Page 285 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 15 Diuretic Agents 271

usually be avoided because it causes NaHCO excretion and can may actually contribute to the syndrome and should be ruled
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exacerbate acidosis. Potassium-sparing diuretics may cause hyper- out before additional therapy is pursued. While spironolactone
kalemia. Thiazide diuretics are thought to be ineffective when has been used for idiopathic edema, it should probably be man-
GFR falls below 30 mL/min, although the exact GFR at which aged with moderate salt restriction alone if possible. Compres-
they no longer prove to be beneficial is still a matter of debate. In sion stockings have also been used but appear to be of variable
addition, it has been found that thiazides can be used to signifi- benefit.
cantly reduce the dose of loop diuretics needed to promote diure-
sis in a patient with a GFR of 5–15 mL/min. Thus, high-dose
loop diuretics (up to 500 mg/d of furosemide) or a combination NONEDEMATOUS STATES
of metolazone (5–10 mg/d) with furosemide (40–80 mg/d) may
be useful in treating volume overload in dialysis or predialysis HYPERTENSION
patients. Finally, although excessive use of diuretics can impair
renal function in all patients, the consequences are obviously more The diuretic and mild vasodilator actions of the thiazides are use-
serious in patients with underlying renal disease. ful in treating virtually all patients with essential hypertension and
may be sufficient in many (see also Chapter 11). Although hydro-
chlorothiazide is the most widely used diuretic for hypertension,
HEPATIC CIRRHOSIS chlorthalidone may be more effective because of its much longer
half-life. Loop diuretics are usually reserved for patients with mild
Liver disease is often associated with edema and ascites in con- renal insufficiency (GFR < 30–40 mL/min) or heart failure. Mod-
junction with elevated portal hydrostatic pressures and reduced erate restriction of dietary Na intake (60–100 mEq/d) has been
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plasma oncotic pressures. Mechanisms for retention of Na by the shown to potentiate the effects of diuretics in essential hyperten-
kidney in this setting include diminished renal perfusion (from sion and to lessen renal K wasting. A K -sparing diuretic can be
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systemic vascular alterations), diminished plasma volume (due to added to reduce K wasting.
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ascites formation), and diminished oncotic pressure (hypoalbu- There has been debate about whether thiazides should be used
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minemia). In addition, there may be primary Na retention due as the initial therapy in the treatment of hypertension. Their mod-
to elevated plasma aldosterone levels. est efficacy sometimes limits their use as monotherapy. However,
When ascites and edema become severe, diuretic therapy can a very large study of over 30,000 participants has shown that
be very useful. However, cirrhotic patients are often resistant to inexpensive diuretics like thiazides result in outcomes that are
loop diuretics because of decreased secretion of the drug into the similar or superior to those found with ACE inhibitor or calcium
tubular fluid and because of high aldosterone levels. In contrast, channel-blocker therapy. This significant result reinforces the
cirrhotic edema is unusually responsive to spironolactone and importance of thiazide therapy in hypertension.
eplerenone. The combination of loop diuretics and an aldosterone Although diuretics are often successful as monotherapy, they
receptor antagonist may be useful in some patients. However, con- also play an important role in patients who require multiple drugs
siderable caution is necessary in the use of aldosterone antagonists to control blood pressure. Diuretics enhance the efficacy of many
in cirrhotic patients with even mild renal insufficiency because of agents, particularly ACE inhibitors. Patients being treated with
the potential for causing serious hyperkalemia. powerful vasodilators such as hydralazine or minoxidil usually
It is important to note that, even more than in heart failure, require simultaneous diuretics because the vasodilators cause sig-
overly aggressive use of diuretics in this setting can be disastrous. nificant salt and water retention. There is also growing evidence
Vigorous diuretic therapy can cause marked depletion of intravas- showing that spironolactone may be the most effective single agent
cular volume, hypokalemia, and metabolic alkalosis. Hepatorenal in the therapy of drug-resistant hypertension, and this effect may
syndrome and hepatic encephalopathy are the unfortunate conse- extend to dialysis patients.
quences of excessive diuretic use in the cirrhotic patient. Vaptans
are relatively contraindicated in patients with liver disease because NEPHROLITHIASIS
a study of tolvaptan in treating patients with autosomal dominant
polycystic kidney disease resulted in increased transaminases in Approximately two thirds of kidney stones contain Ca phosphate
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some patients treated with high-dose tolvaptan. Low-dose tolvap- or Ca oxalate. Although there are numerous medical conditions
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tan, however, may prove to be useful in treating some patients (hyperparathyroidism, hypervitaminosis D, sarcoidosis, malignan-
with cirrhosis (those who do not have ongoing liver damage) who cies, etc) that cause hypercalciuria, many patients with such stones
suffer from hyponatremia or fluid overload. 2+
exhibit a defect in proximal tubular Ca reabsorption. This can
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be treated with thiazide diuretics, which enhance Ca reabsorp-
IDIOPATHIC EDEMA tion in the DCT and thus reduce the urinary Ca concentration.
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Fluid intake should be increased, but salt intake must be reduced,
Idiopathic edema (fluctuating salt retention and edema) is a since excess dietary NaCl will overwhelm the hypocalciuric effect
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syndrome found most often in 20- to 30-year-old women. of thiazides. Dietary Ca should not be restricted, as this can lead
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Despite intensive study, the pathophysiology remains obscure. to negative total body Ca balance. Calcium stones may also be
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Some studies suggest that surreptitious, intermittent diuretic use caused by increased intestinal absorption of Ca , or they may