Ever wonder why some ICU intensivists schedule loop diuretic administration a block of time after thiazide diuretics? First, let's review the three classes of diuretics and their modes of action (MOA):
| Loop Diuretics | Thiazide Diuretics | Potassium-Sparing Diuretics |
MOA | Inhibit the Na-K-2Cl (NKCC2) cotransporter of the thick ascending limb of the loop of Henle. Increase excretion of sodium, chloride, potassium, water, calcium, and magnesium. Can induce renin release. | Blocks sodium-chloride (Na/Cl) channels in the proximal segment of the distal convoluted tubule (DCT). Increase excretion of sodium, chloride, potassium and water. Increases the reabsorption of urea in the proximal convoluted tubule (PCT), which can lead to hyperuricemia and gout. | Acts on the distal parts of the nephron, from the late DCT to the collecting duct. Used in conjunction with other diuretics to prevent hypokalemia. Excretes sodium, chloride, and water. Spironolactone is a competitive inhibitor of aldosterone. |
Meds |
|
|
|
Sodium Reabsorption
Sodium reabsorption from glomerular filtrate occurs at varying levels and different mechanisms along the nephron. The PCT absorbs the most sodium at about 67% while the loop of Henle absorbs about 25%, DCT about 5-10%, and collecting duct only about 3% ¹. Loop, thiazide, and potassium-sparing diuretics achieve diuresis by targeting specific sodium reabsorption mechanisms at different areas of the nephron.
Image 1 - Diuretic Location of Action: There are multiple opportunities along the nephron where sodium and water reabsorption can take place.
What are loop diuretics and what are they used for?
Loop diuretics are approved by the Food and Drug Administration (FDA) for treating edema associated with congestive heart failure, liver cirrhosis, and renal disease. They are used to remove excess fluid from the body and prevent water reuptake from the kidneys. While loop diuretics themselves have different bioavailability and half-life responsible for their varying levels of potency, medications in this class are considered the most potent diuretics available².
How do loop diuretics work?
Loop diuretics achieve their effect by inhibiting the Na-K-2Cl (NKCC2) cotransporter in the apical membrane of the thick ascending limb of the loop of Henle². The function of the cotransporter is to move sodium, potassium, and chloride from the nephron to the medullary interstitium (Image 2). The movement of sodium here generates the salty renal medulla responsible for driving osmosis and reabsorption of water by the neighboring descending loop of Henle, a system called the counter-current multiplier mechanism. By inhibiting the NKCC2 cotransporter, loop diuretics prevent the reabsorption of sodium and promote diuresis. The net effect is the excretion of water, sodium, potassium, chloride, calcium, and magnesium.
Image 2 - Nephron physiology at the thick ascending limb of the loop of Henle: 1) Sodium, potassium, and 2 chloride ions move from the nephron tubule to the epithelial cell via the Na-K-2Cl cotransporter. 2) Sodium moves from the cell to the medullary interstitium in exchange for potassium via the sodium-potassium ATPase. Meanwhile, Cl⁻ moves to the cell via a Cl⁻ channel. 3) Accumulated potassium resulting from the cotransporter and Na/K ATPase is recycled by the nephron by a potassium channel. 4) The positive charge of accumulated potassium ions in the nephron repels passing cations, such as magnesium and calcium, causing them to move out of the tubule for reabsorption via a paracellular process. 5) The high concentration of sodium and solutes in the medullary interstitium drives the osmosis of water, first to the medulla and then to the vasa recta where it enters the bloodstream.
What causes loop diuretic resistance?
Loop diuretic resistance occurs when a therapeutically desired reduction in edema is not achieved despite a full dose of diuretic³. One possible cause is due to a pharmacokinetic abnormality. Decreased renal function reduces and/or delays peak concentration of the drug in the nephron rendering it less effective than in otherwise healthy kidneys.
Another common cause observed in the ICU results from chronic treatment with loop diuretics. Chronic loss of water and electrolytes leads to the development of compensatory mechanisms downstream. More specifically, sodium and water reabsorption is enhanced by the hypertrophy of epithelial cells in the DCT, which serves to counteract the effects of loop diuretics⁴. Autopsies have shown the extent to which the DCT can hypertrophy as a result of chronic impedance of electrolyte homeostasis⁵.
What is done to counteract loop diuretic resistance?
Strategies to overcome diuretic resistance include restriction of sodium intake, changes in dose, changes in timing, and combination diuretic therapy⁴. For example, priming the nephron with IV chlorothiazide inhibits downstream sodium and water reabsorption. Since it takes about 30 minutes for chlorothiazide to take full effect, it is only after this window of time that a loop diuretic, such as bumetanide, is administered. This combination and timing allows for the loop diuretic to bypass compensatory effects of a hypertrophied DCT to promote the full effect of the loop diuretic.
Image 3: Combination therapy with thiazide and loop diuretics. 1. First, administer the thiazide diuretic to inhibit downstream sodium reabsorption. 2. Next, administer the loop diuretic once the thiazide has taken its full effect. 3. The effect of the counter-current multiplier mechanism is reduced and less water is absorbed in the descending loop of Henle.
What are the side effects of diuretics?
Patients receiving diuretics should be monitored regularly for electrolyte imbalances that require replacement, such as hyponatremia, hypokalemia, hypochloremia, and hypomagnesemia. Potassium-sparing diuretics can help reduce the excretion of potassium while aiding in net diuresis. They should also be monitored for signs of dehydration and carefully weighed on a daily basis to determine fluid status. Changes in fluid status can cause headache, dizziness, postural hypotension, and syncope. It is best practice to have the patient sit on the edge of the bed for a few minutes before standing. In addition, thiazide diuretics increase the risk of hyperuricemia and gout. Allopurinol is a medication commonly used to inhibit uric acid synthesis and prevent gouty arthritis.
References:
1. “Tubular Reabsorption Article (Article).” Khan Academy, Khan Academy, https://www.khanacademy.org/test-prep/mcat/organ-systems/the-renal-system/a/tubular-reabsorption-article.
2. Huxel C, Raja A, Ollivierre-Lawrence MD. Loop Diuretics. [Updated 2022 Jul 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK546656/
3. Hoorn EJ, Ellison DH. Diuretic Resistance. Am J Kidney Dis. 2017 Jan;69(1):136-142. doi: 10.1053/j.ajkd.2016.08.027. Epub 2016 Nov 1. PMID: 27814935; PMCID: PMC5182087.
4. De Bruyne LK. Mechanisms and management of diuretic resistance in congestive heart failure. Postgrad Med J. 2003 May;79(931):268-71. doi: 10.1136/pmj.79.931.268. PMID: 12782772; PMCID: PMC1742703.
5. Hunter, Robert W., et al. “Hypertrophy in the Distal Convoluted Tubule of an 11β-Hydroxysteroid Dehydrogenase Type 2 Knockout Model.” Journal of the American Society of Nephrology, vol. 26, no. 7, 2014, pp. 1537–1548., https://doi.org/10.1681/asn.2013060634.