Viva H2(i)

What are the pharmacokinetic properties of furosemide?

• Class: Loop diuretic
• Chemical classification: Anthranilic acid derivative
• Routes of administration: IV, IM, oral, sublingual, and as a neb
  • Acidic drug; pKa 3.6.
  • Poor water solubility at normal pH.
  • Presentation for IV administration contains a substantial amount of sodium hydroxide as an alkalinising excipient to make it water-soluble
  • Better water solubility (and poor lipid solubility) in the relatively alkaline small intestine, as well as in the blood.
• Absorption: Variable oral bioavailability, between 10 and 100% (interindividual variability). Mainly absorbed in the stomach
• Distribution:  VOD = 0.1-0.2L/kg, i.e. mainly confined to the circulating volume. 95% protein bound. Decreased albumin levels increase the volume of distribution and decrease the delivery of the drug to its useful site of action (tubular lumen)
• Metabolism:
  • Clearance is 50% by proximal tubular secretion
  • Metabolism in the kidney (~ 50%)
  • Converted into a glucuronide which has approximately 25% of the parent drug's activity.

What are other substances in the same class?

• bumetanide
• piretanide
• torsemide
• ethyacrynic acid

What is the mechanism of effect of furosemide?

• Blockade of the NKCC2 transporter
• This decreases the reabsorption of sodium potassium and chloride in the thick ascending limb (in the inner medulla)
• The decreased reabsorption of solutes into the inner medulla and the increased delivery of solutes to the distal nephron produces the diuretic effect:
  • The osmolality of the collecting duct fluid increases because of decreased tubular sodium and chloride reabsorption
  • The osmolality of the medullary intestitium decreases for the same reason
  • Ergo, the gradient for osmotic reabsorption of water via the aquaporins in the collecting duct is impaired
  • Thus, more water is excreted, and this is the basis of the diuretic effect 

What are the adverse effects of furosemide?

• Blockade of the NKCC2 transporter increases the delivery of sodium potassium and chloride to the distal nephron.
  • There, sodium is reabsorbed by aldosterone-regulated ENaC channels.
    • As body water volume decreases with frusemide therapy, so the reabsorption of sodium here escalates, as aldosterone is released in response to hypovolemia
    • Potassium removal via the urine is also increased because of sodium and potassium being exchanged with the tubular fluid
  • Chloride and ammonium elimination is also increased, as ammonium is an alternative substrate for NKCC2
  • The consequences of this are:
    • Metabolic alkalosis (hypochloraemia)
    • Hypernatremia (as sodium is retained)
    • Hypokalemia (as potassium excretion is increased by the increased sodium delivery to the distal nephron)
  • The increased delivery of chloride to the distal nephron results in urinary acidification.

Other effects:

• Hypotension (esp. orthostatic)
• RAAS activation
• Ototoxicity, especially in combination with aminoglycosides
• Electrolyte disturbances:
  • Hypokalemia
  • Metabolic alkalosis (hypochloraemia)
  • Hypernatremia (as sodium is retained)
  • Hypomagnesemia
  • Hypophosphatemia
• Pharmacological interactions:
  • Displacement of warfarin from albumin binding sites

What is the mechanism of furosemide-induced hypokalemia?

• This can be described as a “Pseudo-Bartter-Syndrome"
• The ENaC channel reabsorbs sodium in the collecting duct
• This generates an apical transmembrane potential, as positively charged ions are being removed from the lumen of the duct
• This negative apical membrane charge produces a movement of potassium out of the cells via the ROMK channel (Welling, 2016)
• In this fashion, sodium is exchanged for potassium in the collecting duct
• Thus, increasing the delivery of sodium to the distal nephron creates an increased potassium excretion.
• There is further activation and expression of ENaC channels in the context of furosemide therapy because of the volume contraction (which results in aldosterone release).

How does furosemide produce metabolic alkalosis?

• Furosemide decreases the extracellular fluid volume, and produces hypokalemia
• The extracellular volume contraction stimulates the release of aldosterone
• Both aldosterone and hypokalemia stimulate H⁺ ATPase activity in the collecting duct, increasing the elimination of H⁺ into the lumen of the collecting duct
• This loss of acid results in a systemic metabolic alkalosis

How does furosemide produce hypomagnesemia?

• In the thick ascending limb, magnesium and calcium reabsorption is paracellular
• It occurs when potassium reabsorbed by NKCC2 channels is returned to the tubular lumen by the ROMK channel, increasing the positive charge in the tubular fluid
• This increases the electrochemical gradient for cation movement out of the tubular lumen
• Magnesium and calcium are both reabsorbed in this fashion
• Furosemide decreases the reabsorption of chloride by NKCC2, increasing the negative charge in the tubular lumen
• The result is a loss of the electrochemical gradient for magnesium and calcium reabsorption
• This results in a net loss of magnesium and calcium

(Alexander & Dimke, 2017) 

How does hypoalbuminaemia influence the efficacy of furosemide?

• Furosemide is highly protein-bound, mainly to albumin (95-97%)
• In the absence of sufficient albumin to transport it, frusemide has a very large volume of distribution
• As the result, it is not filtered sufficiently in the proximal tubule to be present in the  tubular lumen in effective quantities
• Where albumin is abundant, albumin-bound furosemide is delivered to the proximal tubule in the blood, where OAT transporters on the basal membrane strip in from the albumin and actively secrete it into the tubular lumen
• Thus, hypoalbuminaemia decreases the efficacy of furosemide

What is the "ceiling dose" effect of furosemide?

• Furosemide achieves its effect by increasing the excretion of filtered sodium
• A fractional excretion of about 20% of all filtered sodium is the maximum fractional excretion that can be achieved (as other mechanisms are also involved in reabsorbing sodium at the same time)
• The furosemide dose at which this fractional excretion is achieved is therefore the "ceiling dose", beyond which no further increase in diuresis is possible
• This dose is about 80-200mg in patients with CKD or nephrotic syndrome, and 40-80mg in patients with congestive heart failure or liver cirrhosis.

What is the "threshold dose" of furosemide?

• A "threshold dose" is a minimum dose of furosemide below which one does not detect any clinically relevant increase in urine output
• In healthy kidneys a dose less than 10mg will not produce any diuresis, so it is said
• In patients with chronic renal failure, this dose is likely much higher