weiping zhang, md, ph.d., department of pharmacology zhejiang university school of medicine

Weiping Zhang, MD, Ph.D., Weiping Zhang, MD, Ph.D., Department of PharmacologyDepartment of PharmacologyZhejiang University School of MedicineZhejiang University School of Medicine

2010.6.28

Part 6 Drugs for Treatment of Congestive Heart Failure

Pharmacology for cardiovascular system

ContentsContentsI. IntroductionII. 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

1.1. 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.

I. I. IntroductionIntroduction

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 HFD

Known structural heart diseaseShortness of breath and fatigueReduced exercise tolerance

Symptomatic HFC

Previous MILV systolic dysfunctionAsymptomatic valvular disease

Asymptomatic HFB

HypertensionCAD Diabetes mellitusFamily history of cardiomyopathy

High risk for developing heart failure (HF)A

Patient DescriptionStage

Hunt SA et al. J Am Coll Cardiol. 2001;38:2101–2113.

At Risk

Heart Failure

Myocardial injury Fall in cardiac output

Activation of RAAS, SNS and others

Myocardial toxicityPeripheral vasoconstrictionHemodynamic alterations

Remodeling andprogressive

worsening ofLV function Heart failure symptomsMorbidity and mortality

ANPBNP

Fonarow GC. Rev Cardiovasc Med..2001;2:7–12.

3. Pathophysiology of Heart Failure:

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 IIPathophysiologic Effects of Angiotensin IIand Epinephrine/Norepinephrineand Epinephrine/Norepinephrine

Cardiac Myocyte Fibroblast Peripheral Artery Coronary ArteryHypertrophy

Apoptosis

Increased Wall Stress

Increased O2 Consumption

Cell Sliding

Impaired Relaxation

Collagen Synthesis

Hyperplasia

Decreased ComplianceFibrosis

Vasoconstriction

HypertrophyEndothelial Dysfunction

VasoconstrictionEndothelial DysfunctionAtherosclerosis

ThrombosisRestenosis

Cardiac failureCardiac failure

Cardiac outputCardiac output

Venous pressureVenous pressure

Venous hyperemiaVenous hyperemia

Pulmonary circulaPulmonary circulation:tion:cough, emptysis, cough, emptysis, dyspneadyspnea

Systemic circulationSystemic circulation hyperemiahyperemia ::jugular vein jugular vein distension, edemadistension, edema

Blood supplyBlood supply

Renal blood flowRenal blood flow

Renin - angiotension ⅡRenin - angiotension ⅡAldosterone Aldosterone

Sodium and waterSodium and waterretentionretention

Changes of hemodynamics in CHFChanges of hemodynamics in CHF

3. Pathophysiology of Heart Failure:extrinsic compensatory:• Sympathetic nervous system• RAAs

Cardiac output

Sympatheticdischarge

Angiotensin II

Renin release

Renal blood flow

Remodeling

Rate

force

Preload

Afterload

Carotid sinus firing

Cardiac output (via compensation)

II. 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• Dopamine2. Diuretics3. RAAS inhibitors• ACEI• ARB• Adolsterone antagonists4. Vasodilators5. Beta blockers6. rhBNP

Whether they can decrease the mortality

Stage C patients Stage D patients

2009 guideline2009 guideline


1. Positive Inotropic Drugs• Digitalis Adrenoceptor Stimulants• Dopamine2. Diuretics3. RAAS inhibitors• ACEI• ARB• Adolsterone antagonists4. Vasodilators5. Beta blockers6. 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

XX

Hypokalemia Hyperkalemia


1. Digitalis Pharmacoligical mechanismACTIONS（ 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 mechanismACTIONS（ 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)

Cardiac failureCardiac failure

Cardiac outputCardiac output

Venous pressureVenous pressure

Venous hyperemiaVenous hyperemia

Pulmonary circulaPulmonary circulation:tion:cough, emptysis, cough, emptysis, dyspneadyspnea

Systemic circulationSystemic circulation hyperemiahyperemia ::jugular vein jugular vein distension, edemadistension, edema

Blood supplyBlood supply

Renal blood flowRenal blood flow

Renin - angiotension ⅡRenin - angiotension ⅡAldosterone Aldosterone

Sodium and waterSodium and waterretentionretention

Changes of hemodynamics in CHFChanges of hemodynamics in CHF

DigoxinDigoxin

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

Administration & Dosage


1. Digitalis Clinical usage and toxicity


1. Digitalis Toxicity and prevention

1) Cardiac toxicity Tachyarrhythmia ： various Bradyarrhythmia ： atrial ventricular block, sinus brad

ycardia. Atropine, isoprenaline,. Digoxin immune fab



2) GI responseAnorexia, nausea, vomit, diarrhea. Should be distinguish wit

h 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, He

art rate < 60 times/min

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.



• 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.


Interactions1. Digitalis Toxicity and prevention

Effect of Digoxin on Mortality in Heart Effect of Digoxin on Mortality in Heart FailureFailure: The Digitalis Investigation Group

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.

Digoxin

Placebo

00 4 8 12 16 20 24 28 32 36 40 44 48 52

10

20

30

40

50

Relative Risk 0.9995% CI 0.91–1.07

P=.80

All-cause mortality rates: Placebo 35.1%; Digoxin 34.8%

Mor

talit

y Fr

om A

ny C

ause

(%)

MonthsNumber 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 1,168

734 339Digoxin 3,397 3,269 3,144 3,019 2,882 2,759 2,644 2,531 2,184 1,840 1,475 1,156

737 335

CV Mortality 0%

HF Hospitalizations 28%

Total Hospitalizations 6%

Adrenoceptor Stimulants, e.g. dobutamineResult 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.


2. Other Positive Inotropic Drugs Used in Heart Failure（略）

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.


3. Drugs Without Positive Inotropic Effects Used in Heart Failure

Therapeutic effects of Therapeutic effects of diuretics in CHFdiuretics in CHF


1. Positive Inotropic Drugs• Digitalis• Beta Adrenoceptor Stimulants• Dopamine2. Diuretics3. RAAS inhibitors• ACEI• ARB• Adolsterone antagonists4. Vascular dilators5. Beta inhibitors6. rhBNP

Angiotensinogen

A IRenin

A II

• Antiproliferation• Antifibrotic• NO Release• Differentiation• Vasodilation

• Hypertrophy/proliferation• Vasoconstriction• Sympathetic stimulation• Aldosterone release• Vasopressin

AT1 receptor AT2 receptor

ACE

Degradation products

Bradykinin

RAASt-PACathepsin GToninCAGE

Cathepsin GChymase

Vasodilatation Vascular perm Prostaglandins Inhibits Na/H20

reabsorption

RAAS inhibitorsReduce 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.



Angiotensinogen

A IRenin

A II




ACE


Bradykinin

RAASt-PACathepsin GTonin

CAGECathepsin GChymase


reabsorption

X

X X

X

ACEI

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.



Angiotensinogen

A IRenin

A II




ACE


Bradykinin

RAASt-PACathepsin GToninCAGE

Cathepsin GChymase

xARB

x


reabsorptionx ARB

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.



Aldosterone antagonistsAldosterone antagonists

Spironolactone and Eplerenone get additional functio

n to decrease morbidity and mortality in patients with

severe heart failure who are also receiving ACE inhib

itors and other standard therapy.



Cardiac Myocyte Fibroblast Peripheral Artery KidneyHypertrophy

Norepinephrine Release Collagen Synthesis

Hyperplasia

Decreased ComplianceFibrosis

Vasoconstriction

HypertrophyEndothelial Dysfunction

Potassium LossSodium Retention

Effects of AldosteroneEffects of Aldosterone

RALES: Aldosterone Antagonist Reduces All-Cause Mortality in Chronic HF

*Ejection fraction ≤35% Class III or IV symptoms at some point in prior 2 months.

Spironolactone (25 mg) + standard care (n = 822)Placebo + standard care (n = 841)

Prob

abili

ty o

f Sur

viva

l (%

)

1.000.950.900.850.800.750.700.650.600.550.50

03 6 912 15 18 21 24 27

Months

HR = 0.70 (95% CI, 0.60 to 0.82)

0

0.45

30 33 36

P<.001

Pitt B et al. N Engl J Med. 1999;341:709-717.

HR = hazard ratio; RR = risk reduction.

EPHESUS Co-Primary Endpoint:Total Mortality

Adapted from Pitt B et al. N Engl J Med. 2003;348:1309-1321.

Eplerenone + standard care (n = 3319)

Placebo + standard care (n = 3313)

Cum

ulat

ive

Inci

denc

e (%

)

22201816141210

86420

3 6 912 15 18 21 24 27

Months Since Randomization

HR = 0.85 (95% CI, 0.75 to 0.96)P = .008

0

(16.7%)

(14.4%)

HR = hazard ratio.

VasodilatorsReduction 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.



JCardiacFail 2007;13:331-339

I/H meanes isosorbide dinitrate and hydralazineI/H meanes isosorbide dinitrate and hydralazine

Survival

JCardiacFail 2007;13:331-339

Survival

AmJCardiol2007;100:684(R)C689


1. Positive Inotropic Drugs• Digitalis• Beta Adrenoceptor Stimulants• Dopamine2. Diuretics3. RAAS inhibitors• ACEI• ARB• Adolsterone antagonists4. Vasodilators5. blockers6. rhBNP

Effect of Carvedilol in Heart FailureEffect of Carvedilol in Heart FailureUS Carvedilol Heart Failure Trials Program

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 placeboPacker NEJM 1996;334:1349-55

0 50 100 150 200 250 300 350 400Follow-up (days)

50

60

70

80

90

100Survival Proportion

CarvedilolPlacebo

P<0.001

65%

Effect of Metoprolol CR/XL in Heart FailureEffect of Metoprolol CR/XL in Heart FailureMERIT-HF

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 qdLancet 1999;353:2001-07

0 3 6 9 12 15 18 21Follow-up (months)

80

85

90

95

100Survival Proportion

Metoprolol CR/XLPlacebo

RR 0.66 (0.53-0.81)P=0.0062

The Use of Beta Adrenergic Blocking Agents in Heart Failure

0 6 12 18 24

Time (weeks)

0

5

10

15

-5

-10

LVE

F %

cha

nge

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

Packer M. N Engl J Med. 2001;344:1651–1658. Krum H. JAMA. 2003;289:712–718.

Highest-Risk Subgroup

15

10

All Patients

6.45.1

11.4

8.8

Placebo

Carvedilol

Lower Risk for Worsening CHF

(n=1,133) (n=1,156) (n=316) (n=308)

5

0

Early Mortality Reduction

3

2

1

00 2 4 6 8

Weeks After Randomization

Patie

nts

With

Eve

nt (%

) Placebo(n=1,133)

Carvedilol(n=1,156)

Risk Reduction 25%

(35%–59%)

Event rates: Placebo 2.3%; Carvedilol 1.7%

Effects of SympatheticEffects of SympatheticActivation in Heart FailureActivation in Heart Failure

1-receptors

Cardiac sympathetic activity Sympathetic activity to kidneys+ blood vessels

2-receptors

1-receptors

Activationof RAS

VasoconstrictionSodium retention

Myocyte deathIncreased arrhythmias

Disease progression

1- 1-

CNS sympathetic outflow

Bristow MR. Circulation. 2000;101:558-569.

CompensationCompensationDe-compensationDe-compensation

-Blockers Differ in Their Long-Term Effects on Mortality in HF

Bisoprolol1

Bucindolol2

Carvedilol3-5

Metoprolol tartrate6

Metoprolol succinate7

Nebivolol8

Xamoterol9

Beneficial No effectBeneficialNot well studiedBeneficialNo effectHarmful

1CIBIS II Investigators and Committees. Lancet. 1999;353:9-13. 2The BEST Investigators. N Engl J Med 2001; 344:1659-1667. 3Colucci WS, et al. Circulation 1996;94:2800-2806. 4Packer M, et al. N Engl J Med 2001;344:1651-1658. 5The CAPRICORN Investigators. Lancet. 2001;357:1385-1390. 6Waagstein F, et al. Lancet. 1993;342:1441-1446. 7MERIT-HF Study Group. Lancet. 1999;353:2001-2007. 8SENIORS Study Group. Eur Heart J. 2005; 26:215-225. 9The Xamoterol in Severe heart Failure Study Group. Lancet. 1990;336:1-6.

H, hypertension; HF, heart failure; Post MI, reduction in heart failure or other cardiac events following myocardial infarction.



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

Drugs Used in Heart Failure1. Positive Inotropic Drugs• Digitalis• Beta Adrenoceptor Stimulants• Dopamine2. Diuretics3. RAAS inhibitors• ACEI• ARB• Adolsterone antagonists4. Vasodilators5. Beta blockers6. rhBNP

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):1531-1540.

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): 595-601.

rhBNP

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) : 1487-1491.

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) : 1900-1905

Risk of kidney damage and short –term of death

Also some results showed no effects ??

Drugs Used in Heart Failure

2009 guideline

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



1) Sodium Removal: by dietary salt restriction or a diureticIn 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.




2) ACEI & ARBIn 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.




3) VasodilatorsVasodilators 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 dilatorslow left ventricular output------arteriolar dilatorchronic failure that responds poorly to other therapy-----both




4) Blockers blockers such as bisoprolol, carvedilol, and metoprololare 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.




5) DigitalisDigoxin 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.




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 FailureManagement of Chronic Heart Failure with normal systolic function

constrictive peicarditis

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



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.



Management of Acute Heart Failure

Important Comorbidities inHeart Failure

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

Non-Cardiovascular Obesity Diabetes Anemia Chronic kidney disease Thyroid disease COPD / Asthma Smoking Sleep disordered

breathing Liver disease Arthritis Cancer Depression

Evidence-Based Treatment Across the Contineum of LVD and HF

Control VolumeReduce Mortality

Salt Restriction*Diuretics*

Digoxin*

-BlockerACEIor ARB

AldosteroneAntagonist

Treat Residual SymptomsCRT

an ICD* Hyd/ISDN*

*For select indicated patients.

ICD*

Treat Comorbidities

Aspirin*Warfarin*

Statin*

Enhance Adherence

EducationDisease Management

Performance Improvement Systems

References

Golan DE, et al. Principles of Pharmacology. Lippincott Williams & Wilkins. 2004.

Murphy JE. Clinical Pharmacokinetics, 4th edition. 2006.

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.

weiping zhang, md, ph.d., department of pharmacology zhejiang university school of medicine

Documents

chronic heart failure

diastolic failure

chronic failure

acute failure

systolic failure

heart failureiii

highoutput failure

basic pharmacology of