Thyroid Agents General Statement (Monograph)

Drug class: Thyroid Agents
ATC class: H03AA
VA class: HS851

Introduction

Thyroid agents are natural or synthetic preparations containing tetraiodothyronine (thyroxine, T₄) and/or triiodothyronine (T₃).

Uses for Thyroid Agents General Statement

Hypothyroidism

Thyroid agents are used for supplementation or replacement of diminished or absent thyroid function resulting from primary causes including functional deficiency, primary atrophy, or partial or complete absence of the gland, or from the effects of surgery, radiation, or antithyroid agents; the drugs are not used for the management of transient hypothyroidism during the recovery phase of subacute thyroiditis. Thyroid agents also are used for replacement or supplemental therapy in patients with secondary (pituitary) or tertiary (hypothalamic) hypothyroidism and subclinical hypothyroidism. Therapy must be maintained continuously to control the symptoms of hypothyroidism. Levothyroxine sodium generally is the preferred thyroid agent for replacement therapy because its hormonal content is standardized and its effect is therefore predictable. Levothyroxine sodium also is considered the thyroid agent of choice for the treatment of congenital hypothyroidism (cretinism); however, other thyroid agents have been used. The earlier replacement therapy is initiated in congenital hypothyroidism, the greater is the potential for normal growth and development. (See Cautions: Pediatric Precautions.)

Levothyroxine sodium IV injection is used in the treatment of myxedema coma. Levothyroxine sodium injection has been used in other conditions when rapid thyroid replacement is required^{† [off-label]}; however, this is not an FDA-labeled use for the currently available injection.

Pituitary TSH Suppression

Thyroid agents may be beneficial in the management or prevention of various types of euthyroid goiters, including thyroid nodules, subacute or chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis), and multinodular goiter. In these conditions, thyroid agents act as replacement therapy and may cause a reduction in goiter size by suppressing the secretion of thyrotropin.

Thyroid agents also may be used in conjunction with surgery and radioactive iodine therapy in the management of thyrotropin-dependent well-differentiated, papillary or follicular carcinoma of the thyroid.

Other Uses

Thyroid agents may be used in combination with antithyroid agents in the treatment of thyrotoxicosis to prevent goitrogenesis and hypothyroidism. While administration of thyroid agents may occasionally be useful to prevent antithyroid agent-induced hypothyroidism in the management of thyrotoxicosis during pregnancy, combination therapy generally is considered unnecessary since it may increase the requirement for antithyroid agents and therefore the risk of fetal hypothyroidism, which is not amenable to exogenous thyroid agent therapy.

Thyroid agents may be used diagnostically in suppression tests to differentiate suspected hyperthyroidism from euthyroidism in patients with clinical signs and symptoms compatible with mild hyperthyroidism in whom baseline laboratory tests do not confirm the diagnosis, or to determine thyroid gland autonomy in patients with eye changes compatible with Graves’ ophthalmology who are clinically and biochemically euthyroid and in whom demonstration of thyroid gland autonomy would support the diagnosis.

The use of thyroid agents, alone or in combination with other drugs, in the treatment of obesity and for weight loss is unjustified and has been shown to be ineffective. (See Cautions: Precautions and Contraindications.) The use of thyroid agents for the treatment of male or female infertility also is not justified unless the condition is accompanied by hypothyroidism.

Thyroid Agents General Statement Dosage and Administration

Administration

Thyroid agents usually are administered orally. Levothyroxine sodium (and occasionally liothyronine sodium) may be given by IV injection. Levothyroxine sodium also has been administered by IM injection^{† [off-label]}, however, the IV route is preferred since absorption may be variable following IM administration. IM administration is not an FDA-labeled route of administration for the currently available levothyroxine sodium injection. Oral therapy should replace parenteral therapy as soon as possible.

Dosage

Dosage of thyroid agents must be carefully adjusted according to individual requirements and response. (See Cautions: Precautions and Contraindications.) The age and general physical condition of the patient and the severity and duration of hypothyroid symptoms determine the initial dosage and the rate at which dosage may be increased to the eventual maintenance dosage. Dosage should be initiated at a lower level in geriatric patients; in patients with long-standing disease, other endocrinopathies, or functional or ECG evidence of cardiovascular disease; and in patients with severe hypothyroidism. Adjustment of thyroid replacement therapy should be determined mainly by the patient’s clinical response and confirmed by appropriate laboratory tests.

In infants and children, it is essential to achieve rapid and complete thyroid replacement because of the critical importance of thyroid hormone in sustaining growth and maturation. In general, despite the smaller body size of children, the dosage (on a weight basis) required to sustain a full rate of growth, development, and general thriving is higher in children than in adults.

Laboratory Monitoring

Thyroid function status must be assessed periodically in patients receiving thyroid agents as a guide to therapy. Various laboratory tests are available to monitor thyroid function, and clinicians should consult specialized references for information on specific tests and their use and interpretation. Selection of appropriate tests for the diagnosis and management of hypothyroidism or hyperthyroidism depends on patient-specific variables (e.g., signs and symptoms of thyroid disease, pregnancy, concomitant administration of drugs). A combination of sensitive thyrotropin (thyroid-stimulating hormone, TSH) assay plus free thyroxine (T₄) and/or total or free triiodothyronine (T₃) assay usually is recommended to confirm a diagnosis of thyroid disease. TSH assay alone may be used initially to screen for thyroid disease and to monitor during drug therapy. Other thyroid function tests that may be used include total serum concentrations of T₄ triiodothyronine resin uptake, free T₄ index (the product of total serum T₄ multiplied by the percentage of serum T₃ resin uptake), and thyrotropin-releasing hormone (TRH) stimulation test.

Cautions for Thyroid Agents General Statement

Adverse reactions to thyroid agents result principally from overdosage. (See Toxicity.)

Toxicity

Manifestations

Adverse reactions to thyroid agents result from overdosage and are manifested principally as signs and symptoms of hyperthyroidism including fatigue, weight loss, increased appetite, palpitations, nervousness, hyperactivity, anxiety, irritability, emotional lability, diarrhea, abdominal cramps, vomiting, elevated liver transaminase concentrations, sweating, tachycardia, increased pulse and blood pressures, angina pectoris, cardiac arrhythmias, tremors, muscle weakness, headache, insomnia, intolerance to heat, fever, hair loss, flushing, decreased bone mineral density, impaired fertility, and menstrual irregularities. Complications of severe overdosage may include cardiac decompensation, cardiac failure, myocardial infarction, cardiac arrest, and possibly death secondary to cardiac arrhythmia or failure. Seizures have been reported rarely with levothyroxine therapy. The effects of levothyroxine sodium, thyroid, or thyroglobulin may not appear for 1–3 weeks following initiation of therapy or an increase in dosage, but may appear within 24–72 hours after initiation of therapy or an increase in dosage with liothyronine sodium.

Treatment

Manifestations of overdosage are usually readily reversible following temporary discontinuance of therapy and are obviated by a reduction in dosage. If manifestations of overdosage appear with levothyroxine sodium, thyroid, or thyroglobulin, the drug should be discontinued for 2–7 days, and for 2–3 days in the case of liothyronine sodium, and then resumed at a lower dosage. For information on the treatment of acute overdosage of thyroid agents, see Acute Toxicity: Treatment.

Other Adverse Effects

Hypersensitivity reactions to excipients in formulations of thyroid agents have been reported rarely. Manifestations include urticaria, pruritus, skin rash, flushing, angioedema, various GI symptoms (e.g., abdominal pain, nausea, vomiting, diarrhea), fever, arthralgia, serum sickness, and wheezing. Thyroid also may rarely cause GI intolerance in patients highly sensitive to pork. One manufacturer states that GI intolerance may also rarely occur in patients highly sensitive to corn.

Precautions and Contraindications

Because thyroid agents have a narrow therapeutic index, dosage must be carefully adjusted to avoid the consequences of under or over treatment, including adverse effects on growth and development in pediatric patients, cardiovascular function, bone metabolism, reproductive function, cognitive function, emotional state, GI function, and glucose and lipid metabolism.

Patients receiving thyroid agents must be closely monitored and thyroid function status must be periodically assessed by appropriate laboratory studies. (See Dosage and Administration: Laboratory Monitoring.) Since hypothyroid patients, especially those with myxedema, are particularly sensitive to thyroid agents, replacement therapy should be initiated with low doses and subsequent dosage should be gradually increased in such patients.

Thyroid agents should be used with extreme caution and in reduced dosage in patients with angina pectoris or other cardiovascular disease, including hypertension. If chest pain or other aggravation of cardiovascular disease occurs in patients receiving thyroid agents, dosage should be reduced or temporarily withheld and reinstituted at a lower dosage. Overtreatment with thyroid agents may result in adverse cardiovascular effects (e.g., increased heart rate, cardiac wall thickness, cardiac contractility) and may precipitate angina pectoris or arrhythmias. Because the possibility of precipitating cardiac arrhythmias may be greater in patients receiving thyroid agents, patients with coronary artery disease should be closely monitored during surgery. Thyroid agents should be used with caution in geriatric patients since occult cardiac disease may be present.

Morphologic hypogonadism and nephroses should be ruled out before thyroid agents are administered. In patients whose hypothyroidism is secondary to hypopituitarism, adrenal insufficiency is likely to be present. When adrenal insufficiency and hypothyroidism exist concomitantly, adrenal insufficiency must be corrected by administration of corticosteroids before therapy with thyroid agents is initiated. Initiation of thyroid hormone therapy without prior treatment with corticosteroids may result in increased metabolic clearance of corticosteroids and, thus, may precipitate an acute adrenal crisis. Hypopituitarism, adrenal insufficiency, and other endocrine disorders such as diabetes mellitus and diabetes insipidus are characterized by signs and symptoms which may be diminished in severity or obscured by hypothyroidism. Thyroid agents may aggravate the intensity of previously obscured symptoms in patients with endocrine disorders, and appropriate adjustment of therapy for these concomitant disorders may be required.

Except in patients with transient hypothyroidism or in those receiving a therapeutic trial with an agent, patients should be advised that replacement therapy with a thyroid agent must be maintained continuously to control the symptoms of hypothyroidism and that clinical improvement may not occur until after several weeks of therapy. Patients should be instructed to immediately report any signs or symptoms of thyroid toxicity (hyperthyroidism) (e.g., chest pain, increased pulse rate, palpitations, excessive sweating, heat intolerance, nervousness) or any unusual event which occurs during therapy with a thyroid agent. (See Cautions: Toxicity and Other Adverse Effects.) Because dosage of antidiabetic agents (i.e., insulin, sulfonylureas) may require adjustment during thyroid agent replacement therapy, patients with diabetes mellitus receiving an antidiabetic agent concomitantly should be advised to closely monitor urinary and/or blood glucose concentrations during concomitant therapy. Hypoglycemia may occur in these patients if therapy with a thyroid agent is stopped. Patients should be advised that partial loss of hair may occur during the first few months of therapy, but this effect is usually transient and subsequent regrowth usually occurs. When surgery is required, patients should be advised to inform the attending clinician (e.g., physician, dentist) that they are receiving thyroid hormone therapy.

Although thyroid agents have been used alone and in combination with other drugs for the treatment of obesity, dosages of thyroid agents within the usual range of daily requirements are ineffective for weight reduction in euthyroid individuals. Higher dosages may produce serious and even life-threatening manifestations of toxicity, especially when given in conjunction with sympathomimetic agents (e.g., amphetamines) used for their anorectic effect. The use of thyroid agents for the treatment of obesity or for weight loss is unjustified and contraindicated.

Thyroid agents are generally contraindicated in the presence of thyrotoxicosis and in acute myocardial infarction uncomplicated by hypothyroidism. When hypothyroidism is a complicating or causative factor in myocardial infarction, judicious use of small doses of thyroid agents may be considered. Thyroid agents are contraindicated in patients with uncorrected adrenal insufficiency because the drugs increase tissue demands for adrenal hormones and may precipitate an acute adrenal crisis in these patients. Although there is no well-documented evidence of true allergic or idiosyncratic reactions to thyroid agents, a particular agent should not be used in patients with apparent hypersensitivity to that agent or any ingredient in the formulation.

Pediatric Precautions

Little, if any, maternal thyroid hormone is distributed to the fetus. The incidence of congenital hypothyroidism is relatively high (1:4000) and the hypothyroid fetus probably does not derive any benefit from the small amounts of thyroid hormones that may cross the placental barrier. Routine determination of serum thyroxine and/or thyrotropin (thyroid-stimulating hormone, TSH) concentrations is strongly advised in neonates because of the deleterious effects of thyroid deficiency on growth and development. Normal adult ranges for serum thyroxine concentrations must not be used to evaluate neonatal thyroid function, since failure to diagnose the condition may occur and result in disastrous effects on the prognosis. The Committee on Drugs of the American Academy of Pediatrics (AAP) recommends that physicians caring for children participate in state or regional screening programs for hypothyroidism and maintain a high level of clinical suspicion to assure the earliest possible diagnosis of congenital hypothyroidism. Signs and symptoms of congenital hypothyroidism include lethargy, hypothermia, feeding problems, failure to gain weight, dry skin, skin mottling, thick tongue, hoarse cry, umbilical hernia, persistence of mild jaundice, respiratory problems, and a large anterior and posterior fontanel.

Treatment, preferably with levothyroxine sodium, should be initiated immediately upon diagnosis, and maintained for life, unless transient hypothyroidism is suspected. If receipt of laboratory results will be delayed for several days or weeks, thyroid agent therapy may be initiated in neonates with suspected hypothyroidism pending the results of confirmative tests. The earlier replacement therapy is initiated in congenital hypothyroidism, the greater the potential for normal growth and development. If a positive diagnosis cannot be made on the basis of laboratory findings but there is a strong clinical suspicion of congenital hypothyroidism, a conservative approach would be to ensure euthyroidism with replacement therapy until the child is 1–2 years of age. Thyroid agent therapy can then be discontinued while diagnostic tests are carried out, and reinstituted if indicated; this treatment approach avoids the potential risk of the infant incurring serious, permanent brain damage. When transient hypothyroidism is suspected, therapy may be interrupted (or dosage of the thyroid agent reduced by half in suspected severe hypothyroidism) for 4–8 weeks to reassess the condition when the child is older than 3 years of age. If the diagnosis of permanent hypothyroidism is confirmed, full replacement therapy should be reinstituted. However, if serum concentrations of T₄ and TSH are normal, thyroid agent therapy may be discontinued, and the patient should be carefully monitored; thyroid function tests should be repeated if manifestations of hypothyroidism develop.

During the first 2 weeks of thyroid agent therapy, infants should be closely monitored for cardiac overload, arrhythmias, and aspiration resulting from avid suckling. Evaluation of the infant’s clinical response to thyroid agent therapy should be performed about 6 weeks after initiation of therapy; additional examinations should be performed at least at 6 and 12 months of age and yearly thereafter. Achievement of normal serum thyrotropin concentration must not be used as the sole criterion of the adequacy of the dose in children with congenital hypothyroidism, since thyrotropin concentrations may remain elevated for several months during replacement therapy using proper or even excessive dosages of the thyroid agent. The goal of replacement therapy in these children is to maintain the serum thyroxine concentration at levels appropriate for age throughout infancy and childhood and to achieve and maintain normal intellectual and physical growth and development. Patients should be monitored closely to avoid undertreatment or overtreatment. Undertreatment may result in poor school performance (due to impaired concentration and slowed mentation) and reduced adult height. Overtreatment may result in craniosynostosis in infants and accelerate the aging of bones, resulting in premature epiphyseal closure and compromised adult stature.

Treated children may manifest a period of catch-up growth, which may be adequate in some cases to achieve normal adult height. In children with severe or long-standing hypothyroidism, catch-up growth may not be adequate to achieve normal adult height.

Pseudotumor cerebri and slipped capital femoral epiphysis have been reported in children receiving thyroid agent therapy.

Mutagenicity and Carcinogenicity

Animal studies to determine the mutagenic or carcinogenic potential of thyroid agents have not been performed. Although an apparent association between prolonged thyroid therapy and breast cancer has been reported, the validity of the report has been seriously questioned. Patients receiving thyroid agents for established indications should not discontinue therapy.

Pregnancy and Lactation

Pregnancy

Thyroid agents do not readily cross the placenta, and clinical experience does not indicate any adverse effect on the fetus when thyroid agents are administered during pregnancy. Thyroid agent replacement therapy for hypothyroidism should be continued throughout pregnancy, and if hypothyroidism is diagnosed during pregnancy, treatment should be initiated. Serum thyroxine concentrations are lower than normal during pregnancy, and the diagnosis should be confirmed by determination of serum thyrotropin concentration. In pregnant women dependent on thyroid replacement therapy, increased dosage may be required.

If myxedema coma develops during pregnancy, patients should be treated with IV levothyroxine sodium. Although the manufacturer states that there are no reports of levothyroxine sodium injection use in pregnant women with myxedema, nontreatment is associated with a high probability of maternal or fetal morbidity or mortality.

Lactation

Although only minimal amounts of thyroid hormones are distributed into milk, thyroid agents should be used with caution in nursing women.

Lactating women who develop myxedema coma should be treated with IV levothyroxine sodium. Although the manufacturer states that there are no reports of levothyroxine sodium injection use in lactating women with myxedema coma, nontreatment is associated with a high probability of maternal morbidity or mortality.

Drug Interactions

In addition to the drug interactions described in this section, some drugs can interfere with thyroid function test results and their interpretation. (See Laboratory Test Interferences.)

Oral Anticoagulants

Thyroid agents may potentiate the hypoprothrombinemic effect of warfarin and other oral anticoagulants, apparently by increasing catabolism of vitamin K-dependent clotting factors. When thyroid agents are administered to patients receiving oral anticoagulants, the prothrombin time should be determined frequently and anticoagulant dosage adjusted accordingly, and patients should be observed closely for adverse effects. It has been suggested that the dosage of the oral anticoagulant be reduced by one-third when thyroid therapy is started. No special precautions appear to be necessary when oral anticoagulant therapy is initiated in patients already stabilized on maintenance thyroid replacement therapy.

Antidepressants

Concomitant use of tricyclic (e.g., amitriptyline) or tetracyclic (e.g., maprotiline) antidepressants and levothyroxine may increase the therapeutic and toxic effects (e.g., increased risk of cardiac arrhythmias and CNS stimulation) of both classes of drugs, possibly secondary to increased receptor sensitivity to catecholamines; onset of action of tricyclic antidepressants may be accelerated. Concomitant use of selective serotonin-reuptake inhibitors (SSRIs, e.g., sertraline) in patients stabilized on levothyroxine may result in increased levothyroxine requirements.

Antidiabetic Agents

Hypothyroidism may reduce the severity of diabetes mellitus, resulting in decreased requirements of insulin or oral antidiabetic agents (e.g., sulfonylureas). Administration of thyroid agents to patients with diabetes mellitus may cause an increase in the required dosage of insulin or oral antidiabetic agents. When therapy with thyroid agents is initiated or discontinued or when dosage of a thyroid agent is adjusted in diabetic patients receiving insulin or an oral antidiabetic agent, patients should be closely monitored and appropriate adjustments in dosage of insulin or the oral antidiabetic agent made accordingly if necessary.

Sympathomimetic Agents

Parenteral administration of sympathomimetic agents (e.g., epinephrine) to patients with coronary artery disease may precipitate an episode of coronary insufficiency. Because this reaction may be enhanced in patients receiving thyroid agents, patients with coronary artery disease who are receiving thyroid agents should be carefully observed when catecholamines are administered.

Bile Acid Sequestrants

Bile acid sequestrants (e.g., cholestyramine resin, colestipol) bind thyroid agents in the GI tract and substantially impair their absorption. In vitro studies indicate that the binding is not readily reversible. To minimize or prevent this interaction, these agents should be administered at least 4 hours apart when the drugs must be used concurrently.

GI Drugs

Antacids (e.g., aluminum hydroxide, magnesium hydroxide, calcium carbonate), simethicone, and sucralfate bind thyroid agents in the GI tract and delay or prevent their absorption. Calcium carbonate may form an insoluble chelate with levothyroxine, resulting in decreased levothyroxine absorption and increased serum thyrotropin concentrations; in vitro studies indicate that levothyroxine binds to calcium carbonate at acidic pH levels. To minimize or prevent this interaction, some clinicians recommend that these agents be administered approximately 4 hours apart when the drugs must be used concurrently with thyroid agents.

Drugs Affecting Hepatic Microsomal Enzymes

Drugs that induce hepatic microsomal enzymes (e.g., carbamazepine, phenytoin, phenobarbital, rifampin) may accelerate metabolism of thyroid agents, resulting in increased thyroid agent dosage requirements. Phenytoin and carbamazepine also reduce serum protein binding of levothyroxine, and total- and free-T₄ may be reduced by 20–40%, but most patients have normal serum concentrations of thyrotropin (thyroid-stimulating hormone, TSH) and are clinically euthyroid.

Cardiac Glycosides

Serum concentrations of digitalis glycosides may be decreased in patients with hyperthyroidism or in patients with hypothyroidism in whom a euthyroid state has been achieved. Thus, therapeutic effects of digitalis glycosides may be reduced in these patients.

Growth Hormones

Excessive use of thyroid agents with growth hormones (e.g., somatropin) may accelerate epiphyseal closure. However, untreated hypothyroidism may interfere with growth response to growth hormone.

Xanthine Derivatives

Decreased clearance of xanthine derivatives (e.g., theophylline) may occur in hypothyroid patients; clearance returns to normal when the euthyroid state is achieved.

Other Drugs

Cation-exchange resins (e.g., sodium polystyrene sulfonate) and ferrous sulfate bind thyroid agents in the GI tract and delay or prevent their absorption. To minimize or prevent this interaction, thyroid agents should be administered at least 4 hours apart from these drugs.

Concomitant use of ketamine with thyroid agents may produce marked hypertension and tachycardia; caution is advised when the drug is administered in patients receiving thyroid hormone therapy.

Laboratory Test Interferences

Drugs Affecting Thyroid Function or Thyroid Function Tests

Certain drugs and various pathologic and physiologic conditions can interfere with thyroid function tests and their interpretation, and the resultant effects must be considered.

Use of dopamine hydrochloride (at dosages of 1 mcg/kg per minute or greater), corticosteroids (at hydrocortisone-equivalent dosages of 100 mg daily or greater), or octreotide (at dosages exceeding 100 mcg daily) may result in a transient reduction in thyrotropin (thyroid-stimulating hormone, TSH) secretion. However, because these effects are transient, hypothyroidism is not expected to occur.

Drugs that may decrease thyroid hormone secretion (e.g., aminoglutethimide, amiodarone, iodide [including iodine-containing radiographic contrast agents], lithium, sulfonamides, tolbutamide) may be associated with hypothyroidism. Long-term lithium therapy can result in goiter in up to 50% of patients, and in subclinical or overt hypothyroidism, each in up to 20% of patients. The fetus, neonates, geriatric patients, and euthyroid patients with underlying thyroid disease (e.g., Hashimoto’s thyroiditis, Grave’s disease previously treated with radioiodine or surgery) are particularly susceptible to iodine-induced hypothyroidism. Oral cholecystographic agents and amiodarone are excreted slowly, producing more prolonged hypothyroidism than parenterally administered iodinated contrast agents. Long-term aminoglutethimide therapy may minimally decrease concentrations of T₄ and triiodothyronine (T₃) and increase concentrations of thyrotropin, although all values remain within normal limits in most patients.

Iodide (including iodine-containing radiographic contrast agents) and drugs that contain pharmacologic amounts of iodide may cause hyperthyroidism in euthyroid patients with Grave’s disease previously treated with antithyroid drugs or in euthyroid patients with thyroid autonomy (e.g., multinodular goiter or hyperfunctioning thyroid adenoma). Hyperthyroidism may develop over several weeks and may persist for several months following discontinuance of therapy. Amiodarone may induce hyperthyroidism by causing thyroiditis.

Pregnancy, estrogens, estrogen-containing oral contraceptives, methadone, fluorouracil, mitotane, and tamoxifen increase serum concentrations of thyroxine-binding globulin; in patients with normal thyroid function only a transient decrease in free serum thyroxine concentration results, but in patients receiving thyroid replacement therapy, an increase in thyroid agent dosage may be necessary. Chronic active hepatitis, neonatal state, acute intermittent porphyria, and genetic factors also may increase thyroxine-binding globulin concentrations. Androgens, usual doses of corticosteroids, asparaginase, and sustained release niacin decrease serum concentrations of thyroxine-binding globulin; decreases in serum concentrations of thyroxine-binding globulin also occur in nephrosis, cirrhosis, and acromegaly. Some drugs (e.g., phenylbutazone [no longer commercially available in the US], salicylates) competitively bind to thyroxine-binding globulin and/or thyroxine-binding prealbumin. Familial hyper- or hypo-thyroxine-binding-globulinemias also have been reported.

Concomitant use of levothyroxine sodium with furosemide (at IV dosages exceeding 80 mg), heparin, hydantoins, nonsteroidal anti-inflammatory agents (NSAIAs, e.g., fenamates, phenylbutazone), or salicylates (at dosages exceeding 2 g daily) results in an initial transient increase in concentrations of free T₄. Continued administration results in a decrease in serum T₄ and normal free T₄ and TSH concentrations; therefore, patients are clinically euthyroid. Salicylates inhibit binding of T₄ and T₃ to thyroxine-binding globulin (TBG) and transthyretin. An initial increase in serum free T₄ is followed by return of free T₄ to normal levels with sustained therapeutic serum salicylate concentrations, although total T₄ concentrations may decrease by as much as 30%.

Concomitant use of thyroid agents with amiodarone, β-adrenergic blocking agents (e.g., propranolol hydrochloride at dosages exceeding 160 mg daily), or corticosteroids (e.g., dexamethasone at dosages of 4 mg daily or greater) decreases peripheral conversion of T₄ to T₃, resulting in decreased T₃ concentrations. However, serum T₄ concentrations usually remain within normal range but may occasionally be slightly increased. In patients treated with large doses of propranolol hydrochloride (i.e., exceeding 160 mg/day), T₃ and T₄ concentrations change slightly, TSH levels remain normal, and patients are clinically euthyroid. It should be noted that actions of particular β-adrenergic blocking agents may be impaired when the hypothyroid patient is converted to the euthyroid state. Short-term administration of large doses of corticosteroids may decrease serum T₃ concentrations by 30% with minimal change in serum T₄ levels. However, long-term corticosteroid therapy may result in slightly decreased T₃ and T₄ concentrations because of decreased TBG production.

Therapy with interferon alfa has been associated with the development of antithyroid microsomal antibodies in 20% of patients, and some experience transient hypothyroidism, hyperthyroidism, or both. Patients who have antithyroid antibodies prior to treatment with thyroid agents are at higher risk for thyroid dysfunction during treatment. Interleukin 2 (e.g., aldesleukin) has been associated with transient painless thyroiditis in 20% of patients. Interferon beta and gamma have not been reported to cause thyroid dysfunction.

Other agents that have been associated with alterations in thyroid hormone and/or TSH concentrations include chloral hydrate, diazepam, ethionamide, lovastatin, metoclopramide, mercaptopurine, nitroprusside, aminosalicylate sodium, perphenazine, resorcinol (excessive topical use), and thiazide diuretics.

Other Laboratory Test Interferences

Radioactive iodine uptake tests used in evaluating thyroid function can be interfered with by dietary sources of iodine or iodine- or iodide-containing medications (e.g., potassium iodide).

Thyroid hormones may reduce the uptake of ¹²³I, ¹³¹I, and ^99mTc.

Acute Toxicity

Manifestations

In general, acute overdosage of thyroid agents may be expected to produce signs and symptoms of hyperthyroidism. (See Toxicity.) Cerebral embolism, shock, coma, and death have been reported. In addition, confusion and disorientation may occur. Seizures have occurred in a child who ingested approximately 18 mg of levothyroxine; manifestations of toxicity may not necessarily be evident or may not appear until several days after ingestion of levothyroxine sodium.

Treatment

In the treatment of acute thyroid agent overdosage, symptomatic and supportive therapy should be instituted immediately. Treatment consists principally of reducing GI absorption of the drugs and counteracting central and peripheral effects, mainly those of increased sympathetic activity. Initially, the stomach should be emptied immediately by inducing emesis or by gastric lavage; activated charcoal or cholestyramine resin also may be used to decrease absorption. If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents. Oxygen may be administered and ventilation maintained. If congestive heart failure develops, cardiac glycosides may be administered. Measures to control arrhythmia, fever, hypoglycemia, or fluid loss should be initiated as necessary. β-Adrenergic blocking agents (e.g., propranolol) are useful to counteract many of the effects of increased sympathetic activity. Large doses of antithyroid drugs (e.g., methimazole, propylthiouracil) followed in 1–2 hours by large doses of iodine may be administered to inhibit synthesis and release of thyroid hormones. Corticosteroids may be given to inhibit the conversion of T₄ to triiodothyronine (T₃). Plasmapheresis, charcoal hemoperfusion, and exchange transfusion have been reserved for cases in which continued clinical deterioration occurs despite conventional therapy. Because T₄ is highly protein bound, very little drug will be removed by dialysis.

Pharmacology

Thyroid Hormone Synthesis and Regulation

The extracts of the thyroid gland and hormones secreted by the gland or prepared synthetically are essential hormones that affect the rate of many physiologic processes. The amounts of thyroxine and triiodothyronine released into the circulation from the normally functioning thyroid gland are regulated by thyrotropin (thyroid-stimulating hormone, TSH), which is secreted by the anterior pituitary. Secretion of thyrotropin is in turn controlled by a feedback mechanism effected by concentrations of circulating thyroid hormones and by secretion of thyrotropin-releasing hormone (TRH) from the hypothalamus. Endogenous thyroid hormone secretion is suppressed when exogenous thyroid hormones are administered to euthyroid individuals in excess of the gland’s normal secretion.

Tetraiodothyronine (thyroxine, T₄) and triiodothyronine (T₃) are produced in the thyroid gland by the iodination and coupling of the amino acid tyrosine. Iodine is an essential component of thyroid hormones, thyroxine and triiodothyronine, comprising 65 and 59% of the weights, respectively. Thyroid hormones and thus iodine are essential for human life. The hormones regulate many key biochemical reactions, especially protein synthesis and enzymatic activity, and target the developing brain, muscle, heart, pituitary, and kidneys.

The thyroid gland selectively concentrates iodide in amounts required for adequate thyroid hormone synthesis, with most of the remaining iodide being excreted renally. A sodium/iodide transporter in the thyroidal basal membrane is responsible for iodine concentration in the gland, transferring iodide from systemic circulation into the thyroid gland at a concentration gradient of 20–50 times that of plasma to ensure that the gland receives adequate amounts of iodine for hormone synthesis. During iodine deficiency, the thyroid gland concentrates most of the iodine available from plasma. Iodide participates in a complex series of reactions in the thyroid gland to produce thyroid hormones. Thyroglobulin is synthesized in thyroid cells and serves as an iodination vehicle. Thyroperoxidase and hydrogen peroxide promote the oxidation of iodide and its attachment to tyrosyl residues within the thyroglobulin molecule to produce the hormone precursors diiodotyrosine and monoiodotyrosine. Thyroperoxidase further catalyzes intramolecular coupling of 2 molecules of diiodotyrosine to produce thyroxine (T₄) and coupling of a molecule of diiodotyrosine and a molecule of monoiodotyrosine to produce triiodothyronine (T₃). The average adult thyroid gland in individuals residing in an iodine-sufficient geographic region contains about 15 mg of iodine. Iodine is not released into systemic circulation but instead is stored principally in diiodo and monoiodo tyrosine precursors, removed from the tyrosine moiety by a specific deiodinase, and then recycled within the thyroid gland as a mechanism of iodine conservation.

Once in systemic circulation, thyroxine and triiodothyronine attach to several binding proteins (e.g., thyronine-binding globulin, transthyretin, albumin), which then migrate to target tissues where thyroxine is deiodinated to triiodothyronine, the metabolically active form of thyroid hormone. The iodine that is removed from thyroxine returns to the serum iodine pool and follows the usual iodine cycle or is excreted renally. Thyrotropin is the major thyroid function regulator. Thyrotropin affects several sites within thyrocytes, the principal actions of which are to increase thyroidal uptake of iodine and to break down thyroglobulin to release thyroid hormone into systemic circulation. An elevated serum thyrotropin concentration indicates primary hypothyroidism and a decreased serum concentration indicates hyperthyroidism. The normal thyroid gland takes up the amount of systemically circulating iodine necessary to make the amount of thyroid hormone for the body’s needs. In iodine deficiency, the thyroid gland will concentrate more iodine, and the gland will concentrate less in iodine excess. When iodine equilibrium is present, the mean daily thyroid iodine accumulation and release are similar.

Pharmacologic Effects of Exogenous Thyroid Hormones

The principal pharmacologic effect of exogenous thyroid hormones is to increase the metabolic rate of body tissues. Thyroid hormones affect protein and carbohydrate metabolism, promoting gluconeogenesis, increasing the utilization and mobilization of glycogen stores, and stimulating protein synthesis. Thyroid hormones affect lipid metabolism by decreasing hepatic and serum cholesterol concentrations. Thyroid hormones are also involved in the regulation of cell growth and differentiation. The hormones aid in the development of the brain and CNS (particularly axonal and dendritic networks and myelination), and are involved with somatotropin in the development of bones and teeth and in the broad aspect of growth.

Although the exact mechanism of action by which thyroid hormones affect metabolism and cellular growth and differentiation is not clearly established, it is known that these physiologic effects are mediated at the cellular level, principally via triiodothyronine. A major portion of triiodothyronine (approximately 70–90%) is derived from thyroxine by deiodination in peripheral tissues; approximately 35% of secreted thyroxine is monodeiodinated peripherally to triiodothyronine. Thyroxine is the major component of normal secretions of the thyroid gland and is therefore the principal determinant of normal thyroid function. In normal human thyroid tissue, the thyroxine:triiodothyronine ratio is 10:1 to 15:1; in hyperthyroid patients with Graves’ disease, the ratio is decreased to about 5:1.

Thyroid hormones also exhibit a cardiostimulatory effect which may be the result of a direct action on the heart. Thyroid hormones also may increase the sensitivity of the heart to catecholamines and/or increase the number of myocardial β-adrenergic receptors. Thyroid hormones increase cardiac output, in part, secondary to increased peripheral oxygen consumption. Thyroid hormones may increase renal blood flow and glomerular filtration rate in hypothyroid patients, resulting in a diuresis within 24 hours following administration.

Thyroid hormones will reverse the signs and symptoms of hypothyroidism and myxedema; in hypothyroid children, the hormones increase epiphyseal growth and bone ossification. For thyroid hormones to prevent the developmental abnormalities associated with congenital hypothyroidism (e.g., mental and growth retardation), the condition must be diagnosed and therapy initiated early.

Thyroid Agents General Statement Pharmacokinetics

Absorption

Levothyroxine sodium is variably absorbed from the GI tract (range 40–80%) following oral administration. The extent of absorption is increased in the fasting state and decreased in malabsorption states. Liothyronine sodium is almost completely absorbed from the GI tract (about 95%) following oral administration. The absorption of hormones contained in the natural thyroid agent preparations is similar to that of the synthetic hormones. Absorption of levothyroxine sodium or liothyronine sodium following IM administration may be variable and poor. Thyroxine apparently undergoes enterohepatic circulation.

In healthy individuals, total serum thyroxine (endogenous) concentrations range from about 5–12 mcg/dL, and free (unbound) serum thyroxine concentrations range from about 1–3 ng/dL (about 0.02% of total). Total serum triiodothyronine (endogenous) concentrations range from 70–200 ng/dL (considerable interlaboratory variation) in healthy individuals, and free serum triiodothyronine concentrations range from 0.2–0.4 ng/dL (about 0.2% of total). Total serum reverse triiodothyronine (See Pharmacokinetics: Elimination) concentrations range from 10–60 ng/dL, and free serum reverse triiodothyronine concentrations range from about 0.05–0.15 ng/dL (about 0.5% of total). Serum triiodothyronine concentrations appear to decline slightly with age, are slightly increased in obese individuals, and are decreased in the fetus and neonates. Serum reverse triiodothyronine concentrations appear to be increased in healthy individuals older than 70 years of age and markedly increased in the fetus and neonates. Age-adjusted normal range values for serum thyroid hormone concentrations may be required for proper interpretation of such measurements. Although the normal range for endogenous thyroid hormones is the therapeutic range for exogenously administered hormones in hypothyroid patients, free hormone concentrations are often not easily measured and other measures of thyroid function (e.g., resin triiodothyronine uptake, free thyroxine index) are generally used to monitor thyroid hormone replacement therapy.

The maximum effects of liothyronine sodium are apparent within 24–72 hours following initiation of oral therapy and persist for up to 72 hours following discontinuance of the drug. Levothyroxine sodium, thyroid, and thyroglobulin have a much slower onset and longer duration of action than liothyronine sodium. The full effects of levothyroxine sodium, thyroid, and thyroglobulin do not occur for 1–3 weeks following initiation of oral therapy, and effects are maintained for a similar period of time following discontinuance of the drugs.

Distribution

Distribution of thyroid hormones into human body tissues and fluids has not been fully characterized. Thyroxine is distributed into most body tissues and fluids with highest concentrations in the liver and kidneys. Thyroid hormones do not readily cross the placenta. Placental transfer of thyroid hormones is slow and the importance has not been precisely determined; the mother provides little, if any, thyroid hormone to the developing fetus. Minimal amounts of thyroid hormones are distributed into milk.

Thyroxine and triiodothyronine are more than 99% bound to serum proteins, principally thyronine-binding globulin (thyroxine-binding globulin, TBG) and transthyretin (thyroxine-binding prealbumin, TBPA) (and to a small extent albumin), whose capacities and affinities for the hormones vary. Thyroxine is more extensively and firmly bound than is triiodothyronine. The high affinity of thyroxine for TBG and TBPA is responsible for thyroxine’s high serum concentration and slow metabolic clearance. Certain drugs and various pathologic and physiologic conditions can alter the binding of thyroid hormones to serum proteins and/or the concentrations of the serum proteins that bind the hormones; these effects must be considered when interpreting the results of thyroid function tests. (See Laboratory Test Interferences.)

Elimination

The usual plasma half-lives of thyroxine and triiodothyronine are approximately 6–8 and 1–2 days, respectively. The plasma half-lives of thyroxine and triiodothyronine are decreased in patients with hyperthyroidism and increased in those with hypothyroidism.

In humans, endogenous thyroglobulin within the thyroid gland is proteolytically hydrolyzed, resulting in the release of thyroxine and triiodothyronine into the circulation. Thyroxine is conjugated with glucuronic and sulfuric acids in the liver and distributed into bile; a portion is then hydrolyzed in the intestine and reabsorbed, and a portion reaches the colon unchanged, where it is then hydrolyzed and eliminated unchanged in the feces. About 20–40% of thyroxine is eliminated in feces. About 35% of secreted thyroxine is monodeiodinated at the 5′ position of the phenolic (outer) ring in peripheral tissues, principally liver and kidney, to form triiodothyronine; this accounts for about 80% of the total daily production of triiodothyronine. Thyroxine also undergoes peripheral monodeiodination at the 5 position of the tyrosyl (inner) ring to form reverse triiodothyronine (reverse T₃, rT₃), which is calorigenically inactive. About 85% of thyroxine metabolized daily is deiodinated. Deiodination is apparently an enzymatic process, and probably involves separate iodothyronine 5′- and 5-deiodinases which have a high capacity and are probably subject to some form(s) of regulation. The metabolic fate of triiodothyronine is not clearly established. Triiodothyronine and reverse triiodothyronine undergo peripheral monodeiodination to form 3,3′-diiodothyronine. Additional thyroid hormone metabolites in which the diphenyl ether linkage is either intact or broken have also been detected. Iodine liberated by deiodination reactions is utilized by the thyroid gland for hormone synthesis or is excreted in feces via bile or in urine.

Chemistry

Thyroid agents are natural or synthetic preparations containing tetraiodothyronine (thyroxine, T₄) and/or triiodothyronine (T₃). Thyroxine and triiodothyronine are produced in the human thyroid gland; the commercially available synthetic preparations of these hormones, levothyroxine sodium and liothyronine sodium, respectively, are the sodium salts of the L-isomers of the hormones. Thyroxine and triiodothyronine are produced in the thyroid gland by the iodination and coupling of the amino acid tyrosine. Thyroxine contains 4 iodine atoms and is formed by the coupling of 2 molecules of diiodotyrosine. Triiodothyronine contains 3 iodine atoms and is formed by the coupling of one molecule of diiodotyrosine with one molecule of monoiodotyrosine. Thyroxine and triiodothyronine are stored in the thyroid colloid as thyroglobulin.

Natural thyroid agent preparations, which are derived from animal thyroid, include thyroid and thyroglobulin. USP previously required that thyroid and thyroglobulin be standardized only by their iodine content which is only an indirect indicator of true hormonal biologic activity. Some manufacturers of thyroid perform bioassays of their preparations to assure batch-to-batch reproducibility of metabolic potency, and the manufacturer of thyroglobulin standardizes the levothyroxine and liothyronine contents of the preparation by chromatographic analysis; however, the concentrations of levothyroxine and liothyronine and the ratio of these hormones in these commercially available preparations may vary considerably. Even preparations that are standardized for metabolic potency via a bioassay may differ from other bioassay preparations in the ratio of levothyroxine:liothyronine concentration. Current USP standards specify the measurable amounts of levothyroxine and liothyronine in each 65 mg of thyroid or thyroglobulin; however, because of difficulty in measuring the actual hormonal content of thyroid USP or thyroglobulin USP, these measurable amounts may be less than the clinical equivalent. In guiding dosage adjustment, the clinical equivalent and not the measurable amount should be used.

Synthetic thyroid agent preparations include levothyroxine sodium, liothyronine sodium, and liotrix, a combination preparation containing a ratio of levothyroxine sodium to liothyronine sodium of 4:1 by weight; however, current USP standards do not specify the ratio of levothyroxine sodium and liothyronine sodium in liotrix.

Because some thyroid agent preparations currently may not be standardized by their levothyroxine and/or liothyronine contents and because the measurable amounts of these drugs in thyroid and thyroglobulin may be less than the clinical equivalent, thyroid agent preparations are not necessarily directly comparable; however, the following equivalencies have been suggested based on clinical response:

These approximate clinical equivalents should be used in guiding dosage adjustment; following a change from one type of thyroid hormone preparation to another, patients still may require fine adjustment of dosage since the equivalents are only estimates.

Related Monographs

For further information on chemistry and stability, pharmacology, pharmacokinetics, uses, cautions, and dosage and administration of thyroid agents, see the individual monographs in 68:36.04.

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