Diuretic Pharmacology in Infants and Children

Symposium on Progress in Drug Therapy for Children

Diuretic Pharmacology in Infants and Children Michael D. Bailie, M.D., Ph.D., * Michael A. Linshaw, M.D., t and Vicki G. Stygles, M.S.!

Diuretic drugs are important in a wide variety of pathophysiologic states in which the removal of excess extracellular fluid will produce a beneficial therapeutic result (Table 1). The rational use of diuretics in children requires some basic knowledge concerning: normal renal function; development of certain renal functions pertinent to the action of diuretics; the sites of action of the various diuretic agents; and the clinical pharmacology of diuretics. In this review, we will briefly discuss the present knowledge of these areas. In addition, we will review those conditions in which diuretics are useful and discuss their recommended dosages and potential side effects. Several comprehensive reviews on diuretic therapy are available for the interested reader. 13.23.30

NORMAL RENAL PHYSIOLOGY IN RELATION TO DIURETIC ACTION Since diuretics can be classified as those drugs which cause a water or osmotic diuresis and those which cause a saliuresis (Table 2), the renal handling of sodium chloride and water will be briefly reviewed. Reference should be made to Figure 1 and Table 3 for the site of action of the various diuretics.

The Proximal Tubule The fluid that enters the lumen of the proximal tubule after being filtered across the glomerular membrane is an ultrafiltrate of plasma. 4 •14 The sodium chloride concentration and the osmolality of this fluid are nearly identical to that of the plasma. As the filtrate passes down the lumen of the proximal convoluted tubule, approximately 65 to 70 per cent of the fluid is reabsorbed. 30 Reabsorption along this segment is isotonic, and is probably the result of both active and 'Professor and Chairman. Department of Pediatrics. University of Kansas Medical Center. Kansas City. Kansas t Associate Professor of Pediatrics, and Chief, Division of Pediatric Nephrology, University of Kansas Medical Center, Kansas City, Kansas !Research Associate, Department of Pediatrics, University of Kansas Medical Center, Kansas City, Kansas

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Table 1. Conditions in Which Diuretic Drugs Are Useful CONDITIONS

EXAMPLES

Edematous States Cardiac and Pulmonary Causes Congestive heart failure Pulmonary edema

Cor pulmonale Renal Causes Nephrotic syndrome Acute postinfectious glomerulonephritis Acute renal failure Chronic renal failure Hepatic Causes Hypoalbuminemia Protein-losing enteropathy Severe malnutrition Other Causes Idiopathic edema Cerebral edema N onedematous States Hypertension Fluid overload Hypercalcemia Hyperkalemia Renal tubular acidosis Diabetes inSipidus Removal of toxins Syndrome of inappropriate ADH secretion Diagnostic agent

Table 2.

Congenital and acquired heart diseases Causes other than heart failure including smoke and heat inhalation, shock lung, respiratory distress syndrome, toxins Cystic fibrosis, undetected ventricular septal defect or patent ductus arteriosus Steroid sensitive or nephrotic syndrome associated with other renal diseases Post-streptococcal or shunt nephritis

Cirrhosis due to congenital or acquired liver disease

Anorexia nervosa, marasmus

Shock, meningitis, trauma Primary or secondary Excessive intravenous or oral fluid water intoxication

Proximal or bicarbonate-losing type Nephrogenic Head injury, tumors Stimulation of plasma renin activity

Diuretic Drugs

Water and Osmotic Diuretics Water Sodium Chloride and Bicarbonate Mannitol Glucose Urea Sahuretic Diuretics Furosemide Ethacrynic Acid Thiazides Triamterene Spironolactone Acetazolamide Mercurials Amiloride* *Investigational drug.

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Figure l. Schematic diagram of the renal tubule. Numbers refer to sites of action of diuretics as indicated in Table 3.

COLLECTING TUBULE

@ THICK ASCENDING

LIMB

(---~{A

passive transport. 10,30 Additional sodium chloride reabsorption occurs along the straight portion of the proximal tubule and this segment is also capable of actively secreting organic solutes such as para-aminohippurate or penicillin,5,13,22 Passive factors such as the hydrostatic and oncotic pressure operating across the tubular membrane appear to be important determinants of sodium reabsorption along the proximal tubule,6,20 Maneuvers that tend to increase peritubular hydrostatic pressure and decrease peritubular oncotic pressure such as volume expansion with isotonic saline result in a decrease in fluid reabsorption along the proximal tubule, Conversely, proximal tubular fluid reabsorption increases in sodium-retaining states such as dehydration or heart failure, Several aspects of fluid reabsorption in the proximal tubule have important implications for the use of diuretics, The corticosteroids and aminophylline, which increase glomerular filtration rate, may produce a diuresis since the extra filtrate may exceed the reabsorptive capacity of the tubule,30 A drug that interferes with proximal tubular reabsorption of fluid such as the carbonic anhydrase inhibitor, acetazolamide, or the osmotic diuretic mannitol, will cause considerable loss of fluid if there is no compensation in later segments of the tubule,23

Table 3. Site of Action and Potency of Various Diuretics DIURETIC AGENTS

MAJOR SITE OF ACTION'"

RELA TIVE POTENCY

Mannitol Carbonic anhydrase inhibitors Mercurials, ethacrynic acid, furosemide Thiazide Spironolactone, triamterene Demeclocycline

1 and 2 1

High Low High Moderate Low Moderate

* Numbers refer to those in Figure l.

2

3 4

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The activity of drugs such as furosemide, the thiazides, or acetazolamide, which are transported across the proximal straight tubule, depends in part on their ability to reach the tubule via the peritubular blood and to be secreted into the tubular lumen. 13 •1S Furthermore, drugs such as penicillin or paraaminohippurate, which are secreted into the lumen of the proximal tubule in sufficient amounts to cause the secretion of fluid, might potentially induce a diuresis. The diuretic effect of acetazolamide, a carbonic anhydrase inhibitor, takes advantage of the fact that sodium is reabsorbed along the proximal tubule partially in conjunction with bicarbonate ion. 23 Reabsorption of bicarbonate is greatly accelerated by the enzyme carbonic anhydrase, which is inhibited by the action of acetazolamide. Inhibition of this reaction leads to increased amounts of bicarbonate ion in the tubular fluid. The bicarbonate ion then behaves as an impermeable anion in the urine, carrying out with it an associated cation (sodium or potassium) as well as water.

Loop of Henle ApprOXimately 20 to 25 per cent of the filtrate is reabsorbed along the loop of Henle, the portion of the nephron between the end of the proximal tubule and the beginning of the distal tubule. The descending portion of the loop of Henle is thought to be virtually impermeable to sodium, and movement of fluid out of this segment of the tubule probably occurs by water exchange from the lumen to the renal interstitial space. 5 In the thin ascending limb of the loop, sodium chloride is reabsorbed passively. In the thick ascending limb, however, solute is actively reabsorbed. At present, the chloride ion is thought to be actively transported, 5 although the possibility that sodium is actively reabsorbed has not been eliminated. More solute (sodium chloride) than water is reabsorbed in the loop, resulting in the formation of a dilute urine. 5 Several diuretics (furosemide, ethacrynic acid, mercurials) act on the luminal membrane of the ascending limb of the loop of Henle, causing chloriuresis.

The Distal Tubule The handling of water and salt by the distal convoluted tubule has been confused in part because this segment appears to have several cell types, and because the point at which cells of the cortical collecting tubules, which are responsive to antidiuretic hormone, join those of the distal convoluted tubule vary with the species studied. 5 Thiazide diuretics work along this segment of the tubule. This site of action in the distal tubule is separate from the thiazide effect on carbonic anhydrase activity along the proximal tubule and is the major source of the diuretic response of this class of drugs. 13

The Collecting Tubule Reabsorption of sodium chloride and water takes place in this segment although in smaller quantities than in the more proximal segments of the nephron. Sodium appears to be actively reabsorbed and is partially under the control of aldosterone. 5 This segment of the tubule is sensitive to antidiuretic hormone which allows for reabsorption of considerable quantities of water. 5 In the distal nephron (distal convoluted tubule and collecting tubule), approximately 10 to 15 per cent of the filtered water load can be reabsorbed. Demeoc-

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locycline, a tetracycline antibiotic, blocks the action of antidiuretic hormone on the tubule, probably at this site. 13 Other diuretic agents that affect sodium transport along the collecting tubule include spironolactone, amiloride, and triamterene. 13.23 These drugs interfere with the excretion of potassium which is linked to sodium reabsorption and, therefore, do not cause hypokalemia as a side effect.

DEVELOPMENTAL ASPECTS OF SALT AND WATER REABSORPTION The overall fractional reabsorption of sodium in infants is similar to that of adults. Infants under stress can elaborate urine virtually free of sodium and can also handle a wide variation in dietary salt intake. 22 However, under conditions of salt loading in an infant there is a tendency for the retention of excess sodium,33 an increase in the extracellular fluid compartment, and the potential development of mild edema. Several factors may contribute to this tendency. First, the glomerular filtration rate is extremely low in early infancy.22.33 Second, the distribution of renal blood flow in the neonate is such that the juxtamedullary nephrons are perfused in preference to nephrons in the outer cortex. 33 It has been suggested that the juxtamedullary nephrons, which tend to have longer loops of Henle, may be salt retaining. 6 •33 Therefore, such a distribution of blood flow might impair the excretion of a sodium load. In addition, the concentration of renin, angiotensin, and aldosterone are elevated in the newborn infant compared with the adult. 19.33 The increased concentration of aldosterone may tend to impair the infant's ability to excrete a salt load. It has been known for many ye;p-s that when compared to the adult, the human newborn infant is unable to fully concentrate the urine. 22.33 Several factors may explain this observation. In the newborn infant, the solute concentration of the urine is different from that of the adult,8.33 in part because the infant is in an anabolic state and tends to excrete small amounts of urea. Urea is an important solute in the normal concentrating mechanism.1 7,33 When the newborn infant is fed protein, more urea is formed and the concentrating capacity improves to nearly that of the adult. Furthermore, the length of the loop of Henle, which is a factor in urinary concentrating capacity, increases with age. A progressive increase in the ability to concentrate the urine occurs in the newborn infant, and within the first few months the infant is able to obtain a urine osmolality of about 1000 mOsm per liter when water deprived, In contrast, urine osmolality at birth after water deprivation ranges to 500 to 700 mOsm per liter. 22,33

CLASSIFICATION OF DIURETICS The action of a diuretic is to promote the excretion of sodium and water in urine and thereby decrease the extracellular fluid volume. Diuretics may be classified in several ways; we have chosen to subdivide them ~nto two major categories: the water and osmotic diuretics, and the saliuretic diuretics.

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Increased water intake produces diuresis by inhibiting antidiuretic hormone, leading to an increase in excretion of water. 17,23 A number of other drugs may also be considered to be water diuretics because they either inhibit secretion of antidiuretic hormone or interfere with the action of antidiuretic hormone on the kidney. These are not listed in Table 2 but include the tetracycline derivative, demeclocycline, lithium, and phenytoin. 13,31 However, these drugs generally are not of clinical value, although demeclocycline may prove to be useful in patients with the syndrome of inappropriate secretion of antidiuretic hormone. Water is generally not considered to be a therapeutic diuretic agent, although under conditions in which urine output is low due to volume depletion, the addition of both salt (sodium chloride) and water with expansion of the extracellular fluid volume will increase glomerular filtration rate, suppress antidiuretic hormone, and increase urine output. Several substances act as osmotic diuretics, including sodium chloride and sodium bicarbonate, mannitol, and glucose. While sodium chloride and sodium bicarbonate are generally not used as diuretics, isotonic solutions of sodium chloride are used to expand the extracellular fluid volume in states of dehydration and to promote an increase in excretion of urine. Solutions containing sodium should be used cautiously in edematous patients since they have the potential to enhance the edema. Therefore, sodium intake is generally restricted in conjunction with the use of saliuretic diuretics in the control of edema. Sodium bicarbonate may be used to produce an alkaline urine and to promote the excretion of some organic acids such as salicylates,23 or to enhance the solubility of other compounds such as uric acid so that they will not crystallize in the urine, 23 Mannitol, glucose, and urea are non electrolytes which are freely filterable across the glomerular membrane. Mannitol, in contrast to glucose and urea, is not reabsorbed by the renal tubule. Both glucose and urea will appear in the urine in significant concentrations when their reabsorptive capacity is exceeded. The rising concentration of the osmotic diuretic within the tubular lumen promotes the excretion of water and salt. 23 Mannitol is the most commonly used clinic'aJ. osmotic diuretic. Glucose becomes an osmotic diuretic in the diabetic individual who is developing ketoacidosis, Urea is now used infrequently as an osmotic diuretic. The saliuretic diuretics directly promote the excretion of sodium and/or chloride with accompanying water. These drugs act along various segments of the tubule (see Fig. 1 and Table 3). The two most commonly used drugs in children in this classification are furosemide and the various thiazide preparations. Triamterene has liInited use in pediatrics; acetazolamide and spironolactone also are used but less frequently, Because of the newer, safer agents, mercurials are not commonly used, although for many years they were important.

CLINICAL PHARMACOLOGY OF DIURETICS IN CHILDREN The early developmental changes in renal function may potentially modify the effects of diuretics in the newborn infant and young child. Developmental changes in glomerular filtration rate, renal blood flow, and tubular handling of

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both sodium chloride and water as well as organic anions may modify the diuretic response at different ages. Therefore, it is important to evaluate the response to diuretics in children at various ages. The pharmacology of furosemide has been more completely characterized in infants and children than any of the other diuretics. 9.15 In general, newborn infants and children respond to furosemide with a predictable natriuresis and diuresis. Richardson found that infants ranging in age from three days to six months with edema secondary to heart failure responded to l.0 to l.25 mg per kg of furosemide administered intramuscularly within 20 to 40 minutes of treatment. 27 Mean urine volume was increased 3.5-fold and was accompanied by a lO-fold increase in sodium excretion, a 13-fold increase in chloride excretion, and a 6.5-fold increase in free water clearance. Potassium excretion was not altered by furosemide. 27 Furosemide is also an effective diuretic in infants and children with altered renal function due to renal disease. Repetto et al. 26 observed rapid diuresis and natriuresis in children with either congestive heart failure or glomerulonephritis. Furthermore, oral and parenteral furosemide appear to be equally effective. It should be noted that the response to furosemide when renal function is impaired may not be similar under all circumstances. Woo et al. 36 found that infants asphyxiated in the immediate newborn period responded poorly to furosemide and suggested that renal impairment due to hypoxia led to the diminished response to the diuretic. It is unlikely that the "immature" organic anion secretory system of the neonate can explain this latter finding. Ross et al. 29 evaluated the response to furosemide of low birth weight infants (10 to 57 days, mean gestation 30.7 weeks) with fluid overload secondary to congestive heart failure. The infants responded to furosemide with significant and sustained (3 to 6 hours) increase in urine volume, sodium excretion, potassium excretion, and free water clearance. The increases observed were qualitatively similar to those observed in studies on older children with mature renal function. Although the qualitative response to furosemide is similar in infants and adults, the duration of the response in the infant is somewhat lengthened. In the adult, the duration of action of furosemide may be l.5 to 2 hours, whereas in infants it may be 5 to 6 hours. 29 .36 Furosemide is eliminated partly by glomerular filtration but primarily by secretion by the proximal renal tubule. Both of these routes of elimination are decreased in the newborn infant. Since the site of action of furosemide is on the luminal surface of the thick ascending limb of the loop of Henle and the distal tubule,13 prolonged delivery of drug into the tubular lumen may explain the increased duration of action in infants. Furosemide is highly bound to human albumin, with approximately 2.5 per cent in the unbound form at albumin concentrations of 4 gm per dl. 25 The ability of a drug to bind to plasma protein and to alter plasma bilirubin binding is an important factor in determining the safety of the drug in infants, particularly in the presence of hyperbilirubinemia. Nephrotic children with plasma protein concentrations less than 2 gm per dl have a higher proportion of unbound furosemide. 25 In vitro testing of serum from jaundiced infants demonstrated that furosemide displaced bilirubin from plasma proteins. 35 However, the concentration of the diuretic greatly exceeded those which would occur clinically and the

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authors concluded that furosemide in doses of 1 mg per kg would only slightly alter bilirubin binding. These conclusions were confirmed by Aranda et al. 1 who found that reserve bilirubin binding capacity in neonates was unaltered by furosemide at a dose of 1 to 1. 5 mg per kg. In contrast to furosemide, which may induce a loss of 20 to 30 per cent of the ffitrate into the urine, the thiazide diuretics cause only a modest diuresis (10 to 15 per cent of the ffitrate). Walker and Cumming34 found that 75 mg of chlorothiazide given to seven infants caused a 1.5-fold increase in urine volume, a 5-fold increase in sodium excretion, a 1.5-fold increase in potassium excretion, and a 2.5-fold increase in chloride excretion in an eight-hour period of observation. 34 Chlorothiazide displaced a significant amount of bilirubin from primary albumin binding sites in the serum of jaundiced infants in vitro. 35 The relative displacement of bilirubin by chlorothiazide and furosemide is similar; however, the higher doses of chlorothiazide required to achieve an equivalent diuretic response make bilirubin displacement by this drug more likely in the clinical situation. Walker and Cumming34 also studied the effect of the carbonic anhydrase inhibitor, acetazolamide, in normal infants. At a single dose of 50 mg of acetazolamide, they found a very similar response to that seen with 75 mg of chlorothiazide. Acetazolamide increased urinary pH to approximately 8.0 and the increase was maintained throughout the eight-hour observation period of the study. The diuretic amiloride is presently not available for use in humans but has been studied in newborn animals. It is mentioned here for the sake of completeness and because someday it may be of clinical value. The drug has been shown to inhibit sodium reabsorption more in newborn puppies than in adult dogs, an effect that is accentuated by volume expansion. 3 Increasing doses of amiloride in newborn piglets has been demonstrated to increase sodium and chloride excretion. 24 Thus, in both puppies and in piglets, amiloride causes significant natriuresis.

CONDITIONS IN WHICH DIURETIC DRUGS ARE USEFUL A wide variety of pathophysiologic conditions may be treated with diuretics (see Table 1). The effectiveness of the diuretics will depend to some extent on the state of the extracellular fluid compartment. 13 With plasma volume expansion, the diuretics will usually provoke considerable solute and water loss. During states of plasma volume contraction, as is seen in dehydration, the effect of the diuretic may be considerably diminished.

Edematous States The three most common causes of edema are cardiopulmonary, renal, and hepatic diseases. s Hypoalbuminemia as a cause of edema may be present in both hepatic and renal disease and can also appear because of severe loss of protein through the gastrointestinal tract or severe malnutrition in which protein production by the liver is decreased. In the presence of edema, the kidney is unable to excrete sodium chloride in sufficient quantities to maintain balance. Additional sodium intake results in retention of fluid and more edema.

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In congestive heart failure, cardiac output, renal perfusion, and glomerular filtration rate are reduced. 6 .30 Fluid is retained in the intravascular and extravascular compartments, accounting for both venous congestion and peripheral edema. Reduction of the intravascular volume by the use of a diuretic in conjunction with improved cardiac performance by the use of digitalis results in improved kidney function and elimination of excess fluid and sodium chloride. On the other hand, the pathophysiology of the nephrotic syndrome is different in that glomerular filtration is frequently normal. 30 Albumin is excreted in the urine and serum albumin decreases. Hypoalbuminemia leads to retention of sodium chloride and water by the kidney. Because of the low intravascular oncotic pressure (the pressure due to albumin), fluid leaves the intravascular space and enters the extravascular space. l l Thus, patients with nephrotic syndrome may have a decreased intravascular volume, and the use of diuretics in these patients is not without the danger of inducing hypotension and shock. When the serum albumin is less than 1.5 mg per dl, additional albumin may be needed to prevent complications. Patients with acute renal failure secondary to glomerulonephritis are also in a fluid-retaining state. In these individuals, vascular volume is increased and, therefore, marked hypotension is not as likely to develop when diuretics are used. In hepatic cirrhosis, increased resistance to hepatic blood flow increases portal pressure, causing fluid to move into the extravascular space, primarily the abdomen, with resultant ascites. 6 .30 Liver damage may lead to decreased albumin formation and reduction in plasma oncotic pressure, transudation of vascular fluid to interstitial spaces, and renal salt retention.

Nonedematous States Of the several nonedematous conditions in which diuretics may be of value, hypertension is the most frequent. All patients with hypertension can be helped to some degree by diuretics. However, the pathophysiology of various forms of this disease are different and the response to diuretics is in part related to the cause of elevated blood pressure. 2.32 Hypercalcemia and hyperkalemia may respond to furosemide.1 3 Renal tubular acidosis of the proximal or bicarbonate losing type 7 .28 may be improved by use of thiazide diuretics, perhaps by decreasing intravascular volume and stimulating the reabsorption of bicarbonate by the proximal tubule. In nephrogenic diabetes insipidus, the thiazide diuretics may greatly reduce water output, although the exact mechanism is unknown. 13 The removal of toxic substance may be aided by increasing urinary output with either saliuretic or osmotic diuretics. 23 Finally, diuretics can be used as diagnostic agents. For example, under certain circumstances, furosemide can be used to test whether or not plasma renin activity will increase in patients with hypertension. 13 .18 This may be important in differential diagnoses of hypertension.

DOSAGE OF DIURETIC DRUGS IN CHILDREN While there are a large number of diuretic agents available on the market, not all are of value in children and several should be used only under very specific conditions (Table 4).

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Table 4. Dosages of Clinically Useful Diuretics ROUTE AND FREQUENCY OF DRUG

INITIAL DOSE

MAXIMAL DOSE

Mannitol Hydrochlorothiazide Chlorothiazide Furosemide

0.5 g/kg/dose 1 m g/kg/24 hrs. 10 mg/kg/24 hrs. 2 mg/kg/dose 0.5 mg/kg/dose 1 mg/kg/24 hrs. 1 mg/kg/dose 3 mg/kg/24 hrs. 5- 8 mg/kg/24 hrs.

2.0 g/kg/dose 2 mg/kg/day 20 mg/kg/day 6 mg/kg/dose 6 mg/kg/dose 3 mg/kg/24 hrs.

Spironolactone' Ethacrynic acid t Triamterenet Acetazolamide t

ADMINISTRATION

Intravenous Oral, divided dose every 12 hrs. Oral, divided dose every 12 hrs. Oral 3-4 divided doses Intravenous 3-4 divided doses Oral 3-4 divided doses Oral Oral every 12 hrs. after meals Oral 3- 4 divided doses

'In conjunction with furosemide or thiazides for potassium-sparing effect. tNot recommended for use in children as a diuretic.

Mannitol is used primarily to reduce intracranial pressure in cases of cerebral edema. An initial dose of 0.5 gm per kg given intravenously may be sufficient but higher doses may also be required. While mannitol has been used as a test for the pathogenesis of oliguria, it is probably not as valuable as isotonic sodium chloride for expanding intravascular volume. Patients in whom oliguria is secondary to decreased intravascular volume will usually respond to a challenge of 10 to 20 ml per kg of isotonic sodium chloride. Thiazide diuretics (hydrochlorothiazide and chlorothiazide) are valuable in the treatment of hypertension. 2 They should be given in divided doses every 8 to 12 hours. A saliuretic diuretic which is a non-thiazide but has a similar but longer duration of action is chlorthalidone. This drug can be given in a dose of 1 to 2 mg per kg orally and, because of its duration of action, may be given to some patients on alternate days. Furosemide is an exceedingly potent diuretic and can be given either orally or intravenously. The initial dose varies, depending on the route of administration, and the dose may be increased up to a maximum of 6 mg per kg per dose in ortler to obtain a response (see Table 4). The drug is relatively safe and potentially even higher doses could be used in patients with decreased renal function. While spironolactone, an inhibitor of aldosterone, is potentially a diuretic in its own right, it has relatively little clinical efficacy when used alone. This is primarily because it is difficult to obtain complete inhibition of the effect on aldosterone unless very high doses are used. Therefore, spironolactone is best used in combination with either hydrochlorothiazide, chlorothiazide, or furosemide in order to prevent potassium wasting and hypokalemia. As discussed below, other measures can also be used to prevent this complication of diuretic therapy. The use of spironolactone may be most important in patients with edema secondary to liver disease. Under these circumstances, the metabolic breakdown of aldosterone by the liver is reduced and the development of hypokalemia follOwing thiazide or furosemide treatment can be marked. Finally, ethacrynic acid, triamterene, and acetazolamide, although all potentially useful drugs, are not generally recommended for use in children. Acetazolamide does have some use under circumstances in which alkalinization

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of the urine is required to increase excretion of drugs or toxins or to produce an acidosis in the treatment of epilepsy.

SIDE EFFECTS AND COMPLICATIONS It is important to recognize that diuretics exert their action at a specific site along the nephron (see Fig. 1, Table 3). Nephron segments unaffected by the diuretic may respond in a compensatory manner sufficient to minimize the diuretic effect and to lead to metabolic complications. For example, thiazide diuretics which have their major site of action in the distal tubule may cause sufficient volume depletion to stimulate increased proximal tubular fluid reabsorption. The volume of fluid reaching the distal nephron is thereby decreased and the diuretic effect of the drug is blunted. 13 A similar situation exists in the face of decreased glomerular filtration in which the thiazide diuretics have very limited effect. Several of the complications of diuretic therapy, therefore, relate to compensatory mechanisms by tubular segments unaffected by the drug (Table 5). Disorders of potassium homeostasis are not uncommon following diuretic therapy. Hypokalemia may occur following the use of proximal tubule diuretics such as acetazolamide and mannitol, or loop diuretics such as furosemide, or distal diuretics such as thiazides. 13 ,30,32 These diuretics may impair potassium reabsorption along both the proximal and distal nephron. Potassium loss may be augmented because the volume depletion induced by the diuretic may increase plasma aldosterone, and urine flow rate may increase through the distal nephron. Potassium secretion is dependent to a large extent on the rate of urine flow past the distal nephron, and the higher rates of flow will allow a greater secretion of potassium ion. 12 •13 As hypokalemia supervenes, the secretion of aldosterone may decrease and, as volume depletion continues, the rate of urine flow along the distal nephron will also decrease. These compensatory changes will tend to minimize the continued loss of potassium. In fact, marked potas-

Table 5. Side Effects and Complications of Diuretic Therapy Related to Renal Function or Compensation Dehydration-all potential: furosemide and ethacrynic acid Hypokalemia-thiazides, furosemide Hyperkalemia-spironolactone, triamterene Hyponatremia-thiazides, furosemide, ethacrynic acid Metabolic acidosis-carbonic anhydrase inhibitors Metabolic alkalosis-thiazides, furosemide, ethacrynic acid Hyperuricemia-thiazides, furosemide Hypercalcemia-thiazides Nephrotoxicity - mercurials, thiazides Related to Nonrenal Effects Hyperglycemia-thiazides, loop diuretics Deafness-ethacrynic acid, furosemide Gastrointestinal Skin Hematologic Pancreatitis

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sium loss does not usually occur in the face of diuretic therapy unless considerable amounts of sodium chloride and water are ingested. Therefore, some limitation in sodium intake will help to prevent this complication. It should be pointed out that the use of potassium-sparing diuretics (spironolactone or triamterene) in children to avoid hypokalemia also has some risk. These drugs can be associated with hyperkalemia, particularly in patients with reduced renal function. We have seen a newborn infant develop a serum potassium of 11 mEq per liter while receiving spironolactone. Generally, potassium supplementation in the form of the fruit, bananas, orange juice, or even some of the nonenteric coated preparations of potassium is a much safer approach to avoiding hypokalemia. However, as previously discussed, in patients with cirrhosis, spironolactone may be a useful addition to treatment with furosemide or a thiazide. Hyponatremia may also occur following the use of diuretics. In addition to blocking sodium reabsorption, several other factors probably contribute to the hyponatremia. 13 First, if volume depletion is sufficient, release of antidiuretic hormone will interfere with the renal excretion of water. 13,17 Second, decreased glomerular filtration rate and increased proximal tubular sodium reabsorption, which accompany volume depletion, may impair the excretion of a water load. Third, potassium losses may allow sodium to enter cells, augmenting the hyponatremia. Finally, an extremely low sodium intake in the presence of continued water intake may reduce serum sodium concentration. Metabolic acidosis and alkalosis also may complicate treatment with diuretics.13.30.32 Acidosis may accompany the prolonged use of carbonic anhydrase inhibitors. As serum bicarbonate decreases, bicarbonate excretion will also decrease, blunting the diuresis. Alkalosis is often seen in conjunction with total body potassium depletion following the use of loop diuretics and thiazides. Furthermore, the volume contraction from salt and water loss may lead to "contraction alkalosis." Hyperuricemia, another potential complication of diuretic therapy, occurs with thiazides and furosemide.13.30.32 The hyperuricemia probably occurs secondary to volume depletion which causes enhanced proximal tubular reabsorption of uric acid. The hyperuricemia is usually mild and does not require therapy. Generally, reducing the dose of the diuretic or increasing fluid intake to some extent will minimize the hyperuricemia. Hypercalcemia is another potentially troublesome feature of thiazide therapy. \3.30 There is an initial increase in calcium excretion when the drug is introduced, but prolonged use of thiazide diuretics eventuates in a decrease in urinary calcium excretion and ultimately hypercalcemia. Most of the diuretics are not toxic to renal tissue, although nephrotoxicity has been reported with mercurials, a factor that has led to their virtual elimination from the present day armamentarium. 23 Interstitial nephritis has been reported with patients on thiazides and furosemide 21 but is not common and should not prevent the physician from using the drugs when necessary. Several other complications relate to nomenal effects of diuretics. Thiazides and furosemide are associated with hyperglycemia; ethacrynic acid and furosemide have been associated with deafness; and nearly all of the diuretics may potentially cause gastrointestinal, hematolOgic, or dermal problems. Again, these complications tend to be infrequent and should not preclude the use of the drug.

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SUMMARY Knowledge of applied renal physiology will greatly facilitate the use of diuretics in children and will minimize the risk of potential side effects. It is the authors' opinion that the thiazide diuretics and furosemide are the two most useful drugs available for use in children. Furthermore, in the newborn period, there is little justification for use of any diuretic other than furosemide.

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