitively binding with NIS and also has the ability to discharge iodine from the thyroid gland, reducing intrathyroidal iodine, thereby decreasing thyroid hormone synthesis [
Perchlorate side effects are gastrointestinal irritation, rashes, drug fever, lymphadenopathy, nephrotic syndrome, and agranulocytosis. Furthermore, some cases of perchlorate-induced fatal aplastic anemia in hyperthyroidism treatment between 1961 and 1966 were reported in the literature. These patients received perchlorate doses ranging from 400–1000 mg per day. However, no cases of fatal aplastic anemia in patients receiving perchlorate for amiodarone-induced thyrotoxicosis have been reported [
Previous studies have mostly used the oral form of dexamethasone to demonstrate the effects of glucocorticoid on the thyroid function test. However, both hydrocortisone and dexamethasone are commonly used as an adjuvant drug in the treatment of hyperthyroidism.
The main mechanism of glucocorticoids in controlling thyrotoxicosis is their inhibitory effect on peripheral T4 to T3 conversion. Previous studies have demonstrated that the administration of dexamethasone 2 mg orally every 6 hours for 4 doses to patients with untreated GD decreased serum T3 by around 37–50%, and T3 began to decrease at 24 hours after the first dose of dexamethasone, subsequently decreasing persistently for at least 5 days [
In emergency preoperative preparation for patients with hyperthyroidism, both hydrocortisone and dexamethasone can be used as adjuvant medication. The recommended doses are hydrocortisone 100 mg orally or intravenously every 8 hours or dexamethasone 2 mg orally or intravenously every 6 hours. The glucocorticoid dose should be tapered off in the first 72 hours after surgery [
Glucocorticoids are usually prescribed in high doses and for short durations in the treatment of hyperthyroidism. Therefore, the side effects might include increased blood glucose, increased blood pressure, and suppression of immunological response [
Cholestyramine, an ion exchange resin, is a bile acid sequestrant. It decreases enterohepatic circulation of thyroid hormone and can be used to control hyperthyroidism.
Both T3 and T4 are concentrated in the liver and secreted in the bile in conjugated form and a small amount in unconjugated form. Free hormones are released by bacterial enzyme deconjugation in the large intestine and reabsorbed to the blood circulation, completing the enterohepatic circulation of thyroid hormone [
The common side effects of cholestyramine are bloating, flatulence, and constipation. However, most patients in previous studies could tolerate cholestyramine well. Since cholestyramine might bind to other drugs given concomitantly, it is generally recommended that other drugs be taken at least 1 hour before or 4 to 6 hours after cholestyramine [
In the past few years, the mechanisms underlying GD have been elucidated in more detail [
B cells have many functions contributing to autoimmune thyroid disease including (1) being the precursor of plasma cells, which produce TRAb, a key feature of GD, (2) producing inflammatory cytokines, and (3) functioning as antigen-presenting cells [
Rituximab is a chimeric murine-human monoclonal antibody targeting CD20, which is a transmembrane protein expressed on pre, immature, mature, and memory B cells. Rituximab causes complete peripheral B cell depletion for at least 4–6 months by induction of apoptosis of B cells, antibody-dependent cellular cytotoxicity, and complement-mediated lysis [
The effect of rituximab on thyroid hormone level in GD is inconclusive and is based on a few small phase 2 clinical trials [
El Fassi et al. [
All rituximab studies have reported some side effects with varying prevalence and severity. Before rituximab infusion, all patients were pretreated with acetaminophen, antihistamine, or glucocorticoid. The side effects included mild infusion-related adverse effects such as hypotension, nausea, fever, chill, and tachycardia as well as itching of the nose and throat. Other reported side effects were temporary joint pain, symmetric polyarthritis, serum sickness, and ulcerative colitis [
In GD, the TSHR is continuously stimulated by TRAb, causing an increased rate of thyroid hormone synthesis and secretion. TSHR is a G protein-coupled receptor comprising of three domains including a large amino-terminal ectodomain, a transmembrane domain and an intracellular carboxyl-terminal domain [
SMLs can bind to a pocket within the transmembrane domain of TSHR, consequently inhibiting signaling that regulates the conformational changes of TSHR. SMLs do not affect the TRAb binding site at the ectodomain of TSHR. SMLs that might be developed for the treatment of GD are SML TSHR antagonists and SML TSHR inverse agonists.
NCGC00242595 (NIDDK-CEB-52) is an SML TSHR antagonist. In
TSHRs are receptors that exhibit significant basal or constitutive signaling activity. Inverse agonists are ligands that inhibit receptor activation by agonists and additionally inhibit basal signaling [
Most of these SML TSHR still have a low potency that might not be clinically useful in GD treatment. Therefore, the development of more potent and more specific SML TSHR with antagonist activity is necessary [
TRAb are classified by their actions as stimulating, blocking, and neutral (or cleavage) antibodies [
Until now, only two human MAbs have demonstrated TSHR antagonist effects. K1-70 is a MAb with TSHR antagonist activity, and 5C9 is a MAb with TSHR inverse agonist activity. In previous studies, both K1-70 and 5C9 could inhibit stimulation of TSH and TRAb from the serum of GD patients [
NTADs can be used to control symptoms of hyperthyroidism in some circumstances in which thionamide cannot be used or in combination with drug regimens. The mechanisms of action, indications, and side effects of NTADs are different. Understanding those differences can help the clinician select the appropriate drugs for the patients. Novel medications for GD such as rituximab, SMLs, and MAbs with TSHR antagonist effect are still being investigated.
Amiodarone-induced thyrotoxicosis
Graves’ disease
Potassium iodide
Monoclonal antibodies
Methimazole
Sodium iodide symporter
Nonthionamide antithyroid drugs
Propylthiouracil
Small-molecule ligands
Saturated solution of potassium iodide
Thyrotropin receptor antibodies
Thyroid-stimulating hormone receptor.
The authors declare that they have no conflicts of interest.
Nattakarn Suwansaksri and Lukana Preechasuk contributed equally to this work.
The authors give special thanks to Mr. Sarawuit Auprarat for his assistance with the artwork in Figure