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Chapter: Basic & Clinical Pharmacology : Diuretic Agents

Edematous States

A common reason for diuretic use is for reduction of peripheral or pulmonary edema that has accumulated as a result of cardiac, renal, or vascular diseases that reduce blood flow to the kidney.


A summary of the effects of diuretics on urinary electrolyte excre-tion is shown in Table 15–2.


A common reason for diuretic use is for reduction of peripheral or pulmonary edema that has accumulated as a result of cardiac, renal, or vascular diseases that reduce blood flow to the kidney. This reduction is sensed as insufficient effective arterial blood volume and leads to salt and water retention, which expands blood volume and eventually causes edema formation. Judicious use of diuretics can mobilize this interstitial edema without significant reductions in plasma volume. However, excessive diuretic therapy may compromise the effective arterial blood volume and reduce the perfusion of vital organs. Therefore, the use of diuretics to mobilize edema requires careful monitoring of the patient’s hemo-dynamic status and an understanding of the pathophysiology of the underlying illness.


When cardiac output is reduced by heart failure, the resultant changes in blood pressure and blood flow to the kidney are sensed as hypovolemia and lead to renal retention of salt and water. This physiologic response initially increases intravascular volume and venous return to the heart and may partially restore the cardiac output toward normal .

If the underlying disease causes cardiac output to deteriorate despite expansion of plasma volume, the kidney continues to retain salt and water, which then leaks from the vasculature and becomes interstitial or pulmonary edema. At this point, diuretic use becomes necessary to reduce the accumulation of edema, par-ticularly in the lungs. Reduction of pulmonary vascular conges-tion with diuretics may actually improve oxygenation and thereby improve myocardial function. Reduction of preload can reduce the size of the heart, allowing it to work at a more efficient fiber length. Edema associated with heart failure is generally managed with loop diuretics. In some instances, salt and water retention may become so severe that a combination of thiazides and loop diuretics is necessary.

In treating the heart failure patient with diuretics, it must always be remembered that cardiac output in these patients is being maintained in part by high filling pressures. Therefore, excessive use of diuretics may diminish venous return and further impair cardiac output. This is especially critical in right ventricular heart failure. Systemic, rather than pulmonary vascular, conges-tion is the hallmark of this disorder. Diuretic-induced volume contraction predictably reduces venous return and can severely compromise cardiac output if left ventricular filling pressure is reduced below 15 mm Hg . Reduction in cardiac output, resulting from either left or right ventricular dysfunction, also eventually leads to renal dysfunction resulting from reduced perfusion pressures.

Increased delivery of salt to the TAL leads to activation of the macula densa and a reduction in GFR by tubuloglomerular feed-back. The mechanism of this feedback is secretion of adenosine by macula densa cells, which causes afferent arteriolar vasoconstric-tion through activation of A1 adenosine receptors on the afferent arteriole. This vasoconstriction reduces GFR. Tubuloglomerular feedback–mediated reduction in GFR exacerbates the reduction that was initially caused by decreased cardiac output. Recent work with adenosine receptor antagonists has shown that it may soon be possible to circumvent this complication of diuretic therapy in heart failure patients by blunting tubuloglomerular feedback.

Diuretic-induced metabolic alkalosis, exacerbated by hypo-kalemia, is another adverse effect that may further compromise cardiac function. This complication can be treated with replacement of K+ and restoration of intravascular volume with saline; however, severe heart failure may preclude the use of saline even in patients who have received excessive diuretic therapy. In these cases, adjunc-tive use of acetazolamide helps to correct the alkalosis.

Another serious toxicity of diuretic use in the cardiac patient is hypokalemia. Hypokalemia can exacerbate underlying cardiac arrhythmias and contribute to digitalis toxicity. This can usually be avoided by having the patient reduce Na+ intake while taking diuretics, thus decreasing Na+ delivery to the K+-secreting collect-ing tubule. Patients who are noncompliant with a low Na+ diet must take oral KCl supplements or a K+-sparing diuretic.


A variety of diseases interfere with the kidney’s critical role in volume homeostasis. Although some renal disorders cause salt wasting, most cause retention of salt and water. When renal failure is severe (GFR < 5 mL/min), diuretic agents are of little benefit, because glomerular filtration is insufficient to generate or sustain a natriuretic response. However, a large number of patients, and even dialysis patients, with milder degrees of renal insufficiency (GFR of 5–15 mL/min), can be treated with diuretics when they retain excessive volumes of fluid between dialysis treatments.

There is still interest in the question as to whether diuretic therapy can alter the severity or the outcome of acute renal failure. This is because “nonoliguric” forms of acute renal insufficiency have better outcomes than “oliguric” (< 400–500 mL/24 h urine output) acute renal failure. Almost all studies of this question have shown that diuretic therapy helps in the short-term fluid manage-ment of these patients with acute renal failure, but that it has no impact on the long-term outcome.

Many glomerular diseases, such as those associated with diabe-tes mellitus or systemic lupus erythematosus, exhibit renal reten-tion of salt and water. The cause of this sodium retention is not precisely known, but it probably involves disordered regulation of the renal microcirculation and tubular function through release of vasoconstrictors, prostaglandins, cytokines, and other mediators. When edema or hypertension develops in these patients, diuretic therapy can be very effective.

Certain forms of renal disease, particularly diabetic nephropa-thy, are frequently associated with development of hyperkalemia at a relatively early stage of renal failure. In these cases, a thiazide or loop diuretic will enhance K+ excretion by increasing delivery of salt to the K+-secreting collecting tubule.

Patients with renal diseases leading to the nephrotic syndrome often present complex problems in volume management. These patients may exhibit fluid retention in the form of ascites or edema but have reduced plasma volume due to reduced plasma oncotic pressures. This is very often the case in patients with “minimal change” nephropathy. In these patients, diuretic use may cause further reductions in plasma volume that can impair GFR and may lead to orthostatic hypotension. Most other causes of nephrotic syndrome are associated with primary retention of salt and water by the kidney, leading to expanded plasma volume and hypertension despite the low plasma oncotic pressure. In these cases, diuretic therapy may be beneficial in controlling the volume-dependent component of hypertension.

In choosing a diuretic for the patient with kidney disease, there are a number of important limitations. Acetazolamide must usually be avoided because it causes NaHCO3 excretion and can exacerbate acidosis. Potassium-sparing diuretics may cause hyperkalemia. Thiazide diuretics were previously thought to be ineffective when GFR falls below 30 mL/min. More recently, it has been found that thiazides, which are of little ben-efit when used alone, can be used to significantly reduce the dose of loop diuretics needed to promote diuresis in a patient with GFR of 5–15 mL/min. Thus, high-dose loop diuretics (up to 500 mg of furosemide/d) or a combination of metolazone (5–10 mg/d) and much smaller doses of furosemide (40–80 mg/d) may be useful in treating volume overload in dialysis or predialysis patients. There has been some interest in the use of osmotic diuretics such as mannitol, because this drug can shrink swollen epithelial cells and may theoretically reduce tubular obstruction. Unfortunately, there is no evidence that mannitol can prevent ischemic or toxic acute renal failure. Mannitol may be useful in the management of hemoglobinuria or myoglobinuria. Lastly, although excessive use of diuretics can impair renal function in all patients, the consequences are obviously more serious in patients with underlying renal disease.


Liver disease is often associated with edema and ascites in con-junction with elevated portal hydrostatic pressures and reduced plasma oncotic pressures. Mechanisms for retention of Na+ by the kidney in this setting include diminished renal perfusion (from systemic vascular alterations), diminished plasma volume (due to ascites formation), and diminished oncotic pressure (hypoalbu-minemia). In addition, there may be primary Na+ retention due to elevated plasma aldosterone levels.

When ascites and edema become severe, diuretic therapy can be very useful. However, cirrhotic patients are often resistant to loop diuretics because of decreased secretion of the drug into the tubular fluid and because of high aldosterone levels. In contrast, cirrhotic edema is unusually responsive to spironolactone and eplerenone. The combination of loop diuretics and an aldosterone receptor antagonist may be useful in some patients. However, considerable caution is necessary in the use of aldosterone antago-nists in cirrhotic patients with even mild renal insufficiency because of the potential for causing serious hyperkalemia.

It is important to note that, even more than in heart failure, overly aggressive use of diuretics in this setting can be disastrous. Vigorous diuretic therapy can cause marked depletion of intra-vascular volume, hypokalemia, and metabolic alkalosis. Hepatorenal syndrome and hepatic encephalopathy are the unfortunate consequences of excessive diuretic use in the cir-rhotic patient.


Idiopathic edema (fluctuating salt retention and edema) is a syn-drome found most often in 20–30 year-old women. Despite intensive study, the pathophysiology remains obscure. Some stud-ies suggest that surreptitious, intermittent diuretic use may actu-ally contribute to the syndrome and should be ruled out before additional therapy is pursued. While spironolactone has been used for idiopathic edema, it should probably be managed with moder-ate salt restriction alone if possible. Compression stockings have also been used but appear to be of variable benefit.

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