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Trombose coronária Enfarte do miocárdio Morte súbita Perda de músculo Remodelagem Dilatação ventricular Insuficiência cardíaca Morte Isquemia miocárdica.

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Presentation on theme: "Trombose coronária Enfarte do miocárdio Morte súbita Perda de músculo Remodelagem Dilatação ventricular Insuficiência cardíaca Morte Isquemia miocárdica."— Presentation transcript:

1 Trombose coronária Enfarte do miocárdio Morte súbita Perda de músculo Remodelagem Dilatação ventricular Insuficiência cardíaca Morte Isquemia miocárdica D.Coronária Aterosclerose HVE Factores de risco: Hipertensão Arterial Hiperlipidemia Diabetes Obesidade Tabagismo Adaptado de Dzau V e col., 1991 MORTALIDADE CARDIOVASCULAR Cadeia de eventos ActivaçãoneurohumoralActivaçãoneurohumoral

2 INSUFICIÊNCIA CARDÍACA

3 SINDROME COMPLEXO, COM ETIOLOGIAS VÁRIAS ATINGE CERCA DE 20 MILHÕES DE PESSOAS EM TODO O MUNDO NÚMERO DE CASOS SOBE EXPONENCIAL- MENTE SOBRETUDO NO IDOSO 10% DOS IDOSOS COM IDADE > 75 ANOS TÊM INSUFICIÊNCIA CARDÍACA

4 INSUFICIÊNCIA CARDÍACA O PROGNÓSTICO É MAU A MORBILIDADE É MUITO SIGNIFICATIVA AS ADMISSÕES HOSPITALARES SÃO MUITO FREQUENTES ( CAUSA MAIS HABITUAL DE INTERNAMENTO EM IDADE > 65 ANOS)

5 INSUFICIÊNCIA CARDÍACA PORQUE É QUE A INS. CARDÍACA AUMENTA? POPULAÇÃO MAIS ENVELHECIDA SUCESSO DA TERAPÊUTICA NA MELHORIA DA SOBREVIVÊNCIA PÓS-EAM (trombólise ou outras medidas) AUMENTO NA DURAÇÃO DA SOBREVIDA DOS DOENTES COM INSUFICIÊNCIA CARDÍACA

6 DEFINITION The situation when the heart is incapable of maintaining a cardiac output adequate to accommodate metabolic requirements and the venous return." The situation when the heart is incapable of maintaining a cardiac output adequate to accommodate metabolic requirements and the venous return." E. Braunwald

7 New York Heart Association Functional Classification Class I:No symptoms with ordinary activity Class II:Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, dyspnea, or angina Class III:Marked limitation of physical activity. Comfortable at rest, but less than ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain Class IV:Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency may be present even at rest

8 MERIT-HF Study Group. Effect of Metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). LANCET. 1999;353: Severity of Heart Failure Modes of Death12% 24% 64% CHF Other Sudden Death n = 103 NYHA II 26% 15% 59% CHF Other Sudden Death n = 103 NYHA III 56% 11% 33% CHF Other Sudden Death n = 27 NYHA IV

9 Etiology of Heart Failure What causes heart failure? The loss of a critical quantity of functioning myocardial cells after injury to the heart due to: –Ischemic Heart Disease –Hypertension –Idiopathic Cardiomyopathy –Infections (e.g., viral myocarditis, Chagas disease) –Toxins (e.g., alcohol or cytotoxic drugs) –Valvular Disease –Prolonged Arrhythmias

10 30% 70% Diastolic Dysfunction Systolic Dysfunction (EF < 40%) (EF > 40 %) Left Ventricular Dysfunction Systolic: Impaired contractility/ejection –Approximately two-thirds of heart failure patients have systolic dysfunction 1 Diastolic: Impaired filling/relaxation 1 Lilly, L. Pathophysiology of Heart Disease. Second Edition p 200

11 DETERMINANTS OF VENTRICULAR FUNCTION DETERMINANTS OF VENTRICULAR FUNCTION STROKE VOLUME PRELOAD CONTRACTILITY CARDIAC OUTPUT HEART RATE - Synergistic LV contraction - LV wall integrity - Valvular competence AFTERLOAD

12 Hemodynamic Basis for Heart Failure Symptoms

13 LVEDP Left Atrial Pressure Pulmonary Capillary Pressure Pulmonary Congestion

14 Left Ventricular Dysfunction Systolic and Diastolic Symptoms –Dyspnea on Exertion –Paroxysmal Nocturnal Dyspnea –Tachycardia –Cough –Hemoptysis Physical Signs –Basilar Rales –Pulmonary Edema –S3 Gallop –Pleural Effusion –Cheyne-Stokes Respiration

15 Disfunção miocárdica Retenção H2O e sal Vasoconstrição Redistribuição fluxo Inotropia + Taquicardia Dilatação e hipertrofia Activação neurohumoral ICC - Fase de respostas compensatórias Melhoria transitória Frank-Starling < stress da parede

16 Compensatory Mechanisms Frank-Starling Mechanism Neurohormonal Activation Ventricular Remodeling

17 Compensatory Mechanisms Frank-Starling Mechanism a.At rest, no HF b.HF due to LV systolic dysfunction c.Advanced HF

18 Compensatory Mechanisms Neurohormonal Activation Many different hormone systems are involved in maintaining normal cardiovascular homeostasis, including: Sympathetic nervous system (SNS) Renin-angiotensin-aldosterone system (RAAS) Vasopressin (a.k.a. antidiuretic hormone, ADH)

19 VasodilatoresNatriuréticosAnti-proliferativosAnti-inflamatóriosAntitrombogénicos Equilíbrio sistemas neuro-humorais reguladores perfusãoVasoconstritoresAnti-natriuréticosPró-proliferativosPró-inflamatóriosTrombogénicos Dopamina ANF, BNF, CNF AdrenomedulinaProstaciclinaBradicininaNO Angiotensina 2 AldosteronaAdrenalinaNoradrenalinaEndotelinaVSP TBX A2 Ubaína

20 Initially Adaptive Initially Adaptive Response Short-Term Effects Salt and Water RetentionAugments Preload VasoconstrictionMaintains BP for perfusion of vital organs Sympathetic StimulationIncreases HR and ejection Neurohormonal Responses to Impaired Cardiac Performance Jaski, B, MD: Basics of Heart Failure: A Problem Solving Approach

21 Packer. Progr Cardiovasc Dis. 1998;39(suppl I): CNS sympathetic outflow CNS sympathetic outflow Disease progression Cardiac sympathetic activity Cardiac sympathetic activity receptors receptors receptors Vasoconstriction Sodium retention Myocardial toxicity Increased arrhythmias Sympathetic Sympathetic activity to kidneys + peripheral vasculature Activation of RAS Sympathetic Activation in Heart Failure

22 1 and 2 receptor densities in the failing and non-failing heart Receptor density (ƒ mol/mg) Non-failing Non-failing Failing Failing *p<0.05 **p=NS ** *

23 Vasoconstriction Oxidative Stress Cell Growth Proteinuria LV remodeling Vascular remodeling Angiotensinogen Angiotensin I Angiotensin II AT I receptor Renin AngiotensinConvertingEnzyme Compensatory Mechanisms: Renin-Angiotensin-Aldosterone (RAAS) Na+ retention

24 Other Neurohormones Natriuretic Peptides: Three known types –Atrial Natriuretic Peptide (ANP) Predominantly found in the atria Diuretic and vasodilatory properties –Brain Natriuretic Peptide (hBNP) Predominantly found in the cardiac ventricles Diuretic and vasodilatory properties –C-type Natriuretic Peptide (CNP) Predominantly found in the central nervous system Limited natriuretic and vasodilatory properties

25 Hemodynamic (balanced vasodilation) (balanced vasodilation) veinsveins arteriesarteries coronary arteriescoronary arteriesNeurohormonalaldosteronenorepinephrine Renal diuresis & natriuresis Pharmacological Actions of hBNP Abraham WT and Schrier RW, 1994

26 Produced by a thin lining of cells within the arteries and veins called the endothelium Endothelium-derived relaxing factors (EDRF) – Vasodilators: Nitric Oxide (NO) Bradykinin Prostacyclin Endothelium-derived constricting factors (EDCF) – Vasoconstrictors: Endothelin I Endothelium-Derived Vasoactive Substances

27 Mediators of Heart Failure Cytokines Small protein molecules produced by a variety of tissues and cells Negative inotropes Elevated levels associated with worse clinical outcomes Examples: –Tumor necrosis factor (TNF)-alpha –Interleukin 1-alpha –Interleukin-2 –Interleukin-6 –Interferon-alpha

28 Initially Adaptive, Deleterious if Sustained Initially Adaptive, Deleterious if Sustained Response Short-Term Effects Long-Term Effects Salt and Water RetentionAugments PreloadPulmonary Congestion, Anasarca VasoconstrictionMaintains BP for perfusion of vital organs Exacerbates pump dysfunction (excessive afterload), increases cardiac energy expenditure Sympathetic StimulationIncreases HR and ejectionIncreases energy expenditure Neurohormonal Responses to Impaired Cardiac Performance Jaski, B, MD: Basics of Heart Failure: A Problem Solving Approach

29 Disfunção miocárdica Dilatação ventricular Remodelagem Stress oxidativo Citocinas Apoptose Activação neurohumoral ICC - Fase de descompensação agravamento Mitogénese Proliferação celular Dilatação e hipertrofia Perda de miócitos, necrose e fibrose Alterações estruturais, miocárdio, tecido conjuntivo, vasos

30 General Measures Lifestyle Modifications: Weight reduction Discontinue smoking Avoid alcohol and other cardiotoxic substances Exercise Medical Considerations: Treat HTN, hyperlipidemia, diabetes, arrhythmias Coronary revascularization Anticoagulation Immunization Sodium restriction Daily weights Close outpatient monitoring

31 sobrevida Morbilidade Capacidade de Exercicio Qualidade de vida Alterações Neurohormonais Progressão da CHF Sintomas sobrevida Morbilidade Capacidade de Exercicio Qualidade de vida Alterações Neurohormonais Progressão da CHF Sintomas Objectivos terapêuticos

32 Tratamento da Ins. cardiaca Diureticos e digitalicos Vasodilatadores Directos e nitratos Inibidores da ECA Antagonistas dos receptores AT1 Bloqueadores beta Antiarrítmicos, anticoagulantes Inibidores das fosfodiesterases redutores da produçãode FNT e outras citocinas) Ressincronização cardíaca

33 DRUGS HEMODYNAMIC EFFECTS DRUGS HEMODYNAMIC EFFECTS A A I I A + V V V D D Ventricular Filling Pressure Stroke Volume Stroke Volume Normal CHF

34 Pharmacologic Management Digoxin Enhances inotropy of cardiac muscle Reduces activation of SNS and RAAS Controlled trials have shown long-term digoxin therapy: –Reduces symptoms –Increases exercise tolerance –Improves hemodynamics –Decreases risk of HF progression –Reduces hospitalization rates for decompensated HF –Does not improve survival

35 o CH 3 OH CH 3 = O - o- HO - o oo CH 3 - O - Genina Esteroide Lactona Tri-digitoxose (açucares) Figura 1. Estrutura da digoxina, protótipo dos digitálicos

36 Na + K+K+ K+K+ K+K+ K+K+ Ca ++ Na-K ATPase Na-Ca Exchange Myofilaments DIGOXIN CONTRACTILITY

37 Figura 2. Efeitos inotrópicos e neurais dos digitálicos Efeito simpático-inibidor Adaptado de Opie, 1990 aferências Estimulação simpática Estimulação vagal Taquiarritmias Aumento Ca2+ intracelular Trocador Na+/Ca2+ > Ca 2+ intracelular > saída de sódio 2K + 3Na + Digitálicos > sódio intracelular EFEITO INOTRÓPICO POSITIVO Doses tóxicas doses terapêuticas

38 Normal Conduction Pathway in the Heart and the ECG Sinoatrial (SA) Node Atrioventricular (AV) Node Left Bundle Branches Right Bundle Branch Purkinje Fibers P = Atrial Depolarization QRS = Ventricular Depolarization T = Ventricular Repolarization PT QRS

39 DIGOXIN PHARMACOKINETIC PROPERTIES Oral absorption (%) Protein binding (%) Volume of distribution (l/Kg) Half life Elimination Onset (min) i.v. oral Maximal effect (h) i.v. oral Duration Therapeutic level (ng/ml) Oral absorption (%) Protein binding (%) Volume of distribution (l/Kg) Half life Elimination Onset (min) i.v. oral Maximal effect (h) i.v. oral Duration Therapeutic level (ng/ml) (3-9) 36 (26-46) h Renal days (3-9) 36 (26-46) h Renal days

40 DIGOXIN HEMODYNAMIC EFFECTS Cardiac output LV ejection fraction LVEDP Exercise tolerance Natriuresis Neurohormonal activation Cardiac output LV ejection fraction LVEDP Exercise tolerance Natriuresis Neurohormonal activation

41 DIGOXIN NEUROHORMONAL EFFECTS Plasma Noradrenaline Peripheral nervous system activity RAAS activity Vagal tone Normalizes arterial baroreceptors Plasma Noradrenaline Peripheral nervous system activity RAAS activity Vagal tone Normalizes arterial baroreceptors

42 DIGOXIN LONG TERM EFFECTS Survival similar to placebo Fewer hospital admissions More serious arrhythmias More myocardial infarctions Survival similar to placebo Fewer hospital admissions More serious arrhythmias More myocardial infarctions

43 DIGOXIN CLINICAL USES AF with rapid ventricular response CHF refractory to other drugs Other indications? Can be combined with other drugs AF with rapid ventricular response CHF refractory to other drugs Other indications? Can be combined with other drugs

44 DIGOXIN CONTRAINDICATIONS ABSOLUTE: - Digoxin toxicity RELATIVE - Advanced A-V block without pacemaker - Bradycardia or sick sinus without PM - PVCs and TV - Marked hypokalemia - W-P-W with atrial fibrillation ABSOLUTE: - Digoxin toxicity RELATIVE - Advanced A-V block without pacemaker - Bradycardia or sick sinus without PM - PVCs and TV - Marked hypokalemia - W-P-W with atrial fibrillation

45 DIGOXIN TOXICITY CARDIAC MANIFESTATIONS ARRHYTHMIAS : - Ventricular (PVCs, TV, VF) - Supraventricular (PACs, SVT) BLOCKS: - S-A and A-V blocks CHF EXACERBATION ARRHYTHMIAS : - Ventricular (PVCs, TV, VF) - Supraventricular (PACs, SVT) BLOCKS: - S-A and A-V blocks CHF EXACERBATION

46 DIGOXIN TOXICITY EXTRACARDIAC MANIFESTATIONS GASTROINTESTINAL: - Nausea, vomiting, diarrhea NERVOUS: - Depression, disorientation, paresthesias VISUAL: - Blurred vision, scotomas and yellow-green vision HYPERESTROGENISM: - Gynecomastia, galactorrhea GASTROINTESTINAL: - Nausea, vomiting, diarrhea NERVOUS: - Depression, disorientation, paresthesias VISUAL: - Blurred vision, scotomas and yellow-green vision HYPERESTROGENISM: - Gynecomastia, galactorrhea

47 CARDIAC GLYCOSIDES SYMPATHOMIMETICS Catecholamines ß-adrenergic agonists PHOSPHODIESTERASE INHIBITORS Amrinone Enoximone Others CARDIAC GLYCOSIDES SYMPATHOMIMETICS Catecholamines ß-adrenergic agonists PHOSPHODIESTERASE INHIBITORS Amrinone Enoximone Others Milrinone Piroximone Milrinone Piroximone POSITIVE INOTROPES

48 ß-ADRENERGIC STIMULANTS CLASSIFICATION ß-ADRENERGIC STIMULANTS CLASSIFICATION B 1 Stimulants Increase contractility DobutamineDoxaminolXamoterol ButopaminePrenalterolTazolol B 1 Stimulants Increase contractility DobutamineDoxaminolXamoterol ButopaminePrenalterolTazolol B 2 Stimulants Produce arterial vasodilatation and reduce SVR B 2 Stimulants Produce arterial vasodilatation and reduce SVR Pirbuterol Carbuterol Pirbuterol Carbuterol Rimiterol Fenoterol Rimiterol Fenoterol Tretoquinol Salbutamol Tretoquinol Salbutamol Terbutaline Salmefamol Terbutaline Salmefamol Soterenol Quinterenol Soterenol Quinterenol Mixed Dopamine

49 DOPAMINE AND DOBUTAMINE EFFECTS Receptors Contractility Heart Rate Arterial Press. Renal perfusion Arrhythmia DA (µg / Kg / min) Dobutamine < 2 DA 1 / DA 2 ± ± ± ± ± ± ß1ß1 ß1ß ± ± > 5 ß ± ± ß1ß1 ß1ß1 ± ± + + ± ±

50 POSITIVE INOTROPES CONCLUSIONS May increase mortality Safer in lower doses Use only in refractory CHF NOT for use as chronic therapy May increase mortality Safer in lower doses Use only in refractory CHF NOT for use as chronic therapy

51 Cortex Medulla Thiazides Inhibit active exchange of Cl-Na in the cortical diluting segment of the ascending loop of Henle Thiazides Inhibit active exchange of Cl-Na in the cortical diluting segment of the ascending loop of Henle K-sparing Inhibit reabsorption of Na in the distal convoluted and collecting tubule K-sparing Inhibit reabsorption of Na in the distal convoluted and collecting tubule Loop diuretics Inhibit exchange of Cl-Na-K in the thick segment of the ascending loop of Henle Loop diuretics Inhibit exchange of Cl-Na-K in the thick segment of the ascending loop of Henle Loop of Henle Collecting tubule DIURETICS

52 THIAZIDES MECHANISM OF ACTION Excrete % of filtered Na + Elimination of K Inhibit carbonic anhydrase: increase elimination of HCO 3 No dose - effect relationship Excrete % of filtered Na + Elimination of K Inhibit carbonic anhydrase: increase elimination of HCO 3 No dose - effect relationship

53 LOOP DIURETICS MECHANISM OF ACTION Excrete % of filtered Na + Elimination of K +, Ca + and Mg ++ Resistance of afferent arterioles - Cortical flow and GFR - Release renal PGs - NSAIDs may antagonize diuresis Excrete % of filtered Na + Elimination of K +, Ca + and Mg ++ Resistance of afferent arterioles - Cortical flow and GFR - Release renal PGs - NSAIDs may antagonize diuresis

54 K-SPARING DIURETICS MECHANISM OF ACTION Eliminate < 5% of filtered Na + Inhibit exchange of Na + for K + or H + Spironolactone = competitive antagonist for the aldosterone receptor Amiloride and triamterene block Na + channels controlled by aldosterone Eliminate < 5% of filtered Na + Inhibit exchange of Na + for K + or H + Spironolactone = competitive antagonist for the aldosterone receptor Amiloride and triamterene block Na + channels controlled by aldosterone

55 Volume and preload Improve symptoms of congestion No direct effect on CO, but excessive preload reduction may Improves arterial distensibility Neurohormonal activation Levels of NA, Ang II and ARP Exception: with spironolactone Volume and preload Improve symptoms of congestion No direct effect on CO, but excessive preload reduction may Improves arterial distensibility Neurohormonal activation Levels of NA, Ang II and ARP Exception: with spironolactone DIURETIC EFFECTS

56 DIURETICS ADVERSE REACTIONS Thiazide and Loop Diuretics Changes in electrolytes: Volume Na +, K +, Ca ++, Mg ++ metabolic alkalosis Metabolic changes: glycemia, uremia, gout LDL-C and TG Cutaneous allergic reactions Changes in electrolytes: Volume Na +, K +, Ca ++, Mg ++ metabolic alkalosis Metabolic changes: glycemia, uremia, gout LDL-C and TG Cutaneous allergic reactions

57 DIURETICS ADVERSE REACTIONS Thiazide and Loop Diuretics DIURETICS ADVERSE REACTIONS Thiazide and Loop Diuretics Idiosyncratic effects: Blood dyscrasia, cholestatic jaundice and acute pancreatitis Gastrointestinal effects Genitourinary effects: Impotence and menstrual cramps Deafness, nephrotoxicity ( Loop diuretics ) Idiosyncratic effects: Blood dyscrasia, cholestatic jaundice and acute pancreatitis Gastrointestinal effects Genitourinary effects: Impotence and menstrual cramps Deafness, nephrotoxicity ( Loop diuretics )

58 Pharmacologic Management Diuretics Used to relieve fluid retention Improve exercise tolerance Facilitate the use of other drugs indicated for heart failure Patients can be taught to adjust their diuretic dose based on changes in body weight Electrolyte depletion a frequent complication Should never be used alone to treat heart failure Higher doses of diuretics are associated with increased mortality

59 DIURETICS ADVERSE REACTIONS K-SPARING DIURETICS DIURETICS ADVERSE REACTIONS K-SPARING DIURETICS Changes in electrolytes: Na +, K +, acidosis Musculoskeletal: Cramps, weakness Cutaneous allergic reactions : Rash, pruritis Changes in electrolytes: Na +, K +, acidosis Musculoskeletal: Cramps, weakness Cutaneous allergic reactions : Rash, pruritis

60 CO PRELOAD AFTERLOAD Normal Contractility Diminished Contractility Diminished Contractility Normal Contractility Diminished Contractility Diminished Contractility VV AV VASODILATOR DRUGS PRINCIPLES

61 Venous Vasodilatation Venous Vasodilatation MIXED Calcium antagonists -adrenergic Blockers ACEI Angiotensin II inhibitors K + channel activators Nitroprusside MIXED Calcium antagonists -adrenergic Blockers ACEI Angiotensin II inhibitors K + channel activators Nitroprusside VENOUS Nitrates Molsidomine VENOUS Nitrates Molsidomine ARTERIAL Minoxidil Hydralazine ARTERIAL Minoxidil Hydralazine VASODILATORS CLASSIFICATION VASODILATORS CLASSIFICATION Arterial Vasodilatation Arterial Vasodilatation

62 1- VENOUS VASODILATATION Preload 2- Coronary vasodilatation Myocardial perfusion 3- Arterial vasodilatation Afterload 4- Others 1- VENOUS VASODILATATION Preload 2- Coronary vasodilatation Myocardial perfusion 3- Arterial vasodilatation Afterload 4- Others Pulmonary congestion Ventricular size Vent. Wall stress MVO 2 NITRATES HEMODYNAMIC EFFECTS Cardiac output Blood pressure

63 0.6 PROBABILITY OF DEATH 0 0 Placebo (273) Prazosin (183) Hz + ISDN (186) MONTHS VHefT-1 N Engl J Med 1986;314:1547 VHefT-1 N Engl J Med 1986;314:1547 NITRATES SURVIVAL

64 " Decrease in the effect of a drug when administered in a long-acting form" " Decrease in the effect of a drug when administered in a long-acting form" NITRATES TOLERANCE Develops with all nitrates Is dose-dependent Disappears in 24 h. after stopping the drug Tolerance can be avoided - Using the least effective dose - Creating discontinuous plasma levels Develops with all nitrates Is dose-dependent Disappears in 24 h. after stopping the drug Tolerance can be avoided - Using the least effective dose - Creating discontinuous plasma levels

65 NITRATES TOLERANCE NITRATES TOLERANCE Can be avoided or minimized - Intermittent administration - Use the lowest possible dose - Intersperse a nitrate-free interval Allow peaks and valleys in plasma levels - Vascular smooth muscle recovers its nitrate sensitivity during the nadirs - Patches: remove after 8-10 h Can be avoided or minimized - Intermittent administration - Use the lowest possible dose - Intersperse a nitrate-free interval Allow peaks and valleys in plasma levels - Vascular smooth muscle recovers its nitrate sensitivity during the nadirs - Patches: remove after 8-10 h

66 s.l. NTG ISDN I 5-MN Percutaneous NTG s.l. NTG ISDN I 5-MN Percutaneous NTG TOLERANCETOLERANCE TOLERANCETOLERANCE HALFLIFEHALFLIFE HALFLIFEHALFLIFE NITRATES TOLERANCE

67 NITRATES CONTRAINDICATIONS NITRATES CONTRAINDICATIONS Previous hypersensitivity Hypotension ( < 80 mmHg) AMI with low ventricular filling pressure 1 st trimester of pregnancy Previous hypersensitivity Hypotension ( < 80 mmHg) AMI with low ventricular filling pressure 1 st trimester of pregnancy WITH CAUTION: žConstrictive pericarditis žIntracranial hypertension žHypertrophic cardiomyopathy žConstrictive pericarditis žIntracranial hypertension žHypertrophic cardiomyopathy

68 NITRATES CLINICAL USES Pulmonary congestion Orthopnea and paroxysmal nocturnal dyspnea CHF with myocardial ischemia In acute CHF and pulmonary edema: NTG s.l. or i.v. Pulmonary congestion Orthopnea and paroxysmal nocturnal dyspnea CHF with myocardial ischemia In acute CHF and pulmonary edema: NTG s.l. or i.v.

69 Pharmacologic Management ACE Inhibitors Blocks the conversion of angiotensin I to angiotensin II; prevents functional deterioration Recommended for all heart failure patients Relieves symptoms and improves exercise tolerance Reduces risk of death and decreases disease progression Benefits may not be apparent for 1-2 months after initiation

70 VASOCONSTRICTION VASODILATATION Kininogen Kallikrein Inactive Fragments Angiotensinogen Angiotensin I RENIN Kininase II Inhibitor ALDOSTERONE SYMPATHETIC VASOPRESSIN PROSTAGLANDINS tPA ANGIOTENSIN II BRADYKININ ACEI MECHANISM OF ACTION ACEI MECHANISM OF ACTION A.C.E.

71 Retenção de Na+ Inflamação/procoagulabilidade Stress oxidativo Efeitos centrais Estimulaçãosimpática Estimulação de protooncogenes Libertação de Aldosterona e ET-1 Hipertrofia cardíaca Fibrose intersticial Pro-ateromatose Hipertrofia/Hiperplasia Remodelagem vascular Angiotensina II

72 ACEI HEMODYNAMIC EFFECTS ACEI HEMODYNAMIC EFFECTS Arteriovenous Vasodilatation - PAD, PCWP and LVEDP -SVR and BP -CO and exercise tolerance No change in HR / contractility MVO 2 Renal, coronary and cerebral flow Diuresis and natriuresis Arteriovenous Vasodilatation - PAD, PCWP and LVEDP -SVR and BP -CO and exercise tolerance No change in HR / contractility MVO 2 Renal, coronary and cerebral flow Diuresis and natriuresis

73 ACEI ADVANTAGES Inhibit LV remodeling post-MI Modify the progression of chronic CHF - Survival - Hospitalizations - Improve the quality of life In contrast to others vasodilators, do not produce neurohormonal activation or reflex tachycardia Tolerance to its effects does not develop Inhibit LV remodeling post-MI Modify the progression of chronic CHF - Survival - Hospitalizations - Improve the quality of life In contrast to others vasodilators, do not produce neurohormonal activation or reflex tachycardia Tolerance to its effects does not develop

74 Placebo Enalapril PROBABILITY OF DEATH MONTHS p< p< CONSENSUS N Engl J Med 1987;316:1429 CONSENSUS N Engl J Med 1987;316:1429 ACEI SURVIVAL

75 ACEI INDICATIONS Clinical cardiac insufficiency - All patients Asymptomatic ventricular dysfunction - LVEF < 35 % Clinical cardiac insufficiency - All patients Asymptomatic ventricular dysfunction - LVEF < 35 %

76 ACEI UNDESIRABLE EFFECTS Inherent in their mechanism of action - Hypotension - Hyperkalemia - Angioneurotic edema Due to their chemical structure - Cutaneous eruptions - Neutropenia, thrombocytopenia - Digestive upset Inherent in their mechanism of action - Hypotension - Hyperkalemia - Angioneurotic edema Due to their chemical structure - Cutaneous eruptions - Neutropenia, thrombocytopenia - Digestive upset - Dry cough - Renal Insuff. - Dry cough - Renal Insuff. - Dysgeusia - Proteinuria - Dysgeusia - Proteinuria

77 ACEI CONTRAINDICATIONS Renal artery stenosis Renal insufficiency Hyperkalemia Arterial hypotension Intolerance (due to side effects) Renal artery stenosis Renal insufficiency Hyperkalemia Arterial hypotension Intolerance (due to side effects)

78 IECAS VANTAGENS DESVANTAGENS - reduzem mortalidade - efeitos acessórios e morbilidade (tosse /angioedema) - melhoram sintomas - aumentam tolerância ao esforço - reduzem hospitalizações - eficazes na I C assintomática NEJM 1987: 316;1429 JAMA 1988:259; 539 NEJM 1991:325;293 NEJM 1991: 325; 303 ANN INTERN MED 1992:117 ; 234

79 Mortality trials with ACE inhibitors in heart failure Trial CONSENSUS -1 V-HeFT-II SOLVD (treatment) Treatments Enalapril Placebo Enalapril ISDN/Hydral Enalapril Placebo n Treatment duration 6 months 2 years 41 months Mortality (%) p value ISDN=isosorbide dinitrate; Hydral=hydralazine

80 ACE inhibitor trials in heart failure following AMI Trial AIRE SAVE TRACE n Treatment duration 15 months 42 months 4 years Mortality (%) p value Treatments Ramipril Placebo Captopril Placebo Trandolapril Placebo

81 Estudos de mortalidade com In ECA na insuficiência cardíaca e E. miocárdio 32 estudos randomizados em 7105 doentes Redução significativa da mortalidade global –odds ratio 0.77 (95% C.I ); p<0.001 Redução significativa da mortalidade + hospitali- zações por insuficiência cardíaca de 25% –odds ratio 0.65 (95% C.I ); p<0.001 Maiores benefícios em doentes com maior deterioração da função cardíaca

82 AngiotensinogénioAngiotensinogénio Angiotensina I Angiotensina II BradicininaBradicinina PeptídeosinactivosPeptídeosinactivos Receptores AT 1 Receptores AT 2 Receptores BK 2 Óxido nítrico Renina ChymaseCAGE, Calicreína,... Cathepsin G, Calicreína,Tonina,Tripsina ECA- ? ? SISTEMA RENINA - ANGIOTENSINA PGPG Vasoconstrição Antinatriurese Proliferação celular Inflamação, aterogenese Hipercoagulação ALDO Vasodilatação Efeito antiproliferativo antiaterogenico Antagonistas (AT 1 )

83 ANGIOTENSIN II INHIBITORS MECHANISM OF ACTION ANGIOTENSIN II INHIBITORS MECHANISM OF ACTION RENIN Angiotensinogen Angiotensin I ANGIOTENSIN II Angiotensin I ANGIOTENSIN II ACE Other paths Vasoconstriction Proliferative Action Proliferative Action Vasodilatation Antiproliferative Action Antiproliferative Action AT1 AT2 AT1 RECEPTOR BLOCKERS AT1 RECEPTOR BLOCKERS RECEPTORS

84 Pharmacologic Management Angiotensin Receptor Blockers (ARBs) Block AT 1 receptors, which bind circulating angiotensin II Examples: irbesartan, valsartan, candesartan, losartan Should not be considered equivalent or superior to ACE inhibitors In clinical practice, ARBs should be used to treat patients who are ACE intolerant due to intractable cough or who develop angioedema

85 AT 1 receptor AT 2 receptor VasoconstrictionVasoconstriction Growth PromotionGrowth Promotion Anti-apoptoticAnti-apoptotic Pro-fibroticPro-fibrotic Pro-thromboticPro-thrombotic Pro-oxidantPro-oxidant VasodilationVasodilation Growth inhibitionGrowth inhibition Pro-apoptoticPro-apoptotic ? Fibrosis? Fibrosis ? Thrombosis? Thrombosis ? redox? redox Angiotensin II Receptors

86 AT1 RECEPTOR BLOCKERS DRUGS AT1 RECEPTOR BLOCKERS DRUGS Losartan Valsartan Irbersartan Candesartan Losartan Valsartan Irbersartan Candesartan Competitive and selective blocking of AT1 receptors Competitive and selective blocking of AT1 receptors

87 The ELITE-study Number of patients Adverse events Death and hospitalization Death Losartan Captopril Pitt et al. Lancet 1997: 349: p = 0.035p = 0.075

88 Losartan Heart Failure Survival Study ELITE II Study Design 60 years; NYHA II-IV; EF 40% ACEI/AIIA naive or <7 days in 3 months prior to entry Standard Rx (± Dig/Diuretics), -blocker stratification Captopril 50 mg 3 times daily (n=1574) Losartan 50 mg daily (n=1578) Event-driven (Target 510 Deaths) ~2 years Primary Endpoint:All-Cause Mortality Secondary Endpoint:Sudden Cardiac Death and/or Resuscitated Arrest Other Endpoints:All-Cause Mortality/Hospitalizations Safety and Tolerability

89 Losartan Heart Failure Survival Study – ELITE II Mortality by Cause (Adjudicated) Sudden death Heart failure MIStrokeOther CV Non-CV Losartan (n=1578) Captopril (n=1574) % of Patients

90 INSUFICIÊNCIA CARDÍACA VALOR DOS ANTAGONISTAS DA AII MELHORAM OS SINTOMAS, AUMENTAM A QUALIDADE DE VIDA E AUMENTAM A TOLERÂNCIA AO EXERCÍCIO REDUZEM A MORBILIDADE E O NÚMERO DE HOSPITALIZAÇÕES. AUMENTAM A ADERÊNCIA AO TRATA- MENTO (poucos efeitos secundários). ÓPTIMA ALTERNATIVA AOS IECAS

91 CONCEITO DOS INIBIDORES DAS VASOPEPTIDASES NEP e da ECA - DUPLO BLOQUEIO DA NEP e da ECA

92 Inibição das vasopeptidases ECANEP ANP e peptideos Análogos Adrenomedulina BK Angiotensina II Vasodilatação Excreção sódio Efeitos antihipertróficos Vasoconstrição Retenção sódio Efeitos hipertróficos P ressão arterial Melhoria da performance cardíaca Protecção dos orgãos-alvo

93

94 Cardiomyopathic hamsters Omapatrilat Survival (%) d 221 d 290 d Days of treatment 400 Start treatment CaptoprilPlacebo Omapatrilat: Survival Benefit Trippodo et al. J Cardiovasc Pharmacol 1999;34:782

95 Pharmacologic Management Aldosterone Antagonists Generally well-tolerated Shown to reduce heart failure-related morbidity and mortality Generally reserved for patients with NYHA Class III-IV HF Side effects include hyperkalemia and gynecomastia. Potassium and creatinine levels should be closely monitored REDUÇÂO MORTALIDADE ASSOCIADOS AOS InECA (estudo RALES)

96 ALDOSTERONE Retention Na + Retention H 2 O Excretion K + Excretion Mg 2+ Retention Na + Retention H 2 O Excretion K + Excretion Mg 2+ Collagen deposition Fibrosis - myocardium - vessels Spironolactone Edema Arrhythmias Competitive antagonist of the aldosterone receptor (myocardium, arterial walls, kidney) Competitive antagonist of the aldosterone receptor (myocardium, arterial walls, kidney) ALDOSTERONE INHIBITORS

97 INDICATIONS ALDOSTERONE INHIBITORS INDICATIONS FOR DIURETIC EFFECT Pulmonary congestion (dyspnea) Systemic congestion (edema) FOR ELECTROLYTE EFFECTS Hypo K +, Hypo Mg + Arrhythmias Better than K + supplements FOR NEUROHORMONAL EFFECTS Please see RALES results, N Engl J Med 1999:341: FOR DIURETIC EFFECT Pulmonary congestion (dyspnea) Systemic congestion (edema) FOR ELECTROLYTE EFFECTS Hypo K +, Hypo Mg + Arrhythmias Better than K + supplements FOR NEUROHORMONAL EFFECTS Please see RALES results, N Engl J Med 1999:341:

98 Hyperkalemia Severe renal insufficiency Metabolic acidosis Hyperkalemia Severe renal insufficiency Metabolic acidosis ALDOSTERONE INHIBITORS CONTRAINDICATIONS ALDOSTERONE INHIBITORS CONTRAINDICATIONS

99 Pharmacologic Management Beta-Blockers Cardioprotective effects due to blockade of excessive SNS stimulation In the short-term, beta blocker decreases myocardial contractility; increase in EF after 1-3 months of use Long-term, placebo-controlled trials have shown symptomatic improvement in patients treated with certain beta-blockers 1 When combined with conventional HF therapy, beta- blockers reduce the combined risk of morbidity and mortality, or disease progression 1 1 Hunt, SA, et al ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult, 2001 p. 20.

100 ß-ADRENERGIC BLOCKERS POSSIBLE BENEFICIAL EFFECTS Density of ß 1 receptors Inhibit cardiotoxicity of catecholamines Neurohormonal activation HR Antihypertensive and antianginal Antiarrhythmic Antioxidant Antiproliferative Density of ß 1 receptors Inhibit cardiotoxicity of catecholamines Neurohormonal activation HR Antihypertensive and antianginal Antiarrhythmic Antioxidant Antiproliferative

101 LV EJECTION FRACTION < 30% 30-40% > 40% % % ß Blocker Placebo BHAT JACC 1990;16:1327 BHAT JACC 1990;16:1327 ß BLOCKERS SURVIVAL ß BLOCKERS SURVIVAL

102 ß-ADRENERGIC BLOCKERS IDEAL CANDIDATE? ß-ADRENERGIC BLOCKERS IDEAL CANDIDATE? Suspected adrenergic activation Arrhythmias Hypertension Angina Suspected adrenergic activation Arrhythmias Hypertension Angina

103 Carvedilol (n=696) Placebo (n=398) Survival Days Risk reduction = 65% p<0.001 Packer et al (1996) Lancet (1999) Bisoprolol Placebo Time after inclusion (days) p< Survival Risk reduction = 34% The MERIT-HF Study Group (1999) Months of follow-up Mortality % Placebo Metoprolol CR/XL p= Risk reduction = 34% US Carvedilol Study blockers in heart failure - blockers in heart failure - all-cause mortality CIBIS-II MERIT-HF

104 Antioxidant effects –reduction in myocyte apoptosis –decreased lipid peroxidation Antiproliferative effects –inhibition of vascular smooth muscle cell proliferation Reduction in circulating endothelin-1 Additional benefits of carvedilol in CHF

105 Treatment Approach for the Patient with Heart Failure Stage A At high risk, no structural disease Stage B Structural heart disease, asymptomatic Stage D Refractory HF requiring specialized interventions Therapy Treat HypertensionTreat Hypertension Treat lipid disordersTreat lipid disorders Encourage regular exerciseEncourage regular exercise Discourage alcohol intakeDiscourage alcohol intake ACE inhibitionACE inhibitionTherapy All measures under stage AAll measures under stage A ACE inhibitors in appropriate patientsACE inhibitors in appropriate patients Beta-blockers in appropriate patientsBeta-blockers in appropriate patientsTherapy All measures under stage AAll measures under stage ADrugs: DiureticsDiuretics ACE inhibitorsACE inhibitors Beta-blockersBeta-blockers DigitalisDigitalis Dietary salt restrictionDietary salt restrictionTherapy All measures under stages A,B, and CAll measures under stages A,B, and C Mechanical assist devicesMechanical assist devices Heart transplantationHeart transplantation Continuous (not intermittent) IV inotropic infusions for palliationContinuous (not intermittent) IV inotropic infusions for palliation Hospice careHospice care Stage C Structural heart disease with prior/current symptoms of HF Hunt, SA, et al ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult, 2001

106 Tratamento da Ins. cardiaca Inibidores das fosfodiesterases redutores da produçãode FNT e outras citocinas Pimobendam, vesnarinona, pentoxifilina Ressincronização cardíaca


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