* This is the Veterinary Version. *
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 of these signs. Three classes of diuretics are used to treat CHF in dogs and cats: loop diuretics, thiazide diuretics, and potassium-sparing diuretics. They differ in their relative potency and mechanisms of action. The loop diuretics are the most potent and have a high ceiling, enabling them to be used in a dose-dependent way to treat mild to life-threatening CHF. Additionally, they can be administered orally or parenterally. Thiazide diuretics are mild to moderate in potency. They are typically used in conjunction with a loop diuretic (eg, furosemide) in animals with severe refractory CHF. Historically, the use of potassium-sparing diuretics (eg, spironolactone) has been 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.
All diuretics share a similar 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 used concurrently with an angiotensin-converting enzyme (ACE) inhibitor and/or an NSAID or other potential renal toxin. Diuretics may also increase the risk of digoxin toxicity. 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/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 therapy. These include the potency of the drug, the dosage administered, the duration of action of the drug, the route of administration, renal blood flow, glomerular filtration rate, and nephron function. The plasma concentration depends on the route of administration (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 reduced renal blood flow or hormonal stimulus for sodium and water retention. Therefore, strategies to increase renal blood flow and/or plasma concentration may ameliorate diuretic resistance.
Furosemide is a loop diuretic and the most commonly used diuretic to treat CHF in dogs and cats. Torsemide is another loop diuretic that is ~10 times as potent and has a longer duration of action than furosemide with a similar adverse effect profile. However, current clinical experience with torsemide is far less than that of furosemide; thus, furosemide remains the diuretic of choice in dogs and cats with CHF.
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 reduced 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, but 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 hr, and its onset of action is within 5 min; peak effects occur within 30 min, and duration of effect is 2–3 hr. Approximately 50% of the drug is cleared from the body within the first 30 min, 90% within the first 2 hr, and almost all is eliminated within 3 hr.
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 min, with the second phase half-life of ~7 hr. The initial disposition phase has the most effect on plasma concentration, with concentration decreasing from therapeutic to subtherapeutic within 4–6 hr of PO administration. After PO administration, onset of action occurs within 60 min, peak effects occur within 1–2 hr, and duration of effect is ~6 hr. In healthy dogs, a dose of furosemide given 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, once to twice daily for longterm treatment of pulmonary edema. However, higher dosages may be needed in cats with severe heart failure because of reduced renal blood flow.
Drug interactions and adverse effects/toxicities are typically those described for diuretics as a class. However, some special considerations for furosemide bear mentioning. Furosemide has the 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.
For treatment of life-threatening cardiogenic pulmonary edema in dogs, parenteral dosages of 2–4 mg/kg, every 1–6 hr, IV, IM, or SC in dogs and 0.5–2 mg/kg, every 1–8 hr, IV, IM, or SC in cats are typically used. Dosing intervals depend on the response to therapy; initially, boluses can be given every 1–2 hr and decreased to every 4–8 hr in dogs, and given every 2 hr and decreased to every 6–8 hr in cats. Alternatively, a constant-rate infusion (CRI) of 0.25–1 mg/kg/hr in dogs or 0.25–0.6 mg/kg/hr in cats could be used. Bolus administration and CRI for treatment of life-threatening pulmonary edema is tapered over 12–24 hr as clinical signs resolve. Typical starting dosages for longterm management of CHF in dogs are 2 mg/kg, PO, bid, with a range of 1–5 mg/kg, PO, bid-tid, and in cats are 1 mg/kg/day, PO, with a range of 1–2 mg/kg, PO, once to twice daily to a maximum total daily dose of 4–6 mg/kg.
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 0.9% saline or 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.
The thiazides 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.
Drug interactions 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 are 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, bid).
Compared with that of furosemide, the relative potency of thiazide diuretics is low in dogs and cats when used as monotherapy; thus, they are rarely used as first-line diuretics in these species. Thiazides are primarily used in dogs that have developed furosemide resistance and are commonly referred to as rescue diuretics in dogs. The typical monotherapy dosage for hydrochlorothiazide in dogs is 2–4 mg/kg, PO, bid. When hydrochlorothiazide is added to furosemide, the initial dosage should be 2 mg/kg, PO, bid. The typical monotherapy dosage for hydrochlorothiazide in cats is 0.5–2 mg/kg, PO, once to twice daily.
This class of diuretics acts 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.
In dogs with CHF, particularly those with ascites secondary to right heart failure, an increased plasma aldosterone concentration may be present, and the effect of these diuretics may be enhanced. However, potassium-sparing diuretics 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. Recent studies suggest that 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/antifibrotic effects and not its diuretic effect per se. The dosage of spironolactone for diuretic use is 2–4 mg/kg/day. Lower dosages (0.5–1 mg/kg, bid) may be considered for inhibition of the RAAS. Typical dosages for adjunctive treatment of CHF in dogs are 1–2 mg/kg, PO, bid, or 2 mg/kg/day, PO; similar dosages are used for a cardioprotective indication in dogs. Typical dosages for adjunctive treatment of CHF in cats are 1–2 mg/kg, PO, once to twice daily.
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* This is the Veterinary Version. *