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loop diuretics


  • More rapid onset, shorter action & more potent diuresis than thiazides & thus greater homeostatic responses;
  • Loop diuretics are organic anions that circulate bound to proteins (>90%), limiting their Vd, and do not enter tubular fluid by means of glomerular filtration but, rather, require secretion across proximal tubular cells, through organic anion transporters (OAT1 and OAT2) and the multidrug resistance–associated protein 4
  • Inhibit Na-K-2Cl cotransport (NKCC2) mechanism at the apical surface in thick asc. limb loop of Henle cells which normally are responsible for reabsorption of 25% of filtered sodium
    • bind to the translocation pocket at the extracellular surface of sodium–potassium–chloride cotransporters (NKCCs), blocking ion transport directly
    • results in decreased reabsorption of Na,K,Cl;
  • In addition:
    • inhibit the same symporter at the apical membrane of macula densa cells, stimulating renin secretion (which unfortunately, increases the level of angiotensin II) and inhibiting tubuloglomerular feedback, which normally suppresses glomerular filtration when salt delivery to the macula densa increases, but helps to maintain the glomerular filtration rate.
    • increased renal blood flow without increasing GFR (esp. if IV) → decreased prox.tub.fluid reabsorption → increased diuretic effect;
    • but transient as decreased ECFV → decreased RBF → increased prox. tub.fluid reabsorption
    • some inhibit carbonic anhydrase but too weakly (frusemide/bumetanide);
    • increased K secretion distally as increased urine flow & increased pl. [urate] as for thiazides;
    • increased Ca & Mg excretion in proport. Na excretion - NB. different to thiazides!!
    • increased excretion titratable acid & ammonia → metab. alkalosis;
    • increased systemic venous capacitance in ac.pulm.oedema → decreased pre-load;
    • inhibit a second sodium–potassium–chloride symporter isoform, NKCC1 (gene SLC12A2) which is found throughout the body, including:
      • in ear hair cells which may account in part for direct ototoxic action on hair cells ear @ high concentration
      • in vascular smooth-muscle cells resulting in vasodilation after iv doses
      • cells of the afferent arteriole and in the extraglomerular mesangium (cells near the macula densa), where it suppresses basal renin secretion, thus loop diretics may increase renin secretion via this mechanism

Detailed actions in patients with congestive heart failure

  • the main aim of Rx is to reduce extracellular fluid volume, and loop diuretics are employed to create a net increase in urinary sodium excretion which should result in reduced ECFV
  • the actions of loop diuretics are complex due to:
    • after an initial relatively short natriuresis phase post dose, there is a longer post-diuretic NaCl retention phase
    • the peak of the initial relatively short natriuresis phase post dose declines with subsequent doses - “the braking phenomenon”
    • the natriuretic response to loop diuretics differs from that in healthy persons as the serum concentration needs to be higher to achieve a similar effect, and the maximal effect (“ceiling”) is lower
    • whilst the duration of action of oral frusemide is much longer than that for iv frusemide, the degree of natriuresis is likely to be greater with iv dosing which results in higher serum levels, albeit for a shorter period and, for patients with preserved kidney function, iv doses are approximately twice as potent on a per-milligram basis as oral doses.

causes of loop diuretic resistance

  • inadequate doses
  • compliance issues including excessive salt intake
  • impaired GIT absorption due to gut oedema, while food delays absorption
  • impaired secretion of diuretic into the tubule lumen
  • decreased protein binding - hypoproteinaemia
  • low renal blood flow
    • hypotension
  • nephrotic syndrome
  • antinatriuretic drugs such as non-steroidal anti-inflammatory drugs (NSAIDs), antihypertensive agents
  • nephron remodelling in response to chronic diuretic use
  • neurohormonal activation

Frusemide (Lasix):


  • readily absorbed GIT but food may result in absorption being the limiting factor in its duration of action
  • highly plasma protein bound
  • rapidly secreted by the organic acid transport system in prox. tubule to gain access to luminal fluid & thus site of action (inhib. by Probenecid);
  • excreted by kidney as unchanged & as conjugates with gluc. & with (N-acetyl)cysteine;
  • Short half-life 1-2hrs & duration action 3-6hrs;


  • 2-6mg/kg or 20-600mg/d adults (titrate dose by incr. every 2(IV)-6hrs(oral));
  • incr. dose needed if:
    • uraemic pts as decr. frusemide tub. secretion rate but C/I if anuric!!;
    • nephrotic synd. as proteinuria ? binds luminal frusemide;


  • Mainly electrolyte disturbances;
  • Ototoxicity esp. if high dose or with other ototoxic drug (aminoglycoside);
  • Acute hypoglycaemia in OD;
  • reversible allergic interstitial nephritis;
  • Potentially hepatotoxic metabolites @ high doses;


  • aminoglycosides → risk of ototoxicity increased substantially → C/I;
  • warfarin/clofibrate → compete for protein binding;
  • lithium carbonate renal clearance decreased;
  • oral oral hypoglycaemic agents as decreased CHO tolerance (although less than thiazides);
  • cephalosporins → increased nephrotoxicity;
  • other diuretics may be used as well but not other loop diuretics;


  • More completely absorbed (100% vs 60%) than frusemide;
  • Usually once daily dose 0.5-2mg with 1-2 rest days every 1-4days Rx;

Ethacrynic acid:

  • more GIT reactions, more precipitous dose-response curve than frusemide;
diuretics_loop.txt · Last modified: 2017/12/04 17:53 (external edit)