Hazard
Questionable carcinogen.
Chemical Properties
White to Off White Solid
Originator
Aldactone,Searle,US,1959
Definition
ChEBI: A steroid lactone that is 17alpha-pregn-4-ene-21,17-carbolactone substituted by an oxo group at position 3 and an alpha-acetylsulfanyl group at position 7.
Manufacturing Process
A mixture of approximately 11 parts of 17α-(2-carboxyethyl)-17β-
hydroxyandrosta-4,6-dien-3-one lactone and 10 parts of thioacetic acid is
heated at 85° to 95°C for ? hour. Excess thioacetic acid is removed by
vacuum distillation at this point, and the residue is twice recrystallized from
methanol, affording 7α-acetylthio-17α-(2-carboxyethyl)-17β-hydroxyandrost-
4-en-3-one lactone, melting at approximately 134° to 135°C. Heated above
this melting point, the product solidifies and melts again at approximately
201° to 202°C (with decomposition).
Brand name
Aldactone (Searle);Airolactone;Aldactide 25;Aldactone-a;Aldazida;Aldonorm;Aldospirone;Alpamed;Altexide;Aporasnon;Carditan;Crk 635;Ct-spiro;Digi-aldopur;Dilakton;Hexalacton;Hokulaton;Hokuraton;Hydrospiron;Idrolattone;Lacilactone;Laralmin;Lasitone;Loractone;Mf 218d;Noidouble;Novospiroton;Novospirozine;Novosprioton;Novospriozine;Penantin;Pirolacton;Pirolcaton;Plarenil;Practon 50;Raudazida;Risicordin;Rolactone microfine;Sali-spiroctan;Sas 1060;Servilactone;Spiractin;Spiridazide;Spirix;Spiro comp;Spiro50-d;Spirodigital;Spiro-f;Spironomocompren;Spironone;Spironothiazide;Spiropal;Spirostada;Spirotone;Suprapuren;Synureticum;Tensoflex;Urosonine;Xenalone;Xeualon.
Therapeutic Function
Diuretic
World Health Organization (WHO)
Spironolactone, an aldosterone antagonist, has been widely used
for over 25 years in the treatment of hypertension and in the management of
refractive oedema. Evidence that long-term administration of high doses are
tumorigenic in the rat has recently led to restriction of its use by some national
regulatory authorities although the significance of this finding with respect to
clinical use is not certain. In 1987 spironolactone was transferred from the main list
to the complementary list of the WHO Model List of Essential Drugs. (See also WHO comments for canrenone and potassium canrenoate).
(Reference: (WHODI) WHO Drug Information, 2(1), , 1988)
Biological Functions
Spironolactone (Aldactone) is structurally related to
aldosterone and acts as a competitive inhibitor to prevent
the binding of aldosterone to its specific cellular binding
protein. Spironolactone thus blocks the hormone-induced
stimulation of protein synthesis necessary for Na+ reabsorption
and K+ secretion. Spironolactone, in the presence
of circulating aldosterone, promotes a modest increase in
Na+ excretion associated with a decrease in K+ elimination.
The observations that spironolactone is ineffective in
adrenalectomized patients and that the actions of
spironolactone can be reversed by raising circulating al-dosterone blood levels (surmountable antagonism) support
the conclusion that spironolactone acts by competitive
inhibition of the binding of aldosterone with receptor
sites in the target tissue. Spironolactone acts only when
mineralocorticoids are present.
General Description
Spironolactone, 7α-(acetylthio)-17α-hydroxy-3-oxopregn-4-ene-3-one-21-carboxylic acidγ-lactone (Aldactone) is an aldosterone antagonist of greatmedical importance because of its diuretic activity.
Biological Activity
Competitive mineralocorticoid (aldosterone) receptor antagonist that exhibits antihypertensive activity in vivo . Also displays antiandrogen activity and inhibits steroid hormone biosynthesis.
Biochem/physiol Actions
Spironolactone is a competitive aldosterone receptor antagonist. Used as potassium sparing diuretic.
Mechanism of action
Spironolactone is a potassium sparing diuretic that has a different mechanism of action
than other drugs of this class.
It is a competitive antagonist of aldosterone, and its action is most effective when the
level of circulated aldosterone in the organism is high.
Pharmacology
Spironolactone (Aldactone) is the only diuretic that has
been shown in a double-blind multicenter prospective
clinical trial to improve survival in CHF. The addition
of spironolactone to digitalis and an angiotensinconverting
enzyme (ACE) inhibitor significantly improved
survival among patients with chronic severe
heart failure.
Spironolactone competitively inhibits the binding of
aldosterone to cytosolic mineralocorticoid receptors in
the epithelial cells in the late distal tubule and collecting duct of the kidney. Aldosterone enhances salt and
water retention at the expense of enhanced renal K
and H excretion. Spironolactone enhances diuresis by
blocking sodium and water retention while retaining
potassium. An obvious potential side effect is hyperkalemia,
which is aggravated by the potassium-retaining
properties of the ACE inhibitors. The likely concomitant
use of the loop diuretic furosemide, which depletes
K , dictates careful monitoring of serum potassium to
avoid life-threatening rhythm disturbances.
There is also evidence for the existence of mineralocorticoid
receptors on cardiac myocytes. This raises the
intriguing possibility that spironolactone could mediate
important direct effects on the myocardium in CHF.
Clinical Use
Spironolactone has been used clinically in the following
conditions:
1. Primary hyperaldosteronism. Used as an aid in
preparing patients with adrenal cortical tumors
for surgery.
2. Hypokalemia. Used in patients with low serum K+
resulting from diuretic therapy with other agents.
Its use should be restricted to patients who are unable
to supplement their dietary K+ intake or adequately
restrict their salt intake or who cannot
tolerate orally available KCl preparations.
3. Hypertension and congestive heart failure.
Although spironolactone may be useful in combination
with thiazides, the latter remain the
drugs of first choice. Fixed-dose combinations of
spironolactone and a particular thiazide (e.g.,
Aldactazide) generally offer no therapeutic advantage
over either component given separately
and tend to restrict the ability of the clinician to
determine the optimal dosage of each drug for a
particular patient.
4. Cirrhosis and nephrotic syndrome. Spironolactone
is a mild diuretic and may be useful in treating the
edema that occurs in these two clinical conditions,
that is, when excessive K+ loss is to be avoided.
Side effects
Serum electrolyte balance should be monitored periodically,
since potentially fatal hyperkalemia may occur,especially in patients with impaired renal function or excessive
K+ intake (including the K+ salts of coadministered
drugs, e.g., potassium penicillin). Spironolactone
can induce hyponatremia and in cirrhotic patients, metabolic
acidosis.A variety of gastrointestinal disturbances
may accompany spironolactone administration. These
include diarrhea, gastritis, gastric bleeding, and peptic ulcers.
Spironolactone is contraindicated in patients with
peptic ulcers. Spironolactone may also cause elevated
blood urea nitrogen, drowsiness, lethargy, ataxia, confusion,
and headache. Gynecomastia and menstrual irregularity
in males and females, respectively, can occur.
Painful gynecomastia (directly related to dosage level
and duration of therapy), which is generally reversible,
may necessitate termination of therapy. Animal studies
demonstrating tumorigenic potential support the clinical
judgment that spironolactone alone or in combination
should not be used for most patients who require diuretic
therapy and its unnecessary use should be
avoided.
Synthesis
Spironolactone is the 7-acetate of the |?-lactone of 17-hydroxy-7-mercapto-
3-oxo-17-|á-pregn-4-ene-21-carboxylic acid (21.5.8). Spironolactone is synthesized industrially
in two different ways from androstenolone?a3|?-hydroxy-5-androsten-17-one.
According to the first method, androstenolone undergoes ethynylation by acetylene in a
Normant reaction condition using sodium amide in liquid ammonia, which forms 17
|á-ethynyl-3|?-,17|?-dihydroxy-5-androstene (21.5.1). Subsequent reaction of this with
methylmagnesiumbromide and then with carbon dioxide gives the corresponding propenal
acid (21.5.2). Reduction of the triple bond in this product with hydrogen using a palladium
on calcium carbonate catalyst forms the corresponding acrylic acid derivative (21.5.3), which
is treated with acid without being isolated, which leads to cyclization into an unsaturated lactone
derivative (21.5.4). The double bond is reduced by hydrogen, in this case using a palladium
on carbon catalyst. The resulting lactone 21.5.5 undergoes oxidation in an Oppenauer
reaction, giving an unsaturated keto-derivative?a4-androsten-3,17-dione (21.5.6). Further
oxidation of the product (21.5.6) using chloroanyl gives dienone (21.5.7), which when
reacted with thioacetic acid gives the desired spionolactone (21.5.8).
Veterinary Drugs and Treatments
Spironolactone may be used in patients with congestive heart failure
who do not adequately respond to furosemide and ACE inhibitors,
who develop hypokalemia on other diuretics, and are unwilling or
unable to supplement with exogenous potassium sources. It may
also be effective in treating ascites as it has less potential to increase
ammonia levels than other diuretics.
Drug interactions
Potentially hazardous interactions with other drugs
ACE inhibitors or angiotensin-II antagonists:
enhanced hypotensive effect; risk of severe
hyperkalaemia.
Antibacterials: avoid with lymecycline.
Antidepressants: increased risk of postural
hypotension with tricyclics.
Antihypertensives: enhanced hypotensive effect;
increased risk of first dose hypotensive effect with
post-synaptic alpha-blockers.
Cardiac glycosides: increased digoxin concentration.
Ciclosporin: increased risk of hyperkalaemia.
Cytotoxics: avoid with mitotane; increased risk
of nephrotoxicity and ototoxicity with platinum
compounds.
Lithium: reduced lithium excretion.
NSAIDs: increased risk of hyperkalaemia (especially
with indometacin); increased risk of nephrotoxicity;
diuretic effect of spironolactone antagonised by
aspirin.
Potassium salts: increased risk of hyperkalaemia.
Tacrolimus: increased risk of hyperkalaemia.
Metabolism
Spironolactone is poorly absorbed after oral administration
and has a delayed onset of action; it may take several
days until a peak effect is produced. It has a somewhat
slower onset of action than triamterene and
amiloride (discussed later), but its natriuretic effect is
modestly more pronounced, especially during long-term
therapy. Spironolactone is rapidly and extensively metabolized,
largely to the active metabolite canrenone.
Canrenone and potassium canrenoate, its K+ salt, are
available for clinical use in some countries outside the
United States. Canrenone has a half-life of approximately
10 to 35 hours.The metabolites of spironolactone are excreted
in both the urine and feces. New selective aldosterone
receptor antagonists (SARA), such as eplerenone,
have been developed but have not yet been introduced
into clinical practice. Eplerenone and canrenone exhibit
fewer steroidlike side effects (gynecomastia, hirsutism).
Structure and conformation
Synthetic steroid that resembles aldosterone.
