Glomerular filtration

Beginning in the glomerulus, the nephron forms a cell-free ultrafiltrate, with a relatively small amount of protein, which has the same ionic concentration (e.g., Na⁺, Cl⁻, HCO₃⁻) as plasma. Of the total blood flow that goes through the nephron, 20%, or about 130 mL/min, is filtered through the glomerulus. More than 99% of this glomerular filtrate is reabsorbed in the tubules, and less than 1% of the fluid is excreted as urine. The total urine output for an adult is approximately 0.5 to 1 mL/min, or about 30 to 60 mL/hr. Because diuretics interfere with the reabsorption of water in the tubules of the nephron, they increase the urine output.

Electrolyte filtration and reabsorption

The ions listed in Box 19-1 are filtered and exchanged in the tubules.

Water is also passively reabsorbed or excreted, depending on the concentration of electrolyte, primarily Na⁺, in the filtrate. By inhibiting sodium reabsorption, diuretics cause less water to be retained, and more is excreted in the filtrate.

Aldosterone, a mineralocorticoid secreted by the adrenal cortex, increases sodium and water reabsorption in the distal tubule. Spironolactone is a diuretic that increases sodium and water loss by inhibiting aldosterone.

Acid-base balance

Because a fundamental function of the kidney is the control of buffering substances, especially HCO₃⁻, diuretics may cause acid-base imbalances to occur as they increase water loss. Figure 19-2 illustrates the hydrogen and bicarbonate pathways that regulate pH. The filtration and reabsorption of Na⁺, Cl⁻, and HCO₃⁻, described previously, can be seen in Figure 19-2.

The important exchange for acid-base balance is that of Na⁺. Na⁺ is reabsorbed in the tubules by several means, as follows:

Either low chloride (hypochloremia) or low potassium (hypokalemia) forces Na⁺ to exchange for H⁺, producing a loss of H⁺ and metabolic alkalosis:

< ?xml:namespace prefix = "mml" />HypochloremiaHypokalemia]→Metabolic alkalosis

Finally, preventing HCO₃⁻ in the filtrate from forming CO₂ and water leads to a loss of bicarbonate buffer in the urine and metabolic acidosis.

Osmotic diuretics

Osmotic diuretics (Table 19-2) are freely filtered at the glomerulus but are not reabsorbed. These agents remain in the tubule lumen and impair the ability of the proximal tubule and thick ascending limb of Henle to reabsorb NaCl. The net result is that osmotic substances are potent diuretics that lead to increased excretion of water and NaCl. The resultant increased delivery of sodium and chloride to the distal tubule results in increased exchange of Na⁺ for K⁺, producing a net potassium loss in urine.

Of the four currently available osmotic diuretics (glycerin, isosorbide, mannitol, and urea), mannitol is the typically selected agent because of its lower toxicity. Mannitol has a relatively short half-life and has a rapid onset and quick offset of action. To maintain a continued diuretic action, the drug is frequently administered via continuous infusion. Osmotic diuretics are often used in the management of traumatic brain injury with cerebral edema.

Carbonic anhydrase inhibitors

The primary site of action of carbonic anhydrase inhibitors (CAIs) is within the proximal tubule. Carbonic anhydrases are enzymes that catalyze the hydration of carbon dioxide and the dehydration of bicarbonate: CO₂ + H₂O ↔ HCO₃⁻ + H⁺. CAIs prevent the normal breakdown of carbonic acid and, therefore, decrease bicarbonate reabsorption.

CAIs also inhibit NaCl reabsorption at the proximal tubule. The decreased osmotic gradient for water reabsorption results in increased delivery of NaHCO₃, NaCl, and water from the proximal tubule (Figure 19-4). Much of the NaCl is reabsorbed in the thick ascending loop of Henle. The net result is a moderate increase in sodium and bicarbonate in the urine along with increased water excretion. The potential for metabolic acidosis coupled with their weak diuretic properties limit the use of CAIs as the first-line treatment for patients who require more aggressive management of their hypervolemic status.

Other, more common uses of CAIs include treatment of glaucoma, metabolic alkalosis, and altitude sickness. Carbonic anhydrase is an important enzyme in the formation of intraocular fluid. CAIs effectively decrease intraocular pressure and are used to treat glaucoma. Short-term CAIs may also correct metabolic alkalosis, as a result of the acidosis they produce. Finally, CAIs have been shown to be useful against altitude sickness, although the exact mechanism of action is unknown. The most common adverse effect of CAIs is hypokalemia resulting from the increased amount of sodium presented to the collecting duct, which is reabsorbed in exchange for potassium excretion.

Loop diuretics

Loop diuretics (see Table 19-2) are often called “high ceiling” diuretics because they can cause up to 20% of the filtered load of NaCl and water to be excreted in the urine. They inhibit the reabsorption of NaCl at the thick ascending limb of Henle, where about 20% of filtered NaCl is usually reabsorbed.¹¹ Use of loop diuretics leads to increased Na⁺, K⁺, Cl⁻, and water excretion.

When administered intravenously, loop diuretics produce an acute hemodynamic effect independent of their diuretic properties.¹² Within 5 minutes of the administration of intravenous loop diuretics to cardiac patients, an acute vasodilatory effect is observed. This effect is manifested by a decrease in pulmonary capillary wedge pressure, blood pressure, and systemic vascular resistance. The effect seems to be derived from the renal release of vasodilating prostaglandins.^13,14

Because the diuretic effect of intravenous loop diuretics is typically not seen for 15 to 20 minutes after administration, patients with acute pulmonary edema may derive a clinical benefit from intravenous loop diuretics before the onset of diuresis. The hemodynamic effect is short-lived, with all measurements returning to baseline once diuresis has begun.

The acute hemodynamic effect has also been reported to activate the sympathetic nervous system, resulting in an adverse hemodynamic profile characterized by increased afterload and diminished cardiac function before the onset of diuresis.¹⁵ This effect is also short-lived and dissipates with the onset of diuresis. Because the diuretic effect may last several hours, several doses per day may be required to maintain a net diuretic effect for 24 hours. Patients requiring frequent bolus doses may benefit from continuous infusion.

Administration of loop diuretics to patients with renal dysfunction results in less total drug reaching the site of action within the nephron, and the administration of larger doses is required to achieve a therapeutic effect.16–18 In these patients, differences exist among the effects of furosemide, bumetanide, and torsemide. Furosemide may have a more prolonged effect in patients with renal dysfunction. However, patients may be resistant to furosemide compared with bumetanide. Because loop diuretics are the most potent diuretics, they are effective at very low creatinine clearance levels (a low creatinine clearance level indicates kidney disease). Loop diuretics as single agents should be considered as first-line therapy in patients with creatinine clearance values less than 40 mL/min. If this dose is inadequate to produce diuresis within 20 minutes, the dose can be doubled every 20 minutes until a response occurs or until a maximum dose is reached. Various studies have reported a ceiling effect to furosemide of approximately 250 mg.^19,20 Increasing the dose above this ceiling dose may not produce an increased response.

Although patients with renal dysfunction require larger doses to deliver diuretics into the urine, the remaining nephrons in these patients continue to function normally. Overall, sodium excretion may be limited as a result of diminished sodium filtration. To overcome this relative resistance, an effective response may occur by administering a large enough effective dose several times a day. Certain disease states result in a diminished response that does not improve by administering larger doses. Although the mechanism for this effect is unknown, it has been reported in patients with congestive heart failure, cirrhosis, or nephrotic syndrome.²¹ In these patients, multiple doses should be given rather than larger single doses. This finding implies a modest ceiling dose of loop diuretics in patients with CHF and cirrhosis.

Thiazide diuretics

Thiazide diuretics (see Table 19-2) block NaCl reabsorption at the distal tubule.^21,22 Thiazide diuretics are of moderate potency because only about 5% to 10% of filtered NaCl is reabsorbed in the distal tubule. However, they are considered the first line of therapy for mild hypertension. Thiazide diuretics are effective to a creatinine clearance of approximately 30 mL/min. Thiazide diuretics have a limited dose-response curve compared with loop diuretics. This limited dose-response curve results in a narrow difference between maximal and minimal effective doses. Doses greater than 50 mg may not produce greater diuresis, but they may predispose the patient to increased toxicity.

Doses greater than 50 mg may, however, be useful in the treatment of hypertension. The use of thiazide diuretics in the treatment of hypertension produces an effect initially as a result of diuresis-induced decreases in blood volume.^2,21

Long-term benefits of thiazide diuretics in hypertension are most likely not due to a diuretic response. One proposed mechanism is decreased peripheral vascular resistance.²³ Although the exact mechanism of action is unknown, as mentioned, hypertensive patients may respond to thiazide diuretic doses greater than 50 mg/day.

Potassium-sparing diuretics

Potassium-sparing diuretics include spironolactone, amiloride, and triamterene (see Table 19-2). These agents are weak diuretics that block sodium reabsorption by slightly different mechanisms of action. Amiloride and triamterene block the Na⁺ channels in the luminal membrane of the principal cells of the cortical collecting ducts, whereas spironolactone is a competitive aldosterone antagonist at the cytosolic receptor level. On the basis of its mechanism of action, spironolactone is specifically used for conditions known to have elevated aldosterone concentrations, such as hyperaldosteronism (primary and secondary), cirrhosis and ascites, adrenal hyperplasia, and renal artery stenosis. The most common use is in patients with cirrhosis and ascites. Because the duration of effect of spironolactone is 1 or more days, the dose should be increased every 3 or 4 days until the desired level of diuresis is attained.²⁴

In the distal tubule, sodium is typically exchanged for potassium and hydrogen. Blocking this exchange is what makes these agents potassium-sparing diuretics. Although frequently used in combination with thiazide diuretics to produce better diuresis and to diminish potassium loss, the rationale for this is controversial. Only about 5% of patients receiving thiazide diuretics become potassium depleted.²¹ In addition, potassium-sparing agents may produce hyperkalemia, which is a more life-threatening situation than potassium depletion.

Triamterene is a short-acting agent requiring multiple doses per day. Triamterene must be converted to an active metabolite by the liver, and this agent may be a poor choice in patients with liver dysfunction.²⁵

Amiloride has a moderately long half-life and does not require metabolic activation. Coadministration of potassium supplements, angiotensin-converting enzyme inhibitors, and nonsteroidal antiinflammatory agents and renal dysfunction may predispose patients receiving potassium-sparing diuretics to develop hyperkalemia.

Hypovolemia

Because diuretics promote sodium and fluid excretion, elimination may exceed intake, resulting in hypovolemia. Hypovolemia should be suspected if dizziness, extreme thirst, excessive dryness of the mouth, decreased urine output, dark-colored urine, or constipation is observed. Certain situations may predispose a patient to hypovolemia (Box 19-2). Diuretic-induced hypovolemia should be treated by discontinuation of the diuretic. Mild cases of hypovolemia may respond to liberalization of sodium intake, whereas more severe cases require intravenous volume replacement.

Hypokalemia

Preserving potassium balance has emerged as one of the most important factors in the management of hypertension.²⁹ Potassium is exchanged for sodium in the distal convoluted tubule and collecting duct. Any diuretic that increases sodium delivery to these regions may potentially induce hypokalemia. In addition to a direct potassium loss, diuretic-induced volume depletion produces reabsorption of sodium via release of aldosterone in the distal tubule in an effort to bolster intravascular volume. This additional sodium reabsorption also contributes to potassium excretion. Dietary sodium intake and chloride depletion may also influence potassium excretion.

Diuretic-induced hypokalemia apparently is dose-related, with loop diuretics having a lower incidence than thiazide diuretics.³⁰ Although studies have tried to identify the incidence of diuretic-induced hypokalemia, it is impossible to predict whether a particular patient will develop hypokalemia.^31–33 The issue of potassium supplementation is also controversial. Who to treat, when to treat, and how to treat hypokalemia all are unresolved questions. At the center of this unresolved issue is whether hypokalemia poses a risk for arrhythmias or sudden cardiac death. Supplemental potassium should be considered in patients with a history of cardiac disease, patients with symptoms indicating hypokalemia, patients with a serum potassium level less than 3.0 mEq/L, and patients receiving digitalis therapy.³⁴ Potassium-sparing diuretics may induce a hyperkalemic state in 8.6% of patients receiving spironolactone and in 23% of patients receiving a potassium-sparing diuretic and potassium supplementation.^33,35

Acid-base disorders

With diuresis and volume depletion, hypokalemia and hypochloremia may result. This state may cause metabolic alkalosis, which is responsive to potassium and chloride replacement therapy. Exceptions are CAIs, the use of which may result in metabolic acidosis.

Glucose changes

Loop and thiazide diuretics have been associated with hyperglycemia. The average increase in serum glucose is 6.5 to 9.6 mg/dL, although cases of diabetic ketoacidosis have also been reported.^36,37 The severity of glucose elevation in these reports was related to the dose of diuretic used and to the decrease in potassium levels. Although the cause of hyperglycemia is not completely understood, several possible etiologies have been postulated, including decreased pancreatic insulin release and insulin resistance with impaired uptake of glucose in response to insulin.

Ototoxicity

Loop diuretics may cause a dose-related ototoxicity consisting of tinnitus and clinical or subclinical hearing loss. Ototoxicity results from anatomic and chemical abnormalities produced within the inner ear.³⁴ Ototoxicity is related to the blood level of these agents. Rapid infusion and drug accumulation with large parenteral doses in renal failure both predispose patients to ototoxicity. Reducing the infusion rate or administering the drug orally may alleviate the hearing loss.^38,39 Most ototoxicity is reversible; however, cases of irreversible hearing loss have occurred. Ethacrynic acid has a higher likelihood of causing irreversible hearing loss.^39,40 Limited data on bumetanide indicate that it may have a lower incidence of ototoxicity than furosemide and ethacrynic acid.

To minimize diuretic-induced ototoxicity, ethacrynic acid should be avoided. In addition, long-term doses greater than 500 mg in patients with advanced renal disease and repetitive dosing in patients with acute renal failure and rapid infusions should be avoided.

Acute respiratory distress syndrome

A pathophysiologic landmark of acute respiratory distress syndrome (ARDS) is the presence of noncardiogenic pulmonary edema. The inflammatory process associated with ARDS explains the increase of the endothelial permeability that causes intravascular water leakage into the interstitial and alveolar spaces. Although balancing the risks of increased pulmonary edema versus the risks of decreased vital organ perfusion has proven to be a difficult task for clinicians, a reduction in pulmonary capillary wedge pressure (PCWP) has been associated with increased survival in ARDS patients.⁴³ The ARDS Network published the results of the Fluid And Catheter Treatment Trial (FACTT),⁴⁴ in which patients who were not in shock and who were managed with a protocolized fluid management plus furosemide (conservative fluid management arm) had significantly more ventilator-free days, more ICU-free days, and lower mortality than those in the liberal fluid management arm.

Chronic lung disease in preterm infants

Lung disease in premature infants is complicated by the presence of pulmonary edema. A more recent meta-analysis concluded that in preterm infants older than 3 weeks diagnosed with chronic lung disease (CLD), administration of a single dose of aerosolized furosemide may transiently improve pulmonary mechanics. However, routine or sustained use of aerosolized loop diuretics in infants with (or developing) CLD cannot be recommended based on existing evidence.⁴⁵