This article is more than 5 years old. Information may no longer be current.
Strategies to overcome diuretic resistance in congestive HF
Click Here to Manage Email Alerts
Acute and chronic HF are associated with sodium retention leading to volume overload and edema. Much of the morbidity and reduced quality of life associated with congestive HF is related to symptoms of volume overload. Loop diuretics are a mainstay in the management of volume overload and edema from congestive HF. As the syndrome of congestive HF advances, the resultant symptoms of volume overload can further reduce quality of life. Resistance or tolerance to diuretic therapy can occur over time, making volume management more difficult.
There are many contributors to sodium retention in patients with congestive HF. Activation of baroreceptors in the arterial system triggers sympathetic nervous system activation, which results in sodium retention. The renin-angiotensin-aldosterone system (RAAS) also is activated in congestive HF, resulting in increased sodium retention. Finally, patients with congestive HF often develop renal dysfunction, which causes further activation of neurohormones. As the syndrome of HF progresses, the activation of these neurohormonal systems intensifies and leads to more sodium retention and diuretic resistance.
Mechanism of action of loop diuretics
Loop diuretics inhibit the Na+/K+/2Cl– cotransporter and increase sodium excretion in the thick ascending limb of the loop of Henle. A threshold level of the loop diuretic must be achieved in the lumen of the renal tubules for adequate natriuresis to occur. Loop diuretics are highly protein-bound and are not filtered by the glomerulus. They require active secretion into the lumen to exert their effects on the Na+/K+/2Cl– transporter. Reduced renal function impairs this active secretion, resulting in levels of loop diuretic that do not achieve threshold and do not produce significant natriuresis.
Causes of diuretic resistance
Bryan Robinette
Resistance to loop diuretics is influenced by many factors. Post-diuretic sodium retention is a phenomenon that occurs once the loop diuretic concentrations drop below threshold in the renal tubules. Sodium reabsorption is enhanced in the distal tubules and collecting ducts, and may completely counteract the effects of the loop diuretic. The addition of a second or third daily dose of loop diuretic may be enough to overcome this effect. Dietary indiscretion and increased oral intake of sodium also can overwhelm the effect of loop diuretics and reduce their their effectiveness.
Another factor sometimes referred to as the “braking phenomenon” also can occur with chronic loop diuretic therapy. This is caused by hypertrophy and hyperplasia of the epithelial cells of the distal tubules producing enhanced sodium reabsorption and potentially negating the beneficial effect of the loop diuretic. This phenomenon can be overcome by addition of a thiazide-type diuretic that blocks reabsorption of sodium in the distal tubules and thus greatly enhances the net loss of sodium.
In addition, worsening renal function can reduce the effectiveness of loop diuretics by decreasing the secretion of loop diuretics into the renal tubules due to increased organic ions that compete with loop diuretics for the receptor sites of the organic ion transporter decreasing secretion. Increased doses of loop diuretics may be needed to overcome this effect.
Lastly, reduced renal blood flow delivers less loop diuretic to the kidneys, blunting their response. Improving cardiac output may restore effectiveness to loop diuretics; however, this can be difficult to do in the clinical setting.
Potential strategies
Resistance to loop diuretic therapy in patients with congestive HF can be overcome by assessing several factors.
Source: Bryan Robinette, PharmD, BCPS
First, rule out medication nonadherance. Diuretic therapy will not be effective if it is not taken consistently. Nonadherence to the prescribed diuretic regimen is one of the most common causes of diuretic resistance.
The next step is to rule out dietary indiscretion, another very common cause of diuretic resistance. Decreasing sodium intake can restore responsiveness to loop diuretics in some of these patients. After assessing medication adherence and dietary compliance, assess for the routine use of nonsteroidal anti-inflammatory drugs, which can antagonize the natriuretic response to loop diuretics by inhibiting cyclooxygenase and causing an increase in sodium retention and diuretic resistance. Increasing the dose of the loop diuretic may be effective in restoring responsiveness. Loop diuretics do not appear to have a ceiling effect. Adding additional daily doses also may be effective in overcoming resistance to once-daily diuretic use, producing less time for sodium reaccumulation after the effect of the loop diuretic wears off.
Then it is important to assess oral absorption of the loop diuretic. If impairment of oral absorption is an issue, such as in patients with significant ascites and gut wall edema, switching to a loop diuretic with better oral absorption (for example, torsemide or bumetanide) may be effective at restoring responsiveness.
The next step is to evaluate whether increased post-diuretic sodium reabsorption or the braking phenomenon may be contributing to loop diuretic resistance. The addition of a thiazide-type diuretic such as metolazone to the loop diuretic also can overcome resistance by blocking sodium reabsorption in multiple sites in the nephron, enhancing sodium excretion. This strategy is especially effective in patients in whom the braking phenomenon is suspected.
Lastly, giving the loop diuretic intravenously is generally effective when the patient no longer responds to oral loop diuretics. Once euvolemia is achieved with IV diuresis, responsiveness to oral loop diuretics may be restored. IV loop diuretics may be administered in the clinic setting, reducing the need for ED referral or hospitalization.
Enhancing effectiveness of diuretic therapy
Diuretic resistance is a significant problem in patients with advanced HF. The inability to relieve congestive symptoms leads to increased hospitalizations, ED visits, increased costs of care and worsening quality of life. Overcoming resistance to diuretic therapy using the strategies discussed in this Pharmacology Consult may greatly enhance the effectiveness of diuretic therapy and improve patients’ well-being and quality of life.
Disclosure: Robinette reports no relevant financial disclosures.