DIURETIC THERAPY For PATIENT

WITH HEART FAILURE

JACC State-of-the-Art Review

G. Michael Felker, MD,MHS, David H. Ellison, MD, Wilfried Mullens, MD, PH, Zachary L.Cox, PharmD. Jeffrey M.Testani, MD, MTR
OVERVIEW
Expansion of extracellular fluid volume is
central to the pathophysiology of heart failure

Elevated intracardiac filling pressures,

resulting congestion

Loop diuretics are one of the cornerstones

of treatments for heart failure
RENAL PHYSIOLOGY AND DIURETIC RESPONSE
 Glomerulus and Proximal Tubules
- Glomerular filtration rate (GFR) is determined by the number of functional
glomeruli as well as hydrostatic and colloid osmotic pressure difference
between glomerular capillaries and Bowman’s Space (starling forces)
- Factor can impair GFR: Fewer Functionally active glomeruli, increased
central venous pressure, increased neurohumoral activation contributes to
low renal blood flow
- In addition, Increased intra abdominal pressure  reduced capacitance of the
splanchnic vasculature  abdomimnal congestion  intravascular fulling
insufficient  aggressive decongestive therapy contribute for deterioration of
GFR
- Changes in Hydrostatic and osmotic pressure in the renal interstition and
peritubular capillaries will determined Na and water reabsorption.
- HF facilitates Na and water reabsorption proximaly as consequence of
decreased RBF: increased filtration fraction, passive Na reabsorption as
peritubular capillaries oncotic pressure is high (protein is high), Angiotensin II
as important signal for proximal Na reabsorption
 Loop Of Henle
-One third of filtered volume reaches the loop of henle which plays an important
role in essential subtract concentration of urine , removing more nacl than water
from tubular fluid
-In HF, Natriuresis and maximal free water excretion are decreased
 Macula Densa
-Renal blood flow and GFR autoregulated by 3 major mechanism: the myogenic
response, the macula densa tubuloglomerular feedback response, and renin
secretion.
 Distal convoluted tubule and collecting duct
-The distal fractional Na reabsorption will determine the final urinary Na
concentration and osmolality.
-Reabsorption depends on the tubular flow rate and aldosterone and arginine
vasopressin (AVP) levels
-Insertion of aquaporin channels, expressed when AVP is high, promotes water
absorption
DIURETIC PHARMACOLOGY AND PHARMACODYNAMICS

 4 steps diuretic action effectiveness

a.Ingestion and Gastrointestinal absorption
b.Delivery to kidney
c.Secretion into the tubule lumen
d.Binding to the transport protein
 Gastrointestinal Absorption of Diuretic Agents
-Furosemide’s absorption is slower than its elimination half-life, a
phenomenon called “absorption-limited” or “flip-flop” kinetics
-Diuretics agent have steeps dose response curves minimal
effects until the threshold is reached the response will rapidly
approaches maximum Ceiling
-Once the ceiling is reached, the increasing diuretics dose will not
increase the maximal rate of natriuresis but increasing a dose above
the ceiling will have an additional natriuretic effect because higher
dose will maintain serum diuretic concentrations above the threshold
for longer time
-Gastrointestinal absorption of any loop diuretic agent may be
altered during exacerbations of HF ADHF
-The IV dose achieve higher peak levels, compared to oral dose,
especially if the natriuretic threshold is increased.
 Diuretic Secretion Into Tubule Lumen
-Loop diuretic agents exert their natriuretic actions primarily by
binding to NKCC along the luminal membrane of thick ascending limb
cells.
-Loop diuretic bound to proteins (Albumin) to preventing delivery to
tubule lumen by glomerular filtration
-To access to the tubular fluid where the site of activity, they must be
secreted across the proximal tubule through Peritubular capillaries
-Inhibit diuretics Eficacy: Frequent use of NSAIDs and CKD
 Volume of distribution, metabolism, and Half-lives
-Loop diuretics agents bound to albumin (>90%), the volumes of
distribution are low (in plasma higher than in tissue distribution)
except during extreme Hypoalbuminemia
-There is toxic potential of furosemide in the setting of AKI:
Deafness and tinnitus from loop diuretic agents appear to result
primarily from high serum concentrations, which inhibit the NKCC
isoform (NKCC-1) in the ear
-The initial natriuresis will dicreased within 3-6 hours, single daily
dose will allows some 16-21 hours for the kidneys to reverse salt and
water losses
 Diuretics Adaptations and Nephron Remodeling
-Feature of diuretic action that complicates their effectiveness
derives from the structure of the nephron
- Loop diuretics primarily inhibit NaCl reabsorption along the thick
ascending limb
-The net salt excretion reflects a balance between inhibition of
reabsorption along the ascending limb and the stimulation of
reabsorption distally
-Loop diuretics agent greatly increase the luminal NaCl
concentration in distal convoluted tubule (distal to ascending limb)
that stimulates NaCl reabsorption distaly
-Therefore, chronic diuretics treatment greatly increases the capacity
of distal nephron to reabsorb delivered NaCl secondary decline in
natriuresis  “Braking phenomenon”
 Nephron remodeling : hypertrophy of the distal convoluted tubule,
connecting tubule, and collecting duct
a. Renin Angiotensin Aldosterone System: during chronic furosemide
infusion aldosterone is mediates NaCl transport and activates
epithelial sodium cahnnel
b. Increased luminal solute and fluid delivery to distal segments,
which increases transepithelial solute flux and obligates new
protein synthesis
c. Systemic metabolic effects, including metabolic alkalosis
LOOP DIURETICS DURING HOSPITALIZATION FOR HF
The DOSE Study
This study randomized 308 patients
hospitalized with HF and signs and
symptoms of congestion using a 2 x 2
factorial design.

a. Higher dose furosemide therapy (2,5

times the daily dose) preferable to lower
dose.

b. Either continuous infusion of furosemide

therapy or intermittent boluses are
preferable
Regarding to the larger DOSE study there
were no differences observed in clinical end
points for the comparison between
continuous infusion and intermittent or
boluses loop diuretic
 DIURETICS RESISTANCE

diuretic resistance can be described as an

inadequate rate/quantity of natriuresis despite Intra-renal
Pre-renal an adequate diuretic regimen
Strategies to Overcome Diuretic Resistance
- The strategies Goals are relieve signs and symptoms of congestion
and achieve a net negative sodium balance
- There are two strategies either maximizing loop diuretics or
combining diuretics therapy most experts recommended delaying
combination therapy until the loop diuretic dose is optimized
- The parameter of loop diuretic adequacy is by evaluating urine output
and urinary sodium
- If congestion is persistent despite adequate doses of loop diuretic
agents, sequential nephron blockade with a thiazide (or thiazide-like
agent) is the first line adjunct combination
- Finally, a variety of other adjuncts to diuretic agents have been
evaluated in patients with or at risk for diuretic resistance, including
lowdose dopamine, low-dose nesiritide, and vasopressin antagonists
such as tolvaptan
- Low-dose dopamine did not show a clinical benefit in the ROSE-AHF
study, subgroup analysis did suggest the possibility of benefit in
patients with low ejection fraction
- The sodium-glucose cotransporter 2 inhibitors (SGLT-2i) have
diuretic effects and have improved outcomes in a recent clinical trial
in chronic HF
 LOOP DIURETICS USE IN CHRONIC HF
- Most patient with chronic HF require maintenance dose of loop
diuretic agent to maintain euvolemia and clinical stability
- Loop diuretics are recommend to use twice daily because loop
diuretics agent (furosemide and bumetanide) are short acting (<3 h)
 minimize periods where the concentration in the tubular fluid
declines below a therapeutic level, which may produce post-diuretic
sodium retention
- Withdrawal of diuretics agents  RCT studies shown that withdrawal
of loop diuretic agents was not associated with worsening symptoms
or the need to reinstitute diuretic therapy compared with continuation
of diuretic agents
TERIMAKASIH