Thyroid & Antithyroid Drugs

1. Thyroid & Antithyroid Drugs Dept. of Pharmacology, CIPS

2. Introduction: • Thyroid releases T3 & T4 • The ratio of T4 to T3 is 5:1, so most of the hormone released is thyroxine • Most of the T3 in the blood is derived from thyroxine • T3 is three to four times more potent than T4 • The affinity of the receptor site for T3 is about ten times higher than that for T4 Physiological actions of thyroid hormones • To normalize growth and development, body temperature, and energy levels • Insufficiency→ cretinism (infant & child), and myxedema (adult); • Excess→hyperthyroid • To enhance CNS excitability & sensitivity of CVS to NA

3. Synthesis of thyroid hormones Thyroid hormones triiodothyronine (T3) tetraiodothyronine (T4, thyroxine) Materials iodine & tyrosine Steps: 1. Iodide is trapped by sodium-iodide symporter 2. Iodide is oxidized by thyroidalperoxidase to iodine 3. Tyrosine in thyroglobulin is iodinated and forms MIT & DIT 4. Iodotyrosines condensation MIT+DIT→T3; DIT+DIT→T4

8. hyperthyroid cretinism myxedema

9. Thyroid hormone activation of target cells: • Thyroxine (T4) and triiodothyronine (T3) readily diffuse through the cell membrane. • Much of the T4 is deiodinated to form T3, which interacts with the thyroid hormone receptor, bound as a heterodimer with a retinoid X receptor, of the thyroid hormone response element of the gene. • This causes either increases or decreases in transcription of genes that lead to formation of proteins, thus producing the thyroid hormone response of the cell. • The actions of thyroid hormone on cells of several different systems are shown. mRNA, messenger ribonucleic acid. Thyroid drugs Representative drugs • levothyroxine (L-T4, levoxyl, synthroid) • liothyronine (T3, cytomel, triostat) • liotrix (T4 plus T3) (euthyroid, thyrolar)

11. Pharmacokinetics • po easily absorbed; the bioavailablity of T4 is 80%, and T3 is 95%. • Drugs that induce hepatic microsomal enzymes (e.g., rifampin, phenbarbital, phenytoin, and etc) improve their metabolism. • Levothyroxineis the choice drug for hypothyroidism • T4 is converted to T3intracellularly so levothyroxine produces both hormones • If angina pectoris or cardiac arrhythmia develops, it is essential to stop thyroxineimmediately Clinical use: • Hypothyroidism:cretinism & myxedema; • simple goiter: for pathogenisis remaining unclear Adverse reactions • Overmuch leads tothyrotoxicosis; • Angina or myocardial infarction usually appears in ageds

12. Thyroid Inhibitors: • Thyroid Inhibitors Drugs which are used to lower the functional capacity of hyperactive thyroid gland • Thyrotoxicosis: Grave`s disease and toxic nodular goitre • Signs & Symptoms: Skin flushed, warm, moist muscles weak, Heart rate rapid, heart beat forceful, bounding arterial pulses ↑ energy expenditure & appetite, loss of weight, Insomnia, anxiety, heat intolerance, Diarrhea, Angina, arrhythmia and heart failure, Muscular wasting, thyroid myopathy • Untreated thyrotoxicosis - osteoporosis • Inhibit Hormone synthesis (Antithyroid Drugs): • Propylthiouracil, Carbimazole, Methimazole • Ionic Inhibitors: • Thiocyanates(-SCN), Perchlorates (-ClO4), Nitrates (-NO3) • Inhibits Hormone release: • Iodine, Iodides of Na and K, Organic Iodide • Destroy Thyroid tissue: Radioctive Iodine (131, 125, 123)

13. Antithyroid Drugs: • Reduce formation of thyroid hormone Inhibit oxidation and oraganifiction of iodine – bind to thyroid peroxidase Inhibit coupling of iodotyrosines to form T4 and T3 • Result in intrathyroidal iodine deficiency Maximum effect delayed until existing hormone stores exhausted • High dosage leads to hypothyroidism Propylthiouracil inhibits peripheral conversion of T4 to T3 at high doses used in thyroid storm • Propylthiouracil Vs Carbimazole:

14. Pharmacokinetics: • Orally absorbed well, widely distributed in the body and crosses placenta and enter milk Metabolized in liver and excreted in urine • All are concentrated in thyroid and intrathyroid t½ is longer • Preparation: PTU – 50 mg tabs., Methimzole – 5 & 10 mg tbs. and Carbimzole – 2.5/5 mg tabs. • Adverse effects : • Major: Agranulocytosis, Thrombocytopenia, Acute hepatic necrosis, Cholestatic hepatitis, Vasculitis, Lupus-like syndrome • Minor: Rashes, urticaria, arthralgia, fever, anorexia, nausea, taste and smell abnormalities • Monitor ADR: Blood disorder- first two months of treatment Routine leucocytes counts, Patient advised to stop drugs if symptoms of sore throat, fever, mouth ulcers develop and have leucocytes count performed If agranulocytosis develops – withdraw drug, hospitalization

15. Clinical uses : • Hyperthyroidism: Principal therapy Adjuvant to radioiodine to control disease • To prepare patient for surgery Clinical improvement 2 to 4 wk • Guide to therapy-decrease nervousness, palpitation, increase strength and weight gain and pulse rate • Optimal treatment- decreased gland size Iodine: • Iodine Iodide well absorbed • Selective uptake and 25 times conc. by thyroid • Iodide deficiency ↓ thyroid hormones Hyperplasia, increased vascularity and goiter • Effects related to dose and thyroid status • Hyperthyroidism- moderate excess of iodine ↑ synthesis • Substantial excess inhibits hormone release, promote storage, gland firm, vascularity ↓ Euthyroid

16. Clinical uses: • Large doses for thyroid crisis • Preparation for thyroidectomy KI 60 mg orally 8 hrly produces effects in 1-2 days, maximal 10-24 days KI for 3 days to cover I132 or I123 isotopes • Prophylaxis of endemic cretinism –inj. Iodized oil IM 3-5 years • Antiseptic on skin / surgical scrub, expectorant ADRs : • IODISM- metallic taste, hypersalivation, running eyes and nose, sore throat, cough, diarrhea, skin rashes • Prolonged use- goiter and myxoedema Goiter in asthmatics Neonatal hypothyroidism with topical iodine Flaring of acne

17. Radioiodine (I131): • Swallowed I131 trapped and conc. in thyroid follicles • 90 % Beta radiation (upto 0.5 mm) • Gamma radiation- deep penetration • Radioactive half life 8 days • Used in diffuse toxic goiter (Thyrotoxicosis/Grave’s disease), toxic nodular goiter, thyroid carcinoma • Diagnosis of thyroid disorder • Contraindication- pregnancy, lactation, children • Beneficial effects within one month • Maximal effects –3 months • Life long follow-up • Review at 6 weeks • Add antithyroid drugs and beta-blocker in relapsing thyrotoxicosis Disadvantages: : • Iodism • Hypothyroidism • Long latent period of response • Contraindicated in pregnncy • Young patients are contraindicated – lifelong therapy of T4

18. Beta Blockers: • In hyerthyroidism - increased tissue sensitivity to catecholamine • Palpitation, tremor, nervousness, sweating, myopathy and sweating • Increased second messenger cAMPresponses • Do not alter course of disease and thyroid function tests • Used in: • Preoperative therapy with Iodine • Awaiting response to carbimazole • Propranolol20 – 80 mg 6-8 Hrly Thyroid storm or crisis: • A sudden exacerbation of symptoms of thyrotoxicosis, characterized by fever, sweating, tachycardia, extreme nervous excitability, and pulmonary edema • Life-threatening emergency • Large amount of hormone into circulation occurs in untreated or incompletely treated patient. • Precipitated by infection, trauma, toxemia of pregnancy

19. Thyroid storm or Crisis - Treatment: • Inj. Propranolol IV, slow, 1mg / min. to max. 10 mg followed by 40-80 mg oral every 8 Hrly • Propylthiouracil- large doses 300-400 mg 4-6 Hrly • Potassium Iodide 600 mg to 1 g orally in first 24 hr to inhibit hormone release or Ipanoic acid/ipodate (radioiodine) • Hydrocortisone 100 mg 8 Hrly IV followed by oral prednisolone • Hyperthermia – cooling and aspirin • Heart failure- conventional treatment • Diltiazem: 60-120 mg BD oral Thyroid malfunction and Pregnancy • In a pregnant hypothyroid patient, it is extremely importantthat the dose of thyroxine be adequate. • This is because early development of the fetal brain depends on maternal thyroxine • If thyrotoxicosis occurs, propylthiouracil is used and an elective subtotal thyroidectomy performed

20. Thank you