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

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

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

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

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

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

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

Thyroid Gland-Structure

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

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

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.

Synthesis & secretion of thyroid drugs

4/27/2017

MOA- of T3 & T4

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

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

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

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 t1/2 -5-7 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

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,

4/27/2017

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

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

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)

Hyperthyroidism Graves’ disease Toxic uninodular & multinodular goiters

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.

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

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

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

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

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:

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

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)

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

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

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

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

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

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

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

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

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

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)

THANK YOU !