ACTIONS/CLINICAL PHARMACOLOGY
Mechanism of Action
Spironolactone and hydrochlorothiazide 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.
Spironolactone and hydrochlorothiazide 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 (as tablets)
daily for 15 days. On the 15th day, spironolactone was given immediately after a
low-fat breakfast and blood was drawn thereafter.
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-α-(thiomethyl) spirolactone
(TMS) |
1.25 |
391 ng/mL at 3.2 hr |
13.8 hr (6.4) (terminal) |
6-β-hydroxy-7-α-(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) (β
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, TMS, and HTMS, relative to spironolactone, were 1.1, 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-α-thiospironolactone 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 firstpass 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 spironolactone
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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