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Diuretics
2011.10.19
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Introduction
 among the most commonly used drugs
 diminish sodium reabsorption at different sites in the nephron
→ increase urinary sodium and water losses
→ negative fluid balance
 in the treatment of edematous states(heart failure, cirrhosis, nephrotic
syndrome, renal failure), hypertension, electrolyte imbalance
mannitol
 Carbonic anhydrase inhibitor
(acetazolamide) in proximal
tubule
 Loop diuretics in thick
ascending limb of the loop of
Henle
 Thiazide-type diuretics in
distal tubule
 Potassium-sparing diuretics in
cortical collecting tubule
 Mannitol : osmotic diuresis
N Engl J Med 2009;361:2153-64
Acetazolamide
 Carbonic anhydrase : plays an important role in
proximal bicarbonate, sodium, and chloride
reabsorption
 Inhibits the activity of carbonic anhydrase
→ NaCl and NaHCO3 loss
 The net diuresis is relatively modest
 Most of the excess fluid delivered out of the proximal
tubule is reclaimed in the more distal segments
 The diuretic action is progressively attenuated by the
metabolic acidosis that results from the loss of
bicarbonate in the urine
 edematous patients with metabolic alkalosis,
hypercapnic chronic lung disease with metabolic
alkalosis
Harrison's Principles of Internal Medicine,
18th edition
Mannitol
 a nonreabsorbable sugar alcohol
 filtered by glomerulus but not reabsorbed by the proximal tubule
→ osmotic diuresis
 half-life : 1 to 36hr(may be retained in renal failure)
 preferential water diuresis
→ water defecit, Hypernatremia, plasma osmolarity ↑
 treatment of cerebral edema, elevated ICP
Loop diuretics
 the most potent diuretics
(lead to the excretion of up to 20~25% of filtered Na)
 furosemide, bumetanide, torsemide, ethacrynic
acid
(Sulfonamide derivatives except for ethacrynic acid)
 Inhibits the Na-K-2Cl cotransporter
(compete for the chloride site on this carrier)
 reabsorption of Ca in the loop of Henle
: passive, driven by the electrochemical gradient
created by NaCl transport, paracellular pathway
 → increase Ca excretion
: treatment of hypercalcemia
Harrison's Principles of Internal Medicine,
18th edition
Loop diuretics
 highly protein bound (≥95%)
→ limits the drug to the vascular space,
maximizes its rate of delivery to the kidney
: enter the tubular lumen by secretion in the proximal tubule, not by
glomerular filtration
 furosemide
: Bioavailability of oral preparetion is about 50%
(interpatient and intapatient variability, range 10~100%)
→ dose should be doubled for oral furosemide
※ vs. torsemide, bumetanide : 80~100%
 torsemide
: has a longer half-life
than both furosemide and bumetanide
Am J Physiol Renal Physiol 2003;284:F11–F21
Loop diuretics
 No diuresis seen until a threshold
rate of drug excretion is attained
: If a patient does not respond to
40mg of furosemide, the single
dose should be increased to 60 or
80mg, rather than giving the same
dose twice a day
N Engl J Med 1998;339:387-395
 Maximum effective dose (ceiling
dose)
: a plateau is reached in which
even higher doses produce no
further diuresis
Loop diuretics
 The maximum effective diuretic dose
is higher in patients with heart failure, cirrhosis, or renal failure
: d/t decreased renal perfusion (and therefore decreased drug delivery
to the kidney), diminished proximal secretion (d/t the retention of
competing anions in renal failure), renal vasoconstriction(cirrhosis), and
enhanced activity of sodium-retaining forces (such as the RAAS)
N Engl J Med 1998;339:387-395
Loop diuretics
 Diuresis-related
: hypokalemia, metabolic alkalosis, signs of decreased tissue perfusion
(hypotension, BUN↑, Cr↑, hyperuricemia, hyponatremia)
 Hypersensitivity reaction
 rash, acute interstitial nephritis(rarely)
 similar to those produced by other sulfonamide drugs
 Ototoxicity
 inhibition of an isoform of this cotransporter in the inner ear
 decreased hearing, tinnitus, deafness(may be permanent)
 occur with high-dose IV therapy
Refractory to loop diuretics
 High salt intake
: 24 hour urine Na > 100meq/day
→ adequate diuretic response & high salt intake
 Infusion with albumin
 administration of 40 to 80 mg of furosemide added to 6.25 to 12.5 g
of salt-poor albumin
 increasing diuretic delivery to the kidney by keeping furosemide
within the vascular space
 But, lack of efficacy..
 Posture : supine position
 Renal perfusion ↑ → urinary diuretic delivery ↑
 Upright position : increases in plasma norepinephrine, renin,
aldosterone
Infusion with albumin
60mg of furosemide + 200mL of a 20% albumin solution
a modest increase in sodium excretion
without an increase in the rate of furosemide excretion
J Am Soc Nephrol 2001;12:1010–1016
40mg of furosemide + 25g of albumin
not increase the rate of either furosemide or sodium excretion
Kidney Int 1999;55:629-34
Refractory to loop diuretics
 continuous infusion
 safer (less ototoxicity) and more effective than bolus injections
 maintenance of an effective rate of drug excretion
 bolus therapy results in higher initial serum concentrations and
higher initial rates of urinary diuretic excretion than a continuous
infusion
☞ continuous infusion should not be tried in patients who have not
responded to the maximum bolus doses
 Regimen
- renal insufficiency : initial furosemide infusion rate of 20mg/h, higher of 40 mg/h
- reasonable renal function : initial infusion rate of 5mg/h, higher of 10 mg/h
 The literature has reports of higher infusion rates of up to 240 mg/h
But, ototoxicity and other side effects
→ the addition of a thiazide-type diuretic or fluid removal via
ultrafltration
Diuretic tolerance
 a decrease in the response to a diuretic after the first dose
 Short-term tolerance
 initial reduction in extracellular fluid volume → decline in the drug
level in plasma and tubular fluid to below the diuretic threshold
 activation of the RAAS and the sympathetic nervous system
 Long-term tolerance (diuretic braking phenomenon)
 activation of the RAAS → circulating angiotensin II ↑ → promotes
increased proximal sodium reabsorption
 the up-regulation of sodium transporters downstream from the
primary site of diuretic action
 structural hypertrophy of distal nephron segments
 Sodium restriction, repeated or higher doses, combinations of diuretics
Thiazide diuretics
 hydrochlorothiazide, indapamide,
chlorothiazide, chlorothalidon, metolazone
 Inhibits the Na-Cl cotransporter
 smaller natriuretic effect than loop diuretics
(inhibit the reabsorption of 3~5% of filtered Na)
 First-line agents in the treatment of
hypertension
: proven to reduce cardiovascular mortality
and morbidity in systolic and diastolic forms
of hypertension
Harrison's Principles of Internal Medicine,
18th edition
Thiazide diuretics
 ineffective at GFR <30ml/min
 Metolazone
: efficacy in patients who have renal insufficiency
 The distal tubule is the major site of active Ca reabsorption
: thiazides increase the reabsorption of Ca
→ treatment of recurrent kidney stones d/t hypercalciuria
Potassium-sparing diuretics
 act in the principal cells in the cortical collecting
tubule
 amiloride, triamterene
: epithelial sodium-channel (ENaC) blocker
 spironolactone and eplerenone
: mineralocorticoid receptor
→ primary aldosteronism, heart failure, cirrhosis
 weak natriuretic activity
 hyperkalemia and metabolic acidosis
Harrison's Principles of Internal Medicine,
18th edition
Potassium-sparing diuretics
 Trimethoprim
: can act as a potassium-sparing diuretic when given in high doses
→ nephrotoxicity, hyperkalemia
 Eplerenone
: more selective for aldosterone
less endocrine side effects (eg, gynecomastia, menstrual abnormalities,
impotence, and decreased libido)
Treatment of edema
 Edema = a palpable swelling produced by expansion of the interstitial
fluid volume
 massive and generalized → anasarca
 heart failure, cirrhosis, and the nephrotic syndrome, renal failure as well
as local conditions (venous and lymphatic disease)
 When diuretics are administered,
the fluid that is lost initially comes from the intravascular space
→ venous pressure and capillary hydraulic pressure ↓
→ restoration of the plasma volume by the mobilization of edema fluid
into the vascular space
Treatment of edema
 In heart failure or nephrotic syndrome
: since most capillary beds are involved, the edema fluid can be
mobilized rapidly
→ removal of ≥ 2~3L of edema fluid in 24 hours
 But, cirrhosis - ascites and no peripheral edema
: the excess ascitic fluid can only be mobilized via the peritoneal
capillaries
→ 300~500mL/day is the maximum amount that can be mobilized by
most patients
 If the diuresis proceeds more rapidly,
the ascitic fluid will be unable to completely replenish the plasma
volume
→ resulting in azotemia and possible precipitation of the hepatorenal
syndrome
Treatment of edema
 In venous insufficiency, lymphedema, or ascites due to peritoneal
malignancy
“ fluid removal → reduction in venous and intracapillary pressure →
edema fluid to be mobilized and the plasma volume to be maintained ”
☞ not occurred
 So, diuretics should be used with caution and monitoring of the serum
creatinine monitored in such patients
 The mainstays of therapy of lower extremity edema d/t venous
insufficiency
: leg elevation
well-fitted, knee-high compression stockings
Use of diuretics in heart failure
 Evaluation and optimization of volume status
is an essential component of treatment in patients with HF
 In contrast to ACEi, beta blockers, and aldosterone antagonist,
limited outcomes data are available for diuretic therapy
 3 major manifestations of volume overload
: pulmonary congestion, pph edema, and elevated JVP
 combination of an oral loop diuretic and low sodium diet
Use of diuretics in heart failure
 IV administration of loop diuretics is generally required for acute
decompensation or severe disease
 decreased intestinal perfusion
 reduced intestinal motility
 mucosal edema
reduce the rate of diuretic absorption
 bolus vs. continuous infusion
high dose vs. low dose
< Diuretic Optimization Strategies Evaluation
(DOSE) trial >
 308 pts with acute decompensated heart
failure
 prospective, double-blind, randomized
trial
 bolus every 12 hours or continuous
infusion
 low dose (equivalent to the patient’s
previous oral dose) or high dose (2.5
times the previous oral dose)
Use of diuretics in heart failure
 Daily assessment of patient weight
- the most effective method for documenting effective diuresis
: use the same scale, performed at the same time each day (in the
morning, prior to eating, after voiding)
 decrease in intracardiac filling pressure induced by the diuresis
→ lower the cardiac output
→ reduced tissue perfusion
→ unexplained rise in serum Cr (reflects a reduction in GFR)
: worse prognosis
 IV furosemide in acute pulmonary edema
 venodilatory effect → cardiac filling pr ↓ → pulmonary congestion ↓
 renal production of PG ↑
Reference
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N Engl J Med 2009;361:2153-64
N Engl J Med 1998;339:387-395
Am J Physiol Renal Physiol 2003;284:F11-F21
N Engl J Med 2011;364:797-805
Crit Care Med 2008;36[Suppl.]:S89-S94
Clin J Am Soc Nephrol 2010;5:1893-1903
J Clin Hypertens 2011;13:639-643
J Am Soc Nephrol 2001;12:1010–1016
Kidney Int 1999;55:629-34
Korean J Med 2011;80:8-14
Harrison's Principles of Internal Medicine, 18th edition
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