Describe the biochemical abnormalities, and the mechanisms by which they arise, that may be observed in a patient who is taking frusemide.

[Click here to toggle visibility of the answers]

College Answer

This was a relatively straightforward question with marks available for listing the 
abnormality and then discussing its origin. Many candidates simply listed an abnormality or 
confused the direction of electrolyte change. Few candidates went beyond hypokalaemia, 
hyponatraemia and hypochloraemia. Several candidates gave confused answers as to the 
mechanism(s) or drew pictures of a tubule with directional arrows for electrolytes with 
inadequate explanation. Some candidates simply ran out of time and wrote very little – this 
is a pity as a list would have generated marks. Candidates are reminded to practise the 
exams to time and attempt all questions.

Discussion

Ok, so it sounds - both from the model answer and from the question wording itself - that this answer was expected as a table of biochemical abnormalities and their physiological causes. One must agree, to draw the tubule and make use of diagrams to explain these concepts is a recipe for disaster, as the author himself had discovered in the process of writing the furosemide chapter. There are probably less verbose methods to present this material, but the objective here was to produce a maximally pre-digested answer with minimal ambiguity. One could potentially save some spacetime by removing some of the more obvious steps and restating some elements in a form where phrases like "ergo, the consequence of" and "and this is the basis upon which" are replaced with "→".

Physiological and Biochemical Abnormalities,
Observed in Patients Taking Furosemide
Diuresis and hypovolemia
  • Furosemide blocks the NKCC2 channel in the thick ascending limb
  • 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
Hypernatremia
  • NKCC2 blockade increases the delivery of sodium 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
  • At the same time total body water decreases
  • The consequence is a concentration of total body sodium, leading to hypernatremia
Hypokalemia
  • 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.
Hypomagnesemia
  • Potassium reabsorbed by NKCC2 in the thick ascending limb is recycled, whereas the chloride is not
  • This creates a transepithelial potential difference across the tubule wall, i.e. the tubular lumen is more positive
  • This repels positively charged ions like calcium and magnesium, and they are driven out of the tubule
  • Furosemide decreases this electrical gradient for calcium and magnesium reabsorption, resulting in calcium and magnesium wasting 
Hypocalcemia
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 acidifies the urine down to a pH of 4.5
  • This loss of acid results in a systemic metabolic alkalosis
  • An alternative explanation is the increased strong ion difference (SID) of the extracellular fluid due to the increased sodium reabsorption by ENaC, and the increased chloride elimination.
Urinary acidification

References

Ponto, Laura L. Boles, and Ronald D. Schoenwald. "Furosemide (frusemide) a pharmacokinetic/pharmacodynamic review (part I)." Clinical pharmacokinetics 18.5 (1990): 381-408.

Ponto, Laura L. Boles, and Ronald D. Schoenwald. "Furosemide (frusemide) a pharmacokinetic/pharmacodynamic review (part II)." Clinical pharmacokinetics 18.6 (1990): 460-71

Huang, Xiaohua, et al. "Everything we always wanted to know about furosemide but were afraid to ask." American Journal of Physiology-Renal Physiology 310.10 (2016): F958-F971.

Maxwell, Robert A., and Shohreh B. Eckhardt. "Furosemide." Drug Discovery. Humana Press, Totowa, NJ, 1990. 67-77.

Wile, David. "Diuretics: a review." Annals of clinical biochemistry 49.5 (2012): 419-431.

Lang, H-J., and M. Hropot. "Discovery and development of diuretic agents." Diuretics. Springer, Berlin, Heidelberg, 1995. 141-172.