Diuretics are used to remove inappropriate water volume in animals with edema or volume overload, correct specific ion imbalances, and reduce blood pressure and pulmonary capillary wedge pressure (see Table: Dosages of Diuretics Dosages of Diuretics Diuretics are used to remove inappropriate water volume in animals with edema or volume overload, correct specific ion imbalances, and reduce blood pressure and pulmonary capillary wedge pressure... read more ). 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, whereas 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. See also Diuretics Diuretics Diuretics are the cornerstone of therapy in management of animals with congestive heart failure (CHF) characterized by cardiogenic pulmonary edema, pleural effusion, ascites, or a combination... read more .
Furosemide is a sulfonamide derivative and the most commonly administered diuretic in veterinary medicine. 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 before 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 local synthesis of 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 after 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 angiontensin-converting enzyme (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. 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 NSAIDs may interfere with furosemide's prostaglandin-controlled renal vasodilation and reduce the diuretic effect. Furosemide-induced dehydration of airway secretions may exacerbate respiratory disease.
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, because 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. Thiazides decrease renal excretion of calcium, so they should not be used in hypercalcemic animals.
Potassium-sparing diuretics include spironolactone, amiloride, and triamterene. Spironolactone is the one most frequently used in veterinary medicine and is a competitive antagonist of aldosterone. Aldosterone is increased 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 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 used at low doses with concurrent ACE inhibitor therapy.
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 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 in its place. Mannitol acts as a protectant against further renal tubular damage and initiates an osmotic diuresis. The initial dosage is 0.25–0.5 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 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).