Diuretics are the cornerstone of treatment in management of animals with congestive heart failure (CHF) characterized by cardiogenic pulmonary edema, pleural effusion, ascites, or a combination of these clinical signs.
The three classes of diuretics used to treat CHF in dogs and cats differ in their relative potencies and mechanisms of action:
Loop diuretics: most potent and have a high ceiling, enabling them to be administered in a dose-dependent way to treat mild to life-threatening CHF; can be administered orally or parenterally
Thiazide diuretics: mild to moderate in potency; typically administered in conjunction with a loop diuretic (eg, furosemide) in animals with severe refractory CHF
Potassium-sparing diuretics (eg, spironolactone): historically, reserved for those animals that have right heart failure or have become hypokalemic secondary to the use of other diuretics, or for those animals refractory to other agents; most common use now is for its antifibrotic (cardioprotective) effects related to myocardial aldosterone blockade
All loop and thiazide diuretics share a similar dose-dependent adverse effect profile, including electrolyte and acid-base disturbances, dehydration, and prerenal and renal azotemia. The relative risk of azotemia is increased when a diuretic is administered concurrently with an angiotensin-converting enzyme (ACE) inhibitor or an NSAID or other potential renal toxin. Diuretics may also increase the risk of digoxin toxicosis. In addition, diuretic resistance can develop with longterm treatment.
The most common electrolyte and acid-base abnormalities include hypokalemia, hyponatremia, hypomagnesemia, and metabolic alkalosis. These effects are potentiated by the use of more than one diuretic (sequential nephron blockade), concurrent hyporexia or anorexia, and the use of higher doses. Typically, potential adverse effects are more severe in cats than in dogs.
Numerous factors determine the response to diuretic treatment, including the following:
potency of the drug
dosage administered
duration of action of the drug
route of administration
renal blood flow
glomerular filtration rate
nephron function
The plasma concentration depends on the route of administration (eg, IV administration will produce a higher concentration than PO administration) and the dose. The duration of effect will also determine the total diuretic effect produced in a certain time period.
Animals with CHF may become refractory to furosemide because of decreased delivery of the drug to the nephron as a result of decreased renal blood flow or hormonal stimulus for sodium and water retention. Therefore, strategies to increase renal blood flow or plasma concentration may ameliorate diuretic resistance. Furosemide resistance should be considered when doses exceed 8–10 mg/kg, q 24 h in the dog and approximately 6 mg/kg, q 24 h in the cat.
Furosemide
Furosemide is a loop diuretic and the most commonly administered diuretic to treat CHF in dogs, cats, cattle, and horses.
Preparations and Disposition of Furosemide in Animals
Furosemide is available in oral (tablets, suspensions) and parenteral formulations. Compounded liquids (from tablets) may be better tolerated in cats than the commercially available alcohol-based 1% syrup.
All loop diuretics inhibit sodium, potassium, and chloride reabsorption in the thick portion of the ascending loop of Henle, leading to inhibition of sodium and commensurate water reabsorption in the nephron. Furosemide diuresis results in enhanced excretion of sodium, chloride, potassium, hydrogen, calcium, magnesium, and possibly phosphate. Chloride excretion is equal to or exceeds sodium excretion. Enhanced hydrogen ion excretion without a concomitant increase in bicarbonate excretion can result in metabolic alkalosis. Despite the increase in net acid excretion, urinary pH falls slightly after furosemide administration, while urine specific gravity is generally decreased to approximately 1.006–1.020.
In addition to its diuretic effects, furosemide acts as a mild systemic venodilator, decreasing systemic venous pressure before diuresis occurs, especially after IV administration. Furosemide decreases renal vascular resistance. Thus, it acutely increases renal blood flow (~50%) without changing glomerular filtration rate.
Furosemide is highly protein bound (86%–91%). The ratio of kidney to plasma concentration is 5:1. A small amount of furosemide (1%–14%) is metabolized to a glucuronide derivative in dogs; however, this metabolism does not occur in the liver. In dogs, ~45% of furosemide is excreted in the bile and 55% in the urine.
After IV administration, furosemide has an elimination half-life of ~1 hour, and its onset of action is within 5 minutes; peak effects occur within 30 minutes, and duration of effect is 2–3 hours. Approximately 50% of the drug is cleared from the body within the first 30 minutes, 90% within the first 2 hours, and almost all is eliminated within 3 hours.
Furosemide is rapidly but incompletely absorbed after PO administration with a bioavailability of 40%–50%. The terminal half-life after administration PO is biexponential. The initial phase has a half-life of ~30 minutes, with the second phase half-life of ~7 hours. The initial disposition phase has the most effect on plasma concentration, with concentration decreasing from therapeutic to subtherapeutic within 4–6 hours of PO administration. After PO administration, onset of action occurs within 60 minutes, peak effects occur within 1–2 hours, and duration of effect is ~6 hours.
In healthy dogs, a dose of furosemide administered at 2.5 mg/kg, IM, results in maximal natriuresis (beyond that dose there is no further increase in sodium excretion). This occurs at a plasma concentration of ~0.8 mcg/mL. Because the diuretic effect of furosemide depends on its hematogenous delivery to the kidneys, animals with decreased renal blood flow (eg, those with heart failure) need a higher plasma concentration (higher dose) to produce the same effect observed in healthy dogs. This is achieved by administering higher oral doses or by administering the drug IV.
Cats are more sensitive to furosemide than dogs. Clinically, cats commonly require no more than 1–2 mg/kg, PO, every 12–24 hours for longterm treatment of pulmonary edema. However, higher dosages may be needed in cats with severe heart failure because of decreased renal blood flow.
Drug Interactions and Toxicity of Furosemide in Animals
Drug interactions, adverse effects, and toxic effects of furosemide are typically those described for diuretics as a class. Some special considerations for furosemide include its potential for ototoxicity. When administered as the sole agent, furosemide in dosages > 20 mg/kg, IV, can result in loss of hearing in dogs. Dosages of 50–100 mg/kg result in profound loss of hearing.
Furosemide can also potentiate the ototoxic and nephrotoxic effects of other drugs, such as the aminoglycosides.
Clinical Use of Furosemide in Animals
For treatment of life-threatening cardiogenic pulmonary edema in dogs, parenteral dosages of furosemide of 2–4 mg/kg, every 1–6 hours, IV, IM, or SC in dogs and 0.5–2 mg/kg, every 1–8 hours, IV, IM, or SC in cats are typically used. Dosing intervals depend on the response to treatment; initially, boluses can be administered every 1–2 hours and decreased to every 4–8 hours in dogs, and administered every 2 hours and decreased to every 6–8 hours in cats. Alternatively, a constant-rate infusion (CRI) of 0.25–1 mg/kg/h in dogs or 0.25–0.6 mg/kg/h in cats could be used. Bolus administration and CRI for treatment of life-threatening pulmonary edema are tapered over 12–24 hours as clinical signs resolve.
Typical starting dosages for longterm management of CHF in dogs are 2 mg/kg, PO, every 12 hours (range, 1–5 mg/kg, PO, every 8–12 hours), and in cats are 1 mg/kg, PO, every 24 hours (range, 1–2 mg/kg, PO, every 12–24 hours to a maximum total daily dose of 4–6 mg/kg).
The dosage in the horse is 1 mg/kg, IV, IM, as needed. A loading dose of 0.12 mg/kg followed by a CRI of 0.12 mg/kg/h has been evaluated in the horse and causes more profound diuresis in the first 8 hours of treatment. Oral bioavailability of furosemide in the horse is poor, and IM administration is recommended for ongoing management of CHF.
Furosemide should be stored at 15º–30ºC and protected from light. Parenteral formulations having a yellow color have degraded and should not be used. Furosemide tablets that have been exposed to light may be discolored and should not be used.
Furosemide injection can be mixed with saline (0.9% NaCl) solution or lactated Ringer’s solution. A precipitate may form if the injection is mixed with strongly acidic solutions such as those containing ascorbic acid, tetracycline, adrenaline (epinephrine), or noradrenaline (norepinephrine). Furosemide injection should not be mixed with lidocaine, alkaloids, antihistamines, or morphine.
Torsemide
Torsemide (also spelled torasemide) is a pyridine-sulfonylurea loop diuretic. In the dog, torsemide is approximately 10 times more potent than furosemide at dosages < 0.2 mg/kg, every 24 hours. At dosages > 0.4 mg/kg, every 24 hours, potency may be up to 20 times that of furosemide.
Preparations and Disposition of Torsemide in Animals
Torsemide is available in oral (tablets) and parenteral formulations, although parenteral formulations are rarely administered to veterinary patients.
Torsemide has the same mechanism of action as furosemide, inhibiting sodium and chloride reabsorption in the ascending loop of Henle via interactions with the Na-K-Cl cotransporter 2. Dogs' excretion of potassium is much less with torsemide compared with furosemide (20:1). In dogs, torsemide has been shown to increase plasma aldosterone concentrations.
Torsemide is highly protein bound (98%–99%) and is rapidly and highly absorbed, with a bioavailability of 98% and peak plasma concentrations obtained within 1 hour after administration. Torsemide is metabolized by the hepatic cytochrome P450 system, and the plasma elimination half-life is approximately 6 hours. Approximately 62% of torsemide is excreted in the urine unchanged. In dogs, peak diuresis occurs at 2 hours and persists for 12 hours. In cats, peak diuresis occurs at 4 hours and persists for 12 hours.
Drug Interactions and Toxicity of Torsemide in Animals
Drug interactions with torsemide are similar to those described for other diuretics. Torsemide should not be administered to patients with severe hepatic dysfunction or in patients with known hypersensitivities to sulfonylureas. Given its potent diuretic effects and risk for renal injury, serious consideration is warranted when combining torsemide with other potentially renal toxic medications. The median lethal dose (LD50) of torsemide is > 2 g/kg.
Clinical Use of Torsemide in Animals
Torsemide is used for treatment of cardiogenic pulmonary edema in dogs and cats. Torsemide is most often used when furosemide resistance is encountered or suspected. However, emerging veterinary clinical uses include replacement of furosemide for the treatment of first onset CHF. The typical starting dose when it is used as the initial loop diuretic for the treatment of canine CHF is 0.13 to 0.25 mg/kg, every 24 hours for mild pulmonary edema. Higher dosages (0.26 to 0.4 mg/kg, q 24 h) may be needed initially to stabilize dogs with severe pulmonary edema but can then be decreased to the minimum effective maintenance dose of approximately 0.13 to 0.25 mg/kg, every 24 hours.
Torsemide has a longer duration of action than furosemide due to a slower urinary excretion rate. Torsemide, due to its greater potency and longer duration of action, is used with increasing frequency to manage refractory CHF in dogs. Typically, torsemide is administered in combination with or instead of furosemide to manage refractory CHF in dogs. In cats, it is typically administered to replace furosemide when resistance is encountered (requiring > 6 mg/kg, every 24 hours).
Renal parameters and electrolytes should be reevaluated within approximately 1 week after starting treatment with torsemide or increasing the dose in both the cat and dog.
Thiazide Diuretics
Thiazide diuretics act primarily by reducing membrane permeability to sodium and chloride in the distal convoluted tubule. They promote potassium loss at this site and produce large increases in urine sodium concentration but only mild to moderate increases in urine volume.
The thiazides are ineffective when renal blood flow is low, which may explain their lack of efficacy as a sole agent in animals with severe heart failure.
Preparations and Disposition of Thiazide Diuretics in Animals
Hydrochlorothiazide is available in tablet form. In dogs, thiazides are well absorbed after oral administration. Hydrochlorothiazide has an onset of action within 2 hours, which peaks at 4 hours and lasts 12 hours.
Drug Interactions and Toxicity of Thiazide Diuretics in Animals
Drug interactions with thiazides include a decrease in efficacy of anticoagulants and insulin and an increase in efficacy of digoxin, loop diuretics, vitamin D, and some anesthetics. Thiazide diuretics are also reported to prolong the half-life of quinidine.
The most common adverse effects of thiazide diuretics are electrolyte disturbances. Thiazide diuretics are potassium wasting, and when combined with loop diuretics, the likelihood of adverse effects such as azotemia and hypokalemia is increased. They may also increase calcium reabsorption and thus lead to hypercalcemia.
Adverse effects, including renal failure, can be minimized when hydrochlorothiazide is added to chronic CHF treatment protocols that include high-dose furosemide by reducing the total daily dose of furosemide by approximately 25%–50% and starting at the lower end of the monotherapy dosage range for hydrochlorothiazide (2 mg/kg, PO, every 12 hours).
Clinical Use of Thiazide Diuretics in Animals
Compared with that of furosemide, the relative potency of thiazide diuretics is low in dogs and cats when administered as monotherapy; thus, they are rarely used as first-line diuretics in these species. Thiazides are primarily administered to dogs that have developed furosemide resistance and are commonly referred to as rescue diuretics in dogs. However, torsemide is quickly becoming the preferred rescue diuretic in both dogs and cats that develop furosemide resistance.
The typical monotherapy dosage for hydrochlorothiazide in dogs is 2–4 mg/kg, PO, every 12 hours. When hydrochlorothiazide is added to furosemide, the initial dosage should be 2 mg/kg, PO, every 12 hours. The typical monotherapy dosage for hydrochlorothiazide in cats is 0.5–2 mg/kg, PO, every 12–24 hours.
Potassium-sparing Diuretics
The potassium-sparing diuretics act by inhibiting the action of aldosterone on distal tubular cells or by blocking sodium reabsorption in the latter regions of the distal tubule and collecting tubules, exerting a mild diuretic effect compared with that of furosemide.
Spironolactone is structurally similar to aldosterone and binds competitively to aldosterone-binding sites in the distal tubule. Because of its aldosterone antagonism, spironolactone is also considered an inhibitor of the renin-angiotensin-aldosterone system (RAAS) and thus a neuroendocrine modulator. Spironolactone is the most commonly used potassium-sparing diuretic in veterinary medicine but is more often used for its antifibrotic (cardioprotective) effects in cats and dogs with heart disease and CHF.
Preparations and Disposition of Potassium-Sparing Diuretics in Animals
Spironolactone is available as a tablet for oral administration. It is highly protein bound, metabolized by the liver, and excreted by the kidneys. Peak diuresis occurs as late as 2–3 days after administration.
Drug Interactions and Toxicity of Potassium-Sparing Diuretics in Animals
Potential toxic effects with potassium-sparing diuretics include hyperkalemia, which may be exacerbated by concurrent treatment with an ACE inhibitor, especially if furosemide is not also administered. Facial excoriation has been reported in cats, but initial reports may overestimate the frequency.
Clinical Use of Potassium-Sparing Diuretics in Animals
In dogs with congestive heart failure (CHF), particularly those with ascites secondary to right heart failure, an increased plasma aldosterone concentration may be present, and the effect of potassium-sparing diuretics may be enhanced. However, they are weak diuretics when used alone and thus should never be used as sole agents in animals with heart failure. When potassium-sparing diuretics are administered with other diuretics such as furosemide, potassium loss is decreased, which may be beneficial.
Adding spironolactone to chronic CHF treatment in dogs may improve survival. The increasing use of spironolactone in veterinary medicine is related to these potential cardioprotective and antifibrotic effects and not its diuretic effect per se.
The dosage of spironolactone for diuretic use is 2–4 mg/kg, PO, every 24 hours. Lower dosages (0.5–1 mg/kg, PO, every 12 hours) may be considered for inhibition of the RAAS. Typical dosages for adjunctive treatment of CHF in dogs are 1–2 mg/kg, PO, every 12 hours, or 2 mg/kg, PO, every 24 hours; similar dosages are used for a cardioprotective indication in dogs. Typical dosage for adjunctive treatment of CHF in cats is 1–2 mg/kg, PO, every 12–24 hours.
