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Farmacologia
- 2. USO RACIONAL DE FÁRMACOS MECANISMOS EVIDENCIAS
- 5. Inotrópicos
- 9. Potencial de reposo menos negativo Disminuye duración potencial de acción Aumenta automatismo Digitálicos Efectos electrofisiológicos
- 12. Placebo n=3403 DIGOXINA n=3397 48 0 12 24 36 MORTALIDAD GLOBAL % DIG N Engl J Med 1997;336:525 Meses p = 0.8 50 40 30 20 10 0
- 14. Receptor ß1 Adenil ciclasa ATP AMPc Proteina kinasa inactiva Proteína kinasa activa Calcio MIOCITO AMP FD Aminas simpático-miméticas
- 15. Aminas simpático-miméticas D 1 1 2 perfusión renal vasoconstricción contractilidad vasodilatación + + + + + + + + 0 0 Isoproterenol + + + + + + + + + + 0 Adrenalina 0 + + + + + + + + 0 Noradrenalina + + + + + + 0 Dobutamina + + Dosis mod + + + + Dosis mod/alta + + + + Dosis alta + Dosis baja Dopamina
- 16. Receptor ß1 Adenil ciclasa ATP AMPc Proteina kinasa inactiva Proteína kinasa activa Calcio MIOCITO AMP FD Inhibidores Fosfodiesterasa
- 23. Vasodilatadores Venosos Mixtos Arteriolares Congestión pulmonar Gasto cardíaco Nitratos Nitroprusiato Hidralazina Inhibidores ECA Minoxidil Bloq adren Bloq Calcio Agonistas 2central
- 24. GTP GMPc Oxido Nítrico Oxido Nítrico Vasodilatadores dependientes Endotelio (Ach, serotonina) Nitratos Nitroprusiato CELULA ENDOTELIAL CELULA MUSCULAR LISA Relajación G-ciclasa
- 26. 1- VASODILATACION VENOSA Precarga 2- Vasodilatación coronaria Perfusión miocárdica 3- Vasodilatación arterial Postcarga 4- Otros Congestión pulmonar Tamaño ventricular Tensión pared MVO 2 NITRATOS EFECTOS HEMODINAMICOS • Gasto cardíaco • Preión arterial
- 27. 0.6 Probabilidad de Muerte 0 Placebo (273) Prazosin (183) Hz + ISDN (186) MESES 0.7 0.5 0.3 0.4 0.2 0.1 VHefT-1 N Engl J Med 1986;314:1547 NITRITOS SOBREVIDA 0 6 12 18 24 30 36 42
- 29. Bloqueadores canales de Calcio L-Type Ca 2+ Channel NH 3 + NH 3 + COO - COO - 1C NH 3 + COO - 2 I II III IV COO - NH 3 +
- 30. El músculo liso vascular responde a la entrada de Ca 2+ por canales L-type para la contracción (contracción graduada dependiente de Calcio L-Type Ca 2+
- 31. Células cardíacas responden a los canales L-type Ca 2+ Para contracción y generación de potencial Céls contráctiles (aurículas, ventrículos L-Type Ca 2+ Ca 2+ Ca 2+ Céls respuesta lenta (nodo sinusal y AV) L-Type Ca 2+ Ca 2+
- 34. Efectos diferenciales de bloqueadores Calcio AV SN AV SN Reflejo potencial aumenta FC,contractilidad y demanda O2 Coronaria VD Dihidropiridinas: vasodilatadores No -dihidropiridines: equipotentes Tejido cardiaco y vasculatura Moderan FC Vaodilatación coronaria y periférica Reducen inotropismo Vasodilatación periférica
- 36. V-Heft II ** **p = 0.016 N Engl J Med 1991;325:303-10
- 38. Inótropos y vasodilatadores directos Utiles para el control de los síntomas pero no mejoran significativamente el curso de la enfermedad cardiovascular
- 39. Angiotensinógeno Angiotensina I Angiotensina II Receptor AT 1 Enzima Convertidora Bradiquinina Péptidos inactivos Inhibidores ECA Renina Vasoconstricción Aldosterona Act.simpática
- 42. CONSENSUS I 40% reducción p=0.002 31% reducción p=0.001 CONSENSUS Study Group N Eng J Med 1987
- 43. Angiotensinógeno Angiotensina I Angiotensina II Receptor AT 1 Vasoconstricción Aldosterona Act.simpática Hipertrofia VI Apoptosis y arterias Retención Na Fibrosis VI,vasos Enzima Convertidora Bradiquinina Péptidos inactivos Inhibidores ECA Proteasa quimasa Renina
- 44. Angiotensinógeno Angiotensina I Angiotensina II Receptor AT 1 Vasoconstricción Aldosterona Act.simpática Hipertrofia VI Apoptosis y arterias Retención Na Fibrosis VI,vasos Enzima Convertidora Bradiquinina Péptidos inactivos Antagonista Receptor AT1 Inhibidores ECA Proteasa quimasa Renina Antialdosterónicos
- 48. ALDOSTERONA Retención Na + Retención H 2 O Excreciónn K + Excreciónn Mg 2+ Depósito Colágeno Fibrosis - miocardio - vasos Espironolactona Edema Arritmias ANTIALDOSTERÓNICOS
- 50. Several pathways of Ang II generation Local Ang II synthesis is independent of ACE de Gasparo et al. Pharmacol Rev 2000; 52:415 Angiotensin I Angiotensinogen (Liver) AT 1 AT 2 Angiotensin II ACE inhibitor Valsartan AT 1 receptor blocker Renin inhibitor Bradykinin Peptides Chymase
- 51. Different roles of AT 1 and AT 2 receptors Vasoconstriction Vascular proliferation Aldosterone secretion Cardiac myocyte proliferation Increased sympathetic tone Vasodilation Antiproliferation Apoptosis Angiotensin II de Gasparo et al. Pharmacol Rev 2000; 52:415 AT 1 AT 2
- 53. Antagonistas ß adrenérgicos No selectivos ß1 selectivos Acebutolol Penbutolol Pindolol Con actividad ß - agonista Atenolol Metoprolol Esmolol Bisoprolol Propranolol Nadolol Timolol Labetalol Sin actividad ß - agonista
- 54. Antagonistas y ß adrenérgicos Carvedilol Bucindolol
- 58. -bloqueadores y función ventricular en ICC Hall et al. JACC 1995;25:1154
- 61. SNS RAA Frecuencia Vasoconstricción Contractilidad Retención sodio y agua Cardiotóxico MVO2 Daño miocitos
- 63. Disfunción ventricular Activación SNS-RAA Hipertrofia Isquemia Remodelamiento Depleción energía Apoptosis Necrosis Muerte celular
- 65. Terapia Antiadrenérgica Bloqueo Activación Simpática Efectos clínicos Metoprolol Propranolol Carvedilol Bisoprolol 2 receptores 1 receptores 1 receptores
- 67. Farmacología Cardiovascular NO Volumen RAA Canales Calcio, Na SNS Plaquetas Coagulación
Notes de l'éditeur
- Treatment of heart failure. Digoxin: Effect on survival The results obtained from 3 controlled studies which included patients at low risk (The German and Austrian Xamoterol Study Group, 1988; The Captopril-Digoxin Multicenter Research Group, 1988; DiBianco et al., 1989) indicate that the mortality was similar in the group of patients with placebo. The results of the Digitalis Investigator Group-DIG study, which included 7788 patients with heart failure in sinus rhythm, functional class II-III and LVEF < 45%. The patients were treated with digoxin or placebo, in addition to conventional therapy over a mean of 37 months (28 - 58 months). No differences in mortality were observed between the two treatment groups. Am Coll Cardiol 1996
- Treatment of Heart Failure. Nitrates: Hemodynamic effects At therapeutic doses, nitrates produce venodilatation that reduces systemic and pulmonary venous resistances. As a consequence, right atrial pressure, pulmonary capillary pressure, and LVEDP decrease. The preload reduction improves the signs of pulmonary congestion and decreases myocardial wall tension and ventricular size, which in turn reduce oxygen consumption. With higher doses, nitrates produce arterial vasodilatation that decreases peripheral vascular resistance and mean arterial pressure, leading to a decrease in afterload, and thereby reduce oxygen consumption. This arterial vasodilatation increases cardiac output, counteracting the possible reduction caused by the reduction in preload caused by venodilatation. The overall effect on cardiac output depends on the LVEDP; when LVEDP is high, nitrates increase cardiac output, while when it is normal nitrates can decrease cardiac output. Nitrates can also produce coronary vasodilatation, as much through reducing preload as through a direct effect on the vascular endothelium. This vasodilatation can decrease the mechanical compression of subendocardial vessels and increases blood flow at this level. Additionally, nitrates reduce coronary vascular tone, overcoming vasospasm.
- Treatment of Heart Failure. Nitrates: Survival Mortality curves of heart failure patients. In men with class II-III heart failure, the VHeFT-I study showed that for patients already treated with digoxin and diuretics, the combination of hydralazine (300mg/day) and isosorbide dinitrate (160mg/day) improved symptoms and functional status. More importantly, combination therapy was associated with a 23% reduction in mortality at 3 years; this effect was not seen in patients treated with prazosin (30mg/day). Selection of the treatment arms in this study was based on certain suppositions. The placebo group received digitalis and diuretics, and subsequent to this study the combination has been administered obligatorily in control groups. The combined administration of hydralazine (arterial vasodilator) and a nitrate (venodilator) was designed to provide equilibrated vasodilatation. Prazosin combined both arterial and venous vasodilatory capacities in one medication, and was initially assumed to be better than combination therapy. The lack of effect of prazosin was probably due to development of tolerance. Perhaps the most relevant finding of the study was that, in practice, the effects of a medicine on symptoms or hemodynamic effects do not correlate well with effects on overall survival. Veterans Administration Cooperative Study (VHefT-1). N Engl J Med 1986;314:1547
- Treatment of congestive heart failure. Aldosterone inhibitors: Mechanism of action Aldosterone acts directly on specific receptors. At the renal level it produces retention of sodium and water, resulting in an increase in preload and afterload, edema formation and the appearance of symptoms of pulmonary and systemic venous congestion. In addition, it increases the elimination of potassium and magnesium, creating an electrolyte imbalance which may be responsible in part for cardiac arrhythmias. At the tissue level, aldosterone stimulates the production of collagen, being in large part responsible for the fibrosis that is found in hypertrophied myocardium and in the arterial walls of patients with heart failure. The beneficial effects of spironolactone derive from the direct and competitive blockade of specific aldosterone receptors. Aldosterone inhibitors therefore have three types of effects: - Diuretic effect, which is most noticeable when fluid retention and increased levels of aldosterone are present. - Antiarrhythmic effect, mediated by the correction of hypokalemia and hypomagnesemia. - Antifibrotic effect. This effect, demonstrated in animal models, can contribute to a decrease in the progression of structural changes in patients with heart failure.
- Message: ACE inhibitors do not block the conversion of Ang I to Ang II by alternative enzymes prominent in heart tissue, such as chymase.
- Message: Selective blockade of Ang II at the AT 1 receptor may offer advantages over non specific blockade of the RAS (e.g. by ACE inhibitors).
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