Diuretic therapy and diuretic resistance in cardiac failure.

s 40 venous capacitance within a few minutes before any with oedema is defined as a clinical state where the braking phenomenon occurs before the therapeutic measurable increase in urinary output can be seen [1,2]. This rapid haemodynamic improvement is goal is reached. thought to be due to the release of vasodilatory prostaglandins [3]. However, in a study in patients with severe oedema, i.v. piretanide did not cause a decrease Causes and mechanisms of diuretic resistance in wedge pressure within 120 min ( local oedema preventing venous dilation?) [4]. Acute haemodynamic improvements often are sustained during chronic treatImpaired kidney function. Pre-renal azotaemia is very often present in patients with severe CHF either treated ment [2,5]. For example, an improvement of NYHA functional class (71 vs 10 NYHA III, 80 vs 112 NYHA or untreated [12,13]. In renal failure, tubular delivery of loop diuretics is impaired due to diminished renal II, 0 vs 29 NYHA I at baseline vs 4 weeks) was demonstrated in 151 patients with CHF on 5–10 mg blood flow and to reduced activity of the proximal tubular carrier system caused by competition for the of torasemide for 4 weeks [6,7]. Recent randomized trials have dealt with the treatment of CHF in 17 825 co-transporter from accumulated organic anions [14]. Loop diuretic doses have to be increased considerably patients as given in Table 1. In patients with advanced heart failure (NYHA III/IV ), up to 100% are treated to achieve sufficient drug concentrations within the tubular lumen. with a ( loop) diuretic, whereas in patients with less advanced heart failure the percentage of patients on a Hyponatraemia. Hyponatraemia has been shown frequently to be associated with reduced diuretic efficacy. diuretic is lower (Table 1). Despite the widespread use of diuretics in the treatment of heart failure, a survival Hyponatraemia may be caused by thiazides, but is most often due to CHF with stimulation of thirst, and benefit for patients on a diuretic has never been proven, though this appears to be very likely, at least in severe a non-osmotically stimulated vasopressin system that impairs excretion of free water [15]. This is particularly pulmonary oedema. Sharpe et al. randomized 60 patients with Q wave infarction and asymptomatic left problematic when patients are not compliant with restrictions in free water intake. ventricular dysfunction to treatment with either 40 mg of frusemide or 75 mg of captopril or placebo for 12 Pharmacokinetics. The pharmacokinetics of loop diuretics are altered in CHF (reduced peak concentration, months [9]. Left ventricular volumes increased and ejection fraction decreased slightly in both the frusemprolonged time to peak concentration, but with no significant reduction of the total amount of frusemide ide and placebo groups, whereas during captopril treatment end-systolic volume decreased and ejection absorbed). These differences are not marked and are overcome by a moderate increase in dose [16 ]. fraction increased. Thus, in patients with asymptomatic left ventricular dysfunction, diuretic monotherapy may Furthermore, proximal tubular secretion of the diuretic may be impaired by organic anions that use the same not be sufficient to preserve cardiac function. transport pathway (probenecid, penicillins, endogenous organic acids in uraemia) [14]. Diuretic administration in heart failure Sodium and fluid retention. In severe CHF, proximal and distal tubular reabsorption of sodium is stimulated, due to direct (proximal ) tubular effects of angiotensin A thiazide may be used in less severe CHF; however, in most patients with advanced CHF, a loop diuretic II and catecholamines, to facilitation of passive sodium reabsorption in the proximal tubule and to aldoswill be necessary [6,7,10]. Hypokalaemia and hypomagnesiaemia caused by a loop diuretic or a thiazide terone-mediated sodium reabsorption in the collecting duct [8,13,17]. Furthermore, resistance to the natriurmay be prevented by combination with a potassiumsparing diuretic (e.g. amiloride, triamterene or spironoetic action of atrial natriuretic peptide contributes to sodium retention in CHF [18,19]. Even in asymptolactone) [10]. Most heart failure patients are on an angiotensin-converting enzyme (ACE) inhibitor, matic heart failure, a defective adaptation of sodium reabsorption in the proximal nephron in response to thereby necessitating careful dose titration and control of serum potassium levels, because of the considerable salt intake is present [20]. One main cause for the activation of sodium retention in CHF is a reduction risk of hyperkalaemia with such a combination therapy [10,11]. in ‘effective’ arterial blood volume (reduced cardiac output and/or reduced peripheral vascular resistance) [21]. When patients with severe CHF with increased Diuretic resistance proximal tubular sodium reabsorption are treated with a loop diuretic, the ensuing natriuresis is reduced further by stimulation of sodium reabsorption at more In patients started on a diuretic, there is an initial reduction in body weight and total body sodium. distal sites of the nephron. In animals treated chronically with a loop diuretic, a marked hypertrophy of the However, a new steady state with equal sodium intake and sodium excretion is soon reached. This physiologidistal tubule was observed [22]. The above mechanisms all contribute to the well-known rightward shift of cal diuretic resistance has been termed the ‘braking phenomenon’, which has evolved to prevent excessive frusemide dose–response curves in patients with CHF [23]. fluid and salt losses. Diuretic resistance in a patient Fifth Congress of Nephropharmacology 41 Fig. 1. Overview of diuretic treatment in cardiac failure according to recent large, randomized trials Table 1. Management of diuretic resistance in cardiac failure Concomitant ACE inhibition. ACE inhibition has been proven successful for the treatment of refractory $ Restriction of daily fluid (1.0–1.5 l ) and salt intake oedema in patients with diuretic resistance [12]. These $ Avoid NSAIDs, and overly aggressive vasodilatory therapy beneficial effects may be due to improvement of car$ Start on an ACE inhibitor (careful dose titration; e.g. 6.25 mg diac performance and suppression of angiotensin of captopril t.i.d.) II-mediated effects (stimulation of thirst, vasopressin $ Short-acting loop diuretic p.o. in several divided (and increasing) doses (e.g. 40–80 mg of frusemide b.i.d. release, tubular sodium reabsorption). However, or t.i.d)/i.v. administration of the diuretic/continuous infusion administration of an ACE inhibitor without a loop of the diuretic diuretic was not effective [26 ]. It is suggested to $ Sequential nephron blockade by combination of a loop institute ACE inhibition in patients with severe CHF diuretic and, for example, a thiazide on a loop diuretic with small starting doses [10]. $ Addition of low doses of spironolactone (12.5–25 mg/day) with concomitant ACE inhibition However, standard (‘standard’ as defined in clinical survival trials) doses of ACE inhibitors should be given to all patients with CHF during long-term therapy [10]. Therapeutic measures Diuretic combination therapy. Because of the known stimulation of proximal and distal tubular sodium reabsorption in patients with CHF on a loop diuretic, Control of sodium and fluid intake. A major cause of blockade of sodium reabsorption at different sites in apparent diuretic resistance in clinical practice is nonthe nephron was suggested. The addition of hydrochlocompliance with prescribed sodium/fluid intake. A rothiazide, metolazone or acetazolamide in order to marked increase in sodium absorption 6–24 h after inhibit sodium reabsorption distal and/or proximal to administration of frusemide to healthy subjects on a the thick ascending limb of the loop of Henle has high sodium diet, thereby abolishing any natriuretic proven effective in patients with heart and renal failure effect of a single daily dose of frusemide, has been (acetazolamide use is limited due to development of shown [24]. In contrast, during a low sodium diet, acidosis) [27,28]. Combination of a loop diuretic with such a compensatory increase in sodium reabsorption a thiazide results in (super)additive effects on diuresis did not occur, because sodium reabsorption had been and natriuresis even in advanced renal failure [27,28]. near maximal already at baseline, thus causing a negaSuch diuretic combinations have a considerable potentive sodium balance during a low-sodium diet, only tial for side effects (e.g. hypokalaemia, hypovolaemia). [2]. Brater et al. have shown also in patients with CHF The addition of spironolactone to a regimen including that depending on the mode of administration (bolus a loop diuretic and an ACE inhibitor was also sugvs infusion) of the loop diuretic bumetanide, retention gested to be effective in refractory heart failure [11]. of an i.v. sodium load occurs [25]. Fluid intake should The reason for this combination is that during longtherefore be limited to 1.0–1.5 l/day and salt intake should be restricted in patients with CHF [10]. term ACE inhibition aldosterone secretion is no longer