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

Anatomy Over Trachea Two Lobes connected together by an isthmus

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)

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.

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

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 70-90 g of T4 per day T3 is derived from 2 processes The total daily production rate of T3 is about 15-30 g About 80% of circulating T3 comes from deiodination of T4 in peripheral tissues. About 20% comes from direct thyroid secretion

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.

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

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

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 T4 4.5-11 g/dL T3 60-180 ng/dL (~100-fold less than T4)

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

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

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

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

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)

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

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.

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

Thyroid Disorders Hypothyroidism Hyperthyroidism

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

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

Typical Thyroid Hormone Levels in Thyroid Disease TSH T4 T3 Hypothyroidism High Low Low Hyperthyroidism Low High High

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)

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.

Treatment for Hypothyroidism Replacement therapy with a thyroid hormone preparation

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

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

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

Hormone Preparations Levothyroxine(T4) Liothyronine (T3)

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

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

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

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

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.

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.

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.

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)

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

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.