Congestive Heart Failure Case Study. Congestive Heart Failure.
Chapter 31 Drugs for Treatment of Congestive Heart Failure
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Transcript of 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
A. A. OverviewOverview
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
A. A. OverviewOverview
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
B.B. DigitalisDigitalis
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
B.B. DigitalisDigitalis
B.B. DigitalisDigitalis
(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
B.B. DigitalisDigitalis
B.B. DigitalisDigitalis
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
B.B. DigitalisDigitalis
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.
B.B. DigitalisDigitalis
(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
B.B. DigitalisDigitalis
B.B. DigitalisDigitalis
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
D.D. Angiotensin converting enzyme inhibitorAngiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagoniss (ACEI) and angiotensin receptor antagonis
tsts
D.D. Angiotensin converting enzyme inhibitorAngiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagoniss (ACEI) and angiotensin receptor antagonis
tsts
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
Contraindications:Contraindications: pregnancy and stenosis of re pregnancy and stenosis of renal artery nal artery
D.D. Angiotensin converting enzyme inhibitorAngiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagoniss (ACEI) and angiotensin receptor antagonis
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
D.D. Angiotensin converting enzyme inhibitorAngiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor antagoniss (ACEI) and angiotensin receptor antagonis
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
2. 2. Clinical usesClinical uses
(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.
E.E. receptor blockers receptor blockers
Therapeutic effects of Therapeutic effects of ββ receptor antagonists on receptor antagonists on cardiac function in CHF patientscardiac function in CHF patients
E.E. 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
bronchial asthmabronchial asthma
E.E. receptor blockers receptor blockers
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