2. Factors affecting the change in urinary flow seen during the administration of a diuretic:
• Mechanism of action
• Dose
• Kinetics of entry into the bloodstream
• Delivery to its site of action.
The maximal diuretic effect of these drugs is determined, largely by the transport protein and
nephron site of action.
diuretic
inhibit a transport pathway responsible for reabsorbing
…
loop 25% of the filtered sodium load
DCT 5–10%
mineralocorticoid
antagonists
3%
carbonic anhydrase
inhibitors
weakly natriuretic, due to adaptive changes in the
loop of Henle and DCT
3. Loop diuretics do not have a smooth dose-response curve.
Threshold and ceiling
the dose that produces the maximal
increase in fractional sodium
excretion.
Although increasing a diuretic dose above the ceiling
does not increase the maximal minute-natriuresis , it
often increases the net natriuresis by prolonging the
period during which the diuretic concentration exceeds
the threshold..
Toxicity ??
Minimum dose at which
diuresis/natriuresis will
occur.
detected by:
• ↑ UOP within 2–4 hrs of an oral dose.
• For hospitalized patients ↑ UOP during
the 6 hrs that follow a dose.
5. In normal individuals, the rate of furosemide absorption from the GI tract is not rapid, and a
reservoir of drug can persist long after the diuretic is administered .This reservoir makes the
effective t½ >> actual plasma t½ .
Absorption-limited kinetics “furosemide”
In certain edematous states:
• natriuretic threshold is increased by disease
• total bioavailability is typically maintained.
• GI absorption << elimination t½
• natriuresis may be impaired.
• Increase the dose.
• Shift to IV.
• switching to a different diuretic with better
absorption: torsemide/ bumetanide.
orally administered dose of furosemide can be
more effective than an equivalent single
intravenous dose in individuals with normal GI
absorption
6. – The differences in metabolic fate mean that the t ½ of
furosemide is prolonged in kidney failure, where
excretion is slowed.
– In contrast, the t ½ of torsemide and bumetanide tend to
be preserved in CKD .
– Although the ratio of equipotent doses of furosemide to-
bumetanide is 40:1 in normal individuals, that ratio
declines as kidney disfunction progresses .
Metabolism
Although this apparent increase in furosemide potency may seem beneficial, it
also likely increases the toxic potential of furosemide in the setting of AKI.
7. Loop and thiazide diuretics in very
advanced CKD
Reduced GFR limits the effect of a diuretic in patients with CKD, adaptive increases in
fluid delivery from the proximal tubule, together with transporter overexpression (both in
the loop of henle and the distal tubule), preserves diuretic response even in patients with
very advanced CKD.
Thiazide diuretics CKD 1-3 (metolazone all)
Loop CKD 1-5
8. • All diuretics are highly bound to albumin (95%). Low Vd maximizing its rate of delivery to the kidney
Add albumin?
A relatively recent meta-analysis concluded that the existing data, albeit of poor quality,
suggest transient effects of modest clinical significance (increase in sodium excretion) for
coadministration of albumin with furosemide in hypoalbuminemic patients
Furthermore, the increase in sodium excretion was roughly equivalent to the amount of
sodium contained in the colloid solution, suggesting that volume expansion was a likely
explanation for the enhanced natriuresis. Notably, no net sodium loss occurred.
Nevertheless, most recent studies have enrolled patients whose serum albumin concentrations
exceeded 2 g/dl, so that these considerations may not apply for severely hypoalbuminemic
patients.
9. • All diuretics are highly bound to albumin (95%). Low Vd maximizing its rate of delivery to the kidney
• Administering albumin and diuretics leads to a modest increase in mean daily urine volume and sodium
excretion in adults , However, the addition of albumin to furosemide at the same time has not been
shown to improve diuresis.
• in the nephrotic syndrome. a large fraction of the furosemide that enters the loop of Henle during
diuretic therapy remains bound to albumin and is, therefore, unable to inhibit Na-K-2Cl cotransport.
• Some guidelines continue to suggest that albumin infusion should be used as an adjunct to diuretics
when nephrotic patients appear to have vascular volume depletion
Add albumin?
10. – Deafness and tinnitus from loop diuretics was seen more frequently when very large bolus
doses of loop diuretics were used to forestall dialysis ,(1–3 g daily).
– The tendency of bolus infusion to lead to high peak furosemide concentrations is one reason
that many investigators recommend continuous infusions instead.
– renal failure, infants, patients with cirrhosis, and patients receiving aminoglycosides or cis-
platinum may be at increased risk.
Adverse events
Diuretic-related adverse events are typically dose dependent
11. – little or no benefit from giving two agents of the same class ………….. Shifting??
– When a second class of diuretic is added, the dose of loop diuretic should not be
altered, because the shape of the loop diuretic dose–response curve is not affected by
addition of other classes of diuretic.
– The combination of spironolactone and loop diuretics has not been shown to be
synergistic, but it is effective.
– thiazide diuretics added to loop diuretics are synergistic (the combination is more
effective than the sum of the effects of each drug alone).
Combination diuretic therapy
Thiazide diuretics absorption <<< loop diuretics absorption:
it is sensible to recommend that the distal convoluted tubule diuretic be taken 0.5–1 hour prior to the
loop diuretic, however, this suggestion has not been tested.
12. – oral metolazone has long t ½ (6- 20 hrs) post diuretic NaCl retention may
be attenuated
– For outpatients requiring combined therapy, one approach is to add a
modest dose of metolazone, 2.5–5 mg/day, for 3 days only.
natriuresis and diuresis continued even after metolazone was
discontinued during the fixed regimen.
short fixed-dose course metolazone
13. Diuretic resistance
normal
No/minimal response Short response
UOP
Time
• Increase frequency
• Use continuous infusion
• Use longer acting
diuretic:
Torsemide
Metolazone
chlorthialidone
• Poor absorption
• ↓ GFR
• ↓ effective blood volume
• proteinuria
NS, CHF, Ascites
CKD, AKI
Increase dose
16. • there is no reason to introduce a second daily dose of the same diuretic if the
first dose doesn’t give response (i.e; not exceed the threshold).
• diuretic dose above the ceiling does: no increase the natriuresis rate , but
increases the net natriuresis and Toxicity may be increased.
Furosemide is generally slowly absorbed:
• In outpatients / responsive individuals with normal GI absorption :
use oral furosemide instead of equivalent single IV dose
• In hospitalized patients/ decreased GI absorption: increase the
dose, use IV furosemide or shift to torsemide / bumetanide .
17. • Thiazide diuretics are used in CKD 1-3 (metolazone in all
stages).
• Loop diuretics are used in CKD 1-5.
• Hypoalbuminemia decrease diuretics delivery to kidney.
• Albumin administration results in transient effect of modest
clinical significance, no need to administer it at the same time
with the diuretic.
• Diuretic-related adverse events are typically dose dependent
18. • Don’t combine diuretics of the same class , you can switch .
• Combination of loop with potassium sparing are effective and reduce the
hypokalemia.
• Combination of loop with thiazides are synergistic.
Metolazone has long t ½ and prolonged diuresis and natriuresis new approach
for combination therapy : short fixed-dose course (3 days of 2.5-5 mg /d).
For diuretic resistance:
• Increase dose / frequency / combine with thiazides or potassium sparing
diuretics.
• Salt restriction/ compliance.
Editor's Notes
loop diuretics have a higher ‘ceiling’ action than DCT diuretics. This observation results from the fact that loop diuretics
inhibit a transport pathway responsible for reabsorbing up to 25% of the filtered sodium load, while DCT diuretics inhibit a pathway responsible for reabsorbing only 5–10%. Similarly, mineralocorticoid antagonists have a mild natriuretic effect due to the fact that
they suppress a pathway responsible for reabsorbing only 3% of the
filtered Na load.
There are, of course, exceptions to this rule. The
carbonic anhydrase inhibitors, which reduce proximal tubule reabsorption
are only weakly natriuretic, due to adaptive changes in the
loop of Henle and DCT
Within classes, drugs vary in potency ,
For example, alower dose of bumetanide is required to elicit the same effect as
furosemide, even though the maximal natriuretic effect of each is
similar.
This means a patient not responding to 40mg furosemide should have the dose, rather than frequency dosing, increased (to 80mg once daily, rather than 40mg twice daily).
Although loop diuretics are typically administered twice daily, there is no reason to introduce a second daily dose if the first dose does not exceed the threshold. Once a threshold has been reached, however, most patients will require two daily doses. Although dose recomm
Loop diuretics are absorbed relatively quickly after oral administration , reaching peak concentrations within 0.5–2 hours
when administered intravenously, their effects are nearly instantaneous.
On the basis of oral bioavailability, when a patient is switched from intravenous to oral loop diuretic, the dose of bumetanide or torsemide should be maintained, whereas the dose of furosemide should be doubled (7); in practice, however, and as discussed further below, other factors affect diuretic efficacy, and a fixed intravenous/oral conversion cannot be given (8).
the half-life of bumetanide remains shorter, leaving more time for post-diuretic NaCl retention, when it is administered as a bolus; once again, torsemide has the longest half-life and the most favourable pharmacokinetic profile. Based on these differences, there seems little rational basis to switch from furosemide to bumetanide when given intravenously, although torsemide may still be more effective. Many smaller trials have suggested benefits of continuous infusions.
Based purely
on pharmacokinetic parameters, torsemide’s diuretic profile should
make it the most effective among the three; unfortunately, the data
to support this speculation are limited.
Although the t1/2 of furosemide is short, its duration of action is longer when administered orally, as its gastrointestinal absorption may be slower than its elimination t1/2. This is a phenomenon called “absorption-limited kinetics” This is not the case for bumetanide and torsemide, where oral absorption is rapid
……..
, however, absorption from the gut may be slowed, so that furosemide absorption never reaches the diuretic threshold, rendering it ineffective
This is likely to explain the common observation that intravenous doses of loop diuretics, which achieve higher peak levels, may be effective when oral doses lose their effectiveness, especially if the natriuretic threshold is increased.
To compensate for this, giving a high dose of the drug, or
switching to a different diuretic with better absorption, such as
torsemide or bumetanide, may facilitate a brisker diuresis (Murray
et al., 2001). Another approach is to switch to an intravenous loop
diuretic preparation, which is, of course, 100% bioavailable
Approximately 50% of an administered furosemide dose is excreted unchanged into the urine. The remainder appears to be eliminated by glucuronidation, predominantly also in the kidney.
Torsemide and bumetanide are eliminated both by hepatic processes and urinary excretion, although hepatic metabolism may predominate, especially for torsemide (24).
Patients with a GFR of ∼15 ml/min/1.73 m2 secrete only 10–20% of the amount of loop diuretic that is secreted into tubular fluid in similarly dosed patients with a normal GFR.14,15 Thus, in patients with advanced CKD, an increased diuretic dose must be given to ensure delivery of tubular fluid sufficient to elicit a diuretic response. In so doing, the response is then similar to what is observed in healthy volunteers, unless patients with CKD have a tendency to retain Na+, as might be the case if the patient also has heart failure or the nephrotic syndrome.
All the commonly used diuretics are highly protein-bound. This limits the diuretic to the vascular space, thereby maximizing its rate of delivery to the kidney. The degree of protein-binding is reduced with hypoalbuminemia, resulting in a larger extravascular space of distribution and a slower rate of delivery to the kidney
hypoalbuminemia, resulting in a larger extravascular space of distribution and a slower rate of delivery to the kidney
…………………………………….
compared with their efficacy in some oedematous disorders; loop diuretics are less capable of
provoking a natriuresis
….
Infusion with albumin — Infusion of the furosemide-albumin complex is thought to increase diuretic delivery to the kidney by keeping furosemide within the vascular space. In an initial report, this approach led to a substantial increase in sodium excretion in some patients .
However, a subsequent study in patients with nephrotic syndrome (mean plasma albumin 3.0 g/dL) found that a mixture of loop diuretic and albumin produced only a modest increase in sodium excretion compared with furosemide alone without an increase in the rate of furosemide excretion [27]. Furthermore, the increase in sodium excretion was roughly equivalent to the amount of sodium contained in the colloid solution, suggesting that volume expansion was a likely explanation for the enhanced natriuresis. Notably, no net sodium loss occurred.
A similar lack of efficacy of furosemide plus albumin infusion has been demonstrated in hypoalbuminemic patients with cirrhosis (mean plasma albumin 3.0 g/dL) [28]. Compared with furosemide alone, combination therapy did not increase the rate of either furosemide or sodium excretion.
All the commonly used diuretics are highly protein-bound. This limits the diuretic to the vascular space, thereby maximizing its rate of delivery to the kidney. The degree of protein-binding is reduced with hypoalbuminemia, resulting in a larger extravascular space of distribution and a slower rate of delivery to the kidney
hypoalbuminemia, resulting in a larger extravascular space of distribution and a slower rate of delivery to the kidney
…………………………………….
compared with their efficacy in some oedematous disorders; loop diuretics are less capable of
provoking a natriuresis
….
Infusion with albumin — Infusion of the furosemide-albumin complex is thought to increase diuretic delivery to the kidney by keeping furosemide within the vascular space. In an initial report, this approach led to a substantial increase in sodium excretion in some patients .
However, a subsequent study in patients with nephrotic syndrome (mean plasma albumin 3.0 g/dL) found that a mixture of loop diuretic and albumin produced only a modest increase in sodium excretion compared with furosemide alone without an increase in the rate of furosemide excretion [27]. Furthermore, the increase in sodium excretion was roughly equivalent to the amount of sodium contained in the colloid solution, suggesting that volume expansion was a likely explanation for the enhanced natriuresis. Notably, no net sodium loss occurred.
A similar lack of efficacy of furosemide plus albumin infusion has been demonstrated in hypoalbuminemic patients with cirrhosis (mean plasma albumin 3.0 g/dL) [28]. Compared with furosemide alone, combination therapy did not increase the rate of either furosemide or sodium excretion.
, the half-life of bumetanide remains shorter, leaving more time for post-diuretic NaCl retention, when it is administered as a bolus; once again, torsemide has the longest half-life and the most favourable pharmacokinetic profile. Based on these differences, there seems little rational basis to switch from furosemide to bumetanide when given intravenously, although torsemide may still be more effective. Many smaller trials have suggested benefits of continuous infusions.
differences in the rate of diuretic absorption and the gain from one diuretic being delivered to the tubules in a more efficient manner than another diuretic
, but can prevent hypokalaemia,while maintaining renal Na+ excretion.
an approach to combination therapy may be a short fixed-dose course. Comparison was made of adding a thiazide-type diuretic to furosemide for either a fixed 3-day period or adjusting the dose to achieve targeted volume losses during 5–7 days. Both regimens were equally effective in reducing ECF volume and symptoms.