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Comparison of Captopril and Enalapril in Patients with Severe Chronic Heart Failure
Abstract
To evaluate the concept that long duration of action is an advantageous property of angiotensin-converting enzyme inhibitors in the treatment of severe heart failure, we randomly assigned 42 patients to therapy with either a short-acting inhibitor (captopril, 150 mg daily) or a long-acting inhibitor (enalapril, 40 mg daily) for one to three months while concomitant therapy with digoxin and diuretics was kept constant. The treatment groups had similar hemodynamic and clinical characteristics at base-line evaluation and similar initial responses to converting-enzyme inhibition. During long-term therapy, captopril and enalapril produced similar decreases in systemic blood pressure, but the hypotensive effects of enalapril were more prolonged and persistent than those of captopril. Consequently, although the patients in both groups improved hemodynamically and clinically during the study, serious symptomatic hypotension (syncope and near syncope) was seen primarily among those treated with enalapril. Sustained hypotension also probably accounted for the decline in creatinine clearance (P less than 0.05) and the notable retention of potassium (P less than 0.05) observed in the patients treated with enalapril but not in those treated with captopril. We conclude that when large, fixed doses of converting-enzyme inhibitors are used in the treatment of patients with severe chronic heart failure, long-acting agents may produce prolonged hypotensive effects that may compromise cerebral and renal function, and thus they may have disadvantages in such cases, as compared with short-acting agents.
... Serial measurements by Packer et al. showed that ACEi acutely lowered right and left ventricular filling pressures, mean arterial pressure, heart rate, systemic and pulmonary vascular resistance in severe HF. RAASi decreases preload and afterload through blocking vasoconstrictive effect of angiotensin II [19]. However, hemodynamic parameters in our study revealed patients in AHF (in the absence of cardiogenic shock) and on ACEi/ARB therapy had significantly higher mean SVR and MAP, and lower cardiac index compared to those not on these medications. ...
There are limited data regarding the use of angiotensin
converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs) in acute
heart failure (AHF). The purpose is to determine the patterns of ACEi/ARB use at
the time of admission and discharge in relation to invasive hemodynamic data,
mortality, and heart failure (HF) readmissions. This is a retrospective single-center study in patients with
AHF who underwent right heart catheterization between January 2010 and December
2016. Patients on dialysis, evidence of shock, or incomplete follow up were
excluded. Multivariate logistic regression analysis was used to analyze the
factors associated with continuation of ACEi/ARB use on discharge and its
relation to mortality and HF readmissions. The final sample was 626 patients. Patients on
ACEi/ARB on admission were most likely continued on discharge. The most common
reasons for stopping ACEi/ARB were worsening renal function (WRF), hypotension,
and hyperkalemia. Patients with ACEi/ARB use on admission had a significantly
higher systemic vascular resistance (SVR) and mean arterial pressure (MAP), but
lower cardiac index (CI). Patients with RA pressures above the median received
less ACEi/ARB (P = 0.025) and had significantly higher inpatient mortality
(P = 0.048). After multivariate logistic regression, ACEi/ARB use at admission was
associated with less inpatient mortality; OR 0.32 95% CI (0.11 to 0.93), and
this effect extended to the subgroup of patients with HFpEF. Patients discharged
on ACEi/ARB had significantly less 6-month HF readmissions OR 0.69 95% CI (0.48
to 0.98). ACEi/ARB use on admission for AHF was associated with less
inpatient mortality including in those with HFpEF.
... 68 These effects are related to inhibition of the systemic and intrarenal effects of angiotensin II, and are particularly notable in patients receiving high doses or longer-acting agents. 69,70 Yet, the severity of both reactions can be ameliorated by a decrease in the dose of concomitantly administered diuretics. 68,71 A reduction in the dose of diuretics may also ameliorate the hypotensive response to angiotensin receptor-neprilysin inhibition. ...
Foundational therapy for heart failure and a reduced ejection fraction consists of a combination of an angiotensin receptor neprilysin inhibitor, a beta‐blocker, a mineralocorticoid receptor antagonist and an SGLT2 inhibitor. However, the conventional approach to the implementation is based on a historically‐driven sequence that is not strongly evidence‐based, typically requires ≥6 months, and frequently lead to major gaps in treatment. We propose a rapid sequencing strategy that is based on four principles. First, since drugs act rapidly to reduce morbidity and mortality, patients should be started on all four foundational treatments within 2‐4 weeks. Second, since the efficacy of each foundational therapy is independent of treatment with the other drugs, priority can be determined by considerations of relative efficacy, safety and ease‐of‐use. Third, low starting doses of foundational drugs have substantial therapeutic benefits, and achievement of low doses of all four classes of drugs should take precedence over uptitration to target doses. Fourth, since drugs can influence the tolerability of other foundational agents, sequencing can be based on whether agents started earlier can enhance the safety of agents started simultaneously or later in the sequence. We propose an accelerated 3‐step approach, which consists of the simultaneous initiation of a beta‐blocker and an SGLT2 inhibitor, followed 1‐2 weeks later by the initiation of sacubitril/valsartan, and 1‐2 weeks later by a mineralocorticoid receptor antagonist. The latter two steps can be reordered or compressed depending on patient circumstances. Rapid sequencing is a novel evidence‐based strategy that has the potential to dramatically improve the implementation of treatments that reduce the morbidity and mortality of patients with heart failure and a reduced ejection fraction.
... There are limited data to support the continuation of RAASi in the hemodynamically stable hospitalized patient. Serial hemodynamic measurements by Packer et al. [22] demonstrated that ACEi (captopril and enalapril) acutely lower right and left ventricular filling pressures, mean arterial pressure, heart rate, and systemic and pulmonary vascular resistance, and also increase cardiac, stroke volume, and stroke work index. The interpretation of the hemodynamic measurements provided by right heart catheterization assist the clinician in understanding the filling pressures of the patient and help with the clinical dilemma of diuresis and volume status assessment. ...
Background:
The renin-angiotensin-aldosterone axis plays a pivotal role in the pathophysiology of acute and chronic heart failure (HF) and represents an important target for guideline-directed medical therapy.
Summary:
The use of appropriate directed medical therapies for inhibition of the renin-angiotensin-aldosterone axis in chronic HF has been the subject of several landmark clinical trials, with high levels of adherence exhibited in the outpatient setting. However, less clarity exists with respect to the initiation, continuation, and cessation of renin-angiotensin-aldosterone system inhibitors (RAASi) in the setting of acute HF and exacerbation of HF necessitating hospitalization. In this review, we summarize relevant aspects of the physiology of the renin-angiotensin-aldosterone axis in acute HF and during decongestion. We also summarize the available evidence for the risks and benefits of initiating and continuing RAASi in acute HF. Key Message: We offer a decision-making pathway for the use of RAASi in the setting of acute HF that would help guide the cardiologist and nephrologist caring for patients with acute HF and cardiorenal syndrome.
... Often, however, the components of risk need to be parsed into their components to target more specific intervention. The assessments of risk described during hospitalization in this pathway document focus on those that can guide in-hospital management to improve outcomes after hospital discharge (9,33,(103)(104)(105)(106). For example, strategies to decrease readmission linked to nonadherence may not help patients approaching the end of life. ...
... A prolonged duration of RAS blockade may have an important impact on renal function. Indeed, Packer and colleagues 7 have demonstrated in patients with congestive heart failure that switching from captopril, a shortacting ACE inhibitor, to enalapril, a longer-acting inhibitor, results in an increased incidence of acute renal failure. Therefore, in high-risk situations, physicians have the option to reduce the ACE inhibitor dose or to prescribe a short-acting inhibitor. ...
Heart failure is a health problem worldwide. There are some drugs for it, including digoxin, spironolactone, captopril, and valsartan, but some of these drugs can produce secondary effects, such as arrhythmia, cough, hyperkalemia, hyponatremia and hypotension. The aim of this research was to evaluate the biological activity of coumarin (2H-chromen-2-one) and its derivatives (3BrAcet-C, 3–4Br-Ph-C, 4-CN-7D-C, 4-Me-7-Ph-C and 6Br-3-D-C) against ischemia/reperfusion injury as a therapeutic alternative for heart failure. In addition, the biological activity of the coumarin derivative 4-Me-7-Ph-C on left ventricular pressure (LVP) was determined in the absence or presence of ouabain and nifedipine at a dose of 1 nM using an isolated rat heart model. The results showed that i) the coumarin derivative 4-Me-7-Ph-C significantly decreased the infarct area (p+=+0.05) compared with 3BrAcet-C, 3–4Br-Ph-C, 4-CN-7D-C, and 6Br-3-D-C; and ii) 4-Me-7-Ph-C increased LVP in a dose-dependent manner, which effect was inhibited by nifedipine. These data suggest that coumarin 4-Me-7-Ph-C may act as a type-L calcium channel activator, so it could be a good agent to treat heart failure.
Control of hypertension in the elderly has been shown to reduce cardiovascular morbidity. Although it is not known if this is also true for isolated systolic hypertension, drug treatment should be considered for systolic pressures over 170 mm Hg that cannot be controlled with nondrug therapy.
The diuretics, calcium channel blockers, and the ACE inhibitors are very effective and generally well-tolerated therapy for the elderly. It may be necessary to combine two of these agents for some patients. Beta blockers are particularly useful for patients with ischemic heart disease or prior myocardial infarction. Beta blockers are the only agents which have been shown to be cardioprotective.
For all antihypertensive agents, the elderly should be started on low doses. The drugs should then be titrated slowly if necessary. It is common for the elderly to respond to lower dosages than younger patients, and they should be monitored carefully for adverse reactions to medications. Antihypertensives should be administered once or twice daily whenever possible. If these principles are considered, most patients can be effectively controlled with a minimum of side effects.
Methodology has been developed to evaluate the efficacy and toxicity of two angiotensin converting enzyme (ACE) inhibitors when either was used as an adjuvant to digoxin and diuretic therapy in the treatment of frail elderly heart failure patients. In an open study of enalapril only 11/17 patients mean (SD) age 83 (5) y tolerated its cautious introduction (1 patient died despite uneventful introduction of enalapril). Compliance (pill counts) was excellent in the 9/10 patients continued in the trial. When the functional ability was assessed in a symptom limited walking test (SWT), there was nearly a three-fold increase in distance walked and a two-fold increase in walking speed within one week of starting enalapril. Although performance was maintained at this level for at least 3 months, the patients actually reported a worsening of some of their symptoms. Furthermore, beyond 3 months 8/10 patients experienced adverse effects which necessitated the withdrawal of enalapril. The benefits of captopril an ACE inhibitor with a shorter plasma half-life were examined in a randomised, placebo-balanced, crossover trial. Twenty-six patients, mean (SD) age 82 (6) were recruited. Adverse effects led to withdrawal of captopril in 6 patients in the pre-trial period. Compliance (monitored "pill box") was excellent in the remaining 20 patients who were entered into the trial. This consisted of 3 treatment periods, a twice daily dosage of captopril established during a titration period, once daily captopril (half the above), and the placebo, each treatment period lasting for 3 weeks. Functional ability was assessed by gait analysis (GA) and SWT. Walking tended to be best on the once daily captopril treatment and worst on placebo. When the effects of serum ACE activity and blood pressure were taken into account in a linear model a statistically significant (P=0.04) treatment effect on SWT distance was revealed. No such effect was observed on oxygen consumption or ventilation volume in a tailored exercise protocol. Plasma atrial natriuretic factor (ANF) reflects the degree of cardiac compromise. An analytical method was developed to measure ANF in human plasma. Pre-exercise levels of ANF were significantly lower on the captopril treatments than on placebo, but still remained four-fold higher in patients than in 11 healthy age-matched subjects. Furthermore, unlike the control group, there was no apparent increase in ANF response to exercise in the patients. On completing the crossover study patients entered an open study on twice daily captopril. A slight deterioration in gait was observed in these patients after 3 months. Captopril appeared to be relatively well tolerated during the trial: only 3/20 patients (1 during the crossover, 2 during the open study), experienced adverse effects which led to the withdrawal of captopril.
Adequate renal perfusion pressure is essential to achieve diuretic-induced natriuresis. Hypotension and shock limit renal perfusion, but in many critically ill patients, renal perfusion pressure may not be reflected by the mean arterial pressure, owing to renal artery stenosis or vasoactive drug use. Adrenergic agonists, especially dopamine, have proven useful in increasing urinary salt and water excretion. In some situations, dopamine appears to have unique effects on the kidney. In patients with congestive heart failure, dopamine is clearly effective as a natriuretic and diuretic. Dopamine may also increase urine output in patients with acute renal function, but dopamine does not appear to accelerate recovery, or to be useful prophylactically. The chronic administration of oral dopamine agonists, especially ibopamine, to patients with impaired systolic function may improve cardiac hemodynamics and exercise tolerance, although not all results agree. Yet, it does not appear that these drugs are especially potent as natriuretic and diuretic agents on a chronic basis, as they appear to have little effect on cardiac preload. Effects of these drugs on mortality in this population have not been established, but they do not appear to cause the excess mortality that has been reported during administration of several oral inotropic agents. The role of these drugs in treating patients with congestive heart failure or hypertension remains to be established, but the development of oral dopamine agonists has helped to define the role of endogenous dopamine in cardiorenal function under normal and pathological conditions.
Background:
Approximately half of people with heart failure have chronic kidney disease (CKD). Pharmacological interventions for heart failure in people with CKD have the potential to reduce death (any cause) or hospitalisations for decompensated heart failure. However, these interventions are of uncertain benefit and may increase the risk of harm, such as hypotension and electrolyte abnormalities, in those with CKD.
Objectives:
This review aims to look at the benefits and harms of pharmacological interventions for HF (i.e., antihypertensive agents, inotropes, and agents that may improve the heart performance indirectly) in people with HF and CKD.
Search methods:
We searched the Cochrane Kidney and Transplant Register of Studies through 12 September 2019 in consultation with an Information Specialist and using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.
Selection criteria:
We included randomised controlled trials of any pharmacological intervention for acute or chronic heart failure, among people of any age with chronic kidney disease of at least three months duration.
Data collection and analysis:
Two authors independently screened the records to identify eligible studies and extracted data on the following dichotomous outcomes: death, hospitalisations, worsening heart failure, worsening kidney function, hyperkalaemia, and hypotension. We used random effects meta-analysis to estimate treatment effects, which we expressed as a risk ratio (RR) with 95% confidence intervals (CI). We assessed the risk of bias using the Cochrane tool. We applied the GRADE methodology to rate the certainty of evidence.
Main results:
One hundred and twelve studies met our selection criteria: 15 were studies of adults with CKD; 16 studies were conducted in the general population but provided subgroup data for people with CKD; and 81 studies included individuals with CKD, however, data for this subgroup were not provided. The risk of bias in all 112 studies was frequently high or unclear. Of the 31 studies (23,762 participants) with data on CKD patients, follow-up ranged from three months to five years, and study size ranged from 16 to 2916 participants. In total, 26 studies (19,612 participants) reported disaggregated and extractable data on at least one outcome of interest for our review and were included in our meta-analyses. In acute heart failure, the effects of adenosine A1-receptor antagonists, dopamine, nesiritide, or serelaxin on death, hospitalisations, worsening heart failure or kidney function, hyperkalaemia, hypotension or quality of life were uncertain due to sparse data or were not reported. In chronic heart failure, the effects of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) (4 studies, 5003 participants: RR 0.85, 95% CI 0.70 to 1.02; I2 = 78%; low certainty evidence), aldosterone antagonists (2 studies, 34 participants: RR 0.61 95% CI 0.06 to 6.59; very low certainty evidence), and vasopressin receptor antagonists (RR 1.26, 95% CI 0.55 to 2.89; 2 studies, 1840 participants; low certainty evidence) on death (any cause) were uncertain. Treatment with beta-blockers may reduce the risk of death (any cause) (4 studies, 3136 participants: RR 0.69, 95% CI 0.60 to 0.79; I2 = 0%; moderate certainty evidence). Treatment with ACEi or ARB (2 studies, 1368 participants: RR 0.90, 95% CI 0.43 to 1.90; I2 = 97%; very low certainty evidence) had uncertain effects on hospitalisation for heart failure, as treatment estimates were consistent with either benefit or harm. Treatment with beta-blockers may decrease hospitalisation for heart failure (3 studies, 2287 participants: RR 0.67, 95% CI 0.43 to 1.05; I2 = 87%; low certainty evidence). Aldosterone antagonists may increase the risk of hyperkalaemia compared to placebo or no treatment (3 studies, 826 participants: RR 2.91, 95% CI 2.03 to 4.17; I2 = 0%; low certainty evidence). Renin inhibitors had uncertain risks of hyperkalaemia (2 studies, 142 participants: RR 0.86, 95% CI 0.49 to 1.49; I2 = 0%; very low certainty). We were unable to estimate whether treatment with sinus node inhibitors affects the risk of hyperkalaemia, as there were few studies and meta-analysis was not possible. Hyperkalaemia was not reported for the CKD subgroup in studies investigating other therapies. The effects of ACEi or ARB, or aldosterone antagonists on worsening heart failure or kidney function, hypotension, or quality of life were uncertain due to sparse data or were not reported. Effects of anti-arrhythmic agents, digoxin, phosphodiesterase inhibitors, renin inhibitors, sinus node inhibitors, vasodilators, and vasopressin receptor antagonists were very uncertain due to the paucity of studies.
Authors' conclusions:
The effects of pharmacological interventions for heart failure in people with CKD are uncertain and there is insufficient evidence to inform clinical practice. Study data for treatment outcomes in patients with heart failure and CKD are sparse despite the potential impact of kidney impairment on the benefits and harms of treatment. Future research aimed at analysing existing data in general population HF studies to explore the effect in subgroups of patients with CKD, considering stage of disease, may yield valuable insights for the management of people with HF and CKD.
In der Klinik besitzen die ACE-Hemmer einen festen Stellenwert bei der Therapie der Hypertonie und der Herzinsuffizienz. Für die Indikation bei der Herzinsuffizienz war die Consensus-Studie richtungsweisend. Nach der CAST-Studie erfuhr die Therapie mit Antiarrhythmika bei Patienten nach manifestem Herzinfarkt eine kritische Wertung.
Die Behandlung eines Kranken mit Herzinsuffizienz wird sich als besonders wirksam erweisen, wenn sie individuell erfolgt und nicht nur symptomatisch, sondern darüber hinaus auch kausal betrieben wird.
Die Therapie mit Captopril, dem ersten allgemein verfügbaren ACE-Hemmer, war in ihrer Anfangsphase durch eine hohe Frequenz von Nebenwirkungen stark belastet. Captopril wurde in hoher Dosierung bei schwerer Hypertonie, häufig begleitet von einer Niereninsuffizienz, gegeben. Bei diesen Patienten traten in einem hohen Prozentsatz Exantheme, Geschmacksveränderungen, Proteinurie und Neutropenie auf (DiBianco 1986). Von diesen Nebenwirkungen waren meist Patienten mit Niereninsuffizienz und Autoimmun- oder Kollagenerkrankungen betroffen. Nachdem sich gezeigt hatte, daß ACE-Hemmer auch in niedriger Dosierung wirksam sind, ohne ihre Effektivität zu verlieren (Veterans Administration 1982) und sich diese Erkenntnis schnell in die klinische Praxis umgesetzt hatte, haben sich Anzahl und Schwere der Nebenwirkungen deutlich verringert. Gleichzeitig hat sich das Spektrum der Nebenwirkungen verändert. Die früher üblichen Nebenwirkungen sind selten geworden. Heute stehen andere Komplikationen der Therapie mit ACE-Hemmern, wie der erst spät als Nebenwirkung erkannte trockene Husten, im Vordergrund.
Die Prävalenz der arteriellen Hypertonie liegt zwischen 15 und 20%. Epidemiologische Untersuchungen konnten zeigen, daß eine direkte Beziehung zwischen der Höhe des Blutdrucks und der kardiovaskulären Morbidität und Mortalität besteht [81,156]. Umgekehrt gilt, daß eine Senkung eines erhöhten Blutdrucks mit einer Reduktion kardiovaskulärer Komplikationen einhergeht. Als eine der ersten klinisch kontrollierten Untersuchungen konnte die Veterans Administration Study nachweisen, daß bei Patienten mit schwerer arterieller Hypertonie eine antihypertensive Therapie zu einer signifikanten Abnahme der kardiovaskulären Mortalität führte [178]. Während in dieser Untersuchung nur Patienten mit einem diastolischen Blutdruck ≥ 115 mmHg behandelt wurden, liegen inzwischen Ergebnisse vieler multizentrischer klinischer Untersuchungen bei insgesamt über 40000 Patienten vor, die eine Reduzierung der hypertonieassoziierter kardiovaskulärer Morbidität und Mortalität bei der milden arteriellen Hypertonie (diastolischer Blutdruck 90–104 mmHg) und bei der mäßigen arteriellen Hypertonie (diastolischer Blutdruck 105–114 mmHg) nachwiesen [42,65,75,114,126,170,178,179].
The management of chronic heart failure has two goals. One is to produce short-term relief of symptoms and improvement in quality of life. The other is to slow or halt the progressive process of cardiac and peripheral dysfunction in heart failure that leads to long-term disability and shortened life expectancy. The former strategy is confined to patients with symptoms of heart failure; this may include exertional intolerance, shortness of breath or orthopnea, peripheral edema, or fatigue. It is important to recognize that not all heart failure is accompanied by congestive symptoms. Furthermore, some symptoms of heart failure may be subtle, leading to a reduced quality of life without the usual overt manifestations of heart failure. Therapy aimed at slowing progression of the disease is applicable in patients without symptoms as well as in those with symptoms. Left ventricular (LV) dysfunction may long antedate overt symptoms of heart failure, and the progressive nature of this LV dysfunction can potentially be prevented by aggressive therapeutic efforts. Indeed, treatment of heart failure symptoms must be accompanied by aggressive attempts to prevent progression of the disease, because the presence of symptoms identifies a patient whose condition is likely to progress in the absence of aggressive intervention. We therefore divide the therapeutic approaches for heart failure into these two separate categories.
It is well documented that a reduction in cardiac output elicits compensatory homeostatic responses that are mediated by neurohormonal mechanisms. Activation of the sympathetic nervous system results in systemic vasoconstriction, decreases in renal blood flow and glomerular filtration rate, and an increase in tubular reabsorption of sodium [1]. Activation of the renin-angiotensin system (RAS) contributes further to the increases in vascular tone and sodium avidity. While vasopressin secretion may also be increased during marked reductions in cardiac output, it is unlikely that this hormone contributes significantly to the maintainance of systemic vasoconstriction, as compared to its effects on sodium and water homeostasis [2–4]. The temporal activation of circulating neurohormonal mechanisms are well-illustrated by the study of Watkins et al., in the experimental canine model of cardiac decompensation [5]. In this model, reductions in cardiac output and filling pressure result in the elevations of plasma renin activity and angiotensin II (All) aldosterone, norepinephrine, and vasopressin levels that are associated with vasoconstriction and sodium retention. However, these circulating neurohormonal mechanisms return toward normal during the compensated stage of heart failure as plasma volume and cardiac stroke volume increase. Thus, in experimental heart failure, circulating neurohormonal mechanisms exhibit a time-dependent response, with acute activation and subsequent normalization during the chronic, compensated phase (Fig. 1).
Congestive heart failure (CHF) is the combination of signs and symptoms of abnormal cardiac function resulting in the heart being unable to pump an adequate amount of blood to oxygenate body tissues. In practice, the working definition of heart failure is that of the heart being unable to pump effectively, either because of structural, biochemical, or mechanical abnormalities or because of excessive demands placed on it, such as severe hypertension.1 It then results in loss of work capacity. This definition eliminates other causes of inadequate oxygenation, such as volume loss or fluid overload, and cases of increased oxygen demand, such as Paget’s disease of bone, severe anemia, beriberi, arteriovenous fistula, or thyrotoxicosis.
Heart failure is the final situation in the natural history of the majority of heart diseases. Once the first signs or symptoms appear the prognosis clearly worsens.
Die chronische Herzinsuffizienz ist Folge und Endzustand verschiedenster Herz-, Kreislaufund Allgemeinerkrankungen. Sie bietet ein relative einheitliches Bild, weil mangelhafte Herzleistung und Versorgung der Körperperipherie den verschiedenen Zuständen gemeinsam ist. Mehr als bei der akuten Herzinsuffizienz (Lungenödem S. 28, kardiogener Schock S. 18) können sich chronische Kompensationsmechanismen der Körper-peripherie auswirken und zu Salzwasserretention und Blutvolumenvermehrung führen. Es resultiert das klinische Syndrom der chronischen Herzinsuffizienz mit Dyspnoe, Ödemen und Stauungsorganen im kleinen bzw. großen Kreislauf. Die Pathogenese der Kontraktionsstörung ist jedoch nicht einheitlich. Herzinsuffizienz infolge Herzüberlastung (Hypertonie, Herzfehler) spricht auf positiv inotrope Arzneimittel (Herzglykoside) am besten an.
The systemic use of calcium channel-blocking agents as vasodilators in chronic heart failure has yet to be studied with large numbers of patients.
The “new inotropics” have been studied in restricted numbers of patients. Certain data suggest that the use of these agents is also substantively dependent upon their vasodilator properties. Although short term efficacy in the favorable modification of basic haemodynamics may have been demonstrated, there is no reduction in longterm mortality, and indeed it may be increased in the treated patients.
The potential of vasodilator agents to relieve the symptoms of heart failure and modification of its morbidity and mortality appears to be limited. In what aetiologies? Which patients? At what stage of the disease? For how long? What are the optimal dosage schedules? The role of multiple therapies? Such considerations must also be vital to the development of test protocols to determine the efficacy or lack thereof. A “general” approach to the use of these specific pharmacological inventions in a multifactorial disorder must lead to results which are complex and even misleading.
The fundamental basis of chronic heart failure is ineffective global contraction by too few myocardial contractile elements; an increased mechanical impedance (internal or external) to contraction of existing myocardial elements; or several of the above in combination. Because of the difficulty in solving the basic biological problem, transplantation of the heart now is considered as a practical treatment in many patients with severe advanced heart failure. This is particularly true in the younger patient, in spite of the enormous logistic, psychological and late management problems associated with this procedure. Nevertheless, for patients under the age of 55–60 the results have been remarkably good, with up to 80% survival of patients (all ages) at the end of 1 year compared to 15%–30% survival of patients with heart failure of similar severity not so treated. Experimental approaches of the modification by “training” of skeletal muscle to be used as a localized myocardial replacement represents a new direction born out of the failure of other interventions to improve significantly the current management of chronic heart failure.
Heart failure is characterized by the inability to deliver the volume of blood required by the organism due to a reduction in cardiac pumping performance. This limitation affects all the organs of the organism and results in symptoms typical of heart failure. These symptoms are caused either by reduced blood supply to the organs or by congestion upstream of the right or left ventricle, also referred to as “low output failure.” In contrast, there are also forms of heart failure with a high cardiac output (“high output failure”). This less common form of heart failure is found in reduced afterload (e. g., in sepsis) or metabolic disorders such as hyperthyroidism, anemia, beriberi, Paget’s disease or arteriovenous fistulas. Heart failure occurs in these cases as a consequence of inadequate elevation in cardiac output in response to increased peripheral demand. Furthermore, in both forms of heart failure compensatory reactions take place which in themselves lead to further pathological changes in the heart and other organs, and can thus exacerbate the basic disease and its symptoms. In the following sections, the fundamentals of cardiac muscle contraction, the regulation of contractile force by the sympathetic nervous system, and the specific cardiac changes which result from heart failure will be discussed. In addition, the causes of heart failure, its diagnosis, and the possibilities for drug therapy will be described. Instrumental and surgical therapeutic procedures will not be dealt with.
Angiotensin converting enzyme (ACE) inhibitors reduce morbidity and mortality in patients with heart failure and are a first-line therapy for chronic heart failure. However, the first-dose may be associated with asymptomatic or symptomatic hypotension. In previous small series with different ACE inhibitors, different blood pressure responses have been reported. We defined hypotension as a fall in mean blood pressure greater than or equal to20 mm Hg and an absolute value of systolic blood pressure less than or equal to90 mm Hg and diastolic blood pressure less than or equal to60 mm Hg. We studied the evolution of mean, systolic and diastolic blood pressure after initiation of perindopril and captopril treatments in a multicentre, double-blind, randomised, comparative, prospective study. One hundred seventy-six patients, mean age 64.9 +/- 12.1 years, 116 men, with symptomatic heart failure, NYHA class II-IV, and a left ventricular ejection fraction <40%, were randomised to receive a single dose of captopril 6.25 mg (n = 85) or perindopril 2 mg, (n = 91). Systolic and diastolic blood pressure were recorded with Dinamap every 15 minutes during a baseline period of 2 hours, every 30 minutes from 2 to 7 hours and at 8 hours after the drug administration. Baseline characteristics of both groups were similar (demography, heart failure aetiology, NYHA class and blood pressure). Throughout the study there were 23 asymptomatic episodes of hypotension in the captopril group and 6 in the perindopril group (p = 0.039). One patient in the captopril group had symptomatic episodes. Mean blood pressure falls were significantly higher in the captopril versus perindopril group at 60 minutes (-4.6 mm Hg vs +0.7 mm Hg; p = 0.004), 75 minutes (-4.4 mm Hg vs -1.1 mm Hg; p = 0.042), and 180 minutes (-3.4 mm Hg vs +0.0 mm Hg; p = 0.042). When elderly patients (greater than or equal to70 years) were considered the same pattern of response was found. In summary, first-dose hypotension is not negligible on initiation of therapy with ACE inhibitors in heart failure patients with low ejection fraction. Perindopril results in significantly less reduction in blood pressure and a lower incidence of symptomatic or asymptomatic hypotensive episodes and allows a safer start of therapy than captopril in heart failure patients.
The angiotensin converting enzyme (ACE) inhibitors constitute a major breakthrough in the medical management of congestive heart failure. The incidence of side effects with these agents is surprisingly low when they are used in the appropriate dosage. They produce sustained beneficial hemodynamic and symptomatic improvement in most patients with congestive heart failure and may produce greater symptomatic benefit than digoxin when given as second-line therapy to patients with heart failure on diuretics. Their neurohumoral effects generally are advantageous, resulting in normalization of sodium and potassium balance and a reduction in ventricular arrhythmias. The ACE inhibitors may improve survival in patients with congestive heart failure, and recent data suggest that they may prevent or delay the development of left ventricular dilatation and overt heart failure in patients with asymptomatic left ventricular dysfunction
Heart failure is a public health problem and a great economic burden for patients and healthcare systems. Suppression of the renin–angiotensin system (RAS) by angiotensin-converting enzyme (ACE)-inhibitors remains the mainstay of treatment for heart failure. However, the abundance of ACE inhibitors makes it difficult for doctors to choose.
We performed this network meta-analysis of ACEIs in patients with heart failure in order to address this area of uncertainty.
We searched PubMed, Embase, CENTRAL, and Medline.
Any randomized controlled trial evaluating the efficacy and safety of captopril, enalapril, lisinopril, ramipril, or trandolapril or combined interventions of 2 or more of these drugs.
Two reviewers extracted the data and made the quality assessment. At first, we used Stata software (version 12.0, StataCorp, College Station, TX) to make traditional pairwise meta-analyses for studies that directly compared different interventions. Then, network meta-analysis was performed using WinBUGS (version 1.4.3, MRC Biostatistics Unit, Cambridge, UK).
A total of 29 studies were included. Lisinopril was associated with a higher rate of all-cause mortality compared with placebo (odds ratio 65.9, 95% credible interval 1.91 to 239.6) or ramipril (14.65, 1.23 to 49.5). Enalapril significantly reduced systolic blood pressure when compared with placebo (standardized mean differences −0.6, 95% credible interval −1.03 to −0.18). Both captopril (odds ratio 76.2, 95% credible interval 1.56 to 149.3) and enalapril (274.4, 2.4 to 512.9) were associated with a higher incidence of cough compared to placebo.
Some important outcomes such as rehospitalization and cardiac death were not included. The sample size and the number of studies were limited, especially for ramipril.
Our results suggest that enalapril might be the best option when considering factors such as increased ejection fraction, stroke volume, and decreased mean arterial pressure. However, enalapril was associated with the highest incidence of cough, gastrointestinal discomfort, and greater deterioration in renal function. Trandolapril ranked first in reducing systolic and diastolic blood pressure. Ramipril was associated with the lowest incidence of all-cause mortality. Lisinopril was the least effective in lowering systolic and diastolic blood pressure and was associated with the highest incidence of all-cause mortality.
This study was designed and performed to establish the relationship between plasma and synovial fluid (SF) levels of thioredoxin reductase (TrxR) and disease activity in Chinese patients with rheumatoid arthritis (RA).
This study consisted of a total of 224 patients diagnosed with RA, 224 age and sex-matched healthy controls, and 156 patient controls. The disease activity of RA patients was calculated as diseases activity score that include 28-joint counts (DAS 28), which was divided into low-diseases activity (LDA) and high-diseases activity (HDA) groups.
Increased plasma TrxR was detected in patients with RA than healthy controls (P < 0.0001). With an area under the curve (AUC) of 0.874, plasma TrxR showed a evidently greater discriminatory ability than C-reactive protein (CRP; AUC, 0.815), antistreptolysin-O (ASO; AUC, 0.631), rheumatoid factor (RF, AUC, 0.793), and erythrocyte sedimentation rate (ESR, AUC, 0.789) in diagnosing RA. RA patients with HDA had significantly elevated TrxR levels in plasma and SF than did those with LDA (P < 0.0001). With an AUC of 0.874, plasma TrxR levels as an indicator for screening of HDA showed a significantly greater discriminatory ability than CRP (AUC, 0.690), ASO (AUC, 0.597), RF (AUC, 0.657), and ESR (AUC, 0.603). Similarly, SF TrxR levels as an indicator for screening of HDA also showed a significantly greater discriminatory ability as compared with above biomarkers.
TrxR levels in plasma and SF were positively correlated with the severity of RA. TrxR levels may therefore serve as a new biomarker in addition of the traditional biomarkers for assessing the risk and severity of RA. Further analysis of TrxR release machinery may give us a new understanding of pathogenesis of RA.
The presence of cardiac complications in hypertensive patients should not only influence the selection of antihypertensive agents and the urgency with which they are administered but may also require consideration of ancillary therapeutic and dietary measures.
Decrease in blood pressure after administration of ACE inhibitors, namely following the first dose in patients at risk, can cause anxiety in some physicians anticipating their administration or the continuing in further treatment. Therefore, the authors present a review of the problems on the basis of a review of clinical studies as well as of their own experience. Analyzed are situations under risk and recommendation for the selection of appropriate ACE inhibitors in which the risk of hypotension following the first dose is lower (fosinopril, perindopril). Taking into account the risk as well as the choice of a suitable ACE inhibitor in patients at risk, the launching of therapy with ACE inhibitors in patients under risk as safe.
Angiotensin converting enzyme (ACE) inhibitors reduce morbidity and mortality in patients with heart failure and are a first-line therapy for chronic heart failure. However, the first-dose may be associated with asymptomatic or symptomatic hypotension. In previous small series with different ACE inhibitors, different blood pressure responses have been reported. We defined hypotension as a fall in mean blood pressure ≥20 mm Hg and an absolute value of systolic blood pressure ≤90 mm Hg and diastolic blood pressure ≤60 mm Hg. We studied the evolution of mean, systolic and diastolic blood pressure after initiation of perindopril and captopril treatments in a multicentre, double-blind, randomised, comparative, prospective study. One hundred seventy-six patients, mean age 64.9 ± 12.1 years, 116 men, with symptomatic heart failure, NYHA class II–IV, and a left ventricular ejection fraction <40%, were randomised to receive a single dose of captopril 6.25 mg (n = 85) or perindopril 2 mg, (n = 91). Systolic and diastolic blood pressure were recorded with Dinamap every 15 minutes during a baseline period of 2 hours, every 30 minutes from 2 to 7 hours and at 8 hours after the drug administration. Baseline characteristics of both groups were similar (demography, heart failure aetiology, NYHA class and blood pressure). Throughout the study there were 23 asymptomatic episodes of hypotension in the captopril group and 6 in the perindopril group (p = 0.039). One patient in the captopril group had symptomatic episodes.
Mean blood pressure falls were significantly higher in the captopril versus perindopril group at 60 minutes (−4.6 mm Hg vs +0.7 mm Hg; p = 0.004), 75 minutes (−4.4 mm Hg vs −1.1 mm Hg; p = 0.042), and 180 minutes (−3.4 mm Hg vs +0.0 mm Hg; p = 0.042).
When elderly patients (≥70 years) were considered the same pattern of response was found. In summary, first-dose hypotension is not negligible on initiation of therapy with ACE inhibitors in heart failure patients with low ejection fraction. Perindopril results in significantly less reduction in blood pressure and a lower incidence of symptomatic or asymptomatic hypotensive episodes and allows a safer start of therapy than captopril in heart failure patients.
The treatment of congestive heart failure (CHF) has undergone significant changes in recent years.1 This has occurred as a result of both our improved understanding of the hemodynamic and neurohormonal alterations that underlie the pathophysiology of CHF and the availability of new therapeutic agents. In particular, heart failure is now recognized as a complex syndrome, involving the central and peripheral circulations, neuro-hormonal responses, and alterations of renal and skeletal muscle function, rather than a simple hemodynamic derangement.2 In this chapter we review the neuroendocrine changes that characterize CHF and focus on the use of angiotensin-converting enzyme (ACE) inhibition in its treatment. This discussion is limited to CHF resulting from left ventricular systolic dysfunction, characterized by reduced indices of contractility and left ventricular dilatation. CHF resulting from left ventricular diastolic dysfunction, although now more commonly recognized than previously, is beyond the scope of this chapter.
Diuretics are indispensable in the management of oedema of chronic heart failure (CHF). When given to patients with congestion, diuretics relieve symptoms and improve cardiac performance. However, the use of diuretics in patients without fluid retention may have deleterious effects because they may decrease stroke volume and blood pressure, resulting in neurohormonal activation. Moreover, the effects of diuretics on electrolyte and metabolic imbalance may trigger ventricular arrhythmias with adverse consequences on survival. Whereas treatment of hypertension with diuretics prevents the development of CHF, no randomized trial has assessed the effects of diuretics on mortality in patients with CHF. Reduced mortality using spironolactone in patients with CHF in the RALES trial may not be related to its diuretic effects. Baseline use of a non-potassium-sparing diuretic in the SOLVD prevention and treatment trials was associated with an increased risk of arrhythmic death. As only limited data are available on improved prognosis with diuretics, long-term randomized mortality trials should be conducted. The recent TORIC study may be the first step in this direction.
AimsThe optimal dosing strategies for blocking the renin-angiotensin-aldosterone system in idiopathic dilated cardiomyopathy (IDCM) are poorly known. We sought to determine the long-term efficacy and safety of supramaximal titration of benazepril and valsartan in patients with IDCM.Methods and results480 patients with IDCM in New York Heart Association functional class II–IV and with left ventricular ejection fraction ≤35% were randomly assigned to extended-release metoprolol (mean 152 mg/day, range 23.75–190), low-dose benazepril (20 mg/day), low-dose valsartan (160 mg/day), high-dose benazepril (mean 69 mg/day, range 40–80), and high-dose valsartan (mean 526 mg/day, range 320–640). After a median follow-up of 4.2 years, high-dose benazepril and valsartan, compared with their respective low dosages, resulted in 41% and 52% risk reduction in the primary endpoint of all-cause death or admission for heart failure (P = 0.042 and 0.002), promoted functional improvement, and reversed remodelling as assessed by New York Heart Association classes, quality-of-life scores, and echocardiographic recording of left ventricular ejection fraction, left ventricular end-diastolic volume, mitral regurgitation, and wall motion score index. Compared with metoprolol, high-dose valsartan reduced risk for the primary endpoint by 46% (P = 0.006), whereas high-dose benazepril and both low-dose groups showed no significant difference. Major adverse events involved hypotension and renal impairment but were largely tolerated.Conclusion
Supramaximal doses of benazepril and valsartan were well tolerated and produced extra benefit than their low dosages in clinical outcome and cardiac reverse remodelling in patients with IDCM and modest-severe heart failure. ClinicalTrials.gov identifier: NCT01917149.
The present study enrolled 214 patients, aged 26 to 83 years, with symptomatic New York Heart Association class II through IV congestive heart failure. Patients were continued on their previous therapeutic regimens, which included an angiotensin-converting enzyme (ACE) inhibitor and a loop diuretic with or without digitalis. Patients were randomized to 1 of 5 parallel treatment groups: placebo or spironolactone at a single daily dose of 12.5, 25, 50, or 75 mg for 12 weeks. Serum levels of creatinine, urea nitrogen, potassium, plasma renin activity, and N-terminal proatrial natriuretic factor (pro-ANF), as well as urinary aldosterone levels, were measured periodically. Measurements at 12 weeks versus baseline values indicated significant increases in plasma renin activity and aldosterone excretion and significant decreases in systolic and diastolic blood pressure and pro-ANF. Hypokalemia (serum potassium <3.4 mmol/L) occurred in 10% of placebo-treated patients and in 0.5% of the spironolactone group. The incidence of hyperkalemia (serum potassium ≥5.5 mmol/L) was 5% for the placebo group, whereas it was 5%, 13%, 20%, and 24% for the 12.5-, 25-, 50- and 75-mg spironolactone treatment groups, respectively. Predictors of hyperkalemia included the use of ACE inhibitors other than captopril, ACE inhibitor dose, and baseline elevation of serum creatinine or potassium levels. Thus, daily doses of 12.5 to 25 mg of spironolactone coadministered with conventional therapy of ACE inhibitors, loop diuretics, and digitalis are relatively safe (provided that serum potassium levels are monitored) and effective in blocking the effects of aldosterone, while reducing the potential for hypokalemia in patients with heart failure.
Available information indicates that about 78 new molecules belonging to the class of angiotensin converting enzyme (ACE) inhibitors are under investigation, and that at least 11 or 12 of the newer ACE inhibitors will be available for clinical use. The newer ACE inhibitors can be classified, according to the zinc ion ligand of ACE, into 3 main chemical classes: sulfhydryl-, carboxyl-and phosphoryl-containing ACE inhibitors
All the newer sulfhydryl-containing ACE inhibitors differ from captopril since they are prodrugs, and among them alacepril and probably moveltipril (altiopril, MC 838) are converted in vivo to captopril. When compared with captopril, they show a slower onset and a longer duration of action, and obviously the same route of elimination. Zofenopril, a prodrug that is converted in vivo to the active diacid, shows a greater potency, a similar peak time and a longer duration of action than captopril and, unlike captopril, partial elimination through the liver
The newer carboxyl-containing ACE inhibitors are prodrugs which are converted in vivo to active diacids. Like enalaprilat, they are excreted via the kidney; the exception is spirapril, which is totally eliminated by the liver. Compared to enalapril, benazepril shows an earlier peak time and a slightly shorter terminal half-life, cilazapril and ramipril have an earlier peak time and even longer terminal half-life, perindopril shows similar peak time and terminal half-life, while delapril, quinapril and spirapril show an earlier peak time and a shorter half-life. The phosphoryl-containing ACE inhibitors belong to a new chemical class. Fosinopril is a prodrug which is converted to the active diacid in vivo, shows a relatively late peak time, a long terminal half-life, and is eliminated partially by the liver. SQ 29852, the only newly developed ACE inhibitor which is not a prodrug, seems to be more effective than captopril, with a much longer lasting effect and elimination through the kidney
When the differences in potency between these drugs are compensated by dosage adjustment, all the newer ACE inhibitors are expected to exert a similar amount of inhibition of circulating ACE, and therefore to inhibit to a similar extent the generation of circulating angiotensin II and the breakdown of bradykinin. Obviously they may differ in timing and the duration of circulating ACE inhibition according to their pharmacokinetic properties. With regard to the possibility that they may stimulate prostaglandin synthesis, it is suggested that this action, which does not seem to be specific to this drug class, plays only a minor role in their antihypertensive action; the hypothesis that the sulfhydryl group exerts an additional stimulating action remains to be proved
Experimental data, however, indicate that ACE inhibitors are able to inhibit tissue ACE, that each drug may differ in the amount and duration of ACE inhibition in different tissues, and that tissue bioavailability seems to be the major determinant of these differential effects. These findings raise the theoretical possibility that newer ACE inhibitors might be designed with preferential affinity to various organs, with different therapeutic profiles
As with the systemic humoral effects, it is expected that all the newer ACE inhibitors will exert similar systemic haemodynamic actions. However, the question of whether the different tissue penetration and/or inhibition of the tissue renin-angiotensin system will differentiate the newer ACE inhibitors in terms of regional haemodynamics remains to be answered
The usefulness of the newer ACE inhibitors in the treatment of hypertension and of congestive heart failure is under clinical investigation. Whether these drugs can offer the same or additional advantages or disadvantages as their parent drugs is still in the future
Current data support the existence of an endogenous renin-angiotensin system in the heart. Vascular angiotensin may contribute to the regulation of coronary vascular tone. Enhanced local angiotensin production in areas of vascular injury or inflammation may result in increased vasoconstriction or vasospasm. Cardiac angiotensin may adversely influence myocardial metabolism and provoke ventricular arrhythmia during ischemia and reperfusion-induced myocardial injury. Local angiotensin may stimulate cardiac contractility. In addition, angiotensin may influence cardiac myocyte growth and may contribute to the development of cardiac hypertrophy in hypertension. Recent data show that the pharmacologic inhibition of cardiac angiotensin converting enzyme may have important therapeutic consequences for the ischemic, hypertrophic, or failing heart.
Lisinopril, a long acting, non-sulfhydryl-containing angiotensin-converting enzyme inhibitor, produces an increase in exercise capacity and an improvement in symptoms when administered in a dose of 5 to 20 mg/day to patients with congestive heart failure. There is an increase in left ventricular ejection fraction, and the effectiveness of the drug is not diminished by impairment of renal function (serum creatinine > 71.6 mg/dl). Lisinopril is just as effective in older (> 65 years of age) patients as in younger patients and is well tolerated among patients of all age groups.
Drugs in every major pharmacological category can impair both taste and smell function and do so more commonly than presently appreciated. Impairment usually affects sensory function at a molecular level, causing 2 major behavioural changes — loss of acuity (i.e. hypogeusia and hyposmia) and/or distortion of function (i.e. dysgeusia and dysosmia). These changes can impair appetite, food intake, cause significant lifestyle changes and may require discontinuation of drug administration.
Loss of acuity occurs primarily by drug inactivation of receptor function through inhibition of tastant/odorant receptor: (i) binding; (ii) Gs protein function; (iii) inositol trisphosphate function; (iv) channel (Ca++, Na++) activity; (v) other receptor inhibiting effects; or (vi) some combination of these effects. Distortions occur primarily by a drug inducing abnormal persistence of receptor activity (i.e. normal receptor inactivation does not occur) or through failure to activate: (i) various receptor kinases; (ii) Gi protein function; (iii) cytochrome P450 enzymes; or other effects which usually (iv) turn off receptor function; (v) inactivate tastant/odorant receptor binding; or (vi) some combination of these effects.
Termination of drug therapy is commonly associated with termination of taste/smell dysfunction, but occasionally effects persist and require specific therapy to alleviate symptoms. Treatment primarily requires restoration of normal sensory receptor growth, development and/or function. Treatment which restores sensory acuity requires correction of steps initiating receptor and other pathology and includes zinc, theophylline, magnesium and fluoride. Treatment which inhibits sensory distortions requires reactivation of biochemical inhibition at the receptor or inactivation of inappropriate stimulus receptor binding and/or correction of other steps initiating pathology including dopaminergic antagonists, γ-aminobutyric acid (GABA)-ergic agonists, calcium channel blockers and some orally active local anaesthetic, antiarrhythmic drugs.
There is a growing number of hospitalised patients who develop a drug-induced renal problem because increasing numbers of potent drugs have been added to the therapeutic arsenal in recent years. The 3 clinical syndromes that can be recognised in drug-induced nephropathy are acute renal failure, chronic interstitial nephritis and the nephrotic syndrome. The first can be caused by prerenal problems, acute interstitial nephritis, acute tubular necrosis and intratubular obstruction.
The most important drugs that cause prerenal failure are NSAIDs, captopril and cyclosporin. NSAIDs inhibit the synthesis of prostaglandins, and consequently vasoconstriction of the afferent arteriole leads to lowering of the glomerular filtration rate (GFR); captopril blocks the formation of angiotensin II (which also leads to a lower GFR), and should be used with caution in patients with stenotic renal arteries; cyclosporin causes vasoconstriction of the afferent arteriole, which is probably mediated by the sympathetic system. Combinations of these drugs result in increased nephrotoxicity.
The drugs most likely to cause acute interstitial nephritis are antibiotics and NSAIDs. Normally, signs of an allergic reaction are also present. Acute interstitial nephritis is usually self-limiting, but in some studies it is claimed that steroids may promote recovery.
Four important causal agents of acute tubular necrosis are aminoglycosides, amphotericin B, radiocontrast agents and cyclosporin. Approximately half of the cases of drug-induced renal failure are related to the use of aminoglycosides: generally, 10 days after start of treatment a non-oliguric renal failure develops, with recovery after withdrawal of the drug in almost all cases. The aminoglycosides are particularly nephrotoxic when combined with other nephrotoxic drugs. 80% of amphotericin B-treated patients develop renal insufficiency, a percentage that increases as the cumulative dose exceeds 5g. It is because of its unique antifungal properties that there are still some indications for the use of this highly nephrotoxic drug; the high percentage of nephrotoxicity can probably be prevented in part by sodium loading. The nephrotoxicity of radiocontrast agents is largely dependent on renal function: from 0.6% in patients with normal renal function to 100% in patients with a serum creatinine above 400 μmol/L. Diabetes mellitus does not add greatly to the risk of radiocontrast nephrotoxicity. The nephrotoxicity of cyclosporin is dose-dependent and reversible, although there are some reports of irreversibility after long term use. Cyclosporin can also result in nephrotoxicity in combination therapy. Two mechanisms may be involved: some drugs increase the concentration of cyclosporin (e.g. ketoconazole), and careful monitoring is recommended; other drugs have an additive nephrotoxic effect and these combinations should not be used.
Intratubular obstruction is often associated with chemotherapy, resulting in precipitation of urate, but can also be caused by precipitation of the drug itself (e.g. methotrexate). Chronic interstitial nephritis is also called analgesic nephropathy, and was formerly caused by phenacetin; paracetamol (acetaminophen), particularly in combination with other analgesics, can cause the same disease. Chronic nephritis can also be caused by cyclosporin. Drug-induced nephrotic syndrome is mostly immunologically mediated; membranous glomerulonephritis and minimal change glomerular disease are the most frequently encountered histological abnormalities. Drugs that can cause membranous glomerulonephritis are gold salts, penicillamine, captopril and mercury compounds, but after cessation of these drugs renal function recovers rapidly. Minimal change glomerular disease can be caused by NSAIDs and lithium. Nephrotic syndromes, not related to membranous glomerulonephritis or minimal change glomerular disease, can be caused by several other drugs, of which antiepileptic agents and heroin are well known. It is important to keep in mind that every renal failure of unknown origin may have been caused by drugs.
To evaluate the effect of optimal doses of angiotensin converting enzyme (ACE) inhibitors in the treatment of severe chronic heart failure, in an open, multicentre study, 40 patients with the disease were randomised to receive either 5, 10 or 20mg enalapril daily or 6.25. 12.5, or 25mg captopril 3 times daily, for 3 months. Concomitant therapy with digitalis and diuretics and dietary salt restrictions were kept constant. The treatment groups had similar haemodynamic and clinical characteristics at baseline. Enalapril and captopril did not significantly affect the arterial (mean or 24-hour ambulatory) blood pressure, heart rate, exercise work, ECG profile, blood levels of sodium, potassium, urea nitrogen and creatinine, or creatinine clearance. Although the left ventricular end-diastolic and end-diastolic and end-systolic diameters were reduced (p ⩾ 0.04). other echocardiographic variables were unaffected.
The clinical condition, as assessed by New York Heart Association (NYHA) classification. was improved in the enalapril group (p = 0.02) but not in the captopril group.
We conclude that enalapril, when given in optimal doses, improves the clinical condition of patients with severe heart failure without causing hypotension and associated adverse changes in renal function.
The angiotensin-converting enzyme (ACE) inhibitors represent the gold standard of vasodilator therapy for congestive heart failure through blunting of the endocrinologic manifestations of heart failure. The future role of these agents may be in the asymptomatic and mild stages of heart failure. ACE inhibitors have been shown to decrease morbidity and mortality with the natural history of this disease being altered. The future will bring many new ACE inhibitors to market, with the challenge for physicians and pharmacists to understand the important distinctions of each specific agent. © 1990 by W.B. Saunders Company.
Several studies have shown symptomatic and haemodynamic improvement after the introduction of angiotensin converting enzyme inhibitors in patients with heart failure treated with diuretics. The concomitant long term effects of the new orally effective long acting angiotensin converting enzyme inhibitor, enalapril, on symptoms, exercise performance, cardiac function, arrhythmias, hormones, electrolytes, body composition, and renal function have been further assessed in a placebo controlled double blind cross over trial with treatment periods of eight weeks. Twenty patients with New York Heart Association functional class II to IV heart failure who were clinically stable on digoxin and diuretic therapy were studied. Apart from the introduction of enalapril, regular treatment was not changed over the study period; no order or period effects were noted. Enalapril treatment significantly improved functional class, symptom score for breathlessness, and exercise tolerance. Systolic blood pressure was significantly lower on enalapril treatment. Echocardiographic assessment indicated a reduction in left ventricular dimensions and an improvement in systolic time intervals. In response to enalapril, the plasma concentration of angiotensin II was reduced and that of active renin rose; plasma concentrations of aldosterone, vasopressin, and noradrenaline fell. There were significant increases in serum potassium and serum magnesium on enalapril. Glomerular filtration rate measured both by isotopic techniques and by creatinine clearance declined on enalapril while serum urea and creatinine rose and effective renal plasma flow increased. Body weight and total body sodium were unchanged indicating that there was no overall diuresis. There was a statistically insignificant rise in total body potassium, though the increase was related directly to pretreatment plasma renin (r = 0.5). On enalapril the improvement in symptoms, exercise performance, fall in plasma noradrenaline, and rise in serum potassium coincided with a decline in the frequency of ventricular extrasystoles recorded during ambulatory monitoring. Adverse effects were few. In patients with heart failure, enalapril had a beneficial effect on symptoms and functional capacity. The decline in glomerular filtration rate on enalapril may not be beneficial in early heart failure.
Much current attention focuses on the renin-angiotensin system in relation to mechanisms controlling blood pressure and renal function. Recent demonstrations (ref. 1, ref. 2 and refs therein) that angiotensin-converting enzyme inhibitors show promising clinical antihypertensive properties have been of particular interest. We now report on the design of a novel series of substituted N-carboxymethyl-dipeptides which are active in inhibiting angiotensin-converting enzyme at nanomolar levels. We suggest that these compounds are transition-state inhibitors and that extensions of this design to other metalloendopeptidases merit further study.
Three new angiotensin converting-enzyme inhibitors were given orally to 20 men in single doses ranging from 1.25 to 40 mg. Two of them induced comparable marked inhibition of both the blood pressure response to exogenous angiotensin I and plasma converting-enzyme activity. Onset of action was relatively slow, but 21 to 24 hr after drug plasma converting-enzyme activity was still clearly reduced. The third was less active. There was a close correlation between blood pressure response on administration of angiotensin I and plasma converting-enzyme activity. There were no adverse effects. These new drugs are interesting because of their long duration of action. The measurement of plasma converting-enzyme activity seems useful for monitoring efficacy of converting-enzyme blockade and compliance to therapy.
Enalapril, the new converting enzyme inhibitor, was administered to eight patients with heart failure (NYHA Functional Class II to IV) during standardised and intensive haemodynamic, hormone, and electrolyte monitoring. The first dose (5 mg) of enalapril induced a fall in plasma angiotensin II and noradrenaline levels, and prolonged decrements in systemic vascular resistance, arterial pressure, heart rate, and right heart pressures. Maximum haemodynamic effects were evident four to eight hours after the first dose, with return to baseline by 24 hours. Plasma angiotensin II levels, however, were still suppressed at 24 hours. The magnitude of haemodynamic response was related closely to baseline (pre-enalapril) activity of the renin-angiotensin system and the sympathetic system. Enalapril treatment over three days induced a positive cumulative balance of sodium and potassium, and a small increase in plasma potassium. Urine aldosterone excretion decreased in a stepwise fashion. Continued enalapril administration for four to eight weeks resulted in improved clinical status (NYHA Functional Class) and exercise tolerance in patients who initially were most severely incapacitated, but little change was observed in healthier subjects. We conclude that in heart failure, enalapril is a long acting converting enzyme inhibitor with clear cut beneficial haemodynamic effects in the short term. Long term controlled studies of enalapril in heart failure are warranted.
The effect of the converting enzyme inhibitor captopril as long term treatment was investigated in 14 patients with severe congestive heart failure in a double blind trial. Captopril reduced plasma concentrations of angiotensin II and noradrenaline, with a converse increase in active renin concentration. Effective renal plasma flow increased and renal vascular resistance fell; glomerular filtration rate did not change. Serum urea and creatinine concentrations rose. Both serum and total body potassium contents increased; there were no long term changes in serum concentration or total body content of sodium. Exercise tolerance was appreciably improved, and dyspnoea and fatigue lessened. Left ventricular end systolic and end diastolic dimensions were reduced. There was an appreciable reduction in complex ventricular ectopic rhythms. Adverse effects were few: weight gain and fluid retention were evident in five patients when captopril was introduced and two patients initially experienced mild postural dizziness; rashes in two patients did not recur when the drug was reintroduced at a lower dose; there was a significant reduction in white cell count overall, but the lowest individual white cell count was 4000 X 10(6)/l. Captopril thus seemed to be of considerable value in the long term treatment of severe cardiac failure.
Enalapril is a recently developed angiotensin-converting enzyme inhibitor that improves cardiac function at rest in patients with congestive heart failure. This study investigated the acute effects of enalapril on the cardiovascular response to exercise, and then evaluated the long-term effects of enalapril on exercise capacity and functional status during a 12 week placebo-controlled trial in patients with heart failure. Ten patients underwent hemodynamic monitoring while at rest and during incremental bicycle exercise before and after 5 to 10 mg of enalapril orally. At rest, enalapril decreased mean blood pressure 13% (p < 0.01) and systemic vascular resistance 20% (p < 0.05) and increased stroke volume index 21% (p < 0.01). During maximal exercise, enalapril decreased systemic vascular resistance and increased both cardiac and stroke volume indexes. Enalapril acutely increased exercise duration (p < 0.05) and maximal oxygen consumption (p <0.001).These 10 patients and an additional 13 patients were then randomized to either placebo or enalapril treatment and followed up for 2 weeks. Of the 11 patients assigned to active treatment, 73% considered themselves improved compared with 25% of the patients assigned to placebo treatment (p < 0.02). During long-term treatment, exercise capacity increased in patients receiving enalapril (p < 0.001) but was unchanged in patients receiving placebo (intergroup difference, p < 0.05). During long-term treatment, no adverse effects of enalapril occurred. Thus, enalapril improves cardiac function at rest and during exercise. Compared with placebo, maintenance therapy with enalapril results in symptomatic improvement and increased exercise capacity.
An orally active inhibitor of the angiotensin-converting enzyme, SQ 14,225 (D-2-methyl-3-mercaptopropanoly-L-proline), was administered to fourteen normal male volunteers to evaluate its safety and efficacy in inhibiting pressor responses to exogenous angiotensin I. SQ 14,225 produced significant blockade within 15 min of oral administration. The magnitude and duration of inhibition were dose-related. After a dose of 20 mg, complete blockade was observed for more than 2 h and partial inhibition for over 4 h. There was no effect on pressor responses to angiotensin II. SQ 14,225 promises to provide a new approach to the diagnosis and treatment of disorders involving over-activity of the renin-angiotensin system.
Dogs with thoracic caval constriction retain sodium and develop ascites and edema. The role of the renin-angiotensin-aldosterone system in this model of low output failure was evaluated before, during, and after administration of the new orally active converting enzyme inhibitor, 2-D-methyl-3-mercaptopropanoyl-L-proline (SQ 14225). The acute response to the initial oral dose of SQ 14225 (10 mg/kg) consisted of a striking fall in plasma aldosterone concentration (PAC) from 22.7 and 29.9 ng% to 10.7, 11.9, and 11.0 ng% (P less than 0.05) after 67.5, 112.5, and 157.5 minutes; sodium excretion increased from 1.9 and 1.9 mu Eq/min to 19.9, 22.4, and 17.8 mu Eq/min. Arterial pressure and filtration fraction decreased (P less than 0.05), and plasma renin activity (PRA) increased (P less than 0.05) after the initial dose of SQ 14225; clearance of paraaminohippuric acid (PAH) and creatinine did not change significantly. The daily responses for 3-4 days to SQ 14225 (35 mg/kg per day, given as doses of 10, 10, and 15 mg/kg) were a decrease in PAC from 50 +/- 15 and 32 +/- 10 ng% to 10 +/- 4 ng% on the 4th day, a value not statistically different from normal (P greater than 0.05), and an increase in sodium excretion from 2.9 to 2.0 mEq/day to 5.7, 10.0, 32.4, and 32.9 mEq/day on a sodium intake of 35 mEq/day (P less than 0.05 for the last 2 days). Arterial pressure and creatinine clearance decreased (P less than 0.05). PRA increased transiently on day 1 of SQ 14225 and then returned toward control levels, and clearance of PAH was unchanged. These data demonstrate an important role for aldosterone and the renin-angiotensin system in the retention of sodium and in ascites formation in dogs with thoracic caval constriction.
The role of the renin-angiotensin system (RAS) in autoregulating renal blood flow (RBF) and glomerular filtration rate (GFR) during reductions in renal artery pressure (RAP) was examined in the following groups of anesthetized dogs: group 1, normal controls, n, 10; group 2, normal dogs after intrarenal infusion of angiotensin II antagonist (AIIA), n, 7; group 3, sodium-depleted controls, n, 7; group 4, sodium-depleted dogs after intrarenal infusion of AIIA, n, 10. In groups 1 and 3, RBF and GFR did not change significantly between RAP's of 85-127 mmHg, and decreased only 5-14% below control values at an RAP of approx. 70 mmHg. After AIIA in normal dogs (group 2), RBF increased above control values when RAP was lowered; GFR remained relatively constant in group 2 as RAP was reduced to 85 mmHg, but decreased 71±5% of the control value at 70 mmHg. After AIIA in sodium-depleted dogs (group 4), RBF autoregulation was well maintained, but GFR decreased progressively to 43±6% of the control value when RAP was reduced in steps to 70 mmHg. Although filtration fraction (FF) and calculated efferent arteriolar resistance in groups 1 and 3 remained relatively constant when RAP was reduced, in groups 2 and 4 (in which the RAS was nonfunctional because of angiotensin 2 blockade) FF and efferent arteriolar resistance decreased progressively at all RAP's below control. These observations are consistent with the hypothesis that the RAS plays an important role in controlling GFR through an efferent arteriolar constrictor mechanism, especially during high renin states such as sodium depletion.
Angiotensin-converting enzyme inhibitors are effective vasodilators in the treatment of congestive heart failure. Enalapril, a new angiotensin-converting enzyme inhibitor, or placebo, in addition to digoxin and diuretic drugs, were given to 17 patients with chronic congestive heart failure who were followed up for 12 weeks. In random double-blind fashion, nine patients received enalapril and eight received placebo. Cardiac dimensions and function improved slightly but insignificantly in both groups. Treadmill exercise duration increased from a mean value (+/- standard deviation) of 9.1 +/- 3.2 to 12.0 +/- 3.5 minutes during enalapril administration (p less than 0.025) and was unchanged during placebo administration (10.1 +/- 3.7 versus 11.1 +/- 5.2 minutes). Maximal oxygen consumption also increased during enalapril therapy (15.8 +/- 3.4 to 18.4 +/- 4.4 ml/min per kg, p less than 0.05) and remained unchanged during placebo treatment (16.0 +/- 6.4 versus 17.0 +/- 4.6 ml/min per kg). Clinical functional class (Yale scale) improved 3.1 +/- 1.9 points (p less than 0.01) during enalapril treatment but not during placebo treatment (0.8 +/- 3.5 points, no significant difference). No significant side effects were observed. Thus, enalapril appears to be a clinically effective and useful new angiotensin-converting enzyme inhibitor for the management of chronic congestive heart failure.
Exercise capacity in patients with left heart failure is closely related to the performance of the right ventricle and the pulmonary circulation. To determine the significance of changes in pulmonary resistance during long-term vasodilator therapy, hemodynamic studies were performed before and after 1 to 3 months of treatment with captopril in 75 patients with severe chronic left heart failure. Patients were grouped according to the relative changes in pulmonary and systemic resistances during long-term therapy: patients in Group I (n = 24) showed greater decreases in pulmonary arteriolar resistance (PAR) than in systemic vascular resistance (SVR) (% delta PAR/% delta SVR greater than 1.0), whereas patients in Group II showed predominant systemic vasodilation (% delta PAR/% delta SVR less than 1.0). Despite similar changes in systemic resistance, patients in Group I showed greater increases in cardiac index, stroke volume index and left ventricular stroke work index (p less than 0.01 to 0.001) but less dramatic decreases in mean systemic arterial pressure (p less than 0.02) than did patients in Group II. Despite similar changes in left ventricular filling pressure, patients in Group I showed greater decreases in mean pulmonary artery and mean right atrial pressures (p less than 0.02 to 0.01) than did patients in Group II. Pretreatment variables in Groups I and II were similar, except that plasma renin activity was higher (8.7 +/- 2.1 versus 3.0 +/- 0.6 ng/ml per h) and serum sodium concentration was lower (133.1 +/- 0.9 versus 137.1 +/- 0.6 mEq/liter) in Group II than in Group I (both p less than 0.05). Both groups improved clinically after 1 to 3 months, but symptomatic hypotension occurred more frequently in Group II than in Group I (36 versus 8%) (p less than 0.005). These findings indicate that changes in the pulmonary circulation modulate alterations in both right and left ventricular performance during the treatment of patients with left heart failure. Hyponatremic patients are likely to experience symptomatic hypotension with captopril because they are limited in their ability to increase cardiac output as a result of an inadequate pulmonary vasodilator response to the drug.
The new, long acting converting enzyme inhibitor enalapril was given to 26 patients with moderate to severe heart failure. In 23 cases the mean systolic blood pressure fell from 120 (SD 22) to 108 (25) mm Hg without adverse effects. Profound hypotension with severe bradycardia and sweating, however, occurred in three patients, most pronounced two to four hours after the first dose. The haemodynamic and biochemical changes in these patients were similar to those seen in patients with severe symptomatic hypotension after the first dose of the converting enzyme inhibitor captopril, except that with enalapril the changes occurred later and were longer lasting. Evidence of myocardial damage and reversible renal failure was seen in one patient, and acute reversible deterioration in renal function occurred in one other. In patients with heart failure converting enzyme inhibitors should be administered initially under strict medical supervision with appropriate facilities available for dealing with occasional profound hypotension.
We suspected that patients with severe chronic heart failure may show hemodynamic changes after cardiac catheterization in the absence of drug therapy that could complicate assessment of the hemodynamic effects of new vasodilator and inotropic agents. To evaluate this phenomenon prospectively, hemodynamic variables were measured in 21 patients with heart failure 30 min and 2, 6, 24, and (in 12 patients) 48 hr after right heart catheterization, during which time therapy was not altered. During the first 2 hr we noted a significant increase in cardiac index and decreases in left ventricular filling pressure, mean arterial pressure, mean right atrial pressure, and systemic vascular resistance (p less than .01); a further decline in left ventricular filling pressure was noted over the next 24 hr, after which all hemodynamic variables remained stable. The magnitude of these hemodynamic changes resembled the effects of many established vasodilator drugs and was further enhanced after meals. These data indicate that hemodynamic improvement may be observed without any therapeutic intervention during the course of invasive studies in patients with severe chronic heart failure; such changes may lead investigators to attribute efficacy to ineffective drug therapy. To minimize the occurrence of such responses, we recommend that intravascular catheters be inserted the day before drug evaluation and that hemodynamic measurements be made with patients in a postprandial state.
Enalapril, a new long-acting angiotensin-converting enzyme inhibitor, was administered orally to 12 patients with stable congestive cardiac failure, NYHA function class III-IV. Acute and chronic hemodynamic effects were evaluated in addition to clinical response. The results of this open pilot study indicated marked reduction of pulmonary capillary wedge pressure from 21.8 +/- 5.9 mm Hg (mean +/- 1 SD) to 13.3 +/- 4.5 mm Hg (P less than 0.01) and peripheral resistance from 1837 +/- 860 dynes X sec-1 X cm-5 to 1063 +/- 584 dynes X sec-1 X cm-5 at 6 hr (P less than 0.01). Well-tolerated hypotension with mean arterial pressure from 88.0 +/- 11.6 mm Hg to 73.1 +/- 11.7 mm Hg at 6 hr (P less than 0.01) was recorded. No significant increase in cardiac output was observed. Angiotensin-converting enzyme activity was powerfully inhibited at the time of peak hemodynamic effect from 25.3 +/- 9.8 U/ml to 4.9 +/- 3.4 U/ml (P less than 0.01) and sustained, but attenuated reduction at 24 hr (8.7 +/- 4.7 U/ml) was observed. All patients reported subjective improvement and this clinical improvement has been sustained during follow-up from 19 to 21 months although baseline hemodynamic parameters at chronic re-catheterization did not demonstrate significant improvement. The pharmacodynamics and toxicity of enalapril as compared to captopril are discussed. The long half-life, low toxicity and gradual onset of action are seen as representing a clinical advantage with regard to patient therapy.
Glomerular and tubule functions were assessed by micropuncture in rats with extensive myocardial infarction produced by ligation of the left coronary artery 4 weeks prior to study. When compared to sham-operated control rats, rats with myocardial infarction involving 40 +/- 4% of the left ventricular circumference had lower mean arterial pressure (96 +/- 5 vs. 122 +/- 4 mm Hg, P less than 0.005), and higher left ventricular end-diastolic pressure (24 +/- 3 vs. 5 +/- 0 mm Hg, P less than 0.001). Renal cortical microcirculatory dynamics of rats with myocardial infarction were characterized by reduced glomerular plasma flow rate (75 +/- 8 vs. 165 +/- 17 nl/min, P less than 0.005), but a proportionately lesser decline in single nephron glomerular filtration rate (28.0 +/- 2.8 vs. 41.7 +/- 3.1 nl/min, P less than 0.025), accounting for the observed rise in single nephron filtration fraction (0.38 +/- 0.02 vs. 0.25 +/- 0.02, P less than 0.005). These renal hemodynamic alterations in myocardial-infarcted rats were accompanied by a striking elevation in efferent arteriolar resistance (3.03 +/- 0.31 vs. 0.95 +/- 0.16 X 10(10) dyn X sec X cm-5, P less than 0.001). In addition, fractional proximal fluid reabsorption, assessed by end-proximal tubule fluid-to-plasma inulin concentration ratio, was elevated (2.21 +/- 0.12 vs. 1.64 +/- 0.09, P less than 0.025). The intravenous infusion of teprotide, an angiotensin I-converting enzyme inhibitor, led to the return of glomerular plasma flow rate, single nephron filtration fraction, single nephron glomerular filtration rate, efferent arteriolar resistance, and fractional proximal fluid reabsorption in myocardial-infarcted rats to, or toward, the levels found in control rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Enalapril, a novel long acting angiotensin converting enzyme (ACE) inhibitor, was given orally to 12 patients with chronic heart failure (NYHA functional class III and IV) and cardiomegaly. The optimal dose averaged 17 mg given once-daily. Heart rate, systemic arterial blood pressure, pulmonary arterial pressure, right and left ventricular filling pressures and cardiac index were monitored during dose efficacy titration. Eleven patients were recatheterised 3 months later. After stabilisation of cardiac filling pressures, all patients had left ventricular filling pressures in excess of 20 mmHg. Enalapril increased cardiac index acutely by 34% but at 12 weeks follow-up, cardiac index was not different from control levels. Left ventricular filling pressure was reduced acutely by 36% and by 41% at 3 months. Heart rate, systemic arterial and right atrial pressures and plasma concentrations of aldosterone were reduced during the observation period. ACE activity was inhibited at the time of peak haemodynamic effect from 25.3 +/- 9.8 to 4.9 +/- 3.4 U/ml (P less than 0.01). Renin was markedly elevated. These changes were accompanied by marked and sustained clinical improvement and subjective well-being.
To determine whether temporary cessation of captopril therapy compromises cardiac performance, haemodynamic, hormonal, and electrolyte indices were measured for 2 days before, and 4 days after discontinuation of long-term captopril treatment in 5 patients with heart failure. Captopril withdrawal resulted in a four-fold rise in plasma angiotensin II, higher levels of noradrenaline, and a 13.5mmHg increase in mean arterial pressure. Despite there changes, cardiac output at rest and during exercise was well maintained, and right-heart pressures were unaltered. Although plasma aldosterone levels increased three-fold, neither sodium retention nor potassium depletion occurred. Cortisol levels rose in parallel with angiotensin II levels. These results indicate that in the short term cardiac performance is not impaired and electrolyte balance is not adversely affected by the abrupt withdrawal of captopril.
Although substantial progress has been made in the last 5 years in the development of vasodilator and inotropic drugs for the management of patients with severe chronic heart failure, much of the enthusiasm that surrounded the introduction of many of these agents has subsequently been tempered by reports of drug failure or adverse reactions. In this review and analysis, currently available vasodilator and inotropic agents are critically and comparatively evaluated to assess their respective advantages and limitations. It is apparent that the ability of most of these drugs to produce substantial clinical benefits in patients with severe heart failure has probably been overstated. Therapy fails to achieve the desired clinical results all too frequently, possibly as the result of: the choice of an ineffective drug; the administration of an effective drug in subtherapeutic doses; the administration of an effective drug to improperly selected patients; the failure of initial hemodynamic benefits to be sustained; the occurrence of severe or serious adverse reactions; and the failure to alter concomitant therapy appropriately. The present analysis indicates that there is no uniformly effective or safe vasodilator or inotropic drug for patients with severe heart failure; all agents have important limitations. Of the available therapeutic choices, however, long-term converting enzyme inhibition appears to produce more consistent hemodynamic and clinical benefits with an acceptable degree of adverse reactions than other pharmacologic approaches for the management of these severely ill patients.
In a double-blind randomized study, the dose response to captopril was studied in 12 severely hypertensive patients whose blood pressure had been previously controlled by this converting enzyme inhibitor, either in association with a diuretic (seven patients), or with a diuretic and a beta-blocker (five patients). All patients received in random sequence 32.5, 75, and 150 mg/day of captopril in three divided doses. Significant correlations were revealed between the dose administered and the levels of arterial blood pressure, plasma renin, plasma aldosterone and plasma potassium. Under the conditions of this study, dose-response curves were obtained for concentrations of captopril between 0.5 and 4 mg/day/kg body weight.
Nineteen hypertensive patients were treated with increasing doses of the new angiotensin-converting enzyme inhibitor MK 421. Twenty milligrams orally reduced blood pressure from 180/112 +/- 6.8/3.6 (mean +/- SEM) to 160/100 +/- 6.5/3.3 mm Hg (p less than 0.005) while heart rate increased from 75 +/- 2 to 87 +/- 3 beats/min (p less than 0.005). Plasma converting enzyme activity was still markedly reduced 24 h following 2.5, 5, 10, or 20 mg MK 421 p.o. (p less than 0.001). In nine patients treated with 20 mg b.i.d. for up to 10 months, blood pressure was controlled, with the association of hydrochlorothiazide 50 mg q.d. in five. However, 12 to 16 h following the preceding drug administration, plasma angiotensin II and aldosterone were back to base-line levels. Analysis of plasma angiotensin II-renin relationships strongly suggests that converting enzyme blockade is not complete even 4 h after 20 mg MK 421 and starts to wear off already at 12 h. Thus, MK 421 20 mg taken orally twice daily, effectively reduces blood pressure, but does not constantly suppress plasma angiotensin II and aldosterone. Whether its long duration of action makes once daily administration possible has not yet been established.
Converting enzyme inhibition of the renin-angiotensin system has proved a valuable therapeutic approach in patients with severe chronic congestive heart failure. In the present study, a new long-acting converting enzyme inhibitor (enalapril) was evaluated with acute single dose testing (10, 20 or 40 mg) in nine patients with severe chronic congestive heart failure. Four hours after administration, there was a significant reduction of systemic vascular resistance (-19%) and pulmonary wedge pressure (-19%); in addition, there were related increases of cardiac index (+16%) and stroke index (+19%) (probability [p] less than or equal to 0.05 for all changes). This was associated with an increase of plasma renin activity (9 +/- 3 to 35 +/- 11 ng/ml per hour) and a decrease of plasma aldosterone (19 +/- 4 to 9 +/- 2 ng/100 ml) (p less than 0.02 for both). With long-term therapy (1 month), there was improvement of exercise tolerance time and lessening of symptoms based on the New York Heart Association classification. Hemodynamic improvement was maintained in most, but not all, patients. There was no orthostatic hypotension during head-up tilt and hemodynamic values in the upright position were associated with normalization of intracardiac pressures. Long-term converting enzyme inhibition was indicated by a persistent increase of plasma renin activity (16 +/- 2 ng/ml per hour) and a decrease of plasma aldosterone (8 +/- 3 ng/100 ml). In addition, relative angiotensin II receptor occupancy was decreased as judged by the pharmacodynamic response to infusion of the angiotensin II analog saralasin. In conclusion, the long-acting converting enzyme inhibitor, enalapril, was effective in patients with chronic congestive heart failure; however, additional studies will be necessary to further delineate the optimal dose range and identify those patients who are most likely to respond to the drug.
Captopril, an inhibitor of angiotensin converting enzyme, was administered twice daily to 13 hypertensive patients for a mean period of 9 weeks. Continuous blood pressure control in the ambulatory patients was established with a portable blood pressure recorder. Notwithstanding, in eight patients with normal renal function, plasma converting enzyme was found to resume normal activity before administration of the morning dose of captopril. Only in 5 patients with impaired renal function did some blockade of plasma converting enzyme persist for more than 12 hours. Measured plasma converting enzyme activity seemed to reflect total conversion of angiotensin I, including conversion in the pulmonary vascular bed, since changes in its activity were closely paralled by changes in plasma aldosterone levels. Bradykinin accumulation seems unlikely when converting enzyme and thus, presumably, kininase II has resumed normal activity. Captopril administration does not seem to alter plasma epinephrine or norepinephrine levels. Blood pressure reduction in the face of normal angiotensin converting enzyme activity is probably due to hyporesponsiveness of the arterioles to pressor hormones, which may be due to specific renin-related and/or nonspecific effects of captopril.
Dose-response curves of blood pressure and of the biochemical components of the renin-angiotensin-aldosterone system were determined during long-term treatment with captopril in 21 hypertensive patients. Captopril was given in biweekly, doubling doses starting with 25 mg 3 times a day until control of blood pressure was achieved or a total daily dosage of 600 mg was reached. Recumbent and standing systolic and diastolic blood pressure fell on 75 mg captopril daily. Increasing the captopril dose did not induce further significant hypotensive effects. The pretreatment level of plasma renin activity (PRA) was a poor predictor of the hypotensive effect of captopril. The rises in PRA and plasma angiotensin I level (PA I) and the decrease in plasma angiotensin II level (PA II) and plasma aldosterone level (PAC) provide biochemical evidence for angiotensin-converting enzyme (ACE) inhibition in vivo. These effects were present on daily doses of 75 to 150 mg captopril.
The parent diacid (N-[(S)-1-carboxy-3-phenylpropyl]-L-Ala-L-Pro of MK-421 inhibited hog plasma angiotensin converting enzyme (ACE) by 50% (I50) at a concentration of 1.2 nM and was 17 times more potent than captopril. In vitro the I50 for MK-421, an ethyl ester, was 1200 nM because de-esterification did not occur. Similarly in the guinea-pig ileum, the diacid inhibitor and MK-421 potentiated the contractile effects of bradykinin at an AC50 of 77 pM and 18 nM, respectively. Inhibition of the pressor effects of angiotensin I by the diacid ACE inhibitor occurred at an ID50 of 8.2 micrograms/kg i.v. in rats and 6.4 micrograms/kg i.v. in dogs. Thus, the diacid was approximately 12 times more potent than captopril. The ID50 for MK-421 was 14 and 278 micrograms/kg i.v. in rats and dogs, respectively, because of differences in the rates of de-esterification. Oral ACE inhibitory activity was determined by blockade of the pressor effects of angiotensin I in conscious rats and dogs. In rats, but not in dogs, the diacid inhibitor was poorly absorbed, whereas MK-421 was well absorbed in both species. MK-421 inhibited the pressor effects of angiotensin I at 0.1 to 3.0 mg/kg p.o. for at least 6 hr in rats and dogs, and compared to captopril was 8.6 times more potent in rats and 4.6 times more potent in dogs. These data demonstrate that MK-421 and its parent diacid are potent, long-lasting orally active inhibitors of ACE. In addition, the low activity of MK-421 in vitro contrasts with its substantial in vivo activity, and supports the hypothesis that MK-421 is a prodrug that first must be de-esterified to permit full expression of its significant in vivo pharmacological activity.
The acute effects of the angiotensin converting-enzyme inhibitor captopril on regional blood flow, renal hemodynamics and sodium excretion were studied in 12 patients with severe congestive heart failure. Converting-enzyme inhibition decreased systemic vascular resistance by 27% and increased cardiac index by 16%. Estimated hepatic blood flow decreased 17%, but renal blood flow increased 60%. The ratio of renal-systemic blood flow increased from 0.10 +/- 0.01 to 0.14 +/- 0.02 (p = 0.031). Although renal plasma flow increased from 202.8 +/- 28.8 to 323.7 +/- 42.7 ml/min (p less than 0.008), the glomerular filtration rate did not change significantly from the mean pretreatment value of 82.1 +/- 12.3 ml/min. The filtration fraction decreased from 41.3 +/- 3.8% to 33.4 +/- 4.5% (p = 0.050), while urinary sodium excretion doubled, from 34.5 +/- 9.6 to 68.2 +/- 19.6 muEq/min. The plasma renin activity increased from 12.6 +/- 5.0 to 29.9 +/- 8.4 ng/ml/hr (p = 0.030) as plasma aldosterone concentration decreased from 30.5 +/- 6.5 to 11.3 4/- 1.2 ng/dl (p = 0.010) and norepinephrine concentrations decreased from 774 +/- 105 to 618 +/- 85 pg/ml (p = 0.020). We conclude that converting-enzyme inhibition reverses renal vasoconstriction in congestive heart failure and redistributes regional blood flow. The natriuresis may be mediated by one or more of the following: improved renal plasma flow, reduction in filtration fraction, suppression of hyperaldosteronism, and lowering of circulatory catecholamine concentrations.
Thirty-three hypertensive patients with a wide range of renal function were studied during initiation of angiotensin-converting enzyme inhibition with captopril to evaluate changes in potassium levels concomitant with reduction of aldosterone excretion. Ten patients (Group I) with low levels of plasma renin activity had no change in either aldosterone excretion or potassium during the first week of therapy. Twenty-three other patients (Group II) had decreased aldosterone excretion of an average of 63 percent, often reversing secondary hyperaldosteronism. This was associated with a rise in serum potassium from 3.6 +/- 0.1 to 4.4 +/- 0.1 mEq/liter (p less than 0.001). Serum potassium levels during captopril therapy were inversely related to glomerular filtration rate (creatinine clearance) and transiently exceeded 6.0 mEq/liter in markedly azotemic subjects. Despite rising potassium levels, nine patients had reduced aldosterone excretion to subnormal levels, sometimes for many months. During initiation of converting-enzyme inhibition, potassium-sparing agents and supplements should be discontinued and serum potassium levels should be monitored closely, particularly in patients with imparied renal function.
Thirty-one men with mild, uncomplicated essential hypertension were studied for 18 wk in a double-blind, placebo-controlled, randomized clinical trial. Those whose supine diastolic pressure was 90 to 104 mm Hg after 4 wk of placebo were randomly assigned to three groups. Group I (11 subjects) initially received one 10-mg enalapril capsule in the morning and one placebo capsule in the evening. Group II (10 subjects) received one 5-mg enalapril capsule twice daily. Group III (10 subjects) received one placebo capsule twice daily. Drug dosages were doubled and then quadrupled in all groups at wk 8 and 12. Metabolic, ophthalmologic, and audiometric studies were done on all subjects at wk 2, 4, 8, 12, and 16. Enalapril lowered diastolic pressure in the supine and upright positions in single and divided doses. Its antihypertensive effect was dose dependent, and it was greater in white patients than in black patients. The drug was well tolerated by all subjects and did not cause clinical or metabolic complications. It is concluded that enalapril is effective in lowering the arterial pressure in single and divided daily doses; its effect is dose dependent and is greater on the diastolic arterial pressure than on the systolic pressure; and it is well tolerated.
Enalapril (MK-421) is a new oral angiotensin-converting enzyme inhibitor which was administered to eight patients with chronic congestive heart failure. Four hours after enalapril administration (10 to 20 mg), mean arterial pressure fell from 95.6 +/- 11.4 (SD) to 84.8 +/- 17.6 mm Hg (p less than 0.05), systemic vascular resistance fell from 18.5 +/- 3.0 to 15.8 +/- 4.1 units (p less than 0.02), while pulmonary artery wedge pressure changed insignificantly from 17.5 +/- 9.2 to 14.5 +/- 10.2 mm Hg and cardiac index rose insignificantly from 2.63 +/- 0.46 to 2.82 +/- 0.75 L/min/m2. These hemodynamic effects persisted during one month of enalapril administration. Baseline plasma renin activity of 0.76 +/- 1.07 ng/ml/hr rose to 3.23 +/- 2.87 ng/ml/hr (p less than 0.05) after one month of enalapril administration. During the month of enalapril administration, maximal exercise duration rose from 465.1 +/- 233.0 to 572.3 +/- 233.7 seconds (p less than 0.05), and maximal oxygen uptake increased from 12.3 +/- 2.7 to 16 +/- 11.2 ml/min/kg (p less than 0.05). No major side effect occurred. These sustained effects may be clinically beneficial, and enalapril deserves further evaluation in the long-term treatment of patients with chronic congestive heart failure.
Hemodynamic effects of the new oral angiotensin-converting enzyme inhibitor, enalapril, were evaluated acutely in 15 patients with chronic heart failure and in 7 patients after 4 weeks of maintenance therapy. Initial hemodynamic effects were characterized by a significant increase in cardiac index (from 2.1 +/- 0.7 to 2.6 +/- 0.7 liters/min per m2) and a decrease in pulmonary capillary wedge pressure (from 30 +/- 6 to 24 +/- 7 mm Hg), right atrial pressure (from 14 +/- 5 to 11 +/- 4 mm Hg), mean arterial pressure (from 96 +/- 16 to 80 +/- 17 mm Hg) and systemic vascular resistance (from 1,820 +/- 480 to 1,200 +/- 410 dynes . s . cm-5) without any significant change in heart rate, pulmonary artery pressure and pulmonary vascular resistance. During maintenance therapy, the dose of diuretic drugs had to be increased because of systemic venous hypertension. Repeat hemodynamic study showed that after chronic therapy, cardiac index (2.1 +/- 0.7 vs. 3.0 +/- 0.08 liters/min per m2) and stroke volume index (24 +/- 10 vs. 36 +/- 7 ml/m2) remained elevated and pulmonary capillary wedge pressure was lower than control (30 +/- 6 vs. 16 +/- 6 mm Hg), indicating sustained improvement in left ventricular performance. Plasma renin activity increased and plasma norepinephrine levels decreased after enalapril therapy and these humoral changes persisted during maintenance therapy. All patients receiving chronic therapy had symptomatic improvement. Significant hypotension, which occurred in five patients at the initiation of therapy, appears to be the major side effect.(ABSTRACT TRUNCATED AT 250 WORDS)
Enalapril, a new oral angiotensin converting-enzyme inhibitor, was administered to nine patients with severe congestive heart failure. Short-term hemodynamic response was noted within 2 hr and persisted for up to 24 hr. At peak effect mean arterial pressure fell from 83.4 +/- 10(SD) to 72.1 +/- 16.2 mm Hg (p less than .01), right atrial pressure from 13.6 +/- 6.0 to 10.4 +/- 7.5 mm Hg (p less than .01), pulmonary arterial pressure from 38.9 +/- 4.8 to 31.9 +/- 4.8 mm Hg (p less than .01), pulmonary capillary wedge pressure from 28.2 +/- 3.5 to 22.1 +/- 5.1 mm Hg (p less than .01), and total pulmonary resistance from 875 +/- 304 to 697 +/- 291 dynes-sec-cm-5 (p less than .05). Cardiac index was not changed, but there was a significant redistribution of regional blood flow with an increase of renal blood flow after enalapril. Plasma renin activity rose significantly from 6.2 to 28.6 ng/ml/hr, whereas plasma norepinephrine did not change after enalapril. Seven patients were treated with enalapril for 4 weeks. Five patients reported symptomatic improvement. Five of six patients tested had an increase in both exercise time (NS) and maximum oxygen consumption (NS). Repeat hemodynamic evaluation in six patients after long-term enalapril therapy showed a persistent effect with significant reductions in right atrial pressure from 13.8 +/- 7.2 to 7.1 +/- 4.7 mm Hg and in mean arterial pressure from 82.5 +/- 10.4 to 76.6 +/- 5.3 mm Hg and a significant increase in cardiac index from 2.1 +/- 0.5 to 2.5 +/- 0.5 l/min/m2 (all p less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)
The relation between pretreatment serum sodium concentration and the early and late effects of captopril was examined in 77 consecutive patients with severe chronic heart failure, in whom cardiac catheterization was performed during initiation of treatment and after 2 to 8 weeks. Two groups of patients were defined: 37 patients had hyponatremia (serum sodium less than 135 mEq/liter, group A) and 40 patients had a normal serum sodium concentration (greater than or equal to 135 mEq/liter, group B). With first doses of captopril, patients in group A showed more marked hemodynamic responses than did patients in group B (p less than 0.02). The changes in mean arterial pressure and left ventricular filling pressure seen with first doses of the drug varied linearly and inversely with the pretreatment serum sodium concentration (r = -0.58 and r = -0.53, respectively); this was likely related to the finding that, before administration of captopril, the serum sodium concentration varied linearly and inversely with the logarithm of the plasma renin activity (r = -0.78). However, the pretreatment serum sodium concentration did not predict the long-term hemodynamic or clinical responses to converting enzyme inhibition. Symptomatic hypotension occurred early in the course of therapy (within 24 hours of initiating captopril therapy) in 9 (12%) of the 77 patients; 8 of these 9 had severe hyponatremia (serum sodium less than 130 mEq/liter) and comprised 53% of the 15 patients in our study with such low serum sodium concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
A number of studies have shown short-term hemodynamic and symptomatic improvement in patients with congestive heart failure treated with angiotensin converting-enzyme inhibitors. The long-term efficacy of the oral long-acting converting-enzyme inhibitor enalapril remains to be established in controlled studies. We evaluated this drug in 36 patients with New York Heart Association functional class II to III heart failure who were clinically stable on digoxin and diuretic therapy. After baseline assessment of symptoms, exercise capacity, and results of echocardiographic examination and right heart catheterization, patients were randomly assigned to treatment with 5 mg enalapril twice daily (n = 18) or placebo (n = 18) in a double-blind fashion. The two groups had similar clinical, echocardiographic, and hemodynamic characteristics before treatment. After 3 months of treatment, the enalapril group showed a significant improvement as judged by subjective patient impression, functional class, and exercise duration (9.3 +/- 5.7 vs 17.6 +/- 5.6 min; p less than .001). Diuretic dosage was reduced in six patients and increased in one patient, one patient had died and another had been withdrawn from the study. In the placebo group there was no significant change with respect to patient impression, functional class, or exercise duration; diuretic dosage was increased in seven patients and four patients had died. Echocardiographic left ventricular dimensions were significantly reduced and left ventricular shortening fraction significantly increased in the enalapril group but were unchanged in the placebo group.(ABSTRACT TRUNCATED AT 250 WORDS)
Although many studies have shown acute hemodynamic improvement in patients with congestive heart failure treated with vasodilating drugs, long-term controlled studies with both hemodynamic and exercise capacity measurements are not available. We studied the converting-enzyme inhibitor captopril in 16 ambulatory patients in New York Heart Association functional class II-IV heart failure who were clinically stable on digoxin and diuretics. The acute response to open-label captopril was quantified by blood pool scintigraphy, right-heart catheterization at rest and during exercise, and measurements of exercise capacity. The patients were then randomized to maintenance therapy with captopril or matching placebo and were restudied after 3 months. The two groups were similar in their clinical characteristics and pretreatment rest and exercise hemodynamic measurements. Both displayed similar acute beneficial responses to captopril at rest, with a mean reduction in left ventricular filling pressure from 24 ± 9 to 14 ± 6 mm Hg (p<0.001) and increases in cardiac index, from 2.1 ± 0.5 to 2.5 ± 0.61/min/m2 (p<0.01), and stroke index, from 25 ± 8 to 34 ± 8 ml/m2 (p<0.001). Directionally similar hemodynamic improvement was noted during exercise. After 3 months, these beneficial hemodynamic changes were sustained only in the patients randomized to captopril. Concomitantly, the captopril patients increased their exercise capacity as measured by the duration of bicycle exercise (9.0 ± 2.2 vs 11.7 ± 1.4 min, p<0.01), maximal work load (360 ± 80 vs 460 ± 50 kpm/min, p<0.005) and oxygen consumption (12.9 ± 2.3 vs 15 ± 1.8 ml/kg/min). The placebo group showed either no change or a worsening over the 3 months compared to their pretreatment measurements. These findings demonstrate that captopril is an effective adjunctive agent for the treatment of chronic heart failure and that it produces long-term hemodynamic improvement together with an increase in exercise capacity.
This study examines the role of adrenocortical hormones in the kaliuresis following an acute intragastric KCl load in conscious control (CK) and high potassium diet (HK) rats. Adrenalectomy, 1 day before test, reduced K+ excretion by 35% in CK and 60% in HK rats, leading to minimal differences in K excretion between CK and HK. By contrast, spironolactone inhibited K excretion by only 10%. Glucocorticoids (dexamethasone 3-10 micrograms/100 g) increased K+ excretion in adrenalectomized CK and to a greater extent in adrenalectomized HK rats. Aldosterone (3 micrograms/100 g) alone had a variable effect on urinary potassium excretion in adrenalectomized rats. A combination of dexamethasone (3 micrograms/100 g) and aldosterone (3 micrograms/100 g) in adrenalectomized rats induced potassium excretion equivalent to that in intact rats. Adrenalectomized HK rats had a greater kaliuretic response to dexamethasone and aldosterone than CK rats. These results 1) demonstrate a role for glucocorticoids in K+ excretion in HK rats and 2) illustrate the importance of the increased responsiveness to both glucocorticoids and mineralocorticoids in potassium adaptation.