Common Diuretics Used in the Preterm and Term Infant : What's Changed? Michelle L. Bestic and Michael D.

Reed Neoreviews 2012;13;e410 DOI: 10.1542/neo.13-7-e410

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://neoreviews.aappublications.org/content/13/7/e410

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Common Diuretics Used in the Preterm and Term Infant: Whats Changed?
Michelle L. Bestic, PharmD,* Michael D. Reed, PharmD*

Educational Gaps
Because diuretic therapy is a mainstay of therapy in the treatment of sick term and preterm neonates, clinicians must stay abreast of each drugs pharmacology, adverse event prole, and other factors when deciding on the appropriate diuretic therapy.

Author Disclosure Drs Bestic and Reed have disclosed no nancial relationships relevant to this article. This commentary does contain a discussion of an unapproved/ investigative use of a commercial product/device.

Abstract
Diuretics are administered routinely to sick neonates for the treatment of multiple clinical disorders, including edema, hypertension, congestive heart failure/cardiovascular disease, bronchopulmonary dysplasia, and renal dysfunction. Choosing the safest and most effective regimen of diuretic therapy for both the term and preterm neonate requires thoughtful consideration of several factors. Such factors include an understanding of each drugs pharmacologic principles and safety and efcacy proles as well as outside considerations such as clinically relevant drug interactions and available formulations, among others. This article focuses on the pharmacokinetic and pharmacodynamic characteristics of each of the most commonly employed diuretics in the neonatal population and the factors that may inuence the infants overall response to therapy.

Objectives

After completing this article, readers should be able to:

1. Review the pharmacology of the diuretics most commonly used in the neonatal population. 2. Dene the most frequently occurring adverse events in neonates after diuretic therapy. 3. Consider the determinants for effective diuretic therapy.
Diuretics continue to represent one of the most common classes of drugs administered to sick neonates and infants. Unwanted uid retention arising from myriad neonatal disorders can and does complicate the optimal care of sick infants. In our 2005 article in NeoReviews, we addressed the multifactorial components that inuence a patients response to diuretic therapy and clinical and laboratory monitoring (see The Ontogeny of Human Kidney Development: Inuence on Neonatal Diuretic Therapy[1]). As discussed, diuretic effectiveness is predominantly ultimately guided by the functional capacity of the kidney, which in turn is inuenced by the infants gestational and postnatal ages.

Abbreviations
PDA: patent ductus arteriosus RBF: renal blood ow RDS: respiratory distress syndrome

*Division of Clinical Pharmacology and Toxicology, and the Rebecca D. Considine Research Institute, Childrens Hospital Medical Center of Akron, Akron, OH.

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A second 2005 article (2) focused on Common Diuretics Used in the Preterm and Term Infant. The current article updates the clinician on additional relevant knowledge gained since the last publication and continues to focus on the pharmacokinetic and pharmacodynamic characteristics of each drug relative to the infants postconceptional age combined with other factors that inuence the infants overall response to therapy.

Table 1.

Classes of Diuretic Drugs

Commercially Available Dosage Forms Injection Injection Injection Injection (IV, IM), tablet (IV), tablet (IV, IM), solution, tablet (IV), tablet

Class Loop diuretics Bumetanide Ethacrynic acid Furosemide Torsemide Thiazide diuretics Chlorothiazide Chlorthalidone Hydrochlorothiazide Indapamide Metolazone Potassium-sparing diuretics Thiazidelike Amiloride Triamterene Aldosterone antagonists Eplerenone Spironolactone
IMintramuscular; IVintravenous.

Injection (IV), suspension, tablet Tablet Tablet Tablet Tablet Tablet Capsule Tablet Tablet

Diuretics Commonly Used in Neonates

Loop or High-Ceiling Diuretics
Loop diuretics (Table 1), like most diuretics, are required to reach the renal tubular lumen to exert their pharmacologic effect. Effective diuresis requires a coordinated process of the drug achieving signicant absorption into systemic circulation, a problem rarely encountered with intravenous drug administration, and then adequate concentrations delivered to the renal tubule. Highly protein-bound (primarily to albumin), loop diuretics are ltered minimally at the glomerulus. Instead, these agents are carried to the proximal tubule, where they are secreted into the lumen via the organic acid transport pump. Luminal ow then carries the loop diuretics to their site of action, the thick ascending limb of the loop of Henle. The lower renal blood ow (RBF) and reduced secretory processes found in preterm infants reduce the amount of drug delivered to the kidney, potentially limiting diuretic effectiveness. Once loop diuretics distribute to the thick ascending limb, the agents bind to one of the chloride-binding sites on the Na/K/2Cl transporter, inhibiting the reabsorption of sodium and chloride at this site. (3)(4)(5)(6)(7) Alterations in sodium concentrations affect water transport at the proximal tubule, loop of

Henle, and distal tubules. Proximal and distal tubule involvement is minimal and may be related to reversible carbonic anhydrase inhibition or alteration of renal hemodynamics. (3)(4)(7) Furosemide is the prototype of loop diuretics in neonates because it is the most widely used and studied diuretic in this population; however, bumetanide is sometimes used when there appears to be no response to furosemide. After administration of furosemide, blood ow to the kidneys has been shown to increase as a result of prostaglandin-mediated vasodilation. This increase in prostaglandin production presumably occurs indirectly from furosemides stimulation of the renin-angiotensin pathway. (3)(4)(5)(6)(7) As previously noted, the drugs primary site of action is the ascending limb of the loop of Henle, a site where the majority of tubular sodium is reabsorbed, thus the origin of referring to these agents as high-ceiling diuretics. Minimal to no inhibition of sodium reabsorption

takes place at the distal tubule, but it is this area that is partly responsible for the development of diuretic tolerance or resistance.(3) Chronic, increased sodium concentrations delivered to the distal tubule after diuretic administration result in distal tubular cell hypertrophy in the kidneys attempt to compensate and increase sodium reabsorption. (3) Although hypertrophy of distal tubular cells explains a primary mechanism behind more chronic diuretic resistance, it is important to recognize that increased sodium reabsorption also occurs acutely, most notably after a rapid diuresis. Compensatory postdiuretic sodium reabsorption by the nephron after a diuretic falls below therapeutic concentrations along with hemodynamic and neurohumoral changes account for this nding. (6)(7) The possibility of diuretic resistance should be considered in patients receiving loop diuretic therapy in whom the diuretic response diminishes over time with no change in electrolyte/uid intake or evolving renal dysfunction or in
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those patients who fail to respond to normal therapeutic dosages. The prompt addition of a distal tubule active diuretic (eg, a thiazide) will normally precipitate a brisk diuresis. Ideally, the thiazide should be administered 0.5 to 1 hour before the loopactive agent to effectively antagonize distal-tubule sodium reabsorption when presented with the increased loop diureticinduced urinary sodium concentration. Other factors to consider when assessing possible diuretic resistance include altered absorption of orally administered furosemide; concomitant administration of nonsteroidal anti-inammatory drugs, which results in prostaglandin inhibition, thereby blunting the natriuretic response to loop diuretics; and potential causes for reduced loop delivery to the site of action (hypoalbuminemia, altered RBF). The dependence of a preterm or newborn infants RBF and renal function on effective prostaglandin concentrations underscores the contraindication to the use of prostaglandininhibiting drugs until the infant is w6 months of age. This effect of a prostaglandin-inhibiting druginduced decrease in renal function is most obvious in infants receiving indomethacin or ibuprofen for patent ductus arteriosus (PDA) closure.

Thiazides and Thiazidelike Diuretics

Thiazide diuretics, like the loop diuretics, are delivered into the renal tubular lumen via the organic acid transport system in the straight segment of the proximal tubule. Thiazides exert their diuretic effect by blocking the apical electroneutral sodium chloride transporter by binding to the chloride site at the distal convoluted tubule, collecting tubule, and early collecting duct. (5)(6)(8)(9) Because only w5% to 10% of ltered tubular sodium reabsorption occurs within the distal tubule, thiazides efcacy
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as a diuretic is limited. Additionally, in sufcient doses, thiazides inhibit carbonic anhydrase at the proximal tubule. This inhibition is of little clinical consequence because any effect is quickly overcome by the reabsorption capabilities of the more distal segments of the nephron, particularly the loop of Henle. The limited sodium reabsorption should not and does not decrease the frequency of use of thiazide diuretics in the pediatric population. In fact, when thiazide monotherapy is effective, this approach may be preferred because their chronic use is associated with far less severe electrolyte disturbances and systemic abnormalities than can occur with aggressive loop diuretic therapy. Moreover, thiazide diuretics increase urinary calcium reabsorbtion, reducing the incidence of calcium-based renal stones. An important limitation to the use of thiazide diuretics for diuresis is the decreased response in patients with impaired renal function. (8)(9) Some clinicians think that this decline in response occurs in adult patients with a creatinine clearance of <50 mL per minute, whereas others use caution once the creatinine clearance falls to <15 to 25 mL per minute. The reduced efcacy is presumed to be from the decline in glomerular ltration rate after administration of thiazide diuretics. This decline has not been fully elucidated but appears to result from either a direct effect on renal vasculature or is secondary to either a decrease in vascular volume or a resultant increase in tubular pressure after inhibition of sodium and water reabsorption. The exception to this appears to be the thiazidelike drug metolazone, a medication with limited published ndings in the neonatal population.

Potassium-Sparing Diuretics
Two classes of potassium-sparing diuretics are clinically available: those

that directly inhibit sodium channels (triamterene and amiloride) and those that antagonize aldosterone (spironolactone and eplerenone) by inhibition of mineralocorticoid receptors. Limited clinical experience and published literature are available regarding the use of the sodium channelinhibiting triamterene and amiloride, so the focus of this article remains on the mineralocorticoid receptor antagonists spironolactone and eplerenone; eplerenone is another aldosterone receptor antagonist available in the United States. (10) There are no published reports of eplerenones use in the neonatal population, however, so its clinical utility in this patient population is limited. Although thiazide and loop diuretics require delivery to the tubular lumen, spironolactone does not have to reach this area to exert its pharmacologic effect. Rather, spironolactone competes with aldosterone on the mineralocorticoid receptors, located in the principal cells of the cortical collecting tubule. Sodium reabsorption is stimulated through aldosterone-sensitive channels, yielding a negative electrical gradient that triggers potassium and hydrogen secretion into the lumen. (8)(9)(10) Hence, antagonizing aldosterone results in diminished sodium reabsorption, with a consequent increase in serum concentrations of potassium and hydrogen. The drug is metabolized rapidly to an active metabolite, canrenone, which is eliminated slowly, allowing once or twice daily dosing. Because of the drugs dependency on the mineralocorticoid receptor, however, the use of spironolactone as a diuretic is limited to adjunctive treatment with diuretics in other classes or for those conditions associated with mineralocorticoid excess. Unlike loop and thiazide diuretics, which alter sodium reabsorption via direct inhibition of sodium transporters, aldosterone receptor antagonists

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competitively antagonize the aldosterone receptor.

Adverse Effects of Diuretic Therapy

Like all drugs, diuretics are not without adverse effects. All have at least some impact on intravascular and extravascular uid, serum electrolytes, and acid-base balance and require various monitoring recommendations (Table 2). In addition, the clinically important adverse events attributed to diuretic therapy administration in neonates include renal calcications, ototoxicity, and persistent PDA. (3) (4)(5)(11)(12)(13)(14) A critical assessment of the incidence and severity of these ndings follows. ELECTROLYTE DISTURBANCES. Electrolyte disturbances remain the most common adverse effects associated with diuretic therapy and can lead to a variety of consequences. These ndings are a direct result of the drugs pharmacologic actions and are well characterized. Although most published reports focus on furosemide-associated adverse events, the effects of bumetanide, with few exceptions, are uniform, as detailed later in this article. HYPOKALEMIA AND HYPERKALEMIA. The cellular site of action of the loop diuretics on the Na/K/2Cl transporter on the ascending limb of the loop of Henle effectively blocks tubular reabsorption of potassium. Less potassium reabsorption at the loop abolishes the transepithelial potential difference needed for potassium paracellular absorption. Diuretic increases in renal tubular luminal ow lead to dilution of luminal potassium concentration, providing a favorable gradient for potassium excretion. (3) Furthermore, despite inhibition of the Na/K/ 2Cl transporter, Na/K/ATPase activity within the loop of Henle

Important Monitoring Parameters to Consider in Patients Receiving Chronic Diuretic Therapy

Table 2.

Serum electrolytes Sodium, chloride, potassium, bicarbonate, calcium, magnesium, glucose Renal function Urine output, serum creatinine, blood urea nitrogen, crystalluria Fluid balance Intake and output, body weight Blood pressure Other Hearing, serum uric acid concentrations

and cortical collecting duct continues until a limiting sodium concentration gradient is established. (3) Once established, the gradient increases sodium/hydrogen exchange, leading to alkalinization of the cell-stimulating potassium channels. Conversely, spironolactone increases serum potassium concentrations via the drugs ability to competitively inhibit distal tubular potassium excretion. Because of this effect, spironolactone is being used with increasing frequency in some centers, mostly in combination with a thiazide diuretic, to offset the hypokalemia associated with more traditional diuretics. Because of the decreased excretion of urinary potassium, monitoring of serum potassium concentrations is essential to prevent the development of hyperkalemia, which can be life-threatening. (4)(5) Particular care should be exercised for patients with renal dysfunction, whose impaired potassium excretion capacity, coupled with accumulation of spironolactone and its metabolites, can potentiate hyperkalemia. (4)(5) In patients with decreased renal function (eg, neonates) receiving excessive spironolactone dosing, hyperkalemia can be very difcult to treat, underscoring the need to recognize that spironolactone effect may take a few days to peak and days to reverse.

CALCIUM/MAGNESIUM. In addition to potassium losses, loop diuretics also promote calcium and magnesium losses at the level of the loop of Henle. This excess excretion is also accomplished by the aforementioned process of furosemides ability to eliminate transepithelial potential difference, resulting in less reabsorption of calcium and magnesium. This loop diuretic induced hypercalciuria can lead to several complications, particularly in neonates and infants receiving aggressive, chronic doses. (2)(11)(12) As serum calcium is depleted, compensatory mechanisms, including stimulation of bone resorption owing to parathyroid hormone secretion, lead to bone demineralization as the body attempts to maintain normal serum calcium concentrations. Thus, chronic loop diuretic therapy can lead to metabolic bone disease. Additionally, furosemideassociated hypercalciuria contributes to the development of renal calcications. (11)(12)(13) Renal calcications are fairly common in infants who receive chronic furosemide administration and can lead to hematuria, infection, hydronephrosis, and renal failure. Gimpel et al (15) recently published a study underscoring the importance and frequency of furosemide-associated nephrocalcinosis. In 55 neonates born before 32 weeks gestational age with
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a median birthweight of 1,010 g (5002,070 g), exposure to furosemide therapy >10 mg/kg cumulative dose was the strongest risk factor for the development of nephrocalcinosis. The effects were most noticeable in those infants with lower birthweights and higher degrees of urinary calcium loss. Chronic loop diuretic administration is the most common cause of renal stones in the neonate. Understanding the mechanism for loop diureticinduced hypercalciuria leading to renal calcications permits the same expectations for bumetanide. Although loop diuretics promote calcium loss, thiazide diuretics can increase serum calcium concentrations by increasing renal calcium reabsorption both proximally and distally. (3) (5) This decrease in urinary calcium and oxalate excretion can be used clinically to prevent or treat loop diureticinduced renal calcications. Hufnagle et al (11) examined 10 infants with gestational ages ranging from 26 to 34 weeks who developed renal calcications after chronic furosemide treatment (1244 days). Five of the infants were given chlorothiazide (20 mg/kg per day) in addition to their previously scheduled furosemide therapy. Four of the ve had complete disappearance of renal calcications. In contrast to this study and others, (13) two studies failed to show a reduction in urinary oxalate or calcium excretion with the addition of a thiazide. (3)(12) The hypocalciuric effects of the thiazides may have been blunted by the increased sodium supplementation that the infants received in both studies, however. The infants receiving furosemide and hydrochlorothiazide combination therapy in the study by Campeld et al (12) received a signicantly greater intake of sodium (P < .01). It appears likely that the thiazide diuretics can be used to treat or prevent loop diureticinduced
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renal calcications, but this effect may be blunted in infants receiving above-average sodium supplementation. Considering the renal tubular mechanisms for the loop diuretics and thiazide diuretics as noted previously, reduced doses and lower doseto-effect titrations should be instituted whenever possible when combination diuretic therapy is instituted. Severe uid and electrolyte abnormalities can occur when loop and thiazide diuretics are coadministered to the same patient. OTOTOXICITY. The marginal cell of the cochlear duct is similar to the cells of the thick ascending limb of the loop of Henle. Consequently, loop diuretics can alter ion transport and reduce the endocochlear potential in the marginal cells, resulting in hearing loss. (14) Although the exact mechanism is unknown, the risk appears to be dependent on high serum drug concentrations, patients receiving ethacrynic acid therapy, and the coadministration of other known ototoxic medications. (16)(17)(18) Clinicians can minimize this more ominous adverse event by using continuous infusions rather than bolus doses, when indicated. Infants with prolonged elimination half-lives such as premature neonates <32 weeks postconceptional age or altered clearance mechanisms (ie, developing renal dysfunction) should be monitored closely, and dosing schedules should be adjusted when indicated. Further caution should be taken for patients receiving other known ototoxins (eg, aminoglycosides, vancomycin), because the combination of drugs are known to potentiate ototoxicity. Primarily for this reason, ethacrynic acid therapy has fallen out of favor. Bumetanide is also known to affect the cochlea similarly to furosemide but is thought to be less ototoxic. In an animal study conducted by Brummett

et al, (19) bumetanide administered in equivalent diuretic doses to furosemide produced only one-eighth the ototoxic effects as furosemide. Whether this nding holds true in the human population is unclear, but there are far fewer reports of bumetanideinduced ototoxicity compared with other members of the loop diuretic class. This nding, however, must be interpreted with the knowledge that the use of bumetanide in the neonatal population is miniscule compared with that of furosemide. Since our last publication in NeoReviews, our literature search revealed no further published data or reports of loop diureticinduced ototoxicity. The reviews by de Hoog et al (17) and Rais-Bahrami et al (18) have reported a lack of a relationship between hearing loss in neonates and furosemide monotherapy. Clinical experience, however, underscores the prudent use of the loop diuretics in the neonate, limiting the daily dose and duration tailored to the patients needs. Fortunately, suspected furosemide-induced ototoxicity appears to be almost always reversible, and we were unable to identify any published English reports of permanent furosemide-induced hearing loss in a neonate. PATENT DUCTUS ARTERIOSUS. As previously noted, furosemide administration is known to stimulate prostaglandins. It is this effect that is thought to be responsible for the reported increased incidence of PDA in infants receiving furosemide therapy for respiratory distress syndrome (RDS). In the recent study of Lee et al, (20) the use of furosemide in combination with indomethacintreated preterm infants did not affect the PDA closure rate compared with controls. The 68 infants included in the study, gestational ages <34 weeks and birthweights of <2,000 g,

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received one course of indomethacin followed by a 1 mg/kg dose of intravenous furosemide or placebo. There was no statistical difference (P .437) in the rate of PDA closure; however, a signicant difference was found (P < .001) in the incidence of acute renal failure as dened by a serum creatinine level >1.4 mg/dL in the furosemide group compared with the control group. It is important to note that this study did not look at the chronic administration of furosemide on the incidence of PDA. Green et al (21) evaluated 99 neonates weighing <2,500 g at birth with a history of RDS. The incidence of PDA was signicantly higher in the furosemide-treated group (P < .02) than in those receiving chlorothiazide or no diuretics. The study of Green et al, (21) combined with the recent Cochrane review (22) that found that there are no data to support the routine use of furosemide in preterm infants with RDS, should compel the clinician to exercise caution when administering diuretics to these patients. Diuretic therapy in these patients may increase the risk of PDA and other potential adverse events associated with diuretic therapy, with potentially limited therapeutic benet. OTHER EFFECTS. Although the aforementioned adverse effects represent those that are the most common and clinically relevant, other less common adverse effects can be observed with diuretic therapy. (8)(9) Cholelithiasis and hyperuricemia have been described after both loop and thiazide diuretic administration. (23) Cholelithiasis may be of particular importance in premature neonates receiving total parenteral nutrition. Drug fever, hypersensitivity, and skin eruptions have been described after diuretic therapy. (9)(24)(25) The well-known, long-term effects of thiazide therapy on lipid and carbohydrate

metabolism and spironolactoneassociated gynecomastia described in the adult literature have unknown effects in infants. (5)

Choosing Appropriate Diuretic Therapy

Selecting an appropriate diuretic drug regimen for a patient requires thoughtful consideration of several factors. The advantage of loop diuretics is their overall effectiveness resulting from the most rapid onset of diuresis and greater amount of overall diuresis that is achieved compared with any other agent. Adverse effects, however, including electrolyte disturbances, renal calcications, persistent PDA, and possible drug-induced ototoxicity, must be considered and the patient monitored appropriately for their possible occurrence. Thiazides, historically, were primarily adjunctive for the treatment or prevention of loop diuretic resistance and renal calcications. The most recent Cochrane review, (26) despite relatively few randomized controlled clinical trials, does suggest that both acute and chronic administration of thiazide diuretics with or without the addition of spironolactone may be benecial in preterm infants with chronic lung disease. There are relatively few published studies assessing the use of this combination in preterm and term neonates, however. Nevertheless, as mentioned previously, the use of a thiazide diuretic in combination with spironolactone is increasing in frequency in some centers. Similar to loop diuretics, dosage adjustments are recommended in preterm neonates and in those with renal dysfunction. The limited efcacy of aldosterone antagonists as diuretics limit their use to adjunctive therapy with diuretics in other classes, most notably to increase blood potassium concentrations or in pathophysiologic conditions associated with mineralocorticoid excess. Another limiting factor is the

development of hyperkalemia, most notable in patients with renal impairment. Serum concentrations should be monitored closely in any infant receiving an aldosterone antagonist. Additional monitoring parameters for the thiazide diuretics and aldosterone antagonists are similar to those for loop diuretics.

Route of Administration
One potential limitation to the oral use of diuretic therapy is the relative lack of available liquid (suspension or solution) oral formulations. Furosemide (solution) and chlorothiazide (suspension) are the only commercially available oral formulations in the United States. Alternatively, extemporaneously formulated suspensions can be manufactured by the pharmacist using the available oral tablets for most diuretics. The major limitation of the oral administration of some diuretics is the drugs poor bioavailabilities. (27)(28)(29) Rather than a class effect (ie, all loop diuretics), poor bioavailability is compound-specic and can be related to the formulations used. Furosemide has high interpatient and intrapatient variability and erratic oral absorption, which can limit furosemide efcacy. (27)(28)(29) In contrast, the bioavailability of the two other loop diuretics, bumetanide and torsemide, is nearly complete at 80% to 100%. The most common oral thiazide diuretic in adult patients, hydrochlorothiazide, has a bioavailability of up to 80%, whereas that of chlorothiazide is notoriously poor, with only 20% to 30% of the dose administered being absorbed into systemic circulation. Care should be taken when switching to agents within the same class as the differing potencies and bioavailabilities do not make doses interchangeable. Fortunately, the real need for such a substitution is rarely a concern clinically. The erratic and variable
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nature of oral absorption should be considered in infants not responding to oral therapy, and conversion to intravenous therapy may be warranted. Intravenous administration certainly circumvents the issue of bioavailability but does not represent a long-term solution. The only commercially available thiazide diuretic for intravenous administration in the United States is chlorothiazide. A common misconception when converting intravenous diuretic administration to oral administration is use of the same dose. Oral administration of any drug should be adjusted for bioavailability. When dosed appropriately (either intravenously or per bioavailability-corrected oral administration), the drugs effect on urine volume and electrolyte excretion is identical; the only difference is the much more rapid drug effect with intravenous dosing (w24 hours) as compared with oral administration (usually >6 12 hours).

increase in RBF after loop diuretic administration resulting from presumed prostaglandin release may be blunted in individuals receiving nonsteroidal anti-inammatory drugs, thereby potentially diminishing the therapeutic effect of the diuretic. The role of loop diuretics in the development of ototoxicity, specically in those receiving other known ototoxins, was noted in a preceding section. Nephrotoxicity with diuretic use represents a concern of many clinicians. Our literature search revealed that a diuretic alone has not been identied as a causative agent in the development of nephrotoxicity; however, there are several reports (30)(31) to suggest that furosemide or diuretic use, in combination with other therapies, may increase the risk of nephrotoxicity. (30)(31) Certainly, these ndings require more attention in a randomized, controlled clinical setting.

Pharmacogenomics
Pharmacogenomics represents a rapidly emerging eld that aims to individualize drug therapy with respect to the patients genotype. To date, the clinical applicability of these ndings is limited, particularly in pediatrics, given the nature of the lack of availability of routine testing for various genotypes, an inconsistent correlation of genotype to phenotypical ndings, and the dearth of data regarding the importance of the polymorphisms in the neonatal and pediatric population. Evolving pharmacogenomic data do represent an intriguing and rapidly growing eld, however, that may someday help to explain the variability in patient responses to many drugs, including diuretic therapy. To date, three polymorphisms have been identied that affect loop diuretic response, whereas at least ve have been associated with affecting thiazide response. (32) A study by Vormfelde

Drug Interactions
The likelihood of premature and term neonates requiring only diuretic therapy is small. Consequently, it is important to consider the potential effects that administration of other pharmaceutical agents will have on diuretic therapy, and vice versa. Although probenecid is frequently mentioned owing to the decrease in tubular secretion that may inuence thiazide and loop diuretic drug delivery into the lumen, the drug is used infrequently in this population. The hypokalemia encountered with thiazide and loop diuretic therapy can potentiate the adverse effects of cardiac glycosides (eg, digoxin). Careful monitoring of serum potassium concentrations is necessary for these patients. Likewise, the known antihypertensive effects of diuretics may enhance the effect of other antihypertensive agents. The aforementioned
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and Brockmller (32) evaluated the effects of these polymorphisms in 95 healthy white male subjects, as measured by urinary electrolyte excretion and volume of urine excreted after a single dose of oral furosemide. The authors concluded that the genetic polymorphisms described accounted for one-sixth of the interindividual response to the diuretic. Whether these ndings have clinical relevance remains to be determined. Thiazide diuretics also have been the focus of increased pharmacogenomic research, mostly in the setting of adult hypertension. An excellent summary of the variability of these ndings was published by Citterio et al. (33) Taken in sum, these inconsistent reports highlight that the pharmacogenomics of diuretics are intriguing but have failed to demonstrate consistent clinical applicability in the adult population, with an absence of clinical relevance in the preterm and term infant. Future study is necessary to determine the actual clinical application of pharmacogenomic testing.

Conclusions
Diuretic therapy is necessary as primary or adjunctive therapy in the treatment of a wide variety of indications in the preterm and term neonate. The impact that the degree of prematurity, birthweight, disease, genetics, and other therapies can have in altering renal hemodynamics and an infants response to diuretic therapy is substantial. Combining this impact with our ever-growing knowledge of the ontogeny of renal development and clinical experience with diuretics gives us an evolving understanding of these implications. Despite these many ndings regarding the inuence of diuretic therapy, however, ultimately it is the functional capacity of the maturing kidney that is of greatest importance in directing diuretic effectiveness. In addition to considering the appropriateness

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of diuretic therapy for neonates, clinicians also should consider concomitant disease states and therapies, normal maturational changes in renal function, and diuretic pharmacology to maximize therapy while limiting potential adverse events.

American Board of Pediatrics Perinatal Medicine Content Specications

Know the etiology of electrolyte abnormalities in the neonate. Know the mechanism of action of commonly used diuretic drugs in infants.

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human kidney development: inuence on neonatal diuretic therapy. NeoReviews. 2005;6(8):e366367 2. Bestic M, Reed MD. Common diuretics used in the preterm and term infant. NeoReviews. 2005;6(8):e392e398 3. Eades SK, Christensen ML. The clinical pharmacology of loop diuretics in the pediatric patient. Pediatr Nephrol. 1998;12(7): 603616 4. Chemtob S, Kaplan BS, Sherbotie JR, Aranda JV. Pharmacology of diuretics in the newborn. Pediatr Clin North Am. 1989;36 (5):12311250 5. Wells TG. The pharmacology and therapeutics of diuretics in the pediatric patient. Pediatr Clin North Am. 1990;37(2):463504 6. Brater DC. Pharmacology of diuretics. Am J Med Sci. 2000;319(1):3850 7. Prandota J. Clinical pharmacology of furosemide in children: a supplement. Am J Ther. 2001;8(4):275289 8. Brater DC. Diuretic therapy. N Engl J Med. 1998;349:387395 9. van der Vorst MM, Kist JE, van der Heijden AJ, Burggraaf J. Diuretics in pediatrics: current knowledge and future prospects. Paediatr Drugs. 2006;8(4):245264 10. Pitt B, Remme W, Zannad F, et al; Eplerenone Post-Acute Myocardial Infarc-

tion Heart Failure Efcacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348(14): 13091321 11. Hufnagle KG, Khan SN, Penn D, Cacciarelli A, Williams P. Renal calcications: a complication of long-term furosemide therapy in preterm infants. Pediatrics. 1982;70(3):360363 12. Campeld T, Brade G, Blynn-Valone P, Powell S. Effects of diuretics on urinary oxalate, calcium and sodium excretion in very low birth weight infants. Pediatrics. 1997;99(6):814818 13. Jacinto JS, Modanlou HD, Crade M, Strauss AA, Bosu SK. Renal calcication incidence in very low birth weight infants. Pediatrics. 1988;81(1):3135 14. Rybak LP. Furosemide ototoxicity: clinical and experimental aspects. Laryngoscope. 1985;95(9 pt 2 suppl 38):114 15. Gimpel C, Krause A, Franck P, Krueger M, von Schnakenburg C. Exposure to furosemide as the strongest risk factor for nephrocalcinosis in preterm infants. Pediatr Int. 2010;52(1):5156 16. Bates DE, Beaumont SJ, Baylis BW. Ototoxicity induced by gentamicin and furosemide. Ann Pharmacother. 2002;36 (3):446451 17. de Hoog M, van Zanten BA, Hop WC, Overbosch E, Weisglas-Kuperus N, van den Anker JN. Newborn hearing screening: tobramycin and vancomycin are not risk factors for hearing loss. J Pediatr. 2003;142 (1):4146 18. Rais-Bahrami K, Majd M, Veszelovszky E, Short BL. Use of furosemide and hearing loss in neonatal intensive care survivors. Am J Perinatol. 2004;21(6):329332 19. Brummett RE, Bendrick T, Himes D. Comparative ototoxicity of bumetanide and furosemide when used in combination with kanamycin. J Clin Pharmacol. 1981;21(1112 pt 2):628636 20. Lee BS, Byun SY, Chung ML, et al. Effect of furosemide on ductal closure and renal function in indomethacin-treated preterm infants during the early neonatal period. Neonatology. 2010;98(2):191199 21. Green TP, Thompson TR, Johnson DE, Lock JE. Furosemide promotes patent ductus arteriosus in premature infants with the respiratory-distress syndrome. N Engl J Med. 1983;308(13):743748

22. Stewart A, Brion LP, Soll R. Diuretics for respiratory distress syndrome in preterm infants. Cochrane Database Syst Rev. 2011; 12(12):CD001454 23. Randall LH, Shaddy RE, Sturtevant JE, Reid BS, Molteni RA. Cholelithiasis in infants receiving furosemide: a prospective study of the incidence and one-year followup. J Perinatol. 1992;12(2):107111 24. Ebdrup L, Pedersen CM, Andersen MH, Storgaard M. Prolonged hyperthermia from furosemide infusiona case report. Eur J Clin Pharmacol. 2010;66(2):215 216 25. Noce R, Paredes BE, Pichler WJ, Krhenbhl S. Acute generalized exanthematic pustulosis (AGEP) in a patient treated with furosemide. Am J Med Sci. 2000;320(5): 331333 26. Stewart A, Brion LP, Ambrosio-Perez I. Diuretics acting on the distal renal tubule for preterm infants with (or developing) chronic lung disease. Cochrane Database Syst Rev. 2011;7(9):CD001817 27. Murray MD, Haag KM, Black PK, Hall SD, Brater DC. Variable furosemide absorption and poor predictability of response in elderly patients. Pharmacotherapy. 1997; 17(1):98106 28. Vargo DL, Kramer WG, Black PK, Smith WB, Serpas T, Brater DC. Bioavailability, pharmacokinetics, and pharmacodynamics of torsemide and furosemide in patients with congestive heart failure. Clin Pharmacol Ther. 1995;57(6):601609 29. McCrindle JL, Li Kam Wa TC, Barron W, Prescott LF. Effect of food on the absorption of frusemide and bumetanide in man. Br J Clin Pharmacol. 1996;42(6): 743746 30. McKamy S, Hernandez E, Jahng M, Moriwaki T, Deveikis A, Le J. Incidence and risk factors inuencing the development of vancomycin nephrotoxicity in children. J Pediatr. 2011;158(3):422426 31. Mendes CA, Cordeiro JA, Burdmann EA. Prevalence and risk factors for acute kidney injury associated with parenteral polymyxin B use. Ann Pharmacother. 2009;43(12):19481955 32. Vormfelde SV, Brockmller J. The genetics of loop diuretic effects. Pharmacogenomics J. 2012;12(1):4553 33. Citterio L, Lanzani C, Manunta P. Polymorphisms, hypertension and thiazide diuretics. Pharmacogenomics. 2011;12(11): 15871604

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NeoReviews Quiz New minimum performance level requirements

Per the 2010 revision of the American Medical Association (AMA) Physicians Recognition Award (PRA) and credit system, a minimum performance level must be established on enduring material and journal-based CME activities that are certied for AMA PRA Category 1 CreditTM. In order to successfully complete 2012 NeoReviews articles for AMA PRA Category 1 CreditTM, learners must demonstrate a minimum performance level of 60% or higher on this assessment, which measures achievement of the educational purpose and/or objectives of this activity. Starting with 2012 NeoReviews, AMA PRA Category 1 CreditTM can be claimed only if 60% or more of the questions are answered correctly. If you score less than 60% on the assessment, you will be given additional opportunities to answer questions until an overall 60% or greater score is achieved. 1. You are caring for a 12-week-old preterm neonate, who was born at 24 weeks gestation and now has chronic lung disease and borderline urine output. You decide to use diuretic therapy in this infant. There are several considerations to the use of these agents in these infants. Upon the administration of furosemide: A. Blood ow to the kidneys decreases because of prostaglandin mediated vasoconstriction. B. It is secreted into the proximal tubule lumen and performs its action in the thick ascending loop of Henle where it inhibits the reabsorption of sodium and chloride. C. The use of prostaglandin inhibitors does not interfere with the diuretic function. D. Calcium and magnesium reabsorption are not affected. E. Monotherapy often results in long-term irreversible hearing loss. 2. Most diuretics require sufcient concentrations to be established within the renal tubular lumen in order to exert their pharmacologic effect. Which diuretic is the exception to this? A. B. C. D. E. furosemide metolazone hydrochlorothiazide spironolactone triamterene

3. This 12-week-old preterm neonate is not responding to her enteral furosemide therapy. All of the following represent clinically relevant reasons for this except: A. The recent administration of an NSAID that may be blunting the increase in renal blood ow following furosemide-induced prostaglandin release. B. A compensatory hypertrophy of distal tubular cells for sodium reabsorption C. The recent addition of spironolactone to the infants therapy, resulting in competition for the same binding sites on the Na+/K+/2Cl- channel. D. Erratic bioavailability of enteral furosemide formulations E. An alteration in renal blood ow in the infants clinical course resulting in decreased delivery of furosemide to the site of action. 4. The pharmacogenomics of neonatal diuretic therapy: A. Represents an intriguing and rapidly growing eld that may someday help explain the variability in patient responses but currently lacks clinical relevance. B. Are well characterized and should be recognized as an important piece in the determinants of diuretic therapy. C. Explain the diminished therapeutic response of furosemide when it is given over a period of time. D. While lacking complete clinical relevance, are readily available in commercial testing kits. E. Explain why furosemide precipitates a much more brisk and signicant diuresis than other diuretics.

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5. The thiazide diuretics exert their pharmacologic actions by blocking the electroneutral NaCl transporter within the nephron. Of the following, the principal site of action within the nephron of the thiazide diuretics is the: A. ascending limb of the loop of Henle B. distal tubule C. descending limb of the loop of Henle D. collecting duct E. proximal tubule

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Common Diuretics Used in the Preterm and Term Infant : What's Changed? Michelle L. Bestic and Michael D. Reed Neoreviews 2012;13;e410 DOI: 10.1542/neo.13-7-e410

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including high resolution figures, can be found at: http://neoreviews.aappublications.org/content/13/7/e410 This article cites 33 articles, 7 of which you can access for free at: http://neoreviews.aappublications.org/content/13/7/e410#BIBL This article, along with others on similar topics, appears in the following collection(s): Fetus and Newborn Infant http://neoreviews.aappublications.org/cgi/collection/fetus_newb orn_infant Fluid and Electrolyte Metabolism http://neoreviews.aappublications.org/cgi/collection/fluid_electr olyte_metabolism Renal Disorders http://neoreviews.aappublications.org/cgi/collection/renal_disor ders Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: /site/misc/Permissions.xhtml Information about ordering reprints can be found online: /site/misc/reprints.xhtml

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