Fantastic diuretics lecture

1. DIURETIC RESISTANCE
Kamalanathan Sambandam, M.D.
Associate Professor of Medicine
Division of Nephrology
UT Southwestern
Aug 11, 2016

2. Objectives
• Describe the basic pharmacology of diuretics
• Identify the mechanisms of diuretic resistance
• Discuss the practical aspects of managing
diuretic resistance

3. Pretest: Question 1
A patient is hospitalized for volume overload in the setting of new onset
nephrotic syndrome. Though he initially loses 2.5 kg of weight during
intravenous diuresis with a continuous furosemide drip, his weight plateaus
by hospital day #4. His treating physician switches to an intravenous
bumetanide drip to intensify therapy. Which statement correctly describes
the rationale for this change:
A. The greater potency of bumetanide will augment diuresis beyond what can be
achieved by adjusting the furosemide dose.
B. The greater bioavailability of bumetanide will increase the efficacy of diuresis.
C. There will be less hyponatremia with bumetanide.
D. There is no reason to expect that greater efficacy can be achieved with this maneuver.

4. Pretest: Question 2
Which of the following statements comparing continuous infusions of loop
diuretic to bolus loop diuretic dosing is TRUE?
A. Continuous loop diuretic infusions are superior to bolus loop diuretic doses for
achieving volume control.
B. Equivalent volume removal can be achieved with bolus and continuous infusion loop
diuretic dosing strategies, although a higher total daily dose may be required with
bolus dosing.
C. Continuous loop diuretic infusions result in less hypokalemia than bolus loop diuretic
dosing.
D. Continuous loop diuretic infusions carry greater risk of ototoxicity than bolus dosing
due to greater tendency for progressive drug accumulation to occur.

5. Pretest: Question 3
A patient with CKD, DM, HTN, and CHF is hospitalized for acute systolic heart
failure exacerbation. Intravenous loop diuretics are initiated. Aggressive
afterload reduction is instituted with the addition and up-titration of an ACE
inhibitor. His blood pressure is lowered from 180/95 mmHg on presentation
to 110/65 mmHg. His creatinine increases from 2.0 mg/dL to 2.3 mg/dL.
Despite increasing doses of loop diuretic, weight loss plateaus. He still
remains volume overloaded. What is a reasonable next step?
A. Decrease the dose of the ACE inhibitor, liberalizing blood pressure at the expense of
higher afterload
B. Add inotropes
C. Further increase afterload reduction by increasing the ACE inhibitor dose
D. Further increase afterload reduction with the addition of hydralazine and nitrates

6. Agenda
• Basic pharmacology of diuretics
• General mechanisms of diuretic resistance
• Clinical syndromes of diuretic resistance
– Renal Insufficiency
– Heart Failure
– Nephrotic Syndrome
– Cirrhosis
• Management of diuretic resistance

7. Agenda
• Basic pharmacology of diuretics
• General mechanisms of diuretic resistance
• Clinical syndromes of diuretic resistance
– Renal Insufficiency
– Heart Failure
– Nephrotic Syndrome
– Cirrhosis
• Management of diuretic resistance

8. Sites of Diuretic Action

9. Delivering Diuretics to Their Target
• All diuretics except spironolactone reach their target from the tubular
lumen.
• Most diuretics are highly protein bound (>95%), limiting glomerular
filtration.
• All diuretics except osmotic diuretics and mineralocorticoid receptor
antagonists are secreted by the proximal tubule.
– Acetazolamide, thiazides,
and loop diuretics are
secreted via Organic Anion
Transporters
– Triamterene and amiloride
are secreted via Organic
Cation Transporters

10. The Loop Diuretics
• All but ethacrynic acid are
sulfa drugs
– The risk of cross-reactivity in those
with sulfa allergy is low
• Ethacrynic acid may have
ototoxicity risk
• 40mg furosemide = 20mg
torsemide = 1mg bumetanide
Wall GC. Ann Intern Med. 2003.

11. The Loop Diuretics
• Furosemide is primarily
cleared by kidney
(excreted unchanged
and glucuronidation)
• Hepatic clearance occurs
with torsemide (80%
clearance by liver) and
bumetanide (50%)
• Bioavailibilty of
torsemide and
bumetanide >>
furosemide
Brater C. NEJM. 1998.
Diuretic Bioavail-
ability
Half Life (hrs)
Nmls Renal
Insuff
Cirrhosis CHF
Furosemide 10-100% 1.5-2 2.8 2.5 2.7
Torsemide 80-100% 3-4 4-5 8 6
Bumetanide 80-100% 1 1.6 2.3 1.3

12. Dose Response for Loop Diuretic
FENa
(%)
Serum Conc
(Log mass/vol)
Insufficient Dose
Supramaximal Dose

13. Agenda
• Basic pharmacology of diuretics
• General mechanisms of diuretic resistance
• Clinical syndromes of diuretic resistance
– Renal Insufficiency
– Heart Failure
– Nephrotic Syndrome
– Cirrhosis
• Management of diuretic resistance

14. Mechanism of Resistance: Excess Sodium
Intake
• Clinical Signs of Noncompliance-
– Requirement for large doses of diuretic for GFR
– Requirement for large K replacement
– Dx: 24hr urine Na
• Dietary Na intake (MW Na = 23gm/mol = 2.3 gm/ 100mmol):
– Average American Diet: 3.6gm Na = 156mmol1
– 2gm Na Diet = 87mmol
1. NHANES 2011-2012. http://www.ars.usda.gov/SP2UserFiles/Place/12355000/pdf/1112/Table_1_NIN_GEN_11.pdf (Accessed
4/16)

15. Mechanism of Resistance: Ineffective
Dosing Interval for Loop Diuretics
• Natriuresis
with QD dosing
of furosemide
in 6 pts on high
sodium diet
(270 meQ/d)
Wilcox CS, et al. KI. 1987.

16. Mechanism of Resistance: Increased Distal
Nephron Transport
• Serial biopsies taken from rats
chronically on furosemide
– Increased volume of distal convoluted
tubule cells by nearly 100%
– Increased number of Na/K ATPase pumps
on the basolateral surface
1. Ellison DH, et al. JCI. 1989.
 

17. Agenda
• Basic pharmacology of diuretics
• General mechanisms of diuretic resistance
• Clinical syndromes of diuretic resistance
– Renal Insufficiency
– Heart Failure
– Nephrotic Syndrome
– Cirrhosis
• Management of diuretic resistance

18. Loop Diuretics in Renal
Insufficiency
• Higher diuretic dose is required for equivalent
tubular concentration:
– Drug delivery is impaired from reduced renal mass
– Tubular secretion is diminished from competition by
uremic toxins

19. Loop Diuretic Dosing in Renal
Insufficiency
• Dose for maximal diuresis:
– With normal GFR, IVP 40mg furosemide, 1mg bumetinide,
OR 20mg torsemide.
– With severe renal insufficiency (2-15mL/min)-
• 160-200mg furosemide1
• 150-200mg torsemide (furosemide : torsemide = 1: 1)2
• 6-8mg bumetanide (furosemide : bumetanide = 20:1)1
1. Volker JR, et al. KI. 1987.
2. Brater C, et al. Cardiovasc Drug Ther. 1993.

20. Dose Response for Loop Diuretic in
Renal Insufficiency
FENa
(%)
Serum Conc
(Log mass/vol)
 Urinary
delivery 

21. Dose Response for Loop Diuretic in
Renal Insufficiency
FENa
(%)
Diuretic Excretion Rate
(Log mass/time)

22. Audience Response: Question 1
The previous slide makes the point that patients with renal
insufficiency can achieve equivalent inhibition of tubular
reabsorption of sodium, expressed as fractional excretion of
sodium (FENa), compared to normals. This can be done simply
by increasing the dose of loop diuretic to achieve equivalent
delivery of drug to the tubular lumen. Will this then result in
equivalent sodium excretion (natriuresis)?
A. Yes
B. No

23. Interdependence of FENa, GFR, and
Natriuresis
• FENa = Excreted Na / Total Filtered Na
• FENa = Excreted Na / (Serum Na X GFR)
• Excreted Na = FENa X Serum Na X GFR
– Natriuresis = 0.01 X 140mEq/L X 170L/d
= 238mEq/d
– Natriuresis = 0.005 X 140mEq/L X 170L/d
= 119mEq/d
– Natriuresis = 0.01 X 140mEq/L X 85L/d
= 119mEq/d

24. Natriuresis (mEq/min) = [Na] X GFR X FENa
Shankar SS, Brater C. Am J Physiol Renal Physiol. 2003.
Interdependence of FENa, GFR, and
Natriuresis

25. Audience Response: Question 1
The previous slide makes the point that patients with renal
insufficiency can achieve equivalent inhibition of tubular
reabsorption of sodium, expressed as fractional excretion of
sodium (FENa), compared to normals. This can be done simply
by increasing the dose of loop diuretic to achieve equivalent
delivery of drug to the tubular lumen. Will this then result in
equivalent sodium excretion (natriuresis)?
A. Yes
B. No

26. Agenda
• Basic pharmacology of diuretics
• General mechanisms of diuretic resistance
• Clinical syndromes of diuretic resistance
– Renal Insufficiency
– Heart Failure
– Nephrotic Syndrome
– Cirrhosis
• Management of diuretic resistance

27. Mechanisms of Diuretic Resistance in Heart
Failure
• Decreased GFR:
– Abrupt lowering of preload → ↓CO
– Overdosing of ACEI / ARB
– NSAIDs
– Aggressive afterload reduction in
setting of impaired autoregulation
Shankar SS, Brater C. Am J Physiol Renal Physiol. 2003.

28. Impaired Renal Autoregulation in CHF
Normal
RPF
MAP

29.  ECV
RPF
MAP
Normal
Impaired Renal Autoregulation in CHF

30.  ECV
 ECV + Vasculopathy
RPF
MAP
Risk factors for AKI in CHF: CKD, DM, BP
Normal
Impaired Renal Autoregulation in CHF

31. Mechanisms of Diuretic Resistance in Heart
Failure
• Inadequate diuretic delivery to target:
– Unpredictable gut absorption (often reduced in CHF)
– Reduced diuretic delivery from ↓C.O.
• ↓ECV → Increased solute reabsorption in proximal nephron

32. Dose Response for Loop Diuretic in
Heart Failure
FENa
(%)
Serum Conc
(Log mass/vol)
ECV

CO 

33. Agenda
• Basic pharmacology of diuretics
• General mechanisms of diuretic resistance
• Clinical syndromes of diuretic resistance
– Renal Insufficiency
– Heart Failure
– Nephrotic Syndrome
– Cirrhosis
• Management of diuretic resistance

34. Mechanisms of Diuretic Resistance in
Nephrotic Syndrome
• Proven:
– Increased extravascular distribution of diuretic from diminished protein binding
• Need higher dose to achieve the same serum drug level
– Renal insufficiency
• Possible:
– Unpredictable gut absorption from bowel wall edema
– Decreased availability of free drug in tubular lumen
– ↓ECV with severe hypoalbuminemia → Increased solute reabsorption in proximal
nephron

35. Dose Response Curve for Furosemide in
Nephrotic Syndrome
FENa
(%)
ECV

CKD 
 Urinary free drug
Serum Conc
(Log mass/vol)

36. Albumin & Furosemide Mixtures to Improve Diuretic
Responsiveness?
Inoue M, et al. KI. 1987
Volume of Distribution of Furosemide in Normal and
Analbuminemic Rats
Nml Analbuminemic Analbuminemic +
furosemide/
albumin mixture
59.6 mL/kg 545.5 ml/kg 121.2 mL/kg
• Results of human studies are variable: May
be useful with profound hypoalbuminemia
<2g/dL

37. Agenda
• Basic pharmacology of diuretics
• General mechanisms of diuretic resistance
• Clinical syndromes of diuretic resistance
– Renal Insufficeincy
– Heart Failure
– Nephrotic Syndrome
– Cirrhosis
• Management of diuretic resistance

38. Mechanisms of Diuretic Resistance in
Cirrhosis
• Inadequate diuretic delivery to target:
– Unpredictable gut absorption
– Increased extravascular distribution of diuretic from diminished protein
binding and hyperbilirubinemia
• Need higher dose to achieve the same serum drug level
• ↓ECV → Increased solute reabsorption in proximal nephron

39. Dose Response for Loop Diuretic in
Cirrhosis
FENa
(%)
ECV

Serum Conc
(Log mass/vol)

40. Agenda
• Basic pharmacology of diuretics
• General mechanisms of diuretic resistance
• Clinical syndromes of diuretic resistance
– Renal Insufficiency
– Heart Failure
– Nephrotic Syndrome
– Cirrhosis
• Management of diuretic resistance

41. Management of Diuretic Resistance-
The Players
Natriuresis = FENa X Serum Na X GFR

42. Management of Diuretic Resistance-
The Players
Natriuresis = FENa X Serum Na X GFR
Verify dietary compliance
Treat underlying disease
Maximize drug delivery to target
Dose sufficiently for effective blockade
Synergize with sequential blockade
Avoid overaggressive BP lowering
Avoid overaggressive RAAS inhibition

43. Stepwise Approach to Diuretic Resistance
• Verify dietary and drug compliance.
• Recumbency after diuretic dosing or water immersion.
• Maximize GFR by reducing/withdrawing offending
medications:
• NSAIDs
• RAAS blockade
• Aggressive afterload reduction
• β-blockers for portal HTN

44. Stepwise Approach to Diuretic Resistance
• Bolus loop diuretic with sufficient dose to achieve threshold
– Increase dose to effective response before increasing dosing
frequency
– Risk of ototoxicity is small and generally mild
• Furosemide 3mg/kg q6hrs in 92 patients with GFR ~10mL/min for up to
21 days resulted in reversible deafness in 1 patient1
• Risk factors: cumulative period above toxic level (>100mcg/mL), and
coadministration with other ototoxic drugs
• Bumetanide is less ototoxic in animal models2
– Maximal response with severe CKD occurs with:
• Furosemide 160-200mg IVP3
• Torsemide 150-200mg IVP4
• Bumetanide 6-8mg IVP3
1. Shilliday IR et al. Nephrol Dial Transplant. 1997.
2. Brown RD. J Clin Pharmacol. 1981.
3. Voelker JR, et al. Kidney Int.
4. Brater C, et al. Cardiovasc Drug Ther. 1993.

45. • Continuous infusion of loop diuretic:
– Diuretic Optimization Strategies Evaluation Trial: double blind, RCT in 308 ADHF
pts1
• No difference at 72hrs in treatment failure (AKI, worsened heart failure, need for IVFs, death),
change in wt, change in BNP, dyspnea score, or in length of hospitalization.
• More frequent need for dose increase at 48hrs with bolus vs continuous dosing (21 vs 11%, p =
0.01)
1. Felker GM, et al. NEJM. 2011.
2. van Meyel JJ, et al. J Intern Med. 1994.
Stepwise Approach to Diuretic Resistance
– If GFR >25mL/min , continued  in
efficacy may occur with ↑ing dose up
160mg/hr furosemide while
maintaining drug levels <100 mcg/mL
(presumed ototoxic range).2

46. • Addition of thiazide diuretic to loop diuretic
– Increased risk of hypokalemia, hyponatremia, and
worsening renal function.
– With severe renal insufficiency may require 200mg/d
hydrochlorothiazide.
– No clear difference in efficacy between metolazone and
hydrochlorothiazide.
Stepwise Approach to Diuretic Resistance

47. Ultrafiltration in CHF: CARRESS-HF
• 188 pts with
decompensated
CHF and
worsened renal
function (Cr of
0.3mg/dL)
randomized to UF
200mL/hr vs
intensive medical
therapy
Bart BA, et al. NEJM. 2012.

48. Audience Response: Question 2
Spironolactone is commonly prescribed in the treatment of
hypervolemia due to cirrhosis. Which of the following
statements describes the reason that spironolactone is more
effective in achieving natriuresis than loop diuretics?
A. In fact this statement is untrue. Loop diuretics are more potent diuretics
than spironolactone in cirrhotics.
B. Cirrhotic patients have especially high levels of aldosterone from impaired
clearance by the diseased liver. The sodium retention will therefore be very
sensitive to aldosterone blockade.
C. The hyperbilirubinemia characteristic of cirrhosis impairs tubular secretion
of loop diuretics. Spironolactone is more effective since it does not require
tubular secretion to get to its active site.

49. Is Spironolactone More Effective than
Furosemide in Cirrhosis?
• Physiologic argument
FOR:
– Cirrhosis is
characterized by
uniquely ↑aldosterone
levels
• Physiologic argument
AGAINST:
– Only 1% of filtered Na is
reclaimed in
aldosterone sensitive
Collecting Duct vs 15-
20% in loop diuretic
sensitive Thick
Ascending Limb

50. Is Spironolactone More Effective than
Furosemide in Cirrhosis?
• 40 non-azotemic
cirrhotics with
ascites randomly
assigned:
– Furosemide 80-
160mg QD
– Spironolactone
 150- 300mg
QD
Perez-Ayuso, et al. Gastroenterology. 1983.

51. Is Spironolactone More Effective than
Furosemide in Cirrhosis?
• 40 non-azotemic
cirrhotics with
ascites randomly
assigned:
– Furosemide 80-
160mg QD
– Spironolactone
 150- 300mg
QD
• FUROSEMIDE IS
NOT AN
EFFECTIVE DRUG
WITH ONCE
DAILY DOSING!
Perez-Ayuso, et al. Gastroenterology. 1983.

52. Audience Response: Question 2
Spironolactone is commonly prescribed in the treatment of
hypervolemia due to cirrhosis. Which of the following
statements describes the reason that spironolactone is more
effective in achieving natriuresis than loop diuretics?
A. In fact this statement is untrue. Loop diuretics are more potent diuretics
than spironolactone in cirrhotics.
B. Cirrhotic patients have especially high levels of aldosterone from impaired
clearance by the diseased liver. The sodium retention will therefore be very
sensitive to aldosterone blockade.
C. The hyperbilirubinemia characteristic of cirrhosis impairs tubular secretion
of loop diuretics. Spironolactone is more effective since it does not require
tubular secretion to get to its active site.

53. Spironolactone in Cirrhosis
• Advantages-
– Mild potency limits excessive volume loss
– Long half-life allows less frequent dosing
• Assess response 4d after dose change
– Less incidence of hypokalemia, which may limit risk of
encephalopathy (↓K → ↑NH3)
• Disadvantages-
–  risk of hyperkalemia
– risk metabolic acidosis  muscle wasting
– Anti-androgenic effects
– Ineffective with more profound disease

54. Summary
Natriuresis = FENa X Serum Na X GFR
Verify dietary compliance
Treat underlying disease
Maximize drug delivery to target
Dose sufficiently for effective blockade
Synergize with sequential blockade
Avoid overaggressive BP lowering
Avoid overaggressive RAAS inhibition

55. Post-test: Question 1
A patient is hospitalized for volume overload in the setting of new onset
nephrotic syndrome. Though he initially loses 2.5 kg of weight during
intravenous diuresis with a continuous furosemide drip, his weight plateaus
by hospital day #4. His treating physician switches to an intravenous
bumetanide drip to intensify therapy. Which statement correctly describes
the rationale for this change:
A. The greater potency of bumetanide will augment diuresis beyond what can be
achieved by adjusting the furosemide dose.
B. The greater bioavailability of bumetanide will increase the efficacy of diuresis.
C. There will be less hyponatremia with bumetanide.
D. There is no reason to expect that greater efficacy can be achieved with this maneuver.

56. Post-test: Question 1
A patient is hospitalized for volume overload in the setting of new onset
nephrotic syndrome. Though he initially loses 2.5 kg of weight during
intravenous diuresis with a continuous furosemide drip, his weight plateaus
by hospital day #4. His treating physician switches to an intravenous
bumetanide drip to intensify therapy. Which statement correctly describes
the rationale for this change:
A. The greater potency of bumetanide will augment diuresis beyond what can be
achieved by adjusting the furosemide dose.
B. The greater bioavailability of bumetanide will increase the efficacy of diuresis.
C. There will be less hyponatremia with bumetanide.
D. There is no reason to expect that greater efficacy can be achieved with this
maneuver.

57. Post-test: Question 2
Which of the following statements comparing continuous infusions of loop
diuretic to bolus loop diuretic dosing is TRUE?
A. Continuous loop diuretic infusions are superior to bolus loop diuretic doses for
achieving volume control.
B. Equivalent volume removal can be achieved with bolus and continuous infusion loop
diuretic dosing strategies, although a higher total daily dose may be required with
bolus dosing.
C. Continuous loop diuretic infusions result in less hypokalemia than bolus loop diuretic
dosing.
D. Continuous loop diuretic infusions carry greater risk of ototoxicty than bolus dosing
due to greater tendency for progressive drug accumulation to occur.

58. Post-test: Question 2
Which of the following statements comparing continuous infusions of loop
diuretic to bolus loop diuretic dosing is TRUE?
A. Continuous loop diuretic infusions are superior to bolus loop diuretic doses for
achieving volume control.
B. Equivalent volume removal can be achieved with bolus and continuous infusion loop
diuretic dosing strategies, although a higher total daily dose may be required with
bolus dosing.
C. Continuous loop diuretic infusions result in less hypokalemia than bolus loop diuretic
dosing.
D. Continuous loop diuretic infusions carry greater risk of ototoxicty than bolus dosing
due to greater tendency for progressive drug accumulation to occur.

59. Post-test: Question 3
A patient with CKD, DM, HTN, and CHF is hospitalized for acute systolic heart
failure exacerbation. Intravenous loop diuretics are initiated. Aggressive
afterload reduction is instituted with the addition and up-titration of an ACE
inhibitor. His blood pressure is lowered from 180/95 mmHg on presentation
to 110/65 mmHg. His creatinine increases from 2.0 mg/dL to 2.3 mg/dL.
Despite increasing doses of loop diuretic, weight loss plateaus. He still
remains volume overloaded. What is a reasonable next step?
A. Decrease the dose of the ACE inhibitor, liberalizing blood pressure at the expense of
higher afterload
B. Add inotropes
C. Further increase afterload reduction by increasing the ACE inhibitor dose
D. Further increase afterload reduction with the addition of hydralazine and nitrates

60. Post-test: Question 3
A patient with CKD, DM, HTN, and CHF is hospitalized for acute systolic heart
failure exacerbation. Intravenous loop diuretics are initiated. Aggressive
afterload reduction is instituted with the addition and up-titration of an ACE
inhibitor. His blood pressure is lowered from 180/95 mmHg on presentation
to 110/65 mmHg. His creatinine increases from 2.0 mg/dL to 2.3 mg/dL.
Despite increasing doses of loop diuretic, weight loss plateaus. He still
remains volume overloaded. What is a reasonable next step?
A. Decrease the dose of the ACE inhibitor, liberalizing blood pressure at the expense of
higher afterload
B. Add inotropes
C. Further increase afterload reduction by increasing the ACE inhibitor dose
D. Further increase afterload reduction with the addition of hydralazine and nitrates

61. Questions?