1. Thyroid hormones Thyroxine(T4) & Triiodothyronine(T3)
Dr Bhaskar H Nagaiah

2. Thyroid & Antithyroid Drugs-Lecture Outline
Thyroid Gland
Structure
Hormones
Steps of Thyroid Hormone Synthesis
Thyroid Hormones
Regulation of Secretion
Mechanism of Action
Pharmacodynamic Actions

3. Thyroid & Antithyroid Drugs-Lecture Outline
Thyroid Hormones
Relation between T3 & T4
Therapeutic Uses of T3 & T4
Antithyroid Drugs
Classification
Sites of Action
Thioamides PK

4. Thyroid & Antithyroid Drugs-Lecture Outline
Thioamides PK
Carbimazole vs. Propylthiouracil
Therapeutic Uses
Adverse Effects
Iodine/Iodides
Salient Features

5. Thyroid & Antithyroid Drugs-Lecture Outline
Radioactive Iodine
Salient Features
Therapeutic Uses
Role of β-Blockers
Preparation for Thyroidectomy
Thyroid Crisis/Storm
Exophthalmos
Hyperthyroidism
Choice of Treatment

6. Thyroid hormones - T4 & T3
T4 & T3 - required for normal growth and development and maintaining body temperature and energy level.
T4 & T3 - are very critical for optimal functioning of nervous system, reproductive system and also skeletal growth.
Deficiency of T4 & T3 in early life results in irreversible mental retardation and dwarfism

7. Thyroid hormones The thyroid gland secrets Thyroxine (T4) - 90%
Triiodothyronine (T3) – 10%
Thyroid gland also secrete Calcitonin hormone – lowers the serum calcium level.
Hypothyroidism –Inadequate secretion
Due to def of dietary iodine & Hashimoto’s thyroiditis.
Hyperthyroidism – due to excess of thyroid hormones – Graves’ disease

8. Thyroid Gland-Structure

9. Hypothalamus-pituitary-thyroid axis
TRH of hypothalamus and TSH of ant pituitary gland – control the secretion of thyroid hormones
TRH of hypothalamus – stimulate the anti pituitary gland to synthesize and release of TSH
TSH – in turn stimulate the synthesis and release of T4 & T3 from thyroid gland
High levels of circulating T3 & T4, through negative feed back controls TRH & TSH secretion by
Blocking the action of TRH on ant Pituitary (↓TSH) and
Inhibit synthesis and secretion of TRH from hypothalamus

10. Regulation of thyroid hormone secretion Hypothalamus-pituitary-thyroid axis
High levels of circulating T3 & T4, through negative feed back controls TRH & TSH secretion
Auto-regulation - Thyroid gland regulates its own iodine uptake and hormone synthesis based on blood iodine level
4/27/2017

11. Thyroid hormone synthesis
Iodide (I-) uptake and its storage in follicles
Oxidation Iodine and iodination of tyrosine (organification of iodide) to monoidotyrosine (MIT) and Diiodotyrosine (DIT) are catalyzed by thyroid peroxidase.
Coupling of DIT & MIT leads to T3 or T4.
DIT + DIT → T4 & MIT + DIT →T3
thyroid peroxidase catalyses coupling
Release of T3 & T4 into circulation.
In circulation, T3 & T4 are transported by binding to thyroxin-binding globulin (TBG)
5’-deiodinase converts T4 to 3,5,3’- triiodothyronine - T3 (T3 is 4 times more potent than T4)
5’-deiodinase inhibitors - Beta blockers, propylthiouracil & Corticosteroids. Used in acute thyrotoxicosis.

12. Synthesis & secretion of thyroid drugs

13. 4/27/2017

14. MOA- of T3 & T4

15. Mechanism of action of thyroid hormones
T4 and T3 are dissociated from thyroid binding globulin & enters into cells
In the cells,
T4 is enzymatically deiodinated to T3
T3 enters into nucleus and attaches to the specific receptors,
In nucleus, T3 promotes mRNA formation and protein synthesis (slow response).
Proteins produces the response

16. Actions of thyroid hormones
Thyroid hormones are essential for optimal growth & development, functioning and maintenance of all the tissues in the body
Essential for normal physical and mental development of the fetus
Responsible for linear growth and optimal growth of brain and reproductive organs
hypothyroidism in infants leads to cretinism (dwarfism and irreversible mental retardation)
Affects the metabolism of carbohydrates, proteins, fats and vitamins

17. Actions of thyroid hormones
Increases the BMR and maintains body temperature
Increases blood glucose levels
Increases the synthesis of fatty acids and decrease plasma cholesterol and TGs
Hyperthyroidism – increase in sympathetic activity (HR, BP etc) may due to sensitizing the tissues by increasing number of beta receptors OR signal amplifications
Actions are antagonized by beta blockers, hence used in hyperthyroidism

18. Pharmacokinetics of T3 & T4
More than 99% of T4 & T3 are bound to TBG.
Both are orally well
But poorly absorbed in severe hypothyroidism
T3 t1/2- 1 day; T4 t1/ days (long)
Enzyme inducers (rifampin, phenytoin phenobarbitol, carbamazepine, ) - increase the metabolism of T4 & T3
1. Levothyroxine sodium, L-T4 - Preparation of choice – long acting (hence once daily). converted to T3
Administered orally (routinely) or Injection (emergency)
2. Liothyronine sodium, L-T3 - Not preferred,
More cardiotoxicity and used in myxedema coma

19. Hypothyroidism Syndrome, is due to deficiency of thyroid hormones
Manifested with OR without goiter
Most common disorder and manifested as slowing down of bodily functions
Most common cause in adults (in USA) is autoimmune thyroiditis (Hashimoto’s thyroiditis)
Autoantibodies directed against thyroid peroxidase and less commonly to thyroglobulin
other causes- radiation, thyroidectomy, congenital,
Drugs – iodides, lithium, thiomides, aminosalicylic acid, phenylbutazole, Amiodarone etc
Dietary deficiency of iodine
Myxedema coma – most extreme & untreated hypothyroidism,

20. 4/27/2017

21. Therapeutic uses of thyroid hormones
1. Cretinism – start treatment as early as possible
2. Adult hypothyoidism
3. Myxedema coma
4. Nontoxic goiter – to regress the goiter
Levothyroxine (T4) - treatment of choice
Children & infants require more T4 per kilogram than adults

22. Myxedema coma (myxedema crisis)
An end state of, severe, long-standing and untreated hypothyroidism
Associated with severe weakness, hypothermia hypoventilation, hypoglycemia, shock, coma, and death

23. Myxedema coma (myxedema crisis)
Medical emergency in ICU
All drugs are given intravenously
Rewarming the body with blankets,
Levothyroxine (T4) (IV/ nasogastric)
IV Liothyronine (T3) can also be used
Hypertonic saline with glucose
Hydrocortisone IV (in patients having adrenal or pituitary insufficiency)

24. Hyperthyroidism Graves’ disease Toxic uninodular & multinodular goiters

25. Hyperthyroidism
Graves’ disease, Toxic uninodular & multinodular goiters Rx
Surgical excision
Drugs used in hyperthyroidism
Thioamides: inhibit hormone synthesis (Antithyroid drugs)
Iodide salts: blocks the hormone release
Radioactive iodine: destruction of thyroid tissue
Anion inhibitors: block uptake of iodide by thyroid
Ipodate – prevents peripheral conversion of T4 to T3
Beta-blocker: propranolol, prevents conversion of T4 to T3
Main treatment is surgical
However even before surgery you need to have pharmacological intervention.

26. Thioamides
Propylthiouracil, Methimazole and Carbimazole (prodrug, converted to methimazole & widely used in UK)
Thioamides - inhibit the hormone synthesis by
inhibiting thyroid-peroxidase and thus inhibits oxidation of iodine and iodination of tyrosine residues and coupling reactions of DIT and MIT to T4 & T3 (iodine organification)
Propylthiouracil also inhibits peripheral deiodination (conversion) of T4 to T3 – preferred in thyroid storm
No effect on iodine uptake and release of thyroid hormones
Thyroid storm
You need to make the patient euthyroid for hyperthyroid
You cannot do surgery in pts who are hyperthyroid, hyperglycemic, hypertensive
If surgery is performed you will get thyroid storm

27. Thioamides Slow in onset ~ 4 weeks,
Propylthiouracil - do not cross the placental barrier and safe - preferred in pregnancy
Methimazole and carbimazole in comparison with Propylthiouracil
more potent
longer acting (once daily dosing)
hence preferred over propylthiouracil (except in pregnancy)
CAN BE USED PREOPERATIVELY
Cannot cross the placenta
Longer duration of action because extensively bound with plasma protein
In pregnancy DOC is Propylthiouracil (shorter acting, prevent peripheral conversion T4 to T3)
As far as compliance, methimazole is preferred b/c of longer duration of action

28. Thioamides: ADRs
Common: Maculopapular rashes with fever, lupus like reaction, lymphadenopathy, Hypothyroidism (reversible), Arthralgia,
Agranulocytosis
Rare but serious & fatal
Immediately STOP THE DRUG

29. Thioamides- therapeutic uses
Hyperthyroid conditions
Graves disease
Toxic uninodular and multi nodular goiters
Non toxic goiter
Thyroid storm
Prior to radioactive iodine

30. Iodine and Potassium iodide (Lugol’s solution)
Preparation used is Lugol’s solution (5% Iodine+ 10% Potassium iodide)
MOA - Inhibits hormone release (most important)
Fast / rapid onset of action, pref in emergencies
used in thyroid storm
Decreases the size and vascularity -Gland become firm and less vascular
Easier for surgical excision – less bleeding
Administered for 7-10 days prior to thyroid surgery as preoperative preparation for thyroidectomy:

31. Lugol’s solution Adverse effects:
Acute allergic reactions: In iodine sensitive individuals can cause - Angioedema, Swelling of larynx, lips and eyelids, Skin rashes.
Chronic overdose leads to iodism
Metallic taste, inflammation & ulceration of mucous membranes, salivation, rhinorrhea, sneezing, burning sensation in mouth, drug fever
Long term use - hypothyroidism and goiter

32. Radioactive Iodine (131I)
Radioactive iodine - sodium 131I isotope emits beta particles
131I taken up & concentrated in thyroid follicles.
Emits beta rays, which destroys the thyroid gland
Gland undergo pyknosis, necrosis and fibrosis
Radioactive Iodine 131I used to treat thyrotoxicosis
Grave’s disease
Toxic nodular goiter
Prior to radioactive iodine, thiomides are used to make the gland euthyroid state
With in few weeks, 131I induce euthyroid OR hypothyroid (80%, managed with Levothyroxine)
Contraindicated in children, pregnancy & lactation: Risk of Fetal hypothyroidism (cretinism)

33. Advantages of radioactive iodine
Easy to administer (single dose by oral route)
Very effective
Less expense
Absence of pain
Surgery is not required
Permanent cure
Disadvantage – hypothyroidism
4/27/2017

34. Iodinated contrast media
Ipodate and Iopanoic acid
Acts by
Inhibiting the peripheral conversion of T4 into T3 in the liver, kidney and brain.
Inhibits hormone release
Used in thyroid storm as adjunctive therapy
Produces dramatic improvement in subjective and objective parameters

35. Hyperthyroidism/Throtoxicosis
Graves disease
Auto immune disorder – B-lymphocytes produce antibodies (TSH-R Ab) can stimulate TSH receptors – increase in T4 & T3 synthesis and secretion
Managed with
Antithyroid drugs - Propylthiouracil / methimazole
Thyroidectomy – near total thyroidectomy
Radioactive iodine – used after 21 years of age,
Beta-blockers – Propranolol to control CV complications – tachycardia, AF, HTN,
In Grave’s disease prognosis is good
NOT in toxic nodular goitre
4/27/2017

36. Thyroid storm
Thyrotoxic crisis - sudden and acute exacerbations of all the symptoms of thyrotoxicosis
Patient can develop life threatening complications
Precipitating factors for thyrotoxic crisis are
infections, stress, trauma, thyroidal or nonthyroidal surgery, diabetic ketoacidosis, labor, heart diseases etc.
Clinical features: Fever (temp usually over 38.50C), Tachycardia, Nausea, Vomiting, Diarrhea, Agitation and Confusion, Coma and death

37. Thyroid storm Rx
Supportive measures (IV fluids, antipyretics, cooling blankets, and sedation)
Propylthiouracil (preferred over methimazole**)- administered by nasogastric tube or rectally, inhibits conversion of T4 to T3
Iodides- orally or IV
Ipodate – inhibits hormone release and conversion of T4 to T3.
Propranolol or Diltiazem (If beta blockers are contraindicated)- used to control tachyarrhythmias or cardiovascular diseases
Dexamethasone – supportive therapy of possible relative adrenal insufficiency and also blocks the T4 to T3 conversion
**Blocks conversion of T4 to T3 EXAM EXAM EXAM EXAM

38. Thyroid & Antithyroid Drugs-Lecture Outline(contd.)
Thyroid Gland
Structure
Hormones
Steps of Thyroid Hormone Synthesis
Thyroid Hormones
Regulation of Secretion
Mechanism of Action
Pharmacodynamic Actions

39. Thyroid & Antithyroid Drugs-Lecture Outline(contd.)
Thyroid Hormones
Relation between T3 & T4
Therapeutic Uses of T3 & T4
Antithyroid Drugs
Classification
Sites of Action
Thioamides PK

40. Thyroid & Antithyroid Drugs-Lecture Outline(contd.)
Thioamides PK
Carbimazole vs. Propylthiouracil
Therapeutic Uses
Adverse Effects
Iodine/Iodides
Salient Features

41. Thyroid & Antithyroid Drugs-Lecture Outline(contd.)
Radioactive Iodine
Salient Features
Therapeutic Uses
Role of β-Blockers
Preparation for Thyroidectomy
Thyroid Crisis/Storm
Exophthalmos
Hyperthyroidism
Choice of Treatment

42. For Further Reading!..
Basic & Clinical Pharmacology by Bertram G. Katzung (9th Edition)(Chapter 38)
Clinical Pharmacology by D. R. Laurence, P. N. Bennett & M. J. Brown (8th Edition) (Chapter 37)
Goodman & Gilman’s The Pharmacological Basis of Therapeutics(10th Edition)(Chapter 57)

43. THANK YOU !