DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

696 channels are expressed in IMCD. The first is an amiloride-sensitive,
28pS, nonselective, cyclic nucleotide gated cation (CNG) channel.
This channel is highly selective for cations over anions, has equal
permeability for Na + and K + , and is inhibited by cGMP, PKG, PKC,
ATP, and atrial natriuretic peptides via their capacity to stimulate
membrane-bound guanylyl cyclase activity and elevate cellular cGMP.
Its open probability is increased by rises in intracellular Ca 2+ concentration.
CNG channels are expressed in all nephron segments with the
possible exception of the thin limb of Henle’s loop. The second type
of Na + channel expressed in the IMCD is the low-conductance 4 pS
highly-selective Na + channel ENaC. It appears that the majority of Na +
reabsorption in the IMCD is mediated via the CNG channel.
ANP has a 17 amino acid core ring and a cysteine bridge. It
is produced in the cardiac atria in response to wall stretch. It binds
to the natriuretic peptide receptor (NPR) A and increases intracellular
cyclic GMP resulting in inhibition of the CNG channel and natriuresis.
It also inhibits production of renin and aldosterone. BNP is
produced in the ventricle, also binds to the NPR-A receptor and acts
in a similar fashion as ANP. CNP binds to the NPR-B receptor and
increases cGMP in vascular smooth muscle and mediates vasodilation.
Urodilatin arises from the same precursor molecule as ANP but
has four additional amino acids at the N terminus. It binds with lower
affinity than ANP to the NPR-B receptor and has effects in glomeruli
and IMCD. As a result of these effects, natriuretic peptides have been
utilized to treat congestive heart failure. Human recombinant ANP
(carperitide) is available in Japan but not yet in the U.S., where
human recombinant BNP (nesiritide) is available. Urodilatin (ularitide)
remains in preclinical trials in the U.S. and Europe. Only the
use of nesiritide is discussed in the following sections. Nesiritide
effects renal Na + excretion by inhibiting the CNG nonspecific-cation
channel, as well as through inhibiting both the renin-angiotensinaldosterone
system and endothelin production.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Effects on Urinary Excretion. Nesiritide inhibits Na +
transport in both the proximal and distal nephron but
its primary effect is in the IMCD. Urinary Na + excretion
increases with nesiritide but the effect may be attenuated
by upregulation of Na + reabsorption in upstream
segments of the nephron.
Effects on Renal Hemodynamics. GFR increases
administered nesiritide in normal subjects, but in treated
patients with congestive heart failure GFR may increase,
decrease, or remain unchanged.
Other Actions. Administration of nesiritide decreases systemic and
pulmonary resistances and left ventricular filling pressure, and
induces a secondary increase in cardiac output. In one study, mean
arterial pressure, pulmonary capillary wedge pressure, and right
atrial pressure declined 17%, 48%, and 56%, respectively. Declines
in blood pressure with administration are dose related.
Elimination. Natriuretic peptides are administered intravenously and
have short t 1/2
values. Nesiritide has a distribution t 1/2
of 2 minutes
and a mean terminal t 1/2
of 18 minutes. Its volume of distribution is
small, 0.19 L/kg. It is cleared via three mechanisms: binding to the
NPR-C receptor, degradation via a neutral endopeptidase, and renal
excretion. There is no need to adjust the dose for renal insufficiency.
Toxicity, Adverse Effects, Contraindications, Drug Interactions.
There are concerns about adverse renal effects and reports of
increased short-term mortality in patients treated with nesiritide.
Increases in serum creatinine concentration may be related
to decreases in extracellular fluid volume, higher doses of diuretics
used, decreases in blood pressure, and activation of the
renin-angiotensin-aldosterone system. The Vasodilation in the
Management of Acute CHF (VAMC) trial showed no increased risk
with low or moderate doses of diuretics but an increased risk with
high-dose diuretics (>160 mg furosemide), rising with increasing
doses. The risk of hypotension was 4.4% and lasted an average of 2.2
hours. Oral ACE inhibitors may increase the risk of hypotension with
nesiritide. Data on whether 30-day mortality is increased by nesiritide
are conflicting. There are no data to suggest that nesiritide
reduces mortality in the short term or long term in patients with acute
decompensated CHF.
Therapeutic Uses. Use of nesiritide should be limited
to patients with acutely decompensated CHF with
shortness of breath at rest; the drug should not be used
in place of diuretics. Nesiritide reduces symptoms and
improves hemodynamic parameters in those with dyspnea
at rest who are not hypotensive. Nesiritide is available
for administration as a continuous intravenous
infusion; there is little experience with administering
nesiritide for longer than 48 hours.
CLINICAL USE OF DIURETICS
Site and Mechanism of Diuretic Action. An understanding
of the sites and mechanisms of action of diuretics
enhances comprehension of the clinical aspects of
diuretic pharmacology. Figure 25–13 provides an
overview of the sites and mechanisms of actions of
diuretics. Much of the pharmacology of diuretics can
be deduced from this figure.
Mechanism of Edema Formation. A complex set of
interrelationships (Figure 25–14) exists among the cardiovascular
system, kidneys, CNS (Na + appetite, thirst
regulation), and tissue capillary beds (distribution of
extracellular fluid volume [ECFV]), so perturbations at
one of these sites can affect all other sites. A primary
law of the kidney is that Na + excretion is a steep function
of mean arterial blood pressure (MABP), such that
small increases in MABP cause marked increases in
Na + excretion (Guyton, 1991). Over any given time
interval, the net change in total-body Na + (either positive
or negative) is simply the dietary Na + intake minus
the urinary excretion rate minus other losses (e.g.,
sweating, fecal losses, and vomiting). When a net positive
Na + balance occurs, the Na + concentration in the
extracellular fluid (ECF) will increase, stimulating
water intake (thirst) and reducing urinary water output