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Betabloqueantes

Betabloqueantes. Francisco José de la Prada Alvarez Servicio de Nefrología. Receptores β. β 1: (músculo cardíaco) Incrementa la frecuencia cardíaca. Incrementa la contractilidad cardíaca. Incrementa la conducción AV. Disminuye la refractariedad del nodulo AV.

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Betabloqueantes

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  1. Betabloqueantes Francisco José de la Prada Alvarez Servicio de Nefrología

  2. Receptores β • β1: (músculo cardíaco) • Incrementa la frecuencia cardíaca. • Incrementa la contractilidad cardíaca. • Incrementa la conducción AV. • Disminuye la refractariedad del nodulo AV. • β2: (músculo bronquial y musculo liso vascular, y menos en músculo cardíaco): • Vasodilatación. • Broncodilatción. • β3 (tejido adiposo y músculo cardíaco): • Termogénesis. • Reduce la contractilidad cardíaca. • Dollery, CT, Frishman, WH, Cruickshank, JM. Current cardiovascular drugs, 1st ed, Current Science, London, 1993, p. 83. • Koch-Weser, J, Frishman, WH. beta-Adrenoceptor antagonists: new drugs and new indications. N Engl J Med 1981; 305:500. • Opie, LH. Drugs and the heart. Part 1. Beta blocking agents. Lancet 1980; 1:693.

  3. Características • Cardioselectividad. • Actividad simpaticomimética intrínseca. • Actividad bloqueante alfa adrenérgica.

  4. Características • Cardioselectividad. • Capacidad del fármaco para bloquear preferentemente los receptores cardíacos. • La cardioselectividad es una propiedad relativa. A altas dosis se produce el bloqueo β 2 • Propanolol:no selectivo(igual afinidad por receptores β1 y β2). • Acebutolol, Atenolol, betaxolol, Bisoprolol, Celiprolol y Metoprolol: selectivos (principal afinidad por receptores β1, y menos por β2 que median brocodilatación y vasodilatación periférica). • Son preferibles en pacientes asmáticos y diabéticos. • Koch-Weser, J. Drug therapy: metoprolol. N Engl J Med 1979; 301:698. • Frishman, W. Acebutolol. Cardiovasc Rev Rep 1985; 6:979. • Frishman, WH. Drug therapy: atenolol and timolol, two new systemic beta-adrenoceptor antagonists. N Engl J Med 1982; 306:1456.

  5. Características • Actividad simpaticomimética intrínseca. • Actividad agonista parcial por el receptor. • Producen menor reducción en la frecuencia cardíaca en reposo (pero impiden la taquicardia con el ejercicio), menor depresión de la conducción AV y menos inotropismo negativo que los β-bloqueantes sin activida ISA. • No deberían usarse nen hipertiroidismo, estenosis subaórtica hipertrófica, disección aórtica, fase post-IAM y angina. • Oxprenolol • Celiprolol • Acebutolol • Carteolol • Penbutolol • Frishman, WH, Charlap, S. The alpha- and beta-adrenergic blocking drugs. In: Cardiology, Parmley, WW (Ed), JB Lippincott, Philadelphia, 1990, p.1. •  Frishman, WH. Drug therapy. Pindolol: a new beta-adrenoceptor antagonist with partial agonist activity. N Engl J Med 1983; 308:940. • Magder, S, Sami, M, Ripley, R, et al. Comparison of the effect of pindolol and propranolol on exercise performance in patients with angina pectoris. Am J Cardiol 1987; 59:1289.

  6. Características • Actividad bloqueante alfa adrenérgica. • Labetalol: • Bloqueante β/Bloqueante α: 3/1 a 7/1 (sobre todo por via IV. Por via oral este efecto se reduce con el tratamiento a largo plazo) • β bloqueante: bradicardia, inotropismo negativo. • α bloqueante: • Bloquea la vasoconstricción refleja por el bloqueo β • Disminuye las resistencias vasculares coronarias y periféricas, mejorando el flujo sanguíneo. • Mejora la sensibiliad insulínica en diabéticos y no diabéticos. • Mejoran el perfil lipídico. • Carvedilol: • Los beneficios en insuficiencia cardíaca no están relacionados con el bloqueo α. • Kubo, T, Azevedo, ER, Newton, GE, et al. Lack of evidence for peripheral alpha(1)- adrenoceptor blockade during long-term treatment of heart failure with carvedilol. J Am Coll Cardiol 2001; 38:1463. • Hryniewicz, K, Androne, AS, Hudaihed, A, Katz, SD. Comparative effects of carvedilol and metoprolol on regional vascular responses to adrenergic stimuli in normal subjects and patients with chronic heart failure. Circulation 2003; 108:971.

  7. Características • Actividad bloqueante alfa adrenérgica. • La actividad bloqueante alfa asociada al bloqueo beta tiene un impacto positivo sobre la diabetes y la aterosclerosis, mejorando el control glucémico, reduciendo la hiperinsulinemia compensadora y reduciendo los cambios proaterogénicos sobre los lípidos plasmáticos. • Giugliano D, Acampora R, Marfella R et al. Metabolic and cardiovascular effects of carvedilol and atenolol in non-insulin-dependent diabetes mellitus and hypertension. A randomized, controlled trial. Ann Intern Med 1997; 126: 955–959.  • Jacob S, Rett K, Wicklmayr M et al. Differential effect of chronic treatment with two beta-blocking agents on insulin sensitivity: the carvedilol-metoprolol study. J Hypertens 1996; 14: 489–494. 

  8. Características farmacocinéticas • Metabolismo hepático. • Eliminación inalterada por riñón. • Frishman, W. Clinical pharmacology of the new beta adrenergic blocking drugs. Part 1. Pharmacodynamic and pharmacokinetic properties. Am Heart J 1979; 97:663. • Frishman, WH, Lazar, EJ, Gorodokin, G. Pharmacokinetic optimization of therapy with beta-adrenergic blocking agents. Clin Pharmacokinet 1991; 20:311.

  9. Características farmacocinéticas • Metabolismo hepático: • Liposolubles, absorción completa en intestino delgado y metabolismo hepático. • Biodisponibilidad variable. • Corta vida media. • Atraviesan la BHE aumentando la incidencia de efectos secundarios. • Revisión de estudios randomizados con mas de 35.000 pacientes. • La lipofilia no afecta la aparición de efectos adversos. • Ko, DT, Hebert, PR, Coffey, CS, et al. Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA 2002; 288:351. • Propanolol • Metoprolol • Oxprenolol

  10. Características farmacocinéticas • Eliminación inalterada por riñón: • Hidrosolubles. • No penetran en el SNC • Menos biodisponibilidad. • Larga vida media en plasma. (pueden administrarse 1 ó 2 veces al día). • Requieren ajuste en ERC. • Acebutolol • Atenolol • Nadolol • Sotalol

  11. Efectos secundarios • Bradicardia. (Enfermedad del nódulo sinusal) • Inotropismo negativo. (Insuficiencia cardíaca 6%) • Dromotropismo negativo. (Bloqueo AV) • Broncoconstricción. • No selectivos (Propanolol)contraindicados en asma y EPOC. (usar con precaución los cardioselectivos (atenolol o metoprolol), los que tienen ISA (pindolol y acebutolol) o los α bloqueantes (labetalol y carvedilol). • Vasoconstricción periférica: • No selectivos (Propanolol) pueden empeorar enfermedad vascular periférica severa o el fenómeno de Raynaud. (usar cardioselectivos Atenolol o metoprolol si la enfermedad es leve o moderada). • Koch-Weser, J, Frishman, WH. beta-Adrenoceptor antagonists: new drugs and new indications. N Engl J Med 1981; 305:500. • Wassertheil-Smoller, S, Oberman, A, Blaufox, MD, et al. The trial of antihypertensive interventions and management (TAIM) study. Final results with regard to blood pressure, cardiovascular risk, and quality of life. Am J Hypertens 1992; 5:37.

  12. Efectos secundarios • Efectos sobre el SNC: • Fatiga (pequeños incrementos en su incidencia 18/1000; 1 de cada 57 pacientes tratados/año) • Impotencia. (pequeños incrementos en su incidencia 5/1000; 1 de cada 199 pacientes tratados/año) • Depresión. (no mayor frecuencia) • van Melle, J. Beta-blockers and depression after myocardial infarction. J Am Coll Cardiol 2006; 48:2209. • Insomnio. (no mayor frecuencia) • Alucinaciones. (no mayor frecuencia) • Ko, DT, Hebert, PR, Coffey, CS, et al. Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA 2002; 288:351. • Koch-Weser, J, Frishman, WH. beta-Adrenoceptor antagonists: new drugs and new indications. N Engl J Med 1981; 305:500. • Wassertheil-Smoller, S, Oberman, A, Blaufox, MD, et al. The trial of antihypertensive interventions and management (TAIM) study. Final results with regard to blood pressure, cardiovascular risk, and quality of life. Am J Hypertens 1992; 5:37.

  13. Efectos secundarios • Enmascaran los síntomas simpáticos mediados por la hipoglucemia y retrasan la recuperación de la glucemia plasmática. No selectivos (Propanololy Labetalol). • Hiperpotasemia tras sobrecarga de K (impiden la entrada de K en la célula tras el ejercicio) Más frecuente con los no selectivos (Propanolol)y Labetalol). Pocos efectos sobre el K de los cardioselectivos (atenolol). El bloqueo alfa protege frente a la elevación del K (Carvedilol) • Koch-Weser, J, Frishman, WH. beta-Adrenoceptor antagonists: new drugs and new indications. N Engl J Med 1981; 305:500. • Wassertheil-Smoller, S, Oberman, A, Blaufox, MD, et al. The trial of antihypertensive interventions and management (TAIM) study. Final results with regard to blood pressure, cardiovascular risk, and quality of life. Am J Hypertens 1992; 5:37.

  14. Efectos secundarios • Retirada brusca de β bloqueantes. • Angina acelerada, IAM y muerte incluso en pacientes sin enfermedad coronaria conocida previamente, posiblemente por up-regulation de receptores β tras el bloqueo β. • Más frecuente con atenolol (menor vida media) • Koch-Weser, J, Frishman, WH. beta-Adrenoceptor antagonists: new drugs and new indications. N Engl J Med 1981; 305:500. • Wassertheil-Smoller, S, Oberman, A, Blaufox, MD, et al. The trial of antihypertensive interventions and management (TAIM) study. Final results with regard to blood pressure, cardiovascular risk, and quality of life. Am J Hypertens 1992; 5:37.

  15. Efectos secundarios • Efectos sobre los lípidos: • Depende de las características farmacológicas: • Más importantes en fumadores. • No selectivos y β1 bloqueantes: • Poco efecto sobre los niveles de colesterol total. • Reducen un 10% el HDL colesterol. • Aumentan un 20-40% los TG. • Labetalol y β bloqueates con ISA (acebutolol y pindolol): • No efecto sobre los lípidos. • Carvedilol: • Previene la peroxidación de los lípidos. • Reduce el colesterol total y eleva menos los TG que metoprolol. • Aumenta el HDL-C

  16. Indicaciones • No tienen un efecto específico cardioprotector en pacientes con HTA. • No reducen la Presión arterial central. (no reducen la incidencia de AVC) • Indicaciones: • Pacientes con taquicardia en reposo. • Insuficiencia cardíaca por disfunción diastólica y en algunos casos de disfunción sistólica. • Migrañas. • Glaucoma. • Cardiopatía isquémica previa.

  17. Contraindicaciones • Asma. • EPOC. • Enfermedad vascular periferica severa. • Fenómeno de Raynaud. • Bradicardia. BAV 2º o 3er grado.

  18. Beta blockers in the management of chronic kidney disease Kidney International (2006) 70, 1905–1913. L Bakris, P Hart and E Ritz

  19. Sympathetic overactivity in kidney disease is involved in the genesis of hypertension, in the progression of kidney disease, and in the cardiac complications of kidney failure.

  20. In subtotally nephrectomized rats, nonhypotensive doses of -blockers ameliorated the development of glomerulosclerotic and cardiac lesions. • Salplachta J, Bartosikova L, Necas J. Effects of carvedilol and BL-443 on kidney of rats with cyclosporine nephropathy. Gen Physiol Biophys 2002; 21: 189–195.  • Similar observations concerning kidney disease progression were noted with the central sympathicoplegic agent moxonidine. • Amann K, Nichols C, Tornig J et al. Effect of ramipril, nifedipine, and moxonidine on glomerular morphology and podocyte structure in experimental renal failure. Nephrol Dial Transplant 1996; 11: 1003–1011. • Additionally, moxonidine also reduced albumin excretion in patients with type I diabetes, despite causing no change in ambulatory blood pressure. • Strojek K, Grzeszczak W, Gorska J et al. Lowering of microalbuminuria in diabetic patients by a sympathicoplegic agent: novel approach to prevent progression of diabetic nephropathy? J Am Soc Nephrol 2001; 12: 602–605.  • Vonend O, Marsalek P, Russ H et al. Moxonidine treatment of hypertensive patients with advanced renal failure. J Hypertens 2003; 21: 1709–1717. 

  21. In a separate model of kidney disease (spontaneously hypertensive rats with adriamycin nephropathy), -/-blocker carvedilol decreased systolic blood pressure, decreased renal vascular resistance (RVR), and significantly increased renal blood flow (RBF). Moreover, it significantly decreased interstitial infiltration in the early phase of the study, slowed development of interstitial fibrosis and tubular atrophy, and decreased blood vessel changes. These changes strongly correlated with slowed nephropathy progression as well as decreases in proteinuria. • Jovanovic D, Jovovic D, Mihailovic-Stanojevic N et al. Influence of carvedilol on chronic renal failure progression in spontaneously hypertensive rats with adriamycin nephropathy. Clin Nephrol 2005; 63: 446–453. • In subtotally nephrectomized rats with known microangiopathy, -blockers increased the capillary density in the heart. This is an important observation, as -blockers clearly improve cardiac function and reduce cardiovascular events in hemodialyzed patients. • Amann K, Ritz E. Microvascular disease – the Cinderella of uraemic heart disease. Nephrol Dial Transplant 2000; 15: 1493–1503. • Cice G, Ferrara L, D'Andrea A et al. Carvedilol increases two-year survival in dialysis patients with dilated cardiomyopathy: a prospective, placebo-controlled trial. J Am Coll Cardiol 2003; 41: 1438–1444.

  22. The use of -blockers in CKD patients • As there is overwhelming evidence for sympathetic overactivity in patients with kidney disease, coronary heart disease and heart failure (HF) are the most common causes of death in these patients. • Eknoyan G. On the epidemic of cardiovascular disease in patients with chronic renal disease and progressive renal failure: a first step to improve the outcomes. Am J Kidney Dis 1998; 32: S1–S4.  • This may be due to inadequate treatment, as demonstrated by a recent study in which -adrenergic blockade was used in fewer than 30% of patients on hemodialysis. • Abbott KC, Trespalacios FC, Agodoa LY et al. Beta-blocker use in long-term dialysis patients: association with hospitalized heart failure and mortality. Arch Intern Med 2004; 164: 2465–2471. 

  23. The use of -blockers in CKD patients • This is surprising, as -blockers interfere with the deleterious actions of the SNS on cardiac end points, and are well-established, evidence-based therapy for reducing cardiovascular risk in hypertension and after myocardial infarction. • Cice G, Ferrara L, D'Andrea A et al. Carvedilol increases two-year survival in dialysis patients with dilated cardiomyopathy: a prospective, placebo-controlled trial. J Am Coll Cardiol 2003; 41: 1438–1444. • Zuanetti G, Maggioni AP, Keane W et al. Nephrologists neglect administration of betablockers to dialysed diabetic patients. Nephrol Dial Transplant 1997; 12: 2497–2500. • Chobanian AV, Bakris GL, Black HR et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289: 2560–2572. • Antman EM, Anbe DT, Armstrong PW et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction – executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). Circulation 2004; 110: 588–636. 

  24. Observational studies suggest definite survival benefits derived from the use of -blockers in patients with severe renal disease. • Furthermore, in a prospective, randomized study in hemodialyzed patients with HF, Cice et al. documented an impressive and significant decrease in death and hospitalization rates attributable to cardiovascular causes in patients on carvedilol compared to placebo . Cice G, Ferrara L, D'Andrea A et al. Carvedilol increases two-year survival in dialysis patients with dilated cardiomyopathy: a prospective, placebo-controlled trial. J Am Coll Cardiol 2003; 41: 1438–1444. 

  25. The United States Renal Data System Dialysis Morbidity and Mortality Study found that only 20% of chronic dialysis patients were receiving -blocker therapy. • Abbott KC, Trespalacios FC, Agodoa LY et al. Beta-blocker use in long-term dialysis patients: association with hospitalized heart failure and mortality. Arch Intern Med 2004; 164: 2465–2471. • In another study, only 24% of patients with established coronary heart disease were treated with -blockers. A similar trend occurs in the predialysis patients. • Trespalacios FC, Taylor AJ, Agodoa LY et al. Incident acute coronary syndromes in chronic dialysis patients in the United States. Kidney Int 2002; 62: 1799–1805.  • Wright RS, Reeder GS, Herzog CA et al. Acute myocardial infarction and renal dysfunction: a high-risk combination. Ann Intern Med 2002; 137: 563–570. 

  26. EFFECTS ON KIDNEY FUNCTION • Increased sympathetic activity has been reported consistently in patients with moderate renal failure as well as in those with ESRD undergoing renal dialysis. The level of sympathetic activity is an independent predictor of total as well as cardiovascular mortality in patients with ESRD. • Converse Jr RL, Jacobsen TN, Toto RD et al. Sympathetic overactivity in patients with chronic renal failure. N Engl J Med 1992; 327: 1912–1918. • Parving HH, Andersen AR, Smidt UM et al. Effect of antihypertensive treatment on kidney function in diabetic nephropathy. BMJ (Clin Res Ed) 1987; 294: 1443–1447. 

  27. EFFECTS ON KIDNEY FUNCTION • Bloqueantes no slectivos: • Disminuyen la tasa de FG y el Flujo sanguíneo renal (FSR), al disminuir el gasto cardíaco en pacientes con ERC. • En pacientes con función renal normal no efectan el FG ni el FSR. • Epstein M, Oster JR, Hollenberg NK. -Blockers and the kidney: implications for renal function and renin release. The Physiologist 1985; 28: 53–63.  • Epstein M, Oster JR. Beta blockers and renal function: a reappraisal. J Clin Hypertens 1985; 1: 85–99.  • Abbott KC, Bakris G. Renal effects of antihypertensive medications: an overview. J Clin Pharmacol 1993; 33: 392–399. • Zech P, Pozet N, Labeeuw M et al. Acute renal effects of beta-blockers. Am J Nephrol 1986; 6(Suppl 2): 15–19. 

  28. EFFECTS ON KIDNEY FUNCTION • Bloqueantes cardioselectivos: • No disminuyen el FG y el FSR. • Pueden incrementar las Resistencias Vasculares Renales (RVR). • Metoprolol disminuyen la actividad de renina plasmática. • Atenolol disminuye la progresión a proteinuria en pacientes con microalbuminuria (pero menos que con el bloqueo del SRAA). • Atenolol y Metoprolol en pacientes con ERC no producen efectos adversos en la hemodinámica renal. • En pacientes en HD conmiocardiopatía dilatada, el tratamiento con metoprolol mejoró el tamaño ventricular, la función cardíaca, los niveles de Peptido Auricular Natriurético y Peptido Cerebral Natriuretico.

  29. EFFECTS ON KIDNEY FUNCTION • The African American Study of Kidney Disease and Hypertension compared the long acting, once daily formulation of metoprolol, the ACE inhibitor, ramipril, and the calcium channel blocker, amlodipine in 1094 Black subjects with hypertensive nephropathy (GFR 20–65 ml/min per 1.73 m2) followed for a mean of 4 years. • The primary analysis of the GFR slope did not establish a definitive difference among the three agents. • Significant benefits were seen, however, with ramipril compared to metoprolol and amlodipine on the clinical composite outcome of decline of GFR, ESRD, and death. • The results of the secondary analyses indicated that ramipril treatment slowed the progression of hypertensive kidney disease to a greater extent than either once daily metoprolol or amlodipine. • The once daily metoprolol-treated patients had a significantly lower rate of ESRD or death than those treated with amlodipine. • Wright JT, Bakris G, Greene T. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease. Results from the AASK trial. JAMA 2002; 288: 2421–2431. 

  30. EFFECTS ON KIDNEY FUNCTION • Vasodilatadores • Labetalol: • Pequeños estudios y con resultados contradictorios • En general, no efectos significativoss sobre FG, FSR ni volumen de agua corporal. • Aumenta los niveles de glucosa plasmática sin efectos sobre la insulinemia. • Leve descenso de HDL-C. • Se elimina con la diálisis, pero no aumenta su aclaramiento corporal total • Hay que vigilar la aparición de hiperK sobre todo en pacientes en HD o tras transplante renal.

  31. EFFECTS ON KIDNEY FUNCTION • Vasodilatadores • Carvedilol: • Tiene actividad antioxidante. • No altera la creatinina ni urea plasmáticas. • No favorece la hiperK en pacientes con ERC. • Aumenta los niveles de CsA en un 20%. • Reduce el estress oxidativo, pudiendo prevenir el aumento de las citoquinas profibróticas que ocurre en pacientes trasplantados que toman CsA.

  32. EFFECTS ON KIDNEY FUNCTION • Vasodilatadores • Carvedilol: • Mejora el FSR y el FG en pacientes con IC y ERC. • En pacientes en HD y con miocardiopatía mejoran la FE, reduce los volumnes sistólicos y diastólicos ventriculares, mejorando la supervivencia. • Reduce la albuminuria en pacientes con HTA, DM y noDM, y es capaz de hacer desaparecer la misma hast en un 48-52%. • Carvedilol mejora la sensibilidad a la insulina y el control glucémico. • Tiene pocos efectos proaterogénicos al no alterar el colesterol y los TG.

  33. EFFECTS ON KIDNEY FUNCTION • Vasodilatadores • Nevibolol: • Lipofílico. • ISA. • MSA. • Presenta efectos vasodilatadores mediados por el NO. • No afecta el metabolismo de glucosa y el perfil lipídico. • Tiene efectos protectores sobre la función VI. • Incrementa el FSR y el FG, a traves de la via del NO. • Aumenta la excreción renal de Na y K.

  34. CONCLUSION • CKD, with the frequently associated conditions of hypertension, diabetes, and HF, is a state of overactivity of the SNS. • Antiadrenergic drugs play an important role in its management. Antihypertensive regimens including -blockers slow the deterioration of renal function as assessed by decreasing GFR and worsening albuminuria. • It is therefore deplorable that -blockers are still underutilized out of fear of adversely affecting renal function and glycemic control. • Beta blockers in the management of chronic kidney disease. Kidney International (2006) 70, 1905–1913. L Bakris, P Hart and E Ritz

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