THYROID FUNCTION AND

ANTITHYROID DRUGS
Thyroglobulin
• Thyroglobulin (Tg) is a 660 kDa, dimeric protein produced by
the follicular cells of the thyroid
• The protein is a precursor of the thyroid hormones
• The thyroid hormones (T3 and T4) are produced when
thyroglobulin's tyrosine residues are combined with iodine and the
protein is subsequently cleaved.
• Each thyroglobulin molecule contains approximately 100-120 tyrosine
residues, but only a small number (20) of these are subject to
iodination by thyroperoxidase in the follicular colloid (more in the
next slide).
• Therefore, each Tg molecule forms only approximately 10 thyroid
hormone molecules.
• The same enzyme then catalyses "coupling" of one modified tyrosine
with another, via a free radical-mediated reaction, and when these
iodinated molecules are released by hydrolysis of the protein, T3 and
T4 result hence, each Tg protein molecule ultimately yields very small
amounts of thyroid hormone (experimentally observed to be about 5-
6 molecules of either T4 or T3 per original molecule of Tg).
Synthesis of thyroid hormones

"Medical gallery of Mikael Häggström 2014".

T4, T3, rT3
• T4 is 3,3’,5,5’-tetraiodo-L-thyronine (structures next slides).
• T3 is 3,3’,5-triiodo-L-thyronine.
• Smaller amounts of T2 (3,3’-diodo-L-thyronine) and reverse T3 or rT3
(3,3’,5’-triodo-L-thyronine) also exist.
T4
T3
rT3
Biosynthesis of Thyroid Hormones (Simplified)
• The thyroid gland is the only tissue in the body to accumulate iodine
in large quantities and incorporate into hormones.
• Steps in Biosynthesis (See slide 3)
1. Active uptake of iodine by follicular cells
2. Oxidation of iodide and formation of iodotyrosyl residues of
thyroglobulin (Tg)
3. Iodotyrosines converted to iodothyronines
4. Proteolysis of thyroglobulin to release T3 andT4 into circulation
5. T4 is the prohormone and undergoes conversion to T3.
1. If outer ring undergoes deiodination, T3 is formed.
2. If inner ring undergoes deiodination, rT3 is formed.
Diseases involving Thyroid Gland
• Hypothyrodism
• Goiter: Insufficient thyroid hormone from the gland,
excess TSH (thyroid stimulating hormone) causing
increase in size and subsequently reduced output of the
thyroid gland
• Cretinism: thyroid hormone is not available in early
childhood leading to abnormal bone formation and
abnormal brain growth
• Myxedema: infiltration of intercellular spaces of skin and
muscle with mucopolysaccharide
Hyperthyrodism
• Increased metabolic rate – increased oxygen demand –
increased heart rate – increasing cardiac output leading to
cardiac strain.
• Excessive hormone leads to Toxic Goiter, Toxic adenoma and
thyrotoxicosis
• Grave’s disease: Over activity of thyroid gland. This is an
autoimmune disorder, exhibits diffuse toxic goiter.
• Hashimoto’s disease: this is an autoimmune disorder wherein
plasma cells, lymphocytes, fibrous tissue attack and destroy the
thyroid care. Lifelong treatment is required and may lead to
hypothyroidism.
• Thyroid cancer
Therapeutic agents
• Thyroid Replacement Therapy
1. Natural thyroid hormone preparations
2. Desiccated thyroid preparations
3. Synthetic thyroid hormones: More uniformly absorbed, contains more precise amount of the
active compound.
i. Levothyroxine (T4) is the sodium salt of the levo isomer of thyroxine, which is an active
physiological principle obtained from the thyroid gland of domesticated animals.
It is also prepared synthetically.
Being firmly bound to carrier proteins, has slower onset of action than T3 or desiccated
thyroid preparations.
ii. Liothyronine is crystalline T3, has a rapid and short duration of action.
• Chemical Name: O-(4-hydroxy-3-iodophenyl)-3,5-diiodo-L-thyroxine monosodium salt
• Is the sodium salt of L-3,3',5-triiodothyronine

• Liothyronine sodium occurs in vivo together with levothyroxine sodium; it has the same
qualitative activities as thyroxine but is more active.
• It is absorbed readily from the gastrointestinal tract, is cleared rapidly from the bloodstream, and
is bound more loosely to plasma proteins than levothyroxine, probably because of the less acidic
phenolic hydroxyl group
iii.Liotrix is a mixture of the sodium salts of T4 and T3 in a 4:1 ratio by weight.
Hyperthyrodism
• Hyperthyroidism (excessive production of thyroid hormones) usually requires surgery, but before
surgery the patient must be prepared by preliminary abolition of the hyperthyroidism through the
use of antithyroid drugs.
• Thiourea and related compounds show an antithyroid activity, but they are too toxic.

• The more useful drugs are 2-thiouracil derivatives and a closely related 2-thioimidazole derivative.
• All of these appear to have a similar mechanism of action (i.e. prevention of the iodination of the
precursors of thyroxine and triiodothyronine).
• The main difference in the compounds lies in their relative toxicities.
Antithyroid Drugs
• Thionamides
• Used in nondestructive therapy of hyperthyroidism
• Potent inhibitors of thyroid peroxidase enzyme which is responsible for
iodination of tyrosine residues of thyroglobulin and coupling of
iodotyrosines to form iodothyronines
• No effect on thyroid hormone release
A. Six membered thionamides
• Exist as thioketo or thioenol form (tautomers)
i. Thiouracil: R = H
ii. Methylthiouracil: R = CH3
iii. Propylthiouracil (PTU): R = n-C3H7
Propylthiouracil has maximum activity.
It inhibits the enzyme 5’-deiodinase, thus reducing the peripheral deiodination of T4 to
T3.
B. Five membered thionamides

• Methimazole has greater thyroid peroxidase inhibitory activity than

thiouracils, being more potent than propylthiouracil.
• It is unable to inhibit peripheral deiodination.
• Efforts to improve the taste and release patterns resulted in carbimazole.
This is a prodrug, giving rise to methimazole in vivo.
END