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Reacciones Adversas Causadas Por Fármacos Activos En El Sistema Renina Angiotensina Aldosterona: Descripción De Un Nuevo Síndrome

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Reacciones Adversas Causadas Por Fármacos Activos En El Sistema Renina Angiotensina Aldosterona: Descripción De Un Nuevo Síndrome Programa de Doctorado en Medicina Clínica REACCIONES ADVERSAS CAUSADAS POR FÁRMACOS ACTIVOS EN EL SISTEMA RENINA ANGIOTENSINA ALDOSTERONA: DESCRIPCIÓN DE UN NUEVO SÍNDROME Tesis Doctoral presentada por ANA MARGARITA MONTORO DE FRANCISCO Directores: DR. MELCHOR ÁLVAREZ DE MON SOTO DRA. AMELIA GARCÍA LUQUE Alcalá de Henares, 2016 A mi familia. Agradecimientos Esta tesis doctoral se ha realizado en el Servicio de Alergología del Hospital Central de la Defensa “Gómez Ulla;” quiero agradecer a la Dirección del Hospital y a los Jefes de los Servicios la posibilidad que me han dado para poder llevar a cabo este trabajo desde el año 2009. A la Doctora Amelia García Luque del Servicio de Farmacología Clínica por su orientación, apoyo, ánimo y ayuda desde los momentos preliminares hasta las correcciones del manuscrito. Destacar su afán de superación contagioso y sobre todo su accesibilidad y calor humano. A todos los miembros del Servicio de Alergología, especialmente al Doctor José María Mateos Galván, con quién coincidí en los dos primeros años mi formación como especialista en Alergología por su espíritu crítico y capacidad de análisis. A los médicos internos residentes que he tutorizado desde 2009 por su buena actitud y colaboración. A la Doctora María Rubio Sotés, Jefa de Servicio de Alergología del Hospital General Universitario Gregorio Marañón por su impagable ejemplo y sus consejos durante mis años de formación. A las enfermeras del Servicio de Alergología: Esperanza, Paloma, Teresa y Beatriz por su colaboración desinteresada. A todos los pacientes que han participado en este trabajo por su buena disposición y constancia en su colaboración. A mis padres, porque sin ellos no habría logrado ninguna de las metas que me propuse y no sería lo que soy hoy. A mis hijos Ana, Fernando, Roberto y Clara por ser capaces de prescindir de mi durante tantas horas de dedicación a mis pacientes. Y en especial a mi marido Fernando, por su inestimable colaboración y ayuda. Por su admirable capacidad de trabajo que logró alentarme en los momentos difíciles durante la realización de esta tesis. ÍNDICE ABREVIATURAS ........................................................................................................... i LISTA DE TABLAS ...................................................................................................... v LISTA DE FIGURAS ................................................................................................... viii 1. INTRODUCCIÓN ...................................................................................................... 1 CAPÍTULO 1: ANTECEDENTES HISTÓRICOS Y CRONOLOGÍA ................................. 3 CAPÍTULO 2: SISTEMA RENINA ANGIOTENSINA ALDOSTERONA ........................... 6 CAPÍTULO 3: FÁRMACOS ACTIVOS SOBRE EL SISTEMA RENINA ANGIOTENSINA ALDOSTERONA ................................................................................ 12 CAPÍTULO 4: REACCIONES ADVERSAS CAUSADAS POR MEDICAMENTOS ACTIVOS SOBRE EL SISTEMA RENINA ANGIOTENSINA ALDOSTERONA ............ 22 2. PLANTEAMIENTO .................................................................................................. 97 3. PACIENTES Y MÉTODO ...................................................................................... 101 4. RESULTADOS ..................................................................................................... 117 5. DISCUSIÓN .......................................................................................................... 167 6. RESUMEN ............................................................................................................ 197 7. CONCLUSIONES ................................................................................................. 203 8. REFERENCIAS BIBLIOGRÁFICAS ...................................................................... 207 ANEXOS ANEXO 1: FÁRMACOS ACTIVOS SOBRE EL SISTEMA RENINA ANGIOTENSINA ALDOSTERONA ANEXO 2: INTERACCIONES FARMACOLÓGICAS PRODUCIDAS POR LOS FÁRMACOS ACTIVOS SOBRE EL SISTEMA RENINA ANGIOTENSINA ALDOOSTERONA ANEXO 3: USO DE FÁRMACOS ANTIHIPERTENSIVOS ANEXO 4: CUADERNO DE RECOGIDA DE DATOS CRD Abreviaturas ABREVIATURAS AAS: Ácido Acetil Salicílico A β: Proteína neurotóxica amiliode β AEH: Angioedema Hereditario AEA: Angioedema Adquirido AEMPS: Agencia Española del Medicamento y Productos Sanitarios AGT: Angiotensinógeno AINE: Anti-Inflamatorio No Esteroideo Aminoácidos: Ala: Alanina Arg: Argirina Asn: Asparagina Asp: Ácido aspártico Cys: Cisteína Gln: Glutamina Glu: Ácido glutámico Gly: Glicina His: Histidina Ile: Isoleucina Leu: Leucina Lys: Lisina Met: Meteonina Phe: Fenilalanina Pro: Prolina Ser: Serina Thr: Treonina Trp: Triptófano Tyr: Tirosina Val: Valina APP: Amino-Peptidasa P ARA II: Antagonistas de los Receptores de Angiotensina II AT-1: Receptor de la Angiotensina II 1 Página i Abreviaturas AT-2: Receptor de la Angiotensina II 2 ATC: Clasificación Anotómica Terapéutica química BK: Bradiquinina BPC: Buena Práctica Clínica BPF: Factor Potenciador de Bradiquinina CIOMS: Consejo de Organizaciones Internacionales de las Ciencias Médicas Cox-2: Ciclo-oxigenasa 2 CRD: Cuaderno de Recogida de Datos CS: Centro de Salud CTCL: Linfoma cutáneo de Células T CTD: Costes Totales por Dosis Diaria Definida C1IHN: Inhibidor del Componente del Complemento 1 D: Delección DDD: Dosis Diaria Definida DHD: Dosis Diaria Definida Habitante y Día DHR: Reacciones de Hipersensibilidad causadas por Fármacos (inglés) DM: Diabetes Melitus DRESS: Síndrome de hipersensibilidad a medicamentos con Eosinofilia y Síntomas Sistémicos ECA: Enzima Convertidora de Angiotensina ECP: Proteína Catiónica del Eosinófilo EFM: Exantema Fijo Medicamentoso EPOC: Enfermedad Pulmonar Obstructiva Crónica FASRAA: Fármacos Activos en el Sistema Renina Angiotensina Aldosterona Fc R1: Fracción c del receptor 1 de alta afinidad de mastocitos y basófilos GMPc: Guanocin Monofosfato cíclico HLA: Locus del Antígeno de Histocompatibilidad HMWK: cininógeno de masa molecular elevada HTA: Hipertensión Arterial Página ii Abreviaturas I: Inserción IC: Insuficiencia Cardiaca ID: Intradermo Reacción IDR: Inhibidores Directos de Renina IECA: Inhibidores de la Enzima Convertidora de Angiotensina IFN: Interferón Ig: Immunoglogulinas (A, M, G, E) IL: Interleucina IMAO: Inhibidores de la Mono-Amino Oxidasa IR: Insuficiencia Renal kDa: kilo Daltons HLA: Histocompatibility locus antigen (Locus del antígeno de histocompatibilidad) LECS: Lupus Eritematoso Cutáneo Subagudo LECC: Lupus Eritematoso Cutáneo Crónico LEIF: Lupus Eritematoso Inducido por Fármacos LES: Lupus Eritematoso Sistémico MHC: Major Histocompatibility Complex (Complejo principal de histocompatibilidad) MPE: Exantema Maculo-Papuloso NK1: Receptor de Neuro Kinina 1 de la sustancia P OATP: Polipéptido de Transporte de los Aniones Orgánicos OMS: Organización Mundial de la Salud PAI-1: Factor Activador del Plasminógeno 1 PEAG: Pustulosis Exantemática Aguda Generalizada PG: Prostaglandina pH: potencial Hidrógenico RAM: Reacción Adversa con Medicamentos SEFV: Sistema Español de Fármacovigilancia SJS: Síndrome de Stevens Johnson Página iii Abreviaturas SP: Sustancia P SRAA: Sistema Renina Angiotensina Aldosterona TEN: Necrolisis Epidérmica Tóxica (inglés) VEGF: Factor de crecimiento Endotelial Vascular VSG: Velocidad de Sedimentación Globular Página iv Lista de Tablas LISTA DE TABLAS Tabla 1-1: Efectos de la Estimulación del Receptor AT-1 ............................................. 8 Tabla 1-2: Situaciones Clínicas con Indicación Preferente para el Uso de IECA y ARAII en Pacientes Hipertensos ..................................................................... 15 Tabla 1-3: Clasificación de las RAM según su Frecuencia de Aparición ..................... 23 Tabla 1-4: Clasificación Inmunológica de las DHR ...................................................... 25 Tabla 1-5: Texto Íntegro de la Guía de Prescripción Terapéutica sobre los Efectos Adversos de los IECA y ARA II ................................................................. 28 Tabla 1-6: Efectos Adversos de los IDR según el Medimecum ................................... 28 Tabla 1-7: Ficha Técnica del Rasilez ® ....................................................................... 28 Tabla 1-8: Estudio de Pacientes Ingresados con Procesos Agudos Alergológicos ..... 33 Tabla 1-9: Estudio de Pacientes Ingresados con Angioedema ................................... 35 Tabla 1-10: RAM Cutáneas......................................................................................... 43 Tabla 1-11: Clasificación de la Rinitis ......................................................................... 63 Tabla 1-12: Clasificación Etiológica de la Rinitis ......................................................... 64 Tabla 1-13: Fármacos Relacionados con la Rinitis Inducida ....................................... 66 Tabla 3-1: Población Asignada al HCD por Centros de Salud ................................... 112 Tabla 4-1: Procedencia de la Derivación de los Pacientes con Sospecha de RAM ... 120 Tabla 4-2: Indicaciones de Uso de FASRAA ............................................................. 124 Tabla 4-3: Patología Previa a la Sospecha de RAM ................................................. 125 Tabla 4-4: Circunstancias Concomitantes con las Sospechas de RAM .................... 125 Tabla 4-5: Número de Pacientes que Presentan Sucesivas Sospechas de RAM ..... 126 Tabla 4-6: Número Total de RAM Estudiadas y Sexo de los Pacientes .................... 126 Tabla 4-7:
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