1) Congestive heart failure involves a vicious cycle where the heart and kidneys damage each other through various physiological mechanisms related to congestion. 2) Diuretics are essential for managing heart failure but their use can have side effects like worsening kidney function if given in high doses. 3) Combination diuretic therapy using both loop and thiazide diuretics may help overcome diuretic resistance seen in some patients by blocking sodium reabsorption at different sites along the nephron.

2. Thank you donkey!
You have helped us all understand congestive heart failure physiology and treatment!

3. Pathophysiological course and vicious cycle of HF until clinical congestion,including renal dysfunction
by cardio-renal interaction,subdivided in phases of preclinical medical interventions and
hospitalization, suggesting a window for earlier intervention on hemodynamic congestion

4. The vicious cycle of HF progression with mutual involvement of left and right
sides of the heart and the kidney : key role of congestion

5. Potential factors
contributing to the
development of congestion
in acute heart failure.
LVEDP left ventricular end-diastolic
pressure, PCWP pulmonary capillary
wedge pressure
Congestion in heart failure

8. Nephron parts and functions.

9. Renal handling of sodium and water
DCT diuretic

10. Diuretic therapy.
(1) Acetazolamide functions in the proximal tubule by blocking carbonic anhydrase and increasing NaHCO3 excretion. (2) Mannitol functions in both the
proximal tubule and the loop of Henle by increasing H2O excretion. (3) Loop diuretics function in thick ascending limb of the loop of Henle by blocking
the sodium–chloride–potassium cotransporter and increasing sodium, potassium, and chloride excretion. (4) Thiazide functions in the distal convoluted
tubule by blocking the sodium–chloride transporter and increasing sodium chloride excretion. (5) Mineralocorticoid-receptor antagonists function in the
collecting duct of the distal tubule and antagonize the aldosterone receptor, hence increasing sodium excretion and potassium retention.

12. Diuretics:
A Friend or a Necessary Evil?

13. The use of loop diuretics is essential in the management of HF, particularly during episodes of acute decompensation, therefore more than 90% of
patients admitted with HF receive this drug. The administration of intravenous loop diuretics to patients with heart failure and congestion typically results
in the improvement of dyspnea, pulmonary congestion and in the reduction of Left Ventricular (LV) filling pressures. Several side effects may result from
the administration of high diuretics dose, including worsening kidney function, diuretic resistance and sympathetic overdrive.
Do diuretics do more harm than good?
SNS+

14. Effects of renin-angiotensin-aldosterone and sympathetic
overdrive in different kidney sites

15. RAAS Activation During Decongestion in Acute HF
Friend or Foe?

16. Adverse effects of major diuretics

22. Symptomatic (NYHA Class II-IV) heart failure with reduced ejection fraction

23. Patients with heart failure with preserved ejection fraction and heart failure
with mid-range ejection fraction

24. Hypertension in patients with symptomatic (NYHA Class II-IV)
heart failure with reduced ejection fraction

25. Patients with acute heart failure

26. Renal replacement therapy in patients
with acute heart failure
Ultrafiltration involves the removal of plasma water across a semipermeable membrane in response to a
transmembrane pressure gradient. There is no evidence favouring ultrafiltration over loop diuretics as first-line
therapy in patients with AHF. At the present time, routine use of ultrafiltration is not recommended and should
be confined to patients who fail to respond to diuretic based strategies

27. No single accepted definition of diuretic resistance has
been described.
Of the several definitions proposed, the most frequently
cited is “failure to decongest despite adequate and
escalating doses of diuretics”
DIURETIC RESISTANCE
Why Diuretics Fail Failing Hearts.

28.  Persistent congestion despite adequate and
escalating doses of diuretic with >80 mg
furosemide per day
 Amount of sodium excreted as a percentage
of filtered load <0.2%
 Failure to excrete at least 90 mmol of sodium
within 72 h of a 160 mg oral furosemide dose
given twice daily
Less clinically applicable definitions that include
variables not routinely obtained by clinicians have also
been suggested

29. Metrics of diuretic response
 Weight loss per unit of 40 mg furosemide (or equivalent)
 Net fluid loss per milligram of loop diuretic (40 mg of
furosemide or equivalent) during hospitalization
 Natriuretic response to furosemide as the ratio of urinary
sodium to urinary furosemide
Unresponsiveness to diuretic therapy leading to
persistent signs and symptoms of congestion is usually
considered diuretic resistance.

30. During diuretic-induced extracellular volume depletion, short-term and long-term
adaptive processes serve to protect the intravascular volume

31. There are two forms of diuretic tolerance: (1) Short-term tolerance occurs when the diuretic effect is attenuated after the
first dose has been administered; this can be prevented by restoring diuretic-induced loss of volume. (2) Long-term
tolerance is observed after prolonged administration of a loop diuretic, which leads to avid sodium reabsorption at more
distal sites. This phenomenon argues for the use of sequential nephron blockade with combinations of loop and
thiazide diuretics in patients who do not have adequate responses to optimal doses of a loop diuretic.

32. Pathophysiology and mechanisms of loop diuretic resistance
Organic anion transporter
Sodium delivery into tubular
fluid is determined by GFR

33. Non-adherence to diuretics
Non-adherence to low sodium diet
Dose to low or too infrequent
Use of NSAIDs
Don’t Forget to Check for:
The Truth About Water Pills

34. Sequential nephron blockade
Combination Diuretic Therapy(CDT)
CDT

35. Combination Diuretic Therapy produces true synergism, the
combination of agents is more effective than the sum of the
responses to each agent alone.
Distal convuluted tubule (DCT) diuretics are the class of drug
most commonly combined with loop diuretics.
The distal convuluted tubule (DCT) diuretic is administered 1
hour before the morning dose of the loop diuretic to ensure
that NaCl transport in the distal nephron is blocked when it is
flooded with solute.
Metolazone is the distal convuluted tubule (DCT) diuretic most
commonly combined with loop diuretics, because its half-life is
relatively long and it has been reported to be effective when renal
failure is present. Other thiazide and thiazide-like diuretics
appear to equally effective, even in severe renal failure.

36. Important Considerations Regarding
Combination Diuretic Therapy(CDT)
JACC Vol. 56, No. 19, 2010

37. Potential Benefits and Adverse Effects of combination diuretic therapy (CDT)

39. Stepped pharmacological care; treatment algorithm for patients with heart failure (HF) and volume overload. At each decision, clinical
assessment should include an assessment of symptoms, volume assessment, and appropriate monitoring of vital signs, electrolytes, and
creatinine. Daily weights are more easily and accurately assessed than urine output. *Assumes: (1) volume assessment with each step; (2)
monitoring of electrolytes, renal function, symptoms, and vital signs; (3) daily weights; and (4) urine output not often accurate or obtainable.
y Titrate progressively, according to the degree of hypervolemia, furosemide doses, and creatinine/kidney function. I.V., intravenous.

40. Outpatient diuretic management algorithm for patients with heart failure. At each decision, clinical assessment should
include an assessment of symptoms, volume assessment, and appropriate monitoring of vital signs, electrolytes, and
creatinine. Daily weights are more easily and accurately assessed than urine output. Reassess serum potassium and
creatinine 3-5 days after each diuretic dose change, earlier if concerned, other medication changes, or significant
volume changes. Lowest dose of a diuretic that allows for optimal symptoms is the ideal dose. Dose reductions or
increases should take into account previous response if known, and clinical scenario.

43. Furosemide urinary response tests tubular integrity.
TAL, thick ascending limb.
The effects of diuretic agents depend on the delivery of loop diuretics to their intraluminal
site of action (pharmacokinetics) and on the dynamics of interaction of the diuretic with
its receptor at the site of action (pharmacodynamics).

44. Patients with heart failure require a higher serum diuretic concentration to elicit the same diuretic response (diuretic
resistance) and have diminished responses to ceiling doses of loop diuretics. Providers should attempt to achieve a
diuretic concentration that is on the steep part of the dose-response sigmoidal relationship.
Higher doses required to
achieve same diuretic effect
Patients with heart failure typically
demonstrate a rightward and downward
shift of the sigmoid dose–response curve

52. If resistance to furosemide results or other factors (eg, a high salt meal) dictate that
more diuresis is needed, 1 of 2 strategies may be used: First is to administer a higher
dosage, as shown with the red pharmacodynamic curve. The increase in dosage
increases the urine level of the diuretic but provides only a small increase in time in the
effective range, enhancing diuresis (red arrow) but increasing risk for toxicity.
A better approach, although problematic in terms of owner compliance, is to administer
multiple doses throughout the day. As shown in this figure, administering the same
dosage 3 times triples the time in the effective range and avoids the risk for toxicity.

54. Standardized IV Diuretic Administration Protocol : Patients were assigned to 1 of 4
protocol groups based on their total daily dose of home oral diuretic (maintenance
dose).

57. JACC VOL. 69, NO. 19, 2017
Comparative Characteristics of Loop Diuretic Agents and Isolated ultrafiltration(UF)