ALDACTONE (Spironolactone Tablets, USP) Action And Clinical Pharmacology

Medical Information
Canada
 

In order to provide you with relevant and meaningful content we need to know more about you.

Please choose the category that best describes you.

This content is intended for Canadian Healthcare Professionals. Would you like to proceed?

Mechanism of Action: ALDACTONE (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. ALDACTONE causes increased amounts of sodium and water to be excreted, while potassium loss is minimized.

ALDACTONE 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.

Pharmacodynamics: 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 nephrotic syndrome. By competing with aldosterone for receptor sites, ALDACTONE provides effective therapy for the edema and ascites in those conditions. ALDACTONE counteracts secondary aldosteronism induced by the volume depletion and associated sodium loss caused by diuretic therapy.

ALDACTONE 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, ALDACTONE inhibits the exchange of sodium for potassium in the distal renal tubule and helps to prevent potassium loss.

ALDACTONE has not been demonstrated to elevate serum uric acid, to precipitate gout, or to alter carbohydrate metabolism.

Pharmacokinetics: Spironolactone is rapidly and extensively metabolized to a number of metabolites including canrenone and the sulfur-containing 7-thiomethylspirolactone, both of which are pharmacologically active. Approximately 25 to 30% of the dose administered is converted to canrenone, which attains peak serum levels 2‑4 hours after single oral administration of spironolactone. In the dose range of 25 mg to 200 mg, an approximately linear relationship exists between a single dose of spironolactone and plasma levels of canrenone.

Plasma concentrations of canrenone decline in two distinct phases, the first phase lasting from 3 to 12 hours, being more rapid than the second phase lasting from 12 to 96 hours. Canrenone clearance data, following multiple doses of spironolactone, indicate that accumulation of canrenone in the body with 100 mg once a day would be lower than with 25 mg four times a day. Both spironolactone and canrenone are more than 90‑percent bound to plasma proteins. The metabolites of spironolactone are excreted both in the urine (32‑53%), and through biliary excretion in the feces (14‑36%).

Table 3. Summary of ALDACTONE’s Pharmacokinetic Parameters in Healthy Volunteers Administered 100 mg daily for 15 days

Mean Cmax (ng/mL)

Mean Tmax (h)

Mean Post-Steady State

t½ (h)

Accumulation Factor:

AUC0-24 h, Day 15 / AUC0-24 h, Day 1

7-α-(thiomethyl) spirolactone (TMS)

391

3.2

13.8

1.25

6-Ǝ-hydroxy-7- Ɐ- (thiomethyl) spirolactone (HTMS)

125

5.1

15.0

1.50

Canrenone (C)

181

4.3

16.5

1.41

Spironolactone

80

2.6

~1.4 (t½Ǝ)

1.30

Special Populations

Hepatic Insufficiency

No pharmacokinetic studies have been performed with spironolactone in patients with hepatic insufficiency. Caution is advised in patients with hepatic impairment (see WARNINGS AND PRECAUTIONS – Hepatic/biliary/pancreatic section).

Renal Insufficiency

No pharmacokinetic studies have been performed with spironolactone in patients with renal insufficiency. Aldactone is contraindicated in patients with anuria, acute renal insufficiency or with severe impairment of renal function (GFR < 30 mL/Min/1.73 m2) (see CONTRAINDICATIONS).

Elderly

No pharmacokinetic studies have been performed with spironolactone in the elderly population. Caution is advised in patients with hepatic and/or renal impairment (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS – Hepatic/biliary/pancreatic section).

Pediatrics

No pharmacokinetic studies have been performed with spironolactone in the pediatric population. Therefore, safety and effectiveness in pediatric patients have not been established.