Furosemide has been, and remains, the diuretic of choice for acute and chronic management of CHF in both humans and animals since its release in 1966. However, interesting alternatives and adjunctive therapies are now available, including:<\/p>\n
- \n
- Torsemide, a loop diuretic that can be used as an adjunct or alternative to furosemide<\/li>\n
- Spironolactone, a weak, potassium-sparing diuretic and mineralocorticoid receptor (MR)blocker that is used primarily for additional blockade of the renin\u2013angiotensin\u2013aldosterone system (RAAS). In heart failure, it typically accompanies a more potent diuretic, such as furosemide.<\/li>\n<\/ul>\n
This article, the first in a 2-part series, discusses torsemide, while the second article will address spironolactone.<\/p>\n
Loop Diuretics<\/h2>\n
Loop diuretics, in general, exemplify the phrase \u201cdouble-edged sword\u201d: They are typically necessary\u2014often lifesaving\u2014yet are invariably harmful in some respects, particularly with long-term use (Table 1<\/strong>).2<\/sup> Although adverse effects differ among the loop diuretics, complications are common to all diuretics.<\/p>\n
![\"T1601C12Table01\"](\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2016\/01\/T1601C12Table01.jpg\")
<\/a><\/p>\nLoop diuretics are pyridine-3-sulfonurea drugs that act on the thick portion of the nephron\u2019s ascending loop of Henle, where they inhibit the sodium\u2013potassium\u2013chloride (Na+\u2013K+\u20132Cl\u2013) cotransporter, leaving sodium (and other ions) to be lost, with water, in the urine.<\/p>\n
Furosemide<\/h2>\n
For nearly 50 years, furosemide has been a workhorse for cardiologists and internists. It has undoubtedly saved countless lives when used to manage acute\/emergent heart failure and has increased the longevity of patients when used long term.<\/p>\n
Furosemide is typically not<\/em> used as a monotherapy but rather given concurrently with:<\/p>\n
- \n
- Inotropes:<\/em> Pimobendan, digoxin, or dobutamine<\/li>\n
- Other diuretics:<\/em> Thiazides and\/or potassium-sparing diuretics<\/li>\n
- Vasodilators:<\/em> Angiotensin-converting enzyme (ACE) inhibitors, amlodipine, hydralazine, or nitroprusside<\/li>\n
- Antiarrhythmic agents:<\/em> Lidocaine, sotalol, or amiodarone.<\/li>\n<\/ul>\n
Adverse Effects<\/h3>\n
Furosemide\u2019s popularity is deserved, and most experienced clinicians are comfortable administering this drug. However, negative effects are associated with any potent diuretic (Table 1<\/strong>), which include:<\/p>\n
- \n
- Production of electrolyte disturbances (notably hypokalemia and hypomagnesemia), which may contribute to muscular weakness and arrhythmias<\/li>\n
- Activation of the RAAS due to reduced renal blood flow and sodium loss (Figure 1<\/strong>), which produces adverse effects in the heart, vessels, and kidneys.3-5<\/sup><\/li>\n<\/ul>\n
![\"FIGURE](\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2016\/01\/T1601C12_Fig01-432x300.jpg\")
<\/a>FIGURE 1. Mean urine aldosterone-to-creatinine ratio (A:Cr) in 12 normal dogs challenged with furosemide at 2 mg\/kg Q 12 H. At day 5 and 10, the RAAS is activated and, with continuous treatment, stays activated for at least 10 days. The urine A:Cr ratio indicates the amount of aldosterone found in the urine over 24 hours and reflects RAAS activation.<\/p><\/div>\n
Aldosterone and angiotensin II contribute to congestion and hypertension via sodium retention and vasoconstriction, respectively. Excessive, chronic production of these 2 hormones, therefore, further increases the workload on an already failing heart. Additionally, the activated RAAS stimulates the sympathetic nervous system, which is toxic to cardiac myocytes and increases heart rate, produces vasoconstriction, and predisposes to cardiac arrhythmias.6<\/sup><\/p>\n
Pharmacokinetics<\/h3>\n
Furosemide\u2019s rapid onset of action makes it indispensable in the emergent treatment of cardiogenic pulmonary edema. It does, however, have a relatively short duration of action, which often necessitates repeated bolus dosing in the emergency setting and, at home, up to 3 to 4 times per day dosing in patients with advanced CHF. This characteristic\u2014multiple peaks and valleys in serum drug concentrations\u2014may enhance furosemide\u2019s stimulation of the sympathetic nervous system and RAAS, contributing to diuretic resistance.7 Increasing dosages are required over time and, in many cases, other diuretics are added to maintain patient comfort.<\/p>\n
Resistance<\/h3>\n
Diuretic resistance is multifactorial, resulting from neurohormonal activation as well as:<\/p>\n
- \n
- Enhanced sodium and solute reabsorption at the proximal tubule in response to diuretic-induced contraction of the extracellular fluid volume<\/li>\n
- Nephron hypertrophy in response to increased solute delivery to distal nephron segments<\/li>\n
- Decreased renal responsiveness to natriuretic peptides.8<\/sup><\/li>\n<\/ol>\n
Torsemide appears to be less affected by resistance, but a mechanism for this characteristic has not been identified.<\/p>\n
\nFurosemide Versus Torsemide<\/h2>\n
Furosemide is the diuretic of choice for everyday use because it is potent, rapid in onset, relatively inexpensive, and enjoys a comfort level with clinicians based on years of clinical experience. However, its rapid onset but short duration of action and association with diuretic resistance supports consideration of alternative loop diuretics, such as torsemide.<\/p>\n<\/div>\n
Torsemide<\/h2>\n
Torsemide, like furosemide, is a very potent diuretic.<\/p>\n
In the Literature<\/h3>\n
Although not studied as thoroughly as would be desirable in animals, torsemide\u2019s profile in humans suggests that quality of life and survival are enhanced when compared with furosemide.1,9,10<\/sup><\/p>\n
There are no large clinical trials published to date in veterinary medicine, however:<\/p>\n
- \n
- A study of 7 dogs with clinically stable CHF demonstrated that replacement of furosemide with torsemide was both safe and effective.11<\/sup><\/li>\n
- Another small case series suggested that duration and quality of life in 3 dogs with advanced refractory CHF were prolonged and improved, respectively, with torsemide.12<\/sup><\/li>\n
- One feline and several canine laboratory studies13-15<\/sup> demonstrated drug traits that could potentially make use of torsemide advantageous in treating CHF in veterinary patients (Table 2<\/strong>).<\/li>\n<\/ul>\n
![\"T1601C12Table02\"](\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2016\/01\/T1601C12Table02.jpg\")
<\/a><\/p>\nPharmacokinetics & Pharmacodynamics<\/h3>\n
Diuretics exert their diuretic action at the nephron, and duration of diuretic action is related to urinary excretion rate.<\/p>\n
The pharmacokinetic and pharmacodynamic characteristics of torsemide (when compared with furosemide, Table 2<\/strong>) include, slower release from the plasma to the renal tubular fluid and resultant slower urinary excretion rate. The slower transfer rate of torsemide is hypothesized to be due to inherent properties of torsemide (it is less acidic and less of it exists in an anionic form, as compared with furosemide). The result is greater, smoother, and longer-acting diuresis (Figure 2<\/strong>).13-15<\/sup><\/p>\n
![\"FIGURE](\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2016\/01\/T1601C12_Fig02-502x300.jpg\")
<\/a>FIGURE 2. Urine production in control animals, those receiving standard-dose furosemide, and those receiving torsemide orally. Note the similar peak effect between agents and the brisk and longer-acting diuresis with torsemide. These studies were performed in normal dogs.<\/p><\/div>\n
Two veterinary studies have addressed torsemide pharmacodynamics, each showing superior diuresis when compared with furosemide (Figures 2 and 3<\/strong>), at substantially lower dosage.13,15<\/sup> In addition, furosemide begins to lose efficacy (diuretic resistance) at 14 days of oral therapy in healthy dogs (Figure 3<\/strong>), while torsemide is less affected.7<\/sup> The relevance of the latter finding in clinical cases remains to be seen.<\/p>\n
![\"FIGURE](\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2016\/01\/T1601C12_Fig03-871x300.jpg\")
<\/a>FIGURE 3. Crossover study performed in normal dogs that compared urine volume of dogs receiving oral furosemide (2 mg\/kg Q 12 H) and torsemide (0.2 mg\/kg Q 12 H) acutely and after 14 days of treatment. In the dogs receiving torsemide, note the higher peak at days 1 and 14, slightly later peak, and greater duration of enhanced urine flow compared with dogs that received furosemide. Most important, in the dogs receiving furosemide, note the decline in diuresis on day 14 compared with the lack of resistance on day 14 in dogs receiving torsemide.<\/p><\/div>\n
Diuretic efficacy occurs when diuretic delivery to the kidney is in the appropriate range. As shown in Figure 4<\/strong>, diuresis persists for 3 to 5 hours following once-daily administration. Using this dose of furosemide once daily, there is no risk for toxicity and the time in the therapeutic range is maximized.<\/p>\n
![\"FIGURE](\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2016\/01\/T1601C12_Fig04-367x300.jpg\")
<\/a>FIGURE 4. Diuresis occurs when urine levels of furosemide are within the therapeutic range. Urinary furosemide levels, of course, depend on the plasma concentration delivered to, and filtered by, the glomerulus, which, in turn, is affected by furosemide bioavailability. In this hypothetical example, diuresis begins by 1 hour and persists for 3 to 5 hours. This represents the ideal dosage for once-daily treatment, as corresponding plasma levels (reflected in urinary concentration) are high enough to maximize time in the therapeutic range but not create a risk for ototoxicity.<\/p><\/div>\n
When standard doses of diuretics become inadequate to maintain the patient\u2019s quality of life, several strategies can be used, such as increasing dosage, increasing frequency of administration, adding new drugs (ie, sequential nephron blockade with such agents as hydrochlorothiazide and spironolactone), or changing to another drug (eg, torsemide or bumetanide) to boost diuresis (Figures 5 and 6<\/strong>).<\/p>\n
![\"FIGURE](\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2016\/01\/T1601C12_Fig05-458x300.jpg\")
<\/a>FIGURE 5. If resistance to furosemide results or other factors (eg, a high salt meal) dictate that more diuresis is needed, 1 of 2 strategies may be used: First is to administer a higher dosage, as shown with the red pharmacodynamic curve. The increase in dosage increases the urine level of the diuretic but provides only a small increase in time in the effective range, enhancing diuresis (red arrow) but increasing risk for toxicity. A better approach, although problematic in terms of owner compliance, is to administer multiple doses throughout the day. As shown in this figure, administering the same dosage 3 times triples the time in the effective range and avoids the risk for toxicity.<\/p><\/div>\n
<\/p>\n
![\"FIGURE](\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2016\/01\/T1601C12_Fig06-427x300.jpg\")
<\/a>FIGURE 6. If resistance to furosemide results or other factors (eg, a high salt meal) dictate that more diuresis is needed, another approach (versus the 2 strategies demonstrated in Figure 5) would be to change to a longer-acting diuretic, such as torsemide (yellow curve). Note the higher peak urine level compared with furosemide at the original dosage, slight delay in peak diuresis, and prolonged period of time in the therapeutic range (dashed arrow; 10\u201312 H in this model).<\/p><\/div>\n
RAAS Activation<\/h3>\n
Whereas furosemide is known to activate the RAAS (Figure 1 <\/strong>and Table 1<\/strong>), the reason for high plasma aldosterone concentrations associated with use of torsemide is less clear. Although torsemide may activate the RAAS, evidence suggests that serum aldosterone levels may be elevated because of antialdosterone effects via MR blockade, whereby high dosages of torsemide led to in vivo<\/em> binding of the MR in rat kidney cells.16<\/sup><\/p>\n
A subsequent study,17<\/sup> however, demonstrated that torsemide does not bind the MR in rat cardiomyocytes. This suggests that the increase in serum aldosterone seen in the study by Hori and colleagues15<\/sup> is not entirely the result of MR blockade and likely represents RAAS activation from sodium depletion and diuresis.<\/p>\n
Other antialdosterone and antifibrotic effects of torsemide are postulated, however, and warrant further study.18-20<\/sup> Regardless of whether there is an MR-blocking effect, it seems prudent to administer an ACE inhibitor or spironolactone with torsemide due to the very high plasma aldosterone concentrations associated with its use (Figure 7<\/strong>).<\/p>\n
![\"FIGURE](\"https:\/\/todaysveterinarypractice.com\/wp-content\/uploads\/sites\/4\/2016\/01\/T1601C12_Fig07-345x300.jpg\")
<\/a>FIGURE 7. Serum aldosterone concentrations in normal dogs receiving placebo, furosemide, or torsemide on days 1 (white bar) and 14 (green bar). Note the 6-fold increase with torsemide. This finding is potentially related to RAAS activation or blockade of MR. If the former, this effect would be a disadvantage of using torsemide as opposed to furosemide.
* = value significantly (P < 0.05) different from short-term administration value; \u2020 = value significantly (P = 0.01) different from placebo treatment value; \u2021 = value significantly (P = 0.01) different from value of the corresponding furosemide administration<\/p><\/div>\nElectrolyte Effects<\/h3>\n
One study indicated that in experimental mitral insufficiency, there was less potassium loss with torsemide than with furosemide.12<\/sup> Another study that compared normal dogs receiving an ACE inhibitor alone or an ACE inhibitor with torsemide (0.2 mg\/kg for 28 days) showed no significant decrease in serum magnesium (Mg++) and only a slight decrease in serum potassium (K+), despite an increase in urine fractional excretion of both electrolytes.21<\/sup><\/p>\n
These small studies could not prove whether torsemide is actually less \u201cwasteful\u201d of potassium and magnesium than furosemide.<\/p>\n
Monitoring of serum electrolytes is still advisable (Table 3<\/strong>).<\/p>\n
- Another small case series suggested that duration and quality of life in 3 dogs with advanced refractory CHF were prolonged and improved, respectively, with torsemide.12<\/sup><\/li>\n
- A study of 7 dogs with clinically stable CHF demonstrated that replacement of furosemide with torsemide was both safe and effective.11<\/sup><\/li>\n
- Other diuretics:<\/em> Thiazides and\/or potassium-sparing diuretics<\/li>\n
- Inotropes:<\/em> Pimobendan, digoxin, or dobutamine<\/li>\n