Thyroid Disorders:
A Review of Drug Therapy
Joanne M. Yasuda, PharmD
Dr. Yasuda is Assistant Professor of Pharmacy Practice at Western University of Health Sciences in Pomona, CA.
Thyroid disorder is a general term representing several different diseases involving thyroid hormones and the thyroid
gland.1 Thyroid disorders are commonly separated into two major categories, hyperthyroidism and hypothyroidism, depending on whether serum thyroid hormone levels are increased or decreased, respectively. This article will review the two most common thyroid disorders, Graves’ disease and Hashimoto’s
thyroiditis, with a focus on the associated pharmacotherapy.
The prevalence and incidence of thyroid disorders is influenced primarily by the sex and age of the patient population
(Table 1).2,3 Thyroid disorders are more common in women than men, and in older adults compared with younger age groups.
The prevalence of unsuspected overt hyperthyroidism and hypothyroidism are both estimated to be 0.6% or less in women, based on several epidemiologic
studies.2 The prevalence rates for men are much lower. The association with sex and age is more apparent when the prevalence rate is reported for different age groups. For overt hyperthyroidism, the prevalence rate is 1.4% for women aged 60 or older and 0.45% for women aged 40 to 60. For men more than 60 years of age, the prevalence rate of hyperthyroidism is estimated to be
0.13%
.
A similar pattern is observed for the prevalence rate of hypothyroidism. The prevalence rate of overt hypothyroidism is 2% for women aged 70 to 80, 1.4% for all women 60 years and older, and 0.5% for women aged 40 to 60. In comparison, the prevalence rate of overt hypothyroidism is 0.8% for men 60 years and older. The estimated annual incidence of hyperthyroidism for women ranges from 0.36 to 0.47 per 1,000 women, and for men ranges from 0.087 to 0.101 per 1,000
men.2 In terms of hypothyroidism, the estimated incidence is 2.4 per 1,000 women each year. Overt thyroid dysfunction is uncommon in women less than 40 years of age and in men less than
60 years of age.
Table 1. Prevalence of Thyroid
Disorders
The regulation of endogenous thyroid hormones and their effects on the human body are complex and not yet fully
elucidated.4,5 It is known that the regulation of thyroid hormones operates via a negative feedback system. Both triiodothyronine
(T3) and thyroxine (T4) are secreted by the thyroid gland. However, about 80% of the circulating
T3 originated as T4, which was converted by the enzyme thyroxine
5¢-deiodinase peripherally. The more active T3 interacts with thyroid hormone receptors throughout the body to produce a vast number of physiologic effects.
The secretion of pituitary thyrotropin, also known as thyroid- stimulating hormone
(TSH), is regulated by a negative feedback system dependent on the serum concentration of the thyroid hormones.4-7 Low levels of circulating thyroid hormones
(T3 and T4) stimulate the hypothalamus to release
thyrotropin-releasing hormone (TRH). TRH stimulates the release of thyrotropin
(TSH) from the pituitary gland, which in turn stimulates the thyroid gland to increase hormone
(T3 and T4) synthesis and secretion. High levels of circulating thyroid hormones inhibit the release of thyrotropin
(TSH) from the pituitary. Serum thyrotropin (TSH) levels are a key laboratory measure of thyroid function.
The thyroid hormones have many different complex effects throughout the body, including known effects on the cardiovascular system, lipoprotein metabolism, and
bone.1-7 The large number of affected systems is demonstrated by the variety of clinical manifestations that develop with abnormal levels of circulating thyroid hormones, including effects on temperature regulation, rates of metabolism, skeletal muscle, and heart rate and function. In addition, elevated levels of thyroid hormones are associated with an increased risk for atrial fibrillation and osteoporosis. And reduced levels of circulating thyroid hormones are associated with hypercholesterolemia. The nonspecific clinical presentation of thyroid disorders has prompted evaluations of the risks and benefits of screening for thyroid disease.
The diagnosis of thyroid disease is particularly challenging. Patients often present with vague, general clinical manifestations; in particular, the elderly may not associate the signs and symptoms with a disease process and bring them to the attention of their primary care
provider.3,8-10 It has been suggested that patients should be screened for thyroid disorders with laboratory tests during routine clinic visits.
The primary benefit of routine screening with thyroid function tests is relief of symptoms and improved quality of
life.3,8-10 Another benefit is the potential abatement of progression to more serious consequences, such as atrial fibrillation and osteoporosis (in the case of subclinical hyperthyroidism) and hyperlipidemia (in the case of subclinical hypothyroidism). However, the issue of routine screening is controversial because, given the overall low incidence of thyroid disorders, the cost-effectiveness has not been clearly proven. And while screening will reveal patients with subclinical thyroid disorders, randomized clinical trials have been inconclusive regarding the benefits of treating asymptomatic patients.
The American College of Physicians states it is “reasonable to screen women older than 50 years of age for unsuspected but symptomatic thyroid disease” with a sensitive thyrotropin
(TSH)
test.3,8 Neonates are routinely screened for congenital hypothyroidism, which undetected can lead to mental
retardation.2 And pregnant women may be screened for thyroid disease to protect the outcome of the pregnancy and health of the fetus and neonate from the ill effects of uncontrolled hyperthyroidism (hypothyroidism during pregnancy is uncommon). Despite improved estimates of risk for other patient populations, the evidence that other groups benefit from early detection and treatment is still unclear.
Hyperthyroidism represents a myriad of thyroid disorders characterized by elevated levels of circulating thyroid
hormones.1,11-14 The most common cause of hyperthyroidism is Graves’ disease, a systemic autoimmune process in which the patient’s body is producing autoantibodies against the thyrotropin
(TSH)
receptor.11 The autoantibodies activate the thyrotropin (TSH) receptor and stimulate the uncontrolled production and release of
T4 and T3. Other causes of hyperthyroidism include toxic nodular (multiple nodules, single toxic adenoma) goiter (diffuse enlargement of the thyroid gland) and
thyroiditis.
The majority of patients with elevated thyroid hormones present with one or more of the following: resting
tachycardia, palpitations, exercise intolerance, muscle weakness, cramping, fatigue, irregular menstrual cycles (women), impotence, weight loss (up to an average of 15% less than normal), nervousness, exertional
dyspnea, heat intolerance, irritability, tremor, sleep disturbance, increased perspiration, increased frequency of bowel movements, change in appetite, anxiety, hair loss, exophthalmos (protrusion of the eyeballs), and
goiter.11-14 Additional tissue effects include accelerated metabolism, suppressed serum thyrotropin
(TSH), low serum cholesterol, increased bone turnover and reduced bone density with an increased risk of osteoporosis and fracture (particularly in postmenopausal women), and
ophthalmopathy. Graves’ ophthalmopathy is characterized by excess tearing and photophobia in milder cases, and
diplopia, eye pain, and decreased visual acuity in more severe
cases.1,15
Elevated serum thyroid hormones reduce cholesterol levels, likely caused by interference with the cholesterol metabolism and excretion pathway at several different
points.5 This cholesterol-lowering effect has led investigators to search for thyroid hormone analogues that would selectively decrease cholesterol levels without the associated systemic effects of thyroid hormone, without success to date.
Regardless of the presence of signs and symptoms, the classic presentation of Graves’ disease is a diffusely large thyroid gland,
exophthalmos, and confirming thyroid function
tests.7 An elevated T4 serum level combined with a low to undetectable (depending on the sensitivity of the
radioassay) thyrotropin (TSH) level are diagnostic of overt
hyperthyroidism.3,6-8 In addition, the vast majority of patients with Graves’ disease will have significant titers of thyroid
autoantibodies; however, the specific testing for autoantibodies is not routinely recommended.
Untreated, patients with elevated thyroid hormone levels are at risk for reduced quality of life, atrial fibrillation, and osteoporosis. There are currently three major treatment modalities for Graves’ disease: antithyroid drug therapy, radioactive iodine, and surgical resection of the thyroid gland.
The goal of treatment for hyperthyroidism is resolution of signs and symptoms, normalization of serum thyroid hormone concentrations, remission of disease, and prevention or abatement of potential long-term consequences such as atrial fibrillation and osteoporosis.1,11-13 The three treatment options are antithyroid drugs (ie, methimazole, and propylthiouracil [PTU]), radioiodine, and surgery.
The first therapy available for hyperthyroidism was
iodide.11-13 Iodine-containing agents (eg, potassium iodide, Lugol’s solution) inhibit thyroid hormone release for a few weeks and may be used in preparation for thyroid surgery or for the treatment of thyroid storm; but they are not used routinely for the long-term management of hyperthyroidism. In preparation for thyroid surgery, iodine-containing agents decrease the vascularity and increase the firmness of the gland. The usual dose of Lugol’s solution 8 mg/drop (5% iodine and 10% potassium iodide) is 5 to 10 drops orally three times daily for 10 to 14 days prior to surgery. Additionally, potassium
perchlorate, lithium, and corticosteroids decrease thyroid hormone concentrations, but they are rarely prescribed for the routine treatment of hyperthyroidism. Lithium’s antithyroid action is also of short duration, and its narrow therapeutic window requires extensive drug monitoring.
The primary antithyroid drugs used in the United States to achieve remission of thyroid disease are methimazole
(Tapazole) and propylthiouracil (PTU) of the thionamide
class.1,11-16 Antithyroid drugs are also used to prepare patients for therapy with radioactive iodine or surgery. Both drugs are actively trapped in the thyroid gland where they inhibit the synthesis of
T4 and T3. Both drugs also decrease the concentration of thyrotropin
(TSH)-receptor autoantibodies and increase suppressor T-cell activity, indicating possible immunosuppressive activity. Propylthiouracil also inhibits the peripheral conversion of
T4 to T3.
The initial dose of methimazole is generally 10 to 30 mg orally once daily, and the initial dose of propylthiouracil is 100 mg orally three times daily. Most patients achieve euthyroidism within 6 to 12 weeks; the actual rate depends on the severity of the disease, the size of the thyroid gland, and the antithyroid drug dosing regimen. The dose may be reduced after 4 to 6 weeks as the patient improves. Doses may be adjusted every 4 to 6 weeks thereafter until maintenance doses are attained: methimazole 5 to 15 mg daily or propylthiouracil 50 to 150 mg daily. The maximum methimazole dose is 120 mg/day, and the maximum propylthiouracil dose is 1,200 mg/day.
Thyroid function tests, in addition to observation of resolution of signs and symptoms
(eg, weight gain), are used to monitor drug
therapy.1,11-13 Some symptoms, such as muscle-related complaints, may continue for months despite normalization of thyroid function tests.5 Thyroid function tests should be monitored at each clinic visit every 4 to 6 weeks. During therapy, the serum
T4 and T3 levels should normalize; however, the serum thyrotropin
(TSH) levels may remain suppressed for several months longer and, therefore, should not be used as a sole laboratory monitoring parameter. The patient should also be monitored for adverse drug effects.
Relatively minor adverse effects for both methimazole and propylthiouracil include urticarial rash and pruritus, and both of these effects may resolve with continued therapy; if the rash or pruritus does not resolve, the patient may be switched to the other drug, although cross-reactivity is
possible.11,16,17 Other adverse effects include fever, arthralgias, joint pain, gastrointestinal intolerance, and abnormal taste.
The incidence of serious adverse effects with methimazole or propylthiouracil is estimated to be 0.2% to
0.5%.11,16,17 The most serious adverse effect is idiosyncratic agranulocytosis. The onset may be acute, and patients more than 40 years of age appear to be at greater risk; however, definitive risk factors have not been identified. It also appears to be a dose-related effect for methimazole, but not propylthiouracil. Patients should be counseled to discontinue the medication and notify their physician immediately if they experience a fever, sore throat, or other symptoms of infection.
Other serious but rare adverse effects include cholestatic jaundice (especially methimazole), hepatitis (especially propylthiouracil), lupus-like syndrome, vasculitis, glomerulonephritis, polyarthritis, thrombocytopenia, and aplastic
anemia.11,16,17 Propylthiouracil may cause a transient increase in liver transaminases, which should be monitored but does not necessarily require discontinuation of therapy. Because of the serious nature of these adverse effects, patients receiving thionamide drugs require close follow-up. Patients should be counseled to report jaundice, malaise, or dark urine.
Propylthiouracil may cause hypoprothrombinemia, therefore concomitant warfarin therapy may lead to bleeding. Although methimazole and propylthiouracil both cross the placenta, these drugs have been used during pregnancy to treat hyperthyroidism. These drugs should also be used cautiously in the nursing mother.
Antithyroid drug therapy is continued for 6 to 24 months or longer, until the patient is asymptomatic and
euthyroid. Longer treatment (eg, 24 months) with antithyroid drugs may favor long-term remission of Graves’ disease; however, the factors affecting long-term remission are not fully elucidated. After therapy for hyperthyroidism, some patients develop hypothyroidism; these patients will require either temporary or lifelong thyroid hormone replacement therapy.
Pharmacists can assist their patients first by helping them recognize the signs and symptoms of hyperthyroidism and refer them to their primary care physician or endocrinologist, and, second, by providing pharmaceutical care for the patient receiving antithyroid drugs. Patients receiving either methimazole or propylthiouracil should receive instructions on proper administration, potential adverse effects (especially agranulocytosis and hepatitis), and the importance of adherence to therapy. Propylthiouracil should be taken with food or milk to minimize stomach upset.
The most common treatment modality for hyperthyroidism used in the United States is radioactive
iodine.1 Radioactive iodine, administered via several different dosing schedules, destroys thyroid tissue. The goal of therapy is to affect enough tissue to achieve euthyroidism; however, hypothyroidism and the requirement for temporary or lifelong thyroid hormone replacement therapy may result. Radioactive iodine therapy is considered safe except during pregnancy or lactation, in which cases it is contraindicated. Some patients, particularly the elderly, may be treated with antithyroid drugs prior to radioactive iodine therapy to minimize the risk of exacerbating the hyperthyroidism.
Subtotal thyroidectomy is uncommon today, and primarily reserved for patients who have a particularly large goiter, or those who refuse or are unable to tolerate antithyroid drugs or radioactive iodine
therapy.1 Surgical complications include injury to the recurrent laryngeal nerve, recurrent hyperthyroidism, hypoparathyroidism, hypothyroidism, and all risks inherent to surgical procedures.
Nuclear Scan
of Abnormal Thyroid
Some patients may benefit from symptom relief with adjunctive drug
therapy.1,11-13,18 Many of the clinical manifestations of hyperthyroidism are caused by activation of beta-adrenergic receptors (eg, tachycardia, palpitations, tremor, anxiety). Therefore, beta blockers (eg, propranolol, metoprolol, atenolol) have been prescribed to ameliorate these clinical manifestations. The beta blockers do not alter the course of disease; they only provide symptom relief. Alternatively, calcium channel blockers have also been used in patients in whom beta blockers are contraindicated (eg, patients with
asthma).1
Thyroid storm is a rare, life-threatening manifestation of hyperthyroidism, and treatment should be started immediately (eg, propylthiouracil, potassium iodide, corticosteroids, beta blockers, other supportive care) in the intensive care
unit.1 It is characterized by extreme signs and symptoms of hyperthyroidism, fever, and altered mental status. Thyroid storm may be precipitated by concurrent illness (eg, stress, infection) or injury, withdrawal of antithyroid drug therapy, or following radioactive iodine therapy.
Hypothyroidism represents a group of disorders characterized by low levels of circulating thyroid hormones, and the most common causes are primary gland failure as a result of chronic autoimmune Hashimoto’s
thyroiditis, radioactive iodine therapy, or surgical resection of the thyroid
gland.1
Clinically, patients present with complaints of one or more of the following: fatigue, weakness, cold intolerance, dry skin, hoarseness, constipation, weight gain, joint pain, muscle cramps, mental impairment, depression, and menstrual
disturbances.1,4,5 Upon examination, the patient may also have
bradycardia, prolonged relaxation of deep-tendon reflexes, and
hypercholesterolemia. Patients with low thyroid hormone levels have increased serum thyrotropin
(TSH) levels because of the negative feedback relationship between the different
hormones.7 Therefore, the results of the thyroid function tests for overt hypothyroidism are characterized by a low
T4 serum level and an elevated thyrotropin (TSH) serum
level.3,7,8
The clinical presentation, particularly in elderly patients, may be subtle; therefore, routine screening of thyroid function tests is generally recommended for women more than 50 years of
age.1,3,8
The goal of therapy is clinical and biochemical euthyroidism and prevention of long-term consequences as a result of
hypercholesterolemia.1 Thyroid hormones for replacement therapy are available in several different forms
(Table 2).
Desiccated thyroid (eg, Armour Thyroid) contains natural
T4 and T3 derived from animal (hog, beef, or sheep) thyroid
glands.1,19 A recent study reported improved neuropsychological function for patients receiving the combination product compared to
levothyroxine.20 The concern with thyroid extracts is the potential variance in potency, and the excess of
T3 in these extracts, which may cause adverse cardiovascular effects. The animal protein–derived product may cause allergic reactions in some patients. The usual starting dose is 30 mg daily. The dose is titrated with increments of 15 mg every 2 to 3 weeks until a maintenance dose of 60 to 120 mg/day is achieved.
Table 2. Equipotent Doses of Thyroid Hormones for Replacement Therapy
The combination of T4 and T3 is also available as the synthetic product liotrix
(Thyrolar, Euthyroid).19 The synthetic combination offers T4 and
T3 in a fixed ratio of 4:1; allergenicity and uniform potency are not an issue. The combination products are associated with excessive
T3 serum levels for several hours after each dose, which may cause adverse cardiac effects. The initial dose is 30 mg daily. Liotrix may be increased by 15-mg increments every 2 to 3 weeks until the patient is
euthyroid; the maintenance dose is 60 to 120 mg daily.
Liothyronine (Cytomel, others) is synthetic T3; therefore, it has uniform potency and is free of
antigenicity.1,19 Liothyronine has a faster onset and a shorter duration of action compared with
levothyroxine. During the dosing interval, T3 serum levels fluctuate widely and may lead to cardiac adverse effects. In thyroid cancer patients, liothyronine has been used for short-course therapy prior to radioactive iodine; however, it is not used as first-line therapy for hypothyroidism because it appears to be associated with a higher incidence of iatrogenic hyperthyroidism compared with
levothyroxine.1 The initial dose is 25 mcg/ day, titrated by 12.5 to 25 mcg every 1 to 2 weeks until the patient is
euthyroid; the maintenance dose is generally 25 to 75 mcg/day. Dividing the daily dose into two or three doses may minimize the wide fluctuations in serum
T3 levels.
Levothyroxine (Synthroid, others) is synthetic T4 hormone.1,19 Levothyroxine is converted to
T3 naturally by the body, which allows for physiologic regulation of the hormone. Levothyroxine is generally considered the drug of first choice for thyroid hormone replacement because of its consistent potency, lack of
antigenicity, natural replacement of T3, and prolonged duration of action. It does, however, have a relatively slow onset of action of 3 to 5 days.
Bioequivalence of the various levothyroxine products remains
controversial.1,19,21 At one time, it was recommended that all patients receive the brand Synthroid because of unknown therapeutic equivalency of other levothyroxine products. However, at least one clinical study has demonstrated that Synthroid, Levoxyl, and two generic formulations of levothyroxine are bioequivalent based on FDA
standards.21 Whether Synthroid or a different product is prescribed or dispensed initially, brand interchange is not recommended once a patient is stabilized on a product because of the narrow therapeutic window of thyroid hormone therapy.
The usual levothyroxine starting dose is 50 mcg daily (or 1.6 to 1.7 mcg/kg per
day).1,19 Pregnant women may require a 20% to 50% increase in dosage to achieve normal thyrotropin
(TSH) serum levels. Also, infants may require higher doses (10 to 15 mcg/kg per day). Patients should be monitored every 4 to 8 weeks and the dose titrated by 50-mcg increments until resolution of symptoms and normalization of thyroid function tests. Inadequate dosing will be reflected by continued signs and symptoms of hypothyroidism, a low
T4 level, and an elevated thyrotropin (TSH) level during periodic
evaluation.19 If poor patient compliance is not suspected, then levothyroxine doses are increased and the patient reevaluated at the next clinic visit in 4 to 8 weeks. Elderly patients or patients with cardiac disease should be initiated on low doses (25 to 50 mcg daily) and titrated more slowly. Patients should note improvement in some symptoms
(eg, weight, palpitations) within 2 to 3 weeks, although other symptoms
(eg, hoarseness, skin and hair changes) will take longer to resolve. The maintenance dose typically ranges from 110 to 120 mcg/day. Once the patient is
euthyroid, the frequency of thyroid function test monitoring may be reduced to every 6 to 12 months. In general, many patients remain stabilized on the same dose for years. However, physiologic changes over time or changes in concomitant drug therapy may lead to changes in levothyroxine dose.
Excessive levothyroxine therapy will lead to clinical manifestations of hypothyroidism (eg, weight loss, tremor, irritability, nervousness, excessive perspiration, heat intolerance); therefore, thyroid function tests should be periodically monitored even after the patient has been stabilized on a maintenance
dose.1,19 More serious adverse effects associated with excessive levothyroxine therapy include chest pain and tachycardia, and these patients should have their doses held for a week and then therapy restarted at a lower dose. Hypothyroidism is a known risk factor for osteoporosis, and long-term, excessive levothyroxine therapy may also be associated with decreased bone mineral density. Although the actual risk of osteoporosis is not proven, excessive levothyroxine doses should be
avoided.19,22
Patients receiving levothyroxine for the first time should be counseled to know the specific brand they will be receiving to maintain consistency with future refills. Levothyroxine should be taken orally once daily. Patients should be counseled on the time frame for symptom relief, and they should understand that thyroid hormone replacement therapy is usually lifelong and requires periodic laboratory tests. In addition, patients should learn the common symptoms of hyperthyroidism (eg, sweating, nervousness, tremors, diarrhea) to understand when their levothyroxine dose may need to be adjusted and to monitor for improvement.
Myxedema coma is a rare consequence of untreated, longstanding
hypothyroidism.1 It is a life-threatening condition characterized by coma, hypothermia, bradycardia, respiratory failure, and cardiovascular collapse. Patients should be treated immediately in the intensive care unit with intravenous levothyroxine, corticosteroids, and other supportive measures.
It is not surprising that many drugs can have an effect on the thyroid and thyroid hormones, and therefore have an effect on the results of thyroid function
tests.23,24 The prevalent role of thyroid hormones throughout the human body lends itself to a multitude of potential drug interactions.
Drugs that decrease thyrotropin (TSH) secretion and thereby decrease TSH serum concentrations include dopamine (at doses > 1 mcg/kg per minute), short-course corticosteroids (eg, hydrocortisone doses
> 100 mg/day), and octreotide (doses > 100
mcg/day).23
Certain medications are known to decrease thyroid hormone production or
secretion.23,24 Methimazole and propylthiouracil are used therapeutically to treat hyperthyroidism, as described previously. Long-term therapy with lithium, which disrupts thyroid hormone synthesis and secretion, results in goiter in up to 50% and overt hypothyroidism in up to 20% of patients. Drugs that contain iodine
(eg, inorganic iodide, amiodarone, aminoglutethimide, radiographic contrast agents) decrease the conversion of
T4 and T3; whether the effect is persistent or temporary depends on the patient’s clinical thyroid status.
Drugs containing iodine can also cause hyperthyroidism in euthyroid patients with certain thyroid disorders
(eg, multinodular goiter, hyperfunctioning thyroid
adenoma).23,24 The antiarrhythmic amiodarone may cause thyroid dysfunction via several different mechanisms: (1) it contains iodine; (2) it can cause
thyroiditis; (3) it may decrease conversion of T4 to T3; and (4) it may inhibit the activity of
T3. Most patients treated with amiodarone remain clinically euthyroid despite altered thyroid hormone levels, although 2% to 6% of patients experience either hyperthyroidism or hypothyroidism.
Cholestyramine, colestipol, and aluminum hydroxide bind levothyroxine and decrease its gastrointestinal
absorption.23 Patients taking concomitant ferrous sulfate and sucralfate may also experience decreased absorption of levothyroxine; the clinical significance of this drug-drug interaction varies among patients. However, patients taking any of these drugs should be educated to take levothyroxine at least 2 hours before or 6 hours after one of these agents. Even with dose separation, thyroid hormone levels may still be lowered secondary to enterohepatic circulation of
thyroxine.
Some drugs affect the serum transport of T4 and
T3 by changing the concentrations or affinity of thyroxine-binding globulin
(TBG), the most important of the three primary transport proteins for the thyroid
hormones.23 Estrogen (endogenous and exogenous), tamoxifen, methadone,
mitotane, and fluorouracil increase TBG concentrations. In most cases, the free (biologically active)
T4 and T3 concentrations are unchanged; however, pregnant women with hypothyroidism may require an increase in levothyroxine dose. Drugs that decrease serum TBG concentrations include
corticosteroids, slow-release nicotinic acid, and anabolic steroids; most patients remain clinically
euthyroid. Furosemide (intravenous dose > 80 mg) and salicylates (doses > 2 grams/day) have been shown to inhibit binding of the thyroid hormones to TBG to cause a transient increase in serum free
T4 concentrations.
Several drugs have complex effects on the metabolism of
T4 and T3.23 Phenobarbital and rifampin induce hepatic enzyme activity and increase
T4 and T3 metabolism. Phenytoin and carbamazepine also increase thyroid hormone metabolism; they may also cause a decrease in serum
T4 and T3 concentrations. The vast majority of people taking these drugs experience alteration in thyroid function tests while remaining clinically
euthyroid; however, treated hypothyroid patients taking these drugs may require increased levothyroxine doses.
The enzyme thyroxine 5¢-deiodinase, which converts T4 to
T3, is also a target for drugs that can disrupt thyroid hormone
concentrations.23 As noted previously, amiodarone inhibits this enzyme. Beta blockers and corticosteroids can also inhibit thyroxine
5¢-deiodinase. Most people are able to compensate for these effects and remain clinically
euthyroid.
The degree to which these drugs affect the patient clinically depends on the individual patient’s pituitary-thyroid function and their ability to compensate for the changes. In almost all cases, the patient experiences alterations in thyroid function test results without developing clinically relevant disease. The key is to recognize that patients who are receiving these drugs and who develop signs or symptoms of thyroid disease may have an etiology that can be addressed
(ie, drug discontinuation). It is also important to know which drugs affect the results of laboratory thyroid tests for appropriate interpretation.
Patients often have more questions or concerns than can be adequately addressed during a clinic or pharmacy
visit.25 Thyroid disorders involve complex pathophysiology, several therapeutic options with attendant benefits and risks, and a multitude of sometimes vague signs and symptoms whose interrelationship is confusing. The Thyroid Foundation of America and the International Thyroid Federation were formed to provide education and emotional support to patients with thyroid disorders. The
Thyroid Foundation of
America can be contacted at 800-832-8321 (www.tsh.org); the Thyroid Society for Education and Research can be contacted at 800-849-7643
(www.the-thyroid-society.org).
Thyroid disorders are complex endocrinologic diseases that primarily affect elderly women. The clinical manifestations are widespread and often subtle in presentation. The community pharmacist may play a key role in assisting the patient to recognize that the compilation of certain signs and symptoms may actually be part of a treatable disease state as opposed to the normal aging process. For patients prescribed methimazole or propylthiouracil for hyperthyroidism, patient counseling should include a description and plan for recognizing agranulocytosis and hepatitis. For patients receiving pharmacotherapy for hypothyroidism, the pharmacist is likely providing lifetime pharmaceutical care.
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2. Wang C, Crapo LM. The epidemiology of thyroid disease and implications for screening. Endocrinol Metab Clin North Am 1997: 26:189-218.
3. American College of Physicians. Clinical guideline, Part 2: Screening for thyroid disease: An update. Ann Intern Med 1998: 129:144-158.
4. Brent GA. The molecular basis of thyroid hormone action. New Engl J Med 1994; 331:847-853.
5. Motomura K, Brent GA. Mechanisms of thyroid hormone action: Implications for the clinical manifestation of
thyrotoxicosis. Endocrinol Metab Clin North Am 1998; 27:1-23.
6. Dabon Almirante CL, Surks ML. Clinical and laboratory diagnosis of
thyrotoxicosis. Endocrinol Metab Clin North Am 1998; 27:25-35.
7. Surks ML, Chopra IJ, Mariash CN, Nicoloff JT, Solomon DH. American Thyroid Association guidelines for use of laboratory tests in thyroid disorders. JAMA 1990; 263:1529-1532.
8. American College of Physicians. Clinical guideline, Part 1: Screening for thyroid disease. Ann Intern Med 1998;129:141-143.
9. Danese MD, Powe NR, Sawin CT, Ladenson PW. Screening for mild thyroid failure at the periodic health examination. JAMA 1996;276:285-292.
10. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med
2000;160:526-534.
11. Franklyn JA. The management of hyperthyroidism. New Engl J Med 1994; 330:1731-1738.
12. Gittoes NJL, Franklyn JA. Hyperthyroidism: Current treatment guidelines. Drugs 1998;55:543-553.
13. Stockigt JR, Topliss DJ. Hyperthyroidism: Current drug therapy. Drugs 1989; 37:375-381.
14. McIver B, Morris JC. The pathogenesis of Graves’ disease. Endocrinol Metab Clin North Am 1998; 27:73-89.
15. Gladstone GJ. Ophthalmologic aspects of thyroid- related
orbitopathy. Endocrinol Metab Clin North Am 1998; 27:91-100.
16. Cooper DS. Antithyroid drugs for the treatment of hyperthyroidism caused by Graves’ disease. Endocrinol Metab Clin North Am 1998; 27:225-247.
17. Werner MC, Romaldini JH, Bromberg N, Werner RS, Farah CS. Adverse effects related to thionamide drugs and their dose regimen. Amer J Med Sci 1989; 297:216-219.
18. Geffner DL, Hershman JM. ß-adrenergic blockade for the treatment of hyperthyroidism. Am J Med 1992; 93:61-68.
19. Toft AD. Thyroxine therapy. New Engl J Med 1994; 331:174-180.
20. Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange Jr AJ. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. New Engl J Med 1999; 340:424- 429.
21. Dong BJ, Hauck WW, Gambertoglio JG, Lee L, White JR, Bubp JL, et al. Bioequivalence of generic and brand-name levothyroxine products in the treatment of hypothyroidism. JAMA 1997;
277:1205-1213.
22. Paul TL, Kerrigan J, Kelly AM, Braverman LE, Baran DT. Long-term levothyroxine therapy is associated with decreased hip bone density in premenopausal women. JAMA 1988;
259:3137-3141.
23. Surks MI, Sievert R. Drugs and thyroid function. New Engl J Med 1995; 333:1688-1694.
24. Gittoes NJL, Franklyn JA. Drug-induced thyroid
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25. Wood LC. Support groups for patients with Graves’ disease and other thyroid conditions. Endocrinol Metab Clin North Am 1998; 27:101-107.
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