Pharmacology of Thyroid Hormones and Antithyroid Drugs

Introduction/Overview

The thyroid gland, through the synthesis and secretion of thyroid hormones, exerts a profound influence on nearly every organ system, regulating basal metabolic rate, thermogenesis, and overall cellular metabolism. Disorders of thyroid function, namely hypothyroidism and hyperthyroidism, are among the most prevalent endocrine conditions encountered in clinical practice. Consequently, a thorough understanding of the pharmacology of agents used to modulate thyroid function—both replacement hormones and antithyroid drugs—is fundamental for the safe and effective management of these disorders. This chapter provides a systematic examination of the pharmacodynamics, pharmacokinetics, therapeutic applications, and adverse effect profiles of these critical drug classes.

Clinical Relevance and Importance

Thyroid dysfunction presents a significant global health burden. Hypothyroidism, characterized by insufficient hormone production, requires lifelong hormone replacement therapy. Conversely, hyperthyroidism, resulting from excessive hormone synthesis and release, necessitates therapeutic strategies to reduce hormone production or action. The pharmacological agents used in these conditions are characterized by narrow therapeutic indices, making precise dosing and monitoring paramount. Mastery of their pharmacology is essential to avoid both undertreatment, which fails to alleviate symptoms and metabolic consequences, and overtreatment, which can induce iatrogenic disease states with serious cardiovascular and skeletal complications.

Learning Objectives

• Describe the biosynthesis and physiological roles of endogenous thyroid hormones, triiodothyronine (T₃) and thyroxine (T₄).
• Compare and contrast the mechanisms of action, pharmacokinetic properties, and clinical uses of synthetic thyroid hormone preparations (levothyroxine, liothyronine).
• Explain the molecular mechanisms by which thionamide antithyroid drugs (methimazole, propylthiouracil) inhibit thyroid hormone synthesis and their role in managing hyperthyroidism.
• Analyze the therapeutic applications, dosing strategies, and major adverse effects of iodine and iodinated compounds in thyroid disease.
• Evaluate special considerations for the use of thyroid and antithyroid drugs in specific populations, including pregnant patients, pediatric populations, and those with comorbid conditions.

Classification

Drugs affecting thyroid function are classified into two principal categories based on their therapeutic intent: thyroid hormone preparations used for replacement therapy and antithyroid agents used to suppress hormone overproduction. A third category includes adjunctive agents used for symptomatic control or diagnostic purposes.

Thyroid Hormone Preparations

• Synthetic Hormones:
  • Levothyroxine sodium (L-T₄, T₄)
  • Liothyronine sodium (L-T₃, T₃)
  • Liotrix (a fixed combination of T₄ and T₃ in a 4:1 ratio)
• Natural Thyroid Extracts: Desiccated thyroid (derived from porcine thyroid glands), containing both T₄ and T₃ in non-physiological ratios.

Antithyroid Drugs

• Thionamides (Thiourylene derivatives):
  • Methimazole (Thiamazole)
  • Propylthiouracil (PTU)
  • Carbimazole (a prodrug converted to methimazole)
• Ionic Inhibitors:
  • Iodide salts (e.g., Potassium iodide, Lugol’s solution)
  • Iodinated contrast media (e.g., Iopanoic acid)
• Radioactive Iodine: Sodium iodide I-131 (¹³¹I).

Adjunctive and Other Agents

• Beta-Adrenergic Antagonists: Propranolol, atenolol (for symptomatic control of hyperthyroidism).
• Ionic Inhibitors of Iodide Transport: Perchlorate, thiocyanate (rarely used clinically).
• Cholestyramine: Used to interrupt enterohepatic recycling of thyroid hormones in severe thyrotoxicosis.

Mechanism of Action

Endogenous Thyroid Hormone Synthesis and Regulation

Understanding drug mechanisms requires a foundation in thyroid physiology. Thyroid hormone synthesis within thyroid follicular cells involves a series of coordinated steps: active uptake of circulating iodide via the sodium-iodide symporter (NIS); oxidation of iodide to iodine by thyroid peroxidase (TPO); iodination of tyrosine residues on thyroglobulin (Tg) to form monoiodotyrosine (MIT) and diiodotyrosine (DIT); and coupling of these iodotyrosines, catalyzed by TPO, to form T₃ (MIT + DIT) and T₄ (DIT + DIT). Secretion involves endocytosis and proteolysis of Tg. This process is regulated by thyroid-stimulating hormone (TSH) from the anterior pituitary, which itself is under negative feedback control by circulating T₃ and T₄.

Mechanism of Thyroid Hormone Preparations

Synthetic thyroid hormones are identical to endogenous hormones and exert their effects by binding to nuclear thyroid hormone receptors (TRs), which are ligand-activated transcription factors. TRs exist as isoforms (TRα and TRβ) with differing tissue distributions. The hormone-receptor complex binds to thyroid hormone response elements (TREs) in the promoter regions of target genes, recruiting coactivators or corepressors to modulate gene transcription. The resulting changes in mRNA and protein synthesis mediate the wide-ranging metabolic, developmental, and cardiovascular effects. Levothyroxine (T₄) is considered a prohormone, as it is peripherally deiodinated to the more biologically active T₃ by types 1 and 2 deiodinase enzymes. Liothyronine provides direct T₃ activity, bypassing this conversion step.

Mechanism of Thionamide Antithyroid Drugs

The primary mechanism of thionamides is the inhibition of thyroid peroxidase, the enzyme critical for both the oxidation of iodide and the coupling of iodotyrosines. By covalently binding to TPO, these drugs prevent the synthesis of new T₄ and T₃. Propylthiouracil possesses an additional, extrathyroidal mechanism: it inhibits the peripheral conversion of T₄ to T₃ by type 1 deiodinase, which may provide a more rapid reduction in active hormone levels in severe thyrotoxicosis. At high doses, thionamides may also have immunosuppressive effects, potentially reducing TSH-receptor antibody titers in Graves’ disease over time.

Mechanism of Iodine and Iodides

The effects of iodine are complex and dose-dependent. In pharmacological doses (≥ 6 mg/day), iodide exerts a paradoxical inhibitory effect known as the Wolff-Chaikoff effect. The sudden increase in intratthyroidal iodide concentration transiently inhibits iodide organification and thyroid hormone synthesis. This effect is usually self-limited due to an “escape” phenomenon mediated by downregulation of NIS. Iodide also reduces the vascularity and size of the thyroid gland, making it firmer and potentially easier to operate on. Radioactive iodine (¹³¹I) is actively concentrated by the thyroid via NIS; its beta-particle emissions cause localized follicular cell destruction through ionizing radiation, leading to a controlled ablation of thyroid tissue.

Pharmacokinetics

Thyroid Hormone Preparations

Levothyroxine (T₄): Oral absorption occurs primarily in the jejunum and ileum, with bioavailability ranging from 60% to 80% in the fasting state. Absorption is significantly impaired by food, coffee, fiber, calcium, iron, and proton pump inhibitors. It is highly protein-bound (>99.9%) to thyroxine-binding globulin (TBG), transthyretin, and albumin. The volume of distribution is approximately 10-12 L. Levothyroxine undergoes extensive peripheral deiodination to T₃ and reverse T₃ (rT₃). Its elimination half-life is approximately 7 days in euthyroid individuals, allowing for once-daily dosing. Steady-state concentrations are achieved in 4-6 weeks after a dosage change.

Liothyronine (T₃): Oral bioavailability is approximately 95%. It is also highly protein-bound (99.5%), but with lower affinity for TBG than T₄. The volume of distribution is around 40 L. Liothyronine is not subject to activation by deiodination; it is the active form. Its metabolic clearance is rapid, with a half-life of approximately 1-2 days, necessitating multiple daily doses if used for chronic replacement.

Thionamide Antithyroid Drugs

Methimazole: Well-absorbed orally with nearly 100% bioavailability. It is not significantly protein-bound and concentrates in the thyroid gland, where its half-life is prolonged (> 20 hours). The plasma half-life is 4-6 hours, but its clinical effect lasts much longer due to intrathyroidal accumulation, permitting once-daily dosing. It is metabolized in the liver and excreted in urine.

Propylthiouracil (PTU): Oral bioavailability is 50-80%. It is 75-80% protein-bound. PTU also concentrates in the thyroid. Its plasma half-life is shorter (1-2 hours), typically requiring dosing every 6-8 hours. It is metabolized hepatically and renally excreted. PTU crosses the placenta less readily than methimazole but is present in breast milk.

Iodide Preparations

Inorganic iodide is rapidly and nearly completely absorbed from the gastrointestinal tract. It is distributed extracellularly and actively transported into the thyroid, salivary glands, gastric mucosa, and mammary glands. The kidneys rapidly excrete excess iodide, with a half-life of approximately 8 hours when thyroidal uptake is blocked. The onset of the Wolff-Chaikoff effect occurs within 24-48 hours.

Radioactive Iodine (¹³¹I): Orally administered as a solution or capsule. Its pharmacokinetics mirror stable iodide, with uptake dependent on thyroidal activity. The physical half-life of ¹³¹I is 8 days. The biological effect is determined by the radiation dose delivered to the thyroid tissue, which is a function of the administered activity, the percentage uptake, and the effective half-life within the gland.

Therapeutic Uses/Clinical Applications

Therapeutic Uses of Thyroid Hormone Preparations

• Primary, Secondary, and Tertiary Hypothyroidism: Levothyroxine is the standard of care for lifelong replacement therapy. The goal is to normalize the serum TSH level.
• Myxedema Coma: A medical emergency treated with intravenous levothyroxine, often with adjunctive intravenous liothyronine due to impaired peripheral conversion.
• Thyroid Cancer Suppression Therapy: In differentiated thyroid carcinoma (papillary/follicular), supraphysiological doses of levothyroxine are used to suppress TSH, which can be a growth factor for residual cancer cells.
• Simple (Nontoxic) Goiter: Levothyroxine may be used to shrink goiters by suppressing TSH, particularly in areas of iodine deficiency.
• Diagnostic Use: The T₃ suppression test (now largely historical) assessed thyroid autonomy.

Therapeutic Uses of Antithyroid Drugs

• Graves’ Disease: Thionamides are first-line in many regions, particularly for younger patients, those with mild disease, or as a bridge to definitive therapy. They are used to achieve a euthyroid state prior to radioactive iodine therapy or surgery.
• Other Causes of Hyperthyroidism: Used in toxic multinodular goiter or solitary toxic adenoma when surgery or RAI is not suitable, and in thyroiditis (e.g., subacute, postpartum) for symptomatic control if needed.
• Thyrotoxic Storm: A life-threatening exacerbation treated with high-dose PTU (preferred for its inhibition of peripheral T₄ to T₃ conversion), followed by iodide administration after thionamide blockade is established.
• Preparation for Thyroidectomy: Patients are rendered euthyroid with thionamides preoperatively. Iodide (Lugol’s solution) may be added for 7-10 days prior to surgery to reduce gland vascularity.

Therapeutic Uses of Iodine and Radioactive Iodine

• Radioactive Iodine (¹³¹I): The most common definitive treatment for Graves’ disease and toxic nodular conditions in many countries, particularly North America. It is also the primary treatment for ablation of residual thyroid tissue post-thyroidectomy for differentiated thyroid cancer.
• Pharmacologic Iodide: Used preoperatively in thyroid surgery and in the acute management of thyrotoxic storm (after thionamide administration).
• Iodine Deficiency Prophylaxis: Iodized salt, potassium iodide supplements.

Adverse Effects

Adverse Effects of Thyroid Hormone Preparations

Adverse effects are almost exclusively due to iatrogenic hyperthyroidism (thyrotoxicosis factitia) from excessive dosing. Symptoms mirror those of endogenous hyperthyroidism and include palpitations, tachycardia, arrhythmias (notably atrial fibrillation), angina, tremors, anxiety, insomnia, heat intolerance, sweating, weight loss, and diarrhea. Long-term overtreatment is associated with an increased risk of osteoporosis and fractures due to increased bone turnover, and with increased cardiac strain, potentially leading to heart failure in susceptible individuals. Allergic reactions to excipients in tablet formulations are rare. No black box warnings are issued for thyroid hormone preparations when used appropriately.

Adverse Effects of Thionamide Drugs

Adverse effects are relatively common, occurring in up to 20% of patients, and are often dose-related.

• Minor Reactions: Maculopapular rash, urticaria, arthralgias, fever, and gastrointestinal upset. These may resolve spontaneously or with antihistamines, or may necessitate switching to the other thionamide.
• Major Reactions:
  • Agranulocytosis: The most feared adverse effect, with an incidence of approximately 0.2-0.5%. It typically presents with fever, sore throat, and oral ulcers. It is idiosyncratic but may be more common with higher doses and in older patients. It requires immediate drug discontinuation, infection management, and often granulocyte colony-stimulating factor (G-CSF).
  • Hepatotoxicity: PTU is associated with a risk of severe hepatocellular injury and fulminant hepatic failure, leading to a black box warning restricting its use generally to the first trimester of pregnancy and thyrotoxic storm. Methimazole can cause a cholestatic pattern of injury, which is usually less severe.
  • Vasculitis: ANCA-positive vasculitis, resembling polyarteritis nodosa or lupus-like syndrome, is a rare but serious complication, primarily associated with PTU.

Adverse Effects of Iodine and Radioactive Iodine

Iodide: Adverse effects include iodine-induced hyperthyroidism (Jod-Basedow phenomenon), particularly in individuals with underlying nodular goiter living in iodine-deficient regions. Hypothyroidism can also occur. Chronic excess can lead to iodism, characterized by a metallic taste, salivary gland swelling, acneiform rash, and mucous membrane ulcerations. Severe allergic reactions are possible.

Radioactive Iodine (¹³¹I): The primary adverse effect is the induction of hypothyroidism, which is an expected outcome in most Graves’ disease patients and requires lifelong levothyroxine replacement. There may be an initial transient exacerbation of thyrotoxicosis 5-10 days post-treatment due to radiation-induced thyroiditis and hormone release. Rare risks include radiation thyroiditis, which can be painful, and worsening of Graves’ ophthalmopathy, particularly in smokers and those with pre-existing severe eye disease. There is no proven increased risk of secondary malignancies or teratogenic effects at standard doses for hyperthyroidism, but stringent radiation safety precautions are mandatory.

Drug Interactions

Drug Interactions with Thyroid Hormones

Numerous drugs and substances can alter the absorption, metabolism, or protein binding of thyroid hormones, necessitating dose adjustments and careful monitoring of TSH levels.

• Absorption Inhibitors: Calcium carbonate, iron supplements, aluminum hydroxide (antacids), sucralfate, cholestyramine, colestipol, sevelamer, and high-fiber diets can bind levothyroxine in the gut, significantly reducing its absorption. Administration should be separated by at least 4 hours.
• Metabolism Inducers: Drugs that induce hepatic cytochrome P450 enzymes (e.g., phenytoin, carbamazepine, rifampin, phenobarbital, sertraline) can increase the metabolic clearance of T₄ and T₃, potentially increasing levothyroxine dose requirements.
• Protein-Binding Displacers: Drugs like salicylates, furosemide, and anticonvulsants can displace T₄ from binding proteins, transiently increasing free hormone levels, though this effect is often compensated by increased clearance.
• Altered Thyroid Function Tests: Amiodarone, lithium, interferon-α, and tyrosine kinase inhibitors can directly cause thyroid dysfunction, complicating the interpretation of tests and management.

Drug Interactions with Antithyroid Drugs

Major interactions are less common but noteworthy.

• Warfarin: Both hyperthyroidism and the initiation of antithyroid therapy affect coagulation. Correction of hyperthyroidism with thionamides increases the sensitivity to warfarin, necessitating careful INR monitoring and dose reduction to avoid bleeding.
• Other Bone Marrow Suppressants: Concomitant use of drugs with myelosuppressive potential (e.g., clozapine, some chemotherapies) may theoretically increase the risk of agranulocytosis, though data are limited.
• Beta-Blockers: Often used concomitantly for symptomatic control; no major pharmacokinetic interactions, but additive bradycardia may occur when hyperthyroidism is controlled.

Contraindications

• Thyroid Hormones: Absolute contraindication is uncorrected adrenal insufficiency (Addison’s disease), as thyroid hormone replacement can precipitate an Addisonian crisis by increasing cortisol clearance. Relative contraindications include acute myocardial infarction, thyrotoxicosis, and untreated pheochromocytoma.
• Thionamides: Previous major adverse reaction (agranulocytosis, severe hepatitis, vasculitis) to any thionamide is a contraindication. PTU is generally contraindicated in children and in non-pregnant adults except during the first trimester of pregnancy or in thyroid storm, due to its hepatotoxicity risk.
• Radioactive Iodine: Pregnancy and breastfeeding are absolute contraindications. It is relatively contraindicated in patients with active moderate-to-severe Graves’ ophthalmopathy, in children under 5 years (debated), and in individuals unable to comply with radiation safety instructions.

Special Considerations

Pregnancy and Lactation

Hypothyroidism in Pregnancy: Adequate maternal thyroid hormone is critical for fetal neurodevelopment, especially in the first trimester. Levothyroxine requirements frequently increase by 25-50% during pregnancy, necessitating pre-conception counseling and close TSH monitoring (every 4 weeks). The goal TSH is trimester-specific, generally <2.5 mIU/L in the first trimester and <3.0 mIU/L thereafter.

Hyperthyroidism in Pregnancy: Graves’ disease is the most common cause. Propylthiouracil is preferred during the first trimester due to a possibly lower risk of teratogenic effects (though both drugs carry risk). Methimazole is often preferred after the first trimester due to its superior safety profile regarding hepatotoxicity. The lowest effective dose should be used to maintain maternal free T₄ at or slightly above the upper limit of normal. Radioactive iodine is absolutely contraindicated. Both thionamides cross the placenta and can cause fetal hypothyroidism and goiter; maternal doses should be minimized.

Lactation: Both methimazole (up to 20-30 mg/day) and PTU are considered compatible with breastfeeding, though methimazole is often preferred as less is excreted into milk. The infant’s thyroid function should be monitored. Levothyroxine is safe during lactation.

Pediatric Considerations

Congenital hypothyroidism requires immediate and aggressive levothyroxine replacement to prevent irreversible intellectual disability. Dosing is weight-based and higher than in adults (e.g., 10-15 µg/kg/day for infants). Close monitoring of TSH and free T₄ is essential for dose titration. For hyperthyroidism in children, thionamides are often first-line, with methimazole preferred over PTU due to the hepatotoxicity risk. Definitive therapy with radioactive iodine or surgery is considered after a prolonged course of medication, weighing the risks of long-term drug exposure against the risks of ablation.

Geriatric Considerations

Older patients often present with atypical or subtle symptoms of thyroid dysfunction (“apathetic hyperthyroidism”). The initiation of levothyroxine in elderly patients, particularly those with known or subclinical coronary artery disease, must be done cautiously with low starting doses (e.g., 25 µg/day) and slow titration to avoid precipitating angina or arrhythmias. The target TSH range may be relaxed to 4-6 mIU/L in the very elderly (>80 years) to avoid overtreatment risks. Thionamide-induced agranulocytosis may be more common in older patients.

Renal and Hepatic Impairment

Renal Impairment: No specific dose adjustment is required for levothyroxine, though the presence of nephrotic syndrome with significant proteinuria can increase urinary loss of protein-bound hormone. Thionamides are renally excreted, but dose adjustment is not typically necessary; however, vigilance for adverse effects is warranted.

Hepatic Impairment: Levothyroxine metabolism may be impaired in severe liver disease, potentially requiring dose reduction. Thionamides are metabolized hepatically. PTU is contraindicated in significant hepatic impairment due to its risk of hepatotoxicity. Methimazole should be used with caution and at reduced doses in patients with liver disease, with frequent monitoring of liver function tests.

Summary/Key Points

• Thyroid hormones (T₄ and T₃) are critical regulators of metabolism, growth, and development, acting via nuclear receptors to modulate gene transcription.
• Levothyroxine (synthetic T₄) is the mainstay of hypothyroidism treatment, characterized by a long half-life (~7 days), high protein binding, and peripheral conversion to active T₃. Its absorption is impaired by many common agents.
• Thionamide antithyroid drugs (methimazole, propylthiouracil) inhibit thyroid peroxidase, blocking new hormone synthesis. PTU also inhibits peripheral T₄ to T₃ conversion. Methimazole is generally preferred due to once-daily dosing and a better safety profile, except in the first trimester of pregnancy and thyroid storm.
• Major adverse effects of thionamides include dose-dependent minor reactions (rash, arthralgia) and idiosyncratic major reactions: agranulocytosis (requires immediate cessation) and hepatotoxicity (particularly with PTU).
• Radioactive iodine (¹³¹I) is a common definitive therapy for hyperthyroidism, acting via selective irradiation of thyroid tissue. The expected outcome is hypothyroidism, requiring subsequent levothyroxine replacement.
• Pharmacologic iodide is used preoperatively and in thyroid storm, exerting a rapid inhibitory effect on hormone release (Wolff-Chaikoff effect).
• Management in pregnancy requires careful balancing: levothyroxine doses often need increase; for hyperthyroidism, PTU is used in the first trimester, often switching to methimazole thereafter, with the goal of mild maternal hyperthyroidism to protect the fetus.
• The therapeutic index for these agents is narrow. Management relies heavily on laboratory monitoring (TSH for hypothyroidism, free T₄/T₃ for hyperthyroidism) and individualized dose titration.

Clinical Pearls

• Levothyroxine should be taken on an empty stomach, at least 60 minutes before breakfast and 4 hours apart from calcium, iron, or proton pump inhibitors.
• When initiating levothyroxine in older adults or patients with cardiac disease, “start low and go slow” (e.g., 25 µg daily) to avoid cardiac strain.
• Patients on thionamides must be instructed to discontinue the drug immediately and seek medical attention if they develop fever, sore throat, or mouth ulcers, symptoms suggestive of agranulocytosis.
• The treatment of choice for a pregnant patient with Graves’ disease is generally antithyroid drugs, not surgery or radioactive iodine. Fetal thyroid function should be monitored in the second and third trimesters.
• After radioactive iodine therapy for hyperthyroidism, patients should be monitored for the development of hypothyroidism, which is not a treatment failure but an expected outcome in most cases.

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