Loop diuretics are the strongest tools in your diuretic arsenal, but do you know how to make the most of them? In this video from our Fluids and Electrolytes Masterclass, Dr Joel Topf explains critical differences between loop diuretics, how changes in bioavailability can result in acute situations, and a starting dosage algorithm for patients with renal dysfunction.
[00:00:00] We're going to go through every diuretic and each aspect of the kidney to understand how these diuretics work, and we're not going to do them in anatomic order. Because in truth, the proximal tubule and the cortical collecting duct diuretics, they're just not very strong diuretics. And so we're going to start with the strongest diuretic of all, the loop diuretic. In order to understand the loop diuretic, you need to understand how the thick
[00:00:30] ascending limb of the loop of Henle works. The principal molecule here is sodium potassium t2 chloride cotransporter. Here, two molecules of chloride, a molecule of sodium, and a molecule of potassium all bind this and are transported into the cell. I want you to quickly look and see that sodium and chloride are in much higher concentrations in the tubular fluid. And as this molecule runs and transports these ions across the cell membrane,
[00:01:00] potassium would be quickly depleted. In order to avoid that, potassium is recycled out of the cell through something called the ROMK channel. But when that happens, what is normally an electron neutral movement to cations, sodium and potassium, and two anions, chloride now becomes electrogenic. Because there's no net movement of potassium, you get a positive charge on the tubular side of the membrane.
[00:01:30] This positive charge is a byproduct of the potassium recycling. But the kidney uses this by-product to force the reabsorption of other cations, magnesium, calcium, and sodium specifically are reabsorbed through a paracellular pathway. That means a pathway between the cells, not through the cells and it is driven by that positive charge generated from the recycling of potassium. Let's take a closer look at the loop diuretics. So, loop diuretics are active
[00:02:00] in the tubular fluid. They don't act from the basal lateral membrane. They don't get to their active site via the blood. They need to get into the tubular fluid to work. Now, loop diuretics are highly protein bound, and any molecule that's protein bound can't be filtered at the glomerulus. So, the way that it enters the tubule is it's secreted in the proximal tubule. Now, that secretion is GFR dependent. Hence, the lower the GFR, the less diuretic that makes it to
[00:02:30] the tubule. We're always talking about dosing for kidney disease. And usually, when we talk about renal dosing, we talk about decreasing the dose as your kidney function deteriorates, you either need less of the drug or you need to use the drug less often. That's not the case with diuretics. Here, when we talk about renal dosing, we use more and more of the drug as the kidneys get weaker and weaker. There's a number of ways to figure out a starting dose for furosemide, but I like
[00:03:00] to take the serum creatinine and milligrams per deciliter. And just multiply it by 20 with a ceiling of around 80 milligrams. And once I'm at 80 milligrams, I'll stop the ascent there, give a test dose and see what kind of response. If no response, you can go even higher. Let's take a look at how the loop diuretics actually work at the thick ascending limb of the loop of Henle. Here, the Lasix is a green dot, and it blocks the chloride slot.
[00:03:30] It fits into the chloride slot and shuts down the sodium-potassium 2 chloride transporter. This will increase the renal excretion of sodium, potassium, hydrogen ions causing metabolic alkalosis, calcium, and magnesium. Now, there are three loop diuretics and they all have different characteristics. The one we're most familiar with is furosemide, goes by the trade name, Lasix. But there's two others. There's bumetanide and torsemide. Now, they vary
[00:04:00] primarily from Lasix in terms of bioavailability. I'm going to talk a little bit of bioavailability later. But essentially, bioavailability is the ratio of an IV dose to what you need orally. So, as you can see with Lasix, if you give this much IV, you'll either need the equivalent amount orally or a whole bunch more and it's hard to predict what the case is on any individual patient. While the bioavailability of Bumex and torsemide, it is much more predictable.
[00:04:30] The low dose to the high doses is almost identical to the IV dose, and that makes it much easier to convert patients from IV to oral bumetanide and torsemide. The other big difference is half-life. And you can see that the half-life of Lasix goes from 1.5 to 2 hours, much shorter half-life with bumetanide, and a longer half-life with torsemide. Let's go back to the bioavailability and talk about what the implications are for patients. So here's a
[00:05:00] patient case, this gentleman with a known history of heart failure. He's been taking his medications regularly but despite that, he is at a 30-pound weight gain over the last month, and today, he was unable to put on his regular shoes and is forced to wear his slippers. He comes to the emergency room with dyspnea and shortness of breath. And in the emergency room, he's given a dose of IV Lasix and probably begins making copious amounts of urine. Now, the cynic concludes that with such a brisk diuresis, the patient must not have been
[00:05:30] taking his diuretics. But another possibility that you conclude, that this may be a case where the bioavailability of furosemide has fallen in this individual from 100% to 10%. Now, how may that occur? It can occur because the edema that we see throughout the body also occurs in the intestinal tract. And as you get increased intestinal edema, that can decrease the absorption of furosemide, so what was the appropriate dose at one point is no longer appropriate for giving him the diuresis
[00:06:00] he needs. Moving on to half-life. So, the half-life of furosemide is 1.5 to 2 hours, bumetanide is quicker. It has a half-life of one hour. That means it's gonna have a very quick onset of action. You give the drug and you'll immediately see a response. This is useful in the ICU. Torsemide is on the other half of that stick. It has a long half-life from 3 to 4 hours. This allows once daily dosing. It is optimal for hypertension and heart failure. In fact, there are clinical studies
[00:06:30] that have shown that you could decrease hospitalization, where the only change you do is switch patients from furosemide to torsemide, reduction in hospitalization for heart failure in all causes.