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Chapter Fifteen, part 2: Clinical Use of Diuretics
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Quick takeaways
- Diuretic resistance is influenced by factors like hormonal counteraction and pharmacokinetics, necessitating higher initial doses in advanced disease cases.
- Appropriate dosing of diuretics, particularly through starting high, is critical for achieving optimal natriuresis and effective patient response.
- In treating refractory edema, combining loop and thiazide diuretics alongside sodium restriction and careful patient positioning can enhance treatment outcomes.
Deep dives
Understanding Diuretic Resistance
Diuretic resistance can be influenced by several factors, including the site of action of the diuretic and the presence of counterbalancing hormonal forces such as angiotensin II and aldosterone. The pharmacokinetics also play a critical role; for instance, diuretics need to be secreted into the tubule to exert their effect. In conditions such as advanced renal or liver failure, the effectiveness of loop diuretics may diminish due to competition for tubular transporters. Understanding the mechanisms of diuretic resistance can encourage clinicians to adjust dosing strategies, initiating at higher doses in patients with advanced disease to overcome these barriers.
Importance of Dosing in Diuretic Therapy
The effectiveness of diuretics largely depends on appropriate dosing, with the emphasis on achieving a threshold dose for optimal natriuresis. The concept of 'starting high' is crucial; beginning with a higher initial dosage allows for more immediate effects and the opportunity to adjust as necessary based on the patient's response. The discussion highlights that the renal response to diuretics can be counterintuitive, as patients with reduced kidney function may require higher doses to achieve similar effects compared to those with normal renal function. Engaging in a careful evaluation of patients' sodium excretion and diuretic response can inform further adjustments to the dosing regimen.
Managing Refractory Edema
Refractory edema presents challenges in treatment, requiring a nuanced approach that often involves the use of loop diuretics as the first-line therapy. Clinicians are encouraged not to shy away from high doses of diuretics when dealing with demand for substantial volume removal, particularly in patients experiencing fluid overload due to heart failure or cirrhosis. Additionally, the chapter emphasizes the necessity of sodium restriction in conjunction with diuretic therapy to enhance its efficacy. In cases where patients remain difficult to diurese, combining loop diuretics with thiazide-type diuretics may be beneficial to overcome the limitations of individual agents.
Special Populations: Cirrhosis and Advanced Kidney Disease
In cirrhosis, the distinct hemodynamic and hormonal environment complicates diuretic management. Spironolactone, a potassium-sparing diuretic, is often favored in these patients due to its ability to counteract potassium loss associated with loop diuretics while directly antagonizing aldosterone's effects. The discussion also touches upon the challenges of diuresing patients with advanced liver disease, where traditional loop diuretics may be less effective due to the high levels of endogenous hormones. Adjusting dose ratios, such as using 100 mg of spironolactone in combination with 40 mg of loop diuretics, can yield better results in managing ascites and edema in cirrhotic patients.
The Role of Patient Positioning
Patient positioning can significantly impact diuretic efficacy and fluid dynamics, highlighting the body's physiological responses to changes in body posture. Lying supine or in a head-down position can lead to better venous return and increased cardiac output, which in turn can enhance diuresis. This principle is grounded in the idea that proper positioning can activate various physiological mechanisms that promote fluid balance. Implementing these strategies in conjunction with diuretic therapy may provide additional benefits, especially in patients with heart failure who are dealing with fluid overload.
Diuretics Beyond Edema: Additional Uses
Diuretics have applications beyond the management of edema, including the treatment of metabolic alkalosis and certain types of renal tubular acidosis. The chapter also discusses their role in mitigating hyponatremia caused by conditions such as syndrome of inappropriate antidiuretic hormone secretion (SIADH). Furthermore, diuretics can be beneficial in acute settings, such as managing flashed pulmonary edema, where they help relieve symptoms and improve hemodynamics rapidly. Understanding these diverse applications informs clinicians about the broader utility of diuretics in various clinical scenarios.
References
Proximal Tubule-Specific Deletion of the NHE3 (Na+/H+ Exchanger 3) in the Kidney Attenuates Ang II (Angiotensin II)-Induced Hypertension in Mice Melanie is in love with this paper that shows that sodium retention
Bumetanide and furosemide in heart failure everyone agreed that we love this classic paper from Craig Brater on diuretics (and the source of figure 15-6).
Lety referenced the Cr x 20 formula, a strategy to multiply the serum creatinine by 20 to estimate the initial furosemide dose. We agreed that this is more appropriate than the House of God formula of age + BUN = dose (which may be so much higher).
Joel shared this excellent report Diuretic Optimization Strategies Evaluation (DOSE) trial: https://www.nejm.org/doi/full/10.1056/nejmoa1005419
Amy shared how much she likes the two hour urine sodium (or random urine sodium) Rapid and Highly Accurate Prediction of Poor Loop Diuretic Natriuretic Response in Patients With Heart Failure - PMC
Anna shared this paper which suggests that urinary sodium is more closely linked to outcome compared to urine volume Natriuretic Response Is Highly Variable and Associated With 6-Month Survival: Insights From the ROSE-AHF Trial
and the study showing Substantial Discrepancy Between Fluid and Weight Loss During Acute Decompensated Heart Failure Treatment
Josh worried about obstructive sleep apnea and nocturia: Sleep disordered breathing and nocturnal polyuria: nocturia and enuresis.
WAITING FOR JOSH
JC mentioned this report from a group in the Netherlands regarding solute load and urine volume Determinants of Urine Volume in ADPKD Patients Using the Vasopressin V2 Receptor Antagonist Tolvaptan
We also considered CLICK trail Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease | NEJM (and here’s the Freely Filtered Podcast on this topic- a really great episode! Freely Filtered 040: Double CLICK for BP control in CKD stage 4 — NephJC
Roger shared these articles on albumin and furosemide: Co-administration of albumin-furosemide in patients with the nephrotic syndrome and Albumin and Furosemide Combination for Management of Edema in Nephrotic Syndrome: A Review of Clinical Studies - PMC.
This is an interesting study that showed that the serum and urine albumin does not predict of the response to loop diuretics.Serum and Urine Albumin and Response to Loop Diuretics in Heart Failure | American Society of Nephrology
JC”s abstract on use of loop diuretics in hepatorenal syndrome type 1 was ultimately published in the American Journal of the Medical Sciences: https://doi.org/10.1016/S0002-9629(23)00623-7
Defining the role of albumin infusion in cirrhosis-associated hyponatremia this article explores the Gibbs-Donan Effect that Amy loves teaching us about.
Distal Convoluted Tubule | American Society of Nephrology Figure 1 is a favorite (and a prerequisite to friendship with melanie)
There is also a nice discussion of diuretic resistance in this year’s Nephmadness #NephMadness 2022: Cardiorenal Region – AJKD Blog
Josh is excited about starting an SGLT2 inhibitor for acute heart failure and Anna mentions this article about how they may prevent AKI: The SGLT2 Inhibitor Empagliflozin Might Be a New Approach for the Prevention of Acute Kidney Injury
Josh remembered this Tweetorial from Avi Cooper on the direct effect of furosemide: https://twitter.com/avrahamcoopermd/status/1292134482812604418?lang=en
Roger reminded us about the practice of using bedrest for heart failure: Prolonged Bed Rest in the Treatment of the Dilated Heart and rotating tourniquets Effectiveness of Congesting Cuffs ("Rotating Tourniquets") in Patients with Left Heart Failure | Circulation and Rotating Tourniquets for Acute Cardiogenic Pulmonary Edema | JAMA
Amy’s Voice of God: SGLT2i use in ADHF
CCJM: https://www.ccjm.org/content/91/1/47
EMPA AHF: https://pubmed.ncbi.nlm.nih.gov/38569758/
Joel’s Voice of God
The ADVOR Trial: https://www.nejm.org/doi/full/10.1056/NEJMoa2203094
NephJC coverage: http://www.nephjc.com/news/advor
Freely Filtered’s coverage: http://www.nephjc.com/freelyfiltered/52/advor
Outline Chapter 15 — Clinical Use of Diuretics
Part 2- beginning on page 460
- Determinants of Diuretic responsiveness
- 2 important determinants of diuretic response
- Site of action
- Presence of counterbalancing antinatriuretic forces
- Ang2
- Aldo
- Low systemic BP
- Adds rate of drug excretion as # 2 and a half
- Almost all diuretics are protein bound
- So not well filtered
- Enter tubule through organic anion and organic cation transporter
- This can limit diuretic effectiveness
- Natriuretic response plateaus at higher rates of diuretic excretion due to complete inhibition of the diuretic target
- This plateau in normal people is 1 mg of bumetanide and 40 mg of furosemide given IV
- Double this for oral furosemide, no adjustment needed for bumetanide
- 15-6
- Refractory edema
- Start with a loop diuretic
- Initial aim is to find the effective single dose
- From the paragraph this is about threshold dosing
- Double ineffective doses until good effect
- Suggests maximum furosemide dose is 200 mg IV and 400 mg oral
- Excess sodium intake
- High sodium diet can work to prevent patients from achieving negative sodium balance.
- Suggests diets after leaving the hospital maybe higher in sodium
- Decreased or delayed intestinal absorption
- Decreased intestinal perfusion, reduced intestinal motility and mucosal edema may contribute.
- But why is this worse with furosemide than with bumetidine or torsemide?
- Decreased drug entry into the tubular lumen
- Thiazides don’t work below a GFR of 20
- CLICK
- Renal failure
- Increased organic anions compete for diuretic secretion
- Bumetidine isn’t as dependent as furosemide on GFR
- Use 1/20th rather than 1/40th the dose
- Maximum of 8 to 10 mg
- Furosemide has ototoxicirty at high doses, he advises against 2400 mg/day
- There is a Na-K-2Cl carrier in the endolymph producing cells
- Ethacrynic acid has the most ototoxicity
- Only loop or thiazide that isn’t a sulfonamide derivative
- Cirrhosis
- Spiro is diuretic of choice
- More effective than loops alone
- Does not induce hypokalemia that can cause hepatic encephalopathy
- Cirrhosis causes marked hyperaldo
- Loop diuretics have to compete with bile salts for secretion in the proximal tubule
- Spiro does not need to be secreted in the proximal tubule
- Recommends to 100 to 40 spiro to furosemide ratio
- And can double this to 200 and 80/day
- and a maximum of of 400/160
- Hypoalbuminemia
- <2 g/dL associated with decreased diuretic entry into the lumen
- Protein binding keeps diuretics in the blood, reduces the volume of distribution
- This maximizes the delivery to the kidney
- In nephrotic syndrome tubular albumin can bind diuretic and prevent its activity
- Co administration of albumin with diuretic has resulted in modest improvements in diuretic effectiveness in various studies
- Intravenous infusion of loop diuretics
- Infusions are greater than bolus
- But if patient is not responding to blouses unlikely to respond to infusions since bolus provides a temporary spike in plasma level
- Increased distal reabsorption
- Increased distal sodium reabsorption decreases the effectiveness of proximal diuretics
- Due to aldo and increased sodium delivery
- Mentions that thiazides have a proximal effect (is that inhibition of carbonic anhydrase?)
- 15-8 is very cool
- Says all thiazides are created equal
- Article from 1972 is why people use metolazone in advanced renal disease
- When doing sequential nephron blocked be careful
- Loss of lots of fluid
- Loss of lots of potassium
- Loss of 5 liters and 200 mEq of K a day is possible with sequential nephron blockade
- Decreased loop sodium delivery
- With heart failure and cirrhosis increased proximal resorption mediated by Ang II markedly reduces delivery of fluid to the diuretic sensitive sites.
- Acetazolamide makes sense here
- Supine or 10 degree head down can increase cardiac output possibly increased venous return
- Can double Na excretion
- Increase CrCl 40%
- CAVH enters the chat!
- Other uses of diuretics
- Met alk, RTA, DI, hyponatremia due to SIADH, hypokalemia
- Diuretics and prostaglandins
- Loops and thiazides increase renal generation of prostaglandins
- Can cause venous dilation may help with acute pulmonary edema
- Can help without increased diuresis
- NSAIDS counter the effect of loop diuretics
- Is this natriuretic effect of PGE? Or due to renal ischemia due to unopposed Ang2 and norepi
- They also raise BP and reduce cardiac output due to increased vascular resistance
- Vasoconstrictor effect of loop diuretics
- One hour after loop diuretics increase vasoconstriction and rise in systemic blood pressure
- Increased Renin and norepinephrine, resolved 4 hours later
- Seen in heart failure and cirrhosis
- In cirrhosis decrease in RPF and GFR of 30-40% with furosemide
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