Continuing Education Activity

Loop diuretics are medications used in the management and treatment of fluid overload conditions such as heart failure, nephrotic syndrome or cirrhosis, and hypertension, in addition to edema. This activity reviews the indications, action, and contraindications for loop diuretics as a valuable agent in managing fluid overload and hypertension. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional team in the management of patients with fluid overload and related conditions.

Objectives:

• Identify the mechanism of action of loop diuretics.
• Describe the potential adverse effects of loop diuretics.
• Review types of loop diuretics and understand when to use which particular agent and which side effects belong to which drug.
• Explain the importance of improving care coordination amongst the interprofessional team to enhance care coordination for patients receiving loop diuretics.

Indications

Loop diuretics have been approved by the Food and Drug Administration (FDA) for treating conditions of edema associated with congestive heart failure, liver cirrhosis, and renal disease, including nephrotic syndrome.

According to the 2014 ACCF/AHA Guideline for the Management of Heart Failure, patients admitted with heart failure (Stage C) with signs of fluid overload should be treated with intravenous loop diuretics to reduce morbidity. The ACCF/AHA has given a Class I recommendation for the use of diuretics (including loop diuretics) as the first-line treatment of heart failure with reduced left ventricular ejection fraction (HFrEF) and volume overload.[1][2]

The FDA has approved loop diuretics for treating hypertension alone or with the addition of other anti-hypertensives. However, loop diuretics alone are not used for first-line therapy. In 2014, the panel members of the Eighth Joint National Committee (JNC-8) released a report on the management of high blood pressure in adults. JNC-8 made a Grade B recommendation that first-line anti-hypertensives should include either ACE inhibitors, ARBs, CCBs, or thiazide diuretics in the general population. In several large randomized drug trials, loop diuretics did not provide better outcomes when compared with the first-line drugs.[3] In the American College of Cardiology/American Heart Association Task Force report of clinical practice guidelines, there was a Class I recommendation for using diuretics to treat hypertension in adults with heart failure preserved ejection fraction (HFpEF) who presents with symptoms of fluid overload. Diuretic dosing is important to the success of adding other drugs for hypertension in the setting of HFpEF. If the dosing is too low, it can lead to fluid retention. If the dosing is too high, then volume contraction and results in hypotension and renal injury.[4]

In cases of hepatic cirrhosis with ascites that do not resolve initially with spironolactone, there is a grade A recommendation for the use of diuretics with dosing up to 160 mg/day. In these cases, diuretic administration should typically be in a hospital setting for close monitoring. With the alteration of fluids and electrolytes, the FDA recognizes the need for strict observation as these alterations may precipitate hepatic coma.[5]

Mechanism of Action

Loop diuretics induce its effect by competing with chloride to bind to the Na-K-2Cl (NKCC2) cotransporter at the apical membrane of the thick ascending limb of the loop of Henle and blocking the cotransporter, which inhibits the reabsorption of sodium and chloride. By inhibiting NaCl reabsorption, tonicity in the interstitium decreases, and free water excretion increases as a result. Blocking of the NKCC2 cotransporter makes potassium unable to be reabsorbed back into the lumen, which results in the loss of calcium and magnesium ions.[1]

Administration

Several loop diuretics come in IV and oral forms.

• Furosemide comes in oral tablet form in 20, 40, and 80 mg dosages. Injectable solutions come in 10 mg/mL doses. Oral solutions come in either 8 or 10 mg/mL doses.
• Torsemide comes in tablet form in 5, 10, 20, or 100 mg doses. Injectable solution is 10 mg/mL dosing.
• Bumetanide comes in oral tablets of 0.5, 1 and 2 mg doses. IV solution is 0.25 mg/mL.
• Ethacrynic acid is available with oral tablets of 25 mg and in a powder form for injections at 50 mg.

Bioavailability varies between each member of the loop diuretics. Furosemide has an average bioavailability of 50%, while bumetanide and torsemide are closer to 80%.

The half-life for furosemide is 1.5 to 2 hours but can be up to 2.6 hours in those with renal/hepatic dysfunction or heart failure. Bumetanide has a half-life of 1 hour and can be near 1.3 to 1.6 hours in those with renal/hepatic dysfunction or heart failure. Lastly, torsemide is known to have the longest half-life at 3 to 4 hours and can be as long as 5 to 6 hours in patients with renal/hepatic dysfunction or heart failure. All three loops typically have a similar onset of action. Oral administration between the three averages at 30 to 60 minutes.[6][2][7]

Torsemide provides the longest duration of action and can give even greater diuretic effects in patients with hepatic dysfunction or heart failure.

Adverse Effects

Adverse effects for loops diuretics typically occur from electrolyte imbalances secondary to the diuresis effects, which include: hyponatremia, hypokalemia, hypochloremia, hypomagnesemia, metabolic alkalosis, prerenal azotemia, dehydration, hypertriglyceridemia, hypercholesterolemia,  hyperuricemia, gout, restlessness, headache, dizziness, vertigo, postural hypotension, and syncope. Other adverse reactions include skin photosensitivity, interstitial nephritis, tinnitus, ototoxicity, deafness, and in patients with renal failure who receive high doses, myalgias, and muscle soreness.[8]

Thrombocytopenia, aplastic anemia, hemolytic anemia, leukopenia, agranulocytosis, abdominal cramping, anorexia, diarrhea, constipation, urticaria, anaphylaxis, erythema multiforme, exfoliative dermatitis, Steven-Johnson syndrome, toxic epidermal necrolysis, jaundice, pancreatitis, hepatic coma, fever, pneumonitis, pulmonary edema, necrotizing angiitis, blurred vision, and impotence also have links to diuretic use.[9]

Contraindications

Contraindications to loop diuretics include:

• Anuria
• History of hypersensitivity to furosemide, bumetanide, or torsemide (or sulfonamides)
• Hepatic coma
• Severe states of electrolyte depletion

Monitoring

Prescribers must be cautious with it comes to dosing to achieve diuresis. A black box warning states each loop diuretic is a potent diuretic and, at higher dosages, could lead to a profound diuresis with water and electrolyte depletion. Careful medical supervision is necessary as adjustments to these drugs should be according to the patient's needs. Electrolyte disturbances, including hyponatremia, hypochloremic alkalosis, hypokalemia, hypocalcemia, and hypomagnesemia, can lead to serious cardiac arrhythmias. Electrolyte requires monitoring periodically to assess diuretic tolerance.

Ototoxicity can occur with any of the loop diuretics, especially with the concomitant use of aminoglycosides and renal impairment. Furosemide has an increased risk for ototoxicity in those with hypoproteinemia (those with nephrotic syndrome). Ethacrynic acid has been known to have a more ototoxic potential than the other members and can lead to permanent sensorineural hearing loss without proper caution of its use, especially concomitantly with another loop diuretic.[10][11][12]

Hyperuricemia secondary to loop diuretic use can result in acute gout attacks or flares.[13]

Caution is necessary for patients known to have a sulfonamide allergy. There is a low potential for cross-allergenicity between the two drugs when taken with a loop diuretic, although this has not received extensive study. Allergic reactions could include a maculopapular rash, and extra consideration is necessary before giving a loop diuretic in patients with a history of Stevens-Johnson syndrome or toxic epidermal necrolysis. Since ethacrynic acid is not a sulfonamide derivative like the other members of loop diuretics, it is a safer diuretic to use in a patient with a potential sulfonamide allergy.[14][15]

In those with advanced renal failure with symptoms of fluid overload, physicians should closely monitor fluid status and renal function to prevent the onset of oliguria, BUN, creatinine increases, and azotemia. Close management of aggressive diuresis requires careful surveillance.

Care is necessary when weighing risk vs. reward when considering adding a loop diuretic to a neonate at risk for kernicterus. It is a drug that can displace bilirubin and cause unconjugated hyperbilirubinemia.[16]

Patients with hepatoxicity or cirrhosis also require caution as changes in electrolytes and acid/base balance may precipitate hepatic encephalopathy. An aldosterone antagonist or potassium-sparing diuretic may offer adequate diuresis without the risk of electrolyte imbalance.

Digoxin-diuretic interactions increase the electrolyte imbalances and cardiac arrhythmias noted in several studies. With the setting of hypokalemia, it is a known fact that digoxin toxicity can increase with the administration of a loop diuretic. Studies have shown that loop diuretics carry the greatest risk of digoxin toxicity compared to thiazides or potassium-sparing diuretics.[17] Clinicians should not place patients on this combination of drugs.

Diabetic patients are at risk of hyperglycemia when using a loop diuretic. Caution is prudent, with periodic monitoring of blood glucose levels.

Loop diuretics, especially furosemide, have been used to treat pulmonary edema, severe hypertension accompanying renal disease and, congestive heart failure in pregnant mothers. Loop diuretics have been given a Grade C for their use in pregnancy. Risk versus rewards merits consideration when considering starting a diuretic with a potential side effect of neonatal kernicterus.[18]

Toxicity

Diuretic toxicity can present in the form of electrolyte imbalances (hyponatremia, hypokalemia, hypocalcemia), acid/base disturbances (hypochloremic alkalosis), and dehydration secondary to excessive diuresis. Care is necessary to check electrolytes while the patient is on a diuretic periodically. Treatment would include rehydration, correction of the acid/base disturbance, and electrolyte replacement. If hypotension is unresolved, pressure support may be necessary.

Enhancing Healthcare Team Outcomes

Fluid overload states and alternative treatments of hypertension can be treated effectively with loop diuretic use. However, healthcare workers should be wary of their intended uses, side effect profiles, and contraindications. Caution is necessary when regulating which loop diuretic and the dosage chosen for the desired diuresis effect. Aggressive over diuresis can lead to dehydration, electrolyte imbalances, hypotension, and sudden cardiac arrhythmias in more severe cases. Clinicians should include periodic monitoring of blood pressures, fluid status (including weight), serum electrolytes, and renal function in continued diuretic treatments. Goals for diuresis should consist of dosage adjustments as patients progress with their response to the diuretics.

Pharmacists should always verify the dosing of these and all drugs and perform medication reconciliation for drug-drug interactions. Healthcare workers are responsible for keeping up with current loop diuretic recommendations and providing safe practice to their patients. Nursing can monitor treatment compliance and verify therapy effectiveness as well as monitor for adverse drug reactions. Nursing and pharmacy will report all concerns to the physician and the rest of the interprofessional team, operating collaboratively to achieve optimal therapeutic results. Clinicians, pharmacists, and nurses all need to function as a cohesive interprofessional team when patients receive loop diuretics so therapeutic outcomes can be maximized while limiting or eliminating interactions and adverse effects. [Level 5]