Outline Chapter 15 — Clinical Use of Diuretics

- Among most commonly used drugs

- Block NaCl reabsorption at different sites along the nephron

- The ability to induce negative balance has made them useful in multiple diseases

- Edematous states

- Hypertension

- Mechanism of action

- Three major classes

- Loop

- NaK2Cl

- Up to 25% of filtered sodium excreted

- Thiazide

- NCC

- Up to 3-5% of filtered sodium excreted

- Potassium sparing

- ENaC

- Up to 1-2% of filtered sodium excreted

- Each segment has a unique sodium channel to allow tubular sodium to flow down a concentration gradient into the cell

- Table 15-1 is interesting

- Most of the sodium 55-655 is reabsorbed in the proximal tubule

- Proximal diuretics would be highly effective if it wasn’t for the loop and other distal sites of Na absorption

- Loop Diuretics

- Furosemide

- Bumetanide

- Torsemide

- Ethacrynic acid

- NaK2Cl activated when all four sites are occupied

- Loop diuretic fits into the chloride slot

- In addition to blocking Na reabsorption results in parallel decrease in calcium resorption

- Increase in stones and nephro albinos is especially premature infants which can increase calcium excretion 10-fold

- Thiazide

- Even though they are less potent than loops they are great for hypertension

- “Not a problem in uncomplicated hypertension where marked fluid loss is neither necessary nor desirable”

- Some chlorothiazide and metolazone also inhibit carbonic anhydrase in the proximal tubule

- Increase Calcium absorption. Mentions that potassium sparing diuretics do this also

- Potassium sparing diuretics

- Amiloride

- Spironolactone

- Triamterene

- Act at principal cells in the cortical collecting tubule,

- Block aldosterone sensitive Na channels.

- Discusses the difference between amiloride and triamterene and spiro

- Mentions that trimethoprim can have a similar effect

- Spiro is surprisingly effective in cirrhosis and ascites

- Talks about amiloride helping in lithium toxicity

- Partially reverse and prevent NDI from lithium

- Trial Terence as nephrotoxin?

- Causes crystaluria and casts

- These crystals are pH independent

- Faintly radio opaque

- Acetazolamide

- Blocks carbonic anhydrase

- Causes both NaCl and NaHCO3 loss

- Modest diuresis de to distal sodium reclamation

- Mannitol

- Nonreabsorbable polysaccharide

- Acts mostly in proximal tubule and Loop of Henle

- Causes water diuresis

- Was used to prevent ATN

- Can cause hyperosmolality directly and through the increased water loss

- This hyperosmolality will be associated with osmotic movement of water from cells resulting in hyponatremia, like in hyperglycemia.

- Docs must treat the hyperosmolality not the hyponatremia

- Time course of Diuresis

- Efficacy of a diuretic related to

- Site of action

- Dietary sodium action

- 15-1 shows patient with good short diuretic response but other times of low urine Na resulting in no 24 hour net sodium excretion.

- Low sodium diets work with diuretics to minimize degree of sodium retension while diuretic not working

- Also minimizes potassium losses

- Increase frequency

- Increase dose

- What causes compensatory anti-diuresis

- Activation of RAAS and SNS

- ANG II, aldo, norepi all promote Na reabsorption

- But even when prazosin to block alpha sympathetic and capto[pril to block RAAS sodium retention occurs

- Decrease in BP retains sodium with reverse pressure natriuresis

- Even with effective diuresis there is reestablishment of a new steady state

- Diuresis is countered by

- Increases in tubular reabsorption at non-diuretic sensitive sites (neurohormonal mediated)

- Flow mediated in creases in Tubular reabsorption distal to the diuretic from increased sodium delivery.

- Hypertrophy

- Increased Na-K-ATPase activity

- Decreased tubular secretion of diuretic if renal perfusion is impaired

- Getting to steady state requires

- Diuretic dose and sodium intake be constant

- Sodium balance is reestablished with 3 days of a fixed diuretic dose

- K balance in 6-9 days

- Figure 15-2

- Which means that people on stable doses of diuretics don’t need regular labs, the abnormalities will emerge quickly.

- Maximum diuresis happens with first dose

- Figure 15-3

- Fluid and Electrolyte complications

- Volume depletion

- “Effective circulating volume depletion also can develop in patients who remain edematous. Although fluid persists, there may be a sufficient reduction in intracranial filling pressures and cardiac output to produce a clinically important reduction in tissue perfusion.”

- Azotemia

- Decreased effective circulating volume with diuretic therapy also can diminish renal perfusion and secondarily the GFR.

- Describes the traditional reason for increased BUN:Cr ratio

- Then states that as much as a third of of the rise in BUN may reflect increased urea production; it is possible, for example, that reduced skeletal muscle perfusion leads to enhanced local proteolysis. This increases urea production.

- Hypokalemia

- Loop and thiazide increase urinary potassium losses

- Often lead to hypokalemia

- 50 mg of HCTZ drop K by 0.4 to 0.6 mEq/L with 15% falling below 3.5

- He uses “associated” I think this is a place where we can use cause

- 50 mg of chlorthalidone

- K falls 0.8 to 0.9 mEq/L

- Etiology

- Increased distal delivery of Na and water

- Increased aldo

- From volume depletion

- Underlying disease: cirrhosis and heart failure

- Talk a lot about significance.

- Info sounds dated

- Increased risk of SCD in MRFIT trial

- Association with increased ventricular arrhythmia with hypokalmia

- Increased PVC and complex PVC by 27% with each drop in K of 0.5 mEq/L

- Says that stress can induce epinephrine which can shift potassium inside cells leading to fatal arrhythmia especially if the patient begins at a low potassium concentration

- Says v-fib two fold likely in MI patients with hypokalemia

- Talks about crazy doses of HCTZ and Chlorthalidone 50+mg

- Recommends 12.5 to 15 mg respectively

- Metabolic alkalosis

- Caused by loop and thiazide diuretics

- Two factors cause this

- Increased urinary H loss

- Partly UE to secondary hyperaldo

- Contraction of extracellular volume around remaining bicarb

- Why not contraction hypernatremia, contraction hyperkalemia, etc?

- Aldosterone contributes by stimulate ing H-ATPase

- Stimulating Sodium reabsorption creating lumen negative charge that promotes Hydrogen secretion

- Loop diuretics can also stimulate net H loss by increased Hsecretion in the cortical aspect of the thick limb

- This segment has two luminal entry points for na, the traditional NaK2Cl and Na-H exchanger

- Blocking NaK2Cl with loop diuretic stimulates the Na-H exchanger

- Can use NaCl or acetazolamide to treat

- Metabolic acidosis

- K-sparing diuretics reduce both K and H secretion in the collecting tubule

- Avoid if renal failure or on an ACEi

- Good advice to avoid K supplement with the K sparing diuretic

- Hyponatremia

- Diuretics can cause volume depletion leading to enhanced secretion of ADH and to increased water intake

- Almost always due to a thiazide

- Loops destroy the concentrated medullary gradient making ADH less effective

- Hyperdrive is

- Increased urate reabsorption in the proximal tubule

- Process mediated by parallel Na-H and urate OH exchangers see figure 3-13a

- Urate reabsorption varies directly with proximal Na transport and in patients with diuretic-induced volume deficiency both Na and urate excretion are reduced.

- May be related to Ang II

- Do not need to treat the hyperuricemia in asymptomatic patients

- Do not develop urate nephropathy because tubular urateis actually low

- Hypomagnesemia

- Generally mild

- Loop diuretics since most reabsorbed in the loop

- Thiazides don’t affect Mg (why with gitelmans?)

- Hypokalemia may directly inhibit tubular cell mg uptake

- Aldosterone increases Mg excretion, so K sparing diuretics decrease Mg secretion

- 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

References

Melanie noted that thiazide diuretics were the Project MUSE - Releasing the Flood Waters: Diuril and the Reshaping of Hypertension

Furosemide early review of furosemide effect in a range of different clinical conditions. 

Na+, K+, and BP homeostasis in man during furosemide: Effects of prazosin and captopril This article is quoted in Rose’s book-(Figure 2 is 5-1). The authors provide a figure with a balance study that shows how an initial “diuresis” is followed 

Thiazide-Associated Hyponatremia: Clinical Manifestations and Pathophysiology - American Journal of Kidney Diseases

https://jasn.asnjournals.org/content/30/2/216  

Thiazide induced hyponatremia, a detailed phenotypic and genotypic analysis (NephJC) https://www.sciencedirect.com/science/article/pii/B9780126356908500025

Classic paper on diuretics in NEJM from Craig Brater: https://www.nejm.org/doi/full/10.1056/NEJM199808063390607

Diagnosis and management of Bartter syndrome: executive summary of the consensus and recommendations from the European Rare Kidney Disease Reference Network Working Group for Tubular Disorders https://linkinghub.elsevier.com/retrieve/pii/S0085253820314046

Nephrocalcinosis of 17% in preemies: https://pubmed.ncbi.nlm.nih.gov/35348900/

Nephrocalcinosis with loop diuretics in neonates: https://pubmed.ncbi.nlm.nih.gov/38296790/ and https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941622/

We wondered whether the effect of hypercalemia on loop is complete –did we go too far saying that loop diuretics have no effect  

Anna’s VOG on hypercalciuria and lasix, etc. NEJM Paper describing the dose of lasix needed for calciuria   Meta analysis of lasix used for calciuric effects .  David Ellison and Robert Schrier experiment showing NCC activation with chronic loops. NCC activation occurs with hypercalcemia as well via CASR

Thiazide Treatment in Primary Hyperparathyroidism—A New Indication for an Old Medication? | The Journal of Clinical Endocrinology & Metabolism | Oxford Academic

Thiazide-Associated Hypercalcemia: Incidence and Association With Primary Hyperparathyroidism Over Two Decades - PMC

Major Outcomes in High-Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) | Acute Coronary Syndromes | JAMA

Uromodulin upregulates TRPV5 by impairing caveolin-mediated endocytosis - University of Iowa

Acetazolamide to increase natriuresis in congestive heart failure at high risk for diuretic resistance

Regulation of Potassium Homeostasis | American Society of Nephrology Biff Palmer’s review.

Distal Convoluted Tubule - PMC  we did not discuss this paper by Subramanya and Ellison but it is a gem

It Is Chloride Depletion Alkalosis, Not Contraction Alkalosis | American Society of Nephrology

Thiazide Effects and Adverse Effects | Hypertension

A comparison of the potassium and magnesium-sparing properties of amiloride and spironolactone in diuretic-treated normal subjects. - PMC

SGLT2i case series for hypomag: SGLT2 Inhibitors for Treatment of Refractory Hypomagnesemia: A Case Report of 3 Patients - PMC

 Elevated serum magnesium associated with SGLT2 inhibitor use in type 2 diabetes patients: a meta-analysis of randomized controlled trials

Anti-EGFR monoclonal antibody-induced hypomagnesaemia - The Lancet Oncology