NephropharmacologyCJASN ePress. Published on April 1, 2019 as doi: 10.2215/CJN.09630818 for the Clinician Clinical Pharmacology in Diuretic Use David H. Ellison Clin J Am Soc Nephrol 14: ccc–ccc, 2019. doi: https://doi.org/10.2215/CJN.09630818 Diuretics are among the most commonly prescribed Gastrointestinal Absorption of Diuretics drugs and, although effective, they are often used to The normal metabolism of loop diuretics is shown in treat patients at substantial risk for complications, Figure 2A. Furosemide, bumetanide, and torsemide are Departments of making it especially important to understand and absorbed relatively quickly after oral administration Medicine and appreciate their pharmacokinetics and pharmacody- (see Figure 2B), reaching peak concentrations within Physiology and – Pharmacology, namics (see recent review by Keller and Hann [1]). 0.5 2 hours (3,4); when administered intravenously, Oregon Health & Although the available diuretic drugs possess distinc- their effects are nearly instantaneous. The oral bioavail- Science University, tive pharmacokinetic and pharmacodynamic proper- ability of bumetanide and torsemide typically exceeds Portland, Oregon; and ties that affect both response and potential for adverse 80%, whereas that of furosemide is substantially lower, Renal Section, at approximately 50% (see Table 2) (5). Although the t Veterans Affairs effects, many clinicians use them in a stereotyped 1/2 Portland Health Care manner, reducing effectiveness and potentially in- of furosemide is short, its duration of action is longer System, Portland, creasing side effects (common diuretic side effects are when administered orally, as its gastrointestinal Oregon t listed in Table 1). Diuretics have many uses, but this absorption may be slower than its elimination 1/2. review will focus on diuretics to treat extracellular This is a phenomenon called “absorption-limited Correspondence: fluid (ECF) volume expansion and edema; the reader is kinetics” (3) and may explain the mnemonic that Dr. David H. Ellison, this drug “lasts 6 hours” (6). This is not the case for Oregon Clinical and referred elsewhere for discussion of diuretictreatment Translational Research of hypertension, kidney stones, and other conditions. bumetanide and torsemide, where oral absorption is Institute, SN4N, rapid (7). On the basis of oral bioavailability, when a Oregon Health & Classification and Mechanisms of Action patient is switched from intravenous to oral loop Science University, Diuretic drugs are typically classified first according to diuretic, the dose of bumetanide or torsemide should 3181 SW Sam Jackson Park Road, Portland, their predominant site of action along the nephron and be maintained, whereas the dose of furosemide should OR 97239. Email: second by the mechanism by which they inhibit be doubled (7); in practice, however, and as discussed [email protected] transport (Figure 1A). The loop diuretics furosemide, further below, other factors affect diuretic efficacy, and a bumetanide, and torsemide act from the lumen to inhibit fixed intravenous/oral conversion cannot be given (8). the Na-K-2Cl cotransporter (NKCC2, encoded by The loop diuretics have steep dose-response curves. SLC12A1) along the thick ascending limb and macula This property, although typically taught to students densa. As organic anions, they bind within the transloca- and residents, is often neglected in clinical practice but tion pocket on the transport protein by interacting with the is crucial to optimal use. Figure 2C shows a typical chloride-binding site (2) (Figure 1B, see below for clinical natriuretic response plotted versus the logarithm of relevance). Because they are larger than chloride, they are the plasma diuretic concentration. Inspection reveals not transported through the pocket, and thereby inhibit that there is little diuretic or natriuretic effect below the transporter. Distal convoluted tubule diuretics a given plasma concentration (identified as the (thiazides and thiazide-likedrugs)arealsoorganic “threshold”), above which the response increases anions that act in much the same manner, but bind rapidly. Although such relations are typically plotted to the thiazide-sensitive NaCl cotransporter (NCC, as the logarithm of the diuretic concentration or dose, encoded by SLC12A3) along the distal convoluted clinicians do not typically “think” in logarithmic tubule (Figure 1A). This mechanism of action ac- terms. This underlies the reasoning behind the com- counts for a key aspect of loop and distal convoluted mon recommendation to “double the dose,” if no tubule diuretic action; these drugs both exert their response is obtained. At higher concentrations, a effect from the luminal side of the tubule. plateau or “ceiling” is reached, with progressively Potassium-sparing diuretics include drugs that block higher plasma concentrations failing to elicit more apical sodium channels (amiloride and triamterene) natriuresis. Although this fact has been used to invoke and those that antagonize mineralocorticoid receptors the concept of ceiling doses of loop diuretics, we will (spironolactone and eplerenone). A new nonsteroidal argue that increasing a diuretic dose above this ceiling mineralocorticoid blocker, finerenone, is currently in often elicits more natriuresis, owing to pharmacokinetic phase 3 clinical trials. The mineralocorticoid blockers considerations (see below). and perhaps ethacrynic acid, a more toxic loop As should be evident from Figure 2C, a diuretic diuretic, act within cells and do not require secretion dose must exceed the threshold to be effective; yet the into the tubule lumen. failure to give a dose that exceeds the threshold is one www.cjasn.org Vol 14 August, 2019 Copyright © 2019 by the American Society of Nephrology 1 2 Clinical Journal of the American Society of Nephrology individuals with a variety of edematous disorders. Yet, Table 1. Common side effects of diuretics adherence to algorithms may lead to diuretic failure. Instead, it is often best to approach a patient as an “n of Loop diuretics one trial,” that is, start with a dose consistent with the Hypersensitivity reactions Extracellular fluid volume depletion clinical guidelines (more aggressive for acute edema, more Hypokalemic alkalosis conservative for more chronic processes) and then adjust Hypomagnesemia the dose according to the response. Ototoxicity Although limited bioavailability is a concern with Distal convoluted tubule diuretics Hypersensitivity reactions furosemide, a larger problem may be its inconsistent bio- Hyponatremia availability. Furosemide absorption varies from day to day Hypokalemic alkalosis in an individual, and between individuals (9,10). Absorp- hyperglycemia/diabetes tion is also affected by food consumption, unlike that of Hyperuricemia/gout bumetanide or torsemide (11,12), although the clinical Hypomagnesemia fi Hypokalemia and prerenal azotemia, when signi cance of this effect has been doubted (3). The more combined with loop diuretics consistent bioavailability of torsemide, compared with t Potassium-sparing diuretics furosemide, and its relatively longer 1/2, have suggested Hypersensitivity that it may be a superior loop diuretic, as suggested by two Hyperkalemia – post hoc Metabolic acidosis small, clinical trials (13 16). A recent analysis of the Azotemia large Effect of Nesiritide in Patients with Acute Decompen- Gynecomastia, vaginal bleeding (spironolactone) sated Heart Failure study suggested that patients with heart failure discharged on torsemide might have lower mortality (17). Yet, none of these studies is sufficiently powered or rigorous enough to be considered definitive, and some other of the most common errors in diuretic usage. The problem studies do not suggest such a benefit(18). is that the threshold is not easily estimated in an individ- Gastrointestinal absorption can be slowed, especially ual, especially an individual with kidney or heart disease. during exacerbations of edematous disorders such as Although nearly all healthy individuals will respond to heart failure, although again, this may be true primarily 20 mg furosemide (or its equivalent), given orally, healthy of furosemide (19). Although total bioavailability is individuals are not typically treated. As discussed below, typically maintained in these situations, natriuresis conditions that predispose to ECF volume expansion and may be impaired when absorption is slowed, especially edema alter both the pharmacokinetics and pharmacody- given a concomitant increase in natriuretic threshold, as namics of diuretics. It is little wonder that an empirically shown in Figure 2B. As an example, the areas under the selected dose may be ineffective. Below, we will provide curves for arbitrary intravenous and doubled oral furo- broad generalizations about dose adjustments for semide doses may be similar, but the time above the ABDISTAL TUBULE Lumen Basolateral Afferent Pocket for ions arteriole Macula + loop Diuretics densa Na ATP Bowman’s DCTD capsule 3Na+ 2Cl− 2K Cortical PROXIMAL TUBULE collecting duct Lumen Basolateral CONNECTING TUBULE COLLECTING DUCT Na+ H+ Medullary Lumen Basolateral HCO− ATP collecting 3 duct MR + 3Na 2K + H CO Na 2 3 ATP CAI Aml Aldo CO H O 3Na+ 2K 2 2 K+ F372 Thin Thin descending ascending limb limb NKCC2 THICK ASCENDING LIMB LD Lumen Basolateral Na+ ATP 2Cl− K+ 3Na+ 2K K+ Figure 1. | Sites of sodium reabsorption and diuretic action along the nephron. (A) Nephron figure showing percentages of sodium reabsorption by associated segment. (B) Homology structural