Diuretics

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.

Hydrochlorothiazide is available in tablet form. In dogs, thiazides are well absorbed after oral administration. Hydrochlorothiazide has an onset of action within 2 hr, peaks at 4 hr, and lasts 12 hr.

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.

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.

Potential toxicities include hyperkalemia, which may be exacerbated by concurrent therapy 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.

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.