Furosemide

Mechanism of Action

• Furosemide directly Inhibits the Na+/K+/2Cl- cotransporter within the thick ascending limb of the Loop of Henle (responsible for sodium permeability)
• Approximately 20-25% of filtered NaCl is reabsorbed by Loop of Henle
• The ascending limb of Loop of Henle is water impermeable and sodium permeable and is key to creating a hypertonic medullary interstitium required for water reabsorption
• Furosemide disrupts the creation of the counter-current mechanism as sodium is retained within the lumen → therefore, an excessive amount of water is retained in the lumen with sodium and subsequently excreted
• Potassium loss is accentuated due to increased volume flow through distal tubule and collecting duct
• Loop diuretics also enhance production of prostaglandins → renal and venous dilation

Dosing and Monitoring

• Oral dose = 40-1000mg/day
• IV Dose = 40-200mg / day

 

Bioavailability (PO): 10-100%, average of 50%

Onset of action: 1-1.5 hours (PO), 5 minutes (IV)

Peak response: 2 hours (PO), 30 minutes (IV)

Duration of action: 4-6 hours (PO), 2 hours (IV)

Plasma half-life: 0.5-1 hours (normal renal function), 9 hours (ESRD)

 

Pharmacokinetics

• Oral absorption is variable, the average bioavailability is 50% but ranges from 10-100%
• Furosemide is highly albumin bound (>95%) so only trivial amounts are filtered
• Enters lumen via active secretion by proximal tubule
• 50% of furosemide is metabolised by the kidney and 50% of furosemide is excreted unchanged
• 85% eliminated by kidney

Pharmacodynamics

• The relationship of drug dose and response follows a sigmoid shape; there is a threshold dose for drug response to occur
• In the case of furosemide, this relationship is patient specific given the variable bioavailability
• Individuals achieve a ceiling dose at roughly IV 40mg corresponding to a excretion of 20-25% of filtered sodium (200-250mmol) in 3-4 litres of urine.

Clinical Pearls

• Variable bioavailability of furosemide means that dosing is individual
• Action of furosemide is between 4-6 hours in total and therefore dosing is sensible during the morning and afternoon to maximise diuresis + reduces likelihood of increased sodium excretion in the evening for patient comfort
• The plateau of the dose response curve means that there is a little use of above 400mg intravenous dosing per 24 hours
• Furosemide is primarily eliminated by kidney
• Roughly 50% of furosemide is absorbed orally; when converting from IV to oral therapy, roughly double IV dosing to achieve same effect

Uses

• Hypertension
  • Initially, increased urinary sodium excretion and reduced plasma volume, extracellular fluid volume and cardiac output → drop in BP
  • Long term: decline in peripheral resistance
    • Furosemide enhances prostaglandin production which has a vasodilatory effect → reduces cardiac preload

• Oedema
  • Cardiac (HF)
    • Absorption of furosemide slower than normal in those with decompensated heart failure
      • Oedema of gut wall does not result in malabsorption of diuretics but does take longer to absorb
      • Frequent smaller doses may work effectively
    • Any improvement in cardiac function may reduce this delay in absorption
    • Patient may benefit from combination therapy with more distally acting agents
  • Pulmonary oedema
    • IV furosemide → rapid diuresis due to venodilatory effects seen within 15-30 minutes

• Use in Renal failure
  • In severe renal impairment maximum amount of sodium filtered is 25mmol
  • Therefore, unless severe sodium restriction is instituted fluid balance is hard to achieve
  • Amount of furosemide delivered produces same sigmoid shape response graph but lower ceiling dose

Diuretic Resistance

Acute tolerance

• After dosing, volume depletion invokes sodium retention to conserve volume
• As soon as furosemide dissipates from the site of action, the nephron avidly conserves sodium
  • Between doses, this can nullify natriuresis caused by the diuretic → it is therefore important to enforce dietary restrictions +/- administer multiple doses to main net negative sodium balance
  • Acute tolerance can happen particularly when
    • Diuretic response is low
    • Time of negligible drug effect is long
    • Patient ingests sodium during this interval

Chronic tolerance

• Enhanced resorption in other segments
  • Mechanisms
    • Increased Na+ receptor expression in other segments
    • Hypertrophy of tubular segments
  • Can be combatted with diuretic synergism e.g. thiazides may be used to block compensatory sodium resorption in distal tubule with chronic furosemide therapy
• Activation of RAAS, SNS, depletion of ECF and exposure to high sodium at distal nephron induces distal nephron hypertrophy
  • Nephron remodelling can be combatted with thiazide diuretics

Adverse Reactions

• 3 major types
  • Hypovolaemia and electrolyte imbalance
    • Excessive diuresis –> extracellular fluid volume contraction –> contraction alkalosis
  • Hypersensitivity
  • Ototoxicity
    • Reversible

Drug Interactions

• NSAIDs
  • Increase risk of nephrotoxicity
• ACEi and ARB
  • Increased risk of nephrotoxicity and antihypertensive effect
• Antibiotics:
  • Gentamicin – increased risk of ototoxicity
  • Trimethoprim – increased risk of hyponatraemia
• Digoxin
  • Furosemide induced hypokalaemia increases risk of arrhythmias with digoxin use
• Warfarin
  • Furosemide can displace warfarin from binding sites on blood proteins
  • Therefore, lower dose of warfarin may be needed with concomitant furosemide therapy

 

Author: Dr Sai Arathi Parepalli 

Senior Editor: Dr David Williams 

 

Links to References

https://go.drugbank.com/drugs/DB00695

https://pubmed.ncbi.nlm.nih.gov/22099505/

https://journals.physiology.org/doi/full/10.1152/ajprenal.00476.2015

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695849/

https://www.ncbi.nlm.nih.gov/books/NBK499921/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520883/

https://www.kidney-international.org/article/S0085-2538(15)31522-2/pdf

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269186/

https://pmj.bmj.com/content/80/943/271