Furosemide

Mechanism of Action

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

Pharmacokinetics

Absorption: The onset of action of furosemide is usually within the first hour of oral furosemide intake, and it takes the 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.[7]

Bioavailability:  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.[8] Oral and sublingual administration of furosemide achieves a peak concentration slower than the iv route. Although furosemide is more avidly absorbed with a bioavailability of 59% via the sublingual route 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, the urinary excretion rate of furosemide and sodium and cumulative urine excretion rate was not different between the oral and sublingual administration of furosemide.[9].The bioavailability of furosemide is variable and relatively lesser than that of torsemide in patients with compensated congestive heart failure.[10][11] 

Distribution: 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. 

Metabolism: Furosemide glucuronide is a major biotransformation active product of furosemide, having an active diuretic effect. Contemporary evidence indicates that furosemide is minimally metabolized in the liver.[12]

Excretion: 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.[7] 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. After intravenous administration, furosemide achieves an early and high serum peak concentration and a higher peak excretion rate. A greater extent of furosemide is excreted in urine following the parenteral administration than oral administration.

Administration

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

In patients with normal renal function, the oral dose equivalence of furosemide relative to other oral diuretics is as follows[13]:

• 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.
• Furosemide oral solution is available as 10 mg/ml or 8 mg/ml, i.e., 40 mg furosemide/5 ml of solution.

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." Therefore, 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 a 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 furosemide use becomes chronic in a patient, ECF volume shrinks, and the level of natriuresis also goes down. At that point, the amount of natriuresis equals sodium intake; this is called the "breaking 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 results from increased salt delivery, increased aldosterone, angiotensin II, and 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. Clinicians can overcome this phenomenon by adding thiazide diuretics which block sodium absorption in distal segments of the nephron.[14][15]

Use in Specific Population

Patients with Hepatic Impairment: In patients with hepatic cirrhosis and ascites, furosemide therapy should be initiated in the hospital. In hepatic coma and states of electrolyte depletion, therapy should not be started until the underlying condition is improved. Sudden fluid and electrolyte balance alterations in patients with cirrhosis may precipitate hepatic encephalopathy; therefore, stringent observation is necessary during diuresis.

Patients with Renal Impairment: GFR ≤30 mL/min; increased doses are required to achieve desired diuretic response. If increasing azotemia and oliguria occur during severe progressive renal disease treatment, furosemide should be discontinued.

Pregnancy Considerations: 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 risks and benefits.[16] 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 occur with the pregnant patient, and caution is necessary with the decision to take furosemide during pregnancy; fetal growth will require close monitoring.[17][18]

Breastfeeding Considerations: Because little information is available on using furosemide during breastfeeding and because intense diuresis might decrease lactation, an alternate drug may be preferred, especially while nursing a newborn or preterm infant. Low doses of furosemide may not suppress lactation.[19]

Adverse Effects

Adverse reactions are categorized below by the system organ classification system(soc) and listed by decreasing severity. The following are potential adverse effects associated with furosemide use[10][20]:

Gastrointestinal System

• Hepatic encephalopathy in patients with cirrhosis[21]
• Pancreatitis
• Jaundice (intrahepatic cholestatic jaundice)
• Increased liver enzymes
• Anorexia
• Oral and gastric irritation
• Cramping
• Diarrhea
• Constipation
• Nausea
• Vomiting

Systemic Hypersensitivity Reactions

• Severe anaphylactic or anaphylactoid reactions (e.g., with shock)
• Systemic vasculitis
• Interstitial nephritis
• Necrotizing angiitis

Central Nervous System:

• Ototoxicity[22]
• Paresthesias
• Vertigo
• Dizziness
• Headache
• Blurred vision
• Xanthopsia

Hematologic Reactions

• Aplastic anemia 
• Thrombocytopenia
• Agranulocytosis
• Hemolytic anemia
• Leukopenia
• Anemia
• Eosinophilia

Dermatologic-hypersensitivity Reactions

• Toxic epidermal necrolysis
• Stevens-johnson syndrome
• Erythema multiforme
• Drug rash with eosinophilia and systemic symptoms
• Acute generalized exanthematous pustulosis
• Exfoliative dermatitis
• Bullous pemphigoid
• Purpura
• Photosensitivity
• Rash
• Pruritus
• Urticaria

Cardiovascular System

• Alcohol, barbiturates, or narcotics may aggravate orthostatic hypotension.
• Increase in cholesterol and triglyceride serum levels

Renal Disorders

• Acute kidney injury due to fluid loss[23]

Metabolic Disorders

• Hyperglycemia
• Hyperuricemia
• Hypokalemia
• Hypomagnesemia[24]

Contraindications

• Contraindications to furosemide use include patients with documented allergies to furosemide and patients with anuria.

• A boxed warning suggests the cautious use of furosemide as it is a potent diuretic, which 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.[25]

• Ototoxicity can occur with the use of furosemide, but the following conditions predispose patients to a higher risk of reversible or irreversible hearing impairment[26]:
  • Use of a higher than the recommended dose of furosemide or a fast infusion rate of the drug,
  • Hypoalbuminemia 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 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 there is an improvement in the patient's mental status.[5]

• Patients with the advanced renal disease with fluid overload should be closely monitored for oliguria, azotemia, and volume status. If either oliguria or azotemia develops, furosemide should be discontinued to prevent kidney injury.

• In patients with primary adrenal insufficiency with hypertension, diuretics are a practice clinicians should avoid to treat hypertension. Alternatively, the dosage of glucocorticoid/mineralocorticoid requires adjustment, and, if needed, the Clinician should prefer other classes of antihypertensive agents over diuretics to treat hypertension.[27]

• High-risk patients for radiocontrast-induced nephropathy are more predisposed to having a worsened kidney function if furosemide is given before contrast administration than 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 the initial days of furosemide treatment. After that, they require observation for worsening symptoms as excessive diuresis and urine retention can lead to acute urinary retention leading to acute kidney injury.

• The risk of hypokalemia increases with a high dose of furosemide, decreased oral potassium intake 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.[28]

Monitoring

• Fluid status, BUN and creatinine to prevent oliguria and azotemia
• Obtain potassium before and during rapid diuresis
• Observe for signs of ototoxicity at the higher dose
• Clinicians should check the chart for fluid intake and output.
• NT-proBNP
• Vitals: Orthostatic hypotension[29]

Toxicity

Toxicity with furosemide manifests as extensions of its diuretic activity. The main signs and symptoms of overdose with furosemide are blood volume reduction, dehydration, electrolyte imbalance, hypotension, hypochloremic alkalosis, and hypokalemia.[10]

Treatment of overdosage is supportive, and it consists of replacing excessive fluid and electrolyte losses. Clinicians should frequently determine serum electrolytes, arterial blood gas analysis, and blood pressure. In addition, providers must assure adequate drainage in patients with urinary bladder outlet obstruction (such as prostatic hypertrophy). Hemodialysis does not accelerate furosemide elimination.

Enhancing Healthcare Team Outcomes

American Heart Association (AHA) estimated that there were 6.2 million people with HF in the United States between 2013 and 2016.[30] Managing patients with hypervolemia requires an interprofessional healthcare team 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, pharmacists, and clinicians, including advanced heart failure specialists.

Careful monitoring of the patient's clinical condition, daily weight, fluids intake, 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 of furosemide. For example, if indicated for diuresis with furosemide, replete electrolytes lead to electrolyte depletion, and adjust the dose or even hold off on furosemide if laboratory work shows signs of kidney dysfunction. Similarly, patients who are on furosemide treatment in an ambulatory care setting need close monitoring to evaluate the response to treatment, intermittent electrolytes and kidney function monitoring to replete electrolytes and manage the dose of furosemide as indicated, and to assess for other adverse effects of the furosemide treatment and manage it accordingly.

While the clinician, NP, or 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 inpatient or outpatient monitoring. 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 clinician or nurse if any are present. The pharmacy can also assist the clinician with therapy changes to address the braking phenomenon and ceiling effect. Clinicians can optimize furosemide therapy with a coordinated interprofessional team effort for positive patient results. [Level 5]