This presentation contains pharmacology of thyroid hormones.

1. THYROID GLAND HORMONES
Dr. RupaliA. Patil
Associate Professor, Pharmacology Department
GES’s Sir Dr. M. S.GosaviCollege of Pharmaceutical Education & Research,
Nashik

2. Contents
• Thyroid gland
• Thyroid hormones (TH)
• Biosynthesis
• Storage, Release , Regulation, Metabolism & Excretion
• Relationship betweenT3 &T4
• Mechanism of action
• Actions
• Disorders
• Analogues and their inhibitors.

3. ThyroidGlands
Butterfly-shaped, located just inferior to the larynx (voice box) & in the neck at the back of the Adam’s apple.
Largest endocrine gland

4. • Follicular cells
• Lined with a single layer of epithelial cells
• Centre is filled with colloid
• Parafollicular cells
Parafollicular (c)
cell
Follicular cell
Thyroid follicle
Thyroglobulin
(Tgb) (colloid)
Histology

5. Hormones secreted byThyroid gland
Follicular cells Parafollicular cells/ Interfollicular ‘C’ cells
Thyroid hormones
T3 (tri-iodothyronine)
T4 (tetra-iodothyronine/Thyroxine)
Thyrocalcitonin (Calcitonin)
Affects body metabolism Lowers down theblood calcium level of body

6. Biosynthesis
1. Iodide trapping
2. Synthesis of thyroglobulin
3.Oxidation of iodide
4. Iodination of tyrosine
5.Coupling ofT1 andT2
6. Pinocytosis and digestion of colloid
7. Secretion of thyroid hormones
8.Transport in the blood: More than 99% of
bothT3 &T4 combine with transport proteins
in the blood, mainly thyroxine-binding
globulin (TBG).
Total triiodothyronine (T3): 60–181 ng/dL (0.92–2.79 nmol/L)
Total thyroxine (T4): 4.8–10.4 mcg/dL (62–134 nmol/L)
TSH activates steps 1, 2, 3, 4, and 5; Ionic inhibitors block
step 1; Excess iodide interferes with steps 1, 2, 3 & 5 with primary action on step 3 & 5;
Propylthiouracil inhibits steps 2 & 6; Carbimazole inhibits step 2 only

7. The recommended daily adult iodide (I -) *intake is 150 mcg (200 mcg during pregnancy).

8. Storage & release
• T4 &T3 in plasma : reversibly bound to protein, primarily thyroxine-binding globulin (TBG).
• Free form: 0.04% of totalT4 &
0.4% ofT3.
• Thyroxine,T3 , MIT, & DIT -- released from thyroglobulin by exocytosis & proteolysis of
thyroglobulin at the apical colloid border.
• Within thyroglobulin:T4:T3 = 5:1
• Almost all protein bound iodine (PBI) in plasma is thyroid hormone

9. Binding :
Occurs to 3 plasma proteins in the following decreasing order of affinity forT4:
(i)Thyroxine binding globulin (TBG)
(ii)Thyroxine binding prealbumin (transthyretin/TBPA))
(iii) Albumin
• During pregnancy thyroxine binding globulin is increased—PBI levels are elevated.

10. Regulation
1. TRH
2. TSH
3. Feedback mechanism
4. Cold
5. Stress

11. Peripheral Metabolism
• Reverse T3 / rT 3 : metabolically inactive
• Inhibition of 5’-deiodinase (T4 to T3 ):
amiodarone, iodinated contrast media,
- blockers, corticosteroids, severe illness
or starvation
• lowT3 & high rT3 levels in the serum
• All naturally occurring molecules are levo
(L) isomers
• Synthetic (D) isomer of thyroxine,
dextrothyroxine 4% of the biologic
activity of the L-isomer
• Metabolism by deiodination and
glucuronide/sulfate conjugation
• Site: Liver, Salivary glands & Kidneys

12. Excretion
• The conjugates are excreted in bile, of which a significant fraction is deconjugated in
intestines and reabsorbed (enterohepatic circulation) to be finally excreted in urine.
• Plasma t½ ofT4 is 6–7 days, while that ofT3 is 1–2 days.
• The half-lives are shortened in hyperthyroidism and prolonged in hypothyroidism due
respectively to faster and slower metabolism

13. Relation between T4 andT3
• •Thyroid secretes moreT4 thanT3, but in iodine deficient state this difference is reduced.
• •T4 is the major circulating hormone as it is 15 times more tightly bound to plasma proteins.
• •T3 is 5 times more potent thanT4 & acts faster. Peak effect ofT3 comes in 1–2 days while that of
T4 takes 6–8 days.
• T3 is more avidly bound to the nuclear receptor thanT4 & theT4-receptor complex is unable to
activate/derepress gene transcription.
• • About 1/3 ofT4 is converted toT3 in the thyroid cells, liver & kidney by type 1 deiodinase (D1) &
released into circulation.
• In addition,T3 is generated within the target cells (skeletal muscle, heart, brain, pituitary) by
another type (D2) of deiodinase.

14. Mechanism of action
• TSH on thyroid cells : mediated by enhanced cAMP synthesis.
• High concentration ofTSH : acts via IP3/DAG–increased intracellular Ca2+ pathway in the thyroid cells.
• BothT3 &T4 penetrate cells by active transport & produce majority of their actions by combining with
a nuclear thyroid hormone receptor (TR) which belongs to the steroid & retinoid superfamily of
intracellular receptors.
• TheTR resides in the nucleus even in the unliganded inactive state.
• T3 binds to the ligand-binding domain ofTR, it heterodimerizes with retinoid X receptor (RXR) &
undergoes a conformation change --------- gene transcription → production of specific mRNA & a
specific pattern of protein synthesis → various metabolic & anatomic effects.
• Many of the effects, e.g. tachycardia, arrhythmias, raised BP, tremor, hyperglycaemia are mediated by
sensitization of adrenergic receptors to catecholamines.
• Induction of adenylyl cyclase, proliferation of β adrenoceptors

15. • Apart from the nuclear T3 receptor,
other sites of thyroid hormone action
have been described.
• It acts on cell membrane to enhance
amino acid and glucose entry and on
mitochondria to increase oxygen
consumption.
• At these sites T4 appears to be
equipotent to T3, while at the nuclear
receptor T4 has much lower affinity, &
even when bound to the TR, T4 does not
promote gene transcription

16. Actions
1. Growth & development
2. Metabolism
3. Calorigenesis
4. CVS
5. Nervous system
6. Skeletal muscle
7. GIT
8. Kidney
9. Haemopoiesis
10. Reproduction

17. 1. Growth & development:
• Congenital deficiency ofT4 &T3 : cretinism due to axonal & dendritic ramification, synapse formation
& impaired myelination.
• In adult hypothyroidism: intelligence is impaired and movements are slow.
2. Metabolism:
Lipid : inhibits phosphodiesterase --- increased cAMP ---- increased lipolysis --- increased plasma free
fatty acid level ---- Decreases cholesterol, phospholipids, triglycerides – Increases rate of
cholesterol secretion in bile – Increases number of LDL receptors on liver
Carbohydrate: increased glycogenolysis & gluconeogenesis in liver
• Hyperthyroidism: hyperglycaemia and diabetic-like state with insulin resistance
Protein:
• T3 is catabolic: proteins used as energy source
• Prolonged action results in negative nitrogen balance & tissue wasting
• Hyperthyroidism: weight loss
Actions

18. 3. Calorigenesis
• At very high doses:
• Increase BMR (metabolic rate in brain, gonads, uterus, spleen and lymph nodes is not
significantly affected)
• Calorigenesis: uncoupling of oxidative phosphorylation: excess energy being released
as heat.
4. Nervous system
• Hypothyroidism:
Cretinism : mental retardation
Myxoedema : sluggishness
• Hyperthyroidism: anxiety, nervousness, excited, exhibit tremors and hyperreflexia

19. 5. CVS : Increased Heart rate, contractility & output
Direct action on contractile elements (increasing the myosin fraction having greater Ca2+ -ATPase
activity) & up regulation of β adrenergic receptors.
Increased BP, specially systolic

20. 6. Skeletal muscle :
• Myxoedema: Muscles are flabby and weak
• Thyrotoxicosis : increased muscle tone, tremor and weakness
7. GIT: Increase in Propulsive activity of gut.
• Hypothyroidism: constipation
• Hyperthyroidism: diarrhoea
8. Kidney
• Myxoedema: diuresis

21. 9. Haemopoiesis:
• Hypothyroidism: some degree of anaemia ; restored only byT4 treatment.
T4 facilitates erythropoiesis.
10. Reproduction :
• Indirect effect
• Hypothyroidism: Fertility is impaired ; women -- oligomenorrhoea.
• Normal thyroid function for maintenance of pregnancy & lactation.

22. Pharmacokinetics and interactions
• Oral bioavailability of l-thyroxine is ~ 75%, but severe hypothyroidism can reduce oral
absorption.
• It should be administered in empty stomach to avoid interference by food.
• Sucralfate, iron, calcium and proton pump inhibitors also reduce l-thyroxine
absorption.
• CYP3A4 inducers like rifampin, phenytoin and carbamazepine accelerate metabolism
ofT4; dose of l-thyroxine may need enhancement

23. Disorders of thyroid hormones
HYPOTHYROIDISM
An underactivity of the thyroid gland causing laziness, dullness,
& goiter.
HYPERTHYROIDISM
an active behaviour resulting to loss of weight & insomnia.

24. • Hyposecretion
– Congenital hypothyroidism/ cretinism
• facial thickening,low body temp, lethargy, brain
damage
Delayed physically: Dwarf, teeth erupt later than normal
Delayed mentally &
sexually
Special features:
▪ Depressed nasal bridge
▪ Wide nostrils
▪ Protruding tongue
▪ Protuberant abdomen
– Adults: myxedema
• Low BMR, sluggish, sleepy, weight gain, cold, tissue
swelling
From: http://www.type2hypothyroidism.com/Type1VsType2.html

25. Goiter
Types
Endemic goiter: dietary deficiency of iodine
– NoTH produced so pituitary receives no negative feedback &
more TSH produced
– Results in hypertrophy
Toxic goiter (Grave’s disease)
– Autoimmune disease
– Abnormal antibodies mimicTSH, raising TH levels
• Called thyroid-stimulating immunoglobin
– Causes high BMR & HR, sleeplessness,
weight loss, exophthalmos
From: http://www.medstudents.com.br/image/endoc/imgend1.htm

26. Uses
• Cretinism: sporadic or endemic: thyroxine (8–12 μg/kg) daily
• Adult hypothyroidism (Myxoedema):
• Subclinical hypothyroidism characterized by euthyroid status and normal free serum
thyroxine (FT4) level (> 9 pmol/L) but raisedTSH level
• Myxoedema coma: emergency; with progressive mental deterioration
• Nontoxic goiter: endemic or sporadic, deficient production ofTH
• Thyroid nodule: benign functioning nodules regress whenTSH is suppressed byT4
• Papillary carcinoma of thyroid: responsive toTSH.
• Empirical uses
• Refractory anaemias
• Mental depression
• Menstrual disorders, infertility not corrected by usual treatment
• Chronic/non-healing ulcers.
• Obstinate constipation

27. Thyroid function tests:
• Protein bound iodine
• SerumT4
• SerumTBG
• Free thyroxine index & effective thyroxine ratio
• Scintillography
• T3 suppression test

28. Preparations
• Thyroid USP: Dried thyroid gland extract of cows & pigs
• Thyroglobulin: Purified extract of Frozen hogTG
• Levothyroxine sodium: SyntheticT4; Drug of choice in hypothyroidism
• Liothyronine sodium: SyntheticT3; drug of choice in Myxedema coma
• Liotrix : (T4:T3 4:1)

29. References
• Rang HP, Ritter JM & Flower RJ & Henderson G, Rang & Dale's Pharmacology, 8th
Edition, Churchill Livingstone, 2015.
• Tripathi KD, Essentials of Medical Pharmacology, 7th edition, Jaypee Brothers Medical
Publishers (P) Ltd, 2013.
• Katzung BG, Lange & Katzung Basic & Clinical Pharmacology, 14th edition, McGraw Hill
Professional, 2018.
• Barar FSK, Essentials of Pharmacotherapeutics, 6th revised edition, S. Chand &
Company Ltd., New Delhi, 2011.

30. THANKYOU