Clinical Pharmacology in Diuretic Use

Diuretics are among the most commonly prescribed drugs and, although effective, they are often used to treat patients at substantial risk for complications, making it especially important to understand and appreciate their pharmacokinetics and pharmacodynamics (see recent review by Keller and Hann 1). Although the available diuretic drugs possess distinctive pharmacokinetic and pharmacodynamic properties that affect both response and potential for adverse effects, many clinicians use them in a stereotyped manner, reducing effectiveness and potentially increasing side effects (common diuretic side effects are listed in Table 1). Diuretics have many uses, but this review will focus on diuretics to treat extracellular fluid (ECF) volume expansion and edema; the reader is referred elsewhere for discussion of diuretic treatment of hypertension, kidney stones, and other conditions. Table 1. - Common side effects of diuretics Loop diuretics Hypersensitivity reactions Extracellular fluid volume depletion Hypokalemic alkalosis Hypomagnesemia Ototoxicity Distal convoluted tubule diuretics Hypersensitivity reactions Hyponatremia Hypokalemic alkalosis hyperglycemia/diabetes Hyperuricemia/gout Hypomagnesemia Hypokalemia and prerenal azotemia, when combined with loop diuretics Potassium-sparing diuretics Hypersensitivity Hyperkalemia Metabolic acidosis Azotemia Gynecomastia, vaginal bleeding (spironolactone) Classification and Mechanisms of Action Diuretic drugs are typically classified first according to their predominant site of action along the nephron and second by the mechanism by which they inhibit transport (Figure 1A). The loop diuretics furosemide, bumetanide, and torsemide act from the lumen to inhibit the Na-K-2Cl cotransporter (NKCC2, encoded by SLC12A1) along the thick ascending limb and macula densa. As organic anions, they bind within the translocation pocket on the transport protein by interacting with the chloride-binding site (2) (Figure 1B, see below for clinical relevance). Because they are larger than chloride, they are not transported through the pocket, and thereby inhibit the transporter. Distal convoluted tubule diuretics (thiazides and thiazide-like drugs) are also organic anions that act in much the same manner, but bind to the thiazide-sensitive NaCl cotransporter (NCC, encoded by SLC12A3) along the distal convoluted tubule (Figure 1A). This mechanism of action accounts for a key aspect of loop and distal convoluted tubule diuretic action; these drugs both exert their effect from the luminal side of the tubule.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 model of the loop diuretic–sensitive NKCC2 viewed from the extracellular surface. The pocket for ion translocation and diuretic binding is shown by the arrow. Mutation of a key phenylalanine (F372) alters diuretic binding (reconstruction adapted from Somasekharan et al. 2). Aldo, aldosterone; Aml, amiloride (and triamterene); CAI, carbonic anhydrase inhibitors; DCTD, distal convoluted tubule diuretic; LD, loop diuretics; MR, mineralocorticoid receptor, site of spironolactone and eplerenone action (not shown).Potassium-sparing diuretics include drugs that block apical sodium channels (amiloride and triamterene) and those that antagonize mineralocorticoid receptors (spironolactone and eplerenone). A new nonsteroidal mineralocorticoid blocker, finerenone, is currently in phase 3 clinical trials. The mineralocorticoid blockers and perhaps ethacrynic acid, a more toxic loop diuretic, act within cells and do not require secretion into the tubule lumen. Gastrointestinal Absorption of Diuretics The normal metabolism of loop diuretics is shown in Figure 2A. Furosemide, bumetanide, and torsemide are absorbed relatively quickly after oral administration (see Figure 2B), reaching peak concentrations within 0.5–2 hours (3,4); when administered intravenously, their effects are nearly instantaneous. The oral bioavailability of bumetanide and torsemide typically exceeds 80%, whereas that of furosemide is substantially lower, at approximately 50% (see Table 2) (5). Although the t1/2 of furosemide is short, its duration of action is longer when administered orally, as its gastrointestinal absorption may be slower than its elimination t1/2. This is a phenomenon called “absorption-limited kinetics” (3) and may explain the mnemonic that this drug “lasts 6 hours” (6). This is not the case for bumetanide and torsemide, where oral absorption is rapid (7). On the basis of oral bioavailability, when a patient is switched from intravenous to oral loop diuretic, the dose of bumetanide or torsemide should be maintained, whereas the dose of furosemide should be doubled (7); in practice, however, and as discussed further below, other factors affect diuretic efficacy, and a fixed intravenous/oral conversion cannot be given (8).Figure 2.: (A) Features of absorption, distribution, metabolism, and excretion (so-called ADME) of drugs. (B) Comparing the plasma diuretic concentration as a function of time after oral or intravenous diuretic administration. The dashed lines show natriuretic thresholds in normal individuals and in those with edema. Note that the primary determinant of natriuresis is the time above the threshold, indicating why route of administration has different effects in stable patients and in those with severe edema. In a normal individual, an oral dose may be effective, whereas it may not be in edema despite retained bioavailability. (C) Classic dose-response curve, plotted versus the logarithm of the plasma concentration. Note the threshold for natriuresis and the maximal level, often called the ceiling. IV, intravenous. Table 2. - Pharmacokinetics of commonly used diuretics Diuretic Oral Bioavailability, % Elimination t 1/2, h Normal CKD Cirrhotic Ascites Heart Failure Furosemide 50 (10–100) 1.5–2 2.8 2.5 2.7 Bumetanide 80–100 1 1.6 2.3 1.3 Torsemide 68–100 3–4 4–5 8 6 Hydrochlorothiazide 55–77 6–15 Prolonged Chlorthalidone 61–72 40–60 Prolonged Metolazone 70–90 a 14–20 Prolonged Amiloride ∼50 b 6–26 100 Not changed Spironolactone >90 1.5 c d Data are presented as single reported values or range of reported values. Values for furosemide are given as the mean (range). When precise values were not provided, descriptive terms are provided.aAbsorption may be decreased in heart failure.bDecreased by food.cActive metabolites of spironolactone have t1/2 of >15 hours.dActive metabolites accumulate in CKD. Adapted from Karin (82). The loop diuretics have steep dose-response curves. This property, although typically taught to students and residents, is often neglected in clinical practice but is crucial to optimal use. Figure 2C shows a typical natriuretic response plotted versus the logarithm of the plasma diuretic concentration. Inspection reveals that there is little diuretic or natriuretic effect below a given plasma concentration (identified as the “threshold”), above which the response increases rapidly. Although such relations are typically plotted as the logarithm of the diuretic concentration or dose, clinicians do not typically “think” in logarithmic terms. This underlies the reasoning behind the common recommendation to “double the dose,” if no response is obtained. At higher concentrations, a plateau or “ceiling” is reached, with progressively higher plasma concentrations failing to elicit more natriuresis. Although this fact has been used to invoke the concept of ceiling doses of loop diuretics, we will argue that increasing a diuretic dose above this ceiling often elicits more natriuresis, owing to pharmacokinetic considerations (see below). As should be evident from Figure 2C, a diuretic dose must exceed the threshold to be effective; yet the failure to give a dose that exceeds the threshold is one of the most common errors in diuretic usage. The problem is that the threshold is not easily estimated in an individual, especially an individual with kidney or heart disease. Although nearly all healthy individuals will respond to 20 mg furosemide (or its equivalent), given orally, healthy individuals are not typically treated. As discussed below, conditions that predispose to ECF volume expansion and edema alter both the pharmacokinetics and pharmacodynamics of diuretics. It is little wonder that an empirically selected dose may be ineffective. Below, we will provide broad generalizations about dose adjustments for individuals with a variety of edematous disorders. Yet, adherence to algorithms may lead to diuretic failure. Instead, it is often best to approach a patient as an “n of one trial,” that is, start with a dose consistent with the clinical guidelines (more aggressive for acute edema, more conservative for more chronic processes) and then adjust the dose according to the response. Although limited bioavailability is a concern with furosemide, a larger problem may be its inconsistent bioavailability. Furosemide absorption varies from day to day in an individual, and between individuals (9,10). Absorption is also affected by food consumption, unlike that of bumetanide or torsemide (11,12), although the clinical significance of this effect has been doubted (3). The more consistent bioavailability of torsemide, compared with furosemide, and its relatively longer t1/2, have suggested that it may be a superior loop diuretic, as suggested by two small, clinical trials (13–16). A recent post hoc analysis of the large Effect of Nesiritide in Patients with Acute Decompensated 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 studies do not suggest such a benefit (18). Gastrointestinal absorption can be slowed, especially during exacerbations of edematous disorders such as heart failure, although again, this may be true primarily of furosemide (19). Although total bioavailability is typically maintained in these situations, natriuresis may be impaired when absorption is slowed, especially given a concomitant increase in natriuretic threshold, as shown in Figure 2B. As an example, the areas under the curves for arbitrary intravenous and doubled oral furosemide doses may be similar, but the time above the natriuretic threshold may be different when the natriuretic threshold is increased by disease. This is likely to explain the common observation that intravenous doses of loop diuretics, which achieve higher peak levels, may be effective when oral doses lose their effectiveness, especially if the natriuretic threshold is increased. Volumes of Distribution, Metabolism, and t1/2 Loop diuretics are organic anions that circulate tightly bound to albumin (>95%). Thus, their volumes of distribution are low, except during extreme hypoalbuminemia (20). This has suggested that severe hypoalbuminemia might impair diuretic effectiveness, owing to impaired delivery to the kidney, and that albumin administration might enhance natriuresis. This conjecture was supported in an early proof-of-concept study (20), but subsequent larger studies have produced mixed results. A relatively recent meta-analysis concluded that the existing data, albeit of poor quality, suggest transient effects of modest clinical significance for coadministration of albumin with furosemide in hypoalbuminemic patients (21). A similar assessment is reflected in the Kidney Disease guidelines for diuretic treatment of most recent studies have patients albumin concentrations that these considerations may not for hypoalbuminemic guidelines to suggest that albumin should be used as an to diuretics when patients to have volume depletion (or to be 50% of an administered furosemide dose is into the The to be by also in the Torsemide and bumetanide are both by and although metabolism may especially for torsemide The in mean that the t1/2 of furosemide is in kidney failure, where both excretion by the kidney and are In the t1/2 of torsemide and bumetanide to be in CKD Although the of doses of is in normal that as kidney Although this increase in furosemide may it also likely increases the toxic potential of furosemide in the of and from loop diuretics to primarily from concentrations, which inhibit an Na-K-2Cl encoded by This transport which is different from that along the thick ascending is by the and in secretion of This was more in the when large doses of loop diuretics were used to In one meta-analysis of furosemide use for patients with the for was more than when furosemide was it should be however, that the doses in that analysis those currently The of to lead to peak furosemide concentrations is one that many Loop diuretics exert their by binding to transport along the luminal of thick ascending limb to the fluid and to their of they must be the as their protein binding in plasma Although some suggest that bumetanide is also into the tubule lumen by a of that it also primarily secretion is by the organic and whereas the protein to at a of secretion into the or are to loop and diuretics, the of these Although in have not been these may be by drugs and thereby diuretic drugs inhibit diuretic secretion and alter diuretic and of their are an important of heart failure exacerbations other of and may also with these and metabolites also for diuretic and which accumulate in CKD In all of these situations, the natriuretic dose-response is to the (Figure Pharmacokinetics and pharmacodynamics of diuretic (A) of CKD on diuretic Note that in sodium excretion is to of sodium excretion to is a in the dose-response to the primarily owing to impaired diuretic but no in the ceiling (B) The same plotted versus of sodium The same is but the ceiling is lower, owing to the by (C) Comparing effects of loop diuretics and distal convoluted tubule diuretics on sodium given a retained effect on are that CKD is a loop Metabolic which is in the potential of tubule cells which also organic an effect that may explain why diuretic secretion is by alkalosis In to a in the dose-response curve, patients with CKD and those have a of the ceiling natriuresis, when as sodium excretion than The mechanism for to is Loop diuretic of NaCl reabsorption at the macula both secretion and the When this on to the natriuresis by NaCl transport along the thick ascending limb and block this When used increase the and of NKCC2 along the thick ascending limb loop diuretics inhibit the second which is also by loop diuretics to by this to despite a lower ECF this is on and can be by The clinical of these effects is evident in the between recent use of and risk for in patients with heart failure In the of of drugs that affect of the kidney, loop diuretics, (or and is associated with CKD also the natriuretic response to diuretics through a different It is that the maximal natriuretic of loop diuretics is maintained in the of when natriuresis is as a of (Figure the maximal natriuretic effect of these diuretics, when as the more is (Figure This is as and sodium sodium reabsorption by the tubule to the between and This along the thick ascending that when a diuretic the and the its effect is Thus, and CKD diuretic both by the diuretic dose-response to the can be by higher and by reducing maximal natriuresis Figure A and This phenomenon likely the effectiveness of distal convoluted tubule diuretics in CKD. loop diuretics, maximal sodium excretion as then their modest ceiling will when is (Figure Loop diuretics are by relatively t1/2 (see Table Thus, the natriuresis typically within that a single dose some hours for the to for and individuals in the phenomenon of NaCl that fact that NaCl excretion below the when the diuretic effect This is typically true dose of diuretic is administered It should be however, that although this to patients are at (and thereby their of it is in patients with edema, may during a of NaCl with low, diuretic administration. In this increase in NaCl excretion will be of these the NaCl from a diuretic typically from a of natriuresis and a longer of This accounts for the recommendation to use loop diuretics from of the t1/2, this is most important when bumetanide and with As when CKD the t1/2 of furosemide is increasing its versus when administered however, drug this is most important when NaCl is as NaCl by the will lead to more NaCl to t1/2 at for is to loop diuretics Although the of this approach treatment the basis for this approach is and recent guidelines (see these an of torsemide that torsemide to the hours was reported to and in normal after a single dose, increasing excretion such a which should some of the pharmacokinetic of loop diuretics, as in patients with heart failure or it may the approach to different considerations to patients with gastrointestinal absorption to be with the for in this it is typically to intravenous diuretics, if In this a of furosemide with in a of mg furosemide to 100 mg is in most to and although in patients with concomitant kidney this may to be with the of Diuretics to ECF When diuretics are to treat edema, in a patient with normal or kidney it is to that the dose a tubule concentration that exceeds the threshold (Figure this threshold has been can be by should an increase in volume within hours of an oral A between and in that NaCl is in this sodium to may NaCl although single may not give a dose reaching the threshold should lead to an increase in volume during the 6 hours that a On the basis of the of plasma diuretic concentration and time shown in Figure should more after an intravenous This may be especially if furosemide is the diuretic an effect is not during this it is to the dose, for from 20 to mg of furosemide or from to mg of furosemide, a recommendation on the dose-response shown in Figure The dose is then to a maximal level, as discussed Although loop diuretics are typically administered there is no to a second dose if the first dose not exceed the a threshold has been reached, however, most patients will require two Although dose for loop diuretics have been on the basis of pharmacokinetic and pharmacodynamic considerations or more dose have been in clinical trials. acute heart failure, and compared doses the dose with the dose, given Although in the primary were not the higher dose in this were and were not this and other recent those for patients with for of day for treatment that are more aggressive than often studies for an aggressive approach to is often as as that diuretic drugs might be to the kidney or the likely reflected by when in trials In post hoc of large trials suggest that those a increase in kidney may have than those do not The or natriuretic response to a diuretic is by the between the sodium in the and the sodium Although increasing a diuretic dose above the ceiling not increase the maximal maximal of NaCl excretion given see Figure it often increases the natriuresis by the during which the diuretic concentration exceeds the threshold (see Figure This is one that guidelines for heart failure may doses that exceed ceiling doses and are of or doses (see below and and In both normal individuals and in patients with ECF volume there is a between ECF volume and sodium excretion by This is similar but the natriuresis, which the between mean and Diuretics are to treat ECF volume with and is considered to be in This sodium and by diuretic doses that exceed the threshold (Figure the as treatment chronic At dose, natriuresis as ECF an effect often called the This at the individual to NaCl during which NaCl excretion is to NaCl This however, at a lower ECF volume than chronic diuretic treatment the between ECF volume and to the (see Figure thereby NaCl excretion to albeit with lower ECF It should be however, that although NaCl excretion the of and more that a patient may that the diuretic is increasing between ECF volume and sodium on Diuretics this but may it The sodium excretion is shown by the dashed a diuretic is sodium excretion by to a new 1 to the sodium excretion to the level, but at a new and ECF volume to the phenomenon is ECF volume has been it is when it in the of ECF volume factors primarily from in ECF such as of the kidney and of the likely to but it is that in other than the thick ascending limb also an important of the distal nephron to and especially of distal This from increased delivery increased and concentrations and in The of are that distal increase their transport to that of thick ascending for this more of the NaCl that the loop of is and natriuresis is a or thiazide-like drug will to and may this of and diuretic especially in patients with is as the second although other may be effective at factors may to these by transport along the distal a site transport the of these diuretics will be increased when oral or is used in this its longer t1/2 and 50 hours that NaCl may be these drugs may distal nephron and of the thiazide-sensitive a key of this approach is the substantial potential for As is as the such effects the of a second of In this lower or doses may the as as the Diuretic for ECF Although for loop diuretic have been on the basis of some more recent studies of acute heart failure have on The Diuretic in Patients with Acute Decompensated Heart Failure compared and doses of loop diuretics for acute heart failure and that the higher dose the is and concern about aggressive diuretic in this is kidney which was used as a in this kidney function in this as by a in is associated with than When not a shown in Table has been Although not compared with other this was used in trials and at as effective as such as Table - for heart failure Furosemide a mg Metolazone 1 mg 3 20 mg mg mg furosemide is considered to 1 mg bumetanide 20 mg Adapted from et al. and et al. The in the considerations for or for patients to respond within limited but suggest that patients with are best with a of furosemide and at a of mg This the plasma concentration in most although it may to be if patients with diuretic binding was suggested to to a study the natriuretic effect of loop diuretics with and protein that this was not in this is the of the sodium by recent suggest that this may be a for with or amiloride Diuretics for for and diuretic use in have At the of the diuretic doses were often which can to but were to be associated with and no in mortality in trials A suggested that diuretic use in patients with is associated with increased and suggested that use of diuretics in patients with acute failure should be Yet, cannot the in such this concern and by et al. a post hoc analysis of for patients with from the and In this patients with were to or fluid for those to diuretics were used The of this suggested that patients were to a that more diuretic administration a lower for Although this is not definitive, it suggested that reported adverse from diuretic use in likely by At this it to use diuretics as an in to It is however, to and diuretics to more such as Diuretic that transport along the are used commonly in individuals with normal or kidney diuretic drug has a pharmacokinetic but such may not when the drugs are used clinical trials provide an for diuretic treatment of heart failure. Yet, when such is a of diuretic pharmacokinetics and pharmacodynamics the clinical approach to As the drugs have substantial to and edema, the of their use should clinical The of diuretic drugs has been one of the of the of disorders of ECF volume into the that these drugs will to in practice for the has to was supported by a from the for