Diuretics R3 주혜영

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

N Engl J Med 2009;361:  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 mannitol

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 Harrison's Principles of Internal Medicine, 18th edition  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

 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 Loop diuretics 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  Maximum effective dose (ceiling dose) : a plateau is reached in which even higher doses produce no further diuresis N Engl J Med 1998;339:

 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) Loop diuretics N Engl J Med 1998;339:

 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 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 Refractory to loop diuretics

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 40mg of furosemide + 25g of albumin not increase the rate of either furosemide or sodium excretion J Am Soc Nephrol 2001;12:1010–1016 Kidney Int 1999;55:629-34

 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 Refractory to loop diuretics

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 Harrison's Principles of Internal Medicine, 18th edition  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

 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 Thiazide diuretics

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

 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) Potassium-sparing diuretics

 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

 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 Treatment of edema

 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 Use of diuretics in heart failure

 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)

 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 ↑ Use of diuretics in heart failure

Reference  N Engl J Med 2009;361:  N Engl J Med 1998;339:  Am J Physiol Renal Physiol 2003;284:F11-F21  N Engl J Med 2011;364:  Crit Care Med 2008;36[Suppl.]:S89-S94  Clin J Am Soc Nephrol 2010;5:  J Clin Hypertens 2011;13:  J Am Soc Nephrol 2001;12:1010–1016  Kidney Int 1999;55:  Korean J Med 2011;80:8-14  Harrison's Principles of Internal Medicine, 18th edition 