Use of Diuretics
Diuretics increase saltwater excretion by impairing tubular reabsorption of the sodium filtered by the glomerulus. The diuretic effect is dose-dependent; the maximum response is determined by the diuretic’s site of action within the nephron, the filtered load of sodium, and the amount of sodium reabsorbed by nephron segments unaffected by the diuretic.
Mechanism of action All diuretics except spironolactone are specific inhibitors of luminal transporters and must gain access to the tubular fluid to block sodium reabsorption.5,63 Because diuretic agents are highly protein bound, they are not readily filtered at the glomerulus; instead, they are actively transported into the urine by the organic acid (in the case of agents such as acetazolamide, thiazides, and loop diuretics) or organic base (in the case of agents such as amiloride and triamterene) via secretory pumps in the proximal tubule. A dose-response curve links the amount of drug reaching the urine to the amount of sodium excretion that is elicited [see Figure 4]. Spironolactone binds to the cytosolic receptor for aldosterone, and its diuretic action, unlike that of other diuretics, does not depend on secretion into the tubular lumen.
The most potent agents are those that block sodium transport in the loop of Henle. At high doses, loop diuretics almost totally block sodium reabsorption in this nephron segment, causing about 20% of the filtered load of sodium to be excreted in the urine; at low glomerular filtration rates, the same percentage of filtered sodium is excreted, but the total amount is reduced. Conditions such as volume depletion, heart failure, and cirrhosis, which cause avid sodium reabsorption in the proximal and distal tubules, blunt the maximum response to the diuretic. Because gastrointestinal absorption of diuretics is often delayed in edematous conditions (presumably because of bowel edema), higher oral doses must be used to achieve adequate blood levels. In renal disease and cirrhosis, organic anions such as hippurate and bile acids compete with the diuretic for secretion into the proximal tubule; thus, higher plasma levels may be required to achieve adequate drug levels in the urine. Similarly, severe hy-poalbuminemia can diminish drug secretion into the tubular lumen, because albumin binding of most diuretics maximizes the rate of diuretic delivery to the organic anion secretory pump in the proximal tubule. Reduced renal blood flow also limits delivery of drug to the tubular lumen. Some patients with advanced cirrhosis who are resistant to furosemide respond to spironolac-tone, a generally weak diuretic whose effectiveness does not depend on tubular secretion.
Agents that act in the proximal tubule, loop of Henle, or distal tubule cause potassium wasting and hypokalemia because they increase delivery of tubular fluid to the cortical collecting tubule, where potassium secretion is flow dependent. Potassium-sparing diuretics, which act in the cortical collecting tubule, cause hyperkalemia because sodium reabsorption at this site favors potassium secretion. The carbonic anhydrase inhibitor acetazo-lamide causes metabolic acidosis, as do the potassium-sparing diuretics. Thiazides and loop diuretics cause metabolic alkalosis because of increased distal delivery of sodium to sites where sodium reabsorption stimulates hydrogen ion secretion.
Figure 4 Dose-response curves for a loop diuretic in patients with normal (black line) and reduced (blue line) renal function. Urinary sodium excretion responds to diuretic levels in the tubular lumen (as reflected by urinary drug levels). The diuretic effect reaches a maximum at approximately 20% of the filtered load of sodium regardless of renal function (a). Secretion of the diuretic into the tubular lumen is reduced in renal failure; thus, higher doses are required in azotemic patients to achieve the same urinary drug levels found in patients with normal renal function (b). Because the filtered load of sodium is reduced in patients with renal failure, absolute sodium excretion is also reduced, even at high doses (c and d).
Clinical strategies Diuretic doses should be adjusted to achieve explicit therapeutic goals. Outpatient therapy is usually designed to produce a gradual loss of fluid, with the dose being increased until a desired target weight is reached. The patient should be instructed to keep a daily log that records weight and diuretic dose. Patients are instructed to stop the diuretic if their weight falls too low, resuming at a lower dose when enough saltwater has been retained to restore the target weight.
Inpatient diuretic management should also employ the target-weight concept, but dose adjustments can be made more often and more aggressively, particularly at the start of therapy. It is important to rapidly define the dose that can deliver enough drug to the tubular lumen to reach the steep portion of the dose-response curve. Once an effective dose is defined, larger doses of diuretic provide little benefit. If a greater response is needed, the effective dose should be repeated several times during the day, or alternatively, a continuous infusion can be given to maintain effective urinary drug levels. Continuous infusion of loop diuretics induces a slightly larger natriuretic response than does bolus administration and is associated with a shorter hospital stay in patients with advanced heart failure.66
Diuretic resistance Resistance to high doses of loop diuretics may be overcome by administering loop diuretics in combination with a thiazide or metolazone. Acetazolamide may be used along with or in place of a thiazide or metolazone. This strategy blocks sodium reabsorption at several sites along the nephron, avoiding resistance caused by increased sodium reab-sorption proximal or distal to the loop of Henle. Careful monitoring is extremely important, because these combinations can be extremely potent, causing large potassium and sodium losses.
Diuretic complications All diuretic agents may cause volume depletion and azotemia, but these complications are most likely to occur with loop diuretics.4 Hypokalemic alkalosis, hy-perglycemia, and hyperuricemia (sometimes with clinical gout) are common dose-dependent complications of both thiazides and loop diuretics. Thiazides decrease calcium excretion and may cause hypercalcemia in patients with underlying conditions that increase gastrointestinal calcium absorption (e.g., sar-coidosis) or bone reabsorption (e.g., hyperparathyroidism). Thi-azides are also much more likely to cause hyponatremia than other agents and should be avoided in patients who habitually drink large amounts of fluid. Potassium-sparing agents (e.g., tri-amterene, amiloride, and spironolactone) may cause hyper-kalemia; these agents should generally not be given with potassium supplements, and they should be used with caution in patients with renal insufficiency (particularly diabetic nephrop-athy) and patients taking ACE inhibitors or angiotensin receptor blockers. Loop diuretics can predispose to hearing loss, particularly when high doses are administered by bolus injection to patients receiving other ototoxic drugs.35 Hearing loss from etha-crynic acid is more likely to be permanent.
Disorder of Saltwater Deficiency: Volume Depletion
Pathogenesis
Volume depletion occurs when saltwater is lost from the extracellular fluid at a rate that exceeds intake. Saltwater can be lost from the gastrointestinal tract, kidney, or skin, or it can result from extravascular sequestration (third-space losses) in the abdominal cavity or in traumatized tissues.
Underfilling of the arterial circulation triggers a cascade of physiologic responses that preserve blood flow to vital organs. Volume receptors and baroreceptors activate the sympathetic nervous system and the renin-angiotensin-aldosterone system. Except when renal salt wasting is the cause, these responses reduce urinary sodium excretion so that nearly all ingested salt is retained. Volume-depleted persons also become thirsty; ingested water is retained because vasopressin, released in response to volume depletion, concentrates the urine, decreasing water excretion. The plasma sodium concentration can be high, normal, or low in volume-depleted persons, depending on electrolyte-free water intake and excretion. Vasoconstriction maintains the systemic blood pressure and also reduces renal blood flow. Initially, efferent arteriolar resistance, mediated by angiotensin II, predominates, sustaining intraglomerular pressure and the glomerular filtration rate; in more severe hypovolemia, renal blood flow is further reduced and glomerular filtration falls.
Etiology
Because renal sodium conservation can reduce urinary sodium losses to less than 10 mmol/day, volume depletion is unlikely to occur from decreased intake alone. The small bowel and colon are the most common sources of isotonic fluid loss. Spectacular amounts of isotonic saltwater can be lost in diarrhea. For example, rice-water stool losses in cholera can reach 20 L/day, causing death within a few hours without fluid replacement. Small bowel obstruction causes pooling of several liters of saltwater within the bowel lumen. Fluid may also be sequestrated in the abdominal cavity in patients with pancreatitis or peritonitis. Sequestration of fluid in the soft tissues may also complicate crush injuries with rhabdomyolysis or burns.
Renal salt wasting can cause volume depletion, but only a few disorders can cause enough renal salt loss to be clinically apparent. Diuretics and osmotic diuresis caused by glycosuria are the most frequent causes of renal salt wasting. Transient renal salt wasting may occur in the recovery phases of acute tubular necrosis or obstructive uropathy, and it can also occur in toxic nephropathies. Renal salt wasting also occurs in adrenal insufficiency.
Diagnosis
Clinical Manifestations
Minor degrees of volume depletion (less than 10% of plasma volume, equivalent to the loss of one unit of blood) cause an increase in heart rate and may also be associated with complaints of fatigue, thirst, or muscle cramps. With modest hypovolemia, arteriolar vasoconstriction is sufficient to maintain the blood pressure when the patient is recumbent. However, dizziness and hypotension emerge on standing or during physical exertion. Severe fluid losses cause hypotension in recumbency and, ultimately, signs of tissue ischemia and shock (e.g., cool, clammy extremitites, decreased urine output, lethargy, and confusion). Irreversible tissue injury may occur if this condition is allowed to continue.
Loss of weight within a short period is the most reliable sign of volume depletion. Physical findings include a low jugular venous pulse rate and orthostatic changes in blood pressure and heart rate.67,68 However, because postural hypotension can occur in up to 30% of normovolemic persons older than 65 years, these changes must be interpreted with caution. Decreased skin tur-gor and dry mucous membranes are generally unreliable findings in volume-depleted adults; these signs can be absent in severe hypovolemia, and they can be present (particularly in mouth breathers and the elderly) when the patient is actually volume overloaded. The presence of edema makes true volume depletion unlikely.
Laboratory Tests
Laboratory findings are related to the decreased volume of intravascular saltwater and to decreased renal perfusion. The hematocrit increases in proportion to the contraction of plasma volume, and the serum albumin may be increased as well. Urinary sodium is usually less than 20 mEq/L except in metabolic alkalosis (in which the urine chloride is low) or when renal sodium wasting is the cause of the condition.44,69 Renal blood flow is reduced, but unless the patient is frankly hypotensive, the glomerular filtration rate is maintained by vasoconstriction of the efferent glomerular arteriole. Thus, except in severe volume depletion, the serum creatinine changes very little. Unlike creati-nine, urea is reabsorbed from the glomerular filtrate. Thus, in volume depletion (prerenal azotemia), the BUN is increased disproportionately to the increase in creatinine.69 Azotemia may be blunted in patients with a poor dietary-protein intake and may be exacerbated in patients who are catabolic, bleeding, or receiving steroid therapy.
Treatment
Patients with mild volume depletion can be treated by increasing their dietary intake of salt, relying on normal thirst mechanisms to provide the appropriate amount of water. For most patients, the familiar (but misguided) order to drink fluids should be replaced with an order to salt one’s food. Even severe volume depletion can be treated with oral solutions containing electrolytes, sugar, and amino acids.70 Glucose and amino acids promote intestinal absorption of sodium through cotransport mechanisms similar to those found in the proximal tubule of the kidney. Rice-based oral replacement solutions have been a major advance in the treatment of diarrhea in developing countries.
Intravenous fluids are necessary when fluids cannot be taken orally. If the patient is hypotensive, isotonic saline should be given as rapidly as possible until tissue perfusion is adequate. Colloid-containing solutions have no proven advantage over crys-talloids.71 There is no accurate way to estimate the total fluid deficit in hypovolemia other than continued clinical observation of the patient’s response to therapy.
