Pharmaevals10 Thyroid

LA SALLIAN Pharmacology: TREATMENT

2016

OF THYROID DISORDERS

01.21.2014

Lecturer:

THYROID PHYSIOLOGY The normal thyroid gland secretes sufficient amounts of the thyroid hormones— triiodothyronine (T3 ) and tetraiodothyronine (T4 , thyroxine) —to normalize growth and development, body temperature, and energy levels. These hormones contain 59% and 65% (respectively) of iodine as an essential part of the molecule. The colloid is surrounded by follicular cells wherein the synthesis of thyroid hormone occurs.

---- IODIDE, ANION INHIBITORS

---- THIONAMIDES, IODIDE

---- THIONAMIDES

---- IODIDE

---- PROPYLTHIOURACIL

STEPS IN HORMONE SYNTHESIS

ROLE OF IODINE

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Iodide uptake Active transport via sodium-iodide symporter (NIS) in the follicular cells This iodide enters the follicular lumen from the cytoplasm by the transporter pendrin 2. Oxidation and Iodination aka organification Oxidation of Iodide to its active form by thyroid peroxidase {this enzyme is inhibited by THIONAMIDES} formation of mono-iodomono-iodo-tyrosine tyrosine and  and di-iododi-iodotyrosine residues tyrosine residues in thyroglobulin 3. Formation of Thyroxine and Triiodothyroni Triiodothyronine ne coupling of 2 diiodotyrosine residues to form Thyroxine (T4) [2+2=4] coupling of 1 monoiodotyrosine residue and 1 diiodotyrosine residue to form Tri-iodoTri-iodo-thyronine thyronine (T3) which occurs in the thyroglobulin [1+2=3] these molecules are endocytosed endocytosed by  by the follicular cell Most of the synthesized hormone is T4 and only 20% is T3 T3 is the transcriptionally (biologically) active iodothyronine T3 is also generated by the 5’-deiodination of Thyroxine 4. Secretion of Thyroid hormones proteolysis of proteolysis  of thyroglobulin  release of thyroid hormone from follicle into the blood some are recycled to undergo the process again, while the rest is released immediately to the bloodstream deiodination of T4 in the peripheral tissues accounts for about 80% of circulating T 3 

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Normal thyroid function requires adequate intake of Iodine Simple or nontoxic goiter results because of inadequate dietary intake of Iodine Iodine deficiency increases TSH secretion which in turn results in hyperplasia and hypertrophy of the thyroid gland; also iodine deficiency stimulates the hypothalamus, via negative feedback, to release TRH which then stimulates anterior pituitary to secrete TSH

THYROID DISORDERS Hypothyroidism Common cause is Iodine deficiency (usually in

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mountainous regions e.g., Himalayas)

Hyperthyroidism Most common cause is Graves Disease (autoimmune disorder)

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GOITER 

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swelling in neck due to thyroid hypertrophy both hypo and hyperthyroidism

THYROID HORMONE PREPARATIONS    

Levothyroxine sodium (T4) Liothyronine sodium (T3) Liotrix (T4/T3) Dessicated Thyroid

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LA SALLIAN THYROID HORMONES MECHANISM OF ACTION deiodinated

T3

2016 PHARMACOLOGIC ACTIONS Normal growth and development

T4

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Binds to a transcription factor linked receptor inside the nucleus

Central nervous system

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Increased synthesis of RNA 

Increased synthesis of proteins Metabolism

TWO TYPES THYROID HORMONE RECEPTORS

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There are two genes that en code Thyroid Hormone Receptors: THRA encodes the receptor TRα1 and TRα2 THRB encodes the receptor TRβ1 and TRβ2

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TRα1

major specific roles in the regulation of heart rate, body temperature, skeletal muscle function, and the development of bone and small intestines

TRβ1

TRβ2

demonstrates a specific role in liver metabolism and

role in the negative feedback by T3 hypocholesterolemic on hypothalamic effect of T3 TRH and pituitary TSH and in the development of cones in the retina and inner ear

Thermogenic

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Cardiovascular

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Reproduction

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LEVOTHYROXINE SODIUM     

PHARMACOKINETICS available in tablet and lyophilized powder for injection (INTRAVENOUS route only) oral bioavailability ranges from 40 to 80%. majority absorbed in the jejunum and upper ileum DECREASED absorption with food, antacids, iron, sucralfate, cholestyramine highly (99.96%) bound to serum proteins: thyroxine-binding globulin –TBG (70%) majority! transthyretin or thyroxine-binding pre-albumin (20%) albumin (10%) increase dose requirement in pregnancy due to estrogen-induced increase in TBG major pathway of metabolism is sequential DEIODINATION (by deiodinases) to T3 and reverse T3 (inactive) {refer to the table and diagram in the next page} also undergo glucuronide and sulfate conjugation → biliary excretion → enterohepatic recirculation 40% of T4 is converted each to T3 and rT3 20% is metabolized by sulfate and glucuronide conjugation in the liver conjugated metabolites are excreted in the bile and feces thyroid hormones are primarily excreted through the kidneys approximately 20% of T4 is eliminated in the stool average elimination half-life 6 to 7 days full therapeutic effects in 4 to 6 weeks CLINICAL INDICATIONS long-term replacement or suppressive therapy suppression therapy post-surgery for thyroid cancer  ▫

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available in tablet and injectable form (INTRAVENOUS route only)

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essential for proper development and differentiation of all cells in the human body synergistic with effects of growth hormone critical role in neuronal development deficiency up to 6 months postpartum leads to irreversible mental retardation thyroid hormone supplementation during the first 2 weeks of postnatal life prevents mental retardation increase protein synthesis complex effects on carbohydrates stimulates the expression of hepatic low-density lipoprotein (LDL) receptors and the metabolism of cholesterol to bile acids ↓ Total cholesterol; ↓ LDL- C increase heat production increase oxygen consumption increase basal metabolic rate directly regulates myocardial gene expression (+) Lusitropic (myocardial relaxation) effect, Inotropic effect (contractility), Chronotropic effect (heart rate) vasodilatation enhanced responsiveness of myocardial β receptors to circulating catecholamines follicular development and ovulation in the female spermatogenesis in the male maintenance of pregnancy

LIOTHYRONINE SODIUM (T3)

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↑ protein synthesis

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oral bioavailability is almost 100% peak plasma concentration in 2-4 hrs 99.7% protein bound but not firmly metabolized in the liver to deiodinated and conjugate metabolites

excretion through the urine and feces Half-life: 24 hours maximum response in 2-3 days

rapid replacement therapy in myxedema coma preparation of a patient for 131I therapy for treatment of thyroid cancer 

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LA SALLIAN THREE DEIODINASES FOUND IN HUMANS TYPE 1 (DIO1) found mainly in the liver and kidney

can remove iodine in both rings

TYPE 2 (DIO2) found mainly in skeletal muscle and in the heart, fat, thyroid, and central nervous system can induce deiodination in the outer ring, making it the main activating enzyme

TYPE 3 (DIO3) found in the brain, fetal tissue and placenta

2016 TREATMENT OF HYPERTHYROIDISM   

PHARMACOLOGIC AGENTS 

induces deiodination in the inner ring only and, thus is the main inactivating enzyme

Pharmacologic agents Radioactive Iodine Surgery

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THIONAMIDES Propylthiouracil Carbimazole Methimazole / Thiamazole

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IODIDE Lugol’s solution KISS

BETA BLOCKERS Propranolol Metopr olol

IONIC INHIBITORS Thiocyanate Pertechnetate Perchlor ate

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CORTICOSTEROIDS Dexamethasone Prednisone Hydrocortisone

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DRUGS THAT DECREASE T3 LEVELS

DIFFERENCES BETWEEN T3 AND T4 PREPARATIONS Cost Absorption Onset Half-life Adverse effects

T3 expensive 95 -100% rapid 24 hours more

T4 less expensive 40 – 80% gradual 7 days less

THIONAMIDES PROPYLTHIOURACIL MECHANISM OF ACTION 

CLINICAL INDICATIONS OF THYROID HORMONES 1. 2. 3.

Myxedema coma Cretinism Nodular thyroid disease TSH suppressive therapy 6-12 months 4. Adjunct therapy for Thyroid cancer  

ADVERSE EFFECTS OF THYROID HORMONES 1. 2.

Increased risk for atrial fibrillation Signs and symptoms of hyperthyroidism Tachycardia increased sweating insomnia nervousness tremors Increased risk of osteoporosis     

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HYPERTHYROIDISM HYPERTHYROID STATES 

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associated with Graves Disease, Thyroid cancer, toxic nodular goiter, thyrotoxicosis, thyroid storm excessive release of thyroid hormones due to hyperfunctioning gland

GRAVES DISEASE  

most common cause of hyperthyroidism Triad of Hyperthyroidism, Ophthalmopathy, and Dermopathy Smoking is a risk factor for worsening ophthalmopathy! ▫

inhibits thyroid hormone synthesis by inhibition of thyroid peroxidase inhibition of iodine organification inhibition of coupling of iodotyrosine residues decreases TSH receptor-stimulating antibody (TSH RAB) levels (Immunosuppressive action) inhibits 5’- Monodeiodinase I inhibit peripheral conversion of T4 to T3  

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this action is limited with Methimazole

PHARMACOKINETIC DIFFERENCES BETWEEN THIONAMIDES PTU

METHIMAZOLE 5 mg and 20 mg 10 mg and 30 mg almost 100% 4-6 hrs. 24 hrs (30 mg) Minimal

Preparation 50 mg (Tablet) Oral bioavailability 50-80% Half-life: plasma 75 min. Thyroid gland 7 hrs Protein binding ~75% Frequency of Every 6-8 hrs OD or BID administration (TID) Onset of Action of Thionamides is 3 – 4 weeks.

ADVERSE EFFECTS OF THIONAMIDES Skin rashes

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Agranulocytosis (perform baseline CBC!)

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Arthralgias, Paresthesias Antineutrophilic cytoplasmic antibodies (ANCA) positive vasculitis Liver failure

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most common; 4-6% usually mild most serious 0.44% with PTU 0.12% with Methimazole occur in ~ 50% of patients receiving PTU rarely with Methimazole children, pregnant females greater risk with PTU Page 3 of 5

LA SALLIAN METHIMAZOLE

ANION INHIBITORS

use is associated with a very rare teratogenic syndrome termed “Methimazole embryopathy,” which is characterized by choanal or esophageal atresia occurred in 2 of 241 children of women exposed to Methimazole, as compared with the spontaneous rate of 1 in 2500 to 1 in 10,000 for esophageal atresia and choanal atresia, respectively

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INDICATIONS OF THIONAMIDES 1.

Definitive Treatment of Grave’s disease small goiter; mild hyperthyroidism pregnant females 2. Adjunct to radioactive iodine/RAI therapy 3. In preparation of patients for Thyroid surgery 4. Thyroid crisis / storm

MEMBERS  

inhibitor of Sodium Iodide symporter interfere with the concentration of Iodide by the thyroid gland

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BETA RECEPTOR ANTAGONISTS WITHOUT ISA ISA – Intrinsic Sympathomimetic Activity 

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SATURATED SOLUTION OF POTASSIUM IODIDE (KISS) Contains 50 mg Iodine per drop

ACTIONS decreases the enhanced sensitivity of cardiac myocytes to catecholamines reduction of sympathetic manifestations of hyperthyroidism inhibition of peripheral conversion of T4 to T3

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LUGOL’S SOLUTION

contains 8 mg Iodine per drop

DOSE 100 -300 mg/day in 3 divided doses

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INDICATIONS As adjunct to Thioamides and RAI therapy in: Neonatal thyrotoxicosis Pregnancy Thyroid storm/crisis Preoperative medication prior to thyroid surgery

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MECHANISM OF ACTION

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inhibit hormone release thru inhibition of thyroglobulin proteolysis (major action) inhibit Iodide transport (NIS/sodium-iodide symporter) inhibit hormone synthesis by inhibition of thyroid peroxidase – high doses (Wolff-Chaikoff Block) decrease vascularity, size, and fragility of hyperplastic thyroid gland  WOLFF-CHAIKOFF EFFECT

 Acute inhibition of the synthesis of iodotyrosines and iodothyronines by large doses of iodide

THERAPEUTIC USES 1.

2.

Treatment of thyroid storm/thyroid crisis in conjunction with Antithyroid drugs and Propranolol rapid effect (within 24 hrs) maximum effect in 10-15 days Preoperative preparation for thyroid surgery given 7-10 days prior to surgery Protect thyroid gland from radioactive iodine fallout

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CORTICOSTEROIDS DEXAMETHASONE ACTIONS inhibits peripheral conversion of T4 to T3 enhances production of rT3 (reverse T3)

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INDICATION Adjunct in the treatment of thyroid crisis and thyroiditis

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GOITROGENS

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3.

MAJOR DISADVANTAGES 1.

NOT recommended for long term use “escape” from Wolff –Chaikoff Effect NOT recommended in pregnancy iodide crosses the placenta and may cause fetal goiter

2. 3.

Thiocyanate containing or inducing agents Food (plant products) cabbage broccoli cassava lima beans cauliflower turnips Smoking Drugs Sodium nitroprusside Amiodarone 

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2.

Metoprolol Atenolol Propranolol Esmolol

PROPRANOLOL

IODIDE PREPARATIONS

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Perchlor ate Thiocyanate

MECHANISMS OF ACTION

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IODIDE

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ADVERSE EFFECTS Hypersensitivity

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angioedema, laryngeal edema drug fever, arthralgia, lymphadenopathy, eosinophilia fatal periarteritis nodosa Thrombotic thrombocytopenic purpura

“Iodine escape”

Iodism

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unpleasant brassy taste, increase salivation burning sensation in mouth and throat soreness of the teeth and gums coryza, sneezing swellling of the eyelids, irritation of the eyes

RADIOACTIVE IODINE 131 I 

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I

radioactive isotope used for treatment half-life: 8 days

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radioactive isotope used for diagnosis half-life: 13 hours

MECHANISM OF ACTION Rapid absorption and concentration in the thyroid 

incorporation into the iodoamino acids and deposited in the colloids of follicles 

Slow beta particle emission 

Thyroid parenchymal destruction Page 4 of 5

LA SALLIAN PHARMACOKINETICS

INDICATIONS FOR SURGERY

given orally rapidly absorbed and enters intracellular Iodine pool in the thyroid gland half-life is 8 days effects observed in 3-4 weeks

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Large diffuse goiter Failure of Anti-thyroid drugs Presence of contraindications to Antithyroid drugs or RAI therapy Suspicious/dominant nodule Patient’s preference

INDICATIONS OF RAI 1.

Hyperthyroidism Elderly patients CV disease 2. Recurrent hyperthyroidism (after subtotal thyroidectomy and prolonged antithyroid therapy) 3. Toxic nodular goiter 4. Large nontoxic multinodular goiter  

ADVANTAGES    

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proven efficacy easy to administer low expense does not require hospitalization patient is spared of the risk and discomfort of surgery non fatal

ADVERSE EFFECTS OF THYROIDECTOMY

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emorrhage oarseness (damage to the recurrent laryngeal nerve) ypothyroidism Hypoparathyroidism  Hypocalcemia

DISADVANTAGES 

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high risk of delayed hypothyroidism long period of time required to control hyperthyroidism risk of thyroid storm at initiation of treatment (since follicular cells are destroyed   release of thyroid hormones   thyroid storm)

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poor compliance to long term hormone replacement therapy salivary gland dysfunction risk for worsening ophthalmopathy

”Do all the good you can, By all the means you can, In all the ways you can, In all the places you can, To all the people you can, As long as ever you can. ”  –  JOHN WESLEY  – 

ADVERSE EFFECTS OF RAI 1. 2. 3.

Permanent hypothyroidism Potential for radiation-induced genetic damage Risk of malignancy leukemia, neoplasia 4. May precipitate thyroid crisis 

PRECAUTIONS 1.

Avoid prolonged contact with people, especially children and pregnant women 2. Do not share food and utensils, like glasses, dishes, bottles, water, etc. 3. Drink lots of water and other fluids, that help the radioactive iodine to pass out quickly from the body 4. Wash the laundry of the treated person separately 5. Stop breast feeding as the radioactive iodine is concentrated and excreted in the breast

CONTRAINDICATIONS pregnant women nursing mother patients