Thyroid Hormones and Thyroid Inhibitors - drdhriti

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A PowerPoint presentation on Thyroid hormones and related drugs suitable for reading by Undergraduate medical Students.

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Thyroid Hormones and Thyroid Inhibitors : 

Thyroid Hormones and Thyroid Inhibitors Department of Pharmacology NEIGRIHMS, Shillong

Learning Objectives : 

Learning Objectives Biosynthesis of Thyroid Hormones and their fates Physiological Roles of Thyroid Hormone Different deficiency states of Thyroid Hormone Drugs used as Thyroid inhibitors Pharmacology in relation to different thyroid disease states

Anatomy : 

Anatomy Over Trachea Two Lobes connected together by an isthmus 15 to 20 g

Thyroid gland : 

Thyroid gland Thyroid gland is composed over a million cluster of follicles Follicles are spherical & consists of epithelial cells surrounding a central mass (colloid) Thyroglobulin is storage room Normal thyroid gland secretes thyroid hormones Iodide containing Natural hormone compounds having biological activity L-Thyroxine (T4 or tetraiodo-L-thyroxine) Liothyronine (T3 or triiodo-L-thyronine)

Follicular Cells – the functional unit : 

Follicular Cells – the functional unit

T3 and T4 : 

T3 and T4 Thyroid gland normally secretes mainly T4 70 % of T3 derived from T4 in peripheral tissues T4 is converted to T3 by 5-deiodinase enzyme Both T4 and T3 are in bound form (TBG, pre albumin and albumin) Only 0.025% of T4 and 0.35% of T3 are free Free hormone concentration best correlates with thyroid status T4 production is 5-6 g/kg/day in infancy with gradual decrease to 1.5 g/kg/day in adult

T3 Vs T4 : 

T3 Vs T4 T3 is 5 times more potent > T4 T4 is the major circulating hormone – bound more to plasma proteins T4 is less active and a precursor of T3 - the major mediator of physiological effects The term thyroid hormone is used to comprise both T4 plus T3 Both forms are available for oral use

Thyroid Hormone Chemistry : 

Thyroid Hormone Chemistry 3,5,3`,5`-tetraiodothyronine 3,5,3` triiodothyronine T3 and T4 are iodine containing derivatives of thyronine which is a condensation product of 2 molecules of tyrosine

Thyroid Regulation : 

Thyroid Regulation Regulation of thyroid Function: Negative feedback by Thyroid hormone is Exercised directly on pituitary and hypothalamus

Thyroid Hormone - Biosynthesis : 

Thyroid Hormone - Biosynthesis Sea fish, eggs, milk - dietary sources of iodide, carried in plasma as inorganic iodide Daily Requirement for adult: 150μg (200 μg in pregnancy and lactation) Iodine denotes all form of the element and Iodide denotes only the ionic form (I ) Sources: Food, water or medication 75 μg is utilized daily for hormone synthesis 5 steps of synthesis: Iodide uptake or trapping Oxidation and iodination Coupling Storage and release Peripheral conversion of T4 to T3

Thyroid hormone synthesis : 

Thyroid hormone synthesis 1) Iodide uptake or pump Rate –limiting step in thyroid hormone synthesis which needs energy Follicles have in their basement membrane an iodide trapping mechanism which pumps dietary I - into the cell Normal thyroid: serum iodine is 30-40:1 Iodide uptake enhancers: TSH Iodine deficiency TSH receptors antibody Iodide uptake inhibitors Iodide ion Drugs Digoxin Thiocynate perchlorate

Thyroid hormone synthesis – contd. : 

Thyroid hormone synthesis – contd. 2) Iodide oxidation to iodine and Organification Inside the cells, iodide is oxidized by peroxidase system to more reactive iodine Iodine immediately reacts with tyrosine residue on a thyroid glycoprotein called “thyroglobulin” to form : T1= mono-iodotyrosyl thyroglobulin T2= di-iodotyrosyl thyroglobulin Both processes are catalyzed by thyroid peroxidase enzyme

Thyroid hormone synthesis – contd. : 

Thyroid hormone synthesis – contd. 3) Coupling T1& T2 couple together to form T3 & T4 MIT +DIT = T3 (Tri-iodothyronine) DIT + DIT = T4 (Thyroxin) Normally high amount of T4 is formed In case of Iodine deficiency more MIT is formed and hence more T3 – leading to more active hormone with less Iodine

Thyroid Hormone Production : 

Thyroid Hormone Production NIS (Na+/I- Sympoter) TPO

Storage and Release : 

Storage and Release MIT, DIT, T3 and T4 - all attached to thyroglobulin and stored in the colloid Thyroglobulin molecule This process is stimulated by TSH Taken up by follicular cells by the process of endocytosis and broken down by lisosomal proteases T3 and T4 released and also MIT and DIT MIT and DIT are deiodinated and reutilized T4 & T3 enter circulation directly from follicular cells Free (unbound) hormone is a small percentage, 0.03%T4 and 0.3%T3 of the total plasma hormone Only unbound form has metabolic activity

Peripheral Conversion : 

Peripheral Conversion Peripheral tissues – liver and kidney T4 to T3 1/3rd of t4 undergoes these changes and most of T3 available are derived from liver Equal amounts of T3 and rT3 are produced in periphery Drugs like Propylthiourcil, propranolol and glucocorticoids inhibit peripheral conversion

Transport, Metabolism and Excretion : 

Transport, Metabolism and Excretion Highly bound to plasma protein Only 0.4% of T3 and T4 are in free form All Protein Bound Iodine (PBI) in plasma is thyroid hormone – 95% is T4 Main Plasma proteins are – TGB, TBP and albumin Only free form of hormone is available for action and metabolism Metabolism occurs by deiodination and conjugation, mainly in liver and kidneys T4 is deiodinated to T3 (active) or rT3 (inactive) by deiodination Excreted in urine

Factors altering binding of T4to GTB : 

Factors altering binding of T4to GTB Increase Binding: Estrogens & Estrogen Receptors Modulators Methadone Clofibrate 5-FU Tamoxifen Liver disease HIV infection Porphyria Inheritance Decrease Binding: Glucocorticoids Androgen L-Asparaginase Salicylates Mefenamic acid Phenytoin Carbamazepine Frusemide Acute and chronic illness Inheritance

WHO/UNICEF Recommended daily iodine : 

WHO/UNICEF Recommended daily iodine Age group Iodine requirement(μg) Infants (0 -11mth) 50 Children (12 mnth - 59 mnth) 90 School age child (6-12 year) 120 Adults (above 12 year) 150 Pregnant & lactating women 200

Thyroid Hormones -Pharmacokinetics : 

Thyroid Hormones -Pharmacokinetics T4 –show elimination t1/2 6 to 8 days Hyperthyroidism t1/2 shortened 3 - 4 days During ↑ TBG binding, clearance ↓ T3 t1/2 is 1day T4 & T3 conjugation in liver and entero-hepatic circulation T4 deiodination to T3 or reverse T3 T3 & reverse T3 deiodination to three di-iodothyronines, deiodinated to two monoiodothyronines - (inactive)

Relation of Iodine to Thyroidfunction : 

Relation of Iodine to Thyroidfunction Iodine essential for thyroid hormone Excess TSH, thyroid hyperplasia, hypertropic Adult hypothyrodism and cretinism occurs in severe iodine deficiency Daily adult require 1 to 2 μg / Kg / day. Iodine used for iodine-deficiency goiter – 150 years Iodine or iodate added to table salt (iodized salt) 100 μg of iodine per gram

Actions of thyroid hormones : 

Actions of thyroid hormones T3 binds to high affinity receptors Three thyroid hormone receptor:- TRβ1,TRβ2, TRα1, binds to DNA sequence in specific genes T3 modulates gene transcription and protein synthesis T4 binds with lower affinity than T3 but does not alter gene transcription T3 causes all actions of thyroid hormones at transcriptional level

Actions – contd. : 

Actions – contd. Growth and development Normal growth and development of organism DNA transcription, critical control of protein synthesis and translation of genetic code T3 – Tadpole to frog transformation Brain development Irreversible mental retardation (cretinism) in absence of thyroid hormones during active neurogenesis (upto 6 month postpartum) Severe morphological alteration in brain Supplementation during first 2 weeks of life prevent development of brain changes

Actions – contd. : 

Actions – contd. Metabolism: Lipid: Induce lipolysis (catecholamines), ↑ free plasma fatty acid and all phases of cholesterol metabolism enhanced (bile acid more) Hyperthyroidism – hypercholesterolemia Carbohydrate:Stimulation of carbohydrate metbolism, glycogenolysis, gluconeogenesis Hyperthyroidism – diabetes-like state Protein: Certain protein synthesis increased but overall catabolic action – negative nitrogen balance Hyperthyroidism – Weight loss and wasting

Actions – contd. : 

Actions – contd. Calorigenic & CVS Effects T3 and T4 increases BMR by stimulation of cellular metabolism – maintenance of body temperature Brain, gonads and spleen unresponsive to calorigenic effects Hyperdynamic state of circulation - due to direct CVS action and ↑ peripheral demand Hyperthyroidism: tachycardia, ↑ SV, ↑ TPR Hypothyrodism: bradycardia, ↓ cardic index, pericardial effusion , ↓ TPR, ↓ PP Others: Nervous system – mental retardation, GIT – Increased gut motility, Haematopoiesis – anaemia

Therapeutic Uses : 

Therapeutic Uses As Replacement therapy in deficiency states Available as l-thyroxine sod. 100, 50, 25 mcg tablets Liothyronine is available as 5, 25 mcg tabs and Injection Mixture of T3 and T4 tablets T4-consistent potency and prolonged duration ofaction. 50% - 80% GIT absorption. T3 for quicker onset of action as in myxedema coma or preparation of a patient for I131 therapy in thyroid cancer

Thyroid hormone replacementtherapy : 

Thyroid hormone replacementtherapy Reevaluation: S/TSH conc. not less than 4-6 weeks Goal - achieve S/TSH value in normal range. Over-replacement may ↓ TSH Non compliant young patients – cumulative weekly dose of T4 as single dose Over 60 yrs – lower dose of T4 25 μg / day ↑ dose 25 μg every few months until TSH normalized Cardiac patients: T4 12.5 μg / day, ↑ T4 12.5 to 25 μg / day every 6 to 8 weeks

Cretinism : 

Cretinism Endemic or sporadic Endemic - extreme iodine deficiency Sporadic – failure of thyroid to develop normally or defective hormone synthesis Detectable at birth, may not be recognized until 3-5 mths of age Dwarfism ,mental retardation, short extremities, inactive, listless, puffy & expressionless face, enlarged tongue, skin yellow, dry & cool, bradycardia, low body temp., late teeth eruption, delayed closure of fontanelle Poor appetite, feeding slow, constipation, umbilical hernia Iodine replacement institution prior to pregnancy till end of 2nd trimester

Cretinism - treatment : 

Cretinism - treatment T4 10-15 μg/kg daily T4 levels normalize within 1-2 weeks Adjust dosage at 4-6 weeks in first 6 months and then at 2 month during 6 to 18 month. Thereafter, 3 - 6 month to maintain T4 10 -16 μg/dL and TSH normal range

Adult Hypothyroidism : 

Adult Hypothyroidism Causes: thyroiditis or thyroidectomy Drugs: I131, iodides, lithium and amiodarone May be simple goitre or idiopathic Face: expressionless, puffy, pallid Skin: cold, dry, scaly scalp Hair: coarse, brittle, sparse Fingernails: thickened, brittle Voice: husky, low pitched, slow speech Poor appetite, constipation Voluntary muscles weak and relaxation of deep tendon reflexes delayed Dilated heart, pericardial effusion, ascites, Hyperlipidemia, anaemia Cold intolerance (Subclinical hypothyroidism)

Myxoedema Coma : 

Myxoedema Coma Severe, long-standing hypothyroidism Serious medical emergency, mortality rate high (60%) despite early diagnosis and treatment Elderly patient during winter months Pulmonary infections, CVA, CHF precipitate coma. Sedative, narcotics, antidepressants and tranquillizers Profound hypothermia, respiratory depression, unconscious, bradycardia, delayed reflexes, dry skin Estimate S/free thyroxine index & TSH LP – High proteins

Myxoedema Coma - treatment : 

Myxoedema Coma - treatment Ventilatory support Rewarming Correct hyponatremia IV steroid IV T4 (200 – 300 μg) bolus IV T4 (100 μg ) after 24 hrs Oral T4 (500 μg) < 50 yrs plus inj.T3 IV 10 μg 8 hrly. till patient is conscious Do not exceed T4 > 500 μg / day or T3 > 75 μg / day

Other Uses : 

Other Uses Nontoxic Goitre: May be endemic or sporadic T4 replacement with maintenance dose Thyroid nodule Papillary carcinoma of thyroid

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, apprehension Heat intolerance Diarrhea Angina, arrhythmia and heart failure Muscular wasting, thyroid myopathy Untreated thyrotoxicosis - osteoporosis

Drugs – Thyroid Inhibitors : 

Drugs – Thyroid Inhibitors 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)

Antithyroid Drugs : 

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 : 

Propylthiouracil Vs Carbimazole

Antithyroid Drugs – contd. : 

Antithyroid Drugs – contd. 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 t1/2 is longer Preparation: PTU – 50 mg tabs., Methimzole – 5 & 10 mg tbs. and Carbimzole – 2.5/5 mg tabs.

Adverse effects : 

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

Clinical uses - antithyroid : 

Clinical uses - antithyroid Hyperthyroidism: Principal therapy Adjuvant to radioiodine to control disease To prepare patient for surgery Clinical improvement 2 to 4 wk Euthyroid 4 to 6 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 Related to dose and thyroid status Hyperthyroidism- moderate excess of iodine ↑ synthesis Substantial excess inhibits hormone release, promote storage, gland firm, vascularity ↓ Euthyroid- excess iodine causes goiter, hard nodule become hypothyroid Sources of excess- iodine containing cough medicines, iodine containing radiocontrast media, amiodarone

Clinical uses : 

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 Radiocontrast media using IV test dose For treatment: 5-10 millicuri(mci) orally For diagnosis: 50-100 microcuri

ADRs - Iodine : 

ADRs - Iodine 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

Radioiodine (I131) : 

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: : 

Disadvantages: Iodism Hypothyroidism Long latent period of response Contraindicated in pregnncy Young patients are contraindicated – lifelong therapy of T4

Beta Blockers : 

Beta Blockers In hyerthyroidism - increased tissue sensitivity to catecholamine Palpitation, tremor, nervousness, sweating, myopathy and sweating Increased second messenger i/c cAMP responses Do not alter course of disease and thyroid function tests Used in: Preoperative therapy with Iodine Awaiting response to carbimazole Propranolol 20 – 80 mg 6-8 Hrly

Thyroid storm or crisis : 

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

Thyroid storm or Crisis - Treatment : 

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

Must Know : 

Must Know Biosynthesis of Thyroid Hormone Physiological Effects of Thyroid Hormone Clinical uses of thyroid Hormone Antithyroid Drugs - carbimazole Pharmacotherapy of hyperthyroidism Short Questions: Beta blockers in hyperthyroidism Role of iodine in hyperthyroidism Radioactive iodine (I 131) Thyroid storm or crisis

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