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

694
A
LATE DISTAL TUBULE
AND COLLECTING DUCT
B
Lumen
Interstitial
space
Lumen
Interstitial
space
SECTION III
Cortisol
11-β-HSD
type II
CH
1
7
Cortisone
2
mRNA
AIP
CH
aldosterone
antagonists
CH
MR
MR-ALDO ALDO ALDO
8
Mitochondria
Nucleus
6
5
ATP-
Na + ase
3
Na +
ATPase
4
ATPase
K + Na +
α
β
γ
LM
PY
PY
Nedd4-2
– +
SGK1
Aldosterone
BL
MODULATION OF CARDIOVASCULAR FUNCTION
LM
BL
Figure 25–11. Effects of aldosterone on late distal tubule and collecting duct and diuretic mechanism of aldosterone antagonists.
A. Cortisol also has affinity for the mineralocorticoid receptor (MR), but is inactivated in the cell by 11-β-hydroxysteroid dehydrogenase
(HSD) type II. B. Serum and glucorticoid-regulated kinase (SGK)-1 is upregulated after ~30 minutes by aldosterone.
SGK-1 phosphorylates and inactivates Nedd4-2 a ubiquitin-protein ligase that acts on ENaC, leading to its degradation.
Phosphorylated Nedd4-2 no longer interacts with the PY motif of ENaC. As a result, the protein is not ubiquitinated and remains
in the membrane, the end result of which is increased Na + entry into the cell. 1. Activation of membrane-bound Na + channels. 2.
Na + channel (ENaC) removal from the membrane is inhibited. 3. De novo synthesis of Na + channels. 4. Activation of membranebound
Na + ,K + - ATPase. 5. Redistribution of Na + ,K + -ATPase from cytosol to membrane. 6. De novo synthesis of Na + ,K + -ATPase.
7. Changes in permeability of tight junctions. 8. Increased mitochondrial production of ATP. AIP, aldosterone-induced proteins;
ALDO, aldosterone; MR, mineralocorticoid receptor; CH, ion channel; BL, basolateral membrane; LM, luminal membrane.
aldosterone level, the greater the effects of MR antagonists
on urinary excretion.
Effects on Renal Hemodynamics. MR antagonists have
little or no effect on renal hemodynamics and do not
alter TGF.
Other Actions. Spironolactone has some affinity toward progesterone
and androgen receptors and thereby induces side effects
such as gynecomastia, impotence, and menstrual irregularities.
Owing to the 9,11-epoxide group, eplerenone has very low affinity
for progesterone and androgen receptors (<1% and <0.1%,
respectively) compared with spironolactone. High spironolactone
concentrations were reported to interfere with steroid biosynthesis
by inhibiting steroid hydroxylases (e.g., CYPs 11A1, 11B1, 11B2,
and C21; see Chapters 40 and 41). These effects have limited clinical
relevance.
Absorption and Elimination. Spironolactone is absorbed
partially (~65%), is metabolized extensively (even during
its first passage through the liver), undergoes enterohepatic
recirculation, is highly protein bound, and has a
short t 1/2
(~1.6 hours). The t 1/2
is prolonged to 9 hours in
patients with cirrhosis.
Spironolactone undergoes metabolism by both deacylation
and dethioacetylation to a variety of metabolites with prolonged t 1/2
;
of these, 7α thiomethyl spirononlactone is the primary active
metabolite.
Although not available in the U.S., canrenone and the K + salt
of canrenoate also are in clinical use. Canrenoate is not active per se
but is converted to canrenone. Eplerenone has good oral availability
and is eliminated primarily by metabolism by CYP3A4 to inactive
metabolites, with a t 1/2
of ~5 hours.
Toxicity, Adverse Effects, Contraindications, Drug
Interactions. As with other K + -sparing diuretics, MR
antagonists may cause life-threatening hyperkalemia.
Indeed, hyperkalemia is the principal risk of MR