Page 536 - Fluid, Electrolyte, and Acid-Base Disorders in Small Animal Practice

524 FLUID THERAPY

treatment such as the combination of hydrochlorothia- potency of thiazide diuretics is limited, in part because
zide and spironolactone, which act more in the distal about 90% of the filtrate already has been reabsorbed
nephron. This type of sequential nephron blockade can before the distal nephron has been reached. For this rea-
induce a marked diuresis in some dogs but not without son these agents are low ceiling agents, and in human
risk of volume depletion and acute renal failure. A second patients higher dosages do not lead to proportionate
example pertains to the adverse effects of diuretics. Loop losses in sodium (but do predispose to more serious losses
diuretics increase the delivery of sodium to cells of the late of potassium and magnesium). 70 Nevertheless, when
distal convoluted tubules and collecting ducts. At those even low doses of a thiazide diuretic is combined with
sites, sodium is reabsorbed in exchange for potassium furosemide, dangerous volume depletion and electrolyte
(under the influence of aldosterone) or hydrogen ions losses can result.
that are secreted. 72 These ion exchange mechanisms have The late distal tubules and collecting ducts are sites of
the potential to cause hypokalemia and metabolic alkalo- sodium reabsorption, aldosterone-controlled secretion of
sis, especially with high doses or chronic therapy. potassium ions, ADH-mediated water reabsorption, and
The carbonic anhydrase inhibitors, such as acetazol- urine concentration. Diuretics acting at these sites initiate
amide, act on the proximal tubule by inhibiting bicarbon- diuresis by preventing movement of sodium through
ate reabsorption. These diuretics are limited in luminal channels, either by directly blocking the channels
effectiveness because they induce metabolic acidosis, (e.g., amiloride, triamterene) or by antagonizing the
and the loop of Henle and distal nephron can reabsorb effect of aldosterone (e.g., spironolactone, eplerenone).
much of the increased salt and water that is delivered to These drugs also exert a potassium-sparing effect and
these segments. Carbonic anhydrase inhibitors are not often are classified by that description. They act very dis-
used in treating CHF. tally in the nephron, and their quantitative potential to
Furosemide, ethacrynic acid, bumetanide, and inhibit sodium reabsorption is low, resulting in a weak
torsemide exert their effects on the ascending limb of to nearly absent diuretic effect. 74 The diuretic effect of
Henle’s loop. 112,142,170 These so-called loop diuretics spironolactone depends on prevailing aldosterone
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block the Na -K -2 Cl cotransporter (symport) and concentrations (which are low in animals with mild
prevent the active transport across the tubular lumen of CHF or in those receiving appropriate dosages of ACE
two chloride ions, one sodium ion, and one potassium inhibitors). The main value of these drugs is for mainte-
ion. Loop diuretics are potent with a good dose response, nance of normal serum potassium concentration or
whereas higher dosages result in greater sodium loss antagonism of aldosterone-induced cardiac
(“high ceiling”). This is related to the high capacity for injury. 129,160,161,181
reabsorbing filtrate at this site (normally approximately There are a number of clinically relevant issues
25% of the filtrate is reabsorbed there). Urinary concen- regarding the dosage and administration of
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tration is impaired because blocking the Na -K -2 Cl diuretics. 30,142,153,158 Many of the commonly used
carrier impedes development of a hypertonic renal diuretics are organic anions at physiologic pH and are
interstitium. Urinary dilution also is impaired because highly bound to serum proteins. To be effective, the
dilution of the filtrate is a normal function of this seg- diuretic must be delivered to the urinary space by glomer-
ment. After administration of a loop diuretic, there are ular filtration or active secretion in the proximal renal
substantial losses of chloride, sodium, water, and other tubule. Active secretion is the more important mecha-
electrolytes (including potassium, magnesium, and cal- nism because the drug is concentrated in tubular fluid.
cium) in the urine. In addition to tubular effects, some Reduced renal perfusion associated with heart failure,
hemodynamic and extrarenal effects of loop diuretics as well as primary renal disease or NSAID administration,
may arise from vasodilatation or increased venous capaci- may limit the effectiveness of a diuretic unless a high dos-
32,70
tance. For example, intravenous administration of age is used and the drug is sufficiently concentrated in
furosemide releases vasodilator prostaglandins that renal tubular fluid. This concern about renal perfusion
increase venous capacity and renal blood is one rationale for initial high-dose, intravenous admin-
flow. 13,109,117,124 Dyspnea in human patients is relieved istration of furosemide in patients with life-threatening
even before a reduction in lung water can be identified. 70 CHF. It also explains in part why chronic diuresis may
The thiazide and thiazide-like diuretics act on the cor- be associated with impaired response to diuretics. Drug
tical distal convoluted tubule by competing with the delivery is also relevant in terms of oral dosing of
luminal Na-Cl cotransporter and preventing movement diuretics. Gastrointestinal absorption may be impaired
of NaCl into the distal tubular cells. This effect impairs in CHF, especially with right-sided failure and intestinal
the ability to dilute urine (and excrete solute-free water) edema. More importantly the time course from absorp-
but does not necessarily affect urine concentration, which tion to renal delivery is longer than for parenteral admin-
is a medullary function. Accordingly, in hyponatremia, istration. This reduces the concentration of the drug
when there is impaired free-water clearance, the thiazide acting at the tubules, decreasing the overall diuretic
diuretics are relatively contraindicated. 75,142 The overall effect. Temporarily switching from oral to parenteral