INTRODUCTION
Spironolactone was developed as a mineralocorticoid receptor
antagonist following the observation that spirolactones
block the effect of mineralocorticoids in the late 1950’s. The
resulting increase in salt and water excretion led to spironolactone’s
approval by the US Food and Drug Administration for
management of congestive heart failure, cirrhosis of the liver,
nephrotic syndrome, essential hypertension, hypokalemia, and
primary hyperaldosteronism.1 Additionally, over the past three
decades, spironolactone’s effects outside the distal renal tubule
have led to dermatologic uses in treatment of androgen mediated
conditions, including acne, hirsutism, and alopecia.
Pharmacology
Pharmacokinetics
Spironolactone is formulated as a tablet without a readily available
intravenous form because of the drug’s poor aqueous solubility.2
Spironolactone is partially absorbed, with oral bioavailability estimated
to be in the 65-90% range.2,3 Food increases the bioavailability
of the drug, however the therapeutic impact of this effect remains
unknown.2 Spironolactone undergoes rapid hepatic metabolism,
and more than 90% of available drug is protein bound.1 Multiple
metabolites, including 7α-methylspironolactone, 6β-hydroxy-7-α-
methylspironolactone, and canrenone, are formed and also have
therapeutic effects. The half-life of spironolactone is estimated to be 1.4 hours, however, the half-lives of its metabolites are much
longer. Canrenone, for instance, has a half-life of 16.5 hours, which
may prolong the therapeutic effects of the drug. The half-lives of
spironolactone and its metabolites are significantly increased in the
setting of hepatic dysfunction and cirrhosis, with t1/2 of spironolactone
increased to approximately 9 hours.2 Additionally, dosing
adjustments must be made in the setting of renal dysfunction or
end stage renal disease, as spironolactone and its metabolites are
primarily excreted via the urine, with secondary excretion in bile.1
Mechanism of Action
Spironolactone acts primarily through competitive inhibition of
aldosterone receptors, and its main site of action is the blockade
of the sodium potassium pump in the distal renal tubule.1
The resulting increase in water and sodium excretion is largely
responsible for the diuretic and antihypertensive effects that
are beneficial in its approved indications. This inhibition also
results in retention of potassium.1 It also has direct inhibitory
effects on the cardiovascular system’s reactivity to the adrenergic
and the renin-angiotensin-aldosterone systems.4
In addition, spironolactone produces anti-androgenic effects
by targeting a variety of other mechanisms. Spironolactone
has been shown to competitively inhibit binding of
