Hyles Mechanism of Action

Pharmacodynamics: Mechanism of Action: 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. Spironolactone causes increased amounts of sodium and water to be excreted, while potassium is retained. Spironolactone 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, spironolactone provides effective therapy for the edema and ascites in those conditions. Spironolactone counteracts secondary aldosteronism induced by the volume depletion and associated sodium loss caused by active diuretic therapy.
Spironolactone 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, spironolactone inhibits the exchange of sodium for potassium in the distal renal tubule and helps to prevent potassium loss.
Pharmacokinetics: Absorption: Absorption of spironolactone from the GI tract depends on the formulation in which it is administered. Currently available formulations of spironolactone are well absorbed from the GI tract and bioavailability of the drug exceeds 90% when compared to an optimally absorbed spironolactone solution in polyethylene glycol 400. Following a single oral dose of spironolactone, peak serum concentrations of the drug occur within 1-2 hours, and peak serum concentrations of its principal metabolites are attained within 2-4 hours. When spironolactone is administered concomitantly with food, peak serum concentrations and areas under the serum concentration-time curves (AUCs) of the drug and, to a lesser degree, its principal metabolites are increased substantially compared with the fasting state; however, the clinical importance of these findings is not known.
When administered alone, spironolactone has a gradual onset of diuretic action with the maximum effect being reached on the third day of therapy. The delay in onset may result from the time required for adequate concentrations of the drug or metabolites to accumulate. It has been suggested that a loading dose 2-3 times the usual daily dose be administered on the first day of therapy to overcome the delay in onset of action. After withdrawal of spironolactone, diuresis persists for 2 or 3 days. When a thiazide diuretic is used concomitantly with spironolactone, diuresis usually occurs on the first day of therapy.
Distribution: Spironolactone and canrenone, a major metabolite of the drug, are both more than 90% bound to plasma proteins. Spironolactone or its metabolites may cross the placenta. Canrenone is distributed into milk.
Metabolism: 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.
Spironolactone undergoes deacetylation at its sulfur group to form 7α-thiospironolactone (7α- thiospirolactone), which then undergoes further metabolism. 7α-thiospironolactone is dethiolated to form canrenone and subsequently other non-sulfur-containing metabolites. 7α-Thiospironolactone also undergoes thiomethylation to form 7α-thiomethylspironolactone (7α-thiomethylspirolactone), which undergoes 6β-hydroxylation and subsequent metabolism to other sulfur-containing metabolites. Canrenone, 7α-thiospironolactone, and 7α-thiomethylspironolactone are pharmacologically active but substantially less so than the parent drug.
Excretion: Spironolactone metabolites are excreted principally in urine, but also in feces via biliary elimination.
Following a single oral dose in healthy adults, the half-life of spironolactone averaged 1.3-2 hours, and the half-life of 7α-thiomethylspironolactone average 2.8 hours. The half-life of canrenone reportedly ranges from 13-24 hours. In multiple-dose studies, the steady-state plasma elimination half-life of canrenone averaged 19.2 hours when 200 mg of spironolactone was administered daily as a single dose and averaged 12.5 hours when 200 mg of the drug was administered daily in 4 equally divided doses.