Diuretics Agents which promote the formation of urine by the kidney Greek "dia-", thoroughly + "ourein", to urinate = to urinate thoroughly.
ALLHAT trial (JAMA. 2002;288:2981-2997) randomized, double-blind, active- controlled clinical trial February 1994 through March 2002. Inclusion: ◦ 33357 participants ◦ 55 years or older with hypertension ◦ at least 1 other CHD risk factor ◦ 623 North American centers.
ALLHAT trial Intervention: Randomised to receive ◦ chlorthalidone, 12.5 to 25 mg/d (n=15255); ◦ amlodipine, 2.5 to 10 mg/d (n=9048); ◦ lisinopril, 10 to 40 mg/d (n=9054) Doxazosin arm was prematurely terminated Follow-up of approximately 4 to 8 years. Primary outcome: combined fatal CHD or nonfatal MI Secondary outcomes: all cause mortality, stroke, combined CHD (primary outcome, coronary revascularization, or angina with hospitalization), and combined CVD (combined CHD, stroke, treated angina without hospitalization, heart failure [HF], and peripheral arterial disease).
ALLHAT trial-Results Primary end points: no difference All cause mortality: no difference Five-year systolic blood pressures were significantly higher in the amlodipine (P=.03) and lisinopril (P.001) groups compared with chlorthalidone Amlodipine vs chlorthalidone: secondary outcomes were similar except for a higher 6-year rate of HF with amlodipine Lisinopril vs chlorthalidone : lisinopril had higher 6-year rates of combined CVD
ALLHAT trial Conclusion:“Thiazide-type diuretics are superior in preventing 1 or more major forms of CVD and are less expensive. They should be preferred for first-step antihypertensive therapy.” Fallout:JNC 7 hypertension guidelines recommended that thiazides should be the first line antihypertensive
Hypertension in CKD 50% to 75% of individuals with GFR 60 mL/min/1.73 m2 (CKD Stages 3-5) have hypertension. Central role of kidney in BP homeostasis: Guyton’s Hypothesis
Mechanism of Na retention in CKD Decreased filtered load of Na Sodium and fluid overload Increased compensatory retention in tubulesPatients with CKD have a 10 to 30% increase inextracellular and blood volume, even in the absence ofovert edema Am J Med 72: 536–550, 1982
Diuretics as Antihypertensives in CKDFacilitates responses to otherAntihypertensives Decreased Increased Reverses Lowering tubular Na Na ECF BP absorption excretion expansion Salt Restriction
Classes of Diuretics Loop Diuretics Thiazide and thiazide like diuretics K-sparing diuretics ◦ Aldosterone antagonists ◦ ENaC blockers Carbonic Anhydrase Inhibitors Osmotic Diuretics Misc. Agents(DA agonists, A1 receptor antagonists, vaptans)
Mechanisms of action ofdiuretics
Diuretics used in CKD
Loop diuretics Bumetanide and torsemide have better oral bioavailability than furosemide —› doubling oral dose of furosemide Vd inversely varies with albumin concentration 50% furosemide metabolized by kidney(glucuronidation) Torsemide and bumetanide metabolized exclusively in liver
Loop diuretics Duration of action: torsemide >furosemide>bumetanide In CKD: ◦ t½ of furosemide is prolonged: accumulates leading to toxicity, ◦ Fe of unchanged drug increases: greater natriuresis ◦ Renal clearance of active LD decreased in prop to CCl
Loop diuretics In CKD: ◦ Competition for luminal transport with other OA (eg urate) ◦ Metabolic acidosis decreases tubular secretion ◦ Hypoalbuminemia: increases metabolism in S1 segment and decreases tubular secretion in S2 segment of PT
• % of filtered Na+ load excreted17
Thiazide and thiazide likediuretics ?Class effect as antihypertensives Decreases Ca excretion Decreases urate clearance Impairs maximal urinary dilution but not maximal concentration, along with increases AQP2 expression, makes hyponatremia 12 times more common than loop diuretics.
Thiazide and thiazide likediuretics In CKD: ◦ Poor diuretics when CCl <30ml/min ◦ Indapamide and bendroflumethiazide are metabolized in the liver: limits accumulation in renal failure ◦ Metolazone found to have synergistic action with loop diuretics in very low GFR even where other thiazides are not very effective
Potassium Sparing Diuretics Amiloride and triamterine are organic cations AR antagonists are competitive antagonists These drugs produce only modest natriuresis More effective than furosemide in cirrhotic ascites
Potassium Sparing Diuretics In CKD: ◦ Not very useful as primary drugs ◦ Can be of adjunctive use in resistant hypertension ◦ Hyperkalemia is a dreaded complication ◦ May reduce proteinuria in CKD (?retards disease progression) Kidney Int. 2006 Dec;70(12):2116-23. ◦ Has role in preventing cardiac remodeling
Misc. diuretics Osmotic Diuretics: ◦ have been tried in ARF ◦ In CKD-can cause expansion of ECV, hemodilution, MA, can ppt ARF in high doses CAI: ◦ Development of life threatening MA limits use in CKD
Adverse effects of diuretics
Diuretic drug dosing in CKD
Diuretic Resistance in CKD Highdietary intake of sodium (i.e. Urinary Na >100mmol/day)Pharmacokinetics: Decreased delivery Decreased secretion in PT by OAT-1 Intratubular binding of secreted diuretic to filtered albumin.
Diuretic Resistance in CKDPharmacodynamics: Reduced number of functioning nephrons and decreased Na filtered load Diuretic Braking phenomenon
Braking Phenomenon Postdiuretic fluid and Na retention Compensation by Na retaining hormones/ upregulation of ion transporters along the TALH/ Structural and functional changes in the distal nephron segments Co-administration with thiazide- supraadditive (sequential duiretic
Braking Phenomenon Clinical implications of this phenomenon: ◦ Salt retention should always be advised in all patients who are on diuretics ◦ Addition of a second diuretic increases natriuresis ◦ Use of a long acting drug /more frequent /iv administration has more effect ◦ Diuretic therapy should not be stopped abruptly unless Na intake is curtailed
J Nephrol 6: 118–123, 1993
Rationale for combinationtherapy
Newer agents Adenosine type I receptor antagonists: ◦ Disrupts TGF and GTF and thus decreases proximal resorption and increases GFR ◦ Used in diuretic resistant CHF ◦ Use in CKD is equivocal Vasopressin Antagonists: ◦ Vaptans(conivaptan, tolvaptan, lixivaptan) ◦ Allows free water loss without natriuresis ◦ Predominantly used to treat eu/hypervolemic hyponatremia
KDOQI GUIDELINE 12: USE OF DIURETICSIN CKD 12.1 Most patients with CKD should be treated with a diuretic (A). 12.1.a Thiazide diuretics given once daily are recommended in patients with GFR ≥30 mL/min/1.73 m2 (CKD Stages 1-3) (A); 12.1.b Loop diuretics given once or twice daily are recommended in patients with GFR <30 mL/min/1.73 m2 (CKD Stages 4-5) (A);
KDOQI GUIDELINE 12: USE OFDIURETICS IN CKD 12.1.c Loop diuretics given once or twice daily, in combination with thiazide diuretics, can be used for patients with ECF volume expansion and edema (A). 12.1.d Potassium-sparing diuretics should be used with caution: ◦ 12.1.d.i In patients with GFR <30 mL/min/1.73 m2 (CKD Stages 4-5) (A); ◦ 12.1.d.ii In patients receiving concomitant therapy with ACE inhibitors or ARBs (A); ◦ 12.1.d.iii In patients with additional risk factors for hyperkalemia (A).
KDOQI GUIDELINE 12: USE OFDIURETICS IN CKD 12.2 Patients treated with diuretics should be monitored for: ◦ 12.2.a Volume depletion, manifest by hypotension or decreased GFR (A); ◦ 12.2.b Hypokalemia and other electrolyte abnormalities (A). ◦ 12.2.c The interval for monitoring depends on baseline values for blood pressure, GFR and serum potassium concentration 12.3 Long-acting diuretics and combinations of diuretics with other antihypertensive agents should be considered to increase patient adherence (B).