1. SUJITH HARIDASS.M.Pharm
THYROID DISORDERS
SUJITH HARIDASS.M.Pharm

2. Anatomy Over Trachea Two Lobes connected together by an isthmus

3. Thyroid gland
Thyroid gland is composed over a million cluster of follicles (Functional unit is Follicle)
Follicles are spherical & consists of epithelial cells surrounding a central mass (colloid)

4. The Thyroid Produces and Secretes 2 Metabolic Hormones
Tetraiodothyronine( T4 or Thyroxine)
Triiodothyronine (T3)
Required for homeostasis of all cells
Influence cell differentiation, growth, and metabolism
Considered the major metabolic hormones because they target virtually every tissue.
Also augment sympathetic nervous system function by increasing the number of adrenergic receptors in target tissues.

5. Biosynthesis of T4 and T3 The process includes
Dietary iodine (I) ingestion
Active transport and uptake of iodide (I-) by thyroid gland.
Oxidation of I- and iodination of thyroglobulin (Tg) tyrosine residues
Coupling of iodotyrosine residues (MIT and DIT) to form T4 and T3
Organification & the coupling reactions catalyzed by peroxidase.
Proteolysis of Tg with release of T4 and T3 into the circulation

6. The thyroid secretes approximately 70-90 g of T4 per day
T4 is the primary secretory product of the thyroid gland (80%), which is the only source of T4
The thyroid secretes approximately g of T4 per day
T3 is derived from 2 processes
The total daily production rate of T3 is about g
About 80% of circulating T3 comes from deiodination of T4 in peripheral tissues.
About 20% comes from direct thyroid secretion

7. Release of Thyroid hormones
Secretion of hormones modulated by
TSH or thyrotropin (anterior pituitary hormone )
TRH (hypothalamic hormone)
Release stimulated by TSH
Production controlled by 2 ways
First controlled by T3 which inhibits TRH & TSH secretion.
Secondly by the conversion of T4 to T3.

9. T4 is biologically inactive in target tissues until converted to T3
These hormones are transported to target organs by thyroid-binding globulin,thyroid binding prealbumin, albumin & HDL.
T4 is biologically inactive in target tissues until converted to T3
Activation occurs with 5' iodination of the outer ring of T4
T3 then becomes the biologically active hormone responsible for the majority of thyroid hormone effects

10. Sites of T4 Conversion
The liver is the major extrathyroidal T4 conversion site for production of T3
Some T4 to T3 conversion also occurs in the kidney and other tissues

11. T4 Disposition Normal disposition of T4
About 41% is converted to T3
38% is converted to reverse T3 (rT3), which is metabolically inactive
21% is metabolized via other pathways, such as conjugation in the liver and excretion in the bile
Normal circulating concentrations
T g/dL
T ng/dL (~100-fold less than T4)

12. Changes in TBG Concentration Determine Binding and Influence T4 and T3 Levels.
Increased TBG
Total serum T4 and T3 levels increase
Decreased TBG
Total serum T4 and T3 levels decrease

13. Drugs and Conditions That Increase Serum T4 and T3 Levels by Increasing TBG
Drugs that increase TBG
Oral contraceptives and other sources of estrogen
Methadone
Clofibrate
5-Fluorouracil
Heroin
Tamoxifen
Conditions that increase TBG
Pregnancy
Infectious/chronic active hepatitis
HIV infection
Biliary cirrhosis
Genetic factors

14. Drugs and Conditions That Decrease Serum T4 and T3 by Decreasing TBG Levels or Binding of Hormone to TBG
Drugs that decrease serum T4 and T3
Glucocorticoids
Androgens
L-Asparaginase
Salicylates
Mefenamic acid
Antiseizure medications, eg, phenytoin, carbamazepine
Furosemide
Conditions that decrease serum T4 and T3
Genetic factors
Acute and chronic illness

15. Thyroid Hormone Action
Thyroid hormone plays a major role in growth and development.
- Stimulates formation of proteins, which exert trophic effects on tissues.
- Essential for childhood growth, normal brain development

16. Thyroid Hormones and the Central Nervous System (CNS).
- Essential for neural development and maturation and function of the CNS.
- Decreased thyroid hormone concentrations may lead to alterations in cognitive function.(poor memory, impairment of attention, slowed motor function)

17. Normal thyroid hormone function is important for reproductive function
Hypothyroidism may be associated with menstrual disorders, infertility, risk of miscarriage, and other complications of pregnancy.
Thyroid Hormone is Critical for Normal Bone Growth and Development
- T3 is an important regulator of skeletal maturation

18. Play role in thermal regulation
Thyroid hormones (specifically T3) regulate rate of overall body metabolism
T3 increases basal metabolic rate
Play role in thermal regulation
Stimulates lipolysis and release of free fatty acids and glycerol
Stimulates metabolism of cholesterol to bile acids
Facilitates rapid removal of LDL from plasma
Generally stimulates all aspects of carbohydrate metabolism and the pathway for protein degradation.

19. Cardiovascular system
vasodilatation
↑ blood flow
↑ cardiac output
↑ heart rate

20. Thyroid Disorders
Hypothyroidism
Hyperthyroidism

21. Hypothyroidism
Hypothyroidism is a disorder with multiple causes in which the thyroid fails to secrete an adequate amount of thyroid hormone
The most common thyroid disorder
Usually caused by primary thyroid gland failure
Also may result from diminished stimulation of the thyroid gland by TSH

22. Hyperthyroidism
Hyperthyroidism refers to excess synthesis and secretion of thyroid hormones by the thyroid gland, which results in accelerated metabolism in peripheral tissues.

23. Typical Thyroid Hormone Levels in Thyroid Disease
TSH T T3
Hypothyroidism High Low Low
Hyperthyroidism Low High High

24. Hypothyroidism: Underlying Causes
Congenital hypothyroidism
Defective thyroid hormone biosynthesis due to enzymatic defect
Thyroid tissue destruction as a result of
Chronic autoimmune (Hashimoto) thyroiditis
Radiation (usually radioactive iodine treatment for thyrotoxicosis)
Thyroidectomy
Other infiltrative diseases of thyroid (eg, hemochromatosis)
Drugs with antithyroid actions (eg, lithium, amiodarone ,radiographic contrast agents, interferon alpha)

25. Clinical Features of Hypothyroidism
Enlarged thyroid (goiter)
Impairment of Physical& Mental activity
Slowing of Cardio vascular, gastrointestinal & neuromuscular function.
Complaints of lethargy, cold intolerance, weight gain & constipation.
Menstrual irregularities.
Hoarseness or deepening of voice.
Skin may become coarse, dry & cold
Myxedema –dry waxy swelling of skin.

26. Treatment for Hypothyroidism
Replacement therapy with a thyroid hormone preparation

27. Hyper Thyroidism Underlying Causes
Signs and symptoms can be caused by any disorder that results in an increase in circulation of thyroid hormone
Toxic diffuse goiter (Graves disease-thyroid gland stimulation by thyroid antibodies)
TSH secreting pituitary adenoma
Inflammatory thyroid disease
Increased uptake of Iodine and iodine-containing drugs and radiographic contrast agents.
Exogenous thyroid hormone ingestion

28. Clinical Features of Hyperthyroidism
Nervousness
Emotional liability
Weight loss
Heat intolerence
Palpitations/tachycardia
Menstrual irregularities
Frequent bowel movements.

29. Treatment for Hyperthyroidism
Anti-thyroid agents
Surgery
RAI (Radio Active Iodine )treatment.

30. Hormone Preparations
Levothyroxine(T4)
Liothyronine (T3)

31. Levothyroxine(T4) Drug of choice for patients with hypothyroidism.
Oral bioavailability 80%
Half life 7 days –once daily admistration.
35% of T4 is converted to T3 in peripheral tissues.
Indications :
Hypothyroidism
Prevention of mental retardation in newborns with thyroid deficiency
Myxedema coma
Suppressive therapy in patients with thyroid nodules, diffuse goiter & thyroid cancer

32. interfere with absorption
Adverse effects :
Tachycardia, heat intolerence, tremors
Interactions :
Aluminium hydroxide
Cholestyramine
Ferrous sulfate
Sucralfate
These drugs should be administered 2 hrs before or after levothyroxine is administered
interfere with absorption

33. Liothyronine More potent than levothyroxine
Higher oral bioavailability (95%)
Shorter half life –multiple daily doses (1-3)
More cardiac adverse effects
More expensive.

34. Anti Thyroid agents Thiourea drugs - Methimazole - Propylthiouracil
Beta-adrenergic receptor antagonists
- Propranolol
Other antithyroid agents
- Potassium iodide solution
- Sodium Iodide I 131

35. Methimazole &Propylthiouracil
MOA : Both inhibits peroxide catalyzed iodination & coupling of the thyroglobulin molecule.
In addition propyl thiouracil inhibits the conversion of T4 to T3 in peripheral tissues.
Both are therapeutically equivalent.
Methimazole half life -7 hrs
P ropyl thiouracil half life -2 hrs
Both drugs crosses placenta – caution in pregnancy.
Effects of these drugs are delayed because it takes 4-8 weeks of therapy to deplete glandular hormone stores.

36. Adverse effects :Arthralgia,pruritic maculopapular rashes,lupus erythematosus-like syndrome, GI distress.
Severe agranulocytosis usually develops during the first 3 months.
Patient advised to stop drug immediately if they experience fever,malaise,sore throat or flu like symptoms.
Both drugs exhibit cross-sensivity.

37. Beta-adrenergic receptor antagonists
Thyroid hormones & sympathetic nervous system act synergistically on CVS.
Propranolol used to reduce cardiovascular stimulation associated with hyperthyroidism.
Useful during severe acute thyrotoxicosis(thyroid storm)
Control the symptoms of hyper thyroidism in patients awaiting surgery.

38. Iodide salts KI solution
Short term basis to treat patients with acute thyrotoxicosis,to prepare patients for thyroid surgery & to inhibit the release of thyroid hormones during RAI treatment.
MOA : iodide salts act immediately to inhibit the release of thyroid hormones from thyroid gland.
Symptomatic improvement within 2-7 days.
Administerd to reduce the size & vascularity of the thyroid gland. (7-14 days prior to surgery)

39. Adverse effects :
Skin rashes,salivary gland swelling,hypersensitivity reactions,metalic taste ,sore gums & GI discomfort.

40. Radoiactive Iodine
I 131 rapidly absorbed from gut & concentrated by the thyroid gland.
MOA : it emits beta particles that destroy thyroid tissue.
Half life -8 days
RAI treatment contraindicated in pregnant women.
Adverse effect : high incidence of delayed hypothyroidism.