Pharmacology for cardiovascular system

Pharmacology for cardiovascular system
Part 6 Drugs for Treatment of Congestive Heart Failure Weiping Zhang, MD, Ph.D., Department of Pharmacology Zhejiang University School of Medicine

Contents I. Introduction
II. Basic Pharmacology of Drugs Used in Heart Failure III. Clinical Pharmacology of Drugs Used in Heart Failure Cardiac glycoside Diuretics and vasodilators ACE inhibitors  receptor blockers Others

I. Introduction 1. Heart Failure:
(1) Systolic failure: the mechanical pumping action (contractility) and the ejection fraction of the heart are reduced. (2) Diastolic failure: stiffening and loss of adequate relaxation plays a major role in reducing cardiac output and ejection fraction may be normal. e.g. Pericarditis  铁甲心 (3) High-output failure: can result from hyperthyroidism, beriberi, anemia, and arteriovenous shunts.

2. New Approach to the Classification of Heart Failure
Marked symptoms at rest despite maximal medical therapy (e.g., those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions) Refractory end-stage HF D Known structural heart disease Shortness of breath and fatigue Reduced exercise tolerance Symptomatic HF C Previous MI LV systolic dysfunction Asymptomatic valvular disease Asymptomatic HF B Hypertension CAD Diabetes mellitus Family history of cardiomyopathy High risk for developing heart failure (HF) A Patient Description Stage At Risk Heart Failure Stages A through D show the progressive nature of cardiovascular disease into refractory end-stage heart failure. These patient types, especially Stage A, B, and C patients, are commonly seen by primary care physicians. Hunt SA et al. J Am Coll Cardiol. 2001;38:2101–2113.

3. Pathophysiology of Heart Failure:
Myocardial injury Fall in cardiac output Activation of RAAS, SNS and others ANP BNP Peripheral vasoconstriction Hemodynamic alterations Myocardial toxicity Remodeling and progressive worsening of LV function Morbidity and mortality Heart failure symptoms Fonarow GC. Rev Cardiovasc Med..2001;2:7–12. References: Fonarow GC. Heart failure: recent advances in prevention and treatment. Rev Cardiovasc Med. 2000;1:25–33.

3. Pathophysiology of Heart Failure:
intrinsic compensatory: myocardial hypertrophy: helps maintain cardiac performance at the beginning but can lead to ischemic changes, impairment of diastolic filling, and alterations in ventricular geometry. Remodeling: proliferation of connective tissue cells as well as abnormal myocardial cells with some biochemical characteristics of fetal myocytes.

Pathophysiologic Effects of Angiotensin II
and Epinephrine/Norepinephrine Cardiac Myocyte Fibroblast Peripheral Artery Coronary Artery Hypertrophy Hyperplasia Vasoconstriction Vasoconstriction Apoptosis Collagen Synthesis Endothelial Dysfunction Endothelial Dysfunction Hypertrophy Atherosclerosis Cell Sliding Fibrosis Decreased Compliance Restenosis Increased Wall Stress Thrombosis Increased O2 Consumption Impaired Relaxation

Changes of hemodynamics in CHF
Cardiac failure Cardiac output Blood supply Venous pressure Renal blood flow Renin - angiotension Ⅱ Venous hyperemia Aldosterone Pulmonary circulation: cough, emptysis, dyspnea Systemic circulation hyperemia : jugular vein distension, edema Sodium and water retention Changes of hemodynamics in CHF

Cardiac output (via compensation)
3. Pathophysiology of Heart Failure: extrinsic compensatory: Sympathetic nervous system RAAs  Cardiac output  Carotid sinus firing  Renal blood flow  Sympathetic discharge  Renin release  force  Rate  Angiotensin II  Preload  Afterload Remodeling Cardiac output (via compensation)

II. Basic Pharmacology of Drugs Used in Heart Failure

Positive inotropic agents, very helpful in acute failure and reduce symptoms in chronic failure. ---act on myocardia. ACEI, -blockers, spironolactone (an aldosterone receptor antagonist) and hydralazine + isosorbide can actually prolong life in patients with chronic heart failure. ---act both cardiac and non-cardiac target, such as kidney, adrenergic system, RAA system. To improve the life qualitity, decrease hospitalization and the mortality.

1. Positive Inotropic Drugs Digitalis Beta Adrenoceptor Stimulants Dopamine 2. Diuretics 3. RAAS inhibitors ACEI ARB Adolsterone antagonists 4. Vasodilators 5. Beta blockers 6. rhBNP Whether they can decrease the mortality ?

Stage C patients Stage D patients 2009 guideline

1. Positive Inotropic Drugs Digitalis  Adrenoceptor Stimulants Dopamine 2. Diuretics 3. RAAS inhibitors ACEI ARB Adolsterone antagonists 4. Vasodilators 5. Beta blockers 6. rhBNP

1. Digitalis: Digitalis is the genus name for the family of plants that provide most of the medically useful cardiac glycosides, eg, digoxin. Aglycone (genin)

1. Digitalis  Pharmacokinetics Absorption and Distribution 1Ouabain and digitoxin are no longer in use in the USA.

1. Digitalis  Pharmacokinetics Metabolism and Excretion Almost 2/3 of digoxin is excreted unchanged by the kidneys. Digitoxin is metabolized in the liver and excreted into the gut via the bile. The enterohepatic circulation of digitoxin contributes to the very long half-life. Ouabain must be given parenterally and is excreted, mostly unchanged, in the urine.

1. Digitalis  Pharmacoligical mechanism Hypokalemia Hyperkalemia X (1) K+ and digitalis can inhibit each other’s binding to Na+-K+ ATPase. Hypokalemia increased the toxicity of digtoxin (2) Abnormal cardiac automaticity is inhibited by hyperkalemia. So, moderately increased extracellular K+ therefore reduceds the effects of digitalis, especially the toxic effects.

1. Digitalis  Pharmacoligical mechanism ACTIONS （1）Positive inotropic action - inhibitor of Na+-K+ATPase （2）Negative chronotropic action - inhibits sympathetic activities - improves vagal activities （3）Actions on cardiac electrophysiology - decreases automaticity of sinoatrial node slow conduction - increases automaticity of Pukinje fibres - shortens ERP of fast reaction cells

1. Digitalis  Pharmacoligical mechanism ACTIONS （4） Actions on nervous system - autonomic nervous system - central nervous system（D2 receptor）（5）Actions on neuroendocrine system - inhibits RAAS - increases ANP（心房钠尿肽）（6）Actions on kidney（diuretic effect） - increases blood supply of kidney - decreases Na+ resorption (inhibition of Na+-K+ ATP ase)

Changes of hemodynamics in CHF
Digoxin Cardiac failure Cardiac output Blood supply Venous pressure Renal blood flow Renin - angiotension Ⅱ Venous hyperemia Aldosterone Pulmonary circulation: cough, emptysis, dyspnea Systemic circulation hyperemia : jugular vein distension, edema Sodium and water retention Changes of hemodynamics in CHF

Cardiac output

1. Digitalis  Clinical usage and toxicity Therapeutic uses：（1）CHF Especially associated with atrial fibrillation and ventricular tachycardia （2）Some arrhythmias - atrial fibrillation - atrial flutter - paroxysmal surpraventricular tachycardia

1. Digitalis  Clinical usage and toxicity Administration & Dosage

1. Digitalis  Toxicity and prevention Cardiac toxicity Tachyarrhythmia：various Bradyarrhythmia：atrial ventricular block, sinus bradycardia. Atropine, isoprenaline,. Digoxin immune fab

1. Digitalis  Toxicity and prevention 2) GI response Anorexia, nausea, vomit, diarrhea. Should be distinguish with heart failure. 3) CNS response and visual disturbance Dizzy, headache, fatigue, xanthopsia, chloropsia etc 4) The symptoms to stop digitalis administration： Severe vomit、chromatopsia, Ventricular premature, Heart rate < 60 times/min

1. Digitalis  Toxicity and prevention Serum digitalis and K+ levels and the ECG should be monitored during therapy of significant digitalis toxicity. Of the available antiarrhythmic agents, lidocaine is favored. Digitalis antibodies (digoxin immune fab) are clinically used for severe toxic patients.

1. Digitalis  Toxicity and prevention Interactions Hypokalemia increase the risk of serious digitalis-induced cardiac arrhythmias Quinidine displaces digoxin from tissue binding sites (a minor effect) and depresses renal digoxin clearance (a major effect) . Antibiotics that alter gastrointestinal flora may increase digoxin bioavailability. Agents that release catecholamines may sensitize the myocardium to digitalis induced arrhythmias.

Mortality From Any Cause (%)
Effect of Digoxin on Mortality in Heart Failure: The Digitalis Investigation Group Digoxin Placebo 4 8 12 16 20 24 28 32 36 40 44 48 52 10 30 50 Relative Risk 0.99 95% CI 0.91–1.07 P=.80 All-cause mortality rates: Placebo 35.1%; Digoxin 34.8% Mortality From Any Cause (%) Months Number of patients at risk: Placebo 3,403 3,239 3,105 2,976 2,868 2,758 2,652 2,551 2,205 1,881 1,506 1, Digoxin 3,397 3,269 3,144 3,019 2,882 2,759 2,644 2,531 2,184 1,840 1,475 1, CV Mortality 0% HF Hospitalizations 28% Total Hospitalizations 6% DIG (Digitalis Investigation Group): 6,800 patients with LVEF 45% randomized to digoxin (n=3,403) or placebo (n=3,397) in addition to therapy with diuretics and ACEI followed for 37 months. The DIGITALIS Investigation Group. N Engl J Med. 1997;336:525–532.

2. Other Positive Inotropic Drugs Used in Heart Failure （略）  Adrenoceptor Stimulants, e.g. dobutamine Result in  cardiac output and  ventricular filling pressure. There is potential for producing angina or arrhythmias in patients with coronary artery disease. Side effects: angina, arrhythmias and tachyphylaxis etc

2. Other Positive Inotropic Drugs Used in Heart Failure （略） Dopamine has also been used in acute heart failure and may be particularly helpful if there is a need to raise blood pressure.

1. Positive Inotropic Drugs Digitalis Beta Adrenoceptor Stimulants Dopamine 2. Diuretics 3. RAAS inhibitors ACEI ARB Adolsterone antagonists 4. Vasodilators 5. Beta blockers 6. rhBNP

3. Drugs Without Positive Inotropic Effects Used in Heart Failure Diuretics To reduce venous pressure and ventricular preload. The results are reduction of edema and its symptoms and reduction of cardiac size, which leads to improved pump efficiency.

Therapeutic effects of diuretics in CHF

1. Positive Inotropic Drugs Digitalis Beta Adrenoceptor Stimulants Dopamine 2. Diuretics 3. RAAS inhibitors ACEI ARB Adolsterone antagonists 4. Vascular dilators 5. Beta inhibitors 6. rhBNP

RAAS Angiotensinogen Renin Bradykinin A I ACE Degradation products
Vasodilatation Vascular perm Prostaglandins Inhibits Na/H20 reabsorption RAAS Angiotensinogen Renin t-PA Cathepsin G Tonin Bradykinin A I ACE CAGE Cathepsin G Chymase Degradation products A II AT1 receptor AT2 receptor Hypertrophy/proliferation Vasoconstriction Sympathetic stimulation Aldosterone release Vasopressin Antiproliferation Antifibrotic NO Release Differentiation Vasodilation

3. Drugs Without Positive Inotropic Effects Used in Heart Failure RAAS inhibitors Reduce peripheral resistance and thereby reduce afterload; Reduce salt and water retention (by reducing aldosterone secretion) and in that way reduce preload. Reduces sympathetic activity. Reduce the long-term remodeling of the heart and vessels.

X X X X ACEI RAAS Angiotensinogen Renin Bradykinin A I ACE
Vasodilatation Vascular perm Prostaglandins Inhibits Na/H20 reabsorption RAAS Angiotensinogen Renin t-PA Cathepsin G Tonin X Bradykinin A I ACE CAGE Cathepsin G Chymase Degradation products X A II AT1 receptor AT2 receptor Hypertrophy/proliferation Vasoconstriction Sympathetic stimulation Aldosterone release Vasopressin Antiproliferation Antifibrotic NO Release Differentiation Vasodilation X X

3. Drugs Without Positive Inotropic Effects Used in Heart Failure CV Risk, reduction in future cardiovascular events; DN, diabetic nephropathy; H, hypertension; HF, heart failure; Post MI, reduction in heart failure or other cardiac events following myocardial infarction.

x x x ARB RAAS Angiotensinogen Renin Bradykinin A I ACE
Vasodilatation Vascular perm Prostaglandins Inhibits Na/H20 reabsorption RAAS Angiotensinogen Renin t-PA Cathepsin G Tonin Bradykinin A I ACE CAGE Cathepsin G Chymase Degradation products A II ARB x AT1 receptor AT2 receptor x Hypertrophy/proliferation Vasoconstriction Sympathetic stimulation Aldosterone release Vasopressin Antiproliferation Antifibrotic NO Release Differentiation Vasodilation

3. Drugs Without Positive Inotropic Effects Used in Heart Failure CV Risk, reduction in future cardiovascular events; DN, diabetic nephropathy; H, hypertension; HF, heart failure; Post MI, reduction in heart failure or other cardiac events following myocardial infarction.

3. Drugs Without Positive Inotropic Effects Used in Heart Failure Aldosterone antagonists Spironolactone and Eplerenone get additional function to decrease morbidity and mortality in patients with severe heart failure who are also receiving ACE inhibitors and other standard therapy.

Effects of Aldosterone
Cardiac Myocyte Fibroblast Peripheral Artery Kidney Hypertrophy Slide 9 Activation of the renin-angiotensin-aldosterone system plays a key role in the pathophysiology of heart failure. Hypoperfusion of the kidney stimulates the release of renin which catalyzes the synthesis of angiotensin I from angiotensinogen. The angiotensin converting enzyme (ACE) converts angiotensin I into angiotensin II. Angiotensin II exerts a wide range of biologic actions which contribute to disease progression in heart failure. Angiotensin II is a potent vasoconstrictor contributing to increased systemic vascular resistance. Angiotensin II results in cardiac and vascular cellular hypertrophy as well as myocardial fibrosis. Angiotensin II plays a fundamental role in progressive left ventricular remodeling that occurs in heart failure and following myocardial infarction. Increased oxidative stress and endothelial dysfunction also result. Since the renin-angiotensin-aldosterone system plays such a key role in the pathophysiology of heart failure, medications that block this system would be expected to beneficial in heart failure patient management. (Francis GS. Pathophysiology of the heart failure clinical syndrome. In: Topol EJ, ed. Textbook of Cardiovascular Medicine. Philadelphia: Lippincott-Raven; 1998; ) Hyperplasia Vasoconstriction Potassium Loss Endothelial Dysfunction Norepinephrine Release Collagen Synthesis Sodium Retention Hypertrophy Fibrosis Decreased Compliance

Probability of Survival (%)
RALES: Aldosterone Antagonist Reduces All-Cause Mortality in Chronic HF Added (25 mg) to top key, per Dr Conti Added RR arrow, per Dr Fonarow 1.00 Spironolactone (25 mg) + standard care (n = 822) 0.95 Placebo + standard care (n = 841) 0.90 0.85 0.80 Added asterisk footnote for title, per Dr Conti HR = 0.70 (95% CI, 0.60 to 0.82) 0.75 Probability of Survival (%) 0.70 0.65 The Randomized Aldactone Evaluation Study (RALES) was designed to test the hypothesis that the aldosterone-receptor blocker spironolactone would reduce the risk of death in patients with severe HF from left ventricular systolic dysfunction. Pitt et al enrolled 1663 patients with severe HF and an LVEF of ≤35% who were being treated with an ACE inhibitor (if tolerated) and a loop diuretic. Digoxin and vasodilators were allowed, but potassium-sparing diuretics were not. A total of 833 patients were randomized to spironolactone 25 mg qd plus standard care and 841 patients to placebo plus standard care. The primary endpoint was death from all causes. The trial was terminated early, after a mean follow-up of 24 months, because an interim analysis revealed that the effect of spironolactone on the primary endpoint exceeded the prespecified critical z value. The placebo group experienced 386 deaths (46%), and the spironolactone group experienced 284 deaths (35%). The relative risk of death was 0.70 (95% CI, 0.60 to 0.82, P<.001). The 30% risk reduction in the spironolactone group was attributed to a lower risk of death from progressive HF as well as a lower risk of sudden death from cardiac causes. The incidence of serious hyperkalemia was 1% in the placebo group and 2% in the spironolactone group. However, the incidence of gynecomastia or breast pain in men was 1% in the placebo group and 10% in the spironolactone group (P<.001). Reference Pitt B, Zannad F, Remme W, et al, for the Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341: Figure reprinted with permission. ©1999 Massachusetts Medical Society. All rights reserved. 0.60 0.55 P<.001 0.50 0.45 3 6 9 12 15 18 21 24 27 30 33 36 Months HR = hazard ratio; RR = risk reduction. *Ejection fraction ≤35% Class III or IV symptoms at some point in prior 2 months. Pitt B et al. N Engl J Med. 1999;341:

EPHESUS Co-Primary Endpoint: Total Mortality
Added % values, per Dr Conti Cumulative Incidence (%) 22 20 18 16 14 12 10 8 6 4 2 3 9 15 21 24 27 Months Since Randomization HR = 0.85 (95% CI, 0.75 to 0.96) P = .008 Eplerenone + standard care (n = 3319) (16.7%) Added RR arrow, per Dr Fonarow (14.4%) Placebo + standard care (n = 3313) over the duration of the study, 478 patients in the eplerenone group (14.4%) and 554 patients in the placebo group (16.7%) died. The relative risk of death from any cause for patients receiving eplerenone versus placebo was 0.85 (P = .008), for a relative risk reduction of 15%. The Kaplan-Meier mortality estimate at 1 year was 11.8% in the eplerenone group and 13.6% in patients receiving placebo. Eplerenone maintained a survival benefit throughout the follow-up period. Patients were followed for a mean of 16 months. Improved CV survival was primarily driven by reductions in sudden death, acute MI, and HF. There were 478 deaths (14.4%) in the eplerenone group and 554 deaths (16.7%) in the placebo group. It is important to note that the 15% reduction in total mortality achieved in the eplerenone group was above and beyond that achieved by optimal standard therapy. Reference Pitt B, Remme W, Zannad F, et al, for the Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348: Figure adapted with permission. ©2003 Massachusetts Medical Society. All rights reserved. HR = hazard ratio. Adapted from Pitt B et al. N Engl J Med. 2003;348:

3. Drugs Without Positive Inotropic Effects Used in Heart Failure Vasodilators Reduction in preload (through venous dilation), or reduction in afterload (through arteriolar dilation), or both. Long-term use of hydralazine and isosorbide dinitrate can also reduce damaging remodeling of the heart.

I/H meanes isosorbide dinitrate and hydralazine
Survival I/H meanes isosorbide dinitrate and hydralazine JCardiacFail 2007;13:

Survival JCardiacFail 2007;13:

AmJCardiol2007;100:684(R)C689

1. Positive Inotropic Drugs Digitalis Beta Adrenoceptor Stimulants Dopamine 2. Diuretics 3. RAAS inhibitors ACEI ARB Adolsterone antagonists 4. Vasodilators 5.  blockers 6. rhBNP

Effect of Carvedilol in Heart Failure
US Carvedilol Heart Failure Trials Program 65% P<0.001 Slide 38 The US Carvedilol Heart Failure Trials program was the first study to demonstrated that beta blockers reduce morbidity and mortality in patients with heart failure. Carvedilol is a nonselective beta blocker that also blocks alpha-1 receptors. This multicenter clinical trial randomized 1094 patients to carvedilol versus placebo added to standard background heart failure therapy (ACE inhibitors, diuretics and digoxin). Carvedilol was started at a dose of 6.25 mg PO BID and titrated to a target dose of 25 mg PO BID. The study was terminated early when an interim analysis revealed a 65% reduction in overall mortality with carvedilol (P<0.001). Carvedilol reduced the incidence of hospitalization for cardiovascular causes by 26% (P=0.036) and lowered the combined risk of death or cardiovascular hospitalization by 38% (P<0.001). Benefits were seen across all subgroups of patients and the survival curves diverged early within the first few weeks of therapy. 1094 Class II-IV CHF pts on triple therapy (ACEI, digoxin, diuretics) Carvedilol 6.25 bid test 2 weeks, then 12.5 bid, then 25 bid vs placebo Packer NEJM 1996;334:

Effect of Metoprolol CR/XL in Heart Failure
MERIT-HF Slide 40 The Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) study enrolled 3991 patients with heart failure and LVEF < 40%. Patients were randomized to Metoprolol CR/XL at a starting dose of 12.5 to 25 mg/d versus placebo in addition to standard heart failure treatment. The target dose for Metoprolol CR/XL was 200 mg/d. There was a 34% reduction in all-cause mortality at one year with Metoprolol (P=0.0062). Metoprolol CR/XL reduced cardiovascular mortality by 38% (P=0.0003), lowered the risk of sudden death by 40% and reduced the risk of progressive heart failure by 49%. Treating 1000 heart failure patients with Metoprolol CR/XL over one year would prevent 38 deaths and 70 cardiovascular hospitalizations. 3991 pts with CHF Class II-IV, ave age 64 and LVEF 0.28 Randomized to Metoprolol CR/XL 12.5 mg or 25 mg PO qd, target dose 200 mg qd Lancet 1999;353:

The Use of Beta Adrenergic Blocking Agents in Heart Failure
15 10 5 LVEF % change -5 -10 6 12 18 24 Time (weeks) Initial hemodynamic deterioration followed by reverse remodeling (decrease in EDV and ESV) with improved ventricular function over time (increased LVEF )

Early Benefits and Early Safety of Carvedilol in Severe HF: COPERNICUS
Early Mortality Reduction Lower Risk for Worsening CHF 3 Risk Reduction 25% (35%–59%) 15 Placebo (n=1,133) Placebo Carvedilol 11.4 2 10 8.8 Patients With Event (%) 6.4 1 Carvedilol (n=1,156) 5.1 5 Event rates: Placebo 2.3%; Carvedilol 1.7% 2 4 6 8 All Patients Highest-Risk Subgroup Weeks After Randomization (n=1,133) (n=1,156) (n=316) (n=308) Packer M. N Engl J Med. 2001;344:1651–1658. Krum H. JAMA. 2003;289:712–718.

Effects of Sympathetic Activation in Heart Failure
 CNS sympathetic outflow Compensation De-compensation  Cardiac sympathetic activity  Sympathetic activity to kidneys + blood vessels 1- receptors 2- receptors 1- receptors Activation of RAS  1- 1- At rest, there is no adrenergic support of normally functioning left ventricles. With development of LV dysfunction and HF, however, adrenergic activation is a short-term compensatory mechanism that increases contractility and heart rate and thus maintains cardiac performance. Still, on a long-term basis, chronic activation of the cardiac adrenergic system is toxic to the heart and may contribute to pathogenesis of HF. Three adrenergic receptors on human cardiac myocytes are producing positive inotropic response: b1, b2, and a1. In normal hearts, b1-receptors are predominant, but with prolonged adrenergic stimulation in CHF, these receptors are downregulated whereas a1 receptors are upregulated, so that about half of the receptors are b2 or a1. Chronic b-stimulation can lead to apoptosis of cultured cardiac myocytes and to sudden death in in vivo animal models. Newly published data from animal studies indicate that the detrimental effects of b-adrenergic stimulation are mainly due to activation of b1-receptors, whereas stimulation of b2-receptors has a primarily inotropic effect. Recent large trials of -blockers have proved that inhibiting adrenergic stimulation is effective for reduction of cardiac morbidity and mortality in patients with CHF. In the kidney, adrenergic activity increases vasoconstriction and intraglomerular pressure through stimulation of a1-receptors. At the same time, renin secretion from juxtaglomerular cells is increased through stimulation of b1-receptors. As renin is the rate-limiting enzyme in the production of angiotensin II, the activity of the RAS is increased. Bristow MR. b-adrenergic receptor blockade in chronic heart failure. Circulation. 2000;101: Liggett SB, Tepe NM, Lorenz JN, et al. Early and delayed consequences of beta(2)-adrenergic receptor overexpression in mouse hearts: critical role for expression level. Circulation. 2000;101: Myocyte death Increased arrhythmias Vasoconstriction Sodium retention Disease progression Bristow MR. Circulation. 2000;101:

-Blockers Differ in Their Long-Term Effects on Mortality in HF
Bisoprolol1 Bucindolol2 Carvedilol3-5 Metoprolol tartrate6 Metoprolol succinate7 Nebivolol8 Xamoterol9 Beneficial No effect Not well studied Harmful 1CIBIS II Investigators and Committees. Lancet. 1999;353: The BEST Investigators. N Engl J Med 2001; 344: Colucci WS, et al. Circulation 1996;94: Packer M, et al. N Engl J Med 2001;344: The CAPRICORN Investigators. Lancet. 2001;357: Waagstein F, et al. Lancet. 1993;342: MERIT-HF Study Group. Lancet. 1999;353: SENIORS Study Group. Eur Heart J. 2005; 26: The Xamoterol in Severe heart Failure Study Group. Lancet. 1990;336:1-6.

3. Drugs Without Positive Inotropic Effects Used in Heart Failure H, hypertension; HF, heart failure; Post MI, reduction in heart failure or other cardiac events following myocardial infarction.

Therapeutic effects of β receptor antagonists on cardiac function in heart failure patients

Drugs Used in Heart Failure

rhBNP Nesititide: proved in 2001
1. Publication Committee for the VMAC Investigators. Intravenous nesiritide vs nitroglycerin for treatment of de-compensated congestive heart failure: a randomized controlled trial. JAMA，2002,287(12): 2. Yancy CW, Saltzberg MT，Berkowitz RL,et al. Safety and feasibility of using serial infusions of nesiritide for heart failure in an outpatient setting (from the FUSION I trial). Am J Cardiol,2004,94(5):

rhBNP Risk of kidney damage and short –term of death
The clinical trials after 2005 showed controversial results 1. Sackner2Bernstein JD, Skop icki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely de-compensated heart failure. Circulation, 2005, 111 (12) : 2. Sackner2Bernstein JD, KowalskiM, FoxM, et al. Short-term risk of death after treatment with nesiritide for de-compensated heart failure: a pooled analysis of randomized controlled trials. JAMA, 2005, 293 (15) : Risk of kidney damage and short –term of death Also some results showed no effects ??

Drugs Used in Heart Failure
2009 guideline

4. Clinical Pharmacology of Drugs Used in Heart Failure In the past prescription of a diuretic plus digitalis. At present diuretics, ACE inhibitors, and -blockers

4. Clinical Pharmacology of Drugs Used in Heart Failure Management of Chronic Heart Failure

4. Clinical Pharmacology of Drugs Used in Heart Failure Management of Chronic Heart Failure 1) Sodium Removal: by dietary salt restriction or a diuretic In mild failure, it is reasonable to start with a thiazide diuretic, switching to more powerful agents as required. Hypokalemia can be treated with potassium supplementation or through the addition of a potassium-sparing diuretic such as spironolactone.

4. Clinical Pharmacology of Drugs Used in Heart Failure Management of Chronic Heart Failure 2) ACEI & ARB In patients with left ventricular dysfunction but no edema, an ACE inhibitor should be used first. Additional studies suggest that ACE inhibitors are also valuable in asymptomatic patients with ventricular dysfunction. The angiotensin II receptor antagonists (eg, losartan, valsartan, etc) produce beneficial hemodynamic effects similar to those of the ACE inhibitors.

4. Clinical Pharmacology of Drugs Used in Heart Failure Management of Chronic Heart Failure 3) Vasodilators Vasodilators include arteriolar dilators, venous dilators, and drugs with nonselective vasodilatory effects. The choice of agent should be based on the patient's signs and symptoms and hemodynamic measurements. high filling pressures venous dilators low left ventricular output------arteriolar dilator chronic failure that responds poorly to other therapy-----both

4. Clinical Pharmacology of Drugs Used in Heart Failure Management of Chronic Heart Failure 4)  Blockers  blockers such as bisoprolol, carvedilol, and metoprolol are beneficial to heart failure, which based on the hypothesis that excessive tachycardia and adverse effects of high catecholamine levels on the heart. BUT SHOULD BE VERY CAREFUL.

4. Clinical Pharmacology of Drugs Used in Heart Failure Management of Chronic Heart Failure 5) Digitalis Digoxin is indicated in patients with heart failure and atrial fibrillation or in patients with a dilated heart and third heart sound. Digoxin is reduced hospitalization and deaths from progressive heart failure. But there is an increase in sudden death, especially with serum digoxin concentrations of digoxin levels greater than 1.5 ng/mL. The characteristics of digoxin is long half life and the close of between the therapeutic plasma concentration and the toxic plasma concentration.

4. Clinical Pharmacology of Drugs Used in Heart Failure constrictive peicarditis Management of Chronic Heart Failure with normal systolic function Treatment of patients with predominantly diastolic dysfunction heart failure has not been well studied Direct vasodilators are not indicated Diuretics should be used cautiously, at low dose initially, recognizing that the stiff heart is highly dependent on adequate preload ACE inhibitors, calcium channel blockers, and beta blockers have favorable effects upon hemodynamics Recommend: ACE inhibitors, beta blockers, aldosterone antagonists

4. Clinical Pharmacology of Drugs Used in Heart Failure Management of Acute Heart Failure Acute heart failure occurs frequently in patients with chronic failure. Such episodes are usually associated with increased exertion, emotion, salt in the diet, noncompliance with medical therapy, or increased metabolic demand occasioned by fever, anemia, and acute myocardial infarction, etc

4. Clinical Pharmacology of Drugs Used in Heart Failure Management of Acute Heart Failure Patients with acute myocardial infarction are best treated with emergency revascularization with either coronary angioplasty and a stent or a thrombolytic agent. Measurements of arterial pressure, cardiac output, stroke work index, and pulmonary capillary wedge pressure are particularly useful in patients with acute myocardial infarction and acute heart failure.

Important Comorbidities in Heart Failure
Non-Cardiovascular Obesity Diabetes Anemia Chronic kidney disease Thyroid disease COPD / Asthma Smoking Sleep disordered breathing Liver disease Arthritis Cancer Depression Cardiovascular Hypertension Coronary artery disease Peripheral vascular disease Cerebral vascular disease Hyperlipidemia Atrial fibrillation Horwich and Fonarow, Chapter 40: Impact and Treatment of Comorbidities in Heart Failure

Evidence-Based Treatment Across the Contineum of LVD and HF
Reduce Mortality Control Volume Salt Restriction* Diuretics* ACEI or ARB Aldosterone Antagonist -Blocker Treat Residual Symptoms CRT  an ICD* ICD* Hyd/ISDN* Digoxin* Treat Comorbidities Enhance Adherence Education Disease Management Performance Improvement Systems Aspirin* Warfarin* Statin* *For select indicated patients.

References Golan DE, et al. Principles of Pharmacology. Lippincott Williams & Wilkins Murphy JE. Clinical Pharmacokinetics, 4th edition ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult. 2009 focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults.

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