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Basic & Clinical Pharmacology, 15e

Chapter 38: Thyroid & Antithyroid Drugs

Betty J. Dong

CASE STUDY

CASE STUDY

JP is a 33-year-old woman who presents with complaints of fatigue requiring daytime naps, weight gain, cold intolerance, and muscle weakness for
the last few months*. These complaints are new since she used to always feel “hot,” noted difficulty sleeping, and could eat anything that she
wanted without gaining weight. She also would like to become pregnant in the near future. Because of poor medication adherence to methimazole
and propranolol, she received radioactive iodine (RAI) therapy, developed hypothyroidism, and was started on levothyroxine 100 mcg daily. Other
medications include calcium carbonate three times daily to “protect her bones” and omeprazole for “heartburn.” On physical examination, her
blood pressure is 130/89 mm Hg with a pulse of 50 bpm. Her weight is 136 lb (61.8 kg), an increase of 10 lb (4.5 kg) in the last year. Her thyroid gland
is not palpable and her reflexes are delayed. Laboratory findings include a thyroid-stimulating hormone (TSH) level of 24.9 μIU/mL (normal 0.45–
4.12 μIU/mL) and a free thyroxine level of 8 pmol/L (normal 10–18 pmol/L). Evaluate the management of her past history of hyperthyroidism and
assess her current thyroid status. Identify your treatment recommendations to maximize control of her current thyroid status.

*This chapter is dedicated to Dr. Francis S. Greenspan, co-author, mentor, colleague, and friend who will be sorely missed by his many colleagues and

by his patients for his kindness, generosity, and expert care as chief of the Thyroid Clinic.

THYROID PHYSIOLOGY
The normal thyroid gland secretes sufficient amounts of the thyroid hormones—triiodothyronine (T3 ) and tetraiodothyronine (T4 , thyroxine)—
to normalize growth and development, body temperature, and energy levels. These hormones contain 59% and 65% (respectively) iodine as an
essential part of the molecule. Calcitonin, the second type of thyroid hormone, is important in the regulation of calcium metabolism and is discussed in
Chapter 42.

Iodide Metabolism

The recommended daily adult iodide (I−)† intake is 150 mcg (200 mcg during pregnancy and lactation and up to 250 mcg for children).

Iodide, ingested from food, water, or medication, is rapidly absorbed and enters an extracellular fluid pool. The thyroid gland removes about 75 mcg a
day from this pool for hormone synthesis, and the balance is excreted in the urine. If iodide intake is increased, the fractional iodine uptake by the
thyroid is diminished.

†In this chapter, the term iodine denotes all forms of the element; the term iodide denotes only the ionic form, I−.

Biosynthesis of Thyroid Hormones

Once taken up by the thyroid gland, iodide undergoes a series of enzymatic reactions that incorporate it into active thyroid hormone (Figure 38–1). The
first step is the transport of iodide into the thyroid gland by an intrinsic follicle cell basement membrane protein called the sodium/iodide symporter
(NIS). This can be inhibited by large doses of iodides as well as anions—eg, thiocyanate (SCN−), pertechnetate (TcO4−), and perchlorate (CIO4−). At the

apical cell membrane a second I− transport enzyme called pendrin controls the flow of iodide across the membrane. Pendrin is also found in the
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cochlea of the inner ear. If pendrin is deficient or absent (SLC26A4 mutation), a hereditary syndrome of goiter and deafness, called Pendred
Chapter 38: Thyroid & Antithyroid Drugs, Betty J. Dong Page 1 / 28
syndrome
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tyrosine residues within the thyroglobulin molecule to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). This process is called iodide
organification. Thyroidal peroxidase is transiently blocked by high levels of intrathyroidal iodide and blocked more persistently by thioamide drugs.
Biosynthesis of Thyroid Hormones
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Once taken up by the thyroid gland, iodide undergoes a series of enzymatic reactions that incorporate it into active thyroid hormone (Figure 38–1). The
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first step is the transport of iodide into the thyroid gland by an intrinsic follicle cell basement membrane protein called the sodium/iodide symporter
(NIS). This can be inhibited by large doses of iodides as well as anions—eg, thiocyanate (SCN−), pertechnetate (TcO4−), and perchlorate (CIO4−). At the

apical cell membrane a second I− transport enzyme called pendrin controls the flow of iodide across the membrane. Pendrin is also found in the
cochlea of the inner ear. If pendrin is deficient or absent (SLC26A4 mutation), a hereditary syndrome of goiter and deafness, called Pendred
syndrome (PDS), ensues. At the apical cell membrane, iodide is oxidized by thyroidal peroxidase (TPO) to iodine, in which form it rapidly iodinates
tyrosine residues within the thyroglobulin molecule to form monoiodotyrosine (MIT) and diiodotyrosine (DIT). This process is called iodide
organification. Thyroidal peroxidase is transiently blocked by high levels of intrathyroidal iodide and blocked more persistently by thioamide drugs.
Gene expression of TPO is stimulated by thyroid-stimulating hormone (TSH).

FIGURE 38–1

Biosynthesis of thyroid hormones. The sites of action of various drugs that interfere with thyroid hormone biosynthesis are shown. (Adapted with
permission from Gardner DG, Shoback D: Greenspan’s Basic & Clinical Endocrinology, 8th ed. New York, NY: McGraw Hill; 2007.)

Two molecules of DIT combine within the thyroglobulin molecule to form L-thyroxine (T4). One molecule of MIT and one molecule of DIT combine to
form T3. In addition to thyroglobulin, other proteins within the gland may be iodinated, but these iodoproteins do not have hormonal activity.
Thyroxine, T3, MIT, and DIT are released from thyroglobulin by exocytosis and proteolysis of thyroglobulin at the apical colloid border. The MIT and DIT
are then deiodinated within the gland, and the iodine is reutilized. This process of proteolysis is also blocked by high levels of intrathyroidal iodide.
The ratio of T4 to T3 within thyroglobulin is approximately 5:1, so that most of the hormone released is thyroxine. Eighty percent of T3 circulating in the
blood is derived from peripheral metabolism of thyroxine and the rest from direct thyroid secretion (see below, Figure 38–2).

FIGURE 38–2

Peripheral metabolism of thyroxine. (Adapted with permission from Gardner DG, Shoback D: Greenspan’s Basic & Clinical Endocrinology, 8th ed. New
York, NY: McGraw Hill; 2007.)

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FIGURE 38–2
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Peripheral metabolism of thyroxine. (Adapted with permission from Gardner DG, Shoback D: Greenspan’s Basic & Clinical Endocrinology, 8th ed. New
York, NY: McGraw Hill; 2007.)

Transport of Thyroid Hormones

Thyroxine and T3 in plasma are reversibly bound to protein, primarily thyroxine-binding globulin (TBG). Only about 0.04% of total T4 and 0.4% of T3
exist in the free form (as FT4 and FT3). Many physiologic and pathologic states and drugs affect T4, T3, and thyroid transport. However, the actual levels
of free hormone generally remain normal, reflecting feedback control.

Peripheral Metabolism of Thyroid Hormones

The primary pathway for the peripheral metabolism of thyroxine is deiodination by three 5′-deiodinase enzymes (D1, D2, D3). Deiodination of T4 may
occur by monodeiodination of the outer ring, producing 3,5,3′-triiodothyronine (T3), which is three to four times more potent than T4. The D1 enzyme
is responsible for about 24% of the circulating T3 while 64% of peripheral T3 is generated by D2, which also regulates T3 levels in the brain and pituitary.
D3 deiodination produces metabolically inactive 3,3′,5′-triiodothyronine (reverse T3 [rT3]) (Figure 38–2). The low serum levels of T3 and rT3 in normal
individuals are due to the high metabolic clearances of these two compounds.

Drugs such as amiodarone, iodinated contrast media, β blockers, and corticosteroids, as well as severe illness or starvation, inhibit the 5′-deiodinase
necessary for the conversion of T4 to T3, resulting in low T3 and high rT3 levels in the serum. A polymorphism in the D2 gene can reduce T3 activation
and impair thyroid hormone response. The pharmacokinetics of thyroid hormones are listed in Table 38–1.

TABLE 38–1
Summary of thyroid hormone kinetics.

Variable T4 T3

Volume of distribution 10 L 40 L

Extrathyroidal pool 800 mcg 54 mcg

Daily production 75 mcg 25 mcg

Fractional turnover per day 10% 60%

Metabolic clearance per day 1.1 L 24 L

Half-life (biologic) 7 days 1 day

Serum levels
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Chapter Total
38: Thyroid & Antithyroid Drugs, Betty J. Dong 4.8–10.4 mcg/dL 59–156 ng/dL
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(62–134 nmol/L) (09–2.4 nmol/L)

individuals are due to the high metabolic clearances of these two compounds.
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Drugs such as amiodarone, iodinated contrast media, β blockers, and corticosteroids, as well as severe illness or starvation, inhibit the 5′-deiodinase
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necessary for the conversion of T4 to T3, resulting in low T3 and high rT3 levels in the serum. A polymorphism in the D2 gene can reduce T3 activation
and impair thyroid hormone response. The pharmacokinetics of thyroid hormones are listed in Table 38–1.

TABLE 38–1
Summary of thyroid hormone kinetics.

Variable T4 T3

Volume of distribution 10 L 40 L

Extrathyroidal pool 800 mcg 54 mcg

Daily production 75 mcg 25 mcg

Fractional turnover per day 10% 60%

Metabolic clearance per day 1.1 L 24 L

Half-life (biologic) 7 days 1 day

Serum levels

Total 4.8–10.4 mcg/dL 59–156 ng/dL

(62–134 nmol/L) (09–2.4 nmol/L)

Free 0.8–1.4 ng/dL 169–371 pg/dL

(10–18 pmol/L) (2.6–5.7 pmol/L)

Amount bound 99.96% 99.6%

Biologic potency 1 4

Oral absorption 70% 95%

Evaluation of Thyroid Function

The tests used to evaluate thyroid function are listed in Table 38–2.

TABLE 38–2
Typical adult values for thyroid function tests.

Results in Results in
Name of Test Normal Value1
Hypothyroidism Hyperthyroidism

Total thyroxine (T4) 4.8–10.4 mcg/dL (62–134 Low High

nmol/L)

Total triiodothyronine (T3) 59–156 ng/dL Normal or low High

(0.9–2.4 nmol/L)
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Free T4Thyroid
(FT4) & Antithyroid Drugs, Betty J. Dong 0.8–1.4 ng/dL (10–18 Low High Page 4 / 28
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pmol/L)• Notice • Accessibility

Free T3 (FT3) 169–371 ng/dL (2.6–5.7 Low High

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Evaluation of Thyroid Function Access Provided by:

The tests used to evaluate thyroid function are listed in Table 38–2.

TABLE 38–2
Typical adult values for thyroid function tests.

Results in Results in
Name of Test Normal Value1
Hypothyroidism Hyperthyroidism

Total thyroxine (T4) 4.8–10.4 mcg/dL (62–134 Low High

nmol/L)

Total triiodothyronine (T3) 59–156 ng/dL Normal or low High

(0.9–2.4 nmol/L)

Free T4 (FT4) 0.8–1.4 ng/dL (10–18 Low High

pmol/L)

Free T3 (FT3) 169–371 ng/dL (2.6–5.7 Low High

pmol/L)

Thyrotropic hormone (TSH) 0.45–4.12 μIU/mL High2 Low

(0.45–4.12 mIU/L)

123I uptake at 24 hours 5–35% Low High

Antithyroglobulin antibodies (Tg-Ab) <200 IU/mL Often present Usually present

Thyroperoxidase antibodies (ATPO) ≤100 WHO units Often present Usually present

Isotope scan with 123I or 99mTcO4 Normal pattern Test not indicated Diffusely enlarged gland

Fine-needle aspiration (FNA) biopsy Normal pattern Test not indicated Test not indicated

Serum thyroglobulin Women: 1.5–38.5 mcg/L Test not indicated Test not indicated

Men: 1.4–29.2 mcg/L

TSH receptor-stimulating antibody or thyroid-stimulating Negative <140% of Test not indicated Elevated in Graves
immunoglobulin (TSI) baseline disease

1Results may vary with different laboratories.

2Exception is central hypothyroidism.

A. Thyroid-Pituitary Relationships

Control of thyroid function via thyroid-pituitary feedback is also discussed in Chapter 37. Hypothalamic cells secrete thyrotropin-releasing hormone
(TRH) (Figure 38–3). TRH is secreted into capillaries of the pituitary portal venous system, and in the pituitary gland, TRH stimulates the synthesis and
release of thyrotropin (thyroid-stimulating hormone, TSH). TSH in turn stimulates an adenylyl cyclase–mediated mechanism in the thyroid cell to
increase the synthesis
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the action of TSH and in the hypothalamus to inhibit J. Dong Page 5 / 28
synthesis and secretion of TRH. Other hormones or drugs may also affect the release of TRH or
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TSH.

FIGURE 38–3
A. Thyroid-Pituitary Relationships
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Control of thyroid function via thyroid-pituitary feedback is also discussed in Chapter 37. Hypothalamic cells secrete thyrotropin-releasing hormone
(TRH) (Figure 38–3). TRH is secreted into capillaries of the pituitary portal venous system, and in the pituitary gland, TRH stimulates the synthesis and
release of thyrotropin (thyroid-stimulating hormone, TSH). TSH in turn stimulates an adenylyl cyclase–mediated mechanism in the thyroid cell to
increase the synthesis and release of T4 and T3. T3, the more active of the two hormones, acts in a negative feedback fashion in the pituitary to block
the action of TSH and in the hypothalamus to inhibit the synthesis and secretion of TRH. Other hormones or drugs may also affect the release of TRH or
TSH.

FIGURE 38–3

The hypothalamic-pituitary-thyroid axis. Acute psychosis or prolonged exposure to cold may activate the axis. Hypothalamic thyroid-releasing
hormone (TRH) stimulates pituitary thyroid-stimulating hormone (TSH) release, while somatostatin and dopamine inhibit it. TSH stimulates T4 and T3
synthesis and release from the thyroid, and they in turn inhibit both TRH and TSH synthesis and release. Small amounts of iodide are necessary for
hormone production, but large amounts inhibit T3 and T4 production and release. Solid arrows, stimulatory influence; dashed arrows, inhibitory
influence. H, hypothalamus; AP, anterior pituitary.

B. Autoregulation of the Thyroid Gland

The thyroid gland also regulates its uptake of iodide and thyroid hormone synthesis by intrathyroidal mechanisms that are independent of TSH. These
mechanisms are primarily related to the level of iodine in the blood. Large doses of iodine inhibit iodide organification (Wolff-Chaikoff block; see
Figure 38–1). In certain disease states (eg, Hashimoto thyroiditis), this can inhibit thyroid hormone synthesis and result in hypothyroidism.
Hyperthyroidism can result from the loss of the Wolff-Chaikoff block in susceptible individuals (eg, multinodular goiter).

C. Abnormal Thyroid Stimulators

In Graves disease (see below), lymphocytes secrete a TSH receptor–stimulating antibody (TSH-R Ab [stim]), also known as thyroid-stimulating
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immunoglobulin (TSI).
Chapter 38: Thyroid This immunoglobulin
&amp; binds
Antithyroid Drugs, to J.
Betty the TSH receptor and stimulates the gland in the same fashion as TSH itself. The duration
Dong Page of
6 /its
28
effect, however, is much longer than that of TSH. TSH receptors are also found in orbital fibrocytes,
©2021 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility which may be stimulated by high levels of TSH-R Ab
[stim] and can cause ophthalmopathy.
Figure 38–1). In certain disease states (eg, Hashimoto thyroiditis), this can inhibit thyroid hormone synthesis and result in hypothyroidism.
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Hyperthyroidism can result from the loss of the Wolff-Chaikoff block in susceptible individuals (eg, multinodular goiter).
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C. Abnormal Thyroid Stimulators

In Graves disease (see below), lymphocytes secrete a TSH receptor–stimulating antibody (TSH-R Ab [stim]), also known as thyroid-stimulating
immunoglobulin (TSI). This immunoglobulin binds to the TSH receptor and stimulates the gland in the same fashion as TSH itself. The duration of its
effect, however, is much longer than that of TSH. TSH receptors are also found in orbital fibrocytes, which may be stimulated by high levels of TSH-R Ab
[stim] and can cause ophthalmopathy.

BASIC PHARMACOLOGY OF THYROID & ANTITHYROID DRUGS

THYROID HORMONES

Chemistry

The structural formulas of thyroxine and triiodothyronine as well as reverse triiodothyronine (rT3) are shown in Figure 38–2. All of these naturally
occurring molecules are levo (L) isomers. The synthetic dextro (D) isomer of thyroxine, dextrothyroxine, has approximately 4% of the biologic activity of
the L-isomer as evidenced by its lesser ability to suppress TSH secretion and correct hypothyroidism.

Pharmacokinetics

Thyroxine is absorbed best in the duodenum and ileum; absorption is modified by intraluminal factors such as food, drugs, gastric acidity, and
intestinal flora. Oral bioavailability of current tablet preparations of L-thyroxine averages 70–80% (Table 38–1) and is improved with the Tirosint
formulations (see below). In contrast, T3 is almost completely absorbed (95%). T4 and T3 absorption appears not to be affected by mild hypothyroidism
but may be impaired in severe myxedema with ileus. These factors are important in switching from oral to parenteral therapy. For parenteral use, the
intravenous route is preferred for both hormones.

In patients with hyperthyroidism, the metabolic clearances of T4 and T3 are increased and the half-lives decreased; the opposite is true in patients with
hypothyroidism. Drugs that induce hepatic microsomal enzymes (eg, rifampin, phenobarbital, carbamazepine, phenytoin, tyrosine kinase inhibitors,
HIV protease inhibitors) increase the metabolism of both T4 and T3 (Table 38–3). Despite this change in clearance, the normal hormone concentration
is maintained in the majority of euthyroid patients as a result of compensatory hyperfunction of the thyroid. However, patients dependent on T4
replacement medication may require increased dosages to maintain clinical effectiveness. A similar compensation occurs if binding sites are altered. If
TBG sites are increased by pregnancy, estrogens, or oral contraceptives, there is an initial shift of hormone from the free to the bound state and a
decrease in its rate of elimination until the normal free hormone concentration is restored. Thus, the concentration of total and bound hormone will
increase, but the concentration of free hormone and the steady-state elimination will remain normal. The reverse occurs when thyroid binding sites
are decreased.

TABLE 38–3
Drug effects and thyroid function.

Drug Effect Drugs

Change in thyroid hormone synthesis

Inhibition of TRH or TSH secretion without Bexarotene, dopamine, bromocriptine, cabergoline, levodopa, corticosteroids, somatostatin, octreotide,
induction of hypothyroidism or metformin, interleukin-6, heroin
hyperthyroidism

Inhibition of thyroid hormone synthesis or Iodides (including amiodarone), lithium, aminoglutethimide, thioamides, ethionamide, tyrosine kinase
release with the induction of hypothyroidism inhibitors (eg, sunitinib, sorafenib, imatinib), HIV protease inhibitors
(or occasionally hyperthyroidism)

Alteration of thyroid hormone transport and serum total T3 a n d T4 levels, but usually no modification of FT4 or TSH

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Estrogens, tamoxifen, raloxifene, heroin, methadone, mitotane, 5-fluorouracil, perphenazine
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Decreased TBG Androgens, anabolic steroids, glucocorticoids, danazol, L-asparaginase, nicotinic acid
 Inhibition of thyroid hormone synthesis or Iodides (including amiodarone), lithium, aminoglutethimide, thioamides, ethionamide, tyrosine kinase
release with the induction of hypothyroidism inhibitors (eg, sunitinib, sorafenib, imatinib), HIV protease inhibitors Pontificia Universidad Javeriana
(or occasionally hyperthyroidism) Access Provided by:

Alteration of thyroid hormone transport and serum total T3 a n d T4 levels, but usually no modification of FT4 or TSH

Increased TBG Estrogens, tamoxifen, raloxifene, heroin, methadone, mitotane, 5-fluorouracil, perphenazine

Decreased TBG Androgens, anabolic steroids, glucocorticoids, danazol, L-asparaginase, nicotinic acid

Displacement of T3 and T4 from TBG with Salicylates, fenclofenac, mefenamic acid, intravenous furosemide, heparin

transient hyperthyroxinemia

Alteration of T4 a n d T3 metabolism with modified serum T3 a n d T4 levels but not TSH levels (unless receiving thyroxine replacement

therapy)

Increased hepatic metabolism, enhanced Nicardipine, phenytoin, carbamazepine, primidone, phenobarbital, rifampin, rifabutin, tyrosine kinase
degradation of thyroid hormone inhibitors (eg, sunitinib, sorafenib, imatinib), sertraline, quetiapine

Inhibition of 5′-deiodinase with decreased Iopanoic acid, ipodate, amiodarone, β blockers, corticosteroids, propylthiouracil, flavonoids, interleukin-6
T 3, increased rT3

Other interactions

Interference with T4 absorption from the Oral bisphosphonates, cholestyramine, colesevelam, colestipol, chromium picolinate, charcoal,

gut ciprofloxacin, proton pump inhibitors, sucralfate, Kayexalate, raloxifene, sevelamer hydrochloride,
aluminum hydroxide, ferrous sulfate, calcium carbonate, bran/fiber, soy, coffee, orlistat

Induction of autoimmune thyroid disease Interferon-α, interleukin-2, interferon-β, lithium, amiodarone, tyrosine kinase inhibitors (eg, sunitinib,
with hypothyroidism or hyperthyroidism sorafenib, imatinib)

Effect of thyroid function on drug effects

Anticoagulation Lower doses of warfarin required in hyperthyroidism, higher doses in hypothyroidism

Glucose control Increased hepatic glucose production and glucose intolerance in hyperthyroidism; impaired insulin action
and glucose disposal in hypothyroidism

Cardiac drugs Higher doses of digoxin required in hyperthyroidism; lower doses in hypothyroidism

Sedatives; analgesics Increased sedative and respiratory depressant effects from sedatives and opioids in hypothyroidism;
converse in hyperthyroidism

Mechanism of Action

A model of thyroid hormone action is depicted in Figure 38–4, which shows the free forms of thyroid hormones, T4 and T3, dissociated from thyroid-
binding proteins, entering the cell by the active transporters (eg, monocarboxylate transporter 8 [MCT8], MCT10, and organic anion transporting
polypeptide [OATP1C1]). Transporter mutations can result in a clinical syndrome of mental retardation, myopathy, and low serum T4 levels (Allan-
Herndon-Dudley syndrome). Within the cell, T4 is converted to T3 by 5′-deiodinase, and the T3 enters the nucleus, where T3 binds to a specific T3
thyroid receptor protein, a member of the c-erb oncogene family. (This family also includes the steroid hormone receptors and receptors for vitamins
A and D.) The T3 receptor exists in two forms, α and β. Differing concentrations of receptors in different tissues (eg, α receptors in the brain and β
receptors in the liver) may account for variations in T3 effect on these tissues. Mutations in both α and β genes have been associated with generalized
thyroid hormone resistance. Cigarette smoking and environmental agents (eg, polychlorinated biphenyls) also may interfere with receptor action.

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Model of the interaction of T3 with the T3 receptor. ( A ) Inactive phase—the unliganded T3 receptor dimer bound to the thyroid hormone response
element (TRE) along with corepressors acts as a suppressor of gene transcription. (B) Active phase—T3 and T4 circulate bound to thyroid-binding
thyroid receptor protein, a member of the c-erb oncogene family. (This family also includes the steroid hormone receptors and receptors for vitamins
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A and D.) The T3 receptor exists in two forms, α and β. Differing concentrations of receptors in different tissues (eg, α receptors in the brain and β
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receptors in the liver) may account for variations in T3 effect on these tissues. Mutations in both α and β genes have been associated with generalized
thyroid hormone resistance. Cigarette smoking and environmental agents (eg, polychlorinated biphenyls) also may interfere with receptor action.

FIGURE 38–4

Model of the interaction of T3 with the T3 receptor. ( A ) Inactive phase—the unliganded T3 receptor dimer bound to the thyroid hormone response
element (TRE) along with corepressors acts as a suppressor of gene transcription. (B) Active phase—T3 and T4 circulate bound to thyroid-binding
proteins (TBPs). The free hormones are transported into the cell by a specific transport system. Within the cytoplasm, T4 is converted to T3 by 5′-
deiodinase (5′DI); T3 then moves into the nucleus. There it binds to the ligand-binding domain of the thyroid receptor (TR) monomer. This promotes
disruption of the TR homodimer and heterodimerization with retinoid X receptor (RXR) on the TRE, displacement of corepressors, and binding of
coactivators. The TR-coactivator complex activates gene transcription, which leads to alteration in protein synthesis and cellular phenotype. TR-LBD,
T3 receptor ligand-binding domain; TR-DBD, T3 receptor DNA-binding domain; RXR-LBD, retinoid X receptor ligand-binding domain; RXR-DBD, retinoid
X receptor DNA-binding domain; T3, triiodothyronine; T4, tetraiodothyronine, L-thyroxine. (Adapted with permission from Gardner DG, Shoback D:
Greenspan’s Basic & Clinical Endocrinology, 8th ed. New York, NY: McGraw Hill; 2007.)

Most of the effects of thyroid on metabolic processes appear to be mediated by activation of nuclear receptors that lead to increased formation of RNA
and subsequent protein synthesis, eg, increased formation of Na+/K+-ATPase. This is consistent with the observation that the action of thyroid is
manifested in vivo with a time lag of hours or days after its administration.

Large numbers of thyroid hormone receptors are found in the most hormone-responsive tissues (pituitary, liver, kidney, heart, skeletal muscle, lung,
and intestine), while few receptor sites occur in hormone-unresponsive tissues (spleen, testes). The brain, which lacks an anabolic response to T3,
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contains an intermediate P Your
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of receptors. In congruence with their biologic potencies, the affinity of the receptor site for T4 is about 10 times
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lower
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• Notice altered to preserve body homeostasis. For example, starvation
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lowers both circulating T3 hormone and cellular T3 receptors.
Most of the effects of thyroid on metabolic processes appear to be mediated by activation of nuclear receptors that lead to increased formation of RNA
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and subsequent protein synthesis, eg, increased formation of Na+/K+-ATPase. This is consistent with the observation that the action of thyroid is
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manifested in vivo with a time lag of hours or days after its administration.

Large numbers of thyroid hormone receptors are found in the most hormone-responsive tissues (pituitary, liver, kidney, heart, skeletal muscle, lung,
and intestine), while few receptor sites occur in hormone-unresponsive tissues (spleen, testes). The brain, which lacks an anabolic response to T3,
contains an intermediate number of receptors. In congruence with their biologic potencies, the affinity of the receptor site for T4 is about 10 times
lower than that for T3. Under some conditions, the number of nuclear receptors may be altered to preserve body homeostasis. For example, starvation
lowers both circulating T3 hormone and cellular T3 receptors.

Effects of Thyroid Hormones

The thyroid hormones are responsible for optimal growth, development, function, and maintenance of all body tissues. Excess or inadequate amounts
result in the signs and symptoms of hyperthyroidism or hypothyroidism, respectively (Table 38–4). Since T3 and T4 are qualitatively similar, they may be
considered as one hormone in the discussion that follows.

TABLE 38–4
Manifestations of thyrotoxicosis and hypothyroidism.

System Thyrotoxicosis Hypothyroidism

Skin and Warm, moist skin; sweating; heat intolerance; fine, thin hair; Pale, cool, puffy, yellowish skin, face, and hands; dry and brittle hair;
appendages Plummer’s nails; pretibial dermopathy (Graves disease) brittle nails

Eyes, face Retraction of upper lid with wide stare; periorbital edema; Drooping of eyelids; periorbital edema; loss of temporal aspects of
exophthalmos; diplopia (Graves disease) eyebrows; puffy, nonpitting facies; large tongue, hoarseness

Cardiovascular Decreased peripheral vascular resistance; increased heart Increased peripheral vascular resistance; decreased heart rate, stroke
system rate, stroke volume, cardiac output, pulse pressure; high- volume, cardiac output, pulse pressure; low-output heart failure; ECG:
output heart failure; increased inotropic and chronotropic bradycardia, prolonged PR interval, flat T wave, low voltage;
effects; arrhythmias; angina pericardial effusion

Respiratory Dyspnea; hypoventilation; decreased vital capacity Pleural effusions; hypoventilation and CO2 retention; sleep apnea
system

Gastrointestinal Increased appetite; increased frequency of bowel Decreased appetite; decreased frequency of bowel movements,
system movements; hypoproteinemia constipation; ascites

Central nervous Nervousness; hyperkinesia; emotional lability, agitation Lethargy/fatigue; general slowing of mental processes; neuropathies;
system weakness and muscle cramps

Musculoskeletal Weakness and muscle fatigue; increased deep tendon Stiffness and muscle fatigue; carpal tunnel syndrome; decreased deep
system reflexes; tremors; hypercalcemia; osteoporosis tendon reflexes; increased alkaline phosphatase, LDH, AST

Renal system Mild polyuria; increased renal blood flow; increased Impaired water excretion; decreased renal blood flow; decreased
glomerular filtration rate glomerular filtration rate

Hematopoietic Increased erythropoiesis; anemia1 Decreased erythropoiesis; anemia1

system

Reproductive Menstrual irregularities; amenorrhea; infertility; increased Menorrhagia; infertility; decreased libido; impotence; oligospermia;
system gonadal steroid metabolism decreased gonadal steroid metabolism

Metabolic Increased basal metabolic rate; negative nitrogen balance; Decreased basal metabolic rate; slight positive nitrogen balance;
system hyperglycemia; increased free fatty acids; decreased total delayed degradation of insulin with increased sensitivity; increased
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and triglycerides; increased hormone total cholesterol and triglycerides; hyponatremia; decreased
Chapter 38: Thyroid &amp; Antithyroid Drugs,
degradation; increased Betty J. Dong
requirements for fat- and water-
Page 10 / 28
hormone degradation; decreased requirements for fat- and water-
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soluble vitamins; increased drug metabolism; decreased soluble vitamins; decreased drug metabolism; increased warfarin
warfarin requirement requirement
 Pontificia Universidad Javeriana
The thyroid hormones are responsible for optimal growth, development, function, and maintenance of all body tissues. Excess or inadequate amounts
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result in the signs and symptoms of hyperthyroidism or hypothyroidism, respectively (Table 38–4). Since T3 and T4 are qualitatively similar, they may be
considered as one hormone in the discussion that follows.

TABLE 38–4
Manifestations of thyrotoxicosis and hypothyroidism.

System Thyrotoxicosis Hypothyroidism

Skin and Warm, moist skin; sweating; heat intolerance; fine, thin hair; Pale, cool, puffy, yellowish skin, face, and hands; dry and brittle hair;
appendages Plummer’s nails; pretibial dermopathy (Graves disease) brittle nails

Eyes, face Retraction of upper lid with wide stare; periorbital edema; Drooping of eyelids; periorbital edema; loss of temporal aspects of
exophthalmos; diplopia (Graves disease) eyebrows; puffy, nonpitting facies; large tongue, hoarseness

Cardiovascular Decreased peripheral vascular resistance; increased heart Increased peripheral vascular resistance; decreased heart rate, stroke
system rate, stroke volume, cardiac output, pulse pressure; high- volume, cardiac output, pulse pressure; low-output heart failure; ECG:
output heart failure; increased inotropic and chronotropic bradycardia, prolonged PR interval, flat T wave, low voltage;
effects; arrhythmias; angina pericardial effusion

Respiratory Dyspnea; hypoventilation; decreased vital capacity Pleural effusions; hypoventilation and CO2 retention; sleep apnea
system

Gastrointestinal Increased appetite; increased frequency of bowel Decreased appetite; decreased frequency of bowel movements,
system movements; hypoproteinemia constipation; ascites

Central nervous Nervousness; hyperkinesia; emotional lability, agitation Lethargy/fatigue; general slowing of mental processes; neuropathies;
system weakness and muscle cramps

Musculoskeletal Weakness and muscle fatigue; increased deep tendon Stiffness and muscle fatigue; carpal tunnel syndrome; decreased deep
system reflexes; tremors; hypercalcemia; osteoporosis tendon reflexes; increased alkaline phosphatase, LDH, AST

Renal system Mild polyuria; increased renal blood flow; increased Impaired water excretion; decreased renal blood flow; decreased
glomerular filtration rate glomerular filtration rate

Hematopoietic Increased erythropoiesis; anemia1 Decreased erythropoiesis; anemia1

system

Reproductive Menstrual irregularities; amenorrhea; infertility; increased Menorrhagia; infertility; decreased libido; impotence; oligospermia;
system gonadal steroid metabolism decreased gonadal steroid metabolism

Metabolic Increased basal metabolic rate; negative nitrogen balance; Decreased basal metabolic rate; slight positive nitrogen balance;
system hyperglycemia; increased free fatty acids; decreased total delayed degradation of insulin with increased sensitivity; increased
cholesterol and triglycerides; increased hormone total cholesterol and triglycerides; hyponatremia; decreased
degradation; increased requirements for fat- and water- hormone degradation; decreased requirements for fat- and water-
soluble vitamins; increased drug metabolism; decreased soluble vitamins; decreased drug metabolism; increased warfarin
warfarin requirement requirement

1The anemia of hyperthyroidism is usually normochromic and caused by increased red blood cell turnover. The anemia of hypothyroidism may be normochromic,

hyperchromic, or hypochromic and may be due to decreased production rate, decreased iron absorption, decreased folic acid absorption, or to autoimmune
pernicious anemia. LDH, lactic dehydrogenase; AST, aspartate aminotransferase.

Thyroid hormone is critical for the development and functioning of nervous, skeletal, and reproductive tissues. Its effects depend on protein synthesis
as well as potentiation of the secretion and action of growth hormone. Thyroid deprivation in early life results in irreversible mental retardation and
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Effects on growth and calorigenesis are accompanied by a pervasive influence on metabolism of drugs as well as carbohydrates, fats, proteins, and
vitamins. Many of these changes are dependent upon or modified by activity of other hormones. Conversely, the secretion and degradation rates of
virtually all other hormones, including catecholamines, cortisol, estrogens, testosterone, and insulin, are affected by thyroid status.
 1The anemia of hyperthyroidism is usually normochromic and caused by increased red blood cell turnover. The anemia of hypothyroidism may be normochromic,
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hyperchromic, or hypochromic and may be due to decreased production rate, decreased iron absorption, decreased folic acid absorption, or to autoimmune
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pernicious anemia. LDH, lactic dehydrogenase; AST, aspartate aminotransferase.

Thyroid hormone is critical for the development and functioning of nervous, skeletal, and reproductive tissues. Its effects depend on protein synthesis
as well as potentiation of the secretion and action of growth hormone. Thyroid deprivation in early life results in irreversible mental retardation and
dwarfism—typical of congenital cretinism.

Effects on growth and calorigenesis are accompanied by a pervasive influence on metabolism of drugs as well as carbohydrates, fats, proteins, and
vitamins. Many of these changes are dependent upon or modified by activity of other hormones. Conversely, the secretion and degradation rates of
virtually all other hormones, including catecholamines, cortisol, estrogens, testosterone, and insulin, are affected by thyroid status.

Many of the manifestations of thyroid hyperactivity resemble sympathetic nervous system overactivity (especially in the cardiovascular system),
although catecholamine levels are not increased. Changes in catecholamine-stimulated adenylyl cyclase activity as measured by cAMP are found with
changes in thyroid activity. Thyroid hormone increases the numbers of β receptors and enhances amplification of the β-receptor signal. Other clinical
symptoms reminiscent of excessive epinephrine activity (and partially alleviated by adrenoceptor antagonists) include lid lag and retraction, tremor,
excessive sweating, anxiety, and nervousness. The opposite constellation of effects is seen in hypothyroidism (Table 38–4).

Thyroid Preparations

See the Preparations Available section at the end of this chapter for a list of available preparations. These preparations may be synthetic
(levothyroxine, liothyronine, liotrix) or of animal origin (desiccated thyroid).

Thyroid hormones are not effective and can be detrimental in the management of obesity, abnormal vaginal bleeding, or depression if thyroid
hormone levels are normal. A review of T3 co-administered with antidepressants showed some promising bipolar depression benefits, but further
confirmation of its optimal use is required.

Synthetic levothyroxine is the preparation of choice for thyroid replacement and suppression therapy because of its stability, content uniformity, low
cost, lack of allergenic foreign protein, easy laboratory measurement of serum levels, and long half-life (7 days), which permits once-daily to weekly
administration. In addition, T4 is converted to T3 intracellularly; thus, administration of T4 produces both hormones and T3 administration is
unnecessary. Generic levothyroxine preparations provide comparable efficacy and are more cost-effective than branded preparations. It is preferable
that patients remain on a consistent levothyroxine preparation between refills to avoid changes in bioavailability. Compared to the tablet formulation,
a branded soft gel capsule and solution (Tirosint, Tirosint-SOL) had faster, more complete dissolution with 98% bioavailability, was less affected by
gastric pH or coffee, and produced lower TSH levels. According to the American Thyroid Association guidelines, these newer formulations might be
considered in persons allergic to tablet excipients.

Although liothyronine (T3) is three to four times more potent than levothyroxine, it is not recommended for routine replacement therapy because of its
shorter half-life (24 hours), requirement for multiple daily doses, and difficulty in monitoring its adequacy of replacement by conventional laboratory
tests. T3 should also be avoided in patients with cardiac disease due to significant elevations in peak levels and a greater risk of cardiotoxicity. Using
the more expensive thyroxine and liothyronine fixed-dose combination (Liotrix) and desiccated thyroid has not been shown to be more effective than
T4 administration alone. T3 is best reserved for short-term TSH suppression. Research is ongoing to clarify whether T3 might be more appropriate in
patients with a polymorphism in the D2 receptor or in those who continue to report fatigue, weight gain, and mental impairment while on T4 alone.

The use of desiccated thyroid rather than synthetic preparations is never justified, since the disadvantages of protein antigenicity, product instability,
variable hormone concentrations, and difficulty in laboratory monitoring far outweigh the advantage of lower cost. Significant amounts of T3 found in
some thyroid extracts may produce significant elevations in T3 levels and toxicity. Nevertheless, a large-scale assessment of patient satisfaction with
hormone replacement found that patients were more satisfied with desiccated thyroid rather than T4 or T4 plus T3. Exact equi-effective doses have not
been determined. Approximate equivalence of desiccated thyroid 60 mg (1 grain) to 80–100 mcg of levothyroxine, and approximately 37.5 mcg of
liothyronine has been reported. Any dosage conversions should be re-titrated based on laboratory and clinical response.

The shelf life of synthetic hormone preparations is about 2 years, particularly if they are stored in dark bottles to minimize spontaneous deiodination.
The shelf life of desiccated thyroid is not known with certainty, but its potency is better preserved if it is kept dry.

ANTITHYROID AGENTS

Reduction of thyroid activity and hormone effects can be accomplished by agents that interfere with the production of thyroid hormones, by agents
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thyroid 200.3.152.96
or by glandular destruction with radiation or surgery. Goitrogens are agents that suppress
Chapter 38: Thyroid &amp; Antithyroid Drugs, Betty J. Dong Page 12 / 28
secretion of T 3 and T 4 to subnormal levels and
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turn produces glandular enlargement (goiter). The antithyroid
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compounds used clinically include the thioamides, iodides, and radioactive iodine.
The shelf life of synthetic hormone preparations is about 2 years, particularly if they are stored in dark bottles to minimize spontaneous deiodination.
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The shelf life of desiccated thyroid is not known with certainty, but its potency is better preserved if it is kept dry.
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ANTITHYROID AGENTS

Reduction of thyroid activity and hormone effects can be accomplished by agents that interfere with the production of thyroid hormones, by agents
that modify the tissue response to thyroid hormones, or by glandular destruction with radiation or surgery. Goitrogens are agents that suppress
secretion of T3 and T4 to subnormal levels and thereby increase TSH, which in turn produces glandular enlargement (goiter). The antithyroid
compounds used clinically include the thioamides, iodides, and radioactive iodine.

THIOAMIDES

The thioamides methimazole and propylthiouracil are major drugs for treatment of thyrotoxicosis. In the United Kingdom, carbimazole, which is
converted to methimazole in vivo, is widely used. Methimazole is about 10 times more potent than propylthiouracil and is the drug of choice in adults
and children. Due to a black box warning about severe hepatitis, propylthiouracil should be reserved for use during the first trimester of pregnancy, in
thyroid storm, and in those experiencing adverse reactions to methimazole (other than agranulocytosis or hepatitis). The chemical structures of these
compounds are shown in Figure 38–5. The thiocarbamide group is essential for antithyroid activity.

FIGURE 38–5

Structure of thioamides. The thiocarbamide moiety is shaded in color.

Pharmacokinetics

Methimazole is completely absorbed but at variable rates. It is readily accumulated by the thyroid gland and has a volume of distribution similar to that
of propylthiouracil. Excretion is slower than with propylthiouracil; 65–70% of a dose is recovered in the urine in 48 hours.

In contrast, propylthiouracil is rapidly absorbed, reaching peak serum levels after 1 hour. The bioavailability of 50–80% may be due to incomplete
absorption or a large first-pass effect in the liver. The volume of distribution approximates total body water with accumulation in the thyroid gland.
Most of an ingested dose of propylthiouracil is excreted by the kidney as the inactive glucuronide within 24 hours.

The short plasma half-life of these agents (1.5 hours for propylthiouracil and 6 hours for methimazole) has little influence on the duration of the
antithyroid action or the dosing interval because both agents are accumulated by the thyroid gland. For propylthiouracil, giving the drug every 6–8
hours is reasonable since a single 100 mg dose can inhibit iodine organification by 60% for 7 hours. Since a single 30-mg dose of methimazole exerts
an antithyroid effect for longer than 24 hours, a single daily dose is effective in the management of mild to severe hyperthyroidism.

Both thioamides cross the placental barrier and are concentrated by the fetal thyroid, so caution must be employed when using these drugs in
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pregnancy. Because 7:39
of the riskPofYour IP is 200.3.152.96
fetal hypothyroidism, both thioamides are classified as FDA pregnancy category D (evidence of human fetal risk
Chapter 38: Thyroid &amp; Antithyroid Drugs, Betty J. Dong Page 13 / 28
based on adverse reaction data from investigational or marketing
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Policy • Notice 59). Of the two, propylthiouracil is preferable during the
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first trimester of pregnancy because it is more strongly protein-bound and, therefore, crosses the placenta less readily. In addition, methimazole has
been, albeit rarely, associated with congenital malformations. Both thioamides are secreted in low concentrations in breast milk but are considered
The short plasma half-life of these agents (1.5 hours for propylthiouracil and 6 hours for methimazole) has little influence on the duration of the
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antithyroid action or the dosing interval because both agents are accumulated by the thyroid gland. For propylthiouracil, giving the drug every 6–8
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hours is reasonable since a single 100 mg dose can inhibit iodine organification by 60% for 7 hours. Since a single 30-mg dose of methimazole exerts
an antithyroid effect for longer than 24 hours, a single daily dose is effective in the management of mild to severe hyperthyroidism.

Both thioamides cross the placental barrier and are concentrated by the fetal thyroid, so caution must be employed when using these drugs in
pregnancy. Because of the risk of fetal hypothyroidism, both thioamides are classified as FDA pregnancy category D (evidence of human fetal risk
based on adverse reaction data from investigational or marketing experience, see Chapter 59). Of the two, propylthiouracil is preferable during the
first trimester of pregnancy because it is more strongly protein-bound and, therefore, crosses the placenta less readily. In addition, methimazole has
been, albeit rarely, associated with congenital malformations. Both thioamides are secreted in low concentrations in breast milk but are considered
safe for the nursing infant.

Pharmacodynamics

The thioamides act by multiple mechanisms. The major action is to prevent hormone synthesis by inhibiting the thyroid peroxidase-catalyzed
reactions and blocking iodine organification. In addition, they block coupling of the iodotyrosines. They do not block uptake of iodide by the gland.
Propylthiouracil but not methimazole also inhibits the peripheral deiodination of T4 and T3 (Figure 38–1). Since the synthesis rather than the release of
hormones is affected, the onset of these agents is slow, often requiring 3–4 weeks before stores of T4 are depleted.

Toxicity

Adverse reactions to the thioamides occur in 3–12% of treated patients. Most reactions occur early, especially nausea and gastrointestinal distress. An
altered sense of taste or smell may occur with methimazole. The most common adverse effect is a maculopapular pruritic rash (4–6%), at times
accompanied by systemic signs such as fever. Rare adverse effects include an urticarial rash, vasculitis, a lupus-like reaction, lymphadenopathy,
hypoprothrombinemia, exfoliative dermatitis, polyserositis, and acute arthralgia. An increased risk of severe hepatitis, sometimes resulting in death,
has been reported with propylthiouracil (black box warning), so it should be avoided in children and adults unless no other options are available.
Cholestatic jaundice is more common with methimazole than propylthiouracil. Asymptomatic elevations in transaminase levels can also occur.

The most dangerous complication is agranulocytosis (granulocyte count <500 cells/mm3), an infrequent but potentially fatal adverse reaction. It occurs
in 0.1–0.5% of patients taking thioamides, but the risk may be increased in older patients and usually within the first 90 days in those receiving more
than 40 mg/d of methimazole. The reaction is usually rapidly reversible when the drug is discontinued, but broad-spectrum antibiotic therapy may be
necessary for complicating infections. Colony-stimulating factors (eg, G-CSF; see Chapter 33) may hasten recovery of the granulocytes. The cross-
sensitivity between propylthiouracil and methimazole is about 50%; therefore, switching drugs in patients with severe reactions is not recommended.

ANION INHIBITORS

Monovalent anions such as perchlorate (ClO4−), pertechnetate (TcO4−), and thiocyanate (SCN−) can block uptake of iodide by the gland through
competitive inhibition of the iodide transport mechanism. Since these effects can be overcome by large doses of iodides, their effectiveness is
somewhat unpredictable.

The major clinical use for potassium perchlorate is to block thyroidal reuptake of I− in patients with iodide-induced hyperthyroidism (eg, amiodarone-
induced hyperthyroidism). However, potassium perchlorate is rarely used clinically because it is associated with aplastic anemia.

IODIDES

Prior to the introduction of the thioamides in the 1940s, iodides were the major antithyroid agents; today they are rarely used as sole therapy.

Pharmacodynamics

Iodides have several actions on the thyroid. They inhibit organification and hormone release, and they decrease the size and vascularity of the
hyperplastic gland. In susceptible individuals, iodides can induce hyperthyroidism (Jod-Basedow phenomenon) or precipitate hypothyroidism.

In pharmacologic doses (>6 mg/d), the major action of iodides is to inhibit hormone release, possibly through inhibition of thyroglobulin proteolysis.
Improvement in thyrotoxic symptoms occurs rapidly—within 2–7 days—hence the value of iodide therapy in thyroid storm. In addition, iodides
decrease the vascularity, size, and fragility of a hyperplastic gland, making the drugs valuable as preoperative preparation for surgery.

Clinical Use of Iodide

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Chapter 38: Thyroid
Disadvantages &amp;
of iodide Antithyroid
therapy includeDrugs, Bettyin
an increase J.intraglandular
Dong Page 14 / 28
stores of iodine, which may delay onset of thioamide therapy or prevent use of
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radioactive iodine therapy for several weeks. Thus, iodides should be initiated after onset of thioamide therapy and avoided if treatment with
radioactive iodine seems likely. Iodide should not be used alone, because the gland will escape from the iodide block in 2–8 weeks, and its withdrawal
 Pontificia
In pharmacologic doses (>6 mg/d), the major action of iodides is to inhibit hormone release, possibly through inhibition Universidad
of thyroglobulin Javeriana
proteolysis.
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Improvement in thyrotoxic symptoms occurs rapidly—within 2–7 days—hence the value of iodide therapy in thyroid storm. In addition, iodides
decrease the vascularity, size, and fragility of a hyperplastic gland, making the drugs valuable as preoperative preparation for surgery.

Clinical Use of Iodide

Disadvantages of iodide therapy include an increase in intraglandular stores of iodine, which may delay onset of thioamide therapy or prevent use of
radioactive iodine therapy for several weeks. Thus, iodides should be initiated after onset of thioamide therapy and avoided if treatment with
radioactive iodine seems likely. Iodide should not be used alone, because the gland will escape from the iodide block in 2–8 weeks, and its withdrawal
may produce severe exacerbation of thyrotoxicosis in an iodine-enriched gland. Chronic use of iodides in pregnancy should be avoided, since they
cross the placenta and can cause fetal goiter. In radiation emergencies involving release of radioactive iodine isotopes, the thyroid-blocking effects of
potassium iodide can protect the gland from subsequent damage if administered before radiation exposure.

Toxicity

Adverse reactions to iodine (iodism) are uncommon and in most cases reversible upon discontinuance. They include acneiform rash (similar to that of
bromism), swollen salivary glands, mucous membrane ulcerations, conjunctivitis, rhinorrhea, drug fever, metallic taste, bleeding disorders, and rarely,
anaphylactoid reactions.

RADIOACTIVE IODINE

131I is the only isotope used for treatment of thyrotoxicosis. (Others are used in diagnosis.) Administered orally in solution as sodium 131I, it is rapidly

absorbed, concentrated by the thyroid, and incorporated into storage follicles. Its therapeutic effect depends on emission of β rays with an effective
half-life of 5 days and a penetration range of 400–2000 μm. Within a few weeks after administration, destruction of the thyroid parenchyma is
evidenced by epithelial swelling and necrosis, follicular disruption, edema, and leukocyte infiltration. Advantages of radioiodine include easy
administration, effectiveness, low expense, and absence of pain. Fears of radiation-induced genetic damage, leukemia, and neoplasia have not been
realized after more than 50 years of clinical experience with radioiodine therapy for hyperthyroidism. Radioactive iodine should not be administered to
pregnant women or nursing mothers, since it crosses the placenta to destroy the fetal thyroid gland and it is excreted in breast milk.

ADRENOCEPTOR-BLOCKING AGENTS

Beta blockers without intrinsic sympathomimetic activity (eg, metoprolol, propranolol, atenolol) are effective therapeutic adjuncts in the management
of thyrotoxicosis since many of these symptoms mimic those associated with sympathetic stimulation. Propranolol has been the β blocker most widely
studied and used in the therapy of thyrotoxicosis. Beta blockers cause clinical improvement of hyperthyroid symptoms but do not typically alter
thyroid hormone levels. Propranolol at doses greater than 160 mg/d may also reduce T3 levels approximately 20% by inhibiting the peripheral
conversion of T4 to T3.

CLINICAL PHARMACOLOGY OF THYROID & ANTITHYROID DRUGS

HYPOTHYROIDISM

Hypothyroidism is a syndrome resulting from deficiency of thyroid hormones and is manifested largely by a reversible slowing of all body functions
(Table 38–4). In infants and children, there is striking retardation of growth and development that results in dwarfism and irreversible mental
retardation.

The etiology and pathogenesis of hypothyroidism are outlined in Table 38–5. Hypothyroidism can occur with or without thyroid enlargement (goiter).
The laboratory diagnosis of hypothyroidism in the adult is easily made by the combination of low free thyroxine and elevated serum TSH levels (Table
38–2).

TABLE 38–5
Etiology and pathogenesis of hypothyroidism.

Degree of
Cause Pathogenesis Goiter
Hypothyroidism

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Hashimoto thyroiditis7:39 P Your IP is 200.3.152.96
Autoimmune destruction of thyroid Present early, absent Mild to severe
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Drug-induced1 Blocked hormone formation2 Present Mild to moderate
retardation.
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The etiology and pathogenesis of hypothyroidism are outlined in Table 38–5. Hypothyroidism can occur with or without thyroid enlargement (goiter).
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The laboratory diagnosis of hypothyroidism in the adult is easily made by the combination of low free thyroxine and elevated serum TSH levels (Table
38–2).

TABLE 38–5
Etiology and pathogenesis of hypothyroidism.

Degree of
Cause Pathogenesis Goiter
Hypothyroidism

Hashimoto thyroiditis Autoimmune destruction of thyroid Present early, absent Mild to severe
later

Drug-induced1 Blocked hormone formation2 Present Mild to moderate

Dyshormonogenesis Impaired synthesis of T4 due to enzyme deficiency Present Mild to severe

Radiation, 131I, X-ray, Destruction or removal of gland Absent Severe

thyroidectomy

Congenital (cretinism) Athyreosis or ectopic thyroid, iodine deficiency; TSH receptor- Absent or present Severe
blocking antibodies

Secondary (TSH deficit) Pituitary or hypothalamic disease Absent Mild

1Iodides, lithium, fluoride, thioamides, aminosalicylic acid, phenylbutazone, amiodarone, perchlorate, ethionamide, thiocyanate, cytokines (interferons,

interleukins), bexarotene, tyrosine kinase inhibitors, etc. See Table 38–3.

2See Table 38–3 for specific pathogenesis.

The most common cause of hypothyroidism in the United States at this time is probably Hashimoto thyroiditis, an immunologic disorder in genetically
predisposed individuals. In this condition, there is evidence of humoral immunity in the presence of antithyroid antibodies and lymphocyte
sensitization to thyroid antigens. Genetic mutations as discussed previously and certain medications also can cause hypothyroidism (Table 38–5).

MANAGEMENT OF HYPOTHYROIDISM

Except for hypothyroidism caused by drugs, which can be treated in some cases by simply removing the depressant agent, the general strategy of
replacement therapy is appropriate. The most satisfactory preparation is levothyroxine, administered as either a branded or generic preparation.
Multiple trials have documented that combination levothyroxine plus liothyronine is not superior to levothyroxine alone although some patients
remain unwell on thyroxine alone. Genetic variations in deiodinases or hormone transporters may account for some of this lack of efficacy.

There is some variability in the absorption of thyroxine; dosage will also vary depending on age and weight. Infants and children require more T4 per
kilogram of body weight than adults. The average dosage for an infant 1–6 months of age is 10–15 mcg/kg per day, whereas the average dosage for an
adult is about 1.7 mcg/kg per day (0.8 mcg/lb per day) or 125 mcg/d. Older adults (>65 years of age) may require less thyroxine (1.6 mcg/kg per day or
0.7 mcg/lb per day) for replacement as body mass declines. In patients requiring suppression therapy post-thyroidectomy for thyroid cancer, the
average daily dosage of T4 is 2.2 mcg/kg or 1 mcg/lb. Higher thyroxine requirements have also been reported in patients following bariatric surgery and
with other malabsorptive disorders (eg, atrophic gastritis, Helicobacter pylori gastritis, celiac disease, lactose intolerance); thyroxine doses may be
lower following treatment.

Since interactions with certain foods (eg, bran, soy, coffee) and drugs (Table 38–3) can impair its absorption, thyroxine should be administered on an
empty stomach (eg, 30–60 minutes before meals, 4 hours after meals, or at bedtime) to maintain TSH within an optimal range of 0.5–2.5 mIU/L. Its long
half-life of 7 days permits once-daily dosing. Children should be monitored for normal growth and development. Serum TSH and free thyroxine should
always be measured before a change in dosage to avoid transient serum alterations. It takes 6–8 weeks after starting a given dose of thyroxine to reach
steady-state levels in the bloodstream. Thus, dosage changes should be made slowly.
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In younger patients or those with very mild disease, full replacement therapy may be started immediately. In older patients (>50 years) without cardiac
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disease, levothyroxine can be started at a dosage of 50 mcg/d. In long-standing hypothyroidism and in older patients with underlying cardiac disease, it
is imperative to start with reduced dosages of levothyroxine, 12.5–25 mcg/d for 2 weeks, before increasing by 12.5–25 mcg/d every 2 weeks until
Since interactions with certain foods (eg, bran, soy, coffee) and drugs (Table 38–3) can impair its absorption, thyroxinePontificia
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administered on an
empty stomach (eg, 30–60 minutes before meals, 4 hours after meals, or at bedtime) to maintain TSH within an optimal range
Access of 0.5–2.5
Provided by: mIU/L. Its long
half-life of 7 days permits once-daily dosing. Children should be monitored for normal growth and development. Serum TSH and free thyroxine should
always be measured before a change in dosage to avoid transient serum alterations. It takes 6–8 weeks after starting a given dose of thyroxine to reach
steady-state levels in the bloodstream. Thus, dosage changes should be made slowly.

In younger patients or those with very mild disease, full replacement therapy may be started immediately. In older patients (>50 years) without cardiac
disease, levothyroxine can be started at a dosage of 50 mcg/d. In long-standing hypothyroidism and in older patients with underlying cardiac disease, it
is imperative to start with reduced dosages of levothyroxine, 12.5–25 mcg/d for 2 weeks, before increasing by 12.5–25 mcg/d every 2 weeks until
euthyroidism or drug toxicity is observed. In cardiac patients, the heart is very sensitive to the level of circulating thyroxine, and if angina pectoris or
cardiac arrhythmia develops, it is essential to stop or reduce the thyroxine dosage immediately.

Thyroxine toxicity is directly related to the hormone level. In children, restlessness, insomnia, and accelerated bone maturation and growth may be
signs of thyroxine toxicity. In adults, increased nervousness, heat intolerance, episodes of palpitation and tachycardia, or unexplained weight loss may
be the presenting symptoms. If these symptoms are present, it is important to monitor serum TSH and FT4 levels (Table 38–2), which will determine
whether the symptoms are due to excess thyroxine blood levels. Chronic overtreatment with T4, particularly in elderly patients, can increase the risk of
atrial fibrillation and accelerated osteoporosis.

Special Problems in Management of Hypothyroidism

A. Myxedema and Coronary Artery Disease

Since myxedema frequently occurs in older persons, it is often associated with underlying coronary artery disease. In this situation, the low levels of
circulating thyroid hormone actually protect the heart against increasing demands that could result in angina pectoris, atrial fibrillation, or myocardial
infarction. Correction of myxedema must be done cautiously to avoid provoking these cardiac events. If coronary artery surgery is indicated, it should
be done first, prior to correction of the myxedema by thyroxine administration.

B. Myxedema Coma

Myxedema coma is an end state of untreated hypothyroidism. It is associated with progressive weakness, stupor, hypothermia, hypoventilation,
hypoglycemia, hyponatremia, water intoxication, shock, and death.

Myxedema coma is a medical emergency. The patient should be treated in the intensive care unit, since tracheal intubation and mechanical ventilation
may be required. Associated illnesses such as infection or heart failure must be treated by appropriate therapy. It is important to give all preparations
intravenously, because patients with myxedema coma absorb drugs poorly from other routes. Intravenous fluids should be administered with caution
to avoid excessive water intake. These patients have large pools of empty T3 and T4 binding sites that must be filled before there is adequate free
thyroxine to affect tissue metabolism. Accordingly, the treatment of choice in myxedema coma is to give a loading dose of levothyroxine intravenously
—usually 300–400 mcg initially, followed by 50–100 mcg daily. Intravenous T3 5–20 mcg initially, followed by 2.5–10 mcg every 8 hours, also can be
added but may be more cardiotoxic and more difficult to monitor. Lower T4 and T3 doses should be considered for smaller or older patients, or those
with concomitant cardiac disease or arrhythmias. Intravenous hydrocortisone is indicated if the patient has associated adrenal or pituitary
insufficiency but is probably not necessary in most patients with primary myxedema. Opioids and sedatives must be used with extreme caution.

C. Hypothyroidism and Pregnancy

Hypothyroid women frequently have anovulatory cycles and are therefore relatively infertile until restoration of the euthyroid state. This has led to the
widespread use of thyroid hormone for infertility, although there is no evidence for its usefulness in infertile euthyroid patients. In a pregnant
hypothyroid patient receiving thyroxine, it is extremely important that the daily dose of thyroxine be adequate because early development of the fetal
brain depends on maternal thyroxine. In many hypothyroid patients, an increase in the thyroxine dose (about 25–30%) is required to normalize the
serum TSH level during pregnancy. It is reasonable to counsel women to take one extra dose of their current thyroxine tablet twice a week separated by
several days as soon as they are pregnant. Thyroxine should also be administered apart from prenatal vitamins and calcium by at least 4 hours.
Because of the elevated maternal TBG levels and, therefore, elevated total T4 levels, adequate maternal thyroxine dosages warrant maintenance of TSH
between 0.1 and 3.0 mIU/L (eg, first trimester, 0.1–2.5 mIU/L; second trimester, 0.2–3.0 mIU/L; third trimester, 0.3–3.0 mIU/L) and the total T4 at or
above the upper range of normal.

D. Subclinical Hypothyroidism
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Subclinical
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increases to 20% in women older than age 50. Levothyroxine should be individualized based on the risks and benefits of treatment. The consensus of
most expert thyroid organizations concluded that thyroid hormone therapy might be considered for patients with TSH levels >10 mIU/L despite
several days as soon as they are pregnant. Thyroxine should also be administered apart from prenatal vitamins and calcium by at least 4 hours.
Because of the elevated maternal TBG levels and, therefore, elevated total T4 levels, adequate maternal thyroxine dosages warrant
Pontificia maintenance
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between 0.1 and 3.0 mIU/L (eg, first trimester, 0.1–2.5 mIU/L; second trimester, 0.2–3.0 mIU/L; third trimester, 0.3–3.0 mIU/L) and the
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above the upper range of normal.

D. Subclinical Hypothyroidism

Subclinical hypothyroidism, defined as an elevated TSH level and normal thyroid hormone levels, occurs in 4–10% of the general population and
increases to 20% in women older than age 50. Levothyroxine should be individualized based on the risks and benefits of treatment. The consensus of
most expert thyroid organizations concluded that thyroid hormone therapy might be considered for patients with TSH levels >10 mIU/L despite
conflicting beneficial outcomes, while close TSH monitoring is appropriate for those with lower TSH elevations.

E. Drug-Induced Hypothyroidism

Drug-induced hypothyroidism (Table 38–3) can be satisfactorily managed with levothyroxine therapy if the offending agent cannot be stopped. In the
case of amiodarone-induced hypothyroidism, levothyroxine therapy may be necessary even after discontinuance because of amiodarone’s very long
half-life.

HYPERTHYROIDISM

Hyperthyroidism (thyrotoxicosis) is the clinical syndrome that results when tissues are exposed to high levels of thyroid hormone (Table 38–4).

GRAVES DISEASE

The most common form of hyperthyroidism is Graves disease, or diffuse toxic goiter. The presenting signs and symptoms of Graves disease are set
forth in Table 38–4.

Pathophysiology

Graves disease is considered to be an autoimmune disorder in which a defect in suppressor T lymphocytes stimulates B lymphocytes to synthesize
antibodies (TSH-R Ab [stim]) to thyroidal antigens. The TSH-R Ab [stim] binds and activates the TSH receptor in the thyroid cell membrane and
stimulates growth and biosynthetic activity of the thyroid cell. Genetics, the postpartum state, cigarette smoking, and physical and emotional stress
increase TSH-R Ab [stim] development. A genetic predisposition is shown by a high frequency of HLA-B8 and HLA-DR3 in Caucasians, HLA-Bw46 and
HLA-B5 in Chinese, and HLA-B17 in African Americans. Spontaneous remission occurs rarely, but some patients require years of antithyroid therapy.

Laboratory Diagnosis

In most patients with hyperthyroidism, T3, T4, FT4, and FT3 are elevated and TSH is suppressed (Table 38–2). Radioiodine uptake is usually markedly
elevated as well. Antithyroglobulin, thyroid peroxidase, and TSH-R Ab [stim] antibodies are usually present.

Management of Graves Disease

The three primary methods for controlling hyperthyroidism are antithyroid drug therapy, destruction of the gland with radioactive iodine, and surgical
thyroidectomy. None of these methods alters the underlying pathogenesis of the disease.

A. Antithyroid Drug Therapy

Drug therapy is most useful in young patients with small glands and mild disease. Methimazole (preferred) or propylthiouracil is administered until the
disease undergoes spontaneous remission. This is the only therapy that leaves an intact thyroid gland, but it does require a long period of treatment
and observation (12–18 months), and there is a 50–60% incidence of relapse when therapy is stopped.

Methimazole is preferable to propylthiouracil (except in pregnancy and thyroid storm) because it has a lower risk of serious liver injury and can be
administered once daily, which may improve adherence. Antithyroid drug therapy is usually begun with divided doses, shifting to maintenance therapy
with single daily doses when the patient becomes clinically euthyroid. However, mild to moderately severe thyrotoxicosis can often be controlled with
methimazole given in a single morning dose of 20–40 mg initially for 4–8 weeks to normalize hormone levels. Maintenance therapy requires 5–15 mg
once daily. Alternatively, therapy is started with propylthiouracil, 100–150 mg every 6 or 8 hours until the patient is euthyroid, followed by gradual
reduction of the dose to the maintenance level of 50–150 mg once daily. In addition to inhibiting iodine organification, propylthiouracil also inhibits
the conversion of T4 to T3, so it brings the level of activated thyroid hormone down more quickly than does methimazole. The best clinical guide to
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remission is reduction in the size of the goiter. Laboratory tests most useful in monitoring the course of therapy are serum FT3, FT4, and TSH levels.
Chapter 38: Thyroid &amp; Antithyroid Drugs, Betty J. Dong Page 18 / 28
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Reactions to antithyroid drugs have been described above. A minor rash can often be controlled by antihistamine therapy. Because the more severe
reaction of agranulocytosis is often heralded by sore throat or high fever, patients receiving antithyroid drugs must be instructed to discontinue the
administered once daily, which may improve adherence. Antithyroid drug therapy is usually begun with divided doses, shifting to maintenance therapy
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with single daily doses when the patient becomes clinically euthyroid. However, mild to moderately severe thyrotoxicosis Universidad
can often Javeriana
be controlled with
methimazole given in a single morning dose of 20–40 mg initially for 4–8 weeks to normalize hormone levels. Maintenance Access therapy
Provided by:requires 5–15 mg

once daily. Alternatively, therapy is started with propylthiouracil, 100–150 mg every 6 or 8 hours until the patient is euthyroid, followed by gradual
reduction of the dose to the maintenance level of 50–150 mg once daily. In addition to inhibiting iodine organification, propylthiouracil also inhibits
the conversion of T4 to T3, so it brings the level of activated thyroid hormone down more quickly than does methimazole. The best clinical guide to
remission is reduction in the size of the goiter. Laboratory tests most useful in monitoring the course of therapy are serum FT3, FT4, and TSH levels.

Reactions to antithyroid drugs have been described above. A minor rash can often be controlled by antihistamine therapy. Because the more severe
reaction of agranulocytosis is often heralded by sore throat or high fever, patients receiving antithyroid drugs must be instructed to discontinue the
drug and seek immediate medical attention if these symptoms develop. White cell and differential counts and a throat culture are indicated in such
cases, followed by appropriate antibiotic therapy. Treatment should also be stopped if significant elevations in transaminases (two to three times the
upper limit of normal) occur.

B. Thyroidectomy

A near-total thyroidectomy is the treatment of choice for patients with very large glands or multinodular goiters. Patients are treated with antithyroid
drugs until euthyroid (about 6 weeks). In addition, for 10–14 days prior to surgery, they receive saturated solution of potassium iodide, 5 drops twice
daily, to diminish vascularity of the gland and simplify surgery. About 80–90% of patients will require thyroid supplementation following near-total
thyroidectomy.

C. Radioactive Iodine

Radioiodine therapy (RAI) utilizing 131I is the preferred treatment for most patients over 21 years of age. In patients without heart disease, the
therapeutic dose may be given immediately in a range of 80–120 μCi/g of estimated thyroid weight corrected for uptake. In patients with underlying
heart disease or severe thyrotoxicosis and in elderly patients, it is desirable to treat with antithyroid drugs (preferably methimazole) until the patient is
euthyroid. This medication is stopped for 2 to 3 days before RAI is administered so as not to interfere with RAI retention but can be restarted 3–5 days
later, and then gradually tapered over 4–6 weeks as thyroid function normalizes. Iodides should be avoided to ensure maximal 131I uptake. Six to 12
weeks following the administration of RAI, the gland will shrink in size and the patient will usually become euthyroid or hypothyroid. A second dose
may be required if there is minimal response 3 months post-RAI. Hypothyroidism occurs in about 80% of patients following RAI. Serum FT4 and TSH
levels should be monitored regularly. When hypothyroidism develops, prompt replacement with oral levothyroxine, 50–150 mcg daily, should be
instituted.

D. Adjuncts to Antithyroid Therapy

During the acute phase of thyrotoxicosis, β-adrenoceptor–blocking agents without intrinsic sympathomimetic activity are appropriate in symptomatic
patients aged 60 years or more, in those with heart rates >90 beats/min, and in those with cardiovascular disease. Propranolol, 20–40 mg orally every 6
hours, or metoprolol, 25–50 mg orally every 6–8 hours, will control tachycardia, hypertension, and atrial fibrillation. Beta-adrenoceptor–blocking
agents are gradually withdrawn as serum thyroxine levels return to normal. Diltiazem, 90–120 mg three or four times daily, can be used to control
tachycardia in patients in whom β blockers are contraindicated, eg, those with asthma. Dihydropyridine calcium channel blockers may not be as
effective as diltiazem or verapamil. Adequate nutrition and vitamin supplements are essential. Barbiturates accelerate T4 breakdown (by hepatic
enzyme induction) and may be helpful both as sedatives and to lower T4 levels. Bile acid sequestrants (eg, cholestyramine) can also rapidly lower T4
levels by increasing the fecal excretion of T4.

TOXIC UNINODULAR GOITER & TOXIC MULTINODULAR GOITER

These forms of hyperthyroidism occur often in older women with nodular goiters. Free thyroxine is moderately elevated or occasionally normal, but
FT3 or T3 is strikingly elevated. Single toxic adenomas can be managed either with surgical excision of the adenoma or with radioiodine therapy. Toxic
multinodular goiter is usually associated with a large goiter and is best treated by preparation with methimazole (preferable) or propylthiouracil
followed by subtotal thyroidectomy.

SUBACUTE THYROIDITIS

During the acute phase of a viral infection of the thyroid gland, there is destruction of thyroid parenchyma with transient release of stored thyroid
hormones. A similar state may occur in patients with Hashimoto thyroiditis. These episodes of transient thyrotoxicosis have been termed
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. Supportive therapy is usually all that is necessary, such as β-adrenoceptor–blocking agents without
Chapter 38: Thyroid &amp; Antithyroid Drugs, Betty J. Dong Page 19 / 28
intrinsic sympathomimetic
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fever. Corticosteroids may be necessary in severe cases to control the inflammation.
followed by subtotal thyroidectomy.
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SUBACUTE THYROIDITIS

During the acute phase of a viral infection of the thyroid gland, there is destruction of thyroid parenchyma with transient release of stored thyroid
hormones. A similar state may occur in patients with Hashimoto thyroiditis. These episodes of transient thyrotoxicosis have been termed
spontaneously resolving hyperthyroidism. Supportive therapy is usually all that is necessary, such as β-adrenoceptor–blocking agents without
intrinsic sympathomimetic activity (eg, propranolol) for tachycardia and aspirin or nonsteroidal anti-inflammatory drugs to control local pain and
fever. Corticosteroids may be necessary in severe cases to control the inflammation.

SPECIAL PROBLEMS

Thyroid Storm

Thyroid storm, or thyrotoxic crisis, is sudden acute exacerbation of all of the symptoms of thyrotoxicosis, presenting as a life-threatening syndrome.
Vigorous management is mandatory. Propranolol, 60–80 mg orally every 4 hours, or intravenous propranolol, 1–2 mg slowly every 5–10 minutes to a
total of 10 mg, or esmolol, 50–100 mg/kg per min, is helpful to control the severe cardiovascular manifestations. If β blockers are contraindicated by
the presence of severe heart failure or asthma, hypertension and tachycardia may be controlled with diltiazem, 90–120 mg orally three or four times
daily or 5–10 mg/h by intravenous infusion (asthmatic patients only). Release of thyroid hormones from the gland is retarded by the administration of
saturated solution of potassium iodide, 5 drops orally every 6 hours starting 1 hour after giving thioamides. Hormone synthesis is blocked by the
administration of propylthiouracil, 500–1000 mg as a loading dose, followed by 250 mg orally every 4 hours. If the patient is unable to take
propylthiouracil by mouth, a rectal formulation* can be prepared and administered in a dosage of 400 mg every 6 hours as a retention enema.
Methimazole may also be prepared for rectal administration in a dose of 60–80 mg daily. Hydrocortisone, 50 mg intravenously every 6 hours, will
protect the patient against shock and will block the conversion of T4 to T3, rapidly reducing the level of thyroactive material in the blood.

Supportive therapy is essential to control fever, heart failure, and any underlying disease process that may have precipitated the acute storm. In rare
situations, where the above methods are not adequate to control the problem, oral bile acid sequestrants (eg, cholestyramine), plasmapheresis, or
peritoneal dialysis has been used to lower the levels of circulating thyroxine.

*To prepare a water suspension propylthiouracil enema, grind eight 50-mg tablets and suspend the powder in 90 mL of sterile water.

Ophthalmopathy

Although severe ophthalmopathy is rare, it is difficult to treat. A 15–20% risk of aggravating severe eye disease may occur following RAI, especially in
those who smoke. Management requires effective treatment of the thyroid disease, usually by total surgical excision or 131I ablation of the gland plus
oral prednisone therapy (see below). In addition, local therapy may be necessary, eg, elevation of the head to diminish periorbital edema and artificial
tears to relieve corneal drying due to exophthalmos. Smoking cessation should be advised to prevent progression of the ophthalmopathy. For the
severe, acute inflammatory reaction, prednisone, 60–100 mg orally daily for about a week and then 60–100 mg every other day, tapering the dose over
6–12 weeks, may be effective. If steroid therapy fails or is contraindicated, irradiation of the posterior orbit, using well-collimated high-energy X-ray
therapy, will frequently result in marked improvement of the acute process. Threatened loss of vision is an indication for surgical decompression of
the orbit. Eyelid or eye muscle surgery may be necessary to correct residual problems after the acute process has subsided.

Dermopathy

Dermopathy or pretibial myxedema will often respond to topical corticosteroids applied to the involved area and covered with an occlusive dressing.

Thyrotoxicosis during Pregnancy

Ideally, women in the childbearing period with severe disease should have definitive therapy with 131I or subtotal thyroidectomy prior to pregnancy in
order to avoid an acute exacerbation of the disease during pregnancy or following delivery. If thyrotoxicosis does develop during pregnancy, RAI is
contraindicated because it crosses the placenta and may injure the fetal thyroid. Propylthiouracil (lower teratogenic risks than methimazole) can be
given in the first trimester, and then changed to methimazole for the remainder of the pregnancy in order to avoid potential liver damage. The dosage
of propylthiouracil must be kept to the minimum necessary for control of the disease (ie, <300 mg/d), because it may affect the function of the fetal
thyroid gland. Alternatively, a subtotal thyroidectomy can be safely performed during the mid trimester. It is essential to give the patient a thyroid
supplement during the balance of the pregnancy.

Neonatal Graves Disease

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may occur in Antithyroid
the newborn Drugs,
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due either
Page 20 / 28
to passage of maternal TSH-R Ab [stim] through the placenta, stimulating the thyroid gland
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of the neonate, or to genetic transmission of the trait to the fetus. Laboratory studies reveal an elevated free T4, a markedly elevated T3, and a low TSH
—in contrast to the normal infant, in whom TSH is elevated at birth. TSH-R Ab [stim] is usually found in the serum of both the child and the mother.
given in the first trimester, and then changed to methimazole for the remainder of the pregnancy in order to avoid potential liver damage. The dosage
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of propylthiouracil must be kept to the minimum necessary for control of the disease (ie, <300 mg/d), because it may affect Universidad
the function of theJaveriana
fetal
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thyroid gland. Alternatively, a subtotal thyroidectomy can be safely performed during the mid trimester. It is essential to give the patient a thyroid
supplement during the balance of the pregnancy.

Neonatal Graves Disease

Graves disease may occur in the newborn infant, due either to passage of maternal TSH-R Ab [stim] through the placenta, stimulating the thyroid gland
of the neonate, or to genetic transmission of the trait to the fetus. Laboratory studies reveal an elevated free T4, a markedly elevated T3, and a low TSH
—in contrast to the normal infant, in whom TSH is elevated at birth. TSH-R Ab [stim] is usually found in the serum of both the child and the mother.

If caused by maternal TSH-R Ab [stim], the disease is usually self-limited and subsides over a period of 4–12 weeks, coinciding with the fall in the
infant’s TSH-R Ab [stim] level. However, treatment is necessary because of the severe metabolic stress the infant experiences. Therapy includes
propylthiouracil at a dosage of 5–10 mg/kg daily in divided doses at 8-hour intervals; Lugol solution (8 mg of iodide per drop), 1 drop every 8 hours;
and propranolol, 2 mg/kg daily in divided doses. Careful supportive therapy is essential. If the infant is very ill, oral prednisone, 2 mg/kg daily in divided
doses, will help block conversion of T4 to T3. These medications are gradually reduced as the clinical picture improves and can be discontinued by 6–12
weeks.

SUBCLINICAL HYPERTHYROIDISM

Subclinical hyperthyroidism is defined as a suppressed TSH level (below the normal range) in conjunction with normal thyroid hormone levels. Cardiac
toxicity (eg, atrial fibrillation), especially in older persons and those with underlying cardiac disease, is of greatest concern. The consensus of thyroid
experts concluded that hyperthyroidism treatment is appropriate in those with TSH less than 0.1 mIU/L, while close monitoring of the TSH level is
appropriate for those with less TSH suppression.

Amiodarone-Induced Thyrotoxicosis

In addition to those patients who develop hypothyroidism caused by amiodarone, approximately 3% of patients receiving this drug will develop
hyperthyroidism instead. Two types of amiodarone-induced thyrotoxicosis have been reported: iodine-induced (type I), which often occurs in persons
with underlying thyroid disease (eg, multinodular goiter, Graves disease); and an inflammatory thyroiditis (type II) that occurs in patients without
thyroid disease due to leakage of thyroid hormone into the circulation. Treatment of type I requires therapy with thioamides, while type II responds
best to glucocorticoids. Since it is not always possible to differentiate between the two types, thioamides and glucocorticoids are often administered
together. If possible, amiodarone should be discontinued; however, rapid improvement does not occur due to its long half-life.

NONTOXIC GOITER

Nontoxic goiter is a syndrome of thyroid enlargement without excessive thyroid hormone production. Enlargement of the thyroid gland is often due to
TSH stimulation from inadequate thyroid hormone synthesis. The most common cause of nontoxic goiter worldwide is iodide deficiency, but in the
United States, it is Hashimoto thyroiditis. Other causes include germ-line or acquired mutations in genes involved in hormone synthesis, dietary
goitrogens, and neoplasms (see below).

Goiter due to iodide deficiency is best managed by prophylactic administration of iodide. The optimal daily iodide intake is 150–200 mcg. Iodized salt
and iodate used as preservatives in flour and bread are excellent sources of iodine in the diet. In areas where it is difficult to introduce iodized salt or
iodate preservatives, a solution of iodized poppy-seed oil has been administered intramuscularly to provide a long-term source of inorganic iodine.

Goiter due to ingestion of goitrogens in the diet is managed by elimination of the goitrogen or by adding sufficient thyroxine to shut off TSH
stimulation. Similarly, in Hashimoto thyroiditis and dyshormonogenesis, adequate thyroxine therapy—150–200 mcg/d orally—will suppress pituitary
TSH and result in slow regression of the goiter as well as correction of hypothyroidism.

THYROID NEOPLASMS

Neoplasms of the thyroid gland may be benign (adenomas) or malignant. The primary diagnostic test is a fine-needle aspiration biopsy and cytologic
examination. Benign lesions may be monitored for growth or symptoms of local obstruction, which would mandate surgical excision. Levothyroxine
therapy is not recommended for the suppression of benign nodules, especially in iodine-sufficient areas. Management of thyroid carcinoma requires a
total thyroidectomy, postoperative radioiodine therapy in selected instances, and lifetime replacement with levothyroxine. The evaluation for
recurrence of some thyroid malignancies often involves withdrawal of thyroxine replacement for 4–6 weeks—accompanied by the development of
hypothyroidism. Tumor recurrence is likely if there is a rise in serum thyroglobulin (ie, a tumor marker) or a positive 131I scan when TSH is elevated.
Alternatively, 2021­10­3
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7:39ofPrecombinant human TSH (Thyrogen) can produce comparable TSH elevations without discontinuing thyroxine and
Your IP is 200.3.152.96
Chapter
avoiding hypothyroidism. Recombinant human Betty
38: Thyroid &amp; Antithyroid Drugs, TSH isJ.administered
Dong intramuscularly once daily for 2 days. A rise in serum thyroglobulin orPage 21 / 28
a positive
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131I scan will indicate a recurrence of the thyroid cancer.
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Neoplasms of the thyroid gland may be benign (adenomas) or malignant. The primary diagnostic test is a fine-needle aspiration biopsy and cytologic
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examination. Benign lesions may be monitored for growth or symptoms of local obstruction, which would mandate surgical Universidad
excision. Javeriana
Levothyroxine
therapy is not recommended for the suppression of benign nodules, especially in iodine-sufficient areas. ManagementAccess
of thyroid carcinoma requires a
Provided by:

total thyroidectomy, postoperative radioiodine therapy in selected instances, and lifetime replacement with levothyroxine. The evaluation for
recurrence of some thyroid malignancies often involves withdrawal of thyroxine replacement for 4–6 weeks—accompanied by the development of
hypothyroidism. Tumor recurrence is likely if there is a rise in serum thyroglobulin (ie, a tumor marker) or a positive 131I scan when TSH is elevated.
Alternatively, administration of recombinant human TSH (Thyrogen) can produce comparable TSH elevations without discontinuing thyroxine and
avoiding hypothyroidism. Recombinant human TSH is administered intramuscularly once daily for 2 days. A rise in serum thyroglobulin or a positive
131I scan will indicate a recurrence of the thyroid cancer.

SUMMARY Drugs Used in the Management of Thyroid Disease

Subclass, Mechanism of Action and

Indications Pharmacokinetics, Toxicities, Interactions
Drug Effects

THYROID PREPARATIONS

• Activation of nuclear receptors Hypothyroidism See Table 38–1 • maximum effect seen after 6–8 weeks of
Levothyroxine results in gene expression with therapy • Toxicity: See Table 38–4 for symptoms of thyroid
(T4) RNA formation and protein excess

• synthesis

Liothyronine
(T3)

ANTITHYROID AGENTS

THIOAMIDES

• Inhibit thyroid peroxidase Hyperthyroidism Oral • duration of action: 24 h (methimazole), 6–8 h (PTU) •
Methimazole reactions • block iodine delayed onset of action • Toxicity: Nausea, gastrointestinal
• organification • inhibit distress, rash, agranulocytosis, hepatitis (PTU black box),
Propylthiouracil peripheral deiodination of T4 to hypothyroidism, teratogenicity (methimazole > PTU)
(PTU) T 3 (primarily PTU)

IODIDES

• Lugol Inhibit organification and Preparation for surgical Oral • acute onset within 2–7 days • Toxicity: Rare (see text)
solution hormone release • reduce the thyroidectomy
• Potassium size and vascularity of the gland
iodide

BETA BLOCKERS

• Propranolol, Inhibition of β adrenoreceptors Hyperthyroidism, especially Onset within hours • duration of 4–6 h (oral propranolol) •
other β • inhibit T4 to T3 conversion thyroid storm • adjunct to Toxicity: bronchospasm, AV blockade, hypotension,
blockers lacking (only propranolol) control tachycardia, bradycardia
partial agonist hypertension, and atrial
activity fibrillation

RADIOACTIVE IODINE 1 3 1I (RAI)

Radiation destruction of thyroid Hyperthyroidism • patients Oral • half-life 5 days • onset in 6–12 weeks • maximum effect
parenchyma should be euthyroid or on β in 3–6 months • Toxicity: Sore throat, sialitis, hypothyroidism
blockers before RAI • avoid in
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Chapter 38: Thyroid &amp; Antithyroid Drugs, Betty J. Dong Page 22 / 28
mothers
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hypothyroidism. Tumor recurrence is likely if there is a rise in serum thyroglobulin (ie, a tumor marker) or a positive 131I scan when TSH is elevated.
Alternatively, administration of recombinant human TSH (Thyrogen) can produce comparable TSH elevations withoutPontificia Universidad
discontinuing Javeriana
thyroxine and
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avoiding hypothyroidism. Recombinant human TSH is administered intramuscularly once daily for 2 days. A rise in serum thyroglobulin or a positive
131I scan will indicate a recurrence of the thyroid cancer.

SUMMARY Drugs Used in the Management of Thyroid Disease

Subclass, Mechanism of Action and

Indications Pharmacokinetics, Toxicities, Interactions
Drug Effects

THYROID PREPARATIONS

• Activation of nuclear receptors Hypothyroidism See Table 38–1 • maximum effect seen after 6–8 weeks of
Levothyroxine results in gene expression with therapy • Toxicity: See Table 38–4 for symptoms of thyroid
(T4) RNA formation and protein excess

• synthesis

Liothyronine
(T3)

ANTITHYROID AGENTS

THIOAMIDES

• Inhibit thyroid peroxidase Hyperthyroidism Oral • duration of action: 24 h (methimazole), 6–8 h (PTU) •
Methimazole reactions • block iodine delayed onset of action • Toxicity: Nausea, gastrointestinal
• organification • inhibit distress, rash, agranulocytosis, hepatitis (PTU black box),
Propylthiouracil peripheral deiodination of T4 to hypothyroidism, teratogenicity (methimazole > PTU)
(PTU) T 3 (primarily PTU)

IODIDES

• Lugol Inhibit organification and Preparation for surgical Oral • acute onset within 2–7 days • Toxicity: Rare (see text)
solution hormone release • reduce the thyroidectomy
• Potassium size and vascularity of the gland
iodide

BETA BLOCKERS

• Propranolol, Inhibition of β adrenoreceptors Hyperthyroidism, especially Onset within hours • duration of 4–6 h (oral propranolol) •
other β • inhibit T4 to T3 conversion thyroid storm • adjunct to Toxicity: bronchospasm, AV blockade, hypotension,
blockers lacking (only propranolol) control tachycardia, bradycardia
partial agonist hypertension, and atrial
activity fibrillation

RADIOACTIVE IODINE 1 3 1I (RAI)

Radiation destruction of thyroid Hyperthyroidism • patients Oral • half-life 5 days • onset in 6–12 weeks • maximum effect
parenchyma should be euthyroid or on β in 3–6 months • Toxicity: Sore throat, sialitis, hypothyroidism
blockers before RAI • avoid in
pregnancy and in nursing
mothers

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PREPARATIONS AVAILABLE

GENERIC NAME AVAILABLE AS

THYROID AGENTS

Oral levothyroxine (T4) Generic (also IV), Euthyrox, Levoxyl, Levo-T, Levolet*, Novothyrox, Synthroid (IV also), Tirosint, Tirosint-SOL,
Unithroid

Oral liothyronine (T3) Generic, Cytomel, Triostat (IV)

Oral Liotrix (a 4:1 ratio of T4:T3) Thyrolar

Oral Thyroid desiccated (USP) Generic, Armour, Nature-Throid, Westhroid

ANTITHYROID AGENTS

Radioactive iodine (131I) sodium Iodotope, Sodium Iodide I 131 Therapeutic

Oral methimazole Generic, Tapazole

Potassium iodide

Oral solution (SSKI) ThyroShield

Oral solution (Lugol solution) Lugol solution

Oral potassium iodide tablets IOSAT, Thyro-Block, Thyro-Safe

Oral propylthiouracil [PTU] Generic

DIAGNOSTIC AGENT

Thyrotropin; recombinant human Thyrogen

TSH

*Not available in the United States.

CASE STUDY ANSWER

The initial methimazole treatment was appropriate and preferable to propylthiouracil because of its longer duration of action allowing once-daily
dosing and its improved safety profile. JP presents with the typical signs and symptoms of hypothyroidism following RAI despite levothyroxine
replacement. Either radioactive iodine or thyroidectomy are reasonable and effective strategies for definitive treatment of her hyperthyroidism,
especially before
Downloaded becoming
2021­10­3 7:39pregnant to is
P Your IP avoid an acute hyperthyroid exacerbation during pregnancy or following delivery. Her hypothyroid
200.3.152.96
symptoms
Chapter 38: should
Thyroidhave been
&amp; easily corrected
Antithyroid Drugs,by the J.
Betty addition
Dong of levothyroxine dosed correctly at 1.7 mcg/kg/day or 100 mcg daily. Because she24
Page is / 28
©2021
youngMcGraw Hill.
and has no All Rights
cardiac Reserved.
disease, Terms ofdoses
full replacement Use •were
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appropriate to start.• Accessibility
However, her elevated TSH level indicates inadequate
levothyroxine replacement which may be related to nonadherence, or concomitant calcium and omeprazole co-administration. For optimal
absorption, levothyroxine should be taken orally 30–60 minutes before meals (eg, empty stomach) or at bedtime, and separated by 4 hours from her
 Pontificia Universidad Javeriana
*Not available in the United States. Access Provided by:

CASE STUDY ANSWER

The initial methimazole treatment was appropriate and preferable to propylthiouracil because of its longer duration of action allowing once-daily
dosing and its improved safety profile. JP presents with the typical signs and symptoms of hypothyroidism following RAI despite levothyroxine
replacement. Either radioactive iodine or thyroidectomy are reasonable and effective strategies for definitive treatment of her hyperthyroidism,
especially before becoming pregnant to avoid an acute hyperthyroid exacerbation during pregnancy or following delivery. Her hypothyroid
symptoms should have been easily corrected by the addition of levothyroxine dosed correctly at 1.7 mcg/kg/day or 100 mcg daily. Because she is
young and has no cardiac disease, full replacement doses were appropriate to start. However, her elevated TSH level indicates inadequate
levothyroxine replacement which may be related to nonadherence, or concomitant calcium and omeprazole co-administration. For optimal
absorption, levothyroxine should be taken orally 30–60 minutes before meals (eg, empty stomach) or at bedtime, and separated by 4 hours from her
calcium administration. Lower thyroxine doses may also be sufficient if her omeprazole is stopped. Once-weekly thyroxine injections may be
effective in those with ongoing nonadherence. Thyroid function tests should be monitored after 6–8 weeks of therapy, obtained before thyroxine
administration to avoid transient hormone alterations, and the dosage adjusted to achieve a normal TSH level and resolution of hypothyroid
symptoms.

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General

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Subclinical Hypothyroidism and Hyperthyroidism

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of Use • during
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• Accessibility

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