Spironolactone Digoxin

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... 

Drugs in Class II have low aqueous solubility (but high membrane permeability), and any factor affecting dissolution rate would be expected to have an impact on the absorption of such compounds. Factors that are noted in Fig. 11, such as fluid pH, volume and viscosity, and bile secretion (especially in response to fatty foods), might be expected to play a role in dissolution rate and thereby affect absorption. Compounds that fall into this class include carbamazepine, cyclosporin, digoxin, griseofulvin, and spironolactone. Food would be expected to exert a potentially significant affect on... 

Estrogens, antiandrogens (e.g., luteinizing hormone-releasing hormone superagonists, digoxin, spironolactone, keto-conazole, cimetidine)... 

Drugs that may affect spironolactone include ACE inhibitors, salicylates, and food. Drugs that may be affected by spironolactone include anticoagulants, digitalis glycosides, mitotane, digoxin, and potassium preparations. 

Hydrochlorothiazide A Spironolactone Aldactazide) [Antihypertensive/Thiazide K Sparing Diuretic] Uses Edema, HTN Action Thiazide K -sparing diuretic Dose 25-200 mg each component/d, doses Caution [D, +] Contra Sulfonamide aUa-gy Disp Tabs (HCTZ/spironolactone) 25 mg/25 mg, 50 mg/50 mg SE Photosens, X BP, t or -1-K% -1- Na% hypoglycemia, hyperlipidemia, hyperuricemia Additional Interactions t Risk of hypokalemia W/ ACEIs, K-sparing diuretics, K supls, salt substitutes -1- effects OF digoxin EMS See Hydrochlorothiazide Amiloride OD See Hydrochlorothiazide Amiloride... 

Cardiovascular Acetyldigosin, ajmaline, amiodarone, aprindine, bepridil, bezaflbrate, captopril, dinepazide, clopidogrel, coumarins, diazoxide, digoxin, dipyridamole, disopyramide, doxazosin, enalapril, flurbiprofen, fur-oxemide, hydralazine, lisinopril methyldopa, metolazone, nifedipine, phenindione, procainamide, propanolol, propafenone, quinidine, ramapril, spironolactone, thiazide diuretics, ticlopidine, vesnarinone... 

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. 

Florence, A.T. and Salole, E.G. (1976). Changes in crystallinity and solubility on comminution of digoxin and observations on spironolactone and estradLdpharm. Pharmacol., 28 637-642. 

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. 

Spironolactone may increase the half-life of digoxin, so dosage reduction or increased dosing intervals of digoxin may be necessary, and careful monitoring is recommended. 

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... 

Enalapril, paracetamol, sotalol, dipyrone, vancomycin, captopril, fluconazole, cefazolin, metoprolol, aspirin, ticlopidine, prednisolone, propranolol, digoxin, sildenafil, furosemide, dexamethasone, carvedilol, ketoprofen, nifedipine, terbinafine, acenocoumarol, spironolactone/urine HPLC DAD Column LiChroCART Purospher STAR, RP-18e (250 x 4 mm, 5 pm) Mobile phase MeOH ACN 0.05 % TFA in water (gradient elution) Detection DAD X = 200 50 nm Adjusted to pH 7.0, protein precipitation LOD 0.01-1.44 pg/mL LOQ 0.04-4.35 pg/mL [72]... 

Spironolactone, in low dose, adds further benefit. Digoxin impF oves myocardial contractility most effectively in the dilated, failing heart but also in the longer term, including in patients in sinus rhythm. 

Spironolactone inhibits the active tubular secretion of digoxin by about 25% and in some cases digoxin dosages may have to be reduced (295). 

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

Waldorff S, Andersen JD, HeeboU-Nielsen N, Nielsen OG, Moltke E, Sorensen U, Steiness E. Spironolactone-induced changes in digoxin kinetics. Clin Pharmacol Ther 1978 24(2) 162-7. 

Huffman DH. The effect of spironolactone and canrenone on the digoxin radioinununoassay. Res Commun Chem Pathol Pharmacol 1974 9(4) 787-90. 

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. 

Steimer W, Muller C, Eber B. Digoxin assays frequent, substantial, and potentially dangerous interference by spironolactone, camenone, and other steroids. Clin Chem 2002 48(3) 507-16. 

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. 

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