Terodiline causes polymorphic ventricular tachycardia due to reduced heart rate and prolongation of QT interval

Summary Recent reports have suggested an association between terodiline hydrochloride and cardiac arrhythmias. We report 4 patients presenting over a six month period who developed polymorphic ventricular tachycardia (polymorphic VT) while receiving treatment with this agent. In each case there was prolongation of QT interval on electrocardiogram (ECG). Two patients had hypokalaemia associated with diuretic therapy. In the 3 cases in which follow-up ECG was available, QT interval returned to normal after discontinuation of terodiline.In order to define the effects of terodiline on corrected QT interval (QTc) and heart rate in the elderly, a prospective study was performed in 8 elderly in-patients treated with terodiline for urinary incontinence. After 7 days treatment with terodiline 12.5 mg twice daily, there was a significant increase in QT by a mean of 29 ms, QTc by 15 ms and a decrease in resting heart rate by a mean of 6.7 beats·min^–1.Terodiline increases QTc and reduces resting heart rate in elderly patients. Both these effects may be associated with polymorphic VT, a potentially life threatening arrhythmia. This drug should be avoided in patients with other known risk factors for polymorphic VT, particularly hypokalaemia and cardiac disease.     

Adverse effects of diuretics.

Analysis of the available evidence indicates that diuretics do not increase coronary heart disease morbidity and mortality. The multiclinic trials supporting the cardiotoxicity hypothesis are few in number and flawed in design. The majority of the trials, including the well designed trials, indicate no excess of coronary heart disease (CHD) events in diuretic-treated patients compared with those given other drugs or placebo. Recent studies indicate no increase in cardiac arrhythmias after diuretic treatment. Also, although depletion of intracellular potassium and magnesium occurs in patients with congestive heart failure even without diuretics, intracellular concentration of these ions is not significantly reduced by diuretics in patients with uncomplicated hypertension. Modest elevations of serum cholesterol may occur during the first 6 to 12 months of treatment with thiazide diuretics. However, after this time these elevations fall to or below the pretreatment level. The fall may be greater in patients receiving other drugs but the differences are small and their clinical significance is questionable. The incidences of hyperglycaemia and diabetes were only minimally increased in long term clinical trials while the importance of hyperinsulinism and insulin resistance in causing CHD remains unproven in patients. Thiazides remain, therefore, a safe and effective treatment for patients with hypertension.     

Initial therapy for mild hypertension

The treatment of mild hypertension has been a subject of controversy because its benefits versus risks are not as well established as they are for moderate to severe hypertension. Results of several studies, however, now show that treatment reduces the frequency of stroke in those with milder blood pressure elevations. New guidelines published by the Joint National Committee recommend that treatment of mild hypertension begin with either a diuretic or a beta blocker. The effect on the most common complication of mild hypertension, that is, coronary heart disease (myocardial infarction and sudden cardiac death), has, however, not been encouraging in studies in which diuretics have been used as first-line treatment. Two large-scale primary preventive studies compared the efficacy of diuretics and beta blockers in reducing coronary heart disease in hypertensive patients; results were in favor of beta blocker regimens in men. So far there is some evidence, but no hard scientific proof, that certain beta blockers offer advantages over diuretics in preventing myocardial infarction and sudden cardiac death in hypertensive patients. A major concern with the use of diuretics is the risk of hypokalemia; this can be reduced when they are combined with beta blockers.     

Lisinopril. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension and congestive heart failure

Lisinopril is an orally active angiotensin-converting enzyme (ACE) inhibitor which at dosages of 20 to 80 mg once daily is effective in lowering blood pressure in all grades of essential hypertension. It is at least as effective as usual therapeutic dosages of hydrochlorothiazide, atenolol, metoprolol and nifedipine while direct comparisons with other ACE inhibitors have not been reported. Many patients achieve an adequate blood pressure reduction with lisinopril alone, and in those who do not, most will with the addition of hydrochlorothiazide; lisinopril also attenuates hypokalaemia induced by thiazide diuretics. In patients with congestive heart failure resistant to conventional therapy, lisinopril 2.5 to 20 mg once daily improved indices of cardiac function and appeared to produce greater benefit than captopril in one controlled study. Lisinopril is well tolerated, with few serious adverse effects being reported. Thus, lisinopril is a suitable treatment for essential hypertension and shows promise in the treatment of congestive heart failure. If additional studies confirm these preliminary findings, then lisinopril will have a similar profile of indications to other ACE inhibitors, and like some other drugs in this class it offers the convenience of once daily administration.     

Bumetanide. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use

Bumetanide is a potent 'loop' diuretic for the treatment of oedema associated with congestive heart failure, hepatic and renal diseases, acute pulmonary congestion and premenstrual syndrome and in forced diuresis during and after surgery. Bumetanide may be given orally, intravenously or intramuscularly and produces a rapid and marked diuresis, and increased urinary excretion of sodium, chloride and other electrolytes (within 30 minutes) which persists for 3 to 6 hours. Its principal site of action is on the ascending limb of the loop of Henle, with a secondary action on the proximal tubule. Pharmacologically, bumetanide is about 40-fold more potent than frusemide (furosemide), with the exception of its effects on urinary potassium excretion where its potency is lower. Studies in patients with oedema due to congestive heart failure, pulmonary oedema or hepatic disease show that oral or intravenous bumetanide 0.5 to 2 mg/day produces results comparable to those with frusemide 20 to 80 mg/day. In acute pulmonary oedema, intravenous bumetanide produces a very rapid diuresis. Higher doses of bumetanide may be required (up to 15 mg/day) in patients with chronic renal failure or nephrotic syndrome. In these patients muscle cramps are not uncommon with bumetanide, but glomerular filtration rates are unaffected. In most studies, diuretic effects were accompanied by decreased bodyweight, abdominal girth and improvements in a variety of haemodynamic parameters. Comparison of bumetanide with frusemide at a dose ratio of 1 : 40 reveals no significant differences in clinical response with the exception of renal disease, where patients with oedema appear to respond better to bumetanide. Combination with thiazide diuretics enhances the clinical response to bumetanide. Potassium supplements and spironolactone may be beneficial additions to bumetanide where patients at risk of hypokalaemia can be identified. Clinically important side effects are infrequent, with audiological impairment occurring to a lesser extent than with frusemide. Bumetanide thus offers an important alternative to frusemide when a 'loop' diuretic is indicated.     

Diuretic-related hypokalaemia: the role of diuretics,potassium supplements,glucocorticoids and β2-adrenoceptor agonists

All 5,047 consecutive inpatients admitted to the Internal Medicine Division of a teaching hospital (Zieglerspital, Berne) between 1982 and 1985 were registered in accordance with the CHDM (Comprehensive Hospital Drug Monitoring) questionnaire of adverse drug reactions (ADRs). Of them, 2,439 were treated with at least one potassium losing diuretic. The hospital records of the patients were reviewed with particular regard to serum potassium levels, and on the basis of this evaluation, the patients were assigned to four different diuretic treatment groups, and the incidence of hypokalaemia related to diuretic treatment was estimated. The overall rate of occurrence of hypokalaemia was 21.1% at a serum potassium level <3.5 mmol·1^–1, and 3.8% <3.0 mmol·1^–1. Hypokalaemia of less than 3.5 mml·1^–1 developed 24.9% (217/870) of patients treated with potassium losing diuretics alone; in 19.7% (101/513) treated with potassium losing diuretics in conjunction with potassium substitution, in 15.1% (66/438) treated with a combination of diuretics (potassium losing with potassium sparing), and in 20.0% (12/60) treated with combined diuretics and potassium substitution. Only the differences between the first and the two subsequent groups were statistically significant. The overall incidence of hypokalaemia below 3.0+mmol·1^–1 was significantly lower in the patients on combined diuretics without potassium substitution than in the patients on potassium losing diuretics with potassium substitution.Oral or parenteral administration of glucocorticoids (prednisone 5 to 2,000 mg/d) was a significant risk factor for hypokalaemic events. ₂-Adrenoceptor agonists had not effect. The patient's age, sex, renal function and numbers of drugs received were evaluated in a multivariate analysis, in order to take into account their influence on the risk of developing hypokalaemia. The number of drugs above 12 (and, less importantly, female sex) was the main risk factor for this ADR.The comparison between hypokalaemia and hyperkalaemia in this group of inpatients showed the significance of reduced renal function in the occurrence of hyperkalaemia.     

Heart failure and electrolyte disturbances.

Electrolyte abnormalities are a frequent and potentially hazardous complication in patients with heart failure. This may be due to the pathophysiological alterations seen in the heart failure state leading to neurohumoral activation (stimulation of the renin-angiotensin-aldosterone system, sympathoadrenergic stimulation), and due to the complications of therapy with diuretics, cardiac glycosides or ACE inhibitors. Patients with heart failure may exhibit hyponatremia due to a decrease in water excretion, which may be related to the enhanced release of both angiotensin and vasopressin and can be exaggerated by diuretic therapy. Along with potassium and calcium, magnesium influences cardiovascular function. Magnesium and potassium deficiencies play an important role in the development of cardiac arrhythmias. Magnesium is essential for the maintenance of intracellular potassium concentration. Although there are conflicting data regarding the prevalence of hypomagnesemia in patients with chronic heart failure (the values range from 7-37%), multiple studies have documented lower magnesium concentrations in patients with heart failure than in normal controls. As magnesium and potassium are mainly intracellular ions, measurements in serum or plasma are of limited value to assess magnesium status. There was no correlation between the intracellular electrolyte content and the electrolyte levels in plasma, either for mononuclear cells or erythrocytes or for myocardial and skeletal muscle. Loop diuretics (e.g. furosemide) are supposed to cause a substantial loss of both magnesium and potassium in the plasma and intracellular space. The potassium-sparing diuretics amiloride and triamterene are reported to also exert magnesium-sparing effects. Recently, ACE inhibitors have been documented to have important magnesium-conserving actions, possibly via their effect on glomerular filtration. Hyperkalemia, secondary to the use of ACE inhibitors in patients with heart failure, is well documented. Digoxin directly limits the renal tubular reabsorption of magnesium, therefore increasing magnesium excretion. Low magnesium and potassium concentrations increase cardiac glycoside toxicity. In contrast, elevated levels of magnesium decrease the sensitivity of human myocardium to antiarrhythmogenic actions of cardiac glycosides, without affecting maximally developed tension. Moreover, magnesium increases binding affinity of cardiac glycosides to the receptor. The antiarrhythmic action of magnesium is suspected to be mediated by a reduced sensitivity to electrophysiological changes induced by Ca2+, thus indicating Ca2+ antagonistic properties of magnesium. Magnesium deficiency has also been implicated in sudden death, notably in patients with congestive heart failure. Therefore, when treating congestive heart failure, one must consider how to prevent depletion of electrolytes or how to replete potassium and magnesium in deficiency states.     

Effect of triamterene on leucocyte sodium and potassium levels in heart disease.

Sodium and potassium levels in plasma and leucocytes and the sodium efflux rate constants of leucocytes were measured in patients with congenital heart disease not on treatment, patients with valvular heart disease being treated with digoxin and conventional diuretics, and patients with valvular heart disease receiving digoxin and either conventional diuretics or triamterene or both. The group being treated with digoxin and conventional diuretics showed low cellular potassium levels, low sodium efflux rate constants, and a rise in cellular sodium levels. Patients given triamterene showed a rise in potassium levels in plasma and cells and in the sodium efflux rate constant.     

Current concepts in clinical therapeutics: congestive heart failure

The epidemiology and etiology, pathophysiology, diagnosis, and treatment of congestive heart failure (CHF) are reviewed. CHF affects as many as 4 million Americans and is one of the most prevalent causes of death in hospitalized patients. Major risk factors for developing CHF include advanced age, male sex, hypertension, coronary artery disease, smoking, hypercholesterolemia, diabetes mellitus, and rheumatic heart disease. Heart failure results from decreased intrinsic myocardial contractility caused by one or more of three changes: (1) altered adrenergic nervous system function, (2) impaired delivery of calcium to contractile elements in the heart, and (3) reduced myosin-ATPase activity in the myocardium. The disease is progressive, and no intervention has yet been found to stop it effectively. CHF is diagnosed based on subjective signs and symptoms and objective assessment using auscultation, ECG, chest roentgenogram, laboratory tests, and noninvasive and invasive tests. Treatment of CHF begins with restriction of physical activity and sodium intake. Pharmacologic interventions start with either digitalis glycosides or thiazide diuretics; both may be used concomitantly as the disease progresses. Current studies are focusing on the use of angiotensin-converting enzyme inhibitors as first-line agents for CHF. When CHF worsens, loop diuretics are substituted for or added to the thiazide diuretics, and vasodilators are added to reduce the workload on the heart. Other inotropic agents, including the new bipyridine derivatives, may also be used. In patients not responding to these and other aggressive therapeutic interventions, cardiac transplantation is the only option. Despite advances in management of CHF, little improvement in overall survival has been demonstrated, and no intervention has stopped or reversed the progression of CHF.     

Acute heart failure with dyspnoea: initial treatment. Furosemide and trinitrine, despite the lack of a proven survival benefit

For patients with acute heart failure and dyspnoea due to pulmonary congestion, the risk of death in the short term is high. To determine how best to manage these patients, we reviewed the relevant literature using the standard Prescrire methodology. There are few reliable clinical trial data. None of the available drugs has been shown to improve survival. Loop diuretics such as furosemide improve some haemodynamic parameters and dyspnoea due to congestion, i.e., water and salt retention. The dose is adjusted on the basis of clinical response, renal status and previous use of a loop diuretic, especially in chronic heart failure. The main adverse effects of loop diuretics are hypotension, hyponatraemia, hypokalaemia, renal failure and ototoxicity. Compared with repeated injections, continuous infusion seems to carry a lower risk of death and ototoxicity. High doses are associated with excess mortality. Nitrate derivatives such as trinitrine and isosorbide dinitrate are vasodilators. Only intravenous administration has been assessed in acute heart failure. These drugs improve certain haemodynamic parameters, reduce blood pressure and increase coronary flow.Their effect declines rapidly above a certain dose in about 20% of patients. They seem to improve dyspnoea and, according to a difficult-to-interpret trial of isosorbide dinitrate, may reduce the risk of myocardial infarction. There is no firm evidence that nitrate derivatives improve survival in patients with acute heart failure, but they reduce mortality in patients with myocardial infarction, a frequent cause of acute heart failure. The main adverse effect of nitrate derivatives is hypotension, meaning that these drugs should not be used when blood pressure is low and that blood pressure should be closely monitored during treatment. Randomised trials of another vasodilator, nesiritide, showed excess mortality at 30 days. There are no such trials of nitrate derivatives. In patients with cardiogenic shock, inotropes (mainly dopamine, dobutamine and milrinone) improve symptoms and haemodynamic parameters but may increase mortality.These drugs carry a risk of ventricular and supraventricular arrhythmias and tachycardia. Their use requires continuous monitoring in an intensive care unit. Cardiac glycosides, including digoxin, have been used empirically in acute heart failure. The use of digoxin is mentioned in only one clinical practice guideline, in patients with atrial fibrillation and a rapid heart rate. Its narrow therapeutic margin and its frequent interactions with other drugs make digoxin difficult to use. Oxygen is usually recommended in case of hypoxaemia but its clinical value has not been assessed comparatively in acute heart failure. In some trials, routine oxygen delivery, without taking into account the degree of hypoxia, appeared to be harmful in patients with myocardial infarction. Non-invasive ventilation has been assessed in several comparative randomised trials, in which it was found to improve some physiological parameters. In a trial in 1069 patients, it had no impact on mortality at 30 days, or on the need for endotracheal intubation. It is not appropriate for patients with respiratory distress necessitating intubation, or with altered consciousness, severe dementia, major anxiety. It is often poorly tolerated. Its main adverse effects are aggravation of right heart failure, pneumothorax, and aspiration of gastric contents. Early treatment probably improves outcome. Clinical practice guidelines recommend urgent hospitalisation of patients with acute heart failure. In summary, the choice of initial treatment for patients with acute heart failure and dyspnoea depends largely on blood pressure.Treatment is mainly based on loop diuretics, nitrate derivatives (when blood pressure is not too low) and non-invasive ventilation. It should be emphasised that these patients are highly unstable and that there is a narrow margin between beneficial and harmful effects of available treatments. Patients receiving treatment should always be closely monitored.     

Piretanide. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy

Piretanide is a potent 'loop' diuretic whose principal site of action is in the thick ascending limb of the loop of Henle. When administered orally or intravenously to healthy volunteers it rapidly increases diuresis and electrolyte excretion, and the effects are short-lived. In comparative studies, piretanide has generally been found to be 5 to 7 times more potent than frusemide (furosemide) but only one-tenth as potent as bumetanide, on a weight-for-weight basis. Piretanide 6 to 12 mg/day, in conventional or sustained release formulations, has been shown to significantly lower elevated blood pressure in a large proportion of patients with mild to moderate hypertension. Comparative trials of up to 3 months duration indicate that at this dosage piretanide is of comparable antihypertensive efficacy as hydrochlorothiazide 50 to 100 mg/day, but has significantly less effect on serum potassium levels. Short term studies in patients with oedema caused by renal, hepatic or cardiac failure demonstrated that piretanide 6 to 9 mg is of similar diuretic potency as frusemide 40 mg and bumetanide 1 mg. In medium term trials in patients with congestive heart failure piretanide 6 mg/day produced equivalent symptomatic improvement as frusemide 40 mg/day. When used to treat oedema caused by liver disease, piretanide 12 to 24 mg/day was successful in only about 50% of patients, but spironolactone added to the treatment regimen greatly increased the response rate. Generally, piretanide has been well-tolerated in clinical trials, although the conventional tablet formulation has caused a relatively high incidence of acute adverse effects--these were greatly reduced with the introduction of the sustained release formulation. Serum concentrations of most electrolytes have not shown any consistent adverse trends and hyperuricaemia and hypokalaemia have been encountered infrequently. Thus, piretanide appears to offer an effective alternative to other 'loop' diuretics for the treatment of oedematous diseases and to hydrochlorothiazide for the management of mild to moderate hypertension. However, its relative place in therapy remains to be clarified with wider clinical experience.     

Antihypertensive drugs: diuretics and betablockers are the best assessed

(1) In trials involving hypertensive non diabetic patients under 65, some diuretics and betablockers have prevented strokes, without conferring protection from coronary events or death. In one trial captopril had an effect comparable to that of diuretics or betablockers in terms of overall cardiovascular prevention, but was a little less effective in preventing strokes. (2) In trials involving hypertensive subjects over 65, some diuretics and betablockers have reduced the risk of stroke, coronary events, heart failure, and death. In one trial a diuretic was superior to a betablocker in terms of preventive efficacy and adverse effects. Nitrendipine, in combination with other antihypertensive drugs, prevented strokes in one trial. (3) In a trial involving hypertensive diabetic patients, captopril and atenolol reduced the risk of stroke, heart failure and worsening of retinal disease, without preventing coronary events or death. In two trials coronary events were more frequent on dihydropyridine than on an angiotensin-coverting-enzyme (ACE) inhibitor. (4) In one trial a diuretic reduced the risk of relapse after stroke, even in patients without severe hypertension.     

Ibopamine. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy

Ibopamine is an orally active derivative of dopamine which undergoes hydrolysis to the active moiety epinine. In single-dose and short term studies ibopamine demonstrated inotropic and vasodilating properties. It improved cardiac and systemic haemodynamics by increasing cardiac output and reducing afterload, both at rest and during exercise. In non-comparative clinical studies ibopamine produced benefits in functional class and clinical symptoms for up to 1 year in patients with moderate to severe congestive heart failure. Similarly, short term comparative studies with placebo have indicated ibopamine as a useful adjunct in the treatment of patients maintained on conventional therapy with digoxin, diuretics and vasodilators. Preliminary evidence also suggests that ibopamine is as effective as digoxin in the treatment of patients with moderate congestive heart failure. Should the results of long term comparative studies confirm these encouraging findings, ibopamine will be a useful addition to the drugs available or as an alternative to digoxin for the treatment of congestive heart failure.     

Xipamide and cyclopenthiazide in essential hypertension--comparative effects on blood pressure and plasma potassium.

1 The blood pressure lowering effect of xipamide, a non-thiazide diuretic given for 6 weeks was compared in a randomised cross-over trial with that of cyclopenthiazide in 14 patients with essential hypertension. 2 Xipamide 10 or 20 mg given once daily was as effective in lowering supine blood pressure as daily cyclopenthiazide 0.5 mg. There was no difference in the blood pressure lowering effect of 10 mg xipamide daily for 2 weeks compared to 20 mg daily given for a further 4 weeks. 3 Plasma potassium was reduced by both drugs, but markedly more after both 10 mg and 20 mg xipamide than after cyclopenthiazide 0.5 mg. By the sixth week of treatment 13 of 14 patients on xipamide but only 6 of 14 on cyclopenthiazide has plasma potassium concentrations of, or less than, 3.5 mmol/l. The fall in plasma potassium was significantly greater and the final plasma potassium concentration was significantly lower after either dose of xipamide than after cyclopenthiazide. 4 These results suggest that 10 mg or 20 mg of xipamide daily is effective in lowering blood pressure in hypertensive patients but is associated with hypokalaemia. In view of recent evidence linking diuretic-induced hypokalaemia with cardiac dysrhythmias in patients with essential hypertension we would suggest that thiazide diuretics be used in preference to xipamide for the routine management of essential hypertension. Our results also suggest that the currently recommended dose of xipamide (20 mg) for the treatment of hypertension is excessive, and lower amounts than 10 mg per day might possibly be as effective in lowering blood pressure with less adverse metabolic consequences.     

Eplerenone: new drug. Recent myocardial infarction with heart failure: a spironolactone me too

(1) Heart failure is diagnosed on the basis of both clinical symptoms and evaluation of cardiac function (preferably measured by echocardiography). Left ventricular dysfunction is defined as a left ventricular ejection fraction (LVEF) below 40%. The drugs of choice for chronic heart failure are certain angiotensin-converting-enzyme (ACE) inhibitors, some diuretics, some betablockers, and spironolactone. In one trial, spironolactone greatly reduced mortality at 24 months (35%, compared with 46% on placebo, p <0.001). (2) Eplerenone, a spironolactone derivative, is marketed for the treatment of left ventricular dysfunction in heart failure patients with recent myocardial infarction. (3) The EPHESUS study, a double-blind, placebo-controlled trial involving 6632 patients, showed a significant reduction in the overall mortality rate among patients with heart failure and recent myocardial infarction treated with eplerenone for 16 months (16.7% versus 14.4%; p = 0.008). This improvement was mainly due to a reduction in mortality during the first month of treatment. Eplerenone has not been compared with spironolactone, although the latter was known to be effective before the EPHESUS trial was conducted. (4) Severe hyperkalemia is frequent with eplerenone, occurring in 5.5% of patients. The risk of hyperkalaemia increases with renal failure and co-administration of potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists and nonsteroidal antiinflammatory drugs. (5) In the short term, the incidence of gynecomastia in patients taking eplerenone seems to be low. (6) In patients who develop heart failure after myocardial infarction, an indirect comparison of available data favours spironolactone over eplerenone (better efficacy, lower risk of hyperkalemia). (7) In France, treatment with eplerenone is about 9 times more expensive than spironolactone. (8) Spironolactone remains the treatment of choice for patients with heart failure and incapacitating dyspnea despite ACE inhibitor and diuretic therapy. Eplerenone may possibly be useful for patients who have non severe heart failure after recent myocardial infarction.     

益气复脉治疗冠心病心力衰竭合并心绞痛的疗效观察

目的:观察益气复脉注射液治疗冠心病心力衰竭合并心绞痛的临床疗效。方法:将162例心力衰竭合并心绞痛的患者随机分为两组,对照组予消心痛、血管紧张素转换酶抑制剂(ACEI)及血管紧张素受体拮抗剂(ARB)类、β受体阻滞剂(β-RB)、阿司匹林、他汀类药物,间断服利尿剂常规治疗;治疗组在对照组的基础上加用益气复脉注射液静滴5.2 g.d-1,共10 d。结果:治疗组心绞痛症状改善总有效率为85.36%优于对照组(75.00%,P<0.05);心电图疗效亦优于对照组;两组治疗前后心功能、左心室射血分数(LVEF)、6 min步行距离均得到改善,但治疗组明显优于对照组(P<0.05)。结论:益气复脉注射液养阴生津,可改善心功能、提高活动耐量并缓解心绞痛,对缺血的心肌细胞有明显的保护作用。     

Enalapril. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension and congestive heart failure

Enalapril maleate is an orally active angiotensin-converting enzyme inhibitor. It lowers peripheral vascular resistance without causing an increase in heart rate. Enalapril 10 to 40 mg/day administered either once or twice daily is effective in lowering blood pressure in all grades of essential and renovascular hypertension, and shows similar efficacy to usual therapeutic dosages of hydrochlorothiazide, beta-blockers (propranolol, atenolol and metoprolol) and captopril. Most patients achieve adequate blood pressure control on enalapril alone or with hydrochlorothiazide. In patients with severe congestive heart failure resistant to conventional therapy, enalapril improves cardiac performance by a reduction in both preload and afterload, and improves clinical status long term. Enalapril appears to be well tolerated, with few serious adverse effects being reported. It does not induce the bradycardia associated with beta-blockers or the adverse effects of diuretics on some laboratory values. In fact, the hypokalaemic effect of hydrochlorothiazide is attenuated by the addition of enalapril. The incidence of the main (but rare) side effects of hypotension in hypovolaemic patients and reduced renal function in certain patients with renovascular hypertension, which are also seen with captopril, might be reduced by careful dosage titration, discontinuation of diuretics, and monitoring of at-risk patients. Thus, enalapril is a particularly worthwhile addition to the antihypertensive armamentarium, as an alternative for treatment of all grades of essential and renovascular hypertension. It also shows promise in the treatment of congestive heart failure.     

Antihypertensive,saluretic and hypokalaemic effects of cyclothiazide in comparison with hydrochlorthiazide with amiloride supplement

Summary The antihypertensive, saluretic and hypokalaemic effects of a small dose of cyclothiazide (2.5 mg daily) were compared with those of a conventional dose of an hydrochlorthiazide-amiloride hydrochloride combination (50+5 mg daily). Both preparations were given to 13 patients with mild (WHO I) hypertension in a cross-over manner for six weeks, with an intervening wash-out phase of three weeks. The antihypertensive efficacy of cyclothiazide was well comparable to that of the hydrochlorthiazide-amiloride combination, although cyclothiazide tended to inhibit renal sodium reabsorption less than the combination. Cyclothiazide tended to cause hypokalaemia, apparently due to increased potassium loss, but with the present dosage none of the 13 patients developed marked hypokalaemia (serum potassium less than 3.3 mmol/l). Both drugs led to a comparable increase in serum urate concentration. Neither of the preparations affected creatinine or free-water clearance. The results suggest that even in relatively small doses thiazides effectively decrease blood pressure, and combining thiazides with potassium-sparing diuretics is advantageous only in patients with marked hypokalaemia and its associated risks.     

Diuretics in the treatment of hypertension. Part 2: loop diuretics and potassium-sparing agents

Introduction: Diuretics enhance the renal excretion of Na⁺ and water due to a direct action at different tubular sites of the nephron where solute re-absorption occurs.

Areas covered: This paper focuses on the mechanism of action, pharmacodynamics, antihypertensive effects, adverse effects, interactions and contraindications of loop diuretics and potassium-sparing agents (including mineralocorticoid receptor antagonists (MRAs) and epithelial Na⁺ channel blockers).

Expert opinion: Loop diuretics are less effective than thiazide diuretics in lowering blood pressure, so that their major use is in edematous patients with congestive heart failure (HF), cirrhosis with ascites and nephritic edema. MRAs represent a major advance in the treatment of resistant hypertension, primary and secondary hyperaldosteronism and in patients with systolic HF to reduce the risks of hospitalization and of premature death. Potassium-sparing diuretics when coadministered with diuretics (thiazides and loop diuretics) working at more proximal nephron locations reduce the risk of hypokalemia and hypomagnesemia and the risk of cardiac arrhythmias. At the end of the article, the basis for the combination of diuretics with other antihypertensive drugs to achieve blood pressure targets is presented.     

缬沙坦治疗慢性心力衰竭的临床疗效观察

目的:探讨缬沙坦治疗慢性心力衰竭的疗效和安全性.方法:选择冠心病缺血性心肌病、扩张型心肌病、高血压性心脏病、风湿性心脏病慢性心衰患者26例,在使用常规利尿剂、血管扩张剂、强心剂等治疗的基础上,加用血管紧张素Ⅱ受体拮抗剂缬沙坦口服,采用自身对照观察比较用药前、治疗后8周心脏指标变化,评估临床有效性及安全性.结果:治疗8周后显效8例,有效14例,总有效率88%,无效3例,占12%.结论:在常规治疗的基础上,加用缬沙坦治疗慢性心力衰竭效果显著,可改善心功能及临床症状,提高患者的生活质量.