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

antagonists. Therefore, these drugs are contraindicated
in patients with hyperkalemia and in those at increased
risk of developing hyperkalemia either because of disease
or administration of other medications. MR antagonists
also can induce metabolic acidosis in cirrhotic
patients.
Salicylates may reduce the tubular secretion of canrenone and
decrease diuretic efficacy of spironolactone, and spironolactone may
alter the clearance of digitalis glycosides. Owing to its affinity for
other steroid receptors, spironolactone may cause gynecomastia,
impotence, decreased libido, hirsutism, deepening of the voice, and
menstrual irregularities. Spironolactone also may induce diarrhea,
gastritis, gastric bleeding, and peptic ulcers (the drug is contraindicated
in patients with peptic ulcers). CNS adverse effects include
drowsiness, lethargy, ataxia, confusion, and headache. Spironolactone
may cause skin rashes and, rarely, blood dyscrasias. Breast cancer
has occurred in patients taking spironolactone chronically (cause and
effect not established), and high doses of spironolactone are associated
with malignant tumors in rats. Whether or not therapeutic
spironolactone doses can induce malignancies remains an open question.
Strong inhibitors of CYP3A4 may increase plasma levels of
eplerenone, and such drugs should not be administered to patients
taking eplerenone, and vice versa. Other than hyperkalemia and GI
disorders, the rate of adverse events for eplerenone is similar to that
of placebo (Pitt et al., 2003).
Therapeutic Uses. As with other K + -sparing diuretics,
spironolactone often is coadministered with thiazide or
loop diuretics in the treatment of edema and hypertension,
and spironolactone in combination with
hydrochlorothiazide (ALDACTAZIDE, others) is marketed.
Such combinations result in increased mobilization of
edema fluid while causing lesser perturbations of K +
homeostasis. Spironolactone is particularly useful in the
treatment of resistant hypertension due to primary
hyperaldosteronism (adrenal adenomas or bilateral
adrenal hyperplasia) and of refractory edema associated
with secondary aldosteronism (cardiac failure, hepatic
cirrhosis, nephrotic syndrome, and severe ascites).
Spironolactone is considered the diuretic of choice in
patients with hepatic cirrhosis. Spironolactone, added to
standard therapy, substantially reduces morbidity and
mortality (Pitt et al., 1999) and ventricular arrhythmias
(Ramires et al., 2000) in patients with heart failure
(Chapter 28).
Clinical experience with eplerenone is less than that with
spironolactone. Eplerenone appears to be a safe and effective antihypertensive
drug (Ouzan et al., 2002). It is somewhat more specific for
the MR and therefore the incidience of progesterone-related adverse
effects (e.g., gynecomastia) is lower than with spironolactone. In
patients with acute myocardial infarction complicated by left ventricular
systolic dysfunction, addition of eplerenone to optimal medical
therapy significantly reduces morbidity and mortality (Pitt et al., 2003).
INHIBITORS OF THE NONSPECIFIC
CATION CHANNEL: ATRIAL
NATRIURETIC PEPTIDES
The inner medullary collecting duct (IMCD) is a major
site of action of natriuretic peptides. Although five different
natriuretic peptides exist, only four are relevant
with respect to human physiology: atrial natriuretic
peptide (ANP), brain natriuretic peptide (BNP), C-type
natriuretic peptide (CNP), and urodilatin. ANP and
BNP are produced by the heart in response to wall
stretch, CNP is of endothelial and renal cell origin,
while urodilatin is found in urine and acts as a paracrine
regulator of Na + transport (Lee and Burnett, 2007).
Human recombinant ANP (carperitide, available only
in Japan) and BNP (nesiritide [NATRECOR]) are currently
available therapeutic agents of this class.
Mechanism and Site of Action. The IMCD is the final site along the
nephron where Na + is reabsorbed. Up to 5% of the filtered Na + load
can be reabsorbed here. Na + enters the IMCD cell across the apical
membrane down an electrochemical gradient through Na + channels
and exits via the Na + /K + -ATPase (Figure 25–12). Two types of Na +
Lumen
CNGC
Na + , NH + 4 , K +
ANP
ENaC
Na +
LM
–
cGMP
GTP
–
PKG
BL
Interstitial
space
3 Na +
2 K +
Figure 25–12. Inner medullary collecting duct (IMCD) Na + transport
and its regulation. Na + enters the IMCD cell in one of two
ways. The first is via ENaC, and the second is through a cyclic
nucleotide gated nonspecific cation channel (CNGC) that transports
Na + , K + , and NH 4+
and is gated by cyclic GMP. Na + then
exits the cell via the Na + , K + -ATPase. It is the CNGC that is the primary
pathway for Na + entry, and is inhibited by natriuretic peptides.
Atrial natriuretic peptides (ANP) bind to surface receptors
(natriuretic peptide receptors A, B, and C). The A and B receptors
are isoforms of particulate guanylate cyclase that catalyze the conversion
of GTP to cyclic GMP. Cyclic GMP inhibits the CNGC
directly, and indirectly through PKG. PKG activation also inhibits
Na + exit via the Na + , K + -ATPase.
–
695
CHAPTER 25
REGULATION OF RENAL FUNCTION AND VASCULAR VOLUME