CLINICAL PHARMACOLOGY
Mechanism of Action
Aldactazide is a combination of two diuretic agents with
different but complementary mechanisms and sites of action,
thereby providing additive diuretic and antihypertensive
effects. Additionally, the spironolactone component helps
to minimize the potassium loss characteristically induced
by the thiazide component.
The diuretic effect of spironolactone is mediated through
its action as a specific pharmacologic antagonist of aldosterone,
primarily by competitive binding of receptors at the aldosterone-dependent
sodium-potassium exchange site in the distal convoluted
renal tubule. Hydrochlorothiazide promotes the excretion
of sodium and water primarily by inhibiting their reabsorption
in the cortical diluting segment of the distal renal tubule.
Aldactazide is effective in significantly lowering the
systolic and diastolic blood pressure in many patients
with essential hypertension, even when aldosterone secretion
is within normal limits.
Both spironolactone and hydrochlorothiazide reduce exchangeable
sodium, plasma volume, body weight, and blood pressure.
The diuretic and antihypertensive effects of the individual
components are potentiated when spironolactone and hydrochlorothiazide
are given concurrently.
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.
Hydrochlorothiazide is rapidly absorbed following oral
administration. Onset of action of hydrochlorothiazide
is observed within one hour and persists for 6 to 12 hours.
Hydrochlorothiazide plasma concentrations attain peak
levels at one to two hours and decline with a half-life
of four to five hours. Hydrochlorothiazide undergoes only
slight metabolic alteration and is excreted in urine.
It is distributed throughout the extracellular space,
with essentially no tissue accumulation except in the
kidney.
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