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					     PH402
 Congestive Heart
     Failure
          Chris Hague, PhD
      chague@u.washington.edu

Technical Advisor: Seth Goldenberg, PhD
           References
Brody’s Human Pharmacology, 4th Edition

Guyton Human Physiology

http://www.nlm.nih.gov/medlineplus/tutorials
/congestiveheartfailure/htm/lesson.htm

http://www.nhlbi.nih.gov/health/dci/Diseases/
Hf/HF_WhatIs.html

http://www.americanheart.org/presenter.jhtml
?identifier=337
                  Outline
1. What is congestive heart failure?
2. Cardiac Glycosides
3. Phosphodiesterase inhibitors
4. Beta-adrenergic receptor antagonists
5. Sympathomimetics
6. ACE inhibitors/angiotensin receptor antagonists
7. Vasodilators
8. Diuretics
9. Aldosterone antagonists
Congestive Heart Failure
the heart is unable to provide
adequate perfusion of
peripheral organs to meet
their metabolic requirements

~4.7 million with CHF in USA

survival post diagnosis:
Men       1.7 years
Women 3.2 years

287,000 deaths in 2004
   Patient Classification

Class I (asymptomatic)


Class II (mild)


Class III (moderate)


Class IV (severe)
Factors contributing to CHF
 Ischemic Heart Disease: most prevalent

 CAD: less blood flow to heart, increased damage

 Myocardial Infarct: damaged tissue

 Hypertension: “overworked” heart

 Diabetes

 Lung Disease
Factors contributing to CHF
 Cardiomyopathies: heart muscle disease
   dilated - enlarged chambers (ventricle/atria)
   hypertrophic - thickened ventricle walls
 Abnormal heart valves: inefficient pumping
   causes are genetic, infection or disease
 Congenital heart defects: present at birth
 Severe Anemia
 Hyperthyroidism
 Cardiac Arrhythmia
Effect on Cardiac Output




 Overall decrease in Frank-Starling
          curve with CHF
    Examples of CHF factors




Hypertrophic Cardiomyopathy   Congenital Heart Defects
  Types of Heart Failure
include left, right or both sides
left ventricular heart failure
  most common
  systolic failure: unable to contract
  diastolic failure: unable to relax
right ventricular heart failure
  usually occurs after left failure
  less blood received causes right damage
  less pumping by right side
  venous pooling of blood in legs
        Onset of disease
chronic disease: can take years to develop

endogenous compensatory mechanisms

  enlargement of size

  increased cardiac muscle mass

  increased heart rate

  narrowing of blood vessels: increase BP

  diversion of blood flow (brain, heart)

  increased SNS output
Compensatory Mechanisms
        Symptoms of CHF
shortness of breath
  blood pooling in pulmonary veins
  fluid in lungs
  occurs during activity, rest, or sleeping
persistent coughing/wheezing
  produces white/blood mucus
edema (or excess fluid buildup in body tissues)
  venous pooling
  swelling in extremities
  necrosis
        Symptoms of CHF
tiredness/fatigue

  decreased O2 supply

  diversion of blood supply from limbs

lack of appetite/nausea

  decreased blood supply to digestive tract

confusion/impaired thinking

increased heart rate

  baroreceptor reflex

  SNS output
         Therapeutic Overview

   Problems                            Goals
Reduced force of contraction   alleviate symptoms

Decreased cardiac output       improve quality of life
Increased TPR                  arrest cardiac remodeling
Inadequate organ perfusion     prevent sudden death
Development of edema
Decreased exercise tolerance
Ischemic heart disease
Sudden death
                        Therapies
      Drug                      Non-drug
Chronic heart failure         Reduce cardiac work
  ACE inhibitors              Rest
  Beta-blockers
                              Weight loss
  ATII antagonists
  aldosterone antagonists     low Na+ diet
  digoxin
  diuretics
Acute heart failure
  diuretics
  PDE inhibitors
  vasodilators
     Cardiac Glycosides
discovered by William
Withering
published “An Account of
Foxglove and some of Its
Medical Uses” in 1785
Foxglove plant
  active ingredient digitalis
        Cardiac Glycosides
derived from plants
  Strophanus - Ouabain
  Digitalis lanata - Digoxin,
  Digitoxin
increase force of myocardial
contraction
alters electrophysiological
properties
toxic side-effects
Digoxin most common used        Digitalis lanata
in USA
    Mechanism of Action
inhibitor of Na+/K+
ATPase pump
increased [Na+]i
increased Ca2+ influx
through Na+/Ca2+
exchanger
new Ca2+ steady-state:
increased Ca2+ release
during cardiac action
potential
  Electrophysiological Effects
Direct effects

  spontaneous depolarization of atrial
  cardiomyocytes at high doses
Electrophysiological Effects
Indirect effects

  increased parasympathetic tone

  decreased SA/AV node automaticity

  decreased AV node conduction velocity and
  increased refractory period

  net effect: decrease HR and impair impulse
  transmission in AV node
Overall Effect on Cardiac Function


 increased cardiac output


 increased cardiac efficiency


 decrease in heart rate


 decrease in cardiac size
                                Foxglove
       Therapeutic Uses
only orally effective inotropic agent
approved in US

also for CHF secondary to ischemic heart
disease

contraindicated in patients with Wolff-
Parkinson-White syndrome

does not stop disease progression or
prolong life in CHF patients
      Pharmacokinetics
long half-life (24-36 h): once daily dosing

high bioavailability from oral dosing

large volume of distribution

digoxin excreted in kidneys

digitoxin metabolized in liver, active metabolites

intestinal flora cause variations in toxicity
           Side Effects
extremely low therapeutic index (~2)

most effects caused by inhibition of Na+/K+
ATPase in extracardiac tissues

CNS: malaise, confusion, depression, vertigo,
vision

GI: anorexia, nausea, intestinal cramping,
diarrhea

Cardiac: bradycardia, arrhythmias

anti-digoxin antibody in toxic emergencies
 Serum Electrolytes affect Toxicity
Ca2+

hypercalcemia: increases toxicity

K+

 digitalis competes for K+ binding site on Na+/K+
ATPase

 contraindicated with K+ depleting diuretics or
patients with hypo/hyperkalemia

hypokalemia: increased toxicity

hyperkalemia: decrease toxicity
  Example of cardiac side effects
 action potential
recordings from
purkinje fiber cells

 toxic doses produce
oscillatory after
depolorizations

 leads to ventricular
tachycardia (C)
            Vision Effects
yellow-tinted vision or yellow corona-like spots
     Phosphodiesterase Inhibitors
 primarily used for
management of acute
heart failure

 positive inotropic
effects

 increase rate of
myocardial relaxation

 decrease total
peripheral resistance and
afterload
     Mechanism of Action
inhibitor of type III cAMP
phosphodiesterase
increased [cAMP]
increased PKA
phosphorylation of Ca2+
channels in cardiac muscle
increased cardiac
contraction
relaxes vascular smooth
muscle
           Therapeutic Use
Amrinone (Inocor) and Milrinone (Primacor)

administered IV

milrinone is ~1o fold more potent

T 1/2 = 2.5 h for amrinone and 30-60 min for
milrinone

effective in patients taking Beta-blockers

does not stop disease progression or prolong life
in CHF patients

prescribed to patients non-responsive to other
therapies
           Side Effects
sudden death secondary to ventricular
arrhythmia

hypotension

thrombocytopenia

long term clinical trials associated with
increased adverse effects and increased
mortality

now only prescribed for acute cardiac
decompensation in patients non-responsive to
diuretics or digoxin
  β-adrenergic receptor antagonists
“β-blockers”

 standard therapy for
treatment of CHF

cheap!
                           Propranolol
 reduce sudden death
caused by other drugs

Propranolol: prototype

 Carvedilol: combination
effects                    Carvedilol
     Mechanism of Action
mechanism still unclear
antagonizes β-adrenergic
receptors on cardiac
myocytes
counterbalances increased
SNS activity in CHF
prevents development of
arrhythmias
reduces cardiac
remodeling
prevents renin release
        Therapeutic Use
administered orally

usually given in conjunction with other therapy

  ACE inhibitors

  Digoxin

effective in patients with chronic systolic heart
failure in Class II (mild) to Class III (moderate)

prevents remodeling and cardiac damage
           Side Effects
cardiac decompensation

bradycardia

hypoglycemia

cold extremeties

fluid retention

fatigue
   Direct acting sympathomimetics
 cause immediate
increases in cardiac
inotropy

 goal: to increase cardiac
output but not effect        Dopamine
total peripheral
resistance

 used in treatment of
acute life-threatening
CHF                          Dobutamine
   Mechanism of Action
Norepinephrine/epinephrine: increase CO,
increase TPR
Dopamine:
  activates prejunctional D2 dopamine
  receptors, inhibit NE release of sympathetic
  nerves, vasodilation
  activates cardiac β1-adrenergic receptors,
  increase cardiac output
Dobutamine:
  racemic mixture, stimulates β1-adrenergic
  receptors
  peripheral vasodilation
       Therapeutic Use
administered IV, very short T 1/2
Dopamine
  used in cardiogenic, traumatic or hypovolemic
  shock
  used with furosemide in diuretic resistant
  patients (volume overload)
Dobutamine
  used in patients with low cardiac output and
  increased left ventricular end-diastolic
  pressure
  not for use in hypotensive patients
               Side Effects
restlessness

tremor

headache

cerebral hemorrhage

cardiac arrhythmias

used with caution in patients taking β-
blockers

can develop dobutamine tolerance
   ACE inhibitors/AT1 receptor
           antagonists

Goal: to reduce afterload/preload, reduce
workload on heart


generates positive cardiac inotropy


used in treatment of chronic CHF
    ACE inhibitors/AT1 receptor
            antagonists
orally active

ACE inhibitors

Captopril

Enalopril

AT1 antagonists

Losartan

Valsartan
        Therapeutic Uses
drugs of choice in heart failure
increase survival in long term CHF
ACE inhibitors
  slows progression of left ventricular
  dysfunction in CHF
AT1 receptor antagonists
  more effective then ACE inhibitors
  AT2 receptors still active: vasodilation,
  antiproliferative effects
  used in conjunction with ACE inhibitors for
  increased effectiveness
            Side Effects
ACE inhibitors

    cough

    angioneurotic edema

    hypotension

    hyperkalemia

ACE inhibitors and ATI receptor antagonists
are both teratogenic
              Vasodilators
Goal: reduce TPR without causing large decrease
in BP


reduce preload


reduce afterload


relieves symptoms


increase exercise tolerance
            Drugs Used
NO Donors
 Nitroglycerin
   acute ischemia or acute heart failure
   orally active
   also administered I.V. for peripheral
   vasodilation
   quick onset for acute relief
 Isosorbide dinitrate/hydralazine
   chronic administration for long-term
   symptom relief
   administered I.V.
             Drugs Used
Nesiritide
  recombinant brain-natriuretic peptide (BNP)
  BNP is secreted from ventricular myocytes in
  response to stretch
  vasodilator: increases cGMP in SMCs
    decrease afterload/preload
  inhibits cardiac remodelling
  suppresses aldosterone secretion
  administered IV for acute decompensated CHF
  adverse effects: hypotension, renal failure (?)
               Diuretics
used in CHF to reduce extracellular fluid volume

primarily used in patients with acute CHF with
volume overload

IV infusion causes immediate and predictable
diuresis for immediate relief

Goal: reduce preload/afterload

overdosing can result in excessive reduction in
preload, overreduction in stroke volume

thiazide and loop diuretics (i.e. Furosemide)
commonly used as adjunct therapies in CHF
    Aldosterone Antagonists
elevated AngII levels increase
production of aldosterone in
the adrenal cortex (~20X
increase)
aldosterone activates
mineralocorticoid receptors in
renal epithelial cells in kidney
aldosterone promotes
  Na+ retention, Mg2+ and K+
  loss
  increased SNS activity
  decreased PSNS activity
  myocardial/vascular
  fibrosis
          Therapeutic Use
Goal: inhibit aldosterone
negative effects in CHF
aldosterone receptor
antagonists
  spironolactone
  eplerenone
both antagonists reduce
mortality in patients with
moderate to severe CHF
only use in patients with
normal renal function and K+
levels
use with K+ sparing diuretic
                Side Effects
hyperkalemia
agranulocytosis
anaphylaxis
hepatoxicity
renal failure
Spironolactone:
gynecomastia, sexual
dysfunction
Eplerenone: arrhythmia,
myocardial
infarct/ischemia

				
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posted:8/22/2011
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