Highlighting pharmacokinetics and pharmacodynamics, use of diuretics in specific clinical setting, relevant clinical trials

1. DIURETICS USE IN
KIDNEY DISEASES

2. TOPICS OF
DISCUSSION
Introduction
Basic Concepts
Pharmacology
Diuretic use in Syndromes
Clinical Trials
Diuretic resistance
Conclusion

3. INTRODUCTION
• Proximal Convoluted Tubule
Diuretics
• Osmotic Diuretics: Mannitol, Urea, Glycerol
• Carbonic Anhydrase Inhibitors: Acetazolamide
• Loop Diuretics
• Furosemide, Bumetanide, Ethacrynic Acid, Torsemide
• Distal Convoluted Tubule Diuretics
• Thiazides: Benzthiazide, Chlorthiazide,
Hydrochlorothiazide
• Thiazide like : Metolazone, Indapamide,
Chlorthalidone
• Collecting Duct Diuretics ( K+ sparing
diuretics )
• Aldosterone Antagonist: Spironolactone
• Non-aldosterone Antagonist: Triamterene, Amiloride

5. Key Concepts
• Absorption-limited kinetics1:
• Oral administration : Bioavailability of furosemide is 50%
• Longer duration of action : Gastrointestinal absorption may be slower than its
elimination t1/2
• Dose to be doubled when switched : IV Oral
• Dose Response Curve:
• Natriuretic response plotted versus the log of the
plasma diuretic conc
• Loop diuretics – “ Steep Curve”
• Understanding has clinical relevance in optimal use
1. Hammarlund MM, Paalzow LK, Odlind B: Pharmacokinetics of furosemide in man after intravenous and oral administration. Application of moment
analysis. Eur J Clin Pharmacol 26: 197–207, 1984

6. Key Concepts
• Threshold: No effect below a given plasma concentration
• Most common errors in diuretic usage
• “ Doubling the dose”
• Ceiling: Failing to elicit more natriuresis beyond this plasma conc
• ECF volume expansion & edema: Altered pharmacokinetics
• GI Absorption can be slowed in states of heart failure exacerbations1
• IV drug may attain higher peak levels and may be more effective even when oral dose gives no response
• Correct approach:?
• Volume of distribution:
• Loop diuretics: organic anions - bound to albumin (95%)- Low volume of distribution
• Severe hypoalbuminemia: Impair diuretic effectiveness by reduced delivery
• Coadministration of albumin with furosemide in hypoalbuminemic patients2
1. Vasko MR, Cartwright DB, Knochel JP, Nixon JV, Brater DC: Furosemide absorption altered in decompensated congestive heart failure. Ann Intern Med102:
314–318, 1985
2. Kitsios GD, Mascari P, Ettunsi R, Gray AW: Co-administration of furosemide with albumin for overcoming diuretic resistance in patients with
hypoalbuminemia: A meta-analysis. J Crit Care 29: 253–259, 2014

7. Dose response Curve
• AKI: Increased ototoxicity of loop diuretics –” High serum concentration”
Inhibition of Na-K-2Cl isoform transport protein- expressed by the stria vascularis and participates in secretion
of potassium-rich endolymph1
• Drugs interfering with diuretic response: NSAID’s – Heart failure exacerbations2
• CKD: Furosemide-prolonged t1/2 ( torsemide/bumetanide- preserved)
1. Delpire E, Lu J, England R, Dull C, Thorne T: Deafness and imbalance associated with inactivation of the secretory Na-K-2Cl co-transporter. Nat
Genet 22: 192–195, 1999
2. Heerdink ER, Leufkens HG, Herings RM, Ottervanger JP, Stricker BHC, Bakker A: NSAIDs associated with increased risk of congestive heart failure
in elderly patients taking diuretics. Arch Intern Med158: 1108–1112, 1998

8. • Post diuretic NaCl retention: Urinary NaCl excretion declines below the baseline
when the diuretic effect wears off 1
• Recommendation to use loop diuretics twice daily
• Physiologic basis of use of continued infusion Vs high dose bolus administration2
• Braking phenomenon: Natriuresis wanes as ECF declines
• At steady state, the individual returns to NaCl balance, during which urinary NaCl
excretion is equal to dietary NaCl intake once again
1. Ellison DH, FelkerGM:Diuretic treatment inheart failure. Nengl J Med377: 1964–1975, 2017
2. Salvador DR, Rey NR, Ramos GC, Punzalan FE: Continuous infusion versus bolus injection of loop diuretics in
congestive heart failure. Cochrane Database Syst Rev (3): CD003178, 2005
• After a diuretic is started, urinary sodium excretion rises by
shifting to a new curve (from point 1 to point 2)
• Braking phenomenon: urinary sodium excretion declines back
to the baseline level, but at a new and reduced ECF volume
• Action: Hypertrophy of cells downstream from where loop
diuretics exert their action, particularly in the DCT
•

9. CJASN 14: 1248–1257, 2019. doi: https://doi.org/10.2215/CJN.09630818

10. SPECIFIC
SYNDROMES
Nephrotic syndrome
Acute kidney injury
Chronic kidney disease
Dialysis
Cardiorenal syndrome

11. NEPHROTIC SYNDROME
• Renal albumin losses and reduced hepatic synthesis in the nephrotic syndrome
eventually lead to hypoalbuminemia
• Hypoalbuminemia reduces the binding of furosemide to plasma proteins and
thereby enlarges its volume of distribution1
• 2 studies have shown that patients with a serum albumin level of 2 g/dL can
deliver normal quantities of furosemide into the urine2
• Albumin infusion into nephrotic patients increased renal furosemide excretion,
whereas hypoalbuminemia enhances its metabolic clearance
• Agarwal et al3 found that displacing furosemide from albumin via
coadministration of sulfisoxazole did not affect natriuresis in nephrotic syndrome
1. Akcicek F, Yalniz T, Basci A, et al: Diuretic effect of frusemide in patients with nephrotic syndrome: is it potentiated
by intravenous albumin? [see comments]. Br Med J 310:162–163, 1995
2. Keller E, Hoppe-Seyler G, Schollmeyer P: Disposition and diuretic effect of furosemide in the nephrotic syndrome.
Clin Pharmacol Ther 32:442–449, 1982
3. Agarwal R, Gorski JC, Sundblad K, et al: Urinary protein binding does not affect response to furosemide in patients
with nephrotic syndrome. J Am Soc Nephrol 11:1100–1105, 2000

12. Role of Diuretics -Albumin infusion
• In patients with hypoalbuminemia, it is thought that infusion of furosemide-albumin complex
increases diuretic delivery to the kidney by keeping the drug within the vascular space
• Filser et al ; in patients with nephrotic syndrome (mean S. albumin 3.0g/dl) found that
combination therapy produced only a modest increase in Na excretion Fliser D et al. Kidney Int 1999
• A similar lack of efficacy was demonstrated in hypoalbuminemic patients with cirrhosis
(mean S. albumin 3.0g/dl) Chalasani N et al. JASN 2001
• Infusion of furosemide or other loop diuretic plus albumin - effective in patients with
refractory edema and severe hypoalbuminemia (Albumin < 2.0g/dl)

13. • Diuretic response is suboptimal in some patients with hypoalbuminemia despite the use of high doses
• Blunted response : Low intravascular volume with activation of neurohumoral and RAAS
•
• 16 children with nephrotic syndrome and refractory edema in a randomized cross-over trial to receive either
combination therapy or furosemide alone.
• Urine output, urinary sodium, urinary chloride, urinary potassium, urinary osmolality, urinary osmolal and
free water clearances were measured 3, 6, 12, and 24 h after infusions
• The results from this study suggest a short-term positive effect of the combination therapy on diuresis and
natriuresis
•

14. Diuretics in AKI
• Convert oliguric to nonoliguric AKI
• Review of 11 randomized trials of loop diuretics or mannitol for prophylaxis or
treatment of established AKI found no benefit1
• The Fluid and Catheter Treatment Trial: 2
• Multicenter trial of a fluid-restrictive management strategy for the treatment of
acute lung injury comparing treatment strategies in patients with ARDS
• Fluid-management strategies in patients with ALI, randomizing 1000 ventilated
patients in a either conservative or liberal fluid management with CVP monitoring
• Post hoc analysis of patients with AKI :suggested that patients randomly assigned to
lower central venous pressure (CVP) targets exhibited lower mortality
1. Smirnakis KV, Yu AS: Diuretics in acute renal failure. In Brady HR, Wilcox CS, editors: Therapy in nephrology and hypertension, ed 2,
Philadelphia, 2003, Saunders Inc, pp 33–37
2. Stewart RM, Park PK, Hunt JP, et al: Less is more: improved outcomes in surgical patients with conservative fluid administration and
central venous catheter monitoring. J Am Coll Surg 208:725– 735, discussion 735–727, 2009

15. • In this trial only patients developing AKI within 2 days on-study were included (n =
306)
• Primary outcome : 60-day mortality after randomization
• Association of post-AKI mean fluid balance and furosemide dose with 60-day mortality

16. • Participants with AKI assigned to the fluid-
conservative group received more furosemide (80
mg/d versus 23 mg/d in the fluid-liberal group, P <
0.001)
• Mean cumulative dose of furosemide over the study
period was 562 mg in the restrictive strategy group
and 159 mg in the liberal strategy group (P < 0.001)
• Higher mean furosemide dose was negatively
associated with mortality
• Post-AKI furosemide use had a protective effect on
60-day mortality, except when adjusted for fluid
balance

17. • PICARD STUDY GROUP: AKI in critically ill patients ( n =552)
• Diuretics were used in almost 60% of the patients
• STUDY: Propensity score–adjusted analysis in this population showed that diuretic use was
associated significantly with in-hospital mortality and nonrecovery of renal function (odds ratio,
1.77; 95% confidence interval, 1.14-2.76)
1. Mehta RL, Pascual MT, Soroko S, Chertow GM; PICARD Study Group. Diuretics, mortality, and nonrecovery of
renal function in acute renal failure. JAMA. 2002;288:2547-53.

18. • Loop diuretics :Increase the risk of cast formation in crush syndrome by acidifying
the urine1 and worsen already existing hypocalcemia by inducing hypercalciuria
• Recommend: Do not use loop diuretics routinely for prevention or treatment of
AKI2
1. Better OS, Stein JH. Early management of shock and prophylaxis of acute renal failure in
traumatic rhabdomyolysis. N Engl J Med 1990; 322: 825–829
2. KDIGO Acute Kidney Injury Work Group. KDIGO Clinical Practice Guidelines for Acute Kidney
Injury. Kidney Intl 2012; 2[Suppl]: 1–138

19. • Meta-analysis by Ho et al 1 included six studies that used furosemide to treat AKI, with
doses ranging from 600 to 3,400 mg/day showed that furosemide, when used as a
preventive or therapeutic drug in AKI, did not reduce the risk of requiring renal replacement
therapy (P = .73) or hospital mortality (P=0.23)
• Sampath et al 2 performed Bayesian evidence synthesis to quantify the therapeutic efficacy
of loop diuretics in AKI
• Loop diuretics were not associated with improved survival benefit
• Did show a reduction in the duration of oliguria and a trend toward reduction in the
need for renal replacement therapy with diuretic
1. Ho KM, Power BM. Benefits and risks of furosemide in acute kidney injury. Anaesthesia. 2010;65:283-93
2. Sampath S, Moran JL, Graham PL, Rockliff S, Bersten AD, Abrams KR. The efficacy of loop diuretics in acute
renal failure: assessment using Bayesian evidence synthesis techniques. Crit Care Med. 2007;35:2516-24.

20. Diuretics
in AKI
• 20 RCT (2608 patients: 1330 in the Rx arm and 1278 in control arm)
• 7 studies on AKI prevention and 13 studies AKI treatment with Lasix
• Furosemide had neither an impact on mortality (OR = 1.015; 95% CI
0.825–1.339)
• No impact on the need for RRT (OR = 0.947; 95% CI 0.521–1.721)
1. Joannidis M, Druml W, Forni LG, et al. Prevention of acute kidney injury and protection of renal
function in the intensive care unit: update 2017: expert opinion of the Working Group on Prevention,
AKI section, European Society of Intensive Care Medicine. Intensive Care Med. 2017;43(6):730–49

21. Diuretics
in AKI
• Diuretics are not recommended to treat AKI per se but are suggested to treat volume
overload1
1. Joannidis M, Druml W, Forni LG, et al. Prevention of acute kidney injury and protection of renal function in the intensive care unit: update
2017: expert opinion of the Working Group on Prevention, AKI section, European Society of Intensive Care Medicine. Intensive Care Med.
2017;43(6):730–49

22. CHRONIC KIDNEY DISEASE
• Reduced fractional reabsorption of NaCl and fluid by the renal tubules
proportionate to the fall in GFR
• Maximal increase in fractional excretion of Na+ by furosemide is maintained
quite well in CKD , however shows blunted absolute response
• Rightward shift in the curve : Impaired secretion
• Epidemiologic studies: Diuretic use with CKD
• Diuretic use in presence of residual renal function
was associated with lower interdialytic weight gain,
less hyperkalemia, and lower cardiac-specific
mortality1
1. Bragg-Gresham JL, Fissell RB, Mason NA, et al: Diuretic use, residual renal
function, and mortality among hemodialysis patients in the Dialysis Outcomes
and Practice Pattern Study (DOPPS). Am J Kidney Dis 49:426–431, 2007

23. Choice of diuretic - RENAL INSUFFICIENCY
• Loop diuretic - generally diuretic of choice
• Thiazide-type diuretic
• Initiate diuresis in patients with mild renal insufficiency
• Response in patients with GFR of <50 ml/min/1.73 m2 - lesser wrt loop diuretic
• Higher doses required in renal insufficiency than in those with normal renal function
• Even if correctly dosed for the level of renal function, use is limited
• Low potency
• Flat dose–response curve

24. Choice of diuretic - CKD

25. CEILING DOSES OF COMMON LOOP DIURETICS

26. Hemodialysis-Diuretics and RRF
• In the CHOICE study1, ( n=734) preserved residual renal function at 1 year was
independently associated with lower all-cause mortality and better quality of life
• Diuretics- beneficial in HD patients to decrease IDWG
• Lower UF rates lead to fewer episodes of intradialytic hypotension, also known to
predict mortality , cardiovascular events and preservation of RRF2
1. Shafi T, Jaar BG, Plantinga LC, Fink NE, Sadler JH, Parekh RS, et al.: Association of residual urine output with
mortality, quality of life, and inflammation in incident hemodialysis patients: the Choices for Healthy Outcomes
in Caring for End-Stage Renal Disease (CHOICE) Study. Am J Kidney Dis 56(2):348–358, 2010
2. Flythe JE, Xue H, Lynch KE, Curhan GC, Brunelli SM: Association of mortality risk with various definitions of
intradialytic hypotension. J Am Soc Nephrol 26(3):724–734, 2015

27. • Diuretic use was investigated in 16,420 hemodialysis patients from the Dialysis Outcomes and
Practice Patterns Study, a prospective observational study of hemodialysis
• Diuretic use was associated with lower interdialytic
weight gain and lower odds of hyperkalemia
(potassium > 6.0 mmol/L).
• Patients administered diuretics also had a lower
risk of hypotensive episodes while on dialysis
• Patients with RRF on diuretic therapy had almost
twice the odds of retaining RRF after 1 year in the
study versus patients not on diuretic therapy

28. • Diuretic use was investigated in 16,420 hemodialysis patients from the Dialysis Outcomes and
Practice Patterns Study, a prospective observational study of hemodialysis
• Patients administered diuretics had a 7%
lower all-cause mortality risk (P = 0.12) and
14% lower cardiac-specific mortality risk (P=
0.03) versus patients not administered
diuretics

29. Peritoneal dialysis : RRF and Diuretics
• Medcalf et al 1 demonstrated the efficacy of 250 mg furosemide daily in 60 PD patients
over a 1-year period compared with control, with mean daily urine volume in the
furosemide group higher than that in the control group at 6 months and 12 months
• C(Urea) declined at a constant rate and were unaffected by diuretic administration
• Furosemide has no effect on preserving residual renal function.
• Oldan et al 2 studied the effect of high-dose furosemide in seven PD patients who still had
residual urine.
• High-dose furosemide increased urine volume about 400 mL/day and increased the
urinary sodium excretion 54 mmol/day but did not affect the filtration rate of the kidneys,
urea clearance, creatinine clearance, and peritoneal water and solute clearance.
1. Medcalf JF, Harris KP, Walls J. Role of diuretics in the preservation of residual renal function in patients on continuous ambulatory
peritoneal dialysis. Kidney Int 2001;59:1128-1133.
2. van Olden RW, Guchelaar HJ, Struijk DG, Krediet RT, Arisz L. Acute effects of high-dose furosemide on residual renal function in
CAPD patients. Perit Dial Int 2003;23:339-347.

30. CARDIORENAL SYNDROME

31. DOSE
TRIAL
2011
• Acute decompensated HF: How do continuous vs. intermittent and low- vs.
high-dose IV loop diuretics compare in symptom improvement and
impairment of renal function at 72 hours?
• Multicenter, randomized, double-blind, intention to treat, comparative trial
• Design : N=308 Bolus (n=156) vs. Continuous (n=152)
Low-dose (n=151) vs. high-dose (n=157)
• Follow up : 60 Days
• Primary Outcome : Global assessment of symptoms from baseline to 72 hours
Change in creatinine from baseline to 72 hours
• Interventions: Low dose bolus/infusion( Home dose of diuretic  iv)
• High dose bolus/Infusion (2.5x home dose of diuretic IV

32. 9/22/2019 32

33. • Results: Bolus with continuous infusion,
• There was NO significant difference in patients’ global assessment of
symptoms (mean AUC, 4236±1440 and 4373±1404, respectively; P =
0.47) or in the mean change in the creatinine level (0.05±0.3 mg per
deciliter [4.4±26.5 μmol per liter] and 0.07±0.3 mg per deciliter
[6.2±26.5 μmol per liter], respectively; P = 0.45)
• Conclusion : NO significant differences in patients’ global assessment of
symptoms or in the change in renal function when diuretic therapy was
administered by bolus as compared with continuous infusion or at a high
dose as compared with a low dose
DOSE
TRIAL
2011

34. RCTs on UF Vs Diuretics in HF
9/22/2019 34
Reference Study Design and
protocol
Patient
s (n)
Ultrafiltration Therapy Effect on Renal
Function
Main Findings
Costanzo
(2007),
UNLOAD
Single session early
UF therapy (within
first 24 h of admission).
Duration and rate of
removal at discretion
of physician
200 Maximum rate was 500 ml/h.
The average rate of removal
241 ml/h for 12.3+/-12 h
No significant difference in renal
function between UF and
diuretic groups. Percentage of
patients with .0.3 mg/dl rise in
creatinine consistently higher in
UF group at 24 h, 48 h, and at
discharge
Greater net fluid loss with UF.
Fewer patients in the UF group
rehospitalized at 90 d with
fewer rate of hospitalization,
hospitalization days, and
unscheduled visits
Rogers (2008) Single session UF therapy
(exclusive UF therapy
during the first 24 h of
admission). Substudy of
UNLOAD trial
20 Maximum rate was 500 ml/h.
The target weight and rate of
fluid removal were at the
discretion of the physician.
Fluid removal by UF was 3.7 L
No significant difference in GFR,
RBF, and FF between UF and
diuretic groups. Iothalamate was
used to measure GFR; it
decreased by 3.4 and 3.6 ml/min
in UF and diuretic groups.
No significant difference in net
fluid removal between the two
groups. The changes in renal
hemodynamics were
comparable for UF and diuretic
Giglioli (2011),
ULTRADISCO
Slow continuous UF.
Duration and rate
of removal at discretion
of physician.
Hemodynamic
changes were monitored
by
the Pressure recording
analytical method
30 Median UF time was 46 h.
Maximum UF rate 300 ml/h.
After 36 h, the cumulative
fluid removal was 9.7 L for
the UF group
No significant difference was
observed in serum creatinine
levels between baseline and
post-therapy and between
diuretic and UF groups
Weight loss significantly
greater in the UF group, UF
resulted in better
hemodynamic status, reduction
in serum aldosterone levels
and systemic vascular
resistance, and improvement in
cardiac index and stroke
volume

35. RCTs on UF Vs Diuretics in HF
Reference Study Design and
protocol
Patients (n) Ultrafiltration Therapy Effect on
Renal Function
Main Findings
Hanna (2012) Patients with NYHA
class III/IV heart
failure
and ejection fraction
,40%,UF rate 400
ml/h for 6 h and 200
ml/h thereafter
36 UF group had a fluid
removal rate of 3.4
ml/kg per hour with
a total volume
removal of 5.2 L. The
mean time to
achieve a PCWP of
#18 mmHg was 22 h
in the UF group
No significant
difference in serum
creatinine and
cystatin C levels
before and after
therapy between the
two groups
Fluid removal was
faster and more
efficient in the UF
group with shorter
hospital length of
stay, no change in
inflammatory
markers, NT-pro-
BNP, hospital
readmissions
Bart (2012)
[CARRESS-HF]
UF was used as
rescue
therapy after
patients
had worsening renal
function (UF rate
200 ml/h)
188 Median duration of
UF was 40 h. Post-UF
weight loss was 5.7
kg
Serum creatinine
level increased
significantly after UF.
No change in serum
creatinine level with
medical Therapy
Although weight loss
was similar with UF
and pharmacologic
therapy, patients in
the UF group had
higher rate of
serious adverse
events.
9/22/2019 35

36. ADVERSE EFFECTS
• Extracellular volume depletion
• Hyponatremia: Thiazides, which inhibit urinary dilution, whereas loop diuretics
inhibit urinary concentration and dilution
• Hypokalemia: Increased tubular flow, secretion of AVP and aldosterone, and
alkalosis
• Hypomagnesemia: Loop diuretics inhibit Mg2+reabsorption in the TAL
• Metabolic alkalosis : Thiazides and loop diuretics
• Hyperuricemia: Prolonged thiazide therapy for hypertension increases
the serum urate concentration

37. Ototoxicity
• Common during high dose bolus intravenous therapy in patients with renal
failure, in whom plasma levels are increased, and in hypoalbuminemic subjects
• Crossover trial, no ototoxicity was noted in patients with severe HF when they
were given an infusion of 250 to 2000 mg of furosemide over 8 hours, whereas
reversible deafness occurred in 25% when the same dose was given as a bolus1
• Mechanism2 :
• Interfere with strial adenylate cyclase and Na+/K+-ATPase and inhibit the Na-
K-2Cl cotransporter in the stria vascularis
• Local vasocontriction, disruption of blood cochlear barrier
1. Dormans TP, Gerlag PG: Combination of high-dose furosemide and hydrochlorothiazide in the treatment
of refractory congestive heart failure. Eur Heart J 17:1867–1874, 1996.
2. Ototoxic effects and mechanisms of loop diuretics, Dalian Ding a,b,c,*, Hong Liu b, Weidong Qi d, Haiyan
Jiang. Journal of Otology 11 (2016) 145-156

38. DIURETIC RESISTANCE
• Diuretic resistance is defined as failure to achieve the therapeutically
desired reduction in edema even when a maximal dose of diuretic is
employed1
• Pharmacokinetic and pharmacodynamic effects may contribute to diuretic
resistance
• Compliance issues: Drug , salt and fluids
• Inappropriate / inadequate dosing/Antagonism
• Compensatory mechanisms : RAAS activation2
• Role of hypoalbuminemia
• Recent hypothesis: Role of proteolytic enzymes
1. Am J Kidney Dis. 2017 January ; 69(1): 136–142. doi:10.1053/j.ajkd.2016.08.027
2. Abdallah JG, Schrier RW, Edelstein C, Jennings SD, Wyse B, Ellison DH. Loop diuretic infusion increases thiazide-
sensitive Na(+)/Cl(−)-cotransporter abundance: role of aldosterone. J Am Soc Nephrol. 2001; 12(7):1335–1341

39. DIURETIC RESISTANCE
• Filtered proteases in the setting of nephrotic syndrome activate ENaC
and contribute to sodium retention1
• Definition : Persistent congestion despite adequate and escalating
doses of diuretic equivalent to > 80 mg furosemide/day2
FeNa<0.2 %, Na excretion <90 m Eq within 72 hrs of 160 mg twice daily furosemide
1. Bohnert BN, Menacher M, Janessa A, Wo¨rn M, Schork A, Daiminger S, Kalbacher H, Ha¨ring HU, Daniel C, Amann K,
Sure F, Bertog M, Haerteis S, Korbmacher C, Artunc F: Aprotinin prevents proteolytic epithelial sodium channel (ENaC)
activation andvolume retention in nephrotic syndrome. KidneyInt93: 159– 172, 2018
2. Nat Rev Cardiol. 2015 Mar;12(3):184-92. doi: 10.1038/nrcardio.2014.215. Epub 2015 Jan 6.

40. CAUSES OF
DIURETIC
RESISTANCE

41. Combination of diuretics – Sequential blockade
• Sodium reabsorption in the distal tubule can be blocked by concurrent
administration of a thiazide
• Start with low dose metolazone (2.5 – 5mg daily)
• Long half‐life negates need for more frequent dosing
• Thiazide of choice in patients with refractory edema & advanced renal
failure
• To be administered 30 minutes prior to furosemide
• Caution : high associated incidence of hypokalemia, excessive ECV
depletion, and azotemia1
1. Wollam GL, Tarazi RC, Bravo EL, et al: Diuretic potency of combined hydrochlorothiazide and furosemide
therapy in patients with azotemia. Am J Med 72:929–938, 1982

42. APPROACH TO DIURETIC RESISTANCE
Step 1
• Ensure that the edema
is due to inappropriate
renal NaCl and fluid
retention rather than
lymphatic or venous
obstruction or
redistribution
Step 2
• Exclude non-
adherence, severe
blood volume
depletion, or
concurrent NSAID use
Step 3
• Ensure salt restriction
(24-hour Na+
excretion- values
>100meq/L = non-
compliance to dietary
salt restriction)
Step 4
• Ensure adequate
diuretic dosing

43. Conclusion
• In states of fluid excess- decongestion by diuretics has become a “holy grail”
• Response : Clinical and neurohormonal standpoint
• Need understanding of pharmacokinetics and mechanism of actions
• “Art and science of using diuretics”
• Avoiding common errors
• Management of diuretic resistance