Diuretics

Diuretics are used to remove inappropriate water in animals with edema or volume overload, correct specific ion imbalances, and reduce blood pressure and pulmonary capillary wedge pressure (see Dosages of Diuretics). They are classified by their mechanism of action as loop diuretics, carbonic anhydrase inhibitors, thiazides, osmotic diuretics, and potassium-sparing diuretics. The efficacy and use of each class of diuretic depends on the mechanism and site of action. Patterns of electrolyte excretion vary between classes, while maximal response is the same within a class. 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.

Table 2
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Dosages of Diuretics Drug Dosage Furosemide 4–6 mg/kg IV, IM, or SC for acute therapy Dogs: 2–4 mg/kg, PO, sid-tid Cats:1–2 mg/kg, PO, sid-bid Large animals: 0.5–1.0 mg/kg, IV or IM, sid Hydrochlorothiazide Dogs and cats: 2–4 mg/kg, PO, sid-bid Chlorothiazide Dogs and cats: 20–40 mg/kg, PO, sid-bid Spironolactone Dogs: 2–4 mg/kg, PO, bid Mannitol 0.25–0.50 g/kg, IV Dimethyl sulfoxide Large animals: 1 g/kg, IV or via nasogastric tube

Furosemide

Furosemide is a sulfonamide derivative. It is the most commonly administered diuretic to veterinary patients. Furosemide is a loop diuretic; it 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 prior to the onset of diuresis. Vasodilation increases renal blood flow, thereby increasing renal perfusion and lessening fluid retention. It appears that renal vasodilation depends on the synthesis of local prostaglandins.

The elimination half-life of furosemide is short in most animals (∼15 min). The effect peaks 30 min after IV administration and 1–2 hr after PO administration. The duration of diuretic action is 2 and 6 hr following IV and PO administration, respectively. Furosemide is highly protein bound (91–97%), almost totally to albumin. It is cleared through the kidneys by renal tubular secretion. Bioavailability of oral furosemide is low (only 50% is absorbed).

Furosemide is usually dosed to effect. For acute, short-term therapy, single IV, IM, or SC doses of 4–6 mg/kg are given. The major adverse effect from acute administration of large doses is acute intravascular volume reduction, which worsens cardiac output and hypotension and may precipitate acute renal failure. Chronic therapy in cats and some dogs can be accomplished by therapy every second or third day. Higher than normal doses of furosemide may be required in animals with renal disease due to 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 ACE inhibitor, may help avoid adverse effects.

Furosemide therapy is associated with a number of adverse effects. By nature of its mechanism of action, it causes dehydration, volume depletion, hypokalemia, and hyponatremia, which may be excessive and detrimental. The high degree of protein binding can lead to interactions with other highly protein-bound drugs, and any condition that alters albumin concentrations affects the concentration of free drug available for diuretic action. Furosemide's most important drug interaction 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 antidiuretic hormone secretion and the exchange of sodium ions for lost intracellular potassium ions. Concurrent administration of NSAID may interfere with prostanglandin-controlled renal vasodilation. Furosemide-induced dehydration of airway secretions may exacerbate respiratory disease.

Thiazide Diuretics

The thiazide diuretics, hydrochlorothiazide and chlorothiazide, are not as potent as furosemide and thus are infrequently used in veterinary medicine. The thiazides act on the proximal portion of the distal convoluted tubule to inhibit sodium resorption and promote potassium excretion. They may be administered to animals that cannot tolerate a potent loop diuretic such as furosemide. They should not be administered to azotemic animals, as they decrease renal blood flow. Because the thiazides act on a different site of the renal tubule than other diuretics, they may be combined with a loop diuretic or potassium-sparing diuretic for treatment of refractory fluid retention. Adverse effects are electrolyte and fluid balance disturbances, similar to furosemide.

Potassium-sparing Diuretics

Potassium-sparing diuretics include spironolactone, amiloride, and triamterene (available only in Canada). Spironolactone is used most frequently and is a competitive antagonist of aldosterone. Aldosterone is elevated in animals with congestive heart failure when the renin-angiotensin system is activated in response to hyponatremia, hyperkalemia, and reductions in blood pressure or cardiac output. Aldosterone is responsible for increasing sodium and chloride reabsorption and potassium and calcium excretion from renal tubules. Spironolactone competes with aldosterone at its receptor site, causing a mild diuresis and potassium retention. Spironolactone is well absorbed after administration PO, especially if given with food. It is highly protein bound (>90%) and extensively metabolized by the liver to the active metabolite, canrenone. It is primarily eliminated by the kidneys. The onset of action for spironolactone is slow, and effects do not peak for 2–3 days. Spironolactone is not recommended as monotherapy, but can be added to furosemide or thiazide therapy to treat refractory heart failure cases. Because of the potential for hyperkalemia, spironolactone should not be administered concurrently with potassium supplements or ACE inhibitors.

Carbonic Anhydrase Inhibitors

Carbonic anhydrase inhibitors act in the proximal tubule to noncompetitively and reversibly inhibit carbonic anhydrase, which decreases the formation of carbonic acid from carbon dioxide and water. Reduced 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 resorption step, carbonic anhydrase inhibitors also enhance potassium excretion.

Osmotic Diuretics

Osmotic diuretics include mannitol, dimethyl sulfoxide (DMSO), urea, glycerol, and isosorbide. Mannitol is commonly used in small animals but is expensive for use in adult large animals, so DMSO is often used. Mannitol acts as a protectant against further renal tubular damage and initiates an osmotic diuresis. The initial dosage is 0.25–0.50 g/kg, given IV over 3–5 min. A response should be noted within 20–30 min. If a response is seen, the dose can be repeated every 6–8 hr, or a constant rate infusion of 2–5 mL/min of a 5–10% solution can be given. The total daily dosage should not exceed 2 g/kg. If a diuresis is not seen, the initial dose can be repeated up to a total dosage of 1.5–2 g/kg. However, repeated doses usually are not more effective and 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 very 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. The dosage is 1 g/kg, IV or via nasogastric tube, as a 10% solution diluted in 5% dextrose or lactated Ringer's solution (higher concentrations can cause intravascular hemolysis).

Last full review/revision March 2012 by Patricia M. Dowling, DVM, MSc, DACVIM, DACVCP