CLINICAL PHARMACOLOGY
Mechanism of Action
Aldactone (spironolactone) is a specific pharmacologic
antagonist of aldosterone, acting primarily through competitive
binding of receptors at the aldosterone-dependent sodium-potassium
exchange site in the distal convoluted renal tubule. Aldactone
causes increased amounts of sodium and water to be excreted,
while potassium is retained. Aldactone acts both as a
diuretic and as an antihypertensive drug by this mechanism.
It may be given alone or with other diuretic agents which
act more proximally in the renal tubule.
Aldosterone Antagonist Activity
Increased levels of the mineralocorticoid, aldosterone,
are present in primary and secondary hyperaldosteronism.
Edematous states in which secondary aldosteronism is usually
involved include congestive heart failure, hepatic cirrhosis,
and the nephrotic syndrome. By competing with aldosterone
for receptor sites, Aldactone provides effective therapy
for the edema and ascites in those conditions. Aldactone
counteracts secondary aldosteronism induced by the volume
depletion and associated sodium loss caused by active
diuretic therapy.
Aldactone is effective in lowering the systolic and diastolic
blood pressure in patients with primary hyperaldosteronism.
It is also effective in most cases of essential hypertension,
despite the fact that aldosterone secretion may be within
normal limits in benign essential hypertension.
Through its action in antagonizing the effect of aldosterone,
Aldactone inhibits the exchange of sodium for potassium
in the distal renal tubule and helps to prevent potassium
loss.
Aldactone has not been demonstrated to elevate serum
uric acid, to precipitate gout, or to alter carbohydrate
metabolism.
Pharmacokinetics
Spironolactone is rapidly and extensively metabolized.
Sulfur-containing products are the predominant metabolites
and are thought to be primarily responsible, together
with spironolactone, for the therapeutic effects of the
drug. The following pharmacokinetic data were obtained
from 12 healthy volunteers following the administration
of 100 mg of spironolactone (Aldactone film-coated tablets)
daily for 15 days. On the 15th day, spironolactone was
given immediately after a low-fat breakfast and blood
was drawn thereafter.
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Accumulation Factor:
AUC (0-24 hr,
day 15) / AUC
(0-24 hr, day 1) |
Mean Peak Serum Concentration |
Mean (SD) Post-Steady State Half-Life |
| 7-alpha-(thiomethyl)
spirolactone (TMS) |
1.25 |
391 ng/mL
at 3.2 hr |
13.8 hr
(6.4) (terminal) |
| 6-beta-hydroxy-7-alpha-(thiomethyl)
spirolactone (HTMS) |
1.50 |
125 ng/mL
at 5.1 hr |
15.0 hr
(4.0) (terminal) |
| Canrenone
(C) |
1.41 |
181 ng/mL
at 4.3 hr |
16.5 hr
(6.3) (terminal) |
| Spironolactone |
1.30 |
80 ng/mL
at 2.6 hr |
Approximately
1.4 hr (0.5) (beta half-life) |
The pharmacological activity of spironolactone metabolites
in man is not known. However, in the adrenalectomized
rat the antimineralocorticoid activities of the metabolites
C, T.S. and HTMS, relative to spironolactone, were 1.10,
1.28, and 0.32, respectively. Relative to spironolactone,
their binding affinities to the aldosterone receptors
in rat kidney slices were 0.19, 0.86, and 0.06, respectively.
In humans the potencies of TMS and 7-alpha-thiospirolactone
in reversing the effects of the synthetic mineralocorticoid,
fludrocortisone, on urinary electrolyte composition were
0.33 and 0.26, respectively, relative to spironolactone.
However, since the serum concentrations of these steroids
were not determined, their incomplete absorption and/or
first-pass metabolism could not be ruled out as a reason
for their reduced in vivo activities.
Spironolactone and its metabolites are more than 90%
bound to plasma proteins. The metabolites are excreted
primarily in the urine and secondarily in bile.
The effect of food on spironolactone absorption (two
100-mg Aldactone tablets) was assessed in a single dose
study of 9 healthy, drug-free volunteers. Food increased
the bioavailability of unmetabolized spironolactone by
almost 100%. The clinical importance of this finding is
not known.
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