Dose and Administration

1. 1-3 mg/kg/dose daily PO.

Indications

1. Used in combination with other diuretics in the treatment of congestive heart failure and BPD (situations of increased aldosterone secretion).

Contraindications and Precautions

1. Known hypersensitivity to spironolactone
2. Significant impairment of renal function, especially anuria
3. Caution in neonates with severe liver dysfunction
4. Hyperkalaemia
5. Caution in neonates receiving potassium supplements
6. Should not be used concurrently with other potassium sparing agents.

Clinical Pharmacology

Spironolactone is a specific pharmacological antagonist of aldosterone. Acts primarily through competitive binding of receptors at the aldosterone dependent sodium-potassium exchange site in the distal convoluted renal tubule. Causes increased urinary excretion of sodium and water while potassium is retained. Also has an effect on tubular transported calcium, resulting in increased urinary calcium excretion. Spironolactone has moderate anti-androgenic activity in humans.

Well absorbed from the gastrointestinal tract (bioavailability >90%). Very high protein binding (98%) to human plasma protein. Rapidly and completely metabolised to a large number of metabolites. The major active metabolite is canrenone which has a slow clearance. The activity of canrenone is 10-33 % that of spironolactone. Elimination of canrenone and other metabolites is primarily in the urine (50%) but they also appear in bile (5-33%).

The onset of action of spironolactone is usually observed 2-3 days after commencement of therapy. The effects of aldosterone involve the synthesis of protein or peptide subsequent to its combination with its receptor. The activity of the protein or peptide persist for 2-3 days. With long-term use of spironolactone the elimination half-life is 13-24 hours. The duration of effect persists for 2-3 days following discontinuation of therapy.

Possible Adverse Effects

1. Gastrointestinal disturbances (nausea, vomiting, diarrhoea).
2. Lethargy, irritability.
3. Paraesthesia, weakness, flaccid paralysis and tetany.
4. Rashes
5. Dose dependent androgenic effects (females), gynaecomastia (males).

Special Considerations

1. Monitor urea and electrolytes frequently. Anticipate hyperkalaemia, hypocalaemia, hyponatraemia, transient elevation of urea.
2. Reversible hyperchloraemic metabolic acidosis, usually in association with hyperkalaemia, has been reported in patients with severe liver dysfunction, even in the presence of normal renal function.
3. Spironolactone has been shown to increase the elimination half-life of digoxin. May result in increased serum digoxin levels and subsequent digoxin toxicity.
4. Several reports of possible interference with digoxin radioimmunoassays by spironolactone, or its metabolites, have appeared in the literature. Neither the extent nor the potential clinical significance of its interference has been fully established.