Al-Bayan University / College of Pharmacy

Pharmacology & Toxicology Dept. 2019-2020

Fourth stage / Clinical Pharmacy II - Lecture 4 / presented by
Dr. Atheer S. Alsabah

Heart Failure
 Heart failure (HF) is a condition caused by the inability of the heart to pump
sufficient blood to meet the metabolic needs of the body.

• Classification
1. Systolic failure vs. Diastolic failure
- In systolic failure (problem in contraction), there is a decreased ejection of blood
from the heart during systole. While in diastolic failure (problem in the filling of
ventricles), there is a reduced filling of the ventricles during diastole.

2. Low-output failure vs. High-output failure

- Low output failure (LOP-HF) is a reduced pumping efficiency of the heart due to
impair cardiac function, it includes systolic failure & diastolic failure. While high
output failure (HOP-HF), the cardiac output is normal or elevated but still cannot
meet the metabolic & oxygen demands of the tissues. Its common causes includes
hyperthyroidism (hypermetabolic state) & anemia.

• Etiology
- Heart failure can be classified by the primary underlying etiology as ischemic or
non-ischemic, with 70% of HF related to ischemia (CAD). Non-ischemic
etiologies include hypertension, viral illness, thyroid disease, etc.

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• Pathophysiology
- When the heart fails, compensatory mechanisms attempt to maintain cardiac
output & peripheral perfusion. However, as heart failure progresses, these
mechanisms become pathophysiological. These mechanisms include:

A. Activation of Renin-Angiotensin-Aldosterone System (RAAS)

- The decrease in renal perfusion leading to the release of renin & initiation of the
cascade for production of angiotensin II. Angiotensin II stimulates the synthesis &
release of aldosterone, which stimulates sodium & water retention in an attempt to
increase intravascular volume & hence preload.
- However, in a failing heart there is reduced ability of cardiomyocytes to adapt to
increases in preload. Thus, an increase in preload actually impairs contractile
function in the failing heart & results in a further decrease in cardiac output (CO).
B. Stimulation of sympathetic nervous system
- The sympathetic nervous system is activated in heart failure, as an early
compensatory mechanism which provides inotropic support & maintains cardiac
output. Chronic sympathetic activation, however, has deleterious effects (increase
myocardial oxygen demand, & worsen underlying ischemia), causing a further
deterioration in cardiac function. β-Blockers appear to ameliorate the deleterious
effects of catecholamines.
C. Cardiac Remodeling
- Progression of HF results in a process referred to as cardiac remodeling, ccc by
changes in the shape & mass of the ventricles in response to tissue injury. The
three primary manifestations of cardiac remodeling are chamber dilatation, LV
cardiac muscle hypertrophy, & a resulting spherical shape of the LV chamber.

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• Clinical Manifestations

A. Left-sided failure: if blood cannot be adequately pumped from the left ventricle
to the peripheral circulation, the blood will backs up into the pulmonary alveoli
the result is the development of pulmonary congestion & edema. The pts can
experience a variety of symptoms related to buildup of fluid in the lungs.
1. Exertional dyspnea (SOB), occurs when pts describe breathlessness induced by
physical activity or a lower level of activity than previously known to cause
breathlessness. The pts often state that activities such as stair climbing, carrying
groceries, or walking a particular distance cause shortness of breath (SOB).
2. Orthopnea, is present if a pt is unable to breathe while lying flat on a bed (i.e., in
the recumbent position). It manifests within minutes of a pt lying down & is
relieved immediately when the pt sits upright. The pts can relieve orthopnea by
elevating their head & shoulders with pillows.
3. Paroxysmal nocturnal dyspnea (PND), occurs when pts awaken suddenly with a
feeling of breathlessness & suffocation. PND is caused by increased venous return
& mobilization of interstitial fluid from the extremities, leading to alveolar edema
& usually occurs within 1-4hrs of sleep. In contrast to orthopnea, PND is not
relieved immediately by sitting upright & often takes up to 30min for symptoms
to subside.
4. In cases of pulmonary edema (most severe form of pulmonary congestion), the pts
may produce a pink, frothy sputum & experience extreme breathlessness &
anxiety due to feelings of suffocation & drowning. If not treated aggressively, pts
can become cyanotic & acidotic.
5. Rales or crackling sounds that may be heard through a stethoscope as a result of
fluid accumulation in the lungs.

B. Right-sided failure: when blood is not pumped from the right ventricle, the blood
backs up throughout the body i.e. in veins, liver, legs, & bowels; producing
systemic congestion & edema. Edema appears in legs (ankles edema) because
gravity pulls the fluid into the lower half of the body.
- Abdominal congestion may cause a bloated feeling, abdominal pain, nausea,
anorexia, & constipation. Often pts may have difficulty fitting into their shoes or
pants due to edema.
- Jugular venous distension: which represent a sign of elevated pressures in the
venous system. Although most pts initially have LVF (pulmonary congestion), &
because LVF increases workload of right ventricle, both ventricles eventually fail.

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• Heart failure symptoms' classification
- The New York Heart Association (NYHA) classification is used to assess the
severity of heart failure.

• Investigations
1. Echocardiogram (Echo): used to assess LV size & ejection fraction "EF" (the
fraction of blood pushed during systole from the volume of blood that present at
the end of diastole, normally it is more than 45%).

2. Chest x-ray: useful for detection of cardiac enlargement, pulmonary edema, &
pleural effusions.

3. Electrocardiogram (ECG): To assesses the presence of any other cardiac

problems, such as arrhythmias.

4. Blood tests: full blood to investigate anemia, serum creatinine, urea &
electrolytes to assess renal function.

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• Desired Outcome
- The therapeutic goals for chronic HF is to relieve or reduce symptoms, slow
disease progression, & prolong survival.

• Treatment
- The first step in managing chronic HF is to determine the etiology or precipitating
factors. Treatment of underlying disorders e.g. hyperthyroidism & anemia, may
obviate the need for treating HF.

- Non-pharmacologic treatment
1. Dietary modifications in HF consist of sodium restriction & sometimes fluid
restriction. The pts should routinely practice moderate salt restriction (2-2.5g
sodium or 5-6g salt per day). The pts should be educated to avoid cooking with
salt & to limit intake of foods with high salt content. Fluid restriction may not be
necessary in many pts. When applicable, a general recommendation is to limit
fluid intake from all sources to less than 2 liters per day.
2. Exercise, while discouraged when the pt is acutely decompensated, is
recommended when pts are stable. The heart is a muscle that requires activity to
prevent atrophy. Regular low intensity, aerobic exercise that includes walking,
swimming, or riding a bike is encouraged, while heavy weight training is
discouraged.
3. Modification of classic risk factors, such as tobacco & alcohol consumption, is
important to minimize the potential for further aggravation of heart function.

- Pharmacologic treatment
1. Systolic heart failure
- Agents with proven benefits in improving symptoms, slowing disease progression,
& improving survival in chronic HF, are targeting the neurohormonal blockade.
- These include 1st line drugs (ACEIs, β-blockers, & diuretics), & 2nd line drugs
(ARBs, aldosterone antagonists, hydralazine/nitrates combination, & digoxin) that
used in selected pts.

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- 1st line drugs:

a. ACEIs
- There is strong evidence that ACEIs e.g. captopril, lisinopril, enalapril, etc. are
slow disease progression, decrease hospitalizations, & reduce mortality in HF pts.

- The ACC/AHA (American College of Cardiology & American Heart Association)

guidelines state that ACEIs should be prescribed to all pts with HF caused by left
ventricular systolic dysfunction (LVSD) unless they have a C/I to their use or
have been shown to be unable to tolerate treatment with these drugs. In general,
ACEIs are used together with β-blockers.

- ACEIs should be initiated at low doses, followed by increments in dose if lower

doses have been well tolerated.

b. β-Blockers
- There is strong evidence that certain β-blockers slow disease progression,
decrease hospitalizations, & reduces mortality in HF pts.

- The ACC/AHA guidelines state that β-blockers should be prescribed to all pts
with stable systolic HF unless they have a C/I to their use or are unable to tolerate
the treatment. Extended-release metoprolol succinate, carvedilol, & bisoprolol are
FDA approved for use in HF. Metoprolol & bisoprolol are both partially selective
β1-blockers, & carvedilol is a mixed α1- & nonselective β-blocking agent.

- Note: It cannot be assumed that immediate-release metoprolol (the form used in

Iraq now) will provide benefits equivalent to Extended-release metoprolol.

- β-Blockers should be initiated in stable pts who have no or minimal evidence of

fluid overload. Because of their negative inotropic effects, β-blockers should be
started in very low doses with slow upward dose titration (in a ‘start low, go slow’
fashion) to avoid symptomatic worsening. Doses should be doubled no more often
than every 2 weeks, as tolerated, until the target dose or the maximally tolerated
dose is reached.

c. Diuretics
- Loop & thiazide diuretics have not been shown to improve survival in heart
failure. Consequently, diuretic therapy (in addition to sodium restriction) is
recommended in all pts with clinical evidence of fluid retention (peripheral &
pulmonary edema). The pts who do not have fluid retention would not require
diuretic therapy.

- Loop diuretics e.g. furosemide, bumetanide, & torsemide, are the most widely
used diuretics in HF.

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- 2nd line drugs:
- Used in selected pts like those who remain symptomatic despite optimal therapy
with ACEIs & β-blockers. These agents used for HF-LVSD & have proven
efficacy when combined with 1st line drugs in reducing HF morbidity & mortality.

a. ARBs
- Although some data suggest that ARBs produce equivalent mortality benefits
when compared with ACEIs, the ACC/AHA guidelines recommend use of ARBs
only in pts who are intolerant of ACEIs. Although there are currently many ARBs
in the market, only candesartan & valsartan are FDA-approved for the treatment
of HF & are the preferred agents, whether used alone or combined with ACEIs.
- Combination therapy of ARB & ACEI offers a theoretical advantage over either
agent alone through more complete blockade of the deleterious effects of
angiotensin II. However, clinical trial results indicate that the addition of an ARB
to optimal HF therapy (e.g. ACEIs, β-blockers, & diuretics) offers marginal
benefits at best with increased risk of adverse effects. The addition of an ARB
may be considered with pts who remain symptomatic despite receiving optimal
conventional therapy.

b. Aldosterone antagonists
- There is evidence that aldosterone mediates some of the major effects of renin–
angiotensin–aldosterone system activation, such as myocardial remodeling &
fibrosis, as well as sodium retention & potassium loss at the distal tubules.
- Currently, the aldosterone antagonists available are spironolactone & eplerenone.
Both agents are inhibitors of aldosterone that produce weak diuretic effects while
sparing potassium concentrations. Eplerenone is selective for the
mineralocorticoid receptor & hence does not exhibit the endocrine adverse-effect
profile commonly seen with spironolactone.
- Currently low dose aldosterone antagonists e.g. 25mg/day spironolactone should
be added for pts with symptoms of moderate to severe HF (NYHA class III-IV)
who are receiving standard therapy, & pts with LV dysfunction early after MI,
where HF occurs in 1st 4wks after acute MI.

c. Hydralazine & Nitrates combination

- Hydralazine & nitrates e.g. ISDN, are combined in the treatment of HF because of
their complementary hemodynamic actions. Hydralazine is a potent arteriodilator
that provides symptomatic relief of HF by decreasing afterload, while nitrates
have venodilating properties that decrease preload.
- The combination may be reasonable for pts with persistent symptoms despite
optimized therapy with ACEI (or ARB) & β-blocker. The combination is also
appropriate as 1st line therapy in pts unable to tolerate ACEIs or ARBs.

d. Digoxin
- It does not improve survival in pts with HF but does provide symptomatic benefits
(decreases symptoms, increases exercise performance, & decreases hospital
admissions secondary to HF).
- Current recommendations are for the addition of digoxin for pts who remain
symptomatic despite an optimal HF regimen consisting of ACEI or ARB, β-
blocker, & diuretic.

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- Digoxin is also prescribed routinely in pts with HF & concurrent atrial Fibrillation
(AF) to slow ventricular rate regardless of HF symptoms.
- In the absence of AF a loading dose is not indicated. Digoxin is initiated at a dose
of 0.125 - 0.25mg daily (depending on age, renal function, etc.). The 0.125 mg
daily dose is adequate in the majority of pts. Routine monitoring of serum drug
concentrations is not required but recommended in those with changes in renal
function, suspected toxicity, or after addition or subtraction of an interacting drug.

2. Heart failure caused by diastolic dysfunction

- Diastolic dysfunction, an inadequacy of ventricular relaxation & impaired LV
filling. Diastolic dysfunction ccc by normal or near-normal LVEF (40% to 60%).
- For symptomatic pts, diuretics in conjunction with salt restriction are indicated
initially to relieve congestive symptoms. Thereafter, β-blockers, CCBs e.g.
verapamil, or ACEIs, & ARBs, may be beneficial.
- Note: unlike in systolic HF, non-dihydropyridine CCBs e.g. diltiazem &
verapamil may be useful in heart failure caused by diastolic dysfunction.

• Investigational therapies
- Clinical trials are currently investigating new agents for treatment of HF such as:
a. Sacubitril.
b. Nesiritide.
c. Conivaptan & tolvaptan.

• H.W: Mechanism of action of Investigational therapies?