Page 324 - Basic _ Clinical Pharmacology ( PDFDrive )

310 SECTION IV Drugs with Important Actions on Smooth Muscle

CLINICAL ROLE OF NATRIURETIC (NEP 24.11). The resulting increase in ANP and BNP causes
PEPTIDES natriuresis and vasodilation, as well as a compensatory increase in
renin secretion and plasma ANG II levels. Because of the increase
The serum concentration of endogenous BNP rises in heart in ANG II, these drugs are not effective as monotherapy in the
failure, and monitoring this peptide has been shown to have treatment of heart failure. However, they led to the development
prognostic value. Natriuretic peptides may be administered as of drugs that combine neprilysin inhibition with an ACE inhibi-
recombinant ANP (carperitide), recombinant BNP (nesiritide), tor in order to prevent the increase in plasma ANG II, or with an
or ularitide, the synthetic form of urodilatin (see above). These ARB to block the actions of ANG II.
peptides produce vasodilation and natriuresis and have been inves- Drugs that combine neprilysin inhibition with ACE inhibi-
tigated for the treatment of congestive heart failure. Nesiritide is tion, known as vasopeptidase inhibitors, include omapatrilat,
approved for the treatment of decompensated acute heart failure sampatrilat, and fasidotrilat. Omapatrilat, which received the
(see Chapter 13). Ularitide has demonstrated beneficial effects most attention, lowers blood pressure in animal models of hyper-
in animal models of heart failure and in phase 1 and 2 studies in tension as well as in hypertensive patients, and improves cardiac
heart failure patients (Figure 17–6). It is in phase 3 development function in patients with heart failure. Unfortunately, omapatrilat
as an infusion treatment for acute decompensated heart failure. causes a significant incidence of angioedema and cough, appar-
The circulating levels of natriuretic peptides can also be ently as a result of decreased metabolism of bradykinin, and is not
increased by drugs that inhibit their breakdown by neprilysin approved for clinical use.
The combination of an ANG II receptor antagonist with a
neprilysin inhibitor (ARNI) increases endogenous natriuretic pep-
Pulmonary capillary wedge pressure tide levels while simultaneously blocking the effects of the increase
0
in plasma ANG II. The first-in-class ARNI, LCZ696, is a single
–2
∆PCWP (mmHg) –4 and the ANG II receptor antagonist valsartan.
molecule composed of the neprilysin inhibitor prodrug sacubitril
–6
In healthy subjects, LCZ696 increased plasma ANP and
cGMP levels in combination with increases in plasma renin
–8
–10
demonstrated many beneficial effects of LCZ696, and it was
–12 and ANG II levels. Clinical trials in patients with heart failure
0 2 4 6 8 24 26 superior to ACE inhibition or angiotensin receptor blockade in
reducing the risk of death and hospitalization from heart failure
Systemic vascular resistance
2200 (Figure 17–7). Side effects included hypotension, hyperkale-
mia, renal impairment, and angioedema. LCZ696, marketed as
2000
SVR (dyn/s/cm –5 ) 1800 Angiotensin Angiotensin/
Entresto, is approved by the US Food and Drug Administration
1600
1400
ACE
blocker
inhibitor
1200 0% receptor inhibitor neprilysin
0 1 2 4 6 8 24 26
Cardiac index
2.4 –10%

2.2
CI (L/min/m 2 ) 2.0 % Decrease in mortality –20%

1.8 –30%
–10124 6 8 24 26
Time (h) –40%
Placebo 7.5 ng/kg/min 15 ng/kg/min 30 ng/kg/min FIGURE 17–7 Comparison of the decrease in mortality produced
by an angiotensin receptor blocker, a converting enzyme inhibitor,
FIGURE 17–6 Hemodynamic effects of infusion of three and the combined angiotensin-neprilysin inhibitor LCZ696 (Entresto)
doses of ularitide and placebo in patients with acute decompen- in patients with heart failure. Results for the three drugs are from
sated heart failure. (Modified from Anker SD et al: Ularitide for the treat- separate trials. Each bar represents the drug effect versus placebo.
ment of acute decompensated heart failure: From preclinical to clinical studies. (Adapted from Volpe M et al: The natriuretic peptides system in the pathophysiology
Eur Heart J 2015;36:715.) of heart failure: From molecular basis to treatment. Clin Sci (Lond) 2016;130:57.)