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An 82-year-old woman comes to the emergency department because of acute respiratory distress. Physical examination shows 4+ pitting ankle edema. She is hospitalized with acute decompensated heart failure. One week after appropriate IV diuretic therapy is initiated, red blisters and erosions are present on the dorsal surfaces of her hands. Which of the following is most likely to be found in this skin condition?
Contributors:Evan Debevec-McKenney, Jake Ryan, Kara Lukasiewicz, PhD, MScBMC, Ursula Florjanczyk, MScBMC, Elizabeth Nixon-Shapiro, MSMI, CMI, Viviana Popa, MD
Diuretics are medications that act on the kidneys to increase production of urine - and therefore, eliminates water from the body. There are 5 main types of diuretics - carbonic anhydrase inhibitors; osmotic diuretics; thiazide and thiazide-like diuretics; potassium sparing diuretics; and last but not least, loop diuretics - which we’ll get intimately acquainted with during this video.
Now, the basic unit of the kidney is called a nephron, and each nephron is made up of a glomerulus, which filters the blood. Blood enters the glomerulus with the afferent arteriole, and exits the glomerulus from the efferent arteriole. The filtered content then goes through the renal tubule, where excess waste, and molecules (such as ions and water), are removed or filtered through an exchange between the tubule and the peritubular capillaries. So the renal tubule plays a huge role in secretion and reabsorption of fluid and ions - such as sodium, potassium, and chloride - in order to maintain homeostasis, or the balance of fluid and ions in our body. The renal tubule has a few segments of its own: the proximal convoluted tubule; the U-shaped loop of Henle, with a thin descending, a thin ascending limb, and a thick ascending limb; and finally, the distal convoluted tubule, which empties into the collecting duct, which collects the urine.
Different kinds of diuretics act on different segments of the renal tubule. Now, loop diuretics - as you might have guessed - act on the loop of Henle. To be more specific, they mainly target the thick ascending limb. The thick ascending limb is impermeable to water and it is lined with cuboidal cells that have Na+K+2Cl- cotransporters on the apical surface. These transporters reabsorb sodium, potassium, and chloride from inside the thick ascending limb back into the blood. As such, they shuttle one sodium into the cell, down its concentration gradient, and that powers the movement of one potassium and two chlorides into the cell as well. Think of it as a revolving door where sodium is the guy doing all the pushing, and one potassium and two chlorides just follow him in. This way, approximately 25% of the filtered sodium is reabsorbed in the loop of Henle, mostly in the thick ascending limb. Now, on the basolateral side of the tubule cell, a Na/K ATPase uses energy in the form of ATP to pump three sodium ions into the interstitial fluid in exchange for letting two potassium ions into the cell. This helps to maintain the low sodium concentration inside the cell. Finally, both chloride and potassium move from the cell back into the lumen of the thick ascending limb, through special channels on the apical side of the cells that simply “leak” these ions passively. Funnily enough, the passive movement of potassium generates an electrochemical gradient that increases the reabsorption of calcium and magnesium through a paracellular pathway - meaning, these ions don’t use any channels, but rather they sneak between two epithelial cells and go back in the bloodstream. Now that’s a lot of activity for such a tiny cell!
Ok, now here’s where loop diuretics come into play. Just to get acquainted with our team here, there’s 4 main diuretics - 3 of them: furosemide, bumetanide and torsemide - are chemically related, in that they are sulfonamide derivatives. The last non-sulfonamide loop diuretic, ethacrynic acid, is a phenoxyacetic acid derivative.
These medications can be administered orally or intravenously, and once they’re in the bloodstream, they get secreted from the peritubular capillaries into the proximal tubule. Then, they make their way to the thick ascending limb and bind to the Na+K+2Cl- cotransporters. Loop diuretics bind to the Cl- site on the transporter and block it, so now sodium, potassium, and chloride can’t be reabsorbed into the bloodstream and they get excreted out with the urine. Other ions that depend on sodium reabsorption, like calcium and magnesium are excreted as well. Now remember, water follows where sodium goes. So this means there will be more water molecules in the lumen as well, so more urine is produced. Okay, now regarding calcium, there’s an important distinction from thiazide diuretics, which is another important class of diuretics. Loop diuretics increase calcium excretion, while thiazide diuretics decrease calcium excretion. There’s a mnemonic to help you remember this fact! “Loops lose calcium”!
Okay, now, along with inhibiting these Na+K+2Cl- cotransporters, loop diuretics also stimulate the release of prostaglandins, which dilate the afferent arteriole. As a result, they increase the renal plasma flow and they also increase the glomerular filtration rate, or GFR. However, many individuals who take loop diuretics also take non-steroidal anti-inflammatory drugs, or NSAIDs, which inhibit prostaglandin synthesis and thus, they can decrease the loop diuretics’ effect.
Ok, so the major indication for diuretics is for the management of edematous states, like heart failure, pulmonary edema, cirrhosis with ascites, or nephrotic syndrome, where fluid builds up in the extracellular space. However, they can also be used as an alternative agent for hypertension. Since these medications cause water loss through the urine, it leads to decreased plasma volume and cardiac output, resulting in lower blood pressure.
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- "Cellular mechanism of the action of loop diuretics on the thick ascending limb of Henle's loop" Klin Wochenschr (1983)
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- "Loop Diuretics in Acute Kidney Injury Prevention, Therapy, and Risk Stratification" Kidney and Blood Pressure Research (2019)