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