1. Clinical Use of Diuretics 신장내과 박지영

2. Physiological Classification of Diuretics Diuretics  primary natriuretic agents and secondary diuretics 1. Proximal tubule (PT) diuretics - acetazolamide 2. Loop diuretics -furosemide, torasemide, bumetanide, ethacrynic acid 3. Distal convoluted tubule (DCT) diuretics -hydrochlorothiazide, metolazone, indapamide 4. Collecting duct (CD) diuretics -spironolactone, triamterene, amiloride 5. Osmotic diuretics -mannitol, urea

3. Reabsorption of Sodium along Nephron

4. Potency of Diuretics Diuretic effect: increased FE Na or urine Na + excretion 1. Mildly potent (<5%): PT diuretics (CAI) 2. Moderately potent (7~10%): DCT> CD diuretics 3. Very potent (15~25%): Loop diuretics  Furosemide < Torasemide < Bumetanide Dose titration of diuretics by FE Na

5. Carbonic Anhydrase Inhibitors (CAI) in Proximal Tubule Prox. Tubule: HCO 3 - 의 85% 이상을 재흡수

6. Proximal Tubule (S2-3) Lumen Blood OAT (organic anion transporter)

7. Loop diuretics at thick ascending limb of Henle’s loop

8. Thiazide at distal tubule DCT: Ca 2+ active reabsorption

9. Diuretics at collecting duct

11. Pharmacodynamics Effective dose: the dose that will deliver enough drug to the site of action to reach the steep portion of the curve Maximal dose: the lowest dose that elicits a maximal response and that should therefore not be exceeded (In normal subjects, Furosemide 40mg iv dose  maximal response : the excretion of 200~250mmol of Na + in 3~4 L of urine over a period of 3~4 hours) Maximal response: the excretion of about 20% of filtered Na +

12. Pharmacodynamics of a Loop diuretic Effective dose Maximal dose

13. Pharmacokinetics of Diuretic Drugs (50%)

14. Pharmacokinetic Characteristics of Diuretics Onset (hr)Peak (hr)Duration (hr)T1/2 (hr)Usal dose (/d) PT diuretics Acetazolamidepo1~1.52~48~10-250mg~1g iv2 min15min4~5- Loop diuretics Furosemidepo<11~26~80.820~400mg iv<5min0.52-20~400mg torsemidepo<1<1~26~83.525~100mg bumetanidepo0.5~11~23~61~1.50.5~10mg Ethacrynic acidpo<0.526.8150~100mg DCT diuretics hydrochlorothiazide1~246~121~225~100mg metolazone1212~2482.5~5mg CD diuretics amiloride26~10246~95~20mg spironolactone24~4848~72 2025~400mg triamterene26~812~163200~300mg Osmotic diuretics mannitol0.5~116~80.2~1.550~200g

15. Pharmacodynamic Characteristics of Diuretics

16. Determinants of Response to diuretics Urine concentration: free drug concentration at the target site of action 1. Plasma protein binding - hypoalbuminemia 2. Inhibition at secretary site (PT) -drugs (probenecid) -endogenous organic acids (urate) 3. Protein binding in tubule lumen -albuminuria Time course of diuretics delivery

17. Diuretic Tolerance Short-term tolerance (braking): a decrease in the response to a diuretic after the first dose has been administered :prevented by restoring diuretic-induced loss of volume :mechanism-unclear activation of angiotensin II or sympathetic nervous system Long-term tolerance of a loop diuretic: Increased solute load to distal nephron  hypertrophy of distal nephron segments (DCT and CD)  Increased reabsorption of Na + Thiazide diuretics blocks the nephron sites at which hypertrophy occurs  synergistic response  combinations of a thiazide and a loop diuretic

18. Diuretic Tolerance Diuretic rebound : Loop diuretics  volume depletion  increased Na + reabsorption at DCT and CD (post-diuretic Na + retention)  exacerbation of edema Diuretic resistance Combinations of Therapy of diuretics Loop diuretic ±DCT diuretics± CD diuretics

19. Mechanism of Diuretic resistance in Nephrotic syndrome 1. Decreased diuretic delivery to the kidney : hypoalbuminemia  Vd ↑ & renal diuretic delivery ↓  Diuretics premix with albumin, albumin preinfusion 2. Decreased tubular secretion of active diuretics : hypoalbuminemia  proximal secretion↓  Reduce albuminuria with ACEI or ARB 3. Increase renal glucuronization of furosemide  Torasemide or bumetanide (hepatic metabolism) 4. Decreased blockade of tubular NaCl reabsorption :decreased free diuretics (albumin-binding), defective target site  Reduce albuminuria with ACEI or ARB 5. Distal adaptation in DCT and CD  Combination diuretic therapy, increase dose of diuretics

20. Mechanism of Diuretic resistance in Chronic Renal Failure 1.Decreased diuretic delivery to the kidney :decreased renal perfusion  maintain BP and fluid balance 2.Decreased basal fractional NaCl reabsorption  select a loop diuretics, not a thiazide, as initial diuretics 3.Decreased proximal tubular secretion of active diuretics : competition with urate and OA (drugs) for OAT (organic anion transporters)  Control of hyperuricemia and acidosis, avoid probenecid, NSAIDs, cimetidine, sulfonamides and beta-lactam, valporic acid, methotraxate, antiviral agents 4. Decreased renal clearance of furosemide causing ototoxicity  Torasemide or bumetanide (hepatic metabolism) 5. Distal adaptation in DCT and CD  Combination diuretic therapy, increase dose of diuretics

21. Proximal Tubule (S2-3) Lumen Blood

22. Diuretic Resistance in Chronic Kidney Disease Right shift of dose-response curve of diuretics

23. Clinical Use of Diuretics Nephrotic syndrome Renal failure Liver cirrhosis Congestive heart failure Hypertension Others

24. Diuretic therapy in Nephrotic syndrome Loop diuretics: 1 st choice - Furosemide 80~120mg, torsemide 25~50mg, bumetanide 2~3mg - Maximal dose: furosemide 4~6mg/Kg/day Combination diuretic therapy 1) thiazide or/and CD diuretics 2) albumin: premix or preinfusion

25. Albumin infusion in Nephrotic syndrome No benefit except in severe hypovolemia -No evidence of benefit in the pharmacokinetic/dynamic study (KI 1999;55:629, JASN 2001;12:1010) Potential problems -expensive, high NaCl (20mmol/dL), decreased renal function, hypertension Selective use in 1)severe hypovolemia 2)severe hypoalbuminemia (serum albumin<2.0g/dL)

26. Diuretic therapy in Chronic Renal Failure Target: 1) Control of edema 2) Control of hypertension 3) Correction of hyperkalemia and metabolic acidosis :diuretics  distal delivery of NaCl↑  activity of E Na C ↑ at CD  distal K +, H + secretion ↑ 4) Maintain daily urine volume (> 1L/day)

27. Diuretic therapy in Chronic Renal Failure 1) Loop diuretics: 1 st choice -resistance due to decreased delivery to luminal target -larger dose, preferred morning single dose 2) thiazide -no effect in moderate degree of renal failure (CCr<50ml/min) except metolazone -synergistic effect to loop diuretics in larger dose in mild and moderate degree of renal failure

28. Ceiling Doses (mg) of Loop Diuretics in Renal Failure Bumetanide, torsemide: high bioavailability & non-renal metabolism  iv dose = oral dose

29. Doses for continuous iv infusion of loop diuretics

31. Diuretic therapy in Liver cirrhosis Peripheral arterial vasodilation (unifying hypothesis)  decreased effective blood volume  activation of RAAS, SNS, ADH  Na & water retention decompensated LC & ascites : profound reduction in the rate of renal Na excretion ↓ ↓  aldosterone; major role

32. Norepinephrine angiotensin II aldosterone ADH Pathogenesis of Ascites

33. Diuretic therapy in Liver cirrhosis Diuretics 1) Spironolactone: 1 st choice -50~200 (400) mg/day 2) combination of loop diuretics or/and thiazide 3) albumin: no additional effect (JASN 12:1010, 2001) Target weight reduction 1) natural absorption of ascites : 700~900 ml/day 2) ascites with peripheral edema: 1kg/day 3) ascites only: 0.5kg/day

34. Practical Guideline of Spironolactone in Liver cirrhosis 1) 24hr urine Na excretion (>78mEq/day) or 24hr urinary Na/K ratio (BMJ 1970;4:401/ Hepatology 2004;39:841) -may vary by the intake of Na -incorrect, impractical 2) Spot urine Na/K ratio (Semin Liver Dis 1997;17:249) U K / U Na >1 : increased dose up to 400mg/day (U K / U Na 78mEq/day) U K ↓U Na  : addition of loop diuretics U Na ↑ weight ↑: low salt diet

35. TTKG (transtubular potassium gradient) in Liver cirrhosis 3) TTKG : accurate indicator of aldosterone bioactivity by analysing the renal K excretion  guide for the proper use of the aldosterone antagonist - independent of the delivery rate of Na & osmoles to the distal nephron and also of the reabsorption of water by the ADH in the medullary collecting duct TTKG= [K] urine/ [K] plasma (urine/plasma)osmolality (Liver,2002:22(5):426)

36. TTKG-guided diuretic treatment for cirrhotic ascites TTKG ≤3 : complete blockade of aldosterone bioactivity (Liver 2002:22;426~432)

38. Large volume paracentesis in Liver cirrhosis Properties of ascites albumin 6~8g/L, Na 140mmol/L reaccumulation: 2~3 weeks Replacement of albumin -albumin 8g/1L ascites : 20% albumin 40mL (20% albumin 100mL=albumin 20g) caution in Child C, esophageal varix, bilirubin >10mg/dL, Creatinine >3mg/dL, PT<40%, U Na <10mmol/day

39. Diuretic therapy in Heart failure thiazide: 1 st choice Loop diuretics 1) moderate to severe or refractory heart failure 2) decreased renal function (CCr <25ml/min) 3) pulmonary edema 4) electrolyte imbalance Spironolactone 1) K sparing 2) improved survival (RALES: NEJM 341:709,1999)

40. Dose-response relationship between furosemide and sodium excretion in CHF A diuresis is not seen until a threshold rate of furosemide excretion is reached. Patients with CHF show relative resistance at a given rate of diuretic excretion due to increased sodium reabsorption in other nephron segments. (Kidney Int 1984; 26:183)

41. Diuretics in Hypertension Essential hypertension - thiazide (15~20/10 mmHg) > Loop diuretics (5~10/5 mmHg) Chronic kidney disease -nocturnal hypertension ←volume expansion -essential primary drug (1 st step choice) Specific hypertension 1) primary aldosteronism: spironolactone 2) Liddle syndrome: amiloride, triamterene 3) Gordon syndrome: thiazide

42. Low dose Thiazide as the 1 st Step Antihypertensive Choice (JNC-7) Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT 2002) -33,359 patients 1) lowering systolic BP: thiazide > amlodipine, lisinopril 2) CHF: amlodipine 38% more than thiazide 3) stroke: lisinopril 15% more than thiazide 4) CVD: lisinopril 10% more than thiazide Pattsy et al. (2003)-192,478 on-line registry - good effect, low metabolic adverse effect, preventing fracture Cost vs. Benefit hydrochlorothiazide 25mg: 4 원 / atenolol 50mg: 58 원 / amlodipine 5mg: 528 원 enalapril 10mg: 312 원 / losartan 50mg:806 원

43. ALLHAT 2002 : amlodipine vs. thiazide

44. ALLHAT 2002: lisinopril vs. thiazide

45. PREIMIER (preterax in albuminuria regression) Study (Hypertension 2003,41(5):1063) 457 patients with hypertensive albuminuric type 2 diabetes, for 52 weeks 2 mg perindopril/0.625 mg indapamide vs. 10 mg enalapril ACE/low dose diuretics combination in the first-line treatment of hypertension and end-organ protection (Expert Rev Cardiovasc Ther 2006;4(3):319) RAS inhibitor → diuretic-induced increase in plasma renin activity ↓ diuretic-induced salt loss → effect of RAS inhibitor↑ AER (Albumin excretion rate)

46. Diuretics in other diseases Oliguria -mannitol, loop diuretics, dopamine Increased intracerebral or ocular pressure -mannitol, acetazolamide Hypercalcemia -furosemide with saline Hypercalciuria with/without stone -thiazide Renal tubular defects 1) Gordon syndrome, diabetes insipidus: thiazide 2) Bartter or Gitelman syndrome: CD diuretics 3) renal tubular acidosis: loop diuretics 4) hyperkalemia: loop diuretics

49. Adverse Effects of Diuretics Fluid and electrolytes disorders -azotemia, volume depletion, hyponatremia (esp. thiazide) -hypokalemia, hypomagnesemia, hypocalcemia (furosemide) -hypercalcemia (thiazide), hyperkalemia (spironolactone) -metabolic alkalosis, acidosis Metabolic disorders - hyperglycemia (impaired insulin release secondary to hypokalemia), hyperlipidemia, hyperuricemia Pregnancy: decreased uterine blood flow Allergic reaction - rash, photosensitivity, panceatitis, acute TIN Impotence, ototoxicity (high dose iv loop diuretics)

51. Indapamide ( 후루덱스 ®, 나트릭스 ®) DCT diuretic: Thiazide-related Onset of action: 1-2 hours Duration: ≤36 hours Absorption: Complete Protein binding, plasma: 71% ~ 79% Metabolism: Extensively hepatic Half-life elimination: 14-18 hours Time to peak: 2-2.5 hours Excretion: Urine (~60%) within 48 hours; feces (~16% to 23%) little therapeutic benefit to increasing the dose >5 mg/day Electrolyte disturbances(+): Hypokalemia, hypochloremic alkalosis, hyponatremia Sulfa allergy: Chemical similarities are present among sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid)

52. Metolazone (Zaroxolyn®) Pharmacologic characteristics-similar to those of other thiazides Absorbed poorly and slowly Long elimination half-life (20 hours~2 days)  accumulates over a period of about 10 days Edema: Oral: 2.5-20 mg qd (ACC/AHA 2005 Heart Failure Guidelines) Hypertension: Oral: 2.5-5 mg qd Renal impairment — Not dialyzable (0% to 5%) via HD or PD Onset of action: Diuresis: ~60 minutes Duration: ≥24 hours Distribution: Crosses placenta; enters breast milk Excretion: Urine (80%); bile (10%) Vs> Hydrochlorothiazide -the absorption is more rapid and predictable  preferable to metolazone

53. Torsemide (Torem®) Onset of action: Diuresis: 30-60 minutes Peak effect: 1-4 hours Duration: ~6 hours Absorption: Oral: Rapid Metabolism: Hepatic (80%) via CYP Bioavailability: 80% to 90% (iv dose=oral dose) Half-life elimination: 2-4 hours / Cirrhosis: 7-8 hours Excretion: Urine (20% as unchanged drug) no dosage adjustment in the elderly or patients with hepatic impairment CHF: Oral, I.V.: 10-20 mg once daily CRF: Oral, I.V.: 20 mg once daily LC: Oral, I.V.: 5-10 mg once daily with an aldosterone antagonist or a potassium-sparing diuretic

54. Mannitol The potential to produce ARF; renal vasoconstriction produced by high concentration of mannitol Current recommended dose: 0.25g/Kg every 4 hours (20% mannitol 100ml=20g) (as as effective as with the dose of 0.5~1g/Kg) Serum osmolality<310mOsm/Kg : to control ICP<25mmHg Monitoring of mannitol therapy - “the osmolar gap” instead of the serum osmolality (As mannitol accumulates, serum Na is likely to decline→serum osmolality↓) The osmolar gap= 측정된 serum osmolality – calculated serum osmolality Calculated serum osmolality=[2Na+BUN(mg/dL)/2.8+glucose(g/dL)/18 ] Maintain a mannitol blood level<1000mg/dL (the osmolar gap <55mOsm/Kg water) [Mannitol] =osmolar gap×M.W. of mannitol (182) 10 (to convert mg/dL)

55. Vasopressin receptor antagonists (VRA)

56. Clinical trial of VRA 1.Hyponatremia (SIADH, LC, HF) -SALT study (Study of the Ascending Levels of Tolvaptan in Hyponatremia) (NEJM 2006;355:2099) -Conivaptan in SIADH (Am J Med 2001;110:582) -Satavaptan in SIADH (Clin J Am Soc Nephrol 2006;1:1154) 2.Heart failure -EVEREST study (The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) (JAMA 2007;297:1332, 297:1319) 3.Liver cirrhosis -Lixivaptan (Hepatology 2003;37:182) 4.Polycystic kidney disease- OPC31260 (Nat Med 2003;9:1323) 5.Nephrogenic DI- Recolvaptan(SR49059) (J Am Soc Nephrol 2006;17:232)

59. SUMMARY Take Home Massages

60. Strategies to Overcome Diuretic Resistance Assess compliance Reduced salt intake (< 2~5 g/day) Discontinue drugs interfering diuretic action (NSAIDs, B- lactam, sulfonamides, probenecid, cimetidine) Increase diuretic dose until maximal safe dose (furosemide 4~6mg/kg/day) Increase frequency or continuous infusion Continuous infusion of bumetanide or torasemide Add distal acting diuretics (thiazide, amiloride) ACEI or ARB or Ca 2+ channel blocker Infuse serum albumin with furosemide-before or premix (selected cases with volume depletion)

61. Prescription of Diuretics Never use after 5~6 p.m. to avoid sleep disturbance due to nocturia Divided dose-morning and early afternoon (8 am/4 pm) Single dose-morning ac or p.c. 2~3 hours

62. Monitoring during Diuretic Therapy Initial stage -daily body weight, I/O, volume status -biweekly BUN, Cr, urate, Na, K, Cl, total CO 2 -biweekly urine Na, K, Cl, FE Na Chronic stable period -daily body weight -monthly volume status -monthly BUN, Cr, urate, Na, K, Cl, total CO 2 -monthly urine Na, K, Cl -bimonthly ototoxicity, impotence, glucose, lipid

63. Furosemide dose CRF 20< CCr (ml/min) <50 :starting dose- iv 40mg, po 80mg ceiling dose-iv 80~160mg, po160mg CCr (ml/min) <20 :starting dose- iv 80mg, po 160mg ceiling dose-iv 200mg, po 240mg NS with normal renal function :starting dose- iv 40mg, po 80mg ceiling dose- iv 120mg, po 240mg LC, CHF with normal renal function: ceiling dose-iv 40~80mg, po 80~160mg

65. Algorithm for Diuretic Therapy in Patients with Edema Caused by Renal, Hepatic, or Cardiac disease NEJM 1998;339(6):387

66. 경청해 주셔서 감사합니다