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Medications used for the Treatment of Hyperthyroidism
Propylthiouracil (PTU) PTU, used for the treatment of hyperthyroidism, exerts its actions by decreasing thyroid hormone synthesis, and by blocking the conversion of thyroxine (T4) to triiodothyronine (T3). In patients with Grave's Disease (GD), PTU likely also exerts a beneficial effect on the immune disturbance underlying the development of GD, as discontinuation of PTU after an appropriate treatment course (12-24 months for most patients) is frequently association with disease remission, which may be long lasting or permanent. Some patients experience a bit of nausea, or mild stomach upset and many patients find that PTU leaves a bitter aftertaste.
The initial dosing requirements depend in part on the severity of the hyperthyroidism present, and range from 100-400 mg daily in most patients. Given the short half life of PTU it usually needs to be taken in multiple daily divided doses. More severe hyperthyroidism may require initial treatment with higher doses of PTU. Patients with reduced kidney function or kidney failure often require a reduced dose of PTU.
Drug allergies and side effects
Side effects of PTU are rare, and may range from rash, itching, or hives, to more severe conditions such as agranulocytosis (the white blood cell count decreases or disappears, leading to increased risk of infection). Agranulocytosis is estimated to occur in ~1:400 patients. A warning sign of a problem with your white blood cells is the development of a sore throat, fever, or other indications of severe infection, which should prompt the patient to see their physician and obtain a white blood count test. Routine monitoring of the white blood count is generally not helpful as the low white blood count tends to develop rapidly and precipitously, and not gradually. For an overview of drug-associated agranulocytosis, see Antithyroid-drug-induced agranulocytosis complicated by life-threatening infections. QJM. 1999 Aug;92(8):455-61. Agranulocytosis may occur with the first treatment period of PTU or methimzole, or may occur after exposure to the drug for a second or third time, with no major differences in predictability or natural history Characteristics of Agranulocytosis as an Adverse Effect of Antithyroid Drugs in the Second or Later Course of Treatment
Thyroid. 2013 Dec 16. Systemic allergic reactions such as arthritis, systemic lupus erythematosis, serum sickness or hepatitis have also been described with antithyroid drugs but are much less common. Aplastic anemia, generally reversible after discontinuation of the drug, has also been described with PTU and methimazole, although it is much less common compared to agranulocytosis Antithyroid drug-induced aplastic anemia Thyroid. 2008 Oct;18(10):1043-8
The incidence of PTU-associated liver disease is difficult to accurately determine, but may be as high as 1% or higher in some studies. In most patients, the liver injury is mild and resolves once the drug is discontinued. See The incidence and clinical characteristics of symptomatic propylthiouracil-induced hepatic injury in patients with hyperthyroidism: a single-center retrospective study. Am J Gastroenterol. 2001 Jan;96(1):165-9. There is some evidence that PTU is much more likely, compared to methimazole, to increase the rare but reported risk of liver injury and more severe liver failure in adults and children with Graves' disease. Analysis of Antithyroid Drug-Induced Severe Liver Injury in 18,558 Newly Diagnosed Patients with Graves' Disease in Japan Thyroid. 2019 Oct;29(10):1390-1398. In contrast, liver failure associated with methimazole use in children is rarely reported. Hence, methimazole should be considered the drug of choice for most children with Graves' disease. Dissimilar Hepatotoxicity Profiles of Propylthiouracil and Methimazole in Children J Clin Endocrinol Metab. 2010 Apr 28. [Epub ahead of print]
Patients taking PTU or methimazole are also at risk for the development of inflammatory illnesses such as vasculitis. Although this risk is rare, antibodies characteristic of specific types of vasculitis can rarely be detected even many years after antithyroid drugs have been discontinued, as outlined in Occurrence of antineutrophil cytoplasmic antibodies and associated vasculitis in patients with hyperthyroidism treated with antithyroid drugs: A long-term followup study. Arthritis Rheum. 2005 Feb 15;53(1):108-13.
Methimazole works, as does PTU, to reduce the levels of thyroid hormone by decreasing thyroid hormone synthesis. In contrast to PTU, methimazole does not significantly inhibit T4 to T3 conversion. However, Methimazole is effective when administered either in divided doses or only once a day, which may have some advantage in terms of drug compliance. This issue has been carefully studied, with increased compliance noted in the groups of patients treated with once a day Methimazole dosing. See Single daily dose of methimazole compared to every 8 hours propylthiouracil in the treatment of hyperthyroidism. South Med J 1995 Sep;88(9):973-6 or Treatment of hyperthyroidism with a small single daily dose of methimazole Acta Endocrinol (Copenh) 1988 Sep;119(1):139-44 and Treatment of hyperthyroidism with a small single daily dose of methimazole J Clin Endocrinol Metab 1986 Jul;63(1):125-8.
The initial starting dose of methimazole ranges from 5-30 mg daily, with occasional patients with severe hyperthyroidism requiring higher doses. Methimazole is secreted into breast milk, and nursing mothers should discuss this issue with their physicians. Although methimazole has been used successfully to treat pregnant women, there appears to be more case reports of isolated congenital defects with methimazole, compared to PTU, hence PTU is preferred by many physicians as the drug of choice for treatment of pregnant women.
The side effect profile of methimazole is quite similar to that described for PTU. It is important to remember that while medications will be initially effective in reducing the levels of circulating thyroid hormones in all patients with hyperthyroidism irrespective of the cause, only patients with Grave's disease may experience a long-lasting or permanent remission of the disease once medications are discontinued. Patients with hyperthyroidism due to a hot nodule or toxic nodular goiter frequently need to receive subsequent definitive treatment for their hyperthyroidism, which may involve radioactive iodine or surgery.
Medications such as propranolol (Inderal), metoprolol (Lopressor), and other related drugs are known as b blockers, as they act to block the action of b adrenergic receptors that mediate the actions of adrenaline and noradrenaline. During the hyperthyroid state, our sympathetic nervous system activity is increased, and many of the symptoms that develop overlap with symptoms experienced during states of anxiety. For example, tremor, rapid heart beats, anxiety, restlessness, retraction of the eye lids and increased sweating are all symptoms that may be improved following institution of b blocker treatment. Patients with moderate to severe hyperthyroidism may benefit from treatment with a b blocker for several weeks to months until their hyperthyroidism is better controlled with medications such as PTU or methimazole, or radioactive iodine. Rarely, patients with obstructive lung disease, asthma or congestive heart failure or cardiomyopathy may have an adverse reaction to b blockers leading to increased difficulty with breathing. Accordingly patients with these types of lung or heart conditions should inform their physician about these co-existing problems prior to consideration of b blocker therapy.
Although iodine is taken up by the thyroid and used to make thyroid hormone, it can paradoxically suppress release of thyroid hormones from the thyroid gland for several days. Hence, in some patients with severe hyperthyroidism, iodine may be administered to try and shut off thyroid hormone release after PTU or methimazole has been started. For more information, see Iodine. Some patients with severe hyperthyroidism may also be treated for a few days to weeks with oral cholecystographic agents that are normally used for visualization of the gall bladder. These drugs inhibit conversion of T4 to T3 and also contain iodine that transiently blocks thyroid hormone release. For an overview, see Oral cholecystographic agents and the thyroid. J Clin Endocrinol Metab. 2001 May;86(5):1853-60.
The side effects of methimazole or PTU sound quite scary. What can I do to prevent them from happening to me?
At the present time, we have no way of predicting who will or will not develop a side effect on methimazole or PTU. Most patients taking these medicines have no side effects . Even rash is uncommon, affecting generally less than 10% of patients, and agranulocytosis (low white blood cell count) affects about 1 in 400 people. The other side effects such as lupus, arthritis, and liver disease are quite uncommon, ranging from one in several thousand people to 1:10,000 patients. The risk of agranulocytosis (very low white blood cell count) may be related to the initial dose of medication used to treat hyperthyroidism Methimazole-induced agranulocytosis in patients with Graves' disease is more frequent with an initial dose of 30 mg daily than with 15 mg daily.Thyroid. 2009 Jun;19(6):559-63.
Why can't I have my blood monitored every 4 weeks to detect side effects at the earliest possible point in time?
No studies to date have shown that frequent monitoring influences the detection of drug-induced side effects in patients with thyroid disease. Indeed, patients can be fine one day, and have a precipitous or rapid drop in blood count leading to an infection that happens very rapidly, in only a few days. Hence, although it is important to be aware of the side effects, frequent regular monitoring of blood counts does not appear to be helpful in predicting the development of side effects in this specific instance.
How long will it take me to feel better after I start the medications for hyperthyroidism?
The answer depends on the extent of the hyperthyroidism present at the start of treatment. Patients with severe hyperthyroidism and large thyroid glands may take months to experience significant symptomatic improvement, whereas patients with milder hyperthyroidism may start to feel better in a few weeks. The thyroid gland rapidly escapes from the effects of the medications if even a few doses of medication are missed or skipped. Hence regular compliance, taking the medications daily as prescribed, is extremely important for achieving good control of the hyperthyroid state. Many of the symptoms of hyperthyroidism may be improved rapidly within a few days if b blocker therapy is initiated.
What is the chance of the disease being cured if I take antithyroid medications?
The sustained remission rate for patients with Graves' disease depends on the size of the thyroid gland and the duration of treatment. In most studies, longer durations of treatment (12-24 months) and smaller thyroid glands are associated with longer remission rates compared with shorter courses of antithyroid drug treatment (6-9 months). Depending on the study, long term remissions are seen in 40-60% of patients completing adequate treatment courses.
I am taking PTU and I just developed a fever and a sore throat. What should I do?
Stop taking the medication and contact your physician or nearest medical clinic immediately to get an assessment including a white blood count test to make sure that your white blood count is normal. Most patients with this scenario will just have a routine viral or bacterial cause of the sore throat, but it is important to ensure that the PTU (or methimazole) you were taking did not cause your white blood count to drop, precipitating the infection.
I have heard that I can take a single daily dose of methimazole for my Graves' disease. Is the same true for PTU?
At present, we do not have good evidence to support single daily administration of PTU for most patients with Graves' disease. Where this has been attempted, the success rate has been suboptimal. See Efficacy of single daily dosage of methimazole vs. propylthiouracil in the induction of euthyroidism. Clin Endocrinol (Oxf). 2001 Mar;54(3):385-90.
I was told my chances of being treated successfully were greater if I also took thyroxine in addition to PTU or methimazole. Is this true?
An initial study from Japan suggested that combining antithyroid drugs with thyroxine may increase the duration of remission in patients treated for Graves' disease. Several follow-up studies have not confirmed this data, and this is not done very often any more, except under unusual circumstances. See Lack of effect of thyroxine in patients with Graves' hyperthyroidism who are treated with an antithyroid drug. N Engl J Med. 1996 Jan 25;334(4):220-4 and Medical therapy of Graves' disease: does thyroxine prevent recurrence of hyperthyroidism? J Clin Endocrinol Metab. 1997 Aug;82(8):2410-3 and Effects of l-thyroxine administration, TSH-receptor antibodies and smoking on the risk of recurrence in Graves' hyperthyroidism treated with antithyroid drugs: a double-blind prospective randomized study. Eur J Endocrinol. 2001 May;144(5):475-83.
I have asthma. Are there any medications I should not take?
Patients with asthma make have increased bronchospasm (breathing difficulties) with use of b-blockers. Accordingly, these drugs should generally be avoided, or only used under rare circumstances under direct observation of a physician with regular spirometry and monitoring. Rare isolated case reports of drug allergies and worsening of asthma with antithyroid rugs such as methimazole have also been reported, as in Bronchial Asthma Induced by an Antithyroid Drug. Chest. 2001 May;119(5):1598-9.
Is it true that lithium can be used to treat an overactive thyroid condition?
Lithium does have effects on the thyroid that include reduction in the release of thyroid hormone release. These effects have prompted the occasional transient use of lithium in severely hyperthyroid subjects. Lithium has also been used to reduce the severity of rebound hyperthyroidism and enhance the effectiveness of radioactive iodine treatment in patients withdrawn from medications (such as PTU or methimazole) who are being treated with radioactive iodine. See Treatment with Lithium Prevents Serum Thyroid Hormone Increase after Thionamide Withdrawal and Radioiodine Therapy in Patients with Graves' Disease. J Clin Endocrinol Metab. 2002 Oct 1;87(10):4490-4495.
How long do I need to be treated with the drugs?
The answer depends on the severity of your hyperthyroidism, the size of your thyroid, the rapidity of your response to the treatment, and other associated medical factors specific to each patient. Treatment periods may range from 6 months to several years. For one type of approach using low dose "maintenance therapy" see Practical treatment with minimum maintenance dose of anti-thyroid drugs for prediction of remission in Graves' disease. Endocr J. 2003 Feb;50(1):45-9.
Is there a role for drugs like cholestyramine that bind thyroid hormone and prevent it from being reabsorbed?
Although some physicians have used combinations of methimazole or PTU with cholestyramine with good effect The effect of combination therapy with propylthiouracil and cholestyramine in the treatment of Graves' hyperthyroidism. Clin Endocrinol (Oxf). 2005 May;62(5):521-4, this is generally not commonly done in the management of hyperthyroidism.