Thyroid Hormones

And
Anti – Thyroid Drugs

By
Gunjan Kalyani, M. Pharm.
Assistant Professor
Columbia Institute of Pharmacy
Raipur 493111, Chhattisgarh, India
Mobile: +91-8349204583
Mail ID: kalyani.gunjan@yahoo.in
 
Former Research Fellow
National Center for Natural Resources (NCNR)
Pt. Ravishankar Shukla University, Raipur 492010, India
THYROID HORMONES AND ANTI – THYROID DRUGS
Thyroid Gland
A. The thyroid gland is the largest endocrine organ,
weighing 10 to 20 g in the adult. It is found on the
ventral surface of the trachea below the larynx
and consists of two lobes joined by an isthmus.
B. Two pairs of parathyroid glands are located on the
dorsal surface of the thyroid. The thyroid gland is
supplied by nerves from the autonomic nervous
system; the sympathetics increase thyroid
hormone synthesis and secretion, while the
parasympathetics decrease these functions.
C. The thyroid has an excellent blood supply, with
one of the highest rates of blood flow of any organ
in the body.
 THYROID HORMONES AND ANTI – THYROID DRUGS
D. The thyroid is made up of lobules containing a series of follicles.
The lumen of each follicle is surrounded by a single layer of
epithelial cells, called follicular cells, and the lumen filled with a
pink-staining (with hematoxylin and eosin) proteinaceous
material, called colloid.
E. The follicular cells synthesize thyroglobulin, thyroid hormone
precursor, which is extruded into the lumen of the follicle for
storage.
 Thyroid Hormones
A. Thyroid gland produces thyroid hormones. These hormones are
essential for life and have many effects on body metabolism, growth, and
development.
B. Thyroid hormones are derivatives of the amino acid tyrosine bound
covalently to iodine. The two principal thyroid hormones are:
Thyroxine (also known as T4 or L-3,5,3',5'-tetraiodothyronine)
Triiodotyronine (T3 or L-3,5,3'-triiodothyronine)
C. As shown in the figure-1, the thyroid hormones are basically two
tyrosines linked together with the critical addition of iodine at three or
four positions on the aromatic rings. The number and position of the
iodines is important.
D. Several other iodinated molecules are generated that have little or no
biological activity; so called "reverse T3" (3,3’,5’-T3) is such an example.
Thyroid Hormones
 Thyroid Hormones
E. Thyroid hormones are poorly soluble in water, and more than 99% of the
T3 and T4 circulating in blood is bound to carrier proteins. The principle
carrier of thyroid hormones is thyroxine-binding globulin, a glycoprotein
synthesized in the liver.
F. Two other carriers of import are transthyrein and albumin. Carrier
proteins allow maintenance of a stable pool of thyroid hormones from
which the active, free hormones are released for uptake by target cells.
 Metabolism of Thyroid Hormones
A. The thyroid gland secretes about 100 nmol of T4, about 5 nmol of T3 and
less than 5 nmol of rT3.
B. Over 80% of the plasma pool of T3 is derived from the peripheral
metabolism of T4 to T3 by 5'-deiodination. Most of the rT3 is formed from
the 5 deiodination of T4. The 5'deiodinase found mostly in the liver and
kidney is the most abundant deiodinase. The major function of this enzyme
is the splitting off of the 5' I from T4 to provide T3 to the plasma.
C. 5'deiodinase is increased in hyperthyroidism, which accounts for the high
levels of T4 in this condition.
D. During starvation, fasting, or hypothyroidism, levels of 5' deiodinase
decrease. The decline in this enzyme results in less active hormone, T3 being
available and conserves calories and inhibits proteinolysis.
 Metabolism of Thyroid Hormones
E. Another type of deiodinase takes off iodines from 5 and 5' resulting in 3,3-
Diiodothyronine which has very little activity. Thyroid hormones often are
metabolized further by means of progressive deiodination to thyronine
and the breaking of the ether bond to yield tyrosine.
F. When T4 and T3 undergo a selective decarboxylation and deamination,
the products are, respectively 3,5,3',5' tetraiodothyroacetic acid (Tetrac) and
3,5,3' triiodothyroacetic acid (Triac). It has been estimated that these
metabolites have anywhere from 10% to 50% of the biological activity of
their parent compounds.
G. In the liver, intact T3 and T4 can undergo conjugation to yield thyroid
hormones as sulfates or glucuronates. These hormone conjugates enter the
bile and pass into the intestine, where the conjugate is hydrolyzed and the
free T3 or T4 may be reabsorbed into the enterohepatic circulation to be
reused or excreted in the stool.
 Physiological Actions of T3 and T4
Thyroid hormones have various actions on the body; some of them are as
follows:
A. Calorigenic action: T3 increases the oxygen consumption and heat
production in the body, stimulating Na+- K+ ATPase in cells of all
metabolically active tissues. The exceptions are adult brain, lymph nodes,
spleen, uterus, testes, anterior pituitary gland. This action contributes to
the increased metabolic rate and heat sensitivity in hyperthyroid patients.
It controls the basal metabolic rate (BMR) rate.
B. Metabolic action: Thyroid hormones increase the rate at which
carbohydrates are absorbed from the GI tract. In patients with normal
thyroid activity, glucose levels tend to be normal and glycogen synthesis is
stimulated. However, with hyperthyroidism, T3 increases hepatic
glycogenolysis and gluconeogenesis. An increase in T3 exacerbates
symptoms of diabetes mellitus.
 Physiological Actions of T3 and T4
C. Effect on Fetal Development and Maturation: T3 is necessary for fetal
growth and development. Thyroid hormone and growth hormone act
synergistically in the maturation of the fetus and development of the
CNS. When thyroid hormone is absent, children show mental retardation
and dwarfism. Hypothyroid children often exhibit delayed puberty and
bone growth. In some classic experiments, it was shown that tadpoles
treated with T3 and/or T4 metamorphosed early into frogs, whereas
hypothyroid tadpoles never developed into frogs. This is an example of
how important thyroid hormones are for normal growth and maturation.
D. Effect on Cardiovascular system: T3 has a marked positive chronotropic
and ionotropic effect on the heart. This accounts for the increased cardiac
muscle contractility, cardiac output, and heart rate, and for the increased
heart rate in hyperthyroid patients and the slow rate in hypothyroid
patients.
 Physiological Actions of T3 and T4
E. Effect on Sympathetic Nervous System: Thyroid hormones increase the
number of beta-adrenergic receptors in cardiac and skeletal muscle and
adipose tissue. They increase the body's sensitivity to catecholamine action.
This may account for hyperthyroid patients being treated with beta-
adrenergic blocking agents to control their tachycardia and arrhythmias.
F. Other Effects: Thyroid hormones in the euthyroid individual stimulate the
synthesis of skeletal muscle, maintain muscular tone, and increase the
speed of muscle contraction. With hyperthyroidism, protein turns over
rapidly, muscle is lost, and muscle reflexes are accentuated. T3 stimulates
erythropoiesis.
 Diseases Associated with the Abnormal Thyroid
Thyroid hormones have two major physiological effects.
They increase protein synthesis in virtually every body tissue and increase oxygen consumption dependent upon
Na+ -K+ ATPase (Na pump).

Hyperthyroidism
A. It occurs seven to nine times more likely in women than in men. Hyperthyroidism often occurs between the
ages of twenty and forty, while hypothyroidism often appears after the age of fifty.
B. Certain types of thyroid tumors appear to be more prevalent in certain age groups. In the last few years, case
studies of patients with hyperthyroidism in their youth have shown that, thirty years later, the same
individuals have a greater tendency to develop hypothyroidism.
C. Thyroid problems have a strong genetic component, and may "skip" generations. Family histories may be
useful in suggesting the nature of thyroid problems at early stages.
D. Prematurely gray hair, hair which starts to go gray before the age of thirty, is often a sign of thyroid
dysfunction.
E. Patchy hair loss, usually temporary, is often observed by persons with Graves’ or Hashimoto's disease.
F. A list of conditions related to the thyroid is instructive as to the importance of the thyroid in human disease.
 Diseases Associated with the Abnormal Thyroid
Hypothyroidism in Adults:
It is a state of low serum thyroid hormone resulting from hypothalmic, pituitary, or thyroid insufficiency.
Untreated, can lead to life-threatening myxedema coma (early signs of fatigue, forgetfulness, sensitivity to cold,
unexplained weight gain, constipation progress to decreasing mental stability, dry, flaky inelastic skin; puffy
face, hands, and feet; hoarseness; periorbital edema; upper eyelid droop; dry, sparse hair; and thick, brittle
nails. Underlying decrease in cardiac output and poor peripheral circulation can lead to abrupt coma). Most
common in women, incidence rising significantly in persons aged 40 to 50.

Hypothyroidism in Children (Cretinism)

This is a Deficiency of thyroid hormone secretion during fetal development or early infancy results in infantile
cretinism (congenital hypothyridism). Respiratory difficulties, persistent jaundice, and hoarse crying in infants;
stunted growth (dwarfism), bone and muscle dystrophy, and mental deficiency in older children. 3 times more
common in girls than in boys. Infants not treated within first 3 months or children within two years suffer
irreversible mental retardation.

Thyroiditis
Thyroiditis is the inflammation of thyroid gland can be divided into catagories of autoimmune (long-term
inflammatory disease; Grave's Disease, Hashimoto's Disease), subacute granulomatous (self-limiting
inflamation), Riedel's (rare, invasive fibrotic process), and miscellaneous (acute suppurative, chronic infective,
chronic non-infective). More common in women than in men (5 to 7 times more common).
 Diseases Associated with the Abnormal Thyroid
Hyperthyroidism (Grave's Disease, Basedow's disease, Parry's disease, thyrotoxicosis)
Hyperthyroidism is a metabolic imbalance that results from thyroid hormone overproduction. Most common is
Grave's disease. Only 5% of hyperthyroid patients are under age 15.

Grave's Disease
Toxic goiter is a cause of 80% of hyperthyroidism. A diffusely enlarged thyroid gland associated with
hyperthyroidism is known as Grave's disease. Autoimmune disease. Highest incidence between ages of 30 and
40. Disorder of unknown etiology characterized by exophthalmos, enlarged pulsating thyroid gland, marked
acceleration of heart rate, tendency to profuse sweats, nervous symptoms (fine muscular tremors, restlessness,
irritability), psychic disturbances, emaciation, and increased metabolic rate.

Hashimoto's Disease
Struma (goitre) lymphomatosa (multiple lymphomas in various parts). A progressive disease of the thyroid
gland, with extensive acidophilic (readily acid dye stained cell) degeneration of its epithelial elements and
replacement by lymphoid and fibrous tissue. Hashimoto's disease results in hypothyroidism. Initially, the thyroid
is enlarged and there may be transient hyperthyroidism, followed by a euthyroid state and then hypothyroidism
with eventual atrophy years later. Hashimoto's thyroiditis results from abnormal T cell activation and
subsequent B cell stimulation to secrete a variety of auto-antibodies.
 Diseases Associated with the Abnormal Thyroid
Simple Goitre (nontoxic goitre)
Thyroid gland enlargement not caused by inflamation or a neoplasm. Normally results from inadequate dietary
intake of iodine. Affects no particular segment of the population. Affects more females than males, especially
during adolescence, pregnancy, and menopause when demand for thyroid hormone increases.

Plummer's Syndrome
It is a toxic multinodular goitre (common in women over 60). Nodule's within thyroid independently make T4.
The abnormally high amount suppresses secretion of TSH (thyroid stimulatory hormone) by anterior pituitary,
causing main gland to shut down. [different from Plummer-Vinson's Syndrom: dysphagia (difficulty in
swallowing) with glossitis (tongue inflammation), hypochromic anemia, splenomegaly, and atrophy in the
mouth, pharynx, and upper esophagus.
 Structure Activity Relationship of Iodothyronines

A. Figure shows the three-dimensional shape of the hormonally active thyroxine

molecule. The following observations can be made from the three-dimensional shape.
B. Because of the steric effect of the large iodine atoms in position 3 and 5, the planes of
two aromatic rings are perpendicular to each other and are separated by oxygen atom
which holds the rings at an angle of about 120o.
C. The amino acid side chain has the carboxyl group at the maximum distance from the
aromatic ring bearing the side chain. The phenolic hydroxyl group is coplanar with its
aromatic ring.
Based on many
Structure molecular
Activity modifications
Relationship of the thyroid hormones, a few observations
of Iodothyronines
regarding the structure-activity relationship have been made.

A. The ether oxygen can be replaced isosterically by sulphur or methylene which

also provide an angle of 120o. This change does not qualitatively impair the
activity.
B. A phenolic hydroxyl group at 4’ position is important for hydrogen bonding to
transport proteins. It can, however, be replaced by isosteric groups like NH2 or by
a group that can generate a hydroxyl group after metabolism (OCH3 or
OCOCH3). But such a change results in reduced hormonal activity.
C. The 3’-position ortho to the hydroxyl and away from the other aromatic ring
must be substituted by a lipophilic group. This can be a halogen (preferably
Iodine) or any alkyl group approximately of the same size as Iodine such as an
isopropyl group.
D. The 3’-monosubstituted compounds are more active than the 3’,5’-disubstituted
molecules.
E. Triiodothyronine is four times more potent than thyroxine, while 3’-isopropyl-
3,5-diiodothyronine has seven times the activity.
F. The iodine atoms at 3 and 5 positions can be replaced by non-polar groups
(such as methyl), as long as they keep the aromatic rings perpendicular to each
other.
G. The amino acid side chain can be varied, but should be para to the aromatic
 Thyroid Preparations (Hormones)
Powdered thyroid gland (officially termed as Thyroid) obtained from domesticated animals and the pure
hormones L-Thyroxine and L-Triiodothyronine (Liothyronine), both as sodium salts are the thyroid agents used
as replacement therapy in hypothyroidism to correct thyroid deficiency.

Official drugs
A. Thyroid, I.P.
B. Liothyronine Sodium, B.P.

Use: Liothyronine sodium is a synthetic version of one of the two hormones made by the thyroid gland,
triiodothyronine. It is used for the treatment of hypothyroidism in adults and children. Prolonged
hypothyroidism can result in a condition called myxedema in which patients develop swollen lips, thickened
nose, and unusual deposits of material in the skin that are dry and waxy. These deposits also may appear in
body tissues other than the skin. Liothyronine also is used in a test of the thyroid gland to determine if the
thyroid is functioning normally.
Dose: The usual starting dose of liothyronine is 5 to 25 µg per day.
 Thyroxine Sodium, I.P., B.P.

Levothyroxine occurs as light yellow to buff-coloured powder or fine, slightly coloured crystalline powder. It is
stored in tightly-closed, light-resistant containers.

It is readily absorbed from the gastrointestinal tract. It is eliminated slowly from the body and has a half-life of
6 to 7 days.
Use: It is primarily indicated for the treatment of hypothyroidism.
Treatment is usually long term as it is replacing thyroid hormone the body is not producing.
The dosage is usually adjusted according to response and blood test results.
 Anti-Thyroid Drugs
A. Anti-thyroid drugs (ATDs) are compounds that interfere with the body’s production of thyroid hormone,
thereby reducing symptoms of hyperthyroidism.
B. ATDs were discovered accidentally in the mid-1940’s when thiocyanate compounds used for heart disease
were found to cause hypothyroidism.
C. This led to the development of a number of compounds specifically tailored to reduce thyroid hormone
production.
Classification of Anti-thyroid Drugs
A. These drugs inhibit the synthesis of thyroid hormone.
B. They exert immediate effect since they act at the first stage of iodine incorporation by the gland. They are categorized as
under:
Thioamides; Thiourea and thiouracil derivatives
Thiouracils: Methylthiouracil, Propylthiouracil, etc.
Imidazoles: Methimazole, Carbimazole, Centimizone, etc.
Aniline derivatives
Sulphonamies: Sulphanilamide, Sulphaguanidine, Carbutamide, Para aminosalicylic acid
Polyhydric phenols: Resorcinol
Ionic inhibitors: Potassium perchlorate, Thiocyanate
Miscellaneous agents
Lithium carbonate
Adrenergic blockers: Propranolol
 Structures of Anti-thyroid Drugs

R = CH2CH2CH3
Propylthiouracil Methimazole

Carbimazole Sulphanilamide

Sulphanilamide Para - amionosalicylic acid

Sulphaguanidine Resorcinol
 Mechanism of Action
Thioamides:
Mechanism of Action
A. It prevents thyroid hormone synthesis by inhibiting the thyroid peroxidase-catalyzed reactions &
blocking iodine organification (the major mechanism of action).
B. It blocks coupling of iodotyrosines.
C. It inhibits the peripheral deiodination (deiodinase D1) of T4 to T3.
Potassium Iodide
Mechanism of Action:
D. Iodine has several effects on thyroid function:
E. A major action of iodide is to inhibit hormone release from the thyroid gland.
F. This is the most acute effect of iodine on thyroid status, and occurs within hours after starting therapy
(Ross, 2017). This effect may result from inhibition of thyroglobulin proteolysis (which is necessary for
production/excocytosis of thyroid hormones) (Dong & Greenspan, 2015).
G. Interferes with the synthesis of thyroid hormones by inhibiting thyroidal peroxidase inside the thyroid
gland. This decreases thyroid hormone biosynthesis.
H. The maximal effect of iodine on thyroid hormone concentration occurs after ~10 days of treatment
(Ross, 2017).
I. Iodine therapy is typically given only for a few weeks because the thyroid gland will commonly “escape”
from iodide block in 2-8 weeks.
 Mechanism of Action
Radioactive Iodine
Mechanism of Action:
A. I-131 is rapidly absorbed & is concentrated in the thyroid where it is incorporated into storage follicles.
B. It's therapeutic effect depends on emission of beta rays with an effective half-life of ~56 days.
C. Beta particles act on parenchymal cells with little damage to surrounding tissue.

Propylthiouracil
Mechanism of Action
D. It prevents thyroid hormone synthesis by inhibiting the thyroid peroxidase-catalyzed reactions & blocking
iodine organification (the major mechanism of action).
E. It blocks coupling of iodotyrosines.
F. It inhibits the peripheral deiodination (deiodinase D1) of T4 to T3.
 Acknowledgements
A. D.A.V. Public School, ACC Colony, Jamul – 490024, Durg, Chhattigarh, India (1990 – 2004)
B. University Institute of Pharmacy, Pt. Ravishankar Shukla University, Raipur, Chhattisgarh, India (2005 – 2009)
C. Shri Rawatpura Sarkar Institute of Pharmacy, Kumhari, Durg, Chhattisgarh, India (2010 – 2012)
D. Royal College of Pharmacy, Raipur, Chhattisgarh, India (March – October 2013)
E. National Center for Natural Resources (NCNR), Pt. Ravishankar Shukla University, Raipur, Chhattisgarh, India (2013
– 2017)
F. Columbia Institute of Pharmacy, Raipur 493111, Chhattisgarh, India ( 2017 – till date)
G. Gratitude to Resp. Prof. Shiv Shankar Shukla Sir, Columbia Institute of Pharmacy, Raipur 493111, Chhattisgarh, India
(Mentor)
H. Gratitude to Resp. Prof. Atanu Kumar Pati, Vice Chancellor, Gangadhar Meher University, Sambalpur, Odisha
I. Gratitude to Resp. Prof. Mitashree Mitra, Dept. of Anthropology, PRSU, Raipur, Chhattisgarh.
J. Gratitude to Resp. Vishal S. Deshmukh Sir (M.Pharm. Supervisor)
Thanks for studying !!!!