Feature Article
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Loop Diuretics in the Management of Congestive Heart Failure in the Elderly Despite recent treatment advances, morbidity and mortality due to congestive heart failure (CHF) remain unacceptably high, especially for the elderly population. Although their effects on mortality are unknown, loop diuretics have long been a mainstay in the treatment of edema associated with CHF. Loop diuretics enhance fluid and sodium loss, reducing symptoms of systemic and pulmonary congestion and edema. The elderly do not respond to loop diuretics in the same way as younger patients, and thus special care should be taken when these agents are used in older individuals. The purpose of this article is to familiarize the clinician with the use of loop diuretics--with a focus on furosemide, bumetanide, and torsemide--in the treatment of CHF in the elderly population.
(Annals of Long-Term Care 1999;7[10]:369-374)
Congestive Heart Failure in the Elderly
A study by Croft and colleagues1 showed that, from 1991 to 1992, physician visits regarding prescription drugs for heart failure involved diuretics more than any other drug for this indication. Congestive heart failure (CHF) is the most common cause of hospitalization and rehospitalization in patients 65 years of age or older.2 The five-year mortality rate has been reported to exceed 50% in the general population and is expected to be higher in the elderly.3,4 The one-year mortality rate in limited studies of the elderly has been found to be approximately 20%.5,6 According to the Health Care Financing Administration, yearly hospital costs and total health care expenditures associated with the treatment of this disease exceed $5 billion and $10 billion, respectively.7
The Framingham Heart Study and other long-term studies have provided much information regarding the epidemiology of heart failure in older patients. According to the Framingham study, 400,000 new cases of heart failure can be expected to be diagnosed each year in persons of all ages, although the incidence is greater in the elderly population.8 The incidence for developing heart failure increases dramatically between the ages of 45 and 94, and the prevalence more than doubles for each decade of life from age 50 to 90. Currently, there are 33 million Americans over the age of 65; in this group, 7.9 million are over 80. It is estimated that, by the year 2030, there will be 70 million Americans older than 65, and of that group, 18 million will be older than 80.9,10 As the elderly population increases and treatment costs rise, the economic burden will continue to grow as well.
Mechanism of Action
Loop diuretics are the most potent diuretics available and are considered a first-line choice due to their efficacy in patients with renal impairment, a condition often present in patients with moderate to severe CHF. Available agents include furosemide, bumetanide, torsemide, and ethacrynic acid. All of these agents work in a similar fashion in the nephron by inhibiting the Na+/K+/2Cl–cotransporter in the thick ascending loop of Henle. In addition, furosemide and ethacrynic acid have some effect in the proximal and distal tubules, and bumetanide has additional action in the proximal tubule. The site of action is reached intraluminally by drug secretion via the organic-acid pathway through the proximal tubule.11,12 The net effect is the loss of sodium, potassium, chloride, and water in the urine. In normal subjects, a 40-mg dose of furosemide (see Table I for equivalent doses) will elicit the loss of 200 to 250 mmol of sodium in 3 to 4 liters of urine in 3 to 4 hours.12
Loop diuretics are "high-ceiling" diuretics, which means that increasingly higher doses will result in a greater diuresis before a ceiling is reached.11 Proper use of these agents will help to relieve signs and symptoms of CHF, such as peripheral and pulmonary congestion, orthopnea, paroxysmal nocturnal dyspnea, jugular venous distention, ascites, and dyspnea on exertion, with a net effect of reducing cardiac workload and myocardial oxygen demand. Loop diuretics may increase circulating levels of vasodilatory atrial natriuretic peptide, resulting in a decrease in cardiac filling pressure (preload).11,13 Additionally, a reduction in intravascular volume will reduce cardiac chamber pressures and wall tension, leading to improvement in hemodynamic parameters and cardiac performance. Intravenous doses of furosemide and torsemide have been shown to decrease pulmonary wedge pressures by 20% to 25%, and in conjunction with chronic therapy they have been shown to increase the cardiac index by up to 15%.14 However, their actions also decrease renal perfusion pressures, activate the sympathetic nervous system and renin-angiotensin-aldosterone system, and increase the release of antidiuretic hormone.15,16 Because of these consequences, loop diuretics should be used only in those patients with evidence of volume overload.17
Pharmacokinetics
The pharmacodynamic response to loop diuretics is determined by the amount of drug at the site of action; therefore, the pharmacokinetic properties of these agents are very important (Table II). All of the loop diuretics are absorbed quickly and produce a rapid diuresis following oral administration. Factors affecting absorption include intestinal blood flow, surface area of the absorption site (mostly in the upper jejunum), gastric emptying time, intestinal motility, and physicochemical properties of each agent.18 Patients with advanced heart failure may have a decreased rate but not extent of absorption; therefore, the maximal effects may not be seen for several hours following oral administration.19 Furosemide has a lower and more variable bioavailability than bumetanide and torsemide. The bioavailability of both bumetanide and torsemide is greater than 80% and may present practitioners with a smoother transition between oral and intravenous dosing.20-22
Excretion and metabolism differ between the loop diuretics and may influence choice of agent as well. For example, approximately 50% of an oral dose of furosemide is excreted unchanged in the urine while the other 50% is conjugated in the kidney.23-25 In the presence of renal disease or insufficiency, as is of ten seen in the elderly, the half-life of furosemide is extended.23,24 However, all loop diuretics are dependent on renal blood flow to reach the tubular fluid. Therefore, any condition that decreases glomerular filtration may also decrease the amount of drug that reaches the luminal site of action. The liver primarily metabolizes bumetanide and torsemide, and therefore their half-lives are prolonged in the presence of liver disease or such conditions as CHF, which may decrease liver blood flow.20,23
Dosing and Use
Although thiazide diuretics are sometimes preferred in mild CHF, loop diuretics are necessary with severe edema and in renal insufficiency when the creatinine clearance is less than 30 mL/min. There are a number of factors that determine the dose of loop diuretic to be used in any given patient, including age, renal function, body size, and degree of edema or congestion. (Equivalent doses of the agents, typical dose ranges, and suggested maximum daily doses are shown in Table I.) Dosing in the elderly should be initiated at doses lower than commonly used in younger patients. Initial oral doses of 10 to 20 mg of furosemide (0.25-0.5 mg of bumetanide or 5-10 mg of torsemide) are preferred to avoid overdiuresis. Larger initial doses may result in a first diuresis that may decrease volume so much as to cause circulatory collapse.26 Daily doses should then be titrated to maintain the desired fluid balance. Generally, doubling the daily dose will be effective in providing an increased diuretic response. However, in some patients, it may be necessary to give a second daily dose in the afternoon in order to control volume overload. Patients with severe edema necessitating hospital admission may benefit from intravenous intermittent or continuous doses of these agents. As with oral dosing, there are no ideal intravenous target doses that should be used. Instead, such endpoints as relief of symptoms and the extent of jugular venous distention should be utilized to determine optimal dosing.
Adverse Effects
The major adverse effects of loop diuretics are volume depletion and electrolyte abnormalities. The elderly are especially susceptible to volume depletion, as compensatory mechanisms are impaired with age and disease.26 Hypovolemia can result in orthostatic hypotension and prerenal azotemia; therefore, therapy should be initiated and titrated carefully to the minimum effective doses to avoid this complicating factor. This is especially troublesome in patients with diastolic dysfunction who depend on increased preload to maintain adequate cardiac output.
Close monitoring of electrolytes is necessary when administering loop diuretics due to the substantial losses that can occur. Hypokalemia and hypomagnesemia may cause ventricular arrhythmias and contribute to digitalis toxicity.26,27 Excessive losses of sodium can cause activation of the renin-angiotensin-aldosterone system, thereby decreasing the effectiveness of loop diuretic therapy.2 Loop diuretics increase calcium loss, contributing to hypocalcemia and osteoporosis, which may already exist in the elderly patient.12 However, the short duration of action of loop diuretics may allow for a natural postdiuresis correction of some of these abnormalities.28
Several other important adverse effects have been noted. Patients with hypersensitivity to sulfonamides may experience an allergic reaction to loop diuretics. However, bumetanide has been administered following allergic reactions to furosemide, suggesting a lack of cross-sensitivity between the two agents. Ototoxicity has been found to occur with large oral doses (greater than 1000 mg/day) and high infusion rates (greater than 4 mg/min) of furosemide.11 Ototoxicity is related to direct damage to the stria vascularis;29 it may manifest itself as tinnitus, deafness, or vertigo, and it may be either reversible or irreversible.11 Other adverse effects caused or aggravated by loop diuretic use include blood lipid changes, hyperosmolar nonketotic hyperglycemic states, hyperuricemia, and hyperglycemia.11 In the elderly, nocturia, prostatism, and urinary retention can be associated with intense diuresis.11
Drug Interactions
Elderly patients have a greater propensity for concomitant disease states as they often are taking a number of other medications in addition to those for CHF. Thus, they are at increased risk for drug interactions. Concomitant nonsteroidal anti-inflammatory drug (NSAID) use in the elderly poses a significant concern. NSAIDs decrease the response to diuretic therapy and can also cause a decrease in renal function and contribute to hypokalemia.30 Caution must be taken when using nitrates and other vasodilating agents to avoid hypotension. The risk of digoxin toxicity is increased with concomitant hypokalemic states. Probenecid use also decreases diuretic response by inhibiting proximal tubular secretion of the loop diuretics.
Combination Therapy
In most patients with CHF, maximal doses of loop diuretics are able to reduce fluid accumulation. Patients occasionally will reach a plateau in their response to loop diuretic therapy and present practitioners with a difficult problem. Once the ceiling dose is reached, increasing the dose will provide only an increased risk of adverse effects. This does not necessarily constitute diuretic resistance, and switching to another loop diuretic at a higher equivalent dose will not remedy the situation, as the maximal response to each agent is the same.12 Studies in animals have shown that prolonged therapy with furosemide produces hypertrophy of the distal tubule cells, thereby enhancing sodium reabsorption at that site.31,32 Under normal conditions, approximately 25% of filtered sodium chloride is reabsorbed in the loop of Henle, with another 5% to 10% being absorbed at the distal tubule. However, reabsorption at the distal tubule increases during periods in which an increased sodium chloride load is presented to this portion of the nephron.32-34 Combination therapy with a thiazide diuretic provides a second site of action within the nephron and is a viable course of action in situations where additional diuresis is necessary.
Oral and intravenous doses of thiazide diuretics combined with a loop diuretic have been shown to have synergistic effects in patients with CHF resulting in increased natriuresis, diuresis, and improvement in symptoms and New York Heart Association functional class.35-38 The thiazides block sodium reabsorption at sites proximal and distal to the loop of Henle. By blocking sodium reabsorption distal to the loop of Henle, the diuretic response can be dramatically enhanced. Metolazone, a diuretic similar in structure to the thiazides, is the agent most frequently used in combination with loop diuretics.39-41 In patients with refractory CHF, the addition of metolazone to conventional therapy produced significant effects.37,39 The available formulations of metolazone (Zaroxolyn®, Mykrox®) differ in their rate and extent of absorption and are not directly interchangeable. Mykrox® has a bioavailability of nearly 100%, whereas the absorption of Zaroxolyn® is slow and less predictable, resulting in a longer half-life.42 Neither formulation is available for intravenous administration. Despite its erratic absorption, Zaroxolyn® is the more commonly used formulation due to its longer duration of action, giving rise to a more prolonged diuretic effect.18
To obtain maximal effect from the metolazone–loop diuretic combination, it is important to appropriately time the administration of the agents. Initial doses of metolazone for the elderly ranging from 2.5 mg to 5 mg should be administered at least 30 minutes prior to administration of the loop diuretic to allow for adequate metolazone concentrations to reach the tubular fluid. Although the effects of adding metolazone to a patient regimen can be seen with the first dose, it may take anywhere from several hours to several days and may require a number of doses to see the full synergistic effect because of the drug's long half-life. In the outpatient setting, doses of 2.5 mg to 10 mg are generally adequate for chronic therapy in the elderly and may be administered on a daily to weekly basis. Following the addition of metolazone to a therapeutic regimen, it is very important to assess response to ensure that overdiuresis and electrolyte imbalances do not occur.
Physiologic Changes in the Elderly
Heart failure treatment strategies involving diuretics for the elderly are more complex than those for younger patients for a number of reasons. The clinical presentation of CHF may differ in elderly patients, making it more difficult to make a correct diagnosis due to masking concomitant illnesses and sedentary life styles.43 Classical signs and symptoms--such as dyspnea, pulmonary rales, and peripheral edema--are not as specific for CHF in this population and may be due to a variety of other disease states. Instead, lethargy and confusion due to decreased cerebral perfusion can be the initial presenting symptoms. On x-ray, fluid in the lungs may be due to such conditions as pneumonia, pleural effusions, pulmonary edema and atelectasis, and thoracic malignancies.
Diastolic dysfunction due to impaired left ventricular relaxation is more common in elderly patients than in younger patients and is often overlooked, as it may occur without concomitant systolic dysfunction. It has been demonstrated that 30% to 50% of patients with CHF have normal systolic function.44 Diuretic therapy in this subset of patients must be used with special care, as cardiac output in this condition is dependent on elevated preload for adequate filling of the left ventricle.
Several physiologic changes occur with age, which are compounded by the changes associated with CHF. Changes in body composition, organ function, and compensatory mechanisms contribute to differences in efficacy of loop diuretics in the elderly when compared with younger patients. As people age, often there is a decrease in resting heart rate,45 an increase in systolic and diastolic blood pressure,46 and higher mean arterial pressures and systemic vascular resistance.47 Major cardiac changes can include increased fibrosis and myocardial collagen formation, impaired diastolic function, and myocardial hypertrophy.18 In addition, the aorta and other blood vessels become thicker and lose compliance, and there is impaired response to sympathetic nervous system stimuli.48 The elderly also have a significant decrease in receptor affinity for adrenergic agents.18 This, coupled with the down-regulation of ß1 adrenergic receptors, results in impaired responses to chronotropic and inotropic stimuli. Total renal blood flow declines,49 as does renal blood flow per unit mass50 and glomerular filtration rate,49,51 thereby decreasing loop diuretic delivery to the site of action and reducing efficacy.
All of the above are further complicated by additional changes associated with heart failure. As patients with CHF age, there is a decrease in renal perfusion and gastrointestinal absorption, reducing drug delivery to the kidney. This results in increased elimination half-life, decreased peak concentrations, and reduced diuretic response. There are two important clinical implications of these pharmacokinetic changes.52 Patients with heart failure often need twice-daily administration of loop diuretics to adequately control fluid accumulation. A delayed time to action will cause significant diuresis in the evening following an afternoon dose and may contribute to poor compliance. Secondly, efficacy is reduced, and higher doses are required to achieve the desired response.
There are a number of factors that may stress the already compromised heart in the elderly. Aggressive fluid administration during hospital admissions and corticosteroid and NSAID use may cause fluid accumulation and increase preload. Furthermore, NSAID use can jeopardize already compromised kidney function. Arrhythmias contribute to existing cardiac functional abnormalities, further compromising cardiac output. In addition, anemia, infection, cardiac-depressant medications, and poor compliance with drug regimens all can hasten the development of CHF in elderly patients.
Conclusion
According to the Agency for Health Care Policy and Research practice guidelines for heart failure,53 diuretics should be used in patients with signs and symptoms of fluid overload. When implementing loop diuretic therapy in the elderly, it should be remembered that these are potent agents, and caution should be taken to avoid overdiuresis. Practitioners should avoid excess doses of any single agent. Once a diuresis ceiling is reached, increasing the dose will only increase the occurrence of adverse effects. Instead, if monotherapy is ineffective, the combination of a loop diuretic and a thiazide diuretic, such as metolazone, may be more effective than either agent alone. In addition, it is important to remember that elderly patients do not respond to the pharmacodynamic effects of loop diuretics in the same way as do younger patients. Thus, diuretic regimens should be tailored carefully to fit each patient with CHF in order to maximize benefit while minimizing potential adverse consequences.
About the Author
Dr. Graff is a Cardiovascular Pharmacotherapy Fellow, and Dr. Patterson is Associate Professor of Pharmacy and Research Associate Professor of Medicine, University of North Carolina School of Pharmacy, Chapel Hill. Address for correspondence: J. Herbert Patterson, PharmD, University of North Carolina School of Pharmacy, CB#7360 Beard Hall, Chapel Hill, NC 27599-7360. E-mail: hpatterson@unc.edu.
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