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
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
A. A. OverviewOverview
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
A. A. OverviewOverview
CardiacCardiac
remodelingremodeling
DecreaseDecrease
overloadoverload
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
B.B. Angiotensin converting enzyme inhibitors Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists(ACEI) and angiotensin receptor antagonists
B.B. Angiotensin converting enzyme inhibitors Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists(ACEI) and angiotensin receptor antagonists
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
B.B. Angiotensin converting enzyme inhibitors Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists(ACEI) and angiotensin receptor antagonists
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
B.B. Angiotensin converting enzyme inhibitors Angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagonists(ACEI) and angiotensin receptor antagonists
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
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
2. 2. Clinical usesClinical uses
(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..
D.D. receptor blockers receptor blockers
Therapeutic effects of Therapeutic effects of receptor antagonists on receptor antagonists on cardiac function in CHF patientscardiac function in CHF patients
D.D. receptor blockers receptor blockers
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
D.D. receptor blockers receptor blockers
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.
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
E.E. Cardiac glycosideCardiac glycoside (digitalis)(digitalis)
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
E.E. Cardiac glycosideCardiac glycoside (digitalis)(digitalis)
(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
E.E. Cardiac glycosideCardiac glycoside (digitalis)(digitalis)
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
E.E. Cardiac glycosideCardiac glycoside (digitalis)(digitalis)
2. 2. Clinical usesClinical uses
(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
E.E. Cardiac glycosideCardiac glycoside (digitalis)(digitalis)
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.
E.E. Cardiac glycosideCardiac glycoside (digitalis)(digitalis)
(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.
E.E. Cardiac glycosideCardiac glycoside (digitalis)(digitalis)
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
E.E. Cardiac glycosideCardiac glycoside (digitalis)(digitalis)
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
E.E. Cardiac glycosideCardiac glycoside (digitalis)(digitalis)
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
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