Loop Diuretics

Article Author:
Chris Huxel
Article Author (Archived):
Avais Raja
Article Editor:
Michelle Ollivierre-Lawrence
Updated:
10/15/2019 7:22:40 PM
PubMed Link:
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 the 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 the use of 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 in the general population, first-line anti-hypertensives should include either ACE inhibitors, ARBs, CCBs, or thiazide diuretics. 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 the use of diuretics to treat hypertension in adults with heart failure preserved ejection fraction (HFpEF) who presents with symptoms of fluid overload. Diuretic dosing is important in 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 result 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 that can be dosed 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 a 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 that have 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 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. There is a black box warning that 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. Electrolytes should be checked 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 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. When taken with a loop diuretic, there is a low potential for cross-allergenicity between the two drugs, although it has not had extensive study. Allergic reactions could include a maculopapular rash, and extra consideration should be given before giving a loop diuretic in patients that have a history of Steven 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 that may have a 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, and 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]

Hepatoxicity or those with 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 known that digoxin toxicity can increase with the administration of a loop diuretic. Studies have shown that loop diuretics carries the greatest risk of digoxin toxicity when compared to thiazides or potassium-sparing diuretics.[17] Patients should not be placed on this combination of drugs.

Diabetic patients are at risk of hyperglycemia when using a loop diuretic. Caution should be taken with blood glucose levels being monitored periodically.

Loop diuretics, especially furosemide, have been used to treat pulmonary edema, severe hypertension in the setting of renal disease and, congestive heart failure in pregnant mothers. Loop diuretics have been given a Grade C for its use in pregnancy. Risk versus rewards should be weighed 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 must be taken 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 required.

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 have a responsibility to keep up with current loop diuretic recommendations and provide 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. [Level 5]


References

[1] Ellison DH,Felker GM, Diuretic Treatment in Heart Failure. The New England journal of medicine. 2017 Nov 16     [PubMed PMID: 29141174]
[2] Wang DJ,Gottlieb SS, Diuretics: still the mainstay of treatment. Critical care medicine. 2008 Jan     [PubMed PMID: 18158482]
[3] James PA,Oparil S,Carter BL,Cushman WC,Dennison-Himmelfarb C,Handler J,Lackland DT,LeFevre ML,MacKenzie TD,Ogedegbe O,Smith SC Jr,Svetkey LP,Taler SJ,Townsend RR,Wright JT Jr,Narva AS,Ortiz E, 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014 Feb 5     [PubMed PMID: 24352797]
[4] Whelton PK,Carey RM,Aronow WS,Casey DE Jr,Collins KJ,Dennison Himmelfarb C,DePalma SM,Gidding S,Jamerson KA,Jones DW,MacLaughlin EJ,Muntner P,Ovbiagele B,Smith SC Jr,Spencer CC,Stafford RS,Taler SJ,Thomas RJ,Williams KA Sr,Williamson JD,Wright JT Jr, 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension (Dallas, Tex. : 1979). 2018 Jun     [PubMed PMID: 29133356]
[5] Moore KP,Aithal GP, Guidelines on the management of ascites in cirrhosis. Gut. 2006 Oct     [PubMed PMID: 16966752]
[6] Wargo KA,Banta WM, A comprehensive review of the loop diuretics: should furosemide be first line? The Annals of pharmacotherapy. 2009 Nov     [PubMed PMID: 19843838]
[7] Preobrazhenskiń≠ DV,Sidorenko BA,Tarykina EV,Batyraliev TA,Marenich AV, [Torasemide--new generation loop diuretic: clinical pharmacology and therapeutic application]. Kardiologiia. 2006     [PubMed PMID: 17159856]
[8] Qavi AH,Kamal R,Schrier RW, Clinical Use of Diuretics in Heart Failure, Cirrhosis, and Nephrotic Syndrome. International journal of nephrology. 2015     [PubMed PMID: 26294976]
[9] Sica DA,Carter B,Cushman W,Hamm L, Thiazide and loop diuretics. Journal of clinical hypertension (Greenwich, Conn.). 2011 Sep     [PubMed PMID: 21896142]
[10] Jiang M,Karasawa T,Steyger PS, Aminoglycoside-Induced Cochleotoxicity: A Review. Frontiers in cellular neuroscience. 2017     [PubMed PMID: 29062271]
[11] Schwartz GH,David DS,Riggio RR,Stenzel KH,Rubin AL, Ototoxicity induced by furosemide. The New England journal of medicine. 1970 Jun 18     [PubMed PMID: 5445527]
[12] Rybak LP, Ototoxicity of ethacrynic acid (a persistent clinical problem). The Journal of laryngology and otology. 1988 Jun     [PubMed PMID: 3294319]
[13] Bruderer S,Bodmer M,Jick SS,Meier CR, Use of diuretics and risk of incident gout: a population-based case-control study. Arthritis & rheumatology (Hoboken, N.J.). 2014 Jan     [PubMed PMID: 24449584]
[14] Patel J, Use of furosemide and other sulfonamide nonantibiotics in patients with sulfa allergy. Journal of the American Pharmacists Association : JAPhA. 2008 Jul-Aug     [PubMed PMID: 18653409]
[15] Ponka D, Approach to managing patients with sulfa allergy: use of antibiotic and nonantibiotic sulfonamides. Canadian family physician Medecin de famille canadien. 2006 Nov     [PubMed PMID: 17279201]
[16] Walker PC, Neonatal bilirubin toxicity. A review of kernicterus and the implications of drug-induced bilirubin displacement. Clinical pharmacokinetics. 1987 Jul     [PubMed PMID: 3304769]
[17] Wang MT,Su CY,Chan AL,Lian PW,Leu HB,Hsu YJ, Risk of digoxin intoxication in heart failure patients exposed to digoxin-diuretic interactions: a population-based study. British journal of clinical pharmacology. 2010 Aug     [PubMed PMID: 20653679]
[18] Turmen T,Thom P,Louridas AT,LeMorvan P,Aranda JV, Protein binding and bilirubin displacing properties of bumetanide and furosemide. Journal of clinical pharmacology. 1982 Nov-Dec     [PubMed PMID: 7161408]