PH402 Congestive Heart Failure

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PH402 Congestive Heart Failure

• Chris Hague, PhD
• chague_at_u.washington.edu
• Technical Advisor Seth Goldenberg, PhD

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References

• Brodys Human Pharmacology, 4th Edition
• Guyton Human Physiology
• http//www.nlm.nih.gov/medlineplus/tutorials/conge
  stiveheartfailure/htm/lesson.htm
• http//www.nhlbi.nih.gov/health/dci/Diseases/Hf/HF
  _WhatIs.html
• http//www.americanheart.org/presenter.jhtml?ident
  ifier337

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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

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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

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Patient Classification

• Class I (asymptomatic)
• Class II (mild)
• Class III (moderate)
• Class IV (severe)

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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

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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

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Effect on Cardiac Output
Overall decrease in Frank-Starling curve with CHF
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Examples of CHF factors
Hypertrophic Cardiomyopathy
Congenital Heart Defects
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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

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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

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Compensatory Mechanisms
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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

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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

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Problems
Therapeutic Overview

• Reduced force of contraction
• Decreased cardiac output
• Increased TPR
• Inadequate organ perfusion
• Development of edema
• Decreased exercise tolerance
• Ischemic heart disease
• Sudden death

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Drug
Therapies
Non-drug

• Reduce cardiac work
• Rest
• Weight loss
• low Na diet

• Chronic heart failure
• ACE inhibitors
• Beta-blockers
• ATII antagonists
• aldosterone antagonists
• digoxin
• diuretics
• Acute heart failure
• diuretics
• PDE inhibitors
• vasodilators

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Cardiac Glycosides

• discovered by William Withering
• published An Account of Foxglove and some of Its
  Medical Uses in 1785
• Foxglove plant
• active ingredient digitalis

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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 in USA

Digitalis lanata
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Mechanism of Action

• inhibitor of Na/K ATPase pump
• increased Nai
• increased Ca2 influx through Na/Ca2 exchanger
• new Ca2 steady-state increased Ca2 release
  during cardiac action potential

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Electrophysiological Effects

• Direct effects
• spontaneous depolarization of atrial
  cardiomyocytes at high doses

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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

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Overall Effect on Cardiac Function

• increased cardiac output
• increased cardiac efficiency
• decrease in heart rate
• decrease in cardiac size

Foxglove
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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

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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

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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

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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

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Example of cardiac side effects

• action potential recordings from purkinje fiber
  cells
• toxic doses produce oscillatory after
  depolorizations
• leads to ventricular tachycardia (C)

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Vision Effects

• yellow-tinted vision or yellow corona-like spots

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Phosphodiesterase Inhibitors

• primarily used for management of acute heart
  failure
• positive inotropic effects
• increase rate of myocardial relaxation
• decrease total peripheral resistance and afterload

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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

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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

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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

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ß-adrenergic receptor antagonists

• ß-blockers
• standard therapy for treatment of CHF
• cheap!
• reduce sudden death caused by other drugs
• Propranolol prototype
• Carvedilol combination effects

Propranolol
Carvedilol
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Mechanism of Action

• mechanism still unclear
• antagonizes ß-adrenergic receptors on cardiac
  myocytes
• counterbalances increased SNS activity in CHF
• prevents development of arrhythmias
• reduces cardiac remodeling
• prevents renin release

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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

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Side Effects

• cardiac decompensation
• bradycardia
• hypoglycemia
• cold extremeties
• fluid retention
• fatigue

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Direct acting sympathomimetics

• cause immediate increases in cardiac inotropy
• goal to increase cardiac output but not effect
  total peripheral resistance
• used in treatment of acute life-threatening CHF

Dopamine
Dobutamine
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Mechanism of Action

• Norepinephrine/epinephrine increase CO, increase
  TPR
• Dopamine
• activates prejunctional D2 dopamine receptors,
  inhibit NE release of sympathetic nerves,
  vasodilation
• activates cardiac ß1-adrenergic receptors,
  increase cardiac output
• Dobutamine
• racemic mixture, stimulates ß1-adrenergic
  receptors
• peripheral vasodilation

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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

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Side Effects

• restlessness
• tremor
• headache
• cerebral hemorrhage
• cardiac arrhythmias
• used with caution in patients taking ß-blockers
• can develop dobutamine tolerance

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ACE inhibitors/AT1 receptor antagonists

• Goal to reduce afterload/preload, reduce
  workload on heart
• generates positive cardiac inotropy
• used in treatment of chronic CHF

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ACE inhibitors/AT1 receptor antagonists

• orally active
• ACE inhibitors
• Captopril
• Enalopril
• AT1 antagonists
• Losartan
• Valsartan

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Mechanism of Action

• ACE inhibitors
• inhibits angiotensin converting enzyme (ACE)
• prevents conversion of ATI to ATII

• AT1 receptor antagonists
• selectively inhibits ATI receptor activation

• decreased preload
• decreased afterload
• decreased cardiac remodeling
• decreased SNS effects

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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

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Side Effects

• ACE inhibitors
• cough
• angioneurotic edema
• hypotension
• hyperkalemia
• ACE inhibitors and ATI receptor antagonists are
  both teratogenic

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Vasodilators

• Goal reduce TPR without causing large decrease
  in BP
• reduce preload
• reduce afterload
• relieves symptoms
• increase exercise tolerance

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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.

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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 (?)

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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

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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

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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

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Side Effects

• hyperkalemia
• agranulocytosis
• anaphylaxis
• hepatoxicity
• renal failure
• Spironolactone gynecomastia, sexual dysfunction
• Eplerenone arrhythmia, myocardial
  infarct/ischemia