chapter 31 drugs for treatment of congestive heart failure

Chapter 31Chapter 31

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

ContentsContents

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

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

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

(2) Increased sympathetic activity and down regulat(2) Increased sympathetic activity and down regulation of ion of receptor receptor

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

A. A. OverviewOverview

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 of hemodynamics in CHFChanges of hemodynamics in CHF


2. 2. Grades of CHFGrades of CHF

ⅠⅠ(A):(A): no symptoms no symptoms

Ⅱ Ⅱ(B):(B): physical activities were limited and symp physical activities were limited and symptoms could be induced by general activitytoms could be induced by general activity

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

Ⅳ Ⅳ(D):(D): symptoms appear even at rest symptoms 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) Decrease sympathetic activity (3) Decrease sympathetic activity

(4) Dilating vessels(4) Dilating vessels

(5) Diuresis (5) Diuresis


CardiacCardiac

remodelingremodeling

DecreaseDecrease

overloadoverload

B.B. DigitalisDigitalis

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-contracti excitation-contracti

on coupling on 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



(3) Electrophysiological effects (3) Electrophysiological effects

decreasing automaticity of sinoatrial nodedecreasing automaticity of sinoatrial node

slow conduction slow 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

(4) Other effects(4) Other effects

Nervous systemNervous system

autonomic nervous system: NE autonomic nervous system: NE

central nervous system: CTZ Dcentral nervous system: CTZ D22 receptor receptor

Neuroendocrine systemNeuroendocrine system

inhibiting RAASinhibiting RAAS

increasing ANPincreasing ANP （心房钠尿肽）（心房钠尿肽）

KidneyKidney

increase blood supply of kidneyincrease blood supply of kidney

diuretic effect: decrease Nadiuretic effect: decrease Na++ resorption resorption



2. 2. Clinical usesClinical uses

(1) CHF(1) CHF

especially associated with atrial fibrillation and sespecially associated with atrial fibrillation and s

inus tachycardiainus tachycardia

(2) Arrhythmias(2) Arrhythmias

atrial fibrillationatrial fibrillation

atrial flutter 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 yello yello

w vision w vision 黄视）黄视） ; headache, fatigue, confusion, ; headache, fatigue, confusion, etc.etc.


(3) Cardiac toxicity(3) Cardiac toxicity

arrhythmiasarrhythmias ：： prematural beats,prematural beats, tachycardiatachycardia ，， 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 sodium or lidocaine, KCl, phenytoin sodium 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 , , 去乙酰毛花去乙酰毛花苷苷

acute attack of CHFacute attack of CHF

Different eliminatiDifferent elimination modes of digoxion modes of digoxi

n and digitoxinn and digitoxin

1. 1. Pharmacological effectsPharmacological effects Reduce plasma volumeReduce plasma volume

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

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

mbined with other drugs mbined with other drugs

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

3. Adverse effects3. Adverse effects

plasma level of renin plasma level of renin hypokalemia hypokalemia

hyperuricemia hyperglycemiahyperuricemia hyperglycemia

hyperlipidemiahyperlipidemia

C.C. DiureticsDiuretics

Therapeutic effects of Therapeutic effects of diuretics in CHFdiuretics in 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

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

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 scavenge free radicalsIncreasing ANP and scavenge free radicals

D.D. Angiotensin converting enzyme inhibitorAngiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagoniss (ACEI) and angiotensin receptor antagonis

tsts

Angiotensin II

Angiotensin I

ACEACECirculation and Circulation and

local tissueslocal tissues

ACEIACEIACEACE

Circulation and Circulation and local tissueslocal tissues

(—)B2 receptor

PGI2 NO

ACEIACEI(—)

brandykinin

Inactive peptide

VasodilatationVasodilatationAnti-proliferation, anti-hypertrophyAnti-proliferation, anti-hypertrophy

Actions of ACEIActions of ACEI

Box Box Actions of angiotensin IIActions of angiotensin II• Constricting vessels, increase peripheral resistConstricting vessels, increase peripheral resist

ance 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..

• Inducing expression of Inducing expression of c-fosc-fos 、、 c-mycc-myc 、、 c-jun c-jun rapidly.rapidly.

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

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

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


tsts


tsts


(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

Contraindications:Contraindications: pregnancy and stenosis of re pregnancy and stenosis of renal artery nal artery


tsts

ATAT11 receptor antagonists receptor antagonists

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

Not influencing bradykinin metabolismNot influencing bradykinin metabolism

Protecting renal funtionProtecting renal funtion

Used for CHF and hypertensionUsed for CHF and hypertension


tsts

Conmmonly used:Conmmonly used:

Carvedilol Carvedilol 卡维地洛卡维地洛 , labetalol , labetalol 拉贝洛尔拉贝洛尔

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

sing heart rate and cardiac oxygen demandsing 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- myanti- myocardial hypertrophy and remodeling ocardial hypertrophy and remodeling

(4) Blocking (4) Blocking -receptor and anti- free radical-receptor and anti- free radical

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

E.E. receptor blockers receptor blockers


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

decrease of mortalitydecrease of mortality

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

hypertension, arrhythmias, angina, etc. hypertension, arrhythmias, angina, etc.


Therapeutic effects of Therapeutic effects of ββ 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

bronchial asthmabronchial asthma


1.1. 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.

2. 2. receptor agonists receptor agonists

dobutaminedobutamine 多巴酚丁胺多巴酚丁胺 Positive inotropic drugsPositive inotropic drugs

Arrhythmias, Arrhythmias, 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

ⅣⅣⅢⅢⅡⅡgradsgrads

strategiesstrategies

Low NaLow Na++

thiazidesthiazides Loop diureticsLoop diuretics combinedcombined

DilatorDilator

Positive inotropic drugsPositive inotropic drugs

Limit NaLimit Na++

DigitalisDigitalis

Limit Limit activityactivity

blockersblockers

ACEIACEI

Therapeutic strategies of CHFTherapeutic strategies of CHF

chapter 31 drugs for treatment of congestive heart failure

Documents

cardiac muscles2

vagal activity

intracellular na

na resorption

general activity c

ne central nervous system

digitalis overdose4

digitalis cardiotoxicity4