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Management: diuretics, ACE inhibitors, and nitrates - Clinical Review - ABC of heart failure
From British Medical Journal, 2/12/00 by M K Davies

In the past 15 years several large scale, randomised controlled trials have revolutionised the management of patients with chronic heart failure. Although it is clear that some drugs improve symptoms, others offer both symptomatic and prognostic benefits, and the management of heart failure should be aimed at improving both quality of life and survival.

Diuretics and angiotensin converting enzyme (ACE) inhibitors, when combined with non-pharmacological measures, remain the basis of treatment in patients with congestive heart failure. Digoxin has a possible role in some of these patients, however, and the potential benefits of [Beta] blockers and spironolactone (an aldosterone antagonist) in chronic heart failure are now increasingly recognised.


Diuretics are effective in providing symptomatic relief and remain the first line treatment, particularly in the presence of oedema. Nevertheless, there is no direct evidence that loop and thiazide diuretics confer prognostic benefit in patients with congestive heart failure.

Loop diuretics

Loop diuretics--frusemide (furosemide) and bumetanide--have a powerful diuretic action, increasing the excretion of sodium and water via their action on the ascending limb of the loop of Henle. They have a rapid onset of action (intravenously 5 minutes, orally 1-2 hours; duration of action 4-6 hours). Oral absorption of frusemide may be reduced in congestive heart failure, although the pharmacokinetics of bumetanide may allow improved bioavailability.

Patients receiving high dose diuretics (frusemide [is greater than or equal to] 80 mg or equivalent) should be monitored for renal and electrolyte abnormalities. Hypokalaemia, which may precipitate arrhythmias, should be avoided, and potassium supplementation, or concomitant treatment with a potassium sparing agent, should generally be used unless contraindicated--for example, in renal dysfunction with potassium retention. Acute gout is a relatively common adverse effect of treatment with high dose intravenous diuretics.

Thiazide diuretics

Thiazides--such as bendrofluazide (bendroflumethiazide)--act on the cortical diluting segment of the nephron. They are often ineffective in elderly people, owing to the age related and heart failure mediated reduction in glomerular filtration rate. Hyponatraemia and hypokalaemia are commonly associated with higher doses of thiazide diuretics, and potassium supplementation, or concomitant treatment with a potassium sparing agent, is usually needed with high dose thiazide therapy.

In some patients with chronic severe congestive heart failure, particularly in the presence of chronic renal impairment, oedema may persist despite conventional oral doses (frusemide 40-160 mg daily) of loop diuretics. In these patients, a thiazide diuretic (for example, bendrofluazide) or a thiazide-like diuretic (for example, metolazone) may be combined with a loop diuretic. This combination blocks reabsorption of sodium at different sites in the nephron ("double nephron blockade"), and this synergistic action leads to a greater diuretic effect. The incidence of associated metabolic abnormalities is, however, increased, and such treatment should be started only under close supervision. In some patients, a large diuretic effect may occur soon after a combination regimen (loop diuretic plus either thiazide or metalozone) has been started. It is advisable, therefore, to consider such a combination treatment on a twice weekly basis, at least initially.

Potassium sparing diuretics

Amiloride acts on the distal nephron, while spironolactone is a competitive aldosterone inhibitor. Potassium sparing diuretics have generally been avoided in patients receiving ACE inhibitors, owing to the potential risk of hyperkalaemia. Nevertheless, a recent randomised placebo controlled study, the randomised aldactone evaluation study (RALES), reported that hyperkalaemia is uncommon when low dose spironolactone ([is less than or equal to] 25 mg daily) is combined with an ACE inhibitor. Risk factors for developing hyperkalaemia include spironolactone dose [is greater than] 50 mg/day, high doses of ACE inhibitor, or evidence of renal impairment. It is recommended that measurement of the serum creatinine and potassium concentrations is performed within 5-7 days of the addition of a potassium sparing diuretic to an ACE inhibitor until the levels are stable, and then every one to three months.

ACE inhibitors

ACE inhibitors have consistently shown beneficial effects on mortality, morbidity, and quality of life in large scale, prospective clinical trials and are indicated in all stages of symptomatic heart failure resulting from impaired left ventricular systolic function.

Mechanisms of action

ACE inhibitors inhibit the production of angiotensin II, a potent vasoconstrictor and growth promoter, and increase concentrations of the vasodilator bradykinin by inhibiting its degradation. Bradykinin has been shown to have beneficial effects associated with the release of nitric oxide and prostacyclin, which may contribute to the positive haemodynamic effects of the ACE inhibitors. Bradykinin may also be responsible, however, for some of the adverse effects, such as dry cough, hypotension, and angio-oedema.

ACE inhibitors also reduce the activity of the sympathetic nervous system as angiotensin II promotes the release of noradrenaline and inhibits its reuptake. In addition, they also improve [Beta] receptor density (causing their up regulation), variation in heart rate, baroreceptor function, and autonomic function (including vagal tone).

Clinical effects

Symptomatic left ventricular dysfunction

ACE inhibitors, when added to diuretics, improve symptoms, exercise tolerance, and survival and reduce hospital admission rates in chronic heart failure.

These beneficial effects are apparent in all grades of systolic heart failure--that is, mild to moderate chronic heart failure (as evident, for example, in the Munich mild heart failure study, the vasodilator heart failure trials (V-HeFT), and the studies of left ventricular dysfunction treatment trial (SOLVD-T)) and severe chronic heart failure (as, for example, in the first cooperative north Scandinavian enalapril survival study (CONSENSUS I).

Asymptomatic left ventricular dysfunction

ACE inhibitors have also been shown to be effective in asymptomatic patients with left ventricular systolic dysfunction. The studies of left ventricular dysfunction prevention trial (SOLVD-P) confirmed the benefit of ACE inhibitors in asymptomatic left ventricular systolic dysfunction, where enalapril reduced the development of heart failure and related hospital admissions.

Left ventricular dysfunction after myocardial infarction

Large scale, randomised controlled trials--for example, the acute infarction ramipril efficacy (AIRE) study, the survival and ventricular enlargement (SAVE) study, and the trial of trandolapril cardiac evaluation (TRACE)--have shown lower mortality in patients with impaired systolic function after myocardial infarction, irrespective of symptoms.

Slowing disease progression

ACE inhibitors also seem to influence the natural course of chronic heart failure. The Munich mild heart failure study showed that ACE inhibitors combined with standard treatment slowed the progression of heart failure in patients with mild symptoms, with significantly fewer patients in the active treatment group developing severe heart failure.

Doses and tolerability

ACE inhibitors should be started at a low dose and gradually titrated to the highest tolerated maintenance level. The recent prospective assessment trial of lisinopril and survival (ATLAS) randomised patients with symptomatic heart failure to low dose (2.5-5 mg daily) or high dose (32.5-35 mg daily) lisinopril, and, although there was no significant mortality difference, high dose treatment was associated with a significant reduction in the combined end point of all cause mortality and all cause admissions to hospital. Adverse effects of the ACE inhibitors include cough, dizziness, and a deterioration in renal function, although the overall incidence of hypotension and renal impairment in the CONSENSUS and SOLVD studies was only 5%. Angio-oedema related to ACE inhibitors is rare, although more common in patients of Afro-Caribbean origin than in other ethnic groups.

ACE inhibitors can therefore be regarded as the cornerstone of treatment in patients with all grades of symptomatic heart failure and in patients with asymptomatic left ventricular dysfunction. Every attempt should be made to provide this treatment for patients, unless it is contraindicated, and to use adequate doses.

Angiotensin receptor antagonists

Orally active angiotensin II type 1 receptor antagonists, such as losartan, represent a new class of agents that otter an alternative method of blocking the renin-angiotensin system. The effects of angiotensin II receptor antagonists on haemodynamics, neuroendocrine activity, and exercise tolerance resemble those of ACE inhibitors, although it still remains to be established fully whether these receptor antagonists are an effective substitute for ACE inhibitors in patients with chronic heart failure.

The evaluation of losartan in the elderly (ELITE) study compared losartan with captopril in patients aged 65 or over with mild to severe congestive heart failure. Although the ELITE study was designed as a tolerability study, and survival was not the primary end point, it did report a reduction in all cause mortality (4.8% v 8.7%) in patients treated with losartan. Important limitations of the ELITE study included the limited size and the relatively short follow up. However, the recently reported ELITE II mortality study failed to show that treatment with losartan was superior to captopril, although it confirmed improved tolerability with losartan.

ACE inhibitors, therefore, remain the treatment of choice in patients with left ventricular systolic dysfunction, although angiotensin II receptor antagonists are an appropriate alternative in patients who develop intolerable side effects from ACE inhibitors.

Oral nitrates and hydralazine

The V-HeFT trials showed a survival benefit from combined treatment with nitrates and hydralazine in patients with symptomatic heart failure (New York Heart Association class II-III). The V-HeFT II trial also showed a modest improvement in exercise capacity, although the nitrate and hydralazine combination was less well tolerated than enalapril, owing to the dose related adverse effects (dizziness and headaches). There is no reproducible evidence of symptomatic improvement from other randomised placebo controlled trials, however, and survival rates were higher with ACE inhibitors than with the nitrate and hydralazine combination (V-HeFT II trial).

In general, oral nitrates should be considered in patients with angina and impaired left ventricular systolic function. The combination of nitrates and hydralazine is an alternative regimen in patients with severe renal impairment, in whom ACE inhibitors and angiotensin II receptor antagonists are contraindicated. Although it is rational to consider the addition of a combination of nitrates and hydralazine in patients who continue to have severe symptoms despite optimal doses of ACE inhibitors, no large scale trials have shown an additive effect of these combinations.

Other vasodilators

Long acting dihydropyridine calcium channel blockers generally have neutral effects in heart failure, although others, such as diltiazem and verapamil, have negatively inotropic and chronotropic properties, with the potential to exacerbate heart failure. Two recent trials of the newer calcium channel blockers amlodipine (the prospective randomised amlodipine survival evaluation (PRAISE) trial) and felodipine (V-HeFT III) in patients with heart failure suggest that long acting calcium antagonists may have beneficial effects in non-ischaemic dilated cardiomyopathy, although further studies are in progress--for example, PRAISE II. Importantly, these studies indicate that amlodipine and felodipine seem to be safe in patients with congestive heart failure and could therefore be used to treat angina and hypertension in this group of patients.

The two tables on recommended doses of ACE inhibitors are adapted and reproduced with permission from Remme WJ (Eur Heart J 1997;18: 736-53). The meta-analysis table is adapted and used with permission from Garg R et al (JAMA 1995;273:1450-6). The graph showing the benefit of ACE inhibitors in left ventricular dysfunction is adapted from Davey Smith et al (BMJ 1994;308:73-4).

The ABC of heart failure is edited by C R Gibbs, M K Davies, and G Y H Lip. CRG is research fellow and GYHL is consultant cardiologist and reader in medicine in the university department of medicine and the department of cardiology, City Hospital, Birmingham; MKD is consultant cardiologist in the department of cardiology, Selly Oak Hospital, Birmingham. The series will be published as a book in the spring.


Meta-analysis of effects of ACE inhibitors on mortality and admissions in chronic heart failure

Doses of ACE inhibitors used in large controlled trials

(*) Twice daily;

([dagger]) three times daily.

NA = information not available.

Recommended maintenance doses of ACE inhibitors

(*) Twice daily;

([dagger]) three times daily;

([double dagger]) once daily.

Vasodilator heart failure (V-HeFT) studies

(*) I = asymptomatic, II = mild, III = moderate, IV = severe.

Aims of heart failure management

To achieve improvement in symptoms

* Diuretics

* Digoxin

* ACE inhibitors

To achieve improvement in survival

* ACE inhibitors

* [Beta] blockers (for example, carvedilol and bisoprolol)

* Oral nitrates plus hydralazine

* Spironolactone

How to use diuretics in advanced heart failure

* Optimise diuretic dose

* Consider combination diuretic treatment with a loop and thiazide (or thiazide-like) diuretic

* Consider combining a low dose of spironolactone with an ACE inhibitor, provided that there is no evidence of hyperkalaemia

* Administer loop diuretics (either as a bolus or a continuous infusion) intravenously

Guidelines for using ACE inhibitors

* Stop potassium supplements and potassium sparing diuretics

* Omit (or reduce) diuretics for 24 hours before first dose

* Advise patient to sit or lie down for 2-4 hours after first dose

* Start low doses (for example, captopril 6.25 mg twice daily, enalapril 2.5 mg once daily, lisinopril 2.5 mg once daily)

* Review after 1-2 weeks to reassess symptoms, blood pressure, and renal chemistry and electrolytes

* Increase dose unless there has been a rise in serum creatinine concentration (to [is greater than] 200 [micro]mol/l) or potassium concentration (to [is greater than] 5.0 mmol/l)

* Titrate to maximum tolerated dose, reassessing blood pressure and renal chemistry and electrolytes after each dose titration

If patient is "high risk" consider hospital admission to start treatment

ACE inhibitors: high risk patients warranting hospital admission for start of treatment

* Severe heart failure (NYHA class IV) or decompensated heart failure

* Low systolic blood pressure ([is less than] 100 mm Hg)

* Resting tachycardia [is greater than] 100 beats/minute

* Low serum sodium concentration ([is less than] 130 mmol/l)

* Other vasodilator treatment

* Severe chronic obstructive airways disease and pulmonary heart disease (cor pulmonale)

ELITE II study: the losartan heart failure survival study

* Multicentre, randomised, parallel group trial of captopril v losartan in chronic stable heart failure

* 3152 patients; age [is greater than] 60 years (mean age 71.5 years); NYHA class II-IV heart failure; mean follow up of 2 years

* No significant difference in all cause mortality between the captopril group (15.9%) and losartan group (17.7%)

* Better tolerability with losartan (withdrawal rate 9.4%) than with captopril (14.5%)

In general, diuretics should be introduced at a low dose and the dose increased according to the clinical response. There are dangers, however, in either undertreating or overtreating patients with diuretics, and regular review is necessary

The two main potassium sparing diuretics, amiloride and spironolactone, have a weak diuretic action when used alone; amiloride is most commonly used in fixed dose combinations with a loop diuretic-for example, co-amilofruse

Key references

* Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303-10.

* Cohn JN, Ziesche S, Smith R, Anand I, Dunkman WB, Loeb H, et al. Effect of the calcium antagonist felodipine as supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril. V-HeFT III. Circulation 1997;96:856-63.

* Packer M, O'Connor CM, Ghali JK, Pressler ML, Carson PE, Belkin RN, et al. Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N Engl J Med 1996;335:1107-14.

* Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ, Thomas I, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure. Lancet 1997;349:747-52.

* Remme WJ. The treatment of heart failure. The Task Force of the Working Group on Heart Failure of the European Society of, Cardiology. Eur Heart J 1997; 18:736-53.

* Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709-17.

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