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

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)

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

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.

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

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

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

Acute tolerance

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

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