I. INTRODUCTION

A. Diuretics are drugs that increase urinary loss of sodium ions (Na⁺) and water. By shrinking extracellular fluid (ECF) volume, they mobilize edema fluid from the interstitial space and restore normal tissue perfusion and organ function. Their primary clinical use in veterinary medicine is in the prevention and treatment of generalized edema or severe local edema. Causes of generalized edema include congestive heart failure, liver disease, renal disease, or protein-losing enteropathies. The latter three conditions are characterized by low levels of plasma albumin because of the impaired synthesis (liver disease) or excess loss (renal or intestinal disease). The resulting fall in plasma oncotic pressure results in transudation of fluid from plasma to the interstitial space.

Cerebral, pulmonary, ocular, and udder edema are examples of local edema that arises from infection, inflammation, trauma, or poisons.

B. All diuretics act directly on renal tubular epithelia at specific sites in the nephron (Table 9-1). A brief review of ion and water transport in nephron segments is useful in understanding the action of diuretic drugs.

1. Proximal convoluted tubule (Figure 9-1). Sixty-five percent of the filtered sodium and water is reabsorbed from this segment. Sodium is absorbed by active transport, coupled transport with glucose and amino acids, and passive diffusion. High concentrations of carbonic anhydrase (CA) in tubule cells generate hydrogen ions

which exchange for luminal sodium ions (Na+–H+ antiport). Filtered bicarbonate is reabsorbed from the lumen by a reversal of the above reaction (catalyzed by brush border CA) and the diffusion of CO₂ into the proximal tubule cell. Chloride and potassium are passively reabsorbed. Absorption is isosmotic since water is reabsorbed with ions. Activation of the renin–angiotensin system in response to volume depletion or a fall in blood pressure increases sodium and water reabsorption from this segment.

2. Descending loop of Henle. Sodium and chloride ions are not reabsorbed but become progressively concentrated in luminal fluid as water is osmotically removed into the hypertonic medullary interstitium.

3. Thick portion of the ascending loop of Henle (Figure 9-2). Twenty-five percent of the filtered sodium is reabsorbed in this segment. Sodium, potassium, and chloride are actively transported out of the lumen by a coupled mechanism (Na⁺–K⁺–2Cl⁻symport). The tubule epithelium is impermeable to water. The movement of ions but not water out of the lumen in this segment is essential to the countercurrent multiplier system of the kidney which generates the hypertonic-medullary interstitium. Calcium (Ca++) and magnesium (Mg++) are passively reabsorbed via the paracellular pathway. Luminal fluid is hypotonic as it leaves this segment.

4. Early distal convoluted tubule (Figure 9-3). Ten percent of filtered sodium is reabsorbed in this segment. Chloride ion is cotransported with sodium. Calcium reabsorption is increased by parathyroid hormone (PTH) acting at this segment of the nephron. The tubule epithelium is impermeable to water and thus there is further dilution of tubular urine.

5. Late distal tubule and collecting duct (Figure 9-4). Four percent of filtered sodium is actively reabsorbed in this part of the nephron. Potassium and hydrogen ions are secreted. An increase in the sodium load reaching this segment tends to increase K⁺ and H⁺ secretions as Na⁺ is reabsorbed. Therefore, loop and thiazide diuretics indirectly increase urinary loss of K⁺ and H⁺ and tend to produce hypokalemia and metabolic alkalosis. Aldosterone acts at this segment to increase luminal sodium channels resulting in increased sodium absorption and potassium excretion. Water is reabsorbed only if antidiuretic hormone (ADH) is present.

TABLE 9-1. Site of Actions of Diuretics

Nephron Segment	Diuretic
Proximal convoluted tubule	CA inhibitors (e.g., acetazolamide) Osmotic agents (e.g., mannitol) Xanthines (e.g., aminophylline)
Ascending loop of Henle	Loop diuretics (e.g., furosemide) Osmotic agents
Early distal convoluted tubule	Thiazides (e.g., hydrochlorothiazide)
Late distal tubule and collecting duct	K⁺-sparing diuretics (e.g., triamterene or spironolactone)

FIGURE 9-1. Electrolyte and water transport in the proximal convoluted tubule. Sodium moves into the cell down its concentration gradient—maintained by the Na⁺–K⁺-ATPase pump on the basolateral membrane. Sodium is also absorbed by exchange with H⁺ at the luminal membrane (antiport). Hydrogen ion combines with filtered bicarbonate to form H₂CO₃, which is converted to H₂O and CO₂ by brush border carbonic anhydrase (CA). The reaction is reversed intracellularly. Diuretics that inhibit CA, such as acetazolamide, increase excretion of Na⁺ and .

FIGURE 9-2. Electrolyte and water transport in the thick ascending limb of the loop of Henle. The Na⁺–K⁺–2Cl⁻ symporter at the luminal membrane moves these ions into the cell. Part of the K⁺ diffuses back to the lumen via conductance channels to maintain the lumen-positive transepithelial potential, which provides the driving force for the paracellular absorption of Ca⁺⁺ and Mg⁺⁺. Inhibition of the symporter by loop diuretics, such as furosemide, increase excretion of Na⁺, K⁺, Cl⁻, Ca⁺⁺, and Mg⁺⁺.

II. LOOP (HIGH-CEILING) DIURETICS

A. Preparations and chemistry. Furosemide and bumetanide are structurally related to sulfonamides. Ethacrynic acid is a derivation of phenoxyacetic acid. All are carboxylic acids. Furosemide is the most commonly used loop diuretic in veterinary medicine.

B. Mechanism of action. Loop diuretics inhibit electrolyte reabsorption in the thick ascending limb of the loop of Henle. They act at the luminal face of the epithelial cell to inhibit Na⁺–K⁺–2Cl⁻cotransport into the cell. They have a rapid onset of action with peak diuresis greater than other classes of diuretics. Calcium and magnesium ion absorption from the ascending loop of Henle are also inhibited because of the decreased lumen-positive transepithelial potential. Diuretic action is independent of urinary pH. Loop diuretics produce an increase in systemic venous capacitance which may be due to their ability to stimulate prostaglandin release by the juxtaglomerular apparatus.

FIGURE 9-3. Absorption of sodium and chloride in the distal convoluted tubule is linked by a Na⁺–Cl^– symporter in the luminal membrane. Thiazide diuretics inhibit the symporter and increase excretion of Na⁺ and Cl^–.

FIGURE 9-4. Electrolyte transport in the distal tubule and collecting duct. In the principal cell, sodium moves down its electrochemical gradient into the cell through Na⁺ channels in the luminal membrane. Potassium moves from the cell into the lumen via K⁺ channels in the luminal membrane driven by the lumen-negative transepithelial potential. This potential also aids the transport of H⁺ into the lumen by the H⁺-ATPase pump in the intercalated cell. Potassium-sparing diuretics such as triamterene and amiloride block luminal sodium channels to reduce Na⁺ absorption and K⁺ excretion. Aldosterone stimulates the production of aldosterone-induced proteins (AIP), which increases luminal sodium channels to increase Na⁺ absorption.

C. Therapeutic uses

1. Loop diuretics are the drugs of choice for the rapid mobilization of edema fluid arising from congestive heart failure, liver disease, or other causes of generalized edema, and for pulmonary, cerebral, or udder edema.

2. Furosemide increases urinary calcium excretion and is used in the treatment of hypercalcemia and hypercalcuric nephropathy in dogs and cats.

3. Furosemide may be combined with osmotic diuretics such as mannitol to maintain urine flow in severe oliguria and acute renal failure.

4. Furosemide is used for the prevention of exercise-induced pulmonary hemorrhage (EIPH) and epistaxis in racehorses. Its efficacy in this condition may be related to increased blood vessel capacitance and decreased left atrial pressure.

D. Pharmacokinetics. Furosemide, bumetanide, and ethacrynic acid are well absorbed orally. They are actively secreted into urine by the organic acid transport system of the proximal convoluted tubule and thus rapidly reach their site of action in the loop of Henle. Furosemide is excreted in the urine as unchanged drug (80%) or as the glucuronide (20%). The plasma t_½ is 1–2 hours for most species and the duration of diuresis is 3–6 hours for a single oral dose. If administered intravenously, the onset of diuresis is 2–20 minutes with a duration of 2 hours.

E. Administration

1. For the treatment of edema, furosemide is administered orally or intravenously three times a day for diuresis in dogs and cats and twice a day in cattle and horses. Treatment for udder edema in cattle should not exceed 48 hours postpartum.

2. For the treatment of oliguric renal failure, furosemide is administered intravenously at hourly intervals until diuresis occurs.

3. For the prevention of EIPH, furosemide is administered intravenously to horses 1–2 hours prior to a race for EIPH prevention. Rules of use are governed by state racing authorities.

4. For the treatment of hypercalcemia or hypercalcuric nephropathy in dogs and cats, furosemide is administered in KCl-supplemented saline, intravenously, once or twice a day.

F. Adverse effects

1. Fluid and electrolyte imbalances (especially hypokalemia) are the most common adverse effects. High or prolonged doses may produce dehydration, muscle weakness, CNS depression, volume depletion, and cardiovascular collapse. Cats are more sensitive than dogs to the effects of loop diuretics and lower doses are used in this species.

2. Loop diuretics may alter electrolyte balance in the endolymph of the inner ear. Deafness is a risk if a potentially ototoxic drug (e.g., an aminoglycoside antibiotic) is administered concomitantly. In such circumstances, another class of diuretic should be employed.

3. Transient granulocytopenia and thrombocytopenia may occur.