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

(seeDosages 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.

Dosages of DiureticsDrug 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 InhibitorsCarbonic 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).