Understanding the effects of certain drugs on the thyroid is crucial to prevent adverse outcomes at a later stage. Thyroid abnormalities resulting from specific drugs can often be subclinical in nature and may not be easily recognised without specific screening tests. This article throws light on the drug-induced thyroid dysfunction and the possible outcomes which may help clinicians manage patients appropriately.

Thyroid dysfunction is one of the common problems observed in routine clinical practice. [1] Several drugs are known to adversely affect the functions of the thyroid gland. [2,3] Hypothyroidism represents the most common form of drug-induced thyroid dysfunction. [4] Understanding the physiology of thyroid hormones is important for the knowledge of drug-induced thyroid dysfunction.

Mechanisms involved in the pathogenesis of drug-induced hypothyroidism

Thyrotropin is responsible for the control of the synthesis and release of thyroid hormone. Thyrotropin-releasing hormone (TRH) stimulates the secretion of thyrotropin whereas thyroid hormones inhibit it via a negative feedback mechanism. [5] Drug interactions are possible at almost every step involved in the formation, release, transport and metabolism of thyroid hormone. Several drugs can affect thyroid functions by acting on multiple steps. [5]

Inhibition of production and/or release of thyroid hormone is an important mechanism of drug-induced hypothyroidism. The immune mechanism may be implicated in the development of hypothyroidism with some drugs. Drug-induced thyroiditis, inhibition of thyroid-stimulating hormone (TSH) synthesis and interference with hypothyroidism treatment (i.e. interference with the pharmacokinetics of thyroid hormone), and changes in are other mechanisms are involved in the pathogenesis of drug-induced thyroid dysfunction. [4]

Thionamides, amiodarone, contrast agents, lithium, minocycline, thalidomide, ethionamide can cause inhibit thyroid hormone synthesis and/or release of thyroid hormones. Interferon-alpha can cause hypothyroidism by immune mechanism. [4] Interleukin-2 is also known to cause hypothyroidism. [6] Several drugs (e.g. bexarotene, mitotane, ipilimumab) are known to affect the hypothalamic-pituitary-thyroid axis. [5] Similarly, glucocorticoids and dopamine agonists can cause inhibition of TSH. [4]

In the following section, important drugs/classes of medicines having the potential to cause thyroid dysfunction are discussed.

Amiodarone

Amiodarone is an anti-arrhythmic drug with high iodine content. Amiodarone may cause thyroid dysfunction due to iodine content in it or the drug itself. Women, older patients, and people having auto-immunity are more prone for the development of amiodarone-induced hypothyroidism. The severity of thyroid dysfunction, age of the patient and cardiac condition are the factors considered in the management of amiodarone-induced hypothyroidism. Patients requiring amiodarone need monitoring of their thyroid function before initiation of treatment and regularly after its initiation. [4]

Psychotropic medications

1. Psychotropic medicines can be associated with changes in thyroid function. The incidence of hypothyroidism is more than hyperthyroidism. Patients with risk factors for the development of thyroid dysfunction as well as those having a history of thyroid dysfunction need careful monitoring of whether they are receiving psychotropic medicines. [7]
2. Lithium carbonate is a widely used medication for the treatment of bipolar disorder. It is concentrated more in the thyroid than in plasma. Use of lithium is known to be associated with thyroid dysfunction. It is one of the most common drugs that cause hypothyroidism. [6] Lithium-induced hypothyroidism is more commonly observed in females. Levothyroxine is useful in the treatment of lithium-induced hypothyroidism. Thyroid function test should be performed before initiating lithium and monitored regularly after every 6 to 12 months.
3. Tricyclic antidepressants can cause hypothyroidism by interfering with the synthesis of thyroid hormones. [7] In a prospective study, treatment with fluoxetine or sertraline was not associated with clinically significant changes in thyroid function in patients with primary hypothyroidism or those with normal thyroid function. [8]

Patients with a history of thy­roid dysfunction need careful monitoring for thy­roid function when they are receiving antidepressants. Similarly, patients receiving antipsychotics should also be assessed for thyroid functions. [7]

Anti-epileptic drugs

Despite the availability of several newer anti-epileptic drugs, older anti-epileptics are still commonly used in the management of epilepsy. [9] In a cross-sectional study, out of 298 patients with epilepsy, 17.4% of patients had low levels of free thyroxine. Older age, female gender, and use of multiple (three or more) antiepileptic drugs were significantly associated with low levels of free thyroxine. Similarly, longer duration of epilepsy and intractable epilepsy were also significantly associated with low levels of free thyroxine. Carbamazepine, topiramate, and levetiracetam were significantly associated with the presence of low fT4. Among the antiepileptics, carbamazepine was an independent risk factor for low levels of free thyroxine level. [10] Another study involving reported low levels of serum thyroid hormone in carbamazepine- and oxcarbazepine-treated males. In this study, valproate did not show significant effects on thyroid function. [11]

A meta-analysis conducted by Zhang and colleagues [9] has shown that anti-epileptic drugs such as carbamazepine, phenytoin, and valproic acid are associated with changes in thyroid hormones in patients with epilepsy. The meta-analysis included only observational studies, leaving scope for the possibility of confounding effects of other factors. In addition, there was considerable heterogeneity in the studies. Considering these limitations, it is not certain whether these changes are of significant clinical concern. Based on the evidence, it may be particularly important to consider the thyroid function in patients with hypothyroidism who need long term treatment with anti-epileptic drugs. Evidence regarding association between newer anti-epileptic drugs and thyroid hormone levels are limited.

Interferon-alpha and anti-cancer drugs

1. Interferon-alpha used for chemotherapy or as a long-term therapy for hepatitis C can cause thyroid dysfunction. [12]
2. Some anti-cancer drugs can be associated with thyroid dysfunction, the pathophysiology of which is not clearly known. Tyrosine kinase inhibitors are associated with high rates of thyroid dysfunction. Adverse effects related to thyroid function caused by anti-cancer drugs can generally be well managed without the requirement of dose modification or discontinuation of anticancer agent. [13]

Drugs affecting thyroid function by suppression of TSH level

Glucocorticoids can decrease serum TSH levels because of their effect on TRH in the hypothalamus. However, central hypothyroidism because of them is not clinically evident. Dopamine, bromocryptine, somatostatin analogues too can suppress the levels of serum TSH. These agents also do not cause clinically evident, central hypothyroidism. However, bexarotene, a rexinoid can cause clinically significant central hypothyroidism. [2]

Drugs interfering with the pharmacokinetics of levothyroxine in patients with hypothyroidism

For optimal absorption, levothyroxine should be taken on an empty stomach. [12] In hypothyroid patients receiving levothyroxine, several drugs can interfere with its absorption. Bile acid-binding resins and bran reduce the absorption of thyroid hormones. Proton pump inhibitors, antacids containing aluminium hydroxide or magnesium, iron and sucralfate can also alter the absorption of thyroid hormone. [4]

Inducers of cytochrome P-450 enzyme including rifampin, phenytoin, carbamazepine and phenobarbitone can increase the metabolism of thyroid hormones. Higher doses of thyroid hormone replacement may be needed in patients receiving these drugs. [12]

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author is a Professor of Pharmacology from Mumbai.