DIURETICS
One cannot discuss the
management of heart failure without including comments about the kidney. The
rela-tionship between the heart and the kidney makes intu-itive sense when one
considers the importance of the kidney in maintaining an appropriate volume status
throughout the body. An analogy that may be useful to consider is the situation
in which an individual turns on the faucet at home to find that little water is
flowing. The first assumption is that a leak somewhere in the sys-tem is
responsible for the lower water pressure. An ap-propriate response is to turn
off the water to the house. In an analogous manner, the kidney perceives low
car-diac output from a failing heart as a leak. The kidney be-gins to elaborate
hormones designed to retain fluid. Many of the problems in CHF result from an
inappro- priate neurohumoral activation by the kidney in re-sponse to perceived
volume depletion from hemor-rhage. Mechanisms that result in vasoconstriction
are normally compensatory in the short term for acute bleeding. These same
adaptive mechanisms become damaging in chronic heart failure.
The usefulness of diuretics
in the management of CHF cannot be overstated. Before diuretics were
avail-able, rotating tourniquets were used to diminish venous return by
ligating the lower extremities. Less venous blood returned to the right side of
the heart and pooled in the legs. This procedure diminished the effective
in-travascular volume that would otherwise have accumu-lated in the lungs. The
availability of loop diuretics (par-ticularly furosemide) has resulted in the
virtual elimination of this practice.
Diuretics and their
mechanisms of action will be dis-cussed in detail. Loop diuretics, such as
furosemide (Lasix), block the NA+
–K+ –2Cl- symporter in the ascending limb of the loop of
Henle. The resultant effect is delivery of more NA+ to the distal
tubule and enhanced urinary loss of NA+ and water. Unfortunately,
the resultant increase in urinary excretion of H+ and K+ can
lead to arrhythmias. The potential for arrhythmias is exacerbated by the loss
of Mg and Ca++ and an un-derlying vulnerability of the myocardium in
CHF. However, loop diuretics are still part of the mainstay of therapy for CHF
despite these potential problems and the absence of well-controlled multicenter
clinical trials. The rationale for their use is so compelling that
placebo-controlled studies appear unethical. Moreover, furosemide was accepted
as the standard of care in all of the clinical trials that form the basis for
recom-mended therapy for CHF. The use of the potassium-sparing diuretic
spironolactone has been shown to im-prove survival and is discussed below.
Spironolactone (Aldactone) is the only diuretic that has
been shown in a double-blind multicenter prospective clinical trial to improve
survival in CHF. The addition of spironolactone to digitalis and an
angiotensin-converting enzyme (ACE) inhibitor significantly im-proved survival
among patients with chronic severe heart failure. This study was conducted with
patients who were not taking a β-adrenoceptor blocking agent. It is unclear at present whether the
addition of spirono-lactone to a combination of digitalis,ACE inhibitor, and a
β-blocker will also confer additional benefit.
Spironolactone competitively
inhibits the binding of aldosterone to cytosolic mineralocorticoid receptors in
the epithelial cells in the late distal tubule and collect-ing duct of the
kidney. Aldosterone enhances salt and water retention at the expense of enhanced
renal K+ and H+ excretion. Spironolactone enhances
diuresis by blocking sodium and water retention while retaining potassium. An
obvious potential side effect is hyper-kalemia, which is aggravated by the
potassium-retaining properties of the ACE inhibitors. The likely concomi-tant
use of the loop diuretic furosemide, which depletes K+ , dictates
careful monitoring of serum potassium to avoid life-threatening rhythm
disturbances.
There is also evidence for
the existence of mineralo-corticoid receptors on cardiac myocytes. This raises
the intriguing possibility that spironolactone could mediate important direct
effects on the myocardium in CHF.
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