Spironolactone toxicity

Spironolactone has been shown to be a tumorigen in chronic toxicity studies in rats. 

Quinidine inhibits the tubular secretion of digoxin which consequently raises the plasma digoxin concentration, which may be associated with toxicity. Certain other drugs also increase the digoxin concentration like verapamil, amiodarone, spironolactone etc. 

Spironolactone Block cytoplasmic aldosterone receptors in collecting tubules of nephron possible membrane effect Increased salt and water excretion reduces remodeling reduces mortality Chronic heart failure aldosteronism (cirrhosis, adrenal tumor) hypertension Oral duration 24-72 h (slow onset and offset) Toxicity Hyperkalemia, antiandrogen actions... 

Eplerenone, another aldosterone antagonist, is approved for the treatment of hypertension (see Chapters 11 and 15). This aldosterone receptor antagonist is somewhat more selective than spironolactone and has no reported effects on androgen receptors. The standard dosage in hypertension is 50-100 mg/d. The most common toxicity is hyperkalemia but this is usually mild. 

Concurrent use of lithium with spironolactone is not recommended, as the drug may provoke lithium toxicity by reducing renal clearance [84]. 

DIGITOXIN DIURETICS -SPIRONOLACTONE Conflicting results from volunteer studies some showed t (up to one-third) in the half-life of digitoxin, others a 1 (up to one-fifth) Uncertain at present Watch for either digitoxin toxicity or a poor response, particularly for the first month after starting spironolactone... 

DIGOXIN POTASSIUM-SPARING DIURETICS AND ALDOSTERONE ANTAGONISTS Eplerenone and spironolactone may T plasma concentrations of digoxin Uncertain spironolactone possibly L the volume of distribution of digoxin Monitor digoxin levels watch for digoxin toxicity... 

Selective distal tubular epithelial toxicity by amphotericin can cause hypokalemia, and hypokalemia can cause further tubular damage. There is some evidence that hypokalemia due to amphotericin is mitigated by both spironolactone (83) and amiloride (84). 

Digoxin 0.125 mg q.o.dy q.d. (daily or every other day) 0.25 mg/day 25% 100% 100% 100% In ESRD and total body clearance decreased decrease loading dose by 50% serum level 12 hr after dose is best guide to clearance use digoxin-immune antibodies to treat severe toxicity Radioimmunoassay may overestimate serum levels in uremia clearance decreased by amiodarone, spironolactone, quinidine, and verapamil hypokalemia and hvDomaanesemia enhance toxicitv NC NC Dose for GFR 10-50 ml/min... 

Most of the renal tubular reabsorption ofU occurs in the proximal tubule. Nevertheless, Id retention can be increased by any diuretic that leads to depletion of Na, particularly the thiazides (see Chapter 28). Renal excretion can be increased by administration of osmotic diuretics, aceta-zolamide or aminophylline, and triamterene. Spironolactone does not increase the excretion of LiL Some nonsteroidal anti-inflammatory agents can facilitate renal proximal tubular resorption of Id and thereby increase concentrations in plasma to toxic levels. This interaction appears to be particularly prominent with indomethacin, but also may occur with ibuprofen, naproxen, and COX-2 inhibitors, and possibly less so with sulindac and aspirin. A potential drug interaction can occur with angiotensin-converting enzyme inhibitors, causing lithium retention (see Chapter 29). 

Interactions between Li and diuretics (especially spironolactone and amiloride) and nonsteroidal anti-inflammatory agents have been discussed above (see Absorption, Distribution, and Excretion and Toxic Reactions and Side Effects). Relative to thiazides and other diuretics that deplete Naf... 

The primary concern with the use of spironolactone is the development of hyperkalemia, which can be fatal. Spironolactone may cause hypersensitivity reactions, gastrointestinal disturbances, peptic ulcer, gynecomastia, decreased libido, and impotence. It also has been implicated in tumor production during chronic toxicity studies in rats, but human risk has not been documented. 

A. The toxicity of these drugs is associated with their pharmacologic effects, which decrease fluid volume and promote electrolyte loss, including dehydration, hypokalemia (or hyperkalemia, with spironolactone), hypomagnesemia, hyponatremia, and hypochloremic alkalosis. Electrolyte imbalance may lead to cardiac arrhythmias and may enhance digitalis toxicity (see p 155). Diuret-... 

A report describes a 74-year-old woman with increased lithium levels of 2.3 mmol/L and symptoms of lithium toxicity, which were associated with several drugs including irbesartan, lisinopril, escitalopram, levomepro-mazine, furosemide and spironolactone. It was suggested that these drugs could have delayed lithium excretion or worsened neurotoxic effects. An increase in the lisinopril dose and the addition of irbesartan several weeks before admission may have contributed to the lithium toxicity. ... 

Lithium toxicity developed in a patient taking lithium after she was given chlorothiazide, spironolactone and amiloride. The lithium levels rose iiom 0.6 to 2.2 mmol/L. 

In addition to these studies at least 6 cases of lithium toxicity have been seen when hydrochlorothiazide was given to patients taking lithium. Hydrochlorothiazide was either given with amiloride, " spironolactone or triamterene. See also Lithium + Diuretics Potassium-sparing , p.ll22. 

Wei L, Struthers AD, Fahey T, Watson AD, Macdonald TM. Spironolactone use and renal toxicity population based longitudinal analysis. BMJ 2010 340 cl768. 

VIII. CAROENOLIDES, BUFADIENOLIDES Basic esters derived from cardenolides (cf. 46) possess inotropic activities in the anaesthetized dog, but are less toxic than the corresponding cardenolides. Spironolactone (41) was found to protect rats against otherwise fatal digitoxln poisoning. 

---