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 (Fig. 5.1). The sulfonamide-based 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 at the macula densa. Ethacrynic acid is a non-sulfonamide-based loop diuretic. It is used primarily for patients who are truly allergic to the sulfonamide-based drugs, as it appears to have greater toxicity and is more difficult to use. As organic anions, loop diuretics bind within the translocation pocket on the transport protein by interacting with the chloride-binding site (2). 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 (Fig. 5.1). This mechanism of action accounts for a key aspect of loop and distal convoluted tubule diuretic action; both classes of drug exert their effect from within the lumen of the tubule.

There are 2 major classes of potassium-sparing diuretics, which act along the aldosterone-sensitive distal nephron. The first includes drugs that block apical sodium channels (amiloride and triamterene), whereas the second includes drugs that antagonize mineralocorticoid receptors (spironolactone, eplerenone). A new non-steroidal mineralocorticoid blocker, finerenone, which is structurally unrelated to the others, is currently in phase III clinical trials. The mineralocorticoid blockers act within cells and do not require secretion into the tubular lumen.

Bioavailability of Diuretics Determining the Dose and Frequency of Administration

The normal metabolism of loop diuretics is depicted in simplified form in Fig. 5.2a. Furosemide, bumetanide, and torsemide are absorbed relatively quickly after oral administration (see Fig. 5.2b), reaching peak concentrations within 0.5–2 hours [1, 2]; when administered intravenously (IV), their effects are nearly instantaneous. The oral bioavailability of bumetanide and torsemide typically exceeds 80%, whereas that of furosemide is highly variable and substantially lower, at approximately 50% (see Table 5.2) [3]. Although the half-life of furosemide is short, its duration of action is longer when administered orally, as its gastrointestinal absorption may be slower than its elimination half-life. This is a phenomenon called absorption-limited kinetics [1] and may explain the mnemonic that oral furosemide “lasts 6 hours” [4]. This is not the case for bumetanide and torsemide, where oral absorption is rapid and consistent [5].

Table 5.2

Pharmacokinetics of commonly used diuretics

Diuretic	Oral bioavailability, %	Elimination half-life, hours
		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	70–90a	14–20	Prolonged
Amiloride	~50&	6–26	100	Not changed
Spironolactone	>90	1.5∗	∗∗

Adapted from Ref. [76]

^#Absorption may be decreased in heart failure

^&Decreased by food

^∗Active metabolites of spironolactone have half-lives of >15 hours

^∗∗Active metabolites accumulate in CKD

Based on oral bioavailability, when a patient is switched from an intravenous to oral loop diuretic, the dose of bumetanide or torsemide should be maintained, whereas the dose of furosemide should be doubled [5]; in practice, however, and as discussed further below, other factors affect diuretic efficacy and a fixed intravenous/oral conversion cannot be given [6]. Gastrointestinal absorption of thiazide and other potassium sparing diuretics is fairly rapid and predictable, and oral bioavailability ranges from 65% to 90%.

The loop diuretics have steep dose response curves. This property is often neglected in clinical practice but is crucial to optimal use. Figure 5.2c shows a a schematic of a typical natriuretic response plotted versus the logarithm of the plasma diuretic concentration. Inspection reveals that there is little diuretic or natriuretic effect when the plasma concentration is low. Once the concentration exceeds a certain level, often called the diuretic threshold, the response increases, and even small further increases caused substantially increased sodium excretion. 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 to the first dose. Although the dose response looks steep, when plotted logarithmically, it is less so when plotted in a linear manner, and a small increase will often be ineffective. 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 these plots, 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 cardiorenal syndrome. While nearly all healthy individuals will respond to 20 mg of oral furosemide (or its equivalent), patients with conditions that predispose to ECF volume expansion and edema need higher doses, since these conditions alter both the pharmacokinetics and pharmacodynamics of diuretics as discussed below. It is little wonder that an empirically selected dose may be ineffective. Below, we will provide broad generalizations about dose adjustments for individuals within a variety of settings. Yet adherence to algorithms may lead to diuretic failure. Instead, it is often best to approach a patient as an n of 1 trial. 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 low 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 [7, 8]. Absorption is also affected by food consumption, unlike that of bumetanide or torsemide [9, 10], although the clinical significance of this effect has been doubted [1]. The more consistent bioavailability of torsemide, compared with furosemide, and its relatively longer half-life, have suggested that it may be a superior loop diuretic, as suggested by 2 small clinical trials [11–14]. A recent non-randomized post-hoc analysis of the large Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) has suggested that patients with heart failure discharged on torsemide have lower mortality [15]. In contrast, the bioequivalent doses of 2 loop diuretics given in a double-blind randomized crossover trial, failed to demonstrate superiority of torsemide with respect to natriuresis or 24-h ambulatory blood pressure control in chronic kidney disease (CKD) patients [16]. The compelling differences in pharmacokinetics suggest that torsemide might be superior clinically, but this needs to be tested in sufficiently powered and rigorous trials. ToRsemide compArisoN With furoSemide FORManagement of Heart Failure (TRANSFORM-HF) is a large-scale, pragmatic, randomized, unblinded clinical effectiveness study comparing torsemide versus furosemide as treatment for heart failure. The study is sponsored by National Heart, Lung, and Blood Institute (NHLBI), actively recruiting patients and expected to be complete by 2022 (NCT 03296813).

Gastrointestinal absorption can be slowed, especially during exacerbations of heart failure, although again, this problem is worst with furosemide [17]. Even though 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 diagramed in Fig. 5.2b. As an example, the areas under the curves for arbitrary intravenous and 2× oral furosemide doses may be similar, but the differences in shapes of those curves may lead to a diuretic being effective when given intravenously, but not orally. As the diuretic threshold is higher in cardiorenal syndrome, this difference may be especially relevant in this situation. 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 efficacy, especially if the natriuretic threshold is increased. Not surprisingly, heart failure exacerbation requiring IV diuretics remains one of the major reasons for visits to emergency department and outpatient clinics, and for hospital admissions. In this context, development of subcutaneous (SC) furosemide has garnered increasing optimism as a safe and effective outpatient alternative to the traditional hospital-based IV diuretic strategy. Recently, 2 proof-of-concept studies have demonstrated similar urine output with a pH-neutral formulation of SC furosemide compared to IV furosemide in outpatients presenting with decompensated heart failure [18]; and longer duration at therapeutic plasma levels and more urine output compared to oral furosemide [19]. Subcutaneous administration of buffered furosemide was well tolerated with no evidence of any drug-induced skin reactions. The possibility of delivering an IV equivalent diuretic agent at home, if proved efficacious in larger trials, could be transformative for HF care delivery.

Volumes of Distribution, Metabolism and Half-lives

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 co-administration of albumin with furosemide in hypoalbuminemic patients [21]. One concern about the more recent studies, many of which have been negative, is that most have only enrolled patients whose serum albumin concentrations exceeded 2 g/dL. Owing to physiological plausibility and anecdotal experience, most experts would still consider adding albumin infusion for refractory patients who are severely hypoalbuminemic. Yet, extreme caution should be used when treating patients with cardiorenal syndrome, as their extracellular fluid volume is typically expanded substantially; as albumin infusions expand the extracellular fluid volume, they should be avoided in most patients with cardiorenal syndrome.

Approximately 50% of an administered furosemide dose is excreted unchanged into the urine. The remainder appears to be eliminated by glucuronidation, predominantly also in the kidney. Torsemide and bumetanide are eliminated both by hepatic processes and urinary excretion, although hepatic metabolism may predominate, especially for torsemide [22]. The differences in metabolic fate mean that the half-life of furosemide is prolonged in kidney failure, where both excretion by the kidney and kidney-mediated glucuronidation are slowed. In contrast, the half-lives of torsemide and bumetanide tend to be preserved in patients with kidney dysfunction [23]. While the ratio of equipotent doses of furosemide to bumetanide is 40:1 in normal individuals, that ratio declines as kidney disfunction worsens [24]. Although this apparent increase in furosemide potency may seem beneficial, it also likely increases the toxic potential of furosemide when it is used in very high doses. Deafness and tinnitus from loop diuretics appear to result primarily from high serum concentrations, which inhibit a Na-K-2Cl isoform (NKCC1, encoded by SLC12A2). This transport protein, which is different from that reabsorbs salt in the kidney, is expressed by the stria vascularis and participates in secretion of K⁺-rich endolymph [25, 26]. Although this complication was seen more frequently in the past when very large bolus doses of loop diuretics were employed to forestall dialysis [27], one relatively recent meta-analysis of furosemide use for patients with acute kidney injury, suggested that the odds ratio for hearing loss was >3 when high dose furosemide was used; it should be noted, however, that the doses cited in that analysis (1–3 grams daily) exceeded those currently recommended [28]. The tendency of bolus infusion to lead to high peak furosemide concentrations is one reason that many investigators recommend continuous infusions instead [29].

Although loop diuretics are small molecules, they typically undergo little glomerular filtration. As they exert their actions by binding to transport proteins along the luminal membrane of thick ascending limb cells, to gain access to the tubular fluid and therefore to their sites of activity, they must be secreted. This is likely true for all three loop diuretics, although some data suggest that bumetanide is also delivered into the tubule lumen by filtration [30]. However, most evidence still suggests that bumetanide gains entry primarily via secretion [31]. Peritubular uptake by cells along the proximal tubule is mediated by the organic anion transporters OAT1 and OAT3, whereas the apically located multidrug resistance-associated protein 4 (Mrp-4) appears to mediate at least a portion of secretion into the tubular fluid. Mice lacking OAT1, OAT3 or Mrp-4 are resistant to loop and thiazide diuretics illustrating the functional importance of diuretic secretion for diuretic effectiveness [30, 32].

Impact of Drugs and Chronic Kidney Disease on the Effectiveness of Diuretics

While human mutations in OAT1 have not been described, drugs other than diuretics as well as endogenous toxins also bind to the OATs, thereby competing with diuretics for secretion into the proximal tubule [30]. Non-steroidal anti-inflammatory drugs inhibit diuretic secretion and alter diuretic responsiveness, and because of their frequent use, are an important cause of heart failure exacerbations [33]. Yet other classes of drugs, including antihypertensives,antibiotics and antivirals may also interact with these transporters and cause resistance [34]. Endogenous metabolites also compete for diuretic secretion, including indoxyl sulfate, carboxy-methyl-propyl-furanpropionate, p-cresol sulfate, and kynurenate, all of which accumulate when kidney function is poor [35]. In all of these situations, the natriuretic dose-response curve is shifted to the right (Fig. 5.3a).

There are additional reasons that patients with poor kidney function are resistant to loop diuretics. Metabolic acidosis, which is frequently observed in uremia, depolarizes the membrane potential of proximal tubule cells [36] which also decreases organic anion secretion, an effect that may explain why diuretic secretion is enhanced by alkalosis [37]. In addition to a shift in the dose-response curve, patients with poor kidney function and those taking non-steroidal anti-inflammatory drugs (NSAIDs) have a downward shift of the ceiling natriuresis, when expressed as absolute sodium excretion (rather than fractional). The mechanism for resistance attributable to NSAIDs is complex. Loop diuretic inhibition of NaCl reabsorption at the macula densa stimulates both renin secretion and prostaglandin production, the latter predominantly via cyclooxygenase-2 (COX-2) [38]. When this happens, prostaglandin E2 feeds back on tubules, contributing to the resulting natriuresis by inhibiting NaCl transport along the thick ascending limb and collecting duct [39, 40]. NSAIDs block this prostaglandin-mediated natriuresis. When used chronically, NSAIDs increase the abundance and activity of NKCC2 along the thick ascending limb [41]. Additionally, loop diuretics inhibit the second transporter isoform, NKCC1, mentioned above, which, in addition to being expressed in the ear, is also expressed by vascular smooth muscle cells; loop diuretics contribute to vasodilation of the glomerular afferent arteriole by blocking this transporter [42], thus helping to maintain glomerular filtration rate despite a lower ECF volume. Again, this compensatory adaptation is largely dependent on prostaglandin production and can be blocked by NSAIDs. The clinical impact of these effects is evident in the association between recent use of NSAIDs and risk for hospitalization in patients with heart failure [33]. In fact, in the setting of loop diuretics and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, the addition of a third class of drug that alters intrarenal hemodynamics such as NSAIDs, is associated with acute kidney injury [43].

Intrinsic kidney dysfunction also impairs the natriuretic response to diuretics through a different mechanism (Fig. 5.3b). It is frequently noted that the maximal natriuretic capacity of loop diuretics is maintained in the setting of chronic kidney disease, when natriuresis is measured as a fraction of filtered load (FE_Na). Yet the maximal natriuretic effect of these diuretics, when measured as the more clinically relevant absolute rate, is markedly reduced. This is because, as glomerular filtration rate and filtered sodium load decrease, kidneys suppress sodium reabsorption by the remaining tubules to keep sodium excretion equal to dietary salt intake. This suppression occurs in part along the thick ascending limb, so that even when a diuretic reaches the segment and inhibits the transporter, its net effect is reduced. Thus, NSAIDs and CKD cause diuretic resistance both by shifting the diuretic dose response curve to the right (which can be overcome by higher doses) and by reducing maximal natriuresis (which cannot overcome by higher doses, compare Fig. 5.3a, b).

Loop diuretics are characterized by relatively short half-lives (see Table 5.2). Thus, the initial natriuresis typically wanes within 3–6 hours, so that a single daily dose leaves some 16–21 hours per day for the kidneys to compensate for the diuretic-induced salt and water losses (Fig. 5.4). For individuals in steady state, the phenomenon of post-diuretic NaCl retention defines the fact that urinary NaCl excretion declines below the baseline when the diuretic effect wears off. This is typically true until another dose of diuretic is administered [44]. It should be noted however that while this relationship applies to patients who are at steady state (and thereby excreting their daily intake of salt), it is altered in patients with decompensated edema, such as many patients with cardiorenal syndrome, who may present during a period of a positive NaCl balance, with urinary NaCl very low, even without diuretic administration. In this case, any increase in urinary NaCl excretion will be beneficial.

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