Thyoid hormones and thyroid inhibitors

Thyroid Hormones & Thyroid
Inhibitors
Madan Sigdel
Lecturer
Department of Pharmacology
Gandaki Medical College

Follicular Cells – the
functional unit
THYROID GLAND

THYROID GLAND
 Thyroxine (T4)
 Triiodothyronine (T3)
 Calcitonin

 Thyroid gland is composed over a million cluster
of follicles
 Follicles are spherical & consists of epithelial
cells surrounding a central mass (colloid)
 Normal thyroid gland secretes thyroid hormones
 Natural hormone compounds having biological
activity (Iodide containing ):
 L-Thyroxine (T4 or tetraiodo-L-thyroxine)
 Liothyronine (T3 or triiodo-L-thyronine)
 Both forms are available for oral use
 Parafollicular (C) cells produce calcitonin
Thyroid gland

2 important biological functions
1. Normal human growth & development, esp. CNS
2. In adults, maintain metabolic homeostasis,
affecting all organ systems
3. Large preformed hormone stores in thyroid
4. Metabolism of thyroid hormone occurs in liver
and brain
5. TSH regulates serum thyroid hormones by a
negative feedback system
6. Bind to nuclear thyroid hormone receptors,
modulates gene transcription
Thyroid hormones

Biosynthesis
 The synthesis, storage and release of T4 and
T3 involves the following processes.
1. Iodide uptake or trapping
2. Oxidation and iodination
3. Coupling
4. Storage and release
5. Peripheral conversion of T4 to T3

TG—Thyroglobulin; MIT—Monoiodotyrosine; DIT—Diiodotyrosine; T3—Triiodothyronine;
T4—Thyroxine (Tetraiodothyronine); HOI—Hypoiodous acid; EOI—Enzyme linked
hypoiodate; NIS—Na+-iodide symporter;

1. Iodide uptake
 thyroid cells have an active transport process
Na+: iodide symporter (NIS)

2. Oxidation and iodination
 Iodide trapped by follicular cells is carried across the apical
membrane by another transporter termed ‘pendrin’ and
oxidized by the membrane bound thyroid peroxidase
enzyme to
 iodinium (I+) ions or
 hypoiodous acid (HOI) or
 enzyme-linked hypoiodate (E-OI) with the help of H2O2.
combine with tyrosil residues of thyroglobulin
To form Monoiodotyrosine (MIT) and diiodotyrosine (DIT)

3. Coupling
 Normally much more T4 than T3 is formed
 Oxidation of iodide and coupling are both stimulated by TSH.

4. Storage and release
 MIT, DIT, T3 and T4 - all attached to thyroglobulin
and stored in the colloid Thyroglobulin molecule
 Taken up by follicular cells by the process of
endocytosis and broken down by lisosomal
proteases
 T3 and T4 released and also MIT and DIT
 MIT and DIT are deiodinated and reutilized
 T4 & T3 enter circulation directly from follicular
cells
 Normal human thyroid secretes 60–90 μg of T4
and 10–30 μg of T3 daily.

5. Peripheral conversion of T4 to T3
 Peripheral tissues, especially liver and kidney,
convert T4 to T3 by the enzyme iodothyronine
deiodinase
 Target tissues take up T3 from circulation for their
metabolic need, except brain and pituitary which
take up T4 and convert it to T3 within their own cells.
 Equal amounts of T3 and rT3 are produced in
periphery
 Drugs like Propylthiourcil, amiodarone, propranolol
and glucocorticoids inhibit peripheral conversion

TRANSPORT, METABOLISM AND
EXCRETION
 Highly bound to plasma protein
 Only 0.04% of T4 and 0.2% T3 are in free form
 Main Plasma proteins are – TBG, TBP and
albumin
 Metabolism occurs by deiodination and
conjugation, mainly in liver and kidneys
 Conjugated products are excreted in bile –
enterohepatic circulation
 Finally excreted in urine
 Plasma t½ of T4 is 6–7 days, while that of T3 is
1–2 days.

REGULATION OF SECRETION
The negative
feedback by the
thyroid
hormones is
exercised
directly on the
pituitary as well
as through
hypothalamus.

Growth and development
 Normal growth and development of organism
 DNA transcription, critical control of protein synthesis and
translation of genetic code
 Brain development
Metabolism:
 Lipid: Induce lipolysis (catecholamines), ↑ free plasma fatty
acid
 Carbohydrate: Stimulation of carbohydrate metbolism,
glycogenolysis, gluconeogenesis
 Protein: Certain protein synthesis increased but overall
catabolic action – negative nitrogen balance
 Hyperthyroidism – Weight loss and wasting
Actions – contd.

Actions – contd.
Calorigenic & CVS Effects
 T3 and T4 increases BMR by stimulation of cellular
metabolism – maintenance of body temperature
 Hyperthyroidism: tachycardia, ↑ TPR
 Hypothyrodism: bradycardia, ↓ TPR,
Others: Nervous system – mental retardation,
GIT – Increased gut motility,
Haematopoiesis – anaemia

Mechanism of action
fig: Mechanism of action of thyroid hormone on nuclear thyroid hormone receptor (TR).
T3—Triiodothyronine; T4—Thyroxine; TRE—Thyroid hormone response element; RXR
—Retinoid X receptor; mRNA—Messenger ribonucleic acid; 5’DI—5’Deiodinase

Mechanism of action
T3
binds to the ligand binding domain of TR it heterodimerize
with retinoid X receptor (RXP)
Undergo conformational change releasing corepressor and
binding the coactivator.
Induce gene transcription
Production of specific mRNA, specific protein synthesis
Various metabolic and anatomic effects

20
Mechanism of actions of
thyroid hormones
T3, via its nuclear
receptor, induces new
proteins generation which
produce effects

T3 and T4
 Thyroid gland normally secretes mainly T4
 70 % of T3 derived from T4 in peripheral tissues
 T4 is converted to T3 by 5-deiodinase enzyme
 Both T4 and T3 are in bound form (TBG, pre
albumin and albumin)
 Only 0.025% of T4 and 0.35% of T3 are free

T3 Vs T4
 T3 is 5 times more potent > T4
 T4 is the major circulating hormone – bound
more to plasma proteins
 T4 is less active and a precursor of T3 - the
major mediator of physiological effects
 The term thyroid hormone is used to
comprise both T4 plus T3

Preparations
 L-thyroxine sod
 Triiodothyronine (Liothyronine)
L-thyroxine sod
 Oral bioavailability of L-thyroxine is ~ 75%.
 Food alters its absorption.
 Sucralfate, iron, calcium and proton pump
inhibitors also reduce l-thyroxine absorption.
 CYP3A4 inducers like rifampin, phenytoin and
carbamazepine accelerate metabolism of T4

USES
The most important use of thyroid hormone is for
replacement therapy in deficiency states:
1. Cretinism- thyroxine (8–12 μg/kg) daily should be
started as early as possible
2. Adult hypothyroidism (Myxoedema)- Treatment with
T4 is most gratifying. It is often wise to start with a low
dose—50 μg of l-thyroxine daily and increase every 2–3
weeks to an optimum of 100–200 μg/day (adjusted by
clinical response and serum TSH levels).
3. Myxoedema coma - Drug of choice is l-thyroxine (T4)
200–500 μg i.v. followed by 100 μg i.v. OD till oral
therapy can be instituted

4. Nontoxic goiter: In both types (sporadic, endemic)
deficient production of thyroid hormone leads to excess
TSH → thyroid enlarges, more efficient trapping of iodide
occurs and probably greater proportion of T3 is
synthesized → enough hormone to meet peripheral
demands is produced so that the patient is clinically
euthyroid.
5. Thyroid nodule: Certain benign functioning nodules
regress when TSH is suppressed by T4 therapy.
6. carcinoma of thyroid: This type of cancer is often
responsive to TSH

7. Empirical uses
 Refractory anemia's.
 Mental depression
 Menstrual disorders, infertility not corrected by
usual treatment.
 Chronic/non-healing ulcers.
 Obstinate constipation.

THYROID INHIBITORS
1. Inhibit hormone synthesis (Antithyroid drugs)
Propylthiouracil, Methimazole, Carbimazole
2. Inhibit iodide trapping (Ionic inhibitors)
Thiocyanates (–SCN), Perchlorates (–ClO4), Nitrates
(–NO3).
3. Inhibit hormone release
Iodine, Iodides of Na and K, Organic iodide.
4. Destroy thyroid tissue
Radioactive iodine (131
I, 125
I, 123
I).

 Thyrotoxicosis : excessive secretion of
thyroid hormones.
 Graves disease
 Toxic nodular goiter

Antithyroid drugs
Antithyroid drugs bind to the thyroid peroxidase
and prevent oxidation of iodide/ iodotyrosyl
residues, thereby;
(i) Inhibit iodination of tyrosine residues in
thyroglobulin
(ii) Inhibit coupling of iodotyrosine residues to
form T3 and T4.
Propylthiouracil also inhibits peripheral
conversion of T4 to T3 by D1 type of 5’DI,

 Pharmacokinetics: quickly absorbed orally,
widely distributed in the body, enter milk and
cross placenta; are metabolized in liver and
excreted in urine primarily as metabolites.
 Hypothyroidism and goiter can occur due to
overtreatment, but is reversible on stopping the
drug.
 Important side effects are: g.i. intolerance, skin
rashes and joint pain, Loss or graying of hair, loss
of taste, fever and liver damage are infrequent.
 A rare but serious adverse effect is
agranulocytosis

Uses
 Long term treatment of thyrotoxicosis
 Before thyroidectomy- carbimazole is used to
achieve euthyroidism.
 With 131
I to hasten recovery of thyrotoxicosis.
 Thyrotoxic crisis: polythiouracil is used along
with iodide and propranolol

 Differentiate between propythiouracil and
carbimazole.

IONIC INHIBITORS
 Block uptake of iodide.
 Thiocyanates also inhibits iodination at high
doses.
 Highly toxic effects.

Iodine and iodides
 Excess iodide inhibits its own transport into
thyroid cells by interfering with expression of
NIS on the cell membrane.
 Attenuates TSH and cAMP induced thyroid
stimulation. Excess iodide rapidly and briefly
interferes with iodination of tyrosine residues
of thyroglobulin.

Uses
 Preopertative preparation before thyroidectomy
and thyroid strom.
 Prophylaxis of endemic goiter: “iodized salt’’
Adverse effects
Acute reaction: sweeling of lips, eyelids, angioedema
of larynx, fever joint pain, petechial haemorrhages,
thrombocytopenia, lymphadenopathy.
Chronic overdose (iodism) Inflammation of mucous
membranes, salivation, rhinorrhoea, sneezing,
lacrimation, swelling of eyelids, burning sensation
in mouth, headache, rashes, g.i. symptoms, etc.

Radioactive iodine
 131
I- half life: 8 days
 emits x- rays as well as β particles.
 Radioactive iodine is administered as sodium
salt of 131
I dissolved in water and taken orally.
 Slow acting, cause local soreness in the
neck. Incidence of hypothyroidism is high.

Mention the advantages
of using radioactive iodine.

Advantages
1. Treatment with 131I is simple, conveniently
given on outpatient basis and inexpensive.
2. No surgical risk, scar or injury to parathyroid
glands/recurrent laryngeal nerves.
3. Once hyperthyroidism is controlled, cure is
permanent.

 Thyrotoxic crisis (thyroid storm): This is the
emergency due to uncompensated
hyperthyroidism. Besides the usual features of
hyperthyroidism it is characterized by
 Hyperpyrexia
 Cardiac arrythmias
 Nausea and vomiting diarrhoea and mental
confusion.
 It is precipitated by infection, trauma, surgery,
diabetic ketoacidosis, myocardial infarction

Treatment
1. Hospitalization
2. Supportive care: cooling blankets, hydration,
sedation and treatment of infection
3. Propythiouracil is administered through
nasogastric tube
4. Oral iodides to inhibit the relaese of thyroid
hormones- sodium ipodate inhibits peripheral
conversion of T4 to T3
5. Propanolol- orally or i.v.
6. Inj. Dexamethasone
7. Paracetamol

Thyoid hormones and thyroid inhibitors