Diuretics

Abstract

Diuretics have been recommended as first-line treatment of hypertension and are also valuable in the management of hypervolemia and electrolyte disorders. This review summarizes the key features of the most commonly used diuretics. We then provide an update of clinical trials for diuretics during the past 5 years. Compared to other classes of medications, thiazide diuretics are at least as effective in reducing cardiovascular events (CVEs) in patients with hypertension and are more effective than β-blockers and angiotensin-converting enzyme inhibitors in reducing stroke. Observational cohort data and a network analysis have shown that CVEs are lowered by one-fifth from chlorthalidone when compared to the commonly used thiazide, hydrochlorothiazide. Relative to placebo, chlorthalidone increases life expectancy. In those aged 80 years and older, the diuretic, indapamide, lowers CVEs relative to placebo. The aldosterone antagonist, eplerenone, lowers total mortality in early congestive heart failure. The benefit of eplerenone following acute myocardial infarction (MI) is limited to administration within 3 to 6 days post-MI. Aldosterone antagonists have been shown to lower the incidence of sudden cardiac death and to reduce proteinuria. In the setting of heart failure, long acting loop diuretics azosemide and torasemide are more effective in improving heart failure outcomes than the far more commonly used short acting furosemide. Evening dosing of diuretics appears to lower CVEs relative to morning dosing. In conclusion, diuretics are a diverse class of drugs that remain extremely important in the management of hypertension and hypervolemic states.

Keywords

cardiac pharmacology cardiovascular disease cerebrovascular disease congestive heart failure hypertension diuretics

Introduction

Diuretics are an invaluable and heterogeneous class of agents commonly used in the treatment of hypertension, heart failure, and electrolyte disorders. This review summarizes the basic features of diuretics, including their mechanism of action, indications, adverse effects, and duration of action, followed by a review of recent findings from randomized trials. For the latter, we conducted a systematic review from PubMed covering the last 5 years.

Mechanisms of Action

Diuretics are a heterogenous group of medications, but a few generalizations are possible. With the exception of mannitol and vasopressin receptor antagonists, all diuretics function initially by blocking sodium reabsorption in various sites within the renal tubules. The organic acid secretory pathway delivers carbonic anhydrase inhibitors, loop diuretics, thiazide diuretics, and thiazide-like diuretics into the tubular lumen and thereby arrives at their sites of action. In contrast, aldosterone antagonists reach their site of action, the principal cells of the cortical collecting duct, via the blood stream.

The carbonic anhydrase inhibitor, acetazolamide, impairs reabsorption of Na⁺, HCO3⁻, and water, increasing distal delivery of Na⁺ to the distal collecting duct and K⁺ loss.

Loop diuretics such as furosemide, torasemide, azosemide, and bumetanide act at the thick ascending limb of the loop of Henle, where 20% to 30% of filtered NaCl is reabsorbed. Loop diuretics bind to the Na-K-2Cl transport protein and inhibit its action, impairing reabsorption of Na⁺, K⁺, and Cl⁻ and delivering an increase in Na⁺ to the distal tubule. There it increases exchange of Na⁺ for K⁺ and promotes K⁺ secretion into the distal tubule. These changes decrease the osmotic driving force and concentrating ability of the kidney.

Thiazide and related diuretics act mainly at the distal convoluted tubule, where the NaCl cotransporter is blocked, resulting in impaired Na⁺ and Cl⁻ reabsorption, increased delivery of Na⁺ to collecting ducts, enhanced exchange of Na⁺ and K⁺, and K⁺ wasting. Thiazides impair the kidney’s diluting capacity and impair Mg⁺ reabsorption but stimulate Ca²⁺ reabsorption. This last effect accounts for their role in treating calcium-containing renal stones.

Thiazides decrease peripheral resistance by an unknown mechanism and thereby lower blood pressure (BP). Initially, thiazides decrease extracellular volume (ECF) and cardiac output, but the ECF gradually returns to near normal over the course of several weeks to months.

Potassium sparing diuretics act at the cortical collecting duct and can be divided into 2 subcategories; Pteridine analogs (that is triamterene and amiloride) inhibit reabsorption by the epithelial Na⁺ channel (ENaC) of the collecting duct. Because only 3% of the filtered Na ⁺ is reabsorbed at the collecting duct, these drugs do not result in appreciable diuresis and lead to minimal antihypertensive efficacy as monotherapies. Instead, they are often used with other agents to correct K⁺ deficiency. The aldosterone receptor blocker acts in the cytoplasm of principal cells to downregulate the basolateral Na⁺/K⁺ pump and the aldosterone-sensitive ENaC. The final effect of both subcategories is impairment of Na⁺ reabsorption, coupled with decreased H⁺ and K⁺ secretion that would otherwise occur as a result of voltage changes across the membrane.

The osmotic diuretic, mannitol, exerts its osmotic effect throughout the length of renal tubule regardless of hydration status and impairs normal tubular water reabsorption. Ultimately, mannitol washes out the medullary solute gradient and thereby impairs the kidney’s concentrating ability. As with thiazide and loop diuretics, there is increased Na⁺ delivery to the distal nephron increasing K⁺ loss.

Vasopressin receptor antagonists block vasopressin at V2 receptors and prevent free water reabsorption at the collecting ducts, leading to increased free water excretion.

Indications, Adverse Effects, and Pharmacokinetics

Tables 1 and 2 present the key clinical and pharmacokinetic aspects of each subclass of diuretics. The most important adverse effects are derangements in electrolytes, particularly serum potassium, which may be lowered by thiazides and loop diuretics and elevated by aldosterone antagonists. The longer duration of action of chlorthalidone, torasemide, and azosemide may be partly responsible for their greater efficacy in reducing CVEs relative to their alternatives (see below).

Table 1.

Indications, Contraindications, and Adverse Effects of Diuretics.

Diuretic	Clinical Uses	Contraindication	Adverse Effects
Loop Diuretic	Edematous disorders (congestive heart failure, hepatic cirrhosis, and nephrotic syndrome), hypertension with glomerular filtration rate <30 mL/min, hypercalcemia, SIADH given with NaCl, and renal tubular acidosis	Hypersensitivity to sulfa agents, gout, pregnancy, nonreversible anuria	Volume depletion, decreased serum K⁺, Na⁺, Mg⁺, and H⁺. Increased uric acid, glucose, cholesterol, LDL, and triglycerides. Nausea, ototoxicity, and allergic interstitial nephritis
Thiazides	Nephrogenic diabetes insipidus, mild edema, and renal calcium stones.	Hypersensitivity to sulfa agents, gout, hepatic failure, and renal failure	Orthostatic hypotension. Decreased serum Na⁺, K⁺, Mg⁺, and H⁺. Modest increases in Ca²⁺. Increases in serum uric acid, glucose, cholesterol, LDL, and triglycerides. Erectile dysfunction, impotence, and lithium accumulation
“Thiazide-like” agents (eg, chlorthalidone and indapamide)^a	Hypertension and resistant hypertension	Ditto	Ditto
Potassium Sparing Pteridines: Triameterene & amiloride. Aldosterone antagonists: Spironolactone & Eplerenone.	Pteridine derivatives: Hypertension with K+ &/or Mg+ loss, Liddle's syndrome Aldosterone antagonists: Hypertension with K &/or Mg loss, resistant hypertension, Primary aldosteronism and other mineral corticoid excess,^b CHF^c	Hyperkalemia, concomitant use of ACEIs or ARBs, & renal failure, hepatic failure, pregnancy (particularly triamterene)	Increase serum K+, Cl-, & H+. Nausea, flatulence & skin rash with amiloride or triamterene, nephrolithiasis with triamterene. Gynecomastia & decreased libido in men with spironolactone
Carbonic anhydrase inhibitors	Glaucoma, metabolic alkalosis, altitude sickness, and diuretic resistance	Hypersensitivity to sulfonamides, metabolic acidosis, pregnancy, hepatic failure, and renal failure	Volume depletion, hypokalemia, hyperchloremic metabolic acidosis, light-headedness, circumoral paresthesias, weakness, and confusion
Osmotic agents	Cerebral edema	CHF, volume depletion, and nonreversible anuria	Low volume, K⁺, and H⁺. CHF, headache, nausea, vomit, fever, confusion, and lethargic state
Arginine vasopressin antagonists	Short-term use in euvolemic or hypervolemic hyponatremia, syndrome of inappropriate antidiuretic hormone.		Increased thirst, dry mouth, hypokalemia, hypernatremia. EVEREST trial shows small but statistically significant increase in risk of stroke

Abbreviations: SIADH, syndrome of inappropriate antidiuretic hormone secretion; LDL, low-density lipoprotein; CHF, congestive heart failure; ACEIs, angiotensin-converting enzyme inhibitors; ARBs, Angiotensin II receptor blockers; EVEREST, efficacy of vasopressin antagonism in heart failure outcome study with tolvaptan.

^a Like thiazides, these agents act on the distal convoluted tubule. However, they lack the benzothiadiazine ring framework of the thiazides and are more potent in lowering of blood pressure.

^b Familial hyperaldosteronism type 1 (glucocorticoid remedial hyperaldosteronism) and familial hyperaldosteronism type 2 (apparent mineral corticoid excess).

^c Spironolactone in CHF with New York Heart stages 3 or 4. Eplerenone in CHF with New York Heart stage 2 and in those with decreased ejection fraction following myocardial infarction.

Table 2.

Half-Life, Duration of Action, and Dosage of Diuretics.

Diuretic	Half-Life, hours	Duration of Action, hours	Usual Dosage in Milligram, Daily Unless Otherwise noted (BID, Twice Daily; TID, Thrice Daily)
Loop diuretic
Furosemide	1.5-2 (prolonged in ESRD)	4-6	20-480 (BID or TID)
Torasemide	3-4 (unchanged in ESRD)	12	5-40
Bumetanide	0.3-1.5 (unchanged in ESRD)	4-6	0.5-5 (BID or TID)
Ethacrynic acid	–	12	25-100
Thiazides
Hydrochlorothiazide	3-10	12-18	12.5-50 (daily or BID)
Chlorothiazide	15-25	6-12	125-500 (daily or BID)
Bendroflumethiazide	2.5-5	18	2.5-5
Trichlormethiazide	1-4	24	1-4
“Thiazide like” agents
Chlorthalidone	24-55	24-72	12.5-25
Indapamide	6-15	24-36	1.25-2.5
Metolazone	–	24	0.25-2.5
Quinethazone	10	18-24	25-100
Potassium sparing, pteridine derivatives
Amiloride	17 (prolonged in ESRD)	24	5-10
Triamterene	3	12	50-150
Potassium sparing, aldosterone antagonists
Spironolactone	10-23	48-72	25-100
Eplerenone	3-4	12	25-100
Carbonic anhydrase inhibitor, acetazolamide	13 (prolonged in ESRD)	16	250-1000
Osmotic agent, mannitol	1 (up to 36 in ESRD)	2	50-200 gram (continuous iv infusion or iv infusion every 3-4 hours of 20% solution
Vasopressin receptor antagonists
Tolvaptan	6-8	–	15-60
Lixivaptan	7-10	–	50-100 BID
Conivaptan	14-17	–	40-80
Satavaptan	14-17	–	5-25
Mozavaptan	1-8	–	–

Abbreviation: ESRD: end-stage renal disease.

It should be noted that the diuretic-induced reduction in salt and water activates hormonal systems such as vasopressin, the renin–angiotensin–aldosterone system, and the sympathetic nervous system.¹ This may lead to a relatively flat dose–BP response curve in patients with hypertension. However, in the case of chlorthalidone, these effects can be eradicated by the coadministration of spironolactone.^2,
3

Thiazide and “Thiazide-Like” Diuretics

“Thiazides” are Prominent in the Reduction of CVEs

In 2003, Psaty and colleagues, using both direct and indirect (network) comparisons, demonstrated that low-dose diuretics were superior to other major antihypertensive drug classes for reducing CVEs.⁴ Two recent meta-analyses exclude indirect comparisons and limit comparisons of each drug class with placebo or usual care.^5,
6 (In these analyses, reference to “thiazides” includes both true thiazides, such as hydrochlorothiazide, and “thiazide-like” diuretics, such as chlorthalidone and indapamide.)

In one meta-analysis, data were limited to studies in which 70% or more of the patients had a BP >140/90, and low-dose thiazides had, by far, the most evidence for a benefit in reducing CVEs.⁵ In a second meta-analysis,⁶ wherein data also included trials in patients with primarily normal BP, thiazide and thiazide-like diuretics were at least as effective as other antihypertensives in reducing CVEs (see Figures 1 and 2). For stroke outcomes, based on data in Figure 2, it can be calculated that the relative risk from thiazides and thiazide-like diuretics gave a point estimate significantly lower than that for β-blockers and angiotensin-converting enzyme inhibitors, P = .013 and P = .046, respectively.

Figure 1.

Relative risk estimates of coronary heart disease (CHD) events and stroke in single-drug blood pressure difference trials according to class of drug excluding CHD events in trials of β-blockers in people with the history of CHD. Totals are less than the sum of the individual categories, because some trials include more than 1 category.⁶

Figure 2.

Relative risk estimates of coronary heart disease (CHD) events and stroke in single-drug blood pressure difference trials according to class of drug, excluding CHD events in trials of β-blockers in people with the history of CHD. Totals are less than the sum of the individual categories because some trials include more than one category. Reprinted with permission from the British Medical Journal.⁶

Chlorthalidone is Superior to Hydrochlorothiazide in Reducing CVEs

Hydrochlorothiazide (HCTZ) is the 10th most commonly prescribed drug in the United States⁹ and is 20 times more frequently prescribed than chlorthalidone (CTDN).^10,
11 In the last 5 years, a number of studies have demonstrated the impropriety of these prescribing practices. CTDN has been shown to be superior to HCTZ by 5 to 6 mm Hg in lowering systolic BP,^12,
13 and, with its longer duration of action, has a relatively greater impact on nighttime BP¹² and trough levels.¹³ Compared to HCTZ, CTDN was associated with a lower development of left ventricular hypertrophy in a post hoc analysis of the data of the multiple risk factor intervention (MRFIT) trial.¹⁴

In a further retrospective cohort analysis of MRFIT participants, the relative risk (RR) (95% confidence interval) for CVEs of CTDN versus HCTZ was 0.79 (0.68, 0.92).⁷ In a more recent observational cohort study from the Ontario Drug Benefit database, the RR for the primary health outcome was 0.93 (0.81, 1.06).¹⁵ However, this latter study had methodological problems biasing the results toward finding no difference between the 2 diuretics, including no standardization of cardiovascular outcomes, the use of total mortality as a component of the primary outcome, a duration of follow-up for patients on CTDN of only 8.3 months, and the use of additional nondiuretic drugs on initiation of the diuretics. In a network analysis, the RR for CVEs for CTDN versus HCTZ was 0.79 (0.88, 0.72), P<.0001.⁸ Two other network analyses suggesting equivalence of the 2 drugs suffer from the inclusion of other medications at step 1 of the “HCTZ” arm^16,17 and the omission of 3 large trials, Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack (ALLHAT), Avoiding Cardiovascular events in Combination therapy in Patients Living with Systolic Hypertension (ACCOMPLISH), and Australian National Blood Pressure 2 (ANBP2),¹⁶ all strongly favoring CTDN in network analysis.

Thus, 0.79 is the best estimate of the RR relating CTDN to HCTZ in reducing CVEs as derived from observational and network analyses. Recent guidelines have recommended CTDN over HCTZ for resistant hypertension,¹⁸ hypertension management in Blacks,¹⁹ and in general practice in the United Kingdom.²⁰ The inertia in prescribing patterns is partly due to less flexibility in pharmaceutical preparations for CTDN, which characteristically comes in just 1 dose of 25 mg versus 12.5 mg, 25 mg, and 50 mg for HCTZ and in fewer conventional fixed-dose drug combinations (3 for CTDN versus 21 for HCTZ).

Chlorthalidone Increases Life Expectancy in 22-Year Follow-up of the Systolic Hypertension in the Elderly Program

In the systolic hypertension in the elderly program (SHEP) trial, 4736 patients with a systolic BP of at least 160 mm Hg and age of 60 or more were randomized to 12.5 to 25 mg of CTDN versus placebo. After active treatment and mean follow-up of 4.5 years, the RR (95% CI) in CVEs from the CTDN arm was 0.68 (0.79, 0.58). All patients were then advised to undergo active treatment. Recently, Kostis and colleagues completed a 22-year follow-up of these patients and showed that the CTDN arm gave a gain in life expectancy of 105 days (95% CI 39-242), P = .07, and a gain in time to cardiovascular death of 158 days (95% CI 36-287), P = .009.²¹

This is the first trial of any antihypertensive medication with more than 2 decades of follow-up to demonstrate such a benefit. The results indicate a “legacy effect” that may stem from irreversible changes in arterial vasculature in the placebo group during the first several years of the trial.

Long-Term Follow-up of the ALLHAT Trial

In ALLHAT, patients were randomized to CTDN, lisinopril, or amlodipine. During the active treatment phase (mean 4.9 years), CTDN was superior to lisinopril in preventing CVEs and was superior to amlodipine in preventing congestive heart failure (CHF). Long-term follow-up for a total of 8 to 13 years revealed the persistent advantage of CTDN over amlodipine in preventing CHF and an advantage of CTDN over lisinopril in preventing stroke mortality. The interaction between race and CTDN versus lisinopril in preventing CVEs was observed in both the initial 4.9 years and the long-term follow-up.²²

Patients Aged 80 Years and Older Benefit From Treatment for Hypertension With the Step 1 Drug, Indapamide: The Hypertension in the Very Elderly Trial

Three trials (Systolic Hypertension in the Elderly Program, Systolic Hypertension in Europe, and Systolic Hypertension in China) have shown the benefits of treating hypertension in those aged 60 years and older. The benefit of treating Hypertension in the Very Elderly has been addressed more recently. The international Hypertension in the Very Elderly Trial (HYVET) enrolled 3845 patients without dementia and with age 80+ and systolic BP off treatment of 160+ mm Hg. In double-blind fashion, patients were randomly assigned to indapamide sustained release at 1.5 mg or placebo at step 1 with perindopril or matching placebo at step 2 to achieve a target BP of less than 150/80 mm Hg²³. Whether there was allocation concealment was not reported. Assessment of end points was blinded with respect to treatment arm, and completeness of follow-up was 100%. At 2 years, mean BP was 15/6 mm Hg lower in the treated group. The RR (95% CI) from the indapamide arm for the primary end point (fatal or nonfatal stroke) was 0.70 (1.01, 0.49), P = .06, for heart failure was 0.36 (0.58, 0.22), P < .001, for any CVE was 0.67 (0.82, 0.53), P < .001, and for total mortality was 0.79 (0.65, 0.95), P = .02. At odds with conventional wisdom, there were fewer adverse events in the active treatment group.²³

Aldosterone Antagonists

Eplerenone Reduces Total Mortality in New York Heart Failure Class II: The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure trial

In 1999, Pitt and colleagues reported that spironolactone decreased total mortality in patients with CHF, New York Heart Class III and IV.²⁵ Recently, patients with more mild CHF have also been shown to benefit from the aldosterone antagonist, eplerenone.²⁴ In this double-blinded trial, patients (N = 2 737 from 29 countries) were those with New York Heart Class II with ejection fraction <30% or ejection fraction 31% to 35% with a QRS duration of 131+ milliseconds. Also, patients must have been hospitalized for a cardiovascular reason in the past 6 months or to have had an elevated level of B-type natriuretic peptide (BNP) or N-terminal proBNP. Exclusions were those with acute myocardial infarction (MI) within the past 30 days, glomerular filtration rate (GFR) <30 mL/min, elevated potassium, or those requiring a potassium sparing diuretic.²⁴

Patients were randomized to placebo or eplerenone with a starting dose of 25 mg daily advancing to 50 mg daily, or, for those with compromised renal function, 25 mg every other day advancing to 25 mg daily. Allocation was concealed, outcomes were adjudicated by an independent committee using prespecified criteria, and follow-up was 99% complete.

The trial was terminated prematurely based on prespecified stopping rules with a median follow-up of 21 months. For the primary outcome of cardiovascular death or hospitalization for heart failure, the adjusted hazard ratio (AHR; 95% CI) was 0.63 (0.54-0.74), P < .001, for death from any cause was 0.78 (0.64-0.95), P = .01, and for hospitalization for heart failure was 0.61 (0.50-0.75), P < .001. There was also a trend toward a reduction in sudden cardiac death with an AHR of 0.77 (0.55-1.08), P = .12.

Spironolactone reduced diastolic dysfunction in patients with preserved ejection fraction in a recent report.²⁶ Further, spironolactone reduced left ventricular mass in these patients. Also, spironolactone, but not irbesartan, reduced CTDN-induced sympathetic activation in a study of 13 patients and prevented the development of CTDN-induced insulin resistance.³ It is unknown whether these changes translate into a clinical benefit.

Following an Acute MI, Eplerenone Reduces Total Mortality only When Treated Within 3 to 6 Days: Further Analysis of the Eplerenone Post-Acute MI Heart Failure Efficacy and Survival Trial

In patients with systolic dysfunction following a MI, as reported in 2003,²⁸ the RR (95% CI) from eplerenone for total mortality was 0.85 (0.96, 0.75). In a more recent analysis of the same data, efficacy was shown to be limited to those given eplerenone within 3 to 6 days following the MI. For total mortality, the RR for those given eplerenone versus placebo in the period 3-6 days post-MI was 0.72 (0.81, 0.58), P = .002, whereas for those given treatment or placebo 7 to 14 days post-MI, the RR was 0.93 (0.79, 1.09), P = .37. The interaction effect was statistically significant, P = .003. No important adverse effects were associated with the earlier administration of eplerenone. The authors theorized that the beneficial effect of earlier eplerenone treatment may have been due to prevention of postinfarct remodeling and fibrosis associated with increased aldosterone levels during the first several days following an MI.²⁷

Aldosterone Antagonists Reduce Sudden Cardiac Death

Aldosterone antagonists have been shown to reduce ventricular arrhythmias in animals and clinical trials. Wei and colleagues conducted a systematic review and meta-analysis of aldosterone antagonists in the prevention of sudden cardiac death. In a pooled analysis of 2 trials with 8295 patients, aldosterone antagonists (primarily eplerenone) carried a lower risk of sudden cardiac death with RR (95% CI) equal to 0.79 (0.93-0.67), P < .001. In a pooled analysis of 2 trials, patients randomized to spironolactone had a lower risk of ventricular tachycardia with RR of 0.28 (0.77-0.10), P < .001.²⁹ It should be emphasized that the BP-lowering effect from eplerenone is roughly two-thirds of that from spironolactone, and lumping them together may be inappropriate.²⁹

Aldosterone Antagonists Reduce Proteinuria

New data confirm prior work demonstrating the benefits from aldosterone antagonists added to usual therapy in reducing proteinuria. In a double-blind, crossover randomized trial, patients with type 2 diabetes receiving either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker were given either placebo or spironolactone after a 1 month wash out period.³⁰ The treatment decreased urinary protein by 55%. Likewise, in type 1 diabetes, spironolactone decreased urinary albumin by 60%.³¹ In nondiabetic renal disease, spironolactone decreased proteinuria by 58% to 72%,^32
,
33 whereas eplerenone had a significant but more modest decrease in albuminuria by 22%.³⁵

In hyperaldosteronism, spironolactone was markedly more potent than eplerenone in reducing systolic BP, −27.0 mm Hg versus −9.9 mm Hg, respectively.³⁶

Loop Diuretics

Longer Acting Loop Diuretics Versus Furosemide in Reducing CVEs

Azosemide suppresses the sympathetic nervous system relative to furosemide.³⁶ Masuyama and colleagues randomized 320 patients with New York Heart Class II or III to receive either azosemide 30 to 120 mg or furosemide 20 to 60 mg (dosage increased as needed to control symptoms) in an open-label study with blind determination of the end point.³⁷ Whether there was allocation concealment was not reported. Excluded were those with uncontrolled diabetes, creatinine >2.5 mg/dL, acute coronary syndrome or, in the past 3 months, those with acute MI, percutaneous intervention, or open heart surgery. Follow-up was 98% complete. After a minimum of 2 years, the RR (95% CI) in the primary end point (cardiovascular death or unplanned hospitalization) was 0.55 (0.95-0.32), P = .03, and for the secondary outcome (unplanned admission to hospital for CHF or need to modify treatment of CHF) the RR was 0.60 (1.00-0.36), P = .048. There were no significant differences between the 2 arms in hypokalemia or hypotension. In a pooled analysis of 2 trials, relative to furosemide, torsemide reduced heart failure readmissions, RR = 0.41 (0.28-0.61), P < .001.³⁸ These findings are particularly important in view of the widespread use of furosemide for heart failure.^34

–37

Continuous Versus Bolus Dosing of Furosemide

In acute heart failure, 2 recent studies have shown no difference in changes in serum creatinine between bolus and continuous dosing of furosemide,^39,
40 with the latter study also giving no difference in global symptoms.⁴⁰ However, in patients with chronic kidney disease without acute heart failure, continuous infusion of furosemide was better than bolus administration for natriuresis and diuresis.⁴²

Relative to Morning Dosing, Evening Dosing of Loop Diuretics Improves BP Control

Loop diuretics are generally viewed as a third or fourth choice among diuretics in the treatment of hypertension in patients with normal renal function because of lower antihypertensive efficacy and lack of data showing a reduction in CVEs.⁴¹ However, loop diuretics are first among diuretics in treating patients with hypertension with renal insufficiency (GFR <30 mL/min) and also figure prominently in treating resistant hypertension wherein a central component of the resistance is due to excess salt and water.¹⁸ Recently, a low dose (5 mg/d) of the long-acting agent, torsemide, provided much better BP control among patients with grades 1 and 2 hypertension when administered in the evening when compared to morning: the 24-hour ambulatory systolic BP reduction was 14.8 versus 6.4 mm Hg, respectively, P < .001.⁴³ The percentage of patients achieving control was also higher with evening dosing: 64% versus 23%, respectively, P < .001.⁴³

Evening Dosing of Diuretics (Not Otherwise Specified)

In a randomized open label trial in a single referral center, evening dosing of one or more antihypertensive medications lowered CVEs relative to dosing all medications in the morning.⁴⁴ This result was similar to that for other antihypertensive.⁴⁵ The risk of falls and the occurrence of nocturia were not discussed.

Long-Acting Diuretics and Reduction of CVEs

As reported above, the long-acting agents, chlorthalidone and azosemide, are superior to their short-acting counterparts, hydrochlorothiazide and furosemide, respectively. The long-acting agents may have better BP control in the nighttime with reduction in nondipping, a known risk factor for CVEs. The findings of Hermida et al⁴⁴ as regards evening dosing of antihypertensives are consistent with this concept.

Arginine Vasopressin Receptor Antagonists

These medications have been shown to promote substantial diuresis while maintaining electrolyte balance. In the setting of CHF, both oral tolvaptan and intravenous conivaptan maintained serum sodium in the face of a greater diuresis.^46
–48 Satavaptan minimizes ascites when added to standard therapy with furosemide and spironolactone.^49,
50

Conclusion

Diuretics are a diverse class of drugs that remain extremely important in the management of hypertension and hypervolemic states.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article

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