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Brought to you by an educational grant from Watson Pharmaceuticals. |
After completing this continuing education article, the pharmacist should be able to:
Thyroid hormones, which are synthesized and stored in the thyroid gland, are essential for maintaining normal functioning of virtually all organ systems regulating metabolism and controlling energy expenditure. Normal growth and development of the fetus, neonate, and child are controlled by thyroid hormones.1-3 Hypothyroidism in the fetus or neonate may lead to cretinism, which is characterized by marked neurologic and physiologic retardation. Thyroid disorders are usually separated into two major categories, hyperthyroidism and hypothyroidism, depending on whether serum thyroid levels are increased or decreased, respectively.
More than 13 million Americans are affected by thyroid disease, and more than half remain undiagnosed. The American Association of Clinical Endocrinologists (AACE) has launched a new campaign to increase public awareness of thyroid disorders. The program is called "The Neck's Time Is Now," and it is aimed at educating Americans about key periods, from birth to advanced age, when people are at increased risk for developing a thyroid disorder. Pharmacists can play a key role in counseling patients on the appropriateness of thyroid screening and on therapy once initiated.
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By understanding the pathophysiology of thyroid disorders, the pharmacist can better rationalize the use of certain medications for the management of these diseases. The thyroid gland lies in front of the larynx and consists of two lobes joined by an isthmus. The gland is divided into pseudolobes separated by fibrous septa. The pseudolobes contain follicles (cells) filled with a proteinaceous colloid that contains a glycoprotein called thyroglobulin.1 Thyroid hormone synthesis occurs within the peptide sequence of thyroglobulin. Tyrosine residues are precursors of hormone synthesis.2 The cellular mechanism of action of thyroid hormones is unknown, but they are thought to work at the level of the nucleus to alter genomic expression of various enzymes.1
Thyroid hormones are synthesized and stored in the thyroid gland. Their release into the blood is controlled by the hypothalamus-pituitary-thyroid axis. Small fluctuations in the level of unbound, metabolically active thyroid hormone in the blood produce positive or negative changes in hormone synthesis. The most sensitive index of thyroid hormone control is thyroid-stimulating hormone (TSH), which is controlled by the level of free (unbound) thyroid hormones in the blood and by the hypothalamic thyrotropin-releasing hormone (TRH).4 Too few circulating hormones ("negative" feedback) trigger release of TSH into the blood; rising levels ("positive" feedback) suppress TSH action5 (Figure 1).
Thyroid hormone synthesis is a three-step process. First, iodine is reduced to iodide and actively taken up from the blood into the thyroid gland, where it is oxidized. Tyrosine residues and thyroglobulin are then iodinated to form monoiodotyrosine and diiodotyrosine. These units then couple to form the thyroid hormones (triiodothyronine [T3] and thyroxine [T4]).
Several steps of thyroid hormone synthesis are controlled by the enzyme thyroid peroxidase. T4, which functions as a prohormone or reservoir for T3, is the primary hormone released from the thyroid gland and the body's only source of T4. Only about 20% of T3 in the body is secreted directly from the thyroid gland; the remaining 80% is synthesized in the peripheral circulation from the deiodination of T4 by the enzyme 5'-monodeiodinase. T3 and T4 are degraded in the peripheral circulation by the sequential removal of iodine, which is then available for reuptake into the thyroid gland. T3 and T4 are highly bound (> 98% normally) to thyroxine-binding globulin (TBG) and, to a lesser extent, to albumin and prealbumin. The half-life of T3 is about 1.5 days, whereas the half-life of T4 is about 7 days.1-3
Three thyroid function tests are used to evaluate thyroid status. The development of sensitive TSH testing has been an important advance since the early 1990s. Before the sensitive TSH test was available, there was a gray zone between normal and abnormal thyroid function. The sensitive TSH test clearly defines thyroid disease and allows for precise titration of thyroid replacement therapy.
Assays to measure TSH are conducted using an extremely sensitive radioimmunoassay. The origin of hypothyroidism-whether at the level of the pituitary gland, hypothalamus, or thyroid gland-can be determined by using the test for TSH. Levels of TSH are used to diagnose or screen for hypothyroidism and to evaluate adequacy of replacement therapy. Total T3 and T4 Levels
Both T3 and T4 are measured by radioimmunoassay. The tests measure both bound and unbound hormone. The resin T3 and T4 uptake tests (RT3U and RT4U) estimate binding capacity to TBG and are used to calculate free T3 and T4 levels. The free T3 index (FT3I) and the free T4 index (FT4I), which can be calculated in several different ways, are used to correct for alterations in TBG.2,4
The radioactive iodine uptake test indicates iodine use by the thyroid gland but not hormone synthesis capacity or activity. A tracer dose of radioactive iodine (131I or 123I) is administered intravenously, and the thyroid gland is scanned for iodine uptake. A normal test result is 5% to 15% of the dose taken up within 5 hours and 15% to 35% within 24 hours. This test is primarily used for diagnosis of Graves' disease, in which there is increased uptake. In patients who are iodine deficient, results indicate a greater uptake of iodine, and in those with an iodine excess, lesser uptake.2,4 Additionally, after the administration of radioactive iodine, a thyroid scan can reveal "hot" or "cold" spots indicating areas of increased or decreased iodine uptake, which can be useful in the detection of thyroid carcinoma.
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 thus may not bring them to the attention of their primary care provider.
Complications that can arise from untreated thyroid disease include elevated cholesterol levels and subsequent heart disease, infertility, muscle weakness, and osteoporosis. The issue of routine screening is controversial because cost-effectiveness has not been clearly proven. Although it may not be economically feasible or necessary to test all patients for thyroid dysfunction, there are instances when thyroid screening is appropriate. Pharmacists can counsel patients on the appropriateness of thyroid screening. The AACE advises TSH testing during the following times: (1) birth through adolescence, (2) the reproductive years (pregnancy), (3) midlife (menopause), and (4) the senior years (aging).6
Routine screening for congenital hypothyroidism (which can cause cretinism, a growth and mental disorder caused by a lack of thyroid hormone) is performed on all newborns by administering a heel-pad test. Parents of older children need to be made aware that symptoms such as difficulty concentrating and inattentiveness at school, hyperactivity, unexplained daytime fatigue, delayed puberty, dry and itchy skin, and increased sensitivity to cold and heat all may be symptoms of an underlying thyroid condition. An initial diagnosis of attention deficit disorder (ADD) in a child or adolescent may prompt a parent to consult with a pharmacist about available treatment options. At this time, pharmacists can advise on thyroid screening to possibly rule out ADD.
The AACE advises expectant mothers to take a TSH test before pregnancy or as part of the standard prenatal blood work. Some studies have suggested that undiagnosed hypothyroidism impairs fertility, and in the pregnant patient, it results in a four times greater risk for miscarriage during the second trimester. Another opportunity for pharmacists to counsel on thyroid screening is when a woman is seeking advice on ovulation predictor kits and pregnancy tests.
The symptoms of either hyperthyroidism or hypothyroidism, such as skin dryness, hot flashes, mood swings, depression, and weight gain, mimic the symptoms of menopause. If patients on hormone replacement therapies continue to experience mood swings, depression, or sleep disturbances, it would be appropriate to advise these women to request a thyroid function test. The AACE recommends that all women older than age 40 years have a TSH test, because studies have shown that 10% of these women have undiagnosed thyroid disease.
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Many seniors feel that the onset of symptoms such as fatigue, depression, forgetfulness, insomnia, and appetite changes are just part of the natural aging process. They often seek advice about over-the-counter vitamins or herbs (eg, ginkgo biloba) that can help alleviate these symptoms. At these times, pharmacists can inquire about thyroid screening. One of every five women older than age 65 years has an increased TSH, and approximately 15% of all hyperthyroid patients are older than 60 years.
Decreased thyroid hormone synthesis results in biochemical and/or clinical hypothyroidism. This condition occurs more frequently in women; the overall incidence is about 3% of the general population. Primary thyroid gland failure is the most common cause of hypothyroidism, usually a result of Hashimoto's thyroiditis (autoimmune thyroiditis). Isolated hypothyroidism secondary to pituitary failure is uncommon; most patients have clinical signs of generalized pituitary failure.2
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Hashimoto's thyroiditis is the most common type of gland failure, and it is believed to result from immunologically mediated damage to the thyroid from both antibodies and cell-mediated mechanisms, which can result in gland failure. Patients may develop a goiter or have thyroid atrophy. T lymphocytes directed against normal antigens on the thyroid membrane probably interact with thyroid cell-membrane antigens, which leads to activation of B lymphocytes to produce antibodies. Thyroid peroxidase antibodies, which lead to cellular changes in the thyroid gland, are also found in almost all patients with Hashimoto's thyroiditis. Patients with goiter may have antibodies that stimulate thyroid growth, whereas patients with an atrophic thyroid have antibodies that inhibit the trophic effects of TSH on the gland.3,7
The symptoms of hypothyroidism (Table 1) are nonspecific and variable among patients and could be indicative of other disorders, especially in the elderly. Patients with such symptoms should be screened with thyroid function tests.
An elevated TSH level is the earliest and most definitive indicator of hypothyroidism. TSH levels may be elevated in hypothyroidism long before any alteration occurs in T3 or T4; if hypothyroidism is not treated, T4 levels eventually decline. Subclini-cal hypothyroidism is characterized by elevated TSH levels with normal T3 and T4 and no clinical signs of hypothyroidism. Many clinicians consider thyroid hormone replacement therapy to be necessary in patients with subclinical hypothyroidism.8
Hypothyroidism may occur in the neonate if the mother ingests goitrogens (eg, cabbage or turnips) that inhibit normal feedback mechanisms for regulating thyroid hormone levels, or if the mother becomes hypothyroid through overtreatment with thio-amides. The extent to which thioamide therapy is responsible for hypothyroidism in the fetus or neonate is controversial. If hypothyroidism is treated within 3 months of birth, cretinism is unlikely to occur.9
The goals of treatment for primary hypothyroidism are to restore TSH levels to within normal range, alleviate signs and symptoms, and reverse biochemical abnormalities of hypothyroidism. In infants, restoration of thyroid function is essential to prevent impairment of both central nervous system and physiologic development. For patients with pituitary or hypothalamic causes of hypothyroidism, the goals are to relieve or prevent symptoms of hypothyroidism and other hormone deficiencies.
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Several thyroid replacement preparations are available (Tables 2 and 3). Synthetic thyroxine (levothyroxine) is used most often. It lacks antigenicity and has a long half-life. In the past, a number of preparations of desiccated thyroid from cattle, sheep, or hogs were popular. However, the potency of these products is determined by biologic assay of the iodine content and not by thyroid hormone activity, thus they provide a less predictable response than levothyroxine. Other products, such as liothyronine and liotrix, offer no clinical advantage over levothyroxine and should not be recommended as initial therapy unless a patient has already been stabilized on one of these products.3,7
Orally administered levothyroxine sodium, a sodium salt of the levo isomer of the thyroid hormone thyroxine, is manufactured by several pharmaceutical companies.10 When levothyroxine came to the market (prior to 1962), manufacturers were not required to undergo the FDA's new drug approval (NDA) process, an approval process that confirms that an agent is safe and effective and meets FDA standards for manufacturing, processes, potency, and stability.10 However, in 1997, after receiving reports of potency and stability problems-tablets having less active ingredient than indicated, tablets from different manufacturers and tablets from different lots from the same manufacturer lacking consistency, and the failure of the medication to maintain its potency through the expiration date-the FDA issued a mandate requiring that all manufacturers of levothyroxine have a complete and approved NDA by August 2000; that date, however, was extended. The deadline is currently August 2001.10
To date, only Watson Pharmaceuti-cals/Jerome Stevens' levothyroxine sodium product has received an NDA. Approval of other manufacturers' levothyroxine may follow. Based on the FDA mandate, any levothyroxine without an NDA by the stated deadline will be subject to regulatory action, unless the FDA has determined, based on a submitted citizen petition, that a particular levothyroxine product is not subject to the new drug requirements of the act.
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Bioequivalence between different levothyroxine preparations cannot be assumed. Also, levothyroxine is considered a narrow therapeutic index drug because small variances in drug levels could affect a patient's health. Complications that could occur if dosage strength is inconsistent from the same manufacturer or when a patient is switched to another brand include: if the drug has less potency/bioavailability-suboptimal response, hypothyroidism; if the drug has greater potency/bioavailability-toxic manifestations of hyperthyroidism.10 Thus, patients should be instructed to notify their physicians of any changes in their health and to not change brands of levothyroxine without consulting their physician and pharmacist. To prevent undertreatment or overtreatment, patients should be controlled and maintained on one brand of thyroid replacement therapy, cautioned not to change brands, and monitored over time (Table 4).
Pharmacists should be aware of the expiration date of levothyroxine lots because of the inherent instability of levothyroxine in the presence of light, temperature, air, and humidity.10 Pharmacists also should counsel patients to be aware of the expiration date for this product and should guide them on the proper storage of the drug.
Dosing of Levothyroxine. A number of factors should be evaluated when considering the initial dose of levothyroxine for a hypothyroid patient: patient age, cardiovascular status, and duration of hypothyroidism. For patients older than age 50 years with cardiovascular disease or with long-standing hypothyroidism, the initial dosage of levothyroxine is 0.025 to 0.050 mg/day. Response can be reevaluated in 6 to 8 weeks. An increase of 0.025-mg increments at approximately 1-month intervals avoids rapid increases in cardiac workload and symptoms of ischemic heart disease. If exacerbations of angina pectoris occur, the previous dosage regimen should be administered and titrated up in smaller increments.2,11
In all other patients, levothyroxine therapy can be initiated at a dosage of 1.6 to 1.7 mcg/kg/day, leading to the typical maintenance dosage of 0.1 to 0.125 mg/day. An average mean daily dosage is 0.112 mg/day. In the past, higher doses of levothyroxine were used, but they may be unnecessary and may be associated with adverse effects such as exacerbation of osteoporosis in women.5 It must be stressed that individualization of therapy is important, and patients should be monitored for resolution of clinical signs and symptoms, as well as for maintenance of normal TSH levels. Thyroxine replacement is lifelong, and TSH levels should be checked periodically to assess adequacy of replacement. Dose requirements are usually reduced in the older patient because of an age-associated decrease in T4 clearance.2,5,7
Patients receiving levothyroxine replacement therapy should be instructed to take their medication each day in the morning, preferably before breakfast because absorption is increased on an empty stomach.
Response to therapy should be evident within 2 weeks of initiation. In 2 to 3 weeks, weight gain and facial edema usually resolve, and speech, skin temperature, mental alertness, and physical activity improve. TSH levels begin to fall within hours of replacement therapy but are not within normal range until several weeks later. TSH assays need not be repeated until 4 to 6 weeks after initiating therapy or with dosage changes, because of the long half-life of levothyroxine. Repeat TSH testing continues until levels are normal and the patient's signs and symptoms resolve. Maximal absorption of levothyroxine occurs at 2 hours. Peripheral resistance to T4 is a rare occurrence; a lack of response usually indicates noncompliance with therapy.12
If thyroid hormone replacement therapy is appropriate, few adverse effects occur. Excessive doses are associated with tachycardia, sweating, weight loss, and cardiovascular complications such as angina, myocardial infarction, or congestive heart failure.2,3,11 Allergic reactions to the dye in preparations have been reported. For patients with such allergies, physicians and/or pharmacists should consider levothyroxine products with no dyes (eg, no dyes are used in the 0.05-mg dosages from several levothyroxine manufacturers and some manufacturers do not use any dyes in their various product strengths).
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Hyperthyroidism is associated with remodeling of cortical and trabecular bone, and excessive doses of thyroid supplements can result in similar changes. Effects appear to depend on age and sex, with postmenopausal women being more susceptible than men or premenopausal women. This fact highlights the need for continued monitoring of patients on thyroid hormone replacement therapy. Thyroid hormones should not be used to increase metabolism, aid in weight loss, or taken as a tonic.
Treatment of congenital hypothyroidism requires full doses of thyroid hormone as soon after birth as possible to prevent neurologic damage and impaired development. If treatment is delayed beyond 6 months after birth, full neurologic development is impaired and regression of neurologic deficits is not possible. The dosage of levothyroxine for infants is initially based on weight and is usually 10 mcg/kg/day, but can range as high as 15 mcg/kg/day. The dose is titrated to maintain T4 levels of more than 10 mcg/dL. The dose is decreased as the child ages, so that, by about age 15 years, adult maintenance doses are used (Table 5).11 If hypothyroidism develops in children older than age 2 or 3 years, it will not be associated with neurologic deficits, if treated with thyroid hormone.
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A number of drug-drug interactions have been reported with thyroid medications and thyroid diseases; however, a few can result in significant consequences (Table 6).11 Hypothyroidism develops in up to 15% of patients treated with lithium. Lithium inhibits the release of thyroid hormone from the gland; this interaction most commonly occurs in patients with underlying thyroid disorders. Lithium treatment may also predispose patients to develop thyroid antibodies. Thyroid function tests (eg, TSH) should be undertaken before beginning lithium therapy and repeated annually unless the patient develops symptoms of hypothyroidism or does not respond adequately to lithium therapy.
Amiodarone is high in iodine content (each 200-mg tablet contains 75 mg of elemental iodine) and is associated more often with hypothyroidism than with hyperthyroidism; however, either can occur. This effect is mediated through inhibition of peripheral conversion of T4 to T3, which can be associated with elevated TSH levels, or through excess amounts of iodine available to the thyroid gland. Hypothyroidism can be managed by hormone replacement therapy. For patients who develop hyperthyroidism, the amiodarone dose should be decreased, and, if necessary, the drug should be discontinued. Hyper-thyroidism secondary to amiodarone takes several months to resolve because of the drug's long half-life. If amiodarone cannot be discontinued, methimazole may be used concurrently to control the symptoms of hyperthyroidism.
Hyperthyroidism, or thyrotoxicosis, occurs when exposure of thyroid hormones to tissues exceeds the normal range. The annual incidence of hyperthyroidism is three per 1,000 in the general population, and the condition is eight times more common in women.2,3 Clinically, patients with hyperthyroidism present with nervousness, easy fatigability, emotional lability (insatiability), and heat intolerance, among other signs and symptoms (Table 7). Patients frequently lose weight, although appetite increases.5,7
A number of thyroid abnormalities can cause hyperthyroidism, including TSH-secreting tumors, trophoblastic disease, toxic adenoma, multinodular goiter, subacute or painless thyroiditis, struma ovarii, and metastatic follicular carcinoma. Certain medications (eg, amiodarone, excessive thyroid replacement, inorganic iodide, radiographic contrast agents, aminoglutethimide) and foods (eg, iodine-containing foods [shellfish and kelp]) also may lead to hyperthyroidism.
The most common cause of hyperthyroidism is Graves' disease. Evidence supporting a hereditary component in Graves' disease includes a clustering of the disease in families and a 50% likelihood of a monozygotic (identical) twin developing the disease versus 9% in dizygotic (fraternal) twins. The incidence of other autoimmune diseases, such as Hashimoto's thyroiditis, is also higher in families with Graves' disease than in the general population. Some human leukocyte antigens (HLAs) are increased in patients with Graves' disease.2
The primary characteristics of Graves' disease are diffuse thyroid enlargement-as much as two to three times the normal size-and extrathyroidal manifestations, such as exophthalmos, pretibial myxedema, and thyroid acropachy.2 The cause of these manifestations is unknown, but it is suggested that antibodies may react with orbital muscle and fibroblast tissue to cause or mediate development of exophthalmos and skin changes. Thyroid-stimulating antibodies (TSAb, formerly called long-acting thyroid-stimulating antibodies) directed against the thyrotropin hormone receptors on thyroid cells are found in about 50% to 70% of patients. These antibodies bind to thyroid hormone receptors and activate adenylate cyclase to mediate postreceptor effects similar to those of TSH.
Laboratory findings in Graves' disease and other forms of thyrotoxicosis include increased levels of both T3 and T4, with an increased ratio of T3 to T4. RT3U and FT4I are also elevated. Increased saturation of TBG causes a marked increase in free T3 and free T4.
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The objectives of treatment of thyrotoxicosis are to reduce the excess production and availability of thyroid hormones and to reduce or control symptoms of thyrotoxicosis. Three treatment modalities are available: drug therapy, radiation, and surgery. Therapy is individualized on the basis of patient age, sex, other concurrent medical conditions, and response to previous therapy.2,13
The drugs used to treat thyrotoxicosis include the thioamides and iodides.
Thioamides. The two thiourea drugs (thioamides) most frequently used to treat thyrotoxicosis are methimazole and propylthiouracil (PTU). The thioamides inhibit the peroxidase enzyme system required for oxidation of iodine, "organification" of iodine by the thyroid gland (the process of iodide binding to thyroglobulin to form monoiodotyrosine and diiodotyrosine) of the tyrosine residues, and coupling of the monoiodotyrosine and diiodotyrosine residues. Some clinicians prefer PTU for initial drug therapy in patients with severe symptoms, because it also inhibits peripheral conversion of T4 to T3. Within 24 to 48 hours of commencing therapy with PTU, peripheral T3 production decreases by 25% to 40%, and symptoms are reduced. Because of the long half-life of T4, the full clinical effects of these drugs are not seen until the store of thyroid hormones is reduced, which usually occurs within 4 to 8 weeks.5,7
Although symptoms of hyperthyroidism are relieved within a few days, therapy is usually continued for 6 to 12 months and often for as long as 2 years. Patients are treated, usually for 4 to 5 months, until a euthyroid state (hormone levels in the normal range) is achieved, spontaneous remission of Graves' disease occurs, or both.14 The optimal duration of therapy is unclear: the time to remission is unpredictable and, despite development of apparent complete remission on drug therapy, relapse is common. Relapse rates range from 14% to 75%. Some experts suggest that almost no prolonged remission of disease occurs after therapy is discontinued, if the follow-up period is long enough.14
The natural course of Graves' disease is development of hypothyroidism; patients who remain euthyroid for prolonged periods following treatment with thioamides are thought to have concomitant autoimmune thyroiditis or Hashimoto's thyroiditis. Disease and patient characteristics associated with a favorable and more prolonged response to thio-amides include a small or reduced size goiter, T4 thyrotoxicosis, and mild symptoms of hyperthyroidism.2,3
Although the T4 suppression test and radioactive iodine uptake can be used to predict patients likely to maintain remission, these tests are rarely used in practice. A T3 suppression test of 20% or less is a good indicator of prolonged remission, and some clinicians would recommend treating patients with thioamides until this is achieved. Nonresponsiveness to thioamides may indicate resistance, but other factors, such as noncompliance, insufficient dosing, or a dosing interval that provides too few doses per day, should also be considered.3
Both methimazole and PTU are well absorbed from the gastrointestinal tract, and peak serum concentrations occur about 1 hour after ingestion. Although both drugs have relatively short plasma half-lives (methimazole, 6 to 9 hours; PTU, 1 to 2.5 hours), their intrathyroidal half-lives are longer. This allows for once-daily dosing of methimazole, particularly during maintenance therapy. PTU is usually dosed on a schedule of two to four times a day, although some evidence shows that single-daily dosing may be appropriate in some patients.15 PTU is 60% to 80% protein bound; methimazole is not protein bound. Both drugs are metabolized and only small amounts (PTU, 35%; methimazole, 10%) appear in the urine unchanged.11
Methimazole appears to readily cross the placenta, and it is found in breast milk. Older studies suggested that PTU does not cross the placenta; however, a recent study reported by Gardner et al12 found PTU concentrations to be higher in blood in the fetal umbilical cord than in maternal blood. Mean fetal TSH was elevated to 10.2 mIU/mL, whereas maternal TSH was 0.8 mIU/mL, indicating subclinical hypothyroidism in the fetus. The degree to which a drug crosses the placenta probably varies throughout pregnancy. Caution must be exercised with use of any antithyroid treatment during pregnancy.16
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Methimazole is approximately 10 times more potent than PTU, and care should be taken to avoid dispensing errors with these two drugs. Initial dosages are 300 to 400 mg PTU per day, given in four divided doses, and 15 to 40 mg methimazole per day given in three divided doses. Patients with severe thyrotoxicosis may need higher total daily doses initially to control their symptoms (PTU, 600 to 900 mg/day; methimazole, 30 to 60 mg/day). After the patient achieves a euthyroid state, the dose is titrated down by 50% to 75%. Usual maintenance dosages are 100 to 150 mg PTU per day and 5 to 15 mg methimazole per day. Dosage adjustments should be made on the basis of T4 concentrations, TSH levels, and clinical symptoms. T4 levels should decrease to within normal range, and TSH should increase to within the normal range. Changes should be limited to a monthly basis because of the long half-life of T4. Dosages for pediatric patients are based on weight (Table 8).11
Adverse effects include a mild transient leukopenia, skin reactions, and agranulocytosis. Benign transient leukopenia occurs in up to 12% of adults and 25% of children. A baseline white blood cell count (WBC) will help determine if any later alterations in WBCs are because of drug therapy or the hyperthyroidism. Leukopenia is not predictive of agranulocytosis, and therapy is not contraindicated if the patient is leukopenic. A maculopapular skin rash is reported in 5% to 6% of patients. If the rash is mild, thioamide therapy can be continued and symptoms managed with topical cortico-steroids. Congenital skin defects present at birth have been associated with maternal ingestion of methimazole and carbimazole.
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Agranulocytosis is the most serious adverse drug reaction associated with the thioamides; its incidence is about 0.5% to 6.0%. It is characterized by fever of more than 101°F for 1 or 2 days, malaise, and flu-like symptoms. The reactions manifest within the first 3 months of therapy. An autoimmune etiology has been suggested because antineutrophil antibodies and lymphocyte sensitization have been detected in many patients. Other clinicians have suggested that the agranulocytosis is a direct toxic reaction to drug accumulation in granulocytes. The reaction appears to be dose dependent, because it occurs more frequently in patients on higher doses of methimazole or PTU.16
Routine monitoring of WBCs does not help predict susceptibility to agranulocytosis. Pharmacists should counsel patients to report rash, fever, sore throat, and flu-like symptoms, because they may herald the onset of agranulocytosis (Table 9). Thioamides are contraindicated in patients who develop agranulocytosis. Discontinuation of a thioamide results in prompt recovery of granulocyte counts and clinical improvement, but patients must be carefully monitored for the development of severe infections.
In some patients, if minor adverse effects develop, substituting the other thioamide may allow continuation of therapy. Other adverse effects include arthralgias, hypoprothrombinemia, and gastrointestinal disturbances. Lupus-like symptoms, such as mouth ulcers, vasculitis, and migratory arthritis, may also occur in 4% to 5% of patients.
Iodides. Iodides inhibit thyroid hormone synthesis by blocking iodination of tyrosine residues and preventing release of thyroid hormones from the gland. The phenomenon of iodine-inhibited organification of thyroid hormones is known as the Wolff-Chaikoff effect. It is an autoregulatory mechanism to protect the gland from excess production of thyroid hormones in the presence of a large iodine load. The gland escapes this mechanism within a few days of iodine ingestion because of leakage and/or altered transport of iodine. The effects of these iodides that prevent the thyroid from releasing hormones are overcome by TSH levels that increase in response to lower plasma levels of free thyroid hormone. Iodide-suppressive effects on hormone release can be overcome by most patients within 7 to 14 days.2,3,17
Clinical response to iodides occurs within 2 to 7 days. Iodine treatment, in the form of iodide, is used for short-term, adjunctive management of hyperthyroidism. For example, it is used before surgery to promote a euthyroid state and to reduce vascularity of the gland. Patients most likely to respond to iodides are those with high intrathyroidal iodide levels or toxic adenoma, those on lithium, and some with Hashimoto's thyroiditis. Iodide is usually given as a saturated solution of potassium iodide (SSKI) or Lugol's solution. Lugol's contains 8 mg iodide per drop (5% iodine and 10% potassium iodide), and SSKI contains 40 mg iodide per drop. SSKI is usually given in a dosage of three to 10 drops (150 to 400 mg) per day.2 Doses are usually administered in a small glass of orange juice to increase palatability.
Radioactive iodine (RAI) given as sodium iodide is universally effective ablative therapy in the management of thyrotoxicosis. RAI is actively taken up by the thyroid gland and incorporated into hormone synthesis. Over time, beta-emission radioactivity destroys the follicles. RAI is commonly used in older patients and in those who have failed drug therapy. It is most often given in a single dose, although a few patients may require a supplemental dose.2,3
The aim of RAI treatment is to render the patient permanently hypothyroid. This effect begins about 3 to 6 months after treatment. Thyroid hormone replacement therapy is then initiated to bring the TSH level into the normal range, and replacement therapy is maintained throughout life. Hypothyroidism develops in about 20% of patients 1 year after RAI. The annual rate of development is 2.5% per year thereafter, with 50% of patients hypothyroid by year 10 and 80% by year 20.18 All patients must be monitored for hypothyroidism after RAI therapy.
Because RAI's effects are slow in onset, patients may be made euthyroid with thioamides before beginning RAI therapy. Thioamide therapy may take as long as 6 to 8 weeks. Coadministration of thioamide therapy may prevent uptake of RAI in the thyroid; thus, thioamide therapy should be discontinued about 2 weeks before treatment with RAI. Iodides should not be given before therapy with RAI, because they will interfere with uptake of the radioactive material and reduce treatment response. If iodides are to be used, initiation of iodide therapy should be delayed for 1 to 14 days after RAI treatment. Pregnancy is an absolute contraindication to RAI.2
Surgery is indicated in patients with autonomous adenomas, when drug therapy is ineffective or contraindicated, or in cases of esophageal or respiratory compromise as a result of a large goiter. Before surgery, as with RAI therapy, patients are usually rendered euthyroid with thioamides. Iodides are used preoperatively for 10 to 14 days to reduce gland vascularity and size. Beta blockers may also be used before and after surgery to control the adrenergic symptoms of thyrotoxicosis. Complications of surgery include hypothyroidism (43%), hypoparathyroidism (3.6%), and vocal cord paralysis. Following surgery, patients must be monitored for hypothyroidism, which would be treated with thyroid supplementation.2,7
Thioamides and RAI have slow onset in ameliorating hyperthyroidism. Patients who are thyrotoxic are frequently given concomitant therapy with beta blockers to control cardiovascular symptoms (palpitations, tachycardia), anxiety, tremor, and heat intolerance. In patients who are at risk of cardiac failure because of thyrotoxicosis, intravenous propranolol or esmolol may be required.
Propranolol or nadolol are the beta blockers of choice for ongoing therapy because they not only control adrenergic symptoms but also partially block peripheral conversion of T4 to T3. D-propranolol, the isomer responsible for inhibiting the peripheral conversion of T4 to T3, is devoid of beta-blocking activity. Initial dosages of propranolol are 20 to 40 mg four times a day. The dose is titrated to maintain a heart rate of less than 90 beats per minute. Patients with severe thyroid symptoms may require dosages as high as 240 to 480 mg/day.2,3,7
Beta blockers are contraindicated in patients with congestive heart failure, unless it is high-output failure caused by tachycardia. These agents are also relatively contraindicated in patients who have diabetes mellitus, asthma, obstructive lung disease, or sinus bradycardia. Monotherapy with beta blockers does not block all peripheral effects of excess thyroid hormone, alter thyroid-stimulating antibody levels, or alter the thyroid state; thus, beta blockers should not be used alone to treat hyperthyroidism.
Diltiazem can be used as adjunctive therapy, particularly if beta blockers are contraindicated. Diltiazem appears comparable to propranolol in controlling the hypertension and tachycardia associated with hyperthyroidism. Diltiazem 120 mg every 8 hours is reported to reduce heart rate by 17%.
Approximately 70% of patients using herbal medications do not reveal the use of these products to their physicians.19 Concomitant use of herbal products can lead to serious and sometimes life-threatening drug-herb interactions.20 For example, horseradish, used as an antiseptic and promoted for pulmonary and urinary tract infections, may depress thyroid function.21 Kelp, used for weight loss, heart disease, arthritis, breast cancer, and osteoporosis, contains 0.7 mg of iodine per tablet and can cause hyperthyroidism in people sensitive to iodine.22 Patients should be informed not to use kelp products concomitantly with levothyroxine or other thyroid hormone products. Herbal medicines containing ma huang or stimulants similar to amphetamines or methyl-phenidate could also cause serious adverse consequences in patients with thyroid disorders.19
Some herbal medicine advocates promote desiccated thyroid hormone as "natural" and more effective than synthetic levothyroxine. Pharmacists and physicians should keep in mind that desiccated thyroid products prepared from animal thyroid glands are more rapidly absorbed than T4 and T3. Because T3 is more rapidly absorbed than T4, supraphysiologic concentrations of T3 can occur (resulting in symptoms of hyperthyroidism) and cause adverse cardiovascular effects. Allergic reactions to the protein component of desiccated thyroid may also occur. Therefore, preparations containing desiccated thyroid are not recommended.
Pharmacists can make significant contributions to the care of patients with thyroid disorders. Patients benefit from education about their condition and the role of various medications. Pharmacists can advise on the appropriate use of thyroid screening, and they can counsel patients on proper use of thyroid medications. Patients should also be monitored for adequate response to therapeutic interventions and for potential drug interactions.
Dr. Chase is a Clinical Pharmacy Specialist at Spectrum Health in Grand Rapids, MI, and an Adjunct Assistant Professor of Pharmacy at Ferris State University College of Pharmacy, Big Rapids, MI.
