Spironolactone adverse effects

Potassium-sparing by diuretic agents, particularly spironolactone, enhances the effectiveness of other diuretics because the secondary hyperaldosteronism is blocked. This class of diuretics decreases magnesium excretion, eg, amiloride can decrease renal excretion of potassium up to 80%. The most important and dangerous adverse effect of all potassium-sparing diuretics is hyperkalemia, which can be potentially fatal the incidence is about 0.5% (50). Therefore, blood potassium concentrations should be monitored carehiUy. 

To reduce mortality, administration of an aldosterone antagonist, either eplerenone or spironolactone, should be considered within the first 2 weeks following MI in all patients who are already receiving an ACE inhibitor (or ARB) and have an EF of equal to or less than 40% and either heart failure symptoms or diagnosis of diabetes mellitus.3 Aldosterone plays an important role in heart failure and in MI because it promotes vascular and myocardial fibrosis, endothelial dysfunction, hypertension, left ventricular hypertrophy, sodium retention, potassium and magnesium loss, and arrhythmias. Aldosterone antagonists have been shown in experimental and human studies to attenuate these adverse effects.70 Spironolactone decreases all-cause mortality in patients with stable, severe heart failure.71... 

The diuretic effect of spironolactone develops fully only with continuous administration for several days. Two possible explanations are (1) the conversion of spironolactone into and accumulation of the more slowly eliminated metabolite canrenone (2) an inhibition of aldosterone-stimulated protein synthesis would become noticeable only if existing proteins had become nonfunctional and needed to be replaced by de novo synthesis. A particular adverse effect results from interference with gonadal hormones, as evidenced by the development of gynecomastia (enlargement of male breast). Clinical uses include conditions of increased aldosterone secretion, e.g., liver cirrhosis with ascites. 

Primary advantage of eplerenone over spironolactone is a potentially decreased incidence of endocrine-related adverse effects, such as gynecomastia or sexual dysfunction... 

Eplerenone is a spironolactone analog with much greater selectivity for the mineralocorticoid receptor. It is several hundred-fold less active on androgen and progesterone receptors than spironolactone, and therefore eplerenone has considerably fewer adverse effects. 

Spironolactone as a diuretic is discussed in Chapter 15. The drug has benefits in heart failure greater than those predicted from its diuretic effects alone (see Chapter 13). Adverse effects reported for spironolactone include hyperkalemia, cardiac arrhythmia, menstrual abnormalities, gynecomastia, sedation, headache, gastrointestinal disturbances, and skin rashes. 

In 110 patients with cirrhosis, ascites, and hyponatremia in a multicenter, double-blind, randomized, placebo-con-trolled study of three fixed doses of satavaptan (5,12.5, or 25 mg/day) for 14 days plus spironolactone 100 mg/day, satavaptan was associated with improved control of ascites. Thirst was the main adverse effect (4). 

Adverse effects Renal function may deteriorate with the decreased circulating fluid volume, especially after the addition of another diuretic drug acting on the RAAS system, and careful monitoring of serum creatinine is essential. Serum potassium should be monitored within one week of initiation and at least every four weeks for the first three months and every three months thereafter. It should also be monitored at any dose change in spironolactone or if there is a change in concomitant medications that affects the potassium balance. The spironolactone dose (standard 25 mg per day) should be reduced if potassium levels are <5.4 mEq/L, and treatment should be discontinued if painful gynecomastia or serious renal dysfunction or hyperkalemia result. 

The only frequent adverse effects were gynecomastia, breast pain, or both in 10% of men. The rate of discontinuation because of these events was 2%. The risk of gynecomastia should not be an argument against the use of spironolactone in men with severe heart failure, since it reduces both morbidity and death. 

Epierenone is a potassium-sparing diuretic. It is similar to spironolactone as an aldosterone antagonist, but has less affinity for androgen and progesterone receptors and may therefore have fewer adverse effects (1). 

The main adverse effects of oral potassium salts are hyperkalemia, particularly when they are used in combination with potassium-sparing drugs, such as spironolactone and ACE inhibitors, and gastrointestinal ulceration and perforation, particularly with modified-release formulations. The problems surrounding enteric-coated potassium chloride tablets are unresolved. Despite recommendations that they be withdrawn, some are still available. The risks seem to be less with slow-release potassium chloride tablets. 

Spironolactone is a competitive antagonist at aldosterone receptors. It acts through its active metabohte, canrenone. Canrenone itself has also been used as a potassium-sparing diuretic for intravenous use and its potassium salt has been used orally, in the hope of avoiding the hormonal adverse effects of spironolactone. 

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). 

The major limitation to the use of spironolactone is its liability to cause (sometimes lethal) hyperkalemia, particularly in the elderly, in patients with reduced renal function, and in patients who simultaneously take potassium supplements or ACE inhibitors. As with other diuretics, hyponatremia and dehydration can occur. Other less frequent adverse effects are gastrointestinal intolerance, neurological symptoms, and skin rashes. Hypersensitivity rashes and a lupus-Uke syndrome have been reported rarely. A few cases of mammary carcinoma have been reported and potential human metabolic products of spironolactone are carcinogenic in rodents. Second-generation effects have not been reported. 

Central nervous system effects, such as weakness, drowsiness, and confusion, have been reported in patients taking spironolactone. Because most patients with such adverse effects were taking spironolactone for edema and ascites in hepatic cirrhosis, it is not yet clear whether they were caused by the drug itself or by hepatic encephalopathy. The incidence of these complaints in such patients is quite high (9.8%) (SED-9, 357). 

Other reported adverse effects of spironolactone include urticaria, alopecia, and chloasma (SEDA-14,185). 

The risks and benefits of distal tubular diuretics have been assessed in preterm infants under 3 weeks of age with or developing chronic lung disease (36). Acute and chronic administration of distal diuretics improved pulmonary mechanics adverse effects were not reported. However, additional studies are needed to assess whether thiazide administration improves mortality, duration of oxygen dependency, ventilator dependency, length of hospital stay, and long-term outcome in patients exposed to corticosteroids and bronchodilators, and whether adding spironolactone to thiazides or adding metolazone to furosemide has any beneficial effect. 

Spironolactone, amiloride, and triamterene are K+-sparing, weak diuretic that act at the collecting tubule and duct level. The mechanisms leading to their diuretic actions (Figure 111-6-5) and their clinical uses and adverse effects are discussed. 

Antiandrogenic and progestational symptoms such as gynecomastia, impotence and menstrual irregularities related to the clinical use of spironolactone were observed already at a very early stage [7], and recognized since 1975 as characteristic adverse effects due to the unspecific interactions of spironolactone with the AR and PR [8]. 

The sample of patients selected for a clinical trial may not be representative of the entire population of patients with that disease. Patients entered into a trial usually are selected according to the severity of their disease and other characteristics inclusion criteria) or are excluded because of coexisting disease, concurrent therapy, or specific features of the disease itself (exclusion criteria). It always is important to ascertain that the clinical characteristics of an individual patient correspond with those of patients in the trial. For example, the Randomized Aldactone Evaluation Study (RALES) showed that treatment with the mineralocorticoid-receptor antagonist spironolactone was associated with a 30% reduction in death in patients with severe congestive heart failure. Hyperkalemia, a potential adverse effect, was seen only rarely in this study, which excluded patients with serum creatinine levels >2.5 mg/dL. With the expanded use of spironolactone after RALES was published, numerous patients, many of whom did not meet the RALES inclusion criteria, developed severe hyperkalemia. Therefore, knowledge of the criteria for selecting the patients in a trial must inform the application of study results to a given patient. 

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