Diuretics ppt

Highlighting pharmacokinetics and pharmacodynamics, use of diuretics in specific clinical setting, relevant clinical trials

1. DIURETICS USE IN KIDNEY DISEASES

2. TOPICS OF DISCUSSION

3. INTRODUCTION Proximal Convoluted Tubule Diuretics Osmotic Diuretics : Mannitol, Urea, Glycerol Carbonic Anhydrase Inhibitors : Acetazolamide Loop Diuretics Furosemide, Bumetanide, Ethacrynic Acid, Torsemide Distal Convoluted Tubule Diuretics Thiazides : Benzthiazide , Chlorthiazide , Hydrochlorothiazide Thiazide like : Metolazone , Indapamide , Chlorthalidone Collecting Duct Diuretics ( K + sparing diuretics ) Aldosterone Antagonist : Spironolactone Non-aldosterone Antagonist : Triamterene, Amiloride

4. Key Concepts Absorption-limited kinetics 1 : Oral administration : Bioavailability of furosemide is 50% Longer duration of action : Gastrointestinal absorption may be slower than its elimination t1/2 Dose to be doubled when switched : IV  Oral Dose Response Curve: Natriuretic response plotted versus the log of the plasma diuretic conc Loop diuretics – “ Steep Curve ” Understanding has clinical relevance in optimal use 1. Hammarlund MM, Paalzow LK, Odlind B: Pharmacokinetics of furosemide in man after intravenous and oral administration. Application of moment analysis. Eur J Clin Pharmacol 26: 197–207, 1984

5. Key Concepts Threshold: No effect below a given plasma concentration Most common errors in diuretic usage “ Doubling the dose” Ceiling: Failing to elicit more natriuresis beyond this plasma conc ECF volume expansion & edema : Altered pharmacokinetics GI Absorption can be slowed in states of heart failure exacerbations 1 IV drug may attain higher peak levels and may be more effective even when oral dose gives no response Correct approach:? Volume of distribution : Loop diuretics: organic anions - bound to albumin (95%)- Low volume of distribution Severe hypoalbuminemia: Impair diuretic effectiveness by reduced delivery Coadministration of albumin with furosemide in hypoalbuminemic patients 2 1. Vasko MR, Cartwright DB, Knochel JP, Nixon JV, Brater DC: Furosemide absorption altered in decompensated congestive heart failure. Ann Intern Med102: 314–318, 1985 2. Kitsios GD, Mascari P, Ettunsi R, Gray AW: Co-administration of furosemide with albumin for overcoming diuretic resistance in patients with hypoalbuminemia: A meta-analysis. J Crit Care 29: 253–259, 2014

6. Dose response Curve AKI : Increased ototoxicity of loop diuretics –” High serum concentration” Inhibition of Na-K-2Cl isoform transport protein- expressed by the stria vascularis and participates in secretion of potassium-rich endolymph 1 Drugs interfering with diuretic response : NSAID’s – Heart failure exacerbations 2 CKD : Furosemide-prolonged t1/2 ( torsemide/bumetanide- preserved ) Delpire E, Lu J, England R, Dull C, Thorne T: Deafness and imbalance associated with inactivation of the secretory Na-K-2Cl co-transporter. Nat Genet 22: 192–195, 1999 Heerdink ER, Leufkens HG, Herings RM, Ottervanger JP, Stricker BHC, Bakker A: NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics. Arch Intern Med158: 1108–1112, 1998

7. Post diuretic NaCl retention: Urinary NaCl excretion declines below the baseline when the diuretic effect wears off 1 Recommendation to use loop diuretics twice daily Physiologic basis of use of continued infusion Vs high dose bolus administration 2 Braking phenomenon: Natriuresis wanes as ECF declines At steady state, the individual returns to NaCl balance, during which urinary NaCl excretion is equal to dietary NaCl intake once again Ellison DH, FelkerGM:Diuretic treatment inheart failure. Nengl J Med377: 1964–1975, 2017 Salvador DR, Rey NR, Ramos GC, Punzalan FE: Continuous infusion versus bolus injection of loop diuretics in congestive heart failure. Cochrane Database Syst Rev (3): CD003178, 2005 After a diuretic is started, urinary sodium excretion rises by shifting to a new curve (from point 1 to point 2) Braking phenomenon: urinary sodium excretion declines back to the baseline level, but at a new and reduced ECF volume Action: Hypertrophy of cells downstream from where loop diuretics exert their action, particularly in the DCT

8. CJASN 14: 1248–1257, 2019. doi: https://doi.org/10.2215/CJN.09630818

9. SPECIFIC SYNDROMES

10. NEPHROTIC SYNDROME Renal albumin losses and reduced hepatic synthesis in the nephrotic syndrome eventually lead to hypoalbuminemia Hypoalbuminemia reduces the binding of furosemide to plasma proteins and thereby enlarges its volume of distribution 1 2 studies have shown that patients with a serum albumin level of 2 g/dL can deliver normal quantities of furosemide into the urine 2 Albumin infusion into nephrotic patients increased renal furosemide excretion, whereas hypoalbuminemia enhances its metabolic clearance Agarwal et al 3 found that displacing furosemide from albumin via coadministration of sulfisoxazole did not affect natriuresis in nephrotic syndrome Akcicek F, Yalniz T, Basci A, et al: Diuretic effect of frusemide in patients with nephrotic syndrome: is it potentiated by intravenous albumin? [see comments]. Br Med J 310:162–163, 1995 Keller E, Hoppe- Seyler G, Schollmeyer P: Disposition and diuretic effect of furosemide in the nephrotic syndrome. Clin Pharmacol Ther 32:442–449, 1982 Agarwal R, Gorski JC, Sundblad K, et al: Urinary protein binding does not affect response to furosemide in patients with nephrotic syndrome. J Am Soc Nephrol 11:1100–1105, 2000

11. Role of Diuretics -Albumin infusion In patients with hypoalbuminemia, it is thought that infusion of furosemide-albumin complex increases diuretic delivery to the kidney by keeping the drug within the vascular space Filser et al ; i n patients with nephrotic syndrome (mean S. albumin 3.0g/dl) found that combination therapy produced only a modest increase in Na excretion Fliser D et al. Kidney Int 1999 A similar lack of efficacy was demonstrated in hypoalbuminemic patients with cirrhosis (mean S. albumin 3.0g/dl) Chalasani N et al. JASN 2001 Infusion of furosemide or other loop diuretic plus albumin - effective in patients with refractory edema and severe hypoalbuminemia (Albumin < 2.0g/dl )

12. Diuretic response is suboptimal in some patients with hypoalbuminemia despite the use of high doses Blunted response : Low intravascular volume with activation of neurohumoral and RAAS 16 children with nephrotic syndrome and refractory edema in a randomized cross-over trial to receive either combination therapy or furosemide alone. Urine output, urinary sodium, urinary chloride, urinary potassium, urinary osmolality, urinary osmolal and free water clearances were measured 3, 6, 12, and 24 h after infusions The results from this study suggest a short-term positive effect of the combination therapy on diuresis and natriuresis

13. Diuretics in AKI Convert oliguric to nonoliguric AKI Review of 11 randomized trials of loop diuretics or mannitol for prophylaxis or treatment of established AKI found no benefit 1 The Fluid and Catheter Treatment Trial : 2 Multicenter trial of a fluid-restrictive management strategy for the treatment of acute lung injury comparing treatment strategies in patients with ARDS Fluid-management strategies in patients with ALI, randomizing 1000 ventilated patients in a either conservative or liberal fluid management with CVP monitoring Post hoc analysis of patients with AKI :suggested that patients randomly assigned to lower central venous pressure (CVP) targets exhibited lower mortality Smirnakis KV, Yu AS: Diuretics in acute renal failure. In Brady HR, Wilcox CS, editors: Therapy in nephrology and hypertension, ed 2, Philadelphia, 2003, Saunders Inc, pp 33–37 Stewart RM, Park PK, Hunt JP, et al: Less is more: improved outcomes in surgical patients with conservative fluid administration and central venous catheter monitoring. J Am Coll Surg 208:725– 735, discussion 735–727, 2009

14. In this trial only patients developing AKI within 2 days on-study were included (n = 306) Primary outcome : 60-day mortality after randomization Association of post-AKI mean fluid balance and furosemide dose with 60-day mortality

15. Participants with AKI assigned to the fluid-conservative group received more furosemide (80 mg/d versus 23 mg/d in the fluid-liberal group, P < 0.001) Mean cumulative dose of furosemide over the study period was 562 mg in the restrictive strategy group and 159 mg in the liberal strategy group (P < 0.001) Higher mean furosemide dose was negatively associated with mortality Post-AKI furosemide use had a protective effect on 60-day mortality, except when adjusted for fluid balance

16. PICARD STUDY GROUP : AKI in critically ill patients ( n =552) Diuretics were used in almost 60% of the patients STUDY : Propensity score–adjusted analysis in this population showed that diuretic use was associated significantly with in-hospital mortality and nonrecovery of renal function (odds ratio, 1.77; 95% confidence interval, 1.14-2.76) 1. Mehta RL, Pascual MT, Soroko S, Chertow GM; PICARD Study Group. Diuretics, mortality, and nonrecovery of renal function in acute renal failure. JAMA. 2002;288:2547-53.

17. Loop diuretics :Increase the risk of cast formation in crush syndrome by acidifying the urine 1 and worsen already existing hypocalcemia by inducing hypercalciuria Recommend : Do not use loop diuretics routinely for prevention or treatment of AKI 2 Better OS, Stein JH. Early management of shock and prophylaxis of acute renal failure in traumatic rhabdomyolysis. N Engl J Med 1990; 322: 825–829 KDIGO Acute Kidney Injury Work Group. KDIGO Clinical Practice Guidelines for Acute Kidney Injury. Kidney Intl 2012; 2[Suppl]: 1–138

18. Meta-analysis by Ho et al 1 included six studies that used furosemide to treat AKI, with doses ranging from 600 to 3,400 mg/day showed that furosemide, when used as a preventive or therapeutic drug in AKI, did not reduce the risk of requiring renal replacement therapy (P = .73) or hospital mortality (P=0.23) Sampath et al 2 performed Bayesian evidence synthesis to quantify the therapeutic efficacy of loop diuretics in AKI Loop diuretics were not associated with improved survival benefit Did show a reduction in the duration of oliguria and a trend toward reduction in the need for renal replacement therapy with diuretic Ho KM, Power BM. Benefits and risks of furosemide in acute kidney injury. Anaesthesia . 2010;65:283-93 Sampath S, Moran JL, Graham PL, Rockliff S, Bersten AD, Abrams KR. The efficacy of loop diuretics in acute renal failure: assessment using Bayesian evidence synthesis techniques. Crit Care Med. 2007;35:2516-24.

19. Diuretics in AKI 20 RCT ( 2608 patients : 1330 in the Rx arm and 1278 in control arm) 7 studies on AKI prevention and 13 studies AKI treatment with Lasix Furosemide had neither an impact on mortality (OR = 1.015; 95% CI 0.825–1.339) No impact on the need for RRT (OR = 0.947; 95% CI 0.521–1.721) 1. Joannidis M, Druml W, Forni LG, et al. Prevention of acute kidney injury and protection of renal function in the intensive care unit: update 2017: expert opinion of the Working Group on Prevention, AKI section, European Society of Intensive Care Medicine. Intensive Care Med. 2017;43(6):730–49

20. Diuretics in AKI Diuretics are not recommended to treat AKI per se but are suggested to treat volume overload 1 1. Joannidis M, Druml W, Forni LG, et al. Prevention of acute kidney injury and protection of renal function in the intensive care unit: update 2017: expert opinion of the Working Group on Prevention, AKI section, European Society of Intensive Care Medicine. Intensive Care Med. 2017;43(6):730–49

21. CHRONIC KIDNEY DISEASE Reduced fractional reabsorption of NaCl and fluid by the renal tubules proportionate to the fall in GFR Maximal increase in fractional excretion of Na+ by furosemide is maintained quite well in CKD , however shows blunted absolute response Rightward shift in the curve : Impaired secretion Epidemiologic studies: Diuretic use with CKD Diuretic use in presence of residual renal function was associated with lower interdialytic weight gain, less hyperkalemia, and lower cardiac-specific mortality 1 1. Bragg-Gresham JL, Fissell RB, Mason NA, et al: Diuretic use, residual renal function, and mortality among hemodialysis patients in the Dialysis Outcomes and Practice Pattern Study (DOPPS). Am J Kidney Dis 49:426–431, 2007

22. Choice of diuretic - RENAL INSUFFICIENCY Loop diuretic - generally diuretic of choice Thiazide -type diuretic Initiate diuresis in patients with mild renal insufficiency Response in patients with GFR of <50 ml/min/1.73 m2 - lesser wrt loop diuretic Higher doses required in renal insufficiency than in those with normal renal function Even if correctly dosed for the level of renal function, use is limited Low potency Flat dose–response curve

23. Choice of diuretic - CKD

24. CEILING DOSES OF COMMON LOOP DIURETICS

25. Hemodialysis-Diuretics and RRF In the CHOICE study 1 , ( n=734) preserved residual renal function at 1 year was independently associated with lower all-cause mortality and better quality of life Diuretics- beneficial in HD patients to decrease IDWG Lower UF rates lead to fewer episodes of intradialytic hypotension, also known to predict mortality , cardiovascular events and preservation of RRF 2 Shafi T, Jaar BG, Plantinga LC, Fink NE, Sadler JH, Parekh RS, et al.: Association of residual urine output with mortality, quality of life, and inflammation in incident hemodialysis patients: the Choices for Healthy Outcomes in Caring for End-Stage Renal Disease (CHOICE) Study. Am J Kidney Dis 56(2):348–358, 2010 Flythe JE, Xue H, Lynch KE, Curhan GC, Brunelli SM: Association of mortality risk with various definitions of intradialytic hypotension. J Am Soc Nephrol 26(3):724–734, 2015

26. Diuretic use was investigated in 16,420 hemodialysis patients from the Dialysis Outcomes and Practice Patterns Study, a prospective observational study of hemodialysis Diuretic use was associated with lower interdialytic weight gain and lower odds of hyperkalemia (potassium > 6.0 mmol/L). Patients administered diuretics also had a lower risk of hypotensive episodes while on dialysis Patients with RRF on diuretic therapy had almost twice the odds of retaining RRF after 1 year in the study versus patients not on diuretic therapy

27. Diuretic use was investigated in 16,420 hemodialysis patients from the Dialysis Outcomes and Practice Patterns Study, a prospective observational study of hemodialysis Patients administered diuretics had a 7% lower all-cause mortality risk (P = 0.12) and 14% lower cardiac-specific mortality risk (P= 0.03) versus patients not administered diuretics

28. Peritoneal dialysis : RRF and Diuretics Medcalf et al 1 demonstrated the efficacy of 250 mg furosemide daily in 60 PD patients over a 1-year period compared with control, with mean daily urine volume in the furosemide group higher than that in the control group at 6 months and 12 months C(Urea) declined at a constant rate and were unaffected by diuretic administration Furosemide has no effect on preserving residual renal function. Oldan et al 2 studied the effect of high-dose furosemide in seven PD patients who still had residual urine. High-dose furosemide increased urine volume about 400 mL/day and increased the urinary sodium excretion 54 mmol/day but did not affect the filtration rate of the kidneys, urea clearance, creatinine clearance, and peritoneal water and solute clearance. Medcalf JF, Harris KP, Walls J. Role of diuretics in the preservation of residual renal function in patients on continuous ambulatory peritoneal dialysis. Kidney Int 2001;59:1128-1133. van Olden RW, Guchelaar HJ, Struijk DG, Krediet RT, Arisz L. Acute effects of high-dose furosemide on residual renal function in CAPD patients.  Perit Dial Int 2003;23:339-347.

29. CARDIORENAL SYNDROME

30. DOSE TRIAL 2011 Acute decompensated HF : How do continuous vs. intermittent and low- vs. high-dose IV loop diuretics compare in symptom improvement and impairment of renal function at 72 hours? Multicenter, randomized, double-blind, intention to treat, comparative trial Design : N=308 Bolus (n=156) vs. Continuous (n=152) Low-dose (n=151) vs. high-dose (n=157) Follow up : 60 Days Primary Outcome : Global assessment of symptoms from baseline to 72 hours Change in creatinine from baseline to 72 hours Interventions: Low dose bolus/infusion( Home dose of diuretic  iv) High dose bolus/Infusion (2.5x home dose of diuretic  IV

31. 9/22/2019 32

32. Results : Bolus with continuous infusion , There was NO significant difference in patients’ global assessment of symptoms (mean AUC, 4236±1440 and 4373±1404, respectively; P = 0.47) or in the mean change in the creatinine level (0.05±0.3 mg per deciliter [4.4±26.5 μmol per liter] and 0.07±0.3 mg per deciliter [6.2±26.5 μmol per liter], respectively; P = 0.45) Conclusion : NO significant differences in patients’ global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose DOSE TRIAL 2011

33. RCTs on UF Vs Diuretics in HF 9/22/2019 34 Reference Study Design and protocol Patients (n) Ultrafiltration Therapy Effect on Renal Function Main Findings Costanzo (2007), UNLOAD Single session early UF therapy (within first 24 h of admission). Duration and rate of removal at discretion of physician 200 Maximum rate was 500 ml/h. The average rate of removal 241 ml/h for 12.3+/-12 h No significant difference in renal function between UF and diuretic groups. Percentage of patients with .0.3 mg/dl rise in creatinine consistently higher in UF group at 24 h, 48 h, and at discharge Greater net fluid loss with UF. Fewer patients in the UF group rehospitalized at 90 d with fewer rate of hospitalization, hospitalization days, and unscheduled visits Rogers (2008) Single session UF therapy (exclusive UF therapy during the first 24 h of admission). Substudy of UNLOAD trial 20 Maximum rate was 500 ml/h. The target weight and rate of fluid removal were at the discretion of the physician. Fluid removal by UF was 3.7 L No significant difference in GFR, RBF, and FF between UF and diuretic groups. Iothalamate was used to measure GFR; it decreased by 3.4 and 3.6 ml/min in UF and diuretic groups. No significant difference in net fluid removal between the two groups. The changes in renal hemodynamics were comparable for UF and diuretic Giglioli (2011), ULTRADISCO Slow continuous UF. Duration and rate of removal at discretion of physician. Hemodynamic changes were monitored by the Pressure recording analytical method 30 Median UF time was 46 h. Maximum UF rate 300 ml/h. After 36 h, the cumulative fluid removal was 9.7 L for the UF group No significant difference was observed in serum creatinine levels between baseline and post-therapy and between diuretic and UF groups Weight loss significantly greater in the UF group, UF resulted in better hemodynamic status, reduction in serum aldosterone levels and systemic vascular resistance, and improvement in cardiac index and stroke volume

34. RCTs on UF Vs Diuretics in HF Reference Study Design and protocol Patients (n) Ultrafiltration Therapy Effect on Renal Function Main Findings Hanna (2012) Patients with NYHA class III/IV heart failure and ejection fraction ,40%,UF rate 400 ml/h for 6 h and 200 ml/h thereafter 36 UF group had a fluid removal rate of 3.4 ml/kg per hour with a total volume removal of 5.2 L. The mean time to achieve a PCWP of #18 mmHg was 22 h in the UF group No significant difference in serum creatinine and cystatin C levels before and after therapy between the two groups Fluid removal was faster and more efficient in the UF group with shorter hospital length of stay, no change in inflammatory markers, NT-pro-BNP, hospital readmissions Bart (2012) [CARRESS-HF] UF was used as rescue therapy after patients had worsening renal function (UF rate 200 ml/h) 188 Median duration of UF was 40 h. Post-UF weight loss was 5.7 kg Serum creatinine level increased significantly after UF. No change in serum creatinine level with medical Therapy Although weight loss was similar with UF and pharmacologic therapy, patients in the UF group had higher rate of serious adverse events. 9/22/2019 35

35. ADVERSE EFFECTS Extracellular volume depletion Hyponatremia: Thiazides, which inhibit urinary dilution, whereas loop diuretics inhibit urinary concentration and dilution Hypokalemia: Increased tubular flow, secretion of AVP and aldosterone, and alkalosis Hypomagnesemia: Loop diuretics inhibit Mg2+reabsorption in the TAL Metabolic alkalosis : Thiazides and loop diuretics Hyperuricemia: Prolonged thiazide therapy for hypertension increases the serum urate concentration

36. Ototoxicity Common during high dose bolus intravenous therapy in patients with renal failure, in whom plasma levels are increased, and in hypoalbuminemic subjects Crossover trial, no ototoxicity was noted in patients with severe HF when they were given an infusion of 250 to 2000 mg of furosemide over 8 hours, whereas reversible deafness occurred in 25% when the same dose was given as a bolus 1 Mechanism 2 : Interfere with strial adenylate cyclase and Na+/K+-ATPase and inhibit the Na-K-2Cl cotransporter in the stria vascularis Local vasocontriction , disruption of blood cochlear barrier Dormans TP, Gerlag PG: Combination of high-dose furosemide and hydrochlorothiazide in the treatment of refractory congestive heart failure. Eur Heart J 17:1867–1874, 1996. Ototoxic effects and mechanisms of loop diuretics, Dalian Ding a,b,c ,*, Hong Liu b, Weidong Qi d, Haiyan Jiang. Journal of Otology 11 (2016) 145-156

37. DIURETIC RESISTANCE Diuretic resistance is defined as failure to achieve the therapeutically desired reduction in edema even when a maximal dose of diuretic is employed 1 Pharmacokinetic and pharmacodynamic effects may contribute to diuretic resistance Compliance issues: Drug , salt and fluids Inappropriate / inadequate dosing/Antagonism Compensatory mechanisms : RAAS activation 2 Role of hypoalbuminemia Recent hypothesis: Role of proteolytic enzymes Am J Kidney Dis. 2017 January ; 69(1): 136–142. doi:10.1053/j.ajkd.2016.08.027 Abdallah JG, Schrier RW, Edelstein C, Jennings SD, Wyse B, Ellison DH. Loop diuretic infusion increases thiazide-sensitive Na(+)/Cl(−)-cotransporter abundance: role of aldosterone. J Am Soc Nephrol . 2001; 12(7):1335–1341

38. DIURETIC RESISTANCE Filtered proteases in the setting of nephrotic syndrome activate ENaC and contribute to sodium retention 1 Definition : Persistent congestion despite adequate and escalating doses of diuretic equivalent to > 80 mg furosemide/day 2 FeNa <0.2 %, Na excretion <90 m Eq within 72 hrs of 160 mg twice daily furosemide Bohnert BN, Menacher M, Janessa A, Wo¨rn M, Schork A, Daiminger S, Kalbacher H, Ha¨ring HU, Daniel C, Amann K, Sure F, Bertog M, Haerteis S, Korbmacher C, Artunc F: Aprotinin prevents proteolytic epithelial sodium channel (ENaC) activation andvolume retention in nephrotic syndrome. KidneyInt93: 159– 172, 2018 Nat Rev Cardiol . 2015 Mar;12(3):184-92. doi : 10.1038/nrcardio.2014.215. Epub 2015 Jan 6.

39. CAUSES OF DIURETIC RESISTANCE

40. Combination of diuretics – Sequential blockade Sodium reabsorption in the distal tubule can be blocked by concurrent administration of a thiazide Start with low dose metolazone (2.5 – 5mg daily) Long half‐life negates need for more frequent dosing Thiazide of choice in patients with refractory edema & advanced renal failure To be administered 30 minutes prior to furosemide Caution : high associated incidence of hypokalemia, excessive ECV depletion, and azotemia 1 1. Wollam GL, Tarazi RC, Bravo EL, et al: Diuretic potency of combined hydrochlorothiazide and furosemide therapy in patients with azotemia. Am J Med 72:929–938, 1982

41. APPROACH TO DIURETIC RESISTANCE

42. Conclusion In states of fluid excess- decongestion by diuretics has become a “ holy grail ” Response : Clinical and neurohormonal standpoint Need understanding of pharmacokinetics and mechanism of actions “Art and science of using diuretics” Avoiding common errors Management of diuretic resistance