1. Thyroid pharmacology

2. THYROID GLAND Location 12 to 20 g in size In neck, anterior to trachea
Between cricoid cartilage and suprasternal notch
Highly vascular and soft in consistency.

3. THYROID GLAND Consists of two lobes Connected by an isthmus
4 parathyroid glands
Posterior region of each pole
Laryngeal nerves traverse lateral borders of gland

4. Secretions Produces two related hormones Thyroxine (T4)
Triiodothyronine (T3)

5. Action Play a critical role in Cell differentiation during development
Help to maintain thermogenic and metabolic homeostasis in adult.
Act through nuclear hormone receptors to modulate gene expression

6. Regulation of thyroid hormone synthesis
T4 and T3 feed back to inhibit
Hypothalamic production of thyrotropin-releasing hormone (TRH)
Pituitary production of thyroid-stimulating hormone (TSH)

7. TSH-R, thyroid-stimulating hormone receptor, Tg- thyroglobulin NIS - sodium-iodide symporter; TPO- thyroid peroxidase DIT - di-iodotyrosine; MIT - monoiodotyrosine

8. Thyroid Hormone Synthesis
Thyroid hormones are derived from thyroglobulin
Large iodinated glycoprotein
After secretion into the thyroid follicle
Tg is iodinated on selected tyrosine residues that are subsequently coupled via an ether linkage
Reuptake of Tg into thyroid follicular cell allows proteolysis and the release of T4 and T3.

9. Iodine Metabolism and Transport
Iodide uptake is a critical first step in thyroid hormone synthesis
Ingested iodine is bound to serum proteins (particularly albumin)
Unbound iodine is excreted in urine
Iodine extracts from circulation in a highly efficient manner
10 to 25% of radioactive tracer (e.g., 123I) is taken up by the normal thyroid gland over 24 h; this value can rise to 70 to 90% in Graves' disease.

10. Na+/I- symporter (NIS)
Mediate Iodide uptake
Expressed at basolateral membrane of thyroid follicular cells.
Expressed
Most highly in thyroid gland
Low levels in salivary glands, lactating breast, placenta
Low I2 levels increase amount of NIS & stimulate uptake
High I2 levels suppress NIS expression & uptake

11. Selective expression of NIS in thyroid allows
Treatment of hyperthyroidism
Isotopic scanning
Abolition of thyroid cancer with radioisotopes of iodine
Without significant effects on other organs
Mutation of the NIS gene is a rare cause of congenital hypothyroidism

12. Oranification Iodide enters thyroid 
Trapped and transported to apical membrane of thyroid follicular cells 
Oxidized in an organification reaction (Tyroid PerOxidase & H2O2 )

13. Coupling
Reactive iodine atom is added to selected tyrosyl residues within Tyroglobulin
Iodotyrosines in Tg are then coupled via an ether linkage in a reaction Catalyzed by TPO
Either T4 or T3 can be produced by this reaction
Depending on number of iodine atoms present in iodotyrosines.

14. Storage, Release After coupling, Tg is taken back into thyroid cell
It is processed in lysosomes to release T4 and T3
Uncoupled mono- and diiodotyrosines (MIT, DIT) are deiodinated by enzyme dehalogenase
Recycling any iodide that is not converted into thyroid hormones

15. Factors Influence Synthesis and Release
TSH is the dominant hormonal regulator of thyroid gland growth and function
Variety of growth factors, most produced locally in thyroid gland, also influence synthesis
Insulin-like growth factor I (IGF-I
Epidermal growth factor
Transforming growth factor β (TGF- β)
Endothelins
Various cytokines.

16. Disorders of thyroid hormone synthesis
Rare causes of congenital hypothyroidism
Majority of disorders due to recessive mutations in TPO or Tg
Defects also identified in
TSH-R
NIS
Pendrin anion transporter
Transports I2 from cytoplasm to follicle lumen
H2O2 generation
Dehalogenase

17. Biosynthetic defect of thyroid hormone 
Inadequate amounts of hormone 
Increased TSH synthesis 
Goiter

18. Transport And Metabolism
T4 is secreted from the thyroid gland in at least 20-fold excess over T3
Both circulate bound to plasma proteins
Thyroxine-binding globulin (TBG)
Transthyretin (TTR), formerly known as thyroxine-binding prealbumin (TBPA)
Albumin

19. Functions of serum-binding proteins
Increase pool of circulating hormone
Delay hormone clearance
Modulate hormone delivery to selected tissue sites

20. Con. of TBG is relatively low (1 to 2 mg/dL)
High affinity for thyroid hormones (T4 > T3), it carries about 80% of bound hormones
Albumin has relatively low affinity for thyroid hormones (high plasma con ~3.5 g/dL)
It binds up to 10% of T4 and 30% of T3.
TTR carries about 10% of T4 but little T3.

21. ≈ 99.98% of T4 and 99.7% of T3 are protein-bound
T3 is less tightly bound than T4
Amount of free T3 > free T4
Unbound (free) cons
T4 ~2 ´ M
T3 ~6 ´ M

23. Deiodinases
In many respects, T4 may be thought of as a precursor for more potent T3
T4 is converted to T3 by the deiodinase enzymes
Type I deiodinase
Located primarily in thyroid, liver, kidney
Has a relatively low affinity for T4
Type II deiodinase
Higher affinity for T4
Found primarily in pituitary gland, brain, brown fat, thyroid gland

25. T4 - T3 conversion may be impaired by
Fasting
Acute trauma
Oral contraseptive agents
Propylthiouracil
Propranolol
Amiodarone
Glucocorticoids

26. THYROID HORMONE ACTION
Act by binding to nuclear receptors, termed thyroid hormone receptors (TRs) ά and β
Both ά and β are expressed in most tissues
Both receptors are variably spliced to form unique isoforms

27. Thyroid hormone receptors ά
Highly expressed in
Brain
Kidney
Gonads
Muscle
Heart
TR ά 2 isoform contains a unique carboxy terminus that prevents thyroid hormone binding
It may function to block actions of other TR isoforms

28. Thyroid hormone receptors β
Highly expressed in
Pituitary
Liver
TR β 2 isoform
Has a unique amino terminus
Selectively expressed in hypothalamus & pituitary
Play a role in feedback control of thyroid axis

29. (1) T4 or T3 enters the nucleus (2) T3 binding dissociates CoR from TR (3) Coactivators (CoA) are recruited to the T3-bound receptor (4) gene expression is altered

30. Thyroid Hormone Resistance (RTH)
An autosomal dominant disorder characterized by
Elevated free thyroid hormone levels
Inappropriately normal or elevated TSH
Individuals with RTH (in general) do not exhibit signs and symptoms that are typical of hypothyroidism
Apparently hormone resistance is compensated by increased levels of thyroid hormone

31. HYPOTHYROIDISM
Worldwide most common cause of hypothyroidism - Iodine deficiency
Other causes
Autoimmune disease (Hashimoto's thyroiditis)
Iatrogenic causes (treatment of hyperthyroidism)

32. Treatment T4 - 10 to 15 ug/kg/ day
Dose adjusted by close monitoring of TSH levels
T4 requirements- relatively great during first year of life
High circulating T4 level is usually needed to normalize TSH
Early treatment with T4 results in normal IQ levels

33. Hyperthyroidism Excessive thyroid function Thyrotoxicosis
State of thyroid hormone excess
Major etiologies of thyrotoxicosis
Hyperthyroidism caused by Graves' disease
Toxic multinodular goiter
Toxic adenomas

34. Treatment
Hyperthyroidism of Graves' disease is treated by reducing thyroid hormone synthesis
Antithyroid drugs
Reducing the amount of thyroid tissue with radioiodine (131I)
Subtotal thyroidectomy
No single approach is optimal and that patients may require multiple treatments to achieve remission.
Antithyroid drugs are the predominant therapy in many centers in Europe and Japan
Radioiodine is more often the first line of treatment in North America

35. ANTITHYROID DRUGS (Drugs used in hyperthyroidism)
Thioamides (reduce the synthesis of thyroid hoemones)
Carbimazole
Methimazole
Propylthiouraciliodide
Radioactive iodine (I131)
Iodide ( high doses)
Ionic inhibitors (inhibit iodide uptake) - use is obsolete due to toxicity
Thiocyanates
Perchlorates
Nitrates
Propranolol - Adjunct therapy in thyrotoxicosis

36. Thioamides Mechanism Clinical use
reduce the synthesis of thyroid hormones by inhibiting iodination of tyrosine and coupling of iodotyrosine to form T3 and T4
Clinical use
Carbimazole
Graves disease-till remission of symptoms (30-60mg) maintenance dose(5-15mg)
Propylthiouracil ( mg/d orally) maintenance dose ( mg/d)
Nodular toxic goiter
Prior to surgery for hyperthyroidism
With radioactive iodine to decrease symptoms before radiation effects are manifested
Adverse effects
Hypothyroidism
Vasculitis, agranulocytosis, Hypoprothrombinaemia
Cholestatic jaundice
Hair pigmentation

37. Iodides Mechanism Clinical use
Selectively trapped by the thyroid gland (uptake being increased in hyperthyroidism and reduced in hypothyroidism).
Large doses inhibit secretion of thyroid hormones by inhibition of thyroglobulin proteolysis
Induce involution and decrease vascularity of the gland.
Clinical use
Preoperative use in thyroid surgery(Potassium iodide, 60 mg orally thrice daily)
Thyroid crisis
Accidental over dosage of radioactive iodine (to protect the thyroid follicles)
Prophylactic use in endemic goiter. Added to salt (1 in 100,000 parts )as iodized salts.
As an expectorant, antiseptic for topical use

38. Adverse effects- Thioamides
maculpapular pruritic rash
murticarial rash
Arthralgia
Lymphadenopathy
lupus-like syndrome
Polyserositis

39. Adverse reactions
Acute hypersensitivity reactions (angioneurotic oedema, skin haemorrage, drug fever)
salivation, lacrimation, soreness of throat, conjunctivitis, coryza-like symptoms, skin rashes
Foetal or neonatal goiter

40. Radiioactive iodine Mechanism of action
Trapped by the thyroid follicles and incorporated into
thyroglobulin
Emits both beta and gamma rays(half-life 8 days)
Beta rays - short range and act on thyroid tissue only
The gamma rays are more penetrative and can be
detected by Gieger counter for diagnostic use.

41. Clinical Use Radioactive sodium iodide (5-8 m curie) orally.
Grave’s disease, including relapse after subtotal
thyroidectomy.
Toxic nodular goiter
Thyroid carcinoma
Diagnosis of thyroid function micro curie is administered.
best in patients over 35 years and in the presence of cardiac disease
Clinical response is slow and may take 6-12 weeks for suppression of hyperthyroid symdrome

42. Effects of drugs on thyroid functions
Dopamine, l-dopa, corticosteroids, somatostatin
Inhibition of TRH and TSH secretion.
Iodides, lithium.
Inhibition of thyroxine synthesis, and hypothyroidism
Cholestyramine, colestipol, sucralfate, aluminium salts
Inhibit thyroxine absorption from gut
Phenytoin, carbamazepine, rifampicin, phenobarbitone
Enzyme induction. May enhance T3 and T4 metabolism
Propylthiouracil, amiodarone
Inhibit conversion of T4 to T3
corticosteroids, beta-blockers Androgens, glucocorticoids,
Decrease thyroxine-binding globulin
Oestrogens, tamoxifen, mitotane
Increase thyroxine-binding globulin
Salicylates, mefenamic acid, furosemide
Displace T3 and T4 from thyroxine –binding globulin.