November/December 2013

Evaluating Potential Diuretic Overuse

By Mark D. Coggins, PharmD, CGP, FASCP
Today’s Geriatric Medicine
Vol. 6 No. 6 P. 5

Diuretic medications are commonly used to treat numerous conditions highly prevalent among older adults, including hypertension, heart failure, and edema (pulmonary and systematic). Widely promoted in the medical literature, they often are considered first-line medications in hypertension treatment guidelines because of their well-documented benefits in lowering blood pressure with reduced cardiovascular morbidity and mortality and decreased rates of stroke and heart failure.1

A recent study published in JAMDA has increased discussions surrounding the potential overuse of diuretics in the elderly who are at a significantly greater risk of diuretic-related side effects. The study’s author, Martin Wehling, director of clinical pharmacology at the Mannheim Center for Gerontopharmacology at the University of Heidelberg in Germany, suggests that the low cost of these medications, along with the misinterpretation of treatment guidelines and a failure to adequately address diuretic risks in the elderly, has resulted in dangerous mismanagement and overuse of these medications, a syndrome of overuse he refers to as morbus diureticus.2

Diuretic Categories and Mechanism of Action
Diuretics increase diuresis and natriuresis by inhibiting the reabsorption of sodium at different segments of the kidney. The increased urine output and filtration of excess water from the blood reduces the volume of blood the heart has to pump while also reducing blood pressure.

All diuretics induce renal synthesis of prostaglandins, which increases renal blood flow and redistribution of renal cortical blood flow.3

Loop Diuretics
The most potent diuretic agents, loop diuretics block sodium-chloride transport at the ascending limb of the kidney, which handles a significant portion of sodium reabsorption. Because they are shorter acting than thiazides, they are more appropriate for edema management than longer-term therapy for hypertension.

Thiazide Diuretics
The most commonly used diuretics, alone and in combination with other medications, thiazide diuretics inhibit the sodium-chloride transporter in the distal tubule. They are less effective in producing diuresis and natriuresis than loop diuretics.

Potassium-Sparing Diuretics
With relatively weak effects on sodium, potassium-sparing diuretics antagonize aldosterone at the distal parts of the nephron, from the late distal tubule to the collecting duct. They do not cause hypokalemia and often are used in conjunction with other diuretics to prevent hypokalemia.

Supporting Evidence for Diuretic Use
The Systolic Hypertension in the Elderly Program demonstrated the use of chlorthalidone in elderly patients, reducing strokes by 36%, cardiovascular events by 32%, and all-cause mortality by 13%. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial, chlorthalidone was superior to the alpha-blocking agent doxazosin in stroke prevention and more effective than the angiotensin-converting enzyme (ACE) inhibitor lisinopril in the prevention of stroke in black patients.1

In the Perindopril Protection Against Recurrent Stroke Study, patients with cardiovascular disease receiving the ACE inhibitor perindopril along with the diuretic indapamide had a reduced stroke risk of 43% compared with placebo, while patients receiving perindopril alone experienced only a 5% reduction in stroke risk. In another study, patients with a history of stroke or transient ischemic attack had a 31% stroke risk reduction. In the Hypertension in the Very Elderly Trial, indapamide reduced the rate of heart failure by 64% in the very elderly with hypertension.1

A large meta-analysis study including more than 48,000 patients found that diuretic therapy reduced strokes by 51%, while beta-blockers reduced the risk by only 29%.1

Thiazide diuretics are effective in helping to prevent the development of heart failure in hypertensive patients, with one large meta-analysis of 18 long-term placebo-controlled randomized trials showing that high-dose diuretic therapy reduced the risk of heart failure by 83%, and low-dose diuretic reduced the risk by 42%.1

Diuretic Risk and Misuse Potential
The appropriate use of diuretics can provide tremendous benefits; however, health care providers should increase their focus on monitoring for side effects, utilizing the lowest effective doses, reducing the potential for drug interactions, and monitoring laboratory results to minimize serious events before they occur. These efforts are even more important in older patients who are predisposed to increased side effects and drug interactions because of the polypharmacy commonly seen in elderly patients.

As Wehling noted, health care professionals’ failure to interpret the benefits of diuretic medications without also considering the significant risks associated with these medications can lead to serious negative outcomes that may exceed the benefit. Additionally, a review of adverse drug reactions leading to hospitalization indicates that diuretics are among the five leading drug classes, and these medications have one of the lowest adherence rates for first-line hypertensive treatments, in part because of the increased urge to void.2

Dangerous metabolic alterations can occur with diuretic use if left undiagnosed and untreated. In one study, for example, hyponatremia occurred in 17% of patients.2 The risk of hyponatremia appears to be particularly common in elderly female patients.1 Hyponatremia can lead to confusion, delirium, and irreversible brain damage that may contribute to age-related dementia.2 The utilization of low to medium doses of diuretics, along with issuing patient instructions to limit fluid intake, may help minimize this risk.1 However, limiting fluids also can place patients at a greater risk of dehydration.4

Diuretics can cause hypokalemia as well, which may precipitate cardiac arrhythmias and sudden death.2 Muscle weakness associated with hypokalemia can increase fall risks for older adults. Some patients may require potassium supplementation either through supplements or by increasing their consumption of foods high in potassium, such as tomato juice, orange juice, prunes, and bananas.

Thiazide diuretics have the greatest potential to increase blood glucose levels, which is of greater concern in patients with diabetes or predisposed to diabetes.1,2 Thiazides also can increase total cholesterol, triglyceride, and LDL cholesterol levels. Low-dose thiazide diuretics and loop diuretics can increase uric acid levels, which may exacerbate gout in some patients.1

It’s common to overdose heart failure patients receiving diuretic therapy when they’re prescribed maintenance doses two to three times higher than required once acute recompensation has been achieved following heart failure exacerbations. Patients with severe cardiac or renal failure often are appropriate candidates for combination loop and thiazide therapy; however, patients with less severe disease may not require combination. Diuretics can unintentionally be combined if health care practitioners fail to thoroughly assess a patient’s medication regimen, as many antihypertensive agents, such as ACE inhibitors and angiotensin blockers, may include hydrochlorothiazide.2

Although high-dose vs. low-dose diuretic use has been associated with improved mortality, the studies examining this relationship do not focus on addressing the potential for other risks associated with higher doses of diuretics, including ACE-inhibitor intolerance, reduced renal function, and potential venous thromboembolism.2

Drug interactions with diuretic therapy also present cause for concern. Because diuretics’ effectiveness depends on their ability to induce renal synthesis of prostaglandins, using NSAIDs such as ibuprofen or naproxen can block the effects of prostaglandins in the kidney, resulting in reduced diuretic efficacy.2,4

The combination of NSAIDs with diuretics alone has been shown to double the risk of hospitalization in patients with heart failure. If NSAIDs are given with combination antihypertensive medicationssuch as ACE inhibitors and ARBS containing a diuretic, then these patients are at risk of the triple whammy effect, which describes the significant increase in harm that can result from the combined use of NSAIDs, ACE inhibitors or angiotensin receptor blockers, and diuretics in high-risk individuals. A fatality rate of roughly 10% has been associated with renal failure occurring from this combination.4

Recommendations
To help reduce diuretic risk and overuse, health care providers are encouraged to routinely evaluate patients receiving diuretics. Laboratory monitoring for electrolyte imbalances and increased creatinine (associated with acute kidney injury) should be performed periodically. Patients with chronic heart failure should be evaluated every three to six months for the possibility of stepping down from loop to thiazide diuretics. Diuretic dosing should be assessed to ensure it is reduced to appropriate maintenance dose levels. Monitoring for dehydration and possible drug interactions should be ongoing, with patients made aware of the associated increased risk of taking diuretics along with some other medications, such as NSAIDs, especially in light of their widespread availability over the counter.1-4

— Mark D. Coggins, PharmD, CGP, FASCP, is director of pharmacy services for more than 300 skilled nursing centers operated by Golden Living and a director on the board of the American Society of Consultant Pharmacists. He was recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

References
1. Grossman E, Verdecchia P, Shamiss A, Angeli F, Reboldi G. Diuretic treatment of hypertension. Diabetes Care. 2011;34 Suppl 2:S313-S319.

2. Wehling M. Morbus diureticus in the elderly: epidemic overuse of a widely applied group of drugs. J Am Med Dir Assoc. 2013;14(6):437-442.

3. Klabunde RE. Diuretics: general pharmacology. Cardiovascular Pharmacology Concepts website. http://www.cvpharmacology.com/diuretic/diuretics.htm. Updated October 29, 2012. Accessed September 21, 2013.

4. Coggins M. Medication-related kidney injury. Aging Well. 2013:6(1):8-9.

Diuretic-Related Side Effects and Drug Interactions3,4