Furosemide

Article Author:
Tahir Khan
Article Author (Archived):
Roshan Patel
Article Editor:
Abdul Siddiqui
Updated:
9/16/2019 7:19:58 PM
PubMed Link:
Furosemide

Indications

The Food and Drug Administration (FDA) has approved the use of furosemide in the treatment of conditions with volume overload and edema secondary to congestive heart failure exacerbation, liver failure, or renal failure including the nephrotic syndrome.  

Patients with acutely decompensated heart failure (ADHF) with volume overload who have not received diuretics previously, the initial dose of furosemide should be 20 to 40 mg intravenously, and later, titrate the furosemide dose according to the clinical response of the patients. However, those patients with ADHF with a normal kidney function who are on chronic diuretic therapy, the initial dose of furosemide can be equivalent to or greater than the total oral maintenance dose of furosemide patient takes per day. Subsequently, the diuretic dose adjustments are according to the clinical response of the patient. Nevertheless, the starting with higher doses of furosemide, that is, at a dose of 2.5 times the total daily oral dose of furosemide per day, has shown a significant trend toward a rapid improvement in the global assessment of patients’ symptoms.[1]

Although the FDA approved the use of loop diuretics alone or in combination with other anti-hypertensive medications as an alternative to thiazide diuretics to treat hypertension. However, the clinical guidelines panel report of Eighth Joint National Committee (JNC-8) published in 2014 and the American College of Cardiology/American Heart Association (ACC/AHA) Task Force Panel Guidelines on hypertension treatment published in 2017 do not recommend the use of loop diuretic as a first-line medication to treat hypertension.[2][3] Nevertheless, Furosemide can be a second-line agent in heart failure patients with symptoms, and in patients with advanced kidney disease with estimated glomerular filtration rate, less than 30 ml per minute the loop diuretics (furosemide) are preferred over thiazide diuretics to treat hypertension.[4] 

In patients with liver cirrhosis and ascites, diuretic therapy is recommended, accompanied by dietary sodium restriction. The recommended diuretics are a combination of spironolactone and furosemide, starting at a ratio of 100 mg of spironolactone and 40 mg of furosemide.[5] They are titrated up to the dose of diuretics in an increment of the same ratio until achieving the adequate response to diuretic therapy or reaching a maximum dose of 400 mg of spironolactone plus 160 mg of furosemide.[5] However, in cases of intolerance to diuretics secondary to borderline blood pressure, the diuretics can be started at relatively lower doses of 50 mg of spironolactone with 20 mg of furosemide.

Mechanism of Action

Furosemide inhibits tubular reabsorption of sodium and chloride in the proximal and distal tubules, as well as in the thick ascending loop of Henle by inhibiting sodium-chloride cotransport system resulting in excessive excretion of water along with sodium, chloride, magnesium, and calcium.[6]

Administration

Furosemide is available in the oral and intravenous formulations. The administration of oral furosemide can be in the form of tablets or oral solution. Intravenous furosemide is twice as potent as oral furosemide.

In patients with the normal renal function, the oral dose equivalence of furosemide relative to other oral diuretics is as follows[7]:

  • 40 mg of furosemide = 20 mg of torsemide = 1 mg of bumetanide
  • Furosemide oral tablet formulations are available in 20 mg, 40 mg, and 80 mg dosages.
  • Furosemide oral solution is available as 10 mg of furosemide per ml formulation or 8 mg per ml, i.e., 40 mg furosemide per 5 ml of solution.

Furosemide glucuronide is a major biotransformation active product of furosemide having an active diuretic effect.[8] In healthy individuals, greater than 95% of furosemide is bound to plasma protein, mainly albumin. Only 2.3% to 4.1% of furosemide is existent in an unbound form in therapeutic concentrations. 

The terminal half-life of furosemide is approximately 2 hours, and the total time of therapeutic effect is 6 to 8 hours. However, the half-life of furosemide will prolong in patients with chronic renal disease.

The onset of action of furosemide is usually within the first hour of oral furosemide intake, and it takes first 1 to 2 hours to achieve a peak effect. The mean bioavailability of oral furosemide is 51% compared with the bioavailability of intravenously administered furosemide.[9] Although more furosemide gets excreted in the urine after IV administration, there is no difference in the amount of unchanged furosemide excretion in urine between the two formulations. Furosemide achieves an early and high serum peak concentration and a higher peak excretion rate after intravenous administration. Oral and sublingual administration of furosemide achieves a peak concentration slower as compared with the iv route. Although furosemide is more avidly absorbed with a bioavailability of 59% via sublingual route as compared with the oral route of administration, i.e., 47%,  the half-life and time to peak concentration were not different between the oral and sublingual route of drug delivery. Also, urinary excretion rate of furosemide and sodium, and cumulative urine excretion rate was not different between the oral and sublingual administration of furosemide.[10] Moreover, peak plasma concentration increases proportionately with the increasing doses of furosemide, but time-to-peak plasma level does not vary corresponding to different doses. Average bioavailability of furosemide is approximately 50% with a range of 10 to 100%. Bioavailability of furosemide is variable and also relatively lesser than that of torsemide in patients with compensated congestive heart failure.[11][12] The furosemide absorption is slower than normal in patients with edema, particularly in patients with decompensated heart failure; however, the amount of loop diuretic absorbed is normal.[13] 

Breaking phenomenon and ceiling effect: Normally, when an individual receives furosemide either orally or intravenously, it increases sodium excretion in urine. In a patient with extracellular volume expansion who has never had exposure to furosemide, the first dose of the drug causes significant sodium excretion and diuresis within the first 3 to 6 hours. After that effect of furosemide weans off, the kidney starts retaining sodium and chloride; this is called "post-diuretic sodium retention." It is imperative to repeat the furosemide dose at 6 to 8-hour intervals to avoid post diuretic sodium retention and achieve significant diuresis. When furosemide is prescribed chronically, the patient's weight loss correlates with urine volume. A discrepancy in weight loss and diuresis indicates excessive sodium intake by the patient, which can be detected by 24-hour urine sodium collection.

In normal person and patient with extracellular fluid (ECF) expansion, there is a linear relationship between ECF expansion and natriuresis when receiving furosemide; this means that the patient will have higher natriuresis and urine output if ECF volume expands as compared to a person with normal ECF volume. As the use of furosemide becomes chronic in a patient, ECF volume shrinks, and the amount of natriuresis also goes down. At that point amount of natriuresis is equal to sodium intake; this is called "braking phenomenon." This phenomenon is adaptive when it occurs at low ECF volume. But in chronic heart failure patients with persistent ECF volume expansion, this phenomenon is maladaptive. Natriuresis is lower even when ECF volume becomes expanded. The reason for these maladaptive changes is remodeling in the distal nephron. There are hypertrophy and hyperplasia of distal segments of the nephron. These result from increased salt delivery, increased aldosterone, and angiotensin II as well as a change in potassium concentration. As a result of distal segment hypertrophy, sodium transport capacity increases which rivals furosemide's sodium absorption inhibiting capacity at the level of the thick ascending loop of henley. This phenomenon can be overcome by adding thiazide diuretics which blocks sodium absorption in distal segments of the nephron.[14][15]

Adverse Effects

The following are adverse effects associated with furosemide use[16][11]:

  • Hypokalemia
  • Hypomagnesemia
  • Hypocalcemia
  • Hyperglycemia
  • Glycosuria
  • Hyperuricemia
  • Hypertriglyceridemia
  • Increased cholesterol levels
  • Orthostatic hypotension
  • Vasculitis
  • Thrombophlebitis
  • Dizziness
  • Vertigo
  • Headache
  • Paresthesia
  • Hearing impairment
  • Tinnitus
  • Dehydration
  • Muscle cramps
  • Abdominal cramping
  • Anorexia
  • Constipation or diarrhea
  • Pancreatitis
  • Hepatic encephalopathy
  • Anemia
  • Aplastic anemia
  • Eosinophilia
  • Agranulocytosis
  • Hemolytic anemia
  • Interstitial nephritis
  • Renal injury
  • Hypersensitivity reactions
  • Anaphylaxis
  • Skin photosensitivity
  • Bullous pemphigoid
  • Erythema multiforme
  • Exfoliative dermatitis
  • Acute generalized exanthematous pustulosis
  • Stevens-Johnson syndrome
  • Toxic epidermal necrolysis
  • Urticaria
  • Fever

Contraindications

Contraindications to furosemide use include patients with documented allergy to furosemide and patients with anuria.

Monitoring

Caution is necessary with the use of furosemide.

There is a black box warning suggesting the cautious use of furosemide as it is a potent diuretic, can predispose to excessive loss of water and electrolytes resulting in dehydration with electrolyte depletion.

According to Beers Criteria, caution is necessary when administering diuretics to patients 65 years and older to avoid potential adverse effects of inducing hyponatremia by causing or exacerbating syndrome of inappropriate antidiuretic hormone secretion (SIADH); therefore, close monitoring of serum sodium is advisable at initiation or during the dose adjustment in older adults.[17]

Ototoxicity can occur with the use of furosemide, but the following conditions predispose patients to a higher risk of reversible or irreversible hearing impairment[18]:

  • Use of a higher than the recommended dose of furosemide or a fast infusion rate of the drug,
  • Hypoalbuminemic comorbid illnesses
  • The concomitant use of ethacrynic acid, aminoglycosides, or other ototoxic drugs
  • Patients with underlying severe renal impairment

Caution is also necessary for patients with underlying liver disease, especially those with the decompensated liver disease as rapid electrolytes imbalance secondary to furosemide use can precipitate hepatic encephalopathy and hepatic coma. In patients with hepatic coma, the prescriber should delay giving furosemide until improvement in the mental status of the patient.[5]

In patients with advanced renal disease with fluid overload the patients should be closely monitored for oliguria, azotemia and volume status; and if either of oliguria or azotemia develops the furosemide should use should be discontinued to prevent kidney injury.

In patients with primary adrenal insufficiency with hypertension, the use of diuretics to treat hypertension is a practice clinicians should avoid. Alternatively, the dosage of glucocorticoid/mineralocorticoid should be adjusted, and, if needed, other classes of antihypertensive agents may be preferred over diuretics to treat hypertension.[19]

High-risk patients for radiocontrast-induced nephropathy are more predisposed to having a worsened kidney function if furosemide is given before contrast administration as compared to the high-risk patients receiving gentle hydration before contrast exposure.

Patients with a known history of urinary retention due to, for example, benign prostatic hyperplasia, neurogenic bladder with bladder evacuation abnormalities, or urethral and ureteral strictures, should be observed closely during initial days of furosemide treatment. Thereafter, they require observation for worsening of symptoms as excessive diuresis and retention of urine can lead to acute urinary retention leading to acute kidney injury.

Risk of hypokalemia increases with the use of a high dose of furosemide, decreased oral intake of potassium, in patients with hyperaldosteronism states (liver abnormalities or licorice ingestion) or concomitant use of corticosteroid, ACTH, and laxatives.

Furosemide at high doses, i.e., more than 80 mg per day inhibits thyroid hormone binding to thyroid binding protein leading to a transient increase in free thyroid hormones that subsequently causes a mild decrease in total thyroid hormone.[20]

Furosemide was a pregnancy category C drug under the old FDA categories, and clinicians should use caution in pregnant women after discussion with the patient about risk and benefits. Furosemide is known to cross the placenta, and animal reproduction studies have shown adverse events. Although pregnant women with heart failure have had treatment with furosemide, a risk and benefits discussion should take place with the pregnant patient and caution is necessary with the decision to take furosemide during pregnancy; fetal growth will require close monitoring. Additionally, furosemide is secreted in the breastmilk and may lead to suppression of lactation.[21][22][23]

Toxicity

Toxicity with furosemide manifests as extensions of its diuretic activity. Signs and symptoms of overdose or toxicity include dehydration, reduced blood volume, and electrolyte imbalances.[11]

Enhancing Healthcare Team Outcomes

Managing patients with hypervolemia requires an interprofessional team of healthcare depending upon the healthcare setting, outpatient vs. inpatient care. For symptomatic patients with hypervolemia secondary to any of the following conditions; heart failure, liver cirrhosis, or nephrotic syndrome/chronic kidney disease, patients usually need aggressive diuresis. Hospitalized patients requiring aggressive diuretics need care by an interprofessional team that includes a nurse, laboratory technologists, pharmacist, and physician.

Careful monitoring of the clinical condition of the patient, daily weight, fluids intake, and urine output, electrolytes, i.e., potassium and magnesium, kidney function monitoring with serum creatinine and serum blood urea nitrogen level is vital to monitor the response to furosemide. Replete electrolytes if indicated as diuresis with furosemide lead to electrolyte depletion, and adjust the dose or even hold off on furosemide if laboratory work shows sign of kidney dysfunction. Similarly, patients who are on furosemide treatment in ambulatory care setting need close monitoring to evaluate for the response to treatment, intermittent electrolytes and kidney function monitoring to replete electrolytes and manage dosing of furosemide as indicated, and to assess for other adverse effects of the furosemide treatment and manage it accordingly.

While the physician (MD, DO, NP, PA) will make the initial decision to treat with furosemide, the entire healthcare team must put forth an interprofessional effort to maintain therapy. Nursing will be on the front lines for monitoring, whether inpatient or outpatient. They can also be the first to assess therapeutic effectiveness and watch for adverse drug reactions. Pharmacists should verify that dosing is appropriate, and to do so, they will need to have received renal and liver function testing results from the team. The pharmacist should also look for drug-drug interactions and alert the physician or nurse if any are present. The pharmacy can also assist the clinician with therapy changes to address the braking phenomenon and ceiling effect. Only with a coordinated interprofessional team effort can furosemide therapy be optimized for positive patient results. [Level V]


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