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BEYOND FUROSEMIDE: the ROLE of DIURETICS in CONGESTIVE HEART FAILURE Part 1: Torsemide

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BEYOND FUROSEMIDE: the ROLE of DIURETICS in CONGESTIVE HEART FAILURE Part 1: Torsemide PRACTICAL TECHNIQUES FROM THE NAVC INSTITUTE Peer Reviewed BEYOND FUROSEMIDE: THE ROLE OF DIURETICS IN CONGESTIVE HEART FAILURE Part 1: Torsemide Marisa K. Ames, DVM, Diplomate ACVIM (Cardiology) Colorado State University Clarke E. Atkins, DVM, Diplomate ACVIM (Internal Medicine & Cardiology) North Carolina State University Each year, the NAVC Institute takes place in Orlando, Florida, and top specialists in select areas of veterinary medicine provide hands-on, one-on-one continuing education to the Institute attendees. Practical Techniques from the NAVC Institute—brought to you by the NAVC and Today’s Veterinary Practice—provides the opportunity for you to experience the excellent education provided at the Institute within the pages of this journal. This article reviews information from the session, Cardiology Without Intimidation, presented at the NAVC Institute 2014. The NAVC Institute 2016 takes place in Orlando, Florida, May 15 to 20; visit navc.com/institute for further information. Diuretics are a critical component of the LOOP DIURETICS pharmacotherapy of congestive heart failure Loop diuretics, in general, exemplify the phrase (CHF) (typically pulmonary edema or ascites). “double-edged sword”: They are typically In humans with heart failure, 90% receive necessary—often lifesaving—yet are invariably at least one type of diuretic.1 Of these, loop harmful in some respects, particularly with diuretics—furosemide, bumetanide, and long-term use (Table 1, page 100).2 Although torsemide—are the most potent and commonly adverse effects differ among the loop diuretics, used. When a single drug is administered in complications are common to all diuretics. humans, furosemide is given 87% of the time.1 Loop diuretics are pyridine-3-sulfonurea drugs Furosemide has been, and remains, the diuretic that act on the thick portion of the nephron’s of choice for acute and chronic management of ascending loop of Henle, where they inhibit the CHF in both humans and animals since its release sodium–potassium–chloride (Na+–K+–2Cl–) in 1966. However, interesting alternatives and cotransporter, leaving sodium (and other ions) to adjunctive therapies are now available, including: be lost, with water, in the urine. • Torsemide, a loop diuretic that can be used as an adjunct or alternative to furosemide FUROSEMIDE • Spironolactone, a weak, potassium-sparing For nearly 50 years, furosemide has been a workhorse diuretic and mineralocorticoid receptor (MR) for cardiologists and internists. It has undoubtedly blocker that is used primarily for additional saved countless lives when used to manage acute/ blockade of the renin–angiotensin–aldosterone emergent heart failure and has increased the longevity system (RAAS). In heart failure, it typically of patients when used long term. accompanies a more potent diuretic, such as Furosemide is typically not used as a monothera- furosemide. py but rather given concurrently with: This article, the fi rst in a 2-part series, discusses • Inotropes: Pimobendan, digoxin, or dobutamine torsemide, while the second article will address • Other diuretics: Thiazides and/or potassium- spironolactone. sparing diuretics tvpjournal.com | January/February 2016 | TODAY’S VETERINARY PRACTICE 99 Peer Reviewed PRACTICAL TECHNIQUES FROM THE NAVC INSTITUTE TABLE 1. Potential Adverse Effects of Furosemide & Torsemide in Congestive Heart Failure • Dehydration • Hypotension • Hypokalemia and hypomagnesemia (resulting in arrhythmias and muscular weakness) • Reduced cardiac output (reduced preload with dehydration) • Azotemia, and possibly exacerbation of acute or chronic renal disease • Activation of the RAAS; associated with: FIGURE 1. Mean urine aldosterone-to-creatinine » Increased aldosterone secretion and ratio (A:Cr) in 12 normal dogs challenged with myocardial collagen deposition furosemide at 2 mg/kg Q 12 H. At day 5 and » Myocardial fi brosis 10, the RAAS is activated and, with continuous » Sympathetic nervous system activation treatment, stays activated for at least 10 days. (arrhythmia, vasoconstriction) The urine A:Cr ratio indicates the amount of » Vasoconstriction (angiotensin II) and aldosterone found in the urine over 24 hours increased afterload and refl ects RAAS activation. » Baroreceptor dysfunction » Arrhythmias chronic production of these 2 hormones, therefore, » Sodium and fl uid retention (signs of further increases the workload on an already failing congestion) » Potassium and magnesium wasting heart. Additionally, the activated RAAS stimulates • Ototoxicity is uncommonly, if ever, the sympathetic nervous system, which is toxic to recognized in dogs and cats cardiac myocytes and increases heart rate, produces Note: Data in normal dogs show signi cantly higher plasma vasoconstriction, and predisposes to cardiac aldosterone spot concentrations with torsemide, compared arrhythmias.6 to furosemide, administration. This result may indicate that torsemide has a greater RAAS stimulatory effect than furosemide, torsemide has some mineralocorticoid blocking effects, or both. More studies are indicated. Pharmacokinetics Furosemide’s rapid onset of action makes it indispensable in the emergent treatment of • Vasodilators: Angiotensin-converting enzyme cardiogenic pulmonary edema. It does, however, (ACE) inhibitors, amlodipine, hydralazine, or have a relatively short duration of action, which nitroprusside often necessitates repeated bolus dosing in the • Antiarrhythmic agents: Lidocaine, sotalol, or emergency setting and, at home, up to 3 to 4 times amiodarone. per day dosing in patients with advanced CHF. This characteristic—multiple peaks and valleys in serum Adverse Effects drug concentrations—may enhance furosemide’s Furosemide’s popularity is deserved, and stimulation of the sympathetic nervous system and most experienced clinicians are comfortable RAAS, contributing to diuretic resistance.7 Increasing administering this drug. However, negative effects dosages are required over time and, in many cases, are associated with any potent diuretic (Table 1), other diuretics are added to maintain patient comfort. which include: • Production of electrolyte disturbances (notably Resistance hypokalemia and hypomagnesemia), which may Diuretic resistance is multifactorial, resulting from contribute to muscular weakness and arrhythmias neurohormonal activation as well as: • Activation of the RAAS due to reduced renal 1. Enhanced sodium and solute reabsorption at the blood flow and sodium loss (Figure 1), which proximal tubule in response to diuretic-induced produces adverse effects in the heart, vessels, and contraction of the extracellular fl uid volume kidneys.3,4,5 2. Nephron hypertrophy in response to increased Aldosterone and angiotensin II contribute to solute delivery to distal nephron segments congestion and hypertension via sodium retention 3. Decreased renal responsiveness to natriuretic and vasoconstriction, respectively. Excessive, peptides.8 100 TODAY’S VETERINARY PRACTICE | January/February 2016 | tvpjournal.com PRACTICAL TECHNIQUES FROM THE NAVC INSTITUTE Peer Reviewed Torsemide appears to be less affected by resistance, but a mechanism for this characteristic Furosemide Versus Torsemide has not been identifi ed. 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 TORSEMIDE but short duration of action and association with diuretic resistance Torsemide, like furosemide, is a very potent supports consideration of alternative loop diuretics, such as torsemide. diuretic. 13-15 In the Literature studies demonstrated drug traits that could Although not studied as thoroughly as would be potentially make use of torsemide advantageous desirable in animals, torsemide’s profi le in humans in treating CHF in veterinary patients (Table 2). suggests that quality of life and survival are enhanced when compared with furosemide.1,9,10 Pharmacokinetics & Pharmacodynamics Diuretics exert their diuretic action at the nephron, There are no large clinical trials published to and duration of diuretic action is related to urinary date in veterinary medicine; however: excretion rate. • A study of 7 dogs with clinically stable CHF The pharmacokinetic and pharmacodynamic demonstrated that replacement of furosemide characteristics of torsemide (when compared with with torsemide was both safe and effective.11 furosemide, Table 2) include, slower release from • Another small case series suggested that duration the plasma to the renal tubular fl uid and resultant and quality of life in 3 dogs with advanced slower urinary excretion rate. The slower transfer refractory CHF were prolonged and improved, rate of torsemide is hypothesized to be due to respectively, with torsemide.12 inherent properties of torsemide (it is less acidic • One feline and several canine laboratory and less of it exists in an anionic form, as compared with furosemide). The result is greater, smoother, TABLE 2. and longer-acting diuresis (Figure 2).13-15 Treatment of Congestive Heart Failure: Two veterinary studies have addressed torsemide 13-15 Torsemide Compared With Furosemide pharmacodynamics, each showing superior diuresis ADVANTAGES OF TORSEMIDE when compared with furosemide (Figures 2 and 3, page 102), at substantially lower dosage.13,15 • Better diuresis (greater water loss/mg prescribed); potentially a disadvantage if In addition, furosemide begins to lose effi cacy administration results in excessive
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