1 Dexmedetomidina y CLONIDINADra. Cynthia de Jesús Rodríguez Navarro R1 Anestesiología

2 Dexmedetomidina

3 Generalidades Es un polvo cristalino de color blanco.Un agente anestésico intravenoso.  Selectivo agonista de los receptores α2. Es el D-Enantomero de la medetomidina, 1620. Introducido 1999. Es un compuesto derivado imidazolico de carácter lipófilico, con alta afinidad agonista de los receptores α2.

4 Presentación 200 mcg en 2 ml.

5 Propiedades Sedación Hipnosis AnalgesiaDisminuir los efectos de otros anestésicos y simpaticolítico. Disminuir la liberación de las catecolaminas. Acción antidiurética.

6 IM IV Farmacocinética 0.5-1 y 1.5 Mcg/kg C. Plasmática 1.6-1.7 Hr.Aclaramiento: L/H/Kg Vol. Distribución L/Kg IM 2 Mcg/Kg Dosis Máxima 1.4 Mcg/kg/h VM 5.8 h +/- 2.4 h Aclaramiento / L/m Vol. Distribución: 194 +/-28.7 Litros IV

7 Dolor Post-Operatorio2.5 mcg/kg IM 0.6 Mcg/kg IV Sedación/ Hipnosis 0.4 Mcg/kg IV Dolor Post-Operatorio 1 Mcg/kg-2 gotas Premeditación 0.4 Mcg/kg/h Ajustando Mcg/kg/H Infusión

8 94% 263.7 60 % 7,1. 10-15 Min Unión a Proteínas Peso MolBiodisponibilidad 60 % PK 7,1. Latencia 10-15 Min

9 Metabolismo Metabolitos ExcreciónSe une al Grupo Heme del Citocromo P450 Por hidroxilacion y N- Metilación Metabolismo Glucoronidos Metil Metabolitos Renal 95% Heces 4% Excreción

10 Interacciones Tiopental Relajante muscularEfectos hipotensores y bradicárdicos aumentados con: betabloqueantes. La administración con anestésicos, sedantes, hipnóticos, opioides es probable que conduzca a un aumento de los efectos. Puede ser necesario reducir la dosis de dexmedetomidina o de los otros.

11 Mecanismo de acción

12

13 Mecanismo de acción NE release decreased SEDATION, SYMPATHOLYSISBinding on alpha2 receptor ANALGESIA Inhibit Firing rate & Substance P release ANALGESIA

14 Indicaciones La cirugía bariátrica Apnea del sueño pacientesCraneotomía: Aneurisma, AVM [hipotermia] Cirugía de la columna cervical CABG sin bomba Cirugía vascular Cirugía torácica

15 Hipersensibilidad a dexmedetomidina.Bloqueo cardíaco avanzado (grado 2 ó 3) en ausencia de marcapasos. Hipotensión no controlada Enf. cerebrovascular grave.

16 Embarazo No hay estudios adecuados.No utilizar a menos que sea claramente necesario. Estudios en animales han mostrado toxicidad para la reproducción.

17 Efectos Adversos

18 Efectos Adversos SNC Mareos, Cefaleas, NeuralgiaNeuritis, parestesias, tras. habla Corazón Fluctuaciones de TA, EKG, cianosis. HTP, A VA, Bloqueo AV, Extrasístole, paro Hígado A. Enzimas hepáticas, ictericia.

19 Acidosis láctica, Ac. respiratorios Hiperglicemia, K, hipoproteinemia Trast. Metabólicos Acidosis láctica, Ac. respiratorios Hiperglicemia, K, hipoproteinemia Musculares: Debilidad Piel: Rash, Sudoración Visual: Diplopía y fotofobia Respiratoria: SDRA, Apnea, Tos, disnea, edema pulmonar Urinario, IRA, retención Trast. V: Hemorragia Cerebral, isquemia,

20 Sobredosis: Bloqueo AV de 1er Grado y 2do grado,Bradicardia con o sin hipotensión Paro cardiaco. Se resuelve los síntomas (vagales)

21 Clonidina Derivado de Imidazolina relacionado con la tolazolina y fentolamina Agonista Alfa 2 Adrenérgico Selectivo

22 Clonidina Clonidina Clonidium Catapress Propiedades Físicas:Se suele usar la sal de cloruro (HCl). La molécula presenta dos tautómeros. Se presenta como un polvo cristalino de color blanco. Es una sal soluble en agua y en alcohol deshidratado. Las soluciones en agua al 5% presentan un pH entre , según USP

23 Clonidina Mecanismo de Acción:Se proponen principalmente dos mecanismos de acción: Actuación como agonista α Actuación como agonista de receptores de imidazolina La acción de ambos es central. La acción simpático-inhibitoria es debida a la inhibición de neuronas reticuloespinales simpatoexcitatorias del nucleo reticular medular rostroventrolateral de la médula oblongada (RVLM). clonidine, an α2-adrenergic receptor agonist, lowers arterial pressure (AP) by centrally inhibiting sympathetic nerve activity. The sympathoinhibitory action of clonidine, and related drugs rilmenidine and moxonidine, are believed to result from inhibition of tonically active sympathoexcitatory reticulospinal neurons of the rostroventrolateral medulla reticular nucleus of the medulla oblongata (RVLM) (24). Central inhibition of sympathetic activity has advantages in the treatment of hypertension by decreasing release of renin as well as peripheral resistance (5). In peripheral tissues, clonidine is an agonist at α2-adrenergic receptors (α2AR) (26). It was therefore originally assumed that clonidine’s hypotensive actions were attributable to stimulation of central α2AR. However, even as early as 1976, Karppanen et al. (15) hypothesized that the antihypertensive actions of clonidine administered intracerebroventricularly related to nonadrenergic receptors, possibly histaminergic. More recently, the central effects of clonidine have been attributed to novel imidazoline receptors (6, 28, 32), some of which might be related to amine oxidases (21) or nicotinic ion channels (20). In an important structure-function analysis in 1984, Bousquet et al. (2) directly tested the non-α2AR hypothesis of clonidine’s action. They compared the ability of a panel of drugs to lower AP when microinjected into the RVLM of anesthetized cats. The drugs differed in their functions at known catecholaminergic receptors and in their chemical structures. It was noted that the hypotensive potencies of these drugs related to whether or not they contained an imidazoline ring structure, not necessarily to their affinities at α2AR. It was therefore proposed that clonidine lowered AP by an interaction in the ventral medulla with “sites preferring the imidazoline structure” (I sites). The original concept for imidazoline receptors proposed by Bousquet et al. (2) has been supported by two principal lines of investigation. First, the antihypertensive actions of agents injected into the RVLM of conscious animals have been correlated with radioligand binding affinities to I sites, but not α2AR, as measured in membranes of ventral medulla (6). Although Bousquet’s initial study was criticized because of the possible metabolism of microinjected norepinephrine (29) and because of other possible pathways of action (27), recent studies (3, 12) have upheld the proper rank ordering of affinities to subtype I1-binding sites versus hypotensive efficacies, without including catecholamines or imidazole acetic acid in the correlation. Second, the central administration of imidazolines, either intracerebroventricularly (4,13) or by microinjection into RVLM (9, 22), blocks the antihypertensive actions of systemically administered clonidine and/or rilmenidine or moxonidine. In contrast, a number of selective α2-antagonists appear to have either weak or no blocking effects. Finally, the concept that hypotension relates to stimulation of an imidazoline receptor has found therapeutic use. The development of rilmenidine and moxonidine, by favoring binding to I sites rather than α2AR, has minimized the most limiting side effect of clonidine, namely somnolence, attributable to α2AR (30). The evidence appears strong that imidazoline-binding sites and α2AR are physically distinct entities. Candidate proteins for imidazoline receptors have been isolated (32) that are not related to α2AR. Second, α2AR- and imidazoline-binding sites (I1 and I2) can be differentially downregulated by chronic drug treatments in vivo (11). I1- and α2AR-binding sites also differ in regard to their responses to GTP (8). Recently, I1 receptor activation was linked to diacylglycerol accumulation via phosphatidylcholine-phospholipase C activation, making ultimate expression via arachidonic acid release (28). This pathway has not been previously ascribed to an α2-adrenoceptor. On the other hand, other studies have suggested that the effects on AP of clonidine-like drugs may be entirely attributable to stimulation of α2AR. The first line of evidence is that when selective α2-antagonists are administered systemically, rather than centrally, the antihypertensive responses to intraventricular clonidine are totally blocked (14, 31). Second, the discharges of neurons (single cells) in RVLM, expressing α2AR (25), are inhibited by systemic and/or iontophoretic application of either catecholamines or clonidine (1, 29). Moreover, these effects are antagonized by iontophoretic application of methoxy-idazoxan, a drug that most investigators, except Ernsberger and Haxhiu (7), believe is a selective α2-antagonist. Third, transgenic mice expressing mutated α2AAR, with intact α2BAR and α2CAR subtypes of α2AR, were reported (17, 18) to lack hypotensive responses to two imidazolines, one of which was clonidine (Dr. Lee Limbird, Vanderbilt University; personal communication). It is also noteworthy to realize that ligands for I sites are not limited to imidazolines, but include guanidiniums (e.g., guanabenz, agmatine), an oxazole (e.g., rilmenidine), and a bicycloheptane, AGN (19). Most I site ligands potently agonize or antagonize hypotensive responses when administered centrally, except agmatine (a putative endogenous ligand for I sites) and the bicycloheptane (19,23). The latter two drugs possess moderate (agmatine) to high (AGN ) affinities at I sites but lack hypotensive potencies in vivo (16, 19). However, selective α2-agonists (e.g., guanabenz) and α2-antagonists (e.g., SKF-86466) exist that are nearly devoid of affinity at I1-binding sites. In two accompanying articles (7, 10), these divergent viewpoints are presented. Dr. Patrice Guyenet presents the traditional viewpoint that clonidine’s hypotensive action can be explained sufficiently by postsynaptic α2AR. On the other side of the debate, Drs. Paul Ernsberger and Musa A. Haxhiu contend that clonidine and other imidazolines act primarily via imidazoline receptors in the RVLM. ajpregu.physiology.org/content/273/5/R1569.full

24 Caract. FarmacologicasPros Analgesia y potenciación de anestésicos No producen taquicardia refleja Sedación Efecto persistente Acción Central No requieren infusión continua Pueden utilizarse en patología renal, hepática, coronaria, pulmonar e HTA gestacional No producen Hipertensión rebote al cese de la infusión Contras -Efecto persistente ante cambios hemodinamicos -Precaucion al administrarlo en infusion lenta -Precaucion en paciente que mantienen funcion ventricular en base a tono simpatico (Ej. Insuf Cardiaca)

25 Clonidina DexmedetomidinaAgonista Parcial Alfa2 Afinidad Alfa2/Alfa1 de 1:200 Accion sobre los receptores I1 Vida media 6-9hs Agonista completo Alfa2 Afinidad Alfa2/Alfa1 de 1:1600 Accion casi nula sobre receptores I1 2,3 horas

26 Receptores Alfa 2

27 Farmacodinamia Agonista alfa 2 adrenergico selectivo

28 Efecto Reducen la CAM de compuesto Halogenados.Prolonga y potencia efectos de anestesicos intravenosos. Prolonga potencia la anestesia raquidea, y bloqueos periféricos. Efecto diuretico Moderado Efecto relajante Muscular Efecto Neuroprotector Tratamiento de temblores post-operatorios, Snd de Abstinencia de Alcohol, nicotina, BZD y opiáceos.

29 Locus Coeruleus

30 Manejo del Dolor Mejora la analgesia de analgesicos tradicionales por un mecanismo independiente y por sinergismo con opioides (Dolor post-operatorio agudo y cronico, espasticidad, miofascial, neuropatico, cefalea cronica diaria y neuralgia post-herpetica) (Smith y Elliot 2001) Reduce la sensibilizacion central al dolor (Lavand´homme y col )

31 Bupivacaína Fentanilo Clonidina ml/h 1 9 mg/h 21µg/h 5µg/h 7 ml/h 2Esquemas Optimizados de Analgesia Peridural Torácica Continua para Cirugía Abdominal Mayor (Tomado de Curatolo y col. 2000) Bupivacaína Fentanilo Clonidina ml/h 1 9 mg/h 21µg/h 5µg/h 7 ml/h 2 8 mg/h 30µg/h 9 ml/h 3 13 mg/h 25µg/h

32 Como antihipertensivo perioperatorioVentajas de los agonistas 2-adrenérgicos para el tratamiento de HTA Perioperatoria No se asocian con taquicardia refleja. Estabilidad hemodinámica perioperatoria. Mejoran el balance miocárdico de oxígeno. No afecta la respuesta a los simpaticomiméticos. Puede utilizarse en asmáticos, pacientes con insuficiencia vascular, diabéticos y EPOC. No produce depresión directa de la contractilidad miocárdica. Potencia los efectos de los anestésicos. Provee analgesia y sedación.

33 Criterios para la administracion de agonistas Alfa2 en la HTAAntecedentes de HTA con abandono de la medicacion Registros compatibles con HTA ante situaciones de stress (en la sala, esporadicos, durante chequeo cardiologico pre qx, durante el perioperatorio) Respuesta hipertensiva exagerada ante estimulos intraoperatorios a pesar de evaluarse analgesia y plano anestesico adecuado (gralmente HTA alta y FC baja) Ausencia de fallas en la tecnica anestésica.

34 Dosificacion (para HTA perioperatoria)Clonidina 0,5-1mcg/kg (pudiendose repetir la dosis hasta no mas de 3mcg/kg) Dexmedetomidina 0,3-0,6mcg/kg (pudiendose repetir hasta 1,5mcg/kg) Ambos fcos en infusion en no menos de 10-15min.

35 Embarazo e HTA Gralmente se inicia el tto con alfa-metil-dopa via oral. Ante la falta de respuesta se continua con clonidina via oral (0,15- 0,6 mg /día) Durante las crisis (TA 170/110) la clonidina en infusion ev constituye uno de los tratamientos de eleccion (600mcg en 500ml de dext 5% a 30ml/hora regulando la infusion de acuerdo a la respuesta)

36 DOSIS

37