My name is Paige, I'm a pharmacist at the University of Cincinnati Medical Center in Ohio and for the next portion of this presentation I'm going to be discussing drugs that interfere with thyroid function. In order to preface the discussion, I do want to highlight that the medication effects or disruptions that I'm going to be highlighting on thyroid function are oftentimes unintended consequences of prescribed pharmacologic therapy and those medications are oftentimes chronically prescribed medications rather than the medications that are acutely administered during an ICU stay. Still relevant, however, because these patients will arrive in our unit potentially with manifestations of thyroid dysfunction. That dysfunction and our interactions with medications do have varying degrees of clinical importance or significance that I'll highlight as going through and I'll also touch towards the end on potential medications that actually cause artificial artifacts on lab assays for thyroid function. Medication effects on the thyroid can be classified as causing either hypo or hyperthyroidism. As far as the mechanism by which a medication can cause a hypothyroid state, most commonly either medications either inhibit thyroid hormone synthesis itself or they interfere with thyroid hormone transport or metabolism, whether that be inhibition of thyroid hormone activation in the periphery from T4 to T3 or medications that displace thyroid hormones from their binding proteins, most commonly thyroxine binding globulin. And then a high offender of medications are those that potentially interact or decrease GI absorption of exogenously administered thyroid supplementation. Medications that cause a hyperthyroid state usually do so by stimulation of thyroid hormone synthesis by providing additional substrate. And then, as I've alluded to before, there are medications that actually interfere with thyroid testing itself in euthyroid patients, so those results are falsely elevated or low due to the medication interaction with the assay itself. We will first begin discussing medications that disrupt thyroid hormone synthesis or release. Lithium is prescribed for many CNS disorders. Usually not a drug we use acutely in the ICU, however, it's still worth talking about because it does carry with it a high incidence of hypothyroidism, ranging from 6 to 52% in patients who are prescribed chronic lithium therapy. And of those patients, about half of them will develop a goiter, usually within the first two years of therapy. Lithium interacts with the thyroid on both a synthesis and a secretion level. So from a synthesis standpoint, lithium inhibits a coupling of iodotyrosine residuals to form T4 and T3, and then subsequently it inhibits the release of T4 and T3 as well. Patients who have baseline or underlying chronic autoimmune thyroiditis or have baseline antithyroid antibodies are actually at an increased sensitivity to the antithyroid effects of lithium. It is unknown, however, if lithium itself can cause or induce thyroid autoimmunity. The clinical consideration regarding lithium therapy is that you obtain baseline monitoring of TSH as well as those antithyroid antibody titers. And then repeat monitoring at a minimum of 6 to 12 months. Consider earlier monitoring on the 6-month range if you have existing antithyroid titers. And it is worth noting that patients who develop hypothyroidism or are being treated with T4 supplementation, it does not require that lithium be discontinued. Exposure to iodine can cause both hypo- and hyperthyroidism through different mechanisms in a patient's underlying baseline thyroid function. Keep in mind that iodine is one of the principal substrates for thyroid hormone synthesis. So by exposure to iodine causing hypothyroidism, that's through a mechanism called the Wolff-Chakoff effect. And this effect is a means of rejecting large quantities of iodine to prevent your thyroid from synthesizing inappropriately large amounts of thyroid hormones by acutely inhibiting the organification of iodine. In patients with baseline normal thyroid function, we actually, quote-unquote, escape this interaction in less than a week by downregulating our sodium iodine symporter and restoring normal thyroid homeostasis and synthesis. However, in patients who have baseline thyroid dysfunction, most commonly in patients who have lymphocytic thyroiditis, such as Hashimoto's, or who underwent thyroid ablation, that interaction actually persists until the iodine load has completely cleared, which can take upwards of two to three weeks. Therefore, in those patients, clinical or subclinical hypothyroidism may actually ensue because of the persistent Wolff-Chakoff effect. On the other end of the spectrum, hyperthyroidism can occur after iodine exposure due to the Jod-Bayes-Doe phenomenon, which leads to unregulated thyroid hormone synthesis. Patients that are at increased risk for development of hyperthyroidism, if they have nodular thyroid disease or Graves' disease, because their thyroid itself is unresponsive to the negative feedback from increased circulating thyroid hormones. I do want to highlight those medications that carry with it a significant iodine load. In our settings, we would most likely encounter amiodarone as an antiarrhythmic drug. It does contain about 37% iodine by weight, so 75 milligrams per 200 milligram tablet. However, it does undergo partial deiodination, which results in a net amount of about seven milligrams of circulating iodine, which is still about 45 times the recommended daily intake of iodine for men and non-pregnant women. And then also our contrast agents from an IV preparation standpoint. Most of these agents contain as much as 50% iodine by weight. So when you think about in diagnostic procedures, utilization of usually 100 to 150 cc's, but can get up to about 400 to 500 cc's during coronary angiography. So these are not insignificant amounts of iodine that we could be potentially exposing our patients to. So how do we manage these patients after they have exposure to iodine? The clinical recommendation is that you should obtain or repeat thyroid function tests four to six weeks after exposure in at-risk individuals. So those would be patients who have baseline or existing thyroiditis, such as Hashimoto's, or who have no nodular thyroid disease or Graves. Earlier warranting could be warranted in patients, obviously, who develop acute symptoms or who have a history of iodine-induced thyroid dysfunction. There was a study who included 51 patients who were prescribed antithyroid drugs, such as methimazole or sodium perchlorate, in order to prevent IV contrast-induced hyperthyroidism. And they did see protection against TSH suppression when continued those drugs 14 days after coronary angiography. So you may consider prophylactic methimazole or perchlorate before administration of IV contrast during coronary angiography in at-risk individuals or in patients who have underlying cardiovascular disease where development of hyperthyroidism would be a particular concern. Amiodarone is responsible for multiple disruptions of normal thyroid hormone homeostasis that can lead to both hypo- and hyperthyroidism. Amiodarone's inhibition of peripheral deiodination of T4 to T3 can ultimately lead to hypothyroidism, and amiodarone can also cause direct thyrotoxicosis, leading to hyperthyroidism. There are two different types of amiodarone-induced thyrotoxicosis, type 1 being related to that iodine load that we discussed due to the Jod-Based-O phenomenon, and type 2 being amiodarone's direct cytotoxic effects on thyrocytes. Good news is that despite these multiple levels of interactions, over 70% of patients on chronic amiodarone therapy will remain euthyroid. However, there is a clinical consideration that before you prescribe or commit patient to chronic amiodarone therapy that you obtain baseline and regular TSH monitoring at a minimum of every six months for patients maintained on chronic therapy, and that includes a consideration for ongoing monitoring even after discontinuation up to a year due to the high lipophilicity of amiodarone and its long half-life. Of note, monitoring T3 and free T3 concentrations are less reliable indicators of hypothyroidism during amiodarone therapy due to that peripheral deiodination inhibition of amiodarone. Taking a further dive into amiodarone-induced hypothyroidism, or AIH, the overall incidence is reported at 5 to 20%. There's inconsistencies related to the reporting of incidence of hypothyroidism due to whether the studies counted only actual hormone-level diagnosis of hypothyroidism versus only counting them if they had clinical manifestations of amiodarone-induced hypothyroidism. Regardless, what is consistently true is that those patients who at baseline were euthyroid prior to amiodarone initiation had a lower incidence of development of AIH versus those that had baseline subclinical hypothyroidism. Other risk factors that place patients at an increased risk for development of AIH was older age, female sex at a ratio of 1.5 to 1 to males, if amiodarone was prescribed in iodine-sufficient regions, or if they had baseline subclinical hypothyroidism or Hashimoto's thyroiditis. It is debated whether or not a higher cumulative dose of amiodarone is related more so to hypo versus hyperthyroidism. It's also debated whether it's a dose-related issue versus a duration-related issue. As you can see, the typical onset of AIH is a very wide range, as early as two weeks after initiation all the way out to 39 months. Regardless, what is true is that the longer you are on amiodarone would mean that you have a higher cumulative dose and your patient would be at risk for some sort of amiodarone-induced thyroid dysfunction. As far as management of AIH, if amiodarone is discontinued, patients can have spontaneous remission versus they could need likely T4 supplementation if they have a clinical diagnosis of hypothyroidism. If your patient does develop antithyroid antibodies while on amiodarone, it is known that they have a much higher rate for development of hypothyroidism and that if you have elevations in TSH and antithyroid antibodies, you should immediately prescribe T4 supplementation instead of waiting for T4 levels to drop to levels requiring supplementation. Amiodarone-induced thyrotoxicosis, or AIT, occurs in a lower percentage of patients and less than 10% of patients who are prescribed amiodarone. And those at risk for development of AIT are those that habitat iodine-deficient regions, males in a ratio of 3 to 1 to females, or those who have baseline nodular disease or Graves' disease. As far as management of AIT, it really depends on whether it's diagnosis type 1 versus type 2. To differentiate between those two, most commonly an iodine update test can be utilized to differentiate. Type 1 AIT will have normal to elevated levels of iodine uptake versus type 2 will have minimal to no uptake of iodine because of the direct destructive thyroiditis effects of amiodarone. If you carry a diagnosis of type 1 AIT, antithyroid medications and symptomatic medication control is recommended with methimazole plus beta blockers plus or minus sodium perchlorate. If it is diagnosed of type 2 AIT, glucocorticoids are recommended as initiation and continued for 2 to 3 months at a dose or equivalent of prednisone 4 to 60 milligrams per day. If differentiation between type 1 and type 2 is not possible or it is unknown, then combination treatment can be started immediately with a combination of methimazole plus glucocorticoids. If your patient has a rapid response to that therapy, it is suggestive of AIT 2 and you could consider stopping your antithyroid medications. And then thyroidectomy is reserved for those patients who have refractory cases or who do not respond to the above therapy. Now amiodarone may need to be continued versus reintroduced to a particular subgroup of patients where it's been deemed important or there are no other therapeutic alternatives to amiodarone. Looking at a study of patients, of 170 patients who had a history of AIT who needed amiodarone reintroduced, AIT recurred in about 30% of patients while 44% remained euthyroid. Surprisingly, 26% of those patients with a history of AIT actually developed hypothyroidism. It's important to note that 65% of those patients were classified as type 1 AIT historically. Why that's important is that AIT type 1 has a 4 times higher rate of recurrence because it's related to underlying thyroid disease. So if your patient has a history of AIT type 1 and needs rechallenged or reintroduced amiodarone, ablative therapy, whether that be surgical or radioactive iodine, is actually recommended. If ablative therapy is not immediately available, then you can bridge your patient with antithyroid medications until ablative therapy or confirmation that recurrence is not occurring is possible. If your patient has a history of type 2 AIT and you need to rechallenge amiodarone, those patients can just be closely monitored with possibly a steroid taper after that initial two to three months of prednisone for their first occurrence of type 2 AIT. As far as monitoring, obviously when amiodarone is rechallenged in these at-risk patients for recurrence of AIT, increased monitoring at a rate of every six weeks is what's recommended. We are now going to move to discussing medications that interfere with thyroid hormone transport or metabolism. As far as medications that alter thyroid hormone transport, over 99% of serum T4 and T3 are bound to one of three transport proteins, the most important being thyroxine-binding globulin or TBG. TBG binds over 70% of serum T4 and an even higher fraction of T3. So medications that lead to an increase in circulating TBG lead to increased total T4 by increasing binding to TBG. This could potentially in at-risk populations lead to a decrease in circulating free T4 and then subsequently leading to increases in your TSH. On the other end of the spectrum, medications that reduce circulating TBG lead to a decrease in total T4 concentrations and could potentially lead to an increase in circulating free T4 and a decrease in TSH. Medications responsible for increases in circulating TBG include oral estrogen and your selective estrogen receptor modulators, this is a dose-dependent interaction, as well as it has been reported where increases in TBG have been linked to methadone, heroin, and anti-cancer medications. Reductions in TBG are linked to androgens as well as glucocorticoids and niacin. The most common and clinically relevant interaction leading to downstream effects have to do solely with the sex hormones of estrogen or androgen therapy. So how do we manage these interactions with the sex hormones being the most clinically significant? Well in patients who have baseline normal thyroid function, their compensation remains intact. Therefore, in response to the increased binding of T4 to TBG, we can stimulate T4 synthesis in order to maintain normal circulating free T4 levels. Where this does become an issue, though, is in patients who are baseline hypothyroid requiring T4 supplementation, there will need to be dose adjustment according to the sex hormone prescription, meaning that patients who are prescribed oral estrogen will require a dose increase in their T4, whereas prescription of androgen therapy will require a dose reduction in T4 because of the decreases in TBG. Further clinical considerations is that thyroid function should be assessed at steady state from starting, stopping, or dose adjustment of sex hormone therapy. So usually within six to eight weeks. And T4 doses should be adjusted according to those thyroid function tests. Further considerations for estrogen is that it is recommended to switch from oral to transdermal route of estrogen as the transdermal route does not undergo first pass metabolism and you will maintain consistent levels of circulating TBG. Moving on to thyroid hormone metabolism. So both T4 and T3 undergo deiodination, but they also undergo glucuronidation and sulfation. Glucuronidation specifically renders the hormone more hydrophilic and therefore is more readily excreted into the bile. Therefore, medications that enhance that enzymatic glucuronidation lead to decreases in serum T4 and T3 concentrations. Those medications include rifampin and CNS acting drugs such as carbamazepine, phenytoin, and barbiturates. This is a clinically insignificant reaction for most patients who have a functional and normal pituitary thyroid. However, in patients who are baseline hypothyroid that require supplementation, there needs to be considerations for a dose increase in T4 if patients are started on one of these enzyme inducing medications. Furthermore, if this enzyme inducing medication is discontinued, then hyperthyroidism may occur if that T4 dose is not decreased or adjusted appropriately. Clinical consideration for these patients and maintained on these medications is that serum TSH should be monitored at steady state, whether that be at initiation or discontinuation of these interacting medications. So usually between two to six weeks. I'm now going to be discussing briefly medications that disrupt the hypothalamic pituitary control of thyroid hormone synthesis. Why I said I'm just going to briefly mention these medications is that the medications listed on this screen do have direct thyrotropin or TSH suppressive effects. However, they do so without altering serum T4 or free T4 levels. Therefore, this is a subclinical transient effect of these medications. And a conservative clinical consideration is that you can repeat thyroid tests three to six months after exposure or completion of therapy to the drugs listed, including glucocorticoids, octreotide, dobutamine, and dopamine. I now want to highlight those medications that interfere with thyroid function test interpretations. Now medications listed here, the first one being biotin. Biotin, not very common, but biotin itself does have a direct interaction with the immunoassay for thyroid function tests that can lead to false elevations in free T4 and T3 and a suppression of TSH. So it mimics a condition of primary hyperthyroidism. However, you can avoid this interaction by stopping biotin and repeating tests two days after discontinuation. And noxaparin and heparin, both of those agents stimulate lipoprotein lipase that can generate free fatty acids. So in these patients who have a serum triglyceride concentration over 180 who are maintained on these therapies, it can cause elevations falsely in free T4 and T3. However, to avoid this, you can discontinue these agents and recheck thyroid levels within 24 hours. Now probably the most common thought about interaction of medication are those direct interactions that prevent GI absorption of exogenous thyroid hormone supplementation that we're now going to discuss. The most common form of thyroid hormone supplementation is synthetic T4 in the form of oral levothyroxine. Oral levothyroxine requires an acid milieu for dissolution before being transported to the small bowel for absorption where 80% of the dose is absorbed in the jejunum and ileum two to four hours after administration in the fasting state. Metabolites also undergo enterohepatic recycling. It's not surprising that with those strict stipulations for ideal absorption that there are medications that could impair GI absorption. The first two, ferrous sulfate and calcium supplementation and their various salt forms, if administered in the oral route, can bind and decrease levothyroxine absorption by at least 20%. So it's recommended to separate these agents by at least four hours. It is worth noting that multivitamins have not been specifically studied as an interacting agent to levothyroxine, but they do contain substantial amounts of both iron and calcium, depending on the formulation, that they too should be separated by at least four hours. Aluminum hydroxide, sucraphate, and bile acid sequestrants are all considered binding agents that can decrease gut absorption of levothyroxine as well. So they too are recommended to separate by at least four hours. Riloxifene, due to its mechanism, can decrease the amount of GI epithelial cell uptake of levothyroxine, so it's recommended to separate by two to four hours if possible. Protein pump inhibitors, when maintained chronically for patients, it's debated whether or not they truly have an effect on hormone level absorption. It would make sense because levothyroxine requires a potent acid milieu for dissolution that they could interact, but there's been conflicting reports on that. There has been one observational study looking at 24 patients that were switched from levothyroxine tablets to suspension and monitored for TSH levels and found that patients who were maintained on the suspension maintained normal to lower levels of TSH in comparison to the tablets. So there is a proposed consideration that if you have the availability of a levothyroxine suspension to switch patients from tablets to suspensions if they're maintained on a PPI. It is worth noting, though, that levothyroxine suspension is not routinely commercially available and is more expensive than the tablets. In addition to separating out levothyroxine from interacting medications, it's important to administer in a fasting state, which is defined as 60 minutes before breakfast or at bedtime three or more hours after the evening meal for optimal absorption. Obviously, these strict administration instructions need to be balanced with the ease of medication compliance for patients, where consistency in administration should be most importantly emphasized. As far as ICU-specific considerations for patients who are maintained on continuous enteral nutrition, for patients who are admitted to the ICU and are on continuous enteral nutrition for less than seven days, there are no suggestions regarding levothyroxine dose adjustment or alterations in administration. However, in those patients who are going to be maintained for over a week on continuous enteral nutrition, it is recommended at that point to hold tube feeds one hour pre and post levothyroxine dose administration, with a further consideration to monitor thyroid function weekly and adjust dosing as indicated. At this point, we have likely discussed the pitfalls related to interpretation of thyroid function tests during acute illness. However, the administration alterations of tube feeds need to be weighed with optimal nutrition as well. We've talked mostly about medication effects on the thyroid, but it is also worth noting that thyroid function itself can alter medication metabolism and kinetics. Both hyper- and hypothyroidism can affect the pharmacokinetics, efficacy, and frequency of adverse effects related to medications. Know where the agents are listed below. With warfarin requiring lower doses in hyperthyroid patients, statins carrying increased risk of myopathy in the presence of hypothyroidism, and both propranolol and digoxin having differences in serum concentrations related to hyperthyroidism thought to do with increased rate of clearance, and theophylline having an enhanced metabolism in hyperthyroid patients requiring increased doses. It is also worth noting that as we correct underlying thyroid dysfunction, that dose adjustments of these agents are imperative as well. In conclusion, the knowledge and awareness of these common medication culprits for thyroid dysfunction is key for timely diagnosis and management of patient symptoms. Thyroid function monitoring is imperative in identifying these drug-thyroid interactions, whether that be symptom-driven testing or identification of high-risk populations maintained on these medications that require increased monitoring. Optimization of T4 supplementation occurs in the fasting state and separated by interacting agents by at least four hours. And also keep in mind that disruptive thyroid function can also have an effect on medications just as medications can disrupt thyroid function itself. Thank you for listening, and I have my email listed on this slide if you want to reach out with any questions. Thank you.

medications

thyroid function

interactions

hypothyroidism

hyperthyroidism

pharmacologic therapy