Endocrine Pharmacology: Thyroid Hormones and Antithyroid Drugs

Introduction/Overview

The thyroid gland regulates metabolic rate, growth, and development through secretion of thyroxine (T4) and triiodothyronine (T3). Disruptions in thyroid hormone production or action give rise to a spectrum of endocrine disorders, most notably hyperthyroidism and hypothyroidism. Accurate pharmacologic intervention is essential for restoring euthyroidism and preventing both acute and chronic complications. This chapter delineates the pharmacological principles governing thyroid hormone replacement and antithyroid therapy, emphasizing mechanisms of action, pharmacokinetics, therapeutic indications, safety profiles, and special patient populations. The material is intended to equip medical and pharmacy students with a robust conceptual framework for clinical decision-making.

Learning Objectives

• Describe the biochemical pathways involved in thyroid hormone synthesis and metabolism.
• Explain the pharmacodynamic actions of synthetic thyroid hormones and antithyroid agents.
• Summarize the pharmacokinetic parameters influencing dosing schedules.
• Identify the therapeutic indications and contraindications for each drug class.
• Recognize common and serious adverse effects, and understand strategies to mitigate them.

Classification

Thyroid Hormone Preparations

Thyroid hormone replacement therapy is principally divided into levothyroxine (LT4) and liothyronine (LT3) formulations. Levothyroxine exists as tablets and liquid solutions, whereas liothyronine is available as tablets. Combination preparations containing both LT4 and LT3 are marketed for specific patient subsets, though evidence for superior efficacy remains limited.

Antithyroid Drugs

Antithyroid agents are categorized by their chemical structure and mechanism of action:

• Thionamides – propylthiouracil (PTU) and methimazole (MMI) inhibit thyroid peroxidase, reducing iodination and coupling of iodotyrosines.
• Iodine-based agents – potassium iodide (KI) and radioactive iodine (I-131) exploit the Wolff–Chaikoff effect to transiently suppress hormone synthesis.
• Glucocorticoids – high‑dose steroids may be employed in severe thyrotoxic crisis to inhibit peripheral conversion of T4 to T3.

Chemical Classification

Thionamides share a thiourea core, whereas iodine compounds are inorganic salts or radionuclides. Steroids are characterized by the cyclopentanoperhydrophenanthrene nucleus. Understanding these structural motifs aids in anticipating pharmacokinetic behavior and potential adverse reactions.

Mechanism of Action

Thyroid Hormone Preparations

Levothyroxine is a synthetic analogue of T4; it undergoes peripheral deiodination to T3, the active form, primarily in the liver and kidneys. Binding to thyroid hormone receptors (TRα and TRβ) in the nucleus modulates transcription of target genes involved in basal metabolic rate, protein synthesis, and thermogenesis. Liothyronine directly supplies T3, bypassing conversion steps and achieving more rapid receptor occupancy.

Thionamides

Propylthiouracil and methimazole competitively inhibit thyroid peroxidase, curtailing the iodination of tyrosyl residues and the coupling of iodotyrosines to form T3 and T4. Additionally, PTU possesses the capacity to block peripheral conversion of T4 to T3 by inhibiting 5‑deiodinase. The inhibitory effect is dose‑dependent and reversible upon drug discontinuation.

Iodine-Based Agents

Potassium iodide induces the Wolff–Chaikoff effect, wherein excess intracellular iodine temporarily inhibits thyroid hormone synthesis. The effect is self‑limiting; the gland adapts after 48–72 hours. I-131, a beta‑emitting radionuclide, accumulates in thyroid follicular cells via the sodium/iodide symporter and delivers targeted radiation, leading to selective cytotoxicity of hyperactive thyroid tissue.

Glucocorticoids

High‑dose steroids reduce peripheral conversion of T4 to T3 by inhibiting 5‑deiodinase. They also diminish cytokine‑mediated thyroid hormone release during severe thyrotoxic states. The anti-inflammatory properties may mitigate systemic complications such as cardiovascular instability.

Pharmacokinetics

Levothyroxine

Absorption is variable, influenced by gastric pH and concurrent medications. Peak serum concentrations occur 1–3 hours post‑dose. The drug exhibits extensive protein binding (predominantly to thyroxine-binding globulin). Distribution is widespread; the volume of distribution approximates total body water. Metabolism occurs primarily in the liver via deiodination, with a terminal half‑life of 6–7 days, permitting once‑daily dosing. Renal excretion accounts for a minor fraction of elimination, rendering dose adjustments unnecessary in mild to moderate renal impairment.

Liothyronine

Liothyronine is absorbed rapidly, with peak concentrations within 1–2 hours. It has a shorter half‑life (~6–18 hours) necessitating twice‑daily administration for stable serum levels. Metabolism parallels T3, involving deiodination and subsequent clearance. Renal dysfunction can prolong elimination, and cautious titration is advised.

Thionamides

Propylthiouracil is absorbed within 1–2 hours; peak plasma levels reach within 2–4 hours. It has a half‑life of 2–4 hours, requiring three to four daily doses. Metabolized in the liver via glucuronidation and sulfation, PTU is excreted renally. Methimazole displays a half‑life of 6–12 hours; once‑daily dosing is typical. Both agents exhibit dose‑dependent hepatic metabolism; hepatic impairment may necessitate dose reduction.

Potassium Iodide

Iodide is absorbed rapidly from the gastrointestinal tract, achieving peak plasma concentrations within 30 minutes. It is distributed primarily within the extracellular fluid and excreted unchanged by the kidneys with a half‑life of approximately 1–2 hours. Due to its short duration of action, repeated dosing is required to maintain therapeutic levels.

I-131

Following oral administration, I-131 is absorbed and accumulates in thyroid follicular cells. Its half‑life of 8 days ensures sustained radiation exposure to hyperactive tissue. Radioactive decay results in beta and gamma emissions; the radiation is largely confined to the gland, with minimal systemic exposure. Excretion occurs via renal and biliary pathways.

Glucocorticoids

High‑dose dexamethasone or prednisone achieves peak plasma concentrations within 1–2 hours. The half‑life varies by agent (dexamethasone ~36 hours, prednisone ~3–4 hours). Metabolism is hepatic; renal impairment may prolong action. The drug exerts a systemic effect, with distribution to all tissues.

Therapeutic Uses/Clinical Applications

Thyroid Hormone Replacement

Levothyroxine is the standard therapy for overt and subclinical hypothyroidism, postpartum thyroiditis, and thyroid hormone deficiency following total thyroidectomy. Dosage adjustments are guided by serum TSH and free T4 levels. Liothyronine is reserved for patients who exhibit inadequate response to levothyroxine alone, or in specific clinical contexts such as certain forms of central hypothyroidism. Combination preparations are employed selectively, often in patients reporting persistent symptoms despite adequate levothyroxine therapy.

Antithyroid Therapy

Thionamides constitute first‑line agents for hyperthyroidism, including Graves’ disease, toxic multinodular goiter, and toxic adenoma. PTU is favored in the first trimester of pregnancy and during thyrotoxic crisis due to its dual action on hormone synthesis and peripheral conversion. MMI is preferred in non‑pregnant patients and after the first trimester. Potassium iodide is used acutely to render the gland refractory to hormone synthesis, typically as a bridge before definitive therapy. Radioactive iodine therapy is indicated for persistent hyperthyroidism unresponsive to antithyroid drugs, large goiters, or when surgery is contraindicated. Glucocorticoids are employed in thyroid storm, severe thyrotoxicosis, and in select cases of amiodarone‑induced thyrotoxicosis to suppress peripheral conversion.

Adverse Effects

Thyroid Hormone Preparations

• Excess therapy may precipitate atrial fibrillation, osteoporosis, and hypermetabolism; symptoms include palpitations, tremor, weight loss, and heat intolerance.
• Under‑dosing leads to fatigue, weight gain, cold intolerance, and constipation; serum TSH remains elevated.
• Rare hypersensitivity reactions, such as rash or angioedema, have been reported.

Thionamides

• Gastrointestinal upset, rash, arthralgia, and mild transaminase elevation are common.
• Propylthiouracil carries a risk of severe hepatotoxicity, including fulminant hepatic failure; monitoring of liver enzymes is advised.
• A rare but serious complication is agranulocytosis, presenting with fever, sore throat, and neutropenia; immediate discontinuation is mandatory.

Potassium Iodide

• Thyrotoxic crisis, nausea, vomiting, abdominal pain, and diarrhea may occur with high doses.
• Excess iodine may precipitate hyperthyroidism in susceptible individuals (Jod-Basedow phenomenon).
• Allergic reactions, including anaphylaxis, are infrequent but possible.

I-131

• Transient sialadenitis, dry mouth, and dysphagia; these symptoms are usually self‑limited.
• Long‑term risk of secondary malignancy, particularly leukemia, has been observed but remains low (approx. 1–2% increment).
• Pregnancy contraindicated; ovarian radiation may lead to infertility.

Glucocorticoids

• Metabolic effects: hyperglycemia, hypertension, fluid retention.
• Prolonged use may cause osteoporosis, cataract formation, and psychiatric disturbances.
• Sudden withdrawal can precipitate adrenal insufficiency.

Drug Interactions

Levothyroxine

• Concurrent use of calcium or iron supplements, antacids, and sucralfate may reduce absorption; separation of dosing by 4 hours is advised.
• Beta‑blockers and cholestyramine can decrease bioavailability.
• Oral contraceptives may increase thyroid hormone clearance, necessitating dose adjustments.

Thionamides

• Propylthiouracil may interfere with the metabolism of phenytoin and phenobarbital, potentially increasing their plasma levels.
• Co‑administration with sulfonamides can potentiate hepatotoxicity.
• Methimazole may enhance the anticoagulant effect of warfarin by reducing hepatic synthesis of vitamin K‑dependent clotting factors.

Potassium Iodide

• Interaction with amiodarone can exacerbate thyroid dysfunction.
• High iodine intake may antagonize the action of levothyroxine during thyroid replacement therapy.

I-131

• Concurrent use of iodinated contrast agents may attenuate uptake; timing of administration should be coordinated.
• Thyroid hormone replacement may influence the distribution and retention of I-131; dose adjustments are sometimes necessary.

Glucocorticoids

• Co‑administration with non‑steroidal anti‑inflammatory drugs may increase GI ulcer risk.
• High doses may blunt the hypothalamic‑pituitary‑adrenal axis, affecting cortisol production.

Special Considerations

Use in Pregnancy and Lactation

Levothyroxine is essential for fetal neurodevelopment; dosage should be carefully titrated to maintain euthyroidism. Propylthiouracil is preferred during the first trimester due to lower teratogenic risk, whereas methimazole is used thereafter. Radioactive iodine is contraindicated throughout pregnancy and lactation because of fetal exposure. Potassium iodide offers temporary protection but is not a long‑term solution. Dexamethasone may be used in thyroid storm during pregnancy, although fetal adrenal suppression is a concern.

Pediatric/Geriatric Considerations

Children require weight‑based dosing of levothyroxine, with frequent monitoring of growth parameters. Elderly patients may exhibit altered pharmacokinetics due to reduced hepatic function and increased sensitivity to thyroid hormones, necessitating cautious titration. Polypharmacy increases the risk of drug interactions.

Renal/Hepatic Impairment

In hepatic dysfunction, levothyroxine metabolism may be reduced, but the drug is largely excreted unchanged; dose modifications are rarely required. PTU requires dose reduction in hepatic impairment due to its metabolism. Methimazole is relatively safe but monitoring is prudent. Potassium iodide excretion is renal; patients with severe renal failure may accumulate iodine, raising the risk of hypothyroidism. I-131 therapy is contraindicated in advanced liver disease due to impaired clearance of radiation.

Summary/Key Points

• Levothyroxine remains the cornerstone of hypothyroidism treatment, with dosing guided by TSH and free T4.
• Thionamides (PTU and MMI) inhibit hormone synthesis; PTU also blocks peripheral conversion and is preferred in early pregnancy.
• Potassium iodide provides a short‑term suppression of synthesis through the Wolff–Chaikoff effect; I-131 offers definitive ablation for hyperthyroidism.
• Adverse effects range from mild gastrointestinal upset to life‑threatening agranulocytosis; vigilant monitoring is essential.
• Drug interactions can significantly alter absorption, metabolism, and efficacy; appropriate spacing of medications and dose adjustments mitigate risks.
• Special populations—pregnant, lactating, elderly, and those with organ dysfunction—require individualized therapy and careful monitoring.

References

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