Drugs for Heart Failure (HF)

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Drugs for Heart Failure (HF) DIURETICS loop
diuretics furosemide ALDOSTERONE ANTAGONISTS
(K-sparing diuretics) spironolactone,
eplerenone ?-BLOCKERS carvedilol (non-selective
?-blocker and ?1-blocker) metoprolol
(?1-blocker) VASODILATORS ACE inhibitors
captopril, lisinopril, enalapril Angiotensin II
receptor blockers (ARBs) losartan Ca2 channel
blockers amlodipine Direct acting
hydralazine combined with isosorbide
dinitrate POSITIVE INOTROPIC AGENTS cardiac
glycosides digoxin ?-agonists dobutamine
(dopamine is both non-selective ?- and
?1-agonist) phosphodiesterase inhibitors
milrinone OTHER Brain Natriuetic Peptides
(BNP) Nesiritide (recombinant BNP) - for
decompensated HF Direct Renin Inhibitor
aliskiren (phase III trial for HF)
Fall 09
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?Cardiac Output
Carotid sinus firing
Renal blood flow
Sympathetic discharge
Renin release
Angiotensin II
Force
Heart rate
Preload
Afterload
Remodeling
Cardiac Output (compensated)
Hypertrophy
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NEJM 2003 May
4
Hallmarks of heart failure
Reduced stroke volume and cardiac output for a
given fiber length (i.e., end-diastolic volume)
Systolic dysfunction ? contractility dilated
ventricle (remember Law of LaPlace) myocardial
ischemia Diastolic dysfunction ?
filling decreased compliance decompensated
hypertrophy (slowed relaxation)
LV failure leads to hypoxemia, weakness, fatigue
RV failure leads to peripheral edema
(venous), ultimately leads to LV failure
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? Sympathetic activity to compensate for ? CO
and tissue perfusion with heart failure
Sherwood Fig 9-30
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Compensatory neurohumoral activity in response to
? CO and tissue perfusion are maladaptive

• Sympathetic nervous system activation
• Arterial vasoconstriction
• ? cardiac work against ?TPR
• Heart decompensates further

• Renin-angiotensin-aldosterone-ADH system
  activation
• ? Na and water retention ?
• ? plasma volume (venous pressure)
• ? edema
• ? vasoconstriction ? ? cardiac work

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• ADVERSE EFFECTS OF CHRONIC
• NEUROHORMONAL ACTIVATION
• MVO2
• Afterload, preload, HR
• AngII, vasopressin, aldosterone,
• sympathetic nervous system (SNS)
• Remodeling of LV (change in geometry)
• Cardiac hypertrophy, vascular proliferation
• AngII, aldosterone, SNS
• Cellular necrosis
• SNS

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Strategies for treating HF

• Cardiac load ? ? venous return (preload)
• ? TRP (? afterload)
• End-stage HF may need to ? contractility
• (supportive therapy)

• Diuretics ? ? blood volume ? ? preload and ?
  edema
• ?-blockers inhibit sympathetic reflex
• and slow myocardial remodeling
• Vasodilators ? ? TRP ? ? cardiac work
• ACE-I effective on several levels including
• slowing myocardial and vascular remodeling
• Positive inotropes ? ? contractility (end stage
  failure)

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HEART FAILURE AS A SYMPTOMATIC DISORDER NYHA
CLASSIFICATION

Normal
AsymptomaticLV dysfunction EF lt40
Symptomatic CHF NYHA II
Symptomatic CHF NYHA - III

With ordinary exertion
Symptomatic CHF NYHA - IV
With less exertion
At rest
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HEART FAILURE AS A PROGRESSIVE DISORDER

Normal
Stage A ? risk no sx, no structural disease
HTN, CAD, DM, FHx CM, Toxins
MI, LV dysfunction, valvular disease
Stage B Struct. disease, no sx
Stage C Struct. disease and sx
Shortness of breath, Fatigue, ?Exercise tolerance
Stage D refractory HF

sx symptoms
ACC/AHA Guidelines 2005
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New Classification and Treatment

ACC/AHA Guidelines Circulation 2005
Normal
Stage A ? risk no sx, no structural disease
Stage B Struct. disease, no sx
ACE-I ARB
Stage C Struct. disease and sx
ACE-I ?-Blocker
Stage D refractory HF
Diuretic ACE-I ?-Blocker Digoxin
per Stage A, B, C LVAD Transplant IV inotrope
Secondary prevention Modification of physical
activity Smoking cessation...
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DIURETICS ALDOSTERONE ANTAGONISTS ?-BLOCKERS VASOD
ILATORS/VENODILATORS ACE inhibitors Angiotensin
II receptor blockers (ARBs) POSITIVE INOTROPIC
AGENTS
modified Brenner Fig 12-1
Cardioprotective
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Pharmacologic Therapy (dependent of HF stage)

• ACE inhibitors (or ARB)
• Beta Blockers
• Diuretics
• Spironolactone
• Digoxin
• Positive inotropes

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(from liver)
(from kidney)
(from lungs)
ACE angiotensin converting enzyme
Ganong Fig. 39-2
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ACE-Inhibitor Mechanism of Action
VASOCONSTRICTION
VASODILATATION
ALDOSTERONE
PROSTAGLANDINS
VASOPRESSIN
tPA
Kininogen
SYMPATHETIC
Kallikrein
Angiotensinogen
RENIN
BRADYKININ
Angiotensin I
A.C.E.
Kininase II
Inhibitor
ANGIOTENSIN II
Inactive Fragments
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ANGIOTENSIN II INHIBITORS MECHANISM OF
ACTION (see antihypertensive lecture for specific
drugs)

AT4 R ? ? PAI-1 ? ? tPA (reducing fibrolysis)
Inflammation (via ROS)
modified from AHA 2003
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ACE-Inhibitors Clinical Effects

• Improve symptoms
• Reduce remodelling / progression of HF
• Reduce hospitalization
• Improve survival

Reduce progression of HF, reduce mortality
(SAVE, SOLVD, CONSENUS)
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• ACE-Inhibitors Adverse Effects
• Hypotension or acute renal failure
• (1st dose effect)
• Angioedema
• Worsening renal function
• (particularly with bilateral renal artery
  stenosis)
• Hyperkalemia (by inhibiting Aldosterone)
• Cough (non-productive)
• Rash, neutropenia, ...

If ACE-I is not tolerated, can try an ARB (see
antihypertensive drugs lecture)
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EFFECTS OF PROLONGED ACTIVATION OF SYMPATHETIC
NERVOUS SYSTEM
NE hypertrophy fibrosis tachycardia NE
?1-AR cAMP intracellular calcium
(heart) necrosis (cell death) NE ?1-AR
(heart) stimulates growth and triggers
apoptosis (vascular) stimulates growth TPR
LVEDP MVO2 (demand) Work induces
hypertrophy myocardial perfusion
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ß-Adrenergic Receptor Blockers Therapeutic
actions/results
DECREASE MORTALITY AND DISEASE PROGRESSION

• Inhibit cardiotoxicity of catecholamines?
• ? Neurohormonal activation
• ? HR
• Antiischemic (? myocardial work and MVO2)
• Antihypertensive
• Antiarrhythmic
• Antioxidant

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ß-Adrenergic Blockers Clinical Effects

• Improve symptoms (weeks to months)
• Reduce remodelling / progression
• Reduce hospitalization
• Reduce sudden death
• Improve survival

?-blockers are now recommended at all stages of HF
MERIT-HF (Metoprolol), COPERNICUS (Carvedilol)
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• ?1-, ?2- and ?1- blockers
• Carvedilol
• ?TPR (?vasodilation via ?1-blocking)
• ? cardiac work (? HR, ?afterload,
  ?contractility)
• no sympathetic reflex, but
• may cause orthostatic hypotension

Equally effective in blacks and whites
Carvedilol is now recommended for all stages of
HF (COPERNICUS)
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ß-Adrenergic Blockers Adverse Effects

• Hypotension
• Fluid retention / worsening heart failure
• Fatigue
• Bradycardia / heart block

Precautions/Contraindications

• Asthma (reactive airway disease)
• AV block (unless pacemaker)
• Symptomatic hypotension / Bradycardia
• Diabetes is no longer a contraindication,
• but be cautious when taking insulin

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Achieve euvolemiaDecrease myocardial
work/edema Tx continued as preventative
strategy Typically need to add other drugs
(?-Blockers)Loops furosemide,
bumetanideThiazides hydrochlorothiazide,
chlorthalidone, chlorothiazide, metalozoneK
sparing spironolactone, eplerenone
Diuretics Therapeutic goals
Details discussed in diuretic lecture
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• Positive Inotropic Drugs
• Cardiac glycosides (digitalis) digoxin,
  digitoxin
• ?-agonists dobutamine, dopamine (mixed agonist)
• Phosphodiesterase inhibitors milrinone,
  inamrinone

Usefulness in treating heart failure chronically
is questionable
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Cardiac glycosides (digitalis) Digoxin
Blocks Na / K ATPase gt ?intracellular
Ca2 Positive inotropic effect
(direct) Natriuresis (indirect) Neurohormonal
control (indirect)
NEJM 1988318358
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Mechanism of action of cardiac glycosides
Inhibit Na/K pump
Na/Ca2 exchanger
Positive inotropic effect
Lippincott Fig 16-7
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Increased contraction, therefore increased CO
Decreased preload (more optimal volume) because
of diuresis (increased renal flow with increased
CO)
Brenner Fig 12-3
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• Cardiac glycosides Digoxin
• Low therapeutic index
• Large volume of distribution (accumulates in
  muscle)
• Increase force of contraction (positive
  inotropic)
• Slow A-V nodal conduction (antiarrhythmic)
• Very sensitive to blood K
• (low K, increases dig. affinity, increases
  toxicity)
• must be careful with co-administration of
  diuretics!
• Toxicity includes (pro-arrhythmic effects)
• A-V nodal block
• Triggered after-depolarizations (Ca2 overload)

Although survival rates are not increased,
symptoms are reduced, better quality of
life Note women have higher mortality rate than
men on digoxin
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DIGOXIN PHARMACOKINETIC PROPERTIES
Oral absorption () Protein binding () Volume of
distribution (L/Kg) Half life Elimination Onset
(min) i.v. oral Maximal effect (h) i.v. oral Durat
ion Therapeutic level (ng/ml)????
60 - 75 25 6 (3-9) 36 (26-46) h Renal 5 - 30 30
- 90 2 - 4 3 - 6 2 - 6 days 0.5 - 2
Gil Fraser, PharmD
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Plasma concentrations after IV digoxin
10
Sampling in the distributive phase
Gives prescribers A.Fib!
Plasma (ng/ml)
1
4 h
Time
Gil Fraser PharmD
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Patient Selection for Digoxin(only for
symptomatic patients!)

• As adjunctive treatment to improve symptoms
• For early symptoms relief while awaiting benefits
  of ACE-I and ?-blocker
• For patients with concurrent A.Fib. and HF
• (?-blockers may control ventricular rate better)

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Other positive inotropic drugs
(1)
Dobutamine
(2)
(3)
AMP
(-)
PDE-I
Milrinone
(4)
(6)
(5)
PDE-I phosphodiesterase inhibitor
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• Dobutamine
• ?-AR agonist
• IV administration
• Indicated for acute failure and cardiogenic shock

• Milrinone
• Phosphodiesterase inhibitor (PDE3)
• IV administration
• Increases cAMP ? ? intracellular Ca2 in heart
  muscle cells
• Also a vasodilator ? ? cAMP? reduces TPR
• Indicated for acute failure

Both have been shown to be detrimental and
exacerbate failure when used long-term (last
ditch efforts) Milrinone increased mortality
(PROMISE)
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AHA website
VASODILATORS CLASSIFICATION

Venous Vasodilatation
VENOUS Nitrates
MIXED Calcium antagonists a-adrenergic
Blockers ACE-I Angiotensin II inhibitors
Nitroprusside
ARTERIAL Minoxidil Hydralazine
Arterial Vasodilatation
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Vasodilators for HF (reduces TPR and venous
return)

• ACE Inhibitors Captopril
• ABSOLUTELY use!
• Reduces neurohumoral response (R-A-A effects)
• ?preload, ?afterload, ? MVO2, improves CO
• ?renal and coronary blood flow
• Attenuates myocardial and vascular remodeling
• Good for vascular complications

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Vasodilators for HF (cont)

• Nitrates (see drugs for angina)
• pulmonary congestion
• HF with myocardial ischemia
• in combination with hydralazine in chronic HF
• in combination with loop diuretic in acute HF and
  pulmonary edema

• Hydralazine only in combination with isosorbide
  dinitrate
• good for acute failure (all populations)
• improves survival rates (in black population, not
  white)

African-American Heart Failure Trial (A-HeFT,
NEJM 2004 3512049)
hydralazine is a direct vasodilator, probably
increases cGMP
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In addition to standard therapy for HF

• Spironolactone (K sparing diuretic)
• Reduces risk of morbidity and mortality in severe
  HF
• (Pitt et al., 1999, NEJM) RALES
• Potential for hyperkalemia (especially with
  ACE-I), but not common

• Statins (HMG-CoA reductase inhibitors)
• Beneficial in slowing progression of HF (ischemic
  hearts)
• Probably anti-inflammatory, reducing CAD
• (still not confirmed)
• Emerging role of statins in Tx HF
• Editorial Ramasubbu and Mann JACC 47342-344,
  2006)

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• Notes
• Brain Naturietic Peptide (BNP) in ventricles
• ANP (atria) and BNP are released with elevated
  preload (stretch)
• Elevated BNP appears to be a biomarker for HF
• Human recombinant BNP (hBNP) - Nesiritide
• Recently approved for short-term management of
  acutely decompensated HF
• Decreased systemic vascular resistance, dilates
  venous and arterial vessels (via cGMP)
• Improved cardiac hemodynamics (stroke
  volume/lusitropy)
• HOWEVER, not gained significant use (expensive)

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ACC/AHA Guidelines 2005
41
modified Brenner Fig 12-1

Cardioprotective

42
American College of Cardiology Clinical
Statements/Guidelines Access to and download of
clinical documents is free. http//www.acc.org/qu
alityandscience/clinical/statements.htm http//ww
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m