第2代抗组胺药物心脏毒性研究进展

目的:探讨第2代抗组胺药物心脏毒性,为临床合理用药提供依据.方法:分析药代动力学性质和心脏不良反应(延长QT间期、导致心律失常)的发生机理.结果:第2代抗组胺药物有阻断心脏钾离子通道作用.结论:不同药物引起心脏毒性反应的程度也不同,这与药物的亲脂性、分布容积有关.     

抗组胺药物的合理应用

1 抗组胺药物简介 从1937年第1个抗组胺药开发至今,已有50余种H1受体拮抗剂供临床应用.20世纪80年代以前的为第1代:如苯海拉明、氯苯那敏(扑尔敏)、曲吡那敏(去敏灵)、异丙嗪(非那根)、美喹他嗪(玻丽玛朗)等.这类药物具有以下两项缺点,限制其在临床上的进一步应用.(1)中枢抑制作用:大部分第1代抗组胺药具有脂溶性,能穿透血脑屏障,故均有不同程度的中枢抑制作用,即镇静作用,包括困倦、嗜睡、注意力下降等.(2)H1受体选择性差:药物有部分抗胆碱能作用,因此易产生视力模糊、口干、心动过速及胃肠道等的不良反应.另外,它还可产生a受体阻断作用、局麻作用及5-羟色胺抑制作用等,这些都会使第1代抗组胺药物的安全性下降.     

抗组胺药物的进展

概述和评价了传统且按药,包括第一代、第二代Ｈ１受体拮抗剂及其临床应用中陆续发现的严重心脏毒性。介绍了新型抗组胺药非索非那定的药理作用及临床应用。     

抗组胺药的药物相互作用

介绍了抗组胺药物和其他临床常用药物的相互作用,为患者安全用药提供参考.第一、二代抗组胺药易与多种药物发生相互作用而致心脏毒性等不良反应,第三代抗组胺药联用时不会导致严重的不良反应.所以抗组胺药作为临床和OTC常用抗过敏药,应对其药物相互作用及产生的不良反应引起注意.     

地氯雷他定治疗SAR和CIU的研究进展

变应性鼻炎和荨麻疹的发病机制复杂，其中组胺起主要作用，组胺在靶组织能结合H1组胺受体。因而，H1抗组胺药成为治疗这些疾病的主要药物。第一代H1抗组胺药如扑尔敏和苯海拉明能缓解变异性鼻炎和荨麻疹症状，但在治疗剂量下有中枢神经系统(CNS)影响如镇静、精神活动损害和胆碱能副反应。第二代药物如氯雷他定、西替利嗪、阿司咪唑和特非那丁显示较少的镇静和胆碱能副作用。但后2种药物有心血管副作用.     

特非那定的临床不良反应分析

特非那定 (叔呱丁醇、敏迪 )选择性地阻断组胺 H1受体,具有良好的抗组胺作用,无镇静及抗胆碱作用,作用持久,广泛应用于过敏性鼻炎、荨麻疹及过敏性皮肤病的治疗。本药临床不良反应时有报道,尤以心血管系统、消化系统、中枢神经系统、药疹为多。本文就 1994年至今国内文献报道的特非那定片不良反应 14例进行分析。 1心血管系统 [1～ 5]　　心血管不良反应 5例患者 (占 35． 71％ )中,完全性右束支传导阻滞 1例,阵发性室性心动过速 2例,扭转型室性心动过速 2例;患者均为女性,年龄 23～ 40岁;因荨麻疹、药疹、足癣、阴道炎等服用特…     

特非那定合成工艺改进

特非那定是哌啶类抗组胺药，具有特异的外周H1受体拮抗作用，有抗5-羟色胺的作用，它是无中枢抑制作用、无镇静作用而高效安全的新型组胺受体H1拮抗剂，为目前临床上常用的抗过敏药物，主用于过敏性鼻炎，急慢性荨麻疹，枯草热的治疗。     

几种组胺H_1受体拮抗剂的潜在严重不良反应

阿司咪唑（Astemizole,息斯敏）、特非那定（terfenadine）、氯雷他定（Loratadine,克敏能）为一类新型无中枢镇静和抗胆碱作用,并呈强效及长效组胺H1受体桔抗剂。临床上适用于过敏性鼻炎、结膜炎、慢性尊麻疹和其他过敏性症状等。近年来,随着该类药物的广泛使用及深人研究,其潜在的严重不良反应受到临床的高度关注。为此,FDA[1.2]发布了关于抗组胺药阿司咪唑、特非那定的警告及涉及新的禁忌、注意事项、副作用和药物相互作用。所谓潜在严重不良反应是指,一是该类药物在临床使用时可能引起的严重不良反应如过敏性休克、心律失常、…     

抗组胺药Fexofenadine Hydrochloride

Fexofenadinehydrochloride又名MDL 16 4 5 5A ,属组胺H1受体拮抗剂。组胺H1 受体拮抗剂已于2 0世纪4 0年代应用于临床,实践证明这类药物对多种过敏反应有治疗作用。由于经典的组胺H1 受体拮抗剂有镇静作用,许多制药企业都致力于开发无镇静作用的组胺H1 受体拮抗剂。近12年来,已报道的无镇静作用的抗组胺药物已超过11种。1994年上市的特非那定就是这类非镇静性抗组胺药物中的领先药物。药理活性　特非那定是一种手性药物,治疗中用其外消旋体,口服后被迅速吸收,有肝首过效应,完全代谢后有两种主要产物,其中之一就是羧酸类似物fexofenadin…     

新的非镇静性抗组胺药将代替老药吗

近十年来,人们对抗组胺药及其作用的兴趣重新增加。这是由于开发了特非那定、阿司咪唑和其它可能无镇静作用的抗组胺药如美喹他嗪、BW825C(一种类似安太乐和美克洛嗪的药物)和UCB—PO71(一种新的赛克利嗪类化合物)。另外正在评价一些无镇静作用抗组胺药,其中有SK&F 3944,它正试用于变应性鼻炎。 1.新老非镇静性抗组胺药的活性差别上述各药在常用量时,均不易通过血脑屏障,比较起来,大多数老药由于脂溶性很强,容易透过血脑屏障。理想的纯粹的H_—     

Variations among non-sedating antihistamines: are there real differences?

Most of the modern non-sedating H₁ receptor antagonists (antihistamines) penetrate the brain poorly, allowing the use of doses large enough to counteract allergic processes in peripheral tissues without important central effects. The antihistamines reviewed here are acrivastine, astemizole, cetirizine, ebastine, fexofenadine, loratadine, mizolastine, and terfenadine. However, these drugs are not entirely free from central effects, and there are at least quantitative differences between them. Although psychomotor and sleep studies in healthy subjects in the laboratory may predict that an antihistamine does not cause drowsiness, the safety margin can be narrow enough to cause a central sedating effect during actual treatment. This might result from a patient's individual sensitivity, disease-induced sedation, or drug dosages that are for various reasons relatively or absolutely larger (patient's weight, poor response, reduced drug clearance, interactions). Mild to even moderate sedation is not necessarily a major nuisance, particularly if stimulants need be added to the regimen (e.g. in perennial rhinitis). Furthermore, patients can adjust doses themselves if needed. Sedating antihistamines are not needed for long-term itching, because glucocorticoids are indicated and more effective. It is wise to restrict or avoid using antihistamines (astemizole, terfenadine) that can cause cardiac dysrhythmias, because even severe cardiotoxicity can occur in certain pharmacokinetic drug-drug interactions. Histamine H₁ receptor antagonists (antihistamines) are used in the treatment of allergic disorders. The therapeutic effects of most of the older antihistamines were associated with sedating effects on the central nervous system (CNS) and antimuscarinic effects causing dry mouth and blurred vision. Non-specific “quinidine-like” or local anaesthetic actions often led to cardiotoxicity in animals and man. Although such adverse effects varied from drug to drug, there was some degree of sedation with all old antihistamines. Non-sedating antihistamines have become available during the past 15 years. Some of them also have antiserotonin or other actions that oppose allergic inflammation, and they are not entirely free from sedative effects either. In small to moderate “clinical” concentrations they are competitive H₁ receptor antagonists, although large concentrations of some of them exert non-competitive blockade. Daytime drowsiness and weakness are seldom really important, and they restrict patients' activities less than the old antihistamines. Some new antihistamines share with old antihistamines quinidine-like effects on the cardiac conducting tissues, and clinically significant interactions have raised the question of drug safety [1]. This prodysrhythmic effect has also been briefly mentioned in comparisons of non-sedative H₁ antihistamines.     

Safety of antihistamines in children.

The histamine H1 receptor antagonists (antihistamines) are an important class of medications used for the relief of common symptoms associated with hyperhistaminic conditions occurring in children and adults. This group of drugs may be subdivided into 3 classes, or generations, based upon their propensity to induce sedation and cardiotoxicity. The first generation (classical) antihistamines are highly effective in treating hyperhistaminic conditions. However, they frequently induce sedation and may adversely affect a child's learning ability. First generation antihistamine-induced sedation has been described to occur in more than 50% of patients receiving therapeutic dosages. Serious adverse events are unusual following overdoses of first generation antihistamines although life-threatening adverse events have been described. When the so-called 'second generation' antihistamines terfenadine and astemizole were introduced they were widely embraced and quickly used by clinicians of all specialities, including paediatricians, as nonsedating alternatives to the first generation compounds. These new agents were found to be equally or more effective than first generation antihistamines in relieving symptoms associated with hyperhistaminic conditions without the soporific effects of the first generation agents. Unfortunately, after approximately 10 years of widespread clinical use, disturbing reports of potentially life-threatening dysrhythmias, specifically torsades de pointes, were described. Both terfenadine and astemizole have been shown in vitro to inhibit several ion channels, and in particular the delayed outward rectifier potassium channel in the myocardium, predisposing the heart to dysrhythmias. The potential life-threatening cardiotoxicities of the second generation antihistamines led to the search for noncardiotoxic and nonsedating agents. Loratadine, fexofenadine, mizolastine, ebastine, azelastine and cetirizine are the first of the new third generation antihistamines. These drugs have been shown to be efficacious with few adverse events including no clinically relevant cytochrome P450 mediated metabolic-based drug-drug interactions or QT interval prolongation/cardiac dysrhythmias. Appropriate treatment of an antihistamine overdose depends upon which class of compound has been ingested. There is no specific antidote for antihistamine overdose and treatment is supportive particularly for ingestions of first generation compounds. Ingestion of excessive doses of terfenadine or astemizole requires immediate medical attention. Children who accidentally ingest excessive doses of a third generation compound may usually be adequately managed at home. However, patients ingesting large amounts (approximately >3 to 4 times the normal therapeutic daily dose) should receive medical attention. These patients should be monitored for 2 to 3 hours after the ingestion and patients ingesting cetirizine should be advised about the potential for sedation. The availability of newer generation antihistamine compounds has clearly added to the clinical effectiveness and patient tolerance of a widely prescribed class of drugs. These advances have also been accompanied by improved safety profiles, particularly in the case of third generation antihistamine overdose.     

The use of antihistamines in safety-critical jobs: a meeting report

The use of sedating agents by aircrew and those with safety-critical occupations has raised serious concern and has been extensively debated for several years. This meeting report summarizes the findings of an international panel of experts in aerospace medicine and allergic rhinitis who were brought together to discuss issues related to the use of antihistamines, in particular the selective, H1-receptor antagonist fexofenadine, in pilots. The presentations covered a wide range of topics including methods for accurately assessing sedation and impairment, and the validity of laboratory testing versus simulator assessments. The panel also examined data on sedation and impairment levels with currently available antihistamines and assessed the impact of these data on their use by pilots and aircrew. It was the consensus of the meeting that fexofenadine can be safely recommended for use in individuals involved in skilled activities, such as pilots, without the concern of sedation above recommended therapeutic doses.     

New insights into the second generation antihistamines

Second generation antihistamines are recognised as being highly effective treatments for allergy-based disease and are among the most frequently prescribed and safest drugs in the world. However, consideration of the therapeutic index or the benefit/risk ratio of the H1 receptor antagonists is of paramount importance when prescribing this class of compounds as they are used to treat non-life threatening conditions. There are many second generation antihistamines available and at first examination these appear to be comparable in terms of safety and efficacy. However, the newer antihistamines in fact represent a heterogeneous group of compounds, having markedly differing chemical structures, adverse effects, half-life, tissue distribution and metabolism, spectrum of antihistaminic properties, and varying degrees of anti-inflammatory effects. With regard to the latter, there is growing awareness that some of these compounds might represent useful adjunct medications in asthma therapy. In terms of safety issues, the current second generation grouping includes compounds with proven cardiotoxic effects and others with the potential for adverse drug interactions. Moreover, some of the second generation H1 antagonists have given cause for concern regarding their potential to cause a degree of somnolence in some individuals. It can be argued, therefore, that the present second generation grouping is too large and indistinct since this was based primarily on the concept of separating the first generation sedating compounds from nonsedating H1 antagonists. Although it is too early to talk about a third generation grouping of antihistamines, future membership of such a classification could be based on a low volume of distribution coupled with a lack of sedating effects, drug interactions and cardiotoxicity.     

Fexofenadine: new preparation. Terfenadine, without cardiotoxicity

(1) Fexofenadine, a non anticholinergic non sedative antihistamine, is available in France for oral treatment of allergic rhinitis and chronic urticaria. (2) Fexofenadine is actually an active metabolite of terfenadine, a drug taken off the market because of its cardiotoxicity. (3) In seasonal allergic rhinitis a comparative trial showed that the effect of fexofenadine (120 mg/day in a single intake) was moderate and not different from that of cetirizine. (4) In chronic urticaria a dose-finding study showed that the optimal oral dose of fexofenadine was 180 mg/day. The lack of comparative trials means that the efficacy of fexofenadine in relation to other antihistamines is not known. (5) Fexofenadine seems to be well tolerated. Animal studies and limited clinical experience have failed to detect any cardiotoxicity.     

The Use of Antihistamines in Safety-critical Jobs: A Meeting Report

Summary

The use of sedating agents by aircrew and those with safety-critical occupations has raised serious concern and has been extensively debated for several years. This meeting report summarizes the findings of an international panel of experts in aerospace medicine and L allergic rhinitis who were brought together to discuss issues related to the use of antihistamines, in particular the selective, H1-receptor antagonist fexofenadine, in pilots. The presentations covered a wide range of topics including methods for accurately assessing sedation and impairment, and the validity of laboratory testing versus simulator assessments. The panel also examined data on sedation and impairment levels with currently available antihistamines and assessed the impact of these data on their use by pilots and aircrew. It was the consensus of the meeting that fexofenadine can be safely recommended for use in individuals involved in skilled activities, such as pilots, without the concern of sedation above recommended therapeutic doses.     

Emerging safety issues regarding long-term usage of H1-receptor antagonists

The second generation histamine H₁-receptor antagonists are important therapeutic tools in the treatment of atopic disease and may also have a place as an adjunct therapy for those patients whose allergic asthma coexists with allergic rhinitis. They are amongst the most widely prescribed and safest drugs in the world. However, as second generation H₁-receptor antagonists are used to treat non-life threatening conditions, the risk of adverse effects is of vital importance. For many, the potential for sedation by some of the newer antihistamines still remains an issue, while there have recently been widespread concerns regarding the potential for cardiotoxicity and the impact of drug–drug interactions associated with some second generation H₁-receptor antagonists. Consequently, progress with this class of drugs should involve not only increased efficacy but also improvements in their safety and specificity. Moreover, there is a trend towards using second generation H₁-receptor antagonists as long-term therapy rather than confining their use to treating the short-term manifestations of allergic disease. To this end, a number of novel, potent and safe antihistamines have been developed which are either metabolites of active drugs or enantiomers. This review will examine some of the safety issues associated with established and newer second generation drugs particularly in relation to their long-term usage in adults and children.     

Assessment of the First and Second Generation Antihistamines Brain Penetration and Role of P-Glycoprotein

Purpose The sedating effect of first generation H₁-antihistamines has been associated with their ability to penetrate the blood-brain barrier (BBB) and lack of efflux by P-glycoprotein (Pgp). Second generation H₁-antihistamines are relatively free of sedation and their limited brain penetration has been suggested to arise from Pgp-mediated efflux. The objective of this work was to evaluate the role of Pgp in brain penetration of first and second generation antihistamines. Methods Potential of antihistamines to be Pgp substrates was tested in vitro using Madin Darby canine kidney cells transfected with human Pgp. The role of Pgp in limiting brain penetration of antihistamines was tested by using the in situ brain perfusion technique. Results Majority of antihistamines were Pgp substrates in vitro. Following in situ brain perfusion, the first generation antihistamines substantially penetrated into rat brain independently from Pgp function. The second generation antihistamines terfenadine and loratadine, achieved substantial brain penetration, which was further enhanced by Pgp inhibition by cyclosporin A (CSA). In contrast, fexofenadine and cetirizine, penetrated brain poorly regardless of CSA administration. Conclusions Antihistamines greatly differ in their ability to cross the BBB as well as in the role of Pgp in limiting their transport into the CNS in vivo.     

Therapeutic advantages of third generation antihistamines

A third generation of antihistamines is emerging for the treatment of allergic rhinitis and chronic urticaria. First generation antihistamines are among the most widely used drugs in the world, and provide symptomatic relief from allergies and the common cold to millions of patients, mainly in OTC combination preparations. Their full potential is limited by the sedation caused by their effects on histamine receptors in the brain. Second generation antihistamines (terfenadine, astemizole, loratadine and cetirizine), which block peripheral H₁ receptors without penetrating the blood-brain barrier, were developed and introduced from 1981 onwards to provide comparable therapeutic benefit without the CNS side-effects. Although largely successful in this goal, terfenadine and astemizole were found to cause potentially serious arrhythmias when plasma concentrations became elevated subsequent to impaired metabolism. It was established that the cardiac toxicity was mainly due to the parent drugs. As active metabolites could account for most of the clinical benefit, the goal for the third generation of antihistamines became to develop therapeutically active metabolites that were devoid of cardiac toxicity. The first of these drugs, fexofenadine (the active metabolite of terfenadine), was approved in July 1996, after an unusually rapid development programme. Its introduction set a new standard of safety that led the FDA to request the withdrawal of terfenadine in 1997 on the grounds that a safer version of an equivalent drug was now available. Norastemizole and descarboethoxy loratadine, the metabolites of astemizole and loratadine, respectively, are also in clinical development. These offer comparable or superior clinical benefits.     

Blood-brain barrier in vitro models as tools in drug discovery: assessment of the transport ranking of antihistaminic drugs

In the course of our validation program testing blood-brain barrier (BBB) in vitro models for their usability as tools in drug discovery it was evaluated whether an established Transwell model based on porcine cell line PBMEC/C1-2 was able to differentiate between the transport properties of first and second generation antihistaminic drugs. First generation antihistamines can permeate the BBB and act in the central nervous system (CNS), whereas entry to the CNS of second generation antihistamines is restricted by efflux pumps such as P-glycoprotein (P-gP) located in brain endothelial cells. P-gP functionality of PBMEC/C1-2 cells grown on Transwell filter inserts was proven by transport studies with P-gP substrate rhodamine 123 and P-gP blocker verapamil. Subsequent drug transport studies with the first generation antihistamines promethazine, diphenhydramine and pheniramine and the second generation antihistamines astemizole, ceterizine, fexofenadine and loratadine were accomplished in single substance as well as in group studies. Results were normalised to diazepam, an internal standard for the transcellular transport route. Moreover, effects after addition of P-gP inhibitor verapamil were investigated. First generation antihistamine pheniramine permeated as fastest followed by diphenhydramine, diazepam, promethazine and second generation antihistaminic drugs ceterizine, fexofenadine, astemizole and loratadine reflecting the BBB in vivo permeability ranking well. Verapamil increased the transport rates of all second generation antihistamines, which suggested involvement of P-gP during their permeation across the BBB model. The ranking after addition of verapamil was significantly changed, only fexofenadine and ceterizine penetrated slower than internal standard diazepam in the presence of verapamil. In summary, permeability data showed that the BBB model based on porcine cell line PBMEC/C1-2 was able to reflect the BBB in vivo situation for the transport of antihistaminc drugs and to distinguish between first and second generation antihistamines.