卡维地洛的药理及临床研究进展

卡维地洛是新的第３ 代肾上腺素β受体阻断药,具有α和β受体阻断、钙拮抗、抗氧化、抗细胞增殖及保护细胞等作用。可用于高血压、心绞痛、充血性心力衰竭的治疗,能显著降低充血性心力衰竭病人的死亡率。本文着重介绍了非选择性肾上腺素β受体阻断药卡维地洛的药理作用、临床应用研究进展等。     

卡维地洛的临床应用进展

卡维地洛 (Carvedilol)是第三代 β受体阻滞剂 ,除可非选择性阻滞β肾上腺素受体 ,还可选择性阻滞α1肾上腺素受体 ,高浓度时有阻滞钙通道及抗氧化作用。其 β受体阻滞作用 ,可抑制交感神经兴奋和儿茶酚胺分泌 ,从而减慢心率 ,降低血压 ,减弱心肌收缩力 ,降低心肌耗氧量 ;其α1受体阻滞作用 ,可降低周围血管和容量血管的阻力 ,从而协助降压 ;又因对α受体作用的高选择性 ,能保留对去甲肾上腺素的释放 ,防止心动过速 ,而无不良代谢作用。现将卡维地洛的临床应用进展作一综述。1　治疗充血性心力衰竭在心力衰竭 (CHF)的发展中 ,交感神经活动…     

卡维地洛药理作用与临床应用研究进展

卡维地洛作为肾上腺素β受体阻滞药,对α₁和β受体均有阻断作用,在临床上已广泛应用于高血压、心力衰竭、心律失常等心血管疾病。近年来,在预防动脉粥样硬化、保护不同并发症患者的心脏功能、改善糖尿病患者血糖调节能力、防治乳腺癌和抗阿尔茨海默病等方面进行了多项卡维地洛的临床研究。此外,随着对G蛋白偶联受体(GPCR)的深入研究,发现卡维地洛存在独特的偏向β-抑制蛋白的GPCR信号传导,高选择性作用于靶细胞,可减少药物不良反应的发生。     

美托洛尔和卡维地洛长期治疗心衰病人的作用比较

β阻滞剂由于被认为对慢性心力衰竭 (ＨＦ)有好处而被普遍用于无禁忌证的左心室功能不足的轻度至中度ＨＦ病人的治疗。其中 ,美托洛尔 (ｍｅｔｏｐｒｏｌｏｌ)和比索洛尔能选择性抑制 β1受体 ,但长期使用可使β受体密度和心脏去甲肾上腺素浓度增高。卡维地洛 (ｃａｒｖｅｄｉｌｏｌ)对α1,β1和 β2 受体均有阻滞作用 ,但它能降低心脏去甲肾上腺素和 β受体密度 ,此外 ,它还有一定的抗氧化剂作用和抗增殖作用。因此 ,比较了美托洛尔和卡维地洛对ＨＦ病人的长期作用。150名受试者 ,均为局部缺血或非局部缺血性心肌病所引起的Ⅱ～Ⅳ度慢性Ｈ…     

卡维地洛的临床应用

卡维地洛 (Carvedilol)于 1979年由德国BoehringerMannheim公司研制成功 ,美国FDA批准于 1991年用于临床。 1997年批准用于治疗心力衰竭 ,也是第一个被批准用于治疗心力衰竭的 β受体阻滞剂。1 药理作用1 1β受体阻滞作用 :卡维地洛可竞争性拮抗肾上腺素诱发的心率加速和心肌收缩力加强 (β1作用 ) ,作用持续 15～ 16h ,其作用大于普萘洛尔和拉贝洛尔 ,在缺氧和心肌梗塞动物模型中静注卡维地洛可减少梗塞面积 4 7%～ 89% ,提高生存率。健康人服卡维地洛 12 5～ 2 0 0mg后在降低静息血压时不伴随反射性心率增快。1 2α1受体阻滞作用 :在…     

抗高血压药 卡维地洛(Carvedilol)

药效分类β和α_1肾上腺素能受体阻滞剂开发单位(美)Smithkline Beecham公司上市厂商 (美)Smithkline Beecham公司于1991年上市药理卡维地洛是一种新型的多作用药物,用于治疗轻～中度高血压。本品是β和α_1受体的竞争性拮抗剂,较高浓度时是钙通道拮抗剂。动物和人的抗高血压试验和血液动力学效应表明,本品具β-受体阻滞作用和动脉扩张作用。血管扩张作用主要由于α_1-     

阿罗洛尔——无代谢不良反应的肾上腺素β受体阻滞药

阿罗洛尔除具有肾上腺素α、β受体阻滞药共有的抑制交感及扩张血管特点外,在减慢心率作用方面比常用的卡维地洛、拉贝洛尔明显,与肾上腺素β受体阻滞药美托洛尔相近,但无美托洛尔的糖、脂代谢不良反应。在降压方面,尤其适用于中青年舒张期高血压,能有效地减慢心率、降舒张压。     

卡维地洛治疗慢性充血性心力衰竭

卡维地洛是第三代非选择性肾上腺素能β受体阻滞药,其无内在拟交感活性而兼具α1受体阻滞作用。该药是第一个经美国FDA批准用于慢性充血性心力衰竭(CHF)的β受体阻滞药,可减轻症状,降低发病率和病死率。国外已做了许多试验和临床研究,有足够的证据表明该药独特的疗效。对于这一极有前途的药物,国内使用的效果如何,该药的作用机制、用法等近年来国内的研究者们也作了若干的临床探讨,本文对上述问题综述如下:1CHF的发病机制心力衰竭是指心血管疾病发展至一定的严重程度,心肌收缩力减弱或舒张功能障碍,心排血量减少,不能满足机体需要;同时…     

卡维地洛

<正> 1 概述卡维地洛是一种非选择性β-受体阻滞剂,并具有α-受体阻滞作用,可完全性阻滞β_1、β_2及α_1受体,α_1;β阻滞作用=1:10,无内源性拟交感活性。 2 临床药理学 2.1 结构卡维地洛是立体异构体的外消旋混合物,其非选择性β-受体阻滞效应主要在左旋异构体,而α-受体阻滞作用在两种异构体(左旋、右旋)中都存在。     

卡维地洛的药理作用研究进展

卡维地洛是一种第三代的β-受体阻滞剂，具有β受体和α1受体的双重阻滞、抗氧化、心脏和神经保护、抗心律失常等药理作用，临床已用于治疗心力衰竭、原发性高血压等心血管疾病。     

Expanding role of beta-blockade in the management of chronic heart failure

Although recent advances have been made in the treatment of heart failure, this disease continues to result in significant morbidity and mortality. Among the negative effects associated with progression of heart failure are decline in myocardial reserve, decreased exercise tolerance, decreased contractile function, and altered cardiac gene expression. Guidelines recommend neurohormonal antagonists for treatment and stress the importance of angiotensin-converting enzyme inhibition and beta-blockade in reversing the cardiac remodeling process. beta-Blockade slows or reverses the adverse effects resulting from chronic adrenergic stimulation. Traditionally, beta-blockers were reserved for mild-to-moderate heart failure, based on evidence from large, randomized clinical trials showing their positive effects on myocardial function and clinical outcomes. More recently, clinical data reveal that the agents can be expanded to patients with severe heart failure and those with left ventricular systolic dysfunction after myocardial infarction. Individual beta-blocking agents vary in their pharmacology and dosing requirements. These variations may influence treatment decisions and affect clinical measurements of left ventricular function and ventricular remodeling.     

肾上腺素β受体阻滞剂在心力衰竭治疗中的应用

在心力衰竭治疗中正确和积极使用肾上腺素 β受体 (β受体 )阻滞剂可降低心力衰竭病人的死亡率。本文就心力衰竭时使用 β受体阻滞剂的理论依据、使用 β受体阻滞剂的作用机制、临床研究证据及使用 β受体阻滞剂的注意事项等作一系统介绍     

Gln27→Gluβ2‐Adrenergic Receptor Polymorphism in Heart Failure Patients: Differential Clinical and Oxidative Response to Carvedilol

Abstract: We investigated the clinical response of chronic heart failure patients with β₂‐adrenergic receptor Gln²⁷→Glu polymorphism treated for 6 months with carvedilol, a α/β‐antagonist with antioxidant properties. The 6‐min. walk test, the left ventricular ejection fraction, heart rate, plasma norepinephrine and malondialdehyde, a stress oxidative marker, concentrations were evaluated at baseline and after treatment for 6 months with carvedilol in 33 stable chronic heart failure patients with the Gln²⁷→Gluβ₂‐adrenergic receptor polymorphism. Carvedilol significantly increased the left ventricular ejection fraction, while decreasing the heart rate and malondialdehyde plasma concentrations in chronic heart failure patients with the Glu²⁷β₂‐adrenergic receptor allele. There were however, no significant changes in patients with the Gln²⁷β₂‐adrenergic receptor variant.     

Targeting the myocardial sodium-hydrogen exchange for treatment of heart failure

Although the past number of years have seen a substantial improvement in the therapeutic approaches for the treatment of heart failure, mortality rates continue to be high. Moreover, the incidence of heart failure is expanding rapidly. Sodium-hydrogen exchange (NHE) is a key target for the treatment of heart failure. NHE is a major mechanism for intracellular pH regulation in most cell types, including the cardiac cell. Seven isoforms of NHE have been identified so far although cardiac cells possess primarily the ubiquitous NHE-1 subtype. NHE-1 is a major contributor to ischaemic and reperfusion injury and NHE-1 inhibitors exert marked cardioprotective effects, particularly when administered before ischaemia, findings which have now been extended to clinical trials. It is emerging that NHE-1 also contributes to chronic maladaptive myocardial responses to injury (myocardial remodelling) and may contribute to the development of heart failure. Experimental studies using both in vitro approaches as well as animal models of heart failure have consistently demonstrated a beneficial effect of NHE-1 inhibitors in terms of inhibition of hypertrophy in response to various stimuli as well as inhibiting heart failure after coronary artery ligation. These effects occurred independently of any infarct size reducing effects of NHE-1 inhibitors or on any direct effects on afterload thus indicating a direct effect on the myocardial remodelling process. In fact, it appears that NHE-1 may represent a common downstream mediator for various hypertropic factors such as angiotensin II, endothelin-1 and beta(1) adrenergic receptor activation. NHE-1 inhibition, therefore, represents a potentially effective new therapeutic approach for the treatment of heart failure.     

Reassessment of failed beta-blocker treatment in angina pectoris by peak-exercise heart rate measurements.

Twenty-one patients with angina pectoris were treated with adrenergic beta-receptor antagonists. Previously the resting heart rate had been used as a guide to treatment, a reduction in the rate to 55-60 beats/min without symptomatic improvement indicating failure of medical treatment. These patients were re-evaluated before coronary arteriography using the peak-exercise heart rate as an index of adrenergic beta-receptor antagonism. The dose of beta-blocking drugs was increased to produce a peak-exercise heart rate of less than 100 beats/min or a consistent rate of 100-125 beats/min which would not lessen in spite of progressive dose increments. The resting heart rate was ignored. On these criteria 15 patients previously considered to have responded inadequately to beta-blockade responded satisfactorily and were therefore removed from the waiting list for coronary arteriography. They all remained well up to two years later. Six patients failed to respond and had coronary arteriography with a view to surgical treatment. Reliance on the resting heart rate as the index of optimum adrenergic beta-receptor antagonism is likely to lead to premature or unnecessary referral for surgery; the failure of beta-blockade in the treatment of angina pectoris can be determined simply and accurately by using peak-exercise heart rate.     

Therapeutic targets for heart failure: beyond beta-adrenergic and renin-angiotensin system blockade

Heart failure is a major healthcare problem and leading cause of death in Western countries. Growing evidence has shown recent improvements in pharmacological therapy, such as receptor-regulating agents, in treating heart failure; however, the morbidity and mortality of heart failure is still high. More recent studies have suggested the presence of additional molecular targets for treating heart failure. Several key molecules in the beta adrenergic receptor signaling pathway play an important role in the progression of heart failure, and transgenic mice studies supported beneficial effects of controlling such molecules in heart failure. In addition, molecules in the renin-angiotensin system or calcium signaling pathway may also be potential targets for treating heart failure. In this review, we focused on putative mechanisms underlying the beneficial effects of regulating these molecules on the progression of heart failure including relevant patents on this topic.     

Positive Inotropic Effect without Cyclic AMP Elevation after α–Adrenergic Stimulation of Perfused Hearts from Hypothyroid Rats

Abstract Previous experiments suggested that the positive inotropic response to α–adrenergic stimulation was unrelated to cyclic AMP in contrast to the inotropic effect of β–adrenergic stimulation. In order to elucidate this question further we perfused hearts from rats made hypothyroid by treatment with propyl–thiouracil, since this treatment is known to augment the myocardial α–adrenergic effects. α–stimulation (phenylephrine in the presence of propranolol) caused a marked inotropic response and no increase in cyclic AMP. In contrast β–stimulation (isoprenaline) increased the cyclic AMP content. The time–courses of the inotropic responses to α– and β–stimulation were different. The aortic pressure waves indicated a shorter duration of each contraction phase after isoprenaline than after phenylephrine in the presence of propranolol. This difference is probably due to the cyclic AMP accumulated after isoprenaline. The findings support the hypothesis that the positive inotropic effect of α–adrenergic stimulation is caused by mechanisms independent of cyclic AMP, while the β–adrenergic inotropic effect involves cyclic AMP mediated processes. Such a dual mechanism of action for adrenergic agents might serve to maintain responsiveness of the heart under various conditions.     

The rational use of beta-adrenoceptor blockers in the treatment of heart failure. The changing face of an old therapy

Heart failure is one of the commonest debilitating conditions of industrialized society, with mortality and morbidity comparable with that of the common neoplastic diseases. The role of antagonists of the adrenergic beta-receptor (beta-blockers) in heart failure has been the subject of debate for many years. Data from studies of the therapeutic use of beta-blockers in patients following acute myocardial infarction suggest that in this circumstance these agents confer at least as much benefit to patients with heart failure as they do to those without. Similarly retrospective analysis of a number of the studies of angiotensin converting enzyme (ACE) inhibitors in heart failure suggest a greater effect of the combination of beta-blocker with ACE inhibitor compared with ACE inhibitor alone. The results of recent prospective, placebo-controlled studies of the addition of beta-blocker to standard therapy in patients with chronic heart failure have confirmed a significant beneficial effect. beta-blocker therapy in these studies was well tolerated and in addition to improved mortality, beta-blocker therapy is associated with improved morbidity in terms of progressive heart failure and numbers of hospitalizations. Initiation of beta-blocker therapy in heart failure may be associated with deterioration of cardiac function in the short term. Treatment should be started at a low dose of beta-blocker with slow up-titration in a number of steps over several weeks. In spite of the established benefits of ACE inhibition in patients with heart failure, this treatment is under-utilized. Part of this shortfall is due to physicians' perceptions regarding potential unwanted effects of ACE inhibition. Perceptions regarding unwanted effects of beta-adrenoceptor blocker therapy are likely to be at least as great. While beta-blockade represents a welcome addition to the therapeutic armoury of physicians caring for patients with heart failure, initiation and stabilization of beta-adrenoceptor blocker therapy should be undertaken under specialist supervision.     

Dobutamine: ten years later

Dobutamine is a commonly used positive inotrope for the short-term management of heart failure. It is commercially available as a 50:50 mixture of two isomers with unique effects on alpha- and beta adrenergic receptors. In dosages of 2-15 micrograms/kg/minute, dobutamine has been shown to increase cardiac output (mainly through stroke volume), reduce systemic vascular resistance, lower central venous and pulmonary artery wedge pressures, improve renal blood flow, and relieve signs and symptoms of congestive heart failure. At higher dosages it can increase heart rate and induce arrhythmias. Recent evidence indicates that effects of dobutamine last long after the drug has been eliminated from the plasma, and some work has been done on ambulatory use of this agent. Dobutamine has been used successfully in several circumstances, such as after cardiac surgery, in patients with myocardial infarction, and in various shock states. An understanding of the pathophysiology of the underlying disorder is important in deciding which catecholamine to use. With this in mind, monotherapy or combination therapy with inodilators such as dobutamine, or inopressors like dopamine will follow logically.     

Na~+/H~+交换泵1激活与心肌肥大

钠氢交换泵 1介导缺血及再灌流引起的心肌损伤。近期的研究提示钠氢交换泵 1也介导长期不良刺激引起的心肌肥大和心衰。钠氢交换泵 1可能是引起心肌肥大的多种因素信息传导下游区的共同媒介 ,比如血管紧张素Ⅱ ,肾上腺α1、β1受体兴奋等。抑制钠氢交换泵 1可能会成为防治心衰的一种新方法。