Thyroid Hormones: T3 and T4

Thyroid Hormones

• T4 is tetraiodothyronine, also known as L-thyroxine
• T3 is triiodothyronine
• The numbers 3 and 4 indicate the number of iodine molecules in each hormone
• These hormones are synthesized from two amino acids linked together, with iodine attached
• T3 is more biologically active compared to T4
• The Hypothalamus releases Releasing Factors to trigger the release of thyroid hormones
• In response to Releasing Factors, the Pituitary releases Thyroid Stimulating Hormone (TSH) into the blood
• TSH travels to the thyroid gland
• TSH stimulates the thyroid to release T4 and T3
• T4 in the plasma gets converted to T3 by 5'deiodinase
• Target cells take up T3, which then binds to nuclear receptors
• T3 binding to nuclear receptors alters gene transcription
• These actions on the DNA level have widespread metabolic effects across the body

Iodide

• The thyroid removes iodide from circulation, which comes from the diet
• The sodium/iodide symporter (NIS) actively transports iodide into the thyroid gland from the blood
• Thyroidal peroxidase converts iodide into iodine
• Iodine then iodinates tyrosine, to form monoiodotyrosine (MIT) and diiodotyrosine (DIT)
• T3 is formed from MIT and DIT
• T4 is formed from two DIT molecules
• Thyroxine binding globulin (TBG) is the plasma protein that carries both T3 and T4 in the blood

Hormone Levels

• T4 is present in micrograms per deciliter (ug/dL), while T3 is in nanograms per deciliter (ng/dL)
• T3 is more potent, despite its lower concentration
• For comparison, T4 blood levels are between 4.8 - 10.4 mcg/dL, and T3 levels are between 0.06 - 0.181 mcg/dL
• T3 is 3-4 times more potent than T4

Regulation

• 5'-deiodinase is the enzyme that converts T4 to T3
• A feedback mechanism regulates the thyroid gland
• The hypothalamus releases thyrotropin releasing hormone (TRH)
• TRH stimulates the pituitary to release TSH
• TSH stimulates the thyroid gland to release T4 and T3

Pharmacology of Thyroid Hormones

• Only the free forms of T4 and T3 are active
• Both T4 and T3 hormones enter cells like steroids
• 5'-deiodinase converts T4 to T3 inside cells
• T3 binds to specific receptors in the nucleus
• Nuclear receptor activation leads to increased RNA formation and protein synthesis
• This explains the lag times observed with thyroid hormones and drugs
• Thyroid hormones regulate a wide array of functions due to their effect on gene transcription
• Conversion of T4 to T3 happens both inside and outside of cells

Thyroid Hormones as Drugs

• Thyroid hormone drugs are available as synthetic or animal-derived forms
• Desiccated thyroid is of animal origin but is rarely used
• Animal-derived material is dangerous due to protein antigenicity
• Levothyroxine is synthetic T4, is the most common form, with a long half-life of 7 days and is converted to T3
• Liothyronine is synthetic T3 and has a shorter half-life of 24 hours
• Liotrix is a combination drug with a fixed dose of thyroxine and liothyronine
• Levothyroxine is the most widely used thyroid drug

Antithyroid Drugs: Thioamides

• Examples include methimazole and propylthiouracil
• They inhibit thyroid peroxidase reactions
• They prevent hormone synthesis by blocking iodine incorporation onto the amino acid complex
• The most common adverse drug reaction (ADR) is maculopapular pruritic rash
• Agranulocytosis is the most dangerous ADR

Antithyroid Drugs: Anion Inhibitors

• Examples include perchlorate, pertechnetate, and thiocyanate
• They function by blocking iodide uptake by the thyroid gland

Antithyroid Drugs: Iodides

• Iodides inhibit organification and hormone release
• They can impair thyroid gland function in instances of excess iodine

Antithyroid Drugs: Radioactive Iodine

• Radioactive iodine-125 is administered orally
• The thyroid gland concentrates it, and beta rays destroy the gland tissue
• Radioactive iodine destroys the thyroid gland, known as radioactive ablation

Clinical Pharmacology: Hypothyroidism

• Characterized by low free T4 and elevated TSH levels
• Hashimoto's thyroiditis is the most common cause
• It is an immune disorder in which the patient develops thyroid-destroying antibodies
• The thyroid does not produce T4 and T3, and the pituitary continuously sends TSH signals
• Treatment includes thyroid replacement drugs such as levothyroxine

Clinical Pharmacology: Hyperthyroidism

• Graves' disease is a common cause
• Patients produce TSH-like antibodies that stimulate the thyroid gland
• These antibodies acts as agonists and stimulate T4 and T3 release
• Elevated T4, T3, and free hormone levels, coupled with low TSH levels indicate hyperthyroidism
• Treatment consists of antithyroid drugs or thyroid gland removal by partial or complete thyroidectomy
• Radioactive iodine is also used

Thyroid-Related Conditions

• Goiter describes a nodule in the neck over the thyroid gland, can occur in either hyper- or hypothyroidism
• Thyroid storm is a life-threatening form of thyrotoxicosis
• Propranolol or esmolol (beta blockers) are administered to control the cardiac effects of excess T4 and T3
• Potassium iodide helps shut down the thyroid gland

Other drugs affecting the thyroid

• Propythiouracil stops hormone synthesis
• Hydrocortisone and propranolol both block the conversion of T4 to T3

Summary of Thyroid-Related Drugs:

• Thyroid replacement hormones: levothyroxine (T4), liothyronine (T3), liotrix (T4 plus T3), and thyroid desiccated, activate gene expression in cells for protein synthesis
• Thyrotropin: recombinant human TSH
• Thioamides: methimazole and propylthiouracil, inhibit thyroid peroxidase, block iodine organification, and inhibit peripheral deiodination
• Iodides: Lugol solution and potassium iodide, inhibit organification and hormone release
• Beta blockers: propranolol and esmolol, inhibit conversion of T4 to T3
• Radioactive iodine: 131I iodine, radiation destruction for thyroid cancer treatment