Describe the pharmacology of frusemide.
Most candidates presented a well-structured answer and provided a basic understanding. Answers that provided accurate indications and details of the mechanism underlying the actions of frusemide attracted more marks. Those recognising the increased delivery of sodium and chloride to the distal tubule (exceeding resorptive capacity) were awarded more marks that those answers that attributed the diuretic action solely to reduction in the medullary gradient. Frusemide has many potential adverse effects and a reasonable list was expected. Conflicting information was common (e.g. highly bound to albumin – Vd 4 L/kg) and better answers avoided this.
|Chemistry||Anthranilic acid derivative|
|Routes of administration||IV, IM, oral, sublingual, and as a neb|
|Absorption||Variable oral bioavailability, between 10 and 100% (interindividual variability).
Mainly absorbed in the stomach
|Solubility||Acidic drug; pKa 3.6. Highly ionised (therefore poorly lipid soluble) in the relatively alkaline small intestine, as well as in the blood|
|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)|
|Target receptor||Binds competitively to the chloride binding site of the NKCC2 sodium-potassium-0chloride transport protein in the thick ascending limb of the loop of Henle|
|Metabolism||50% of the dose is metabolised in the kidney into an active glucouronide (which has only 25% of the parent drug agctivity)|
|Elimination||Cleared renally - 50% of the administered dose is eliminated in this way, mainly by active secretion via the OAT organic anion transport proteins in the proximal convoluted tubule. Half life is about 30-120 minutes|
|Time course of action||Effect lasts for six hours|
|Mechanism of action||Blockade of the NKCC2 transporter decreases the reabsorption of sodium potassium and chloride in the thick ascending limb
This increases the delivery of sodium potassium and chloride to the distal nephron. The increased solutes in the collecting duct lumen decrease the osmotic gradient between the duct and inner medulla, preventing water reabsorption in the collecting duct, resulting in diuresis.
Because of the main site of sodium reabsorption being the proximal tubule, theoretically only up to 20% of filtered sodium can be excreted by the blockade of all NKCC2 channels, which means loop diuretic therapy has a ceiling effect.
|Clinical effects||Hypovolemia (diuretic effect)
- Hypotension (esp.orthostatic)
- Metabolic alkalosis (hypochloraemia)
- Hypernatremia (as sodium is retained by ENaC)
- Acidification of the urine
|Single best reference for further information||FDA PI data sheet|
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.