1. FARMACOLOGIA CLINICA DE LOS
VASOPRESORES E INOTROPICOS
KATHERINE CARVAJAL CANIZALES
RESIDENTE MEDICINA CRITICA Y CUIDADO INTENSIVO
DEPARTAMENTO DE FARMACOLOGIA CLINICA Y TERAPEUTICA
UNIVERSIDAD DE LA SABANA
SEPTIEMBRE 2015
8. J. Vincent. Clinical Reviews: Circulatory shock. N Engl J Med. 2013;369(18):1726–34.
9. Rocha LL, Pessoa CMS, Corrêa TD, Pereira AJ, de Assunção MSC, Silva E. Current concepts on hemodynamic
support and therapy in septic shock. Brazilian J Anesthesiol. 2015
10. METAS MACRO Y MICROCIRCULATORIAS
J. Vincent. Clinical Reviews: Circulatory shock. N Engl J Med. 2013;369(18):1726–34.
11. METAS MACRO Y MICROCIRCULATORIAS
J. Vincent. Clinical Reviews: Circulatory shock. N Engl J Med. 2013;369(18):1726–34.
19. NORADRENALINA
• Mayor neurotransmisor adrenérgico liberado a nivel
posganglionar
• Agonista α 1 potente, en menor medida β1
• Vasoconstrictor e inotrópico. Efectos cronotrópicos mínimos
Bangash MN, Kong ML, Pearse RM. Use of inotropes and vasopressor agents in critically ill patients. Br J
Pharmacol. 2012;165(7)
20. NORADRENALINA
ESTRUCTURA QUIMICA
Catecol ( orto dihidroxibenceno)
Bangash MN, Kong ML, Pearse RM. Use of inotropes and vasopressor agents in critically ill patients. Br J
Pharmacol. 2012;165(7)
28. ADRENALINA
Vida media 2 minVida media 2 min pKa 8.59pKa 8.59pKa 8.59pKa 8.59
http://www.drugs.com/pro/adrenalin-injection.html
Christopher B. Overgaard, and Vladimír Džavík Circulation. 2008;118:1047-1056
35. DOPAMINA
Christopher B. Overgaard, and Vladimír Džavík Circulation. 2008;118:1047-1056
Bangash MN, Kong ML, Pearse RM. Use of inotropes and vasopressor agents in critically ill patients. Br J Pharmacol. 2012
38. POLIMORFISMO ADRENORRECEPTORES
Ahles A, Engelhardt S. Polymorphic Variants of Adrenoceptors: Pharmacology, Physiology, and Role in
Disease. Pharmacol Rev. 2014
39. Ahles A, Engelhardt S. Polymorphic Variants of Adrenoceptors: Pharmacology, Physiology, and Role in
Disease. Pharmacol Rev. 2014
40. + Arg389
Ahles A, Engelhardt S. Polymorphic Variants of Adrenoceptors: Pharmacology, Physiology, and Role in
Disease. Pharmacol Rev. 2014
44. VASOPRESINA
MECANISMOS DE ACCIÓN
Receptores V1Receptores V1
Modulación de
canales de KATP
Modulación ON
Potenciación actividad
catecolaminas
Holmes CL. Vasoactive drugs in the intensive care unit. Curr Opin Crit Care. 2005
50. • No diferencia en la mortalidad al ser
comparada con la NA en shock séptico.
– 52,5% vs. 48,5% (IC: 0.97 – 1.12 p=0.1).
• Mayor incidencia de arritmias en el grupo de
dopamina.
N Engl J Med 2010;362:779-89
51. Chest 2003;123;1266-1275
• Bajas dosis de Dopa no mejoran la función renal por el contrario
empeora la circulación esplácnica, función endocrina y el sistema
inmune; y atenúa el esfuerzo ventilatorio.
– Dósis baja es impredecible en pacientes de UCI “Invalida”
– Incemento de la actividad de renina plasmática Vasoconst Art Aferente.
– Taquifilaxia del efecto (2h)
– Incrementa el trabajo tubular.
56. DOBUTAMINA
• Catecolamina sintética. Mezcla racémica
• Las sustituciones del grupo metilo confieren resistencia a metabolismo por
la MAO
• Las interacciones fármaco-receptor están también influenciadas por
polimorfismos de los receptores adrenérgicos
• Afinidad por B1 y B2 . A dosis más altas efecto α1
Bangash MN, Kong ML, Pearse RM. Use of inotropes and vasopressor agents in critically
ill patients. Br J Pharmacol. 2012
58. DOBUTAMINA
Bangash MN, Kong ML, Pearse RM. Use of inotropes and vasopressor agents in critically
ill patients. Br J Pharmacol. 2012
59. DOBUTAMINA
Bangash MN, Kong ML, Pearse RM. Use of inotropes and vasopressor agents in critically
ill patients. Br J Pharmacol. 2012
Metabolizado por la COMT a 3-O-metildobutaminaMetabolizado por la COMT a 3-O-metildobutaminapKa 9.27pKa 9.27
60. DOBUTAMINA
EFECTOS ADVERSOS
Taquicardia, aumento del
VO2, Taquifilaxia.
Taquiarrítmias, temblor ,
hipotensión.
CONTRAINDICACIONES
• Estenosis aórtica
• Relativa: Arritmias
• Hipersensibilidad a los
simpaticomiméticos
Bangash MN, Kong ML, Pearse RM. Use of inotropes and vasopressor agents in critically
ill patients. Br J Pharmacol. 2012
62. INHIBIDOR DE FOSFODIESTERASA III:
MILRINONE
Bangash MN, Kong ML, Pearse RM. Use of inotropes and vasopressor agents in critically
ill patients. Br J Pharmacol. 2012
63.
64. INHIBIDOR DE FOSFODIESTERASA III:
MILRINONE
α
β
GTP
γ
Estimula la
actividad de la
adenil ciclasa
Activación de la
proteína G
ATP
AMPc
PKA
Calcio
ATPasa
Retículo
sarcoplásmico
Complejo actina
miosina
Canal de calcio
dependiente de
voltaje tipo L
Receptor
β
5´ AMP
PDE
Bangash MN, Kong ML, Pearse RM. Use of inotropes and vasopressor agents in critically
ill patients. Br J Pharmacol. 2012
65. INHIBIDORES DE FOSFODIESTERASA III:
MILRINONE
Bangash MN, Kong ML, Pearse RM. Use of inotropes and vasopressor agents in critically
ill patients. Br J Pharmacol. 2012
pKa 4.82 – 7. 54pKa 4.82 – 7. 54
66. INHIBIDORES DE FOSFODIESTERASA III:
EFECTOS ADVERSOS
Bangash MN, Kong ML, Pearse RM. Use of inotropes and vasopressor agents in critically
ill patients. Br J Pharmacol. 2012
71. LEVOSIMENDAN
pKa 4.9 -10.5pKa 4.9 -10.5
Bangash MN, Kong ML, Pearse RM. Use of inotropes and vasopressor agents in critically
ill patients. Br J Pharmacol. 2012
72. LEVOSIMENDAN
EFECTOS ADVERSOS
Hipotensión
Taquicardia
Cefalea, hipocalcemia,
naúseas, mareo.
CONTRAINDICACIONES
• Hipotensión severa
• Obstrucción mecánica que afecte
el llenado ventricular, el flujo de
salida o ambos.
• Deterioro renal severo
(depuración de creatinina < 30
ml/minuto) y deterioro hepático
severo.
• Historia de torsade de pointes
Bangash MN, Kong ML, Pearse RM. Use of inotropes and vasopressor agents in critically
ill patients. Br J Pharmacol. 2012
Figure 1. Simplified schematic of postulated intracellular actions of β-adrenergic agonists. β-Receptor stimulation, through a stimulatory Gs-GTP unit, activates the adenyl cyclase system, which results in increased concentrations of cAMP. In cardiac myocytes, β1-receptor activation through increased cAMP concentration activates Ca2+ channels, which leads to Ca2+-mediated enhanced chronotropic responses and positive inotropy by increasing the contractility of the actin-myosin-troponin system. In vascular smooth muscle, β2-stimulation and increased cAMP results in stimulation of a cAMP-dependent protein kinase, phosphorylation of phospholamban, and augmented Ca2+ uptake by the sarcoplasmic reticulum (SR), which leads to vasodilation. Adapted from Gillies et al3 with permission of the publisher.
Figure 2. Schematic representation of postulated mechanisms of intracellular action of α1-adrenergic agonists. α1-Receptor stimulation activates a different regulatory G protein (Gq), which acts through the phospholipase C system and the production of 1,2-diacylglycerol (DAG) and, via phosphatidyl-inositol-4,5-biphosphate (PiP2), of inositol 1,4,5-triphosphate (IP3). IP3 activates the release of Ca2+ from the sarcoplasmic reticulum (SR), which by itself and through Ca2+-calmodulin–dependent protein kinases influences cellular processes, leading in vascular smooth muscle to vasoconstriction. Adapted from Gillies et al3 with permission of the publisher.
La norepinefrina es una catecolamina y una fenetilamina. El estereoisómero natural es L-(−)-(R)-norepinefrina. El término &quot;norepinefrina&quot; se deriva del prefijo químico nor-, que indica que la norepinefrina es el siguiente menor homólogo de la epinefrina. Las dos estructuras difieren sólo en que la epinefrina tiene un grupo metil unido a su nitrógeno, mientras que el grupo metil es reemplazado por un átomo de hidrógeno en la norepinefrina. El prefijo nor- es probablemente derivado como una abreviación de la palabra &quot;normal&quot;, usado para indicar un compuesto desmetilado.8 9 10
Los anestésicos ciclopropano y halotano incrementan el automatismo cardiaco sensibilizando el miocardio a la acción intravenosa de la norepinefrina, por lo que se ha contraindicado su uso durante la anestesia con estos gases (riesgo de producir taquicardia ventricular y fibrilación).
Antihistaminicos: proteína Gi receptores H3 normalemnte facilitan la recaptacion
Los anestésicos ciclopropano y halotano incrementan el automatismo cardiaco sensibilizando el miocardio a la acción intravenosa de la norepinefrina, por lo que se ha contraindicado su uso durante la anestesia con estos gases (riesgo de producir taquicardia ventricular y fibrilación).
Antihistaminicos: proteína Gi receptores H3 normalemnte facilitan la recaptacion
Hiperlactatemia : glucolisis
Dopaminergic terminal neurotransmission in
relation to mode of action of dopamine (DA) reuptake inhibitors
and amphetamine; (b) Effects of dopamine reuptake inhibitors
at the dopaminergic nerve terminal; (a) DA transporter
(DAT) is one of the most important molecules located at the
dopaminergic nerve terminals and regulate dopaminergic neurotransmission.
(1) Amphetamine interacts with the DAT carrier
to facilitate DA release from the cytoplasm through an
exchange diffusion mechanism (c). At higher intracellular concentrations,
amphetamine also (2) disrupts vesicular storage of
DA, and (3) inhibits the Monoamine Oxidase (MAO). Both
these actions increase cytoplasmic DA concentrations. (4)
Amphetamine also inhibits DA uptake by virtue of its binding
to and transport by the DAT. AADC aromatic acid decarboxylase;
AC adenylyl cyclase; cAMP cyclic adenosine monophosphate;
COMT catechol-O-methyltransferase; D1–D5 dopamine
receptors 1–5; DA dopamine; DAT dopamine transporter; DOPA
3,4-dihydroxyphenylalanine; DOPAC dihydroxyphenylacetic
acid; Gi, Go, and Gs protein subunits; HVA homovanillic acid;
MAO monoamine oxidase; TH tyrosine hydroxylase; VMAT
vesicular monoamine transporter. (b) Sodium and chloride bind
to the DAT to immobilize it at the extracellular surface. This
alters the conformation of the DA binding site on the DAT to
facilitate substrate (i.e., DA) binding. DAT reuptake inhibitors
bind to DAT competitively and inhibit DA–DAT bindings,
resulting increasing DA concentrations in the synaptic cleft. (c)
Amphetamine, in competition with extracellular DA, binds to the
transporter. Substrate binding allows the movement of the carrier
to the intracellular surface of the neuronal membrane,
driven by the sodium and amphetamine concentration gradients,
resulting in a reversal of the flow of DA uptake.
Amphetamine dissociates from the transporter, making the
binding site available to cytoplasmic DA. DA binding to the
transporter enables the movement of the transporter to the
extracellular surface of the neuronal membrane, as driven by
the favorable DA concentration gradient. DA dissociates from
the transporter, making the transporter available for amphetamine,
and thus another cycle
Los anestésicos ciclopropano y halotano incrementan el automatismo cardiaco sensibilizando el miocardio a la acción intravenosa de la norepinefrina, por lo que se ha contraindicado su uso durante la anestesia con estos gases (riesgo de producir taquicardia ventricular y fibrilación).
Antihistaminicos: proteína Gi receptores H3 normalemnte facilitan la recaptacion
HALOPERIDOL PUEDE SUPRIMIR LA VASODILATACION RENAL
Elaboration and control of arginine vasopressin (AVP). Osmotic control. An increase in serum osmolality is detected by osmoreceptors in the supraoptic and paraventricular neurons of the hypothalamus. Granules of AVP are elaborated and axonally transported to the posterior lobe of the pituitary gland. From there they are released into the circulation to reach the V2 receptors in the distal tubule, where they retain water and restore the serum osmolality. Hemodynamic control. Decreases in venous volume are sensed by stretch receptors in the atria and great veins, and decreases in arterial pressure are sensed by baroreceptors in the aortic arch and carotid sinus. The afferent arc is via the vagal and glossopharyngeal nerves to the solitary nucleus in the medulla oblongata (vasomotor center). The efferent arc, from the vasomotor center to the hypothalamic nuclei, induces AVP release. At low levels (&lt; 5 pg/mL), AVP stimulation of V2 receptors may cause inappropriate water retention. At high levels (&gt; 20 pg/mL), AVP stimulation of V1a receptors causes vasoconstriction and participates in the baroreceptor reflex.
Figure 1. Vasopressin V1 receptor activation. The binding of arginine vasopressin (AVP) to its V1 receptor (V1R) stimulates membrane-bound phospholipase (PLCB) via stimulation of a G-coupled protein (Gq), which in turn results in inositol triphosphate (IP3) formation and mobilization of intracellular Ca2+ (icCa2+). A separate phosphorylation cascade occurs via diacylglycerol (DAG) and protein kinase C (PKC), which has downstream effects, including vascular smooth muscle (VSM) vasoconstriction, cell growth, adrenocorticotrophic hormone (ACTH) release, and platelet aggregation.
Vasopressin V2 receptor activation. The binding of arginine vasopressin (AVP) to the V2 vasopressin receptor (V2R) stimulates a Gs-coupled protein that activates adenylyl cyclase, in turn causing production of cAMP to activate protein kinase A (PKA). This pathway increases the exocytosis of aquaporin water channel–containing vesicles (AQMCV) and inhibits endocytosis of the vesicles, both resulting in increases in aquaporin 2 (AQ2) channel formation and apical membrane insertion. This allows an increase in the permeability of water from the collecting duct (CD).
1) Inactiva los canales de K ATP-dependientes
2) Bloquea el incremento de GMPc inducido por el óxido nítrico
3) Disminuye la síntesis de la enzima inducible óxido nítrico sintasa estimulada por endotoxinas
4) Revierte la regulación a la baja de los receptores adrenérgicos.
LITIO INHIBICION DE LA ESTUMULACION DE LOS RECEPTORES V2 Y EL AUMENTO DE LA ADENICICLASA MEDIADA POR AV
1679 pacientes no diferencia en la mortalidad a 28 días, mayor arrítmias con dopa
Revisión de RTC
30 años
1984 y 1995 Estudios en perros
1679 pacientes no diferencia en la mortalidad a 28 días, mayor arrítmias con dopa
Los anestésicos ciclopropano y halotano incrementan el automatismo cardiaco sensibilizando el miocardio a la acción intravenosa de la norepinefrina, por lo que se ha contraindicado su uso durante la anestesia con estos gases (riesgo de producir taquicardia ventricular y fibrilación).
Antihistaminicos: proteína Gi receptores H3 normalemnte facilitan la recaptacion
HALOPERIDOL PUEDE SUPRIMIR LA VASODILATACION RENAL
Los anestésicos ciclopropano y halotano incrementan el automatismo cardiaco sensibilizando el miocardio a la acción intravenosa de la norepinefrina, por lo que se ha contraindicado su uso durante la anestesia con estos gases (riesgo de producir taquicardia ventricular y fibrilación).
Antihistaminicos: proteína Gi receptores H3 normalemnte facilitan la recaptacion
HALOPERIDOL PUEDE SUPRIMIR LA VASODILATACION RENAL