[09.08] Thyroid Hormones and Anti-thyroid Drugs V2.1

Growth and development, body temperature, and energy levels

The thyroid gland maintains metabolic homeostasis by regulating what three factors?

Triiodothyronine T3 and Tetraiodothyronine/Thyroxine T4

What are the two main hormones produced by the thyroid gland?

Rapidity and intensity of action

T3 and T4 functions are qualitatively the same, but how do they differ?

A phenyl ring attached via an ether linkage to a tyrosine molecule

What is the shared chemical structure of T3 and T4?

Two

How many iodine atoms do both T3 and T4 have on their inner tyrosine ring?

One

How many iodine atoms does T3 have on its outer phenyl ring?

Two

How many iodine atoms does T4 have on its outer phenyl ring?

1 MIT and 1 DIT

What is the molecular composition of T3?

2 DIT molecules

What is the molecular composition of T4?

59 percent

What is the iodine content percentage of T3?

65 percent

What is the iodine content percentage of T4?

5 to 1

What is the approximate ratio of T4 to T3 within thyroglobulin?

Thyroglobulin

What is the main substrate that combines with iodine to form thyroid hormones?

T4

Which thyroid hormone is released in the greatest amount from the thyroid gland?

Iodine trapping

What is the first step in the biosynthesis of thyroid hormones?

Concentrating iodide into the cell

What occurs during the iodine trapping step?

75 mg

How much iodine does the thyroid gland remove daily from the extracellular pool?

Sodium iodine Na+/I- symporter or NIS

What transporter moves iodide across the basement membrane into the thyroid cell?

One iodide ion and two sodium ions

What does the NIS symporter co transport across the membrane?

Na+/K+ ATPase pump

What provides the energy for transporting iodide across the concentration gradient?

Apical membrane

Where is Pendrin located in the thyroid cell?

Oxidation

What is step 2a of thyroid hormone biosynthesis?

Iodide ions I- to an oxidized form of iodine I0

Oxidation involves the conversion of what to what?

Peroxidase or TPO

Which enzyme promotes the oxidation of iodine?

Hydrogen peroxide H2O2

What chemical is required for the peroxidase enzyme to function in oxidation?

Organification or Iodination

What is step 2b of thyroid hormone biosynthesis?

Thyroid peroxidase TPO

Which enzyme acts on thyroglobulin to allow iodine binding?

Monoiodotyrosine MIT

What is formed when tyrosine is first oxidized with one iodine?

Diiodotyrosine DIT

What is formed when tyrosine is oxidized with two iodines?

Coupling or Conjugation

What is step 3 of thyroid hormone biosynthesis?

MIT plus DIT

Which two molecules couple to produce Triiodothyronine T3?

DIT plus DIT

Which two molecules couple to produce Thyroxine T4?

Reverse T3 or rT3

What is produced by the coupling of MIT and DIT besides T3?

The ability to store large amounts of hormones

What makes the thyroid gland unusual among endocrine glands?

Proteolysis of Thyroglobulin

What is step 4 of thyroid hormone biosynthesis?

Pseudopod extensions

What cell structure closes around colloid to form pinocytic vesicles?

Lysosomes

Which organelle fuses with pinocytic vesicles to digest thyroglobulin?

Recycling of iodine

What is step 5 of thyroid hormone biosynthesis?

Three fourths

What fraction of iodinated tyrosine never actually becomes thyroid hormone?

Dehalogenase

Which enzyme is responsible for the deiodination of MIT and DIT for recycling?

T4 Conversion

What is step 6 of thyroid hormone biosynthesis?

Deiodinase

Which enzyme performs the intrathyroidal 5 prime deiodination of T4 to T3?

Thyroxine binding globulin TBG

To what protein are T3 and T4 mostly bound in the blood?

Free or unbound hormones

Which forms of thyroid hormones are metabolically active?

0.03 percent

What percentage of T4 is free or unbound?

0.3 percent

What percentage of T3 is free or unbound?

T3

What is the active form of thyroid hormone in most target tissues?

3 to 4 times more potent

How much more potent is T3 compared to T4?

Reverse T3

Which form of thyroid hormone is metabolically inactive?

T4

Between T3 and T4, which has higher total serum levels?

T3

Between T3 and T4, which has a faster metabolic clearance?

T4

Between T3 and T4, which has a longer half life?

95 percent

What is the oral absorption percentage of T3?

70 percent

What is the oral absorption percentage of T4?

One day

What is the half life of T3?

Seven days

What is the half life of T4?

c-erb

T3 receptors belong to what superfamily of nuclear receptors?

Pituitary, liver, kidney, heart, skeletal muscle, lungs, and intestines

Name four tissues responsive to T3.

Transthyretin TTR or Albumin

Besides TBG, what two proteins do T3 and T4 dissociate from before entering cells?

Diffusion or transport

By what two methods do thyroid hormones enter target cells?

5 prime deiodinase

Which specific enzyme converts T4 to T3 in the cytoplasm?

Retinoic acid X receptor RXR

The T3 receptor TR monomer interacts with which receptor to form a heterodimer?

Co repressor complex

In the absence of T3, what binds to the TR RXR heterodimer to inhibit gene expression?

Coactivators

In the presence of T3, what forms to stimulate gene expression?

Hormone replacement therapy in hypothyroidism

What is the major clinical use for thyroid hormones?

Resolution of signs and symptoms and physiological markers

What are the goals of thyroid hormone replacement therapy?

1.6 mcg/kg/day

What is the standard adult replacement dose for thyroid hormone?

10 to 15 mcg/kg/day

What is the replacement dose for infants aged 1 to 6 months?

Higher requirements in infants

Why is the infant thyroid hormone dose higher than the adult dose?

Slow gradual increments

How should thyroid hormone treatment be initiated in elderly patients or those with heart disease?

Obesity, abnormal vaginal bleeding, or depression

Thyroid hormones are detrimental if used for what three conditions in euthyroid patients?

Suppression of nodule growth

What is the goal of using thyroid hormones in thyroid cancer management?

2.2 to 3.0 mcg/kg/day

What is the dosage range of thyroid hormone for thyroid cancer suppression?

Duodenum and ileum

In which two parts of the small intestine is thyroxine best absorbed?

Food, drugs, gastric acidity, and intestinal flora

What four intraluminal factors modify thyroxine absorption?

Bisphosphonates, cholestyramine, and charcoal

Name three drugs that interfere with T4 absorption.

Proton pump inhibitors and sucralfate

Name two gastrointestinal medications that interfere with T4 absorption.

Aluminum hydroxide, ferrous sulfate, and calcium carbonate

Name three mineral supplements that interfere with T4 absorption.

Bran/fiber, soy, and coffee

Name three dietary items that interfere with T4 absorption.

Synthetic Levothyroxine T4

What is the thyroid preparation of choice?

Stability, uniform content, low cost, and long half life

Name four reasons why Levothyroxine is the preferred preparation?

12.5, 25, 50, 100, and 150 mcg

What are the common tablet dosages for Levothyroxine?

Consistent preparations between refills

What should patients be advised regarding different brands of levothyroxine?

Empty stomach at least 1 hour before breakfast

When and how should levothyroxine be taken?

Liothyronine T3

Which thyroid preparation is 3 to 4 times more active than Levothyroxine?

Short term TSH therapy

What is the best clinical use for Liothyronine T3?

Cardiotoxicity

What is a major potential risk of using Liothyronine?

Antigenicity, instability, and variable content

Why is desiccated thyroid no longer recommended for replacement?

Liotrix

What is the 4 to 1 synthetic combination of T4 and T3 called?

Thionamides or Thioureylenes

Which drug class includes Methimazole and Propylthiouracil?

Methimazole MMI

What is the primary drug in the thionamide class?

Carbimazole

Which thionamide is a pro drug of methimazole?

Inhibiting TPO mediated catalyzed reactions

What is the primary mechanism of action of thionamides?

Iodine organification and coupling

What two specific processes do thionamides block?

Propylthiouracil PTU

Which thionamide inhibits the peripheral conversion of T4 to T3 at high doses?

Propylthiouracil

What is the drug of choice for thyroid storm?

Synthesis

Do thionamides affect the synthesis or the release of thyroid hormones?

10

What is the relative potency of Methimazole compared to PTU?

6 hours

What is the serum half life of Methimazole?

1.5 hours

What is the serum half life of PTU?