Part 4 Drugs for Treatment of Congestive Heart Failure

Part 4Part 4

Drugs for Treatment of Drugs for Treatment of Congestive Heart FailureCongestive Heart Failure

ContentsContents

OverviewOverview ACE inhibitorsACE inhibitors DiureticsDiuretics receptor blockersreceptor blockers Cardiac glycosideCardiac glycoside OthersOthers

Heart (cardiac) failure is said to have occurred when the heart is no Heart (cardiac) failure is said to have occurred when the heart is no longer able to maintain the circulation to the tissues for normal longer able to maintain the circulation to the tissues for normal metabolism.metabolism.

1.1. Pathophysiological changes of congestive heart failPathophysiological changes of congestive heart failure (CHF)ure (CHF)

(1) Function and structure changes(1) Function and structure changes

(2) Increased sympathetic activity and (2) Increased sympathetic activity and

down-regulation of down-regulation of receptor receptor

(3) Activated renin-angiotensin-aldosterone system (3) Activated renin-angiotensin-aldosterone system (RAAS)(RAAS)

A. A. OverviewOverview

Pathophysiological Pathophysiological changes of CHFchanges of CHF

Pathophysiological changes of CHFPathophysiological changes of CHF

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 Ⅱ

Aldosterone Aldosterone

Sodium and waterSodium and waterretentionretention

Changes in hemodynamics of CHFChanges in hemodynamics of CHF


2. 2. Grades of CHFGrades of CHF

I (A):I (A): no symptomsno symptoms

II (B):II (B): physical activities were limited and symptoms physical activities were limited and symptoms

could be induced by general activitycould be induced by general activity

III (C):III (C): physical activities were markedly limitedphysical activities were markedly limited

IV (D):IV (D): symptoms appear even at restsymptoms appear even at rest

3. 3. Therapeutic strategies in CHF Therapeutic strategies in CHF

(1) Increasing contractility of the cardiac muscles(1) Increasing contractility of the cardiac muscles

(2) Inhibiting RAAS (2) Inhibiting RAAS

(3) Reducing sympathetic activity (3) Reducing sympathetic activity

(4) Dilating vessels(4) Dilating vessels

(5) Diuresis (5) Diuresis


CardiacCardiac

remodelingremodeling

DecreaseDecrease

overloadoverload

Drug therapy for CHFDrug therapy for CHF

ACEI:ACEI: captopril captopril 卡托普利卡托普利

enalapril enalapril 依那普利依那普利

ATAT11 receptor antagonists: receptor antagonists:

losartan losartan 氯沙坦氯沙坦

irbesartan irbesartan 伊白沙坦伊白沙坦

B.B. Angiotensin converting enzyme iAngiotensin converting enzyme inhibitors (ACEI) and angiotensin rnhibitors (ACEI) and angiotensin receptor antagonistseceptor antagonists

Cardiovascular remodelingCardiovascular remodelingvasodilatationvasodilatation

Systemic and localSystemic and local

ACEIACEI

1. 1. Pharmacological effectsPharmacological effects Inhibiting the production of Ang IIInhibiting the production of Ang II vasoconstriction vasoconstriction ; sodium retention ; sodium retention ; ;

cardiac remodeling (myocardial hypertrophy) cardiac remodeling (myocardial hypertrophy)

Inhibiting the degradation of bradykinin Inhibiting the degradation of bradykinin vasodilatation vasodilatation

Increasing ANP and scavenging free radicalsIncreasing ANP and scavenging free radicals

B.B. Angiotensin converting enzyme inhibitors Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists(ACEI) and angiotensin receptor antagonists

Box Box Actions of angiotensin IIActions of angiotensin II

through activating AT1 receptors

• Constricting vessels, increase peripheral resistConstricting vessels, increase peripheral resistance and returned blood volume.ance and returned blood volume.

• Increasing sympathetic tension, promote releaIncreasing sympathetic tension, promote release of sympathetic transmitter.se of sympathetic transmitter.

• Stimulating release of aldosteroneStimulating release of aldosterone..

• Rapidly inducing expression of Rapidly inducing expression of c-fos, c-jun, Egc-fos, c-jun, Egr-1, c-myc, etc.r-1, c-myc, etc.

Cardiovascular effectsCardiovascular effects Decrease resistance of peripheral vessels Decrease resistance of peripheral vessels

Dilate coronary artery, increase blood supply Dilate coronary artery, increase blood supply of heart and kidney, improve cardiac and renal of heart and kidney, improve cardiac and renal functionfunction

Reverse myocardial hypertrophy and Reverse myocardial hypertrophy and ventricular remodeling ventricular remodeling



2. 2. Clinical usesClinical uses

(1) CHF (1) CHF

increase motor toleranceincrease motor tolerance

decrease mortalitydecrease mortality

(2) Hypertension(2) Hypertension

3. 3. Adverse effectsAdverse effects

HypotensionHypotension

Cough and angioedemaCough and angioedema

HyperpotassemiaHyperpotassemia

Rashes and altered tastesRashes and altered tastes

Contraindications:Contraindications: pregnancy and stenosis of ren pregnancy and stenosis of renal artery al artery


ATAT11 receptor antagonists receptor antagonists

Compared with ACEI:Compared with ACEI: Blocking actions of angiotensin II directlyBlocking actions of angiotensin II directly

Not affecting bradykinin metabolismNot affecting bradykinin metabolism

Protecting renal functionProtecting renal function

Used for CHF and hypertensionUsed for CHF and hypertension


1. 1. Pharmacological effectsPharmacological effects Reduce blood volume by increasing NaReduce blood volume by increasing Na++ and water excretion and water excretion

Reduce NaReduce Na++-Ca-Ca2+2+ exchange in vascular smooth muscle cells exchange in vascular smooth muscle cells

2.2. Clinical uses Clinical uses CHF: CHF: grand I – IV (mainly used in II –III),grand I – IV (mainly used in II –III), alone or combinalone or combin

ed with other drugs ed with other drugs

Edema, hypertension, Edema, hypertension, etc.etc.

3. Adverse effects3. Adverse effects

imbalance of electrolytes/acid-base;imbalance of electrolytes/acid-base;

plasma level of renin plasma level of renin ; hypokalemia; hyper; hypokalemia; hyperuricemia; hyperglycemia/hyperlipidemiauricemia; hyperglycemia/hyperlipidemia

C.C. DiureticsDiuretics

Therapeutic effects of Therapeutic effects of diuretics in CHFdiuretics in CHF

Commonly used: Commonly used: carvedilol carvedilol 卡维地洛卡维地洛 , bisoprolol , bisoprolol 比索比索

洛尔洛尔 , sustained-release metoprolol , sustained-release metoprolol 缓释型美托洛尔缓释型美托洛尔

1. 1. Pharmacological effectsPharmacological effects(1) Blocking effects of catecholamines on myocardium: (1) Blocking effects of catecholamines on myocardium: decreasindecreasin

g heart rate and cardiac oxygen demandg heart rate and cardiac oxygen demand

(2) Up-regulating (2) Up-regulating receptor receptor

(3) Inhibiting RAAS and VP (vosopressin, (3) Inhibiting RAAS and VP (vosopressin, 加压素加压素 ): ): anti- myocaranti- myocardial hypertrophy and remodeling dial hypertrophy and remodeling

(4) Reducing cardiac oxygen remand, vasodilatation (4) Reducing cardiac oxygen remand, vasodilatation (( receptor bloc receptor bloc

k)k)

(5) Anti-arrhythmic and anti-hypertensive effects(5) Anti-arrhythmic and anti-hypertensive effects

D.D. receptor blockers receptor blockers


(1) CHF:(1) CHF: grand II - IIIgrand II - III

decreasing mortalitydecreasing mortality

(2) Other uses:(2) Other uses:

hypertension, arrhythmias, angina, hypertension, arrhythmias, angina, etcetc..


Therapeutic effects of Therapeutic effects of receptor antagonists on receptor antagonists on cardiac function in CHF patientscardiac function in CHF patients


3.3. Adverse effects Adverse effects

Inhibition of cardiac functionInhibition of cardiac function

Contraindications:Contraindications: severe heart failuresevere heart failure

severe A-V blocksevere A-V block

hypotensionhypotension

worsening bronchial asthmaworsening bronchial asthma


E.E. Cardiac glycosideCardiac glycoside (digitalis)(digitalis)

Cardiac glycosideCardiac glycoside : : It is a kind of It is a kind of glycoside compounds which can glycoside compounds which can selectively act on cardiac muscle, and selectively act on cardiac muscle, and increase the force of myocardial increase the force of myocardial contraction.contraction.

Digoxin Digoxin 地高辛地高辛


1. 1. Pharmacological effectsPharmacological effects

(1) Positive inotropic effects(1) Positive inotropic effects

inhibiting Nainhibiting Na++-K-K++-ATPase -ATPase free Ca free Ca2+2+ excitation-c excitation-c

ontraction coupling ontraction coupling

cardiac output cardiac output organ blood supply organ blood supply

Vmax Vmax diastolic duration diastolic duration venous return venous return

coronary blood supply coronary blood supply

cardiac oxygen consumption cardiac oxygen consumption


Inhibition of NaInhibition of Na++-K-K++-ATPase by digitalis and pote-ATPase by digitalis and potentiation of cardiac muscle contractionntiation of cardiac muscle contraction

(2) Negative chronotropic effects(2) Negative chronotropic effects

Reflex inhibition of sympathetic activityReflex inhibition of sympathetic activity cardiac output cardiac output Sympathetic activity Sympathetic activity HR HR

Increasing vagal activityIncreasing vagal activity directlydirectly

Reducing AV conduction: Reducing AV conduction: ventricular rate ventricular rate


(3) Electrophysiological effects (3) Electrophysiological effects

decreasing automaticity of sinoatrial nodedecreasing automaticity of sinoatrial node

slow conduction, slow conduction, especially AV conductionespecially AV conduction

increasing automaticity of increasing automaticity of PurkinjePurkinje fibres fibres

shortening ERP of fast response cellsshortening ERP of fast response cells

Mechanisms:Mechanisms:

intracellular Naintracellular Na+ + , K, K++ , Ca, Ca2+2+

MDP MDP , afterdepolarization, afterdepolarization


Overdose:Overdose:

NaNa++ , K, K++ , Ca, Ca2+2+

MDP MDP

afterdepolarizationafterdepolarization

Electrophysiological basis for digitalis overdoseElectrophysiological basis for digitalis overdose

ECG:ECG: P-R P-R ; S-T/T wave ; S-T/T wave ; various arrhythmias; various arrhythmias

P-R P-R

S-T/T wave S-T/T wave prematural ventricular beatprematural ventricular beat

(4) Other effects(4) Other effects

Vessels:Vessels: vasoconstrictionvasoconstriction

Central nervous system:Central nervous system:

CTZ dopamine DCTZ dopamine D22 receptor receptor

mental and vision disordersmental and vision disorders

Kidney:Kidney:

increase blood supply of kidneyincrease blood supply of kidney

diuretic effect: decrease Nadiuretic effect: decrease Na++ reabsorption reabsorption



(1) Congestive heart failure (CHF)(1) Congestive heart failure (CHF)

especially associated with atrial fibrillation and sinus tacespecially associated with atrial fibrillation and sinus tachycardiahycardia

(2) Arrhythmias(2) Arrhythmias atrial fibrillation / atrial flutter:atrial fibrillation / atrial flutter:

paroxysmal surpraventricular tachycardiaparoxysmal surpraventricular tachycardia


3. 3. Adverse effectsAdverse effects

(1) Gastrointestinal effects(1) Gastrointestinal effects

nausea, vomiting, nausea, vomiting, etc.etc.

(2) CNS effects(2) CNS effects

alteration of color perceptionalteration of color perception （（色视色视 , , such assuch as yellow vision yellow vision

黄视黄视）） ; headache, fatigue, confusion, ; headache, fatigue, confusion, etc.etc.


(3) Cardiac toxicity(3) Cardiac toxicity

arrhythmiasarrhythmias ：： prematural beats, tachycardiaprematural beats, tachycardia ，， atrioventricular block, sinus bradycardia, atrioventricular block, sinus bradycardia, etc.etc.

PreventionPrevention ：： Dose individualizationDose individualization

Avoiding provocation factors: plasma KAvoiding provocation factors: plasma K+ + , a, and drug interactions, nd drug interactions, etc.etc.

TreatmentTreatment ：： KCl, phenytoin or lidocaine, KCl, phenytoin or lidocaine, i.v.i.v.

Atropine:Atropine: A-V block, sinus bradycardia A-V block, sinus bradycardia

Fab segment of digoxin antibody, Fab segment of digoxin antibody, i.v.i.v.


Drug interactions Drug interactions that probably indthat probably ind

uce digitalis cardiouce digitalis cardiotoxicitytoxicity

4. 4. AdministrationAdministration

(1) Loading + maintaining doses(1) Loading + maintaining doses full dose (digitalization) + maintaining dosesfull dose (digitalization) + maintaining doses

for severe patientsfor severe patients

(2) Maintaining dose given daily(2) Maintaining dose given daily

reaching steady state of plasma concentration wireaching steady state of plasma concentration with 1 week (digoxin)th 1 week (digoxin)

for stable patientsfor stable patients


5. 5. ADME and properties of different digitalis druADME and properties of different digitalis drugsgs

(1) Moderate-acting:(1) Moderate-acting: digoxin digoxin 地高辛地高辛

(2) Long-acting(2) Long-acting ：： digitoxin digitoxin 洋地黄毒苷洋地黄毒苷

digitalization + maintaining dosesdigitalization + maintaining doses

(3) Short-acting(3) Short-acting ：： deslanoside deslanoside 西地兰西地兰 , , 去乙酰毛花苷去乙酰毛花苷

acute attack of CHFacute attack of CHF


1. 1. receptor agonists receptor agonists dobutaminedobutamine 多巴酚丁胺多巴酚丁胺

Positive inotropic drugsPositive inotropic drugs

Arrhythmias, Arrhythmias, etc.etc.

2.2. PDE-III inhibitors PDE-III inhibitors

milrinone milrinone 米力农米力农 , vesnarinone , vesnarinone 维司力农维司力农，， amrinoneamrinone 安力农安力农

Positive inotropic drugsPositive inotropic drugs

Hypotension, Hypotension, thrombocytopeniathrombocytopenia, , etc.etc.

F.F. Other drugsOther drugs

3. 3. VasodilatorsVasodilators

cardiac preload and afterload cardiac preload and afterload , output , output

4. 4. Calcium channel blockerCalcium channel blocker

5. 5. Calcium sensitizersCalcium sensitizers

F.F. Other drugsOther drugs

Action modes of positive inotropic drugsAction modes of positive inotropic drugs

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Part 4 Drugs for Treatment of Congestive Heart Failure