1 Aldosterone Inhibitors in Infants and Children

PEDIATRIC PHARMACOTHERAPY A Monthly Newsletter for Health Care Professionals from the Children’s Medical Center at the University of Virginia • celebrating 10 years of publication • Volume 10 Number 1 January 2004 Aldosterone Inhibitors in Infants and Children Marcia L. Buck, Pharm.D., FCCP pironolactone has been available in the and hydrogen ions. By inhibiting aldosterone S United States since the 1950s; but over the activity, spironola ctone reduces sodium past several decades, its use ha s been supplanted reabsorption, producing diuresis. It is considered by newer agents, such as the angiotensin a relatively weak diuretic, blocking less than 2% converting enzyme inhibitors and angiotensin of the total filtered sodium load. 4 receptor blocking agents. With the 1999 publication of the Randomized Aldactone While the diuretic effect of spironolactone has Evaluation Study (RALES) 1 which showed a 30 long been considered its primary mechanism of percent reduction in risk o f death when action, more recent studies have focused on its spironolactone was added to standard therapy for role in blocking aldosterone production in the severe heart failure, there has been a renewed vascular tissue of patients with heart failure. interest in aldosterone inhibitors. The Local production of aldosterone may lead to subsequent development of eplerenone, a new myocardial and aortic remodeling, with fibrosis, agent with fewer adverse effects than and nephrosclerosis . In addition, the sustained spironolactone, has furt her increased the utility elevations in aldosterone concentrations seen in of aldosterone inhibitors in adults. 2 patients with heart failure may cause abnormal vasomotor reactivity and baroreceptor In children, spironolactone has been used for responsiveness. Inhibition of aldosterone by more than 40 years to treat heart failure either spironolactone or eplerenone appears t o associated with congenital heart disease and to prevent these fibrotic changes and improves alleviate pulmonary congestion in neonates with cardiac sympathetic nerve function in adults. 4-7 chron ic lung disease. Despite the frequency of No studies have been published yet to confirm its use in children, there have been very few these benefits in children with heart failure. studies to document the efficacy and safety of spironolactone in this population. In an effort to Use of Spironolactone in Chronic Lung Disease stimulate new research, the Food and Drug The first reported use of spironolactone in Administration placed spir onolactone on its “List children was in a series of experiments with of Drugs for Which Pediatric Studies Are diuretics in newborns conducted by Walker and Needed” in 2003. 3 This issue of Pediatric Cummings in 1964. 8 In this study, three infants Pharmacotherapy will review the available were given 50 mg spironolactone in divided information on spironolactone in children and doses. The drug produced a modest increase in highlight potential areas for further research with urine flow, from a baseline of 445 to 469 ml/24 the aldo sterone inhibitors. hours after treatment. Sodium excretion increased from 24.1 to 27.2 mEq/24 hours, while Mechanisms of Action potassium excretion was unchanged. In 1974, Spironolactone and eplerenone are competitive Sole and Knorr studied intravenous aldosterone receptor antagonists. Aldosterone is spironolactone in 9 newborns and 13 inf ants and primarily secreted by the adrenal gland in reported similar findings of mild diuresis with response to intravascular volume depletion decreased potassium excretion. 9 and/or excessive sodium loss. Higher concentrations are secreted during periods of Since these initial reports, several investigators physiologic stress. In the renal collecting duct have studied the effectiveness of spironolactone and distal tubule, aldosterone increases in the management of pulmonary edema in absorption of sodium in exchange for potassium preterm neonates with bron chopulmonary dysplasia/chronic lung disease (CLD), with In 1994, Kao and colleagues published an mixed results. In 1984, Kao and colleagues additional study to confirm their earlier work. 14 published the first clinical trial of spironolactone Forty -three infants were randomized to the in this population. 10 Using a randomized, chlorothiazide and spironolactone combination double -blind, cross -over design, 10 infants were used in their earlier trials, or placebo, for as long evaluated d uring treatment with the combination as supplemental oxygen was required. Patients of chlorothiazide (20 mg/kg twice daily) and were followed until 1 year of age. Between the spironolactone (1.5 mg/kg twice daily), and again first and second pulmonary function tests, the during administration of placebo. Treatment infants in the diuretic group showed significant with diuretics for one week produced a improvement, while there was no change in the significant reduction in mean airway res istance, placebo group. By week 4, patients in the with an increase in airway conductance and diuretic group required less supplemental pulmonary compliance, while results for the oxygen; however, there was no difference in the placebo phase were unchanged. As anticipated, total days of supplemental oxygen required during the diuretic phase, there was also overall between the two groups. significantly greater urine output, osmolar clearance, and potassium a nd phosphorus In the most recent study, published in 2000, clearance. The authors concluded that diuretics Hoffman, Gerdes, and Abbasi compared improved lung function in infants with CLD. chlorothiazide (20 mg/kg twice daily) to the combination of chlo rothiazide and Three years later, the same investigators studied spironolactone (1.5 mg/kg twice daily) for 2 the effects of theophylline, with or without weeks in 33 infants. 15 The addition of diuretics for 4 days, on lung function in 16 spironolactone did not produce an improvement infants with CLD. 11 After treatment with in pulmonary mechanics over thiazide alone and diuretics (the same chlorothiazide and did not reduce the need for electrolyte spironolactone regimens used earlier), dynamic supplementation. lung compliance increased, airway resistance decreased and maximal expiratory flow at Whi le the conflicting findings from these studies function residual capacity increased. The make interpretation difficult, the results are not combinat ion of diuretics plus theophylline surprising. Few pharmacologic therapies have produced an additive benefit on all parameters. been shown conclusively to affect lung function in neonates with CLD because of the large In the April 1989 issue of the Journal of number of variables af fecting outcome. In Pediatrics , two additional articles were published clinical practice, most institutions continue to use on diuretic therapy for CLD. 12,13 In the first long -term combination diuretic therapy in the article, Albersheim and colleag ues conducted a management of neonatal CLD. randomized, double -blind, placebo -controlled 8 - week trial of diuretics in 34 infants with CLD. 13 Use of Spironolactone in Pediatric Heart Disease Patients in the treatment group received Although spironolactone has become a key hydrochlorothiazide 2 mg/kg and spironolactone component in the management of heart failure in 1.5 mg/kg every 12 hours. There were infants and children with congenital heart significantly mo re patients in the treatment group defects, very little has been written about this who survived to discharge (84% versus 47% in population. 16-18 In 1980, Baylen and colleagues the controls). There were no significant documented elevated serum aldosterone differences, however, in length of stay or concentrations in 15 infants with congesti ve heart duration of mechanical ventilation. failure (average 151 +38 ng/dl compared to a Measurement at 4 weeks revealed a higher total mean of 29 +7 ng/ml in 20 normal controls). 17 In respira tory system compliance with diuretics. four of the heart failure patients, spironolactone produced a significant improvement in urine The second article, by Engelhart and colleagues, output and a reduction in aldosterone levels. produced different results. 13 In their trial of 21 infants with CLD, patients were randomized to The follow ing year, Hobbins and colleagues placebo or a combination of hydrochlorothiazide studied spironolactone in 21 infants with and spironolactone (3 mg/kg/day of each). congestive heart failure related to congenital Patients were treated for a 6 to 8 day period. heart defects. 18 All patients were already Although urine output increased in the treatment receiving digoxin and chlorothiazide. Ten of the group, the authors found no differences in lung patients were given potassium supplement ation, mechanics or oxygenation. while the remaining 11 were given spironolactone (1 to 2 mg/kg every 12 hours). By the end of one week, bodyweight and liver size were decreased in the spironolactone group potassium concentrations. Although these agents compared to baseline. There were less are “potassium -sparing,” their use in significant decreases in the potassiu m patients. combination diuretic therapy (with a thiazide or The authors concluded that spironolactone loop diuretic) may still result in hypoka lemia. In produced a clinically significant benefit in their patients on combination therapy who require patients on standard therapy for congestive heart potassium supplementation, or who are receiving failure. an angiotensin converting enzyme inhibitor, potassium levels should

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