Page 229 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 13 Drugs Used in Heart Failure 215

influx through voltage-gated channels, which occurs as a normal
part of almost all cardiac action potentials, is another determi- Cardiac output
nant, although the amount of sodium that enters with each action
potential is much less than 1% of the total intracellular sodium.
+
+
Na /K -ATPase appears to be the primary target of digoxin and
other cardiac glycosides. Carotid sinus firing Renal blood flow
Pathophysiology of Heart Failure
Sympathetic Renin
Heart failure is a syndrome with many causes that may involve one discharge release
or both ventricles. Cardiac output is usually below the normal range
(“low-output” failure). Systolic dysfunction, with reduced cardiac
output and significantly reduced ejection fraction (EF < 45%; Angiotensin II
normal > 60%), is typical of acute failure, especially that resulting
from myocardial infarction. Diastolic dysfunction often occurs Force
as a result of hypertrophy and stiffening of the myocardium, and Rate
although cardiac output is reduced, ejection fraction may be nor- Preload Afterload Remodeling
mal. Heart failure due to diastolic dysfunction does not usually
respond optimally to positive inotropic drugs. Cardiac output
“High-output” failure is a rare form of heart failure. In (via compensation)
this condition, the demands of the body are so great that even
increased cardiac output is insufficient. High-output failure can FIGURE 13–2 Some compensatory responses (orange boxes)
result from hyperthyroidism, beriberi, anemia, and arteriovenous that occur during congestive heart failure. In addition to the effects
shunts. This form of failure responds poorly to the drugs discussed shown, sympathetic discharge facilitates renin release, and angioten-
in this chapter and should be treated by correcting the underlying sin II increases norepinephrine release by sympathetic nerve endings
cause. (dashed arrows).
The primary signs and symptoms of all types of heart failure
include tachycardia, decreased exercise tolerance, shortness of
breath, and cardiomegaly. Peripheral and pulmonary edema (the protein-effector system take place that result in diminished stimu-
congestion of congestive heart failure) are often but not always latory effects. Beta receptors are not down-regulated and may
2
present. Decreased exercise tolerance with rapid muscular fatigue develop increased coupling to the inositol 1,4,5-trisphosphate–
is the major direct consequence of diminished cardiac output. diacylglycerol (IP -DAG) cascade. It has also been suggested that
3
The other manifestations result from the attempts by the body to cardiac β receptors (which do not appear to be down-regulated in
3
compensate for the intrinsic cardiac defect.
Neurohumoral (extrinsic) compensation involves two major
mechanisms (previously presented in Figure 6–7)—the sym-
pathetic nervous system and the renin-angiotensin-aldosterone 1 Cardiac performance
hormonal response—plus several others. Some of the detrimental CO 2
as well as beneficial features of these compensatory responses are CO
illustrated in Figure 13–2. The baroreceptor reflex appears to be NE, A EF CO B
reset, with a lower sensitivity to arterial pressure, in patients with ET NE, A EF
heart failure. As a result, baroreceptor sensory input to the vaso- ET NE, A
motor center is reduced even at normal pressures; sympathetic Afterload ET EF
outflow is increased, and parasympathetic outflow is decreased. Afterload
Increased sympathetic outflow causes tachycardia, increased car- Afterload
diac contractility, and increased vascular tone. Vascular tone is Time
further increased by angiotensin II and endothelin, a potent vaso-
constrictor released by vascular endothelial cells. Vasoconstriction FIGURE 13–3 Vicious spiral of progression of heart failure.
increases afterload, which further reduces ejection fraction and Decreased cardiac output (CO) activates production of neurohor-
mones (NE, norepinephrine; AII, angiotensin II; ET, endothelin), which
cardiac output. The result is a vicious cycle that is characteristic of cause vasoconstriction and increased afterload. This further reduces
heart failure (Figure 13–3). Neurohumoral antagonists and vaso- ejection fraction (EF) and CO, and the cycle repeats. The downward
dilators reduce heart failure mortality by interrupting the cycle spiral is continued until a new steady state is reached in which CO
and slowing the downward spiral. is lower and afterload is higher than is optimal for normal activity.
After a relatively short exposure to increased sympathetic drive, Circled points 1, 2, and B represent points on the ventricular function
complex down-regulatory changes in the cardiac β -adrenoceptor–G curves depicted in Figure 13–4.
1