MD 2016 Pharmacology: TREATMENT OF THYROID DISORDERS

LA SALLIAN

01.21.2014

Lecturer: Maria Luisa D. Dela Cruz, MD

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

1. 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 Oxidation and Iodination aka organification Oxidation of Iodide to its active form by thyroid peroxidase {this enzyme is inhibited by THIONAMIDES} formation of mono-iodo-tyrosine and di-iodotyrosine residues in thyroglobulin Formation of Thyroxine and Triiodothyronine coupling of 2 diiodotyrosine residues to form Thyroxine (T4) [2+2=4] coupling of 1 monoiodotyrosine residue and 1 diiodotyrosine residue to form Tri-iodo-thyronine (T3) which occurs in the thyroglobulin [1+2=3] these molecules are endocytosed 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 Secretion of Thyroid hormones 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 T3

ROLE OF IODINE
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

2.

3.

THYROID DISORDERS
Hypothyroidism Common cause is Iodine deficiency (usually in
mountainous regions e.g., Himalayas)

Hyperthyroidism Most common cause is Graves Disease (autoimmune disorder)

GOITER
swelling in neck due to thyroid hypertrophy both hypoand hyperthyroidism

THYROID HORMONE PREPARATIONS

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

4.

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MD 2016
PHARMACOLOGIC ACTIONS
protein synthesis essential for proper development and differentiation of all cells in the human body synergistic with effects of growth hormone Central nervous critical role in neuronal development system 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 Metabolism 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 Thermogenic increase heat production increase oxygen consumption increase basal metabolic rate Cardiovascular directly regulates myocardial gene expression (+) Lusitropic (myocardial relaxation) effect, Inotropic effect (contractility), Chronotropic effect (heart rate) vasodilatation enhanced responsiveness of myocardial receptors to circulating catecholamines Reproduction follicular development and ovulation in the female spermatogenesis in the male maintenance of pregnancy Normal growth and development

THYROID HORMONES MECHANISM OF ACTION T3

deiodinated

T4

Binds to a transcription factor linked receptor inside the nucleus Increased synthesis of RNA Increased synthesis of proteins

TWO TYPES THYROID HORMONE RECEPTORS

There are two genes that encode Thyroid Hormone Receptors: THRA encodes the receptor TR1 and TR2 THRB encodes the receptor TR1 and TR2 TR1 major specific roles in the regulation of heart rate, body temperature, skeletal muscle function, and the development of bone and small intestines TR1 demonstrates a specific role in liver metabolism and hypocholesterolemic effect of T3 TR2 role in the negative feedback by T3 on hypothalamic TRH and pituitary TSH and in the development of cones in the retina and inner ear

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

LIOTHYRONINE SODIUM (T3)

available in tablet and injectable form
(INTRAVENOUS route only)

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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TREATMENT OF HYPERTHYROIDISM
Pharmacologic agents Radioactive Iodine Surgery

THREE DEIODINASES FOUND IN HUMANS

TYPE 1 (DIO1) found mainly in the liver and kidney 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

PHARMACOLOGIC AGENTS
THIONAMIDES Propylthiouracil Carbimazole Methimazole / Thiamazole IODIDE Lugols solution KISS IONIC INHIBITORS Thiocyanate Pertechnetate Perchlorate

can remove iodine in both rings

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

BETA BLOCKERS Propranolol Metoprolol

CORTICOSTEROIDS Dexamethasone Prednisone Hydrocortisone

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
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
this action is limited with Methimazole

CLINICAL INDICATIONS OF THYROID HORMONES

1. 2. 3. Myxedema coma Cretinism Nodular thyroid disease TSH suppressive therapy 6-12 months Adjunct therapy for Thyroid cancer

4.

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

PHARMACOKINETIC DIFFERENCES BETWEEN THIONAMIDES

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

3.

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

ADVERSE EFFECTS OF THIONAMIDES

Skin rashes Agranulocytosis
(perform baseline CBC!)

GRAVES DISEASE
most common cause of hyperthyroidism Triad of Hyperthyroidism, Ophthalmopathy, and Dermopathy Smoking is a risk factor for worsening ophthalmopathy! Arthralgias, Paresthesias Antineutrophilic cytoplasmic antibodies (ANCA) positive vasculitis Liver failure

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
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ANION INHIBITORS
MEMBERS
Perchlorate Thiocyanate

METHIMAZOLE
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

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

INDICATIONS OF THIONAMIDES
1. Definitive Treatment of Graves disease small goiter; mild hyperthyroidism pregnant females Adjunct to radioactive iodine/RAI therapy In preparation of patients for Thyroid surgery Thyroid crisis / storm

BETA RECEPTOR ANTAGONISTS WITHOUT ISA

ISA Intrinsic Sympathomimetic Activity

2. 3. 4.

Metoprolol Atenolol Propranolol Esmolol

IODIDE
IODIDE PREPARATIONS
SATURATED SOLUTION OF POTASSIUM IODIDE (KISS) Contains 50 mg Iodine per drop LUGOLS SOLUTION contains 8 mg Iodine per drop

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

DOSE
100 -300 mg/day in 3 divided doses

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

MECHANISM OF ACTION
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

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

INDICATION
Adjunct in the treatment of thyroid crisis and thyroiditis

THERAPEUTIC USES
1. 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

GOITROGENS
Thiocyanate containing or inducing agents 1. Food (plant products) cabbage broccoli cassava lima beans cauliflower turnips 2. Smoking 3. Drugs Sodium nitroprusside Amiodarone

2. 3.

MAJOR DISADVANTAGES
1. 2. NOT recommended for long term use escape from Wolff Chaikoff Effect NOT recommended in pregnancy iodide crosses the placenta and may cause fetal goiter

ADVERSE EFFECTS
Hypersensitivity angioedema, laryngeal edema drug fever, arthralgia, lymphadenopathy, eosinophilia fatal periarteritis nodosa Thrombotic thrombocytopenic purpura Iodine escape Iodism 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 131I

radioactive isotope used for treatment half-life: 8 days

123I

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
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INDICATIONS FOR SURGERY
Large diffuse goiter Failure of Anti-thyroid drugs Presence of contraindications to Antithyroid drugs or RAI therapy Suspicious/dominant nodule Patients preference

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

INDICATIONS OF RAI
1. Hyperthyroidism Elderly patients CV disease Recurrent hyperthyroidism (after subtotal thyroidectomy and prolonged antithyroid therapy) Toxic nodular goiter Large nontoxic multinodular goiter

ADVERSE EFFECTS OF THYROIDECTOMY

2. 3. 4.

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

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

DISADVANTAGES
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)

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

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

ADVERSE EFFECTS OF RAI

1. 2. 3. 4. Permanent hypothyroidism Potential for radiation-induced genetic damage Risk of malignancy leukemia, neoplasia May precipitate thyroid crisis

PRECAUTIONS
1. 2. 3. 4. 5. Avoid prolonged contact with people, especially children and pregnant women Do not share food and utensils, like glasses, dishes, bottles, water, etc. Drink lots of water and other fluids, that help the radioactive iodine to pass out quickly from the body Wash the laundry of the treated person separately Stop breast feeding as the radioactive iodine is concentrated and excreted in the breast

CONTRAINDICATIONS

131

pregnant women nursing mother patients <20 yrs old I crosses placental barrier and secreted in breast milk.

SURGERY
Thyroidectomy Total Partial Lobectomy Lobectomy Lobectomy with isthmusectomy Subtotal

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