PHA 467 - (L2) Thyroid Physiology and Pharmacology

Where is the thyroid gland located, and what hormones does it secrete?

The thyroid is a butterfly-shaped gland located on the trachea just below the larynx. It secretes thyroxine (T4, ~93%), triiodothyronine (T3, ~7%), and calcitonin, which regulates Ca²⁺ homeostasis.

Describe the structure of the thyroid gland and its follicles.

The thyroid contains numerous closed follicles filled with colloid. Follicles are lined with cuboidal epithelial cells that secrete into the colloid. The major colloid component is thyroglobulin (TG), a glycoprotein containing thyroid hormones and iodine.

What are parafollicular cells, and what do they secrete?

Parafollicular cells (C cells) are found between thyroid follicles and secrete calcitonin, which participates in calcium homeostasis.

How do thyroid hormones produce their effects at the cellular level?

T4 enters target cells and is converted to the more active T3 by deiodinase. T3 binds intracellular nuclear thyroid hormone receptors associated with retinoid X receptors (RXR), regulating gene transcription, mRNA formation, and synthesis of new proteins and enzymes.

What cardiovascular effects do T3 and T4 produce?

Thyroid hormones increase cardiac output, tissue blood flow, heart rate, cardiac contractile strength, and respiration. They also increase sensitivity to sympathetic nervous system stimulation.

What metabolic processes are stimulated by thyroid hormones?

Increased mitochondrial activity, Na⁺/K⁺-ATPase activity, oxygen consumption, glucose absorption, gluconeogenesis, glycogenolysis, lipolysis, protein synthesis, and basal metabolic rate (BMR).

Compare the effects of hypothyroidism and hyperthyroidism on BMR, temperature, appetite, and weight.

Hypothyroidism: decreased BMR, cold intolerance, decreased appetite, weight gain, and reduced SNS responses. Hyperthyroidism: increased BMR, heat intolerance, increased appetite, weight loss, and increased SNS sensitivity.

Compare carbohydrate, lipid, and protein metabolism in hypothyroidism versus hyperthyroidism.

Hypothyroidism: decreased glucose metabolism, elevated cholesterol and triglycerides, decreased proteins, and edema. Hyperthyroidism: increased catabolism of glucose, proteins, and fats, resulting in weight loss and loss of muscle mass.

Compare the CNS effects of hypothyroidism and hyperthyroidism.

Hypothyroidism: slowed or deficient development and intellectual disability in infants; depression, paresthesias, memory impairment, and decreased reflexes in adults. Hyperthyroidism: irritability, restlessness, insomnia, and personality changes.

Compare cardiovascular effects of hypothyroidism versus hyperthyroidism.

Hypothyroidism: decreased cardiac pumping action, decreased heart rate and BP, potentially heart failure. Hyperthyroidism: increased sympathetic sensitivity, heart rate, BP, and potentially heart failure.

Compare skeletal effects of hypothyroidism versus hyperthyroidism.

Hypothyroidism: stunted growth in children and joint pain in adults. Hyperthyroidism: excessive initial growth followed by stunting in children and bone demineralization in adults.

Compare GI effects of hypothyroidism versus hyperthyroidism.

Hypothyroidism: decreased GI motility, tone, and secretion, causing constipation. Hyperthyroidism: excessive GI motility, diarrhea, and loss of appetite.

Compare reproductive effects of hypothyroidism versus hyperthyroidism.

Hypothyroidism: decreased ovarian function, fertility, and lactation. Hyperthyroidism: decreased ovarian function and menstrual abnormalities, including oligomenorrhea or amenorrhea.

Compare skin and hair changes in hypothyroidism versus hyperthyroidism.

Hypothyroidism: pale, thick, dry skin; facial edema; coarse, thick hair. Hyperthyroidism: flushed, thin, moist skin; fine, soft hair; thin, soft nails.

Describe the hypothalamic-pituitary-thyroid (HPT) axis.

Hypothalamic neurons synthesize and release TRH into the hypothalamic-pituitary portal circulation. TRH binds GPCRs on anterior pituitary thyrotrophs, stimulating TSH release. TSH stimulates the thyroid gland to synthesize and secrete T3 and T4.

How does negative feedback regulate the HPT axis?

Increased circulating T3 and T4 inhibit TRH secretion from the hypothalamus and TSH secretion from the anterior pituitary, reducing further thyroid hormone production.

How does body temperature affect TRH secretion?

Cold exposure stimulates hypothalamic TRH release to increase thyroid hormone production and metabolic heat generation. Heat exposure suppresses this response. Thyroid hormones maintain energy homeostasis and regulate energy expenditure.

Which major tissues are affected by thyroid hormones?

Cardiovascular system, adipose tissue, liver, musculoskeletal system, CNS, and other tissues involved in metabolism, growth, and development.

How much iodine is required for thyroid hormone synthesis, and how is it obtained?

Approximately 1 mg/week of dietary iodine is required in the form of iodide (I⁻). Iodized table salt contains approximately 1 part NaI per 100,000 parts NaCl. About 1/5 of ingested iodide is removed from blood by the thyroid; the remainder is largely excreted through the kidneys.

What is iodide trapping, and how does it occur?

Iodide trapping is active transport of iodide from blood into thyroid follicular cells through the basolateral Na⁺/I⁻ symporter (NIS). It concentrates iodide approximately 30–250 times above blood concentrations and is primarily stimulated by TSH.

How does TSH activate iodide trapping?

TSH binds its Gs-coupled receptor (TSH-R) on thyroid follicular cells, activating adenylyl cyclase → cAMP → protein kinase A (PKA). PKA stimulates phosphorylation and activation of the Na⁺/I⁻ symporter, increasing iodide uptake.

What is the role of pendrin in thyroid hormone biosynthesis?

Pendrin is an apical membrane transporter that moves iodide from the thyroid follicular cell into the colloid, where iodide is used to synthesize thyroid hormones.

What is thyroglobulin, and what role does it play in thyroid hormone synthesis?

Thyroglobulin (TG) is a large glycoprotein synthesized by thyroid follicular cells and secreted by exocytosis into the colloid. Its tyrosine residues undergo iodination and coupling to form T3 and T4.

What is thyroid peroxidase (TPO), and what reactions does it catalyze?

TPO uses H₂O₂ to oxidize iodide (I⁻) into reactive iodine, catalyzes organification (iodination of thyroglobulin tyrosine residues), and couples iodotyrosines to form T3 and T4.

What are MIT and DIT?

MIT = monoiodotyrosine, containing one iodine atom. DIT = diiodotyrosine, containing two iodine atoms. Both are formed by TPO-mediated iodination of tyrosine residues on thyroglobulin.

How are T3 and T4 synthesized through coupling reactions?

T3 (triiodothyronine) forms through coupling of DIT + MIT, containing 3 iodine atoms. T4 (thyroxine) forms through coupling of DIT + DIT, containing 4 iodine atoms. Both reactions are catalyzed by TPO.

How are T3 and T4 released from the thyroid gland?

Iodinated thyroglobulin is taken from the colloid into follicular cells by endocytosis/pinocytosis. Lysosomes enzymatically degrade thyroglobulin, releasing T3 and T4, which enter the bloodstream. TSH stimulates this process.

What are the five major effects of TSH on the thyroid gland?

1. Activates the Na⁺/I⁻ symporter to increase iodide uptake. 2. Activates TPO-mediated iodide oxidation. 3. Stimulates TPO-mediated organification of thyroglobulin. 4. Stimulates TPO-mediated MIT/DIT coupling. 5. Promotes release of T3 and T4.

What causes Graves disease, and what happens to TSH, T3, and T4?

Graves disease is an antibody-mediated autoimmune disorder in which stimulatory antibodies activate TSH receptors, causing excessive thyroid hormone synthesis and release. T3/T4 increase, while TSH decreases due to negative feedback.

What are characteristic clinical manifestations of Graves disease?

Hyperthyroidism, goiter (thyroid enlargement), and Graves ophthalmopathy. Stimulating autoantibodies activate thyroid TSH receptors independently of pituitary TSH.

How does iodine deficiency cause endemic goiter and hypothyroidism?

Insufficient dietary iodide decreases T3/T4 synthesis. Reduced negative feedback increases TRH and TSH. Persistent TSH stimulation enlarges the thyroid and increases colloid growth without adequate hormone production, producing a large goiter.

What is the typical thyroid hormone pattern in primary hypothyroidism?

Decreased T3 and T4 with elevated TSH because reduced thyroid hormone production decreases negative feedback on the hypothalamus and anterior pituitary.

What causes Hashimoto thyroiditis?

Hashimoto thyroiditis is the most common cause of hypothyroidism in the lecture. It involves autoimmune thyroid destruction through T-lymphocyte activity, B-cell production of antithyroid antibodies, complement activation, and cytotoxicity. Goiter may or may not be present.

Which thyroid proteins are involved in autoimmune responses in Hashimoto disease?

Thyroid peroxidase (TPO), thyroglobulin (TG), and thyroid cell-surface proteins including TSH receptors are depicted in the lecture's autoimmune mechanism diagram.

How are T3 and T4 transported in blood?

Approximately 99% of circulating T3/T4 is bound to plasma proteins, primarily thyroxine-binding globulin (TBG), with lesser binding to thyroxine-binding prealbumin and albumin. Only free hormone is readily available to tissues.

Compare the protein-binding and receptor-binding properties of T3 and T4.

T4 has greater plasma protein binding and is released slowly. T3 has lower plasma protein affinity but much higher affinity for thyroid hormone receptors, making it more biologically potent.

How long are T3 and T4 retained by binding proteins?

Approximately half of protein-bound T4 is released every 6 days, compared with approximately 1 day for T3. Both hormones also bind intracellular proteins and are released gradually.

Compare the onset and peak effects of T3 versus T4.

T4 has a latent period after administration and reaches peak activity after approximately 10–12 days. T3 acts approximately 4 times faster, with a 6–12 hour latent period and maximum activity within 2–3 days.

How is T4 converted into active T3 versus reverse T3?

Outer-ring deiodination by deiodinases I and II converts T4 into active T3. Inner-ring deiodination by deiodinases I and III converts T4 into reverse T3 (rT3), which is biologically inactive.

How are T3 and reverse T3 further metabolized?

T3 undergoes deiodination by deiodinases I and III to form T2. Reverse T3 undergoes deiodination by deiodinases I and II to form T2.

What does the lecture describe as Wilson's syndrome or reverse T3 dominance?

The lecture describes cortisol inhibiting conversion of T4 to active T3, favoring reverse T3 production and hypothyroid-like symptoms. Note: Wilson's syndrome/rT3 dominance is not an established clinical diagnosis.

What is the preferred pharmacologic treatment for hypothyroidism, and why?

Thyroid hormone replacement with levothyroxine (T4) is preferred because it has consistent potency and a prolonged duration of action. T4 has a half-life of 6–8 days versus approximately 1 day for T3.

Describe levothyroxine absorption and bioavailability.

Levothyroxine is absorbed in the small intestine, with variable and incomplete absorption. The lecture reports approximately 50–80% bioavailability and attributes variability partly to CYP3A4 genomics. Taking it on an empty stomach improves absorption consistency.

Which drugs and substances decrease levothyroxine absorption?

Bile acid sequestrants, iron, calcium, aluminum-containing products, proton pump inhibitors (PPIs), H2 receptor antagonists, and food. These interfere with absorption and may reduce levothyroxine effectiveness.

Which drugs increase levothyroxine clearance through enzyme induction?

Phenytoin, carbamazepine, and rifampin. The lecture describes induction of hepatic CYP3A4 and increased biliary excretion, reducing circulating thyroid hormone levels.

How does amiodarone interfere with thyroid hormone metabolism?

Amiodarone inhibits conversion of T4 into T3. The lecture emphasizes its iodine content and interference with deiodinase activity.

How is levothyroxine metabolized?

Levothyroxine (L-T4) undergoes deiodination by deiodinases I and II to form T3. It also undergoes phase II metabolism in the liver or gut through glucuronidation and sulfation.

What is liotrix (Thyrolar)?

Liotrix is a combination thyroid hormone product containing thyroxine (T4) and triiodothyronine (T3) in a 4:1 ratio.

What is desiccated thyroid (Armour Thyroid), and where does it come from?

Desiccated thyroid is cleaned, dried, powdered thyroid gland obtained from domesticated animals, usually porcine or bovine. It contains a mixture of T4 (~80%) and T3 (~20%) by hormone content and may raise vegetarian, vegan, or religious concerns.

What does 1 grain of desiccated thyroid contain?

One grain (~60 mg) contains approximately 40 mcg T4 and 10 mcg T3. The remaining mass consists of non-hormonal thyroid gland material.

What is liothyronine (Cytomel), and when is it used?

Liothyronine sodium is synthetic T3 with approximately 100% oral absorption. It is used when rapid onset or termination of thyroid hormone effects is desired.

Why is liothyronine used less frequently than levothyroxine?

Liothyronine has a shorter duration of action, requires more frequent dosing, costs more, and causes greater transient fluctuations in circulating T3 concentrations.

What liothyronine dosing and thyroid hormone equivalences are given in the lecture?

10–15 mcg liothyronine three times daily produces normal T3 levels in an athyreotic patient. The lecture states 25 mcg T3 ≈ 100 mcg levothyroxine ≈ 60 mg porcine thyroid in functional effect.

What are the four major classes of antithyroid agents?

1. Antithyroid drugs that directly inhibit thyroid hormone synthesis. 2. High-concentration iodide that decreases hormone release and synthesis. 3. Radioactive iodine that destroys thyroid tissue. 4. Ionic inhibitors that interfere with iodide transport.

What are examples of ionic inhibitors of iodide transport?

Perchlorate (ClO4⁻), thiocyanate (SCN⁻), and lithium are listed. These agents are not used clinically to a great extent. Cigarettes, certain foods, and environmental exposures may also contribute to hypothyroidism.

What is the mechanism of action of propylthiouracil (PTU) and methimazole?

Both inhibit thyroid peroxidase (TPO), preventing iodide organification onto tyrosine residues of thyroglobulin and coupling of MIT/DIT to form T3/T4.

Which thionamide-related drugs and structures are shown in the lecture?

Propylthiouracil (PTU), methimazole (Tapazole), and carbimazole. PTU and methimazole inhibit TPO-mediated thyroid hormone synthesis.

Why do PTU and methimazole take several weeks to produce their full effect?

The thyroid stores large amounts of thyroglobulin and T3/T4 for several months. PTU and methimazole inhibit new hormone synthesis but do not immediately eliminate stored hormones. Full effects may not become apparent until stored hormone is depleted, often after >6 weeks.

What additional effect do PTU and methimazole have during Graves disease treatment?

The lecture states that antithyroid drug treatment decreases concentrations of TSH receptor-stimulating antibodies associated with Graves disease.

What additional mechanism does PTU have that methimazole does not?

PTU inhibits peripheral deiodination of T4 to T3 by inhibiting deiodinase activity. Methimazole does not have this additional peripheral effect.

What is the Wolff-Chaikoff effect?

The Wolff-Chaikoff effect is acute inhibition of thyroid hormone synthesis caused by high circulating concentrations of iodide.

What effects do high concentrations of iodide have on the thyroid gland?

High iodide concentrations acutely decrease iodide trapping, thyroglobulin organification, colloid endocytosis, and thyroid hormone secretion. The lecture describes concentrations around 0.2 mg/L to ~1 µM (100 times normal), with effects lasting up to 10 days.

Why is high-concentration iodide administered before thyroid surgery?

It rapidly decreases thyroid hormone secretion, thyroid gland size, and thyroid blood supply. The lecture describes administration for approximately 2–3 weeks before thyroid surgery or removal.

How does potassium iodide protect the thyroid during radioactive iodine exposure?

High concentrations of stable iodide saturate the thyroid and inhibit uptake of radioactive iodine-131, reducing radioactive iodine accumulation and thyroid radiation exposure.

What are the sources and harmful effects of radioactive iodine-131?

I-131 is produced during nuclear fission of uranium-235 or plutonium-239 and can contaminate soil, food, and water after nuclear accidents or other exposures. It has an approximately 8-day half-life and emits beta and gamma radiation that damages thyroid DNA and proteins.

What emergency potassium iodide dose is described in the lecture?

130 mg KI per day, providing approximately 100 mg iodide. The lecture compares this with a normal nutritional iodine intake of 0.15 mg/day, describing the emergency dose as approximately 700 times greater.

What is SSKI, and what is its concentration?

SSKI is saturated solution of potassium iodide, containing approximately 1,000 mg KI per mL. Each drop provides approximately 50 mg iodide.

How does SSKI compare with a 130 mg potassium iodide tablet?

Two drops of SSKI provide approximately 100 mg iodide, equivalent to one 130 mg KI tablet. The lecture states that one drop provides approximately 333 times the daily nutritional iodine requirement.

What is Lugol's solution, and what does it contain?

Lugol's solution (strong iodine solution) contains 5% iodine and 10% potassium iodide. It provides approximately 8 mg iodide per drop and also has antiseptic/disinfectant uses, including drinking water purification.

Which OTC potassium iodide products are listed for radiation emergencies?

ThyroShield, IOSTAT, and ThyroSafe. The lecture lists 130 mg KI daily for radiation emergencies.

Compare iodine-123 and iodine-131 used for medical purposes.

I-123 is a short-lived gamma emitter with a half-life of approximately 13 hours. I-131 emits both beta and gamma radiation and has a half-life of approximately 8 days.

How does radioactive iodine-131 destroy thyroid tissue?

I-131 emits beta particles that travel approximately 1–2 mm, damage thyroid cell DNA, and cause apoptosis and local destruction of thyroid tissue. The lecture describes approximately 90% tissue destruction.

What are the effects of beta versus gamma radiation from radioiodine?

Beta particles produce localized thyroid tissue destruction through DNA damage and apoptosis. Gamma radiation penetrates farther and, at higher cancer-treatment doses, can affect other tissues, including bone marrow.

What thyroid conditions are illustrated by the nuclear medicine scans in the lecture?

Normal thyroid, Graves disease, toxic multinodular goiter, and toxic adenoma. The scans demonstrate differing patterns of thyroid radioactive tracer uptake.

In what formulations are iodine-123 and iodine-131 available, and what determines dosing?

Both are available as capsules or solutions. Radioiodine dosing is complex and requires evaluation of thyroid size, iodine uptake, hormone release, and colloid size.

What iodine-131 treatment dose values are provided in the lecture?

Approximately 7,000–10,000 rads per gram of thyroid tissue, corresponding to approximately 4–15 mCi (0.004–0.015 Ci) of I-131.

What historical nuclear accident radioactivity comparisons are provided?

The lecture cites approximately 50 million Ci released from Chernobyl and approximately 4 million Ci from Fukushima, comparing these values with the much smaller therapeutic I-131 doses.