Drugs Used in Heart Failure: Pharmacology (2) PHAR 342

Drugs Used in Heart Failure
Chapter 13
Pharmacology (2)
PHAR 342
Heart Failure (HF)
• Heart failure (HF) is a complex, progressive disorder
in which the heart is unable to pump sufficient blood
to meet the needs of the body.
• It is a highly lethal condition, with a 5-year mortality
rate conventionally said to be about 50%.
↓ cardiac output  reduced O2 supply to the body.

• Most common cause of heart failure in the USA is
coronary artery disease, with hypertension also an
important factor.
Types of HF
1) Systolic failure (Young; 50%)↓mechanical pumping action
(↓contractility) & ↓ejection fraction ((HFrEF)<45%)
2) Diastolic failure  hypertrophy, stiffening and loss of adequate

relaxation  ↓filling & ↓CO  ejection fraction may be normal
(preserved, HFpEF) even though stroke volume is significantly
reduced. Diastolic failure increases with age. Does not usually
respond optimally to positive inotropic drugs.
“High-output” failure  demands of the body are so great that even

increased cardiac output is insufficient  result from hyperthyroidism,
beriberi, anemia and arteriovenous shunts responds poorly to the
drugs and should be treated by correcting the underlying cause
•Causes of HF include
• Arteriosclerotic heart disease

• Myocardial infarction
• Hypertensive heart disease
• Valvular heart disease
Causes of •
•
Dilated cardiomyopathy
Congenital heart disease.
HF include •Treatment is directed at two somewhat different goals:
• Reducing symptoms and slowing progression as
much as possible during relatively stable periods
and
• Managing acute episodes of decompensated
failure.
FIGURE 13–1 Schematic diagram of a cardiac
muscle sarcomere, with sites of action of several
drugs that alter contractility. (Mitochondria,
which are critical for the generation of ATP, are
omitted for simplicity.) Na+/K+-ATPase, the
sodium pump, is the site of action of cardiac
glyco- sides. NCX is the sodium-calcium
exchanger. Cav-L is the voltage-gated, L-type
calcium channel. SERCA (sarcoplasmic
endoplasmic reticulum
Ca2+-ATPase) is a calcium transporter ATPase
that pumps calcium into the sarcoplasmic
reticulum. CalS is calcium bound to
calsequestrin, a high-capacity Ca2+-binding
protein. RyR (ryanodine RyR2 receptor) is a
calcium-activated calcium channel in the
membrane of the SR that is triggered to release
stored calcium. Z is the Z-line, which delimits
the sarcomere. Calcium sensitizers act at the
actin-troponin-tropomyosin complex where
activator calcium brings about the contractile
interaction of actin and myosin. Black arrows
represent processes that initiate contraction or
support basal tone. Green arrows represent
processes that promote relaxation.
Pathophysiology of HF
The primary signs & symptoms of all types of HF include:
- Tachycardia.
- Decreased exercise tolerance.
- Shortness of breath.
- Cardiomegaly.
- Peripheral & pulmonary edema (the congestion of congestive heart
failure) are often but not always present.
 Decreased exercise tolerance with rapid muscular fatigue is the

major direct consequence of diminished cardiac output.
 The other manifestations result from the attempts by the body to

compensate for the intrinsic cardiac defect.
Neuro-humoral compensation (extrinsic) involves 2 major mechanisms  the
sympathetic nervous system & the renin-angiotensin-aldosterone hormonal
response—plus several others.
The baroreceptor reflex  lower

sensitivity to arterial pressure in HF
patients  input to the vasomotor
center is reduced even at normal
pressures  ↑sympathetic outflow
& ↓ parasympathetic outflow 
tachycardia, ↑cardiac contractility, &
↑vascular tone.
Angiotensin II & endothelin 

vasoconstriction  ↑afterload 
↓ejection fraction & cardiac output.
- The result is a vicious cycle that is characteristic of heart failure ( Figure 13–3 ).
Compensatory Mechanisms During HF
Cardiac
• Frank-Starling mechanism (ability of the heart to change its force of contraction
and therefore stroke volume in response to changes in venous return).
• Ventricular dilation or hypertrophy (The most important intrinsic compensatory

mechanism) .
• Tachycardia
Autonomic Nerves
• Increased sympathetic adrenergic activity
• Reduced vagal activity to heart
Hormones
• Renin-angiotensin-aldosterone system
• Vasopressin (antidiuretic hormone)
• Circulating catecholamines
• Natriuretic peptides
Beta-adrenergic Receptors
- After a relatively short exposure to increased sympathetic drive, complex down-
regulatory changes in the cardiac β1 –adrenoceptor–G protein-effector system
take place that result in decreased stimulatory effects.
- Excessive β activation can lead to leakage of Ca+2 from the SR via RyR channels
and contributes to stiffening of the ventricles and arrhythmias.
- Reuptake of Ca2+ into the SR by SERCA may also be impaired.

- Upregulation of protein phosphatase 1 (PP1), enzyme that responsible for RYR
dephosphorylation.
- Prolonged β activation also increases caspases, the enzymes responsible for

apoptosis.
Increased angiotensin II production leads to increased aldosterone secretion (with
Na+ & water retention), to increased afterload, & to remodeling of both heart and
vessels.
Other hormones are released, including natriuretic peptide, endothelin, &

vasopressin---- N-terminal pro-brain natriuretic peptide (NT-proBNP) use as
surrogate biomarker in HF.
-The most important intrinsic compensatory mechanism is myocardial hypertrophy.
-This increase in muscle mass helps maintain cardiac performance. However, after
an initial beneficial effect, hypertrophy can lead to ischemic changes, impairment
of diastolic filling, & alterations in ventricular geometry.
Pathophysiology of Cardiac Performance
Cardiac performance is a function of 4 primary factors:
1. Preload.
2. Afterload.
3. Contractility.
4. Heart rate.
Preload
Preload is usually increased in heart failure because of increased blood volume
and venous tone.. left ventricular function curve----Frank-Starling relation
FIGURE 13–4 Relation of left ventricular (LV)
performance to filling pressure in patients with
acute myocardial infarction, an important cause
of heart failure. The upper line indicates the
range for normal, healthy individuals. At a given
level of exercise, the heart operates at a stable
point, eg, point A. In heart failure, function is
shifted down and to the right, through points 1
and 2, finally reaching point B. A “pure” positive
inotropic drug (+ Ino) would move the
operating point upward by increasing cardiac
stroke work. A vasodilator (Vaso) would move
the point leftward by reducing filling pressure.
Successful therapy usually results in both
effects. (Adapted, with permission,
from Swan HJC, Parmley WW: Congestive heart
failure. In: Sodeman WA Jr, Sodeman
TM [editors]: Pathologic Physiology, 7th ed.
Saunders, 1985. Copyright Elsevier.)
Reduction of high filling pressure is the goal of salt
restriction and diuretic therapy in heart failure.
Venodilator drugs (eg, nitroglycerin) also reduce preload
by redistributing blood away from the chest into peripheral
veins.
Afterload
Afterload is the resistance against which the heart must pump blood
and is represented by aortic impedance and systemic vascular
resistance.
As cardiac output falls in chronic failure, a reflex increase in systemic

vascular resistance occurs, mediated in part by increased sympathetic
outflow & circulating catecholamines & in part by activation of the
renin-angiotensin system.
Endothelin, a potent vasoconstrictor peptide, is also involved. This

sets the stage for the use of drugs that reduce arteriolar tone in heart
failure.
Contractility
Heart muscle obtained by biopsy from patients with chronic low-
output failure demonstrates a reduction in intrinsic contractility.
As contractility decreases in the patient, there is a reduction in the

velocity of muscle shortening and the stroke output achieved
However, the heart is usually still capable of some increase in all of

these measures of contractility in response to inotropic drugs.
Heart Rate
The heart rate is a major determinant of cardiac output.
As the intrinsic function of the heart decreases in failure and stroke

volume diminishes, an increase in heart rate—through sympathetic
activation of β adrenoceptors—is the first compensatory mechanism
that comes into play to maintain cardiac output.
However, tachycardia limits diastolic filling time and coronary flow,

further stressing the heart. Thus, bradycardic drugs may benefit
patients with high heart rates.

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Drugs Used in Heart Failure

↓ cardiac output  reduced O2 supply to the body.

2) Diastolic failure  hypertrophy, stiffening and loss of adequate

“High-output” failure  demands of the body are so great that even

• Arteriosclerotic heart disease

 Decreased exercise tolerance with rapid muscular fatigue is the

 The other manifestations result from the attempts by the body to

The baroreceptor reflex  lower

Angiotensin II & endothelin 

• Ventricular dilation or hypertrophy (The most important intrinsic compensatory

- Reuptake of Ca2+ into the SR by SERCA may also be impaired.

- Prolonged β activation also increases caspases, the enzymes responsible for

Other hormones are released, including natriuretic peptide, endothelin, &

-The most important intrinsic compensatory mechanism is myocardial hypertrophy.

Cardiac performance is a function of 4 primary factors:

As cardiac output falls in chronic failure, a reflex increase in systemic

Endothelin, a potent vasoconstrictor peptide, is also involved. This

As contractility decreases in the patient, there is a reduction in the

However, the heart is usually still capable of some increase in all of

The heart rate is a major determinant of cardiac output.

As the intrinsic function of the heart decreases in failure and stroke

However, tachycardia limits diastolic filling time and coronary flow,

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