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- 2. • 2017, J. Brent et al. (eds.), Critical Care Toxicology, DOI 10.1007/978-3-319-17900-1_27 • Hein, L. (2008). α‐Adrenergic System. In: Offermanns, S., Rosenthal, W. (eds) Encyclopedia of Molecular Pharmacology. Springer, Berlin, Heidelberg • Alberts, Biología molecular 5 ed. • Ehab Farag. Basic sciences in anesthesia, 2017 Springer Link. • Claudia Lucía Arroyave H., José Julian Aristizábal, Lina María Peña A., Ubier Eduardo Gómez, Fundamentos de medicina: Toxicología clínica , CIB, 2010. • Peña, Lina. Z. Andrés. Protocolos de manejo de paciente intoxicado, 2017. 20/10/2022 Agonistas Alfa-2 2
- 4. Medicamentos agonistas Alfa 2 y de receptores de imidazolina Diego A. Latorre, Md. R1 Toxicología Clínica UdeA.
- 5. Agenda 20/10/2022 Agonistas Alfa-2 5 Medicamentos receptores alfa 2 e imidazoles Mecanismos de acción Dexmedetomidina Otros antihipertensivos, sedantes y descongestionantes de la vía alfa- 2
- 6. 9700 exposiciones tóxicas sólo de clonidina (2014, FDA – USA) 1 en 5 intox. síntomas moderados o severos de intoxicación No solamente uso humano (Xylazina). Múltiples funciones – área gris. 20/10/2022 Agonistas Alfa-2 6 Alfa 1 • Contracción de músculo liso • Inotropismo Alfa 2 • Inhibidor de neurotransmisión central. • ¿Contracción m. liso? B1 • Corazón principalmente. • Ino y cronotropismo. B2 • Relajación de músculo liso. • Inotropismo. Otros • B3 • D
- 7. Generalidades • Actúa por receptores acoplados a proteína G • Activados en mayor o menor medida con adrenalina y noradrenalina. • “pelear y huir” 20/10/2022 Agonistas Alfa-2 7 Hein, L. (2008). α‐Adrenergic System. In: Offermanns, S., Rosenthal, W. (eds) Encyclopedia of Molecular Pharmacology. Springer, Berlin, Heidelberg. https://doi- org.udea.lookproxy.com/10.1007/978-3-540-38918-7_5 Tirosin hidroxilasa Descarboxilasa de aa’s aromáticos Dopamina – B- hidroxilasa
- 10. Acoplados a proteína G Acoplamiento a proteínas: QISSS Q A1: Proteína Gq I A2: G I inhibitoria S B2: S “stimulant” S B3: S “stimulant” S D: S “stimulant” 20/10/2022 Agonistas Alfa-2 10 Alberts, Biología molecular 5 ed.
- 11. 20/10/2022 Agonistas Alfa-2 11
- 12. Receptores alfa 2 20/10/2022 Agonistas Alfa-2 12 Terminales nerviosas presinápticas centrales. Acoplados G i, inhibe vía adenilato ciclasa= ATP AMPc. Inhiben en neurona postsináptica central Ach y NE. Periféricamente, alfa-2: Inh. Célula beta pancreática Inhibe lipólisis Modula agregación plaquetaria Ehab Farag. Basic sciences in anesthesia, 2017 Springer Link.
- 14. Agonistas Alfa-2
- 16. Receptor Alfa-2 adrenérgico 20/10/2022 Agonistas Alfa-2 16
- 17. Tipos de receptor a2 Inhibición de adenilato ciclasa por prot G. También se conocen funciones al parecer reguladoras en ERK1-2 extracelular (vía adrenérgica alfa 2 extracelular). Estimulación experimental a dosis altas en modelos animales : inhibe funciones adrenérgias en SNC 20/10/2022 Agonistas Alfa-2 La potencia de agonistas a2-a es, en orden: Oximetazolina Clonidina Epinefrina Norepinefrina Fenilefrina ¿Serotonina? Antagonistas: • Fentolamina • Clorpromazina • Prazosin • Propranolol • Otros Alfa 2A 17
- 18. Tipos de receptor a2 Inhibición de adenilato ciclasa por prot G. También señalización alfa 2 extracelular vía “(ERK1/2) pathways” quinasas. Inhibición en modelo animal en receptores alfa 2b periféricos causa vasoconstricción refleja. 20/10/2022 Agonistas Alfa-2 Potencia para agonismo a-2b: Oximetazolina Epinefrina Norepinefrina Fenilefrina Dopamina Antagonistas de a-2b: Fentolamina Clorpromazina Prazosina Propranolol Alfa 2B 18
- 19. Tipos de receptor a2 Rol crítico en la modulación de norepinefrina en SNC vía proteína G. 20/10/2022 Agonistas Alfa-2 Alfa 2a y 2c se requieren para transmisión simpática/noradrenérgica central. 2a modula las frecuencias de estimulación neurocentral alta, las frecuencias bajas se modulan por 2c. alpha 2c 19
- 20. Clasificación de compuestos agonistas adrenérgicos: según su selectividad. a 1: Fenilefrina. a 2: Clonidina B 1: Dobutamina B 2: Salbutamol, terbutalina, salmeterol. 20/10/2022 Agonistas Alfa-2 A 1 y 2: Oximetazolina B1 y B2: Isoproterenol Alfas y betas: Adrenalina A 1 y 2, B1: Noradrenalina, D: Dopa. Selectivos: No selectivos: • Liberadores: Anfetaminas. • IMAO: Segitina • Inh. COMT: Entacapone. • Inh. Recaptación: cocaína. Mecanismos alternos: 20 Ehab Farag. Basic sciences in anesthesia, 2017 Springer Link. Efectos adversos: ¡¡¡¡¡MATHS!!!!! Midriasis, Malignant Disrrythmia, Agitación, Angina, Alucinaciones, Ansiedad, Taquicardia, Temblores, HIC, Hipertermia, Hiperglucemia, Hipertensión, Sudoración, Simpaticomimesis.
- 21. 20/10/2022 Agonistas Alfa-2 21
- 22. Oxazolinas • Actúan en el receptor de imidazolina y/o alfa 2 • Clonidina tiene la mayor carga de intoxicacíon • Simpaticolíticos / hipotensores 20/10/2022 Agonistas Alfa-2 Generalidades Receptores I-1: hidrólisis de fosfatidilcolina. I: Eleva ácido araquidónico y eleva eicosanoides. I: bloquea antiporter Na+/H+ en SNC. “neurocitoquina”. (Rilmenidina) Otros 22
- 23. 20/10/2022 Agonistas Alfa-2 23
- 24. Clonidina • Onset: 30-60 • +-100% biodisponibilidad • Pico 2-3 hr • Tmax 8hr • Excreción renal sin cambios +-100% • Ésta y otros vienen también en parches • Potencia 200 a 1 entre a2 y a1. 20/10/2022 Agonistas Alfa-2 24 Tratamiento: • ABCDE • No descontaminación TGI – neurodepresor • Cristaloides inicialmente, si no hay respuesta a reto de líquidos – Dopamina o NE • Atropina a dosis medias-altas en caso de bradicardia. Dosis menores a 0,5 adultos y 0,02mg/kg/dosis en niños – bradicardia paradójica. Seger, Donna L. (2002). Clonidine Toxicity Revisited. Clinical Toxicology, 40(2), 145–155. doi:10.1081/CLT-120004402
- 25. Clonidina • Clínica: coma, bradicardia, hipotensión y apnea. • Pupilas puntiformes. • Hipotermia. • No sigue estrictamente dosis/respuesta. Desde 0,2 adultos cuadros graves. 20/10/2022 Agonistas Alfa-2 25 Seger, Donna L. (2002). Clonidine Toxicity Revisited. Clinical Toxicology, 40(2), 145–155. doi:10.1081/CLT-120004402
- 26. Clonidina: Toxicología Poblaciones especiales • En algunas poblaciones dosis eq. 1-2 mg de clonidina intox. grave Mecanismos •Activación de α2- adrenérgicos. •Inhibición de tr. N. Solitario. •Inhibición relativa de NE neurocentral. •Cambios CV y SNC. •Inhibición locus cerúleo Aumento de GABA e inh. NE. ¿NO vascular? Efectos • Bradicardia, Hiper- hipotensión, Sedación/ sedoanalgesia. Efectos adversos • Hipo o hipertensión, nauseas, • bradicardia, FA, BAV, otros. • ¿Hipertensión de rebote? Interacciones • No usar inh. CYP1A2 • Contribuciones menores de CYP3A4, CYP1A1, • y CYP3A5. 1 2 3 4 5 20/10/2022 Agonistas Alfa-2 26
- 27. Dexmedetomidina • Agonista adrenérgico que tiene afinidad también para repectores de imidazolinas. • Sedación profunda y amnesia. • En sobredosis BAV 2do gr. • Se usa como ahorrador BZD en Alcohol y opioides. • Metabolizada vía glucoronidación o CYP450 • Especificidad 1620:1. a2:a1. • Modula la respuesta CV a estresores quirúrgicos. Mínimo efecto en mecánica respiratoria. 20/10/2022 Agonistas Alfa-2 27 Anesth Prog 62:31–38 2015
- 28. Dexmedetomidina • Altamente lipofílica, VD 118Lt • Onset rápido 6-8 min • Reduce requerimiento de BZD y opioides • uP% 94% • Metabolismo • N-glucoronidación • Hidroxilación alifática CYP2a6 ppalmente • Otros metabolitos • Eliminación Clearance 39 lt/hr 20/10/2022 Agonistas Alfa-2 28
- 30. 20/10/2022 Agonistas Alfa-2 30 Verificar toxicidad incluso con cargas bajas Ciclos coma/agitación Tratamiento puede ser de soporte ¿Naloxona? ¿Atipamezol? ¿Atropina? ¿Yohimbina? No hay antídoto específico (no usar anagonistas a- 2)
- 32. ? 20/10/2022 Agonistas Alfa-2 32 Dato resumen Tipo de ingestión Accidental (Alcohólico) Vol. Aprox. Calculado 10 gr AMTZ Ingreso 1-2hr post ¿Estado? Estable HD. GCS 7/15. ¿Complicaciones? IOT, FA RVR +Digital. 5to día alta. ¿Tratamiento? Únicamente soporte
- 33. 10/20/2022 Agonistas Alfa-2 33
- 34. 10/20/2022 Agonistas Alfa-2 34 (2017, Med. CO) “en su mayoría por analgésicos (51.1%), antihipertensivos (12.8%) y anticonvulsivantes (10.6%). Los medicamentos psiquiátricos utilizados fueron antidepresivos y antipsicóticos (27.8%)”.
- 35. Estado mental alterado AMS en pediatría 20/10/2022 Agonistas Alfa-2 35
- 36. Estado mental alterado AMS en pediatría 20/10/2022 Agonistas Alfa-2 36 Clonidina Organofosforados Tetrahidrozolina ¿Algunos opioides?
- 37. ¿Cuáles agonistas o antagonistas se podrían referenciar en la imagen? (urgencia o emergencia hipertensiva en niños) 20/10/2022 Agonistas Alfa-2 37
- 38. ¿Cuáles agonistas o antagonistas se indican en la imagen? 20/10/2022 Agonistas Alfa-2 38
Notas del editor
- Supraspinal Sites The catecholaminergic cell groups A5, A6 (locus coeruleus, LC), and A7 in the dorsolateral pons of the brainstem have been identified as the most important supraspinal sites for a antinociception. These areas express a 2 2 2ª 2 AR-mediated ARs and send and receive projections to and from other pain-modulating parts of the brain, for instance, the periaqueductal gray (PAG) and the rostral ventromedial medulla (RVM).
- a-Adrenergic System. Figure 1 Synthesis and release of noradrenaline and adrenaline from sympathetic nerve endings (left) and from the adrenal gland (right). Noradrenaline and adrenaline are synthesized from the precursor amino acid tyrosine and are stored at high concentrations in synaptic vesicles. Upon activation of sympathetic nerves or adrenal chromaffin cells, noradrenaline and adrenaline are secreted and can activate adrenergic receptors on surrounding cells (sympathetic nerve), or they enter the blood circulation (adrenaline released from the adrenal gland). Release of noradrenaline from nerve terminals is controlled by presynaptic inhibitory a - and activating ß -adrenergic receptors. Actions of noradrenaline are terminated by uptake into nerve terminals and synaptic vesicles by active transporters (NET, EMT, VMAT) and by uptake into neighboring cells (not shown). Abbreviations: AADC, aromatic L-amino acid decarboxylase; COMT, catechol O-methyltransferase; DßH, dopamine ß-hydroxylase; EMT, extraneuronal noradrenaline transporter; MAO, monoamine oxidase; NET, noradrenaline transporter; PNMT, phenylethanolamine-N-methyltransferase; TH, tyrosine hydroxylase; VMAT, vesicular monoamine transporter.
- Figure 3-15. Signaling mechanisms for neurotransmitters. This simplifi ed scheme depicts major cellular signaling mechanisms that are operational in many neurons and muscle and exocrine cells. Chemicals acting on the numbered elements are listed in Table 3-5 . Fast signaling is initiated by the opening of ligandgated Na + /Ca 2+ channels (1, 2). The resultant cation infl ux decreases the inside negative potential (ie, evokes depolarization) and thus triggers the opening f the voltage-gated Na + and Ca 2+ channels (7, 8). As a second messenger, the infl uxed Ca 2+ activates intracellular Ca 2+ -binding proteins such as calmodulin (CM) and troponin C (TC), which, in turn, enhance the phosphorylation of specifi c proteins, causing activation of specifi c cellular functions. The signal is terminated by channels and transporters (eg, 9, 10) that remove cations from the cells and thus reestablish the inside negative resting potential (ie, cause repolarization) and restore the resting Ca 2+ level. Fast signaling can be suppressed by opening the ligand-activated Cl - or K + channels (3–6), which increases the inside negativity (ie, induces hyperpolarization) and thus counteracts opening of the voltage-gated Na + and Ca 2+ channels (7, 8). Signal transduction from other receptors (11–13) that are coupled to G q proteins involves generation of the second messenger inositol 1,4,5-trisphosphate (IP ) and diacylglycerol (DAG) by phospholipase C (PLC), whereas signaling from receptor 14 that is coupled to G s 3 protein involves production of cyclic AMP (cAMP) by adenylyl cyclase (AC). These second messengers in turn infl uence cellular activities by mobilizing Ca 2+ from the sarcoplasmic or endoplasmic reticulum (SR and EPR), as IP does, or by activating protein kinases, as cAMP and DAG do, which activate PKA and PKC, respectively. For clarity, this fi gure does not depict what inhibitory receptors 5 and 6 are G channels, they also inhibit AC. Ach, acetylcholine; Glu, glutamate; GABA, γ-aminobutyric acid; Gly, glycine; Op, opioid peptides; NE, norepinephrine; E, epinephrine; 5HT, 5-hydroxytryptamine; G, G protein; PIP i protein–coupled and that besides opening K + , phosphatidylinositol 4,5-bisphosphate. Encircled positive and negative signs indicate activation and inhibition, respectively.
- Signs and symptoms of poisoning mimicked those of a -adrenergic receptor agonists such as clonidine, and included nausea, hypotension, hyperglycemia, bradycardia, and miosis. No deaths occurred. A series of acute amitraz poisonings has been recently reported in South Africa, with CNS depression as the most common clinical sign (Veale et al. , 2011). Although a adrenoceptor antagonists such as yohimbine have proven useful as antidotes in animals (Andrade and Sakate, 003), their usefulness in managing amitraz poisoning in humans has not been evaluated. 2
- The same signal molecule can activate many different GPCR family members; for example, adrenaline activates at least 9 distinct GPCRs, acetylcholine another 5, and the neurotransmitter serotonin at least 14. The different receptors for the same signal are usually expressed in different cell types and elicit different responses.
- A 2 -Adrenergic receptors regulate a wide range of signalling pathways viainteraction with multiple heterotrimeric G proteins including inhibition of adenylyl cyclase, stimulation of phospholipase D, stimulation of mitogen-activated protein kinases, stimulation of K + i/o currents and inhibition of Ca2+ currents. The three a -receptor subtypes have unique patterns of tissue distributionin the central nervous system and in peripheral tissues. The a 2 -receptor is expressed widely throughout the central nervous system including the locus coeruleus, brain stem nuclei, cerebral cortex, septum, hypothalamus, and hippocampus. In the periphery, a 2ª 2ª -receptors are expressed in kidney, spleen, thymus, lung, and salivary gland. The a –receptor primarily shows peripheral expression (kidney, liver, lung, and heart) and only lowlevel expression in thalamic nuclei of the central nervous system. The a –receptor appears to be expressed primarily in the central nervous system (striatum, olfactory tubercle, hippocampus, and cerebral cortex), although very low levels of its mRNA are present in the kidney. A 2ª -, a 2B , and a -receptors are located presynaptically in order to inhibit noradrenaline release from 2C sympathetic nerves. Activation of these receptors leads to decreased sympathetic tone, decreased blood pressure and heart rate. Central a -receptors mediate sedation and analgesia. A 2B 2ª -Receptors mediate contraction of vascular smooth muscle, and in the spinal cord they are essential components of the analgesic effect of nitrous oxide At present, no drugs exist that can selectively activate a 2 1 -receptor subtypes. Clonidine stimulates all three a subtypes with similar potency. Clonidine lowers blood pressure in patients with hypertension and it decreases sympathetic overactivity during opioid withdrawal. In intensive and postoperative care, clonidine is a potent sedative and analgesic and can prevent postoperative shivering. Clonidine and its derivative brimonidine lower intraocular pressure of glaucoma patients when applied locally. Moxonidine may have less sedative side effects than clonidine when used as an antihypertensive. It has been suggested that moxonidine activates “imidazoline receptors” instead of a2 -receptors. The a –receptor agonists oxymetazoline and xylometazoline are being used as nasal decongestants. At present, a –receptor antagonists are not used in human medicine. However, in veterinary practice the a -receptor antagonist atipamezole can rapidly reverse anaesthesia mediated by the a 2 agonist medetomidine. In the future, subtype-selective drugs may greatly improve the therapy of diseases involving a 1 –or a 2 -adrenergic receptor systems.
- FIGURE 13–5. Noradrenergic nerve ending. The postsynaptic membrane may represent an end organ or another neuron in the CNS. Brief examples of effects resulting from postsynaptic receptor activation are shown. Xenobiotics in Tables 13・ and 13・ produce effects by inhibiting transport of dopamine (DA) or norepinephrine (NE) into vesicles through VMAT2 [1]; causing movement of NE and DA from vesicles into the cytoplasm [2]; activating or antagonizing postsynaptica- and ß-adrenergic receptors [3・]; modulating NE release by activating or antagonizing presynaptic a 2 -autoreceptors [6], dopamine ) heteroreceptors [10], or ß -autoreceptors [11]; blocking reuptake of NE (NET inhibition) [7]; causing reverse transport of NE from the cytoplasm into the synapse via NET by raising cytoplasmic NE concentrations [8]; inhibiting monoamine oxidase (MAO) to prevent NE degradation [9]; or inhibiting COMT to prevent NE degradation [12]. Controversy exists as to whether COMT筑s enzymatic action mainly occurs in the synapse r intracellularly. AADC = aromatic l-amino acid decarboxylase; ß-hydroxylase = dopamine-ß-hydroxylase; COMT = catechol-O-methyltransferase; CNS = central nervous system; DOPGAL = 3,4-dihydroxyphenylglycoaldehyde; G = G protein; NET = membrane NE reuptake transporter; NME = normetanephrine; VMAT2 = vesicle uptake transporter for NE. 2 2 (D 2
- Actúan como paracrinos y autocrinos, inhiben vías de NE en autorreceptores de células adrenérgicas del SNC. Disminuye adenilato ciclasa y por ende vías adrenérgicas en SNC que dependen de éste. Microbiologists have been able to subdivide the various classes of a-2 receptors based upon affinities for agonists and antagonists. The a2 receptors constitute a family of G-protein–coupled receptors with 3 pharmacological subtypes, a-2A, a-2B, and a-2C. Endogenous agonists, such as norepinephrine and epinephrine, have similar affinities for all 3 subtypes. However, prazosin, a selective a-antagonist drug used to treat high blood pressure, has a 60-fold affinity for the a2A receptor on rat lung cells. The a-2A and -2C subtypes are found mainly in the central nervous system. Stimulation of these receptor subtypes may be responsible for sedation, analgesia, and sympatholytic effects. 9 The a-2B receptors are found more frequently on vascular smooth muscle and have been shown to mediate vasopressor effects. All 3 subtypes have been shown to inhibit adenylyl cyclase, in turn reducing the levels of cyclic adenosine monophosphate and causing hyperpolarization of noradrenergic neurons in the medial dorsal pons, specifically in the locus ceruleus. 10 As cyclic adenosine monophosphate is inhibited, potassium efflux through calciumactivated channels prevents calcium ions from entering the nerve terminal, leading to a suppression of neural firing. This suppression inhibits norepinephrine release and reduces activity of the ascending noradrenergic pathways, resulting in hypnosis and sedation. Stimulation of a-2 receptors in the dorsal horn of the spinal column inhibits nociceptive neurons and reduces the release of substance P
- A 2 -Adrenergic receptors regulate a wide range of signalling pathways viainteraction with multiple heterotrimeric G proteins including inhibition of adenylyl cyclase, stimulation of phospholipase D, stimulation of mitogen-activated protein kinases, stimulation of K + i/o currents and inhibition of Ca2+ currents. The three a -receptor subtypes have unique patterns of tissue distributionin the central nervous system and in peripheral tissues. The a 2 -receptor is expressed widely throughout the central nervous system including the locus coeruleus, brain stem nuclei, cerebral cortex, septum, hypothalamus, and hippocampus. In the periphery, a 2ª 2ª -receptors are expressed in kidney, spleen, thymus, lung, and salivary gland. The a –receptor primarily shows peripheral expression (kidney, liver, lung, and heart) and only lowlevel expression in thalamic nuclei of the central nervous system. The a –receptor appears to be expressed primarily in the central nervous system (striatum, olfactory tubercle, hippocampus, and cerebral cortex), although very low levels of its mRNA are present in the kidney. A 2ª -, a 2B , and a -receptors are located presynaptically in order to inhibit noradrenaline release from 2C sympathetic nerves. Activation of these receptors leads to decreased sympathetic tone, decreased blood pressure and heart rate. Central a -receptors mediate sedation and analgesia. A 2B 2ª -Receptors mediate contraction of vascular smooth muscle, and in the spinal cord they are essential components of the analgesic effect of nitrous oxide At present, no drugs exist that can selectively activate a 2 1 -receptor subtypes. Clonidine stimulates all three a subtypes with similar potency. Clonidine lowers blood pressure in patients with hypertension and it decreases sympathetic overactivity during opioid withdrawal. In intensive and postoperative care, clonidine is a potent sedative and analgesic and can prevent postoperative shivering. Clonidine and its derivative brimonidine lower intraocular pressure of glaucoma patients when applied locally. Moxonidine may have less sedative side effects than clonidine when used as an antihypertensive. It has been suggested that moxonidine activates “imidazoline receptors” instead of a2 -receptors. The a –receptor agonists oxymetazoline and xylometazoline are being used as nasal decongestants. At present, a –receptor antagonists are not used in human medicine. However, in veterinary practice the a -receptor antagonist atipamezole can rapidly reverse anaesthesia mediated by the a 2 agonist medetomidine. In the future, subtype-selective drugs may greatly improve the therapy of diseases involving a 1 –or a 2 -adrenergic receptor systems.
- Centrally within the locus ceruleus, for example, a-2 agonists are able to produce sedation, analgesia, and euphoric effects and partially block acute withdrawal symptoms in chronic opioid users. 4 More potent a-2 selective drugs, such as dexmedetomidine, have been formulated for clinical use as sole sedative agents or as adjuncts to drastically reduce the patient’s requirement for additional sedatives or general anesthetics. Adverse Effects >10% Hypotension (25-28%) Hypertension (12-16%) Nausea (9-11%) 1-10% Bradycardia (5-7%) Pyrexia (4-5%) Atrial fibrillation (4%) Dry mouth (3-4%) Vomiting (3-4%) Hypoxia (2-4%) Hypovolemia (3%) Atelectasis (3%) Tachycardia (2-3%)
- glucuronidation and CYP2A6-mediated metabolism. Approximately 80–90% is excreted in the urine, and 5–13% is found in the feces. 25