Diuretics are used to remove extra water volume in animals with edema or volume overload, to correct specific ion imbalances, and to decrease blood pressure and pulmonary capillary wedge pressure. These drugs are grouped by their mechanism of action into the following classes: loop diuretics, thiazides, potassium-sparing diuretics, carbonic anhydrase inhibitors, and osmotic diuretics.
The efficacy and use of each diuretic class depends on the mechanism and site of action. Patterns of electrolyte excretion vary between classes; within a class, however, maximal response is the same. Therefore, if one drug within a class is ineffective, a different drug from the same class will likely be ineffective as well.
Combining diuretics from different classes can lead to additive and potentially synergistic effects.
Also see Diuretics for Use in Animals in the cardiovascular system pharmacotherapeutics chapter.
Loop Diuretics Used to Treat Urinary Disease in Animals
Furosemide
Furosemide is a sulfonamide derivative and the most commonly administered diuretic in veterinary medicine. Furosemide is a loop diuretic that inhibits the reabsorption of sodium and chloride in the thick, ascending loop of Henle, resulting in loss of sodium, chloride, and water into the urine.
Furosemide induces beneficial hemodynamic effects before the onset of diuresis. Vasodilation increases renal blood flow, thereby increasing renal perfusion and decreasing fluid retention. Renal vasodilation appears to depend on the local synthesis of prostaglandins.
The elimination half-life of furosemide is short in most animals (~15 minutes). The effect peaks 30 minutes after IV administration and 1–2 hours after PO administration. The diuretic action of furosemide lasts 2 hours after IV administration and 6 hours after PO administration. Administration of furosemide by constant-rate infusion (CRI) results in greater natriuresis and diuresis compared to IV bolus treatment.
Furosemide is highly protein bound (91%–97%), almost exclusively to albumin. It is cleared through the kidneys by renal tubular secretion. The bioavailability of oral furosemide is low in small animals (only 50% is absorbed) and too low in large animals to be useful.
Furosemide is usually dosed to effect. The major adverse effect from acute administration of large doses is acute decrease in intravascular volume, which worsens cardiac output and hypotension and may precipitate acute renal failure. For chronic treatment in cats and some dogs, furosemide may be administered every 48 or 72 hours.
Higher-than-normal doses of furosemide may be required in patients with renal disease because of functional abnormalities of the renal tubule and binding of furosemide to protein in the urine. If escalating doses of furosemide are required to control fluid retention, adding other types of volume-modifying medications, such as a potassium-sparing diuretic or an angiotensin-converting enzyme (ACE) inhibitor, may help avoid adverse effects.
A number of adverse effects are associated with treatment with furosemide. Its mechanism of action leads to dehydration, volume depletion, hypokalemia, and hyponatremia, which may be excessive and detrimental.
The most important drug interaction of furosemide is with the digitalis glycosides digoxin and digitoxin. The hypokalemia induced by furosemide diuresis potentiates digitalis toxicity. As long as animals continue to eat, hypokalemia does not usually develop. Hypokalemia also predisposes animals to hyponatremia by enhancing the secretion of antidiuretic hormone and the exchange of sodium ions for lost intracellular potassium ions.
Concurrent administration of NSAIDs may interfere with furosemide's prostaglandin-controlled renal vasodilation and decrease its diuretic effect. Furosemide-induced dehydration of airway secretions may exacerbate respiratory disease. If administered in a CRI, furosemide is unsuitable for coadministration in the same IV administration set with amiodarone, esmolol, dobutamine, diltiazem, dopamine, or magnesium sulfate.
Torsemide
Torsemide is a loop diuretic with a mechanism of action similar to that of furosemide, but at much lower dosages. Torsemide is approved for veterinary use in some countries.
Its oral bioavailability in dogs is higher than that of furosemide, regardless of whether food is withheld. Unlike furosemide, which has been found to lose efficacy (diuretic tolerance) at 14 days of repeated administration, torsemide retains its diuretic effect.
Secondary pharmacological effects of torsemide include an antialdosterone effect, as well as antihypertensive and antifibrotic effects. These effects may be beneficial in dogs with congestive heart failure. The drug interactions of torsemide may be similar to those of furosemide.
Thiazide Diuretics Used to Treat Urinary Disease in Animals
The thiazide diuretics—hydrochlorothiazide and chlorothiazide—are not as powerful as the loop diuretics and thus are infrequently used in veterinary medicine.
The thiazides act on the proximal portion of the distal convoluted tubule to inhibit sodium reabsorption and promote potassium excretion. They may be administered to patients that cannot tolerate a loop diuretic such as furosemide. They should not be administered to patients with azotemia, because they decrease renal blood flow.
Because the thiazides act on a different site of the renal tubule than do other diuretics, they may be combined with a loop diuretic or a potassium-sparing diuretic to treat refractory fluid retention. As with furosemide, adverse effects include electrolyte and fluid balance disturbances. Thiazides decrease the renal excretion of calcium, so they should not be used in hypercalcemic patients.
Potassium-Sparing Diuretics Used to Treat Urinary Disease in Animals
Potassium-sparing diuretics include spironolactone, amiloride, and triamterene. Of these, spironolactone is the most frequently used in veterinary medicine.
Spironolactone is a mineralocorticoid receptor antagonist. It competes with aldosterone at its receptor site, resulting in mild diuresis and potassium retention.
Aldosterone is increased in animals with congestive heart failure when the renin-angiotensin-aldosterone system (RAAS) is activated in response to hyponatremia, hyperkalemia, and decreases in blood pressure or cardiac output. Aldosterone is responsible for increasing sodium and chloride reabsorption and potassium and calcium excretion from renal tubules.
Spironolactone is well absorbed after oral administration, especially if given with food. It is highly protein bound (> 90%) and extensively metabolized by the liver to the active metabolite canrenone. Spironolactone is eliminated primarily by the kidneys. Its onset of action is slow, and effects do not peak for 2–3 days.
Spironolactone is not recommended as monotherapy; however, it can be used in combination with furosemide or a thiazide to treat cases of refractory heart failure. Because of the potential for hyperkalemia, spironolactone should not be administered concurrently with potassium supplements. It has been shown to be safe when administered at low doses concurrently with ACE inhibitors.
Carbonic Anhydrase Inhibitors Used to Treat Urinary Disease in Animals
Carbonic anhydrase inhibitors (eg, acetazolamide, methazolamide) act in the proximal tubule to noncompetitively and reversibly inhibit carbonic anhydrase, which decreases the formation of carbonic acid from carbon dioxide and water. Decreased formation of carbonic acid results in fewer hydrogen ions within proximal tubule cells. Because hydrogen ions are normally exchanged with sodium ions from the tubule lumen, more sodium is available to combine with urinary bicarbonate.
Diuresis occurs when water is excreted with sodium bicarbonate. As bicarbonate is eliminated, systemic acidosis results. Because intracellular potassium can substitute for hydrogen ions in the sodium reabsorption step, carbonic anhydrase inhibitors also enhance potassium excretion.
Osmotic Diuretics Used to Treat Urinary Disease in Animals
Osmotic diuretics include mannitol, dimethyl sulfoxide (DMSO), urea, glycerol, and isosorbide.
Mannitol is commonly used in small animals; however, it is expensive for use in adult large animals, so DMSO is often used in its place. Mannitol protects against further renal tubular damage and initiates an osmotic diuresis. A response should be noted within 20–30 minutes.
If a response is observed, the dose may be repeated, or a CRI of a 5%–10% solution may be administered. The total daily dosage should not exceed 2 g/kg.
If diuresis is not observed, the initial dose may be repeated up to a total dosage of 1.5–2 g/kg. However, repeated doses usually are not more effective, and they increase the likelihood of complications (eg, edema).
DMSO is an oxygen-derived free radical scavenger and an osmotic diuretic. It is used in large animals to treat inflammatory and edematous conditions. It is a potent solvent that can penetrate intact skin and carry other chemicals along with it. It penetrates all body tissues and produces an odor that many people cannot tolerate. It is dosed IV or via nasogastric tube, as a 10% solution diluted in 5% dextrose or lactated Ringer’s solution (higher concentrations can lead to intravascular hemolysis).
