Escolar Documentos
Profissional Documentos
Cultura Documentos
Dr. Juan Rodrguez-Tafur D Profesor Asociado de Farmacologa e Inmunologa Clnica Facultad de Medicina Universidad Nacional Mayor de San Marcos
sh m
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Grupo numeroso y heterogneo de frmacos que comparten algunas actividades teraputicas y efectos adversos. El frmaco prototipo es la Aspirina.
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CLASIFICASIN A) Segn su estructura qumica.I.- Derivados del Acido Saliclico : Aspirina, Sulfasalazina. 2.-Derivados del Paraaminofenol : Acetaminofen . 3.-Derivados Indlicos : Indometacina, Sulindac, Etodolaco. 4.-Ac. Heteroarilacticos : Tolmetina, Diclofenaco, Ketorolaco. 5.-cidos Arilpropionicos :Ibuprofeno, Naproxeno, Ketoprofeno. 6.-Acidos Antranlicos : Ac. Mefenamico, Ac. Meclofenamico. 7.-Acidos Enlicos : Oxican( Piroxican, Meloxican).
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CLASIFICASIN 8.-Alcanonas (No acdicos) : Nabumetona 9.Sulfonanilidas : Nimesulida 10.-Furanonas con sustitucin de diaril : Rofecoxib 11.Pirazoles con sustitucin de diaril: Celecoxib
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EFECTOS FARMACOLGICOS Efectos analgsicos Efectos antipirticos Efectos antiinflamatorios
MECANISMO DE ACCION
HIPOTESIS DE VANE
En 1971 demuestra que los frmacos similares a la aspirina actuan por inhibicion de enzimas que sintetizan prostaglandinas, ademas sugiere que esta inhibicin es la base de su accin analgsica.
Vane JR Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 1971 Jun 23;231(25):232-5
ACIDO ARAQUIDONICO
Ciclo-oxigenasa
Prostaglandinas: PGD2 PGE2 PGF2 Tromboxano A2 Prostaciclina I2
Lipo-oxigenasa
Leucotrienos: LTB4 LTC4 LTD4 LTE4
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MECANISMO DE ACCION
Inhiben a la enzima ciclooxigenasa y por consiguiente la produccin de prostaglandinas y tromboxano. Este efecto se logra gracias a la unin del AINE al sitio activo de la enzima, el cual corresponde a un bolsillo hidrofbico que permite la unin con cido araquidnico Existen varios tipos de COX.
ESTRUCTURA DE LA COX
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TIPOS DE COX
COX I, COX 2, COX3. COX-1 y COX-2 : reemplazo del aminocido isoleucina en la posicin 523, por valina. El sustrato cido araquidnico se une al aminocido arginina 120 y serina 530 de ambas COX. Los AINEs por su parte, se unen irreversiblemente a la posicin 530 de ambas isoenzimas, bloqueando as su actividad al impedir la unin con el sustrato
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TIPOS DE COX Los inhibidores no selectivos se unen al residuo serina 530 de COX-1 y COX-2, sitio destinado a la colocacin de cido araquidnico. Los inhibidores selectivos, se unen a la enzima COX-2 mediante el residuo valina 523, dejando libre la posicin serina 530
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CLASIFICASION B) Basada en la inhibicin COX1/COX2 CATEGORIA 1 : COX1 especfica (aspirina)
CATEGORIA 2 : COX no especfica
Derivados Indlicos Acidos Heteroarilaceticos Acidos Arilpropionico Acidos Antranlicos Acidos Enlicos Alcanonas
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CLASIFICASIN CATEGORIA 3 : COX2 preferencial (Meloxican, Nimesulida) CATEGORIA 4 : COX2 especfica (Celecoxib, Rofecoxib, Valdecoxib,
Etoricoxib)
Cicloxigenasas: Cicloxigenasas: Hipotesis del Papel de Hipotesis del Papel de las Isoformas en la las Isoformas en la Inflamacin Inflamacin
Hiptesis del Papel exclusivo del COX2 Hiptesis del Papel combinado de COX1 y COX2
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ESTIMULOS INFLAMATORIOS
COX-2 inducida
TxA2 Plaquetas
PGE2 Rion
Clulas Inflamatorias
PGs
INFLAMACION
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Inducible cyclooxygenase may have anti-inflammatory properties. Inducible cyclooxygenase may have anti-inflammatory properties.
Gilroy DW, Colville-Nash PR, Willis D, Chivers J, Paul-Clark MJ, Willoughby DA Gilroy DW, Colville-Nash PR, Willis D, Chivers J, Paul-Clark MJ, Willoughby DA
.. In carrageenin-induced pleurisy in rats, the predominant cells at 2 hours are .. In carrageenin-induced pleurisy in rats, the predominant cells at 2 hours are polymorphonuclear leucocytes, whereas mononuclear cells dominate from 24 hours until resolution at 48 polymorphonuclear leucocytes, whereas mononuclear cells dominate from 24 hours until resolution at 48 hours. hours. In this model, COX-2 protein expression peaked initially at 2 hours, associated with maximal In this model, COX-2 protein expression peaked initially at 2 hours, associated with maximal prostaglandin E2 synthesis. prostaglandin E2 synthesis. However, at 48 hours there was a second increase in COX 2 expression, 350% greater than that However, at 48 hours there was a second increase in COX 2 expression, 350% greater than that at 2 hours. Paradoxically, this coincided with inflammatory resolution and was associated with minimal at 2 hours. Paradoxically, this coincided with inflammatory resolution and was associated with minimal prostaglandin E2 synthesis. In contrast, levels of prostaglandin D2, and 15deoxy delta(12prostaglandin E2 synthesis. In contrast, levels of prostaglandin D2, and 15deoxy delta(1214)prostaglandin J2 were high at 2 hours, decreased as inflammation increased, but were increased again 14)prostaglandin J2 were high at 2 hours, decreased as inflammation increased, but were increased again at 48 hours. at 48 hours. The selective COX-2 inhibitor NS-398 and the dual COX 1/COX 2 inhibitor indomethacin The selective COX-2 inhibitor NS-398 and the dual COX 1/COX 2 inhibitor indomethacin inhibited inflammation at 2 hours but significantly exacerbated inflammation at 48 hours. inhibited inflammation at 2 hours but significantly exacerbated inflammation at 48 hours. This exacerbation was associated with reduced exudate prostaglandin D2 and 15deoxy This exacerbation was associated with reduced exudate prostaglandin D2 and 15deoxy delta(12-14)prostaglandin J2 concentrations, and was reversed by replacement of these prostaglandins. delta(12-14)prostaglandin J2 concentrations, and was reversed by replacement of these prostaglandins. Thus, COX-2 may be pro-inflammatory during the early phase of a carrageenin-induced pleurisy, Thus, COX-2 may be pro-inflammatory during the early phase of a carrageenin-induced pleurisy, dominated by polymorphonuclear leucocytes, but may aid resolution at the later, mononuclear celldominated by polymorphonuclear leucocytes, but may aid resolution at the later, mononuclear celldominated phase by generating an alternative set of anti-inflammatory prostaglandins. dominated phase by generating an alternative set of anti-inflammatory prostaglandins.
Pico de Inflamacin
Inicio
Resolucin
Cox1+Cox2
Cox1
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1989
1990
1994
1998
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RECEPTOR
X
Protenas G
FLC
PIP2
IP3 DAG
Liberacin de Grnulos
Adhesin Clula-Clula
Abramson,S.B. y Weissmann G. Abramson,S.B. y Weissmann G. The mechanism of action of nonsteroidal The mechanism of action of nonsteroidal antiinflammatory drugs antiinflammatory drugs Arthritis & Rheumatism 32(1):1-9; 1989 Arthritis & Rheumatism 32(1):1-9; 1989
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Inhibition of Leukocyte Adhesion: an alternative mechanism of action for anti-inflammatory drugs. Daz-Gonzalez F. and Snchez-Madrid F. Immunology Today Vol.119(4):169-172; 1998 Union 1 1 Activacion 2 2 ACTIVATION
Inhiben 1: Inhiben 1: Acelofenaco, Aspirina, Diclofenaco, Acelofenaco, Aspirina, Diclofenaco, Indometacina, Acido Mefenmico, Indometacina, Acido Mefenmico, Acido Flufenmico Acido Flufenmico
Inhiben 2: Inhiben 2: Nimesulida, piroxicam, meloxicam, Nimesulida, piroxicam, meloxicam, fenilbutazona. fenilbutazona.
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Cell 1995 Nov 3;83(3):483-92 Cell 1995 Nov 3;83(3):483-92 Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. inflammation and indomethacin-induced gastric ulceration. Langenbach R, Morham SG, Tiano HF, Loftin CD, Ghanayem BI, Chulada PC, Mahler Langenbach R, Morham SG, Tiano HF, Loftin CD, Ghanayem BI, Chulada PC, Mahler JF, Lee CA, Goulding EH, Kluckman KD, et al JF, Lee CA, Goulding EH, Kluckman KD, et al Cyclooxygenases 1 and 2 (COX-1 and COX-2) are key enzymes in prostaglandin Cyclooxygenases 1 and 2 (COX-1 and COX-2) are key enzymes in prostaglandin biosynthesis and the target enzymes for the widely used nonsteroidal antibiosynthesis and the target enzymes for the widely used nonsteroidal antiinflammatory drugs. To study the physiological roles of the individual isoforms, we inflammatory drugs. To study the physiological roles of the individual isoforms, we have disrupted the mouse Ptgs1 gene encoding COX-1. Homozygous Ptgs1 mutant have disrupted the mouse Ptgs1 gene encoding COX-1. Homozygous Ptgs1 mutant mice survive well, have no gastric pathology, and show less indomethacin-induced mice survive well, have no gastric pathology, and show less indomethacin-induced gastric ulceration than wild-type mice, even though their gastric prostaglandin E2 gastric ulceration than wild-type mice, even though their gastric prostaglandin E2 levels are about 1% of wild type. The homozygous mutant mice have reduced platelet levels are about 1% of wild type. The homozygous mutant mice have reduced platelet aggregation and a decreased inflammatory response to arachidonic acid, but not to aggregation and a decreased inflammatory response to arachidonic acid, but not to tetradecanoyl phorbol acetate. Ptgs1 homozygous mutant females mated to tetradecanoyl phorbol acetate. Ptgs1 homozygous mutant females mated homozygous mutant males produce few live offspring. COX-1-deficient mice provide a homozygous mutant males produce few live offspring. COX-1-deficient mice provide a useful model to distinguish the physiological roles of COX-1 and COX-2. useful model to distinguish the physiological roles of COX-1 and COX-2.
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Cell 1995 Nov 3;83(3):473-82 Cell 1995 Nov 3;83(3):473-82 Prostaglandin synthase 2 gene disruption causes severe renal pathology in the Prostaglandin synthase 2 gene disruption causes severe renal pathology in the mouse. mouse. Morham SG, Langenbach R, Loftin CD, Tiano HF, Vouloumanos N, Jennette JC, Mahler Morham SG, Langenbach R, Loftin CD, Tiano HF, Vouloumanos N, Jennette JC, Mahler JF, Kluckman KD, Ledford A, Lee CA, et al JF, Kluckman KD, Ledford A, Lee CA, et al The prostaglandin endoperoxide H synthase isoform 2, cyclooxygenase 2 (COX-2), is The prostaglandin endoperoxide H synthase isoform 2, cyclooxygenase 2 (COX-2), is induced at high levels in migratory and other responding cells by pro-inflammatory induced at high levels in migratory and other responding cells by pro-inflammatory stimuli. COX-2 is generally considered to be a mediator of inflammation. Its isoform, stimuli. COX-2 is generally considered to be a mediator of inflammation. Its isoform, COX-1, is constitutively expressed in most tissues and is thought to mediate COX-1, is constitutively expressed in most tissues and is thought to mediate "housekeeping" functions. These two enzymes are therapeutic targets of the widely "housekeeping" functions. These two enzymes are therapeutic targets of the widely used nonsteroidal anti-inflammatory drugs (NSAIDs). To investigate further the used nonsteroidal anti-inflammatory drugs (NSAIDs). To investigate further the different physiologic roles of these isoforms, we have used homologous different physiologic roles of these isoforms, we have used homologous recombination to disrupt the mouse gene encoding COX-2 (Ptgs2). Mice lacking recombination to disrupt the mouse gene encoding COX-2 (Ptgs2).
develop severe nephropathy and are susceptible to peritonitis. develop severe nephropathy and are susceptible to peritonitis.
COX-2 have normal inflammatory responses to treatments with tetradecanoyl phorbol acetate or with arachidonic acid. However, they However, they
Nature
Volume 378(6555) November 23, Volume 378(6555) November 23, 1995 pp 406-409 1995 pp 406-409
Renal abnormalities and an Renal abnormalities and an altered inflammatory response in altered inflammatory response in mice lacking cyclooxygenase II mice lacking cyclooxygenase II
Dinchuk, Joseph E.; Car, Bruce D.; Focht, Dinchuk, Joseph E.; Car, Bruce D.; Focht, Richard J.; Johnston, Jennifer J.; Jaffee, Richard J.; Johnston, Jennifer J.; Jaffee, Bruce D.; Covington, Maryanne B.; Contel, Bruce D.; Covington, Maryanne B.; Contel, Nancy R.; Eng, Vicki M.; Collins, Robert J.; Nancy R.; Eng, Vicki M.; Collins, Robert J.; Czerniak, Philip M.; Gorry, Stewart A.; Czerniak, Philip M.; Gorry, Stewart A.; Trzaskos, James M. Trzaskos, James M. Here we present an animal model of COX-2 Here we present an animal model of COX-2 deficiency that was generated by gene deficiency that was generated by gene targeting. Defects in null mice correlating targeting. Defects in null mice correlating with reduced viability included renal with reduced viability included renal alterations, characteristic of renal dysplasia alterations, characteristic of renal dysplasia (100% penetrance), and cardiac fibrosis (100% penetrance), and cardiac fibrosis (50% penetrance). Female Cox-2 -/- mice (50% penetrance). Female Cox-2 -/- mice were infertile. COX-2 deficiency failed were infertile. COX-2 deficiency failed
to alter inflammatory responses in to alter inflammatory responses in several standard models, but striking several standard models, but striking
mitigation of endotoxin-induced mitigation of endotoxin-induced hepatocellular cytotoxicity was observed. hepatocellular cytotoxicity was observed.
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Cyclooxygenase-2 in human platelets as a possible factor in aspirin resistence Cyclooxygenase-2 in human platelets as a possible factor in aspirin resistence Weber, A-A; Zimmermann K C; Meyer-Kirchrath J; Schror K. Weber, A-A; Zimmermann K C; Meyer-Kirchrath J; Schror K. The Lancet Vol.353(9156):900; March 1999 The Lancet Vol.353(9156):900; March 1999
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The New England Journal of Medicine The New England Journal of Medicine
Vol. 336(15) Apr 10, 1997 pp 1066-1071 Vol. 336(15) Apr 10, 1997 pp 1066-1071 Mechanisms of Disease: Nuclear Factor-(kappa)B -Mechanisms of Disease: Nuclear Factor-(kappa)B -a Pivotal Transcription Factor in Chronic a Pivotal Transcription Factor in Chronic Inflammatory Diseases. Barnes, Peter J.; Karin, Inflammatory Diseases. Barnes, Peter J.; Karin, Michael. Michael.
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Science
Volume 265(5174) August 12, Volume 265(5174) August 12, 1994 pp 956-959 1994 pp 956-959 Inhibition of NF-kappa B by Inhibition of NF-kappa B by Sodium Salicylate and Aspirin Sodium Salicylate and Aspirin
Kopp, Elizabeth; Ghosh Sankar. Kopp, Elizabeth; Ghosh Sankar.
The transcription factor nuclear The transcription factor nuclear factor-kappa B (NF-kappa B) is factor-kappa B (NF-kappa B) is critical for the inducible critical for the inducible expression of multiple cellular expression of multiple cellular and viral genes involved in and viral genes involved in inflammation inflammation and and infection infection including interleukin-1 (IL-1), ILincluding interleukin-1 (IL-1), IL6, and adhesion molecules. The 6, and adhesion molecules. The anti-inflammatory drugs sodium anti-inflammatory drugs sodium salicylate and aspirin inhibited salicylate and aspirin inhibited the activation of NF-kappa B, the activation of NF-kappa B, which further explains the which further explains the mechanism of action of these mechanism of action of these drugs. drugs.
Science Science Vol. 270(5244):2017-2018; 1995 Vol. 270(5244):2017-2018; 1995 The Effect of Sodium Salicylate and The Effect of Sodium Salicylate and Aspirin on NF-kappa B Aspirin on NF-kappa B Frantz, Betsy; O'Neill, Edward A. Frantz, Betsy; O'Neill, Edward A. Elizabeth Kopp and Sankar Ghosh find Elizabeth Kopp and Sankar Ghosh find that activation of the transcription that activation of the transcription factor nuclear factor-kappa B (NF-kappa factor nuclear factor-kappa B (NF-kappa B) is inhibited by aspirin and salicylate, B) is inhibited by aspirin and salicylate, which suggests an explanation for the which suggests an explanation for the anti-inflammatory nature of these drugs. anti-inflammatory nature of these drugs. Because the conclusion has significant Because the conclusion has significant implications for the development of implications for the development of novel anti-inflammatory agents, we novel anti-inflammatory agents, we explored the phenomenon further. We explored the phenomenon further. We found that at concentrations required for found that at concentrations required for inhibition of NF-kappa B-dependent inhibition of NF-kappa B-dependent transcription, sodium salicylate inhibits transcription, sodium salicylate inhibits activation of a variety of transcription activation of a variety of transcription factors. This appears to result from the factors. This appears to result from the
ability of salicylate to nonspecifically ability of salicylate to nonspecifically inhibit cellular kinases. inhibit cellular kinases.
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CONCLUSION: This study is the first to CONCLUSION: This study is the first to report that the anti-inflammatory effects report that the anti-inflammatory effects of NIM, an NSAID, may be partly related to of NIM, an NSAID, may be partly related to its activation of the GR system. its activation of the GR system.
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Vane JR Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 1971 Jun 23;231(25):232-5 HIPOTESIS DE VANE En 1971 demuestra que los frmacos similares a la aspirina actuan por inhibicion de enzimas que sintetizan prostaglandinas, ademas sugiere que esta
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prostaglandin synthesis, inflammation and nociception in rats. The R-form had much less effect on prostaglandin synthesis and did not affect inflammation. It did, however, block nociception in rats almost as potently as the S-form. S-flurbiprofen, in contrast to the R-form, was clearly ulcerogenic in the S-flurbiprofen, in contrast to the R-form, was clearly ulcerogenic in the gastrointestinal mucosa. These results indicate additional molecular gastrointestinal mucosa. mechanisms of analgesia and suggest the use of R-arylpropionic acids as analgesics.
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Los R-enantimeros de los arilpropinicos no inhiben COX in vitro, y fueron tan efectivos como los S-enantimeros los cuales inhiben la sntesis de prostaglandinas en diferentes modelos de dolor y nocicepcin. (SIC)
Comportamiento de los ismeros S y R del Flurbiprofeno en la Analgsia. Flubiprofeno COX-1 COX-2 Efect. antinociceptivo S ++ + + R +
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Clin Pharmacol Ther 1999 Mar;65(3):336-47 Characterization of rofecoxib as a cyclooxygenase-2 isoform inhibitor and demonstration of analgesia in the dental pain model.
Ehrich EW, Dallob A, De Lepeleire I, Van Hecken A, Riendeau D, Yuan W, Ehrich EW, Dallob A, De Lepeleire I, Van Hecken A, Riendeau D, Yuan W, Porras A, Wittreich J, Seibold JR, De Schepper P, Mehlisch DR, Gertz BJ Porras A, Wittreich J, Seibold JR, De Schepper Mehlisch DR, Gertz BJ
CONCLUSIONS: El ROFECOXIB inhibio COX-2 sin evidencia de inhibicin de COX-1, a dosis orales por encima de 1000 mg. As mismo ROFECOXIB mostr actividad analgsica indistinguible de la observada con ibuprofeno, una isoforma no selectiva de inhibidor COX. Estos resultados sostienen la
hiptesis que los efectos analgsicos de los AINES primariamente derivan de la inhibicin de COX-2.
www.pnas.org/cgi/doi/10.1073/pnas.162468699
Se encontr: Corteza cerebral y corazn humano COX-3 es inhibida por: Acetaminofen, fenacetina dipirona as como por algunos Aines. COX-3 tiene un papel central en el dolor y posiblemente en la fiebre
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PCOX-1a PCOX-1b
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Aliment Pharmacol Ther 1997 Dec;11(6):1101-8 Aspirin causes rapid up-regulation of cyclooxygenase-2 expression in the stomach of rats.
Davies NM, Sharkey KA, Asfaha S, Macnaughton WK, Wallace JL
CONCLUSIONS: Estos resultados muestran un rapido incremento de la expresin de COX-2 en respuesta a la Aspirina, posiblemente representa una respuesta compensatoria a la inhibicin de la sintesis de prostagladina gstrica.
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Davies, N. M.; Sharkey, K. A.; Asfaha, S.; Macnaughton, W. K.; Wallace, J. L. Davies, N. M.; Sharkey, K. A.; Asfaha, S.; Macnaughton, W. K.; Wallace, J. L. Aspirin causes rapid up-regulation of cyclo-oxygenase-2 expression in the Aspirin causes rapid up-regulation of cyclo-oxygenase-2 expression in the stomach of rats stomach of rats Alimentary Pharmacology & Therapeutics Alimentary Pharmacology & Therapeutics Volume 11(6) Dec. 1997 pp 1101-1108 Volume 11(6) Dec. 1997 pp 1101-1108
Selective cyclo-oxygenase-2 inhibitors and their influence on the protective effect of a mild irritant in the rat stomach.
Gretzer B, Ehrlich K, Maricic N, Lambrecht N, Respondek M, Peskar BM Gretzer B, Ehrlich K, Maricic N, Lambrecht N, Respondek M, Peskar BM Department of Experimental Clinical Medicine, Ruhr-University of Bochum, Department of Experimental Clinical Medicine, Ruhr-University of Bochum, Germany. Germany.
aunque hasta el presente un mecanismo no COX-2 relacionado subyace en el aunque hasta el presente un mecanismo no COX-2 relacionado subyace en el efecto de los inhibidores selectivos COX-2 ensayados en la proteccin efecto de los inhibidores selectivos COX-2 ensayados en la proteccin inducida por irritantes no ha sido completamente excluda. inducida por irritantes no ha sido completamente excluda.
Los hallazgos muestran que los inhibidores selectivos de COX-2, aunque pierden en actividad ulcerognica, evitan la proteccin conferida contra irritantes.. Las prostaglandinas COX-2 constitutivas pueden as contribuir a las funciones fisiolgicas que estan involucradas en homeostasis gstrica,,
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Trends Pharmacol Sci 1999 Jan;20(1):4-6 Selective COX-2 inhibitors: is the water becoming muddy?
Wallace JL Roles de las Prostaglandinas derivadas de COX-1 y COX-2 en el estmago Roles de las Prostaglandinas derivadas de COX-1 y COX-2 en el estmago
Condicin Condicin Normal Normal Injuria Aguda o Injuria Aguda o Inflamacin Inflamacin Ulcera Ulcera PGs derivadas COX-1 PGs derivadas COX-1 Estimula produc. de moco Estimula produc. de moco yybicarbonato bicarbonato Estimula produc. de moco Estimula produc. de moco yybicarbonato bicarbonato Desconocido Desconocido PGs derivadas COX-2 PGs derivadas COX-2 Desconocido Desconocido Citoproteccin adaptativa Citoproteccin adaptativa resistencia a la injuria por resistencia a la injuria por irritantes tpicos irritantes tpicos Reparacin: proliferacin Reparacin: proliferacin celular, angiogenesis, celular, angiogenesis, maduracin del tejido de maduracin del tejido de granulacin granulacin
Nitroaspirina Nitroflurbiprofeno
Presentan en su estructura un radical nitrobutilester.
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Control 05
Control 06
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EFECTOS ADVERSOS
1.- GASTROINTESTINALES.Gastritis. Ulcera Pptica. Diarrea. Vlvulas en el intestino delgado (uso prolongado). Trastornos de la motilidad. 2.-RENALES. Disminucin del flujo renal y de la filtracin glomerular. Retencion de sodio y agua. Insuficiencia Renal Aguda Nefritis intersticial
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EFECTOS ADVERSOS 3.- HEMATOLOGICOS. Inhibicin de la agregacin plaquetaria. Prolongacin del tiempo de sangra. 4.-HEPATICOS. Dao hepatocelular dosis dependiente.
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EFECTOS ADVERSOS 5.-HIPERSENSIBILIDAD. RAM tipo 2, hipersensibilidad
alergica (Triada de Samter, Sd de Widal). 6.-SNC. Cefalea, confusin, mareos.
7.-EMBARAZO:
Disminucion de la motilidad uterina y contractibilidad aumento del sangrado. Prolongacin de la gestacin o trabajo de parto espontneo. Cierre prematuro del conducto arterioso (Hipertensin Pulmonar)
+ + + +
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