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

Table 25–7
Mineralocorticoid Receptor Antagonists (Aldosterone Antagonists, Potassium-Sparing Diuretics)
ORAL
ROUTE OF
DRUG STRUCTURE AVAILABILITY t 1/2
(HOURS) ELIMINATION
Spironolactone O
~65% ~1.6 M
(ALDACTONE)
O
CH 3
CH 3
H
O
H
H
S
O CH 3
Canrenone a O
ID ~16.5 M
O
CH 3
CH 3
H
H H
O
Potassium OH
O
ID ID M
canrenoate a
CH 3
O – K +
H
CH 3
CH 3
CH 3
H H
O
Eplerenone (INSPRA) H 3C O
ID ~5 M
O
O
O
H
H
O
O
a
Not available in United States. M, metabolism; ID, insufficient data.
higher concentration than mineralocorticoids, it was unclear how
mineralocorticoids would ever bind to their receptor. The mineralocorticoid
receptor would be predominantly occupied
by glucocorticoids. This mystery was solved with the cloning of
the enzyme type II 11-β-hydroxysteroid dehydrogenase (HSD).
Mineralocorticoid target tissues expresses type II 11-β-HSD,
which converts cortisol to the inactive cortisone. This allows mineralocorticoids
to bind to the receptor. The type II 11-β-HSD
enzyme is genetically absent in the inherited disorder of apparent
mineralocorticoid excess.
Drugs such as spironolactone and eplerenone competitively
inhibit the binding of aldosterone to the MR. Unlike the MR-aldosterone
complex, the MR-spironolactone complex is not able to
induce the synthesis of AIPs. Since spironolactone and eplerenone
block biological effects of aldosterone, these agents also are referred
to as aldosterone antagonists.
MR antagonists are the only diuretics that do
not require access to the tubular lumen to induce
diuresis.
Effects on Urinary Excretion. The effects of MR antagonists
on urinary excretion are very similar to those
induced by renal epithelial Na + -channel inhibitors.
However, unlike Na + -channel inhibitors, the clinical
efficacy of MR antagonists is a function of endogenous
aldosterone levels. The higher the endogenous