diuretics

1. Dr. MOHD FAIZ ANSARI
Senior Resident-CCM

6.  Reversibly inhibits CA in PT cells.
 Mainly acts on Na + H+ antiporter.
 Inhibit NaHCO3 reabsorption & cause diuresis
 ↑ in urine pH from the HCO3 (alkalinizes the urine)

7.  Metabolic Alkalosis-useful when metabolic alkalosis coexists or caused by loop diuretics.
• For management of metabolic alkalosis, following regimen is proven to be safe among ICU patients in
the DIABOLO trial:
• Patients receiving simultaneous loop diuretics: 1000 mg IV acetazolamide q12hr.
• Patients not receiving simultaneous loop diuretics: 500 mg IV acetazolamide q12hr.
 Theoretically by correcting metabolic alkalosis may increase minute ventilation & improve
oxygenation→ could facilitate weaning from mechanical ventilation.
 In 2016, Faisy et al.- RCT evaluating the effect of acetazolamide vs. placebo on the duration of
invasive mechanical ventilation in patients with COPD -found no differences

8.  2nd option after thiazides-decompensated heart failure, COPD with mixed pH
disorders(controversial)
 Develop tolerance used >48 h with decrease in natriuresis b/c-Reduced HCO3 in the glomerular
filtrate & HCO3 depletion→enhanced NaCl reabsorption by the remainder of the nephron)
Not recommended to use for >3–4 days per week or for more than two consecutive days in order
to sustain its desired diuretic properties
 ADVERSE EFFECT-
 Significant HCO3 losses & hyperchloremic metabolic acidosis
 Nephrocalcinosis(d/t increased urinary pH & decrease in urinary citrate)
 immunological reactions with skin manifestations (TEN/SJS)-sulfonamide family
 C/I in patients with cirrhosis –development of hyperammonaemia & encephalopathy
 Note: Patients with an allergy to sulfa antibiotics can safely receive loop diuretics

10.  Furosemide, bumetanide, torsemide- sulfonamide derivatives
 Note: Patients with an allergy to sulfa antibiotics can safely receive loop diuretics
 Ethacrynic acid- phenoxyacetic acid derivative

11. MECHANISM OF ACTION & PHYSIOLOGIC EFFECTS
• Blockade of the Na/K/Cl channel, which is located predominantly on the thick ascending LOH.
• (1) Increased magnesium and calcium wasting.
• Mg & Ca are reabsorbed between cells in the thick ascending LOH, driven by a lumen-positive
electrochemical gradient. Loop diuretics reduce this electrochemical gradient.
• (2) Contraction alkalosis.
• (3) Blockade of NaCl entry into the macula densa (via the NKCC2 channel).
• Blockage of tubuloglomerular feedback. increase RBF(via increases in prostaglandin E2).-protective,
vasodilator effect)
• Increased renin production: increases AT-II levels (increase BP and potentially defend the glomerular
perfusion).
• Also increases aldosterone levels ( may increase sodium retention by the distal nephron, potentially impairing further
diuresis).

12.  Bioavailability of loop diuretics-(50%- 90%) (torsemide=bumetanide>furosemide)
 More consistent bioavailability of torsemide compared with furosemide and its relatively
longer t1/2- suggest may be a superior loop diuretic
 Ratio of equipotent dose: 40 mg of furosemide = 1 mg of bumetanide = 20 mg of torsemide
 On the basis of oral bioavailability IV to PO conversion- dose of bumetanide or torsemide
should be maintained (dose of furosemide should be doubled)

13.  Reduce pulmonary congestion & LV filling pressure
IV furosemide cause prompt ↑ in systemic venous capacitance(venodilation)-↑ PGs → ↓
LV filling pressure ↓ Preload → shifting of fluid from pulmonary to systemic circulation →
immediate relief in dyspnoea ( quick relief in LVF & pulmonary edema)
Diuretic actions of loop diuretics may be decreased by the concomitant use of NSAIDs(inhibits renal
prostaglandin synthesis).
 Other edematous conditions (ascites, nephrotic syndrome)
 Serve as an effective anti-hypertensive agent(especially in the presence of renal
insufficiency)
 Hyperkalemia
 Hypercalcaemic states-Furosemide was once used as a treatment for hypercalcemia, but this has largely fallen
out of favor.

14.  Testing of renal tubular integrity with furosemide in early AKI
 Cutoff for predicting AKI progression during the first 2 h following
FST- urine volume < 200 ml (100 ml/h)- sensitivity- 87.1% &
specificity 84.1%.
 Patients who did not have urine output of 200 mL within 2 hours
after furosemide administration- more likely to progress to AKIN-
III.
 Koyner et al. compared the performance of FST to a multitude of
biomarkers for predicting the severity of AKI. (biomarkers did not
perform significantly better than the FST for predicting
progression to stage III AKI, the need for RRT, or mortality.
when FST was combined with other biomarkers of AKI, there was
an improvement in risk prediction for all outcomes

15.  Loop diuretics circulate largely bound to albumin (~95%)→ Vd is low(except during extreme
hypoalbuminemia)
 severe hypoalbuminemia might impair diuretic effectiveness(Hypoalbuminemia reduces
the amount of loop diuretic that is delivered to the tubular lumen) albumin administration
might enhance natriuresis ??
 Recommendation of albumin infusion- patients with diuretic resistance and albumin levels
<2 g/dl.
 recommended proportion is 10 g of albumin for each 40 mg of furosemide.
 Recent meta-analysis concluded that the existing data, albeit of poor quality, suggest
transient effects of modest clinical significance for coadministration of albumin with
furosemide in hypoalbuminemic patients

17. • Thiazides inhibit sodium reabsorption in the DCT.
• Thiazide monotherapy- relatively weak diuretic effect
• Patients treated with loop diuretics→ reabsorb more sodium in the
DCT→ adding thiazide with loop diuretic may augment the efficacy of the
loop diuretic
• Thiazides reduce the serum sodium level (↑ in Na excretion and
enhance water absorption) -thiazide do not impair the ADH-dependent
concentrating ability of the collecting ducts→ higher net sodium loss in
comparison with water → hyponatremia
• Thiazides increase K wasting (d/t stimulation of aldosterone &
increased distal tubule flow).
• Reduce Ca2+ excretion: Thiazide-induced volume depletion →
enhanced Ca2+ reabsorption in the proximal tubule

18.  Like loop diuretics, thiazides bound to albumin & secreted into the tubule via organic anion transporters.
(OAT1 and OAT3.)
 Secretion into the tubule is delayed in renal failure(reducing diuretic efficacy).
• I.V chlorothiazide- only intravenous thiazide available(option for patients who are NPO)
• IV chlorothiazide-fastest onset, preferred in emergent situations (critical hyperkalemia). Limitations- more
expensive, relatively short t1/2 (~2 hours).

19. INDAPAMIDE OR METOLAZONE
• longer half-lives (~24 h for indapamide, ~12 h for metolazone).
may be useful to promote ongoing diuretic pressure (preventing the kidneys from retaining sodium in
between doses of diuretic).
• Metolazone is supported by more evidence in acute decompensated heart failure (5 mg PO daily or BD
is a classic dose used in the AVOID-HF trial, CARESS-HF, 3T trial).
• Reno-protective properties of indapamide preferred choice as add-on agent for de-resuscitation in the
ICU
• There is no solid data comparing these two agents.
• Oral hydrochlorothiazide could be used (less evidence regarding its use in critical care).

20.  Hypertension(↑ excretion of NaCl & water →↓ ECF fluid volume →↓ venous return ↓
CO →↓ BP)
 Congestive cardiac failure
 Nephrolithiasis d/t idiopathic hypercalciuria
 Nephrogenic diabetes insipidus.

21. BENEFITS OF USING A THIAZIDE DIURETIC AS A SECOND LINE AGENT (IN COMBINATION
WITH A LOOP DIURETIC)
• Avoiding hypernatremia: Loop diuretic therapy promote excretion of dilute/hypotonic urine→leads to
hypernatremia( must be treated by administering free water).
Addition of thiazide diuretic to a loop diuretic promotes excretion of sodium (natriuresis), leading to
more effective volume loss .
• Improved responsiveness to furosemide: Addition of thiazide diuretic prevent or reverse resistance to
loop diuretics.
• Chronic furosemide use leads to up-regulation of sodium reabsorption in the DCT which impairs furosemide's
effectiveness.
Administration of a thiazide may restore responsiveness to furosemide.
• Avoidance of sodium retention: long-acting thiazide (metolazone or indapamide) can
act continuously to prevent sodium retention (even in-between doses of loop diuretic).

22.  Direct blocking epithelial Na+ channel
(ENaC) – Amiloride, Triamterene
 Antagonists of the mineralocorticoid
receptor (MRA) – Spironolactone,
Eplerenone
 MOA & physiologic effects-Spironolactone-
mineralocorticoid inhibitor, impair the effects of
aldosterone on the distal tubule in conditions of
elevated aldosterone activity→promote sodium
excretion, potassium retention, cause non-anion-gap
metabolic acidosis.

23. • Greatest efficacy when renin-angiotensin-aldosterone system is highly activated (cirrhosis, heart
failure).
situations where basal aldosterone tone low (spironolactone have little clinical effect)
• Spironolactone takes 1-2 days to have maximal effect(limits its utility in emergent situations)
• Spironolactone-“potassium-sparing” diuretic.
In patients undergoing large-volume diuresis, addition of spironolactone may reduce hypokalemia
and contraction alkalosis.
• Volume removal in cirrhosis(reducing cirrhotic ascites).
• Counteracting neurohormonal activation in patients with heart failure with reduced ejection fraction
(dose is limited to 50 mg/day when used solely for this indication).

25. • Eplerenone- indicated to prevent cardiac remodeling & systolic dysfunction in the setting of
recent myocardial infarction
• Amiloride acts via blocking the ENaC channel in the distal nephron.
• Decreases the serum bicarbonate level (either causing a non-anion-gap metabolic acidosis, or
treating a metabolic alkalosis).
• Increases serum potassium (“potassium-sparing diuretic”).
• Reduces urinary excretion of calcium and magnesium.
 Triamterene-same MOA as amiloride- blocking passive potassium efflux out of the distal
nephron (via the ENaC channel).
 Unique nephrotoxic properties(nephrolithiasis, interstitial nephritis, ARF d/t effects on the
prostaglandin system)

26.  Novel, nonsteroidal, selective MRA with anti-inflammatory and antifibrotic effects
 Finerenone blocks mineralocorticoid receptors- potassium-sparing diuretic.
 Dose:
 Prior to initiating therapy- verify serum K < 5 meq/L(Do not initiate therapy if S.K > 5 Meq/L)
 If serum K (>4.8 -5) may consider initiation( with increased K monitoring in the first 4 weeks)
 CKD associated with type II DM
 eGFR >60 ml/min/1.732m2 then 20 mg OD
 eGFR>25 to <60 ml/min/1.732m2 then 10 mg OD
 eGFR < 25 ml/min/1.732m2 – not recommended

28.  Osmotic diuretic agents function as aquaretics – stimulate the loss of electrolyte-free water.
 Osmotic diuretics are freely filtered at the glomerulus but poorly reabsorbed in the tubules.
 Mannitol(prototype) sorbitol and glycerol have similar actions
 recommended for Mx of severe head injury(reduction of ICP/treatment of cerebral edema)
 A trial of mannitol therapy for cerebral oedema complicating hepatic failure demonstrated a markedly
better survival of 47%, compared with only 6% in the control group
 DOSE- Infused IV 1.5- 2.0 g/kg 20% mannitol over 30-60 minutes to treat raised intraocular or
intracranial pressure

29. • These agents increase the sodium conc.(In hyponatremia may be beneficial).
• For patients with diuretic resistance d/t hyponatremic hypochloraemia-osmotic diuretics could
theoretically re-establish normal chloride concentrations, which might theoretically improve diuretic
responsiveness.
 Renal indication for prevention of AKI- removal of obstructing tubular casts, dilution
of nephrotoxic substances in the tubular fluid & reduction in the swelling of tubular
elements via osmotic extraction of water, release of intrarenal vasodilating
prostaglandins and natriuretic peptides & oxygen-free radical scavenger properties
 Mannitol can reverse the dialysis disequilibrium syndrome

30.  Mannitol not used for management of volume overload- d/t its extracellular expansion
effect→can precipitate pulmonary edema in susceptible patients
 Inhibit water transport & consequently decrease the tubular ability to reabsorb Na+ →
Increased distal delivery of Na+ ions → K+ loss (Initially, Hypertonic hyponatremia and
hypochloremia)
 If kidneys are unable to excrete mannitol- lead to volume overload and dilutional
hyponatremia (S. osmolarity is normal/high- pseudohyponatremia).
 High doses of mannitol (>200 g/day or accumulated doses of >800 g) a/w AKI due to renal
vasoconstriction and tubular toxicity(osmotic nephrosis)
 Plasma osmolality and the osmolal gap should be monitored frequently
therapy should be discontinued if adequate diuresis is not achieved or if the osmolal gap
rises >55 mOsm/kg.

31.  3.4.1: We recommend not using diuretics to prevent AKI. (1B)
 3.4.2: We suggest not using diuretics to treat AKI, except in the management of
volume overload. (2C)
 Conceivable benefits:– control of volume overload, oliguric to non-oliguric AKI,
reduction in renal energy expenditure, Improve GFR by inhibiting TGF, “renal
flushing,” prognostication
 Limitations:– Precipitation of intravascular volume depletion, Non-oliguric AKI
may reflect underlying severity of illness, delay RRT, Nephroprotective
mechanisms unproven

32. ARE DIURETICS NEPHROTOXIC?
 Diuretics are not intrinsically nephrotoxic-
• Diuretics don't seem to directly cause harm to the kidneys (exception- triamterene).
• Diuretics often block various ion channels in the renal tubules→ reduces the amount of energy expended by
the nephron→decreasing oxygen consumption(theoretically protect the kidneys in poor perfusion.
 Diuretics can induce renal failure
• If sufficient diuretics are administered to provoke volume depletion (hypovolemic shock)-can surely cause
→indirectly (via induction of hypovolemia) – not directly.
Close attention to volume status & hemodynamics during diuresis should reduce the risk of kidney injury.

33. DIURETICS CAN IMPROVE RENAL FUNCTION
• Systemic venous congestion can impair renal function (“congestive nephropathy”):
• Elevating central venous pressure chokes off blood flow through the kidneys.
• Venous congestion can cause intra-renal interstitial edema→compartment syndrome within the kidney!
• In patients with venous congestion- diuresis may relieve congestion(improve renal function).
• In the FACTT trial of patients with ARDS- patients randomized to the conservative fluid arm
received higher doses of diuretics (mostly loop diuretics) and had improved renal outcomes.

34. RISING CREATININE FOLLOWING INITIATION OF DIURESIS
• . Any creatinine rise in the ICU look for D/D:
• Diuretic-induced hypovolemic shock causing renal hypoperfusion?/Random daily fluctuations in creatinine?/AKI d/t other
medications or sepsis.
• If creatinine elevation is substantial-should be evaluated similarly of any other patient with AKI.
• At a minimum, hemodynamic re-evaluation should occur (USG to image the heart & assess for systemic venous congestion).
• Whether or not diuretics should be held is ultimately a clinical decision:
• If patient clearly remains congested- continuing diuresis may be beneficial.
Some patients with congestive nephropathy will have minor elevation in creatinine with diuresis, but this recovers with ongoing
decongestion.
• If the patient isn't definitely congested-holding diuretics may be sensible(if diuresis appears to cause hypotension).

35. KDOQI CLINICAL PRACTICE GUIDELINES USE OF DIURETICS IN CKD
 Choice of diuretic agents depends-level of GFR & need for reduction in ECF
volume
 12.1 Most patients with CKD should be treated with a diuretic (A).
 12.1.a Thiazide diuretics given once daily are recommended in patients with GFR
≥30 mL/min/1.73 m2 (CKD Stages 1-3) (A)
 12.1.b Loop diuretics given once or twice daily are recommended in patients with
GFR <30 mL/min/1.73 m2 (CKD Stages 4-5) (A)
 12.1.c Loop diuretics given once or twice daily, in combination with thiazide
diuretics, can be used for patients with ECF volume expansion and edema (A).

36.  12.1.d Potassium-sparing diuretics should be used with caution:
 12.1.d.i In patients with GFR <30 mL/min/1.73 m2 (CKD Stages 4-5) (A)
 12.1.d.ii In patients receiving concomitant therapy with ACE inhibitors or ARBs (A)
 12.1.d.iii In patients with additional risk factors for hyperkalemia (A)
 12.2 Patients treated with diuretics should be monitored for:
 12.2.a Volume depletion, manifest by hypotension or decreased GFR (A)
 12.2.b Hypokalemia and other electrolyte abnormalities (A).
 12.2.c The interval for monitoring depends on baseline values for blood pressure, GFR
and serum potassium concentration(B).

37.  The Diuretic Optimization Strategies Evaluation in AHF (DOSE-AHF) trial -
diuretic dosing and the route of administration in patients with AHF
 DOSE-AHF trial demonstrated:
High loop diuretic dose (2.5 times the usual home dose) vs low dose (equal to home
dose) resulted in a favorable effect on secondary endpoints of dyspnea relief,
change in weight and net fluid loss.
Worsening of renal function (increase in creatinine by > 0.3 mg/dL) occurred more
in the high-dose group.
However, a post-hoc analysis of the DOSE-AHF trial illustrated that this increase
in creatinine did not signify a worse outcome.
No significant difference between the bolus and continuous infusion.

40.  Splanchnic arterial vasodilation d/t portal hypertension→reduced effective volemia &
subsequent Na retention due to the activation of RAAS and SNS→ ascites formation.
 Before starting treatment diagnostic paracentesis is recommended in all patients with
new-onset ascites to rule out SBP.
 Diuretics are needed to counteract renal sodium retention in decompensated cirrhosis
with ascites and edema.
 Current guidelines for cirrhosis-use with furosemide in a ratio of 100 mg spironolactone : 40 mg furosemide.
The maximal recommended dose of spironolactone is 400 mg daily

41.  Recommended target net fluid loss of 1 L/d in patients with ascites & edema or 0.5 L/d
in ascites without edema.
 Aggressive diuresis in patients without edema risks intravascular volume depletion
and Acute kidney injury(only 0.4 L/d ascites may be mobilized into the systemic
circulation).
 Once ascites is refractory to diuretics- guidelines recommend to discontinue them.
 When renal sodium excretion on diuretics exceeds 30 mmol/day, maintenance of
diuretic therapy can be considered, if well tolerated.

43.  .

44.  SGLT2 inhibitors-slowing the progression of diabetic and
nondiabetic CKD, decreasing the risk of AKI, CHF
hospitalization, and cardiovascular mortality.
 Act by inhibiting (SGLT-2)- located in the PCT reduce sodium
and glucose reabsorption from the proximal tubule → promote
glucosuria→increase urine osmolality forcing an osmotic effect →
diuresis.
 SGLT2 inhibitors acutely reduce GFR during the first few weeks
by restoring tubuloglomerular feedback but preserve kidney
function with long term use, possibly by attenuating glomerular
hypertension.
 diuresis is reduced/even disappears after 72 h(d/t activation of
urinary concentration through stimulation of urea production
and vasopressin action).
 S/E- uricosuria, genital & urinary tract infection, and euglycemic
diabetic ketoacidosis.

45.  The DAPA-CKD (Dapagliflozin in Patients With Chronic Kidney Disease) trial
investigated primary composite kidney outcomes in 4,304 participants with CKD
(eGFR 25–75 ml/min & albumin/creatinine ratio 200–5,000 mg/g with or without
diabetes-
found that the risk of CKD progression was significantly lower in those treated with
dapagliflozin compared to placebo with a median follow-up of 2.4 years.
 The EMPEROR-reduced trial recruited people with eGFR down to 20 ml/min/1.73
m2 (mean 62 ml/min/1.73 m2) noted that use of empagliflozin reduced a renal composite
(sustained decline in eGFR, dialysis or renal transplantation) by 50%.
decline in eGFR was significantly slower with empagliflozin than placebo (mean –0.55
versus –2.28 ml/min/1.73 m2/year).