Page 234 - Basic _ Clinical Pharmacology ( PDFDrive )

220 SECTION III Cardiovascular-Renal Drugs

signs of heart failure in animal models, and a small initial phase 2 Angiotensin AT receptor blockers such as losartan (see
1
clinical trial in patients with heart failure showed increased systolic Chapters 11 and 17) appear to have similar beneficial effects. In
time and stroke volume and reduced heart rate and end-systolic combination with sacubitril, valsartan is now approved for HFrEF.
and diastolic volumes. A larger trial in patients with acute heart Angiotensin receptor blockers should be considered in patients
failure was disappointing, but another trial in those with chronic intolerant of ACE inhibitors because of incessant cough.
failure is under way. Aliskiren, a renin inhibitor approved for hypertension, was
found to have no definitive benefit in clinical trials for heart
DRUGS WITHOUT POSITIVE failure.
INOTROPIC EFFECTS USED IN VASODILATORS
HEART FAILURE

Vasodilators are effective in acute heart failure because they pro-
These agents—not positive inotropic drugs—are the first-line thera-
pies for chronic heart failure. The drugs most commonly used are vide a reduction in preload (through venodilation), or reduction
diuretics, ACE inhibitors, angiotensin receptor antagonists, aldo- in afterload (through arteriolar dilation), or both. Some evidence
sterone antagonists, and β blockers (Table 13–1). In acute failure, suggests that long-term vasodilation by hydralazine and isosorbide
diuretics and vasodilators play important roles. dinitrate can also reduce damaging remodeling of the heart.
A synthetic form of the endogenous peptide brain natriuretic
peptide (BNP) is approved for use in acute (not chronic) cardiac
DIURETICS failure as nesiritide. This recombinant product increases cGMP
in smooth muscle cells and reduces venous and arteriolar tone
Diuretics, especially furosemide, are drugs of choice in heart in experimental preparations. It also causes diuresis. However,
failure and are discussed in detail in Chapter 15. They reduce salt large trials with this drug have failed to show an improvement in
and water retention, edema, and symptoms. They have no direct mortality or rehospitalizations. The peptide has a short half-life of
effect on cardiac contractility; their major mechanism of action in about 18 minutes and is administered as a bolus intravenous dose
heart failure is to reduce venous pressure and ventricular preload. followed by continuous infusion. Excessive hypotension is the
The reduction of cardiac size, which leads to improved pump effi- most common adverse effect. Reports of significant renal damage
ciency, is of major importance in systolic failure. In heart failure and deaths have resulted in extra warnings regarding this agent,
associated with hypertension, the reduction in blood pressure also and it should be used with great caution. A newer approach to
reduces afterload. Spironolactone and eplerenone, the aldoste- modulation of the natriuretic peptide system is inhibition of the
rone (mineralocorticoid) antagonist diuretics (see Chapter 15), neutral endopeptidase enzyme, neprilysin, which is responsible for
have the additional benefit of decreasing morbidity and mortality the degradation of BNP and atrial natriuretic peptide (ANP), as
in patients with severe heart failure who are also receiving ACE well as angiotensin II, bradykinin, and other peptides. Sacubitril
inhibitors and other standard therapy. One possible mechanism is a prodrug that is metabolized to an active neprilysin inhibi-
for this benefit lies in accumulating evidence that aldosterone tor plus an ARB. A combination of valsartan plus sacubitril has
may also cause myocardial and vascular fibrosis and barorecep- recently been approved for use in HFrEF.
tor dysfunction in addition to its renal effects. Finerenone is an Plasma concentrations of endogenous BNP rise in most
investigational mineralocorticoid antagonist that may be less likely patients with heart failure and are correlated with severity. Mea-
to induce hyperkalemia. surement of the plasma precursor NT-proBNP is a useful diag-
nostic or prognostic test and has been used as a surrogate marker
ANGIOTENSIN-CONVERTING ENZYME in clinical trials.
Related peptides include ANP and urodilatin, a similar peptide
INHIBITORS, ANGIOTENSIN RECEPTOR produced in the kidney. Carperitide and ularitide, respectively,
BLOCKERS, & RELATED AGENTS are investigational synthetic analogs of these endogenous pep-
tides and are in clinical trials (see Chapter 15). Bosentan and
ACE inhibitors such as captopril were introduced in Chapter 11 tezosentan, orally active competitive inhibitors of endothelin (see
and are discussed again in Chapter 17. These versatile drugs Chapter 17), have been shown to have some benefits in experi-
reduce peripheral resistance and thereby reduce afterload; they mental animal models with heart failure, but results in human
also reduce salt and water retention (by reducing aldosterone trials have been disappointing. Bosentan is approved for use in
secretion) and in that way reduce preload. The reduction in tis- pulmonary hypertension. It has significant teratogenic and hepa-
sue angiotensin levels also reduces sympathetic activity through totoxic effects.
diminution of angiotensin’s presynaptic effects on norepinephrine Several newer agents are thought to stabilize the RyR chan-
2+
release. Finally, these drugs reduce the long-term remodeling nel and may reduce Ca leak from the SR. They are currently
of the heart and vessels, an effect that may be responsible for denoted only by code numbers (eg, TRV027, JTV519, S44121).
the observed reduction in mortality and morbidity (see Clinical This action, if confirmed to reduce diastolic stiffness, would be
Pharmacology). especially useful in diastolic failure with preserved ejection fraction.