DOCSLIB.ORG

Clinical Pharmacology in Diuretic Use

Total Page：16

File Type：pdf, Size：1020Kb

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

Recommended publications
  • DIURETICS Diuretics Are Drugs That Promote the Output of Urine Excreted by the Kidneys
    DIURETICS Diuretics are drugs that promote the output of urine excreted by the Kidneys. The primary action of most diuretics is the direct inhibition of Na+ transport at one or more of the four major anatomical sites along the nephron, where Na+ reabsorption takes place. The increased excretion of water and electrolytes by the kidneys is dependent on three different processes viz., glomerular filtration, tubular reabsorption (active and passive) and tubular secretion. Diuretics are very effective in the treatment of Cardiac oedema, specifically the one related with congestive heart failure. They are employed extensively in various types of disorders, for example, nephritic syndrome, diabetes insipidus, nutritional oedema, cirrhosis of the liver, hypertension, oedema of pregnancy and also to lower intraocular and cerebrospinal fluid pressure. Therapeutic Uses of Diuretics i) Congestive Heart Failure: The choice of the diuretic would depend on the severity of the disorder. In an emergency like acute pulmonary oedema, intravenous Furosemide or Sodium ethacrynate may be given. In less severe cases. Hydrochlorothiazide or Chlorthalidone may be used. Potassium-sparing diuretics like Spironolactone or Triamterene may be added to thiazide therapy. ii) Essential hypertension: The thiazides usually sever as primary antihypertensive agents. They may be used as sole agents in patients with mild hypertension or combined with other antihypertensives in more severe cases. iii) Hepatic cirrhosis: Potassium-sparing diuretics like Spironolactone may be employed. If Spironolactone alone fails, then a thiazide diuretic can be added cautiously. Furosemide or Ethacrymnic acid may have to be used if the oedema is regractory, together with spironolactone to lessen potassium loss. Serum potassium levels should be monitored periodically.
    [Show full text]
  • Nephropharmacology for the Clinician
    Nephropharmacology for the Clinician Clinical Pharmacology in Diuretic Use David H. Ellison CJASN 14: 1248–1257, 2019. doi: https://doi.org/10.2215/CJN.09630818 Diuretics are among the most commonly prescribed Gastrointestinal Absorption of Diuretics drugs and, although effective, they are often used to The normal metabolism of loop diuretics is shown in treat patients at substantial risk for complications, Figure 2A. Furosemide, bumetanide, and torsemide are Departments of making it especially important to understand and absorbed relatively quickly after oral administration Medicine and appreciate their pharmacokinetics and pharmacody- (see Figure 2B), reaching peak concentrations within Physiology and – Pharmacology, namics (see recent review by Keller and Hann [1]). 0.5 2 hours (3,4); when administered intravenously, Oregon Health & Although the available diuretic drugs possess distinc- their effects are nearly instantaneous. The oral bioavail- Science University, tive pharmacokinetic and pharmacodynamic proper- ability of bumetanide and torsemide typically exceeds Portland, Oregon; and ties that affect both response and potential for adverse 80%, whereas that of furosemide is substantially lower, Renal Section, at approximately 50% (see Table 2) (5). Although the t Veterans Affairs effects, many clinicians use them in a stereotyped 1/2 Portland Health Care manner, reducing effectiveness and potentially in- of furosemide is short, its duration of action is longer System, Portland, creasing side effects (common diuretic side effects are when administered orally, as its gastrointestinal Oregon t listed in Table 1). Diuretics have many uses, but this absorption may be slower than its elimination 1/2. review will focus on diuretics to treat extracellular This is a phenomenon called “absorption-limited Correspondence: fluid (ECF) volume expansion and edema; the reader is kinetics” (3) and may explain the mnemonic that Dr.
    [Show full text]
  • Chlorothiazide Versus Metolazone in Hospitalized Patients with Heart
    Chlorothiazide Versus Metolazone in Hospitalized Patients with Heart Failure Receiving Loop Diruetics Barry Nicholson, PharmD; Halley Gibson, PharmD, BCPS Lahey Hospital & Medical Center, Burlington, MA Background Baseline Characteristics Secondary Outcomes Results • Heart failure (HF) is the primary diagnosis in > 1 million hospitalizations annually Characteristic Metolazone Chlorothiazide p-value • Loop diuretics are first-line treatment for edema for most patients with HF, and Secondary Outcome Metolazone Chlorothiazide p-value (n=62) (n=59) thiazide diuretics may be used as an adjuvant option for additional diuresis1 (n=62) (n=59) • Previous trials have shown that oral metolazone is non-inferior to intravenous chlorothiazide with regards to safety and efficacy2,3 Age (years) ± SD 75.6 ± 12.1 74.8 ± 12.1 0.55 Hypokalemia within 24 hours 13 (21) 14 (23.7) 0.89 • There is currently no institution-specific policy to guide thiazide diuretic post-thiazide, n (%) Male, n (%) 40 (64.5) 34 (56.7) 0.55 selection in patients with heart failure at Lahey Hospital & Medical Center Hypokalemia within 72 hours 10 (16.1) 5 (8.5) 0.32 post-thiazide, n (%) Objective Weight (kg) ± SD 92 ± 32.8 95.5 ± 31.1 0.54 To evaluate the safety and efficacy of chlorothiazide versus metolazone for Hypomagnesemia within 24 hours 5 (8.1) 7 (11.9) 0.69 Non-ICU, n (%) 48 (77.4) 39 (65) 0.24 augmented diuresis in hospitalized heart failure patients receiving loop diuretics post-thiazide, n (%) Endpoints Progressive Care Unit, n (%) 12 (19.4) 3 (5.1) 0.07 Hypomagnesemia within 72 hours 9 (14.5) 6 (10.2) 0.66 post-thiazide, n (%) Primary Endpoint Change in net urine output (UOP) pre and post-initiation Intensive Care Unit, n (%) 2 (3.2) 17 (28.8) <0.01* of either study thiazide diuretic at 24 and 72 hours Length of Stay, days ± SD 14.7 ± 6.6 17 ± 11.8 0.2 Serum creatinine, mg/dL ± SD 2.2 ± 1.2 2.2 ± 1.1 0.91 Secondary Endpoints - Incidence of the following at 24 and 72 hours: # patients needing additional 27 (43.5) 37 (62.7) 0.05 1.
    [Show full text]
  • MELT-HF Metolazone As Early Add on Therapy for Acute Decompensated
    MELT-HF MEtolazone as Early add on Therapy for acute decompensated Heart Failure. A single center pilot study. Muhammad A. Chaudhry, MD MELT-HF Protocol [Amendment 5.0; 17-Jan-2017] Page 1 of 10 INTRODUCTION Background Heart failure is a major source of morbidity, mortality and growing public health cost. In US, the number of congestive heart failure patients is more than 4 million with more than 550,000 new annually reported cases. The annual cost of heart failure management exceeds 35 billion dollars per year. The heart failure readmissions and average length of hospital stay cost approximately $11,000 per patient. Loop diuretics are used alone in the majority of cases to promote diuresis. An association of increased creatinine and increased risk of renal dysfunction, the cardiorenal syndrome, in the face of high dose loop diuretics has raised questions regarding the safety and toxicity of high dose loop diuretics. While the dose of diuretics is ubiquitous, little data exists to guide their use and many clinicians are uncertain as to when and how to initiate and limit therapy. In many cases, a “stepped approach” with oral loop diuretics advancing to intravenous and finally combination high dose diuretics is employed. PREVIOUS TRIALS DOSE( Diuretic strategies in patients with ADHF) Trial Prospective, randomized double blinded trial of 308 patients with ADHF. Showed that high dose diuretics (2.5 times the outpatient daily dose) were associated with improved urine output at 72 hours (3575± 2635 in low dose group vs. 4899±3479 in high dose group). There was no significant difference between the high and low dose groups in mean creatinine change (0.08±0.3 mg per deciliter in high-dose group as compared to 0.04±0.3 mg per deciliter in low-dose group, P=0.21.
    [Show full text]
  • Diuretic Renal Scintigraphy in Patients with Sulfonamide Allergies: Possible Alternative Use of Ethacrynic Acid
    J of Nuclear Medicine Technology, first published online October 15, 2015 as doi:10.2967/jnmt.115.161331 Diuretic Renal Scintigraphy in Patients with Sulfonamide Allergies: Possible Alternative Use of Ethacrynic Acid. Ba D. Nguyen, M.D. Michael C. Roarke, M.D. Jason Robert Young*, M.D. Ming Yang, M.D. Howard H. Osborn R.N. Department of Radiology, Mayo Clinic, Scottsdale, AZ (attributed to work) *Department of Radiology, Maricopa Integrated Health System, Phoenix, AZ Correspondence and first author: Ba D Nguyen, M.D., Department of Radiology, Mayo Clinic, 13400 E. Shea Blvd., Scottsdale, AZ 85259. Telephone: 480 3016865, Fax: 480 3014303, Email: [email protected] Word Count: 999 Financial Support: None Disclosures: Nothing to disclose Short running title: Ethacrynic Acid for Renal Scintigraphy Diuretic Renal Scintigraphy in Patients with Sulfonamide Allergies: Possible Alternative Use of Ethacrynic Acid. Abstract Furosemide may trigger life threatening sulfonamide cross-hypersensitivity reactions, posing an imaging decision dilemma for patients who need diuretic renal scintigraphy. Methods: The authors present the experience using ethacrynic acid as a non-sulfonamide alternative diuretic in five patients with discussion of diuretic molecular structure, potential side effects, protocol development and imaging results. Results: Diuretic renal scintigraphy using ethacrynic acid provided useful information about the obstructive syndrome status in all cases with no adverse clinical impact. Conclusion: Ethacrynic acid is a potential alternative to furosemide for patients with severe sulfonamide reactions. Key words: Ethacrynic Acid, Diuretic Renal Scintigraphy, Sulfonamide allergy. The objective of this essay is to raise awareness of ethacrynic acid as a possible alternative to furosemide for provocative diuretic renal scintigraphy.
    [Show full text]
  • Azosemide Is More Potent Than Bumetanide and Various Other Loop
    www.nature.com/scientificreports OPEN Azosemide is more potent than bumetanide and various other loop diuretics to inhibit the sodium- Received: 21 November 2017 Accepted: 14 June 2018 potassium-chloride-cotransporter Published: xx xx xxxx human variants hNKCC1A and hNKCC1B Philip Hampel 1,2, Kerstin Römermann1, Nanna MacAulay 3 & Wolfgang Löscher1,2 The Na+–K+–2Cl− cotransporter NKCC1 plays a role in neuronal Cl− homeostasis secretion and represents a target for brain pathologies with altered NKCC1 function. Two main variants of NKCC1 have been identifed: a full-length NKCC1 transcript (NKCC1A) and a shorter splice variant (NKCC1B) that is particularly enriched in the brain. The loop diuretic bumetanide is often used to inhibit NKCC1 in brain disorders, but only poorly crosses the blood-brain barrier. We determined the sensitivity of the two human NKCC1 splice variants to bumetanide and various other chemically diverse loop diuretics, using the Xenopus oocyte heterologous expression system. Azosemide was the most potent NKCC1 inhibitor (IC50s 0.246 µM for hNKCC1A and 0.197 µM for NKCC1B), being about 4-times more potent than bumetanide. Structurally, a carboxylic group as in bumetanide was not a prerequisite for potent NKCC1 inhibition, whereas loop diuretics without a sulfonamide group were less potent. None of the drugs tested were selective for hNKCC1B vs. hNKCC1A, indicating that loop diuretics are not a useful starting point to design NKCC1B-specifc compounds. Azosemide was found to exert an unexpectedly potent inhibitory efect and as a non-acidic compound, it is more likely to cross the blood-brain barrier than bumetanide. Te Na+–K+–2Cl− cotransporter NKCC1 (encoded by SLC12A2) plays an important role in Cl- uptake in neu- rons both in developing brain and in adult sensory neurons1,2.
    [Show full text]
  • Drug Classes Other Diuretics
    DRUG CLASSES OTHER DIURETICS Loop diuretics and potassium sparing diuretics have limited roles in the management of hypertension although accumulating evidence suggests that potassium-sparing diuretics may have an important place in apparently resistant hypertension. LOOP DIURETICS Examples Bumetamide Furosemide Torasemide Mechanism of action Loop diuretics act on the nephron mainly in the thick ascending links of the Loop of Henle. Although loop diuretics have diuretic efficacy greater than that of thiazide or thiazide-like agents, effects on blood pressure are relatively brief and reflex stimulation of the renin-angiotensin system tends to counter the fall in blood pressure. Pharmacokinetics Loop diuretics are well absorbed after oral administration. Elimination is largely by the renal route with a small contribution from liver metabolism. Like thiazide and thiazide- like diuretics, the renal effects depend on access to the luminal side of the renal tubule; unlike thiazide and thiazide-like diuretics, loop diuretics retain some efficacy in renal impairment. Adverse effects As with thiazide and thiazide-like diuretics, these are mainly metabolic Hypokalaemia is even less common than with low-dose thiazides or thiazide-like diuretics Hyperglycaemia is less marked than with thiazide or thiazide-like diuretics 1 Urate retention risk of acute gout Hypocalcaemia due to increased renal clearance of calcium small risk of ureteric calculi Practical issues Bumetamide and furosemide have a rapid onset and short duration of action. Twice daily dosing is more effective in lowering blood pressure. However, persistent diuresis may limit utility. Torasemide has a longer duration of action and can be given once daily but metabolic complications, particularly hypokalaemia, are more marked than with other loop- diuretics.
    [Show full text]
  • Which Diuretics Are Safe and Effective for Patients with a Sulfa Allergy?
    From the CLINIcAL InQUiRiES Family Physicians Inquiries Network Ron Healy, MD University of Washington, Which diuretics are safe Seattle; Alaska Family Medicine Residency, Anchorage and effective for patients Terry Ann Jankowski, MLS University of Washington, Seattle with a sulfa allergy? Evidence-based answer Diuretics that do not contain a sulfonamide subsequent allergic reactions to commonly group (eg, amiloride hydrochloride, used sulfonamide-containing diuretics eplerenone, ethacrynic acid, spironolactone, (eg, carbonic anhydrase inhibitors, loop and triamterene) are safe for patients with an diuretics, and thiazides) (strength of allergy to sulfa. The evidence is contradictory recommendation: C, based on case series ® as to whether a history Dowdenof allergy to Healthand poor Media quality case-control and cohort sulfonamide antibiotics increases the risk of studies). Copyright Clinical commentaryFor personal use only Are all sulfa drugs created equal? agents and off-patent, with no company Historical bromides commonly fall by the to take up their cause, no one has been FAST TRACK wayside as better evidence becomes willing to challenge outdated package Reasonable available. Who would have thought 15 insert warnings. years ago that we would be promoting As clinicians who regularly work evidence supports beta-blockers for patients with congestive without a net, we are accustomed to what many of us heart failure? prescribing medications in less than ideal are doing: Using Likewise, with closer inspection, we circumstances. Thankfully, reasonable cheap thiazides have learned that not all sulfa drugs are evidence is available to support what many created equal. The stereospecificity due of us are already doing—using cheap for patients to the absence of aromatic amines in thiazides for patients despite a history of with a history common diuretics means they are safe sulfa allergy.
    [Show full text]
  • Optimal Diuretic Strategies in Heart Failure
    517 Review Article on Heart Failure Update and Advances in 2021 Page 1 of 8 Optimal diuretic strategies in heart failure Sarabjeet S. Suri, Salpy V. Pamboukian Division of Cardiovascular Diseases, University of Alabama at Birmingham, Birmingham, AL, USA Contributions: (I) Conception and design: SS Suri; (II) Administrative support: SV Pamboukian; (III) Provision of study materials or patients: Both authors; (IV) Collection and assembly of data: Both authors; (V) Data analysis and interpretation: Both authors; (VI) Manuscript writing: Both authors; (VII) Final approval of manuscript: Both authors. Correspondence to: Dr. Sarabjeet S. Suri, MD. University of Alabama at Birmingham, 1900 University Blvd, THT 321, Birmingham, AL 35223, USA. Email: [email protected]. Abstract: Heart failure (HF) is one of the major causes of morbidity and mortality in the world. According to a 2019 American Heart Association report, about 6.2 million American adults had HF between 2013 and 2016, being responsible for almost 1 million admissions. As the population ages, the prevalence of HF is anticipated to increase, with 8 million Americans projected to have HF by 2030, posing a significant public health and financial burden. Acute decompensated HF (ADHF) is a syndrome characterized by volume overload and inadequate cardiac output associated with symptoms including some combination of exertional shortness of breath, orthopnea, paroxysmal nocturnal dyspnea (PND), fatigue, tissue congestion (e.g., peripheral edema) and decreased mentation. The pathology is characterized by hemodynamic abnormalities that result in autonomic imbalance with an increase in sympathetic activity, withdrawal of vagal activity and neurohormonal activation (NA) resulting in increased plasma volume in the setting of decreased sodium excretion, increased water retention and in turn an elevation of filling pressures.
    [Show full text]
  • Chlortalidone and Bumetanide in Advanced Chronic Kidney Disease: Hebe-Ckd Trial
    CHLORTALIDONE AND BUMETANIDE IN ADVANCED CHRONIC KIDNEY DISEASE: HEBE-CKD TRIAL NCT03923933 RESEARCH PROTOCOL 20/03/19 FABIO SOLIS JIMENEZ M.D. PRINCIPAL INVESTIGATOR LUCIA MONSERRAT PÉREZ NAVARRO RESEARCH ASSOCIATE RAFAEL VALDEZ ORTIZ M.D. PhD RESPONSIBLE INVESTIGATOR HOSPITAL GENERAL DE MEXICO "DR. EDUARDO LICEAGA” NEFROLOGY DEPARTMENT CHLORTALIDONE AND BUMETANIDE IN ADVANCED CHRONIC KIDNEY DISEASE: HEBE-CKD TRIAL 1. BACKGROUND 1.1 INTRODUCTION Nowadays, chronic kidney disease (CKD) is considered a public health problem due to its marked increase in prevalence and incidence that currently far exceeds estimates made in previous years. (1) One of the main features of CKD is volume overload, which is accentuated as the disease progresses and confers multiple complications that directly impact the morbidity and mortality of patients suffering from it. (2) The treatment of choice for volume overload, decrease extracellular fluid (ECF) and control of hypertension in CKD, is the use of diuretics, manly loop diuretics. (3) However, adaptive changes in the distal nephron secondary to prolonged use of loop diuretics, may decrease its effectiveness, so it is necessary to change the treatment for a more potent diuretic such as Bumetanide, or add another diuretic that acts at a different site from the nephron, as thiazide diuretics. (4) Although the effect of thiazides on advanced CKD has been studied, most studies are observational and there are no randomized clinical trials with adequate statistical power that strongly recommend the use of thiazides in these patients. (5) CONSERVATIVE TREATMENT IN CHRONIC RENAL DISEASE Although renal function replacement therapy is the treatment of choice in patients with stage 5 chronic kidney disease of the KDIGO classification (ERC-5), approximately 15% of them prefer not to undergo dialysis and remain in conservative treatment in order to reduce symptoms and improve the quality of life.
    [Show full text]
  • Aldactone® Spironolactone Tablets, USP
    NDA 12-151/S-062 Page 2 Aldactone® spironolactone tablets, USP WARNING Aldactone has been shown to be a tumorigen in chronic toxicity studies in rats (see Precautions). Aldactone should be used only in those conditions described under Indications and Usage. Unnecessary use of this drug should be avoided. DESCRIPTION Aldactone oral tablets contain 25 mg, 50 mg, or 100 mg of the aldosterone antagonist spironolactone, 17-hydroxy-7α-mercapto-3-oxo-17α-pregn-4-ene-21-carboxylic acid γ-lactone acetate, which has the following structural formula: Spironolactone is practically insoluble in water, soluble in alcohol, and freely soluble in benzene and in chloroform. Inactive ingredients include calcium sulfate, corn starch, flavor, hypromellose, iron oxide, magnesium stearate, polyethylene glycol, povidone, and titanium dioxide. ACTIONS / CLINICAL PHARMACOLOGY Mechanism of action: Aldactone (spironolactone) is a specific pharmacologic antagonist of aldosterone, acting primarily through competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted renal tubule. Aldactone causes increased amounts of sodium and water to be excreted, while potassium is retained. Aldactone acts both as a diuretic and as an antihypertensive drug by this mechanism. It may be given alone or with other diuretic agents which act more proximally in the renal tubule. Aldosterone antagonist activity: Increased levels of the mineralocorticoid, aldosterone, are present in primary and secondary hyperaldosteronism. Edematous states in which secondary aldosteronism is usually involved include congestive heart failure, hepatic cirrhosis, and the nephrotic syndrome. By competing with aldosterone for receptor sites, Aldactone provides effective therapy for the edema and ascites in those conditions.
    [Show full text]
  • Outcomes Associated with a Strategy of Adjuvant Metolazone Or
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by University of Groningen University of Groningen Outcomes Associated With a Strategy of Adjuvant Metolazone or High-Dose Loop Diuretics in Acute Decompensated Heart Failure Brisco-Bacik, Meredith A.; ter Maaten, Jozine M.; Houser, Steven R.; Vedage, Natasha A.; Rao, Veena; Ahmad, Tariq; Wilson, F. Perry; Testani, Jeffrey M. Published in: Journal of the American Heart Association DOI: 10.1161/JAHA.118.009149 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2018 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Brisco-Bacik, M. A., ter Maaten, J. M., Houser, S. R., Vedage, N. A., Rao, V., Ahmad, T., ... Testani, J. M. (2018). Outcomes Associated With a Strategy of Adjuvant Metolazone or High-Dose Loop Diuretics in Acute Decompensated Heart Failure: A Propensity Analysis. Journal of the American Heart Association, 7(18), [009149]. https://doi.org/10.1161/JAHA.118.009149 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
    [Show full text]