Digoxin with spironolactone

MEIA Falsely lowered semm digoxin concentrations during therapy with spironolactone, canrenone. 

Patients with CHF and a normal ejection fraction are considered to have diastolic dysfunction. The frequency of CHF with diastolic dysfunction increases with age. Such patients benefit from treatment of the underlying cause such as hypertension or ischaemia. Inotropic agents such as digoxin should be avoided. Diuretics, -blockers, ACE inhibitors can be used. Aldosterone inhibition, using spironolactone or epleronone, may be beneficial. Carvedilol improves diastolic dysfunction in diastolic CHF. However the long-term benefit of different drug therapies has not yet been defined. 

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 [NE] Decreased renal digoxin excretion and interfers with some serum digoxin assays. 

Potassium-sparing diuretics (amiloride, spironolactone, triamterene) Additive effects with other agents increasing serum potassium concentration. May alter renal excretion of substances other than potassium (eg, digoxin, hydrogen ions). ACE inhibitors [NE] Additive hyperkalemic effect. 

At Cynthia s pharmacy, patients with heart disease are usually on several medications for their heart disease a diuretic, a beta blocker, and an angiotensin-converting enzyme (ACE) inhibitor. Patients with more severe disease may also be on an aldosterone inhibitor such as spironolactone, digoxin, hydralazine nitrate, and/or an angiotensin-receptor blocker (ARB). Some patients are... 

Spironolactone interferes with some digoxin radioimmunoassays, because it and its metabolites, such as canrenone and 7-alpha-thiomethylspironolactone, are... 

Pleasants RA, Williams DM, Porter RS, Gadsden RH Sr. Reassessment of cross-reactivity of spironolactone metabolites with four digoxin immunoassays. Ther Drug Monit 1989 ll(2) 200-4. 

In the Randomized Aldactone Evaluation Study (RALES) in 1663 patients with New York Heart Association (NYHA) class III (70%) or IV (30%) symptoms and an ejection fraction less than 35%, the addition of spironolactone 25 mg/day to conventional treatment (an ACE inhibitor, a loop diuretic, in most cases digoxin, and in 11% a beta-blocker) for an average of 24 months lowered the risk of all-cause mortality by 30% (from 46% to 35%), death from progressive heart failure, and sudden death (28). There were similar reductions in hospital admissions for worsening heart failure and for all cardiac causes. The magnitude of the overall effect was similar and additional to the proven benefit from ACE inhibition in severe heart failure. 

A 50-year-old man with heart failure and a valve prosthesis, taking digoxin, furosemide, and spironolactone, was given enalapril 5 mg/day. Two days later, after increasing the dose to 10 mg, he developed a fever with cough and clear sputum, with a normal chest X-ray. Enalapril was withdrawn and 24 hours later the fever resolved. It recurred immediately after rechallenge. 

A 69-year-old man with hypertension and heart failure took losartan 25 mg/day, increasing to 50 mg/day after 2 weeks. He also took spironolactone 50 mg/day, furo-semide 40 mg/day, digoxin 0.25 mg/day, acenocou-marol, and allopurinol. Two weeks later he developed acute renal insufficiency with a plasma creatinine concentration of 725 pmol/l (previously 115 pmol/l). Within 24 hours after losartan withdrawal (it was not stated whether spironolactone was also stopped) and hemodialysis, he recovered renal function (plasma creatinine 124 mg/1). He was later found to have bilateral renal artery stenosis, which is a contraindication to angiotensin II receptor antagonists. 

Although spironolactone has been available for more than 30 years, its efficacy and safety in patients with heart failure have only recently been recognized in the Randomized Aldosterone Evaluation Study (RALES), in which it reduced mortahty (1). Based on this and numerous smaller trials, the use of spironolactone, in conjunction with ACE inhibitors, other diuretics, and possibly beta-blockers or digoxin, represents a promising strategy for patients with severe heart failure. Its main adverse effects are hyperkalemia and antiadrenergic complications (SED-14, 675). 

Spironolactone increases steady-state digoxin concentrations by about 30%, probably by inhibiting the renal tubular secretion of digoxin by P glycoprotein. There may also be a pharmacodynamic interaction with digoxin. The clinical importance of these observations is uncertain (SEDA-9, 209). 

Spironolactone can alter the results of some digoxin radioimmunoassays, because it and its metabohtes, such as canrenone and 7-alpha-thiomethylspironolactone, are immunoreactive with some forms of antidigoxin antibody (29-31). This results in an overestimate of the true digoxin concentration, because the assay reads the interfering substances as digoxin. 

Clinically important, potentially hazardous interactions with amiloride, aminoglycosides, amphotericin B, ampicillin, anisindione, anticoagulants, armodafinil, atorvastatin, azathioprine, azithromycin, bacampicillin, basiliximab, bezafibrate, bosentan, bupropion, carbenicillin, caspofungin, cholestyramine, clarithromycin, cloxacillin, co-trimoxazole, corticosteroids, cyclophosphamide, daclizumab, danazol, dicloxacillin, dicumarol, digoxin, diltiazem, disulfiram, echinacea, erythromycin, ethotoin, etoposide, ezetimibe, flunisolide, fluoxymesterone, fluvastatin, foscarnet, fosphenytoin, gemfibrozil, hemophilus B vaccine, HMG-CoA reductase inhibitors, imatinib, imipenem/cilastatin, influenza vaccines, ketoconazole, lanreotide, lopinavir, lovastatin, mephenytoin, methicillin, methoxsalen, methylphenidate, methylprednisolone, methyltestosterone, mezlocillin, mizolastine, mycophenolate, nafcillin, nisoldipine, NSAIDs, orlistat, oxacillin, penicillins, phellodendron, phenytoin, pravastatin, prednisolone, prednisone, pristinamycin, ranolazine, red rice yeast, rifabutin, rifampin, rifapentine, ritonavir, rosuvastatin, simvastatin, sirolimus, spironolactone, St John s wort, sulfacetamide, sulfadiazine, sulfamethoxazole, sulfisoxazole, sulfonamides, tacrolimus, telithromycin, tenoxicam, testosterone, ticarcillin, tolvaptan, trabectedin, triamterene, troleandomycin, ursodeoxycholic acid, vaccines, vecuronium, warfarin, zofenopril... 

Recent trials have shown that, in mild/moderate and severe heart failure, the addition of a p-bliicker (bottom, left) further decreases mortality in patients taking ACE inhibitors and diuretics (with or without digoxin). In patients with severe heart failure and with symptoms uncontrolled wdih standard therapy, iltc addition of spironolactone (Chapter 14) has been shown to reduce (2-year) mortality from 46% to 35%. 

High dietary potassium has been linked to lower blood pressure, and dietary supplementation with moderate amounts of potassium has been found to lower blood pressure. Many drugs have effects in either raising or lowering potassium levels in the body. Levels are raised by digoxin, trimethoprim-sulfamethoxazole, ibuprofen, ACE inhibitors, angiotensin receptor blockers, spironolactone and heparin. Levels of potassium are lowered by diuretics, corticosteroids pseudoephedrine, some penicillins, carbenoxolone, caffeine and theophylline. 

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