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 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 16  |  Issue : 2  |  Page : 60-67

Diuretic strategies in medical disorders


1 Department of Nephrology, INHS Klayani, Vishakhapatnam, Andhra Pradesh, India
2 Department of Medicine and GE Medicine, INHS Klayani, Vishakhapatnam, Andhra Pradesh, India
3 Department of Cardiology, INHS Klayani, Vishakhapatnam, Andhra Pradesh, India

Date of Web Publication20-Jun-2018

Correspondence Address:
Dr. Vijoy Kumar Jha
INHS Kalyani, Vishakhapatnam - 530 005, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/cmi.cmi_15_18

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  Abstract 

Diuretics are often the cornerstone of treatment for volume overload in the emergency setting. The pharmacokinetic and pharmacodynamic properties of diuretics differ in various clinical scenarios. The choice of a diuretic, its maximum dosage, and spacing of doses are important clinical issues which every medical practitioner needs to be aware of. In this review, we discuss the pharmacokinetic and pharmacodynamic properties of diuretics, their therapeutic implications, and best strategies for use in various clinical conditions.

Keywords: Acute kidney injury, congestive heart failure, glomerular filtration rate, pharmacokinetics, pharmacodynamics


How to cite this article:
Jha VK, Padmaprakash K V, Pandey R. Diuretic strategies in medical disorders. Curr Med Issues 2018;16:60-7

How to cite this URL:
Jha VK, Padmaprakash K V, Pandey R. Diuretic strategies in medical disorders. Curr Med Issues [serial online] 2018 [cited 2019 Dec 14];16:60-7. Available from: http://www.cmijournal.org/text.asp?2018/16/2/60/234828


  Introduction Top


Diuretics are drugs that interfere with sodium reabsorption in the renal tubules and this effect on sodium balance induces important hemodynamic changes that reduce peripheral vascular resistance and blood pressure. Diuretics are commonly used to treat edema from extracellular fluid volume accumulation caused by heart failure, cirrhosis of the liver, nephrotic syndrome, and chronic kidney disease. These drugs are also indicated for a wide variety of nonedematous disorders such as hypertension, nephrolithiasis, hypercalcemia, hyperkalemia, and hyponatremia.

The physiological classification of diuretics is given in [Table 1].
Table 1: Classification of diuretics

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  Pharmacokinetics and Pharmacodynamics of Diuretics Top


Pharmacokinetics refers to how a drug reaches its site of action. Any condition that interferes with such access alters diuretic response, and therapeutic strategies should be altered accordingly. Pharmacodynamics refers to how the target organ responds to the particular drug or how the kidney responds to the diuretic reaching its site of action. Therapeutic strategies to solve pharmacokinetic problems may be totally different from the strategies to overcome pharmacodynamic problems. Patients with kidney disease may have changes in pharmacokinetics of loop diuretics with minor changes in pharmacodynamics, while patients with chronic liver disease may have normal pharmacokinetics with significant changes in pharmacodynamics of diuretics. Therefore, therapeutic strategies in patients with renal disease and patients with normal renal function may differ. There is no pharmacological basis for the presumption that a patient who does not respond to maximal dose of one loop diuretic will respond to a different loop diuretic if used in comparable doses. There may be a better response due to larger doses or improvement in the patient's clinical condition or other medications that maximize diuretic response.[1]

The site of action of almost all diuretics, except spironolactone and eplerenone, is the luminal as opposed to the basolateral surface of the tubular epithelial cells, and they should be excreted in the urine to exert their effect. Except in case of osmotic diuretics, they are secreted actively into the urine at the proximal convoluted tubule because they are highly protein bound, thus limiting the amount that can be filtered at the glomerulus. Instead, they are trapped in the vascular space and delivered to the peritubular capillaries, from where they reach the proximal tubules and are secreted loop diuretics, thiazide diuretics, and acetazolamide through the organic acid pathway and amiloride and triamterene through the organic base pathway.[2]

The organ responsible for diuretic metabolism also influences the choice of diuretic. In case of renal failure, since furosemide is metabolized and eliminated by the kidney, torsemide or bumetanide would be the better choices as they are metabolized by the liver and do not accumulate. Triamterene is metabolized by the liver, so in case of liver dysfunction, amiloride would be a better choice.[3] Other than the site of metabolism, bioavailability and elimination half-life are also important. About 50% of a dose of furosemide is absorbed as compared with 80%–100% for bumetanide and torsemide. Therefore, while converting from intravenous (IV) to oral therapy, the dose of furosemide is doubled whereas that for bumetanide and torsemide remains almost the same. There is high degree of variability in the absorption of furosemide, ranging from 10% to 100%, and it is difficult to predict how much of the administered dose a patient will absorb. Hence, in routine clinical practice, close individualized titration is required to determine the appropriate dose in patients receiving oral furosemide. In case of an edematous disorder such as congestive heart failure (CHF), due to intestinal edema, the diuretic absorption rate may be slowed down, but the total amount of absorbed drug would be comparable to that in a healthy individual.[4]

The elimination half-life of drugs determines their frequency of administration. Thiazide and distal acting diuretics have long half-lives and should be administered once or twice a day; however, in case of loop diuretics, the duration of effect varies from 2.5–3 h for bumetanide to 4–6 h for torsemide, while for furosemide, it is intermediate.[5] If loop diuretics are given 1–2 times a daily, there may be a significant period in the dosing interval during which there is no diuretic at the site of action. During this period, the majority of sodium taken is retained, a phenomenon called “rebound” sodium retention.[6] This results in a net sodium gain despite the fact that they undergo dieresis. This is especially common if the time duration when there is no drug effect is long, if the patient takes sodium during the time interval when no diuretic reaches the site of action, and/or if the patient's dietary sodium intake is very high relative to diuretic response. The timing of diuretic intake is important: patients should take their diuretic shortly before a meal so that the salt ingested is eliminated.

Most drugs of a particular class have almost the same efficacy but different potencies, i.e. different milligram amounts are required to attain the same natriuretic effect. Hence, if a patient has no response to maximum prescribed doses of one loop diuretic, there will be no benefit in administering a different one.[4] The maximal natriuretic response in a healthy person is defined as excretion of 200–250 mEq of sodium in a urine volume of 3–4 L over 3–4 h. The pharmacodynamics of distally acting diuretics though not well investigated is the same as loop and thiazide diuretics.

There may be various reasons for decreased potency of diuretics/diuretic resistance [Table 2]. Acute tolerance of diuretics, also called braking, means that within a short period, response to the diuretic at the site of action diminishes. This is often seen with the first dose of a diuretic, and it can be prevented by restoring diuretic-induced sodium losses. The nephron is primed to reabsorb sodium for the rest of the dosing interval until the next dose is administered. This is why dietary sodium is restricted and multiple doses of loop diuretics are administered to maintain a net negative sodium balance.[7] The trigger for acute tolerance is mainly intravascular volume depletion, but no mediator is yet known.[8] Chronic tolerance is due to flooding of sodium to more distal nephron sites by loop diuretics that cause hypertrophy of distal nephron segments with increase in the reabsorption of sodium. Sodium if not reabsorbed from the loop of Henle can be reclaimed at distal sites, causing decrease in loop diuretic response.[9],[10],[11] Thiazides block the nephron site at which hypertrophy occurs and so have an additive, synergistic natriuretic effect with loop diuretics.
Table 2: Causes of diuretic resistance

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  Diuretic Strategies in Chronic Kidney Disease Top


Patients with chronic kidney disease may have inadequate delivery of diuretic at the site of action. Hence, in patients with chronic kidney disease Stage 5, only about one-fifth to one-tenth of loop diuretic will be excreted into the urine [Table 3]. To overcome this problem, large doses are often required to deliver effective amounts in the urine.
Table 3: Pharmacokinetics of diuretics

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Varying doses of loop diuretics have been administered in patients with severe renal failure. “Ceiling dose” is the largest dose necessary in a patient with renal insufficiency to deliver amounts of diuretic in the urine that result in maximum response. This usually involves IV administration of a bolus dose usually given over 20–30 min to minimize risk of toxicity. As already mentioned, bumetanide and torsemide are completely absorbed, and so, the IV and oral doses are almost the same. Average bioavailability of furosemide is assumed to be 50%; therefore, on average, the oral dose is twice the IV dose, namely 320–400 mg.[1]

Furosemide absorption varies between 10% and 100% from patient to patient and also within the same patient due to diurnal variation. For example, in a patient who only absorbs 10% of a dose, the oral dose equivalent to the IV ceiling dose is 2000 mg. In patients with low glomerular filtration rate (GFR), the maximal amount of sodium that is excreted is also very small, i.e. about 25 mEq in contrast to healthy subjects who excrete 200–250 mEq of sodium. In these patients, if a loop diuretic is being used alone, strict dietary sodium restriction is very important in maintaining fluid balance.

In patients with severe renal insufficiency, an additional natriuretic effect may be obtained by adding a thiazide diuretic.[11],[12] All thiazides if used in adequate doses are very effective as combinations with loop diuretics even in patients with renal insufficiency. The action of metolazone is different from a thiazide and also has unpredictable pharmacokinetics as it is poorly and erratically absorbed. Its elimination half-life of about 2 days means that it accumulates in patients for 10 days.[4],[13] In an acute setting, this makes dose titration a challenge while other thiazides are more predictably absorbed and they do not accumulate over a long period, making them easier to use.[13] Thiazides also act from the luminal side of the nephron, and so, large doses should be given to attain effective amounts in the urine. For example, in patients with mild-to-moderate renal insufficiency, the required dose of hydrochlorothiazide is 50–100 mg/day, and in those with more severe disease, it is 100–200 mg/day. All thiazides have a long half-life, and so, they can be given once a day.[14]

A continuous IV infusion is required to maintain adequate and effective amounts of the diuretic at the site of action at all times, and it results in an increase in the total amount of sodium excreted.[15] On starting therapy, a loading dose should be administered; otherwise, four times the half-life of the loop diuretic which has been chosen will be required to reach a steady state, approximately 6–20 h. After a loading dose is given, a continuous infusion should be administered at the initial rate indicated according to the patient's level of renal function [Table 4]. If the response is inadequate after an hour of the infusion, the infusion rate can be either increased or another loading dose can be given.
Table 4: Doses for continuous intravenous infusion of loop diuretics (before increasing to a higher infusion rate, a repeat loading dose should be administered)

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In patients with renal insufficiency, gradual titration is required by careful doubling of dose until an effective dose is attained or the ceiling dose is reached. The decision regarding how frequently the dose is to be administered is based on the patient's overall response, their total sodium intake, and the diuretic's duration of action. For admitted patients, if a continuous IV infusion is being given, a loading dose is to be administered followed by a continuous infusion. If the response is inadequate after a few hours, another loading dose is to be given followed by an increase in the infusion rate as discussed previously. If response to the loop diuretic alone is inadequate after reaching the ceiling dose, another diuretic such as a thiazide can be added.


  Diuretic Strategies in Acute Kidney Injury Top


In acute kidney injury (AKI), there is reduction in blood flow which slows the delivery of loop diuretics into renal tubular fluid. Metabolic acidosis associated with renal dysfunction depolarizes the membrane potential of proximal tubular cells and reduces secretion of organic acids such as loop diuretics.[16] The diuretic response may also be altered by the accumulation of organic acids (due to renal dysfunction or drugs used for various conditions or those associated with AKI) which competitively inhibits access to the organic acid secretory pump at the proximal tubule.[17] Therefore, in patients with AKI, the dose of loop diuretics needed to achieve an effective diuretic response is several-fold higher.

The diuretic response to furosemide in a patient is severely compromised with increasing severity of AKI. In the setting of acute-on-chronic kidney disease, there is a reduction in total nephron mass which contributes to diminished efficacy of loop diuretics. However, the remaining nephrons respond adequately when adequate doses of loop diuretics are administered.[18]

In AKI, administration of the diuretic agent as a continuous infusion [Table 4] increases effectiveness due to the prolonged inhibition of Na-K-Cl2 cotransporters. Continuous dieresis, even with low doses of IV infusion, produces a greater cumulative response compared to bolus therapy.[15] It has been shown experimentally that loop diuretics increase oxygenation of renal tissue and prevent renal adenosine 5'-triphosphate depletion, improve renal blood flow and prevent tubular obstruction by increasing tubular flow and removing tubular debris, and also increase GFR.[19] It has also been shown that low-dose furosemide reduces ischemia/reperfusion injury by improving renal hemodynamics, attenuating ischemia-related changes in angiogenic gene transcription, and attenuating ischemia/reperfusion-induced apoptosis.[20] There are significant differences between loop diuretics in their effect on cortical and medullary blood flow.

Several studies have looked at the role of diuretics in AKI. The Project to Improve Care in Ácute Renal Disease (PICARD) study was a large cohort study of severe AKI in critically ill patients, where diuretics were used in almost 60% of the patients at the time of consultation with a nephrologist, and an additional 12% were prescribed diuretics after the consultation.[21] In this study, loop diuretics were given with thiazide diuretics in approximately one-third of patients. Diuretic use increased with age presumed nephrotoxic AKI, a lower blood urea nitrogen level, acute respiratory failure, and a history of CHF. A propensity score-adjusted analysis in this population showed that diuretic use was associated significantly with in-hospital mortality and nonrecovery of renal function [21] although the effect of confounding by indication still remains unclear.

The Beginning and Ending Supportive Therapy for the Kidney study was a multicenter, multination (54 centers, 23 countries) project with a cohort of 1713 patients. The investigators reported that 70% of critically ill patients with AKI in the study had been given diuretic agents at the time of study enrollment and that furosemide was the most commonly used diuretic.[22] Unlike the PICARD study, combination diuretic therapy was seldom used (98 of 1713 patients) and diuretic use on multivariable analysis was not associated with increased mortality.[22] Two surveys, one involving members of the European Workgroup of Cardiothoracic Intensivists and another involving nephrologists and intensive care physicians, looked at the use of diuretics in different clinical settings. Furosemide was the most commonly used diuretic in both surveys. There was no clear consensus, however, that diuretics could improve clinical outcomes such as mortality, need, and duration for renal replacement therapy, or renal recovery in the setting of AKI.[23],[24] A meta-analysis by Ho et al. showed that furosemide, when used either as a preventive or therapeutic drug in AKI, did not reduce the risk for requirement of renal replacement therapy (relative risk [RR], 1.02; 95% confidence interval [CI], 0.90–1.16; P = 0.73) or hospital mortality (RR, 1.12; 95% CI, 0.93–1.34; P = 0.23).[17]

Several other randomized controlled trials (RCTs) have clarified the role of loop diuretics in the prevention and management of AKI. All these studies have shown improvement in urine output with loop diuretic administration without significant improvements on clinical outcomes such as mortality or renal survival. Most of these studies showed that diuretic use did not reduce the requirement for renal replacement therapy although there were major limitations in study design. None of these trials had adequate power to establish the influence of loop diuretics on clinical outcomes such as mortality or requirement for renal replacement therapy.[25] In spite of all these clinical data and observational studies, widespread use of loop diuretics in the management of AKI is quite common.

Thiazides are often used in combination with loop diuretics to enhance the maximal diuretic effect of the latter. However, there have been no RCTs to evaluate their role in AKI. Although mannitol is often used in patients with rhabdomyolysis, most data come from animal studies and no RCT supports its use in this setting.[26],[27] In a retrospective study involving patients admitted to the Intensive Care Unit with rhabdomyolysis, mannitol administration did not have an impact on outcomes such as incidence of AKI, need for renal replacement therapy, or mortality.[28],[29] Moreover, the administration of mannitol is associated with significant risks which include volume depletion and hypernatremia produced by strong osmotic diuretic effects. Hyponatremia, hyperkalemia, and metabolic acidosis may result when hypertonic mannitol is retained and cumulative doses of mannitol with high plasma concentrations are associated with AKI.[30],[31] In spite of lack of beneficial evidence in terms of clinical outcomes and potential for harm, prophylactic mannitol use is quite common in certain high-risk scenarios such as cardiac surgery, vascular surgery, and biliary surgery. Mannitol is used in these settings because it increases urine output, and the higher tubular flow rates may have a benefit in preventing tubular obstruction which is commonly seen in acute tubular necrosis.[32] In renal transplantation, mannitol along with volume expansion has been shown to reduce the incidence of postsurgery AKI; however, it is still doubtful whether this benefit resulted from the action of mannitol or whether it is due to volume resuscitation in the perioperative period.[33],[34]


  Diuretic Strategies in Nephrotic Syndrome Top


Nephrotic syndrome alters the pharmacodynamics of diuretics, which means that higher doses of loop diuretic, frequent dosing, and addition of thiazide diuretics may be required.

Since loop diuretics are highly protein bound, they are trapped in the vascular space and delivered to basolateral proximal tubular secretory sites from where they are secreted into the lumen of the nephron. In nephrotic syndrome, hypoalbuminemia results in less bound and trapped diuretic and lower delivery to the sites of action in the kidney. This does not mean that there is a decrease in diuretic reaching the urine because even lower than normal plasma albumin concentrations may be able to trap sufficient amounts of diuretic in the plasma. In several pharmacokinetic studies, patients with nephrotic syndrome [35] show normal amounts of furosemide in the urine unless the patient has concomitant renal insufficiency.

Administering a larger dose is another approach that can be used to increase the amount of diuretic in the urine. When the serum albumin concentration is <2%g and the response to loop diuretic is less than adequate, using a mixture of a loop diuretic and salt-poor albumin could be considered. In addition, albuminuria in patients with nephrotic syndrome could have a pharmacokinetic effect, namely urinary albumin could bind diuretic in the urine, thereby decreasing the amount of unbound, active drug available to block the Na-K-2Cl pump, resulting in diminished diuretic response.[36],[37]In vivo microperfusion studies in experimental animals have shown that nephrotic range proteinuria binds one-half to two-thirds of the diuretic reaching the urine and coadministering a compound that displaces the diuretic from albumin restores diuretic response.[38] As a consequence, doses two to three times greater than normal doses are required to deliver sufficient amounts of unbound, pharmacologically active drug to the site of action. If the patient with nephrotic syndrome has concomitant renal dysfunction, doses need to be increased to account for this.

There is also a pharmacodynamic component of diminished response which occurs within the loop of Henle itself because microperfusion studies in nephrotic animals show a diminished effect of furosemide.[39] Increased proximal and/or distal reabsorption of sodium also could contribute. Therefore, one must administer doses more frequently and/or use adjunctive therapies such as concomitant use of thiazides.[40] In practice, one needs to administer a dose two to three times higher than normal to attain normal amounts of unbound diuretic in the urine, and in patients with considerable degrees of renal insufficiency, enormous doses of loop diuretics may be required.


  Diuretic Strategies in Cirrhosis Top


Spironolactone is the first diuretic started in patients with cirrhosis, to which other diuretics may be added if response is inadequate.[41] This drug causes a modest diuresis, which is typical of distally acting diuretics. Cirrhotic patients are often very sensitive to intravascular volume depletion. The usual starting dose of spironolactone is 50 mg/day, and since the drug and its active metabolites have long elimination half-lives, once daily dosing is required.[42] Its biological half-life is very long because it interferes with protein synthesis and 3–4 days of daily dosing is required before steady-state concentration is achieved; therefore, dose modification should occur after at least 3 days. Doses as high as 400 mg/day are required to get adequate effect at times. If spironolactone at maximal tolerated doses does not result in adequate diuresis, a loop diuretic can be started along with spironolactone.

The pharmacokinetics of loop diuretics in cirrhosis is normal, but there may be alteration in pharmacodynamics leading to diminished diuretic response since bile salts compete with loop diuretics for tubular secretion. In addition, there is increased proximal and/or distal tubular reabsorption of sodium because of activation of the renin-angiotensin system in response to low effective arterial blood volume secondary to splanchnic vasodilation. A maximally effective dose of a loop diuretic in a healthy subject would cause excretion of 200–250 mEq of sodium, while in a patient with cirrhosis, a maximally effective dose might cause excretion of only 25–30 mEq of sodium. Modest, effective doses need to be given more frequently rather than administering high doses. Vigorous diuresis and intravascular volume depletion are to be avoided. Coadministration with spironolactone reduces the risk of hypokalemia, which can precipitate encephalopathy by enhancing renal ammonia synthesis.


  Diuretic Strategies in Congestive Heart Failure Top


Patients with CHF do not have a decreased absorption of diuretics in spite of significant gut edema though there may be a delay in absorption, as a result of which peak diuretic concentrations at the site of action are achieved as late as 4 h instead of 1 h in patients with CHF. Therefore, IV dosing may be necessary if an immediate response is desired. Decreased renal perfusion also limits the amount of diuretic delivered to the kidney. Because of the diminished response to loop diuretics and the challenge of decreasing dietary sodium sufficiently to control volume status, addition of a thiazide is frequently required.

The sequential nephron blockade of loop diuretic in combination with thiazide diuretics causes significant hypokalemia that can be compensated with distal agents such as spironolactone or eplerenone, which conserve potassium and improve survival due to their effect on cardiac remodeling.[43] It should be emphasized that any improvement in cardiac function decreases gut wall edema and improves renal perfusion, thus enhancing natriuresis. In acute decompensated heart failure, IV administration of loop diuretics is recommended to provide rapid alleviation of symptoms of fluid overload such as dyspnea and overcome the delay in oral absorption due to gut wall edema. The Diuretic Optimization Strategies Evaluation trial evaluated the approach to diuretic dosing (high vs. low dose, defined as 2.5 times the previous oral dose and equal to the previous oral dose, respectively) and the mode of IV administration (bolus vs. continuous infusion) in patients with acute decompensated heart failure.[44] There was no significant difference between the bolus (every 12 h) and continuous IV infusion approaches with respect to the primary end points: the patients' global assessment of symptoms and the change in the serum creatinine level at 72 h. While high-dose IV furosemide achieved greater fluid loss and relief of dyspnea, the incidence of transient worsening of kidney function was also higher.


  Diuretic Strategies in Hypercalcemia Top


In the past, administration of a loop diuretic was initiated routinely once fluid repletion had been attained to increase urinary calcium excretion. However, this practice was based upon an approach that involved intensive administration of furosemide (80–100 mg every 1–2 h) with aggressive fluid hydration (10 L daily).[45] While volume expansion with isotonic saline to achieve a urine output of 100–150 ml/h is still the mainstay of therapy, the use of loop diuretics has fallen out of favor due to side effects and the availability of potent agents that inhibit bone resorption, such as bisphosphonates and calcitonin, whose use can dramatically lower serum calcium levels within a short span of time. The only indication for the use of loop diuretics in this scenario is in patients with renal or CHF, who run the risk of volume overload with aggressive volume expansion.


  Diuretic Strategies in Hypertension Top


When used in patients with primary hypertension and relatively normal renal function, the thiazide diuretics, particularly chlorthalidone and indapamide, are more effective antihypertensive drugs than loop diuretics. This difference in efficacy is due to their duration of action. The short duration of action of commonly used loop diuretics is counteracted by activation of the renin-angiotensin-aldosterone system, leading to sodium retention after the diuretic effect has worn off.[9] The efficacy of all diuretics is diminished in patients with renal dysfunction. Both thiazide and loop diuretics must reach the lumen of the renal tubule to be taken up by the organic acid transporters in the proximal tubule. As GFR decreases, organic acids are retained and these acids compete with diuretics for transport in the tubular lumen. Thiazides are less effective in competing with accumulating organic acids than loop diuretics in the setting of renal dysfunction and so are less effective in patients with GFR <30 ml/min.[46] The potassium-sparing agents, triamterene and amiloride, have a minimal antihypertensive effect and are not widely used as initial therapy for primary hypertension although they may be useful in treating resistant hypertension. Mineralocorticoid receptor antagonists, spironolactone and eplerenone, provide a significant antihypertensive effect when added to existing multiple drug regimens in patients with resistant hypertension. This effect may be due to significantly higher plasma aldosterone level in patients with resistant hypertension compared with individuals who have normal blood pressure or controlled hypertension on one or two medications.[47]


  Conclusion Top


The pathogenesis of diminished response to diuretics differs across various medical disorders, and so, the therapeutic strategies we use must also differ. There may be various reasons for diuretic resistance, and these should be looked for. The diuretic strategy should be directed first to the primary disease process and then to the individual patient [Table 5].
Table 5: Therapeutic strategies for loop diuretics

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Financial support and sponsorship

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Conflicts of interest

There are no conflicts of interest.

 
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