Part 4 Drugs for Treatment of Congestive Heart Failure ??????

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Part 4Drugs for Treatment of Congestive Heart
Failure??????
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Contents
Heart (cardiac) failure is said to have occurred
when the heart is no longer able to maintain the
circulation to the tissues for normal metabolism.

• Overview
• ACE inhibitors
• Diuretics
• ? receptor blockers
• Cardiac glycoside
• Others

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A. Overview

• 1. Pathophysiological changes of congestive
  heart failure (CHF) ?????????????
• (1) Function and structure changes
• ???????
• (2) Increased sympathetic activity and
• down-regulation of ? receptor
• ????????? ?????
• (3) Activated renin-angiotensin-aldosterone
  system (RAAS) RAAS??

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Pathophysiological modulation of CHF
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Chronic heart failure (CHF)
Cardiac output
Blood supply
Venous pressure
Renal blood flow
Renin-angiotension ?
Venous hyperemia
Aldosterone
Pulmonary circulation cough, emptysis, dyspnea
Systemic circulation hyperemia jugular vein
distension, edema
Sodium and water retention
Changes in hemodynamics of CHF
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A. Overview
2. Grades of CHF I (A) no symptoms
II (B) physical activities were limited and
symptoms could be induced by general activity
III (C) physical activities were markedly
limited IV (D) symptoms appear even at rest
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A. Overview

• 3. Therapeutic strategies in CHF CHF????
• (1) Increasing contractility of the cardiac
  muscles
• ???????
• (2) Inhibiting RAAS ??RAAS
• (3) Reducing sympathetic activity
• ????????
• (4) Dilating vessels ????
• (5) Diuresis ??

? Cardiac remodeling

Decrease in overload
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Drug therapy for CHF
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B. Angiotensin converting enzyme inhibitors
(ACEI) and angiotensin receptor antagonists

• ACEI
• captopril ????
• enalapril ????
• AT1 receptor antagonists
• losartan ???
• irbesartan ????

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

• ACEI
• 1. Pharmacological effects ????
• Inhibiting the production of Ang II
• vasoconstriction ? sodium
  retention ?
• cardiac remodeling (myocardial
  hypertrophy) ?
• Inhibiting the degradation of bradykinin
• vasodilatation ?
• Increasing ANP and scavenging free radicals

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Effects of ACEIs on heart failure
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• Box Actions of angiotensin II
• through activating AT1 receptors
• Constricting vessels, increase peripheral
  resistance and returned blood volume.
• Increasing sympathetic tension, promote release
  of sympathetic transmitter.
• Stimulating release of aldosterone.
• Rapidly inducing expression of c-fos, c-jun,
  Egr-1, c-myc, etc.

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

• Cardiovascular effects ?????
• Decrease resistance of peripheral vessels
• Dilate coronary artery, increase blood supply
  of heart and kidney, improve cardiac and renal
  function
• Reverse myocardial hypertrophy and
  ventricular remodeling

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B. Angiotensin converting enzyme inhibitors
(ACEI) and angiotensin receptor antagonists
2. Clinical uses ???? (1) CHF increase
motor tolerance decrease mortality (2)
Hypertension ???
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B. Angiotensin converting enzyme inhibitors
(ACEI) and angiotensin receptor antagonists

• 3. Adverse effects ????
• Hypotension
• Cough and angioedema
• Hyperpotassemia
• Rashes and altered tastes
• Contraindications pregnancy and stenosis of
  renal artery

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

• AT1 receptor antagonists AT1?????
• Compared with ACEI
• Blocking actions of angiotensin II directly
• Not affecting bradykinin metabolism
• Protecting renal function
• Used for CHF and hypertension

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C. Diuretics

• 1. Pharmacological effects ????
• Reduce blood volume by increasing Na and water
  excretion
• Reduce Na-Ca2 exchange in vascular smooth
  muscle cells
• 2. Clinical uses ????
• CHF grand I IV (mainly used in II III),
  alone or combined with other drugs
• Edema, hypertension, etc.
• 3. Adverse effects ????
• imbalance of electrolytes/acid-base
• plasma level of renin ? hypokalemia
  hyperuricemia
  hyperglycemia/hyperlipidemia

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Therapeutic effects of diuretics in
CHF ?????CHF???
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D. ? receptor blockers

• Commonly used carvedilol ????, bisoprolol ????,
  sustained-release metoprolol ???????
• 1. Pharmacological effects ????
• (1) Blocking effects of catecholamines on
  myocardium decreasing heart rate and cardiac
  oxygen demand
• (2) Up-regulating ? receptor
• (3) Inhibiting RAAS and VP (vosopressin, ???)
  anti- myocardial hypertrophy and remodeling
• (4) Reducing cardiac oxygen remand,
  vasodilatation (? receptor block)
• (5) Anti-arrhythmic and anti-hypertensive effects

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D. ? receptor blockers

• 2. Clinical uses ????
• (1) CHF grand II - III
• decreasing mortality
• (2) Other uses
• hypertension, arrhythmias, angina, etc.

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D. ? receptor blockers
Therapeutic effects of ? receptor antagonists on
cardiac function in CHF patients
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D. ? receptor blockers
Decreased mortality of CHF patients after
treatment with metoprolol, a ? receptor blocker
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D. ? receptor blockers

• 3. Adverse effects ????
• Inhibition of cardiac function
• Contraindications
• severe heart failure
• severe A-V block
• hypotension
• worsening bronchial asthma

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E. Cardiac glycoside (digitalis)
Cardiac glycoside (???) A kind of glycoside
compounds which can selectively act on cardiac
muscle, and increase the force of myocardial
contraction.
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E. Cardiac glycoside (digitalis)
Digoxin ???
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E. Cardiac glycoside (digitalis)

• 1. Pharmacological effects ????
• (1) Positive inotropic effects ??????
• inhibiting Na-K-ATPase ? free Ca2 ? ?
  excitation-contraction coupling ?
• cardiac output ? ? organ blood supply ?
• Vmax ? ? diastolic duration ? ? venous
  return ?
• 
  ? coronary blood supply ?
• cardiac oxygen consumption ?

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Inhibition of Na-K-ATPase by digitalis and
potentiation of cardiac muscle contraction
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E. Cardiac glycoside (digitalis)
(2) Negative chronotropic effects ?????? Reflex
inhibition of sympathetic activity cardiac
output ? ? Sympathetic activity ? ? HR
? Increasing vagal activity directly Reducing
AV conduction ventricular rate ?
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E. Cardiac glycoside (digitalis)
(3) Electrophysiological effects ?????
decreasing automaticity of sinoatrial node
slow conduction, especially AV conduction
increasing automaticity of Purkinje fibres
shortening ERP of fast response
cells Mechanisms intracellular Na ?, K
?, Ca2 ?? ? MDP
?, afterdepolarization
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Overdose Na ?, K ?, Ca2 ? ? ? MDP ? ?
afterdepolarization
Electrophysiological basis for digitalis overdose
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P-R ?
prematural ventricular beat
S-T/T wave ?
ECG P-R ? S-T/T wave ? various arrhythmias
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E. Cardiac glycoside (digitalis)
(4) Other effects ?? Vessels vasoconstriction
Central nervous system CTZ dopamine D2
receptor mental and vision
disorders Kidney increase blood supply of
kidney diuretic effect decrease Na
reabsorption
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E. Cardiac glycoside (digitalis)
2. Clinical uses ???? (1) Congestive heart
failure (CHF) especially associated with
atrial fibrillation and sinus tachycardia (2)
Arrhythmias ???? atrial fibrillation /
atrial flutter preventing paroxysmal
surpraventricular tachycardia
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E. Cardiac glycoside (digitalis)
3. Adverse effects ???? (1) Gastrointestinal
effects ????? nausea, vomiting, etc. (2)
CNS effects ?????? alteration of color
perception(??, such as yellow vision ??)
headache, fatigue, confusion, etc.
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E. Cardiac glycoside (digitalis)
(3) Cardiac toxicity ????
arrhythmiasprematural beats, tachycardia,
atrioventricular block, sinus bradycardia,
etc. PreventionDose individualization
Avoiding provocation factors
plasma K ?, and drug interactions,
etc. Treatment KCl, phenytoin or lidocaine,
i.v. Atropine A-V
block, sinus bradycardia
Fab segment of digoxin antibody, i.v.
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Drug interactions that probably induce digitalis
cardiotoxicity
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E. Cardiac glycoside (digitalis)

• 4. Administration ????
• (1) Loading maintaining doses
• full dose (digitalization) maintaining doses
• for severe patients
• (2) Maintaining dose given daily
• reaching steady state of plasma
  concentration with 1 week (digoxin)
• for stable patients

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E. Cardiac glycoside (digitalis)
5. ADME and properties of different digitalis
drugs ??????? (1) Moderate-acting digoxin
??? (2) Long-actingdigitoxin ?????
digitalization
maintaining doses (3) Short-actingdeslanoside
???, ??????
acute attack of CHF
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F. Other drugs

• 1. ? receptor agonists ??????
• dobutamine ?????
• Positive inotropic drugs
• Arrhythmias, etc.
• 2. PDE-III inhibitors ????????
• milrinone ???, vesnarinone ????,
• amrinone ???
• Positive inotropic drugs
• Hypotension, thrombocytopenia, etc.

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Action modes of positive inotropic drugs
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F. Other drugs

• 3. Vasodilators ?????
• cardiac preload and afterload ?, output ?
• 4. Calcium channel blocker ??????
• 5. Calcium sensitizers ??????

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Therapeutic strategies of CHF
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Therapeutic strategies of CHF
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Therapeutic strategies of CHF