Farmacología de tiroides Universidad de Costa Rica Facultad de Farmacia Departamento de Farmacología Toxicología y Farmacodependencia Farmacología de tiroides Dra. Beatriz Badilla B. II Ciclo 2009

Emil Theodor Kocher The Nobel Prize in Physiology or Medicine 1909 “”for his work on the physiology, pathology and surgery of the thyroid gland" Emil Theodor Kocher Switzerland Berne University Berne, Switzerland b. 1841 d. 1917

Epidemiología de problemas tiroideos Fernandez-Olaechea et al. Bocio en la provincia de Cartago. Acta Médica Costarricense 2001,43(1) 27-31. “Las primeras encuestas sobre bocio endémico en C.R. realizadas en los años 1952 y 1966, señalaron una prevalencia del 18% de la población, por lo que fue declarado problema de salud pública.”

“Guanacaste es la zona donde aún se detectan casos de bocio por deficiencia de yodo”. “En los últimos años las notificacciones de los casos de bocio en la provincia de Cartago han ido aumentando”. Fernandez-Olaechea et al. Acta Médica Costarricense 2001,43(1) 27-31.

“En 1995, se observó que el 24,1% de Guanacaste y el 22,5 % de Cartago presentaban yodurias bajas.” Yoduria baja: <10 g/dl Ascensio M. et al. Control de los desórdenes por deficiencia de yodo. Costa Rica 1997 “Costa Rica se encuentra entre los países latinoamericanos que tiene menos problemas de déficit de yodo.” Fernandez-Olaechea et al. Acta Médica Costarricense 2001,43(1) 27-31.

Prevalencia de bocio endémico en CA. Guatemala E. Salvador Honduras Nicaragua Costa Rica Panamá 20,4% (1987) 25% (1990) 8,8% 3,9% 3,7 % 11,4% G 13,2 % (1991) Molina et al. Principales deficiencias de micronutrientes en CA. OPS, INCAP, 1995.

Yoduria en Costa Rica: Mediana 23,3 g/dl Zona endémica: ≥ 10% Molina et al. Principales deficiencias de micronutrientes en CA. OPS, INCAP, 1995. Yoduria en Costa Rica: Mediana 23,3 g/dl Ministerio de Salud. Instittuto Costarricense de Investigación y Enseñanza en Nutrición y Salud. Encuesta Nacional de Nutrición. Micronutrientes. San José, Costa Rica, 1997.

Glándula tiroides

Requerimientos diarios de ioduro Adultos 1-2 g/kg 1 mg/semana Adicionar 25-50 g al día en embarazo*

Glándula tiroides (folículos)

Síntesis de hormonas tiroideas NIS T4= 90% T3= 10% rT3< 1% 1:20-50

Synthesis of Thyroxine and Triiodothyronine Figure 2. Synthesis of Thyroxine and Triiodothyronine. In Panel A, thyroid peroxidase (TPO), a heme-containing glycoprotein, is anchored within the thyroid follicular-cell membrane at the luminal side of the thyroid follicle. In Panel B, the first step in thyroid hormone synthesis involves generation of an oxidized enzyme promoted by endogenously produced hydrogen peroxide. In Panel C, the oxidized enzyme reacts with trapped iodide to form an "iodinating intermediate" (TPO-Iox), the nature of which is not entirely understood. Some investigators favor the formation of a heme-linked iodinium ion (TPO-I+), whereas others suggest the formation of hypoiodite (TPO-O-I-). In Panel D, in the absence of an antithyroid drug, the iodinating intermediate reacts with specific tyrosine residues in thyroglobulin (Tg) to form monoiodotyrosine and diiodotyrosine. Subsequent intramolecular coupling of MIT and DIT forms triiodothyronine, and the coupling of two DIT molecules forms thyroxine. In the presence of an antithyroid drug (e.g., methimazole, shown in Panel E), the drug serves as an alternative substrate for the iodinating intermediate, competing with thyroglobulin-linked tyrosine residues and diverting oxidized iodide away from hormone synthesis. The drug intermediate with a sulfur-linked iodide is a theoretical reaction product.6 In Panel F, the oxidized drug forms an unstable drug disulfide7 that spontaneously degrades to an inactive desulfurated molecule, shown as methylimidazole. Antithyroid drugs also impair the coupling reaction in vitro, but it is uncertain whether this occurs in vivo. Cooper D. N Engl J Med 2005;352:905-917

Synthesis of Thyroxine and Triiodothyronine Figure 2. Synthesis of Thyroxine and Triiodothyronine. In Panel A, thyroid peroxidase (TPO), a heme-containing glycoprotein, is anchored within the thyroid follicular-cell membrane at the luminal side of the thyroid follicle. In Panel B, the first step in thyroid hormone synthesis involves generation of an oxidized enzyme promoted by endogenously produced hydrogen peroxide. In Panel C, the oxidized enzyme reacts with trapped iodide to form an "iodinating intermediate" (TPO-Iox), the nature of which is not entirely understood. Some investigators favor the formation of a heme-linked iodinium ion (TPO-I+), whereas others suggest the formation of hypoiodite (TPO-O-I-). In Panel D, in the absence of an antithyroid drug, the iodinating intermediate reacts with specific tyrosine residues in thyroglobulin (Tg) to form monoiodotyrosine and diiodotyrosine. Subsequent intramolecular coupling of MIT and DIT forms triiodothyronine, and the coupling of two DIT molecules forms thyroxine. In the presence of an antithyroid drug (e.g., methimazole, shown in Panel E), the drug serves as an alternative substrate for the iodinating intermediate, competing with thyroglobulin-linked tyrosine residues and diverting oxidized iodide away from hormone synthesis. The drug intermediate with a sulfur-linked iodide is a theoretical reaction product.6 In Panel F, the oxidized drug forms an unstable drug disulfide7 that spontaneously degrades to an inactive desulfurated molecule, shown as methylimidazole. Antithyroid drugs also impair the coupling reaction in vitro, but it is uncertain whether this occurs in vivo. Cooper D. N Engl J Med 2005;352:905-917

Síntesis de hormonas tiroideas

Síntesis de hormonas tiroideas NIS

Síntesis de hormonas tiroideas Peroxidases NIS

T4 T3 T4 70-90 g/día 15-30 g/día (20%) 41% T3 38% rT3 21% met. HIGADO T4 41% T3 38% rT3 21% met.

Isoenzimas de la desyodasa Aporta T3 intracelular Selenoproteínas Brain Pituitary BAT Heart Skeletal muscle rT3 T4 T3 D3 D1 Usada en casi todos los tej. blanco periféricos Placenta Skin Brain Liver Kidney Thyroid “Up y Down regulation” PTU D1-D2 = 5´desyodasas

Estructuras de T4, T3, y T3 Reversa Figure 2. Structures of T4, T3, and Reverse T3. Sulfation at the 4'-hydroxyl position produces the sulfate conjugates of T4, T3, and reverse T3. Burrow, G. N. et al. N Engl J Med 1994;331:1072-1078

G&G. The Pharmacological Basis of Therapeutics 11th Ed. 2006 Conditions and Factors That Inhibit Type I 5´-Deiodinase Activity (D1) Acute and chronic illness Caloric deprivation (specially carbohydrate) Malnutrition Glucocorticoids -Adrenergic receptors antagonists (e.g., propranolol in high doses) Oral cholecystographic agents (e.g., iopanoic acid, sodium ipodate) Amiodarone Propylthiouracil Fatty acids Fetal/neonatal period Selenium deficiency G&G. The Pharmacological Basis of Therapeutics 11th Ed. 2006

Globulina de unión a la tiroxina (TBG) (T3-T4) Transtiretina Transporte de hormonas tiroideas Globulina de unión a la tiroxina (TBG) (T3-T4) Transtiretina (prealbúmina de unión a la tiroxina) (T4) Albúmina Apolipoproteínas de las lipoproteínas HDL2 y HDL3 G&G. The Pharmacological Basis of Therapeutics 11th Ed. 2006

Factors That Alter Binding of Thyroxine to Thyroxine-Binding Globulin INCREASE BINDING DECREASE BINDING Drugs Estrogens Methadone Clofibrate 5-Fluorouracil Heroin Tamoxifen Selective estrogen receptor modulators Glucocorticoids Androgens L-Asparaginase Salicylates Mefenamic Acid Antiseizure medications (phenytoin, carbamazepine) Furosemide Systemic Factors Liver disease Porphyria HIV infection Inheritance Acutate and chronic illness G&G. The Pharmacological Basis of Therapeutics 11th Ed. 2006

Control de la secreción de las hormonas tiroideas

The Hypothalamic-Pituitary-Thyroid Axis and Extrathyroidal Pathways of Thyroid Hormone Metabolism Figure 1. The Hypothalamic-Pituitary-Thyroid Axis and Extrathyroidal Pathways of Thyroid Hormone Metabolism. Triiodothyronine (T3) and thyroxine (T4) inhibit the secretion of thyrotropin (TSH) both directly and indirectly, by inhibiting the secretion of thyrotropin-releasing hormone (TRH). TSH stimulates the synthesis and secretion of T4 and T3 by the thyroid gland. T4 is converted to T3 in the liver (and many other tissues) by the action of T4 monodeiodinases. Some of the T4 and T3 is conjugated with glucuronide and sulfate in the liver, excreted in the bile, and partially hydrolyzed in the intestine; the T4 and T3 formed there may be reabsorbed. Drug interactions can occur at any of these sites. Surks, M. I. et al. N Engl J Med 1995;333:1688-1694

Control de la secreción hormonas tiroideas Katzung B.G. Basic and Clinical Pharmacology 10th Ed.

The Thyrotropin Receptor Figure 1. The Thyrotropin Receptor. The location of constitutively activating mutations1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16 and inactivating mutations15,17,18 of the thyrotropin-receptor gene is shown, as is the location of somatic mutations found in thyroid carcinomas.10,19,20 At some locations, several different amino acid substitutions have been described. All gain-of-function mutations are in exon 10 except Ser281Asn/Thr, which is in exon 9. Gain-of-function mutations are denoted by circles in the case of hyperfunctioning thyroid adenomas, squares in the case of familial autosomal dominant hyperthyroidism, diamonds in the case of sporadic congenital hyperthyroidism, and octagons in the case of thyroid carcinomas. Loss-of-function mutations are denoted by triangles. Letters indicate the amino acid in the wild-type receptor. The asterisk and double asterisk indicate deletions resulting in a gain of function in hyperfunctioning thyroid adenomas. Paschke R and Ludgate M. N Engl J Med 1997;337:1675-1681

Secretion of TSH

Acción de h. tiroidea en el núcleo celular

Mecanismo intracelular de hormona tiroidea

La HT es crítica para el desarrollo y funcionamiento Efectos de la hormona tiroidea El efecto mas evidente de la HT es la estimulación del consumo de oxígeno, de la utilización de de sustratos y de la producción de calor. Boron y Boulpaep.Medical Physiology 2005 La HT es crítica para el desarrollo y funcionamiento de los nervios, el esqueleto, y los tejidos reproductivos. Sus efectos dependen de la síntesis proteica así como de la potenciación, de la secreción y de la acción de la hormona de crecimiento. Katzung B 11 th Ed. 2009

Efectos de la hormona tiroidea La HT es imprescindible para el desarrollo del SNC. Berne y Levi. Fisiología.2000 El efecto que mejor resume la acción de la HT es el incremento generalizado de la actividad metabólica, lo que implica un aumento en la utilización de los sustratos, de la actividad de las enzimas y de la secreción de otras hormonas. Florez J. 4ª Ed. 2004

Interrelations of Maternal, Placental, and Fetal Thyroid Metabolism Figure 3. Interrelations of Maternal, Placental, and Fetal Thyroid Metabolism. I, II, and III denote type I, type II, and type III iodothyronine deiodinases, respectively; T4S T4 sulfate; rT3 reverse T3; rT3S reverse T3 sulfate; SO4 a sulfation pathway; -SO4 a desulfation pathway; and T2S T2 sulfate. Burrow, G. N. et al. N Engl J Med 1994;331:1072-1078

Relative Changes in Maternal and Fetal Thyroid Function during Pregnancy Figure 1. Relative Changes in Maternal and Fetal Thyroid Function during Pregnancy. The effects of pregnancy on the mother include a marked and early increase in hepatic production of thyroxine-binding globulin (TBG) and placental production of human chorionic gonadotropin (hCG). The increase in serum TBG, in turn, increases serum T4 concentrations; hCG has thyrotropin-like activity and stimulates maternal T4 secretion. The transient hCG-induced increase in serum free T4 inhibits maternal secretion of thyrotropin. Burrow, G. N. et al. N Engl J Med 1994;331:1072-1078

H.tiroidea. Crecimiento y desarrollo

H. Tiroidea. Crecimiento y desarrollo

por hipotiroidismo congénito (HC) por las siguientes razones: Todos los recién nacidos deben ser estudiados por hipotiroidismo congénito (HC) por las siguientes razones: El hipotiroidismo congénito (HC) ocurre en 1x 4000 recién nacidos. Solo el 10% de los recién nacidos con HC es reconocido clínicamente durante los tres primeros meses de edad. Si la terapia tiroidea se establece en los tres primeros meses de vida, se producirá un desarrollo intelectual normal en el niño.

TH TH y formación ósea Osteoblastos Osteoclastos Fostasa alcalina y OSTEOCALCINA . Calcificación y formación ósea Resorción ósea This is a placeholder text. This text can be replaced with your own text. Osteoblastos Osteoclastos Resorción ósea Porosidad Pérdida de grosor trabecular OSTEOPOROSIS

↑ Gen Milein Basic Protein (MBP) H. Tiroidea y SNC ↑ Gen Milein Basic Protein (MBP) Laminina

Efecto de H. tiroidea en el sistema cardiovascular Figure 1. Effects of Thyroid Hormone on Cardiovascular Hemodynamics. The diagram shows the way in which triiodothyronine increases cardiac output by affecting tissue oxygen consumption (thermogenesis), vascular resistance, blood volume, cardiac contractility, and heart rate. Adapted from Klein and Levey,6 with the permission of the publisher. Klein, I. et al. N Engl J Med 2001;344:501-509

Triiodothyronine on Cardiac Myocytes Sites of Action of Triiodothyronine on Cardiac Myocytes Figure 2. Sites of Action of Triiodothyronine on Cardiac Myocytes. Triiodothyronine enters the cell, possibly by a specific transport mechanism, and binds to nuclear triiodothyronine receptors. The complex then binds to thyroid hormone response elements of the genes for several cell constituents and regulates transcription of these genes, including those for Ca2 -ATPase and phospholamban in the sarcoplasmic reticulum, myosin, {beta}-adrenergic receptors, adenylyl cyclase, guanine-nucleotide-binding proteins, Na /Ca2 exchanger, Na /K -ATPase, and voltage-gated potassium channels. Nonnuclear triiodothyronine actions on ion channels for sodium (Na ), potassium (K ), and calcium (Ca2 ) ions are indicated at the cell membrane. Dashed arrows indicate pathways with multiple steps, and mRNA denotes messenger RNA. Klein, I. et al. N Engl J M. 2001;344:501-509

Weetman, A. P. N Engl J Med 2000;343:1236-1248

Table 1. Changes in Cardiovascular Function Associated with Thyroid Disease. Klein, I. et al. N Engl J Med 2001;344:501-509

Cardiac rate and output Efectos de la hormona tiroidea Cardiac rate and output

Efectos metabólicos de HT Col ABiliares Conservan acoplamiento R/ β3 LDL R/hepático ↑Resp. lipolìtica Figure 1. Effects of Thyroid Hormone on Cardiovascular Hemodynamics. The diagram shows the way in which triiodothyronine increases cardiac output by affecting tissue oxygen consumption (thermogenesis), vascular resistance, blood volume, cardiac contractility, and heart rate. Adapted from Klein and Levey,6 with the permission of the publisher. Hipercolesterolemia ↓R/LDL

Acción calorigénica de HT 30-40% Estimulación de la contracción cardiaca 4% Estimulación de lipogénesis

Efectos de la hormona tiroidea

Datos de Laboratorio CR Valores Normales Total T4 4-12 g/dL Serum T3 90-185 ng/dL Indice de tiroxina libre (FT4I) 6-10.5 TSH 0.4-4.0 lU/mL 0.4-10 (>80a)

0.4-4 Normal < O.1 Probable hiperfunción 0.1-0.3 Datos de Laboratorio (CR )TSH en diversas situaciones funcionales TSH (lU/mL Valores < O.1 Probable hiperfunción 0.1-0.3 Situación dudosa ( controlar) 0.4-4 Normal 4.0-10.0 Hipotiroidismo subclínico >10.0 Hipotiroidismo clínico Vinocour M. Utilidad clínica de las pruebas de función tiroidea AMPMD.

Hipotiroidismo subclínico Hipertiroidismo subclínico Asociación Americana de Tiroides Hipotiroidismo subclínico Se define como una concentración de TSH sérico sobre el límite superior normal, cuando T4 es normal. Hipertiroidismo subclínico Se define como una concentración de TSH sérico < 0.1 uU/L, cuando T3 y T4 son normales.

Medir TSH en todos los adultos mayores de 35 años Asociación Americana de Tiroides Medir TSH en todos los adultos mayores de 35 años y repetir cada 5 años. Tamizaje mas frecuente en individuos de alto riesgo sintomáticos.

Vinocour M. Utilidad clínica de las pruebas de función tiroidea AMPMD

Estados de hipofunción tiroidea Hipotiroidismo- Mixedema Bocio hipotiroideo Hipotiroidismo primario, secundario Hipotiroidismo subclínico Tiroiditis de Hashimoto Enfermedad tiroidea nodular Cretinismo Coma mixedematoso

Estados asociados con una disminución de la conversión periférica de T4 en T3 FISIOLÓGICO Vida Fetal y Neonatal Precoz ¿Ancianos? PATOLÓGICO Ayuno Desnutrición Enfermedad sistémica Estado postoperatorio Fármacos (propiltiouracilo, propranolol, amiodarona) Contrastes radiológicos (ipodato, ipanoato)

Sintomas neurosiquiátricos de hipotiroidismo                                                                                                                           Disturbios en la concentración, memoria e intelecto. Falta de ambición Pensamiento y habla lentos Depresión, sicosis Sonnolencia, letargo. Dificultad para despertarse Aumento de la necesidad de sueño Alucinaciones auditivas y visuales.

Farmacología de H. tiroideas Variable cinética T4 T3 Volumen de distribución 10L 40L Producción diaria 75 ug 25 ug Vida media 7 días 1 día Potencia biológica 1 4 Unión a proteínas 99.96% 99.6% Absorción oral 50-80% 95% Katzung B. Basic & Clinic Pharmacolog 10 th. Ed. 2009

Terapia de reemplazo en hipotiroidismo; supresión de TSH pituitaria Levotiroxina (T4) Levotiroxina Indicaciones y uso Terapia de reemplazo en hipotiroidismo; supresión de TSH pituitaria D.I.H. 18th ED. 2009-2010

Levotiroxina Farmacocinética Inicio de acción terapéutica: vo 3-5 d, iv 6-8h Abs. Oral: Errática (50-80%) (I. delg) Metabolismo: Hepático Vida ½ elimin: 6-7 d (eutiroideo) 9-10 d (hipot.), 3-4 d (hipert.) Excreción: Orina y heces Est. vacío D.I.H. 18th ED. 2009-2010

Control periódico Precauciones Insuficiencia adrenal Diabetes  respuesta exagerada Mixedema  respuesta exagerada Arritmias cardíacas Angina pectoris o enf. C.V. Contraindicaciones Control periódico Tirotoxicosis IM reciente Insuficiencia adrenal no corregida

alopecia

Levotiroxina Interacciones * Interferencia con la absorción gastrointestinal ( efecto) Colestiramina Sulfato ferroso Sucralfato Antiácidos con hidróxido de aluminio Suplementos de calcio *Tomar 1 h antes o 2 h después de comidas TOMAR CON ESTÓMAGO VACÍO D.I.H. 18th ED. 2009-2010

Aumento del metabolismo por Inductores Enzimáticos Carbamazepina Rifampicina Fenitoína LT Aumenta efecto de hipoprotrombinemia de warfarina. Aumenta las necesidades de hipoglicemiantes orales e insulina

Categoría A T4+ADT aumento de efectos tóxicos de ambos. Estrógenos aumentan la proteína fijadora de Tiroxina (TBG) Dosis de T4 puede requerir aumento cuando se agrega ISRS

Medicamentos que pueden afectar la función tiroidea y los requerimientos de levotiroxina

Medicamentos que pueden afectar la función tiroidea y los Requerimientos de levotiroxina

Factors That Alter Binding of Thyroxine to Thyroxine-Binding Globulin INCREASE BINDING DECREASE BINDING Drugs Estrogens Methadone Clofibrate 5-Fluorouracil Heroin Tamoxifen Selective estrogen receptor modulators Glucocorticoids Androgens L-Asparaginase Salicylates Mefenamic Acid Antiseizure medications (phenytoin, carbamazepine) Furosemide Systemic Factors Liver disease Porphyria HIV infection Inheritance Acutate and chronic illness

Levotiroxina Toxicidad Sobredosis crónica Efectos: síntomas de hipertiroidismo El eje H-A-T retornará a la normalidad en 6-8 semanas. Sobredosis aguda: T4 sérica no correlaciona con la toxicidad.

Levotiroxina Medidas de soporte general Falla cárdíaca: digitálicos Actividad adrenégica excesiva: propranolol Fiebre: acetaminofen

Dosis Levotiroxina Usual: Muy variable Incrementos de 50 ug cada 3-4 semanas 25 ug en intervalos de 2-3 semanas Dosis promedio ( adulto) 100-150 (200) ug/día. Maxima 200 ug Coma mixedematoso: 200-500 ug una vez 100-300 ug día siguiente si PRN. SEMANAL? D.I.H. 18th ED. 2009-2010

H. tiroidea Presentación CCSS Levotiroxina (T4) 25 y 100 ug Levotironina (T3) 25 mg Eurirox (T4) Litiroxin (T4) Levoriroxina(T4) 25 ug, 100 ug Triyotex (T3) 25 mg

Estados de hiperfunción tiroidea Tirotoxicosis Hipertiroidismo dif. de Tirotoxicosis Enfermedad de Graves Bocio tóxico difuso Hipertiroidismo subclínico Tormenta tiroidea

Hipertiroidismo Nerviosismo Pérdida de peso Intolerancia al calor y fatiga Taquicardia Temblor Reflejos vivos Piel lisa Hiperhidrosis Mirada fija Aumento de la motilidad intestinal Exoftalmos Diplopía Inflamación corneal

Clinical Manifestations Of Graves' Disease Figure 1. Clinical Manifestations of Graves' Disease. Panel A shows diffuse goiter in a 28-year-old woman with Graves' hyperthyroidism. Panels B and C show ophthalmopathy in a 55-year-old woman with Graves' disease, with periorbital edema, chemosis, scleral injection, and proptosis; the lid retraction in this patient is obscured by periorbital edema. Panel D shows localized dermopathy, occurring as an indurated, noninflamed plaque on the anterolateral aspect of the shin of a 47-year-old woman. Weetman A. N Engl J Med 2000;343:1236-1248

Pathogenesis of Graves' Disease Figure 2. Pathogenesis of Graves' Disease. Excess production of thyroid hormone is caused by the activation of thyrotropin receptors by thyroid-stimulating antibodies produced within and outside the thyroid gland. The intrathyroidal inflammatory cells also produce cytokines, such as interleukin-1, tumor necrosis factor {alpha}, and interferon-{gamma}, that induce the expression of adhesion molecules such as CD54, regulatory molecules such as CD40, and HLA class II molecules, which in turn activate local inflammatory cells. These cytokines also induce thyroid cells to synthesize cytokines that may help sustain the intrathyroidal autoimmune process. Antithyroid drugs reduce the production of thyroidal cytokines -- an ability that may explain their immunomodulatory effects (which include a decrease in the production of thyroid-stimulating antibody) -- contributing to remission in some patients. Weetman, A. P. N Engl J Med 2000;343:1236-1248

Pathogenesis of Graves' Ophthalmopathy Figure 3. Pathogenesis of Graves' Ophthalmopathy. There is an inflammatory-cell infiltrate composed predominantly of activated T cells in the extraocular muscles and orbital connective tissue. This infiltrate may localize in the orbit through the recognition by T cells of an orbital antigen that cross-reacts with a thyroid antigen, such as the thyrotropin receptor expressed in preadipocyte fibroblasts. Cytokines produced by the infiltrate activate fibroblasts, stimulating the production of glycosaminoglycans (mainly hyaluronate and chondroitin sulfate) and leading to edema and fibrosis. Weetman, A. P. N Engl J Med 2000;343:1236-1248

Fármacos antitiroideos e inhibidores tiroideos

Fármacos antitiroideos e inhibidores tiroideos Clasificación 1. Antitiroideos: Interferencia directa con la síntesis de HT 2. Inhibidores iónicos: Bloqueo del mecanismo de transporte de ioduro. 3.Yodo en altas concentraciones: Disminución de la síntesis de HT. 4. Yodo radioactivo: Lesión a la glándula por radiaciones ionizantes.

Chemical Structures of Propylthiouracil and Methimazole, as Compared with Thiourea Figure 1. Chemical Structures of Propylthiouracil and Methimazole, as Compared with Thiourea. Cooper D. N Engl J Med 2005;352:905-917

Chemical Structures of Propylthiouracil and Methimazole, as Compared with Thiourea

Tioamidas ( Tiocarbamida) G&G. Tha Pharmacological Basis of Therapeutics 10th Ed. 2001

Fármacos antiroideos * *

Efecto de derivados de tiourea Cooper D. N Engl J Med 2005;352:905-917 Figure 2. Synthesis of Thyroxine and Triiodothyronine. In Panel A, thyroid peroxidase (TPO), a heme-containing glycoprotein, is anchored within the thyroid follicular-cell membrane at the luminal side of the thyroid follicle. In Panel B, the first step in thyroid hormone synthesis involves generation of an oxidized enzyme promoted by endogenously produced hydrogen peroxide. In Panel C, the oxidized enzyme reacts with trapped iodide to form an "iodinating intermediate" (TPO-Iox), the nature of which is not entirely understood. Some investigators favor the formation of a heme-linked iodinium ion (TPO-I+), whereas others suggest the formation of hypoiodite (TPO-O-I-). In Panel D, in the absence of an antithyroid drug, the iodinating intermediate reacts with specific tyrosine residues in thyroglobulin (Tg) to form monoiodotyrosine and diiodotyrosine. Subsequent intramolecular coupling of MIT and DIT forms triiodothyronine, and the coupling of two DIT molecules forms thyroxine. In the presence of an antithyroid drug (e.g., methimazole, shown in Panel E), the drug serves as an alternative substrate for the iodinating intermediate, competing with thyroglobulin-linked tyrosine residues and diverting oxidized iodide away from hormone synthesis. The drug intermediate with a sulfur-linked iodide is a theoretical reaction product.6 In Panel F, the oxidized drug forms an unstable drug disulfide7 that spontaneously degrades to an inactive desulfurated molecule, shown as methylimidazole. Antithyroid drugs also impair the coupling reaction in vitro, but it is uncertain whether this occurs in vivo.

Desyodación periferica de T4 a T3 Mecanismo de acción Inactivación de la PEROXIDASA (grupo hem en el estado oxidado) Interfiere en la incorporación del yodo en los residuos tirosil Interfiere en la Oxidación de yodo PTU Desyodación periferica de T4 a T3 Inmunosupresor (??)

Effects of Antithyroid Drugs Figure 3. Effects of Antithyroid Drugs. The multiple effects of antithyroid drugs include inhibition of thyroid hormone synthesis and a reduction in both intrathyroidal immune dysregulation and (in the case of propylthiouracil) the peripheral conversion of thyroxine to triiodothyronine. Tyrosine-Tg denotes tyrosine residues in thyroglobulin, I+ the iodinating intermediate, and TPO thyroid peroxidase. Cooper D. N Engl J Med 2005;352:905-917

Inducción de apoptosis en linfocitos intratiroideos Efectos inmunosupresores Figure 2. Pathogenesis of Graves' Disease. Excess production of thyroid hormone is caused by the activation of thyrotropin receptors by thyroid-stimulating antibodies produced within and outside the thyroid gland. The intrathyroidal inflammatory cells also produce cytokines, such as interleukin-1, tumor necrosis factor {alpha}, and interferon-{gamma}, that induce the expression of adhesion molecules such as CD54, regulatory molecules such as CD40, and HLA class II molecules, which in turn activate local inflammatory cells. These cytokines also induce thyroid cells to synthesize cytokines that may help sustain the intrathyroidal autoimmune process. Antithyroid drugs reduce the production of thyroidal cytokines -- an ability that may explain their immunomodulatory effects (which include a decrease in the production of thyroid-stimulating antibody) -- contributing to remission in some patients. Weetman, A. P. N Engl J Med 2000;343:1236-1248

1:1 D Goodman & Gilman's Pharmacology > XII. Hormones and Hormone Antagonists >  Chapter 56. Thyroid and Antithyroid Drugs > Antithyroid Drugs and Other Thyroid Inhibitors  > Antithyroid Drugs > Absorption, Metabolism, and Excretion >

Características farmacocinéticas de los fármacos antitiroideos PTU Metimazol Unión a proteínas plasmáticas 80-90% Nula Duración de la acción 2-3 h 36-72h Excreción Urinaria Vida media eliminación 1.5 h 4-13 h Volumen de distribución 20 L (Conc. en Tiroides 40 L (Conc. en tiroides) Metabolismo durante enfermedad Nefropatía grave Normal Paso trasplacentario Bajo Alto Concentraciones en leche materna Bajas 1:1 DIH.18 th Ed. 2009-2010

Side Effects of Antithyroid Drugs Table 1. Side Effects of Antithyroid Drugs. Cooper D. N Engl J Med 2005;352:905-917 3%PTU 7% M

Ac. citoplasmáticos contra neutrófilos (ANCA). Side Effects of Antithyroid Drugs Ac. citoplasmáticos contra neutrófilos (ANCA). Table 1. Side Effects of Antithyroid Drugs. Cooper D. N Engl J Med 2005;352:905-917

Seguimiento estrecho de los valores séricos de T4 y TSH del bebé. Lactancia materna Las cantidades muy pequeñas que aparecen en leche no parecen afectar la función tiroidea del lactante.(PTU) G&G 11Th Ed. 2006 Seguimiento estrecho de los valores séricos de T4 y TSH del bebé.                                       

Farmacos antitiroideos Interacciones Aumenta su toxicidad: litio, yoduro de potasio. Warfarina: El efecto anticoagulante puede verse aumentado Requieren ajuste de dosis en el tx de hipertiroidismo: beta bloqueadores, digoxina y teofilina Información al paciente Tomar con comidas D.I.H. 12th ED. 2005-2006

Farmacos antitiroideos Tx en hipertiroidismo para: Usos terapéuticos Tx en hipertiroidismo para: Tx definitivo para Enf de Graves. + Yodo radioactivo mientras efecto. Para control del problema tiroideo en la preparación a la cirugía.

Tx coadyuvante Propranolol Dexametasona 0.5-1 mg qid Atenolol Ac. Yopanoico 0.5-1 mg qid Bloq. C. Ca++ Colestiramina

Sustancias que interfieren con la concentración Inhibidores iónicos Sustancias que interfieren con la concentración de yodo en la glándula tiroidea. Bloqueo competitivo de la bomba de ioduro TIOCIANATO (SCN) PERCLORATO (ClO4) 10 veces + potente LITIO ( disminución de la secreción T4 y T3) G&G. The Pharmacological Basis of Therapeutics 11th Ed. 2006

G&G. The Pharmacological Basis of Therapeutics 11th Ed. 2006 Yodo o Yoduro Altas concentraciones producen el efecto de Wolff-Chaikoff. Efecto muy rápido (24h). Efecto máximo a10-15d. Efecto por corto tiempo. ↓ Vascularidad ↓ Tamaño de la célula Yoduro i / Yoduro e G&G. The Pharmacological Basis of Therapeutics 11th Ed. 2006

G&G. The Pharmacological Basis of Therapeutics 11th Ed. 2006 Yodo o Yoduro Uso Tx de hipertiroidismo en: -Período preparatorio de preparación para tiroidectomía. -Tx de crisis tirotoxicósica -Protección de la tiroides contra la precipitación de yodo radioactivo después de un accidente nuclear. G&G. The Pharmacological Basis of Therapeutics 11th Ed. 2006

Solución de yodo fuerte (Sol. Lugol) Yodo 5% y KI 10% Yoduro.. Solución de yodo fuerte (Sol. Lugol) Yodo 5% y KI 10% (6,3 mg yodo/gota) 3-5 gotas tid Solución saturada de yoduro de potasio 38 mg yodo/gota 1-3 gotas/ tid G&G. The Pharmacological Basis of Therapeutics 11th Ed. 2006

Yoduro. Efectos secundarios Sabor metálico y ardor en boca garganta , dientes y encías. Yodismo leve resfriado Inflamación de faringe, laringe y amígdalas (parotiditis?) Lesiones cutáneas acneiformes Irritación gástrica, diarrea sanguinolenta. Yodismo desaparece al ss Tx. G&G. The Pharmacological Basis of Therapeutics 11th Ed. 2006

Yodo radiactivo 131I

Rayos gama y partículas beta Yodo radiactivo 131I T ½= 8 días Rayos gama y partículas beta Gama pasa a través del tejido para cuantificación Beta destructivas dentro del folículo

Precautions after using this medication Following treatment of hyperthyroidism or thyroid carcinoma. To prevent radiation contamination of other persons or environment: For 48 to 96 hours after receiving radioiodide. Not kissing anyone and not handling or using another person's eating or drinking utensils, toothbrush, or bathroom glass. Not engaging in sexual activities. Avoiding close and prolonged contact with others, especially children and pregnant women Sleeping alone Washing sink and tub after use (including brushing teeth) Washing hands after using or cleaning toilet Using separate towels and washcloths Laundering clothes and linens separately Double-flushing toilet to decrease radiation exposure to the urinary bladder Increasing intake of fluids to promote more frequent voiding to help eliminate radioactive iodine Following treatment of hyperthyroidism: Periodic blood tests to check thyroid hormone concentration

Fármacos capaces de inhibir la síntesis de hormona tiroidea

Features of Amiodarone-Induced Thyroid Dysfunction Table 3. Features of Amiodarone-Induced Thyroid Dysfunction. Pearce, E. N. et al. N Engl J Med 2003;348:2646-2655

Amiodarona En eutiroideo  T3 en 20-25% Hipotiroidismo 5-25% T4 T3 en todos los tejidos Inhibición de síntesis y secreción de HT En eutiroideo  T3 en 20-25% Hipotiroidismo 5-25% Hipertiroidismo 2-10%

Monitoring Thyroid Function in Patients Receiving Amiodarone Therapy Figure 3. Monitoring Thyroid Function in Patients Receiving Amiodarone Therapy. Adapted from Martino et al.,57 with the permission of the publisher. Pearce, E. N. et al. N Engl J Med 2003;348:2646-2655