Chapter 38: Thyroid & Antithyroid Drugs

A. Synthesis and Transport of Thyroid Hormones

The thyroid secretes 2 iodine-containing hormones: thyroxine (T₄) and triiodothyronine (T₃). The iodine necessary for the synthesis of these molecules comes from food or iodide supplements. Iodide ion is actively taken up by and highly concentrated in the thyroid gland, where it is converted to elemental iodine by thyroidal peroxidase (Figure 38–1). The protein thyroglobulin serves as a scaffold for thyroid hormone synthesis. Tyrosine residues in thyroglobulin are iodinated to form monoiodotyrosine (MIT) or diiodotyrosine (DIT) in a process known as iodine organification. Within thyroglobulin, 2 molecules of DIT combine to form T₄, while 1 molecule each of MIT and DIT combine to form T₃. Proteolysis of thyroglobulin liberates the T₄ and T₃, which are then released from the thyroid. After release from the gland, T₄ and T₃ are transported in the blood by thyroxine-binding globulin, a protein synthesized in the liver.

Thyroid function is controlled by the pituitary through the release of thyrotropin (thyroid-stimulating hormone [TSH]) (see Figure 37–1) and by the availability of iodide. Thyrotropin stimulates the uptake of iodide as well as synthesis and release of thyroid hormone. It also has a growth-promoting effect that causes thyroid cell hyperplasia and an enlarged gland (goiter). High levels of thyroid hormones inhibit the release of TSH, providing an effective negative feedback control mechanism. In Graves’ disease, an autoimmune disorder, B lymphocytes produce an antibody that activates the TSH receptor and can cause a syndrome of hyperthyroidism called thyrotoxicosis. Because these lymphocytes are not susceptible to negative feedback, patients with Graves’ disease can have very high blood concentrations of thyroid hormone at the same time that their blood concentrations of TSH are very low.

B. Mechanisms of Action of T₄ and T₃

T₃ is about 10 times more potent than T₄. Because T₄ is converted to T₃ in target cells, the liver, and the kidneys, most of the effect of circulating T₄ is probably due to T₃. Thyroid hormones bind to intracellular receptors that control the expression of genes responsible for many metabolic processes. The proteins synthesized under T₃ control differ depending on the tissue involved; these proteins include, for example, Na⁺/K⁺ ATPase, specific contractile proteins in smooth muscle and the heart, enzymes involved in lipid metabolism, and important developmental components in the brain. T₃ may also have a separate membrane receptor-mediated effect in some tissues.

1. Effects of thyroid hormone

The organ-level actions of the thyroid hormones include normal growth and development of the nervous, skeletal, and reproductive systems and control of metabolism of fats, carbohydrates, proteins, and vitamins. The key features of excess thyroid activity (thyrotoxicosis) and hypothyroidism are listed in Table 38–1.

2. Clinical use

Thyroid hormone therapy can be accomplished with either T₄ or T₃. Synthetic levothyroxine (T₄) is usually the form of choice. T₃ (liothyronine) is faster acting but has a shorter half-life and is more expensive.

3. Toxicity

Toxicity is that of thyrotoxicosis (Table 38–1). Older patients, those with cardiovascular disease, and those with longstanding myxedema are highly sensitive to the stimulatory effects of T₄ on the heart. Such patients should receive lower initial doses of T₄.

Like many neurotransmitters and hormones, TSH mediates its effects in thyroid cells by activating the cAMP (cyclic adenosine monophosphate) second-messenger system (Chapter 2). Draw a diagram that shows the key events in this pathway, beginning with the binding of an agonist to its receptor and ending with cellular responses.

The Skill Keeper Answer appears at the end of the chapter.

A. Thioamides

Methimazole and propylthiouracil (PTU) are small sulfur-containing thioamides that inhibit thyroid hormone synthesis by blocking peroxidase-catalyzed reactions, iodination of the tyrosine residues of thyroglobulin, and coupling of DIT and MIT (Figure 38–1). Propylthiouracil and, to a much lesser extent, methimazole inhibit peripheral conversion of T₄ to T_3. Because the thioamides do not inhibit the release of preformed thyroid hormone, their onset of activity is usually slow, often requiring 3–4 wk for full effect. The thioamides can be used by the oral route and are effective in young patients with small glands and mild disease. Methimazole is generally preferred because it can be administered once per day. However, PTU is preferred in pregnancy because it is less likely than methimazole to cross the placenta and enter breast milk. Toxic effects include skin rash (common) and severe reactions (rare) such as vasculitis, agranulocytosis, hypoprothrombinemia, and liver dysfunction. These effects are usually reversible.

B. Iodide Salts and Iodine

Iodide salts inhibit iodination of tyrosine and thyroid hormone release (Figure 38–1); these salts also decrease the size and vascularity of the hyperplastic thyroid gland. Because iodide salts inhibit release as well as synthesis of the hormones, their onset of action occurs rapidly, within 2–7 d. However, the effects are transient; the thyroid gland “escapes” from the iodide block after several weeks of treatment. Iodide salts are used in the management of thyroid storm and to prepare patients for surgical resection of a hyperactive thyroid. The usual forms of this drug are Lugol’s solution (iodine and potassium iodide) and saturated solution of potassium iodide. Adverse effects include rash, drug fever, metallic taste, bleeding disorders, and, rarely, anaphylactic reactions.

C. Radioactive Iodine

Radioactive iodine (¹³¹I) is taken up and concentrated in the thyroid gland so avidly that a dose large enough to severely damage the gland can be given without endangering other tissues. Unlike the thioamides and iodide salts, an effective dose of ¹³¹I can produce a permanent cure of thyrotoxicosis without surgery. ¹³¹I should not be used in pregnant or nursing women.

D. Anion Inhibitors

Anions such as thiocyanate (SCN^–) and perchlorate (ClO₄^–) block the uptake of iodide by the thyroid gland through competitive inhibition of the iodide transporter. Their effectiveness is unpredictable and ClO₄^– can cause aplastic anemia, so these drugs are rarely used clinically.

E. Other Drugs

An important class of drugs for the treatment of thyrotoxicosis is the β blockers. These agents are particularly useful in controlling the tachycardia and other cardiac abnormalities of severe thyrotoxicosis. Propranolol also inhibits the peripheral conversion of T₄ to T₃.

The iodine-containing antiarrhythmic drug amiodarone (Chapter 14) can cause hypothyroidism through its ability to block the peripheral conversion of T₄ to T₃. It also can cause hyperthyroidism either through an iodine-induced mechanism in persons with an underlying thyroid disease such as multinodular goiter or through an inflammatory mechanism that causes leakage of thyroid hormone into the circulation. Amiodarone-associated hypothyroidism is treated with thyroid hormone. Iodine-associated hyperthyroidism caused by amiodarone is treated with thioamides, whereas the inflammatory version is best treated with corticosteroids.

Iodinated radiocontrast media (eg, oral diatrizoate and intravenous iohexol) rapidly suppress the conversion of T₄ to T₃ in the liver, kidney, and other peripheral tissues.

Questions 1-3. A 24-year-old woman was found to have mild hyperthyroidism due to Graves’ disease. She appears to be in good health otherwise.

1. In Graves’ disease, the cause of the hyperthyroidism is the production of an antibody that does which of the following?

   • (A) Activates the pituitary thyrotropin-releasing hormone (TRH) receptor and stimulates TSH release

   • (B) Activates the thyroid gland TSH receptor and stimulates thyroid hormone synthesis and release

   • (C) Activates thyroid hormone receptors in peripheral tissues

   • (D) Binds to thyroid gland thyroglobulin and accelerates its proteolysis and the release of its supply of T₄ and T₃

   • (E) Binds to thyroid-binding globulin (TBG) and displaces bound T₄ and T₃

2. The decision is made to begin treatment with methimazole. Methimazole reduces serum concentration of T₃ primarily by which of the following mechanisms?

   • (A) Accelerating the peripheral metabolism of T₃

   • (B) Inhibiting the proteolysis of thyroid-binding globulin

   • (C) Inhibiting the secretion of TSH

   • (D) Inhibiting the uptake of iodide by cells in the thyroid

   • (E) Preventing the addition of iodine to tyrosine residues on thyroglobulin

3. Though rare, a serious toxicity associated with the thioamides is which of the following?

   • (A) Agranulocytosis

   • (B) Lupus erythematosus-like syndrome

   • (C) Myopathy

   • (D) Torsades de pointes arrhythmia

   • (E) Thrombotic thrombocytic purpura (TTP)

4. A 56-year-old woman presented to the emergency department with tachycardia, shortness of breath, and chest pain. She had had shortness of breath and diarrhea for the last 2 d and was sweating and anxious. A relative reported that the patient had run out of methimazole 2 wk earlier. A TSH measurement revealed a value of <0.01 mIU/L (normal 0.4–4.0 mIU/L). The diagnosis of thyroid storm was made. Which of the following is a drug that is a useful adjuvant in the treatment of thyroid storm?

   • (A) Amiodarone

   • (B) Betamethasone

   • (C) Epinephrine

   • (D) Propranolol

   • (E) Radioactive iodine

5. A 65-year-old man with multinodular goiter is scheduled for a near-total thyroidectomy. Which of the following drugs will be administered for 10–14 d before surgery to reduce the vascularity of his thyroid gland?

   • (A) Levothyroxine

   • (B) Liothyronine

   • (C) Lugol’s solution

   • (D) Prednisone

   • (E) Radioactive iodine

6. Which of the following is a sign or symptom that would be expected to occur in the event of chronic overdose with exogenous T₄?

   • (A) Bradycardia

   • (B) Dry, puffy skin

   • (C) Large tongue and drooping of the eyelids

   • (D) Lethargy, sleepiness

   • (E) Weight loss

7. When initiating T₄ therapy for an elderly patient with longstanding hypothyroidism, it is important to begin with small doses to avoid which of the following?

   • (A) A flare-up of exophthalmos

   • (B) Acute renal failure

   • (C) Hemolysis

   • (D) Overstimulation of the heart

   • (E) Seizures

8. A 27-year-old woman underwent near total thyroidectomy. She was started on levothyroxine. What hormone is produced in the peripheral tissues when levothyroxine is administered?

   • (A) Methimazole

   • (B) T₃

   • (C) T₄

   • (D) TSH

   • (E) FSH

9. A 62-year-old woman presents with complaints of fatigue, sluggishness, and weight gain. She needs to nap several times a day, which is unusual for her. She has been taking T₄ for the past 15 yr without significant problems regarding her energy level. Her recent history is significant for diagnosis of arrhythmia, and she is currently taking an antiarrhythmic drug. What is the most likely cause of her current condition?

   • (A) Amiodarone

   • (B) Lidocaine

   • (C) Procainamide

   • (D) Sotalol

   • (E) Verapamil

10. A 25-year-old woman presents with insomnia and fears she may have “something wrong with her heart.” She describes “her heart jumping out of her chest.” She feels healthy otherwise and reports she has lots of energy. Lab tests confirm hyperthyroidism. Which of the following is a drug that produces a permanent reduction in thyroid activity?

    • (A) ¹³¹I

    • (B) Methimazole

    • (C) Propylthiouracil

    • (D) Thiocyanate (SCN^–)

    • (E) Thyroglobulin

1. The antibodies produced in Graves’ disease activate thyroid gland TSH receptors. Their effects mimic those of TSH. The answer is B.

2. The thioamides (methimazole and propylthiouracil) act in thyroid cells to prevent conversion of tyrosine residues in thyroglobulin to MIT or DIT. The answer is E.

3. Rarely, the thioamides cause severe adverse reactions that include agranulocytosis, vasculitis, hepatic damage, and hypoprothrombinemia. The answer is A.

4. In thyroid storm, β blockers such as propranolol are useful in controlling the tachycardia and other cardiac abnormalities, and propranolol also inhibits peripheral conversion of T₄ to T₃. The answer is D.

5. Iodides inhibit the synthesis and release of thyroid hormone and decrease the size and vascularity of the hyperplastic gland. Lugol’s solution contains a mixture of potassium iodide and iodine. The answer is C.

6. In hyperthyroidism, the metabolic rate increases, and even though there is increased appetite, weight loss often occurs. The other choices are symptoms seen in hypothyroidism. The answer is E.

7. Patients with longstanding hypothyroidism, especially those who are elderly, are highly sensitive to the stimulatory effects of T₄ on cardiac function. Administration of regular doses can cause overstimulation of the heart and cardiac collapse. The answer is D.

8. The thioamides (methimazole and propylthiouracil) act in thyroid cells to prevent conversion of tyrosine residues in thyroglobulin to MIT or DIT. Levothyroxine (T₄) is converted into T₃ in the periphery. FSH is follicle-stimulating hormone. The answer is B.

9. Amiodarone is an iodine-containing antiarrhythmic drug with complex effects on the thyroid gland and thyroid hormones. One of its actions is to inhibit peripheral conversion of T₄ to T₃. Note that propranolol also reduces conversion of T₄ to T₃. Procainamide (class 1A), lidocaine (class 1B), sotalol (class III), and verapamil (class IV) are antiarrhythmics and have no effect on T₄ conversion. The answer is A.

10. Propylthiouracil and, to a much lesser extent, methimazole inhibit peripheral conversion of T₄ to T₃. Thyroglobulin is not a drug. Radioactive iodine is the only medical therapy that produces a permanent reduction of thyroid activity. Anions such as thiocyanate (SCN^–) and perchlorate (ClO₄^–) block the uptake of iodide by the thyroid gland through competitive inhibition of the iodide transporter. Their effectiveness is unpredictable and ClO₄^– can cause aplastic anemia, so these drugs are rarely used. The answer is A.

Your drawing should show that receptor (Rec) stimulation acts through the G protein G_s to activate the enzyme adenylyl cyclase (AC) (Chapter 2). Adenylyl cyclase converts ATP to cAMP, which binds to the regulatory subunit (R) of cAMP-dependent protein kinases and thereby frees the catalytic subunit (C) of the kinase so it can transfer phosphate from ATP to substrate proteins (S) that mediate the ultimate cellular responses. These responses are varied and include immediately apparent effects that stem from phosphorylation of substrates such as enzymes and ion channels as well as delayed effects that follow changes in gene transcription. “Brakes” are applied to the pathway by phosphodiesterases (PDE) that hydrolyze cAMP and phosphatases (P’ase) that dephosphorylate substrates.

(Reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 2–13.)

When you complete this chapter, you should be able to:

• ❑ Sketch the biochemical pathway for thyroid hormone synthesis and release and indicate the sites of action of antithyroid drugs.

• ❑ List the principal drugs for the treatment of hypothyroidism.

• ❑ List the principal drugs for the treatment of hyperthyroidism and compare the onset and duration of their action.

• ❑ Describe the major toxicities of thyroxine and the antithyroid drugs.