Diuretic-related side effects: development and treatment

Diuretics are important therapeutic tools. First, they effectively reduce blood pressure and have been shown in numerous hypertension clinical trials to reduce both cardiovascular and cerebrovascular morbidity and mortality. In addition, their use has been equally effective in controlling cardiovascular events as angiotensin-converting enzyme inhibitors or calcium channel blockers. Diuretics are currently recommended by the Seventh Report of the Joint National Commission on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure report as first-line therapy for the treatment of hypertension. In addition, they remain an important aspect of congestive heart failure treatment in that they improve the congestive symptomatology, which typifies the more advanced stages of congestive heart failure. This article reviews the commonly encountered side effects with the various diuretic classes. Where indicated, the mechanistic basis and treatment of such side effects is further discussed.     

Diuretic therapy in congestive heart failure

The principal goals of treatment of the patient in heart failure are the relief of their symptoms and improvement in their prognosis. Of all antiheart failure drugs currently available, the diuretics are therapeutically superior in their efficacy in relieving clinical symptoms and signs. Whether administered intravenously or orally, all diuretics result in a substantial reduction in the raised pulmonary vascular pressures in combination with a small reduction in cardiac output. Diuretics stimulate release of renin with subsequent activation of the renin-angiotensin-aldosterone system, particularly if used in large doses, although their quantitative impact on the neuroendocrine profile at different stages of heart failure remains to be defined. In patients with mild heart failure, diuretics reduce plasma catecholamine concentrations, but their sympatholytic effects in more severe cases are unknown, as are their effects on the metabolically active tissues in these patients. Diuretic resistance can be circumvented by segmental nephron blockade with a combination of low-dose diuretics that simultaneously block sodium reabsorption in the proximal tubule, the loop of Henle, the distal tubule, and the collecting duct. Diuretics improve symptoms of breathlessness and signs of peripheral edema in patients with congestive heart failure in direct relationship to the induced diuresis. These benefits are frequently associated with a substantial improvement in patients' appreciation of quality of life and economic capacity. There are few adverse reactions to chronic diuretic therapy, but the serum electrolytes should be monitored for hypokalemia and hypomagnesemia. The impact of diuretics on prognosis of patients with congestive heart failure is unknown; however, diuretics have been a major ingredient of the therapies used in all the survival trials with vasodilators, angiotensin-converting enzyme inhibitors, and beta-blocking drugs. In addition to their clinical benefits, diuretics are the most cost-effective treatment of any single drug group currently available for the treatment of patients with congestive heart failure.     

Diuretic therapy in congestive heart failure

Diuretics are a mainstay of therapy in patients with congestive heart failure. A small number of patients can achieve adequate diuresis with a thiazide diuretic alone, but most require a loop diuretic. Some patients with severe disease require combinations of diuretics. Most patients with congestive heart failure manifest resistance to diuretics by having a diminished natriuresis compared with healthy counterparts. This diminished response even to potent diuretics means that dietary sodium may exceed sodium excretion, resulting in patient decompensation. The pharmacokinetics and pharmacodynamics of loop diuretics have been characterized in patients with congestive heart failure, thereby allowing rational therapeutic strategies in terms of what type of doses should be administered, how often, and when to use diuretic combinations. The purpose of this review is to show how understanding pharmacokinetics and pharmacodynamics results in logical diuretic use. (c)2000 by CHF, Inc.     

Therapy of dilated cardiomyopathy with digitalis, diuretics and vasodilators

The treatment of dilated cardiomyopathy is primarily concerned with that of congestive heart failure. Digitalis is widely use in dilated cardiomyopathy but an improvement in the prognosis has not yet been demonstrated. Furthermore, the effects of digitalis in patients with sinus rhythm are debatable. If dilated cardiomyopathy induces atrial fibrillation and tachyarrhythmia, digitalis should be used. Diuretics are helpful in the treatment of congestive heart failure associated with dilated cardiomyopathy. By reducing hypervolemia and by venous dilatation, diuretics lower preload and afterload. This leads to relief of congestion and termination of the vicious cycle of congestive heart failure. Accordingly, the prognosis of dilated cardiomyopathy might be improved by diuretics. There are numerous diuretics acting differently on the renal tubules, the choice of which depends on the renal function and serum electrolyte concentrations. Reduction of preload and afterload improves congestive heart failure as has been demonstrated repeatedly. Many substances have therefore been used for arterial and venous dilation with differing results. At least for short-term periods, congestion is reduced and cardiac output increases. Especially inhibitors of angiotensin II converting enzyme are very effective since they act both in the arterial and venous systems. Additionally, inhibition of the action of angiotensin may be regarded as causal therapy since the renin-angiotensin system is the trigger for vasoconstriction and fluid retention in congestive heart failure. Unlike other substances, ACE inhibitors have been demonstrated to improve prognosis of patients with congestive heart failure. At present, combined diuretic therapy and angiotensin conversion enzyme inhibition would seem the most reasonable treatment for patients with dilated cardiomyopathy and sinus rhythm. If atrial fibrillation and tachyarrhythmia develop, additional digitalis therapy is effective.     

Diuretika bei Herzinsuffizienz

Diuretics are useful and inevitable in acute congestive heart failure with pulmonary congestion and edema. The use of low-dose thiazide diuretics is well established in arterial hypertension. In acute heart failure, diuretics are recommended for the treatment of fluid overload and pulmonary edema. No evidence is available so far regarding any benefit of diuretics on the outcome of patients with chronic heart failure, whereas evidence-based blockade of the renin-angiotensin system and sympathetic nervous system reduces the risk of congestion and improves survival. Several types of diuretics are relevant: loop diuretics, thiazides, and potassium-sparing diuretics. All diuretics have significant side effects, mainly electrolyte disorders, metabolic acidosis/alkalosis, insulin resistance, and ototoxicity. Diuretics have no benefit in acute or acute-on-chronic renal failure; moreover, they even increase mortality and reduce the chance of renal recovery in these patients. Increased mortality with the use of diuretics also seems to be associated with a higher risk of lethal arrhythmias. Sequential tubular blockade may be useful for the short term in potentiating the natriuresis in renocardiac syndromes. Furthermore, ultrafiltration or renal replacement therapy may have an additional beneficial effect in these patients, although controlled trials are still lacking.     

Hypertension and diastolic heart failure

In patients with hypertension, pressure overload leads to left ventricular hypertrophy (LVH), myocardial fibrosis, and impaired diastolic filling without systolic dysfunction. Presently, diastolic heart failure accounts for about 50% of the heart failure population. Fatigue, dyspnea, reduced exercise tolerance, and peripheral edema are common presenting complaints. As a group, patients with diastolic heart failure are older and predominantly female. Diuretics are effective for treating congestive symptoms. β Blockers and heart rate-lowering calcium blockers show benefit in smaller studies but have not been evaluated in definitive clinical trials. Renin-angiotensin-aldosterone system blockers reduce blood pressure, LVH, and myocardial fibrosis; however, long-term studies with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers demonstrate little effect on symptoms or survival, and inconsistent effects on heart failure hospitalization. At present, evidence-based treatment includes antihypertensive therapy to reduce progression from hypertension to heart failure. In patients with established heart failure, diuretics and other empiric treatments are used to control symptoms.     

The role of diuretics in the treatment of chronic heart failure

Altered renal function with renal NaCl-retention can be observed early in the course of congestive heart failure. The afferent pathway of this altered regulation involves changes occurring in the high pressure system as a consequence of foreward failure such as an increase in baroreceptor reflex activity. Efferent pathways may include the renin-angiotensin-aldosterone system, the sympathetic nervous system, prostaglandins, dopamine, ANF, and AVP. At present, the relative importance of these systems in mediating renal NaCl-retention in heart failure is still unclear. Expansion of the extracellular fluid volume as a consequence of renal NaCl-retention may, at least acutely, compensate for compromised myocardial function via the Frank-Starling mechanism. As a consequence of volume expansion, chronically increased cardiac preload and possibly afterload may however even aggravate cardiac failure. Diuretics may therefore induce variable effects in patients with congestive heart failure. Acutely, they may ameliorate symptoms of congestion in spite of the possibility of a further decrease in cardiac index. Chronically, they may reduce cardiac pre- and afterload. Through a variety of mechanisms, they may therefore increase cardiac performance in spite of a fall in filling pressures.     

Diuretics for the treatment of acute decompensated heart failure

Diuretics have been a mainstay for the treatment of acute decompensated heart failure (ADHF) for the past four decades, though their short-term gains have been questioned recently given their potential long-term deleterious systemic effects. The methods of diuretic administration as well as the optimal dosing regimen of these agents are both areas that have been increasingly coming under scrutiny. The lack of rigorous clinical trials examining diuretic use in ADHF, however, has led to a general adoption of non-evidence based treatment algorithms for this patient population. Though the use of intravenous vasodilators for the treatment of decompensated heart failure has grown tremendously over the last few years, the fact remains that diuretics are still indispensable for alleviating congestive symptoms. Given this reality and until further information is available about the most ideal utilization of these medications, diuretics will continue to represent a double-edged sword for physicians treating this disease process.     

Dyspnoe bei normaler systolischer Funktion

30-50% of patients presenting with symptoms of congestive heart failure exhibit a near normal left ventricular systolic function at rest, and an impaired diastolic function of the heart may be causative. Despite a better prognosis than in systolic heart failure, frequency of hospitalizations due to diastolic heart failure is comparable with systolic heart failure. According to the criteria of Vasan and Levy diagnosis of diastolic heart failure is probable, if symptoms and signs of heart failure are accompanied in proximity (within 72 h) by objective evidence of normal left ventricular systolic function. Newer echocardiographic techniques (e. g., tissue Doppler) aid to confirm the diagnosis and to determine the severity of dysfunction and may substitute invasive demonstration of impaired left ventricular relaxation, filling, compliance or stiffness for standardized diagnosis. Incorporation of biochemical test (BNP [brain natriuretic peptide]) allows differential diagnosis and may increase the accuracy of diagnosis. Due to inconsistent diagnostic criteria, data from prospective randomized controlled trials for the treatment of diastolic heart failure are rare. Basic principles include treatment of the underlying disease, i. e., control of hypertension, diabetes, or obstructive airway disease. Angiotensin 1 antagonists (ARB) have proven effective in regression of left ventricular hypertrophy (LIFE) and may reduce morbidity, but not mortality (CHARM). Maintenance of sinus rhythm, heart rate control (beta-blockers, calcium channel blockers) and anti-ischemic therapy may be indicated in view of pathophysiological aspects. Diuretics should be administered with caution in patients with symptoms of congestion, digitalis is not useful in the treatment of isolated diastolic heart failure. The results of ongoing trials (e. g., I-Preserve) may offer new therapeutic options, and evidence-based guidelines for the so far often unsatisfactory treatment of diastolic dysfunction/heart failure are awaited.     

Balancing diuretic therapy in heart failure: loop diuretics,thiazides, and aldosterone antagonists

In heart failure, sodium is retained by the kidneys despite increases in extracellular volume. There is activation of renin secretion, which culminates in the production of angiotensin II, causing vasoconstriction and aldosterone secretion. These synergistically produce an increase in tubular reabsorption of sodium and water. Diuretics are the mainstay of symptomatic treatment to remove excess extracellular fluid in heart failure. Diuretics that affect the ascending loop of Henle are most commonly used. Thiazide diuretics promote a much greater natriuretic effect when combined with a loop diuretic in patients with refractory edema. Recently, spironolactone, an aldosterone receptor blocking agent, has been recommended to attenuate some of the neurohormonal effects of heart failure. Regardless of the diuretic, patients need to be counseled on the importance of avoiding sodium in their diet     

Use of diuretics in the treatment of heart failure in the elderly

Diuretics are tools of considerable therapeutic importance. First, they effectively reduce blood pressure, while at the same time decreasing the morbidity and mortality associated with hypertension. Diuretics are currently recommended as first-line therapy for the treatment of hypertension. In addition, they remain an important component of heart failure therapy, in that they improve the symptoms of congestion, which typify the more advanced stages of heart failure. This article reviews the mode of action of the various diuretic classes and the physiologic adaptations that follow; sets up the basis for their use in the treatment of volume-retaining states, particularly as applies to the elderly; and reviews diuretic-related side effects that are normally encountered.     

Use of diuretics in the treatment of heart failure in the elderly

Diuretics are tools of considerable therapeutic importance. First, they effectively reduce blood pressure, while at the same time decreasing the morbidity and mortality associated with hypertension. Diuretics are currently recommended as first-line therapy for the treatment of hypertension. In addition, they remain an important component of heart failure therapy, in that they improve the symptoms of congestion, which typify the more advanced stages of heart failure. This article reviews the mode of action of the various diuretic classes and the physiologic adaptations that follow; sets up the basis for their use in the treatment of volume-retaining states, particularly as applies to the elderly; and reviews diuretic-related side effects that are normally encountered.     

Hypertension: an important precursor of heart failure

Hypertension is an important risk factor for cardiovascular morbidity and mortality. Hypertension is associated with the development of congestive heart failure by way of left ventricular hypertrophy, with left ventricular dilatation and through myocardial ischemia and left ventricular damage. Reports on the natural history of untreated hypertension indicate that at least 50% of affected subjects develop congestive heart failure. Hypertension is an important precursor of heart failure, and still the most common risk factor for congestive heart failure in the population. In clinical trials, particularly in elderly patients, a reduction in the incidence of congestive heart failure has been observed. Despite increments in the use of antihypertensive drugs, mortality from congestive heart failure among the elderly is increasing. Moreover, several patients with hypertension are unaware, untreated and uncontrolled for the most important risk factor for congestive heart failure. For the primary prevention of heart failure, improvements in blood pressure control are of vast importance.     

Hypertension: an important precursor of heart failure

Hypertension is an important risk factor for cardiovascular morbidity and mortality. Hypertension is associated with the development of congestive heart failure by way of left ventricular hypertrophy, with left ventricular dilatation and through myocardial ischemia and left ventricular damage. Reports on the natural history of untreated hypertension indicate that at least 50% of affected subjects develop congestive heart failure. Hypertension is an important precursor of heart failure, and still the most common risk factor for congestive heart failure in the population. In clinical trials, particularly in elderly patients, a reduction in the incidence of congestive heart failure has been observed. Despite increments in the use of antihypertensive drugs, mortality from congestive heart failure among the elderly is increasing. Moreover, several patients with hypertension are unaware, untreated and uncontrolled for the most important risk factor for congestive heart failure. For the primary prevention of heart failure, improvements in blood pressure control are of vast importance.     

Effect of propranolol after acute myocardial infarction in patients with congestive heart failure

The incidence of congestive heart failure was studied in the Beta Blocker Heart Attack Trial in which postmyocardial infarction patients between the ages of 30 and 69 years, with no contraindication to propranolol, were randomly assigned to receive placebo (n = 1921) or propranolol 180 or 240 mg daily (n = 1916) 5 to 21 days after admission to the hospital for the event. Survivors of acute myocardial infarction with compensated or mild congestive heart failure, including those on digitalis and diuretics, were included in the study. A history of congestive heart failure before randomization characterized 710 (18.5%) patients: 345 (18.0%) in the propranolol group and 365 (19.0%) in the placebo group. The incidence of definite congestive heart failure after randomization and during the study was 6.7% in both groups. In patients with a history of congestive heart failure before randomization, 51 of 345 (14.8%) in the propranolol group and 46 of 365 (12.6%) in the placebo group developed congestive heart failure during an average 25 month follow-up. In the patients with no history of congestive heart failure, 5% in the propranolol group developed congestive heart failure and 5.3% in the placebo group developed congestive heart failure. Baseline characteristics predictive of the occurrence of congestive heart failure by multivariate analyses included an increased cardiothoracic ratio, diabetes, increased heart rate, low baseline weight, prior myocardial infarction, age, and more than 10 ventricular premature beats per hour.(ABSTRACT TRUNCATED AT 250 WORDS)     

The brain in congestive heart failure

In the present paper we discuss two issues about relationships between congestive heart failure and the brain. First, major acute cerebrovascular events are very frequent among elderly people, but stroke does not appear to be frequently associated with congestive heart failure. Second, some cardiovascular conditions may determine progressive damage of cerebral tissue, with consequent impairment of cognitive functions. The association of cognitive impairment and cardiovascular diseases may dramatically increase morbility and mortality risks in the elderly. Recent studies seem to show that hypotension and congestive heart failure are risk factors for dementia in elderly people. In view of this data, an Italian multicentric study on congestive heart failure in hospitalized elderly patients (CHF Italian Study I) included a brief screening of cognitive abilities (MMSE). The presence of congestive heart failure induced a significant decrease of MMSE scores: mean MMSE score after statistical adjustment for the other variables was about one point lower in patients with congestive heart failure respect to elderly patients affected by heart disease but without congestive heart failure. A novel multicentric study (CHF Italian Study II) has been performed to identify cognitive functions more specifically impaired during congestive heart failure in the elderly. Preliminary data relative to 385 patients, confirmed that congestive heart failure may induce a generalized impairment of cognitive functions. These data have relevant clinical implications because they demonstrate that a multidisciplinary approach is necessary in these patients, both for prevention and rehabilitation therapy.     

脑利钠肽浓度评估慢性充血性心力衰竭

目的　探讨血浆脑利钠肽 (BNP)浓度在慢性充血性心力衰竭 (心衰 ,CHF)时的变化及其临床诊断价值。方法　 83例心脏病患者 ,根据有无并发心衰分为心衰组和非心衰组 ,在入院时测定血浆BNP浓度 ,并行心电图、胸部X线摄片、超声心动图检查。两位心脏科医生独立分析BNP结果 ,并结合患者所有的临床资料做出判断。结果　心衰组 5 7例 ,非心衰组 2 6例 ,BNP水平心衰组较非心衰组显著升高 (P <0 .0 0 1) ;BNP浓度随着心功能分级的增加而升高 ;BNP与超声心动图指标有很好的相关性。BNP诊断心衰的ROC曲线下面积 (AUC)为 0 .95 [( 95 %CI:0 .90～ 0 .99) ,P <0 .0 0 1]。结论　血浆BNP水平在慢性充血性心衰患者中明显升高 ,有助于确定心衰的诊断并能反映其严重程度。     

Diuretic resistance in heart failure

The use of diuretics for the treatment of heart failure (HF) is ubiquitous in any basic HF medical regimen. Although initially these drugs clearly show benefit by relieving symptomatic episodes of decompensated HF, long-term use of these drugs can lead to a ‘diuretic-resistant’ state and is associated with an increased risk of morbidity and mortality. A number of factors may be responsible for this, including dietary noncompliance, inadequate diuretic dosing or methods of administration, and concomitant use of certain medications. Diuretics themselves may set in motion an iatrogenic cardiorenal syndrome leading to worsening renal function and diuretic resistance. The methods for overcoming this resistance are varied and require a focused approach with emphasis on relieving the congestive symptoms related to HF while attempting to preserve renal function and minimize any untoward systemic effects.     

培哚普利对充血性心力衰竭患者的影响

目的：观察培哚普利对充血性心力衰竭患者的影响。方法：对30例充血性心力衰竭患者在常规强心、利尿、扩血管治疗基础上，加用培哚普利；另外30例充血性心力衰竭患者为对照组，进行常规抗心力衰竭治疗。比较两种方法治疗心力衰竭后心功能的变化。结果：治疗组心功能改善总有效率（93．3％），左室射血分数（58％），明显高于对照组（P〈0．05）。结论：培哚普利对充血性心力衰竭患者能明显改善心功能，心力衰竭的症状。     

Role of diabetes in congestive heart failure: the Framingham study

The incidence of congestive heart failure was determined in relation to prior diabetic status in 5,209 men and women aged 30 to 62 years followed up for 18 years in the Framingham study. Men aged 45 to 74 years had more than twice the frequency of congestive failure as their nondiabetic cohorts, and diabetic women had a fivefold increased risk. This excessive risk appears to be caused by factors other than accelerated atherogenesis and coronary heart disease. Even when patients with prior coronary or rheumatic heart disease were excluded, the diabetic subjects had a four- to fivefold increased risk of congestive heart failure. In women (but not men) with prior coronary disease, diabetes also imposed a threefold increased risk of congestive failure. Furthermore, the increased risk of heart failure in the diabetic patients persisted after taking into account age, blood pressure, weight and cholesterol values as well as coronary heart disease. Women with diabetes appeared to be especially vulnerable and, irrespective of coronary disease status, had twice the frequency of congestive heart failure as men. The excessive risk of heart failure among diabetic subjects was confined to those treated with insulin. The data suggest that diabetes is another discrete cause of congestive heart failure and that some form of cardiomyopathy is associated with diabetes, as a result of either small vessel disease or metabolic disorders.