Pharmacology of Thyroid Hormones and Antithyroid Drugs

Introduction/Overview

Thyroid hormones are pivotal regulators of metabolic homeostasis, influencing cellular respiration, protein synthesis, and thermogenesis. Dysregulation of thyroid function leads to significant morbidity, necessitating precise pharmacologic intervention. This monograph is intended to provide a detailed, evidence-based synthesis of the pharmacology of endogenous thyroid hormones and the principal antithyroid agents employed in clinical practice. The discussion is geared toward medical and pharmacy students who require a thorough understanding of both therapeutic and adverse pharmacodynamic and pharmacokinetic principles.

Learning Objectives

• Identify the chemical and biological classification of thyroid hormones and major antithyroid drugs.
• Describe the mechanisms of action at the receptor and cellular levels for both hormone replacement and antithyroid therapy.
• Summarize key pharmacokinetic parameters influencing dosing strategies.
• Recognize therapeutic indications, contraindications, and common adverse effect profiles.
• Understand interactions with concurrent medications and special patient populations.

Classification

Thyroid Hormones

• Triiodothyronine (T₃) – biologically active form with a rapid onset of action.
• Thyroxine (T₄) – prohormone converted to T₃ by deiodinases; longer half‑life.
• Reverse T₃ (rT₃) – inactive metabolite, often measured in hyperthyroid states.

Antithyroid Drugs

• Thionamides – methimazole, propylthiouracil (PTU), and carbimazole (prodrug of methimazole).
• Iodine preparations – potassium iodide, Lugol’s solution, used for rapid symptom control.
• Lithium – inhibits thyroid hormone synthesis and release; traditionally used in bipolar disorder but occasionally employed for hyperthyroidism.

Mechanism of Action

Thyroid Hormone Pharmacodynamics

Thyroid hormones exert their effects primarily through nuclear thyroid hormone receptors (TRα and TRβ) located in the cytoplasm and nucleus of target tissues. Binding of T₄ or T₃ to TRs induces conformational changes that facilitate recruitment of coactivator proteins and displacement of corepressors, thereby modulating transcription of target genes involved in basal metabolic rate.

Deiodination by type I, II, and III deiodinases allows conversion of T₄ to the more active T₃ within peripheral tissues; reverse T₃ is generated by type III deiodination. The balance of these processes determines the local tissue response to circulating hormone levels.

Thionamine Pharmacodynamics

Thionamides inhibit the thyroid peroxidase (TPO)-mediated iodination of tyrosyl residues within thyroglobulin, thereby blocking organification of iodine and subsequent coupling reactions that generate T₃ and T₄. This inhibition leads to a reduction in synthesis and secretion of thyroid hormones.

Propylthiouracil possesses an additional mechanism: it inhibits the 5′-deiodinase enzyme responsible for peripheral conversion of T₄ to T₃, which may be advantageous during thyrotoxic crises.

Iodine Preparations

High‐dose iodine exerts an acute inhibitory effect on hormone synthesis and release via the Wolff–Chaikoff effect. The effect is transient, with the thyroid gland typically resuming normal hormone production after the iodine load is cleared.

Lithium Pharmacodynamics

Lithium competitively inhibits thyroid hormone release by interfering with the exocytosis of vesicles containing thyroglobulin. It also reduces thyroglobulin synthesis and inhibits the conversion of T₄ to T₃ at the post‑transcriptional level.

Pharmacokinetics

Thyroid Hormone Pharmacokinetics

Absorption: Oral levothyroxine is absorbed in the proximal small intestine with a bioavailability of approximately 70–80% when taken on an empty stomach. Food, especially calcium and iron supplements, can markedly reduce absorption.

Distribution: T₄ exhibits high protein binding (~99%), primarily to thyroxine-binding globulin (TBG), transthyretin, and albumin. Tissue distribution is extensive, with significant uptake in the brain, heart, and skeletal muscle.

Metabolism: Peripheral conversion of T₄ to T₃ by type I and II deiodinases occurs predominantly in the liver, kidney, and skeletal muscle. Reverse T₃ is generated by type III deiodination.

Excretion: Unbound T₄ and T₃ are primarily excreted via the kidneys; a portion is also eliminated through feces after biliary excretion.

Half‑life: T₄ has a mean t_1/2 of ≈7 days; T₃ exhibits a shorter t_1/2 of ≈1–2 days. The long half‑life of T₄ necessitates careful titration to avoid overtreatment or undertreatment.

Antithyroid Drug Pharmacokinetics

Thionamides

• Methimazole – absorbed rapidly with a bioavailability of ≈95%. Plasma half‑life is 6–8 hours, but its effect on hormone synthesis persists for several days due to long‑term inhibition of organification.
• Propylthiouracil (PTU) – oral absorption is rapid; half‑life is 2–3 hours. PTU is metabolized primarily by hepatic glucuronidation and sulfation.
• Carbimazole – a prodrug converted to methimazole; pharmacokinetics mirror methimazole.

Iodine Preparations

Iodine is absorbed quickly from the gastrointestinal tract; its plasma half‑life is short (<1 hour). The Wolff–Chaikoff effect is transient, as the gland adapts after 24–48 hours.

Lithium

After oral ingestion, lithium is absorbed with a bioavailability of 70–80%. It is not metabolized and is eliminated unchanged primarily by glomerular filtration; the t_1/2 ranges from 4 to 12 hours depending on renal function.

Therapeutic Uses/Clinical Applications

Thyroid Hormone Replacement

• Hypothyroidism due to autoimmune thyroiditis, surgical or radioactive ablation, or iodine deficiency.
• Secondary hypothyroidism requiring hormone supplementation in the context of pituitary or hypothalamic disease.
• Adjunctive therapy in certain cancers (e.g., differentiated thyroid carcinoma) to facilitate radioactive iodine uptake.

Antithyroid Therapy

• Graves disease and toxic nodular goiter: initial or definitive treatment with thionamides.
• Thyroid storm: high‑dose iodine followed by PTU and beta‑blockers to mitigate sympathetic overdrive.
• Pre‑operative management of hyperthyroid patients to reduce peri‑operative risk.
• Lithium used as a bridge in severe thyrotoxicosis when thionamides are contraindicated or ineffective.

Off‑Label Uses

• Low‑dose PTU for the treatment of hyperthyroidism in pregnancy when the risk of fetal thyrotoxicosis is high.
• Thionamides employed to manage subclinical hyperthyroidism in select high‑risk populations, though evidence remains limited.

Adverse Effects

Thyroid Hormone Replacement

• Excessive dosing may precipitate atrial fibrillation, osteoporosis, and cardiac arrhythmias.
• Inadequate dosing can produce symptoms of hypothyroidism such as fatigue, weight gain, and cold intolerance.
• Rarely, hypersensitivity reactions to levothyroxine formulations have been reported, presenting as urticaria or angioedema.

Thionamides

• Common side effects: rash, arthralgia, and taste disturbances.
• Serious adverse reactions: agranulocytosis, hepatotoxicity (particularly with PTU), and, rarely, Stevens–Johnson syndrome.
• Black box warning: agranulocytosis can present abruptly; patients should be instructed to seek immediate care if fever or sore throat develops.

Iodine Preparations

• Transient hyperthyroidism may occur during the initial 24–48 hours of therapy.
• Gastrointestinal irritation and metallic taste are frequently reported.
• In susceptible individuals, iodine overload can precipitate thyroiditis.

Lithium

• Neuropsychiatric effects: tremor, ataxia, and cognitive slowing.
• Renal effects: nephrogenic diabetes insipidus, especially with chronic use.
• Cardiovascular: arrhythmias, particularly atrial fibrillation in patients with pre‑existing conduction abnormalities.

Drug Interactions

Thyroid Hormone Replacement

• Calcium carbonate, iron salts, and sucralfate can impair absorption; spacing administration by at least 4 hours is recommended.
• Antacids and H₂ blockers may reduce bioavailability; proton pump inhibitors have minimal impact.
• Oral contraceptives can increase clearance of levothyroxine, potentially requiring dose adjustment.

Thionamides

• Concurrent use with azathioprine may increase the risk of myelosuppression.
• In patients receiving PTU, concurrent use of high‑dose glucocorticoids may alter hepatic metabolism, potentially reducing efficacy.
• Anticoagulants: PTU can potentiate the effects of warfarin, warranting close INR monitoring.

Iodine Preparations

• High‑dose iodine may interfere with the measurement of serum TSH and free T₄ by certain immunoassays.
• Concurrent use of iodinated contrast agents increases iodine load; monitoring thyroid function is advisable in susceptible patients.

Lithium

• NSAIDs and ACE inhibitors can elevate serum lithium levels by reducing renal clearance.
• Diuretics may also increase lithium concentrations; dose adjustment may be necessary.
• Thyroid hormone replacement can alter lithium pharmacokinetics, necessitating monitoring of therapeutic drug levels.

Special Considerations

Pregnancy and Lactation

• Levothyroxine is safe and essential for fetal neurodevelopment; dose titration is required to maintain maternal euthyroidism.
• Thionamides cross the placenta; PTU is preferred in the first trimester due to lower teratogenicity, whereas methimazole is acceptable after the first trimester.
• Lithium is teratogenic (anhydramnios, Ebstein anomaly) and is generally avoided; if used, strict monitoring of maternal thyroid function is required.

Pediatric Considerations

• Dosing of levothyroxine is weight‑based (≈1.6–2.0 µg/kg/day) and requires frequent monitoring of TSH and free T₄ levels.
• Thionamides may be used in hyperthyroid children, but agranulocytosis risk necessitates vigilance.

Geriatric Considerations

• Older adults exhibit increased sensitivity to thyroid hormone excess; lower target TSH ranges (<2.5 mIU/L) are often recommended.
• Polypharmacy increases the risk of drug interactions; monitoring is essential.

Renal and Hepatic Impairment

• Levothyroxine clearance is largely hepatic; mild to moderate hepatic impairment may not significantly alter dosing, but severe hepatic dysfunction warrants caution.
• PTU and methimazole are metabolized hepatically; hepatic impairment reduces clearance and increases the risk of hepatotoxicity.
• Lithium clearance is primarily renal; dose adjustment is required in renal insufficiency to avoid toxicity.

Summary/Key Points

• Thyroid hormones modulate metabolism through TRα and TRβ nuclear receptors; peripheral conversion of T₄ to T₃ is critical for tissue‑specific effects.
• Thionamides inhibit thyroid peroxidase, reducing hormone synthesis; PTU uniquely blocks peripheral conversion of T₄ to T₃.
• High‑dose iodine induces a temporary Wolff–Chaikoff effect, useful in acute thyrotoxic crises.
• Levothyroxine therapy requires careful titration, monitoring of TSH, and consideration of drug interactions that affect absorption.
• Agranulocytosis is the most serious adverse effect of thionamides; patients should be educated to report fever or sore throat promptly.
• Special populations (pregnancy, pediatrics, geriatrics, renal/hepatic impairment) demand individualized dosing strategies and close monitoring.

References

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