ACE inhibitors in pediatric patients with heart failure

This article reviews reports of ACE inhibitor use in pediatric heart failure and summarizes the present implications for clinical practice. Captopril, enalapril, and cilazapril are orally active ACE inhibitors, and widely used in pediatric cardiology, although more than ten other ACE inhibitors have been applied clinically in adults. Effects of ACE inhibitors on the renin-angiotensin-aldosterone system in pediatric patients are similar to those in adults. ACE inhibitors lower aortic pressure and systemic vascular resistance, do not affect pulmonary vascular resistance significantly, and lower left atrial and right atrial pressures in pediatric patients with heart failure. In infants with a large ventricular septal defect and pulmonary hypertension, ACE inhibitors decrease left-to-right shunt in those infants with elevated systemic vascular resistance. ACE inhibitors induce a small increase in left ventricular ejection fraction, left ventricular fractional shortening, and systemic blood flow in children with left ventricular dysfunction, mitral regurgitation, and aortic regurgitation. These beneficial effects usually persist long term without the development of tolerance. Therapeutic trials of ACE inhibitors have been reported in children with heart failure and divergent hemodynamics, including myocardial dysfunction, left-to-right shunt, such as large ventricular septal defect and pulmonary hypertension, aortic or mitral regurgitation, and Fontan circulation.Hypotension and renal failure usually occur within 5 days after starting ACE inhibition or increasing the dose and, in most cases, recovery is seen after reduction or cessation of the drug. With all ACE inhibitors, smaller doses are administered initially to prevent excessive hypotension, and doses are increased gradually to the target dose. Captopril is administered orally, usually every 8 hours. Daily doses range from 0.3 to 1.5 mg/kg in children. Enalapril is administered orally, once or twice a day, and daily doses range from 0.1 to 0.5 mg/kg. Enalaprilat is administered intravenously, one to three times a day, in doses ranging from 0.01 to 0.05 mg/kg/dose.For the treatment of chronic heart failure in children, ACE inhibitors are essential along with other medications including diuretics, digoxin, and beta-blockers (beta-adrenoceptor antagonists).     

Interaction between aspirin and ACE inhibitors in patients with heart failure.

Both aspirin (acetylsalicylic acid) and ACE inhibitors are often used concomitantly, especially in patients with both heart failure and ischaemic heart disease, which is the most common underlying cause of heart failure. The safety of the association has been questioned because both drugs affect a related prostaglandin-mediated pathway. Thanks to their vasodilating properties, prostaglandins play an important role in heart failure where peripheral vasoconstriction occurs. Some of the beneficial effects of ACE inhibitors might be related to reduced degradation of bradykinin that enhances the synthesis of prostaglandins, while aspirin, through inhibiting the enzyme cyclo-oxygenase, inhibits the production of prostaglandins. To date no prospective study has been conducted to investigate the effect of long term aspirin treatment in the postinfarction period allowing the possible impact of the interaction between aspirin and ACE inhibitors upon survival to be confirmed or negated. However, the practitioner needs to know how to optimise the treatment of his or her patients. In order to stimulate arguments for and against the use of aspirin in patients with heart failure receiving ACE inhibitors, we searched MEDLINE from 1960 to 2000 using the key words heart failure, aspirin, and ACE inhibitors for English language articles and conducted a review of the available data. We report on the potential mechanisms of the interaction and the results of experimental studies on haemodynamic parameters. Results of retrospective clinical studies, subgroup analysis that were undertaken to evaluate the overall action upon haemodynamic parameters and survival of the association are summarised. Conflicting conclusions have been reported in the literature. Many explanations can be advanced to try to understand these conflicting conclusions: differences in study design (results of retrospective trials have to be interpreted with caution); differences in the choice of the evaluation parameter (problem of the clinical relevance of haemodynamic parameters); differences in the characteristics of the patient (different underlying cardiopathy, e.g. heart failure, hypertension or ischaemic cardiopathy); and differences in the type and the dosage of each treatment (especially ACE inhibitors and aspirin since an interaction might occur more often with dosage of aspirin greater than 250mg).     

Underutilization of ACE inhibitors in heart failure.

Although the beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in patients with ventricular systolic dysfunction are well documented, historically, a large proportion of patients have not received optimal therapy. Published studies to describe the trends in ACE inhibitor utilization and determinants of their use were reviewed. In recent years the number of patients treated with ACE inhibitors has increased; however, a relatively small proportion of these patients received adequate therapeutic dosages. Attention to factors that impair proper use of these agents is essential to realize improved outcomes in these patients.     

Comparative haemodynamic responses to the first dose of short- and long-acting ACE inhibitors in patients with congestive heart failure

BACKGROUND: Angiotensin Converting Enzyme inhibitors (ACEi's) confer significant mortality and morbidity benefits in all functional grades of chronic heart failure (CHF). However, physicians' concerns regarding the possible occurrence of first-dose hypotension appear to be a contributing factor to their under-utilisation in both hospital and primary care settings. We investigated whether long-acting and short-acting ACEi's differ in their haemodynamic responses to the first-dose in patients with CHF. METHOD: This was a multicentre, randomised, open, two-parallel-group study of captopril 6.25 mg and perindopril 2 mg. 240 patients with CHF, age 68.9 +/- 8.9 years, of whom 66% were male, NYHA II-IV, with average blood pressure baseline values of 132.2 +/- 16.2/78.5 +/- 10.5 mmHg for systolic and diastolic blood pressure, and left ventricular ejection fraction (LVEF) of 31.3 +/- 7.4% received either captopril (n = 124) or perindopril (n = 116). Blood pressure was continuously monitored during the 8 h following drug intake. Minimum levels and maximum decreases in systolic, diastolic and mean arterial pressures were measured, along with the incidence of hypotensive episodes defined as mean blood pressure (MBP) fall > 20 mmHg, whether symptomatic or not. Subgroups of patients distributed according to age, baseline blood pressure (BP) and LVEF were subsequently analysed. RESULTS: Overall, a statistically significant treatment effect in favour of perindopril was observed. First-dose hypotension was observed more frequently following captopril than perindopril administration, with lower MAP minimal levels (78.0 +/- 8.9 vs. 84.5 +/- 10.1 mmHg, p < 0.0001), greater maximum falls (17.6 +/- 8.3 vs. 12.8 +/- 7.3 mmHg, p < 0.0001) and more frequent hypotensive episodes (42% vs. 15%, p < 0.0001). The incidence of at least one symptomatic episode was also significantly higher with captopril (10 patients vs. one patient, p = 0.029). Subgroup analyses according to age (< or = 70 years or > 70 years) or LVEF (< or = 30% or > 30%) reflected the main result. CONCLUSION: Initiation of treatment with ACE inhibitors is associated with different haemodynamic and clinical tolerances in CHF patients, regardless of their risk for hypotension, with possible clinical implications.     

Pharmacokinetics of hydrochlorothiazide in patients with congestive heart failure.

1. Hydrochlorothiazide (HCT, 50-75 mg) was administered orally to seven patients with cardiac failure. 2. Plasma levels and urinary concentration of HCT were determined by GLC. 3. The gastrointestinal uptake of the diuretic in three patients was reduced to approximately half that seen in healthy controls. 4. Plasma halflife of HCT was correlated with endogenous creatinine clearance. 5. Pharmacokinetics of HCT are considerably changed in cardiac failure.     

Digoxin-felodipine interaction in patients with congestive heart failure

Summary A possible interaction between felodipine and digoxin was studied in 23 patients with congestive heart failure before and after 8 weeks treatment with both drugs.A modest, non-significant increase in serum digoxin level 2 h postdose (+15%) was found in the felodipine group (n=11) compared to placebo (n=12), with no change in the trough and 6 h postdose levels.There was a bimodal distribution of the observed changes in serum digoxin level 2 h postdose: a significant increase (p<0.001) was observed only in patients with a high plasma felodipine level, which may have been caused by changes in the absorption rate in those patients. Changes in the elimination of digoxin after felodipine therapy appeared unlikely, since the trough and 6 h post-dose levels were unchanged.Analysis of the clinical characteristics, haemodynamics and laboratory values revealed no significant differences between the subgroups. The observed increase in serum digoxin warrants monitoring the trough and peak levels digoxin in patients with congestive heart failure who are also being treated with felodipine.     

The pharmacokinetics of midazolam in patients with congestive heart failure.

The disposition of midazolam was investigated in six patients with congestive heart failure (CHF) and six age- and weight-matched healthy subjects by administering two single doses of the drug (3.75 mg i.v. and 7.5 mg p.o.) separated by 1 week. Serial blood samples were collected for 24 h after each dose and plasma was assayed for midazolam by GC-MS. In the CHF patients, the elimination half-life was prolonged (4 to 4.5 vs less than 3 h), the systemic clearance was lowered (376 vs 551 ml min-1) and the peak plasma drug concentration after the p.o. dose was higher (76 vs 42 ng ml-1). The systemic availability (45 vs 41%), the steady state volume of distribution (111 vs 108 l) and the time of peak plasma drug concentration after the p.o. dose (0.9 vs 0.9 h) were unchanged. The predominant effect of CHF was on the clearance of midazolam which was decreased by 30%. The drug was well tolerated and did not cause any adverse effects.     

The pharmacoeconomics of ACE inhibitors in chronic heart failure

Because heart failure is common and disabling, patients with this condition utilise healthcare resources to a considerable extent. In particular, patients with heart failure frequently require hospital admission, and inpatient care is often protracted. Patients with the most advanced stages of heart failure make the greatest demands on the healthcare system. Expenditure related to the consumption of healthcare resources accounts for the 1 to 2% of total healthcare spending related to heart failure. Between two-thirds and three-quarters of this is due to the costs of hospital care. ACE inhibitors reduce progression of heart failure and also reduce the need for hospitalisation by approximately 30%. In so doing, these drugs substantially or totally offset their cost and the cost of extended life. Five independent economic analyses collectively show ACE inhibitors, at worst, to be very cost effective (in comparison to other cardiovascular therapies), cost neutral or to lead to overall cost savings when used to treat heart failure.     

Oxaprozin pharmacokinetics in patients with congestive heart failure

12 patients aged 26-71 years with stable, compensated congestive heart failure (CHF) and 12 healthy controls matched for age, sex, height, weight, and serum albumin, received a 1200-mg oral dose of the nonsteroidal antiinflammatory agent 4,5-diphenyl-2-oxazolepropionic acid (oxaprozin). Serum oxaprozin levels were measured by high pressure liquid chromatography during the next 14 days. Oxaprozin elimination half-life was not different between controls and CHF patients (63 vs 69 h), but peak serum levels were lower (79 vs 63 micrograms/ml, p less than 0.01), apparent volume of distribution was larger (0.22 vs 0.29 l/kg, p less than 0.05) and clearance tended to be higher, although not significantly so, (0.042 vs 0.053 ml/min/kg) in CHF patients. These differences might have been due to reduced serum protein binding (increased free fraction) in CHF patients (0.25 vs 0.44% unbound, p less than 0.1). After correction for individual values of free fraction, groups did not differ in peak free oxaprozin serum levels (0.20 vs 0.26 micrograms/ml), unbound volume of distribution (92 vs 83 l/kg), or unbound clearance (17.5 vs 15.0 ml/min/kg). Thus protein binding of oxaprozin in the present study was reduced in CHF due either to the underlying disease or to the concurrent medications. This in turn caused reciprocal reduction in total (free plus bound) oxaprozin levels and elevated estimates of volume of distribution and clearance. Although protein binding is altered, CHF causes no significant alteration in distribution of free oxaprozin nor free clearance of oxaprozin, which is accomplished by a combination of oxidation and conjugation.     

氨力农治疗心力衰竭的疗效

目的：观察氨力农治疗心力衰竭（心衰）的临床疗效。方法：３６例心衰的病人，男性２４例，女性１２例；年龄５４±ｓ１４ａ，分为２组，其中３２例给氨力农０．５～１．０ｍｇ／ｋｇ用０．９％氯化钠注射液稀释至１０～２０ｍＬ，静脉注射，５～１０ｍｉｎ注射完，继以５～１０μｇ／ｋｇ氨力农用０．９％氯化钠注射液稀释至１８０ｍＬ，静脉滴注（静滴）６ｈ，共１０ｄ为治疗组；另１６例为用０．９％氯化钠注射液作为安慰剂对照组（其中１２例为安慰剂治疗无效后改为氨力农组），用药方法同治疗组。结果∶氨力农组治疗后总有效率９１％（２９／３２），对照组全部无效，组间比较Ｐ＜０．０１。氨力农组６例于用药ｄ１０的药前及药后２ｈ测血药浓度，发现有效血药浓度为１．１～３．２１μｇ／ｍＬ。结论：氨力农对慢性难治性心衰有效且安全。     

The pharmacokinetics of enalapril in hospitalized patients with congestive heart failure.

The pharmacokinetics of the converting enzyme inhibitor, enalapril, were studied in an open, randomized, balanced crossover design in 12 hospitalized patients with stable, chronic congestive heart failure (CHF). Enalapril maleate is a prodrug requiring in vivo hepatic esterolysis to yield the active diacid inhibitor enalaprilat. CHF results in changes in regional blood flow that may affect the gastrointestinal absorption, hepatic hydrolysis and renal excretion of enalapril and enalaprilat. In order to evaluate the pharmacokinetics of enalapril in CHF, the following treatments were given: enalapril maleate 10 mg orally, enalapril maleate 5 mg intravenously and enalaprilat 5 mg intravenously. Each dose was followed by a 72 h period with frequent blood sampling and fractionated urine collection for the radioimmunoassay of enalaprilat, before and after sample hydrolysis. Mean absorption for the oral dose was 69%, hydrolysis 55%, bioavailability 38%, urinary recovery 77% and estimated first-pass effect 10%. The results were compared with available data in normal subjects. After oral administration of 10 mg enalapril maleate, the extent of absorption, the degree of hydrolysis and the bioavailability in CHF patients appear to be similar to those in normals with differences less than 10%. The rate of absorption and hydrolysis appear to be slightly slower in CHF. The serum concentrations of enalaprilat were consistently greater in CHF and maximal concentrations were reached at 6 h in CHF as compared to 4 h in normal subjects. We conclude that the presence of CHF does not appreciably alter the pharmacokinetic behaviour of enalapril. The observed differences may be associated with age as well as the disease state.     

The pharmacokinetics of lisinopril in hospitalized patients with congestive heart failure.

1. The pharmacokinetics of the angiotensin converting enzyme inhibitor, lisinopril, were studied in an open, randomized, balanced, two-period, crossover design in 12 in-patients with stable, chronic congestive heart failure (CHF). 2. To evaluate the pharmacokinetics of lisinopril in CHF, lisinopril was administered orally (10 mg) and intravenously (5 mg) in each patient. Each dose was followed by a 72 h period with frequent blood sampling and fractional urine collections for radioimmunoassay of lisinopril. 3. Mean urinary recovery of lisinopril was 15 and 88% following oral and intravenous administration, respectively; absorption/bioavailability of lisinopril based on urinary recovery ratios was 16%, less than that found in normal subjects. 4. Serum concentrations of lisinopril following intravenous administration were higher in this study than those previously observed in normal subjects. 5. The results of this study suggest a reduced absorption of lisinopril in CHF and altered disposition, possibly associated with age as well as the disease state.     

Oral enoximone pharmacokinetics in patients with congestive heart failure

The pharmacokinetics of enoximone and its sulfoxide metabolite were determined following administration of a single oral dose of 1 or 2 mg/kg in seven patients with congestive heart failure, and in two normal volunteers following a single 75-mg capsule, and were compared to those published previously. Plasma concentrations of the metabolite were higher than enoximone, and their terminal slopes were parallel. Enoximone and enoximone sulfoxide plasma concentration-time data were fitted to a simple model that included a lag time. Absorption half-lives in patinets and normal volunteers averaged 17 minutes; the elimination half-life of enoximone in patients averaged 2.9 hours, and was slightly prolonged as compared with normal volunteers. The elimination half-life of enoximone sulfoxide averaged 17 minutes in patients and normal volunteers, and was considerably shorter than that reported in other studies. The oral clearance of enoximone in patients averaged 99 L/hr, and was lower than that observed in normal volunteers. The ratio of the area under the plasma concentration time curve of enoximone sulfoxide to enoximone averaged 4.7 in patients, and was similar to that observed in normal subjects. Enoximone oral clearance and the ratio of metabolite to parent were related to liver blood flow (determined by indocyanine green). Enoximone is 65% bound to albumin, which accounts for most of the drug bound to human plasma protein.     

Decreased vancomycin clearance in patients with congestive heart failure

Purpose

Congestive heart failure (CHF) alters the pharmacokinetics of various drugs, including cardiovascular agents, due to decreased cardiac output and decreased renal blood flow. The purpose of this study was to evaluate the influence of CHF on the clearance of vancomycin, a glycopeptide antibacterial agent.

Methods

After reviewing more than 1,500 clinical charts of patients who received vancomycin therapy and whose serum vancomycin level was monitored, we identified 101 patients who also had the left ventricular ejection fraction (LVEF) assessed at that time. The fluorescence polarization immunoassay method was used to measure vancomycin serum concentrations in these patients 1 h after the end of vancomycin infusion and just before the next administration. Using these two measurements, we calculated the pharmacokinetic parameters using the Bayesian estimator.

Results

Patients with an LVEF of?<40 % (16 patients) or those with an LVEF of ≥ 40 %? and <60 % (40 %?≤?LVEF?<?60 % ; 32 patients) had a significantly lower vancomycin clearance than patients with LVEF of?≥60 % (53 patients) (2.29?±?0.95 or 2.79?±?0.99 vs. 3.50?±?1.04 L/h; p?<?0.001 or p?<?0.01, respectively). Vancomycin clearance was strongly correlated not only with estimated creatinine clearance (CLcr) in patients with an LVEF of?<40 % (r?=?0.828) and 40 %?≤?LVEF?<?60 % (r?=?0.773), but also with an LVEF in patients with a CLcr of?<60 mL/min (r?=?0.646). Consistent with these findings, multiple regression analysis revealed that CLcr, LVEF and body weight were important independent variables for vancomycin clearance (r ²?=?0.649).

Conclusions

Vancomycin clearance decreased with decreasing cardiac function (LVEF) and decreasing CLcr. This finding suggests that vancomycin clearance is affected by cardiac function and would be predicted not only CLcr but also by LVEF.     

GM-CSF与P-选择素在充血性心力衰竭中的研究

目的检测充血性心力衰竭(CHF)患者血清粒细胞-巨噬细胞集落刺激因子(GMCSF)及P-选择素(P-sd)的水平,并探讨它们在CHF中的关系.方法CHF患者59例和年龄、性别相匹配的健康对照组19例,根据NYHA分级将CHF患者分成心功能Ⅱ、Ⅲ、Ⅳ级3组,测定血清GM-CSF及血浆P-sel水平.GM-CSF采用放射免疫法检测,P-sel用ELISA法检测.结果CHF组血清GM-CSF及血浆P-sel水平与对照组比较差异有显著意义(P＜0.01),CHF患者在心功能Ⅱ、Ⅲ、Ⅳ级各组GM-CSF、P-sel较对照组升高差异有显著意义(P＜0.01),且Ⅲ、Ⅳ级组与Ⅱ级组比较显著升高(P＜0.01),其中GM-CSF在心功能Ⅳ级组较Ⅲ级组升高有统计学意义(P＜0.05).不同病因的CHF患者之间差异无显著意义(P＞0.05).CHF患者血清GM-CSF与血浆P-sel呈显著正相关(r=0.7035,P＜0.01).结论(1)CHF患者外周血GM-CSF、、P--sel水平增高,提示它们可能参与了CHF的病理生理过程;(2)GM-CSF可能与CHF时血小板活化有关.     

Current status of phosphodiesterase inhibitors in the treatment of congestive heart failure.

The phosphodiesterase inhibitors have been recognised as potent inotropic and vasodilating drugs. In acute congestive heart failure they increase cardiac output, decrease left pulmonary capillary wedge pressure, and reduce total peripheral resistance with an improvement in loading conditions of the failing heart. Their potency in reversal of symptoms of acute congestive heart failure is quite similar to, or even better than, treatment with intravenous catecholamines and sodium nitroprusside. In chronic congestive heart failure, however, these agents increase mortality and have deleterious effects in the outcome of patients with severe left ventricular dysfunction.     

冠心病患者中无心功能不全与合并心功能不全的脂联素水平观察

目的血清脂联素（adiponectin,APN）,一种脂肪组织来源的胶原样血浆蛋白,具有抗动脉粥样硬化、抗炎及改善胰岛素敏感性等作用,本文旨在探讨冠心病无合并心功能不全组与冠心病合并心功能不全组血清脂联素水平及其与NTproBNP的关系,及探讨脂联素在冠心病合并慢性心功能不全发病机制中的作用。方法收集连续入院的冠心病合并NYHAⅡ-Ⅳ级患者60例和冠心病无心功能不全患者60例的血清和临床资料,选取性别与年龄与病例组相匹配对照组25例,测定空腹血清脂联素水平、N末端前脑钠肽（N-terminal portion of proBNP,NTproBNP）、hsCRP（high sensitivity C-Reactive Protein）及生化指标,比较各组间脂联素水平及与NTproBNP、hsCRP及生化指标的关系。结果冠心病患者中无心功能不全组血清脂联素显著低于对照组,而冠心病合并心功能不全组显著高于冠心病无心功能不全组及对照组,且冠心病合并心功能不全组随着心功能不全分级的增加,脂联素水平是升高的。Spearson偏相关分析显示经年龄、性别及BMI校正后冠心病组脂联素水平与NT-proBNP、hs-CRP呈正相关,与LVEF、TC、TG呈负相关,多元逐步回归分析显示NTproBNP、HDL-C、TC是影响血浆APN的独立因素。结论本文研究发现冠心病无心功能不全患者血清脂联素水平明显低于对照组,而在冠心病合并心功能不全组血清脂联素是明显高于其他二组,且随着心功能不全分级的增加而明显递增,同时冠心病患者血清脂联素与NTproBNP及hsCRP呈正相关,提示脂联素可能参与冠心病及心功能不全的发病机制,其确凿的作用机制还有待进一步的深入研究证明,血清脂联素的变化趋势对于心功能不全的进展及转归可能有一定的指导意义。     

Population pharmacokinetics of levosimendan in patients with congestive heart failure

AIMS: The aim of this study was to characterize the population pharmacokinetics of levosimendan in patients with heart failure (NYHA grades III and IV) and its relationship to demographic factors, disease severity and concomitant use of digoxin and beta-blocking agents. METHODS: Data from two efficacy studies with levosimendan administered by intravenous infusion were combined (190 patients in total). The data were analysed using a nonlinear mixed-effects modelling approach as implemented in the NONMEM program. The model development was done in three sequential steps. First the best structural model was determined (e.g. a one-, two- or three-compartment pharmacokinetic model). This was followed by the identification and incorporation of important covariates into the model. Lastly the stochastic part of the model was refined. RESULTS: A two-compartment model best described levosimendan pharmacokinetics. Clearance and the central volume of distribution were found to increase linearly with bodyweight. No other covariates, including concomitant use of digoxin and beta-blocking agents, influenced the pharmacokinetics. In the final model, a 76-kg patient was estimated to have a clearance +/- s.e. of 13.3 +/- 0.4 l h-1 and a central volume of distribution of 16.8 +/- 0.79 l. The interindividual variability was estimated to be 39% and 60% for clearance and central volume of distribution, respectively. Weight changed clearance by 1.5% [95% confidence interval (CI) 0.9%, 2.1%] and the central volume of distribution by 0.9% (95% CI 0.5%, 1.3%) per kg. CONCLUSIONS: The population pharmacokinetics parameters of levosimendan in this patient group were comparable to those obtained by traditional methods in healthy volunteers and patients with mild heart failure. Bodyweight influenced the clearance and the central volume of distribution, which in practice is accounted for by weight adjusting doses. None of the other covariates, including digoxin and beta-blocking agents, significantly influenced the pharmacokinetics of levosimendan.