Katzung & Trevor's Pharmacology Examination and Board Review, 9th Edition

Chapter 38. Thyroid & Antithyroid Drugs

Thyroid & Antithyroid Drugs: Introduction

The thyroid secretes 2 types of hormones: iodine-containing amino acids (thyroxine and triiodothyronine) and a peptide (calcitonin). Thyroxine and triiodothyronine have broad effects on growth, development, and metabolism. Calcitonin is important in calcium metabolism and is discussed in Chapter 42. This chapter describes the drugs used in the treatment of hypothyroidism and hyperthyroidism.

High-Yield Terms to Learn

Goiter Enlargement of the thyroid gland Graves' disease Autoimmune disorder that results in hyperthyroidism during the early phase and can progress to hypothyroidism if there is destruction of the gland in later phases Thyroglobulin A protein synthesized in the thyroid gland; its tyrosine residues are used to synthesize thyroid hormones Thyroid-stimulating hormone (TSH) The anterior pituitary hormone that regulates thyroid gland growth, uptake of iodine and synthesis of thyroid hormone Thyroid storm Severe thyrotoxicosis Thyrotoxicosis Medical syndrome caused by an excess of thyroid hormone (Table 38-1) Thyroxine-binding globulin (TBG) Protein synthesized in the liver that transports thyroid hormone in the blood

Thyroid Hormones

Synthesis & 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 iodineorganification. 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.

FIGURE 38-1

Sites of action of some antithyroid drugs. I-, iodide ion; I°, elemental iodine. Not shown: radioactive iodine (131I), which destroys the gland through radiation.

(Modified and reproduced, with permission, from Katzung BG, editor: Basic & Clinical Pharmacology, 11th ed. McGraw-Hill, 2009: Fig. 38-1.)

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.

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.

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.

TABLE 38-1 Key features of thyrotoxicosis and hypothyroidism.

Thyrotoxicosis Hypothyroidism Warm, moist skin Pale, cool, puffy skin Sweating, heat intolerance Sensation of being cold Tachycardia, increased stroke volume, cardiac output, and pulse pressure Bradycardia, decreased stroke volume, cardiac output, and pulse pressure Dyspnea Pleural effusions, hypoventilation, and CO2 retention

Increased appetite Reduced appetite Nervousness, hyperkinesia, tremor Lethargy, general slowing of mental processes Weakness, increased deep tendon reflexes Stiffness, decreased deep tendon reflexes Menstrual irregularity, decreased fertility Infertility, decreased libido, impotence, oligospermia Weight loss Weight gain Exophthalmos (Graves' disease)

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.

Toxicity

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

Skill Keeper: The Cyclic AMP Second-Messenger System

(Chapter 2)

Like many neurotransmitters and hormones, TSH mediates its effects in thyroid cells by activating the cAMP (cyclic adenosine monophosphate) second-messenger system. 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 Answers appear at the end of the chapter.

Antithyroid Drugs

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 T3. 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.

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.

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.

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.

Other Drugs

An important class of drugs for the treatment of thyrotoxicosis is the  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.

Skill Keeper Answer: The Cyclic AMP Second Messenger System

(Chapter 2)

Your drawing should show that receptor (Rec) stimulation acts through the G protein Gs to activate the enzyme adenylyl cyclase (AC). 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.)

Checklist

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.

Drug Summary Table: Thyroid & Antithyroid Drugs

Subclass Mechanism of Action Clinical Applications Pharmacokinetics Toxicities, Drug Interactions Thyroid preparations Levothyroxine (T4) Liothyronine (T3) Activation of nuclear receptors results in gene expression with RNA formulation and protein synthesis Hypothyroidism T4 is converted to T3 in target cells, the liver, and the kidneys; T3 is 10 x more potent than T4

See Table 38-1 for symptoms of thyroid excess Thioamides Propylthiouracil (PTU) Methimazole Inhibit thyroid peroxidase reactions, iodine organification, and peripheral conversion of T4 to T3

Hyperthyroidism Oral administrations, delayed onset of activity Nausea, gastrointestinal disturbances, rash, agranulocytosis, hepatitis, hypothyroidism Iodides Lugol's solution Potassium iodide Inhibit iodine organification and hormone release; reduce size and vascularity of thyroid gland Preparation for surgical thyroidectomy Oral administration, acute onset of activity within 2-7 days Rare Radioactive iodine (131I)

Radiation-induced destruction of thyroid parenchyma Hyperthyroidism Oral administration Sore throat, hypothyroidism Beta blockers Propranolol Inhibition of  receptors; inhibition of conversion of T4 to T3

Thyroid storm Rapid onset of activity Asthma, AV blockade, hypertension, bradycardia



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