DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

686 cardiac arrhythmias, particularly in patients taking cardiac glycosides.
Increased Mg 2+ and Ca 2+ excretion may result in hypomagnesemia
(a risk factor for cardiac arrhythmias) and hypocalcemia
(rarely leading to tetany). Recent evidence suggests that loop diuretics
should be avoided in postmenopausal osteopenic women, in
whom increased Ca 2+ excretion may have deleterious effects on bone
metabolism (Rejnmark et al., 2003).
Loop diuretics can cause ototoxicity that manifests as tinnitus,
hearing impairment, deafness, vertigo, and a sense of fullness in
the ears. Hearing impairment and deafness are usually, but not
always, reversible. Ototoxicity occurs most frequently with rapid
intravenous administration and least frequently with oral administration.
Ethacrynic acid appears to induce ototoxicity more often
than do other loop diuretics and should be reserved for use only in
patients who cannot tolerate other loop diuretics. Loop diuretics also
can cause hyperuricemia (occasionally leading to gout) and hyperglycemia
(infrequently precipitating diabetes mellitus) and can
increase plasma levels of low-density lipoprotein (LDL) cholesterol
and triglycerides while decreasing plasma levels of high-density
lipoprotein (HDL) cholesterol. Other adverse effects include skin
rashes, photosensitivity, paresthesias, bone marrow depression, and
GI disturbances. Glucose intolerance frequently can be demonstrated
but precipitation of diabetes mellitus has been reported only rarely.
Contraindications to the use of loop diuretics include severe
Na + and volume depletion, hypersensitivity to sulfonamides (for sulfonamide-based
loop diuretics), and anuria unresponsive to a trial
dose of loop diuretic.
Drug interactions may occur when loop diuretics are coadministered
with:
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
• aminoglycosides, carboplatin, paclitaxel and several other
agents (synergism of ototoxicity)
• anticoagulants (increased anticoagulant activity)
• digitalis glycosides (increased digitalis-induced arrhythmias)
• lithium (increased plasma levels of lithium)
• propranolol (increased plasma levels of propranolol)
• sulfonylureas (hyperglycemia)
• cisplatin (increased risk of diuretic-induced ototoxicity)
• NSAIDs (blunted diuretic response and salicylate toxicity
when given with high doses of salicylates)
• probenecid (blunted diuretic response)
• thiazide diuretics (synergism of diuretic activity of both drugs
leading to profound diuresis)
• amphotericin B (increased potential for nephrotoxicity and
toxicity and intensification of electrolyte imbalance)
Therapeutic Uses. All loop diuretics except torsemide
are available as oral and injectable formulations.
Bumetanide is labeled for once daily administration and
may be used in patients allergic to furosemide (the
bumetamide:furosemide conversion ratio is approximatly
1:40). A major use of loop diuretics is in the treatment
of acute pulmonary edema. A rapid increase in
venous capacitance in conjunction with a brisk natriuresis
reduces left ventricular filling pressures and thereby
rapidly relieves pulmonary edema. Loop diuretics also
are used widely for treatment of chronic congestive
heart failure when diminution of extracellular fluid volume
is desirable to minimize venous and pulmonary
congestion (Chapter 28). In this regard, a meta-analysis
of randomized clinical trials demonstrates that diuretics
cause a significant reduction in mortality and the risk of
worsening heart failure, as well as an improvement in
exercise capacity (Faris et al., 2002).
Diuretics are used widely for treatment of hypertension
(Chapter 28), and controlled clinical trials
demonstrating reduced morbidity and mortality have
been conducted with Na + -Cl – symport (thiazides and thiazide-like
diuretics) but not Na + -K + -2Cl – symport
inhibitors. Nonetheless, Na + -K + -2Cl – symport inhibitors
appear to lower blood pressure as effectively as Na + -Cl –
symport inhibitors while causing smaller perturbations
in the lipid profile. However, the relative potency and
short elimination half-lives of loop diuretics render them
less useful for hypertension than thiazide-type diuretics.
The edema of nephrotic syndrome often is refractory to less
potent diuretics, and loop diuretics often are the only drugs capable
of reducing the massive edema associated with this renal disease.
Loop diuretics also are employed in the treatment of edema and
ascites of liver cirrhosis; however, care must be taken not to induce
volume contraction. In patients with a drug overdose, loop diuretics
can be used to induce a forced diuresis to facilitate more rapid renal
elimination of the offending drug. Loop diuretics, combined with
isotonic saline administration to prevent volume depletion, are used
to treat hypercalcemia. Loop diuretics interfere with the kidney’s
capacity to produce a concentrated urine. Consequently, loop diuretics
combined with hypertonic saline are useful for the treatment of
life-threatening hyponatremia.
Loop diuretics also are used to treat edema associated with
chronic kidney disease. Higher doses of loop diuretics are often
required in patients with chronic kidney disease. The dose-response
curve is shifted to the right (Figure 25–8). Animal studies have
demonstrated that loop diuretics increase P GC
by activating the reninangiotensin
system, an effect that could accelerate renal injury (Lane et
al., 1998). Most patients with ARF receive a trial dose of a loop diuretic
in an attempt to convert oliguric ARF to nonoliguric ARF. However,
there is no evidence that loop diuretics prevent ATN or improve outcome
in patients with ARF, and as mentioned earlier, the appearance of
undesired effects increases with dose.
INHIBITORS OF Na + -Cl – SYMPORT
(THIAZIDE AND THIAZIDE-LIKE
DIURETICS)
Benzothiadiazides were synthesized in an effort to
enhance the potency of inhibitors of carbonic anhydrase.
However, unlike carbonic anhydrase inhibitors (that primarily
increase NaHCO 3
excretion), benzothia diazides
predominantly increase NaCl excretion, an effect shown
to be independent of carbonic anhydrase inhibition.